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 efficacy of the N-halamine com Surfactants which may present in amounts up to 5 w/v '%. pound. Preferred chlorite compounds are alkali metal chlo Surfactants that may be used with certain embodiments of the rites such as Sodium or potassium chlorite, transition metal present invention include, but are not limited to, polyethylene chlorites, and stabilized sodium chlorite. Sigma-Aldrich glycol ethers or esters of fatty acids, polyoxyethylene-poly Company (St. Louis, Mo.) sells an 80% solution of sodium oxypropylene block copolymers of ethylene diamine (e.g., chlorite with sodium chlorate. Certain stabilized sodium poloxamines such as Tetronic 1304 or 1107), polyoxypropy chlorite products are commercially available (e.g., PURITE lene-polyoxyethylene glycol nonionic block copolymers and ANTHIUM DIOXIDE). Sodium chlorite can be easily (e.g., poloxamers, such as Pluronic F-127), p-isooctylpoly obtained commercially (e.g., ADOX). Generally, the chlorite ethylen phenol formaldehyde polymers (e.g., Tyloxapol), and compound is present at a concentration that has minimal Pluronix and Tetronic R derivatives such as Pluronic 17R. antimicrobial activity by itself, but provides synergistic 0024. In certain embodiments of the present invention, enhancement of the antimicrobial effects of the N-halamine. Suitable cosolvents include glycerin, propylene glycol and A preferred concentration range for the chlorite compound in polyethylene glycol. formulations of the present invention is 0.001 to 0.010 w/v%, 0025 Buffering agents which may be incorporated into with a most preferred concentration of 0.006 w/v '%. formulations of the present invention include, but are not 0019. In addition to an N-halamine, the formulations of limited to, alkaline metal salts, such as potassium or sodium the present invention optionally comprise one or more addi carbonates, acetates, borates, phosphates and citrates, and tional components. Such components include, but are not weak acids. Such as acetic acids and boric acids. The preferred limited to, tonicity agents, preservatives, chelating agents, buffering agents are alkaline metal borates, such as Sodium or buffering agents, Surfactants, co-solvents, and antioxidants. potassium borates. Other pH-adjusting agents, such as inor Other components used in certain embodiments are solubi ganic acids and bases, may also be utilized. For example, lizing agents, stabilizing agents, comfort-enhancing agents, hydrochloric acid or sodium hydroxide may be employed in polymers, emollients, pH-adjusting agents and/or lubricants. concentrations suitable for ophthalmic compositions. The Components that may be used in certain formulations of the above-described buffering agents are generally present in present invention including water, mixtures of water and amounts from about 0.1 to about 2.5 w/v '%, preferably from water-miscible solvents, such as C1-C7-alkanols, vegetable about 0.5 to about 1.5% w/v '%. oils or mineral oils comprising from 0.5 to 5% non-toxic 0026. The formulations of the present invention are pref water-soluble polymers, natural products, such as alginates, erably isotonic, or slightly hypotonic, and generally have an pectins, tragacanth, karayagum, Xanthan gum, carrageenin, osmolality in the range of 210-320 mOsm/kg, and preferably agar and acacia, starch derivatives, such as starch acetate and have an osmolality in the range of 235-300 mOsm/kg. This hydroxypropyl Starch, and also other synthetic products. Such may require a tonicity agent to bring the osmolality of the as polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl methyl formulation to the desired level. Tonicity-adjusting agents ether, polyethylene oxide, preferably cross-linked poly include, but are not limited to, sodium chloride, glycerin, acrylic acid, and mixtures of those products. Sorbitol, or mannitol. 0020. In addition to an N-halamine compound of Formula 0027. The formulations set forth herein may comprise one (I) and a chlorite compound, the compositions of the present or more preservatives. Examples of preservatives include invention may comprise additional compounds having anti p-hydroxybenzoic acid ester, alkyl-mercury salts of thiosali US 2010/0303930 A1 Dec. 2, 2010 cylic acid, such as, for example, thiomersal, phenylmercuric dose ampoule which may preferably be sterile and thus render nitrate, phenylmercuric acetate or phenylmercuric borate, bacteriostatic components of the formulation unnecessary. quaternary ammonium compounds Such as, for example, Alternatively, the drops may be delivered from a multi-dose polyduaternium-1, Sodium perborate, Sodium chlorite (and bottle which may preferably comprise a device which extracts combinations with sodium perborate), parabens, such as, for preservative from the formulation as it is delivered, such example, methylparaben or propylparaben, alcohols, such as, devices being known in the art. for example, chlorobutanol, benzyl alcohol or phenylethanol, 0033. In certain topical ophthalmic applications, the guanidine derivatives, such as, for example, polyhexameth N-halamine compound may be formulated in a formulation ylene biguanide, Sodium perborate, or Sorbic acid. In pre that comprises one or more tear Substitutes. A variety of tear ferred embodiments, the formulation may be self-preserved Substitutes are known in the art and include, but are not that no preservation agent is required. limited to: monomeric polyols, such as, glycerol, propylene 0028. In contact lens disinfection applications, it is glycol, and ethylene glycol; polymeric polyols such as poly imperative that the disinfection activity of a formulation of ethylene glycol, cellulose esters such hydroxypropylmethyl the present invention should be maximized so that a minimum cellulose, carboxy methylcellulose sodium and hydroxy pro amount of active ingredient is used. The amount of the pylcellulose; dextrans such as dextran 70; vinyl polymers, N-halamine and the chlorite compound required to achieve Such as polyvinyl alcohol; and carbomers, such as carbomer the desired disinfection activity can be determined by persons 934P. carbomer 941, carbomer 940 and carbomer 974P. Oph skilled in the art. The concentration required to achieve the thalmic formulations for in situ disinfection generally have a desired activity as a disinfectant while retaining acceptable viscosity of 0.5-100 cps, preferably 0.5-50 cps, and most safety and toxicity properties is referred to herein as “an preferably 1-20 cps. This relatively low viscosity insures that effective amount'. An effective amount will possess antimi the product is comfortable, does not cause blurring, and is crobial activity Sufficient to meet generally accepted Stan easily processed during manufacturing, transfer and filling dards for activity, such as EN ISO 14729:2001 Ophthalmic operations. optics—Contact lens care products—Microbiological 0034 Certain embodiments of the present invention com requirements and test methods for products and regimens for prise an N-halamine of the present invention in a tablet form hygienic management of contact lenses. with a chlorite compound. A tablet form of the present inven 0029. It is also contemplated that the concentrations of the tion may comprise in addition to an N-halamine and a chlorite compounds (including, but not limited to N-halamines) com one or more excipients, binders, neutralizing agents and con prising the formulations of the present invention can vary. A trolled release agents such as Eudgragit, HPMC, pharmacoat person of ordinary skill in the art would understand that the 603, simeticon, macrogolum 6000, trisodium phosphate concentrations can vary depending on the addition, Substitu monohydrate, sodium ascorbate, sodium borohydride, and tion, and/or Subtraction of ingredients in a given formulation. lactose monohydrate. U.S. Pat. No. 6,440,411 to Scherer et In non-limiting aspects, the percentage can be calculated by al., herein incorporated by reference in its entirety, discloses weight or volume of the total formulation. the generation of tablets that may be used with the 0030. For ophthalmic applications, the pH of the formu N-halamines and chlorites of the present invention. The tab lations generally is in an ophthalmically acceptable range of lets may be added to water or an aqueous Solution to form a 6.0 to 8.0. Preferred ophthalmic formulations are prepared disinfecting aqueous Solution that may be used, for example, using a buffering system that maintains the formulation at a as a contact lens disinfectant. These tablets may be added to pH of about 6.5 to a pH of about 7.8. aqueous Solutions (such as peroxide or sodium perborate 0031. In certain contact lens disinfection applications, a solutions) that slowly neutralize the N-halamine and/or chlo pH range of 3.0 to 8.0 is utilized as part of an indicator system. rite over a period of time to allow for disinfection yet result in At pH ranges of lower than about 6.0, N-halamine and chlo a formulation suitable for installation into an eye following rite aqueous formulations can develop a yellow color due to neutralization. An indicator System as described above can be the formation of chlorine dioxide. The presence or absence of utilized with certain of these embodiments. coloration can be used as an indicator of the progress of contact lens disinfection. If the pH is returned to a more EXAMPLES neutral value such as 6.0 to 8.0 via oxidation reactions over a 0035. The following examples are presented to further given time or via neutralization of the N-halamine or chlorite illustrate selected embodiments of the present invention. using a tablet containing a neutralization compound Such as sodium perborate, the yellow colorization due to chlorine Example 1 dioxide is eliminated. Thus, the change from a yellow formu lation to a clear formulation can be used as an indication that 0.036 the formulation is no longer active or that the contact lens disinfection process has been completed. 0032. In particular embodiments, formulations of the Ingredient % ww. present invention are Suitable for topical application to mam 1-chloro-2,2,6,6-tetramethyl-4-piperidinol O.OO6 malian eyes. For example, for ophthalmic administration, the Pluronic 17R4 O.OS formulation may be a solution, a suspension, a gel, water-in Boric Acid O3S oil and oil-in-water emulsions, oran ointment. Preferred for Sodium Borate O.11 mulations for ophthalmic administration will be acqueous Sodium Chloride 0.7 Sodium Chlorite O.OO6 solution in the form of drops. The term “aqueous' typically Sodium Hydroxide? Hydrochloric Acid pH adjust to 7.0 denotes an aqueous formulation wherein the excipient is Purified Water QS >50%, more preferably >75% and in particular >90% by weight water. These drops may be delivered from a single US 2010/0303930 A1 Dec. 2, 2010

Example 2 formulations, almost no microbe survivors were recovered 0037. The antimicrobial activity of N-halamine formula from any of the samples tested using formulations 4-7. tions with and without the addition of sodium chlorite are TABLE 2 compared the antimicrobial efficacy of solutions compared. TABLE 1 below presents the results of the experi comprising either an N-halamine or a chlorite. While the ments. All concentrations in the tables below are in wiv% chlorite formulations (formulations 11-14) showed weak unless otherwise indicated. Total chlorine was also measured activity against S. aureus, they are not effective disinfectants using a common technique known to those of skill in the art. at the concentrations tested. The N-halamine formulations 0038 TABLE 1 presents data showing that the tested (formulations 8-10) showed better efficacy than the N-halamine of the present invention had good antimicrobial chlorite formulations, but were not very effective against C. activity against S. aureus by itself, but was not as effective albicans at the concentrations tested. In Sum, the data dem against C. albicans and S. marcescens at lower concentrations onstrates the synergistic antimicrobial properties of the for informulations 2 and 3. When sodium chlorite is added to the mulations of the present invention.

TABLE 1 Component 1 2 3 4 5 6 7

1-chloro-2,2,.6,6-tetramethyl- O.O12S O.OO6 O.OO3 O.OO6 O.OO3 O.OO6 O.OO3 4-piperidinol Available chlorine (ppm) 79 53 62 26S 283 26S 239 Pluronic 17R4 O.OS O.OS Boric Acid O3S O.35 O.35 O3S O.35 O3S O.35 Sodium Borate O.11 O.11 O.11 O.11 O.11 O.11 O.11 Sodium Chloride 0.7 0.7 0.7 0.7 0.7 0.7 0.7 Sodium Chlorite O.OO6 O.OO6 OOO6 O.OO6 Assay (Sodium Chlorite) 110 110 117 107 pH 7.0 7.0 7.0 7.0 7.0 7.0 7.0 Osmolality (mCs/kg) 295 295 295 295 295 293 293

Time Microorganism (hrs) 1 2 3 4 5 6 7

C. albicans 6 6.1 2.4 O.3 6.1 6.1 6.1 2.O 1.2 x 10 24 6.1 6.1 6.1 6.1 6.1 6.1 6.1 S. marCescens 6 6.1 5.4 3.0 6.1 6.1 6.1 6.1 1.3 x 10 24 6.1 6.1 6.1 6.1 6.1 6.1 6.1 S. airetts 6 6.2 6.2 6.2 6.2 6.2 6.2 6.2 1.5 x 10 24 6.2 6.2 6.2 6.2 6.2 6.2 6.2 Underlined number indicates no survivors (<10 CFU/mL) recovered

TABLE 2 Component 8 9 10 11 12 13 14

1-chloro-2,2,.6,6-tetramethyl- O.OOOS O.OO1 O.OO2 4-piperidinol Pre-test assay, ppm 5 10.8 23 Post-test assay, ppm 4 9.7 22.5 Boric Acid O3S O3S O.35 O3S O.35 O3S O.35 Sodium Borate O.11 O.11 O.11 O.11 O.11 O.11 O.11 Sodium Chloride 0.7 0.7 0.7 0.7 0.7 0.7 0.7 Sodium Chlorite O.OO1 O.OO2S O.OO4 O.OO6 Pre-test assay (sodium 12.9 21.6 46.6 88.8 chlorite) Post test assay (sodium 11.1 20.1 45.9 97.4 chlorite) pH 7.03 6.98 6.97 6.98 7.1 7.0 7.0 Osmolality 285 282 275 281 28O 284 286 Time Logo Reduction of Survivors Microorganism (hrs) 8 9 10 11 12 13 14

C. albicans 6 -0.2 -0.1 0.4 -0.2 -0.1 -0.2 -0.2 9.5 x 10 24 O.1 1.2 4.8 -0.2 -0.1 -0.2 -0.2 S. marceScens 6 0.4 1.8 3.2 O.1 O.2 O.2 O.3 1.1 x 10 24 3.1 S.O 6.0 0.4 O.S 1.1 3.8 S. airetts 6 2.9 3.9 6.1 -0.2 -0.1 -0.1 O.3 1.3 x 10 24 6.1 6.1 .1 2.2 4.0 6.1 6.1 Underlined number indicates no survivors (<10 CFU/mL) recovered US 2010/0303930 A1 Dec. 2, 2010

0039. The present invention and its embodiments have 4. A composition according to claim 3 wherein said been described in detail. However, the scope of the present N-halamine is presentata concentration of from 0.005 to 0.01 invention is not intended to be limited to the particular w/v '% and said chlorite compound is present at a concentra embodiments of any process, manufacture, composition of tion of 0.001 to 0.01 w/v '%. matter, compounds, means, methods, and/or steps described 5. A composition according to claim 1 wherein said in the specification. Various modifications, Substitutions, and N-halamine is 1-chloro-2.2.6,6-tetramethyl-4-piperidinol variations can be made to the disclosed material without and said chlorite is sodium chlorite. departing from the spirit and/or essential characteristics of the 6. A composition according to claim 5 wherein said present invention. Accordingly, one of ordinary skill in the art N-halamine is present at a concentration of 0.006 and said sodium chlorite is present at a concentration of 0.006. will readily appreciate from the disclosure that later modifi 7. A composition according to claim 1 wherein said cations, Substitutions, and/or variations performing Substan N-halamine and said chlorite compound are present in a tially the same function or achieving Substantially the same quantity Sufficient to preserve said composition. result as embodiments described herein may be utilized 8. A method for disinfecting and/or cleaning a contact lens according to Such related embodiments of the present inven comprising: tion. Thus, the following claims are intended to encompass contacting a contact lens with a composition according to within their scope modifications, Substitutions, and variations claim 1. to processes, manufactures, compositions of matter, com 9. A method according to claim 8 wherein said composition pounds, means, methods, and/or steps disclosed herein. has a pH of 6.0 to 8.0 10. A method according to claim 9 wherein said composi 1. A sterile, aqueous ophthalmic composition comprising tion has a pH of 6.5 to 7.8. an N-halamine of Formula (I): 11. A disinfecting tablet Soluble in aqueous solution, said tablet comprising an N-halamine of Formula (I) Formula (I) i Formula (I) R4 N Rs i R4 N Rs R, R R6 R7

OR OR where R–H, where R–H, R R -ing-e- R, or - sci-eo. R O - HC- e. Rs, or - HC- i O O; R2 O n=1-10; X—Cl, Br, or I: n=1-10; R. R. and Rare, independently, H, CH, CHs, or CH, X—Cl, Br, or I; R. R. and Rare, independently, H, CH, CHs, or CH, R. R. R. and R7 are, independently, H, CH, CH5, CH, R. R. R. and R, are, independently, H, CH, CH5, CH7 or t-butyl: ort-butyl, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, and a quan and tity of sodium chlorite sufficient to enhance the antimi a quantity of Sodium chlorite Sufficient to enhance the crobial efficacy of the N-halamine and a pharmaceuti antimicrobial efficacy of the N-halamine when dis cally acceptable vehicle therefor. Solved in aqueous solution and a pharmaceutically 2. A composition according to claim 1 wherein said acceptable vehicle therefor. N-halamine is 1-chloro-2,2,6,6-tetramethyl-4-piperidinol. 12. A method for disinfecting Surfaces comprising: 3. A composition according to claim 1 wherein said contacting the Surface to be disinfected with a composition N-halamine is presentata concentration of from 0.0001 to 0.1 according to claim 1. w/v '% and said chlorite compound is present at a concentra tion of 0.001 to 0.01 w/v '%. c c c c c