Cabazitaxel phospholipid composition, preparation method thereof and application

Abstract

The invention discloses a cabazitaxel phospholipid composition, a preparation method thereof and an application. The cabazitaxel phospholipid composition comprises a cabazitaxel lipid complex, phospholipid and cholesterol and solves the problems that drugs are unstable, preparation steps before clinical use are complicated, an existing lipid preparation has poor in vitro and vivo stability and the like, in vivo circulation time of the drugs is prolonged, the composition has a certain targeting function, the drugs are enriched on a tumor site, toxic and side effects are reduced, and bioavailability is greatly improved.

Description

technical field [0001] The invention belongs to the field of pharmaceutical preparations, in particular to a cabazitaxel phospholipid composition. At the same time, the present invention also relates to the preparation method of the cabazitaxel phospholipid composition and its use in the preparation of drugs for treating tumors. Background technique [0002] Cabazitaxel is a semi-synthetic taxane compound whose precursor is extracted from the needles of the yew tree. The chemical name is 4-acetoxy-2α-benzoyloxy-5β, 20- Epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotaxane-11-en-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy- 3-Phenylpropionate. The US FDA approved it for marketing on June 17, 2010. It is used in combination with prednisone to treat patients with hormone-refractory metastatic prostate cancer (HRPC) who have previously received a docetaxel-containing regimen. Treatment with cabazitaxel significantly prolonged overall survival and reduced the risk of death by 30%...

AI Technical Summary

Problems solved by technology

This makes the drug injection have some problems in clinical use: (1) Tween 80 is prone to adverse reactions and causes more complications in clinical use, and the more common ones include severe allergic reactions, fluid retention, etc., so Before use, antihistamines and non-steroidal anti-inflammatory drugs must be used for pretreatment. Even after treatment, patients may still have different degrees of allergic reactions, and they need to be observed at any time

In addition, Tween 80 also has problems such as hemolysis, high viscosity, and cannot be used with PVC delivery devices (it tends to leach highly toxic diethylhexyl phthalate), which poses a problem for clinical application. Numerous inconveniences and safety concerns

(2) The preparation process before drug use is too cumbersome and inconvenient for patients to use

[0005] Aiming at the problems existing in the preparations of cabazitaxel on the market, professionals in the field of preparations have proposed many solutions: Chinese patent CN103768018A discloses a liposome injection of cabazitaxel and its preparation method. Prepared by the dispersion method, this process is only suitable for the preparation of liposomes on a laboratory scale, and it is difficult to achieve industrial production

Chinese patent CN104473873A has announced a kind of cabazitaxel long circulation liposome injection and preparation method thereof, contains surfactant polyethylene glycol 1000 vitamin E succinate (TPGS) in this liposome prescription, may bring some Potential safety hazard; in addition, the prescription does not contain cholesterol, which will greatly reduce the stability of liposomes in vivo and in vitro, thereby affecting the curative effect

Chinese patent CN104306333A discloses a cabazitaxel lipid microsphere injection and its preparation method. The prescription composition includes surfactants (Tween type) and amphiphilic polyamino acids, which may still cause allergies and hemolysis in clinical use. and other adverse reactions

Chinese patents CN103393632A and CN104224750A both disclose cabazitaxel albumin nano-preparation. The albumin nano-preparation itself has the disadvantages of poor stability in vivo and in vitro and is easily cleared by the endothelial reticular system, thus limiting the improvement of the efficacy of the system.

Chinese patent CN104856973A discloses a cabazitaxel micellar drug-loading system. In addition to the safety problems of the carrier material itself, the instability of the micellar preparation in the body is another major obstacle to the clinical application of the system

Although the disclosed cabazitaxel liposomes have certain advantages compared with commercially available injections, there are following defects: (1) liposomes have poor stability in vivo and in vitro, and liposomes are easy to aggregate during long-term storage; liposomes enter the body Finally, due to the effects of various factors such as albumin, opsonin, and antibodies in the blood, and the phase transition temperature of the lipid used is lower than body temperature, the encapsulated drug leaks rapidly, which greatly weakens the advantages of liposome preparations and limits its curative effect. to play

(2) The liposome preparation method and technique adopted are difficult to realize industrialized production, and the liposome particle size of making is difficult to control, and distribution is uneven, and encapsulation efficiency is low, poor stability

(3) Surfactant is also contained in the existing liposome prescription, and there are still safety problems

Considering that the structure of cabazitaxel contains a large number of ester bonds, which are easy to hydrolyze and unstable, the novel cabazitaxel phospholipid composition disclosed in this patent makes a lipid complex from cabazitaxel and negatively charged phospholipids. On the one hand, cabazitaxel Taxazitaxel lipid complex not only improves the chemical stability of cabazitaxel, but also increases the stability of cabazitaxel phospholipid composition preparation by utilizing the interaction between cabazitaxel and negatively charged phospholipids, reduces the leakage of drugs, and solves the problem of The present invention solves the problem of poor stability in vivo and in vitro of the current cabazitaxel liposome preparations; in addition, aiming at the problem that the current cabazitaxel liposome preparations are all prepared by the film dispersion method and it is difficult to realize industrial production, the present invention discloses the preparation of phospholipids by spray drying process. composition method

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