| Prazosin hydrochloride(PRH) was the first selective antagon of postsynapticα1 receptor for hypertension therapeutics.Now,only general tablet was sold in China,but its clinical application was restricted because of strong first-dose response,short half-time and frequent administration. Transdermal drug delivery system has good application perspective for the characteristics of avoiding first-pass effect of oral administration, remaining persistent and steady effective blood drug level,improving the compliance of patients,elevating the safety of medication,and so on. Hydrophilic gel-matrix patch has become the research emphasis for its good biocompatibility,simple preparation craft and cheap cost increasingly. Therefore,the application of PRH in the form of transdermal permeation can enhance therapeutic effect,improve the compliance of patients,elevate the safety of medication,and promote the control rate and therapeutic levels of hypertension.We discovered PRH patch based on polyvinyl alcohol and gelatin,studied the formulation,preparation craft,influence factors of transdermal permeation behavior,quality indexes,skin irritation, initial pharmacokinetics and bioavailability. The main work and conclusion in the topic included these parts as below:1.The necessity and feasibility of the preparation of PRH patch were sure.After studying the literatures and analysising its physical-chemical properties,the permeation rate of PRH could satisfy the transdermal drug delivery system.2.A high performance liquid chromatography(HPLC) method which was rapid,accurate and reproducible for determining prazosin hydrochloride in transdermal permeation solution was developed.The linear range of concentration and area was good from 0.100μg·mL-1 to 10.020μg·mL-1(A=104.4C+3.1674,r=0.9999).3.Screeninged and definited the optimal formulation,orthogonal design and integrated weighted score method were used to inspect single elements and optimize formulatin with steady state flux and time lag as indexes.The optimal formulation was composed of azone(2%),propylene glycol(15%),the ratio of gel-matrix material(5:4),and dosage content (1.0%).And the steady percutaneous rate,time lag and synthetic score were 7.30μg·cm-2·h-1,0.86h and 81.80.The in vitro release behavior was expressed with Higuchi model(r＞0.99) and nearly Zero-order equation model(r＞0.95).4.A high performance liquid chromatography(HPLC) method was established to determine the content of PRH in patch which was accurate, reliable and reproducible,The linear range of concentration and area was good from 0.252μg·mL-1 to 4.040μg·mL-1(A=98.525C+1.8288,v=0.9999).5.The initial stability of the patch was studied.Content uniformity of PRH in patches was determinated and differential scanning calorimeter was used for the research of state of PRH in patches,the results indicated that content uniformity of PRH in patches were qualified and PRH was dispersed in the gel-matrix material in the molecular or amorphous state. The initial stability of the patch was studied with Physical characteristic, content,transdermal permeation behavior viscosity as indexes.The results indicated that physical characteristic of the patch was stable,content and transdermal permeation behavior had no significant different in the condition of temperature(25±3℃) and relative humidity(60±10%) after 3 months.Stability of the patch was good.6.Sensitization tests of the patch were studied,and irritation on rabbits' skin was observed.Results of rabbits' abdomen skin and back skin sensitization tests indicated that PRH patch had no irritation on rabbits' skin,and its biocompatibility was good.7.A high performance liquid chromatography(HPLC) method was established to determine the content of PRH in the plasma,which was accurate,reliable and reproducible.The linear range of concentration and R (ratio of reference sample and internal standard) was good frorn 10.0ng·mL-1 to 500.0ng·mL-1(R=0.0073C-0.0386,r=0.9999).The mothod could satisfy the determination of biological samples.8.We studied pharmacokinetics of PRH patch.The results indicated that the effective blood level could retain in 2 days after transdermal administration,the steady blood level was from 71.10ng·mL-1 to 88.83ng·mL-1,the absolute bioavailability of the patch was 25.06%,relative bioavailability was 84.99%.MRT,Tmax and C max of the patch and intragastric administration were 30.27h and 4.62h,18h and 4h,85.96ng·mL-1 and 182.65ng·mL-1 respectively.MRT and Tmax of the patch were longer(P＜0.05),and Cmax was lower obviously(P＜0.05),characteristics of sustained-release of the patch was obviously.In summary,We prepared PRH patch successfully,the patch not only had characteristics of drug release steadily,but also had good biocompatibility and no irritation on the rabbit skin.So,the purpose of decreasing administration frequency,improving the compliance of patients and the safety of medication were observed. |
PDF Full Text Request