Sustained release drug delivery systems with reduced impurities and related methods
Inventors
Miksztal, Andrew R. • JOICE, JUDY • AUTIO, SUSAN • DAVIS, MARK P.
Assignees
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Publication Number
US-11771624-B2
Publication Date
2023-10-03
Expiration Date
Abstract
The present disclosure relates to sustained release drug delivery systems. In some cases, a composition comprises an active pharmaceutical agent; at least one of sucrose acetate isobutyrate and a polyorthoester; an organic solvent; and 2,6-dimethylaniline, wherein the 2,6-dimethylaniline is present at a level less than 500 ppm. In some cases, a composition comprises N-oxide of active pharmaceutical agent at a level less than 1 wt %, based on weight of the composition. In some case, a composition comprises metal present at a level less than 5 ppm. Dosage forms and methods are also provided.
Core Innovation
The invention relates to a method of treating post-surgical pain in a human in need thereof by parenterally administering an effective amount of a pharmaceutical composition. The pharmaceutical composition comprises bupivacaine free base, sucrose acetate isobutyrate, benzyl alcohol, benzyl acetate, and 2,6-dimethylaniline, with defined amounts of bupivacaine free base, sucrose acetate isobutyrate, and benzyl alcohol. The composition is sterile, and the formulation constrains both the active system and excipient system while imposing impurity-related limits.
A key aspect is controlling the levels of benzyl acetate and 2,6-dimethylaniline and maintaining stability under defined conditions, including effects from gamma irradiation and light. The document describes photostability outcomes showing light protection by packaging and reports storage studies and container/closure compatibility evaluations, including maintaining low degradant levels and potency retention after storage while assessing degradation, analytical measures, and performance for post-operative pain control.
The disclosed approach further addresses degradation risks including bupivacaine N-oxide and genotoxic 2,6-dimethylaniline. It also refers to polyorthoester polymers with polar aprotic solvents and triglycerides as viscosity reducing agents within a sustained-release delivery vehicle, and to formulation and container/closure concepts aimed at reducing degradation and leaching-related impurities.
Claims Coverage
The independent claims are directed to methods of treating post-surgical pain by parenterally administering a pharmaceutical composition with the same core component set and quantitative impurity/limit constraints; one independent claim further specifies that the composition is sterile. Across the independent claims, the inventive features are centered on the defined bupivacaine free base, sucrose acetate isobutyrate, and benzyl alcohol composition and the controlled limits of benzyl acetate and 2,6-dimethylaniline.
Parenteral treatment of post-surgical pain with defined bupivacaine and excipient composition
A method of treating post-surgical pain in a human in need thereof comprising parenterally administering an effective amount of a pharmaceutical composition comprising bupivacaine free base in an amount ranging from 10 wt % to 15 wt %, sucrose acetate isobutyrate present in an amount ranging from 63 wt % to 67 wt %, benzyl alcohol present in an amount ranging from 20 wt % to 25 wt %, benzyl acetate, and 2,6-dimethylaniline.
Impurity-level constraints on benzyl acetate and 2,6-dimethylaniline
The method wherein benzyl acetate is present in the pharmaceutical composition at a level less than 30 mg/mL, and wherein 2,6-dimethylaniline is present in the pharmaceutical composition at a level less than 12 ppm.
Sterile pharmaceutical composition for parenteral treatment
A method of treating post-surgical pain in a human in need thereof comprising parenterally administering an effective amount of a pharmaceutical composition comprising bupivacaine free base (10 wt % to 15 wt %), sucrose acetate isobutyrate (63 wt % to 67 wt %), benzyl alcohol (20 wt % to 25 wt %), benzyl acetate, and 2,6-dimethylaniline, wherein the benzyl acetate is present at a level less than 30 mg/mL, the 2,6-dimethylaniline is present at a level less than 12 ppm, and wherein the pharmaceutical composition is sterile.
The independent claims cover parenteral treatment of post-surgical pain using a defined multi-component pharmaceutical composition with specific impurity limits for benzyl acetate and 2,6-dimethylaniline; one claim additionally requires sterility.
Stated Advantages
Analgesic benefit for Formulation A over placebo in certain primary endpoints, including pain intensity measures and opioid-sparing effects in early postoperative periods.
Safety findings indicate no clinically significant lab/ECG/hemodynamic differences in the main assessment.
Adverse event rates generally similar across groups.
Prolonged release is supported by pharmacokinetics observations described in the partial content.
Cardiovascular safety monitoring using Holter/QTc evaluations is described in the partial content as supporting safety.
Reduces impurities and improves storage stability and safety.
Maintains benzyl acetate and 2,6-dimethylaniline below specified limits.
Improves stability by addressing degradation effects associated with gamma irradiation and light-induced degradation.
Documented Applications
Orthopedic surgical setting: orthopedic subacromial decompression (arthroscopic subacromial decompression; assessment including Constant-Murley score in the described context).
General surgery surgical setting: laparoscopic cholecystectomy; abdominal surgery cohorts are described in the partial content.
General surgery surgical setting: open inguinal hernia repair.
Treating post-surgical pain in a human in need thereof by parenterally administering an effective amount of the specified pharmaceutical composition.
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