Buspirone Hydrochloride Sustained Release Tablets Preparation And In Vivo And In Vitro Release Study

Objective:Buspirone hydrochloride?BUS?is new generation of non-benzodiazepine anti-anxiety drugs.It has a significant effect on the treatment of generalized anxiety disorder and also treat depression,attention deficit disorder and schizophrenia.Compared with other psychoactive drugs for the treatment of generalized anxiety disorder,BUS has almost no dependence and drug resistance,it can be taken for a long time and has no hypnotic sedation,so that there is no feeling of sleepiness and weakness after taking it,it does not affect cognitive function and the therapeutic effect is good,so far BUS is an ideal anti-anxiety drug,widely used in clinical practice.This topic uses modern preparation technology to make BUS into a skeleton sustained-release tablet,which can maintain a stable therapeutic concentration in the body for a long time,avoid the phenomenon of“peak and valley”of plasma-drug concentration,and improve the bioavailability of the preparation,at the same time reducing taken medication times to improve patient compliance.In this study,we first studied the absorption kinetics of BUS in the intestine of rats and guided the design of drug dosage forms;Then,we determined the preparation process and screened the formulation prescriptions through single factor experiments,further optimized the Preparation prescriptions by the central composite design-response surface methodology;Establish a method for content determination of the drug in the preparation and evaluate the drug release performance in vitro,in order to speculate the release of the drug in the body;Finally,conduct a preliminary pharmacokinetic study in the rabbit to further investigate the release of the sustained release drug in the body and Pharmacokinetic characteristics.Methods:1.Study on Intestine Absorption of Buspirone Hydrochloride in Rats in vivoUsing the characteristics of rat's intestinal physiology to be similar to the human body,using rats as a model animal,the rats intestinal perfusion method was used to study the BUS intestinal absorption dynamics.Establish a analyzing method for determination the concentration of BUS and phenol red in intestinal circulating fluid;study the absorption of drugs under different intestinal segments,different drug concentrations,and different pH environ-ments;use SPSS software to statistically analyze the drug concentration data in different intestinal segments to explore the best absorption site,providing an experimental basis for the development of subsequent sustained-release preparations.2.Study on the preparation process and formulation research of buspirone hydrochloride sustained-release tabletsDetermine the preparation process and method of BUS sustained-release tablets;taking the cumulative release percentage of BUS as the inspection index,and respectively studying the cumulative release percentage of the drug in vitro of the sustained-release tablets at 1h?4h and 8h,so as to evaluate the release behavior in vitro of the BUS sustained-release tablets.By investigating the effects of different dissolution media,dissolution methods and rotation speed on the dissolution of BUS sustained-release tablets,a dissolution method was developed;The ratio and dosage of the framework materials including konjac glucomannan?KGM?and sodium alginate?SA?,KGM viscosity,lactose and microcrystalline cellulose?MCC?dosage were carried on single factors investigation,and the formulation of sustained-release tablets was preliminariy screened;on this basis,the central composite design-response surface method-ology was used to further optimize the formulation;Determine the best formulation prescription and conduct prescription verification.3.Content Determination of BUS skeleton Sustained-release Tablets and Study on Its Drug Release Characteristics in vitroAn HPLC method was established to determine the content of buspirone hydrochloride sustained-release tablets,and the methodology was studied.By investigating the release of BUS sustained-release tablets under different pH conditions,a three-dimensional release characteristic diagram of“in vitro release amount-pH-time”was made to study its release performance;The in vitro drug release curve of BUS sustained-release tablets was fitted to study the drug release mechanism.4.Preliminary study on pharmacokinetics of buspirone hydrochloride sustained-release tablets in rabbitsEstablishing an HPLC method for the determination of BUS plasma-drug concentration in rabbits;Raising BUS sustained-release tablets and ordinary tablets to rabbits to determine the plasma-drug concentration,using DAS software to fit pharmacokinetic parameters and evaluating the drug release process in rabbits;providing experimental basis for the development of subsequent sustained-release preparations and human pharmacokinetic studies.Results:1.The absorption rate of BUS in various intestinal segments of rats is:duodenum>jejunum>ileum>colon,the absorption rate constants of each intestinal segment are:?0.164?0.012???0.146?0.017???0.094?0.014???0.070?0.008?h^-1;under different concentrations and different pH conditions,there is no significant difference between the intestinal absorption parameters of BUS;the intestinal absorption of BUS in rats conforms to the apparent first-order kinetic process,and the absorption is mainly passive diffusion;In view of the certain degree of absorption of the drug throughout the intestine,it is suggested that BUS is suitable for making sustained-release and controlled-release preparations.2.After preliminary research,it is proposed to use powder direct compression method to prepare BUS sustained-release tablets;the dissolution method adopts the rotating basket method,and the dissolution conditions:the release medium is pH 6.8 PBS buffer 900 mL,the temperature is 37?±0.5?,and the rotation speed is 100 r/min;Through single-factor screening,the comp-onents and dosage of the formulation prescription are initially determined;the central composite design-response surface methodology is further used to optimize the formulation prescription,obtaining the best formulation of BUS sustained-release tablets:BUS 10 mg,KGM 43.7 mg,SA40.0 mg,MCC 73.4 mg,lactose 31.9 mg,magnesium stearate 0.5%.3.Established a method for determining the content of BUS sustained-release tablets by HPLC,which is simple,accurate and reproducible;formulated the in vitro release standard for BUS sustained-release tablets,it provides a standardized and reliable method for the quality control of BUS sustained-release tablets method.The preparation of the BUS sustained-release tablets“release-pH-time”three-dimensional in vitro release characteristic map suggests that changes in the pH of the gastrointestinal fluid interfere less with drug release in the formulation.The in vitro release curves of BUS sustained-release tablets were fitted with four release models,and the correlation coefficients were high,indicating that BUS sustained-release tablets have better sustained-release and controlled-release effects;Ritger-Peppas equation fits the experimental data best?r²=0.9950?,and its diffusion index n=0.6334,suggesting that the release of BUS sustained-release tablets in the body is non-Fick's diffusion,and the release is carried out in the way of diffusion and corrosion.4.HPLC was used to establish the BUS plasma-drug concentration measurement method.The plasma-drug concentration data was curve-fitted using DAS2.1.1 software.The results showed that,BUS is a two-compartment model distribution in rabbits;the main pharmacokinetic parameters of sustained-release tablets:K_a=1.976 h^-1?T_max=2.5 h?t_1/2?=0.913 h?C_max=0.87?g/mL?AUC_?0-??=3.428?g·h/mL?MRT_?0-??=3.508 h,ordinary tablets:K_a=6.103 h^-1?T_max=1.0 h?t_1/2?=0.53 h?C_max=1.53?g/mL?AUC_?0-??=2.389?g·h/mL?MRT_?0-??=1.433 h;the absorption rate constant K_a of BUS sustained-release tablets decreases significantly,biological half-life t_1/2?prolonged,the T_maxax at the peak of blood concentration and the average residence time MRT_?0-t?are significantly higher than BUS ordinary tablets,and the bioavailability of sustained-release tablets is higher than ordinary tablets,and the AUC_?0-??of sustained-release tablets is higher than that ordinary tablets;It shows that the sustained-release effect is good,the bioavailability is higher,and it can maintain a stable plasma-drug concentration in the body for a longer time.Conclusions:Based on the above research,this subject firstly confirmed that BUS is well absorbed in the whole intestine of rats through the intestinal absorption study of rats in vivo.Therefore,it is feasible to make BUS into a sustained-release preparation;By using natural skeleton sustained-release materials,screening and optimizing formulations by single factor investigation and the central composite design-response surface methodology to determine the best formulation and preparation process of BUS sustained-release tablets;through the“release-pH-time”three-dimensional release characteristic curve and fitting different drug release models to study the release performance and release mechanism of BUS sustained-release tablets,suggesting that the sustained-release tablets can release drugs better under various pH conditions in the gastrointestinal tract and have better effect of sustained-release and controlled-release;this study also conducted a preliminary study on the pharmacokinetics of BUS sustained-release tablets in rabbits,fitted the pharmacokinetic parameters and evaluated the release performance in vivo.It also showed that BUS sustained-release tablets have better sustained-release effect in vivo,the plasma-drug concentration is stable,and the bioavailability is higher.Studies have shown that BUS sustained-release tablets meet the requirements of dosage form design,This study provides an experimental basis for the further development of this formulation and creates new ideas for the research of dosage forms for the treatment of generalized anxiety disorder.