Research Of Oral Enteric Preparation Of Panax Notoginseng Saponions

Xueshuantong injection has been widely used to treat coronary disease in clinic. In this paper, its main group that is panax notoginseng saponions (PNS) was used as model drug. The objective was to study absorption mechanism of PNS and to develop oral enteric preparation of PNS which could avoid being destroyed by stomach acid and enzymes, on the basis of principles in biopharmaceutics and pharmacokinetics.This paper fell into four parts.In partâ… , HPLC-UV (high-performance liquid chromatography-ultraviolet) method was established to analysis main saponins of PNS. The method which was sensitive, effective and repeatable can meet the requirement to the chemical and biological samples. The content percentages were 9.64%, 36.38% and 51.10% for notoginsenoside R₁ (R₁), ginsenoside Rb₁ (Rb₁) and ginsenoside Rg1 (Rg₁) in PNS, respectively. In additional, physical and chemical properties and stabilities of PNS were investigated. Octanol-water system was used to determine the apparent partition coefficients of R₁,Rb₁ and Rg₁, and the effects of pH, heat, light and humidity on stability of R₁,Rb₁ and Rg₁ were studied. Results showed that PNS was week acid in water, the apparent partition coefficient was between 1 and 2 for both of R₁ and Rb₁, but Rg₁ was between 5 and 8. All of them were sensitive to light, humidity and acid condition, and were relatively stable in normal and alkalescence condition.In partâ…¡, rat in situ intestinal perfusion model which was employed to study the absorption mechanism of PNS was established. It investigated orderly absorptive kinetics of the main components of PNS on small intestine and effects of some common absorptive promoters on the absorptive mechanism of PNS. The results clearly indicated that the concentration of PNS from 40.084 to 400.840μg·mL^-1 had no distinctive effect on the absorptive kinetics, and the main components of PNS have high solubility and low permeability. The absorption mechanism of PNS across the intestinal epithelium is mainly passive diffusion. Paracellular pathway transportation and drug flux pump may also play a part in this process. The main components of PNS have a low absolute bioavailability, as process of acrossing the intestinal epithelium limits the rate and extent of absorption. Combination of PNS with borneol or carbomer or polysorbate 80 was administered to rats by oral, in which the absorption rate of the main components was improved. It may be related to the increase of paracellular pathway transportation or the inhibition of drug flux pump.In partâ…¢, on the basis of preliminary conclusion of the absorptive mechanism and pharmacokinetics about PNS, it was chosen as drug model for investigation the preparation of process, characters of agents, release characteristics in vitro and stability of common enteric capsules, enteric microcapsules (capsule) and enteric micropellets (capsule). Three samples of enteric capsules of PNS were produced respectively by the optimized prescription. The f₂ factor analysis showed that the reproducibility of release degree of the three samples was stable, and there was no significant difference among R₁, Rb₁ and Rg₁ that only one group that Rg₁ was selected finally needed to be controlled. The release data were intended to be single index model, Weibull model, Higuchi model, Ritger-Peppas model, zero levels release model, first levels release model, Hixcon Crowell model and Niebergull model. The best model of common enteric capsules, enteric microcapsules (capsule) and enteric micropellets (capsule) were Hixcon Crowell model, Weibull model and Weibull model respectively. Referred to appendix of Ch.P. 20₁0(â…¡)"drug stability in the guidelines", the stabilities of enteric capsules of PNS were studied elementarily. The results suggested that the shape of enteric capsules were still complete and the color of contents had no changes. Release degree, the content and water content all conformed to the requirements.In partâ…£, pharmacokinetics and bioavailability of PNS in rat and its enteric capsules in Beagle dog were investigated. This part was designed to develop a novel integrated pharmacokinetic approach to assess the holistic pharmacokinetic properties of traditional Chinese medicines (TCM). After calculating pharmacokinetic parameters of R₁, Rb₁ and Rg₁, a novel approach of self-defined weight coefficient based on the area under the curve from zero to infinity (AUC_{0→∞}) has been created to obtain the holistic pharmacokinetic profiles of PNS. The integrated pharmacokinetic parameters of PNS were then calculated. This study would be useful for guiding the holistic pharmacokinetic study in consistence with the intrinsic theory and characteristics of TCM. A novel integrated pharmacokinetic thought and approach to describe the holistic pharmacokinetic properties of TCM has been successfully developed. The results suggested that after intragastric and intravenous administration of PNS, the concentration-time curve of R₁, Rb₁ and Rg₁ belonged to two compartment model, the absolute bioavailability was 1.76%, 0.78% and 2.44% respectively after correction. Study on pharmacokinetics and bioavailability of PNS enteric capsules in comparison with Xueshuantong injection and Xueshuantong capsule showed significant differences of single dosage. Bioavailabilities of PNS enteric capsules are 1.08⁵.71 times as Xueshuantong capsule and MRT is longer. Moreover absolute bioavailability is improved. Evaluation on in vivo-in vitro correlation of the PNS enteric capsules according to Wagner-Nelson (W-N) method proved different correlation results. The reason is possible that the absorption process of PNS is not only passive diffusion but also active transport. The result in vivo further proved exact effects of enteric capsules as we anticipated.According to principles of biopharmaceutics and pharmacokinetics, we based preparation research on the absorption kinetics of PNS in stomach and intestine that reduced blindness of preparation development. The study provides references for other formulation of PNS in process, quality evaluation, stability, pharmacokinetics in vivo, and so on.