U.S. patent application number 11/180752 was filed with the patent office on 2006-01-12 for ophthalmic compositions and methods for treating ophthalmic conditions.
This patent application is currently assigned to ALLERGAN, INC.. Invention is credited to Scott M. Whitcup.
Application Number | 20060009498 11/180752 |
Document ID | / |
Family ID | 35519924 |
Filed Date | 2006-01-12 |
United States Patent
Application |
20060009498 |
Kind Code |
A1 |
Whitcup; Scott M. |
January 12, 2006 |
Ophthalmic compositions and methods for treating ophthalmic
conditions
Abstract
Compositions, and methods of using such compositions, useful for
placement, for example injection, into the interior of human or
animal eyes are provided. Such compositions include a therapeutic
component, such as one or more corticosteroids, a biocompatible
polymeric component, and a solvent component. The composition is in
a fluid form before placement in the interior of an eye, and
becomes less fluid after the composition is placed in the eye to
form an extended or delayed release drug delivery element or
system. The drug delivery element is formed by the dissipation of
the solvent from the composition when the composition is placed in
the interior of an eye. One example of a composition includes
triamcinolone acetonide as a therapeutic agent. A method of
treating an ophthalmic condition, or otherwise improving or
enhancing vision of a patient, comprises placing the fluid
composition in the interior of the eye. The method may be practiced
by injecting the fluid composition into the interior of the
eye.
Inventors: |
Whitcup; Scott M.; (Laguna
Niguel, CA) |
Correspondence
Address: |
Stephen Donovan;Allergan, Inc.
2525 Dupont Drive
Irvine
CA
92612
US
|
Assignee: |
ALLERGAN, INC.
Irvine
CA
|
Family ID: |
35519924 |
Appl. No.: |
11/180752 |
Filed: |
July 11, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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60587092 |
Jul 12, 2004 |
|
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Current U.S.
Class: |
514/357 |
Current CPC
Class: |
A61P 33/02 20180101;
A61P 29/00 20180101; A61K 31/575 20130101; A61K 9/0051 20130101;
A61K 31/57 20130101; A61K 31/44 20130101; A61K 31/58 20130101; A61P
35/00 20180101; A61K 31/573 20130101; A61P 31/12 20180101; A61K
45/06 20130101; A61P 27/02 20180101; A61K 47/34 20130101; A61K
9/0048 20130101; A61K 9/0024 20130101; Y10S 514/912 20130101; A61K
47/38 20130101; A61K 31/56 20130101 |
Class at
Publication: |
514/357 |
International
Class: |
A61K 31/44 20060101
A61K031/44 |
Claims
1. An ophthalmic composition useful for intraocular placement in an
eye of a human or animal comprising: a corticosteroid component
present in a therapeutically effective amount; a biocompatible
polymeric component in an amount effective to delay release of the
corticosteroid component into the interior of the eye after the
composition is intraocularly placed in the eye; and an
ophthalmically compatible solvent component in an amount effective
to solubilize the polymeric component, the composition being
effective, after being intraocularly placed into the interior of
the eye, to form a delayed release composition effective to delay
the release of the corticosteriod component in the eye relative to
intraocular placement of a substantially identical composition
without the polymeric component.
2. The composition of claim 1 wherein the solvent component is
effective to dissipate after the composition is placed into the
eye.
3. The composition of claim 1 wherein the corticosteroid component
is soluble in the composition.
4. The composition of claim 1 wherein the corticosteroid component
is insoluble in the composition.
5. The composition of claim 1 wherein the corticosteroid component
is selected from the group consisting of alclometasone
dipropionate, amcinonide, amcinafel, amcinafide, beclamethasone,
betamethasone, betamethasone dipropionate, betamethasone valerate,
clobetasone propionate, chloroprednisone, clocortelone, cortisol,
cortisone, cortodoxone, difluorosone diacetate, descinolone,
desonide, defluprednate, dihydroxycortisone, desoximetasone,
dexamethasone, deflazacort, diflorasone, diflorasone diacetate,
dichlorisone, esters of betamethasone, fluazacort, flucetonide,
flucloronide, fludrotisone, fluorocortisone, flumethasone,
flunisolide, fluocinonide, fluocinolone, fluocinolone acetonide,
flucortolone, fluperolone, fluprednisolone, fluroandrenolone
acetonide, fluocinolone acetonide, flurandrenolide,
fluorametholone, fluticasone propionate, hydrocortisone,
hydrocortisone butyrate, hydrocortisone valerate, hydrocortamate,
loteprendol, medrysone, meprednisone, methylprednisone,
methylprednisolone, mometasone furoate, paramethasone,
paramethasone acetate, prednisone, prednisolone, prednidone,
triamcinolone acetonide, triamcinolone hexacatonide, and
triamcinolone, salts thereof, derivatives thereof, and mixtures
thereof.
6. The composition of claim 1 wherein the corticosteroid component
is triamcinolone acetonide.
7. The composition of claim 1 wherein the polymeric component is
effective, after the composition is placed in the eye, to be
included in a solid or gelatinous polymer matrix.
8. The composition of claim 7 wherein the polymer matrix is
microporous.
9. The composition of claim 7 wherein the polymer matrix is
biocompatible.
10. The composition of claim 1 wherein the polymeric component
comprises a water coagulable polymer material.
11. The composition of claim 10 wherein the polymer material is a
thermoplastic polymer material.
12. The composition of claim 1 wherein the polymeric component is
selected from the group consisting of polylactides, polyglycolides,
polycaprolactones, polyanhydrides, polyamides, polyurethanes,
polyesteramides, polyorthoesters, polydioxanones, polyacetals,
polyketals, polycarbonates, polyorthoesters, polyphosphazenes,
polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates,
polyalkylene succinates, poly(malic acid), poly(amino acids),
poly(methyl vinyl ether), poly(maleic anhydride), chitin, chitosan,
copolymers thereof, combinations thereof and mixtures thereof.
13. The composition of claim 1 wherein the polymeric component is
selected from the group consisting of poly lactic acid, poly
glycolic acid, poly lactic acid/glycolic acid and mixtures
thereof.
14. The composition of claim 1 wherein the solvent component is
non-aqueous.
15. The composition of claim 1 wherein the solvent component is
water-miscible.
16. The composition of claim 1 wherein the solvent component is
organic.
17. The composition of claim 1 wherein the solvent is liquid.
18. The composition of claim 1 wherein the solvent component is
selected from the group consisting of dimethyl sulfoxide,
methyl-2-pyrrolidone, 2-pyrrolidone, C.sub.2 to C.sub.6 alkanols,
propylene glycol, acetone, alkyl esters such as methyl acetate,
ethyl acetate, ethyl lactate, alkyl ketones such as methyl ethyl
ketone, dialkylamides such as dimethylformamide, dimethyl
sulfoxide, dimethyl sulfone, tetrahydrofuran, cyclic alkyl amides
such as caprolactam, decylmethylsulfoxide, oleic acid, propylene
carbonate, aromatic amides such as N,N-diethyl-m-toluamide,
1-dodecylazacycloheptan-2-one, and the like. Preferred solvents
according to the invention include N-methyl-2-pyrrolidone,
2-pyrrolidone, dimethyl sulfoxide, ethyllactate, propylene
carbonate and mixtures thereof.
19. The composition of claim 18 wherein the solvent component
comprises dimethyl sulfoxide.
20. The composition of claim 1 which includes no preservative
component.
21. The composition of claim 1 which includes a preservative
component.
22. A method of treating a condition of an eye of a human or animal
comprising intraocularly placing the composition of claim 1 into
the interior of the eye of the human or animal.
23. A method of treating a condition of an eye of a human or animal
comprising intraocularly placing the composition of claim 2 into
the interior of the eye of the human or animal.
24. A method of treating a condition of an eye of a human or animal
comprising intraocularly placing the composition of claim 5 into
the interior of the eye of the human or animal.
25. A method of treating a condition of an eye of a human or animal
comprising intraocularly placing the composition of claim 6 into
the interior of the eye of the human or animal.
26. A method of treating a condition of an eye of a human or animal
comprising intraocularly placing the composition of claim 7 into
the interior of the eye of the human or animal.
27. A method of treating a condition of an eye of a human or animal
comprising intraocularly placing the composition of claim 10 into
the interior of the eye of the human or animal.
28. A method of treating a condition of an eye of a human or animal
comprising intraocularly placing the composition of claim 11 into
the interior of the eye of the human or animal.
29. A method of treating a condition of an eye of a human or animal
comprising intraocularly placing the composition of claim 13 into
the interior of the eye of the human or animal.
30. A method of treating a condition of an eye of a human or animal
comprising intraocularly placing the composition of claim 14 into
the interior of the eye of the human or animal.
31. A method of treating a condition of an eye of a human or animal
comprising intraocularly placing the composition of claim 18 into
the interior of the eye of the human or animal.
32. A method of treating a condition of an eye of a human or animal
comprising intraocularly placing the composition of claim 19 into
the interior of the eye of the human or animal.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims the benefit of U.S.
Application No. 60/587,092, filed Jul. 12, 2004, the content of
which in its entirety is hereby incorporated by reference.
BACKGROUND
[0002] The present invention relates to ophthalmic compositions
that are delivered to the interior of an eye of a human or animal.
More particularly, the invention relates to ophthalmically
acceptable compositions including one or more therapeutic agents.
Such compositions are advantageously intraocularly placed into the
interior of an eye and form solid or semi-solid drug delivery
elements in situ that are effective in providing extended or
delayed release of the therapeutic agent or agents into the
eye.
[0003] Steroids, for example corticosteroids, among other agents,
are utilized to treat a wide variety of ophthalmic diseases that
affect the posterior segment of an eye. Examples of some diseases
treated with corticosteroids include: central retinal vein
occlusion (CRVO), branch retinal vein occlusion (BRVO), choroidal
macular edema (CME), diabetic macular edema (DME), diabetic macular
retinopathy, uveitis, telangitis, and age related macular
degeneration (ARMD) as well as other diseases or conditions of the
eye, for example of the posterior segment of the eye.
[0004] In treating ocular diseases or disorders, steroids can be
administered systemically. However, systemic administration of
steroids is often associated with side effects that are often too
substantial for ophthalmic use. Thus, topical, suprachoroidal,
subconjunctival, retrobulbar, and intravitreal administration have
also been studied. These administration techniques typically employ
aqueous compositions containing a steroid.
[0005] The desired site of action for therapeutic agents
administered to the posterior segment of an eye generally, and
corticosteroids in particular, is the retinal pigmented epithelium
(RPE). The RPE is a single cell layer responsible for maintenance
of the blood-retinal barrier as well as subretinal fluid volume and
composition. The cells of the RPE comprise the outer blood retinal
barrier and are joined by zonulae occludente tight junctions. As
such, permeation of compounds into the RPE is quite limited. Thus,
regardless of the administration route, penetration of a
therapeutic agent through the outer blood-retinal barrier is
limited. To overcome these limitations extremely high and
potentially toxic doses of drugs are frequently used.
[0006] In certain situations, drugs are administered by controlled
or sustained release technologies to attempt to increase their
duration of action or reduce the toxicity of transient high general
concentrations.
[0007] Some poorly soluble therapeutic agents, such as
corticosteroids, however, are well tolerated locally and have a
prolonged duration of action by virtue of their own intrinsic
dissolution rates. For example, triamcinolone acetonide has been
successfully administered by direct intravitreal injection in an
aqueous composition due to its slow dissolution rate and
tolerability. Unfortunately, side effects from the existing
triamcinolone acetonide formulation often include endophthalmitis
as well as retinal toxicity from the benzyl alcohol preservative.
Glaucoma and cataract are also observed.
[0008] Reducing the lens concentration of a corticosteroid may help
mitigate the cataractogenic potential of these drugs. Additionally,
reducing the anterior segment concentration of the corticosteroids
relative to the posterior concentrations may reduce the chance of
elevating the TIGR (MYOC, GLC1A) gene activity in the trabecular
meshwork thought to be associated with steroid induced
glaucoma.
[0009] Some extended release compositions containing therapeutic
agents have been described. For example, U.S. Pat. No. 5,077,049
discloses a biodegradable system for regenerating the periodontium.
U.S. Pat. No. 5,324,519 discloses a biodegradable polymer
composition. U.S. Pat. Nos. 5,487,897 and 6,395,293 disclose a
biodegradable implant precursor. U.S. Pat. No. 5,702,716 discloses
polymeric compositions useful as controlled release implants. U.S.
Pat. No. 5,717,030 discloses an adjunctive polymer system for use
with medical device. U.S. Pat. No. 5,780,044 discloses liquid
delivery compositions. U.S. Pat. No. 6,143,314 discloses controlled
release liquid delivery compositions with low initial drug burst.
U.S. Pat. No. 6,261,583 discloses a moldable solid delivery system.
U.S. Pat. No. 6,461,631 discloses a biodegradable polymer
composition. U.S. Pat. No. 6,565,874 discloses polymeric delivery
formulations of leuprolide with improved efficacy.
[0010] Thus, there is a need for new ophthalmic compositions for
injection into the interior of eyes of humans or animals and
methods for providing desired therapeutic effects of ophthalmic
conditions of eyes of humans or animals.
SUMMARY OF THE INVENTION
[0011] New compositions and methods for treating ophthalmic
conditions of eyes of humans or animals are provided. The present
compositions are highly suitable for intraocular administration
into the interior of an eye and provide therapeutic effects to the
eye, which may be effective in stabilizing, enhancing or improving
a patient's vision.
[0012] In one broad embodiment, an ophthalmic composition comprises
a therapeutic component, a biocompatible polymeric component, and a
solvent component. The solvent component is effective in
maintaining the polymeric component in a fluid state. For example,
the composition may be a liquid. The liquid may be a suspension or
a solution, that is, the therapeutic component may be provided as
particles in suspension, or the therapeutic component may be
solubilized in a solution. The fluid composition when placed in the
interior of an eye becomes less fluid and forms a solid or
semi-solid drug delivery element, which is effective in releasing
the therapeutic component for extended periods of time. The
composition may be used in a method to enhance or improve vision of
a patient by treating one or more ophthalmic conditions.
[0013] In one embodiment, a composition useful for intraocular
placement in an eye of a human or animal comprises a corticosteroid
component present in a therapeutically effective amount; a
biocompatible polymeric component in an amount effective to delay
release of the corticosteroid component into the interior of the
eye after the composition is placed in the eye; and an
ophthalmically compatible solvent component in an amount effective
to solubilize the polymeric component.
[0014] The composition is effective, after being placed into the
interior of the eye, to form a delayed release composition, such as
a drug delivery element, effective to delay or extend the release
of the corticosteriod component in the eye relative to intraocular
placement of a substantially identical composition without the
polymeric component.
[0015] Methods of treating patients are also disclosed and are
included within the scope of the present invention. In general,
such methods comprise placing or administering, e.g. injecting a
liquid therapeutic agent-containing composition, for example, a
composition in accordance with the present intention, into the
interior of an eye of a human or animal. Such administering is
effective in providing a desired therapeutic effect. The
administering step advantageously comprises at least one of
intravitreal injecting, subconjunctival injecting, sub-tenon
injecting, retrobulbar injecting, suprachoroidal injecting and the
like. The liquid composition forms a solid or semi-solid drug
delivery element when the liquid composition is placed in the eye.
The administration of the composition into the eye typically occurs
without placing the composition in the cul-de-sac of the eye.
[0016] Each and every feature described herein, and each and every
combination of two or more of such features, is included within the
scope of the present invention provided that the features included
in such a combination are not mutually inconsistent. In addition,
any feature or combination of features may be specifically excluded
from any embodiment of the present invention.
[0017] These and other aspects and advantages of the present
invention are apparent in the following detailed description,
examples and claims.
DETAILED DESCRIPTION
[0018] The present invention involves compositions, such as
ophthalmic compositions, that provide therapy to a patient. In
accordance with the disclosure herein, compositions are disclosed
that are useful for placement, preferably by injection, into the
interior of an eye of a human or animal, and preferably a living
human or animal. Such compositions are preferably administered into
an eye of a patient in a fluid form, such as a liquid. By
administering the compositions as a fluid, the administration may
occur without forming an incision in the eye. The liquid
composition becomes less fluid when placed in the eye, thereby
forming an extended release drug delivery element. For example, the
composition becomes a solid, a semi-solid, or a moldable
drug-releasing element when placed in the eye. The element is
effective in providing prolonged delivery of a therapeutic agent or
agents to the eye, for example, to a posterior segment of the eye,
or an anterior segment of the eye. The element is biodegraded
and/or bioeroded as the implant element is releasing the
therapeutic agent or agents. The components of the element are
absorbed by the patient's body thereby reducing, and preferably
eliminating, the need to surgically remove the element after the
therapeutic agent or agents have been released.
[0019] In general, the present compositions comprise a therapeutic
component, a biocompatible polymeric component, and an
ophthalmically compatible solvent component. The composition is
effective, after being placed into the interior of an eye of a
patient, to form a delayed release composition, such as a drug
delivery element, effective in delaying the release of the
therapeutic component in the eye. The delay of release is relative
to intraocular placement of a substantially identical composition
without the polymeric component.
[0020] As used herein, a "therapeutic component" refers to a
portion of the ophthalmic composition or a portion of the drug
delivery element that is formed in the eye of a patient, which
comprises one or more therapeutic agents or substances used to
treat a medical ophthalmic disease or condition of the eye and/or
to otherwise beneficially affect a patient's vision. The
therapeutic component may be provided in a discrete region of drug
delivery element, or it may be homogenously distributed throughout
the drug delivery element. 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 composition is placed in an eye.
[0021] In one embodiment of the present compositions, the
therapeutic component may comprise one or more anti-inflammatory
agents. For example, the therapeutic component of the composition
may comprise at least one steroidal anti-inflammatory agent, at
least one non-steroidal anti-inflammatory agent, or combinations
thereof. The anti-inflammatory agent may be soluble in the
ophthalmic composition or it may be insoluble in the ophthalmic
composition.
[0022] Examples of poorly soluble therapeutic agents include
ophthalmically acceptable therapeutic agents that have a limited
solubility in a fluid, such as water, for example, at 25.degree. C.
or at 37.degree. C. For example, the therapeutic agent may have a
solubility in water at 25.degree. C. or at 37.degree. C. of less
than 10 mg/ml.
[0023] Examples of steroidal anti-inflammatory agents include
corticosteroids. In view of the above, the ophthalmic compositions
may comprise a corticosteroid component. For example, the
corticosteroid component may comprise one or more corticosteroids.
The corticosteroid component is provided in a therapeutically
effective amount, such as an amount which is effective in providing
a therapeutic effect when the corticosteroid component is released
from the drug delivery element in the eye. The corticosteroid
component may be soluble or insoluble in the composition. The
corticosteroid component may include without limitation, one or
more corticosteroids selected from the group consisting of
alclometasone dipropionate, amcinonide, amcinafel, amcinafide,
beclamethasone, betamethasone, betamethasone dipropionate,
betamethasone valerate, clobetasone propionate, chloroprednisone,
clocortelone, cortisol, cortisone, cortodoxone, difluorosone
diacetate, descinolone, desonide, defluprednate,
dihydroxycortisone, desoximetasone, dexamethasone, deflazacort,
diflorasone, diflorasone diacetate, dichlorisone, esters of
betamethasone, fluazacort, flucetonide, flucloronide, fludrotisone,
fluorocortisone, flumethasone, flunisolide, fluocinonide,
fluocinolone, fluocinolone acetonide, flucortolone, fluperolone,
fluprednisolone, fluroandrenolone acetonide, fluocinolone
acetonide, flurandrenolide, fluorametholone, fluticasone
propionate, hydrocortisone, hydrocortisone butyrate, hydrocortisone
valerate, hydrocortamate, loteprendol, medrysone, meprednisone,
methylprednisone, methylprednisolone, mometasone furoate,
paramethasone, paramethasone acetate, prednisone, prednisolone,
prednidone, triamcinolone acetonide, triamcinolone hexacatonide,
and triamcinolone, salts thereof, derivatives thereof, and mixtures
thereof.. In one embodiment of the present ophthalmic composition,
the corticosteroid component comprises, consists essentially of, or
consists only of triamcinolone acetonide.
[0024] As used herein, the term "derivative" refers to any
substance which is sufficiently structurally similar to the
material which it is identified as a derivative so as to have
substantially similar functionality or activity, for example,
therapeutic effectiveness, as the material when the substance is
used in place of the material. The functionality of any derivative
disclosed herein may be determined using conventional routine
methods well known to persons of ordinary skill in the art.
[0025] Other steroids which may be useful in the present
compositions include, without limitation, glucocorticoids,
androgenic steroids, estrogenic steroids, and non-estrogenic
steroids.
[0026] In certain embodiments, the composition comprises a
therapeutically effective amount of the therapeutic agent or agents
before the composition is administered to an eye. In other
embodiments, the composition may comprise a sub-therapeutically
effective amount of the therapeutic agent before it is administered
to the eye. The dissipation of the solvent when the composition is
placed in the interior of the eye may be effective to form a drug
delivery element comprising a relatively more concentrated amount
of the therapeutic agent or agents. Thus, the drug delivery element
that is formed in the interior of the eye may have a
therapeutically effective amount of a therapeutic agent or agents
although the initial composition had a sub-therapeutically
effective amount of the agent or agents.
[0027] The therapeutic component of the compositions may be present
in an amount in the range of about 1% or less to about 5% or about
10% or about 20% or about 25% or about 30% or more (w/v) of the
composition. In accordance with the disclosure herein, reduced
amounts of the composition may be required to be placed or injected
into the interior of the eye in order to provide the same amount or
more of the therapeutic agent in the interior of the eye relative
to existing compositions, such as Kenalog.RTM.-40.
[0028] As used herein, a "biocompatible polymeric component" refers
to a portion of the ophthalmic composition or drug delivery element
which comprises one or more biocompatible polymers, such as
polymers that do not cause an adverse reaction when placed in an
eye, that is, the polymers should have substantially no significant
or undue detrimental effect of the eye structures or tissues. The
biocompatible polymer or polymers may be cross-linked together, or
may be associated with each other in a matrix or network of
polymers.
[0029] The biocompatible polymeric component is provided in an
amount in the composition that is effective in delaying release of
the therapeutic component into the interior of the eye after the
composition is placed in the eye. When the therapeutic component is
a corticosteroid component, the biocompatible polymeric component
is effective in delaying the release of the corticosteroid
component into the interior of the eye after the composition is
placed in the eye.
[0030] The biocompatible polymeric component of the ophthalmic
composition may be effective, after the composition is placed in
the eye, to be included in a solid or gelatinous polymer matrix. In
certain embodiments, the polymer matrix may be porous, for example,
microporous.
[0031] The biocompatible polymeric component may comprise a water
coagulable polymeric material. For example, the polymeric component
may comprise one or more thermoplastic polymers or thermosetting,
as disclosed in U.S. Pat. Nos. 5,077,049; 5,324,519; 5,487,897;
6,395,293; 5,702,716; 5,717,030; 5,780,044; 6,143,314; 6,261,583;
6,461,631; and 6,565,874. The polymers may comprise thermoplastic
or thermosetting polymers. Thermoplastic polymers comprises a
biodegradable polymer or copolymer dissolved in a solvent, such as
pharmaceutically acceptable solvents and organic solvents.
[0032] In certain compositions, the polymeric component is selected
from the group consisting of polylactides, polyglycolides,
polycaprolactones, polyanhydrides, polyamides, polyurethanes,
polyesteramides, polyorthoesters, polydioxanones, polyacetals,
polyketals, polycarbonates, polyorthoesters, polyphosphazenes,
polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates,
polyalkylene succinates, poly(malic acid), poly(amino acids),
poly(methyl vinyl ether), poly(maleic anhydride), chitin, chitosan,
and copolymers, terpolymers, derivatives thereof and mixtures
thereof.
[0033] For example, the biocompatible polymeric component of the
present compositions may be selected from the group consisting of
poly lactic acid, poly glycolic acid, poly lactic acid/glycolic
acid (PLGA) and copolymers and mixtures thereof.
[0034] The polymers of the biocompatible polymeric component may be
crosslinked or blended or used as copolymers in this invention.
[0035] As used herein, an "ophthalmically compatible solvent
component" refers to a portion of the composition which comprises
one or more solvents, including organic solvents which, when placed
into the interior of the eye, has no substantial or undue or
significant deterimental effect on the eye. Of course, such
solventshould function in accordance with the present invention, as
disclosed elsewhere herein.
[0036] The ophthalmically compatible solvent component of the
present compositions is provided in an amount effective to
solubilize the polymeric component, for example, before the
composition is placed in the interior of an eye. Thus, the solvent
component is effective in maintaining the therapeutic component,
such as the corticosteroid component, and the polymeric component
in a fluid form, such as a liquid. The solvent is preferably
non-toxic and water miscible and enables the biodegradable polymer
or copolymer to be provided in solution before placement in an
eye.
[0037] In certain embodiments of the present compositions, the
solvent component is effective in dissipating or passively or
actively being removed from the composition after the composition
is placed into the interior of the eye. For example, the solvent
component is effective in dissipating from the liquid composition
when the composition is placed in the interior of the eye. The
dissipation is effective in permitting the composition to form a
less fluid drug releasing composition, such as a solid, or
semi-solid drug delivery implant. The drug delivery implant may be
formed by a coagulation or other solidification process.
[0038] The solvent component of the present ophthalmic compositions
may be non-aqueous. Alternatively or in addition, the solvent
component may be water-miscible. In certain compositions, the
solvent component may be organic. The solvent component may also be
a liquid in the ophthalmic compositions.
[0039] The solvent component of the present compositions may be
selected from the group consisting of dimethyl sulfoxide,
methyl-2-pyrrolidone, 2-pyrrolidone, C.sub.2 to C.sub.6 alkanols,
propylene glycol, acetone, alkyl esters such as methyl acetate,
ethyl acetate, ethyl lactate, alkyl ketones such as methyl ethyl
ketone, dialkylamides such as dimethylformamide, dimethyl
sulfoxide, dimethyl sulfone, tetrahydrofuran, cyclic alkyl amides
such as caprolactam, decylmethylsulfoxide, oleic acid, propylene
carbonate, aromatic amides such as N,N-diethyl-m-toluamide,
1-dodecylazacycloheptan-2-one, and the like. Preferred solvents
according to the invention include N-methyl-2-pyrrolidone,
2-pyrrolidone, dimethyl sulfoxide, ethyllactate, propylene
carbonate and mixtures thereof.
[0040] In certain of the present ophthalmic compositions, the
solvent component comprises dimethyl sulfoxide.
[0041] The present ophthalmic compositions may also be provided
with or without a preservative component. Or, stated differently,
the present compositions may include a preservative component, or
may include no preservative component. Such preservative components
are preferably more compatible with or friendly to the tissues in
the interior of the eye into which the composition is placed than
benzyl alcohol. Examples of such preservative components include,
without limitation, benzalkonium, chloride, methyl and ethyl
parabens, hexetidine, chlorite components, such as stabilized
chlorine dioxide, metal chlorites and the like, other
ophthalmically acceptable preservatives and the like and mixtures
thereof. The concentration of the preservative component, if any,
in the present compositions is a concentration effective to
preserve the composition, and is often in a range of about 0.00001%
to about 0.05% or about 0.1% (w/v) of the composition.
[0042] The present compositions may also comprise one or more
pore-forming agents. The pore-forming agents are effective in
forming pores in the composition as the composition becomes less
fluid or solidifies. Pores may be formed in the drug delivery
element by incorporating water-soluble materials into the polymer
solution. Examples of pore-forming agents include sugars, salts,
and polymers, such as polymers that are not soluble in the
biodegradable polymeric component or its carrier solvent. For
example, the pore-forming agents may include one or more of
sucrose, dextrose, sodium chloride, sodium carbonate,
hydroxypropylcellulose, carboxymethylcellulose, polyethylene
glycol, and polyvinylpyrollidone. The pores may have a diameter
from about 3 .mu.m to about 500 .mu.m. For example, the pores may
have a diameter from about 10 .mu.m to about 250 .mu.m. In certain
drug delivery implants, the pores have a diameter from about 75
.mu.m to about 150 .mu.m.
[0043] The therapeutic component may also act as a pore forming
agent for the drug delivery element. For example, dissolution of
the therapeutic component from the solid or semi-solid drug
delivery element may be effective in forming pores in the drug
delivery element.
[0044] The present intraocular drug delivery implants which are
formed in the interior of the eye are effective in releasing the
therapeutic component for a prolonged period of time. For example,
the therapeutic component may be released for at least about one
week. In certain embodiments, the therapeutic component may be
released for at least six months, such as for nine months or more.
Typically, a major portion of the therapeutic component will be
released within about three years from when the ophthalmic fluid
composition is placed into the interior of the eye. Thus, the
present compositions may be effective in providing a prolonged
therapeutic effect to one or more intraocular structures of a
patient. For example, the intraocular drug delivery elements that
are formed in situ may provide a prolonged therapeutic effect to
the retinal pigment epithelium, or other posterior ocular
structure, of an eye.
[0045] The present compositions may also include one or more
controlled release components, such as one or more agents were are
effective in controlling the release rate of the therapeutic
component from the drug delivery element. Thus, it is possible to
provide pulsatile or continuous or substantially constant release
profiles of the therapeutic component into the interior of the eye.
In addition, the release profile may be controlled by the rate at
which pores are formed in the drug delivery element. For example, a
relatively higher rate of pore formation may result in a more rapid
rate of release of the therapeutic component due to enhanced
diffusion effects and the like.
[0046] Advantageously, it has been found that in certain
situations, the drug delivery element that is formed in the
interior of the eye is formed before the polymeric component of the
fluid composition adheres to a surface or structure of the eye. For
example, the liquid ophthalmic composition may form a drug delivery
element in the interior of the eye without contacting or being
dispensed onto a substrate, such as an ocular substrate. For
example, the liquid composition may form an implant when the
composition is injected into a cavity located in the eye, such as
the posterior chamber or the anterior chamber of the eye.
[0047] In other situations, the drug delivery element may be formed
upon contacting an intraocular substrate, such as a posterior
intraocular substrate, of the eye. This substrate-induced formation
of the drug delivery element may be effective in providing enhanced
localized delivery of the therapeutic component to the eye of the
patient.
[0048] In one embodiment, an ophthalmic composition suitable for
forming an in situ solid implant in an animal comprises a liquid
formulation of a biodegradable, bioerodible, biocompatible
thermoplastic polymer that is insoluble in aqueous or body fluid,
and a biocompatible organic solvent that is miscible or dispersible
in aqueous or body fluid and dissolves the thermoplastic polymer.
The composition is capable of coagulating or solidifying or
hardening to form a solid or gelatinous microporous matrix upon its
contact with aqueous or body fluid. The matrix may be a core
surrounded by a an outer layer, the core containing pores of
diameters from about 1 to about 1000 microns, and the outer layer
containing pores of smaller diameters than those of the core
pores.
[0049] The fluid ophthalmic compositions may be manufactured by
adding one or more therapeutic agents to the polymer solution to
form a homogenous solution, or a suspension, or a dispersion of the
agent. The polymer solution is formed by combining the
biocompatible polymeric component with the solvent component. The
components are mixed, blended, or otherwise processed using
conventional techniques. The composition may be stored for long
term use in sterile conditions, such as in sterile packages. The
preparation processing should be chosen to provide the present
compositions in forms which are useful for placement or injection
into the interior of eyes of humans or animals. The ingredients may
be mixed to disperse the therapeutic component and then may be
autoclaved to sterilize the composition.
[0050] The present ophthalmic compositions may comprise other
therapeutic agents instead of or in addition to the
anti-inflammatory agents disclosed herein. For example, therapeutic
agents may include without limitation retinoids, prostaglandins,
tyrosine kinase inhibitors, adrenoreceptor agonists or antagonists,
dopaminergic agonists, cholinergic agonists, carbonic anhydrase
inhibitors, guanylate cyclase activators, cannabinoids, endothelin,
adenosine agonists, antianagiogenic compounds, angiostatic
compounds, neuroprotectants, and the like and mixtures thereof. The
therapeutic component may also include, analgesics, or
antipyretics; antihistamines, antibiotics, beta blockers,
anti-neoplastic agents, immunosupressive agents, antiviral agents,
antioxidants and the like and mixtures thereof.
[0051] Non-limiting examples of non-steroidal anti-inflammants,
analgesics, and antipyretics, include aspirin, acetaminophen,
ibuprofen, naproxen, diclofenac, etodolac, fenoprofen,
indomethacin, ketoprofen, oxaprozin, piroxicam, sulindac,
diflunisal, mefenamic acid, derivatives thereof, and the like and
mixtures thereof.
[0052] Examples of antihistamines include, and are not limited to,
loradatine, hydroxyzine, diphenhydramine, chlorpheniramine,
brompheniramine, cyproheptadine, terfenadine, clemastine,
triprolidine, carbinoxamine, diphenylpyraline, phenindamine,
azatadine, tripelennamine, dexchlorpheniramine, dexbrompheniramine,
methdilazine, and trimprazine doxylamine, pheniramine, pyrilamine,
chiorcyclizine, thonzylamine, derivatives thereof, and the like and
mixtures thereof.
[0053] Examples of antibiotics include without limitation,
cefazolin, cephradine, cefaclor, cephapirin, ceftizoxime,
cefoperazone, cefotetan, cefutoxime, cefotaxime, cefadroxil,
ceftazidime, cephalexin, cephalothin,, cefamandole, cefoxitin,
cefonicid, ceforanide, ceftriaxone, cefadroxil, cephradine,
cefuroxime, ampicillin, amoxicillin, cyclacillin, ampicillin,
penicillin G, penicillin V potassium, piperacillin, oxacillin,
bacampicillin, cloxacillin, ticarcillin, azlocillin, carbenicillin,
methicillin, nafcillin, erythromycin, tetracycline, doxycycline,
minocycline, aztreonam, chloramphenicol, ciprofloxacin
hydrochloride, clindamycin, metronidazole, gentamicin, lincomycin,
tobramycin, vancomycin, polymyxin B sulfate, colistimethate,
colistin, azithromycin, augmentin, sulfamethoxazole, trimethoprim,
derivatives thereof, and the like and mixtures thereof.
[0054] Examples of beta blockers include without limitation
acebutolol, atenolol, labetalol, metoprolol, propranolol,
derivatives thereof, and the like and mixtures thereof.
[0055] Examples of antineoplastic agents include without limitation
adriamycin, cyclophosphamide, actinomycin, bleomycin, duanorubicin,
doxorubicin, epirubicin, mitomycin, methotrexate, fluorouracil,
carboplatin, carmustine (BCNU), methyl-CCNU, cisplatin, etoposide,
interferons, camptothecin and derivatives thereof, phenesterine,
taxol and derivatives thereof, taxotere and derivatives thereof,
vinblastine, vincristine, tamoxifen, etoposide, piposulfan,
cyclophosphamide, and flutamide, derivatives thereof, and the like
and mixtures thereof.
[0056] Examples of immunosuppressive agents include without
limitation cyclosporine, azathioprine, tacrolimus, derivatives
thereof, and the like and mixtures thereof.
[0057] Examples of antiviral agents include without limitation
interferon gamma, zidovudine, amantadine hydrochloride, ribavirin,
acyclovir, valciclovir, dideoxycytidine, derivatives thereof, and
the like and mixtures thereof.
[0058] Examples of antioxidant agents include without limitation
ascorbate, alpha-tocopherol, mannitol, reduced glutathione, various
carotenoids, cysteine, uric acid, taurine, tyrosine, superoxide
dismutase, lutein, zeaxanthin, cryotpxanthin, astazanthin,
lycopene, N-acetyl-cysteine, carnosine, gamma-glutamylcysteine,
quercitin, lactoferrin, dihydrolipoic acid, citrate, Ginkgo Biloba
extract, tea catechins, bilberry extract, vitamins E or esters of
vitamin E, retinyl palmitate, derivatives thereof, and the like and
mixtures thereof.
[0059] Other therapeutic agents include without limitation
squalamine, carbonic anhydrase inhibitors, alpha agonists,
prostamides, prostaglandins, antiparasitics, antifungals,
derivatives thereof, and the like and mixtures thereof. Further
examples include aminosterols other than squalamine that have
antiangiogenic activity. Another therapeutic agent may be
anecortave acetate, or similar agents or compounds which have
antiangiogenic properties without substantial undesirable
effects.
[0060] The therapeutic agent of the present compositions may
include any and all salts, and prodrugs or precursors of the
therapeutic agents, including those specifically identified
herein.
[0061] The present compositions may be, and are preferably,
sterile, for example, prior to being used in the eye.
[0062] Such a composition may be marketed in pre-filled syringes to
facilitate administration of the composition into the interior of
the eye of a patient.
[0063] The present compositions may be administered to a patient to
provide a treatment to a patient. For example, the composition may
be administered to a human or animal patient to treat an ocular
condition or disease.
[0064] Among the diseases/conditions which can be treated or
addressed in accordance with the present invention include, without
limitation, the following:
[0065] MACULOPATHIES/RETINAL DEGENERATION: Non-Exudative Age
Related Macular Degeneration (ARMD), Exudative Age Related Macular
Degeneration (ARMD), wet macular degeneration, Choroidal
Neovascularization, Diabetic Retinopathy, Acute Macular
Neuroretinopathy, Central Serous Chorioretinopathy, Cystoid Macular
Edema, Diabetic Macular Edema.
[0066] UVEITIS/RETINITIS/CHOROIDITIS: Acute Multifocal Placoid
Pigment Epitheliopathy, Behcet's Disease, Birdshot
Retinochoroidopathy, Infectious (Syphilis, Lyme, Tuberculosis,
Toxoplasmosis), Intermediate Uveitis (Pars Planitis), Multifocal
Choroiditis, Multiple Evanescent White Dot Syndrome (MEWDS), Ocular
Sarcoidosis, Posterior Scleritis, Serpignous Choroiditis,
Subretinal Fibrosis and Uveitis Syndrome, Vogt-Koyanagi-Harada
Syndrome.
[0067] 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.
[0068] TRAUMATIC/SURGICAL: Sympathetic Ophthalmia, Uveitic Retinal
Disease, Retinal Detachment, Trauma, Laser, PDT, Photocoagulation,
Hypoperfusion During Surgery, Radiation Retinopathy, Bone Marrow
Transplant Retinopathy.
[0069] PROLIFERATIVE DISORDERS: Proliferative Vitreal Retinopathy
and Epiretinal Membranes, Proliferative Diabetic Retinopathy.
[0070] INFECTIOUS DISORDERS: Ocular Histoplasmosis, Ocular
Toxocariasis, Presumed Ocular Histoplasmosis Syndrome (POHS),
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, Myiasis.
[0071] GENETIC DISORDERS: Retinitis Pigmentosa, Systemic Disorders
with Accosiated Retinal Dystrophies, Congenital Stationary Night
Blindness, Cone Dystrophies, Stargardt's Disease and Fundus
Flavimaculatus, Best's Disease, Pattern Dystrophy of the Retinal
Pigmented Epithelium, X-Linked Retinoschisis, Sorsby's Fundus
Dystrophy, Benign Concentric Maculopathy, Bietti's Crystalline
Dystrophy, pseudoxanthoma elasticum.
[0072] RETINAL TEARS/HOLES: Retinal Detachment, Macular Hole, Giant
Retinal Tear.
[0073] 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.
[0074] MISCELLANEOUS: Punctate Inner Choroidopathy, Acute Posterior
Multifocal Placoid Pigment Epitheliopathy, Myopic Retinal
Degeneration, Acute Retinal Pigment Epithelitis and the like.
[0075] The present compositions may be placed into the interior of
an eye using a syringe, a needle, a cannula, a catheter, a pressure
applicator, and the like.
[0076] In one embodiment, a composition, such as the compositions
disclosed herein, is administered to a posterior segment of an eye
of a human or animal patient, and preferably, a living human or
animal. In at least one embodiment, a composition is administered
without accessing the subretinal space of the eye. For example, a
method of treating a patient may include injecting the composition
directly into the posterior chamber of the eye. In other
embodiments, a method of treating a patient may comprise
administering a composition to the patient by at least one of
intravitreal injection, subconjuctival injection, sub-tenon
injections, retrobulbar injection, and suprachoroidal injection. In
certain situations, the method may comprise a step of applying an
anesthetic to the patient, such as to the eye of the patient,
before the composition is placed into the interior of the eye.
[0077] A syringe apparatus including an appropriately sized needle,
for example, a 27 gauge needle or a 30 gauge needle, can be
effectively used to inject the composition with the posterior
segment of an eye of a human or animal. The present methods may
comprise a single injection into the posterior segment of an eye or
may involve repeated injections, for example over periods of time
ranging from about one week or about 1 month or about 3 months to
about 6 months or about 1 year or longer.
[0078] The compositions of the present invention may be placed into
the eye, for example the vitreous chamber of the eye, by a variety
of methods, without making an incision in the eye. The method of
placement may influence the therapeutic component or drug release
kinetics. 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).
[0079] In one embodiment, a liquid ophthalmic composition, such as
the compositions disclosed herein, is administered to a posterior
segment of an eye of a human or animal patient, and preferably, a
living human or animal. In at least one embodiment, a composition
is administered without accessing the subretinal space of the eye.
For example, a method of treating a patient may include placing the
composition directly into the posterior chamber of the eye. In
other embodiments, a method of treating a patient may comprise
administering the present composition to the patient by at least
one of intravitreal injection, subconjuctival injection, sub-tenon
injections, retrobulbar injection, and suprachoroidal injection. In
certain situations, the compositions are administered to the
interior of the eye without placing the composition in the
cul-de-sac of the eye.
[0080] In another aspect of the present invention, the present
compositions are used in the manufacture of a medicament that is
effective to treat one or more ocular conditions, such as an ocular
condition affecting the posterior segment of an eye of a patient,
and including the conditions identified herein.
[0081] While this invention has been described with respect to
various specific examples and embodiments, it is to be understood
that the invention is not limited thereto and that it can be
variously practiced within the scope of the following claims.
[0082] A number of patents have been identified herein. Each of
these patents in its entirety is hereby incorporated by
reference.
* * * * *