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-11234974-B2
Publication Date
2022-02-01
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 concerns injectable, extended-release pharmaceutical formulations that include sebacoyl dinalbuphine ester (SDE) together with an oil-miscible retaining solvent and a pharmaceutically acceptable oil. The formulation is suitable for administration by intramuscular or subcutaneous injection and is configured to release SDE in an extended manner. The disclosed compositions use defined concentrations and specific solvent and oil selections to achieve prolonged action.
The oil-miscible retaining solvent is specified as benzyl benzoate, benzyl alcohol, or a mixture thereof, and the pharmaceutically acceptable oil is specified as soybean oil, peanut oil, sesame oil, or a mixture thereof. The weight ratio of the oil-miscible retaining solvent to the pharmaceutically acceptable oil is defined as greater than 1 and less than about 19, and extended release is characterized by a duration of action equal to or greater than about 5 days and/or a release period equal to or greater than about 14 days. The disclosed approach states that a retaining solvent and oil combination functions as an in vivo matrix to retain drug and modulate release duration.
The formulation can be prepared as a homogeneous solution suitable for filtration sterilization, and solubilizing agents may be included to raise solubility and enable lower injection volumes. Optional neutralizing agents may be included to mitigate injection-site irritation. In vitro dissolution profiles are reported as correlated with pharmacokinetics of nalbuphine, and clinical outcomes are reported for extended pain control in human studies.
Claims Coverage
The independent claim is directed to a specific extended-release injectable pharmaceutical formulation containing SDE, an oil-miscible retaining solvent, and a pharmaceutically acceptable oil, with defined concentrations and a defined solvent-to-oil weight-ratio, configured for intramuscular or subcutaneous injection and prolonged release (at least about 5 days of action and/or at least about 14 days of release).
Extended-release SDE formulation with defined concentrations and solvent/oil matrix
A pharmaceutical formulation comprising sebacoyl dinalbuphine ester (SDE), an oil-miscible retaining solvent, and a pharmaceutically acceptable oil, wherein the concentration of SDE is from 50 to 150 mg/mL and the formulation releases SDE in an extended manner for intramuscular or subcutaneous injection, with duration of action equal to or greater than about 5 days and/or a release period equal to or greater than about 14 days.
Oil-miscible retaining solvent and pharmaceutically acceptable oil selections
The oil-miscible retaining solvent is benzyl benzoate, benzyl alcohol, or a mixture thereof, and the pharmaceutically acceptable oil is soybean oil, peanut oil, sesame oil, or a mixture thereof.
Retaining solvent-to-oil weight-ratio range for prolonged release
The weight ratio of the oil-miscible retaining solvent to the pharmaceutically acceptable oil is greater than 1 and less than about 19.
Across the independent claim, the key coverage is the combination of SDE (50–150 mg/mL), a specified oil-miscible retaining solvent (benzyl benzoate and/or benzyl alcohol), a specified pharmaceutically acceptable oil (soybean/peanut/sesame oil or mixtures), and a defined retaining solvent-to-oil weight ratio (greater than 1 and less than about 19), configured for intramuscular or subcutaneous injection to provide extended action (≥ about 5 days) and/or extended release (≥ about 14 days).
Stated Advantages
Provides extended manner release of SDE suitable for intramuscular or subcutaneous injection with duration of action equal to or greater than about 5 days and/or a release period equal to or greater than about 14 days.
Documented Applications
Treatment of pain for at least 5 days by administering a therapeutically effective amount of the pharmaceutical formulation to a subject to eliminate or control one or more pain symptoms.
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