| With the increasing proportion of insoluble drugs in new drugs,it has become a major challenge for pharmaceutical industry to improve the water solubility of insoluble drugs.And the interest in fabricating a supersaturated drug delivery system has increased.In this study,pioglitazone hydrochloride(PGH)was used as a model drug for the treatment of type II diabetes mellitus.The dissolution and crystal change properties of PGH were fully explored through the results of pre-prescription analysis,and the corresponding functional excipients were selected based on the above results.The mechanism of crystal inhibition and solubilization effects of the excipients were preliminarily explored.A pH-independent supersaturated drug delivery system was constructed by solid dispersion technology to screen the formulation,and then electrospray was used to design and build the system,to optimize the drug delivery system.Part One:ReviewsThis part first summarized the basic principle of electrospray technology and its application in pharmaceutical field,and pointed out the biggest advantage of electrospray and its future technology prospect,that is,building complex drug delivery systems with integrated structure and function based on mode design.The background and construction ideas of supersaturated drug delivery system which has attracted much attention in recent years were introduced,and two main lines of the whole concept of the subject were put forward.The first was to put forward the mode and direction of prescription selection and preparation of this kind of drug delivery system through the construction of supersaturated drug delivery system of PGH;The second was to solve the practical problems in the process of constructing supersaturated drug delivery system by introducing electrospray technology,and further demonstrated the advantages of electrospray technology in the pharmaceutical field.Part Two:Preformulation studiesIn this part,the in vitro analytical method of PGH was established and verified.The results showed that the method had good specificity,high precision,the same retention time of drugs in different media,and the blank excipients had no interference on drug detection.The linearity was good in the range of 0.5~50?g/mL;The limit of detection was 17 ng/mL and the limit of quantitation limit was 43 ng/mL.The solubility behavior of pioglitazone hydrochloride showed a highly pH-dependent character.The dissolution test in vitro showed that pioglitazone hydrochloride had a strong pH dependent dissolution property,and the difference of accumulative release rate of pioglitazone hydrochloride was almost 100%when it reached the platform in acid/base medium.It is proved that the solubility of pioglitazone hydrochloride in alkaline medium decreased with the rapid change of crystal form by observation of PLM and Raman spectrum.Part Three:Prescription selection and evaluation of the supersaturated delivery system of PGH based on solid dispersion technologyIn this part,the in vitro crystallization inhibition test was used to determine the crystallization inhibition effect of each candidate excipient on PGH,and the results showed that Soluplus~?had the best crystallization inhibition performance among the tested excipients.PGH solid dispersion was prepared by solvent method,and the optimal formula was selected by single factor experiment design and response surface design,that is,the ratio of Soluplus~?to drug was 14.22,that of Eudragit~?L100-55 to drug was 7.92.In vitro dissolution test showed that the supersaturated delivery system had pH-independent release characteristics,and the accumulative drug release rate in acid/alkaline medium was about 80%within 6 hours.Part Four:Construction of PGH supersaturated drug delivery system via electrospray mode designIn this part,on the basis of the prescription screening of PGH supersaturated delivery system in the early stage,the drugs,Soluplus~?were placed in the core layer and enteric excipient Eudragit~?L100-55,sustained release excipient Eudragit~?RSPO were placed in the shell layer,then the core-shell structured submicron particles were successfully prepared by electrospray technology.The in vitro dissolution test showed that the accumulative release rate of PGH in acid/alkali medium was the same,and the burst release of PGH in acid/alkali medium was significantly modified.Part Five:Study on the mechanism of crystallization inhibition and solubilization effect of excipients within PGH supersaturated delivery systemIn this part,the mechanism of solubilization and crystallization inhibition effect of excipients was investigated from the aspects of microenvironmental pH regulation ability of excipients and the interaction between drug and excipients.Eudragit~?L100-55 exhibited a slight microenvironmental pH regulation effect in the evaluation in vitro.The turbid phenomenon of the mixture system of drug and excipients in methanol and its corresponding particle size changes,it is proved that self-assembled micelle will be formed based on Soluplus~?.TEM image showed that the particle size of the self-assembled micelle was between 100~200 nm.The formation of the self-assembled micelle was based on the interaction of acid-base functional groups.XRD showed that the drug existed in the system in the form of amorphous.Part Six:Pharmacokinetic study of PGH supersaturated delivery system in ratsIn this part,an in vivo analytical method of PGH was established based on HPLC.The RSD of precision and recovery were less than 5%,which met the requirements of methodology.Rosiglitazone was selected as internal standard.The linearity of internal standard curve was satisfying between 0.05 and 20?g/mL,the detection limit and quantitative limit were 73 and 177 ng/mL respectively.In vivo pharmacokinetic test of rats showed that there was no significant difference in pharmacokinetic parameter between PGH and commercial preparations.The other pharmacokinetic parameters of O-SD except elimination half-life were significantly higher than that of API,and the relative bioavailability was 177.89%.Compared with PGH,PGH commercial tablets and O-SD,the pharmacokinetic parameters of ESP were significantly increased.Compared with API,the relative bioavailability of ESP was 330.02%,compared with O-SD,that was 185.53%. |
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