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.

What is claimed is: 
     
         1 . A composition for aerosol administration of a medicament, comprising a first population of particles having a first effective average particle size and a second population of particles having a second effective average particle size, wherein the first effective average particle size is at least 1.5 times that of the second effective average particle size. 
     
     
         2 . The composition of  claim 1 , wherein the medicament comprises at least one benzodiazepine. 
     
     
         3 . The composition of  claim 2 , wherein the medicament comprises at least one benzodiazepine selected from the group consisting of: alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam, flumazenil, flurazepam, halazepam, midazolam, nordazepam, medazepam, diazepam, nitrazepam, oxazepam, medazepam, lorazepam, mexazolam, prazepam, quazepam, triazolam, temazepam, loprazolam, and pharmaceutically acceptable salts and combinations thereof. 
     
     
         4 . The composition of  claim 1 , wherein the medicament comprises at least one member of the group consisting of other anticonvulsants (such as aromatic allylic alcohols, barbiturates, bromides, carbamates, carboxamides, fatty acids, topiramate, Gaba analogs, hydantoins, oxazolidinediones, propionates, pyrimidinediones, pyrrolidines, succinimides, sulfonamides, triazines, ureas, valproylamides, etc.), insulin, calcitonins, enkephalins, LHRH and analogs, GHRH (growth hormone releasing hormone), nifedipin, THF (thymic humoral factor), CGRP (calcitonin gene related peptide), atrial natriuretic peptide, antibiotics, metoclopramide, ergotamine, Pizotizin, nasal vaccines (particularly HIV vaccines, measles, rhinovirus Type 13 and respiratory syncitial virus), pentamidine, CCK (Cholecystikinine), DDVAP, Interferons, growth hormone, secretin, bradykinin antagonists, GRF (Growth releasing factor), THF, TRH (Thyrotropin releasing hormone), ACTH analogues, IGF (Insulin like growth factors), CGRP (Calcitorin gene related peptide), Atrial Natriuretic peptide, Vasopressin and analogs (DDAVP, Lypressin), Metoclopramide, Migraine treatment (e.g. Dihydroergotamine, Ergometrine, Ergotamine, Pizotizin), Nasal Vaccines (Particularly AIDS vaccines), FACTOR VIII, Colony Stimulating factors, G-CSF (granulocyte-colony stimulating factor), EPO (Erythropoitin) PTH (Parathyroid hormone), antibiotics and antimicrobial agents (such as tetracyline hydrochloride, leucomycin, penicillin, penicillin derivatives, erythromycin, gentamicin, sulphathiazole and nitrofurazone), local anaesthetics, vasoconstrictors, tetrahydrozoline hydrochloride, naphazoline nitrate, oxymetazoline hydrochloride and tramazoline hydrochloride, cardiotonics, vasodilators, antiseptics, enzymes, vitamin D, active vitamin D, vitamin C, sex hormones, hypotensives, sedatives, anti-tumor agents, steroidal anti-inflammatory agents, non-steroidal anti-inflammatory agents, enzymatic anti-inflammatory agents, anti-allergic agents, antitussive-expectorant agents, antasthmatic agents, pain medications, antiproliferative or anticancer chemotherapeutic drugs, insomnia drugs, antibiotics, drugs for treating spasticity, antiemetics, antipsychotics, long-acting Beta 2 -adrenertic agonists, short-acting Beta 2 -adrenergic agonists, muscarinic antagonists, corticosteroids, atypical antipsychotics, serotonin reuptake inhibitors, tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, or pharmaceutically acceptable salts or combinations thereof. 
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein the first population of particles has a average size in the range of about 25 to about 7000 nm and the second population of particles has a average size in the range of about 500 to about 10,000 nm. 
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein the difference between the average particle size of the first and second populations is greater than about 100 nm, greater than about 200 nm, greater than about 500 nm, greater than about 1000 nm, greater than about 2000 nm, greater than about 3000 nm, greater than about 4000 nm, greater than about 5000 nm, greater than about 6000 nm, greater than about 7000 nm, greater than about 8000 nm, greater than about 9000 nm or greater than about 10,000 nm. 
     
     
         7 . The pharmaceutical composition of  claim 1 , wherein the difference between the average particle size of the first and second particle populations is greater than about 10%, greater than about 20% or greater than about 30% of the average particle size of the second population of particles. 
     
     
         8 . The pharmaceutical composition of  claim 1 , wherein the composition is a dry powder or a suspension of particles in a liquid carrier or diluent. 
     
     
         9 . The pharmaceutical composition of  claim 1 , comprising at least first and second populations of particles, wherein the first population of particles has a particle size distribution having a first node between about 0.5 μm and about 5.0 μm and the second population of particles has a particle size distribution having a second node greater than about 5.0 μm. 
     
     
         10 . The pharmaceutical composition of  claim 1 , comprising at least first, second and third populations of particles, wherein the first population of particles has a particle size distribution having a first node between about 0.5 μm and about 2.0 μm, the second population of particles has a particle size distribution having a second node between about 2.0 μm and about 5.0 μm, and the third population of particles has a particle size distribution having a third node greater than about 5.0 μm. 
     
     
         11 . The pharmaceutical composition of  claim 1 , adapted for nasal or pulmonary delivery. 
     
     
         12 . A method of using a composition of  claim 1 , wherein the medicament is administered to at least one nostril. 
     
     
         13 . The method of  claim 12 , wherein the medicament is an amount of benzodiazepine effective for acute treatment of seizure, reduction in the frequency of seizure and or reduction in severity of seizure. 
     
     
         14 . A method of using a composition of  claim 1 , wherein the medicament is administered with a pulmonary delivery device. 
     
     
         15 . The method of using a composition of  claim 14 , wherein the pulmonary delivery device is selected from a nebulizer, a dry powder inhaler and a metered dose inhaler. 
     
     
         16 . A pharmaceutical particulate composition for aerosol delivery of a medicament comprising particulates having a multimodal particle size distribution. 
     
     
         17 . The pharmaceutical particulate composition of  claim 16 , wherein the particulates have a bimodal particle size distribution. 
     
     
         18 . The pharmaceutical composition of  claim 16 , wherein the medicament comprises at least one benzodiazepine. 
     
     
         19 . The pharmaceutical composition of  claim 18 , wherein the medicament comprises at least one benzodiazepine selected from the group consisting of alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam, flumazenil, flurazepam, halazepam, midazolam, nordazepam, medazepam, diazepam, nitrazepam, oxazepam, medazepam, lorazepam, mexazolam, prazepam, quazepam, triazolam, temazepam, loprazolam, and pharmaceutically acceptable salts and combinations thereof. 
     
     
         20 . The pharmaceutical composition of  claim 16 , wherein the medicament comprises at least one member of the group consisting of other anticonvulsants (such as aromatic allylic alcohols, barbiturates, bromides, carbamates, carboxamides, fatty acids, topiramate, Gaba analogs, hydantoins, oxazolidinediones, propionates, pyrimidinediones, pyrrolidines, succinimides, sulfonamides, triazines, ureas, valproylamides, etc.), insulin, calcitonins, enkephalins, LHRH and analogs, GHRH (growth hormone releasing hormone), nifedipin, THF (thymic humoral factor), CGRP (calcitonin gene related peptide), atrial natriuretic peptide, antibiotics, metoclopramide, ergotamine, Pizotizin, nasal vaccines (particularly HIV vaccines, measles, rhinovirus Type 13 and respiratory syncitial virus), pentamidine, CCK (Cholecystikinine), DDVAP, Interferons, growth hormone, secretin, bradykinin antagonists, GRF (Growth releasing factor), THF, TRH (Thyrotropin releasing hormone), ACTH analogues, IGF (Insulin like growth factors), CGRP (Calcitorin gene related peptide), Atrial Natriuretic peptide, Vasopressin and analogs (DDAVP, Lypressin), Metoclopramide, Migraine treatment (e.g. Dihydroergotamine, Ergometrine, Ergotamine, Pizotizin), Nasal Vaccines (Particularly AIDS vaccines), FACTOR VIII, Colony Stimulating factors, G-CSF (granulocyte-colony stimulating factor), EPO (Erythropoitin) PTH (Parathyroid hormone), antibiotics and antimicrobial agents (such as tetracyline hydrochloride, leucomycin, penicillin, penicillin derivatives, erythromycin, gentamicin, sulphathiazole and nitrofurazone), local anaesthetics, vasoconstrictors, tetrahydrozoline hydrochloride, naphazoline nitrate, oxymetazoline hydrochloride and tramazoline hydrochloride, cardiotonics, vasodilators, antiseptics, enzymes, vitamin D, active vitamin D, vitamin C, sex hormones, hypotensives, sedatives, anti-tumor agents, steroidal anti-inflammatory agents, non-steroidal anti-inflammatory agents, enzymatic anti-inflammatory agents, anti-allergic agents, antitussive-expectorant agents, antasthmatic agents, pain medications, antiproliferative or anticancer chemotherapeutic drugs, insomnia drugs, antibiotics, drugs for treating spasticity, antiemetics, antipsychotics, long-acting Beta 2 -adrenertic agonists, short-acting Beta 2 -adrenergic agonists, muscarinic antagonists, corticosteroids, atypical antipsychotics, serotonin reuptake inhibitors, tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, or pharmaceutically acceptable salts or combinations thereof. 
     
     
         21 . The pharmaceutical composition of  claim 16 , wherein the particles have an effective average size greater than about 500 nm, 1000 nm, greater than about 2000 nm, greater than about 4000 nm or greater than 5000 nm. 
     
     
         22 . The pharmaceutical composition of  claim 16 , wherein the composition is a dry powder or a suspension of particles in a liquid. 
     
     
         23 . The composition of  claim 22 , wherein the composition is a non-aqueous dispersion or suspension of nanoparticulate benzodiazepine particles. 
     
     
         24 . The pharmaceutical composition of  claim 16 , comprising at least first and second populations of particles, wherein the first population of particles has a particle size distribution having a first node between about 0.5 μm and about 5.0 μm and the second population of particles has a particle size distribution having a second node greater than about 5.0 μm. 
     
     
         25 . The pharmaceutical composition of  claim 16 , comprising at least first, second and third populations of particles, wherein the first population of particles has a particle size distribution having a first node between about 0.5 μm and about 2.0 μm, the second population of particles has a particle size distribution having a second node between about 2.0 μm and about 5.0 μm, and the third population of particles has a particle size distribution having a third node greater than about 5.0 μm. 
     
     
         26 . The pharmaceutical composition of  claim 16 , adapted for nasal or pulmonary delivery. 
     
     
         27 . A method of using a composition of  claim 16 , wherein the medicament is administered to at least one nostril. 
     
     
         28 . A method of using a composition of  claim 16 , wherein the medicament is administered with a pulmonary delivery device. 
     
     
         29 . The method of using a composition of  claim 28 , wherein the pulmonary delivery device is selected from a nebulizer, a dry powder inhaler and a metered dose inhaler. 
     
     
         30 . An aerosol composition of an aqueous suspension or dispersion of nanoparticulate medicament particles, wherein droplets of the aerosol have a mass median aerodynamic diameter (MMAD) less than or equal to about 1000 μm and the nanoparticulate particles have an effective average particle size of less than about 5000 nm. 
     
     
         31 . The aerosol composition of  claim 30 , wherein the nanoparticular medicament particles comprise at least one benzodiazepine. 
     
     
         32 . The aerosol composition of  claim 31 , wherein the medicament particles comprise at least one benzodiazepine selected from the group consisting of: alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam, flumazenil, flurazepam, halazepam, midazolam, nordazepam, medazepam, diazepam, nitrazepam, oxazepam, medazepam, lorazepam, mexazolam, prazepam, quazepam, triazolam, temazepam, loprazolam, and pharmaceutically acceptable salts and combinations thereof. 
     
     
         33 . A method of using a composition of  claim 32 , wherein the medicament is administered to at least one nostril. 
     
     
         34 . The method of  claim 33 , wherein the medicament is an amount of benzodiazepine effective for acute treatment of seizure, reduction in the frequency of seizure and or reduction in severity of seizure 
     
     
         35 . A method of using a composition of  claim 32 , wherein the medicament is administered with a pulmonary delivery device. 
     
     
         36 . The method of using a composition of  claim 35 , wherein the pulmonary delivery device is selected from a nebulizer, a dry powder inhaler and a metered dose inhaler. 
     
     
         37 . The aerosol composition of  claim 30 , wherein the nanoparticular medicament particles comprise at least one member of the group consisting of other anticonvulsants (such as aromatic allylic alcohols, barbiturates, bromides, carbamates, carboxamides, fatty acids, topiramate, Gaba analogs, hydantoins, oxazolidinediones, propionates, pyrimidinediones, pyrrolidines, succinimides, sulfonamides, triazines, ureas, valproylamides, etc.), insulin, calcitonins, enkephalins, LHRH and analogs, GHRH (growth hormone releasing hormone), nifedipin, THF (thymic humoral factor), CGRP (calcitonin gene related peptide), atrial natriuretic peptide, antibiotics, metoclopramide, ergotamine, Pizotizin, nasal vaccines (particularly HIV vaccines, measles, rhinovirus Type 13 and respiratory syncitial virus), pentamidine, CCK (Cholecystikinine), DDVAP, Interferons, growth hormone, secretin, bradykinin antagonists, GRF (Growth releasing factor), THF, TRH (Thyrotropin releasing hormone), ACTH analogues, IGF (Insulin like growth factors), CGRP (Calcitorin gene related peptide), Atrial Natriuretic peptide, Vasopressin and analogs (DDAVP, Lypressin), Metoclopramide, Migraine treatment (e.g. Dihydroergotamine, Ergometrine, Ergotamine, Pizotizin), Nasal Vaccines (Particularly AIDS vaccines), FACTOR VIII, Colony Stimulating factors, G-CSF (granulocyte-colony stimulating factor), EPO (Erythropoitin) PTH (Parathyroid hormone), antibiotics and antimicrobial agents (such as tetracyline hydrochloride, leucomycin, penicillin, penicillin derivatives, erythromycin, gentamicin, sulphathiazole and nitrofurazone), local anaesthetics, vasoconstrictors, tetrahydrozoline hydrochloride, naphazoline nitrate, oxymetazoline hydrochloride and tramazoline hydrochloride, cardiotonics, vasodilators, antiseptics, enzymes, vitamin D, active vitamin D, vitamin C, sex hormones, hypotensives, sedatives, anti-tumor agents, steroidal anti-inflammatory agents, non-steroidal anti-inflammatory agents, enzymatic anti-inflammatory agents, anti-allergic agents, antitussive-expectorant agents, antasthmatic agents, pain medications, antiproliferative or anticancer chemotherapeutic drugs, insomnia drugs, antibiotics, drugs for treating spasticity, antiemetics, antipsychotics, long-acting Beta 2 -adrenertic agonists, short-acting Beta 2 -adrenergic agonists, muscarinic antagonists, corticosteroids, atypical antipsychotics, serotonin reuptake inhibitors, tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, or pharmaceutically acceptable salts or combinations thereof. 
     
     
         38 . A method of using a composition of  claim 37 , wherein the medicament is administered to at least one nostril. 
     
     
         39 . A method of using a composition of  claim 37 , wherein the medicament is administered with a pulmonary delivery device. 
     
     
         40 . The method of using a composition of  claim 39 , wherein the pulmonary delivery device is selected from a nebulizer, a dry powder inhaler and a metered dose inhaler.