Preliminary Study On Loading Of Omeprazole By Cyclodextrin-metal-organic Frameworks

Omeprazole（OME）is the first generation of proton pump inhibitors（PPI）and also one of the benzimidazole compound.Due to the presence of sulfoxide groups in its molecular structure,the whole molecule is unstable.Under high temperature,humidity,light and acid conditions will cause OME degradation to various degrees,which is very unfavorable for the actual clinical application.The cyclodextrin metal-organic framework（CD-MOF）is a frame structure synthesized with cyclodextrin as an organic ligand.It was confirmed by characterization that it has a large surface area and a high porosity,making This frame structure has application potential in gas separation and drug loading.As a common material,cyclodextrin（CD）is often used to improve the water insolubility and instability of drugs due to its inclusion ability.γ-CD-MOF,which made with CD as one of the constituent elements,has a larger cavity structure than CD.It is considered to be equally applicable to the improvement of water solubility and stability,even to achieve better results.The main research contents are as follows:KOH and K₂CO₃ was used as the potassium ion inorganic metal center,γ-CD was used as organic ligand to prepareγ-CD-MOF by solvothermal method.Through SEM,XRPD,FT-IR and BET characterization methods,it was proved that this method obtained uniformed cubic crystals with large specific surface area and high porosity.The loading process of OME-K₂CO₃-γ-CD-MOF（OME-MOF）was optimized by examining the influence of time,dosage,temperature,drug loading and size of CD-MOF on drug loading.The drug loading of OME in micron-sized K₂CO₃-γ-CD-MOF was 17.4%approximately,and in nano-sized K₂CO₃-γ-CD-MOF was 13.2%.The transport of OME-MOF in Caco-2 cells was similar to that experiment with OME alone,demonstrating that there was no effect on the transport of OME in cells after loading withγ-CD-MOF.The influencing factor experiments were carried out on the drug-loaded samples.The stability of OME-MOF and other samples was investigated under high temperature,high humidity,and strong light conditions respectively.The results showed that the high temperature had the greatest effect on the stability of OME.γ-CD-MOF has a certain protective effect on the stability after OME loading in MOF.The effect of residual solvents in MOF on the stability of OME-MOF was investigated.After 10 days accelerated stability experiments,it was proved that the residual solvent in MOF had almost no effect on the stability of OME-MOF.The effect of washing on the stability of OME-MOF was also investigated.This experiment’s result showed that washing once with methanol had no effect on the stability of OME-MOF,which indicated thatγ-CD-MOF not only protected the OME molecules in the cavity but also adsorbed the OME on the surface of the MOF.The results of a comprehensive stability experiment demonstrated that the using K₂CO₃-γ-CD-MOF with OME can improve the stability of OME under light,heat and humidity conditions.Screened different lipids try to improve the solubility of OME-MOF in water,thereby improving the stability in acid and the stability of OME-MOF under acidic conditions.After material screening and optimization of the process,cholesterol is preferred as the encapsulation material.The stability of OME in OME-MOF after encapsulation with cholesterol（N-COM）was significantly improved in the acid degradation experiments at pH 3.0 and pH 4.0,and its protective effect was superior to OME-MOF.The 10-day stability test’s result shows that N-COM and OME-MOF have the same protective effect on the stability of OME under the conditions of light,heat and humidity.That means cholesterol encapsulation will not affect the stability of OME.The formulations like capsules and tablets were being used to design OME prescriptions.In the formulation of the capsules,only the N-COM powder was filled in the HPMC capsules without other excipients.The dissolution test results showed that the use of cholesterol encapsulation can only improve the stability and dissolution of OME weekly.The OME was designed as a gel matrix sheet,trying to protect the internal OME drug substance after forming the film by sacrificing OME on the surface.The dissolution test results proved that the structure can form a complete film,but in the pH 1.2 medium,after 2 hours,the OME content decreased as high as 80%.Thet results indicate that using such a structure alone cannot improve the stability of OME in gastric acid.In summary,the use of K₂CO₃-γ-CD-MOF loading OME improves the stability of OME under strong light,high temperature,and high humidity conditions.After being encapsulated with cholesterol,the stability of OME under acidic conditions is improved.However,its role in strong acid conditions is limited.In the dosage form design experiments,capsules and tablets were tried simply.The current prescriptions what we tried do not highlight the advantages ofγ-CD-MOF,and it is still necessary to continue the screening optimization.This article demonstrates thatγ-CD-MOF plays an important role improving the stability of unstable drugs,and new formulation designing.