Preparation of docetaxel long-circulating liposome and freeze-dried powder injection thereof

Abstract

The invention discloses a preparation technique of non-pegylation docetaxel long-circulating liposome which meets clinical and large-scale production requirements and a freeze-dried powder-injection; the liposome consists of docetaxel, neutral phospholipid, charged phospholipid, cholesterin, antioxidant, excipient, buffering agent and water for injection; the preparation technique includes the following steps: preparing multivesicular liposome, homogenizing the liposome, fixing volume, sterilizing, split charging, freeze drying, etc. The liposome increases the solubility of drugs, overcomes poor stability of docetaxel injection and toxicity caused by complex solvent and prolongs the in vivo circulating time of drugs; compared with pegylation long-circulating liposome, the toxicity is decreased and the inhibiting effect on tumor cells is strengthened.

Description

technical field [0001] The invention belongs to the field of pharmaceutical preparations, and relates to a long-circulating liposome containing an insoluble anticancer drug docetaxel, a freeze-dried powder injection and a preparation method thereof. Background technique [0002] Docetaxel is a taxane anticancer drug that is semi-synthesized from the precursor extracted from the needles of yew berry. Its anti-cancer mechanism is to stimulate the polymerization of cathelicidin, promote the assembly of microtubule dimers into microtubules, and cause cell proliferation to stop at the stage of mitotic quiescence (G2 / M). FDA approved docetaxel for the treatment of breast cancer, ovarian cancer, non-small cell lung cancer and pancreatic cancer, and has certain effects on primary and metastatic cancers such as head and neck squamous cell carcinoma and malignant melanoma. Due to its anti-cancer mechanism and exact curative effect, it has become one of the most valuable anti-cancer d...

AI Technical Summary

Problems solved by technology

Although PEGylated liposomes can increase the circulation time of liposomes in the blood, due to the presence of PEG, new toxic effects have emerged, such as liposome formulations containing PEGylated phospholipids can cause Cutaneous toxicity, commonly known as "hand-foot syndrome," which causes rashes / sores on the palms and soles of the feet

Another disadvantage of PEGylated liposomes is the presence of macromolecules (polyethylene glycol) on the liposome surface, which may weaken liposome-cell interactions and prevent liposome entry into tumor tissue , thus potentially reducing the accumulation of liposomal drugs in tumor tissue

[0005] The docetaxel liposome drug content reported by people such as Maria Laura Immordino is only 0.75mg / mL, and the stability is poor, and 4 ℃ places one day and just leaks more than 50% (Maria Laura Immordino, Brusa Paola, Arpicco, Silvia et al. Preparation, characterization, cytotoxicity and pharmacokinetics of liposomes containing docetaxel.Journal ofControlled Release 91(2003):417-429), the liposomes are not suitable for clinical application

[0006] Existing research results at home and abroad show that the key factors of liposome production at present mainly contain: the one, the particle size and uniformity of liposome, especially liposome through freeze-drying, the liposome particle after reconstitution The diameter will increase in varying degrees; the second is the degree of chemical degradation of the lipids forming liposomes and the drug encapsulated in the liposome; the third is that the large-scale industrial production of liposomes is difficult; the fourth is that the drug loading is low, Not suitable for clinical application

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