| The research background:Chinese medicine dispersible tablet is based on traditional Chinese medicine extracts,effective parts or monomer as materials,coupled with appropriate auxiliary materialsand made of can rapidly disintegrating and evenly dispersed in’the water.The prescription contains a lot of efficient disintegrating agent,so can quickly collapse without adding acid and alkali effervescent agent and water soluble materials in a short time.Its characteristics for application is convenient,fast absorption,high bioavailability and can disperse oral or water after swallowing,also can chew or suck on.Chinese medicine dispersible tablet is applicable to the old,young and difficulty swallowing patients.Dispersible tablet has made considerable progress on the varieties,quality after 20 years of development,Chinese medicine dispersible tablet as an important part of dispersible tablets,its research status is not optimistic."Chinese pharmacopoeia" 2010 contains varieties of traditional Chinese medicine dispersible tablet is zero,and there was no definition of dispersible tablets in the general principles of the preparation and standards.According to the latest figures on SFDA in 2014,the production batch number of dispersible tablets were 706,traditional Chinese medicine(TCM)for batches of dispersible tablet for 127,a total of 56 species,the percentage of the production batch number is about 18%.Therefore,the development of traditional Chinese medicine dispersible tablet in our country is still in infancy.In the research and preparation of traditional Chinese medicine dispersible tablets,the following several aspects which limits the development of traditional Chinese medicine dispersible tablet:(1)drug selection range is small;(2)disintegration time is long;(3)drug dissolution is low;(4)hard to taste masking.How to solve these common problems in the development of traditional Chinese medicine dispersible tablet has become the key points.Pubescent Holly Root is the root of Ilex pubescens,Itcontain flavonoids ingredients,phenolic compounds,coumarin,terpenoids,sterol,tannins,sugars,amino acids and other chemical composition.Pubescent Holly Rootcanpromoting coronary circulation,reduce swelling and ease pain,heat-clearing and detoxicating.Often used in the treatment of anemopyretic cold,dyspnea and cough due to lung-heat,pharyngalgia,swelling and aching of gum,chest pain,hemiplegia,thromboangiitis obliterans.Three kind of drugs of Pubescent Holly Root in the market are Mao Dongqing capsule(WS3-B-1290-93),MaoDongqing injection(WS3-B-3786-98),MaoDongqing tablet[WS-11521(ZD-1521)-2002].Mao Dongqing capsule and Mao Dongqing injection quality standard for the chemical reaction of effective components from the differential Mao Dongqing,using the qualitative identification of the physical and chemical properties of effective components from the Mao Dongqing is not accurate,content determination of total flavonoids content is determined by UV,the flavonoids content is only a relative content,does not represent the real content,and determined by UVare low assay sensitivity and specificity is poorer.Mao Dongqingtablet quality standard was improved,qualitative identification of protocatechuic aldehyde,was used to quantitatively the flavonoids content is determined by UV and determination of protocatechuic aldehyde content by HPLC,but just use protocatechuic aldehyde is not comprehensive in TLC,should joinPubescent holly Rootcontrast in the identification of medicinal materials.Protocatechuic aldehyde content is very low in the Pubescent Holly Root,are not suitable for as an index composition for content determination.In Pubescent holly Root the original medicinal materials quality control,generally choose determine saponins class components by HPLC,such as:IlexsaponinA1,IlexgeninA,Ilexsaponin B1,Ilexsaponin B2.etc.The quality standard has not been used in more effective components.Pubescent Holly root preparation,therefore,the improvement of quality standards,developed the pubescent Holly root preparation is one of the important problems need to be solved.PurposeIn the study,we use the enterprise’s own varieties Mao Dongqing capsule of Huizhou Jiuhui Pharmaceutical Co.,Ltd as the model drug,Depth research the hygroscopicity of extracts from Pubescent Holly Root and drug-excipient compatibility.Study on the preparation technology and prescription on this basis.Disintegration time limit and taste as the index to screening optimum prescription of dispersible tablets,and to establish the quality standard of Pubescent Holly Root dispersible tablet and investigate drug dissolution.This topic research can solve the difficulty problem in the development of traditional Chinese medicine dispersible tablet,found the new problems in the research of traditional Chinese medicine dispersible tablet,summarizes some law of Chinese medicine dispersible tablets preparation,has provided the new mentality for the development of traditional Chinese medicine dispersible tablet and theoretical basis.MethodsPart Ⅰ Pr-fomulation studies on ethanol extracts from Pubescent Holly Root.Determined wet absorption of ethanol extracts and its mixture with excipients,drew moisture absorotion rate plot of hygroscopic-time,and quadratic equation regression analysis.the moisture absorption rate,moisture absorption velocity,aceeleration,balance absorption rate,equilibrium moisture content,moisture absorption time critical relative humidity and so on moisture absorption parameters as an index,Study on theexcipient to its influence by the moisture absorption rate,moisture absorption velocity,acceleration,balance absorption rate,equilibrium moisture content,critical relative humidity and so on moisture absorption parameters as indexs.Establish a method to determine the content of protocatechuic aldehyde by HPLC.Reference drug stability influence factors in the guiding principles of experimental methods,we studied the compatibility between medicine and excipient,and mixedthe medicine and diluent(1:1),disintegrating agent(5:1),lubricants(20:1).Mixture be exposed to the high temperature(60℃),high humidity[RH(90±5)%]and illumination[(4500±500)lx]for 10 days.To investigatethe character,content and related substancesat 0,5,10 days.Part Ⅱ Preparation technology research of Pubescent Holly Root dispersible tablet.Using single factor screening of the types of excipients with tablet disintegration time limit and disperse uniformity as index.Again the star design-response surface method(RSM-CCD)was used for optimization the prescription of dispersible tablet.Using the dosage of MCC,PVPP,and CMS-Na as factors index,investigate its influence on dispersible tablet disintegration time limit and select the best formulation.Determine the angle of repose and bulk density and critical relative humidity of intermediate particle,provide reference for production.Part Ⅲ Quality standards research of Pubescent Holly Root dispersible tabletEstablish TLC identification method of Pubescent Holly Root dispersible tablet.Used the flavonoids as index ingredient to establish dissolution test method and set a dissolution specified limit.Establish the the content determination method of total flavonoids by UV.Establish the the content determination method of h Protocatechuic aldehyde by HPLC.Determine the content of three batch of pilot products,set the content limit.Part IV Stability test ofPubescent Holly Root dispersible tablet.Simulation listed packaging,three batch of Pubescent Holly Root dispersible tablets were exposed to the condition of(400±2)oC and(75±5)%for 3 months.Investigate the characteristics of dispersible tablets,the difference of weight,dispersing uniformity and dissolution in accordingto the quality standard.Determine the content of flavone and protocatechuic aldehyde.ResultPart Ⅰ Pr-fomulation studies on ethanol extracts from Pubescent Holly Root.Ethanol extracts binomial regression moisture absorption equation for y=0.0221 t2+1.2694+0.7328 t,acceleration of hygroscopic was0.0442g·h·-2,velocity of hygroscopic was 0.7328 g·h-1,around 16 hours reach moisture balance,the balance of moisture absorption rate was 7.34%,and the critical relative humidity was 78.1%.PVPP,CMS-Na3 CCMC-Na,starch and dextrin increased the equilibrium amount of moisture absorption and moisture absorption acceleration of ethanol extracts significantly.The results ranking was PVPP>CMS-Na>CCMC-Na>starch>dextrin.Calcium hydrogen phosphate,talcum powder,lactose,magnesium stearate werereduced the hygroscopic acceleration,balance the amount of moisture absorption and balance the moisture absorption time of extracts in different degree.The results ranking was calcium hydrogen phosphate>talcum powder lactose>magnesium stearate>powder silica>MCC.The calcium hydrogen phosphate,talcum powder,lactose,magnesium stearate can improve the critical relative humidity of ethanol extracts from Pubescent Holly Root.A method to determine the content of protocatechuic aldehyde was established by HPLC.The chromatography conditions as follows:C18 column;1%glacial acetic acid with methanol(15:85)as mobile phase;Detection wavelength was 312 nm;Flow rate:1.00 1.00ml·min-1;Column temperature:30℃.Measured the content of protocatechuic aldehydewas 0.261mg·g-1.The protocatechuic aldehyde content of ethanol extracts from Pubescent Holly Root in high temperature,illumination and high humidity environment was stable.The content of protocatechuic aldehyde of mixture of extract and PVPP,CMS-Na,CCMC-Na using SPSS13.0 compared with 0 days when the 10th day,P<0.01,indicating that extract with PVPP,CMS-Na,CCMC-Na under the environment of high temperature was instability.Under high humidity and illumination conditions,extract mixture with excipientswas stable.Part Ⅱ Preparation technology research of Pubescent Holly Root dispersible tablet.By using single factor screening,screening Pubescent Holly Root dispersible tablet filler was calcium hydrogen phosphate and MCC,disintegrating agent was PVPP and CMS-Na,disintegrating combination ratio of PVPP:CMS-Na was 2:1,wetting agent was 3%PVP solution,lubricant was magnesium stearate,dosage was 0.8%,taste masking agent for sucralose,dosage was 0.2%.RSM-CCD was preferredthe usage of MCC,PVPP,CMS-Na,optimizing the usage of MCC was 18%,PVPP was 9%,CMS-Na was 5%.Intermediate Pubescent Holly Root dispersible tablet particles repose angle is 28.35°,bulk density was 0.50 g·ml-1,the critical relative humidity was 72.5%.Part Ⅲ Quality standards research of Pubescent Holly Root dispersible tablet.Three batch of pilot sample results show:TLC identificationshow the same color spots in the same position,negative without interference.Pubescent Holly Root dispersible tablet vitro dissolution more than 80%in 30min.The limit of total flavonoids was not less than 44mg per tablet by UV.The limit of protoeatechuic aldehyde was not less than 34μg per tablet by HPLC.Part IV Stability test of Pubescent Holly Root dispersible tablet.Pubescent Holly Root dispersible tablet Stability test undergo 3 months.The dissolution of pilot product was 88.0%at 3rd month,the average content of flavonoids was 52.67 mg per piece,the average content of protocatechuic aldehyde was 40.37 mg per piece.ConclusionPart Ⅰ Elcohol extract from Pubescent Holly Root around 16 h reach moisture balance,balance moisture absorption rate was 7.34%,the critical relative humidity was 78.1%.Show that hygroscopic of extract is not strong.Mixes with common pharmaceutical excipients,high disintegrating agent such as:PVPP,CMS-Na,CCMC-Na can significantly enhance the hygroscopicity of extract,other excipients such as starch,dextrin,also can improve the hygroscopicity of extract,but the effect is relatively weak.Calcium hydrogen phosphate,MCC,talcum powder,lactose,magnesium stearate can significantly reduce the extract from the balanee of moisture absorption and moisture absorption acceleration,improved its critical relative humidity of different level,in terms of thermodynamics and kinetics are have played an important role to improve,and dosage,the greater the effect is better.Medicine moisture absorption stability directly affect the quality of traditional Chinese medicine dispersible tablet,Medicine and the stronger hygroscopicity,the preparation process of the higher environmental requirements,packaging and preservation of dispersible tablet and the higher requirements,increased its production cost.Moisture absorption of active pharmaceutical ingredients and materials to study the influence of its hygroscopicity,optimization can reduce API hygroscopicity of complementary makings,can be in the process of the preparation of dispersible tablets for traditional Chinese medicine provides the basis for prevention.Part Ⅱ The method to determine the content of protocatechuic aldehyde by HPLC is simple,mobile phase is easy preparation,preparation of the test is simple.The methodis specificity,stability and good reproducibility.The extract in high temperature,light and high humidity environment is stable,but extract with PVPP,CMS-Na,CCMC-Na in high temperature is not stable,The extract has good compatibility with other material.In the formulation of traditional Chinese medicine dispersible tablet,proportion of complementary makings is larger,the probability of various reactions between materials and active pharmaceutical ingredients in also increases,which affects the stability of the traditional Chinese medicine dispersible tablet.Before prescribing was studied for the raw materials,can be filtered on material type,reduce the incidence of the API and accessories.Part Ⅲ The prescription of tablet is drug(40%),calcium hydrogen phosphate(27%),MCC(18%),PVPP(9%),CMS-Na(5%),magnesium stearate(0.8%),sucralose(0.2%)and 3%PVP solution right amount.The prescriptionis disperse uniformity,short disintegration time.Intermediate dispersible tablet particles repose angle is 28.35°,bulk density of 0.50 g· ml-1,the critical relative humidity is 72.5%,suit for industrial production.Part Ⅳ Good specificityto identify by TLC.Dissolution test method is simple and accurate.The methods of content determination byUV and HPLC are comprehensive effective part and components two indicators.Most of the quality of traditional Chinese medicine dispersible tablet disintegration time limit,disperse uniformity for the standard,the research of Chinese medicine dispersible tablet dissolution is less,and improve the drug dissolution is the biggest characteristic of dispersible tablets.Therefore,dissolution should be one of the standard of quality control of traditional Chinese medicine dispersible tablet.Part Ⅴ Pubescent Holly Root dispersible tablet Stability test undergo 3 months.The character,identification,weight variation and disperse uniformity,dissolution and content determination of all meet the requirements,shows good stability.Because prescription to add a lot of traditional Chinese medicine dispersible tablet disintegrants,if from the extermal environment effect is bad,will seriously affect the stability of dispersible tablets.Chinese medicine dispersible tablet packaging should use aluminum-plastic film packaging,and pay attention to control the storage environment humidity. |
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