Study On The Modification Dosage Forms Of ShenGu Tablet

Objective:On the basis of previous research,Shengu Tablet（national medicine approval number:Z20090258）was used as the original preparation agent,and its relative bioavailability was improved through the modification of dosage form.At the same time,the preparation technology of the new dosage form was investigated,and the quality standard of the new dosage form was preliminarily established.Objective to establish a method for the determination of Ca²⁺in Beagle dog plasma by inductively coupled plasma mass spectrometry（ICP-MS）,and to investigate the relative bioavailability of the new preparation in Beagle dogs.Methods:（1）Pre-prescription study and dosage form selection:the fluidity,critical relative humidity and influencing factors of oyster extract were investigated,and a method for the determination of calcium content by ultraviolet visible spectrophotometry was established.At the same time,the relevant items of Shengu tablet were examined to find out its shortcomings and select the appropriate dosage form to improve its dosage form.（2）Establishment of a method for the determination of plasma Ca²⁺concentration in Beagle dogs.In this paper,ICP-MS was used to determine the content of Ca²⁺in plasma of Beagle dogs,and the methodology was investigated,including the treatment,linearity,precision,stability and recovery of plasma samples.（3）Study on the preparation technology of Shengu capsule:to select suitable excipients and the proportion of drug and excipients according to the relative bioavailability.Single factor method was used to optimize the molding process conditions of oyster extract,taking the properties of oyster extract（fluidity,hygroscopicity）and the properties of oyster granule（molding rate,granulation difficulty,hygroscopicity）as the indexes.（4）Study on the quality standard of Shengu capsule:According to the relevant provisions under the general principle of"capsule"in Chinese Pharmacopoeia（2020 Edition）.Physical and chemical identification was used to qualitatively identify the effective component of calcium in the capsule;the appearance,shape,loading difference,disintegration time limit and moisture content of Shengu capsule were examined.The content of calcium in Shengu capsule was determined by ultraviolet-visible Spectrophotometer method,and the method was studied.According to the Small Cup method in the 2020 edition of the Chinese Pharmacopoeia,"the dissolution and release method of 0931",the dissolution of Shengu capsule was investigated,and the factors affecting the stability of Shengu capsule were studied.The influence of high temperature,high humidity and strong light on the stability of Shengu capsule was investigated.To establish the quality standard of Shengu capsule by the above tests,and to provide a feasible and reliable method for the quality control of the preparation.（5）Study on the relative bioavailability of Shengu capsule in Beagle dogs:Six male Beagle dogs,three in each group,were cross-administered.The same dose of Shengu tablet and Shengu capsule was given orally in fasting state for12 hours,blood samples were collected from Hind limb veins of Beagle dogs before and 15 min,30 min,45 min,1 h,1.5 h,2 h,3 h,4 h,6 h,8 h,12 h,24 h,48 h after administration,determination of Ca²⁺in Beagle dog plasma by ICP-MS.The pharmacokinetic parameters of Beagle dogs were calculated by software and the relative bioavailability was calculated by analyzing the pharmacokinetic data.Results:（1）The average calcium content of oyster extract is 22.49±0.27%;Angle of repose is 34.17°;The critical relative humidity is 73.38%,and the storage environment humidity of oyster extract should be less than 73%.It is hardly affected by strong light and high temperature environment,but some hygroscopicity appears in high humidity environment.The filling volume difference,hardness and fragility of Shengu tablet all met the requirement of pharmacopoeia.The average disintegration time limit of Shengu Tablets is18min,which is longer than the 15min stipulated in the Pharmacopoeia,and the disintegration is slower.The dissolution test showed that the Shengu tablet was dissolved 80%in 45min and 95%in 90min.The dissolution was almost complete,but the dissolution rate was slow.By referring to relevant literature and relative bioavailability experiment,oyster extract was finally selected to prepare into capsules.（2）A method for the determination of Ca²⁺in Beagle dog plasma by inductively coupled plasma mass spectrometry（ICP-MS）was established.The linear equation was:y=1.0015x+0.0102（R2=0.9994）,which had a good linear relationship in the range of 1.0mg·L^-1～8.0mg·L^-1.The method is stable,accurate and reliable,and can be used for the study of pharmacokinetics of Shengu capsule in Beagle.（3）According to the relative bioavailability test results,the excipient is chitosan,and the ratio of API and excipient is 3:2.The preparation process of Shengu Capsules was as follows:accurately weighing an appropriate amount of oyster extract raw material and fully mixing chitosan（ratio 3:2）,using 10%starch slurry as adhesive,making soft material,and making it pass through12-mesh sieve.The drying temperature was 80℃,and the drying time was 1h.Shengu capsule was obtained by filling the whole capsule into No.0 hard capsule.（4）The quality standard of Shengu Capsules（draft）was preliminarily established.The physical and chemical identification of Shengu Capsules showed that Shengu Capsules showed the differential reaction of calcium salt and acetate.The appearance,shape,volume difference,disintegration time limit,water content,content,dissolution of Shengu capsule were checked,and all of them met the relevant requirements of Chinese Pharmacopoeia 2020 edition.（5）Relative bioavailability of Shengu capsule in Beagle dogs:The pharmacokinetics and bioavailability of Shengu capsule in beagle dogs were studied with the original Shengu tablet as the control.The relative bioavailability of Shengu capsule was 156.01%by cross administration.The results showed that Shengu capsule improved the bioavailability of the drug in Beagle dogs.Conclusions:（1）The pre-prescription study of oyster extract,was simple and feasible;The improvement of dosage form is reasonable and feasible,and the capsule is selected as the improved dosage form.（2）The method for the determination of Ca²⁺in plasma of Beagle dogs by Inductively coupled plasma mass spectrometry（ICP-MS）is stable,accurate and reliable,and can be used for the study of pharmacokinetics in Beagle dogs.（3）The formulation of Shengu capsule is reasonable,the preparation process is simple,safe,stable and reliable,and can be used in enterprise production.（4）The quality standard of the preparation is stable and feasible,and the quality is controllable.The dissolution speed of the prepared Shengu capsule is fast and the dissolution is complete.All the inspection items meet the requirements of the Chinese Pharmacopoeia 2020 edition,which provides a reliable basis for the quality standard of the preparation and certain reference data for clinical safe drug use.（5）The relative bioavailability of Shengu capsule in Beagle dogs was156.01%.Compared with the original Shengu tablet,the relative bioavailability of Shengu capsule was greatly improved,which achieved the purpose of changi the dosage form.