Triptolide derivative, preparation method and preparation thereof

Abstract

The invention discloses a triptolide derivative, a preparation method and a preparation thereof, wherein the chemical structure of the triptolide derivative is represented by a formula (I) defined in the specification, R represents straight chain alkyl acyl having a carbon atom number of 2n, and n is 2-9. The present invention discloses the preparation method of the compound, wherein triptolide and saturated fatty acid are subjected to an esterification reaction to obtain the compound. According t the present invention, the hydroxyl forms the ester by bonding the saturated fatty acid on the C14 site OH of TP so as to reduce the polarity while the fatty acid is introduced so as to effectively enhance the fat-solubility, the property is stable, the oxidation is not easily generated, and the drug forming property of the TP nanometer preparation can be significantly improved; liposomes, micelles, nanoparticles, fat emulsions and other nanometer preparations prepared from the compound of the present invention have good packing effect; and the prepared nanometer preparation has advantages of high drug loading, high entrapment efficiency, stable property, significant toxicity reducing, half-life prolonging, and the like.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a triptolide derivative and a preparation method and preparation thereof. Background technique [0002] Triptolide (Triptolide, TP), also known as triptolide and triptolide alcohol, is an epoxy diterpenoid lactone compound isolated from the traditional Chinese medicine Tripterygium wilfodii Hook F. Biological activities, including anti-inflammatory, immunosuppressive, anti-tumor, anti-fertility, etc. (Liu Q. Triptolide and its expanding multiple pharmacological functions [J]. International Immunopharmacology, 2011, 11(3): 377-383). As the main active ingredient of Triptolide, its anti-tumor value has been extensively studied. Up to now, at least 60 tumor cell lines have been studied and can be inhibited by TP (Luo Yongwei, Shi Chang, Liao Mingyang. Research progress on the mechanism of triptolide’s anti-tumor action[J ]. Chinese Journal of Traditional Chinese Medicine, 2009, 34...

AI Technical Summary

Problems solved by technology

Lin Sui and others tried to prepare TP nanoliposomes, but the maximum drug loading was still only 0.016% (Chinese patent CN105816428A); Zhang Cong prepared TP lipid nanoparticles, and the optimal prescription process lipid / drug = 50:1~ Under the condition of 100:1, the encapsulation rate still does not exceed 60%, which is far below the requirements of the Chinese Pharmacopoeia (Zhang Cong. Triptolide lipid nanoparticles research [D]. Huazhong University of Science and Technology, 2014); Wang Shujuan on the preparation The stability investigation of the obtained liposomes showed that the newly prepared TP liposomes aggregated after being placed at room temperature for 10 days, and basically precipitated after one month. Compared with before drying, the encapsulation efficiency is still reduced in different degrees, and the encapsulation efficiency is less than 40% (Wang Shujuan. Preliminary research on the preparation and quality of triptolide liposomes [D]. Yangzhou University, 2010)

Chinese patent CN105263475A discloses a TP prodrug "MRx102", but MRx102 does not have druggability, or has poor druggability, which is mainly reflected in: ①In the embodiment, the amount of oil phase used in the MRx102 emulsion formula is large, and most of the emulsion oil The amount of the phase is 40%, just as the patent says, "the classic emulsion formula contains 10-30% triglycerides", and the 40% oil phase will directly cause the emulsion of the preparation to be a thick cream (Fidler J M ,An J,Carter B Z,et al.Preclinical antileukemic activity,toxicology,toxicokinetics and formulation development of triptolidederative MRx102[J].Cancer Chemotherapy and Pharmacology,2014,73(5):961-974), which will inevitably affect the sterilization of the preparation 22 μm filter membrane or autoclaving, and the potential lack of needle penetration may cause smooth injection and poor patient compliance; ②The solubility in oil is too poor, regardless of the safety of tricaprylic acid glyceride , even if 29.4% tricaprylic acid glyceride is used as the emulsion prepared in the oil phase in Table 4 of this patent, the solubility of MRx102 is only 0.681 μg / mL, which directly leads to too low drug loading; ③The stability is too poor. In Table 5 of this patent, Even if 40% tricaprylic acid glyceride is used as the emulsion prepared by the oil phase (taking E-3 as an example), the emulsion of 2 mg / mL drug loading is prepared, and its drug content (solubility) varies from 0 hour, 1 hour, 24 hours, 8 days were 1529, 1514, 1353, 1176 μg / mL respectively, that is to say, the drug loading of the prepared emulsion was reduced by 41.2% after 8 days of storage, and it was not druggable; ④ MRx102 emulsion formulations all contain high content of tricaprylic acid glyceride, the It is clear in the patent that substituting part or all of tricaprylin with soybean oil will reduce the solubility of MRx102 in the emulsion, indicating that tricaprylin is indispensable, and this ingredient is currently mainly used in skin care products and cosmetics for intravenous administration. There are hidden dangers in its safety in pharmaceutical preparations; ⑤ In order to increase the dissolution of MRx102 in the emulsion, the ionic surfactant sodium cholate was added to the formula for solubilization, which also shows that the prodrug does not have the effect of significantly improving fat solubility. features

In addition, the patent does not involve the preparation of other nano-preparations such as liposomes and micelles, or the development of fat emulsions is a helpless choice

[0010] In summary, although there have been a lot of researches on triptolide, the druggability of triptolide preparations is still outstanding, and further research and development is urgently needed to improve the above problems, and develop high-efficiency drugs targeting TP for anti-tumor therapy

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