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Covalent anesthetic-polymer conjugates for prolonged local anesthesia

A technology of local anesthesia and polymers, which is applied in drug combination, drug delivery, antipyretics, etc., and can solve the problems of inconvenient clinical use, cumbersome preparation schemes, and time-consuming liposome formulations

Active Publication Date: 2020-10-30
CHILDRENS MEDICAL CENT CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Furthermore, time-consuming and cumbersome preparation protocols make liposomal formulations inconvenient for clinical use

Method used

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  • Covalent anesthetic-polymer conjugates for prolonged local anesthesia
  • Covalent anesthetic-polymer conjugates for prolonged local anesthesia
  • Covalent anesthetic-polymer conjugates for prolonged local anesthesia

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0242] Example 1: Conjugates of anesthetics with amphiphilic polymers and PEG

[0243] Amphiphilic, biodegradable conjugates of poly(glyceryl sebacate) (PGS), PEG and TTX were designed, produced and assayed according to the following method.

[0244] method

[0245] Material

[0246] Sebacic acid (99%), poly(ethylene glycol) (PEG, 200, 1000, 2000kDa), N,N'-diisopropylcarbodiimide (DIC, 99%), 4-dimethylamino Pyridine (DMAP, 99%), anhydrous N,N-dimethylformamide (DMF, 99.8%), anhydrous dimethyl sulfoxide (DMSO, 99.9%), anhydrous dichloromethane (DCM, 99.8%) , glycerol (99%), dexamethasone (98%), fluorescein isothiocyanate isomer I (FITC, 90%), phosphate buffered saline (PBS, pH7.4, 0.15M, 138mM NaCl, 2.7 mMKC1), chloroform-d (100%, 99.96 atomic % D), hexamethylene diisocyanate (99.0%), and dibutyltin dilaurate (95.0%) were purchased from Sigma-Aldrich (St. Louis, MO). Cyanine 5.5 carboxylic acid (Cy5.5, 95%) was purchased from Lumiprobe (Hallandale Beach, FL). Tetrodotoxi...

example 2

[0343] Example 2: TTX-PGS / PEG provides long-duration in vitro drug release without cytotoxicity

[0344] result

[0345] To assess the potential of TDP-TTX conjugates to provide sustained nerve block, release kinetics were studied in vitro under physiological conditions (PBS, pH 7.4, 37°C). HPLC of the release sample showed a peak at about 5.0 minutes. Liquid chromatography-mass spectrometry (LC-MS) confirmed that the molecular weight of the molecules in this fraction corresponded to that of TTX (m / z 320.1 is [TTX+H] + ), thus confirming that TTX was released from TDP-TTX junction conjugation in its native form. The TTX release half-life (the time it takes to release half of the loaded TTX) was studied. All TDP-TTX conjugates significantly increased the duration of TTX release compared to free TTX ( Figure 4A and 4B ).

[0346] f of TDP polymer Phil Determine the release rate of TTX. with f Phil Decreasing from 83.5 to 0%, TTX release half-life increased from 25±5 ...

example 3

[0356]Example 3: Manufacture of Syringe Injectable Formulations

[0357] result

[0358] Injectable solutions and suspensions have the potential to be injected into the body by any route of administration (Mastropietro, D., Nimroozi, R. and Omidian, H. "Rheology of pharmaceutical formulations-A perspective perspective)” "Journal of Pharmaceutical Development 2, 108(2013)), however, despite the high f phil (83.5%) T g D. 8 P 2000 Can be homogeneously suspended in PBS for injectable formulations, but others have low f phil The TDP polymer cannot be uniformly suspended in PBS ( Figure 3A and 3B ). To administer the TDP-TTX conjugate by injection into a patient, a homogenous TDP-TTX / PEG200 formulation was made by solvent evaporation ( Figure 7 ). Briefly, TDP-TTX conjugate was dissolved in DCM to make a homogeneous solution, followed by the addition of PEG200, which is miscible with DCM. DCM was removed by rotary evaporation and lyophilization, leaving a homogeneous ...

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Abstract

Anesthetics covalently conjugated onto biodegradable and biocompatible hydrophilic polymers via hydrolysable linkages provide controlled release of local anesthetics in vivo in an effective amount fornerve blockade with reduced toxicity relative to the unconjugated anesthetic agent. The rate of anesthetic release can be tuned by changing the hydrophilicity of the polymer. Exemplary formulations of Poly (glycerol sebacate) (PGS), optionally including Poly ethylene glycol (PEG) polymers conjugated to Tetrodotoxin (TTX) (PGS-PEG-TTX and PGS-TTX), and methods of use thereof are provided Nerve blockade from PGS-PEG-TTX and PGS-TTX was associated with minimal systemic and local toxicity to the muscle and the peripheral nerves. TDP-TTX conjugates homogeneously dispersed into PEG200 are also described. PEG200 not only worked as a medium, but also worked as a chemical permeation enhancer (CPE) to enhance the effectiveness of TTX.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of and priority to U.S.S.N. 62 / 593,784, filed December 1, 2017, which is hereby incorporated by reference in its entirety. technical field [0003] This is typically in the areas of prolonged nerve blocks, local anesthesia and analgesia with reduced toxicity, especially formulations of tetrodotoxin covalently linked to biocompatible polymers for controlled release. [0004] governmental support [0005] This invention was made with government support under Grant Nos. 5R01GM073626-12 and 1R01GM116920-01 awarded by the National Institute of General Medical Sciences. The government has certain rights in this invention. Background technique [0006] Prolonged duration of local anesthesia following a single injection has been the focus of clinical and scientific research over the past two decades. However, there are a number of limitations associated with conventional aminoester and...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/60A61K47/10A61P29/02
CPCA61K9/0019A61K47/10A61K47/60A61K31/519
Inventor D·S·寇汉赵超
Owner CHILDRENS MEDICAL CENT CORP
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