U.S. patent application number 16/821738 was filed with the patent office on 2020-07-23 for extended release microparticles and suspensions thereof for medical therapy.
This patent application is currently assigned to Graybug Vision, Inc.. The applicant listed for this patent is Graybug Vision, Inc.. Invention is credited to Jeffrey L. Cleland, Joshua Kays, Ming Yang, Weiling Yu, Yun Yu.
Application Number | 20200230246 16/821738 |
Document ID | / |
Family ID | 64095930 |
Filed Date | 2020-07-23 |
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United States Patent
Application |
20200230246 |
Kind Code |
A1 |
Yang; Ming ; et al. |
July 23, 2020 |
EXTENDED RELEASE MICROPARTICLES AND SUSPENSIONS THEREOF FOR MEDICAL
THERAPY
Abstract
An improved microparticle or lyophilized or otherwise
reconstitutable microparticle composition thereof for medical
therapy, including ocular therapy.
Inventors: |
Yang; Ming;
(Lutherville-Timonium, MD) ; Cleland; Jeffrey L.;
(San Carlos, CA) ; Yu; Yun; (Baltimore, MD)
; Yu; Weiling; (Perry Hall, MD) ; Kays;
Joshua; (Baltimore, MD) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Graybug Vision, Inc. |
Redwood City |
CA |
US |
|
|
Assignee: |
Graybug Vision, Inc.
Redwood City
CA
|
Family ID: |
64095930 |
Appl. No.: |
16/821738 |
Filed: |
March 17, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15976847 |
May 10, 2018 |
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16821738 |
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62508355 |
May 18, 2017 |
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62504366 |
May 10, 2017 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 27/02 20180101;
A61K 31/542 20130101; A61K 47/54 20170801; A61K 31/5377 20130101;
A61K 31/216 20130101; A61K 9/5031 20130101; A61K 31/404 20130101;
A61K 31/4155 20130101; A61K 31/382 20130101; A61K 9/0051 20130101;
A61K 31/498 20130101 |
International
Class: |
A61K 47/54 20060101
A61K047/54; A61K 9/50 20060101 A61K009/50; A61K 31/382 20060101
A61K031/382; A61K 31/542 20060101 A61K031/542; A61P 27/02 20060101
A61P027/02; A61K 31/404 20060101 A61K031/404; A61K 31/498 20060101
A61K031/498; A61K 31/5377 20060101 A61K031/5377; A61K 31/4155
20060101 A61K031/4155; A61K 31/216 20060101 A61K031/216; A61K 9/00
20060101 A61K009/00 |
Claims
1. Solid aggregating biodegradable microparticles comprising a
prodrug of a therapeutically active compound encapsulated in (a)
poly(lactic-co-glycolic acid) (PLGA) and/or polylactic acid (PLA)
and (b) poly(lactic-co-glycolic acid) conjugated to polyethylene
glycol (PLGA-PEG), and a surfactant, wherein the microparticles (i)
have a mean diameter between 10 .mu.m and 60 .mu.m; (ii) have been
surface-modified with a surface treatment agent to partially
degrade surface polymer at a temperature less than about 18.degree.
C. wherein the surface treatment agent comprises an aqueous base
and an organic solvent; (iii) aggregate in vivo to form at least
one pellet of at least 500 .mu.m in vivo that provide sustained
drug delivery in vivo for at least three months; and (v) wherein
the prodrug is selected from the formula: ##STR00779## or a
pharmaceutically acceptable salt thereof wherein R.sup.31a is
hydrogen, --C(O)alkyl, aryl, alkyl, cycloalkyl, cycloalkylalkyl,
heterocyclyl, heterocycloalkyl, arylalkyl, heteroaryl,
heteroarylalkyl, polylactic acid, or polygylcolic acid; R.sup.106
is selected from: ##STR00780## R.sup.123 is selected from:
##STR00781## R.sup.311 is hydroxy, amino, A, alkyl, alkoxy,
alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,
heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
aryloxy, or polyethylene glycol; A is selected from H, alkyl,
cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl,
arylalkyl, heteroaryl, heteroarylalkyl, aryloxy, and alkyloxy; x
and y are independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9,
and 10; x' and y' are independently selected from 1, 2, 3, 4, 5, 6,
7, 8, 9, and 10; z is independently selected from 0, 1, 2, 3, 4, 5,
6, 7, 8, 9, and 10.
2. The solid aggregating microparticles of claim 1, wherein
R.sup.123 is selected from ##STR00782##
3. The solid aggregating microparticles of claim 2, wherein
R.sup.123 is selected from ##STR00783##
4. The solid aggregating microparticles of claim 1, wherein
R.sup.106 is selected from ##STR00784##
5. The solid aggregating microparticles of claim 4, wherein
R.sup.106 is selected from ##STR00785##
6. The solid aggregating microparticles of claim 1, wherein
R.sup.31a is --C(O)alkyl.
7. The solid aggregating microparticles of claim 1, wherein x and y
are independently selected from 1, 2, 3, 4, 5, and 6.
8. The solid aggregating microparticles of claim 1, wherein x' and
y' are independently selected from 1, 2, 3, 4, 5, and 6.
9. The solid aggregating microparticles of claim 1, of the formula
##STR00786## or a pharmaceutically acceptable salt thereof.
10. The solid aggregating microparticles of claim 9, wherein y is
1, 2, 3, 4, 5, or 6 and y' is 1, 2, 3, 4, 5, or 6.
11. The solid aggregating microparticles of claim 9, wherein y is
2, 3, or 4 and y' is 2, 3, or 4.
12. The solid aggregating microparticles of claim 9, of the formula
##STR00787## or a pharmaceutically acceptable salt thereof.
13. The solid aggregating microparticles of claim 12, wherein y is
1, 2, 3, 4, 5, or 6 and y' is 1, 2, 3, 4, 5, or 6.
14. The solid aggregating microparticles of claim 12, wherein y is
2, 3, or 4 and y' is 2, 3, or 4.
15. The solid aggregating microparticles of claim 12, of the
formula ##STR00788## or a pharmaceutically acceptable salt
thereof.
16. The solid aggregating microparticles of claim 12, of the
formula ##STR00789## or a pharmaceutically acceptable salt
thereof.
17. The solid aggregating microparticles of claim 12, of the
formula ##STR00790## or a pharmaceutically acceptable salt
thereof.
18. The solid aggregating microparticles of claim 1, wherein the at
least one pellet provides sustained drug delivery for at least 4
months.
19. The solid aggregating microparticles of claim 1, wherein at
least one pellet provides sustained drug delivery for at least 5
months.
20. The solid aggregating microparticles of claim 1, wherein at
least one pellet provides sustained drug delivery for at least 6
months.
21. The solid aggregating microparticles of claim 1, wherein the
aqueous base is a hydroxide base.
22. The solid aggregating microparticles of claim 21, wherein the
organic solvent is an alcohol.
23. The solid aggregating microparticles of claim 22, wherein the
alcohol is ethanol.
24. The solid aggregating microparticles of claim 1, wherein the
surface treatment agent comprises ethanol and sodium hydroxide.
25. The solid aggregating microparticles of claim 1, wherein the
surface has been modified at a temperature not more than 16.degree.
C.
26. The solid aggregating microparticles of claim 1, wherein the
surface has been modified at a temperature not more than 14.degree.
C.
27. The solid aggregating microparticles of claim 1, wherein the
surface has been modified at a temperature not more than 12.degree.
C.
28. The solid aggregating microparticles of claim 1, wherein the
surface has been modified at a temperature not more than 10.degree.
C.
29. A pharmaceutical composition comprising the solid aggregating
microparticles of claim 1, optionally in a pharmaceutically
acceptable carrier.
30. The pharmaceutical composition of claim 29, suitable for use as
an ocular implant.
31. The pharmaceutical composition of claim 29 suitable for a
delivery route selected from the group consisting of intravitreal,
intrastromal, intracameral, subtenon, sub-retinal, retrobulbar,
peribulbar, suprachoroidal, subchoroidal, conjunctival,
subconjunctival, episcleral, posterior juxtascleral, circumcorneal,
and tear duct injections.
32. The pharmaceutical composition of claim 31 suitable for
intravitreal injection.
33. The pharmaceutical composition of claim 31 suitable for
suprachoroidal injection.
34. A method for the treatment of an ocular disorder selected from
glaucoma, wet-age related macular degeneration, dry-age related
macular degeneration, a disorder related to an increase in
intraocular pressure, optic nerve damage caused by high intraocular
pressure, and diabetic retinopathy comprising administering an
effective amount of the solid aggregating microparticles of claim
1, optionally in a pharmaceutically acceptable carrier.
35. The method of claim 34 for the treatment of glaucoma.
36. The method of claim 34 for the treatment of wet-age related
macular degeneration.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. application Ser.
No. 15/976,847, filed May 10, 2018, which claims the benefit of
provisional U.S. Application Nos. 62/504,366, filed May 10, 2017
and 62/508,355, filed May 18, 2017. The entirety of these
applications is hereby incorporated by reference for all
purposes.
FIELD OF THE INVENTION
[0002] This invention is in the area of improved microparticles,
lyophilized or otherwise solidified microparticles, or
microparticle suspensions, and processes thereof, which can,
optimally, be loaded with an active drug or a prodrug of an active
drug, for use in medical drug delivery, including for ocular drug
delivery.
BACKGROUND
[0003] The structure of the eye can be divided into two segments
referred to as the anterior and posterior. The anterior segment
comprises the front third of the eye and includes the structures in
front of the vitreous humor: the cornea, iris, ciliary body, and
lens. The posterior segment includes the back two-thirds of the eye
and includes the sclera, choroid, retinal pigment epithelium,
neural retina, optic nerve, and vitreous humor.
[0004] Important diseases affecting the anterior segment of the eye
include glaucoma, allergic conjunctivitis, anterior uveitis, and
cataracts. Diseases affecting the posterior segment of the eye
include dry and wet age-related macular degeneration (AMD),
cytomegalovirus (CMV) infection, diabetic retinopathy, choroidal
neovascularization, acute macular neuroretinopathy, macular edema
(such as cystoid macular edema and diabetic macular edema),
Behcet's disease, retinal disorders, diabetic retinopathy
(including proliferative diabetic retinopathy), retinal arterial
occlusive disease, central retinal vein occlusion, uveitis retinal
disease, retinal detachment, ocular trauma, damage caused by ocular
laser treatment or photodynamic therapy, photocoagulation,
radiation retinopathy, epiretinal membrane disorders, branch
retinal vein occlusion, anterior ischemic optic neuropathy,
non-retinopathy diabetic retinal dysfunction and retinitis
pigmentosa. Glaucoma is sometimes also considered a posterior
ocular condition because a therapeutic goal of glaucoma treatment
is to prevent or reduce the loss of vision due to damage or loss of
retinal cells or optic nerve cells.
[0005] Typical routes of drug administration to the eye include
topical, systemic, intravitreal, intraocular, intracameral,
subconjunctival, sub-tenon, retrobulbar, and posterior
juxtascleral. (Gaudana, R., et al., "Ocular Drug Delivery", The
American Association of Pharmaceutical Scientist Journal,
12(3)348-360, 2010).
[0006] A number of types of delivery systems have been developed to
deliver therapeutic agents to the eye. Such delivery systems
include conventional (solution, suspension, emulsion, ointment,
inserts, and gels), vesicular (liposomes, niosomes, discomes, and
pharmacosomes), advanced materials (scleral plugs, gene delivery,
siRNA, and stem cells), and controlled-release systems (implants,
hydrogels, dendrimers, iontophoresis, collagen shields, polymeric
solutions, therapeutic contact lenses, cyclodextrin carriers,
microneedles, microemulsions, and particulates (microparticles and
nanoparticles)).
[0007] Treatment of posterior segment diseases remains a daunting
challenge for formulation scientists. Drug delivery to the
posterior segment of the eye is typically achieved via an
intravitreal injection, the periocular route, implant, or by
systemic administration. Drug delivery to the posterior segment by
way of the periocular route can involve the application of a drug
solution to the close proximity of the sclera, resulting in high
retinal and vitreal concentrations.
[0008] Intravitreal injection is often carried out with a 30 gauge
or less needle. While intravitreal injections offer high
concentrations of drug to the vitreous chamber and retina, they can
be associated with various short-term complications such as retinal
detachment, endophthalmitis, and intravitreal hemorrhages.
Experience shows that injection of small particles can lead to the
rapid dispersal of the particles that can obstruct vision
(experienced by the patient as "floaties" or "floaters") and the
rapid removal of the particles from the injection site (which can
occur via the lymphatic drainage system or by phagocytosis). In
addition, immunogenicity can occur upon recognition of the
microspheres by macrophages and other cells and mediators of the
immune system.
[0009] Complications in periocular injections include increased
intraocular pressure, cataract, lur, strabismus, and corneal
decompensation. Transscleral delivery with periocular
administration is seen as an alternative to intravitreal
injections. However, ocular barriers such as the sclera, choroid,
retinal pigment epithelium, lymphatic flow, and general blood flow
can compromise efficacy. Systemic administration, which is not
advantageous given the ratio of the volume of the eye to the entire
body, can lead to potential systemic toxicity.
[0010] A number of companies have developed microparticles for
treatment of eye disorders. For example, Allergan has disclosed a
biodegradable microsphere to deliver a therapeutic agent that is
formulated in a high viscosity carrier suitable for intraocular
injection or to treat a non-ocular disorder (U.S. publication
2010/0074957 and U.S. publication 2015/0147406 claiming priority to
a series of applications back to Dec. 16, 2003). In one embodiment,
the '957 application describes a biocompatible, intraocular drug
delivery system that includes a plurality of biodegradable
microspheres, a therapeutic agent, and a viscous carrier, wherein
the carrier has a viscosity of at least about 10 cps at a shear
rate of 0.1/second at 25.degree. C.
[0011] Allergan has also disclosed a composite drug delivery
material that can be injected into the eye of a patient that
includes a plurality of microparticles dispersed in a media,
wherein the microparticles contain a drug and a biodegradable or
bioerodible coating and the media includes the drug dispersed in a
depot-forming material, wherein the media composition may gel or
solidify on injection into the eye (WO 2013/112434 A1, claiming
priority to Jan. 23, 2012). Allergan states that this invention can
be used to provide a depot means to implant a solid sustained drug
delivery system into the eye without an incision. In general, the
depot on injection transforms to a material that has a viscosity
that may be difficult or impossible to administer by injection.
[0012] In addition, Allergan has disclosed biodegradable
microspheres between 40 and 200 .mu.m in diameter, with a mean
diameter between 60 and 150 .mu.m that are effectively retained in
the anterior chamber of the eye without producing hyperemia (US
2014/0294986). The microspheres contain a drug effective for an
ocular condition with greater than seven-day release following
administration to the anterior chamber of the eye. The
administration of these large particles is intended to overcome the
disadvantages of injecting 1-30 .mu.m particles which are generally
poorly tolerated.
[0013] Regentec Limited has filed a series of patent applications
on the preparation of porous particles that can be used as tissue
scaffolding (WO 2004/084968 and U.S. publication 2006/0263335
(filed Mar. 27, 2003) and U.S. publication 2008/0241248 (filed Sep.
20, 2005) and WO 2008/041001 (filed Oct. 7, 2006)). The porosity of
the particles must be sufficient to receive cells to be held in the
particle. The cells can be added to the matrix at, or prior to,
implantation of the matrix or afterward in the case of recruitment
from endogenous cells in situ. Regentec also published an article
on tissue scaffolding with porous particles (Qutachi et al.
"Injectable and porous PLGA microspheres that form highly porous
scaffolds at body temperature", Acta Biomaterialia, 10, 5080-5098,
(2014)).
[0014] In addition, Regentec Limited also filed patent applications
on the preparation of large porous particles that can be used in
drug delivery (WO 2010/100506 and U.S. publication 2012/0063997
(filed Mar. 5, 2009)). The porosity of the particles allows for
quick delivery of the therapeutic agent. The particles are intended
to form a scaffold that fills the space in which they are injected
by a trigger such as a change in temperature.
[0015] Additional references pertaining to highly porous
microparticles include publications by Rahman and Kim. Rahman et
al. "PLGA/PEG-hydrogel composite scaffolds with controllable
mechanical properties" J. of Biomedical Materials Research, 101,
648-655, (2013) describes hydrogels of approximately 50 percent
porosity and their corresponding mechanical properties. Kim et al.
"Biodegradable polymeric microspheres with "open/closed" pores for
sustained release of human growth hormone" J. of Controlled
Release, 112, 167-174, (2006) describes PLGA polymers with pores
for the delivery of human growth hormone.
[0016] EP 2125048 filed by Locate Therapeutics Limited (filed Feb.
1, 2007) as well as WO 2008/093094, U.S. publication 2010/0063175
(filed Feb. 1, 2007), and WO 2008/093095 (filed Feb. 1, 2007) filed
by Regentec Limited disclose the preparation of particles that are
not necessarily porous but that when exposed to a trigger (such as
temperature) form a tissue scaffold useful in the repair of damaged
or missing tissue in a host.
[0017] U.S. Pat. No. 9,161,903 issued on Oct. 20, 2015 to Warsaw
Orthopedic and U.S. publication 2016/0038407 filed by Warsaw
Orthopedic Inc. disclose a flowable composition for injection at a
target tissue site beneath the skin that includes a flowable
composition that hardens at or near the target tissue site.
[0018] Bible et al. "Attachment of stem cells to scaffold particles
for intra-cerebral transplantation", Nat. Protoc., 10, 1440-1453,
(2009) describes a detailed process to make microparticles of PLGA
that do not clump or aggregate.
[0019] U.S. Patent Application Publication 2011/0123446 filed by
Liquidia Technologies titled "Degradable compounds and methods of
use thereof, particularly with particle replication in non-wetting
templates" describes degradable polymers that utilize a silyl core
and can form rapidly degrading matrixes.
[0020] Additional references pertaining to particles for ocular
delivery include the following. Ayalasomayajula, S. P. and
Kompella, U. B. have disclosed the subconjunctival administration
of celecoxib-poly(lactide co-glycolide) (PLGA) microparticles in
rats (Ayalasomayajula, S. P. and Kompella, U. B.,
"Subconjunctivally administered celecoxib-PLGA microparticles
sustain retinal drug levels and alleviate diabetes-induced
oxidative stress in a rat model", Eur. J. Pharm., 511, 191-198
(2005)). Danbiosyst UK Ltd., has disclosed a microparticle
comprising a mixture of a biodegradable polymer, a water soluble
polymer of 8,000 Daltons or higher and an active agent (U.S. Pat.
No. 5,869,103). Poly-Med, Inc. has disclosed compositions
comprising a hydrogel mass and a carrier having a biological active
agent deposited on the carrier (U.S. Pat. No. 6,413,539). MacroMed
Inc. has disclosed the use of an agent delivery system comprising a
microparticle and a biodegradable gel (U.S. Pat. Nos. 6,287,588 and
6,589,549). Novartis has disclosed ophthalmic depot formulations
for periocular or subconjunctival administration where the
pharmacologically acceptable polymer is a polylactide-co-glycolide
ester of a polyol (U.S. publication 2004/0234611, U.S. publication
2008/0305172, U.S. publication 2012/0269894, and U.S. publication
2013/0122064). The Universidad De Navarra has disclosed oral
pegylated nanoparticles for carrying biologically active molecules
comprising a pegylated biodegradable polymer (U.S. Pat. No.
8,628,801). Surmodics, Inc. has disclosed microparticles containing
matrices for drug delivery (U.S. Pat. No. 8,663,674). Minu, L.L.C.,
has disclosed the use of an agent in microparticle of nanoparticle
form to facilitate transmembrane transport. Emory University and
Georgia Tech Research Corporation have disclosed particles
dispersed in a non-Newtonian fluid that facilitates the migration
of the therapeutic particles from the insertion site in the
suprachoroidal space to the treatment site (U.S. 2016/0310417).
Pfizer has disclosed nanoparticles as injectable depot formulations
(U.S. publication 2008/0166411). Abbott has disclosed a
pharmaceutical dosage form that comprises a pharmaceutically
acceptable polymer for the delivery of a tyrosine kinase inhibitor
(U.S. publication 2009/0203709). The Brigham and Woman's Hospital,
Inc. has disclosed modified poly(lactic-co-glycolic) polymers
having therapeutic agents covalently bound to the polymer (U.S.
2012/0052041). BIND Therapeutics, Inc. has disclosed therapeutic
nanoparticles comprising about 50 to 99.75 weight percent of a
diblock poly (lactic) acid-poly(ethylene)glycol copolymer or a
diblock poly (lactic acid-co-glycolic acid)-poly(ethylene)glycol
copolymer wherein the therapeutic nanoparticle comprises 10 to
about 30 weight percent poly(ethylene)glycol (U.S. publication
2014/0178475). Additional publications assigned to BIND
Therapeutics, Inc. include U.S. publication 2014/0248358 and U.S.
publication 2014/0249158. Allergan has disclosed the use of
biodegradable microspheres containing a drug to treat an ocular
condition (U.S. publication 2010/0074957, U.S. publication
2014/0294986, U.S. publication 2015/0147406, EP 1742610, and WO
2013/112434). Allergan has also disclosed a biocompatible implant
containing a prostamide component, which can exist in particle
form, and a biodegradable polymer that allows for slow release of
the drug over the course of 1 week to 6 months for the treatment of
an ocular condition, such as glaucoma (U.S. application
2015/0157562 and U.S. application 2015/0099805). Jade Therapeutics
has disclosed formulations containing an active agent and a polymer
matrix that can be delivered directly to the target tissue or
placed in a suitable delivery device (U. S. publication
2014/0107025). Bayer Healthcare has disclosed a topical
ophthalmological pharmaceutical composition comprising sunitinib
and at least one pharmaceutically acceptable vehicle (WO
2013/188283). pSivida Us, Inc. has disclosed biodegradable drug
eluting particles comprising a microporous or mesoporous silicon
body for intraocular use (U.S. Pat. No. 9,023,896). Additional
patents assigned to pSivida Us, Inc. include: U.S. Pat. Nos.
8,871,241; 8,815,284; 8,574,659; 8,574,613; U.S. Pat. Nos.
8,252,307; 8,192,408 and 7,998,108. ForSight Vision4, Inc. has
disclosed therapeutic devices for implantation in the eye (U.S.
Pat. No. 8,808,727). Additional patents assigned to ForSight
Vision4, Inc. include: U.S. Pat. Nos. 9,125,735; 9,107,748;
9,066,779; 9,050,765; 9,033,911; 8,939,948; 9,905,963; 8,795,712;
8,715,346; 8,623,395; 8,414,646; 8,399,006; 8,298,578; 8,277,830;
8,167,941; 7,883,520; 7,828,844 and 7,585,075. The Nagoya
Industrial Science Research Institute has recently disclosed the
use to liposomes to deliver a drug to the posterior segment of the
eye (U.S. Pat. No. 9,114,070).
[0021] Johns Hopkins University has filed a number of patents
claiming formulations for ocular injections including WO2013/138343
titled "Controlled Release Formulations for the Delivery of HIF-1
Inhibitors", WO2013/138346 titled "Non-linear Multiblock
Copolymer-drug Conjugates for the Delivery of Active
Agents",WO2011/106702 titled "Sustained Delivery of Therapeutic
Agents to an Eye Compartment", WO2016/025215 titled
"Glucorticoid-loaded Nanoparticles for Prevention of Corneal
Allograft Rejection and Neovascularization", WO2016/100392 titled
"Sunitinib Formulations and Methods for Use Thereof in Treatment of
Ocular Disorders", WO2016/100380 titled "Sunitinib Formulation and
Methods for Use Thereof in Treatment of Glaucoma", WO2016/118506
titled "Compositions for the Sustained Release of Anti-Glaucoma
Agents to Control Intraocular Pressure", WO2013/166385 titled
"Nanocrystals, Compositions, and Methods that Aid Particle
Transport in Mucus", WO2005/072710 titled "Drug and Gene Carrier
Particles that Rapidly move Through Mucus Barriers," WO2008/030557
titled "Compositions and Methods for Enhancing Transport through
Mucus", WO2012/061703 titled "Compositions and Methods Relating to
Reduced Mucoadhesion," WO2012/039979 titled "Large Nanoparticles
that Penetrate Tissue," WO2012/109363 titled "Mucus Penetrating
Gene Carriers", WO2013/090804 titled "Biodegradable Stealth
Nanoparticles Prepared by a Novel Self-Assembly Emulsification
Method," WO2013/110028 titled "Nanoparticles Formulations with
Enhanced Mucosal Penetration", and WO2013/166498 titled
"Lipid-based Drug Carriers for Rapid Penetration through Mucus
Linings".
[0022] GrayBug Vision, Inc. discloses prodrugs for the treatment of
ocular therapy in US 2018-0036416, US 2018-0064823, US
2018-0110865, US 2018-0104350, granted U.S. Pat. Nos. 9,808,531 and
9,956,302 and PCT application WO2017/053638. Aggregating
microparticles for ocular therapy are described in US 2017-0135960
and WO2017/083779.
[0023] In order to treat ocular diseases, and in particular
diseases of the posterior segment, the drug must be delivered in
therapeutic levels and for a sufficient duration to achieve
efficacy. This seemingly straightforward goal is difficult to
achieve in practice.
[0024] The object of this invention is to provide compositions and
methods to treat ocular disorders.
SUMMARY
[0025] The present invention has at least the following aspects:
[0026] (i) A lyophilized microparticle solid material that has less
propensity to result in floating microparticles than the same
microparticle solid material that has not been processed as
described herein, when resuspended in fluid for example buffered
aqueous solution or aqueous hyaluronic acid, for in vivo delivery.
The process as described herein is based on the discovery that very
small air bubbles or gas or a thin layer of air adhered to
microparticles can adversely affect the quality of the resuspended
microparticle of the present invention, and that improved
microparticles for lyophilization can be provided by removing
adhered air or gas by treating the microparticles with a vacuum,
sonication, or excipient addition or other method that removes or
decreases the adhered air or gas prior to lyophilization, or by
doing so after resuspending the lyophilized microparticle material.
It has been discovered that the issue of air adhered to the
microparticle can be more pronounced if the microparticle has been
surface treated even under mild conditions to remove or decrease
surface surfactant, such as those described in U.S. Ser. No.
15/349,985 and PCT/US 16/61706 (see nonlimiting Example 2 below).
[0027] (ii) An improved lyophilized microparticle, microparticle
suspension, and method for manufacture thereof, processed as
described in (i) that is loaded with a pharmaceutically active
agent, including those listed below, which can be active in the
form delivered or is a prodrug, with non-limiting examples provided
herein, for in vivo treatment of a patient in need thereof. [0028]
(iii) Microparticles as described herein, and lyophilized or
suspended materials thereof, whether treated to remove adhered air
or gas, and which include any of the active drugs, including
prodrugs, described herein.
[0029] For example, it has been identified that for certain
applications, the processes and materials in U.S. Ser. No.
15/349,985 and PCT/US16/61706 provide acceptable aggregating
microparticles in vivo, however, there are occasions when if
surface-treated microparticles are overtreated (e.g., treated under
strong chemical conditions or for an extended period of time), they
may have a tendency to float upon injection into an aqueous
solution with low viscosity (e.g., PBS buffer solution or sometimes
vitreal fluid, wherein the viscosity may decrease with age of the
patient), which is disadvantageous for forming a pellet that
remains out of the visual axis. Since ocular disorders increase
with age, it is important to provide a particle suspension that
still aggregates to a pellet in lower viscosity vitreous fluid.
Certain aspects of this invention address those certain situations,
where a thin layer of air, air bubbles or gas generally can adhere
to the surface of some microparticles and prevent the particles
from being completely wetted. If this tiny layer of air or bubbles
is high enough to create buoyancy, the microparticles will be less
likely to aggregate to the desired pellet.
[0030] Thus, according to the present invention, microparticles and
microparticle suspensions are provided that have improved
aggregation to a pellet for medical therapy due to enhanced
wettability in vivo. Examples of processes that provide improved
aggregation of particles to the desired ocular pellet include, but
are not limited to, one or a combination of 1) applying a vacuum to
the particle suspension to facilitate the disassociation of air
from particles; 2) adding one or more excipients to reduce surface
hydrophobicity of particles and thus reduce the amount of air
adhering to the particles; and, 3) sonication to facilitate the
disassociation of air from the particles, either prior to
lyophilization or other drying means to make a solid
reconstitutable microparticle material, or by carrying out one or
more of these processes after reconstitution. These processes are
described in more detail below.
[0031] In the third independent aspect of the invention, solid
microparticles that aggregate in vivo to a pellet and provide
release of a therapeutic agent in vivo are provided. In certain
embodiments, the therapeutic agent is a lipophilic prodrug as
described herein. In certain embodiments, the lipophilic prodrug
releases a prostaglandin, carbonic anhydrase inhibitor, receptor
tyrosine kinase inhibitor (RTKIs), Rho kinase (ROCK) inhibitor,
beta-blocker, alpha-adrenergic agonist, or loop diuretic. In
certain embodiments, the therapeutic agent is the active agent
itself not in prodrug form, such as a prostaglandin, a carbonic
anhydrase inhibitor, a receptor tyrosine kinase inhibitor (RTKIs),
a Rho kinase (ROCK) inhibitor, a beta-blocker, an alpha-adrenergic
agonists, or a loop diuretic. Nonlimiting examples of prodrugs and
active agents that can be used in the present invention are
provided herein. For example, one or more of the processes can be
used at the time the particles are being prepared to produce the
powder or material that is stored and then later resuspended (for
example, prior to lyophilization) for injection. In one example,
the vessel with the dried microparticles can be placed under
pressure for storage before use. In another non-limiting example,
the container storing the surface-treated microparticles can be
placed under vacuum directly before administration. In other
embodiments, it is not necessary to remove air or gas from the
active-loaded microparticle at any stage of manufacture to achieve
a suitable therapeutic effect.
[0032] In typical embodiments of invention (i) above, the process
to prepare the improved suspension for medical use, including for
administration into low viscosity fluids, is conducted following
mild surface treatment, isolation, and reconstitution in an
appropriate diluent. Non-limiting illustrations in Examples 32-37
establish that treatments to provide an improved suspension of
microparticles upon injection in an aqueous solution result in less
floatation and better aggregation compared to microparticles that
have not been treated for enhanced wettability. FIGS. 22A-22C and
23A-23L illustrate the effect of vacuum strength on particle
floatation and aggregation, and FIGS. 27A-27L illustrate the effect
of excipient addition on particle floatation and aggregation. FIGS.
29A, 29B and 30 depict the effect of sonication on particle
floatation and aggregation.
[0033] In one embodiment of a selected aspect of the invention, the
microparticles are mildly surface treated prior to treatments for
enhanced wettability. In one embodiment, the solid biodegradable
microparticles are suitable for ocular injection, at which point
the particles aggregate to form a pellet that remains outside the
visual axis so as not to significantly impair vision. The particles
can aggregate into one or several pellets. The size of the
aggregate depends on the concentration and volume of the
microparticle suspensions injected and the diluent in which the
microparticles are suspended.
[0034] In one aspect of the invention, the improved process of (i)
for preparing a microparticle or lyophilized or otherwise
solidified material thereof or a suspension thereof, leading to an
aggregated pellet in vivo, can be used in combination with a
selected method and for forming aggregating microparticles
described in U.S. Ser. No. 15/349,985 and PCT/US16/61706 (and the
resulting materials thereof). For example, methods include
providing solid aggregating microparticles that include at least
one biodegradable polymer, wherein the solid aggregating
microparticles have a solid core, include a therapeutic agent, have
a modified surface which has been treated under mild conditions at
a temperature, that may optionally be at or less than about
18.degree. C., to remove surface surfactant, are sufficiently small
to be injected in vivo, and are capable of aggregating in vivo to
form at least one pellet of at least 500 .mu.m in vivo to provide
sustained drug delivery in vivo for at least three months, four
months, five months, six months seven months, eight months, nine
months or more. In certain embodiments, sustained drug deliver in
vivo is provided for up to one year. The solid aggregating
microparticles are suitable, for example, for an intravitreal
injection, implant, including an ocular implant, periocular
delivery, or delivery in vivo outside of the eye. In certain
embodiments, the therapeutic agent is a prodrug as described
herein.
[0035] As an illustration, the present invention includes a process
for the preparation of surface-modified solid aggregating
microparticles that are advantageous for pellet formation in vivo,
and microparticle materials made thereby, that includes: [0036] A.
a first step of preparing microparticles comprising one or more
biodegradable polymers by dissolving or dispersing the polymer(s)
and a therapeutic agent in one or more solvents to form a polymer
and therapeutic agent solution or dispersion, mixing the polymer
and the therapeutic agent solution or dispersion with an aqueous
phase containing a surfactant to produce solvent-laden
microparticles and then removing the solvent(s) to produce polymer
microparticles that contain the therapeutic agent, polymer and
surfactant; and [0037] B. a second step of mildly treating the
surface of microparticles of step (i) at a temperature at or below
about 18, 15, 10, 8 or 5.degree. C. optionally up to about 1, 2, 3,
4, 5, 10, 30, 40, 50, 60, 70, 80, 90 100, 11, 120 or 140 minutes
with an agent that removes surface surfactant, surface polymer, or
surface oligomer in a manner that does not significantly produce
internal pores; and [0038] C. isolating the surface treated
microparticles; and [0039] D. subjecting the microparticles to at
least one process selected from 1) vacuum treatment prior to
lyophilization or other form of reconstitutable solidification, or
after the step of reconstitution wherein the microparticles are
suspended in a diluent and the suspension is placed under vacuum
prior to use; 2) excipient addition, wherein an excipient is added
prior to lyophilization; and 3) sonication, prior to lyophilization
or other form of reconstitutable solidification, or after the step
of reconstitution; 4) sealing the vial containing the dry powder of
particles under vacuum, including but not limited to high vacuum;
or 5) pre-wetting (i.e., resuspending) the surface-treated
microparticles in a diluent for 2-24 hours before injecting into
the eye, for example in a hyaluronic acid solution or other sterile
solution suitable for ocular injection.
[0040] The process of these steps can be achieved in a continuous
manufacturing line or via one step or in step-wise fashion as
appropriate. The process of step D. above can be carried out
following isolation of the microparticles and/or upon
reconstitution prior to injection. In one embodiment, the surface
treated solid biodegradable microparticles do not significantly
aggregate during the manufacturing process. In another embodiment,
the surface treated solid biodegradable microparticles do not
significantly aggregate when resuspended and loaded into a syringe.
In some embodiments, the syringe is approximately 30, 29, 28, 27,
26 or 25 gauge, with either normal or thin wall.
[0041] In another nonlimiting embodiment, a process for preparing a
suspension comprising a microparticle and a pharmaceutically active
compound encapsulated in the microparticle and the resulting
materials thereof; which process comprises: [0042] (a) preparing a
solution or suspension (organic phase) comprising: (i) PLGA or PLA
or PLA and PLGA, (ii) PLGA-PEG or PLA-PEG (iii) a pharmaceutically
active compound, for example, as described herein and (iv) one or
more organic solvents; [0043] (b) preparing an emulsion in an
aqueous polyvinyl alcohol (PVA) solution (aqueous phase) by adding
the organic phase into the aqueous phase and mixing them until
particle formation (for example at about 3,000 to about 10,000 rpm
for about 1 to about 30 minutes); (c) removing additional solvent
as necessary using known techniques; [0044] (d) centrifuging or
causing the sedimentation of the microparticle that is loaded with
a pharmaceutically active compound or prodrug thereof, [0045] (e)
optionally removing additional solvent and/or washing the
microparticle loaded with the pharmaceutically active compound or
prodrug thereof with water; [0046] (f) filtering the microparticle
loaded with pharmaceutically active compound or prodrug thereof to
remove aggregates or particles larger than the desired size; [0047]
(g) optionally lyophilizing the microparticle comprising the
pharmaceutically active compound and storing the microparticle as a
dry powder in a manner that maintains stability for up to about 6,
8, 10, 12, 20, 22, or 24 months or more; and [0048] (h) optionally
improving the aggregation potential of the particles by subjecting
the particles to at least one process selected from 1) vacuum
treatment prior to step (g), or after reconstitution wherein the
microparticles are suspended in a diluent and the suspension is
placed under vacuum; 2) excipient addition, wherein an excipient is
added prior to lyophilization; and 3) sonication prior to step (g),
or during reconstitution wherein the microparticles are suspended
in a diluent and sonicated; 4) sealing the vial containing the dry
powder of particles under vacuum, including but not limited to high
vacuum; or 5) pre-wetting (i.e., resuspending) the surface-treated
microparticles in a diluent for 2-24 hours before injecting into
the eye, for example in a hyaluronic acid solution or other sterile
solution suitable for ocular injection.
[0049] In one embodiment, a process for preparing an improved
lyophilized material or a suspension of microparticles following
reconstitution includes suspending the particles in a diluent and
subjecting the particles to vacuum treatment at a pressure of about
less than about 500, 400, 300, 200, 150, 100, 75, 50, 40, 35, 34,
33, 32, 31, 30, 29, 28 or 25 Torr for a suitable amount of time to
substantially remove air attached to the particles, which in some
embodiments can be up to 3, 5, 8, 10, 20, 30, 40, 50, 60, 70, 80,
or 90 minutes or up to 2, 3, 4, 5, or 6, 10, 15 or 24 or more
hours. In one embodiment, the vacuum treatment is conducted with a
VacLock syringe in a size of up to at least 10, 20, 30, or 60
mL.
[0050] In certain non-limiting embodiments, the microparticles are
vacuumed at a strength of less than 40 Torr for about 3, 5, 8, 10,
20, 30, 45, 60, 75, or 90 minutes. In certain non-limiting
embodiments, the microparticles are vacuumed at a strength less
than 40 Torr from about 1 to 90 minutes, from about 1 to 60
minutes, from about 1 to 45 minutes, from about 1 to 30 minutes,
from about 1 to 15 minutes, or from about 1 to 5 minutes.
[0051] In certain embodiments, the diluent for suspending particles
is ProVisc. In some embodiments, the microparticles are diluted
from about 10-fold to about 40-fold, from about 15-fold to about
35-fold, or from about 20-fold to about 25-fold. In some
embodiments, the diluent for suspending particles is a
10.times.-diluted ProVisc (0.1% HA in PBS) solution, a
20.times.-diluted ProVisc (0.05% HA in PBS) solution, or a
40.times.-diluted ProVisc (0.025% HA in PBS) solution. In some
embodiment, the particles are suspended in the diluent at a
concentration of at least about 100 mg/mL, 200 mg/mL, 300 mg/mL,
400 mg/mL, or 500 mg/mL.
BRIEF DESCRIPTION OF THE FIGURES
[0052] FIG. 1 illustrates the aggregation of non-surface treated
microparticles (NSTMP) (S-1 and S-5) and surface treated
microparticles (STMP) (S-3 and S-8) after injection into PBS and
incubation at 37.degree. C. for 2 hours. The NSTMP, S-1 and S-5,
started to disperse immediately when the tubes were inverted after
the 2 hour-incubation, while the STMP, S-3 and S-8, remained
aggregated at the bottom of the tubes without dispersion throughout
the entire period of observation (about 10 minutes). Samples from
left to right are S-1, S-3, S-5 and S-8 (Example 5).
[0053] FIG. 2 illustrates the aggregation of surface treated
microparticles (STMP) (S-3 and S-8) after injection into HA and
incubation at 37.degree. C. for 2 hours. Samples left to right are
S-1, S-3, S-5 and S-8 (Example 5).
[0054] FIG. 3 illustrates the result of in vitro aggregation and
dispersion of particles after a 2-hour incubation in PBS at
37.degree. C. followed by agitation to detach the aggregates from
the bottom of the tubes. Top row from left to right samples: S-1,
S-2, S-3, S-4; Bottom row from left to right samples: S-5, S-6, S-7
and S-8 (Example 5).
[0055] FIG. 4 illustrates in vitro aggregation of representative
surface treated microparticles (STMP) treated with PBS/EtOH (sample
S-21) after a 2-hour incubation in PBS at 37.degree. C. followed by
agitation by tapping and flicking the tube (Example 6).
[0056] FIG. 5 illustrates the in vitro accelerated drug release
profile of a representative batch of surface treated microparticles
(STMP) (S-12) (Example 12). The x-axis is time measured in days and
the y-axis is cumulative release percent.
[0057] FIG. 6 illustrates the in vitro drug release profiles for
samples S-1, S-2, and S-3 in PBS with 1% Tween 20 at 37.degree. C.
(Example 13). The x-axis is time measured in days and the y-axis is
cumulative release percent.
[0058] FIG. 7 illustrates the in vitro drug release profile of
S-13, S-14, S-15 and S-16 in PBS with 1% Tween 20 at 37.degree. C.
(Example 15). The x-axis is time measured in days and the y-axis is
cumulative release percent.
[0059] FIG. 8A illustrates the in vitro aggregation of surface
treated microparticles (STMP) in 5-fold diluted ProVisc at a
concentration of 100 mg/mL into 4 mL of PBS after incubation at
37.degree. C. for 2 hours (top) and after incubation at 37.degree.
C. for 2 hours followed by shaking at 250 rpm for 2 minutes on an
orbital shaker (bottom) (Example 17).
[0060] FIG. 8B illustrates the in vitro aggregation of surface
treated microparticles (STMP) in 5-fold diluted ProVisc at a
concentration of 100 mg/mL into 4 mL of HA (5 mg/mL solution) after
incubation at 37.degree. C. for 2 hours (top) and after incubation
at 37.degree. C. for 2 hours followed by shaking at 250 rpm for 2
minutes on an orbital shaker (bottom) (Example 17).
[0061] FIG. 8C illustrates the in vitro aggregation of surface
treated microparticles (STMP) in 5-fold diluted ProVisc at a
concentration of 200 mg/mL into 4 mL of PBS after incubation at
37.degree. C. for 2 hours followed by shaking at 250 rpm for 2
minutes on an orbital shaker (bottom) (Example 17).
[0062] FIG. 8D illustrates the in vitro aggregation of surface
treated microparticles (STMP) in 5-fold diluted ProVisc at a
concentration of 200 mg/mL into 4 mL of HA (5 mg/mL solution) after
incubation at 37.degree. C. for 2 hours followed by shaking at 250
rpm for 2 minutes on an orbital shaker (bottom) (Example 17).
[0063] FIG. 9 illustrates photos of aggregates of particles in an
ex vivo cow eye 2 hours after injection (Example 18).
[0064] FIG. 10A are photos of particle aggregates in the vitreous
(left) and out of the vitreous (right) following injection of STMP,
S-10, suspended in PBS into the central vitreous of rabbit eyes
(Example 19).
[0065] FIG. 10B are photos of particle aggregates in the vitreous
(left) and out of the vitreous (right) following injection of STMP,
S-10, suspended in 5-fold diluted ProVisc into the central vitreous
of rabbit eyes (Example 19).
[0066] FIG. 11A illustrates representative 1-month histology images
of rabbit eyes injected with surface treated microparticles (STMP)
(Example 20).
[0067] FIG. 11B illustrates representative 1-month histology images
of rabbit eyes injected with non-surface treated microparticles
(NSTMP) (Example 20).
[0068] FIG. 12 illustrates the size distribution of a
representative batch of surface treated microparticles (STMP)
(S-12) (Example 22). The x-axis represents particle diameter
measured in micrometers and the y-axis represents volume
percent.
[0069] FIG. 13A illustrates select PK profiles for sunitinib in the
retina following a bilateral injection of sunitinib malate (free
drug) at a dose of 0.0125 mg/eye or 0.00125 mg/eye in pigmented
rabbits (Example 24). The x-axis is time measured in hours and the
y-axis is the concentration of sunitinib in ng/g.
[0070] FIG. 13B illustrates select PK profiles for sunitinib in the
vitreous following a bilateral injection of sunitinib malate (free
drug) at a dose of 0.0125 mg/eye or 0.00125 mg/eye in pigmented
rabbits (Example 24). The x-axis is time measured in hours and the
y-axis is the concentration of sunitinib in ng/g.
[0071] FIG. 13C illustrates select PK profiles for sunitinib in the
plasma following a bilateral injection of sunitinib malate (free
drug) at a dose of 2.5 mg/eye, 0.25 mg/eye, or 0.025 mg/eye in
pigmented rabbits (Example 24). The x-axis is time measured in
hours and the y-axis is the concentration of sunitinib in ng/g.
[0072] FIG. 14 illustrates sunitinib levels (ng/g) in rabbits
injected with 10 mg of STMP containing 1 mg sunitinib for 7-months
post-dose. The rabbits were sacrificed at 7 months and sunitinib
levels (ng/g) were determined in the vitreous, retina, plasma, and
RPE-Choroid. Sunitinib levels were above the Ki for sunitinib
against VEGFR and PDGFR (Example 20). The x-axis represents time
post-dose in month and the y-axis represents the concentration of
sunitinib measured in ng/g.
[0073] FIG. 15 illustrates sunitinib levels (ng/g) in rabbits
injected with 2 mg of STMP containing 0.2 mg sunitinib (10% w/w
STMP) for 4-months post-dose. The rabbits were sacrificed at 4
months and sunitinib levels (ng/g) were determined in the vitreous,
retina, plasma, and RPE-Choroid. Sunitinib levels were above the
K.sub.i for sunitinib against VEGFR and PDGFR in the RPE-Choroid
and retina (Example 20). The x-axis represents time post-dose in
months and the y-axis represents the concentration of sunitinib
measured in ng/g.
[0074] FIG. 16 illustrates sunitinib levels (ng/g) in rabbits
injected with 10 mg of STMP containing 0.2 mg sunitinib (2% w/w
STMP). The rabbits were sacrificed at 4 months and sunitinib levels
(ng/g) were determined in the vitreous, retina, plasma, and
RPE-Choroid. Sunitinib levels were above the K.sub.i for sunitinib
against VEGFR and PDGFR in the RPE-Choroid and retina (Example 20).
The x-axis represents time post-dose in month and the y-axis
represents the concentration of sunitinib measured in ng/g.
[0075] FIG. 17 illustrates the aggregation of surface treated
microparticles (STMP) (S-28 to S-37 and S-12) after injection into
PBS and incubation at 37.degree. C. for 2 hours. After the 2
hour-incubation, the non-surface treated microparticles (NSTMP),
S-27, became dispersed when the test tube was placed on an orbital
shaker at 400 rpm for 30 seconds, while the surface treated
microparticles (STMP), S-28 to S-37 and S-12, remained aggregated
under the same agitation condition. Samples from left to right, top
row to bottom row are S-28, S-29, S-30, S-31, S-32, S-33, S-34,
S-35, S-36, S-37, S-12 and S-27 (Example 10).
[0076] FIG. 18 illustrates the aggregation of surface treated
microparticles (STMP) (S-39 to S-45) after injection into PBS and
incubation at 37.degree. C. for 2 hours. After the 2
hour-incubation, the non-surface treated microparticles (NSTMP),
S-38, became dispersed when the test tube was placed on an orbital
shaker at 400 rpm for 30 seconds, while the surface treated
microparticles (STMP), S-39 to S-45, remained aggregated under the
same agitation condition. Samples from left to right, top row to
bottom row are S-39, S-40, S-41, S-42, S-43, S-44 and S-45 (Example
10).
[0077] FIG. 19 is a graph depicting PK after a single IVT injection
of STMP containing 1 mg sunitinib malate in rabbits. The rabbits
were sacrificed at 10 days and 3 months and sunitinib levels (ng/g)
were determined in the vitreous, retina, and RPE-Choroid. Sunitinib
levels were above the K.sub.i for sunitinib against VEGFR and PDGFR
in the RPE-Choroid and retina (Example 29). The x-axis represents
time post-dose in moths and the y-axis represents the concentration
of sunitinib measured in ng/g.
[0078] FIG. 20A is a schematic representation of the locking
mechanism of the VacLock syringe highlighting the locking fins and
stopping pin as described in Example 31A.
[0079] FIG. 20B is a schematic representation of the VacLock
syringe when the apparatus is being used for normal sliding use.
The stopping pin is positioned in such a way that the pin does not
make contact with a locking fin as described in Example 31A.
[0080] FIG. 20C is a schematic representation of the VacLock
syringe when the apparatus is capable of being locked to hold
vacuum. The stopping pin is positioned to make contact with the
locking fins as described in Example 31A.
[0081] FIG. 21 is an image of a 60 mL VacLok syringe attached to a
suspension vial through a vial adapter as described in Example 31A.
The syringe plunger is locked at 50 mL to create a pressure of
approximately 40 Torr inside the vial. The parts of the apparatus
are as follows: 1) syringe plunger, which can be locked in
different positions to create different pressures inside the glass
vial; 2) 60 mL lockable syringe; 3) vial adapter; and, 4) 2 mL
glass vial containing the particle suspension.
[0082] FIG. 22A is an image depicting the effect of vacuum
treatment as described in Example 31A. The image was taken
following the injection of particles into 37.degree. C. phosphate
buffered saline solution (PBS). Compared to the FIG. 22B, the
microparticles floated following injection.
[0083] FIG. 22B is an image depicting the effect of vacuum
treatment as described in the optimized procedure of Example 31B.
The image was taken following the injection of particles into
37.degree. C. phosphate buffered saline solution (PBS). Compared to
FIG. 22A, microparticle floatation was reduced.
[0084] FIG. 22C is a comparison of microparticles subjected to the
vacuum procedure of Example 31A (left) and the optimized vacuum
procedure of Example 31B (right). The images were taken following
the injection of particles into 37.degree. C. phosphate buffered
saline solution (PBS). Microparticles subjected to the optimized
procedure were less dispersed compared to the particles subjected
to the procedure in Example 31A.
[0085] FIG. 23A is an image depicting the effect of vacuum
treatment as described in Example 32 on particle floatation during
injection. The image was taken during the injection of particles
into a glass tube containing 37.degree. C. phosphate buffered
saline solution (PBS).
[0086] FIG. 23B is an image depicting the effect of vacuum
treatment as described in Example 32 on particle floatation during
injection. The image was taken during the injection of particles
into a glass tube containing 37.degree. C. phosphate buffered
saline solution (PBS). The particles had been subjected to vacuum
treatment for 10 minutes at 143 Torr prior to injection.
[0087] FIG. 23C is an image depicting the effect of vacuum
treatment as described in Example 32 on particle floatation during
injection. The image was taken during the injection of particles
into a glass tube containing 37.degree. C. phosphate buffered
saline solution (PBS). The particles had been subjected to vacuum
treatment for 10 minutes at 87 Torr prior to injection.
[0088] FIG. 23D is an image depicting the effect of vacuum
treatment as described in Example 32 on particle floatation during
injection. The image was taken during the injection of particles
into a glass tube containing 37.degree. C. phosphate buffered
saline solution (PBS). The particles had been subjected to vacuum
treatment for 10 minutes at 32 Torr prior to injection.
[0089] FIG. 23E is an image depicting the effect of vacuum
treatment as described in Example 32 on particle floatation 10
seconds after injection. The image was taken after the injection of
particles into a glass tube containing 37.degree. C. phosphate
buffered saline solution (PBS). The particles had not been
subjected to vacuum treatment prior to injection (no vacuum was
pulled, but the pressure in the vial attached to the VacLock
syringe was approximately 550 Torr due to the slight vacuum
introduced before vial capping).
[0090] FIG. 23F is an image depicting the effect of vacuum
treatment as described in Example 32 on particle floatation 10
seconds after injection. The image was taken after the injection of
particles into a glass tube containing 37.degree. C. phosphate
buffered saline solution (PBS). The particles had been subjected to
vacuum treatment for 10 minutes at 143 Torr prior to injection.
[0091] FIG. 23G is an image depicting the effect of vacuum
treatment as described in Example 32 on particle floatation 10
seconds after injection. The image was taken after the injection of
particles into a glass tube containing 37.degree. C. phosphate
buffered saline solution (PBS). The particles had been subjected to
vacuum treatment for 10 minutes at 87 Torr prior to injection.
[0092] FIG. 23H is an image depicting the effect of vacuum
treatment as described in Example 32 on particle floatation 10
seconds after injection. The image was taken after the injection of
particles into a glass tube containing 37.degree. C. phosphate
buffered saline solution (PBS). The particles had been subjected to
vacuum treatment for 10 minutes at 32 Torr prior to injection.
[0093] FIG. 23I is an image depicting the effect of vacuum
treatment as described in Example 32 on particle aggregation. The
image was taken after particles were allowed to incubate for 2
hours in a glass tube containing 37.degree. C. phosphate buffered
saline solution (PBS) and the particles were detached from the
bottom of the glass by gently tapping. The particles had not been
subjected to vacuum treatment prior to injection (no vacuum was
pulled, but the pressure in the vial attached to the VacLock
syringe was approximately 550 Torr due to the slight vacuum
introduced before vial capping).
[0094] FIG. 23J is an image depicting the effect of vacuum
treatment as described in Example 32 on particle aggregation. The
image was taken after particles were allowed to incubate for 2
hours in a glass tube containing 37.degree. C. phosphate buffered
saline solution (PBS) and the particles were detached from the
bottom of the glass by gently tapping. The particles had been
subjected to vacuum treatment for 10 minutes at 143 Torr prior to
injection.
[0095] FIG. 23K is an image depicting the effect of vacuum
treatment as described in Example 32 on particle aggregation. The
image was taken after particles were allowed to incubate for 2
hours in a glass tube containing 37.degree. C. phosphate buffered
saline solution (PBS) and the particles were detached from the
bottom of the glass by gently tapping. The particles had been
subjected to vacuum treatment for 10 minutes at 87 Torr prior to
injection.
[0096] FIG. 23L is an image depicting the effect of vacuum
treatment as described in Example 32 on particle aggregation. The
image was taken after particles were allowed to incubate for 2
hours in a glass tube containing 37.degree. C. phosphate buffered
saline solution (PBS) and the particles were detached from the
bottom of the glass by gently tapping. The particles had been
subjected to vacuum treatment for 10 minutes at 32 Torr prior to
injection.
[0097] FIG. 24A is an image depicting the effect of particle
concentration on vacuuming outcome as described in Example 33. The
image was taken after particles (200 mg/mL) were injected into a
glass tube containing 37.degree. C. phosphate buffered saline
solution (PBS) following vacuuming treatment for 20 minutes at
approximately 30 Torr. In the image, as measured by visual
assessment, less than 5% of the particles floated.
[0098] FIG. 24B is an image depicting the effect of particle
concentration on vacuuming outcome as described in Example 33. The
image was taken after particles (400 mg/mL) were injected into a
plastic tube containing 37.degree. C. phosphate buffered saline
solution (PBS) following vacuuming treatment for 20 minutes at
approximately 30 Torr. In the image, as measured by visual
assessment, approximately 40% of the particles floated.
[0099] FIG. 25A is an image depicting the effect of vacuum
treatment time on particle floatation as described in Example 34.
The image was taken after particles (400 mg/mL) were injected into
a plastic tube containing 37.degree. C. phosphate buffered saline
solution (PBS) following vacuuming treatment for 10 minutes at
approximately 30 Torr. In the image, as measured by visual
assessment, approximately 20% of the particles floated.
[0100] FIG. 25B is an image depicting the effect of vacuum
treatment time on particle floatation as described in Example 34.
The image was taken after particles (400 mg/mL) were injected into
a plastic tube containing 37.degree. C. phosphate buffered saline
solution (PBS) following vacuuming treatment for 30 minutes at
approximately 30 Torr. In the image, as measured by visual
assessment, approximately 8% of the particles floated.
[0101] FIG. 26A is an image depicting the effect of vacuum
treatment on particle floatation as described in Example 35. The
image was taken after particles (400 mg/mL) were injected into a
plastic tube containing 37.degree. C. phosphate buffered saline
solution (PBS) following high vacuuming treatment for 10 minutes at
approximately 35 Torr.
[0102] FIG. 26B is an image depicting the effect of vacuum
treatment on particle floatation as described in Example 35. The
image was taken after particles (400 mg/mL) were injected into a
plastic tube containing 37.degree. C. phosphate buffered saline
solution (PBS) following low vacuuming treatment for 10 minutes at
approximately 550 Torr.
[0103] FIG. 27A is an image depicting the effects of excipient type
and concentration on particle floatation as described in Example
36. The image was taken after particles were injected into a glass
tube containing phosphate buffered saline solution (PBS) following
lyophilization in 1% sucrose.
[0104] FIG. 27B is an image depicting the effects of excipient type
and concentration on particle floatation as described in Example
36. The image was taken after particles were injected into a glass
tube containing phosphate buffered saline solution (PBS) following
lyophilization in 10% sucrose.
[0105] FIG. 27C is an image depicting the effects of excipient type
and concentration on particle floatation as described in Example
36. The image was taken after particles were injected into a glass
tube containing HA solution (5 mg/mL) following lyophilization in
1% sucrose.
[0106] FIG. 27D is an image depicting the effects of excipient type
and concentration on particle floatation as described in Example
36. The image was taken after particles were injected into a glass
tube containing HA solution (5 mg/mL) following lyophilization in
10% sucrose.
[0107] FIG. 27E is an image depicting the effects of excipient type
and concentration on particle floatation as described in Example
36. The image was taken after particles were injected into a glass
tube containing phosphate buffered saline solution (PBS) following
lyophilization in 1% mannitol.
[0108] FIG. 27F is an image depicting the effects of excipient type
and concentration on particle floatation as described in Example
36. The image was taken after particles were injected into a glass
tube containing phosphate buffered saline solution (PBS) following
lyophilization in 10% mannitol.
[0109] FIG. 27G is an image depicting the effects of excipient type
and concentration on particle floatation as described in Example
36. The image was taken after particles were injected into a glass
tube containing HA solution (5 mg/mL) following lyophilization in
1% mannitol.
[0110] FIG. 27H is an image depicting the effects of excipient type
and concentration on particle floatation as described in Example
36. The image was taken after particles were injected into a glass
tube containing HA solution (5 mg/mL) following lyophilization in
10% mannitol.
[0111] FIG. 27I is an image depicting the effects of excipient type
and concentration on particle floatation as described in Example
36. The image was taken after particles were injected into a glass
tube containing HA solution (5 mg/mL) following lyophilization in
1% trehalose.
[0112] FIG. 27J is an image depicting the effects of excipient type
and concentration on particle floatation as described in Example
36. The image was taken after particles were injected into a glass
tube containing HA solution (5 mg/mL) following lyophilization in
10% trehalose.
[0113] FIG. 27K is an image depicting the effects of excipient type
and concentration on particle floatation as described in Example
36. The image was taken after particles were injected into a glass
tube containing phosphate buffered saline solution (PBS) without
any lyophilization pre-treatment.
[0114] FIG. 27L is an image depicting the effects of excipient type
and concentration on particle floatation as described in Example
36. The image was taken after particles were injected into a glass
tube containing HA solution (5 mg/mL) without any lyophilization
pre-treatment.
[0115] FIG. 28 is an image depicting the effects of excipient type
and concentration on particle aggregation as described in Example
36. The image was taken after particles were allowed to incubate
for 2 hours in a glass tube containing phosphate buffered saline
solution (PBS) and the particles were detached from the bottom of
the glass by gently tapping. Prior to injection, the particles were
subjected to lyophilization in mannitol, sucrose, or trehalose
solution. Particles with excipients aggregated, while the control
had poor aggregation. Excipient solutions for lyophilization (in
order from left to right) included 10% mannitol, 10% sucrose, 10%
trehalose, 1% sucrose, 10% sucrose, and control.
[0116] FIG. 29A is an image depicting the effect of sonication on
particle floatation as described in Example 37. The image was taken
after particles suspended in HA were injected into a glass tube
containing PBS solution before the particles were sonicated.
[0117] FIG. 29B is an image depicting the effect of sonication on
particle floatation as described in Example 37. The image was taken
after particles suspended in HA were injected into a glass tube
containing PBS solution after the particles were sonicated.
[0118] FIG. 30 is an image depicting the effect of sonication on
particle aggregation as described in Example 37. The image was
taken after particles suspended in HA were allowed to incubate for
2 hours in a glass tube containing phosphate buffered saline
solution (PBS) and the particles were detached from the bottom of
the glass by gently tapping. Sample 1 in an image of particle
aggregation when the particles were not subjected to sonication
prior to incubation in PBS. Sample 2 is an image of particle
aggregation when the particles were subjected to sonication prior
to incubation in PBS. Aggregation was improved when particles were
pre-treated with sonication.
[0119] FIG. 31 is a graft depicting the in vitro drug release
profile determined at 37.degree. C. of the compounds of Table 13 in
Example 38. The x-axis is time measured in days and the y-axis is
cumulative release percent.
[0120] FIG. 32 is a graft depicting the in vitro drug release
profile of the microparticles Table 14 at 37.degree. C. as
described in Example 38. The x-axis is time measured in days and
the y-axis is cumulative release percent.
[0121] FIG. 33 is a graft depicting the in vitro drug release
profile of the microparticles Table 15 at 37.degree. C. as
described in Example 38. The x-axis is time measured in days and
the y-axis is cumulative release percent.
[0122] FIG. 34 is a graft depicting the in vitro drug release
profile at 37.degree. C. of the microparticles SM60, SM72, a 7:3
blend of SM60 and SM72, and a 7:3 blend of SM79 and SM78 as
described in Example 38. The x-axis is time measured in days and
the y-axis is cumulative release percent.
[0123] FIG. 35 is a graft depicting the in vitro drug release
profile of the microparticles SM90, SM91, SM92, and SM93 as
described in Table 18A and Table 18B as described in Example 38. SM
72 is also shown for comparison. The x-axis is time measured in
days and the y-axis is cumulative release percent.
[0124] FIG. 36 is a graft depicting the in vitro drug release
profile of the microparticles SM94, SM61, and SM93 as described in
Table 19A and Table 19B as described in Example 38. The x-axis is
time measured in days and the y-axis is cumulative release
percent.
[0125] FIG. 37 is a graft depicting the in vitro drug release
profile of microparticle blends as described in Example 39. The
x-axis is time measured in days and the y-axis is cumulative
release percent.
[0126] FIG. 38 is a graph depicting the in vivo release of the
microparticles SM72, SM60, and a 7:3 mass ratio blend of SM60 and
SM72 in a rabbit vitreous after a single intravitreal injection as
described in Example 40. The x-axis is time measured in months and
the y-axis is cumulative release percent.
[0127] FIG. 39A is a graph depicting the in vivo release profile of
the microparticles SM72, SM60, and a 7:3 mass ratio blend of SM60
and SM72 in a rabbit RPE-Choroid as described in Example 40. The
x-axis is time measured in months and the y-axis is the level of
sunitinib (ng/g).
[0128] FIG. 39B is a graph depicting in vivo release profile of the
microparticles SM72, SM60, and a 7:3 mass ratio blend of SM60 and
SM72 in a rabbit retina as described in Example 40. The x-axis is
time measured in months and the y-axis is the level of sunitinib
(ng/g).
[0129] FIG. 40A is a graph depicting the sunitinib levels in the
central retina and the RPE/choroid area following dosing with SM74,
SM75, and SM76 as described in Example 40. The x-axis is time
measured in days and the y-axis is the level of sunitinib
(ng/g).
[0130] FIG. 40B is a graph depicting the remaining sunitinib
encapsulated in particles after dosing with SM74, SM75, and SM76 as
described in Example 40. The x-axis is time measured in days and
the y-axis is sunitinib remaining measured in percent.
DETAILED DESCRIPTION
[0131] The present invention has at least the following aspects:
[0132] (i) A lyophilized or otherwise reconstitutable microparticle
composition that has less propensity to result in floating
microparticles than the same microparticle composition that has not
been processed as described herein, when resuspended in fluid, such
as including but not limited to buffered aqueous solution or
aqueous hyaluronic acid, for in vivo delivery. The process as
described herein is based on the discovery that very small air
bubbles or gas or a thin layer of air adhered to microparticles can
adversely affect the quality of the resuspended microparticle of
the present invention, and that improved microparticles for
lyophilization can be provided by removing adhered air or gas by
treating the microparticles with a vacuum, sonication, or excipient
addition or other method that removes or decreases the adhered air
or gas prior to lyophilization, or by doing so after resuspending
the lyophilized microparticle material. It has been discovered that
the issue of air adhered to the microparticle can be more
pronounced if the microparticle has been surface treated even under
mild conditions to remove or decrease surface surfactant, such as
those described in U.S. Ser. No. 15/349,985 and PCT/US16/61706 (see
nonlimiting Example 2 below). [0133] (ii) An improved lyophilized
microparticle, microparticle suspension, and method for manufacture
thereof, processed as described in (i) that is loaded with a
pharmaceutically active agent, including those listed below, which
can be active in the form delivered or is a prodrug, with
non-limiting examples provided herein, for in vivo treatment of a
patient in need thereof. [0134] (iii) Microparticles as described
herein, and lyophilized or suspended materials thereof, whether
treated to remove adhered air or gas, and which include any of the
active drugs, including prodrugs, described herein.
[0135] For example, it has been identified that for certain
applications, the processes and materials in U.S. Ser. No.
15/349,985 and PCT/US16/61706 provide acceptable aggregating
microparticles in vivo, however, there are occasions when if
surface-treated microparticles are overtreated (e.g., treated under
strong chemical conditions or for an extended period of time), they
may have a tendency to float upon injection into an aqueous
solution with low viscosity (e.g., PBS buffer solution or sometimes
vitreal fluid, wherein the viscosity may decrease with age of the
patient), which can be disadvantageous for forming a pellet that
remains out of the visual axis. Since ocular disorders increase
with age, it is important to provide a particle suspension that
still aggregates to a pellet in lower viscosity vitreous fluid.
Certain aspects of this invention address those certain situations,
where a thin layer of air, air bubbles or gas generally can adhere
to the surface of some microparticles and prevent the particles
from being completely wetted. If this tiny layer of air or bubbles
is high enough to create buoyancy, the microparticles will be less
likely to aggregate to the desired pellet.
[0136] Thus, according to the present invention, microparticles and
microparticle suspensions are provided that have improved
aggregation to a pellet for medical therapy due to enhanced
wettability in vivo. Examples of processes that provide improved
aggregation of particles to the desired ocular pellet include, but
are not limited to, one or a combination of 1) applying a vacuum to
the particle suspension to facilitate the disassociation of air
from particles; 2) adding one or more excipients to reduce surface
hydrophobicity of particles and thus reduce the amount of air
adhering to the particles; and, 3) sonication to facilitate the
disassociation of air from the particles, either prior to
lyophilization or other drying means to make a solid
reconstitutable microparticle material, or by carrying out one or
more of these processes after reconstitution. These processes are
described in more detail below.
[0137] In the third independent aspect of the invention, solid
microparticles that aggregate in vivo to a pellet and provide
release of a therapeutic agent in vivo are provided. In certain
embodiments, the therapeutic agent is a lipophilic prodrug as
described herein. In certain embodiments, the lipophilic prodrug
releases a prostaglandin, carbonic anhydrase inhibitor, receptor
tyrosine kinase inhibitor (RTKIs), Rho kinase (ROCK) inhibitor,
beta-blocker, alpha-adrenergic agonist, or loop diuretic. In
certain embodiments, the therapeutic agent is the active agent
itself not in prodrug form, such as a prostaglandin, a carbonic
anhydrase inhibitor, a receptor tyrosine kinase inhibitor (RTKIs),
a Rho kinase (ROCK) inhibitor, a beta-blocker, an alpha-adrenergic
agonists, or a loop diuretic. Nonlimiting examples of prodrugs and
active agents that can be used in the present invention are
provided herein. For example, one or more of the processes can be
used at the time the particles are being prepared to produce the
powder or material that is stored and then later resuspended (for
example, prior to lyophilization) for injection. In one example,
the vessel with the dried microparticles can be placed under
pressure for storage before use. In another non-limiting example,
the container storing the surface-treated microparticles can be
placed under vacuum directly before administration. In other
embodiments, it is not necessary to remove air or gas from the
active-loaded microparticle at any stage of manufacture to achieve
a suitable therapeutic effect.
[0138] In typical embodiments of invention (i) above, the process
to prepare the improved suspension for medical use, including for
administration into low viscosity fluids, is conducted following
mild surface treatment, isolation, and reconstitution in an
appropriate diluent. Non-limiting illustrations in Examples 32-37
establish that treatments to provide an improved suspension of
microparticles upon injection in an aqueous solution result in less
floatation and better aggregation compared to microparticles that
have not been treated for enhanced wettability. FIGS. 22A-22C and
23A-23L illustrate the effect of vacuum strength on particle
floatation and aggregation, and FIGS. 27A-27L illustrate the effect
of excipient addition on particle floatation and aggregation. FIGS.
29A, 29B and 30 depict the effect of sonication on particle
floatation and aggregation.
[0139] In one embodiment of a selected aspect of the invention, the
microparticles are mildly surface treated prior to treatments for
enhanced wettability. In one embodiment, the solid biodegradable
microparticles are suitable for ocular injection, at which point
the particles aggregate to form a pellet that remains outside the
visual axis so as not to significantly impair vision. The particles
can aggregate into one or several pellets. The size of the
aggregate depends on the concentration and volume of the
microparticle suspensions injected and the diluent in which the
microparticles are suspended.
[0140] In one aspect of the invention, the improved process of (i)
for preparing a microparticle or lyophilized or otherwise
solidified material thereof or a suspension thereof, leading to an
aggregated pellet in vivo, can be used in combination with a
selected method and for forming aggregating microparticles
described in U.S. Ser. No. 15/349,985 and PCT/US16/61706 (and the
resulting materials thereof). For example, methods include
providing solid aggregating microparticles that include at least
one biodegradable polymer, wherein the solid aggregating
microparticles have a solid core, include a therapeutic agent, have
a modified surface which has been treated under mild conditions at
a temperature, that may optionally be at or less than about
18.degree. C., to remove surface surfactant, are sufficiently small
to be injected in vivo, and are capable of aggregating in vivo to
form at least one pellet of at least 500 tm in vivo to provide
sustained drug delivery in vivo for at least three months, four
months, five months, six months seven months, eight months, nine
months or more. In certain embodiments, sustained drug deliver in
vivo is provided for up to one year. The solid aggregating
microparticles are suitable, for example, for an intravitreal
injection, implant, including an ocular implant, periocular
delivery, or delivery in vivo outside of the eye. In certain
embodiments, the therapeutic agent is a prodrug as described
herein.
[0141] As an illustration, the present invention includes a process
for the preparation of surface-modified solid aggregating
microparticles that are advantageous for pellet formation in vivo,
and microparticle materials made thereby, that includes: [0142] A.
a first step of preparing microparticles comprising one or more
biodegradable polymers by dissolving or dispersing the polymer(s)
and a therapeutic agent in one or more solvents to form a polymer
and therapeutic agent solution or dispersion, mixing the polymer
and the therapeutic agent solution or dispersion with an aqueous
phase containing a surfactant to produce solvent-laden
microparticles and then removing the solvent(s) to produce polymer
microparticles that contain the therapeutic agent, polymer and
surfactant; and [0143] B. a second step of mildly treating the
surface of microparticles of step (i) at a temperature at or below
about 18, 15, 10, 8 or 5.degree. C. optionally up to about 1, 2, 3,
4, 5, 10, 30, 40, 50, 60, 70, 80, 90 100, 11, 120 or 140 minutes
with an agent that removes surface surfactant, surface polymer, or
surface oligomer in a manner that does not significantly produce
internal pores; and [0144] C. isolating the surface treated
microparticles; and [0145] D. subjecting the microparticles to at
least one process selected from 1) vacuum treatment prior to
lyophilization or other form of reconstitutable solidification, or
after the step of reconstitution wherein the microparticles are
suspended in a diluent and the suspension is placed under vacuum
prior to use; 2) excipient addition, wherein an excipient is added
prior to lyophilization; and 3) sonication, prior to lyophilization
or other form of reconstitutable solidification, or after the step
of reconstitution; 4) sealing the vial containing the dry powder of
particles under vacuum, including but not limited to high vacuum;
or 5) pre-wetting (i.e., resuspending) the surface-treated
microparticles in a diluent for 2-24 hours before injecting into
the eye, for example in a hyaluronic acid solution or other sterile
solution suitable for ocular injection.
[0146] The process of these steps can be achieved in a continuous
manufacturing line or via one step or in step-wise fashion as
appropriate. The process of step D. above can be carried out
following isolation of the microparticles and/or upon
reconstitution prior to injection. In one embodiment, the surface
treated solid biodegradable microparticles do not significantly
aggregate during the manufacturing process. In another embodiment,
the surface treated solid biodegradable microparticles do not
significantly aggregate when resuspended and loaded into a syringe.
In some embodiments, the syringe is approximately 30, 29, 28, 27,
26 or 25 gauge, with either normal or thin wall.
[0147] In another nonlimiting embodiment, a process for preparing a
suspension comprising a microparticle and a pharmaceutically active
compound encapsulated in the microparticle and the resulting
materials thereof; which process comprises: [0148] (i) preparing a
solution or suspension (organic phase) comprising: (i) PLGA or PLA
or PLA and PLGA, (ii) PLGA-PEG or PLA-PEG (iii) a pharmaceutically
active compound, for example, as described herein and (iv) one or
more organic solvents; [0149] (j) preparing an emulsion in an
aqueous polyvinyl alcohol (PVA) solution (aqueous phase) by adding
the organic phase into the aqueous phase and mixing them until
particle formation (for example at about 3,000 to about 10,000 rpm
for about 1 to about 30 minutes); [0150] (k) removing additional
solvent as necessary using known techniques; [0151] (l)
centrifuging or causing the sedimentation of the microparticle that
is loaded with a pharmaceutically active compound or prodrug
thereof, [0152] (m)optionally removing additional solvent and/or
washing the microparticle loaded with the pharmaceutically active
compound or prodrug thereof with water; [0153] (n) filtering the
microparticle loaded with pharmaceutically active compound or
prodrug thereof to remove aggregates or particles larger than the
desired size; [0154] (o) optionally lyophilizing the microparticle
comprising the pharmaceutically active compound and storing the
microparticle as a dry powder in a manner that maintains stability
for up to about 6, 8, 10, 12, 20, 22, or 24 months or more; and
[0155] (p) optionally improving the aggregation potential of the
particles by subjecting the particles to at least one process
selected from 1) vacuum treatment prior to step (g), or after
reconstitution wherein the microparticles are suspended in a
diluent and the suspension is placed under vacuum; 2) excipient
addition, wherein an excipient is added prior to lyophilization;
and 3) sonication prior to step (g), or during reconstitution
wherein the microparticles are suspended in a diluent and
sonicated; 4) sealing the vial containing the dry powder of
particles under vacuum, including but not limited to high vacuum;
or 5) pre-wetting (i.e., resuspending) the surface-treated
microparticles in a diluent for 2-24 hours before injecting into
the eye, for example in a hyaluronic acid solution or other sterile
solution suitable for ocular injection.
[0156] In one embodiment, a process for preparing an improved
lyophilized material or a suspension of microparticles following
reconstitution includes suspending the particles in a diluent and
subjecting the particles to vacuum treatment at a pressure of about
less than about 500, 400, 300, 200, 150, 100, 75, 50, 40, 35, 34,
33, 32, 31, 30, 29, 28 or 25 Torr for a suitable amount of time to
substantially remove air attached to the particles, which in some
embodiments can be up to 3, 5, 8, 10, 20, 30, 40, 50, 60, 70, 80,
or 90 minutes or up to 2, 3, 4, 5, or 6, 10, 15 or 24 or more
hours. In one embodiment, the vacuum treatment is conducted with a
VacLock syringe in a size of up to at least 10, 20, 30, or 60
mL.
[0157] In certain non-limiting embodiments, the microparticles are
vacuumed at a strength of less than 40 Torr for about 3, 5, 8, 10,
20, 30, 45, 60, 75, or 90 minutes. In certain non-limiting
embodiments, the microparticles are vacuumed at a strength less
than 40 Torr from about 1 to 90 minutes, from about 1 to 60
minutes, from about 1 to 45 minutes, from about 1 to 30 minutes,
from about 1 to 15 minutes, or from about 1 to 5 minutes.
[0158] In certain embodiments, the diluent for suspending particles
is ProVisc. In some embodiments, the microparticles are diluted
from about 10-fold to about 40-fold, from about 15-fold to about
35-fold, or from about 20-fold to about 25-fold. In some
embodiments, the diluent for suspending particles is a
10.times.-diluted ProVisc (0.1% HA in PBS) solution, a
20.times.-diluted ProVisc (0.05% HA in PBS) solution, or a
40.times.-diluted ProVisc (0.025% HA in PBS) solution. In some
embodiment, the particles are suspended in the diluent at a
concentration of at least about 100 mg/mL, 200 mg/mL, 300 mg/mL,
400 mg/mL, or 500 mg/mL.
I. Terminology
[0159] Although specific terms are employed herein, they are used
in a generic and descriptive sense only and not for purposes of
limitation. Unless otherwise defined, all technical and scientific
terms used herein have the same meaning as commonly understood by
one of ordinary skill in the art to which this presently described
subject matter belongs.
[0160] Compounds are described using standard nomenclature. Unless
defined otherwise, all technical and scientific terms used herein
have the same meaning as is commonly understood by one of skill in
the art to which this invention belongs.
[0161] The terms "a" and "an" do not denote a limitation of
quantity, but rather denote the presence of at least one of the
referenced items.
[0162] Recitation of ranges of values are merely intended to serve
as a shorthand method of referring individually to each separate
value falling within the range, unless otherwise indicated herein,
and each separate value is incorporated into the specification as
if it were individually recited herein. The endpoints of all ranges
are included within the range and are independently combinable. All
methods described herein can be performed in a suitable order
unless otherwise indicated herein or otherwise clearly contradicted
by context. The use of examples, or exemplary language (e.g., "such
as"), is intended merely to better illustrate the invention and
does not pose a limitation on the scope of the invention unless
otherwise claimed.
[0163] The term "carrier" refers to a diluent, excipient, or
vehicle.
[0164] A "dosage form" means a unit of administration of a
composition that includes a surface treated microparticle and a
therapeutically active compound. Examples of dosage forms include
injections, suspensions, liquids, emulsions, implants, particles,
spheres, creams, ointments, inhalable forms, transdermal forms,
buccal, sublingual, topical, gel, mucosal, and the like. A "dosage
form" can also include, for example, a surface treated
microparticle comprising a pharmaceutically active compound in a
carrier.
[0165] The term "microparticle" means a particle whose size is
measured in micrometers (.mu.m). Typically, the microparticle has
an average diameter of from about 1 .mu.m to 100 .mu.m. In some
embodiments, the microparticle has an average diameter of from
about 1 .mu.m to 60 .mu.m, for instance from about 1 .mu.m to 40
.mu.m; from about 10 .mu.m to 40 .mu.m; from about 20 .mu.m to 40
.mu.m; from about 25 .mu.m to 40 .mu.m; from about 25 .mu.m to
about 30 .mu.m; from about 20 .mu.m to 35 .mu.m. For example, the
microparticle may have an average diameter of from 20 .mu.m to 40
.mu.m, and in certain embodiments, 20, 21, 22, 23, 24, 25, 26, 27,
28, 29, 30, 31, 32 or 33. As used herein, the term "microsphere"
means a substantially spherical microparticle.
[0166] A "patient" or "host" or "subject" is typically a human,
however, may be more generally a mammal. In an alternative
embodiment it can refer to, for example, a cow, sheep, goat, horse,
dog, cat, rabbit, rat, mouse, bird and the like.
[0167] The term "mild" or "mildly" when used to describe the
surface modification of the microparticles means that the
modification (typically the removal of surfactant from the surface,
as opposed to the inner core, of the particle) is less severe,
pronounced or extensive than when carried out at room temperature
with the otherwise same conditions. In general, the surface
modification of the solid microparticles of the present invention
is carried out in a manner that does not create significant
channels or large pores that would significantly accelerate the
degradation of the microparticle in vivo, yet serves to soften and
decrease the hydrophilicity of the surface to facilitate in vivo
aggregation.
[0168] The term "solid" as used to characterize the mildly surface
treated microparticle means that the particle is substantially
continuous in material structure as opposed to heterogeneous with
significant channels and large pores that would undesirably shorten
the time of biodegradation.
[0169] The term "sonicate" means to subject the microparticle
suspension to ultrasonic vibration, or high frequency sound
waves.
II. Processes for Producing Improved Suspensions of Surface-Treated
Aggregating Microparticles for Therapeutic Purposes
[0170] In one embodiment, the present invention provides processes
for producing suspensions of surface-treated aggregating
microparticles for therapeutic purposes that aggregate in vivo to
form pellet(s). The processes include improving the wettability of
surface-treated microparticles by removing air or air bubbles from
the surface of the microparticle. The treatment for enhanced
wettability is conducted following mild surface treatment,
isolation, and reconstitution in an appropriate diluent.
[0171] In one embodiment, the invention is thus solid aggregating
microparticles treated for improved wettability that include at
least one biodegradable polymer, wherein the surface-modified solid
aggregating microparticles have a solid core, include a therapeutic
agent, have a modified surface which has been treated under mild
conditions at a temperature at or less than about 18.degree. C. to
remove surface surfactant or cause surface polymer to partially
degrade, have been treated by at least one or more processes
selected from vacuum treatment, the addition of an excipient, and
sonication to improve wettability upon injection, are sufficiently
small to be injected in vivo, and aggregate in vivo to form at
least one pellet of at least 500 .mu.m in vivo in a manner that
provides sustained drug delivery in vivo for at least one, two,
three, four, five, six or seven months or more. The surface
modified solid aggregating microparticles are suitable, for
example, for an intravitreal injection, implant, including an
ocular implant, periocular delivery or delivery in vivo outside of
the eye.
[0172] The present invention further includes a process for the
preparation of surface-modified solid aggregating microparticles
that have also been treated for enhanced wettability that includes
[0173] (i) a first step of preparing microparticles comprising one
or more biodegradable polymers by dissolving or dispersing the
polymer(s) and a therapeutic agent in one or more solvents to form
a polymer and therapeutic agent solution or dispersion, mixing the
polymer and the therapeutic agent solution or dispersion with an
aqueous phase containing a surfactant to produce microparticles
that contain the therapeutic agent, polymer and surfactant; and
[0174] (ii) a second step of mildly treating the surface of
microparticles of step (i) at a temperature at or below about 18,
15, 10, 8 or 5.degree. C. optionally up to about 1, 2, 3, 4, 5, 10,
30, 40, 50, 60, 70, 80, 90 100, 11, 120 or 140 minutes with an
agent that removes surface surfactant, surface polymer, or surface
oligomer in a manner that does not significantly produce internal
pores; and [0175] (iii) isolating the surface treated
microparticles; and [0176] (iv) improving the aggregation potential
of the particles by subjecting the particles to at least one
process selected from 1) vacuum treatment, wherein the
microparticles are suspended in a diluent and the suspension is
placed under vacuum prior to use; 2) excipient addition, wherein an
excipient is added prior to lyophilization; and 3) sonication,
wherein the microparticles are suspended in a diluent and
sonicated; 4) sealing the vial containing the dry powder of
particles under vacuum, including but not limited to high vacuum;
or 5) pre-wetting (i.e., resuspending) the surface-treated
microparticles in a diluent for 2-24 hours before injecting into
the eye, for example in a hyaluronic acid solution or other sterile
solution suitable for ocular injection.
[0177] In one embodiment, the surface treatment includes treating
microparticles with aqueous base, for example, sodium hydroxide and
a solvent (such as an alcohol, for example ethanol or methanol, or
an organic solvent such as DMF, DMSO or ethyl acetate) as otherwise
described above. More generally, a hydroxide base is used, for
example, potassium hydroxide. An organic base can also be used. In
other embodiments, the surface treatment as described above is
carried out in aqueous acid, for example hydrochloric acid. In one
embodiment, the surface treatment includes treating microparticles
with phosphate buffered saline and ethanol.
[0178] In some embodiments, the surface treatment is carried out at
a temperature of not more than 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,
15, 16, 17 or 18.degree. C., at a reduced temperature of about 5 to
about 18.degree. C., about 5 to about 16.degree. C., about 5 to
about 15.degree. C., about 0 to about 10.degree. C., about 0 to
about 8.degree. C., or about 1 to about 5.degree. C., about 5 to
about 20.degree. C., about 1 to about 10.degree. C., about 0 to
about 15.degree. C., about 0 to about 10.degree. C., about 1 to
about 8.degree. C., or about 1 to about 5.degree. C. Each
combination of each of these conditions is considered independently
disclosed as if each combination were separately listed.
[0179] The pH of the surface treatment will of course vary based on
whether the treatment is carried out in basic, neutral or acidic
conditions. When carrying out the treatment in base, the pH may
range from about 7.5 to about 14, including not more than about 8,
9, 10, 11, 12, 13 or 14. When carrying out the treatment in acid,
the pH may range from about 6.5 to about 1, including not less than
1, 2, 3, 4, 5, or 6. When carrying out under neutral conditions,
the pH may typically range from about 6.4 or 6.5 to about 7.4 or
7.5.
[0180] A key aspect of the present invention is that the treatment,
whether done in basic, neutral or acidic conditions, includes a
selection of the combination of the time, temperature, pH agent and
solvent that causes a mild treatment that does not significantly
damage the particle in a manner that forms pores, holes or
channels. Each combination of each of these conditions is
considered independently disclosed as if each combination were
separately listed.
[0181] The treatment conditions should simply mildly treat the
surface in a manner that allows the particles to remain as solid
particles, be injectable without undue aggregation or clumping, and
form at least one aggregate particle of at least 500.mu.m.
[0182] In one embodiment, the surface treatment includes treating
microparticles with an aqueous solution of pH=6.6 to 7.4 or 7.5 and
ethanol at a reduced temperature of about 1 to about 10.degree. C.,
about 1 to about 15.degree. C., about 5 to about 15.degree. C., or
about 0 to about 5.degree. C. In one embodiment, the surface
treatment includes treating microparticles with an aqueous solution
of pH=6.6 to 7.4 or 7.5 and an organic solvent at a reduced
temperature of about 0 to about 10.degree. C., about 5 to about
8.degree. C., or about 0 to about 5.degree. C. In one embodiment,
the surface treatment includes treating microparticles with an
aqueous solution of pH=1 to 6.6 and ethanol at a reduced
temperature of about 0 to about 10.degree. C., about 0 to about
8.degree. C., or about 0 to about 5.degree. C. In one embodiment,
the surface treatment includes treating microparticles with an
organic solvent at a reduced temperature of about 0 to about
18.degree. C., about 0 to about 16.degree. C., about 0 to about
15.degree. C., about 0 to about 10.degree. C., about 0 to about
8.degree. C., or about 0 to about 5.degree. C. The decreased
temperature of processing (less than room temperature, and
typically less than 18.degree. C.) assists to ensure that the
particles are only "mildly" surface treated.
[0183] In yet another embodiment, a method for the treatment of an
ocular disorder is provided that includes administering to a host
in need thereof solid aggregating microparticles described herein
that include an effective amount of a therapeutic agent, wherein
the solid aggregating microparticles are injected into the eye and
aggregate in vivo to form at least one pellet of at least 500 tm
that provides sustained drug delivery for at least approximately
one, two, three, four, five, six, seven, eight, nine, ten, eleven,
twelve or more months in such a manner that the pellet stays
substantially outside the visual axis so as not to significantly
impair vision. In one embodiment, the solid biodegradable
microparticles release about 1 to about 20 percent, about 1 to
about 15 percent, about 1 to about 10 percent, or about 5 to 20
percent, for example, up to about 1, 5, 10, 15 or 20 percent, of
the therapeutic agent over the first twenty-four-hour period.
[0184] Vacuum Treatment
[0185] In one embodiment, the process for providing an improved
microparticle suspension prior to injection includes vacuum
treatment wherein the particles are suspended in a diluent and
subjected to negative pressure to remove unwanted air at the
surface of the microparticles. Nonlimiting examples of the negative
pressure can be about or less than 300, 200, 100, 150, 145, 143,
90, 89, 88, 87, 86, 85, 75, 50, 35, 34, 33, 32, 31, or 30 Torr for
any appropriate time to achieve the desired results, including but
not limited to 120, 110, 100, 90, 80, 70, 60, 50, 40, 30, 20, 10,
8, 5, or 3 minutes.
[0186] In one embodiment, microparticles are stored under negative
pressure following the manufacturing and isolation process, wherein
negative pressure is defined as any pressure lower than the
pressure of ambient room temperature (approximately 760 Torr). In
one embodiment, the microparticles are stored at a pressure of less
than about 700 Torr, 550 Torr, 500 Torr, 450 Torr, 400 Torr, 350
Torr, 300 Torr, 250 Torr, 200 Torr, 150 Torr, 100 Torr, 90 Torr, 80
Torr, 60 Torr, 40 Torr, 35 Torr, 32 Torr, 30 Torr, or 25 Torr
following the manufacturing and isolation process. In one
embodiment, the microparticles are stored at a pressure of about
500 Torr to about 25 Torr following the manufacturing and isolation
process. In one embodiment, the microparticles are stored at a
pressure of about 300 Torr to about 25 Torr following the
manufacturing and isolation process. In one embodiment, the
microparticles are stored at a pressure of about 100 Torr to about
25 Torr following the manufacturing and isolation process. In one
embodiment, the microparticles are stored at a pressure of about 90
Torr to about 25 Torr following the manufacturing and isolation
process. In one embodiment, the microparticles are stored at a
pressure of about 50 Torr to about 25 Torr following the
manufacturing and isolation process. In one embodiment, the
microparticles are stored at a pressure of about 40 Torr to about
25 Torr following the manufacturing and isolation process. In one
embodiment, the microparticles are stored at a pressure of about 35
Torr to about 25 Torr following the manufacturing and isolation
process. In a further embodiment, the microparticles are stored at
a temperature of between about 2-8.degree. C. at a pressure that is
less than about 700, 550, 500, 450, 400, 350, 300, 250, 200, 150,
100, 80, 60, 50, 40, 35, 32, 30, or 25 Torr.
[0187] In one embodiment, the microparticles are stored at pressure
for up to 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3
months, 4 months, or more following the manufacture and isolation
process. In one embodiment, the microparticles are stored for up to
1 week to up to 4 weeks at a pressure that is less than 700, 550,
500, 450, 400, 350, 300, 250, 200, 150, 100, 80, 60, 50, 40, 35,
32, or 30 Torr. In one embodiment, the microparticles are stored
for up to 1 month to up to 2 months at a pressure that is less than
700, 550, 500, 450, 400, 350, 300, 250, 200, 150, 100, 80, 60, 50,
40, 35, 32, or 30 Torr. In one embodiment, the microparticles are
stored for up to 3 months at a pressure that is less than 700, 550,
500, 450, 400, 350, 300, 250, 200, 150, 100, 80, 60, 50, 40, 35,
32, or 30 Torr
[0188] In one embodiment, the microparticles are stored at a
temperature of between about 2-8.degree. C. following the
manufacturing and isolation process and the microparticles are
vacuumed less than about 2 hours, 1 hour, 30 minutes, 15 minutes,
or 10 minutes prior to in vivo injection. In one embodiment, the
microparticles are stored at a temperature of between about
2-8.degree. C. following the manufacturing and isolation process
and the microparticles are vacuumed 1 hour to 30 minutes prior to
in vivo injection. In one embodiment, the microparticles are stored
at a temperature of between about 2-8.degree. C. following the
manufacturing and isolation process and the microparticles are
vacuumed 30 minutes to 10 minutes prior to in vivo injection. In
one embodiment, the microparticles are stored at a temperature of
between about 2-8.degree. C. following the manufacturing and
isolation process and the microparticles are vacuumed immediately
prior to in vivo injection.
[0189] In one embodiment, the microparticles are stored at a
temperature of between about 2-8.degree. C. and the microparticles
are vacuumed for less than 1 hour, 30 minutes, 20 minutes, 15
minutes, or 10 minutes at a strength of less than about 35 Torr
immediately prior to in vivo injection. In one embodiment, the
microparticles are stored at a temperature of between about
2-8.degree. C. and the microparticles are vacuumed for 1 hour to 30
minutes at a strength of less than about 35 Torr immediately prior
to in vivo injection. In one embodiment, the microparticles are
stored at a temperature of between about 2-8.degree. C. and the
microparticles are vacuumed for 30 minutes to 10 minutes at a
strength of less than about 35 Torr immediately prior to in vivo
injection. In one embodiment, the particles are suspended in a
glass vial that is attached to a vial adapter and the vial adapter
is in turn attached to a VacLok syringe (FIG. 21). A negative
pressure is created in the vial by pulling the plunger of the
syringe into a locking position as shown in FIG. 20C. In one
embodiment, the vacuum treatment is conducted in a syringe of the
60 mL, 30 mL, 20 mL, or 10 mL size. The vacuum is then held in the
syringe with the vial facing up and the large syringe attached for
up to at least 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50
minutes, 60 minutes, 70 minutes, 90 minutes, 100 minutes, or 129
minutes. The vacuum is released, the large syringe is detached, and
a syringe is attached for in vivo injection.
[0190] In one embodiment, the particles are subjected to vacuum
treatment at a strength of about 143 Torr for about at least 10
minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60
minutes, 70 minutes, 80 minutes, 90 minutes, 100 minutes, or 120
minutes. In one embodiment, the particles are subjected to vacuum
treatment at a strength of at least about 90, 89, 88, 87, 86, or 85
Torr for at least about at 10 minutes, 20 minutes, 30 minutes, or
40 minutes. In one embodiment, the particles are subjected to
vacuum treatment at a strength of at least about 87 Torr for at
least about 10 minutes, 20 minutes, 30 minutes, 40 minutes, 60
minutes, 90 minutes, or 120 minutes. In one embodiment, the
particles are subjected to vacuum treatment at a strength of at
least about 35, 34, 33, 32, 31, or 30 Torr for at least 5 minutes.
In one embodiment, the particles are subjected to vacuum treatment
at a strength of at least about 35, 34, 33, 32, 31, or 30 Torr for
at least 8 minutes. In one embodiment, the particles are subjected
to vacuum treatment at a strength of at least about 35, 34, 33, 32,
31, or 30 Torr for at least 10 minutes. In one embodiment, the
particles are subjected to vacuum treatment at a strength of at
least about 35, 34, 33, 32, 31, or 30 Torr for at least 20 minutes.
In one embodiment, the particles are subjected to vacuum treatment
at a strength of at least about 35, 34, 33, 32, 31, or 30 Torr for
at least 30 minutes. In one embodiment, the particles are subjected
to vacuum treatment at a strength of at least about 35, 34, 33, 32,
31, or 30 Torr for at least 40 minutes. In one embodiment, the
particles are subjected to 30 Torr for at least 5, 10, 15, 20, 25,
30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90 minutes. In
one embodiment, the particles are subjected to vacuum treatment at
a strength of about 35 Torr for at least 90 minutes. In one
embodiment, the particles are subjected to vacuum treatment at a
strength of about 35 Torr for at least 60 minutes. In one
embodiment, the particles are subjected to vacuum treatment at a
strength of about 35 Torr for at least 30 minutes. In one
embodiment, the particles are subjected to vacuum treatment at a
strength of about 35 Torr for at least 15 minutes. In one
embodiment, the particles are subjected to vacuum treatment at a
strength of about 35 Torr for at least 5 minutes. In one
embodiment, the particles are subjected to vacuum treatment at a
strength of about 32 Torr for at least 30 minutes. In one
embodiment, the particles are subjected to vacuum treatment at a
strength of about 32 Torr for at least 15 minutes. In one
embodiment, the particles are subjected to vacuum treatment at a
strength of about 32 Torr for at least 5 minutes. In one
embodiment, the particles are subjected to vacuum treatment at a
strength of about 30 Torr for at least 30 minutes. In one
embodiment, the particles are subjected to vacuum treatment at a
strength of about 30 Torr for at least 15 minutes. In one
embodiment, the particles are subjected to vacuum treatment at a
strength of about 30 Torr for at least 5 minutes.
[0191] In an alternative embodiment, the particles are suspended in
a diluent in a vial attached to a vial adapter that is further
attached to a 60 mL VacLok syringe containing a plunger (as shown
in FIG. 21) wherein the plunger is pulled to the 50 mL mark and
locked to create a negative pressure of approximately 30 Torr and
the pressure is held for at least about 3, 5, 8, 10, 15, 20, 25,
30, or 35 minutes. In an alternative embodiment, the particles are
suspended in a diluent in a vial attached to a vial adapter that is
further attached to a 60 mL VacLok syringe containing a plunger
wherein the plunger is pulled to the 45 mL mark, locked, and held
for at least about 3, 5, 8, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55,
60, 65, 70, 75, 80, 85, or 90 minutes. In an alternative
embodiment, the particles are suspended in a diluent in a vial
attached to a vial adapter that is further attached to a 60 mL
VacLok syringe containing a plunger wherein the plunger is pulled
to the 40 mL mark, locked, and the pressure is held for at least
about 3, 5, 8, 10, 15, 20, 25, 30, or 35 minutes. In an alternative
embodiment, the particles are suspended in a diluent in a vial
attached to a vial adapter that is further attached to a 60 mL
VacLok syringe containing a plunger wherein the plunger is pulled
to the 35 mL mark, locked, and held for about at least 3, 5, 8, 10,
15, 20, 25, 30, or 35 minutes. In an alternative embodiment, the
particles are suspended in a diluent in a vial attached to a vial
adapter that is further attached to a 60 mL VacLok syringe
containing a plunger wherein the plunger is pulled to the 30 mL
mark, locked, and held for at least about 3, 5, 8, 10, 15, 20, 25,
30, or 35 minutes. In an alternative embodiment, the particles are
suspended in a diluent in a vial attached to a vial adapter that is
further attached to a 60 mL VacLok syringe containing a plunger
wherein the plunger is pulled to the 25 mL mark, locked, and held
for at least about 3, 5, 8, 10, 15, 20, 25, 30, or 35 minutes.
[0192] In certain embodiments, the particles are suspended in a
diluent and the suspension is exposed to a pressure of less than 40
Torr for between about 90 minutes and 1 minute, between about 60
minutes and 1 minute, between about 45 minutes and 1 minute,
between about 30 minutes and 1 minute, between about 15 minutes and
1 minute, or between about 5 minutes and 1 minute.
[0193] In certain embodiments, the particles are suspended in a
diluent and the suspension is exposed to a pressure of less than 30
Torr for between about 90 minutes and 1 minute, between about 60
minutes and 1 minute, between about 45 minutes and 1 minute,
between about 30 minutes and 1 minute, between about 15 minutes and
1 minute, or between about 5 minutes and 1 minute.
[0194] In one embodiment, the microparticles are suspended in a
diluent of 10.times. ProVisc-diluted (0.1% HA in PBS) solution. In
one embodiment, the microparticles are suspended in a diluent of
20.times.-diluted ProVisc (0.05% HA in PBS). In one embodiment, the
microparticles are suspended in a diluent of 40.times.-diluted
ProVisc (0.025% HA in PBS).
[0195] In one embodiment, the particles are suspended in the
diluent at a concentration of 100 mg/mL, 150 mg/mL, 200 mg/mL, 250
mg/mL, 300 mg/mL, 350 mg/mL, 400 mg/mL, 450 mg/mL or 500 mg/mL. In
one embodiment, the particles are suspended in 10.times.-diluted
ProVisc (0.1% HA in PBS) solution and the suspension has a final
concentration of 200 mg/mL. In one embodiment, the particles are
suspended in 10.times.-diluted ProVisc (0.1% HA in PBS) solution
and the suspension has a final concentration of 400 mg/mL. In one
embodiment, the particles are suspended in a 20.times.-diluted
ProVisc (0.05% HA in PBS) and the suspension has a final
concentration of 200 mg/mL.
[0196] In one embodiment, the particles are suspended in a
20.times.-diluted ProVisc (0.05% HA in PBS) and the suspension has
a final concentration of 400 mg/mL. In one embodiment, the
particles are suspended in a 40.times.-diluted ProVisc (0.025% HA
in PBS) and the suspension has a concentration of 200 mg/mL. In one
embodiment, the particles are suspended in a 40.times.-diluted
ProVisc (0.025% HA in PBS) and the suspension has a concentration
of 400 mg/mL.
[0197] The Addition of an Excipient
[0198] In one embodiment, the process for preparing an improved
microparticle suspension prior to injection is the addition of at
least one excipient, typically prior to lyophilization that reduces
the amount of air adhering to the particles. Particles are
suspended in an aqueous solution and sonicated before being flash
frozen in -80.degree. C. ethanol and lyophilized overnight. In one
embodiment, the particles are suspended in an aqueous sugar
solution that is 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%,
13%, 14%, or 15% sugar. In one embodiment, the sugar is sucrose. In
one embodiment, the sugar is mannitol. In one embodiment, the sugar
is trehalose. In one embodiment, the sugar is glucose. In one
embodiment, the sugar is selected from arabinose, fucose, mannose,
rhamnose, xylose, D-xylose, glucose, fructose, ribose, D-ribose,
galactose, dextrose, dextran, lactose, maltodextrin, maltose,
glycerol, erythritol, threitol, arabitol, xylitol, ribitol,
sorbitol, galactitol, fucitol, iditol, inositol, volemitol,
isomalt, maltitol, lactitol, maltotriitol, maltotetraitol, and
polyglycitol. In an alternative embodiment, the sugar is selected
from aspartame, saccharin, stevia, sucralose, acesulfame potassium,
advantame, alitame, neotame, and sucralose. In one embodiment, the
particles are suspended in an aqueous sugar solution that is 1%,
2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15%
sucrose. In one embodiment, the particles are suspended in a 1%
sucrose solution. In one embodiment, the particles are suspended in
a 10% sucrose solution. In one embodiment, the particles are
suspended in an aqueous sugar solution that is 1%, 2%, 3%, 4%, 5%,
6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15% mannitol. In one
embodiment, the particles are suspended in a 1% mannitol solution.
In one embodiment, the particles are suspended in a 10% mannitol
solution. In one embodiment, the particles are suspended in a 1%
trehalose solution. In one embodiment, the particles are suspended
in a 10% trehalose solution. In one embodiment, the particles are
suspended in an aqueous sugar solution that is 1%, 2%, 3%, 4%, 5%,
6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15% trehalose. In an
alternative embodiment, the particles are suspended in a small
surfactant molecule, including, but not limited to tween 20 or
tween 80. In an alternative embodiment, the particles are flash
frozen in -80.degree. C. methanol or isopropanol.
[0199] Sonication
[0200] In one embodiment, a process for providing an improved
microparticle suspension prior to injection is sonication wherein
particles are suspended in a diluent and the suspension of
microparticles is sonicated for at least 30 minutes, at least 25
minutes, at least 20 minutes, at least 15 minutes, at least 10
minutes, at least 8 minutes, at least 5 minutes, or at least 3
minutes. In one embodiment, the particle solutions are sonicated at
a frequency of 40 kHz. In one embodiment, the particles are
suspended in the diluent at a concentration of 100 mg/mL, 150
mg/mL, 200 mg/mL, 250 mg/mL, 300 mg/mL, 350 mg/mL, 400 mg/mL, 450
mg/mL or 500 mg/mL. In one embodiment, the diluent is hyaluronic
acid. In an alternative embodiment, the diluent is selected from
hyaluronic acid, hydroxypropyl methylcellulose, chondroitin
sulfate, or a blend of at least two diluents selected from
hyaluronic acid, hydroxypropyl methylcellulose, and chondroitin
sulfate. In an alternative embodiment, the diluent is selected from
aacia, tragacanth, alginic acid, carrageenan, locust bean gum,
gellan gum, guar gum, gelatin, starch, methylcellulose, sodium
carboxymethylcellulose, hydroxyethylcellulose, hydroxypropyl
cellulose, Carbopol.RTM. homopolymers (acrylic acid crosslinked
with allyl sucrose or allyl pentaerythritol), and Carbopol.RTM.
copolymers (acrylic acid and C.sub.10-C.sub.30 alkyl acrylate
crosslinked with allyl pentaerythritol).
[0201] In certain embodiments, a combination of vacuum treatment,
the addition of excipients, and sonication can be used following
isolation and reconstitution of the microparticles. In certain
embodiments, the methods for enhancing wettability are conducted at
least 1 hour prior to in vivo injection, at least 45 minutes prior
to in vivo injection, at least 30 minutes prior to in vivo
injection, at least 25 minutes prior to in vivo injection, at least
20 minutes prior to injection, at least 15 minutes prior to in vivo
injection, at least 10 minutes prior to in vivo injection, or at
least 5 minutes prior to in vivo injection. In one embodiment, the
vacuum treatment, addition of an excipient, and/or sonication is
conducted immediately before in vivo injection. In one embodiment,
the particles are vacuumed at a strength of less than 35 Torr for
less than 30 minutes and are immediately injected in vivo. In an
alternative embodiment, the particles are vacuumed at a strength of
less than 35 Torr for less than 20 minutes and are immediately
injected in vivo. In an alternative embodiment, the particles are
vacuumed at a strength of less than 35 Torr for less than 15
minutes and are immediately injected in vivo. In an alternative
embodiment, the particles are vacuumed at a strength of less than
35 Torr for less than 10 minutes and are immediately injected in
vivo.
[0202] In one embodiment, the microparticles are stored at a
temperature of between about 2-8.degree. C. following the
manufacturing and isolation process and the microparticles are held
under negative pressure for about 24, 12, 8, 6, 2 hours, 1 hour, 30
minutes, 15 minutes, or 10 minutes or less prior to in vivo
injection. In one embodiment, the microparticles are stored at a
temperature of between about 2-8.degree. C. following the
manufacturing and isolation process and the microparticles are held
under negative pressure 1 hour to 30 minutes prior to in vivo
injection. In one embodiment, the microparticles are stored at a
temperature of between about 2-8.degree. C. following the
manufacturing and isolation process and the microparticles are
vacuumed 30 minutes to 10 minutes prior to in vivo injection. In
one embodiment, the microparticles are stored at a temperature of
between about 2-8.degree. C. following the manufacturing and
isolation process and the microparticles are vacuumed immediately
prior to in vivo injection.
[0203] In one embodiment, the microparticles are stored at a
temperature of between about 2-8.degree. C. and the microparticles
are vacuumed for less than 1 hour, 30 minutes, 20 minutes, 15
minutes, or 10 minutes at a strength of less than about 35 Torr
immediately prior to in vivo injection. In one embodiment, the
microparticles are stored at a temperature of between about
2-8.degree. C. and the microparticles are vacuumed for 1 hour to 30
minutes at a strength of less than about 35 Torr immediately prior
to in vivo injection. In one embodiment, the microparticles are
stored at a temperature of between about 2-8.degree. C. and the
microparticles are vacuumed for 30 minutes to 10 minutes at a
strength of less than about 35 Torr immediately prior to in vivo
injection.
[0204] In one embodiment, the microparticles are stored at negative
pressure for up to 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2
months, 3 months, 4 months, or more following the manufacture and
isolation process. In one embodiment, the microparticles are stored
for up to 1 week to up to 4 weeks at a negative pressure that is
less than 700, 550, 500, 450, 400, 350, 300, 250, 200, 150, 100,
80, 60, 50, 40, 35, 32, or 30 Torr. In one embodiment, the
microparticles are stored for up to 1 month to up to 2 months at a
negative pressure that is less than 700, 550, 500, 450, 400, 350,
300, 250, 200, 150, 100, 80, 60, 50, 40, 35, 32, or 30 Torr. In one
embodiment, the microparticles are stored for up to 3 months at a
negative pressure that is less than 700, 550, 500, 450, 400, 350,
300, 250, 200, 150, 100, 80, 60, 50, 40, 35, 32, or 30 Torr.
III. Mildly Surface Treated Aggregating Microparticles and
Methods
[0205] In one aspect, the improved microparticles and microparticle
suspensions are made from mildly surface treated solid
biodegradable microparticles that upon injection in vivo, aggregate
to a larger particle (pellet) in a manner that reduces unwanted
side effects of the smaller particles and are suitable for long
term (for example, up to or at least three month, up to four month,
up to five month, up to six months, up to seven months, up to eight
months, up to nine months or longer) sustained delivery of a
therapeutic agent. In one embodiment, the lightly surface treated
solid biodegradable microparticles are suitable for ocular
injection, at which point the particles aggregate to form a pellet
and thus remains outside the visual axis as not to significantly
impair vision. The particles can aggregate into one or several
pellets. The size of the aggregate depends on the mass (weight) of
the particles injected.
[0206] The mildly surface treated biodegradable microparticles
provided herein are distinguished from "scaffold" microparticles,
which are used for tissue regrowth via pores that cells or tissue
material can occupy. In contrast, the present microparticles are
designed to be solid materials of sufficiently low porosity so that
they can aggregate to form a larger combined particle that erodes
primarily by surface erosion for long-term controlled drug
delivery.
[0207] The surface modified solid aggregating microparticles of the
present invention are suitable, for example, for intravitreal
injection, implant, periocular delivery, or delivery in vivo
outside the eye.
[0208] The surface modified solid aggregating microparticles of the
present invention are also suitable for systemic, parenteral,
transmembrane, transdermal, buccal, subcutaneous, endosinusial,
intra-abdominal, intra-articular, intracartilaginous,
intracerebral, intracoronal, dental, intradiscal, intramuscular,
intratumor, topical, or vaginal delivery in any manner useful for
in vivo delivery.
[0209] In one embodiment, the invention is thus surface-modified
solid aggregating microparticles that include at least one
biodegradable polymer, wherein the surface-modified solid
aggregating microparticles have a solid core, include a therapeutic
agent, have a modified surface which has been treated under mild
conditions at a temperature at or less than about 18.degree. C. to
remove surface surfactant or cause surface polymer to partially
degrade, are sufficiently small to be injected in vivo, and
aggregate in vivo to form at least one pellet of at least 500 .mu.m
in vivo in a manner that provides sustained drug delivery in vivo
for at least one, two, three, four, five, six seven, eight, nine,
ten, eleven, twelve months or more. The surface modified solid
aggregating microparticles are suitable, for example, for an
intravitreal injection, implant, including an ocular implant,
periocular delivery or delivery in vivo outside of the eye. In
certain embodiments, the therapeutic agent is a prodrug as
described herein. In certain embodiments, microparticles have also
been treated for enhanced wettability.
[0210] Alternatively, the surface treatment is conducted at a
temperature at or less than about 10.degree. C., 8.degree. C. or
5.degree. C.
[0211] The surface treatment can be carried out at any pH that
achieves the desired purpose. Nonlimiting examples of the pH are
between about 6 and about 8, 6.5 and about 7.5, about 1 and about
4; about 4 and about 6; and 6 and about 8. In one embodiment, the
surface treatment can be conducted at a pH between about 8 and
about 10. In one embodiment, the surface treatment can be conducted
at a pH between about 10.0 and about 13.0. In one embodiment, the
surface treatment can be conducted at a pH between about 10.0 and
about 12.0. In one embodiment, the surface treatment can be
conducted at a pH between about 12 and about 14. In one embodiment,
the surface treatment can be conducted with an organic solvent. In
one embodiment, the surface treatment can be conducted with
ethanol. In other various embodiments, the surface treatment is
carried out in a solvent selected from methanol, ethyl acetate and
ethanol. Nonlimiting examples are ethanol with an aqueous organic
base; ethanol and aqueous inorganic base; ethanol and sodium
hydroxide; ethanol and potassium hydroxide; an aqueous acidic
solution in ethanol; aqueous hydrochloric acid in ethanol; and
aqueous potassium chloride in ethanol.
[0212] Examples of solid cores included in the present invention
include solid cores comprising a biodegradable polymer with less
than 10 percent porosity, 8 percent porosity, 7 percent porosity, 6
percent porosity, 5 percent porosity, 4 percent porosity, 3 percent
porosity, or 2 percent porosity. Porosity as used herein is defined
by ratio of void space to total volume of the surface-modified
solid aggregating microparticle.
[0213] The surface-modified solid aggregating microparticles of the
present invention provides sustained delivery for at least one
month, or at least two months, or at least three months, or at
least four months, or at least five months, or at least six months,
or at least seven months, or at least eight months, or at least
nine months, or at least ten months, or at least eleven months, or
at least twelve months.
[0214] The therapeutic agent delivered by the surface-modified
solid aggregating microparticle is in one embodiment a
pharmaceutical drug or a biologic. In nonlimiting examples, the
pharmaceutical drugs include sunitinib, another tyrosine kinase
inhibitor, an anti-inflammatory drug, an antibiotic, an
immunosuppressing agent, an anti-VEGF agent, an anti-PDGF agent, or
other therapeutic agents as described below. In one embodiment, the
tyrosine kinase inhibitor is selected from Tivosinib, Imatinib,
Gefitinib, Erlotinib, Lapatinib, Canertinib, Semaxinib,
Vatalaninib, Sorafenib, Axitinib, Pazopanib, Dasatinib, Nilotinib,
Crizotinib, Ruxolitinib, Vandetanib, Vemurafenib, Bosutinib,
Cabozantinib, Regorafenib, Vismodegib, and Ponatinib.
[0215] In one embodiment the surface-modified solid aggregating
microparticle has a mean diameter between 10 and 60 .mu.m, 20 and
50 .mu.m, 20 and 40 .mu.m, 20 and 30 .mu.m, 25 and 40 .mu.m, or 25
and 35 .mu.m.
[0216] Further, the surface-modified solid aggregating
microparticles of the disclosed invention can aggregate to produce
at least one pellet when administered in vivo that has a diameter
of at least about 300 .mu.m, 400 .mu.m, 500 .mu.m, 600 .mu.m, 700
.mu.m, 1 mm, 1.5 mm, 2 mm, 3 mm, 4 mm, or 5 mm.
[0217] In one embodiment, the surface-modified solid aggregating
microparticles of the present invention produces a pellet in vivo
that releases the therapeutic agent without a burst of more than
about 10 percent or 15 percent of the total payload of the
therapeutic agent over a one week, or a five, four, three, two day
or one day period.
[0218] In some embodiments, the long-term controlled drug delivery
is accomplished by a combination of surface erosion of an
aggregated microparticle over several months (for example, one,
two, three, or four months or more) followed by erosion of
remaining parts of the aggregated microparticle, followed by slow
release of active material from in vivo proteins to which it has
bound over the period of long term release from the aggregated
particle. In another embodiment, the microparticle degrades
substantially by surface erosion over a period of at least about
one, two, three, four, five or six months or more.
[0219] In another embodiment, the surface-modified solid
aggregating microparticles of the present invention have a drug
loading of 1-40 percent, 5-25 percent, or 5-15 percent
weight/weight.
[0220] Examples of polymeric compositions included in
surface-modified solid aggregating microparticles of the present
invention include, but are not limited to: poly(lactide
co-glycolide); poly(lactide-co-glycolide) covalently linked to
polyethylene glycol; more than one biodegradable polymer or
copolymer mixed together, for example, a mixture of
poly(lactide-co-glycolide) and poly(lactide-co-glycolide)
covalently linked to polyethylene glycol, a mixture of poly(lactic
acid) and poly(lactide-co-glycolide) covalently linked to
polyethylene glycol, or a mixture of poly(lactic acid),
poly(lactide-co-glycolide) and poly(lactide-co-glycolide)
covalently linked to polyethylene glycol; poly(lactic acid); a
surfactant, such as polyvinyl alcohol (which can be hydrolyzed
polyvinyl acetate).
[0221] In another embodiment, the invention is an injectable
material that includes the microparticles of the present invention
in a pharmaceutically acceptable carrier for administration in
vivo. The injectable material may include a compound that inhibits
aggregation of microparticles prior to injection and/or a viscosity
enhancer and/or a salt. In one embodiment, the injectable material
has a range of concentration of the surface-modified solid
aggregating microparticles of about 50-700 mg/ml, 500 or less
mg/ml, 400 or less mg/ml, 300 or less mg/ml, 200 or less mg/ml, or
150 or less mg/ml.
[0222] The present invention further includes a process for the
preparation of surface-modified solid aggregating microparticles
that includes [0223] (i) a first step of preparing microparticles
comprising one or more biodegradable polymers by dissolving or
dispersing the polymer(s) and a therapeutic agent in one or more
solvents to form a polymer and therapeutic agent solution or
dispersion, mixing the polymer and the therapeutic agent solution
or dispersion with an aqueous phase containing a surfactant to
produce microparticles that contain the therapeutic agent, polymer
and surfactant; and [0224] (ii) a second step of mildly
surface-only treating the microparticles of step (i) at a
temperature at or below about 18.degree. C. for optionally up to
about 140, 120, 110, 100, 90, 80, 70, 60, 50, 40, 30, 10, 8, 5, 4,
3, 2, or 1 minutes with an agent that removes surface surfactant,
surface polymers, or surface oligomers in a manner that does not
significantly produce internal pores; and [0225] (iii) isolating
the surface treated microparticles.
[0226] In one embodiment, the process for the preparation of
surface-treated solid aggregating microparticles includes a fourth
step for improving the aggregation potential of the particles by
subjecting the particles to at least one process selected from 1)
vacuum treatment, wherein the microparticles are suspended in a
diluent and the suspension is placed under vacuum prior to use; 2)
excipient addition, wherein an excipient is added prior to
lyophilization; and 3) sonication, wherein the microparticles are
suspended in a diluent and sonicated; 4) sealing the vial
containing the dry powder of particles under vacuum, including but
not limited to high vacuum; or 5) pre-wetting (i.e., resuspending)
the surface-treated microparticles in a diluent for 2-24 hours
before injecting into the eye, for example in a hyaluronic acid
solution or other sterile solution suitable for ocular
injection.
[0227] In certain embodiments step (ii) above is carried out at a
temperature below 17.degree. C., 15.degree. C., 10.degree. C., or
5.degree. C. Further, step (iii) is optionally carried out at a
temperature below 25.degree. C., below 17.degree. C., 15.degree.
C., 10.degree. C., 8.degree. C. or 5.degree. C. Step (ii), for
example, can be carried out for less than 8, less than 6, less than
4, less than 3, less than 2, or less than 1 minutes. In one
embodiment, step (ii) is carried out for less than 60, 50, 40, 30,
20, or 10 minutes.
[0228] In one embodiment, the process of manufacturing
surface-modified solid aggregating microparticles includes using an
agent that removes surface surfactant. Nonlimiting examples include
for example, those selected from: aqueous acid, phosphate buffered
saline, water, aqueous NaOH, aqueous hydrochloric acid, aqueous
potassium chloride, alcohol or ethanol.
[0229] In one embodiment, the process of manufacturing
surface-modified solid aggregating microparticles includes using an
agent that removes surface surfactant which comprises, for example,
a solvent selected from an alcohol, for example, ethanol; ether,
acetone, acetonitrile, DMSO, DMF, THF, dimethylacetamide, carbon
disulfide, chloroform, 1,1-dichloroethane, dichloromethane, ethyl
acetate, heptane, hexane, methanol, methyl acetate, methyl t-butyl
ether (MTBE), pentane, propanol, 2-propanol, toluene, N-methyl
pyrrolidinone (NMP), acetamide, piperazine, triethylenediamine,
diols, and CO.sub.2.
[0230] The agent that removes the surface surfactant can comprise a
basic buffer solution. Further, the agent that removes surface
surfactant can comprise a base selected from sodium hydroxide,
lithium hydroxide, potassium hydroxide, calcium hydroxide,
magnesium hydroxide, lithium amide, sodium amide, barium carbonate,
barium hydroxide, barium hydroxide hydrate, calcium carbonate,
cesium carbonate, cesium hydroxide, lithium carbonate, magnesium
carbonate, potassium carbonate, sodium carbonate, strontium
carbonate, ammonia, methylamine, ethylamine, propylamine,
isopropylamine, dimethylamine, diethylamine, dipropylamine,
diisopropylamine, trimethylamine, triethylamine, tripropylamine,
triisopropylamine, aniline, methylaniline, dimethylaniline,
pyridine, azajulolidine, benzylamine, methylbenzylamine,
dimethylbenzylamine, DABCO, 1,5-diazabicyclo[4.3.0]non-5-ene,
1,8-diazabicyclo[5.4.0]non-7-ene, 2,6-lutidine, morpholine,
piperidine, piperazine, Proton-sponge,
1,5,7-Triazabicyclo[4.4.0]dec-5-ene, tripelennamine, ammonium
hydroxide, triethanolamine, ethanolamine, and Trizma.
[0231] In one embodiment, the process of manufacturing
surface-modified solid aggregating microparticles includes using an
agent that removes surface surfactant, for example, those selected
from the following: aqueous acid, phosphate buffered saline, water,
or NaOH in the presence of a solvent such as an alcohol, for
example, ethanol, ether, acetone, acetonitrile, DMSO, DMF, THF,
dimethylacetamide, carbon disulfide, chloroform,
1,1-dichloroethane, dichloromethane, ethyl acetate, heptane,
hexane, methanol, methyl acetate, methyl t-butyl ether (MTBE),
pentane, ethanol, propanol, 2-propanol, toluene, N-methyl
pyrrolidinone (NMP), acetamide, piperazine, triethylenediamine,
diols, and CO.sub.2.
[0232] In one embodiment, the agent that removes the surface
surfactant can comprise an aqueous acid. The agent that removes the
surface surfactant can comprise an acid derived from inorganic
acids including, but not limited to, hydrochloric, hydrobromic,
sulfuric, sulfamic, phosphoric, nitric and the like; or organic
acids including, but not limited to, acetic, propionic, succinic,
glycolic, stearic, lactic, malic, tartaric, citric, ascorbic,
pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic,
salicylic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic,
fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic,
oxalic, isethionic, HOOC--(CH.sub.2).sub.n--COOH where n is 0-4,
and the like.
[0233] In one embodiment, the agent that removes surface surfactant
is not a degrading agent of the biodegradable polymer under the
conditions of the reaction. The hydrophilicity of the
microparticles can be decreased by removing surfactant.
[0234] In one embodiment, the process of manufacturing
surface-modified solid aggregating microparticles comprises using
an agent that removes surface surfactant that comprises a solvent
selected from an alcohol, for example, ethanol, ether, acetone,
acetonitrile, DMSO, DMF, THF, dimethylacetamide, carbon disulfide,
chloroform, 1,1-dichloroethane, dichloromethane, ethyl acetate,
heptane, hexane, methanol, methyl acetate, methyl t-butyl ether
(MTBE), pentane, ethanol, propanol, 2-propanol, toluene, N-methyl
pyrrolidinone (NMP), acetamide, piperazine, triethylenediamine,
diols, and CO.sub.2. In a typical embodiment the process of surface
treating, comprises an agent that removes surface surfactant that
comprises ethanol.
[0235] The encapsulation efficiency of the process of manufacturing
surface-modified solid aggregating microparticles depends on the
microparticle forming conditions and the properties of the
therapeutic agent. In certain embodiments, the encapsulation
efficiency can be greater than about 50 percent, greater than about
75 percent, greater than about 80 percent, or greater than about 90
percent.
[0236] In one embodiment, the process of manufacturing
surface-modified solid aggregating microparticles includes 5/95,
10/90, 15/85, 20/80, 25/75, 30/70, 35/65, 40/60, 45/55, 50/50,
55/45, 60/40, 65/35, 70/30, 75/25, 80/20, 85/15, 90/10, 95/5 PLGA
as a biodegradable polymer. In one embodiment, the process of
manufacturing surface-modified solid aggregating microparticles
includes 50/50 PLGA as a biodegradable polymer.
[0237] In one embodiment, the process of manufacturing
surface-modified solid aggregating microparticles includes PLA as a
biodegradable polymer. In one embodiment, the process of
manufacturing surface-modified solid aggregating microparticles
includes PLA and PLGA as a biodegradable polymer. In one
embodiment, the process of manufacturing surface-modified solid
aggregating microparticles includes PLA and 75/25 PLGA as a
biodegradable polymer. In one embodiment, the process of
manufacturing surface-modified solid aggregating microparticles
includes PLA and 50/50 PLGA as a biodegradable polymer. In one
embodiment, the process of manufacturing surface-modified solid
aggregating microparticles includes PLGA as a biodegradable
polymer.
[0238] In one embodiment, the process of manufacturing
surface-modified solid aggregating microparticles is carried out
below about a pH of 14 and above a pH of 12, below a pH of 12 and
above a pH of 10, below a pH of about 10 and above a pH of 8, below
about a pH of 8 and above a pH of about 6, neutral pH, below about
a pH of 7 and above a pH of 4, below about a pH of 4 and above a pH
of about 1.0.
[0239] In one embodiment, step (ii) above is carried out for a time
of about less than 140, 120, 110, 100, 90, 60, 40, 30, 20, 10, 3,
2, or 1 minutes.
[0240] In yet another embodiment, a method for the treatment of an
ocular disorder is provided that includes administering to a host
in need thereof surface-modified solid aggregating microparticles
that include an effective amount of a therapeutic agent, wherein
the therapeutic agent containing surface-modified solid aggregating
microparticles are injected into the eye and in vivo aggregate to
form at least one pellet of at least 500 .mu.m that provides
sustained drug delivery for at least one, two, or three, four,
five, six, seven, eight, nine, ten, eleven, twelve or more months
in such a manner that the pellet stays substantially outside the
visual axis as not to significantly impair vision. In one
embodiment, the therapeutic agent is a prodrug as described
herein.
[0241] In an alternative embodiment, the weight percent of
surface-modified solid aggregating microparticles that are not
aggregated into a larger pellet in vivo is about 10 percent or
less, 7 percent or less, 5 percent or less, or 2 percent or less by
total weight administered.
[0242] In one embodiment, the surface-modified solid aggregating
microparticles do not cause substantial inflammation in the
eye.
[0243] In another embodiment, the surface-modified solid
aggregating microparticles do not cause an immune response in the
eye.
[0244] In one embodiment, the surface-modified microparticles of
the present invention, as described herein, are used to treat a
medical disorder which is glaucoma, a disorder mediated by carbonic
anhydrase, a disorder or abnormality related to an increase in
intraocular pressure (IOP), a disorder mediated by nitric oxide
synthase (NOS), or a disorder requiring neuroprotection such as to
regenerate/repair optic nerves. In another embodiment more
generally, the disorder treated is allergic conjunctivitis,
anterior uveitis, cataracts, dry or wet age-related macular
degeneration (AMD), or diabetic retinopathy.
[0245] Another embodiment is provided that includes the
administration of a surface treated microparticle comprising an
effective amount of a pharmaceutically active compound or a
pharmaceutically acceptable salt thereof, optionally in a
pharmaceutically acceptable carrier, to a host to treat an ocular
or other disorder that can benefit from topical or local delivery.
The therapy can be delivered to the anterior or posterior chamber
of the eye. In specific aspects, a surface treated microparticle
comprising an effective amount of a pharmaceutically active
compound is administered to treat a disorder of the cornea,
conjunctiva, aqueous humor, iris, ciliary body, lens sclera,
choroid, retinal pigment epithelium, neural retina, optic nerve, or
vitreous humor.
[0246] Any of the compositions described can be administered to the
eye as described further herein in any desired form of
administration, including via intravitreal, intrastromal,
intracameral, subtenon, sub-retinal, retrobulbar, peribulbar,
suprachoroidal, subchoroidal, conjunctival, subconjunctival,
episcleral, posterior juxtascleral, circumcorneal, tear duct
injections, or through a mucus, mucin, or a mucosal barrier, in an
immediate or controlled release fashion.
[0247] In one embodiment, the disclosure provides a beta-adrenergic
antagonist for ocular therapy, which can be released from a surface
treated microparticle while maintaining efficacy over an extended
time such as up to at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or
12 months.
[0248] In one embodiment, the disclosure provides a prostaglandin
or a prodrug thereof for ocular therapy, which can be released from
a surface treated microparticle while maintaining efficacy over an
extended time such as up to at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, or 12 months.
[0249] In one embodiment, the disclosure provides an adrenergic
agonist for ocular therapy, which can be released from a surface
treated microparticle while maintaining efficacy over an extended
time such as up to at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or
12 months.
[0250] In one embodiment, the disclosure provides a carbonic
anhydrase inhibitor for ocular therapy, which can be released from
a surface treated microparticle while maintaining efficacy over an
extended time such as up to at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, or 12 months.
[0251] In one embodiment, the disclosure provides a
parasympathomimetic agent for ocular therapy, which can be released
from a surface treated microparticle while maintaining efficacy
over an extended time such as up to at least 1, 2, 3, 4, 5, 6, 7,
8, 9, 10, 11, or 12 months.
[0252] In one embodiment, the disclosure provides a dual
anti-VEGF/anti-PDGF agent for ocular therapy, which can be released
from a surface treated microparticle while maintaining efficacy
over an extended time such as up to at least 1, 2, 3, 4, 5, 6, 7,
8, 9, 10, 11, or 12 months.
[0253] In one embodiment, the disclosure provides a loop diuretic
for ocular therapy, which can be released from a surface treated
microparticle while maintaining efficacy over an extended time such
as up to at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12
months.
[0254] In one embodiment, the disclosure provides a Rho kinase
(ROCK) inhibitor for ocular therapy, which can be released from a
surface treated microparticle while maintaining efficacy over an
extended time such as up to at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, or 12 months.
[0255] In one embodiment, the disclosure provides a prodrug as
described herein for ocular therapy, which can be released from a
surface treated microparticle while maintaining efficacy over an
extended time such as up to at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, or 12 months.
[0256] Methods of treating or preventing ocular disorders,
including glaucoma, a disorder mediated by carbonic anhydrase, a
disorder or abnormality related to an increase in intraocular
pressure (IOP), a disorder mediated by nitric oxide synthase (NOS),
a disorder requiring neuroprotection such as to regenerate/repair
optic nerves, allergic conjunctivitis, anterior uveitis, cataracts,
dry or wet age-related macular degeneration (AMD) or diabetic
retinopathy are disclosed comprising administering a
therapeutically effective amount of a surface treated microparticle
comprising a pharmaceutically active compound to a host, including
a human, in need of such treatment. In one embodiment, the host is
a human.
[0257] In another embodiment, an effective amount of a surface
treated microparticle comprising a pharmaceutically active compound
is provided to decrease intraocular pressure (IOP) caused by
glaucoma. In an alternative embodiment, the surface treated
microparticle comprising a pharmaceutically active compound can be
used to decrease intraocular pressure (IOP), regardless of whether
it is associated with glaucoma.
[0258] In one embodiment, the disorder is associated with an
increase in intraocular pressure (IOP) caused by potential or
previously poor patient compliance to glaucoma treatment. In yet
another embodiment, the disorder is associated with potential or
poor neuroprotection through neuronal nitric oxide synthase (NOS).
The surface treated microparticle comprising a pharmaceutically
active compound provided herein may thus dampen or inhibit glaucoma
in a host, by administration of an effective amount in a suitable
manner to a host, typically a human, in need thereof.
[0259] Methods for the treatment of a disorder associated with
glaucoma, increased intraocular pressure (IOP), optic nerve damage
caused by either high intraocular pressure (IOP) or neuronal nitric
oxide synthase (NOS) are provided that includes the administration
of an effective amount of a surface treated microparticle
comprising a pharmaceutically active compound are also
disclosed.
[0260] In one aspect of the present invention, an effective amount
of a pharmaceutically active compound as described herein is
incorporated into a surface treated microparticle, e.g., for
convenience of delivery and/or sustained release delivery. The use
of materials in micrometer scale provides one the ability to modify
fundamental physical properties such as solubility, diffusivity,
and drug release characteristics. These micrometer scale agents may
provide more effective and/or more convenient routes of
administration, lower therapeutic toxicity, extend the product life
cycle, and ultimately reduce healthcare costs. As therapeutic
delivery systems, surface treated microparticles can allow targeted
delivery and sustained release.
[0261] In another aspect of the present invention, the surface
treated microparticle is coated with a surface agent. The present
invention further comprises a method of producing surface treated
microparticles comprising a pharmaceutically active compound. The
present invention further comprises methods of using the surface
treated microparticles comprising a pharmaceutically active
compound to treat a patient.
[0262] In one embodiment, surface treated microparticles including
a pharmaceutically active compound are obtained by forming an
emulsion and using a bead column as described in, for example, U.S.
Pat. No. 8,916,196.
[0263] In one embodiment, surface treated microparticles including
a pharmaceutically active compound are obtained by using a
vibrating mesh or microsieve.
[0264] In one embodiment, surface treated microparticles including
a pharmaceutically active compound are obtained by using slurry
sieving.
[0265] The processes of producing microspheres described herein are
amenable to methods of manufacture that narrow the size
distribution of the resultant particles. In one embodiment, the
particles are manufactured by a method of spraying the material
through a nozzle with acoustic excitation (vibrations) to produce
uniform droplets. A carrier stream can also be utilized through the
nozzle to allow further control of droplet size. Such methods are
described in detail in: Berkland, C., K. Kim, et al. (2001).
"Fabrication of PLG microspheres with precisely controlled and
monodisperse size distributions." J Control Release 73(1): 59-74;
Berkland, C., M. King, et al. (2002). "Precise control of PLG
microsphere size provides enhanced control of drug release rate." J
Control Release 82(1): 137-147; Berkland, C., E. Pollauf, et al.
(2004). "Uniform double-walled polymer microspheres of controllable
shell thickness." J Control Release 96(1): 101-111.
[0266] In another embodiment, microparticles of uniform size can be
manufactured by methods that utilize microsieves of the desired
size. The microsieves can either be used directly during production
to influence the size of microparticles formed, or alternatively
post production to purify the microparticles to a uniform size. The
microsieves can either be mechanical (inorganic material) or
biological in nature (organic material such as a membrane). One
such method is described in detail in U.S. Pat. No. 8,100,348.
[0267] In one embodiment, the surface treated microparticles
comprise a therapeutically active compound and have a particle size
of 25<Dv50<40 .mu.m, Dv90<45 .mu.m.
[0268] In one embodiment, the surface treated microparticles
comprise a therapeutically active compound and have a particle size
of Dv10 >10 .mu.m.
[0269] In one embodiment, the surface treated microparticles
comprise a therapeutically active compound and have only residual
solvents that are pharmaceutically acceptable.
[0270] In one embodiment, the surface treated microparticles
comprise a therapeutically active compound and afford a total
release of greater than eighty percent by day 14.
[0271] In one embodiment, the surface treated microparticles
comprise a therapeutically active agent and have syringeability
with a regular-walled 26-, 27-, 28-, 29- or 30-gauge needle of 200
mg/ml with no clogging of the syringe.
[0272] In one embodiment, the surface treated microparticles
comprise a therapeutically active agent and have syringeability
with a thin-walled 26-, 27-, 28-, 29- or 30-gauge needle of 200
mg/ml with no clogging of the syringe.
[0273] In one embodiment, the surface treated microparticles
comprises sunitinib have a particle size of 25<Dv50<40 .mu.m,
Dv90<45 .mu.m.
[0274] In one embodiment, the surface treated microparticles
comprising sunitinib have a particle size of Dv10 >10 .mu.m.
[0275] In one embodiment, the surface treated microparticles
comprising sunitinib have only residual solvents that are
pharmaceutically acceptable.
[0276] In one embodiment, the surface treated microparticles
comprising sunitinib afford a total release of greater than eighty
percent by day 14.
[0277] In one embodiment, the surface treated microparticles
comprising sunitinib have syringeability with a regular-walled 26-,
27-, 28-, 29- or 30-gauge needle of 200 mg/ml with no clogging of
the syringe.
[0278] In one embodiment, the surface treated microparticles
comprising sunitinib have syringeability with a thin-walled 26-,
27-, 28-, 29- or 30-gauge needle of 200 mg/ml with no clogging of
the syringe.
[0279] In one embodiment, the surface treated microparticles
comprising sunitinib have an endotoxin level of less than 0.02
EU/mg.
[0280] In one embodiment, the surface treated microparticles
comprising sunitinib have a bioburden level of less than 10
CFU/g.
[0281] Biodegradable Polymers
[0282] The surface treated microparticles can include one or more
biodegradable polymers or copolymers. The polymers should be
biocompatible in that they can be administered to a patient without
an unacceptable adverse effect. Biodegradable polymers are well
known to those in the art and are the subject of extensive
literature and patents. The biodegradable polymer or combination of
polymers can be selected to provide the target characteristics of
the microparticles, including the appropriate mix of hydrophobic
and hydrophilic qualities, half-life and degradation kinetics in
vivo, compatibility with the therapeutic agent to be delivered,
appropriate behavior at the site of injection, etc.
[0283] For example, it should be understood by one skilled in the
art that by manufacturing a microparticle from multiple polymers
with varied ratios of hydrophobic, hydrophilic, and biodegradable
characteristics that the properties of the microparticle can be
designed for the target use. As an illustration, a microparticle
manufactured with 90 percent PLGA and 10 percent PEG is more
hydrophilic than a microparticle manufactured with 95 percent PLGA
and 5 percent PEG. Further, a microparticle manufactured with a
higher content of a less biodegradable polymer will in general
degrade more slowly. This flexibility allows microparticles of the
present invention to be tailored to the desired level of
solubility, rate of release of pharmaceutical agent, and rate of
degradation.
[0284] In certain embodiments, the microparticle includes a
poly(a-hydroxyacid). Examples of poly(a-hydroxyacids) include poly
lactic acid (PLA), polyglycolic acid (PGA),
poly(D,L-lactide-co-glycolide)(PLGA), and poly D,L-lactic acid
(PDLLA). polyesters, poly (E-caprolactone), poly
(3-hydroxy-butyrate), poly (s-caproic acid), poly (p-dioxanone),
poly (propylene fumarate), poly (ortho esters), polyol/diketene
acetals, polyanhydrides, poly (sebacic anhydride) (PSA), poly
(carboxybis-carboxyphenoxyphosphazene) (PCPP), poly [bis
(p-carboxyphenoxy) methane](PCPM), copolymers of SA, CPP and CPM
(as described in Tamat and Langer in Journal of Biomaterials
Science Polymer Edition, 3, 315-353, 1992 and by Domb in Chapter 8
of The Handbook of Biodegradable Polymers, Editors Domb A J and
Wiseman R M, Harwood Academic Publishers), and poly (amino
acids).
[0285] In one embodiment, the microparticle includes about at least
90 percent hydrophobic polymer and about not more than 10 percent
hydrophilic polymer. Examples of hydrophobic polymers include
polyesters such as poly lactic acid (PLA), polyglycolic acid (PGA),
poly(D,L-lactide-co-glycolide)(PLGA), and poly D,L-lactic acid
(PDLLA); polycaprolactone; polyanhydrides, such as polysebacic
anhydride, poly(maleic anhydride); and copolymers thereof. Examples
of hydrophilic polymers include poly(alkylene glycols) such as
polyethylene glycol (PEG), polyethylene oxide (PEO), and
poly(ethylene glycol) amine; polysaccharides; poly(vinyl alcohol)
(PVA); polypyrrolidone; polyacrylamide (PAM); polyethylenimine
(PEI); poly(acrylic acid); poly(vinylpyrolidone) (PVP); or a
copolymer thereof.
[0286] In one embodiment, the microparticle includes about at least
85 percent hydrophobic polymer and at most 15 percent hydrophilic
polymer.
[0287] In one embodiment, the microparticle includes about at least
80 percent hydrophobic polymer and at most 20 percent hydrophilic
polymer.
[0288] In one embodiment, the microparticle includes PLA. In one
embodiment, the PLA is acid-capped. In one embodiment, the PLA is
ester-capped.
[0289] In one embodiment, the microparticle includes PLA and
PLGA-PEG.
[0290] In one embodiment, the microparticle includes PLA and
PLGA-PEG and PVA.
[0291] In one embodiment, the microparticle includes PLA, PLGA, and
PLGA-PEG.
[0292] In one embodiment, the microparticle includes PLA, PLGA, and
PLGA-PEG and PVA.
[0293] In one embodiment, the microparticle includes PLGA.
[0294] In one embodiment, the microparticle includes a copolymer of
PLGA and PEG.
[0295] In one embodiment, the microparticle includes a copolymer of
PLA and PEG.
[0296] In one embodiment, the microparticle comprises PLGA and
PLGA-PEG, and combinations thereof.
[0297] In one embodiment, the microparticle comprises PLA and
PLA-PEG.
[0298] In one embodiment, the microparticle includes PVA.
[0299] In one embodiment, the microparticles include PLGA,
PLGA-PEG, PVA, or combinations thereof.
[0300] In one embodiment, the microparticles include the
biocompatible polymers PLA, PLA-PEG, PVA, or combinations
thereof.
[0301] In one embodiment, the microparticles have a mean size of
about 20 .mu.m to about 50 .mu.m, m to about 45 .mu.m, 25 .mu.m to
about 30 .mu.m and a median size of about 29 .mu.m to about 31 m
before surface treatment.
[0302] In one embodiment, the microparticles after surface
treatment have about the same mean size and median size. In another
embodiment, the microparticles after surface treatment have a mean
size which is larger than the median size. In another embodiment,
the microparticles after surface treatment have a mean size which
is smaller than the median size.
[0303] In one embodiment, the microparticles have a mean size of
about 20 .mu.m to about 50 .mu.m, m to about 45 rpm, 25 .mu.m to
about 30 .mu.m, or 30 to 33 .mu.m and a median size of about 31 m
to about 33 .mu.m after surface treatment with approximately 0.0075
M NaOH/ethanol to 0.75 M NaOH/ethanol (30:70, v:v).
[0304] In one embodiment, the microparticles have a mean size of
about 20 .mu.m to about 50 .mu.m, m to about 45 .mu.m, 25 .mu.m to
about 30 .mu.m or 30 to 33 .mu.m and a median size of about 31 m to
about 33 .mu.m after surface treatment with approximately 0.75 M
NaOH/ethanol to 2.5 M NaOH/ethanol (30:70, v:v).
[0305] In one embodiment, the microparticles have a mean size of
about 20 .mu.m to about 50 .mu.m, about 25 .mu.m to about 45 .mu.m,
about 25 .mu.m to about 30 .mu.m or 30 to 33 .mu.m and a median
size of about 31 .mu.m to about 33 .mu.m after surface treatment
with approximately 0.0075 M HCl/ethanol to 0.75 M NaOH/ethanol
(30:70, v:v).
[0306] In one embodiment, the microparticles have a mean size of
about 20 .mu.m to about 50 .mu.m, about 25 .mu.m to about 45 .mu.m,
about 25 .mu.m to about 30 .mu.m or 30 to 33 .mu.m and a median
size of about 31 .mu.m to about 33 .mu.m after surface treatment
with approximately 0.75 M NaOH/ethanol to 2.5 M HCl/ethanol (30:70,
v:v).
[0307] In one embodiment, a surface-modified solid aggregating
microparticle is manufactured using a wet microparticle.
[0308] In one embodiment, the surface-modified solid aggregating
microparticle can release a therapeutic agent over a longer period
of time when compared to a non-surface treated microparticle.
[0309] In one embodiment, a surface-modified solid aggregating
microparticle contains less surfactant than a microparticle prior
to the surface modification.
[0310] In one embodiment, a surface-modified solid aggregating
microparticle is more hydrophobic than a microparticle prior to the
surface modification.
[0311] In one embodiment, a surface-modified solid aggregating
microparticle is less inflammatory than a non-surface treated
microparticle.
[0312] In one embodiment, the agent that removes the surface
surfactant of a surface-modified solid aggregating microparticle
comprises a solvent that partially dissolves or swells the
surface-modified solid aggregating microparticle.
[0313] In one aspect of the present invention, an effective amount
of a pharmaceutically active compound as described herein is
incorporated into a surface treated microparticle, e.g., for
convenience of delivery and/or sustained release delivery. The use
of materials provides the ability to modify fundamental physical
properties such as solubility, diffusivity, and drug release
characteristics. These micrometer scale agents may provide more
effective and/or more convenient routes of administration, lower
therapeutic toxicity, extend the product life cycle, and ultimately
reduce healthcare costs. As therapeutic delivery systems, surface
treated microparticles can allow targeted delivery and sustained
release.
[0314] Surfactants
[0315] In one embodiment, the manufacture of the microparticle
includes a surfactant. Examples of surfactants include, for
example, polyoxyethylene glycol, polyoxypropylene glycol, decyl
glucoside, lauryl glucoside, octyl glucoside, polyoxyethylene
glycol octylphenol, Triton X-100, glycerol alkyl ester, glyceryl
laurate, cocamide MEA, cocamide DEA, dodecyldimethylamine oxide,
and poloxamers. Examples of poloxamers include, poloxamers 188,
237, 338 and 407. These poloxamers are available under the trade
name Pluronic.RTM. (available from BASF, Mount Olive, N.J.) and
correspond to Pluronic.RTM. F-68, F-87, F-108 and F-127,
respectively. Poloxamer 188 (corresponding to Pluronic.RTM. F-68)
is a block copolymer with an average molecular mass of about 7,000
to about 10,000 Da, or about 8,000 to about 9,000 Da, or about
8,400 Da. Poloxamer 237 (corresponding to Pluronic.RTM. F-87) is a
block copolymer with an average molecular mass of about 6,000 to
about 9,000 Da, or about 6,500 to about 8,000 Da, or about 7,700
Da. Poloxamer 338 (corresponding to Pluronic.RTM. F-108) is a block
copolymer with an average molecular mass of about 12,000 to about
18,000 Da, or about 13,000 to about 15,000 Da, or about 14,600 Da.
Poloxamer 407 (corresponding to Pluronic.RTM. F-127) is a
polyoxyethylene-polyoxypropylene triblock copolymer in a ratio of
between about E101 P56 E101 to about E106 P70 E106, or about E101
P56E101, or about E106 P70 E106, with an average molecular mass of
about 10,000 to about 15,000 Da, or about 12,000 to about 14,000
Da, or about 12,000 to about 13,000 Da, or about 12,600 Da.
[0316] Additional examples of surfactants that can be used in the
invention include, but are not limited to, polyvinyl alcohol (which
can be hydrolyzed polyvinyl acetate), polyvinyl acetate, Vitamin
E-TPGS, poloxamers, cholic acid sodium salt, dioctyl sulfosuccinate
sodium, hexadecyltrimethyl ammonium bromide, saponin, TWEEN.RTM.
20, TWEEN.RTM. 80, sugar esters, Triton X series,
L-a-phosphatidylcholine (PC), 1,2-dipalmitoylphosphatidycholine
(DPPC), oleic acid, sorbitan trioleate, sorbitan mono-oleate,
sorbitan monolaurate, polyoxyethylene (20) sorbitan monolaurate,
polyoxyethylene (20) sorbitan monooleate, natural lecithin, oleyl
polyoxyethylene (2) ether, stearyl polyoxyethylene (2) ether,
lauryl polyoxyethylene (4) ether, block copolymers of oxyethylene
and oxypropylene, synthetic lecithin, diethylene glycol dioleate,
tetrahydrofurfuryl oleate, ethyl oleate, isopropyl myristate,
glyceryl monooleate, glyceryl monostearate, glyceryl
monoricinoleate, cetyl alcohol, stearyl alcohol, cetylpyridinium
chloride, benzalkonium chloride, olive oil, glyceryl monolaurate,
corn oil, cotton seed oil, sunflower seed oil, lecithin, oleic
acid, and sorbitan trioleate.
[0317] It should be recognized by one skilled in the art that some
surfactants can be used as polymers in the manufacture of the
microparticle. It should also be recognized by one skilled in the
art that in some manufacture the microparticle may retain a small
amount of surfactant which allows further modification of
properties as desired.
IV. Biodegradable Polymeric-Containing Microparticles
[0318] In certain aspects, solid aggregating microparticles are
provided that include a poly(a-hydroxyacid) biodegradable polymer,
for example poly-lactic acid (PLA) biodegradable polymer, and a
hydrophobic polymer covalently bound to a hydrophilic polymer, for
example PLGA-PEG biodegradable polymer, wherein the solid
aggregating microparticles have a solid core, include a therapeutic
agent, are sufficiently small to be injected in vivo, and are
capable of aggregating in vivo. In one embodiment, the
microparticles aggregate in vivo to form at least one pellet of at
least 500 .mu.m in vivo to provide sustained drug delivery in vivo
for at least one month, two months, three months, four months, five
months, six months, seven months, eight months, nine months, or
more. In one embodiment, the microparticles are about 10 .mu.m to
about 50 .mu.m, from about 20 .mu.m to about 45 .mu.m, from about
25 .mu.m to about 35 .mu.m.
[0319] It has been discovered that the inclusion of PLA in certain
microparticle formulations allows for the achievement of long-term
slow substantially surface erosion for example, 9 months, 10
months, 11 months, 12 months or greater. In some embodiments,
nearly zero-order or linear release drug delivery in vivo, can be
achieved.
[0320] As contemplated herein, PLA for use in the present invention
can include any known variant, for example, but not limited to,
PLLA (Poly-L-lactic Acid), racemic PLLA (Poly-L-lactic Acid), PDLA
(Poly-D-lactic Acid), and PDLLA (Poly-DL-lactic Acid), or a mixture
thereof. In one embodiment, the PLA is Poly-L-lactic Acid. The PLA
can be ester end-capped or acid end-capped.
[0321] In one embodiment, the PLA comprises at least about 40%,
45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%,
98%, 99%, 99.5%, or 99.9% of the microparticle. In one embodiment,
the PLA has a molecular weight between about 30 and 60 kD, about 35
and 55kD, or about 40 and 50kD. The microparticle further includes
a hydrophobic polymer covalently bound to a hydrophilic
biodegradable polymer. Hydrophobic degradable polymers are known in
the art, and include, but are not limited to, polyglycolic acid
(PGA), poly(D,L-lactide-co-glycolide)(PLGA), and poly D,L-lactic
acid (PDLLA); polycaprolactone; polyanhydrides, such as polysebacic
anhydride, poly(maleic anhydride); and copolymers thereof.
Hydrophilic polymers are known in the art and include, for example
poly(alkylene glycols) such as polyethylene glycol (PEG),
polyethylene oxide (PEO), and poly(ethylene glycol) amine;
polysaccharides; poly(vinyl alcohol) (PVA); polypyrrolidone;
polyacrylamide (PAM); polyethylenimine (PEI); poly(acrylic acid);
poly(vinylpyrolidone) (PVP); or a copolymer thereof. Hydrophobic
polymers covalently bound to hydrophilic polymers include, for
example, PLGA-PEG, PLA-PEG, PCL-PEG in an amount from about 0.5
percent to about 10 percent, about 0.5 percent to about 5 percent,
about 0.5 percent to about 4 percent, about 0.5 percent to about 3
percent, or about 0.1 percent to about 1, 2, 5, or 10 percent. In
one embodiment, the hydrophobic polymer covalently bound to the
hydrophilic polymer is PLGA-PEG.
[0322] In one embodiment, the ratio of PLA/hydrophobic polymer
covalently bound to a hydrophilic polymer in the microparticle is
between about 40/1 to about 120/1. In one embodiment, the ratio of
PLA/hydrophobic polymer covalently bound to hydrophilic polymer in
the microparticle is about 45/1, 50/1, 55/1, 60/1, 65/1, 70/1,
75/1, 80/1, 85/1, 90/1, 95/1, 96/1, 97/1, 98/1, 99/1, 99.5/1,
99.9/1, 100/1, 101/1, 102/1, 103/1, 104/1, 105/1, or greater than
105/1. In one embodiment, the hydrophobic polymer covalently bound
to a hydrophilic polymer is PLGA-PEG.
[0323] In one embodiment, the PLA/hydrophobic polymer covalently
bound to hydrophilic polymer microparticle further comprises an
additional hydrophobic biodegradable polymer, for example
polyglycolic acid (PGA), poly(D,L-lactide-co-glycolide)(PLGA), and
poly D,L-lactic acid (PDLLA); polycaprolactone; polyanhydrides,
such as polysebacic anhydride, poly(maleic anhydride); and
copolymers thereof. In one embodiment, the additional hydrophobic
biodegradable polymer comprises about 1%, 5%, 10%, 15%, 20%, 25%,
30%, 35%, 40%, 45%, 50%, or 55% of the microparticle. In one
embodiment, the additional hydrophobic polymer is PLGA. In one
embodiment, the ratio of lactide/glycolide in the PLGA is about
5/95, 10/90, 15/85, 20/80, 25/75, 30/70, 35/65, 40/60, 45/55,
50/50, 55/45, 60/40, 65/35, 70/30, 75/25, 80/20, 85/15, 90/10, or
95/5. The PLGA can be acid end-capped or ester end-capped. The PLA
can be acid end-capped or ester end-capped.
[0324] In one embodiment, the microparticle contains PLA, PLGA, and
PLGA-PEG. In one embodiment, the ratio of PLA/PLGA/PLGA-PEG in the
microparticle is about 5/95/1, 10/90/1, 15/85/1, 20/80/1, 25/75/1,
30/70/1, 35/65/1, 40/60/1, 45/55/1, 40/60/1, 45/55/1, 50/50/1,
55/45/1, 60/40/1, 65/35/1, 70/30/1, 75/25/1, 80/20/1, 85/15/1,
90/10/1, 95/5/1, or 100/1/1. In one embodiment, PLA-PEG or PLC-PEG
is substituted for PLGA-PEG.
[0325] In one embodiment, the microparticles comprise
PLA/PLGA45k-PEG5k. The PLA can be ester or acid end-capped. In one
embodiment, the PLA is acid end-capped. In one embodiment, the
microparticles comprise PLA/PLGA45k-PEG5k in a ratio of between
about 100/1 to 80/20, about 100/1, 95/5, 90/10, 85/15, or 80/20. In
one embodiment, the microparticles comprise
PLA/PLGA7525/PLGA45k-PEG5k in a ratio of between about 99/1/1 to
1/99/1, about 99/1/1, 95/5/1, 90/10/1, 85/15/1, 80/20/1, 75/25/1,
70/30/1, 65/35/1, 60/40/1, 55/45/1, 50/50/1, 45/55/1, 40/60/1,
35/65/1, 30/70/1, 25/75/1, 20/80/1, 15/85/1, 10/90/1, 5/95/1, or
1/99/1. The PLGA7525 and PLA can be acid or ester end capped. In
one embodiment, both the PLGA7525 and PLA are acid end-capped. In
one embodiment, the microparticles comprise
PLA/PLGA5050/PLGA45k-PEG5k. In one embodiment, the microparticles
comprise PLA/PLGA5050/PLGA45k-PEG5k in a ratio of about 99/1/1,
95/5/1, 90/10/1, 85/15/1, 80/20/1, 75/25/1, 70/30/1, 65/35/1,
60/40/1, 55/45/1, 50/50/1, 45/55/1, 40/60/1, 35/65/1, 30/70/1,
25/75/1, 20/80/1, 15/85/1, 10/90/1, 5/95/1, or 1/99/1. The PLA and
PLGA5050 can be acid or ester end-capped. In one embodiment, both
the PLA and PLGA are acid end-capped.
[0326] In one embodiment, the PLA microparticles described herein
is surface modified. In one embodiment, the microparticles have a
modified surface which has been treated under mild conditions at a
temperature at or less than about 18.degree. C. to remove surface
surfactant or cause surface polymer to partially degrade. The solid
aggregating microparticles are suitable, for example, for an
intravitreal injection, implant, including an ocular implant,
periocular delivery, or delivery in vivo outside of the eye.
[0327] In one embodiment, the aggregate formed in vivo is a blend
or mix of microparticles, wherein at least one of the
microparticles includes a poly-lactic acid (PLA) biodegradable
polymer and a hydrophobic biodegradable polymer covalently linked
to a hydrophilic polymer, for example PLGA-PEG biodegradable
polymer. In one embodiment, the mix or blend includes one or more
microparticles comprised of a non-PLA polymer. In one embodiment,
the mix or blend includes PLA/PLGA-PEG microparticles and
PLGA/PLGA-PEG microparticles. In one embodiment, the mix or blend
comprises a ratio of PLA/PLGA-PEG to PLGA/PLGA-PEG of about 1/99,
5/95, 10/90, 15/85, 20/80, 25/75, 30/70, 35/65, 40/60, 45/55,
50/50, 55/45, 60/40, 65/35, 70/30, 75/25, 80/20, 85/15, 90/10,
95/5, or 99/1. In one embodiment, the ratio of lactide/glycolide in
the PLGA or PLGA-PEG is about 5/95, 10/90, 15/85, 20/80, 25/75,
30/70, 35/65, 40/60, 45/55, 50/50, 55/45, 60/40, 65/35, 70/30,
75/25, 80/20, 85/15, 90/10, or 95/5. The PLGA can be acid end
capped or ester end capped. In one embodiment, the PLGA is a block
co-polymer, for example, diblock, triblock, multiblock, or
star-shaped block. In one embodiment, the PLGA is a random
co-polymer.
[0328] In one embodiment, the mix or blend includes PLA/PLGA-PEG
microparticles and PLA/PLGA/PLGA-PEG microparticles. In one
embodiment, the mix or blend comprises a ratio of PLA/PLGA-PEG to
PLA/PLGA/PLGA-PEG of about 1/99, 5/95, 10/90, 15/85, 20/80, 25/75,
30/70, 35/65, 40/60, 45/55, 50/50, 55/45, 60/40, 65/35, 70/30,
75/25, 80/20, 85/15, 90/10, 95/5, or 99/1. In one embodiment, the
ratio of lactide/glycolide in the PLGA or PLGA-PEG is about 5/95,
10/90, 15/85, 20/80, 25/75, 30/70, 35/65, 40/60, 45/55, 50/50,
55/45, 60/40, 65/35, 70/30, 75/25, 80/20, 85/15, 90/10, or 95/5. In
one embodiment, the PLGA is in a lactide/glycolide ratio of 95/5,
90/10, 85/15, 80/20, 75/25, 70/30, 65/35, 60/40, 55/45, 50/50,
45/55, 40/60, 35/65, 30/70, 25/75, 20/80, 15/85, 10/90, 5/95. The
PLGA can be acid end capped or ester end capped. In one embodiment,
the PLGA is a block co-polymer, for example, diblock, triblock,
multiblock, or star-shaped block. In one embodiment, the PLGA is a
random co-polymer.
[0329] In one embodiment, the blend or mix of microparticles is
comprised of a PLA/PLGA-PEG microparticle, wherein the PLA
comprises from about 80% to 99.9% of the microparticle, and a
PLGA/PLGA-PEG microparticle, wherein the PLGA comprises from about
80% to 99.9% of the microparticle. In one embodiment, the blend or
mix of microparticles is comprised of a PLA/PLGA45k-PEG5k
microparticle and a PLGA7525/PLGA45k-PEG5k microparticle in a ratio
of from about 1/99 to about 99/1, about 1.99, 5/95, 10/90, 15/85,
20/80, 25/75, 30/70, 35/65, 40/60, 45/55, 50/50, 55/45, 60/40,
65/35, 70/30, 75/25, 80/20, 85/15, 90/10, 95/5, or 99/1. In one
embodiment, the ratio of PLA/PLGA45k-PEG5k microparticle to
PLGA7525/PLGA45k-PEG5k microparticles is between about 20/80 to
40/60, about 20/80, 25/75, 30/70, 35/65, or 40/60. The PLA and PLGA
can be ester or acid end capped. In one embodiment, the blend or
mix of microparticles is comprised of a PLA 4A/PLGA45k-PEG5k
microparticle and a PLGA7525 4A/PLGA45k-PEG5k microparticle in a
ratio of from about 1/99 to about 99/1, about 1.99, 5/95, 10/90,
15/85, 20/80, 25/75, 30/70, 35/65, 40/60, 45/55, 50/50, 55/45,
60/40, 65/35, 70/30, 75/25, 80/20, 85/15, 90/10, 95/5, or 99/1. In
one embodiment, the ratio of PLA 4A/PLGA45k-PEG5k microparticle to
PLGA7525 4A/PLGA45k-PEG5k microparticles is between about 20/80 to
40/60, about 20/80, 25/75, 30/70, 35/65, or 40/60.
[0330] In one embodiment, the blend or mix of microparticles is
comprised of a PLA/PLGA45k-PEG5k microparticle and a
PLGA5050/PLGA45k-PEG5k microparticle in a ratio of from about 1/99
to about 99/1, about 1.99, 5/95, 10/90, 15/85, 20/80, 25/75, 30/70,
35/65, 40/60, 45/55, 50/50, 55/45, 60/40, 65/35, 70/30, 75/25,
80/20, 85/15, 90/10, 95/5, or 99/1. In one embodiment, the ratio of
PLA/PLGA45k-PEG5k microparticle to PLGA5050/PLGA45k-PEG5k
microparticles is between about 20/80 to 40/60, about 20/80, 25/75,
30/70, 35/65, or 40/60. The PLA and PLGA can be ester or acid end
capped. In one embodiment, the blend or mix of microparticles is
comprised of a PLA 4A/PLGA45k-PEG5k microparticle and a PLGA5050
4A/PLGA45k-PEG5k microparticle in a ratio of from about 1/99 to
about 99/1, about 1.99, 5/95, 10/90, 15/85, 20/80, 25/75, 30/70,
35/65, 40/60, 45/55, 50/50, 55/45, 60/40, 65/35, 70/30, 75/25,
80/20, 85/15, 90/10, 95/5, or 99/1. In one embodiment, the ratio of
PLA 4A/PLGA45k-PEG5k microparticle to PLGA5050 4A/PLGA45k-PEG5k
microparticles is between about 20/80 to 40/60, about 20/80, 25/75,
30/70, 35/65, or 40/60.
[0331] In one embodiment, the blend or mix of microparticles is
comprised of a PLA/PLGA/PLGA-PEG microparticle and a PLGA/PLGA-PEG
microparticle, In one embodiment, the blend or mix of
microparticles is comprised of a PLA/PLGA/PLGA45k-PEG5k
microparticle and a PLGA/PLGA45k-PEG5k microparticle in a ratio of
from about 1/99 to about 99/1, about 1.99, 5/95, 10/90, 15/85,
20/80, 25/75, 30/70, 35/65, 40/60, 45/55, 50/50, 55/45, 60/40,
65/35, 70/30, 75/25, 80/20, 85/15, 90/10, 95/5, or 99/1. In one
embodiment, the blend or mix of microparticles is comprised of a
PLA/PLGA7525/PLGA45k-PEG5k microparticle and a
PLGA7525/PLGA45k-PEG5k microparticle in a ratio of from about 1/99
to about 99/1, about 1.99, 5/95, 10/90, 15/85, 20/80, 25/75, 30/70,
35/65, 40/60, 45/55, 50/50, 55/45, 60/40, 65/35, 70/30, 75/25,
80/20, 85/15, 90/10, 95/5, or 99/1. In one embodiment, the blend or
mix of microparticles is comprised of a PLA/PLGA7525/PLGA45k-PEG5k
microparticle and a PLGA5050/PLGA45k-PEG5k microparticle in a ratio
of from about 1/99 to about 99/1, about 1.99, 5/95, 10/90, 15/85,
20/80, 25/75, 30/70, 35/65, 40/60, 45/55, 50/50, 55/45, 60/40,
65/35, 70/30, 75/25, 80/20, 85/15, 90/10, 95/5, or 99/1. In one
embodiment, the blend or mix of microparticles is comprised of a
PLA/PLGA5050/PLGA45k-PEG5k microparticle and a
PLGA7525/PLGA45k-PEG5k microparticle in a ratio of from about 1/99
to about 99/1, about 1.99, 5/95, 10/90, 15/85, 20/80, 25/75, 30/70,
35/65, 40/60, 45/55, 50/50, 55/45, 60/40, 65/35, 70/30, 75/25,
80/20, 85/15, 90/10, 95/5, or 99/1. The PLA and PLGA can be acid
end capped or ester end capped.
[0332] In one embodiment, the microparticle comprises a blend or
mix of ratio of PLA4A/PLGA45k-PEG5k and PLGA7525 4A/PLGA45k-PEG5k.
In one embodiment, the blend or mix of microparticles comprise a
ratio of PLA 4A/PLGA45k-PEG5k microparticle to PLGA7525
4A/PLGA45k-PEG5k microparticles is between about 20/80 to 40/60,
about 20/80, 25/75, 30/70, 35/65, or 40/60. In one embodiment, the
blend or mix of microparticles is comprised of a PLA
4A/PLGA45k-PEG5k microparticle and a PLGA5050 4A/PLGA45k-PEG5k
microparticle in a ratio of from about 1/99 to about 99/1, about
1.99, 5/95, 10/90, 15/85, 20/80, 25/75, 30/70, 35/65, 40/60, 45/55,
50/50, 55/45, 60/40, 65/35, 70/30, 75/25, 80/20, 85/15, 90/10,
95/5, or 99/1. In one embodiment, the ratio of PLA 4A/PLGA45k-PEG5k
microparticle to PLGA5050 4A/PLGA45k-PEG5k microparticles is
between about 20/80 to 50/50, about 20/80, 25/75, 30/70, 35/65,
40/60, or 50/50.
[0333] As contemplated herein, PLA, as utilized herein, can be
replaced with a different poly(a-hydroxyacid) biodegradable
polymer, for example, polyglycolic acid (PGA),
poly(D,L-lactide-co-glycolide)(PLGA), and poly D,L-lactic acid
(PDLLA). polyesters, poly (E-caprolactone), poly
(3-hydroxy-butyrate), poly (s-caproic acid), poly (p-dioxanone),
poly (propylene fumarate), poly (ortho esters), polyol/diketene
acetals, polyanhydrides, poly (sebacic anhydride) (PSA), poly
(carboxybis-carboxyphenoxyphosphazene) (PCPP), poly [bis
(p-carboxyphenoxy) methane](PCPM), copolymers of SA, CPP, CPM, and
poly(amino acids).
[0334] Non-limiting embodiments of solid aggregating
microparticles, injections, and suspensions include:
[0335] (I) A solid aggregating microparticle comprising surface
surfactant and a prodrug disclosed herein encapsulated in at least
one biodegradable polymer selected from PLA and PLGA and at least
one hydrophobic polymer covalently bound to a hydrophillic polymer,
wherein the microparticle has a mean diameter between 10 .mu.m and
60 .mu.m that: [0336] (i) has a solid core with less than 10%
porosity by ratio of void space to total volume; [0337] (ii) has a
modified surface which has been treated under mild conditions at a
temperature less than about 18.degree. C. to remove surface
surfactant; and [0338] (iii) is capable of aggregating in vivo to
form at least one pellet of at least 500 m in vivo capable of
sustained drug delivery in vivo for at least three months.
[0339] (II) A solid aggregating microparticle comprising surface
surfactant and a tyrosine kinase inhibitor selected from Tivosinib,
Imatinib, Gefitinib, Erlotinib, Lapatinib, Canertinib, Semaxinib,
Vatalaninib, Sorafenib, Axitinib, Pazopanib, Dasatinib, Nilotinib,
Crizotinib, Ruxolitinib, Vandetanib, Vemurafenib, Bosutinib,
Cabozantinib, Regorafenib, Vismodegib, and Ponatinib encapsulated
in at least one biodegradable polymer selected from PLA and PLGA
and at least one hydrophobic polymer covalently bound to a
hydrophillic polymer, wherein the microparticle has a mean diameter
between 10 .mu.m and 60 .mu.m that: [0340] (i) has a solid core
with less than 10% porosity by ratio of void space to total volume;
[0341] (ii) has a modified surface which has been treated under
mild conditions at a temperature less than about 18.degree. C. to
remove surface surfactant; and [0342] (iii) is capable of
aggregating in vivo to form at least one pellet of at least 500
.mu.m in vivo capable of sustained drug delivery in vivo for at
least three months.
[0343] (III) A solid aggregating microparticle comprising surface
surfactant and a loop diuretic selected from furosemide,
bumetanide, piretanide, ethacrynic acid, etozolin, and ozolinone,
encapsulated in at least one biodegradable polymer selected from
PLA and PLGA and at least one hydrophobic polymer covalently bound
to a hydrophillic polymer, wherein the microparticle has a mean
diameter between 10 .mu.m and 60 .mu.m that: [0344] (i) has a solid
core with less than 10% porosity by ratio of void space to total
volume; [0345] (ii) has a modified surface which has been treated
under mild conditions at a temperature less than about 18.degree.
C. to remove surface surfactant; and [0346] (iii) is capable of
aggregating in vivo to form at least one pellet of at least 500
.mu.m in vivo capable of sustained drug delivery in vivo for at
least three months.
[0347] (IV) An injectable material that comprises the
microparticles of (I), (II), or (III) in a pharmaceutically
acceptable carrier for administration in vivo.
[0348] (V) A composition comprising a mixture or blend of solid
aggregating microparticles wherein the microparticles are capable
of aggregating in vivo to form at least one pellet of at least 500
.mu.m in vivo capable of sustained drug delivery in vivo for at
least four months wherein the composition comprises: [0349] (i) a
first microparticle with a solid core comprising surface surfactant
and a therapeutic agent encapsulated in PLA and PLGA-PEG; and
[0350] (ii) a second microparticle with a solid core comprising
surface surfactant and a therapeutic agent encapsulated in PLGA and
PLGA-PEG; and
[0351] (VI) A composition comprising a mixture or blend of solid
aggregating microparticles wherein the microparticles are capable
of aggregating in vivo to form at least one pellet of at least 500
.mu.m in vivo capable of sustained drug delivery in vivo for at
least four months wherein the composition comprises: [0352] (i) a
first microparticle with a solid core comprising surface surfactant
and a therapeutic agent encapsulated in PLA and PLGA-PEG; and
[0353] (ii) a second microparticle with a solid core comprising
surface surfactant and a therapeutic agent encapsulated in PLA/PLGA
and PLGA-PEG.
[0354] (VII) A composition comprising a mixture or blend of solid
aggregating microparticles wherein the microparticles are capable
of aggregating in vivo to form at least one pellet of at least 500
.mu.m in vivo capable of sustained drug delivery in vivo for at
least four months wherein the composition comprises: [0355] (i) a
first microparticle with a solid core comprising surface surfactant
and a therapeutic agent encapsulated in PLGA and PLGA-PEG; and
[0356] (ii) a second microparticle with a solid core comprising
surface surfactant and a therapeutic agent encapsulated in PLA/PLGA
and PLGA-PEG.
[0357] (VIII) An injectable material that comprises the composition
of (V), (VI), or (VII) in a pharmaceutically acceptable carrier for
administration in vivo.
[0358] Particular embodiments include:
[0359] The solid aggregating microparticles of (I), (II), or (III),
suitable for a delivery route selected from the group consisting of
intravitreal, intrastromal, intracameral, subtenon, sub-retinal,
retrobulbar, peribulbar, suprachoroidal, subchoroidal,
conjunctival, subconjunctival, episcleral, posterior juxtascleral,
circumcorneal, and tear duct injections.
[0360] The solid aggregating microparticles of (I), (II), or (III),
wherein the at least one pellet is capable of sustained delivery
for at least four months, at least five months, at least six
months, at least seven months, at least eight months, at least nine
months, or at least ten months.
[0361] The solid aggregating microparticles of (I), (II), or (III),
wherein the surface modification is carried out at a pH between
about 14 and about 12.
[0362] The solid aggregating microparticles of (I), (II), or (III),
wherein the surface modification is carried out at a pH between
about 12 and about 10.
[0363] The solid aggregating microparticles of (I), (II), or (III),
wherein the surface modification is carried out at a pH between
about 10 and about 8.
[0364] The solid aggregating microparticles of (I), (II), or (III),
wherein the surface modification is carried out at a pH between
about 6.5 and about 7.5.
[0365] The solid aggregating microparticles of (I), (II), or (III),
wherein the surface modification is carried out at a pH between
about 1 and about 6.
[0366] The solid aggregating microparticles of (I), (II), or (III),
wherein the surface modification is carried out at a temperature of
less than about 16.degree. C.
[0367] The solid aggregating microparticles of (I), (II), or (III),
wherein the surface modification is carried out at a temperature of
less than about 10.degree. C.
[0368] The solid aggregating microparticles of (I), (II), or (III),
wherein the surface modification is carried out at a temperature of
less than about 8.degree. C.
[0369] The solid aggregating microparticles of (I), (II), or (III),
wherein the surface modification is carried out at a temperature of
less than about 5.degree. C.
[0370] The solid aggregating microparticles of (I), (II), or (III),
wherein the surface modification is carried out at a temperature of
less than about 2.degree. C.
[0371] The solid aggregating microparticles of (I), (II), or (III),
wherein the hydrophobic polymer covalently bound to a hydrophilic
polymer is poly(D,L-lactide-co-glycolide) covalently bound to
polyethylene glycol (PLGA-PEG).
[0372] The solid aggregating microparticles of (I), (II), or (III),
wherein the microparticles comprise PLA and PLGA-PEG.
[0373] The solid aggregating microparticles of (I), (II), or (III),
wherein the microparticles comprise PLA PLGA-PEG the ratio of PLA
to PLGA-PEG is between about 99/1.
[0374] The solid aggregating microparticles of (I), (II), or (III),
wherein the microparticles comprise PLGA PLGA-PEG.
[0375] The solid aggregating microparticles of (I), (II), or (III),
wherein the microparticles comprise PLGA and PLGA-PEG the ratio of
PLA to PLGA-PEG is between about 99/1.
[0376] The solid aggregating microparticles of (I), (II), or (III),
wherein the microparticles comprise PLA/PLGA PLGA-PEG.
[0377] The solid aggregating microparticles of (I), (II), or (III),
wherein the microparticles comprise PLA/PLGA PLGA-PEG and the ratio
of PLA/PLGA/PLGA-PEG is about 5/95/1, 10/90/1, 15/85/1, 20/80/1,
25/75/1, 30/70/1, 35/65/1, 40/60/1, 45/55/1, 50/50/1, 55/45/1,
60/40/1, 65/35/1, 70/30/1, 75/25/1, 80/20/1, 85/15/1, 90/10/1,
95/5/1, or 100/1/1.
[0378] The solid aggregating microparticles of (I), (II), or (III),
wherein the microparticles comprise PLA/PLGA PLGA-PEG and the ratio
of PLA/PLGA/PLGA-PEG is about 95/5/1.
[0379] The solid aggregating microparticles of (I), (II), or (III),
wherein the microparticles comprise PLA/PLGA PLGA-PEG and the ratio
of PLA/PLGA/PLGA-PEG is about 90/10/1.
[0380] The solid aggregating microparticles of (I), (II), or (III),
wherein the microparticles comprise PLA/PLGA PLGA-PEG and the ratio
of PLA/PLGA/PLGA-PEG is about 70/30/1.
[0381] The solid aggregating microparticles of (I), (II), or (III),
wherein the microparticles comprise (i) PLGA; (ii) PLGA wherein the
PLGA in (ii) has a different ratio of lactide to glycolide than the
PLGA in (i); and, PLGA-PEG.
[0382] The solid aggregating microparticles of (I), (II), or (III),
wherein the microparticles comprise PLGA50:50, PLGA75:25, and
PLGA-PEG.
[0383] The solid aggregating microparticles of (I), (II), or (III),
wherein the microparticles comprise PLGA50:50, PLGA85:15, and
PLGA-PEG.
[0384] The solid aggregating microparticles of (I), (II), or (III),
wherein the microparticles comprise PLGA85:15, PLGA75:25, and
PLGA-PEG.
[0385] The solid aggregating microparticles of (I), (II), or (III),
wherein the PLA is ester end-capped.
[0386] The solid aggregating microparticles of (I), (II), or (III),
wherein the PLA is acid end-capped.
[0387] The solid aggregating microparticles of (I), (II), or (III),
wherein the microparticles have a mean diameter between about 20
and 30 .mu.m.
[0388] The solid aggregating microparticles of (I), (II), or (III),
wherein the microparticles have a mean diameter between about 20
and 50 .mu.m.
[0389] The solid aggregating microparticles of (I), (II), or (III),
wherein the microparticles have a mean diameter between about 25
and 35 .mu.m.
[0390] The solid aggregating microparticles of (I), (II), or (III),
wherein the microparticles have a mean diameter between about 20
and 40 .mu.m.
[0391] The solid aggregating microparticles of (I), (II), or (III),
wherein the microparticles have a mean diameter between about 25
and 40 .mu.m.
[0392] The injectable material of (IV), wherein the injectable
material comprises a compound that inhibits aggregation of the
microparticles prior to injection.
[0393] The injectable material of (IV), wherein the injectable
material comprises a sugar.
[0394] The injectable material of (IV), wherein the injectable
material comprises mannitol, sucrose, trehalose, glucose, or
lactose.
[0395] The injectable material of (IV), wherein the injectable
material comprises a viscosity enhancer.
[0396] The injectable material of (IV), wherein the injectable
material comprises hyaluronic acid.
[0397] The injectable material of (IV), wherein the injectable
material comprises sodium hyaluronate.
[0398] The injectable material of (IV), wherein the injectable
material has a range of concentration of the solid aggregating
microparticles of about 100-600 mg/ml.
[0399] The injectable material of (IV), wherein the injectable
material has a range of concentration of the solid aggregating
microparticles of about 500 or less mg/ml.
[0400] The injectable material of (IV), wherein the injectable
material has a range of concentration of the solid aggregating
microparticles of about 300 or less mg/ml.
[0401] The injectable material of (IV), wherein the injectable
material has a range of concentration of the solid aggregating
microparticles of about 200 or less mg/ml.
[0402] The injectable material of (IV), wherein the injectable
material has a range of concentration of the solid aggregating
microparticles of about 150 or less mg/ml.
[0403] The composition of (V) or (VI), wherein the ratio of PLA to
PLGA-PEG in the first microparticle is between about 105/1 to about
80/10.
[0404] The composition of (V) or (VI), wherein the ratio of PLA to
PLGA-PEG in the first microparticle is between about 100/1.
[0405] The composition of (V), wherein the ratio of PLGA to
PLGA-PEG in the second microparticle is between about 105/1 to
about 80/10.
[0406] The composition of (V), wherein the ratio of PLGA to
PLGA-PEG in the second microparticle is between about 100/1.
[0407] The composition of (V), (VI), or (VII), wherein the PLGA-PEG
is PLGA45k-PEG5k.
[0408] The composition of (V), (VI), or (VII), wherein the ratio of
first microparticles to second microparticles is between about 1/99
to 99/1.
[0409] The composition of (V), (VI), or (VII), wherein the ratio of
first microparticles to second microparticles is about 99/1.
[0410] The composition of (V), (VI), or (VII), wherein the ratio of
first microparticles to second microparticles is about 95/5.
[0411] The composition of (V), (VI), or (VII), wherein the ratio of
first microparticles to second microparticles is about 90/10.
[0412] The composition of (V), (VI), or (VII), wherein the ratio of
first microparticles to second microparticles is about 85/15.
[0413] The composition of (V), (VI), or (VII), wherein the ratio of
first microparticles to second microparticles is about 80/20.
[0414] The composition of (V), (VI), or (VII), wherein the ratio of
first microparticles to second microparticles is about 75/25.
[0415] The composition of (V), (VI), or (VII), wherein the ratio of
first microparticles to second microparticles is about 70/30.
[0416] The composition of (V), (VI), or (VII), wherein the ratio of
first microparticles to second microparticles is about 65/35.
[0417] The composition of (V), (VI), or (VII), wherein the ratio of
first microparticles to second microparticles is about 60/40.
[0418] The composition of (V), (VI), or (VII), wherein the ratio of
first microparticles to second microparticles is about 55/45.
[0419] The composition of (V), (VI), or (VII), wherein the ratio of
first microparticles to second microparticles is about 50/50.
[0420] The composition of (V), (VI), or (VII), wherein the ratio of
first microparticles to second microparticles is about 45/55.
[0421] The composition of (V), (VI), or (VII), wherein the ratio of
first microparticles to second microparticles is about 40/60.
[0422] The composition of (V), (VI), or (VII), wherein the ratio of
first microparticles to second microparticles is about 1/99.
[0423] The composition of (VI) or (VII), wherein the ratio of
PLA/PLGA/PLGA-PEG in the second microparticle is 90/10/1.
[0424] The composition of (VI) or (VII), wherein the ratio of
PLA/PLGA/PLGA-PEG in the second microparticle is 85/15/1.
[0425] The composition of (VI) or (VII), wherein the ratio of
PLA/PLGA/PLGA-PEG in the second microparticle is 80/20/1.
[0426] The composition of (VI) or (VII), wherein the ratio of
PLA/PLGA/PLGA-PEG in the second microparticle is 75/25/1.
[0427] The composition of (VI) or (VII), wherein the ratio of
PLA/PLGA/PLGA-PEG in the second microparticle is 70/30/1.
[0428] The composition of (VI) or (VII), wherein the ratio of
PLA/PLGA/PLGA-PEG in the second microparticle is 65/35/1.
[0429] The composition of (VI) or (VII), wherein the ratio of
PLA/PLGA/PLGA-PEG in the second microparticle is 60/40/1.
[0430] The composition of (VI) or (VII), wherein the ratio of
PLA/PLGA/PLGA-PEG in the second microparticle is 55/45/1.
[0431] The composition of (VI) or (VII), wherein the ratio of
PLA/PLGA/PLGA-PEG in the second microparticle is 50/50/1.
[0432] The composition of (VI) or (VII), wherein the ratio of
PLA/PLGA/PLGA-PEG in the second microparticle is 45/55/1.
[0433] The composition of (VI) or (VII), wherein the ratio of
PLA/PLGA/PLGA-PEG in the second microparticle is 40/60/1.
[0434] The composition of (VI) or (VII), wherein the ratio of
PLA/PLGA/PLGA-PEG in the second microparticle is 35/65/1.
[0435] The composition of (VI) or (VII), wherein the ratio of
PLA/PLGA/PLGA-PEG in the second microparticle is 30/70/1.
[0436] The composition of (VI) or (VII), wherein the ratio of
PLA/PLGA/PLGA-PEG in the second microparticle is 25/75/1.
[0437] The composition of (VI) or (VII), wherein the ratio of
PLA/PLGA/PLGA-PEG in the second microparticle is 20/80/1.
[0438] The composition of (VI) or (VII), wherein the ratio of
PLA/PLGA/PLGA-PEG in the second microparticle is 15/85/1.
[0439] The composition of (VI) or (VII), wherein the ratio of
PLA/PLGA/PLGA-PEG in the second microparticle is 10/90/1.
[0440] The composition of (V), (VI) or (VII), wherein the PLGA is
acid end-capped.
[0441] The composition of (V), (VI) or (VII), wherein the PLGA is
ester end-capped.
[0442] The composition of (V), (VI) or (VII), wherein the PLA is
acid end-capped.
[0443] The composition of (V), (VI) or (VII), wherein the PLA is
ester end-capped.
[0444] The composition of (V), (VI) or (VII), wherein the
microparticles are surface-modified.
[0445] The composition of (V), (VI) or (VII), wherein the
therapeutic agent is a pharmaceutical drug.
[0446] The composition of (V), (VI) or (VII), wherein the
therapeutic agent is an prodrug as described herein.
[0447] The composition of (V), (VI) or (VII), wherein the
therapeutic agent is sunitinib or a pharmaceutically acceptable
salt thereof.
[0448] The composition of (V), (VI) or (VII), wherein the
therapeutic agent is sunitinib malate.
[0449] The composition of (V), (VI) or (VII), wherein the
therapeutic agent is selected from Tivosinib, Imatinib, Gefitinib,
and Erlotinib.
[0450] The composition of (V), (VI) or (VII), wherein the
therapeutic agent is selected from Lapatinib, Canertinib,
Semaxinib, and Vatalaninib, The composition of (V), (VI) or (VII),
wherein the therapeutic agent is selected from Sorafenib, Axitinib,
Pazopanib, and Dasatinib.
[0451] The composition of (V), (VI) or (VII), wherein the
therapeutic agent is selected from Nilotinib, Crizotinib,
Ruxolitinib, Vandetanib, and Vemurafenib.
[0452] The composition of (V), (VI) or (VII), wherein the
therapeutic agent is selected from Bosutinib, Cabozantinib,
Regorafenib, Vismodegib, and Ponatinib.
[0453] The composition of(V), (VI) or (VII), wherein the
therapeutic agent is selected furosemide, bumetanide, piretanide,
ethacrynic acid, etozolin, and ozolinone.
[0454] The composition of (V), (VI) or (VII), wherein the
microparticles have a mean diameter between about 20 and 30 m.
[0455] The composition of (V), (VI) or (VII), wherein the
microparticles have a mean diameter between about 20 and 50 m.
[0456] The composition of (V), (VI) or (VII), wherein the
microparticles have a mean diameter between about 25 and 35 m.
[0457] The composition of (V), (VI) or (VII), wherein the
microparticles have a mean diameter between about 20 and 40
.mu.m.
[0458] The composition of (V), (VI) or (VII), wherein the
microparticles have a mean diameter between about 25 and 40
.mu.m.
[0459] The injectable material of (VIII), wherein the injectable
material comprises a compound that inhibits aggregation of the
microparticles prior to injection.
[0460] The injectable material of (VIII), wherein the injectable
material comprises a sugar.
[0461] The injectable material of (VIII), wherein the injectable
material comprises mannitol, sucrose, trehalose, glucose, or
lactose.
[0462] The injectable material of (VIII), wherein the injectable
material comprises a viscosity enhancer.
[0463] The injectable material of (VIII), wherein the injectable
material comprises hyaluronic acid.
[0464] The injectable material of (VIII), wherein the injectable
material comprises sodium hyaluronate.
[0465] The injectable material of (VIII), wherein the injectable
material has a range of concentration of the solid aggregating
microparticles of about 100-600 mg/ml.
[0466] The injectable material of (VIII), wherein the injectable
material has a range of concentration of the solid aggregating
microparticles of about 500 or less mg/ml.
[0467] The injectable material of (VIII), wherein the injectable
material has a range of concentration of the solid aggregating
microparticles of about 300 or less mg/ml.
[0468] The injectable material of (VIII), wherein the injectable
material has a range of concentration of the solid aggregating
microparticles of about 200 or less mg/ml.
[0469] The injectable material of (VIII), wherein the injectable
material has a range of concentration of the solid aggregating
microparticles of about 150 or less mg/ml.
V. Examples of Disorders to be Treated
[0470] In one embodiment, the microparticles described herein and a
pharmaceutically active compound encapsulated in the microparticle
optionally in combination with a pharmaceutically acceptable
carrier, excipient, or diluent are used for the treatment of a
disorder, including a human disorder. In one embodiment, the
composition is a pharmaceutical composition for treating an eye
disorder or eye disease.
[0471] Non-limiting exemplary eye disorders or diseases treatable
with the composition include age related macular degeneration,
alkaline erosive keratoconjunctivitis, allergic conjunctivitis,
allergic keratitis, anterior uveitis, Behcet's disease,
blepharitis, blood-aqueous barrier disruption, chorioiditis,
chronic uveitis, conjunctivitis, contact lens-induced
keratoconjunctivitis, corneal abrasion, corneal trauma, corneal
ulcer, crystalline retinopathy, cystoid macular edema,
dacryocystitis, diabetic keratopathy, diabetic macular edema,
diabetic retinopathy, dry eye disease, dry age-related macular
degeneration, eosinophilic granuloma, episcleritis, exudative
macular edema, Fuchs' Dystrophy, giant cell arteritis, giant
papillary conjunctivitis, glaucoma, glaucoma surgery failure, graft
rejection, herpes zoster, inflammation after cataract surgery,
iridocorneal endothelial syndrome, iritis, keratoconjunctivitis
sicca, keratoconjunctivitis inflammatory disease, keratoconus,
lattice dystrophy, map-dot-fingerprint dystrophy, necrotic
keratitis, neovascular diseases involving the retina, uveal tract
or cornea, for example, neovascular glaucoma, corneal
neovascularization, neovascularization resulting following a
combined vitrectomy and lensectomy, neovascularization of the optic
nerve, and neovascularization due to penetration of the eye or
contusive ocular injury, neuroparalytic keratitis, non-infectious
uveitis ocular herpes, ocular lymphoma, ocular rosacea, ophthalmic
infections, ophthalmic pemphigoid, optic neuritis, panuveitis,
papillitis, pars planitis, persistent macular edema,
phacoanaphylaxis, posterior uveitis, post-operative inflammation,
proliferative diabetic retinopathy, proliferative sickle cell
retinopathy, proliferative vitreoretinopathy, retinal artery
occlusion, retinal detachment, retinal vein occlusion, retinitis
pigmentosa, retinopathy of prematurity, rubeosis iritis, scleritis,
Stevens-Johnson syndrome, sympathetic ophthalmia, temporal
arteritis, thyroid associated ophthalmopathy, uveitis, vernal
conjunctivitis, vitamin A insufficiency-induced keratomalacia,
vitritis, and wet age-related macular degeneration.
VI. Therapeutically Active Agents to be Delivered
[0472] A wide variety of therapeutic agents can be delivered in a
long term sustained manner in vivo using the present invention.
[0473] A "therapeutically effective amount" of a pharmaceutical
composition/combination of this invention means an amount
effective, when administered to a patient, to provide a therapeutic
benefit such as an amelioration of symptoms of the selected
disorder, typically an ocular disorder. In certain aspects, the
disorder is glaucoma, a disorder mediated by carbonic anhydrase, a
disorder or abnormality related to an increase in intraocular
pressure (IOP), a disorder mediated by nitric oxide synthase (NOS),
a disorder requiring neuroprotection such as to regenerate/repair
optic nerves, allergic conjunctivitis, anterior uveitis, cataracts,
dry or wet age-related macular degeneration (AMD), or diabetic
retinopathy.
[0474] A "pharmaceutically acceptable salt" is formed when a
therapeutically active compound is modified by making an inorganic
or organic, non-toxic, acid or base addition salt thereof. Salts
can be synthesized from a parent compound that contains a basic or
acidic moiety by conventional chemical methods. Generally, such a
salt can be prepared by reacting a free acid form of the compound
with a stoichiometric amount of the appropriate base (such as Na,
Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by
reacting a free base form of the compound with a stoichiometric
amount of the appropriate acid. Such reactions are typically
carried out in water or in an organic solvent, or in a mixture of
the two. Generally, non-aqueous media like ether, ethyl acetate,
ethanol, isopropanol, or acetonitrile are typical, where
practicable. Examples of pharmaceutically acceptable salts include,
but are not limited to, mineral or organic acid salts of basic
residues such as amines; alkali or organic salts of acidic residues
such as carboxylic acids; and the like. The pharmaceutically
acceptable salts include the conventional non-toxic salts and the
quaternary ammonium salts of the parent compound formed, for
example, from non-toxic inorganic or organic acids. For example,
conventional non-toxic acid salts include those derived from
inorganic acids such as hydrochloric, hydrobromic, sulfuric,
sulfamic, phosphoric, nitric and the like; and the salts prepared
from organic acids such as acetic, propionic, succinic, glycolic,
stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic,
hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic,
esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric,
toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic,
isethionic, HOOC--(CH.sub.2).sub.n--COOH where n is 0-4, and the
like. Lists of additional suitable salts may be found, e.g., in
Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing
Company, Easton, Pa., p. 1418 (1985).
[0475] In one embodiment, the microparticles of the present
invention can comprise a compound for the treatment of glaucoma,
for instance a beta-adrenergic antagonists, a prostaglandin analog,
an adrenergic agonist, a carbonic anhydrase inhibitor, a
parasympathomimetic agent, a dual anti-VEGF/Anti-PDGF therapeutic
or a dual leucine zipper kinase (DLK) inhibitor. In another
embodiment, the microparticles of the present invention can
comprise a compound for the treatment of diabetic retinopathy. Such
compounds may be administered in lower doses according to the
invention as they may be administered at the site of the ocular
disease.
[0476] Examples of loop diuretics include furosemide, bumetanide,
piretanide, ethacrynic acid, etozolin, and ozolinone.
[0477] Examples of beta-adrenergic antagonists include, but are not
limited to, timolol (Timoptic.RTM.), levobunolol (Betagan.RTM.),
carteolol (Ocupress.RTM.), Betaxolol (Betoptic), and metipranolol
(OptiPranolol.RTM.).
[0478] Examples of prostaglandin analogs include, but are not
limited to, latanoprost (Xalatan.RTM.), travoprost (Travatan.RTM.),
bimatoprost (Lumigan.RTM.) and tafluprost (Zioptan.TM.).
[0479] Examples of adrenergic agonists include, but are not limited
to, brimonidine (Alphagan.RTM.), epinephrine, dipivefrin
(Propine.RTM.) and apraclonidine (Lopidine.RTM.).
[0480] Examples of carbonic anhydrase inhibitors include, but are
not limited to, dorzolamide (Trusopt.RTM.), brinzolamide
(Azopt.RTM.), acetazolamide (Diamox.RTM.) and methazolamide
(Neptazane.RTM.), see structures below:
[0481] Examples of tyrosine kinase inhibitors include Tivosinib,
Imatinib, Gefitinib, Erlotinib, Lapatinib, Canertinib, Semaxinib,
Vatalaninib, Sorafenib, Axitinib, Pazopanib, Dasatinib, Nilotinib,
Crizotinib, Ruxolitinib, Vandetanib, Vemurafenib, Bosutinib,
Cabozantinib, Regorafenib, Vismodegib, and Ponatinib. In one
embodiment, the tyrosine kinase inhibitor is selected from
Tivosinib, Imatinib, Gefitinib, and Erlotinib. In one embodiment,
the tyrosine kinase inhibitor is selected from Lapatinib,
Canertinib, Semaxinib, and Vatalaninib. In one embodiment, the
tyrosine kinase inhibitor is selected from Sorafenib, Axitinib,
Pazopanib, and Dasatinib. In one embodiment, the tyrosine kinase
inhibitor is selected from Nilotinib, Crizotinib, Ruxolitinib,
Vandetanib, and Vemurafenib. In one embodiment, the tyrosine kinase
inhibitor is selected from Bosutinib, Cabozantinib, Regorafenib,
Vismodegib, and Ponatinib.
[0482] An example of a parasympathomimetic includes, but is not
limited to, pilocarpine.
[0483] DLK inhibitors include, but are not limited to, Crizotinib,
KW-2449 and Tozasertib, see structure below.
[0484] Drugs used to treat diabetic retinopathy include, but are
not limited to, ranibizumab (Lucentis.RTM.).
[0485] In one embodiment, the dual anti-VEGF/Anti-PDGF therapeutic
is sunitinib malate (Sutent.RTM.).
[0486] In one embodiment, the compound is a treatment for glaucoma
and can be used as an effective amount to treat a host in need of
glaucoma treatment.
[0487] In another embodiment, the compound acts through a mechanism
other than those associated with glaucoma to treat a disorder
described herein in a host, typically a human.
[0488] In one embodiment, the therapeutic agent is selected from a
phosphoinositide 3-kinase (PI3K) inhibitor, a Bruton's tyrosine
kinase (BTK) inhibitor, or a spleen tyrosine kinase (Syk)
inhibitor, or a combination thereof.
[0489] PI3K inhibitors that may be used in the present invention
are well known. Examples of PI3 kinase inhibitors include but are
not limited to Wortmannin, demethoxyviridin, perifosine,
idelalisib, Pictilisib, Palomid 529, ZSTK474, PWT33597, CUDC-907,
and AEZS-136, duvelisib, GS-9820, BKM120, GDC-0032 (Taselisib)
(2-[4-[2-(2-Isopropyl-5-methyl-1,2,4-triazol-3-yl)-5,6-dihydroimidazo[1,2-
-d][1,4]benzoxazepin-9-yl]pyrazol-1-yl]-2-methylpropanamide),
MLN-1117 ((2R)-1-Phenoxy-2-butanyl hydrogen (S)-methylphosphonate;
or Methyl(oxo) {[(2R)-1-phenoxy-2-butanyl]oxy} phosphonium)),
BYL-719
((2S)--N1-[4-Methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl]-
-2-thiazolyl]-1,2-pyrrolidinedicarboxamide), GSK2126458
(2,4-Difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyrid-
inyl}benzenesulfonamide) (omipalisib), TGX-221
((+)-7-Methyl-2-(morpholin-4-yl)-9-(1-phenylaminoethyl)-pyrido[1,2-a]-pyr-
imidin-4-one), GSK2636771
(2-Methyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-1H-benzo[d]-
imidazole-4-carboxylic acid dihydrochloride), KIN-193
((R)-2-((1-(7-methyl-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)et-
hyl)amino)benzoic acid), TGR-1202/RP5264, GS-9820
((S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-mohydroxypropan-1-one),
GS-1101
(5-fluoro-3-phenyl-2-([S)]-1-[9H-purin-6-ylamino]-propyl)-3H-quin-
azolin-4-one), AMG-319, GSK-2269557, SAR245409
(N-(4-(N-(3-((3,5-dimethoxyphenyl)amino)quinoxalin-2-yl)sulfamoyl)phenyl)-
-3-methoxy-4 methylbenzamide), BAY80-6946
(2-amino-N-(7-methoxy-8-(3-morpholinopropoxy)-2,3-dihydroimidazo[1,2-c]qu-
inaz), AS 252424
(5-[1-[5-(4-Fluoro-2-hydroxy-phenyl)-furan-2-yl]-meth-(Z)-ylidene]-thiazo-
lidine-2,4-dione), CZ 24832
(5-(2-amino-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-tert-butylpyri-
dine-3-sulfonamide), Buparlisib
(5-[2,6-Di(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinami-
ne), GDC-0941
(2-(1H-Indazol-4-yl)-6-[[4-(methylsulfonyl)-1-piperazinyl]methyl]-4-(4-mo-
rpholinyl)thieno[3,2-d]pyrimidine), GDC-0980
((S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]p-
yrimidin-6 yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (also
known as RG7422)), SF1126
((8S,14S,17S)-14-(carboxymethyl)-8-(3-guanidinopropyl)-17-(hydroxymethyl)-
-3,6,9,12,15-pentaoxo-1-(4-(4-oxo-8-phenyl-4H-chromen-2-yl)morpholino-4-iu-
m)-2-oxa-7,10,13,16-tetraazaoctadecan-18-oate), PF-05212384
(N-[4-[[4-(Dimethylamino)-1-piperidinyl]carbonyl]phenyl]-N-[4-(4,6-di-4-m-
orpholinyl-1,3,5-triazin-2-yl)phenyl]urea) (gedatolisib),
LY3023414, BEZ235
(2-Methyl-2-{4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-1H-im-
idazo[4,5-c]quinolin-1-yl]phenyl} propanenitrile) (dactolisib),
XL-765
(N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-
-methoxy-4-methylbenzamide), and GSK1059615
(5-[[4-(4-Pyridinyl)-6-quinolinyl]methylene]-2,4-thiazolidenedione),
PX886 ([(3
aR,6E,9S,9aR,10R,11aS)-6-[[bis(prop-2-enyl)amino]methylidene]-5-hydroxy-9-
-(methoxymethyl)-9a, 11 a-dimethyl-1,4,7-trioxo-2,3,3
a,9,10,11-hexahydroindeno[4,5h]isochromen-10-yl] acetate (also
known as sonolisib)), LY294002, AZD8186, PF-4989216, pilaralisib,
GNE-317, PI-3065, PI-103, NU7441 (KU-57788), HS 173, VS-5584
(SB2343), CZC24832, TG100-115, A66, YM201636, CAY10505, PIK-75,
PIK-93, AS-605240, BGT226 (NVP-BGT226), AZD6482, voxtalisib,
alpelisib, IC-87114, TGI100713, CH5132799, PKI-402, copanlisib (BAY
80-6946), XL 147, PIK-90, PIK-293, PIK-294, 3-MA (3-methyladenine),
AS-252424, AS-604850, apitolisib (GDC-0980; RG7422), and the
structure described in WO2014/071109 having the formula:
##STR00001##
[0490] BTK inhibitors for use in the present invention are well
known. Examples of BTK inhibitors include ibrutinib (also known as
PCI-32765)(Imbmvica.TM.)(1-[(3R)-3-[4-amino-3-(4-phenoxy-phenyl)pyrazolo[-
3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one),
dianilinopyrimidine-based inhibitors such as AVL-101 and
AVL-291/292
(N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino-
)phenyl)acrylamide) (Avila Therapeutics) (US Patent publication No
2011/0117073, incorporated herein in its entirety), Dasatinib
([N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-m-
ethylpyrimidin-4-ylamino)thiazole-5-carboxamide], LFM-A13
(alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-ibromophenyl)
propenamide), GDC-0834
([R--N-(3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-
-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrob-
enzo[b]thiophene-2-carboxamide], CGI-560
4-(tert-butyl)-N-(3-(8-(phenylamino)imidazo[1,2-a]pyrazin-6-yl)phenyl)ben-
zamide, CGI-1746
(4-(tert-butyl)-N-(2-methyl-3-(4-methyl-6-((4-(morpholine-4-carbonyl)phen-
yl)amino)-5-oxo-4, 5-dihydropyrazin-2-yl)phenyl)benzamide), CNX-774
(4-(4-((4-((3-acrylamidophenyl)amino)-5-fluoropyrimidin-2-yl)amino)phenox-
y)-N-methylpicolinamide), CTA056
(7-benzyl-1-(3-(piperidin-1-yl)propyl)-2-(4-(pyridin-4-yl)phenyl)-1H-imid-
azo[4,5-g]quinoxalin-6(5H)-one), GDC-0834
((R)--N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methy-
l-5-oxo-4,
5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[-
b]thiophene-2-carboxamide), GDC-0837
((R)--N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methy-
l-5-oxo-4,
5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[-
b]thiophene-2-carboxamide), HM-71224, ACP-196, ONO-4059 (Ono
Pharmaceuticals), PRT062607
(4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl-
)amino)pyrimidine-5-carboxamide hydrochloride), QL-47
(1-(1-acryloylindolin-6-yl)-9-(1-methyl-1H-pyrazol-4-yl)benzo[h][1,6]naph-
thyridin-2(1H)-one), and RN486
(6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-pip-
erazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-
-isoquinolin-1-one), and other molecules capable of inhibiting BTK
activity, for example those BTK inhibitors disclosed in Akinleye et
ah, Journal of Hematology & Oncology, 2013, 6:59, the entirety
of which is incorporated herein by reference.
[0491] Syk inhibitors for use in the present invention are well
known, and include, for example, Cerdulatinib
(4-(cyclopropylamino)-2-((4-(4-(ethylsulfonyl)piperazin-1-yl)phenyl)amino-
)pyrimidine-5-carboxamide), entospletinib
(6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine)-
, fostamatinib
([6-({5-Fluoro-2-[(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl}amino)-2,2-
-dimethyl-3-oxo-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl]methyl
dihydrogen phosphate), fostamatinib disodium salt (sodium
(6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2--
dimethyl-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methyl
phosphate), BAY 61-3606
(2-(7-(3,4-Dimethoxyphenyl)-imidazo[1,2-c]pyrimidin-5-ylamino)-ni-
cotinamide HCl), RO9021
(6-[(1R,2S)-2-Amino-cyclohexylamino]-4-(5,6-dimethyl-pyridin-2-ylamino)-p-
yridazine-3-carboxylic acid amide), imatinib (Gleevac;
4-[(4-methylpiperazin-1-yl)methyl]-N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimi-
din-2-yl]amino}phenyl)benzamide), staurosporine, GSK143
(2-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-4-(p-tolylamino)pyrim-
idine-5-carboxamide), PP2
(1-(tert-butyl)-3-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine),
PRT-060318
(2-(((1R,2S)-2-aminocyclohexyl)amino)-4-(m-tolylamino)pyrimidine-5-carbox-
amide), PRT-062607
(4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl-
)amino)pyrimidine-5-carboxamide hydrochloride), R112
(3,3'-((5-fluoropyrimidine-2,4-diyl)bis(azanediyl))diphenol), R348
(3-Ethyl-4-methylpyridine), R406
(6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2--
dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3 (4H)-one), piceatannol
(3-Hydroxyresveratol), YM193306 (Singh et al. Discovery and
Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med.
Chem. 2012, 55, 3614-3643), 7-azaindole, piceatannol, ER-27319
(Singh et al. Discovery and Development of Spleen Tyrosine Kinase
(SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in
its entirety herein), Compound D (Singh et al. Discovery and
Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med.
Chem. 2012, 55, 3614-3643 incorporated in its entirety herein),
PRT060318 (Singh et al. Discovery and Development of Spleen
Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643
incorporated in its entirety herein), luteolin (Singh et al.
Discovery and Development of Spleen Tyrosine Kinase (SYK)
Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in its
entirety herein), apigenin (Singh et al. Discovery and Development
of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55,
3614-3643 incorporated in its entirety herein), quercetin (Singh et
al. Discovery and Development of Spleen Tyrosine Kinase (SYK)
Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in its
entirety herein), fisetin (Singh et al. Discovery and Development
of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55,
3614-3643 incorporated in its entirety herein), myricetin (Singh et
al. Discovery and Development of Spleen Tyrosine Kinase (SYK)
Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in its
entirety herein), morin (Singh et al. Discovery and Development of
Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55,
3614-3643 incorporated in its entirety herein).
[0492] In one embodiment, the therapeutic agent is a MEK inhibitor.
MEK inhibitors for use in the present invention are well known, and
include, for example, trametinib/GSK1120212
(N-(3-{3-Cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7--
trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H-yl}
phenyl)acetamide), selumetinib
(6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimi-
dazole-5-carboxamide), pimasertib/AS703026/MSC1935369
((S)--N-(2,3-dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)isonicotina-
mide), XL-518/GDC-0973
(1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S-
)-piperidin-2-yl]azetidin-3-ol), refametinib/BAY869766/RDEAl 19
(N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-d-
ihydroxypropyl)cyclopropane-1-sulfonamide), PD-0325901
(N-[(2R)-2,3-Dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)ami-
no]-benzamide), TAK733
((R)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-me-
thylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione), MEK162/ARRY438162
(5-[(4-Bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl--
1H-benzimidazole-6-carboxamide), R05126766
(3-[[3-Fluoro-2-(methylsulfamoylamino)-4-pyridyl]methyl]-4-methyl-7-pyrim-
idin-2-yloxychromen-2-one), WX-554, R04987655/CH4987655
(3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3--
oxo-1,2-oxazinan-2yl)methyl)benzamide), or AZD8330
(2-((2-fluoro-4-iodophenyl)amino)-N-(2 hydroxyethoxy)-1,
5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide), U0126-EtOH,
PD184352 (CI-1040), GDC-0623, BI-847325, cobimetinib, PD98059, BIX
02189, BIX 02188, binimetinib, SL-327, TAK-733, PD318088, and
additional MEK inhibitors as described below.
[0493] In one embodiment, the therapeutic agent is a Raf inhibitor.
Raf inhibitors for use in the present invention are well known, and
include, for example, Vemurafinib
(N-[3-[[5-(4-Chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-di-
fluorophenyl]-1-propanesulfonamide), sorafenib tosylate
(4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]
carbamoylamino]phenoxy]-N-methylpyridine-2-carboxamide;
4-methylbenzenesulfonate), AZ628
(3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(3-methyl-4-oxo-3,4-dihydroquinazol-
in-6-ylamino)phenyl)benzamide), NVP-BHG712
(4-methyl-3-(1-methyl-6-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylam-
ino)-N-(3-(trifluoromethyl)phenyl)benzamide), RAF-265
(1-methyl-5-[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridin-4-yl]oxy-N-[-
4-(trifluoromethyl)phenyl]benzimidazol-2-amine), 2-Bromoaldisine
(2-Bromo-6,7-dihydro-1H,5H-pyrrolo[2,3-c]azepine-4,8-dione), Raf
Kinase Inhibitor IV
(2-chloro-5-(2-phenyl-5-(pyridin-4-yl)-1H-imidazol-4-yl)phenol),
Sorafenib N-Oxide (4-[4-[[[[4-Chloro-3 (trifluoroMethyl)phenyl]
aMino] carbonyl]aMino]phenoxy]-N-Methyl-2pyridinecarboxaMide
1-Oxide), PLX-4720, dabrafenib (GSK2118436), GDC-0879, RAF265, AZ
628, SB590885, ZM336372, GW5074, TAK-632, CEP-32496, LY3009120, and
GX818 (Encorafenib).
[0494] In one embodiment, the therapeutic agent is a programmed
death protein 1 (PD-1) inhibitor, a programmed death protein ligand
1 (PDL1) inhibitor, or a programmed death protein ligand 2 (PDL2)
inhibitor. PD-1, PDL 1, and PDL2 inhibitors are known in the art,
and include, for example, nivolumab (BMS), pembrolizumab (Merck),
pidilizumab (CureTech/Teva), AMP-244 (Amplimmune/GSK), BMS-936559
(BMS), and MEDI4736 (Roche/Genentech), and MPDL3280A
(Genentech).
[0495] In one embodiment, a therapeutic agent can be administered
in a sustained fashion.
[0496] In one embodiment, the therapeutic agent is a monoclonal
antibody (MAb). Some MAbs stimulate an immune response that
destroys cancer cells. Similar to the antibodies produced naturally
by B cells, these MAbs "coat" the cancer cell surface, triggering
its destruction by the immune system. For example, bevacizumab
targets vascular endothelial growth factor(VEGF), a protein
secreted by tumor cells and other cells in the tumor's
microenvironment that promotes the development of tumor blood
vessels. When bound to bevacizumab, VEGF cannot interact with its
cellular receptor, preventing the signaling that leads to the
growth of new blood vessels. Similarly, cetuximab and panitumumab
target the epidermal growth factor receptor (EGFR), and trastuzumab
targets the human epidermal growth factor receptor 2 (HER-2). MAbs
that bind to cell surface growth factor receptors prevent the
targeted receptors from sending their normal growth-promoting
signals. They may also trigger apoptosis and activate the immune
system to destroy tumor cells.
[0497] Other agents may include, but are not limited to, at least
one of tamoxifen, midazolam, letrozole, bortezomib, anastrozole,
goserelin, an mTOR inhibitor, a PI3 kinase inhibitor as described
above, a dual mTOR-PI3K inhibitor, a MEK inhibitor, a RAS
inhibitor, ALK inhibitor, an HSP inhibitor (for example, HSP70 and
HSP 90 inhibitor, or a combination thereof), a BCL-2 inhibitor as
described above, apopototic inducing compounds, an AKT inhibitor,
including but not limited to, MK-2206, GSK690693, Perifosine,
(KRX-0401), GDC-0068, Triciribine, AZD5363, Honokiol, PF-04691502,
and Miltefosine, a PD-1 inhibitor as described above including but
not limited to, Nivolumab, CT-011, MK-3475, BMS936558, and AMP-514
or a FLT-3 inhibitor, including but not limited to, P406,
Dovitinib, Quizartinib (AC220), Amuvatinib (MP-470), Tandutinib
(MLN518), ENMD-2076, and KW-2449, or a combination thereof.
Examples of mTOR inhibitors include but are not limited to
rapamycin and its analogs, everolimus (Afinitor), temsirolimus,
ridaforolimus, sirolimus, and deforolimus. Examples of MEK
inhibitors include but are not limited to tametinib/GSKll1120212
(N-(3-{3-Cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,
8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H-yl}
phenyl)acetamide), selumetinob
(6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimi-
dazole-5-carboxamide), pimasertib/AS703026/MSC1935369
((S)--N-(2,3-dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)isonicotina-
mide), XL-518/GDC-0973
(1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}
carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol) (cobimetinib),
refametinib/BAY869766/RDEAl19
(N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-d-
ihydroxypropyl)cyclopropane-1-sulfonamide), PD-0325901
(N-[(2R)-2,3-Dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)ami-
no]-benzamide), TAK733
((R)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-me-
thylpyrido[2,3d]pyrimidine-4,7(3H,8H)-dione), MEK162/ARRY438162
(5-[(4-Bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl--
1H-benzimidazole-6 carboxamide), R05126766
(3-[[3-Fluoro-2-(methylsulfamoylamino)-4-pyridyl]methyl]-4-methyl-7-pyrim-
idin-2-yloxychromen-2-one), WX-554, R04987655/CH.sub.4987655
(3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3--
oxo-1,2-oxazinan-2 yl)methyl)benzamide), or AZD8330
(2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo--
1,6-dihydropyridine-3-carboxamide). Examples of RAS inhibitors
include but are not limited to Reolysin and siGl2D LODER. Examples
of ALK inhibitors include but are not limited to Crizotinib,
Ceritinib (Zykadia), AP26113, and LDK378. HSP inhibitors include
but are not limited to Geldanamycin or
17-N-Allylamino-17-demethoxygeldanamycin (17AAG), and
Radicicol.
[0498] In certain aspects, the therapeutic agent is an
anti-inflammatory agent, a chemotherapeutic agent, a
radiotherapeutic, an additional therapeutic agent, or an
immunosuppressive agent.
[0499] In one embodiment, a chemotherapeutic is selected from, but
not limited to, imatinib mesylate (Gleevac.RTM.), dasatinib
(Sprycel.RTM.), nilotinib (Tasigna.RTM.), bosutinib (Bosulif.RTM.),
trastuzumab (Herceptin.RTM.), trastuzumab-DM1, pertuzumab
(Perjeta.TM.), lapatinib (Tykerb.RTM.), gefitinib (Iressa.RTM.),
erlotinib (Tarceva.RTM.), cetuximab (Erbitux.RTM.), panitumumab
(Vectibix.RTM.), vandetanib (Caprelsa.RTM.), vemurafenib
(Zelboraf.RTM.), vorinostat (Zolinza.RTM.), romidepsin
(Istodax.RTM.), bexarotene (Tagretin.RTM.), alitretinoin
(Panretin.RTM.), tretinoin (Vesanoid.RTM.), carfilizomib
(Kyprolis.TM.), pralatrexate (Folotyn.RTM.), bevacizumab
(Avastin.RTM.), ziv-aflibercept (Zaltrap.RTM.), sorafenib
(Nexavar.RTM.), sunitinib (Sutent.RTM.), pazopanib (Votrient.RTM.),
regorafenib (Stivarga.RTM.), and cabozantinib (Cometriq.TM.).
[0500] Additional chemotherapeutic agents include, but are not
limited to, a radioactive molecule, a toxin, also referred to as
cytotoxin or cytotoxic agent, which includes any agent that is
detrimental to the viability of cells, and liposomes or other
vesicles containing chemotherapeutic compounds. General anticancer
pharmaceutical agents include: vincristine (Oncovin.RTM.) or
liposomal vincristine (Marqibo.RTM.), daunorubicin (daunomycin or
Cerubidine.RTM.) or doxorubicin (Adriamycin.RTM.), cytarabine
(cytosine arabinoside, ara-C, or Cytosar.RTM.), L-asparaginase
(Elspar.RTM.) or PEG-L-asparaginase (pegaspargase or
Oncaspar.RTM.), etoposide (VP-16), teniposide (Vumon.RTM.),
6-mercaptopurine (6-MP or Purinethol.RTM.), Methotrexate,
cyclophosphamide (Cytoxan.RTM.), Prednisone, dexamethasone
(Decadron), imatinib (Gleevec.RTM.), dasatinib (Sprycel.RTM.),
nilotinib (Tasigna.RTM.), bosutinib (Bosulif.RTM.), and ponatinib
(Iclusig.TM.). Examples of additional suitable chemotherapeutic
agents include but are not limited to 1-dehydrotestosterone,
5-fluorouracil decarbazine, 6-mercaptopurine, 6-thioguanine,
actinomycin D, adriamycin, aldesleukin, an alkylating agent,
allopurinol sodium, altretamine, amifostine, anastrozole,
anthramycin (AMC)), an anti-mitotic agent, cis-dichlorodiamine
platinum (II) (DDP) cisplatin), diamino dichloro platinum,
anthracycline, an antibiotic, an antimetabolite, asparaginase, BCG
live (intravesical), betamethasone sodium phosphate and
betamethasone acetate, bicalutamide, bleomycin sulfate, busulfan,
calcium leucouorin, calicheamicin, capecitabine, carboplatin,
lomustine (CCNU), carmustine (BSNU), chlorambucil, cisplatin,
cladribine, colchicin, conjugated estrogens, cyclophosphamide,
cyclothosphamide, cytarabine, cytarabine, cytochalasin B, cytoxan,
dacarbazine, dactinomycin, dactinomycin (formerly actinomycin),
daunirubicin HCL, daunorucbicin citrate, denileukin diftitox,
Dexrazoxane, Dibromomannitol, dihydroxy anthracin dione, docetaxel,
dolasetron mesylate, doxorubicin HCL, dronabinol, E. coli
L-asparaginase, emetine, epoetin-.alpha., Erwinia L-asparaginase,
esterified estrogens, estradiol, estramustine phosphate sodium,
ethidium bromide, ethinyl estradiol, etidronate, etoposide
citrororum factor, etoposide phosphate, filgrastim, floxuridine,
fluconazole, fludarabine phosphate, fluorouracil, flutamide,
folinic acid, gemcitabine HCL, glucocorticoids, goserelin acetate,
gramicidin D, granisetron HCL, hydroxyurea, idarubicin HCL,
ifosfamide, interferon a-2b, irinotecan HCL, letrozole, leucovorin
calcium, leuprolide acetate, levamisole HCL, lidocaine, lomustine,
maytansinoid, mechlorethamine HCL, medroxyprogesterone acetate,
megestrol acetate, melphalan HCL, mercaptipurine, mesna,
methotrexate, methyltestosterone, mithramycin, mitomycin C,
mitotane, mitoxantrone, nilutamide, octreotide acetate, ondansetron
HCL, paclitaxel, pamidronate disodium, pentostatin, pilocarpine
HCL, plimycin, polifeprosan 20 with carmustine implant, porfimer
sodium, procaine, procarbazine HCL, propranolol, rituximab,
sargramostim, streptozotocin, tamoxifen, taxol, teniposide,
tenoposide, testolactone, tetracaine, thioepa chlorambucil,
thioguanine, thiotepa, topotecan HCL, toremifene citrate,
trastuzumab, tretinoin, valrubicin, vinblastine sulfate,
vincristine sulfate, and vinorelbine tartrate.
[0501] Additional therapeutic agents can include bevacizumab,
sutinib, sorafenib, 2-methoxyestradiol or 2ME2, finasunate,
vatalanib, vandetanib, aflibercept, volociximab, etaracizumab
(MEDI-522), cilengitide, erlotinib, cetuximab, panitumumab,
gefitinib, trastuzumab, dovitinib, figitumumab, atacicept,
rituximab, alemtuzumab, aldesleukine, atlizumab, tocilizumab,
temsirolimus, everolimus, lucatumumab, dacetuzumab, HLL1,
huN901-DM1, atiprimod, natalizumab, bortezomib, carfilzomib,
marizomib, tanespimycin, saquinavir mesylate, ritonavir, nelfinavir
mesylate, indinavir sulfate, belinostat, panobinostat, mapatumumab,
lexatumumab, dulanermin, ABT-737, oblimersen, plitidepsin,
talmapimod, P276-00, enzastaurin, tipifarnib, perifosine, imatinib,
dasatinib, lenalidomide, thalidomide, simvastatin, celecoxib,
bazedoxifene, AZD4547, rilotumumab, oxaliplatin (Eloxatin),
PD0332991 (palbociclib), ribociclib (LEE011), amebaciclib
(LY2835219), HDM201, fulvestrant (Faslodex), exemestane (Aromasin),
PIM447, ruxolitinib (INC424), BGJ398, necitumumab, pemetrexed
(Alimta), and ramucirumab (IMC-1121B).
[0502] In one aspect of the present invention, an immunosuppressive
agent is used, preferably selected from the group consisting of a
calcineurin inhibitor, e.g. a cyclosporin or an ascomycin, e.g.
Cyclosporin A (NEORAL.RTM.), FK506 (tacrolimus), pimecrolimus, a
mTOR inhibitor, e.g. rapamycin or a derivative thereof, e.g.
Sirolimus (RAPAMUNE.RTM.), Everolimus (Certican.RTM.),
temsirolimus, zotarolimus, biolimus-7, biolimus-9, a rapalog,
e.g.ridaforolimus, azathioprine, campath 1H, a S1P receptor
modulator, e.g. fingolimod or an analogue thereof, an anti-IL-8
antibody, mycophenolic acid or a salt thereof, e.g. sodium salt, or
a prodrug thereof, e.g. Mycophenolate Mofetil (CELLCEPT.RTM.), OKT3
(ORTHOCLONE OKT3.RTM.), Prednisone, ATGAM.RTM., THYMOGLOBULIN.RTM.,
Brequinar Sodium, OKT4, T10B9.A-3A, 33B3.1, 15-deoxyspergualin,
tresperimus, Leflunomide ARAVA.RTM., CTLAI-Ig, anti-CD25,
anti-IL2R, Basiliximab (SIMULECT.RTM.), Daclizumab (ZENAPAX.RTM.),
mizorbine, methotrexate, dexamethasone, ISAtx-247, SDZ ASM 981
(pimecrolimus, Elidel.RTM.), CTLA41g (Abatacept), belatacept,
LFA31g, etanercept (sold as Enbrel.RTM. by Immunex), adalimumab
(Humira.RTM.), infliximab (Remicade.RTM.), an anti-LFA-1 antibody,
natalizumab (Antegren.RTM.), Enlimomab, gavilimomab, antithymocyte
immunoglobulin, siplizumab, Alefacept efalizumab, pentasa,
mesalazine, asacol, codeine phosphate, benorylate, fenbufen,
naprosyn, diclofenac, etodolac and indomethacin, aspirin and
ibuprofen.
[0503] Examples of types of therapeutic agents that can be eluted
from the microparticles include anti-inflammatory drugs,
antimicrobial agents, anti-angiogenesis agents, immunosuppressants,
antibodies, steroids, ocular antihypertensive drugs and
combinations thereof. Examples of therapeutic agents include
amikacin, anecortane acetate, anthracenedione, anthracycline, an
azole, amphotericin B, bevacizumab, camptothecin, cefuroxime,
chloramphenicol, chlorhexidine, chlorhexidine digluconate,
clortrimazole, a clotrimazole cephalosporin, corticosteroids,
dexamethasone, desamethazone, econazole, eftazidime,
epipodophyllotoxin, fluconazole, flucytosine, fluoropyrimidines,
fluoroquinolines, gatifloxacin, glycopeptides, imidazoles,
itraconazole, ivermectin, ketoconazole, levofloxacin, macrolides,
miconazole, miconazole nitrate, moxifloxacin, natamycin, neomycin,
nystatin, ofloxacin, polyhexamethylene biguanide, prednisolone,
prednisolone acetate, pegaptanib, platinum analogues, polymicin B,
propamidine isethionate, pyrimidine nucleoside, ranibizumab,
squalamine lactate, sulfonamides, triamcinolone, triamcinolone
acetonide, triazoles, vancomycin, anti-vascular endothelial growth
factor (VEGF) agents, VEGF antibodies, VEGF antibody fragments,
vinca alkaloid, timolol, betaxolol, travoprost, latanoprost,
bimatoprost, brimonidine, dorzolamide, acetazolamide, pilocarpine,
ciprofloxacin, azithromycin, gentamycin, tobramycin, cefazolin,
voriconazole, gancyclovir, cidofovir, foscarnet, diclofenac,
nepafenac, ketorolac, ibuprofen, indomethacin, fluoromethalone,
rimexolone, anecortave, cyclosporine, methotrexate, tacrolimus and
combinations thereof.
[0504] Examples of immunosuppressive agents are calcineurin
inhibitor, e.g., a cyclosporin or an ascomycin, e.g., Cyclosporin A
(NEORAL.RTM.), FK506 (tacrolimus), pimecrolimus, a mTOR inhibitor,
e.g., rapamycin or a derivative thereof, e.g., Sirolimus
(RAPAMUNE.RTM.), Everolimus (Certican.RTM.), temsirolimus,
zotarolimus, biolimus-7, biolimus-9, a rapalog, e.g.,
ridaforolimus, azathioprine, campath 1H, a S1P receptor modulator,
e.g., fingolimod or an analogue thereof, an anti IL-8 antibody,
mycophenolic acid or a salt thereof, e.g., sodium salt, or a
prodrug thereof, e.g., Mycophenolate Mofetil (CELLCEPT.RTM.), OKT3
(ORTHOCLONE OKT3.RTM.), Prednisone, ATGAM.RTM., THYMOGLOBULIN.RTM.,
Brequinar Sodium, OKT4, T10B9.A-3A, 33B3.1, 15-deoxyspergualin,
tresperimus, Leflunomide ARAVA.RTM., CTLAI-Ig, anti-CD25,
anti-IL2R, Basiliximab (SIMULECT.RTM.), Daclizumab (ZENAPAX.RTM.),
mizorbine, methotrexate, dexamethasone, ISAtx-247, SDZ ASM 981
(pimecrolimus, Elidel.RTM.), CTLA41g (Abatacept), belatacept,
LFA31g, etanercept (sold as Enbrel.RTM. by Immunex), adalimumab
(Humira.RTM.), infliximab (Remicade.RTM.), an anti-LFA-1 antibody,
natalizumab (Antegren.RTM.), Enlimomab, gavilimomab, antithymocyte
immunoglobulin, siplizumab, Alefacept efalizumab, pentasa,
mesalazine, asacol, codeine phosphate, benorylate, fenbufen,
naprosyn, diclofenac, etodolac and indomethacin, aspirin and
ibuprofen.
[0505] In certain embodiments, the surface-treated microparticles
of the present invention can comprise a prodrug as disclosed below.
In all of the polymer moieties described in this specification,
where the structures are depicted as block copolymers (for example,
blocks of "x" followed by blocks of "y") it is intended that the
polymer can alternately be a random or alternating copolymer (for
example, "x" and "y", are either randomly distributed or
alternate). Unless stereochemistry is specifically indicated, each
individual moiety of each oligomer that has a chiral center can be
presented at the chiral carbon in (R) or (S) configuration or a
mixture thereof, including a racemic mixture.
[0506] In addition, prodrug moieties that have repetitive units of
the same or varying monomers, for example including but not limited
to an oligomer of polylactic acid, polylactide-coglycolide, or
polypropylene oxide, that has a chiral carbon can be used with the
chiral carbons all having the same stereochemistry, random
stereochemistry (by either monomer or oligomer), racemic (by either
monomer or oligomer) or ordered but different stereochemistry such
as a block of S enantiomer units followed by a block of R
enantiomer units in each oligomeric unit. In some embodiments
lactic acid is used in its naturally occurring S enantiomeric
form.
Prostaglandin Prodrugs
[0507] The disclosure provides prostaglandin prodrugs of Formula
IA:
##STR00002##
[0508] or a pharmaceutically acceptable composition, salt, or
isotopic derivative thereof wherein
[0509] L.sup.1 is selected from:
##STR00003##
[0510] L.sup.2 is selected from:
##STR00004##
[0511] A is selected from: H, alkyl, cycloalkyl, cycloalkylalkyl,
heterocycle, heterocycloalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, aryloxy, and alkyloxy wherein each group can be
optionally substituted with another desired substituent group which
is pharmaceutically acceptable and sufficiently stable under the
conditions of use, for example selected from R.sup.5;
[0512] R.sup.1, R.sup.2, and R.sup.3 are selected from:
--C(O)R.sup.4, C(O)A, and hydrogen wherein in Formula IA either
R.sup.1 or R.sup.2 cannot be hydrogen and wherein R.sup.1, R.sup.2,
and R.sup.3 can be further optionally substituted with R.sup.5;
[0513] R.sup.4 is selected from: [0514] (i)
--C.sub.10-C.sub.30alkylR.sup.5, --C.sub.10-C.sub.30alkenylR.sup.5,
--C.sub.10-C.sub.30alkynylR.sup.5,
--C.sub.10-C.sub.30alkenylalkynylR.sup.5, --C.sub.10-C.sub.30alkyl,
--C.sub.10-C.sub.30alkenyl, --C.sub.10-C.sub.30alkynyl,
--C.sub.10-C.sub.30alkenylalkynyl; and [0515] (ii) an unsaturated
fatty acid residue including but not limited to the carbon chains
from linoleic acid
(--(CH.sub.2).sub.8(CH).sub.2CH.sub.2(CH).sub.2(CH.sub.2).sub.4CH.su-
b.3)), docosahexaenoic acid
(--(CH.sub.2).sub.3(CHCHCH.sub.2).sub.6CH.sub.3)), eicosapentaenoic
acid (--(CH.sub.2).sub.4(CHCHCH.sub.2).sub.5CH.sub.3)),
alpha-linolenic acid
(--(CH.sub.2).sub.8(CHCHCH.sub.2).sub.3CH.sub.3)), stearidonic
acid, y-linolenic acid, arachidonic acid, docosatetraenoic acid,
palmitoleic acid, vaccenic acid, paullinic acid, oleic acid,
elaidic acid, gondoic acid, euric acid, nervonic acid and mead
acid, and wherein, if desired, each of which can be substituted
with R.sup.5; and
[0516] R.sup.5 is selected from: halogen, hydroxyl, cyano,
mercapto, amino, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl,
cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl, aryloxy, --S(O).sub.2alkyl,
--S(O)alkyl, --P(O)(Oalkyl).sub.2, B(OH).sub.2,
--Si(CH.sub.3).sub.3, --COOH, --COOalkyl, and --CONH.sub.2, each of
which except halogen, cyano, and --Si(CH.sub.3).sub.3 may be
optionally substituted, for example with halogen, alkyl, aryl,
heterocycle or heteroaryl if desired and if the resulting compound
achieves the desired purpose, wherein the group cannot be
substituted with itself, for example alkyl would not be substituted
with alkyl.
[0517] Non-limiting examples of R.sup.4 include:
##STR00005## ##STR00006## ##STR00007##
[0518] wherein n, m, and o are independently selected from any
integer between 0 and 29 (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,
13, 14, 15, 16, 17,18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 or
29) wherein n+m+o is 7 to 30 carbons and wherein mm is any integer
between 1 and 30 (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,
15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30).
In one embodiment mm is independently selected from the following
ranges: 1 to 5, 6 to 11, 12 to 17, 18 to 23, and 24 to 30 (e.g., 1,
2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,
21, 22, 23, 24, 25, 26, 27, 28, 29 or 30).
[0519] In one embodiment, --C.sub.10-C.sub.30 as used in the
definition of R.sup.4 is --C.sub.10-C.sub.28, --C.sub.10-C.sub.26,
--C.sub.10-C.sub.24, --C.sub.10-C.sub.22, --C.sub.10-C.sub.20,
--C.sub.10-C.sub.18, --C.sub.10-C.sub.16, --C.sub.10-C.sub.14, or
--C.sub.10-C.sub.12.
[0520] Non-limiting examples of Formula IA include:
##STR00008##
[0521] The disclosure provides prostaglandin prodrugs of Formula
IIA:
##STR00009##
[0522] or a pharmaceutically acceptable composition, salt, or
isotopic derivative thereof wherein
[0523] R.sup.6 is selected from: [0524] (i) polyethylene glycol,
polypropylene glycol, polypropylene oxide, polylactic acid, and
poly(lactic-co-glycolic acid) including:
##STR00010##
[0524] or polyglycolic acid, or a polyester, polyamide, or other
biodegradable polymer, each of which can be capped to complete the
terminal valence. In some embodiments, the compound can be capped
with hydrogen, or can be capped to create a terminal ester or
ether. For example, the moiety can be capped with a terminal
hydroxyl or carboxy which can be further derivatized to an ether or
ester; [0525] (ii) --C.sub.10-C.sub.30alkylR.sup.5,
--C.sub.10-C.sub.30alkenylR.sup.5,
--C.sub.10-C.sub.30alkynylR.sup.5,
--C.sub.10-C.sub.30alkenylalkynylR.sup.5, --C.sub.10-C.sub.30alkyl,
--C.sub.10-C.sub.30alkenyl, --C.sub.10-C.sub.30alkynyl,
--C.sub.10-C.sub.30alkenylalkynyl; [0526] (iii) an unsaturated
fatty acid residue including but not limited the carbon fragment
taken from linoleic acid
(--(CH.sub.2).sub.8(CH).sub.2CH.sub.2(CH).sub.2(CH.sub.2).sub.4CH.su-
b.3)), docosahexaenoic acid
(--(CH.sub.2).sub.3(CHCHCH.sub.2).sub.6CH.sub.3)), eicosapentaenoic
acid (--(CH.sub.2).sub.4(CHCHCH.sub.2).sub.5CH.sub.3)),
alpha-linolenic acid
(--(CH.sub.2).sub.8(CHCHCH.sub.2).sub.3CH.sub.3)) stearidonic acid,
y-linolenic acid, arachidonic acid, docosatetraenoic acid,
palmitoleic acid, vaccenic acid, paullinic acid, oleic acid,
elaidic acid, gondoic acid, euric acid, nervonic acid or mead acid;
[0527] (iv) alkyl, cycloalkyl, cycloalkylalkyl, heterocycle,
heterocycloalkyl, arylalkyl, heteroarylalkyl;
[0528] wherein R.sup.6 can only be selected from (ii), (iii), and
(iv) in Formula IIA if at least one of R.sup.7 and R.sup.8 is
selected to be R.sup.50;
[0529] R.sup.7 and R.sup.8 are independently selected from:
--C(O)R.sup.4, --C(O)A, hydrogen, and R.sup.50;
[0530] R.sup.50 is selected from carbonyl derivatives of
polyethylene glycol, polypropylene glycol, polypropylene oxide,
polylactic acid, and poly(lactic-co-glycolic acid) including:
##STR00011## ##STR00012## ##STR00013##
or polyglycolic acid, or a polyester, polyamide, or other
biodegradable polymer, each of which can be capped to complete the
terminal valence. In some embodiments, the compound can be capped
with hydrogen, or can be capped to create a terminal ester or
ether. For example, the moiety can be capped with a terminal
hydroxyl or carboxy which can be further derivatized to an ether or
ester; and
[0531] R.sup.311 is hydroxy, amino, A, alkyl, alkoxy, alkenyl,
alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,
heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
aryloxy, or polyethylene glycol;
[0532] R.sup.31 is hydrogen, A, --COOH, --C(O)A, alkyl, alkoxy,
alkenyl, alkynyl cycloalkyl, cycloalkylalkyl, heterocyclyl,
heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
aryloxy, hydroxy, and polyethylene glycol; and
[0533] R.sup.31a is hydrogen, --C(O)alkyl, aryl, alkyl, cycloalkyl,
cycloalkylalkyl, heterocyclyl, heterocycloalkyl, arylalkyl,
heteroaryl, heteroarylalkyl, polylactic acid, polygylcolic acid,
polyethylene glycol, stearoyl, or
##STR00014##
[0534] x and y are independently selected from any integer between
1 and 30 (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,
17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30). In one
embodiment x and y are independently selected from the following
ranges: 1 to 5, 6 to 11, 12 to 17, 18 to 23, and 24 to 30 (e.g., 1,
2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,
21, 22, 23, 24, 25, 26, 27, 28, 29 or 30) and in a preferred
embodiment, x and y are independently selected from an integer
between 1 and 12 (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12);
[0535] z is independently selected from any integer between 0 and
20 (0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,
18, 19, or 20) and in a preferred embodiment, z is an integer
between 0 and 12 (0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) or
between 0 and 6 (0, 1, 2, 3, 4, 5, or 6);
[0536] zz is independently selected from any integer between 1 and
20 (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,
19, or 20) and in a preferred embodiment, z is an integer between 1
and 12 (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) or between 1 and
6 (1, 2, 3, 4, 5, or 6); and
[0537] wherein all other variables are defined herein.
[0538] Non-limiting examples of R.sup.50 include:
##STR00015## ##STR00016## ##STR00017## ##STR00018##
[0539] In one embodiment, --C.sub.10-C.sub.30 as used in the
definition of R.sup.6 is --C.sub.10-C.sub.28, --C.sub.10-C.sub.26,
--C.sub.10-C.sub.24, C.sub.10-C.sub.22, --C.sub.10-C.sub.20,
C.sub.10-C.sub.18, --C.sub.10-C.sub.16, --C.sub.10-C.sub.14, or
--C.sub.10-C.sub.12
[0540] In one embodiment R.sup.6 is isopropyl.
[0541] Non-limiting examples of Formula IIA include:
##STR00019##
[0542] The disclosure provides prostaglandin prodrugs of Formula
IIIA:
##STR00020##
[0543] or a pharmaceutically acceptable composition, salt, or
isotopic derivative thereof wherein
[0544] L.sup.3 is selected from:
##STR00021##
[0545] wherein all other variables are defined herein.
[0546] In one embodiment, --C.sub.10-C.sub.30 as used in the
definition of R.sup.6 is --C.sub.12-C.sub.28, --C.sub.12-C.sub.26,
--C.sub.12-C.sub.24, --C.sub.14-C.sub.22, --C.sub.14-C.sub.20,
--C.sub.14-C.sub.18, --C.sub.14-C.sub.16, or
--C.sub.12-C.sub.14.
[0547] Non-limiting examples of Formula IIIA include:
##STR00022##
[0548] The disclosure provides prostaglandin prodrugs of Formula
IVA:
##STR00023##
[0549] or a pharmaceutically acceptable composition, salt, or
isotopic derivative thereof wherein
[0550] R.sup.11 is selected from: [0551] (i) R.sup.12; [0552] (ii)
--NH--C.sub.4-C.sub.30alkenyl-C(O)R.sup.12,
--NH--C.sub.4-C.sub.30alkynyl-C(O)R.sup.12,
--NH--C.sub.4-C.sub.30alkenylalkynyl-C(O)R.sup.12,
--NH--C.sub.2-C.sub.30alkyl-C(O)R.sup.12,
--O--C.sub.4-C.sub.30alkenyl-C(O)R.sup.12,
--O--C.sub.4-C.sub.30alkynyl-C(O)R.sup.12,
--O--C.sub.4-C.sub.30alkenylalkynyl-C(O)R.sup.12, and
--O--C.sub.2-C.sub.30alkyl-C(O)R.sup.12; [0553] (iii)
--NH--C.sub.4-C.sub.30alkenyl=R.sup.13,
--NH--C.sub.4-C.sub.30alkynyl=R.sup.13,
--NH--C.sub.4-C.sub.30alkenylalkynyl=R.sup.13,
--NH--C.sub.2-C.sub.30alkyl=R.sup.13,
--O--C.sub.4-C.sub.30alkenyl=R.sup.13,
--O--C.sub.4-C.sub.30alkynyl=R.sup.13,
--O--C.sub.4-C.sub.30alkenylalkynyl=R.sup.13,
--O--C.sub.2-C.sub.30alkyl=R.sup.13; [0554] (iv) polyethylene
glycol, polypropylene glycol, polypropylene oxide, polylactic acid,
and poly(lactic-co-glycolic acid), polyglycolic acid, or a
polyester, polyamide, or other biodegradable polymer, each of which
is substituted with at least one L.sup.4-R.sup.12 including:
[0554] ##STR00024## ##STR00025## [0555] (v) polyethylene glycol,
polypropylene glycol, polypropylene oxide, polylactic acid, and
poly(lactic-co-glycolic acid), polyglycolic acid, or a polyester,
polyamide, or other biodegradable polymer, each of which is
substituted with at least one moiety of L.sup.5=R.sup.13
including
##STR00026##
[0556] wherein R.sup.11 can be further substituted with R.sup.5 if
valence permits, a stable compound is formed, and the resulting
compound is pharmaceutically acceptable;
[0557] R.sup.12 is selected from:
##STR00027##
[0558] R.sup.13 is selected from:
##STR00028##
and
[0559] R.sup.15 is selected from R.sup.16 and R.sup.17;
[0560] R.sup.16 is selected from: [0561] (i)
--C(O)C.sub.3-C.sub.30alkylR.sup.5,
--C(O)C.sub.3-C.sub.30alkenylR.sup.5,
--C(O)C.sub.3-C.sub.30alkynylR.sup.5,
--C(O)C.sub.3-C.sub.30alkenylalkynylR.sup.5,
--C(O)C.sub.3-C.sub.30alkyl, --C(O)C.sub.3-C.sub.30alkenyl,
--C(O)C.sub.3-C.sub.30alkynyl, and
--C(O)C.sub.3-C.sub.30alkenylalkynyl; [0562] (ii) an unsaturated
fatty acid residue including but not limited the carbonyl fragment
taken from linoleic acid
(--C(O)(CH.sub.2).sub.7(CH).sub.2CH.sub.2(CH).sub.2(CH.sub.2).sub.4CH.sub-
.3)), docosahexaenoic acid
(--C(O)(CH.sub.2).sub.2(CHCHCH.sub.2).sub.6CH.sub.3)),
eicosapentaenoic acid
(--C(O)(CH.sub.2).sub.3(CHCHCH.sub.2).sub.5CH.sub.3)),
alpha-linolenic acid
(--C(O)(CH.sub.2).sub.7(CHCHCH.sub.2).sub.3CH.sub.3)) stearidonic
acid, y-linolenic acid, arachidonic acid, docosatetraenoic acid,
palmitoleic acid, vaccenic acid, paullinic acid, oleic acid,
elaidic acid, gondoic acid, euric acid, nervonic acid and mead
acid; [0563] (iii) polyethylene glycol, polypropylene glycol,
polypropylene oxide, polylactic acid, and poly(lactic-co-glycolic
acid) including:
##STR00029##
[0563] or polyglycolic acid, or a polyester, polyamide, or other
biodegradable polymer, each of which can be capped to complete the
terminal valence. In some embodiments, the compound can be capped
with hydrogen, or can be capped to create a terminal ester or
ether. For example, the moiety can be capped with a terminal
hydroxyl or carboxy which can be further derivatized to an ether or
ester;
[0564] R.sup.17 is selected from: H and --C(O)A;
[0565] L.sup.4 is bond, alkyl, alkenyl, alkynyl, --C(O)--,
--C(S)--, --NH--, --N(alkyl)-, --O--, or alkyl-C(O)--;
[0566] L.sup.5 is double bond, alkyl, or alkenyl; and
[0567] wherein all other variables are defined herein.
[0568] In one embodiment R.sup.11 is selected from:
--NH--C.sub.4-C.sub.29alkenyl-CH=R.sup.13,
--NH--C.sub.4-C.sub.29alkynyl-CH=R.sup.13,
--NH--C.sub.4-C.sub.29alkenylalkynyl-CH=R.sup.13,
--NH--C.sub.2-C.sub.29alkyl-CH=R.sup.13,
--O--C.sub.4-C.sub.29alkenyl-CH=R.sup.13,
--O--C.sub.4-C.sub.29alkynyl-CH=R.sup.13,
--O--C.sub.4-C.sub.29alkenylalkynyl-CH=R.sup.13, and
--O--C.sub.2-C.sub.29alkyl-CH=R.sup.13
[0569] In various different embodiments, --C.sub.4-C.sub.29 as used
in the definition of R.sup.11 may be --C.sub.4-C.sub.28,
--C.sub.4-C.sub.26, --C.sub.4-C.sub.24, --C.sub.6-C.sub.22,
--C.sub.6-C.sub.20, --C.sub.8-C.sub.18, --C.sub.8-C.sub.16,
--C.sub.8-C.sub.14, --C.sub.8-C.sub.12, --C.sub.8-C.sub.20, or
--C.sub.6-C.sub.24.
[0570] Non-limiting examples of R.sup.11 include:
##STR00030## ##STR00031## ##STR00032## ##STR00033##
wherein n, m, o, x, and y are as defined above.
[0571] Non-limiting examples of R.sup.16 include:
##STR00034## ##STR00035##
[0572] Non-limiting examples of Formula IVA include:
##STR00036## ##STR00037## ##STR00038## ##STR00039##
[0573] The disclosure provides prostaglandin prodrugs of Formula
VA:
##STR00040##
[0574] or a pharmaceutically acceptable composition, salt, or
isotopic derivative thereof wherein
[0575] R.sup.103 is selected from: H, alkyl, cycloalkyl,
cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, arylalkyl,
heteroaryl, and heteroarylalkyl wherein each group other than
hydrogen can be optionally substituted with another desired
substituent group which is pharmaceutically acceptable and
sufficiently stable under the conditions of use, for example
selected from R.sup.5;
[0576] R.sup.100 is selected from: [0577] (i)
C.sub.1-C.sub.10alkyl,
--C.sub.0-C.sub.10alkyl(C.sub.3-C.sub.7cycloalkyl), heterocycle,
--C.sub.0-C.sub.10alkyl(C.sub.3-C.sub.7heterocycloalkyl),
-arylC.sub.0-C.sub.10alkyl, -heteroarylalkyl,
--C.sub.0-C.sub.10alkylC.sub.2-C.sub.10alkenyl, and
C.sub.2-C.sub.10alkynyl; [0578] (ii) an unsaturated fatty acid
residue including but not limited the carbon fragment taken from
linoleic acid
(--(CH.sub.2).sub.8(CH).sub.2CH.sub.2(CH).sub.2(CH.sub.2).sub.4CH.sub.3))-
, docosahexaenoic acid
(--(CH.sub.2).sub.3(CHCHCH.sub.2).sub.6CH.sub.3)), eicosapentaenoic
acid (--(CH.sub.2).sub.4(CHCHCH.sub.2).sub.5CH.sub.3)),
alpha-linolenic acid
(--(CH.sub.2).sub.8(CHCHCH.sub.2).sub.3CH.sub.3)) stearidonic acid,
y-linolenic acid, arachidonic acid, docosatetraenoic acid,
palmitoleic acid, vaccenic acid, paullinic acid, oleic acid,
elaidic acid, gondoic acid, euric acid, nervonic acid and mead
acid; [0579] (iii) --C.sub.10-C.sub.30alkylR.sup.5,
--C.sub.10-C.sub.30alkenylR.sup.5,
--C.sub.10-C.sub.30alkynylR.sup.5,
--C.sub.10-C.sub.30alkenylalkynylR.sup.5, --C.sub.10-C.sub.30alkyl,
--C.sub.10-C.sub.30alkenyl, --C.sub.10-C.sub.30alkynyl,
--C.sub.10-C.sub.30alkenylalkynyl; and [0580] (iv) R.sup.50;
[0581] wherein R.sup.100 in Formula VA can only be selected from
(i), (ii), and (iii) above if at least one of R.sup.7 and R.sup.8
is selected to be R.sup.50; and
[0582] wherein all other variables are defined herein.
[0583] In one embodiment, --C.sub.0-C.sub.30 as used in the
definition of R.sup.100 is --C.sub.12-C.sub.28,
--C.sub.12-C.sub.26, --C.sub.12-C.sub.24, --C.sub.14-C.sub.22,
--C.sub.14-C.sub.20, --C.sub.14-C.sub.18, --C.sub.14-C.sub.16, or
--C.sub.12-C.sub.14.
[0584] Non-limiting examples of Formula VA include:
##STR00041##
[0585] The disclosure provides prostaglandin prodrugs of Formula
VIA:
##STR00042##
[0586] or a pharmaceutically acceptable composition, salt, or
isotopic derivative thereof
[0587] wherein all variables are as defined herein.
[0588] Non-limiting examples of Formula VIA include:
##STR00043##
[0589] In one embodiment, R.sup.100 is ethyl and R.sup.103 is
hydrogen.
[0590] In one embodiment, R.sup.50 is
##STR00044##
[0591] The disclosure provides prostaglandin prodrugs of Formula
VIIA:
##STR00045##
[0592] or a pharmaceutically acceptable composition, salt, or
isotopic derivative thereof.
[0593] L.sup.2' is selected from:
##STR00046##
[0594] B is selected from: heterocycle, heterocycloalkyl, aryl,
arylalkyl, heteroaryl, heteroarylalkyl, aryloxy, and alkyloxy
wherein each group can be optionally substituted with another
desired substituent group which is pharmaceutically acceptable and
sufficiently stable under the conditions of use, for example
selected from R.sup.5; and
[0595] R.sup.1, R.sup.2, and R.sup.3 are independently selected
from: --C(O)R.sup.4, C(O)A, and hydrogen,
[0596] wherein in Formula VIIA, R.sup.1 or R.sup.2 is
--C(O)R.sup.4;
[0597] R.sup.124 is selected from: [0598] (i) an unsaturated fatty
acid residue containing at least 22 carbon atoms including but not
limited to the carbon chains from docosahexaenoic acid
(--(CH.sub.2).sub.3(CHCHCH.sub.2).sub.6CH.sub.3)), alpha-linolenic
acid (--(CH.sub.2)s(CHCHCH.sub.2).sub.3CH.sub.3)), docosatetraenoic
acid, and nervonic acid, [0599] (ii)
--C.sub.22-C.sub.30alkylR.sup.5, --C.sub.22-C.sub.30alkenylR.sup.5,
--C.sub.22-C.sub.30alkynylR.sup.5,
--C.sub.22-C.sub.30alkenylalkynylR.sup.5, --C.sub.22-C.sub.30alkyl,
--C.sub.22-C.sub.30alkenyl, --C.sub.22-C.sub.30alkynyl,
--C.sub.22-C.sub.30alkenylalkynyl; and wherein, if desired, each
R.sup.124 can be substituted with R.sup.5; and [0600] wherein all
other variables are defined herein.
[0601] Non-limiting examples of Formula VIIA include:
##STR00047##
[0602] In one embodiment, --C.sub.22-C.sub.30 as used in the
definition of R.sup.4 is --C.sub.22-C.sub.28, --C.sub.22-C.sub.26,
or --C.sub.22-C.sub.24.
[0603] The disclosure provides prostaglandin prodrugs of Formula
VIIIA:
##STR00048##
[0604] or a pharmaceutically acceptable composition, salt, or
isotopic derivative thereof.
[0605] R.sup.111 is selected from: [0606] (i) R.sup.102; [0607]
(ii) --NH--C.sub.2-C.sub.30alkenyl-C(O)R.sup.102,
--NH--C.sub.2-C.sub.30alkynyl-C(O)R.sup.102,
--NH--C.sub.2-C.sub.30alkenylalkynyl-C(O)R.sup.102,
--NH--C.sub.1-C.sub.30alkyl-C(O)R.sup.102,
--O--C.sub.2-C.sub.30alkenyl-C(O)R.sup.102,
--O--C.sub.2-C.sub.30alkynyl-C(O)R.sup.102,
--O--C.sub.2-C.sub.30alkenylalkynyl-C(O)R.sup.102, and
--O--C.sub.1-C.sub.30alkyl-C(O)R.sup.102;
[0607] ##STR00049## [0608] (iv) polyethylene glycol, polypropylene
glycol, polypropylene oxide, polylactic acid, and
poly(lactic-co-glycolic acid) capped with R.sup.102,
##STR00050## ##STR00051## ##STR00052##
[0609] Wherein R.sup.111 can be further substituted with R5 if
valence permits, a stable compound is formed, and the resulting
compound is pharmaceutically acceptable;
[0610] R.sup.102 is
##STR00053##
and
[0611] wherein all other variables are as defined herein.
[0612] In various different embodiments, --C.sub.2-C.sub.30 as used
in the definition of R.sup.111 may be --C.sub.2-C.sub.28,
--C.sub.4-C.sub.26, --C.sub.4-C.sub.24, --C.sub.6-C.sub.22,
--C.sub.6-C.sub.20, --C.sub.8-C.sub.18, --C.sub.8-C.sub.16,
--C.sub.8-C.sub.14, --C.sub.8-C.sub.12, --C.sub.8-C.sub.20, or
--C.sub.6-C.sub.24
[0613] Non-limiting examples of Formula VIIIA include:
##STR00054##
[0614] The disclosure also provides prostaglandin prodrugs of
Formula IXA, Formula XA, Formula XIA, and Formula XIIA:
##STR00055##
[0615] or a pharmaceutically acceptable composition, salt, or
isotopic derivative thereof wherein
[0616] R.sup.310 is alkyl or hydrogen;
[0617] L.sup.7 is selected from:
##STR00056##
[0618] R.sup.208 and R.sup.209 are independently selected from:
--C(O)R.sup.4b, --C(O)A, hydrogen, R.sup.211, and
L.sup.8-R.sup.212;
[0619] R.sup.4b is selected from: [0620] (i)
--C.sub.10-C.sub.30alkylR.sup.5, --C.sub.10-C.sub.30alkenylR.sup.5,
--C.sub.10-C.sub.30alkynylR.sup.5,
--C.sub.10-C.sub.30alkenylalkynylR.sup.5, --C.sub.10-C.sub.30alkyl,
--C.sub.10-C.sub.30alkenyl, --C.sub.10-C.sub.30alkynyl,
--C.sub.10-C.sub.30alkenylalkynyl; [0621] (ii) an unsaturated fatty
acid residue including but not limited to the carbon chains from
linoleic acid
(--(CH.sub.2).sub.8(CH).sub.2CH.sub.2(CH).sub.2(CH.sub.2).sub.4CH.sub.3))-
, docosahexaenoic acid
(--(CH.sub.2).sub.3(CHCHCH.sub.2).sub.6CH.sub.3)), eicosapentaenoic
acid (--(CH.sub.2).sub.4(CHCHCH.sub.2).sub.5CH.sub.3)),
alpha-linolenic acid
(--(CH.sub.2).sub.8(CHCHCH.sub.2).sub.3CH.sub.3)) stearidonic acid,
y-linolenic acid, arachidonic acid, docosatetraenoic acid,
palmitoleic acid, vaccenic acid, paullinic acid, oleic acid,
elaidic acid, gondoic acid, euric acid, nervonic acid or mead acid,
and wherein, if desired, each of which can be substituted with
R.sup.5.
[0622] wherein either at least one of R.sup.208 and R.sup.209 is
R.sup.211 or L.sup.8-R.sup.212; or L.sup.7 is selected from
##STR00057##
[0623] L.sup.8 is --C(O)-alkyl-C(O)--, and
--C(O)-alkenyl-C(O)--;
[0624] R.sup.210 is
##STR00058##
[0625] R.sup.211 is selected from:
[0626] polyethylene glycol, polypropylene glycol, polypropylene
oxide, polylactic acid, a biodegradable polymer and
poly(lactic-co-glycolic acid) each of which is optionally linked by
a carbonyl and each is capped with R.sup.212 including:
##STR00059## ##STR00060##
[0627] R.sup.212 is selected from:
##STR00061## ##STR00062##
and
[0628] wherein all other variables are defined herein.
[0629] In one embodiment R.sup.212 is
##STR00063##
Carbonic Anhydrase Inhibitor Prodrugs
[0630] The disclosure provides carbonic anhydrase inhibitor
prodrugs of Formula IB, Formula IIB, Formula IIIB and Formula
IVB:
##STR00064##
[0631] or a pharmaceutically acceptable composition, salt, or
isotopic derivative thereof wherein
[0632] R.sup.10 is selected from: [0633] (i)
N=C.sub.4-C.sub.30alkenylR.sup.5,
--N.dbd.C.sub.4-C.sub.30alkynylR.sup.5,
--N.dbd.C.sub.4-C.sub.30alkenylalkynylR.sup.5,
--N.dbd.C.sub.1-C.sub.30alkylR.sup.5,
--N.dbd.C.sub.4-C.sub.30alkenyl, --N.dbd.C.sub.4-C.sub.30alkynyl,
--N.dbd.C.sub.4-C.sub.30alkenylalkynyl,
--N.dbd.C.sub.1-C.sub.30alkyl,
--N.dbd.CH--C.sub.3-C.sub.30alkenylR.sup.5,
--N.dbd.CH--C.sub.3-C.sub.30alkynylR.sup.5,
--N.dbd.CH--C.sub.3-C.sub.30alkenylalkynylR.sup.5,
--N.dbd.C.sub.1-C.sub.30alkylR.sup.5,
--N.dbd.CH--C.sub.3-C.sub.30alkenyl,
--N.dbd.CH--C.sub.3-C.sub.30alkynyl,
--N.dbd.CH--C.sub.3-C.sub.30alkenylalkynyl,
--N.dbd.C.sub.1-C.sub.30alkyl, --NHC.sub.3-C.sub.30alkenylR.sup.5,
--NH--C.sub.3-C.sub.30alkynylR.sup.5,
--NH--C.sub.5-C.sub.30alkenylalkynylR.sup.5,
--NHC.sub.0-C.sub.30alkylR.sup.5,
--NHC.sub.3-C.sub.30alkenylR.sup.16,
--NH--C.sub.3-C.sub.30alkynylR.sup.16,
--NH--C.sub.5-C.sub.30alkenylalkynylR.sup.16,
--NHC.sub.0-C.sub.30alkylR.sup.16; [0634] (ii) an imine-, amine- or
amide-linked unsaturated fatty acid residue including but not
limited to derivatives of linoleic acid
(--N.dbd.CH(CH.sub.2).sub.7(CH).sub.2CH.sub.2(CH).sub.2(CH.sub.2).sub.4CH-
.sub.3,
--NHCH.sub.2(CH.sub.2).sub.7(CH).sub.2CH.sub.2(CH).sub.2(CH.sub.2)-
.sub.4CH.sub.3, or --NHC
(O)(CH.sub.2).sub.7(CH).sub.2CH.sub.2(CH).sub.2(CH.sub.2).sub.4CH.sub.3),
docosahexaenoic acid
(--N.dbd.CH(CH.sub.2).sub.2(CHCHCH.sub.2).sub.6CH.sub.3,
--NIH(CH.sub.2).sub.3(CHCHCH.sub.2).sub.6CH.sub.3, or
--NHC(O)(CH.sub.2).sub.2(CHCHCH.sub.2).sub.6CH.sub.3),
eicosapentaenoic acid
(--N.dbd.CH(CH.sub.2).sub.3(CHCHCH.sub.2).sub.5CH.sub.3,
--NH(CH.sub.2).sub.4(CHCHCH.sub.2).sub.5CH.sub.3, or
--NHC(O)(CH.sub.2).sub.3(CHCHCH.sub.2).sub.5CH.sub.3),
alpha-linolenic acid
(--N.dbd.CH(CH.sub.2).sub.7(CHCHCH.sub.2).sub.3CH.sub.3,
--NIH(CH.sub.2).sub.4(CHCHCH.sub.2).sub.5CH.sub.3, or
--NHC(O)(CH.sub.2).sub.3(CHCHCH.sub.2).sub.5CH.sub.3), stearidonic
acid, y-linolenic acid, arachidonic acid, docosatetraenoic acid,
palmitoleic acid, vaccenic acid, paullinic acid, oleic acid,
elaidic acid, gondoic acid, euric acid, nervonic acid or mead acid,
each of which can be further substituted with R.sup.5 (including
for example a second R.sup.5) if valence permits, a stable compound
is formed, and the resulting compound is pharmaceutically
acceptable; [0635] (iii) an imine-, amine- or amide-linked
polypropylene glycol, polypropylene oxide, polylactic acid, or
poly(lactic-co-glycolic acid) including:
##STR00065## ##STR00066##
[0635] or polyglycolic acid, or a polyester, polyamide, or other
biodegradable polymer, each of which can be capped to complete the
terminal valence. In some embodiments, the compound can be capped
with hydrogen, or can be capped to create a terminal ester or
ether. For example, the moiety can be capped with a terminal
hydroxyl or carboxy which can be further derivatized to an ether or
ester. And wherein each of which can be further substituted with
R.sup.5 if valence permits, a stable compound is formed, and the
resulting compound is pharmaceutically acceptable; and wherein in
some embodiments a terminal hydroxy or carboxy group can be
substituted to create an ether or ester, respectively; [0636]
(iv)-NHC(O)C.sub.1-20alkyl, --NHC(O)C.sub.1-20alkenyl,
--NHC(O)C.sub.1-20alkynyl, --NHC(O)(C.sub.1-20alkyl with at least
one R.sup.5 substituent on the alkyl chain),
--NHC(O)(C.sub.1-20alkenyl with at least one R.sup.5 substituent on
the alkenyl chain) --NHC(O)(C.sub.1-20alkynyl with at least one
R.sup.5 substituent on the alkynyl chain), --NH(lactic
acid).sub.2-20C(O)C.sub.1-20alkyl, --NH(lactic
acid).sub.2-10C(O)C.sub.1-20alkyl, --NH(lactic
acid).sub.4-20C(O)C.sub.1-20alkyl, --NH(lactic
acid).sub.2-20C(O)C.sub.1-10alkyl, --NH(lactic
acid).sub.2-20C(O)C.sub.4-10alkyl, --NH(lactic
acid).sub.2-20C(O)OH, --NH(lactic acid).sub.2-10C(O)OH, --NH(lactic
acid).sub.4-20C(O)OH, --NH(lactic acid).sub.2-10C(O)OH, --NH(lactic
acid).sub.4-10C(O)OH,
--NH(lactide-co-glycolide).sub.2-10C(O)C.sub.1-20alkyl,
--NH(lactide-co-glycolide).sub.4-10C(O)C.sub.1-20alkyl,
--NH(lactide-co-glycolide).sub.2-10C(O)C.sub.1-10alkyl,
--NH(lactide-co-glycolide).sub.2-10C(O)C.sub.4-20alkyl,
--NH(glycolic acid).sub.2-10C(O)C.sub.1-10alkyl, --NH(glycolic
acid).sub.4-10C(O)C.sub.1-10alkyl, --NH(lactic
acid).sub.4-10C(O)C.sub.1-10alkyl, --NH(lactic
acid).sub.2-10C(O)C.sub.1-10alkyl, NH(lactic
acid).sub.2-10C(O)C.sub.4-10alkyl, --NH(lactic
acid).sub.2-10C(O)C.sub.4-10alkyl, or --NH(lactic
acid).sub.2-10C(O)C.sub.4-10alkyl;
##STR00067## ##STR00068## ##STR00069##
[0636] and [0637] (vi) NH.sub.2 wherein R.sup.15 is R.sup.16;
[0638] R.sup.620 is selected at each instance from hydrogen, alkyl,
alkenyl, alkynyl cycloalkyl, cycloalkylalkyl, heterocyclyl,
heterocycloalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl,
each of which except hydrogen may be optionally substituted with
R.sup.5 if the resulting compound is stable and achieves the
desired purpose and wherein the group cannot be substituted with
itself, for example alkyl would not be substituted with alkyl;
[0639] R.sup.622 is hydrogen, hydroxy, amino, A, alkyl, alkoxy,
alkenyl, alkynyl cycloalkyl, cycloalkylalkyl, heterocyclyl,
heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
aryloxy, or stearoyl;
[0640] In one embodiment, --C.sub.3-C.sub.30 as used in the
definition of R.sup.10 is --C.sub.3-C.sub.28, --C.sub.3-C.sub.26,
--C.sub.3-C.sub.24, --C.sub.3-C.sub.22, --C.sub.3-C.sub.20,
--C.sub.3-C.sub.18, --C.sub.3-C.sub.16, --C.sub.3-C.sub.14,
--C.sub.3-C.sub.12, --C.sub.5-C.sub.12, --C.sub.7-C.sub.12, or
--C.sub.7-C.sub.10.
[0641] In one embodiment R.sup.10 is selected from
--N.dbd.CH--C.sub.3-C.sub.30alkenylR.sup.5,
--N.dbd.CH--C.sub.3-C.sub.30alkynylR.sup.5,
--N.dbd.CH--C.sub.3-C.sub.30alkenylalkynylR.sup.5,
--N.dbd.C.sub.1-C.sub.30alkylR.sup.5,
--N.dbd.CH--C.sub.3-C.sub.30alkenyl,
--N.dbd.CH--C.sub.3-C.sub.30alkynyl,
--N.dbd.CH--C.sub.3-C.sub.30alkenylalkynyl,
--N.dbd.C.sub.1-C.sub.30alkyl;
[0642] In one embodiment, R.sup.10 is selected from
##STR00070##
and R.sup.15 is hydrogen.
[0643] In one embodiment of Formula IIB, R.sup.10 is
##STR00071##
x is an integer selected from 1, 2, 3, 4, 5, 6, 7, or 8, and
R.sup.15 is hydrogen. In a further embodiment, x is 2, 4, or 6.
[0644] In one embodiment of Formula IIB, R.sup.10 is selected from
--NH(lactide-co-glycolide).sub.2-10C(O)C.sub.1-20alkyl,
--NH(lactide-co-glycolide).sub.4-10C(O)C.sub.1-20alkyl,
--NH(lactide-co-glycolide).sub.2-10C(O)C.sub.1-10alkyl, and
--NH(lactide-co-glycolide).sub.2-10C(O)C.sub.4-20alkyl and R.sup.15
is hydrogen.
[0645] Non-limiting examples of R.sup.10 include:
##STR00072## ##STR00073## ##STR00074## ##STR00075##
##STR00076##
wherein all other variables are as defined herein. Non-limiting
Examples of Formula IIB include
##STR00077## ##STR00078## ##STR00079##
[0646] In one embodiment, the compound of Formula IIB is
##STR00080##
[0647] The disclosure provides carbonic anhydrase inhibitor
prodrugs of Formula VB, Formula VIB, and Formula VIIB:
##STR00081##
or a pharmaceutically acceptable composition, salt, or isotopic
derivative thereof wherein
[0648] R.sup.118 is selected from: [0649] (i)
--C(O)C.sub.5-C.sub.30alkylR.sup.5,
--C(O)C.sub.2-C.sub.30alkenylR.sup.5,
--C(O)C.sub.2-C.sub.30alkynylR.sup.5,
--C(O)C.sub.4-C.sub.30alkenylalkynylR.sup.5,
--C(O)C.sub.5-C.sub.30alkyl, --C(O)C.sub.2-C.sub.30alkenyl,
--C(O)C.sub.2-C.sub.30alkynyl, and
--C(O)C.sub.4-C.sub.30alkenylalkynyl; [0650] (ii)
--C(O)(C.sub.1-30alkyl with at least one R.sup.5 substituent on the
alkyl chain), --C(O)(C.sub.1-30alkenyl with at least one R.sup.5
substituent on the alkenyl chain), --C(O)(C.sub.1-30alkynyl with at
least one R.sup.5 substituent on the alkynyl chain), -(lactic
acid).sub.1-20C(O)C.sub.1-30alkyl, -(lactic
acid).sub.1-10C(O)C.sub.1-30alkyl, -(lactic
acid).sub.4-20C(O)C.sub.1-30alkyl, -(lactic
acid).sub.1-20C(O)C.sub.1-10alkyl, -(lactic
acid).sub.1-20C(O)C.sub.4-10alkyl, -(lactic acid).sub.1-20C(O)OH,
-(lactic acid).sub.1-10C(O)OH, -(lactic acid).sub.4-20C(O)OH,
-(lactic acid).sub.1-10C(O)OH, -(lactic acid).sub.4-10C(O)OH,
-(lactide-co-glycolide).sub.1-10C(O)C.sub.1-30alkyl,
-(lactide-co-glycolide).sub.4-10C(O)C.sub.1-30alkyl,
-(lactide-co-glycolide).sub.1-10C(O)C.sub.1-12alkyl,
-(lactide-co-glycolide).sub.1-10C(O)C.sub.4-22alkyl, -(glycolic
acid).sub.1-10C(O)C.sub.1-10alkyl, -(glycolic
acid).sub.4-10C(O)C.sub.1-10alkyl, -(lactic
acid).sub.4-10C(O)C.sub.1-10alkyl, -(lactic
acid).sub.1-10C(O)C.sub.1-10alkyl, -(lactic
acid).sub.1-10C(O)C.sub.4-10alkyl, -(lactic
acid).sub.1-10C(O)C.sub.4-10alkyl, and -(lactic
acid).sub.1-10C(O)C.sub.4-10alkyl; [0651] (iii) an unsaturated
fatty acid residue including but not limited to the carbonyl
fragment taken from linoleic acid
(--(CH.sub.2)s(CH).sub.2CH.sub.2(CH).sub.2(CH.sub.2).sub.4CH.sub.3)),
docosahexaenoic acid
(--(CH.sub.2).sub.3(CHCHCH.sub.2).sub.6CH.sub.3)), eicosapentaenoic
acid (--(CH.sub.2).sub.4(CHCHCH.sub.2).sub.5CH.sub.3)),
alpha-linolenic acid (--(CH.sub.2)s(CHCHCH.sub.2).sub.3CH.sub.3)),
stearidonic acid, y-linolenic acid, arachidonic acid,
docosatetraenoic acid, palmitoleic acid, vaccenic acid, paullinic
acid, oleic acid, elaidic acid, gondoic acid, euric acid, nervonic
acid and mead acid, each of which can be further optionally further
substituted with R.sup.5 (including for example a second R.sup.5)
if valence permits, a stable compound is formed, and the resulting
compound is pharmaceutically acceptable; [0652] (iv) polyethylene
glycol, polypropylene glycol, polypropylene oxide, polylactic acid,
poly(lactic-co-glycolic acid), polyglycolic acid, polyester,
polyamide, and other biodegradable polymers, each of which can be
capped to complete the terminal valence or to create a terminal
ether or ester; [0653] (v)
[0653] ##STR00082## [0654] (vi)
--(C(O)CH.sub.2O).sub.1-20C(O)C.sub.1-30alkyl,
--(C(O)CH(CH.sub.3)O).sub.1-20C(O)C.sub.1-30alkyl,
--(C(O)CH.sub.2O).sub.1-10C(O)C.sub.1-30alkyl,
--(C(O)CH(CH.sub.3)O).sub.1-10C(O)C.sub.1-30alkyl,
--(C(O)CH.sub.2O).sub.4-20C(O)C.sub.1-30alkyl,
--(C(O)CH(CH.sub.3)O).sub.4-20C(O)C.sub.1-30alkyl,
--(C(O)CH.sub.2O).sub.1-20C(O)C.sub.1-10alkyl,
--(C(O)CH(CH.sub.3)O).sub.1-20C(O)C.sub.1-10alkyl,
--(C(O)CH.sub.2O).sub.1-20C(O)C.sub.4-10alkyl,
--(C(O)CH(CH.sub.3)O).sub.1-20C(O)C.sub.4-10alkyl,
--(C(O)CH(CH.sub.3)O).sub.4-10C(O)C.sub.1-10alkyl,
--(C(O)CH.sub.2O).sub.4-10C(O)C.sub.1-10alkyl,
--(C(O)CH(CH.sub.3)O).sub.1-10C(O)C.sub.1-10alkyl,
--(C(O)CH.sub.2O).sub.1-10C(O)C.sub.1-10alkyl,
--(C(O)CH(CH.sub.3)O).sub.1-10C(O)C.sub.4-10alkyl,
(C(O)CH.sub.2O).sub.1-10C(O)C.sub.4-10alkyl,
--(C(O)CH.sub.2O).sub.1-10C(O)C.sub.4-10alkyl,
--(C(O)CH(CH.sub.3)O).sub.1-10C(O)C.sub.4-10alkyl,
--(C(O)CH.sub.2O).sub.1-10C(O)C.sub.4-10alkyl,
--(C(O)CH(CH.sub.3)O).sub.1-10C(O)C.sub.4-10alkyl,
--(C(O)CH.sub.2O).sub.1-10(C(O)CH(CH.sub.3)O).sub.1-10C(O)C.sub.1-30alkyl-
,
--(C(O)CH.sub.2O).sub.2-10(C(O)CH(CH.sub.3)O).sub.2-10C(O)C.sub.1-30alky-
l,
--(C(O)CH.sub.2O).sub.1-10(C(O)CH(CH.sub.3)O).sub.1-10C(O)C.sub.1-12alk-
yl,
--(C(O)CH.sub.2O).sub.1-10(C(O)CH(CH.sub.3)O).sub.1-10C(O)C.sub.4-22al-
kyl,
--(C(O)CH(CH.sub.3)O).sub.1-10(C(O)CH.sub.2O).sub.1-10C(O)C.sub.1-30a-
lkyl,
--(C(O)CH(CH.sub.3)O).sub.2-10(C(O)CH.sub.2O).sub.2-10C(O)C.sub.1-30-
alkyl,
--(C(O)CH(CH.sub.3)O).sub.1-10(C(O)CH.sub.2O).sub.1-10C(O)C.sub.1-1-
2alkyl, and
--(C(O)CH(CH.sub.3)O).sub.1-10(C(O)CH.sub.2O).sub.1-10C(O)C.sub.4-22alkyl-
; and
[0655] wherein all other variables are as defined herein.
[0656] In various different embodiments, --C.sub.10-C.sub.30 as
used in the definition of R.sup.118 is --C.sub.10-C.sub.18,
--C.sub.10-C.sub.16, --C.sub.10-C.sub.14, --C.sub.10-C.sub.12,
--C.sub.19-C.sub.28, --C.sub.19-C.sub.26, --C.sub.19-C.sub.24,
--C.sub.19-C.sub.22, --C.sub.19-C.sub.20, --C.sub.20-C.sub.28,
--C.sub.20-C.sub.26, --C.sub.20-C.sub.24, --C.sub.20-C.sub.22,
--C.sub.22-C.sub.28, --C.sub.22-C.sub.26, --C.sub.22-C.sub.24, or
--C.sub.26-C.sub.28.
[0657] Non-limiting examples of Formula VB include:
##STR00083##
Compounds of Formula VIIB are drawn as
##STR00084##
where the bond between the aromatic ring and the imidazole ring is
drawn as a wavy line. In one embodiment, compounds of Formula VIIB
are the Z isomer. In one embodiment, compounds of Formula VIIB are
the E isomer. For example, in one embodiment,
##STR00085##
is the Z isomer:
##STR00086##
and in an alternative embodiment, is the E isomer:
##STR00087##
[0658] The disclosure provides carbonic anhydrase inhibitor
prodrugs of Formula VIIIB and Formula IXB:
##STR00088##
[0659] or a pharmaceutically acceptable composition, salt, or
isotopic derivative thereof wherein
[0660] wherein R.sup.323 is independently selected from
polyethylene glycol, polypropylene glycol, polypropylene oxide,
polylactic acid, poly(lactic-co-glycolic acid), polyglycolic acid,
polyester, polyamide,
##STR00089## ##STR00090##
[0661] In certain embodiments of Formula VIIIB or Formula IXB,
R.sup.323 is
##STR00091##
and R.sup.31a is --C(O)alkyl.
[0662] In certain embodiments of Formula VIIIB or Formula IXB,
R.sup.323 is
##STR00092##
and R.sup.31a is --C(O)alkyl.
##STR00093##
[0664] In certain embodiments of Formula VIIIB or Formula IXB,
R.sup.323 is O 4 and R.sup.31a is --C(O)alkyl.
[0665] Non-limiting Examples of Formula VIIIB include
##STR00094##
Compounds of Formula VIIIB are drawn as
##STR00095##
where the bond between the aromatic ring and the imidazole ring is
drawn as a wavy line. In one embodiment, compounds of Formula VIIIB
are the Z isomer. In one embodiment, compounds of Formula VIIIB are
the E isomer.
[0666] The disclosure provides carbonic anhydrase inhibitor
prodrugs of Formula XB, Formula XIB, Formula XIIB, Formula XIIIB,
Formula XIVB, and Formula XVB:
##STR00096##
[0667] or a pharmaceutically acceptable composition, salt, or
isotopic derivative thereof wherein
[0668] R.sup.119 is selected from: acyl, R.sup.120, polyethylene
glycol, polypropylene glycol, polypropylene oxide, polylactic acid,
poly(lactic-co-glycolic acid), a polyglycolic acid, a polyester,
polyamide, or other biodegradable polymer, wherein each R.sup.119
other than R.sup.120 is substituted with at least one
L.sup.4-R.sup.121.
[0669] R.sup.120 is selected from:
##STR00097## ##STR00098## ##STR00099## ##STR00100##
##STR00101##
R.sup.121 is selected from:
##STR00102## ##STR00103## ##STR00104## ##STR00105## ##STR00106##
##STR00107## ##STR00108## ##STR00109## ##STR00110## ##STR00111##
##STR00112## ##STR00113## ##STR00114## ##STR00115##
[0670] Q is selected from: N, CH, and CR.sup.23;
[0671] R.sup.23, R.sup.24, and R.sup.25 are independently selected
from: hydrogen, halogen, hydroxyl, cyano, mercapto, nitro, amino,
aryl, alkyl, alkoxy, alkenyl, alkynyl cycloalkyl, cycloalkylalkyl,
heterocyclyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, aryloxy, --S(O).sub.2alkyl, --S(O)alkyl,
--P(O)(Oalkyl).sub.2, B(OH).sub.2, --Si(CH.sub.3).sub.3, --COOH,
--COOalkyl, --CONH.sub.2,
##STR00116##
each of which except halogen, nitro, and cyano, may be optionally
substituted, for example with halogen, alkyl, aryl, heterocycle or
heteroaryl.
[0672] R.sup.26 is selected from H, C(O)A,
--C.sub.0-C.sub.10alkylR.sup.5, --C.sub.2-C.sub.10alkenylR.sup.5,
--C.sub.2-C.sub.10alkynylR.sup.5, --C.sub.2-C.sub.10alkenyl, and
--C.sub.2-C.sub.10alkynyl.
[0673] R.sup.141 is selected from hydrogen,
--C(O)NR.sup.161R.sup.162, --C(O)R.sup.161, --C(O)OR.sup.161,
nitro, amino, --NR.sup.134R.sup.135, alkyl, alkoxy, alkylalkoxy,
alkoxyalkoxy, haloalkoxy, cycloalkyl, heterocycloalkyl, heteroaryl,
aryl, and halogen;
[0674] R.sup.134 and R.sup.135 are independently selected from H,
alkyl, --SO.sub.2CH.sub.3, --C(O)CH.sub.3, and --C(O)NH.sup.2;
[0675] R.sup.161 and R.sup.162 are independently selected from
hydrogen, aryl, alkyl, cycloalkyl, arylalkyl, heteroaryl,
heteroarylalkyl, and heterocyclyl;
[0676] R.sup.301 is selected from hydrogen,
--C(O)NR.sup.161R.sup.162, --C(O)R.sup.161, --C(O)OR.sup.161,
nitro, amino, --NR.sup.134R.sup.135, alkyl, alkoxy, alkylalkoxy,
alkoxyalkoxy, haloalkoxy, cycloalkyl, heterocycloalkyl, heteroaryl,
aryl, halogen, --O(CH.sub.2).sub.2NR.sup.134R.sup.135, and
--N(CH.sub.3)(CH.sub.2).sub.2NR.sup.134R.sup.135;
[0677] or R.sup.134 and R.sup.135 can together form a
heterocycloalkyl;
[0678] R.sup.180 is C.sub.1-C.sub.6 alkyl, acyl, or hydrogen;
[0679] R.sup.191 is selected from:
##STR00117##
and R.sup.195;
[0680] t is independently selected from 0, 1, 2, 3, and 4;
[0681] R.sup.192 is independently selected from alkyl, cycloalkyl,
aryl, heteroaryl, heterocycle, cyano, amino, hydroxyl, and acyl,
each of which R.sup.192 is optionally substituted with a R.sup.175
group;
[0682] R.sup.193 is independently selected from alkyl, cycloalkyl,
aryl, heteroaryl, heterocycle, amino, hydroxyl, and acyl;
[0683] or two R.sup.193 groups with the carbon to which they are
linked form a carbonyl group;
[0684] or two R.sup.193 groups with the carbon(s) to which they are
linked form a fused or spirocyclic ring;
[0685] R.sup.194 is selected from alkyl, cycloalkyl, R.sup.175, and
acyl; and
[0686] R.sup.195 is selected from aryl, heteroaryl, cycloalkyl, and
heterocycle, wherein each R.sup.195 is optionally substituted with
1, 2, 3, or 4 R.sup.192 groups;
[0687] R.sup.175 is selected from: C(O)A, C(O)R.sup.4, and
R.sup.178;
[0688] R.sup.178 is selected from: [0689] (i) carbonyl linked
polyethylene glycol, carbonyl linked polypropylene glycol, carbonyl
linked polypropylene oxide, polylactic acid,
poly(lactic-co-glycolic acid), polyglycolic acid, polyester,
polyamide,
##STR00118##
[0689] and other biodegradable polymers, wherein each R.sup.178 is
optionally substituted with R.sup.31a or R.sup.311, and wherein
each of R.sup.178 with a terminal hydroxy or carboxy group can be
substituted to create an ether or ester; [0690] (ii) -(lactic
acid).sub.1-20C(O)C.sub.1-22alkyl, -(lactic
acid).sub.1-10C(O)C.sub.1-22alkyl, -(lactic acid).sub.4-20
C(O)C.sub.1-22alkyl, -(lactic acid).sub.1-20C(O)C.sub.1-10alkyl,
-(lactic acid).sub.1-20C(O).sub.C4-10alkyl, -(lactic
acid).sub.1-20C(O)OH, -(lactic acid).sub.1-10C(O)OH, -(lactic
acid).sub.4-20C(O)OH, -(lactic acid).sub.1-10C(O)OH, -(lactic
acid).sub.4-10C(O)OH,
-(lactide-co-glycolide).sub.1-10C(O)C.sub.1-22alkyl,
-(lactide-co-glycolide).sub.4-10C(O)C.sub.1-22alkyl,
-(lactide-co-glycolide).sub.1-10C(O)C.sub.1-12alkyl,
-(lactide-co-glycolide).sub.1-10C(O)C.sub.4-22alkyl, -(glycolic
acid).sub.1-10C(O)C.sub.1-10alkyl, -(glycolic
acid).sub.4-10C(O)C.sub.1-10alkyl, -(lactic
acid).sub.4-10C(O)C.sub.1-10alkyl, -(lactic
acid).sub.1-10C(O)C.sub.1-10alkyl, -(lactic
acid).sub.1-10C(O)C.sub.4-10alkyl, -(lactic
acid).sub.1-10C(O)C.sub.4-10alkyl, or -(lactic
acid).sub.1-10C(O)C.sub.4-10alkyl; [0691] (iii)
--(C(O)CH.sub.2O).sub.1-20C(O)C.sub.1-30alkyl,
--(C(O)CH(CH.sub.3)O).sub.1-20C(O)C.sub.1-30alkyl,
--(C(O)CH.sub.2O).sub.1-10C(O)C.sub.1-30alkyl,
--(C(O)CH(CH.sub.3)O).sub.1-10C(O)C.sub.1-30alkyl,
--(C(O)CH.sub.2O).sub.4-20C(O)C.sub.1-30alkyl,
--(C(O)CH(CH.sub.3)O).sub.4-20C(O)C.sub.1-30alkyl,
--(C(O)CH.sub.2O).sub.1-20C(O)C.sub.1-10alkyl,
--(C(O)CH(CH.sub.3)O).sub.1-20C(O)C.sub.1-10alkyl,
--(C(O)CH.sub.2O).sub.1-20C(O)C.sub.4-10alkyl,
--(C(O)CH(CH.sub.3)O).sub.1-20C(O)C.sub.4-10alkyl,
--(C(O)CH(CH.sub.3)O).sub.4-10C(O)C.sub.1-10alkyl,
--(C(O)CH.sub.2O).sub.4-10C(O)C.sub.1-10alkyl,
--(C(O)CH(CH.sub.3)O).sub.1-10C(O)C.sub.1-10alkyl,
--(C(O)CH.sub.2O).sub.1-10C(O)C.sub.1-10alkyl,
--(C(O)CH(CH.sub.3)O).sub.1-10C(O)C.sub.4-10alkyl,
(C(O)CH.sub.2O).sub.1-10C(O)C.sub.4-10alkyl,
--(C(O)CH.sub.2O).sub.1-10C(O)C.sub.4-10alkyl,
--(C(O)CH(CH.sub.3)O).sub.1-10C(O)C.sub.4-10alkyl,
--(C(O)CH.sub.2O).sub.1-10C(O)C.sub.4-10alkyl,
--(C(O)CH(CH.sub.3)O).sub.1-10C(O)C.sub.4-10alkyl,
--(C(O)CH.sub.2O).sub.1-10(C(O)CH(CH.sub.3)O).sub.1-10C(O)C.sub.1-30alkyl-
,
--(C(O)CH.sub.2O).sub.2-10(C(O)CH(CH.sub.3)O).sub.2-10C(O)C.sub.1-30alky-
l,
--(C(O)CH.sub.2O).sub.1-10(C(O)CH(CH.sub.3)O).sub.1-10C(O)C.sub.1-12alk-
yl,
--(C(O)CH.sub.2O).sub.1-10(C(O)CH(CH.sub.3)O).sub.1-10C(O)C.sub.4-22al-
kyl,
--(C(O)CH(CH.sub.3)O).sub.1-10(C(O)CH.sub.2O).sub.1-10C(O)C.sub.1-30a-
lkyl,
--(C(O)CH(CH.sub.3)O).sub.2-10(C(O)CH.sub.2O).sub.2-10C(O)C.sub.1-30-
alkyl,
--(C(O)CH(CH.sub.3)O).sub.1-10(C(O)CH.sub.2O).sub.1-10C(O)C.sub.1-1-
2alkyl, and
--(C(O)CH(CH.sub.3)O).sub.1-10(C(O)CH.sub.2O).sub.1-10C(O)C.sub.4-22alkyl-
;
##STR00119## ##STR00120## ##STR00121## ##STR00122##
[0692] R.sup.615 and R.sup.616 are independently selected from:
--C(O)R.sup.618, C(O)A, and hydrogen, each of which except hydrogen
can be optionally substituted with R.sup.5;
[0693] R.sup.617 is selected from: [0694] (i) polyethylene glycol,
polypropylene glycol, polypropylene oxide, polylactic acid, and
poly(lactic-co-glycolic acid), polyglycolic acid, or a polyester, a
polyamide, or other biodegradable polymers, wherein a terminal
hydroxy or carboxy group can be substituted to create an ether or
ester, respectively; [0695] (ii) --C.sub.10-C.sub.30alkylR.sup.5,
--C.sub.10-C.sub.30alkenylR.sup.5,
--C.sub.10-C.sub.30alkynylR.sup.5,
--C.sub.10-C.sub.30alkenylalkynylR.sup.5, --C.sub.10-C.sub.30alkyl,
--C.sub.10-C.sub.30alkenyl, --C.sub.10-C.sub.30alkynyl,
--C.sub.10-C.sub.30alkenylalkynyl; [0696] (iii) an unsaturated
fatty acid residue including but not limited the carbon fragment
taken from linoleic acid
(--(CH.sub.2).sub.8(CH).sub.2CH.sub.2(CH).sub.2(CH.sub.2).sub.4CH.su-
b.3)), docosahexaenoic acid
(--(CH.sub.2).sub.3(CHCHCH.sub.2).sub.6CH.sub.3)), eicosapentaenoic
acid (--(CH.sub.2).sub.4(CHCHCH.sub.2).sub.5CH.sub.3)),
alpha-linolenic acid
(--(CH.sub.2).sub.8(CHCHCH.sub.2).sub.3CH.sub.3)) stearidonic acid,
y-linolenic acid, arachidonic acid, docosatetraenoic acid,
palmitoleic acid, vaccenic acid, paullinic acid, oleic acid,
elaidic acid, gondoic acid, euric acid, nervonic acid or mead acid;
and [0697] (iv) alkyl, cycloalkyl, cycloalkylalkyl, heterocycle,
heterocycloalkyl, arylalkyl, heteroarylalkyl;
[0698] R.sup.618 is selected from: [0699] (iii)
--C.sub.10-C.sub.30alkylR.sup.5, --C.sub.10-C.sub.30alkenylR.sup.5,
--C.sub.10-C.sub.30alkynylR.sup.5,
--C.sub.10-C.sub.30alkenylalkynylR.sup.5, --C.sub.10-C.sub.30alkyl,
--C.sub.10-C.sub.30alkenyl, --C.sub.10-C.sub.30alkynyl,
--C.sub.10-C.sub.30alkenylalkynyl; and [0700] (iv) an unsaturated
fatty acid residue including but not limited to the carbon chains
from linoleic acid
(--(CH.sub.2).sub.8(CH).sub.2CH.sub.2(CH).sub.2(CH.sub.2).sub.4CH.su-
b.3)), docosahexaenoic acid
(--(CH.sub.2).sub.3(CHCHCH.sub.2).sub.6CH.sub.3)), eicosapentaenoic
acid (--(CH.sub.2).sub.4(CHCHCH.sub.2).sub.5CH.sub.3)),
alpha-linolenic acid
(--(CH.sub.2).sub.8(CHCHCH.sub.2).sub.3CH.sub.3)), stearidonic
acid, y-linolenic acid, arachidonic acid, docosatetraenoic acid,
palmitoleic acid, vaccenic acid, paullinic acid, oleic acid,
elaidic acid, gondoic acid, euric acid, nervonic acid and mead
acid, and wherein, if desired, each of which can be substituted
with R.sup.5;
[0701] R.sup.636 is selected from C(O)A,
##STR00123##
[0702] R.sup.637 is selected from hydrogen, --C(O)A, --C(O)alkyl,
aryl, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,
heterocycloalkyl, arylalkyl, heteroaryl, and heteroarylalkyl;
and
[0703] L.sup.33 is selected from: bond,
--OC.sub.1-C.sub.30alkyl-O--, --NHC.sub.1-C.sub.30alkyl-O--,
N(alkyl)C.sub.1-C.sub.30alkyl-O--, --NHC.sub.1-C.sub.30alkyl-NH-,
N(alkyl)C.sub.1-C.sub.30alkyl-NH-,
--NHC.sub.1-C.sub.30alkyl-N(alkyl)-,
--N(alkyl)C.sub.1-C.sub.30alkyl-N-(alkyl)-,
--OC.sub.1-C.sub.30alkenyl-O--, --NHC.sub.1-C.sub.30alkenyl-O--,
N(alkyl)C.sub.1-C.sub.30alkenyl-O--,
--NHC.sub.1-C.sub.30alkenyl-NH-,
N(alkyl)C.sub.1-C.sub.30alkenyl-NH-,
--NHC.sub.1-C.sub.30alkenyl-N(alkyl)-,
--N(alkyl)C.sub.1-C.sub.30alkenyl-N-(alkyl)-,
--OC.sub.1-C.sub.30alkynyl-O--, --NHC.sub.1-C.sub.30alkynyl-O--,
N(alkyl)C.sub.1-C.sub.30alkynyl-O--,
--NHC.sub.1-C.sub.30alkynyl-NH-,
N(alkyl)C.sub.1-C.sub.30alkynyl-NH-,
--NHC.sub.1-C.sub.30alkynyl-N(alkyl)-, and
--N(alkyl)C.sub.1-C.sub.30alkynyl-N-(alkyl)-; and
[0704] wherein all other variables are as defined herein.
[0705] The disclosure provides carbonic anhydrase inhibitor
prodrugs of Formula XVIB, Formula XVIIB, and Formula XVIIIB:
##STR00124##
[0706] or a pharmaceutically acceptable composition, salt, or
isotopic derivative thereof wherein
[0707] R.sup.116 is selected from: R.sup.117, alkyl, alkyloxy,
acyl, polyethylene glycol, polypropylene glycol, polypropylene
oxide, polylactic acid, poly(lactic-co-glycolic acid), a
polyglycolic acid, a polyester, polyamide, or other biodegradable
polymer, wherein each R.sup.116 other than R.sup.117 is substituted
with at least one L.sup.4-R.sup.121;
[0708] wherein R.sup.116 can be further substituted with R.sup.5 if
valence permits, a stable compound is formed, and the resulting
compound is pharmaceutically acceptable.
[0709] R.sup.117 is selected from:
##STR00125## ##STR00126## ##STR00127##
and
[0710] wherein all other variables are as defined herein.
[0711] The disclosure provides carbonic anhydrase inhibitor
prodrugs of Formula XIXB:
##STR00128##
[0712] or a pharmaceutically acceptable composition, salt, or
isotopic derivative thereof wherein
[0713] R.sup.341a and R.sup.341b are independently selected from
hydrogen and alkyl.
[0714] In one embodiment of Formula XIXB, R.sup.341a and R.sup.341b
are hydrogen.
[0715] In one embodiment of Formula XIXB, R.sup.341a is hydrogen
and R.sup.341b is methyl.
[0716] In one embodiment of Formula XIXB, R.sup.341a is methyl and
R.sup.341b is hydrogen.
[0717] In one embodiment of Formula XIXB is the malic salt.
[0718] In one embodiment of Formula XIXB is the maleate salt.
Sunitinib Prodrugs
[0719] The disclosure provides Sunitinib prodrugs of Formula IC and
Formula IIC:
##STR00129##
[0720] or a pharmaceutically acceptable composition, salt, or
isotopic derivative thereof. This structure is related to Sunitinib
(marketed in the form of the (-)-malic acid salt as SUTENT.RTM. by
Pfizer, and previously known as SU11248), which is an oral,
small-molecule, multi-targeted receptor tyrosine kinase (RTK)
inhibitor that was approved by the FDA for the treatment of renal
cell carcinoma (RCC) and imatinib-resistant gastrointestinal
stromal tumor (GIST) on Jan. 26, 2006. Sunitinib was the first
cancer drug simultaneously approved for two different indications.
Sunitinib inhibits cellular signaling by targeting multiple
receptor tyrosine kinases (RTKs).These include all receptors for
platelet-derived growth factor (PDGF-Rs) and vascular endothelial
growth factor receptors (VEGFRs), which play a role in both tumor
angiogenesis and tumor cell proliferation. The simultaneous
inhibition of these targets leads to both reduced tumor
vascularization and cancer cell death, and, ultimately, tumor
shrinkage. Sunitinib and derivatives thereof are described in U.S.
Pat. Nos. 7,211,600; 6,573,293; and 7,125,905.
[0721] R.sup.30 is selected from: [0722] (i) polyethylene glycol,
polypropylene glycol, polypropylene oxide, polylactic acid,
poly(lactic-co-glycolic acid), a polyglycolic acid, a polyester,
and a polyamide
##STR00130##
[0722] wherein R.sup.30 is optionally substituted with R.sup.31,
and wherein each R.sup.30 with a terminal hydroxy or carboxy group
can be substituted to create an ether or ester, respectively;
##STR00131## ##STR00132## ##STR00133## ##STR00134##
and
[0723] wherein all other variables are defined herein.
[0724] The disclosure provides Sunitinib prodrugs of Formula
IIIC:
##STR00135##
[0725] or a pharmaceutically acceptable composition, salt, or
isotopic derivative thereof wherein
[0726] L.sup.10 is --O--, --NH--, or --N(alkyl)-;
[0727] R.sup.314 is an unsaturated fatty acid residue including but
not limited to the carbon chains from linoleic acid
(--(CH.sub.2).sub.8(CH).sub.2CH.sub.2(CH).sub.2(CH.sub.2).sub.4CH.sub.3))-
, docosahexaenoic acid
(--(CH.sub.2).sub.3(CHCHCH.sub.2).sub.6CH.sub.3)), eicosapentaenoic
acid (--(CH.sub.2).sub.4(CHCHCH.sub.2).sub.5CH.sub.3)),
alphalinolenic acid
(--(CH.sub.2).sub.8(CHCHCH.sub.2).sub.3CH.sub.3)), stearidonic
acid, y-linolenic acid, arachidonic acid, docosatetraenoic acid,
palmitoleic acid, vaccenic acid, paullinic acid, oleic acid,
elaidic acid, gondoic acid, euric acid, nervonic acid and mead
acid, and wherein, if desired, each of which can be substituted
with R.sup.5; and
[0728] R.sup.5 is defined above.
[0729] In one embodiment, R.sup.314 is
##STR00136##
[0730] The disclosure provides Sunitinib prodrugs of Formula
IVC:
##STR00137##
[0731] or a pharmaceutically acceptable composition, salt, or
isotopic derivative thereof wherein
[0732] R.sup.121 is as defined herein.
[0733] The disclosure provides Sunitinib prodrugs of Formula
VIC:
##STR00138##
[0734] or a pharmaceutically acceptable composition, salt, or
isotopic derivative thereof wherein
[0735] R.sup.32 is selected from: R.sup.35, R.sup.121, alkyl,
alkyloxy, polyethylene glycol, polypropylene glycol, polypropylene
oxide, polylactic acid, poly(lactic-co-glycolic acid), a
polyglycolic acid, a polyester, polyamide, or other biodegradable
polymer, wherein each R.sup.32 other than R.sup.35 and R.sup.121 is
substituted with at least one L.sup.4-R.sup.121;
[0736] wherein R.sup.32 can be further substituted with R.sup.5 if
valence permits, a stable compound is formed, and the resulting
compound is pharmaceutically acceptable.
[0737] R.sup.35 is selected from:
##STR00139## ##STR00140## ##STR00141##
[0738] wherein all other variables are as defined herein.
[0739] In one embodiment, R.sup.35 is selected from
##STR00142##
and R.sup.121 is
##STR00143##
[0740] and R.sup.15 is hydrogen.
[0741] In a further embodiment, x and y are independently selected
from 1, 2, 3, 4, 5, and 6.
[0742] In one embodiment, R.sup.35 is
##STR00144##
R.sup.121
##STR00145##
[0743] and R.sup.15 is hydrogen.
[0744] Non-limiting examples of Formula VC include
##STR00146## ##STR00147##
[0745] The disclosure provides Sunitinib prodrugs of Formula
VIC:
##STR00148##
[0746] or a pharmaceutically acceptable composition, salt, or
isotopic derivative thereof wherein
[0747] L.sup.6 is selected from --O--, --NH--, --N(alkyl).sub.1-4-,
--C(O)O--, --S--, --C(O)-- and --OC(O)--;
[0748] R.sup.37 is selected from: R.sup.121, polyethylene glycol,
polypropylene glycol, polypropylene oxide, polylactic acid,
poly(lactic-co-glycolic acid), a polyglycolic acid, a polyester, a
polyamide, or other biodegradable polymer, wherein each R.sup.37
other than R.sup.38 and R.sup.121 is substituted with at least one
L.sup.6-R.sup.121;
[0749] R.sup.38 is selected from:
##STR00149## ##STR00150##
and
[0750] wherein all other variables are as defined herein.
Timolol Prodrugs
[0751] The disclosure provides Timolol prodrugs of Formula ID:
##STR00151##
or a pharmaceutically acceptable composition, salt, or isotopic
derivative thereof wherein R.sup.33 is selected from: [0752] (i)
carbonyl linked polyethylene glycol, carbonyl linked polypropylene
glycol, carbonyl linked polypropylene oxide, polylactic acid,
poly(lactic-co-glycolic acid), a polyglycolic acid, a polyester,
and a polyamide;
##STR00152## ##STR00153##
[0752] or other biodegradable polymer, wherein each R.sup.33 is
optionally substituted with R.sup.31a or R.sup.311, and wherein
each of R.sup.33 with a terminal hydroxy or carboxy group can be
substituted to create an ether or ester, respectively; and [0753]
(iii) --C(O)C.sub.17-30alkyl, --C(O)C.sub.10-30alkenyl,
--C(O)C.sub.10-30alkynyl, --C(O)(C.sub.10-30alkyl with at least one
R.sup.5 substituent on the alkyl chain), --C(O)(C.sub.10-30alkenyl,
with at least one R.sup.5 substituent on the alkenyl chain), and
--C(O)(C.sub.10-30alkynyl, with at least one R.sup.5 substituent on
the alkynyl chain); [0754] (iv)-(lactic
acid).sub.1-20C(O)C.sub.1-30alkyl, -(lactic
acid).sub.1-10C(O)C.sub.1-30alkyl, -(lactic
acid).sub.4-20C(O)C.sub.1-30alkyl, -(lactic
acid).sub.1-20C(O)C.sub.1-10alkyl, -(lactic
acid).sub.1-20C(O)C.sub.4-10alkyl, -(lactic acid).sub.1-20C(O)OH,
-(lactic acid).sub.1-10C(O)OH, -(lactic acid).sub.4-20C(O)OH,
-(lactic acid).sub.1-10C(O)OH, -(lactic acid).sub.4-10C(O)OH,
-(lactide-co-glycolide).sub.1-10C(O)C.sub.1-22alkyl,
-(lactide-co-glycolide).sub.4-10C(O)C.sub.1-22alkyl,
-(lactide-co-glycolide).sub.1-10C(O)C.sub.1-12alkyl,
-(lactide-co-glycolide).sub.1-10C(O)C.sub.4-22alkyl, -(glycolic
acid).sub.1-10C(O)C.sub.1-10alkyl, -(glycolic
acid).sub.4-10C(O)C.sub.1-10alkyl, -(lactic
acid).sub.4-10C(O)C.sub.1-10alkyl, -(lactic
acid).sub.1-10C(O)C.sub.1-10alkyl, -(lactic
acid).sub.1-10C(O)C.sub.4-10alkyl, -(lactic
acid)I-loC(O)C.sub.4-10alkyl, or -(lactic
acid).sub.1-10C(O)C.sub.4-10alkyl; [0755] (v)
--(C(O)CH.sub.2O).sub.1-20C(O)C.sub.1-30alkyl,
--(C(O)CH(CH.sub.3)O).sub.1-20C(O)C.sub.1-30alkyl,
--(C(O)CH.sub.2O).sub.1-10C(O)C.sub.1-30alkyl,
--(C(O)CH(CH.sub.3)O).sub.1-10C(O)C.sub.1-30alkyl,
--(C(O)CH.sub.2O).sub.4-20C(O)C.sub.1-30alkyl,
--(C(O)CH(CH.sub.3)O).sub.4-20C(O)C.sub.1-30alkyl,
--(C(O)CH.sub.2O).sub.1-20C(O)C.sub.1-10alkyl,
--(C(O)CH(CH.sub.3)O).sub.1-20C(O)C.sub.1-10alkyl,
--(C(O)CH.sub.2O).sub.1-20C(O)C.sub.4-10alkyl,
--(C(O)CH(CH.sub.3)O).sub.1-20C(O)C.sub.4-10alkyl,
--(C(O)CH(CH.sub.3)O).sub.4-10C(O)C.sub.1-10alkyl,
--(C(O)CH.sub.2O).sub.4-10C(O)C.sub.1-10alkyl,
--(C(O)CH(CH.sub.3)O).sub.1-10C(O)C.sub.1-10alkyl,
--(C(O)CH.sub.2O).sub.1-10C(O)C.sub.1-10alkyl,
--(C(O)CH(CH.sub.3)O).sub.1-10C(O)C.sub.4-10alkyl,
(C(O)CH.sub.2O).sub.1-10C(O)C.sub.4-10alkyl,
--(C(O)CH.sub.2O).sub.1-10C(O)C.sub.4-10alkyl,
--(C(O)CH(CH.sub.3)O).sub.1-10C(O)C.sub.4-10alkyl,
--(C(O)CH.sub.2O).sub.1-10C(O)C.sub.4-10alkyl,
--(C(O)CH(CH.sub.3)O).sub.1-10C(O)C.sub.4-10alkyl,
--(C(O)CH.sub.2O).sub.1-10(C(O)CH(CH.sub.3)O).sub.1-10C(O)C.sub.1-30alkyl-
,
--(C(O)CH.sub.2O).sub.2-10(C(O)CH(CH.sub.3)O).sub.2-10C(O)C.sub.1-30alky-
l,
--(C(O)CH.sub.2O).sub.1-10(C(O)CH(CH.sub.3)O).sub.1-10C(O)C.sub.1-12alk-
yl,
--(C(O)CH.sub.2O).sub.1-10(C(O)CH(CH.sub.3)O).sub.1-10C(O)C.sub.4-22al-
kyl,
--(C(O)CH(CH.sub.3)O).sub.1-10(C(O)CH.sub.2O).sub.1-10C(O)C.sub.1-30a-
lkyl,
--(C(O)CH(CH.sub.3)O).sub.2-10(C(O)CH.sub.2O).sub.2-10C(O)C.sub.1-30-
alkyl,
--(C(O)CH(CH.sub.3)O).sub.1-10(C(O)CH.sub.2O).sub.1-10C(O)C.sub.1-1-
2alkyl, and
--(C(O)CH(CH.sub.3)O).sub.1-10(C(O)CH.sub.2O).sub.1-10C(O)C.sub.4-22alkyl-
;
##STR00154## ##STR00155## ##STR00156## ##STR00157##
[0756] R.sup.433 is selected from hydrogen, --C(O)A, acyl, aryl,
alkyl, alkenyl, alkynyl cycloalkyl, cycloalkylalkyl, heterocyclyl,
heterocycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl;
and
[0757] wherein all other variables are as defined herein.
[0758] In one embodiment R.sup.31 is --C(O)A, alkyl, or PEG.
[0759] In one embodiment R.sup.31 is --C(O)A, wherein A is
methyl.
[0760] In one embodiment R.sup.33 is
##STR00158##
and R.sup.433 is hydrogen.
[0761] In one embodiment, R.sup.33 is
--C(O)(CH.sub.2).sub.16CH.sub.3 and R.sup.433 is hydrogen.
[0762] In one embodiment, R.sup.433 is hydrogen and R.sup.33 is
##STR00159##
[0763] In one embodiment, R.sup.33 is
##STR00160##
and R.sup.433 is hydrogen.
[0764] In one embodiment, R.sup.33 is
##STR00161##
and R.sup.433 is hydrogen.
[0765] In one embodiment, R.sup.33 is
##STR00162##
and R.sup.433 is hydrogen.
[0766] In one embodiment, R.sup.33 is
##STR00163##
and R.sup.433 is hydrogen.
[0767] In one embodiment, R.sup.33 is
##STR00164##
and R.sup.433 is hydrogen.
[0768] In one embodiment, R.sup.33 is
##STR00165##
and R.sup.433 is hydrogen.
[0769] In one embodiment, R.sup.33 is
##STR00166##
and R.sup.433 is hydrogen.
[0770] In one embodiment, R.sup.33 is
##STR00167##
and R.sup.433 is hydrogen.
[0771] In one embodiment, R.sup.33 is
##STR00168##
and R.sup.433 is hydrogen.
[0772] In one embodiment, R.sup.33 is
##STR00169##
and R.sup.433 is hydrogen.
[0773] In one embodiment, R.sup.33 is
##STR00170##
R.sup.433 is hydrogen, x is selected from 1, 2, 3, 4, 5, and 6, and
R.sup.31 is --C(O)Me.
[0774] In one embodiment, a compound of Formula ID is the
pharmaceutically acceptable HCl salt.
[0775] In one embodiment, a compound of Formula ID is the
pharmaceutically acceptable maleic salt.
[0776] Non-limiting Examples of ID include
##STR00171## ##STR00172##
[0777] The disclosure provides Timolol prodrugs of Formula IID:
##STR00173##
[0778] or a pharmaceutically acceptable composition, salt, or
isotopic derivative thereof.
[0779] R.sup.123 is selected from: [0780] (ii) polyethylene glycol,
polypropylene glycol, polypropylene oxide, polylactic acid,
poly(lactic-co-glycolic acid), polyglycolic acid, polyester,
polyamide,
[0780] ##STR00174## ##STR00175## [0781] wherein each R.sup.123 is
optionally substituted with R.sup.311 or R.sup.31a, and wherein
each of R.sup.123 with a terminal hydroxy or carboxy group can be
substituted to create an ether or ester; [0782] (ii)
--C(O)C.sub.17-30alkyl, --C(O)C.sub.10-30alkenyl,
--C(O)C.sub.10-30alkynyl, --C(O)(C.sub.10-30alkyl with at least one
R.sup.5 substituent on the alkyl chain), --C(O)(C.sub.10-30alkenyl,
with at least one R.sup.5 substituent on the alkenyl chain)
--C(O)(C.sub.10-30alkynyl, with at least one R.sup.5 substituent on
the alkynyl chain), -(lactic acid).sub.1-20C(O)C.sub.1-30alkyl,
-(lactic acid).sub.1-10C(O)C.sub.1-30alkyl, -(lactic
acid).sub.4-20C(O)C.sub.1-30alkyl, -(lactic
acid).sub.1-20C(O)C.sub.1-10alkyl, -(lactic
acid).sub.1-20C(O)C.sub.4-10alkyl, -(lactic acid).sub.1-20C(O)OH,
-(lactic acid).sub.1-10C(O)OH, -(lactic acid).sub.4-20C(O)OH,
-(lactic acid).sub.1-10C(O)OH, -(lactic acid).sub.4-10C(O)OH,
-(lactide-co-glycolide).sub.1-10C(O)C.sub.1-22alkyl,
-(lactide-co-glycolide).sub.4-10C(O)C.sub.1-22alkyl,
-(lactide-co-glycolide).sub.1-10C(O)C.sub.1-12alkyl,
-(lactide-co-glycolide).sub.1-10C(O)C.sub.4-22alkyl, -(glycolic
acid).sub.1-10C(O)C.sub.1-10alkyl, -(glycolic
acid).sub.4-10C(O)C.sub.1-10alkyl, -(lactic
acid).sub.4-10C(O)C.sub.1-10alkyl, -(lactic
acid).sub.1-10C(O)C.sub.1-10alkyl, -(lactic
acid).sub.1-10C(O)C.sub.4-10alkyl, -(lactic
acid).sub.1-10C(O)C.sub.4-10alkyl, or -(lactic
acid).sub.1-10C(O)C.sub.4-10alkyl; [0783] (iii)
--(C(O)CH.sub.2O).sub.1-20C(O)C.sub.1-30alkyl,
--(C(O)CH(CH.sub.3)O).sub.1-20C(O)C.sub.1-30alkyl,
--(C(O)CH.sub.2O).sub.1-10C(O)C.sub.1-30alkyl,
--(C(O)CH(CH.sub.3)O).sub.1-10C(O)C.sub.1-30alkyl,
--(C(O)CH.sub.2O).sub.4-20C(O)C.sub.1-30alkyl,
--(C(O)CH(CH.sub.3)O).sub.4-20C(O)C.sub.1-30alkyl,
--(C(O)CH.sub.2O).sub.1-20C(O)C.sub.1-10alkyl,
--(C(O)CH(CH.sub.3)O).sub.1-20C(O)C.sub.1-10alkyl,
--(C(O)CH.sub.2O).sub.1-20C(O)C.sub.4-10alkyl,
--(C(O)CH(CH.sub.3)O).sub.1-20C(O)C.sub.4-10alkyl,
--(C(O)CH(CH.sub.3)O).sub.4-10C(O)C.sub.1-10alkyl,
--(C(O)CH.sub.2O).sub.4-10C(O)C.sub.1-10alkyl,
--(C(O)CH(CH.sub.3)O).sub.1-10C(O)C.sub.1-10alkyl,
--(C(O)CH.sub.2O).sub.1-10C(O)C.sub.1-10alkyl,
--(C(O)CH(CH.sub.3)O).sub.1-10C(O)C.sub.4-10alkyl,
(C(O)CH.sub.2O).sub.1-10C(O)C.sub.4-10alkyl,
--(C(O)CH.sub.2O).sub.1-10C(O)C.sub.4-10alkyl,
--(C(O)CH(CH.sub.3)O).sub.1-10C(O)C.sub.4-10alkyl,
--(C(O)CH.sub.2O).sub.1-10C(O)C.sub.4-10alkyl,
--(C(O)CH(CH.sub.3)O).sub.1-10C(O)C.sub.4-10alkyl,
--(C(O)CH.sub.2O).sub.1-10(C(O)CH(CH.sub.3)O).sub.1-10C(O)C.sub.1-30alkyl-
,
--(C(O)CH.sub.2O).sub.2-10(C(O)CH(CH.sub.3)O).sub.2-10C(O)C.sub.1-30alky-
l,
--(C(O)CH.sub.2O).sub.1-10(C(O)CH(CH.sub.3)O).sub.1-10C(O)C.sub.1-12alk-
yl,
--(C(O)CH.sub.2O).sub.1-10(C(O)CH(CH.sub.3)O).sub.1-10C(O)C.sub.4-22al-
kyl,
--(C(O)CH(CH.sub.3)O).sub.1-10(C(O)CH.sub.2O).sub.1-10C(O)C.sub.1-30a-
lkyl,
--(C(O)CH(CH.sub.3)O).sub.2-10(C(O)CH.sub.2O).sub.2-10C(O)C.sub.1-30-
alkyl,
--(C(O)CH(CH.sub.3)O).sub.1-10(C(O)CH.sub.2O).sub.1-10C(O)C.sub.1-1-
2alkyl, and
--(C(O)CH(CH.sub.3)O).sub.1-10(C(O)CH.sub.2O).sub.1-10C(O)C.sub.4-22alkyl-
; [0784] (iv) hydrogen, --C(O)A, aryl, alkyl, alkenyl, alkynyl
cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl,
arylalkyl, heteroaryl, and heteroarylalkyl;
[0785] R.sup.106 is selected from: [0786] (i)
[0786] ##STR00176## [0787] (ii) --C(O)C.sub.10-30alkyl,
--C(O)C.sub.10-30alkenyl, --C(O)C.sub.10-30alkynyl,
--C(O)(C.sub.10-30alkyl with at least one R.sup.5 substituent on
the alkyl chain), --C(O)(C.sub.10-30alkenyl, with at least one
R.sup.5 substituent on the alkenyl chain)
--C(O)(C.sub.10-30alkynyl, with at least one R.sup.5 substituent on
the alkynyl chain), -(lactic acid) 1-20C(O)C.sub.1-30alkyl,
-(lactic acid).sub.1-10C(O)C.sub.1-30alkyl, -(lactic
acid).sub.4-20C(O)C.sub.1-30alkyl, -(lactic
acid).sub.1-20C(O)C.sub.1-10alkyl, -(lactic
acid).sub.1-20C(O).sub.4-10alkyl, -(lactic acid).sub.1-20C(O)OH,
-(lactic acid).sub.1-10C(O)OH, -(lactic acid).sub.4-20C(O)OH,
-(lactic acid).sub.1-10C(O)OH, -(lactic acid).sub.4-10C(O)OH,
-(lactide-co-glycolide).sub.1-10C(O).sub.C1-22alkyl,
-(lactide-co-glycolide).sub.4-10C(O).sub.C1-22alkyl,
-(lactide-co-glycolide).sub.1-10C(O).sub.C1-12alkyl,
-(lactide-co-glycolide).sub.1-10C(O).sub.C4-22alkyl, -(glycolic
acid).sub.1-10C(O).sub.C1-10alkyl, -(glycolic
acid).sub.4-10C(O).sub.C1-10alkyl, -(lactic
acid).sub.4-10C(O).sub.C1-10alkyl, -(lactic
acid).sub.1-10C(O)C.sub.1-10alkyl, -(lactic
acid).sub.1-10C(O)C.sub.4-10alkyl, -(lactic
acid).sub.1-10C(O)C.sub.4-10alkyl, and -(lactic
acid).sub.1-10C(O)C.sub.4-10alkyl; [0788] (iii)
--(C(O)CH.sub.2O).sub.1-20C(O)C.sub.1-30alkyl,
--(C(O)CH(CH.sub.3)O).sub.1-20C(O)C.sub.1-30alkyl,
--(C(O)CH.sub.2O).sub.1-10C(O)C.sub.1-30alkyl,
--(C(O)CH(CH.sub.3)O).sub.1-10C(O)C.sub.1-30alkyl,
--(C(O)CH.sub.2O).sub.4-20C(O)C.sub.1-30alkyl,
--(C(O)CH(CH.sub.3)O).sub.4-20C(O)C.sub.1-30alkyl,
--(C(O)CH.sub.2O).sub.1-20C(O)C.sub.1-10alkyl,
--(C(O)CH(CH.sub.3)O).sub.1-20C(O)C.sub.1-10alkyl,
--(C(O)CH.sub.2O).sub.1-20C(O)C.sub.4-10alkyl,
--(C(O)CH(CH.sub.3)O).sub.1-20C(O)C.sub.4-10alkyl,
--(C(O)CH(CH.sub.3)O).sub.4-10C(O)C.sub.1-10alkyl,
--(C(O)CH.sub.2O).sub.4-10C(O)C.sub.1-10alkyl,
--(C(O)CH(CH.sub.3)O).sub.1-10C(O)C.sub.1-10alkyl,
--(C(O)CH.sub.2O).sub.1-10C(O)C.sub.1-10alkyl,
--(C(O)CH(CH.sub.3)O).sub.1-10C(O)C.sub.4-10alkyl,
(C(O)CH.sub.2O).sub.1-10C(O)C.sub.4-10alkyl,
--(C(O)CH.sub.2O).sub.1-10C(O)C.sub.4-10alkyl,
--(C(O)CH(CH.sub.3)O).sub.1-10C(O)C.sub.4-10alkyl,
--(C(O)CH.sub.2O).sub.1-10C(O)C.sub.4-10alkyl,
--(C(O)CH(CH.sub.3)O).sub.1-10C(O)C.sub.4-10alkyl,
--(C(O)CH.sub.2O).sub.1-10(C(O)CH(CH.sub.3)O).sub.1-10C(O)C.sub.1-30alkyl-
,
--(C(O)CH.sub.2O).sub.2-10(C(O)CH(CH.sub.3)O).sub.2-10C(O)C.sub.1-30alky-
l,
--(C(O)CH.sub.2O).sub.1-10(C(O)CH(CH.sub.3)O).sub.1-10C(O)C.sub.1-12alk-
yl,
--(C(O)CH.sub.2O).sub.1-10(C(O)CH(CH.sub.3)O).sub.1-10C(O)C.sub.4-22al-
kyl,
--(C(O)CH(CH.sub.3)O).sub.1-10(C(O)CH.sub.2O).sub.1-10C(O)C.sub.1-30a-
lkyl,
--(C(O)CH(CH.sub.3)O).sub.2-10(C(O)CH.sub.2O).sub.2-10C(O)C.sub.1-30-
alkyl,
--(C(O)CH(CH.sub.3)O).sub.1-10(C(O)CH.sub.2O).sub.1-10C(O)C.sub.1-1-
2alkyl, and
--(C(O)CH(CH.sub.3)O).sub.1-10(C(O)CH.sub.2O).sub.1-10C(O)C.sub.4-22alkyl-
;
[0789] x' and y' are independently selected from any integer
between 1 and 30 (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,
15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30).
In one embodiment x' and y' are independently selected from the
following ranges: 1 to 5, 6 to 11, 12 to 17, 18 to 23, and 24 to 30
(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,
18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30). In a
preferred embodiment, x and y are independently selected from any
integer between 1 and 10 (1, 2, 3, 4, 5, 6, 7, 8, 9, or 10);
and
[0790] wherein all other integers are as defined herein.
[0791] In one embodiment, R.sup.106 is
--C(O)(CH.sub.2).sub.16CH.sub.3 and R.sup.123 is hydrogen.
[0792] In one embodiment, R.sup.123 is hydrogen and R.sup.106
is
##STR00177##
[0793] In one embodiment, R.sup.123 is
##STR00178##
[0794] In one embodiment, R.sup.123 is
##STR00179##
[0795] In one embodiment, R.sup.123 is
##STR00180##
[0796] In one embodiment, R.sup.106 is
[0797] In one embodiment, R.sup.123 is
##STR00181##
x is 1, and R.sup.123 is --C(O)A.
[0798] In one embodiment, R.sup.106 is
##STR00182##
and R.sup.31a is --C(O)alkyl.
[0799] In one embodiment, R.sup.106 is
##STR00183##
and R.sup.31a is --C(O)alkyl wherein alkyl is methyl.
[0800] In one embodiment R.sup.123 is selected from
##STR00184##
[0801] In one embodiment R.sup.31a is selected from --C(O)alkyl,
stearoyl, and
##STR00185##
[0802] Non-limiting Examples of Formula IID include
##STR00186## ##STR00187## ##STR00188## ##STR00189##
##STR00190##
[0803] The disclosure provides Timolol prodrugs of Formula IIID and
Formula IVD:
##STR00191##
[0804] or a pharmaceutically acceptable composition, salt, or
isotopic derivative thereof.
[0805] R.sup.34 is selected from: R.sup.381, carbonyl linked
polyethylene glycol, carbonyl linked polypropylene glycol, carbonyl
linked polypropylene oxide, polylactic acid, and
poly(lactic-co-glycolic acid), a polyglycolic acid, a polyester,
polyamide,
##STR00192## ##STR00193##
or other biodegradable polymer, wherein each R.sup.34 other than
R.sup.381 is substituted with at least one L.sup.4-R.sup.121;
[0806] R.sup.31b is hydrogen, aryl, alkyl, cycloalky, cycloalkyl,
cycloalkylalkyl, heterocyclyl, heterocycloalkyl, arylalkyl,
heteroaryl, heteroarylalkyl, and polyethylene glycol;
[0807] R.sup.381 is selected from:
##STR00194## ##STR00195## ##STR00196## ##STR00197## ##STR00198##
[0808] wherein all other variables are as defined herein.
[0809] The disclosure provides Timolol prodrugs of Formula VD and
Formula VID:
##STR00199##
[0810] or a pharmaceutically acceptable composition, salt, or
isotopic derivative thereof.
[0811] R.sup.364 is selected from: acyl, carbonyl linked
polyethylene glycol, carbonyl linked polypropylene glycol, carbonyl
linked polypropylene oxide, polylactic acid,
poly(lactic-co-glycolic acid), polyglycolic acid, polyester,
polyamide,
##STR00200## ##STR00201##
[0812] R.sup.360 is selected from
##STR00202## ##STR00203##
and
[0813] wherein all other variables are as defined herein.
[0814] In one embodiment, R.sup.364 is
##STR00204##
and R.sup.31a is --C(O)alkyl.
[0815] In one embodiment, R.sup.364 is
##STR00205##
and R.sup.31a is --C(O)Me.
[0816] In one embodiment, R.sup.364 is
##STR00206##
R.sup.31a is --C(O)Me, and x' is an integer between 1 and 6 (1, 2,
3, 4, 5, or 6);
[0817] In one embodiment, R.sup.364 is
##STR00207##
and R.sup.31a is stearoyl;
[0818] In one embodiment, R.sup.364 is
##STR00208##
x' is an integer between 1 and 6 (1, 2, 3, 4, 5, or 6), and y is 11
or 17, or in an alternative embodiment, y is 10 or 16.
[0819] In one embodiment, R.sup.360 is
##STR00209##
R.sup.121 is
##STR00210##
[0820] and R.sup.15 is hydrogen.
[0821] In one embodiment, R.sup.360 is
##STR00211##
R.sup.121 is
##STR00212##
[0822] and R.sup.15 is hydrogen.
[0823] In one embodiment, R.sup.360 is
##STR00213##
R.sup.121 is
##STR00214##
[0825] In one embodiment, R.sup.360 is
##STR00215##
and R.sup.121 is
##STR00216##
[0827] In certain embodiments, R.sup.360 is
##STR00217##
x and y are independently selected from 1, 2, 3, 4, 5, and 6, and z
is 1, 2, or 3.
[0828] In certain embodiments, R.sup.360 is
##STR00218##
x and y are independently selected from 1, 2, and 3, and z is 1, 2,
or 3.
[0829] In certain embodiments, R.sup.360 is
##STR00219##
x and y are independently selected from 1, 2, and 3, z is 1, 2, or
3, and R.sup.364 is
##STR00220##
[0830] In certain embodiments, x' and x are 1 and y and y' are
independently selected from 1, 2, 3, 4, 5, and 6.
[0831] In certain embodiments, x' and x are 2 and y and y' are
independently selected from 1, 2, 3, 4, 5, and 6.
[0832] In certain embodiments, x' and x are 3 and y and y' are
independently selected from 1, 2, 3, 4, 5, and 6.
[0833] In certain embodiments, x' and x are 1 and y and y' are
independently selected from 1, 2, or 3.
[0834] In certain embodiments, x' and x are 2 and y and y' are
independently selected from 1, 2, or 3.
[0835] In certain embodiments, y' and y are 1 and x and x' are
independently selected from 1, 2, 3, 4, 5, and 6.
[0836] In certain embodiments, y' and y are 2 and x and x' are
independently selected from 1, 2, 3, 4, 5, and 6.
[0837] In certain embodiments, y' and y are 3 and x and x' are
independently selected from 1, 2, 3, 4, 5, and 6.
[0838] In certain embodiments, y' and y are 1 and x and x' are
independently selected from 1, 2, and 3.
[0839] In certain embodiments, y' and y are 2 and x and x' are
independently selected from 1, 2, and 3.
[0840] Non-limiting examples of compounds of Formula VD include
##STR00221## ##STR00222## ##STR00223## ##STR00224##
[0841] Non-limiting Examples of Compound of Formula VID
include:
##STR00225## ##STR00226##
[0842] The disclosure provides Timolol prodrugs of Formula
VIID:
##STR00227##
or a pharmaceutically acceptable composition, salt, or isotopic
derivative thereof
[0843] wherein
[0844] R.sup.366 is selected from
##STR00228## ##STR00229##
[0845] R.sup.316 is selected from
##STR00230## ##STR00231## ##STR00232## ##STR00233## ##STR00234##
##STR00235## ##STR00236## ##STR00237## ##STR00238## ##STR00239##
##STR00240## ##STR00241## ##STR00242## ##STR00243##
##STR00244##
[0846] wherein all other variables are as defined herein.
[0847] Non-limiting examples of R.sup.617 include:
##STR00245## ##STR00246##
[0848] In one embodiment, R.sup.360 is
##STR00247##
and R.sup.366 is
##STR00248##
[0850] In one embodiment, R.sup.360 is
##STR00249##
and R.sup.366 is
##STR00250##
[0852] In one embodiment, R.sup.360 is
##STR00251##
x is 1, 2, 3, or 4, and z is 1, 2, 3, or 4.
[0853] In one embodiment, R.sup.366 is
##STR00252##
x' an integer between 0 and 4 (0, 1, 2, 3, or 4), and z is an
integer between 1 and 4 (1, 2, 3, or 4).
[0854] In one embodiment, R.sup.360 is
##STR00253##
R.sup.366
##STR00254##
[0855] R.sup.121 is
##STR00255##
[0856] and R.sup.316 is
##STR00256##
[0858] In one embodiment, R.sup.360 is
##STR00257##
R.sup.366 is
##STR00258##
[0859] R.sup.121 is
##STR00259##
[0860] and R.sup.316 is
##STR00260##
[0862] Non-limiting Examples of Compounds of Formula VIID
include:
##STR00261## ##STR00262## ##STR00263## ##STR00264##
[0863] In certain embodiments of Formula VIID, x and x' are
independently selected from 1, 2, 3, 4, 5, or 6; y and y' are
independently selected from 1, 2, 3, 4, 5, or 6; and z is
independently selected at each instance from 1, 2, and 3.
[0864] In certain embodiments of Formula VIID, x and x' are
independently selected from 1, 2, or 3; y and y' are independently
selected from 1, 2, or 3; and z is independently selected at each
instance from 1, 2, and 3.
[0865] In certain embodiments of Formula VIID, x and x' are
independently selected from 1, 2, or 3; y and y' are independently
selected from 1, 2, or 3; and z in at least one instance is 1.
[0866] In certain embodiments of Formula VIID, x and x' are
independently selected from 1, 2, or 3; y and y' are independently
selected from 1, 2, or 3; and z in at least one instance is 2.
[0867] In certain embodiments of Formula VIID, x and x' are
independently selected from 1, 2, or 3; y and y' are independently
selected from 1, 2, or 3; and z in at least one instance is 3.
[0868] In certain embodiments of Formula VIID, x and x' are 1; y
and y' are independently selected from 1, 2, or 3; and z is
independently selected at each instance from 1, 2, and 3.
[0869] In certain embodiments of Formula VIID, x and x' are 2; y
and y' are independently selected from 1, 2, or 3; and z is
independently selected at each instance from 1, 2, and 3.
[0870] In certain embodiments of Formula VIID, x and x' are 3; y
and y' are independently selected from 1, 2, or 3; and z is
independently selected at each instance from 1, 2, and 3.
[0871] In certain embodiments of Formula VIID, x and x' are
independently selected from 1, 2, or 3; y and y' are 1; and z is
independently selected at each instance from 1, 2, and 3.
[0872] In certain embodiments of Formula VIID, x and x' are
independently selected from 1, 2, or 3; y and y' are 2; and z is
independently selected at each instance from 1, 2, and 3.
[0873] In certain embodiments of Formula VIID, x and x' are
independently selected from 1, 2, or 3; y and y' are 3; and z is
independently selected at each instance from 1, 2, and 3.
Duel Leucine Zipper Kinase Prodrugs
[0874] The disclosure provides duel leucine zipper kinase prodrugs
of Formula IE:
##STR00265##
or a pharmaceutically acceptable composition, salt, or isotopic
derivative thereof.
[0875] R.sup.18 is selected from:
--C(O)CH.sub.2CH.sub.2C.sub.19-C.sub.30alkylR.sup.5,
--C(O)CH.sub.2CH.sub.2C.sub.19-C.sub.30alkenylR.sup.5,
--C(O)CH.sub.2CH.sub.2C.sub.19-C.sub.30alkynylR.sup.5,
--C(O)CH.sub.2CH.sub.2C.sub.19-C.sub.30alkenylalkynylR.sup.5,
--C(O)CH.sub.2CH.sub.2C.sub.19-C.sub.30alkyl,
--C(O)CH.sub.2CH.sub.2C.sub.19-C.sub.30alkenyl,
--C(O)CH.sub.2CH.sub.2C.sub.19-C.sub.30alkynyl,
--C(O)CH.sub.2CH.sub.2C.sub.19-C.sub.30alkenylalkynyl, and R.sup.19
wherein R.sup.18 can be further optionally further substituted with
R.sup.5 (including for example a second R.sup.5) if valence
permits, a stable compound is formed, and the resulting compound is
pharmaceutically acceptable;
[0876] In various different embodiments, --C.sub.19-C.sub.30 as
used in the definition of R.sup.18 is --C.sub.19-C.sub.28,
--C.sub.19-C.sub.26, --C.sub.19-C.sub.24, --C.sub.19-C.sub.22,
--C.sub.19-C.sub.20, --C.sub.20-C.sub.28, --C.sub.20-C.sub.26,
--C.sub.20-C.sub.24, --C.sub.20-C.sub.22, --C.sub.22-C.sub.28,
--C.sub.22-C.sub.26, --C.sub.22-C.sub.24, or
--C.sub.26-C.sub.28.
[0877] R.sup.19 is selected from: [0878] (i) an unsaturated fatty
acid residue including but not limited to the carbonyl fragment
taken from docosahexaenoic acid
(--C(O)(CH.sub.2).sub.2(CHCHCH.sub.2).sub.6CH.sub.3)),
docosatetraenoic acid, euric acid, or nervonic acid; [0879] (ii)
polyethylene glycol, polypropylene glycol, polypropylene oxide,
polylactic acid, or poly(lactic-co-glycolic acid) including:
##STR00266##
[0879] or polyglycolic acid, or a polyester, polyamide, or other
biodegradable polymer, each of which can be capped to complete the
terminal valence or to create a terminal ether.
[0880] The disclosure provides duel leucine zipper kinase prodrugs
of Formula IIE:
##STR00267##
[0881] or a pharmaceutically acceptable composition, salt, or
isotopic derivative thereof.
[0882] R.sup.20 is selected from:
--C(O)CH.sub.2CH.sub.2C.sub.9-C.sub.30alkylR.sup.5,
--C(O)CH.sub.2CH.sub.2C.sub.9-C.sub.30alkenylR.sup.5,
--C(O)CH.sub.2CH.sub.2C.sub.9-C.sub.30alkynylR.sup.5,
--C(O)CH.sub.2CH.sub.2C.sub.9-C.sub.30alkenylalkynylR.sup.5,
--C(O)CH.sub.2CH.sub.2C.sub.9-C.sub.30alkyl,
--C(O)CH.sub.2CH.sub.2C.sub.9-C.sub.30alkenyl,
--C(O)CH.sub.2CH.sub.2C.sub.9-C.sub.30alkynyl,
--C(O)CH.sub.2CH.sub.2C.sub.9-C.sub.30alkenylalkynyl, and
R.sup.21.
[0883] In one embodiment, --C.sub.9-C.sub.30 as used in the
definition of R.sup.20 is --C.sub.10-C.sub.28, --C.sub.11-C.sub.26,
--C.sub.11-C.sub.24, --C.sub.12-C.sub.22, --C.sub.12-C.sub.20,
--C.sub.12-C.sub.18, --C.sub.12-C.sub.16, or --C.sub.12-C.sub.14
R.sup.21 is selected from: [0884] (i) an unsaturated fatty acid
residue including but not limited the carbonyl fragment taken from
linoleic acid
(--C(O)(CH.sub.2).sub.7(CH).sub.2CH.sub.2(CH).sub.2(CH.sub.2).sub.4CH.sub-
.3)), docosahexaenoic acid
(--C(O)(CH.sub.2).sub.2(CHCHCH.sub.2).sub.6CH.sub.3)),
eicosapentaenoic acid
(--C(O)(CH.sub.2).sub.3(CHCHCH.sub.2).sub.5CH.sub.3)),
alpha-linolenic acid
(--C(O)(CH.sub.2).sub.7(CHCHCH.sub.2).sub.3CH.sub.3)) stearidonic
acid, y-linolenic acid, arachidonic acid, docosatetraenoic acid,
palmitoleic acid, vaccenic acid, paullinic acid, oleic acid,
elaidic acid, gondoic acid, euric acid, nervonic acid and mead
acid, each of which can be further substituted with R.sup.5 if
valence permits, a stable compound is formed, and the resulting
compound is pharmaceutically acceptable; [0885] (ii) polyethylene
glycol, polypropylene glycol, polypropylene oxide, polylactic acid,
and poly(lactic-co-glycolic acid) including:
##STR00268##
[0885] or polyglycolic acid, or a polyester, polyamide, or other
biodegradable polymer, each of which can be capped to complete the
terminal valence or to create a terminal ether. [0886] (iii) The
disclosure provides duel leucine zipper kinase prodrugs of Formula
IIIE:
##STR00269##
[0887] or a pharmaceutically acceptable composition, salt, or
isotopic derivative thereof.
[0888] Q is selected from: N, CH, and CR.sup.23.
[0889] R.sup.22 is selected from:
--C(O)CH.sub.2CH.sub.2C.sub.11-C.sub.30alkylR.sup.5,
--C(O)CH.sub.2CH.sub.2C.sub.11-C.sub.30alkenylR.sup.5,
-C(O)CH.sub.2CH.sub.2C.sub.11-C.sub.30alkynylR.sup.5,
--C(O)CH.sub.2CH.sub.2C.sub.11-C.sub.30alkenylalkynylR.sup.5,
--C(O)CH.sub.2CH.sub.2C.sub.11-C.sub.30alkyl,
--C(O)CH.sub.2CH.sub.2C.sub.11-C.sub.30alkenyl,
--C(O)CH.sub.2CH.sub.2C.sub.11-C.sub.30alkynyl,
--C(O)CH.sub.2CH.sub.2C.sub.11-C.sub.30alkenylalkynyl and R.sup.21
and wherein R.sup.22 can be further substituted with R.sup.5
(including for example a second R.sup.5) if valence permits, a
stable compound is formed, and the resulting compound is
pharmaceutically acceptable.
[0890] In one embodiment, --C.sub.11-C.sub.30 as used in the
definition of R.sup.22 is --C.sub.12-C.sub.28, --C.sub.13-C.sub.26,
--C.sub.13-C.sub.24, --C.sub.13-C.sub.22, --C.sub.13-C.sub.20,
--C.sub.13-C.sub.18, --C.sub.13-C.sub.16, or
--C.sub.13-C.sub.14.
[0891] R.sup.23, R.sup.24, and R.sup.25 are independently selected
from: hydrogen, halogen, hydroxyl, cyano, mercapto, nitro, amino,
aryl, alkyl, alkoxy, alkenyl, alkynyl cycloalkyl, cycloalkylalkyl,
heterocyclyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, aryloxy, --S(O).sub.2alkyl, --S(O)alkyl,
--P(O)(Oalkyl).sub.2, B(OH).sub.2, --Si(CH.sub.3).sub.3, --COOH,
--COOalkyl, --CONH.sub.2,
##STR00270##
each of which except halogen, nitro, and cyano, may be optionally
substituted, for example with halogen, alkyl, aryl, heterocycle or
heteroaryl.
[0892] R.sup.26 is selected from H, C(O)A,
--C.sub.0-C.sub.10alkylR.sup.5, --C.sub.2-C.sub.10alkenylR.sup.5,
--C.sub.2-C.sub.10alkynylR.sup.5, --C.sub.2-C.sub.10alkenyl, and
--C.sub.2-C.sub.10alkynyl.
[0893] In one embodiment, --C.sub.2-C.sub.10 as used in R.sup.26 is
--C.sub.4-C.sub.10, --C.sub.6-C.sub.10, or --C.sub.8-C.sub.10.
[0894] The disclosure also provides a prodrug of Formula IVE:
##STR00271##
[0895] or a pharmaceutically acceptable composition, salt, or
isotopic derivative thereof.
[0896] R.sup.27 is selected from:
--C(O)CH.sub.2CH.sub.2C.sub.0-C.sub.30alkylR.sup.5,
--C(O)CH.sub.2CH.sub.2C.sub.0-C.sub.30alkenylR.sup.5,
--C(O)CH.sub.2CH.sub.2C.sub.0-C.sub.30alkynylR.sup.5,
--C(O)CH.sub.2CH.sub.2C.sub.0-C.sub.30alkenylalkynylR.sup.5,
--C(O)CH.sub.2CH.sub.2C.sub.0-C.sub.30alkyl,
--C(O)CH.sub.2CH.sub.2C.sub.0-C.sub.30alkenyl,
--C(O)CH.sub.2CH.sub.2C.sub.0-C.sub.30alkynyl,
--C(O)CH.sub.2CH.sub.2C.sub.0-C.sub.30alkenylalkynyl, and
R.sup.21.
[0897] In various different embodiments, --C.sub.0-C.sub.30 as used
in R.sup.27 is --C.sub.0-C.sub.28, --C.sub.0-C.sub.26,
--C.sub.0-C.sub.24, --C.sub.0-C.sub.22, --C.sub.0-C.sub.20,
--C.sub.0-C.sub.18, --C.sub.0-C.sub.16, --C.sub.0-C.sub.14,
--C.sub.0-C.sub.12, or --C.sub.0-C.sub.11, --C.sub.0-C.sub.10,
--C.sub.0-C.sub.8, --C.sub.0-C.sub.6, --C.sub.0-C.sub.4,
--C.sub.0-C.sub.2, --C.sub.2-C.sub.28, --C.sub.4-C.sub.26,
--C.sub.4-C.sub.24, --C.sub.4-C.sub.22, --C.sub.4-C.sub.20,
--C.sub.6-C.sub.18, --C.sub.6-C.sub.16, --C.sub.6-C.sub.14,
--C.sub.6- C.sub.12, --C.sub.4-C.sub.11, --C.sub.0-C.sub.10,
--C.sub.0-C.sub.8, --C.sub.0-C.sub.6, --C.sub.0-C.sub.4, or
--C.sub.0-C.sub.2.
[0898] The disclosure also provides a prodrug of Formula VE,
Formula VIE, Formula VIIE, Formula VIIIE, Formula IXE, and Formula
XE:
##STR00272## ##STR00273## ##STR00274##
[0899] or a pharmaceutically acceptable composition, salt, or
isotopic derivative thereof wherein
[0900] R.sup.39 is selected from: R.sup.40, carbonyl linked
polyethylene glycol, carbonyl linked polypropylene glycol, carbonyl
linked polypropylene oxide, polylactic acid, and
poly(lactic-co-glycolic acid), a polyglycolic acid, a polyester,
polyamide,
##STR00275##
or other biodegradable polymer, wherein each R.sup.39 Other than
R.sup.40 is substituted with at least one L.sup.4-R.sup.121;
[0901] R.sup.40 is selected from:
##STR00276## ##STR00277##
Rho Kinase (ROCK) Inhibitor Prodrugs
[0902] The disclosure provides ROCK inhibitor prodrugs of Formula
IF, Formula IIF, Formula IIIF, Formula IVF, and Formula VF:
##STR00278##
[0903] or a pharmaceutically acceptable composition, salt, or
isotopic derivative thereof.
[0904] Z is CR.sup.130 or N;
[0905] t is independently selected from 0, 1, 2, 3, and 4;
[0906] R.sup.130, R.sup.131, and R.sup.133 are independently
selected at each occurrence from H, C.sub.1-C.sub.30alkyl,
--C(O)C.sub.1-C.sub.30alkyl, C.sub.1-C.sub.30heteroalkyl, and
R.sup.136;
[0907] R.sup.132 is selected from R.sup.136, C.sub.1-C.sub.30alkyl,
C.sub.1-C.sub.30cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and
alkylaryl, any of which can be optionally substituted with one or
more of hydroxyl, --CH.sub.2OH, --C(O)NH.sub.2, acetyl, carbonyl,
alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, any of
which can be optionally substituted with one or more of hydroxyl,
nitro, amino, --NR.sup.134R.sup.135, alkyl, alkoxy, alkylalkoxy,
alkoxylalkoxy, haloalkoxy, heteroarylcarbonyl, heteroaryl,
--OCH.sub.3, --OCF.sub.3, --OCHF.sub.2, --OCH.sub.2F,
--OSO.sub.2CH.sub.3, tosyl, or halogen;
[0908] R.sup.140 is selected from R.sup.136, hydrogen, alkyl,
cycloalkyl, heterocycloalkyl, and aryl, any of which except
hydrogen can be optionally substituted with one or more of
hydroxyl, --CH.sub.2OH, --C(O)NH.sub.2, acetyl, carbonyl, alkyl,
cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, any of which
can be optionally substituted with one or more of hydroxyl, nitro,
amino, --NR.sup.134R.sup.135, alkyl, alkoxy, alkylalkoxy,
alkoxylalkoxy, haloalkoxy, heteroarylcarbonyl, heteroaryl,
--OCH.sub.3, --OCF.sub.3, --OCHF.sub.2, --OCH.sub.2F,
--OSO.sub.2CH.sub.3, tosyl, or halogen;
[0909] R.sup.136 is selected from: R.sup.137, acyl, alkyl,
alkyloxy, polyethylene glycol, polypropylene glycol, polypropylene
oxide, polylactic acid, poly(lactic-co-glycolic acid), a
polyglycolic acid, a polyester, polyamide, or other biodegradable
polymer, wherein each R.sup.136 other than R.sup.137 is substituted
with at least one L.sup.4-R.sup.121;
[0910] or R.sup.136 is L.sup.4-R.sup.121 or R.sup.121;
[0911] wherein at least one of R.sup.130, R.sup.131, and R.sup.133
is R.sup.136; and [0912] R.sup.137 is selected from:
##STR00279## ##STR00280##
[0912] and wherein all other variables are as defined herein.
[0913] In one embodiment, Formula IF is Formula IFa
##STR00281##
wherein:
[0914] R.sup.142 and R.sup.143 are independently selected from H,
--OH, acetyl, --C(O)NH.sub.2, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6cycloalkyl, hereterocycloalkyl, aryl, or heteroaryl,
wherein any one of the C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6cycloalkyl, hereteroC.sub.1-C.sub.6cycloalkyl, aryl,
or heteroaryl groups is optionally substituted with one or more of
hydroxyl, --CH.sub.2OH, --C(O)NH.sub.2, acetyl, carbonyl, alkyl,
cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, any of which
can be optionally substituted with one or more of hydroxyl, nitro,
amino, --NR.sup.134R.sup.135, alkyl, alkyl-O--R.sup.136, alkoxy,
alkylalkoxy, alkoxylalkoxy, heteroarylcarbonyl, heteroaryl,
--OCH.sub.3, --OCF.sub.3, --OCHF.sub.2, --OCH.sub.2F;
[0915] R.sup.139 is selected from cycloalkyl, heterocycloalkyl,
aryl, or heteroaryl, any of which is optionally substituted with
one or more of hydroxyl, --CH.sub.2OH, --C(O)NH.sub.2, acetyl,
carbonyl, alkyl, cycloalkyl, heterocycloalkyl, aryl, and
heteroaryl, any of which can be optionally substituted with one or
more of hydroxyl, nitro, amino, --NR.sup.134R.sup.135, alkyl,
alkoxy, alkylalkoxy, alkoxylalkoxy, haloalkoxy, heteroarylcarbonyl,
heteroaryl, --OCH.sub.3, --OCF.sub.3, --OCHF.sub.2, --OCH.sub.2F,
--OSO.sub.2CH.sub.3, tosyl, or halogen;
[0916] p is 1, 2, or 3; and
[0917] wherein all other variables are as defined herein.
[0918] In one embodiment, Formula IF is Formula IFb
##STR00282##
wherein:
[0919] R.sup.230 and R.sup.231 are independently selected at each
occurrence from H, C.sub.1-C.sub.30alkyl,
--C(O)C.sub.1-C.sub.30alkyl, C.sub.1-C.sub.30heteroalkyl, and
R.sup.136;
[0920] R.sup.242 and R.sup.243 are independently selected at each
instance from H, --OH, acetyl, --C(O)NH.sub.2,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6cycloalkyl,
hereterocycloalkyl, aryl, or heteroaryl, wherein any one of the
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6cycloalkyl,
hereteroC.sub.1-C.sub.6cycloalkyl, aryl, or heteroaryl groups is
optionally substituted with one or more substituents selected from
hydroxyl, nitro, amino, --NR.sup.134R.sup.135, alkyl,
alkyl-O--R.sup.136, --O--R.sup.136, alkoxy, alkylalkoxy,
alkoxylalkoxy, heteroarylcarbonyl, heteroaryl, --OCH.sub.3,
--OCF.sub.3, --OCHF.sub.2, --OCH.sub.2F;
[0921] wherein at least one instance of R.sup.230, R.sup.231,
R.sup.242, or R.sup.243 is R.sup.136 or contains a O-R.sup.136
substituent; and
[0922] wherein all other variables are as defined herein.
[0923] In one embodiment the compound is:
##STR00283##
wherein:
[0924] R.sup.230a and R.sup.231a are independently selected at each
occurrence from H, C.sub.1-C.sub.30alkyl,
--C(O)C.sub.1-C.sub.30alkyl, and C.sub.1-C.sub.30heteroalkyl;
and
[0925] wherein all other variables are as defined herein.
[0926] Non-limiting examples of Formula IF include
##STR00284##
[0927] In one embodiment, Formula IIF is Formula IIFa
##STR00285##
[0928] wherein all other variables as defined herein.
[0929] In one embodiment, Formula IIF is Formula IIFb
##STR00286##
wherein:
[0930] R.sup.230, R.sup.231, and R.sup.233 are independently
selected at each occurrence from H, C.sub.1-C.sub.30alkyl,
--C(O)C.sub.1-C.sub.30alkyl, C.sub.1-C.sub.30heteroalkyl, and
R.sup.136;
[0931] wherein at least one instance of R.sup.230, R.sup.231,
R.sup.233, R.sup.242, Or R.sup.243 is R.sup.136 Or contains a
O-R.sup.136 substituent;
[0932] wherein all other variables are as defined herein.
[0933] Non-limiting examples of Formula IIF include
##STR00287## ##STR00288##
[0934] In one embodiment, Formula IIIF is Formula IIIFa
##STR00289##
[0935] wherein all other variables are as defined herein.
[0936] In one embodiment, Formula IIIF is Formula IIIFb
##STR00290##
[0937] wherein at least one instance of R.sup.230, R.sup.231,
R.sup.242, or R.sup.243 is R.sup.136 or contains a O-R.sup.136
substituent; and
[0938] wherein all other variables are as defined herein.
[0939] In one embodiment the compound is:
##STR00291##
[0940] wherein all variables are as defined herein.
[0941] Non-limiting examples of Formula IIIF include
##STR00292## ##STR00293##
[0942] The disclosure provides ROCK inhibitor prodrugs of Formula
VIF, Formula VIIF, and Formula VIIIF:
##STR00294##
[0943] or a pharmaceutically acceptable composition, salt, or
isotopic derivative thereof wherein
[0944] R.sup.303, R.sup.304, and R.sup.344 are independently
selected at each occurrence from H, C.sub.1-C.sub.30alkyl,
--C(O)C.sub.1-C.sub.30alkyl, C.sub.2-C.sub.30alkenyl,
C.sub.1-C.sub.30heteroalkyl, and R.sup.336;
[0945] wherein at least one of R.sup.303, R.sup.304, and R.sup.344
is R.sup.336;
[0946] R.sup.336 is selected from:
##STR00295## ##STR00296## ##STR00297## ##STR00298##
[0947] wherein all other variables are as defined herein.
[0948] In one embodiment, R.sup.141 is OCH.sub.3.
[0949] In one embodiment, R.sup.301 is selected from
--N(CH.sub.3).sub.2,
##STR00299##
[0950] In one embodiment, R.sup.301 is
##STR00300##
[0951] In one embodiment, R.sup.301 is --OCH.sub.3.
[0952] In one embodiment, R.sup.301 is selected from F and Cl.
[0953] In one embodiment, R.sup.304 is hydrogen.
[0954] In one embodiment, R.sup.304 is CH.sub.3.
[0955] In one embodiment, R.sup.304 is CH.sub.2H.sub.5.
[0956] In one embodiment, R.sup.303 is
##STR00301##
[0957] In one embodiment, R.sup.303 is
##STR00302##
and R.sup.121 is
##STR00303##
[0959] In one embodiment, R.sup.303 is
##STR00304##
and R.sup.121 is
##STR00305##
[0961] In a further embodiment, x is 2 and z is 2.
[0962] Non-limiting Examples of Formula VIF and Formula VIIF
include
##STR00306## ##STR00307##
[0963] The disclosure provides ROCK inhibitor prodrugs of Formula
IXF, Formula XF, and Formula XF
##STR00308##
[0964] or a pharmaceutically acceptable composition, salt, or
isotopic derivative thereof wherein
[0965] Y is CR.sup.15 or N;
[0966] R.sup.150 and R.sup.151 are independently selected at each
occurrence from H, C.sub.1-C.sub.30alkyl,
--C(O)C.sub.1-C.sub.30alkyl, C-C.sub.30heteroalkyl, and
R.sup.156;
[0967] R.sup.152 is selected from C.sub.1-C.sub.30alkyl,
C.sub.1-C.sub.30cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or
alkylaryl, any of which can be optionally substituted with one or
more of hydroxyl, --CH.sub.2OH, --C(O)NH.sub.2, acetyl, carbonyl,
alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, any of
which can be optionally substituted with one or more of hydroxyl,
nitro, amino, --NR.sup.134R.sup.135, alkyl, alkoxy, alkylalkoxy,
alkoxylalkoxy, haloalkoxy, heteroarylcarbonyl, heteroaryl,
--OCH.sub.3, --OCF.sub.3, --OCHF.sub.2, --OCH.sub.2F,
--OSO.sub.2CH.sub.3, tosyl, or halogen;
[0968] or R.sup.151 and R.sup.152 can together form a cycloalkyl or
heterocycloalkyl;
[0969] R.sup.160 is selected from H, C.sub.1-C.sub.30alkyl,
C.sub.1-C.sub.30cycloalkyl, heterocycloalkyl, and aryl, any of
which except hydrogen can be optionally substituted with one or
more of hydroxyl, --CH.sub.2OH, --C(O)NH.sub.2, acetyl, carbonyl,
alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, any of
which can be optionally substituted with one or more of hydroxyl,
nitro, amino, --NR.sup.134R.sup.135, alkyl, alkoxy, alkylalkoxy,
alkoxylalkoxy, haloalkoxy, heteroarylcarbonyl, heteroaryl,
--OCH.sub.3, --OCF.sub.3, --OCHF.sub.2, --OCH.sub.2F,
--OSO.sub.2CH.sub.3, tosyl, or halogen; or R.sup.151 and R.sup.152
can together form a cycloalkyl or heterocycloalkyl;
[0970] wherein at least one of R.sup.150 and R.sup.151 is
R.sup.156;
[0971] R.sup.156 is selected from: [0972] (i) polyethylene glycol,
polypropylene glycol, polypropylene oxide, polylactic acid,
poly(lactic-co-glycolic acid) polyglycolic acid, polyester,
polyamide, and other biodegradable polymers, each of which can be
capped to complete the terminal valence or to create a terminal
ether or ester, in one embodiment the capping group is selected
from R.sup.311; and [0973] (ii)
##STR00309##
[0973] and
[0974] wherein all other variables are as defined herein.
[0975] In one embodiment R.sup.156 is selected from:
##STR00310##
[0976] The disclosure provides ROCK inhibitor prodrugs of Formula
XIIF, Formula XIIIF, and Formula XIVF:
##STR00311##
or a pharmaceutically acceptable composition, salt, or isotopic
derivative thereof wherein
[0977] R.sup.302 and R.sup.333 are independently selected from H,
C.sub.1-C.sub.30alkyl, --C(O)C.sub.1-C.sub.30alkyl,
C.sub.1-C.sub.30heteroalkyl, C.sub.2-C.sub.30alkenyl, and
R.sup.356;
[0978] R.sup.350 is selected from H, C.sub.1-C.sub.30alkyl,
--C(O)C.sub.1-C.sub.30alkyl, C.sub.1-C.sub.30heteroalkyl,
C.sub.2-C.sub.30alkenyl, and R.sup.356;
[0979] R.sup.356 is selected from [0980] (i) polyethylene glycol,
polypropylene glycol, polypropylene oxide, polylactic acid,
poly(lactic-co-glycolic acid) polyglycolic acid, polyester,
polyamide, and other biodegradable polymers, each of which can be
capped to complete the terminal valence or to create a terminal
ether or ester;
##STR00312## ##STR00313##
[0981] wherein at least one of R.sup.302, R.sup.333 and R.sup.350
is R.sup.356; and
[0982] wherein all other variables are as defined herein.
[0983] In one embodiment, R.sup.141 is OCH.sub.3.
[0984] In one embodiment, R.sup.301 is selected from
--N(CH.sub.3).sub.2,
##STR00314##
[0985] In one embodiment, R.sup.301 is
##STR00315##
[0986] In one embodiment, R.sup.301 is --OCH.sub.3.
[0987] In one embodiment, R.sup.301 is selected from F and
C.sub.1.
[0988] In one embodiment, R.sup.350 is hydrogen.
[0989] In one embodiment, R.sup.350 is CH.sub.3.
[0990] In one embodiment, R.sup.350 is CH.sub.2H.sub.5.
[0991] In one embodiment, R.sup.356 is
##STR00316##
and R.sup.31a is --C(O)CH.sub.3.
[0992] In one embodiment, R.sup.356 is
##STR00317##
and R.sup.31a is stearoyl.
[0993] In one embodiment, R.sup.356 is
##STR00318##
and R.sup.31a is --C(O)CH.sub.3.
[0994] In one embodiment, R.sup.356 is
##STR00319##
and R.sup.31a is --C(O)CH.sub.3.
[0995] In one embodiment, R.sup.356 is
##STR00320##
and x is an integer between 1 and 6.
[0996] In one embodiment, R.sup.356 is
##STR00321##
and y is 11.
[0997] In one embodiment, R.sup.356 is
##STR00322##
and y is 17.
[0998] In one embodiment, R.sup.333 is
##STR00323##
and R.sup.31a is --C(O)alkyl.
[0999] Non-limiting Examples of Formula XIF and Formula XIIF
include
##STR00324## ##STR00325##
Beta-Blocker Prodrugs
[1000] The disclosure provides beta-blocker prodrugs of Formula IG,
Formula IIG, Formula IIIG, Formula IVG, Formula VG, Formula VIG,
Formula VIIG, and Formula VIIIG:
##STR00326##
[1001] or a pharmaceutically acceptable composition, salt, or
isotopic derivative thereof.
[1002] R.sup.170, R.sup.171, and R.sup.172 are independently
selected from: R.sup.1, R.sup.173, acyl, carbonyl linked
polyethylene glycol, carbonyl linked polypropylene glycol, carbonyl
linked polypropylene oxide, polylactic acid,
poly(lactic-co-glycolic acid), polyglycolic acid, polyester,
polyamide, or other biodegradable polymer, each of which R.sup.170,
R.sup.171, and R.sup.172 other than R.sup.173 are optionally
substituted with L.sup.8-R.sup.121;
[1003] wherein at least one of R.sup.170, R.sup.171, and R.sup.172
is R.sup.173 or substituted with L.sup.8-R.sup.121
[1004] R.sup.180 is C.sub.1-C.sub.6 alkyl, acyl, or hydrogen;
[1005] R.sup.181 is selected from:
##STR00327##
and R.sup.185;
[1006] R.sup.182 is independently selected from alkyl, cycloalkyl,
aryl, heteroaryl, heterocycle, cyano, amino, hydroxyl, and acyl,
each of which R.sup.182 is optionally substituted with a R.sup.170
group;
[1007] R.sup.183 is independently selected from alkyl, cycloalkyl,
aryl, heteroaryl, heterocycle, amino, hydroxyl, and acyl;
[1008] or two R.sup.183 groups with the carbon to which they are
linked form a carbonyl group; or two R.sup.183 groups with the
carbon(s) to which they are linked form a fused or spirocyclic
ring;
[1009] R.sup.184 is selected from alkyl, cycloalkyl, R.sup.170, and
acyl;
[1010] R.sup.185 is selected from aryl, heteroaryl, cycloalkyl, and
heterocycle, wherein each R.sup.185 is optionally substituted with
1, 2, 3, or 4 R.sup.182 groups;
[1011] R.sup.173 is selected from:
##STR00328## ##STR00329## ##STR00330## ##STR00331##
##STR00332##
and [1012] wherein all other variables are defined herein.
[1013] The disclosure provides beta-blocker prodrugs of Formula
IXG, Formula XG, Formula IIIG, Formula XIG, Formula XIIG, Formula
XIIIG, Formula XIVG, Formula XVG, and Formula XVIG:
##STR00333##
[1014] or a pharmaceutically acceptable composition, salt, or
isotopic derivative thereof wherein
[1015] R.sup.175, R.sup.176, and R.sup.177 are independently
selected from: C(O)A, C(O)R.sup.4, and R.sup.178; wherein at least
one of R.sup.175, R.sup.176, and R.sup.177 is R.sup.178; and
[1016] wherein all other variables are as defined herein.
[1017] In some embodiments the compounds of Formula IXG to Formula
XVIG can be used in the form of an R enantiomer, an S enantiomer,
or a mixture of enantiomers including a racemic mixture.
[1018] In some embodiments the compounds of Formula IXG to Formula
XVIG have the same stereochemistry as the corresponding commercial
drug.
Loop Diuretic Prodrugs, Including Ethacrynic Acid Prodrugs
[1019] The disclosure provides ethacrynic acid prodrugs of Formula
IH:
##STR00334##
[1020] or a pharmaceutically acceptable composition, salt, or
isotopic derivative thereof.
[1021] R.sup.611 is selected from: [1022] (i)
--C(O)OC.sub.5-C.sub.30alkylR.sup.5,
--C(O)OC.sub.2-C.sub.30alkenylR.sup.5,
--C(O)OC.sub.2-C.sub.30alkynylR.sup.5,
--C(O)OC.sub.4-C.sub.30alkenylalkynylR.sup.5,
--C(O)OC.sub.5-C.sub.30alkyl, --C(O)OC.sub.2-C.sub.30alkenyl,
--C(O)OC.sub.2-C.sub.30alkynyl, and
--C(O)OC.sub.4-C.sub.30alkenylalkynyl; [1023] (ii)
--C(O)O(C.sub.1-30alkyl with at least one R.sup.5 substituent on
the alkyl chain, --C(O)O(C.sub.1-30alkenyl, with at least one
R.sup.5 substituent on the alkenyl chain, and
--C(O)O(C.sub.1-30alkynyl, with at least one R.sup.5 substituent on
the alkynyl chain; [1024] (iii)
--C(O)(OCH.sub.2C(O)).sub.1-20C.sub.1-30alkyl,
--C(O)(OCH(CH.sub.3)C(O)).sub.1-20C.sub.1-30alkyl,
--C(O)(OCH.sub.2C(O)).sub.1-10C.sub.1-30alkyl,
--C(O)(OCH(CH.sub.3)C(O)).sub.1-10C.sub.1-30alkyl,
--C(O)(OCH.sub.2C(O)).sub.4-20C-30alkyl,
--C(O)(OCH(CH.sub.3)C(O)).sub.4-20C.sub.1-30alkyl,
--C(O)(OCH.sub.2C(O)).sub.1-20C.sub.1-10alkyl,
--C(O)(OCH(CH.sub.3)C(O)).sub.1-20C.sub.1-10alkyl,
--C(O)(OCH.sub.2C(O)).sub.1-20C.sub.4-10alkyl,
--C(O)(OCH(CH.sub.3)C(O)).sub.1-20C.sub.4-10alkyl,
--C(O)(OCH.sub.2C(O)).sub.1-20OH,
--C(O)(OCH(CH.sub.3)C(O)).sub.1-20OH,
--C(O)(OCH.sub.2C(O)).sub.1-10OH,
--C(O)(OCH(CH.sub.3)C(O)).sub.1-10OH,
--C(O)(OCH.sub.2C(O)).sub.4-20OH,
--C(O)(OCH(CH.sub.3)C(O)).sub.4-20OH,
--C(O)(OCH.sub.2C(O)).sub.4-10OH,
--C(O)(OCH(CH.sub.3)C(O)).sub.4-10OH,
--C(O)(OCH(CH.sub.3)C(O)).sub.4-10OC.sub.1-10alkyl,
--C(O)(OCH.sub.2C(O)).sub.4-10OC.sub.1-10alkyl,
--C(O)(OCH(CH.sub.3)C(O)).sub.1-10OC.sub.1-10alkyl,
--C(O)(OCH.sub.2C(O)).sub.1-10OC.sub.1-10alkyl,
--C(O)(OCH(CH.sub.3)C(O)).sub.1-10C.sub.4-10alkyl,
--C(O)(OCH.sub.2C(O)).sub.1-10C.sub.4-10alkyl,
--C(O)(OCH.sub.2C(O)).sub.1-10C.sub.4-10alkyl,
--C(O)(OCH(CH.sub.3)C(O)).sub.1-10C.sub.4-10alkyl,
--C(O)(OCH.sub.2C(O)).sub.1-10C.sub.4-10alkyl,
--C(O)(OCH(CH.sub.3)C(O)).sub.1-10C.sub.4-10alkyl,
--C(O)(OCH.sub.2C(O)).sub.1-10(OCH(CH.sub.3)C(O)).sub.1-10C.sub.1-30alkyl-
,
--C(O)(OCH.sub.2C(O)).sub.2-10(OCH(CH.sub.3)C(O)).sub.2-10OC-30alkyl,
--C(O)(OCH.sub.2C(O)).sub.1-10(OCH(CH.sub.3)C(O)).sub.1-10C.sub.1-12alkyl-
,
--C(O)(OCH.sub.2C(O)).sub.1-10(OCH(CH.sub.3)C(O)).sub.1-10C.sub.4-22alky-
l,
--C(O)(OCH(CH.sub.3)C(O)).sub.1-10(OCH.sub.2C(O)).sub.1-10OC.sub.1-30al-
kyl,
--C(O)(OCH(CH.sub.3)C(O)).sub.2-10(OCH.sub.2C(O)).sub.2-10OC.sub.1-30-
alkyl,
--C(O)(OCH(CH.sub.3)C(O)).sub.1-10(OCH.sub.2C(O)).sub.1-10C.sub.1-1-
2alkyl, and
--C(O)(OCH(CH.sub.3)C(O)).sub.1-10(OCH.sub.2C(O)).sub.1-10OC.sub.4-22alky-
l; [1025] (iv) polypropylene glycol, polypropylene oxide,
polylactic acid, poly(lactic-co-glycolic acid), polyglycolic acid,
polyester, polyamide, and other biodegradable polymers, each of
which can be capped to complete the terminal valence or to create a
terminal ether or ester; and [1026] (v)
##STR00335## ##STR00336## ##STR00337##
[1027] R.sup.620 is hydrogen, alkyl, alkenyl, alkynyl cycloalkyl,
cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, arylalkyl,
heteroaryl, or heteroarylalkyl, each of which except hydrogen, may
be optionally substituted, for example with halogen, alkyl, aryl,
heterocycle or heteroaryl if desired and if the resulting compound
is stable and achieves the desired purpose, wherein the group
cannot be substituted with itself, for example alkyl would not be
substituted with alkyl;
[1028] tt is any integer between 4 and 10 (4, 5, 6, 7, 8, 9, or
10); and
[1029] wherein all other integers are as defined herein.
[1030] In one embodiment, x, y, and z are independently an integer
between 1 and 12 (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12).
[1031] In one embodiment, x, y, and z are independently an integer
between 1 and 10 (1, 2, 3, 4, 5, 6, 7, 8, 9, or 10).
[1032] In one embodiment, x, y, and z are independently an integer
between 1 and 8 (1, 2, 3, 4, 5, 6, 7, or 8).
[1033] In one embodiment, x, y, and z are independently an integer
between 1 and 6 (1, 2, 3, 4, 5, or 6).
[1034] In one embodiment, x, y, and z are independently an integer
between 4 and 10 (4, 5, 6, 7, 8, 9, or 10).
[1035] In one embodiment, x is an integer between 1 and 12 (1, 2,
3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) and y is an integer between 1
and 6 (1, 2, 3, 4, 5, or 6).
[1036] In one embodiment, y is an integer between 1 and 12 (1, 2,
3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) and x is an integer between 1
and 6 (1, 2, 3, 4, 5, or 6).
[1037] In one embodiment, x is an integer between 1 and 6 (1, 2, 3,
4, 5, or 6) and y is an integer between 1 and 3 (1, 2, or 3).
[1038] In one embodiment, y is an integer between 1 and 6 (1, 2, 3,
4, 5, or 6) and x is an integer between 1 and 3 (1, 2, or 3).
[1039] In one embodiment x is 1 and y is 1.
[1040] In one embodiment x is 1 and y is 2.
[1041] In one embodiment x is 1 and y is 3.
[1042] In one embodiment x is 1 and y is 4.
[1043] In one embodiment x is 1 and y is 5.
[1044] In one embodiment x is 1 and y is 6.
[1045] In one embodiment x is 1 and y is 7.
[1046] In one embodiment x is 1 and y is 8.
[1047] In one embodiment x is 2 and y is 1.
[1048] In one embodiment x is 2 and y is 2.
[1049] In one embodiment x is 2 and y is 3.
[1050] In one embodiment x is 2 and y is 4.
[1051] In one embodiment x is 2 and y is 5.
[1052] In one embodiment x is 2 and y is 6.
[1053] In one embodiment x is 2 and y is 7.
[1054] In one embodiment x is 2 and y is 8.
[1055] In certain embodiments, x and y are independently selected
from 1, 2, 3, 4, 5, or 6, and z is 1.
[1056] In certain embodiments, x and y are independently selected
from 1, 2, 3, 4, 5, or 6, and z is 2.
[1057] In one embodiment, R.sup.611 is
##STR00338##
[1058] In one embodiment, R.sup.611 is
##STR00339##
[1059] In one embodiment, R.sup.611 is
##STR00340##
[1060] In one embodiment, R.sup.611 is
--C(O)(OCH(CH.sub.3)C(O)).sub.4-20CH.sub.2CH.sub.3.
[1061] In one embodiment, R.sup.611 is
--C(O)(OCH(CH.sub.3)C(O)).sub.4-20O(CH.sub.2).sub.10CH.sub.3.
[1062] In one embodiment, R.sup.611 is
--C(O)(OCH(CH.sub.3)C(O)).sub.4-20O(CH.sub.2).sub.16CH.sub.3.
[1063] In one embodiment, R.sup.611 is
--C(O)(OCH(CH.sub.3)C(O)).sub.4OCH.sub.2CH.sub.3.
[1064] In one embodiment, R.sup.611 is
--C(O)(OCH(CH.sub.3)C(O)).sub.4O(CH.sub.2).sub.10CH.sub.3.
[1065] In one embodiment, R.sup.611 is
--C(O)(OCH(CH.sub.3)C(O)).sub.4OCH.sub.2).sub.16CH.sub.3.
[1066] In one embodiment, R.sup.611 is
--C(O)(OCH(CH.sub.3)C(O)).sub.6COCH.sub.2CH.sub.3.
[1067] In one embodiment, R.sup.611 is
--C(O)(OCH(CH.sub.3)C(O)).sub.6O(CH.sub.2).sub.1OCH.sub.3.
[1068] In one embodiment, R.sup.611 is
--C(O)(OCH(CH.sub.3)C(O)).sub.6O(CH.sub.2).sub.16CH.sub.3.
[1069] In one embodiment, R.sup.611 is
--C(O)(OCH(CH.sub.3)C(O)).sub.8OCH.sub.2CH.sub.3.
[1070] In one embodiment, R.sup.611 is
--C(O)(OCH(CH.sub.3)C(O)).sub.8O(CH.sub.2).sub.1OCH.sub.3.
[1071] In one embodiment, R.sup.611 is
--C(O)(OCH(CH.sub.3)C(O)).sub.8O(CH.sub.2).sub.16CH.sub.3.
[1072] In one embodiment, R.sup.611 is
--C(O)(OCH(CH.sub.3)C(O)).sub.4-20O(CH.sub.2).sub.9-17CH.sub.3.
[1073] In one embodiment, R.sup.611 is
--C(O)(OCH(CH.sub.3)C(O)).sub.4-20O(CH.sub.2).sub.11-17CH.sub.3.
[1074] In one embodiment, R.sup.611 is
--C(O)(OCH(CH.sub.3)C(O)).sub.4-20O(CH.sub.2).sub.13-17CH.sub.3.
[1075] In one embodiment, R.sup.611 is
--C(O)(OCH(CH.sub.3)C(O)).sub.4-20O(CH.sub.2).sub.15-17CH.sub.3.
[1076] In one embodiment, R.sup.611 is
--C(O)(OCH(CH.sub.3)C(O)).sub.4-20O(CH.sub.2).sub.11CH.sub.3.
[1077] In one embodiment, R.sup.611 is
--C(O)(OCH(CH.sub.3)C(O)).sub.4-20O(CH.sub.2).sub.17CH.sub.3.
[1078] In one embodiment, R.sup.611 is
--C(O)(OCH.sub.2C(O)).sub.1-2(OCH(CH.sub.3)C(O)).sub.4-2OCH.sub.2CH.sub.3-
.
[1079] In one embodiment, R.sup.611 is
--C(O)(OCH.sub.2C(O)).sub.1-2(OCH(CH.sub.3)C(O)).sub.4-20O(CH.sub.2).sub.-
11CH.sub.3.
[1080] In one embodiment, R.sup.611 is
--C(O)(OCH.sub.2C(O)).sub.1-2(OCH(CH.sub.3)C(O)).sub.4-20O(CH.sub.2).sub.-
17CH.sub.3.
[1081] In one embodiment, R.sup.611 is
--C(O)(OCH.sub.2C(O)).sub.1-2(OCH(CH.sub.3)C(O)).sub.4-20O(CH.sub.2).sub.-
9-17CH.sub.3.
[1082] In one embodiment, R.sup.611 is
--C(O)(OCH.sub.2C(O)).sub.1-2(OCH(CH.sub.3)C(O)).sub.4-20O(CH.sub.2).sub.-
11-17CH.sub.3.
[1083] In one embodiment, R.sup.611 is
--C(O)(OCH.sub.2C(O)).sub.1-2(OCH(CH.sub.3)C(O)).sub.4-20O(CH.sub.2).sub.-
13-17CH.sub.3.
[1084] In one embodiment, R.sup.611 is
--C(O)(OCH.sub.2C(O)).sub.1-2(OCH(CH.sub.3)C(O)).sub.4-20O(CH.sub.2).sub.-
15-17CH.sub.3.
[1085] In one embodiment, C.sub.1-30alkyl as used in the definition
of R.sup.611 is C.sub.1-28, C.sub.1-26, C.sub.1-24, C.sub.1-22,
C.sub.1-20, C.sub.1-18, C.sub.1-16, C.sub.1-14, C.sub.1-12,
C.sub.1-10, C.sub.1-8, C.sub.1-6, or C.sub.1-4.
[1086] The disclosure provides ECA prodrugs of Formula IIH and
Formula IIIH:
##STR00341##
[1087] or a pharmaceutically acceptable composition, salt, or
isotopic derivative thereof.
[1088] R.sup.613 is selected from:
##STR00342## ##STR00343##
R.sup.122 is selected from:
##STR00344## ##STR00345## ##STR00346## ##STR00347## ##STR00348##
##STR00349## ##STR00350## ##STR00351## ##STR00352## ##STR00353##
##STR00354## ##STR00355## ##STR00356## ##STR00357##
and
[1089] wherein all other variables are as defined herein.
[1090] In one embodiment of Formula IIH, R.sup.613 is
##STR00358##
and x is 4.
[1091] In one embodiment of Formula IIH, R.sup.121 is selected
from
##STR00359## ##STR00360##
[1092] In one embodiment, x and y are independently an integer
between 1 and 12 (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12).
[1093] In one embodiment, x and y are independently an integer
between 1 and 10 (1, 2, 3, 4, 5, 6, 7, 8, 9, or 10).
[1094] In one embodiment, x and y are independently an integer
between 1 and 8 (1, 2, 3, 4, 5, 6, 7, or 8).
[1095] In one embodiment, x and y are independently an integer
between 1 and 6 (1, 2, 3, 4, 5, or 6).
[1096] In one embodiment, x and y are independently an integer
between 4 and 10 (4, 5, 6, 7, 8, 9, or 10).
[1097] In one embodiment, x is an integer between 1 and 12 (1, 2,
3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) and y is an integer between 1
and 6 (1, 2, 3, 4, 5, or 6).
[1098] In one embodiment, y is an integer between 1 and 12 (1, 2,
3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) and x is an integer between 1
and 6 (1, 2, 3, 4, 5, or 6).
[1099] In one embodiment, x is an integer between 1 and 6 (1, 2, 3,
4, 5, or 6) and y is an integer between 1 and 3 (1, 2, or 3).
[1100] In one embodiment, y is an integer between 1 and 6 (1, 2, 3,
4, 5, or 6) and x is an integer between 1 and 3 (1, 2, or 3).
[1101] In one embodiment x is 1 and y is 1.
[1102] In one embodiment x is 1 and y is 2.
[1103] In one embodiment x is 1 and y is 3.
[1104] In one embodiment x is 1 and y is 4.
[1105] In one embodiment x is 1 and y is 5.
[1106] In one embodiment x is 1 and y is 6.
[1107] In one embodiment x is 1 and y is 7.
[1108] In one embodiment x is 1 and y is 8.
[1109] In one embodiment x is 2 and y is 1.
[1110] In one embodiment x is 2 and y is 2.
[1111] In one embodiment x is 2 and y is 3.
[1112] In one embodiment x is 2 and y is 4.
[1113] In one embodiment x is 2 and y is 5.
[1114] In one embodiment x is 2 and y is 6.
[1115] In one embodiment x is 2 and y is 7.
[1116] In one embodiment x is 2 and y is 8.
[1117] The disclosure provides loop diuretic prodrugs of Formula
IVH, Formula VH, Formula VIH, Formula VIIH, and Formula VIIIH:
##STR00361##
[1118] or a pharmaceutically acceptable composition, salt, or
isotopic derivative thereof.
[1119] R.sup.701 is selected from: [1120] (i)
--OC.sub.15-C.sub.30alkylR.sup.5,
--OC.sub.2-C.sub.30alkenylR.sup.5,
--OC.sub.2-C.sub.30alkynylR.sup.5,
--OC.sub.4-C.sub.30alkenylalkynylR.sup.5,
--OC.sub.15-C.sub.30alkyl, --OC.sub.2-C.sub.30alkenyl,
--OC.sub.2-C.sub.30alkynyl, and --OC.sub.4-C.sub.30alkenylalkynyl;
[1121] (ii) --OC.sub.15-30alkyl with at least one R.sup.5
substituent on the alkyl chain, --OC.sub.1-30alkenyl with at least
one R.sup.5 substituent on the alkenyl chain, and
--OC.sub.1-30alkynyl with at least one R.sup.5 substituent on the
alkynyl chain; [1122] (iii)
--(OCH.sub.2C(O)).sub.1-20C.sub.1-3alkyl,
--(OCH(CH.sub.3)C(O)).sub.1-20C.sub.1-3alkyl,
--(OCH.sub.2C(O)).sub.1-10C.sub.1-30alkyl,
--(OCH(CH.sub.3)C(O)).sub.1-10OC.sub.1-30alkyl,
--(OCH.sub.2C(O)).sub.4-20C.sub.1-30alkyl,
--(OCH(CH.sub.3)C(O)).sub.4-20C.sub.1-30alkyl,
--(OCH.sub.2C(O)).sub.1-20C.sub.1-10alkyl,
--(OCH(CH.sub.3)C(O)).sub.1-20C.sub.1-10alkyl,
--(OCH.sub.2C(O)).sub.1-20C.sub.4-10alkyl,
--(OCH(CH.sub.3)C(O)).sub.1-20C.sub.4-10alkyl,
--(OCH.sub.2C(O)).sub.1-20OH, --(OCH(CH.sub.3)C(O)).sub.1-20OH,
--(OCH.sub.2C(O)).sub.1-10OH, --(OCH(CH.sub.3)C(O)).sub.1-10OH,
--(OCH.sub.2C(O)).sub.4-20OH, --(OCH(CH.sub.3)C(O)).sub.4-20OH,
--(OCH.sub.2C(O)).sub.4-10OH, --(OCH(CH.sub.3)C(O)).sub.4-10OH,
--(OCH(CH.sub.3)C(O)).sub.4-10OC.sub.1-10alkyl,
--(OCH.sub.2C(O)).sub.4-10OC.sub.1-10alkyl,
--(OCH(CH.sub.3)C(O)).sub.1-10OC.sub.1-10alkyl,
--(OCH.sub.2C(O)).sub.1-10OC.sub.1-10alkyl,
--(OCH(CH.sub.3)C(O)).sub.1-10OC.sub.4-10alkyl,
--(OCH.sub.2C(O)).sub.1-10C.sub.4-10alkyl,
--(OCH.sub.2C(O)).sub.1-10OC.sub.4-10alkyl,
--(OCH(CH.sub.3)C(O)).sub.1-10OC.sub.4-10alkyl,
--(OCH.sub.2C(O)).sub.1-10OC.sub.4-10alkyl,
--(OCH(CH.sub.3)C(O)).sub.1-10OC.sub.4-10alkyl,
--(OCH.sub.2C(O)).sub.1-10(OCH(CH.sub.3)C(O)).sub.1-10OC.sub.1-30alkyl,
--(OCH.sub.2C(O)).sub.2-10(OCH(CH.sub.3)C(O)).sub.2-10OC.sub.1-30alkyl,
--(OCH.sub.2C(O)).sub.1-10(OCH(CH.sub.3)C(O)).sub.1-10OC.sub.1-12alkyl,
--(OCH.sub.2C(O)).sub.1-10(OCH(CH.sub.3)C(O)).sub.1-10C.sub.4-22alkyl,
--(OCH(CH.sub.3)C(O)).sub.1-10(OCH.sub.2C(O)).sub.1-10OC.sub.1-3alkyl,
--(OCH(CH.sub.3)C(O)).sub.2-10(OCH.sub.2C(O)).sub.2-10OC.sub.1-3alkyl,
--(OCH(CH.sub.3)C(O)).sub.1-10(OCH.sub.2C(O)).sub.1-10OC.sub.1-12alkyl,
and
--(OCH(CH.sub.3)C(O)).sub.1-10(OCH.sub.2C(O)).sub.1-10OC.sub.4-22alky-
l; [1123] (iv) polypropylene glycol, polypropylene oxide,
polylactic acid, poly(lactic-co-glycolic acid), polyglycolic acid,
a polyester, a polyamide, and other biodegradable polymers, each of
which can be capped to complete the terminal valence or to create a
terminal ether or ester;
##STR00362## ##STR00363##
[1123] and [1124] (v) --OH;
[1125] wherein R.sup.701 cannot be OH when R.sup.751 and R.sup.752
are both hydrogen;
[1126] R.sup.751 and R.sup.752 are independently selected from
hydrogen,
##STR00364##
and
[1127] wherein all other variables are as defined herein.
[1128] In certain embodiments, x and y are independently selected
from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.
[1129] In certain embodiments, x and y are independently selected
from 1, 2, 3, 4, 5, and 6.
[1130] In certain embodiments, x and y are independently selected
from 1, 2, 3, 4, 5, and 6.
[1131] In certain embodiments, x and y are independently selected
from 1, 2, 3, and 4.
[1132] In certain embodiments, x and y are independently selected
from 1, 2, and 3.
[1133] In certain embodiments, x is selected from 1, 2, 3, 4, 5,
and 6 and y is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and
12.
[1134] In certain embodiments, y is selected from 1, 2, 3, 4, 5,
and 6 and x is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and
12.
[1135] In certain embodiments, x is selected from 1, 2, 3, 4, 5,
and 6 and y is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and
12.
[1136] In certain embodiments, y is selected from 1, 2, 3, 4, 5,
and 6 and x is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and
12.
[1137] In certain embodiments, x is selected from 1, 2, and 3 and y
is selected from 1, 2, 3, 4, 5, and 6.
[1138] In certain embodiments, x is selected from 1, 2, 3, 4, 5,
and 6, and y is selected from 1, 2, and 3.
[1139] In certain embodiments, x is selected from 1, 2, 3, 4, 5, 6,
7, 8, 9, 10, 11, and 12 and xx is selected from 1, 2, 3, 4, 5, and
6.
[1140] In certain embodiments, x is selected from 1, 2, 3, 4, 5,
and 6 and xx is selected from 1, 2, and 3.
[1141] In certain embodiments, x is 1, 2, or 3 and xx is 1.
[1142] In certain embodiments, x is 1, 2, or 3 and xx is 2.
[1143] In certain embodiments, x is 1, 2, or 3 and xx is 3.
[1144] In one embodiment, R.sup.701 is
##STR00365##
[1145] In one embodiment, R.sup.701 is
##STR00366##
[1146] In one embodiment, R.sup.701 is
##STR00367##
[1147] In one embodiment, R.sup.701 is
##STR00368##
[1148] In one embodiment, R.sup.701 is
##STR00369##
[1149] In one embodiment, R.sup.701 is
##STR00370##
[1150] In one embodiment, R.sup.701 is
##STR00371##
[1151] In one embodiment, R.sup.701 is
--(OCH(CH.sub.3)C(O)).sub.4-20CH.sub.2CH.sub.3.
[1152] In one embodiment, R.sup.701 is
--(OCH(CH.sub.3)C(O)).sub.4-20O(CH.sub.2).sub.11CH.sub.3.
[1153] In one embodiment, R.sup.701 is
--(OCH(CH.sub.3)C(O)).sub.4-20O(CH.sub.2).sub.17CH.sub.3.
[1154] In one embodiment, R.sup.701 is
--(OCH(CH.sub.3)C(O)).sub.4OCH.sub.2CH.sub.3.
[1155] In one embodiment, R.sup.701 is
--(OCH(CH.sub.3)C(O)).sub.4O(CH.sub.2).sub.11CH.sub.3.
[1156] In one embodiment, R.sup.701 is
--(OCH(CH.sub.3)C(O)).sub.4OCH.sub.2).sub.17CH.sub.3.
[1157] In one embodiment, R.sup.701 is
--(OCH(CH.sub.3)C(O)).sub.6COCH.sub.2CH.sub.3.
[1158] In one embodiment, R.sup.701 is
--(OCH(CH.sub.3)C(O)).sub.6O(CH.sub.2).sub.11CH.sub.3.
[1159] In one embodiment, R.sup.701 is
--(OCH(CH.sub.3)C(O)).sub.6O(CH.sub.2).sub.17CH.sub.3.
[1160] In one embodiment, R.sup.701 is
--(OCH(CH.sub.3)C(O)).sub.8OOCH.sub.2CH.sub.3.
[1161] In one embodiment, R.sup.701 is
--(OCH(CH.sub.3)C(O)).sub.8O(CH.sub.2).sub.11CH.sub.3.
[1162] In one embodiment, R.sup.701 is
--(OCH(CH.sub.3)C(O)).sub.8O(CH.sub.2).sub.17CH.sub.3.
[1163] In one embodiment, R.sup.701 is
--(OCH.sub.2C(O))(OCH(CH.sub.3)C(O)).sub.4-2OCH.sub.2CH.sub.3.
[1164] In one embodiment, R.sup.701 is
--(OCH.sub.2C(O)).sub.2(OCH(CH.sub.3)C(O)).sub.4-2OCH.sub.2CH.sub.3.
[1165] In one embodiment, R.sup.701 is
--(OCH.sub.2C(O))(OCH(CH.sub.3)C(O)).sub.4-10OCH.sub.2CH.sub.3.
[1166] In one embodiment, R.sup.701 is
--(OCH.sub.2C(O)).sub.2(OCH(CH.sub.3)C(O)).sub.4-10OCH.sub.2CH.sub.3.
[1167] In one embodiment, R.sup.701 is
--(OCH.sub.2C(O))(OCH(CH.sub.3)C(O)).sub.6OCH.sub.2CH.sub.3.
[1168] In one embodiment, R.sup.701 is
--(OCH.sub.2C(O)).sub.2(OCH(CH.sub.3)C(O)).sub.6OCH.sub.2CH.sub.3.
[1169] In one embodiment, R.sup.701 is
--(OCH(CH.sub.3)C(O)).sub.4-20O(CH.sub.2).sub.9-17CH.sub.3.
[1170] In one embodiment, R.sup.701 is
--(OCH(CH.sub.3)C(O)).sub.4-20O(CH.sub.2).sub.11-17CH.sub.3.
[1171] In one embodiment, R.sup.701 is
--(OCH(CH.sub.3)C(O)).sub.4-20O(CH.sub.2).sub.13-17CH.sub.3.
[1172] In one embodiment, R.sup.701 is
--(OCH(CH.sub.3)C(O)).sub.4-20O(CH.sub.2).sub.15-17CH.sub.3.
[1173] In one embodiment, R.sup.701 is
--(OCH(CH.sub.3)C(O)).sub.4-20O(CH.sub.2).sub.11CH.sub.3.
[1174] In one embodiment, R.sup.701 is
--(OCH(CH.sub.3)C(O)).sub.4-20O(CH.sub.2).sub.17CH.sub.3.
[1175] In one embodiment, R.sup.701 is
--(OCH.sub.2C(O)).sub.1-2(OCH(CH.sub.3)C(O)).sub.4-2OCH.sub.2CH.sub.3.
[1176] In one embodiment, R.sup.701 is
--(OCH.sub.2C(O)).sub.1-2(OCH(CH.sub.3)C(O)).sub.4-20O(CH.sub.2).sub.11CH-
.sub.3.
[1177] In one embodiment, R.sup.701 is
--(OCH.sub.2C(O)).sub.1-2(OCH(CH.sub.3)C(O)).sub.4-20O(CH.sub.2).sub.17CH-
.sub.3.
[1178] In one embodiment, R.sup.701 is
--(OCH.sub.2C(O)).sub.1-2(OCH(CH.sub.3)C(O)).sub.4-20O(CH.sub.2).sub.9-17-
CH.sub.3.
[1179] In one embodiment, R.sup.701 is
--(OCH.sub.2C(O)).sub.1-2(OCH(CH.sub.3)C(O)).sub.4-20O(CH.sub.2).sub.11-1-
7CH.sub.3.
[1180] In one embodiment, R.sup.701 is
--(OCH.sub.2C(O)).sub.1-2(OCH(CH.sub.3)C(O)).sub.4-20O(CH.sub.2).sub.13-1-
7CH.sub.3.
[1181] In one embodiment, R.sup.701 is
--(OCH.sub.2C(O)).sub.1-2(OCH(CH.sub.3)C(O)).sub.4-20O(CH.sub.2).sub.15-1-
7CH.sub.3.
[1182] In one embodiment, C.sub.1-30alkyl as used in the definition
of R.sup.701 is C.sub.1-28, C.sub.1-26, C.sub.1-24, C.sub.1-22,
C.sub.1-20, C.sub.1-18, C.sub.1-16, C.sub.1-14, C.sub.1-12,
C.sub.1-10, C.sub.1-8, C.sub.1-6, or C.sub.1-4.
[1183] In one embodiment the prodrug of Formula IVH, Formula VH, or
Formula VIH is selected from:
##STR00372##
[1184] The disclosure provides loop diuretic prodrugs of Formula
IXH, Formula XH, Formula XIH, Formula XIIH, and Formula XIIIH:
##STR00373##
[1185] or a pharmaceutically acceptable composition, salt, or
isotopic derivative thereof.
[1186] R.sup.740 is selected from: [1187] (i)
##STR00374## ##STR00375##
[1187] and [1188] (ii) --OH
[1189] wherein R.sup.740 cannot be --OH when R.sup.61 and R.sup.62
are both hydrogen;
[1190] R.sup.61 and R.sup.62 are independently selected from
hydrogen,
##STR00376##
[1191] wherein all other variables are as defined herein.
[1192] In one embodiment, R.sup.740 is
##STR00377##
and R.sup.121 is
##STR00378##
[1194] In one embodiment, R.sup.740 is
##STR00379##
and R.sup.121 is
##STR00380##
[1196] In one embodiment R.sup.740 is
##STR00381##
and R.sup.121 is
##STR00382##
[1198] In one embodiment, R.sup.740 is selected from
##STR00383##
and R.sup.121 is
##STR00384##
[1200] In certain embodiments, x and y are independently selected
from 1, 2, 3, 4, 5, and 6.
[1201] In certain embodiments, x and y are independently selected
from 1, 2, 3, and 4.
[1202] In certain embodiments, x and y are independently selected
from 1, 2, and 3.
[1203] In certain embodiments, x is selected from 1, 2, 3, 4, 5,
and 6 and y is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and
12.
[1204] In certain embodiments, y is selected from 1, 2, 3, 4, 5,
and 6 and x is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and
12.
[1205] In certain embodiments, x is selected from 1, 2, and 3 and y
is selected from 1, 2, 3, 4, 5, and 6.
[1206] In certain embodiments, x is selected from 1, 2, 3, 4, 5,
and 6, and y is selected from 1, 2, and 3.
[1207] In certain embodiments, x is selected from 1, 2, 3, 4, 5, 6,
7, 8, 9, 10, 11, and 12 and xx is selected from 1, 2, 3, 4, 5, and
6.
[1208] In certain embodiments, x is selected from 1, 2, 3, 4, 5,
and 6 and z is selected from 1, 2, and 3.
[1209] In certain embodiments, x is 1, 2, or 3 and z is 1.
[1210] In certain embodiments, x is 1, 2, or 3 and z is 2.
[1211] In certain embodiments, x is 1, 2, or 3 and z is 3.
[1212] In one embodiment the prodrug of Formula IXH, Formula XH, or
Formula XIH is selected from:
##STR00385##
[1213] The disclosure provides loop diuretic prodrugs of Formula
XIVH, Formula XVH, Formula XVIH, Formula XVIIH, Formula XVIIIH, and
Formula XIXH:
##STR00386##
[1214] or a pharmaceutically acceptable composition, salt, or
isotopic derivative thereof.
[1215] wherein:
[1216] R.sup.29 is selected from:
##STR00387## ##STR00388##
[1217] R.sup.624 is
##STR00389##
[1218] a, b, and c are independently an integer selected from 0 to
30 (0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,
18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) wherein a
and c cannot both be 0; and
[1219] wherein all other variables are as defined herein.
[1220] The polymer moieties described in Formula XIIC, Formula IXD,
Formula XD, Formula XID, Formula XIID, and Formula XIID' above are
depicted as block copolymers (for example, blocks of "a" followed
by blocks of "b" followed by blocks of "c"), but it is intended
that the polymer can be a random or alternating copolymer (for
example, "a" "b" and "c" are either randomly distributed or
alternate).
[1221] In one embodiment, a, b, and c are independently selected
from an integer between 1 and 12 (1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, or 12).
[1222] In one embodiment, a, b, and c are independently selected
from an integer between 1 and 8 (1, 2, 3, 4, 5, 6, 7, or 8).
[1223] In one embodiment, a, b, and c are independently selected
from an integer between 1 and 6 (1, 2, 3, 4, 5, or 6).
[1224] In one embodiment, a, b, and c are independently selected
from an integer between 1 and 3 (1, 2, or 3).
[1225] In one embodiment, a and c are independently selected from
an integer between 1 and 6 (1, 2, 3, 4, 5, or 6) and b is 1.
[1226] In one embodiment, a and c are independently selected from
an integer between 1 and 3 (1, 2, or 3) and b is 1.
[1227] In one embodiment, a and c are independently selected from
an integer between 1 and 12 (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or
12) and b is selected from an integer between 1 and 6 (1, 2, 3, 4,
5, or 6).
[1228] In one embodiment, a and c are independently selected from
an integer between 1 and 6 (1, 2, 3, 4, 5, or 6) and b is selected
from an integer between 1 and 3 (1, 2, or 3).
[1229] In one embodiment, a and c independently selected from an
integer between 1, 2, 3, and 4 and b is 1.
[1230] In one embodiment, a and c are 2 and b is 1.
[1231] In one embodiment, a and c are 3 and b is 1.
[1232] In one embodiment, a and c are 4 and b is 1.
[1233] In one embodiment the prodrug of Formula XVH, Formula XVIH
or Formula XVIIH is selected from:
##STR00390##
[1234] Table A-Table I show illustrative prodrugs encapsulated in
the microparticles of the present invention. In one aspect of the
invention, a mildly surface-treated microparticle comprising one of
more biodegradable polymers and a prodrug selected from Table
A-Table I encapsulated in the biodegradable polymer is
provided.
[1235] An aspect of the invention is a method for the treatment of
a disorder, comprising administering to a host in need thereof
solid aggregating microparticles comprising an effective amount of
a therapeutic agent selected from a prodrug disclosed herein,
wherein the therapeutic agent containing solid aggregating
microparticles are injected into the body and aggregate in vivo to
form at least one pellet of at least 500 Lm that provides sustained
drug delivery for at least one month.
TABLE-US-00001 TABLE A Non-limiting Examples of Prodrugs Comp. #
Structure 1 ##STR00391## 2 ##STR00392## 3 ##STR00393## 4
##STR00394## 5 ##STR00395## 6 ##STR00396## 7 ##STR00397## 8
##STR00398## 9 ##STR00399## 10 ##STR00400## 11 ##STR00401## 12
##STR00402## 13 ##STR00403## 14 ##STR00404## 15 ##STR00405## 16
##STR00406## 17 ##STR00407## 18 ##STR00408## 19 ##STR00409## 20
##STR00410## 21 ##STR00411## 22 ##STR00412## 23 ##STR00413## 24
##STR00414## 25 ##STR00415## 26 ##STR00416## 27 ##STR00417## 28
##STR00418## 29 ##STR00419## 30 ##STR00420## 31 ##STR00421## 32
##STR00422## 33 ##STR00423## 34 ##STR00424## 35 ##STR00425## 36
##STR00426## 37 ##STR00427## 38 ##STR00428## 39 ##STR00429## 40
##STR00430## 41 ##STR00431## 42 ##STR00432## 43 ##STR00433## 44
##STR00434##
TABLE-US-00002 TABLE B Non-limiting Examples of Prodrugs 45
##STR00435## 46 ##STR00436## 47 ##STR00437## 48 ##STR00438## 49
##STR00439## 50 ##STR00440## 51 ##STR00441## 52 ##STR00442## 53
##STR00443## 54 ##STR00444## 55 ##STR00445## 56 ##STR00446## 57
##STR00447## 58 ##STR00448## 59 ##STR00449## 60 ##STR00450## 61
##STR00451## 62 ##STR00452## 63 ##STR00453## 64 ##STR00454## 65
##STR00455## 66 ##STR00456## 67 ##STR00457## 68 ##STR00458## 69
##STR00459## 70 ##STR00460## 71 ##STR00461## 72 ##STR00462## 73
##STR00463## 74 ##STR00464## 75 ##STR00465## 76 ##STR00466## 77
##STR00467## 78 ##STR00468## 79 ##STR00469## 80 ##STR00470## 81
##STR00471## 82 ##STR00472## 83 ##STR00473## 84 ##STR00474## 85
##STR00475## 86 ##STR00476## 87 ##STR00477## 88 ##STR00478## 89
##STR00479## 90 ##STR00480## 91 ##STR00481## 92 ##STR00482## 93
##STR00483## 94 ##STR00484## 95 ##STR00485## 96 ##STR00486##
TABLE-US-00003 TABLE C Non-limiting Examples of Prodrugs 97
##STR00487## 98 ##STR00488## 99 ##STR00489## 100 ##STR00490## 101
##STR00491## 102 ##STR00492## 103 ##STR00493## 104 ##STR00494## 105
##STR00495## 106 ##STR00496## 107 ##STR00497## 108 ##STR00498## 109
##STR00499## 110 ##STR00500## 111 ##STR00501## 112 ##STR00502## 113
##STR00503## 114 ##STR00504## 115 ##STR00505## 116 ##STR00506## 117
##STR00507## 118 ##STR00508## 119 ##STR00509## 120 ##STR00510## 121
##STR00511## 122 ##STR00512## 123 ##STR00513## 124 ##STR00514## 125
##STR00515## 126 ##STR00516## 127 ##STR00517## 128 ##STR00518## 129
##STR00519## 130 ##STR00520## 131 ##STR00521## 132 ##STR00522## 133
##STR00523## 134 ##STR00524## 135 ##STR00525## 136 ##STR00526## 137
##STR00527## 138 ##STR00528## 139 ##STR00529## 140 ##STR00530## 141
##STR00531## 142 ##STR00532## 143 ##STR00533## 144 ##STR00534## 145
##STR00535## 146 ##STR00536## 147 ##STR00537## 148 ##STR00538## 149
##STR00539## 150 ##STR00540## 151 ##STR00541## 152 ##STR00542## 153
##STR00543## 154 ##STR00544## 155 ##STR00545## 156 ##STR00546## 157
##STR00547## 158 ##STR00548## 159 ##STR00549## 160 ##STR00550## 161
##STR00551## 162 ##STR00552## 163 ##STR00553## 164 ##STR00554## 165
##STR00555## 166 ##STR00556## 167 ##STR00557## 168 ##STR00558## 169
##STR00559## 170 ##STR00560## 171 ##STR00561## 172 ##STR00562## 173
##STR00563## 174 ##STR00564## 175 ##STR00565## 176 ##STR00566## 177
##STR00567## 178 ##STR00568## 179 ##STR00569## 180 ##STR00570## 181
##STR00571## 182 ##STR00572## 183 ##STR00573## 184 ##STR00574## 185
##STR00575## 186 ##STR00576## 187 ##STR00577## 188 ##STR00578## 189
##STR00579## 190 ##STR00580## 191 ##STR00581## 192 ##STR00582## 193
##STR00583## 194 ##STR00584## 195 ##STR00585## 196 ##STR00586## 197
##STR00587## 198 ##STR00588## 199 ##STR00589## 200 ##STR00590## 201
##STR00591## 202 ##STR00592## 203 ##STR00593## 204 ##STR00594##
TABLE-US-00004 TABLE D Non-limiting Examples of Prodrugs 205
##STR00595## 206 ##STR00596## 207 ##STR00597## 208 ##STR00598## 209
##STR00599## 210 ##STR00600## 211 ##STR00601## 212 ##STR00602## 213
##STR00603## 214 ##STR00604## 215 ##STR00605## 216 ##STR00606## 217
##STR00607## 218 ##STR00608## 219 ##STR00609## 220 ##STR00610## 221
##STR00611## 222 ##STR00612## 223 ##STR00613## 224 ##STR00614## 225
##STR00615## 226 ##STR00616## 227 ##STR00617## 228 ##STR00618## 229
##STR00619## 230 ##STR00620## 231 ##STR00621## 232 ##STR00622## 233
##STR00623## 234 ##STR00624## 235 ##STR00625## 236 ##STR00626## 237
##STR00627## 238 ##STR00628## 239 ##STR00629## 240 ##STR00630## 241
##STR00631## 242 ##STR00632## 243 ##STR00633## 244 ##STR00634## 245
##STR00635## 246 ##STR00636## 247 ##STR00637## 248 ##STR00638## 249
##STR00639## 250 ##STR00640## 251 ##STR00641## 252 ##STR00642## 253
##STR00643## 254 ##STR00644## 255 ##STR00645## 256 ##STR00646## 257
##STR00647## 258 ##STR00648## 259 ##STR00649## 260 ##STR00650## 261
##STR00651## 262 ##STR00652## 263 ##STR00653## 264 ##STR00654## 265
##STR00655## 266 ##STR00656## 267 ##STR00657## 268 ##STR00658## 269
##STR00659## 270 ##STR00660## 271 ##STR00661## 272 ##STR00662## 273
##STR00663## 274 ##STR00664## 275 ##STR00665## 276 ##STR00666## 277
##STR00667## 278 ##STR00668## 279 ##STR00669## 280 ##STR00670## 281
##STR00671## 282 ##STR00672## 283 ##STR00673##
TABLE-US-00005 TABLE E Select Compounds of the Present Invention
284 ##STR00674## 285 ##STR00675## 286 ##STR00676## 287 ##STR00677##
288 ##STR00678## 289 ##STR00679## 290 ##STR00680## 291 ##STR00681##
292 ##STR00682## 293 ##STR00683## 294 ##STR00684## 295 ##STR00685##
296 ##STR00686## 297 ##STR00687## 298 ##STR00688## 299 ##STR00689##
300 ##STR00690## 301 ##STR00691## 302 ##STR00692## 303 ##STR00693##
304 ##STR00694## 305 ##STR00695## 306 ##STR00696## 307 ##STR00697##
308 ##STR00698## 309 ##STR00699## 310 ##STR00700## 311 ##STR00701##
312 ##STR00702## 313 ##STR00703## 314 ##STR00704## 315 ##STR00705##
316 ##STR00706## 317 ##STR00707## 318 ##STR00708## 319 ##STR00709##
320 ##STR00710##
TABLE-US-00006 TABLE F Compounds of the Present Invention Compd No.
Structure 321 ##STR00711## 322 ##STR00712## 323 ##STR00713## 324
##STR00714## 325 ##STR00715## 326 ##STR00716## 327 ##STR00717## 328
##STR00718## 329 ##STR00719## 330 ##STR00720## 331 ##STR00721## 332
##STR00722## 333 ##STR00723## 334 ##STR00724## 335 ##STR00725## 336
##STR00726## 337 ##STR00727## 338 ##STR00728## 339 ##STR00729## 340
##STR00730## 341 ##STR00731## 342 ##STR00732## 343 ##STR00733## 344
##STR00734## 345 ##STR00735## 346 ##STR00736## 347 ##STR00737##
TABLE-US-00007 TABLE G Compounds of the Present Invention 348
##STR00738## 349 ##STR00739## 350 ##STR00740## 351 ##STR00741## 352
##STR00742## 353 ##STR00743## 354 ##STR00744## 355 ##STR00745## 356
##STR00746## 357 ##STR00747## 358 ##STR00748## 359 ##STR00749## 360
##STR00750## 361 ##STR00751## 362 ##STR00752##
TABLE-US-00008 TABLE H Additional Compounds of the Present
Invention 363 ##STR00753## 364 ##STR00754## 365 ##STR00755## 366
##STR00756## 367 ##STR00757##
TABLE-US-00009 TABLE I Additional Compounds of the Present
Invention 368 ##STR00758## 369 ##STR00759## 370 ##STR00760## 371
##STR00761## 372 ##STR00762## 373 ##STR00763## 374 ##STR00764## 375
##STR00765##
[1236] In one embodiment, a mildly surface-treated microparticle
comprising one or more biodegradable polymers and a compound of
formula:
##STR00766##
encapsulated in the biodegradable polymer is provided.
[1237] In one embodiment, a mildly surface-treated microparticle
comprising one or more biodegradable polymers and a compound of
formula:
##STR00767##
encapsulated in the biodegradable polymer is provided.
[1238] In one embodiment, a mildly surface-treated microparticle
comprising one or more biodegradable polymers and a compound
selected from:
##STR00768##
encapsulated in the biodegradable polymer is provided.
[1239] In one embodiment, a mildly surface-treated microparticle
comprising one or more biodegradable polymers and a compound
selected from:
encapsulated in the biodegradable polymer is provided.
[1240] In one embodiment, a mildly surface-treated microparticle
comprising one or more biodegradable polymers and a compound
selected from:
##STR00769## ##STR00770##
[1241] In one embodiment, a mildly surface-treated microparticle
comprising one or more
##STR00771##
encapsulated in the biodegradable polymer is provided.
[1242] In one embodiment, a mildly surface-treated microparticle
comprising one or more biodegradable polymers and a compound
selected from:
##STR00772##
encapsulated in the biodegradable polymer is provided.
[1243] In one embodiment, a mildly surface-treated microparticle
comprising one or more biodegradable polymers and a compound
selected from:
##STR00773##
encapsulated in the biodegradable polymer is provided.
##STR00774##
[1244] In one embodiment, a mildly surface-treated microparticle
comprising one or more biodegradable polymers and a compound
selected from:
##STR00775##
encapsulated in the biodegradable polymer is provided.
[1245] In one embodiment, a mildly surface-treated microparticle
comprising one or more
##STR00776## ##STR00777##
encapsulated in the biodegradable polymer is provided.
[1246] In one embodiment, a mildly surface-treated microparticle
comprising one or more biodegradable polymers and a compound
selected from:
##STR00778##
encapsulated in the biodegradable polymer is provided.
VII. Pharmaceutically Acceptable Carriers
[1247] Any suitable pharmaceutically acceptable carrier, for
example, ophthalmically acceptable viscous carrier, may be employed
in accordance with the invention. The carrier is present in an
amount effective in providing the desired viscosity to the drug
delivery system. Advantageously, the viscous carrier is present in
an amount in a range of from about 0.5 wt percent to about 95 wt
percent of the drug delivery particles. The specific amount of the
viscous carrier used depends upon a number of factors including,
for example and without limitation, the specific viscous carrier
used, the molecular weight of the viscous carrier used, the
viscosity desired for the present drug delivery system being
produced and/or used and like factors. Examples of useful viscous
carriers include, but are not limited to, hyaluronic acid, sodium
hyaluronate, carbomers, polyacrylic acid, cellulosic derivatives,
polycarbophil, polyvinylpyrrolidone, gelatin, dextrin,
polysaccharides, polyacrylamide, polyvinyl alcohol (which can be
partially hydrolyzed polyvinyl acetate), polyvinyl acetate,
derivatives thereof and mixtures thereof.
[1248] The carrier can also be an aqueous carrier. Example of
aqueous carriers include, but are not limited to, an aqueous
solution or suspension, such as saline, plasma, bone marrow
aspirate, buffers, such as Hank's Buffered Salt Solution (HBSS),
HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid), Ringers
buffer, ProVisc.RTM., diluted ProVisc.RTM., ProVisc.RTM. diluted
with PBS, Krebs buffer, Dulbecco's PBS, normal PBS; sodium
hyaluronate solution (HA, 5 mg/mL in PBS), simulated body fluids,
plasma platelet concentrate and tissue culture medium or an aqueous
solution or suspension comprising an organic solvent.
[1249] In one embodiment, the carrier is PBS.
[1250] In one embodiment, the carrier is HA, 5 mg/mL in PBS.
[1251] In one embodiment, the carrier is ProVisc.RTM. diluted with
water.
[1252] In one embodiment, the carrier is ProVisc.RTM. dilution in
PBS.
[1253] In one embodiment, the carrier is ProVisc.RTM. 5-fold
diluted with water.
[1254] In one embodiment, the carrier is ProVisc.RTM. 5-fold
dilution in PBS.
[1255] In one embodiment, the carrier is ProVisc.RTM. 10-fold
diluted with water.
[1256] In one embodiment, the carrier is ProVisc.RTM. 10-fold
dilution in PBS.
[1257] In one embodiment, the carrier is ProVisc.RTM. 20-fold
dilution with water.
[1258] In one embodiment, the carrier is ProVisc.RTM. 20-fold
dilution in PBS.
[1259] In one embodiment, the carrier is HA, 1.25 mg/mL in an
isotonic buffer solution with neutral pH.
[1260] In one embodiment, the carrier is HA, 0.625 mg/mL in an
isotonic buffer solution with neutral pH.
[1261] In one embodiment, the carrier is HA, 0.1-5.0 mg/mL in
PBS.
[1262] In one embodiment, the carrier is HA, 0.5-4.5 mg/mL in
PBS.
[1263] In one embodiment, the carrier is HA, 1.0-4.0 mg/mL in
PBS.
[1264] In one embodiment, the carrier is HA, 1.5-3.5 mg/mL in
PBS.
[1265] In one embodiment, the carrier is HA, 2.0-3.0 mg/mL in
PBS.
[1266] In one embodiment, the carrier is HA, 2.5-3.0 mg/mL in
PBS.
[1267] The carrier may, optionally, contain one or more suspending
agent. The suspending agent may be selected from carboxy
methylcellulose (CMC), mannitol, polysorbate, poly propylene
glycol, poly ethylene glycol, gelatin, albumin, alginate, hydroxyl
propyl methyl cellulose (HPMC), hydroxyl ethyl methyl cellulose
(HEMC), bentonite, tragacanth, dextrin, sesame oil, almond oil,
sucrose, acacia gum and xanthan gum and combinations thereof.
[1268] The carrier may, optionally, contain one or more
plasticizers. Thus the carrier may also include a plasticizer. The
plasticizer may, for example, be polyethylene glycol (PEG),
polypropylene glycol, poly (lactic acid) or poly (glycolic acid) or
a copolymer thereof, polycaprolactone, and low molecule weight
oligomers of these polymers, or conventional plasticizers, such as,
adipates, phosphates, phthalates, sabacates, azelates and citrates.
The carrier can also include other known pharmaceutical excipients
in order to improve the stability of the agent.
[1269] In one embodiment, one or more additional excipients or
delivery enhancing agents may also be included e.g., surfactants
and/or hydrogels, in order to further influence release rate.
VIII. Sustained Release of Pharmaceutically Active Compound
[1270] The rate of release of the pharmaceutically active compound
can be related to the concentration of pharmaceutically active
compound dissolved in the surface treated microparticle. In some
embodiments, the polymeric composition of the surface treated
microparticle includes non-therapeutic agents that are selected to
provide a desired solubility of the pharmaceutically active
compound. The selection of the polymeric composition can be made to
provide the desired solubility of the pharmaceutically active
compound in the surface treated microparticle, for example, a
hydrogel may promote solubility of a hydrophilic material. In some
embodiments, functional groups can be added to the polymer to
increase the desired solubility of the pharmaceutically active
compound in the surface treated microparticle. In some embodiments,
additives may be used to control the release kinetics of the
pharmaceutically active compound, for example, the additives may be
used to control the concentration of the pharmaceutically active
compound by increasing or decreasing the solubility of the
pharmaceutically active compound in the polymer so as to control
the release kinetics of the pharmaceutically active compound. The
solubility may be controlled by including appropriate molecules
and/or substances that increase and/or decrease the solubility of
the dissolved form of the pharmaceutically active compound in the
surface treated microparticle. The solubility of the
pharmaceutically active compound may be related to the hydrophobic
and/or hydrophilic properties of the surface treated microparticle
and the pharmaceutically active compound. Oils and hydrophobic
molecules can be added to the polymer(s) to increase the solubility
of a pharmaceutically active compound in the surface treated
microparticle.
[1271] Instead of, or in addition to, controlling the rate of
migration based on the concentration of the pharmaceutically active
compound dissolved in the surface treated microparticle, the
surface area of the polymeric composition can be controlled to
attain the desired rate of drug migration out of the surface
treated microparticle comprising a pharmaceutically active
compound. For example, a larger exposed surface area will increase
the rate of migration of the pharmaceutically active compound to
the surface, and a smaller exposed surface area will decrease the
rate of migration of the pharmaceutically active compound to the
surface. The exposed surface area can be increased in any number of
ways, for example, by castellation of the exposed surface, a porous
surface having exposed channels connected with the tear or tear
film, indentation of the exposed surface, or protrusion of the
exposed surface. The exposed surface can be made porous by the
addition of salts that dissolve and leave a porous cavity once the
salt dissolves. In the present invention, these trends can be used
to decrease the release rate of the active material from the
polymeric composition by avoiding these paths to quicker release.
For example, the surface area can be minimized, or channels can be
avoided.
[1272] Where more than one type of polymer is used, each surface
treated microparticle may have a different solidifying or setting
property. For example, the surface treated microparticles may be
made from similar polymers but may have different gelling pHs or
different melting temperatures or glass transition points.
[1273] In order for the surface treated microparticles to form a
consolidated aggregate, the temperature around the particles, for
example in the human or non-human animal where the composition is
administered, is approximately equal to, or greater than, the glass
transition temperature (T.sub.g) of the polymer particles. At such
temperatures the polymer particles will cross-link to one or more
other polymer particles to form a consolidated aggregate. By
cross-link it is meant that adjacent polymer particles become
joined together. For example, the particles may cross-link due to
entanglement of the polymer chains at the surface of one particle
with polymer chains at the surface of another particle. There may
be adhesion, cohesion or fusion between adjacent particles.
[1274] Typically, the injectable surface treated microparticles
which are formed of a polymer or a polymer blend have a glass
transition temperature (T.sub.g) either close to or just above body
temperature (such as from about 30.degree. C. to 45.degree. C.,
e.g., from about 35.degree. C. to 40.degree. C., for example, from
about 37.degree. C. to 40.degree. C.). Accordingly, at room
temperature the surface treated microparticles are below their
T.sub.g and behave as discrete particles, but in the body the
surface treated microparticles soften and interact/stick to
themselves. Typically, agglomeration begins within 20 seconds to
about 15 minutes of the raise in temperature from room to body
temperature.
[1275] The surface treated microparticles may be formed from a
polymer which has a T.sub.g from about 35.degree. C. to 40.degree.
C., for example from about 37.degree. C. to 40.degree. C., wherein
the polymer is a poly(a-hydroxyacid) (such as PLA, PGA, PLGA, or
PDLLA or a combination thereof), or a blend thereof with PLGA-PEG.
Typically, these particles will agglomerate at body temperature.
The injectable surface treated microparticles may comprise only
poly(a-hydroxyacid) particles or other particle types may be
included. The microparticles can be formed from a blend of
poly(D,L-lactide-co-glycolide)(PLGA), PLGA-PEG and PVA which has a
T.sub.g at or above body temperature. In one embodiment, at body
temperature the surface treated microparticles will interact to
form a consolidated aggregate. The injectable microparticle may
comprise only PLGA/PLGA-PEG/PVA surface treated microparticles or
other particle types may be included.
[1276] The composition may comprise a mixture of temperature
sensitive surface treated microparticles and non-temperature
sensitive surface treated microparticles. Non-temperature sensitive
surface treated microparticles are particles with a glass
transition temperature which is above the temperature at which the
composition is intended to be used. Typically, in a composition
comprising a mixture of temperature sensitive surface treated
microparticles and non-temperature sensitive particles the ratio of
temperature sensitive to non-temperature sensitive surface treated
microparticles is about 3:1, or lower, for example, 4:3. The
temperature sensitive surface treated microparticles are
advantageously capable of crosslinking to each other when the
temperature of the composition is raised to or above the glass
transition of these microparticles. By controlling the ratio of
temperature sensitive surface treated microparticles to
non-temperature sensitive surface treated microparticles it may be
possible to manipulate the porosity of the resulting consolidated
aggregate. The surface treated microparticles may be solid, that is
with a solid outer surface, or they may be porous. The particles
may be irregular or substantially spherical in shape.
[1277] The surface treated microparticles can have a size in their
longest dimension, or their diameter if they are substantially
spherical, of less than about 100 .mu.m and more than about 1 m.
The surface treated microparticles can have a size in their longest
dimension, or their diameter, of less than about 100 m. The surface
treated microparticles can have a size in their longest dimension,
or their diameter, of between about 1 .mu.m and about 40 .mu.m,
more typically, between about 20 .mu.m and about 40 .mu.m. Polymer
particles of the desired size will pass through a sieve or filter
with a pore size of about 40 .mu.m.
[1278] Formation of the consolidated aggregate from the
composition, once administered to a human or non-human animal,
typically takes from about 20 seconds to about 24 hours, for
example, between about 1 minute and about 5 hours, between about 1
minute and about 1 hour, less than about 30 minutes, less than
about 20 minutes. Typically, the solidification occurs in between
about 1 minute and about 20 minutes from administration.
[1279] Typically, the composition comprises from about 20 percent
to about 80 percent injectable surface treated microparticle
material and from about 20 percent to about 80 percent carrier;
from about 30 percent to about 70 percent injectable surface
treated microparticle material and from about 30 percent to about
70 percent carrier; e.g., the composition may comprise from about
40 percent to about 60 percent injectable surface treated
microparticle material and from about 40 percent to about 60
percent carrier; the composition may comprise about 50 percent
injectable surface treated microparticle material and about 50
percent carrier. The aforementioned percentages all refer to
percentage by weight.
[1280] The surface treated microparticles are loaded, for example,
in the surface treated microparticle or as a coating on the surface
treated microparticle, with a pharmaceutically active compound.
[1281] The system of the invention can allow for the
pharmaceutically active compound release to be sustained for some
time, for example, release can be sustained for at least about 2
hours, at least about 4 hours, at least about 6 hours, at least
about 10 hours, at least about 12 hours, at least about 24 hours,
at least 48 hours, at least a week, more than one week, at least a
month, at least two months, at least three months, at least four
months, at least five months, at least six months, at least seven
months, at least eight months, at least nine months, at least ten
months, at least eleven months, at least twelve months, or
more.
[1282] In one embodiment, the solid aggregating microparticles that
produce a pellet in vivo release the therapeutic agent without a
burst of more than about 1 percent to about 5 percent of total
payload over a 24 hour period.
[1283] In one embodiment, the solid aggregating microparticles that
produce a pellet in vivo release the therapeutic agent without a
burst of more than about 10 percent of total payload over a 24 hour
period.
[1284] In one embodiment, the solid aggregating microparticles that
produce a pellet in vivo release the therapeutic agent without a
burst of more than about 15 percent of total payload over a 24 hour
period.
[1285] In one embodiment, the solid aggregating microparticles that
produce a pellet in vivo release the therapeutic agent without a
burst of more than about 20 percent of total payload over a 24 hour
period.
[1286] In one embodiment, the solid aggregating microparticles that
produce a pellet in vivo release the therapeutic agent without a
burst of more than about 1 percent to about 5 percent of total
payload over a 12 hour period.
[1287] In one embodiment, the solid aggregating microparticles that
produce a pellet in vivo release the therapeutic agent without a
burst of more than about 5 percent to about 10 percent of total
payload over a 12 hour period.
[1288] In one embodiment, the solid aggregating microparticles that
produce a pellet in vivo release the therapeutic agent without a
burst of more than about 10 percent of total payload over a 12 hour
period.
[1289] In one embodiment, the solid aggregating microparticles that
produce a pellet in vivo release the therapeutic agent without a
burst of more than about 15 percent of total payload over a 12 hour
period.
[1290] In one embodiment, the solid aggregating microparticles that
produce a pellet in vivo release the therapeutic agent without a
burst of more than about 20 percent of total payload over a 12 hour
period.
[1291] In one embodiment, the pharmaceutically active compound is
released in an amount effective to have a desired local or systemic
physiological or pharmacologically effect.
[1292] In one embodiment, delivery of a pharmaceutically active
compound means that the pharmaceutically active compound is
released from the consolidated aggregate into the environment
around the consolidated aggregate, for example, the vitreal
fluid.
[1293] In one embodiment, a microparticle comprising a
pharmaceutically active compound of the invention allows a
substantially zero or first order release rate of the
pharmaceutically active compound from the consolidated aggregate
once the consolidated aggregate has formed. A zero order release
rate is a constant release of the pharmaceutically active compound
over a defined time; such release is difficult to achieve using
known delivery methods.
IX. Manufacture of Microparticles
[1294] Microparticle Formation
[1295] Microparticles can be formed using any suitable method for
the formation of polymer microparticles known in the art. The
method employed for particle formation will depend on a variety of
factors, including the characteristics of the polymers present in
the drug or polymer matrix, as well as the desired particle size
and size distribution. The type of drug(s) being incorporated in
the microparticles may also be a factor as some drugs are unstable
in the presence of certain solvents, in certain temperature ranges,
and/or in certain pH ranges.
[1296] Particles having an average particle size of between 1
micron and 100 microns are useful in the compositions described
herein. In typical embodiments, the particles have an average
particle size of between 1 micron and 40 microns, more typically
between about 10 micron and about 40 microns, more typically
between about 20 micron and about 40 microns. The particles can
have any shape but are generally spherical in shape.
[1297] In circumstances where a monodisperse population of
particles is desired, the particles may be formed using a method
which produces a monodisperse population of microparticles.
Alternatively, methods producing polydispersed microparticle
distributions can be used, and the particles can be separated using
methods known in the art, such as sieving, following particle
formation to provide a population of particles having the desired
average particle size and particle size distribution.
[1298] Common techniques for preparing microparticles include, but
are not limited to, solvent evaporation, hot melt particle
formation, solvent removal, spray drying, phase inversion,
coacervation, and low temperature casting. Suitable methods of
particle formulation are briefly described below. Pharmaceutically
acceptable excipients, including pH modifying agents,
disintegrants, preservatives, and antioxidants, can optionally be
incorporated into the particles during particle formation.
[1299] In one embodiment, surface treated microparticles are
prepared using continuous chemistry manufacturing processes. In one
embodiment, surface treated microparticles are prepared using
step-wise manufacturing processes.
[1300] In one embodiment, microparticles containing a therapeutic
agent can be prepared as described in PCT/US2015/065894. In one
embodiment, the microparticles are prepared by: [1301] (i)
dissolving or dispersing the therapeutic agent or its salt in an
organic solvent optionally with an alkaline agent; [1302] (ii)
mixing the solution/dispersion of step (i) with a polymer solution
that has a viscosity of at least about 300 cPs (or perhaps at least
about 350, 400, 500, 600, 700 or 800 or more cPs); [1303] (iii)
mixing the therapeutic agent polymer solution/dispersion of step
(ii) with an aqueous non-acidic or alkaline solution (for example
at least approximately a pH of 7, 8, or 9 and typically not higher
than about 10) optionally with a surfactant or emulsifier, to form
a solvent-laden therapeutic agent encapsulated microparticle,
[1304] (iv) isolating the microparticles. In one embodiment, the
therapeutic agent is sunitinib.
[1305] It has been found that it may be useful to include the
alkaline agent in the organic solvent. However, as described in
PCT/US2015/065894, it has been found that adding an acid to the
organic solvent can improve drug loading of the microparticle.
Examples demonstrate that polyesters such as PLGA, PEG-PLGA(PLA)
and PEG-PLGA/PLGA blend microparticles display sustained release of
the therapeutic agent or its pharmaceutically acceptable salt.
Polymer microparticles composed of PLGA and PEG covalently
conjugated to PLGA (Mw 45 kDa) (PLGA45k-PEG5k) loaded with the
therapeutic agent were prepared using a single emulsion solvent
evaporation method. The therapeutic agent loading was further
increased by increasing the pH of the aqueous solution. Still
further significant increases in therapeutic agent loading in the
microparticles was achieved by increasing polymer concentration or
viscosity. In one embodiment, the therapeutic agent is
sunitinib.
[1306] Solvent Evaporation
[1307] In this method, the drug (or polymer matrix and drug) is
dissolved in a volatile organic solvent, such as methylene
chloride, acetone, acetonitrile, 2-butanol, 2-butanone, t-butyl
alcohol, benzene, chloroform, cyclohexane, 1,2-dichloroethane,
diethyl ether, ethanol, ethyl acetate, heptane, hexane, methanol,
methyl tert-butyl ether, pentane, petroleum ether, iso-propanol,
n-propanol, tetrahydrofuran, or mixtures thereof. The organic
solution containing the drug is then suspended in an aqueous
solution that contains a surface active agent such as poly(vinyl
alcohol). The resulting emulsion is stirred until most of the
organic solvent is evaporated, leaving solid microparticles. The
resulting microparticles are washed with water and dried overnight
in a lyophilizer. Microparticles with different sizes and
morphologies can be obtained by this method.
[1308] Microparticles which contain labile polymers, such as
certain polyanhydrides, may degrade during the fabrication process
due to the presence of water. For these polymers, the following two
methods, which are performed in completely anhydrous organic
solvents, can be used.
[1309] Oil-In-Oil Emulsion Technique
[1310] Solvent removal can also be used to prepare particles from
drugs that are hydrolytically unstable. In this method, the drug
(or polymer matrix and drug) is dispersed or dissolved in a
volatile organic solvent such as methylene chloride, acetone,
acetonitrile, benzene, 2-butanol, 2-butanone, t-butyl alcohol,
chloroform, cyclohexane, 1,2-dichloroethane, diethyl ether,
ethanol, ethyl acetate, heptane, hexane, methanol, methyl
tert-butyl ether, pentane, petroleum ether, iso-propanol,
n-propanol, tetrahydrofuran, or mixtures thereof. This mixture is
then suspended by stirring in an organic oil (such as silicon oil,
castor oil, paraffin oil, or mineral oil) to form an emulsion.
Solid particles form from the emulsion, which can subsequently be
isolated from the supernatant. The external morphology of spheres
produced with this technique is highly dependent on the identity of
the drug.
[1311] Oil-In-Water Emulsion Technique
[1312] In this method, the drug (or polymer matrix and drug) is
dispersed or dissolved in a volatile organic solvent such as
methylene chloride, acetone, acetonitrile, benzene, 2-butanol,
2-butanone, t-butyl alcohol, chloroform, cyclohexane,
1,2-dichloroethane, diethyl ether, ethanol, ethyl acetate, heptane,
hexane, methanol, methyl tert-butyl ether, pentane, petroleum
ether, iso-propanol, n-propanol, tetrahydrofuran, or mixtures
thereof. This mixture is then suspended by stirring in an aqueous
solution of surface active agent, such as poly(vinyl alcohol), to
form an emulsion. Solid particles form from the emulsion, which can
subsequently be isolated from the supernatant. The external
morphology of spheres produced with this technique is highly
dependent on the identity of the drug.
[1313] As described in PCT/US2015/065894, microparticles with a
therapeutic agent can be prepared using the oil-in-water emulsion
method. In one example, sunitinib microparticles were prepared by
dissolving 100 mg PEG-PLGA (5K, 45) in 1 mL methylene chloride, and
dissolving 20 mg sunitinib malate in 0.5 mL DMSO and triethylamine.
The solutions were then mixed together, homogenized at 5000 rpm, 1
minute into an aqueous solution containing 1% polyvinyl alcohol
(PVA) and stirred for 2 hours. The particles were collected, washed
with double distilled water, and freeze dried. In another example,
sunitinib microparticles were also prepared according to
PCT/US2015/065894 by dissolving 200 mg PLGA (2A, Alkermers) in 3 mL
methylene chloride, and 40 mg sunitinib malate in 0.5 mL DMSO and
triethylamine. The solutions were then mixed together and
homogenized at 5000 rpm, 1 minute in 1% PVA and stirred for 2
hours. The particles were collected, washed with double distilled
water, and freeze dried.
[1314] Spray Drying
[1315] In this method, the drug (or polymer matrix and drug) is
dissolved in an organic solvent such as methylene chloride,
acetone, acetonitrile, 2-butanol, 2-butanone, t-butyl alcohol,
benzene, chloroform, cyclohexane, 1,2-dichloroethane, diethyl
ether, ethanol, ethyl acetate, heptane, hexane, methanol, methyl
tert-butyl ether, pentane, petroleum ether, iso-propanol,
n-propanol, tetrahydrofuran, or mixtures thereof. The solution is
pumped through a micronizing nozzle driven by a flow of compressed
gas, and the resulting aerosol is suspended in a heated cyclone of
air, allowing the solvent to evaporate from the microdroplets,
forming particles. Particles ranging between 0.1-10 microns can be
obtained using this method.
[1316] Phase Inversion
[1317] Particles can be formed from drugs using a phase inversion
method. In this method, the drug (or polymer matrix and drug) is
dissolved in a solvent, and the solution is poured into a strong
non solvent for the drug to spontaneously produce, under favorable
conditions, microparticles or nanoparticles. The method can be used
to produce nanoparticles in a wide range of sizes, including, for
example, about 100 nanometers to about 10 microns, typically
possessing a narrow particle size distribution.
[1318] Coacervation
[1319] Techniques for particle formation using coacervation are
known in the art, for example, in GB-B-929 406; GB-B-929 40 1; and
U.S. Pat. Nos. 3,266,987, 4,794,000, and 4,460,563. Coacervation
involves the separation of a drug (or polymer matrix and drug)
solution into two immiscible liquid phases. One phase is a dense
coacervate phase, which contains a high concentration of the drug,
while the second phase contains a low concentration of the drug.
Within the dense coacervate phase, the drug forms nanoscale or
microscale droplets, which harden into particles. Coacervation may
be induced by a temperature change, addition of a non-solvent or
addition of a micro-salt (simple coacervation), or by the addition
of another polymer thereby forming an interpolymer complex (complex
coacervation).
[1320] Low Temperature Casting
[1321] Methods for very low temperature casting of controlled
release microspheres are described in U.S. Pat. No. 5,019,400 to
Gombotz et al. In this method, the drug (or polymer matrix and
sunitinib) is dissolved in a solvent. The mixture is then atomized
into a vessel containing a liquid non-solvent at a temperature
below the freezing point of the drug solution which freezes the
drug droplets. As the droplets and non-solvent for the drug are
warmed, the solvent in the droplets thaws and is extracted into the
non-solvent, hardening the microspheres.
[1322] Scale Up
[1323] The processes for producing microparticles described in the
Examples are amenable to scale up by methods known in the art.
Examples of such methods include U.S. Pat. Nos. 4,822,534;
5,271,961; 5,945,126; 6,270,802; 6,361,798; U.S. Pat. No.
8,708,159; and U.S. publication 2010/0143479. U.S. Pat. No.
4,822,534 describes a method of manufacture to provide solid
microspheres that involves the use of dispersions. These
dispersions could be produced industrially and allowed for scale
up. U.S. Pat. No. 5,271,961 disclosed the production of protein
microspheres which involved the use of low temperatures, usually
less than 45 OC. U.S. Pat. No. 5,945,126 describes the method of
manufacture to produce microparticles on full production scale
while maintaining size uniformity observed in laboratory scale.
U.S. Pat. Nos. 6,270,802 and 6,361,798 describe the large scale
method of manufacture of polymeric microparticles whilst
maintaining a sterile field. U.S. Pat. No. 8,708,159 describes the
processing of microparticles on scale using a hydrocyclone
apparatus. U.S. publication 2010/0143479 describes the method of
manufacture of microparticles on large scale specifically for slow
release microparticles.
[1324] XSpray has disclosed a device and the use of supercritical
fluids to produce particles of a size below 10 .mu.M (U.S. Pat. No.
8,167,279). Additional patents to XSpray include U.S. Pat. Nos.
8,585,942 and 8,585,943. Sun Pharmaceuticals has disclosed a
process for the manufacture of microspheres or microcapsules, WO
2006/123359, herein incorporated by reference. As an example,
Process A involves five steps that include 1) the preparation of a
first dispersed phase comprising a therapeutically active
ingredient, a biodegradable polymer and an organic solvent 2)
mixing the first dispersed phase with an aqueous phase to form an
emulsion 3) spraying the emulsion into a vessel equipped to remove
an organic solvent and 4) passing the resulting microspheres or
microcapsules through a first and second screen thereby collecting
a fractionated size of the microspheres or microcapsules and 5)
drying the microspheres or microcapsules.
[1325] Xu, Q. et al. have disclosed the preparation of
monodispersed biodegradable polymer microparticles using a
microfluidic flow-focusing device (Xu, Q., et al "Preparation of
Monodispersed Biodegradable Polymer Microparticles Using a
Microfluidic Flow-Focusing Device for Controlled Drug Delivery",
Small, Vol 5(13): 1575-1581, 2009).
[1326] Duncanson, W. J. et al. have disclosed the use of
microfluidic devices to generate microspheres (Duncanson, W. J. et
al. "Microfluidic Synthesis of Monodisperse Porous Microspheres
with Size-tunable Pores", Soft Matter, Vol 8, 10636-10640,
2012).
[1327] U.S. Pat. No. 8,916,196 to Evonik describes an apparatus and
method for the production of emulsion based microparticles that can
be used in connection with the present invention.
X. Process of Preparation of Surface Treated Microparticles
Abbreviations
[1328] DCM, CH.sub.2Cl.sub.2 Dichloromethane DL Drug loading DMSO
Dimethyl sulfoxide
EtOH Ethanol
[1329] HA Sodium hyaluronate
hr, h Hour
min Minute
[1330] NaOH Sodium hydroxide NSTMP Non-surface treated
microparticles PBS Dulbecco's phosphate-buffered saline
PCL Polycaprolactone
[1331] PEG Polyethylene glycol PLA Poly(lactic acid) PLGA
Poly(lactic-co-glycolic acid) PVA Polyvinyl alcohol Rpm Revolutions
per minute RT, r.t. Room temperature SD Standard deviation STMP
Surface treated microparticles
UV Ultraviolet
[1332] Examples 1-30 and FIGS. 1-19 were first presented in U.S.
Ser. No. 15/349,985 and PCT/US16/61706 and are provided again
herein for background information for the improved invention
described herein.
General Methods
[1333] All non-aqueous reactions were performed under an atmosphere
of dry argon or nitrogen gas using anhydrous solvents. The
structure of starting materials, intermediates, and final products
was confirmed by standard analytical techniques, including NMR
spectroscopy and mass spectrometry.
Materials
[1334] Sodium hydroxide (NaOH, catalog #: S318-1, Fisher Chemical),
ethanol (EtOH, catalog #: A405-20, Fisher Chemical), Dulbecco's
phosphate-buffered saline (PBS, catalog #: SH3085003, GE Healthcare
HyClone.TM.), sodium hyaluronate (HA, catalog #: AC251770010, Acros
Organics) and Tween 20 (catalog #: BP337-100, Fisher BioReagents)
were purchased from Fisher Scientific. Polyvinyl alcohol (PVA) (88
percent hydrolyzed, MW approximately 25kD) (catalog #: 02975) was
purchased from Polysciences, Inc. Sunitinib malate was purchased
from LC Laboratories (catalog #: S-8803). ProVisc.RTM. (10 mg/mL,
0.85 mL, catalog #: 21989, Alcon) was purchased from Besse Medical.
Poly(lactic-co-glycolic acid) (PLGA) polymer, poly(lactic-acid)
(PLA) polymer, and diblock co-polymers of PLGA and polyethylene
glycol (PLGA-PEG) were purchased from the Evonik Corporation
(RESOMER Select 5050 DLG mPEG 5000 (10 wt percent PEG)). A FreeZone
4.5 liter benchtop freeze dry system was used for
lyophilization.
[1335] ProVisc.RTM. OVD (Ophthalmic Viscosurgical Device) is a
sterile, non-pyrogenic, high molecular weight, non-inflammatory
highly purified fraction of sodium hyaluronate dissolved in
physiological sodium chloride phosphate buffer. It is FDA approved
and indicated for use as an ophthalmic surgical aid. Sodium
hyaluronate is a derivative of hyaluronan for clinical use.
Hyaluronan, also known as hyaluronic acid, is a naturally occurring
glycosaminoglycan found throughout the body including in the
aqueous and vitreous humors of the eye.
Example 1. Preparation of Biodegradable Non-Surface Treated
Microparticles (NSTMP) Containing PLGA
[1336] Polymer microparticles comprising PLGA and diblock copolymer
of PLGA and PEG with or without sunitinib malate were prepared
using a single emulsion solvent evaporation method. Briefly, PLGA
(560 mg) and PLGA-PEG (5.6 mg) were co-dissolved in dichloromethane
(DCM) (4 mL). Sunitinib malate (90 mg) was dissolved in dimethyl
sulfoxide (DMSO) (2 mL). The polymer solution and the drug solution
were mixed to form a homogeneous solution (organic phase). For
empty NSTMP, DMSO (2 mL) without drug was used. For drug-loaded
NSTMP, the organic phase was added to an aqueous 1% PVA solution in
PBS (200 mL) and homogenized at 5,000 rpm for 1 minute using an
L5M-A laboratory mixer (Silverson Machines Inc., East Longmeadow,
Mass.) to obtain an emulsion. For empty NSTMP, 1 percent PVA
solution in water (200 mL) was used.
[1337] The emulsion (solvent-laden microparticles) was then
hardened by stirring at room temperature for more than 2 hours to
allow the DCM to evaporate. The microparticles were collected by
sedimentation and centrifugation, washed three times in water, and
filtered through a 40-.mu.m sterile Falcon.RTM. cell strainer
(Corning Inc., Corning, N.Y.). The non-surface treated
microparticles (NSTMP) were either used directly in the surface
treatment process or dried by lyophilization and stored as a dry
powder at -20.degree. C. until used.
Example 2. Surface Treatment of Non-Surface Treated Microparticles
(NSTMP) Using NaOH(Aq)/EtOH
[1338] A pre-chilled solution containing 0.25 M NaOH (aq) and
ethanol at a predetermined ratio was added to microparticles in a
glass vial under stirring in an ice bath at approximately 4.degree.
C. to form a suspension at 100 mg/mL. The suspension was then
stirred for a predetermined time (e.g., 3, 6 or 10 minutes) on ice
and poured into a pre-chilled filtration apparatus to remove the
NaOH (aq)/EtOH solution. The microparticles were further rinsed
with pre-chilled water and transferred to a 50-mL centrifuge tube.
The particles were then suspended in pre-chilled water and kept in
a refrigerator for 30 minutes to allow the particles to settle.
Following removal of the supernatant, the particles were
resuspended and filtered through a 40-.mu.m cell strainer to remove
large aggregates. Subsequently, the particles were washed twice
with water at room temperature and freeze-dried overnight. Detailed
formulation information and conditions of NaOH(aq)/EtOH surface
treatment experiments are listed in Table 1.
TABLE-US-00010 TABLE 1 Detailed batch information on NaOH(aq)/EtOH
surface treated microparticles Ratio of Batch 0.25M NaOH Treatment
Microparticles before size (aq) to EtOH Time STMP surface treatment
(mg) (v/v) (min) ID S-1 (99% PLGA 7525 4A, 200 30/70 3 S-2 1%
PLGA-PEG) 200 6 S-3 DL = 18.0% 200 10 S-4 S-5 (90% PLGA 7525 4A,
200 50/50 3 S-6 10% PLGA-PEG) 200 6 S-7 DL = 18.9% 200 30/70 6 S-8
S-9 (99% PLGA 7525 4A, 1000 30/70 3 S-10 1% PLGA-PEG) DL = 18.3%
S-11 (99% PLGA 7525 2300 30/70 3 S-12 4A, 1% PLGA-PEG) DL = 11.1%
S-13 (99% PLGA 7525 3600 30/70 3 S-14 4A, 1% PLGA-PEG) DL = 11.9%
S-15 (99% PLGA 7525 2000 30/70 3 S-16 4A, 1% PLGA-PEG) DL = 2.15%
S-17 (99% PLGA 7525 2000 30/70 3 S-18 4A, 1% PLGA-PEG) DL = 2.21%
DL = Drug loading.
Example 3. In Vitro Assessment of Particle Aggregability
[1339] Surface treated microparticles (STMP) were suspended in
phosphate buffered saline (PBS) at a concentration of 200 mg/mL.
Thirty or fifty microliters of the suspension were injected into
1.5-2.0 mL of PBS or sodium hyaluronate solution (HA, 5 mg/mL in
PBS) pre-warmed at 37.degree. C. in a 2 mL microcentrifuge tube
using a 0.5 mL insulin syringe with a permanent 27-gauge needle
(Terumo or Easy Touch brand). The microcentrifuge tube was then
incubated in a water bath at 37.degree. C. for 2 hours. The
aggregability of the microparticles was assessed by visual
observation and/or imaging under gentle agitation by inverting
and/or tapping and flicking the tubes containing the
microparticles. Non-surface treated microparticles (NSTMP) were
used as a control.
[1340] A successful surface treatment process is expected to result
in STMP that maintain good suspendability, syringeability and
injectability. Most importantly, after the injection into PBS or
sodium hyaluronate and the 2-hour incubation at 37.degree. C., the
STMP are expected to form consolidated aggregate(s) that do not
break into smaller aggregates or free-floating particles under
gentle agitation, a key feature that differentiates STMP from NSTMP
and STMP with low aggregability.
Example 4. Effect of Temperature During Surface Treatment on
Microparticle Properties
[1341] The effect of temperature on surface treatment was studied
by comparing particles treated at room temperature vs. treated at
4.degree. C. The procedure for surface treatment at room
temperature was identical to the procedure described in Example 2
except that it was conducted at room temperature instead of at
4.degree. C.
[1342] When the surface treatment process was carried out at room
temperature in a mixture of 0.25 M NaOH and EtOH (v/v: 30/70 or
70/30), the particles aggregated quickly and irreversibly during
surface treatment. In contrast, particles treated at 4.degree. C.
in a mixture of NaOH/EtOH at the same volume ratio did not
aggregate during the surface treatment process and maintained good
suspendability and injectability upon reconstitution. For surface
treatment at room temperature in 0.25 M NaOH without EtOH, the
particles did not aggregate during the 1-hour surface treatment. In
addition, STMP treated in NaOH failed to aggregate following
incubation at 37.degree. C. In contrast, STMP treated around
4.degree. C. did not aggregate during surface treatment, but
aggregated following incubation at 37.degree. C. After
lyophilization and reconstitution in a particle diluent, the STMP
were easily loaded into syringes through a 27-gauge needle and
injected without needle blockage.
Example 5. Effect of PEG Content on the Aggregability of Surface
Treated Microparticles
TABLE-US-00011 [1343] TABLE 2 NSTMP and STMP containing different
percentages of PLGA:PLGA-PEG PLGA PLGA-PEG Surface Treatment
Formulation # (wt %) (wt %) Condition S-1 99% 1% None S-3 99% 1%
0.25M NaOH/EtOH (30/70, v/v), 6 min S-5 90% 10% None S-8 90% 10%
0.25M NaOH/EtOH (30/70, v/v), 6 min
[1344] Two batches of NSTMP (S-1 and S-5) and two batches of STMP
(S-3 and S-8) containing different weight percentages of
PLGA/PLGA-PEG were surface treated following the procedure
described below and their aggregability in both PBS and HA gel were
evaluated.
[1345] As listed in Table 2 above, formulation S-3 contained 1%
PLGA-PEG and S-8 contained 10% of PLGA-PEG. Samples S-3 and S-8
were individually treated in a mixture of 0.25M NaOH and EtOH at a
volume ratio of 30/70 at 4.degree. C. for 6 minutes. Following
injection in PBS and incubation at 37.degree. C. for 2 hours, the
microcentrifuge tubes were inverted and the aggregability of the
particles was assessed by visual inspection. As illustrated in FIG.
1, the NSTMP S-1 and S-5 started to disperse immediately after the
tubes were inverted, while the STMP, S-3 and S-8, remained
aggregated at the bottom of the tubes without dispersion throughout
the entire period of observation (about 10 minutes).
[1346] A similar second experiment was conducted by injecting the
same particle suspensions into HA solutions and incubating the
samples at 37.degree. C. for 2 hours. Immediately after the tubes
were inverted, none of the particles became dispersed, including
NSTMP; refer to FIG. 2. This is likely due to the higher viscosity
of HA that prevents particles from diffusing rapidly in the gel
solution. Different from S-1 which remained aggregated throughout
the experiment, S-5 started to become dispersed in HA 2 minutes
after the tube was inverted. Without wishing to be bound to any one
theory, this may be related to the higher PEG content in S-1 that
affects the interaction between particles and between the particle
surfaces and HA, and thus the diffusion of S-5 in HA was less
hindered than that of S-1. Though S-8 remained aggregated after
injection and incubation in PBS, it appeared more dispersive in HA
solution. In contrast, S-3, which contains less PEG than S-8, was
able to aggregate in both PBS and HA solution. These data indicate
that the aggregation and dispersion of STMP can be affected by both
the particle composition and properties of the medium where the
STMP are injected.
[1347] In a third experiment, samples containing S-1, S-2, S-3,
S-4, S-5, S-6, S-7 and S-8 were incubated in PBS at 37.degree. C.
for 2 hours. After assessing the aggregability by inverting the
tubes, stronger agitation was applied by tapping the tubes on the
bench, which caused the particle aggregates to detach from the
bottom of the tubes. The integrity of the aggregates was then
examined and compared among different formulations. As shown in
FIG. 3, S-3 (1 percent PLGA-PEG) remained as an integrated single
aggregate after detachment from the bottom of the tube. In
comparison, though most particles in S-8 (10% PLGA-PEG) remained as
one large aggregate, many dispersed small aggregates or particles
were visible in the tube. The assay with stronger agitation allowed
further differentiation of the aggregability of different particle
formulations. Overall, the data suggest that STMP with lower PEG
content generally form stronger and more consolidated aggregates
than STMP with higher PEG content.
Example 6. Effect of Surface Treatment with PBS/EtOH on
Microparticles
[1348] Since NaOH is a strong base that may cause partial
degradation of polymers and lead to rapid modification of the
surface properties of particles, a neutral phosphate buffered
saline (PBS) solution at pH 7.4 was evaluated as an alternative to
NaOH and the effect of surface treatment using PBS/EtOH on
microparticles was studied. The surface treatment procedure was
identical to that described in Example 2, except that the NaOH
solution was replaced with PBS (pH 7.4). The experiment was
performed in an ice bath at approximately 4.degree. C. Detailed
formulation composition and surface treatment conditions are listed
in Table 3. The aggregability of the surface treated microparticles
(STMP) was tested following the procedure described in Example
3.
TABLE-US-00012 TABLE 3 Formulation composition and conditions of
surface treatment with PBS/EtOH Particle ID Batch PBS/ Treatment
before Drug size EtOH Time STMP treatment Composition Loading (mg)
(v/v) (min) ID S-11 99% PLGA 11.1% 200 30/70 3 S-21 S-19 7525 4A,
1% 11.8% 500 S-22 PLGA--PEG 500 S-23 500 6 S-24 S-20 0% 200 6 S-25
200 12 S-26
[1349] The results of the aggregability test demonstrated that
similar to surface treatment with NaOH/EtOH, all of the STMP
treated with PBS/EtOH were able to form an aggregate after
injection into PBS and incubation for 2 hours at 37.degree. C. The
aggregates appeared stable and resistant to gentle agitation; refer
to FIG. 4, a photo of S-21. There was no apparent difference in
particle aggregability under in vitro aggregation assay (procedure
was conducted as described in Example 3) between these STMP and the
STMP generated by treatment in NaOH/EtOH. Both drug-loaded STMP and
empty STMP were able to aggregate in PBS, suggesting the surface
treatment process likely has good compatibility with various
particle formulations with or without drug.
Example 7. Modification of the Surface Treatment Conditions Using
NaOH(Aq)/EtOH
[1350] To further optimize the surface treatment conditions with
NaOH(aq)/EtOH, the impact of various parameters, such as NaOH
concentration, aqueous/EtOH ratio, and treatment time, on surface
treatment were studied (Table 4). It is worth noting that in this
Example, the overall molar concentration of NaOH in the entire
aqueous/EtOH mixture was used as a variable independent of the
ratio of aqueous solution to EtOH instead of using the molarity of
NaOH in the aqueous phase only as in Example 2. For example, 0.25M
NaOH(aq)/EtOH (v/v: 30/70) in Example 2 is equivalent to 0.075M of
NaOH in an aqueous/EtOH (v/v: 30/70) mixture. Thus, the volume
ratio of aqueous to EtOH was modified from 30/70 to 50/50 and 70/30
with the same total amount of NaOH in the mixture. In addition, the
amount of NaOH was decreased by 10- or 100-fold without changing
the ratio of aqueous solution to EtOH. The different treatment time
was chosen to achieve comparable effectiveness of surface
treatment. The procedure for surface treatment on microparticles
was the same as Example 2.
TABLE-US-00013 TABLE 4 Detailed batch information on modified
NaOH(aq)/EtOH STMP NaOH concentration Microparticles before Batch
in H.sub.2O/EtOH H.sub.2O/EtOH Treatment surface treatment size
(mg) mixture (M) ratio (v/v) Time (min) STMP ID S-27 (99% PLGA 7525
200 0.075 50/50 10 S-28 4A, 1% PLGA-PEG) 200 50/50 20 S-29 DL =
11.3% 200 70/30 15 S-30 200 70/30 30 S-31 200 0.0075 30/70 3 S-32
200 30/70 10 S-33 200 0.00075 30/70 3 S-34 200 30/70 10 S-35
[1351] Example 8. Effect of surface treatment using HCl/EtOH on
microparticles As surface treatment using an aqueous solution of
basic pH (Example 2 and Example 7) or neutral pH (Example 6) had
been tested previously, the effect of aqueous solution of acidic pH
was evaluated in Example 8. HCl was selected as a representative
acid. As shown in Table 5, microparticles were treated for 3
minutes in 0.075 M or 0.0075 M of HCl in H.sub.2O/EtOH (v/v: 30/70)
mixture, respectively. The procedure for HCl/EtOH surface treatment
was the same as in Example 2 except that HCl (aq) was used to
replace NaOH (aq).
TABLE-US-00014 TABLE 5 Detailed batch information of HCl/EtOH
treated STMP HCl concentration Final surface Microparticles before
Batch in H.sub.2O/EtOH H.sub.2O/EtOH Treatment treated surface
treatment size (mg) mixture (M) ratio (v/v) Time (min) particles
S-27 (99% PLGA 7525 200 0.075 30/70 3 S-36 4A, 1% PLGA-PEG) 200
0.0075 30/70 3 S-37 DL = 11.3%
Example 9. Surface Treatment on Wet Microparticles
[1352] In addition to conducting surface treatment on NSTMP by
first re-suspending NSTMP dry powder in an aqueous solution as
illustrated in the previous examples, the feasibility of surface
treatment on NSTMP prior to drying (i.e., "wet" microparticles) was
also evaluated. It is expected to be easier to integrate a surface
treatment step using "wet" NSTMP into the entire process of
scale-up production of STMP than a step using dry powder of NSTMP.
After obtaining "wet" NSTMP prior to lyophilization as shown in
Example 1, an aliquot of the suspension was lyophilized to
determine the particle mass per volume. The particle suspension was
then concentrated or diluted accordingly to reach desired
concentration and cooled down to desired temperature. Other
reagents needed for surface treatment were then added to the
suspension to reach desired conditions (e.g., concentration of each
chemical reagent) as described in Table 6 to start the surface
treatment process. The rest of the surface treatment process is the
same as described on dry particles in Example 2. The detailed batch
information and experimental conditions are listed in Table 6.
TABLE-US-00015 TABLE 6 Detailed batch information and experimental
conditions of surface treatment on "wet" microparticles Final
Micro- surface treatment solvent particles Solute Solute H.sub.2O/
Treat- before Batch (base, concentration EtOH ment surface size
acid or in H.sub.2O/EtOH ratio Time STMP treatment (mg) salt)
mixture (M) (v/v) (min) ID S-38 (99% 450 NaOH 0.075 30/70 3 S-39
PLGA 7525 450 0.0075 30/70 10 S-40 4A, 1% 450 0.075 70/30 15 S-41
PLGA--PEG) 450 0.00075 70/30 30 S-42 DL = 11.6% 450 HCl 0.0075
30/70 3 S-43 450 KCl 0.075 30/70 20 S-44 450 0.35 30/70 20 S-45
Example 10. Optimized Method for Assessing Particle Aggregability
In Vitro
[1353] To improve the method for assessing particle aggregability
in vitro, an orbital shaker was used to replace the manual
agitation used in Example 3.
[1354] Fifty microliters of STMP suspension in PBS at 200 mg/mL was
injected in 2 mL of PBS pre-warmed at 37.degree. C. in a 16-mm
round-bottom glass test tube using a 1 mL insulin syringe with a
permanent 27-gauge needle (Terumo or Easy Touch brand). The test
tube was then incubated in a water bath at 37.degree. C. for 2
hours. The aggregability of the microparticles was assessed by
visual inspection and/or imaging after shaking for 30 seconds at
400 rpm on an orbital shaker (Thermo Scientific.TM. Multi-Platform
Shakers: Catalog No. 13-687-700). The test tube containing
particles/aggregates was then turned horizontally for visual
assessment of the particle aggregability. NSTMP were used as a
control.
[1355] As shown in FIG. 17, all the STMP in Examples 7 and 8 formed
an aggregate after the 2-hour incubation and the aggregates
remained mostly intact following 30-second shaking on an orbital
shaker. In contrast, NSTMP in S-27 became fully dispersed following
the same agitation. S-12 described in Example 2 was also included
in this assessment to compare the aggregability of microparticles
treated under different conditions. The results suggest all the
modified surface treatment conditions in Examples 7 and 8 resulted
in STMP with aggregability similar to that of S-12.
[1356] As shown in FIG. 18, all the STMP (S-39, S-40, S-41, S-42,
S-43, S-44, S-45) in Example 9 formed an aggregate after the 2-hour
incubation and the aggregates remained mostly intact following
30-second shaking on an orbital shaker, while NSTMP (S-38) became
fully dispersed following the same agitation. S-42, S-44 and S-45
appeared to aggregate better than other STMP samples in FIG. 18 and
as well as surface treatment on dry particle in FIG. 17. The
results demonstrate the success and feasibility of surface
treatment on wet microparticles.
Example 11. Determination of Drug Loading
[1357] Drug loading was determined by UV-Vis spectrophotometry.
Microparticles containing sunitinib (10 mg total weight) were
dissolved in anhydrous DMSO (1 mL) and further diluted until the
concentration of drug was in the linear range of the standard curve
of UV absorbance of the drug. The concentration of the drug was
determined by comparing the UV absorbance to a standard curve. Drug
loading is defined as the weight ratio of drug to
microparticles.
Example 12. In Vitro Drug Release Study
[1358] Microparticles containing sunitinib (10 mg total weight)
were suspended in PBS (4 mL) containing 1% Tween 20 in a 6-mL glass
vial and incubated at 37.degree. C. under shaking at 150 rpm. At
predetermined time points, 3 mL of the supernatant was withdrawn
after particles settled to the bottom of the vial and replaced with
3 mL of fresh release medium. The drug content in the supernatant
was determined by UV-Vis spectrophotometry or HPLC. Alternatively,
the above procedure can be run at 50.degree. C. to determine an
accelerated in vitro drug release rate as shown in FIG. 5.
Example 13. Studies on the Effects of Surface Treatment on
Microparticles
[1359] Besides aggregability, the effect of surface treatment on
other properties of microparticles was also studied to fully
evaluate the feasibility of surface treatment. As shown in Table 7,
in general, the yield and drug loading of STMP (in Example 2)
treated for longer periods of time were slightly lower than those
treated for shorter period of time, suggesting that at 0.25M
NaOH/EtOH (v/v: 3:7), the time window for producing STMP with high
yield and loading is narrow (on the order of minutes). However,
under the modified conditions presented in Example 7, the treatment
time can be further extended to tens of minutes without reducing DL
and yield (Table 7) as well as aggregability (Example 10). STMP
treated with HCl(aq)/EtOH in Example 8 maintained the DL prior to
surface treatment with relatively high yield (S-36 and S-37). In
addition, STMP (S-42, S-44 and S-45) produced by surface treatment
on wet microparticles in Example 9 also maintained the DL prior to
surface treatment with comparable yield as STMP produced by surface
treatment on dry particles in Example 7 and 8.
TABLE-US-00016 TABLE 7 Yield and drug loading of STMP Drug loading
(DL) prior Drug loading after Sample Yield to surface treatment
surface treatment S-2 51% 18.0% 14.2% S-3 50% 18.0% 15.3% S-4 36%
18.0% 6.3% S-6 30% 18.9% 15.0% S-7 35% 18.9% 14.7% S-8 28% 18.9%
11.6% S-10 67% 18.3% 18.6% S-12 68% 11.1% 11.6% S-14 70% 11.9%
12.0% S-16 56% 2.15% 2.11% S-28 43% 11.3% 11.8% S-29 49% 11.3%
11.0% S-30 60% 11.3% 10.1% S-31 61% 11.3% 10.6% S-32 44% 11.3%
12.0% S-33 48% 11.3% 11.5% S-34 49% 11.3% 11.5% S-35 58% 11.3%
12.0% S-36 61% 11.3% 10.3% S-37 69% 11.3% 11.6% S-42 44% 11.6%
11.2% S-44 50% 11.6% 12.0% S-45 43% 11.6% 12.1%
[1360] FIG. 6 illustrates representative in vitro drug release
profiles of NSTMP (S-1) and the corresponding STMP (S-2 and S-3)
generated from the same batch of NSTMP. Overall, the release
profiles are similar for microparticles before and after surface
treatment except that the initial release rate of STMP was lower
than that of NSTMP. This suggests that under the surface treatment
conditions drug molecules that are bound to or near the
microparticle surface may have been removed during the surface
treatment process.
Example 14. Wettability of Surface Treated Microparticles
[1361] The wettability of representative batches of STMP and NSTMP
was characterized using the Washburn method. Briefly, two glass
capillary tubes with filter bases were separately filled with
equivalent masses of STMP and NSTMP dry powder. The bottom of the
capillary tubes was then inserted into a beaker with water and
water was drawn into the tubes over time due to capillary action.
The increase in mass of the tube and the height of water in the
tubes were determined as a function of time. The rate of water
absorption was relatively rapid in the tube containing NSTMP, but
relatively slow for STMP. Similarly, at the end of the test, the
mass increase of the tubes was much higher for NSTMP than for STMP,
indicating that the surface modification leads to reduction of
wettability of the microparticles likely due to removal of
surfactant or both surfactant and polymer from particle
surface.
Example 15. Preparation of Samples S-10, S-12, S-14, S-16, and S-18
and the Study of their Drug Release Profiles
[1362] Samples S-10 to S-16 and S-18 were prepared at a larger
scale of 1 to 3.6 grams. The yield and drug loading of these
batches are shown in Table 6 above. It is worth noting that the
drug loading was not significantly changed by surface treatment.
The average particle size of these STMP samples was similar to that
of the corresponding NSTMP prior to surface treatment (data not
shown). As shown in FIG. 7, the release profiles of the STMP
prepared at a larger scale (S-14 and S-16) were similar to the
corresponding NSTMP as well, indicating that the surface treatment
process had minimal effect on the overall drug release.
Example 16. Injectability and Dosing Consistency of Surface Treated
Microparticles (STMP)
[1363] A suspension of STMP (ST-1-5, approximately 10 percent drug
loading) at approximately 200 mg/mL was prepared by suspending the
microparticles in 5-fold diluted ProVisc.RTM. solution containing 2
mg/mL of HA. After an incubation period of 2 hours at room
temperature, 10 .mu.L of the STMP suspension was loaded into a 50
.mu.L Hamilton syringe with an attached 27-gauge needle. Following
brief vortexing to fully suspend the STMP, the syringe was held
horizontally for 2 minutes and vertically for 2 minutes prior to
injection into a microcentrifuge tube. The injection was repeated
using 3 different syringes and each syringe was tested 3 times. The
STMP in each tube was then dissolved in DMSO and the dose of drug
was determined by UV-Vis spectrophotometry. As shown in Table 8,
excellent dosing consistency between injections using the same
syringe and between different syringes was observed, suggesting
that the STMP suspension in diluted ProVisc.RTM. remained stable at
room temperature for a sufficient amount of time to allow
consistent dosing of the relatively small volume of injection
(e.g., 10.mu.L).
TABLE-US-00017 TABLE 8 Injectability and dosing consistency of STMP
Average dose Standard Standard Standard Standard Sample UV Dose per
syringe deviation deviation Average dose deviation deviation Name
Reading (mg) n = 3 (mg) (mg) (%) n = 9 (mg) (mg) (%) Syringe 1.019
.1966 .1974 .0140 7.0942 1-a Syringe .953 .1838 1-b Syringe 1.098
.2118 1-c Syringe 1.136 .2191 .2058 .0122 5.9332 .2031 .0129 6.3345
2-a Syringe 1.052 .2029 2-b Syringe 1.012 .1952 2-c Syringe 1.052
.2029 .2062 .0156 7.5633 3-a Syringe 1.157 .2232 3-b Syringe .998
.1925 3-c
Example 17. Impact of Microparticle Concentration and Particle
Diluent on the Aggregation of Surface Treated Microparticles
(STMP)
[1364] To investigate the effect of particle concentration and
diluent on the aggregation of STMP, STMP suspensions (50.mu.L) in
5-fold diluted ProVisc.RTM. at 2 different microparticle
concentrations (100 mg/mL and 200 mg/mL) were injected into 4 mL of
PBS or HA solution and incubated at 37.degree. C. for 2 hours.
[1365] As illustrated in the top panel of FIG. 8C and FIG. 3D, the
STMP at 200 mg/mL in diluted ProVisc.RTM. were able to form a
consolidated aggregate in both PBS and HA following a 2-hour
incubation at 37.degree. C. Compared to 200 mg/mL STMP suspended in
PBS, the aggregation of 200 mg/mL STMP in diluted ProVisc.RTM.
appeared slower, but the aggregate became more consolidated over
time, suggesting the HA molecules in the particle diluent may
hinder the contact between STMP and slow down the aggregation
process. On the other hand, due to its viscoelastic properties, HA
may help keep particles localized and allow sufficient time for
STMP to form an aggregate. The particle aggregates formed in HA
also appeared to have a more spherical morphology than those formed
in PBS, suggesting that if a viscoelastic solution is used as the
particle diluent, an optimal range of diluent concentration needs
to be identified to improve the overall performance of STMP
aggregation.
[1366] After the 2-hour incubation, the strength of the aggregates
was tested by shaking the test tubes at 250 rpm on an orbital
shaker. As illustrated in the bottom panel of FIG. 8C and FIG. 8D,
the aggregates were able to endure the shear stress generated by
shaking with no or limited dispersion of microparticles.
[1367] In comparison, even though the STMP of 100 mg/mL appeared to
form an aggregate in PBS (top panel, FIG. 8A), the aggregate
appeared less dense than that of the 200 mg/mL STMP in PBS (top
panel, FIG. 8C) and tended to disaggregate into individual
microparticles under agitation (bottom panel, FIG. 8A). In
addition, the STMP of 100 mg/mL was not able to form one
consolidated aggregate in HA at the end of the 2-hour incubation
period (top panel, FIG. 8B) and many STMP became dispersed in HA
upon shaking at 250 rpm (bottom panel, FIG. 8B). Similar to HA
molecules in particle diluent, the HA molecules in the test medium
may further decrease particle-particle contact and reduce the
chance of forming a consolidated aggregate. The results suggest
that the aggregability of STMP decreases at lower microparticle
concentration, possibly due to increased average particle-particle
distance and decreased chance of direct contact between particles.
The aggregation may also be further hindered by other molecules,
such as HA, in the test medium.
[1368] In summary, the aggregation of STMP can be affected by
particle concentration, particle diluent and the environment into
which the particles are delivered. Overall the data demonstrate
that under appropriate conditions, the STMP have good aggregability
in different particle diluents and test media.
Example 18. Aggregation of Surface Treated Microparticles (STMP) in
Cow Eyes Ex Vivo
[1369] To evaluate the aggregability of STMP following intravitreal
injection ex vivo, enucleated cow eyes (J.W. Treuth & Sons,
Catonsville, Md.) were utilized. The eyes were kept on ice prior to
use. Briefly, 30 .mu.L of 200 mg/mL STMP, S-10, suspended in 5-fold
diluted ProVisc.RTM. was injected into the central vitreous of cow
eyes using a 0.5 mL insulin syringe (Terumo) with a 27-gauge needle
and three injections were performed in each cow eye at different
locations. After a 2-hour incubation at 37.degree. C., the eyes
were cut open and the aggregates of STMP were examined using a
dissecting microscope. As shown in FIG. 9, the injected STMP formed
consolidated aggregates in cow vitreous and no apparent particle
dispersion was observed.
Example 19. Aggregation of Surface Treated Microparticles (STMP) in
Rabbit Eyes In Vivo
[1370] To study the aggregation of surface treated microparticles
in rabbit eyes in vivo, 50 .mu.L of 200 mg/mL STMP S-10 suspended
in PBS (FIG. 10A) or 5-fold diluted ProVisc.RTM. (FIG. 10B) were
injected to the central vitreous of Dutch Belted rabbit eyes using
a 0.5 mL insulin syringe (Terumo) with a 27-gauge needle. Four days
after the dosing, the rabbits were sacrificed and the eyes were
nucleated and frozen immediately. The frozen eyes were cut into
halves and the posterior half of the eye was thawed at room
temperature for 3 minutes to allow isolation of the vitreous from
the eye cup, as shown in the left photo of FIG. 10A and FIG. 10B.
The frozen vitreous containing particles was placed in a cassette
to allow the vitreous to thoroughly thaw. The aggregates of STMP in
the vitreous could be easily separated from vitreous using forceps,
proving the formation of consolidated STMP aggregates in rabbit
eyes.
Example 20. Distribution, Tolerability and Pharmacokinetics of
Sunitinib-Encapsulated Surface Treated Microparticles (STMP)
Following an Intravitreal (IVT) Injection in Rabbits
[1371] The distribution and tolerability of STMP and NSTMP were
studied in pigmented New Zealand rabbits (F 1) following an
intravitreal injection of the microparticles. ProVisc.RTM. was
diluted 5-fold in PBS and used as a diluent to prepare particle
suspensions of about 200 mg/mL for injection. Detailed study groups
and conditions are presented in Table 9.
[1372] Complete ocular examinations were performed for up to 7
months after the dosing, using a slit lamp biomicroscope and an
indirect ophthalmoscope, to evaluate ocular surface morphology,
anterior segment and posterior segment inflammation, cataract
formation, and retinal changes. A retinal lens was used to examine
the location, morphology and distribution of the microspheres in
vitreous. Histological analysis was also performed on enucleated
and fixed eyes for up to 7 months. At pre-determined time points
for up to 7 months, the drug levels of sunitinib (ng/g) in various
ocular tissues (e.g. vitreous, retina, and RPE/choroid) and plasma
were also analyzed. FIG. 11A illustrates a representative 1-month
histology image following injection with surface treated
microparticles (STMP) and FIG. 11B illustrates a representative
1-month histology images following injection with non-surface
treated microparticles (NSTMP).
TABLE-US-00018 TABLE 9 Detailed information on rabbit study groups
and dosing conditions Microsphere Microsphere *SM Microsphere
Injection Type Group # Mass Dose Drug Loading Volume With Drug- #1
2 mg 0.2 mg 10% 10 uL surface loaded #2 10 mg 1.0 mg 10% 50 uL
treatment #3 10 mg 0.2 mg 2% 50 uL Empty #7 2 and 10 mg None None
10 uL (Left eye) 50 uL (Right eye) Without Drug #4 2 mg 0.2 mg 10%
10 uL surface loaded #5 10 mg 1.0 mg 10% 50 uL treatment #6 10 mg
0.2 mg 2% 50 uL Empty #8 2 and 10 mg None None 10 uL (Left eye) 50
uL (Right eye) *SM = Sunitinib Malate Dose
[1373] Immediately following dosing, the microspheres remained
localized at the site of injection in the vitreous as a depot for
all the injections. At 1 and 2 months, fundus examination using a
retina lens showed that in the eyes injected with STMP, most
particle injections remained consolidated in the vitreous without
dispersion and no vision impairment or disturbance was observed. In
contrast, particle dispersion was more commonly observed in the
eyes injected with NSTMP.
[1374] Histological analysis for up to 7 months showed that overall
the injections were well tolerated with minimal evidence of ocular
inflammation or toxicity. No evidence of retinal toxicity (thinning
and degeneration, etc.) was observed with any treatment. With STMP,
the only eyes with observed inflammation were those with
injection-related lens trauma/cataract and associated secondary
lens-induced uveitis, which is believed to be associated with the
injection procedure and not the STMP; no other evidence of
inflammation in eyes dosed with surface treated microspheres was
observed (FIG. 11, left). In some of the eyes dosed with NSTMP,
very mild, but present, inflammation in the vitreous that may be
associated with the NSTMP was observed (FIG. 11, right). The
results suggest that surface treatment not only reduces the chance
of particle dispersion in the vitreous that can cause visual
impairment or disturbance, but it may also reduce potential
intraocular inflammation associated with microspheres and improve
the overall safety of the treatment.
[1375] As shown in FIGS. 14, 15, and 16, the sunitinib levels in
the retina or RPE/choroid of rabbits receiving STMP containing 1 or
0.2 mg of sunitinib malate were above the K.sub.i for sunitinib
against VEGFR and PDGFR at 1, 2, and 4 months, respectively. Low
levels of sunitinib were detected in plasma only at 1 and 2
months.
Example 21. Determination of Drug Purity and Impurities in
Particles
[1376] Sample S-12 (10.5 mg) was measured into an amber vial.
N,N-dimethylacetamide (0.3 mL) and acetonitrile (0.6 mL) were added
to dissolve the particles. Water (2.1 mL) was added and the mixture
was thoroughly mixed. The final concentration of particles in the
N,N-dimethylacetamide/acetonitrile/water (v/v 1:2:7) mixture was
3.5 mg/mL. The purity of active compound in STMP S-12 was
determined by HPLC and is reported in Table 10. The results suggest
that the surface treatment did not affect the purity of
encapsulated drug.
TABLE-US-00019 TABLE 10 HPLC analysis of drug purity in STMP Peak
Number Retention time Area (%) 1 0.24 0.157 2 0.78 0.283 3 0.82
0.044 4 1.00 99.39 5 1.12 0.046 6 1.41 0.084
Example 22. Measurement of Average Size and Size Distribution of
Surface Treated Microparticles (STMP)
[1377] Several milligrams of S-12 were suspended in water. The mean
particle size and distributions were determined using a Coulter
Multisizer IV (Beckman Coulter, Inc., Brea, Calif.). The
distribution shown in FIG. 12 has the following statistics: D10 of
20.98 .mu.m, D50 of 32.32 m, D90 of 41.50 .mu.m, mean of 31.84
.mu.m, and standard deviation of 8.07 m.
Example 23. Determination of Endotoxin Level in Particle
Suspension
[1378] Microparticles (5-10 mg, S-12) were added to a sterile vial
in a biosafety cabinet. The particles were suspended in
endotoxin-free PBS. Using a ToxinSensor.TM. chromogenic LAL
endotoxin assay kit (GenScript USA Inc., Piscataway, N.J.) and the
instructions provided by the manufacture, the sample's total level
of endotoxin was measured. S-12 had a low endotoxin level of less
than 10 EU/mg.
Example 24. Toxicity Studies
[1379] An acute, non-GLP IVT study was conducted to evaluate the
ocular tolerability and toxicity of sunitinib malate (free drug)
for up to 7 days following a single IVT injection. Sunitinib malate
was formulated in phosphate buffered saline and injected
bilaterally (0.1 mL) at 0.125 or 1.25 mg per eye. At the 1.25
mg/eye dose, histologically significant findings related to
sunitinib included residual test article, lenticular
vacuoles/degeneration, mild to minimal inflammatory cell
infiltration in vitreous, retinal degeneration, detachment, and
necrosis. No toxicologically significant findings were observed at
the 0.125 mg/eye dose, which is considered the
no-observed-adverse-effect-level (NOAEL) dose.
[1380] FIG. 13A, FIG. 13B, and FIG. 13C illustrate select PK
profiles for sunitinib malate in the retina, vitreous, and plasma,
respectively, from pigmented rabbits.
Example 25. Preparation of Sunitinib Microparticles (not Surface
Treated)
[1381] PLGA (555 mg) and PLGA-PEG5K (5.6 mg) were dissolved in DCM
(4 mL). Sunitinib malate (90 mg) was dissolved in DMSO (2 mL). The
polymer and drug solutions were then mixed. The resulting reaction
mixture was filtered through a 0.22 .mu.m PTFE syringe filter. The
resulting reaction mixture was diluted with 1% PVA in PBS (200 mL)
in a 250 mL beaker and then homogenized at 5,000 rpm for 1 minute.
(The polymer/drug solution was poured into the aqueous phase using
homogenization conditions and homogenized at 5,000 rpm for 1
minute) The reaction was next stirred at 800 rpm at room
temperature for 3 hours in a biosafety cabinet. The particles were
allowed to settle in the beaker for 30 minutes and approximately
150 mL of the supernatant was decanted off. The microparticle
suspension underwent centrifugation at 56.times.g for 4.5 minutes,
the solvent was removed, and the microparticles were then washed
three times with water. The microparticle size and size
distribution was determined using a Coulter Multisizer IV prior to
lyophilization. The microparticles were lyophilized using a
FreeZone 4.5-liter benchtop lyophilizer. Light exposure was avoided
throughout the entire process.
Example 26. General Procedure for the Preparation of Surface
Treated Sunitinib Microparticles
[1382] Microparticle dry powder was weighed and placed in a small
beaker and a stirring bar was added. The beaker was placed in an
ice bath and cooled to about 4.degree. C. A NaOH/EtOH solution was
prepared by mixing NaOH in water (0.25M) with EtOH at 3:7 (v/v) and
cooling to about 4.degree. C. The cold NaOH/EtOH solution was added
with stirring to the beaker containing the microparticles to afford
a particle suspension of 100 mg/mL. The suspension was stirred for
3 minutes at about 4.degree. C. and poured into a filtration
apparatus to quickly remove the NaOH/EtOH solution. (The filtration
apparatus needed to be pre-chilled in a -20.degree. C. freezer
prior to use.) Following filtration, the microparticles were rinsed
in the filtration apparatus with ice cold deionized water and
transferred to 50 mL centrifuge tubes. Each 50 mL centrifuge tube
with filled with cold water to afford a 40 mL particle suspension
at a concentration of 5-10 mg/mL. The centrifuge tubes were placed
in a regenerator and the particles were allowed to settle for 30
minutes. The supernatant was then decanted. The particles were
resuspended in cold water and filtered through a 40 .mu.m cell
strainer to remove any large aggregates. The particles were
collected by centrifugation (56.times.g for 4.5 minutes) and washed
twice with water. The product was lyophilized using a FreeZone 4.5
liter benchtop lyophilizer. The surface treatment process was
conducted at approximately 4.degree. C. and light exposure was
avoided throughout the entire process.
Example 27. Method for Determining Accelerating In Vitro Drug
Release at 50.degree. C.
[1383] Microparticles (10 mg) were added to glass scintillation
vials. Four milliliters of the release medium (1% Tween 20 in
1.times.PBS at pH 7.4) was added into the vials and the mixtures
were vortexed. The vials were shaken on an orbital shaker at 150
rpm in a Fisher general-purpose incubator at 50.degree. C. At
pre-determined time points, the appropriate vial was cooled and the
particles were allowed to settle for 10 minutes. Release medium (3
mL) was then carefully removed from the top of the vial and
replaced with fresh release medium (3 mL). The vial was then
returned to the orbital shaker and the amount of drug in the
release medium was measured by UV spectroscopy. The concentration
of drug was determined by comparing to a standard curve for the
drug.
Example 28. Preparation of Biodegradable Surface-Treated
Microparticles (STMP) Comprising PLA
[1384] NSTMP were first produced similarly as described in Example
1. Briefly, PLA and PLGA-PEG were co-dissolved in dichloromethane
(DCM) and sunitinib malate was dissolved in dimethyl sulfoxide
(DMSO). The polymer solution and the drug solution were mixed to
form a homogeneous solution (organic phase). For empty
microparticles, DMSO without drug was used. The organic phase was
added to an aqueous 1% PVA solution and homogenized at 5,000 rpm
for 1 minute using an L5M-A laboratory mixer (Silverson Machines
Inc., East Longmeadow, Mass.) to obtain an emulsion. The emulsion
(solvent-laden microparticles) was then hardened by stirring at
room temperature for more than 2 hours to allow the DCM to
evaporate. The microparticles were collected by sedimentation and
centrifugation, washed three times in water, and filtered through a
40-.mu.m sterile Falcon.RTM. cell strainer (Corning Inc., Corning,
N.Y.). The non-surface-treated microparticles (NSTMP) were either
used directly in the surface treatment process or dried by
lyophilization and stored as a dry powder at -20.degree. C. until
used.
[1385] A pre-chilled solution containing NaOH and ethanol was added
to microparticles in a glass vial under stirring in an ice bath at
approximately 4.degree. C. to form a suspension. The suspension was
then stirred for a predetermined time on ice and poured into a
pre-chilled filtration apparatus to remove the NaOH (aq)/EtOH
solution. The microparticles were further rinsed with pre-chilled
water and transferred to a 50-mL centrifuge tube. The STMP were
then suspended in pre-chilled water and kept in a refrigerator for
30 minutes to allow the particles to settle. Following removal of
the supernatant, the particles were resuspended and filtered
through a 40-.mu.m cell strainer to remove large aggregates.
Subsequently, the particles were washed twice with water at room
temperature and freeze-dried overnight.
TABLE-US-00020 TABLE 11 Detailed formulation information of STMP
comprising PLA NSTMP Surface Treatment STMP Aqueous Particle
Treatment ID Polymer Drug Phase Mixing Solution Conc. Time S-46 800
mg PLA 100 100 mg 200 mL of 5000 0.075M 200 3 min 4A and 8 mg
sunitinib 1% PVA in rpm 1 NaOH and mg/mL PLGA--PEG in 4 malate in 1
PBS min 50% EtOH mL DCM mL DMSO S-47 800 mg PLA 100 1 mL DMSO 200
mL of 5000 0.075M 200 3 min 4A and 8 mg 1% PVA in rpm 1 NaOH and
mg/mL PLGA--PEG in 4 water min 50% EtOH mL DCM S-48 640 mg PLA 100
2 mL DMSO 200 mL of 5000 0.075M 200 3 min 4A and 6.4 mg 1% PVA in
rpm 1 NaOH and mg/mL PLGA--PEG in 4 water min 50% EtOH mL DCM
[1386] The in vitro aggregability of the STMP was characterized
similarly as described in Example 3. Briefly, STMP were suspended
in PBS at 200 mg/mL and 30-50 uL of the suspension was injected
into 1.5-2.0 mL of PBS pre-warmed at 37.degree. C. After incubation
at 37.degree. C. for 2 hours, the aggregability of the
microparticles was assessed by visual observation and/or imaging
following gentle mechanical agitation. Overall all STMP described
in Table 11 were able to aggregate upon incubation at 37.degree. C.
for 2 hours.
Example 29. Distribution, Tolerability and Pharmacokinetics of
Sunitinib-Encapsulated STMP Comprising PLA Following an
Intravitreal (IVT) Injection in Rabbits
[1387] Sunitinib-encapsulated STMP comprising PLA were suspended in
ProVisc.RTM. diluted 5-fold in PBS to achieve a target dose of 1 mg
sunitinib malate in a 50 uL particle suspension. The tolerability
and pharmacokinetics were studied in pigmented New Zealand rabbits
(F 1) following an intravitreal injection of the STMP suspension.
At pre-determined time points after the dosing, complete ocular
examinations were performed and the drug levels of sunitinib (ng/g)
in various ocular tissues (e.g. vitreous, retina, and RPE/choroid)
were also analyzed (FIG. 19).
[1388] Ocular examinations for up to 6 months showed that the STMP
were well tolerated in rabbit eyes and remained consolidated in the
vitreous without dispersion and no vision impairment or disturbance
was observed. As shown in FIG. 19, the sunitinib levels in retina
or RPE/choroid of rabbits receiving STMP containing 1 mg of
sunitinib malate were above the K.sub.i for sunitinib against VEGFR
and PDGFR at 10 days and 3 months.
Example 30. Production of Surface-Treated Microparticles (STMP) on
a Larger Scale (100 g and Higher)
[1389] NSTMP were produced using a continuous flow, oil-in-water
emulsification method. The scale of the pilot batches was 100-200
g. A dispersed phase (DP) and a continuous phase (CP) were first
prepared. For placebo microparticles, the DP was prepared by
co-dissolving PLGA and PLGA-PEG polymers in DCM. The CP was a 0.25%
PVA solution in water. For drug-loaded microparticles, the DP was
prepared by dissolving sunitinib malate in DMSO and mixing with the
polymer solution in DCM. The CP was a 0.25% PVA solution in PBS (pH
approximately 7). Detailed formulation parameters are listed in
Table 12. An emulsion was produced by mixing the DP and the CP
using a high shear inline mixer. The solvents in the DP were
diluted by the CP, causing the emulsion droplets to solidify and
become polymer microparticles. The microparticles were then washed
with water using the volume exchange principle with the addition of
fresh water and removal of solvent-containing water with a hollow
fiber filter. The washed microparticles were subsequently suspended
in a solution containing NaOH and ethanol for surface modification
of the NSTMP. This step was performed in a jacketed vessel and the
temperature of the suspension was maintained around 8.degree. C.
Several surface treatment conditions have been tested as shown in
Table 12. Following additional washing in water and analysis of the
microparticle and drug concentration of in-process samples, the
STMP suspension was adjusted to target concentration prior to
filling of glass vials. In some batches, mannitol was added to the
final suspension. The vials were then lyophilized and sealed. The
manufacturing process can be completed aseptically and the final
product in vials may also be terminally sterilized by E-Beam or
gamma irradiation.
TABLE-US-00021 TABLE 12 Formulation and process parameters of STMP
produced on larger scale NSTMP DP PLGA Sunitinib Mixing Surface
Treatment 7525 4A PLGA-- DCM Malate DMSO speed Time NaOH (g) PEG5k
(g) (g) (g) (g) (rpm) (min) EtOH (mM) Excipient 86 0.86 640 16.5
260 4000 30 30% 0.53 86 0.86 640 16.5 260 4000 60 30% 75 86 0.86
640 15.3 260 4000 30 40% 0.075 86 0.86 640 15.3 260 4000 30 40%
0.75 86 0.86 640 15.3 260 4000 30 40% 0.75 86 0.86 640 15.3 260
4000 30 40% 0.75 86 0.86 640 3600 30 50% 0.75 86 0.86 640 3600 30
40% 0.75 86 0.86 640 260 3300 30 50% 0.75 86 0.86 640 15.3 260 4000
30 40% 0.75 86 0.86 640 3600 30 60% 0.75 86 0.86 640 15.3 260 4000
30 40% 0.75 86 0.86 640 3600 30 70% 0.75 86 0.86 640 15.3 260 4000
30 50% 0.75 Mannitol 86 0.86 640 15.3 260 4000 30 60% 0.75 Mannitol
86 0.86 640 15.3 260 4000 30 70% 0.75 Mannitol 172 1.72 1280 30.6
520 4000 30 70% 0.75 Mannitol 172 1.72 1280 3600 30 70% 0.75 172
1.72 1280 3600 25 70% 0.75 172 1.72 1280 30.6 520 4000 30 60% 0.75
Mannitol 172 1.72 1280 30.6 520 4000 30 60% 0.75 Mannitol 172 1.72
1280 3600 25 70% 0.75 Mannitol 172 1.72 1280 30.6 520 3800 30 60%
0.75 Mannitol 172 1.72 1280 30.6 520 4000 30 60% 0.75 172 1.72 1280
30.6 520 4000 30 60% 0.75
[1390] The in vitro aggregability of the STMP was characterized by
a similar method to that in Example 3. Briefly, STMP was suspended
in PBS at 200 mg/mL and 30-50 uL of the suspension was injected
into 1.5-2.0 mL of PBS pre-warmed to 37.degree. C. After incubation
at 37.degree. C. for 2 hours, the aggregability of the
microparticles was assessed by visual observation and/or imaging
following gentle mechanical agitation. In general, all STMP treated
with a solution containing 0.75 mM NaOH and EtOH of 40% or higher
were able to aggregate upon incubation at 37.degree. C. Following
suspension in hyaluronate solution and injection in PBS, STMP
treated with a higher concentration of EtOH showed a higher
tendency of floatation in PBS, suggesting reduced wettability as a
result of the surface treatment.
Example 31A: Particle Vacuum Treatment Procedure
[1391] Particles were machine-filled into 2 mL glass vials and
sealed with rubber septum. A vial adapter with a luer-lock opening
(source) was attached to the vial and diluents (e.g., hyaluronic
solution (HA)) were injected into the vial through the vial
adapter. Particles were mixed with the diluent in the vial by
manual tapping or vortex to yield a homogeneous suspension. A 60 mL
VacLok syringe (Merit Medical, South Jordan, Utah) was attached to
the vial adapter and its plunger was pulled to a predetermined
volume and locked by turning the plunger per the manufacturer's
instruction (FIG. 20A, FIG. 20C, and FIG. 21). This creates a
negative pressure in the vial containing particle suspension as low
as approximately 30 Torr depending on the plunger locking position.
This negative pressure pulls air bubbles away from the particles
and the suspension and thus reduces particle floatation upon
injection later. The vial was then rested in an upright position
for a predetermined period (i.e., 10-30 minutes) to allow most of
the air to be removed. After the vacuuming procedure, the 60 mL
syringe plunger was released and the syringe was detached from the
vial adapter. The suspension was remixed by gentle tapping and
loaded into syringe for injection.
Example 31B: Optimized Particle Vacuum Treatment Procedure
[1392] The vacuuming step described in Example 31A was optimized.
In the method described in Example 31B, particles were mixed after
negative pressure was created in the vial and the particles were
allowed to rest for a period of 10-60 minutes. In the method
described in Example 31A, a negative pressure was created in the
vial prior to mixing and particles were allowed to rest for 10-30
minutes.
[1393] Particles were filled into 2 mL glass vial with rubber
septum. A vial adapter with a luer-lock opening was attached to the
vial and diluent (e.g., hyaluronic solution (HA)) was injected into
the vial through the vial adapter. A 60 mL VacLok syringe (Merit
Medical, South Jordan, Utah) was attached to the vial adapter and
its plunger was pulled to a predetermined volume and locked by
turning the plunger per the manufacturer's instruction (FIG. 20A,
FIG. 20C, and FIG. 21).
[1394] This created a negative pressure in the vials as low as
approximately 30 Torr depending on the plunger locking position.
Particles were mixed with the diluent in the vial by manual tapping
or vortexing under the vacuum created by the VacLok syringe to
yield a homogeneous suspension. Due to the vacuum, less air bubbles
were generated in the suspension upon mixing. The vial was then
rested in an upright position for a predetermined period (i.e.,
10-60 minutes). This further allowed formed air bubbles to be
pulled out of the suspension, thus reducing particle floatation
upon injection later. After the vacuuming step, the plunger of the
60 mL syringe was released and the syringe was detached from the
vial adapter. The suspension was remixed by gentle tapping and
loaded into a dosing syringe for injection.
[1395] With the optimized reconstitution procedure, microparticle
floatation during injection was further reduced as compared to the
procedure in Example 31A, especially when the viscosity of the
suspension was high (e.g. particle concentration higher than 200
mg/mL). (FIGS. 22A and 22B are images comparing microparticles that
were exposed to the vacuum treatment of Example 31A (FIG. 22A) and
Example 31B (FIG. 22B). As a result, a more consolidated
aggregate/depot was formed by the microparticles and less particle
dispersion was observed as shown in FIG. 22C comparing
microparticles exposed to the vacuum treatment of Example 31A
(left) and Example 31B (right).
Example 32. Effect of Vacuum Strength During Vacuum Treatment on
Particle Floatation and Aggregation
[1396] Particles were suspended in 10.times. ProVisc (0.125% HA in
PBS) to afford a final concentration of 200 mg/mL. The particle
suspensions were vacuumed for 10 minutes at different strengths of
approximately 550 Torr, 143 Torr, 87 Torr, and 32 Torr. Following
vacuum treatment, the suspension was injected into a 37.degree. C.
phosphate buffered saline (PBS) in glass tubes and the particle
floatation during and after injection was monitored. Particles were
incubated in the glass tubes at 37.degree. C. for 2 hours after
injection to assess degree of aggregation. After the 2-hour
incubation, the particle aggregate was detached from the bottom of
glass tubes by gentle tapping and rotation.
[1397] Vacuuming strength inversely correlated with the degree of
particle floatation (FIG. 23A-23L). At 32 Torr, almost no particle
floatation was observed after injection (FIG. 23H) and the
resulting aggregation (FIG. 23L) was very good with one large
aggregate and minimal free flowing particles. When no vacuum was
pulled, most of the particles floated after injection (FIG. 23A)
and the aggregation was poor (FIG. 23I). The intermediate vacuum
strengths yielded floatation (FIGS. 23B, 23C, 23F, and 23G) and
aggregation (FIGS. 23K and 23L) results in between the two extreme
cases.
Example 33. Impact of Particle Concentration on Vacuuming
Outcome
[1398] Particle suspensions with concentrations of 200 mg/mL and
400 mg/mL were prepared by dissolving particles in a 10.times.
ProVisc solution (0.125% HA in PBS) and a 20.times. ProVisc
solution (0.063% HA in PBS), respectively. The particles were
vacuumed as described in Example 31. Under the same conditions
(vacuum treatment for 20 minutes at approximately 30 Torr), the
suspension with 400 mg/mL particles had significantly more
floatation compared to the 200 mg/mL particles (FIG. 24A and FIG.
24B). Without wishing to be bound by any particular one theory,
this could be because more particles were present in the 400 mg/mL
suspension and trapped more air, rendering a longer time and/or
higher vacuuming strength needed to remove the air. Higher particle
concentration also increased the suspension viscosity and slowed
down the traveling speed of air out of the suspension.
Example 34. Effect of Vacuum Time on Particle Floatation
[1399] Particle suspensions with concentrations of 400 mg/mL were
prepared by dissolving particles in a 40.times. ProVisc solution
(0.031% HA in PBS). The particles were vacuumed as described in
Example 31. Under the same vacuuming strength of approximately 0
Torr and the same particle concentration of 400 mg/mL, the longer
the vacuuming time, the less floatation was observed. As shown in
FIG. 25A, floatation percentage was approximately 20% after 10
minutes of vacuuming treatment compared to approximately 8%
floatation after 30 minutes of vacuuming treatment (FIG. 25B).
Without wishing to be bound by any particular one theory, this is
because more air was removed after a longer vacuuming time.
Example 35. Effect of High Vacuum Pre-Treatment Compared to Low
Vacuum Pre-Treatment on Particle Floatation
[1400] Particle suspensions with concentrations of 400 mg/mL were
prepared by dissolving particles in a 20.times. ProVisc solution
(0.063% HA in PBS). Particle vials were sealed under a high vacuum
of approximately 35 Torr and the suspensions were vacuumed as
described in Example 31. Compared to particles sealed under a low
vacuum of approximately 550 Torr (FIG. 26B), the particles
subjected to high vacuum treatment (FIG. 26A) exhibited less
floatation especially when the suspension was concentrated (e.g.,
400 mg/mL). FIG. 26A and FIG. 26B show the degree of particle
floatation after injection from suspensions with 400 mg/mL
particles vacuumed at approximately 35 Torr and 550 Torr for 10
minutes. The suspension prepared in the vial sealed under
approximately 35 Torr had significantly less floatation than the
suspension sealed at approximately 550 Torr. Without being bound to
any one theory, this is because less air was present in the vial
sealed under high vacuum, resulting in less air associated with the
particles.
Example 36. Effects of Excipient Type Concentration on
Floatation
[1401] Particles were suspended in solutions of 1% or 10% sucrose,
mannitol, or trehalose to afford solutions with concentrations of
approximately 60 mg/mL. The particles were then sonicated for a few
minutes, flash frozen in -80.degree. C. ethanol and lyophilized
overnight. The lyophilized particles were then suspended in water
and injected into 37.degree. C. PBS or hyaluronic acid (HA)
solution (5 mg/mL) to assess floatation and aggregation. Control
particles had no excipients added.
[1402] Upon injection into PBS and HA solution, particles with
excipients (FIGS. 27A-27J) had less floatation compared to controls
(FIGS. 27K and 27L). Particle sonicated in 10% sucrose excipient
(FIGS. 27B and 27D) yielded less floatation than 1% sucrose (FIGS.
27A and 27C), while 1% and 10% mannitol (FIGS. 27E-27H) or
trehalose (FIGS. 27I and 27J) yielded similar degree of
floatation.
[1403] Particles were incubated in the glass tubes at 37.degree. C.
for 2 hours after injection to assess degree of aggregation. After
the 2-hour incubation, the particle aggregate was detached from the
bottom of glass tubes by gentle tapping and rotation. Particles
with excipients exhibited aggregation whereas particles without
excipients had poor aggregation (FIG. 28).
Example 37. The Effect of Sonication on Particle Floatation and
Aggregation
[1404] Particles were suspended in HA solution, sonicated for a few
minutes, and injected into 37.degree. C. PBS. The sonicated
particles had less floatation and better aggregation compared to
the control (FIGS. 29A and 29B). Without wishing to be bound to any
one theory, this is because sonication introduces high frequency
agitation and can remove the air associated with the particles,
reduce floatation, and improve aggregation as shown in FIG. 30.
Example 38: Longer-Lasting Sunitinib-Encapsulated Polymer
Microparticles
Preparation of Sunitinib Particles
[1405] Polymer microparticles comprising PLA, PLGA and/or diblock
copolymer of PLGA and PEG encapsulating sunitinib malate were
prepared using a single emulsion solvent evaporation method. PLA,
PLGA and PLGA-PEG were purchased from Evonik Corporation
(Birmingham, Ala.). Sunitinib malate (SM) was purchased from Teva
Pharmaceutical Industries Ltd. (Parsippany, N.J.) or LC Laboratory
(Woburn, Mass.).
[1406] Briefly, PLA, PLGA and PLGA-PEG of selected ratios were
weighed and co-dissolved in dichloromethane (DCM) at pre-determined
concentration. Sunitinib malate was dissolved in an organic solvent
such as dimethyl sulfoxide (DMSO) at pre-determined concentration.
After mixing the polymer solution and the drug solution to form a
homogeneous solution (organic phase), the organic phase was
homogenized in an aqueous solution of polyvinyl alcohol (PVA) (Mw
25kD, 88% hydrolyzed) in a phosphate buffer saline (PBS) solution
with a pH .about.7.4 using an L5M-A laboratory mixer or a Verso
laboratory in-line mixer (Silverson Machines Inc., East Longmeadow,
Mass.) to form particles. Detailed formulation and process
parameters are presented in Table 13.
[1407] Particles were hardened by stirring at room temperature for
>2 hr to allow DCM to evaporate, and then collected by
centrifugation and washed prior to drying by lyophilization. Mean
particle sizes and particle size distributions were determined
using a Coulter Multisizer IV (Beckman Coulter, Inc., Brea,
Calif.). Lyophilized particles were stored at -20.degree. C. until
use.
Determination of Drug Loading and Encapsulation Efficiency
[1408] Drug loading was determined by UV absorbance. 10 mg of
particles containing sunitinib malate were dissolved in 1 mL of
anhydrous DMSO. Appropriate dilutions of this solution were made in
DMSO until the concentration of drug was in the linear range of the
standard curve of UV absorbance for the drug. The concentration of
the drug was determined by comparison to the standard curve.
In Vitro Drug Release at Body Temperature
[1409] 5 mg of dried particles were suspended in 1 mL of PBS (pH
7.4) and incubated at 37.degree. C. on a rotating platform (140
rpm). At selected time points, supernatant was collected by
centrifugation and particles were resuspended in 1 mL of fresh PBS.
The UV absorbance of the collected release medium was measured and
the concentration of drug at each time point was determined by
comparison to a standard curve for the drug.
Influence of Polymer Composition on the Release Kinetics of
Sunitinib Particles composed of a polymer blend including PLA,
PLGA, and PLGA5050-PEG5k (10% PEG) were made as described above.
Polymers with different hydrophobicity (LA/GA ratio) and MW were
tested. The drug loading and encapsulation efficiency were
characterized. The polymer composition, formulation parameters, and
in vitro characterization data of select formulations are shown in
Table 13, Table 14, Table 15, Table 16, and Table 17.
TABLE-US-00022 TABLE 13 Polymer Composition, Formulation
Parameters, and In Vitro Characterization of Sunitinib-encapsulated
Microparticles. Ratio and Polymer Sunitinib conc. of conc. in
Malate in DCM to Drug Mean In Polymer polymer DCM DMSO DMSO loading
Size Vitro ID Composition composition (mg/mL) (mg/mL) ratio (wt %)
(.mu.m) burst % SM PLGA 75:25.sup.a 100/1 140 45 2:1 12.0 31 0.92
72 4A/ (99% PLGA PLGA--PEG and 1% PLGA--PEG) SM PLA 100/1 200 100
4:1 13.3 26 0.41 60 4A/ (99% PLA PLGA--PEG and 1% PLGA--PEG) SM PLA
100/1 200 100 2:1 18.5 40 2.08 61 4A/ (99% PLA PLGA--PEG and 1%
PLGA--PEG) SM PLA 4A/ 90/10/1 200 100 2:1 18.6 40 1.81 62 PLGA/
(99% PLA, PLGA--PEG PLGA blend and 1% PLGA--PEG) SM PLA 4A/ 70/30/1
200 100 2:1 18.5 38 2.23 63 PLGA/ (99% PLA, PLGA--PEG PLGA blend
and 1% PLGA--PEG) SM PLA 4A/ 50/50/1 200 100 2:1 17.6 38 1.92 64
PLGA/ (49.5% PLGA--PEG PLA, 49.5% PLGA and 1% PLGA--PEG) .sup.aPLGA
75:25 is a PLGA polymer where the ratio of lactide units to
glycolide units is 75 to 25
TABLE-US-00023 TABLE 14 Polymer Composition, Formulation
Parameters, and In Vitro Characterization of Sunitinib-encapsulated
Microparticles. Ratio and Polymer Sunitinib conc. of conc. in
Malate in DCM to Drug Mean In Polymer polymer DCM DMSO DMSO loading
Size Vitro ID Composition composition (mg/mL) (mg/mL) ratio (wt %)
(.mu.m) burst % SM PLA 95/5/1 200 100 2:1 18.2 26 2.16 65 4A/PLGA
(99% PLA, 5050.sup.a PLGA blend 4A/ and 1% PLGA--PEG = PLGA--PEG)
95/5/1 SM PLA 90/10/1 200 100 2:1 20.3 22 2.49 66 4A/PLGA (99% PLA,
5050.sup.a PLGA blend 4A/ and 1% PLGA--PEG = PLGA--PEG) 90/10/1 SM
PLA 95/5/1 200 100 2:1 17.4 25 1.75 67 4A/PLGA (99% PLA, 5050.sup.a
PLGA blend 5A/ and 1% PLGA--PEG = PLGA--PEG) 95/5/1 SM PLA 70/30/1
200 100 2:1 18.1 25 2.03 68 4A/PLGA (99% PLA, 5050.sup.a PLGA blend
5A/ and 1% PLGA--PEG = PLGA--PEG) 70/30/1 SM PLA 90/10/1 200 100
2:1 16.5 27 1.07 69 4A/PLGA (99% PLA, 5050.sup.a PLGA blend 5E/ and
1% PLGA--PEG = PLGA--PEG) 90/10/1 SM PLA 70/30/1 200 100 2:1 15.2
24 6.61 70 4A/PLGA (99% PLA, 7525.sup.b PLGA blend 3A/ and 1%
PLGA--PEG = PLGA--PEG) 70/30/1 SM PLA 90/10/1 200 100 2:1 18.1 25
3.78 71 4A/PLGA (99% PLA, 7525.sup.b PLGA blend 3A/ and 1%
PLGA--PEG = PLGA--PEG) 90/10/1 .sup.aPLGA 50:50 is a PLGA polymer
where the ratio of lactide units to glycolide units is 50 to 50
.sup.bPLGA 75:25 is a PLGA polymer where the ratio of lactide units
to glycolide units is 75 to 25
TABLE-US-00024 TABLE 15 Polymer Composition, Formulation
Parameters, and In Vitro Characterization of Sunitinib-encapsulated
Microparticles. Ratio and Polymer Sunitinib conc. of conc. in
Malate in DCM to Drug Mean In Polymer polymer DCM DMSO DMSO loading
Size Vitro ID Composition composition (mg/mL) (mg/mL) ratio (wt %)
(.mu.m) burst % SM PLA 4A/ 90/10/1 200 110 2:1 19.0 26 0.87 74 PLGA
75:25.sup.a (99% PLA, 4A/ PLGA blend PLGA--PEG and 1% PLGA--PEG) SM
PLA 4A/ 70/30/1 200 110 2:1 18.8 25 1.78 75 PLGA 75:25.sup.a (99%
PLA, 4A/ PLGA blend PLGA--PEG and 1% PLGA--PEG) SM PLA 4A/ 50/50/1
200 110 2:1 18.1 28 3.03 76 PLGA 75:25.sup.a (49.5% 4A/ PLA, 49.5%
PLGA--PEG PLGA and 1% PLGA--PEG) SM PLA 4A/ 100/1 200 110 2:1 18.8
28 1.52 77 PLGA--PEG (99% PLA and 1% PLGA--PEG) .sup.aPLGA 75:25 is
a PLGA polymer where the ratio of lactide units to glycolide units
is 75 to 25
TABLE-US-00025 TABLE 16 Polymer Composition, Formulation
Parameters, and In Vitro Characterization of Sunitinib-encapsulated
Microparticles. Ratio and Polymer Sunitinib conc. of conc. in
Malate in DCM to Drug Mean In Polymer polymer DCM DMSO DMSO loading
Size Vitro ID Composition composition (mg/mL) (mg/mL) ratio (wt %)
(.mu.m) burst % SM PLGA 75:25.sup.a 100/1 140 45 2:1 13.3 28 n/a 78
4A/ (99% PLGA PLGA--PEG and 1% PLGA--PEG) SM PLA 100/1 200 100 4:1
12.0 24 n/a 79 4A/ (99% PLA PLGA--PEG and 1% PLGA--PEG) .sup.aPLGA
75:25 is a PLGA polymer where the ratio of lactide units to
glycolide units is 75 to 25
[1410] The in vitro release kinetics of the formulations in Table
13 are presented in FIG. 31. SM62 and SM63 exhibit release kinetics
that are relatively linear over 180 days. The in vitro release
kinetics of the formulations in Table 14 are presented in FIG. 32.
SM65 exhibits release kinetics that are relatively linear by 100
days with a slight increase in release rate beyond 120 days. SM 66
exhibits relatively linear release by 100 days and faster release
in the first 40 days. There is also a slight increase in release
rate beyond 120 days. SM71 exhibits relative higher burst and
relatively linear release by 100 days with a slight increase in
release rate past 100 days. A previously developed formulation
(SM72) that does not contain PLA was included for comparison. The
in vitro release kinetics of the formulations in Table 15 are
presented in FIG. 33. The in vitro release kinetics of the
formulations of SM60, SM72, and a 7:3 mass ratio blend of SM79/SM78
described in Table 16 are presented in FIG. 34. As shown in FIG.
31, all formulations containing PLA have substantially longer
duration of release than SM72 which does not contain PLA. As shown
in FIG. 31, FIG. 32, and FIG. 33, by changing the composition of
the polymer blend including the choice of PLGA and/or varying the
ratio between polymers, the release kinetics can be fine-tuned to
improve the linearity of drug release. Alternatively, a more linear
release profile may also be obtained by blending different particle
formulations that have different release kinetics, as demonstrated
in FIG. 34.
[1411] To further improve the drug loading and extend the release
duration of microparticle formulations shown in Tables 13-16,
formulations described in Table 17 were made using different
polymers with longer MW. The digit in the name of polymer, such as
4A, 6E, or 8E, indicates the viscosity rank of these polymers.
Therefore, the larger the number, the higher the viscosity and
larger the molecular weight.
[1412] Polymer utilized in the formulations described in Table 17
have viscosity ranks of 6E and 8E, while the polymer formulations
described in Tables 13-16 have viscosity ranks of 3A, 4A, 5A, and
5E. Formulations SM81, SM82, SM83, and SM84 contain PLGA 75:25 8E,
which has an approximate Mw (weight-average molecular weight) of
141 KDa and an Mn (number-average molecular weight) of 84 KDa. As
shown in Table 17, drug loading of these formulations was
significantly improved from approximately 20% as shown in Tables
13-16 to approximately 30-40% as shown in Table 17.
TABLE-US-00026 TABLE 17 Polymer Composition, Formulation
Parameters, and In Vitro Characterization of Sunitinib-encapsulated
Microparticles. Polymer Sunitinib DCM conc. Malate to Drug Mean
Polymer in DCM in DMSO DMSO loading Size ID Composition (mg/mL)
(mg/mL) ratio (wt %) (.mu.m) SM PLA 6E/ 100 105 2:1 27.0 28.1 80
PLGA--PEG = 100/1 (99% PLA and 1% PLGA--PEG) SM PLGA 7525 80 105
2:1 30.1 24.5 81 8E/PLGA--PEG 100/1 (99% PLGA and 1% PLGA--PEG) SM
PLGA 7525 100 105 2:1 27.9 32.7 82 8E/PLGA--PEG 100/1 (99% PLGA and
1% PLGA--PEG) SM PLGA 7525 50 75 2:1 31.0 22.9 83 8E/PLGA--PEG
100/1 (99% PLGA and 1% PLGA--PEG) SM PLGA 7525 50 105 2:1 37.2 25.0
84 8E/PLGA--PEG 100/1(99% PLGA and 1% PLGA--PEG)
[1413] Four additional lots of sterile longer-lasting formulations
are described in Tables 18A. The mean, median, standard deviation,
d10, d50, and d90 of the microparticles are give in Table 18B. All
microparticles were formulated with different ratios of PLA 4A/PLGA
7525 4A/PLGA-PEG. All four lots exhibited good aggregation in vitro
and exhibited release rates of approximately 20%. The in vitro
release data following dosing in rabbits of the four lots
characterized in Table 18A and 18B is shown in FIG. 35. The release
rate of microparticles formulated without PLA (SM 72) is shown for
comparison. The formulations shown in Tables 18A and 18B were
produced by an in-line mixer, sterilized, and surface-treated.
TABLE-US-00027 TABLE 18A Characterization of PLA/PLGA/PLGA--PLA
Blended Microparticles Composition In (PLA vitro 4A/PLGA In vitro
burst 7525 In vitro aggregation at Mean 4A/ DL Endotoxin
aggregation (10X 37.degree. C. Yield Yield size ID PLGA--PEG) (%)
(surface) (PBS/PBS) PV/PBS) (~3 h) (g) (%) (um) SM 90/10/1 19.02
0.000055 Good Good 0.87 4.55 34.7 25.17 90 (99% PLA, PLGA blend and
1% PLGA--PEG) SM 70/30/1 18.78 0.000034 Good Good 1.88 6.01 46.6
25.33 91 (99% PLA, PLGA blend and 1% PLGA--PEG) SM 50/50/1 18.09
0.00022 Good Good 3.28 3.58 27.6 27.84 92 (99% PLA, PLGA blend and
1% PLGA--PEG) SM 100/0/1 18.76 0.00023 Good Good 1.59 4.24 32.9
28.15 93 (99% PLA and 1% PLGA--PEG)
TABLE-US-00028 TABLE 18B Characterization of PLA/PLGA/PLGA--PLA
Blended Microparticles Composition (PLA 4A/PLGA 7525 Mean Median
S.D. ID 4A/PLGA--PEG) (.mu.m) (.mu.m) (.mu.m) d10 (.mu.m) d50
(.mu.m) d90 (.mu.m) SM90 90/10/1 (99% PLA, 25.17 25.69 6.685 16.33
25.69 32.84 PLGA blend and 1% PLGA--PEG) SM91 70/30/1 (99% PLA,
25.33 25.87 7.866 14.48 25.87 34.92 PLGA blend and 1% PLGA--PEG)
SM92 50/50/1 (99% PLA, 27.84 27.82 8.6 16.81 27.82 38.98 PLGA blend
and 1% PLGA--PEG) SM93 100/0/1 (99% PLA 28.15 28.15 8.704 16.8
28.15 39.37 and 1% PLGA--PEG)
[1414] A comparison of the in vitro release of three lots of PLA 4A
particles is shown in FIG. 36. Two of the microparticle lots (SM 94
and SM 61) were homogenized via a small probe, while one lot (SM
93) was homogenized via an in-line mixer. SM 94 and SM 61 were not
surface-treated, while SM 93 was surface-treated. Further
characterization details for the three lots are shown in Tables 19A
and 19B.
TABLE-US-00029 TABLE 19A Characterization of Microparticles
formulated with PLA Polymer Homo- Surface conc. API conc. DCM to
genizer treated in DCM in DMSO DMSO ID Composition type (YIN)
(mg/mL) (mg/mL) ratio SM 99% PLA Small N 200 100 4:1 94 4A/1% probe
PLGA--PEG SM 100% PLA Small N 200 100 2:1 61 4A/1% probe PLGA--PEG
SM 100% PLA In-line Y 200 110 93 4A/1% mixer PLGA--PEG
TABLE-US-00030 TABLE 19B Drug loading, mean size, and in vitro
burst percent of microparticles formulated with PLA Drug loading
Mean Size ID Composition (wt %) (.mu.m) In vitro burst % SM94 99%
PLA 13.3 26 0.41 4A/1% PLGA- PEG SM61 100% PLA 18.5 40 2.08 4A/1%
PLGA- PEG SM93 100% PLA 18.8 28 1.59 4A/1% PLGA- PEG
Example 39. In Vitro Release of Particle Blending
[1415] The in vitro release of particle blending is shown in FIG.
37. The release rate of blends of different formulations of
microspheres (9:1 PLA:PLGA, 7:3 PLA:PLGA, and 5:5 PLA:PLGA) are
shown and compared to formulations SM 94 and SM 72. The calculated
release rate and the actual release rate is shown for each of the
blends.
Example 40. In Vivo Injection of Sunitinib Encapsulated
Microparticles
[1416] Ocular Drug Levels after an Intravitreal Injection
[1417] Drug-containing microparticles (1 mg sunitinib) were
injected (0.05 mL) into the vitreous of pigmented New Zealand
rabbits using a 27G needle and the ocular levels of sunitinib were
assessed for 9 months. Complete ocular examinations were performed
10 days after dosing and monthly thereafter for 9 months, using a
slit lamp biomicroscope and an indirect opthalmoscope, to evaluate
ocular surface morphology, anterior segment and posterior segment
inflammation, cataract formation, and retinal changes. A retinal
lens was used to examine the location, morphology and distribution
of the microspheres in vitreous. At time points of 3, 6, and 9
months, the drug levels of sunitinib (ng/g) in various ocular
tissues (e.g. vitreous, retina, and RPE/choroid) and plasma were
also analyzed.
[1418] After injection, microparticles were shown to coalesce in
the inferior vitreous into an immobile, implant-like depot that
remains outside of the visual axis. Slit-lamp and fundus
examinations showed no OE findings in any of the eyes dosed with
the formulations or with the placebo formulation for the entire
in-life portion (9-months post dose).
[1419] Both SM60 and a blend of SM60 and SM72 at a 7:3 mass ratio
were evaluated. The in vivo release profiles of the formulations
are shown in FIG. 38. The data show that the duration of release of
both SM60 and the blend of SM60 and SM72 was significantly longer
than that of SM72. The release profile of the blend of SM60 and
SM72 is also more linear than that of SM60. In addition, as shown
in FIGS. 39A and 39B, relatively high drug levels were maintained
in the rabbit eyes injected with SM60 or the blend of SM60 and SM72
for at least 9 months.
[1420] As shown in FIGS. 33, 34A, and 34B (in vitro and in vivo
drug release kinetics), the inclusion of PLA in the formulation
extends the duration of drug release by up to 6 months with a good
correlation seen between in vitro and in vivo release kinetics. In
addition, the PLA-based formulations maintain pharmacologically
active levels in retina/RPE choroid for at least 9-months
post-dose.
Pharmacokinetics (PK) and Toxicity Study for Longer-Lasting
Sunitinib-Encapsulated Polymer Microparticles
[1421] Drug-containing microparticles (.about.0.75 mg sunitinib)
(SM74, 75 and 76) were injected (0.02 mL) into the vitreous of
pigmented Dutch Belted rabbits using a 27G needle and the ocular
levels of sunitinib were assessed for up to 8 months. To evaluate
ocular surface morphology, anterior segment and posterior segment
inflammation, cataract formation, and retinal changes, ocular
examinations were performed 10 days and 1, 2, 4, 6 and 8 months
post-injection using a slit lamp biomicroscope and fundus
examination A retinal lens was used to examine the location,
morphology and distribution of the microspheres in vitreous. At
time points of 10 days and 1, 2, 4, 6 and 8 months the drug levels
of sunitinib (ng/g) in various ocular tissues (e.g. retina and
RPE/choroid) were also analyzed. FIG. 40A illustrates the remaining
drug in the central retina and RPE/choroid area and FIG. 40B
illustrates the remaining drug in the eye. The in vivo data
indicate that these formulations can safely and effectively last at
least 8 months in rabbit eyes.
[1422] After injection, microparticles were shown to coalesce in
the inferior vitreous into an immobile, implant-like depot that
remains outside of the visual axis. Slit-lamp and fundus
examinations showed no OE findings in any of the eyes dosed with
the formulations or with the placebo formulation for the partial
in-life portion (8-months post dose).
[1423] As shown in FIG. 40A and FIG. 40B, increasing the PLA ratio
in the formulation extends the duration of drug release in vivo.
SM76 with a ratio of PLA:PLGA:PLGA-PEG of 50:50:1 exhibited drug
release of 6 months, while SM75 (ratio of 70:30:1) exhibited a drug
release of 8 months. SM74, which was formulated with a
PLA:PLGA:PLGA-PEG ratio of 90:10:1 exhibited a drug release rate of
greater than >8 months.
[1424] This specification has been described with reference to
embodiments of the invention. However, one of ordinary skill in the
art appreciates that various modifications and changes can be made
without departing from the scope of the invention as set forth
herein. Accordingly, the specification is to be regarded in an
illustrative rather than a restrictive sense, and all such
modifications are intended to be included within the scope of
invention.
* * * * *