Preparation And Drug Release Behavior Studies Of Drug-Loaded Microspheres Using Carrageenan As Matrix

Carrageenan is an important component of the marine resources. It has attracted people's attentions for that carrageenan can be used to develop anti-tumor, anti-virus(anti-HSV, anti-HIV), anti-aging medicines as its unique efficacy, low toxicity. It is often used as the skeleton, embedded and microencapsulated materials for sustained release taking advantages of its solubility, polyelectrolyte and gel properties.In this paper, low molecular weight carrageenan microspheres and composite carrageenan / starch microspheres were prepared using carrageenan as matrix. The optimized processes were studied. Drug release behavior was investigated through model calculations and analysis, combined with the results of experiments. The mechanisms were also explored. The specific studies were as follows:1. Preparation of low molecular weight carrageenanFirst of all, the carrageenan raw materials were purified by KCl classification method, and then low-molecular-weight carrageenan were prepared by the degradation of hydrogen peroxide. Through discussion of factors (carrageenan concentration, H2O2 dosage, reaction temperature, time) on the impact of degradation products, the relationship between the reaction conditions and molecular weight was obtained. In addation, via IR analysis, the results show that structures of raw materials and final products were not changed. The carrageenan's molecular weight range is controllable by this method which is convenient and effective. The products yield was high. 2. Preparation of drug-loaded carrageenan microspheres and the properties researchSynthesis of microspheres: Carrageenan microspheres were synthesized in water-in-oil emulsion under high speed stirring, and cyclohexane and chloroform were used as oil phase, alkaline solution of Low-Molecular-Weight-κ-Carrageenan (LMW-κC) as water phase, Levofloxacin(LVFX) as model drug and Epichlorohydrin as cross-linking agent.In the preparing process, the concentration of carrageenan, carrageenan and drug mass ratio, emulsifier, oil-water ratio, the amount of crosslinking agent, crosslinking time were investigated according to their influences on the size and encapsulation efficiency and drug loading of microspheres. Through the central composite design– response surface method, the mathematical models of evaluation indicators and impact factors were established, the process were optimized.The microspheres with good spherical, the average drug loading to 5.20%, entrapment efficiency to 20.81%, could be obtained when using Span80 for 2%, alkaline solution of LMW-κC for 8%, cyclohexane and chloroform as oil phase, carrageenan and drug mass ratio for 3:1.Infrared spectroscopy and differential thermal analysis indicates that Levofloxacin was wrapped in the microspheres. The morphological and physicochemical properties of carrageenan microspheres were also studied. They were white or light yellow, spherical particles, with size ranging approximately from 5 to 18μm. Rest angle of the microsphers was 32.40°, and bulk density was 0.54g/ml. Water swelling for 24h was 30.86±2.44%. The residue of cyclohexane was <3.88mg/g, chloroform residual was <0.06mg/g, epichlorohydrin residues was <0.05mg/g.3. Study of carrageenan and starch composite microspheresPreparation and characteristics of carrageenan and starch blend films: Carrageenan and starch composite membrane were prepared by cast using solution blending method. Water resistance, tensile strength, transparency and thermal stability of the blend films were examined. The results show that with an increase of starch content, water resistance increased, tensile strength increased first then decreased, transparency reduced, thermal stability improved. Preparation of composite carrageenan and starch microspheres: Composite carrageenan and starch microspheres were prepared by emulsion cross-linking method, and the best conditions were identified. Under optimum conditions, the average diameter of composite microspheres was 11.18μm, particle size distribution range was 7 to 22μm, accounted for 92.4 % of the total number, the average drug loading was 9.44%, and the encapsulation efficiency was 30.69%. All the three batches have uniform particle size, good dispersion, and fine flow characteristics. Infrared spectroscopy studies have shown that blends materials have a stronger role between the hydroxy and epichlorohydrin. Drug was encapsulated in microspheres.4. Explore the in vitro release and doing model calculationsThe in vitro release of drug-loaded carrageenan microspheres and composite carrageenan/starch microspheres were researched. Different drug-carrier mass ratio, amount of cross-linker, cross-linking time on drug release rate were investigated. Commonly used models in vitro release were fitted. It was found that Weibull model and Peppas model can be in line with the release characteristics better. As was calculated by Peppas model, t1/2 of Levofloxacin was approximately 24.16min, LVFX-κCMS 51.41min, composite LVFX-κC-St-MS 65.12min. It showed that after prepared into microspheres, the drug had sustained release significantly, and composite LVFX-κC-St-MS was more obviously.