(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property
`Organization
`International Bureau
`
`11111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111
`
`( 43) International Publication Date
`20 October 2005 (20.10.2005)
`
`PCT
`
`(10) International Publication Number
`WO 2005/097067 Al
`
`(51) International Patent Classification7: A61K 9/00,47/02
`
`(21) International Application Number:
`PCT/US2005/009742
`
`MG, MK, MN, MW, MX, MZ, NA, NI, NO, NZ, OM, PG,
`PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL, SM, SY, TJ,
`TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, YU, ZA,
`ZM, ZW.
`
`(22) International Filing Date: 24 March 2005 (24.03.2005)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`10/812,543
`
`29 March 2004 (29.03.2004) US
`
`(71) Applicant (for all designated States except US): BAUSCH
`& LOMB INCORPORATED [US/US]; One Bausch &
`Lomb Place, Rochester, NY 14604-2701 (US).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): XIA, Erning
`[US/US]; 93 Chippenham Drive, Penfield, NY 14526
`(US). SALAMONE, Joseph, C. [US/US]; 8 Woodcliff
`Terrace, Fairport, NY 14450 (US). BORAZJANI, Roya,
`N. [US/US]; 36 Woodcliff Terrace, Fairport, NY 14450
`(US).
`
`(74) Agents: LAVOIE, Paul, T. et a!.; Bausch & Lomb In(cid:173)
`corporated, One Bausch & Lomb Place, Rochester, NY
`14604-2701 (US).
`
`(84) Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, Fl,
`FR, GB, GR, HU, IE, IS, IT, LT, LU, MC, NL, PL, PT, RO,
`SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN,
`GQ, GW, ML, MR, NE, SN, TD, TG).
`
`Declaration under Rule 4.17:
`as to the identity of the inventor (Rule 4.17(i)) for the fol(cid:173)
`lowing designations AE, AG, AL, AM, AT, AU, AZ, BA, BB,
`BG, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE,
`DK, DM, DZ, EC, EE, EG, ES, Fl, GB, GD, GE, GH, GM,
`HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK,
`LR, LS, LT, LV, LV, MA, MD, MG, MK, MN, MW, MX, MZ,
`NA, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RU, SC, SD,
`SE, SG, SK, SL, SM, SY, TJ, TM, TN, TR, TT, TZ, VA, UG,
`UZ, VC, VN, YU, ZA, ZM, ZW, ARIPO patent (BW, GH,
`GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, ZW),
`Eurasian patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European patent (AT, BE, BG, CH, CY, CZ, DE, DK, EE,
`ES, Fl, FR, GB, GR, HU, IE, IS, IT, LT, LV, MC, NL, PL,
`PT, RO, SE, Sf, SK, TR), OAPI patent ( BF, BJ, CF, CG, CI,
`CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG)
`
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN,
`CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, Fl,
`GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE,
`KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD,
`
`Published:
`with international search report
`
`For two-letter codes and other abbreviations, refer to the "Guid(cid:173)
`ance Notes on Codes and Abbreviations" appearing at the begin(cid:173)
`ning of each regular issue of the PCT Gazette.
`
`---iiiiiiii
`
`iiiiiiii
`iiiiiiii
`!!!!!!!!
`
`iiiiiiii
`
`!!!!!!!! --!!!!!!!!
`
`iiiiiiii --
`
`!!!!!!!!
`iiiiiiii
`
`iiiiiiii ----
`,..-.! <
`
`t--(cid:173)
`\0
`0
`t--(cid:173)
`O\
`0
`' - -----------------------------------------------------------------------------------------
`~ (54) Title: ZINC PRESERVATNE COI'vrPOSITION AND METHOD OF USE
`0
`M
`0 than a preservative-effective amount of a primary preservative agent--preferably no primary preservative agent. In one aspect of the
`> present invention, there is a method of enhancing an ophthalmic composition, process for making a composition and a method of
`
`(57) Abstract: The present invention is a composition comprising a preservative-effective amount of a zinc compound and less
`
`~ treating a patient using one or more compositions according to the present invention.
`
`

`
`wo 2005/097067
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`PCT /US2005/0097 42
`
`ZINC PRESERVATIVE COMPOSITION AND METHOD OF USE
`
`FIELD OF THE INVENTION
`
`The present invention relates to the methods and/or compositions, particularly
`
`ophthalmic compositions such as eye drop and contact lens treating solutions.
`
`BACKGROUND
`
`The contact of eye tissue with bacteria may lead to various eye infections, such as
`
`microbial keratitis. The contact of eye tissue with bacteria may result when an
`
`ophthalmic solution contaminated with bacteria is instilled directly in the eye. Examples
`
`of such ophthalmic solutions instilled directly in the eye are eye drop solutions (for
`
`example, for treating dry eye) or contact lens drop solutions (for example, for
`
`conditioning a contact lens while worn). Additionally, eye tissue may be contacted with
`
`bacteria by placing a contact lens on the eye where the contact lens is contaminated with
`
`bacteria. The risk of eye infection is increased when bacteria is adhered to a contact lens,
`
`since the bacteria may remain in contact with eye tissue for a prolonged period of time.
`
`For this reason, ophthalmic compositions, such as eye drop and contact lens
`
`treating solutions, conventionally include a preservative agent that acts to inhibit growth
`
`of bacteria and/or fungi, as well as other infectious organisms, in case the solution
`
`becomes contaminated with such organisms. For contact lens treating solutions, the
`
`preservative agents used to preserve the solution may also serve to disinfect contact
`
`lenses when rinsed or soaked with the solution. Alternately, ophthalmic compositions
`
`may include no preservative, but in such cases, the compositions are packaged in a
`
`special container that prevents contamination of the container contents, an example being
`
`single unjt-dose packages where each dosage of solution is separately packaged.
`
`Various preservative agents are lmown for use in ophthalmic compositions. Such
`
`preservative agents should have a broad spectrum of preservative activity and be non(cid:173)
`
`irritating to the eye. However, many preservative agents have a tendency to irritate eye
`
`tissue, especially at higher concentrations. Therefore, it is generally advantageous to
`
`employ as low as possible concentration of preservative agent to avoid the risk of eye
`
`irritation.
`
`

`
`wo 2005/097067
`
`PCT /US2005/0097 42
`
`U.S. Patent Nos. 6,323,165 and 6,274,133 disclose compositions and methods for
`
`blocking protein and/or lipid deposits on hydrophilic contact lenses with polyquatemium
`
`polymers or cationic cellulose polymers that bind to lenses and block the deposits from
`
`binding.
`
`U.S. Patent No. 4,443,429 discloses the use in a contact lens disinfecting solution
`
`of a dimethyldiallylammonium chloride homopolymer commercially known as
`
`Merquat™ 100 (i.e., which has a molecular weight of about 10,000 to about 1 ,000,000).
`
`Preferred disinfecting solution concentrations were recited therein as 0.0004 wt.% to
`
`about 0.02 wt.% (4 ppm to 200 ppm).
`
`WO 02/34308 discloses inhibiting adhesion ofbacteria to the surface of a
`
`biomedical device, such as a contact lens, by binding a cationic polysaccharide to the
`
`surface of the device.
`
`Pending U.S. Ser. Nos. 10/427,056 filed April30, 2003, and 10/427,084 filed
`
`April30, 2003, disclose the use ofpolycations such as Polymer JR (Polyquatemium-10)
`
`as a preservative-enhancing additive. Polymer JR was less of an initant than traditional
`
`preservatives but enhanced the perfonnance of the traditional preservative. U.S. Patent
`
`No. 5,460,834 discloses a physiological tear composition that may contain a zinc
`
`compound at a concentration having a minimum of about 0.005 and/or a maximum of
`
`about 0.015 mmol/L in addition to other salts known to be present in tears.
`
`U.S. Patent No. 2,230, 748 discloses an impregnating solution that prevents rot
`
`fungus in textiles or other organic materials. The impregnating solution includes sugar
`
`or sachcariferous substances. Soluble salts of zinc and copper are disclosed as
`
`ingredients in the solution.
`
`A National Eye Institute Study entitled, NEI Study: Antioxidants and Zinc May
`
`Reduce AMD Risk, Review of Optometry, pp. 138-49, volume 6(1) (November 15,
`
`200 1 ), concluded that high levels of antioxidants and zinc was believed to significantly
`
`reduce the risk of advanced age related macular degeneration. Zinc was administered
`
`orally in the study.
`
`2
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`

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`PCT /US2005/0097 42
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`Grahn, B.H. et al., Zinc and the Eye, Journal of the American College of
`
`Nutrition, vol. 20 (2) pp. 106-118 (April2001) indicated that zinc played an important
`
`role in maintaining normal ocular function. Zinc was administered orally to patients.
`
`It would be desirable to provide an ophthalmic composition with enhanced
`
`preservative efficacy that is safe, convenient and economical to use and non-irritating to
`
`eye tissue. The present invention addresses these and other problems encountered in the
`
`art.
`
`SUMMARY OF THE INVENTION
`
`The present invention relates to a composition that includes a preservative(cid:173)
`
`effective amount of a soluble zinc compound and has less than a preservative-effective
`
`amount of a primary preservative agent, preferably no primary preservative agent. The
`
`composition has the benefit of being adequately preserved without having a harsh
`
`physiological effect such as irritation or discomfort caused by at least some traditional
`
`preservative agents. The present invention relates to processes for manufacture, methods
`
`of enhancing compositions, and methods of use of the composition related to the above
`
`composition.
`
`According to another embodiment, the composition further comprises a
`
`polycationic material including but not limited to a cationic cellulosic Polymer such as,
`
`for example, Polymer JR.
`
`According to one embodiment, the composition is an ophthalmic solution that
`
`optionally includes at least one component selected :from the group consisting of tonicity
`
`adjusting agents, buffering agents, chelating agents, pH adjusting agents, viscosity
`
`modifying agents, and therapeutic agents.
`
`In one embodiment, the composition is an eye drop solution. In another
`
`embodiment, the composition is a contact lens treating solution. Typically, the
`
`composition is suitable for direct instillation in the eye without irritation to eye tissue.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`The present invention relates to a composition that includes a preservative(cid:173)
`
`effective amount of a soluble zinc compound and has less than a preservative-effective
`3
`
`

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`wo 2005/097067
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`PCT /US2005/0097 42
`
`amount of a primary preservative agent, preferably no primary preservative agent. The
`
`composition has the benefit of being adequately preserved without having a harsh
`
`physiological effect such as irritation or discomfort caused by at least some traditional
`
`preservative agents. Likewise in another embodiment, there is an ophthalmic
`
`composition comprising a preservative-effective amount of a zinc compound. The
`
`ophthalmic composition comprises a less than a preservative-effective amount of a
`
`primary antimicrobial compound-preferably no primmy preservative agent.
`
`The term "preservative" or like terms denotes agents included in the ophthalmic
`
`compositions for the purpose of inhibiting the growth of microorganisms in the product,
`
`thereby helping to maintain sterility of the composition. The tenn "preservative agent"
`
`denotes the specific active agent, which provides the preservative efficacy. As
`
`mentioned, the composition has less than a preservative-effective amount of a primary
`
`preservative agent. Primary preservative agents are defined as non-zinc containing
`
`compounds that derive their preservative activity through a chemical or physiochemical
`
`interaction with the microbial organisms.
`
`A "preservative-effective amount" is defined as an amount sufficient to reduce
`
`the cell population by three log orders of the five following microorganisms,
`
`Staphylococcus aureus, Pseudomonas aeruginosa, Eschreclzia coli, Candida albicans
`
`and Aspergillus niger. The phrase, "a preservative-effective amount," as it pertains to an
`
`amount of a primary preservative agent in a subject composition containing zinc, is
`
`defined as the amount of the primary preservative agent that would be required to reduce
`
`the cell population by three log orders of the five following microorganisms,
`
`Staphylococcus aureus, Pseudomonas aeruginosa, Eschrechia coli, Candida albicans,
`
`and Aspergillus niger in a comparative composition that is the same as the subject
`
`composition except that all zinc containing compounds are removed from the
`
`comparative compound.
`
`The term "soluble amount" as it pertains to a zinc compound is defined as an
`
`amount of a zinc compound that either dissolves completely in the composition or
`
`exceeds the saturation level by an amount that is not noticeable to the patient when the
`
`composition is applied to the patient's eye. Preferably, the zinc compound is completely
`
`dissolved.
`
`4
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`

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`PCT /US2005/0097 42
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`According to this invention, there is one embodiment where the zinc compound is
`
`in the +2 valence state. In another embodiment, the composition has a minimum of
`
`about 0.001 wt.%, about 0.005 wt.%, about 0.01 wt.% or about 0.05 wt.% of a zinc
`
`compound per total weight of the composition and/or a maximum of about 1 wt.%, about
`
`0.5 wt.%, about 0.1 wt.% or about 0.05 wt.% of the zinc compound per total weight of
`
`the composition. In one embodiment, the zinc compound is selected from the group
`
`comprising zinc citrate, zinc chloride, zinc acetate, zinc bromide, zinc fluoride, zinc
`
`iodide, zinc ammonium sulfate, zinc nitrate and zinc sulfate. Preferably, the zinc
`
`compound is selected from the group comprising zinc citrate and zinc chloride in one
`
`embodiment. Zinc citrate and zinc chloride can be obtained from Sigma-Aldrich
`
`Chemical Company, St. Louis, Missouri.
`
`In one embodiment, the method further comprises adding a polycationic material.
`
`The compositions of the present invention include a polycationic material. The term
`
`"polycation" material denotes a material having multiple cationic moieties, such as
`
`quaternary ammonium groups, in the same molecule.
`
`Many of the polycationic materials, by themselves, do not have sufficient
`
`preservative efficacy to adequately preserve an ophthalmic composition against a broad
`
`spectrum of microorganisms but can enhance preservative efficacy when used in
`
`conjunction with a soluble zinc compound. Illustrative polycationic materials include
`
`cationic polysaccharides, cationic proteins, cationic polynucleotides, cationic
`
`glycoproteins, cationic glycosaminoglycans and ionene polymers, having multiple
`
`cationic molecules in the same molecule.
`
`In general, polyquaternium polymers suitable for use in the present invention are
`
`a well-known class of polymers of which many valiations are commercially available.
`
`The polyquaternium polymer preferably includes an ophthalmologically suitable anionic
`
`organic or inorganic counterion. A preferred countelion may include, but are not limited
`
`to fluolide ions, chloride ions, bromide ions, iodide ions and the like.
`
`For example, the polyquaterniums designated Polyquaternium-1 through
`
`Polyquatemium-44 (CTF A International Cosmetic Ingredient Dictionary) includes a
`
`number of materials that are useful, based on the present teachings, in the present
`
`invention. The polymerization techniques for the preparation of such materials are
`
`5
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`PCT /US2005/0097 42
`
`similarly well known to those skilled in the art and many variations of such techniques
`
`are similarly in practice in commerce.
`
`In general, the polyquatemium polymers suitable for use in the present invention
`
`have a weight average molecular weight is a minimum of about 500 Daltons, about 1000
`
`Daltons or about 2000 Daltons and/or a maximum of about 5,000,000 Daltons, about
`
`500,000 Daltons or about 200,000 Daltons. One preferred class ofpolycationic materials
`
`is cationic polysaccharides, and especially, cationic cellulosic polymers. Specific
`
`examples of cationic cellulosic polymers include but are not limited to cellulosic
`
`polymers containing N,N-dimethylaminoethyl groups (either protonated or quatemized)
`
`and/or N,N-dimethylamino-2-hydroxylpropyl groups (either protonated or quatemized).
`
`Cationic cellulosic polymers are commercially available or can be prepared by methods
`
`known in the art. As an example, quatematy nitrogen-containing ethoxylated glucosides
`
`is prepared by reacting hydroxyethyl cellulose with a trimethylammonium-substituted
`
`epoxide, according to one embodiment.
`
`In another embodiment, the composition has a minimum of about 0.001 wt.%,
`
`about 0.005 wt.%, about 0.01 wt.% and 0.05 wt.% and/or a maximum of about 0.5 wt.%
`
`about 0.1 wt.% or about 0.05 wt.% cationic cellulose polymer based upon the total
`
`weight of the composition.
`
`Various preferred cationic cellulosic polymers are commercially available, for
`
`example water-soluble polymers available under the CTF A (Cosmetic, Toiletry, and
`
`Fragrance Association) designation Polyquatemium-10 (hereinafter defined as Polymer
`
`JR). Such polymers are commercially available under the tradename UCARE® Polymer
`
`from Amerchol Corp., Edison, N.J., USA. These polymers contain quatemized N,N(cid:173)
`
`dimethylamino groups along the cellulosic polymer chain. Suitable cationic cellulosic
`
`materials have the following formula:
`
`- - 0
`
`6
`
`

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`wo 2005/097067
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`PCT /US2005/0097 42
`
`Wherein R1 R2 and R3 are selected from H, derivatives of C1-C20 carboxylic acid,
`C1-C20 alkyl groups, C1 to C3 monohydric and dihydric alkanols, hydroxyethyl groups,
`hydroxypropyl groups, ethylene oxide groups, propylene oxide groups, phenyl groups,
`"Z" groups and combinations thereof. One or more ofR1 R2 and R3 is a Z group.
`
`The nature of the "Z" groups is:
`
`R'
`
`Z= x-
`
`IH
`"
`"R--_.~+_ --(CH2)x--(CH2)y---(CH2)z--
`
`~
`~
`
`~·
`
`wherein:
`
`R', R" and R'" can be H, CH3, C2H5, CH2CH20H and
`CH2CH(OH)CH20H
`
`x=0-5, y=0-4, and z=0-5
`X= cr, Br-, r, HS04-, CHS04-, H2P04- N03-
`
`Various commercially available grades of polymer JR are summarized below:
`
`Brookfield Viscosity at 25°C,
`centipoises, 2.0 wt.% (1.7 wt.%
`to 2.2 wt.%)
`
`JR-125
`
`JR-400
`
`JR-30M
`
`110-120 cps
`
`400-440 cps 12,000-13,000 cps
`
`In one embodiment, the cationic polymer is Polymer JR. In another embodiment,
`
`the composition comprises a minimum of0.001 wt.%, about 0.005 wt.%, about 0.01
`
`wt.% or about 0.05 wt.% and/or a maximum of about 0.5 wt.%, about 0.1 wt.% or about
`
`0.05 wt.% Polymer JR (including JR-125, JR-400 and JR-30M) based upon the total
`
`weight of the composition. In the case of eye drop solutions, the cationic
`
`polysaccharides offer the additional advantage of being further effective as an active
`
`agent for treatment of dry eye. In one embodiment, the ratio of zinc compound to
`
`7
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`PCT /US2005/0097 42
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`polycationic material in the composition is a minimum of about 0.001, about 0.01 or
`
`about 0.1 and/or a maximum of about 10, about 5, about 1 or about 0.01.
`
`As mentioned, other polycationic materials besides the cationic polysaccharides
`
`may be used in this invention. Examples include: polyquaternium-28, a polyquaternary
`
`ammonium salt based on N-vinylpyrrolidone and dimethylaminopropyl methacrylamide
`
`monomers (available under the tradename Gafquat HS-100, GAF Chemicals, Wayne,
`
`New Jersey, USA); hexadimethrine bromide, a polymer ofN,N,N' ,N'(cid:173)
`
`tetramethylhexamethylene-diamine and trimethylene bromide; hydroxypropyl guar
`
`triammonium chloride, a quaternary ammonium derivative of guar gum (available from
`
`Carbomer, Inc., Westborough, Massachusetts, USA); copolymers ofvinyl
`
`caprolactam/PVP/dimethylaminoethyl methacrylate (such as those available under the
`
`tradename Gaffix VC-713, GAF Chemicals, Wayne, New Jersey, USA).
`
`Other examples are polymers containing quaternary-amine-functional repeat
`
`units, defined as repeat units each comprising a quaternary-amine group, in which a
`
`positively charged nitrogen atom is covalently bonded to four radicals (no hydrogen
`
`atoms) and ionically bonded to a negatively charged counterion such as chloride.
`
`Specific polyquaternium polymers useful as a polycationic material in the present
`
`invention may include, but are not limited to, C()polymers in which the quaternary(cid:173)
`
`amine-functional repeat units are derived from one or more of the following kinds of
`
`monomers: N,N-dimethyl-N-ethyl-aminoethyl acrylate and methacrylate, 2-
`
`methacry loxyethyltrimethylammonium, N -(3-methacrylamidopropyl)-N ,N ,N(cid:173)
`
`trimethylammonium, 1-vinyl and 3-methyl-1-vinylimidazole, N-(3-acrylamido-3-
`
`methylbutyl)-N,N,N-trimethylammonium, N-(3-methacryloyloxy-2-hydroxypropyl)-
`
`N ,N,N -trimethylammonium, dially ldimethylammonium, dially ldiethylammonium,
`
`vinylbenzyltrimethylammonium, their halides or other salt forms, and derivatives
`
`thereof.
`
`A specific example of a polyquaternium copolymer is Luviquat™ FC 370
`
`polymer (CTFA International Cosmetic Ingredient Dictionary designation
`
`polyquaternium-16 commercially available from BASF, Ludwigshafen, Germany) which
`
`is the polyn1erization product of a mixture of comonomers of which 70% is
`
`8
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`
`vinylpyrrolidone and 30% is 1-vinylimidazolium methylchloride, commercially available
`
`as a composition with a solids content of about 40% by weight in water.
`
`The polycation component may be employed in the compositions in a minimum
`
`amount of about 0.001 wt.%, about 0.005 wt.% or about 0.01 wt.% based upon the total
`
`weight of the composition and/ or a maximum amount of about 1 wt. %, about 0. 5 wt.% or
`
`about 0.1 wt.% based upon the total weight of the composition.
`
`As noted, the composition has less than a preservative-effective amount of a
`
`primary preservative agent. In one embodiment, the composition has no primary
`
`preservative agent. Primary preservative agents include, but are not limited to, sorbic
`
`acid. Typically, sorbic acid is added in an amount greater than about 0.15 wt.% based
`
`upon the total weight of the composition to be preservative-effective. According to the
`
`present invention the sorbic acid is present in a less than preservative-effective amount.
`
`Primary preservative agents include known organic nitrogen-containing agents
`
`such as biguanides. The biguanides include the free bases or salts of alexidine,
`
`chlorhexidine, hexamethylene biguanides and their polymers, and/or combinations of the
`
`foregoing. The biguanide salts are typically gluconates, nitrates, acetates, phosphates,
`
`sulfates, halides and the like. A preferred biguanide is the hexamethylene biguanide
`
`commercially available from Zeneca, Wilmington, DE under the trademark Cosmocil™
`
`CQ. Generally, the hexamethylene biguanide polymers, also referred to as
`
`polyaminopropyl biguanide (PAPB), have molecular weights of up to about 100,000 as
`
`disclosed in U.S. Patent No. 5,453,435 and WO 94/04028 the entire contents of which
`
`are incorporated herein by reference. Yet another example of a lmown primary
`
`preservative agent is various materials available as polyquatemium-1. Other primary
`
`preservative agents include, chlorhexidine as disclosed in U.S. Patent No. 5,453,435;
`
`peptides as disclosed in WO 03/006046 and US Publ. 2003/0092612; peroxide and
`
`peroxide producing compounds as disclosed in U.S. Patent No. 4,899,914 and WO
`
`02/40062; imidazolium salts as disclosed in 5,200,453; EDTA in combination with
`
`scorbic acid as disclosed in U.S. Patent No. 4,529,535; and EDTA in combination with
`
`propylene glycol and/or chlorhexidine as disclosed in WO 01/24837, of which all such
`
`patents and publications are fully incorporated herein by reference.
`
`9
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`
`The amount of the primary preservative agent may vary depending on the
`
`specific agent employed, but in each instance must be present in an amount no greater
`
`than a preservative-effective amount as defined above. For the aforementioned organic
`
`nitrogen-containing agent, typically, such agents, if present, are present in a maximum
`
`amount of about 1 ppm, about 10 ppm, about 100 ppm or about 0.1 wt.% based upon the
`
`total weight of the composition. It is preferred that the primary preservative agent is
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`used in an amount that will at least partially reduce no more than two of S aureus, P.
`
`aeruginosa, E. coli, C. albicans, and A. niger. It is preferred that the primary
`
`preservative agent is used in an amount that will at least partially reduce no more than
`
`one of S aureus, P. aeruginosa, E. coli, C. albicans, and A. niger. If present, the primaty
`
`preservative agent added will reduce the microbial bioburden by no more than two log
`
`orders in forty eight hours and more preferably by no more than one log order in forty
`
`eight hours. Preferably, the primary preservative agent is present in an amount in the
`
`composition that is a maximum of about 90%, about 80%, about 70%, about 60%, about
`
`50%, about 40%, about 30% about 20%, about 10%, about 5%, about 1% or about 0.5%
`of a preservative effective amount.
`The aqueous solutions employed in one embodiment of the present invention
`
`contains, in addition to the ingredients described above, one or more other components
`
`that are commonly present in ophthalmic solutions, for example, tonicity adjusting
`
`agents; buffering agents; chelating agents; pH adjusting agents, viscosity modifying
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`agents, and demulcents and the like, which aid in making ophthalmic compositions more
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`comfortable to the user and/or more effective for their intended use.
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`The aqueous solutions of the present invention are typically adjusted with tonicity
`
`agents to approximate the tonicity of nonnallacrimal fluids (approximately equivalent to
`
`a 0.9 wt.% solution of sodium chloride or 2.8 wt.% glycerol solution). Typically, the
`
`solutions are hypotonic or substantially isotonic with physiological saline used alone or
`
`in combination with other adjusting agents. The ophthalmic compositions preferably
`
`have an osmolality that is a minimum of about 225 mOsm/kg, about 240 mOsm/kg or
`
`about 280 mOsm/kg and/or a maximum of about 400 mOsm/kg, about 360 mOsm/kg,
`
`about 340 mOsm/kg or about 320 mOsm/kg.
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`The compositions may include chelating or sequestering agents in order to
`
`chelate or bind metal ions, which might otherwise react with the lens and/or protein
`
`deposits and collect on the lens. Examples of such preferred materials may include, but
`
`are not limited to, ethylenediaminetetraacetic acid (EDTA) and its salts (disodium),
`
`which are usually added in amounts ranging from about 0.01 wt.% to about 0.2 wt.%.
`
`Compositions, such as aqueous solutions, for use in the present invention, may ·be
`
`formulated as lens conditioning solutions or eye-drops and sold in a wide range of small(cid:173)
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`volume containers from about 1 ml to about 30 ml in size. Such containers can be made
`
`from HDPE (high density polyethylene), LDPE (low density polyethylene),
`
`polypropylene, poly( ethylene terepthalate) and the like. For eye drops, flexible bottles
`
`having conventional dispensing tops are especially suitable for use with the present
`
`invention. The eye-drop formulation of the invention is used by instilling, for example,
`
`about one (1) or three (3) drops in the eye(s) as needed.
`
`In the case of contact lens treating solutions, the methods and/or compositions of
`
`the present invention may be applicable to the conventional contact lens categories: (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, (4) silicone
`
`hydrogel lenses and (5) non-hydrogel elastomer lenses.
`
`As an example, soft hydrogel contact lenses are made of a hydrogel polymeric
`
`material, hydrogels being defined as a cross-linked polymeric systems containing water
`
`in an equilibrium state. In general, hydro gels 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 include a
`
`crosslinking monomer, i.e., a monomer having at least two polymerizable radicals, such
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`as ethylene glycol dimethacrylate, tetraethylene glycol dimethacrylate, and
`
`methacryloxyethyl vinylcarbonate. Alternately, either the silicone-containing monomer
`
`or the hydrophilic monomer may function as a crosslinking agent.
`
`The pH of the composition of one embodiment of the present invention is a
`
`minimum of about 5, about 6, about 6.5 or about 7. The pH of composition of one
`
`embodiment of the present invention is a maximum of about 7. 6 or about 7. 8. Suitable
`
`buffers may be added, such as borate, citrate, bicarbonate,
`
`tris(hydroxymethyl)aminomethane (TRIS-Base), amino alcohols and various mixed
`
`phosphate buffers (which may include combinations ofNa2HP04, NaH2P04 and
`KH2P04) and mixtures thereof. Borate buffers are preferred when the primary
`preservative agent is PHMB. Generally, buffers will be used in amounts having a
`
`minimum of about 0.05 wt.% or 0.1 wt.% and/or a maximum of about 1.5 wt.%, 2.0
`
`wt.% or 2.5 wt.% based upon the total weight of the composition.
`
`The therapeutic agents are any agent that, when administered in a therapeutically
`
`effective amount, results in a desired local or systemic physiological or pharmacological
`
`effect. Ophthalmic therapeutic agents include all ophthalmic agents, which can be
`
`topically applied. Such ophthalmic therapeutic agents include, but are not limited to,
`
`glaucoma agents, such as beta-blockers, muscarinics and carbonic anhydrase inhibitors;
`
`dopaminergic agonists and antagonists; anti-infectives; non-steroidal and steroidal anti(cid:173)
`
`inflammatories, prostaglandins; proteins; growth factors and anti-allergies. Therapeutic
`
`agents according to one or more embodiments of the present invention include
`
`combinations of two or more ophthalmic agents.
`
`As used herein, the term "ophthalmic composition" denotes a composition
`
`intended for application in the eye or intended for treating a medical device to be placed
`
`in contact with the eye such as a contact lens. Ophthalmic compositions specifically
`
`include compositions for direct instillation in the eye, including eye drop solutions such
`
`as for treating dry eye, and contact lens treating solutions distilled directly in the eye
`
`such as for rewetting a contact lens while worn. Ophthalmic compositions also include
`
`compositions instilled indirectly in the eye, such as contact lens treating solutions for
`
`treating the contact lens prior to the lens being inserted on the eye.
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`The materials suitable for use in the present invention may also be useful as a
`
`component of a cleaning, disinfecting or conditioning composition. Such compositions
`
`also may include, preservative agents, surfactants, toxicity adjusting agents, buffers and
`
`the like that are known to be used components of conditioning and/or cleaning solutions
`
`for contact lenses. Examples of suitable formulations for cleaning and/or disinfecting
`
`solutions are taught in U.S. Patent 5,858,937 to Richard et al., which is incorporated by
`
`reference as if set forth at length herein. Preferably, compositions of the present
`
`invention may be fonnulated as a "multi-purpose solution," meaning that such
`
`compositions are used, in one embodiment, for cleaning, chemical disinfection, storing,
`
`and rinsing a contact lens. A multi-purpose solution preferably has a viscosity