Studies On Drug Delivery System With Drug-resinate Complex And Its Pharmacokinetics

Ion-exchange resin (IER), as a new drug-delivery vehicle, has been extensively studied in the development of novel drug delivery system (DDS) because of its versatile properties. The drug-resinate complex (DRC) can be formed when a drug is mixed with the appropriate IER. The DRC has the same good flowability as the initiative IER, and can be further applied in pharmaceutical process. This dissertation describes fundamental studies on DDS of IER and its Pharmacokinetics, including as followings:1 The physical-chemical properties of pharmaceutical IER were thorough investigated, which laid a foundation for application of IER in the DDS.Results showed that the average diameter (do.5)of Amberlite IRP-64,Amberlite IRP-88 and Amberlite IRP-69 was 52.95μm,57.33μm and 62.31μm respectively. Those powders belong to the finest powders specified in the Chinese Pharmacopoeia (2005 edition). But, they have good flowability and their angle of repose is all less than 30°. IER has strong moisture absorption ability, it can swell in water. After it swells, the average particle size (do.5) of Amberlite IRP-69 increases by about 10μm. IRE, a kind of three-dimensional network polymer, is not soluble in water or the majority of solvents. But DRC can be formed by ion exchange reaction between IRE and drug-ions in water.2 The quantitive analysis methods of model drugs-----pseudoephedrine-resinate complex, azithromycin-resinate complex, codeine-resinate complex (microcapsule) and chlorpheniramine-resinate complex (microcapsule) were established as a basis for the further quality analysis of the DRC preparation. In order to determine the drug-loading capacity of DRC accurately, DRC dissociation should be carried out firstly to make sure the drug dissociates from the drug-resinate complex completely. Results showed:1g pseudoephedrine-resinate complexes (the drug-loading capacity was about 15%), as long as the dissociation medium contained more than 0.15 mol exchange ion, reached a dissociation balance in an hour and the drug was sufficiently released; 1g azithromycin-resinate complexes should be stirred 2 hours in 250ml dissociation medium [0.2 mol·L-1 KCl methanol-water (2:1)solution] to make sure drug was fully released;1g codeine- and chlorpheniramine-resinate complexes, as long as the dissociation medium contained more than 0.5 mol exchange ion, reached a dissociation balance in an hour and the drug was sufficiently released.3 Pseudoephedrine hydrochloride with moisture absorbability, as a model drug, was applied to study the preparation process of DRC.With Amberlite IRP 69,Amberlite IRP 64 and Amberlite IRP 88 as the drug carriers respectively, a stable pseudoephedrine-resinate complex under high humidity environment has been prepared by batch method of ion exchange. The moisture absorption-liquefaction problem of the capsules containing pseudoephedrine hydrochloride (for example, paracetamol, pseudoephedrine hydrochloride and dexromethorphan hydrobromide capsules) has been successfully solved, so the usual aluminum-plastic blister packaging can ensure the product quality in validity period. Results showed that the amount of IRE, pseudoephedrine hydrochloride and purified water had a direct impact on the drug-loading capacity of DRC and the drug adsorption efficiency. From the prospective of saving industrial production costs, the ratio of the three material above is reasonable for 10:2:100. The rise of temperature can improve both the drug adsorption efficiency and the drug-loading capacity of DRC.The rise of temperature was conducive to promoting exchange reaction because the drug-ion exchange reaction is endothermic.4 With IER as a drug carrier to prepare the bitter medicine-----azithromycin-resinate complexes, the drug bitterness was successful covered. Azithromycin, as a non-ionic drug, should be inonized in the acidic conditions, then absorbed to IER through ion-exchange reaction to prepare the DRC.The experiment showed that the citric acid was a good ionization reagent for azithromycin, and 0.37g:2g was the best ratio of citric acid to azithromycin. Azithromycin suspension without bitter taste could be prepared with azithromycin-resinate complexes and a suitable suspending medium [mixed 0.2% xanthan gum and 1.0% Avicel CL611 (microcrystalline cellulose and CMC-Na)].Results showed that the influence factors of drugs and ion exchange resins were miscellaneous, including the drug concentration, the reaction medium amount, mixing speed, mixing time, and so on.5 With the codeine phosphate and chlorpheniramine maleate as model drugs, the detailed study on preparation process of the compound drug-resinate complexes were carried out. Ion exchange process of codeine phosphate and chlorpheniramine maleate on Amberlite IRP-69 is exothermic, so the lower reaction temperature is conducive to the progression of ion exchange reaction, enhancing the drug utilization rate and the drug-loading capacity of DRC.Results showed that codeine phosphate and chlorpheniramine maleate had competitive relationship on the same ion-exchange resins, and the latter one had stronger combination ability. Therefore, chlorpheniramine maleate had a higher proportion in the compound drug-resinate complexes. But, as the ion exchange resins amount increased, the utilization rate of both codeine phosphate and chlorpheniramine maleate was improved. At the same time, the theory inventory rating was quite close to the drug-loading capacity of DRC.In clinical practice, Codeine phosphate and chlorpheniramine maleate are often used as compound preparation. It not only simplified the production process, but also increased production efficiency, by combining them in a given ratio to form codeine-and chlorphenramine-resinate complexes.6 Through X-ray diffraction and DSC analysis, it's found that the drug in DRC is combined with ion-exchange resins by chemical bond. The DRC, like ion exchange resin, is in amorphous state, with its crystallization peak disappearing. The DRC release dynamics can be defined by Viswanathan equation. It shows that the release kinetics is a diffusion process which is mainly correlated with composition and ionic strength of the release medium, and its diffusion coefficient affects the drug release.7 With IRE as the core material, through fluidized bed coating, solvent evaporation and surface coating, microencapsulated coating of DRC a small size(<100μm) was achieved to control drug release better. Furthermore, a sustained-release suspension of compound drug-resinate complex microcapsules was prepared to obtain a good sustained-release performance of liquid formulations. With organic solvents coating systems and water dispersion coating systems, codeine-resinate complexes and chlorpheniramine-resinate complexes was microencapsulated coated by fluidized bed coating. The influences of core material prosperity,coating liquid formulation and fluidized bed process parameters on the release of drug-resinate complexes microcapsules were investigated. Ethanol (95%), instead of acetone, was used as solvent of encapsulation to microencapsule codeine-resinate complexes and chlorpheniramine-resinate complexes. The formulation and process parameters were optimized by methods of single-factor evaluation and orthogonal experimental design. The surface coating process parameters and fotmulation parameters of codeine-resinate complexes and chlorpheniramine-resinate complexes were optimized with materials containing quaternary ammonium group (such as Eudragit RS100, etc.). Results showed that the drug-loaded capacity of DRC, concentration of coating materials, amount of reaction medium and reaction temperature all had significant influence on drug release of the DRC microcapsules.8 Based on the IRE, a sustained-release suspension of compound codeine-resinate and chlorpheniramine-resinate complexes microcapsules was prepared. Results showed that this suspension had good sustained-release properties in vitro. As ionic strength of release medium increased, the release of codeine-resinate complexes and chlorpheniramine-resinate complexes became faster. But they still maintained good sustained-release performance in a simulated human gastric juice and intestinal fluid medium. HPLC-MS/MS method was adopted to analyze blood drug concentration, and a detailed study of pharmacokinetics of the sustained-release suspension of compound codeine-resinate complex and chlorpheniramine-resinate complex microcapsules in beagle dogs was carried out. Results showed that, compared with chlorpheniramine maleate tablets and codeine phosphate tablets on the market, the sustained-release suspension of compound codeine-resinate complex and chlorpheniramine-resinate complex microcapsules had obvious sustained-release characteristics:longer Tmax, lower Cmax, extented t1/2 and MRT, but the extent of absorption was similar. The further study on its pharmacokinetics in the healthy adults is desirable.With IER as carrier, researches in this dissertation solved the moisture absorption and liquefaction problem of the capsules containing the moisture absorbable drug----pseudoephedrine hydrochloride, and improved the compliance of oral suspensions containing the bitter drug----azithromycin. We carried out comprehensive and in-depth studies on the application of IER in drug delivery systems and the drug pharmacokinetics of DRC.Meanwhile, we established systematic experimental methods and industrialized preparation process. These studies have important academic value and practical significance, in improving the technology of pharmaceutical preparations and promoting the development of pharmacy industry in China.