| DL1502 is a monomeric compound extracted from Polygonaceae Chinese herbal medicine plant,which has a significant anti-inflammatory pharmacological effects.But oral administration of it would cause the side effects of diarrhea,which led to the DL1502 impossibile be a drug and qiut from drug market.By converting the crystal form of the drug and the mode of administration,it may it may be possible to reduce or eliminate side effects on the basis of efficacy.In this paper,the graininess size,equilibrium solubility of DL1502 polymorph and the suspension of DL1502 and 1% hyaluronic acid were tested,and a further study was made to investigate the pharmacokinetics of SD rats in vivo,and obtain the F crystal form which has the advantage of in vivo absorption.At the last,the pharmacological effects of DL1502 F crystal form in oral and injection administration on osteoarthritis were studied.The results showed that the difference of crystal form change the solubility of the drug,mode of oral and injection administration of DL1502 were both effective in the treatment of knee osteoarthritis in rats.1.Detection of the particle size of DL1502 polymorphicChanges in the crystal form may cause difference of the physical and chemical properties of the compound,in which the particle size is an important indicator.This chapter examines the particle size of DL1502 compounds with different crystal forms.The results show that the new crystal forms have significantly difference in particle size.2.The balance solubility of DL1502 polymorphic in waterThe crystal form of the drug has a significant effect on the stability and solubility,which are important factors affecting on the quality and efficacy of the drug.Therefore,the study on the physical and chemical properties of the drug polycrystalline is also wery important.In this chapter,the five new crystalline DL1502 were dissolved in purified water at 37 ? and p H 7.24.The balance solubility of water in each crystal was detected by HPLC-DAD method.The results showed that the size of the granules was positively correlated with the dissolution rate and the equilibrium solubility,and the crystal with the smallest particle size has the greatest dissolution rate and the maximum of dissolved concentration.3.Quality standard testing of DL1502 and hyaluronic acid suspension injectionIn this chapter,the five new crystals DL1502 were dissolved in 1% hyaluronic acid to prepare a suspension with a concentrations of 0.125,0.25,0.5,1.0,2.0 mg·m L-1.We examined the absorbance of these five crystals at different concentrations,the standard curve,the precision of the instrument,the precision of the method and the stability of the method were calculated.The dispersibility of the dissolved drug particles was observed by the naked eye,which did as a preliminary study on the quality control of injections.The results showed a good linear relationship,accurate and reliable,and the precision of the method was good in the range of 0.125 ~ 2 mg·m L-1.The precision of the instrument,the precision of the method and the stability in 72 h is good.It has a guiding role in the quality control of the manufacture of suspension injection preparations.4.The study of Pharmacokinetics of DL1502 PolymorphicIn this chapter,a HPLC-DAD method was used to detect the differences of pharmacokinetic of DL1502 in SD rats.The Cmax of the DL1502 crystals were 1.05 ± 1.44 ?g · m L-1,2.77 ± 1.17 ?g · m L-1,3.97 ± 0.54 ?g · m L-1,7.45 ± 4.49 ?g · m L-1 and 5.89 ± 3.56 ?g · m L-1,after solid administrate of DL1502 crystals C,D,E,F and Y(100 mg· kg-1).The AUC(0-t)of the five crystal form drugs was 34.10 ± 14.85 ?g · h · m L-1,18.34 ± 10.51 ?g · h · m L-1,15.49 ± 8.26 ?g · h · m L-1,61.07 ± 36.43 ?g ·h · m L-1 and 16.01 ± 8.39 ?g · h · m L-1.The results showed that the peak concentration of Cmax and the area under the curve AUC(0-t)of the DL1502 compound F crystal were significantly better than those of other crystals,which indicated that the absorption of crystal F in rats was superior in the DL1502 the C,D,E,F,Y(mixed crystal)crystal,is the dominant crystal.5.Study on the characteristics of the anti-osteoarthritis polymorphic drugs DL1502In this chapter,a rat model of knee osteoarthritis was established by classical intraarticular injection(4% papain)method.Scoring the spontaneous activities,the pain threshold,the gait of the rats.The diameter of the knee was measured to determine the degree of swelling.The effect of joint space narrow of osteoarthritis was evaluated by X-Ray plain film to determine the cartilage wear,thinning situation.After the success of modeling,administration for two weeks,test the above indicators once again,to evaluation the pharmacological effects.And at the same time,the establishment of injection group,to study the DL1502 directly to the lesion injection of drug efficacy.The results showed that compared with the normal group,the pain threshold of the knee joint in the model group was significantly lower(P<0.05),while the oral administration group and the injection group of F crystal type DL1502 could significantly improve the symptoms of joint tenderness(P <0.05).The group of F-type DL1502 on the dose of 1.125 and 4.5 mg·kg-1 and the method of injection can significantly reduce the swelling caused by osteoarthritis(P < 0.0001? P < 0.0001 ? P < 0.05).The result of X-Ray plain film showed that F-type DL1502 oral dose group could significantly improve the degree of joint space narrow caused by osteoarthritis,and the effect of high-dose group was better than that of low-dose group.As same as the DL1502 drug injection group.In this chapter,the rat knee osteoarthritis model was established by the classical drug injection method,and the therapeutic effect of DL1502 F crystal on osteoarthritis model was evaluated.The results showed that DL1502 had a good protective effect on the knee joint osteoarthritis caused by knee osteoarthritis,and had the effect of swelling and pain caused by osteoarthritis.Injection of DL1502 for the above symptoms,also has a significant pharmacological effect. |
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