Multimodal particulate formulations

Abstract

Multimodal particulate formulations of medicaments and methods for their use, e.g. by nasal or pulmonary administration for the treatment of various medical conditions, are provided.

1 - 40 . (canceled) 
     
     
         41 . A bimodal particulate composition for nasal administration of benzodiazepine particulates, comprising:
 a first population of particles comprising a benzodiazepine and having a first effective average particle size and a second population of particles comprising a benzodiazepine and having a second effective average particle size, and   a penetration enhancer;   wherein said first effective average particle size is greater than 5.0 μm;   said second effective average particle size is between 0.5 and 5.0 μm;   said first effective average particle size is at least 10% greater than said second effective average particle size;   said benzodiazepine comprises at least one member selected from the group consisting of: alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam, flumazenil, flurazepam, halazepam, midazolam, nordazepam, medazepam, diazepam, nitrazepam, oxazepam, lorazepam, mexazolam, prazepam, quazepam, triazolam, temazepam, loprazolam, and pharmaceutically acceptable salts and combinations thereof.   
     
     
         42 . The bimodal particulate composition of  claim 41 , wherein the composition is a suspension of said particulates in a liquid carrier or diluent. 
     
     
         43 . The composition of  claim 41 , wherein the penetration enhancer comprises at least one member of the group consisting 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 and octyl β-D-thioglucopyranoside. 
     
     
         44 . A method of using a bimodal particulate composition of  claim 41 , wherein the bimodal particulate composition is administered intranasally to a patient in need of benzodiazepine. 
     
     
         45 . The method of  claim 44 , wherein the bimodal particulate composition comprises an amount of benzodiazepine effective for acute treatment of seizure, reduction in the frequency of seizure and/or reduction in severity of seizure. 
     
     
         46 . An aerosol composition of an aqueous suspension or dispersion of nanoparticulate benzodiazepine, comprising an aerosol-forming solvent and benzodiazepine particles, wherein
 droplets of the aerosol have a mass median aerodynamic diameter (MMAD) less than or equal to 1000 μm; and   said nanoparticulate benzodiazepine particles comprise:   a first population of particles comprising a benzodiazepine and having a first effective average particle size and a second population of particles comprising a benzodiazepine and having a second effective average particle size, and   wherein said first effective average particle size is greater than 5.0 μm;   said second effective average particle size is between 0.5 and 5.0 μm;   said first effective average particle size is at least 10% greater than said second effective average particle size;   said benzodiazepine comprises at least one member selected from the group consisting of: alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam, flumazenil, flurazepam, halazepam, midazolam, nordazepam, medazepam, diazepam, nitrazepam, oxazepam, lorazepam, mexazolam, prazepam, quazepam, triazolam, temazepam, loprazolam, and pharmaceutically acceptable salts and combinations thereof.   
     
     
         47 . The composition of  claim 46 , wherein the composition further comprises at least one penetration enhancer selected from the group consisting 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 and octyl β-D-thioglucopyranoside. 
     
     
         48 . A method of using an aerosol composition of  claim 47 , wherein the aerosol composition is administered to at least one nostril. 
     
     
         49 . The method of  claim 48 , wherein the aerosol composition comprises an amount of benzodiazepine effective for acute treatment of seizure, reduction in the frequency of seizure and or reduction in severity of seizure. 
     
     
         50 . A method of using an aerosol composition of  claim 48 , wherein the composition is administered with a pulmonary delivery device. 
     
     
         51 . The method of using an aerosol composition of  claim 48 , wherein the pulmonary delivery device is selected from a nebulizer, a dry powder inhaler and a metered dose inhaler.