Design And Evaluation Of Skin Delivery System Of Docetaxel

The novel antitumor mechanism and the unique efficacy in clinical trials make docetaxel (DTX) one of the promising new generations of antitumor drugs. DTX and its combination therapy were widely used in the treatment of many cancers, such as breast, non-small-cell lung, ovarian, and prostate cancer etc. Severe allergies are seen in clinical test of the market formulation (Taxotere) by utilizing Tween 80 as the solubilizer. To develop a safe and effective new formulation of DTX would overcome the problems of current formulation and improve the life quality of tumor patients, which has great importance for tumor therapy.Improving the skin permeability of poorly water-soluble DTX was the main focus of this paper. Both the solubility and the cutaneous safety of DTX were significantly improved by loading DTX into elastic liposomes. Combining elastic liposomes with microneedle pretreatment, the skin permeability of DTX was remarkably improved. The in vitro/in vivo pharmacokinetic behavior of skin permeation of DTX and the relevant mechanism were thoroughly studied to provide new idea and materials on the study of new formulation of high molecular weight and poor water-soluble drugs of DTX kind.In the review sections of this work, the skin drug delivery system was briefly introduced. Pharmaceutical, physical and chemical methods to improve skin drug delivery were described in detail. Recent development on DTX application and formulation study was also reviewed. In the experimental sections, a series of research work was performed in association with the development of DTX elastic liposomes and the in vitro/in vivo pharmacokinetics of DTX elastic liposomes-microneedle combination system. The main works are described below:1. Preparation of DTX elastic liposomes. The DTX elastic liposomes prepared under optimized formulation were unilamellar and spherical. The drug loading dosage of DTX in elastic liposomes was more than 1000 times higher than that in water. The DTX elastic liposomes were confirmed stable in the stability test.2. The permeability of DTX through porcine skin from elastic liposomes, conventional liposomes and control solution was investigated and compared in vitro. The steady-state flux of DTX from elastic liposomes is 3-fold higher than that from conventional liposomes (P<0.05). In the meantime, concentration of DTX in the receptor cell from control solution was below the limit of determination. The above results indicated that using elastic liposomes could significantly improve the skin delivery of DTX. The mechanism of elastic liposomes to improve skin delivery of DTX was studied by blank formulation pretreatment experiment and laser confocal scanning microscopy (CLSM), which indicated that both the penetration enhancing effect and intact liposomal permeation into the stratum corneum mechanism play a role in it. Furthermore, the penetration enhancing effect may indirectly influence the skin delivery of DTX, and the intact liposomal permeation into the stratum corneum mechanism seems to play a predominant role through the DTX permeation.3. The effect and mechanism of improvement of skin drug delivery by combining elastic liposomes with microneedle skin drug delivery system were studied for the first time. Microneedle pretreatment can improve the permeation of DTX loaded elastic liposomes, so as to further improve skin delivery of DTX. Combining with microneedle pretreatment, steady-state flux of DTX from elastic liposomes is 1.7-fold higher than that from control solution. Furthermore, the lag time of DTX from elastic liposomes is only a quarter of that from conventional liposomes by microneedle pretreatment. The results above showed that combining DTX elastic liposomes with microneedle pretreatment significantly improved the skin delivery of DTX, and showed great potential application value. The skin deposition study showed that after DTX elastic liposomes entering the microchannels created by microneedle pretreatment, intact liposomes will be difficult to permeate through the skin, but to deposit in the skin and release DTX.4. The pharmacokinetic behavior and antitumor effect of DTX elastic liposomes -microneedle combination system in mice were preliminarily studied. Only little DTX can enter the systemic circulation after enter the skin by the combination system, if any. Both the tumor volume and tumor weight of the human breast carcinoma xenografts in nude mice were remarkably inhibited by treatment of DTX elastic liposomes-microneedle system. These results demonstrated that DTX elastic liposomes-microneedle system could improve the local antitumor activity to some extent. Skin irritation test in rabbits showed that the DTX elastic liposomes can decrease the irritation of DTX to the skin.