U.S. patent application number 11/039192 was filed with the patent office on 2005-08-18 for compositions and methods for localized therapy of the eye.
This patent application is currently assigned to Allergan, Inc.. Invention is credited to Burke, James A., Hughes, Patrick M., Olejnik, Orest, Whitcup, Scott M..
Application Number | 20050181017 11/039192 |
Document ID | / |
Family ID | 34825933 |
Filed Date | 2005-08-18 |
United States Patent
Application |
20050181017 |
Kind Code |
A1 |
Hughes, Patrick M. ; et
al. |
August 18, 2005 |
Compositions and methods for localized therapy of the eye
Abstract
Compositions, and methods of using such compositions, useful for
injection into the posterior segments of human or animal eyes are
provided. Such compositions include small particles of a poorly
soluble therapeutic agent that facilitates formation of
concentrated regions of the therapeutic agent in the retinal
pigmented epithelium of an eye. The particles are formed by
combining a therapeutic agent with an ophthalmically acceptable
polymer component. The particles have sizes less than about 3000
nanometers, and in some cases, less than about 200 nanometers. One
example of a composition includes particles of triamcinolone
acetonide and hyaluronic acid have a size less than about 3000
nanometers.
Inventors: |
Hughes, Patrick M.; (Aliso
Viejo, CA) ; Olejnik, Orest; (Coto De Caza, CA)
; Whitcup, Scott M.; (Laguna Hills, CA) ; Burke,
James A.; (Santa Ana, CA) |
Correspondence
Address: |
STOUT, UXA, BUYAN & MULLINS LLP
4 VENTURE, SUITE 300
IRVINE
CA
92618
US
|
Assignee: |
Allergan, Inc.
Irvine
CA
|
Family ID: |
34825933 |
Appl. No.: |
11/039192 |
Filed: |
January 19, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60537620 |
Jan 20, 2004 |
|
|
|
Current U.S.
Class: |
424/427 |
Current CPC
Class: |
Y10S 514/912 20130101;
A61K 9/0048 20130101; A61K 31/00 20130101; A61P 27/02 20180101;
A61K 9/0051 20130101; A61K 9/10 20130101; A61K 47/36 20130101; A61P
5/42 20180101; A61K 9/14 20130101; A61P 29/00 20180101; A61K 38/13
20130101 |
Class at
Publication: |
424/427 |
International
Class: |
A61K 009/14 |
Claims
What is claimed is:
1. A pharmaceutical composition for placement in a posterior
segment of an eye of a living human or animal, the composition
comprising: a therapeutic component comprising a poorly soluble
therapeutic agent in the form of particles having a size effective
to form concentrated regions of the therapeutic agent in the
retinal pigmented epithelium (RPE) of the eye which are effective
to provide a desired therapeutic effect to the human or animal when
the composition is administered to a posterior segment of an eye of
a human or animal.
2. The composition of claim 1, wherein the particles have a size
effective to form concentrated regions having a concentration of
the therapeutic agent that is greater relative to the concentration
of the therapeutic agent in the composition when administered to
the eye.
3. The composition of claim 1, wherein the particles are sized to
be distributed in the eye to reduce toxicity associated with the
therapeutic agent in an anterior tissue of the eye.
4. The composition of claim 1, wherein the particles comprise the
therapeutic agent and a polymer suitable for administration to the
posterior segment of an eye.
5. The composition of claim 1, further comprising a polysaccharide
component positioned relative to the particles to stabilize the
particles.
6. The composition of claim 5, wherein the polymer is hyaluronic
acid.
7. The composition of claim 1, wherein the particles have an
average size effective to promote phagocytosis of the particles by
the RPE.
8. The composition of claim 1, wherein the particles have an
average size effective to promote pinocytosis by the RPE.
9. The composition of claim 1 wherein the therapeutic agent is
formed as particles having an effective average particle size less
than about 3000 nanometers.
10. The composition of claim 1 wherein the therapeutic agent is
formed as particles having an effective average particle size of
less than about 500 nanometers.
11. The composition of claim 1 wherein the therapeutic agent is
formed as particles having an effective average particle size of
less than about 400 nanometers.
12. The composition of claim 1 wherein the therapeutic agent is
formed as particles having an effective average particle size of
less than about 200 nanometers.
13. The composition of claim 1 wherein the therapeutic component
comprises a first population of particles having an effective
average particle size of less than about 200 nanometers, a second
population of particles having an effective average particle size
in a range of about 200 nanometers to less than 400 nanometers, and
a third population of particles having an effective average
particle size in a range of about 400 nanometers to less than about
3000 nanometers.
14. The composition of claim 1 wherein the therapeutic agent has a
solubility in water at 25.degree. C. of less than about 10
mg/ml.
15. The composition of claim 1 wherein the therapeutic agent
comprises a corticosteroid.
16. The composition of claim 1 which further comprises an effective
amount of a pharmaceutically acceptable vehicle component.
17. The composition of claim 16 wherein the vehicle component is
aqueous-based.
18. The composition of claim 16 wherein the therapeutic agent is
present in an amount of up to about 25% (w/v) of the
composition.
19. A pharmaceutical composition for placement in a posterior
segment of an eye of a living human or animal, the composition
comprising: a therapeutic component comprising a poorly soluble
steroid in the form of particles sized and distributed in the
composition to form concentrated regions of the steroid in the
retinal pigmented epithelium (RPE) of the eye which are effective
to provide a desired therapeutic effect to the human or animal when
the composition is administered to a posterior segment of an eye of
a human or animal.
20. The composition of claim 19 wherein the therapeutic component
comprises a corticosteroid.
21. The composition of claim 19, wherein the therapeutic component
comprises a first population of particles containing a poorly
soluble steroid, and a second population of particles containing
the poorly soluble steroid, the second population having an
effective average particle size that is different than the first
population.
22. The composition of claim 19, wherein the particles have a size
from about 200 nanometers to about 3000 nanometers.
23. The composition of claim 19, further comprising an
ophthalmically acceptable vehicle component.
24. An ophthalmically acceptable composition comprising a
population of particles including triamcinolone acetonide having an
effective average particle size less than about 3000
nanometers.
25. The composition of claim 24, wherein the population of
particles has an effective average particle size less than about
500 nanometers.
26. The composition of claim 24, wherein the population of
particles has an effective average particle size less than about
200 nanometers.
27. The composition of claim 24, comprising a first population of
particles including triamcinolone acetonide, and a second
population of particles including triamcinolone acetonide having an
effective average particle size that is different from an effective
average particle size of the first population.
28. The composition of claim 24, further comprising an
ophthalmically acceptable vehicle component.
29. The composition of claim 24, wherein the particles comprise a
combination of triamcinolone acetonide and an ophthalmically
acceptable polymer component.
30. The composition of claim 24, further comprising a polymer
component positioned relative to the particles to stabilize the
particles.
31. The composition of claim 30, wherein the polymer component is
hyaluronic acid.
32. The composition of claim 24, wherein the particles are sized to
be distributed in the eye to reduce toxicity associated with the
triamcinolone acetonide in an anterior tissue of the eye.
33. The composition of claim 24, wherein the particles are sized to
form one or more concentrated regions of triamcinolone acetonide in
the retinal pigment epithelium of an eye.
34. A population of particles comprising triamcinolone acetonide
having an effective average particle size less than about 3000
nanometers.
35. The particles of claim 34 provided in a liquid carrier
component.
36. The particles of claim 35 provided in a dispensing
apparatus.
37. The particles of claim 34, wherein the particles comprise a
combination of triamcinolone acetonide and hyaluronic acid.
38. The particles of claim 34, wherein the particles have a size
effective to facilitate transfer of the particles into the retinal
pigmented epithelium (RPE) when the particles are administered to
an eye.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application 60/537,620, filed Jan. 20, 2004, the entire content of
which is hereby incorporated by reference.
[0002] The present invention relates to compositions that are
delivered to the posterior segment of an eye of a human or animal.
More particularly, the invention relates to compositions including
one or more poorly soluble therapeutic agents present in particles
that are sized and/or distributed to provide localized therapy to
the posterior of an eye.
[0003] 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 includes: 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 of the posterior segment.
[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 generally
too great for ophthalmic use. Thus, topical, suprachoroidal,
subconjunctival, retrobulbar, and intravitreal administration have
also been studied.
[0005] Although direct intravitreal administration of current
therapeutic agents may address some problems associated with
systemic administration, intravitreal administration of existing
ophthalmic compositions may result in ocular hypertension, as well
as steroid glaucoma and posterior subcapsular cataracts, when
steroids are administered. For example, approximately 25% of
patients receiving intraocular corticosteroid therapy will
experience an elevation of intraocular pressure (IOP) with about
10% of the patients having an IOP as high as 28 to 30 mm Hg. The
IOP is thought to be due to increased outflow resistance resulting
from changes in the trabecular meshwork cells. The ocular
hypertension is particularly common in "steroid responders".
[0006] In addition, the formulation currently used in clinical
practice contains excipients that are toxic to the internal ocular
structures. For example, Kenalog.RTM., is a commercially available
formulation of triamcinolone acetonide containing such undesirable
excipients. Kenalog has been shown to cause ERG changes in rabbits
and its preservative, benzyl alcohol, has been implicated in such
changes.
[0007] 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.
[0008] 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.
[0009] 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 do to
its slow dissolution rate and tolerability. Unfortunately, side
effects from the existing triamcinolone acetonide formulation
include endophthalmitis as well as retinal toxicity from the benzyl
alcohol preservative. Glaucoma and cataract are also observed.
[0010] 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, GLClA) gene activity in the trabecular
meshwork thought to be associated with steroid induced
glaucoma.
[0011] Thus, there is a need for new compositions for injection
into the posterior segments of eyes of humans or animals and
methods for providing desired therapeutic effects in the posterior
segments of eyes of humans or animals.
SUMMARY OF THE INVENTION
[0012] New compositions and methods for treating posterior segments
of eyes of humans or animals have been discovered. The present
compositions are highly suitable for intravitreal administration
into the posterior segments of eyes and provide localized
therapeutic effects to the posterior portion of an eye and reduced
adverse side-effects to anterior structures or tissues of an
eye.
[0013] In one broad embodiment, the present compositions include a
therapeutic component that includes a therapeutic agent in the form
of or present in particles. The particles are sized to form one or
more concentrated regions of the therapeutic agent in the RPE of an
eye of a human or animal patient. The particles are sized to be
phagocytized or pinocytized by the cells of the RPE, thereby
circumventing the blood-retinal barrier to treat ocular diseases or
disorders. In certain embodiments, the therapeutic agent is a
steroid, such as a corticosteroid.
[0014] The particles may include a combination of a poorly soluble
therapeutic agent and an ophthalmically acceptable polymer
component. For example, a composition may include a triamcinolone
acetonide in combination with a particulate polymer, such as a
bead. In another embodiment, the therapeutic agent may be formed as
particles in a vehicle suspension or carrier. For example, and in
at least one embodiment, the particles comprise a combination of a
corticosteroid and a polysaccharide, such as hyaluronic acid. In
other words, the particles may include particles of a
corticosteroid that have been stabilized with hyaluronic acid. The
particles may have a size less than about 3000 nanometers, and in
certain embodiments, the particles may have a size less than about
200 nanometers.
[0015] In another embodiment, an ophthalmically acceptable
composition comprises a population of particles of triamcinolone
acetonide having an effective average particle size less than about
3000 nanometers. In one specific embodiment, the particles are
formed by subjecting or exposing the triamcinolone acetonide to
hyaluronic acid.
[0016] In an additional embodiment, a population of particles
including triamcinolone acetonide is provided. The population of
particles has an effective average particle size less than about
3000 nanometers. The particles may be provided in a liquid vehicle
or carrier component before administration to an eye. One example
of such a carrier component includes hyaluronic acid. The particles
and carrier component may also be provided in a dispensing
apparatus prior to administration to an eye.
[0017] Methods of treating patients are also disclosed and are
included within the scope of the present invention. In general,
such methods comprise administering, e.g. injecting a particulate
therapeutic agent-containing composition, for example, a
composition in accordance with the present intention, to a
posterior segment 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.
[0018] 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.
[0019] These and other aspects and advantages of the present
invention are apparent in the following detailed description,
examples and claims.
DETAILED DESCRIPTION
[0020] 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 a
posterior segment of an eye of a human or animal, and preferably a
living human or animal. Such compositions in the posterior, e.g.,
vitreous, of the eye are therapeutically effective against one or
more conditions and/or diseases of the posterior of the eye, and/or
one or more symptoms of such conditions and/or diseases of the
posterior of the eye, among other things.
[0021] In general, the present compositions comprise a therapeutic
component which comprises a poorly soluble therapeutic agent in the
form of or present in small particles. The particles typically have
a size, for example, a length, a width, a diameter, a cross-
sectional area, a surface area, or a volume, on the order of
micrometers or nanometers. The therapeutic agent may be shaped or
otherwise manufactured as particles, or may be coupled to particles
of other materials. The particles including the therapeutic agent
have a size that is effective to form concentrated regions of the
therapeutic agent in the retinal pigmented epithelium (RPE) of an
eye to which the composition or particles are administered. The
concentrated regions of the therapeutic agent are effective to
provide a desired therapeutic effect to the human or animal, such
as a therapeutic effect to a posterior portion of the eye.
[0022] In comparison, existing pharmaceutical compositions which
are used to provide ocular therapy contain a therapeutic agent
which does not form concentrated regions of the therapeutic agent
in the RPE of an eye. Thus, the ophthalmically-acceptable
pharmaceutical compositions disclosed herein are effective to
provide more localized drug delivery to a posterior portion of an
eye of a patient relative to existing compositions containing a
substantially identical therapeutic agent.
[0023] The concentrated regions of the poorly soluble therapeutic
agent are localized to the posterior portion of an eye of a
patient, such as the RPE. In certain aspects, the particles are
sized to form one or more discrete regions of concentrated
therapeutic agent in the RPE relative to other regions of the RPE.
In other words, administration of the particles disclosed herein to
a posterior portion of an eye of a patient may result in one or
more areas of the RPE having a relatively higher concentration of
therapeutic agent, and one or more regions having a relatively
lower concentration of therapeutic agent.
[0024] The concentrated regions may be understood to be or to
function as RPE depots of the therapeutic agent. By sizing the
particles appropriately to form concentrated regions of the
therapeutic agent, the delivery of the therapeutic agent to the
patient can be prolonged for periods of time, such as days, weeks,
or months. Thus, the particles disclosed herein may be effective to
provide extended-release of the therapeutic agent into the
posterior portion of the eye. The release rate may be substantially
continuous occurring by relatively passive biological and/or
chemical processes, or the release rate may be discontinuous, for
example pulsatile or periodic, to achieve a desired therapeutic
effect.
[0025] In certain embodiments, the composition comprises a
therapeutically effective amount of the therapeutic agent 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, and
the concentrated regions of the therapeutic agent are formed to
have a therapeutically effective amount of the therapeutic agent.
In other words, the concentrated regions may have a concentration
of the therapeutic agent that is greater than the concentration of
the therapeutic agent of the composition before the composition is
administered to an eye.
[0026] The concentrated regions may also have a concentration of
the therapeutic agent that is greater relative to the concentration
of the therapeutic agent in the composition when the composition is
administered to the eye, for example, the concentration of the
therapeutic agent that is present in the vitreous of the eye.
[0027] In addition, or alternatively, the concentrated regions may
have a concentration of particles that is greater than the
concentration of the particles in the composition, either before
administration to the eye, or after administration to the eye and
as present in the vitreous of the eye. The concentrated regions of
the therapeutic agent may be effective to provide an enhanced
therapeutic effect relative to substantially identical compositions
in which the therapeutic agent is not provided as particles, or as
particles having the same or similar sizes to that disclosed
herein.
[0028] For example, the therapeutic agent may be present in the
composition in an amount of at least about 10 mg per ml of the
composition. One advantage of certain embodiments of the present
invention is the effective ability of the present compositions to
include relatively smaller amounts or concentrations of the
therapeutic agent in the composition while obtaining a relatively
larger amount or concentration of the therapeutic agent at a target
site, such as the RPE. Thus, the therapeutic agent may be present
in the present compositions 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 posterior segment of the
eye in order to provide the same amount or more therapeutic agent
in the posterior segment of the eye relative to existing
compositions, such as Kenalog.RTM.-40.
[0029] The particles including the therapeutic agent are sized so
that the particles are distributed in the composition when
administered to the eye to reduce toxicity associated with the
therapeutic agent in the anterior tissues of the eye, such as the
lens, the iris-ciliary body, the aqueous humor, and the like. Thus,
by sizing the particles appropriately, a targeted delivery of the
therapeutic agent can be obtained that is effective to reduce, and
preferably prevent, toxicity to anterior structures of the eye.
[0030] Examples of therapeutic agents that can be formed as
particles, as disclosed herein, include, without limitation, any
conventional poorly soluble ophthalmic therapeutic agent. Such
therapeutic agents advantageously 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 preferably has a
solubility in water at 25.degree. C. or at 37.degree. C. of less
than 10 mg/ml. Of course, the therapeutic agent should be
ophthalmically acceptable, that is, should have substantially no
significant or undue detrimental effect of the eye structures or
tissues.
[0031] For example, therapeutic agents may include 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, and neuroprotectants. When a
therapeutic agent is not poorly soluble, it may be physically or
chemically modified to become poorly soluble using conventional
methods known to persons of ordinary skill in the art.
[0032] More specifically, the therapeutic agent may include
non-steroidal anti-inflammants, analgesics, or antipyretics;
antihistamines, antibiotics, beta blockers, steroids, such as
corticosteroids, anti-neoplastic agents, immunosupressive agents,
antiviral agents, and antioxidants.
[0033] 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, and derivatives thereof.
[0034] 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.
[0035] 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, and derivatives thereof.
[0036] 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,
and derivatives thereof.
[0037] Examples of beta blockers include acebutolol, atenolol,
labetalol, metoprolol, propranolol, and derivatives thereof.
[0038] Examples of corticosteroids include cortisone, prednisolone,
triamcinolone, flurometholone, dexamethasone, medrysone,
loteprednol, fluazacort, hydrocortisone, prednisone triamcinolone,
betamethasone, prednisone, methylprednisolone, triamcinolone
acetonide, triamcinolone hexacatonide, paramethasone acetate,
diflorasone, fluocinolone and fluocinonide, derivatives thereof,
and mixtures thereof.
[0039] Examples of antineoplastic agents include 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, and derivatives thereof.
[0040] Examples of immunosuppresive agents include cyclosporine,
azathioprine, tacrolimus, and derivatives thereof.
[0041] Examples of antiviral agents include interferon gamma,
zidovudine, amantadine hydrochloride, ribavirin, acyclovir,
valciclovir, dideoxycytidine, and derivatives thereof.
[0042] Examples of antioxidant agents include 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, and derivatives thereof.
[0043] Other therapeutic agents include squalamine, carbonic
anhydrase inhibitors, alpha agonists, prostamides, prostaglandins,
antiparasitics, antifungals, and derivatives thereof.
[0044] In a preferred embodiment of the invention, the
therapeutically active agent or therapeutic agent comprises a
retinoid, a prostaglandin, a tyrosine kinase inhibitor, a
glucocorticoid, an androgenic steroid, an estrogenic steroid, or a
non-estrogenic steroid, an intracellular adhesion molecule
inhibitor, or an alpha-2-adrenergic receptor agonist. In one
specific embodiment, the therapeutic agent is triamcinolone
acetonide.
[0045] The therapeutic agent of the present compositions may
include any or all salts and prodrugs or precursors of the
therapeutic agents, including those specifically identified
herein.
[0046] In certain embodiments, the therapeutic component of the
composition may comprise particles including more than one
therapeutic agent. In other words, the therapeutic component of the
composition may include a first therapeutic agent, and a second
therapeutic agent, or a combination of therapeutic agents. Examples
of therapeutic agents include those identified above in any
combination. One or more of the therapeutic agents in such
compositions may be formed as or present in particles, as disclosed
herein.
[0047] The compositions disclosed herein may include a therapeutic
component that comprises, consists essentially of, or consists of,
a population of particles including a therapeutic agent. Each of
the particles have a size. When the particles are grouped to define
a population of particles, the population may have an effective
average particle size that corresponds to the average size of the
particles of that population. The size of the particles may be
uniformly distributed in any given population. For example, the
size of particles in a population may be symmetrically distributed
about the mean size of the particles. Or, the size of the particles
may be distributed asymmetrically. For example, a population of
particles may have an effective average particle size that is
skewed away from the median particle size for a population of
particles.
[0048] In certain embodiments, the compositions comprise a
population of particles including a first therapeutic agent and a
population of particles including a second therapeutic agent. Thus,
in at least one embodiment, a composition comprises a population of
particles having an effective average particle size that is
effective to form concentrated regions of the therapeutic agent. In
certain embodiments, a population of particles has an average size
effective to promote phagocytosis of the particles by RPE cells. In
other embodiments, a population of particles has an average size
effective to promote pinocytosis by RPE cells. The compositions
disclosed herein may thus have a population of a predetermined
number of particles with a desired or predetermined size. This may
provide enhanced therapeutic effects relative to existing
compositions that do not have populations of a predetermined number
of particles of a specific size. For example, some compositions may
include "fines" of therapeutic agent particles. Fines, as used
herein, may be understood to be particles that are randomly formed
during the manufacture of the particles. Fines may be relatively
small, but because they occur randomly, they do not provide a
desired therapeutic effect.
[0049] In certain embodiments, such as embodiments in which the
particles promote phagocytosis, the particles may have an average
size of about 3000 nanometers. Usually, the particles will have an
effective average size less than about 3000 nanometers. In more
specific embodiments, 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 further
embodiments, 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. Reducing the
size of the particles may be effective to cause the particles to
form concentrated regions by pinocytosis mechanisms as compared to
phagocytosis mechanisms.
[0050] In addition, a composition may include a therapeutic
component with more than one population of particles, each
population having a different effective average particle size. In
one specific embodiment, the therapeutic component may comprise a
first population of particles including a therapeutic agent having
an effective average particle size of less than about 200
nanometers, a second population of particles having an effective
average particle size in a range of about 200 nanometers to about
400 nanometers, and a third population of particles having an
effective average particle size in a range of about 400 nanometers
to about 3000 nanometers.
[0051] In at least one embodiment, the particles of the composition
may comprise, consist essentially of, or consist of, a therapeutic
agent and a polymer suitable for administration to the posterior
segment of an eye. The polymer in combination with the therapeutic
agent may be understood to be a polymeric component. In some
embodiments, the particles comprise materials other than
D,L-polylactide (PLA) or latex (carboxylate modified polystyrene
beads). In certain embodiments, the polymer component may comprise
a polysaccharide. For example, the polymer component may comprise a
mucopolysaccharide. In at least one specific embodiment, the
polymer component is hyaluronic acid.
[0052] However, in additional embodiments, the polymeric component
may comprise any polymeric material useful in a body of a mammal,
whether derived from a natural source or synthetic. Some additional
examples of useful polymeric materials for the purposes of this
invention include carbohydrate based polymers such as
methylcellulose, carboxymethylcellulose, hydroxymethylcellulose
hydroxypropylcellulose, hydroxyethylcellulose, ethyl cellulose,
dextrin, cyclodextrins, alginate, hyaluronic acid and chitosan,
protein based polymers such as gelatin, collagen and
glycolproteins, hydroxy acid polyesters such as
polylactide-coglycolide (PLGA), polylactic acid (PLA),
polyglycolide, polyhydroxybutyric acid, polycaprolactone,
polyvalerolactone, polyphosphazene, and polyorthoesters. Polymers
can also be crosslinked, blended or used as copolymers in the
invention. Other polymer carriers include albumin, polyanhydrides,
polyethylene glycols, polyvinyl polyhydroxyalkyl methacrylates,
pyrrolidone and polyvinyl alcohol.
[0053] Some examples of non-erodible polymers include silicone,
polycarbonates, polyvinyl chlorides, polyamides, polysulfones,
polyvinyl acetates, polyurethane, ethylvinyl acetate derivatives,
acrylic resins, crosslinked polyvinyl alcohol and crosslinked
polyvinylpyrrolidone, polystyrene and cellulose acetate
derivatives.
[0054] These additional polymeric materials may be useful with any
of the therapeutic agents. For example, particles of PLA or PLGA
may be coupled to triamcinolone acetonide, in one embodiment.
[0055] The particles of the therapeutic agent or agents may also be
combined with a pharmaceutically acceptable vehicle component in
the manufacture of a composition. In other words, a composition, as
disclosed herein, may comprise a therapeutic component, as
discussed above, and an effective amount of a pharmaceutically
acceptable vehicle component. In at least one embodiment, the
vehicle component is aqueous-based. For example, the composition
may comprise water.
[0056] In certain embodiments, the vehicle component may also
include an effective amount of at least one of a viscosity inducing
component, a resuspension component, a preservative component, a
tonicity component and a buffer component. In some embodiments, the
compositions disclosed herein include no added preservative
component. In other embodiments, a composition may include an added
preservative component. In addition, the composition may be
included with no resuspension component.
[0057] The aqueous vehicle component is advantageously
ophthalmically acceptable and may also include one or more
conventional excipients useful in ophthalmic compositions.
[0058] The present compositions preferably include a major amount
of liquid water. The present compositions may be, and are
preferably, sterile, for example, prior to being used in the
eye.
[0059] The present compositions preferably include at least one
buffer component in an amount effective to control the pH of the
composition and/or at least one tonicity component in an amount
effective to control the tonicity or osmolality of the
compositions. More preferably, the present compositions include
both a buffer component and a tonicity component.
[0060] The buffer component and tonicity component may be chosen
from those which are conventional and well known in the ophthalmic
art.
[0061] Examples of such buffer components include, but are not
limited to, acetate buffers, citrate buffers, phosphate buffers,
borate buffers and the like and mixtures thereof. Phosphate buffers
are particularly useful. Useful tonicity components include, but
are not limited to, salts, particularly sodium chloride, potassium
chloride, any other suitable ophthalmically acceptably tonicity
component and mixtures thereof.
[0062] The amount of buffer component employed preferably is
sufficient to maintain the pH of the composition in a range of
about 6 to about 8, more preferably about 7 to about 7.5. The
amount of tonicity component employed preferably is sufficient to
provide an osmolality to the present compositions in a range of
about 200 to about 400, more preferably about 250 to about 350,
mOsmol/kg respectively. Advantageously, the present compositions
are substantially isotonic.
[0063] The present compositions may include one or more other
components in amounts effective to provide one or more useful
properties and/or benefits to the present compositions. For
example, although the present compositions may be substantially
free of added preservative components, in other embodiments, the
present compositions include effective amounts of preservative
components, preferably such components which are more compatible
with or friendly to the tissue in the posterior segment 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.
[0064] In addition, the present composition may include an
effective amount of resuspension component effective to facilitate
the suspension or resuspension of the therapeutic component
particles in the present compositions. As noted above, in certain
embodiments, the present compositions are free of added
resuspension components. In other embodiments of the present
compositions effective amounts of resuspension components are
employed, for example, to provide an added degree of insurance that
the therapeutic component particles remain in suspension, as
desired and/or can be relatively easily resuspended in the present
compositions, such resuspension be desired. Advantageously, the
resuspension component employed in accordance with the present
invention, if any, is chosen to be more compatible with or friendly
to the tissue in the posterior segment of the eye into which the
composition is placed then polysorbate 80.
[0065] Any suitable resuspension component may be employed in
accordance with the present invention. Examples of such
resuspension components include, without limitation, surfactants
such as poloxanes, for example, sold under the trademark
Pluronic.RTM.; tyloxapol; sarcosinates; polyethoxylated castor
oils, other surfactants and the like and mixtures thereof.
[0066] One very useful class of resuspension components are those
selected from vitamin derivatives. Although such materials have
been previously suggested for use as surfactants in ophthalmic
compositions, they have been found to be effective in the present
compositions as resuspension components. Examples of useful vitamin
derivatives include, without limitation, Vitamin E tocopheryl
polyethylene glycol succinates, such as Vitamin E tocopheryl
polyethylene glycol 1000 succinate (Vitamin E TPGS). Other useful
vitamin derivatives include, again without limitation, Vitamin E
tocopheryl polyethylene glycol succinamides, such as Vitamin E
tocopheryl polyethylene glycol 1000 succinamide (Vitamin E TPGSA)
wherein the ester bond between polyethylene glycol and succinic
acid is replaced by an amide group.
[0067] The presently useful resuspension components are present, if
at all, in the compositions in accordance with the present
invention in an amount effective to facilitate suspending the
particles in the present compositions, for example, during
manufacture of the compositions or thereafter. The specific amount
of resuspension component employed may vary over a wide range
depending, for example, on the specific resuspension component
being employed, the specific composition in which the resuspension
component is being employed and the like factors. Suitable
concentrations of the resuspension component, if any, in the
present compositions are often in a range of about 0.01% to about
5%, for example, about 0.02% or about 0.05% to about 1.0% (w/v) of
the composition.
[0068] The compositions disclosed herein may include a viscosity
inducing component in an amount effective in providing an increased
viscosity to the composition relative to an identical composition
without the viscosity inducing component. The viscosity inducing
component may comprise at least one viscoelastic agent.
[0069] Any suitable viscosity inducing component, for example,
ophthalmically acceptable viscosity inducing component, may be
employed in accordance with the present invention. Many such
viscosity inducing components have been proposed and/or used in
ophthalmic compositions used on or in the eye. The viscosity
inducing component is present in an amount effective in providing
the desired viscosity to the composition. Advantageously, the
viscosity inducing component is present in an amount in a range of
about 0.5% or about 1.0% to about 5% or about 10% or about 20%
(w/v) of the composition. The specific amount of the viscosity
inducing component employed depends upon a number of factors
including, for example and without limitation, the specific
viscosity inducing component being employed, the molecular weight
of the viscosity inducing component being employed, the viscosity
desired for the present composition being produced and/or used and
the like factors. The viscosity inducing component is chosen to
provide at least one advantage, and preferably multiple advantages,
to the present compositions, for example, in terms of each of
injectability into the posterior segment of the eye, viscosity,
sustainability of the corticosteroid component particles in
suspension, for example, in substantially uniform suspension, for a
prolonged period of time without resuspension processing,
compatibility with the tissues in the posterior segment of the eye
into which the composition is to be placed and the like advantages.
More preferably, the selected viscosity inducing component is
effective to provide two or more of the above-noted benefits, and
still more preferably to provide all of the above-noted
benefits.
[0070] The viscosity inducing component preferably comprises a
polymeric component and/or at least one viscoelastic agent, such as
those materials which are useful in ophthalmic surgical
procedures.
[0071] Examples of useful viscosity inducing components include,
but are not limited to, hyaluronic acid, carbomers, polyacrylic
acid, cellulosic derivatives, polycarbophil, polyvinylpyrrolidone,
gelatin, dextrin, polysaccharides, polyacrylamide, polyvinyl
alcohol, polyvinyl acetate, derivatives thereof and mixtures
thereof.
[0072] The molecular weight of the presently useful viscosity
inducing components may be in a range of about 10,000 Daltons or
less to about 2 million Daltons or more. In one particularly useful
embodiment, the molecular weight of the viscosity inducing
component is in a range of about 100,000 Daltons or about 200,000
Daltons to about 1 million Daltons or about 1.5 million Daltons.
Again, the molecular weight of the viscosity inducing component
useful in accordance with the present invention, may vary over a
substantial range based on the type of viscosity inducing component
employed, and the desired final viscosity of the present
composition in question, as well as, possibly one or more other
factors.
[0073] In one very useful embodiment, a viscosity inducing
component is a hyaluronate component, for example, a metal
hyaluronate component, preferably selected from alkali metal
hyaluronates, alkaline earth metal hyaluronates and mixtures
thereof, and still more preferably selected from sodium
hyaluronates, and mixtures thereof. The molecular weight of such
hyaluronate component preferably is in a range of about 50,000
Daltons or about 100,000 Daltons to about 1.3 million Daltons or
about 2 million Daltons. In one embodiment, the present
compositions include a hyaluronate component in an amount in a
range about 0.05% to about 0.5% (w/v). In a further useful
embodiment, the hyaluronate component is present in an amount in a
range of about 1% to about 4% (w/v) of the composition. In this
latter case, the very high polymer viscosity forms a gel that slows
particle sedimentation rate to the extent that often no
resuspension processing is necessary over the estimated shelf life,
for example, at least about 2 years, of the composition. Such a
composition may be marketed in pre-filled syringes since the gel
cannot be easily removed by a needle and syringe from a bulk
container.
[0074] In at least one embodiment, the viscosity inducing component
is selected from the group consisting of hyaluronic acid,
carbomers, polyacrylic acid, cellulosic derivatives, polycarbophil,
polyvinylpyrrolidone, gelatin, dextrin, polysaccharides,
polyacrylamide, polyvinyl alcohol, polyvinyl acetate, derivatives
thereof and mixtures thereof. In certain embodiments, the viscosity
inducing component comprises a hyaluronate component, such as a
sodium hyaluronate. Advantageously, it has been discovered that
compositions which include a therapeutic component comprising a
therapeutic agent in the form of particles fabricated from a
hyaluronic acid component provide an effective viscosity to the
composition as well as the desired formation of concentrated
regions of the therapeutic agent
[0075] In at least one embodiment, an ophthalmically acceptable
composition comprises a population of particles of triamcinolone
acetonide having an effective average particle size less than about
3000 nanometers. As discussed herein, when a pinocytotic mechanism
is desired for the formation of concentrated regions of the
therapeutic agent, the composition may have at least a major
portion of the population of particles with a size less than about
500 nanometers.
[0076] In at least one other embodiment of the invention, a
population of particles of triamcinolone acetonide has an effective
average particle size less than about 3000 nanometers. For example,
the population of particles may have an effective average particle
size less than about 500 nanometers. In at least one embodiment,
the population of particles has an effective average particle size
of between about 200 and about 400 nanometers.
[0077] The population of particles of triamcinolone acetonide may
be provided in a liquid carrier component, and preferably, an
ophthalmically acceptable liquid carrier component. One example of
a liquid carrier component may include hyaluronic acid. The
combination of the particles and the liquid carrier component may
be provided in a container, such as a vial and/or a dispensing
apparatus. For example, when the population of particles is
administered to a posterior segment of an eye of a patient, the
population may be provided in a syringe that is configured to
administer the particles to an eye, and preferably, to a posterior
segment of an eye, as discussed herein.
[0078] In at least one embodiment, the particles comprise a
combination of triamcinolone acetonide and hyaluronic acid. The
hyaluronic acid is believed to stabilize the particles of
triamcinolone acetonide. The particles have a size, such as a
width, a length, a diameter, an area, or a volume, effective to
facilitate transfer of the particles into the RPE when the
particles are administered to an eye.
[0079] In at least one other embodiment of the invention, a poorly
soluble steroid, such as a corticosteroid, is provided as small
particles. The particles preferably have an effective average
particle size less than about 3000 nanometers, preferably less than
about 400 nanometers, and more preferably, less than about 200
nanometers. The steroid preferably has a solubility of less than
about 10 mg/mL. In at least one embodiment, the poorly soluble
steroid is triamcinolone acetonide. The particles may be formed by
mixing the poorly soluble steroid with a hyaluronate component.
Stabilization of the particles may be obtained by one or more
surface modifications of the steroid with hyaluronic acid or sodium
hyaluronate.
[0080] The particles may be provided in a pharmaceutical
composition, such as compositions disclosed herein. In at least one
embodiment, a composition comprises a first population of particles
having a size less than 200 nanometers, a second population of
particles having an effective average particle size between about
200 nanometers and about 400 nanometers, and a third population of
particles having an effective average particle size between about
400 nanometers and about 3000 nanometers. In additional
embodiments, a composition may have only two populations of
particles with different effective average particle sizes. Such
compositions are substantially free, and preferably are entirely
free, of fines of the therapeutic agent, as discussed herein.
[0081] The particles of the therapeutic agent disclosed herein,
including triamcinolone acetonide, may be manufactured by
subjecting a composition, which may not necessarily be an
ophthalmic composition, of relatively large particles of the
therapeutic agent and a polymeric component acceptable for
administration into a posterior segment of an eye of a patient to
conditions that are effective to reduce the relatively large
particles to smaller particles having an effective average particle
size that is effective to form concentrated regions of the
therapeutic agent when placed in an eye. For example, the particles
may be reduced to about 3000 nanometers or less in size. The
polymeric component may be present in an amount effective in
stabilizing the smaller particles in the product composition.
[0082] In at least one embodiment, the product composition is
subjected to a milling step. For example, the particles may be
exposed to a ball mill. As one example, hyaluronic acid can be
added to particles of the therapeutic agent in an amount from about
10% to about 200% of the active therapeutic agent on a weight
basis. Hyaluronic acid may be added in the form of an aqueous
solution. The therapeutic agent may then be milled in the
hyaluronic acid solution until the mean average particle size
equals the desired range.
[0083] The particles may be sorted into different populations
according to size differences. For example, the particles may be
sorted by passing the particles through a series of filters having
a series of openings of different sizes allowing progressively
larger particles to be separated from smaller particles.
[0084] In certain embodiments, the particles may be prepared using
methods such as those disclosed in U.S. Pat. Nos. 6,387,409;
5,565,188; and/or 5,552,160, the contents of all of which are
hereby incorporated by reference.
[0085] Compositions can be prepared using suitable
blending/processing techniques or techniques, for example, one or
more conventional blending techniques. The preparation processing
should be chosen to provide the present compositions in forms which
are useful for placement or injection into the posterior segments
of eyes of humans or animals. In one embodiment a concentrated
therapeutic component dispersion is made by combining therapeutic
agent in the form of particles, as discussed herein, with water and
the excipients to be included in the final ophthalmic composition.
The ingredients may be mixed to disperse the therapeutic component
and then may be autoclaved.
[0086] A composition including particles, such as the particles
described above, 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.
[0087] Among the diseases/conditions which can be treated or
addressed in accordance with the present invention include, without
limitation, the following:
[0088] MACULOPATHIES/RETINAL DEGENERATION: Non-Exudative Age
Related Macular Degeneration (ARMD), Exudative Age Related Macular
Degeneration (ARMD), Choroidal Neovascularization, Diabetic
Retinopathy, Acute Macular Neuroretinopathy, Central Serous
Chorioretinopathy, Cystoid Macular Edema, Diabetic Macular
Edema.
[0089] 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.
[0090] 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.
[0091] TRAUMATIC/SURGICAL: Sympathetic Ophthalmia, Uveitic Retinal
Disease, Retinal Detachment, Trauma, Laser, PDT, Photocoagulation,
Hypoperfusion During Surgery, Radiation Retinopathy, Bone Marrow
Transplant Retinopathy.
[0092] PROLIFERATIVE DISORDERS: Proliferative Vitreal Retinopathy
and Epiretinal Membranes, Proliferative Diabetic Retinopathy.
[0093] 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.
[0094] 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.
[0095] RETINAL TEARS/HOLES: Retinal Detachment, Macular Hole, Giant
Retinal Tear.
[0096] 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.
[0097] MISCELLANEOUS: Punctate Inner Choroidopathy, Acute Posterior
Multifocal Placoid Pigment Epitheliopathy, Myopic Retinal
Degeneration, Acute Retinal Pigment Epithelitis and the like.
[0098] 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.
[0099] In at least one embodiment, a method of treating a posterior
segment ocular disease comprises administering a population of
particles, or a composition containing such particles, as disclosed
herein to a patient by at least one of intravitreal injection,
subconjuctival injection, sub-tenon injection, retrobulbar
injection, and suprachoroidal injection. 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.
[0100] In another aspect of the present invention, the particles
and/or compositions disclosed herein 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.
[0101] 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.
* * * * *