Nanoparticulate bisphosphonate compositions

Abstract

Nanoparticulate bisphosphonate compositions, having an effective average particle size of less than 2000 nm, are described. The compositions are useful in treating bone resorption in a mammal.

1 . A bisphosphonate dispersion comprising:
 (a) an aqueous dispersion medium;   (b) particles of at least one bisphosphonate complexed with a multivalent cation and having an effective average particle size of less than about 2000 nm, wherein the bisphosphonate-cation complex particles are dispersed in the aqueous dispersion medium; and   (b) at least one surface stabilizer adsorbed on the surface of the bisphosphonate-cation complex particles.   
     
     
         2 . The dispersion of  claim 1 , wherein the bisphosphonate is selected from the group consisting of alendronate, cimadronate, clodronate, tiludronate, etidronate, ibandronate, incadronate, olpadronate, neridronate, risedronate, peridronate, pamidronate, zolendronate, pharmaceutically acceptable salts thereof, pharmaceutically acceptable acids thereof, and mixtures thereof. 
     
     
         3 . The dispersion of  claim 2 , wherein the bisphosphonate is alendronate sodium or alendronate sodium trihydrate. 
     
     
         4 . The dispersion of  claim 1  formulated into an injectable dosage form. 
     
     
         5 . The dispersion of  claim 4 , wherein the multivalent cation is selected from the group consisting of Ca ++ , Zn ++ , Mn ++ , a poorly water soluble salt, a poorly water soluble ester, and a poorly water soluble prodrug. 
     
     
         6 . The dispersion of  claim 4 , wherein upon injection the composition forms a subcutaneous or intramuscular depot for extended bisphosphonate release. 
     
     
         7 . The dispersion of  claim 4 , wherein the bisphosphonate concentration in composition ranges from about 0.1% up to about 60% (w/v). 
     
     
         8 . The dispersion of  claim 1 , wherein the bisphosphonate dosage is about 1.5 to about 6,000 μg/kg body weight. 
     
     
         9 . The dispersion of  claim 6 , wherein the extended release is over a time period selected from the group consisting of up to about 1 week, up to about 2 weeks, up to about 3 weeks, up to about 4 weeks, up to about 1 month, up to about 2 months, up to about 3 months, up to about 4 months, up to about 5 months, up to about 6 months, up to about 7 months, up to about 8 months, up to about 9 months, up to about 10 months, up to about 11 months, up to about 12 months, up to about 18 months, up to about 2 years, up to about 30 months, up to about 3 years, up to about 3½ years, up to about 4 years, up to about 4½ years, and up to about 5 years. 
     
     
         10 . The dispersion of  claim 1 , wherein the bisphosphonate particles have a size 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 650 nm, less than about 600 nm, less than about 550 nm, less than about 500 nm, less than about 450 nm, less than about 400 nm, less than about 350 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, or less than about 50 nm. 
     
     
         11 . The dispersion of  claim 1  further comprising a biodegradable polymer, a lipid complex, an oil solution, or a combination thereof. 
     
     
         12 .- 15 . (canceled) 
     
     
         16 . The dispersion of  claim 1 , comprising a blend of at least two different populations of bisphosphonate particles which have different in vitro dissolution profiles. 
     
     
         17 . The dispersion of  claim 1 , wherein the dispersion further comprises one or more pharmaceutically acceptable excipients, carriers, or a combination thereof. 
     
     
         18 . The dispersion of  claim 1 , wherein the at least one surface stabilizer is present in an amount selected from the group consisting of from about 0.5% to about 99.999% by weight, from about 5.0% to about 99.9% by weight, and from about 10% to about 99.5% by weight, based on the total combined dry weight of the bisphosphonate and at least one surface stabilizer, not including other excipients. 
     
     
         19 . The dispersion of  claim 1 , wherein the bisphosphonate 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 bisphosphonate and at least one surface stabilizer, not including other excipients. 
     
     
         20 . The dispersion of  claim 1 , comprising at least two surface stabilizers. 
     
     
         21 . The dispersion of  claim 1 , wherein the surface stabilizer is selected from the group consisting of an anionic surface stabilizer, a cationic surface stabilizer, a zwitterionic surface stabilizer, a non-ionic surface stabilizer, and an ionic surface stabilizer. 
     
     
         22 . The dispersion of  claim 1 , wherein the at least one surface stabilizer is selected from the group consisting of cetyl pyridinium chloride, gelatin, casein, phosphatides, dextran, glycerol, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, dodecyl trimethyl ammonium bromide, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, hydroxypropyl celluloses, hypromellose, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hypromellose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone, 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde, poloxamers; poloxamines, a charged phospholipid, dioctylsulfosuccinate, dialkylesters of sodium sulfosuccinic acid, sodium lauryl sulfate, alkyl aryl polyether sulfonates, mixtures of sucrose stearate and sucrose distearate, p-isononylphenoxypoly-(glycidol), decanoyl-N-methylglucamide; n-decyl β-D-glucopyranoside; n-decyl β-D-maltopyranoside; n-dodecyl β-D-glucopyranoside; n-dodecyl β-D-maltoside; heptanoyl-N-methylglucamide; n-heptyl-β-D-glucopyranoside; n-heptyl β-D-thioglucoside; n-hexyl β-D-glucopyranoside; nonanoyl-N-methylglucamide; n-noyl β-D-glucopyranoside; octanoyl-N-methylglucamide; n-octyl-β-D-glucopyranoside; octyl β-D-thioglucopyranoside; lysozyme, PEG-phospholipid, PEG-cholesterol, PEG-cholesterol derivative, PEG-vitamin A, PEG-vitamin E, random copolymers of vinyl acetate and vinyl pyrrolidone, a cationic polymer, a cationic biopolymer, a cationic polysaccharide, a cationic cellulosic, a cationic alginate, a cationic nonpolymeric compound, a cationic phospholipids, cationic lipids, polymethylmethacrylate trimethylammonium bromide, sulfonium compounds, polyvinylpyrrolidone-2-dimethylamino ethyl methacrylate dimethyl sulfate, hex adecyltrimethyl ammonium bromide, phosphonium compounds, quarternary ammonium compounds, 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 chloride bromide, C 12-15 -dimethyl hydroxyethyl ammonium chloride, C 12-15 -dimethyl hydroxyethyl ammonium chloride 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 -trimethyl ammonium bromides, C 15 -trimethyl ammonium bromides, 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, amine salts, amine oxides, imide azolinium salts, protonated quaternary acrylamides, methylated quaternary polymers, and cationic guar. 
     
     
         23 . The dispersion of  claim 1 , comprising as a surface stabilizer a povidone polymer having a molecular weight of about 40,000 daltons or less. 
     
     
         24 . The dispersion of  claim 1 , additionally comprising one or more non-bisphosphonate active agents. 
     
     
         25 . The dispersion of  claim 1 , wherein the composition redisperses in a biorelevant media such that the bisphosphonate particles have an effective average particle size selected from the group consisting of less than about 2 microns, 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 650 nm, less than about 600 nm, less than about 550 nm, less than about 500 nm, less than about 450 nm, less than about 400 nm, less than about 350 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. 
     
     
         26 . A method of making a nanoparticulate bisphosphonate dispersion comprising:
 (a) complexing at least one bisphosphonate with a multivalent cation;   (b) reducing the particle size of the bisphosphonate to an effective average particle size of less than about 2000 nm in the presence of an aqueous dispersion medium;   wherein at least one surface stabilizer is combined with the bisphosphonate either before, during, or after particle size reduction.   
     
     
         27 . A method of inhibiting bone resorption in a mammal in need thereof comprising administering a bisphosphonate dispersion comprising:
 (a) an aqueous dispersion medium;   (b) particles of at least one bisphosphonate complexed with a multivalent cation and having an effective average particle size of less than about 2000 nm, wherein the bisphosphonate-cation complex particles are dispersed in the aqueous dispersion medium; and   (b) at least one surface stabilizer adsorbed on the surface of the bisphosphonate-cation complex particles.   
     
     
         28 . The method of  claim 27 , wherein the dispersion is in an injectable dosage forms that forms a depot following administration. 
     
     
         29 . The method of  claim 28 , wherein the administration is given to the mammal in need of such therapy at frequency intervals of greater than one week up to and including one year and up to once a lifetime. 
     
     
         30 . The method of  claim 27  which does not produce significant esophageal and upper gastrointestinal tract discomfort resulting from the administration of a bisphosphonate.