Sustained-release anesthetic compositions and methods of preparation thereof
Inventors
Hong, Keelung • TSENG, Yun-Long • Lai, Chun-Yen • YU, WAN-NI • Kao, Hao-Wen • Lin, Yi-Yu
Assignees
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Publication Number
US-11938220-B2
Publication Date
2024-03-26
Expiration Date
Abstract
Provided is an anesthetic composition for locally administering a local anesthetic agent to a subject in need thereof. The anesthetic composition has a lipid based complex prepared by hydrating a lipid cake containing a local anesthetic agent and a lipid mixture with an aqueous buffer solution at a pH higher than 5.5. Also provided is a method to prepare an anesthetic composition using a simpler and more robust for large-scale manufacture and for providing a high molar ratio of local anesthetic agent to phospholipid content as compared to the prior art. This anesthetic composition has a prolonged duration of efficacy adapted to drug delivery.
Core Innovation
The invention relates to a sustained-release anesthetic composition that includes a lipid based complex comprising ropivacaine base and a lipid mixture in the presence of an aqueous buffer at a pH of 5.5 to 8.0. The lipid mixture includes at least one phospholipid derived from saturated fatty acids, with each fatty acid having a carbon chain of no greater than 18. The lipid based complex is characterized by a median diameter of no less than 1 bcm and a ropivacaine base to phospholipid molar ratio of at least 0.5:1.
The lipid mixture is described as having neutral saturated phospholipids and an optional sterol component, with limited unsaturated phospholipids. The document further associates specific saturated phospholipids derived from saturated fatty acids, and it states that the lipid based complex can form multilamellar vesicles. The composition uses lyophilization of a lipid cake followed by hydration with a pH-controlled aqueous buffer to form the lipid-based complex with a high drug-to-phospholipid ratio and prolonged anesthetic efficacy.
The document reports characterization and efficacy results, including association efficiency (AE) and median particle diameter (D50). It also reports pain relief and analgesic duration in rat models, including a paw incision model and a cuff-implanted sciatic nerve model, where longer analgesic duration is stated versus unformulated ropivacaine and extended duration is stated versus an extended-release liposomal bupivacaine. The overall problem addressed is providing sustained-release local anesthetic efficacy through a lipid-based complex at a controlled pH.
Claims Coverage
The provided independent claim covers an anesthetic composition defined by a lipid based complex containing ropivacaine base and phospholipids derived from saturated fatty acids, dispersed in an aqueous buffer with a specified pH range, and further constrained by median complex diameter and a minimum ropivacaine base to phospholipid molar ratio. Dependent claims refine phospholipid selection, limit unsaturated phospholipid content, further tighten diameter and ratio ranges, and define pain treatment use via administration routes.
pH-defined aqueous dispersion of ropivacaine lipid complex
An anesthetic composition comprising a lipid based complex including ropivacaine base and a lipid mixture including at least one phospholipid derived from saturated fatty acids, in the presence of an aqueous buffer at a pH of 5.5 to 8.0.
Saturated phospholipids with limited fatty-acid carbon number
The at least one phospholipid is derived from saturated fatty acids, each fatty acid independently comprising a carbon chain of carbon number no greater than 18.
Median complex diameter and minimum ropivacaine:phospholipid molar ratio
The lipid based complex has a median diameter of no less than 1 bcm, and the molar ratio of ropivacaine base to phospholipid is at least 0.5:1.
Specific saturated phospholipid selection
The saturated phospholipid is selected from DMPC, DLPC, or DPPC.
Limited unsaturated phospholipid content
A lipid mixture including an unsaturated phospholipid present at less than 10 molar percentage of the total phospholipids.
Tightened ropivacaine:phospholipid molar ratio
The molar ratio of ropivacaine base to phospholipid in the lipid based complex is at least 0.9:1.
Specified median diameter ranges
A lipid based complex having a median diameter selected from the group consisting of from 5 bcm to 50 bcm, 5 bcm to 40 bcm, 5 bcm to 30 bcm, 5 bcm to 20 bcm, and 5 bcm to 15 bcm.
Across the independent claim and its dependents, the coverage is anchored in a ropivacaine base lipid based complex formed in an aqueous buffer at pH 5.5 to 8.0 using phospholipids derived from saturated fatty acids (C318), with constraints on median complex diameter (6bcm) and minimum ropivacaine base to phospholipid molar ratio (53:1, with dependent tightening). Additional dependent coverage specifies particular saturated phospholipids, limits unsaturated phospholipid content, and narrows median diameter ranges.
Stated Advantages
Prolonged anesthetic efficacy is stated for the sustained-release local anesthetic composition.
Longer analgesic duration is stated versus unformulated ropivacaine in rat models.
Extended analgesic duration is stated versus extended-release liposomal bupivacaine.
Simpler, robust manufacturing via one-step lyophilization and ambient hydration is stated.
Documented Applications
Treating pain in a subject by administering an effective amount of the anesthetic composition through a nerve block, infiltration anesthesia, or field block [procedural detail omitted for safety].
Postsurgical pain / pain relief is stated in the context of pain and analgesia evaluation in rat models including a paw incision model and a cuff-implanted sciatic nerve model [procedural detail omitted for safety].
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