U.S. patent application number 14/013830 was filed with the patent office on 2014-01-09 for method for determining optimum intraocular locations for drug delivery systems.
This patent application is currently assigned to Allergan, Inc.. The applicant listed for this patent is Allergan, Inc.. Invention is credited to Joan-En Chang-Lin, Patrick M. Hughes, Michael R. Robinson, Devin F. Welty, Scott M. Whitcup.
Application Number | 20140010823 14/013830 |
Document ID | / |
Family ID | 39381959 |
Filed Date | 2014-01-09 |
United States Patent
Application |
20140010823 |
Kind Code |
A1 |
Robinson; Michael R. ; et
al. |
January 9, 2014 |
METHOD FOR DETERMINING OPTIMUM INTRAOCULAR LOCATIONS FOR DRUG
DELIVERY SYSTEMS
Abstract
A method for determining the optimum location for placement of
an intraocular implant containing used to treat an ocular
condition, particularly implants comprised of a biodegradable
polymer and a therapeutic agent for the treatment of retinal
tissue.
Inventors: |
Robinson; Michael R.;
(Irvine, CA) ; Chang-Lin; Joan-En; (Tustin,
CA) ; Welty; Devin F.; (Watertown, MA) ;
Hughes; Patrick M.; (Aliso Viejo, CA) ; Whitcup;
Scott M.; (Laguna Hills, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Allergan, Inc. |
Irvine |
CA |
US |
|
|
Assignee: |
Allergan, Inc.
Irvine
CA
|
Family ID: |
39381959 |
Appl. No.: |
14/013830 |
Filed: |
August 29, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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11948411 |
Nov 30, 2007 |
8571802 |
|
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14013830 |
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60868291 |
Dec 1, 2006 |
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Current U.S.
Class: |
424/158.1 ;
514/172; 514/179; 514/180 |
Current CPC
Class: |
A61P 27/02 20180101;
A61K 39/3955 20130101; A61K 9/0048 20130101; A61K 31/573 20130101;
A61K 31/58 20130101; A61F 9/0017 20130101 |
Class at
Publication: |
424/158.1 ;
514/172; 514/179; 514/180 |
International
Class: |
A61K 39/395 20060101
A61K039/395; A61K 31/573 20060101 A61K031/573; A61K 31/58 20060101
A61K031/58 |
Claims
1.-7. (canceled)
8. A method for treating age related macular degeneration with a
drug delivery system, the drug delivery system comprising a
therapeutic agent and a biodegradable polymer associated with the
therapeutic agent, the method comprising the step of placing the
drug delivery system in the vitreous at a position x that is 1.3 cm
from the aqueous humor and 0.8 cm from the macula thereby treating
the age related macular degeneration.
9. The method of claim 8, wherein the drug delivery system is a
biodegradable intraocular implant produced by an extrusion
method.
10. The method of claim 9, wherein the placing step is carried out
using an applicator with a 1/2 inch needle comprising a canula, in
which canula the implant resides, wherein the needle has a length
designed to permit placement of the drug delivery system into the
vitreous at the position x.
11. The method according to any one of claim 8 or 9, wherein said
therapeutic agent is a corticosteroid or an anti-VEGF antibody,
wherein the corticosteroid is selected from the group consisting of
fluocinolone, triamcinolone, and dexamethasone.
12. The method according to claim 11, wherein said therapeutic
agent is at least one member selected from the group consisting of
dexamethasone and fluocinolone, and said biodegradable polymer
comprises at least one member selected from the group consisting of
polylactides (PLA), polyglycolides (PGA), poly(lactide co-glycolide
(PLGA), polycaprolactone, polyanhydride, poly methyl vinyl ether
maleic anhydride, polycarbonates, polyarylates, polydioxanone,
polyhydroxyalkanoates, and chitosan.
13. The method of claim 11, wherein the therapeutic agent is an
anti-VEGF antibody.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a continuation of U.S.
application Ser. No. 11/948,411, filed on Nov. 30, 2007, which
claims the benefit of U.S. Application No. 60/868,291, filed Dec.
1, 2006, the content of which in its entirety is hereby
incorporated by reference. The entire disclosure of U.S.
application Ser. No. 11/948,411 is incorporated herein by
reference.
BACKGROUND
[0002] The present invention relates to methods for determining the
optimum location for placement of an intraocular drug delivery
system (i.e. an implant) containing a therapeutic agent for
treating an ocular condition, particularly drug delivery systems
comprised of a biodegradable polymer and a therapeutic agent for
the treatment of a retinal disease or condition. Additionally, the
present invention relates to methods for determining the optimal
amount of a therapeutic agent to load into an intraocular drug
delivery device to effectively treat an ocular condition.
[0003] An ocular condition can include a disease, aliment or
condition which affects or involves the eye or one of the parts or
regions of the eye. Broadly speaking the eye includes the eyeball
and the tissues and fluids which constitute the eyeball, the
periocular muscles (such as the oblique and rectus muscles) and the
portion of the optic nerve which is within or adjacent to the
eyeball. FIG. 1 is a schematic diagram of the human eye, from which
it can be seen that the anterior segment is the front third of the
eye (those portions of the eye in front of the vitreous humour)
including the iris, cornea, ciliary body and lens. The posterior
segment of the eye then contains the vitreous humour, retina,
choroids and the optic nerve. FIG. 2 is a cross sectional view of
the eye showing the positions of the macula (an oval yellow spot
near the center of the retina, with the fovea being the center most
part of the macula), retina, and retinal blood vessels.
[0004] An anterior ocular condition is a disease, ailment or
condition which affects or which involves an anterior (i.e. front
of the eye) ocular region or site, such as a periocular muscle, an
eye lid or an eye ball tissue or fluid which is located anterior to
the posterior wall of the lens capsule or ciliary muscles. Thus, an
anterior ocular condition primarily affects or involves, the
conjunctiva, the cornea, the conjunctiva, the anterior chamber, the
iris, the posterior chamber (behind the retina but in front of the
posterior wall of the lens capsule), the lens or the lens capsule
and blood vessels and nerve which vascularize or innervate an
anterior ocular region or site. A posterior ocular (also referred
to herein synonymously as a "posterior segment") condition is a
disease, ailment or condition which primarily affects or involves a
posterior ocular region or site such as choroid or sclera (in a
position posterior to a plane through the posterior wall of the
lens capsule), vitreous, vitreous chamber, retina, optic nerve
(i.e. the optic disc), and blood vessels and nerves which
vascularize or innervate a posterior ocular (or posterior segment)
region or site.
[0005] Thus, a posterior ocular condition can include a disease,
ailment or condition, such as for example, macular degeneration
(such as non-exudative age related macular degeneration and
exudative age related macular degeneration); choroidal
neovascularization; acute macular neuroretinopathy; macular edema
(such as cystoid macular edema and diabetic macular edema);
Behcet's disease, retinal disorders, diabetic retinopathy
(including proliferative diabetic retinopathy); retinal arterial
occlusive disease; central retinal vein occlusion; uveitis
(including intermediate and anterior uveitis); retinal detachment;
ocular trauma which affects a posterior ocular site or location; a
posterior ocular condition caused by or influenced by an ocular
laser treatment; posterior ocular conditions caused by or
influenced by a photodynamic therapy; photocoagulation; radiation
retinopathy; epiretinal membrane disorders; branch retinal vein
occlusion; anterior ischemic optic neuropathy; non-retinopathy
diabetic retinal dysfunction, retinitis pigmentosa and glaucoma.
Glaucoma can be considered a posterior ocular condition because a
therapeutic goal can be to prevent the loss of or reduce the
occurrence of loss of vision due to damage to or loss of retinal
cells or optic nerve cells (i.e. neuroprotection).
[0006] An anterior ocular condition can include a disease, ailment
or condition, such as for example, aphakia; pseudophakia;
astigmatism; blepharospasm; cataract; conjunctival diseases;
conjunctivitis; corneal diseases;, corneal ulcer; dry eye
syndromes; eyelid diseases; lacrimal apparatus diseases; lacrimal
duct obstruction; myopia; presbyopia; pupil disorders; refractive
disorders and strabismus. Glaucoma can also be considered to be an
anterior ocular condition because a clinical goal of glaucoma
treatment can be to reduce a hypertension of aqueous fluid in the
anterior chamber of the eye (i.e. reduce intraocular pressure).
[0007] Macular edema is a condition characterized by thickening and
swelling of the macula of the eye, often caused by the collection
of fluids and protein on or under the macula. This condition can
significantly impair vision, such as by distorting the patient's
central vision since the macula is near the center of the retina at
the back of the eye. Macular edema is a major cause of visual loss
in patients with diabetes, central retinal vein occlusion (CRVO)
and branch retinal vein occlusion (BRVO). Although laser
photocoagulation can reduce further vision loss in patients with
diabetic macular edema (DME), vision that has already been
decreased by macular edema usually does not improve by use of laser
photocoagulation. Currently, there is no FDA (U.S. Food and Drug
Administration) approved treatment for macular edema associated
with CRVO. For macular edema associated with BRVO, grid laser
photocoagulation may be an effective treatment for some
patients.
[0008] Diabetic macular edema results from abnormal leakage of
macromolecules, such as lipoproteins, from retinal capillaries into
the extravascular space followed by an oncotic influx of water into
the extravascular space. Abnormalities in the retinal pigment
epithelium may also cause or contribute to diabetic macular edema.
These abnormalities can allow increased fluid from the
choriocapillaries to enter the retina or they may decrease the
normal efflux of fluid from the retina to the choriocapillaries.
The mechanism of breakdown of the blood-retina barrier at the level
of the retinal capillaries and the retinal pigment epithelium may
be due to changes to tight junction proteins such as occludin.
Antcliff R., et al Marshall J., The pathogenesis of edema in
diabetic maculopathy, Semin Ophthalmol 1999; 14:223-232.
[0009] Macular edema from venous occlusive disease can result from
thrombus formation at the lamina cribrosa or at an arteriovenous
crossing. These changes can result in an increase in retinal
capillary permeability and accompanying retinal edema. The increase
in retinal capillary permeability and subsequent retinal edema can
ensue from of a breakdown of the blood retina barrier mediated in
part by vascular endothelial growth factor (VEGF), a 45 kD
glycoprotein, as it is known that VEGF can increase vascular
permeability. VEGF may regulate vessel permeability by increasing
phosphorylation of tight junction proteins such as occludin and
zonula occluden. Similarly, in human non-ocular disease states such
as ascites, VEGF has been characterized as a potent vascular
permeability factor (VPF).
[0010] Damage to the optic nerve can be due to increased pressure
in the eye (i.e. elevated intraocular pressure). Elevated
intraocular pressure (IOP) (ocular hypertension) can result from
excess aqueous humor accumulating because the eye either produces
too much or drains too little aqueous humor.
[0011] It is known to make and use an intraocular implant to treat
an ocular condition. See for example U.S. Pat. Nos. 4,521,210;
4,853,224; 4,997,652; 5,164,188; 5,443,505; 5,766,242; 5,824,072;
5,869,079; 6,331,313; 6,726,918; 6,699,493; 5,501,856; 6,074,661;
and; 6,369,116, and U.S. patent application Ser. Nos. 11/070,158;
11/292,544; 10/966,764; 11/117,879; 11/119,463; 11/116,698;
11/119,021; 11/118,519; 11/119,001; 11/118,288; 11/119,024;
10/340,237; 10/837,357; 10/837,355; 10/837,142; 10/837,356;
10/836,911; 10/837,143; 10/837,260; 10/837,379; 10/836,880, and
10/918,597, each of which is hereby incorporated by reference.
[0012] U.S. Pat. No. 6,713,081 discloses ocular implant devices
made from polyvinyl alcohol and used for the delivery of a
therapeutic agent to an eye in a controlled and sustained manner.
The implants may be placed subconjunctivally or intravitreally in
an eye. Devices for ocular implantation are also known, such as
those described in U.S. Pat. No. 6,899,717; U.S. Pat. No.
7,090,681; US 2005 0203542 and US 2005 0154399. Each of these
publications is hereby incorporated by reference.
[0013] Various treatments are known for the treatment of retinal
diseases, including macular edema from diabetic retinopathy, venous
occlusive disease and uveitis, such as treatment with
corticosteroid implants. Unfortunately, known implants have been
placed in the vitreous to treat an ocular condition in a somewhat
haphazard manner. Thus, if an implant is inserted into the anterior
vitreous (i.e. in proximity to the cilliary body and trabecular
meshwork) elevated intraocular pressure and a high incidence of
cataract can result. For example, drug (therapeutic agent) exposure
to the anterior segment can lead to myocilin accumulation in the
trabecular meshwork cells, leading to undesired elevation in
intraocular pressure (IOP). On the other hand, placing the implant
in the posterior vitreous can deliver an excess of the therapeutic
agent contained by the implant to the target retinal tissues.
[0014] A recent study has shown that invitreal treatment with
Kenalog.RTM. (4 mg triamcinalone) can result in about 15 to 30% of
the patients at 6 months having IOP of .gtoreq.10 mm Hg.
Additionally, treatment with intravitreal Retisert.TM. (about 120
or 80 .mu.g of fluocinolone) released over 8 months or longer can
result in 59% of patients having IOP increase of .gtoreq.10 mm HG.
Furthermore, treatment with intravitreal POSURDEX.RTM. (700 .mu.g
dexamethasone released over about 1 to 2 months) can result in
about 15% of patients having an IOP increase of .gtoreq.10 mm Hg.
(see Jaffe et al, Ophthalmology, 2006; 113:1020-1027).
Determination of an optimal intraviteal implant placement location
and/or the amount of therapeutic agent to load in the implant may
permit reduction or elimination of these undesirable side effects
subsequent to intravitreal administration of a drug delivery
system.
[0015] What is needed therefore is a method for determining the
optimal location for an intraocular implant which can deliver a
therapeutically effective amount of an active agent to the desired
tissue (e.g. retinal tissue) over a sustained period without
causing undesirable side effects or with reduced side effects.
DRAWINGS
[0016] FIGS. 1 and 2 are schematic representations of the human
eye.
[0017] FIGS. 3-4 present results from the predicted drug
concentration analysis according to the invention.
[0018] FIGS. 5-7 are graphical representation of the data presented
in FIGS. 3-4.
[0019] FIGS. 8-9 are representations of implant positions of
current ocular implants.
[0020] FIG. 10 shows an implant position according to the present
invention.
SUMMARY
[0021] The present invention meets this need by providing a method
for determining the optimum location for placement of an
intraocular implant containing a therapeutic agent used to treat an
ocular condition, particularly implants comprised of a
biodegradable polymer and a therapeutic agent for the treatment of
a condition of retinal tissue.
DETAILED DESCRIPTION OF THE INVENTION
[0022] Definitions
[0023] As used herein, the words or terms set forth below have the
meanings shown.
[0024] "About" means that the item, parameter or term so qualified
encompasses a range of plus or minus ten percent above and below
the value of the stated item, parameter or term.
[0025] "Administration", or "to administer" means the step of
giving (i.e. administering) a pharmaceutical composition to a
subject. The pharmaceutical compositions disclosed herein can be
"locally administered", that is administered at or in the vicinity
of the site at which a therapeutic result or outcome is desired.
For example to treat an ocular condition (such as for example
glaucoma, a macular edema, uveitis or macular degeneration)
intravitreal injection or implantation of a sustained release
device such as active agent containing polymeric implant can be
carried out. "Sustained release" means release of an active agent
(such as a vasoactive agent) over a period of at least about five
to seven days and for as long as several years.
[0026] "Associated with" means mixed with, dispersed within,
coupled to, covering, or surrounding.
[0027] "Biodegradable polymer" means a polymer or polymers which
degrade in vivo, and wherein erosion of the polymer or polymers
over time occurs concurrent with or subsequent to release of the
therapeutic agent. Specifically, hydrogels such as methylcellulose
which act to release drug through polymer swelling are specifically
excluded from the term "biodegradable polymer". The terms
"biodegradable" and "bioerodible" are equivalent and are used
interchangeably herein. A biodegradable polymer may be a
homopolymer, a copolymer, or a polymer comprising more than two
different polymeric units.
[0028] "Entirely free (i.e. "consisting of" terminology) means that
within the detection range of the instrument or process being used,
the substance cannot be detected or its presence cannot be
confirmed.
[0029] "Essentially free" (or "consisting essentially of") means
that only trace amounts of the substance can be detected.
[0030] "Intraocular implant" means a device or element that is
structured, sized, or otherwise configured to be placed in an eye.
Intraocular implants are generally biocompatible with physiological
conditions of an eye and do not cause unacceptable adverse side
effects. Intraocular implants can be placed in an eye without
disrupting vision of the eye.
[0031] "Pharmaceutical composition" (synonymously a composition) is
a formulation that contains at least one active ingredient as well
as, for example, one or more excipients, buffers, carriers,
stabilizers, preservatives and/or bulking agents, and is suitable
for administration to a patient to achieve a desired effect or
result. means a formulation in which an active ingredient (the
active agent) can be a vasoactive agent, such as a vasodilator.
[0032] "Substantially free" means present at a level of less than
one percent by weight of the pharmaceutical composition.
[0033] "Therapeutic component" means a portion of an intraocular
implant comprising one or more therapeutic agents or substances
used to treat a medical condition of the eye. The therapeutic
component may be a discrete region of an intraocular implant, or it
may be homogenously distributed throughout the implant. The
therapeutic agents of the therapeutic component are typically
ophthalmically acceptable, and are provided in a form that does not
cause adverse reactions when the implant is placed in an eye.
[0034] "Therapeutically effective amount" means the level or amount
of agent needed to treat an ocular condition, or reduce or prevent
ocular injury or damage without causing significant negative or
adverse side effects to the eye or a region of the eye.
[0035] "Treat", "treating", or "treatment" means reduction or
resolution or prevention of an ocular condition, ocular injury or
damage, or to promote healing of injured or damaged ocular
tissue.
Drug Delivery Systems Useful with the Invention
[0036] The present invention provides a method for determining the
optimal location in the eye for implantation/placement of a drug
delivery system, for extended or sustained drug release into the
eye tissue to best achieve one or more desired therapeutic effects,
while avoiding or decreasing undesirable side effects, such as an
increased IOP. Additionally, the present invention also provides a
method for determining the optimal amount of a therapeutic agent to
load into a drug delivery device (such an an implant) intended for
intravitreal administration at a particular intravitreal location
in order to effectively treat an ocular condition (such as a
retinal disease or condition) with little or no side effects. The
drug delivery systems are in the form of implants or implant
elements that may be placed in an eye and can be of various types,
including known implants for the treatment of ocular
conditions.
[0037] Intraocular drug delivery systems useful with the method of
the invention can comprise a therapeutic component (i.e. a
therapeutic agent or drug) and a drug release sustaining component
(i.e. a polymeric carrier) associated with the therapeutic
component. In accordance with the present invention, the
therapeutic component comprises, consists essentially of, or
consists of, a therapeutic agent useful for treating an ocular
condition, such as macular edema. The drug release sustaining
component is associated with the therapeutic component to sustain
release of an amount of the therapeutic agent into an eye in which
the implant is placed. The amount of the therapeutic agent is
released into the eye for a period of time greater than about one
week after the implant is placed in the eye and is effective in
reducing or treating an ocular condition (such as glaucoma, or
macular edema) to improve or maintain vision of an eye of a
patient.
[0038] The drug release sustaining component (which is associated
with the therapeutic component) can be a polymer such as a
biodegradable polymer or polymer matrix For example, the matrix may
comprise a polymer selected from the group consisting of
polylactides, poly (lactide-co-glycolides), polycaprolactones, and
combinations thereof.
[0039] The biodegradable polymer of the implant can be for example
a polylactides (PLA), polyglycolide (PGA), poly(lactide
co-glycolide (PLGA), polycaprolactone, polyanhydride, poly methyl
vinyl ether maleic anhydride, polycarbonates, polyarylates,
polydioxanone, polyhydroxyalkanoates, and chitosan.
[0040] The drug delivery system can be an implant, microsphere,
capsule, tablet, fiber, rod, filament, disc and the like. A drug
delivery system, such as an implant, can be structured to be placed
in the vitreous of the eye, the implant of can be formed as a rod,
a wafer, or a particle and the implant can be made by an extrusion
process.
[0041] The implant can be placed in the posterior of the eye, for
example using a trocar or a 25-30 gauge syringe. Alternately, the
implant can be intravitreally administered using one or more of the
applicators shown in related U.S. patents and published U.S. Pat.
Nos. 6,899,717; 7,090,681; 2005 0203542, and; 2005 01543399. The
applicator can comprise a needle with a canula which contains the
implant.
[0042] Finally, the present invention also encompasses a method to
preventing vision loss by intraocular placement of an intraocular
implant comprising a therapeutic agent and a carrier.
[0043] In one embodiment of the present invention, an intraocular
implant comprises a biodegradable polymer matrix. The biodegradable
polymer matrix is one type of a drug release sustaining component.
The biodegradable polymer matrix is effective in forming a
biodegradable intraocular implant. The biodegradable intraocular
implant comprises a therapeutic agent associated with the
biodegradable polymer matrix. The matrix degrades at a rate
effective to sustain release of an amount of the therapeutic agent
for a time greater than about one week from the time in which the
implant is placed in ocular region or ocular site, such as the
vitreous of an eye.
[0044] The therapeutic agent can be a corticosteriod, an
aminoglycoside or an anti-VEGF antibody such as set forth in
published U.S. patent application 2006 0182783, publish Aug. 17,
2006.
[0045] Useful implants can also include salts of the disclosed
therapeutic agents. Pharmaceutically acceptable acid addition salts
of the compounds of the invention are those formed from acids which
form non-toxic addition salts containing pharmaceutically
acceptable anions, such as the hydrochloride, hydrobromide,
hydroiodide, sulfate, or bisulfate, phosphate or acid phosphate,
acetate, maleate, fumarate, oxalate, lactate, tartrate, citrate,
gluconate, saccharate and p-toluene sulphonate salts.
[0046] The therapeutic agent may be in a particulate or powder form
and entrapped by the biodegradable polymer matrix. Usually,
therapeutic agent particles in intraocular implants will have an
effective average size less than about 3000 nanometers. In certain
implants, the particles may have an effective average particle size
about an order of magnitude smaller than 3000 nanometers. For
example, the particles may have an effective average particle size
of less than about 500 nanometers. In additional implants, the
particles may have an effective average particle size of less than
about 400 nanometers, and in still further embodiments, a size less
than about 200 nanometers.
[0047] The therapeutic agent of the implant is preferably from
about 10% to 90% by weight of the implant. More preferably, the
therapeutic agent is from about 20% to about 80% by weight of the
implant. In a preferred embodiment, the therapeutic agent comprises
about 40% by weight of the implant (e.g., 30%-50%). In another
embodiment, the therapeutic agent comprises about 60% by weight of
the implant.
[0048] Suitable polymeric materials or compositions for use in the
implant include those materials which are compatible, that is
biocompatible, with the eye so as to cause no substantial
interference with the functioning or physiology of the eye. Such
materials preferably are at least partially and more preferably
substantially completely biodegradable or bioerodible.
[0049] Examples of useful polymeric materials include, without
limitation, such materials derived from and/or including organic
esters and organic ethers, which when degraded result in
physiologically acceptable degradation products, including the
monomers. Also, polymeric materials derived from and/or including,
anhydrides, amides, orthoesters and the like, by themselves or in
combination with other monomers, may also find use. The polymeric
materials may be addition or condensation polymers, advantageously
condensation polymers. The polymeric materials may be cross-linked
or non-cross-linked, for example not more than lightly
cross-linked, such as less than about 5%, or less than about 1% of
the polymeric material being cross-linked. For the most part,
besides carbon and hydrogen, the polymers will include at least one
of oxygen and nitrogen, advantageously oxygen. The oxygen may be
present as oxy, e.g. hydroxy or ether, carbonyl, e.g.
non-oxo-carbonyl, such as carboxylic acid ester, and the like. The
nitrogen may be present as amide, cyano and amino. The polymers set
forth in Heller, Biodegradable Polymers in Controlled Drug
Delivery, In: CRC Critical Reviews in Therapeutic Drug Carrier
Systems, Vol. 1, CRC Press, Boca Raton, Fla. 1987, pp 39-90, which
describes encapsulation for controlled drug delivery, can find use
in the present implants.
[0050] Of additional interest are polymers of hydroxyaliphatic
carboxylic acids, either homopolymers or copolymers, and
polysaccharides. Polyesters of interest include polymers of
D-lactic acid, L-lactic acid, racemic lactic acid, glycolic acid,
polycaprolactone, and combinations thereof. Generally, by employing
the L-lactate or D-lactate, a slowly eroding polymer or polymeric
material is achieved, while erosion is substantially enhanced with
the lactate racemate.
[0051] Among the useful polysaccharides are, without limitation,
calcium alginate, and functionalized celluloses, particularly
carboxymethylcellulose esters characterized by being water
insoluble, a molecular weight of about 5 kD to 500 kD, for
example.
[0052] Other polymers of interest include, without limitation,
polyesters, polyethers and combinations thereof which are
biocompatible and may be biodegradable and/or bioerodible.
[0053] Some preferred characteristics of the polymers or polymeric
materials for use in the present invention may include
biocompatibility, compatibility with the therapeutic component,
ease of use of the polymer in making the drug delivery systems of
the present invention, a half-life in the physiological environment
of at least about 6 hours, preferably greater than about one day,
not significantly increasing the viscosity of the vitreous, and
water insolubility.
[0054] The biodegradable polymeric materials which are included to
form the matrix are desirably subject to enzymatic or hydrolytic
instability. Water soluble polymers may be cross-linked with
hydrolytic or biodegradable unstable cross-links to provide useful
water insoluble polymers. The degree of stability can be varied
widely, depending upon the choice of monomer, whether a homopolymer
or copolymer is employed, employing mixtures of polymers, and
whether the polymer includes terminal acid groups.
[0055] Equally important to controlling the biodegradation of the
polymer and hence the extended release profile of the implant is
the relative average molecular weight of the polymeric composition
employed in the implant. Different molecular weights of the same or
different polymeric compositions may be included in the implant to
modulate the release profile. In certain implants, the relative
average molecular weight of the polymer will range from about 9 to
about 64 kD, usually from about 10 to about 54 kD, and more usually
from about 12 to about 45 kD.
[0056] In some implants, copolymers of glycolic acid and lactic
acid are used, where the rate of biodegradation is controlled by
the ratio of glycolic acid to lactic acid. The most rapidly
degraded copolymer has roughly equal amounts of glycolic acid and
lactic acid. Homopolymers, or copolymers having ratios other than
equal, are more resistant to degradation. The ratio of glycolic
acid to lactic acid will also affect the brittleness of the
implant, where a more flexible implant is desirable for larger
geometries. The % of polylactic acid in the polylactic acid
polyglycolic acid (PLGA) copolymer can be 0-100%, preferably about
15-85%, more preferably about 35-65%. In some implants, a 50/50
PLGA copolymer is used.
[0057] The biodegradable polymer matrix of the intraocular implant
may comprise a mixture of two or more biodegradable polymers. For
example, the implant may comprise a mixture of a first
biodegradable polymer and a different second biodegradable polymer.
One or more of the biodegradable polymers may have terminal acid
groups.
[0058] Release of a drug from an erodible polymer is the
consequence of several mechanisms or combinations of mechanisms.
Some of these mechanisms include desorption from the implants
surface, dissolution, diffusion through porous channels of the
hydrated polymer and erosion. Erosion can be bulk or surface or a
combination of both. As discussed herein, the matrix of the
intraocular implant may release drug at a rate effective to sustain
release of an amount of the therapeutic agent for more than one
week after implantation into an eye. In certain implants,
therapeutic amounts of the therapeutic agent are released for more
than about one month, and even for about six months or more.
[0059] The release of the therapeutic agent from the intraocular
implant comprising a biodegradable polymer matrix may include an
initial burst of release followed by a gradual increase in the
amount of the therapeutic agent released, or the release may
include an initial delay in release of the therapeutic agent
followed by an increase in release. When the implant is
substantially completely degraded, the percent of the therapeutic
agent that has been released is about one hundred. Compared to
existing implants, the implants disclosed herein do not completely
release, or release about 100% of the therapeutic agent, until
after about one week of being placed in an eye.
[0060] It may be desirable to provide a relatively constant rate of
release of the therapeutic agent from the implant over the life of
the implant. For example, it may be desirable for the therapeutic
agent to be released in amounts from about 0.01 .mu.g to about 2
.mu.g per day for the life of the implant. However, the release
rate may change to either increase or decrease depending on the
formulation of the biodegradable polymer matrix. In addition, the
release profile of the therapeutic agent may include one or more
linear portions and/or one or more non-linear portions. Preferably,
the release rate is greater than zero once the implant has begun to
degrade or erode.
[0061] The implants may be monolithic, i.e. having the active agent
or agents homogenously distributed through the polymeric matrix, or
encapsulated, where a reservoir of active agent is encapsulated by
the polymeric matrix. Due to ease of manufacture, monolithic
implants are usually preferred over encapsulated forms. However,
the greater control afforded by the encapsulated, reservoir-type
implant may be of benefit in some circumstances, where the
therapeutic level of the drug falls within a narrow window. In
addition, the therapeutic component, including the therapeutic
agent(s) described herein, may be distributed in a non-homogenous
pattern in the matrix. For example, the implant may include a
portion that has a greater concentration of the therapeutic agent
relative to a second portion of the implant.
[0062] The intraocular implants disclosed herein may have a
diameter size of between about 0.4 mm and about 12 mm, or between
about 0.4 mmm and about 10 mm for administration with a needle
applicator. The vitreous chamber in humans is able to accommodate
relatively large implants of varying geometries, having lengths of,
for example, 1 to 10 mm. The implant may be a cylindrical pellet
(e. g., rod) with dimensions of about 2 mm.times.0.75 mm diameter.
Or the implant may be a cylindrical pellet with a length of about 7
mm to about 10 mm, and a diameter of about 0.75 mm to about 1.5
mm.
[0063] The implants may also be at least somewhat flexible so as to
facilitate both insertion of the implant in the eye, such as in the
vitreous, and accommodation of the implant. The total weight of the
implant is usually about 250-5000 .mu.g, more preferably about
500-1000 .mu.g. For example, an implant may be about 500 .mu.g, or
about 1000 .mu.g. For non-human individuals, the dimensions and
total weight of the implant(s) may be larger or smaller, depending
on the type of individual. For example, humans have a vitreous
volume of approximately 3.8 ml, compared with approximately 30 ml
for horses, and approximately 60-100 ml for elephants. An implant
sized for use in a human may be scaled up or down accordingly for
other animals, for example, about 8 times larger for an implant for
a horse, or about, for example, 26 times larger for an implant for
an elephant.
[0064] Thus, implants can be prepared where the center may be of
one material and the surface may have one or more layers of the
same or a different composition, where the layers may be
cross-linked, or of a different molecular weight, different density
or porosity, or the like. For example, where it is desirable to
quickly release an initial bolus of drug, the center may be a
polylactate coated with a polylactate-polyglycolate copolymer, so
as to enhance the rate of initial degradation. Alternatively, the
center may be polyvinyl alcohol coated with polylactate, so that
upon degradation of the polylactate exterior the center would
dissolve and be rapidly washed out of the eye.
[0065] The implants may be of any geometry including fibers,
sheets, films, microspheres, spheres, circular discs, plaques and
the like. The upper limit for the implant size will be determined
by factors such as toleration for the implant, size limitations on
insertion, ease of handling, etc. Where sheets or films are
employed, the sheets or films will be in the range of at least
about 0.5 mm.times.0.5 mm, usually about 3-10 mm.times.5-10 mm with
a thickness of about 0.1-1.0 mm for ease of handling. Where fibers
are employed, the fiber diameter will generally be in the range of
about 0.05 to 3 mm and the fiber length will generally be in the
range of about 0.5-10 mm. Spheres may be in the range of about 0.5
.mu.m to 4 mm in diameter, with comparable volumes for other shaped
particles.
[0066] The size and form of the implant can also be used to control
the rate of release, period of treatment, and drug concentration at
the site of implantation. Larger implants will deliver a
proportionately larger dose, but depending on the surface to mass
ratio, may have a slower release rate. The particular size and
geometry of the implant are chosen to suit the site of
implantation.
[0067] The proportions of therapeutic agent, polymer, and any other
modifiers may be empirically determined by formulating several
implants with varying proportions. A USP approved method for
dissolution or release test can be used to measure the rate of
release (USP 23; NF 18 (1995) pp. 1790-1798). For example, using
the infinite sink method, a weighed sample of the implant is added
to a measured volume of a solution containing 0.9% NaCl in water,
where the solution volume will be such that the drug concentration
is after release is less than 5% of saturation. The mixture is
maintained at 37.degree. C. and stirred slowly to maintain the
implants in suspension. The appearance of the dissolved drug as a
function of time may be followed by various methods known in the
art, such as spectrophotometrically, HPLC, mass spectroscopy, etc.
until the absorbance becomes constant or until greater than 90% of
the drug has been released.
[0068] In addition to the therapeutic agent included in the
intraocular implants disclosed hereinabove, the intraocular
implants may also include one or more additional ophthalmically
acceptable therapeutic agents. For example, the implant may include
one or more antihistamines, one or more different antibiotics, one
or more beta blockers, one or more steroids, one or more
antineoplastic agents, one or more immunosuppressive agents, one or
more antiviral agents, one or more antioxidant agents, and mixtures
thereof.
[0069] Pharmacologic or therapeutic agents which may find use in
the present systems, include, without limitation, those disclosed
in U.S. Pat. No. 4,474,451, columns 4-6 and U.S. Pat. No.
4,327,725, columns 7-8.
[0070] The amount of active agent or agents employed in the
implant, individually or in combination, will vary widely depending
on the effective dosage required and the desired rate of release
from the implant. As indicated herein, the agent will be at least
about 1, more usually at least about 10 weight percent of the
implant, and usually not more than about 80, more usually not more
than about 40 weight percent of the implant.
[0071] In addition to the therapeutic component, the intraocular
implants disclosed herein may include effective amounts of
buffering agents, preservatives and the like.
[0072] Suitable water soluble buffering agents include, without
limitation, alkali and alkaline earth carbonates, phosphates,
bicarbonates, citrates, borates, acetates, succinates and the like,
such as sodium phosphate, citrate, borate, acetate, bicarbonate,
carbonate and the like. These agents advantageously present in
amounts sufficient to maintain a pH of the system of between about
2 to about 9 and more preferably about 4 to about 8. As such the
buffering agent may be as much as about 5% by weight of the total
implant. Suitable water soluble preservatives include sodium
bisulfite, sodium bisulfate, sodium thiosulfate, ascorbate,
benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric
acetate, phenylmercuric borate, phenylmercuric nitrate, parabens,
methylparaben, polyvinyl alcohol, benzyl alcohol, phenylethanol and
the like and mixtures thereof. These agents may be present in
amounts of from 0.001 to about 5% by weight and preferably 0.01 to
about 2% by weight.
[0073] In addition, the implants may include a solubility enhancing
component provided in an amount effective to enhance the solubility
of the therapeutic agent relative to substantially identical
implants without the solubility enhancing component. For example,
an implant may include a .beta.-cyclodextrin, which is effective in
enhancing the solubility of the therapeutic agent. The
.beta.-cyclodextrin may be provided in an amount from about 0.5%
(w/w) to about 25% (w/w) of the implant. In certain implants, the
.beta.-cyclodextrin is provided in an amount from about 5% (w/w) to
about 15% (w/w) of the implant
[0074] In some situations mixtures of implants may be utilized
employing the same or different pharmacological agents. In this
way, a cocktail of release profiles, giving a biphasic or triphasic
release with a single administration is achieved, where the pattern
of release may be greatly varied.
[0075] Additionally, release modulators such as those described in
U.S. Pat. No. 5,869,079 may be included in the implants. The amount
of release modulator employed will be dependent on the desired
release profile, the activity of the modulator, and on the release
profile of the therapeutic agent in the absence of modulator.
Electrolytes such as sodium chloride and potassium chloride may
also be included in the implant. Where the buffering agent or
enhancer is hydrophilic, it may also act as a release accelerator.
Hydrophilic additives act to increase the release rates through
faster dissolution of the material surrounding the drug particles,
which increases the surface area of the drug exposed, thereby
increasing the rate of drug bioerosion. Similarly, a hydrophobic
buffering agent or enhancer dissolve more slowly, slowing the
exposure of drug particles, and thereby slowing the rate of drug
bioerosion.
[0076] Various techniques may be employed to produce the implants
described herein. Useful techniques include, but are not
necessarily limited to, solvent evaporation methods, phase
separation methods, interfacial methods, molding methods, injection
molding methods, extrusion methods, co-extrusion methods, carver
press method, die cutting methods, heat compression, combinations
thereof and the like.
[0077] Specific methods are discussed in U.S. Pat. No. 4,997,652.
Extrusion methods may be used to avoid the need for solvents in
manufacturing. When using extrusion methods, the polymer and drug
are chosen so as to be stable at the temperatures required for
manufacturing, usually at least about 85 degrees Celsius. Extrusion
methods use temperatures of about 25 degrees C. to about 150
degrees C., more preferably about 65 degrees C. to about 130
degrees C. An implant may be produced by bringing the temperature
to about 60 degrees C. to about 150 degrees C. for drug/polymer
mixing, such as about 130 degrees C., for a time period of about 0
to 1 hour, 0 to 30 minutes, or 5-15 minutes. For example, a time
period may be about 10 minutes, preferably about 0 to 5 min. The
implants are then extruded at a temperature of about 60 degrees C.
to about 130 degrees C., such as about 75 degrees C.
[0078] In addition, the implant may be coextruded so that a coating
is formed over a core region during the manufacture of the
implant.
[0079] Compression methods may be used to make the implants, and
typically yield implants with faster release rates than extrusion
methods. Compression methods may use pressures of about 50-150 psi,
more preferably about 70-80 psi, even more preferably about 76 psi,
and use temperatures of about 0 degrees C. to about 115 degrees C.,
more preferably about 25 degrees C.
[0080] The implants of the present invention may be inserted into
the eye, for example the vitreous chamber of the eye, by a variety
of methods, including placement by forceps or by trocar following
making a 2-3 mm incision in the sclera. One example of a device
that may be used to insert the implants into an eye is disclosed in
U.S. Patent Publication No. 2004/0054374. The method of placement
may influence the therapeutic component or drug release kinetics.
For example, delivering the implant with a trocar may result in
placement of the implant deeper within the vitreous than placement
by forceps, which may result in the implant being closer to the
edge of the vitreous. The location of the implant may influence the
concentration gradients of therapeutic component or drug
surrounding the element, and thus influence the release rates
(e.g., an element placed closer to the edge of the vitreous may
result in a slower release rate).
[0081] The implants used with the method of the invention may also
be configured to release additional therapeutic agents, as
described above. The implants can be used to treat a variety of
ocular conditions including:
[0082] Glaucoma, maculopathies/retinal degeneration: macular
degeneration, including age related macular degeneration (ARMD),
such as non-exudative age related macular degeneration and
exudative age related macular degeneration, choroidal
neovascularization, retinopathy, including diabetic retinopathy,
acute and chronic macular neuroretinopathy, central serous
chorioretinopathy, and macular edema, including cystoid macular
edema, and diabetic macular edema. Uveitis/retinitis/choroiditis:
acute multifocal placoid pigment epitheliopathy, Behcet's disease,
birdshot retinochoroidopathy, infectious (syphilis, lyme,
tuberculosis, toxoplasmosis), uveitis, including intermediate
uveitis (pars planitis) and anterior uveitis, multifocal
choroiditis, multiple evanescent white dot syndrome (MEWDS), ocular
sarcoidosis, posterior scleritis, serpignous choroiditis,
subretinal fibrosis, uveitis syndrome, and Vogt-Koyanagi-Harada
syndrome. Vascular diseases/exudative diseases: retinal arterial
occlusive disease, central retinal vein occlusion, disseminated
intravascular coagulopathy, branch retinal vein occlusion,
hypertensive fundus changes, ocular ischemic syndrome, retinal
arterial microaneurysms, Coat's disease, parafoveal telangiectasis,
hemi-retinal vein occlusion, papillophlebitis, central retinal
artery occlusion, branch retinal artery occlusion, carotid artery
disease (CAD), frosted branch angitis, sickle cell retinopathy and
other hemoglobinopathies, angioid streaks, familial exudative
vitreoretinopathy, Eales disease. Traumatic/surgical: sympathetic
ophthalmic, uveitic retinal disease, retinal detachment, trauma,
laser, PDT, photocoagulation, hypoperfusion during surgery,
radiation retinopathy, bone marrow transplant retinopathy.
Proliferative disorders: proliferative vitreal retinopathy and
epiretinal membranes, proliferative diabetic retinopathy.
Infectious disorders: ocular histoplasmosis, ocular toxocariasis,
presumed ocular histoplasmosis syndrome (PONS), endophthalmitis,
toxoplasmosis, retinal diseases associated with HIV infection,
choroidal disease associated with HIV infection, uveitic disease
associated with HIV Infection, viral retinitis, acute retinal
necrosis, progressive outer retinal necrosis, fungal retinal
diseases, ocular syphilis, ocular tuberculosis, diffuse unilateral
subacute neuroretinitis, and myiasis. Genetic disorders: retinitis
pigmentosa, systemic disorders with associated retinal dystrophies,
congenital stationary night blindness, cone dystrophies,
Stargardt's disease and fundus flavimaculatus, Bests disease,
pattern dystrophy of the retinal pigmented epithelium, X-linked
retinoschisis, Sorsby's fundus dystrophy, benign concentric
maculopathy, Bietti's crystalline dystrophy, pseudoxanthoma
elasticum. Retinal tears/holes: retinal detachment, macular hole,
giant retinal tear. Tumors: retinal disease associated with tumors,
congenital hypertrophy of the RPE, posterior uveal melanoma,
choroidal hemangioma, choroidal osteoma, choroidal metastasis,
combined hamartoma of the retina and retinal pigmented epithelium,
retinoblastoma, vasoproliferative tumors of the ocular fundus,
retinal astrocytoma, intraocular lymphoid tumors. Miscellaneous:
punctate inner choroidopathy, acute posterior multifocal placoid
pigment epitheliopathy, myopic retinal degeneration, acute retinal
pigment epithelitis and the like.
Method of Determining Optimal Location for Intraocular Drug
Delivery System
[0083] Intravitreal sustained-release implants are generally placed
in the anterior vitreous to treat macular diseases, such as
diabetic macular edema, and diffuse retinal diseases such as
retinitis pigmentosa. Periocular administration of medications in
the sub-Tenon's space or in the orbital floor is often performed
without specific regard to the location of the disease. The present
inventors sought to develop a method to optimize the location of
ocular implants to best treat ocular conditions. In particular, the
present inventors sought to determine how best to treat macular
edema with corticosteroid-releasing ocular implants, while limiting
IOP elevation, and have determined that the best method is to
maximize macular drug exposure and reduce or minimize the anterior
segment exposure of the corticosteroid (both the duration and the
dose).
[0084] Fick's Second Law of Diffusion was developed by Adolf Fick
in about 1855. It is a diffusion equation to explain the behavior
of non-steady state diffusion, i.e. diffusion that change with
time. Fick's Second Law is as follows:
.differential. C .differential. t = D .differential. 2 C
.differential. x 2 ##EQU00001##
[0085] Boundary Conditions:
C ( x , 0 ) = 0 ##EQU00002## C ( 0 , t ) = C 0 ##EQU00002.2## C (
.eta. ) = C 0 [ 1 - 2 .pi. .intg. 0 .eta. - s 2 s ] .ident. C 0 [ 1
- erf ( .eta. ) ] .ident. C 0 erfc ( .eta. ) ##EQU00002.3## .eta. =
x 2 ( Dt ) 1 / 2 ##EQU00002.4## C ( x , t ) = C 0 erfc [ x / ( 2 Dt
) ] ##EQU00002.5## [0086] C.sub.o=constant concentration in the
tissue adjacent to the source (implant) [0087] D=the coefficient
for solution diffusion through the tissue [0088] t=time [0089]
erfc=complementary error function [0090] x=distance between the
source and the measurement position. The inventors used a solution
to Fick's 2.sup.nd Law to understand, predict and analyze the
ocular distribution of drugs released from implants. According to
the invention, diffusion of drug can be predicted with the
following solution to Fick's Second Law:
[0090] C=C.sub.oerfc[x/(2 {square root over (Dt)})]
[0091] C.sub.o is the drug concentration in the tissue adjacent to
the source (implant),
[0092] D is the coefficient for solution diffusion through the
vitreous,
[0093] t is time,
[0094] erfc is the complementary error function,
[0095] x is the distance between the implant and the measurement
position (i.e. macula),
[0096] and C is the drug concentration at the measurement
position.
[0097] The inventors used the 2 boundary conditions to solve for
the solution C(x,t). The first boundary condition, C(x, 0)=0, means
that initially (time=0 seconds), there is no drug anywhere. The
other boundary condition, C(0, t)=C.sub.o, means that at any time
point, the concentration at the implant site is C.sub.o.
[0098] The present inventors have thereby understood that the drug
concentrations in the ocular tissues, such as the retina, closest
to an intravitreal implant would be highest, and more therapeutic,
compared with drug concentrations away from the implant. Therefore,
the ideal position for a diffusion-based vitreous implant to treat
macular diseases would be in the posterior half of the vitreous
cavity, preferably away from the visual axis. Using this approach,
a corticosteroid-eluting implant will result in higher drug
concentrations in the macula, and in addition, lower drug
concentrations will result in the anterior segment which will
reduce the risk of corticosteroid-induced ocular hypertension.
[0099] To treat diffuse retinal diseases, such as retinitis
pigmentosa, an implant located more centrally in the vitreous
cavity, slightly below fixation, will result in a more equal
distribution of drug throughout the retina. C can be influenced by
the drug concentrations immediately around the implant (C.sub.o)
and this is most affected by the implant release rate. In the case
of an implant placed in the posterior vitreous to treat macular
diseases, increase drug concentrations to the macula will be
expected by increasing the release rate of the implant. Preferred
implant release rates will depend on the potency of the drug but
generally range in the 0.1 to 15 microgram per day. The amount of
drug loading in the implant will influence the duration of release.
Implants weighing greater that 0.5 to 1 milligram may not stay
suspended well in the vitreous cavity to delivery drug to the
macula. Therefore, vitreous implants that require greater drugs
loads should be segmented such that they will not sink in the
vitreous cavity and lay on the inferior retinal surface. For
example, if the required drug load plus polymer combination in a
bioerodible implant system is 2 milligram in weight and 6
millimeter long, the implant should be injected into the vitreous
in a total of 3 segments, each weighing approximately 0.66
milligram and measuring 2 millimeter in length.
[0100] The charge of the drug released from the vitreous implant
can also influence the clearance pathway from the eye. For example,
cationic drugs, such as the aminoglycosides, are not well
eliminated across the retina and have a preferred elimination
anteriorly though the trabecular meshwork. In contrast, anionic
compounds, such as the fluoroquinilones, favor trans-retinal
elimination and anterior segment exposure is minimized. Therefore,
the drug charge can be manipulated to influence ocular drug
distribution. The molecular weight of the drug can also influence
the elimination from the eye. In general terms, drugs less than 40
KD can be delivered through the retina, 40 to 70 KD compounds are
intermediate between clearance interiorly vs. posteriorly, and
drugs between 70 and 155 KD are generally eliminated anteriorly. An
exception to the latter are drugs that are in high concentrations
at the retinal interface, that can overcome the barriers such as
the internal limiting membrane and the plexiform layers. Mueller
cell transport may also facilitate macromolecule transit through
the retina. Therefore, drugs, such as anti-VEGF monoclonal
antibodies with molecular weights approximately 150 KD, can be
transported to the subretinal space to treat choroidal
neovascularization after release from a vitreous implant assuming
the concentrations gradients are sufficient at the retinal
interface.
[0101] The relationship of molecular weight (MW) to diffusion is
discussed in Kim et al, Controlled Drug Release from an Ocular
Implant: An Evaluation Using Dynamic Three-Dimensional Magnetic
Resonance Imaging, Investigative Ophthalmology & Visual
Science, August 2004, Vol. 45, No. 8, wherein page 2728, discusses
the Peclet number (convection/diffusion ration), where high numbers
(with high MW compounds) mean transport by convection currents, low
numbers mean transport by diffusion, typical of low MW
compounds
[0102] Thus, in another aspect of the invention, compounds that are
high MW, such as Fabs and monoclonal antibodies, move with low
velocity in the vitreous and depend nearly solely on the convection
currents to be delivered to the retina. Once at the retinal
interface, there is some dependence on Muller cells to transport
the compounds to the posterior retina/subretinal space. Thus, a
location for a drug delivery system, especially those that are of
high MW, would be very close to the retina, in the case of
subfoveal choroidal neovascularization, the DDS should be in close
approximation to the macula. Thus, in accordance with the present
invention, implants can be appropriately positioned in the optimal
location of the eye to maximize efficacy and minimize potential
adverse effects; whereas, previous implants that must be maintained
at the pars plana will not be able to give you this improved
result.
[0103] The lipophilicity of a drug released from a vitreous
implant, such as those with Log P values over 2 to 3, favors
transretinal elimination, and there can also be significant
partitioning into the retina that may be of therapeutic value.
[0104] The movement of drugs to the retina released from implants
placed in the subconjunctival, intrascleral, or suprachoroidal
space cannot be simply explained by the above equation since there
are significant clearance mechanisms that ultimately reduce C.
Transscleral drug delivery is impacted by drug clearance occurring
through blood vessels (conjunctiva and choroid) and by the
conjunctival lymphatics. Counter directional convection flow of
fluids, such as those that occur with uveoscleral flow, and the
flow generated from the hydrostatic and osmotic pressure
differences between the vitreous cavity and choroid, can also have
an impact on the transscleral movement of drugs. Metabolic enzymes
and transporter proteins in the choroid and RPE can also impact the
transit of drugs in the region. Drugs with lower molecular weights,
preferably <1000 KD, higher log P, and neutral charge,
facilitate transscleral delivery to the retina. Since the venous
blood flow in the choroid is significantly higher than that of the
ciliary body, drugs released from implants in the subconjunctival,
intrascleral, or suprachoroidal space can enter into the ciliary
body region and anterior chamber with greater facility. This may be
an advantage when treating diseases such as glaucoma. The best
location of implants in the subconjunctival, intrascleral, or
suprachoroidal space will depend on the disease being treated.
Implants located more posteriorly will facilitate treating macular
diseases and implants positioned more anteriorly will facilitate
delivery of drug to the anterior segment. Since there are
significant clearance mechanisms that inhibit the transscleral
movement of drugs, a compensatory increase in the implant release
rate is required to effectively deliver drug to the retina,
generally in the range of 1 log unit higher than that of a vitreous
implant.
EXAMPLE
[0105] The following non-limiting Example is presented to exemplify
aspects of the present invention.
Example 1
[0106] Based on several known intraocular drug delivery systems,
the present inventors determined the concentrations of the
respective active therapeutic agents for different drug delivery
system positions, specifically the macula and anterior humour
concentrations. Those drug delivery systems comprised the
therapeutic agents dexamethasone and fluocinolone. These drug
delivery systems are utilized for the treatment of ocular
conditions, specifically macula edema, and are utilized by
implantation or insertion into a patient's eye. The present
inventors analyzed the concentration of the therapeutic agent that
would be found in selected eye tissue, namely the aqueous humour
(AH) and the retina in order to determine the optimal location for
such drug delivery systems to increase that concentration at the
site of the tissue to be treated (the retina), while minimizing the
concentration at other tissue (aqueous humour) so as to enhance
efficacy and reduce undesirable side effects, such as IOP.
[0107] Those results are presented in tabular form in FIGS. 3 and
4, wherein the location of the implant from the tissue is noted in
cm, specifically "x_AH [cm] D_AH" for the distance of the implant
from the aqueous humour and "x_mac [cm] D_retina" for the distance
of the implant from the macula. Concentration of the active
ingredients is also presented for each implant expected at 13 days,
3 months and 6 months post implant. The results are also plotted
with respect to the implant location and shown in FIGS. 5-7.
[0108] From these results, it is concluded that concentration of
the desired active ingredient is increased in the desired tissue
(e.g. the macula) as the implant in positioned closer to that
tissue.
[0109] From a practical view point, the inventors have concluded
that the known pars plana inserted corticosteroid eluting implants
are the most inefficient method of delivering drug to the macula In
fact, each millimeter that the implant is moved closer to the
macula, creates a higher macular concentration (and lower anterior
concentration which is good for avoiding IOP). In particular, at 13
days after implantation in the human eye, using a standard
applicator, concentration of the therapeutic agent (e.g.
dexamethasone) concentration of the agent can be 2.5 .mu.g/g at the
macula, and 0.0215 in the aqueous. Using a 1/2 inch needle, and
placing the implant 4 mm deeper into the vitreous, macula
concentration is increased 12 fold to 30.5 .mu.g/g at the macula
and aqueous levels are reduced to undetectable. As such, an implant
located at the pars plana is not the ideal place for a
corticosteroid implant, since it maximizes aqueous exposure and
minimizes macular drug exposure. Accordingly, corticosteroid
implants located posterior to the equator increase drug
concentration to the macula 12 fold and decrease the aqueous humor
concentrations to undetectable, as compared to placement anterior
to the equator.
[0110] The differences in implantation position can also be seen in
FIGS. 8-10, wherein FIGS. 8 and 9 show the current standard
implantation locations for two available products Retisert and
Posurdex, respectively. FIG. 10 shows the more optimal position for
a Posurdex implant according to the present invention wherein the
implant is positioned closer to the macula to provide increase
concentration of the active ingredient to the macula and
nondetectable amounts of the active ingredient in the aqueous
humour.
[0111] All references, articles, publications and patents and
patent applications cited herein are incorporated by reference in
their entireties.
* * * * *