U.S. patent application number 17/206890 was filed with the patent office on 2021-07-08 for methods for treating ocular inflammatory diseases.
This patent application is currently assigned to SUN PHARMA GLOBAL FZE. The applicant listed for this patent is SUN PHARMA GLOBAL FZE. Invention is credited to Lyle M BOWMAN, Kamran HOSSEINI.
Application Number | 20210205330 17/206890 |
Document ID | / |
Family ID | 1000005462334 |
Filed Date | 2021-07-08 |
United States Patent
Application |
20210205330 |
Kind Code |
A1 |
BOWMAN; Lyle M ; et
al. |
July 8, 2021 |
METHODS FOR TREATING OCULAR INFLAMMATORY DISEASES
Abstract
A method of treating non-infectious, inflammatory blepharitis
includes administering to the affected eye of a subject an
effective amount of an active ingredient in an ophthalmically
acceptable vehicle for a sufficient period of time to treat the
non-infectious, inflammatory blepharitis. The active ingredient
consists essentially of a glucocorticoid in an ophthalmically
acceptable vehicle that includes an aqueous polymer suspension that
when mixed with tear fluid provides a sustained release of said
active ingredient. The aqueous polymer suspension includes a
carboxyl-containing polymer having less than about 5% by weight
cross-linking agent and has a viscosity in a range from about 1,000
to about 30,000 centipoises. A kit includes: (a) a composition
comprising about 0.1% by weight dexamethasone in this
ophthalmically acceptable vehicle and (b) instructions for using
the composition of (a) for the treatment of blepharitis.
Inventors: |
BOWMAN; Lyle M; (Pleasanton,
CA) ; HOSSEINI; Kamran; (Los Altos, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SUN PHARMA GLOBAL FZE |
Sharjah |
|
AE |
|
|
Assignee: |
SUN PHARMA GLOBAL FZE
Sharjah
AE
|
Family ID: |
1000005462334 |
Appl. No.: |
17/206890 |
Filed: |
March 19, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16237110 |
Dec 31, 2018 |
10980818 |
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17206890 |
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12399729 |
Mar 6, 2009 |
10201548 |
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16237110 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/573 20130101;
A61P 27/02 20180101; A61K 47/34 20130101; A61K 9/0051 20130101 |
International
Class: |
A61K 31/573 20060101
A61K031/573; A61P 27/02 20060101 A61P027/02; A61K 9/00 20060101
A61K009/00; A61K 47/34 20060101 A61K047/34 |
Claims
1. A kit comprising: (a) a topical pharmaceutical formulation for
administering to an eye of a subject, the composition comprising an
effective amount of a glucocorticoid in an ophthalmically
acceptable vehicle comprising an aqueous polymer suspension,
wherein said aqueous polymer suspension comprises a
carboxyl-containing polymer having less than about 5% by weight
cross-linking agent and has a viscosity in a range from about 1,000
to about 30,000 centipoises, and (b) instructions for using the
composition of (a) for the treatment of non-infectious,
inflammatory blepharitis.
2. The kit of claim 1, wherein the glucocorticoid is selected from
the group consisting of hydrocortisone, cortisone acetate,
prednisone, prednisolone, methylprednisolone, dexamethasone,
betamethasone, triamcinolone, and beclometasone,
fluorometholone.
3. The kit of claim 2, wherein the glucocorticoid is
dexamethasone.
4. The kit of claim 1, wherein the glucocorticoid is present in a
range from about 0.05% and to about 0.5% by weight.
5. The kit of claim 4, wherein the glucocorticoid is present in a
range from about 0.08% to about 0.12% by weight.
6. The kit of claim 3, wherein the glucocorticoid is present in at
about 0.1% by weight.
7. The kit of claim 1, wherein said ophthalmically acceptable
vehicle further comprises a preservative.
8. The kit of claim 1, wherein said preservative comprises
benzalkonium chloride.
9. The kit of claim 8, wherein said preservative is present in a
range from about 0.001 to about 0.005% by weight.
10. The kit of claim 1, wherein the average particle size of the
carboxyl-containing-polymer particles is in the range of 6 .mu.m to
50 .mu.m.
11. The kit of claim 1, wherein the carboxyl-containing-polymer is
present from about 0. 1% to about 6.5% by weight, based on the
total weight of the suspension.
12. The kit of claim 1, wherein the pharmaceutical formulation
further comprises a second polymer as a viscosifier.
13. The kit of claim 12, wherein the second polymer is chitosan or
a chitosan salt in an amount from about 0.01% to 0.5% by
weight.
14. The kit of claim 13, wherein chitosan or chitosan salt has a
molecular weight in a range from between about 50 kDa to about 100
kDa.
15. The kit of claim 13, wherein chitosan or chitosan salt has a
molecular weight in a range from between about 1000 kDa to about
3000 kDa.
16. The kit according to claim 1, where the origin of blepharitis
is not related to bacteria.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation of U.S. patent
application Ser. No. 16/237,110, filed Dec. 31, 2018, which is a
continuation-in-part of U.S. patent application Ser. No.
12/399,729, filed on Mar. 6, 2009, now U.S. Pat. No. 10,201,548,
issued on Feb. 12, 2019, the disclosure of which are incorporated
by reference herein in their entirety .
BACKGROUND OF THE INVENTION
[0002] This invention relates generally to methods for treating
ocular inflammatory diseases and, more specifically to methods for
treating blepharitis.
[0003] Blepharitis is an ocular disease characterized by
inflammation of the eyelid margins. Blepharitis may cause redness
of the eyes, itching and irritation of the eyelids in one or both
eyes. The pathophysiology of blepharitis is a complex combination
of any number of factors, including abnormal lid-margin secretions,
bacterial organisms, and abnormalities of the tear film. Other
causative agents of blepharitis can be fungal or viral in origin
including, for example, herpes simplex and varicella zoster.
Blepharitis can appear along with various dermatological conditions
including, for example, seborrheic dermatitis, rosacea, and
eczema.
[0004] Blepharitis occurs in two main forms. The first type,
anterior blepharitis, affects the outside front of the eyelid near
the eyelashes. The two most common causes of anterior blepharitis
are Staphylococcus bacterial infection and seborrheic dermatitis.
The second type, posterior blepharitis, affects the inner eyelid
and can be caused by problems with the meibomian glands. Two skin
disorders that commonly cause this form of blepharitis are acne
rosacea, which leads to red and inflamed skin, and seborrheic
dermatitis. Other conditions may give rise to blepharitis, whether
they be infectious or non-infectious, including, but not limited
to, bacterial infections or allergies.
[0005] Blepharitis has a strong tendency to recur and if left
untreated can lead to conjunctivitis and the eyelids can begin to
ulcerate in some circumstances. It is most commonly treated,
although not cured, via a thorough hygiene regimen that helps
remove crusts and some bacterial organisms. Under duress to prevent
or treat ulcerative blepharitis, pharmaceutical interventions have
utilized mixtures of anti-inflammatory agents in conjunction with
topical or systemic antibacterial agents. With the ubiquitous usage
of antibacterial agents, there is the risk that organisms will
develop drug resistance.
[0006] Thus, there exists a need for improved treatments for
blepharitis. The present invention satisfies this need and provides
related advantages as well.
SUMMARY OF THE INVENTION
[0007] In some aspects, embodiments of the present invention relate
to a method of treating non-infectious, inflammatory blepharitis
that includes administering to the affected eye of a subject an
effective amount of an active ingredient in an ophthalmically
acceptable vehicle for a sufficient period of time to treat
blepharitis. The active ingredient consists essentially of a
glucocorticoid which is provided in an ophthalmically acceptable
vehicle. The vehicle includes an aqueous polymer suspension that
when mixed with tear fluid provides a sustained release of the
active ingredient. The aqueous polymer suspension includes a
carboxyl-containing polymer having less than about 5% by weight
cross-linking agent and has a viscosity in a range from about 1,000
to about 30,000 centipoises.
[0008] In other aspects, embodiments of the present invention
relate to a kit that includes a composition that includes about
0.1% by weight dexamethasone in an ophthalmically acceptable
vehicle. The ophthalmically acceptable vehicle includes an aqueous
polymer suspension that when mixed with tear fluid provides a
sustained release of said active ingredient. The aqueous polymer
suspension includes a carboxyl-containing polymer having less than
about 5% by weight cross-linking agent and has a viscosity in a
range from about 1,000 to about 30,000 centipoises. The kit further
includes instructions for using the composition of (a) for the
treatment of blepharitis.
DETAILED DESCRIPTION OF THE INVENTION
[0009] This invention is directed, in part, to a method of treating
non-infectious, inflammatory blepharitis with a glucocorticoid as a
primary active ingredient in the presence a slow release ophthalmic
carrier vehicle. This combination has been found effective in
ameliorating the clinical signs and symptoms associated with
non-infectious, inflammatory blepharitis. This is in contrast to
the standard pharmaceutical intervention which utilizes an
antibiotic in combination with an anti-inflammatory agent. Such
formulations known in the art are exemplified by TOBRADEX.RTM.
(0.3% tobramycin and dexamethasone alcohol), CORTISPORIN.RTM.
(neomycin or polymyxin B (10,000 units) with hydrocortisone),
Maxitrol (neomycin or polymyxin B (10,000 units) with
dexamethasone), BLEPHAMIDE.RTM. (10% sulfacetamide and prednisolone
acetate), and VASOCIDIN.RTM. (100 mg/mL sulfacetamide &
prednisolone sodium phosphate), all of which use relatively high
dosage of antibacterial agent. In addition to undesirable
side-effects associated with a number of the aforementioned
antibiotics, increased concern for the development of
drug-resistant bacterial strains provides the impetus for the
development of new treatment regimens that move away from using
such broad spectrum antibiotics. The need for reduced dependence on
these antibiotics for treating non-infectious, inflammatory
blepharitis is met by the present invention.
[0010] Thus, in one embodiment, the invention provides a method of
treating non-infectious, inflammatory blepharitis that includes
administering to the eye of a subject an effective amount of an
active ingredient in an ophthalmically acceptable vehicle for a
sufficient period of time to treat non-infectious, inflammatory
blepharitis. The active ingredient consists essentially of a
glucocorticoid, while the ophthalmically acceptable vehicle
includes an aqueous polymer suspension that when mixed with tear
fluid of the eye provides a sustained release of the active
ingredient. The aqueous polymer suspension includes a
carboxyl-containing polymer having less than about 5% by weight
cross-linking agent and has a viscosity in a range from about 1,000
to about 30,000 centipoises.
[0011] As used herein, the term "blepharitis" includes all types of
ocular disease characterized by inflammation of the eyelid margins,
including the broad categories of anterior blepharitis and
posterior blepharitis. The term encompasses blepharitis
characterized by its pathophysiological origins, including for
example, staphylococcal, seborrheic, mixed staphylococcal and
seborrheic, and meibomian gland dysfunction (MGD). Other conditions
may give rise to blepharitis, whether they be infectious or
non-infectious, including, but not limited to, bacterial infections
or allergies. Pathophysiological origins for which a glucocorticoid
is contraindicated are not encompassed by the term and include the
less common viral and fungal forms of blepharitis.
[0012] As used herein, "administering to the eye of a subject"
means administering the active ingredient in an ophthalmically
acceptable vehicle in the form of an eye drop directly to the eye
and/or in the eyelid margins, such administration techniques being
familiar to persons skilled in the art.
[0013] As used herein, "an effective amount" when used in
connection with treating non-infectious, inflammatory blepharitis
is intended to qualify the amount of a glucocorticoid used in the
treatment of treating non-infectious, inflammatory blepharitis
and/or prophylaxis against blepharitis. This amount will achieve
the goal of preventing, reducing, or eliminating blepharitis. An
effective amount includes from about 0.01 (mg/mL or .mu.g/mL) to
100 per dose in one embodiment and from about n to m dose in
another embodiment. An "effective amount" can include a dose
regimen once per day, twice per day, thrice per day, and so on.
[0014] As used herein an "ophthalmically acceptable vehicle" is one
which allows delivery of an active ingredient to treat treating
non-infectious, inflammatory blepharitis without deleterious
effects on the eye. An ophthalmically acceptable vehicle is one
that can maintain proper intraocular pressure and provide solutions
that are either isotonic, mildly hypotonic, or mildly hypertonic.
To maintain such conditions one can include various non-ionic
osmolality-adjusting compounds such as polyhydric alcohols,
including for example, glycerol, mannitol, sorbitol, or propylene
glycol. Alternatively, osmolality adjusting compounds can include
ionic salts such as sodium or potassium chloride. An ophthalmically
acceptable vehicle can also include buffers to adjust to an
acceptable pH, which can range from about 3 to 7.4. Such buffer
systems include, for example, acetate buffers, citrate buffers,
phosphate buffers, borate buffers and mixtures thereof. Specific
buffer components useful in the present invention include citric
acid/sodium citrate, boric acid, sodium borate, sodium phosphates,
including mono, di- and tri-basic phosphates, such as sodium
phosphate monobasic monohydrate and sodium phosphate dibasic
heptahydrate, and mixtures thereof. It should be noted that any
other suitable ophthalmically acceptable buffer components can be
employed to maintain the pH of the ophthalmic formulation so that
the ophthalmic formulation is provided with an acceptable pH, and
the foregoing buffer components are merely exemplary of such buffer
components.
[0015] As used herein, a "sufficient period" for treatment of
treating non-infectious, inflammatory blepharitis means a
sufficient time to prevent, reduce, or eliminate the occurrence of
clinical signs and symptoms associated with treating
non-infectious, inflammatory blepharitis in the eye of a subject.
Such an amount of time can be assessed, for example, by evaluating
eradication and/or reduction in the clinical signs or symptoms of
treating non-infectious, inflammatory blepharitis and the subject
no longer suffers its debilitating effects. For blepharitis of a
particular pathophysiological origin, the frequency, dosage, and
length of time can be determined in consultation with a
physician.
[0016] As used herein, "clinical signs or symptoms of blepharitis"
include redness and burning sensation of the eyes, itching, gritty
irritation of the eyelids, flaking of skin around the eyes, redness
and swelling of the eyelids, crusted scales on the eyelashes,
frothy tears, sensitivity to light, loss of eyelashes, misdirected
growth of eyelashes, a greasy appearance to the eyelids, sticky
secretions near the eyelashes, dry eye sensation, redness in the
eyelid margins, tearing, and any combination thereof.
[0017] As used herein "active ingredient" refers to the primary
compound responsible for reducing, preventing, or eliminating the
clinical signs and symptoms of blepharitis. Exemplary active
ingredients are the glucocorticoids, as disclosed herein.
[0018] As used herein "an ophthalmically acceptable salt" will
include those that exhibit no deleterious effects on the eye as
well as being compatible with the active ingredient itself and the
components of the ophthalmically acceptable vehicle. Salts or
zwitterionic forms of the active ingredient glucocorticoids of the
present invention can be water or oil-soluble or dispersible. The
salts can be prepared during the final isolation and purification
of the glucocorticoid or separately by adjusting the pH of the
appropriate glucocorticoid formulation with a suitable acid or
base.
[0019] In some embodiments, the invention provides a method of
treating treating non-infectious, inflammatory blepharitis that
includes administering to the affected eye of a subject an
effective amount of an active ingredient in an ophthalmically
acceptable vehicle for a sufficient period of time to treat
treating non-infectious, inflammatory blepharitis. The active
ingredient consists of essentially a glucocorticoid. The
ophthalmically acceptable vehicle includes an aqueous polymer
suspension that when mixed with tear fluid provides a sustained
release of the active ingredient. An exemplary aqueous polymer
suspension includes a carboxyl-containing polymer having less than
about 5% by weight cross-linking agent and has a viscosity in a
range from about 1,000 to about 30,000 centipoises.
[0020] In some embodiments, an effective amount of an active
ingredient is the amount used in the treatment of treating
non-infectious, inflammatory blepharitis and/or prophylaxis against
blepharitis. This amount will achieve the goal of preventing,
reducing, or eliminating treating non-infectious, inflammatory
blepharitis. An effective amount includes from about 0.1 .mu.g to
100 .mu.g per dose in one embodiment, and from about 1 .mu.g to 10
.mu.g per dose in another embodiment. An effective amount includes
all values in between and fractions thereof, for example, about 0.1
.mu.g, 0.5 .mu.g, 1 .mu.g, 5 .mu.g, 10 .mu.g, 15 .mu.g, 20 .mu.g,
30 .mu.g, 40 .mu.g, 50 .mu.g, 60 .mu.g, 70 .mu.g, 80 .mu.g, 90
.mu.g, up to about 100 .mu.g per dose. An effective amount can
administered in a dosing regimen once per day, twice per day,
thrice per day, or any number of times per day and can be
determined in consultation with a physician. An effective amount
can be administered as a solution in eye drop form as about 0.05%
to about 0.50% by weight solution of the active ingredient,
including for example, about 0.05%, 0.06%, 0.07%, 0.08%, 0.09%,
0.10%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%,
0.19%, 0.20%, 0.25%, 0.30%, 0.35%, 0.40%, 0.45%, and about 0.50%
and all values in between and fractions thereof.
[0021] In some embodiments, an active ingredient consists
essentially of a glucocorticoid. Glucocorticoids are potent
anti-inflammatory agents and can often be successfully administered
independent of the underlying cause of inflammation. Without being
bound by theory, glucocorticoids' primary anti-inflammatory
mechanism are reported to be related to lipocortin-1 (annexin-1)
synthesis. Lipocortin-1 suppresses phospholipase A2, thereby
blocking eicosanoid production, and inhibits various leukocyte
inflammatory events. In addition, glucocorticoids have been shown
to suppress cyclooxygenases, including COX-1 and COX-2.
[0022] Glucocorticoids can initiate an anti-inflammatory effect by
binding to the cytosolic glucocorticoid receptor (GR). After
binding GR, the receptor-ligand complex translocates to the cell
nucleus, where it can bind to glucocorticoid response elements
(GRE) in the promoter region of target genes. The proteins encoded
by these upregulated genes have a wide range of effects including
anti-inflammatory effects mediated, for example, by lipocortin I as
described above. Glucocorticoids can also reduce the transcription
of pro-inflammatory genes by a mechanism of transrepression. Thus,
inflammation associated with blepharitis can be ameliorated by
glucocorticoid treatment.
[0023] Accordingly, in some embodiments, the active ingredient of
the compositions and methods of the invention consists essentially
of a glucocorticoid including, for example, hydrocortisone,
cortisone acetate, prednisone, prednisolone, methylprednisolone,
dexamethasone, betamethasone, triamcinolone, and beclomethasone,
fluorometholone. Other glucocorticoids useful in the method for
treating blepharitis include, for example, 21-acetoxypregnenolone,
alclometasone, algestone, amcinonide, budesonide, chloroprednisone,
clobetasol, clobetasone, clocortolone, cloprednol, corticosterone,
cortisone, cortivazol, deflazacort, desonide, desoximetasone,
diflorasone, diflucortolone, difluprednate, enoxolone, fluazacort,
flucloronide, flumethasone, flunisolide, fluocinolone acetonide,
fluocinonide, fluocortin butyl, fluocortolone, fluperolone acetate,
fluprednidene acetate, fluprednisolone, flurandrenolide,
fluticasone propionate, formocortal, halcinonide, halobetasol
propionate, halometasone, halopredone acetate, hydrocortarnate,
loteprednol etabonate, mazipredone, medrysone, meprednisone,
mometasone furoate, paramethasone, prednicarbate, prednisolone
25-diethylamino-acetate, prednisolone sodium phosphate, prednival,
prednylidene, rimexolone, tixocortol, triamcinolone acetonide,
triamcinolone benetonide, triamcinolone hexacetonide, their
opthalmically acceptable salts, combinations thereof, and mixtures
thereof. In one embodiment, the glucocorticoid includes
dexamethasone, prednisone, prednisolone, methylprednisolone,
medrysone, triamcinolone, loteprednol etabonate, opthalmically
acceptable salts thereof, combinations thereof, and mixtures
thereof.
[0024] The effects of treating treating non-infectious,
inflammatory blepharitis with dexamethasone, in particular, with
the aid of the slow-release ophthalmically acceptable carrier, are
shown in the Example below, although any of the aforementioned
glucocorticoids are useful in the treatment of treating
non-infectious, inflammatory blepharitis. In accordance with
various embodiments of the invention, dexamethasone includes, for
example, dexamethasone sodium phosphate, dexamethasone (alcohol),
dexamethasone acetate, dexamethasone dimethylbutyrate,
dexamethasone trimethylacetate, dexamethasone dipropionate,
dexamethasone acefurate, and mixtures thereof.
[0025] In some embodiments the glucocorticoid is present in a range
from about 0.05% and to about 0.5% by weight, while in other
embodiments the glucocorticoid is present in a range from about
0.08% to about 0.12% by weight. The amount of glucocorticoid based
on weight percent can be any value between these values, including
for example, 0.05%, 0.060%, 0.07%, 0.08%, 0.09%, 0.10%, 0.11%,
0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.20%,
0.25%, 0.30%, 0.35%, 0.40%, 0.45%, and about 0.50% by weight and
all values in between and fractions thereof. A standard solution of
dexamethasone, in particular, for ophthalmic use is about 0.10% by
weight.
[0026] In some embodiments, the ophthalmically acceptable vehicle
uses insoluble polymers to provide a gel or liquid drops which
release the drug over time. The polymer is about 0.1 to about 6.5%
in some embodiments, and, in other embodiments about 1.0 to about
1.3% by weight based on the total weight of the suspension of a
cross-linked carboxy-containing polymer. Suitable
carboxy-containing polymers are described, for example, in U.S.
Pat. No. 5,192,535 to Davis et al. which is hereby incorporated by
reference. These polymer carriers include lightly crosslinked
carboxy-containing polymers (such as polycarbophil, or Noveon AA-1)
dextran, cellulose derivatives, polyethylene glycol 400 and other
polymeric demulcents such as polyvinylpyrolidone, polysaccaride
gels and GELRITE.RTM.. A carboxy-containing polymer system known by
the tradename DuraSite.RTM., containing polycarbophil, is a
sustained release topical ophthalmic delivery system that releases
the drug at a controlled rate, can also be used.
[0027] In accordance with some embodiments, a sustained release
topical ophthalmically acceptable carrier includes an aqueous
suspension at a pH of from about 3 to about 6.5 and an osmotic
pressure of from about 10 to about 400 mOsM containing from about
0.1% to about 6.5% by weight, based on the total weight of the
suspension, of a carboxyl-containing polymer prepared by
polymerizing one or more carboxyl-containing monoethylenically
unsaturated monomers and less than about 5% by weight of a
cross-linking agent, such weight percentages of monomers being
based on the total weight of monomers polymerized. The suspension
has an initial viscosity of from about 1,000 to about 30,000
centipoises and is administrable to the eye in drop form at that
initial viscosity. The polymer has average particle size of not
more than about 50 .mu.m, preferably not more than about 30 .mu.m,
in equivalent spherical diameter. It is lightly cross-linked to a
degree such that although the suspension is administrable in drop
form, upon contact of the lower pH suspension with the higher pH
tear fluid of the eye, the suspension is rapidly gellable to a
substantially greater viscosity than the viscosity of the
suspension as originally administered in drop form. Accordingly,
the resulting more viscous gel can remain in the eye for a
prolonged period of time so as to release a medicament contained
therein in sustained fashion.
[0028] The polymer is, in one embodiment, prepared from at least
about 50% by weight, and in other embodiments from at least about
90% by weight, of one or more carboxyl-containing monoethylenically
unsaturated monomers. The polymer can be prepared by suspension or
emulsion polymerizing acrylic acid and a non-polyalkenyl polyether
difunctional cross-linking agent to a particle size of not more
than about 50 .mu.m in one embodiment, and not more than about 30
.mu.m, in equivalent spherical diameter, in other embodiments. In
one embodiment, the cross-linking agent is divinyl glycol. In other
embodiments, one can replace up to about 40% by weight of the
carboxyl-containing monoethylenically unsaturated monomers by one
or more non-carboxyl-containing monoethylenically unsaturated
monomers containing only physiologically and ophthamologically
innocuous substituents.
[0029] The osmotic pressure is, in some embodiments, achieved by
using a physiologically and ophthalmologically acceptable salt in
an amount of from about 0.01% to about 1% by weight, based on the
total weight of the suspensions. Exemplary salts include potassium
and sodium chlorides.
[0030] In some embodiments, in a method of preparing sustained
release topical ophthalmically acceptable vehicles, the foregoing
suspensions are prepared and packaged at the desired viscosity of
from 1,000 to about 30,000 centipoises for administration to the
eye in drop form. In one exemplary delivery method, the foregoing
suspensions, containing the active ingredient, are administered to
the eye at the initial viscosity in drop form to cause the
administered suspension, upon contact with the higher pH tear fluid
of the eye, to rapidly gel in situ to a substantially greater
viscosity than the viscosity of the suspension as originally
administered in drop form. The more viscous gel remains in the eye
for a prolonged period of time so as to release the active
ingredient, entrapped in the more viscous gel formed in the eye, in
sustained fashion.
[0031] In contrast to other systems, the present invention provides
an ophthalmically acceptable vehicle that not only has the benefits
of administration in drop form, but also does not suffer from
breakdown limitations due to administration at a viscosity suitable
for drops. Through administration at a viscosity such that the
suspension can be reliably administered in drop form, but which
actually increases when the suspension is so administered,
controlled release of the active ingredient is significantly
enhanced.
[0032] As mentioned above, viscosities substantially over 30,000
cps are not useful for drop formulations. When the viscosities are
substantially lower than 1,000 cps, the ability to gel upon contact
with tears can be impeded. The increased gelation occurs with a pH
change when the suspension at a pH of from about 3 to about 6.5 and
an osmotic pressure of from about 10 to about 400 mOsM contacts the
tear fluid. As will be appreciated, tear fluid is at a higher pH of
about 7.2 to about 7.4. With the pH increase, the carboxylic acid
(COOH) functional group replaces the ionizable hydrogen cation with
sodium (to COONa), and the sodium form disassociates, causing the
polymer to expand.
[0033] This is where relationships of cross-linking and particle
size become quite significant. Because the particles are present in
a suspension, the degree of cross-linking is necessarily at a level
to avoid substantial dissolution of the polymer. On the other hand,
since rapid gelation is achieved at the time of the pH change, the
degree of cross-linking is necessarily not so great that gelation
is precluded. Moreover, if the polymer particle size is too large,
induced swelling tends to take up voids in the volume between large
particles that are in contact with one another, rather than causing
gelation.
[0034] If the polymer were in a dissolved state, as it would be if
there were insufficient cross-linking due to, e.g., an
insufficiently low ratio of cross-linker to monomer, particle size
would be basically irrelevant. In a therapeutic, topical
suspension, particle size can be relevant to patient comfort.
However, it has been found that in the system of the present
invention, the small particle size and light cross-linking
synergistically yield rapid gelation to provide a substantially
increased viscosity when the pH changes. In fact, above the 50
.mu.m size this advantage of substantially increased viscosity is
not realized, but at the 50 .mu.m size, there is also reasonably
good eye comfort.
[0035] In some embodiments, the particles are not only subject to
the upper size limits described above, but also to a narrow
particle size distribution. Such use of a monodispersion of
particles, which aids in good particle packing, yields a maximum
increased viscosity upon contact of the suspension with the tears
and increases eye residence time. At least about 80% in some
embodiments, at least about 90% in other embodiments, and at least
about 95% in still other embodiments, of the particles should be
within a 10 .mu.m or less band of major particle size distribution,
and overall (i.e., considering particles both within and outside
such band) there should be no more than about 20%, in some
embodiments, and no more than about 10%, in other embodiments, and
no more than about 5%, in still other embodiments, fines (i.e.,
particles of a size below 1 .mu.m). In some embodiments, the
average particle size is lowered from the upper limit of 50 .mu.m,
such as 30 .mu.m, and to lower sizes such as 6 .mu.m, that the band
of major particle size distribution be also narrowed, for example
to 5 .mu.m. In some embodiments, sizes for particles within the
band of major particle distribution are less than about 30 .mu.m,
less than about 20 .mu.m in other embodiments, and from about 1
.mu.m to about 5 .mu.m in still other embodiments.
[0036] The lightly cross-linked polymers of acrylic acid or related
alpha, beta-unsaturated carboxylic acids used in ophthalmically
acceptable vehicle are well known in the art. In one embodiment
such polymers are prepared from at least about 90%, or about 95%,
or about 99.9% by weight, based on the total weight of monomers
present, of one or more carboxyl-containing monoethylenically
unsaturated monomers. Acrylic acid is a common carboxyl-containing
monoethylenically unsaturated monomer, but other unsaturated,
polymerizable carboxyl-containing monomers, such as methacrylic
acid, ethacrylic acid, .beta.-methylacrylic acid (crotonic acid),
cis-.alpha.-methylcrotonic acid (angelic acid),
trans-.alpha.-methylcrotonic acid (tiglic acid),
.alpha.-butylcrotonic acid, .alpha.-phenylacrylic acid,
.alpha.-benzylacrylic acid, .alpha.-cyclohexylacrylic acid,
.beta.-phenylacrylic acid (cinnamic acid), coumaric acid
(o-hydroxycinnamic acid), umbellic acid (p-hydroxycoumaric acid),
and the like can be used in addition to or instead of acrylic
acid.
[0037] Such polymers are cross-linked by using a small percentage,
i.e., less than about 5%, such as from about 0.5% or from about
0.1% to about 5%, and in other emboidments from about 0.2% to about
1%, based on the total weight of monomers present, of a
polyfunctional cross-linking agent. Included among such
cross-linking agents are non-polyalkenyl polyether difunctional
cross-linking monomers such as divinyl glycol;
2,3-dihydroxyhexa-1,5-diene; 2,5-dimethyl-1,5-hexadiene;
divinylbenzene; N,N-diallylacrylamide; N,N-di allylmethacrylamide
and the like. Also included are polyalkenyl polyether cross-linking
agents containing two or more alkenyl ether groupings per molecule,
preferably alkenyl ether groupings containing terminal H.sub.2
C.dbd.C<groups, prepared by etherifying a polyhydric alcohol
containing at least four carbon atoms and at least three hydroxyl
groups with an alkenyl halide such as allyl bromide or the like,
e.g., polyallyl sucrose, polyallyl pentaerythritol, or the like;
see, e.g., Brown U.S. Pat. No. 2,798,053. Diolefinic
non-hydrophilic macromeric cross-linking agents having molecular
weights of from about 400 to about 8,000, such as insoluble di- and
polyacrylates and methacrylates of diols and polyols,
diisocyanate-hydroxyalxyl acrylate or methacrylate reaction
products, and reaction products of isocyanate terminated
prepolymers derived from polyester diols, polyether diols or
polysiloxane diols with hydroxyalkylmethacrylates, and the like,
can also be used as the cross-linking agents; see, e.g., Mueller et
al. U.S. Pat. Nos. 4,192,827 and 4,136,250.
[0038] The lightly cross-linked polymers can be made from a
carboxyl-containing monomer or monomers as the sole
monoethylenically unsaturated monomer present, together with a
cross-linking agent or agents. They can also be polymers in which
up to about 40%, and in some embodiments, from about 0% to about
20% by weight, of the carboxyl-containing monoethylenically
unsaturated monomer or monomers has been replaced by one or more
non-carboxyl-containing monoethylenically unsaturated monomers
containing only physiologically and ophthalmologically innocuous
substituents, including acrylic and methacrylic acid esters such as
methyl methacrylate, ethyl acrylate, butyl acrylate,
2-ethylhexylacrylate, octyl methacrylate,
2-hydroxyethyl-methacrylate, 3-hydroxypropylacrylate, and the like,
vinyl acetate, N-vinylpyrrolidone, and the like; see Mueller et al.
U.S. Pat. No. 4,548,990 for a more extensive listing of such
additional monoethylenically unsaturated monomers. Particularly
preferred polymers are lightly cross-linked acrylic acid polymers
wherein the cross-linking monomer is 2,3-dihydroxyhexa-1,5-diene or
2,3-dimethylhexa-1,5-diene.
[0039] Exemplary commercially available lightly cross-linked
polymers useful in the invention include, for example,
polycarbophil (available, for example, from Lubizol,), a
polyacrylic acid cross-linked with divinyl glycol. Without being
bound by theory, this polymer benefits from its mucoadhesive
properties which aid in increasing the residence time of the active
ingredient in the eye. Other mucoadhesive polymers can be used in
conjunction with, or in lieu of the lightly cross-linked polymers
disclosed herein, for example, Carbopol 934P, Carbopol 980 or
hyaluronic acid. The latter has been demonstrated to be an
effective mucoadhesive polymer in ocular formulations (Saettone et
al. Int. J. Pharm. 51: 203-212, (1989)).
[0040] The lightly cross-linked polymers used in practicing this
invention can be prepared by suspension or emulsion polymerizing
the monomers, using conventional free radical polymerization
catalysts, to a dry particle size of not more than about 50 .mu.m
in equivalent spherical diameter; e.g., to provide dry polymer
particles ranging in size from about 1 to about 30 .mu.m, and in
other embodiments from about 3 to about 20 .mu.m, in equivalent
spherical diameter. In general, such polymers will range in
molecular weight estimated to be about 250,000 to about
4,000,000,000 and in some embodiments, about 500,000 to about
2,000,000,000.
[0041] Aqueous suspensions containing polymer particles prepared by
suspension or emulsion polymerization whose average dry particle
size is appreciably larger than about 50 .mu.m in equivalent
spherical diameter are less comfortable when administered to the
eye than suspensions otherwise identical in composition containing
polymer particles whose equivalent spherical diameters are, on the
average, below about 50 .mu.m. Moreover, above the average 50 .mu.m
size, the advantage of substantially increased viscosity after
administration is not realized. It has also been discovered that
lightly cross-linked polymers of acrylic acid or the like prepared
to a dry particle size appreciably larger than about 50 .mu.m in
equivalent spherical diameter and then reduced in size, e.g., by
mechanically milling or grinding, to a dry particle size of not
more than about 50 .mu.m in equivalent spherical diameter do not
work as well as polymers made from aqueous suspensions. While not
being bound by any theory or mechanism advanced to explain the
functioning of this invention, one possible explanation for the
difference of such mechanically milled or ground polymer particles
as the sole particulate polymer present is that grinding disrupts
the spatial geometry or configuration of the larger than 50 .mu.m
lightly cross-linked polymer particles, perhaps by removing
uncross-linked branches from polymer chains, by producing particles
having sharp edges or protrusions, or by producing ordinarily too
broad a range of particle sizes to afford satisfactory delivery
system performance. A broad distribution of particle sizes will
impair the viscosity-gelation relationship. In any event, such
mechanically reduced particles are less easily hydratable in
aqueous suspension than particles prepared to the appropriate size
by suspension or emulsion polymerization, and also are less able to
gel in the eye under the influence of tear fluid to a sufficient
extent and are less comfortable once gelled than gels produced in
the eye using the aqueous suspensions of this invention. However,
up to about, 40% by weight, e.g., from about 0% to over 20% by
weight, based on the total weight of lightly cross-linked particles
present, of such milled or ground polymer particles can be admixed
with solution or emulsion polymerized polymer particles having dry
particle diameters of not more than about 50 .mu.m when practicing
this invention. Such mixtures will also provide satisfactory
viscosity levels in the ophthalmically acceptable vehicle and in
the in situ gels formed in the eye coupled with ease and comfort of
administration and satisfactory sustained release of the active
ingredient to the eye, particularly when such milled or ground
polymer particles, in dry form, average from about 0.01 to about 30
.mu.m, and in other embodiments, from about 1 to about 5 .mu.m, in
equivalent spherical diameter.
[0042] In some embodiments, the particles have a narrow particle
size distribution within a 10 .mu.m band of major particle size
distribution which contains at least 80%, in other embodiments at
least 90%, and in still other embodiments at least 95% of the
particles. Also, there is no more than 20%, and in other
embodiments no more than 10%, and in still other embodiments no
more than 5% particles of a size below 1 .mu.m. The presence of
large amounts of such fines has been found to inhibit the desired
gelation upon eye contact. Apart from that, the use of a
monodispersion of particles will give maximum viscosity and an
increased eye residence time of the active ingredient in the
ophthalmically acceptable vehicle for a given particle size.
Monodisperse particles having a particle size of 30 .mu.m and below
are present in some embodiments. Good particle packing is aided by
a narrow particle size distribution.
[0043] The aqueous suspensions of this invention can contain
amounts of lightly cross-linked polymer particles ranging from
about 0.1% to about 6.5% by weight, and in other embodiments from
about 0.5% to about 4.5% by weight, based on the total weight of
the aqueous suspension. They can be prepared using pure, sterile
water, preferably deionized or distilled, having no physiologically
or ophthalmologically harmful constituents, and will be adjusted to
a pH of from about 3.0 to about 6.5, and in other embodiments from
about 4.0 to about 6.0, using any physiologically and
ophthalmologically acceptable pH adjusting acids, bases or buffers,
e.g., acids such as acetic, boric, citric, lactic, phosphoric,
hydrochloric, or the like, bases such as sodium hydroxide, sodium
phosphate, sodium borate, sodium citrate, sodium acetate, sodium
lactate, THAM (trishydroxymethylaminomethane), or the like and
salts and buffers such as citrate/dextrose, sodium bicarbonate,
ammonium chloride and mixtures of the aforementioned acids and
bases.
[0044] When formulating the aqueous suspensions of this invention,
their osmotic pressure (.lamda.) will be adjusted to from about 10
milliosmolar (mOsM) to about 400 mOsM, and preferably from about
100 to about 250 mOsM, using appropriate amounts of physiologically
and ophthalmologically acceptable salts. Sodium chloride can be
used to approximate physiologic fluid, and amounts of sodium
chloride ranging from about 0.01% to about 1% by weight, and in
other embodiments from about 0.05% to about 0.45% by weight, based
on the total weight of the aqueous suspension, will give
osmolalities within the above-stated ranges. Equivalent amounts of
one or more salts made up of cations such as potassium, ammonium
and the like and anions such as chloride, citrate, ascorbate,
borate, phosphate, bicarbonate, sulfate, thiosulfate, bisulfite and
the like, e.g., potassium chloride, sodium thiosulfate, sodium
bisulfite, ammonium sulfate, and the like can also be used in
addition to or instead of sodium chloride to achieve osmolalities
within the above-stated ranges.
[0045] The amounts of lightly cross-linked polymer particles, the
pH, and the osmotic pressure chosen from within the above-stated
ranges can be correlated with each other and with the degree of
cross-linking to give aqueous suspensions having viscosities
ranging from about 1,000 to about 30,000 centipoise, and in other
embodiments from about 5,000 to about 20,000 centipoise, as
measured at room temperature (about 25.degree. C.) using a
Brookfield Digital LVT Viscometer equipped with a number 25 spindle
and a 13R small sample adapter at 12 rpm. The correlations of those
parameters are also such that the suspensions will gel on contact
with tear fluid to give gels having viscosities estimated to range
from about 75,000 to about 500,000 centipoise, e.g., from about
200,000 to about 300,000 centipoise, measured as above, depending
on pH as observed, for example, from pH-viscosity curves. This
effect is noted by observing a more viscous drop on the eye as a
set cast. The cast, after setting, can be easily removed.
[0046] The viscous gels that result from fluid eyedrops delivered
by means of the aqueous suspensions of this invention have
residence times in the eye ranging from about 2 to about 12 hours,
e.g., from about 3 to about 6 hours. The active ingredients
contained in these ophthalmically acceptable vehicles can be
released from the gels at rates that depend on such factors as the
active ingredient itself and its physical form, the extent of drug
loading and the pH of the system, as well as on any drug delivery
adjuvants, such as ion exchange resins compatible with the ocular
surface, which can also be present. For fluorometholone, for
example, release rates in the rabbit eye in excess of four hours,
as measured by fluorometholone contained in the aqueous humor, have
been observed.
[0047] The active ingredient-ophthalmically acceptable vehicle can
be formulated in any of several ways. For example the active
ingredient, the lightly cross-linked polymer particles, and the
osmolality-adjusting salt can be preblended in dry form, added to
all or part of the water, and stirred vigorously until apparent
polymer dispersion is complete, as evidenced by the absence of
visible polymer aggregates. Sufficient pH adjusting agent is then
added incrementally to reach the desired pH, and more water to
reach 100 percent formula weight can be added at this time, if
necessary. Another convenient method involves adding the drug to
about 95 percent of the final water volume and stirring for a
sufficient time to saturate the solution. Solution saturation can
be determined in known manner, e.g., using a spectrophotometer. The
lightly cross-linked polymer particles and the osmolality-adjusting
salt are first blended in dry form and then added to the
drug--saturated suspension and stirred until apparent polymer
hydration is complete. Following the incremental addition of
sufficient pH adjusting agent to reach the desired pH, the
remainder of the water is added, with stirring, to bring the
suspension to 100 percent formula weight.
[0048] These aqueous suspensions can be packaged in
preservative-free, single-dose non-reclosable containers. This
permits a single dose of the active ingredient to be delivered to
the eye one drop at a time, with the container then being discarded
after use. Such containers eliminate the potential for
preservative-related irritation and sensitization of the corneal
epithelium, as has been observed to occur particularly from
ophthalmic medicaments containing mercurial preservatives.
Multiple-dose containers can also be used, if desired, particularly
since the relatively low viscosities of the aqueous suspensions of
this invention permit constant, accurate dosages to be administered
dropwise to the eye as many times each day as necessary.
[0049] In those vehicles where preservatives are to be included,
suitable preservatives include, for example, chlorobutanol,
Polyquat, benzalkonium chloride, cetyl bromide, benzethonium
chloride, cetyl pyridinium chloride, benzyl bromide, EDTA,
phenylmercury nitrate, phenylmercury acetate, thimerosal,
merthiolate, acetate and phenylmercury borate, chlorhexidine,
polymyxin B sulphate, methyl and propyl parabens, phenylethyl
alcohol, quaternary ammonium chloride, sodium benzoate, sodium
proprionate, sorbic acid, and sodium perborate, and combinations
thereof. In particular embodiments, the preservative includes
benzalkonium chloride.
[0050] In some embodiments, the preservative is present in a range
from about 0.001 to about 0.005% by weight. The preservative can be
present at about 0.001, 0.002, 0.003, 0.004, 0.005 and any amount
in between these amounts. In particular, the present invention has
the benefit of substantial reduction in the use of a bactericidal
component. Thus, in some embodiments, the present invention
provides an ophthalmically acceptable vehicle having less than
about 0.02% of a preservative with bactericidal activity in one
embodiment, and less than about 0.01%, 0.009%, 0.008%, 0.007%,
0.006%, 0.005%, 0.004%, 0.003%, 0.002%, or 0.001%, in other
embodiments.
[0051] In some embodiments, the ophthalmically acceptable vehicle
includes a wetting agent. Such agents can be useful in distributing
the active ingredient in an otherwise predominantly aqueous
environment. Such wetting agents include, for example, Poloxamer
407, a triblock copolymer consisting of a central hydrophobic block
of polypropylene glycol flanked by two hydrophilic blocks of
polyethylene glycol. Other wetting agents that can be used include
carboxymethylcellulose, hydroxypropyl methylcellulose, glycerin,
mannitol, polyvinyl alcohol, hydroxyethylcellulose, and
combinations thereof.
[0052] In some embodiments, the ophthalmically acceptable vehicle
can include a thickening agent, a second polymer or viscosfier that
modulates the viscosity of the vehicle. These include, without
limitation, polyvinyl alcohol, polyacrylic acid, polyethylene
oxide, chitosan, chitosan salts, cellulosic polymers, such as
hydroxypropylmethyl cellulose (HPMC), and hydroxymethyl cellulose
(HMC), polysaccharide gels/gums such as gum arabic, locust bean
gum, gellan gum and xanthan gum.
[0053] The second polymer can be any polymer that can enhance the
viscosity and mucoadhesive properties of the vehicle where the
combination is greater than each individual polymer alone and is
also ophthalmically acceptable. Numerous examples of ophthalmically
acceptable polymers are disclosed in Wagh et al. Asian J.
Pharmaceutics (2008), which is incorporated by reference herein in
its entirety. Exemplary second polymers include, without
limitation, hydroxyproplymethyl cellulose (HPMC), hydroxypropyl
cellulose (HPC), methyl cellulose (MC), hydroxyethyl cellulose
(HEC), polyacrylic acid (PAA), polyvinyl alcohol, carbomers, sodium
hyaluronate, chitosan, cyclodextrins, polygalacturonic acid,
polyitaconic acid, xyloglucan, xanthan gum, gellan gum,
polyorthoesters, celluloseacetophthalate, poloxamer 407,
polyethyleneimine, and polyethylene oxide. In some embodiments, the
second polymer can be a neutral polymer, a cationic polymer, or a
second anionic polymer.
[0054] In particular embodiments, the second polymer can be a
cationic polymer. Cationic polymers include any ophthalmically
acceptable polyamine polymer capable of modulating the Theological
and/or mucoadhesive properties of the vehicle. Such polyamines
include, for example, poly-L-lysine (PLL), chitosan, a naturally
occurring polysaccharide containing D-glucosamine,
polyethyleneimine (PEI), and polyquaternium compounds that include
but not limited to Polyquaternium 1, Polyquaternium 7, and
Polyquarternium 10. Without being bound by theory, a cationic
polymer can impact the vehicle characteristics in at least two
different ways. Firstly, the cationic polymer can enhance
electrostatic interactions between the carrier and the negatively
charged mucins of the corneal epithelium. Such an interaction can
confer beneficial mucoadhesive properties to the vehicle. Secondly,
the viscosity of the aqueous suspension of the carboxy-containing
polymer is increased by the addition of a cationic polymer, even
prior to administration to the eye. Again, without being bound by
theory, the cationic polyamine polymer can assist in particle
aggregation through hydrogen bonding and/or by electrostatic
interactions to effectively generate larger molecular weight
constructs which increase the aqueous suspension's viscosity. In
order to realize the benefits of the added cationic polymer, it
should present in an amount that allows the particles of the
carboxy-containing polymer to remain suspended, since these
advantages are lost upon removal of the carboxy-containing
particles from a suspended state. The increased viscosity of the
dual cationic polymer/carboxy-containing polymer system can also
help counter the effects of the clearance mechanisms in the
eye.
[0055] In some embodiments, the cationic polymer is chitosan.
Chitosan is obtained by deacetylation of chitin and possesses
mucoadhesive properties due to electrostatic interaction between
positively charged chitosan ammonium groups and negatively charged
mucosal surfaces. Chitosan is a linear polysaccharide composed of
randomly distributed .beta.-(1-4)-linked D-glucosamine and
N-acetyl-D-glucosamine. Chitosan is available with varying degrees
of deacetylation (% DA) and is generally produced in a range from
between about 60 to about 100% deacetylation. The amino group in
chitosan has a pKa value of about 6.5, thus, chitosan is positively
charged and soluble in acidic to neutral solution with a charge
density dependent on pH and the % DA-value. Chitosan can enhance
the transport of polar drugs across epithelial surfaces, and is
considered biocompatible and biodegradable.
[0056] In some embodiments, chitosan used in the vehicle has a
molecular weight in a range from between about 50 kDa to about 100
kDa, including any weights in between, while in other embodiments,
chitosan used in the vehicle has a molecular weight in a range from
between about 1,000 to about 3,000 kDa, and any weights in between.
As shown in U.S. Pat. No. 8,501,800 and Example II below, the range
between about 1,000 kDa and about 3,000 kDa appears to have a
larger impact on viscosity of the vehicle, even at very small
concentrations of the cationic polymer. In order to achieve
comparable viscosities with chitosan alone, solutions of chitosan
several orders of magnitude more concentrated have been used, for
example, from between about 2% to about 4%.
[0057] In the ophthalmically acceptable vehicle of the present
invention, chitosan or other second polymer is present in an amount
ranging from between about 0.01% to about 0.5% when using a
cationic polymer having a molecular weight ranging from about 50
kDa to about 100 kDa. The amount of cationic polymer or chitosan
can be any amount in between, including about 0.01%, 0.025%, 0.05%.
0.075%, 0.10%, 0.15%, 0.20%, 0.25%, 0.30%, 0.35%, 0.40%, 0.45%, and
0.50% and any amount in between these values. When using higher
molecular weight cationic polymers, such as between about 1,000 to
about 3,000 kDa, the amount of cationic polymer necessary to
achieve favorable viscosities can be substantially reduced. For
example, the amount of 1,000 kDa to about 3,000 kDa chitosan can be
in a range between about 0.01% and 0.5%, or any amount in between
including, for example, 0.01%, 0.015%, 0.020%, 0.025%, 0.030%,
0.035%, 0.040%, 0.045%, 0.05%, 0.1%, 0.15%, 0.20%, 0.25%, 0.30%,
0.35%, 0.40%, 0.45%, and 0.50%.
[0058] In some embodiments, the viscosity is in a range from about
1,000 to about 30,000 centipoise, and in other embodiments from
about 5,000 to about 20,000 centipoise. In yet other embodiments,
the viscosity is in a range from about 10,000 to about 15,000
centipoise. The viscosity range can also be between about 1,000 and
5,000 centipoise, including 1,000, 1,500, 2,000, 2,500, 3,000,
3,500, 4,000, 4500, and 5,000 and all values in between. The
viscosity range can also be between about 5,000 to about 10,000
centipoise, including 5,000, 5,500, 6,000, 6,500, 7,000, 7,500,
8,000, 8,500, 9,000, 9,500, and 10,000 and all values in between.
The viscosity range can also be between about 10,000 to about
15,000 centipoise, including 10,000, 10,500, 11,000, 11,500,
12,000, 12,500, 13,000, 13,500, 14,000, 14,500, and 15,000 and all
values in between. The viscosity range can also be between about
15,000 to about 20,000 centipoise, including 15,000, 15,500,
16,000, 16,500, 17,000, 17,500, 18,000, 18,500, 19,000, 19,500, and
20,000 and all values in between. The viscosity range can also be
between about 20,000 to about 30,000 centipoise, including 20,000,
21,000, 22,000, 23,000, 24,000, 25,000, 26,000, 27,000, 28,000,
29,000, and 30,000 and all values in between. In particular
embodiments the viscosity is in a range from between about 1000 to
about 2000, including, for example, about 1,000, 1,050, 1,100,
1,150, 1,200, 1,250, 1,300, 1,350, 1,400, 1,450, 1,500, 1,550,
1,600, 1,650, 1,700, 1,750, 1,800, 1,850, 1,900, 1,950, and 2,000
and all values in between.
[0059] In some embodiments, the invention is directed to a kit
which includes: (a) a composition comprising about 0.1% by weight
dexamethasone in an ophthalmically acceptable capable of slow
release as detailed herein and (b) instructions for using the
composition of (a) for the treatment of blepharitis.
[0060] In some embodiments, the kit further includes a means for
administering the composition. In some embodiments, the means for
administering can include a bottle, dropper, cup, specialized
eye-wash apparatus, wetted towel or sponge. In some embodiments,
the kit includes a cleaning apparatus (e.g., a towel, pad, cloth,
brush, sponge, etc.) and/or a cleaning solution (e.g., purified
water, a detergent solution, a boric acid solution, etc.). In some
embodiments of the present invention, the ocular area is cleaned
prior to administration of the composition of the present
invention.
[0061] The composition can be individually packaged for a single
dose administration; e.g., in a bottle, jar, ampoule, tube,
syringe, envelope, container, or vial. When the composition is
individually packaged, in some embodiments, the composition does
not include a preservative. Alternatively, the composition can be
contained in a package that is capable of holding multiple units;
e.g., in resealable glass or plastic packages. In some kits, the
components of the composition are mixed together immediately
preceding their usage. For example, in some embodiments one or more
dry components of the composition of the kit are packaged in a
separate container; e.g., a plastic bottle, and then mixed with one
or more of the liquid components of the composition immediately
prior to use. Optionally, the kit of the present invention can
include a dropper or other device for transferring or administering
the composition to a subject.
[0062] The kit can further include instructions for using the
composition of the present invention. For example, such
instructions can be in a form prescribed by a governmental agency
regulating the manufacture, use or sale of pharmaceuticals or
biological products, which reflects approval by the agency of the
manufacture, use or sale for human application. In some
embodiments, the kit further includes information on the use of the
composition or a pre-recorded media device which, e.g., provides
information on the use of the method of the present invention.
[0063] The kit can also include a container for storing the
components of the kit. The container can be, for example, a bag,
box, envelope or any other container suitable for use in the
present invention. In some embodiments, the container is large
enough to accommodate each component of the present invention.
However, in some cases, it can be desirable to have a smaller
container which is large enough to carry only some of the
components.
[0064] It is understood that modifications which do not
substantially affect the activity of the various embodiments of
this invention are also included within the definition of the
invention provided herein. Accordingly, the following examples are
intended to illustrate but not limit the present invention.
EXAMPLE I
Dexamethasone to Treat Blepharitis
[0065] This Example shows a composition with 0.1% Dexamethasone
that is useful in a method for treating blepharitis.
[0066] Table 1 below provides an exemplary formulation of the
glucocorticoid dexamethasone as a 0.1% in an exemplary
ophthalmically acceptable vehicle of the invention.
TABLE-US-00001 TABLE 1 INGREDIENT CONCENTRATION (% W/W)
Dexamethasone, USP 0.10 Mannitol, USP 1.0 Citric Acid Anhydrous,
USP 0.20 Sodium Citrate Dihydrate, USP 0.14 Poloxamer 407, NF 0.20
Benzalkonium Chloride, NF 0.003 Polycarbophil, USP 0.90 Sodium
Chloride, USP 0.45 Edetate Disodium Dihydrate, 0.10 USP Sodium
Hydroxide, 2N Adjust to pH 6.3 Water For Injection, USP q.s. to
100%
[0067] In this example, a clinical study was to evaluate the
clinical and anti-microbial efficacy and safety of three
compositions, 1) 1.0% Azithromycin and 0.1% Dexamethasone in the
DURASITE vehicle (Az+Dex) 2) 1.0% Azithromycin alone in the
DURASITE vehicle (Az) and 3) dexamethasone alone in the DURASITE
vehicle (Dex) (Table 1) in the treatment of subjects with
blepharoconjunctivitis.
[0068] In this Example, 417 subjects were enrolled, and 386
completed the study. 417 subjects received at least one dose of
study drug, 417 subjects had at least one post-dose clinical
assessment and were included in the Intent-to-Treat (ITT)
population, 301 subjects in the ITT population had positive
bacterial cultures at baseline and were included in the modified
ITT (mITT) population, and 382 subjects in the ITT population had
no significant protocol violations and were included in the Per
Protocol (PP) Population.
[0069] For clinical diagnosis of blepharoconjunctivitis, subjects
had a minimum score of `1` for: [0070] one of the lid signs (lid
margin redness or lid swelling) [0071] one of the conjunctival
signs (bulbar conjunctival redness, palpebral conjunctival redness,
or ocular discharge); and, [0072] one of the symptoms (lid
irritation, itchy eyelids, gritty eyes, or painful/sore eyes) in at
least one eye. Subjects must also have had a minimum total score of
5 in this eye to be eligible for entry.
[0073] Subjects were randomly assigned to three groups with a 1:1:1
ratio: Az+Dex, Az, and Dex. Subjects were dosed with Az+Dex, Az, or
Dex BID at approximately 12-hour intervals for 14 days in both
eyes. Subjects were instructed to place one drop on their eyelids
and one drop into their eyes. This was a multi-center, randomized,
double-masked, 3-arm, parallel-group, comparative clinical trial,
with one interim analysis.
[0074] After subjects met all entry criteria and signed informed
consent, they underwent evaluations for visual acuity,
biomicroscopy, ophthalmoscopy, and IOP. Signs and symptoms were
evaluated, and lid and conjunctival cultures were obtained.
Subjects were randomized to receive their first dose of study
medication at the study site, and received instructions for dosing
at home and completing a diary.
[0075] The clinical signs were lid margin redness, lid swelling,
bulbar conjunctival redness, palpebral conjunctival redness, and
ocular discharge. The clinical symptoms were lid irritation, itchy
eyelids, gritty eyes, and painful/sore eyes. The clinical
resolution of clinical signs and symptoms were the primary efficacy
variable. Bacterial eradication of baseline bacterial counts were
the secondary efficacy variable.
Primary Efficacy Endpoint: Clinical Resolution
[0076] The primary endpoint of the study is clinical resolution,
defined as the absence of all study clinical signs and symptoms.
The ITT population with last observation carried forward (LOCF)
data was used in these analyses for Visit 5 clinical
resolution.
TABLE-US-00002 TABLE 2 Az + Dex Dex p-value 27.1% 23.5% 0.5807
[0077] As shown in Table 2, above, there was no significant
difference between the group treated with the combination of 1%
azithromycin and dexamethasone and the group receiving
dexamethasone alone. Dex was as effective as the Dex+Az combination
in treating blepharitis.
Secondary Efficacy Endpoint: Bacterial Eradication
[0078] The secondary efficacy endpoint is bacterial eradication of
baseline bacterial species at Visit 5. Eradication was assessed for
the conjunctiva and lid separately as well as combined. The mITT
population with LOCF data was used in these analyses for Visit 5
clinical resolution.
Combined (Eye Lid and Conjunctiva)
TABLE-US-00003 [0079] TABLE 3 Az + Dex Dex p-value 60.0% 40.2%
0.0068
[0080] As shown in Table 3, above, there was some improvement in
the group treated with the combination of 1% azithromycin and
dexamethasone relative to the group receiving dexamethasone alone.
However, the moderate antibacterial effect of dexamethasone alone
in the ophthalmically acceptable carrier of Table 1 provides an
improvement in bacterial eradication more than double of that
reported by Schulman et al. (supra).
Eye Lid Only
TABLE-US-00004 [0081] TABLE 4 Az + Dex Dex p-value 63.8% 40.9%
0.0029
[0082] As shown in Table 6, above, there was, again, some
improvement in the group treated with the combination of 1%
azithromycin and dexamethasone relative to the group receiving
dexamethasone alone. However, as above, the moderate antibacterial
effect of dexamethasone alone in the ophthalmically acceptable
carrier of Table 1 provides an improvement in bacterial eradication
more than double of that reported by Schulman et al. (supra).
Conjunctiva Only
TABLE-US-00005 [0083] TABLE 5 Az + Dex Dex p-value 79.6% 64.3%
0.1569
[0084] As shown in Table 5, above, there was, again, some
improvement in the group treated with the combination of 1%
azithromycin and dexamethasone relative to the group receiving
dexamethasone alone. However, as above, the antibacterial effect of
dexamethasone alone in the ophthalmically acceptable carrier of
Table 1 provides an improvement in bacterial eradication more than
triple of that reported by Schulman et al. (supra).
EXAMPLE II
Dexamethasone to Treat Blepharitis
[0085] This Example shows a composition with 0.1% Dexamethasone
that is useful in a method for treating blepharitis.
[0086] Table 6 below provides an exemplary formulation of the
glucocorticoid dexamethasone as a 0.1% in an exemplary
ophthalmically acceptable vehicle of the invention that included
chitosan hydrochloride (U.S. Pat. No. 8,501,800).
TABLE-US-00006 TABLE 6 Concentration Ingredient (% w/w) Amount Per
g (mg) Dexamethasone, Micronized 0.100 1.00 Mannitol, 1.100 11.00
Citric Acid Anhydrous, 0.200 2.00 Sodium Citrate Dihydrate 0.140
1.40 Poloxamer 407 0.200 2.00 Benzalkonium Chloride 0.003 0.03
Polycarbophil 0.8125 8.125 Chitosan Hydrochloride 0.025 0.25 Sodium
Chloride 0.450 4.50 Edetate Disodium Dihydrate 0.100 1.00 Sodium
Hydroxide Adjust to pH 6.3 Adjust to pH 6.3 Water for Injection qs
to 100% qs to 1 g
[0087] In this example, a clinical study was to evaluate the
clinical safety of dexamethasone and polymer vehicle (DURASITE II,
Table 6) as compared to the polymer vehicle alone in the treatment
of subjects with blepharitis.
[0088] In this Example, 550 subjects presenting with blepharitis
were enrolled, 366 treated with dexamethasone and polymer vehicle
and 184 treated only with the polymer vehicle. The two groups of
subjects presenting with blepharitis were treated twice daily (BID)
for 14 days.
[0089] For clinical diagnosis of blepharitis, subjects had a
minimum score of `1` for: [0090] eyelid redness [0091] eyelid
swelling [0092] eyelid debris [0093] eyelid irritation
[0094] Subjects presenting with blepharitis were randomly assigned
to the two groups with a 2:1 ratio: Dexamethasone and polymer
vehicle or polymer vehicle alone. Subjects were dosed with
Dexamethasone and polymer vehicle or polymer vehicle alone BID at
approximately 12-hour intervals for 14 days in both eyes. Subjects
were instructed to place one drop on their eyelids. This was a
multi-center, randomized, double-masked, 3-arm, parallel-group,
comparative clinical trial, with one interim analysis.
[0095] After subjects met all entry criteria and signed informed
consent, they underwent evaluations for visual acuity,
biomicroscopy, ophthalmoscopy, and IOP. Signs and symptoms were
evaluated. Subjects were randomized to receive their first dose of
study medication at the study site, and received instructions for
dosing at home and completing a diary.
[0096] The clinical signs were eyelid margin redness, eyelid
swelling, eyelid debris, and eyelid irritation. The clinical
symptoms were lid irritation, itchy eyelids, gritty eyes, and
painful/sore eyes. The clinical resolution of clinical signs and
symptoms were the primary efficacy variable.
Primary Efficacy Endpoint: Clinical Resolution
[0097] The primary endpoint of the study is clinical resolution,
defined as the absence of all study clinical signs and
symptoms.
[0098] The effect of dexamethasone and the ophthalmically
acceptable carrier of Table 1 as compared to the ophthalmically
acceptable carrier alone provides a significant improvement in
subjects presenting with non-infectious, inflammatory
blepharitis.
[0099] Throughout this application various publications have been
referenced within parentheses. The disclosures of these
publications in their entireties are hereby incorporated by
reference in this application in order to more fully describe the
state of the art to which this invention pertains.
[0100] Although the invention has been described with reference to
the disclosed embodiments, those skilled in the art will readily
appreciate that the specific examples and studies detailed above
are only illustrative of the invention. It should be understood
that various modifications can be made without departing from the
spirit of the invention. Accordingly, the invention is limited only
by the following claims.
* * * * *