U.S. patent application number 10/966764 was filed with the patent office on 2005-05-12 for compositions and methods for treating a posterior segment of an eye.
This patent application is currently assigned to Allergan, Inc.. Invention is credited to Chang, James N., Lyons, Robert T., Trogden, John T., Whitcup, Scott M..
Application Number | 20050101582 10/966764 |
Document ID | / |
Family ID | 34557415 |
Filed Date | 2005-05-12 |
United States Patent
Application |
20050101582 |
Kind Code |
A1 |
Lyons, Robert T. ; et
al. |
May 12, 2005 |
Compositions and methods for treating a posterior segment of an
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 corticosteroid
component-containing particles present in a therapeutically
effective amount, a viscosity inducing component, and an aqueous
carrier component. The compositions have viscosities of at least
about 10 cps or about 100 cps at a shear rate of 0.1/second. In a
preferred embodiment, the viscosity is in the range of from about
140,000 cps to about 300,000 cps. The compositions advantageously
suspend the particles for prolonged periods of time.
Inventors: |
Lyons, Robert T.; (Laguna
Hills, CA) ; Chang, James N.; (Newport Beach, CA)
; Trogden, John T.; (Anaheim, CA) ; Whitcup, Scott
M.; (Laguna Hills, CA) |
Correspondence
Address: |
STOUT, UXA, BUYAN & MULLINS LLP
4 VENTURE, SUITE 300
IRVINE
CA
92618
US
|
Assignee: |
Allergan, Inc.
Irvine
CA
|
Family ID: |
34557415 |
Appl. No.: |
10/966764 |
Filed: |
October 14, 2004 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
60519237 |
Nov 12, 2003 |
|
|
|
60530062 |
Dec 16, 2003 |
|
|
|
Current U.S.
Class: |
514/179 |
Current CPC
Class: |
A61K 31/573 20130101;
A61P 31/12 20180101; A61P 41/00 20180101; A61P 35/04 20180101; A61K
9/0048 20130101; A61P 35/00 20180101; A61P 31/18 20180101; A61P
9/10 20180101; A61P 27/02 20180101; A61P 33/00 20180101; A61K 47/36
20130101; A61P 33/02 20180101; A61P 31/00 20180101; A61P 31/04
20180101; A61K 31/58 20130101; A61P 31/06 20180101; A61P 5/40
20180101 |
Class at
Publication: |
514/179 |
International
Class: |
A61K 031/573 |
Claims
What is claims is:
1. A composition useful for injection into a posterior segment of
an eye of a human or animal comprising: a corticosteroid component
present in a therapeutically effective amount, the corticosteroid
component being present in a plurality of particles; a viscosity
inducing component in an amount effective in increasing the
viscosity of the composition; and an aqueous carrier component, the
composition having a viscosity of at least about 10 cps at a shear
rate of 0.1/second and being effectively injectable into a
posterior segment of an eye of a human or animal.
2. The composition of claim 1 which has a viscosity of at least 100
cps at a shear rate of 0.1/second.
3. The composition of claim 1 which has a viscosity of at least
10,000 cps at a shear rate of 0.1/second.
4. The composition of claim 1 which has a viscosity of from about
140,000 cps--about 300,000 cps at a shear rate of 0.1/second.
5. The composition of claim 1 which is effectively injectable
through a 27 gauge needle into a posterior segment of an eye of a
human or animal.
6. The composition of claim 1 which is effectively injectable
through a 30 gauge needle into a posterior segment of an eye of a
human or animal.
7. The composition of claim 1 wherein the particles are
substantially uniformly suspended in the composition.
8. The composition of claim 7 wherein the particles remain
substantially uniformly suspended in the composition for at least
about 1 week without requiring resuspension processing.
9. The composition of claim 7 wherein the particles remain
substantially uniformly suspended in the composition for at least
about 1 month without requiring resuspension processing.
10. The composition of claim 7 wherein the particles remain
substantially uniformly suspended in the composition for at least
about 6 months without requiring resuspension processing.
11. The composition of claim 7 wherein the particles remain
substantially uniformly suspended in the composition for at least
about 1 year without requiring resuspension processing.
12. The composition of claim 7 wherein the particles remain
substantially uniformly suspended in the composition for at least
about 2 years without requiring resuspension processing.
13. The composition of claim 1 wherein the corticosteroid component
is present in an amount of up to about 25% (w/v) of the
composition.
14. The composition of claim 1 wherein the corticosteroid component
is present in an amount of at least about 10 mg per ml of
composition.
15. The composition of claim 1 wherein the corticosteroid component
is present in an amount in a range of about 1% to about 20% (w/v)
of the composition.
16. The composition of claim 1 wherein the corticosteroid component
is present in an amount in a range of about 1% to about 10% (w/v)
of the composition.
17. The composition of claim 1 wherein the corticosteroid component
has a solubility in water at 25.degree. C. of less than 10
mg/ml.
18. The composition of claim 1 wherein the corticosteroid component
is selected from the group consisting of cortisone, prednisolone,
triamcinolone, fluorometholone, dexamethasone, medrysone,
loteprednol, derivatives thereof and mixtures thereof.
19. The composition of claim 1 wherein the corticosteroid component
is triamcinolone acetonide.
20. The composition of claim 1 wherein the carrier component
includes an effective amount of at least one of a preservative
component, a tonicity component and a buffer component.
21. The composition of claim 1 which includes no added preservative
component.
22. The composition of claim 1 which includes no added resuspension
component.
23. The composition of claim 1 wherein the viscosity inducing
component is present in an amount in a range of about 0.05% to
about 20% (w/v) of the composition.
24. The composition of claim 1 wherein the viscosity inducing
component comprises a polymeric component.
25. The composition of claim 1 wherein the viscosity inducing
component comprises at least one viscoelastic agent.
26. The composition of claim 1 wherein the viscosity inducing
component is selected from the group consisting of polymeric
hyaluronic acid, carbomers, polyacrylic acid, cellulosic
derivatives, polycarbophil, polyvinylpyrrolidone, gelatin, dextrin,
polysaccharides, polyacrylamide, polyvinyl alcohol, polyvinyl
acetate, derivatives thereof and mixtures thereof.
27. The composition of claim 1 wherein the viscosity inducing
component comprises a hyaluronate component.
28. The composition of claim 27 wherein the hyaluronate component
comprises sodium hyaluronate.
29. A method of treatment comprising administering the composition
of claim 1 to a posterior segment of an eye of a human or animal,
thereby obtaining a desired therapeutic effect.
30. The method of claim 29 wherein the administering step comprises
intravitreal injecting.
31. The method of claim 29 wherein the administering step comprises
subconjunctival injecting.
32. The method of claim 29 wherein the administering step comprises
sub-tenon injecting.
33. The method of claim 29 wherein the administering step comprises
retrobulbar injecting.
34. The method of claim 29 wherein the administering step comprises
suprachoroidal injecting.
35. A composition useful for injection into a posterior segment of
an eye of a human or animal comprising: a corticosteroid component
present in a therapeutic effect amount, the corticosteroid
component being present in a plurality of particles; a viscosity
inducing component in an amount effective in increasing the
viscosity of the composition; and an aqueous carrier component, the
particles being substantially uniformly suspended in the
composition and remaining substantially uniformly suspended in the
composition for at least about 1 week without requiring
resuspension processing.
36. The composition of claim 35 wherein the particles remain
substantially uniformly suspended in the composition for at least
about 2 weeks without requiring resuspension processing.
37. The composition of claim 35 wherein the particles remain
substantially uniformly suspended in the composition for at least
about 1 month without requiring resuspension processing.
38. The composition of claim 35 wherein the particles remain
substantially uniformly suspended in the composition for at least
about 6 months without requiring resuspension processing.
39. The composition of claim 35 wherein the particles remain
substantially uniformly suspended in the composition for at least
about 1 year without requiring resuspension processing.
40. The composition of claim 35 wherein the particles remain
substantially uniformly suspended in the composition for at least
about 2 years without requiring resuspension processing.
41. The composition of claim 35 wherein the corticosteroid
component is present in an amount of up to about 25% (w/v) of the
composition.
42. The composition of claim 35 wherein the corticosteroid
component is present in an amount of at least about 10 mg per ml of
composition.
43. The composition of claim 35 wherein the corticosteroid
component is present in an amount in a range of about 1% to about
20% (w/v) of the composition.
44. The composition of claim 35 wherein the corticosteroid
component is present in an amount in a range of about 1% to about
10% (w/v) of the composition.
45. The composition of claim 35 wherein the corticosteroid
component has a solubility in water at 25.degree. C. of less than
10 mg/ml.
46. The composition of claim 35 wherein the corticosteroid
component is selected from the group consisting of cortisone,
prednisolone, triamcinolone, fluorometholone, dexamethasone,
medrysone, loteprednol, derivatives thereof and mixtures
thereof.
47. The composition of claim 35 wherein the corticosteroid
component is triamcinolone acetonide.
48. The composition of claim 35 wherein the carrier component
includes an effective amount of at least one of a preservative
component, a tonicity component and a buffer component.
49. The composition of claim 35 which includes no added
preservative component.
50. The composition of claim 35 which includes no added
resuspension component.
51. The composition of claim 35 wherein the viscosity inducing
component is present in an amount in a range of about 0.05% to
about 20% (w/v) of the composition.
52. The composition of claim 35 wherein the viscosity inducing
component comprises a polymeric component.
53. The composition of claim 35 wherein the viscosity inducing
component comprises at least one viscoelastic agent.
54. The composition of claim 35 wherein the viscosity inducing
component is selected from the group consisting of polymeric
hyaluronic acid, carbomers, polyacrylic acid, cellulosic
derivatives, polycarbophil, polyvinylpyrrolidone, gelatin, dextrin,
polysaccharides, polyacrylamide, polyvinyl alcohol, polyvinyl
acetate, derivatives thereof and mixtures thereof.
55. The composition of claim 35 wherein the viscosity inducing
component comprises a hyaluronate component.
56. The composition of claim 55 wherein the hyaluronate component
comprises sodium hyaluronate.
57. A method of treatment comprising administering the composition
of claim 35 to a posterior segment of an eye of a human or animal,
thereby obtaining a desired therapeutic effect.
58. The method of claim 57 wherein the administering step comprises
intravitreal injecting.
59. The method of claim 57 wherein the administering step comprises
subconjunctival injecting.
60. The method of claim 57 wherein the administering step comprises
sub-tenon injecting.
61. The method of claim 57 wherein the administering step comprises
retrobulbar injecting.
62. The method of claim 57 wherein the administering step comprises
suprachoroidal injecting.
Description
RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Patent Application Ser. No. 60/519,237, filed Nov. 12, 2003 and
U.S. Provisional Patent Application Ser. No. 60/530,062, filed Dec.
16, 2003, which are hereby incorporated by reference in their
entireties.
[0002] This invention relates to compositions and methods for
treating posterior segments of eyes of humans or animals. More
particularly, the invention relates to compositions including
corticosteroid components which can be effectively injected into
posterior segments of such eyes and to methods of using such
compositions to provide desired therapeutic effects.
[0003] Among the therapies currently being practiced to treat
ocular posterior segment disorders, such as uveitis, macular
degeneration, macular edema and the like, is intravitreal injection
of a corticosteroid, such as triamcinolone acetonide (TA). See, for
example, Billson et al U.S. Pat. No. 5,770,589, the disclosure of
which is incorporated in its entirety herein by reference.
[0004] One medication commonly employed for this ophthalmic therapy
is Kenalog.RTM. 40. Each milliliter (ml) of the Kenalog.RTM. 40
composition includes 40 milligrams (mg) of TA, sodium chloride as a
tonicity agent, 10 mg of benzyl alcohol as a preservative, and 7.5
mg of carboxymethylcellulose and 0.4 mg of polysorbate 80 as
resuspension aids. Although widely used by ophthalmologists, this
commercially available formulation suffers from several important
limitations.
[0005] For example, the presence of benzyl alcohol preservative and
polysorbate 80 surfactant tends to lead to unnecessary and/or undue
cell damage or other toxicities in sensitive ocular tissues. Even
though some clinicians routinely "wash" the TA precipitate several
times with saline to reduce the concentration of these undesirable
materials, such washing is inconvenient, time consuming, and most
importantly, increases the probability of microbial or endotoxin
contamination that could lead to intraocular infection and
inflammation.
[0006] Moreover, the TA in the Kenalog.RTM. 40 tends to rapidly
separate and precipitate from the remainder of the composition. For
example, this composition, if left standing for 1 to 2 hours,
results in a substantial separation of a TA precipitate from the
remainder of the composition. Thus, if the composition is to be
injected into the eye, it must be vigorously shaken and used
promptly after being so shaken in order to provide a substantially
uniform suspension in the eye. In addition, resuspension processing
requires the use of the resuspension aids noted above, at least one
of which is less than totally desirable for sensitive ocular
tissues.
[0007] 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
[0008] 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 without requiring any "washing
step", while providing for reduced ocular, for example, retinal,
damage when used in an eye. The present compositions are
advantageously substantially free of added preservative components,
for example, contain no benzyl alcohol preservative. In addition,
the present compositions advantageously require no resuspension aid
or aids. Overall, the present compositions are easily and
effectively injectable into the posterior segment of an eye of a
human or animal and can be maintained as a substantially uniform
suspension for long periods of time, for example, at least about
one week or more, without resuspension processing, for example,
without requiring shaking or other agitating of the composition to
obtain substantial suspension uniformity. In short, the present
compositions and methods provide substantial enhancements and
advantages, for example, relative to the prior art Kenalog.RTM. 40
composition and methods of using such prior art composition, in the
posterior segments of human or animal eyes.
[0009] In one broad aspect of the present invention, compositions
useful for injection into a posterior segment of an eye of a human
or animal are provided. Such compositions comprise a corticosteroid
component, a viscosity inducing component, and an aqueous carrier
component. The corticosteroid component is present in a
therapeutically effective amount. The corticosteroid component is
present in the compositions in a plurality of particles.
[0010] The present compositions may include a corticosteroid
component in an amount of up to about 25% (w/v) or more of the
composition. In one very useful embodiment, the corticosteroid
component is present in an amount of at least about 80 mg/ml of
composition. Preferably, the corticosteroid component is present in
an amount in a range of about 1% to about 10% or about 20% (w/v) of
the composition.
[0011] In one very useful embodiment, the corticosteroid component
comprises triamcinolone acetonide.
[0012] The viscosity inducing component is present in an amount
effective in increasing the viscosity of the composition.
[0013] Any suitable, preferably 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. Advantageously, the viscosity inducing component is
present in an amount in a range of about 0.5% to about 20% (w/v) of
the composition. In one particularly useful embodiment, the
viscosity inducing component is a hyaluronic acid polymer
component, such as sodium hyaluronate.
[0014] In one embodiment, the present compositions have a viscosity
of at least about 10 cps or at least about 100 cps, preferably at
least about 1,000 cps, more preferably at least about 10,000 cps
and still more preferably at least about 70,000 cps, for example,
up to about 250,000 cps, or about 300,000 cps, at a shear rate of
0.1/second. The present compositions are structured or have
make-ups so as to be effectively, for example, manually, injected
into a posterior segment of an eye of a human or animal, preferably
through a 27 gauge needle, more preferably through a 29 or 30 gauge
needle.
[0015] Without wishing to limit the invention to any particular
theory of operation, it is believed that the use of relatively high
viscosity compositions, as described herein, provides for
effective, and preferably substantially uniform, suspension of the
steroid component particles while, at the same time, being
injectable into the posterior segment of an eye through
conventionally, or even smaller than conventionally, used
needles.
[0016] In one embodiment of the invention, the corticosteroid
component is present in a plurality of particles which are
substantially uniformly suspended in the composition and remain
substantially uniformly suspended in the composition for at least
about 1 week, preferably at least about 2 weeks or at least about 1
month, and still more preferably at least about 6 months or at
least about 1 year or at least about 2 years, without requiring
resuspension processing, that is, without requiring being shaken or
otherwise agitated to maintain the corticosteroid component
particles substantially uniformly suspended in the composition.
[0017] Compositions having such substantially uniform suspension of
corticosteroid component particles provide substantial advantages
relative to the prior art. In particular, the present compositions
may be manufactured, shipped and stored for substantial periods of
time without the corticosteroid component particles precipitating
from the remainder of the composition. Having the corticosteroid
component particles maintained substantially uniformly suspended in
the composition allows the composition to be quickly and
effectively used to provide treatment to the posterior segment of
an eye of a human or animal without concern for having to resuspend
such particles.
[0018] The aqueous carrier component is advantageously
ophthalmically acceptable and may include one or more conventional
expedients useful in ophthalmic compositions.
[0019] For example, the carrier component may include an effective
amount of at least one of a preservative component, a tonicity
component and a buffer component.
[0020] In one advantageous embodiment, the present compositions
include no added preservative component. This feature reduces or
minimizes or even substantially eliminates adverse reactions in the
eye which may be caused by or linked to the presence of a
preservative component.
[0021] Although a resuspension component may be employed in
accordance with the present invention, in many instances, because
of the ability of the present composition to remain a substantially
uniform suspension for a long period of time without requiring
resuspension processing, the compositions advantageously contain no
added resuspension components.
[0022] Methods of treating posterior segments of the eyes of humans
or animals are also disclosed and are included within the scope of
the present invention. In general, such methods comprise
administering, e.g. injecting a corticosteroid component-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.
[0023] 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.
[0024] These and other aspects and advantages of the present
invention are apparent in the following detailed description,
examples and claims.
DETAILED DESCRIPTION
[0025] The present invention involves compositions useful for
placement, preferably by injection, into a posterior segment of an
eye of a 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.
[0026] In general, the present compositions comprise a
corticosteroid component; a viscosity inducing component; and an
aqueous carrier component. The compositions are advantageously
ophthalmically acceptable.
[0027] One of the important advantages of the present compositions
is that they are more compatible with or friendly to the tissues in
the posterior segment of the eye, for example, the retina of the
eye, relative to compositions previously proposed for intravitreal
injection into a posterior segment of an eye, for example, a
composition sold under the trademark Kenalog.RTM.-40. In
particular, the present compositions advantageously are
substantially free of added preservative components or include
effective preservative components which are more compatible with or
friendly to the posterior segment, e.g., retina, of the eye
relative to benzyl alcohol, which is included in the
Kenalog.RTM.-40 composition as a preservative.
[0028] In addition, the present compositions preferably include no
added resuspension component or a resuspension component which is
more compatible with or friendly to the posterior segment, e.g.,
retina, of the eye relative to polysorbate-80, which is included in
the Kenalog.RTM.-40 composition. Many of the other features of the
present compositions, as described elsewhere herein, also render
the present compositions more compatible with or friendly to the
posterior segments of the eyes into which the compositions are
placed relative to prior art compositions, such as
Kenalog.RTM.-40.
[0029] As noted above, the present compositions include a
corticosteroid component. Such corticosteroid component is present
in the compositions in a therapeutically effective amount, that is
in an amount effective in providing a desired therapeutic effect in
the eye into which the composition is placed. The corticosteroid
component is present in the composition in a plurality of
particles.
[0030] Any suitable corticosteroid component may be employed in
according to the present invention. Such corticosteroid component
advantageously has a limited solubility in water, for example, at
25.degree. C. For example, the corticosteroid component preferably
has a solubility in water at 25.degree. C. of less than 10 mg/ml.
Of course, the corticosteroid component should be ophthalmically
acceptable, that is, should have substantially no significant or
undue detrimental effect of the eye structures or tissues. One
particularly useful characteristic of the presently useful
corticosteroid components is the ability of such component to
reduce inflammation in the posterior segment of the eye into which
the composition is placed caused by the result of one or more
diseases and/or conditions in the posterior segment of the eye.
[0031] Examples of useful corticosteroid components include,
without limitation, cortisone, prednesolone, triamcinolone,
triamcinolone acetonide, fluorometholone, dexamethosone, medrysone,
loteprednol, derivatives thereof and mixtures thereof. As used
herein, the term "derivative" refers to any substance which is
sufficiently structurally similar to the material of 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.
[0032] In one very useful embodiment, the corticosteroid component
comprises triamcinolone acetonide.
[0033] The corticosteroid component advantageously is present in an
amount of at least about 10 mg per ml of the composition. One
important advantage of the present invention is the effective
ability of the present compositions to include relatively large
amounts or concentrations of the corticosteroid component. Thus,
the corticosteroid component 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 30% or more (w/v) of the
composition. Providing relatively high concentrations or amounts of
corticosteroid component in the present compositions is beneficial
in that 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 corticosteroid component in the
posterior segment of the eye relative to compositions, such as
Kenalog.RTM.-40, which include less than 4% (w/v) of the
corticosteroid component. Thus, in one very useful embodiment, the
present compositions include more than about 4% (w/v), for example
at least about 5% (w/v), to about 10% (w/v) or about 20% (w/v) or
about 30% (w/v) of the corticosteroid component.
[0034] The viscosity inducing component is present in an effective
amount in increasing, advantageously substantially increasing, the
viscosity of the composition. Without wishing to limit the
invention to any particular theory of operation, it is believed
that increasing the viscosity of the compositions to values well in
excess of the viscosity of water, for example, at least about 100
cps at a shear rate of 0.1/second, compositions which are highly
effective for placement, e.g., injection, into the posterior
segment of an eye of a human or animal are obtained. Along with the
advantageous placement or injectability of the present compositions
into the posterior segment, the relatively high viscosity of the
present compositions are believed to enhance the ability of the
present compositions to maintain the corticosteroid component
particles in substantially uniform suspension in the compositions
for prolonged periods of time, for example, for at least about one
week, without requiring resuspension processing. The relatively
high viscosity of the present compositions may also have an
additional benefit of at least assisting the compositions to have
the ability to have an increased amount or concentration of the
corticosteroid component, as discussed elsewhere herein, for
example, while maintaining such corticosteroid component in
substantially uniform suspension for prolonged periods of time.
[0035] Advantageously, the present compositions have viscosities of
at least about 10 cps or at least about 100 cps or at least about
1000 cps, more preferably at least about 10,000 cps and still more
preferably at least about 70,000 cps or more, for example up to
about 200,000 cps or about 250,000 cps, or about 300,000 cps or
more, at a shear rate of 0.1/second. The present compositions not
only have the relatively high viscosity as noted above but also
have the ability or are structured or made up so as to be
effectively placeable, e.g., injectable, into a posterior segment
of an eye of a human or animal, preferably through a 27 gauge
needle, or even through a 30 gauge needle.
[0036] The presently useful viscosity inducing components
preferably are shear thinning components in that as the present
composition containing such a shear thinning viscosity inducing
component is passed or injected into the posterior segment of an
eye, for example, through a narrow space, such as 27 gauge needle,
under high shear conditions the viscosity of the composition is
substantially reduced during such passage. After such passage, the
composition regains substantially its pre-injection viscosity so as
to maintain the corticosteroid component particles in suspension in
the eye.
[0037] 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.
[0038] 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.
[0039] 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.
[0040] 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.
[0041] In one very useful embodiment, a viscosity inducing
component is a polymeric 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 polymeric 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.
[0042] The aqueous carrier component is advantageously
ophthalmically acceptable and may include one or more conventional
excipients useful in ophthalmic compositions.
[0043] 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.
[0044] 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.
[0045] The buffer component and tonicity component may be chosen
from those which are conventional and well known in the ophthalmic
art.
[0046] 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.
[0047] 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.
[0048] 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, chlorhexidine, PHMB (polyhexamethylene
biguanide), 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.
[0049] In addition, the present composition may include an
effective amount of resuspension component effective to facilitate
the suspension or resuspension of the corticosteroid 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 corticosteroid 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 than polysorbate 80.
[0050] 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.
[0051] 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.
[0052] 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.
[0053] The availability of minimally soluble corticosteroid
components, such as triamcinolone acetonide, to intraocular tissues
may be limited by the dissolution rate for these substances. Slow
dissolution is both good and bad for the patient. On the one hand,
after a single intravitreal injection of the present composition,
the mean elimination half-life for triamcinolone acetonide is
advantageously quite long, for example, about 19 days in
nonvitrectonized patients and measurable drug levels are detected
for up to about 3 months. On the other hand, therapeutic drug
levels in the vitreous compartment of the eye may not be achieved
for about 1 to about 3 days, due to the slow dissolution rate of
the corticosteroid component particles.
[0054] In one embodiment of the present invention, an effective
amount of a solubilizing component is provided in the composition
to solubilize a minor amount, that is less than 50%, for example in
a range of 1% or about 5% to about 10% or about 20% of the
corticosteroid component. For example, the inclusion of a
cyclodextrin component, such as .beta.-cyclodextrin,
sulfo-butylether .beta.-cyclodextrin (SBE), other cyclodextrins and
the like and mixtures thereof, at about 0.5 to about 5.0% (w/v)
solubilizes about 1 to about 10% of the initial dose of
triamcinolone acetonide. This presolubilized fraction provides a
readily bioavailable loading dose, thereby avoiding any delay time
in therapeutic effectiveness.
[0055] The use of such a solubilizing component is advantageous to
provide any relatively quick release of the corticosteroid
component into the eye for therapeutic effectiveness. Such
solubilizing component, of course, should be ophthalmically
acceptable or at least sufficiently compatible with the posterior
segment of the eye into which the composition is placed to avoid
undue damage to the tissue in such posterior segment.
[0056] The pharmacokinetics of the corticosteroid component, for
example, triamcinolone acetonide, following intravitreal
administration may involve both the rate of drug dissolution and
the rate of drug efflux via the anterior route. For example,
following a single intravitreal injection of a composition
containing 4% (w/v) of triamcinolone acetonide, TA concentration
peaks (monitored in aqueous humor) after several days at thousands
of nanograms per mL. This peak (C.sub.max) is followed by a rapid
decrease lasting about 200 hours, and ends in a slow elimination
phase with a half-life of about 19 days. Patients typically require
repeat dosing, for example about every three months.
[0057] In one embodiment of the present invention, the compositions
further contain sustained release components, for example,
polymers, such as poly (D,L,-lactide) or poly(D,L-lactide
co-glycolide), in amounts effective to reduce local diffusion rates
and/or corticosteroid particle dissolution rates. The result is a
flatter elimination rate profile with a lower C.sub.max and a more
prolonged therapeutic window, thereby extending the time between
required injections for many patients.
[0058] Any suitable, preferably conditionally acceptable, release
component may be employed. Useful examples are set forth above. The
sustained release component is preferably biodegradable or
bioabsorbable in the eye so that no residue remains over the long
term. The amount of the delayed release component included may very
over a relatively wide range depending, for example, on the
specific sustained release component is being employed, the
specific release profile desired and the like factors. Typical
amounts of delayed release components, if any, included in the
present compositions are in a range of about 0.05 to 0.1 to about
0.5 or about 1 or more percent (w/v) of the composition.
[0059] The present 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 useful embodiment a
concentration corticosteroid component dispersion is made by
combining the corticosteroid component with water, and the
excipient (other than the viscosity inducing component) to be
included in the final composition. The ingredients are mixed to
disperse the corticosteroid component and then autoclaved.
Alternatively, the steroid powder may be .gamma.-irradiated before
addition to the sterile carrier. The viscosity inducing component
may be purchased sterile or sterilized by conventional processing,
for example, by filtering a dilute solution followed by
lyophylization to yield a sterile powder. The sterile viscosity
inducing component is combined with water to make an aqueous
concentrate. Under aseptic conditions, the concentrated
corticosteroid component dispersion is mixed and added as a slurry
to the viscosity inducing component concentrate. Water is added in
a quantity sufficient (q.s.) to provide the desired composition and
the composition is mixed until homogenous.
[0060] Methods of using the present composition are provided and
are included within the scope of the present invention. In general,
such methods comprise administering a composition in accordance
with the present invention to a posterior segment of an eye of a
human or animal, thereby obtaining 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. 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.
[0061] Among the diseases/conditions which can be treated or
addressed in accordance with the present invention include, without
limitation, the following:
[0062] 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.
[0063] 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.
[0064] 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.
[0065] TRAUMATIC/SURGICAL: Sympathetic Ophthalmia, Uveitic Retinal
Disease, Retinal Detachment, Trauma, Laser, PDT, Photocoagulation,
Hypoperfusion During Surgery, Radiation Retinopathy, Bone Marrow
Transplant Retinopathy.
[0066] PROLIFERATIVE DISORDERS: Proliferative Vitreal Retinopathy
and Epiretinal Membranes, Proliferative Diabetic Retinopathy.
[0067] 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.
[0068] 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.
[0069] RETINAL TEARS/HOLES: Retinal Detachment, Macular Hole, Giant
Retinal Tear.
[0070] 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.
[0071] MISCELLANEOUS: Punctate Inner Choroidopathy, Acute Posterior
Multifocal Placoid Pigment Epitheliopathy, Myopic Retinal
Degeneration, Acute Retinal Pigement Epithelitis and the like.
[0072] 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.
[0073] The following non-limiting Examples illustrate certain
aspects of the present invention.
EXAMPLES 1 TO 4
[0074] Four compositions are as follows:
1 Ingredient Example 1 Example 2 Example 3 Example 4 Triacinolone
acetonide 2% 2% 4% 4% (w/v) (w/v) (w/v) (w/v) Sodium Hyaluronate
0.05% 0.5% 0.05% 0.5% (0.6 .times. 10.sup.6 DALTONS) (w/v) (w/v)
(w/v) (w/v) Sodium Phosphate 0.4% 0.4% 0.4% 0.4% (w/v) (w/v) (w/v)
(w/v) Vitamin E-TPGS 0.5% 0.5% 0.0 0.0 (w/v) (w/v)
.lambda.-cyclodextrin 0.5% 0.5% 0.0 0.0 (w/v) (w/v) Water for
Injection q.s. q.s. q.s. q.s. Viscosity at shear rate 20 cps 500
cps 20 cps 500 cps 0.1/second
[0075] Each of these compositions is prepared as follows.
[0076] A concentrated triamcinolone acetonide dispersion is made by
combining triamcinolone acetonide with water, Vitamin E-TPGS and
.lambda.-cyclodextrin, if any. These ingredients are mixed to
disperse the triamcinolone acetonide, and then autoclaved. The
sodium hyaluronate may be purchased as a sterile powder or
sterilized by filtering a dilute solution followed by
lyophylization to yield a sterile powder. The sterile sodium
hyaluronate is dissolved in water to make an aqueous concentrate.
The concentrated triamcinolone acetonide dispersion is mixed and
added as a slurry to the sodium hyaluronate concentrate. Water is
added q.s. and the mixture is mixed until homogenous.
[0077] Each of these compositions produced a loose floctuation of
triamcinolone acetonide that is easily re-suspended by gentle
inversion. These compositions can be marketed in small volume
pharmaceutical grade glass bottles, and are found to be
therapeutically effective against macular edema when injected
intravitreally into human eyes.
EXAMPLES 5 TO 7
[0078] Three compositions are as follows:
2 Ingredient Example 5 Example 6 Example 7 Triamcinolone 2.0% (w/v)
4.0% (w/v) 8.0% (w/v) acetonide Sodium hyaluronate 3.0% (w/v) 2.5%
(w/v) 2.0% (w/v) Sodium Phosphate 0.4% (w/v) 0.4% (w/v) 0.4% (w/v)
Water for Injection q.s. q.s. q.s. Viscosity at shear 180,000 cps
120,000 cps 80,000 cps rate 0.1/second
[0079] These compositions are prepared in a manner substantially
analogous to that set forth in Example 1.
[0080] The high viscosities of the compositions substantially slows
the particle sedimentation rate to an extent that no resuspension
processing is necessary or required over the estimated shelf life,
e.g., about 2 years, of the compositions. These compositions can be
marketed in prefilled syringes since they can not easily be removed
by a needle and syringe from a container. However, with the
compositions in prefilled syringes, the compositions can be
effectively injected into the posterior segment of an eye of a
human using a 27 gauge or a 30 gauge needle to provide a desired
therapeutic effect in the human eye.
[0081] The compositions of Examples 5 to 7 employ or contain a
sufficient concentration of high molecular weight sodium
hyaluronate so as to form a gelatinous plug or drug depot upon
intravitreal injection into a human eye. Triamcinolone acetonide
particles are, in effect, trapped or held within this viscous plug,
so that undesirable "pluming" does not occur, and the risk of drug
particles disadvantageously settling directly on the retinal tissue
is substantially reduced, for example, relative to using a
composition with a water like viscosity, such as Kenalog.RTM. 40.
Since sodium hyaluronate solutions are subject to dramatic shear
thinning, these formulations are easily injected through 27 gauge
or even 30 gauge needles.
EXAMPLES 8 AND 9
[0082] Two compositions are as follows:
3 Ingredient Example 8 Example 9 Triamcinolone acetonide 2.0% (w/v)
8.0% (w/v) Sodium hyaluronate 2.5% (w/v) 2.3% (w/v) Sodium chloride
0.63% (w/v) 0.6% (w/v) dibasic sodium phosphate, 0.30% (w/v) 0.30%
(w/v) heptahydrate Monobasic sodium phosphate, 0.04% (w/v) 0.04%
(w/v) monohydrate Water for Injection q.s. q.s. Viscosity at shear
rate 170,000 .+-. 25% cps 200,000 .+-. 25% cps 0.1/second
[0083] These compositions are prepared in a manner substantially
analogous to that set forth in Example 1.
[0084] The high viscosities of the compositions substantially slows
the particle sedimentation rate to an extent that no resuspension
processing is necessary or required over the estimated shelf life,
e.g., about 2 years, of the compositions. These compositions can be
marketed in prefilled syringes since they can not easily be removed
by a needle and syringe from a container. However, with the
compositions in prefilled syringes, the compositions can be
effectively injected into the posterior segment of an eye of a
human using a 27 gauge or a 30 gauge needle to provide a desired
therapeutic effect in the human eye.
[0085] The sodium hyaluronate powders used in these compositions
(as well as in the other compositions identified in the Examples
herein) have water contents in a range of about 4% to about 20%,
preferably about 4% to about 8%, by weight. The water content of
the powder, and in particular the variation in water contents for
powder to powder, can result in variations in the viscosities of
two or more compositions in accordance with the present invention
which have the same "nominal" chemical make-ups. Thus, the
viscosities indicated herein should be understood to be target
viscosities, with the composition being acceptable for use if the
actual viscosity of the composition is within plus or minus (.+-.)
about 25% or about 30% or about 35% of the target viscosity.
[0086] Because each of the compositions set forth in the Examples
has a density of about 1 gm/ml, the percentages set forth herein as
being based on weight per volume (w/v) can also be considered as
being based on weight per weight (w/w).
[0087] The compositions of Examples 8 and 9 employ or contain a
sufficient concentration of high molecular weight sodium
hyaluronate so as to form a gelatinous plug or drug depot upon
intravitreal injection into a human eye. Triamcinolone acetonide
particles are, in effect, trapped or held within this viscous plug,
so that undesirable "pluming" does not occur, and the risk of drug
particles disadvantageously settling directly on the retinal tissue
is substantially reduced, for example, relative to using a
composition with a water like viscosity, such as Kenalog.RTM. 40.
Since sodium hyaluronate solutions are subject to dramatic shear
thinning, these formulations are easily injected through 27 gauge
or even 30 gauge needles.
[0088] 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.
* * * * *