| Polymorphous sunlight eruption(PLME)is the light-sensitive skin disease with the highest prevalence rate,accounting for about 60%of light-sensitive skin disease,and the incidence rate reaches 10%-20%in temperate regions.The specific pathogenesis is not fully understood,so there is no effective treatment in clinical practice.In addition to light therapy,the current clinical treatment method of PLME is drug therapy,the drugs used mainly include glucocorticoids,hydroxychloroquine,non-steroidal anti-inflammatory drugs,antihistamines and immune suppressants.However,these drugs have different degrees of side effects on the body.For example,glucocorticoids can aggravate the glaucoma and mental diseases,and induce and aggravate infections.Hydroxychloroquine is easy to cause retinal pigmentation and visual field defect.Non-steroidal anti-inflammatory drugs have liver damage,kidney damage,gastric ulcer and other problems.Antihistamines have obvious central neurotoxicity and cardiotoxicity,and long-term use of immunosuppressants is carcinogenic.Therefore,it indicates that there is an urgent need for a high effective and low toxicity drug to treat of PLME.Dihydroartemisinin,as a first-line antimalarial drug,has the advantages of quick effect,high efficiency and low toxicity.It also has a good therapeutic effect on systemic lupus erythematosus.In view of the current weak research and development of new molecular entities,dihydroartemisinin has a huge research and development potential.According to reports and preliminary test results of our team,it was found that dihydroartemisinin had a good therapeutic effect on PLME.In this study,taking dihydroartemisinin as the research object,by investigating the equilibrium solubility,apparent oil-water partition coefficient,influencing factors of stability,gastrointestinal absorption characteristics of normal rats,and the preparation process and evaluation method,a safe and effective dihydroartemisinin gastric retention sustained-release preparation was developed,which is expected to be an effective treatment drug for PLME.ObjectiveTo prepare dihydroartemisinin gastric retention sustained-release tablets in order to provide a safe and effective preparation for the treatment of PLME.Methods1.Research on physicochemical properties and factors affecting the stability:The UPLC for the determination of dihydroartemisinin in different solvents was established and verified.The stability and equilibrium solubility of dihydroartemisinin in aqueous solutions with different pH values were investigated.Shake-flask method was employed to determine the oil-water partition coefficient of dihydroartemisinin in different media.Taking the contents of dihydroartemisinin and diketo aldehyde as indicators,the effects of high temperature,high humidity and strong light on the stability of dihydroartemisinin were investigated with the dihydroartemisinin placed under the conditions of high temperature at 40?±1?,high humidity with RH 92.5%±0.5%,and strong light with 4500 Lux±500 Lux,respectively.2.In situ intestinal absorption test of normal rats:Experimental model of in situ single-pass intestinal perfusion and in situ gastric perfusion model of rats were used to investigate the absorption parameters of dihydroartemisinin with different mass concentrations in the rat stomach,duodenum,jejunum and ileum.The concentration of dihydroartemisinin before and after perfusion was determined by UPLC and the change of water volume in intestine corrected by weight method.Verapamil hydrochloride,a P-glycoprotein inhibitor,was added to the intestinal perfusate to compare changes in the absorption parameters of dihydroartemisinin,and to further study whether dihydroartemisinin is the substrate of P-glycoprotein.3.Preparation of sustained-release tablets:UPLC was used to determine the contents of dihydroartemisinin and diketo aldehyde,the compatibility of dihydroartemisinin with different excipients was investigated under the conditions of high temperature,high humidity and strong light.Taking in vitro release rate of the sustained-release tablets as the main index,the effects of specification and dosage of hydroxypropyl methylcellulose,dosage of stearyl alcohol,species and dosage of fillers,species and dosage of disintegrants,dosage of lubricants and preparation technology on the in vitro release rate of dihydroartemisinin were studied.Based on the above results,the formulation and preparation process of dihydroartemisinin sustained-release tablets were determined,and in vitro dissolution of dihydroartemisinin conventional tablets and sustained-release tablets were investigated and compared.Results1.Study on factors affecting physicochemical properties and stability:The equilibrium solubility of dihydroartemisinin in aqueous solutions containing 3.5%SDS with different pH was in the range of 1.61?2.56mg,scarcely solbluted in water,and it showed that its solubility was low,while the 1gP in n-octanol solution system with different pH was in the range of 0.8-1.50,it indicated that its had good liposolubility.Dihydroartemisinin degraded rapidly in aqueous solutions with pH<1.5,and it was basically undetectable above pH of 6.8,while it was relatively stable in the solution with pH of 3-5.The contents of dihydroartemisinin in high temperature environment were 90.25%and 83.22%on the 5th and 10th day,and the contents of diketo aldehyde increased to more than 2%with poor stability,indicating its poor stability.The moisture absorption rate and the contents of diketo aldehyde of dihydroartemisinin in high humidity environment were lower than 0.1%and 0.4%,respectively,which showed good stability.The content of dihydroartemisinin in the strong light environment was basically unchanged,and the contents of diketo aldehyde increased to 0.23%and 1.07%on the 5th and 10th day,respectively,indicating that the stability of dihydroartemisinin was affected by the strong light irradiation.2.In situ gastrointestinal absorption test of dihydroartemisinin in rats:In the concentration range of 0.032-0.128 mg·mL-1,there was no significant difference of the absorption constant(Ka)and the effective permeability coefficient(Peff)of dihydroartemisinin in the same intestinal segment,the Peff was greater than 1.2×10-3,indicating that the absorption of dihydroartemisinin in the whole intestinal segment was complete and not affected by the drug concentration.At the same concentration,Ka and Peff of dihydroartemisinin in duodenum were significantly higher than those of other intestinal segments(P<0.05),there was no significant difference between jejunum and ileum,and the order of Peff was duodenum>jejunum?zileum.The absorption rate per hour of dihydroartemisinin in rat stomach was more than 40%,which was significantly higher than that in small intestine(P<0.05).Before and after the addition of verapamil hydrochloride,there was no significant difference in Ka,Peff and absorption percentage of dihydroartemisinin in the small intestine,suggesting that dihydroartemisinin was not the substrate of P-glycoprotein.3.Preparation of the sustained release tablets:In the study of the compatibility of dihydroartemisinin with tablet excipients,all excipients had good compatibility with dihydroartemisinin except for poloxamer under the high humidity conditions.Lactose,microcrystalline cellulose,pre-gelatinized starch,?-cyclodextrin,sodium carboxymethyl starch and ethyl cellulose can slow down the decrease of dihydroartemisinin content and the increase of diketo aldehyde.The optimal formulation was 40 mg of dihydroartemisinin,24 mg of HPMC-K4M,14 mg of octadecanol,26 mg of sodium bicarbonate,57 mg of lactose,19 mg of microcrystalline cellulose,6 mg of sodium dodecyl sulfate,6 mg of magnesium stearate,5.3 mg of cross-linked povidone and 2.7 mg of cross-linked carboxymethyl cellulose sodium.The weight of each tablet was 0.2 g.In the preparation process,the pressure of 30 kg was used for dry granulation,and the hardness of the sustained-release tablets was controlled at 30-35 N.The cumulative release rate of the optimal formulation reached 75%in 10 hours,which met the requirements for in vitro release of the sustained-release preparations.Compared with the conventional tablets,the release of dihydroartemisinin sustained-release tablets was slow and persistent with no obvious peak-valley phenomenon and ideal sustained release effect.ConclusionIn this study,the physicochemical properties of dihydroartemisinin,the influencing factors of its stability and its absorption in the gastrointestinal tract of rats were studied.Through the optimization of the formulation and preparation process,dihydroartemisinin gastric retention sustained-release preparation is prepared.It is safe,effective and convenient to take,which is expected to be an effective treatment drug for PLME. |
PDF Full Text Request