Administration of benzodiazepine compositions

Abstract

The invention relates to pharmaceutical compositions comprising one or more benzodiazepine drugs for nasal administration, methods for producing and for using such compositions.

1 . A pharmaceutical composition for nasal administration comprising:
 (a) a benzodiazepine drug,   (b) one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 30% to about 95% (w/w); and   (c) one or more alcohols or glycols, or any combinations thereof, in an amount from about 10% to about 70% (w/w),   
     in a pharmaceutically-acceptable formulation for administration to one or more nasal mucosal membranes of a patient. 
   
   
       2 . The pharmaceutical composition of  claim 1 , wherein the benzodiazepine drug is dissolved in the one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 30% to about 95% (w/w); and the one or more alcohols or glycols, or any combinations thereof, in an amount from about 10% to about 70% (w/w). 
   
   
       3 . The pharmaceutical composition of  claim 2 , wherein the benzodiazepine drug is selected from the group consisting of: alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam, diazepam, flumazenil, flurazepam, halazepam, midazolam, nordazepam, medazepam, nitrazepam, oxazepam, medazepam, lorazepam, prazepam, quazepam, triazolam, temazepam, loprazolam, any pharmaceutically-acceptable salts thereof, and any combinations thereof. 
   
   
       4 . The pharmaceutical composition of  claim 3 , wherein the benzodiazepine drug is diazepam, or a pharmaceutically-acceptable salt thereof. 
   
   
       5 . The pharmaceutical composition of  claim 1 , wherein the benzodiazepine drug comprises benzodiazepine microparticles, nanoparticles, or combinations thereof. 
   
   
       6 . The pharmaceutical composition of  claim 5 , wherein the benzodiazepine nanoparticles have an effective average particle size of less than about 5000 nm. 
   
   
       7 . The pharmaceutical composition of  claim 1 , wherein the one or more natural or synthetic tocopherols or tocotrienols are selected from the group consisting of: α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, α-tocotrienol, β-tocotrienol, γ-tocotrienol, δ-tocotrienol, tocophersolan, any isomers thereof, any esters thereof, any analogs or derivatives thereof, and any combinations thereof. 
   
   
       8 . The pharmaceutical composition of  claim 1 , wherein the one or more alcohols are selected from the group consisting of: ethanol, propyl alcohol, butyl alcohol, pentanol, benzyl alcohol, any isomers thereof, or any combinations thereof. 
   
   
       9 . The pharmaceutical composition of  claim 1 , wherein the one or more glycols are selected from the group consisting of: ethylene glycol, propylene glycol, butylene glycol, pentylene glycol, any isomers thereof, and any combinations thereof. 
   
   
       10 . The pharmaceutical composition of  claim 1 , wherein the benzodiazepine drug is present in the pharmaceutical composition in a concentration from about 1 mg/mL to about 600 mg/mL. 
   
   
       11 . The pharmaceutical composition of  claim 1 , wherein the benzodiazepine drug is present in the pharmaceutical composition in a concentration from about 10 mg/mL to about 250 mg/mL. 
   
   
       12 . The pharmaceutical composition of  claim 11 , wherein the benzodiazepine is present in the pharmaceutical composition in a concentration from about 20 mg/mL to about 50 mg/mL. 
   
   
       13 . The pharmaceutical composition of  claim 1 , wherein the one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, is in an amount from about 45% to about 85% (w/w). 
   
   
       14 . The pharmaceutical composition of  claim 13 , wherein the one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, is in an amount from about 60% to about 75% (w/w). 
   
   
       15 . The pharmaceutical composition of  claim 1 , wherein the one or more alcohols or glycols, or any combinations thereof, is in an amount from about 15% to about 55% (w/w). 
   
   
       16 . The pharmaceutical composition of  claim 15 , wherein the one or more alcohols or glycols, or any combinations thereof, is in an amount from about 25% to about 40% (w/w). 
   
   
       17 . The composition of one of  claims 1 - 16 , further comprising at least one additional ingredient selected from the group consisting of: active pharmaceutical ingredients; enhancers; excipients; and agents used to adjust the pH, buffer the composition, prevent degradation, and improve appearance, odor, or taste. 
   
   
       18 . The composition of  claim 1 , wherein the pharmaceutically-acceptable formulation comprises at least about 0.01% (w/w) of an alkyl glycoside. 
   
   
       19 . The composition of  claim 18 , wherein the pharmaceutically-acceptable formulation about 0.01% to 1% (w/w) of an alkyl glycoside. 
   
   
       20 . A method of treating a patient with a disorder which may be treatable with a benzodiazepine drug, comprising:
 (a) administering to one or more nasal mucosal membranes of a patient a pharmaceutical composition for nasal administration comprising a benzodiazepine drug, one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 30% to about 95% (w/w), and one or more alcohols or glycols, or any combinations thereof, in an amount from about 10% to about 70% (w/w).   
   
   
       21 . The method of  claim 20 , wherein the benzodiazepine drug is dissolved in the one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 30% to about 95% (w/w); and the one or more alcohols or glycols, or any combinations thereof, in an amount from about 10% to about 70% (w/w). 
   
   
       22 . The method of  claim 21 , wherein said patient is a human. 
   
   
       23 . The method of  claim 20 , wherein the benzodiazepine drug is selected from the group consisting of: alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam, diazepam, flumazenil, flurazepam, halazepam, midazolam, nordazepam, medazepam, nitrazepam, oxazepam, medazepam, lorazepam, prazepam, quazepam, triazolam, temazepam, loprazolam, or any pharmaceutically-acceptable salts thereof, and any combinations thereof. 
   
   
       24 . The method of  claim 23 , wherein the benzodiazepine drug is diazepam, or a pharmaceutically-acceptable salt thereof. 
   
   
       25 . The method of  claim 20 , wherein the benzodiazepine drug comprises benzodiazepine microparticles, nanoparticles, or combinations thereof. 
   
   
       26 . The method of  claim 25 , wherein the benzodiazepine nanoparticles have an effective average particle size of less than about 5000 nm. 
   
   
       27 . The method of  claim 20 , wherein the one or more natural or synthetic tocopherols or tocotrienols are selected from the group consisting of: α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, α-tocotrienol, β-tocotrienol, γ-tocotrienol, δ-tocotrienol, tocophersolan, any isomers thereof, any esters thereof, any analogs or derivatives thereof, and any combinations thereof. 
   
   
       28 . The method of  claim 20 , wherein the one or more alcohols are selected from the group consisting of: ethanol, propyl alcohol, butyl alcohol, pentanol, benzyl alcohol, any isomers thereof, and any combinations thereof. 
   
   
       29 . The method of  claim 20 , wherein the one or more glycols are selected from the group consisting of: ethylene glycol, propylene glycol, butylene glycol, pentylene glycol, any isomers thereof, and any combinations thereof. 
   
   
       30 . The method of  claim 20 , wherein the benzodiazepine drug is present in the pharmaceutical composition in a concentration from about 1 mg/mL to about 600 mg/mL. 
   
   
       31 . The method of  claim 30 , wherein the benzodiazepine drug is present in the pharmaceutical composition in a concentration of from about 10 mg/mL to about 250 mg/mL. 
   
   
       32 . The method of  claim 31 , wherein the benzodiazepine drug is present in the pharmaceutical composition in a concentration of from about 20 mg/mL to about 50 mg/mL. 
   
   
       33 . The method of  claim 20 , wherein the pharmaceutical composition comprises one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 45% to about 85% (w/w). 
   
   
       34 . The method  claim 33 , wherein the pharmaceutical composition comprises one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 60% to about 75% (w/w). 
   
   
       35 . The method of  claim 20 , wherein the pharmaceutical composition comprises one or more alcohols or glycols, or any combinations thereof, in an amount from about 15% to about 55% (w/w). 
   
   
       36 . The method of  claim 35 , wherein the pharmaceutical composition comprises one or more alcohols or glycols, or any combinations thereof, in an amount from about 25% to about 40% (w/w). 
   
   
       37 . The method of  claim 20 , wherein the composition comprises at least one additional ingredient selected from the group consisting of: active pharmaceutical ingredients; enhancers; excipients; and agents used to adjust the pH, buffer the composition, prevent degradation, and improve appearance, odor, or taste. 
   
   
       38 . The method of  claim 20 , wherein the composition is in a pharmaceutically-acceptable spray formulation. 
   
   
       39 . The method of  claim 38 , wherein the benzodiazepine is administered in a therapeutically effective amount from about 1 mg to about 20 mg. 
   
   
       40 . The method of  claim 39 , wherein said pharmaceutical composition is in a pharmaceutically-acceptable spray formulation having volume from about 10 μL to about 200 μL. 
   
   
       41 . The method of  claim 40 , wherein the administration of the pharmaceutical composition comprises spraying at least a portion of the therapeutically effective amount of the benzodiazepine into at least one nostril. 
   
   
       42 . The method of  claim 40 , wherein the administration of the pharmaceutical composition comprises spraying at least a portion of the therapeutically effective amount of the benzodiazepine into each nostril. 
   
   
       43 . The method of  claim 42 , wherein the administration of the pharmaceutical composition comprises spraying a first quantity of the pharmaceutical composition into the first nostril, spraying a second quantity of the pharmaceutical composition into a second nostril, and optionally after a pre-selected time delay, spraying a third quantity of the pharmaceutical composition into the first nostril. 
   
   
       44 . The method of  claim 43 , further comprising, optionally after a pre-selected time delay, administering at least a fourth quantity of the pharmaceutical composition to the second nostril. 
   
   
       45 . The method of  claim 43 , wherein nasal administration of the pharmaceutical composition begins at any time before or after onset of symptoms of a disorder which may be treatable with the pharmaceutical composition. 
   
   
       46 . The composition of  claim 20 , wherein the pharmaceutically-acceptable formulation comprises at least about 0.01% (w/w) of an alkyl glycoside. 
   
   
       47 . The composition of  claim 21 , wherein the pharmaceutically-acceptable formulation about 0.01% to 1% (w/w) of an alkyl glycoside.