| Malaria is a global infectious diseases spread by mosquitoes,which is a serious harm to human health.Together with AIDS and tuberculosis.Malaria was regarded as one of the world’s urgently-needed control of the three public health issues by the World Health Organization,which are widely popular in Asia.Africa and 107 countries or regions of Latin America.Many drugs can be used to treat Malaria,but some resistance occour inevitably,because they have been used of a long time in the development of new antimalarial drugs,the compound preparation of original drug is an effective method for the treatment of malaria,the combination of artemether and Lumefantrine compound preparation,as the World Health Organization recommended.,has played a huge role in the treatment of malaria.However,artemether andLumefantrine have poor solubility in water and have low bioavailability,so it is necessary to increase their water solubility so as to improve bioavailability,thereby reducing the dosage and side effects.In this paper,the problems of the Artemisin/Lumefantrine tablets were studied in the production of enterprises.Then artemether was used to prepare the inclusion complex and Lumefantrine to prepare nano-lipid carrier to improve the solubility and bioavailability of artemether and Lumefantrine,animal experiments were performed to verify the improvement of solubility and bioavailability of compound Artemether/Lumefantrine.This paper provide a basis for the development of new formulations.1.Prescription Artemether/Lumefantrine tablets of the prescription process improvementAt present,the main problems of "compound Artemether/Lumefantrine tablets"in enterprises are:poor pressure,sticky red,disintegration time is long andlow dissolution.The Artemether and Lumefantrine were granulated and compressed tablet separately todetermine the cause of sticking.The disintegration time,friability and stickiness were used as evaluation indexes.lactose,mannitol,MCC,the mixture of lactose and MCC were selected as filler to adjust Pressure difference problem by changing the composition and the proportion of the prescription;the use of thin film method to change the granulation process to solve the sticky production process in the sticky problem;to ensure that the film hardness and fragility qualified at the same time,the tablet pressure was reduced,L-HPC,CMS-Na and PVPP were used as the disintegrating agent to adjust the disintegration time and dissolution of the tablet by adjusting the type,dosage and adding method The results showed that the method is simple and effective,which is convenient for mass production.MCC was selected as the best filler.The HPMC E50 solution was selected as the adhesive,and 3%HPMC E50 solution was used as the binder to solve the sticky problem.L-HPC and PVPP were used as the disintegration by adding 75%and 25%,tablet thickness was 2.7mm andtablet speed was 15rpm.The tablets,appearance,content,content uniformity and fragility of the tablets prepared by the three batches of reproducibility tests all meet the requirements.The dissolution rate of the compound artemether and Lumefantrine tablets was improved,but the dissolution of artemether was still slow and much surfactant were added to the dissolution medium.to meet the dissolution requirements of Lumefantrine which is quite different with the in-vivo environment,therefore,finding a new method to improve the solubility and bioavailability of artemether and Lumefantrine,is very important.2.Artemether-2-HP-β-CD inclusion complexBe aimed at the structure and physicochemical properties of artemether,2-HP-β-CD was selected as carrier to increase the solubility.(1)The derivatized reaction of artemether with 1mol/L hydrochloric acid was carried out,and the content of artemether in inclusion compound was determined by UV method.(2)The inclusion complex of artemether was prepared by solution stirring method,.Feed ratio.the stirring time and the stirring temperature were investigated respectively.The prescription process factors were optimized by the drug loading and inclusion rate as the evaluation index,the stability of the prescription was determined by the reproducibility test.;(3)The inclusion complexes were validated by infrared spectroscopy,differential scanning calorimetry,solubility test and melting point method,and the stability of the inclusion complex was also investigated.(4)Method for the determination of the concentration of plasma samples by HPLC Artemether was established and conducted methodological investigation,taking rats as the research object,were taken Artemether API and clathrate by intragastric administration respectively.Blood samples(approximately 0.5 ml)were collected from the jugular sinusat at 0.25,0.5.0.75,1.0.2.0,3.0,4.0,6.0 and 8.0 h post-dosing.The diagrams with time and plasma drug concentration of ARM were drawn.DAS2.0 software was used to calculate the related pharmacokinetic parameters,and the in vivo release of the drug substance and the inclusion compound were analyzed and compared.The results show that:(1)The method of the determination of artemether by UV method is feasible.Artemether derivative in 1mol/L hydrochloric acid solution,the linear relationship is good,precision,high recovery,accessories do not interfere with the determination of ARM.The enamel inclusion complexes were prepared by grinding method,solution stirring method and ultrasonic method respectively.Finally,choose solution stirring method.The mixing ratio was 1:36.the stirring temperature was 50℃,the stirring time was 1h.and the three batches were reproduced.The results showed that the drugloading and inclusion rate of the inclusion compound as 2.63%±0.01%and 97.53%±0.36%,respectively.The method was simple and reproducible.(2)The results of infrared spectroscopy showed that the infrared spectrum of the inclusion complex was basically the same as that of the 2-HP-β-CD.and the map of the physical mixture of artemether and 2-HP-β-CD was slightly different.The results of differential scanning calorimetry show the endothermic and exothermic peaks of the drug in the inclusion compound,indicating that the problem is dissipated with the physical mixture.The solubility test results show that the solubility of artemether inclusion complex was 11.28±2.24mg/ml,which was significantly higher than that of the raw material in the water solubility of I.I8μg/ml.The melting point of artemether inclusion complex was determined by capillary method.226-229℃,the melting point of artemether is 86-89℃ and the melting point of 2-HP-β-CD is 278℃.The melting point of artemether inclusion compound is obviously different from that of API and carrier material.The above four verification methods have shown that the inclusion complex has been formed.(3)The stability of the experimental results show that under high temperature and light conditions,the inclusion compound in the drug content decreased less,high humidity conditions,the decline in drug content decreased the number of large,with a strong wet,The preparation of storage,should be sealed moisture preservation.(4)The concentration of Artemether in plasma samples was determined by high performance liquid chromatography.The specificity was linear and the linearity was good..the precision and stability were in accordance with the determination requirements.The endogenous components did not interfere with the determination of the main drugs and meet the requirements of the biological sample measurement.The results showed that the elimination half-life(t1/2z)of the drug group and the inclusion group was 2.73h and 1.80h respectively,and the average residence time(MRT0-∞)was 3.94h and 3.72h respectively.Cmax were 4.19μg/ml and 8.86μg/ml.respectively.The area under the blood concentration-time curve(AUC0-∞)was 25.55μg/mL h and 36.88μg/mL·h,the plasma AUC0-∞ of inclusion group is 1.44 times of the drug group.After Artemether prepared into the inclusion compounds,absorbed faster and taken effect more quickly.3.Study onLumefantrine loaded NLCThe nanostructured lipid carrier(NLC)was used to increase the solubility of benflurine.(1)The content ofLumefantrine was determined by UV and the methodology was investigated.(2)Lumefantrine loaded NLC was prepared by ultrasonic dispersion method.Then,the prescription and process was studied with particle size,entrapment efficiency and drug loading as evaluation indexes by single-factor test.The factors of prescription included ratio of drug to lipid.ratio of liquid lipid to solid lipid and ratio of phase volume.The factors of process involved dropping speed,emulsifying time and stirring time.The reproducibility test was performed to verify the stability of the prescription and process.(3)The lyophilized powder ofLumefantrine loaded NLC was prepared by freeze-drying technique.The content of mannitol was screened with particle size and entrapment efficiency as the evaluation index.(4)The stability ofbenflumetol NLC was investigated.(5)Method for the determination of the concentration of plasma samples by HPLC Lumefantrine was established and conducted methodological investigation.taking rats as the research object,were taken Lumefantrine API and clathrate by intragastric administration respectively.Blood samples(approximately 0.5 ml)were collected from the jugular sinusat at 0.5,2.0.5.0.8.0.24.0,30.0.48.0.54.0,72.0 and 120.Oh post-dosing.The diagrams with time and plasma drug concentration of LUF were drawn.DAS2.0 software was used to calculate the related pharmacokinetic parameters,and the in vivo release of the drug substance and the NLC were analyzed and compared.The results showed that:(1)with good linearity,high precision and recovery rate,the UV method could be used for the determination ofLumefantrine content.Moreover,the excipient did not interfere with the determination of the main drug.(2)TheLumefantrine loaded NLC was prepared by melt-emulsification-low temperature curing method,ultrasonic dispersion method and high pressure homogenization method,respectively.Finally,ultrasonic dispersion method was applied to prepare NLC.In addition,the optimal prescription was as follows:the ratio of drug to lipid was 1:8.the ratio of liquid lipid to solid lipid and ratio of phase volume were 1:3 and 1:4,respectively.The concentration of poloxamer 188 was 0.50%.The optimum technology conditions were as follows:the dropping speed and stirring speed were 12ml/h and 1000rpm,respectively.The emulsification time and ultrasonic time were 40min and 15min,respectively.Three batches of samples were prepared according to the optimal prescription and process.The TEM photograph showed that they were uniformly spherical with a size of 213.30±8.54 nm.The pH was 6.43±0.19.the encapsulation efficiency and drug loading were 94.90±0.51%and 9.05±0.19%,respectively.Therefore,the prescription and process had good stability and reproducibility.(3)In the preparation process of NLC lyophilized powder,the amount of mannitol was determined with the particle size and entrapment efficiency as the index.As a result,the average particle size was 295.7±11.9 nm and the encapsulation efficiency was 93.70±1.52%,indicating that the formulation was stable and reproducible.(4)The results of stability test showed that,the content ofLumefantrine in NLC decreased less under low temperature and light conditions but decreased more under high humidity condition.Thus Lumefantrine loaded NLC had strong hygroscopicity and should be preserved under sealed and moisture-proof conditions.(5)The concentration of Lumefantrine in plasma samples was determined by high performance liquid chromatography.The specificity was linear and the linearity was good.,the precision and stability were in accordance with the determination requirements.The endogenous components did not interfere with the determination of the main drugs and meet the requirements of the biological sample measurement.The results showed that the elimination half-life(t1/2z)of the drug group and the NLC group was 23.09h and 42.89h respectively,and the average residence time(MRTO-∞)was 43.81 h and 42.00h respectively.Cmax were 2.57μg/ml and 4.81 μg/ml.respectively.The area under the blood concentration-time curve(AUC0-∞)was 111.07μg/mL·h and 182.93μg/mL·h,the plasma AUC0-∞ of NLC group is 1.65 times of the drug group.After Lumefantrine prepared into the NLC.absorbed faster and taken effect more quickly.4.ConclusionFilm liquid method is an effective and convenient method to produce large-scale production;The solubility of artemether inclusion complex prepared by solution stirring method was significantly improved compared to raw material and the bioavailability was also improved.This method has certain guiding significance for the industrial production of clathrates and solve the solubility of poorly soluble drugs;Bifumerol NLC was prepared by ultrasonic dispersion method,the method can effectively improve the bioavailability of benflumetrone.The method has certain guiding significance for the preparation of NLC.it provides an effective means in order to improve the solubility of other insoluble drugs. |
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