Studies On Cyclodextrin Nanosponges And Application For Loading Artemether

Objective: Due to unique structural characteristics and physico-chemical properties,cyclodextrin(CD)have become excellent units in construction of various functional materials.Cyclodextrin nanosponges,one kind of new nanometer sized architecture delivery vehicle based on CD,have three dimensional network structures.Nanosponges can be used as effective drug carriers to solve the problems of low solubility,poor stability and bioavailability of drug.Nanosponges have broad application prospects in the environment,medicine,cosmetics and other related fields.This thesis prepares different kinds of CD nanosponges using various CDs and appropriate molar ratio of diphenyl carbonate(cross-linking agent).Artemether was selected as a model drug for drug loading.Then,the release behaviors of drug loaded samples were investigated.Methods:1.Preparation and characterization of CD nanosponges.Various reaction conditions such as temperature,stirring speed and time,molar ratio of CD to cross-linking agent,catalyst concentration were optimized.Different CDs types including α,β,γ-CD and CD derivatives(M-β-CD,HP-β-CD,SBE-β-CD)were taken into account for the nanosponges synthesis.The obtained materials were subjected to infrared spectroscopy,X-ray powder diffraction,differential scanning calorimetry,thermogravimetric analysis and scanning electron microscopy analysis.2.Establishment of quantitative method and pre-formulation studies about artemether.Artemether was applied as a model drug.The HPLC method for the determination of artemether was established and the solubility,stability and release behavior of the recrystallization samples were investigated.3.CD nanosponges loaded with artemether.Using the drug loading capacity as evaluation indexes,single factor experiments were performed to determine the optimal drug loading method of β-CD nanosponges.A series of characterizations of the relatedsamples were carried out.Then,the optimal drug loading method was applied to other CD nanosponges,and the drug loading and release behaviors were also investigated.Results:1.Different kinds of CD nanosponges have been prepared.The preparation process was optimized as: temperature 80 oC,stirring time 3 h,molar ratio of CDs to crosslinking agent as 1:4 and 1:6,the amount of catalyst(TEA)as 150 μL,mechanical stirring speed 400 rpm with solvent washing method to remove unreacted reactants and by-products.The yields of the samples with 1:6 molar ratio were obviously higher than that of 1:4,and the yields of α,β,γ-CD nanosponges were higher than that of the nanosponges prepared from β-CD derivatives.The C=O stretching vibration absorption peaks in the FTIR spectra indicating that the successful cross-linking.However,the obvious differences such as crystal behaviors,thermal stability were also noticed among different nanosponges types.2.Establishment of quantitative method and pre-formulation studies about artemether.The solubility of artemether in water is poor,while sodium dodecyl sulfate can significantly increase its solubility.It is not stable under the condition of strong acid and high temperature.Besides,it is light sensitive molecule.The recrystallized samples obtained by methanol,dichloromethane and ethanol could significantly increase the rate of dissolution of artemether in phosphate buffer solution of pH 6.8 with 0.4% sodium dodecyl sulfate,while the recrystallized sample obtained by hexane reduced the dissolution rates.3.Artemether was used as a model drug and successfully loaded to the CD nanosponges.The loading process parameters were optimized as follow: loading solvent as absolute ethanol,temperature 40 oC,mechanical stirring speed 200 rpm,the mass ratio of artemether and CD nanosponges as 1:1,and the loading time was set to 6 h.The drug loading capacity of nanosponges with molar ratio as 1:6 was recorded higher than that of 1:4.And the drug loading capacity of the different nanosponges were found in the following order of γ-CD nanosponges > α-CD nanosponges > β-CD nanosponges.In vitro release tests showed that artemether completely released within 6 h while drug-loaded samples released quickly,the cumulative release rates reached more than 85% in 5 min,and could release completely within 20-30 min,with significant immediate release effects.Conclusion: In this study,twelve CD nanosponges have been prepared using six types CDs and two molar ratios of CD to crosslinking agent.Artemether was used as a model drug and successfully loaded to the CD nanosponges.Drug-loaded samples showed significant improvement in immediate release compared to artemether raw material.