Nanocrystal of camptothecin drugs and preparation method thereof

Abstract

The invention provides a nanocrystal composition of a slightly-soluble antitumor drug, i.e., camptothecin and derivatives thereof, and a preparation method thereof. According to the invention, an optimized alkali-dissolution acid-precipitation high-pressure-homogenization process is employed; drug powder is subjected to alkali dissolution and then acid is added at a gradient speed to allow a nanocrystal to be precipitated; acid precipitation is carried out in two steps, and a produced salt is removed through a centrifugation step; and high-pressure homogenization is carried out to further decease a particle size. Preferably, the camptothecin nanocrystal has an average particle size of 100 to 150 m and is uniformly distributed; the camptothecin nanocrystal can be preserved for a long time in the form of freeze-drying powder only by adding a minute quantity of poloxamer 188 as a freeze-drying protection agent; and in use of the camptothecin nanocrystal, a glucose solution with a concentration of 5% is added and shaken out, so the camptothecin nanocrystal directly recovers to a state before freeze-drying. The method is simple, good in repeatability and suitable for large-scale production. The prepared nanocrystal has good slow release effect; and compared with commercially available injections, the nanocrystal has prolonged circulation time in blood plasma, improves distribution of the drug in human tissue and has beeter antineoplastic effect and good development prospects.

Description

Technical field [0001] The invention relates to the field of pharmaceutical preparations, in particular to a nanocrystal of camptothecin drugs without a stabilizer and an organic solvent-free preparation process, and a preparation method and application thereof. Background technique [0002] Camptothecin drugs include camptothecin, 10-hydroxycamptothecin, 7-ethylcamptothecin, 7-ethyl-10-hydroxycamptothecin, 9-nitrocamptothecin, etc., all of which are poorly soluble drugs , Both have a lactone ring and good anti-tumor activity, of which 10-hydroxycamptothecin (10-HCPT) is the most widely used in clinical practice. [0003] Camptothecin drugs are trace alkaloids and their derivatives with anticancer effects extracted from Camptotheca acuminata. They are cell cycle-specific drugs and mainly act in the DNA synthesis phase (S-phase). HCPT is a specific inhibitor of topoisomerase I (Topo I). It inhibits the reconnection step during the relaxation of the DNA supercoil structure, causing ...

AI Technical Summary

Problems solved by technology

[0004] At present, the camptothecin drugs represented by hydroxycamptothecin are mainly used in the clinical application of injections. The main problems in the clinical application of injections are: (1) short half-life (intravenous distribution half-life (t1 / 2a) is 4.5min, and the elimination half-life (t1 / 2β) is 29min), requiring repeated administration or prolonging the course of treatment, resulting in increased dose-limiting toxicity-bone marrow suppression and gastrointestinal toxicity

(2) After intravenous administration, it is mainly distributed in the gallbladder, but the distribution of cancer-prone tissues and organs such as liver, lung, stomach, etc. is not ideal

(3) Hydroxycamptothecin has poor fat solubility and water solubility, and the anticancer activity of water-soluble sodium salt is reduced by 90%, and the toxic and side effects are increased; the stability is poor, and the lactone ring of the drug is sensitive to light and pH, which is antitumor The closed-loop lactone structure with strong biological function is transformed into the open-ring carboxylate structure with weak function, and the pharmacological activity is greatly reduced

Due to the above reasons, hydroxycamptothecin is hindered from fully exerting its anti-tumor effect, which limits its clinical application.

[0005] At present, there is a method for preparing hydroxycamptothecin soyphospholipid nano-lyophilized preparations by solvent evaporation at home and abroad. Although the hydroxycamptothecin soyphospholipid nano-lyophilized preparation prepared by this method can overcome the deficiencies of existing injections to a certain extent , but this method requires a large amount of low-boiling organic solvents, which is not good for environmental protection, and it is easy to cause organic solvents to remain in the preparation, affecting the therapeutic effect of the drug

[0006] The nanocrystalline composition of camptothecin drugs can also be prepared by utilizing the property that the camptothecin lactone ring can be dissolved in water by adding an alkali to open the ring, and precipitate by adding an acid ring, but the process needs to be prepared before the preparation and the final product. Adding excipient stabilizers to the drug, and the nano-particle size is also large, the resolubility after freeze-drying is not good, which is not conducive to clinical application

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