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Publication Number
US-11083797-B2
Publication Date
2021-08-10
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 invention relates to an aqueous and depot composition and to long-acting pain-relief pharmaceutical compositions that include a delivery vehicle, an amide local anesthetic, and a non-steroidal anti-inflammatory drug (NSAID). The ratio of the amide local anesthetic to the NSAID ranges from about 15:1 to 50:1, the NSAID is present in an amount between about 0.005 and 0.75 wt %, and the composition contains no additional active agents. In the disclosed examples and context, the amide local anesthetic includes bupivacaine and/or ropivacaine, and the NSAID includes meloxicam.
The disclosure further addresses delivery vehicles for controlled release, including polyorthoester-based delivery vehicles and other sustained-release systems such as liposomes, microspheres, microparticles, microcapsules, implantable depot-type devices, and non-polymeric liquid carriers. Low-viscosity polyorthoester delivery systems are achieved by adding a triglyceride viscosity-reducing agent to a polar aprotic solvent system, with minimal alteration of drug release kinetics and pharmacokinetics. The disclosed triglyceride viscosity-reducing agents include triacetin, tripropionin, and tributyrin, and the polar aprotic solvents include NMP, DMSO, and DMAC.
The patent further describes that adding an enolic-acid NSAID to the local anesthetic unexpectedly restores and/or extends analgesic efficacy from early hours to multiple days. The disclosure indicates that synergistic pain relief is produced and that plasma and pharmacokinetic-pharmacodynamic correlations are observed, with reported in vitro release and in vivo PK/PD findings using the local anesthetic plus meloxicam combination.
Claims Coverage
The independent claim covers a pharmaceutical composition defined by a delivery vehicle, an amide local anesthetic, and an NSAID with a specific anesthetic-to-NSAID ratio range, an NSAID wt% window, and exclusions for diclofenac and/or ketoprofen. Dependent claims refine NSAID selection, vehicle components, narrower loading ranges, and administration context.
Defined anesthetic-to-nsaid ratio composition
A composition, consisting essentially of a delivery vehicle, an amide local anesthetic, and an NSAID, wherein the ratio of the amide local anesthetic to the NSAID ranges from about 15:1 to 50:1, and the NSAID is present in the composition in an amount between about 0.005-0.75 wt %.
Exclusion of diclofenac and ketoprofen; no additional active agents
The composition wherein the NSAID is not diclofenac and/or ketoprofen, and wherein the composition contains no additional active agents.
Meloxicam NSAID selection
The composition wherein the NSAID is meloxicam.
Delivery vehicle with polyorthoester, polar aprotic solvent, and triacetin
The composition wherein the delivery vehicle is made from specified weight percentages of polyorthoester, dimethyl sulfoxide, and triacetin, and wherein the amide local anesthetic is present at about 1 wt% to 5 wt%.
Optional maleic acid in the delivery vehicle
The composition wherein the delivery vehicle further includes maleic acid at 0.01 wt% to 0.3 wt%.
Administration perineurally or to a surgical wound
The composition is administered perineurally or to a surgical wound.
Claim coverage centers on a consisting-essentially pharmaceutical composition combining an amide local anesthetic with an NSAID under a defined 15:1 to 50:1 anesthetic-to-NSAID ratio and a defined NSAID wt% window, while excluding diclofenac and ketoprofen and excluding additional active agents. Dependent coverage further specifies meloxicam as the NSAID, refines the delivery vehicle using polyorthoester with polar aprotic solvent and triacetin, optionally including maleic acid, and includes administration perineurally or to a surgical wound.
Stated Advantages
Unexpectedly improved analgesia versus either agent alone.
Restores and/or extends analgesic efficacy from early hours to multiple days.
Produces synergistic pain relief.
Provides plasma and pharmacokinetic-pharmacodynamic correlations.
Low-viscosity delivery systems can maintain similar in vitro and in vivo release kinetics.
Extended measurable plasma levels, for example through about 96 h, and maintained/deepened analgesia over days.
Documented Applications
A porcine postoperative pain model and a nerve block model are used to evaluate analgesia, including von Frey assays and pharmacokinetic measurements.
Long-acting pain relief.
Pain relief/prophylactic treatment.
Postsurgical pain.
Perineural injection or to a surgical wound.
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