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
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Publication Number
US-10183018-B2
Publication Date
2019-01-22
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 relates to injectable extended-/sustained-release pharmaceutical formulations in which sebacoyl dinalbuphine ester (SDE) is dissolved in a pharmaceutically acceptable oil using an oil-miscible retaining solvent. The formulation includes SDE dissolved in sesame oil and benzyl benzoate, provided as a solution suitable for administration by injection.
The formulation is characterized by a specified SDE concentration and a specified weight ratio of benzyl benzoate to sesame oil. The described formulation includes an SDE concentration of about 75 mg/mL and a benzyl benzoate:sesame oil weight ratio of about 1.12:1, with the retaining solvent/oil ratio used to achieve predetermined release durations.
The injectable solution is prepared by dissolving SDE in benzyl benzoate and then mixing the solution with sesame oil to give a solution. The description further characterizes the formulation by stability and absence of precipitates/particles, and includes in vitro dissolution–in vivo release correlation and pharmacokinetic/pharmacodynamic findings supporting prolonged nalbuphine exposure.
In the described clinical context, administration of the specific formulation provides prolonged nalbuphine plasma/whole-blood exposure and is associated with reduced postoperative pain and reduced rescue analgesic use after hemorrhoidectomy, with pharmacokinetic metrics reported such as Tmax and apparent t1/2.
Claims Coverage
The claim set covers a defined injectable pharmaceutical solution containing sebacoyl dinalbuphine ester (SDE) dissolved in sesame oil and benzyl benzoate, with specified SDE concentration and specified benzyl benzoate:sesame oil weight ratio, and preparation steps that yield a solution suitable for injection. Four inventive features are identified across the independent and dependent claims.
SDE dissolved in sesame oil and benzyl benzoate injectable solution
A pharmaceutical formulation comprising sebacoyl dinalbuphine ester (SDE) dissolved in sesame oil and benzyl benzoate, wherein the pharmaceutical formulation is a solution suitable for administration by injection.
Specified SDE concentration in the solution
The formulation wherein the concentration of the SDE in the formulation is about 75 mg/mL.
Specified benzyl benzoate:sesame oil weight ratio
The formulation wherein the weight ratio of benzyl benzoate to sesame oil is about 1.12:1.
Preparation by dissolving SDE in benzyl benzoate and mixing with sesame oil
The pharmaceutical formulation is a solution suitable for administration by injection prepared by dissolving SDE in benzyl benzoate and mixing the solution resulting from that step with sesame oil to give a solution.
Intramuscular or subcutaneous administration suitability
The formulation is suitable for administration by intramuscular or subcutaneous injection.
Treatment of post-surgical pain by therapeutic administration
Treating post-surgical pain by administering a therapeutically effective amount of the pharmaceutical formulation to a subject in need thereof.
Total SDE dose up to about 160 mg
The formulation is administered to deliver a total dose of up to about 160 mg of SDE.
Overall, the claims focus on a specific injectable SDE formulation with a fixed SDE concentration and benzyl benzoate:sesame oil weight ratio, prepared by dissolving SDE in benzyl benzoate and mixing with sesame oil, with dependent claims limiting administration routes and claiming therapeutic use for post-surgical pain within a total SDE dose bound.
Stated Advantages
Prolonged nalbuphine plasma/whole-blood exposure after administration of the specific formulation.
Reduced postoperative pain after hemorrhoidectomy.
Reduced rescue analgesic use after hemorrhoidectomy.
Documented Applications
Postoperative pain treatment, including after hemorrhoidectomy, by administering a therapeutically effective amount of the pharmaceutical formulation.
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