| Aim:Paclitaxel is a broad-spectrum anti-cancer drug that is widely used in clinical practice.The preparations on the market are all injections.The medication is not convenient and safe,and there are serious side effects of intravenous injection.Because paclitaxel has poor water solubility and is a P-glycoprotein substrate,oral bioavailability is extremely low,which greatly limits the further development of clinical applications.At present,there is no oral preparation of paclitaxel on the market in China,and only the registration and application of paclitaxel capsules Oraxol and paclitaxel oral solution DHP107 have been registered.The former has a bioavailability of 54.255% in animals,but the use of patented P-glycoprotein inhibitors has certain technical barriers.Although the latter is already listed in Korea,its bioavailability in animals is only 23%.The widespread clinical application of paclitaxel is difficult to satisfy the drug accessibility of patients with only two paclitaxel oral preparations.Therefore,it is very necessary to develop a paclitaxel oral administration system that can significantly improve the bioavailability and can effectively evade technical barriers to provide more choices for clinical application.The main purpose of this study is to establish a paclitaxel oral administration system that can effectively improve the bioavailability,solubilize paclitaxel with the selfmicroemulsifying drug delivery system,and screen and optimize the prescription.Taking this paclitaxel self-microemulsion oral drug delivery system as the research object,it conducted a series of appearance characterization and stability studies,preliminary study of in vivo and external pharmaceutical behaviors,and mechanism studies.In order to obtain a novel paclitaxel self-microemulsion oral administration system with higher bioavailability and application prospect than the existing paclitaxel oral preparations.Methods:1.Establishment and optimization of paclitaxel self-microemulsion oral drug delivery systemExplore the hydrophilic and lipophilic properties of paclitaxel API,and then determine the microemulsion system by the solubility of paclitaxel in each excipient,the compatibility of emulsifier and oil phase,pseudo-ternary phase diagram,response surface and stabilizer screening prescription composition.2.Characteristic study and stability evaluation of paclitaxel self-microemulsion oral administration systemThe characteristics of paclitaxel self-microemulsion system were studied by appearance,particle size and distribution,Differential Scanning Calorimetry and Fourier Transform Infrared Spectrometer.The stability of paclitaxel self-microemulsion system was evaluated by influencing factor test(high temperature,high humidity and strong light irradiation test),accelerated test and long-term test.3.Preliminary study on the in vitro pharmaceutical behavior of paclitaxel from microemulsion oral administration systemBy simulating the different physiological p H and digestive enzyme environment of the gastrointestinal tract in vitro,the specific conditions of the paclitaxel selfmicroemulsion system and the paclitaxel drug substance system in the biological gastrointestinal tract were explored.4.Preliminary study on the in vivo pharmaceutical behavior of paclitaxel from microemulsion oral administration systemThe bioavailability was calculated by comparing the drug-time curves of paclitaxel self-microemulsion oral administration system,paclitaxel bulk drug oral administration system and marketed paclitaxel injection taxol in rats and mice.5.Preliminary study on the absorption mechanism of paclitaxel from microemulsion oral administration systemThe mechanism of paclitaxel from microemulsion system to promote absorption and improve oral bioavailability was preliminarily explored through in vivo gastric perfusion test,in vivo intestinal perfusion test,isolated intestinal valgus test and mouse lymphatic suppression test.Results:1.Paclitaxel has poor water solubility but good lipophilicity,and belongs to category IV of the biopharmaceutical classification,suggesting that it may be solubilized by the microemulsion preparation and promote absorption.After multiple screenings,the best prescription was paclitaxel: RH-40: PR-214: n-butanol: GTCC: P-303 = 1: 28: 28:28: 9: 6,and its substitution number was named YLP214.2.YLP214 is a clear and transparent liquid state at room temperature.The particle size is 36.463 ± 0.186 nm,and the polydispersity coefficient PDI is 0.196 ± 0.007,indicating that the small particle size of the sample is nanoemulsion,with a narrow distribution range and uniform distribution.Differential Scanning Calorimetry、Fourier Transform Infrared Spectrometer and other tests show that the paclitaxel drug molecules are contained in the self-microemulsion system,rather than a simple physical mixing state.Stability test results suggest that YLP214 should be stored in the dark at 4 ° C,consistent with DHP107.3.YLP214 in the physiological environment of different p H of the gastrointestinal tract,about 85% paclitaxel API can still be tightly wrapped inside the self-microemulsion after 48 hours of simulating the in vivo environment without recovering the insoluble drug molecular state.In vitro digestion tests have shown that even though YLP214 can be digested and destroyed by lipases in large quantities,about 80% of the paclitaxel API can still be solubilized in various forms such as micelles,mixed micelles,vesicles and milk droplets,which is beneficial to promote absorption.4.In SD rats,the absolute bioavailability of YLP214 is 64.29% compared with the marketed paclitaxel injection taxol.The absolute bioavailability of YLP214 compared to Taxol in KM mice is 66.66%,which is significantly higher than that of Korean oral preparation DHP107(bioavailability is about 23%).Rat gastric infusion and intestinal perfusion tests showed that YLP214 can effectively improve the absorption of paclitaxel in the gastrointestinal tract,especially the absorption of ileum and colon,compared with the drug substance system.Colon valgus experiments show that YLP214 can effectively avoid or inhibit the efflux of Pglycoprotein on paclitaxel.The results of lymphatic inhibition tests show that YLP214 can promote the lymphatic transport of drugs,which may be an important way to effectively improve the oral bioavailability of paclitaxel.Conclusion:In view of the difficult development characteristics of paclitaxel oral preparations and the deficiencies of registered and declared preparations,in order to meet the accessibility of clinical patients,this article used a self-microemulsifying drug delivery system to solubilize paclitaxel,screened and optimized prescriptions,and successfully established a model that can significantly promote oral administration Paclitaxel with good absorption and stability from microemulsion oral administration system YLP214.The system effectively circumvented the technical barriers of capsule Oraxol and oral solution DHP107,and significantly improved oral bioavailability.Taking the taxol for injection as a control,the absolute bioavailability of rats and mice reached 64.29% and66.66%,The bioavailability of rats is 1.19 times that of capsule Oraxol,and the bioavailability of mice is 2.90 times that of Korean preparation DHP107,showing good clinical application prospects. |
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