Administration of benzodiazepine compositions
Inventors
Cartt, Steve • MEDEIROS, DAVID • Gwozdz, Garry Thomas • Loxley, Andrew • Mitchnick, Mark • Hale, David • Maggio, Edward T.
Assignees
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Publication Number
US-12337061-B2
Publication Date
2025-06-24
Expiration Date
Abstract
The invention relates to pharmaceutical compositions comprising one or more benzodiazepine drugs for nasal administration, methods for producing and for using such compositions.
Core Innovation
The invention relates to treating bouts of intermittent and stereotypic episodes of increased seizure activity in an epilepsy patient that is distinguishable from other seizures suffered by the patient. A stable pharmaceutical solution is administered intranasally by administering a single spray of 100 μL to a nostril, or a second single spray to a second nostril. The pharmaceutical solution contains vitamin E USP, diazepam, dodecyl maltoside, benzyl alcohol, and a sufficient quantity of ethanol.
The stable vitamin E-containing intranasal pharmaceutical solution is defined to achieve bioavailability relative to an equivalent dose of diazepam administered intravenously. The single spray method achieves 96% to 97% of the bioavailability of an equivalent intravenous diazepam dose, or in alternative embodiments achieves 92.5% to 107.5% of the bioavailability. The dosing is defined to be safe and effective for treating the bouts of intermittent and stereotypic episodes of increased seizure activity.
The invention further defines treatment outcomes selected from reduction in the severity of the seizure, reduction in the probability that the patient will experience a repeat seizure, increase in the interval between a current seizure and a next seizure in the patient, and reduction in the frequency of seizure in the patient, including combinations thereof. The intranasal administration format is a single metered spray of 100 μL to a nostril, or two single metered sprays, one per nostril.
Claims Coverage
The provided excerpt includes six independent claims. Across these claims, the inventive features center on intranasal administration of a stable vitamin E-containing diazepam solution with specific excipients, achieving defined intravenous-equivalent bioavailability and producing defined seizure-treatment outcomes; the claims differ mainly in single-nostril versus two-nostril spraying and in specified quantitative ranges for bioavailability and diazepam amounts.
Single intranasal spray of vitamin E-containing diazepam solution with intravenous-equivalent bioavailability
Administering a single spray of 100 μL of a stable pharmaceutical solution to a nostril, the pharmaceutical solution containing vitamin E USP, diazepam, dodecyl maltoside, benzyl alcohol, and a sufficient quantity of ethanol, wherein administering the single spray achieves 96% to 97% of the bioavailability of an equivalent dose of diazepam administered intravenously; and wherein administering the single spray is safe and effective in treating bouts of intermittent and stereotypic episodes of increased seizure activity, resulting in treatment selected from reduction in seizure severity, reduction in probability of repeat seizure, increase in interval between seizures, reduction in seizure frequency, and combinations thereof.
Two intranasal single sprays achieving intravenous-equivalent bioavailability
Administering a single spray of 100 μL to a nostril and administering a second single spray of 100 μL to a second nostril, each containing vitamin E USP, diazepam, dodecyl maltoside, benzyl alcohol, and a sufficient quantity of ethanol, wherein administering the single spray and administering the second single spray achieves 96% to 97% of the bioavailability of an equivalent dose of diazepam administered intravenously; and wherein administering the sprays are safe and effective and results in treatment selected from reduction in seizure severity, reduction in probability of repeat seizure, increase in interval between seizures, reduction in seizure frequency, and combinations thereof.
Single intranasal spray with bounded intravenous-equivalent bioavailability
Administering a single spray of 100 μL ±5% of a stable pharmaceutical solution to a nostril, the pharmaceutical solution containing vitamin E USP ±5%, diazepam, dodecyl maltoside ±5%, benzyl alcohol ±5%, and a sufficient quantity of ethanol, wherein administering the single spray achieves 92.5% to 107.5% of the bioavailability of an equivalent dose of diazepam administered intravenously; and wherein administering the single spray is safe and effective and results in treatment selected from reduction in seizure severity, reduction in probability of repeat seizure, increase in interval between seizures, reduction in seizure frequency, and combinations thereof.
Two intranasal single sprays with bounded intravenous-equivalent bioavailability
Administering a single spray of 100 μL ±5% to a nostril and administering a second single spray of 100 μL ±5% to a second nostril, each containing vitamin E USP ±5%, diazepam, dodecyl maltoside ±5%, benzyl alcohol ±5%, and a sufficient quantity of ethanol, wherein administering the single spray and administering the second single spray achieves 92.5% to 107.5% of the bioavailability of an equivalent dose of diazepam administered intravenously; and wherein administering the sprays are safe and effective and results in treatment selected from reduction in seizure severity, reduction in probability of repeat seizure, increase in interval between seizures, reduction in seizure frequency, and combinations thereof.
Two intranasal single sprays with reduced diazepam amount and bounded intravenous-equivalent bioavailability
Administering a single spray of 100 μL ±5% to a nostril and administering a second single spray of 100 μL ±5% to a second nostril, each containing vitamin E USP ±5%, 7.5 mg of diazepam, dodecyl maltoside ±5%, benzyl alcohol ±5%, and a sufficient quantity of ethanol, wherein administering the single spray and administering the second single spray achieves 92.5% to 107.5% of the bioavailability of an equivalent dose of diazepam administered intravenously; and wherein administering the sprays are safe and effective and results in treatment selected from reduction in seizure severity, reduction in probability of repeat seizure, increase in interval between seizures, reduction in seizure frequency, and combinations thereof.
Single intranasal spray producing bounded intravenous-equivalent bioavailability for seizure treatment outcomes
Administering a single spray of 100 μL ±5% of a stable pharmaceutical solution to a nostril, the pharmaceutical solution containing vitamin E USP ±5%, 5 mg of diazepam, dodecyl maltoside ±5%, benzyl alcohol ±5%, and a sufficient quantity of ethanol, wherein administering the single spray achieves 92.5% to 107.5% of the bioavailability of an equivalent dose of diazepam administered intravenously; and wherein administering the single spray is safe and effective in treating bouts of intermittent and stereotypic episodes of increased seizure activity in the patient, resulting in treatment selected from reduction in seizure severity, reduction in probability of repeat seizure, increase in interval between seizures, reduction in seizure frequency, and combinations thereof.
Across the independent claims, the core coverage is methods of treating intermittent and stereotypic increased seizure activity in an epilepsy patient using intranasal administration of a stable vitamin E-containing pharmaceutical solution of diazepam with dodecyl maltoside and benzyl alcohol in ethanol, with defined intravenous-equivalent bioavailability (either 96% to 97% or 92.5% to 107.5%) and seizure-treatment outcomes selected from severity reduction, repeat-seizure probability reduction, increased seizure interval, frequency reduction, and combinations thereof; the key differences among claims relate to single versus two-nostril administration and specific diazepam amounts and bioavailability bounds.
Stated Advantages
Improved bioavailability versus intravenous diazepam, reported as 96% to 97% and 92.5% to 107.5% of equivalent intravenous bioavailability.
Avoidance of first-pass effects.
Fast onset of therapeutic benefit, reported as down to less than 5 to 30 minutes.
Safe and effective treatment of bouts of intermittent and stereotypic episodes of increased seizure activity in an epilepsy patient.
Reduction in the severity of seizures.
Reduction in the probability that the patient will experience a repeat seizure.
Increase in the interval between a current seizure and a next seizure in the patient.
Reduction in the frequency of seizure in the patient.
Documented Applications
Treatment of bouts of intermittent and stereotypic episodes of increased seizure activity in an epilepsy patient that is distinguishable from other seizures suffered by the patient.
Treatment selected from reduction in seizure severity, reduction in probability of repeat seizure, increase in interval between current and next seizure, reduction in seizure frequency.
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