Study On Solubilization And Prolonging Release Of Ethinylestradiol By Cyclodextrin/cellulose Hydrogel

Ethinylestradiol is a potent estrogen steroid hormoneused in clinical settings to treat breast cancer,prostate cancer and menopausal syndrome.However,ethinylestradiol’s low water solubility(4.8 mg/L)limits its bioavailability,necessitating solubility enhancement studies to improve its solubility.Cyclodextrins are ideal candidates for improving the solubility of ethinylestradiol because they can form host-guest inclusion complexes with hydrophobic substances,enhancing drug solubility.Cellulose-based hydrogels are often used as drug carriers to control drug release due to their good environmental sensitivity.Therefore,cellulose-based hydrogels were chosen to prepare p H-responsive drug slow release carriers to control ethinylestradiol release.Based on the above idea,the preparation of cyclodextrin derivative/ethinylestradiol/cellulose composite hydrogel capsule and its preliminary study on the slow release performance were studied in this thesis.(1)Construction of ethinylestradiol/cyclodextrin derivatives drug delivery system.In this study,a series of highly water-soluble aminocyclodextrin derivatives were successfully obtained by modification of ethylenediamine,diethylenetriamine,triethylenetetetramine and tetraethylenepentamine with β-cyclodextrin as the raw material.To address the low bioavailability of ethinylestradiol for oral administration,,aminocyclodextrin derivatives were used as main molecule to encapsulate ethinylestradiol by saturated aqueous solution method and mechanical grinding method,resulting in ethinylestradiol/cyclodextrin derivative inclusion complexes.Characterization analysis(infrared spectroscopy,scanning electron microscopy,nuclear magnetic resonance,etc.)showed that the aminocyclodextrin derivatives/ethinylestradiol inclusion complexes were formed by conjugation rather than simple adsorption.High-performance liquid chromatography(HPLC)tests demonstrated the ability of cyclodextrin derivative inclusion to solubilize ethinylestradiol,and diethylenetriamine-β-cyclodextrin(DETA-β-CD)was identified as the best guest molecule for solubilization,increasing ethinylestradiol solubility 100 times to 496 mg/L.The formation of soluble inclusion complexes was confirmed using phase solubility analysis in 1:1 stoichiometry.Molecular simulations confirmed the existence of multiple forces between the hydrophobic alkyl groups of DETA-β-CD and ethinylestradiol,which made the docked molecules more stable and significantly improved the stability and water solubility of ethinylestradiol.This cyclodextrin-based drug delivery vehicle is expected to improve ethinylestradiol’s low aqueous solubility and low bioavailability problems in clinical therapy.(2)Construction of pH-responsive cellulose-based hydrogel capsule slow release system.In this study,the capsule core was prepared with DETA-β-CD/ethinylestradiol,aldehyde cellulose and hydroxyethyl cellulose,and the capsule shell was prepared by the cross-linking of sodium alginate with calcium ions.Schiff base reaction with DETA-β-CD transformed aldehyde cellulose into the main body of the drug delivery matrix to achieve sustained release of ethinylestradiol,and hydroxyethyl cellulose served as the carrier.The shell prepared by crosslinking sodium alginate with calcium ions enables controlled rupture of the hydrogel capsule under simulated gastrointestinal fluid conditions to achieve controlled ethinylestradiol release.The microstructure of the core and shell of the hydrogel capsules was observed by scanning electron microscopy.The stability,swelling,slow release properties and biocompatibility of the core-shell hydrogel capsules were also carefully investigated.The stability,swelling,slow release properties,and biocompatibility of the core-shell hydrogel capsules were also carefully investigated.In vitro release experiments showed that the core-shell structured hydrogel capsules were p H-responsive and could achieve controlled release of ethinylestradiol,with the release rate of ethinylestradiol rapidly increasing,and the release rate of ethinylestradiol reached more than 90% within 9 h.The core-shell composite hydrogel capsules established a highly stable ethinylestradiol slow release system,which is beneficial for medical applications in oral drug delivery.