Compositions comprising methylphenidate-prodrugs, processes of making and using the same
Inventors
Mickle, Travis • Guenther, Sven • Chi, Guochen
Assignees
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Publication Number
US-11505537-B2
Publication Date
2022-11-22
Expiration Date
Abstract
The present technology is directed to compositions comprising d-threo-methylphenidate conjugates and/or unconjugated methylphenidate. The present technology also relates to compositions and oral formulations comprising d-threo-methylphenidate conjugated to nicotinoyl-L-serine, and/or a pharmaceutically acceptable salt thereof, and unconjugated methylphenidate and/or a pharmaceutically acceptable salt thereof. The present technology additionally relates to a pharmaceutical kit containing the composition comprising d-threo-methylphenidate conjugated to nicotinoyl-L-serine, and/or a pharmaceutically acceptable salt thereof, and unconjugated methylphenidate and/or a pharmaceutically acceptable salt thereof.
Core Innovation
The invention relates to compositions and methods for treating excessive daytime sleepiness associated with central hypersomnolence disorders, obstructive sleep apnea, or a shift work disorder by administering a composition comprising a conjugate of d-methylphenidate. The compound includes at least one salt thereof or a mixture thereof, and the disclosure places the treatment in the context of reducing excessive daytime sleepiness in conditions associated with excessive daytime sleepiness.
The technology further includes formulations and related prodrugs in which a conjugate of d-methylphenidate is used together with unconjugated d-methylphenidate or unconjugated methylphenidate. The disclosure characterizes the conjugate approach as providing controlled or extended-release pharmacokinetics, extended exposure, reduced or shifted Cmax and Tmax, and reduced interpatient variability versus unmodified d-methylphenidate.
The document further describes increased water solubility, reduced metabolite exposure including reduced ritalinic acid, and reduced or less pharmacological activity via intranasal or parenteral routes in relation to abuse potential. It also references oral dosage forms, oral thin films, strips, blister packs, and kit concepts.
Claims Coverage
The independent claim covers administering a composition containing a conjugate of d-methylphenidate for treating excessive daytime sleepiness associated with central hypersomnolence disorders, obstructive sleep apnea, or a shift work disorder. The coverage is supported by dependent claims that refine the treated disorders, salt forms, molar-equivalent dosing, dosage forms, and excipient categories.
Conjugate of d-methylphenidate for excessive daytime sleepiness treatment
Administering to a human or animal subject a composition comprising a compound that is a conjugate of d-methylphenidate, wherein the compound is at least one salt thereof, or mixture thereof.
Treating specified central hypersomnolence disorders
The method where the central hypersomnolence disorder is selected from narcolepsy type 1 (with cataplexy), narcolepsy type 2, idiopathic hypersomnia, Kleine-Levin syndrome, hypersomnia due to a medical condition, hypersomnia due to a medication or substance, hypersomnia associated with a psychiatric condition, or insufficient sleep syndrome.
Selecting pharmaceutically or therapeutically acceptable salt forms
Selecting at least one pharmaceutically or therapeutically acceptable salt form of the compound from a specified group of named salts and combinations thereof.
Molar-equivalent dosing range based on d-methylphenidate hydrochloride
Administering a dosing composition where the administered dose is the molar equivalent of about 0.1 mg to about 500 mg per dose of d-methylphenidate hydrochloride.
Formulating in selected dosage forms
Formulating the composition in one of several specified dosage forms selected from sublingual, gummy, chewable tablet, rapidly dissolving tablet, tablet, capsule, caplet, troche, lozenge, oral powder, solution, thin strip, oral thin film (OTF), oral strip, rectal film, syrup, suspension, or suppository.
Excipients selected from specified functional categories
Selecting excipients from antiadherents, binders, coatings, disintegrants, gel forming agents, fillers, flavors and colors, glidants, lubricants, preservatives, sorbents, and sweeteners.
Overall, the claim coverage centers on a conjugate of d-methylphenidate, including salt forms, administered for treating excessive daytime sleepiness in specified disorder contexts, with additional restrictions on salt selection, molar-equivalent dosing based on d-methylphenidate hydrochloride, selected dosage forms, and specified excipient categories.
Stated Advantages
Controlled or extended-release pharmacokinetics versus unmodified d-methylphenidate.
Reduced interpatient variability (CV) versus unmodified d-methylphenidate.
Increased water solubility.
Reduced metabolite exposure, including reduced ritalinic acid.
Reduced or less pharmacological activity via intranasal or parenteral routes to address abuse potential.
Extended exposure and prolonged d-methylphenidate release compared with unconjugated d-methylphenidate.
Reduced or shifted Cmax and Tmax.
Long duration and slow elimination as a treatment goal.
Low abuse potential as a treatment goal.
Documented Applications
Treating excessive daytime sleepiness associated with central hypersomnolence disorders, obstructive sleep apnea, or a shift work disorder.
Treating central hypersomnolence disorders including narcolepsy type 1 (with cataplexy), narcolepsy type 2, idiopathic hypersomnia, Kleine-Levin syndrome, hypersomnia due to a medical condition, hypersomnia due to a medication or substance, hypersomnia associated with a psychiatric condition, and insufficient sleep syndrome.
Kit concepts for dosing that include a prodrug conjugate plus unconjugated methylphenidate.
Pharmaceutical packaging and delivery concepts including oral thin films, strips, and blister packs.
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