Silymarin (SLM) is a new flavonoid compound extracted from silybum marianum. It is a yellowish powder substance containing silybinin, isosilybinin, silydianin and silychristin. Amongst these components the content of silybinin is the highest and its activity is the highest as well. Silymarin presents a large variety of physiological effects, such as liver protection, blood lipid reduction, anti-oxidation, diabetes prevention, myocardial protection, anti-platelet aggregation and antineoplasm. [see: Flora K, Hahn M, Rahn H, et, al. “Milk Thistle (silybum marianum) for the Therapy of Liver Diseases.” Am J Gastroenterol 93.13 (1998):139; Yan Yufeng & Yu Jiandong. “Chemical Composition of Silymarin Marianus and Recent Development of Its Pharmacological Research.” Chinese Pharmaceutical Affairs 14.5 (2000): 335.] However, the bioavailability of silymarin remains considerably low due to its poor solubility in water. In recent years, the research on new dosage forms and preparation methods of silymarin focuses on increasing its oral bioavailability, for example, preparing silymarin in the form of lecithin complex, solid dispersion or cyclodextrin inclusion compound [see: Giacomellis S, Gallo D, Apollonio P, et, al. “Silybin and Its Bioavailable Phospholipid Complex (IdB 1016) Potentiate in vitro and in vivo the Activity of Cisplatin.” Life Sci 70.12 (2002):1447; Li Fengqian, Hu Jinhong, Zhu Quangang, et, al. “Determination of total flavonoids in Silybinin Solid Dispersion.” Chinese Traditional and Herbal Drugs 33.1 (2002): 31; Li Fengqian, Hu Jinhong, Wang Hui, et, al. “Solubilization and Lattice Changing Effect of PEG 6000 Solid Dispersion System on Poorly Soluble Silymarin.” Pharmaceutica Sinica 37.4 (2002):294; Lirussi F, Beccarello A, Zanette G, et, al. “Silybin-beta-cyclodextrin in the Treatment of Patients with Diabetes Mellitus and Alcohol Liver Disease: Efficacy Study of a New Preparation of an Anti-oxidant Agent.” Diabets Nutr Metab 15.4 (2003):222.].
Compared with other said methods, solid dispersion technique is more extensively utilized in virtue of its simple preparation procedure and outstanding solubilization effect [see: Deng Li, et, al. “Research on Preparation Methods and in vitro Dissolution of Silymarin Solid Dispersion.” Journal of the Second Military Medical University 21.10 (2000):961; Wei Zhenping, Mao Shirui, Bi Dianzhou, et, al. “Dissolution Improvement of Cisapride by Solid Dispersion with HPMC,” Journal of Chinese Pharmaceutical Science 13.4 (2004):254; Cui Fude, Yang Mingshi, Jiang Yanyan. “Design of Sustained-release Nitrendipine Microspheres Having Solid Dispersion Structure by Quasi-emulsion Solvent Diffusion Method.” Journal of Controlled Release 97.3 (2003):375.]. When being prepared in the form of solid dispersion, the solubility and dissolution rate of the poorly soluble drug are enhanced, which consequently improve absorbability of the drug and increase its bioavailability. But such defects of the poorly soluble drug as frequent administrations and big difference between peak and trough concentrations remain unchanged. Controlled release preparation of drugs is being widely used in virtue of its less total amount and frequency of administration, which consequently avoids peak and trough phenomenon of plasma concentration, reduces toxic and side effects and improves patients' adaptability [see: Lee K, Nguyen T, Hanley T, et, al. “Nanostructure of Liquid Crystalline Matrix Determines in vitro Sustained Release and in vivo Oral Absorption Kenetics for Hydrophilic Model Drugs.” International Journal of Pharmaceutics 365.1-2 (2009): 190; Wang Jiexin, Wang Zhihui, Chen Jianfeng, et, al. “Direct Encapsulation of Water-soluble Drug into Silica Microcapsules for Sustained Release Applications.” Materials Research Bulletin 43.12 (2008): 3374.]. Therefore, the defects such as great fluctuation of plasma concentration and frequent administrations of the poorly soluble drug can be effectively avoided when the drug is prepared in slow-release form after having been solubilized.
In recent years, much attention has been attracted to the special structure and features of the mesoporous material. It refers to a type of material containing multiple pores with diameter between 2 to 50 nanometers. A mesoporous material can be disordered or ordered according to the structure of the mesopores. The ordered mesoporous material enjoys the following structural characteristics: 1. long-range structure being ordered; 2. pore size distribution being narrow and adjustable between 1.5 to 10 nanometers; 3. specific surface area reaching as high as 1000 m2/g; 4. high porosity and 5. rich unsaturated radicals on its surface. When used as a drug carrier, the ordered mesoporous material presents the following advantages: 1. being nontoxic, nonphysioactive and biocompatible; 2. having evenly distributed, adjustable pore canals, within which its rich silanic radicals act as active sites for combining organic guest molecules; the drug molecules, through combining with these radicals, distribute within the canals evenly as well. Since the drug is absorbed within the ordered mesoporous material, it acts in a slow-release way; 3. protecting the integrity of molecular structure of the drug. Therefore, an ideal controlled release can be achieved for the hydrophobic drug when the mesoporous material is adopted as the controlled release carrier. The release effect varies in relation to the structure of the pore canal of the ordered mesoporous material.
On the basis of “triple release” mechanism comprising quick-release of the solid dispersion, regular slow-release of the hydrophilic gel matrix and the long-acting slow-release of the ordered mesoporous material, this invention is intended to prepare a 72-hour controlled release formulation of silymarin encompassing both quick-release and double slow-release, and presenting double pharmacokinetic effects of high-efficacy and long action.