U.S. patent application number 13/652208 was filed with the patent office on 2013-02-14 for ophthalmic compositions containing a synergistic combination of two polymers.
This patent application is currently assigned to Novartis AG. The applicant listed for this patent is Novartis AG. Invention is credited to Huagang Chen, Masood A. Chowhan.
Application Number | 20130039879 13/652208 |
Document ID | / |
Family ID | 46123716 |
Filed Date | 2013-02-14 |
United States Patent
Application |
20130039879 |
Kind Code |
A1 |
Chowhan; Masood A. ; et
al. |
February 14, 2013 |
Ophthalmic Compositions Containing A Synergistic Combination Of Two
Polymers
Abstract
Ophthalmic compositions suitable for use as artificial tears or
as vehicles for ophthalmic drugs are disclosed. The compositions
contain a combination of two polymers that have a synergistic
effect on viscosity.
Inventors: |
Chowhan; Masood A.;
(Arlington, TX) ; Chen; Huagang; (Arllington,
TX) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Novartis AG; |
Basel |
|
CH |
|
|
Assignee: |
; Novartis AG
Basel
CH
|
Family ID: |
46123716 |
Appl. No.: |
13/652208 |
Filed: |
October 15, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13083823 |
Apr 11, 2011 |
8313754 |
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13652208 |
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11673070 |
Feb 9, 2007 |
7947295 |
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13083823 |
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10863169 |
Jun 8, 2004 |
7709012 |
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11673070 |
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60478253 |
Jun 13, 2003 |
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Current U.S.
Class: |
424/78.04 ;
424/195.18; 514/57; 514/7.6 |
Current CPC
Class: |
A61P 35/00 20180101;
A61P 27/06 20180101; A61P 27/02 20180101; A61K 47/32 20130101; A61K
47/38 20130101; A61P 31/00 20180101; A61P 27/04 20180101; A61P
27/14 20180101; A61K 47/26 20130101; A61P 37/06 20180101; A61K
9/0048 20130101; A61P 29/00 20180101; A61K 47/36 20130101 |
Class at
Publication: |
424/78.04 ;
424/195.18; 514/57; 514/7.6 |
International
Class: |
A61K 31/717 20060101
A61K031/717; A61P 27/04 20060101 A61P027/04; A61K 38/18 20060101
A61K038/18; A61K 36/48 20060101 A61K036/48; A61K 31/765 20060101
A61K031/765 |
Claims
1. An aqueous composition suitable for ophthalmic administration
comprising a viscosity enhancing amount of combination of two
polymers having a synergistic effect on the composition's viscosity
and wherein the combination of two polymers is selected from the
group consisting of hydroxypropyl methylcellulose and guar gum;
hydroxypropyl methylcellulose and a carboxyvinyl polymer; a
carboxyvinyl polymer and guar gum; hydroxypropyl methylcellulose
and hydroxyethylcellulose; hyaluronic acid and hydroxypropyl
methylcellulose; hyaluronic acid and a carboxyvinyl polymer; and
hyaluronic acid and guar gum, provided that if the composition
comprises a carboxyvinyl polymer then the composition does not
contain sodium chloride or boric acid.
2. The composition of claim 1 wherein the combination of two
polymers is a combination of a hydroxypropyl methylcellulose and
guar gum.
3. The composition of claim 1 wherein the combination of two
polymers is a combination of hydroxypropyl methylcellulose and a
carboxyvinyl polymer,
4. The composition of claim 1 wherein the combination of two
polymers is a combination of a carboxyvinyl polymer and guar
gum.
5. The composition of claim 1 wherein the combination of two
polymers is a combination of hydroxypropyl methylcellulose and
hydroxyethylcellulose.
6. The composition of claim 1 wherein the combination of two
polymers is a combination of hyaluronic acid and hydroxypropyl
methylcellulose,
7. The composition of claim 1 wherein the combination of two
polymers is a combination of hyaluronic acid and a carboxyvinyl
polymer.
8. The composition of claim 1 wherein the combination of two
polymers is a combination of hyaluronic acid and guar gum.
9. The composition of claim 1 wherein the carboxyvinyl polymer is a
polymer of acrylic acid crosslinked with allyl sucrose or
allylpentaerythritol, the hydroxypropyl methylcellulose has a
number average molecular weight of approximately 86,000 dalton, the
guar gum is hydroxypropyl guar, and the hyaluronic acid is sodium
hyaluronate.
10. The composition of claim 1 wherein the total concentration of
the two polymers ranges from 0.05-3.0% (w/w).
11. composition of claim 9 wherein the total concentration of the
two polymers ranges from 0.2-2.0% (w/w).
12. The composition of claim 1 further comprising an ingredient
selected from the group consisting of pharmaceutically acceptable
buffering agents; preservatives; tonicity-adjusting agents;
surfactants; solubilizing agents; stabilizing agents;
comfort-enhancing agents; emollients; pH-adjusting agents; and
lubricants.
13. composition of claim 1 further comprising an ophthalmic
drug.
14. The composition of claim 13 wherein the ophthalmic drug is
selected from the group consisting of anti-glaucoma agents;
anti-angiogenesis agents; anti-infective agents; non-steroidal and
steroidal anti-inflammatory agents; growth factors;
immunosuppressant agents; and anti-allergic agents,
15. A method of alleviating the symptoms of dry eye comprising
topically administering to the eye an aqueous composition
comprising a viscosity enhancing amount of a combination of two
polymers having a synergistic effect on the composition's viscosity
and wherein the combination of two polymers is selected from the
group consisting of hydroxypropyl methylcellulose and guar gum;
hydroxypropyl methylcellulose and a carboxyvinyl polymer; a
carboxyvinyl polymer and guar gum; hydroxypropyl methylcellulose
and hydroxyethylcellulose; hyaluronic acid and hydroxypropyl
methylcellulose; hyaluronic acid and a carboxyvinyl polymer; and
hyaluronic acid and guar gum, provided that if the composition
comprises a carboxyvinyl polymer then the composition does not
contain sodium chloride or boric acid.
16. A method of treating a disease or condition of the eye
comprising administering to the eye a composition comprising an
ophthalmic drug and a carrier wherein the carrier comprises a
viscosity enhancing amount of a combination of two polymers having
a synergistic effect on the composition's viscosity and wherein the
combination of two polymers is selected from the group consisting
of hydroxypropyl methylcellulose and guar gum; hydroxypropyl
methylcellulose and a carboxyvinyl polymer; a carboxyvinyl polymer
and guar gum; hydroxypropyl methylcellulose and
hydroxyethylcellulose; hyaluronic acid and hydroxypropyl
methylcellulose; hyaluronic acid and a carboxyvinyl polymer; and
hyaluronic acid and guar gum, provided that if the composition
comprises a carboxyvinyl polymer then the composition does not
contain sodium chloride or boric acid.
17. The method of claim 16 wherein the composition is administered
topically to the eye.
18. The method of claim 16 wherein the composition is injected.
19. The method of claim 18 wherein the composition is injected as
an intravitreal injection, subconjunctival injection, sub-tenon
injection, retrobulbar injection, suprachoroidal injection, or
periocular injection.
20. The method of claim 16 wherein the total concentration of the
two polymers ranges from 0.05-3.0% (w/w).
Description
[0001] This application is a continuation-in-part of U.S. Ser. No.
10/863,169, filed Jun. 8, 2004, which claims priority to U.S.
Provisional Application, U.S. Ser. No. 60/478,253, filed Jun. 13,
2003.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to pharmaceutical
compositions. In particular, this invention relates to topically
administrable ophthalmic compositions that contain certain
combinations of two polymeric components.
[0004] 2. Description of Related Art
[0005] The use of polymeric ingredients in topically administrable
ophthalmic compositions is well known. Polymeric ingredients are
typically used in suspension compositions as physical stability
aids, helping to keep the insoluble ingredients suspended or easily
redispersible. In solution compositions, polymeric ingredients are
typically used to increase the composition's viscosity.
[0006] Many polymers have been used in topically administrable
ophthalmic compositions. Included among these are cellulosic
polymers, such as hydroxypropyl methylcellulose, hydroxyethyl
cellulose, and ethylhydroxyethyl cellulose. Also included are
synthetic polymers, such as carboxyvinyl polymers and polyvinyl
alcohol. Still others include polysaccharides such as xanthan gum,
guar gum, and dextran.
[0007] Combinations of polymers have also been used in ophthalmic
compositions. Certain combinations of polymers are known to provide
synergistic effects on viscosity and, in some cases, even a phase
transition from a liquid to a gel. For example, U.S. Pat. No.
4,136,173 discloses ophthalmic compositions containing a
combination of xanthan gum and locust bean gum.
[0008] One approach to achieving a target viscosity in a topically
administrable ophthalmic composition might involve simply adding a
sufficient amount of one polymeric ingredient. Often, however, it
is desirable to minimize the total amount of polymeric additives in
topically administrable ophthalmic compositions. A mixed polymer
system containing more than one polymer can significantly enhance
the viscosity and lubrication property of a composition while
minimizing total polymer concentration and cost of materials.
SUMMARY OF THE INVENTION
[0009] The present invention is directed toward aqueous ophthalmic
compositions suitable for topical ophthalmic administration that
comprise a viscosity enhancing amount of a polymeric ingredient
wherein the polymeric ingredient consists of a certain combination
of two polymeric ingredients. The ophthalmic compositions comprise
a combination of polymeric ingredients selected from the group
consisting of: hydroxypropyl methylcellulose and guar gum;
hydroxypropyl methylcellulose and a carboxyvinyl polymer;
carboxyvinyl polymer and guar gum; hydroxypropyl methylcellulose
and hydroxyethylcellulose; hyaluronic acid and hydroxypropyl
methylcellulose; hyaluronic acid and a carboxyvinyl polymer; and
hyaluronic acid and guar gum. The compositions containing one of
these select combinations of polymeric ingredients are useful as
artificial tear products, and can also serve as vehicles for
delivering ophthalmic drugs.
[0010] The present invention is based upon the finding that these
select combinations of two polymers have a synergistic effect on
viscosity.
DETAILED DESCRIPTION OF THE INVENTION
[0011] Unless otherwise indicated, all ingredient concentrations
are listed as a weight/volume percentage basis (% w/v).
[0012] The ophthalmic compositions of the present invention are
aqueous compositions that include a select combination of two
polymeric ingredients. The combination is one of the following:
hydroxypropyl methylcellulose and guar gum; hydroxypropyl
methylcellulose and a carboxyvinyl polymer; a carboxyvinyl polymer
and guar gum; hydroxypropyl methylcellulose and
hydroxyethylcellulose; hyaluronic acid and hydroxypropyl
methylcellulose; hyaluronic acid and a carboxyvinyl polymer; and
hyaluronic acid and guar gum. All five types of individual polymers
are known and have been used in ophthalmic compositions. All five
types of polymers are also commercially available.
[0013] HPMC is commercially available from the Dow Chemical Company
under the brand name Methocel.RTM.. HPMC is available in a variety
of grades. Most preferred for use in the compositions of the
present invention is Methocel E4M, (HPMC 2910), which has a number
average molecular weight of approximately 86,000 dalton. The
concentration of HPMC in the compositions of the present invention
will generally range from 0.05-0.5%, and will preferably be
0.3%.
[0014] The guar gum ingredient can be guar gum or a guar gum
derivative, such as the hydroxypropyl or hydroxypropyltrimonium
chloride derivatives of guar gum. Guar and its derivatives are
described in U.S. Pat. No. 6,316,506, the entire contents of which
are hereby incorporated by reference. For purposes of the present
application, "guar gum" includes unsubstituted guar gum and its
substituted derivatives. Guar gum and many of its derivatives are
commercially available from Rhone-Poulenc (Cranbury, N.J.),
Hercules, Inc. (Wilmington, Del.) and TIC Gum, Inc, (Belcamp, Md.).
A preferred derivative for use in the compositions of the present
invention is hydroxypropyl guar ("HP-Guar"). The concentration of
guar in the compositions of the present invention will generally
range from 0.01-0.2%, and will preferably be 0.1%.
[0015] Carboxyvinyl polymers suitable for use in the present
invention are also known as "carbomers" or carboxypolymethylene.
They are commercially available from sources such as Noveon, Inc.
(Cleveland, Ohio), which distributes them under the trade name
Carbopol.RTM.. Carbopol polymers are crosslinked, acrylic
acid-based polymers. They are crosslinked with allyl sucrose or
allylpentaerythritol. Carbopol copolymers are polymers of acrylic
acid, modified by C.sub.10-30 alkyl acrylates, and crosslinked with
allylpentaerythritol. A preferred carboxyvinyl polymer for use in
the compositions of the present invention is a polymer of acrylic
acid crosslinked with allyl sucrose or allylpentaerythritol, which
is commercially available as Carbopol.RTM. 974P. The concentration
of carbomer in the compositions of the present invention will
generally range from 0.01-0.2%, and will preferably be 0.1%.
[0016] HEC is commercially available from Hercules Inc. (Aqualon
Division) in a variety of grades, including Natrasol 250 LR,
Natrasol 250 MR and Natrasol 250 HR. A preferred HEC for use in the
compositions of the present invention is the NE grade material,
which is commercially available as Natrasol 250HR. The
concentration of HEC in the compositions of the present invention
will generally range from 0.05-0.5%, and will preferably range from
0.1-0.2%.
[0017] Hyaluronic acid is commercially available from a variety of
sources, including Genzyme and Hyaluron Inc. Hyaluronic acid is
available in many grades, with molecular weights ranging from
100,000 to greater than 3 million dalton, As used herein,
hyaluronic acid also encompasses the sodium salt form of hyaluronic
acid, known as sodium hyaluronate, which is also commercially
available.
[0018] The aqueous compositions of the present invention contain
one of the specified combinations of polymers in a total polymer
concentration range of 0.05-3.0%, preferably 0.2-2.0%.
[0019] In addition to the required combination of two polymeric
ingredients, the aqueous compositions of the present invention may
contain other ingredients as excipients. For example, the
compositions may include one or more pharmaceutically acceptable
buffering agents, preservatives (including preservative adjuncts),
tonicity-adjusting agents, surfactants, solubilizing agents,
stabilizing agents, comfort-enhancing agents, emollients,
pH-adjusting agents and/or lubricants. Preferably, the aqueous
composition does not contain any polymeric ingredients, other than
the synergistic combination of the two polymeric ingredients
specified above, with the exception of polymeric preservatives for
compositions that contain a preservative. If the compositions
contain a carbomer as one of the two polymers, then the
compositions of the present invention do not contain any ionic
tonicity-adjusting agent, such as sodium chloride, or other ionic
excipients, such as boric acid, as these ingredients have a
significant, detrimental effect on the composition's viscosity.
[0020] The compositions of the invention have a pH in the range of
4-9, preferably 6-8, and most preferably 6.5-7.5. If the
compositions contain a carbomer, it is critical that the
compositions are formulated so that the target pH is not exceeded.
Once a target pH has been exceeded in compositions containing a
carbomer, adding an acid such as hydrochloric acid to adjust the pH
downward can compromise the synergistic viscosity. It is known that
relatively small amounts of acid or salts, on the order of 0.005%,
can have a significant effect on the viscosity of compositions
containing a carbomer.
[0021] The compositions of the present invention generally have an
osmolality in the range of 220-340 mOsm/kg, and preferably have an
osmolality in the range of 235-300 mOsm/kg.
[0022] The aqueous compositions of the present invention are
suitable for use as artificial tear products to relieve symptoms of
dry eye. Alternatively, the compositions of the present invention
may act as a vehicle for an ophthalmic drug. The compositions of
the present invention may also be used as irrigating solutions for
ophthalmic or other surgical procedures. Ophthalmic drugs suitable
for use in the compositions of the present invention include, but
are not limited to: anti-glaucoma agents, such as beta-blockers
including timolol, betaxolol, levobetaxolol, carteolol, miotics
including pilocarpine, carbonic anhydrase inhibitors,
prostaglandins, seretonergics, muscarinics, dopaminergic agonists,
adrenergic agonists including apraclonidine and brimonidine;
anti-angiogenesis agents; anti-infective agents including
quinolones such as ciprofloxacin, and aminoglycosides such as
tobramycin and gentamicin; non-steroidal and steroidal
anti-inflammatory agents, such as suprofen, diclofenac, ketorolac,
rimexolone and tetrahydrocortisol; growth factors, such as EGF;
immunosuppressant agents; and anti-allergic agents including
olopatadine. The ophthalmic drug may be present in the form of a
pharmaceutically acceptable salt, such as timolol maleate,
brimonidine tartrate or sodium diclofenac. Compositions of the
present invention may also include combinations of ophthalmic
drugs, such as combinations of (i) a beta-blocker selected from the
group consisting of betaxolol and timolol, and (ii) a prostaglandin
selected from the group consisting of latanoprost; 15-keto
latanoprost; travoprost; and unoprostone isopropyl.
[0023] Although the amount of drug included in the compositions of
the present invention will be whatever amount is therapeutically
effective and will depend upon a number of factors, including the
identity and potency of the chosen drug, the total concentration of
drug will generally be about 5% or less.
[0024] The compositions of the present invention are preferably not
formulated as solutions that gel upon administration to the eye.
The compositions illustrated in the Examples below do not gel upon
administration to the eye.
[0025] The compositions of the present invention may be topically
applied to the eye or injected into the eye, depending upon the
target site and disease or condition to be treated. To treat
diseases or conditions inside the eye rather than at the surface of
the eye, the compositions of the present invention may, for
example, be administered by intravitreal injection, subconjunctival
injection, sub-tenon injection, retrobulbar injection,
suprachoroidal injection, or periocular injection. A syringe
apparatus including an appropriately sized needle, for example, a
27 gauge needle or a 30 gauge needle, can be effectively used to
inject the composition into the posterior segment of an eye of a
human or animal. The combination of polymers may be particularly
advantageous for injections into the eye for the following reasons:
prevention of reflux, prolonged duration of action so as to
increase the period of time between repeat injections, and
reduction in the total amount of polymer required to achieve a
target viscosity, thereby reducing the polymer disposition from
back of the eye.
[0026] The following examples are presented to illustrate further
various aspects of the present invention, but are not intended to
limit the scope of the invention in any respect.
EXAMPLES
Example 1
Artificial Tear Composition
[0027] A representative formulation for an artificial tear product
according to the present invention is shown in Table 1.
TABLE-US-00001 TABLE 1 Ingredients Concentration (% w/v) Carbopol
974P 0.1 HP-Guar 0.1 Mannitol 4.0 NaOH/HCl Qs to pH 7.0 Purified
water Qs to 100
[0028] The composition shown in Table 1 can be prepared by at least
two methods. One method involves adding the following ingredients
slowly and in the following order to heated purified water
(70-80.degree. C.) (approximately 80% of the desired batch volume)
with mixing: mannitol, Carbopol 974P, and HP-Guar (waiting until
each ingredient is mixed well before adding the next). pH is then
adjusted with IN NaOH, and the remaining amount of purified water
is added. The composition is then autoclaved at 121.degree. C. for
thirty minutes and subsequently cooled to room temperature with
constant stirring.
[0029] An alternative method of preparing the composition shown in
Table 1 is as follows. In a first container, add heated purified
water (70-80 .pi.C.) (approximately 60% of the desired batch
volume), then mix in mannitol, and then Carbopol 974P, waiting
until each ingredient is mixed well before adding the next.
Autoclave the resulting composition at 121.degree. C. for thirty
minutes, then allow the composition to cool to room temperature
with constant stirring ("the Carbopol composition"). In a separate
container, add purified water (approximately 30% of the desired
batch volume), then mix in HP-Guar. Adjust the pH of the HP-Guar
composition with 1N NaOH to pH 9. Autoclave the HP-Guar composition
at 121.degree. C. for thirty minutes, then allow it to cool to room
temperature with constant stirring ("the HP-Guar composition"),
then aseptically combine the HP-Guar composition with the Carbopol
composition, and aseptically adjust the final pH to 7.0, if
necessary, with 1N NaOH,
Example 2
Synergistic Effect on Viscosity (HPMC+Guar; HPMC+Carbomer;
Carbomer+Guar)
[0030] The compositions shown in Table 2 were prepared and their
viscosity was determined using a Brookfield cone/plate viscometer
with number 42 cone/plate set (30 rpm, at 25.degree. C.) for less
viscous samples (viscosity less than 20 cps) and number 52
cone/plate set (3 rpm, at 25.degree. C.) for more viscous samples
(viscosity more than 20 cps). Two people independently prepared the
indicated samples and measured their viscosity values (n=1) for
each person. The averages of each set of results are shown in Table
2.
TABLE-US-00002 TABLE 2 Composition (% w/v) Ingredient 1 2 3 4 5 6 7
Mannitol 4.0 4.0 4.0 4.0 4.0 4.0 4.0 HPMC 2910 -- 0.3 -- -- 0.3 0.3
-- Carbopol 974P -- -- 0.1 -- 0.1 -- 0.1 HP-Guar -- -- -- 0.1 --
0.1 0.1 NaOH/HCl q.s. q.s. q.s. q.s. q.s. q.s. q.s. pH pH pH pH pH
pH pH 7.0 7.0 7.0 7.0 7.0 7.0 7.0 Purified Water q.s. q.s. q.s.
q.s. q.s. q.s. q.s. 100 100 100 100 100 100 100 Viscosity (cps) 1.1
8.2 488.1 5.3 1339.5 32.3 1273.0 Subst. Synergy.sup.@ -- -- -- --
Yes Yes Yes .sup.@Subst. Synergy = substantial synergy: greater
than 150% of the simple sum of the two respective single polymer
solutions
Example 3
Synergistic Effect on Viscosity (HPMC HEC)
[0031] The compositions shown in Table 3 were prepared and their
viscosity determined using a Brookfield cone/plate viscometer with
number 42 cone/plate set (30 rpm, at 25.degree. C.) for less
viscous samples (viscosity less than 20 cps) and number 52
cone/plate set (3 rpm, at 25.degree. C.) for more viscous samples
(viscosity more than 20 cps). The HEC used in this experiment was
Natrasol 250HR as shown in the following Table. Two people
independently prepared the indicated samples and measured their
viscosity values (n=1) for each person. The averages of each set of
results are shown in Table 3.
TABLE-US-00003 TABLE 3 Composition (% w/v) Ingredient 8 9 10 11 12
13 14 15 Mannitol 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 HPMC 2910 -- 0.3
-- -- -- 0.3 -- -- HP-Guar -- -- 0.1 -- -- -- 0.1 -- Carbopol 974P
-- -- -- 0.1 -- -- -- 0.1 Natrasol -- -- -- -- 0.1 0.1 0.1 0.1
250HR NaOH/HCl q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. pH pH pH pH
pH pH pH pH 7.0 7.0 7.0 7.0 7.0 7.0 7.0 7.0 Purified Water q.s.
q.s. q.s. q.s. q.s. q.s. q.s. q.s. 100 100 100 100 100 100 100 100
Viscosity (cps) 1.0 8.0 5.2 465.9 3.0 27.7 10.9 642.0 Subst. -- --
-- -- -- Yes No No Synergy.sup.@ .sup.@Subst. Synergy = substantial
synergy: greater than 150% of the simple sum of the two respective
single polymer solutions
Example 4
Lack of Synergistic Effect on Viscosity (Polyvinyl
Alcohol+Chondroitin Sulfate; Polyvinyl
Alcohol+Polyvinylpyrrolidone; Chondroitin
Sulfate+Polyvinylpyrrolidone)
[0032] The compositions shown in Table 4 were prepared and their
viscosity determined using a Brookfield cone/plate viscometer with
number 42 cone/plate set (30 rpm, at 25.degree. C.). Two people
independently prepared the indicated samples and measured their
viscosity values (n=1) for each person. The averages of each set of
results are shown in Table 4. Airvol 523S is a commercially
available polyvinyl alcohol polymer. Chondroitin sulfate is a
commercially available polymer. PVP K90 is a commercially available
polyvinyl pyrrolidone polymer.
TABLE-US-00004 TABLE 4 Composition (% w/v) Ingredient 16 17 18 19
20 21 22 Mannitol 4.0 4.0 4.0 4.0 4.0 4.0 4.0 PVA (Airvol 523S) --
0.2 -- -- 0.2 0.2 -- Chondroitin Sulfate -- -- 0.2 -- 0.2 -- 0.2
PVP (K90) -- -- -- 0.2 -- 0.2 0.2 NaOH/HCl q.s. q.s. q.s. q.s. q.s.
q.s. q.s. pH pH pH pH pH pH pH 7.0 7.0 7.0 7.0 7.0 7.0 7.0 Purified
Water q.s. q.s. q.s. q.s. q.s. q.s. q.s. 100 100 100 100 100 100
100 Viscosity (cps) 1.0 1.5 1.3 1.4 1.7 1.9 1.8 Subst.
Synergy.sup.@ -- -- -- -- No No No * slight, transparent
precipitate observed .sup.@Subst. Synergy = substantial synergy:
greater than 150% of the simple sum of the two respective single
polymer solutions
Example 5
Lack of Synergistic Effect on Viscosity (Polyvinyl
Alcohol+Carbomer; Chondroitin Sulfate+Carbomer; Polyvinyl
pyrrolidone Carbomer)
[0033] The compositions shown in Table 5 were prepared and their
viscosity determined using a Brookfield cone/plate viscometer with
number 42 cone/plate set (30 rpm, at 25.degree. C.) for less
viscous samples (viscosity less than 20 cps) and number 52
cone/plate set (3 rpm, at 25.degree. C.) for more viscous samples
(viscosity more than 20 cps). Two people independently prepared the
indicated samples and measured their viscosity values (n=1) for
each person. The averages of each set of results are shown in Table
5. Airvol 523S is a commercially available polyvinyl alcohol
polymer. Chondroitin sulfate is a commercially available polymer.
K90 is a commercially available polyvinylpyrrolidone polymer.
TABLE-US-00005 TABLE 5 Composition (% w/v) Ingredient 17 18 19 23
24 25 26 Mannitol 4.0 4.0 4.0 4.0 4.0 4.0 4.0 PVA 0.2 -- -- -- 0.2
-- -- (Airvol 523S) Chondroitin -- 0.2 -- -- -- 0.2 -- Sulfate PVP
-- -- 0.2 -- -- -- 0.2 (K90) Carbopol -- -- -- 0.1 0.1 0.1 0.1 974P
NaOH/HCl q.s. q.s. q.s. q.s. q.s. q.s. q.s. pH pH pH pH pH pH pH
7.0 7.0 7.0 7.0 7.0 7.0 7.0 Purified Water q.s. q.s. q.s. q.s. 100
q.s. 100 q.s. 100 q.s. 100 100 100 100 Viscosity (cps) 1.5 1.3 1.4
441.6 323.8 12.7 N/A* Subst. -- -- -- -- No No No Synergy.sup.@
*PVP was incompatible with Carbopol 974P - it formed a precipitate.
.sup.@Subst. Synergy = substantial synergy: greater than 150% of
the simple sum of the two respective single polymer solutions
Example 6
Lack of Synergistic Effect on Viscosity (HPMC Dextran;
Guar+Dextran; Carbomer Dextran)
[0034] The compositions shown in Table 6 were prepared and their
viscosity determined using a Brookfield cone/plate viscometer with
number 42 cone/plate set (30 rpm, at 25.degree. C.) for less
viscous samples (viscosity less than 20 cps) and number 52
cone/plate set (3 rpm, at 25.degree. C.) for more viscous samples
(viscosity more than 20 cps). Two people independently prepared the
indicated samples and measured their viscosity values (n=1) for
each person. The averages of each set of results are shown in Table
6.
TABLE-US-00006 TABLE 6 Composition (% w/v) Ingredient 27 28 29 30
31 32 33 34 Mannitol 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 HPMC 2910 --
0.3 -- -- -- 0.3 -- -- HP-Guar -- -- 0.1 -- -- -- 0.1 -- Carbopol
-- -- -- 0.1 -- -- -- 0.1 974P Dextran 70 -- -- -- -- 0.1 0.1 0.1
0.1 NaOH/HCl q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. pH pH pH pH pH
pH pH pH 7.0 7.0 7.0 7.0 7.0 7.0 7.0 7.0 Purified Water q.s. q.s.
q.s. q.s. q.s. q.s. q.s. q.s. 100 100 100 100 100 100 100 100
Viscosity 1.1 7.9 5.2 461.6 1.4 8.4 5.2 379.3 (cps) Subst. -- -- --
-- -- No No No Synergy.sup.@ .sup.@Subst. Synergy = substantial
synergy: greater than 150% of the simple sum of the two respective
single polymer solutions
Example 7
Effect of Salt on Viscosity for a Polymer Combination that Contains
Carbomer
[0035] The compositions shown below in Table 7 were prepared to
determine the effect of the addition of salt (NaCI) on viscosity.
The viscosity of each sample was determined using a Brookfield
cone/plate viscometer (52 cone, 3 rpm). The results are shown in
Table 7.
TABLE-US-00007 TABLE 7 Composition (% w/v) INGREDIENT 35 36 37 38
39 Mannitol 4.0 4.0 4.0 4.0 4.0 HPMC 2910 0.3 0.3 0.3 0.3 0.3
Carbopol 974P 0.1 0.1 0.1 0.1 0.1 NaCl 0 0.001 0.005 0.01 0.05
NaOH/HCl q.s. q.s. q.s. q.s. q.s. pH 7.0 pH 7.0 pH 7.0 pH 7.0 pH
7.0 Purified Water q.s. 100 q.s. 100 q.s. 100 q.s. 100 q.s. 100
Viscosity (cps) 737 430 359 212 49
Example 8
Effect of Boric Acid on Viscosity for a Polymer Combination that
Contains Carbomer
[0036] The compositions shown below in Table 8 were prepared to
determine the effect of the addition of boric acid on viscosity.
The viscosity of each sample was determined using a Brookfield
cone/plate viscometer (52 cone, 3 rpm). The results are shown in
Table 8.
TABLE-US-00008 TABLE 8 Composition (% w/v) INGREDIENT 40 41 42 43
44 Mannitol 4.0 4.0 4.0 4.0 4.0 HPMC 2910 0.3 0.3 0.3 0.3 0.3
Carbopol 974P 0.1 0.1 0.1 0.1 0.1 Boric acid 0 0.001 0.005 0.01
0.05 NaOH/HCl q.s. q.s. q.s. q.s. q.s. pH 7.0 pH 7.0 pH 7.0 pH 7.0
pH 7.0 Purified Water q.s. 100 q.s. 100 q.s. 100 q.s. 100 q.s. 100
Viscosity (cps) 657 534 362 233 65
Example 9
Synergistic Effect on Viscosity (HA+HPMC; HA+Carbomer; HA+Guar)
[0037] The compositions shown in Table 9 were prepared. The
viscosity of each composition was determined using a Brookfield
cone/plate viscometer with number 42 cone/plate set (30 rpm, at
25.degree. C.) for less viscous samples (viscosity less than 20
cps) and number 52 cone/plate set (6 rpm, at 25.degree. C.) for
more viscous samples (viscosity more than 20 cps). The results are
shown in Table 9.
TABLE-US-00009 TABLE 9 Composition (% w/v) Ingredient 45 46 47 48
49 50 51 Mannitol 4.0 4.0 4.0 4.0 4.0 4.0 4.0 Sodium Hyaluronate
0.1 -- -- -- 0.1 0.1 0.1 HPMC 2910 -- 0.3 -- -- 0.3 -- -- Carbopol
974P -- -- 0.1 -- -- 0.1 -- HP-Guar -- -- -- 0.1 -- -- 0.1 NaOH/HCl
q.s. q.s. q.s. q.s. q.s. q.s. q.s. pH pH pH pH pH pH pH 7.0 7.0 7.0
7.0 7.0 7.0 7.0 Purified Water q.s. 100 q.s. 100 q.s. 100 q.s. 100
q.s. 100 q.s. 100 q.s. 100 Final pH 6.93 7.06 6.96 6.99 7.08 7.06
6.94 Viscosity (cps) 125.9 8.0 432.3 5.6 267 873.5 232.3 Subst.
Synergy.sup.@ -- -- -- -- Yes Yes Yes .sup.@Subst. Synergy =
substantial synergy: greater than 150% of the simple sum of the two
respective single polymer solutions
Example 10
Synergistic Effect on Viscosity (HA+Carbomer; HA+Guar;
Carbomer+Guar)
[0038] The compositions shown in Table 10 were prepared. The
viscosity of each composition was determined using a Brookfield
cone/plate viscometer with number 42 cone/plate set (30 rpm, at
25.degree. C.) for less viscous samples (viscosity less than 20
cps) and number 52 cone/plate set (6 rpm, at 25.degree. C.) for
more viscous samples (viscosity more than 20 cps). The results are
shown in Table 10.
TABLE-US-00010 TABLE 10 Sample 55 56 57 Descriptions 52 53 54 Two
Component System Mannitol (%) 4 4 4 4 4 4 Sodium 0.1 0.1 0.1
Hyaluronate Carbopol 974P 0.1 0.1 0.1 (%) HP Guar 0.1 0.1 0.1 pH
7.0 7.0 7.0 7.0 7.0 7.0 To Make: Mannitol (g) 4 4 4 4 4 4 Sodium
0.1 0.1 0.1 0 Hyaluronate (g) Carbopol 974P 0.1 0.1 0 0.1 (g) HP
Guar (g) 0.1 0 0.1 0.1 Total Volume 100 100 100 100 100 100 (mL)
Physical Parameter Final pH 7.02 7.08 6.93 6.93 7.04 6.96 Mean
Viscosity 125.5 466.5 4.55 930 257.5 1184 (cps) (n = 2) Viscosity
Synergy Analysis % Viscosity NA NA NA 157% 198% 251% Increased
*
[0039] The invention has been described by reference to certain
preferred embodiments; however, it should be understood that it may
be embodied in other specific forms or variations thereof without
departing from its spirit or essential characteristics. The
embodiments described above are therefore considered to be
illustrative in all respects and not restrictive, the scope of the
invention being indicated by the appended claims rather than by the
foregoing description.
* * * * *