U.S. patent application number 16/784081 was filed with the patent office on 2021-01-07 for compositions for the treatment of dry eye.
The applicant listed for this patent is Allergan, Inc.. Invention is credited to Peter A. Simmons, Joseph G. Vehige.
Application Number | 20210000859 16/784081 |
Document ID | / |
Family ID | |
Filed Date | 2021-01-07 |
United States Patent
Application |
20210000859 |
Kind Code |
A1 |
Vehige; Joseph G. ; et
al. |
January 7, 2021 |
COMPOSITIONS FOR THE TREATMENT OF DRY EYE
Abstract
The present invention relates to ophthalmic compositions and
methods useful to treat dry eye, or to diagnose, cure, mitigate,
treat, or prevent dry eye syndrome in man or other animals.
Inventors: |
Vehige; Joseph G.; (Laguna
Niguel, CA) ; Simmons; Peter A.; (Yorba Linda,
CA) |
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Applicant: |
Name |
City |
State |
Country |
Type |
Allergan, Inc. |
Irvine |
CA |
US |
|
|
Appl. No.: |
16/784081 |
Filed: |
February 6, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16129385 |
Sep 12, 2018 |
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16784081 |
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14601781 |
Jan 21, 2015 |
10105386 |
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16129385 |
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13645035 |
Oct 4, 2012 |
8957048 |
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14601781 |
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61544151 |
Oct 6, 2011 |
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Current U.S.
Class: |
1/1 |
International
Class: |
A61K 31/717 20060101
A61K031/717; A61K 9/00 20060101 A61K009/00; A61K 47/10 20060101
A61K047/10; A61K 47/26 20060101 A61K047/26; A61K 47/32 20060101
A61K047/32; A61K 47/38 20060101 A61K047/38; A61K 31/205 20060101
A61K031/205; A61K 33/22 20060101 A61K033/22; A61K 36/47 20060101
A61K036/47; A61K 31/047 20060101 A61K031/047; A61K 31/34 20060101
A61K031/34; A61K 31/745 20060101 A61K031/745 |
Claims
1. An ophthalmic composition comprising polyoxyethylene (80)
sorbitan monooleate, carboxymethylcellulose sodium, glycerin, boric
acid, acrylates/C10-30 alkyl acrylate crosspolymer, castor oil,
erythritol, levocarnitine, sodium hydroxide, and water.
2. The composition of claim 1, wherein the polyoxyethylene (80)
sorbitan monooleate is present at a concentration of about 0.1% w/w
to about 2% w/w.
3. The composition of claim 1 wherein the carboxymethylcellulose
sodium is present at a concentration of about 0.1 w/w to about 2%
w/w.
4. The composition of claim 1, wherein the glycerin is present at a
concentration of about 0.2% w/w to about 5% w/w.
5. The composition of claim 1, wherein the boric acid is present at
a concentration of about 0.02% to about 2% w/w.
6. The composition of claim 1, wherein the acrylates/C10-30 alkyl
acrylate crosspolymer is present at a concentration of about 0.02%
to about 0.5% w/w.
7. The composition of claim 1, wherein the castor oil is present at
a concentration of about 0.05% to about 0.5% w/w.
8. The composition of claim 1, wherein the erythritol is present at
a concentration of about 0.05% or about 3% w/w.
9. The composition of claim 1, wherein the levocarnitine is present
at a concentration of about 0.05% or about 3% w/w.
10. The composition of claim 1, wherein the pH is about 7.3.
11. The composition of claim 1, comprising about 0.5% w/w
polyoxyethylene (80) sorbitan monooleate, about 0.5% w/w
carboxymethylcellulose sodium, about 1.0% w/w glycerin, about 0.6%
w/w boric acid, about 0.1% w/w acrylates/C10-30 alkyl acrylate
crosspolymer, about 0.25% w/w castor oil, about 0.25% w/w
erythritol, about 0.25% w/w levocarnitine, sodium hydroxide, a pH
of about 7.3 and water.
12. A method of treating, diagnosing, curing, mitigating or
preventing dry eye syndrome comprising administering an effective
amount of an ophthalmic composition according to claim 1 to an eye
of a man or other animal in need thereof.
13. The method according to claim 12, wherein the ophthalmic
composition comprises about 0.5% w/w polyoxyethylene (80) sorbitan
monooleate, about 0.5% w/w carboxymethylcellulose sodium, about
1.0% w/w glycerin, about 0.6% w/w boric acid, about 0.1% w/w
acrylates/C10-30 alkyl acrylate crosspolymer, about 0.25% w/w
castor oil, about 0.25% w/w erythritol, about 0.25% w/w
levocarnitine, sodium hydroxide, a pH of about 7.3 and water.
14. The composition of claim 1, further comprising stabilized
oxychloro complexes.
15. The composition of claim 14, wherein the stabilized oxychloro
complexe is present at a concentration of about 0.002% or about
0.05% w/w.
16. The ophthalmic composition of claim 11, further comprising
about 0.01% w/w of stabilized oxychloro complexes.
17. A method of treating, diagnosing, curing, mitigating or
preventing dry eye syndrome comprising administering an effective
amount of an opthalmic composition according to claim 14 to an eye
of a man or other animal in need thereof.
18. The method according to claim 17, wherein the ophthalmic
composition comprises about 0.5% w/w polyoxyethylene (80) sorbitan
monooleate, about 0.5% w/w carboxymethylcellulose sodium, about
1.0% w/w glycerin, about 0.01% w/w of stabilized oxychloro
complexes, about 0.6% w/w boric acid, about 0.1 w/w
acrylates/C10-30 alkyl acrylate crosspolymer, about 0.25% w/w
Castor Oil, about 0.25% w/w erythritol, about 0.25% w/w
levocarnitine, sodium hydroxide to obtain a pH of about 7.3 and
water.
Description
CROSS REFERENCE
[0001] This application is a continuation of U.S. patent
application Ser. No. 16/129,385, filed Sep. 12, 2018, which is a
continuation of U.S. patent application Ser. No. 14/601,781, filed
Jan. 21, 2015, now U.S. Pat. No. 10,105,386, issued Oct. 23, 2018,
which is a continuation application of U.S. patent application Ser.
No. 13/645,035, filed Oct. 4, 2012, now U.S. Pat. No. 8,957,048,
issued Feb. 17, 2015, which claims priority to U.S. Provisional
Patent Application No. 61/544,151, filed Oct. 6, 2011, each of
which are incorporated herein by reference in their entireties, and
serves as the basis for a priority and/or benefit claim of the
present application.
BACKGROUND OF THE INVENTION
1. Field of the Invention
[0002] The present invention relates to ophthalmic compositions and
methods useful to treat dry eye, or to diagnose, cure, mitigate,
treat, or prevent dry eye syndrome in man or other animals.
2. Background of the Art
[0003] Dry eye is a multifactorial disease of the tears and ocular
surface that results in symptoms of discomfort, visual disturbance,
and tears film instability with potential damage to the ocular
surface. The normal tear film is a relatively stable, thin film
composed of a superficial lipid layer and an aqueous layer
intermixed with a mucus gel layer which is partially adherent to
the corneal and conjunctival surface epithelium. Natural tear film
is important for the lubrication and maintenance of the refractive
surface of the eye. Dry eye syndrome is a complex disease
characterized by a dysfunction of one or more components of the
tear film, leading to the loss of tear film stability, a
hyperosmotic shift in the tear film osmotic balance, and/or an
inadequate amount of fluid on the ocular surface. This is
characterized by rapid break-up of the tear film and numerous
symptoms, including burning/stinging, foreign body sensation,
itching, and photophobia.
[0004] The majority of patients with dry eye syndrome are
prescribed or recommended artificial tears. Also recommended are
lid compresses and scrubs, and addition of essential fatty acids to
the diet.
[0005] Dry Eye Syndrome is a common disorder of the normal tear
film that results from one of the following: decreased tear
production, excessive tear evaporation, an abnormality in the
production of mucus or lipids normally found in the tear layer.
[0006] Aqueous (watery) tear deficiency is caused by either poor
production of watery tears or excessive evaporation of the watery
tear layer.
[0007] Poor production of tears by the tear glands may be a result
of age, hormonal changes, or various autoimmune diseases, such as
primary Sjogren syndrome, rheumatoid arthritis, or lupus.
[0008] Evaporative loss of the watery tear layer is usually a
result of an insufficient overlying lipid layer. Some medications,
such as antihistamines, antidepressants, beta-blockers, and oral
contraceptives, may decrease tear production. If blinking is
decreased or if the eyelids cannot be closed, the eyes may dry out
because of tear evaporation.
[0009] Reading, watching TV, or performing a task that requires
close attention with the eyes, may decrease the blinking, allowing
excessive evaporation of the tears.
[0010] LASIK and other vision correction procedures can cause dry
eyes after they penetrate the eye's surface and reduce corneal
nerve sensitivity. Afterwards the eye fails to sense the need for
lubrication and inadequate tear production results. New ophthalmic
compositions for treating eyes and methods of treating dry eyes
have been discovered.
SUMMARY OF THE INVENTION
[0011] It has now been discovered novel ophthalmic compositions for
treating dry eye syndrome, which may include a combination of a
demulcent or film forming material and a tonicity agent. These
compositions may be used to treat dry eye, or to diagnose, cure,
mitigate, treat, or prevent dry eye syndrome in man or other
animals. These formulations are sterile, buffered, oil and water
emulsion artificial tear products formulated for the relief of
ocular surface irritation and symptoms of dryness.
[0012] These compositions are typically ophthalmically acceptable
liquids. An ophthalmically acceptable liquid includes a liquid
formulated that is tolerable to a patient for topical ophthalmic
use. Additionally, an ophthalmically acceptable liquid could either
be packaged for single use, or for multiple uses containing a
preservative to prevent contamination.
[0013] For ophthalmic application, solutions or medicaments may be
prepared using a physiological saline solution as a major vehicle.
Ophthalmic solutions may be maintained at a comfortable pH with an
appropriate buffer system. The formulations may also contain
conventional, pharmaceutically acceptable preservatives,
stabilizers and surfactants.
[0014] An ophthalmically acceptable liquid may include demulcents
or film forming materials. Examples of demulcents may include, but
are not limited to polymers such as polyvinyl alcohol, povidone,
hydroxypropyl methyl cellulose, poloxamers, carboxymethyl
cellulose, hydroxyethyl cellulose, acrylates; surfactants such as
polyoxyethylene (20) sorbitan monooleate and glycerin. The amount
of demulcent may vary. In some embodiments, the amount of any
demulcent such as those listed above may be from about 0.1% w/w to
about 2% w/w, or from about 0.3% w/w to about 0.7% w/w, or from
about 0.3% w/w to about 0.5% w/w, or about 0.5% w/w.
[0015] An ophthalmically acceptable liquid may include a buffer.
The buffer may vary, and may include any weak conjugate acid-base
pair suitable for maintaining a desirable pH range. Examples
include, but are not limited to, acetate buffers, citrate buffers,
phosphate buffers, borate buffers, or a combination thereof. Acids
or bases may be used to adjust the pH of these formulations as
needed. The amount of buffer used may vary. In some embodiments,
the buffer may have a concentration in a range of about 1 nM to
about 100 mM. The pH of a buffered solution may be increased by the
addition of sodium hydroxide or another base, or decreased by the
addition of hydrochloric acid or another acid. In some embodiments,
the pH of a composition may be from about 7 to about 7.5, or from
about 7.2 to about 7.4, or about 7.3.
[0016] An ophthalmically acceptable liquid may include a
preservative. The preservative may vary, and may include any
compound or substance suitable for preventing microbial
contamination in an ophthalmic liquid subject to multiple uses from
the same container. Preservatives that may be used in the
pharmaceutical compositions disclosed herein include, but are not
limited to, cationic preservatives such as quaternary ammonium
compounds including benzalkonium chloride, polyquad, and the like;
guanidine-based preservatives including polyhexamethylene biguanide
(PHMB), chlorhexidine, and the like; chlorobutanol; mercury
preservatives such as thimerosal, phenylmercuric acetate and
phenylmercuric nitrate; and oxidizing preservatives such as
stabilized oxychloro complexes (e.g. Purite.RTM.). Purite.RTM. is a
registered trademark of Allergan, Inc.
[0017] In some embodiments, the amount of preservative in the
liquid may be from about 0.0001% w/w to about 25% w/w, or from
about 0.002% w/w to about 0.05% w/w, or from about 0.005% w/w to
about 0.02% w/w, or about 0.01% w/w.
[0018] An ophthalmically acceptable liquid may include a
surfactant. The surfactant may vary, and may include any compound
that is surface active or can form micelles. A surfactant may be
used for assisting in dissolving an excipient or an active agent,
dispersing a solid or liquid in a composition, enhancing wetting,
modifying drop size, stabilizing an emulsion, or a number of other
purposes. Useful surfactants include, but are not limited to,
surfactants of the following classes: alcohols; amine oxides; block
polymers; carboxylated alcohol or alkylphenol ethoxylates;
carboxylic acids/fatty acids; ethoxylated alcohols; ethoxylated
alkylphenols; ethoxylated arylphenols; ethoxylated fatty acids;
ethoxylated fatty esters or oils (animal and vegetable); fatty
esters; fatty acid methyl ester ethoxylates; glycerol esters;
glycol esters; lanolin-based derivatives; lecithin and lecithin
derivatives; lignin and lignin derivatives; methyl esters;
monoglycerides and derivatives; polyethylene glycols; polymeric
surfactants; propoxylated and ethoxylated fatty acids, alcohols, or
alkyl phenols; protein-based surfactants; sarcosine derivatives;
sorbitan derivatives; sucrose and glucose esters and derivatives.
In some embodiments, the surfactant may include polyethylene glycol
(15)-hydroxystearate (CAS Number 70142-34-6, available as Solutol
HS 15.RTM. from BASF), polyoxyethylene-polyoxypropylene block
copolymer (CAS No. 9003-11-6, available as Pluronic.RTM. F-68 from
BASF), polyoxyethylene 40 stearate (POE40 stearate), polysorbate 80
or polyoxyethylene (20) sorbitan monooleate (CAS No. 9005-65-6),
sorbitan monostearate (CAS No. 1338-41-6, available as Span.TM. 60
from Croda International PLC), polyoxyethylenglyceroltriricinoleat
35 (CAS No. 61791-12-6, available as Cremophor EL.RTM. from BASF).
The amount of surfactant may vary. In some embodiments, the amount
of any surfactant such as those listed above may be from about
0.001% w/w to about 5% w/w, or from about 0.1% w/w to about 2 w/w
%, or from about 0.3% to about 0.7%, or from about 0.3% w/w to
about 0.5% w/w, or from about 0.1% w/w to about 1% w/w, or about
0.5% w/w.
[0019] An ophthalmically acceptable liquid may include a
stabilizer. Examples of suitable stabilizers include, but are not
limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl
cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl
cellulose, and acrylates such as acrylates/C10-30 alkyl acrylate
crosspolymer (e.g. Pemulen.TM. RTM, Pemulen.TM. TR-2).
Acrylates/C10-30 alkyl acrylate crosspolymer is sold and is known
as Pemulen.TM. TR-2. In some embodiments, the amount of stabilizer
may be from about 0.01% to about 1%, or from about 0.1% w/w to
about 1% w/w, or about 0.1% w/w.
[0020] An ophthalmically acceptable liquid may include a tonicity
agent. The tonicity agent may vary, and may include any compound or
substance useful for adjusting the tonicity of an ophthalmic
liquid. Examples include, but are not limited to, salts,
particularly sodium chloride, potassium chloride, mannitol and
glycerin, or any other suitable ophthalmically acceptable tonicity
adjustor. The amount of tonicity agent may vary depending upon
whether an isotonic, hypertonic, or hypotonic liquid is desired. In
some embodiments, the amount of a tonicity agent such as those
listed above may be at least from about 0.0001% w/w to about 5%
w/w, or from about 0.2% to about 5% w/w, or from about 0.5% w/w to
about 2% w/w, or about 1.0% w/w.
[0021] An ophthalmically acceptable liquid may include an
antioxidant. The antioxidant may vary, and may include any compound
or substance that is useful in reducing oxidation of any compound
present in an ophthalmically acceptable liquid. Examples, not
limited to, are: sodium metabisulfite, sodium thiosulfate,
acetylcysteine, butylated hydroxyanisole, and butylated
hydroxytoluene.
[0022] An ophthalmically acceptable liquid may include a chelating
agent. The chelating agent may vary, and may include any compound
or substance that is capable of chelating a metal. A useful
chelating agent is edetate disodium, although other chelating
agents may also be used in place or in conjunction with it.
[0023] Compositions may be aqueous solutions or emulsions, or some
other acceptable liquid form. For an emulsion, one or more oils may
be used to form the emulsion. Suitable oils include, but are not
limited to anise oil, castor oil, clove oil, cassia oil, cinnamon
oil, almond oil, corn oil, arachis oil, cottonseed oil, safflower
oil, maize oil, linseed oil, rapeseed oil, soybean oil, olive oil,
caraway oil, rosemary oil, peanut oil, peppermint oil, sunflower
oil, eucalyptus oil, sesame oil, and the like. In some embodiments,
the amount of oil such as those listed above may be from about
0.0001% w/w to about 5% w/w, or from about 0.005% w/w to about 1
w/w %, or from about 0.01% w/w to about 0.2 w/w %, or from about
0.05% w/w to about 0.5% w/w, or from about 0.2% w/w to about 5%
w/w, or from about 0.5% w/w to about 2% w/w, or from about 0.1 to
about 0.2%, or about 0.175% w/w, or about 0.075% w/w.
[0024] Other excipients may include erytritol, a carnitine,
including L-carnitine (levocarnitine) or R-carnitine. In some
embodiments, the amount of erythritol may be from about 0.05% to
about 3% w/w, or from about 0.1% w/w to about 0.5% w/w, or about
0.25% w/w.
[0025] In some embodiments, the amount of levocarnitine may be from
about 0.05% to about 3% w/w, or from about 0.1% w/w to about 0.5%
w/w or about 0.25% w/w. Table 1 includes a list of components that
may be used in a dry eye composition.
TABLE-US-00001 TABLE 1 Ingredient Amount Polyoxyethylene (20)
omitted, or about 0.1-2%, about 0.3%- sorbitan monooleate 0.7%, or
about 0.5% w/w Carboxymethylcellulose omitted, or about 0.1-2%,
about 0.3%- sodium (low viscosity) 0.7%, or about 0.5% w/w Glycerin
omitted, or about 0.2-5%, about 0.5-2%, or about 1.0% w/w Purite
.RTM. omitted, or about 0.002%-0.05%, about 0.005%-0.02%, or about
0.01% w/w Boric Acid omitted, or about 0.02-2%, about 0.5- 0.7%, or
about 0.6% w/w A C10-30 alkyl acrylate omitted, or about 0.02-0.5%,
about crosspolymer 0.05-0.2%, or about 0.1% w/w Castor Oil omitted,
or about 0.05-0.5%, about 0.1- 0.2%, or about 0.175% w/w Olive Oil,
Super Refined omitted, or about 0.005-1%, about 0.01-
(non-preserved) 0.2%, or about 0.075% w/w Erythritol omitted, or
about 0.05-3%, about 0.1- 0.5%, or about 0.25% w/w Levocarnitine
omitted, or about 0.05-3%, about 0.1- 0.5%, or about 0.25% w/w
Sodium hydroxide omitted, or add to pH of about 7-7.5, 7.2-7.4, or
about 7.3. Water QS 100% w/w
DETAILED DESCRIPTION OF THE INVENTION
[0026] Some embodiments of the invention comprise, or consist of,
Polyoxyethylene (20) sorbitan monooleate, carboxymethylcellulose
sodium (low viscosity), glycerin, Purite.RTM., boric acid, an
acrylates/C10-30 alkyl acrylate crosspolymer (Pemulen.TM. TR-2),
castor oil, olive oil, erythritol, levocarnitine, sodium hydroxide,
and water.
[0027] Some embodiments of the invention comprise, or consist of,
Polyoxyethylene (20) sorbitan monooleate, carboxymethylcellulose
sodium (low viscosity), glycerin, Purite.RTM., boric acid, an
acrylates/C10-30 alkyl acrylate crosspolymer (Pemulen.TM. TR-2),
castor oil, erythritol, levocarnitine, sodium hydroxide, and
water.
[0028] Some embodiments of the invention comprise, or consist of,
Polyoxyethylene (20) sorbitan monooleate, carboxymethylcellulose
sodium (low viscosity), glycerin, boric acid, an acrylates/C10-30
alkyl acrylate crosspolymer (Pemulen.TM. TR-2), castor oil,
erythritol, levocarnitine, sodium hydroxide, and water.
[0029] Some embodiments of the invention comprise, or consist of
polyoxyethylene (20) sorbitan monooleate, carboxymethylcellulose
sodium, glycerin, boric acid, acrylates/C10-30 alkyl acrylate
crosspolymer, castor oil, erythritol, levocarnitine, sodium
hydroxide, and water.
[0030] Some embodiments of the invention comprise, or consist of
polyoxyethylene (20) sorbitan monooleate, carboxymethylcellulose
sodium, glycerin, boric acid, acrylates/C10-30 alkyl acrylate
crosspolymer, stabilized oxychloro complexes, castor oil,
erythritol, levocarnitine, sodium hydroxide, and water.
EXAMPLE 1
[0031] A formulation is prepared for use as an artificial tears
product according to Table 2:
TABLE-US-00002 TABLE 2 Ingredient Amount Polysorbate 80 0.5% w/w
Carboxymethylcellulose sodium (low 0.5% w/w viscosity) Glycerin
1.0% w/w Purite .RTM. 0.01% w/w Boric Acid 0.6% w/w Pemulen .TM.
TR-2 0.1% w/w Castor Oil 0.175% w/w Olive Oil, Super Refined
(non-preserved) 0.075% w/w Erythritol 0.25% w/w Levocarnitine 0.25%
w/w Sodium hydroxide Add to pH 7.3 Water QS 100% w/w
The formulation of Table 2 is administered to a person suffering
from dry eye syndrome about 1-10 times per day for relief of dry
eye symptoms.
EXAMPLE 2
[0032] A formulation is prepared for use as an artificial tears
product according to Table 3:
TABLE-US-00003 TABLE 3 Ingredient Amount Polysorbate 80 0.5% w/w
Carboxymethylcellulose sodium (low 0.5% w/w viscosity) Glycerin
1.0% w/w Purite .RTM. 0.01% w/w Boric Acid 0.6% w/w Pemulen .TM.
TR-2 0.1% w/w Castor Oil 0.25% w/w Erythritol 0.25% w/w
Levocarnitine 0.25% w/w Sodium hydroxide Add to pH 7.3 Water QS
100% w/w
[0033] The formulation of Table 3 is administered to a person
suffering from dry eye syndrome about 1-10 times per day for relief
of dry eye symptoms.
[0034] Some embodiments of the present invention include:
[0035] 1. An ophthalmic composition comprising polyoxyethylene (20)
sorbitan monooleate, carboxymethylcellulose sodium, glycerin, boric
acid, acrylates/C10-30 alkyl acrylate crosspolymer, castor oil,
erythritol, levocarnitine, sodium hydroxide, and water.
[0036] 2. The composition of paragraph 1, wherein the
polyoxyethylene (20) sorbitan monooleate is present at a
concentration of about 0.1% w/w to about 2% w/w.
[0037] 3. The composition of paragraph 1 wherein the
carboxymethylcellulose sodium is present at a concentration of
about 0.1% w/w to about 2% w/w.
[0038] 4. The composition of paragraph 1, wherein the glycerin is
present at a concentration of about 0.2% w/w to about 5% w/w.
[0039] 5. The composition of paragraph 1, wherein the boric acid is
present at a concentration of about 0.02% to about 2% w/w.
[0040] 6. The composition of paragraph 1, wherein the
acrylates/C10-30 alkyl acrylate crosspolymer is present at a
concentration of about 0.02% to about 0.5% w/w.
[0041] 7. The composition of paragraph 1, wherein the castor oil is
present at a concentration of about 0.05% to about 0.5% w/w.
[0042] 8. The composition of paragraph 1, wherein the erythritol is
present at a concentration of about 0.05% or about 3% w/w.
[0043] 9. The composition of paragraph 1, wherein the levocarnitine
is present at a concentration of about 0.05% to about 3% w/w.
[0044] 10. The composition of paragraph 1, wherein the pH is about
7.3.
[0045] 11. The composition of paragraph 1, comprising about 0.5%
w/w polyoxyethylene (20) sorbitan monooleate, about 0.5% w/w
carboxymethylcellulose sodium, about 1.0% w/w glycerin, about 0.6%
w/w boric acid, about 0.1% w/w acrylates/C10-30 alkyl acrylate
crosspolymer, about 0.25% w/w castor oil, about 0.25% w/w
erythritol, about 0.25% w/w levocarnitine, sodium hydroxide, a pH
of about 7.3 and water.
[0046] 12. A method of treating, diagnosing, curing, mitigating or
preventing dry eye syndrome comprising administering an effective
amount of an ophthalmic composition according to paragraph 1 to an
eye of a man or other animal in need thereof.
[0047] 13. The method according to paragraph 12, wherein the
ophthalmic composition comprises about 0.5% w/w polyoxyethylene
(20) sorbitan monooleate, about 0.5% w/w carboxymethylcellulose
sodium, about 1.0% w/w glycerin, about 0.6% w/w boric acid, about
0.1% w/w acrylates/C10-30 alkyl acrylate crosspolymer, about 0.25%
w/w castor oil, about 0.25% w/w erythritol, about 0.25% w/w
levocarnitine, sodium hydroxide, a pH of about 7.3 and water.
[0048] 14. The composition of paragraph 1, further comprising
stabilized oxychloro complexes.
[0049] 15. The composition of paragraph 14, wherein the stabilized
oxychloro complex is present at a concentration of about 0.002% or
about 0.05% w/w.
[0050] 16. The ophthalmic composition of paragraph 11, further
comprising about 0.01% w/w of stabilized oxychloro complex.
[0051] 17. A method of treating, diagnosing, curing, mitigating or
preventing dry eye syndrome comprising administering an effective
amount of an ophthalmic composition according to paragraph 14 to an
eye of a man or other animal in need thereof.
[0052] 18. The method according to paragraph 17, wherein the
ophthalmic composition comprises about 0.5% w/w polyoxyethylene
(20) sorbitan monooleate, about 0.5% w/w carboxymethylcellulose
sodium, about 1.0% w/w glycerin, about 0.01% w/w of stabilized
oxychloro complexes, about 0.6% w/w boric acid, about 0.1% w/w
acrylates/C10-30 alkyl acrylate crosspolymer, about 0.25% w/w
Castor Oil, about 0.25% w/w erythritol, about 0.25% w/w
levocarnitine, sodium hydroxide to obtain a pH of about 7.3 and
water.
[0053] Unless otherwise indicated, all numbers expressing
quantities of ingredients, properties such as molecular weight,
reaction conditions, and so forth used in the specification and
claims are to be understood as being modified in all instances by
the term "about." Accordingly, unless indicated to the contrary,
the numerical parameters set forth in the specification and
attached claims are approximations that may vary depending upon the
desired properties sought to be obtained. At the very least, and
not as an attempt to limit the application of the doctrine of
equivalents to the scope of the claims, each numerical parameter
should at least be construed in light of the number of reported
significant digits and by applying ordinary rounding
techniques.
[0054] The terms "a," "an," "the" and similar referents used in the
context of describing the invention (especially in the context of
the following claims) are to be construed to cover both the
singular and the plural, unless otherwise indicated herein or
clearly contradicted by context. All methods described herein can
be performed in any suitable order unless otherwise indicated
herein or otherwise clearly contradicted by context. The use of any
and all examples, or exemplary language (e.g., "such as") provided
herein is intended merely to better illuminate the invention and
does not pose a limitation on the scope of any claim. No language
in the specification should be construed as indicating any
non-claimed element essential to the practice of the invention.
[0055] Groupings of alternative elements or embodiments disclosed
herein are not to be construed as limitations. Each group member
may be referred to and claimed individually or in any combination
with other members of the group or other elements found herein. It
is anticipated that one or more members of a group may be included
in, or deleted from, a group for reasons of convenience and/or
patentability. When any such inclusion or deletion occurs, the
specification is deemed to contain the group as modified thus
fulfilling the written description of all Markush groups used in
the appended claims.
[0056] Certain embodiments are described herein, including the best
mode known to the inventors for carrying out the invention. Of
course, variations on these described embodiments will become
apparent to those of ordinary skill in the art upon reading the
foregoing description. Accordingly, the claims include all
modifications and equivalents of the subject matter recited in the
claims as permitted by applicable law. Moreover, any combination of
the above-described elements in all possible variations thereof is
contemplated unless otherwise indicated herein or otherwise clearly
contradicted by context.
Clinical Aspects:
[0057] A completed clinical study had for objective to evaluate the
safety, efficacy and acceptability of the two candidates:
Formulation A and Formulation B in comparison with Allergan's
existing OPTIVE.TM. Eye drops in subjects with signs and symptoms
of dry eye disease.
[0058] The results showed that Formulation A and Formulation B are
clinically safe and effective in subjects with signs and symptoms
of dry eye disease.
[0059] Formulation A is a multidose (MD) formulation containing
polysorbate 80, carboxymethylcellulose sodium, glycerin,
Purite.RTM., boric acid, Pemulen.TM. TR-2, castor oil, erythritol,
levocarnitine, sodium hydroxide, and purified water for injection,
supplied in 15 ml multidose bottles. The solution is clinically
safe and effective in subjects with signs and symptoms of dry eye
disease.
[0060] Formulation B is an unit-dose (UD) formulation containing
polysorbate 80, carboxymethylcellulose sodium, glycerin, boric
acid, Pemulen.TM. TR-2, castor oil, erythritol, levocarnitine,
sodium hydroxide, and purified water for injection, supplied in 0.4
ml unit-dose vials. This solution is clinically safe and effective
in subjects with signs and symptoms of dry eye disease.
[0061] The study was a multicenter, investigator-masked,
randomized, active-controlled, 4-arm, parallel group study designed
to compare the safety, efficacy, and acceptability of Formulation A
to OPTIVE.TM. Lubricant Eye Drops Multidose (OPTIVE MD) and
Formulation B to OPTIVE.TM. Sensitive Preservative-free Lubricant
Eye Drops Unit-dose (OPTIVE UD).
[0062] Control solution OPTIVE.TM. Lubricant Eye Drops Multidose
(OPTIVE MD) contained carboxymethylcellulose sodium, glycerin,
boric acid, sodium borate, sodium citrate, potassium chloride,
levocarnitine, erythrol, calcium chloride, magnesium chloride,
Purite.RTM., purified water and sodium hydroxide to adjust pH to
7.3, supplied in 15 ml multidose bottles.
[0063] Control solution OPTIVE.TM. Sensitive Preservative-free
Lubricant Eye Drops Unit-dose (OPTIVE UD) contained
carboxymethylcellulose sodium, glycerin, boric acid, sodium borate,
sodium citrate, potassium chloride, levocarnitine, erythrol,
calcium chloride, magnesium chloride, purified water for injection
and sodium hydroxide to adjust pH to 7.3, supplied in 0.4 ml
unit-dose vials.
[0064] The duration of the study was 30 days for each subject and
consisted of up to 3 scheduled visits (day 1 [baseline], day 7, and
day 30 [exit]). On day 1, eligible subjects with signs and symptoms
of dry eye disease were assigned according to a 2:2:1:1 treatment
allocation ratio to use Formulation A, OPTIVE MD, Formulation B, or
OPTIVE UD, respectively.
[0065] Approximately 300 subjects were enrolled at 13 to 14 sites
within the USA in order to have 288 completed subjects assuming a
dropout rate of approximately 5%. For enrollment into the study,
each subject had to meet certain inclusion criteria and none of the
exclusion criteria.
[0066] Subjects were instructed to instill 1 to 2 drops of their
assigned study product in each eye, as needed, but at least 2 times
daily for 30 days. Subjects could have voluntarily withdrawn from
the study at any time. Additionally, subjects could have been
discontinued from the study by an investigator for reasons such as
adverse events, loss to follow-up, protocol violations, or lack of
efficacy.
[0067] Subjects randomized to Formulation A, OPTIVE MD received
kits containing 2 multidose bottles (15 mL in each bottle) of study
product, and were instructed to use 1 bottle until it was empty and
then to use the second bottle.
[0068] Subjects randomized to Formulation B and OPTIVE UD received
kits containing 180 unit-dose vials (0.4 mL in each vial) of study
product, and were instructed to use 1 vial per dosing for both
eyes.
[0069] Each subject was instructed to instill 1 to 2 drops of study
product in each eye, as needed, but at least 2 times daily for the
entire duration of the study (from day 1 after randomization
through day 30, prior to exiting the study).
[0070] Subjects and all investigative site staff were masked to the
study treatment. To maintain product masking, both the Formulation
B and the OPTIVE UD drops were provided in identical 0.4 mL
unit-dose vials while the Formulation A and the OPTIVE MD drops
were provided in identical 15 mL multidose bottles.
Primary Efficacy Measurements:
[0071] The primary efficacy measure was the Ocular Surface Disease
Index.RTM. (OSDI) Questionnaire at day 30 in the intent-to-treat
(ITT) population. The OSDI Questionnaire consisted of 12 questions
with a 5-point scale (0=none of the time; 1=some of the time;
2=half of the time; 3=most of the time; 4=all of the time; some
questions had a possible "N/A" [not applicable] response)
(Schiffman et al, 2000). Subjects were asked to evaluate the
frequency of various symptoms, related visual functions, and
environmental triggers of dry eye using the 5-point scale. Subjects
were asked to base their evaluation on the frequency of their
symptoms over the last week before the study visit. This was
evaluated overall, not per eye.
[0072] The primary efficacy analysis was performed on the change
from baseline in OSDI score at day 30 via a 2-way analysis of
variance (ANOVA) model with treatment and baseline OSDI
stratification as the main effects. Last observation carried
forward (LOCF) was used to impute missing data. Noninferiority was
tested using a 2-sided confidence interval (CI). The treatment
difference and 95% CI in change from baseline in OSDI score at day
30 between Formulation B and OPTIVE UD (Formulation B minus OPTIVE
UD) were calculated based on the ANOVA model. Non-inferiority was
established if the upper limit of the 95% CI was less than the
prespecified margin of 7.3. The primary efficacy endpoint was met.
At day 30, no statistically significant difference was observed
between the Formulation B and the OPTIVE UD groups in the mean
change from baseline in OSDI score (95% confidence interval [-5.42,
2.51]), in the ITT population. The Formulation B was noninferior to
the OPTIVE UD formulation in reducing the severity of symptoms of
dryness as measured by the change from baseline in OSDI score.
[0073] Similar to the ITT population, there was no statistically
significant difference between the Formulation B and OPTIVE UD
groups of the per-protocol (PP) population in the mean change from
baseline in OSDI score at day 30. The 95% confidence interval at
the day 30 visit was (-5.72, 2.37); with an upper limit that is
lower than the clinically relevant margin of 7.3.
[0074] In all 4 treatment groups, there was a statistically
significant difference (p<0.001) in the mean change from
baseline in OSDI score at the day 7 and day 30 visits for both the
ITT and the PP population.
[0075] The Formulation B group was noninferior to the Formulation A
group in the mean change from baseline in OSDI score at day 30.
[0076] Overall, there were no statistically significant differences
between the Formulation B and OPTIVE UD groups, Formulation B and
Formulation A groups, or Formulation A and OPTIVE MD groups.
Efficacy:
[0077] The results of this study demonstrate that Formulation B is
noninferior to the OPTIVE UD formulation in reducing the severity
of symptoms of dryness in subjects with mild to severe dry eye.
Safety:
[0078] Formulation B appeared to be well tolerated during the
study. Throughout the study, there were no treatment-related
serious adverse events. The safety profile was consistent with
OPTIVE UD, OPTIVE MD, and Formulation A. This is supportive of the
safety of the Formulation B in clinical use, and confirms the
safety of the Formulation A.
Secondary Efficacy Measurements:
[0079] The Secondary efficacy measures included (tear break-up
time) TBUT, corneal staining, conjunctival staining, and Schirmer
test.
[0080] TBUT was measured (in seconds) 3 times in each eye during
the 2 minute wait for corneal staining. Fluorescein supplied for
the study was applied onto the superior bulbar conjunctiva. This 1
instillation of sodium fluorescein was used for TBUT and corneal
staining. However, if needed, the fluorescein could have been
reapplied for the corneal staining after the TBUT. The examination
was performed with the slit lamp at 10.times.magnification using
cobalt blue illumination and the yellow barrier filter. Three
consecutive TBUTs were performed in each eye and all 3 measurements
were timed with the stopwatch provided.
[0081] The Schirmer Test (with Anesthesia) was performed in each
eye after all other ophthalmic testing. One drop of anesthetic was
instilled and the test begun precisely 4 minutes after
instillation. The test was conducted in a dimly lit room. While the
subject looked upward, the lower lid was gently drawn downward and
temporally. The rounded bent end of the sterile strip was hooked in
the lower conjunctival sac over the junction of the temporal and
central one-third of the lower eyelid margin in each eye. After 5
minutes, the tear front was marked and measured on each of the
sterile strips.
[0082] The raw values of these measures were summarized for the ITT
population, with missing data imputation using LOCF at each
scheduled follow-up visit. The treatment difference and 95% CI for
between-treatment comparisons were calculated. The treatment
differences and 95% CIs in change from baseline in OSDI score at
day 30 between Formulation B and Formulation A, Formulation A and
OPTIVE MD were also analyzed as secondary efficacy variables.
[0083] The Formulation B group was noninferior to the OPTIVE UD and
Formulation A groups in the secondary efficacy measures of TBUT,
corneal staining, conjunctival staining, and Schirmer test.
Efficacy Conclusions:
[0084] The objective of the current study was to evaluate the
safety, efficacy and acceptability of the Formulation B in subjects
with signs and symptoms of dry eye disease. The study was performed
to compare the Formulation B to existing OPTIVE UD formulation and
also to the Formulation A. The primary efficacy endpoint was met in
this study.
[0085] There was no difference between the Formulation B group and
the control OPTIVE UD group in the mean change from baseline in
OSDI score at day 30. The Formulation B formulation was noninferior
to OPTIVE UD and Formulation A in reducing the severity of symptoms
of dryness as measured by the OSDI questionnaire. Although there
were statistically significant differences between the Formulation
B and Formulation A group in the overall analyses and subgroup
analyses (by OSDI stratum) of the primary efficacy measure,
favoring the Formulation B group, the study was not designed to
test statistical superiority between the two groups, therefore firm
conclusions regarding the superiority of Formulation B versus
Formulation A cannot be made. Since this was a 4-arm study,
efficacy comparisons between the Formulation A and OPTIVE MD
formulations were also performed. Overall there was no difference
in efficacy between the Formulation A and OPTIVE MD
formulations.
[0086] The Formulation B formulation appeared to have an acceptable
safety profile.
[0087] Efficacy: The results of this study demonstrate that the
Formulation B formulation is noninferior to the OPTIVE UD
formulation in reducing the severity of symptoms of dryness in
subjects with mild to severe dry eye.
[0088] In a different study, it has been shown that Formulation B
reduces evaporation of tears, helping therefore the tear film
stability and protecting the tear film osmotic balance in case a
hyperosmotic shift should occur. Formulation B reduced evaporation
in subjects with and without dry eye syndrome.
[0089] The following non-limiting examples illustrate further
certain aspects of the present invention:
EXAMPLE 3
[0090] Eye drops of Formulation B, are administered to the eye of a
patient, Caucasian 52 year old male, complaining about dry eyes.
After applying the eye drops twice daily in each eye for two days
the patient has relief from dry eye symptoms.
EXAMPLE 4
[0091] A drop of Formulation A is administered to the each eye of a
person suffering from dry eye, one to three times a day. After two
days the person feels relief from the dry eye symptoms.
[0092] It is to be understood that the embodiments disclosed herein
are illustrative of the principles of the claims. Other
modifications that may be employed are within the scope of the
claims. Thus, by way of example, but not of limitation, alternative
embodiments may be utilized in accordance with the teachings
herein. Accordingly, the claims are not limited to embodiments
precisely as shown and described.
* * * * *