Method of treatment using nanoparticulate compositions having lysozyme as a surface stabilizer

Abstract

The present invention is directed to nanoparticulate active agent compositions comprising lysozyme as a surface stabilizer. Also encompassed by the invention are pharmaceutical compositions comprising a nanoparticulate active agent composition of the invention and methods of making and using such nanoparticulate and pharmaceutical compositions.

1 . A bioadhesive nanoparticulate composition comprising at least one active agent having lysozyme adsorbed on the surface thereof as a surface stabilizer in an amount sufficient to maintain the active agent particles at an effective average particle size of less than about 2000 nm. 
     
     
         2 . The composition of  claim 1 , wherein the at least one active agent is:
 (a) selected from the group consisting of a drug, vitamin, herb, cosmetic agent, coloring agent, flavor agent, fragrance agent, sunscreen, moisturizer, deodorant, hair conditioner agent, hair dye, hair spray agent, hair cosmetic agent, hair cleanser agent, depilatory agent, insecticide, fertilizer, pesticide, herbicide, germicide, and plant growth regulating agent; or   (b) selected from the group consisting of proteins, peptides, nutraceuticals, carotenoids, anti-obesity agents, corticosteroids, elastase inhibitors, analgesics, anti-fungals, oncology therapies, anti-emetics, analgesics, cardiovascular agents, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, antibiotics, anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytic sedatives, astringents, beta-adrenoceptor blocking agents, blood products and substitutes, cardiac inotropic agents, contrast media, cough suppressants, diagnostic agents, diagnostic imaging agents, diuretics, dopaminergics, haemostatics, immunological agents, lipid regulating agents, muscle relaxants, parasympathomimetics, parathyroid calcitonin and biphosphonates, prostaglandins, radio-pharmaceuticals, sex hormones, anti-allergic agents, stimulants and anoretics, sympathomimetics, thyroid agents, vasodilators, xanthines, acne medication, alpha-hydroxy formulations, cystic-fibrosis therapies, asthma therapies, emphysema therapies, respiratory distress syndrome therapies, chronic bronchitis therapies, chronic obstructive pulmonary disease therapies, organ-transplant rejection therapies, therapies for tuberculosis and other infections of the lung, and respiratory illness therapies associated with acquired immune deficiency syndrome.   
     
     
         3 .- 4 . (canceled) 
     
     
         5 . The composition of  claim 1 , wherein:
 (a) the at least one active agent is present in an amount selected from the group consisting of from about 99.5% to about 0.001%, from about 95% to about 0.1%, and from about 90% to about 0.5%, by weight based on the total combined weight of the active agent and surface stabilizer, not including other excipients;   (b) lysozyme is present in an amount selected from the group consisting of from about 0.5% to about 99.999%, from about 5.0% to about 99.9%, and from about 10% to about 99.5%, by weight, based on the total combined dry weight of the active agent and lysozyme, not including other excipients; or   (c) any combination thereof.   
     
     
         6 . (canceled) 
     
     
         7 . The composition of  claim 1 , wherein the at least one active agent is selected from the group consisting of a crystalline phase, an amorphous phase, a semi-crystalline phase, and mixtures thereof. 
     
     
         8 . The composition of  claim 1 , further comprising at least one secondary surface stabilizer which is not lysozyme, and which is a cationic surface stabilizer. 
     
     
         9 .- 10 . (canceled) 
     
     
         11 . The composition of  claim 8 , wherein the at least one cationic surface stabilizer is selected from the group consisting of:
 (a) a polymer, a biopolymer, a polysaccharide, a cellulosic, an alginate, a nonpolymeric compound, a phospholipid, zwitterionic stabilizers, poly-n-methylpyridinium, anthryul pyridinium chloride, chitosan, polylysine, polyvinylimidazole, polybrene, polymethylmethacrylate trimethylammoniumbromide bromide (PMMTMABr), hexyldesyltrimethylammonium bromide (HDMAB), polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethyl sulfate, 1,2 Dipalmitoyl-sn-Glycero-3-Phosphoethanolamine-N-[Amino(Polyethylene Glycol)2000] (sodium salt), Poly(2-methacryloxyethyl trimethylammonium bromide), poloxamines, lysozyme, alginic acid, carrageenan, and POLYOX; or   (b) cationic lipids, sulfonium, phosphonium, quarternary ammonium compounds, stearyltrimethylammonium chloride, benzyl-di(2-chloroethyl)ethylammonium bromide, coconut trimethyl ammonium chloride, coconut trimethyl ammonium bromide, coconut methyl dihydroxyethyl ammonium chloride, coconut methyl dihydroxyethyl ammonium bromide, decyl triethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium bromide, C 12-15 -dimethyl hydroxyethyl ammonium chloride, C 12-15 -dimethyl hydroxyethyl ammonium bromide, coconut dimethyl hydroxyethyl ammonium chloride, coconut dimethyl hydroxyethyl ammonium bromide, myristyl trimethyl ammonium methyl sulphate, lauryl dimethyl benzyl ammonium chloride, lauryl dimethyl benzyl ammonium bromide, lauryl dimethyl(ethenoxy) 4  ammonium chloride, lauryl dimethyl(ethenoxy) 4  ammonium bromide, N-alkyl(C 12-18 )dimethylbenzyl ammonium chloride, N-alkyl(C 14-18 )dimethyl-benzyl ammonium chloride, N-tetradecylidmethylbenzyl ammonium chloride monohydrate, dimethyl didecyl ammonium chloride, N-alkyl and (C 12-14 )dimethyl 1-napthylmethyl ammonium chloride, trimethylammonium halide, alkyl-trimethylammonium salts, dialkyl-dimethylammonium salts, lauryl trimethyl ammonium chloride, ethoxylated alkyamidoalkyldialkylammonium salt, an ethoxylated trialkyl ammonium salt, dialkylbenzene dialkylammonium chloride, N-didecyldimethyl ammonium chloride, N-tetradecyldimethylbenzyl ammonium, chloride monohydrate, N-alkyl(C 12-14 )dimethyl 1-naphthylmethyl ammonium chloride, dodecyldimethylbenzyl ammonium chloride, dialkyl benzenealkyl ammonium chloride, lauryl trimethyl ammonium chloride, alkylbenzyl methyl ammonium chloride, alkyl benzyl dimethyl ammonium bromide, C 12 , C 15 , C 17  trimethyl ammonium bromides, dodecylbenzyl triethyl ammonium chloride, poly-diallyldimethylammonium chloride (DADMAC), dimethyl ammonium chlorides, alkyldimethylammonium halogenides, tricetyl methyl ammonium chloride, decyltrimethylammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyl trioctylammonium chloride. POLYQUAT 10™, tetrabutylammonium bromide, benzyl trimethylammonium bromide, choline esters, benzalkonium chloride, stearalkonium chloride compounds, cetyl pyridinium bromide, cetyl pyridinium chloride, halide salts of quaternized polyoxyethylalkylamines, MIRAPOL™, ALKAQUAT™, alkyl pyridinium salts, amines, protonated quaternary acrylamides, methylated quaternary polymers, and cationic guar; or   (c) a nonpolymeric compound selected from the group consisting of benzalkonium chloride, a carbonium compound, a phosphonium compound, an oxonium compound, a halonium compound, a cationic organometallic compound, a quarternary phosphorous compound, a pyridinium compound, an anilinium compound, an ammonium compound, a hydroxylammonium compound, a primary ammonium compound, a secondary ammonium compound, a tertiary ammonium compound, behenalkonium chloride, benzethonium chloride, cetylpyridinium chloride, behentrimonium chloride, lauralkonium chloride, cetalkonium chloride, cetrimonium bromide, cetrimonium chloride, cethylamine hydrofluoride, chlorallylmethenamine chloride (Quaternium-15), distearyldimonium chloride (Quaternium-5), dodecyl dimethyl ethylbenzyl ammonium chloride(Quaternium-14), Quaternium-22, Quaternium-26, Quaternium-18 hectorite, dimethylaminoethylchloride hydrochloride, cysteine hydrochloride, diethanolammonium POE (10) oletyl ether phosphate, diethanolammonium POE (3)oleyl ether phosphate, tallow alkonium chloride, dimethyl dioctadecylammoniumbentonite, stearalkonium chloride, domiphen bromide, denatonium benzoate, myristalkonium chloride, laurtrimonium chloride, ethylenediamine dihydrochloride, guanidine hydrochloride, pyridoxine HCl, iofetamine hydrochloride, meglumine hydrochloride, methylbenzethonium chloride, myrtrimonium bromide, oleyltrimonium chloride, polyquaternium-1, procainehydrochloride, cocobetaine, stearalkonium bentonite, stearalkoniumhectonite, stearyl trihydroxyethyl propylenediamine dihydrofluoride, tallowtrimonium chloride, and hexadecyltrimethyl ammonium bromide.   
     
     
         12 . (canceled) 
     
     
         13 . The composition of  claim 11 , wherein the amine is selected from the group consisting of alkylamines, dialkylamines, alkanolamines, polyethylenepolyamines, N,N-dialkylaminoalkyl acrylates, vinyl pyridine, amine salts, lauryl amine acetate, stearyl amine acetate, alkylpyridinium salt, alkylimidazolium salt, amine oxides, and, imide azolinium salts. 
     
     
         14 . (canceled) 
     
     
         15 . The composition of  claim 1 , wherein the effective average particle size of the nanoparticulate composition is selected from the group consisting of less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1000 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 150 nm, less than about 100 nm, less than about 75 nm, and less than about 50 nm. 
     
     
         16 . The composition of  claim 15 , wherein at least about 70%, at least about 90%, or at least about 95% of the active agent particles have a particle size less than the effective average particle size. 
     
     
         17 . The composition of  claim 1 , wherein the composition further comprises one or more pharmaceutically acceptable excipients, carriers, or a combination thereof. 
     
     
         18 . The composition of  claim 1 , wherein the composition adsorbs to a biological surface selected from the group consisting of an insect, teeth, bone, nails, chitin, feathers, scales, mucous, skin, hair, and plant tissue. 
     
     
         19 . The composition of  claim 1  in a dry powder form. 
     
     
         20 . A method of making a bioadhesive, nanoparticulate composition comprising at least one active agent having lysozyme adsorbed on the surface thereof in an amount sufficient to maintain the active agent particles at an effective average particle size of less than about 2000 nm,
 said method comprising contacting said at least one active agent with lysozyme for a time and under conditions sufficient to provide an active agent/lysozyme composition having an effective average particle size of less than about 2000 nm.   
     
     
         21 . The method of  claim 20 , wherein said contacting comprising grinding, wet grinding, homogenizing. 
     
     
         22 .- 23 . (canceled) 
     
     
         24 . The method of  claim 20 , wherein said contacting comprises:
 (a) dissolving the active agent particles in a solvent;   (b) adding the resulting active agent solution to a solution comprising lysozyme; and   (c) precipitating the solubilized active agent/lysozyme composition by the addition thereto of a non-solvent.   
     
     
         25 . The method of  claim 20 , wherein the at least one active agent is selected from the group consisting of a drug, vitamin, herb, cosmetic agent, coloring agent, flavor agent, fragrance agent, sunscreen, moisturizer, deodorant, hair conditioner agent, hair dye, hair spray agent, hair cosmetic agent, hair cleanser agent, depilatory agent, insecticide, fertilizer, pesticide, herbicide, germicide, and plant growth regulating agent. 
     
     
         26 . The method of  claim 20 , wherein the at least one active agent is selected from the group consisting of proteins, peptides, nutraceuticals, carotenoids, anti-obesity agents, corticosteroids, elastase inhibitors, analgesics, anti-fungals, oncology therapies, anti-emetics, analgesics, cardiovascular agents, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, antibiotics, anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytic sedatives, astringents, beta-adrenoceptor blocking agents, blood products and substitutes, cardiac inotropic agents, contrast media, cough suppressants, diagnostic agents, diagnostic imaging agents, diuretics, dopaminergics, haemostatics, immunological agents, lipid regulating agents, muscle relaxants, parasympathomimetics, parathyroid calcitonin and biphosphonates, prostaglandins, radio-pharmaceuticals, sex hormones, anti-allergic agents, stimulants and anoretics, sympathomimetics, thyroid agents, vasodilators, xanthines, acne medication, alpha-hydroxy formulations, cystic-fibrosis therapies, asthma therapies, emphysema therapies, respiratory distress syndrome therapies, chronic bronchitis therapies, chronic obstructive pulmonary disease therapies, organ-transplant rejection therapies, therapies for tuberculosis and other infections of the lung, and respiratory illness therapies associated with acquired immune deficiency syndrome. 
     
     
         27 .- 29 . (canceled) 
     
     
         30 . The method of  claim 20 , further comprising at least one secondary surface stabilizer which is not lysozyme, and which is a cationic surface stabilizer. 
     
     
         31 .- 36 . (canceled) 
     
     
         37 . The method of  claim 20 , wherein the effective average particle size of the nanoparticulate composition is selected from the group consisting of less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 150 nm, less than about 100 nm, less than about 75 nm, and less than about 50 nm. 
     
     
         38 . The method of  claim 37 , wherein at least about 70%, at least about 90%, or at least about 95% of the active agent particles have a particle size less than the effective average particle size. 
     
     
         39 . A method of treating a mammal in need with a bioadhesive nanoparticulate composition comprising:
 (a) at least one active agent; and   (b) lysozyme as a surface stabilizer adsorbed on the surface of the active agent,   wherein the method comprises administering to said mammal a therapeutically effective amount of the nanoparticulate composition, wherein the active agent particles have an effective average particle size of less than about 2000 nm.   
     
     
         40 .- 44 . (canceled) 
     
     
         45 . The method of  claim 39 , further comprising at least one secondary surface stabilizer which is not lysozyme, and which is a cationic surface stabilizer. 
     
     
         46 .- 53 . (canceled)