The Study On Long Time Controlled Release Of Microporous Osmotic Pump Tablets Of Water Soluble Drug By PH Regulation

LS-Ligustrazine?LS-TMP?is a new type of calcium antagonists,Which has wide pharmacological effects,mainly been used to the treatment of diseases about the cardiovascular system in clinic.At present,ThereareLS-ligustrazineinjections,ordinarytablets,capsules,without sustained-release preparations and controlled-release preparations.Although the clinical curative effect is precise,it biological half-life is very short,about 4 hours.The microporous osmotic pump preparation implements drugs release to a zero-order release rate,and maintain concentration of drug within the scope of treatment.At the same time the preparation can reduce the"valley-peak"phenomenon of blood drug concentration;Frequent drug dosing dose not need,in addition,it can improve the compliance of patients.This paper used the LS-ligustrazine as the model drug,the two tablet cores containing sodium citrate and sodium tartrate of LS-ligustrazine microporous osmotic pump prescriptions were made respectively.Through the weak alkalinity of sodium citrate and sodium tartrate,the pH of the core was controlled,and the drug was released in the long time.The formulation?preparation process and release behavior of both LS-ligustrazine microporous osmotic pump tablets were investigated,besides the preparation stability was tested.This paper selected sodium citrate?or sodium tartrate?and lactose for main excipients materials of the core.Polyethylene glycol-400?PEG-400?,triethyl citrate?TEC?,cellulose acetate?CA?were chosen for coating materials,and the acetone?isopropyl alcohol used as the organic coating solvents.In these conditions the LS-ligustrazine microporous osmotic pump tablets releasing in 16-24 hours were prepared successfuly.The f₂ similarity factor method recommended by FDA was used as the evaluation index of release degree in vitro,studied its core prescription such as the coating fluid prescription,coating process,release condition in vitro impacted on the drug release behavior.Through single factor experiment investigation found out the significant influenced factors about 16 hours cumulative release degree?R?in vitro and curve fitting degree?r?:content of pH regulator?Factor A,A1 sodium citrate,A2 sodium tartrate?of the core,the pore formers content of PEG-400?Factor B?and the content of plasticizer TEC?Factor C?of coating,and the coating weight?Factor D?.Choosing the above four factors as the independent variable,16h cumulative release degree?R?and release curve fitting degree?r?as the dependent variable,the L9?3⁴?orthogonal experimental design with four factors at three levels was used to optimize the prescription.Through the intuitive analysis results got the optimal prescription:?1?tablet core:LS-TMP 100mg,sodium citrate40mg;coating liquid:CA 3%,PEG 400 90%,TEC 20%?percent of the CA quality?;coating weight:4.5%;?2?tablet core:LS-TMP 100mg,sodium tartrate 60mg;coating liquid:CA 3%,PEG-400 80%,TEC 20%;coating weight 3.5%.According to the two optimal prescriptions,three batches of LS-ligustrazine microporous osmotic pump tablets were made by amplification test.The experimental results shown that the optimal prescription of drug release curve in vitro fitting result accorded with zero-order model,the fitting degree was good?r=0.9950?,and the cumulative release of 16h was more than 85%.The three batchs verification results f₂ were between 84 and 97,shown it's good reproducibility.Finally,this paper examined the stability of LS-ligustrazine microporous osmotic pump tablets homemaded.Influencing factors experiment shown that this tablets under high temperature 60?and4500Lx±500Lx light conditions were stable after 10 days,but placed in RH92.5%±5%after 10 days,coating tablet inflated slightly,tablet core appeared moisture absorption phenomenon,weight gain closed to 4%,shown that the tablets were sensitive to humidity,so it should choose packaging materials of better sealing performance;Accelerated test results shown that:in the condition of 40?,relative humidity of 75%±5%,for the three batches samples packaging,the examining indexes were within the normal range,did not seen changes within three months,subsequent test is in progress;Long-term experimental results shown that under the condition of 25?,RH60%,three batches samples packaging were tested for a Long-term experimental,the examining indexes were not seen obvious changes within 3 months,subsequen test is underway.