Preparation And Properties Of LDHs-based Drug Sustained Release Systems Of Betamethasone Derivatives

Layered double hydroxides(LDHs)are a kind of inorganic lamellar materials,consisting of the brucite-like layers with structural positive charges and exchangeable anions between the layers.The application of LDHs as drug carriers has attracted much attention.Drug molecules can be intercalated into the gallery of LDHs to form drug-LDHs nanohybrids,and LDHs can also be used as crosslinker to construct nanocomposite(NC)hydrogels for drug delivery and controlled release.However,there are many problems that need to be studied to achieve clinical applications of LDHs-based drug carriers.For example,the industrial green synthesis of LDHs single layer nanosheets(SLNSs),the effective loading of water-insoluble drugs on LDHs,and the effective methods to enhance dispersion stability of drug-LDHs nanohybrids.In addition,there have been few reports on LDH/polymer hydrogels,and understanding for their characteristics,drug loading and release behaviors is still limited.Betamethasone is a clinically applied anti-inflammatory,anti-rheumatic and anti-allergic non-steroidal drug,and its main components are two betamethasone derivatives,namely water-soluble betamethasone phosphate(BMP)and hydrophobic betamethasone propionate(BDP).It has a good effect for the treatment of rheumatism,lupus erythematosus and acute leukemia.However,its clinical application has been limited by side effects and short period of validity.Therefore,the development of its sustained-release dosage forms has great importance for its clinical application.In the current work,the aqueous phase synthesis of LDH SLNSs was first studied,to provide a green route for their large-scale application.Subsequently,drug(BMP and BDP)-LDHs nanohybrids were prepared via a co-assembly method to explore the effective loading route for hydrophobic drugs,and the nanohybrids were coated using liposome to explore an effective way to enhance the dispersion stability of nanohybrids.Finally,the preparation,properties and drug loading and release behavior of LDH/poly(N-isopropylaciylamide)(PNIPAm)NC hydrogels were studied,to evaluate its possible application as drug carriers.This work may provide the basis for the development and application of LDHs-based drug delivery and controlled release systems.Main research contents and conclusions:(1)The aqueous phase synthesis method of Mg2Al-NO3 LDH SLNSs was studied,to provide materials for the follow-up research of drug-LDHs nanohybrids and LDH/PNIPAm hydrogels.LDH SLNSs are conventionally synthesized with the help of organic modifiers or in organic solvents such as toxic formamide,and so-obtained products are loaded with organic substances or dispersed in organic solvents,which limits their application.In this work,a simple and green synthesis route,namely,"aqueous coPrecipitation-water Washing-reDispersion in water"(PWD)route,was developed for the LDH SLNSs.Elemental analysis,XRD,TEM,AFM,and dynamic light scattering(DLS)techniques were used to characterize the composition,crystal structure,morphology,and size distribution of the SLNSs nanosheets.The effects of concentration,temperature and other factors on the stability of SLNS dispersions were investigated,and the preparation mechanism was discussed.In addition,the co-assembly of LDH SLNSs with sodium cholate and graphene oxide was studied,demonstrating that the SLNSs can be directly used as building blocks to construct functional materials.Using the developed PWD method,Mg2Al-Cl,Zn2Al-NO3,Mg-2Fe-NO3,and Ni2Al-NO3 LDH SLNSs were also successfully synthesized,indicating that this method is universal.This method has the advantages of simple process,environment-friendly,low cost,and easy industrial production.(2)The BMP-LDHs nanohybrids were prepared by a co-assembly method,using LDH SLNSs as the building blocks and BMP as an anionic water-soluble drug model.Their composition,crystal structure and morphology were characterized,and the drug loading and release behavior were studied.The nanocomposites of BMP-LDHs coated with liposome were prepared by reverse evaporation,using soy lecithin and cholesterol as membrane materials.The dispersion stability,re-dispersibility,and drug release behavior were investigated.The results show that,compared with the traditional methods,the co-assembly method for preparing drug-LDHs nanohybrids has the advantages of simple process,mild conditions,no drug loss and controllable drug loading.The liposome-encapsulated modification of drug-LDHs nanohybrids can significantly improve the water dispersion stability and drug release performance of the nanohybrids.(3)BDP-LDHs nanohybrids were prepared using a drug modification-coassembly method,namely,BDP molecules were first incorporated into sodium cholate(Ch)micelles,and the negatively charged BDP-loaded micelles were then coassembled with positively charged LDH SLNSs,forming a BDP/Ch intercalated LDHs(BDP-Ch-LDHs)nanohybrids.The composition,crystal structure and morphology were characterized.Subsequently,(BDP-Ch-LDHs)@liposome nanocomposites were prepared by liposome encapsulation of the nanohybrids.The dispersion stability,redispersibility,and drug release behaviors were investigated.The results show that the drug modification-coassembly method can realize the effective loading of hydrophobic drugs;liposome coating modification is an effective way to enhance the water dispersion stability and sustained release performance of drug-LDHs nanohybrids.(Drug-LDHs)@Liposome nanocomposites are promising drug delivery-controlled release system.(4)The temperature-sensitive LDH/PNIPAm NC hydrogels were prepared by in situ radical polymerization using LDH SLNSs as cross-linkers.The microstructure,mechanical properties and thermal response of hydrogels were characterized,and the effect of LDHs dosage on hydrogel properties was also investigated.The results show that,compared with hydrogels synthesized with traditional organic cross-linkers,the prepared NC hydrogels have excellent mechanical properties,high swelling rate,sensitive temperature responsiveness,and these properties can be controlled by changing the LDHs content.Especially,it was found that the horizontal and vertical sections of the hydrogels have different microstructures.The loading capacity of BMP and BDP on the LDH/PNIPAm hydrogels and their release behavior were studied.The results show that the LDH/PNIPAm hydrogel can simultaneously load hydrophilic BMP and hydrophobic BDP.The drug-loaded hydrogels exhibit good sustained release.LDH/PNIPAm NC hydrogels can be considered as a potential drug carrier and may also have potential applications such as in biological tissue engineering and adsorbents.