Pharmaceutical formulations for sustained release of sebacoyl dinalbuphine ester
Inventors
LI, Chan-Jung • CHOU, David Chih-Kuang • HUANG, Jin-Ding • Tsai, Shin-Jr • Kuo, Shu-Wen • TIEN, Yu-En
Assignees
Shanghai Lumosa Therapeutics Co Ltd • Lumosa Therapeutics Co Ltd
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11241424-B2
Publication Date
2022-02-08
Expiration Date
Abstract
The present invention relates to injectable, extended-release, pharmaceutical formulations comprising a nalbuphine ester prodrug homogenously dissolved in a solution comprising a pharmaceutically acceptable oil and an oil-miscible retaining solvent, as well as manufacturing processes and medical uses of the formulations. The invention further provides methods for adjusting the duration of action of the formulations by varying the ratio of the pharmaceutically acceptable oil and the oil-miscible retaining solvent.
Core Innovation
The invention provides an extended release pharmaceutical formulation comprising sebacoyl dinalbuphine ester (SDE), benzyl benzoate, and sesame oil. The formulation contains a specific benzyl benzoate to sesame oil weight ratio greater than 1 and less than 19, and the SDE concentration is from about 50 to about 150 mg/mL. The formulation is a homogeneous solution substantially free of solid particles and suitable for administration to a human subject by intramuscular injection.
The invention addresses the problem of providing an injectable extended/sustained-release SDE formulation that releases nalbuphine over an extended period. The approach uses a release-controlling oil/retaining-solvent system in which adjusting the retaining solvent-to-oil weight ratio tunes solubility and extends release duration. Higher ratios increase SDE solubility and prolong in vitro dissolution and in vivo nalbuphine exposure.
The invention further targets physical stability and manufacturability such that the formulation forms clear, particle-free homogeneous solutions suitable for filtration sterilization and remains homogeneous during storage. Reported stability includes remaining homogeneous after freeze-thaw and stored at 2–8°C for at least 24 months.
The disclosed formulations are supported by human pharmacokinetics and bioavailability results, including Phase 1 data for a representative formulation. The mean whole-blood nalbuphine exposure is sustained, and clinical evaluation in Phase 2/3 hemorrhoidectomy patients shows statistically significant improvements versus placebo in adjusted pain metrics with reduced rescue analgesic use consistent with an extended duration of action.
Claims Coverage
The independent claim is directed to an extended release formulation with composition constraints, a defined physical state, and sustained nalbuphine exposure in human subjects. The claim set also includes preparation and storage-related homogeneity requirements and pharmacokinetic constraints described in dependent claims.
Extended release formulation composition with benzyl benzoate and sesame oil weight ratio
An extended release pharmaceutical formulation comprising sebacoyl dinalbuphine ester (SDE), benzyl benzoate, and sesame oil, wherein the weight ratio of the benzyl benzoate to the sesame oil is greater than 1 and less than 19.
SDE concentration range
The extended release pharmaceutical formulation has a concentration of the SDE in the formulation from about 50 to about 150 mg/mL.
Homogeneous, particle-free intramuscularly administrable solution
The formulation is a homogeneous solution substantially free of solid particles and suitable for administration to a human subject by intramuscular injection.
Sustained nalbuphine exposure via whole blood concentration at 12 hours
The mean whole blood concentration of nalbuphine is at least about 1 ng/mL at 12 hours after intramuscular administration of a single dose of the formulation to human subjects.
Minimum mean apparent elimination half-life
The formulation has a mean apparent elimination half-life of nalbuphine of at least about 50 hours after a single intramuscular dose in human subjects.
Whole blood nalbuphine concentration at 24 hours
The mean whole blood concentration of nalbuphine is at least about 3 ng/mL at 24 hours after a single intramuscular dose in human subjects.
Time to maximum plasma concentration constraint
The mean time to maximum plasma concentration of nalbuphine is at least about 45 hours, ± about 25 hours, after a single intramuscular dose in human subjects.
Preparation sequence to obtain a homogeneous solution
The formulation is prepared by dissolving the SDE in benzyl benzoate and mixing the resulting solution with sesame oil to obtain a homogeneous solution.
Long-term homogeneity storage constraint
The formulation remains homogeneous at 2–8°C for at least 24 months.
Overall, the claim coverage concentrates on an extended release SDE formulation built from SDE, benzyl benzoate, and sesame oil with defined composition ranges and a homogeneous, particle-free state for intramuscular injection. The inventive features are tied to sustained nalbuphine exposure in humans, including minimum whole-blood nalbuphine levels at 12 hours and 24 hours and additional pharmacokinetic constraints, with dependent claims also adding preparation and storage-related homogeneity requirements.
Stated Advantages
Provides an extended release formulation suitable for intramuscular injection with sustained nalbuphine whole-blood exposure in humans.
Achieves a homogeneous, substantially particle-free formulation state suitable for administration and aimed at maintaining homogeneity during storage.
In clinical use in hemorrhoidectomy patients, improves adjusted pain metrics versus placebo and reduces rescue analgesic use.
Documented Applications
Use in Phase 2/3 clinical evaluation in hemorrhoidectomy patients, including administration as a single intramuscular dose pre-surgery with measured pain outcomes and rescue medication use.
Interested in licensing this patent?