Formulation Optimization And Evaluation Of Fufang Danshen Adhesive Pellets

For oral formulations,the time through the gastrointestinal tract is one of the main factors of drugs release,absorption and bioavailability.Bioadhesive formulation is thought to be an effective way solving insufficient retention time problem of drugs.This can be achieved by the interaction between drugs and the intestinal mucosa,prolonging residence time,promoting the absorption,and finally,improving the bioavailability.As a famous large varieties of Chinese medicines,Fufang Danshen preparations are widely and effectively used in clinical coronary heart disease,angina and other cardiovascular diseases.Salvia miltiorrhiza Bge.as sovereign drug,its active pharmaceutical ingredients(APIs)-are Sal B represents as for the water-soluble phenolic acids and fat-soluble tanshinone ?A represents for diterpenoid quinone compound.Phenolic acids have better dissolution,however,their absorption is relatively poor due to the absorption mainly occurred in the duodenum and their passive diffusion absorption behavior,absorption is relatively poor,resulting in lower bioavailability.And for tanshinones,the fat-soluble ingredients are poorly soluble in the gastrointestinal tract,and what's worse,the presence of absorption saturation phenomenon,therefore their bioavailability is heavily affected.Sanqi,for the official medicine in this prescription,has the API of PNS which also resents a low bioavailability due to its unstablitye in acid.Finally,borneol can be rapid absorption through the gastrointestinal mucosa as adjuvant medicine in prescription,but there is a strong irritantion to the mucous membrane,causing stomach irritation,discomfort,pain,long-term use potentially leads to bleeding.Based on above mentioned problems,on the one hand,we use ?-CD inclusion borneol,according to a certain proportion of investment than Danshen Tablets extract,by extrusion spheronization,thus prepared Compound Danshen adhesion pellets,adhesion materials are HPMCK100M,chitosan and carbomer 934P which are our previous experiment selected.On the other hand,we further optimize the formulation pellets and screening.By increasing the drug retention time in the body and increasing the contact area between the film and absorption of the drug to improve the bioavailability of the drug1 The investigation of compound Danshen extraction process by indicators of efficacy and the active ingredient contentDanshen was extracted by three processes including 70%ethanol extracting,different solvents extracting three times(Compound Danshen tablets of Danshen extraction process),and water extraction and alcohol precipitation.Sanqi was extracted with 70%ethanol,Panax powder(Compound Danshen Tablets of Sanqi extraction process),water extraction and alcohol precipitation and compared with panax notoginseng saponins(PNS).Results shows that for Sal B,the content in the extractive,70%alcohol extracting>different solvents extracting three times>water extraction and alcohol precipitation;The results of tanshinone ?-A was similar to Sal B,70%alcohol extracting>different solvents extracting three times>water extraction and alcohol precipitation,and have significant difference(P<0.05);for Sanqi,notoginsenoside R1,ginsenoside Rg1,ginsenoside Re,ginsenoside Rb1,ginsenoside Rd content in 70%alcohol extractive is higher than Panax powder and water extraction and alcohol precipitation,but lower than PNS.The extraction was selected according to myocardial ischemia model of pharmacological experiments.Results shows that the extractive of Danshen anti-myocardial ischemia was 70%alcohol extracting>water extraction and alcohol precipitation>different solvents extracting three times(compared with model group,there were significant different.P<0.05).The results of pharmacodynamics and the content of Sal B and tanshinone ?-A had some relevance,but not entirely positive correlation.For Sanqi,the anti-myocardial ischemia was 70%alcohol extract>water extraction and alcohol precipitation>PNS>powder,the anti-myocardial ischemia ability and the content of PNS had some relevance,but not entirely positive correlation.2 The selection and optimization of Pellets prescriptionWe prepared HPMCK100M:chitosan(1:1),HPMCK100M:carbomer(1:l),chitosan:carbomer(1:1),HPMCK100M:chitosan:Carbopol 934P(1:1:1)of the pellets using HPMCK100M,chitosan,Carbopol 934P as adhesion material which our group previous screened.Adhesion material accounted for 30%of the and 40%respectively.Using adhesion test in vivo and in vitro experiment,residual rate and cumulative release rate to evaluate Pellets comprehensively.The adhesion results showed that the pellets of adhesive material accounted for 40%has strong adhesion.And in vivo experiment showed that the retention time in the stomach is too long,more than 4 h,and then chose the pellets of adhesion materials accounted for 30%to determine the residual rate and the cumulative release.The results showed that HPMCK100M:chitosan:carbomer 934P(1:1:1)has a higher cumulative release and residual rate,and adhesion is better.At last,we selected HPMCK100M,chitosan and carbomer 934P as adhesion material which accounted for 30%,microcrystalline cellulose as excipients,and orthogonal experiment to optimize the forming process.3 Optimization of forming process by orthogonal experiment and the establishment of method for determination of content in pelletsTaking the formability of pellets as index,optimized drug loading and selected the appropriate adhesive for pellets forming index.The final decision is 40%drug load and 30%aqueous sodium chloride solution as wetting agent.Taking the roundness,yield,bulk density as index optimize the amount of wetting agent,extrusion speed,rounding speed,rounding time and other parameters.Orthogonal experiment were carried out in a given prescription.Ultimately,putting into 25 g of raw materials,adding 12 mL of wetting agent,extrusion speed of 25 r·min-1,spheronization speed of 1600 r·min-1,spheronization time was 4 min,prepared targeted pellets yield,roundness and bulk density are better.Verification tests indicate that the optimization process and formulation is feasible and have a good reproducibility.Based on the above results,our group selected Compound Danshen adhesion pellets from the multiple perspectives,preferably a better adhesion in vivo and in vitro and higher residual rate and cumulative release rate prescriptions.And finally determine prescription,optimizing forming process,preparing higher yield and better roundness and bulk density pellets,and evaluating pellets then.Our group mainly in terms of the way selecting of adhesion pellets prescription in order to provide a reference for the development of new formulations of traditional Chinese medicine.