A kind of anti-inflammatory, analgesic medicine and preparation thereof

Abstract

The present invention belongs to the technical field of medicine. The present invention relates to a synthesis process of 2-[(2,6-dichlorophenyl)amino]phenylacetic acid 1-(acetoxyl)ethyl ester and the preparation of a fat emulsion injection thereof. Diclofenac sodium is reacted with 1-bromoethylacetic ester to obtain 2-[(2,6-dichlorophenyl)amino]phenylacetic acid 1-(acetoxyl)ethyl ester (referred to as diclofenac ester for short), in the presence of a basic catalyst, the chemical structure of which is as follows. The compound of the present invention is a non-steroidal anti-inflammatory drug, which is prepared into a fat emulsion injection which can be used for intravenous injection. Compared with diclofenac sodium intravenous injectable preparations sold abroad, the diclofenac sodium fat emulsion injection is not only highly safe when used, but also has better anti-inflammatory and analgesic effects in vivo.

Description

technical field [0001] The invention belongs to the technical field of medicine, and the invention relates to a kind of 2-[(2,6-dichlorophenyl)amino]phenylacetic acid 1-(acetoxy)ethyl ester and its synthesis method, and its fat emulsion injection preparation. Background technique [0002] Diclofenac sodium (Diclofenac sodium, DS), the chemical name is 2-[(2,6-dichlorophenyl) amino] sodium phenylacetate, which belongs to the phenylacetic acid non-steroidal anti-inflammatory drugs. Its mechanism of action is to block the conversion of arachidonic acid into prostaglandins (PGs) by inhibiting the activity of cyclooxygenase, thereby producing analgesic and anti-inflammatory effects. At the same time, compared with other non-selective non-steroidal anti-inflammatory drugs, due to DS to inhibit 50% cyclooxygenase-2 activity required blood concentration (IC 50 ) is lower, and shows similar inhibitory activity to cyclooxygenase-1 in vitro, so its efficacy is better and side effects...

AI Technical Summary

Problems solved by technology

But this preparation has the following problems in clinical use: Due to the use of organic solvents to dissolve DS, it needs to be diluted with a large amount of alkaline saline before intravenous injection, and at the same time, it needs to be slowly infused intravenously to reduce the incidence of phlebitis, which generally takes more than 30-120 minutes (see ampoule instructions), so the patient's compliance and safety of drug use are poor

[0005] Chinese patent CN200810101867.0, (publication number CN101244278A) discloses an intravenous injection preparation using hydroxypropyl-β-cyclodextrin inclusion DS, which improves the solubility of DS in water and reduces the impact of DS on direct injection. Irritation of blood vessels, but we have to point out that: in recent years, there have been a large number of literature reports that intravenous injection of hydroxypropyl-β-cyclodextrin has nephrotoxicity and causes bone loss, etc. (Liu Yan, Cheng Xiaoxiang, Guo Chuanmin, etc. Experimental study on the toxicity of hydroxypropyl-β-cyclodextrin administered intraperitoneally and intravenously in rats[J].Modern Medicine and Clinic,2009,24(6):361-364.)(Rosseels M L A, Delaunois A G, Hanon E, et al.Hydroxypropyl-β-cyclodextrin impacts renal and systemic hemodynamics in the anesthetized dog[J].Regulatory Toxicology and Pharmacology,2013,67(3):351-359.)(Kantner I,Erben R G.Long-Term Parenteral Administration of2-Hydroxypropyl-β-Cyclodextrin Causes Bone Loss[J].Toxicologic pathology,2012,40(5):742-750.), so the DS injection containing hydroxypropyl-β-cyclodextrin still has There are certain potential safety hazards, and how to develop a safer and more effective DS intravenous injection is still an urgent problem to be solved

Then preparing DS as a fat emulsion preparation may be a good DS intravenous injection preparation, but the solubility of DS and diclofenac in soybean oil or other approved oils for intravenous injection is low, if it is directly made into a fat emulsion , its drug loading will be very low

For example, Cui Yue etc. have studied the diclofenac fat emulsion preparation, and the drug content of the DS fat emulsion prepared by using more oily phase (20%, mass fraction) is only 2.5mg / ml, and the preparation prescription also contains co-emulsifier Tween-80 and poloxamer 188 (Cui Yue. Research on Diclofenac Sodium Lipid Microsphere Injection [D]. Shenyang Pharmaceutical University, 2009.), and there are reports that Tween-80 has serious pathogenicity Sensitization (Luo Xia, Wang Qing, Zhou Lian, et al. Research on the relationship between Tween-80 contained in traditional Chinese medicine injections and allergic reactions[J]. Journal of Adverse Drug Reactions, 2010,12(3):160-165.), Therefore, the preparation needs to be improved in terms of safety in use

The clinically required dose of diclofenac sodium is relatively large (75mg). If the DS fat emulsion in the above study is used for administration, at least 30ml or more is required. Such a large-volume preparation requires a long infusion time when used, delaying sedation. The exertion of the pain effect also affects the patient's compliance. In addition, in terms of drug cost, the amount of excipients is increased, the production cost is increased, the price of the drug is increased, and the economic burden of the patient is increased. At present, DS fat emulsion preparations have not been listed yet.

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