Nanoparticulate formulations and methods for the making and use therof

Abstract

The present invention is directed to size-stabilized drug nanoparticulate compositions and methods of preparation thereof.

1 . Drug complexed particles having a volume weighted median diameter (D50) from about 50 nm to about 500 nm, each of the particles comprising in association (i) a drug capable of forming a cyclodextrin inclusion complex and having an aqueous solubility of less than 1 mg/ml in a pH of about 7.4, (ii) a surface stabilizer, and (iii) a complexing agent capable of forming a cyclodextrin inclusion complex when the particles are cured for at least about 3 days. 
     
     
         2 . The drug complexed particles of  claim 1 , wherein the complexing agent is included in an amount effective to cause an initial increase in the size of the particles, wherein the volume weighted median diameter (D50) of the particles before the initial growth is from about 100 to about 400 nm and the D50 at the end of the curing time is 20% to 300% larger than the D50 measured before the curing period. 
     
     
         3 . The drug complexed particles of  claim 1 , wherein the surface stabilizer is at least one non-ionic material selected from the group consisting of binders, fillers, surfactants/wetting agents; and/or at least one ionic surface stabilizer. 
     
     
         4 . The drug complexed particles of  claim 2 , wherein the complexing agent is selected from the group consisting of phenol, parabens, ascorbic acid, methyl anthranilate, salicylic acid, acetosalicyclic acid, tocopherol, organic acids, carboxylic acids, aromatic acids, aromatic esters, acid salts of amino acids, benzaldehyde, cinnimaldehyde, imidazole, menthol, thiophenol, m-aminobenzoic acid, anthranilic acid, picolinic acids and alkyl esters thereof, toluidides, sodium benzoate, para-aminobenzoic acid and esters, sorbic and benzoic acids, 2,6-di-t-butyl-alpha-dimethylamino-p-cresol, t-butylhydroquinone, di-t-amylhydroquinone, di-t-butylhydroquinone, butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), pyrocatechol, pyrogallol, esters, isomeric compounds thereof, pharmaceutically acceptable salts thereof, and mixtures of any of the foregoing. 
     
     
         5 . The drug complexed particles of  claim 4 , wherein the complexing agent is selected from the group consisting of methylparaben, propylparaben, potassium methylparaben, sodium methylparaben, methyl anthranilate, benzoic acid, sodium benzoate, and any combinations or mixtures thereof. 
     
     
         6 . The drug complexed particles of  claim 4 , which comprise from about 0.1% to about 8%, w/w of the complexing agent. 
     
     
         7 . The drug complexed particles of  claim 5 , wherein the surface stabilizer is selected from the group consisting of cellulosics, polyvinylpyrrolidones, polyethylene glycols, pluronics and any combinations or mixtures thereof. 
     
     
         8 . The drug complexed particles of  claim 5 , wherein the surface stabilizer is selected from the group consisting of hydroxypropylmethylcellulose, polyvinyl alcohol, docusate sodium, sodium lauryl sulfate, polyvinylpyrrolidone, Plasdone, and mixtures thereof. 
     
     
         9 . The drug complexed particles of  claim 2 , wherein the volume weighted diameter (D50) of the complexed particles does not change by more than 10% after a time in consecutive measurements separated by about 72 hours. 
     
     
         10 . The drug complexed particles of  claim 2 , wherein the complexed particles increase in effective particle size from about 0% to about 200% upon dispersion in simulated gastric or intestinal fluid as compared to dispersion in water under the same conditions. 
     
     
         11 . The drug complexed particles of  claim 2 , wherein the D50 after the endpoint is reached is less than about 500 nm. 
     
     
         12 . A pharmaceutical composition, comprising the drug complexed particles of  claim 1  together with at least one pharmaceutically acceptable excipient. 
     
     
         13 . The pharmaceutical composition of  claim 12 , which is in a form of a solid dosage form. 
     
     
         14 . The pharmaceutical composition of  claim 12 , which is in a form of a liquid suspension. 
     
     
         15 . A method of treatment, comprising administering an effective dose of the pharmaceutical composition of  claim 13  to a human or animal in need thereof. 
     
     
         16 . A method of treatment, comprising administering an effective dose of the pharmaceutical composition of  claim 14  to a human or animal in need thereof. 
     
     
         17 . Size-stabilized drug complexed particles comprising a drug capable of forming a cyclodextrin inclusion complex and having an aqueous solubility of less than 1 mg/ml in a pH of about 7.4 in association with effective amounts of a surface stabilizer and a complexing agent capable of forming a cyclodextrin inclusion complex, the size-stabilized drug complexed particles having a volume weighted median diameter (D50) from about 50 nm to about 500 nm; the drug complexed particles exhibiting an increase in volume weighted median diameter (D50) of from 0% to not more than about 200% when the formulation is dispersed in simulated gastric fluid (SGF) or simulated intestinal fluid (SIF) at a concentration of 0.5 to 1 mg drug/mL and placed in a heated bath at 36° to 38° C. for 1 hour using a Type I or II dissolution apparatus and a stirring rate of 75 RPM, as compared to the D50 of the drug particles when the formulation is dispersed in distilled water under the same conditions. 
     
     
         18 . The size-stabilized drug complexed particles of  claim 16 , wherein the surface stabilizer is at least one non-ionic material selected from the group consisting of binders, fillers, surfactants/wetting agents; and/or at least one ionic surface stabilizer; and the complexing agent is selected from the group consisting of phenol, parabens, ascorbic acid, methyl anthranilate, salicylic acid, acetosalicyclic acid, tocopherol, organic acids, carboxylic acids, aromatic acids, aromatic esters, acid salts of amino acids, benzaldehyde, cinnimaldehyde, imidazole, menthol, thiophenol, m-aminobenzoic acid, anthranilic acid, picolinic acids and alkyl esters thereof, toluidides, sodium benzoate, para-aminobenzoic acid and esters, phosphoric acids, sorbic and benzoic acids, 2,6-di-t-butyl-alpha-dimethylamino-p-cresol, t-butylhydroquinone, di-t-amylhydroquinone, di-t-butylhydroquinone, butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), pyrocatechol, pyrogallol, esters, isomeric compounds thereof, pharmaceutically acceptable salts thereof, and mixtures of any of the foregoing. 
     
     
         19 . A pharmaceutical composition, comprising the drug complexed particles of  claim 17  together with at least one pharmaceutically acceptable excipient. 
     
     
         20 . The pharmaceutical composition of  claim 19 , which is in a form of a solid dosage form. 
     
     
         21 . The pharmaceutical composition of  claim 19 , which is in a form of a liquid suspension. 
     
     
         22 . The size stabilized drug complexed particles of  claim 17 , wherein the complexing agent is selected from the group consisting of methylparaben, propylparaben, potassium methylparaben, sodium methylparaben, methyl anthranilate, benzoic acid, sodium benzoate, and any combinations or mixtures thereof. 
     
     
         23 . The size-stabilized drug complexed particles of  claim 15 , wherein the complexing agent is methyl anthranilate. 
     
     
         24 . A method of treatment, comprising administering an effective dose of the pharmaceutical composition of  claim 20  to a human or animal in need thereof. 
     
     
         25 . A method of treatment, comprising administering an effective dose of the pharmaceutical composition of  claim 21  to a human or animal in need thereof. 
     
     
         26 . The size-stabilized drug complexed particles of  claim 17 , which comprise from about 0.1% to about 8%, w/w of the complexing agent. 
     
     
         27 . The pharmaceutical composition of  claim 20 , which is an oral solid dosage form providing an immediate, delayed, sustained, or pulsatile release of the drug when orally administered to a human or animal. 
     
     
         28 . The pharmaceutical composition of  claim 27 , wherein the oral solid dosage form is a tablet or a capsule. 
     
     
         29 . The pharmaceutical composition of  claim 19 , wherein the drug complexed particles are spray-layered along with effective amounts of a water soluble spacer and an ionic dispersion modulator onto a plurality of inert beads. 
     
     
         30 . The pharmaceutical composition of  claim 29 , wherein the ionic dispersion modulator is in an amount effective to provide a satisfactory redispersibility of the beads with acceptable particle size and stability. 
     
     
         31 . The composition of  claim 29 , wherein the ionic dispersion modulator is an organic or inorganic salt selected from the group consisting of a magnesium salt, a calcium salt, a lithium salt, a potassium salt, a sodium salt, a citrate salt, a succinate salt, a fumarate salt, malate salt, maleate salt, a tartrate salt, a glutarate salt, a lactate salt and mixtures thereof. 
     
     
         32 . A method for preparing stabilized drug particles, comprising:
 a) reducing the size of drug particles capable of forming a cyclodextrin inclusion complex and having an aqueous solubility of less than 1 mg/ml in a pH of about 7.4 into a size range of about 50 nm to about 200 nm;   b) adding an effective amount of a surface stabilizer to the drug particles before, during or after reducing the size of the drug particles to form particles comprising the drug and the surface stabilizer; and   c) further stabilizing the particles of step b) by adding an effective amount of a complexing agent capable of forming a cyclodextrin inclusion complex to provide particles that attain a stabilized size such that the volume weighted median diameter (D50) of the particles is from about 50 nm to about 500 nm.   
     
     
         33 . The method of  claim 32 , wherein the complexing agent can be added to the stabilized drug particles of step b) to provide particles that attain a stabilized size such that the volume weighted median diameter (D50) of the particles is from about 50 nm to about 500 nm. 
     
     
         34 . The method of  claim 33 , further comprising spraying layering inert beads with a suspension of the stabilized drug particles together with a water soluble spacer and an ionic dispersion modulator in an amount effective to reduce the amount of water soluble spacer needed to redisperse the spray-layered beads. 
     
     
         35 . The method of  claim 34 , wherein the water soluble spacer comprises from about 0 to about 60% and the ionic modulator comprises from about 0 to about 40% of the spray-layered particles, by weight stabilized drug particles. 
     
     
         36 . The method of  claim 35 , wherein the ionic dispersion modulator is selected from the group consisting of an organic salt, an inorganic salt, and mixtures thereof. 
     
     
         37 . The method of  claim 36 , wherein the inorganic salts is selected from the group consisting of a magnesium salt, a calcium salt, a lithium salt, a potassium salt, a sodium salt and mixtures thereof; and the organic salt is selected from the group consisting of a citrate salt, a succinate salt, a fumarate salt, a malate salt, maleate salt, a tartrate salt, a glutarate salt, a lactate salt and mixtures thereof. 
     
     
         38 . A method of treatment, comprising administering the composition of  claim 33  to a human or animal in need thereof. 
     
     
         39 . A solid pharmaceutical composition, comprising a plurality of inert beads spray layered with a coating comprising (a) drug complexed particles having a volume weighted median diameter (D50) from about 50 nm to about 500 nm, each of the particles comprising in association (i) a drug capable of forming a cyclodextrin inclusion complex and having an aqueous solubility of less than 1 mg/ml in a pH of about 7.4, (ii) a surface stabilizer, (iii) a complexing agent capable of forming a cyclodextrin inclusion complex; together with effective amounts of (b) a water soluble spacer and (c) an ionic dispersion modulator. 
     
     
         40 . The pharmaceutical composition, of  claim 39 , further comprising one or more pharmaceutically acceptable excipients. 
     
     
         41 . The pharmaceutical composition, of  claim 40 , which is a liquid suspension of said coated inert beads. 
     
     
         42 . The pharmaceutical composition, of  claim 40 , wherein a therapeutically effective dose of the coated inert beads are incorporated into a hard gelatin capsule. 
     
     
         43 . The pharmaceutical composition, of  claim 42 , wherein the coated inert beads are further over-coated with a coating which imparts a sustained or delayed release of the drug from the formulation when the formulation is exposed to simulated gastrointestinal fluid. 
     
     
         44 . The pharmaceutical composition, of  claim 42 , wherein a portion of the coated inert beads incorporated into the hard gelatin capsule are in immediate release form and a portion of the inert beads incorporated into the hard gelatin capsule are in modified release form selected from the group consisting of sustained release, delayed release and a mixture of the foregoing, to provide a pulsatile release of drug from the formulation when the formulation is exposed to simulated gastrointestinal fluid. 
     
     
         45 . An orally ingestible tablet, comprising a compressed mixture of (a) drug complexed particles having a volume weighted median diameter (D50) from about 50 nm to about 500 nm, each of the particles comprising in association (i) a drug capable of forming a cyclodextrin inclusion complex and having an aqueous solubility of less than 1 mg/ml in a pH of about 7.4, (ii) a surface stabilizer, (iii) a complexing agent capable of forming a cyclodextrin inclusion complex; together with effective amounts of (b) a water soluble spacer and (c) an ionic dispersion modulator; an inert diluent; and a tableting lubricant. 
     
     
         45 . The orally ingestible tablet of  claim 45 , further comprising one or more excipients which impart a sustained or delayed or pulsatile release of the drug from the formulation when the formulation is exposed to simulated gastrointestinal fluid. 
     
     
         47 . A size-stabilized nanoparticulate liquid composition comprising a drug capable of forming a cyclodextrin inclusion complex and having an aqueous solubility of less than 1 mg/ml in a pH of about 7.4 in association with effective amounts of a surface stabilizer and a complexing agent capable of forming a cyclodextrin inclusion complex, wherein the volume weighted median diameter (D50) of the size-stabilized particles is from about 50 nm to about 500 nm after curing. 
     
     
         48 . The nanoparticulate liquid composition of  claim 47 , wherein the composition further contains at least one additional pharmaceutically acceptable excipient selected from the group consisting of a hydrophilic polymer, a wetting agent, an ionic dispersion modulator, a water soluble spacer, and any combinations or mixture thereof. 
     
     
         49 . The nanoparticulate liquid composition of  claim 47 , wherein the liquid composition is converted to a solid nanoparticulate composition by removal of solvent.