U.S. patent application number 12/131549 was filed with the patent office on 2008-12-18 for ophthalmic composition with hyaluronic acid.
Invention is credited to Susan E. Burke, David J. Heiler, Srini Venkatesh.
Application Number | 20080311070 12/131549 |
Document ID | / |
Family ID | 40132537 |
Filed Date | 2008-12-18 |
United States Patent
Application |
20080311070 |
Kind Code |
A1 |
Burke; Susan E. ; et
al. |
December 18, 2008 |
OPHTHALMIC COMPOSITION WITH HYALURONIC ACID
Abstract
An ophthalmic composition comprising a polymeric biguanide
composition having less than 18 mol % of terminal amine groups and
55 mol % or greater of terminal guanidine groups as measured by
.sup.13C NMR, and 0.005 w/v % to 0.04 w/v % hyaluronic acid.
Alternatively, the ophthalmic composition comprises a polymeric
biguanide composition comprising less than 18 mol % of terminal
amine groups and 40 mol % or greater of terminal cyanoguanidino
groups as measured by .sup.13C NMR, and 0.005 w/v % to 0.04 w/v %
hyaluronic acid. The compositions can be used for cleaning,
disinfecting or packaging a contact lens.
Inventors: |
Burke; Susan E.; (Batavia,
NY) ; Venkatesh; Srini; (Pittsford, NY) ;
Heiler; David J.; (Avon, NY) |
Correspondence
Address: |
Bausch & Lomb Incorporated
One Bausch & Lomb Place
Rochester
NY
14604-2701
US
|
Family ID: |
40132537 |
Appl. No.: |
12/131549 |
Filed: |
June 2, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60943620 |
Jun 13, 2007 |
|
|
|
Current U.S.
Class: |
424/78.04 ;
510/112 |
Current CPC
Class: |
C11D 3/48 20130101; C11D
3/222 20130101; C11D 1/90 20130101; C11D 3/3723 20130101; A61P
27/02 20180101; C11D 1/92 20130101; C11D 3/227 20130101; A61L
12/142 20130101; C11D 3/0078 20130101 |
Class at
Publication: |
424/78.04 ;
510/112 |
International
Class: |
A61K 31/785 20060101
A61K031/785; C11D 3/37 20060101 C11D003/37; A01P 1/00 20060101
A01P001/00 |
Claims
1. An ophthalmic composition comprising: a polymeric biguanide
composition comprising less than 18 mol % of terminal amine groups,
and 55 mol % or greater of terminal guanidine groups as measured by
.sup.13C NMR; and 0.005 w/v % to 0.04 w/v % hyaluronic acid.
2. The composition of claim 1 wherein the polymeric biguanide
composition comprises less than 15 mol % of terminal amine groups,
and 60 mol % or greater of terminal guanidine groups.
3. The composition of claim 2 wherein the polymeric biguanide
composition comprises less than 10 mol % of terminal amine groups
and 65 mol % or greater of terminal guanidine groups.
4. The composition of claim 1 wherein the weight ratio of
hyaluronic acid to the polymeric biguanide composition in the
composition is from 55:1 to 90:1.
5. The composition of claim 1 further comprising 0.01 wt. % to 0.8
wt. % of an amphoteric surfactant of general formula I ##STR00014##
wherein R.sup.1 is R or --(CH.sub.2).sub.n--NHC(O)R, wherein R is a
C.sub.8-C.sub.30alkyl optionally substituted with hydroxyl and n is
2, 3 or 4; R.sup.2 and R.sup.3 are each independently selected from
the group consisting of hydrogen and C.sub.1-C.sub.4alkyl; R.sup.4
is a C.sub.2-C.sub.8alkylene optionally substituted with hydroxyl;
and Y is CO.sub.2.sup.- or SO.sub.3.sup.-.
6. The composition of claim 1 further comprising 1 ppm to 3 ppm
polyquaternium-1.
7. The composition of claim 1 wherein the hyaluronic acid is
obtained via a fermentation mixture comprising Streptococcus
equi.
8. The composition of claim 4 wherein the hyaluronic acid is
present from 0.01 wt. % to 0.025 wt. %.
9. The use of the composition of claim 1 to clean, disinfect or
package contact lenses, as a preservative in a pharmaceutical
composition that includes a pharmaceutical agent, or as a
preservative in a health care product.
10. An ophthalmic composition comprising: a polymeric biguanide
composition comprising less than 18 mol % of terminal amine groups
and 40 mol % or greater of terminal cyanoguanidino groups as
measured by .sup.13C NMR; and 0.005 w/v % to 0.04 w/v % hyaluronic
acid, wherein the weight ratio of hyaluronic acid to the polymeric
biguanide composition in the composition is from 55:1 to 90:1; and
an amphoteric surfactant of general formula I ##STR00015## wherein
R.sup.1 is R or --(CH.sub.2).sub.n--NHC(O)R, wherein R is a
C.sub.8-C.sub.30alkyl optionally substituted with hydroxyl and n is
2, 3 or 4; R.sub.2 and R.sub.3 are each independently selected from
the group consisting of hydrogen and C.sub.1-C.sub.4alkyl; R.sup.4
is a C.sub.2-C.sub.8alkylene optionally substituted with hydroxyl;
and Y is CO.sub.2.sup.- or SO.sub.3.sup.-.
11. The composition of claim 10 wherein the polymeric biguanide
composition comprises less than 15 mol % of terminal amine groups
and 50 mol % or greater of terminal cyanoguanidino groups.
12. The composition of claim 10 wherein the polymeric biguanide
composition comprises from 10 mol % to 30 mol % of terminal
guanidine groups.
13. The composition of claim 10 wherein the hyaluronic acid is
obtained via a fermentation mixture comprising Streptococcus
equi.
14. The composition of claim 10 wherein the hyaluronic acid is
present from 0.01 wt. % to 0.025 wt. %.
15. The use of the composition of claim 10 to clean, disinfect or
package contact lenses, as a preservative in a pharmaceutical
composition that includes a pharmaceutical agent, or as a
preservative in a health care product.
16. A method of cleaning, disinfecting or packaging a contact lens
comprising contacting said contact lens with the ophthalmic
composition of claim 1.
17. A method of cleaning, disinfecting or packaging a contact lens
comprising contacting said contact lens with the ophthalmic
composition of claim 10.
Description
[0001] This application claims priority to U.S. provisional
application No. 60/943,620 filed Jun. 13, 2007 under 35 U.S.C.
.sctn.119(e).
[0002] The present invention relates to an ophthalmic composition
with hyaluronic acid and a biguanide, and to a method of cleaning,
disinfecting or packaging contact lenses with the composition.
BACKGROUND OF THE INVENTION
[0003] Biguanides, including polymeric biguanides, as a class are
known to have antimicrobial activity. Poly(hexamethylene biguanide)
also known as PHMB or PAPB has been used as an antimicrobial
component in many applications including topical disinfectants and
as a preservative in health care products. PHMB is commonly
represented by the following formula, though it is known to exist
as a complex mixture of polymeric biguanides with various terminal
groups including guanidine (not shown).
##STR00001##
The value n represents the number of repeating units of the
biguanide polymer. GB 1434040 describes the use of PHMB and several
other biguanide structures and their effectiveness as antimicrobial
components.
[0004] PHMB has been used in ophthalmic compositions, e.g., in
contact, lens care solutions. Ophthalmic lens care solutions that
contain PHMB represent a significant improvement in patient comfort
and antimicrobial effectiveness compared to most other
antimicrobial components. However, as with any antimicrobial
component there remains a tradeoff between the concentration of the
antimicrobial component in the solution and the comfort experienced
by the patient. Due to its wide commercial acceptance, extensive
efforts have been made to improve the antimicrobial efficacy or the
comfort level to the patient by chemically modifying PHMB. For
example, many derivatives of PHMB have been reported that alter the
length of the alkylene group, place substituents on the alkylene
repeating unit, change the length of the polymer, i.e., molecular
weight or n, or modify the terminal groups.
[0005] EP701821 describes a biguanide derivative having 1 to 500
polymeric repeat units that is formulated with a phosphoric acid
and phosphoric acid salt. EP788797 describes the use of PHMB having
a molecular weight of less than 5000 Da, e.g., 3000 Da to 4000 Da
for treatment of urogenital disease and parasites of the abdominal
cavity.
[0006] U.S. Pat. No. 6,121,327 describes a PHMB derivative in which
the amino terminal groups are replaced by amido groups, RC(O)NH--.
The R group can include alkyls, cycloalkyls, polyethyleneoxides and
polypropyleneoxides. In the case of poly(ethyl)propylene oxides,
the added surfactant character is said to provide good efficacy and
lower toxicity.
[0007] U.S. Pat. No. 5,965,088 describes a PHMB derivative in which
the terminal groups are replaced by a branched or unbranched alkyl,
cycloalkyl, ether or sulfide having four to twelve carbon
atoms.
[0008] Hyaluronic acid is a linear polysaccharide (long-chain
biological polymer) formed by repeating disaccharide units
consisting of D-glucuronic acid and N-acetyl-D-glucosamine linked
by .beta.(1-3) and .beta.(1-4) glycosidic linkages. Hyaluronic acid
is distinguished from the other glycosaminoglycans, as it is free
from covalent links to protein and sulphonic groups. Hyaluronic
acid is ubiquitous in animals, with the highest concentration found
in soft connective tissue. It plays an important role for both
mechanical and transport purposes in the body; e.g., it gives
elasticity to the joints and rigidity to the vertebrate disks, and
it is also an important component of the vitreous body of the
eye.
[0009] Hyaluronic acid, because of its high degree of hydration, is
likely responsible for increasing the resistance of biological
tissues or cells to compression. This is a role based on hyaluronic
acid's capacity to hold more water than any other natural or
synthetic polymer. Also, the viscoelastic properties of hyaluronic
acid, that is, hard elastic under static conditions though less
viscous under small shear forces enables hyaluronic acid to
basically function as a shock absorber for cells and tissues. The
hyaluronic acid properties are dependent on the molecular weight,
the solution concentration, and physiological pH. In low
concentrations, the individual chains entangle and form a
continuous network in solution, which gives the system interesting
properties, such as pronounced viscoelasticity and pseudoplasticity
that is unique for a water-soluble polymer at low
concentration.
[0010] There remains an interest and need for an improved
antimicrobial biguanide composition that offers a greater comfort
level to the patient without sacrificing antimicrobial
efficacy.
SUMMARY OF THE INVENTION
[0011] The invention is directed to an ophthalmic composition
comprising a polymeric biguanide composition having less than 18
mol % of terminal amine groups and 55 mol % or greater of terminal
guanidine groups as measured by .sup.13C NMR, and 0.005 w/v % to
0.04 w/v % hyaluronic acid.
[0012] The invention is also directed to an ophthalmic composition
comprising a polymeric biguanide composition comprising less than
18 mol % of terminal amine groups and 40 mol % or greater of
terminal cyanoguanidino groups as measured by .sup.13C NMR, and
0.005 w/v % to 0.04 w/v % hyaluronic acid.
[0013] The invention is also directed to a method of cleaning,
disinfecting or packaging a contact lens with the ophthalmic
compositions
BRIEF DESCRIPTION OF THE FIGURES
[0014] FIG. 1 is a .sup.13C NMR spectrum of PHMB-CG;
[0015] FIG. 2 shows the assigned peak assignments of a .sup.13C NMR
spectrum of a commercial sample of PHMB; and
[0016] FIG. 3 shows the median comfort profile of an ophthalmic
solution of the invention verses Opti-Free Replenish.RTM., a
commercial solution from Alcon Laboratories, Inc.
DETAILED DESCRIPTION OF THE INVENTION
[0017] PHMB is a mixture of various biguanide polymers that can
include different combinations of terminal groups, e.g., amine,
cyanoguanidino, and guanidine. Based only on these three terminal
groups, at least six possible biguanide polymers can exist. There
can be one biguanide polymer with two terminal amine groups, which
we refer to as PHMB-AA, one with two terminal cyanoguanidino
groups, which we refer to as PHMB-CGCG, and one with two terminal
guanidine groups, which we refer to as and PHMB-GG (see, below).
There are also the three possible biguanide polymers having a
combination of two different terminal groups. Again, based on the
above terminal groups they include amine-cyanoguanidino (PHMB-ACG),
amine-guanidino (PHMB-AG) and guanidine-cyanoguanidino (GCG).
Accordingly, a commercial sample of PHMB will likely comprise a
mixture of polymeric biguanides with the three mentioned terminal
groups though how these terminal groups are arranged on each
polymer and what the molar concentration of each type of terminal
groups is in the mixture provides a relatively complex picture of
the polymeric biguanide composition. Moreover, some of the
composition can include in-chain polymeric guanide (not shown). The
subscript "n" represents the average number of repeating groups,
and a distribution of polymer length exists for each of the
polymers shown below
##STR00002##
[0018] Using .sup.13C NMR we have estimated the molar concentration
of terminal amine groups in commercial PHMB (Cosmocil.RTM.-type
PHMB) to range from 20% to 30%. Similarly, we have estimated the
molar concentration of terminal guanidine groups and terminal
cyanoguanidino groups to range from 38% to 49% and 30% to 32%,
respectively (see, Table 1).
[0019] In contrast, the polymeric biguanide present in the
compositions of the invention are characterized by a relatively low
molar concentration of terminal amine groups than the commercial
samples of PHMB, that is, Cosmocil.RTM. type PHMB. The polymeric
biguanide compositions are also characterized by a relatively high
molar concentration of terminal guanidine groups or terminal
cyanoguanidino groups than the commercial samples of PHMB. At
times, we shall refer to these novel polymeric biguanide
compositions in this patent application as PHMB-CG.
[0020] The ophthalmic compositions of the invention also includes
hyaluronic acid or the corresponding metal salts including, for
example, sodium hyaluronate (the sodium salt), potassium
hyaluronate, zinc hyaluronate, magnesium hyaluronate, and calcium
hyaluronate (hereafter, collectively as hyaluronic acid). It is
well understood by one of ordinary skill in the art that the term
"hyaluronic acid" includes the corresponding metal salts of the
acid form.
[0021] Hyaluronic acid is a natural polymer comprising repeating
disaccharide units (glucuronic acid and N-acetyl glycosamine).
Hyaluronic acid is produced in the body by connective tissue cells
of most animals, and is present in large amounts in such tissues as
the vitreous humor of the eye and the synovial fluids of
joints.
[0022] Hyaluronic acid can be isolated from a variety of natural
sources and is commercially available from various commercial
suppliers. In its natural form, hyaluronic acid has a molecular
weight in the range of 5.times.10.sup.4 up to 1.times.10.sup.7
daltons. Its molecular weight may be reduced via a number of
cutting processes such as exposure to acid, heat (e.g. autoclave,
microwave, dry heat) or ultrasound.
[0023] Alternatively, hyaluronic acid can be prepared by
fermentation of bacteria such as streptococci. The bacteria are
incubated in a sugar rich broth, and the produced hyaluronic acid
is separated from impurities and purified. The molecular weight of
hyaluronic acid produced via fermentation can be set by the sugars
placed in the fermentation broth. Hyaluronic acid produced via
fermentation is commercially available.
PHMB-CG
[0024] In one instance, PHMB-CG comprises less than 18 mol % of
terminal amine groups, and 55 mol % or greater of terminal
guanidine groups as measured by .sup.13C NMR. In another instance,
PHMB-CG comprises less than 15 mol %, or less than 10 mol %, of
terminal amine groups, and 60 mol % or greater, or 65 mol % or
greater, of terminal guanidine groups, as measured by .sup.13C NMR.
The term "measured by .sup.13C NMR" means to relatively quantify
specific carbon peaks associated with each type of terminal group
or in-chain biguanide/guanide for a polymeric biguanide composition
using the pulse technique described in this application under the
subheading Examples.
[0025] Alternatively, PHMB-CG can be described as a polymeric
biguanide composition that comprises 55 mol % to 90 mol % terminal
guanidino groups, 5 mol % to 35 mol % terminal cyanoguanidino
groups and less than 18 mol % terminal amine groups, as measured by
.sup.13C NMR. In another instance, PHMB-CG comprises 60 mol % to 90
mol % terminal guanidino groups, 8 mol % to 25 mol % terminal
cyanoguanidino groups and less than 12 mol % terminal amine groups,
as measured by .sup.13C NMR.
[0026] Alternatively, PHMB-CG can be described as a biguanide
composition that comprises polymeric biguanides of formula (1),
formula (2), formula (3) and optionally formula (4), and has a
molar ratio of
[0027] [mol % formula (1)+mol % formula (2)]:[mol % formula (3)+mol
% formula (4)] from 70:30 or greater, as measured by .sup.13C
NMR
##STR00003##
[0028] and each TG is the same or different and is selected from CG
or G. R.sub.1, R.sub.2 and R.sub.3 are divalent radicals of an
aliphatic hydrocarbon independently selected from the group
consisting of a C.sub.3-C.sub.12 alkylene, C.sub.4-C.sub.12
oxyalkylene and C.sub.4-C.sub.12 thioalkylene. In one embodiment,
R.sub.1, R.sub.2 and R.sub.3 are independently selected from a
C.sub.4-C.sub.8 alkylene. R.sub.4 is selected from the group
consisting of a C.sub.2-C.sub.12 alkylene, C.sub.4-C.sub.12
oxyalkylene and C.sub.4-C.sub.12 thioalkylene, preferably a
C.sub.4-C.sub.12 alkylene. The value n represents a number average
of repeat units between 1 and 20, and the value m is independently
selected for each of formulas (2), (3) and (4) and represents a
number average of repeat units between 1 and 20.
[0029] It is believed that the increase in terminal guanidine
groups results in part from the cleavage of the in-chain biguanide
over time during preparation of the polymeric biguanide
composition. This is supported in-part by the observed decrease of
the in-chain biguanide content as the preparation heating time is
increased from one to four hours at the same temperature.
[0030] Ordinarily, with cleavage of the in-chain biguanide one
should observe a decrease in the number average molecular weight
(M.sub.N) of the biguanide composition. We observe, however, a
slight increase in M.sub.N, which is also dependent upon the
preparation heating time (longer heating times results in higher
M.sub.N). These observations suggest that the preparation may also
involve formation of in-chain biguanide by the reaction of a
terminal amine group of one polymer with a terminal cyanoguanidino
group of another polymer, and thus, resulting in a composition of
slightly higher M.sub.N. In combination, these two processes will
tend to lower the mol % of terminal amine groups and increase the
mol % of terminal guanidine groups.
[0031] In addition, as a result of the two above described
processes, one would expect that on average, polymers of formula
(1) will likely have a lower MN, and consequently, the average
value of n in formula (1) should be lower than the average value of
m in formula (2) or formula (3).
[0032] Alternatively, PHMB-CG can be described as a biguanide
composition that comprises polymeric biguanides of formula (1) and
formula (2)
##STR00004##
[0033] wherein the polymeric biguanides of formula (1) and formula
(2) account for at least 80 mol %, or at least 90 mol %, of the
total moles of polymeric biguanides in the composition, as measured
by .sup.13C NMR, wherein
##STR00005##
[0034] and each TG is the same or different and is selected from CG
or G;
[0035] R.sub.1, R.sub.2 and R.sub.3 are divalent radicals of an
aliphatic hydrocarbon independently selected from the group
consisting of a C.sub.3-C.sub.12 alkylene, C.sub.4-C.sub.12
oxyalkylene and C.sub.4-C.sub.12 thioalkylene;
[0036] R.sub.4 is selected from the group consisting of a
C.sub.2-C.sub.12 alkylene, C.sub.4-C.sub.12 oxyalkylene and
C.sub.4-C.sub.12 thioalkylene, preferably a C.sub.4-C.sub.12
alkylene; and
[0037] n and m represent a number average of repeat units between 1
and 20. Again, for the reasons described above, one can expect the
average value of n in formula (1) should be lower than the average
value of m in formula (2).
[0038] Alternatively, PHMB-CG can be described as a biguanide
composition that comprises less than 18 mol % of terminal amine
groups and 40 mol % or greater of terminal cyanoguanidino groups as
measured by .sup.13C NMR. The polymeric biguanide composition also
is characterized by a relative decrease in the molar concentration
of terminal guanidine groups. This biguanide composition is
prepared by using a similar synthetic route as that of conventional
PHMB, e.g., the preparation of Cosmocil.RTM. type PHMB, with the
exception that one adds from 15% to 40% by weight of a
cyanoguanidino agent, e.g., hexamethylene bis(cyanoguanidino)
(HMBDA), to the reaction mixture.
[0039] In one instance, PHMB-CG comprises less than 15 mol % of
terminal amine groups, and 45 mol % or greater of terminal
cyanoguanidino groups, as measured by .sup.13C NMR. Also, the
biguanide composition will comprise from 10 mol % to 30 mol % of
terminal guanidine groups, as measured by .sup.13C NMR. In another
instance, PHMB-CG comprises 45 mol % to 70 mol % terminal
cyanoguanidino groups, 10 mol % to 30 mol % of terminal guanidine
groups and 7 mol % to 15 mol % terminal amine groups, as measured
by .sup.13C NMR.
[0040] The polymeric biguanide composition with the relatively high
terminal cyanoguanidino groups is typically characterized by
in-chain biguanide concentration of 90 mol % or greater, or 92 mol
% or greater, as measured by .sup.13C NMR, which is similar to, and
typically greater than that observed in commercial PHMB (89 mol %
to 92 mol %). One particular preparation provided an in-chain
biguanide concentration of about 95 mol %.
[0041] Similar to the first described biguanide composition, the
polymeric biguanide composition with high terminal cyanoguanidino
groups can comprise polymeric biguanides of formula (1) and formula
(2)
##STR00006##
[0042] wherein the polymeric biguanides of formula (1) and formula
(2) account for at least 80 mol % of the total moles of polymeric
biguanides in the composition, as measured by .sup.13C NMR,
wherein
##STR00007##
[0043] and each TG is the same or different and is selected from CG
or G;
[0044] R.sub.1, R.sub.2 and R.sub.3 are divalent radicals of an
aliphatic hydrocarbon independently selected from the group
consisting of a C.sub.3-C.sub.12 alkylene, C.sub.4-C.sub.12
oxyalkylene and C.sub.4-C.sub.12 thioalkylene;
[0045] R.sub.4 is selected from the group consisting of a
C.sub.2-C.sub.12 alkylene, C.sub.4-C.sub.12 oxyalkylene and
C.sub.4-C.sub.12 thioalkylene, preferably a C.sub.4-C.sub.12
alkylene; and
[0046] n and m represent a number average of repeat units between 1
and 20.
[0047] The M.sub.N of the biguanide polymers compositions of the
inventions will range from 700 Da to 12,000 Da, from 1000 Da to
8,000 Da, or from 1000 Da to 4000 Da. Accordingly, the average
values of m, n and p, and R.sub.1, R.sub.2 and R.sub.3 are selected
to provide biguanide polymers within this range of average number
molecular weight.
[0048] Any one of the above PHMB-CG compositions can be used as an
antimicrobial component in an ophthalmic composition of the
invention with hyaluronic acid. For example, the ophthalmic
compositions can be used as a component in a contact lens solution
to clean, disinfect or package the lens. Alternatively, the
ophthalmic composition can be as a preservative in a pharmaceutical
formulation that includes a pharmaceutical agent.
[0049] As used herein, the term "ophthalmic composition" defines a
composition intended for application in the eye or intended for
treating a device to be placed in contact with the eye such as a
contact lens. Ophthalmic compositions can include compositions for
direct placement in the eye, including eye drop solutions such as
for treating dry eye, and contact lens treating solutions.
Ophthalmic compositions also include those compositions formulated
as multi-purpose solutions for cleaning and disinfecting contact
lenses or to package contact lens.
[0050] The term "preservative" or "to preserve" refers to the use
of the compositions for the purpose of inhibiting the growth of
microorganisms in a particular product, e.g., in an eye drop
formulation.
Preparation of the PHMB-CG Compositions
[0051] The PHMB-CG biguanide can be prepared from commercially
available polymeric biguanide compositions. For example, PHMB can
be used as a starting material to which is added a cyanoguanidino
agent, guanidine agent or a mixture thereof in the presence of a
mineral acid or an organic acid. The resulting product is
characterized by an increase concentration of guanidine or
cyanoguanidino terminal groups at the expense of the amino terminal
groups. The amount of cyanoguanidino agent or guanidine agent added
will depend upon the desired degree of
cyanoguanidino(guanidine)/amine exchange. Theoretically, to
exchange most, if not all, of the amine terminal groups in a
commercial sample of PHMB, one would add approximately four molar
equivalents of cyanoguanidino agent, guanidine agent or a mixture
thereof for each mole equivalent of PHMB as there are about four
molar equivalents of terminal amine groups for every mole of
PHMB.
[0052] In one embodiment, a reaction mixture is prepared by
grinding together fine particles of a commercial sample of PHMB and
a bis-cyanoguanidino alkane. The ground mixture is added to a
reaction flask along with a small amount of acid, e.g., a mineral
acid or an organic acid, to facilitate the exchange reaction. The
reaction flask is heated to 120.degree. C. or more, e.g., above
140.degree. C. or 150.degree. C., for a period of about one to
about four hours. It is to be understood by one of ordinary skill,
that in general, lower reaction temperatures would require longer
reaction times. The reaction mixture is cooled and the resulting
solids dissolved in a first solvent and then precipitated by the
addition of a second solvent. For example, the first solvent can be
water and the second solvent can be acetone.
[0053] Alternatively, one can use a dicyanamide such as sodium
dicyanamide or zinc dicyanamide as the cyanoguanidino agent. Again,
to theoretically exchange all of the amino terminal groups one
would add about four molar equivalents of the dicyanamide for each
molar equivalent of commercial PHMB. The PHMB and dicyanamide are
added to a reaction vessel and heated. After heating at about
150.degree. C. for about one to about four hours the reaction is
cooled to room temperature under nitrogen overnight. The resulting
solids are dissolved in water and reprecipitated with acetone.
[0054] Dialysis can be used as an alternative approach to remove
reaction impurities and undesired, low molecular weight products
and reactants from the resulting reaction solids. In this case, the
reaction solids are dissolved in water and the solution undergoes
dialysis (100 MWCO tubing) overnight. The resulting product is then
freeze-dried.
[0055] In another embodiment, the polymeric biguanide compositions
can be prepared using a modified synthetic preparation of
commercial PHMB. In this case, approximately, 10 mol % to 50 mol %,
or 20 mol % to 40 mol % (based on the moles of diamine), of the
cyanoguanidino agent, guanidine agent or mixture thereof, is added
to the reaction mixture. A preparation of PHMB is reported in U.S.
Pat. No. 3,428,576 (Examples 1 to 3).
Hyaluronic Acid
[0056] The isolation of hyaluronic acid from rooster combs
typically includes an enzymatic digestion followed by one or more
separation steps to remove proteins and provide a crude extract.
Additional purification steps include precipitation in ethanol and
redissolution in sodium chloride solution. Thus, a typical process
for isolating hyaluronic acid from rooster comb includes removal of
epithelium from the combs, grinding of combs, treatments in acetone
and multiple treatments with ethanol and sodium chloride solutions.
Several U.S. patents describe methods to isolate and purify
hyaluronic acid including U.S. Pat. Nos. 4,141,973; 4,784,990;
5,099,013; 5,166,331; 5,316,926; 5,411,874; 5,559,104 and
5,925,626.
[0057] The hyaluronic acid used to prepare the compositions was
obtained via a fermentation process and commercially supplied from
Shandong Freda Biochem Co. Ltd., China. The hyaluronic acid
produced by fermentation can have several commercial advantages
over hyaluronic acid produced from extraction and purification of
natural sources. Hyaluronic acid obtained from a fermentation
mixture comprising Streptococcus equi is particularly advantageous.
Also, it is advantageous that the hyaluronic acid have a glucuronic
acid content that is greater than 42% by weight.
[0058] The hyaluronic acid is present in the ophthalmic
compositions of the invention over a relatively limited
concentration range from 0.005 wt. % to 0.04 wt. %. In many of the
compositions, the hyaluronic acid concentration is from 0.01 wt. %
to 0.025 wt. %. If the concentration of the hyaluronic acid is
below 0.002 wt. % the commercial advantages of improved patient
comfort is virtually non-existent. If on the other hand, the
hyaluronic acid concentration is too high relative to the amount of
PHMB present, e.g., if the hyaluronic acid concentration is about
0.02 wt. % and the PHMB concentration is about 1 to about 1.3 ppm
(a calculated weight ratio of hyaluronic acid to PHMB of about 150
to 200), one begins to notice a decrease in the biocidal efficacy
of the compositions over time, and in particular, with respect to
the microorganism, C. albicans. In many of the compositions, the
hyaluronic acid concentration is from 0.0075 wt. % to 0.015 wt. %
and the PHMB concentration is from 0.8 ppm to 2.0 ppm, though one
must keep in mind a weight ratio of the two solution components as
explained below.
[0059] The weight ratio of hyaluronic acid to PHMB is critical to
maintaining patient comfort and biocidal efficacy over an extended
period of time at 30.degree. C. If the weight ratio of hyaluronic
acid to PHMB is above 120, one begins to observe a decrease in
biocidal efficacy over time though patient comfort is acceptable.
On the other hand, if the weight ratio hyaluronic acid to PHMB is
below 45, one begins to notice a decrease in patient comfort though
the compositions are able to maintain the requisite biocidal
properties for many months at 30.degree. C. One of the preferred
weight ratios of hyaluronic acid to PHMB is from 55:1 to 90:1.
Still another preferred weight ratio of hyaluronic acid to PHMB is
from 60:1 to 80:1.
PHMB-CG/HA Compositions and the Use Thereof In Antimicrobial
Formulations
[0060] The compositions of the invention can be used for eye drops,
ophthalmic solutions, gels or ointments. In particular, the
compositions can be formulated as an antimicrobial component for an
ophthalmic lens care solution, which can be used to clean,
disinfect or package contact lenses. In this case, the PHMB-CG/HA
compositions will be formulated with a number of other solution
components that provide additional properties required of such
solutions.
[0061] The PHMB-CG/HA compositions can be formulated with other
cationic antimicrobial components. Suitable antimicrobial
components include, but are not limited to, quaternary salts used
in ophthalmic applications such as cetylpyridinium chloride,
.alpha.-[4-tris(2-hydroxyethyl)ammonium
chloride-2-butenyl]poly[1-dimethylammonium
chloride-2-butenyl]-.omega.-tris(2-hydroxyethyl)ammonium chloride
(available as Polyquaternium-1.RTM.). Polyquaternium-42, often
referred to as polixetonium (see, U.S. Pat. No. 5,300,296 is
another polyquaternium of particular interest. Polixetonium is
present in the compositions from 1 ppm to 10 ppm. For example, a
preferred composition will comprise from 0.6 ppm to 1.2 ppm PHMB-CG
and from 1.5 ppm to 4 ppm polixetonium. Other cationic
antimicrobial components include enzalkonium halides, and
biguanides such as salts of alexidine, alexidine-free base, salts
of chlorhexidine, antimicrobial polypeptides and mixtures
thereof.
[0062] Exemplary cationic disinfecting antimicrobial component used
in combination with PHMB-CG is cetylpyridinium chloride or
polyquaternium-1. For example, a preferred composition will
comprise from 0.4 ppm to 1.1 ppm PHMB-CG and from 0.2 ppm to 0.8
ppm cetylpyridinium chloride or from 0.4 ppm to 1.1 ppm PHMB-CG and
from 1 ppm to 3 ppm polyquaternium-1. The term "cationic" when
referring to an antimicrobial component refers to the predominant
form of the antimicrobial component at neutral pH having a positive
charge and a counteranion.
[0063] The lens care solutions will very likely comprise effective
amounts of one or more known lens care formulation components such
as a detergent or surfactant component, a secondary comfort or
wetting agent, a chelating or sequestering component, a buffer or a
tonicity component.
[0064] Suitable surfactants can be either amphoteric or nonionic,
and are typically present (individually or in combination) in
amounts up to about 2% (w/v). The surfactant should be soluble in
the lens care solution and non-irritating to ocular tissues. The
presence of nonionic surfactants comprising one or more chains or
polymeric components having oxyalkylene (--O--R--) repeats units
wherein R has 2 to 6 carbon atoms are common to lens care
solutions. Satisfactory non-ionic surfactants include polyethylene
glycol esters of fatty acids, e.g. coconut, polysorbate,
polyoxyethylene or polyoxypropylene ethers of higher alkanes
(C.sub.12-C.sub.18). Examples of this class include polysorbate 20
(available under the trademark Tween.RTM. 20), polyoxyethylene (23)
lauryl ether (Brij.RTM. 35), polyoxyethyene (40) stearate
(Myrj.RTM.52), polyoxyethylene (25) propylene glycol stearate
(Atlas.RTM. G 2612). Still other preferred surfactants include
tyloxapol, polysulfates, polyethylene glycol, alkyl esters and any
mixture thereof. The foregoing surfactants will generally be
present in a total amount from 0.1% to 2% (w/v), or from 0.1% to
1.0% (w/v). Often the amount of surfactant is from 0.005% or 0.01%,
to 0.1% or 0.5% or 0.8% (w/v).
[0065] A particular non-ionic surfactant consisting of a
poly(oxypropylene)-poly(oxyethylene) adduct of ethylene diamine
having a molecular weight from about 7,500 to about 27,000 wherein
at least 40 weight percent of said adduct is poly(oxyethylene) has
been found to be particularly advantageous for use in cleaning and
conditioning both soft and hard contact lenses when used in amounts
from about 0.05 to about 2.0 wt. %. The CTFA Cosmetic Ingredient
Dictionary's adopted name for this group of surfactants is
poloxamine. Such surfactants are available from BASF Wyandotte
Corp., Wyandotte, Mich., under Tetronic.RTM.. Particularly good
results are obtained with Tetronic.RTM.1107, Tetronic.RTM.1304 and
Tetronic.RTM.904.
[0066] An analogous of series of surfactants, for use in the lens
care compositions, is the poloxamer series which is a
poly(oxyethylene) poly(oxypropylene) block polymers available under
Pluronic.RTM. (commercially available form BASF). In accordance
with one embodiment of a lens care composition the
poly(oxyethylene)-poly(oxypropylene) block copolymers will have
molecular weights from 2500 to 13,000 daltons or from 6000 to about
12,000 daltons. Specific examples of surfactants which are
satisfactory include: poloxamer 108, poloxamer 188, poloxamer 237,
poloxamer 238, poloxamer 288 and poloxamer 407. Particularly good
results are obtained with poloxamer 237.
[0067] The amphoteric surfactants of general formula I are
surface-active compounds with both acidic and alkaline properties.
The amphoteric surfactants of general formula I include a class of
compounds known as betaines. The betaines are characterized by a
fully quaternized nitrogen atom and do not exhibit anionic
properties in alkaline solutions, which means that betaines are
present only as zwitterions at near neutral pH. An amphoteric
surfactant of general formula I
##STR00008##
[0068] wherein R.sup.1 is R or --(CH.sub.2).sub.n--NHC(O)R, wherein
R is a C.sub.8-C.sub.30alkyl optionally substituted with hydroxyl
and n is 2, 3 or 4; R.sup.2 and R.sup.3 are each independently
selected from the group consisting of hydrogen and
C.sub.1-C.sub.4alkyl; R.sup.4 is a C.sub.2-C.sub.8alkylene
optionally substituted with hydroxyl; and Y is CO.sub.2.sup.- or
SO.sub.3.sup.-, can be present in the ophthalmic compositions,
typically from 0.01 wt. % to 2 wt. %. Often the amount of
amphoteric surfactant is from 0.005% or 0.01%, to 0.1% or 0.5% or
0.8% (w/v).
[0069] All betaines are characterized by a fully quaternized
nitrogen. In alkyl betaines, one of the alkyl groups of the
quaternized nitrogen is an alkyl chain with eight to thirty carbon
atoms. One class of betaines is the sulfobetaines or
hydroxysulfobetaines in which the carboxylic group of alkyl betaine
is replaced by sulfonate. In hydroxysulfobetaines a hydroxy-group
is positioned on one of the alkylene carbons that extend from the
quaternized nitrogen to the sulfonate. In alkylamido betaines, an
amide group is inserted as a link between the hydrophobic
C.sub.8-C.sub.30alkyl chain and the quaternized nitrogen.
[0070] In many embodiments, the amphoteric surfactant of general
formula I is a sulfobetaine of general formula II
##STR00009##
[0071] wherein R.sup.1 is a C.sub.8-C.sub.30alkyl; R.sup.2 and
R.sup.3 are each independently selected from a
C.sub.1-C.sub.4alkyl; and R.sup.4 is a C.sub.2-C.sub.8alkylene.
[0072] Certain sulfobetaines of general formula II are more
preferred than others. For example, Zwitergent.RTM.3-10 available
from Calbiochem Company, is a sulfobetaine of general formula I
wherein R.sup.1 is a straight, saturated alkyl with ten (10)
carbons, R.sup.2 and R.sup.3 are each methyl and R.sup.4 is
--CH.sub.2CH.sub.2CH.sub.2-- (three carbons, (3)). Other
sulfobetaines that can be used in the ophthalmic compositions
include the corresponding Zwitergent.RTM.3-08 (R.sup.1 is a is a
straight, saturated alkyl with eight carbons), Zwitergent.RTM.3-12
(R.sup.1 is a is a straight, saturated alkyl with twelve carbons),
Zwitergent.RTM.3-14 (R.sup.1 is a is a straight, saturated alkyl
with fourteen carbons) and Zwitergent.RTM.3-16 (R.sup.1 is a is a
straight, saturated alkyl with sixteen carbons). Accordingly, some
of the more preferred the ophthalmic composition will include a
sulfobetaine of general formula II wherein R.sup.1 is a
C.sub.8-C.sub.16alkyl and R.sup.2 and R.sup.3 is methyl.
[0073] In another embodiment, the amphoteric surfactant of general
formula I is a hydroxysulfobetaine of general formula III
##STR00010##
[0074] wherein R.sup.1 is a C.sub.8-C.sub.30alkyl substituted with
at least one hydroxyl; R.sup.2 and R.sup.3 are each independently
selected from a C.sub.1-C.sub.4alkyl; and R.sup.4 is a
C.sub.2-C.sub.8alkylene substituted with at least one hydroxyl.
[0075] In another embodiment, the amphoteric surfactant is an
alkylamido betaine of general formula IV
##STR00011##
[0076] wherein R.sup.1 is a C.sub.8-C.sub.30alkyl, and m and n are
independently selected from 2, 3, 4 or 5; R.sup.2 and R.sup.3 are
each independently selected from a C.sub.1-C.sub.4alkyl optionally
substituted with hydroxyl; R.sup.4 is a C.sub.2-C.sub.8alkylene
optionally substituted with hydroxyl; and Y is CO.sub.2.sup.- or
SO.sub.3.sup.-. The most common alkylamido betaines are
alkylamidopropyl betaines, e.g., cocoamidopropyl dimethyl betaine
and lauroyl amidopropyl dimethyl betaine.
[0077] In addition to removing contaminants from the lens, the
presence of an amphoteric surfactant of general formula I appears
to counter the interaction between the hyaluronic acid and both
PHMB and polyquaternium-1. The result is a lens care solution that
exhibits exceptional biocidal activity and biocidal stability over
time with minimal or little impact on the observed patient comfort
profile that the hyaluronic acid provides. Accordingly, an
amphoteric surfactant of general formula I is the surfactant of
choice for the ophthalmic compositions.
[0078] The lens care solutions can also include a phosphonic acid,
or its physiologically compatible salt, that is represented by the
following formula:
##STR00012##
[0079] wherein each of a, b, c, and d are independently selected
from integers from 0 to 4, preferably 0 or 1; X.sup.1 is a
phosphonic acid group (i.e., P(OH).sub.2O), hydroxy, amine or
hydrogen; and X.sup.2 and X.sup.3 are independently selected from
the group consisting of halogen, hydroxy, amine, carboxy,
alkylcarbonyl, alkoxycarbonyl, or substituted or unsubstituted
phenyl, and methyl. Exemplary substituents on the phenyl are
halogen, hydroxy, amine, carboxy and/or alkyl groups. A
particularly preferred species is that wherein a, b, c, and d in
are zero, specifically the tetrasodium salt of
1-hydroxyethylidene-1,1-diphosphonic acid, also referred to as
tetrasodium etidronate, commercially available from Monsanto
Company as DeQuest.RTM. 2016 diphosphonic acid sodium salt or
phosphonate.
[0080] The lens care solutions can also include dexpanthenol, which
is an alcohol of pantothenic acid, also called Provitamin B5,
D-pantothenyl alcohol or D-panthenol. In some formulations of the
lens care compositions, dexpanthenol can exhibit good cleansing
action and can stabilize the lachrymal film at the eye surface when
placing a contact lens on the eye. Dexpanthenol is preferably
present in the contact lens care compositions in an amount from
0.2% to 10% (w/v), from 0.5% to 5% (w/v), or from 1% to 3%
(w/v).
[0081] The lens care solutions can also include sorbitol, which is
a hexavalent sugar alcohol. Typically, dexpanthenol is used in
combination with sorbitol. In specific formulations the combination
dexpanthenol and sorbitol can provide enhanced cleansing action and
can also stabilize the lachrymal film following placement of the
contact lens on the eye. These formulations can substantially
improve patient comfort when wearing contact lenses. Sorbitol is
present in the lens care compositions in an amount from 0.4% to 10%
(w/v), from 0.8% to 6% (w/v) or from 1% to 3% (w/v).
[0082] The lens care solutions can also include one or more neutral
or basic amino acids. The neutral amino acids include: the
alkyl-group-containing amino acids such as alanine, glycine,
isoleucine, valine, leucine and proline; hydroxyl-group-containing
amino acids such as serine, threonine and 4-hydroxyproline;
thio-group-containing amino acids such as cysteine, methionine and
asparagine. Examples of the basic amino acid include lysine,
histidine and arginine. The one or more neutral or basic amino
acids are present in the compositions at a total concentration of
from 0.1% to 5% (w/v).
[0083] The lens care solutions can also include glycolic acid,
asparatic acid or any mixture of the two at a total concentration
of from 0.001% to 4% (w/v) or from 0.01% to 2.0% (w/v). In
addition, the combined use of one or more amino acids and glycolic
acid and/or asparatic acid can lead to a reduction in the change of
the size of the contact lens due to swelling and shrinkage
following placement of the lens on the eye. The stated combination
provides a higher degree of compatibility with the contact lens
compared to the absence of one of the two components in the
composition.
[0084] The lens care solutions can also include glycolic acid,
asparatic acid or any mixture of the two, in combination with
2-amino-2-methyl-1,3-propanediol or a salt thereof. In some cases,
solutions that contain a mixture of two of the three, or all three,
compounds minimize the change of the lens size following placement
of the contact lens in the eye. The
2-amino-2-methyl-1,3-propanediol (AMPD) or the salt thereof is
added to the solutions in an amount to satisfy a predetermined
molar ratio of glycolic acid, asparatic acid or any mixture of the
two and AMPD. The molar ratio of the two components glycolic acid
and/or asparatic acid to AMPD is 1:20 to 1.3:1. The glycolic acid,
asparatic acid or any mixture of the two is present in the
compositions at a concentration of 0.01% to 5% (w/v) or at a
concentration of 0.05% to 1% (w/v).
[0085] The contact lens care solutions will very likely include a
buffer system. By the terms "buffer" or "buffer system" is meant a
compound that, usually in combination with at least one other
compound, provides a buffering system in solution that exhibits
buffering capacity, that is, the capacity to neutralize, within
limits, either acids or bases (alkali) with relatively little or no
change in the original pH. Generally, the buffering components are
present from 0.05% to 2.5% (w/v) or from 0.1% to 1.5% (w/v).
[0086] The term "buffering capacity" is defined to mean the
millimoles (mM) of strong acid or base (or respectively, hydrogen
or hydroxide ions) required to change the pH by one unit when added
to one liter (a standard unit) of the buffer solution. The buffer
capacity will depend on the type and concentration of the buffer
components. The buffer capacity is measured from a starting pH of 6
to 8, preferably from 7.4 to 8.4.
[0087] Borate buffers include, for example, boric acid and its
salts, for example, sodium borate or potassium borate. Borate
buffers also include compounds such as potassium tetraborate or
potassium metaborate that produce borate acid or its salt in
solutions. Borate buffers are known for enhancing the efficacy of
certain polymeric biguanides. For example, U.S. Pat. No. 4,758,595
to Ogunbiyi et al. describes that a contact-lens solution
containing a polyaminopropyl biguanide (PAPB), also known as PHMB,
can exhibit enhanced efficacy if combined with a borate buffer.
[0088] A phosphate buffer system preferably includes one or more
monobasic phosphates, dibasic phosphates and the like. Particularly
useful phosphate buffers are those selected from phosphate salts of
alkali and/or alkaline earth metals. Examples of suitable phosphate
buffers include one or more of sodium dibasic phosphate
(Na.sub.2HPO.sub.4), sodium monobasic phosphate (NaH.sub.2PO.sub.4)
and potassium monobasic phosphate (KH.sub.2PO.sub.4). The phosphate
buffer components frequently are used in amounts from 0.01% or to
0.5% (w/v), calculated as phosphate ion.
[0089] Other known buffer compounds can optionally be added to the
lens care compositions, for example, citrates, citric acid, sodium
bicarbonate, TRIS, and the like. Other ingredients in the solution,
while having other functions, may also affect the buffer capacity.
For example, EDTA, often used as a complexing agent, can have a
noticeable effect on the buffer capacity of a solution.
[0090] A preferred buffer system is based upon boric acid/borate or
a combined boric/phosphate buffer system. For example a combined
boric/phosphate buffer system can be formulated from a mixture of
sodium borate and phosphoric acid, or the combination of sodium
borate and the monobasic phosphate.
[0091] In a combined boric/phosphate buffer system, the solution
comprises about 0.05 to 2.5% (w/v)of a phosphoric acid or its salt
and 0.1 to 5.0% (w/v)of boric acid or its salt. The phosphate
buffer is used (in total) at a concentration of 0.004 to 0.2 M
(Molar), preferably 0.04 to 0.1 M. The borate buffer (in total) is
used at a concentration of 0.02 to 0.8 M, preferably 0.07 to 0.2
M.
[0092] Another particular buffer system is based on diglycine.
Diglycine can be used in the composition as the sole buffer system
or in combination with another buffer system. The amount of
diglycine or salts thereof in the composition is from 0.01 wt. % to
2 wt. %, 0.05 wt. % to 2 wt. %, 0.1 wt. % to 2 wt. % or from 0.1
wt. % to 0.5 wt. %.
[0093] The lens care solutions can also include one or more
secondary comfort or wetting agents in addition to the hyaluronic
acid. The secondary comfort agent can enhance and/or prolong the
cleaning and wetting activity of the surfactant component and/or
condition the lens surface rendering it more hydrophilic (less
lipophilic) and/or to act as a demulcent on the eye.
[0094] Suitable secondary comfort or wetting agents include, but
are not limited to, water soluble natural gums, cellulose-derived
polymers and the like. Useful natural gums include guar gum, gum
tragacanth and the like. Useful cellulose-derived comfort
components include cellulose-derived polymers, such as
hydroxypropyl cellulose, hydroxypropylmethyl cellulose,
carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose
and the like. A very useful comfort component is
hydroxypropylmethyl cellulose (HPMC). Some non-cellulose comfort
components include propylene glycol or glycerin. The comfort
components are typically present in the solution from 0.01% to 1%
(w/v).
[0095] One preferred secondary comfort agent that is
polyvinylpyrrolidone (PVP). PVP is a linear homopolymer or
essentially a linear homopolymer comprising at least 90% repeat
units derived from 1-vinyl-2-pyrrolidone monomer, the remainder of
the monomer composition can include neutral monomer, e.g., vinyl or
acrylates. Other synonyms for PVP include povidone, polyvidone,
1-vinyl-2-pyrolidinone, and 1-ethenyl-2-pyrolionone (CAS registry
number 9003-39-8). The PVP will preferably have a weight average
molecular weight from 10,000 to 250,000 or from 30,000 to 100,000.
Such materials are sold by various companies, including ISP
Technologies, Inc. under the trademark PLASDONE.RTM.K-29/32, from
BASF under the trademark KOLLIDON.RTM., for example, KOLLIDON.RTM.
K-30 or K-90. It is also preferred that one use pharmaceutical
grade PVP.
[0096] The lens care solutions can also include one or more
chelating components to assist in the removal of lipid and protein
deposits from the lens surface following daily use. Typically, the
ophthalmic compositions will include relatively low amounts, e.g.,
from 0.005% to 0.05% (w/v) of ethylenediaminetetraacetic acid
(EDTA) or the corresponding metal salts thereof such as the
disodium salt, Na.sub.2EDTA.
[0097] One possible alternative to the chelator Na.sub.2EDTA or a
possible combination with Na.sub.2EDTA, is a disuccinate of formula
IV below or a corresponding salt thereof;
##STR00013##
[0098] wherein R.sub.1 is selected from hydrogen, alkyl or
--C(O)alkyl, the alkyl having one to twelve carbons and optionally
one or more oxygen atoms, A is a methylene group or an oxyalkylene
group, and n is from 2 to 8. In one embodiment, the disuccinate is
S,S-ethylenediamine disuccinate (S,S-EDDS) or a corresponding salt
thereof. One commercial source of S,S-EDDS is represented by
Octaquest.RTM. E30, which is commercially available from Octel. The
chemical structure of the trisodium salt of S,S-EDDS is shown
below. The salts can also include the alkaline earth metals such as
calcium or magnesium. The zinc or silver salt of the disuccinate
can also be used in the ophthalmic compositions.
[0099] Still another class of chelators include alkyl
ethylenediaminetriacetates such as nonayl
ethylenediaminetriacetate. See, U.S. Pat. No. 6,995,123 for a more
complete description of such agents.
[0100] The lens care solutions will typically have an osmolality in
the range of at least about 200 mOsmol/kg for example, about 300 or
about 350 to about 400 mOsmol/kg. The lens care solutions are
substantially isotonic or hypertonic (for example, slightly
hypertonic) and are ophthalmically acceptable. Accordingly, the
lens care solutions will typically include an effective amount of a
tonicity adjusting component. Among the suitable tonicity adjusting
components that can be used are those conventionally used in
contact lens care products such as various inorganic salts. Sodium
chloride and/or potassium chloride and the like are very useful
tonicity components. The amount of tonicity adjusting component is
effective to provide the desired degree of tonicity to the
solution.
[0101] One exemplary ophthalmic composition is formulated as a
contact lens disinfecting solution prepared with the components and
amounts of each listed in Table 1.
TABLE-US-00001 TABLE 1 Preferred Minimum Maximum Amount Component
Amount (wt. %) Amount (wt. %) (wt. %) boric acid 0.10 1.0 0.64
sodium borate 0.01 0.20 0.1 sodium chloride 0.20 0.80 0.49
Zwitergent .RTM. 3-10 0.005 0.5 0.05 hyaluronic acid 0.005 0.015
0.01 Tetronic .RTM. 1107 0.05 2.0 1.00 Na.sub.2EDTA 0.005 0.15 0.03
PHMB-CG 0.2 ppm 3 ppm 1.3 ppm polyquaternium-1 0.5 ppm 5 ppm 1
ppm
[0102] Another contact lens solution according to the present
invention includes the following ingredients listed in Table 2.
TABLE-US-00002 TABLE 2 Preferred Minimum Maximum Amount Component
Amount (wt. %) Amount (wt. %) (wt. %) sorbitol or xylitol 0.5 5 3
poloxamer 407 0.05 1.0 0.10 phosphate monobasic 0.10 0.8 0.46
dexpanthenol 0.01 1.0 0.03 Zwitergent .RTM. 3-10 0.01 0.2 0.05
hyaluronic acid 0.005 0.015 0.01 Na.sub.2EDTA 0.005 0.3 0.1 PHMB-CG
0.2 ppm 2 ppm 1 ppm
[0103] Another contact lens solution according to the present
invention includes the following ingredients listed in Table 3.
TABLE-US-00003 TABLE 3 Preferred Minimum Maximum Amount Component
Amount (wt. %) Amount (wt. %) (wt. %) NaCl/KCl 0.2 1.0 0.50
propylene glycol 0.1 1.0 0.50 poloxamer 237 0.01 0.20 0.05
phosphate monobasic 0.05 0.40 0.10 phosphate dibasic 0.05 0.4 0.12
hyaluronic acid 0.005 0.015 0.008 Na.sub.2EDTA 0.005 0.3 0.1
PHMB-CG 0.2 ppm 2 ppm 1.1 ppm polyquaternium-1 0.5 ppm 5 ppm 1
ppm
[0104] Another contact lens solution according to the present
invention includes the following ingredients listed in Table 4.
TABLE-US-00004 TABLE 4 Preferred Minimum Maximum Amount Component
Amount (wt. %) Amount (wt. %) (wt. %) NaCl/KCl 0.05 0.5 0.10
phosphate monobasic 0.05 0.40 0.12 phosphate dibasic 0.05 0.4 0.21
sorbitol 0.5 2.0 1.0 Tetronic .RTM. 904 0.02 0.5 0.10 Povidone K90
0.05 0.5 0.10 hyaluronic acid 0.005 0.015 0.01 Na.sub.2EDTA 0.005
0.3 0.1 PHMB-CG 0.2 ppm 2 ppm 1 ppm
[0105] As described, the ophthalmic compositions can be used to
clean and disinfect contact lenses. In general, the contact lens
solutions can be used as a daily or every other day care regimen
known in the art as a "no-rub" regimen. This procedure includes
removing the contact lens from the eye, rinsing both sides of the
lens with a few milliliters of solution and placing the lens in a
lens storage case. The lens is then immersed in fresh solution for
at least two hours. The lens is the removed from the case,
optionally rinsed with more solution, and repositioned on the
eye.
[0106] Alternatively, a rub protocol would include each of the
above steps plus the step of adding a few drops of the solution to
each side of the lens, followed by gently rubbing the surface
between ones fingers for approximately 3 to 10 seconds. The lens
can then be, optionally rinsed, and subsequently immersed in the
solution for at least two hours. The lenses are removed from the
lens storage case and repositioned on the eye.
[0107] The formulated contact lens solutions can be used with many
different types of contact lenses including: (1) hard lenses formed
from materials prepared by polymerization of acrylic esters, such
as poly(methyl methacrylate) (PMMA), (2) rigid gas permeable (RGP)
lenses formed from silicone acrylates and fluorosilicone
methacrylates, (3) soft, hydrogel lenses, and (4) non-hydrogel
elastomer lenses.
[0108] As an example, soft hydrogel contact lenses are made of a
hydrogel polymeric material, a hydrogel being defined as a
crosslinked polymeric system containing water in an equilibrium
state. In general, hydrogels exhibit excellent biocompatibility
properties, i.e., the property of being biologically or
biochemically compatible by not producing a toxic, injurious or
immunological response in a living tissue. Representative
conventional hydrogel contact lens materials are made by
polymerizing a monomer mixture comprising at least one hydrophilic
monomer, such as (meth)acrylic acid, 2-hydroxyethyl methacrylate
(HEMA), glyceryl methacrylate, N,N-dimethacrylamide, and
N-vinylpyrrolidone (NVP). In the case of silicone hydrogels, the
monomer mixture from which the copolymer is prepared further
includes a silicone-containing monomer, in addition to the
hydrophilic monomer. Generally, the monomer mixture will also
include a crosslink monomer such as ethylene glycol dimethacrylate,
tetraethylene glycol dimethacrylate, and methacryloxyethyl
vinylcarbonate. Alternatively, either the silicone-containing
monomer or the hydrophilic monomer may function as a crosslink
agent.
[0109] The ophthalmic compositions can also be formulated for use
as a preservative solution or packaging solution for contact
lenses. One of ordinary skill in the art would know how to adjust
the formulation for each of these respective applications. The term
"preservative" or "to preserve" refers to the use of the
compositions for the purpose of inhibiting the growth of
microorganisms in a particular product, e.g., in an eye drop
formulation.
[0110] The ophthalmic compositions can be used as a preservative in
ophthalmic formulations for treating patients with dry eye. In such
a method, the ophthalmic formulation is administered to the
patient's eye, eye lid or to the skin surrounding the patient's
eye. The formulation can be administered to the eyes irrespective
of whether contact lenses are present in the eyes of the patient.
For example, many people suffer from temporary or chronic eye
conditions in which the eye's tear system fails to provide adequate
tear volume or tear film stability necessary to remove irritating
environmental contaminants such as dust, pollen, or the like.
[0111] Alternatively, the ophthalmic compositions can be used as a
preservative in ophthalmic formulations for treating an ocular
disease or ocular condition. In many instances, the ophthalmic
compositions will include one or more active pharmaceutical agents.
Generally, the active pharmaceutical agent is in one or more
classes of ocular pharmaceuticals including, but not limited to
anti-inflammatory agents, antibiotics, immunosuppressive agents,
antiviral agents, antifungal agents, anesthetics and pain killers,
anticancer agents, anti-glaucoma agents, peptide and proteins,
anti-allergy agents.
EXAMPLES
[0112] Hexamethylene bis(cyanoguanidine) (HMBDA) is prepared
according to the method described in U.S. Pat. No. 5,965,088
(Example 1).
.sup.13C NMR Pulse Sequence and Acquisition Parameters
[0113] The resulting polymeric biguanide compositions provided by
the Examples I to 5 above are analyzed by .sup.13C NMR to determine
the molar concentration of terminal end groups in each Example
composition. The special pulse technique used to acquire the
.sup.13C spectra allows one to quantify the relative concentration
of each terminal end group, that is, a guanidine, a cyanoguanidino
or an amine. The .sup.13C NMR data is also used to quantify the
relative concentrations of in-chain biguanide groups and in-chain
guanide. A representative .sup.13C NMR spectrum of one of the
polymeric biguanides of the invention is shown in FIG. 1. As
indicated, the alpha-methylene carbon associated with the terminal
amine group is indicated by peak A, the guanidine carbon associated
with the terminal guanidine group is indicated by peak B and the
guanidine carbon associated with the terminal cyanoguanidino group
is indicated by peak C. Also, the carbon associated with the
in-chain biguanide is indicated by peak D, and the carbon
associated with the in-chain guanide is indicated by peak E.
[0114] The samples for .sup.13C NMR analysis are prepared using 2.2
ml of polymeric biguanide (20 wt %) in water and 0.3 ml D.sub.2O is
added. High-resolution .sup.13C NMR is acquired using a Bruker
AVANCE 300 MHz spectrometer operating at 75.5 MHz for .sup.13C
nuclei. For quantitative analysis, spectra are acquired using
single-pulse excitation with inverse-gated decoupling for
suppression of NOE effects, 1024 transients, and a relaxation delay
that is five times longer than the longest .sup.13C T.sub.1 in the
sample. At 300 MHz, the longest T.sub.1 observed is 9.0 seconds for
the terminal guanidine carbon at .about.157 ppm. A relaxation delay
of 45 seconds is used to acquire quantitative spectra at 300 MHz.
Since T.sub.1's are magnetic field dependent, it will be necessary
to run a relaxation experiment if acquiring at a different field
strength. All spectra are acquired at 300 K using a 10 mm BBO
probe.
Example 1
[0115] PHMB (Cosmocil CG.RTM., 6.0 g, 3.3 mmol), hexamethylene
bis(cyanoguanido) (HMBDA) (0.9 g, 3.6 mmol) and concentrated
hydrochloric acid (360 .mu.L) are added to a reaction flask and
heated to 100.degree. C. until most of the liquid dissipates from
the flask. The temperature of the reaction mixture is then heated
to 155.degree. C. for four hours. The reaction is allowed to cool
overnight to room temperature over a flow of nitrogen. The
resulting solids are dissolved in 50 mL of distilled water and
solution purified by dialysis (100 MWCO tubing) overnight. The
purified product is freeze dried, 4.81 g.
Example 2
[0116] PHMB (Cosmocil.RTM.CQ, 6.0 g, 3.3 mmol), hexamethylene
bis(cyanoguanido) (HMBDA) (1.8 g, 7.2 mmol) and concentrated
hydrochloric acid (720 .mu.L) are added to a reaction flask and
heated to 100.degree. C. until most of the liquid dissipates from
the flask. The temperature of the reaction mixture is then heated
to 155.degree. C. for four hours. The reaction is allowed to cool
overnight to room temperature over a flow of nitrogen. The
resulting solids are dissolved in 60 mL of distilled water and the
solution purified by dialysis (100 MWCO tubing) overnight. The
purified product is freeze dried, 5.3 g.
[0117] Examples 1 and 2 were analyzed by .sup.13C NMR (see, below)
to determine the molar concentration of terminal end groups. The
.sup.13C NMR data for Examples 1 and 2 along with commercial
samples of PHMB are summarized in Table 5.
TABLE-US-00005 TABLE 5 terminal groups in-chain M.sub.n M.sub.n
(mol %) (mol %) Example (GPC) (NMR) amine CG G GG G Cosmocil .RTM.
1568 1419 30.2 31.7 38.0 91.7 8.3 CQ Cosmocil .RTM. 1695 1383 20.8
29.9 49.3 89.6 10.4 100 1 1392 1276 8.4 25.9 65.7 89.4 10.6 2 1089
829 0 11.7 88.3 84.3 15.7
Examples 3A to 3C
[0118] For each of the preparations, PHMB (Cosmocil.RTM.100, 6.0 g,
3.3 mmol) (Cosmocil.RTM.100 is a solid form of PHMB), hexamethylene
bis(cyanoguanido) (HMBDA) (1.8 g, 7.2 mmol) and concentrated
hydrochloric acid (720 .mu.L) are added to a reaction flask and
heated to 100.degree. C. until most of the liquid dissipates from
the flask. The temperature of the reaction mixture is then heated
to 155.degree. C. for four hours. The reaction is allowed to cool
overnight to room temperature over a flow of nitrogen. The
resulting solids are dissolved in 60 mL of distilled water and the
solution purified by dialysis (100 MWCO tubing) overnight. The
purified product is then freeze dried overnight.
[0119] The .sup.13C NMR data for Examples 3A to 3C are summarized
in Table 6.
TABLE-US-00006 TABLE 6 terminal groups in-chain M.sub.n M.sub.n
(mol %) (mol %) Example (GPC) (NMR) amine CG G GG G 3A 1808 1466
9.5 20.0 70.5 86.9 13.1 3B 1758 1460 7.5 23.0 69.5 87.9 12.1 3C
1751 1449 11.5 20.0 68.5 87.2 12.8
Examples 4A to 4D
[0120] For each of the preparations, PHMB (Cosmocil.RTM.100, 6.0 g,
3.3 mmol) (Cosmocil.RTM.100 is a solid form of PHMB), hexamethylene
bis(cyanoguanido) (HMBDA) (1.8 g, 7.2 mmol) and concentrated
hydrochloric acid (720 RL) are added to a reaction flask and heated
to 100.degree. C. until most of the liquid dissipates from the
flask. The temperature of the reaction mixture is then heated to
155.degree. C. for one hour (Example 4A), two hours (Example 4B),
three hours (Example 4C) and four hours (Example 4D). The reaction
is allowed to cool overnight to room temperature over a flow of
nitrogen. The resulting solids are dissolved in 60 mL of distilled
water and the solution purified by dialysis (100 MWCO tubing)
overnight. The purified product is then freeze dried overnight. The
.sup.13C NMR data for Examples 4A to 4D are summarized in Table
7.
TABLE-US-00007 TABLE 7 terminal groups in-chain M.sub.n M.sub.n
(mol %) (mol %) Example (GPC) (NMR) amine CG G GG G 4A 1581 1593
15.4 33.8 50.7 89.6 10.4 4B 1679 1444 13.9 27.9 58.2 89.0 11.0 4C
2036 1515 10.5 32.5 57.0 88.9 11.1 4D 2002 1437 9.5 28.1 62.3 88.5
11.5
Example 5
[0121] An aqueous solution containing sodium dicyanimide (8.9 g),
hexamethylene (11.6 g), HMBDA (8.9 g), 36% hydrochloric acid (19 g)
and water (7.3 g) is prepared with a pH from 6.5 to 7.5. The
solution is heated to 120.degree. C. to remove all of the water.
The reaction vessel is then heated to 150.degree. C. and this
temperature is maintained for four hours. The reaction is cooled
overnight under nitrogen. The resulting solids are dissolved in 60
mL of distilled water and the solution purified by dialysis (100
MWCO tubing) overnight. The purified product is then freeze dried
overnight. A biguanide product comprising less than 18 mol % of
terminal amine groups and 40 mol % and greater of terminal
cyanoguanidino groups is obtained as measured by .sup.13C NMR.
Example 6A
Multipurpose Solution Formulation
[0122] A multipurpose solution were formulated with the components
and amounts listed in Table 8A. A compounding vessel was charged
with 85 to 90 percent of the batch weight in purified water. The
following materials were then added in the order listed: sodium
chloride, edentate disodium, boric acid, sodium borate,
hydroxyalkyl phosphonate (Dequest.RTM. 30%), and Tetronic.RTM. 1107
and the solution stirred for not less than 10 mins. The sodium
hyaluronate was added to the solution at a temperature not less
than 70.degree. C. with stirring, and the solution was stirred for
not less than 20 mins. The pH with was adjusted with 1N NaOH or 1N
HCl if required. The solution was put through a sterilization
cycle: Autoclave, 30-40 min at 121-124.degree. C.; cool batch to
less than 40 .degree. C.
[0123] An appropriate volume of purified water was charged to a
second compounding vessel with a 20% w/w PAPB-CG hydrochloride
solution. The biguanide solution was mixed for not less than 10
mins, and transferred to the main compounding tank through a
sterilizing filter (0.22 .mu.m). An additional amount of water is
added to bring to batch weight, and the final solution stirred for
not less than 15 mins.
TABLE-US-00008 TABLE 8A Component w/w % boric acid 0.64 sodium
borate 0.11 Dequest .RTM. 30% 0.1 Na.sub.2EDTA 0.11 Tetronic .RTM.
1107 1.0 hyaluronic acid Na salt.sup.a 0.02 PHMB-CG (Ex. 5) 0.8 ppm
sodium chloride 0.5 purified water Q.S. to 100% w/w
.sup.aCommercial product from Shandong Freda Biochem Co. Ltd.
Example 6B
[0124] A multipurpose solution is formulated with the components
and amounts listed in Table 8B using the procedure described for
Example 6A with the exception that cetylpyridinium chloride is
added to the second compounding vessel instead of the PHMB.
TABLE-US-00009 TABLE 8B Component w/w % Tris HCl 0.055 Tris base
0.021 Dequest .RTM. 30% 0.1 Na.sub.2EDTA 0.01 Tetronic .RTM. 1107
1.0 hyaluronic acid Na salt.sup.a 0.02 cetylpyridinium chloride 2
ppm propylene glycol 0.3 sodium chloride 0.5 purified water Q.S. to
100% w/w .sup.aCommercial product from Shandong Freda Biochem Co.
Ltd.
Example 6C
[0125] A multipurpose solution is formulated with the components
and amounts listed in Table 8C using the procedure described for
Example 6A with the exception that the cetylpyridinium chloride is
added to the second compounding vessel in combination with
PHMB-CG.
TABLE-US-00010 TABLE 8C Component w/w % boric acid 0.64 sodium
borate 0.11 Dequest .RTM. 30% 0.1 Na.sub.2EDTA 0.05 Tetronic .RTM.
1107 1.0 hyaluronic acid Na salt.sup.a 0.02 cetylpyridinium
chloride 0.6 ppm PHMB-CG (Ex. 5) 0.8 ppm propylene glycol 0.2
sodium chloride 0.5 purified water Q.S. to 100% w/w
.sup.aCommercial product from Shandong Freda Biochem Co. Ltd.
Example 7
Biocidal Efficacy without Organic Soil
[0126] The microbiocidal efficacy of the composition of Example 6A
was evaluated after three (3) months at 25.degree. C. and
40.degree. C. based upon the performance requirement referred to as
the "Stand-Alone Procedure for Disinfecting Products" Protocol
GG120706-3 as set the U.S. Food and Drug Administration, Division
of Ophthalmic Devices. The microorganisms challenged in this
procedure include: Pseudomonas aeruginosa (ATCC 9027),
Staphylococcus aureus (ATCC 6538), Serratia marcescens (ATCC
13880), Candida albicans (ATCC 10231) and Fusarium solani (ATCC
36031). The log reduction of microorganisms determined from this
testing for each formulation are shown in Table 9.
Example 8
[0127] The stand alone biocidal efficacy test described in Example
7 was also conducted in the presence of 10% organic soil and
reported in Table 10.
TABLE-US-00011 TABLE 9 microorganism time, hr 25.degree. C.
40.degree. C. S. Aureus 1 3.0 3.0 2 >4.8 4.4 3 >4.8 >4.8 4
>4.8 >4.8 24 nd nd P. Aeruginosa 1 >4.8 >4.8 2 >4.8
>4.8 3 >4.8 >4.8 4 >4.8 >4.8 24 nd nd S. Marcescens
1 3.9 4.8 2 >4.8 >4.8 3 >4.8 >4.8 4 >4.8 >4.8 24
nd nd C. Albicans 1 2.6 2.1 2 3.2 2.5 3 3.3 2.8 4 3.1 2.8 24 3.9
3.6 F. Solani 1 2.3 1.9 2 2.3 2.1 3 2.8 2.2 4 2.8 2.3 24 4.0
3.1
TABLE-US-00012 TABLE 10 microorganism time, hr 25.degree. C.
40.degree. C. S. Aureus 1 3.5 2.8 2 4.4 >4.8 3 >4.8 >4.8 4
>4.8 >4.8 24 nd nd P. Aeruginosa 1 >4.6 >4.6 2 >4.6
>4.6 3 >4.6 >4.6 4 >4.6 >4.6 24 nd nd S. Marcescens
1 2.2 2.2 2 3.4 3.6 3 4.4 4.5 4 >4.6 >4.6 24 nd nd C.
Albicans 1 1.8 1.6 2 2.5 1.8 3 2.7 2.0 4 2.7 2.1 24 3.5 2.5 F.
Solani 1 2.1 1.8 2 2.6 2.2 3 2.9 2.9 4 3.2 3.2 24 >4.2
>4.2
Example 8
[0128] A three-day, daily wear, dispensing study with twenty-three
(23) patients was conducted to compare the clinical performance of
the ophthalmic composition of Example 6A to Alcon's Opti-Free
Replenish Multi-Purpose Solution, hereafter "Replenish", with
PureVision lenses in contact lens wearers with a history of dry eye
symptomology. The Example 6A solution soaked lenses exhibited
statistically significant better comfort and less dryness at the
in-office visits, and better morning visual quality scores compared
to the Replenish soaked lenses. While the test solution soaked
lenses demonstrated statistically significant less dryness compared
to the control solution soaked lenses, the differences in dryness
scores are not considered to be clinically significant.
[0129] There was also a trend for the Example 6A soaked PureVision
lenses to exhibit better comfort (with the exception of mean
morning comfort on Day 2) compared to Replenish soaked PureVision
lenses. This is particularly seen at the end of Day 1 where the
mean end-of-day comfort scores were 92.9 and 84.6 for the test and
control solution soaked lenses, respectively; this difference is
considered to be clinically significant.
[0130] There were no statistically significant differences noted
between Example 6A and Replenish soaked lenses with respect to
movement, inferior overlap, horizontal decentration, sting/burn,
normalized visual acuity, deposition and wettability, normalized
corneal and conjunctival staining, normalized bulbar and limbal
injection, end-of day visual quality, morning and end-of-day
comfort and lens cleanness, and forced choice preference for
comfort.
Clinical Procedure
[0131] A randomized, double-masked, repeated measures,
contralateral eye study evaluation was conducted. Each well of the
lens cases was pre-treated (a single, 4-hour minimum soak) with
either Example 6A (test solution) or Replenish (control solution).
For each case, the well treated with Example 6 solution was
randomly determined and the opposite well received the Replenish.
All Bausch & Lomb PureVision lenses were pre-treated (4-hour
minimum soak), with either the Example 6A solution or Replenish in
the pre-treated lens cases, following the same randomization used
for the lens case wells.
[0132] Prior to lens insertion, bulbar and limbal injection, and
corneal and conjunctival staining was assessed with the slit lamp.
A spherical refraction was performed, through which high
contrast/high illumination (HCHI), low contrast/high illumination
(LCHI) and high contrast/low illumination (HCLI) visual acuity was
measured. Each patient inserted a pre-treated test/control lens
pair. Sting/burn and dryness were immediately rated. After the
lenses settled, each lens was evaluated for movement, centration,
comfort, wettability and deposition according to methods well
recognized in the art of evaluating contact lens solutioins.
[0133] A forced-choice preference for comfort was made. A spherical
over-refraction was performed, through which LogMAR visual acuity
under all three testing conditions (HCHI, LCHI and HCLI) was
measured. After approximately 2 hours of lens wear, each patient
returned and the above tests were repeated, with the exception that
the refraction and forced-preference for comfort was not repeated.
Lenses were removed, corneal and conjunctival staining, and bulbar
and limbal injection were reassessed, followed by reinsertion of
the lenses.
[0134] Lenses were worn between eight and sixteen hours per day,
for three days. Every evening, just prior to lens removal, patients
recorded their daily wear time; and evaluated comfort, lens
cleanness and visual quality. Patients were instructed to remove
their right lens and thoroughly rinse each side of the lens for 5
seconds with the solution that was assigned for the right eye,
place the contact lens in the lens case and fill with the same
solution. This was repeated for the left lens with the solution
assigned for the left eye. Upon daily lens insertion, patients
evaluated comfort, lens cleanness and visual quality on the
recording forms.
[0135] The patients returned on the fourth day. At the Day 4 (am)
visit, the aforementioned tests were repeated. A forced-choice
preference for comfort was completed. The lenses were stored in
sensitive eyes saline. The 2-way repeated measures ANOVA was used
to test for differences in each of the parametric dependent
variables. Non-parametric data were analyzed using the Wilcoxon
Matched Pairs test. Forced-choice data was assessed using the
chi-square test. Differences at the alpha=0.05 level were
considered statistically significant.
[0136] There was a statistically significant difference for mean
comfort (measured at the in-office visits, ANOVA, p<0.04). The
test solution soaked lenses exhibited better comfort compared to
the control solution soaked lenses with means of 96.2 and 93.26,
respectively (test=96.3 at Insertion, 96.6 at 2 Hours and 95.7 at
Day 4; control=94.2 at Insertion, 94.1 at 2 Hours and 91.5 at Day
4), see FIG. 3.
Example 9
Lens Compatibility Testing
[0137] The ophthalmic compositions also satisfied ISO
Specifications for lens compatibility for several commercial
contact lenses including PureVision.RTM., Soflens 38.RTM.,
Acuvue.RTM., O2Optix.RTM. and Acuvue Advance.RTM.).
* * * * *