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Publication Number
US-10632199-B2
Publication Date
2020-04-28
Expiration Date
Abstract
Compositions comprised of a delivery vehicle or delivery system and an active agent dispersed within the delivery vehicle or system, wherein the delivery vehicle or system contains a polyorthoester polymer and a polar aprotic solvent. Also disclosed are low viscosity delivery systems for administration of active agents. The low viscosity delivery systems have a polyorthoester polymer, a polar aprotic solvent and a solvent containing a triglyceride viscosity reducing agent. Compositions described include an amide- or anilide-type local anesthetic of the “caine” classification, and a non-steroidal anti-inflammatory drug (NSAID), along with related methods, e.g., for treatment of post-operative pain or for prophylactic treatment of pain. The compositions are suitable for delivery via, e.g., direct application and instillation, intradermal injection, subcutaneous injection, and nerve block (perineural).
Core Innovation
The disclosure concerns compositions and delivery systems that include bupivacaine and meloxicam together with a delivery vehicle for pain relief, including sustained-release polymeric systems. Combinations of an amide anesthetic and an enolic-acid NSAID are reported to provide unexpectedly effective, longer-lasting pain relief compared with either agent alone.
A central aspect is a composition that consists essentially of a delivery vehicle, bupivacaine, and meloxicam, with a defined bupivacaine-to-meloxicam ratio and meloxicam wt % range, and with no additional active agents. The delivery vehicle comprises polyorthoester together with dimethyl sulfoxide and triacetin, and optional maleic acid can tailor in vitro release and in vivo pharmacokinetics/pharmacodynamics, including sustained analgesia in post-operative pain models.
The disclosure also introduces low viscosity delivery systems that use polyorthoester together with a polar aprotic solvent and a short-chain triglyceride viscosity reducer, such as triacetin. These systems reduce viscosity substantially without substantially changing drug-release kinetics or plasma pharmacokinetics, enabling needle/small-gauge nerve block delivery, and the triglyceride-viscosity approach is extended to non-pain actives such as granisetron.
Claims Coverage
The independent claim coverage centers on a three-component composition with quantitative constraints on the bupivacaine-to-meloxicam ratio, meloxicam wt %, and exclusion of additional active agents. Additional features refine delivery-vehicle chemistry and components, including polyorthoester, DMSO, triacetin, and optional maleic acid, and one independent method claim addresses perineural or surgical wound administration.
Bupivacaine and meloxicam combination with constrained ratio and no additional active agents
A composition consisting essentially of a delivery vehicle, bupivacaine, and meloxicam, wherein the ratio of bupivacaine to meloxicam ranges from about 15:1 to 50:1, meloxicam is present in an amount between about 0.005-0.75 wt %, and the composition contains no additional active agents.
Delivery vehicle comprising polyorthoester with DMSO and triacetin
A composition in which the delivery vehicle comprises specified weight-percent ranges of polyorthoester, dimethyl sulfoxide, and triacetin, with bupivacaine present at about 1 to 5 wt %.
Delivery vehicle including maleic acid in a defined wt% range
A composition in which the delivery vehicle further includes maleic acid in an amount of 0.01 wt % to 0.3 wt %.
Administration of the composition perineurally or to a surgical wound
A method wherein the composition is administered perineurally or to a surgical wound.
The claim coverage is limited to the constrained bupivacaine and meloxicam composition with no additional active agents, together with dependent refinements to delivery-vehicle composition and a method of administration perineurally or to a surgical wound.
Stated Advantages
Unexpectedly effective, longer-lasting pain relief versus either agent alone.
Sustained analgesia and maintained withdrawal-force profiles in post-operative pain models.
Improved efficacy of the bupivacaine–meloxicam combination versus monotherapies.
Synergistic pain relief.
Improved and/or delayed efficacy with meloxicam versus other NSAIDs such as diclofenac.
Low viscosity delivery enabling needle/small-gauge nerve block delivery while maintaining release kinetics and plasma pharmacokinetics to a substantial extent.
Viscosity reduction enables room-temperature injection without changing release kinetics.
Pain-relief performance correlates with plasma concentration and/or plasma PK/PD relationships.
Documented Applications
Post-operative pain treatment, including improved efficacy in post-surgical pain study outlines.
Postsurgical pain treatment using the composition.
Perineural delivery for nerve block, including nerve block described for sciatic nerve.
Perineural/nerve block administration of the composition.
Administration to a surgical wound, including surgical contexts described such as hernioplasty and bunionectomy.
Surgical wound administration of the composition.
Extension of the triglyceride-viscosity delivery approach to non-pain actives, including granisetron (5-HT3 antagonist).
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