ADMINISTRATION OF BENZODIAZEPINE COMPOSITIONS
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 method of treating a human patient with an epileptic seizure comprising: administering to a nostril of the human patient a pharmaceutical solution suitable for nasal administration comprising a therapeutically effective amount of diazepam, or a pharmaceutically acceptable salt thereof, 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 combination thereof, in an amount from about 5% to about 70% (w/w), wherein the epileptic seizure is treated.
2 . The method of claim 1 , wherein the epileptic seizure is treated by treating the seizure, protecting against seizure, reducing the intensity of seizure, reducing the frequency of seizure, preventing re-occurrence of seizure and any combination thereof.
3 . The method 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, tocophersol an, any isomers thereof, any esters thereof, any analogs or derivatives thereof, and any combinations thereof.
4 . The method 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, and any combinations thereof.
5 . The method 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.
6 . The method of claim 1 , wherein the diazepam, or a pharmaceutically acceptable salt thereof, is present in the pharmaceutical solution in a concentration of from about 1 mg/mL to about 600 mg/mL.
7 . The method of claim 1 , wherein the diazepam, or a pharmaceutically acceptable salt thereof, is present in the pharmaceutical solution in a concentration of from about 10 mg/mL to about 250 mg/mL.
8 . The method of claim 1 , wherein the diazepam, or a pharmaceutically acceptable salt thereof, is present in the pharmaceutical solution in a concentration of from about 20 mg/mL to about 50 mg/mL.
9 . The method 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).
10 . The method of claim 1 , 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).
11 . The method of claim 1 , wherein the one or more alcohols or glycols, or any combinations thereof, in an amount from about 15% to about 55% (w/w).
12 . The method of claim 1 , wherein the one or more alcohols or glycols, or any combinations thereof, from about 25% to about 40% (w/w).
13 . The method of claim 1 , wherein the pharmaceutical solution is in a pharmaceutically-acceptable spray formulation.
14 . The method of claim 1 , wherein the diazepam, or a pharmaceutically-acceptable salt thereof, is administered in a therapeutically effective amount of about 1 mg to about 20 mg.
15 . The method of claim 1 , wherein the diazepam, or a pharmaceutically-acceptable salt thereof, is administered in a therapeutically effective amount of about 2 mg to about 10 mg.
16 . The method of claim 1 , wherein the pharmaceutical solution is in a pharmaceutically-acceptable spray formulation having volume from about 10 μL to about 200 μL.
17 . The method of claim 1 , wherein the pharmaceutical solution is in a pharmaceutically-acceptable spray formulation having volume from about 50 μL to about 150 μL.
18 . The method of claim 1 , wherein the pharmaceutical solution is in a pharmaceutically-acceptable spray formulation having volume of about 100 μL.
19 . The method of claim 1 , wherein the administration of the pharmaceutical solution comprises spraying a portion of the therapeutically effective amount of the diazepam, or a pharmaceutically acceptable salt thereof, into each nostril.
20 . The method of claim 1 , wherein the administration of the pharmaceutical solution comprises spraying a first quantity of the pharmaceutical solution into the first nostril, spraying a second quantity of the pharmaceutical solution into a second nostril, and optionally after a pre-selected time delay, spraying a third quantity of the pharmaceutical solution into the first nostril.
21 . The method of claim 20 , further comprising, optionally after a pre-selected time delay, administering at least a fourth quantity of the pharmaceutical solution to the second nostril.
22 . The method of claim 1 , wherein nasal administration of the pharmaceutical solution begins at any time before or after onset of symptoms of the epileptic seizure.
23 . The method of claim 1 , wherein the pharmaceutical solution comprises at least one additional inactive ingredient selected from a stabilizer, a coloring agent, a ph adjuster, a buffering agent, a preservative, a wetting agent, and a flavoring agent.
24 . The method of claim 1 , wherein the pharmaceutical solution further comprises 0.02% to 20% (w/v) of an absorption enhancer.
25 . The method of claim 24 , wherein the absorption enhancer is a biological detergent selected from the group consisting of an anionic biological detergent, a cationic biological detergent, a zwitterionic biological detergent, and a nonionic biological detergent.
26 . The method of claim 24 , wherein the abosprtion enhancer is a is a non-ionic biological detergent selected from the group consisting of n-Decyl β-D-glucopyranoside, digitonin, n-Dodecyl β-D-glucopyranoside, n-Dodecyl β-D-maltoside, n-Heptyl β-D-glucopyranoside, n-Octyl β-D-glucopyranoside, n-Octyl α-D-glucopyranoside, Nonidet P-40, n-Nonyl β-D-glucopyranoside, and Triton X-100.
27 . The method of claim 24 , wherein the absorption enhancer is n-Dodecyl β-D-maltoside.
28 . A method of treating a human patient with an epileptic seizure comprising: administering to a nostril of the human patient a pharmaceutical solution suitable for nasal administration comprising a therapeutically effective amount of diazepam, or a pharmaceutically acceptable salt thereof, 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 combination thereof, in an amount from about 10% to about 70% (w/w), wherein the epileptic seizure is treated.
29 . The method of claim 28 , wherein the epileptic seizure is treated by treating the seizure, protecting against seizure, reducing the intensity of seizure, reducing the frequency of seizure, preventing re-occurrence of seizure, increasing an interval between the current seizure and a next seizure and any combination thereof.
30 . The method of claim 28 , 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.
31 . The method of claim 28 , 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.
32 . The method of claim 28 , 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.
33 . The method of claim 28 , wherein the diazepam, or a pharmaceutically acceptable salt thereof, is present in the pharmaceutical solution in a concentration of from about 1 mg/mL to about 600 mg/mL.
34 . The method of claim 28 , wherein the diazepam, or a pharmaceutically acceptable salt thereof, is present in the pharmaceutical solution in a concentration of from about 10 mg/mL to about 250 mg/mL.
35 . The method of claim 28 , wherein the diazepam, or a pharmaceutically acceptable salt thereof, is present in the pharmaceutical solution in a concentration of from about 20 mg/mL to about 50 mg/mL.
36 . The method of claim 28 , 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).
37 . The method of claim 28 , 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).
38 . The method of claim 28 , wherein the one or more alcohols or glycols, or any combinations thereof, in an amount from about 15% to about 55% (w/w).
39 . The method of claim 28 , wherein the one or more alcohols or glycols, or any combinations thereof, from about 25% to about 40% (w/w).
40 . The method of claim 28 , wherein the pharmaceutical solution is in a pharmaceutically-acceptable spray formulation.
41 . The method of claim 28 , wherein the diazepam, or a pharmaceutically-acceptable salt thereof, is administered in a therapeutically effective amount of about 1 mg to about 20 mg.
42 . The method of claim 28 , wherein the diazepam, or a pharmaceutically-acceptable salt thereof, is administered in a therapeutically effective amount of about 2 mg to about 10 mg.
43 . The method of claim 28 , wherein the pharmaceutical solution is in a pharmaceutically-acceptable spray formulation having volume from about 10 μL to about 200 μL.
44 . The method of claim 28 , wherein the pharmaceutical solution is in a pharmaceutically-acceptable spray formulation having volume from about 50 μL to about 150 μL.
45 . The method of claim 28 , wherein the pharmaceutical solution is in a pharmaceutically-acceptable spray formulation having volume of about 100 μL.
46 . The method of claim 28 , wherein the administration of the pharmaceutical solution comprises spraying a portion of the therapeutically effective amount of the diazepam, or a pharmaceutically acceptable salt thereof, into each nostril.
47 . The method of claim 28 , wherein the administration of the pharmaceutical solution comprises spraying a first quantity of the pharmaceutical solution into the first nostril, spraying a second quantity of the pharmaceutical solution into a second nostril, and optionally after a pre-selected time delay, spraying a third quantity of the pharmaceutical solution into the first nostril.
48 . The method of claim 47 , further comprising, optionally after a pre-selected time delay, administering at least a fourth quantity of the pharmaceutical solution to the second nostril.
49 . The method of claim 28 , wherein nasal administration of the pharmaceutical solution begins at any time before or after onset of symptoms of the epileptic seizure.
50 . The method of claim 28 , wherein the pharmaceutical solution comprises at least one additional inactive ingredient selected from a stabilizer, a coloring agent, a ph adjuster, a buffering agent, a preservative, a wetting agent, and a flavoring agent.
51 . The method of claim 28 , wherein the pharmaceutical solution comprises at least one alkyl glycoside.
52 . The method of claim 51 , wherein the at least one alkyl glycoside is present in the pharmaceutical solution in an amount of about 0.01% (w/v) to about 1% (w/v).
53 . The method of claim 51 , wherein the at least one alkyl glycoside is selected from dodecyl maltoside, tetradecyl maltoside, sucrose dodecanoate, sucrose monostearate, sucrose distearate, and any combination thereof.
54 . The method of claim 51 , wherein the at least one alkyl glycoside is dodecyl maltoside.
55 . The method of claim 52 , wherein the at least one alkyl glycoside is dodecyl maltoside.