Hydroxycamptothecin nano crystal lyophilized powder for injection preparation and preparation method thereof

Abstract

The invention discloses a method for preparing a nanometer hydroxycamptothecin crystal freeze-dried powder preparation. Main raw materials of the nanometer hydroxycamptothecin crystal freeze-dried powder preparation consist of an active raw material, namely hydroxycamptothecin, phospholipids, a surfactant, namely poloxamer 188 or polyethylene glycol stearate-15, and a freeze-dried auxiliary material excipient. The method for preparing the nanometer hydroxycamptothecin crystal freeze-dried powder preparation comprises the following steps: after the hydroxycamptothecin is added into an alkaline solution to be dissolved, the phospholipids are added in an ultrasonic water bath, and the poloxamer 188 or the polyethylene glycol stearate-15 is added into the mixture under magnetic stirring to be dissolved; the pH value of glacial acetic acid is adjusted to be between 4.0 and 6.0, and hydroxycamptothecin crystals are precipitated; and then the high-pressure homogenization is performed to obtain a nanometer hydroxycamptothecin crystal suspension, and then the freeze-dried auxiliary material excipient is added to be freezely dried to obtain the nanometer hydroxycamptothecin crystal freeze-dried powder preparation. The method is simple and easy to operate. Nanometer crystal freeze-dried powder has the advantages of high dispersity, good stability and so on. The average size of the crystals is 355.6nm, the average content of the hydroxycamptothecin in a sample is 98.5 percent of labeled amount, and the effect of inhibiting and killing liver cancer and gastric cancer cells of the preparation is remarkably stronger than that of a hydroxycamptothecin injection.

Description

technical field [0001] The invention relates to an anticancer drug, in particular to a hydroxycamptothecin nano crystal freeze-dried powder preparation, and also relates to a preparation method of the preparation. Background technique [0002] Hydroxycamptothecin is a trace alkaloid with the strongest anti-cancer effect among similar anti-tumor monomers extracted from Camptotheca sinensis in the 1960s and 1970s. It is a cell cycle-specific drug and mainly acts on the DNA synthesis phase (S- Expect). HCPT is a specific inhibitor of topoisomerase I (Topo I), which triggers cell death by inhibiting the religation step in the relaxation process of DNA supercoil structure, resulting in single- and double-strand DNA breaks. Clinically, it is mainly used for radiotherapy and chemotherapy of malignant tumors such as primary liver cancer, gastric cancer, head and neck cancer, adenogenic epithelial cancer, leukemia, and bladder cancer; toxic reactions are mainly manifested in the inh...

AI Technical Summary

Problems solved by technology

At present, hydroxycamptothecin is mainly used in the clinical application of injection, and the main problems in the clinical application of injection are: (1) short half-life (intravenous distribution half-life (t 1 / 2a ) is 4.5min, and the elimination half-life (t 1 / 2β ) was 29min), requiring repeated dosing or prolonging the course of treatment, resulting in dose-limiting toxicity—myelosuppression and gastrointestinal toxicity also increased

(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.

[0003] At present, there is a method for preparing hydroxycamptothecin soyphospholipid nano-freeze-dried preparations by solvent evaporation at home and abroad. The hydroxycamptothecin soyphospholipid nano-freeze Although dry preparations can overcome the shortcomings of existing injections to a certain extent, this method requires a large amount of low-boiling organic solvents, which is not conducive to environmental protection, and it is easy to cause organic solvents to remain in the preparation, affecting the therapeutic effect of the drug.

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