Administration of benzodiazepine compositions
Inventors
Cartt, Steve • MEDEIROS, DAVID • Gwozdz, Garry Thomas • Loxley, Andrew • Mitchnick, Mark • Hale, David F. • Maggio, Edward T.
Assignees
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Publication Number
US-11793786-B2
Publication Date
2023-10-24
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 a pharmaceutical solution for nasal administration that includes a therapeutically effective amount of diazepam or a pharmaceutically acceptable salt thereof. The formulation further includes one or more natural or synthetic tocopherols or tocotrienols selected from an explicit group, present in an amount from 30% to 95% (w/w).
The nasal formulation also includes one or more alcohols in an amount from 10% to 70% (w/w), wherein the alcohol component comprises benzyl alcohol. In addition, the solution includes n-dodecyl beta-D-maltoside as a further component of the nasal solution.
In the described embodiments, the formulation is characterized by selecting specific tocopherols or tocotrienols, including α-tocopherol defined as Vitamin E USP, and by constraining the alcohol system to include benzyl alcohol together with a defined selection of additional alcohols. The diazepam component and the n-dodecyl beta-D-maltoside component are also constrained by quantitative ranges.
Claims Coverage
The partial content provides two independent claims covering nasal pharmaceutical solutions for diazepam. Across the independent claims, three main formulation systems are defined: diazepam, a specified tocopherol or tocotrienol component, and a defined alcohol system together with n-dodecyl beta-D-maltoside; dependent claims refine quantitative ranges and specific component selections.
Nasal diazepam solution with tocopherol or tocotrienol at 30% to 95% (w/w)
A pharmaceutical solution for nasal administration comprising a therapeutically effective amount of diazepam or a pharmaceutically acceptable salt thereof, and one or more natural or synthetic tocopherols or tocotrienols 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, and any combinations thereof, in an amount from 30% to 95% (w/w).
Alcohol system including benzyl alcohol at 10% to 70% (w/w) in a nasal solution
A pharmaceutical solution for nasal administration comprising one or more alcohols in an amount from 10% to 70% (w/w), wherein the one or more alcohols comprises benzyl alcohol.
N-dodecyl beta-D-maltoside as a nasal formulation component
A pharmaceutical solution for nasal administration including n-dodecyl beta-D-maltoside together with diazepam or a pharmaceutically acceptable salt, tocopherols or tocotrienols at 30% to 95% (w/w), and alcohols comprising benzyl alcohol at 10% to 70% (w/w).
Across the independent claims, the core coverage is directed to a nasal diazepam pharmaceutical solution defined by diazepam or a pharmaceutically acceptable salt, a specified natural or synthetic tocopherol or tocotrienol component in 30% to 95% (w/w), an alcohol component in 10% to 70% (w/w) comprising benzyl alcohol, and n-dodecyl beta-D-maltoside. Dependent claims further refine quantitative concentration ranges and specify particular component selections such as α-tocopherol as Vitamin E USP and defined alcohol combinations.
Stated Advantages
Improved solubility of the nasal benzodiazepine formulation.
Bypass of first-pass/liver portal route associated with delivery constraints.
Enhanced intranasal absorption.
Limiting nasal irritation.
Documented Applications
Nasal administration of benzodiazepine drugs including diazepam, lorazepam, midazolam, flurazepam, temazepam, and alprazolam using a carrier system of natural/synthetic tocopherols or tocotrienols plus alcohols and n-dodecyl beta-D-maltoside.
Intranasal delivery using metered sprays and multiple sprays over time as described for the nasal pharmaceutical solution.
Stability testing of diazepam formulations showing impurity growth of related compounds under stress conditions.
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