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(12) Patent Application Publication (10) Pub. No.: US 2010/0303930 A1 Carey Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2010/0303930 A1 Carey Et Al US 2010O3O3930A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0303930 A1 Carey et al. (43) Pub. Date: Dec. 2, 2010 (54) N-HALAMINE FORMULATIONS WITH (22) Filed: May 28, 2010 ENHANCEDANTIMICROBAL ACTIVITY Related U.S. Application Data (75) Inventors: Thomas Christopher Carey, Fort (60) Provisional application No. 61/182,539, filed on May Worth, TX (US); Nissanke L. 29, 2009. Dassanayake, Fort Worth, TX Publication Classification (US); Ronald L. Schlitzer, Fort Worth, TX (US); Howard Allen (51) Int. Cl. Ketelson, Dallas, TX (US) AOIN 59/08 (2006.01) AOIP I/00 (2006.01) Correspondence Address: (52) U.S. Cl. ........................................................ 424/665 ALCON (57) ABSTRACT IP LEGAL, TB4-8, 6201 SOUTH FREEWAY FORTWORTH, TX 76134 (US) The present invention relates to antimicrobial formulations comprising an N-halamine and a quantity of sodium chlorite sufficient to enhance the antimicrobial efficacy of the (73) Assignee: ALCON RESEARCH, LTD., Fort N-halamine. The present invention is further directed to for Worth, TX (US) mulations for disinfecting a contact lens comprising an N-halamine and a quantity of sodium chlorite sufficient to (21) Appl. No.: 12/789,965 enhance the antimicrobial efficacy of the N-halamine. US 2010/0303930 A1 Dec. 2, 2010 N-HALAMINE FORMULATIONS WITH N-halamine compounds in aqueous formulations. The ENHANCEDANTIMICROBAL ACTIVITY enhancement is achieved by combining an N-halamine with a chlorite compound Such as Sodium chlorite, as described CROSS-REFERENCE TO RELATED herein. APPLICATION 0008. The present invention further relates to aqueous ophthalmic formulations having antimicrobial activity that 0001. This application claims priority under 35 U.S.C. comprise N-halamine compounds and a chlorite compound S119 to U.S. Provisional Patent Application No. 61/182,539, Such as sodium chlorite. filed May 29, 2009, the entire contents of which are incorpo 0009. One embodiment of the present invention is a rated herein by reference. method for disinfecting and/or cleaning a contact lens com TECHNICAL FIELD OF THE INVENTION prising contacting a contact lens with an aqueous formulation comprising a N-halamine of the present invention and a chlo 0002 The present invention relates to methods for enhanc rite compound for a time sufficient to disinfect and/or clean ing the antimicrobial efficacy of N-halamine compounds in the lens. aqueous formulations. The present invention further relates to 0010 Yet another embodiment is an aqueous pharmaceu formulations for contact lens cleaning and disinfection com tical composition comprising an N-halamine and a chlorite prising N-halamine compounds and a chlorite compound compound in a quantity Sufficient to preserve the composi Such as Sodium chlorite. tion. 0011. The foregoing brief summary broadly describes the BACKGROUND OF THE INVENTION features and technical advantages of certain embodiments of 0003 Compounds possessing antimicrobial activity are the present invention. Additional features and technical used in a variety of applications such as Surface disinfection, advantages will be described in the detailed description of the Solution preservation, and therapeutic treatments. For appli invention that follows. Novel features which are believed to cations such as the disinfection of tissues, medical devices, be characteristic of the invention will be better understood and contact lenses, there is an ongoing need for formulations from the detailed description of the invention. with good safety profiles and antimicrobial efficacy. In gen eral, it is desirable to use antimicrobial compounds at as low DETAILED DESCRIPTION OF THE INVENTION a concentration as possible to minimize harmful side effects, 0012. The present inventors have discovered that the while ensuring that the compounds have the desired antimi N-halamines of the present invention have enhanced antimi crobial efficacy. crobial properties when present in an aqueous composition 0004. There is also a need for an improved means of pre comprising a concentration of a chlorite compound Such as serving pharmaceutical compositions from microbial con Sodium chlorite. When combined in an aqueous formulation, tamination. This need is particularly prevalent in the fields of the combination of an N-halamine with a chlorite compound ophthalmic and otic compositions. The antimicrobial utilized Such as sodium chlorite appears to result in a beneficial Syn to preserve aqueous ophthalmic and otic compositions must ergistic effect on the formulation's antimicrobial properties. be effective in preventing microbial contamination of the As used herein, the term “antimicrobial refers to the ability compositions when used at concentrations that are non-toxic to kill or inhibit the growth of microbes (to include, without to ophthalmic and otic tissues. limitation, bacteria, viruses, yeast, fungi, spores, protozoa, 0005. Many halogenated amine compounds have demon parasites, etc.). strated efficacy as disinfectants and biocides and have good 0013 The N-halamines used in the formulations of the safety profiles. For example, chloramine compounds have present invention have a structure according to the following been shown to be useful as contact lens disinfectants. See U.S. Formula (I) Pat. No. 4,780,152 to Itagaki et al. The disinfection of contact lenses is required to avoid the buildup of infectious and non infectious contaminants on the contact lens surfaces. Daily Formula (I) cleaning and disinfection may be necessary, particularly for hydrophilic (soft) contact lenses. The failure to clean and i disinfect lenses properly has consequences for a lens wearer R4 - N - R5 ranging from eye irritation to serious infections. Ocular infec R, R tions caused by particularly virulent microbes, such as P aeruginosa, can lead to loss vision if left untreated or if allowed to reach an advanced stage before treatment is initi OR ated. 0006 U.S. Pat. No. 4,931,562 to Akabane discloses cer tain N-halamine compounds that are useful for bleaching and where R–H, industrial applications. U.S. Pat. No. 5,902,818 and U.S. Pat. No. 6,020,491 disclose that certain N-halamines are useful biocides. These references do not disclose the combination of R an N-halamine and a chlorite compound in an aqueous for mulation. —i.e.-- O —incl-seo R2 O BRIEF SUMMARY OF THE INVENTION 0007. The present invention is directed in certain embodi 0014 n=1-10; ments to methods for enhancing the antimicrobial efficacy of 0.015 X-Cl, Br, or I; US 2010/0303930 A1 Dec. 2, 2010 0016 R, R2, and Rare, independently, H, CH, CHs. microbial properties. Suitable antimicrobial agents include, or CH 7, and R. Rs. Re, and R-7 are, independently, H. but are not limited to those generally used in contact lens care CH, CH5, CH, or t-butyl. Pharmaceutically accept Solutions or in other ophthalmic solutions such as polyduater able salts of the N-halamines of the present invention are nium-1, which is a polymeric quaternary ammonium com also contemplated for use in embodiments of the present pound; myristamidopropyl dimethylamine (“MAPDA), invention. Such salts may include, but are not limited to, which is a N,N-dialkyl, N'-alkyl, ethylene diamine; polyhex those formed by combination with halide anions such as amethylene biguanide (“PHMB) or polyaminopropylbigu chloride or bromide, phosphates, alkalications, and qua anide (PAPB), which is a polymeric biguanide; and hydrogen ternary ammonium cations. A preferred N-halamine of peroxide. The additional antimicrobial agents that may be the present invention is 1-chloro-2.2.6,6-tetramethyl-4- utilized in the present invention also include the aminobigu piperidinol where R—H and X—C1. anides described in U.S. Pat. No. 6,664.294, the entire con 0017 N-halamines of the present invention may be pre tents of which are hereby incorporated in the present specifi pared using synthetic methods known to those of skill in the cation by reference. The preferred additional antimicrobial art. In addition, publications are available that describe other agents are polyduaternium-1, MAPDA and the amino bigu methods that may be used to synthesize compounds of the anide identified in U.S. Pat. No. 6,664.294 as “Compound present invention. These publications include the Zakrewski Number 1. J., “A simple method for the synthesis of sterically hindered 0021 Suitable antioxidants include, but are not limited to, chloramines”. Synthetic Communications, Vol. 18(16&17): sulfites, ascorbates, butylated hydroxyanisole (BHA) and 2135-2140 (1988), herein incorporated by reference in its butylated hydroxytoluene (BHT). entirety. A general method for synthesis uses a reaction 0022 Stabilizing agents including phosphonic acid and its between sodium chlorite or sodium hypochlorite and piperi derivatives such as Dequest, chelating agents to remove trace dinol to form N-chloropiperidinol. Generally, the formula metals, phosphates such as tetrabutyl ammonium phosphate, tions of the present invention comprise an N-halamine at a and quaternary ammonium compounds Such as tetrabutyl concentration of 0.001 to 0.1 w/v '% in aqueous solution, with ammonium chloride and tetrabutyl ammonium hydroxide. a most preferred concentration of 0.006 w/v '%. 0023 Surfactants utilized in the compositions of the 0018. The formulations of the present invention addition present invention can be cationic, anionic, nonionic or ally comprise a chlorite compound in a quantity Sufficient to amphoteric. Preferred Surfactants are neutral or noninonic enhance the antimicrobial
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