| Compound gestodene oral tablets have been listed, but there is no long-acting formulation of the product. This article intends to provide a theoretical basis, research methods, and technical support for compound compositions containing gestodene and ethinyl estradiol to create to the long-term sustained-release intravaginal ring.Part I:Preformulation studies and structural design of compound gestodene intravaginal ring(IVR)The solubilities of gestodene (GEST) and ethinyl estradiol (EE) in the controlling membrane material C6-165 and Q7-4750 were determined by DSC, which provided a theoretical basis for the selection of controlling membrane. The raw materials compatibility results suggested that placed in strong light (4500 ± 500 lx), high temperature (60 ℃), humidity (relative humidity of 90% ± 5%) condition for 10 days, the drugs and mixture of drugs with a certain proportion of the silicone rubber, showed no new impurities in chromatogram of HPLC, and the single as well as total impurities on 5 and 10 days were less than 5% compared with 0 day, mass range was ± 3%, indicating that raw materials and pharmaceutical excipients have good compatibilityMatrix type, reservoir type and block structure intravaginal rings were prepared, the releasing results of which showed that the block structure intravaginal rings could achieve zero order release of both GEST and EE (r=0.9998, r=0.9992, respectively), which reduced the burst release of drugs, and met the requirements of drug release for 21 days.Part Ⅱ:Release mechanism, in vitro accelerated testing and prescription optimizationThis study investigated the factors affecting reservoir-type intravaginal ring’s drug release, taking gestodene as a model. In summary, GEST reservoir-type IVR could be adjusted by the thickness of controlling sheath, the loading of drug, the material properties of controlling sheath, the dispersion state of drug, the prescription composition and structure of intravaginal ring, to control the drug release behavior and achieve the desired drug release rate.This paper examined the drug release situation under 45 ℃ and 55 ℃, the results showed that for GEST, the cumulative release of 11.71 h at 45 ℃was equal to one day’s release at 37 ℃, and 5.91h at 55 ℃; for EE the cumulative release of 4.82 h at 45 ℃ was equal to one day’s release at 37 ℃, and 3.87 h at 55 ℃.To achieve the goal of controlling release of GEST and EE (GEST 60 ug/d, EE 15 μg/d), we did a lot of minor adjustments for drug loading and thickness of the sheath, and ultimately determined the structure prescription of compound gestodene intravaginal ring for block type. The block length of gestodene is 3.8 cm, the drug core cross-sectional diameter is 4 mm, the controlling membrane thickness is 0.8 mm, the drug loading is 4.0% and 21 days average release rate is 64.42 μg/d; ethinyl estradiol block length is 2.1 cm, cored cross-sectional diameter is 4 mm, the controlling membrane thickness is 1.5 mm, the drug loading is 0.60% and 21 days average release rate is 16.44 μh/d.Part III:Pharmacokinetics studies of gestodene intravaginal ringNew Zealand female rabbits were being as research subjects to investigate the concentration of gestodene absorbed into the bloodstream through the mucous membrane and the connection between its dynamic process in the body with the release in vitro. The concentrations of gestdone in the blood of rabbits were monitored with LC-MS/MS method established by our laboratory. The results showed that, the gestodene concentration in rabbit plasma ranged from 0.50 to 6.0ng·mL-1 with good linear relationship (r= 0.9995). The blood monitoring results of 6 New Zealand female rabbits after administrated gestodene intravaginal ring showed that gestodene was able to maintain relatively stable concentrations in rabbits, and in vitro-in vivo correlation was better.During the vaginal mucosa irritation test, we made rabbit vaginal tissue paraffin sections and observed under an optical microscope. The results showed that silicone rubber carrier had no significant stimulation on rabbit vaginal tissue, proofing that histocompatibility between intravaginal ring material and rabbit was good.In summary, the prescription screening, optimization studies and in vivo pharmacokinetics for compound gestodene intravaginal ring with liquid silicone rubber as a carrier were studied, which provided a basis for its preclinical studies.
|
PDF Full Text Request