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-11400019-B2
Publication Date
2022-08-02
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 sustained-release drug delivery formulations and pharmaceutical compositions for human parenteral use. The disclosed compositions comprise bupivacaine free base, sucrose acetate isobutyrate, and benzyl alcohol, with benzyl acetate and 2,6-dimethylaniline present under controlled limits, and in one embodiment the pharmaceutical composition is sterile.
The composition is defined by bupivacaine free base in an amount ranging from 10 wt% to 15 wt%, sucrose acetate isobutyrate in an amount ranging from 63 wt% to 67 wt%, and benzyl alcohol in an amount ranging from 20 wt% to 25 wt%, based on weight of the pharmaceutical composition. Benzyl acetate is present at a level less than 30 mg/mL and 2,6-dimethylaniline is present at a level less than 12 ppm.
The disclosure also addresses impurity and degradation profiles, including bupivacaine N-oxide and genotoxic 2,6-dimethylaniline, and states that gamma irradiation and light exposure increase degradants. It further addresses sterilization, packaging, and storage stability, including filtration sterilization followed by aseptic processing, light-resistance measures, container/closure compatibility, and materials intended to prevent silicone oil leaching.
Claims Coverage
The independent claim coverage includes two claims directed to a human parenteral pharmaceutical composition. The inventive features center on specific wt% ranges for bupivacaine free base, sucrose acetate isobutyrate, and benzyl alcohol, together with limits on benzyl acetate and 2,6-dimethylaniline, and sterility in one claim.
Quantitative bupivacaine free base, SAIB, and benzyl alcohol composition
A pharmaceutical composition suitable for parenteral use in humans comprising bupivacaine free base in an amount ranging from 10 wt% to 15 wt%, sucrose acetate isobutyrate in an amount ranging from 63 wt% to 67 wt%, and benzyl alcohol in an amount ranging from 20 wt% to 25 wt%, based on weight of the pharmaceutical composition.
Controlled benzyl acetate and 2,6-dimethylaniline levels
The pharmaceutical composition further comprises benzyl acetate and 2,6-dimethylaniline, wherein the benzyl acetate is present at a level less than 30 mg/mL and the 2,6-dimethylaniline is present at a level less than 12 ppm.
Sterile defined composition
A sterile pharmaceutical composition comprising the same bupivacaine free base, sucrose acetate isobutyrate, and benzyl alcohol ranges, further comprising benzyl acetate and 2,6-dimethylaniline at less than 30 mg/mL and less than 12 ppm, respectively.
The inventive coverage is anchored by a specifically defined bupivacaine free base/sucrose acetate isobutyrate/benzyl alcohol formulation with controlled benzyl acetate and 2,6-dimethylaniline levels, together with an independent sterile version of the same composition.
Stated Advantages
Provides opioid-sparing analgesia versus placebo after surgery.
Reduces median cumulative rescue opioid IV morphine equivalents over 0–72 h versus placebo.
Increases the proportion opioid-free at 72 h versus placebo.
Prolongs time to first opioid use versus placebo.
Reduces pain intensity at rest AUC over 1–72 hours.
Extended release with measurable bupivacaine at 96 h.
Low protein binding (~5.2%).
No apparent cardiovascular (QT/QRS) effect correlation.
General safety profile similarity across groups with no deaths; TEAEs mostly mild/moderate and no unexpected surgical healing signals observed.
Reduces formation of 2,6-dimethylaniline, N-oxide, and related degradation products by maintaining low peroxide and low water.
Improves impurity control by limiting 2,6-dimethylaniline levels and optionally limiting active pharmaceutical agent N-oxide.
Avoids increased genotoxic 2,6-dimethylaniline associated with gamma irradiation by using filtration sterilization followed by aseptic processing.
Supports formulation and package stability by using light-resistance and container/closure approaches intended to prevent silicone oil leaching and reduce related stability risks.
Provides a pharmaceutical composition suitable for parenteral use in humans.
Controls impurities and degradants by maintaining 2,6-dimethylaniline below 12 ppm and benzyl acetate below 30 mg/mL in the composition as claimed.
Supports storage-stable performance criteria under defined vial conditions with retention limits for 2,6-dimethylaniline and benzyl acetate.
Supports claimed sterility of the pharmaceutical composition.
Documented Applications
Surgical pain context in clinical trials evaluating opioid-sparing analgesia versus placebo.
Exploratory/phase trial contexts including arthroscopic shoulder, laparoscopic cholecystectomy, general surgery, and inguinal hernia with efficacy trends, opioid use reduction, and safety monitoring.
Parenteral use in humans for the pharmaceutical compositions described in the independent claims.
Storage-stable formulation use in sealed, upright clear glass vial conditions, including maintaining impurity levels such as 2,6-dimethylaniline below 12 ppm after storage under defined conditions.
A dosage system/container architecture that reduces ambient visible light using first and second containers and reduces visible-light exposure for the pharmaceutical composition.
Local anesthesia delivery in orthopedic surgical models, including post-operative pain control with clinical trial evidence in an orthopedic surgical context.
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