| Otitis media is a common ear disease with high incidence in clinic.At present,it is mainly treated by the combination of systemic administration and local administration of ear drops.However,most of the drugs used are antibiotics,which have ototoxicity to some extent,and long-term application will cause drug-induced hearing loss.In addition,the abuse of antibiotics can easily bring about antibiotic resistance,which has some impact on the therapeutic effect.Traditional Chinese medicine is an important part of the treasure of medicine in China.Its unique compatibility rule and safety and effectiveness have been proved by thousands of years of clinical practice.At present,the main problem facing the modernization of Chinese medicine is that most of them are poorly soluble drugs,which leads to the low bioavailability of medicines,limits the further application of Chinese medicines in clinical practice.Therefore,combining modern pharmacy research result,a modern Chinese medicine compound delivery system is reasonably constructed to provide reference for the application of new traditional Chinese medicine compound prescriptions.In this project,a sound-sensitive cocrystal drug delivery system composed of tanshinone IIA and curcumin was designed and applied to the treatment of otitis media.In order to improve the solubility of tanshinone ?A and curcumin,API-API drug cocrystal was made by Tanshinone ?A and curcumin,so that the drug can give full play to good synergistic antibacterial effect.In addition,we utilized the sound-sensitive properties of curcumin to organically combine sonodynamic therapy with chemotherapy,which use the sonodynamic antibacterial chemical therapy mediated by the sound-sensitive agent.It further develops the synergistic antibacterial effect,and builds a better antibacterial performance.A new cocrystal compound delivery system with better antibacterial effect,without potential drug resistance and obvious side effects was constructed and applied to the treatment of otitis media.Firstly,Tanshinone IIA-Curcumin cocrystal complex was prepared by solution crystallization method.The prescription process of Tanshinone IIA-Curcumin cocrystal complex was screened by changing the solvent,the ratio of good solvent to bad solvent,drug concentration and chitosan concentration.The Tanshinone IIA-Curcumin cocrystal complex was characterized by Dynamic Light Scattering(DLS)and Zeta Potential(ZP),Scanning Electron Microscope(SEM),X-ray Diffraction(XRD),Fourier Transform Infrared Spectrometer(FTIR)and Differential Scanning Calorimetry(DSC).The results showed that the Tanshinone IIA-Curcumin cocrystal complex showed a needle like crystal with a fibrous appearance under the SEM,with an average particle size of about 650 nm,good dispersion and a large amount of positive charge.The results of XRD,FTIR and DSC results exhibited that Tanshinone IIA-Curcumin cocrystal complex was successfully prepared.Secondly,the antibacterial activity of Tanshinone IIA-Curcumin cocrystal complex was evaluated separately by ?-B disc diffusion assay,2-fold serial microdilution method,micro dilution method of chessboard and time-killing curves.The results showed that the Tanshinone IIA-Curcumin cocrystal complex has good antibacterial effect and there was a synergistic antibacterial effect between tanshinone ?A and curcumin.The antibacterial mechanism was studied by fluorescence imaging co-localization and SEM.The results showed that the antibacterial mechanism of Tanshinone IIA-Curcumin cocrystal complex might be to change the permeability of bacterial cell membrane and then destroy the integrity of bacterial cell membrane,so as to achieve excellent antibacterial effect.The guinea pig model of acute suppurative otitis media was established by tympanic injection of Staphylococcus aureus suspension.After three days,the model was administered continuously for another three days,and the bacterial culture colony count was taken on the seventh day.The results showed that the bacterial colony count of Tanshinone IIA-Curcumin cocrystal complex was significantly lower than model group,which indicated that the cocrystal complex had good antibacterial effect and could be used for the treatment of suppurative otitis media.Then,the antibacterial effect of curcumin-mediated sonodynamic antibacterial therapy on Staphylococcus aureus was investigated.The results showed that the concentration of curcumin and bacterial suspension had a positive correlation with the antibacterial effect.Compared with curcumin,Tanshinone IIA-Curcumin cocrystal complex has similar sonodynamic antibacterial activity,which further shows that Tanshinone IIA-Curcumin cocrystal complex can significantly improve the solubility of tanshinone IIA and curcumin,and can achieve good sonodynamic antibacterial effect as a sound sensitive agent.Finally,the delivery system of Tanshinone IIA-Curcumin cocrystal complex was preliminarily established.The microtube made of biocompatible materials was used as the "gun barrel",the perfluorononane emulsion was used as the launching power,and the Tanshinone IIA-Curcumin cocrystal complex was used as the "bullet".It was expected that triggered by ultrasound,the perfluorononane emulsion would generate bubbles based on the principle of droplet evaporation caused by ultrasound,and promote the delivery of drugs across the tympanic membrane,and give full play to acoustic dynamic antibacterial.However,only the delivery system has been established,and its delivery capacity and efficacy need further investigation.To summarize,this study combines the active components of traditional Chinese medicine with modern science and technology to design an ultrasonic sensitive cocrystal complex drug delivery system with good antibacterial activity,which provides a new design idea for the design of a new drug delivery system,and it will have a high potential application value in the treatment of otitis media in the future. |
PDF Full Text Request