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Publication Number
US-10952963-B2
Publication Date
2021-03-23
Expiration Date
Abstract
Disclosed herein is a ready-to-use liquid formulation comprising ropivacaine, epinephrine, clonidine, and ketorolac (collectively referred to as RECK). Also disclosed herein is a process for preparing the RECK-containing liquid formulation, as well as methods for using the same.
Core Innovation
The invention relates to a ready-to-use “RECK” liquid formulation for post-operative arthroplasty pain management. The formulation includes ropivacaine hydrochloride, epinephrine hydrochloride based on epinephrine free base, clonidine hydrochloride, and ketorolac tromethamine, together with sodium chloride, sodium metabisulfite, EDTA sodium, optional citric acid, sterile water for injection, and a pH adjuster.
A key aspect is an incompatibility-driven formulation strategy in which the stability of epinephrine and ketorolac depends on pH and additives. The invention states that epinephrine and ketorolac stability is achieved by selecting a pH range that provides acceptable combined stability, with a final pH of about 4.6 to about 4.9, including a target region around about 4.8.
The invention also addresses stability and packaging constraints. It states that each API retains at least about 90% potency after about 90 days at about 25°C in syringes, and specifies a light-resistant container with low light transmission performance, including light transmission below about 5% across wavelengths from about 290 nm to about 450 nm down to about less than 1% in at least a portion of the range.
Claims Coverage
The independent claims are directed to a ready-to-use liquid formulation containing specific concentrations of ropivacaine hydrochloride, epinephrine hydrochloride based on epinephrine free base, clonidine hydrochloride, and ketorolac tromethamine, together with specified excipients and a pH adjuster to reach a defined pH range. Two inventive features are recited across the independent claims.
Ready-to-use liquid formulation with specified RECK concentrations and pH 4.6-4.9
A ready-to-use liquid formulation comprising ropivacaine hydrochloride about 2.5 mg/mL, epinephrine hydrochloride about 5 mcg/mL based on epinephrine free base, clonidine hydrochloride about 0.8 mcg/mL, ketorolac tromethamine about 0.3 mg/mL, sodium chloride about 8.5 mg/mL, sodium metabisulfite about 2.6 mcg/mL, EDTA sodium about 0.2 mg/mL, optionally citric acid about 2 mg/mL, sufficient sterile water for injection, and sufficient pH adjuster to obtain a pH from about 4.6 to about 4.9.
Ready-to-use liquid formulation with specified RECK concentrations and pH 4.6-4.9
A ready-to-use liquid formulation consisting of ropivacaine hydrochloride about 2.5 mg/mL, epinephrine hydrochloride about 5 mcg/mL based on epinephrine free base, clonidine hydrochloride about 0.8 mcg/mL, ketorolac tromethamine about 0.3 mg/mL, sodium chloride about 8.5 mg/mL, sodium metabisulfite about 2 mcg/mL to about 10 mcg/mL, EDTA sodium about 0.2 mg/mL, optionally citric acid about 2 mg/mL, sufficient sterile water for injection, and sufficient pH adjuster to obtain a pH from about 4.6 to about 4.9.
Across the independent claims, the inventive coverage centers on a ready-to-use RECK liquid formulation having fixed concentrations for ropivacaine hydrochloride, epinephrine hydrochloride based on epinephrine free base, clonidine hydrochloride, and ketorolac tromethamine, with specified excipients and a pH adjuster to reach a final pH from about 4.6 to about 4.9; one independent claim fixes sodium metabisulfite at about 2.6 mcg/mL while the other allows sodium metabisulfite about 2 mcg/mL to about 10 mcg/mL.
Stated Advantages
Retains at least about 90% potency for each API after about 90 days at about 25°C in syringes.
Provides acceptable combined stability for epinephrine and ketorolac by selecting a pH range and additives.
Uses light-resistant packaging constraints with low light transmission below about 5% across about 290 nm to about 450 nm for a light-sensitive container.
Documented Applications
Post-operative arthroplasty pain management using the ready-to-use RECK liquid formulation.
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