U.S. patent application number 17/400298 was filed with the patent office on 2021-12-16 for ophthalmic formulations providing durable ocular lubrication.
This patent application is currently assigned to EternaTear, Inc.. The applicant listed for this patent is EternaTear, Inc.. Invention is credited to Ralph P. Stone, Timothy R. Willis.
Application Number | 20210386671 17/400298 |
Document ID | / |
Family ID | 1000005808139 |
Filed Date | 2021-12-16 |
United States Patent
Application |
20210386671 |
Kind Code |
A1 |
Willis; Timothy R. ; et
al. |
December 16, 2021 |
OPHTHALMIC FORMULATIONS PROVIDING DURABLE OCULAR LUBRICATION
Abstract
This disclosure is directed to an ophthalmic formulation for dry
eye and other ocular indications that provides long-lasting
benefits. The formulations described herein provide durable relief
and last two to ten longer on the eye than currently marketed
products. The disclosure also provides methods of alleviating the
symptoms of dry eye, methods for delivering ophthalmic
pharmaceuticals, and methods of manufacture of the long-lasting
ophthalmic formulations.
Inventors: |
Willis; Timothy R.;
(Raleigh, NC) ; Stone; Ralph P.; (Fort Worth,
TX) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
EternaTear, Inc. |
Raleigh |
NC |
US |
|
|
Assignee: |
EternaTear, Inc.
Raleigh
NC
|
Family ID: |
1000005808139 |
Appl. No.: |
17/400298 |
Filed: |
August 12, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16708120 |
Dec 9, 2019 |
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17400298 |
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62777588 |
Dec 10, 2018 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 35/644 20130101;
A61K 47/44 20130101; A61K 9/0048 20130101; A61K 9/107 20130101 |
International
Class: |
A61K 9/107 20060101
A61K009/107; A61K 9/00 20060101 A61K009/00; A61K 35/644 20060101
A61K035/644; A61K 47/44 20060101 A61K047/44 |
Claims
1.-50. (canceled)
51. A method for alleviating the symptoms of dry eye, the method
comprising the step of: contacting an eye with an ophthalmic
solution, the ophthalmic solution comprising a wax dispersion
comprising natural beeswax, an anionic polar surfactant and water;
and an oil-in-water emulsion comprising an oil and water, wherein:
(i) the oil is a mixture of a lighter molecular weight and a
heavier molecular weight oil and is present in a concentration of
about 1.0 to about 6.25 weight percent; (ii) the anionic polar
surfactant is a mixture of a Polysorbate 80 in a concentration of
about 0.35 to about 0.45 weight percent and an anionic polar
dimyristoylphosphatidylglyerol in a concentration of about 0.35 to
about 0.45 weight percent; and (iii) the natural beeswax is present
in a concentration of about 0.20 to about 1.25 weight percent; and
wherein the ophthalmic solution: (i) forms a meta stable emulsion
which separates into an oil phase and a water phase on contact with
an eye; (ii) provides a dwell time on the eye of at least two
hours; and (iii) is formulated as a free flowing liquid at room
temperature.
52. The method of claim 51, wherein on contact with an eye, the
ophthalmic solution interacts with: a lipid layer; an aqueous
layer; a mucin layer; an interface between the lipid layer and the
aqueous layer; and an interface between the aqueous layer and the
mucin layer of the eye and or the corneal cells.
53. The method of claim 51, wherein the natural beeswax is Cera
alba or Cera flava.
54. The method of claim 51, wherein the lighter molecular weight
oil and heavier molecular weight oil are each a mineral oil.
55. The method of claim 51, wherein the ophthalmic solution has an
osmolality of from about 230 to about 260 mOsmol/kg.
56. The method of claim 51, wherein the ophthalmic solution is
packaged in a sterile multi-use or sterile single use
container.
57. The method of claim 51, wherein the ophthalmic solution is
packaged in a multi-dose non-preserved (MDNP) container.
58. The method of claim 51, wherein the ophthalmic solution further
comprises hyaluronic acid.
59. A method for rebuilding tear film in a subject in need thereof,
the method comprising the step of: contacting an eye with an
ophthalmic solution, the ophthalmic solution comprising a wax
dispersion comprising natural beeswax, an anionic polar surfactant
and water; and an oil-in-water emulsion comprising an oil and
water, wherein: (i) the oil is a mixture of a lighter molecular
weight and a heavier molecular weight oil and is present in a
concentration of about 1.0 to about 6.25 weight percent; (ii) the
anionic polar surfactant is a mixture of a Polysorbate 80 in a
concentration of about 0.35 to about 0.45 weight percent and an
anionic polar dimyristoylphosphatidylglyerol in a concentration of
about 0.35 to about 0.45 weight percent; and (iii) the natural
beeswax is present in a concentration of about 0.20 to about 1.25
weight percent; and wherein on contact with an eye, the ophthalmic
solution rebuilds the tear film.
60. The method of claim 59, wherein the ophthalmic solution: (i)
forms a meta stable emulsion which separates into an oil phase and
a water phase on contact with an eye; (ii) provides a dwell time on
the eye of at least two hours; and (iii) is formulated as a free
flowing liquid at room temperature.
61. The method of claim 59, wherein on contact with an eye, the
ophthalmic solution interacts with: a lipid layer; an aqueous
layer; a mucin layer; an interface between the lipid layer and the
aqueous layer; and an interface between the aqueous layer and the
mucin layer of the eye and or the corneal cells.
62. The method of claim 59, wherein the natural beeswax is Cera
alba or Cera flava.
63. The method of claim 59, wherein the lighter molecular weight
oil and heavier molecular weight oil are each a mineral oil.
64. The method of claim 59, wherein the ophthalmic solution has an
osmolality of from about 230 to about 260 mOsmol/kg.
65. The method of claim 59, wherein the ophthalmic solution further
comprises hyaluronic acid.
66. A method for durable lubrication of an eye, the method
comprising the step of: contacting an eye with an ophthalmic
solution, the ophthalmic solution comprising a wax dispersion
comprising natural beeswax, an anionic polar surfactant and water;
and an oil-in-water emulsion comprising an oil and water, wherein:
(i) the oil is a mixture of a lighter molecular weight and a
heavier molecular weight oil and is present in a concentration of
about 1.0 to about 6.25 weight percent; (ii) the anionic polar
surfactant is a mixture of a Polysorbate 80 in a concentration of
about 0.35 to about 0.45 weight percent and an anionic polar
dimyristoylphosphatidylglyerol in a concentration of about 0.35 to
about 0.45 weight percent; and (iii) the natural beeswax is present
in a concentration of about 0.20 to about 1.25 weight percent; and
wherein on contact with an eye, the ophthalmic solution provides
durable eye lubrication for at least two hours.
67. The method of claim 66, wherein on contact with an eye, the
ophthalmic solution provides durable eye lubrication for greater
than three hours.
68. The method of claim 66, wherein the lighter molecular weight
oil and heavier molecular weight oil are each a mineral oil.
69. The method of claim 66, wherein the ophthalmic solution has an
osmolality of from about 230 to about 260 mOsmol/kg.
70. The method of claim 66, wherein the ophthalmic solution further
comprises hyaluronic acid.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application 62/777,588 filed Dec. 10, 2018, inventors Timothy
Willis and Ralph Stone, entitled "OPHTHALMIC FORMULATIONS PROVIDING
LONG-LASTING EYE LUBRICATION" which is hereby incorporated by
reference in its entirety
1. FIELD
[0002] The present disclosure provides a novel long-lasting
ophthalmic formulation for ocular therapy for dry eye and other
ocular indications. The formulation described herein provides
relief for dry eye that lasts two to ten times longer on the eye
than currently marketed products. Methods of treatment, methods of
delivery of pharmaceuticals, and methods of preparation are also
provided.
2. BACKGROUND
2.1. Introduction
[0003] The "background" description provided herein is for the
purpose of generally presenting the context of the disclosure. Work
of the presently named inventors, to the extent it is described in
this background section, as well as aspects of the description
which may not otherwise qualify as prior art at the time of filing,
are neither expressly admitted or impliedly admitted as prior art
against the present disclosure.
[0004] Dry eye is an ophthalmic medical condition which is
currently exhibited in over 320 million patients worldwide and over
15% of the US population. The discomfort resulting from a dry eye
condition may include ocular dryness, grittiness, burning,
soreness, scratching, or foreign body reaction. The degree of
discomfort is dependent upon the subject and the condition of the
subject. Proposed causes for dry eye, treatment, and symptoms are
described in a compendium of papers edited by Holly, The Preocular
Tear Film in Health, Disease, and Contact Lens Wear, The Dry Eye
Institute, Lubbock, Tex. 1986; edited by David A. Sullivan,
Lacrimal Gland, Tear Film, and Dry Eye Syndromes, 1994, Plenum
Press, New York; edited by David A. Sullivan et. al, Lacrimal
Gland, Tear Film, and Dry Eye Syndromes 2, 1998, Plenum Press, New
York; edited by David A. Sullivan et. al, Lacrimal Gland, Tear
Film, and Dry Eye Syndromes 3, Part A and B, 2002, Kluwer
Academic/Plenum Publishers, New York, The 2007 DEWS Report Ocular
Surface July 2007, The DEWS II Report Ocular Surface July 2017
incorporated herein by reference for their teachings of the dry eye
condition and the treatment thereof.
[0005] In addition, for many patients the symptoms associated with
dry eye are often exacerbated by use ocular prostheses such as
contact lenses. In some cases, individuals will stop wearing
contact lenses due, either solely or in part, to dry eye and its
symptoms. Further, the rate of evaporation from the eye is
accelerated by the nature of the contact lens material and surface.
The physical presence of the contact lens results in menisci
formation with additional physical and evaporative effects, even
with subjects having an adequate tear film. For many subjects,
contact lens intolerance is not overcome by topical application of
tear substitutes. Therefore, there is a need for improved
compositions and processes for treatment of the dry eye condition
and for improving tolerance to ocular prostheses. Moreover, the
patient may present with ocular signs including lid wiper
epitheliopathy and corneal staining either when experiencing dry
eye or when wearing an ocular prostheses.
[0006] The most common treatment for dry eye involves temporary
alleviation of dry eye symptoms by topical application of an
artificial tear substitute that provide a volume of liquid to the
surface of the eye and neighboring tissues, e.g., eyelids, cornea.
Typical commercially available tear substitute compositions
comprise water soluble polymer solutions. These water soluble
polymer solutions only provide limited relief due to an average on
eye dwell time being less than 15 minutes. Examples of such
solutions include saline solutions of polyvinyl alcohol,
hydroxypropylmethyl cellulose, or carboxymethyl cellulose. U.S.
Pat. No. 4,421,748 teaches an artificial tear composition
comprising an aqueous hypotonic solution of lecithin and a
viscosity-adjusting agent such as a solution of a soluble
cellulose. An aqueous tear film extends over the ocular surface and
maintains a moist and lubricated ocular surface. It is also known
that dehydration of moisture from the eye may result in discomfort.
Further, compositions are available in the market intended for dry
eye treatment. Commercially available compositions are primarily
aqueous materials that supplement the tear film by adding a film of
a water soluble polymer over the surface of the eye. These films
are short lived and provide limited relief.
[0007] A number of improved compositions for dry eye treatment are
disclosed in U.S. Pat. Nos. 4,914,088; 5,278,151; 5,294,607;
5,578,586, and 9,161,905, each incorporated herein by reference for
its teaching of how to form an oil film over the surface of the eye
including compositions and uses. U.S. Pat. No. 4,914,088 teaches
the use of certain charged phospholipids for the treatment of dry
eye symptoms. The addition of a charged phospholipid to the eye is
believed to assist in replicating the tear film that would
naturally occur in the eye. In accordance with the patent, the
phospholipid composition, preferably in the form of an aqueous
emulsion, is topically applied to the eye where it is believed to
disperse over the ocular surface and form a film that replicates a
lipid layer that would be formed by the spreading of a naturally
occurring lipid secreted principally from the Meibomian glands
during blinking. Because the phospholipid, when applied to the eye
carries a net negative charge, it is believed that aligned
molecules repel each other preventing complex aggregate formation
thereby resulting in a stable phospholipid film. The patent
theorizes that the film formed from the charged phospholipid
assists in the formation of a barrier film reducing evaporation of
the aqueous layer, thereby preserving the tear film. Others have
theorized that the phospholipid also functioned as a surfactant
maintaining the emulsion stability.
[0008] The above referenced U.S. Pat. Nos. 5,278,151; 5,294,607;
5,578,586; 9,279,095; and 9,375,401 disclose additional
improvements in dry eye treatment. In these patents, the dry eye
treatment composition of U.S. Pat. No. 4,914,088 is improved by the
addition of an oil to the eye treatment composition, preferably a
non-polar oil such as mineral oil comprised of hydrocarbon
ingredients. The oil is added to improve the performance of a dry
eye treatment composition by increasing the longevity of the tear
film formed on the eye as a consequence of the formation of an oil
film over the ocular surface that functions as an evaporation
barrier--i.e., by providing and/or thickening the dehydration
barrier (the oil layer) on the outer surface of the tear film.
Thus, the oil increases the efficacy of the dry eye treatment
solution and reduces performance variability from subject to
subject. It also supplements the oils provided from the Meibomium
gland which in many cases of dry eye does not provide sufficient
oils to provide an adequate lipid tear layer. A preferred
embodiment disclosed in the above referenced patents is a dry eye
treatment composition comprising a meta stable oil-in-water
emulsion where the water phase includes the charged phospholipid
believed to function both as an emulsifier and as a surfactant that
assists in spreading of the oil over the eye to form a non-blurring
film bonding of the oil to the aqueous layer of the tear film. The
emulsion is desirably "meta" stable so that when the emulsion is
applied to the eye, it will rapidly break and spread over the
ocular surface when it first comes into contact with the ocular
environment.
[0009] In the patent literature described above, meta stable
emulsions were formulated whereby the total amount of oil added to
the eye preferably does not exceed 25 .mu.L, more preferably varies
between about 1 and 10 .mu.L and most preferably varies between
about 1 and 5 .mu.L. If the amount of oil added to the eye is in
excess of 25 .mu.L, the oil layer on the surface of the eye may be
of excessive thickness resulting in formation of oil globules on
the surface of the eye. These globules are likely to result in
prolonged blurred vision. To achieve control of the amount of oil
added to the eye, the concentration limits of the oil in the
emulsion are controlled within reasonable limits. An emulsion
containing the oil in a concentration of at least 0.1 percent by
weight of the total composition provides some benefits, a preferred
concentration is at least 1.0 percent of the weight of the
treatment composition, and the most preferred oil content varies
between about 2.5 and 12.5 percent by weight of the emulsion.
[0010] U.S. Pat. No. 5,371,108 teaches a method for creating a gel
comprising oil and wax to form a tear film on the ocular surface
and the presence of wax in the gel can prolong the residence time
of oil. A wax-containing gel has not been produced and marketed
commercially because of the difficulty in homogenizing the wax in
such a way that does not induce visual blurring beyond what would
be acceptable by most consumers. Specifically, autoclaving to
sterilize the wax contain formulation leads to increased particle
size which leads to irritation and blurred vision. Gels are
semi-solid formulations with low viscosity. In contrast, this
disclosure is directed to metastable emulsions that behave as
flowing liquids at room temperature. Emulsions behave as liquids
and as such do not exhibit a static internal structure.
[0011] U.S. Pat. No. 5,278,151 teaches that an oil-in-water
emulsion can contain a natural wax.
[0012] With regard to natural tears, Shimizu and coworkers have
reported a typical tear volume is 12.4.+-.6.2 .mu.L. Shimizu et
al., 1993 Nippon Ganka Gakkai Zasshi. 97(9):1047-52. Others have
reported small volumes, 6.2.+-.2.0 .mu.L. Mishima et al., 1996,
IOVS 1966; 5:264-76.
[0013] Current commercially available products, including oil and
water emulsion products, often supplement one or more layers of the
tear film through various combinations of oils, aqueous solutions,
and mucomimetics. These lipid emulsions provide sufficient
lubrication and prevention against desiccation, but they remain
inadequate in terms of their ability to remain on the eye and
provide lasting relief, which is the most desired clinical result.
However, these compositions fail to bind the interstitial layers,
causing those layers to lose their natural stability on the surface
of the eye and thus have limited relief due to their on eye dwell
time being less than 45 minutes. Without connectivity to each
subsequent layer of the film, the lipid, aqueous, and mucin layers,
whether natural, artificial or some combination thereof, tend to be
expressed in a period of time too short to provide lasting comfort
from the symptoms of dry eye. See FIG. 1 for an enlarged view of
the eye and the components of the layers and interfaces of the tear
film. The normal tear film is 3-6 .mu.M thick. The two insets with
lines to the tear film show enlarged views of the lipid/aqueous
interface and the aqueous/mucin interface. The third inset shows
the thinning of the layers and interfaces associated with dry eye.
In particular, it shows the thinning of (i) the aqueous layer, (ii)
the unbound mucin layer, and (iii) the bound mucin layer on the
surface of the corneal epithelial cells. Existing products do not
stabilize, the different layers and interfaces of the tear film
including the lipid layer. Thus, the existing products do not
create a stable lipid layer and provide long term benefits.
[0014] Methods used to quantify the effectiveness of tear
substitutes for dry eye treatment solutions have historically not
been standardized, and many methods used to quantify the results
obtained using such tear substitute compositions are often
inaccurate. For this reason, reported relief of dry eye symptoms
using known tear substitutes varies considerably from subject to
subject, and regardless of the method used to quantify relief using
a tear substitute, relief often does not exceed several
minutes.
[0015] For a therapy to provide lasting relief, it would have to
supplement not only the deficient layers of the tear film, but also
have the chemical and binding properties necessary to promote
homeostasis of those layers on the ocular surface. For any solution
to be viable for a large number of patients with symptoms that vary
greatly in cause and magnitude, the therapy would need to mimic as
closely as possible the properties of the natural human tear film.
Though research has reported the presence of waxes within the tear
film, their purpose has not been well-understood.
[0016] Because the purpose of the tear film is to protect the
ocular surface and provide lubrication to the ocular surface as
well as can be used to provide ocular delivery of active
pharmaceutical ingredients (API) in small concentrations has been a
challenge to industry. See Patel et al. 2013, "Ocular drug delivery
systems: An overview" World J. Pharmacol 2(2) 47-64. For an
excipient to be a good carrier of active pharmaceutical ingredients
(APIs) it needs to mimic the properties and osmolarity of the
natural tear film and remain on the eye for an extended period of
time. Such a product would increase the bioavailability of the API
to the corneal epithelial cells, a long desired pathway for ocular
drugs.
3. SUMMARY OF THE DISCLOSURE
[0017] Disclosed herein is an oil-in-water emulsion with the
inclusion of natural or synthetic wax esters or suitable
combination of wax esters in the tear film which rebuilds the tear
film in a several ways. In particular it rebuilds the tear film by
increasing the integrity of the interstitial layers themselves,
binds mucin to aqueous and or the corneal cells and aqueous to
lipid as well as builds and thickens the mucin, aqueous and lipid
layers themselves. The binding and thickening process and
subsequent homeostasis enabled by the wax esters and their
hydrolysis products allows the layers of the tear film to cling to
each other, thus mimicking the natural tear film and providing a
tear film that remains on the eye for extended periods of time.
This vehicle mimics the tear film as well as providing a vehicle to
be used for pharmaceutical drug delivery as noted herein.
[0018] In one embodiment, this disclosure provides an ophthalmic
solution which comprises an oil-in-water emulsion comprising water;
an oil; a surfactant; a wax ester, which may be a beeswax or
suitable combination of wax esters; and wherein the ophthalmic
solution (i) forms a meta stable emulsion which separates into an
oil phase and a water phase on contact with an eye; and (ii)
provides lubrication for about 2 to about 12 hours on the eye. In
some embodiments, the ophthalmic solution provides lubrication for
about 2 to about 5 hours on the eye. In other embodiments, the
ophthalmic solution provides lubrication for about 2 to about 8
hours or 1 to 10 hours on the eye. Alternatively, it may provide
greater than 3 hours of lubrication, greater than 5 hours, greater
than 8 hours, or greater than 10 hours of lubrication on the
eye.
[0019] An ophthalmic solution which comprises an oil-in-water
emulsion comprising water; an oil; a surfactant; a wax ester such
as beeswax comprising wax esters and other wax ester compositions
in addition to partial hydrolysis products of theses esters;
wherein the wax ester composition in the ophthalmic solution
interacts with a mucin layer, an aqueous layer, and a lipid layer
in an eye of a subject and act to maintain the integrity of an
interstitial layer between the mucin layer and the aqueous layer,
an interstitial layer between the aqueous layer and the lipid
layer.
[0020] An ophthalmic solution which comprises a metastable emulsion
comprising water; an lipid; a surfactant; an anti-inflammatory
ingredient such as deactivated brewer's yeast or derivative such as
ADP Ribose, wax esters and other wax ester compositions in addition
to partial hydrolysis products of theses esters; wherein wax ester
composition in the ophthalmic solution binding a mucin layer, an
aqueous layer, and a lipid layer in an eye of a subject and act to
maintain the integrity of an interstitial layer between the mucin
layer and the aqueous layer, an interstitial layer between the
aqueous layer and the lipid layer while enhancing the tear film and
reducing ocular inflammation caused by dry eye.
[0021] In another embodiment, this disclosure provides an
ophthalmic solution which comprises an lipid and wax based emulsion
comprising water; an oil and wax or wax esters ingredient such as
whale or seal oil or synthetic version ingredients thereof; a
surfactant; and other wax ester compositions in addition to partial
hydrolysis products of theses esters; wherein wax ester composition
in the ophthalmic solution binding the mucin layer, the aqueous
layer, and the lipid layer in an eye of a subject and act to
enhance and maintain the integrity of an interstitial layer between
the mucin layer and the aqueous layer, an interstitial layer
between the aqueous layer and the lipid layer.
[0022] In another embodiment, this disclosure provides a method for
alleviating the symptoms of dry eye which comprises contacting an
eye with an ophthalmic solution comprising an oil-in-water emulsion
which emulsion comprises: water; an oil; a surfactant; a wax ester
such as beeswax and the products of partial hydrolysis; and wherein
the ophthalmic solution (i) forms a meta stable emulsion which
separates into an oil phase and a water phase on contact with an
eye; and (ii) provides lubrication for about 2 to about 12 hours on
the eye. In some embodiments, the method provides lubrication for
about 2 to about 5 hours on the eye. In other embodiments, the
method provides lubrication for about 2 to about 8 hours or 1 to 10
hours on the eye. Alternatively, the method may provide greater
than 3 hours of lubrication, greater than 5 hours, greater than 8
hours, or greater than 10 hours of lubrication on the eye.
[0023] In another embodiment, this disclosure provides the method
of preparing an ophthalmic solution providing lubrication for about
2 to about 12 hours on the eye, wherein the solution is a meta
stable oil-in-water emulsion, wherein the method comprises:
preparation of a wax ester dispersion comprising a wax ester such
as a beeswax and a surfactant in a deionized water solution;
preparation of an oil-in-water emulsion comprising an oil in a
deionized water solution; separately autoclaving the beeswax
dispersion and the oil-in-water emulsion under appropriate
conditions; and aseptically blending the autoclaved wax ester
dispersion and the oil-in-water emulsion so as to prepare the meta
stable oil-in-water emulsion ophthalmic solution which provides
lubrication for about 2 to about 12 hours on the eye. In a
preferred embodiment, the lipid fraction is a homogenous
oil-beeswax emulsified droplet. In one embodiment, the composition
is used to deliver an over-the-counter or a prescription (generic
or proprietary) medication.
4. BRIEF DESCRIPTION OF THE FIGURES
[0024] FIG. 1 shows an enlarged view of the tear film with the
different regions. The normal tear film is 3-6 microns thick. The
figure shows the lipid layer, the lipid/aqueous interface, the
aqueous layer, the aqueous/mucin interface, the mucin layer, and
the cornea. Two of the insets show enlarged views of the
lipid/aqueous interface and the aqueous/mucin interface. The third
inset shows the thinning of the layers and interfaces associated
with dry eye. In particular, the third inset shows the thinning of
(i) the aqueous layer, (ii) the unbound mucin layer, and (iii) the
bound mucin layer which is bound the surface of the corneal
epithelial cells.
[0025] FIG. 2 shows the tear film score over time in minutes (or
the dwell time in minutes) for the 1% wax ester prototype product
(solid line) vs a commercially available water soluble polymer
solutions (dashed line) (n=2).
[0026] FIG. 3 shows the tear film score over time in minutes (or
the dwell time in minutes) for the 1% wax ester prototype product
(solid line) vs a commercially available water soluble polymer
solutions (dashed line) (n=5).
[0027] FIG. 4 shows the tear film score over time in minutes (or
the dwell time in minutes) for the 1% wax ester prototype product
(solid line) vs a commercially available water soluble polymer
solutions (dashed line) (n=5).
[0028] FIG. 5 shows a graph showing some of the comparative data
for the dwell time in minutes and tear film score for 1% wax ester
prototype product vs several commercially available solutions. The
gray solid lines are two experiments with the EternaTear.TM.
prototype 1% wax ester product, the gray dashed line is a first
generation commercially available eye product. The black dashed
line is a second generation commercially available eye product.
[0029] FIG. 6 shows the change in emulsion particle size
distribution after autoclaving a 2.times. (solid line), 3.times.
(dashed line), and 4.times. (open circles) concentrated emulsion.
The top panel shows the particle size distribution for the `as
made` product, while the bottom panel shows the effect of
autoclaving these samples.
[0030] FIG. 7 shows particle size distributions of submicron wax
ester particles before (solid black line) and after (dashed line)
autoclaving.
[0031] FIG. 8 shows the particle size distributions for wax ester
particles obtained in the emulsification process in water with
Octoxynol-40. The solid black line is for the sample as made, while
the dashed line is the resulting distribution after
autoclaving.
5. DETAILED DESCRIPTION OF THE DISCLOSURE
[0032] This invention relates to an emulsion composition for the
formation of an artificial tear film over the ocular surface of the
eye capable of providing enhanced ocular lubrication while reducing
evaporation and remaining on the eye two to ten times longer than
products currently available. The composition is also useful for
delivering medication to the ocular surface and for treating
individuals wearing ocular prostheses such as contact lenses as the
composition wets and provides lubrication for both the ocular
surface and the surface of the prosthesis. More particularly, the
invention relates to emulsion compositions capable of augmenting
and maintaining a stable tear film over the ocular surface for a
period of time between two and six hours and/or delivering a
medication to the eye without causing substantial blurring of
vision nor discomfort. The emulsion is desirably in the form of an
emulsion and is characterized by the use of wax or wax esters in
combination with oils and appropriate surfactants and interstitial
ingredients to increase dwell time on the ocular surface while
providing a combination suitable for formation such an emulsion and
maintaining the integrity of the emulsion during autoclaving.
[0033] In some embodiments the invention is an oil-in-water
emulsion with natural wax esters such as beeswax dissolved in such
a way that it can be delivered in a controlled manner and that its
presence in an artificial tear film composition leads to
dramatically increased dwell time on the eye by specifying the
composition, concentration, and particle size of the wax ester in
the meta stable oil-in-water emulsion. This wax-containing emulsion
may use one or more surfactants to achieve the meta-stable
properties one skilled in the art would accept as desirable for
manufacture, storage, and application to the ocular surface.
Further, one or both of these surfactants may be an anionic polar
phospholipid.
[0034] The addition of natural or synthetic wax esters and their
partial hydrolysis products, such as beeswax and its normal
distribution throughout the various phases of the emulsion has the
effect of improving the efficacy of the composition by allowing the
lubricating elements to remain on the eye for a period of greater
than one and up to twelve hours under normal conditions.
[0035] The chemical makeup of the invention and the manufacturing
process by which that makeup is achieved replicates not only the
discrete layers of the tear film by use of lipids, aqueous
solutions and a mucomimetic, but also supplements its interstitial
binding properties and builds and thickens the tear film by
introducing the homogenized wax ester in concentrations that
closely mimic the natural tear film. In so doing, significant
improvement in the duration of relief offered by ocular lubricants
and co-occurring medications is achieved.
[0036] It is proposed that the role of wax esters and their
hydrolysis products in the tear film maintains the integrity of the
interstitial layers themselves, binding the mucin layer to the
aqueous layer and aqueous layer to the lipid layer. In addition,
the wax esters serve to build up an thicken the mucin, the aqueous
layer, and the lipid layer themselves. The binding process and
subsequent homeostasis enabled by the wax esters allows the layers
of the tear film to cling to each other, thus allowing the entire
tear film to remain on the eye for extended periods of time. The
ophthalmic composition penetrates all layers of the tear film
including the interstitial layers of which no product has
incorporated previously. While understanding of this on normal tear
films are not fully know or understood internal research has helped
us conclude that the glands of the eyelid which include the gland
of Krause, gland of Wolfring and gland of Moll excrete wax and wax
esters that in combination with the Meibomian gland that excrete
lipids and the lachrymal gland aqueous secretions with lip wiper
effect of the eyelid due to normal blinking action builds a normal
and stable ocular tear film.
[0037] The viscosity of the ophthalmic solutions described herein
may be measured using techniques well-known to those skilled in the
art. Non-limiting examples of methods to measure viscosity include
falling ball viscometers, viscosity cups, consistometers (measuring
flow on an incline), capillary glass viscometers, or rotational
viscometers. A variety of instruments are commercially available
(Cole-Palmer Instrument Co., Vernon Hills, Ill., USA).
[0038] The extended dwell time on the eye and the shared
characteristics with the natural tear film further gives the
emulsion the ability to act not only as a lubricant for the eye and
ocular prostheses, but also as an excipient that enables enhanced
bioavailability for delivering medications.
[0039] This wax-containing emulsion is maintained at a
physiological pH between 7.0 and 7.7 so as not to cause discomfort
to the patient and will be maintained with a suitable buffering
system. The oil phase in a concentration between about 1.0 percent
up to about 12.5 percent by weight. Preferably, the oil is present
in a range from about 1 percent to about 7.5 percent. In a
preferred embodiment, the mineral oil is a mixture of two oils of
differing molecular weight.
[0040] Formulations for the invention may include combinations of
the above ingredients, some of which may necessitate the addition
of a preservative that have been recognized by those skilled in the
art as safe and acceptable for use on the eye. Examples of
preservatives include benzalkonium chloride, PURITE.RTM. (Bio-Cide
International Inc., Norman, Okla., USA), POLYQUAD.RTM. (Alcon
Laboratories, Inc., Fort Worth, Tex., USA), GENAQUA.RTM. (Novartis
Ophthalmics, East Hanover, N.J., USA), Polyhexamthylene biguanide
(ICI), OcuPure.RTM. (Abbott Laboratories Inc., Chicago, Ill., USA),
DISSIPATE.RTM. (OCuSOFT, Rosenberg, Tex., USA). See Moshirfar et
al., 2014, "Artificial tears potpourri: a literature review" Clin
Ophthalmol. 8: 1419-1433. In formulations with a preservative,
typically ethylene diamine tetraacetate (EDTA) will also be
included.
[0041] The formulations whether prepared for a sterile multi-dose
container or including a preservative may also include a borate
buffer. Alternatively, a phosphate buffer may be used.
[0042] In a preferred embodiment, the ophthalmic solution is
preservative-free. In some embodiments, preservative-free solutions
are delivered in single use packages because of the risk of
bacterial contamination associated with conventional multi-use
applications. In another embodiment, the ophthalmic solution is
delivered in a sterile multidose bottle. Several configurations are
known. As an example, Aptar Pharma (Crystal Lake, Ill., USA) sells
a multidose squeeze dispenser which operates mechanically and
utilizes a filter membrane. See PCT Publication Nos. WO 2017/074420
and WO 2017/132190 (Aptargroup, Inc.). This technology is used to
deliver a cyclosporin ophthalmic emulsion for the ALLEGAN RESTASIS
MULTIDOSE.TM. product. It is also used to deliver the CLEAR
EYES.RTM. PURE RELIEF.RTM. product. Another sterile multi-use
system is the JOT.TM. product. It is eye drop dispenser that uses
pressure to deliver controlled drops and provides a horizontal
delivery alternative to current dispensers.
http://jotteq.com/about/.
[0043] The treatment composition of the invention is an
oil-in-water emulsion having an aqueous phase and the wax component
containing oil droplets present in each, in addition to a
surfactant combination used for the dual purpose of stabilizing the
emulsion and spreading the emulsion over the ocular surface
following its application to the eye. The surfactant combination
may comprise a primary surfactant and secondary surfactant and is
one that enables formation of an emulsion that is stable in
manufacture and during storage, but desirably meta stable when
applied to the ocular surface--i.e., one that rapidly
differentiates when applied to the eye whereby a non-blurring film
of oil is rapidly formed over the ocular surface and disseminates
the wax ester through each phase of the emulsion. A stable emulsion
during manufacture and storage is one that may separate into
separate phases during standing but can be reconstituted by simple
shaking. An unstable emulsion is one that breaks apart typically
forming an oil film or slick that cannot be eliminated by simple
shaking. In some embodiments, the surfactant is a non-ionic
surfactant, such as polysorbate 80, Octoxynol 40 or a
diphosphatidylglycerol such as dimyristoylphosphatidylglycerol. In
other embodiments, the surfactant is an anionic surfactant. The
anionic surfactant may be an anionic polar phospholipid, such as a
lysophosphatidylcholine, a phosphatidic acid, a
phosphatidylcholine, a phosphatidylethanolamine, a
phosphatidylglycerol, or a phosphatidylserine. In a preferred
embodiment, the anionic surfactant is a diphosphatidylglycerol. In
a preferred embodiment, the surfactant is a mixture of two
surfactants.
[0044] A meta stable emulsion during use is desirable for purposes
of this invention. Though useable for alleviation of dry eye
symptoms, a stable emulsion, as opposed to a meta stable emulsion,
will not differentiate rapidly when applied to the ocular surface.
This is undesirable for the following reasons. An emulsion is
typically optically opaque due to the presence of two distinct
phases. Therefore, an opaque emulsion over the surface of the eye
is likely to cause blurring. The duration of blur is dependent upon
the time required for the emulsion to differentiate and form
separate layers replicating a tear film. In addition, the emulsion
is most easily added to the eye as a standard drop from an
eyedropper. The eye is capable of holding a limited volume of fluid
of volume that is less than 25 .mu.L. A volume of 25 .mu.L is
substantially less than the volume of a standard drop. Therefore,
if the emulsion is stable and fails to differentiate rapidly
following application to the eye, excess emulsion will be
discharged from the eye during blinking. Discharge of the emulsion
from the eye will result in discharge of efficacious components of
the treatment solution from the eye before a long-lasting tear film
can be formed. For this reason, efficacious components may not be
available in sufficient quantity to form the desired tear film.
Consequently, though a stable emulsion might alleviate the symptoms
of dry eye for a limited period of time, it is a lesser preferred
embodiment of the invention.
[0045] A meta stable emulsion, as the term is used herein, is one
that is either stable in storage, or differentiated into two
separate layers, but is readily reconstituted by simple shaking
prior to use. When a meta stable emulsion is added to the eye as a
standard drop, it quickly differentiates permitting rapid formation
of an oil film over the corneal surface without excessive oil
discharge by blinking. Preferably, the emulsion will differentiate
within about 10 blinks following application to the eye, more
preferably in a time of less than about 1 minute. Blurring may
occur during the time required to move the bulk of the excess
liquid to be discharged from the eye. During and following
differentiation of the emulsion, the formation of the oil film is
assisted by use of the surfactant combination which serves to help
form the emulsion and facilitate the spread of the oil over the
surface of the eye as the emulsion breaks. Consequently, a meta
stable emulsion is the preferred embodiment of this invention.
[0046] The emulsions of the invention comprise an oil-in-water
emulsion. The oil used to form the emulsion may be derived from
animals, plants, nuts, petroleum, etc. Those derived from animals,
plant seeds, and nuts are similar to fats and are primarily
glycerides or fatty acids and consequently, contain a significant
number of acid and/or ester groups rendering the same polar and
lesser preferred for purposes of the invention. Examples of these
oils are safflower oil, corn oil, canola oil, whale oil and seal
oil or chemically similar oils. Alternatively, oils derived from
petroleum are usually aliphatic or aromatic hydrocarbons that are
essentially free of polar substitution and therefore suitable for
purposes of the present invention provided the oil is refined so as
to be compatible with human tissue such as the ocular surface.
Preferably, the oil is a linear hydrocarbon oil having from 10 to
150 carbon atoms and more preferably, the oil is a saturated
n-alkane or isoalkane hydrocarbon having from 10 to 26 carbon
atoms. Unsaturated alkene hydrocarbons may be used but are less
chemically stable. In a preferred embodiment, the oil is a mixture
of two oils of differing molecular weight. In some embodiments
mineral oil is the preferred oil for purposes of this invention.
Examples of preferred mineral oils are DRAKEOL.RTM. 15 and
DRAKEOL.RTM. 35.
[0047] Additional oils that could be used to formulate an
appropriate oil in water emulsion may be a vegetable oil such as a
castor oil, almond oil, myrcia oil, corn oil, peanut oil, canola
oil, safflower oil, kola nut oil, light olive oil, bay leaf oil, or
other generally recognized as safe (GRAS) oils listed as being
appropriate for ocular formulation. Alternatively, the oil may be
one suitable for forming liposomes.
[0048] The oil component within the emulsion may vary within
reasonable limits provided the amount of oil retained on the eye
following its application to the eye is within controlled volumes
and does not exceed 25 .mu.L. Preferably, the volume does not
exceed 15 .mu.L. More preferably varies between about 1 and 10
.mu.L and most preferably varies between about 1 and 5 82 L. If the
amount of oil added to the eye is in excess of 15 .mu.L, the oil
layer on the surface of the eye may be of excessive thickness and
resulting in prolonged blurring. A treatment composition containing
the oil in a concentration of at least 0.1 percent by weight of the
total composition provides some benefits. A preferred concentration
for the oil is at least 1.0 percent of the weight of the treatment
composition. Preferably, the oil content of the treatment solution
varies between about 1 and 12.5 percent by weight of the
composition.
[0049] In one preferred embodiment, the beeswax is Cera alba or
Cera flava. It may be USDA Certified Organic beeswax or convention
natural beeswax. Alternatively, it may be a synthetic wax that may
be purchased from a variety of sources including Koster Keunen
(Watertown, Conn., USA). Such waxes may contain partial hydrolysis
products during the preparation of the emulsion.
[0050] The quantity of wax used in the formulations described
herein may vary. In some embodiments, when the percentage oil tends
to the upper portion of the range .about.7.5 wt. %, the relative
weight percent beeswax will be lower, e.g., 0.5 wt. % or less.
Similarly, when the oil tends to the lower portion of its range,
the relative weight percent beeswax will be higher 0.75 to 1.25 wt.
%.
[0051] Other additives may be present in the treatment composition.
Such materials include minor amounts of neutral lipids and oils
such as one or more triglycerides, partially hydroylyzed esters,
cholesterol esters, high molecular weight isoprenoids; stabilizers,
additional surfactants; anti-inflammatory compounds; mucomimetics;
preservatives; pH adjusters to provide a composition preferably
having a pH between about 6.5 and 7.8 and most preferably, between
about 7.2 and 7.5; salt, buffer, glycerol, or sugar in sufficient
concentration to form a mildly hypotonic composition such that the
emulsion is not stable in the ocular environment.; etc., all as
would be obvious to those skilled in the art.
5.1. Formulations with Medications
[0052] Another useful class of additives comprises medications. As
a consequence of the long term stability of the oil film formed
over the surface of the eye using the emulsion compositions of the
invention, prolonged and improved delivery of the medication to the
eye results due to increased contact time of the medication on the
eye. Medications suitable for delivery to the eye using the film
forming compositions of the invention are those soluble in either
the aqueous or oil phase of the composition though it is preferable
that the medication be soluble in the oil phase. Illustrative
medications include antibiotics, antiviral agents,
anti-inflammatory agents and antiglaucoma agents such as
illustrated in part in published European Patent Application No. 0
092 453 published Oct. 26, 1983, sections 5.3.1 and 5.3.2, or PCT
Pub. No. WO 2015/05531 published Apr. 23, 2015, page 5, lines 5-22,
incorporated herein by reference.
[0053] Some common ophthalmic drugs or active agents suitable for
use in this invention include, but are not limited to, adenosine
diphosphate ribose, antazoline, apraclonidine, apraclonidine,
atropine, azelastine, bepotastine, betaxolol, betaxolol,
bimatoprost, brimonidine, brinzolamide, bromfenac, bromfenac,
carteolol, cetrimide, chloramphenicol, ciprofloxacin,
dexamethasone, diclofenac, dorzolamide, emedastine, epinastine,
epinastine, flurbiprofen, framycetin sulphate, gentamycin,
gramicidin, hamamelis water, homatropine, hyaluronic acid,
ketotifen fumarate, latanoprost, levobunolol, levofloxacin,
lodoxamide loteprednol, moxifloxacin, naphazoline, naphazoline,
nedocromil maleate, ofloxacin, olopatadine, pegaptanib,
pheniramine, pilocarpine, pranoprofen, prednisolone, ranibizumab,
rimexolone, sodium, tetracaine, tetrahydrozoline, thiomersal,
timolol, tobramycin, trafluprost, travoprost, ketorolac trometamol,
trometamol, xylometazoline, and combinations such a
travoprost/timolol, dorzolamide/timolol, bimatoprost/timolol,
brimonidine/timolol, latanoprost/timolol, brinzolamide/timolol. In
a preferred embodiment, the ophthalmic drugs are water or oil phase
soluble.
5.2. Preferred Composition Formulation
[0054] An example of a preferred formulation is the following in
weight percent:
[0055] Wax ester: Preferred 0.25% to 1.0% Range: 0.01-1.25%. In
some embodiments, the wax ester may be present from 0.25% to 0.35%;
0.30% to 0.40%; 0.35% to 0.45%; 0.40% to 0.50%; 0.45% to 0.55%;
0.50% to 0.60%; 0.55% to 0.65%; 0.60% to 0.70%; 0.65% to 0.75%;
0.70% to 0.80%; 0.75% to 0.85%; 0.80% to 0.90%; 0.85% to 0.95%;
0.90% to 1.00%; 0.95% to 1.05%; 1.00% to 1.10%; 1.05% to 1.15%;
1.10% to 1.20%; or 1.15% to 1.25%. In some embodiments the wax
ester may be a beeswax, e.g., a naturally occurring beeswax or a
synthetic beeswax.
[0056] Oil: Preferred 3.5% to 5.5% using two different weights of
oil (e.g., 1.0% DRAKEOL.RTM. 15 & 4.5% DRAKEOL.RTM. 35). Range:
1.0% to 6.5%. In some embodiments, the oil may be present from 1.0%
to 1.5%; 1.25% to 1.75%; 1.5% to 2.0%; 1.75% to 2.25%; 2.0% to
2.5%; 2.25% to 2.75%; 2.5% to 3.0%; 2.75% to 3.25%; 3.0% to 3.5%;
3.25% to 3.75%; 3.5% to 4.0%; 3.75% to 4.25%; 4.0% to 4.5%; 4.25%
to 4.75%; 4.5% to 5.0%; 5.75% to 6.25%; or 6.0% to 6.5%.
[0057] Polysorbate 80: Preferred 0.4% Range: 0.2% to 0.7%. In some
embodiments, the Polysorbate 80 may be present from 0.2% to 0.4%;
0.3% to 0.5%; 0.4% to 0.6%; 0.5% to 0.7%.
[0058] In a preferred embodiment, a second surfactant is used,
which may be Octoxynol 40 or anionic polar phospholipid (APP). If
the second surfactant is Octoxynol 40: Preferred 0.3% Range 0.1% to
0.6%. In some embodiments, the Octoxynol 40 may be present in 0.1%
to 0.2%; 0.15% to 0.25%; 0.2% to 0.3%; 0.25% to 0.35%; 0.3% to
0.4%; 0.35% to 0.45%; 0.4% to 0.5%; 0.45% to 0.55%; or 0.5% to
0.6%. If the second surfactant is anionic polar phospholipid (APP),
it is preferably a diphosphatidylglycerol such as
dimyristoylphosphatidylglycerol: Preferred 0.25%, Range of 0.1% to
0.75%. In some embodiments, the APP may be present in 0.1% to 0.2%;
0.15% to 0.25%; 0.2% to 0.3%; 0.25% to 0.35%; 0.3% to 0.4%; 0.35%
to 0.45%; 0.4% to 0.5%; 0.45% to 0.55%; 0.5% to 0.6%; 0.55% to
0.65%; 0.6% to 0.7%; or 0.65% to 0.75%.
[0059] Monobasic and Dibasic Phosphate: 0.25% and 0.03% with range
of 0.01% to 0.5%.
[0060] Sodium Chloride: 0.67% range 0.60% to 0.75%
[0061] Formulation pH of 7.6+0.1, -0.6
[0062] Osmolality: preferred 230 to 260 mOsmol/kg, range 210 to 260
mOsmol/kg
[0063] Deionized Water
[0064] Optionally EDTA. If present preferred 0.01%, range 0.007% to
0.02% by weight. Typically, EDTA will be used if there is a
preservative in the formulation.
[0065] Optionally an anti-inflammatory compound such as deactivated
brewer's yeast or adenosine diphosphate ribose, if present
preferred 0.02% to 1% by weight.
[0066] Optionally, a mucomimetic, such as HP Guar, a
glycosylaminoglycan such as hyaluronic acid (HA) or sodium
hyaluronate may be included. Typical HA concentrations for an
ophthalmic solution range from 0.1% to 0.4%. Other additives such
as an emollient or demulcent may be incorporated. Non-limiting
examples include polymers of ethylene oxide, propylene oxide, or
butylene oxide. Additional examples are carboxymethylcellulose
(CMC), hydroxypropyl methylcellulose (HPMC), polyacrylic acid
(PAA), polyethylene glycol, (PEG) propylene glycol (PG) or
polyvinyl alcohol (PVA). Specific concentrations ranges for liquid
polyols: glycerin, 0.2% to 1%; polyethylene glycol 300, 0.2% to 1%;
polyethylene glycol 400, 0.2% to 1%; propylene glycol, 0.2% to 1%;
or polyvinyl alcohol, 0.1% to 4%. Specific concentrations ranges
for cellulose derivatives carboxymethylcellulose sodium, 0.2% to
2.5%; hydroxyethyl cellulose, 0.2% to 2.5%; hydroxypropyl
methylcellulose, 0.2% to 2.5%; and methylcellulose, 0.2% to 2.5%
See Pucker, A D et al., 2016, "Over the counter (OTC) artificial
tear drops for dry eye syndrome", Cochrane Database Syst Rev.
February 23; 2:CD009729.
[0067] The ophthalmic solutions are brought to the appropriate pH
by use of an acid such as HCl or citric acid or a base such as
NaOH.
5.3. Definitions
[0068] While the following terms are believed to be well understood
by one of ordinary skill in the art, the following definitions are
set forth to facilitate explanation of the presently disclosed
subject matter.
[0069] As used herein "wax ester" means a that have long or very
long carbon chains and are solids up to 60 or 100.degree. C. They
may be natural from animal, vegetal, bacterial sources or synthetic
such as beeswax, Chinese wax, Shellac Wax and Spermaceti wax. The
preferred wax ester is beeswax, a mixture a wax or wax ester of
several components with a typical approximate chemical formula of
C.sub.15H.sub.31COOC.sub.30H.sub.61. For natural beeswax, the
primary components are palmitate, palmitoleate, and oleate esters
of long-chain aliphatic alcohols, with the ratio of triacontanyl
palmitate
CH.sub.3(CH.sub.2).sub.29--O--CO--(CH.sub.2).sub.14CH.sub.3 to
cerotic acid CH3(CH.sub.2).sub.24COOH, the two principal
components, being approximately 6:1. The chemical composition of
beeswax is monoesters, 30 to 55%; hydrocarbons, 10 to 18%; free
fatty acids, 10 to 15%; di- & complex esters, 8 to 18%; hydroxy
monoesters, 3 to 6%; hydroxy polyesters, 7 to 10%; free fatty
alcohols, 1 to 2%; minor components 2 to 7%. See Leray, Claude,
"Waxes" Kirk-Othmer Encyclopedia of Chemical Technology, Sep. 15,
2016, John Wiley & Sons, vol. 25, pp. 1-25; www.wikipedia.org
"Beeswax" accessed Sep. 27, 2018. Natural beeswax is also
commercially available as Cera alba or Cera flava (White or Yellow
Beeswax). Alternatively, the beeswax may be a synthetic beeswax.
Typically, a synthetic beeswax is a blend of fatty esters (C32 to
C62), high-molecular-weight hydrocarbons (C21 to C34), fatty acids
(C16 to C36), and fatty alcohols (C16 to C36). For synthetic
beeswax, esters are the most abundant, the hydrocarbons next, the
acids, and then the alcohols. Examples of synthetic beeswax may be
found in Anderson, U.S. Pat. No. 4,151,001. During the preparation
of the emulsion, the wax esters may hydrolyze forming additional
acids and/or alcohols as part of the commercial process.
[0070] Throughout the present specification, the terms "about"
and/or "approximately" may be used in conjunction with numerical
values and/or ranges. The term "about" is understood to mean those
values near to a recited value. For example, "about 40 [units]" may
mean within .+-.25% of 40 (e.g., from 30 to 50), within .+-.20%,
.+-.15%, .+-.10%, .+-.9%, .+-.8%, .+-.7%, .+-.6%, .+-.5%, .+-.4%,
.+-.3%, .+-.2%, .+-.1%, less than .+-.1%, or any other value or
range of values therein or there below. Alternatively, depending on
the context, the term "about" may mean .+-.one half a standard
deviation, .+-.one standard deviation, or .+-.two standard
deviations. Furthermore, the phrases "less than about [a value]" or
"greater than about [a value]" should be understood in view of the
definition of the term "about" provided herein. The terms "about"
and "approximately" may be used interchangeably.
[0071] Throughout the present specification, numerical ranges are
provided for certain quantities. It is to be understood that these
ranges comprise all subranges therein. Thus, the range "from 50 to
80" includes all possible ranges therein (e.g., 51-79, 52-78,
53-77, 54-76, 55-75, 60-70, etc.). Furthermore, all values within a
given range may be an endpoint for the range encompassed thereby
(e.g., the range 50-80 includes the ranges with endpoints such as
55-80, 50-75, etc.).
[0072] As used herein, the verb "comprise" as used in this
description and in the claims and its conjugations are used in its
non-limiting sense to mean that items following the word are
included, but items not specifically mentioned are not
excluded.
[0073] Throughout the specification the word "comprising," or
variations such as "comprises" or "comprising," will be understood
to imply the inclusion of a stated element, integer or step, or
group of elements, integers or steps, but not the exclusion of any
other element, integer or step, or group of elements, integers or
steps. The present disclosure may suitably "comprise", "consist
of", or "consist essentially of", the steps, elements, and/or
reagents described in the claims.
[0074] It is further noted that the claims may be drafted to
exclude any optional element. As such, this statement is intended
to serve as antecedent basis for use of such exclusive terminology
as "solely", "only" and the like in connection with the recitation
of claim elements, or the use of a "negative" limitation.
[0075] Unless defined otherwise, all technical and scientific terms
used herein have the same meanings as commonly understood by one of
ordinary skill in the art to which this disclosure belongs.
Preferred methods, devices, and materials are described, although
any methods and materials similar or equivalent to those described
herein can be used in the practice or testing of the present
disclosure. All references cited herein are incorporated by
reference in their entirety.
5.4. Methodologies to Evaluate the Tear Film
[0076] There are a number of methods to diagnose dry eye including
patient reported symptoms and ocular tests to evaluate the tear
film. Some have expressed concern about the lack of a diagnostic
gold standard. See Pucker et al. 2016.
[0077] One method is the LIPIVIEW.RTM. II Ocular surface
interferometer. It is an FDA cleared non-contact diagnostic
instrument that measures the lipid layer thickness, blink rates and
images the Meibomian gland. TearScience, Morrisville, N.C., USA.
See Eom et al., 2013, "Correlation between quantitative
measurements of tear film lipid layer thickness and Meibomian gland
loss in patients with obstructive Meibomian gland dysfunction and
normal controls" Am J Ophthalmol. 155(6) 1104-1110; King-Smith et
al., 2010, "Application of a novel interferometric method to
investigate the relation between lipid layer thickness and tear
film thinning" Invest Ophthalmol Vis Sci. 2010; 51(5):2418-2423;
King-Smith et al., 2009, "The contribution of lipid layer movement
to tear film thinning and breakup" Invest Ophthalmol Vis Sci. 2009;
50(6):2747-2756; Blackie et al., 2009, "The relationship between
dry eye symptoms and lipid layer thickness" Cornea 28(7) 789-794.
See also Korb et al., U.S. Pat. Nos. 9,545,197; 8,915,592;
8,746,883; and 8,591,033, the contents of which are incorporated
herein by reference.
[0078] Another method to measure the tear film is the tear breakup
time (TBUT). In this test a fluorescein dye is used to stain the
eye while the patient does not blink. The time for the tear film to
breakup is recorded where >10 seconds is considered normal, 5-10
seconds is marginal and <5 seconds is low. Wang and Craig, 2018,
"Comparative Evaluation of Clinical Methods of Tear Film Stability
Assessment: A Randomized Crossover Trial" JAMA Ophthalmol.
136(3):291-294.
5.4.1. Interference Patterns to Evaluate the Tear Film
[0079] Yet another method to analyze the tear film using light and
the observed interference patterns is described below. In this
method, a tear film is formed over an ocular surface by either
adding one standard drop of treatment solution (40 to 50 .mu.L).
Thereafter, the tear film formed is evaluated by projecting a light
source onto the ocular surface and viewing the reflected images
from the light source on a video screen. The light source and its
location are configured to illuminate a surface area on the ocular
surface of approximately 10 mm.sup.2. Interference patterns are
formed, the color(s) of which are indicative of the thickness of
the oil layer over the ocular surface. The color of the waves is
correlated with standards of known film thickness. In this way,
tear film is evaluated over a period of real time and first rated
in accordance with the following scale. Also see Yokoi et al.,
1996, "Correlation of tear lipid layer interference patterns with
the diagnosis and severity of dry eye" Am J Ophthalmol 122 818-824.
The lipid film thickness determined by the interference patterns in
the Film Characteristics column of Table 1 below are known to
correlate with the actual lipid film thickness in the tear film.
The thickness of the actual lipid film in turn correlates with the
overall thickness of the tear film on the eye. See FIG. 1 for the
different layers of the tear film.
TABLE-US-00001 TABLE 1 Rating Film Characteristics Quality A
Colored waves-particularly greens and blues. Excellent Waves extend
from lower lid to above the lower pupillary border. Film thickness
is in excess of 170 nm. B Colored waves-reds, browns, yellows, but
Very no blues. Waves extend from lower lid to Good above the lower
pupillary border. Film thickness of approximately 140 nm. C Colored
waves-only yellow is present. Good Waves extend from lower lid to
Good lower pupillary border. Film thickness of approximately 90 nm.
D Waves visible but no color present or no Fair color other than
grayish white. Waves extend from lower lid to lower pupillary
border. Film thickness of less than 55 nm. F No waves and no color.
An absence of Poor any observable tear film movement. Film
thickness of less than 25 nm.
[0080] With respect to the above categories, it should be
recognized that because of the extensive degradation of thin films
evaluated for the D and F categories, the film thickness is a rough
approximation. Having rated the tear film as described above, a
numerical format is then utilized to express change in tear film
thickness. A numerical grade of 1.0 indicates a change of one
letter grade-e.g., if a C baseline finding prior to the application
of a drop of treatment composition improved the tear film to a B
rating, a numerical grade of 1.0 would be given. A 2.0 numerical
grade would indicate a two-letter grade improvement; and a 3.0
numerical grade would indicate a three-letter grade improvement.
For many of the following examples: a 3.0 numerical grade
represents an improvement from a D to an A, the maximum improvement
in accordance with the testing method used because subjects with a
grade of F were screened and eliminated from testing. These scales
are used in the tables.
[0081] In some of the examples, a rating in excess of 3.0 is given.
In such instances, the films formed were exceptional and off scale.
In most examples, the evaluation of the tear films formed using the
treatment composition was over a period of four hours to determine
residence time of the film on the eye. Therefore, with time, the
numerical rating decreases but in all cases, the numerical rating
is based upon the baseline tear film prior to addition of the
treatment composition.
[0082] The following Examples further illustrate the disclosure and
are not intended to limit the scope. In particular, it is to be
understood that this disclosure is not limited to particular
embodiments described, as such may, of course, vary. It is also to
be understood that the terminology used herein is for the purpose
of describing particular embodiments only, and is not intended to
be limiting, since the scope of the present disclosure will be
limited only by the appended claims.
6. EXAMPLES
6.1. Wax Ester Containing Formulations
[0083] This section discusses several primary goals: ophthalmic
formulations for improved tear film stability; a controlled,
reproducible method for the manufacture of colloidal wax ester
particles to be incorporated into the final emulsion at 0.1 to 1.5
wt. % levels, and the formation of a meta-stable emulsion meeting
the requirements for over-the-counter (OTC) use.
[0084] Readily re-emulsifiable formulations were prepared by
replacing the phospholipid
1,2-dimyristoyl-sn-glycero-3-(phospho-rac-(1-glycerol) salt
(disodium DMPG) with glyceryl monostearate (GMS), and a
reproducible method for the formation of wax particles for addition
to these emulsions was established.
6.1.1. Tear Film Stability for Wax Ester Containing Products
[0085] In this set of experiments, a wax ester containing
oil-in-water emulsion was compared to several other commercially
available products.
[0086] A beeswax containing ophthalmic solution: H714: 5.0 Dr-21,
10.0% Bee's Milk (Beeswax, Sesame Oil, Lecithin, Methyl Paraben,
and Water) (Koster Keunan), 0.18 Tween-80, 0.1 EDTA, and b.a./NaCl
to 100 mOsm.
[0087] Water soluble polymer solution #1: *DUASORB* (polymeric
system containing 0.1% Dextran 70, 0.3% hydroxypropyl
methylcellulose 2910), 0.001% polyquaternium-1, sodium borate, KCl,
NaCl, H.sub.2O, and HCl and/or NaOH.
6.1.2. Water Soluble Polymer Solution #1 vs. Wax Ester for Tear
Film Efficacy
[0088] Tear film performance was evaluated using the standard
contralateral eye experiments by observation of the interference
patterns as described in Sec. 5.4.1 above.
[0089] Method of Delivery
[0090] A standard full drop of approximately 50 .mu.L was delivered
to the eyes of five subjects.
[0091] Results
[0092] Wax-ester formulation H714 versus to water soluble polymer
solution #1: H714 performed very well in the interference analysis
of tear film thickness. Initially, H714 scored 2.5 grades above
baseline for the first two hours and returning to baseline after
three hours. In one set of experiments the water soluble polymer
solution, on the other hand, was 2.0 grades above baseline
initially but faded quite rapidly within 30 minutes. In another set
of experiments, after instillation both the H714 and the water
soluble polymer were at about 1.8 grades above baseline. After 15
minutes water soluble polymer solution #1 went virtually back to
baseline, while H714 (.about.1% beeswax) remained on the eye for
over two hours. The water soluble polymer #1 which showed an
initial a 2.0 score change showed a return to essentially baseline
at 1 hour. (see FIG. 2).
[0093] In another experiment, the H714 formulation was tested
versus a second water soluble formulation. The wax ester
formulation showed a 2 score increase initially and returned to
baseline (less than 0.5 score change) between 3 and 4 hours. The
water soluble polymer formula #2 after only showing an
approximately 0.7 score change initially, and returned to below 0.5
score change in less than 30 minutes (See FIG. 3). In a third
experiment the wax ester formulation was evaluated versus water
soluble polymer #1. Initially both formulations showed a score
increase of 1.8 grades. The water soluble formula returned
essentially to base line in 15 minutes while the wax ester
formulation retained its score improvement to beyond 3 hours (see
FIG. 4). The results of the tear film analysis for the wax
containing formulation, H714 vs. water soluble polymer solution #1
are shown in FIG. 4. The figure shows that the wax ester containing
product protects the tear film for significantly longer than the
commercially available water soluble polymer solution products.
FIG. 5 shows a composite of the results shown in FIG. 3 and FIG. 4.
The data demonstrates that the wax ester containing products
provide substantially longer duration of protection of the tear
film than the other commercially available products. In other
words, the wax ester formulations provide durable eye lubrication
for greater than 3 hours.
[0094] Qualitatively, the second water soluble polymer solutions'
appearance was natural throughout the testing period, while H714's
appearance ranged from natural to beady to wispy to synthetic,
depending on the individual. Within 15 minutes, however, the H714
product yielded natural-looking, colorful, and high-riding waves in
all subjects. No blur was reported with either one of the wax ester
formulations, but 2/5 of the subjects reported mild sting upon
delivery of H714.
6.1.3. Emulsions
[0095] The initial research aims were to meet several requirements,
including the removal of sodium DMPG (allowing for its replacement
by another surfactant) and minimization or elimination of disodium
EDTA to increase user comfort. To this end, the disodium EDTA
component was excluded from the formulations investigated.
[0096] Previous work indicated that sodium DMPG played a crucial
role in the creation of the meta-stable emulsion. Thus, a different
surfactant may be used to replace the sodium DMPG in order to form
a commercially acceptable emulsion.
[0097] Initial experiments showed that `stable` emulsions from
mineral oil can be manufactured by optimizing the
hydrophile-lipophile-balance (HLB) level of a surfactant mixture of
SPAN-80.RTM. and polysorbate-80, along with the optimization of
concentration and processing parameters (temperature,
homogenization). The product was a `stable` emulsion from a
chemical degradation point of view but not necessarily from a
colloidal kinetic point of view. In fact, it is desired that the
emulsion be metastable with respect to phase separation.
[0098] In studies described below, the emulsion formulation was
used as the model system in which we replaced components as
necessary to meet commercial requirements.
6.1.4. Emulsions without Phospholipid (Replacement of DMPG Sodium
with GMS)
[0099] Emulsions were prepared by replacing the Na-DMPG by GMS at
surfactant concentrations of 0.15 and 0.30 wt. % based on total
composition. (In these experiments, disodium EDTA was not added to
the formulation). The ratio of Myrj-52 and GMS was varied to adjust
the calculated HLB of the surfactant mixture. The emulsified phase
consisted of .about.5.0 wt. % Drakeol-35 mineral oil. The sample
compositions are listed in Table 2. The aqueous phase contained
0.67 g NaCl and 0.05 g of Na.sub.2HPO.sub.4 (anhydrous) per 100 ml
of the water phase.
TABLE-US-00002 TABLE 2 Sample compositions and calculated HLB
values for emulsions without DMPG sodium HLB g Myrj-52 g GMS g
Drakeol 35 Surfactant Content 1 11.1 0.094 0.065 5.700 0.15% 2 12.0
0.102 0.054 5.334 0.15% 3 13.0 0.112 0.042 5.508 0.15% 4 13.7 0.127
0.037 5.404 0.15% 11 14.2 0.130 0.030 5.284 0.15% 12 15.1 0.139
0.020 5.284 0.15% 13 14 16.1 0.298 0.017 5.309 0.30% 15 15.0 0.279
0.042 5.300 0.30% 16 14.0 0.258 0.065 5.283 0.30% 17 12.9 0.233
0.091 5.308 0.31% 18 12.0 0.207 0.108 5.303 0.30%
[0100] The described conditions produced emulsions which were
readily re-emulsified after phase separation. In general, an
increasing value of the calculated HLB lead to a more complete
phase separation on standing, as indicated by a decrease in the
turbidity of the aqueous phase. After an extended period, some of
the oil in the formulations shown in Table 2 did not remain in the
dispersed state.
[0101] Since the compositions listed in Table 2 appear promising,
further investigations were performed to determine the effects of
increased surfactant concentrations, 0.1 wt. % of disodium EDTA,
and a light mineral oil added to the formulation.
6.1.5. Emulsions with Wax Esters (Particles Dispersed in Aqueous
Phase)
[0102] Emulsion and dispersed beeswax particle blends were prepared
by the addition of beeswax particle dispersions (in high ionic
strength media) to previously prepared emulsions with the
compositions shown in Table 2. The resulting beeswax (BW)
concentrations in the blends are shown in Table 3.
TABLE-US-00003 TABLE 3 Emulsion beeswax loading after blending
emulsions with wax ester particle dispersions. HLB BW content
Surfactant content 11.05 0.11% 0.13% 11.99 0.11% 0.12% 13.03 0.10%
0.12% 13.70 0.10% 0.13% 15.11 0.09% 0.13% 16.13 0.09% 0.26% 15.04
0.09% 0.26% 14.04 0.09% 0.26% 12.91 0.10% 0.26% 12.03 0.09%
0.26%
[0103] It was found that BW particles dispersed in an aqueous phase
which was similar in composition to the continuous phase of the
emulsion could be blended with the emulsions successfully without
aggregation of the BW particles.
6.2. Wax Ester Containing Emulsions and Autoclaving
[0104] Because of the limitations of many of the existing products
for dry eye various methods for the preparation of the
second-generation product were investigated. An example was
prepared by a co-emulsification technique. Although this was a
clinically viable product as mentioned above, this sample did not
exhibit adequate commercial stability characteristics.
[0105] In general, it was noted that the ocular emulsions, which
showed good clinical results and adequate stability in the
autoclave, fail when autoclaved with added wax esters such as those
disclosed above. In a typical experiment, the failure consisted of
gross wax aggregation with an exclusion of the wax ester as a
separate phase: the beeswax particles do not remain dispersed after
the autoclaving is completed. If aggregation occurs the
concentrations delivered to the eye become erratic and the wax
particles may irritate the eye.
[0106] In order to establish the cause of this failure, the
behavior of emulsions and beeswax particle dispersions were
investigated separately, with the eventual goal of forming an
appropriate blend for clinical testing. This work lead to a method
to manufacture a wax ester containing `second generation` ocular
emulsion with improved stability and performance.
[0107] Research indicated that the method used for producing a
product will need to be modified to successfully make a wax ester
containing emulsion that is also shelf stable. The modified
procedure consists of the separate preparation and autoclaving of
the wax ester particle dispersion and emulsion components, followed
by an aseptic blending step to ensure product sterility. The
different steps are described separately below.
6.2.1. Wax Ester Emulsion Component Processing
[0108] Since it was not possible to create with a single
autoclaving step the final wax ester containing emulsion product, a
two-step preparation method was developed, with a final sterile
blending step, which combined the components. This was done to
prevent the chemistry of the emulsion from influencing the
stability of the wax ester particles under autoclave
conditions.
[0109] Due to the mutual dilution effect, which occurs during
blending, the emulsion component was prepared as described above,
but with concentrations of all the contents doubled with respect to
water. The increased concentration of the emulsified oil mixture
affected the behavior of the emulsions in the autoclave, where
increased loading (amounts of the dispersed emulsion components)
eventually lead to emulsion failure during autoclaving. FIG. 6
shows an overlay of the particle size distributions obtained from
2.times. (solid line), 3.times. (dashed line), and 4.times. (open
circles) concentrated emulsions before (top panel) and after
(bottom panel) autoclaving.
[0110] FIG. 6 shows that doubly or triply concentrated beeswax
emulsion samples with adequate autoclave stability can be prepared
and then diluted with stable wax ester dispersions to attain a
desired wax ester concentration in the samples. The primary result
of these findings is that a production method can be defined where
the emulsions are prepared in concentrated form, autoclaved, and
then aseptically blended in a final packaging step with a
previously autoclaved wax particle dispersion. The consequences of
the autoclaving are a concomitant concentration dependent increase
in the mean size of the particle size distribution-resulting in
increased meta-stability.
[0111] The final blending step (with the wax ester dispersion
described below) dilutes the emulsion components back to the
desired final concentrations and supplies the wax particles for the
`second generation` ocular emulsion. This step also provides a
method for `fine-tuning` the relative concentrations of wax ester
and mineral oil to provide for optimum clinical performance.
6.2.2. Formulation of Wax Ester Particle Dispersions
[0112] The wax particle dispersions were prepared by homogenization
of melted beeswax (.about.1.0%) in distilled water with added
Octoxynol-40 (.about.0.2%) at .about.75.degree. C. for example. The
high cloud point of octoxynol-40 (>100.degree. C.) means that
it's emulsifying efficiency increases at higher temperatures by a
decrease in its water solubility (effective lowering of the HLB
value). Therefore, under autoclave conditions, it is expected that
Octoxynol-40 will stabilize the melted wax droplets by
re-partitioning from the dissolved state in the aqueous phase onto
the particle/droplet surfaces and preventing flocculation.
[0113] Since the melting point of beeswax is .about.63.degree. C.,
it is completely melted under autoclave conditions, and the
dispersion consists of beeswax droplets in water and surfactant. As
the sample temperature continuously increases during the
autoclaving process, the Octoxynol-40 becomes increasingly
insoluble in water, and tends to migrate towards the particle
surface (droplet/aqueous interface) helping to stabilize the melted
beeswax droplet. However, at the low surfactant concentrations
utilized in these experiments, this mechanism alone may not provide
sufficient stabilization for these particles/droplets.
[0114] Previous experiments showed that sub-micron beeswax
particles in water are highly negatively charged (high negative
value of the zeta potential), and the resulting electrostatic
repulsion is a substantial contribution to their stabilization. In
fact, the sub-micron sized particles can be autoclaved with only a
small change in their particle size distribution. However, there is
no surfactant present in these dispersions. This fact demonstrates
the importance of the electrostatic repulsion model as a
stabilization mechanism, even in the absence of a surfactant.
[0115] The size distributions of the sub-micron sized particles
before (black line) and after (red line) autoclaving are shown in
FIG. 7. However, due to complicated processing, the sub-micron
sized particles are not expected to be useful in a commercial
product for dry eye with long-lasting effects.
[0116] The large sized particle dispersions cannot be prepared in
the absence of added surfactant. The operating particle formation
mechanism is different from a simple nucleation and particle growth
model used in the formation of submicron sized dispersions. In this
case, an emulsification technique is used, where the added
surfactant stabilizes the growing beeswax droplets during the
homogenization sequence. The surfactant is also important in
preventing droplet aggregation during the cooling period after
autoclaving.
[0117] In addition to chemical considerations, processing methods
assume a critical role: the success or failure in the autoclaving
of these particles is completely dependent on the method used. The
chemistry of the system yields particle dispersions that are stable
in the autoclave (as melted beeswax droplets), but which aggregate
irreversibly once the decreasing sample temperature during sample
cooling approaches the melting point (crystallization temperature)
of the beeswax.
[0118] Although the zeta potential values cannot be measured under
autoclave conditions, it is visually observed that sealed beeswax
particles/droplets dispersions remain stable at 121.degree. C.
(with gentle stirring) when dispersed in water. FIG. 8 shows
typical particle size distributions of the wax ester particles in
water and Octoxynol-40 (obtained by the emulsification process)
before and after autoclaving.
[0119] In view of the importance of the wax particle charge in its
stability, the salt content also becomes an essential parameter.
That is, at high ionic strength (salt concentration) the particles
tend to aggregate, which in the case of soft wax results in
irreversible coalescence under autoclave conditions (even in the
presence of some surfactant). The consequence of this finding is
that the beeswax particles cannot be autoclaved in an aqueous
phase, which contains large salt concentrations (high ionic
strength systems).
6.2.3. Emulsion Blending
[0120] The blending step (concentrated emulsions and beeswax
dispersions) ensures that proper amounts can be combined to achieve
the desired final concentrations of mineral oil, beeswax, and other
components in the submitted product. This procedure also allows
variation of the total beeswax content in the final product, while
maintaining a constant emulsion component composition. Essentially,
in this procedure, the emulsion is formulated with increased
component levels, while the beeswax particles are emulsified in
distilled water with an added surfactant. The concentrations of the
various components in the two fractions (before autoclaving) can be
tailored to permit a relatively wide variation of final emulsion
compositions.
[0121] The mechanism involved in the irreversible aggregation of
the wax (wax breakout) under autoclave conditions appears to
involve the presence of relatively high (approximately isotonic)
salt concentrations. This high ionic loading serves to
significantly decrease the zeta-potential of the wax ester
particles, which essentially removes an important stabilization
mechanism when these dispersions are subjected to autoclave
conditions. The presence of the Octoxynol-40 helps stabilize the
beeswax emulsions at the high temperatures present in the
autoclave.
[0122] Laser diffraction analysis shows that the emulsions are not
subjected to significant amounts of particle aggregation when
prepared in this fashion. This is the primary reason why the
blended emulsions are expected to show good long-term stability
characteristics.
[0123] Both components were then autoclaved separately and mixed in
equal proportions (by mass) to yield the final product containing
either 0.5 wt. % or 1.0 wt. % wax ester.
7. GENERALIZED STATEMENTS OF THE DISCLOSURE
[0124] The following numbered statements provide a general
description of the disclosure and are not intended to limit the
appended claims.
[0125] Statement 1: This disclosure provides an ophthalmic solution
which comprises an oil-in-water emulsion comprising water; an oil;
a surfactant; a present in a concentration of about 0.1 to about
1.5 weight percent; and wherein the ophthalmic solution (i) forms a
meta stable emulsion which separates into an oil phase and a water
phase on contact with an eye; and (ii) provides lubrication for
about 2 to about 12 hours on the eye. The ophthalmic solution
provides a stable and appropriately normal tear film thickness that
can be demonstrated by interferometry or Tear Film Breakup Time
(TBUT) or other methods of diagnosis.
[0126] Statement 2: This disclosure provides the ophthalmic
solution of Statement 1, wherein on contact with an eye interacts
with: (iii) a lipid layer; (iv) an aqueous layer; (v) a mucin
layer; (vi) an interface between the lipid layer and the aqueous
layer; and (vii) an interface between the aqueous layer and the
mucin layer of the eye andor the corneal cells.
[0127] Statement 3: This disclosure provides the ophthalmic
solution of any of Statements 1-2, wherein the wax ester is a
natural or a synthetic beeswax such as Cera alba or Cera flava.
[0128] Statement 4: This disclosure provides the ophthalmic
solution of any of Statements 1-3, wherein the wax ester is present
in a concentration of about 0.1 to about 1.25 weight percent.
[0129] Statement 5: This disclosure provides the ophthalmic
solution of any of Statements 1-4, wherein the oil is a mixture of
a lighter molecular weight oil and a heavier molecular weight
oil.
[0130] Statement 6: This disclosure provides the ophthalmic
solution of any of Statements 1-5, wherein the mineral oil is
present in a concentration of about 1.0 to about 7.5 weight
percent.
[0131] Statement 7. The ophthalmic solution of Statement 6, wherein
the oil is a mineral oil.
[0132] Statement 8. The ophthalmic solution of Statement 6, wherein
the oil is a vegetable oil.
[0133] Statement 9 The ophthalmic solution of any Statements 1-8,
wherein the surfactant comprises a phospholipid.
[0134] Statement 10. The ophthalmic solution of any of Statements
1-9, wherein the surfactant comprises a non-ionic surfactant.
[0135] Statement 11. The ophthalmic solution of any of Statements
1-10, wherein the surfactant is a mixture of two or more
surfactants.
[0136] Statement 12. The ophthalmic solution of Statement 10,
wherein the mixture of two or more surfactants comprises a
Polysorbate 80, an Octoxynol 40 or an anionic polar phospholipid
(APP).
[0137] Statement 13, The ophthalmic solution of Statement 1,
wherein (i) the oil is a mixture of a lighter molecular weight and
a heavier molecular weight oil and is present in a concentration of
about 1 to about 5.5 weight percent; (ii) the surfactant mixture of
a Polysorbate 80 in a concentration of about 0.35 to about 0.45
weight percent and a dimyristoylphosphatidylglyerol in a
concentration of about 0.3 to about 0.4 weight percent; (iii) the
beeswax is Cera alba or Cera flava in a concentration of about 0.25
to about 1.0 weight percent; and the ophthalmic solution has an
osmolality of about 230 to about 260 mOsmol/kg.
[0138] Statement 14. The ophthalmic solution of any of Statements
1-13, further comprising a medication.
[0139] Statement 15. The ophthalmic solution of any of Statements
1-14, packaged in a sterile multi-use or single use container.
[0140] Statement 16. The ophthalmic solution of any of Statements
1-15, packaged in a multi-dose non-preserved (MDNP) container.
[0141] Statement 17, The ophthalmic solution of any of Statements
1-14, further comprising a preservative such as stabilized
oxychloro complex (PURITE.RTM.) or polyhexamethylene biguanide
(PHMB) or Polyquaterium-1 (Alcon).
[0142] Statement 18. The ophthalmic solution of any of Statements
1-14, for use as a rewetting and/or lubricating solution for an
ocular prosthesis.
[0143] Statement 19. An ophthalmic solution which comprises an
oil-in-water emulsion comprising water; an oil; a surfactant; a
beeswax comprising wax esters and partially hydrolyzed ester;
wherein wax esters and partially hydrolyzed esters in the
ophthalmic solution binding a mucin layer, an aqueous layer, and a
lipid layer in an eye of a subject and act to maintain the
integrity of an interstitial layer between the mucin layer and the
aqueous layer, an interstitial layer between the aqueous layer and
the lipid layer.
[0144] Statement 20 The ophthalmic solution of Statement 18,
wherein the wax esters act to increase the thickness of the mucin
layer, the aqueous layer, or the lipid layer.
[0145] Statement 21. The ophthalmic solution of Statement 19,
wherein the wax esters act to augment the mucin layer, the aqueous
layer, and the lipid layer.
[0146] Statement 22. The ophthalmic solution of any of Statements
19-21, wherein the binding and homeostasis enabled by the wax
esters allows the mucin layer, the aqueous layer and the lipid
layer of a tear film to interact with to each other allowing the
tear film to remain on the eye for extended periods of time.
[0147] Statement 23. A method for delivering a medication or active
agent to a subject which comprises administering to an eye of the
subject an ophthalmic solution which comprises a medication and an
oil-in-water emulsion comprising water; an oil; a surfactant; a
beeswax; and wherein the ophthalmic solution (i) forms a meta
stable emulsion which separates into an oil phase and a water phase
on contact with an eye; and (ii) provides lubrication for about 2
to about 12 hours on the eye.
[0148] Statement 24. The method of Statement 23, wherein the
medication is a water soluble medication.
[0149] Statement 25. The method of Statement 23, wherein the
medication is an oil soluble medication.
[0150] Statement 26. A method for alleviating the symptoms of dry
eye which comprises contacting an eye with an ophthalmic solution
comprising an oil-in-water emulsion which emulsion comprises:
water; an oil; a surfactant; a beeswax or wax ester combination;
and wherein the ophthalmic solution (i) forms a meta stable
emulsion which separates into an oil phase and a water phase on
contact with an eye; and (ii) provides lubrication for about 2 to
about 12 hours on the eye.
[0151] Statement 27. The method of Statement 26 wherein on contact
with an eye the ophthalmic solution interacts with: (iii) a lipid
layer; (iv) an aqueous layer; (v) a mucin layer; (vi) an interface
between the lipid layer and the aqueous layer; and (vii) an
interface between the aqueous layer and the mucin layer of the
eye.
[0152] Statement 28. The method of any of Statements 26-27, wherein
the beeswax is Cera alba or Cera flava.
[0153] Statement 29. The method of any of Statements 26-28 wherein
the oil is a mixture of a lighter molecular weight oil and a
heavier molecular weight oil.
[0154] Statement 30. The method of any of Statements 26-29, wherein
the oil is present in a concentration of about 1.0 to about 7.5
weight percent.
[0155] Statement 31. The method of Statement 30, wherein the oil is
a mineral oil.
[0156] Statement 32. The method of Statement 30, wherein the oil is
a vegetable oil.
[0157] Statement 33. The method of any of Statements 26-30, wherein
the surfactant is a mixture of two or more surfactants.
[0158] Statement 34. The method of any of Statements 26, wherein
(i) the oil is a mixture of a lighter molecular weight oil and a
heavier molecular weight oil and is present in a concentration of
about 1.0 to about 5.5 weight percent; (ii) the surfactant is a
mixture of a Polysorbate 80 in a concentration of about 0.35 to
about 0.45 weight percent and a dimyristoylphosphatidylglyerol in a
concentration of about 0.3 to about 0.4 weight percent; (iii) the
beeswax is Cera alba or Cera flava in a concentration of about 0.25
to about 1.0 weight percent; and the ophthalmic solution has an
osmolality of about 230 to about 260 mOsmol/kg.
[0159] Statement 35. The method of any of Statements 26, wherein
(i) the oil is a mixture of a lighter molecular weight oil and a
heavier molecular weight oil and is present in a concentration of
about 1.0 to about 5.5 weight percent; (ii) the surfactant is a
mixture of a Polysorbate 80 in a concentration of about 0.35 to
about 0.45 weight percent and a dimyristoylphosphatidylglyerol in a
concentration of about 0.3 to about 0.4 weight percent; (iii) the
artificial beeswax, a combination of wax esters and partially
hydrolyzed wax esters in a concentration of about 0.25 to about 1.0
weight percent; and the ophthalmic solution has an osmolality of
about 230 to about 260 mOsmol/kg.
[0160] Statement 35. The method of any of Statements 26-35, wherein
the ophthalmic solution is packaged in a sterile multi-use or
sterile single use container.
[0161] Statement 36. The method of any of Statements 25-35, wherein
the ophthalmic solution is packaged in a multi-dose non-preserved
(MDNP) container.
[0162] Statement 37. A method of preparing an ophthalmic solution
providing lubrication for about 2 to about 12 hours on the eye,
wherein the solution is a meta stable oil-in-water emulsion,
wherein the method comprises: preparation of a wax dispersion
comprising a beeswax or artificial beeswax and a surfactant in a
deionized water solution; preparation of an oil-in-water emulsion
comprising an oil in a deionized water solution; separately
autoclaving the beeswax dispersion and the oil-in-water emulsion;
and aseptically blending the autoclaved beeswax dispersion and the
oil in water emulsion so as to prepare the meta stable oil-in-water
emulsion ophthalmic solution which provides lubrication for about 2
to about 12 hours on the eye.
[0163] Statement 38. The method of Statement 37, wherein on contact
with an eye the ophthalmic solution penetrates: (iii) a lipid
layer; (iv) an aqueous layer; (v) a mucin layer; (vi) an interface
between the lipid layer and the aqueous layer; and (vii) an
interface between the aqueous layer and the mucin layer of the
eye.
[0164] Statement 39. The method of any of Statements 37-38, wherein
the beeswax is Cera alba or Cera flava.
[0165] Statement 40. The method of any of statements 37-38, wherein
the wax is an artificial beeswax
[0166] Statement 41. The method of any of Statements 37-40, wherein
the oil is a mixture of a lighter molecular weight oil and a
heavier molecular weight oil.
[0167] Statement 42. The method of any of Statements 37-40, wherein
the surfactant is a mixture of two or more surfactants.
[0168] Statement 41. The method of Statement 37, wherein (i) the
oil is a mixture of a lighter molecular weight oil and a heavier
molecular weight oil and is present in a concentration of about 1.0
to about 5.5 weight percent; (ii) the surfactant is a mixture of a
Polysorbate 80 in a concentration of about 0.35 to about 0.45
weight percent and a dimyristoylphosphatidylglyerol in a
concentration of about 0.3 to about 0.4 weight percent; (iii) the
beeswax is Cera alba or Cera flava in a concentration of about 0.25
to about 1.0 weight percent; and the ophthalmic solution has an
osmolality of about 230 to about 260 mOsmol/kg.
[0169] Statement 43. The method of any of Statements 37-42, wherein
the ophthalmic solution is packaged in a sterile multi-use or
sterile single use container.
[0170] Statement 44. The method of any of Statements 37-42, wherein
the ophthalmic solution is packaged in a multi-dose non-preserved
(MDNP) container.
[0171] Statement 45 A method of preparing an ophthalmic solution
which comprises an oil-in-water emulsion comprising water; an oil;
a surfactant; beeswax or artificial beeswax comprising wax esters;
wherein wax esters or hydrolysis products in the ophthalmic
solution bind to a mucin layer, an aqueous layer, and a lipid layer
in an eye of a subject and act to maintain the integrity of an
interstitial layer between the mucin layer and the aqueous layer,
and an interstitial layer between the aqueous layer and the lipid
layer.
[0172] Statement 46. The method of Statement 45, wherein the wax
esters or hydrolysis products act to increase the thickness of the
mucin layer, the aqueous layer, or the lipid layer.
[0173] Statement 47. The method of any of Statements 45-46, wherein
the wax esters act to increase the thickness of the mucin layer,
the aqueous layer, and the lipid layer.
[0174] Statement 48. The method of any of Statements 45-46, wherein
the binding and homeostasis enabled by the wax esters or hydrolysis
products allows the mucin layer, the aqueous layer and the lipid
layer of a tear film to interact with to each other allowing the
tear film to remain stable on the eye for extended periods of
time.
[0175] Statement 49. A method for delivering a medication to a
subject which comprises administering to an eye of the subject an
ophthalmic solution which comprises a medication and an
oil-in-water emulsion comprising: (a) water; (b) an oil; (c) a
surfactant; (d) a beeswax; and (e) wherein the ophthalmic solution
(i) forms a meta stable emulsion which separates into an oil phase
and a water phase on contact with an eye; and (ii) provides
lubrication for about 2 to about 12 hours on the eye by providing a
stable and appropriately normal tear film thickness that can be
demonstrated by interferometry or Tear Film Breakup Time (TBUT) or
other methods of diagnosis.
[0176] It should be understood that the above description is only
representative of illustrative embodiments and examples. For the
convenience of the reader, the above description has focused on a
limited number of representative examples of all possible
embodiments, examples that teach the principles of the disclosure.
The description has not attempted to exhaustively enumerate all
possible variations or even combinations of those variations
described. That alternate embodiments may not have been presented
for a specific portion of the disclosure, or that further
undescribed alternate embodiments may be available for a portion,
is not to be considered a disclaimer of those alternate
embodiments. One of ordinary skill will appreciate that many of
those undescribed embodiments, involve differences in technology
and materials rather than differences in the application of the
principles of the disclosure. Accordingly, the disclosure is not
intended to be limited to less than the scope set forth in the
following claims and equivalents.
INCORPORATION BY REFERENCE
[0177] All references, articles, publications, patents, patent
publications, and patent applications cited herein are incorporated
by reference in their entireties for all purposes. However, mention
of any reference, article, publication, patent, patent publication,
and patent application cited herein is not, and should not be taken
as an acknowledgment or any form of suggestion that they constitute
valid prior art or form part of the common general knowledge in any
country in the world. It is to be understood that, while the
disclosure has been described in conjunction with the detailed
description, thereof, the foregoing description is intended to
illustrate and not limit the scope. Other aspects, advantages, and
modifications are within the scope of the claims set forth below.
All publications, patents, and patent applications cited in this
specification are herein incorporated by reference as if each
individual publication or patent application were specifically and
individually indicated to be incorporated by reference.
* * * * *
References