Nanoparticulate and Controlled Release Compositions Comprising Aryl-Heterocyclic Compounds

Abstract

The present invention provides a composition comprising ziprasidone useful in the treatment and prevention of schizophrenia and similar psychiatric disorders. In one embodiment, the composition comprises nanoparticulate particles comprising ziprasidone and at least one surface stabilizer. The nanoparticulate particles have an effective average particle size of less than about 2000 nm. In another embodiment, the composition comprises a modified release composition that, upon administration to a patient, delivers ziprasidone in a bimodal, multimodal or continuous manner. The invention also relates to dosage forms containing such compositions, and to methods for the treatment and prevention of schizophrenia and similar psychiatric disorders.

1 . A stable nanoparticulate composition comprising: (A) particles comprising ziprasidone, said particles having an effective average particle size of less than about 2000 nm in diameter; and (B) at least one surface stabilizer. 
     
     
         2 . The composition of  claim 1 , wherein said particles are in a crystalline phase, an amorphous phase, a semi-crystalline phase, a semi amorphous phase, or a mixture thereof. 
     
     
         3 . The composition of  claim 1 , wherein the effective average particle size of said particles 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 100 nm, less than about 75 nm, and less than about 50 nm in diameter. 
     
     
         4 . The composition of  claim 1 , wherein the composition is formulated:
 (A) for administration selected from the group consisting of parenterally, orally, vaginally, nasally, rectally, otically, ocularly, locally, buccally, intracisternally, intraperitoneally, or topically;   (B) into a dosage form selected from the group consisting of tablets, capsules, sachets, solutions, dispersions, gels, aerosols, ointments, creams, and mixtures thereof;   (C) into a formulation selected from the group consisting of controlled release formulations, fast melt formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, and mixed immediate release and controlled release formulations; or   (D) any combination of (A), (B), or (C).   
     
     
         5 . The composition of  claim 1  further comprising one or more pharmaceutically acceptable excipients, carriers, or a combination thereof. 
     
     
         6 . The composition of  claim 1 , wherein:
 (A) said ziprasidone is present in said composition in an amount selected from the group consisting of from about 99.5% to about 0.001%, from about 95% to about 0.1%, or from about 90% to about 0.5%, by weight of the total combined dry weight of ziprasidone and surface stabilizer in the composition, not including other excipients;   (B) said surface stabilizer or surface stabilizers are present in a total amount of from about 0.5% to about 99.999%, from about 5.0% to about 99.9%, or from about 10% to about 99.5% by weight, based on the total combined dry weight of ziprasidone and surface stabilizer in the composition not including other excipients; or   (C) a combination of (A) and (B).   
     
     
         7 . The composition of  claim 1 , wherein the surface stabilizer is selected from the group consisting of a non-ionic surface stabilizer, an anionic surface stabilizer, a cationic surface stabilizer, a zwitterionic surface stabilizer, and an ionic surface stabilizer. 
     
     
         8 . The composition of  claim 1 , wherein the 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, lysozyme, 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 phospholipid, cationic lipids, polymethylmethacrylate trimethylammonium bromide, sulfonium compounds, polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethyl sulfate, hexadecyltrimethyl 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. 
     
     
         9 . The composition of  claim 1 , wherein the composition does not produce significantly different absorption levels when administered under fed as compared to fasting conditions. 
     
     
         10 . The composition of  claim 1 , wherein administration of the composition to a subject in a fasted state is bioequivalent to administration of the composition to a subject in a fed state. 
     
     
         11 . The composition of  claim 1 , wherein the pharmacokinetic profile of the composition is not significantly affected by the fed or fasted state of a subject ingesting said composition. 
     
     
         12 . A composition of  claim 1  wherein, upon administration of said composition to a mammal, the composition produces therapeutic results at a dosage which is less than that of a non-nanoparticulate dosage form of ziprasidone. 
     
     
         13 . A composition of  claim 1  which has:
 (a) a C max  for ziprasidone when assayed in the plasma of a mammalian subject following administration, that is greater than the C max  for the same ziprasidone when administered at the same dose using a non-nanoparticulate formulation; 
 (b) an AUC for ziprasidone when assayed in the plasma of a mammalian subject following administration, that is greater than the AUC for the same ziprasidone when administered at the same dose using a non-nanoparticulate formulation; 
 (c) a T max  for ziprasidone when assayed in the plasma of a mammalian subject following administration, that is less than the T max  for the same ziprasidone when administered at the same dose using a non-nanoparticulate formulation; or 
 (d) any combination of (a), (b), and (c). 
 
     
     
         14 . The composition of  claim 1 , additionally comprising one or more active compounds useful for the prevention and treatment of schizophrenia and similar psychiatric disorders 
     
     
         15 . The composition of  claim 14 , wherein the one or more active compounds is selected from the group consisting of compounds useful in the treatment of a condition selected from the group consisting of headaches, soreness, fever, and combinations thereof. 
     
     
         16 . The composition of  claim 1  wherein said particles contain a reservoir which contains ziprasidone said reservoir being enclosed by a semi-permeable membrane which allows for water to be imbibed into said particles, thus generating pressure which forces said ziprasidone out of said particles. 
     
     
         17 . The composition of  claim 1  wherein said reservoir comprises also an osmotic agent. 
     
     
         18 . A method of preparing the composition of  claim 1  comprising contacting particles comprising said ziprasidone with at least one surface stabilizer for a period of time and under conditions sufficient to provide a nanoparticulate composition comprising ziprasidone having an effective average particle size of less than about 2000 nm in diameter. 
     
     
         19 . The method of  claim 18 , wherein the contacting comprises grinding, wet grinding, homogenization, precipitation, template emulsion, or supercritical fluid particle generation techniques. 
     
     
         20 . The method of  claim 18 , wherein the effective average particle size of the nanoparticulate particles 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 100 nm, less than about 75 nm, and less than about 50 nm in diameter. 
     
     
         21 . A method of preventing and/or treating schizophrenia or a similar psychiatric disorders comprising administering a composition according to  claim 1 . 
     
     
         22 . The method of  claim 21 , wherein the effective average particle size of the particles 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 100 nm, less than about 75 nm, and less than about 50 nm in diameter. 
     
     
         23 . A pharmaceutical composition comprising a first component of active ingredient-containing particles and at least one subsequent component of active ingredient-containing particles, wherein at least one of said components comprises ziprasidone and at least one of said components further comprises a modified release coating, a modified release matrix material, or both, such that the composition, following oral delivery to a subject, delivers the active ingredient in a bimodal or multimodal manner. 
     
     
         24 . The composition of  claim 23  wherein each component comprises ziprasidone-containing particles. 
     
     
         25 . The composition of  claim 23  wherein the composition comprises a first component of ziprasidone-containing particles and one subsequent component of ziprasidone-containing particles. 
     
     
         26 . The composition of  claim 25 , wherein the first component comprises an immediate release component and the second component comprises a modified release component. 
     
     
         27 . The composition of  claim 23 , wherein the active ingredient-containing particles are erodable. 
     
     
         28 . The composition of  claim 23 , wherein at least one of said components further comprises a modified-release coating. 
     
     
         29 . The composition of  claim 23 , wherein at least one of said components further comprises a modified-release matrix material. 
     
     
         30 . The composition of  claim 29 , wherein said modified release matrix material is selected from the group consisting of hydrophilic polymers, hydrophobic polymers, natural polymers, synthetic polymers and mixtures thereof. 
     
     
         31 . The composition of  claim 30  wherein the ziprasidone is released to the surrounding environment by erosion. 
     
     
         32 . The composition of  claim 31  wherein said composition further comprises an enhancer. 
     
     
         33 . The composition of  claim 30  comprising from about 0.1 mg to about 1 g of ziprasidone. 
     
     
         34 . A pharmaceutical composition comprising a first component of active ingredient-containing particles and at least one subsequent component of active ingredient-containing particles, wherein at least one of said components comprises ziprasidone and at least one of said components further comprises a modified release coating, a modified release matrix material, or both, such that the composition, following oral delivery to a subject, delivers the active ingredient in a continuous manner. 
     
     
         35 . The composition of  claim 34  wherein each component comprises ziprasidone-containing particles. 
     
     
         36 . The composition of  claim 34  wherein the composition comprises a first component of ziprasidone-containing particles and one subsequent component of ziprasidone-containing particles. 
     
     
         37 . The composition of  claim 36 , wherein the first component comprises an immediate release component and the second component comprises a modified release component. 
     
     
         38 . The composition of  claim 34 , wherein the active ingredient-containing particles are erodable. 
     
     
         39 . The composition of  claim 34 , wherein at least one of said components further comprises a modified-release coating. 
     
     
         40 . The composition of  claim 34 , wherein at least one of said components further comprises a modified-release matrix material. 
     
     
         41 . The composition of  claim 40 , wherein said modified release matrix material is selected from the group consisting of hydrophilic polymers, hydrophobic polymers, natural polymers, synthetic polymers and mixtures thereof. 
     
     
         42 . The composition of  claim 41  wherein the ziprasidone is released to the surrounding environment by erosion. 
     
     
         43 . The composition of  claim 42  wherein said composition further comprises an enhancer. 
     
     
         44 . The composition of  claim 41  comprising from about 0.1 mg to about 1 g of ziprasidone. 
     
     
         45 . A dosage form comprising the composition of  claim 23 . 
     
     
         46 . The dosage form of  claim 45  comprising a blend of active ingredient-containing particles contained within a hard gelatin or soft gelatin capsule. 
     
     
         47 . The dosage form of  claim 46 , wherein the active ingredient-containing particles are in the form of mini-tablets and the capsule contains a mixture of said mini-tablets. 
     
     
         48 . The dosage form of  claim 47  in the form of tablet. 
     
     
         49 . The dosage form of  claim 48  wherein the ziprasidone-containing particles are provided in a rapidly dissolving dosage form. 
     
     
         50 . The dosage form of  claim 48  wherein the tablet is a fast-melt tablet. 
     
     
         51 . A dosage form comprising the composition of  claim 34 . 
     
     
         52 . The dosage form of  claim 51  comprising a blend of active ingredient-containing particles contained within a hard gelatin or soft gelatin capsule. 
     
     
         53 . The dosage form of  claim 52 , wherein the active ingredient-containing particles are in the form of mini-tablets and the capsule contains a mixture of said mini-tablets. 
     
     
         54 . The dosage form of  claim 53  in the form of tablet. 
     
     
         55 . The dosage form of  claim 54  wherein the ziprasidone-containing particles are provided in a rapidly dissolving dosage form. 
     
     
         56 . The dosage form of  claim 54  wherein the tablet is a fast-melt tablet. 
     
     
         57 . A method for preventing and/or treating schizophrenia or a similar psychiatric disorders comprising the step of administering a therapeutically effective amount of the composition of  claim 23 . 
     
     
         58 . A method for preventing and/or treating schizophrenia or a similar psychiatric disorders comprising the step of administering a therapeutically effective amount of the composition of  claim 34 . 
     
     
         59 . The composition of  claim 28  wherein the modified-release coating comprises a pH-dependent polymer coating for releasing a pulse of the active ingredient in said patient following a time delay of about 6 to about 12 hours after administration of said composition to said patient. 
     
     
         60 . The composition of  claim 59 , wherein said polymer coating comprises methacrylate copolymers. 
     
     
         61 . The composition of  claim 59 , wherein the polymer coating comprises a mixture of methacrylate and ammoniomethacrylate copolymers in a ratio sufficient to achieve a pulse of the active ingredient following a time delay of at least about 6 hours. 
     
     
         62 . The composition of  claim 61 , wherein the ratio of methacrylate to ammonio methacrylate copolymers is approximately 1:1. 
     
     
         63 . The composition of  claim 39  wherein the modified-release coating comprises a pH-dependent polymer coating for releasing a pulse of the active ingredient in said patient following a time delay of about 6 to about 12 hours after administration of said composition to said patient. 
     
     
         64 . The composition of  claim 63 , wherein said polymer coating comprises methacrylate copolymers. 
     
     
         65 . The composition of  claim 64 , wherein the polymer coating comprises a mixture of methacrylate and ammoniomethacrylate copolymers in a ratio sufficient to achieve a pulse of the active ingredient following a time delay of at least about 6 hours. 
     
     
         66 . The composition of  claim 65 , wherein the ratio of methacrylate to ammonio methacrylate copolymers is approximately 1:1. 
     
     
         67 . A controlled release composition comprising a population of nanoparticulate particles which comprise: (A) ziprasidone; and (B) a modified release coating or, alternatively or additionally, a modified release matrix material; such that the composition following oral delivery to a subject delivers the ziprasidone in a pulsatile or continuous manner. 
     
     
         68 . The composition of  claim 67 , wherein said composition does not produce significantly different absorption levels when administered under fed as compared to fasting conditions. 
     
     
         69 . The composition of  claim 67 , wherein the pharmacokinetic profile of said composition is not significantly affected by the fed or fasted state of a subject ingesting said composition. 
     
     
         70 . The composition of  claim 67 , wherein administration of said composition to a subject in a fasted state is bioequivalent to administration of said composition to a subject in a fed state. 
     
     
         71 . The composition of  claim 67 , wherein the population comprises modified-release particles. 
     
     
         72 . The composition of  claim 67 , wherein the population is an erodable formulation. 
     
     
         73 . The composition of  claim 67 , wherein said particles are each in the form of an osmotic device. 
     
     
         74 . The composition of  claim 71 , wherein the modified release particles comprise a modified-release coating. 
     
     
         75 . The composition of  claim 71 , wherein the modified release particles comprise a modified-release matrix material. 
     
     
         76 . The composition of  claim 71  wherein said modified release particles are combined in a formulation that releases said ziprasidone by erosion to the surrounding environment. 
     
     
         77 . The composition of  claim 71 , further comprising an enhancer. 
     
     
         78 . The composition of  claim 71 , wherein the amount of active ingredient contained therein is from about 0.1 mg to about 1 g. 
     
     
         79 . A dosage form comprising the composition of  claim 67 . 
     
     
         80 . The dosage form of  claim 79  comprising a blend of active ingredient-containing particles contained within a hard gelatin or soft gelatin capsule. 
     
     
         81 . The dosage form of  claim 80 , wherein the active ingredient-containing particles are in the form of mini-tablets and the capsule contains a mixture of said mini-tablets. 
     
     
         82 . The dosage form of  claim 81  in the form of tablet. 
     
     
         83 . The dosage form of  claim 82  wherein the ziprasidone-containing particles are provided in a rapidly dissolving dosage form. 
     
     
         84 . The dosage form of  claim 82  wherein the tablet is a fast-melt tablet. 
     
     
         85 . A method for the prevention and/or treatment of schizophrenia or a similar psychiatric disorder comprising administering a therapeutically effective amount of a composition of  claim 67 . 
     
     
         86 . The composition of  claim 71 , wherein the modified-release particles comprise a pH-dependent polymer coating which is effective in releasing a pulse release of the active ingredient following a time delay of six to twelve hours. 
     
     
         87 . The composition of  claim 86 , wherein the polymer coating comprises methacrylate copolymers. 
     
     
         88 . The composition of  claim 86 , wherein the polymer coating comprises a mixture of methacrylate and ammonio methacrylate copolymers in a ratio sufficient to achieve a pulse release of the active ingredient following a time delay. 
     
     
         89 . The composition of  claim 88 , wherein the ratio of methacrylate to ammonio methacrylate copolymers is approximately 1:1. 
     
     
         90 . The composition of  claim 67 , wherein said particles are each in the form of an osmotic device. 
     
     
         91 . The composition of  claim 1 , wherein the composition is formulated as a depot dosage form. 
     
     
         92 . The composition of  claim 1 , wherein the composition comprises a pharmaceutically acceptable salt of ziprasidone, said salt selected from the group consisting of tosylate, napsylate, besylate, hydrochloride, aspartate, tartrate, esylate, and mesylate salts of ziprasidone.