| [Background]In2000, the world health organization officially defined the "pain" become the fifth vital signs after breathing, temperature, plus and blood pressure. People pay more attention to the knowledge of pain. At the present there are no large-scale and multi-center epidemiologic data on pain in China, but it is the main reason for patient to the hospital.The current treatment of pian is still in the initial stage. The means of pain management is single, and the drug therapy is the controllable analgesia, how to improve pain treatment has been an important issue which people from different fields commonly cares.Along with the study of traditional Chinese medicine and modern pharmacology, it is found that much Chinese herbal medicine has obvious analgesic effect of various pain, definite effect of analgesia. At the same time it has no obvious addition, tolerance and side effect, etc. It become the hot pot of analgesic drug research.Panax notoginseng(Burk.)F. H. Chen(Araliaceae), a well-known traditional Chinese medical plant, is commonly used for treatment of all kinds of diseases for a long time. Phytochemical and pharmacological studies on panax notoginseng, it keeps the functions of astrictive action, enriching blood, protecting cardiac muscle, anti-atherosclerosis, protecting brain tissues, cardiovascular protection, cranial nerve nutrition, improving memory, immune regulation, analgesia, sedative effect,antinflammation, antiaging and so on. Some notoginseng preparations were widely applied in clinic in recent years, such as Xuesaitong injection, yunnan baiyao powde, Capsula Mollis of LTPI, Xuesaitong, lulutong injection.Transdermal drug delivery system(TDDS) is one type of the drug adminstrations that drug gets into blood circulation by the absorption of skin and reaches effective blood level for the purpose of preventing disease and therapy.The fundamental type of TDDS are membrance-moderated type, adhensive-dispersion type, matrix-diffusion type and microreservoir type.TDDS is a new type of the drug adminstrations, it presents mainly the features as followings:First, GI degradation and first-pass effect could be avoided after transdermal delivery. Second, because of sustained-release effect, administered frequency could be decreased.Third, achieve a long period of drug release and maintain an adequate blood concentration. Fourth, reduce the drugs on the gastrointestinal tract irritation, so as to enhance drug compliance in patients, promote rational drug application.Chemical methods and physical methods can be considered to promote skin permeability of drugs, azone, dimethylsulfoxide, dimethylformamide, dimethylaceta-mide are the most common penetration enhancers. The physical methods are iontophoresis, electroporation, sonophoresis,laser, magnetophoresis,thermal phoresis.Cream is one of the transdermal preparation, and made of emulsifying agent. It plays an important role in protecting wounds, lubricating skin. Cream is stable and show a good solubility, easy to use for clinical. Due to its advantages, more and more pharmaceutical raw materials were used to prepare cream.[Objective]To confirm the prescription and the preparation process of panax notoginseng cream, and examine its stability. Applying HPLC method to study on the determination of notoginsenoside Ri, ginsenoside Rg1, Rb1and Rd in panax notoginseng cream, and to investigate the ability of percutaneous penetration of Panax Notoginseng cream.[Methods]1、The study on screening the prescription and the preparation process of panax notoginseng cream.We prepared panax notoginseng cream with the carrier of O/W emulsion matrix and panax notoginseng as the model drug. To screen the materials and its amount by appearance, centrifugal experiment, low-high temperature experiment, speed up experiment and the long-term experiment, containing oil phrase, water phrase and emulsifier. To optimize the best preparation process of cream by emulsifying way, emulsifying temperature and ways of adding drugs.2、The study on the stability of panax notoginseng cream.According to the relevant requirement of Chinese Pharmacopoeia, we observed the stability of panax notoginseng cream. The observation items are centrifugal experiment, low-high temperature experiment, speed up experiment and the long-term experiment.3、To establish method for study on the percutaneous penetration and determination of panax notoginseng.The preparation of the reference solution:Dissolve2.47mg of notoginsen-oside R1,2.51mg of ginsenoside Rg1,2.48mg of ginsenoside Rb1and2.50mg of Rd in25%methanol, and dilute with25%methanol to10ml.Establish standard curve:Pipette0,1,2,3,4,5mL each of reference solution in25%methanol, and dilute with25%methanol to10ml, and then sample10μL each time. The standard curve was establish by concentration as X-axis and peak area as Y-axis.Precision experiments:The standard solution sample6times, each time10μL. The RSD was computed using peak area. Stability experiment:The test solution sample in1,2,4,6,8,10,12,14h, each time10μL. The RSD was computed using peak area.Recovery experiments:Put the standard substance into the pre-weighed test sample, and calculate the RSD.4、The study on in vitro transdermal experiments.Improved Franz type diffusion cells were used in vitro permeation studies, and nude mouse skin were employed as transdermal barrier. The concentration of notoginsenoside R1, ginsenoside Rg1, Rb1and Rd in the receptor solution was determined by HPLC to investigate the cumulative permeation quantities at different time respectively. Under the condition:an effective area of2.92cm2, the volume of7ml, temperature of32℃±0.5, rotating speed of200r-min-1, and the receive solution ethanol to normal saline=3:7(V:V), it was found that the result was stable.[Result]1、The preparation of panax notoginseng cream.The best preparation:Span-801g, tween-804g, as the emulsifier. Stearic acid5g, glyceryl monostearate4g, white vaseline3g, liquid paraffin10g, as oil phrase, glycerin10g, water61.8g, as water phrase, ethyl hydroxy benzoate0.2g, as the preservative. The best preparation process:The drug added to water, the emulsifier added to the oil and water phrase, emulsifying temperature85℃, emulsifying speed1000rpm, emulsifying time15min.2、The study on the stability of panax notoginseng cream.The appearance didn’t change significantly and was in a line relevant provisions of the Chinese Pharmacopoeia.3、Method for study on the percutaneous penetration and determination of panax notoginseng.Chromatographic condition:This assay was performed on Thermo C18column (250mm×4.6mm,5μm) with acetonitrilewater as mobile phase in gradient elution at a flow rate of1.0mL/min. The detection wavelength was at203nm. The regression equation of R1, Rg1, Rb1and Rd were:Y=0.1079X-2.636(0.9999), Y=0.1129X-2.774(0.9997), Y=0.1082X-2.657(0.9997), Y=0.1120X-2.792(0.9999).It showed a good linear relationship in the range of24.7～123.5μg·mL-1for R1,25.1～125.5μg-mL-1for Rg1,24.8～124.0μg/mL-1for Rb1, and25.0-125.0μg-mL-1for Rd.Precision experiments:The RSD of R1,Rg1, Rb1and Rd were1.71%,1.65%,1.87%,0.82%. The method showed a good precision.Stability experiment:The RSD of R1, Rg1, Rb1and Rd were1.53%,1.24%,2.18%,0.92%. It showed that panax notoginseng was stable in14hours.Recovery experiments:The average recovery of R1, Rg1, Rb1and Rd were96.67%,99.30%,96.87%,98.23%. And RSD were2.62%,1.83%,1.93%,2.13%.4、The effects of Ri, Rgi, Rb1and Rd on the transdermal penetration Higuchi equations of R1, Rgi, Rbi and Rd were:Qn=4.83t+40.23,Qn=8.15t+51.56, Qn=5.02t+39.42,Qn=4.68t+41.35. Js were4.83μg·cm-2·h-1,8.15μg-cm·h-1,5.02μg·cm-2·h-1,4.68μg·cm-2·h-1. The percutaneous penetration of notoginseng cream conformed to the zero kinetic equation.[Conclusion]The formulation of panax notoginseng is reasonable and the preparation process is feasible, the stability and good transdermal characteristics of cream can meet the industrial production needs. The HPLC method is simple, sencitive and accurate with a good reproducibility, which is suitable for analysis of panax notoginseng in vitro transdermal penetration. The percutaneous penetration of notoginseng cream conformed to the zero kinetic equation. The research will provide experimental data for skin administration of panax notoginseng. |
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