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-9763876-B2
Publication Date
2017-09-19
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 nasal administration of benzodiazepine pharmaceutical solutions or compositions. A patient with a disorder treatable with a benzodiazepine drug is treated by administering to one or more nasal mucosal membranes a pharmaceutical solution for nasal administration that consists of a benzodiazepine drug together with natural or synthetic tocopherols or tocotrienols, ethanol and benzyl alcohol, and an alkyl glycoside.
The tocopherols or tocotrienols are present in an amount from about 30% to about 95% (w/w) or from about 45% to about 85% (w/w), and the combined ethanol and benzyl alcohol are present in an amount from about 10% to about 70% (w/w) or from 15% to about 55% (w/w). The alkyl glycoside is included as a penetration enhancer, and the document identifies the composition as a nasal solution for spraying onto nasal mucosa.
The document also states that the formulation supports nasal dosing for acute treatment and/or prevention of seizures, including seizure-associated events such as aura. It further discusses substantially water-free nasal solutions, alternative embodiments including fully dissolved solutions as well as microparticle or nanoparticle suspensions, and comparative performance information including bioavailability relative to intravenous administration.
Claims Coverage
The independent claim coverage centers on two closely related core inventive concepts: a nasal treatment method using a benzodiazepine-containing pharmaceutical solution with tocopherols or tocotrienols, ethanol plus benzyl alcohol, and an alkyl glycoside, and a comparative bioavailability relationship to intravenous administration. Dependent claims refine benzodiazepine selection, concentration ranges, delivery by spraying into nostrils, and the bioavailability comparison.
Nasal benzodiazepine solution with vitamin E, ethanol and benzyl alcohol, and alkyl glycoside
A method of treating a patient with a disorder treatable with a benzodiazepine drug by administering to one or more nasal mucosal membranes a pharmaceutical solution for nasal administration consisting of a benzodiazepine drug, one or more natural or synthetic tocopherols or tocotrienols, ethanol and benzyl alcohol in a combined amount, and an alkyl glycoside, with specified weight ranges.
Benzodiazepine selection for the nasal solution
The benzodiazepine drug is selected from alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam, diazepam, flumazenil, flurazepam, halazepam, midazolam, nordazepam, medazepam, nitrazepam, oxazepam, lorazepam, prazenam, quazepam, triazolam, temazepam, loprazolam, and pharmaceutically-acceptable salts and combinations thereof.
Defined tocopherol/tocotrienol concentration range
The natural or synthetic tocopherols and/or tocotrienols are present in an amount from about 30% to about 95% (w/w) or from about 45% to about 85% (w/w).
Defined ethanol plus benzyl alcohol co-amount range
Ethanol and benzyl alcohol are in a combined amount from about 10% to about 70% (w/w) or from 15% to about 55% (w/w).
Nostril spraying of at least part of a therapeutically effective amount
Administering the pharmaceutical solution includes spraying at least part of a therapeutically effective amount of a benzodiazepine into at least one nostril.
Bioavailability relative to intravenous administration
The bioavailability is from about 80 to 125% of that achieved with the same benzodiazepine administered intravenously.
Overall, the claim coverage is directed to nasal mucosal membrane administration of a benzodiazepine-containing, tocopherol or tocotrienol-containing, ethanol and benzyl alcohol-containing, alkyl glycoside-containing pharmaceutical solution within specified concentration ranges, with refinements including spraying into nostrils and comparative bioavailability versus intravenous administration.
Stated Advantages
Provides bioavailability that is from about 80% to about 125% of that achieved with the same benzodiazepine administered intravenously.
Nasal administration enables solubility and rapid onset relative to oral, intravenous, and rectal routes and may bypass first-pass effects.
Documented Applications
Treating a patient with a disorder which is treatable with a benzodiazepine drug by administering a benzodiazepine-containing nasal pharmaceutical solution to one or more nasal mucosal membranes.
Acute treatment and/or prevention of seizures via spraying a benzodiazepine into one or more nostrils on nasal mucosa.
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