U.S. patent application number 11/278472 was filed with the patent office on 2006-07-27 for short duration depot formulations.
Invention is credited to Guohua Chen, David Priebe.
Application Number | 20060165800 11/278472 |
Document ID | / |
Family ID | 34103124 |
Filed Date | 2006-07-27 |
United States Patent
Application |
20060165800 |
Kind Code |
A1 |
Chen; Guohua ; et
al. |
July 27, 2006 |
SHORT DURATION DEPOT FORMULATIONS
Abstract
Methods and compositions for systemically or locally
administering by implantation a beneficial agent to a subject are
described, and include, for example, depot gel compositions that
can be injected into a desired location and which can provide
controlled release of a beneficial agent over a short duration of
time. The compositions include a low molecular weight biocompatible
polymer, a biocompatible solvent having low water miscibility that
forms a viscous gel with the polymer and limits water uptake by the
implant, and a beneficial agent.
Inventors: |
Chen; Guohua; (Sunnyvale,
CA) ; Priebe; David; (Bellevue, WA) |
Correspondence
Address: |
WOODCOCK WASHBURN LLP
ONE LIBERTY PLACE
46TH FLOOR
PHILADELPHIA
PA
19103
US
|
Family ID: |
34103124 |
Appl. No.: |
11/278472 |
Filed: |
April 3, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10606969 |
Jun 25, 2003 |
|
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11278472 |
Apr 3, 2006 |
|
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60391867 |
Jun 25, 2002 |
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Current U.S.
Class: |
424/486 |
Current CPC
Class: |
A61P 23/00 20180101;
A61K 47/34 20130101; A61K 9/0024 20130101; A61K 38/27 20130101;
A61K 9/06 20130101; A61K 47/10 20130101; A61K 9/0014 20130101; A61P
23/02 20180101; A61K 31/445 20130101; A61K 47/14 20130101; A61K
9/0019 20130101 |
Class at
Publication: |
424/486 |
International
Class: |
A61K 9/14 20060101
A61K009/14 |
Claims
1. An injectable depot composition for sustained delivery of a
beneficial agent to a subject comprising: (a) a low molecular
weight bioerodible, biocompatible polymer; (b) a solvent selected
from the group consisting of aromatic alcohols, esters of aromatic
acids, aromatic ketones, and mixtures thereof, said solvent having
miscibility in water of less than or equal to 7% at 25.degree. C.,
and present in an amount effective to plasticize the polymer and
form a gel therewith; and (c) a beneficial agent; wherein the
beneficial agent is delivered in a controlled manner over a
duration equal to or less than two weeks.
2. The injectable depot composition of claim 1 wherein the
beneficial agent is delivered systemically.
3. The injectable depot composition of claim 1 wherein the
beneficial agent is delivered locally.
4. The injectable depot composition of claim 1 wherein the low
molecular weight polymer has a molecular weight ranging from about
3000 to about 10,000.
5. The injectable depot composition of claim 1, wherein the polymer
is selected from the group consisting of polylactides,
polyglycolides, polyanhydrides, polyamines, polyesteramides,
polyorthoesters, polydioxanones, polyacetals, polyketals,
polycarbonates, polyphosphoesters, polyorthocarbonates,
polyphosphazenes, succinates, poly(malic acid), poly(amino acids),
polyvinylpyrrolidone, polyethylene glycol, polyhydroxycellulose,
chitin, chitosan, hylauronic acid and copolymers, terpolymers and
mixtures thereof.
6. The injectable depot composition of claim 5, wherein the polymer
is a lactic acid-based polymer.
7. The injectable depot composition of claim 1, wherein the polymer
represents about 10 wt. % to about 85 wt. % of the composition.
8. The injectable depot composition of claim 1, wherein the
aromatic alcohol is benzyl alcohol and the ester of an aromatic
acid is a lower alkyl ester or an aralkyl ester of benzoic
acid.
9. The injectable depot composition of claim 1 wherein the
beneficial agent is selected from a drug, proteins, enzymes,
hormones, polynucleotides, nucleoproteins, polysaccharides,
glycoproteins, lipoproteins, polypeptides, steroids, analgesics,
local anesthetics, antibiotic agents, chemotherapeutic agents,
immunosuppressive agents, anti-inflammatory agents,
antiproliferative agents, antimitotic agents, angiogenic agents,
antipsychotic agents, central nervous system (CNS) agents,
anticoagulants, fibrinolytic agents, growth factors, antibodies,
ocular drugs, and metabolites, analogs, derivatives, and fragments
thereof.
10. The injectable depot composition of claim 9 wherein the
beneficial agent is in the form of particles wherein the particle
further comprises a component selected from the group consisting of
a stabilizing agent, bulking agent, chelating agent and a buffering
agent.
11. A method of administering a beneficial agent to a subject in a
controlled manner over a duration equal to or less than two weeks,
comprising administering an injectable depot composition
comprising: (a) a low molecular weight bioerodible, biocompatible
polymer; (b) a solvent selected from the group consisting of
aromatic alcohols, esters of aromatic acids, aromatic ketones, and
mixtures thereof, said solvent having miscibility in water of less
than or equal to 7% at 25.degree. C., and present in an amount
effective to plasticize the polymer and form a gel therewith; and
(c) a beneficial agent.
12. The method of claim 11, wherein wherein the beneficial agent is
delivered systemically in a controlled manner over a duration equal
to or less than two weeks.
13. The method of claim 11, wherein the system releases within 24
hours after implantation less than or equal to 20% by weight of the
amount of beneficial agent to be delivered over the duration of the
delivery period, wherein the delivery period is 2 weeks.
14. The method of claim 11, wherein wherein the beneficial agent is
delivered systemically in a controlled manner over a duration equal
to or less than two weeks.
15. The method of claim 11 wherein the low molecular weight polymer
has a molecular weight ranging from about 3000 to about 10,000.
16. The method of claim 11, wherein the polymer is selected from
the group consisting of polylactides, polyglycolides,
polyanhydrides, polyamines, polyesteramides, polyorthoesters,
polydioxanones, polyacetals, polyketals, polycarbonates,
polyphosphoesters, polyorthocarbonates, polyphosphazenes,
succinates, poly(malic acid), poly(amino acids),
polyvinylpyrrolidone, polyethylene glycol, polyhydroxycellulose,
chitin, chitosan, hylauronic acid and copolymers, terpolymers and
mixtures thereof.
17. The method of claim 16, wherein the polymer is a lactic
acid-based polymer.
18. The method of claim 11, wherein the polymer represents about 10
wt. % to about 85 wt. % of the composition.
19. The method of claim 11, wherein the beneficial agent is
selected from a drug, proteins, enzymes, hormones, polynucleotides,
nucleoproteins, polysaccharides, glycoproteins, lipoproteins,
polypeptides, steroids, analgesics, local anesthetics, antibiotic
agents, chemotherapeutic agents, immunosuppressive agents,
anti-inflammatory agents, antiproliferative agents, antimitotic
agents, angiogenic agents, antipsychotic agents, central nervous
system (CNS) agents, anticoagulants, fibrinolytic agents, growth
factors, antibodies, ocular drugs, and metabolites, analogs,
derivatives, and fragments thereof.
20. The method of claim 19 wherein the beneficial agent is in the
form of particles wherein the particle further comprises a
component selected from the group consisting of a stabilizing
agent, bulking agent, chelating agent and a buffering agent.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application is a divisional of U.S. application Ser.
No. 10/606,969, filed Jun. 25, 2003, entitled "SHORT DURATION DEPOT
FORMULATIONS" which claims the benefit of U.S. Provisional
Application No. 60/391,867, filed on Jun. 24, 2002. The contents of
the above referenced applications are hereby incorporated in their
entirety by reference.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to a depot gel composition
that can be injected into a desired location and which can provide
controlled release of a beneficial agent over a short duration of
time. The present invention also relates to a method of preparing
and administering the composition.
[0004] 2. Description of the Related Art
[0005] Biodegradable polymers have been used for many years in
medical applications. Illustrative devices composed of the
biodegradable polymers include sutures, surgical clips, staples,
implants, and drug delivery systems. The majority of these
biodegradable polymers have been based upon glycolide, lactide,
caprolactone, and copolymers thereof.
[0006] The biodegradable polymers can be thermoplastic materials,
meaning that they can be heated and formed into various shapes such
as fibers, clips, staples, pins, films, etc. Alternatively, they
can be thermosetting materials formed by crosslinking reactions,
which lead to high-molecular-weight materials that do not melt or
form flowable liquids at high temperatures. Although thermoplastic
and thermosetting biodegradable polymers have many useful
biomedical applications, there are several important limitations to
their use in the bodies of various animals including humans,
animals, birds, fish, and reptiles.
[0007] Solid implant drug delivery systems containing a drug
incorporated in thermoplastic or thermosetting biodegradable
polymers have been widely used successfully. Such implants have to
be inserted into the body through an incision which is sometimes
larger than desired by the medical profession and occasionally lead
to a reluctance of the patients to accept such an implant or drug
delivery system. The following patents U.S. Pat. Nos. 5,456,679;
5,336,057; 5,308,348; 5,279,608; 5,234,693; 5,234,692; 5,209,746;
5,151,093; 5,137,727; 5,112,614; 5,085,866; 5,059,423; 5,057,318;
4,865,845; 4,008,719; 3,987,790 and 3,797,492 are believed to be
representative of such drug delivery systems and are incorporated
herein by reference. These patents disclose reservoir devices,
osmotic delivery devices and pulsatile delivery devices for
delivering beneficial agents.
[0008] Injecting drug delivery systems as small particles,
microspheres, or microcapsules avoids the incision needed to
implant drug delivery systems. However, these materials do not
always satisfy the demand for a biodegradable implant. These
materials are particulate in nature, do not form a continuous film
or solid implant with the structural integrity needed for certain
prostheses, the particles tend to aggregate and thus their behavior
is hard to predict. When inserted into certain body cavities such
as a mouth, a periodontal pocket, the eye, or the vagina where
there is considerable fluid flow, these small particles,
microspheres, or microcapsules are poorly retained because of their
small size and discontinuous nature. Further, if there are
complications, removal of microcapsule or small-particle systems
from the body without extensive surgical intervention is
considerably more difficult than with solid implants. Additionally,
manufacture, storage and injectability of microspheres or
microcapsules prepared from these polymers and containing drugs for
release into the body present problems.
[0009] The art has developed various drug delivery systems in
response to the aforementioned challenges. The following patents
U.S. Pat. Nos. 5,990,194; 5,780,044; 5,733,950; 5,620,700;
5,599,552; 5,556,905 5,278,201; 5,242,910 and 4,938,763; and PCT
publication WO 98/27962 are believed to be representative and are
incorporated herein by reference. These patents disclose polymer
compositions for injectable implants using solvents and/or
plasticizers.
[0010] Previously described polymer compositions for injectable
implants have used solvent/plasticizers that are very or relatively
soluble in aqueous body fluids to promote rapid solidification of
the polymer at the implant site and promote diffusion of drug from
the implant. Rapid migration of water into such polymeric implants
utilizing water soluble polymer solvents when the implants are
placed in the body and exposed to aqueous body fluids presents a
serious problem. The rapid water uptake often results in implants
having pore structures that are non-homogeneous in size and shape.
Typically, the surface pores take on a finger-like pore structure
extending for as much as one-third of a millimeter or more from the
implant surface into the implant, and such finger-like pores are
open at the surface of the implant to the environment of use. The
internal pores tend to be smaller and less accessible to the fluids
present in the environment of use. The rapid water uptake
characteristic often results in uncontrolled release of beneficial
agent that is manifested by an initial, rapid release of beneficial
agent from the polymer composition, corresponding to a "burst" of
beneficial agent being released from the implant. The burst often
results in a substantial portion of the beneficial agent, if not
all, being released in a very short time, e.g., hours or 1-2 days.
Such an effect can be unacceptable, particularly in those
circumstances where a controlled delivery is desired, i.e.,
delivery of beneficial agent in a controlled manner over a period
of greater than or equal to 3 days or up to a month, or where there
is a narrow therapeutic window and release of excess beneficial
agent can result in adverse consequences to the subject being
treated, or where it is necessary to mimic the naturally-occurring
daily profile of beneficial agents, such as hormones and the like,
in the body of the subject being treated.
[0011] Accordingly, when such devices are implanted, the
finger-like pores allow very rapid uptake of aqueous body fluids
into the interior of the implant with consequent immediate and
rapid dissolution of significant quantities of beneficial agent and
unimpeded diffusion of beneficial agent into the environment of
use, producing the burst effect discussed above.
[0012] Furthermore, rapid water uptake can result in premature
polymer precipitation such that a hardened implant or one with a
hardened skin is produced. The inner pores and much of the interior
of the polymer containing beneficial agent are shut off from
contact with the body fluids and a significant reduction in the
release of beneficial agent can result over a not insignificant
period of time ("lag time"). That lag time is undesirable from the
standpoint of presenting a controlled, sustained release of
beneficial agent to the subject being treated. What one observes,
then, is a burst of beneficial agent being released in a short time
period immediately after implantation, a lag time in which no or
very little beneficial agent is being released, and subsequently
continued delivery of beneficial agent (assuming beneficial agent
remains after the burst) until the supply of beneficial agent is
exhausted.
[0013] Various approaches to control burst and modulate and
stabilize the delivery of the beneficial agent have been described.
The following patents U.S. Pat. Nos. 6,130,200; 5,990,194;
5,780,044; 5,733,950; 5,656,297; 5,654,010; 4,985,404 and 4,853,218
and PCT publication WO 98/27962 are believed to be representative
and are incorporated herein by reference. Notwithstanding some
success, those methods have not been entirely satisfactory for the
large number of beneficial agents that would be effectively
delivered by implants.
SUMMARY OF THE INVENTION
[0014] The present invention provides a method and an injectable
depot gel composition for systemic and local delivery of a
beneficial agent to a subject over a short duration of time. In
particular, the invention provides controlled release of the
beneficial agent to the subject being treated, the release being
controlled over a period equal to or less than two weeks after
administration, prefereably a period of about 3 to about 7 days.
Additionally, the invention provides a method of preparing the
injectable depot gel composition.
[0015] In one aspect, the invention pertains to an injectable depot
composition comprising a low molecular weight bioerodible,
biocompatible polymer; a solvent having a miscibility in water of
less than or equal to 7 wt. % at 25.degree. C., in an amount
effective to plasticize the polymer and form a gel therewith; and a
beneficial agent dissolved or dispersed in the gel. Preferably the
solvent has a miscibility in water of less than 7 wt. %, more
preferably less than 5 wt %, and more preferably less than 3 wt
%.
[0016] In another aspect, the invention pertains to an injectable
depot composition for systemic delivery of a beneficial agent to a
subject in a controlled manner over a duration equal to or less
than two weeks comprising a low molecular weight bioerodible,
biocompatible polymer; a solvent having a miscibility in water of
less than or equal to 7 wt. % at 25.degree. C., in an amount
effective to plasticize the polymer and form a gel therewith; and a
beneficial agent dissolved or dispersed in the gel.
[0017] In an additional aspect, the invention pertains to an
injectable depot composition for sustained delivery of a beneficial
agent to a subject comprising a low molecular weight bioerodible,
biocompatible polymer; a solvent having a miscibility in water of
less than or equal to 7 wt. % at 25.degree. C., in an amount
effective to plasticize the polymer and form a gel therewith; and a
beneficial agent dissolved or dispersed in the gel; wherein the
beneficial agent is delivered systemically in a controlled manner
over a duration equal to or less than two weeks, preferably about
24 hours to about 2 weeks, preferably about 10 days or shorter;
preferably about 7 days or shorter, more preferably about 3 days to
about 7 days.
[0018] In an additional aspect, the invention pertains to an
injectable depot composition for sustained delivery of a beneficial
agent to a subject comprising a low molecular weight bioerodible,
biocompatible polymer; a solvent having a miscibility in water of
less than or equal to 7 wt. % at 25.degree. C., in an amount
effective to plasticize the polymer and form a gel therewith; and a
beneficial agent dissolved or dispersed in the gel; wherein the
beneficial agent is delivered locally in a controlled manner over a
duration equal to or less than two weeks, preferably about 24 hours
to about 2 weeks, preferably about 10 days or shorter; preferably
about 7 days or shorter, more preferably about 3 days to about 7
days.
[0019] In another aspect, the invention pertains to an injectable
depot composition as described above, further including at least
one of the following: a pore former; a solubility modulator for the
beneficial agent; and an osmotic agent; and optionally including an
emulsifying and/or a thixotropic agent.
[0020] In another aspect, the invention pertains to an injectable
depot composition as described above, wherein the low molecular
weight polymer has a weight average molecular weight ranging from
about 3000 to about 10,000; preferably from about 3000 to about
9,000; more preferably from about 4000 to about 8,000; and more
preferably the low molecular weight polymer has a molecular weight
of about 7000, about 6000, about 5000, about 4000 and about
3000.
[0021] In another aspect, the invention pertains to an injectable
depot composition as described above, wherein the polymer is
selected from the group consisting of polylactides, polyglycolides,
polyanhydrides, polyamines, polyesteramides, polyorthoesters,
polydioxanones, polyacetals, polyketals, polycarbonates,
polyphosphoesters, polyorthocarbonates, polyphosphazenes,
succinates, poly(malic acid), poly(amino acids),
polyvinylpyrrolidone, polyethylene glycol, polyhydroxycellulose,
chitin, chitosan, hylauronic acid and copolymers, terpolymers and
mixtures thereof. In preferred embodiments, the polymer is a lactic
acid-based polymer; preferably the polymer is a copolymer of lactic
acid and glycolic acid.
[0022] In another aspect, the invention pertains to an injectable
depot composition as described above, wherein the solvent is
selected from an aromatic alcohol having the structural formula (I)
Ar-(L).sub.n--OH (I)
[0023] in which Ar is a substituted or unsubstituted aryl or
heteroaryl group, n is zero or 1, and L is a linking moiety; and a
solvent selected from the group consisting of esters of aromatic
acids, aromatic ketones, and mixtures thereof.
[0024] In preferred embodiments, the solvent is selected from the
aromatic alcohol, lower alkyl and aralkyl esters of aryl acids;
aryl, aralkyl and lower alkyl ketones; and lower alkyl esters of
citric acid. Preferably, the solvent is selected from benzyl
alcohol, benzyl benzoate and ethyl benzoate. In preferred
embodiments, the composition is free of solvents having a
miscibility in water that is greater than 7 wt. % at 25.degree.
C.
[0025] In additional aspects, the invention pertains to methods of
administering a beneficial agent to a subject in a controlled
manner over a duration equal to or less than two weeks, comprising
administering an injectable depot composition as described above.
In certain embodiments, the beneficial agent is delivered
systemically in a controlled manner over a duration equal to or
less than two weeks. In additional embodiments, the beneficial
agent is delivered locally in a controlled manner over a duration
equal to or less than two weeks. In preferred embodiments, the
beneficial agent is delivered over a duration of about 24 hours to
about 2 weeks, preferably about 10 days or shorter; preferably
about 7 days or shorter, more preferably about 3 days to about 7
days.
[0026] In additional aspects, the invention pertains to a kit for
administration of a beneficial agent to a subject comprising:
[0027] (a) a low molecular weight bioerodible, biocompatible
polymer;
[0028] (b) a solvent having a miscibility in water of less than or
equal to 7 wt. % at 25.degree. C. that is suitable for dissolving
the polymer and forming a viscous gel;
[0029] (c) a beneficial agent; and optionally, one or more of the
following:
[0030] (d) an emulsifying agent;
[0031] (e) a pore former;
[0032] (f) a solubility modulator for the beneficial agent,
optionally associated with the beneficial agent; and
[0033] (g) an osmotic agent;
[0034] wherein at least the beneficial agent, optionally associated
with the solubility modulator, is maintained separated from the
solvent until the time of administration of the beneficial agent to
a subject.
[0035] In another aspect, the invention pertains to an injectable
depot composition and a method of administering such composition as
described above, wherein the beneficial agent is selected from a
drug, proteins, enzymes, hormones, polynucleotides, nucleoproteins,
polysaccharides, glycoproteins, lipoproteins, polypeptides,
steroids, analgesics, local anesthetics, antibiotic agents,
chemotherapeutic agents, immunosuppressive agents,
anti-inflammatory agents, antiproliferative agents, antimitotic
agents, angiogenic agents, antipsychotic agents, central nervous
system (CNS) agents, anticoagulants, fibrinolytic agents, growth
factors, antibodies, ocular drugs, and metabolites, analogs,
derivatives, fragments, and purified, isolated, recombinant and
chemically synthesized versions of these species. In preferred
embodiments, the beneficial agent is human growth hormone,
methionine-human growth hormone; des-phenylalanine human growth
hormone, alpha-, beta- or gamma-interferon, erythropoietin,
glugacon, calcitonin, heparin, interleukin-1, interleukin-2, Factor
VIII, Factor IX, luteinizing hormone, relaxin, follicle-stimulating
hormone, atrial natriuretic factor, filgrastim epidermal growth
factors (EGFs), platelet-derived growth factor (PDGFs),
insulin-like growth factors (IGFs), fibroblast-growth factors
(FGFs), transforming-growth factors (TGFs), interleukins (ILs),
colony-stimulating factors (CSFs, MCFs, GCSFs, GMCSFs), Interferons
(IFNs), endothelial growth factors (VEGF, EGFs), erythropoietins
(EPOs), angiopoietins (ANGs), placenta-derived growth factors
(PlGFs), and hypoxia induced transcriptional regulators (HIFs).
Preferably, the beneficial agent is present in an amount of from
0.1 to 50% by weight of the combined amounts of the polymer, the
solvent and the beneficial agent. In preferred embodiments, the
beneficial agent is in the form of particles dispersed or dissolved
in the viscous gel, wherein the beneficial agent is in the form of
particles having an average particle size of from 0.1 to 250
microns. In certain preferred embodiments, the beneficial agent is
in the form of particles wherein the particle further comprises a
component selected from the group consisting of a stabilizing
agent, bulking agent, chelating agent and a buffering agent.
[0036] These and other embodiments of the present invention will
readily occur to those of ordinary skill in the art in view of the
disclosure herein.
BRIEF DESCRIPTION OF THE DRAWINGS
[0037] The foregoing and other objects, features and advantages of
the present invention will be more readily understood upon reading
the following detailed description in conjunction with the drawings
as described hereinafter.
[0038] FIG. 1 is a graph illustrating the in vivo release profile
of bupivacaine hydrochloride obtained from depot formulations of
the present invention (formulations 1-2).
[0039] FIG. 2 is a graph illustrating the in vivo release profile
of bupivacaine base obtained from depot formulations of the present
invention (formulations 3-4).
[0040] FIG. 3 is a graph illustrating the in vivo release profile
of bupivacaine base obtained from a depot formulation of the
present invention (formulation 4).
[0041] FIG. 4 is a graph illustrating the in vivo release profile
of human growth hormone (hGH) obtained from depot formulations of
the present invention (formulations 5-6).
[0042] FIG. 5 is a graph illustrating the in vivo release profile
of hGH obtained from a depot formulation of the present invention
(formulation 6).
[0043] FIG. 6 is a graph illustrating the in vivo release profile
of hGH obtained from depot formulations of the present invention
(formulations 6-7)
[0044] FIG. 7 is a graph illustrating the in vivo release profile
of bupivacaine obtained from depot formulations of the present
invention (formulations 8-9).
[0045] FIG. 8 is a graph illustrating the in vivo release profile
of bupivacaine obtained from depot formulations of the present
invention (formulations 9-10).
[0046] FIG. 9 is a graph illustrating the in vivo release profile
of bupivacaine obtained from depot formulations of the present
invention (formulations 10-11).
[0047] FIG. 10 is a graph illustrating the in vivo release profile
of bupivacaine obtained from depot formulations of the present
invention (formulations 11-12).
[0048] FIG. 11 is a DSC diagram of the low molecular weight PLGA
with an ester end group used to make various formulations of the
present invention (formulations 2, 4, 6, 7, 11, and 12).
[0049] FIG. 12 is a DSC diagram of the low molecular weight PLGA
with a carboxyl end group used to make a various formulations of
the present invention (formulations 8, 9, and 10).
[0050] FIG. 13 is a graph illustrating the in vitro degradation
profile of PLGA polymers of varying molecular weights with
different end groups.
DETAILED DESCRIPTION OF THE INVENTION
[0051] The present invention is directed to an injectable depot
composition that serves as an implanted sustained release
beneficial agent delivery system after injection into a patient's
body. The composition is a gel formed from a low molecular weight
bioerodible, biocompatible polymer; a solvent having a miscibility
in water of less than or equal to 7 wt. % at 25.degree. C., in an
amount effective to plasticize the polymer and form a gel
therewith; and a beneficial agent dissolved or dispersed in the
gel. The present invention is also directed to a method of
systemically or locally administering a beneficial agent to a
subject by implanting in the subject an injectable depot
composition as described above. By appropriate choice of solvent,
water migration from the aqueous environment surrounding the
implant system is restricted, and beneficial agent is released to
the subject over a period of time, thus providing for delivery of
the beneficial agent with a controlled burst of beneficial agent
and sustained release thereafter. The duration and the rate of
release of the beneficial agent are controlled by appropriate
choice of the low molecular weight biodegradable polymer. The
composition provides controlled sustained release of the beneficial
agent by restricting water migration from the aqueous environment
surrounding the implant system, thus delivering the beneficial
agent over a short duration, preferably a period equal to or less
than two weeks, preferably about 24 hours to about 2 weeks,
preferably about 10 days or shorter; preferably about 7 days or
shorter, more preferably about 3 days to about 7 days. Because the
polymer of the composition is bioerodible, the implant system does
not have to be surgically removed after beneficial agent is
depleted from the implant.
[0052] Generally, the compositions of the invention are gel-like
and form with a substantially homogeneous non-porous structure
throughout the implant upon implantation and during drug delivery,
even as it hardens. Furthermore, while the polymer gel implant will
slowly harden when subjected to an aqueous environment, the
hardened implant may maintain a rubbery (non-rigid) composition
with the glass transition temperature T.sub.g being below
37.degree. C.
[0053] It has been discovered that when a solvent having a
solubility in water of less than 7% by weight in water is present
in the system, suitable burst control and sustained delivery of
beneficial agent is achieved, whether or not a solubility modulator
of the beneficial agent is present in the system. Typically, the
implant systems useful in this invention will release, in the first
24 hours after implantation, 40% or less of the total amount of
beneficial agent to be delivered to the subject from the implant
system, preferably 30% or less and more preferably 20% or less. In
certain embodiments, within 24 hours after implantation the system
releases less than or equal to 20% by weight of the amount of
beneficial agent to be delivered over the duration of the delivery
period, wherein the delivery period is 2 weeks. In additional
embodiments, within 24 hours after implantation the system releases
less than or equal to 40% by weight of the amount of beneficial
agent to be delivered over the duration of the delivery period,
wherein the delivery period is one week. In additional embodiments,
within 24 hours after implantation the system releases less than or
equal to 50% by weight of the amount of beneficial agent to be
delivered over the duration of the delivery period, wherein the
delivery period is three days.
[0054] When the composition is intended for implantation by
injection, the viscosity optionally may be modified by emulsifiers
and/or thixotropic agents to obtain a gel composition having a
viscosity low enough to permit passage of the gel composition
through a needle. Also, pore formers and solubility modulators of
the beneficial agent may be added to the implant systems to provide
desired release profiles from the implant systems, along with
typical pharmaceutical excipients and other additives that do not
change the beneficial aspects of the present invention. The
addition of a solubility modulator to the implant system may enable
the use of a solvent having a solubility of 7% or greater in the
implant system with minimal burst and sustained delivery under
particular circumstances. However, it is presently preferred that
the implant system utilize at least one solvent having a solubility
in water of less than 7% by weight, whether the solvent is present
alone or as part of a solvent mixture. It has also been discovered
that when mixtures of solvents which include a solvent having 7% or
less by weight solubility in water and one or more miscible
solvents, optionally having greater solubility, are used, implant
systems exhibiting limited water uptake and minimal burst and
sustained delivery characteristics are obtained.
Definitions
[0055] In describing and claiming the present invention, the
following terminology will be used in accordance with the
definitions set out below.
[0056] The singular forms "a," "an" and "the" include plural
referents unless the context clearly dictates otherwise. Thus, for
example, reference to "a solvent" includes a single solvent as well
as a mixture of two or more different solvents, reference to "a
beneficial agent" includes a single beneficial agent as well as two
or more different beneficial agents in combination, and the
like.
[0057] The term "beneficial agent" means an agent that effects a
desired beneficial, often pharmacological, effect upon
administration to a human or an animal, whether alone or in
combination with other pharmaceutical excipients or inert
ingredients.
[0058] As used herein, the term "polynucleotide" refers to a
polymeric form of nucleotides of any length, either ribonucleotides
or deoxyribonucleotides, and includes double- and single-stranded
DNA and RNA. It also includes known types of modifications,
substitutions, and internucleotide modifications, which are known
in the art.
[0059] As used herein, the term "recombinant polynucleotide" refers
to a polynucleotide of genomic, cDNA, semisynthetic, or synthetic
origin which, by virtue of its origin or manipulation: is not
associated with all or a portion of a polynucleotide with which it
is associated in nature; is linked to a polynucleotide other than
that to which it is linked in nature; or does not occur in
nature.
[0060] As used herein, the term "polypeptide" refers to a polymer
of amino acids, inlcuding for example, peptides, oligopeptides, and
proteins and derivatives, analogs and fragments thereof, as well as
other modifications known in the art, both naturally occurring and
non-naturally occurring.
[0061] As used herein, the term "purified" and "isolated" when
referring to a polypeptide or nucleotide sequence means that the
indicated molecule is present in the substantial absence of other
biological macromolecules of the same type. The term "purified" as
used herein preferably means at least 75% by weight, more
preferably at least 85% by weight, more preferably still at least
95% by weight, and most preferably at least 98% by weight, of
biological macromolecules of the same type present.
[0062] The term "AUC" means the area under the curve obtained from
an in vivo assay in a subject by plotting blood plasma
concentration of the beneficial agent in the subject against time,
as measured from the time of implantation of the composition, to a
time "t" after implantation. The time t will correspond to the
delivery period of beneficial agent to a subject.
[0063] The term "burst index" means, with respect to a particular
composition intended for systemic delivery of a beneficial agent,
the quotient formed by dividing (i) the AUC calculated for the
first time period after implantation of the composition into a
subject divided by the number of hours in the first time period
(t.sub.1), by (ii) the AUC calculated for the time period of
delivery of beneficial agent, divided by the number of hours in the
total duration of the delivery period (t.sub.2). For example the
burst index at 24 hours is the quotient formed by dividing (i) the
AUC calculated for the first twenty-four hours after implantation
of the composition into a subject divided by the number 24, by (ii)
the AUC calculated for the time period of delivery of beneficial
agent, divided by the number of hours in the total duration of the
delivery period.
[0064] The phrase "dissolved or dispersed" is intended to encompass
all means of establishing a presence of beneficial agent in the gel
composition and includes dissolution, dispersion, suspension and
the like.
[0065] The term "systemic" means, with respect to delivery or
administration of a beneficial agent to a subject, that the
beneficial agent is detectable at a biologically-significant level
in the blood plasma of the subject.
[0066] The term "local" means, with respect to delivery or
administration of a beneficial agent to a subject, that the
beneficial agent is delivered to a localized site in the subject
but is not detectable at a biologically significant level in the
blood plasma of the subject.
[0067] The terms "short period" or "short duration" are used
interchangeably and refer to a period of time over which release of
a beneficial agent from the depot gel composition of the invention
occurs, which will generally be equal to or less than two weeks,
preferably about 24 hours to about 2 weeks, preferably about 10
days or shorter; preferably about 7 days or shorter, more
preferably about 3 days to about 7 days.
[0068] The term "gel vehicle" means the composition formed by
mixture of the polymer and solvent in the absence of the beneficial
agent.
[0069] The term "initial burst" means, with respect to a particular
composition of this invention, the quotient obtained by dividing
(i) the amount by weight of beneficial agent released from the
composition in a predetermined initial period of time after
implantation, by (ii) the total amount of beneficial agent that is
to be delivered from an implanted composition. It is understood
that the initial burst may vary depending on the shape and surface
area of the implant. Accordingly, the percentages and burst indices
associated with initial burst described herein are intended to
apply to compositions tested in a form resulting from dispensing of
the composition from a standard syringe.
[0070] The term "solubility modulator" means, with respect to the
beneficial agent, an agent that will alter the solubility of the
beneficial agent, with reference to polymer solvent or water, from
the solubility of beneficial agent in the absence of the modulator.
The modulator may enhance or retard the solubility of the
beneficial agent in the solvent or water. However, in the case of
beneficial agents that are highly water soluble, the solubility
modulator will generally be an agent that will retard the
solubility of the beneficial agent in water. The effects of
solubility modulators of the beneficial agent may result from
interaction of the solubility modulator with the solvent, or with
the beneficial agent itself, such as by the formation of complexes,
or with both. For the purposes hereof, when the solubility
modulator is "associated" with the beneficial agent, all such
interactions or formations as may occur are intended. Solubility
modulators may be mixed with the beneficial agent prior to its
combination with the viscous gel or may be added to the viscous gel
prior to the addition of the beneficial agent, as appropriate.
[0071] The terms "subject" and "patient" mean, with respect to the
administration of a composition of the invention, an animal or a
human being.
[0072] Since all solvents, at least on a molecular level, will be
soluble in water (i.e., miscible with water) to some very limited
extent, the term "immiscible" as used herein means that 7% or less
by weight, preferably 5% or less, of the solvent is soluble in or
miscible with water. For the purposes of this disclosure,
solubility values of solvent in water are considered to be
determined at 25.degree. C. Since it is generally recognized that
solubility values as reported may not always be conducted at the
same conditions, solubility limits recited herein as percent by
weight miscible or soluble with water as part of a range or upper
limit may not be absolute. For example, if the upper limit on
solvent solubility in water is recited herein as "7% by weight,"
and no further limitations on the solvent are provided, the solvent
"triacetin," which has a reported solubility in water of 7.17 grams
in 100 ml of water, is considered to be included within the limit
of 7%. A solubility limit in water of less than 7% by weight as
used herein does not include the solvent triacetin or solvents
having solubilities in water equal to or greater than
triacetin.
[0073] The term "bioerodible" refers to a material that gradually
decomposes, dissolves, hydrolyzes and/or erodes in situ. Generally,
the "bioerodible" polymers herein are polymers that are
hydrolyzable, and bioerode in situ primarily through
hydrolysis.
[0074] The term "thixotropic" is used in its conventional sense to
refer to a gel composition that can liquefy or at least exhibit a
decrease in apparent viscosity upon application of mechanical force
such as shear force. The extent of the reduction is in part a
function of the shear rate of the gel when subjected to the
shearing force. When the shearing force is removed, the viscosity
of the thixotropic gel returns to a viscosity at or near that which
it displayed prior to being subjected to the shearing force.
Accordingly, a thixotropic gel may be subjected to a shearing force
when injected from a syringe which temporarily reduces its
viscosity during the injection process. When the injection process
is completed, the shearing force is removed and the gel returns
very near to its previous state.
[0075] A "thixotropic agent" as used herein is one that increases
the thixotropy of the composition in which it is contained,
promoting shear thinning and enabling use of reduced injection
force.
[0076] The term "low molecular weight (LMW) polymer" refers to
bioerodible polymers having a weight average molecular weight
ranging from about 3000 to about 10,000; preferably from about 3000
to about 9,000; more preferably from about 4000 to about 8,000; and
more preferably the low molecular weight polymer has a molecular
weight of about 7000, about 6000, about 5000, about 4000 and about
3000 as determined by gel permeation chromatography (GPC).
[0077] The term "high molecular weight (HMW) polymer" refers to
bioerodible polymers having a weight average molecular weight
greater than 10,000 as determined by gel permeation chromatography
(GPC).
[0078] The polymer, solvent and other agents of the invention must
be "biocompatible"; that is they must not cause irritation,
inflammation or necrosis in the environment of use. The environment
of use is a fluid environment and may comprise a subcutaneous,
intramuscular, intravascular (high/low flow), intramyocardial,
adventitial, intratumoral, or intracerebral portion, wound sites,
tight joint spaces or body cavity of a human or animal.
[0079] The following definitions apply to the molecular structures
described herein:
[0080] As used herein, the phrase "having the formula" or "having
the structure" is not intended to be limiting and is used in the
same way that the term "comprising" is commonly used.
[0081] The term "alkyl" as used herein refers to a saturated
hydrocarbon group typically although not necessarily containing 1
to about 30 carbon atoms, such as methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, t-butyl, octyl, decyl, and the like,
as well as cycloalkyl groups such as cyclopentyl, cyclohexyl and
the like. Generally, although again not necessarily, alkyl groups
herein contain 1 to about 12 carbon atoms. The term "lower alkyl"
intends an alkyl group of 1 to 6 carbon atoms, preferably 1 to 4
carbon atoms. "Substituted alkyl" refers to alkyl substituted with
one or more substituent groups, and the terms
"heteroatom-containing alkyl" and "heteroalkyl" refer to alkyl in
which at least one carbon atom is replaced with a heteroatom. If
not otherwise indicated, the terms "alkyl" and "lower alkyl"
include linear, branched, cyclic, unsubstituted, substituted,
and/or heteroatom-containing alkyl or lower alkyl.
[0082] The term "aryl" as used herein, and unless otherwise
specified, refers to an aromatic substituent containing a single
aromatic ring or multiple aromatic rings that are fused together,
linked covalently, or linked to a common group such as a methylene
or ethylene moiety. Preferred aryl groups contain one aromatic ring
or two fused or linked aromatic rings, e.g., phenyl, naphthyl,
biphenyl, diphenylether, diphenylamine, benzophenone, and the like,
and most preferred aryl groups are monocyclic. "Substituted aryl"
refers to an aryl moiety substituted with one or more substituent
groups, and the terms "heteroatom-containing aryl" and "heteroaryl"
refer to aryl in which at least one carbon atom is replaced with a
heteroatom. Unless otherwise indicated, the term "aryl" includes
heteroaryl, substituted aryl, and substituted heteroaryl
groups.
[0083] The term "aralkyl" refers to an alkyl group substituted with
an aryl group, wherein alkyl and aryl are as defined above. The
term "heteroaralkyl" refers to an alkyl group substituted with a
heteroaryl group. Unless otherwise indicated, the term "aralkyl"
includes heteroaralkyl and substituted aralkyl groups as well as
unsubstituted aralkyl groups. Generally, the term "aralkyl" herein
refers to an aryl-substituted lower alkyl group, preferably a
phenyl substituted lower alkyl group such as benzyl, phenethyl,
1-phenylpropyl, 2-phenylpropyl, and the like.
[0084] The term "heteroatom-containing" as in a
"heteroatom-containing hydrocarbyl group" refers to a molecule or
molecular fragment in which one or more carbon atoms is replaced
with an atom other than carbon, e.g., nitrogen, oxygen, sulfur,
phosphorus or silicon. Similarly, the term "heterocyclic" refers to
a cyclic substituent that is heteroatom-containing, the term
"heteroaryl" refers to an aryl substituent that is
heteroatom-containing, and the like.
[0085] By "substituted" as in "substituted alkyl," "substituted
aryl" and the like, as alluded to in some of the aforementioned
definitions, is meant that in the alkyl or aryl moiety,
respectively, at least one hydrogen atom bound to a carbon atom is
replaced with one or more non-interfering substituents such as
hydroxyl, alkoxy, thio, amino, halo, and the like.
I. Injectable Depot Compositions:
[0086] As described previously, injectable depot compositions for
delivery of beneficial agents over a short duration of time may be
formed as viscous gels prior to injection of the depot into a
subject. The viscous gel supports dispersed beneficial agent to
provide appropriate delivery profiles, which include those having
low initial burst, of the beneficial agent as the beneficial agent
is released from the depot over time.
[0087] The polymer, solvent and other agents of the invention must
be biocompatible; that is they must not cause irritation or
necrosis in the environment of use. The environment of use is a
fluid environment and may comprise a subcutaneous, intramuscular,
intravascular (high/low flow), intramyocardial, adventitial,
intratumoral, or intracerebral portion, wound sites, tight joint
spaces or body cavity of a human or animal. In certain embodiments,
the beneficial agent may be administered locally to avoid or
minimize systemic side effects. Gels of the present invention
containing a beneficial agent may be injected/implanted directly
into or applied as a coating to the desired location, e.g.,
subcutaneous, intramuscular, intravascular, intramyocardial,
adventitial, intratumoral, or intracerebral portion, wound sites,
tight joint spaces or body cavity of a human or animal.
[0088] Typically, the viscous gel will be injected from a standard
hypodermic syringe, a catheter or a trocar, that has been
pre-filled with the beneficial agent-viscous gel composition as the
depot. It is often preferred that injections take place using the
smallest size needle (i.e., smallest diameter) or catheter to
reduce discomfort to the subject when the injection is in a
subcutaneous, intramuscular, intravascular (high/low flow),
intramyocardial, adventitial, intratumoral, or intracerebral
portion, wound sites, tight joint spaces or body cavity of a human
or animal. It is desirable to be able to inject gels through a
needle or a catheter ranging from 16 gauge and higher, preferably
20 gauge and higher, more preferably 22 gauge and higher, even more
preferably 24 gauge and higher. With highly viscous gels, i.e.,
gels having a viscosity of about 100 poise or greater, injection
forces to dispense the gel from a syringe having a needle in the
20-30 gauge range may be so high as to make the injection difficult
or reasonably impossible when done manually. At the same time, the
high viscosity of the gel is desirable to maintain the integrity of
the depot after injection and during the dispensing period and also
facilitate desired suspension characteristics of the beneficial
agent in the gel.
[0089] A composition of a polymer and polymer solvent that
optionally includes an agent that imparts thixotropic
characteristics to the viscous gel formed by the polymer solvent
and polymer provides certain advantages. A thixotropic gel exhibits
reduced viscosity when subjected to shear force. The extent of the
reduction is in part a function of the shear rate of the gel when
subjected to the shearing force. When the shearing force is
removed, the viscosity of the thixotropic gel returns to a
viscosity at or near that which it displayed prior to being
subjected to the shearing force. Accordingly, a thixotropic gel may
be subjected to a shearing force when injected from a syringe or a
catheter, which temporarily reduces its viscosity during the
injection process. When the injection process is completed, the
shearing force is removed and the gel returns very near to its
previous state.
[0090] Significant shear thinning properties of the injectable
composition allow for a minimally invasive delivery, via a needle
or a catheter, of a beneficial agent to various sites on an
external and/or internal surface of the body. Further injection
through the needle or injection catheter permits precise
administration of a desirable amount of the composition at a
desired location, with significant retention of the depot gel
composition at the site of delivery while providing for sustained
delivery of the beneficial agent from the site of administration.
In certain embodiments, the injection catheter may include a
metering device or an additional device to assist in the precise
delivery of the composition.
A. The Bioerodible, Biocompatible Polymer:
[0091] Polymers that are useful in conjunction with the methods and
compositions of the invention are bioerodible, i.e., they gradually
degrade e.g., enzymatically or hydrolyze, dissolve, physically
erode, or otherwise disintegrate within the aqueous fluids of a
patient's body. Generally, the polymers bioerode as a result of
hydrolysis or physical erosion, although the primary bioerosion
process is typically hydrolysis or enzymatic degradation.
[0092] Such polymers include, but are not limited to polylactides,
polyglycolides, polyanhydrides, polyamines, polyesteramides,
polyorthoesters, polydioxanones, polyacetals, polyketals,
polycarbonates, polyorthocarbonates, polyphosphazenes, succinates,
poly(malic acid), poly(amino acids), polyvinylpyrrolidone,
polyethylene glycol, polyhydroxycellulose, polyphosphoesters,
chitin, chitosan, hylauronic acid and copolymers, terpolymers and
mixtures thereof.
[0093] The low molecular weight bioerodible polymers have weight
average molecular weight ranging from about 3000 to about 10,000;
preferably from about 3000 to about 9,000; more preferably from
about 4000 to about 8,000; and more preferably the low molecular
weight polymer has a molecular weight of about 7000, about 6000,
about 5000, about 4000 and about 3000 as determined by gel
permeation chromatography (GPC).
[0094] Presently preferred polymers are polylactides, that is, a
lactic acid-based polymer that can be based solely on lactic acid
or can be a copolymer based on lactic acid and glycolic acid which
may include small amounts of other comonomers that do not
substantially affect the advantageous results which can be achieved
in accordance with the present invention. As used herein, the term
"lactic acid" includes the isomers L-lactic acid, D-lactic acid,
DL-lactic acid and lactide while the term "glycolic acid" includes
glycolide. Most preferred are poly(lactide-co-glycolide)copolymers,
commonly referred to as PLGA. The polymer may have a monomer ratio
of lactic acid/glycolic acid of from about 100:0 to about 15:85,
preferably from about 60:40 to about 75:25 and an especially useful
copolymer has a monomer ratio of lactic acid/glycolic acid of about
50:50.
[0095] The lactic acid-based polymer has a weight average molecular
weight ranging from about 3000 to about 10,000; preferably from
about 3000 to about 9,000; more preferably from about 4000 to about
8,000; and more preferably the low molecular weight polymer has a
molecular weight of about 7000, about 6000, about 5000, about 4000
and about 3000 as determined by gel permeation chromatography
(GPC). As indicated in aforementioned U.S. Pat. No. 5,242,910, the
polymer can be prepared in accordance with the teachings of U.S.
Pat. No. 4,443,340. Alternatively, the lactic acid-based polymer
can be prepared directly from lactic acid or a mixture of lactic
acid and glycolic acid (with or without a further comonomer) in
accordance with the techniques set forth in U.S. Pat. No.
5,310,865. The contents of all of these patents are incorporated by
reference. Suitable lactic acid-based polymers are available
commercially. For instance, 50:50 lactic acid:glycolic acid
copolymers having weight average molecular weight ranging from
about 3000 to about 10,000; preferably from about 3000 to about
9,000; more preferably from about 4000 to about 8,000; and more
preferably the low molecular weight polymer has a molecular weight
of about 7000, about 6000, about 5000, about 4000 and about 3000,
and a wide variety of end groups to alter susceptibility to
hydrolysis and subsequent breakdown of the polymer chain are
available from Boehringer Ingelheim (Petersburg, Va.).
[0096] Examples of polymers include, but are not limited to, Poly
(D,L-lactide-co-glycolide) 50:50 Resomer.RTM. RG502, code 0000366,
Poly (D,L-lactide-co-glycolide) 50:50 Resomer.RTM. RG502H,
PLGA-502H, code no. 260187, Poly D,L Lactide (Resomer.RTM. R 202,
Resomer.RTM. R 203); Poly dioxanone (Resomer.RTM. X 210)
(Boehringer Ingelheim Chemicals, Inc., Petersburg, Va.).
[0097] Additional examples include, but are not limited to,
DL-lactide/glycolide 100:0 (MEDISORB.RTM. Polymer 100 DL High,
MEDISORB.RTM. Polymer 100 DL Low); DL-lactide/glycolide 85/15
(MEDISORB.RTM. Polymer 8515 DL High, MEDISORB.RTM. Polymer 8515 DL
Low); DL-lactide/glycolide 75/25 (MEDISORB.RTM. Polymer 7525 DL
High, MEDISORB.RTM. Polymer 7525 DL Low); DL-lactide/glycolide
65/35 (MEDISORB.RTM. Polymer 6535 DL High, MEDISORB.RTM. Polymer
6535 DL Low); DL-lactide/glycolide 54/46 (MEDISORB.RTM. Polymer
5050 DL High, MEDISORB.RTM. Polymer 5050 DL Low); and
DL-lactide/glycolide 54/46 (MEDISORB.RTM. Polymer 5050 DL 2A(3),
MEDISORB.RTM. Polymer 5050 DL 3A(3), MEDISORB.RTM. Polymer 5050 DL
4A(3)) (Medisorb Technologies International L.P., Cincinatti,
Ohio); and Poly D,L-lactide-co-glycolide 50:50; Poly
D,L-lactide-co-glycolide 65:35; Poly D,L-lactide-co-glycolide
75:25; Poly D,L-lactide-co-glycolide 85:15; Poly DL-lactide; Poly
L-lactide; Poly glycolide; Poly .epsilon.-caprolactone; Poly
DL-lactide-co-caprolactone 25:75; and Poly
DL-lactide-co-caprolactone 75:25 (Birmingham Polymers, Inc.,
Birmingham, Ala.).
[0098] It has been surprisingly found that injectable depot gel
formulations of the invention comprising low molecular weight
polymers provide a controlled, sustained release of a beneficial
agent over a short duration of time equal to or less than two
weeks. The release rate profile can be controlled by the
appropriate choice of a low molecular weight polymer, a water
immiscible solvent, the polymer/solvent ratio, emulsifying agent,
thixotropic agent, pore former, solubility modifier for the
beneficial agent, an osmotic agent, and the like
[0099] The biocompatible polymer is present in the gel composition
in an amount ranging from about 5 to about 90% by weight,
preferably from about 10 to about 85% by weight, preferably from
about 15 to about 80% by weight, preferably from about 20 to about
75% by weight, preferably from about 30 to about 70% by weight and
typically from about 35 to about 65%, and often about 40 to about
60% by weight of the viscous gel, the viscous gel comprising the
combined amounts of the biocompatible polymer and the solvent. The
solvent will be added to polymer in amounts described below, to
provide injectable depot gel compositions.
B. Solvents and Agents:
[0100] The injectable depot composition of the invention contains a
water-immiscible solvent in addition to the bioerodible polymer and
the beneficial agent. In preferred embodiments, the compositions
described herein are also free of solvents having a miscibility in
water that is greater than 7 wt. % at 25.degree. C.
[0101] The solvent must be biocompatible, should form a viscous gel
with the polymer, and restrict water uptake into the implant. The
solvent may be a single solvent or a mixture of solvents exhibiting
the foregoing properties. The term "solvent", unless specifically
indicated otherwise, means a single solvent or a mixture of
solvents. Suitable solvents will substantially restrict the uptake
of water by the implant and may be characterized as immiscible in
water, i.e., having a solubility in water of less than 7% by
weight. Preferably, the solvents are five weight percent or less
soluble in water; more preferably three weight percent or less
soluble in water; and even more preferably one weight percent or
less soluble in water. Most preferably the solubility of the
solvent in water is equal to or less than 0.5 weight percent.
[0102] Water miscibility may be determined experimentally as
follows: Water (1-5 g) is placed in a tared clear container at a
controlled temperature, about 20.degree. C., and weighed, and a
candidate solvent is added dropwise. The solution is swirled to
observe phase separation. When the saturation point appears to be
reached, as determined by observation of phase separation, the
solution is allowed to stand overnight and is re-checked the
following day. If the solution is still saturated, as determined by
observation of phase separation, then the percent (w/w) of solvent
added is determined. Otherwise more solvent is added and the
process repeated. Solubility or miscibility is determined by
dividing the total weight of solvent added by the final weight of
the solvent/water mixture. When solvent mixtures are used, for
example 20% triacetin and 80% benzyl benzoate, they are pre-mixed
prior to adding to the water.
[0103] Solvents useful in this invention are generally less than 7%
water soluble by weight as described above. Solvents having the
above solubility parameter may be selected from aromatic alcohols,
the lower alkyl and aralkyl esters of aryl acids such as benzoic
acid, the phthalic acids, salicylic acid, lower alkyl esters of
citric acid, such as triethyl citrate and tributyl citrate and the
like, and aryl, aralkyl and lower alkyl ketones. Among preferred
solvents are those having solubilities within the foregoing range
selected from compounds having the following structural formulas
(I), (II) and (III)
The aromatic alcohol has the structural formula (I)
Ar-(L).sub.n--OH (I)
[0104] wherein Ar is a substituted or unsubstituted aryl or
heteroaryl group, n is zero or 1, and L is a linking moiety.
Preferably, Ar is a monocyclic aryl or heteroaryl group, optionally
substituted with one or more noninterfering substituents such as
hydroxyl, alkoxy, thio, amino, halo, and the like. More preferably,
Ar is an unsubstituted 5- or 6-membered aryl or heteroaryl group
such as phenyl, cyclopentadienyl, pyridinyl, pyrimadinyl,
pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thiophenyl,
thiazolyl, isothiazolyl, or the like. The subscript "n" is zero or
1, meaning that the linking moiety L may or may not be present.
Preferably, n is 1 and L is generally a lower alkylene linkage such
as methylene or ethylene, wherein the linkage may include
heteroatoms such as O, N or S. Most preferably, Ar is phenyl, n is
1, and L is methylene, such that the aromatic alcohol is benzyl
alcohol.
[0105] The aromatic acid ester or ketone may be selected from the
lower alkyl and aralkyl esters of aromatic acids, and aryl and
aralkyl ketones. Generally, although not necessarily, the aromatic
acid esters and ketones will respectively have the structural
formula (II) or (III) ##STR1##
[0106] In the ester of formula (III), R.sup.1 is substituted or
unsubstituted aryl, aralkyl, heteroaryl or heteroaralkyl,
preferably substituted or unsubstituted aryl or heteroaryl, more
preferably monocyclic or bicyclic aryl or heteroaryl optionally
substituted with one or more non-interfering substituents such as
hydroxyl, carboxyl, alkoxy, thio, amino, halo, and the like, still
more preferably 5- or 6-membered aryl or heteroaryl such as phenyl,
cyclopentadienyl, pyridinyl, pyrimadinyl, pyrazinyl, pyrrolyl,
pyrazolyl, imidazolyl, furanyl, thiophenyl, thiazolyl, or
isothiazolyl, and most preferably 5- or 6-membered aryl. R.sup.2 is
hydrocarbyl or heteroatom-substituted hydrocarbyl, typically lower
alkyl or substituted or unsubstituted aryl, aralkyl, heteroaryl or
heteroaralkyl, preferably lower alkyl or substituted or
unsubstituted aralkyl or heteroaralkyl, more preferably lower alkyl
or monocyclic or bicyclic aralkyl or heteroaralkyl optionally
substituted with one or more non-interfering substituents such as
hydroxyl, carboxyl, alkoxy, thio, amino, halo, and the like, still
more preferably lower alkyl or 5- or 6-membered aralkyl or
heteroaralkyl, and most preferably lower alkyl or 5- or 6-membered
aryl optionally substituted with one or more additional ester
groups having the structure --O--(CO)--R.sup.1. Most preferred
esters are benzoic acid and phthalic acid derivatives.
[0107] In the ketone of formula (III), R.sup.3 and R.sup.4 may be
selected from any of the R.sup.1 and R.sup.2 groups identified
above.
[0108] Art recognized benzoic acid derivatives from which solvents
having the requisite solubility may be selected include, without
limitation: 1,4-cyclohexane dimethanol dibenzoate, diethylene
glycol dibenzoate, dipropylene glycol dibenzoate, polypropylene
glycol dibenzoate, propylene glycol dibenzoate, diethylene glycol
benzoate and dipropylene glycol benzoate blend, polyethylene glycol
(200) dibenzoate, isodecyl benzoate, neopentyl glycol dibenzoate,
glyceryl tribenzoate, pentaerylthritol tetrabenzoate, cumylphenyl
benzoate, trimethyl pentanediol dibenzoate.
[0109] Art recognized phthalic acid derivatives from which solvents
having the requisite solubility may be selected include: Alkyl
benzyl phthalate, bis-cumyl-phenyl isophthalate, dibutoxyethyl
phthalate, dimethyl phthalate, dimethyl phthalate, diethyl
phthalate, dibutyl phthalate, diisobutyl phthalate, butyl octyl
phthalate, diisoheptyl phthalate, butyl octyl phthalate, diisononyl
phthalate, nonyl undecyl phthalate, dioctyl phthalate, di-isooctyl
phthalate, dicapryl phthalate, mixed alcohol phthalate,
di-(2-ethylhexyl) phthalate, linear heptyl, nonyl, phthalate,
linear heptyl, nonyl, undecyl phthalate, linear nonyl phthalate,
linear nonyl undecyl phthalate, linear dinonyl, didecyl phthalate
(diisodecyl phthalate), diundecyl phthalate, ditridecyl phthalate,
undecyldodecyl phthalate, decyltridecyl phthalate, blend (50/50) of
dioctyl and didecyl phthalates, butyl benzyl phthalate, and
dicyclohexyl phthalate.
[0110] Many of the solvents useful in the invention are available
commercially (Aldrich Chemicals, Sigma Chemicals) or may be
prepared by conventional esterification of the respective
arylalkanoic acids using acid halides, and optionally
esterification catalysts, such as described in U.S. Pat. No.
5,556,905, which is incorporated herein by reference, and in the
case of ketones, oxidation of their respective secondary alcohol
precursors.
[0111] Preferred solvents include aromatic alcohols, the lower
alkyl and aralkyl esters of the aryl acids described above.
Representative acids are benzoic acid and the phthalic acids, such
as phthalic acid, isophthalic acid, and terephathalic acid. Most
preferred solvents are benzyl alcohol and derivatives of benzoic
acid and include, but are not limited to, methyl benzoate, ethyl
benzoate, n-propyl benzoate, isopropyl benzoate, butyl benzoate,
isobutyl benzoate, sec-butyl benzoate, tert-butyl benzoate, isoamyl
benzoate and benzyl benzoate, with benzyl benzoate being most
especially preferred.
[0112] The composition may also include, in addition to the
water-immiscible solvent(s), one or more additional miscible
solvents ("component solvents"), provided that any such additional
solvent is other than a lower alkanol. Component solvents
compatible and miscible with the primary solvent(s) may have a
higher miscibility with water and the resulting mixtures may still
exhibit significant restriction of water uptake into the implant.
Such mixtures will be referred to as "component solvent mixtures."
Useful component solvent mixtures may exhibit solubilities in water
greater than the primary solvents themselves, typically between 0.1
weight percent and up to and including 50 weight percent,
preferably up to and including 30 weight percent, and most
preferably up to an including 10 weight percent, without
detrimentally affecting the restriction of water uptake exhibited
by the implants of the invention.
[0113] Component solvents useful in component solvent mixtures are
those solvents that are miscible with the primary solvent or
solvent mixture, and include, but are not limited, to triacetin,
diacetin, tributyrin, triethyl citrate, tributyl citrate, acetyl
triethyl citrate, acetyl tributyl citrate, triethylglycerides,
triethyl phosphate, diethyl phthalate, diethyl tartrate, mineral
oil, polybutene, silicone fluid, glylcerin, ethylene glycol,
polyethylene glycol, octanol, ethyl lactate, propylene glycol,
propylene carbonate, ethylene carbonate, butyrolactone, ethylene
oxide, propylene oxide, N-methyl-2-pyrrolidone, 2-pyrrolidone,
glycerol formal, methyl acetate, ethyl acetate, methyl ethyl
ketone, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran,
caprolactam, decylmethylsulfoxide, oleic acid, and
1-dodecylazacyclo-heptan-2-one, and mixtures thereof.
[0114] Preferred solvent mixtures are those in which benzyl
benzoate is the primary solvent, and mixtures formed of benzyl
benzoate and either triacetin, tributyl citrate, triethyl citrate
or N-methyl-2-pyrrolidone. Preferred mixtures are those in which
benzyl benzoate is present by weight in an amount of 50% or more,
more preferably 60% or more and most preferably 80% or more of the
total amount of solvent present. Especially preferred mixtures are
those of 80/20 mixtures by weight of benzyl benzoate/triacetin and
benzyl benzoate/N-methyl-2-pyrrolidone. In additional embodiments,
the preferred solvent is benzyl alcohol, and mixtures formed of
benzyl alcohol and either benzyl benzoate or ethyl benzoate.
Preferred mixtures of benzyl alcohol/benzyl benzoate and benzyl
alcohol/ethyl benzoate are 1/99 mixtures by weight; 20/80 mixtures
by weight; 30/70 mixtures by weight; 50/50 mixtures by weight;
70/30 mixtures by weight; 80/20 mixtures by weight; 99/1 mixtures
by weight. Especially preferred mixtures of benzyl alcohol/benzyl
benzoate and benzyl alcohol/ethyl benzoate are 25/75 mixtures by
weight and 75/25 mixtures by weight.
[0115] In an especially preferred embodiment, the primary solvent
is selected from an aromatic alcohol and lower alkyl and aralkyl
esters of benzoic acid and the polymer is a lactic-acid based
polymer, most preferably PLGA, having weight average molecular
weight ranging from about 3000 to about 10,000; preferably from
about 3000 to about 9,000; more preferably from about 4000 to about
8,000; and more preferably the low molecular weight polymer has a
molecular weight of about 7000, about 6000, about 5000, about 4000
and about 3000. Presently, the most preferred solvents are benzyl
alcohol, benzyl benzoate and the lower alkyl esters of benzoic
acid, e.g. ethyl benzoate. The primary solvents, e.g., aromatic
alcohol and benzoic acid esters may be used alone or in a mixture
with other miscible solvents, e.g., triacetin, as described
herein.
[0116] The solvent or solvent mixture is capable of dissolving the
polymer to form a viscous gel that can maintain particles of the
beneficial agent dissolved or dispersed and isolated from the
environment of use prior to release. The compositions of the
present invention provide implants useful both for systemic and
local administration of beneficial agent, the implants having a low
burst index. Water uptake is controlled by the use of a solvent or
component solvent mixture that solublizes or plasticizes the
polymer but substantially restricts uptake of water into implant.
Additionally, the preferred compositions may provide viscous gels
that have a glass transition temperature that is less than
37.degree. C., such that the gel remains non-rigid for a period of
time after implantation of 24 hours or more.
[0117] The importance of restriction of water uptake and the
appropriate choice of a low molecular weight polymer and a water
immiscible solvent for a controlled, sustained delivery over a
short duration can be appreciated by reference to FIGS. 1-10
illustrating in vivo release rate profiles for various compositions
as a function of time.
[0118] The solvent or solvent mixture is typically present in an
amount of from about 95 to about 10% by weight, preferably from
about 80 to about 20% by weight, preferably about 75 to about 15%
by weight, preferably from about 70 to about 20% by weight,
preferably about 65 to about 20% by weight, preferably about 65 to
about 30% by weight and often about 60 to about 40% by weight of
the viscous gel, i.e., the combined amounts of the polymer and the
solvent. The polymer to solvent ratio ranges from about 30:70 to
about 90:10 by weight; preferably about 40:60 to about 80:20 by
weight; preferably about 50:50 to about 75:25 by weight; and more
preferably about 55:45 to about 65:35 by weight.
[0119] In addition to the control of water uptake and associated
initial burst by choice of solvent, agents that modulate the water
solubility of the beneficial agent can also be utilized in
conjunction with the preferred solvents to control burst of
beneficial agent from the implant. Burst indices and percent of
beneficial agent released in the first twenty-four hours after
implantation may be reduced by one-third to two-thirds or more by
the use of solubility modulators associated with the beneficial
agent. Such modulators are typically coatings, substances that form
complexes or otherwise associate with or stabilize the beneficial
agent such as metallic ions, other stabilizing agents, waxes,
lipids, oils, non-polar emulsions, and the like. Use of such
solubility modulators may permit the use of more highly water
soluble solvents or mixtures and achieve burst indices of 8 or less
for systemic applications, or with respect to local applications,
release of beneficial agent in the first 24 hours after
implantation of not greater than 40% of the beneficial agent
administered. Preferably that release will be not greater than 30%
and more preferably not greater than 20%.
[0120] Limited water uptake by the compositions of this invention
can often provide the opportunity to prepare compositions without
solubility modulators when in other compositions such modulators
would be necessary.
[0121] In instances where the choice of solvent and polymer result
in compositions severely restricting water uptake by themselves, it
may be desirable to add osmotic agents or other agents and
hydroattractants that facilitate water uptake to desired levels.
Such agents may be, for example, sugars and the like, and are well
known in the art.
[0122] Limited water uptake by the solvent-polymer compositions of
the present invention results in the implant compositions being
formed without the finger-like pores in the surface of implants
formed using prior art processes. Typically, a composition of the
present invention takes the form of a substantially, homogeneous,
sponge-like gel, with the pores in the interior of the implant
being much the same as the pores on the surface of the implant.
Compositions of the present invention retain their gel-like
consistency and administer a beneficial agent in a controlled
manner, at a sustained rate over a short duration of time than do
prior art devices. This is possible with the appropriate choice of
low molecular weight polymers and water immiscible solvents, and
further since the injectable depot gel compositions of the present
invention generally have a glass transition temperature, Tg, of
less than body temperature of the subject, e.g. 37.degree. C. for
humans. Because of the immiscibility of the solvents that are
useful in this invention with water, water uptake by the implant is
restricted and the pores that do form tend to resemble a closed
cell structure without significant numbers of larger pores or pores
extending from the surface into the interior of the implant being
open at the surface of the implant. Furthermore, the surface pores
offer only a limited opportunity for water from body fluids to
enter the implant immediately after implantation, thus controlling
the burst effect. Since the compositions often will be highly
viscous prior to implantation, when the composition is intended for
implantation by injection, the viscosity optionally may be modified
by the use of viscosity-reducing, miscible solvents or the use of
emulsifiers, or by heating to obtain a gel composition having a
viscosity or shear resistance low enough to permit passage of the
gel composition through a needle.
[0123] The limit on the amount of beneficial agent released in the
first 24 hours that is either desired or required will depend on
circumstances such as the overall duration of the delivery period,
the therapeutic window for the beneficial agent, potential adverse
consequences due to overdosing, cost of beneficial agent, and the
type of effect desired, e.g., systemic or local. Preferably, 40% or
less of the beneficial agent will be released in the first 24 hours
after implantation, where the percentage is based on the total
amount of beneficial agent to be delivered over the duration of the
delivery period. Typically, higher percentages of release in the
first 24 hours can be tolerated if the duration of the delivery
period is relatively short, e.g., a period equal to or less than
two weeks, preferably about 10 days or shorter; preferably about 7
days or shorter, more preferably about 3 days to about 7 days, or
if the beneficial agent has a wide therapeutic window with little
likelihood of side effects, or if the beneficial agent acts
locally. In certain embodiments, within 24 hours after implantation
the system releases less than or equal to 20% by weight of the
amount of beneficial agent to be delivered over the duration of the
delivery period, wherein the delivery period is 2 weeks. In
additional embodiments, within 24 hours after implantation the
system releases less than or equal to 40% by weight of the amount
of beneficial agent to be delivered over the duration of the
delivery period, wherein the delivery period is one week. In
additional embodiments, within 24 hours after implantation the
system releases less than or equal to 50% by weight of the amount
of beneficial agent to be delivered over the duration of the
delivery period, wherein the delivery period is three days.
[0124] Depending on the particular solvent or solvent mixture
selected, the polymer and beneficial agent, and optionally
solubility modulators of the beneficial agent, the compositions of
the present invention intended for systemic delivery may provide a
gel composition having a burst index of 8 or less, preferably 6 or
less, more preferably 4 or less and most preferably 2 or less.
Compositions of PLGA weight average molecular weight ranging from
about 3000 to about 10,000; preferably from about 3000 to about
9,000; more preferably from about 4000 to about 8,000; and more
preferably the low molecular weight polymer has a molecular weight
of about 7000, about 6000, about 5000, about 4000 and about 3000
with solvents having a miscibility in water of less than 7% by
weight, optionally combined with the other solvents, providing
implants intended for systemic delivery of beneficial agent having
a burst index of 10 or less, preferably 7 or less, more preferably
5 or less and most preferably 3 or less, are particularly
advantageous. The use of solvent mixtures as discussed herein can
be particularly advantageous as a means of providing sufficient
plasticizing of the polymer to obtain viscous gel formation and at
the same time meet the desired burst indices and percentage release
objectives of the compositions of the invention.
[0125] Compositions intended for local delivery of beneficial agent
are formed in the same manner as those intended for systemic use.
However, because local delivery of beneficial agent to a subject
will not result in detectable plasma levels of beneficial agent,
such systems have to be characterized by a percentage of beneficial
agent released in a predetermined initial period, rather than a
burst index as defined herein. Most typically, that period will be
the first 24 hours after implantation and the percentage will be
equal to the amount by weight of the beneficial agent released in
the period (e.g. 24 hours) divided by the amount by weight of the
beneficial agent intended to be delivered in the duration of the
delivery period; multiplied by the number 100. Compositions of the
present invention will have initial bursts of 40% or less,
preferably 30% or less, most preferably 20% or less, for most
applications.
[0126] In many instances, it may be desirable to reduce the initial
burst of beneficial agent during local administration to prevent
adverse effects. For example, implants of the invention containing
chemotherapeutic agents are suitable for direct injection into
tumors. However, many chemotherapeutic agents may exhibit toxic
side effects when administered systemically. Consequently, local
administration into the tumor may be the treatment method of
choice. It is necessary, however, to avoid administration of a
large burst of the chemotherapeutic agent if it is possible that
such agent would enter the vascular or lymphatic systems where it
may exhibit side affects. Accordingly, in such instances the
implantable systems of the present invention having limited burst
as described herein are advantageous.
[0127] The gel formed by mixing the polymer and the solvent
typically exhibits a viscosity of from about 100 to about 50,000
poise, preferably from about 500 to about 30,000 poise, more
preferably from about 500 to about 10,000 poise measured at a 1.0
sec-1 shear rate and 25.degree. C. using a Haake Rheometer at about
1-2 days after mixing is completed. Mixing the polymer with the
solvent can be achieved with conventional low shear equipment such
as a Ross double planetary mixer for from about 10 minutes to about
1 hour, although shorter and longer periods may be chosen by one
skilled in the art depending on the particular physical
characteristics of the composition being prepared. Since the depot
gel composition of the invention are administered as an injectable
composition, a countervailing consideration when forming depot gel
compositions that are viscous gels is that the
polymer/solvent/beneficial agent composition have sufficiently low
viscosity in order to permit it to be forced through a small
diameter, e.g., 18-20 gauge needle. If necessary, adjustment of
viscosity of the gel for injection can be accomplished with
emulsifying agents or thixotropic agents as described herein. Yet,
such compositions should have adequate dimensional stability so as
to remain localized and be able to be removed if necessary. The
particular gel or gel-like compositions of the present invention
satisfy such requirements.
[0128] If the polymer composition is to be administered as an
injectable gel, the level of polymer dissolution will need to be
balanced with the resulting gel viscosity, to permit a reasonable
force to dispense the viscous gel from a needle, and the potential
burst effect. Highly viscous gels enable the beneficial agent to be
delivered without exhibiting a significant burst effect, but may
make it difficult to dispense the gel through a needle. In those
instances, an emulsifying agent may optionally be added to the
composition. Also, since the viscosity may generally be lowered as
the temperature of the composition increases, it may be
advantageous in certain applications to reduce the viscosity of the
gel by heating to provide a more readily injectable composition.
The shear thinning characteristics of the depot gel compositions of
the present invention allow them to be readily injected into an
animal including humans using standard gauge needles without
requiring undue dispensing pressure.
[0129] When the emulsifying agent is mixed with the viscous gel
formed from the polymer and the solvent using conventional static
or mechanical mixing devices, such as an orifice mixer, the
emulsifying agent forms a separate phase composed of dispersed
droplets of microscopic size that typically have an average
diameter of less than about 100 microns. The continuous phase is
formed of the polymer and the solvent. The particles of the
beneficial agent may be dissolved or dispersed in either the
continuous phase or the droplet phase. In the resulting thixotropic
composition, the droplets of emulsifying agent elongate in the
direction of shear and substantially decrease the viscosity of the
viscous gel formed from the polymer and the solvent. For instance,
with a viscous gel having a viscosity of from about 5,000 to about
50,000 poise measured at 1.0 sec-1 at 25.degree. C., one can obtain
a reduction in viscosity to less than 100 poise when emulsified
with a 10% ethanol/water solution at 25.degree. C. as determined by
Haake Rheometer.
[0130] When used, the emulsifying agent typically is present in an
amount ranging from about 5 to about 80%, preferably from about 20
to about 60% and often 30 to 50% by weight based on the amount of
the injectable depot gel composition, that is the combined amounts
of polymer, solvent, emulsifying agent and beneficial agent.
Emulsifying agents include, for example, solvents that are not
fully miscible with the polymer solvent or solvent mixture.
Illustrative emulsifying agents are water, alcohols, polyols,
esters, carboxylic acids, ketones, aldehydes and mixtures thereof.
Preferred emulsifying agents are alcohols, propylene glycol,
ethylene glycol, glycerol, water, and solutions and mixtures
thereof. Especially preferred are water, ethanol, and isopropyl
alcohol and solutions and mixtures thereof. The type of emulsifying
agent affects the size of the dispersed droplets. For instance,
ethanol will provide droplets that have average diameters that can
be on the order of ten times larger than the droplets obtained with
an isotonic saline solution containing 0.9% by weight of sodium
chloride at 21.degree. C.
[0131] The thixotropic agent, i.e. an agent that imparts
thixotropic properties to the polymer gel, is selected from the
lower alkanols. Lower alkanol means an alcohol that contains 2-6
carbon atoms and is straight chain or branched chain. Such alcohols
may be exemplified by ethanol, isopropanol, and the like.
Importantly, such a thixotropic agent is not a polymer solvent.
(See e.g., Development of an in situ forming bidegradable
poly-lactide-co-glycolide system for controlled release of
proteins, Lambert, W. J., and Peck, K. D., Journal of Controlled
Release, 33 (1995) 189-195). When used, the thixotropic agent may
be present in amounts of 0.01 to 15 weight percent, preferably in
amounts of 0.1 to 5 weight percent, and often in amounts of 0.5 to
5 weight percent of the combined weight of the solvent and the
thixotropic agent.
[0132] It is to be understood that the emulsifying agent and/or the
thixotropic agent do not constitute a mere diluent or a
polymer-solvent that reduces viscosity by simply decreasing the
concentration of the components of the composition. The use of
conventional diluents can reduce viscosity, but can also cause the
burst effect mentioned previously when the diluted composition is
injected. In contrast, the injectable depot composition of the
present invention can be formulated to avoid the burst effect by
selecting the appropriate low molecular weight polymer, the solvent
and emulsifying agent so that once injected into place, the
emulsifying agent has little impact on the release properties of
the original system.
[0133] Although the injectable depot gel composition of the present
invention preferably are formed as viscous gels, the means of
administration of the implants is not limited to injection,
although that mode of delivery may often be preferred. Where the
injectable depot gel composition will be administered as a
leave-behind product, it may be formed to fit into a body cavity
existing after completion of surgery or it may be applied as a
flowable gel by brushing or palleting the gel onto residual tissue
or bone. Such applications may permit loading of beneficial agent
in the gel above concentrations typically present with injectable
compositions.
Beneficial Agents:
[0134] The beneficial agent can be any physiologically or
pharmacologically active substance or substances optionally in
combination with pharmaceutically acceptable carriers and
additional ingredients such as antioxidants, stabilizing agents,
permeation enhancers, etc. that do not substantially adversely
affect the advantageous results that can be attained by the present
invention. The beneficial agent may be any of the agents which are
known to be delivered to the body of a human or an animal and that
are preferentially soluble in water rather than in the
polymer-dissolving solvent. These agents include drug agents,
medicaments, vitamins, nutrients, or the like. Included among the
types of agents which meet this description are lower molecular
weight compounds, proteins, peptides, genetic material, nutrients,
vitamins, food supplements, sex sterilants, fertility inhibitors
and fertility promoters.
[0135] Drug agents which may be delivered by the present invention
include drugs which act on the peripheral nerves, adrenergic
receptors, cholinergic receptors, the skeletal muscles, the
cardiovascular system, smooth muscles, the blood circulatory
system, synoptic sites, neuroeffector junctional sites, endocrine
and hormone systems, the immunological system, the reproductive
system, the skeletal system, autacoid systems, the alimentary and
excretory systems, the histamine system and the central nervous
system. Suitable agents may be selected from, for example,
proteins, enzymes, hormones, polynucleotides, nucleoproteins,
polysaccharides, glycoproteins, lipoproteins, polypeptides,
steroids, analgesics, local anesthetics, antibiotic agents,
chemotherapeutic agents, immunosuppressive agents,
anti-inflammatory agents including anti-inflammatory
corticosteroids, antiproliferative agents, antimitotic agents,
angiogenic agents, antipsychotic agents, central nervous system
(CNS) agents, anticoagulants, fibrinolytic agents, growth factors,
antibodies, ocular drugs, and metabolites, analogs (including
synthetic and substituted analogs), derivatives (including
aggregative conjugates/fusion with other macromolecules and
covalent conjugates with unrelated chemical moieties by means known
in the art) fragments, and purified, isolated, recombinant and
chemically synthesized versions of these species.
[0136] Examples of drugs that may be delivered by the composition
of the present invention include, but are not limited to, procaine,
procaine hydrochloride, tetracaine, tetracaine hydrochloride,
cocaine, cocaine hydrochloride, chloroprocaine, chloroprocaine
hydrochloride, proparacaine, proparacaine hydrochloride,
piperocaine, piperocaine hydrochloride, hexylcaine, hexylcaine
hydrochloride, naepaine, naepaine hydrochloride, benzoxinate,
benzoxinate hydrochloride, cyclomethylcaine, cyclomethylcaine
hydrochloride, cyclomethylcaine sulfate, lidocaine, lidocaine
hydrochloride, bupivicaine, bupivicaine hydrochloride, mepivicaine,
mepivacaine hydrochloride, prilocalne, prilocalne hydrochloride,
dibucaine and dibucaine hydrochloride, etidocaine, benzocaine,
propoxycaine, dyclonin, pramoxine, oxybuprocaine, prochlorperzine
edisylate, ferrous sulfate, aminocaproic acid, mecamylamine
hydrochloride, procainamide hydrochloride, amphetamine sulfate,
methamphetamine hydrochloride, benzamphetamine hydrochloride,
isoproterenol sulfate, phenmetrazine hydrochloride, bethanechol
chloride, methacholine chloride, pilocarpine hydrochloride,
atropine sulfate, scopolamine bromide, isopropamide iodide,
tridihexethyl chloride, phenformin hydrochloride, methylphenidate
hydrochloride, theophylline cholinate, cephalexin hydrochloride,
diphenidol, meclizine hydrochloride, prochlorperazine maleate,
phenoxybenzamine, thiethylperzine maleate, anisindone, diphenadione
erythrityl tetranitrate, digoxin, isoflurophate, acetazolamide,
methazolamide, bendroflumethiazide, chloropromaide, tolazamide,
chlormadinone acetate, phenaglycodol, allopurinol, aluminum
aspirin, methotrexate, acetyl sulfisoxazole, erythromycin,
hydrocortisone, hydrocorticosterone acetate, cortisone acetate,
dexamethasone and its derivatives such as betamethasone,
triamcinolone, methyltestosterone, 17-S-estradiol, ethinyl
stradiol, ethinyl estradiol 3-methyl ether, prednisolone,
17.alpha.-hydroxyprogesterone acetate, 19-nor-progesterone,
norgestrel, norethindrone, norethisterone, norethiederone,
progesterone, norgesterone, norethynodrel, aspirin, indomethacin,
naproxen, fenoprofen, sulindac, indoprofen, nitroglycerin,
isosorbide dinitrate, propranolol, timolol, atenolol, alprenolol,
cimetidine, clonidine, imipramine, levodopa, chlorpromazine,
methyldopa, dihydroxyphenylalanine, theophylline, calcium
gluconate, ketoprofen, ibuprofen, cephalexin, erythromycin,
haloperidol, zomepirac, ferrous lactate, vincamine, diazepam,
phenoxybenzamine, diltiazem, milrinone, mandol, quanbenz,
hydrochlorothiazide, ranitidine, flurbiprofen, fenufen, fluprofen,
tolmetin, alclofenac, mefenamic, flufenamic, difuinal, nimodipine,
nitrendipine, nisoldipine, nicardipine, felodipine, lidoflazine,
tiapamil, gallopamil, amlodipine, mioflazine, lisinolpril,
enalapril, enalaprilat, captopril, ramipril, famotidine,
nizatidine, sucralfate, etintidine, tetratolol, minoxidil,
chlordiazepoxide, diazepam, amitriptyline, and imipramine. Further
examples are proteins and peptides which include, but are not
limited to, bone morphogenic proteins, insulin, colchicine,
glucagon, thyroid stimulating hormone, parathyroid and pituitary
hormones, calcitonin, renin, prolactin, corticotrophin, thyrotropic
hormone, follicle stimulating hormone, chorionic gonadotropin,
gonadotropin releasing hormone, bovine somatotropin, porcine
somatotropin, oxytocin, vasopressin, GRF, somatostatin, lypressin,
pancreozymin, luteinizing hormone, LHRH, LHRH agonists and
antagonists, leuprolide, interferons such as interferon alpha-2a,
interferon alpha-2b, and consensus interferon, interleukins, growth
factors such as epidermal growth factors (EGF), platelet-derived
growth factors (PDGF), fibroblast growth factors (FGF),
transforming growth factors-.alpha. (TGF-.alpha.), transforming
growth factors-.beta. (TGF-.beta.), erythropoietin (EPO),
insulin-like growth factor-I (IGF-I), insulin-like growth factor-II
(IGF-II), interleukin-1, interleukin-2, interleukin-6,
interleukin-8, tumor necrosis factor-.alpha. (TNF-.alpha.), tumor
necrosis factor-.beta. (TNF-.beta.), Interferon-.alpha.
(INF-.alpha.), Interferon-.beta. (INF-.beta.), Interferon-.gamma.
(INF-.gamma.), Interferon-.omega. (INF-.omega.), colony stimulating
factors (CGF), vascular cell growth factor (VEGF), thrombopoietin
(TPO), stromal cell-derived factors (SDF), placenta growth factor
(PlGF), hepatocyte growth factor (HGF), granulocyte macrophage
colony stimulating factor (GM-CSF), glial-derived neurotropin
factor (GDNF), granulocyte colony stimulating factor (G-CSF),
ciliary neurotropic factor (CNTF), bone morphogeneic proteins
(BMP), coagulation factors, human pancreas hormone releasing
factor, analogs and derivatives of these compounds, and
pharmaceutically acceptable salts of these compounds, or their
analogs or derivatives.
[0137] Additional examples of drugs that may be delivered by the
composition of the present invention include, but are not limited
to, antiproliferative/antimitotic agents including natural products
such as vinca alkaloids (i.e. vinblastine, vincristine, and
vinorelbine), paclitaxel, epidipodophyllotoxins (i.e. etoposide,
teniposide), antibiotics (dactinomycin, actinomycin D,
daunorubicin, doxorubicin and idarubicin), anthracyclines,
mitoxantrone, bleomycins, plicamycin (mithramycin) and mitomycin,
enzymes (L-asparaginase which systemically metabolizes L-asparagine
and deprives cells which do not have the capacity to synthesize
their own asparagine); antiplatelet agents such as
G(GP)II.sub.bIII.sub.a inhibitors and vitronectin receptor
antagonists; antiproliferative/antimitotic alkylating agents such
as nitrogen mustards (mechlorethamine, cyclophosphamide and
analogs, melphalan, chlorambucil), ethylenimines and
methylmelamines (hexamethylmelamine and thiotepa), alkyl
sulfonates-busulfan, nirtosoureas (carmustine (BCNU) and analogs,
streptozocin), trazenes-dacarbazinine (DTIC);
antiproliferative/antimitotic antimetabolites such as folic acid
analogs (methotrexate), pyrimidine analogs (fluorouracil,
floxuridine, and cytarabine), purine analogs and related inhibitors
(mercaptopurine, thioguanine, pentostatin and
2-chlorodeoxyadenosine (cladribine)); platinum coordination
complexes (cisplatin, carboplatin), procarbazine, hydroxyurea,
mitotane, aminoglutethimide; hormones (i.e. estrogen);
antipsychotic agents, (such as antipsychotic drugs, neuroleptic
drugs, tranquillisers and antipsychotic agents binding to dopamine,
histamine, muscarinic cholinergic, adrenergic and serotonin
receptors, including but not limited to phenothiazines,
thioxanthenes, butyrophenones, dibenzoxazepines, dibenzodiazepines
and diphenylbutylpiperidines); central nervous system (CNS) agents;
anticoagulants (heparin, synthetic heparin salts and other
inhibitors of thrombin); fibrinolytic agents (such as tissue
plasminogen activator, streptokinase and urokinase), aspirin,
dipyridamole, ticlopidine, clopidogrel, abciximab; antimigratory;
antisecretory (breveldin); antiinflammatory: such as adrenocortical
steroids (cortisol, cortisone, fludrocortisone, prednisone,
prednisolone, 6.alpha.-methylprednisolone, triamcinolone,
betamethasone, and dexamethasone), non-steroidal agents (salicylic
acid derivatives i.e. aspirin; para-aminophenol derivatives i.e.
acetominophen); indole and indene acetic acids (indomethacin,
sulindac, and etodalac), heteroaryl acetic acids (tolmetin,
diclofenac, and ketorolac), arylpropionic acids (ibuprofen and
derivatives), anthranilic acids (mefenamic acid, and meclofenamic
acid), enolic acids (piroxicam, tenoxicam, phenylbutazone, and
oxyphenthatrazone), nabumetone, gold compounds (auranofin,
aurothioglucose, gold sodium thiomalate); immunosuppressives:
(cyclosporine, tacrolimus (FK-506), sirolimus (rapamycin),
azathioprine, mycophenolate mofetil); angiogenic agents: vascular
endothelial growth factor (VEGF), fibroblast growth factor (FGF);
angiotensin receptor blocker; nitric oxide donors; anti-sense
oligionucleotides and combinations thereof; cell cycle inhibitors,
mTOR inhibitors, and growth factor signal transduction kinase
inhibitors, analogs and derivatives of these compounds, and
pharmaceutically acceptable salts of these compounds, or their
analogs or derivatives.
[0138] In certain preferred embodiments, the beneficial agent
includes chemotactic growth factors, proliferative growth factors,
stimulatory growth factors, and transformational peptide growth
factors including genes, precursors, post-translational-variants,
metabolites, binding-proteins, receptors, receptor agonists and
antagonists of the following growth factor families: epidermal
growth factors (EGFs), platelet-derived growth factor (PDGFs),
insulin-like growth factors (IGFs), fibroblast-growth factors
(FGFs), transforming-growth factors (TGFs), interleukins (ILs),
colony-stimulating factors (CSFs, MCFs, GCSFs, GMCSFs), Interferons
(IFNs), endothelial growth factors (VEGF, EGFs), erythropoietins
(EPOs), angiopoietins (ANGs), placenta-derived growth factors
(PlGFs), and hypoxia induced transcriptional regulators (HIFs).
[0139] The present invention also finds application with
chemotherapeutic agents for the local application of such agents to
avoid or minimize systemic side effects. Gels of the present
invention containing chemotherapeutic agents may be injected
directly into the tumor tissue for sustained delivery of the
chemotherapeutic agent over time. In some cases, particularly after
resection of the tumor, the gel may be implanted directly into the
resulting cavity or may be applied to the remaining tissue as a
coating. In cases in which the gel is implanted after surgery, it
is possible to utilize gels having higher viscosities since they do
not have to pass through a small diameter needle. Representative
chemotherapeutic agents that may be delivered in accordance with
the practice of the present invention include, for example,
carboplatin, cisplatin, paclitaxel, BCNU, vincristine,
camptothecin, etopside, cytokines, ribozymes, interferons,
oligonucleotides and oligonucleotide sequences that inhibit
translation or transcription of tumor genes, functional derivatives
of the foregoing, and generally known chemotherapeutic agents such
as those described in U.S. Pat. No. 5,651,986. The present
application has particular utility in the sustained delivery of
water soluble chemotherapeutic agents, such as for example
cisplatin and carboplatin and the water soluble derivatives of
paclitaxel. Those characteristics of the invention that minimize
the burst effect are particularly advantageous in the
administration of water soluble beneficial agents of all kinds, but
particularly those compounds that are clinically useful and
effective but may have adverse side effects.
[0140] To the extent not mentioned above, the beneficial agents
described in aforementioned U.S. Pat. No. 5,242,910 can also be
used. One particular advantage of the present invention is that
materials, such as proteins, as exemplified by the enzyme lysozyme,
and cDNA, and DNA incorporated into vectors both viral and
nonviral, which are difficult to microencapsulate or process into
microspheres can be incorporated into the compositions of the
present invention without the level of degradation caused by
exposure to high temperatures and denaturing solvents often present
in other processing techniques.
[0141] The beneficial agent is preferably incorporated into the
viscous gel formed from the polymer and the solvent in the form of
particles typically having an average particle size of from about
0.1 to about 250 microns, preferably from about 1 to about 200
microns and often from 30 to 125 microns. For instance, particles
having an average particle size of about 5 microns have been
produced by spray drying or freeze drying an aqueous mixture
containing 50% sucrose and 50% chicken lysozyme (on a dry weight
basis) and mixtures of 10-20% hGH and 15-30 mM zinc acetate. Such
particles have been used in certain of the examples illustrated in
the figures. Conventional lyophilization processes can also be
utilized to form particles of beneficial agents of varying sizes
using appropriate freezing and drying cycles.
[0142] To form a suspension or dispersion of particles of the
beneficial agent in the viscous gel formed from the polymer and the
solvent, any conventional low shear device can be used such as a
Ross double planetary mixer at ambient conditions. In this manner,
efficient distribution of the beneficial agent can be achieved
substantially without degrading the beneficial agent.
[0143] The beneficial agent is typically dissolved or dispersed in
the composition in an amount of from about 0.1% to about 50% by
weight, preferably in an amount of from about 1% to about 40%, more
preferably in an amount of about 2% to about 30%, and often 2 to
20% by weight of the combined amounts of the polymer, solvent, and
beneficial agent. Depending on the amount of beneficial agent
present in the composition, one can obtain different release
profiles and burst indices. More specifically, for a given polymer
and solvent, by adjusting the amounts of these components and the
amount of the beneficial agent, one can obtain a release profile
that depends more on the degradation of the polymer than the
diffusion of the beneficial agent from the composition or vice
versa. In this respect, at lower beneficial agent loading rates,
one generally obtains a release profile reflecting degradation of
the polymer wherein the release rate increases with time. At higher
loading rates, one generally obtains a release profile caused by
diffusion of the beneficial agent wherein the release rate
decreases with time. At intermediate loading rates, one obtains
combined release profiles so that if desired, a substantially
constant release rate can be attained. In order to minimize burst,
loading of beneficial agent on the order of 30% or less by weight
of the overall gel composition, i.e., polymer, solvent and
beneficial agent, is preferred, and loading of 20% or less is more
preferred.
[0144] Release rates and loading of beneficial agent will be
adjusted to provide for therapeutically-effective delivery of the
beneficial agent over the intended sustained delivery period.
Preferably, the beneficial agent will be present in the polymer gel
at concentrations that are above the saturation concentration of
beneficial agent in water to provide a drug reservoir from which
the beneficial agent is dispensed. While the release rate of
beneficial agent depends on the particular circumstances, such as
the beneficial agent to be administered, release rates on the order
of from about 0.1 to about 100 micrograms/day, preferably from
about 1 to about 10 micrograms per day, for periods of from about 3
to about two weeks can be obtained. Greater amounts may be
delivered if delivery is to occur over shorter periods. Generally,
higher release rate is possible if a greater burst can be
tolerated. In instances where the gel composition is surgically
implanted, or used as a "leave behind" depot when surgery to treat
the disease state or another condition is concurrently conducted,
it is possible to provide higher doses that would normally be
administered if the implant was injected. Further, the dose of
beneficial agent may be controlled by adjusting the volume of the
gel implanted or the injectable gel injected.
[0145] FIGS. 1-9 illustrate representative release profiles of
various beneficial agents obtained in rats from preferred
compositions of this invention. As illustrated in the figures, the
injectable depot gel formulations of the invention comprising low
molecular weight polymers provide a controlled, sustained release
of a beneficial agent over a short duration of time equal to or
less than two weeks.
Optional Additional Components:
[0146] Other components may be present in the injectable depot gel
composition, to the extent they are desired or provide useful
properties to the composition, such as polyethylene glycol,
hydroscopic agents, stabilizing agents, pore forming agents, and
others. When the composition includes a peptide or a protein that
is soluble in or unstable in an aqueous environment, it may be
highly desirable to include a solubility modulator, that may, for
example, be a stabilizing agent, in the composition. Various
modulating agents are described in U.S. Pat. Nos. 5,654,010 and
5,656,297 which are incorporated herein by reference. In the case
of hGH, for example, it is preferable to include an amount of a
salt of a divalent metal, preferably zinc. Examples of such
modulators and stabilizing agents, which may form complexes with
the beneficial agent or associate to provide the stabilizing or
modulated release effect, include metal cations, preferably
divalent, present in the composition as magnesium carbonate, zinc
carbonate, calcium carbonate, magnesium acetate, magnesium sulfate,
zinc acetate, zinc sulfate, zinc chloride, magnesium chloride,
magnesium oxide, magnesium hydroxide, other antacids, and the like.
The amounts of such agents used will depend on the nature of the
complex formed, if any, or the nature of the association between
the beneficial agent and the agent. Molar ratios of solubility
modulator or stabilizing agent to beneficial agent of about 100:1
to 1:1, preferably 10:1 to 1:1, typically can be utilized.
[0147] Pore forming agents include, biocompatible materials that
when contacted with body fluids dissolve, disperse or degrade to
create pores or channels in the polymer matrix. Typically, organic
and non-organic materials that are water soluble such as sugars
(e.g., sucrose, dextrose), water soluble salts (e.g., sodium
chloride, sodium phosphate, potassium chloride, and sodium
carbonate), water soluble solvents such as N-methyl-2-pyrrolidone
and polyethylene glycol and water soluble polymers (e.g.,
carboxmethylcellulose, hydroxypropylcellulose, and the like) can
conveniently be used as pore formers. Such materials may be present
in amounts varying from about 0.1% to about 100% of the weight of
the polymer, but will typically be less than 50% and more typically
less than 10-20% of the weight of polymer.
Utility and Administration:
[0148] The means of administration of the depot gel compositions is
not limited to injection, although that mode of delivery may often
be preferred. Where the depot gel composition will be administered
as a leave-behind product, it may be formed to fit into a body
cavity existing after completion of surgery or it may be applied as
a flowable gel by brushing or palleting the gel onto residual
tissue or bone. Such applications may permit loading of beneficial
agent in the gel above concentrations typically present with
injectable compositions.
[0149] Compositions of this invention without beneficial agent are
useful for wound healing, bone repair and other structural support
purposes.
[0150] To further understand the various aspects of the present
invention, the results set forth in the previously described
figures were obtained in accordance with the following
examples.
EXAMPLE 1
Depot Gel Preparation
[0151] A gel vehicle for use in an injectable depot of the
composition was prepared as follows. A glass vessel was tared on a
Mettler PJ3000 top loader balance. Poly (D,L-lactide-co-glycolide)
(PLGA), available as 50:50 DL-PLG with an inherent viscosity of
0.15 (PLGA-BPI, Birmingham Polymers, Inc., Birmingham, Ala.) and
50:50 Resomer.RTM. R RG502 (PLGA RG 502), was weighed into the
glass vessel. The glass vessel containing the polymer was tared and
the corresponding solvent was added. Amounts expressed as
percentages for various polymer/solvent combinations are set forth
in Table 1, below. The polymer/solvent mixture was stirred at
250.+-.50 rpm (IKA electric stirrer, IKH-Werke GmbH and Co.,
Stanfen, Germany) for about 5-10 minutes, resulting in a sticky
paste-like substance containing polymer particles. The vessel
containing the polymer/solvent mixture was sealed and placed in a
temperature controlled incubator equilibrated to 37.degree. C. for
1 to 4 days, with intermittent stirring, depending on solvent and
polymer type and solvent and polymer ratios. The polymer/solvent
mixture was removed from the incubator when it appeared to be a
clear amber homogeneous solution. Thereafter, the mixture was
placed in an oven (65.degree. C.) for 30 minutes. It was noted that
the PLGA was dissolved in the mixture upon removal from the
oven.
[0152] Additional depot gel vehicles are prepared with the
following solvents or mixtures of solvents: benzyl benzoate ("BB"),
benzyl alcohol ("BA"), ethyl benzoate ("EB"), BB/BA, BB/Ethanol,
BB/EB and the following polymers: Poly (D,L-lactide-co-glycolide)
50:50 Resomer.RTM. RG502, code 0000366, Poly
(D,L-lactide-co-glycolide) 50:50 Resomer.RTM. RG502H, PLGA-502H,
code no. 260187, Poly D,L Lactide (Resomer.RTM. R 202, Resomer.RTM.
R 203); Poly dioxanone (Resomer.RTM. X 210) (Boehringer Ingelheim
Chemicals, Inc., Petersburg, Va.); DL-lactide/glycolide 100:0
(MEDISORB.RTM. Polymer 100 DL High, MEDISORB.RTM. Polymer 100 DL
Low); DL-lactide/glycolide 85/15 (MEDISORB.RTM. Polymer 8515 DL
High, MEDISORB.RTM. Polymer 8515 DL Low); DL-lactide/glycolide
75/25 (MEDISORB.RTM. Polymer 7525 DL High, MEDISORB.RTM. Polymer
7525 DL Low); DL-lactide/glycolide 65/35 (MEDISORB.RTM. Polymer
6535 DL High, MEDISORB.RTM. Polymer 6535 DL Low);
DL-lactide/glycolide 54/46 (MEDISORB.RTM. Polymer 5050 DL High,
MEDISORB.RTM. Polymer 5050 DL Low); and DL-lactide/glycolide 54/46
(MEDISORB.RTM. Polymer 5050 DL 2A(3), MEDISORB.RTM. Polymer 5050 DL
3A(3), MEDISORB.RTM. Polymer 5050 DL 4A(3)) (Medisorb Technologies
International L.P., Cincinatti, Ohio); and Poly
D,L-lactide-co-glycolide 50:50; Poly D,L-lactide-co-glycolide
65:35; Poly D,L-lactide-co-glycolide 75:25; Poly
D,L-lactide-co-glycolide 85:15; Poly DL-lactide; Poly L-lactide;
Poly glycolide; Poly .epsilon.-caprolactone; Poly
DL-lactide-co-caprolactone 25:75; and Poly
DL-lactide-co-caprolactone 75:25 (Birmingham Polymers, Inc.,
Birmingham, Ala.).
EXAMPLE 2
hGH Particle Preparation
[0153] Human growth hormone (hGH) particles (optionally containing
zinc acetate) were prepared as follows: hGH solution (5 mg/ml)
solution in water (BresaGen Corporation, Adelaide, Australia) was
concentrated to 10 mg/mL using a Concentration/Dialysis Selector
diafiltering apparatus. The diafiltered hGH solution was washed
with 5 times volume of tris or phosphate buffer solution (pH 7.6).
Particles of hGH were then formed by spray drying or lyophilization
using conventional techniques. Phosphate buffer solutions (5 or 50
mM) containing hGH (5 mg/mL) (and optionally various levels of zinc
acetate (0 to 30 mM) when Zn complexed particles were prepared)
were spray-dried using a Yamato Mini Spray dryer set at the
following parameters: TABLE-US-00001 Spray Dryer Parameter Setting
Atomizing Air 2 psi Inlet Temperature 120.degree. C. Aspirator Dial
7.5 Solution Pump 2-4 Main Air Valve 40-45 psi
[0154] hGH particles having a size range between 2-100 microns were
obtained. Lyophilized particles were prepared from tris buffer
solutions (5 or 50 mM: pH 7.6) containing hGH (5 mg/mL) using a
Durastop .mu.P Lyophilizer in accordance with the following
freezing and drying cycles: TABLE-US-00002 Freezing Ramp down at
2.5 C/min to -30.degree. C. and hold for 30 min cycle Ramp down at
2.5 C/min to -30.degree. C. and hold for 30 min Drying Ramp up at
0.5 C/min to 10.degree. C. and hold for 960 min cycle Ramp up at
0.5 C/min to 20.degree. C. and hold for 480 min Ramp up at 0.5
C/min to 25.degree. C. and hold for 300 min Ramp up at 0.5 C/min to
30.degree. C. and hold for 300 min Ramp up at 0.5 C/min to
5.degree. C. and hold for 5000 min
hGH particles having a size range between 2-100 microns were
obtained.
EXAMPLE 3
hGH-Stearic Acid Particle Preparation
[0155] Human growth hormone (hGH) particles were prepared as
follows: Lyophilized hGH (3.22 grams, Pharmacia-Upjohn, Stockholm,
Sweden) and stearic acid (3.22 grams, 95% pure, Sigma-Aldrich
Corporation, St. Louis, Mo.) were blended and ground. The ground
material was compressed in a 13 mm round die, with a force of
10,000 pounds for 5 minutes. Compressed tablets were ground and
sieved through a 70 mesh screen followed by a 400 mesh screen to
obtain particles having a size range between 38-212 microns.
EXAMPLE 4
Bupivacaine Base Preparation
[0156] Bupivacaine hydrochloride (Sigma-Aldrich Corporation, St.
Louis, Mo.) was dissolved in de-ionized (DI) water at a
concentration of 40 mg/ml (saturation). A calculated amount of
sodium hydroxide (1 N solution) was added to the solution and the
pH of the final mixtures was adjusted to 10 to precipitate the BP
base. The precipitated product was filtered, and further washed
with DI water for at least three times. The precipitated product
was dried at approximately 40.degree. C. in vacuum for 24 h.
EXAMPLE 5
Bupivacaine Particle Preparation
[0157] Bupivacaine drug particles using bupivacaine hydrochloride
(Sigma-Aldrich Corporation, St. Louis, Mo.) or bupivacaine base
prepared according example 4 and hydrochloride salt, were prepared
as follows. Bupivicaine was grounded and then sieved to a fixed
range using 3'' stainless steel sieves. Typical ranges include 25
.mu.m to 38 .mu.m, 38 .mu.m to 63 .mu.m, and 63 .mu.m to 125
.mu.m.
EXAMPLE 6
Bupivacaine-Stearic Acid Particle Preparation
[0158] Bupivacaine particles were prepared as follows: Bupivacaine
hydrochloride (100 g, Sigma-Aldrich Corporation, St. Louis, Mo.)
was grounded and sieved through 63-125 micron sieves. The
bupivacaine particles and stearic acid (100 g, 95% pure,
Sigma-Aldrich Corporation, St. Louis, Mo.) were blended and ground.
The ground material was compressed in a 13 mm round die, with a
force of 5,000 pounds for 5 minutes. Compressed tablets were ground
and sieved through a 120 mesh screen followed by a 230 mesh screen
to obtain particles having a size range between 63-125 microns.
EXAMPLE 7
Drug Loading
[0159] Particles comprising beneficial agent with or without
stearic acid prepared as above were added to a gel vehicle in an
amount of 10-30% by weight and blended manually until the dry
powder was wetted completely. Then, the milky light yellow
particle/gel mixture was thoroughly blended by conventional mixing
using a Caframo mechanical stirrer with an attached square-tip
metal spatula. Resulting formulations are illustrated in Tables 1,
2 and 3 below. TABLE-US-00003 TABLE 1 PLGA RG502.sup.a LMW
PLGA.sup.b Benzyl Benzoate Formulation (wt %) (wt %) (wt %) 1.sup.c
45 0 45 2.sup.c 0 45 45 3.sup.d 45 0 45 4.sup.d 0 45 45 .sup.a=
PLGA RG 502, MW = 16,000. .sup.b= Low Molecular Weight (LMW, MW =
8000) PLGA with an ester end group. .sup.c= 10% bupivacaine
hydrochloride loading. .sup.d= 10% bupivacaine base loading.
[0160] TABLE-US-00004 TABLE 2 PLGA RG502.sup.a LMW PLGA.sup.e
Benzyl Benzoate Formulation (wt %) (wt %) (wt %) 5.sup.f 45 0 45
6.sup.f 0 45 45 7.sup.f 0 63 27 .sup.a= PLGA RG 502, MW = 16,000.
.sup.e= Low Molecular Weight (LMW, MW - 7,000) PLGA with an ester
end group. .sup.f= 5% hGH loading.
[0161] TABLE-US-00005 TABLE 3 LMW LMW Benzyl Benzyl PLGA.sup.g
PLGAc.sup.h Benzoate Alcohol Formulation (wt %) (wt %) (wt %) (wt
%) 8.sup.i 58.5 0 31.5 0 9.sup.i 58.5 0 0 31.5 10.sup.i 67.5 0 0
22.5 11.sup.i 0 67.5 22.5 12.sup.j 0 60 20 .sup.g= Low Molecular
Weight (LMW, MW = 8,000) PLGA with an ester end group. .sup.h= Low
Molecular Weight (LMW, MW = 10,000) PLGA with a carboxyl end group.
.sup.i= 10% bupivacaine hydrochloride loading. .sup.j= 10%
bupivacaine hydrochloride and 10% SA loading.
[0162] A representative number of implantable depots gel
compositions were prepared in accordance with the foregoing
procedures and tested for in vitro release of beneficial agent as a
function of time and also in in vivo studies in rats to determine
release of the beneficial agent as determined by blood plasma
concentrations of beneficial agent as a function of time.
EXAMPLE 8
Bupivacaine In Vivo Studies
[0163] In vivo studies in rats (4 or 5 per group) were performed
following an open protocol to determine plasma levels of
bupivacaine upon systemic administration of bupivicaine via the
implant systems of this invention. Depot gel bupivacaine
formulations were loaded into customized 0.5 cc disposable
syringes. Disposable 18 gauge needles were attached to the syringes
and were heated to 37.degree. C. using a circulator bath. Depot gel
bupivacaine formulations were injected into rats and blood was
drawn at specified time intervals (1 hour, 4 hours and on days 1,
2, 5, 7, 9, 14, 21 and 28) and analyzed for bupivacaine using
LC/MS.
[0164] FIGS. 1, 2 and 3 illustrate representative in vivo release
profiles of bupivacaine hydrochloride and bupivacaine base obtained
in rats from various depot formulation, including those of the
present invention. The in vivo release profile of the depot
formulations with low molecular weight PLGA (formulations 2 and 4
in FIGS. 1, 2 and 3) exhibited short release duration for
approximately 7 days, comparable to the control formulations (with
higher molecular weight PLGA). Thus, the injectable depot gel
formulations of the invention comprising low molecular weight
polymers provide a controlled, sustained release of a beneficial
agent over a short duration of time equal to or less than two
weeks.
EXAMPLE 9
hGH In Vivo Studies
[0165] In vivo hGH studies in rats were performed following an open
protocol to determine serum levels of hGH upon systemic
administration of hGH via the injectable depot gel compositions of
this invention. Depot gel hGH formulations were loaded into
customized 0.5 cc disposable syringes. Disposable 16 gauge needles
were attached to the syringes and were heated to 37.degree. C.
using a circulator bath. Depot gel hGH formulations were injected
into immunosuppressed rats and blood was drawn at specified time
intervals. All serum samples were stored at 4.degree. C. prior to
analysis. Samples were analyzed for intact hGH content using a
radio immuno assay (RIA).
[0166] FIGS. 4, 5 and 6 illustrate representative in vivo release
profiles of human growth hormone ("hGH") obtained in rats from
various depot formulation, including those of the present
invention. The in vivo release profile of the depot formulations
with low molecular weight PLGA (formulations 6 and 7 in FIGS. 4, 5
and 6) exhibited short release duration for approximately 7-14
days, comparable to the control formulations (with higher molecular
weight PLGA). Thus, the injectable depot gel formulations of the
invention comprising low molecular weight polymers provide a
controlled, sustained release of a beneficial agent over a short
duration of time equal to or less than two weeks.
EXAMPLE 10
In Vivo Studies on Bupivacaine Depot Formulation
[0167] As illustrated in Table 3, various depot formulations can be
made from the low molecular weight PLGA with either an ester end
group or a carboxyl end group using different solvents such as
benzyl benzoate (BB), benzyl alcohol (BA), ethyl benzoate (EB),
mixtures of BB/Ethanol, BB/BA, BB/EB etc., with varying
polymer/solvent ratios. The drug particles can be made either with
or without hydrophobic excipients such as stearic acid (SA).
[0168] FIG. 7 illustrates representative in vivo release profiles
of bupivacaine obtained in rats from depot formulations made of low
molecular weight PLGA in either BB or BA. FIG. 8 illustrates
representative in vivo release profiles of bupivacaine obtained in
rats from depot formulations made of low molecular weight PLGA in
BA with various polymer/solvent ratios. FIG. 9 illustrates
representative in vivo release profiles of bupivacaine obtained in
rats from depot formulations made of low molecular weight PLGA in
BA with different end groups. FIG. 10 illustrates representative in
vivo release profiles of bupivacaine obtained in rats from depot
formulations made of low molecular weight PLGA in BA with the drug
particles formulated either with or without SA.
[0169] As illustrated in this example, by using low molecular
weight PLGA either end-capped with an ester or carboxyl group, the
short duration release of active agent from depot can be achieved.
The formulations can be made in various solvents or solvent
mixtures with various polymer/solvent ratios. The release profiles
of the active agent from the depots can be varied accordingly.
EXAMPLE 11
Differential Scanning Calorimeter (DSC) Measurements on PLGA
Polymers
[0170] The glass transition temperature of various low molecular
PLGA polymers used in the present invention was determined using a
differential scanning calorimeter (DSC) (Perkin Elmer Pyris 1,
Shelton, Conn.). The DSC sample pan was tarred on a Mettler PJ3000
top loader balance. At least 20 mg of polymer sample was placed in
the pan. The weight of the sample was recorded. The DSC pan cover
was positioned on to the pan and a presser was used to seal the
pan. The temperature was scanned in 10.degree. C. increments from
-50.degree. C. to 90.degree. C.
[0171] FIGS. 11 and 12 illustrate the differences in the DSC
diagrams of low molecular weight PLGA used in the formulations
presented in this invention end-capped with either an ester group
or the carboxyl terminated. These data demonstrate that the low
molecular weight PLGA polymers used in this invention have a glass
transition temperatures ("Tg") above 30.degree. C.
EXAMPLE 12
In Vitro Degradation of PLGA Polymers
[0172] The degradation profiles of low molecular weight PLGA
polymers used in the present invention were performed in vitro at
37.degree. C. in PBS buffer to determine the mass loss rate of the
PLGA polymer as a function of time. Each of the copolymers
comprised one sample set. Approximately 25 discs (100.+-.5 mg each)
were pressed using a 13 mm stainless steel die. The sample was
pressed with 10 tons of force for approximately 10 minutes using
the Carver Press. The discs were kept in a glass vial in a vacuum
oven at ambient temperature and 25 mm Hg until ready for use in the
degradation bath. This procedure was repeated for each polymer
tested. Phosphate buffered saline (PBS) solution (50 mM, pH 7.4)
with sodium azide (0.1N) was prepared. One sample disc was weighed
into the tarred vial and recorded as initial weight
(M.sub.initial). PBS (10 mL) was pipetted into each vial. The vial
was capped securely and placed in a 37.degree. C. shaking water
bath. The buffer was changed twice a week, prior to which the pH of
the solution was recorded. At pre-designated time points, the
samples were removed from the buffer bath, rinsed with de-ionized
Milli-Q water, dried superficially, and weighed. The sample weight
was recorded as wet weight (M.sub.wet). The sample was placed in a
10 mL lyophilization vial and placed in a freezer (-20.degree. C.)
prior to lyophilization. After lyophilization, the samples were
weighed again and recorded as dry weight (M.sub.lyophilized). The
percent mass loss was defined as
{(M.sub.lyophilized-M.sub.initial)/M.sub.initial}.times.100%.
[0173] FIG. 13 illustrates the mass loss profiles of the three
PLGAs used in the formulations described above. From this it can be
seen that each of the three polymers used has significantly
different degradation rates. The low molecular weight PLGA with
either an ester end group or carboxyl end group have a
significantly faster degradation rate than the one with higher
molecular weight. This represents more favorable towards short
duration depots which prefers the polymer degrades as soon as the
active agents are released from the depot. In accordance with
various aspects of the present invention, one or more significant
advantages can be obtained. More specifically, using simple
processing steps, one can obtain a depot gel composition that can
be injected into place in an animal without surgery using a low
dispensing force through standard needles. Once in place, the
composition will quickly return to its original viscosity and may
exhibit rapid hardening so as to substantially avoid a burst effect
and provide the desired beneficial agent release profile.
Furthermore, once the beneficial agent has been fully administered,
there is no need to remove the composition since it is fully
biodegradable. As a still further advantage, the present invention
avoids the use of microparticle or microcapsulation techniques
which can degrade certain beneficial agents, like peptide and
nucleic acid-based drugs and which microparticles and microcapsules
maybe difficult to remove from the environment of use. Since the
viscous gel is formed without the need for water, temperature
extremes, or other solvents, suspended particles of beneficial
agent remain dry and in their original configuration, which
contributes to the stability of thereof. Further, since a mass is
formed, the injectable depot gel composition may be retrieved from
the environment of use if desired.
[0174] The above-described exemplary embodiments are intended to be
illustrative in all respects, rather than restrictive, of the
present invention. Thus the present invention is capable of many
variations in detailed implementation that can be derived from the
description contained herein by a person skilled in the art. All
such variations and modifications are considered to be within the
scope and spirit of the present invention.
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