| Purpose:Chemotherapy is one of the main methods of treating cancer,but it can cause side effects of nausea and vomiting,resulting in poor patient compliance and reduced therapeutic effect.As the first anti-emetic NK-1 receptor antagonist on the market,aprepitant has the advantages of strong specificity,high affinity,and few adverse reactions,and is widely used in clinical practice.Aripiptan preparations that have been marketed abroad include Yimei Capsules（EMEND?）,Aprepitant oral suspension,and Fosapitam meglumine injection,etc.Among them,Yimei capsules are solid dosage forms,which are inconvenient for children or patients with difficulty swallowing;The aprepitant oral suspension needs to be prepared immediately before use,which is cumbersome and complicated in clinical use and has poor compliance;The excipient of Forxapitam Meglumine Injection contains Tween-80,which can easily cause allergic reactions.At present,there are a number of domestic companies researching aripipan capsule preparation,which uses nanocrystal technology,imitation has technical difficulties and technical barriers,and consistency evaluation has great challenges.Aprepitant is a class IV drug of the Biopharmaceutical Classification System（BCS）,which has low solubility and low permeability,resulting in low oral bioavailability.Self-microemulsion as a nano-level drug carrier can effectively solve the problems of low solubility and low permeability of aprepitant.In summary,the development of a new self-emulsifying oral delivery system of aprepitant is particularly important.This study screened and optimized the self-microemulsion drug delivery system that can effectively carry aprepitant to plasma and brain tissue through pseudo-ternary phase diagram and response surface-star point design.Taking the optimized self-microemulsion system of aprepitant as the research object,a series of characteristics and stability were studied in vitro;Preliminary investigation of the oral absorption mechanism in vivo,and through pharmacokinetic studies and brain tissue distribution studies,compared with the marketed preparation EMEND?,to obtain a new aprepitant self-micreoemulsion oral preparation which has high bioavailability,high brain tissue concentration,good clinical compliance and using safe ingredients.Methods:1.Establishment of aprepitant slef-microemulsion systemThe basic physical and chemical properties of aprepitant were studied through the solubility test,the apparent oil-water partition coefficient test and the auxiliary material compatibility test,to investigate the solubility of aprepitant in each auxiliary material,the compatibility of each auxiliary material and preparation from microemulsion conditions.Determine the type of surfactant and oil phase by using the compatibility test of auxiliary materials,draw a pseudo-ternary phase diagram to determine the type of co-surfactant,determine the oil proportion and Km value by the response surface-star point design method,and screen the stabilizer according to the results of the accelerated test type and dosage.The self-microemulsion system of aprepitant was initially established to provide a basis for subsequent research.2.Study on the characteristics of aprepitant self-microemulsion oral administration system in vitroCharacterization of aprepitant self-microemulsion drug delivery system,including appearance characteristics,drug loading,particle size and distribution,differential scanning calorimetry,Fourier infrared spectroscopy and X-ray diffraction.And in vitro simulation of the physiological environment in vivo,using the release test and lipolysis dynamic model,to investigate the stability and drug loading of aprepitant self-microemulsion.3.Study on the stability of aprepitant self-microemulsion oral administration systemThe stability study was conducted according to the requirements of the 2015 edition of the Chinese Pharmacopoeia.Aprepitant self-microemulsion is an oral liquid preparation,and its stability,content,stratification and related substances are its stability inspection items.Through the influence factor test（high light irradiation test,high temperature test,high humidity test）,accelerated test and long-term test,examine its stability.4.Study of aprepitant self-microemulsion in rat gastrointestinal absorptionEstablish a method for determining the content of aprepitant in intestinal perfusate and gastric perfusate,and explore the self-microemulsion of aprepitant and aprepitant API by conducting gastric perfusion test,intestinal perfusion test and lymph transport inhibition test on SD rats The gastrointestinal absorption situation,preliminary exploration of the oral absorption mechanism of aprepitant.5.Study on the pharmacological behavior of aprepitant self-microemulsion in miceTaking EMEND?as the reference preparation,the pharmacokinetic behavior and brain tissue distribution of aprepitant orally taken from microemulsion in Kunming mice after oral administration were compared,and the relative bioavailability was calculated.Result:1.To study the establishment of aprepitant self-microemulsion system,the solubility test and the compatibility test of excipients determined that GTCC was used as the oil phase and RH-40/TW-80=1:1 as the surfactant;When the co-surfactant is PEG-400,the area of the pseudo-ternary phase diagram from the microemulsion area is the largest;The star point design test results show that the Km value of the aprepitant self-microemulsion prescription=1.50,the oil ratio=11.67%,the formation of microemulsion has the highest encapsulation rate,the highest light transmittance,and the shortest emulsification time;Stabilizer screening test results show that when the stabilizer is p-214 and the dosage is5%,it produces the least amount of impurities.2.The characteristics of the aprepitant microemulsion system were studied.The sample was clear and transparent,and had good fluidity.The microemulsion droplets formed after adding water were clear.Compared with water,it had a pale blue opalescence.The particle size is 24.67±0.04nm,and the polydispersity coefficient（PDI）is 0.162±0.003.The distribution range is very small and uniform,which can form a nanoemulsion;Differential scanning calorimetry,Fourier infrared spectroscopy and X-ray diffraction showed that the aripipan molecule was wrapped in microemulsion in an amorphous state;The results of the in vitro release test showed that under the simulated physiological environment in the body,most aprepitant exists in the form of microemulsion droplets,and a small amount exists as free molecules,and it has the ability to continuously deliver drugs;The results of in vitro digestion tests show that after a microemulsion is digested with pancreatic lipase,aprepitant still has a solubilizing effect on aprepitant.3.The stability of aprepitant microemulsion was investigated.The test results showed that the aprepitant self-emulsion was left under strong light,high temperature,and high humidity for 10 days.60%±10%)for 6 months and long-term conditions（temperature 6℃±2℃,relative humidity 75%±5%）for 9 months,good stability.4.The gastric perfusion test results showed that both the aripipent self-microemulsion and the aprepitant drug substance solution were absorbed in the rat stomach,and there was a certain concentration-dependent absorption,and the percentage of aprepitant self-microemulsion absorption was obvious higher than the drug solution of aprepitant;The results of intestinal perfusion test showed that the drug solution of aprepitant self-microemulsion and aprepitant were both absorbed in the small intestine and colon,and the absorption rate of aprepitant self-microemulsion was significantly higher than that of aprepitant.There is no obvious correlation between the absorption of the two preparations in each intestinal segment and the physiological p H environment;The results of lymph transport inhibition test showed that the oral administration of aprepitant self-microemulsion,the AUC value in rats is 4.21 times the AUC value after lymphatic inhibition,proving that self-microemulsion can effectively promote the absorption of aprepitant via lymph.5.Using EMEND?as a reference preparation,the pharmacokinetic behavior of aprepitant self-microemulsion mice was compared.After a single oral administration,the AUC（0-36h）=135.34±0.25μg.h/m L,EMEND?AUC（0-36h）=93.24±0.13μg.h/m L,mouse brain tissue distribution study shows that aripiptan is faster than EMEND?after oral administration from microemulsion reaching the brain,the Cmax of aprepitant in mouse brain tissue is 1.28 times that of EMEND?,which has a higher concentration of brain tissue than EMEND?.Conclusion:In order to solve the poor clinical compliance of the marketed aprepitant oral preparations and improve the oral bioavailability and brain tissue concentration of aprepitant,this article successfully established a biological by screening and optimizing the preparation of aprepitant self-microemulsion Aripiptan is a self-administered microemulsion oral administration system with high utilization and high brain tissue concentration and good clinical compliance,and preliminary exploration of its absorption mechanism in vivo.Compared with the marketed preparation EMEND?,this system has a plasma AUC（036h）value of 1.45 times that of EMEND?.In the brain tissue of mice,the Cmax of aprepitant is 1.28 times that of EMEND?Brain tissue concentration. |
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