Study On Preparation And Pharmacokinetics Of Ziprasidone Hydrochloride Hollow Microspheres

As a new type and multiple-unit gastric floating dosage form,hollow microspheres can prolong the gastric residence time of drug,reduce the influence of various physiological environment on drug release and absorption.Thus,hollow microspheres offer some advantages,including the improving bioavailability,extending action time,a reduce of the administration frequency and improving patient compliance.They have been considered to be the most potential floating drug delivery system and much attention was payed to them by pharmacy workers.Ziprasidone hydrochloride(ZIP) is a atypia antipsychotic drug which has fortis avidity with 5HT2A acceptor.At present,the oral dosage forms of ZIP are tablet and capsule.They have been administed twice everyday, which have some disadvantages such as short half life(4h) and low bioavailability(60%).Moreover,the dissolubility of ZIP in gastric is relatively high.So,ZIP hollow microspheres were prepared in this study to increase the residence time in gastric for increasing drug absorption, improve bioavailability,reduce the administration frequency and improve patient compliance.In this study,the hollow microspheres containing ZIP were prepared by a solvent diffusion and evaporation method using ethyl cellulose(EC) and polyvinylpyrrolidone(PVP) as the compound carrier material and alcohol and ether as the compound solvent.The preparation technology,the factors on in vitro floating ratio and drug release from microspheres,physical and chemical character,stability and the pharmacokinetics in dog of ZIP hollow microspheres were investigated.The mainly content and conclusion in this paper as follows:1.A UV mothod for determination of of ZIP loaded hollow microspheres was developed.This mothod was rapid,accurate, reproducible and reliable for determining ZIP,the linear correlation of ZIP was good over the concentration range of 1.00-50.00μg·mL^-1. (A=0.0142C+0.0023,r=0.9999).2.A UV mothod for determination of the drug release from ZIP loaded hollow microspheres was established.0.25%sodium dodecyl sulfate(SDS) HC1 solution(0.1mol·L^-1) was chosen as the release medium, this mothod was rapid,accurate,reproducible and reliable for determining ZIP,the linear correlation of ZIP was good over the concentration range of 1.00-50.00gg·mL^-1(A=0.0146C-0.0063,r=0.9999).3.A HPLC mothod for determination of ZIP in the dog plasma was established.This method could was accurate,reproducible,ZIP and diazepam were separated well,the linear correlation of ZIP was good over the concentration range of 25.00-800.00ng·mL^-1(A=0.006C+0.0315, r=0.9999).4.In this study,the yield,loading efficiency(LE) and shape of microspheres were used to evaluate the influence of different formulation and technology on quality of ZIP hollow microspheres.The results showed the viscosity of EC,the content of PVP and ZIP influenced the quality of hollow microspheres significantly.On the basis of single factor experiment, the orthogonal design L9(3⁴) was used to optimize the formulation and technology with yield,LE,drug release behavior in vitro and in vivo as index.The results showed the best formulation was composed of PVP (3.6%),the content of EC₁₀ in the mixture of EC₁₀ and EC₄₅(33%),the content of ZIP(23%).The scanning electron microscope showed ZIP hollow microspheres prepared by the optimized formulation were spherical in shape with hollow cavity,the result of infrared spectrum and scanning electron microscope indicated that ZIP was crystal in hollow microsphere carriers,and there was no interaction between ZIP and the carriers.The yield and LE of ZIP hollow microspheres were 60.2%and 17.69%, respectively.77%of ZIP hollow microspheres could flow for 24h,the accumulative release amount was about 5%in 1h and over 90%in 24h,and the release curve was flat.ZIP hollow microspheres could maintaine the effective plasma drug concentration for about 24h.4.The stability of ZIP hollow microspheres was investigated.The results showed ZIP hollow microspheres were well stable at high temperature(40℃),high humidity(25℃,RH90%±5%),lighting(4500LX±500LX) for 10 days and the accelerated test(40℃±2℃,RH75%±5%) for 3 months.5.The pharmacokinetics of ZIP hollow microspheres was studied in dog.Compared with that of ZIP common capsule,ZIP hollow microspheres could maintain effective plasma drug concentration for about 24h,the T_max and t_1/2βwere prolonged from 4h and 4.94h to 8h and 6.53h,respectively,and the relative bioavailability was 168.5%.In brief,the hollow microspheres containing ZIP prepared using EC and PVP as the compound carrier material had excellent floatability and a combination of steady and controlled-sustained drug release,could improve the bioavailability and prolong the action time to reduce the administration frequency to improve patient compliance.Meanwhile,the risk of drug toxication caused by patient which chewed the single-unit dosage forms was reduced.Therefore,ZIP hollow microspheres were the most potential multi-units flowable drug delivery system as a new dosage form.