The Study On The Xiaoqinglong Patch's Pharmaceutical Engineering

Objective:To reform the traditional decoction dosage form of Xiaoqinglong to the patch dosage form.This patch can be adhered on the skin to treat bronchitis.Study on extraction technology, manufacturing technology,quality standards,release rate,in vitro percutaneous absorption,stability tests,etc.to establish the foundation for the Xiaoqinglong patch preparation.Methods:1,The research on the extraction technology:â‘ The mount of extracts and contents of ephedrine hydrochloride and paeoniflorin extracted were regarded as the index observed to optimize and compare the technology of ethanol refluxing extraction and ethanol percolation extraction for the five chinese herbal medicines including Herba Ephedrae,Radix Paeoniae Alba,Rhizoma Pinelliae, FructusSchisandrae,RadixGlycyrrhizae,in which contents of ephedrine hydrochloride and paeoniflorin were determined by HPLC, and the L₉(3⁴)table was used.The technological condition of Ethanol refluxing extraction was optimized,in which four influence factors such as ethanol density,amount of ethanol,time for extraction and number of time for extraction were considered.The technological condition of ethanol percolation extraction was optimized,in which four influence factors such as ethanol density,amount of ethanol, time for soakage and percolation speed were considered.â‘¡The volume of volatile oil extracted by distillation method was regarded as the index observed to optimize the extraction process of the volatile oil for the three chinese herbal medicines including Rhizoma Zingiberis,Ramulus Cinnamomi,Herba Asari in prescription of Xiaoqinglong patch,in which three influence factors such as time of soakage,amount of water and time of extraction were considered and the L₉(3⁴) table was used.2.The research on the manufacturing technology:According to the preliminary test,the matrixes and the range of their dosages were selected to optimize manufacturing technology for Xiaoqinglong Patch by L₁₆(4⁵) orthogonal design,in which the adhesion and scoring synthetically on some other aspects such as the smoothness,glossiness,degree of softness,uniformity, quantity of remains on skin and permeability of back lining of the patchs together were considered as indexes.The manufacturing technology of the cataplasmata was optimized by L₁₆(4⁵) orthogonal design,in which the adhesive ability and appearance were regared as indexes.3.The study on the quality standards:TLC was used to identify nerba Ephedrae,Radix Paeoniae Alba,Rhizoma Zingiberis, Ramulus Cinnamomi,Herba Asari,Radix Glycyrrhizae and Fructus Schisandrae in the patch preparation.The limited content of Aristolochic Acid A in the Herba Asari and the patch preparation was determinated by TLC.The content of ephedrine hydrochloride in Xiaoqinglong Patch was determined by HPLC,in which the chromatography conditions were that the Agilent TC-C18(4.6mm×250mm,5μm) column was used,that mobile phase was composed of methanol-0.1%phosphoric acid(lO:90),that flow rate was lml·min^-1, with UV detection at 207nm and that the column temperature was 30℃.The content of paeoniflorin in Xiaoqinglong Patch was determined by HPLC in which,the chromatography conditions were that the Agilent ZORBAX SB-Cl8(4.6mm x 250mm,5μm)column was used, that mobile phase was composed of methanol-water(23:77),that flow rate was lml·min^-1,with UV detection at 230nm and that the column temperature was 35℃.The content of the extraction,adhesive ability,heat resisting property and weight variation were determined.4.The study on the release rate and the in vitro percutaneous rate:The equipment of release and percutaneous rate were used respectively to carry out the experiments.The content of ephedrine hydrochloride released and in vitro permeated from Xiaoqinglong Patch and cataplasmata were determined by HPLC.5.The study on the stable property:The Xiaoqinglong Patch was placed in the constant temperature and constant humidity box under the conditions of 40℃for 10 days.The high -temperature experiment was studied with the investigation items such as characteristics,identification and the content of extraction, adhesive ability,the content of ephedrine hydrochloride.The Xiaoqinglong Patch was placed in the airtight container with saturated solution of KNO₃(25℃,RH92.5%) for 10 days.The high-humidity experiment was studied with the investigation items such as characteristics,identification and the content of extraction,adhesive ability,weighting percentage of moisture absorption,the content of ephedrine hydrochloride. Results:1.The optimum extraction technologies were as follows:â‘ The optimum technology of ethanol percolation extraction was as follows:the medicinal materials was soaked with 55%alcohol for 12h,then was percolated with 10 times amount of 55%of alcohol, and the percolate speed was 3ml·min^-1·kg^-1;The optimum technology of ethanol reflux extraction was as follows:the medicinal materialswas extracted 3 times with8-fold of 70%alcohol,2 hour for the first time and then 1 hour next two times.The percolation method was better than the reflux method.â‘¡The optimum technology of volatile oil extraction was that the medicinal materials was soaked for 1 hours and then extracted with 12 times of water for 6 hours continuously.2.The optimum manufacturing technology for Xiaoqinglong Patch was as follows:Paraffin 2 copies,monoglyceride 0.9 copies, microcrystalline cellulose 0.4 copies,gelatin 0.5 copies,sodium polyacrylate(1%) 0.6copies,glycerol 0.2 copies,sodium dodecyl sulphate(SDS) 0.02 copies,extract 1 copy,the patch was prepared by melt mixing.The optimum ingredients of the matrix of the cataplasmata were:Gelatin:PAA(S)(70%):PVP K-30:glycerol: PEG-400 = 4:2:4:2:1.3.The research on the quality standards:The TLC methods of Herba Ephedrae,Radix Paeoniae Alba,Rhizoma Zingiberis, Ramulus Cinnamomi,Herba Asari,Radix Glycyrrhizae, Fructus Schisandrae in the patch preparation were simple and the spots on the TLC pictures were clear.Study on the limited amount of AristolochicAcid A had shown that there is not the same spot of Aristolochic Acid A on the TLC picture of the Xiaoqinglong patch and the medicinal materials.The minimum detectable level of Aristolochic Acid A was 0.031μg.Study on the determination of ephedrine hydrochloride had shown that the liner rang was 0.0404μg～0.404μg(r=0.9999),and the precision(RSD) was 1.16%.The average content of the ephedrine hydrochloride was 0.09663%with RSD 1.79%,and the average recovery was 100.21%with RSD 1.82%. Study on the determination of paeoniflorin had shown that the liner rang was 0.1005μg～1.005μg(r=0.9999),and the precision(RSD) was 0.995%.The average content of the paeoniflorin was 0.152%with RSD 1.65%,and the average recovery was 99.45%with RSD 1.87%.The content of the extraction,the adhesive ability,the heat resisting property and the weight variation of the patch preparation were right to the regulation.4.The study on the release rate and the in vitro percutaneous rate:The release rate of the ephedrine hydrochloride from Xiaoqinglong patch in the water was 55.14%in 150 minutes and the cumulative permeation rate within 48 hours was 30.30%respectively. The release rate of the ephedrine hydrochloride from Xiaoqinglong cataplasmata in the water,was 85.61%in 150 minutes and the cumulative permeation rate within 48 hours was 28.48%respectively.5.The study on the stable property:The sample was stable at the condition of 40℃,and all indexes detected were not seen obviously changeable.In the humidity conditions,it must besealed packaging in order to ensure quality and stability.Conclusion:The Xiaoqinglong patch developed can be easily adhered to skin, and the compounds in it are easy to be released and to permeate into skin.Through the study on extraction technology,manufacturing technology,qualitystandards,releaserate,in vitro percutaneous rate,stable property of influecned factors,development of new type of Xiaoqinglong patch has laid a good foundation.