药学学报, 2015, 50(8): 1045-1051
引用本文:
李金凤, 高明月, 王慧敏, 刘巧钰, 毛世瑞. 载白藜芦醇泊洛沙姆403/407混合胶束的制备及其体外性质[J]. 药学学报, 2015, 50(8): 1045-1051.
LI Jin-feng, GAO Ming-yue, WANG Hui-min, LIU Qiao-yu, MAO Shi-rui. Optimization and in vitro characterization of resveratrol-loaded poloxamer 403/407 mixed micelles[J]. Acta Pharmaceutica Sinica, 2015, 50(8): 1045-1051.

载白藜芦醇泊洛沙姆403/407混合胶束的制备及其体外性质
李金凤, 高明月, 王慧敏, 刘巧钰, 毛世瑞
沈阳药科大学药学院, 辽宁 沈阳 110016
摘要:
本文制备了载白藜芦醇的泊洛沙姆403/407混合聚合物胶束, 并通过优化处方实现药物的高负载和缓慢释放。首先采用薄膜分散法制备混合胶束, 并以包封产率、载药量和粒径为考察指标, 通过星点设计效应面法优化处方。测定空白载体的临界胶束浓度, 模拟生理条件下研究胶束的稀释稳定性, 透析法考察胶束的体外释放行为。结果表明, 实验所得最优处方的载药量和包封产率分别为11.78% 和82.51%, 粒子均一, 平均粒径为24 nm。在混合胶束中, 药物的溶解度为5.92 mg·mL-1, 与药物本身溶解度相比, 提高了约197倍。混合胶束具有很强的抗稀释能力, 且白藜芦醇可从混合胶束中缓慢释放达20 h以上, 其释放行为符合Higuchi方程。因此, 该混合胶束体系不仅可以显著提高白藜芦醇的溶解度, 还能实现药物的缓慢释放。
关键词:   
Optimization and in vitro characterization of resveratrol-loaded poloxamer 403/407 mixed micelles
LI Jin-feng, GAO Ming-yue, WANG Hui-min, LIU Qiao-yu, MAO Shi-rui
School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China
Abstract:
The objectives of this study are to prepare resveratrol loaded mixed micelles composed of poloxamer 403 and poloxamer 407, and optimize the formulation in order to achieve higher drug solubility and sustained drug release. Firstly, a thin-film hydration method was utilized to prepare the micelles. By using drug-loading, encapsulation yield and particle size of the micelles as criteria, influence of three variables, namely poloxamer 407 mass fraction, amount of water and feeding of resveratrol, on the quality of the micelles was optimized with a central composite design method. Steady fluorescence measurement was carried out to evaluate the critical micelle concentration of the carriers. Micelle stability upon dilution with simulated gastric fluid and simulated intestinal fluid was investigated. The in vitro release of resveratrol from the mixed micelles was monitored by dialysis method. It was observed that the particle size of the optimized micelle formulation was 24 nm, with drug-loading 11.78%, and encapsulation yield 82.51%. The mixed micelles increased the solubility of resveratrol for about 197 times. Moreover, the mixed micelles had a low critical micelle concentration of 0.05 mg·mL-1 in water and no apparent changes in particle size and drug content were observed upon micelles dilution, indicating improved kinetic stability. Resveratrol was released from the micelles in a controlled manner for over 20 h, and the release process can be well described by Higuchi equation. Therefore, resveratrol-loaded poloxamer 403/407 mixed micelles could improve the solubility of resveratrol significantly and sustained drug release behavior can be achieved.
Key words:   
收稿日期: 2015-05-07
基金项目: 国家自然科学基金资助项目 (81273446); 高等学校博士点基金资助项目 (20122134110005).
通讯作者: 毛世瑞
Email: maoshirui@syphu.edu.cn
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参考文献:
[1] Singh G, Pai RS. Recent advances of resveratrol in nanos­tructured based delivery systems and in the management of HIV/AIDS [J]. J Control Release, 2014, 194: 178-188.
[2] Zhang YH, Guo JG, Guo ZH, et al. Involvement of p38-p53 signal pathway in resveratrol-induced apoptosis in MCF-7 cells [J]. Acta Pharm Sin (药学学报), 2011, 46: 1332-1337.
[3] Wenzel E, Somoza V. Metabolism and bioavailability of trans-resveratrol [J]. Mol Nutr Food Res, 2005, 49: 472-481.
[4] Planas JM, Alfaras I, Colom H, et al. The bioavailability and distribution of trans-resveratrol are constrained by ABC transporters [J]. Arch Biochem Biophys, 2012, 527: 67-73.
[5] Chen D, Ding PT, Deng YH, et al. Advances in the study of polymeric micelles used in oral administration [J]. Acta Pharm Sin (药学学报), 2010, 45: 560-564.
[6] Kim S, Shi Y, Kim JY, et al. Overcoming the barriers in micellar drug delivery: loading efficiency, in vivo stability, and micelle-cell interaction [J]. Expert Opin Drug Del, 2010, 7: 49-62.
[7] Jokerst JV, Lobovkina T, Zare RN, et al. Nanoparticle PEGylation for imaging and therapy [J]. Nanomedicine, 2011, 6: 715-728.
[8] Mao SR, Tian Y, Wang LL. Research progress on drug nanocontainer-polymeric micelles [J]. J Shenyang Pharm Univ (沈阳药科大学学报), 2010, 27: 979-986.
[9] Dahmani FZ, Yang H, Zhou J, et al. Enhanced oral bioavailability of paclitaxel in pluronic/LHR mixed polymeric micelles: preparation, in vitro and in vivo evaluation [J]. Eur J Pharm Sci, 2012, 47: 179-189.
[10] Tian Y, Mao SR. Amphiphilic polymeric micelles as the nanocarrier for peroral delivery of poorly soluble anticancer drugs [J]. Expert Opin Drug Del, 2012, 9: 687-700.
[11] Zhang W, Shi Y, Chen YZ, et al. Multifunctional Pluronic P123/F127 mixed polymeric micelles loaded with paclitaxel for the treatment of multidrug resistant tumors [J]. Biomaterials, 2011, 32: 2894-2906.
[12] Guan YB, Huang JG, Zuo L, et al. Effect of Pluronic P123 and F127 block copolymer on P-glycoprotein transport and CYP3A metabolism [J]. Arch Pharm Res, 2011, 34: 1719- 1728.
[13] Li D, Sheng L, Li Y. Methods for the study of drug transporters [J]. Acta Pharm Sin (药学学报), 2014, 49: 963- 970.
[14] Chen LC, Sha XY, Jiang XY, et al. Pluronic P105/F127 mixed micelles for the delivery of docetaxel against Taxol-resistant non-small cell lung cancer: optimization and in vitro, in vivo evaluation [J]. Int J Nanomedicine, 2013, 8: 73-84.
[15] Zhao LY, Du JC, Duan YW, et al. Curcumin loaded mixed micelles composed of Pluronic P123 and F68: preparation, optimization and in vitro characterization [J]. Colloid Surf B Biointerfaces, 2012, 97: 101-108.
[16] Lee ES, Oh YT, Youn YS, et al. Binary mixing of micelles using Pluronics for a nano-sized drug delivery system [J]. Colloid Surf B Biointerfaces, 2011, 82: 190-195.
[17] Kulthe SS, Inamdar NN, Choudhari YM, et al. Mixed micelle formation with hydrophobic and hydrophilic Pluronic block copolymers: implications for controlled and targeted drug delivery [J]. Colloid Surf B Biointerfaces, 2011, 88: 691-696.
[18] Pandita D, Kumar S, Poonia N, et al. Solid lipid nanoparticles enhance oral bioavailability of resveratrol, a natural polyphenol [J]. Food Res Int, 2014, 62: 1165-1174.
[19] Narayanan NK, Nargi D, Randolph C, et al. Liposome encapsulation of curcumin and resveratrol in combination reduces prostate cancer incidence in Pten knockout mice [J]. Int J Cancer, 2009, 125: 1-8.
[20] Amri A, Chaumeil JC, Sfar S, et al. Administration of resveratrol: what formulation solutions to bioavailability limitations? [J]. J Control Release, 2012, 158: 182-193.
[21] Lu XW, Ji CB, Xu H, et al. Resveratrol-loaded polymeric micelles protect cells from Aβ-induced oxidative stress [J]. Int J Pharm, 2009, 375: 89-96.
[22] Carlson LJ, Cote B, Alani AWG, et al. Polymeric micellar co-delivery of resveratrol and curcumin to mitigate in vitro doxorubicin-induced cardiotoxicity [J]. J Pharm Sci, 2014, 103: 2315-2322.
[23] Gao Y, Li LB, Zhai GX. Preparation and characterization of Pluronic/TPGS mixed micelles for solubilization camptothecin [J]. Colloid Surf B Biointerfaces, 2008, 64: 194-199.
[24] Zhang W, Shi Y, Chen YZ, et al. The potential of Pluronic polymeric micelles encapsulated with paclitaxel for the treatment of melanoma using subcutaneous and pulmonary metastatic mice models [J]. Biomaterials, 2011, 32: 5934-5944.
[25] Zhang W, Hao JG, Shi Y, et al. Paclitaxel-loaded Pluronic P123/F127 mixed polymeric micelles: formulation, optimization and in vitro characterization [J]. Int J Pharm, 2009, 376: 176- 185.
[26] Mohanty ME, Rao VJ, Mishra AK. A fluorescence study on the interaction of telmisartan in triblock polymers pluronic P123 and F127 [J]. Spectrochim Acta A Mol Biomol Spectrosc, 2014, 121: 330-338.
[27] Vasilescu M, Bandula R, Lemmetyinen H. Micropolarity and microviscosity of Pluronics L62 and L64 core-shell aggregates in water at various concentrations and additives examined by absorption and fluorescence probes [J]. Colloid Polym Sci, 2010, 288: 1173-1184.
[28] Owen SC, Chan DPY, Shoichet MS. Polymeric micelle stability [J]. Nano Today, 2012, 7: 53-65.
[29] Chaibundit C, Ricardo NMPS, Costa VdMLL, et al. Micellization and gelation of mixed copolymers P123 and F127 in aqueous solution [J]. Langmuir, 2007, 23: 9229-9236.
[30] Chiappetta DA, Sosnik A. Poly(ethylene oxide)-poly(propylene oxide) block copolymer micelles as drug delivery agents: improved hydrosolubility, stability and bioavailability of drugs [J]. Eur J Pharm Biopharm, 2007, 66: 303-317.
[31] Hurst S, Loi CM, Brodfuehrer J, et al. Impact of physiological, physicochemical, and biopharmaceutical factors in absorption and metabolism mechanisms on the drug oral bioavailability of rats and humans [J]. Expert Opin Drug Metab Toxicol, 2007, 3: 469-489.
[32] Sawamoto T, Haruta S, Kurosaki Y, et al. Prediction of the plasma concentration profiles of orally administered drugs in rats on the basis of gastrointestinal transit kinetics and absorbability [J]. J Pharm Pharmacol, 1997, 49: 450-457.
[33] Gaucher G, Satturwar P, Jones MC, et al. Polymeric micelles for oral drug delivery [J]. Eur J Pharm Biopharm, 2010, 76: 147-158.
[34] Plapied L, Duhem N, des Rieux A, et al. Fate of polymeric nanocarriers for oral drug delivery [J]. Curr Opin Colloid Int Sci, 2011, 16: 228-237.
[35] Parmar A, Singh K, Bahadur A, et al. Interaction and solubi­lization of some phenolic antioxidants in Pluronic® micelles [J]. Colloid Surf B Biointerfaces, 2011, 86: 319-326.