Study On Preparation Of Xiqingguo Buccal Tablets

Background and objectivesWith the development of pharmaceutical sciences,researchers pay more attention to the Buccal Drug Delivery Systems(BDDS).The advantages of BDDS are listed as follows: it can access to the lesion site directly without blood circulation or first-pass effect after administration;it would not be affected by gastrointestinal environment either;rapid onset and easy to carry;Furthermore,when serious adverse drug events happen,it could be immediately terminated.Buccal tablet is one form of the BDDS that widely used as anti-infection,anti-bacterial agents in clinical application for treating or preventing throat and oral disease.Buccal tablets such as watermelon frost buccal tablets,grass coral buccal tablets,Yinhuang buccal tablets,Cydiodine Buccal Tablets and Dequalinium Chloride Buccal Tablets are widely used in China.Xiqingguo,also known as zangqingguo,one of the commonly used traditional Chinese medicines,is the dry immature fruit of Terminalia chebula Retz.According to the Chinese Pharmacopeia 2015 edition(S1)records,it shows clearing heat and detoxification activity,mainly used for the treatment of Yin diphtheria.The main formulations are xiqingguo tea and particles,often used for the treatment of chronic pharyngitis and chronic tonsillitis.Previous studies had extracted the extractum from Xiqingguo and analyzed the main components by High performance liquid Chromatograph,HPLC).Results showed that the main components in Xiqingguo extractum were gallic acid,chebulinic acid,chebulagic acid,corilagin,chebulaninand other phenolic compounds with anti-inflammatory,anti-viral,anti-bacterial and anti-oxidative effects.Based on the pharmacological characteristics of the Xiqingguo,the aim of this study is to prepare Xiqingguo buccal tablets,which can access to the lesion site directly,rapid onset andeasy to carry.The appearance,hardness,solubility and taste were selected asquality indexs,taking orthogonal design to optimize the prescription and dosage of main material s,select the best prescription compositions,establish quality standards according to the Chinese Pharmacopeia 2015 edition(S4)and evaluate the anti-bacterial and anti-inflammatory in vitro and in vivo.Provide the basis for future study.MethodsPart 1 Study on preparation technology of Xiqingguo Buccal Tablets1.1 Wettability and fluidity investigation.We investigated the Wettability of xiqingguo extractum according to the drug Wettability Test guideline in Chinese Pharmacopeia 2015 edition(S4);we also utilized fixed cone method to evaluate the liquidity of xiqingguo extractum.1.2 Screening tableting method.Wet granulation method,dry granulation method,direct powder compression method and other methods were evaluated based on the quality of the prepared tablets and one of them was chosen as the most suitable method.1.3 Determined the lozenge diameter,weight,thickness of buccal tablets.According to the experimental purpose,combined with the commonly used tablet size,shape,siz e and thickness,we designed appropriate tablets.1.4 Quality indexs establishment.According to the common tablets and Chinese Pharmacopeia 2015 edition(S4),combined with the purpose of the experiment,we chose the tablet appearance,hardness,solubility and effects of taste as quality indexs.1.5 Selection of the drying time of wet particles.The drying time was established according to the moisture content of the dried particles and the quality of the tablets.1.6 Prescription selection.The type and amount of tablet diluents,wetting agent,lubricantand flavoring agents were screened and selected based on the results from single factor test and orthogonal design.1.7 Process validation under the laboratory conditions.We preparedthree batches of samples according to the optimized and selected prescription and assessed the quality.1.8 Measurement of Critical Relative Humidity.We prepared six different supersaturated salt solution and placed the particles under the condition of 25 ? for 48 h,measured the weight of moisture absorption,taking the relative humidity of the supersaturated salt solution as the abscissa and the particle moisture absorption rate as the ordinate,draw moisture curve,the abscissa value corresponding to the tangent intersection point of the curve is the critical relative humidity.Part 2 Study on quality standard of Xiqingguo Buccal Tablets2.1 Character investigation.Use sensory to investigate shape,smell and taste.2.2 Solubility determination.We took three batches of Xiqingguo Buccal Tablets,six pieces per batch(Batch number: 160530,160531 and 160601),the solubility was determined in accordance with Chinese Pharmacopeia 2015 edition(S4)general rules 0921 disintegration time limit.2.3 Weight variation investigation.We took twenty Xiqingguo buccal tablets from three batches(160530,160531and160601)randomly and checked the weight variationin accordance with the Chinese Pharmacopoeia 2015 edition(S4)general rules 0101.2.4 Uniformity investigation.The principal agents in Xiqingguo Buccal Tablets were phenolic acids(Gallic acid and other 5 components)which were lower than a single dose of twenty-five percent,thus,according to the Chinese Pharmacopoeia requirements,we need to investigate the uniformity of Xiqingguo Buccal Tablets according to Chinese Pharmacopoeia 2015 Edition(S4)0941 of the content uniformity test method.2.5 Content determination.We used HPLC to quantitative determine the concentration of gallic acid,chebulanin,corilagin,chebulagic acid,chebulinic acid in Xiqingguo Buccal Tablets.Part 3 Pharmacodynamics Preliminary Investigation of Xiqingguo Buccal Tablets in vitro and in vivo.3.1 The principal agents in Xiqingguo Buccal Tablets were phenolic acids(Gallic acid,chebuninic acid,chebulagic acid,corilagin and chebulanin),which had been reported as showinganti-bacterial,anti-inflammatory and other effects.In this paper,we assessed the anti-bacterial effect in vitro by determining the minimal inhibitory concentration(MIC)of Xiqingguo Buccal Tablets against to Streptococcus mutans,Staphylococcus aureus and Staphylococcus epidermidis.We also assessedthe anti-inflammatory effect Xiqingguo Buccal Tablets in vivo by using dimethylbenzene inducing ear edema model.ResultsPart 1 Study on preparation technology of Xiqingguo Buccal Tablets.1.1 Wettability and fluidity investigation.According to wettability and fluidity investigation,we found that the wettability and fluidity of xiqingguo extractum were poor.1.2 Prescription composition.By using single factor test and orthogonal design the optimal formulation,we selected the optimal prescription composition: The ratio of lactose and mannitol was 1:3,ethanol concentration was 60%,magnesium stearate was 0.9% of the weight dry particles weight,aspartame dosage was 2% of the weight of dry particles,adding proper amount of orange flavor and menthol.1.3 Preparation technology.Proper amount of Xiqingguo extractum and lactose were weighed according to the prescription composition results and through over 100 mesh sieve,after mixing,added some mannitol and mixed,then added 60% ethanol dissolved menthol to the mixture to make the soft materials and granulation;Vacuum compression dried,weighed and after that,added magnesium stearate of prescriptions,aspartame and the amount of orange flavor and mixed,finally,tableting the particles by using 13 mm shallow round die.1.4 Quality investigation and process validation.The appearance,hardness,solubility,taste were selected as quality indexes,the quality of prepared xiqingguo buccal tablets were assessed as qualified.The three batches of Xiqingguo Buccal Tablets samples appearance complete smooth,hardness moderated,taste good,which indicated that the Xiqingguo Buccal Tablets prescription meet the requirements.Part 2 Study on quality standard of Xiqingguo Buccal Tablets2.1 The prepared Xiqingguo Buccal Tablets looks like grayish white round shaped tablets,with good glossiness,light fragrance and sweet;weight variation and uniformity investigation of tablets were in line with the requirements.2.2 Establish and validate of the method for determination of Xiqingguo Buccal Tablets.Gallic acid,corilagin,chebulanin,chebulagic acid,chebulinic acid were in a good linear relationship with the range of 0.62 ~ 10?g/m L,0.64 ~ 10.20?g/m L,1.27 ~ 20.30?g/m L,2.58 ~ 41.3?g/m L,0.64 ~ 10.30?g/m L,respectively.The investigation of the precision,stability,repeatability and recovery of the sample showed that the method was reasonable and feasible.Part 3 Pharmacodynamics Preliminary Investigation of Xiqingguo Buccal Tablets in vitro and in vivo.3.1 The results showed that the Xiqingguo Buccal Tablets had inhibitory effects on Streptococcus mutans,Staphylococcus aureus and Staphylococcus epidermidis,MIC were more than 1.25 mg/ m L,more than 2.5 mg/ m L,more than 2.5 mg/ m L,that Xiqingguo Buccal Tablets had anti-bacterial effect.3.2 Anti-inflammatory effects of Xiqingguo Buccal Tablets in vivo by using dimethylbenzene inducing ear edema model showed that Xiqingguo Buccal Tablets had obvious anti-inflammatory effect.Conclusions1.Prescription and preparation process: The optimal prescription composition was add one portion of xiqingguo extractum with 13 portion of lactose and mannitol mixture(1:3,mass ratio),ethanol concentration was 60%,magnesium stearate was 0.9% of the weight dry particles weight,aspartame dosage is 2% of the weight of dry particles,adding proper amount of orange flavor.The preparing process was weighing proper amount of Xiqingguo extractumand lactose were weighed and through over 100 mesh sieve,after mixing,added some mannitol and mixed,then added 60% ethanol dissolved menthol to the mixture to make the soft materials and granulation;Vacuum compression dried,weighed and after that,added magnesium stearate of prescriptions,aspartame and the amount of orange flavor and mixed,finally,tableting the particles by using 13 mm shallow round die.2.The prepared Xiqingguo Buccal Tablets samples appearance complete smooth,hardness moderated,taste good,which indicated that the Xiqingguo Buccal Tablets prescription meet the requirements.We also Establish and validate of the method for determination of Xiqingguo Buccal Tablets.3.In vitro and in vivo test results indicated that Xiqingguo Buccal Tablets showed stronger anti-bacterial effects and obvious anti-inflammatory effect.