| Musk Hemorrhoids Suppository is an external preparation of traditional Chinese medicine contained in the 2015 edition of the Pharmacopoeia of the People’s Republic of China.It belongs to the national second-class protected varieties of traditional Chinese medicine.The prescription consists of 8 kinds of traditional Chinese medicine or extracts of traditional Chinese medicine,such as artificial musk,pearl,borneol,calamine powder,notoginseng,gallnut,artificial bezoar,belladonna juice extract,etc.It has the functions of clearing heat,detoxifying,relieving swelling and pain,stopping bleeding and generating muscle.It is mainly used for stool hemorrhage,bright red blood and burning pain of anus caused by high fever of large intestine,various kinds of hemorrhoids and anal fissures.Calamine is a mineral component in Musk Hemorrhoids Suppository,and it accounts for about two-thirds of the prescription in Musk Hemorrhoids Suppository,and it is also the main component of the therapeutic effect.Relevant studies have shown that the content of lead in calamine is high.At the same time,calamine still has some problems,such as inconsistent origin mineral,,overflow of counterfeit products,irregular processing and shortage of resources.Therefore,these problems may become a potential risk of quality control of Musk Hemorrhoids Suppository.However,the quality standard of Musk Hemorrhoids Suppository is relatively weak in the quality control of Calamine and heavy metal elements.In order to improve the quality standard of Musk Hemorrhoids Suppository,strengthen the quality control level of Calamine,heavy metals and harmful elements in Musk Hemorrhoids Suppository,and formulate the limit standard of heavy metals and harmful elements in Musk Hemorrhoids Suppository,this paper makes relevant research from the following aspects:1、In this paper,some quality problems of mineral medicine Calamine and Calcined Calamine are found standing on the determination and analysis of the quality parameters of a large number of market samples,and summarize the results of the research team for ten years to try to put forward countermeasures.X-ray diffraction(XRD)method was used to analyze the structure and composition of Calamine and Calcined Calamine samples.According to the XRD results,as well as the results of tests included in Pharmacopoeia of the People’s Republic of China(2005-2015 edition),the authenticity of Calamine and Calcined Calamine samples were identified.The content of zinc oxide in samples were determined by the method of determination in Pharmacopoeia of the People’s Republic of China.Individually,Inductively Coupled Plasma Mass Spectrometry(ICP-MS),Inductively Coupled Plasma Atomic Emission Spectrometry(ICP-AES)and Atomic Fluorescence Spectrometry(AFS)method was used for the determination of impurity elements and harmful elements in Calamine and Calcined Calamine samples.Four kinds of impurity elements of magnesium,iron,aluminum,calcium and five harmful elements of lead,cadmium,arsenic,copper,mercury were measured.The study showed that:(1)Fake Calamine products on the market were overflowing.In the past ten years,our team has collected samples sold as " Calamine" and "Calcined Calamine" from the pharmaceutical market,and the number of counterfeit batches has reached half to two-thirds of the total batches of samples.(2)The mineral origin of the mainstream Calamine in the market is inconsistent with that stipulated in the Pharmacopoeia of the People’s Republic of China(2015 edition).Calamine whose mineral source is smithsonite stipulated in the Chinese Pharmacopoeia is seldom sold,while the calamine of hydrozincite accounts for the mainstream of Pharmaceutical market.(3)The contents of harmful elements Pb and Cd in Calamine and calcined Calamine are generally higher,while the contents of harmful elements As and Cu in some inferior Calamine are higher.(4)Parts of calcined Calamine were improperly or inadequately processed.In view of these quality problems,the countermeasures are put forward as follows:(1)It is suggested that hydrozincite should be approved as the mineral source of Calamine,and be included by the Pharmacopoeia of the People’s Republic of China;(2)Strengthen the research on the specificity of Calamine identification methods to improve the quality control level;(3)Strengthen the research on the processing of Calamine,ensure the full calcination of Calamine and reduce the content of harmful elements such as Pb and Cd in Calamine through the industrialization study of the processing technology,and formulate the limit standards for the content of Pb and Cd in Calamine;(4)Carry out research on the artificial synthesis of Calamine and Calcined Calamine,in order to cope with the current shortage of Calamine resources and ensure the sustainable development of Calamine medicinal materials.2、Zinc element and lead element were gauged to reveal their occurrence forms and distribution characteristics in raw Calamine and calcined Calamine in order to get ready for the deducting of lead.X-ray diffraction(XRD)mothed was used to analysis the occurrence form,main carrier mineral of zinc and lead.Electron probe microanalysis(EPMA)method was used to perform region-wide scanning of elements,qualitative and quantitative analysis of micro-area components of the raw and calcined CalamineStood on the XRD data of 21 batches samples,hydrozincite(Zn5(CO3)2(OH)6)was proved to be the main mineral species in raw Calamine,while there were only three batches of samples containing a small amount of smithsonite(ZnCO3).which was a symbiotic body of hydrozincite and smithsonite.As impurity minerals,hemimorphite(2n4(OH)2(H2O)(Si2O7),calcite(CaCO3),dolomite(CaMg(CO3)2),quartz(SiO2)were detected.For comparison with the raw Calamine,the main mineral of calcined Calamine was zinc oxide(ZnO).the impurity minerals were zinc silicate(Zn2SiO4)and calcium Calcite(CaCO3),while zinc ferrite(ZnFe2O4)was occasionally.Zinc is the subject element of Calamine.According to 21 batches of raw Calamine,Zn existed generally as the main mineral species as hydrozincite(Zn5(CO3)2(OH)6),and the impurity mineral species as hemimorphite(Zn4(OH)2(H2O)(Si2O7),occasionally as smithsonite(ZnCO3).The backscatter electron images and element distribution data from EPMA of raw Calamine samples illustrated that:Zn and Pb were simultaneously existent in hydrozincite area;Zn and Si were simultaneously existent in the hemimorphite area;Ca and Mg were simultaneously existent in the dolomite area;Ca was individually existent in the calcite area.In raw Calamine samples,Pb was mainly existent in hydrozincite area,closely associating with Zn element.Quantitative inspection of electron probes in a large number of hydrozincite sites showed that,the ratio of ZnO/PbO content in hydrozincite tended to be fixed,and Pb was statistically evenly distributed in hydrozincite,verifying that Pb occurs mainly in the lattice of hydrozincite in isomorphism.But Pb content was much lower in the area of hemimorphite,calcite nor dolomite of raw Calamine,even can’t be detected.Zn and Pb in the lattice of hydrozincite respectively transformed into ZnO and PbO after calcination.Zinc distributed continuously in calcined Calamine,mainly existed in the form of zinc oxide,and less of zinc silicate(Zn2SiO4).Lead distributed in isolation in calcined Calamine,mainly existed in the form of lead oxide,which no longer had correlation with zinc element.Calcination destroyed the lattice structure of hydrozincite,broke the symbiotic state of zinc and lead in Calamine,changed the distribution characteristics of the elements and enhanced the feasibility of deducting lead.3、In this paper,the removal of heavy metal elements such as Pb,Cd and impurity minerals such as Calcite(CaC03)in calcined Calamine by water flying processing was studied,and the mechanism of lead reduction and impurity removal by water flying processing of Calamine was explored.The contents of Pb,Cd,Ca and Fe in calcined and water flying Calamine products were determined by ICP-MS/AES technology,and the changes of the contents of each element before and after water flying processing were compared.Afterwards,the mechanism of lead reduction and impurity removal in Calamine by water flying processing was analyzed through mineral flotation principle.The contents of Pb and Ca in calcined Calamine products decreased significantly after six times of water flying.In fact,the contents of Pb and Ca decreased by 28.02%and 41.29%respectively,while the contents of Fe and Cd did not change significantly.The contents of heavy metal Pb(mainly in the form of PbO)and impurity minerals such as Calcite in Calamine can be partially removed by water flying processing.Furthermore,the mechanism of reduction may be related to the wettability and specific gravity of lead oxide and Calcite.4、Calamine,a mineral component of Musk Hemorrhoids Suppository,was analyzed qualitatively and quantitatively in this experiment.A method for the determination of heavy metals and harmful elements Pb,Cd,Cu,As and Hg in Musk Hemorrhoids Suppository was established.Using chloroform to dissolve the matrix of Musk Hemorrhoids Suppository as a pretreatment method,eliminating the interference of matrix in Musk Hemorrhoids Suppository,the qualitative analysis method of calamine in Musk Hemorrhoids Suppository was established by X-ray diffraction technology.The sample of Musk Hemorrhoids Suppository was digested by microwave digestion method,and the content of Zn in Musk Hemorrhoids Suppository was determined by ICP-AES,which was converted into calamine content(calculated by ZnO).At the same time,the quantitative analysis method of Pb,Cd,Cu,As and Hg by ICP-MS was established.The results showed that the mineral composition of Musk Hemorrhoids Suppository was the raw calamine and the origin mineral was hydrozincite;the content of calamine powder measured by ICP-AES method was higher than that measured by pharmacopoeia method,and all met the requirements of Chinese Pharmacopoeia 2015 on the content of calamine powder.The contents of Pb,Cd,As and Hg in Musk Hemorrhoids Suppository are lower than the limit standard requirements of Pb,Cd,As and Hg(Hg except Japan)in cosmetics of 8 countries and regions.And there is no limit standard for the content of copper in cosmetics in 8 countries and regions.By dissolving the matrix,the powder of Musk Hemorrhoids Suppository can be prepared,which can realize the qualitative identification of Calamine,a mineral medicine in Musk Hemorrhoids Suppository.The method is accurate,simple and reproducible.It is suitable for the quality control of calamine powder and harmful elements such as Pb,Cd,Cu,As and Hg in Musk Hemorrhoids Suppository.It also provides a reference and basis for the formulation of the limit standard of harmful elements in Musk Hemorrhoids Suppository.5、In this study,based on the rat model of hemorrhoids,the safety evaluation of musk hemorrhoids suppository was carried out,and the possible pathological damage of heavy metal lead in Musk Hemorrhoid Suppository to hemorrhoid model rats was evaluated.Rats were divided into normal control group,model control group(0.45 g/kg,3 times clinical equivalent dose suppository matrix),low dose group(0.15 g/kg,clinical equivalent dose)and high dose group(0.45 g/kg,3 times clinical equivalent dose),20 rats in each group,half male and half female.The model control group,the low-dose group and the high-dose group of Musk Hemorrhoids Suppository were used to replicate the model of Hemorrhoids in rats.The rats were administered with continuous rectal administration for 8 days,twice a day.The normal control group was not administered,and was normally reared.At the end of the experiment,urine,blood and organ tissues of rats were collected for biochemical indicators and lead content determination,and pathological analysis of related organ tissues was carried out.The results showed that the low dose group of Musk Hemorrhoids Suppository could significantly improve the pathological changes of hemorrhoids model induced by acetic acid in rats,but the high dose group had no significant improvement compared with the model group.Musk Hemorrhoids Suppository had no significant effect on the visceral coefficients of rats,while the changes of heart,spleen,thymus,testis and seminal vesicle coefficients may be caused by pathological reactions induced by model building.Musk Hemorrhoids Suppository had no significant effect on protoporphyrin in blood,zinc porphyrin and fecal porphyrin in urine of rats.Musk Hemorrhoids Suppository did not significantly change the levels of aminolevulinic acid dehydratase in liver,lung,heart and whole blood of rats.The levels of lead in blood,urine,liver,kidney and brain of rats in normal control group,model group,low dose group of Musk Hemorrhoids Suppository and high dose group were all at low levels,and there was no significant difference between the groups.Pathological analysis showed that Musk Hemorrhoids Suppository had no obvious toxicity to brain,lung,kidney,heart and ovary of rats.However,the seminal vesicles of male rats in low-dose group and high-dose group of Musk Hemorrhoids Suppository had obvious pathological changes,and the seminal vesicles of male rats in model group had similar pathological changes,but the degree was slight.Therefore,it is believed that the lesion may be caused by acetic acid modeling.Comprehensive analysis of the above results shows that Musk Hemorrhoids Suppository has no obvious lead toxicity to hemorrhoids model rats. |
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