Study On The Pharmacokinetics Of APIC In Animals And Preparation Of APIC Solid Dispersion Enteric-coated Capsules

This paper summarizes the pharmacokinetics of the crude drug of Angelica sinensis polysaccharide-iron complex (APIC) in vivo in animals, and preparation of the APIC solid dispersion enteric-coated capsules based on the absorption characteristic in vivo and dissolution characteristic in vitro of APIC. The main contents of the paper were consisted of three parts: the study of the pharmacokinetics of the crude drug of APIC on rats and dogs in vivo; the absorption characteristic in vivo of Angelica sinensis polysaccharide on mice; the preparation of APIC solid dispersion enteric-coated capsules.Part I Study on the Pharmacokinetics of Angelica Sinensis(Oliv.)Diels Polysaccharide-iron Complex in Rats and DogsTo study the pharmacokinetics of Angelica Sinensis(Oliv.)Diels Polysaccharide-iron Complex(APIC) in rats and dogs. SD rats and Beagle dogs were divided into groups at random,and then administrated with APIC low dose,medium dose,and high dose respectively. The plasma of dogs and whole blood of rats were collected in sequential time after a single oral dose as well as before dosing. APIC in plasma and whole blood were measured by atomic absorption spectrophotometry, and pharmacokinetic parameters were calculated with DAS2.0 software package. The tissues distribution of APIC in rats was studied as well.The results showed that the pharmacokinetic process of APIC in rats fitted one compartment model. AUC0～24 and Cmax were not in proportion to the dosage and Tmax was independent of the dosage either. After a single of 12.5 mg·kg -1 APIC to rats, drug was rapidly and extensively distributed to all tissues, especially in liver, spleen and lung. The pharmacokinetic process of APIC in dogs fitted two compartment model. After a single dose administration, the AUC0-24 for medium dose group, low dose group was (11.646±1.479,11.095±1.543) mg·h·L-1,respectively, which were remarkable higher than that of high dose group and control group which were (2.484±1.157) mg·h·L-1,(4.524±0.641 ) mg·h·L-1,respectively. The conclusion showed that there was remarkable difference in pharmacokinetic profiles between rats and dogs . The AUC0-24 for medium dose group and low dose group are larger than the AUC0-24 for high dose group and control group.Part II Study on the Absorption Characteristic in Vivo of Angelica Sinensis Polysaccharide in AnimalsThe absorption characteristic of Angelica sinensis polysaccharide in vivo in animals was studied by the GOD method and pharmacodynamics effect method respectively. The results of the GOD method which indicating there was no significant difference between the changes of the blood sugar of APIC group and those of negative control group showed the GOD method can not be used in the study of the absorption characteristic of Angelica sinensis polysaccharide in vivo in animals. The Smolen method, one of the pharmacodynamics effect methods, was used to study the pharmacokinetics of Angelica sinensis polysaccharide in anemia mice, taking Hb as index. The minimum effective dose of APIC group and ASP group was 52.12 mg·kg-1 and 7.38 mg·kg-1 respectively. The equivalence of the minimum effective dose between APIC group and ASP group showed that the Angelica sinensis polysaccharide was the mainly effective compound which improving the Hb of the anemia mice. The maximum of the curve(299.78 mg·kg-1) and AUC(0-∞)( 3764.135 mg·L-1h-1) of APIC group were much higher than that of ASP group(211.58 mg·kg-1,1746.958 mg·L-1h-1). The results indicated that for the two mechanism of the treatment effect of APIC on anemia mice, it showed more powerful effect in improving Hb in anemia mice than that of ASP. The MRT of APIC and ASP in mice was 20.895h and 13.726h respectively. It was also showed that pharmacodynamics effect method was more feasible than GOD method in the study of absorption characteristic of Angelica sinensis polysaccharide in vivo in animals. PartⅢPreparation of APIC Solid Dispersion Enteric-coated CapsulesTo improve the dissolution rate and bioavailability of APIC in duodenum, we prepared APIC solid dispersion enteric-coated capsules with modern preparation technology. Considering the clinical need and advantage of dispersing technology of solid, Eurdgit L100 was regarded as carriers and HPMC was regarded as releasing controller and Vcaps was regarded as loric, solid dispersion was prepared by freeze drying method. DSC and IR technology were used to test the dispersed state of APIC. In addition, we determined the dissolution rate of APIC in artificial gastric juice and artificial intestinal juice respectively, making Niferex as the reference preparation. The results showed there was significant difference in the DSC and IR diagram between the APIC solid dispersions and the simple mixture of APIC and adjuvant, which indicats the APIC exists within the molecular state mainly in solid dispersion. The results of the dissolution test in vitro showed APIC solid dispersions dissolution rate was 40% in artificial gastric juice within 6h, and 80% in artificial intestinal juice within 5min. From above we can see, APIC solid dispersions capsules have a good dissolution rate in artificial intestinal juice and sustained released in artificial gastric juice, which means APIC solid dispersion capsule is a successful enteric-coated capsule.