| Parkinson’s disease (PD) is the second most frequently occurring progressive neurodegenerative disorder, with the coming of aging society, PD will afflict more and more people. Pramipexole (PPX) is a highly effective and selective dopamine (DA) receptor agonist, used for the treatment for the motor symptoms of PD. However, the half-life of PPX is short, and PD patients must orally take PPX tablets frequently, the blood drug concentration "peak-valley"’fluctuation associated with oral administration will aggravate "on-off" complication, additionally, PD patients suffer from dysfunction and swallowing difficulty disorders, which make oral administration significantly decreasing drug safety and patient compliance. Therefoe. development of a prolonged-release PPX transdermal drug delivery system (TDDS) is of important significance for PD treatment.In this thesis, blended PSAs matrix was used as drug-loading matrix, and a single-layer drug in adhesive (DIA) type transdermal patch was constructed according to in vitro/in vivo studies, and this patch could mantian extended-release of PPX for 7 days. Then, quality and stability of PPX patch were evaluated. Finally, the potential efficacy of optimized PPX patch was assessed through pharmacokinetics study in rat and pharmacodynamics study in PD mice. The main contents and results are summarized as follows:Firstly, the feasibility of constructing a prolonged PPX-TDDS was assessed through physicochemical properties measurements and percutaneous permeability evaluation of PPX. The results showed that PPX had suitable physicochemical properties, like LogPo/w (1.20±0.19), melting point (129 ℃) and solubility, for TDDS. PPX exhibited good stability in fresh rat skin, and showed a skin binding of 54.88% in strutum corneum (SC). Permeation kinetics of PPX through human cadaver skin (HCS) indicated that SC was the main barrier in the permeation path of PPX, but PPX could easily distribute into viable skin (Ks/N.= 1.01±0.09), which is conducive to its total skin permeability. Compared to hairless mouse and mouse skins, the permeability of PPX through rat skin was closer (ablut 1.2-fold, p>0.05) to that through HCS, indicating that rat skin can be used as substitute of HCS in the following in vitro permeation experimrnts.Secondly, in vitro/in vivo skin permeation studies were used to construct and optimize a prolonged-release PPX patch, including PSA type and their blend ratios, formulations and preparation processs. The results showed that PPX exhibited different drug release, solubility and stability in four types of Duro-Tak(?) PSAs, PSA Ⅰ (-COOH) and PSA Ⅱ (-OH) could be blended to combine their high drug-loading and good drug release to obtain a desirable matrix for PPX. Drug release and drug-loading of PSA Ⅰ/PSA Ⅱ blended PSAs varied with the content of PSA Ⅱ in contrary ways, when PSA Ⅰ/PSA Ⅱ= 70/30. the blended PSA matrix showed desirable drug-loading and prolonged drug release, this was attributed to the drug "reservoir" function of PSA I and the good drug release of PSA Ⅱ. Isopropyl myristate (IPM) significantly improved skin permeability of PPX (ER=8.58), and tackifier B (10%) significantly increased the adhesivity of PPX patch, the PU membrane 3 M CotranTM 9700 was chosen as backing membrane of PPX patch for its better water and oxygen permeability. The optimized PPX patch showed obvious sustained-release characteristics through human skin both in vitro and in vivo, Jss were 7.13±0.89μg/(cm2-h) and 6.95 μg/(cm2h), respectively. Moreover, the optimized preparation process of PPX patch was:drug mixing time 120 min, coating thickness 550 μ and a programmed heating (80-90 ℃,20 min) was employed to dry the patch.Moreover, the quality control methods of PPX patch were established and methodogy verifications were performed, and then, quality and stability of PPX patch were evaluated. The results showed that the drug content of PPX patch was 98.57-100.76%, the total impurities was less than 1%, the release degrees of PPX patch were 12%(1 h),70-72%(72 h) and 82-85%(168 h). PPX patch showed good adhesivity and no residual solvents and microbials were detected, the qualit met the requirements of transdermal patch in Chinese Pharmacopoeia (vesion 2015). Stability tests results showed that no obvious changes occurred in drug content, impurity content and release degree of PPX patches, indicating its good stability.Finally, pharmacokinetics and pharmacodynamics evaluations of PPX patch were performed in animals with PPX immediated-release tablets Sifrol(?) as control. PPX patch showed sustained-release characteristics in rats, produced equal blood drug level to Sifrol(?) in 7 days. Prolonged t1/2 and MRT were obtained from PPX patch,t1/2 was 26.7-fold than Sifrol(?) (75.16±17.37 h VS 2.81±0.34 h), MRT was 41.8-fold than Sifrol(?)(135.89±24.12 h VS 3.25±0.99 h). Pharmacodynamics study in PD mice showed that middle and high doses of PPX patch obviously improved the behavior ability of PD mice; obviously restored striatum DA depletion to 84.09% and 94.71% compared to the control group, respectively; significantly restored striatum DA neurons; the medium dose PPX patch achieved equal efficacy to high dose Sifrol". Moreover, PPX patch didn’t produce any phototoxicity and skin allergic reaction on guinea pigs. Therefore, PPX patch developed in this thesis has the potentical feasibility to replace oral administration for the long-term treatment of PD, and has good skin security. |
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