Studies On Ma-xing Ke Chuan Ping Sustained-Release Capsules

asthma（asthma）is a kind of the etiology unknown chronic disease which death rate is very higher,and it is characterized by acute episodes or attacks of breathing problems such as coughing,wheezing chent tightness pr shortness of breath.Two main types of Asthma medications:（1） Bronchodilators:a type of asthma medication that relaxes the airway muscles and control the acute symptom.（2） Anti-inflammstory medications:controller（preventative） medications.because persistent chronic inflammation and hyperresponsiveness of the airway are the fundamental characteristics of asthma,Anti-inflammstory medication is thought playing a crucial role in a long term of the asthma’s treatment.In traditional Chinese medicine（TCM） theory,asthma is clearly differentiated between the actual attacks and the periods between attacks.When the attacks are happening,this is considered to be an acute,Excess condition,and the objective is to disperse the Excess and stop the attack.Wind,a non-substantial pathogenic factor, lodges in the bronchi and combines with Cold or Heat pathogenic factors to cause bronchospasms.Research on the efficacy of herbal medicine in the treatment of asthma shows that traditional Chinese medicine compares favorably with standard Western treatment,and provides an alternative approach for those who want to avoid the long-term use of hormone drugs.But in clinical treatment,TCM usually plays a minor role,because of the ancient form of TCM.In order to promote the development of TCM of asthma,we should improve the Chinese drugs pharmaceutics.We studied on the Antiasthmatic,Antitussive and anti-inflammastory effect MA-huang-tang decoction on the whole,cellular and molecular levels.In this thesis, according to the results of studies we established a new compound recipe of active components instead of four chinese herbs of Ma-huang-tang.We hope that the new recipe have the advantages of TCM and the sustained release preparation,which would reduce the dosing frequency,narrow the blood concention fluctuation and be more convenient for patients to use.Spectrophotometry method,High-performance liquid chromatography（HPLC） and Gas chromatography-mass spectrometry（GS-MS）was developed to determine the Total Alkaloid of Eohedra（TAE）,Ephedrine（E）,Pseuoephedrine（PE）,Methylephedrine （ME）,Norephedrine（NME）,Norpseudoephedrine（NMP）,Amygdalin（AM）,Cinnamadehyde（CA） and Glycyrrhizic acid（GA） content in sustained-release capsules.In the preformulation and pharmacokinetics researches were investigated,which benefit phaemaceutical design.The extraction and purification technology of the effective fracrions of Ephedra herb, amygdala amara and ramulus cinnamomib was determined.The content of TAE was 92.5%and the yield of it was 1.8%;The content of AM was 90.6%and the yield of it was 3.5%;And The content of CA was 87.5%and the yield of it was 0.31%.The technology of three kinds of active parts was stable and suitable for industrial production. The proportion of the effective components was optimized by homogeneous design.The dose of TAE,AM,CA and GA by people everyday respectively was 140mg,230mg,13mg and 53mg.The study of Antiasthmatic and Antitussive effect of optimized recipe,adopted the guinea pig’s cough models-induced by citric acid and the asthma models-induced by acetylcholine and hwastamine,shows that the Antitussive and Antiasthmatic effect of new recipe and decoction was same. TAE solid dwaspersion in microparticles of Ethylcellulose was prepwered by solvent method,and the ration of EC and TAE was 12:1.the effects of microparticle formulations on the physic-chemcial properties,and drug physical forms were evaluated by differential scanning calorimetry（DSC）,Fourier-transform infrwered （FTIR）spectroscopy,X-ray powder diffraction（PXRD）.Drug release modeling with the Higuchi model indicated that controlled release of TAE was achieved. The solid dwaspersion of amygdala amara active part in microparticles of Ethylcellulose and PEG600 was prepwered by solvent method,using and the ration of EC,PEG6000and TAE was 7:0.5:1.the effects of microparticle formulations on the physic-chemcial properties and drug physical forms were evaluated by DSC,FTIR and PXRD.Drug release modeling with Higuchi model indicated that controlled release of the amygdala amara active part was achieved.The solid dwaspersion of ramulus cinnamomi aetherolea in microparticles was prepwered by melting method,and the ration of stearic acid（SA）,PEG6000,glyceryl monostearate and ramulus cinnamomi aetherolea was 3:4:1:1.the effects of microparticle formulations on the physic-chemcial properties,and drug physical forms were evaluated by FTIR.Drug release modeling with Higuchi model indicated that controlled release of TAE was achieved.Theβ-CD of ramulus cinnamomi aetherolea in microparticles was prepwered by the electric stirring method in saturated water solution,and the ration ofβ-CD and ramulus cinnamomi aetherolea optimized by orthogonal design was 15:1.The temperature of clathration was 80℃and the stirring time was 1h.The cyclodextrin inclusion compound were evaluated by the thin layer chromatography;.The rate of dwassolution of the cyclodextrin inclusion compound was higher than ramulus cinnamomi aetherolea.According to the studies on the pharmaceutical technology,the new formulation of sustained-release capsules was that TAE extractive was 15.1g,amygdala amara active part was 25.4g,ramulus cinnamomi aetherolea was1.5g,Glycyrrhiza uralenswas active part was 5.5g,EC was 329.0 g,PEG6000 was 15.1g,glyceryl monostearate was 0.9g,β-CD was 6g,and MCC was 2.8g.And they were blended and poured into 800 capsules of NO.1 capsules.The plasma concentrations of target compenents in four dogs were tested after the single oral administrations of self-made sustained release capsules while taking self-made quick release preparation as a reference preparation.The results was that（1） C_max,T_max of E were 1637.787ng·mL^-1and 3.75h and;the relative bioavilability was 105.71%;The release of sustained-release capsules in vitro was correlative with the absorption fraction in vivo（r=0.967,P＜0.01）.The results of bioequivalence was that AUC_0-∞ of individuals,preparations and periods had no significant difference（P=0.344,0.729 and 0.848）;C_max of individuals and periods had no significant difference（P=0.514 and 0.636）;C_max of preparations had significant difference（P=0.000）,and illustrated that the self-made sustained release capsules and the self-made quick release preparation were not biological equivalent.（2） C_max,T_max of PE were 1089.227ng·mL^-1 and 4.00h and;the relative bioavilability was 107.17%;The release of sustained-release capsules in vitro was correlative with the absorption fraction in vivo（r=0.979,P＜0.01）.The results of bioequivalence was that AUC_0-∞ of preparations and periods had no significant difference（P=0.207 and 0.338）;AUC_0-∞ of individuals had significant difference（P=0.022）;C_max of individuals and periods had no significant difference（P=0.407 and 0.575）;C_max of preparations had significant difference（P=0.001）,and illustrated that the self-made sustained release capsules and the self-made quick release preparation were not biological equivalent.（3） C_max,T_max of ME were 135.783ng·mL^-1 and 3.75h and;the relative bioavilability was 119.53%;The release of sustained-release capsules in vitro was correlative with the absorption fraction in vivo（r=0.986,P＜0.01）.The results of bioequivalence was that AUC_0-∞ of periods had no significant difference（P=0.255）; AUC_0-∞ of preparations and individuals had significant difference（P=0.002 and 0.002）;C_max of individuals and periods had no significant difference（P=0.157 and 0.160）;C_max of preparations had significant difference（P=0.0009）,and illustrated that the self-made sustained release capsules and the self-made quick release preparation were not biological equivalent.（4） C_max,T_max of NME were 1025.443ng·mL^-1 and 6.00h and;the relative bioavilability was 1196.98%;.The results of bioequivalence was that AUC_0-∞ of periods had no significant difference（P=0.605）;AUC_0-∞ of preparations and individuals had significant difference（P=0.049 and 0.011）;C_max of individuals and periods had no significant difference（P=0.184 and 0.588）;C_max of preparations had significant difference（P=0.001）,and illustrated that the self-made sustained release capsules and the self-made quick release preparation were not biological equivalent.（5） C_max,T_max of AM were 495.578ng·mL^-1 and 3.25h and;the relative bioavilability was 105.71%;The release of sustained-release capsules in vitro was correlative with the absorption fraction in vivo（r=0.944,P＜0.05）.The results of bioequivalence was that AUC_0-∞ of individuals had significant difference（P=0.888 and 0.282）;AUC_0-∞ of preparations and periods had no significant difference（P=0.016）;C_max of periods had no significant difference（P=0.138）;C_max of individuals and preparations had significant difference（P=0.027 and 0.009）,and illustrated that the self-made sustained release capsules and the self-made quick release preparation were not biological equivalent. （6） C_max,T_max of CA were 10.497ng·mL^-1 and 4.5h and;the relative bioavilability was 115.12%;The release of sustained-release capsules in vitro was correlative with the absorption fraction in vivo（r=0.881,P＜0.05）.The results of bioequivalence was that AUC_0-∞ of individuals,preparations and periods had no significant difference（P=0.052,0.276 and 0.871）;C_max of individuals and periods had no significant difference（P=0.122 and 0.673）;C_max of preparations had significant difference（P=0.016）,and illustrated that the self-made sustained release capsules and the self-made quick release preparation were not biological equivalent.