Study Of Microwave-assisted Preparation And Properties Of Inorganic Layered Mineral-drug Composites

Montmorillonite(MMT) and Layered Double Hydroxides(LDHs) are typical nano-sized inorganic layered minerals. The former is known for high good cation exchange capacity, while the latter have excellent anion exchange capacity. Due to their special layered structures and non-toxic efficacy, MMT and LDHs have been used as a new carrier for sustained release systems, which have been paid highly attention by researchers both at home and abroad.In this dissertation, study on a new mineral processing machine and methods has been combined with theoretical studies on mineral application in the new sustained-release drug systems. Microwave and mechanochemical were successfully used in the preparation of mineral-drug composites, and the application of MMT, LDHs in the new sustained-release drug systems has been also studied. Meanwhile, the interaction mechanism between medicinal minerals (MMT, LDHs, etc.) and a series of Western medicine as well as active ingredients in traditional Chinese medicine was clarified. Systematic and in-depth studies were finally conducted on the drug adsorption characteristics of the inorganic layered minerals together with the sustained-release theory of the composites.First of all, in order to improve the preparation and modification devices of mineral materials, a multi-functional microwave stirring ball mill was successfully developed based on both microwave and mechanochemical principle, and the device had access to certificate of Utility Model Patent of State Intellectual Property Office of the People's Republic of China (ZL 2008 2 0029685.2). In this device, Sodium-montmorillonite (Na-MMT) was successfully prepared using natural Ca-montmorillonite (Ca-MMT) as raw materials. X-ray diffraction (XRD), thermal gravimetric analysis (TG), and Fourier transform infrared spectroscopy (FTIR) were carried out for the structural characterization, and the microwave-mechanochemical effect on the Na-modification was also explored. The results showed that the device could produce good synergistic effect of microwave and mechanochemical actions, which markedly increased the preparation and modification effect of ultra-fine powder. Compared with the traditional Na-modification methods, co-actions of microwave and mechanochemistry can significantly increase the Na-modification efficiency of Ca-MMT.Microwave assisted action was successfully applied to the active ingredients extraction (Tanshinoneâ…¡A and Danshensu) of Chinese medicine Danshen as well as the preparation process of Al-pillared montmorillonite (Al-pillared MMT) and MgAl-NO3-LDHs. The factors of microwave assisted preparation process were studied, and the process conditions of microwave assisted preparation and extraction were also optimized. Compared with conventional extraction methods, the microwave-assisted extraction of effective components from Chinese medicine are characteristic of a high yield, high quality of products, a non-pollution and time-saving process.Tramadol hydrochloride (TH), Ambroxol hydrochloride (ABH), Cetirizine hydrochloride (CTH), Salbutamol sulfate (SS), Tanshinoneâ…¡A and Danshensu were chosen for the preparation of six kinds of inorganic layered mineral-drug composites, according to their molecular structure and characteristics, the efficacy, as well as the side effects. XRD, TG, FTIR and Scanning Electron Microscopy (SEM) analysis and High Performance Liquid Chromatography (HPLC) were used to characterize the structure of the composites. The adsorption characteristics and the adsorption dynamics of different drugs from aqueous solution onto Na-MMT and LDHs were studied respectively, and in vitro release characteristics were further determined in artificial simulated digestive juice.In inorganic layered mineral-drug composites, drug molecule configuration in the layered inorganic minerals depends on the drug molecule size and its functional group. For Na-MMT-TH (ABH, CTH, SS) composites, drugs TH, ABH, CTH, and SS in the Na-MMT laminates were with single-layer arrangement, titled at the angle of about 90o, 23.79o, 6.28o, 41.53o to the laminate respectively. Tanshinoneâ…¡A existed in the Al-pillared MMT interlayer with the obliquity of 54.85o. Danshensu exsited parallel with the MgAl-NO3-LDHs laminates for MgAl-NO3-LDHs-Danshensu composites. Drugs and inorganic layered minerals interacted in the form of hydrogen bonds. The temperature range and weight loss amount for the second weight loss phase of the composites were correlated with the drug categories.Initial drug concentration has a great influence on Na-MMT drug loading. During the initial stage of adsorption, Na-MMT drug loading increases significantly as initial drug concentration increase. For the systems with drug concentration beyond certain a value, the amplitude of Na-MMT drug loading improvement decreases. The effects of adsorption temperature and time on the Na-MMT drug loading are not so obvious. Na-MMT-ABH and LDHs-Danshensu are corresponding to the Langmuir isotherm model; Na-MMT-TH, Na-MMT-CTH and Na-MMT-SS fit the Freundlich isotherm model. The adsorption processes of the above drugs onto inorganic layered minerals are following the secondary kinetic model. For TH, ABH, CTH and SS, it is conferred that the intercalated structures are formed with Na-MMT. An intercalated structure was also formed between Danshensu and LDHs. Tanshinone IIA can be effectively adsorpted onto Al-pillared MMT, but the adsorption process does not fit the Freundlich isotherm model or the Langmuir isotherm model.In the artificial simulated digestive juice, Na-MMT-TH (ABH, CTH, SS) composites and LDHs-Danshensu composite can achieve drug sustained-release. In artificial simulated gastric juice, TH and ABH drug release from the composites are in line with the proliferation mechanism; ABH, CTH, SS and Danshensu release are consistent with non-Fick diffusion mechanism. Danshensu release is also in line with the concentration gradient proliferation and dissolved release mechanism. In the artificial simulated intestinal fluid, drug TH, ABH, CTH, SS, and Danshensu release from the composites follow the particle diffusion mechanism, while the release of TH, ABH and CTH is also consistent with the non-Fick diffusion mechanism. CTH and Danshensu release mechanism follow the concentration gradient mechanism. Since TanshinoneIIA reacts with the metal ions on the Al-pillared MMT laminates, the sustained TanshinoneIIA release can not be achieved.MMT and LDHs as novel sustained release drug carrier not only richen mineral material applied theoretical research, but also possesss important scientific significance and high social economic value.