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    Compatible stability study of XingNaoJing injection based on physical-chemical properties analysis

    2019-11-01 03:01:08DongLiQiChunXiaLiangYueLinZhangYanQuanGaoYueXingHongLiYanBingZhangJiaRongXieZhiDongLiu
    TMR Modern Herbal Medicine 2019年4期

    Dong-Li Qi,Chun-Xia Liang,Yue-Lin Zhang,Yan-Quan Gao,Yue Xing,Hong-Li Yan,Bing Zhang,Jia-Rong Xie,Zhi-Dong Liu*

    1Tianjin State Key Laboratory of Modern Chinese Medicine,Tianjin University of Traditional Chinese Medicine,Tianjin,China.

    2Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique,Ministry of Education,Tianjin University of Traditional Chinese Medicine,Tianjin,China.

    Abstract

    Keywords:Xingnaojing injection,Stability,Compatibility,Physical-chemical properties,Adverse drug reaction,Muscone,d-borneol

    Background

    Traditional Chinese Medicine Injections(TCMI)has the characteristics of quick action and convenience.Clinically,it is mostly used in complex,urgent,critically ill patients[1].In recent years,the stability and safety of TCMI are serious issues related to its clinical application[2-4].The annual report on national adverse drug reaction monitoring in 2017 showed that adverse reactions(ADRs)caused by TCMI accounted for 54.6%of ADRs in traditional Chinese medicines[5,6].“The Notice on further strengthening the production,management and rational use of TCMI”has been jointly released by the Health Department,State Food and Drug Administration and State Administration of Traditional Chinese Medicine of the People’s Republic of China(SATCM)on 24th December 2008.The document sets out seven basic principles to ensure the safe clinical application of TCMI[7].Improper combination of TCMI is one of the important causes of adverse events.The injections mixing administration may change the physical and chemical environment,and directly affect the physicochemical parameters of the injections,such as clarity,particle size,pH,osmolality,the content of active ingredient,etc.[8,9].Therefore,assessing the compatibility of TCMI with in combination with other injectables is essential for the proper use of TCMI.

    Xingnaojing injection(Jemincare?,XNJ injection),is one of the TCMI approved by the SFDA[10],and was extracted by modern biotechnology from a well-known Traditional Chinese Medicine named AnGongNiuHuang Pill[11].Its main components are Moschus,Curcumae radix,Borneolum,and Gardeniae fructus[12].Modern pharmacologicalstudies have confirmed thatXNJ injection can directly act on the central nervous system through blood-brain barrier(BBB),which can effectively protect the brain,reduce brain edema and improve brain microcirculation[13].Thus,XNJ injection is widely used to treat cerebral infarction [14],consciousness disturbance[15],stroke[16],craniocerebral trauma[17],encephalitis[18],acute alcoholism and epilepsy[19].Recently,the application of XNJ injection has been increased each year due to its clinical efficacy[20].Use of XNJ injection alone or in combination with other medicines has a positive effect on patients with fever-,poison-,and stroke-induced coma[21].XNJ injection has commonly been used in combination with Edaravone injection,Deproteinized culf blood extractives injection,Ginkgo biloba extract injection,Naloxone hydrochloride injection,and Vinpocetine injection for the treatment of stroke,acute cerebral infarction,severe craniocerebral injury,alcoholism and other symptoms[22,23].However,despite the effectiveness of XNJ injection intreating some diseases,several adverse drug reactions(ADRs)of XNJ injection,including local swelling,urticaria,convulsions,phlebitis,fever,anaphylactic shock,dyspnea and arrhythmia,have been reported in clinical studies[24].At the same time,the investigation of drug compatible stability is gradually receiving attention in the clinical use of XNJ[25].The influence of the drug combinations on the stability of XNJ injection has not been systematically explored either.Due to the emergency,XNJ injection is often combined with other injectionsand used in combination,however,the problem of compatibility is still cannot be completely avoided[23,26].Thus,it is particularly important to evaluate safety of compatible stability of XNJ injection in combination with other injectables.

    In this work,we studied the compatibility of XNJ injection with 13 commonly used injectables based on the solvent of 250mL 5%glucose injection.Under the guidance of the Chinese Pharmacopoeia(2015 version),we determined the clarity,particle size,pH,osmolality,and the degradation rate of volatile components(d-borneol,camphor,and muscone).By monitoring the stability within 6 h of compatibility,the physical-chemical properties after compatibility were analyzed and the safety was evaluated.The purpose of this study is to reveal the safety hazards during the use of XNJ injection,thus provide a theoretical basis for its clinical application.

    Materials and Methods

    Materials

    XNJ injection was obtained from the Jemincare Pharmaceutical Co.,Ltd(Jiangsu,China).250mL/12.5g 5% Glucose injection(GS)was procured from Shijiazhuang No.4 Pharmaceutical Co.,Ltd(Shijiazhuang,China,).References standard of d-borneol and muscone were purchased from the National Institute for the Control of Biological and Pharmaceutical Drugs(Beijing,China).References standard of camphor was purchased from the Solarbio science technology co.,Ltd(Beijing,China).The naphthaline(IS)was purchased from the Merck(Sigma,USA).Ultrapure water was prepared by a Milli-Q system(Merck Millipore,USA).Cleanert S C18 Solid Phase Extraction waspurchased from Agela Technologies Co.,Ltd (Tianjin,China).Allother chemicals used in the experiment were of chromatographic grade.

    Preparation of compatible solutions

    According to the drug clinical application,10mL of XNJ injection was dissolved in 250 mL of 5%GS using a disposable syringe.(Note:In order to avoid a foam formation,the liquid bottle should be put down first,the mouth of the bottle is facing the operator,and then the liquid should be slowly injected into the bottle with the syringe,taking care not to expose the liquid surface of the injection needle),and then the compatible injections(Table 1)were added and mixed well,sealed with butyl rubber plug,and stored at room temperature(25°C)for different times(0h,1h,2h,4h,and 6h)for physical and chemical analysis.

    Table 1.Dosage of compatible injections

    Physical properties analysis

    The clarity,particle size,osmolality,and pH of compatible solutions were measured at 0h,1h,2h,4h,and 6h aftercombination,respectively.Anyone ofthe following conditions was judged to be incompatible:obvious appearance changes such as discoloration,bubbles,sedimentation and turbidity;particle size,osmolality and pH fluctuations.Determination of clarity

    A volume of 20 mL of compatible solutions was added into the turbidity vessel,then the turbidity was determined by the turbidimeter(HACH 2100Q,UK)at room temperature(25 ± 1°C).

    Determination of the particle size

    A volume of 1 mL of compatible solutions was added into the particle size vessel,then evaluated by the Zeta-sizer(Malvern Nano ZS,UK)at room temperature(25 ± 1°C).The mass median diameter(d 0.5)was recorded for analysis.

    Determination of osmolality

    The osmolality of compatible solutions was measured at room temperature(25 ± 1)°C after calibration of the osmometer(YASN 3250,UK)with 50 and 850 mOsm standard liquids.

    Determination of pH

    The pH of compatible solutions were assessed at room temperature(25 ± 1)°C following the calibration of the pH meter(Mettler Toledo,Switzerland)with standard liquids of pH 4.01,pH 6.86 and pH 9.18.

    Volatile chemical composition analysis

    The concentration of d-borneol,camphor,and muscone of compatible solutions were analyzed at 0h,1h,2h,4h,and 6h,respectively.The changesin volatile chemical component content<90%)was considered significant and judged to be incompatible.The relative content percentage of d-borneol,camphor and muscone were determined using the formula:

    Compatible solutions processing solid phase extraction

    The Cleanert S C18 solid phase extraction was activated by appropriate volumes (2mL) of methanol and equilibrated with water followed by compatible solutions loading of 30 mL,with the volume flow of 3.0 mL/min.A washing procedure was performed using 4 mL of ethanol into a volumetric flask(5 mL),0.5 mL of the IS solution(0.8 mg/mL)was added,and then diluted with ethanol as a sample solution for content determination.

    Preparation of mixed standard solutions and IS solution

    The stock mixed standard solutions ofd-borneol,camphor,and muscone were prepared with absolute ethanol at the concentration of 1 mg/mL,0.1 mg/mL,and 0.1 mg/mL,respectively.The concentration of IS solution was 0.8 mg/mL.All the solutions were stored at 4°C until used.

    Gas chromatographic (GC) determination of d-borneol,camphor and muscone

    D-borneol,camphor,and muscone of sample solutions were analyzed by a GC-FID system(Agilent 7980B,USA).The chromatographic separation was accomplished on a capillary column(Agilent DB-624,30 m ×0.25 mm,1.4μm).The injection port temperature was 230°C.The flame ionization detector(FID)was 250°C.The oven temperature was programmed to rise from an initial temperature of 90°C(remained for 3 min)to 150 °C at a rate of 15 °C/min and held isothermally at 150 °C for 3 min,then to rise to 230 °C at a rate of 5°C/min remained for 10 min.The flow of nitrogen was 25 mL/min.The flow of hydrogen was 40 mL/min.The flow of air was 350 mL/min.The ratio of the split was 10:1.Then 2μL of sample solutions were injected automatically.

    Method validation

    Based on the condition of GC,the sample solution(XNJ-GS),mixed standard solution,and blank(ethanol)were analyzed for the specificity.Construction of calibration curves were performed by using the mixed standard solution of d-borneol,camphor,and muscone to validate linearity of the method in the range of 20-500,2-50,2-50 μg/mL,respectively.Subsequently,linear regression equation analysis was performed with IS method.The concentration of IS was 79.4 μg/mL.The precision of intra-day was analyzed by the relative standard deviations(RSD)of the concentration level(d-borneol:200 μg/mL,camphor:20 μg/mL,muscone:20 μg/mL)on the same day.The stability study involved the stability of analytes stored at room temperature for 12 h.The reproducibility ofanalytes were analyzed by preparing sample solutions (n=6) by solid phase extraction.The reproducibility results were statistically evaluated in terms of RSD.The extraction recoveries of analytes were reckoned by contrasting the concentration ratio of analytes obtained from solid phase extraction with the actual concentration of the mixed standard solutions.

    Results

    Stability of XNJ injection in GS

    Before evaluation of compatibility stability of compatible injections,the physical and chemical stability of XNJ injection dissolved in GS were assessed by dissolving 10 mL of XNJ injection in 250mL GS.Table 2 showed that the physical properties of the solution were stable within 6 h.As shown in Figure 1,the relative content changes of camphor,d-borneol and muscone were between 95%and 105%.Thus,the physical and chemical properties of XNJ injection in GS were stable within 6 h,if the physical and chemical properties showed significant changes when XNJ injection was mixed with other injections based on the solvent of 250mL 5%GS,which must be due to the compatible injections.

    Figure 1.The relative content changes of camphor,d-borneol and muscone upon mixing of XNJ injection with GS at different time

    Table 2.The physical properties of XNJ injection was mixed with GS in different time(Mean±SD,n=3)

    Physical properties analysis

    SIMCA 14.0 software was used to conduct principal component analysis(PCA)of 13 groups of compatible solutions before and after they were placed at room temperature(6 h)with the physical property analysis indexes as variables.PC1,PC2 and PC3 were respectively used to establish the coordinate system,and the latent variables were projected on the two-dimensional or three-dimensional space to fit and analyze the PCA score diagram and load diagram of 13 groups of compatible solutions,which were respectively used to observe the sample distribution and analyze the contribution of each analysis index to the classification.The PCA score diagram of 13 groups of compatibility samples was shown in Figure 2,13 groups of compatible solution samples can be well distinguished from each other in two-dimensional and three-dimensional scoring charts.As shown in Figure 2A,according to similar principles,they are obviously divided into two categories.The samples of R and A-L group were mixed together,indicating that the physical characteristics of XNJ injection did not change significantly before and after the compatibility of the 12 groups.The distribution of samples of group M on the right was another category,which was mainly related to(d 0.5).(d 0.5)was between 225 and 233 nm when XNJ injection was mixed with Alprostadil injection based on the solvent of GS for a different time.This is due to the fact that Alprostadil injection is in emulsion form,and the formula contains ethanol as a surfactant.During the compatibility process,the volatilization of ethanolleads to insufficient co-emulsifier to reduce the interface strength,which leads to the change of particle size[9].As shown in Figure 2B,the cumulative contribution rates of principal components PC1,PC2 and PC3 reached 92.5%,which can represent most of the information of compatible solutions.According to PCA analysis,13 groups of compatible solution samples were classified into two groups according to physical characteristic index analysis,which were consistent with the experimental data.

    Figure 2.PCA score diagram of 13 groups of compatibility samples two-dimensionalA and three-dimensional B

    Method validation

    As shown in Figure 3.the spectra of gas chromatograms show that the blank doesn’t interfere with the determination of analytes and IS.Table 3 shows the calibration curves,linear ranges and correlation coefficients for analytes.Accordingly,all three calibration curvesexhibited good linearregressionsand high correlation coefficient(r>0.999).As it can be seen in Table 4,the intra-day precision of the method were 0.05%,0.22%and 0.37%for camphor,d-borneol,and muscone,respectively.And analytes remained stable for 12 h at room temperature.Sample solution processing method has good reproducibility,which was maintained within 3%.The method recoveries of camphor,d-borneol and muscone were 81.18%,92.63%and 37.29%,respectively.

    Volatile chemical composition analysis

    Figure 4-(1)and Figure 4-(2)showed the relative content changes of camphor,d-borneol,and muscone upon the combination of XNJinjection with the compatible injections based on the solvent of GS at 0h,1h,2h,4h,and 6h,respectively.The samples limited within the red lines were accepted as stable compatibility.The circled part represents a combination of significant changes in relative content within 6 h.Among them,the content of muscone was decreased by 12% at 6 h after the combination of XNJ injection and DanHong injection(Figure 4-(2)-L).The content of muscone was decreased by 19%at 6 h after the combination of XNJ injection and Alprostadil injection(Figure 4-(2)-M).The content of camphorand d-borneol wereincreased when XNJ injection combined with MS injection and VI injection(Figure 4-(1)-E and Figure 4-(1)-H).

    Figure 3.Gas chromatograms of samples

    Table 3.The linearity of camphor,d-borneol and muscone

    Table 4.The precision,reproducibility and method recovery of camphor,d-borneol and muscone(n=6,RSD(%))

    Figure 4.The relative content changes of camphor,d-borneol and muscone when XNJ injection was mixed with compatible injections at different time

    Discussion

    The change in clarity of compatible solutions is the most intuitive safety warning,indicating that the compatible stability of the XNJ injection has changed and should not be used.The change in clarity may be due to changes of pH,the solubility of the drug component,destruction of the collosol state,and oxidation or reduction of active ingredient[27].In the extraction and refining process of TCMI,due to the complex composition,some pigments,tannins,starch or proteins may be found in the form of colloids,which tend to oxidize and polymerize forming insoluble particles when used in combination with other injection and will directly affect the clarity of compatible solutions[28].These insoluble particles are responsible for ARDs.The intravenous drugs avoid the gastrointestinal barrier,and directly enter the bloodstream.The incidence and severity of ARDs are higher than other methods of administration.

    When a large number of particles enter the human body through transfusion,these particles are swallowed by macrophages,which can be enlarged to form granuloma[29].In addition,the diameter of the human capillaries is only 4~7μm[30],and the increase of the particles may cause adverse reactions such as granuloma,phlebitis and thrombosis,which is an important part of the compatible stability research.

    Reasonable osmolality of TCMI is also the safety guarantee of intravenous injection.The osmolality of normal human blood ranges from 285 to 310mOsmol/kg.When the solution is hypotonic(osmolality is lower than 150 mOsm/kg),it can cause red blood cell swelling and hemolysis,while hypertonic(osmolality is higher than 600 mOsm/kg)is prone to cause cell shrinkage and significant pain[16,30].It is generally accepted that the osmolality of 240 mOsm/kg proposed by the European pharmacopoeia for monoclonal antibodies is the minimum safety value.

    Additionally,having a pH similar to blood is an important prerequisite for TCMI to avoid pain or tissue necrosis and other side effects.We know that the normal pH of the human body is equal to 7.4,so it is required that the pH value of intravenous injection should be equal or close to that of blood[31].The pH of TCMI is generally between 4.0 and 9.0,and beyond this range will reduce its stability and increase the risk of ARDs.Fluctuations in pH can cause red blood cells to carry less oxygen and nutrients,thus reduce the efficiency of blood microcirculation and enzyme reactions and ultimately lead to immune system dysfunction[32].The acidity or alkalinity of the injection may cause pain or tissue necrosis and other side effects.Avoid alkaline solutions in particular,as alkaline injections with a higher pH are more likely to cause phlebitis[33].

    The chemicals contained in TCMI were derived from plants,animals and minerals,which had diverse chemical information and complex compound structures[34].The changeofthe principalcomponentof TCMIwas monitored according to the actual situation of compatibility.The purpose was to study the change of stability after compatibility from the perspective of chemical substance basis.

    The degradation of muscone in DanHong injection may be caused by the organic acids of para-coumaric acid,rosmarinic acid and salvianolic acid B[35].Hydroxyl radicals are highly oxidized radicals that may collide with each other to form new compounds[36].Alprostadil injection is an emulsion type injection and ethanol is used as an emulsifier to prepare nanoemulsions.It may volatilize during the process of determination,which affects the stability of nanoemulsions and results in degradation of muscone[9].These combinations may increase the solubility and permeability of camphor and d-borneol.The content of camphor and d-borneol were increased when XNJ injectionco mbined with MS injection and VI injection.The results are consistent with reports that the combination drug enhanced the blood-brain barrier permeability[37,38].

    Conclusion

    In this paper,the compatible stability of XNJ injection in combination with 13 other injectables were investigated following the Chinese Pharmacopoeia.The relative content of the main ingredients together with clarity,particle size,osmolality,and pH of compatible solutions were evaluated within 6 h of combination.According to PCA of physical-chemical properties,the change of particle size or degradation of muscone content were the main factors affecting the compatibility stability of XNJ injection,indicating that there are some problems in compatibility stability,which may be one of the causes of clinical adverse reactions.This study suggests that XNJ injection mixing with other injections during intravenous administration should be done cautiously to minimize the risk of ADRs.This study will provide a reference for the safe clinical application of XNJ injection.

    Author contributions

    Conceptualization,Dong-LiQiand Zhi-Dong Liu;methodology,Chun-Xia Liang and Dong-Li Qi;formal analysis,Chun-Xia Liang,Dong-Li Qi,Yue-Lin Zhang,Yan-Quan Gao and Yue Xing;data curation,Chun-Xia Liang,Hong-Li Yan,Bing Zhang and Jia-Rong Xie;writing—original draft preparation,Chun-Xia Liang;writing—review and editing,Dong-Li Qi and Chun-Xia Liang;supervision,Dong-Li Qi and Zhi-Dong Liu;projectad ministration,Dong-LiQi,Zhi-Dong Liu;funding acquisition,Dong-Li Qi.

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