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Application of conjugate of polyethylene glycol and local anesthetic to non-narcotic analgesia
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A technology of local anesthetics and polyethylene glycol, applied in the field of medicine, can solve problems such as unfavorable patient compliance, abdominal muscle incoordination, and life-threatening
Active Publication Date: 2018-03-13
JENKEM TECH CO LTD (LIAONING)
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However, with the wide application of local anesthetics in clinical practice, their toxic and side effects are increasingly prominent, such as "Li Shuai, Li Wanli. Adverse reactions and prevention of local anesthetics. Naval Medical Journal, 2011 (4): 383-383. Local adverse reactions described in "such as local tissue reactions, nervous tissue reactions, cytotoxic reactions, systemic adverse reactions such as hypersensitivity reactions, allergic reactions (such as airwayedema, bronchospasm, dyspnea, urticaria, etc.), central nervous Toxic reactions (such as perioral numbness, headache, dizziness, tinnitus, blurred vision, muscle twitching, unconsciousness, convulsions, etc.), cardiotoxic reactions (such as tachycardia, hypertension, arrhythmia, inhibition of myocardial systolic function, etc.), In particular, the prominent manifestation of severe toxicity of local anesthetics is convulsions. At this time, due to the uncoordinated and strong contraction of the airway and chest and abdominal muscles, the respiratory and cardiovascular systems are bound to be affected, which can be life-threatening.
The occurrence of the above-mentioned adverse reactions will additionally increase the pain and danger of the patient, and significantly reduce the patient's compliance
[0004] The inventors of the present invention have found through experiments and research that reducing the dosage of local anesthetics to an appropriate range can achieve non-narcotic analgesic effects, and can reduce some adverse reactions of local anesthetics, such as the motor nerveblock effect on experimental animals. Decreased, but the maintenance time of non-narcotic analgesic effect is short. For example, the non-narcotic analgesic effect of a single administration of bupivacaine can only last for 1 hour at most. For analgesia, especially for chronic pain, frequent administration is required to achieve Long-acting analgesic effect is very inconvenient to use, which is not conducive to the compliance of patients who need analgesia, and the high and low dose window of local anesthetics that can play a non-narcotic analgesic effect is very small, which is difficult to control, so local anesthetics alone Medicine not suitable for non-narcotic analgesia
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Embodiment 1
[0143] Synthesis of embodiment 1 connecting chain (L1)
[0144]
[0145] Add 4-pentynoic acid (1.96g, 20mmol) and N,N-dicyclohexylcarbodiimide (DCC, 5.16g, 25mmol) into dichloromethane (50mL), cool in an ice-water bath, and then add p-hydroxyl Benzaldehyde (2.68g, 22mmol), the ice bath was removed after the addition, and reacted at room temperature overnight. After filtration, the filter cake was washed with ethyl acetate, and the filtrate was evaporated to dryness to obtain a crude product, which was purified by column chromatography to obtain 3.52 g of product 1a.
[0146] Compound 1a (3.23g, 16mmol) was added to anhydrousmethanol (35mL), cooled to 0°C, then sodiumborohydride (365mg, 9.6mmol) was added, reacted at the same temperature for 10min, and then quenched with 1M HCl, Methanol was spin-dried, ethyl acetate and saturated brine were added, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried, fil...
[0150] Lidocaine (0.50 g, 2.13 mmol) and compound L1 (1.00 g, 3.19 mmol) were added into acetonitrile (20 mL), and reacted overnight at 50°C. TLC monitoring showed that the reaction of lidocaine was complete, and the reaction solution was concentrated to obtain a crude product. Purification by column chromatography yielded 1.19 g of product Y1. 1 H NMR: (CDCl 3 ): 1.59(m, 6H), 2.06(s, 2H), 2.31(s, 6H), 2.64(m, 2H), 2.87(m, 2H), 3.49(m, 2H), 3.71(m, 2H) , 4.89 (s, 2H), 4.93 (s, 2H), 7.06 (m, 3H), 7.28 (d, 2H), 7.62 (d, 2H), 9.79 (s, 1H).
Embodiment 3
[0151] Synthesis of Example 3 lidocaine conjugate 1 (mPEG-lidocaine, 20K)
[0152]
[0153] mPEG-N 3 (20K, 2.00g, 0.10mmol), compound Y1 (65.8mg, 0.12mmol), vitamin C (52.8mg, 0.30mmol) were added to N,N-dimethylformamide (20mL), stirred rapidly to dissolve , and then coppersulfate pentahydrate (30.0 mg, 0.12 mmol) in water (4.4 mL, 2.2 mL / g PEG) was added, reacted overnight at room temperature, and precipitated with isopropanol to obtain 1.90 g of product. 1 H NMR: (CDCl 3 ): 1.42(m, 6H), 2.19(s, 6H), 3.02(m, 4H), 3.23(m, 4H), 3.31(s, 3H), 3.50(m, 1800H), 3.80(m, 2H) , 4.20(m, 2H), 4.50(s, 2H), 4.82(s, 2H), 7.12(m, 3H), 7.30(d, 2H), 7.64(d, 2H), 7.91(s, 1H), 10.28(s, 1H).
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Abstract
The invention discloses application of a conjugate of polyethylene glycol and local anesthetic to non-narcotic analgesia. The local anesthetic is made into a prodrug or a sustained release preparation, wherein high-molecular polymers such as polyethylene glycol in the prodrug are covalently bonded with local anesthetic, and auxiliary materials with a sustained release function in the sustained release preparation are covalently bonded with the local anesthetic. After application of the conjugate, anesthesia and analgesia effects are not achieved until release of free local anesthetic, and an analgesia effect is achieved after release of the free local anesthetic. Due to low release speed of the prodrug or the sustained release preparation of the local anesthetic, drug concentration can bestably and enduringly kept in an effective concentration range of non-narcotic analgesia, long-acting non-narcotic analgesia effects can be achieved while remarkable reduction of clinical untoward effects of the local anesthetic and reduction of dosing frequency are realized, drug effectiveness is improved, and a clinical application range of the local anesthetic is expanded.
Description
technical field [0001] The invention relates to the technical field of medicine, in particular to the application of a combination of polyethylene glycol and local anesthetic in non-narcotic analgesia, especially long-acting non-narcotic analgesia. Background technique [0002] Chronic pain, especially postoperative pain, is a common clinical symptom. The diseases involved include various clinical departments. While making patients feel painful, it will also produce a series of pathophysiological changes, such as affecting the body's autonomic nervous system, Accelerate heart rate, shortness of breath, and increase blood pressure; affect emotions, cause irritability, depression, and then affect the recovery of digestive system function and physical strength; affect endocrine and hormone levels, directly and indirectly disrupt the internal environment of the body. Therefore, reasonable analgesia can play the following roles: (1) reduce the pain and discomfort of patients, rel...
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