| BackgroundPediatric Suhuang Zhike Granules is a developing new drug for the clinical cough variant asthma(CVA).Cough Variant Asthma is a chronic,persistent,recurrent cough.Because the respiratory system,immune system,etc.are not yet well developed for children,they are easily induced by the effects of cold air,fumes,dust,viruses,etc.It is mainly treated with asthma drugs for western medicine,there is no specific treatment method.Because of the potential adverse drug reactions and poor children’s compliance,etc,the cough variant asthma treatment efficiency is not high.Chinese medicine is mainly treated with decoction,but due to its "color,aroma,taste" and other effects,children are not easy to swallow.Searching the CNKI database at the same time,it has not yet traditional chinese medicine patent prescription for children with cough variant asthma.Therefore,there is an urgent need to develop a traditional chinese medicine patent prescription that are suitable for pediatric use and has a significant effect on the symptoms of cough variant asthma.Suhuang Zhike Capsule was developed for adults with cough variant asthma.It was approved for marketing in 2008,and was recommended as the treatment for cough variant asthma in the 2015 edition of the "Guide to the diagnosis and treatment of cough",with significant efficacy and safety.In addition.After years of clinical observation,it was found that Suhuang Zhike Capsules can be used to treat cough variant asthma for children.It was also very effective in relieving symptoms and accelerating the cure of diseases,and has shown very good curative effect.Purpose and SignificanceThe development of Pediatric Suhuang Zhike Granules is urgently needed clinically.The incidence of cough variant asthma in children is high in clinical practice;there is suitable for children with less medication;Suhuang Zhike Capsules is effective for children,but there are many problems:First,the drug is approved for adults,so the science,standardization,and rigorousness used for children are not sufficient;second,capsules are not easy to swallow for children,and their compliance is poor.The development of Pediatric Suhuang Zhike Granules can regulate the usage and dosage of children’s medications,and at the same time can improve the compliance of children’s medications,thereby improving the clinical treatment of children with cough variant asthma.Experimental ResearchIn the early stage of the research,Pediatric Suhuang Zhike Granules was developed.The idea was that the type of drug was changed first,and then the applicable population was added.In the previous period,in order to solve the problem of particle melting,the method of adding additives to prevent the aggregation of insoluble ingredients in the process of concentration and drying was studied.The melting of the particles was improved,but the operation was cumbersome and the controllability was poor.This study is tried to develop directly Suhuang Zhike Capsule into Pediatric Suhuang Zhike Granules,and to pharmacy research according to the change of the composition quality.First of all,on the basis of the preparation technology of Suhuang Zhike Capsule,combined with the traditional preparation process and the characteristics of granule formulations,the preparation process of Pediatric Suhuang Zhike Granules was optimized.Secondly,based on the quality standards for Suhuang Zhike Capsules,according to the "Chinese Pharmacopoeia"2015 version and related regulatory requirements,the quality standards for Pediatric Suhuang Zhike was formulated.1 Preparation process research:Based on the preparation technology of Suhuangzhike Capsule,this study combined with the characteristics of granule formulations,according to the formulation of the compatibility of the drug taste,the main active ingredients,pharmacological effects and physicochemical properties,etc.,investigatived a reasonable and stable preparation.The feasibility of the preparation method mainly includes the following aspects:1.1 Extraction process of volatile oils:the steam distillation method was adopted and the index was volatile oil extraction rate.The L9(34)orthogonal test method was used to investigate the effect of water addition,soaking time,and extraction time on the volatile oil extraction process.According to the results of the orthogonal test,the best extraction process was determined as follows:it was soaked 1 h,added 9 times of water by steam distillation for 8 hours.1.2 Volatile oil inclusion process:the high-speed emulsifying homogenizer was applied.The L9(34)orthogonal test was used to examine the effect of volatile oil,β-cyclodextrin and water,with volatile oil rate,inclusion rate as indicators.According to the results of the orthogonal test,the optimum inclusion process was determined as follows:the proportion of volatile oil and βcyclodextrin was 1:8,the proportion of β-cyclodextrin and water was 1:8,inclusion time was 30 minutes.1.3 Water extraction process:the transfer rate of arctiin and rosmarinicacid were indicators,and L9(34)orthogonal test method was used to examine the amount of water,extraction times,extraction time.According to the orthogonal test results,the optimum extraction process was determined as follows:It was extracted 3 times,each time for 1 hour,added 10 times,8 times,8 times the amount of water.1.4 Ethanol extraction process:first,the schizandrin transfer rate as an indicator,using a single factor test method,to investigate the schisandra chinensis smashing on the ethanol extraction process.Then,the transfer rate of schizandrin were indicators,using a single factor test method,to investigate the alcohol concentration on the ethanol extraction process.Then,the transfer rates of epherine and pseudoephedrine and schizandrin were indicators,and L9(34)orthogonal test was used to examine the effects of the amount of alcohol,reflux times,and reflux time on the alcohol extraction process.According to the single factor test,schisandra was squashed and extracted with 80%ethanol.According to the orthogonal test results,the optimal extraction process was determined as follows:It was extracted 2 times,each time for 1.5 hours,added 8 times,6 times the amount of 80%ethanol.1.5 Concentration and drying process:the extracts were respectively concentrated at under pressure to a thick paste with relative density of 1.25～1.30(50℃),and combined and decompressed and dried at under 70℃(vacuum degree ≤-0.07 MPa).Dry paste crushed after the formation process inspection.1.6 Molding process:the amount of excipients,wetting agents,and flavoring agents were examined,taking the particle size,yield,and texture,and the appropriate molding process as indexes.The results showed that dextrin was used as an excipient with a daily dose of 3.93 g;aspartame as a flavoring agent,the daily dosage was 0.06 g;65%ethanol was used as wetting agent and the amount was 15%.The particle size,meltability,and yield of the obtained particles were all acceptable and the taste was appropriate.2 Research on quality standards:in order to ensure the quality of the preparations,this subject conducted routine inspections.Qualitative and quantitative were studied on three batches of small-scale test samples,and establishing a set of stable and controllable quality control methods.2.1 Qualitative research:using thin-layer chromatography,qualitative studies were conducted on ephedra,Folium Perillae,Peucedanum praeruptorum Dunn,Schisandra chinensls,Fructus Arctii.The identification results of the thin layer were that:there were clear main spots,negative interference,high reproducibility.2.2 Quantitative study:the HPLC was used to establish the determination method for the content of arctiin,ephedrine and pseudoephedrine in the granules.Determination method of arctiin content:C18 column(4.6mm*150mm,5μm);mobile phase:methanol-water(47.6:52.4);detection wavelength:280nm,flow rate:1mL/min,column temperature:room temperature.There was a good linearity in the range of 0.42～3.36 μg of arbriside,the recovery rate was 100.35%,the RSD was 1.19%,and the content of arctiin was not less than 16mg/bag.Determination method of ephedrine and pseudoephedrine content:polar ether-linked phenyl-bonded silica gel column(4.6mm*250mm,5μm);mobile phase:methanol-0.092%phosphoric acid(containing.0.125%triethylamine)(1.5:98.5).Detection wavelength:210nm,flow rate:1mL/min,column temperature:room temperature.Ephedrine showed a good linear relationship in the range of 0.062 to 0.8428μg.The recovery rate was 97.70%,the RSD was 1.27%,and the pseudoephedrine showed a good linear relationship in the range of 0.0546 to 0.7644 μg.The recovery rate was 100.21%.The RSD was 1.93%.The content of ephedrine and pseudoephedrine in the Pediatric Suhuang Zhike Granules was not less than 2.7mg/bag.ConclusionPreparation process research:the establishment of the preparation process for Pediatric Suhuang Zhike Granule is reasonable,stable and feasible.Compared with Suhuang Zhike Capsule technology,the inclusion process of volatile oil was optimized to make it more suitable for mechanized production;the alcohol extraction process was optimized,the extraction rate of schisandra chinensis active ingredient was improved,and the production cost was reduced;at the same time,the process was changed from alcohol-saturated to non-alcoholic,making it more in line with the characteristics of traditional medicine and granule formulations.Quality standards study:the established standard for Pediatric Suhuang Zhike Granules had good repeatability and accuracy,and could be used for the quality control of the preparation.Compared with the quality standards for Suhuang Zhike Capsules,the identification method for the thin layer of Peucedanum praeruptorum Dunn and the determination method for the content of arctiin and pseudoephedrine were added to better control the product quality.This study provides the basis for qualified samples of the pharmacodynamic toxicology and clinical trials,which is of great significance for the clinical treatment of cough variant asthma for children with definite curative effect and controllable quality. |
PDF Full Text Request