Study On The Preparation And Quality Of Phillygenin Solid Self-Microemulsion Capsule System

Phillygenin exsit in dry fruits of forsythia,which belong to the bisepoxylignan compound monomer,phillygenin have extensive biological activties,such as treatment of rheumatoid arthritis,rh eumatic arthritis,anti-tumor,anti-oxidation,anti-liver injury,anti-liver failure,hypolipidemic,etc.pharmac ological experiments of rats indicated that phillyenin can increase the pain threshold in rats with arthritis,reduce foot swell value and the influence of inflammatory factor TNF-a.But phillyenin is insoluble in water that have bringing great challenges in formulation and clinical application.Microe mulsion drug delivery system is composed of three components,oil phase,surfactant and cosurfactant respectively.Self-emulsification process was formed under the action of gastrointestinal motility and gastrointestinal fluid,could improve the solubility of insoluble drugs and improve bioavailability of drugs in vivo significantly.But the liquid SMEDDS has some problem on stability、dosage form and storage.Solid self-mocroemulsifying drug delivery system(S-SMEDDS)combining the SMEDDS and Solid adsorbent、preparation technology could improve the stability of SMEDDS,increasing the diversity of dosage forms,improve the compliance of patients,so that it can better be used in clinic al,.may not only overcome shortcoming that mentioned above,but also help to improve patient com pliance.The aim of the study was to develop S-SMEDDS of phillygenin.The HPLC method is developed for the phillygenin S-SMEDDS capsule content determin ation and dissolution determination,and the gradient elution method for the related substances of phillygenin and the phillygenin S-SMEDDS capsules.After themethodological validation,the method established is accurate,reliable,stable and applicable to the quality control of the product in vitro.The physicochemical properties of the phillygenin were stuied,such as melting point,Solubi lity in different organic solvents,equilibrium solubility in different components,powdery parameters,and the coefficient of oil-water partitioning in different ph solutions.Oil phase,surfactant,cosurfactant were screened out by the compatibility experiment of oil phase and surfactant,pseudo ternary phase diagram drawing experiment and the emulsion classification experiment,The compatibility of compo nents,microemulsion area,emulsifying properties and the solubility of APIs were taken as indicator s,Finally Capryol 90,Kolliphor RH40,Transcutol HP as oil phase,surfactant,co-surfactant respectively.Adopting the Origin 8.0 software draw pseudo phase diagram,Capryol 90,Kolliphor RH40,Transcut ol HP as the the three vertices,The final microemulsion area was obtained.Central composite design-response surface method was used to optimize and select best composition,13 sets of experiments were designed,Oil percentage and Km as the most influent experimental factors,The mean particl e size,Zeta potential and equilibrium solubility as the response index.Investigating the preparation process of SMEDDS and examining quality and stability evaluation of the SMEDDS.The phillygenin S-SMEDDS was prepared by solid adsorption.The maximum adsorption capacity 、 release capacity of pharmaceutical solid carriers for phillygenin SMEDDS were studied and Neusilin US2 was selected as the best adsorbent,The liquidity,dissolution,loading were taken as the factors,and optimizing the phillygenin SMEDDS:US2 is 7:3.To determine the final consisted o fcapsule was phillygenin 15.00mg、Capryol 90 114.12mg、Kolliphor RH40 158.69mg、Transcutol HP182.41mg、NeusilinUS2 201.52 mg.After the preparation process was determined.The dissolution be havior of phillygenin S-SMEDDS、physical mixture、phillygenin capsule in water,0.1M HCL,pH 4.0 acetate buffer,pH6.8 PBS buffer dissolution behavior was studied and compared with each other.Result showed that phillygenin S-SMEDDS capsule could improve dissolution rate and dissolutionextent of phillygenin in different dissolution media significantly compared to others.After the soli dmicroemulsion powder was filled into the capsule,According to the requirements of pharmacopoeia,the appearance and quantity of the products were investigated,the results were meet the requirem ents.Redispersibility study revealed that the average particle size was 26.45 nm and PDI was 0.076.Fourier Transform Infrared Rpectroscopy(FT-IR),Differential Scanning Calorimetry(DSC),Powder X-R ay Diffraction(PXRD)were used to validate the properties of phillygenin S-SMEDDS.The result showed that there was interaction between phillygenin and solid carrier,crystalline of drug was tran sformated and exited as amorphousstate structure in S-SMEDDS.The content and dissolution were determined of three batches of phillygenin S-SMEDDS capsules,and the Content was uniform,the dissolution rate was above 90 % in pH6.8 media.The str ess testing studies showed that phillygenin S-SMEDDS capsule was sensitive to the humid,should pay attention to control of humidity conditions during the storage.The results of accelerated experi ment of 6 months showed that the indexes of S-SMEDDS capsules were stable under condition of humidity of 75±5 % and temperature of 40±2 ℃,Indicated that the formulation was stable under capsule packaging.In conclusion,phillygenin S-SMEDDS have good emulsified ability in aqueous media and good dissolution rate、extent,stability is good,preparation process is simple,Which provide strong reference for its further formulation research and development.