Compositions comprising enzyme-cleavable oxycodone prodrug
Inventors
Jenkins, Thomas E. • Husfeld, Craig O.
Assignees
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Publication Number
US-9499581-B2
Publication Date
2016-11-22
Expiration Date
Abstract
The embodiments provide Compound KC-8, N-1-[3-(oxycodone-6-enol-carbonyl-methyl-amino)-2,2-dimethyl-propylamine]-arginine-glycine-malonic acid, or acceptable salts, solvates, and hydrates thereof. The present disclosure also provides compositions, and their methods of use, where the compositions comprise a prodrug, Compound KC-8, that provides controlled release of oxycodone. Such compositions can optionally provide a trypsin inhibitor that interacts with the enzyme that mediates the controlled release of oxycodone from the prodrug so as to attenuate enzymatic cleavage of the prodrug.
Core Innovation
The patent describes Compound KC-8 as N-1-[3-(oxycodone-6-enol-carbonyl-methyl-amino)-2,2-dimethyl-propylamine]-arginine-glycine-malonic acid, including pharmaceutically acceptable salts, and links it to a series of synthetic preparation of multiple intermediates and related KC-series entities. The prodrug architecture uses an enzyme-cleavable moiety and a cyclizable spacer leaving group so that enzymatic cleavage in the GI environment enables intramolecular cyclization and subsequent oxycodone release in vivo.
A central aspect presented in the document is trypsin-mediated prodrug cleavage coupled with spacer cyclization, where Compound KC-22 is described in relation to cyclization rate and trypsin cleavage. The document further characterizes a trypsin inhibition mechanism and an assay concept involving BAEE-U, and describes categories of trypsin inhibitors including protein, peptide, and small molecule inhibitors, reversible and irreversible inhibition types, and competitive and non-competitive types.
The document describes pharmaceutical compositions that include Compound KC-8 or a salt thereof for controlled release of oxycodone in vivo, with formulation-related concepts including pharmaceutically acceptable salts, solvates, and hydrates. The disclosure also provides an optional approach for attenuating enzymatic cleavage by co-formulating with a trypsin inhibitor described as a GI protease inhibitor, and associates inhibitor levels with plasma Cmax and Tmax.
Claims Coverage
The partial claims include two independent claims directed to a defined prodrug compound and a pharmaceutical composition containing that compound. Across these claims, the main inventive features are centered on the specific KC-8 molecular entity including salt forms and its use in a formulated composition, with optional constraints on dose range, formulation components, and oral administration plus dosage form types.
Compound KC-8 identity and salt forms
N-1-[3-(Oxycodone-6-enol-carbonyl-methyl-amino)-2,2-dimethyl-propylamine]-arginine-glycine-malonic acid, Compound KC-8, or a salt thereof.
Pharmaceutical composition containing Compound KC-8
A composition comprising N-1-[3-(oxycodone-6-enol-carbonyl-methyl-amino)-2,2-dimethyl-propylamine]-arginine-glycine-malonic acid, Compound KC-8, or a salt thereof.
Pharmaceutically acceptable salt of Compound KC-8
The composition where the salt is a pharmaceutically acceptable salt.
Compound KC-8 dosage range
The composition containing Compound KC-8 or an acceptable salt at a dose ranging from 0.01 mg/kg to 20 mg/kg body weight.
Excipients selection for the composition
The composition further comprising one or more formulation excipients selected from a carrier, binder, lubricant, pH modifier, sweetener, bulking agent, and coloring agent.
Oral administration formulation
The composition is formulated for oral administration.
Oral dosage forms
The composition is formulated as a tablet, capsule, thin film, powder, suspension, solution, syrup, dispersion, or emulsion.
The claim coverage focuses on the specific Compound KC-8 definition including salts and a pharmaceutical composition that contains Compound KC-8 or a salt thereof. Dependent claim refinements include pharmaceutically acceptable salt constraints, formulation excipient categories, a defined dose range in mg/kg body weight, and limitations to oral administration and multiple dosage form types.
Stated Advantages
Dose-proportional increases in oxycodone exposure after oral administration of KC-8 in rats and dogs.
Oral pharmacokinetics of oxycodone from KC-8 compared with Compound KC-3 and OxyContin, including Cmax, Tmax, and AUC.
In vitro trypsin cleavage and spacer cyclization measurements, with release modulation by co-dosing a trypsin inhibitor (Compound 109).
Provides controlled release of oxycodone in vivo via GI enzyme cleavage followed by intramolecular cyclization.
Co-formulation with a trypsin inhibitor attenuates enzymatic cleavage and is associated with changes in plasma Cmax and Tmax with inhibitor levels.
Attenuates trypsin-mediated oxycodone release.
Provides modified pharmacokinetic (PK) profiles characterized by Cmax, Tmax, and exposure/AUC.
Documented Applications
Oral administration application assessed by oral pharmacokinetics of oxycodone released from Compound KC-8 in rats and dogs, including comparisons to Compound KC-3 and OxyContin.
Biological evaluation of trypsin-related release behavior using in vitro trypsin cleavage and spacer cyclization rates, including modulation by co-dosing a trypsin inhibitor (Compound 109).
Pharmaceutical use for controlled release of oxycodone in vivo through GI enzyme cleavage followed by intramolecular cyclization.
Formulation application involving co-formulation with a trypsin inhibitor to attenuate GI enzymatic cleavage and influence plasma Cmax and Tmax.
Treating or preventing pain using oral formulations.
Reducing side effects and overdose/misuse risk.
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