U.S. patent application number 11/225230 was filed with the patent office on 2006-01-12 for ophthalmic compositions for lubricating eyes and methods for making and using same.
This patent application is currently assigned to Allergan, Inc.. Invention is credited to James N. Chang, Teresa H. Kuan.
Application Number | 20060008443 11/225230 |
Document ID | / |
Family ID | 21784697 |
Filed Date | 2006-01-12 |
United States Patent
Application |
20060008443 |
Kind Code |
A1 |
Chang; James N. ; et
al. |
January 12, 2006 |
Ophthalmic compositions for lubricating eyes and methods for making
and using same
Abstract
Ophthalmic compositions include an ophthalmically acceptable
carrier component, for example, an aqueous-based carrier, and a
plurality of polyanionic component portions having different
molecular weights. In one embodiment, the polyanionic component
includes a first polyanionic component portion having a first
molecular weight; and a second polyanionic component portion having
a different second molecular weight. Each of the first and second
polyanionic component portions is present in an amount effective to
provide lubrication to an eye when the composition is administered
to an eye. Methods of making and using such compositions are also
disclosed.
Inventors: |
Chang; James N.; (Newport
Beach, CA) ; Kuan; Teresa H.; (Placentia,
CA) |
Correspondence
Address: |
STOUT, UXA, BUYAN & MULLINS LLP
4 VENTURE, SUITE 300
IRVINE
CA
92618
US
|
Assignee: |
Allergan, Inc.
Irvine
CA
|
Family ID: |
21784697 |
Appl. No.: |
11/225230 |
Filed: |
September 12, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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10017817 |
Dec 14, 2001 |
|
|
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11225230 |
Sep 12, 2005 |
|
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Current U.S.
Class: |
424/78.04 |
Current CPC
Class: |
A61K 9/0048 20130101;
Y10S 514/912 20130101; A61K 47/38 20130101 |
Class at
Publication: |
424/078.04 |
International
Class: |
A61K 31/74 20060101
A61K031/74 |
Claims
1-40. (canceled)
41. An ophthalmic composition comprising: an ophthalmically
acceptable carrier component; and a blended polyanionic component
including a first polyanionic component portion having a first
average molecular weight; and a second polyanionic component
portion having a second average molecular weight which is at least
50,000 Daltons less than the first average molecular weight,
wherein the first and second polyanionic component portions are
each present in an amount effective to provide lubrication to an
eye when the composition is administered to an eye and wherein the
first and second polyanionic component portions are each selected
from the group consisting of anionic cellulosic derivatives and
mixtures thereof.
42. The composition of claim 41 wherein the composition has an
increased ability to adhere to an eye when the composition is
administered to an eye relative to a substantially identical
composition having an equal total amount of the polyanionic
component and substantially no first polyanionic component
portion.
43. The composition of claim 41 wherein the composition has a
reduced ability to cause blurriness of vision in an eye when the
composition is administered to an eye relative to a substantially
identical composition having an equal total amount of the
polyanionic component and substantially no second polyanionic
component portion.
44. The composition of claim 42 wherein the composition has a
reduced ability to cause blurriness of vision in an eye when the
composition is administered to an eye relative to a substantially
identical composition having an equal total amount of polyanionic
component and substantially no second polyanionic component.
45. The composition of claim 41 wherein each of the first and
second polyanionic component portions is present in an amount of at
least about 0.1% (w/v) of the composition.
46. The composition of claim 41 which has a viscosity in a range of
about 15 cps to about 200 cps.
47. The composition of claim 41 wherein the blended polyanionic
component is present in an amount in a range of about 0.2% to about
5% (w/v) of the composition.
48. The composition of claim 41 wherein the blended polyanionic
component is present in an total amount within a range of about
0.6% to about 1.8% (w/v).
49. The composition of claim 41 wherein the weight ratio of the
first polyanionic component portion and the second polyanionic
component portion is in a range of about 0.02 to about 50
(w/v).
50. The composition of claim 41 wherein the weight ratio of the
first polyanionic component portion and the second polyanionic
component portion is in a range of about 0.25 to about 4 (w/v).
51. The composition of claim 41 wherein the blended polyanionic
component further comprises a third polyanionic component portion
having a third average molecular weight different from the first
and second average molecular weights, the third polyanionic
component portion being present in an amount effective to provide
lubrication to an eye when the composition is administered to an
eye.
52. The composition of claim 41 wherein the carrier component
includes at least one of the following: an effective amount of a
buffer component; an effective amount of a tonicity component; an
effective amount of a preservative component; and water.
53. A composition comprising a blended polyanionic component
comprising a first polyanionic component portion and a second
polyanionic component portion having a higher average molecular
weight than that of the first polyanionic component portion,
wherein the first and second polyanionic component portions each
have an average molecular weight between about 90,000 Daltons and
about 700,000 Daltons, provided that the average molecular weights
of the first and second portions differ by at least about 50,000
Daltons, and wherein the first or second polyanionic component
portion comprises an anionic cellulose derivative or mixture
thereof.
54. The composition of claim 53 wherein the composition has an
increased ability to adhere to an eye when the composition is
administered to an eye relative to a substantially identical
composition having an equal total amount of the polyanionic
components and substantially no first polyanionic component
portion.
55. The composition of claim 53 wherein the composition has a
reduced ability to cause blurriness of vision in an eye when the
composition is administered to an eye relative to a substantially
identical composition having an equal total amount of the
polyanionic components and substantially no second polyanionic
component portion.
56. The composition of claim 53, wherein said composition is
therapeutically effective in the treatment of dry eye when
administered topically.
57. The composition of claim 53 wherein each of the first and
second polyanionic component portions is present in an amount of at
least about 0.1% (w/v) of the composition.
58. The composition of claim 53 which has a viscosity in a range of
about 15 cps to about 200 cps.
59. The composition of claim 53 wherein the blended polyanionic
component is present in an amount in a range of about 0.2% to about
5% (w/v) of the composition.
60. The composition of claim 53 wherein the blended polyanionic
component is present in an total amount within a range of about
0.6% to about 1.8% (w/v).
61. The composition of claim 53 wherein the weight ratio of the
first polyanionic component portion and the second polyanionic
component portion is in a range of about 0.02 to about 50
(w/v).
62. The composition of claim 53 wherein the weight ratio of the
first polyanionic component portion and the second polyanionic
component portion is in a range of about 0.25 to about 4 (w/v).
Description
BACKGROUND OF THE INVENTION
[0001] The present invention relates to ophthalmic compositions
useful for lubricating eyes to which such compositions are
administered. More particularly, the present invention relates to
compositions including mixtures of components which are very
effective in providing desired eye lubrication without unduly
interfering with vision, to methods for making ophthalmic
compositions and to methods for lubricating eyes and treating eyes
having dry eye syndrome using ophthalmic compositions.
[0002] Mammalian eyes, such as human eyes, advantageously are
adequately lubricated to provide eye comfort and to more
effectively provide good, clear vision. Ordinarily, such
lubrication is obtained naturally from a tear film, which is formed
over the outer, exposed surface of the eye. However, in many
instances, this tear film is not present in a sufficient amount to
effectively lubricate the eye. A condition known as "dry eye" can
result from inadequate lubrication of the eye.
[0003] A relatively large number of compositions have been
suggested for use in providing eye lubrication. For example,
artificial tears, that is materials having chemical compositions
which mimic or resemble natural tears, have been used. Such
artificial tears often require very frequent use since they are
rapidly lost from the eye. In addition, although they wet the eye,
their value in lubricating the eye is somewhat less than optimal.
Compositions which include specific lubricants have been suggested.
For example, a number of materials including carboxy
methylcelluloses (CMCs) have been used in eyes. These compositions,
which are generally effective, have certain shortcomings. For
example, certain low viscosity CMC-containing materials require
frequent administration since they are rapidly lost from the eye.
In other words, such materials do not adhere to the eye
sufficiently to provide effective lubrication without frequent
replenishment. High viscosity CMC-containing materials effectively
adhere to eyes but are disadvantageously disruptive to clear vision
for relatively long periods of time after administration.
[0004] There continues to be a need for compositions which are
effective to provide lubrication to eyes that can be conveniently
used, e.g., administered over acceptable intervals of time, rather
than very frequently, and without being unduly disruptive to clear
vision.
SUMMARY OF THE INVENTION
[0005] New ophthalmic compositions-for providing lubrication to
eyes, and methods for making and using same, have been discovered.
The present compositions very effectively lubricate eyes, for
example, eyes suffering from "dry eye" syndrome. These compositions
are relatively straightforward, can be easily and cost effectively
manufactured and can be used much like prior art eye lubricating
materials. Importantly, the present compositions include
combinations of materials which preferably provide relatively long
lasting effective eye lubrication, for example, without the need
for very frequent readministration or replenishment to the eye, and
which are advantageously not unduly disruptive to clear vision from
the eye being treated.
[0006] In one broad aspect, the present invention is directed to
ophthalmic compositions comprising an ophthalmically acceptable
carrier component and a polyanionic component including at least
two polyanionic component portions. Each polyanionic component
portion has a different molecular weight. In one very useful
embodiment, the polyanionic component includes a first polyanionic
component portion having a first molecular weight; and a second
polyanionic component having a second molecular weight.
Advantageously each of the polyanionic component portions is
present in an amount effective to provide lubrication to an eye
when the composition is administered to the eye. Preferably, each
of the polyanionic component portions is present in an amount of at
least about 0.1% w/v of the composition.
[0007] As noted above, each of the polyanionic component portions
has a different average molecular weight. In one embodiment, the
first polyanionic component portion has a first average molecular
weight which is greater than the second average molecular weight of
the second polyanionic component portion. The difference in average
molecular weight between the polyanionic component portions, for
example, between the first and second polyanionic component
portions, preferably is at least about 10,000 and more preferably
is at least about 50,000.
[0008] As used herein the term "molecular weight" refers to weight
average molecular weight, as that term is commonly known within the
polymer art, and can be measured or determined using procedures
and/or techniques well known in this art.
[0009] Any suitable polyanionic component may be employed in
accordance with the present invention. Such polyanionic component
should be ophthalmically acceptable, compatible with the other
components of the composition, and effective, in ophthalmically
reasonable concentrations, to provide lubrication to the eye when
administered to the eye and to otherwise function in accordance
with the present invention. In one useful embodiment, at least one,
and preferably all of the polyanionic component portions be
selected from anionic cellulosic derivatives and mixtures thereof.
A very useful embodiment provides that at least one, and preferably
all, of the polyanionic component portions be selected from the
group consisting of carboxy methyl celluloses and mixtures
thereof.
[0010] Other suitable polyanionic components may be employed. For
example, at least one, and preferably all, of the polyanionic
component portions may be selected from anionic homopolymers and
copolymers comprising units of one or more of acrylic acid,
methacrylic acid, metal acrylates and metal methacrylates, and
mixtures thereof. A very useful polyanionic component from which at
least one, and preferably all, of the first and second polyanionic
component portions may be selected are homopolymers and copolymers
comprising units of one or more of acrylic acid, metal acrylates
and mixtures thereof.
[0011] The present compositions preferably are solutions, although
other forms, such as ointments, gels, and the like, may be
employed.
[0012] The carrier component is ophthalmically acceptable and may
include one or more components which are effective in providing
such ophthalmic acceptability and/or otherwise benefitting the
composition and/or the eye to which the composition is administered
and/or the patient whose eye is being treated. Advantageously, the
carrier component is aqueous-based, for example, comprising a major
amount that is at least about 50% by weight, of water.
[0013] The present compositions may be prepared using conventional
procedures and techniques. For example, the present compositions
can be prepared by blending the components together, such as in one
bulk.
[0014] In another broad aspect of the present invention, methods
for providing lubrication to eyes are provided. Such methods
comprise administering an effective amount of a composition in
accordance with the present invention to an eye in need of
lubrication. In one very useful embodiment, the eye to which the
composition is administered has dry eye syndrome or has a
propensity toward dry eye syndrome. Preferably, the present
administering step is repeated at least once, and more preferably
as needed to effectively lubricate the eye to which the composition
is administered.
[0015] Each and every feature described herein, and each and every
combination of two or more of such features, is included within the
scope of the present invention provided that the features included
in such a combination are not mutually inconsistent.
[0016] These and other aspects and advantages of the present
invention are apparent in the following detailed description,
examples and claims.
DETAILED DESCRIPTION
[0017] The present invention involves ophthalmic compositions,
which are advantageously ophthalmically acceptable, comprising an
ophthalmically acceptable carrier component and a polyanionic
component including at least two polyanionic component
portions.
[0018] A composition, carrier component or other material is
"ophthalmically acceptable" when it is compatible with ocular
tissue, that is, it does not cause significant or undue detrimental
effects when brought into contact with ocular tissue. Preferably,
the ophthalmically acceptable material is also compatible with
other components of the present compositions.
[0019] As used herein, the term "polyanionic component" refers to a
chemical entity, for example, an ionically charged species, such as
an ionically charged polymeric material, which includes more than
one discrete anionic charge, that is multiple discrete anionic
charges. Preferably, the polyanionic component is selected from the
group consisting of polymeric materials having multiple anionic
charges and mixtures thereof.
[0020] Each polyanionic component portion has a different molecular
weight. In one very useful embodiment, the polyanionic component
includes a first polyanionic component portion having a first
molecular weight; and a second polyanionic component having a
second molecular weight. Advantageously each of the polyanionic
component portions is present in an amount effective to provide
lubrication to an eye when the composition is administered to the
eye. Preferably, each of the polyanionic component portions is
present in an amount of at least about 0.1% w/v of the
composition.
[0021] Preferably, the composition has an increased ability to
adhere to an eye when the composition is administered to an eye
relative to a substantially identical composition having an equal
total amount of the polyanionic component and substantially no
first polyanionic component portion. With regard to the increased
ability to adhere to an eye feature noted above, the present
composition preferably is effective to provide effective
lubrication over a longer period of time before requiring
readministration relative to a substantially identical composition
having an equal total amount of the polyanionic component and
substantially no first polyanionic component portion.
[0022] Advantageously, the composition has a reduced ability to
cause blurriness of vision in an eye when the composition is
administered to the eye relative to a substantially identical
composition having an equal total amount of the polyanionic
component and substantially no second polyanionic component
portion. The reduced ability to cause blurriness of vision in an
eye can be looked at as being a measure of the amount of time
required, after the composition is administered to the eye, for the
eye to regain clear vision, that is vision not blurred by the
administration of the composition. In other words, the present
composition, after being administered to the eye, preferably allows
the eye to provide clear vision in a reduced amount of time
relative to a substantially identical composition having an equal
total amount of the polyanionic component and substantially no
second polyanionic component portion.
[0023] In one embodiment, the at least two polyanionic component
portions, for example, the first and second polyanionic component
portions, other than having different molecular weights, have
substantially similar chemical structures. However, the at least
two polyanionic component portions may have different chemical
structures. Each of the polyanionic component portions, for
example, the first and second polyanionic component portions,
preferably is separately derived. In other words, it is preferred
that each of the polyanionic component portions be combined into
the present compositions as separate materials.
[0024] Any suitable polyanionic component may be employed in
accordance with the present invention provided that it functions as
described herein and has no substantial detrimental effect on the
composition as a whole or on the eye to which the composition is
administered. The polyanionic component is preferably
ophthalmically acceptable at the concentrations used. The
polyanionic component preferably includes three (3) or more anionic
(or negative) charges. In the event that the polyanionic component
is a polymeric material, it is preferred that each of the repeating
units of the polymeric material include a discrete anionic charge.
Particularly useful anionic components are those which are water
soluble, for example, soluble at the concentrations used in the
present compositions at ambient (room) temperature.
[0025] Examples of suitable polyanionic components useful in the
present compositions include, without limitation, anionic cellulose
derivatives, anionic acrylic acid-containing polymers, anionic
methacrylic acid-containing polymers, anionic amino acid-containing
polymers and mixtures thereof. Anionic cellulose derivatives are
very useful in the present invention.
[0026] A particularly useful class of polyanionic components are
one or more polymeric materials having multiple anionic charges.
Examples include, but are not limited to:
[0027] metal carboxy methylcelluloses
[0028] metal carboxy methylhydroxyethylcelluloses
[0029] metal carboxy methylstarchs
[0030] metal carboxy methylhydroxyethylstarchs
[0031] hydrolyzed polyacrylamides and polyacrylonitriles
[0032] heparin
[0033] gucoaminoglycans
[0034] hyaluronic acid
[0035] chondroitin sulfate
[0036] dermatan sulfate
[0037] peptides and polypeptides
[0038] alginic acid
[0039] metal alginates
[0040] homopolymers and copolymers of one or more of: [0041]
acrylic and methacrylic acids [0042] metal acrylates and
methacrylates [0043] vinylsulfonic acid [0044] metal vinylsulfonate
[0045] amino acids, such as aspartic acid, glutamic [0046] acid and
the like [0047] metal salts of amino acids [0048] p-styrenesulfonic
acid [0049] metal p-styrenesulfonate [0050]
2-methacryloyloxyethylsulfonic acids [0051] metal
2-methacryloyloxethylsulfonates [0052]
3-methacryloyloxy-2-hydroxypropylsulonic acids [0053] metal
3-methacryloyloxy-2-hydroxypropylsulfonates [0054]
2-acrylamido-2-methylpropanesulfonic acids [0055] metal
2-acrylamido-2-methylpropanesulfonates [0056] allylsulfonic acid
[0057] metal allylsulfonate and the like.
[0058] Excellent results are achieved using polyanionic components
selected from carboxy methylcelluloses and mixtures thereof, for
example, alkali metal and/or alkaline earth metal carboxy
methylcelluloses.
[0059] The present compositions preferably are solutions, although
other forms, such as ointments gels, and the like, may be
employed.
[0060] The carrier component is ophthalmically acceptable and may
include one or more components which are effective in providing
such ophthalmic acceptability and/or otherwise benefitting the
composition and/or the eye to which the composition is administered
and/or the patient whose eye is being treated. Advantageously, the
carrier component is aqueous-based, for example, comprising a major
amount that is at least about 50% by weight, of water. Other
components which may be included in the carrier components include,
without limitation, buffer components, tonicity components,
preservative-components, pH adjustors, components commonly found in
artificial tears, such as one or more electrolytes, and the like
and mixtures thereof.
[0061] The present compositions preferably have viscosities in
excess of the viscosity of water. In one embodiment, the viscosity
of the present compositions is at least about loops (centipoise),
more preferably in a range of about 10 cps to about 500 cps or
about 1,000 cps. Advantageously, the viscosity of the present
composition is in a range of about 15 cps or about 30 cps or about
70 to about 150 cps or about 200 cps or about 300 cps or about 500
cps. The viscosity of the present composition may be measured in
any suitable, for example, conventional manner. A conventional
Brookfield viscometer measuring such viscosities.
[0062] As noted previously, each of the polyanionic component
portions, that is, for example, at least the first and second
polyanionic component portions, present in an amount of at least
about 0.1% (w/v) of the composition. In one very useful embodiment,
the polyanionic component is present in an amount in a range of
about 0.2% to about 5%, preferably about 0.4% to about 2.5%, more
preferably about 0.6k to about 1.8% and still more preferably about
0.8% to about 1.3% (w/v) of the composition.
[0063] The weight ratio of the first polyanionic component portion
to the second polyanionic component portion may vary over a wide
range. In one embodiment, the ratio weight of the first portion to
the second portion is in the range of about 0.02 to about 50,
preferably about 0.1 to about 10, and more preferably about 0.25 to
about 4.
[0064] The different, for example, first and second, polyanionic
component portions of the present compositions preferably are
separately derived. Put another way, it is preferred that the
different, e.g., first and second, polyanionic component portions
be blended into the present compositions from different sources.
The molecular weights of the different polyanionic component
portions preferably differ by at least about 10,000, and more
preferably at least about 50,000.
[0065] In a very useful embodiment, the polyanionic component
further comprises a third polyanionic component portion having a
third molecular weight which is different from the first and second
molecular weights. The third polyanionic component portion
preferably is present in an amount effective to provide lubrication
to an eye when the composition is administered to an eye and/or at
least about 0.1% (w/v) of the composition.
[0066] Other components which may be included in the carrier
components include, without limitation, buffer components, tonicity
components, preservative-components, pH adjustors, components
commonly found in artificial tears, such as one or more
electrolytes, and the like and mixtures thereof. In one very useful
embodiment the carrier component includes at least one of the
following: an effective amount of a buffer component; an effective
amount of a tonicity component; an effective amount of a
preservative component; and water.
[0067] These additional components preferably are ophthalmically
acceptable and can be chosen from materials which are
conventionally employed in ophthalmic compositions, for example,
compositions used to treat eyes afflicted with dry eye syndrome,
artificial tear formulations and the like.
[0068] Acceptable effective concentrations for these additional
components in the compositions of the invention are readily
apparent to the skilled practitioner.
[0069] The carrier component preferably includes an effective
amount of a tonicity adjusting component to provide the composition
with the desired tonicity. The carrier component preferably
includes a buffer component which is present in an amount effective
to maintain the pH of the composition in the desired range. Among
the suitable tonicity adjusting components that may be employed are
those conventionally used in ophthalmic compositions, such as one
or more various inorganic salts and the like. Sodium chloride,
potassium chloride, mannitol, dextrose, glycerin, propylene glycol
and the like and mixtures thereof are very useful tonicity
adjusting components. Among the suitable buffer components or
buffering agents that may be employed are those conventionally used
in ophthalmic compositions. The buffer salts include alkali metal,
alkaline earth metal and/or ammonium salts. Conventional organic
buffers, such as Goode's buffer and the like, may also be
employed.
[0070] Any suitable preservative component may be included in the
present compositions provided that such components is effective as
a preservative in the presence of the polyanionic component. Thus,
it is important that the preservative component be substantially
unaffected by the presence of the polyanionic component. Of course,
the preservative component chosen depends on various factors, for
example, the specific polyanionic component present, the other
components present in the composition, etc. Examples of the useful
preservative components include, but are not limited to, per-salts,
such as perborates, percarbonates and the like; peroxides, such as
very low concentrations, e.g., about 50 to about 200 ppm (w/v), of
hydrogen peroxide and the like; alcohols, such as benzyl alcohol,
chlorbutanol and like; sorbic acid and ophthalmically acceptable
salts thereof and mixtures thereof.
[0071] The amount of preservative component included in the present
compositions containing such a component varies over a relatively
wide range depending, for example, on the specific preservative
component employed. The amount of such component preferably is in
the range of about 0.000001% to about 0.05% or more (w/v) of the
present composition.
[0072] One particularly useful class of preservative components are
chlorine dioxide precursors. Specific examples of chlorine dioxide
precursors include stabilized chlorine dioxide (SCD), metal
chlorites, such as alkali metal and alkaline earth metal chlorites,
and the like and mixtures thereof. Technical grade sodium chlorite
is a very useful chlorine dioxide precursor. Chlorine
dioxide-containing complexes, such as complexes of chlorine dioxide
with carbonate, chlorine dioxide with bicarbonate and mixtures
thereof are also included as chlorine dioxide precursors. The exact
chemical composition of many chlorine dioxide precursors, for
example, SCD and the chlorine dioxide complexes, is not completely
understood. The manufacture or production of certain chlorine
dioxide precursors is described in McNicholas U.S. Pat. No.
3,278,447, which is incorporated in its entirety herein by
reference. Specific examples of useful SCD products include that
sold under the trademark Purite.RTM. by Bio-Cide International,
Inc. that sold under the trademark Dura Klor by Rio Linda Chemical
Company, Inc., and that sold under the trademark Anthium Dioxide by
International Dioxide, Inc.
[0073] The chlorine dioxide precursor is included in the present
compositions to effectively preserve the compositions. Such
effective preserving concentrations preferably are in the range of
about 0.0002 or about 0.002 to about 0.02% (w/v) of the present
compositions.
[0074] In the event that chlorine dioxide precursors are employed
as preservative components, the compositions preferably have an
osmolality of at least about 200 mOsmol/kg and are buffered to
maintain the pH within an acceptable physiological range, for
example, a range of about 6 to about 8 or about 10.
[0075] The present compositions preferably include an effective
amount of an electrolyte component, that is one or more
electrolytes, for example, such as is found in natural tears and
artificial tear formulations. Examples of particularly useful such
electrolytes for inclusion in the present compositions include,
without limitation, alkaline earth metal salts, such as alkaline
earth metal inorganic salts, and mixtures thereof, e.g., calcium
salts, magnesium salts and mixtures thereof. Very good results are
obtained using an electrolyte component selected from calcium
chloride, magnesium chloride and mixtures thereof.
[0076] The amount or concentration of such electrolyte component in
the present compositions can vary widely and depends on various
factors, for example, the specific electrolyte component being
employed, the specific composition in which the electrolyte is to
be included and the like factors. In one useful embodiment, the
amount of the electrolyte component is chosen to at least partially
resemble, or even substantially resemble, the electrolyte
concentration in natural human tears. Preferably, the concentration
of the electrolyte component is in the range of about 0.01 to about
0.5 or about 1% of the present composition.
[0077] The present compositions may be prepared using conventional
procedures and techniques. For example, the present compositions
can be prepared by blending the components together, such as in one
bulk.
[0078] To illustrate, in one embodiment, the polyanionic component
portions are combined with purified water and caused to disperse in
the purified water, for example, by mixing and/or agitation. The
other components, such as the buffer component, tonicity component,
electrolyte component, preservative component and the like, are
introduced as the mixing continues. The final mixture is
sterilized, such as steam sterilized, for example, at temperatures
of at least about 100.degree. C., such as in a range of about
120.degree. C. to about 130.degree. C., for a time of at least
about 15 minutes or at least about 30 minutes, such as in a range
of about 45 to about 60 minutes. In one embodiment, the
preservative component preferably is added to the mixture after
sterilization. The final product preferably is filtered, for
example, through a 20 micron sterilized cartridge filter, such as a
20 micron clarity filter cartridge, e.g., sold by Pall under the
tradename HDC II, to provide a clear, smooth solution, which is
then aseptically filled into containers, for example, low density
polyethylene teal containers.
[0079] Alternately, each of the polyanionic component portions can
be mixed with purified water to obtain individual polyanionic
component portion solutions. By mixing the individual polyanionic
component portion solutions together, a blend is easily and
effectively obtained having the desired, controlled ratio of the
individual polyanionic component portions. The blended solution can
then be combined with the other components, sterilized and filled
into containers, as noted above.
[0080] In one particularly useful embodiment, a solution of the
polyanionic component portions and purified water is obtained, as
noted above. This solution is then sterilized, for example, as
noted above. Separately, the other components to be included in the
final composition are solubilized in purified water. This latter
solution is sterile filtered, for example, through a 0.2 micron
sterilizing filter, such as that sold by Pall under the tradename
Suporflow, into the polyanionic component-containing solution to
form the final solution. The final solution is filtered, for
example, as noted above, to provide a clear, smooth solution which
is then aseptically filled into containers, as noted above.
[0081] The present compositions may be effectively used, as needed,
by methods which comprise administering an effective amount of the
composition to an eye in need of lubrication, for example, an eye
afflicted with dry eye syndrome or having a propensity toward dry
eye syndrome. The administering step may be repeated as needed to
provide effective lubrication to such eye. The mode of
administration of the present composition depends on the form of
the composition. For example, if the composition is a solution,
drops of the composition may be applied to the eye, e.g., from a
conventional eye dropper. In general, the present compositions may
be applied to the surface of the eye in substantially the same way
as conventional ophthalmic compositions are applied. Such
administration of the present compositions does provide substantial
and unexpected benefits, as described elsewhere herein.
[0082] The following non-limiting examples illustrate certain
aspects of the present invention.
EXAMPLE 1
[0083] An ophthalmic formulation in accordance with the present
invention is prepared as follows:
[0084] A mixture of purified water, high molecular weight sodium
carboxy methyl celluloses (HCMC) and medium molecular weight sodium
carboxy methyl celluloses (MCMC) is produced by blending the
components together with mixing. The HCMC has a weight average
molecular weight of about 700,000, while the MCMC has a weight
average molecular weight of about 250,000. Both the HCMC and the
MCMC are commercially available and are sold by Hercules under the
trademark AQUALON.RTM..
[0085] Various other materials are blended with this mixture to
form a solution having the following composition: TABLE-US-00001
Ingredient Concentration, % (w/v) HCMC 0.30 MCMC 0.70 Sodium
Chloride 0.37 Boric Acid 0.60 Sodium Borate Decahydrate 0.045
Potassium-chloride 0.14 Calcium Chloride Dihydrate 0.006 Magnesium
Chloride Hexahydrate 0.006 Purite .RTM..sup.1 0.0075 Sodium
Hydroxide 1N Adjust pH to 7.2 Hydrochloric Acid 1N Adjust pH to 7.2
Purified water q.s. ad .sup.1Purite .RTM. is a registered trademark
of Bio-Cide International, Inc. for stabilized chlorine dioxide.
This material is added to the mixture after heat sterilization.
[0086] The viscosity of this solution, measured by a conventional
Brookfield viscometer, is 136 cps.
[0087] The solution is then heat sterilized in a closed autoclave,
at 123.degree. C. for 45 minutes.
[0088] The viscosity of the sterilized solution measured by a
conventional Brookfield viscometer, is 80 cps.
[0089] The sterilized solution, in the form of eye drops, is
administered to the eyes of a human patient having dry eye
syndrome. Such administration is effective to lubricate the
patient's eyes and at least reduce the severity (for example, in
terms of reducing the symptoms) of the dry eye syndrome. Moreover,
such lubrication/symptom reduction advantageously lasts for a
longer period of time (per administration) that is achieved by
administering a substantially identical composition including the
same total amount of sodium carboxy methylcellulose without the
HCMC. In addition, the human patient regains clear vision (that is
non-blurry vision) more rapidly after administration of the
sterilized solution relative to the time required to regain clear
vision after administration of a substantially identical
composition including the same total amount of sodium carboxy
methylcellulose without the MCMC.
[0090] In short, the sterilized solution, when administered to the
eyes of the human patient, effectively provides relief from dry eye
syndrome for relatively long periods of time (between
administrations) with reduced interference with the patient's
ability to see clearly.
EXAMPLES 2 TO 4
[0091] Example 1 is repeated three times except that different
amounts of HCMC and MCMC are employed. The amounts of HCMC and MCMC
in each of these formulations and the viscosities of each of these
formulations are as follows: TABLE-US-00002 Example 2 Example 3
Example 4 HCMC, % (w/v) 0.45 0.35 0.25 MCMC, % (w/v) 0.55 0.65 0.75
Viscosity Before sterilization (not measured) (not measured) 108
cps After sterilization 101 cps 78 cps 62 cps
[0092] Each of these sterilized solutions is administered to the
eyes of a human patient having dry eye syndrome. Each such
administration is effective to lubricate the patient's eyes and to
at least reduce the severity of the dry eye syndrome. As described
in detail with regard to the formulation of Example 1, each of the
sterilized solutions of Examples 2, 3 and 4, when administered to
the eyes of a human patient, effectively provides relief from the
dry eye condition for relatively long periods of time (between
administrations) with reduced interference with the patient's
ability to see clearly.
EXAMPLES 5 TO 10
[0093] Example 1 is repeated an additional six (6) times except
that the MCMC is replaced by low molecular weight sodium carboxy
methylcellulose (LCMC), and various different ratios of HCMC and
LCMC are used. The weight average molecular weight of the LCMC is
90,000. The LCMC is commercially available and is sold by Hercules
under the trademark AQUALON.RTM..
[0094] The amounts of HCMC and LCMC in each of these formulations
and the viscosities of each of these formulations are as follows:
TABLE-US-00003 Example 5 Example 6 Example 7 Example 8 Example 9
Example 10 HCMC, % w/v 0.80 0.70 0.60 0.50 0.45 0.40 LCMC, % w/v
0.20 0.30 0.40 0.50 0.55 0.60 Viscosity Before not not not not 102
cps not Sterilization measured measured measured measured measured
After 247.7 cps 132 cps 93.8 cps 59.4 cps 63 cps 38.2 cps
Sterilization
[0095] Each of these sterilized solutions, in the form of eye
drops, is administered to the eyes of a human patient having dry
eye syndrome. Each such administration is effective to lubricate
the patient's eyes and at least reduce the severity (for example,
in terms of reducing the symptoms) of the dry eye condition.
Moreover, such lubrication/symptom reduction lasts advantageously
for a longer period of time (per administration) that is achieved
by administering a substantially identical composition including
the same total amount of sodium carboxy methyl-cellulose without
the HCMC. In addition, each of the human patients regain clear
vision (that is non-blurry vision) more rapidly after
administration of the sterilized solution relative to the time
required to regain clear vision after administration of a
substantially identical composition including the same total amount
of sodium carboxy methylcellulose without the LCMC.
[0096] In short, the sterilized solutions of Examples 5 to 10, when
administered to the eyes of the human patient, effectively provide
relief from the dry eye condition for relatively long periods of
time (between administrations) with reduced interference with the
patient's ability to see clearly.
EXAMPLES 11 TO 14 (COMPARATIVE)
[0097] Example 1 is repeated four (4) further times except that
only a single molecular weight sodium carboxy methyl-cellulose is
used in each formulation.
[0098] The amount and type of sodium carboxy methyl-cellulose in
each of these formulations and the viscosities of each of these
formulations are as follows: TABLE-US-00004 Example Example Example
Example 11 12 13 14 HCMC, % (w/v) 1.0 1.0 -- -- MCMC, % (w/v) -- --
1.0 LCMC, % (w/v) -- -- -- 1.0 Viscosity Before sterilization 1002
cps 1002 cps 40 cps 6.1 cps After sterilization 407 cps 442 cps 34
cps 5.2 cps
[0099] These results indicate that heat sterilization has a
significant effect on the viscosity of the formulations of Examples
11 and 12 which both include HCMC. Without wishing to limit the
invention to any particular theory of operation, it is believed
that the heat sterilization degrades the HCMC so that the weight
average molecular weight of this material is somewhat reduced after
such sterilization. However, it is important to note that even
after such sterilization a clear and substantial distinction, for
example, in terms of viscosity, exists between the HCMC-containing
formulations (Example 11 and 12) and the MCMC-containing
formulation (Example 13) and the LCMC-containing formulation
(Example 14). In other words, even after heat sterilization, the
HCMC-containing formulation includes effective amounts of carboxy
methyl-cellulose with a substantially higher molecular weight than
the carboxy methylcellulose present in the heat sterilized
MCMC-containing and LCMC-containing formulations. The difference
between the weight average molecular weight of the carboxy
methylcellulose in the sterilized HCMC-containing composition and
the sterilized MCMC-containing composition is believed to be (based
on a correlation of viscosities before and after sterilization) at
least about 75,000 or about 80,000. Similarly the difference
between the weight average molecular weight of the carboxy
methylcellulose in the sterilized MCMC-containing composition and
the sterilized LCMC-containing composition is believed to be at
least about 125,000.
[0100] While this invention has been described with respect to
various specific examples and embodiments, it is to be understood
that the invention is not limited thereto and that it can be
variously practiced with the scope of the following claims.
* * * * *