U.S. patent application number 10/288637 was filed with the patent office on 2003-05-22 for composition and method for inhibiting uptake of biguanide antimicrobials by hydrogels.
This patent application is currently assigned to Bausch & Lomb Incorporated. Invention is credited to Franklin, Rebecca, Smerbeck, Richard V., Xia, Erning.
Application Number | 20030096717 10/288637 |
Document ID | / |
Family ID | 25462196 |
Filed Date | 2003-05-22 |
United States Patent
Application |
20030096717 |
Kind Code |
A1 |
Xia, Erning ; et
al. |
May 22, 2003 |
Composition and method for inhibiting uptake of biguanide
antimicrobials by hydrogels
Abstract
The invention provides a method for inhibiting the binding of a
biguanide antimicrobial in aqueous solution to a hydrogel in
contact with said solution comprising providing in said solution an
amount of cyclodextrin sufficient to inhibit sorption of the
biguanide antimicrobial to a hydrogel.
Inventors: |
Xia, Erning; (Penfield,
NY) ; Smerbeck, Richard V.; (Pittsford, NY) ;
Franklin, Rebecca; (Webster, NY) |
Correspondence
Address: |
Bausch & Lomb Incorporated
One Bausch & Lomb Place
Rochester
NY
14604-2701
US
|
Assignee: |
Bausch & Lomb
Incorporated
Rochester
NY
|
Family ID: |
25462196 |
Appl. No.: |
10/288637 |
Filed: |
November 5, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10288637 |
Nov 5, 2002 |
|
|
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09932356 |
Aug 17, 2001 |
|
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Current U.S.
Class: |
510/112 |
Current CPC
Class: |
A61L 12/141 20130101;
Y10S 514/84 20130101; Y10S 514/839 20130101; A61L 12/142
20130101 |
Class at
Publication: |
510/112 |
International
Class: |
C11D 001/00 |
Claims
What is claimed:
1. A method for inhibiting the binding of a biguanide antimicrobial
in aqueous solution to a hydrogel in contact with said solution
comprising providing in said solution an amount of cyclodextrin
sufficient to inhibit binding of the biguanide antimicrobial to the
hydrogel.
2. The method of claim 1 wherein the biguanide antimicrobial is
selected from the group consisting of poly(hexamethylene) biguanide
and alexidine.
3. The method of claim 1 wherein said hydrogel is a silicone
hydrogel.
4. The method of claim 1 wherein said solution further comprises at
least one buffer.
5. The method of claim 1 wherein said solution further comprises at
least one chelating agent or sequestering agent.
6. The method of claim 1 wherein said solution further comprises at
least one tonicity adjusting agent.
7. The method of claim 1 wherein said solution further comprises at
least one surfactant.
8. The method of claim 1 wherein said solution comprises at least
one pH adjusting agent.
9. The method of claim 1 wherein said solution comprises at least
one viscosity builder.
10. The method of claim 1 wherein said solution comprises from
about 0.0001 to about 10 weight percent cyclodextrin.
11. The method of claim 10 wherein said solution comprises from
about 0.01 to about 2.0 weight percent cyclodextrin.
12. A composition for rewetting, disinfecting and/or cleaning
contact lenses comprising at least one biguanide antimicrobial and
an amount of cyclodextrin that is insufficient of itself to
effectively clean contact lenses if that amount of cyclodextrin
were present in the solution in the absence of at least one other
cleaning agent.
13. The composition of claim 12 wherein the biguanide antimicrobial
is selected from the group consisting of poly(hexamethylene)
biguanide and alexidine.
14. The method of claim 12 wherein said solution further comprises
at least one buffer.
15. The method of claim 12 wherein said solution further comprises
at least one chelating agent or sequestering agent.
16. The method of claim 12 wherein said solution further comprises
at least one tonicity adjusting agent.
17. The composition of claim 12 wherein said aqueous solution
further comprises buffers, chelating and/or sequestering agents,
tonicity adjusting agents, surfactants, pH adjusting agents and
viscosity builders.
18. The composition of claim 12 wherein said solution comprises
from about 0.0001 to about 10 weight percent cyclodextrin.
19. The composition of claim 18 wherein said solution comprises
from about 0.01 to about 2.0 weight percent cyclodextrin.
20. The composition of claim 12 wherein said amount of cyclodextrin
is at least sufficient to inhibit sorption of a biguanide
antimicrobial to said contact lenses.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is related by disclosure of similar subject
matter to pending application Ser. No. 09/738,808, filed Dec. 15,
2000 (Attorney Docket No. P02389).
FIELD OF THE INVENTION
[0002] This invention relates generally to a composition and method
for storing, preserving and dispensing solutions for cleaning and
disinfecting contact lenses.
BACKGROUND
[0003] Biguanide antimicrobials such as alexidine and PHMB are
widely used as antimicrobials in ophthalmic solutions, for example,
contact lens cleaning, disinfecting and have been commercialized in
various products, typically at levels of about 1 ppm or less for
use with soft contact lenses. It is generally desirable to provide
the lowest possible level of antimicrobial that is consistent with
reliable disinfection in order to provide a generous margin for
safety and comfort.
[0004] U.S. Pat. No. 4,758,595 to Ogunbiyi et al. discloses a
contact-lens solution containing a polyaminopropyl biguanide
(PAPB), also known as polyhexamethylene biguanide (PHMB) in
combination with a borate buffer. These disinfecting and
preservative solutions are especially noteworthy for their broad
spectrum of bactericidal and fungicidal activity at low
concentrations coupled with very low toxicity when used with
soft-type contact lenses.
[0005] Some of the most popular products for disinfecting lenses
are multipurpose solutions that can be used to clean, disinfect and
wet contact lenses, followed by direct insertion (placement on the
eye) without rinsing. Obviously, the ability to use a single
solution for contact-lens care is an advantage. Such a solution,
however, must be particularly gentle to the eye, since, as
indicated above, some of the solution will be on the lens when
inserted and will come into contact with the eye.
[0006] With conventional contact-lens cleaners or disinfectants,
including multi-purpose solutions, lens wearers typically need to
digitally or manually rub the contact lenses (typically between a
finger and palm or between fingers) during treatment of the contact
lenses. The necessity for the daily "rubbing" of contact lenses
adds to the time and effort involved in the daily care of contact
lenses. Many contact-lens wearers dislike having to perform such a
regimen or consider it to be an inconvenience. Some wearers may be
negligent in the proper "rubbing" regimen, which may result in
contact-lens discomfort and other problems. Sometimes rubbing, if
performed too rigorously, which is particularly apt to occur with
beginning lens wearers, may damage the lenses. This can be
problematic when a replacement lens is not immediately
available.
[0007] Contact lens solutions that qualify as a "Chemical
Disinfecting Solution" do not require rubbing to meet biocidal
performance criteria (for destroying representative bacteria and
fungi) set by the US Food and Drug Administration (FDA) under the
Premarket Notification (510k) Guidance Document For Contact Lens
Care Products, May 1, 1997. In contrast, a contact-lens solution,
referred to as a "Chemical Disinfecting System," that does not
qualify as a Chemical Disinfecting Solution, requires a rubbing
regimen to pass biocidal performance criteria. Traditionally,
multi-purpose solutions (used for disinfecting and wetting or for
disinfecting, cleaning, and wetting) have qualified as a Chemical
Disinfecting System, but not as a Chemical Disinfecting
Solution.
[0008] A Chemical Disinfecting Solution would generally require a
more efficacious or stronger disinfectant than a Chemical
Disinfecting System. The stronger the biocidal effect of a
solution, however, the more likely that it may exhibit toxic
effects or adversely effect lens-wearer comfort. For example, many
very efficacious bactericides used in other contexts, such as
mouthwashes, cosmetics, or shampoos, while being sufficiently safe
for use in such products, would be too toxic for ophthalmic use,
especially for use with soft lenses because of the above-mentioned
tendency of soft lenses to bind chemicals and the sensitivity of
eye tissues. Similarly, the concentrations of certain bactericides
may need to be within lower limits in solutions for use with soft
contact lenses than in other products or in solutions for other
types of lenses, especially when such solutions are not rinsed from
the contact lens before placing the lens in the eye.
[0009] It would be desirable to obtain a contact-lens solution that
would simultaneously provide both (1) an increased level and/or
broader spectrum of biocidal activity, and (2) a low order of
toxicity to eye tissue, such that the solution can be used to treat
a contact lens such that the lens can subsequently be placed on the
eye without rinsing the solution from the lens. While challenging
to develop, it would be especially desirable to obtain a Chemical
Disinfecting Solution that could be used for soft contact lenses
and that would allow direct placement of a contact lens on an eye
following soaking in the solution and/or rinsing and rewetting with
the solution. Such a product may provide increased efficacy,
resulting in greater protection to the lens wearer against
infection caused by microorganisms, while providing maximum
convenience. Finally, it would be desirable for the biocidal
efficacy of the disinfecting solution to be sufficiently high to
achieve the efficacious disinfection, or at least not inherently
inefficacious disinfection, of a contact lens with respect to
bacteria and fungi in the event, for whatever reason, that the
contact lens wearer does not carry out a regimen involving
mechanical rubbing or the like using the contact-lens solution.
SUMMARY OF THE INVENTION
[0010] The invention provides, in a first aspect, a method and
composition for inhibiting the binding of a biguanide antimicrobial
in aqueous solution to a hydrogel in contact with said solution
comprising providing in said solution an amount of cyclodextrin
sufficient to inhibit binding of the biguanide antimicrobial to the
hydrogel. The composition of the invention may comprise additional
components, for example, at least one selected from the group
consisting of buffers, sequestering and/or chelating agents,
tonicity adjusting agents, surfactants, pH adjusting agents and
viscosity builders.
[0011] The invention also provides a method and composition for
cleaning contact lenses is provided comprising contacting the
lenses with a composition containing an effective amount of one or
more biguanide antimicrobials and from 0.0001% to about 10% by
weight of one or more cyclodextrins for a time sufficient to clean
the lenses. In a preferred embodiment, the composition is a
multipurpose contact lens solution for cleaning and disinfecting
contact lenses, and contains other components such as including
buffers, chelating and/or sequestering agents, tonicity adjusting
agents, surfactants, pH adjusting agents and viscosity
builders.
[0012] The invention still further provides a composition for
rewetting, disinfecting and/or cleaning hydrogel contact lenses
comprising at least one biguanide antimicrobial and an amount of
cyclodextrin that is:
[0013] (a) insufficient of itself to effectively clean contact
lenses if that amount of cyclodextrin were present in the solution
in the absence of at least one other cleaning agent; and
[0014] (b) at least sufficient to inhibit the sorption of a
biguanide antimicrobial to the hydrogel contact lenses.
[0015] In a preferred embodiment, the composition comprises a
biguanide antimicrobial selected from the group consisting of
poly(hexamethylene) biguanide and alexidine. The composition
preferably comprises at least one buffer at least one chelating
agent or sequestering agent. The composition may suitably comprise
at least one tonicity-adjusting agent, as well as surfactants, pH
adjusting agents and viscosity builders.
DESCRIPTION OF THE INVENTION
[0016] The composition of the present invention is, in one
embodiment, an aqueous biguanide-containing solution disinfecting
solution, for example, a multipurpose contact lens solution. The
composition of the invention contains one or more cyclodextrins
together with one or more biguanide antimicrobials in a suitable
carrier. Other active or inactive components can also be employed
in the compositions, including buffers, chelating and/or
sequestering agents, tonicity adjusting agents, surfactants, pH
adjusting agents and viscosity builders.
[0017] The cyclodextrins useful in the present invention are cyclic
oligosaccharides that may be produced by the enzymatic degradation
of starch and have multiple glucose or glucopyranose units, usually
6 to 8 units. Depending on the particular preparation reaction
conditions employed, cyclodextrins generally contain six, seven or
eight of such units, connected by alpha-(1,4) bonds. The six, seven
or eight unit cyclodextrins are commonly known as alpha-, beta-,
and gamma-cyclodextrins, respectively.
[0018] Cyclodextrins have the shape of truncated cones with primary
and secondary hydroxyl groups located at opposite ends of the
torus. The glucosyl-o-bridges point into the center of the molecule
and the primary hydrogel groups project from one outer edge while
the secondary hydroxyl groups project from the other edge. The
result is a molecule with a relatively hydrophobic center and a
hydrophilic outer surface. These shapes and hydrophilic/hydrophobic
domains provide for inclusion or incorporation of guest molecules
into the center of the molecule.
[0019] Cyclodextrins are well known and are commercially produced
by the enzymatic degradation of starch. For example,
beta-cyclodextrin is the major product of the reaction between the
enzyme cyclodextrin transglycosylase and a starch solution
pretreated with gamma-amylase.
[0020] As used herein, the term "cyclodextrins" includes all
cyclodextrin derivatives, such as cyclodextrin carbonates, ethers,
esters, and polyethers; polymers or copolymers of polymerized
cyclodextrins, such as polymerized beta-cyclodextrins; and
substituted cyclodextrins such as those with functional groups
bonded to one or more of the hydroxyl groups. Suitable function
groups include, but are not limited to, methyl, ethyl,
hydroxyethyl, and hydroxypropyl and acetyl groups. The cyclodextrin
derivatives can also include cyclodextrins with functional groups
replacing one or more of the hydroxyl groups such as
amino-cyclodextrin, iodo-cyclodextrin and cyclodextrin sulfate.
Some of these functional groups may also contribute preserving or
disinfecting properties.
[0021] The preferred cyclodextrins are the beta-cyclodextrins and
most preferred are beta-cyclodextrin selected from
beta-cyclodextrin, hydroxypropyl beta-cyclodextrin, methyl
beta-cyclodextrin and hydroxyethyl beta-cyclodextrin when the
cyclodextrin compositions are employed at elevated
temperatures.
[0022] The present invention employs an effective amount of
cyclodextrin to inhibit the sorption of the biguanide by hydrogels,
especially hydrogels suitable for fabricating contact lenses. The
term "effective amount of cyclodextrin" as used herein means an
amount of cyclodextrin sufficient to inhibit the sorption of the
biguanide antimicrobial present in solution to the hydrogel. The
amount of cyclodextrin may also vary with the required contact time
between the hydrogel and the solution. For example, if the solution
is a multipurpose solution for cleaning and disinfecting hydrogel
contact lenses, the amount of cyclodextrin present in the
multipurpose solution is preferably at least sufficient to inhibit
the sorption of the biguanide antimicrobial.
[0023] In addition to multipurpose solutions, the invention is
useful with ophthalmic solutions generally, including moisturizing
eye drops and rewetting solutions, merely to name two examples.
[0024] The biguanide disinfectant is suitably present in
concentration of from about 0.5 to about 10 ppm, preferably from
about 1 to about 4 ppm. The cyclodextrin is suitably present in
concentration of from about 0.1 to about 1.0 weight percent,
preferably from about 0.2 to about 0.4 weight percent.
[0025] Hydrogels comprise hydrated, crosslinked polymeric systems
containing water in an equilibrium state. Conventional hydrogel
lens materials include polymers containing monomers such as
2-hydroxyethyl methacrylate (HEMA), glyceryl methacrylate,
N-vinylpyrrolidone (NVP) and dimethacrylamide.
[0026] Flexible ophthalmic lens materials useful in the present
invention include silicone hydrogels as well as conventional
hydrogels and low-water elastomeric materials. Examples of flexible
ophthalmic lens materials useful in the present invention are
taught in U.S. Pat. Nos. 5,908,906 to Kunzler et al.; 5,714,557 to
Kunzler et al.; 5,710,302 to Kunzler et al.; 5,708,094 to Lai et
al.; 5,616,757 to Bambury et al.; 5,610,252 to Bambury et al.;
5,512,205 to Lai; 5,449,729 to Lai; 5,387,662 to Kunzler et al. and
5,310,779 to Lai; which patents are incorporated by reference as if
set forth at length herein.
[0027] U.S. Pat. Nos. 6,037,328, 6,008,317, 5,981,675, 5,981,669,
5,969,076, 5,945,465, 5,914,355, 5,858,937, 5,824,719 and 5,726,733
teach ophthalmic lens materials containing HEMA monomers.
[0028] U.S. Pat. Nos. 6,071,439, 5,824,719, 5,726,733, 5,708,094,
5,610,204, 5,298,533, 5,270,418, 5,236,969 and 5,006,622 teach
ophthalmic lens materials containing glyceryl methacrylate
monomers.
[0029] U.S. Pat. Nos. 6,008,317, 5,969,076, 5,908,906, 5,824,719,
5,726,733, 5,714,557, 5,710,302, 5,708,094, 5,648,515 and 5,639,908
teach ophthalmic lens materials containing NVP monomers.
[0030] U.S. Pat. Nos. 5,539,016, 5,512,205, 5,449,729, 5,387,662,
5,321,108 and 5,310,779 teach ophthalmic lens materials containing
dimethacrylamide monomers.
[0031] The preferred conventional hydrogel materials typically
contain HEMA, NVP and TBE (4-t-butyl-2-hydroxycyclohexyl
methacrylate). Polymacon.TM. materials, for example the Soflens
66.TM. brand contact lenses (commercially available from Bausch
& Lomb Incorporated of Rochester, N.Y.) are examples of
particularly preferred conventional hydrogel materials.
[0032] Silicone hydrogels generally have a water content greater
than about five weight percent and more commonly between about ten
to about eighty weight percent. Materials are usually prepared by
polymerizing a mixture containing at least one silicone-containing
monomer and at least one hydrophilic monomer. Either the
silicone-containing monomer or the hydrophilic monomer may function
as a crosslinking agent (a crosslinker being defined as a monomer
having multiple polymerizable functionalities) or a separate
crosslinker may be employed. Applicable silicone-containing
monomeric units for use in the formation of silicone hydrogels are
well known in the art and numerous examples are provided in U.S.
Pat. Nos. 4,136,250; 4,153,641; 4,740,533; 5,034,461; 5,070,215;
5,260,000; 5,310,779; and 5,358,995.
[0033] A preferred silicone hydrogel material comprises (in the
bulk monomer mixture that is copolymerized) 5 to 50 percent,
preferably 10 to 25, by weight of one or more silicone
macromonomers, 5 to 75 percent, preferably 30 to 60 percent, by
weight of one or more polysiloxanylalkyl (meth)acrylic monomers,
and 10 to 50 percent, preferably 20 to 40 percent, by weight of a
hydrophilic monomer. In general, the silicone macromonomer is a
poly(organosiloxane) capped with an unsaturated group at two or
more ends of the molecule. In addition to the end groups in the
above structural formulas, U.S. Pat. No. 4,153,641 to Deichert et
al. discloses additional unsaturated groups, including acryloxy or
methacryloxy. Fumarate-containing materials such as those taught in
U.S. Pat. Nos. 5,512,205; 5,449,729; and 5,310,779 to Lai are also
useful substrates in accordance with the invention. Preferably, the
silane macromonomer is a silicon-containing vinyl carbonate or
vinyl carbamate or a polyurethane-polysiloxane having one or more
hard-soft-hard blocks and end-capped with a hydrophilic
monomer.
[0034] Suitable hydrophilic monomers include those monomers that,
once polymerized, can form a complex with poly(acrylic acid). The
suitable monomers form hydrogels useful in the present invention
and include, for example, monomers that form complexes with
poly(acrylic acid) and its derivatives. Examples of useful monomers
include amides such as N,N-dimethyl acrylamide, N,N-dimethyl
methacrylamide, cyclic lactams such as N-vinyl-2-pyrrolidone and
poly(alkene glycol)s functionalized with polymerizable groups.
Examples of useful functionalized poly(alkene glycol)s include
poly(diethylene glycol)s of varying chain length containing
monomethacrylate or dimethacrylate end caps. In a preferred
embodiment, the poly(alkene glycol) polymer contains at least two
alkene glycol monomeric units. Still further examples are the
hydrophilic vinyl carbonate or vinyl carbamate monomers disclosed
in U.S. Pat. No. 5,070,215, and the hydrophilic oxazolone monomers
disclosed in U.S. Pat. No. 4,910,277. Other suitable hydrophilic
monomers will be apparent to one skilled in the art. In a
particularly preferred embodiment, the hydrophilic monomers used in
the contact lens material are capable of forming a stable complex
with a cationic polysaccharide.
[0035] Rigid ophthalmic lens materials include rigid-gas-permeable
("RGP") materials. RGP materials typically comprise a hydrophobic
crosslinked polymer system containing less than 5 wt. % water. RGP
materials useful in accordance with the present invention include
those materials taught in U.S. Pat. Nos. 4,826,936 to Ellis;
4,463,149 to Ellis; 4,604,479 to Ellis; 4,686,267 to Ellis et al.;
4,826,936 to Ellis; 4,996,275 to Ellis et al.; 5,032,658 to Baron
et al.; 5,070,215 to Bambury et al.; 5,177,165 to Valint et al.;
5,177,168 to Baron et al.; 5,219,965 to Valint et al.; 5,336,797 to
McGee and Valint; 5,358,995 to Lai et al.; 5,364,918 to Valint et
al.; 5,610,252 to Bambury et al.; 5,708,094 to Lai et al; and
5,981,669 to Valint et al. U.S. Pat. No. 5,346,976 to Ellis et al.
teaches a preferred method of making an RGP material. The patents
mentioned above are incorporated by reference as if set forth at
length herein.
[0036] The cyclodextrin concentrations useful herein may be
adjusted by one of ordinary skill in the art depending upon the
desired contact time between the biguanide-containing solution and
the poly(ethylene).
[0037] The cyclodextrin composition may contain a preserving or
disinfecting amount of one or more antimicrobial agents in addition
to the biguanide antimicrobial. The subject solution preferably
includes at least one antimicrobial agent. As used herein,
antimicrobial agents are defined as non-oxidative organic chemicals
that derive their antimicrobial activity through a chemical or
physiochemical interaction with the microbial organisms. Preferred
antimicrobials are the quaternary ammonium compounds and
biguanides.
[0038] Representative examples of the quaternary ammonium compounds
are compositions comprised of benzalkonium halides or, for example,
balanced mixtures of n-alkyl dimethyl benzyl ammonium chlorides.
Other examples include polymeric quaternary ammonium salts used in
ophthalmic applications such as
poly[(dimethyliminio)-2-butene-1,4-diyl chloride],
[4-tris(2-hydroxyethyl) ammonio]-2-butenyl-w-[tris
(2-hydroxyethyl)ammonio]dichloride (chemical registry number
75345-27-6) generally available as Polyquaternium 1.RTM. from ONYX
Corporation.
[0039] Representative biguanides are the bis(biguanides), such as
alexidine or chlorhexidine or salts thereof, and polymeric
biguanides such as polymeric hexamethylene biguanides (PHMB).
[0040] Polymeric hexamethylene biguanides (commercially available
from Zeneca, Wilmington, Del.), their polymers and water-soluble
salts being most preferred. Generally, the hexamethylene biguanide
polymers, also referred to as polyaminopropyl biguanide (PAPB),
have molecular weights of up to about 100,000. Such compounds are
known and are disclosed in U.S. Pat. No. 4,758,595 which patent is
incorporated herein be reference.
[0041] A disinfecting amount of antimicrobial agent is an amount
that will at least partially reduce the microorganism population in
the formulations employed. Preferably, a disinfecting amount is
that which will reduce the microbial burden by two log orders in
four hours and more preferably by one log order in one hour. Most
preferably, a disinfecting amount is an amount which will eliminate
the microbial burden on a contact lens when used in regimen for the
recommended soaking time (FDA Chemical Disinfection Efficacy
Test--July, 1985 Contact Lens Solution Draft Guidelines).
Typically, such agents are present in concentrations ranging from
about 0.00001 to about 0.5% (w/v), and more preferably, from about
0.00003 to about 0.5% (w/v).
[0042] A second disinfectant/germicide can be employed as a
solution preservative, but it may also function to potentiate,
compliment or broaden the spectrum of microbiocidal activity of
another germicide. This includes microbiocidally effective amounts
of germicides which are compatible with and do not precipitate in
the solution, in concentrations ranging from about 0.00001 to about
0.5 weight percent, and more preferably, from about 0.0001 to about
0.1 weight percent. Suitable complementary germicidal agents
include, but are not limited to thimerosal or other phenylmercuric
salts, sorbic acid, alkyl triethanolamines, and mixtures
thereof.
[0043] The acid-addition salts of the germicides used in the
present composition may be derived from an inorganic or organic
acid. In most circumstances it is preferable that the salts be
derived from an acid which is readily water-soluble and which
affords an anion which is suitable for human usage, for example a
pharmaceutically acceptable anion. Examples of such acids are
hydrochloric, hydrobromic, phosphoric, sulphuric, acetic,
D-gluconic, 2-pyrrolidino-5-carboxylic, methanesulphonic, carbonic,
lactic and glutamic acids. The hydrochloride salt is preferred.
[0044] In the present application, the amount of the germicide or
other components in a solution according to the present invention
refers to the amount formulated and introduced into the solution at
the time the solution is made.
[0045] Suitable chemical antimicrobial agents, as the term is used
herein, include quaternary ammonium salts and polymers used in
ophthalmic applications such as
poly[(dimethyliminio)-2-butene-1,4-diyl chloride],
[4-tris(2-hydroxyethyl) ammonio]-2-butenyl-W-[tris (2-hydroxyethyl)
ammonio]dichloride (chemical registry number 75345-27-6),
commercially available from ONYX Corporation; halides;
trialkylammonium halides; biguanides such as salts of alexidine,
alexidine free base, salts of chlorhexidine, hexamethylene
biguanides and their polymers; and the like. The salts of alexidine
and chlorhexidine can be either organic or inorganic and are
typically gluconates, nitrates, acetates, phosphates, sulfates,
halides and the like.
[0046] Suitable oxidative antimicrobial agents, as the term is used
herein, include any peroxide sources which produce active oxygen in
solution and any iodine liberating sources which produce preserving
or disinfecting amounts of iodine compounds in solution. Examples
of such agents include hydrogen peroxide and its alkali metal
salts; alkali metal perborates and persulfates; alkali metal
carbonate peroxide; diperisophthalic acid; peroxydiphosphate salts;
sodium aluminium aminohydroperoxide; iodine and iodophors.
Preferred oxidative antimicrobial agents are peroxides and
iodophors. The antimicrobial agents can also be employed after the
cleaning step using the cyclodextrin composition. In this
application, the cleaning step would be followed with a
disinfecting step in a conventional regimen.
[0047] A preserving amount of an antimicrobial agent is an amount
that will substantially inhibit the microorganism population from
growing while a disinfecting amount is an amount that will reduce
the microorganism population. Preferably, a preserving amount of
antimicrobial agent will substantially inhibit the microorganism
population growth for at least thirty (30) days after exposure to
environmental air. Preferably, a disinfecting amount of an
antimicrobial agent is that which will reduce the microbial burden
by about two log orders in four hours and, more preferably, by
about one log order in one hour. Typically, such agents are present
in concentrations ranging from about 0.00001% to about 0.5% (w/v),
and more preferably, from about 0.00003% to about 0.05% (w/v).
[0048] The pH of the present solutions should be maintained within
the range of 5.0 to 8.0, more preferably about 6.0 to 8.0, most
preferably about 6.5 to 7.8, suitable buffers may be added, such as
boric acid, sodium borate, potassium citrate, citric acid, sodium
bicarbonate, TRIS, and various mixed phosphate buffers (including
combinations of Na.sub.2HPO.sub.4, NaH.sub.2PO.sub.4 and
KH.sub.2PO.sub.4) and mixtures thereof. Borate buffers are
preferred, particularly for enhancing the efficacy of
biguanides.
[0049] Generally, buffers will be used in amounts ranging from
about 0.05 to 2.5 percent by weight, and preferably, from 0.1 to
1.5 percent. The disinfecting/preserving solutions of this
invention preferably contain a borate or mixed phosphate buffer,
containing one or more of boric acid, sodium borate, potassium
tetraborate, potassium metaborate or mixtures of the same. In one
embodiment, the solution of the invention may include a buffering
system having a buffering capacity up to 40 ml of 0.01N HCl to
change pH from pH 7.4 to 6.4 and up to 25 ml of 0.01 N NaOH to
change pH from pH 7.4 to 8.4 and comprising 0.05.about.2.5% by
weight of phosphate salt and 0.1.about.5.0% by weight of boric
acid. The composition optionally further comprises an alkali or
alkaline earth metal carbonates including sodium bicarbonate,
sodium carbonate, potassium carbonate, potassium bicarbonate, and
sodium bicarbonate. The most preferred carbonate is sodium
carbonate.
[0050] If a carbonate buffer is used, it is suitably present in the
amount of a buffering system having a buffering capacity up to 40
ml of 0.01 NHCl to change pH from pH 7.4 to 6.4 and up to 25 ml of
0.01.about.NaOH to change pH from pH 7.4 to 8.4 and comprising
0.05.about.2.5% by weight of phosphate salt and 0.1.about.5.0% by
weight of boric acid.
[0051] The composition of the present invention may optionally
includes a phosphonic acid, or its physiologically compatible salt,
that is represented by the following Formula (I): 1
[0052] wherein Z is a connecting radical equal in valence to n,
wherein n is an integer from 1 to 6, preferably 1 to 3.
[0053] If the solution contains a phosphonic acid buffer, the
phosphonic acid buffer is suitably present in a concentration of at
least 0.003 percent weight by volume of the subject phosphonic
compound in the total solution, preferably 0.005 to 2.5 percent
weight by volume and more preferably about 0.01 to 0.5 percent
weight by volume in the total solution.
[0054] In a preferred embodiment, the solution comprises both a
phosphate buffer and a borate buffer.
[0055] In addition to buffering agents, in some instances it may be
desirable to include chelating and/or sequestering agents in the
present solutions in order to bind metal ions which might otherwise
react with the lens and/or protein deposits and collect on the
lens. Dequest 2016 and its salts (disodium) are preferred examples.
They are usually added in amounts ranging from about 0.01 to about
0.3 weight percent. Other suitable sequestering agents include
gluconic acid, citric acid, tartaric acid (EDTA) and their salts,
e.g. sodium salts.
[0056] Typically, the aqueous solutions of the present invention
for treating contact lenses are also adjusted with tonicity agents,
to approximate the osmotic pressure of normal lacrimal fluids which
is equivalent to a 0.9 percent solution of sodium chloride or 2.5
percent of glycerol solution. The solutions are made substantially
isotonic with physiological saline used alone or in combination,
otherwise if simply blended with sterile water and made hypotonic
or made hypertonic the lenses will lose their desirable optical
parameters. Correspondingly, excess saline may result in the
formation of a hypertonic solution that will cause stinging and eye
irritation.
[0057] Examples of suitable tonicity adjusting agents include, but
are not limited to: sodium and potassium chloride, dextrose,
glycerin, calcium and magnesium chloride. These agents are
typically used individually in amounts ranging from about 0.01 to
2.5% (w/v) and preferably, form about 0.2 to about 1.5% (w/v).
Preferably, the tonicity agent will be employed in an amount to
provide a final osmotic value of 200 to 450 mOsm/kg and more
preferably between about 250 to about 350 mOsm/kg, and most
preferably between about 280 to about 320 mOsm/Kg.
[0058] The present solution comprises at least one surfactant.
Suitable surfactants can be either amphoteric, cationic, anionic,
or nonionic which may be present (individually or in combination)
in amounts up to 15 percent, preferably up to 5 percent weight by
volume (w/v) of the total composition (solution). Preferred
surfactants are amphoteric or nonionic surfactants, which when used
impart cleaning and conditioning properties. The surfactant should
be soluble in the eye care solution and non-irritating to eye
tissues. Many nonionic surfactants comprise one or more chains or
polymeric components having oxyalkylene (--O--R--) repeats units
wherein R has 2 to 6 carbon atoms. Preferred non-ionic surfactants
comprise block polymers of two or more different kinds of
oxyalkylene repeat units, which ratio of different repeat units
determines the HLB of the surfactant. 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 the preferred 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). One non-ionic
surfactant in particular 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 0.01 to about 15 weight percent. 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 the registered trademark "Tetronic".
An analogous of series of surfactants, suitable for use in the
present invention, is the poloxamer series which is a
poly(oxyethylene) poly(oxypropylene) block polymers available under
the trademark "Pluronic" (commercially available form BASF).
[0059] Various other ionic as well as amphoteric and anionic
surfactants suitable for in the invention can be readily
ascertained, in view of the foregoing description, from
McCutcheon's Detergents and Emulsifiers, North American Edition,
McCutcheon Division, MC Publishing Co., Glen Rock, N.J. 07452 and
the CTFA International Cosmetic Ingredient Handbook, Published by
The Cosmetic, Toiletry, and Fragrance Association, Washington,
D.C.
[0060] Amphoteric surfactants suitable for use in a composition
according to the present invention include materials of the type
are offered commercially under the trade name "Miranol." Another
useful class of amphoteric surfactants is exemplified by
cocoamidopropyl betaine, commercially available from various
sources.
[0061] The foregoing surfactants will generally be present in a
total amount from 0.01 to 5.0 percent weight by volume (w/v),
preferably 0.1 to 5.0 percent, and most preferably 0.1 to 1.5
percent.
[0062] It may also be desirable to include water-soluble viscosity
builders in the solutions of the present invention. Because of
their demulcent effect, viscosity builders have a tendency to
enhance the lens wearer's comfort by means of a film on the lens
surface cushioning impact against the eye. Included among the
water-soluble viscosity builders are the cellulose polymers like
hydroxyethyl or hydroxypropyl cellulose, carboxymethyl cellulose
and the like. Such viscosity builders may be employed in amounts
ranging from about 0.01 to about 4.0 weight percent or less. The
present solutions may also include optional demulcents.
[0063] In a first embodiment of a method according to the present
invention, the method comprises cleaning a contact lens with an
aqueous solution comprising 0.005 to 1.0 percent by weight of at
least one phosphonic acid compound, or its physiologically
compatible salt, having 1 to 12, preferably 1 to 10 carbon atoms.
The carbon atoms may be in the form of a substituted or
unsubstituted branched or unbranched aliphatic, cyclic aliphatic,
or aromatic groups or combinations thereof. Exemplary phosphonic
acid compounds are those according to Formula (I) above. Preferably
the phosphonic acid compound has 1 or 2 phosphonic acid groups
which may be in salt form.
[0064] Preferably, the present method comprises soaking (no
rubbing) a lens in the solution for a total period of time that is
within a range of 2 hours to overnight, prior to direct placement
of the lens in the eye. By the term "direct placement" is herein
meant that the solution is not diluted or rinsed off the lens with
a different contact-lens solution prior to "insertion" or placement
on the eye.
[0065] In yet another embodiment of a method according to the
present invention, the claimed solution may be used to clean a
frequent replacement lens (FRL) that is planned for replacement
after not more than about three months of use in the eye, or that
is planned for replacement after not more than about 30 days of use
in the eye, or that is planned for replacement after not more than
about two weeks in the eye. Preferably, the lens is made from a
polymer comprising about 0.0 to 5 mole percent repeat units derived
from methacrylic acid (MAA), 10 to 99 mole percent of repeat units
derived from hydroxyethyl methacrylate, and about 0.5 to 5 mole
percent of cross-linking repeat units. Cross-linking repeat units
may be derived, for example, from such monomers as ethyleneglycol
dimethacrylate, divinylbenzene, and trimethylpropane
trimethacrylate.
[0066] Separately from, or supplementally to, immersing a contact
lens in a contact lens solution according to the present invention
while the contact lens is outside the eye, the accumulation of
proteins on hydrophilic contact lens can be further prevented by
applying such a solution as eye drops. Thus, an opthalmologically
safe solution comprising the claimed compound can be packaged in a
container adapted for applying the solution as drops to the
eye.
[0067] The hydroxypropyl methylcellulose (HPMC) functions to
provide a desired level of viscosity and to provide demulcent
activity. It is characterized as a mixed ether of cellulose
containing a variable proportion of methoxyl and 2-hydroxypropoxyl
groups and is purchased from Dow Chemical under the trademark
Methocel E 15 LV-Premium. It is to be understood that the invention
is not limited to any specific hydroxypropyl methylcellulose and
that any equivalent HPMC of pharmaceutical grade may be used.
[0068] The ophthalmic solutions of this invention preferably
contain a buffer system to control pH. Any pharmaceutically
acceptable buffer system may be utilized. A preferred buffer system
is provided by sodium borate/boric acid in amounts necessary to
produce a pH of about 6.0 to 8.0. A preferred pH range is about
6.5-7.8 and a most preferred range is about 7.1-7.5.
[0069] The ophthalmic solutions of this invention are isotonic with
respect to the fluids of the human eye. These solutions are
characterized by osmolalities of 270-330 mOsm/kg. Osmolality of the
solution of the invention is adjusted by means of sodium chloride
and potassium chloride.
[0070] The solutions of the present invention may be formulated
into specific contact lens care products, such as wetting
solutions, soaking solutions, cleaning and conditioning solutions,
as well as purpose type lens care solutions, etc. and mixtures
thereof.
[0071] The solutions according to the present invention are
physiologically compatible. Specifically, the solution must be
"ophthalmically safe" for use with a contact lens, meaning that a
contact lens treated with the solution is generally suitable and
safe for direct placement on the eye without rinsing, that is, the
solution is safe and comfortable for daily contact with the eye via
a contact lens that has been wetted with the solution. An
ophthalmically safe solution has a tonicity and pH that is
compatible with the eye and comprises materials, and amounts
thereof, that are non-cytotoxic according to ISO standards and U.S.
FDA (Food & Drug Administration) regulations. The solution
should be sterile in that the absence of microbial contaminants in
the product prior to release must be statistically demonstrated to
the degree necessary for such products.
[0072] The present invention can be used with all contact lenses
such as conventional hard, soft, rigid and soft gas permeable, and
silicone (including both hydrogel and non-hydrogel) lenses, but is
preferably employed with soft lenses. Such lenses are commonly
prepared from monomers such as hydroxyethyl methacrylate,
hydroxyethylmethyl methacrylate, vinylpyrrolidone,
glycerolmethacrylate, methacrylic acid or acid esters and the like.
Such lenses absorb significant amounts of water, which amounts
range from about 4 to about 80 percent by weight. Preferably, the
invention is formulated as a "multipurpose solution," meaning that
the solution may be used for cleaning, chemical disinfection,
storing, and rinsing a contact lens. Such solutions may be part of
a "multipurpose solution system" or "multipurpose solution
package." The procedure for using a multi-purpose solution, system
or package is referred to as a "multi-functional disinfection
regimen." Multi-purpose solutions do not exclude the possibility
that some wearers, for example, wearers particularly sensitive to
chemical disinfectants or other chemical agents, may prefer to
rinse or wet a contact lens with another solution, for example, a
sterile saline solution prior to insertion of the lens. The term
"multipurpose solution" also does not exclude the possibility of
periodic cleaners not used on a daily basis or supplemental
cleaners for removing proteins, for example enzyme cleaners, which
are typically used on a weekly basis. By the term "cleaning" is
meant that the solution contains one or more cleaning agents in
sufficient concentrations to loosen and remove loosely held lens
deposits and other contaminants on the surface of a contact lens,
especially if used in conjunction with digital manipulation (for
example, manual rubbing of the lens with a solution) or with an
accessory device that agitates the solution in contact with the
lens, for example, a mechanical cleaning aid. The critical micelle
concentration of a surfactant-containing solution is one way to
evaluate its cleaning effectiveness.
[0073] A multipurpose solution preferably has a viscosity of less
than 75 cps, preferably 1 to 50 cps, and most preferably 1 to 25
cps and is preferably is at least 95 percent weight by volume water
in the total composition.
[0074] As stated, the multipurpose solution of the invention is
useful for cleaning contact lenses. Although the multipurpose
solution effectively cleans and disinfects by simply soaking a lens
in the subject solution, the multipurpose solution cleans more
effectively if a few drops of the solution are initially placed on
each side of the lens, and the lens is rubbed for a period of time,
for example, approximately 20 seconds. The lens can then be
subsequently immersed within several milliliters of the subject
solution. Preferably, the lens is permitted to soak in the solution
for at least four hours. Furthermore, the lens is preferably rinsed
with fresh solution after the rubbing step and again after being
immersed within the solution. If the subject solution includes an
antimicrobial agent, the subject solution not only cleans the lens,
but also disinfects. However, it will be appreciated that other
"non-chemical" disinfection means may be used, e.g. heat
disinfection.
[0075] Although not generally necessary, enzymatic cleaners may
also be used with the multipurpose contact lens solutions of the
invention, especially for patients susceptible to high levels of
protein deposition. If used, enzymatic tablets may be placed
directly within the subject solution, is a manner like that
described in U.S. Pat. No. 5,096,607.
EXAMPLES
[0076] The following examples evaluate whether the addition of
cyclodextrin reduced the sorption of the biguanide Alexidine on
SureVue.RTM. brand hydrogel contact lenses (commercially available
from Johnson & Johnson Vision Care Incorporated of
Jacksonville, Fla.).
1TABLE 1 Formulation Ingredients % W/W Sodium Chloride 0.45% Sodium
Borate 0.09% Boric Acid 0.85% Alexidine HCl 2-10 ppm
Beta-Cyclodextrin 0.1-0.3% Purified Water Qs = 1000 ml
[0077] Materials
[0078] Alexidine Solution (2-10 ppm)
[0079] Alexidine/0.1% .beta.-Cyclodextrin Solution
[0080] Alexidine/0.3% .beta.-Cyclodextrin Solution
[0081] 15 SureVue.RTM. Lenses
[0082] 8 Standard Lens Cases
[0083] Methods
[0084] 1. Eighty-five gm of water was added into a beaker.
[0085] 2. Sodium chloride, sodium borate, boric acid and
beta-cyclodextrin were added and the mixture was stirred until each
ingredient dissolved.
[0086] 3. Then Alexidine HCl was added into the above mixture and
mixed for more than five hours.
[0087] 4. The final mixture was brought to 100 gm of total weight
by adding purified water. The final solution has a pH of 7.0 and
osmolality of 294 mOsm/kg.
[0088] 5. 3-mL of each test solution, as well as the control
solution, were placed into the lens cases for a total of 5 samples
per solution.
[0089] 6. SureVue.RTM. lenses were placed into each lens well
aseptically.
[0090] 7. Each lens was "dipped" into double-distilled water for
approximately 2 seconds prior to installation into the lens
cases.
[0091] 8. Lenses were allowed to soak for approximately 18 hours
(overnight).
[0092] 9. 1-mL of solution from each of the lens wells was removed,
analyzed and returned to the lens cases.
2TABLE 2 Effect of Beta-Cyclodextrin on the uptake of Alexidine by
SureVue .RTM. Lenses Uptake of Alexidine by Uptake of Alexidine by
Uptake of Alexidine SureVue .RTM. Lenses SureVue .RTM. Lenses By
SureVue .RTM. (0.1% Beta- (0.3% Beta- Lenses Cyclodextrin)
Cyclodextrin) 75.26 ppm 62.10 ppm 31.04 ppm 17.50% Inhibition
58.75% Inhibition
[0093]
3TABLE 3 ISO Stand Alone Microbiology Test Alexidine Alexidine
Solution Solution with Beta-Cyclodextrin Fill Volume 15 ml 15 ml
Bottle Size 15 ml 15 ml Test Disposition Pass Pass Staphylococcus
10 minutes >4.7 2.5 aureus 1 hour >4.7 4.3 2 hours >4.7
>4.7 4 hours >4.7 >4.7 Pseudomonas 10 minutes >4.6 3.6
aeruginasa 1 hour >4.6 >4.6 2 hours >4.6 >4.6 4 hours
>4.6 >4.6 Serratia marcescens 10 minutes 2.3 3.6 1 hour 4.6
>4.6 2 hours >4.6 >4.6 4 hours >4.6 >4.6 Candida
albicans 10 minutes 2.8 1.4 1 hour 3.5 3.0 2 hours 4.6 4.3 4 hours
>4.6 >4.6 24 Hours >4.6 >4.6 Fusarium solani 10 minutes
2.9 3.0 1 hour 3.8 3.7 2 hours 3.7 4.1 4 hours 4.0 4.1 24 hours
>4.1 >4.1
* * * * *