U.S. patent application number 12/429942 was filed with the patent office on 2009-10-29 for polymeric artificial tear system.
This patent application is currently assigned to ALCON RESEARCH, LTD.. Invention is credited to James W. DAVIS, Howard Allen KETELSON, David L. MEADOWS.
Application Number | 20090270345 12/429942 |
Document ID | / |
Family ID | 40886688 |
Filed Date | 2009-10-29 |
United States Patent
Application |
20090270345 |
Kind Code |
A1 |
KETELSON; Howard Allen ; et
al. |
October 29, 2009 |
POLYMERIC ARTIFICIAL TEAR SYSTEM
Abstract
The present invention relates to artificial tear formulations
and ophthalmic formulations suitable for drug delivery. The
formulations comprise galactomannans such as guar or hydroxypropyl
guar and a borate source such as boric acid. The formulations
further comprise a cis-diol such as sorbitol that interferes with
the cross-linking of galactomannan and borate. Optionally, the
formulations are substantially free of divalent cations.
Inventors: |
KETELSON; Howard Allen;
(Dallas, TX) ; DAVIS; James W.; (Argyle, TX)
; MEADOWS; David L.; (Colleyville, TX) |
Correspondence
Address: |
ALCON
IP LEGAL, TB4-8, 6201 SOUTH FREEWAY
FORT WORTH
TX
76134
US
|
Assignee: |
ALCON RESEARCH, LTD.
Fort Worth
TX
|
Family ID: |
40886688 |
Appl. No.: |
12/429942 |
Filed: |
April 24, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61048175 |
Apr 26, 2008 |
|
|
|
Current U.S.
Class: |
514/54 |
Current CPC
Class: |
A61K 47/10 20130101;
A61K 47/36 20130101; A61K 31/736 20130101; A61K 47/26 20130101;
A61K 47/02 20130101; A61P 27/04 20180101; A61K 9/0048 20130101;
A61K 31/08 20130101; A61P 27/02 20180101 |
Class at
Publication: |
514/54 |
International
Class: |
A61K 31/715 20060101
A61K031/715; A61P 27/02 20060101 A61P027/02 |
Claims
1. An ophthalmic formulation comprising a galactomannan, borate,
and a cis-diol, wherein said formulation is substantially free of
divalent cations.
2. A formulation according to claim 1 wherein said galactomannan is
present at a concentration of about 0.1 w/v % to about 2.0 w/v %
and said borate is present at a concentration of about 0.2 w/v % to
about 2.0 w/v %.
3. A formulation according to claim 1 wherein said galactomannan is
present at a concentration of about 0.16 w/v % to about 0.19 w/v %
and said borate is present at a concentration of about 0.7 w/v
%.
4. A formulation according to claim 1 wherein said galactomannan is
selected from the group consisting of: guar, hydroxylpropyl guar,
and combinations thereof.
5. A formulation according to claim 1 wherein said cis-diol is
selected from the group consisting of sorbitol, mannitol,
polyethylene glycols, polypropylene glycols,
polyethyleneoxide-polybutyleneoxide block copolymers, and
combinations thereof.
6. A formulation according to claim 1 wherein said cis-diol is
sorbitol or mannitol.
7. A formulation according to claim 6 wherein said cis-diol is
present at a concentration of about 1.4 w/v %.
8. A formulation according to claim 1 wherein said borate is boric
acid.
9. A formulation according to claim 1 further comprising a
demulcent selected from the group consisting of: glycerin,
polyvinyl pyrrolidone, polyethylene oxide, polyethylene glycol,
propylene glycol, polyacrylic acid, and combinations thereof.
10. A formulation according to claim 9 wherein said demulcent is
polypropylene glycol or polyethylene glycol.
11. In an ophthalmic formulation comprising a galactomann and
borate, the improvement comprising adding a cis-diol to prevent
galactomann and borate cross-linking, thereby reducing the
viscosity of the formulation.
12. A formulation according to claim 11, said formulation further
being substantially free of divalent cations, thereby reducing the
viscosity of the formulation.
13. A method for lubricating the eye comprising administering to
the eye a formulation of claim 1.
14. A method for delivering a pharmaceutically active agent to the
eye comprising: administering to the eye a formulation of claim 1
further comprising a pharmaceutically active agent.
15. An improved ophthalmic formulation comprising galactomannan and
borate, said formulation comprising a cis-diol that is eliminated
from tear film more rapidly than said galactomannan when the
formulation is instilled in an eye.
16. An improved ophthalmic formulation according to claim 15
wherein said galactomannan is present at a concentration of about
0.16 w/v % to about 0.19 w/v % and said borate is present at a
concentration of about 0.7 w/v %.
17. An improved ophthalmic formulation according to claim 16
wherein said galactomannan is selected from the group consisting
of: guar, hydroxylpropyl guar, and combinations thereof.
18. An improved ophthalmic formulation according to claim 15
wherein said cis-diol is selected from the group consisting of
sorbitol, mannitol, polyethylene glycols, polypropylene glycols,
polyethyleneoxide-polybutyleneoxide block copolymers, and
combinations thereof.
19. An improved ophthalmic formulation according to claim 18
wherein said cis-diol is sorbitol or mannitol.
20. An improved ophthalmic formulation according to claim 15, said
formulation further being substantially free of divalent cations,
thereby reducing the viscosity of the formulation.
21. An improved ophthalmic formulation according to claim 15, said
formulation further comprising a demulcent selected from the group
consisting of: glycerin, polyvinyl pyrrolidone, polyethylene oxide,
polyethylene glycol, propylene glycol, polyacrylic acid, and
combinations thereof.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims priority under 35 U.S.C. .sctn.119
to U.S. Provisional Patent Application No. 61/048,175, filed Apr.
26, 2008, the entire contents of which are incorporated herein by
reference.
TECHNICAL FIELD OF THE INVENTION
[0002] The present invention relates to artificial tear
formulations and formulations for ophthalmic drug delivery, and
more specifically to galactomannan-borate polymer systems
comprising a cis-diol.
BACKGROUND OF THE INVENTION
[0003] Many ophthalmic formulations comprise compounds that provide
lubricity and other desirable properties. When these formulations
are instilled in the eye, the properties of such compounds can
prevent undesirable problems such as bioadhesion and the formation
of friction-induced tissue damage, as well as encourage the natural
healing and restoration of previously damaged tissues.
[0004] Many marketed artificial tear solution products contain
polymers that display thixotropic and viscoelastic properties. Some
of these polymers include hydroxypropylmethylcellulose,
galactomannans such as guar and hydroxypropyl guar,
carboxymethylcellulose, hyaluronic acid, and sodium alginate. The
shear thinning and viscoelastic profiles of polymers play important
roles when mixed with the tear film.
[0005] The retention profile, lubrication and mucomimetic
properties of polymers in artificial tear solution products may
play an important role by to helping stabilize the tear film and
providing improved comfort to patients with dry eye disease. For
example, the product Systane.RTM. (Alcon, Inc.) containing
hydroxypropyl guar and the active ingredients polyethylene glycol
400 and propylene glycol has been reported by Paugh, et al. (2008)
to be more effective at eliminating eye discomfort than similar
viscosity enhancing polymers such as carboxymethyl cellulose.
[0006] The bulk rheology of polymers used in artificial tear
solutions is often characterized by steady state shear (shear
thinning) and dynamic oscillation tests (viscoelasticity). Although
these tests are valuable, these bulk rheology experiments may not
fully characterize the interfacial properties of such polymers. An
understanding of the polymers' interfacial properties is critical,
as these properties may play important roles in the interactions
with tear film components at both the cornea/tear film interface
and tear film/air interface. Another rheology test that can aid in
understanding the dynamic and interfacial properties of polymers
used in artificial tears is the oscillation drop experiment,
described herein.
[0007] Ophthalmic formulations have been previously described that
utilize galactomannan-borate gelling systems. U.S. Pat. No.
6,403,609 to Asgharian, entitled "Ophthalmic compositions
containing galactomannan polymers and borate," describes such
systems and is herein incorporated by reference in its entirety.
The cross-linking of galactomannan and borate is responsible for
the gel-forming behavior of the described formulations.
BRIEF SUMMARY OF THE INVENTION
[0008] The present invention generally relates to ophthalmic
formulations comprising galactomannan, including galactomannans
such as guar or hydroxypropyl guar. The formulations of the present
invention also comprise a borate source such as boric acid. A
cis-diol, such as sorbitol or propylene glycol, is present in the
formulations and interferes with the cross-linking of the
galactomannan and borate. The cis-diol is selected based on its
diffusion characteristics relative to the galactomannan. Typically,
the ophthalmic formulations of the present invention comprise a
cis-diol that is a relatively small molecule such as sorbitol that
diffuses more rapidly than the galactomannan in the ocular tear
film. Upon installation in the eye, the concentration of the
cis-diol decreases at a different rate than the galactomannan,
allowing the galactomannan and borate to cross-link a form a
structured polymer network in situ. Thus, the gelling behavior and
rheological characteristics of the formulations after installation
into the eye are controlled via selection of the cis-diol.
[0009] The formulations of the present invention are substantially
free of divalent cations such as magnesium, zinc and calcium that
can strengthen cross-linking of the galactomannan and borate. Once
a formulation is instilled in the eye, divalent cations present in
the tear film enhance formation of a structured
galactomannan-borate polymer network.
[0010] The formulations of the present invention are also useful as
drug delivery vehicles for ophthalmic therapeutics. Upon
installation of a formulation in the eye, a galactomannan-borate
polymer network is formed; this network is able to hold various
therapeutic agents on the eye, including demulcents.
[0011] The foregoing brief summary broadly describes the features
and technical advantages of certain embodiments of the present
invention. Additional features and technical advantages will be
described in the detailed description of the invention that
follows.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] A more complete understanding of the present invention and
the advantages thereof may be acquired by referring to the
following description, taken in conjunction with the figures of the
accompanying drawing in which like reference numbers indicate like
features and wherein:
[0013] FIG. 1 is a diagram of the cross-linking behavior of borate
and galactomannan;
[0014] FIG. 2 is a graph showing steady state flow (SSF) viscosity
as a function of shear rate for galactomannan-borate formulations
at pH 7.9 and 7.6;
[0015] FIG. 3 is a graph showing steady state flow (SSF) vs.
viscosity as a function of shear rate for formulations comprising
0.0 w/v %, 0.5 w/v %, 1.0 w/v % and 1.4 w/v % sorbitol;
[0016] FIG. 4 is a graph showing oscillating drop amplitude sweep
elastic moduli (Re|E1*|) as a function of amplitude of drop for a
formulations at pH 7.9 and 7.6;
[0017] FIG. 5 is a graph showing stress sweep tan(.delta.) as a
function of torque for formulations having 0.0 w/v %, 0.5 w/v %,
1.0 w/v % and 1.4 w/v % sorbitol;
[0018] FIG. 6 is a graph showing oscillating drop amplitude sweep
elastic moduli (RE|E1*|) as a function of amplitude of drop for a
formulation having 0.0 w/v % and 1.4 w/v % sorbitol;
[0019] FIG. 7 is a graph showing the average coefficient of
friction, 1 and 2 minutes after application to tissue in a friction
screening model for saline control, OPTIVE.RTM., blink Tears.RTM.
and a galactomannan-borate formulation without sorbitol at pH 7.6
(to simulate conditions after application of the formulation to the
eye);
[0020] FIG. 8 is a graph of the average % decrease in coefficient
of friction for test formulations, compared to baseline
(Unisol.RTM., saline control) at 1 & 2 minutes after
application of formulation; and after each of 3 blot/Unisol.RTM.
applications (post-rinses 1, 2 and 3) for saline control,
OPTIVE.RTM., blink Tears.RTM. and a galactomannan-borate
formulation at pH 7.6 and without sorbitol;
[0021] FIG. 9 is a bar graph comparing the mean retention time of
Unisol.RTM. saline control to a galactomannan-borate artificial
tear formulation of the present invention; and
[0022] FIG. 10 is a bar graph summarizing the result of a study
comparing Optive.RTM. (a carboxymethylcellullose (CMC) and glycerin
based artificial tear) and a galactomannan-borate artificial tear
formulation of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0023] The formulations of the present invention utilize a
galactomannan-borate system in aqueous solution. A borate anion
will condense onto the cis-diol groups of a galactomannan molecule,
and may cross-link with a second galactomannan molecule as shown in
FIG. 1. Cross-linking of borate and galactomannan is influenced by
factors such as pH, among others, and such cross-linking in turn
influences the viscosity of the solution. The present invention is
directed to the use of cis-diols such as sorbitol and propylene
glycol to interfere with the cross-linking of borate and
galactomannan in ophthalmic formulations, thereby affecting the
gelling and other rheological characteristics of the formulations.
In the presence of cis-diols, borate and galactomannan exhibit
reduced cross-linking behavior in aqueous solution, resulting in a
lower solution viscosity. When used in a droppable ophthalmic
formulation, the low viscosity solution has a reduced likelihood of
causing unwanted effects on vision, such as blurring.
[0024] In a preferred embodiment of the present invention, the
cis-diol sorbitol is used in galactomannan- and borate-containing
formulations. Sorbitol is present at a first concentration that
inhibits cross-linking of the galactomannan and borate. Once
instilled in the eye, the sorbitol is diluted by the natural tear
film allowing a gradual increase in the cross-linking of the
galactomannan and borate and a corresponding gradual increase in
viscosity and elasticity. This gradual increase in viscosity,
cross-linking, and elasticity allows for effective spreading and
less blurring upon contact, yet provides long lasting lubrication
and corneal surface protection.
[0025] Divalent cations such as calcium generally interact with
galactomannan and borate to strengthen cross-linking behavior. When
present in galactomannan- and borate-containing formulations,
divalent cations can increase the overall viscosity of such
formulations. The formulations of the present invention are
substantially free of divalent cations that would otherwise
contribute to unwanted variations in galactomannan-borate
cross-linking and, accordingly, formulation viscosity. Divalent
cations include, but are not limited to, magnesium, chloride, and
zinc cations. As used herein, the term "substantially free of
divalent cations" means that the formulation contains divalent
cation concentrations that do not interfere with the cross-linking
of the galactomannan-borate polymer systems of the formulations.
Generally, concentrations of divalent cations should be less than 5
parts per million to avoid interference with the
galactomannan-borate polymer systems.
[0026] The types of galactomannans that may be used in the present
invention are typically derived from guar gum, locust bean gum and
tara gum. As used herein, the term "galactomannan" refers to
polysaccharides derived from the above natural gums or similar
natural or synthetic gums containing mannose or galactose moieties,
or both groups, as the main structural components. Preferred
galactomannans of the present invention are made up of linear
chains of (1-4)-.beta.-D-mannopyranosyl units with
.alpha.-D-galactopyranosyl units attached by (1-6) linkages. With
the preferred galactomannans, the ratio of D-galactose to D-mannose
varies, but generally will be from about 1:2 to 1:4. Galactomannans
having a D-galactose:D-mannose ratio of about 1:2 are most
preferred. Additionally, other chemically modified variations of
the polysaccharides are also included in the "galactomannan"
definition. For example, hydroxyethyl, hydroxypropyl and
carboxymethylhydroxypropyl substitutions may be made to the
galactomannans of the present invention. Non-ionic variations to
the galactomannans, such as those containing alkoxy and alkyl
(C1-C6) groups are particularly preferred when a soft gel is
desired (e.g., hydroxylpropyl substitutions). Substitutions in the
non-cis hydroxyl positions are most preferred. An example of
non-ionic substitution of a galactomannan of the present invention
is hydroxypropyl guar, with a molar substitution of about 0.4.
Anionic substitutions may also be made to the galactomannans.
Anionic substitution is particularly preferred when strongly
responsive gels are desired. A galactomannan is typically present
in a formulation of the present invention at a concentration of
about 0.01 to about 10 w/v %, preferably at about 0.1 w/v % to
about 2.0 w/v %, and most preferably at about 0.16 to about 0.19
w/v %. Preferred galactomannans of the present invention are guar
and hydroxypropyl guar.
[0027] The cis-diol compounds that may be used with embodiments of
the present invention include, but are not limited to, hydrophilic
carbohydrates such as sorbitol or mannitol that comprise cis-diol
groups (hydroxyl groups attached to adjacent carbon atoms).
Preferred cis-diol compounds of the present invention include
polyethylene glycols, polypropylene glycols, and
polyethyleneoxide-polybutyleneoxide block copolymers. Particularly
preferred cis-diol compounds are sorbitol and mannitol. The
cis-diol compounds are present at concentrations of about 0.5 to
5.0 w/v % in the formulations of the present invention, and are
preferably present at a concentration of about 1.4%. The molecular
weights of the cis-diol compounds are selected to ensure that the
cis-diol diffuses and is eliminated from tear film at a faster rate
than the galactomannan, allowing for increased galactomannan-borate
cross-linking. Generally, the molecular weight of such cis-diol
compounds is between 400 g/mol to 5 million g/mol.
[0028] Borate is typically present at a concentration of about 0.2
to about 2.0 w/v %, and preferably at about 0.7 w/v %. As used
herein, the term "borate" refers to all pharmaceutically suitable
forms of borates, including but not limited to boric acid, and
alkali metal borates such as sodium borate and potassium borate.
Boric acid is the preferred borate used with embodiments of the
present invention.
[0029] The borate compounds which may be used in the compositions
of the present invention are boric acid and other pharmaceutically
acceptable salts such as sodium borate (borax) and potassium
borate. As used herein, the term "borate" refers to all
pharmaceutically suitable forms of borates. Borates are common
excipients in ophthalmic formulations due to good buffering
capacity at physiological pH and well known safety and
compatibility with a wide range of drugs and preservatives. Borates
also have inherent bacteriostatic and fungistatic properties, and
therefore aid in the preservation of the compositions.
[0030] The formulations of the present invention may optionally
comprise one or more additional excipients and/or one or more
additional active ingredients. Excipients commonly used in
pharmaceutical formulations include, but are not limited to,
demulcents, tonicity agents, preservatives, chelating agents,
buffering agents, and surfactants. Other excipients comprise
solubilizing agents, stabilizing agents, comfort-enhancing agents,
polymers, emollients, pH-adjusting agents and/or lubricants. Any of
a variety of excipients may be used in formulations of the present
invention including water, mixtures of water and water-miscible
solvents, such as C1-C7-alkanols, vegetable oils or mineral oils
comprising from 0.5 to 5% non-toxic water-soluble polymers, natural
products, such as alginates, pectins, tragacanth, karaya gum,
xanthan gum, carrageenin, agar and acacia, starch derivatives, such
as starch acetate and hydroxypropyl starch, and also other
synthetic products such as polyvinyl alcohol, polyvinylpyrrolidone,
polyvinyl methyl ether, polyethylene oxide, preferably cross-linked
polyacrylic acid and mixtures of those products.
[0031] Demulcents used with embodiments of the present invention
include, but are not limited to, glycerin, polyvinyl pyrrolidone,
polyethylene oxide, polyethylene glycol, propylene glycol and
polyacrylic acid. Particularly preferred demulcents are propylene
glycol and polyethylene glycol 400.
[0032] Suitable tonicity-adjusting agents include, but are not
limited to, mannitol, sodium chloride, glycerin, and the like.
Suitable buffering agents include, but are not limited to,
phosphates, acetates and the like, and amino alcohols such as
2-amino-2-methyl-1-propanol (AMP). Suitable surfactants include,
but are not limited to, ionic and nonionic surfactants, though
nonionic surfactants are preferred, RLM 100, POE 20 cetylstearyl
ethers such as Procol.RTM. CS20 and poloxamers such as
Pluronic.RTM. F68.
[0033] The formulations set forth herein may comprise one or more
preservatives. Examples of such preservatives include
p-hydroxybenzoic acid ester, sodium perborate, sodium chlorite,
alcohols such as chlorobutanol, benzyl alcohol or phenyl ethanol,
guanidine derivatives such as polyhexamethylene biguanide, sodium
perborate, polyquaternium-1, or sorbic acid. In certain
embodiments, the formulation may be self-preserved so that no
preservation agent is required.
[0034] Formulations of the present invention are ophthalmically
suitable for application to a subject's eyes. The term "aqueous"
typically denotes an aqueous formulation wherein the excipient is
>50%, more preferably >75% and in particular >90% by
weight water. These drops may be delivered from a single dose
ampoule which may preferably be sterile and thus render
bacteriostatic components of the formulation unnecessary.
Alternatively, the drops may be delivered from a multi-dose bottle
which may preferably comprise a device which extracts any
preservative from the formulation as it is delivered, such devices
being known in the art.
[0035] The formulations of the present invention are preferably
isotonic, or slightly hypotonic in order to combat any
hypertonicity of tears caused by evaporation and/or disease. This
may require a tonicity agent to bring the osmolality of the
formulation to a level at or near 210-320 milliosmoles per kilogram
(mOsm/kg). The formulations of the present invention generally have
an osmolality in the range of 220-320 mOsm/kg, and preferably have
an osmolality in the range of 235-300 mOsm/kg. The ophthalmic
formulations will generally be formulated as sterile aqueous
solutions.
[0036] The compositions of the present invention can also be used
to administer pharmaceutically active compounds. Such compounds
include, but are not limited to, glaucoma therapeutics, pain
relievers, anti-inflammatory and anti-allergy medications, and
anti-microbials. More specific examples of pharmaceutically active
compounds include betaxolol, timolol, pilocarpine, carbonic
anhydrase inhibitors and prostglandins; dopaminergic antagonists;
post-surgical antihypertensive agents, such as para-amino clonidine
(apraclonidine); anti-infectives such as ciprofloxacin,
moxifloxacin, and tobramycin; non-steroidal and steroidal
anti-inflammatories, such as naproxen, diclofenac, nepafenac,
suprofen, ketorolac, tetrahydrocortisol and dexamethasone; dry eye
therapeutics such as PDE4 inhibitors; and anti-allergy medications
such as H1/H4 inhibitors, H4 inhibitors, and olopatadine.
[0037] It is also contemplated that the concentrations of the
ingredients comprising the formulations of the present invention
can vary. A person of ordinary skill in the art would understand
that the concentrations can vary depending on the addition,
substitution, and/or subtraction of ingredients in a given
formulation.
[0038] Preferred formulations are prepared using a buffering system
that maintains the formulation at a pH of about 6.5 to a pH of
about 8.0. Topical formulations (particularly topical ophthalmic
formulations, as noted above) are preferred which have a
physiological pH matching the tissue to which the formulation will
be applied or dispensed.
[0039] In particular embodiments, a formulation of the present
invention is administered once a day. However, the formulations may
also be formulated for administration at any frequency of
administration, including once a week, once every 5 days, once
every 3 days, once every 2 days, twice a day, three times a day,
four times a day, five times a day, six times a day, eight times a
day, every hour, or greater frequency. Such dosing frequency is
also maintained for a varying duration of time depending on the
therapeutic regimen. The duration of a particular therapeutic
regimen may vary from one-time dosing to a regimen that extends for
months or years. One of ordinary skill in the art would be familiar
with determining a therapeutic regimen for a specific
indication.
[0040] The following examples are presented to further illustrate
selected embodiments of the present invention.
EXAMPLES
[0041] Example 1 is a formulation according to an embodiment of the
present invention. Examples 2 and 3 summarize studies performed on
formulations according to embodiments of the present invention.
Example 1
TABLE-US-00001 [0042] Ingredient % w/v Hydroxypropyl Guar 0.16 to
0.19 Boric Acid 0.7 Sorbitol 1.4 Polyethylene Glycol 0.4 Propylene
Glycol 0.3 Potassium Chloride 0.12 Sodium Chloride 0.1
Polyquaternium-1 0.001 + 10% excess 2-Amino-2-methylpropanol 0.57
Sodium Hydroxide/Hydrochloric Acid q.s. pH 7.9 Purified Water q.s.
100%
Example 2
[0043] Various solutions containing hydroxypropyl guar, borate and
sorbitol were characterized in vitro to explore how the use of a
cis-diol such as sorbitol can modify the bulk rheology, interfacial
rheology and lubrication properties of hydroxypropyl guar-borate
formulations. The experiments conducted show the effect of sorbitol
in pH 7.9 formulations comprising a galactomannan-borate
cross-linking system, and simulate the introduction of such
formulations into the eye at a lower pH (7.6). Hydroxypropyl guar
(M.sub.n=3.times.10.sup.6 g/mol, polydispersity ratio (PD)=2-3) was
used in the preparation of the artificial tear solution (ATDS) used
in these experiments. The ATDS used for these experiments is the
formulation of Example 1 above, pH adjusted to 7.9 or 7.6, and with
varying concentrations of sorbitol.
[0044] Bulk rheology experiments were conducted using a controlled
stress rheometer (AR 2000ex, TA Instruments, Inc.). The measurement
system was a 40 mm acrylic 2.degree. cone and plate with a sample
volume of 0.58 mL. A temperature of 25.degree. C..+-.0.1.degree. C.
was maintained and a cover was placed over the measurement system
to prevent evaporation of the solutions. For Steady State Flow
(SSF) experiments, the instrument applies a controlled stress which
in turn gives the result as viscosity vs. shear rate. Two dynamic
tests were conducted: oscillation stress sweep and oscillation
frequency sweep. The oscillation stress sweep holds the frequency
of the solution constant while measuring a range of stresses. The
oscillation stress sweep measures G' (elastic/storage modulus) and
G'' (viscous, loss modulus). From this information the Linear
Viscoelastic Region (LVR) can be determined. The LVR is a region in
the stress sweep, obtained from G', where the solution holds its
elasticity, G', over a range of stresses. A measure of relative
elasticity, tan(.delta.)=G''/G', is obtained from these
experiments. The oscillation frequency sweep holds the stress
constant within the LVR while measuring a range of frequencies.
This measurement can determine G', G'' and tan(.delta.) as well.
The oscillation frequency sweep shows how well a solution maintains
its structure.
[0045] Interfacial rheology experiments were conducted using an
optical oscillating drop generator device (OCA20, Dataphysics
Instruments) equipped with a piezoelectric device and amplifier
that controlled the oscillations of the drop. The drop, suspended
in a temperature and humidity controlled cell at the tip of a
stainless steel needle of 1.65 mm external diameter, was observed
with a CCD camera (768.times.576 pixels) at 500 images per second.
The oscillating drop generator (ODG) technique characterizes the
mechanical strength of the films formed by analyzing the drop shape
at a set frequency over a range of amplitudes. (See Li et al.
(1999); Padday, et al. (1969); Miano et al. (2006); and Miano et
al. (2005). The amplitude changes the volume and shape of the drop
and therefore the surface area.
[0046] The dynamic interfacial tension was determined by analyzing
the drop shape profile. The Young-Laplace model of a pendant drop
of density p under gravity g, gives the surface tension y by the
following:
.lamda. = ( .rho. gD 1 2 H ( s ) ) , s = D 1 D 2 ##EQU00001##
[0047] Once the drop equilibrates, the drop volume is varied
sinusoidally at a set frequency while the amplitude of the
oscillation changes. This technique assumes that the surface
tension of the drop remains uniform over the drop surface in the
course of the dynamic variation of its surface. From this it is
possible to determine the interfacial dilatational modulus E*
according to the Gibbs equation:
E * = - .lamda. ln ( A ) = Re E 1 * + lm E 1 * ##EQU00002##
where Re|E1*| is the elastic modulus of the interface. The elastic
modulus of the interface shows the significance of interface
structure and is indicative of interfacial elastic properties.
Im|E1*| is the loss modulus of the interface.
[0048] Friction screening experiments were conducted using a
pin-on-disc tribometer with tissue-on-tissue
(pericardium-on-pericardium) substrates using the method of Meyer
et al. (2006). New tissue-tissue couples were used for all new
solutions used in this study. The solutions used included
Unisol.RTM. saline control (Alcon, Inc.), OPTIVE.RTM. (Allergan,
Inc.), blink.RTM. Tears (Abbott Medical Optics, Inc.) and the ATDS
to simulate in-eye conditions (without sorbitol and at pH of 7.6).
Of the four solutions tested, only the ATDS exhibits gelling
behavior when applied to the eye. The apparatus conditions were set
at 30 full cycles per minute for blink rate, 2.5 cm/seconds for
blink velocity, and 8 kPa for blink pressure. The friction
screening protocol comprised the following steps. First, a baseline
measurement using 50 .mu.l Unisol.RTM. saline control was made.
Next, a simulation of solution spreading, wetting and initial
retention to eye before rinsing and blinking was performed by
applying 50.mu.l of the test formulation to the tissue. The tissue
couple was then brought back into contact. Measurements were taken
at 1 and 2 minutes post application, and following each of three
tissue rinses with 50 .mu.l Unisol.RTM..
Results
[0049] FIG. 2 is a graph showing steady state slow (SSF) viscosity
as a function of shear rate for the ATDS at pH 7.9 and 7.6. The SSF
data demonstrates that the viscosity decreased as the pH decreased
from 7.9 to 7.6, and that the ATDS at pH 7.6 and 7.9 showed some
shear thinning properties. Accordingly, the ATDS at pH 7.9 will
shear thin when mixed with the tear film and through adjustment to
a lower pH 7.6 there will be effective spreading and less blurring
upon contact.
[0050] FIG. 3 is a graph showing steady state flow (SSF) viscosity
as a function of shear rate for the ATDS with 0.0 w/v %, 0.5 w/v %,
1.0 w/v %, and 1.4 w/v % sorbitol. The SSF data shows the
modulation effect of sorbitol on the SSF flow properties of the
ATDS, and that a reduction in sorbitol concentration leads to an
increase in viscosity. FIG. 3 shows that as the sorbitol
concentration of a galactomannan and borate solution increases, the
measured viscosity of that solution decreases.
[0051] FIG. 4 is a graph showing oscillating drop amplitude stress
sweep elastic moduli (Re|E1*|) as a function of amplitude of drop
for the ATDS at pH 7.9 and 7.6. In these experiments, a high
elastic moduli correlates to more structure at the water/air
interface. The Stress Sweep data show the significance of the
elastic contribution of the ATDS at the water/air interface. At
both pH 7.9 and at pH 7.6, the ATDS was elastic dominant at the
interface. This data indicates that the ATDS retained elastic
structure despite its thinning and spreading characteristics
demonstrated by the data presented in FIG. 2.
[0052] FIG. 5 is a graph showing stress sweep tan(.delta.) as a
function of torque for the ATDS with 0.0 w/v %, 0.5 w/v %, 1.0 w/v
% and 1.4 w/v % sorbitol. A low tan(.delta.) correlates to more
elasticity. A decrease in Sorbitol increases the elasticity of the
ATDS. The formulation with no sorbitol has the most elasticity and
the lowest tan(.delta.). This experiment shows that polymer
structure of a galactomannan borate solution increases through the
dilution of sorbitol, which reflects the availability of more
borate for galactomannan-borate cross linking.
[0053] FIG. 6 is a graph showing oscillating drop amplitude sweep
elastic moduli (Re|E1*|) as a function of amplitude of drop for the
ATDS with 0.0 w/v % and 1.4 w/v % sorbitol. As with the FIG. 3
data, a high elastic moduli correlates to more structure at the
interface. The experiment shows that dilution of sorbitol increases
the surface elasticity of the ATDS. Further, the ODG data show that
both ATDS's are elastic dominant and have gel-like properties at
the aqueous/air interface.
[0054] FIG. 7 is a graph showing average coefficient of friction
(Cof), 1 and 2 minutes after application of test solutions to the
tissue in the friction screening model. The test solutions used
were saline control, Optive.RTM., blink Tears.RTM. and the ATDS in
eye simulation solution (without Sorbitol, pH 7.6). The Cof data
showed significant differences between the test solutions following
measurement at times t=1 min and t=2 min. The saline control had
the highest Cof for both t=1 min and t=2 min followed by blink
Tears.RTM. and Optive.RTM.. The ATDS containing the active
ingredients polyethylene glycol 400 and propylene glycol with
hydroxypropyl guar showed the lowest Cof of the test solutions.
[0055] FIG. 8 is a graph showing average percent decrease in
coefficient of friction, compared to baseline (Unisol.RTM., saline
control) at 1 & 2 minutes after application of formulation; and
after each of 3 blot/Unisol.RTM. applications (post-rinses 1, 2 and
3) for saline control, Optive.RTM., blink Tears.RTM. and the ATDS
without sorbitol.
[0056] The coefficient of friction (Cof) is a measurement of
formulation lubricity on a surface. The Cof data show significant
differences between the test solutions following the post-rinse
cycles, and demonstrate the ability of the ATDS to maintain a low
friction coefficient through the rinse cycles. For example, the %
Cof data for the ATDS at t=1 min, t=2 min, post-rinse 1 and
post-rinse 3 were 82%, 83%, 85% and 75%, respectively. The average
% Cof at the post-rinse 3 timepoint for the saline control, blink
Tears.RTM., Optive.RTM. and the ATDS were 3%, 6%, 11% and 75%,
respectively. The ATDS maintained the lowest Cof of the test
solutions for the pericardium tissue substrates. The low Cof data
upon application of the ATDS to the tissue substrates and
persistence of the low Cof data following rinse cycles was believed
to reflect the bulk and interfacial Theological properties of the
ATDS, as shown in FIGS. 2-6.
Example 3
[0057] The ATDS formulation of Example 1 was compared in two in
vivo studies against saline control solution (Unisol.RTM.) and the
carboxymethylcellulose/glycerin formulation Optive.RTM..
Retention Time Studies
[0058] An important measure of a lubricant eye drop is the
assessment of ocular surface retention or swell time. The mean
retention time of a galactomannan-borate solution of the present
invention (the ATDS formulation of Example 1) was compared to a
saline control solution (Unisol.RTM.) using a fluorophotometric
technique. Briefly, a fluorescein labeled dextran tracer of
approximately 70 kD (Molecular Probes, Eugene, Oregon) was added to
each test formulation at a concentration of 0.1 w/v %. A scanning
fluorophotometer (Ocumetrics, Mountain View, Calif.) was used to
monitor signal decay corresponding to elimination of the
formulations. 25 dry eye patients were studied, and measurements
were taken roughly every two minutes after application of the test
formulation.
[0059] The results of the study, as reported by Lane et al. (2009),
show that the ATDS formulation was retained significantly longer
than the saline control solution (mean retention time of 31 minutes
vs. 22 minutes for control). This statistically significant
(p=0.0003) data is consistent with the in vitro studies above. For
example, FIG. 8 shows that the ATDS maintains a low coefficient of
friction (Cof) compared to other solutions (including Unisol.RTM.
and Optive.RTM.) in vitro despite several washes simulating the
effects of blinking. Thus, the Theological properties of the ATDS
solution appear to result in superior retention time performance
when applied to the eye.
Interblink Interval Visual Acuity Decay
[0060] The effects of dry eye on visual function can be assessed by
testing interblink interval visual acuity decay (IVAD) using a
real-time measurement of visual acuity degradation between blinks.
FIG. 10 is a bar graph summarizing the result of a study comparing
Optive.RTM. (a carboxymethylcellullose (CMC) and glycerin based
artificial tear) and the ATDS formulation of Example 1.
[0061] In the study, 48 dry eye patients received both products in
a randomized fashion with a 7-day washout between periods. Baseline
measurements of IVAD, recorded as time (sec) that the patient could
maintain best corrected visual acuity (BCA) within an interblink
period were performed. Following a single drop of test solution,
IVAD measurements were repeated at 15, 45, and 90 minutes.
[0062] As reported by Torkildsen et al. (2009), patients treated
with the ATDS formulation had a significantly prolonged median time
to a one-line loss of BCVA at 90 minutes post-installation compared
to the Optive.RTM. formulation. The ATDS formulation allowed a 58%
increase in time at BCVA within the interblink period compared to
baseline and was significantly longer (33%) than the CMC/glycerin
Optive.RTM. formulation.
[0063] The present invention and its embodiments have been
described in detail. However, the scope of the present invention is
not intended to be limited to the particular embodiments of any
process, manufacture, composition of matter, compounds, means,
methods, and/or steps described in the specification. Various
modifications, substitutions, and variations can be made to the
disclosed material without departing from the spirit and/or
essential characteristics of the present invention. Accordingly,
one of ordinary skill in the art will readily appreciate from the
disclosure that later modifications, substitutions, and/or
variations performing substantially the same function or achieving
substantially the same result as embodiments described herein may
be utilized according to such related embodiments of the present
invention. Thus, the following claims are intended to encompass
within their scope modifications, substitutions, and variations to
processes, manufactures, compositions of matter, compounds, means,
methods, and/or steps disclosed herein.
REFERENCES
[0064] The following publications are incorporated herein by
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