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Research Paper
Journal of Pharmacy And Pharmacology
Preparation, characteristic and pharmacological study on inclusion complex of sulfobutylether-β-cyclodextrin with glaucocalyxin A Lili Rena, Jianghui Jinga, Guoguang Chena, Yanfei Miaoa and Ping Weib a
School of Pharmaceutical Sciences, bSchool of Life Science and Pharmaceutical Engineering, Nanjing University of Technology, Nanjing, China
Keywords characterization; cyclodextrin; glaucocalyxin A; inclusion complex Correspondence Ping Wei, School of Life Science and Pharmaceutical Engineering, Nanjing University of Technology, 5th Mofan Road, Nanjing, 210009, China. E-mail: [email protected] Received October 14, 2013 Accepted December 15, 2013 doi: 10.1111/jphp.12219
Abstract Objectives The objective of this study was to improve the water solubility and solubility of glaucocalyxin A (GLA) by producing its inclusion complex with sulfobutylether-β-cyclodextrin (SBE-β-CD). Methods The formation of its 1 : 1 complex with SBE-β-CD in solution was confirmed by phase-solution and spectral-shift studies. The interaction of GLA and SBE-β-CD was examined by differential scanning calorimetry, powder X-ray diffraction, Fourier transform infrared spectroscopy, proton nuclear magnetic resonance spectroscopy and ultraviolet-visible spectroscopy to determine the formation of the GLA–SBE-β-CD inclusion complex. Key findings The solubilities of GLA and its complexes were 2.38 × 102 and 1.82 × 104 μg/ml, respectively, and the values of the inclusion complexes were significantly improved by 76-fold compared with the solubility of free GLA. Moreover, a higher area under the curve0–∞ after inclusion technique was observed in the pharmacokinetics study. Conclusions The aforementioned results indicate that GLA–SBE-β-CD could be useful with a better solubility and sustained function in drug delivery.
Introduction Glaucocalyxin A (GLA) is a diterpenoid isolated from the etheral extract of the leaves of Rabdosia japonica (Burm. f.) Hara var. glaucocalyx (Maxim.) Hara, a traditional Chinese medicinal herb that grows in northeastern China.[1,2] GLA has been shown to have various biological activity such as inhibition of platelet aggregation induced by plateletactivating factor,[3] immunosuppression,[4] antioxidative and DNA-protecting activity,[5] and cytotoxicity.[6,7] However, GLA has poor solubility in water. Shang et al. investigated the inclusion complex of GLA with hydroxyproply-βcyclodextrin, and the increase of the aqueous solubility of GLA was only 13-fold.[8] At present, further study to achieve better aqueous solubility and dissolution rate of GLA by forming complexes with alternative natural cyclodextrins (CDs) have not been reported. Sulfobutylether β-CD (SBE-β-CD) is a chemically modified CD. It is a cyclic hydrophilic oligosaccharide that is negatively charged in aqueous media.[9] The water solubility of SBE-β-CD is significantly higher than that of β-CD.[10] Additionally, it does not exhibit the nephrotoxicity associ-
ated with β-CD. Nagase et al. reported that the drug inclusion complex with SBE-β-CD provides a protective effect against drug-induced cytotoxicity.[11] Because of these advantages, SBE-β-CD has been used as an excipient material to improve the physicochemical properties of poorly water-soluble drugs.[10,12] Hence, the present work aimed to investigate the possibility of improving the release properties of GLA via complexation with SBE-β-CD. The stoichiometry of the inclusion complex of GLA–SBE-β-CD system in aqueous media is reported. Ultraviolet-visible (UV/VIS) spectroscopy was adopted to evaluate the absorption spectrum of the GLA–SBE-β-CD complex in aqueous solution. In addition, the formation of the inclusion complexes in the solid state were characterized by differential scanning calorimetry (DSC) and Fourier transform infrared (FTIR) spectroscopy to verify the formation of the inclusion complex. Finally, the dissolution behaviours of GLA−SBE-β-CD in vitro and in vivo were compared with those of the pure drug.
© 2014 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 66, pp. 927–934
927
Inclusion complex of glaucocalyxin A
Lili Ren et al.
Materials and Methods
Dissolution studies
Materials
Dissolution studies on the complexes and pure GLA were carried out using a ZRS-8G dissolution tester (Haiyida, China). The paddle was set to rotate at 50 rpm, and the temperature of the dissolution medium was kept at 25 ± 0.5°C. Each formulation contained 1.0 mg GLA. Aliquots of the sample solutions in pure water were withdrawn at 2, 6, 10, 15, 20, 30, 40 and 60 min, and then filtered through a membrane filter (pore size 0.45 μm). The filtrates were analysed by HPLC.
GLA was obtained from the College of Pharmaceutical Science, Soochow University (Jiangsu, China), andSBEβ-CD was purchased from Nhwa Pharmaceutical Corporation (Xuzhou, China). All other chemicals and solvents were of analytical grade. The water used in the study was doubledistilled and deionized.
Preparation The 1 : 1 molar ratio GLA–SBE-β-CD inclusion complex was prepared using the co-evaporated method. An accurately weighed amount of SBE-β-CD was dissolved in double-distilled water.[13] Subsequently, the solution of GLA in ethanol was added slowly to the SBE-β-CD aqueous solution. The resulting suspension was stirred at room temperature for 24 h. It was then filtered through a 0.22-μm membrane filter and then dried under reduced pressure (
Research Paper
Journal of Pharmacy And Pharmacology
Preparation, characteristic and pharmacological study on inclusion complex of sulfobutylether-β-cyclodextrin with glaucocalyxin A Lili Rena, Jianghui Jinga, Guoguang Chena, Yanfei Miaoa and Ping Weib a
School of Pharmaceutical Sciences, bSchool of Life Science and Pharmaceutical Engineering, Nanjing University of Technology, Nanjing, China
Keywords characterization; cyclodextrin; glaucocalyxin A; inclusion complex Correspondence Ping Wei, School of Life Science and Pharmaceutical Engineering, Nanjing University of Technology, 5th Mofan Road, Nanjing, 210009, China. E-mail: [email protected] Received October 14, 2013 Accepted December 15, 2013 doi: 10.1111/jphp.12219
Abstract Objectives The objective of this study was to improve the water solubility and solubility of glaucocalyxin A (GLA) by producing its inclusion complex with sulfobutylether-β-cyclodextrin (SBE-β-CD). Methods The formation of its 1 : 1 complex with SBE-β-CD in solution was confirmed by phase-solution and spectral-shift studies. The interaction of GLA and SBE-β-CD was examined by differential scanning calorimetry, powder X-ray diffraction, Fourier transform infrared spectroscopy, proton nuclear magnetic resonance spectroscopy and ultraviolet-visible spectroscopy to determine the formation of the GLA–SBE-β-CD inclusion complex. Key findings The solubilities of GLA and its complexes were 2.38 × 102 and 1.82 × 104 μg/ml, respectively, and the values of the inclusion complexes were significantly improved by 76-fold compared with the solubility of free GLA. Moreover, a higher area under the curve0–∞ after inclusion technique was observed in the pharmacokinetics study. Conclusions The aforementioned results indicate that GLA–SBE-β-CD could be useful with a better solubility and sustained function in drug delivery.
Introduction Glaucocalyxin A (GLA) is a diterpenoid isolated from the etheral extract of the leaves of Rabdosia japonica (Burm. f.) Hara var. glaucocalyx (Maxim.) Hara, a traditional Chinese medicinal herb that grows in northeastern China.[1,2] GLA has been shown to have various biological activity such as inhibition of platelet aggregation induced by plateletactivating factor,[3] immunosuppression,[4] antioxidative and DNA-protecting activity,[5] and cytotoxicity.[6,7] However, GLA has poor solubility in water. Shang et al. investigated the inclusion complex of GLA with hydroxyproply-βcyclodextrin, and the increase of the aqueous solubility of GLA was only 13-fold.[8] At present, further study to achieve better aqueous solubility and dissolution rate of GLA by forming complexes with alternative natural cyclodextrins (CDs) have not been reported. Sulfobutylether β-CD (SBE-β-CD) is a chemically modified CD. It is a cyclic hydrophilic oligosaccharide that is negatively charged in aqueous media.[9] The water solubility of SBE-β-CD is significantly higher than that of β-CD.[10] Additionally, it does not exhibit the nephrotoxicity associ-
ated with β-CD. Nagase et al. reported that the drug inclusion complex with SBE-β-CD provides a protective effect against drug-induced cytotoxicity.[11] Because of these advantages, SBE-β-CD has been used as an excipient material to improve the physicochemical properties of poorly water-soluble drugs.[10,12] Hence, the present work aimed to investigate the possibility of improving the release properties of GLA via complexation with SBE-β-CD. The stoichiometry of the inclusion complex of GLA–SBE-β-CD system in aqueous media is reported. Ultraviolet-visible (UV/VIS) spectroscopy was adopted to evaluate the absorption spectrum of the GLA–SBE-β-CD complex in aqueous solution. In addition, the formation of the inclusion complexes in the solid state were characterized by differential scanning calorimetry (DSC) and Fourier transform infrared (FTIR) spectroscopy to verify the formation of the inclusion complex. Finally, the dissolution behaviours of GLA−SBE-β-CD in vitro and in vivo were compared with those of the pure drug.
© 2014 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 66, pp. 927–934
927
Inclusion complex of glaucocalyxin A
Lili Ren et al.
Materials and Methods
Dissolution studies
Materials
Dissolution studies on the complexes and pure GLA were carried out using a ZRS-8G dissolution tester (Haiyida, China). The paddle was set to rotate at 50 rpm, and the temperature of the dissolution medium was kept at 25 ± 0.5°C. Each formulation contained 1.0 mg GLA. Aliquots of the sample solutions in pure water were withdrawn at 2, 6, 10, 15, 20, 30, 40 and 60 min, and then filtered through a membrane filter (pore size 0.45 μm). The filtrates were analysed by HPLC.
GLA was obtained from the College of Pharmaceutical Science, Soochow University (Jiangsu, China), andSBEβ-CD was purchased from Nhwa Pharmaceutical Corporation (Xuzhou, China). All other chemicals and solvents were of analytical grade. The water used in the study was doubledistilled and deionized.
Preparation The 1 : 1 molar ratio GLA–SBE-β-CD inclusion complex was prepared using the co-evaporated method. An accurately weighed amount of SBE-β-CD was dissolved in double-distilled water.[13] Subsequently, the solution of GLA in ethanol was added slowly to the SBE-β-CD aqueous solution. The resulting suspension was stirred at room temperature for 24 h. It was then filtered through a 0.22-μm membrane filter and then dried under reduced pressure (
