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Publication Number
US-9283280-B2
Publication Date
2016-03-15
Expiration Date
Abstract
The present invention provides compositions and methods and for increasing the bioavailability of therapeutic agents in a subject, as well as compositions and methods for providing migraine pain relief. The compositions include at least one alkyl glycoside and at least one therapeutic agent, such as a 5-HT receptor agonist, wherein the alkylglycoside has an alkyl chain length from about 10 to about 16 carbon atoms.
Core Innovation
The invention relates to non-irritating alkyl glycoside/saccharide alkyl ester surfactants formulated with therapeutic agents to enhance bioavailability and stability. The compositions include an alkylsaccharide with an alkyl chain including between 10 to 16 carbons, and are applied to formulations for intranasal administration to improve systemic exposure of the therapeutic agent.
The problem addressed is that therapeutic agents delivered via mucosal routes can show reduced or inconsistent bioavailability and may cause mucosal irritation. The disclosed compositions exhibit pharmacokinetic characteristics including a Tmax of less than about 20 minutes and a Cmax greater than 15 ng/mL, and are described as improving bioavailability and stability of the therapeutic agent.
The invention is exemplified with migraine treatment using 5-HT receptor agonists, including sumatriptan and related triptans, administered via mucosal routes such as intranasal administration. The disclosed formulations are associated with reduced mucosal irritation, increased and more consistent bioavailability, stabilization of drugs over extended storage conditions, and increased Cmax with reduced Tmax.
Claims Coverage
The independent claim covers an intranasal pharmaceutical composition that combines a therapeutically effective amount of a 5-HT receptor agonist with an alkylsaccharide having an alkyl chain of 10 to 16 carbons, with a targeted pharmacokinetic profile defined by Tmax and Cmax thresholds. Dependent claims further refine the profile using additional quantitative thresholds and specify particular alkylsaccharide identities and comparative exposure improvements.
Intranasal 5-HT receptor agonist plus C10-C16 alkylsaccharide for rapid Tmax and high Cmax
A composition comprising a therapeutically effective amount of a 5-HT receptor agonist that is sumatriptan, naratriptan, rizatriptan, eletriptan, frovatriptan, almotriptan, zolmitriptan, a salt thereof, or a combination thereof; and an alkylsaccharide having an alkyl chain including between 10 to 16 carbons, where the composition is formulated for intranasal administration, exhibits a Tmax of less than about 20 minutes, and exhibits a Cmax greater than 15 ng/mL.
Higher Cmax threshold for the intranasal composition
The composition of the intranasal formulation exhibits a Cmax of at least about 17 ng/mL.
Stricter Tmax cutoff for the intranasal composition
The composition of the intranasal formulation exhibits a Tmax of less than about 15 minutes.
Exposure improvement metric based on AUC0-1 hr
The composition provides an AUC0-1 hr greater than about 10 ng*hr/mL.
Specific alkylsaccharide identities within the C10-C16 range
The alkylsaccharide is one of undecyl-beta-D-maltoside, dodecyl-beta-D-maltoside, tridecyl-beta-D-maltoside, tetradecyl-beta-D-maltoside, or a combination of these.
Comparative AUC0-1 hr increase relative to absence of the alkylsaccharide
The composition increases the AUC0-1 hr of a 5-HT agonist relative to the absence of an alkylsaccharide by about 1.3-fold, 1.5-fold, or greater.
Across the independent claim and its dependents, the core coverage is directed to intranasal formulations combining specified 5-HT receptor agonists with C10-C16 alkylsaccharides, with a pharmacokinetic profile characterized by rapid Tmax and elevated Cmax. Dependent claims further specify tighter Tmax/Cmax thresholds, an AUC0-1 hr exposure threshold, particular named alkylsaccharide maltoside identities, and comparative AUC0-1 hr increases versus absence of the alkylsaccharide.
Stated Advantages
Reduced mucosal irritation.
Increased and more consistent bioavailability.
Improved pharmacokinetic performance, including faster systemic absorption (reduced Tmax) and increased Cmax.
Stabilization of drugs over extended storage conditions (described as about 6 months at about 4-25°C).
Documented Applications
Migraine pain relief using 5-HT receptor agonists (including sumatriptan and triptans) via intranasal administration.
Mucosal delivery of pharmaceutical compositions via intranasal administration and other mucosal routes referenced in the partial content (e.g., oral cavity).
Formulations discussed in relation to insulin and exendin-4 and a range of peptides in intranasal/ocular delivery contexts.
Use of alkyl saccharides described with antibacterial activity.
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