口服磷酸奥司他韦缓释混悬液的制备及其体内外评价

doi:10.5246/jcps.2025.03.021

中国药学(英文版) ›› 2025, Vol. 34 ›› Issue (3): 269-283.DOI: 10.5246/jcps.2025.03.021

• 【药事管理与临床药学专栏】 • 上一篇

口服磷酸奥司他韦缓释混悬液的制备及其体内外评价

辛渊蓉¹, 窦玉甜¹, 陈晓琳¹, 冯颖淑³, 刘学盛¹, Caleb Kesse Firempong¹, 杨丹⁶, 刘宏飞¹^,²^,^*(), 何海冰⁴^,⁵^,^*()

^1. 江苏大学药学院, 江苏镇江 212013
^2. 江苏苏南药业工业有限公司, 江苏镇江 212400
^3. 镇江医学院医学化学研究所, 镇江市功能化学重点实验室, 江苏镇江 212028
^4. 沈阳药科大学药学院, 辽宁沈阳 110016
^5. 江苏海之宏生物医药有限公司, 江苏南通 226001
^6. 扬子江药业集团南京海陵药业有限公司, 江苏南京 210046

收稿日期:2024-06-17 修回日期:2024-07-21 接受日期:2024-10-23 出版日期:2025-03-31 发布日期:2025-04-01
通讯作者: 刘宏飞, 何海冰

Synthesis and in vitro/in vivo assessment of sustained-release oral oseltamivir phosphate suspension

Yuanrong Xin¹, Yutian Dou¹, Xiaolin Chen¹, Yingshu Feng³, Xuesheng Liu¹, Caleb Kesse Firempong¹, Dan Yang⁶, Hongfei Liu¹^,²^,^*(), Haibing He⁴^,⁵^,^*()

¹ College of Pharmacy, Jiangsu University, Zhenjiang 212013, Jiangsu, China
² Jiangsu Sunan Pharmaceutical Industrial Co., LTD., Zhenjiang 212400, Jiangsu, China
³ Zhenjiang Key Laboratory of Functional Chemistry, Institute of Medicine & Chemical Engineering, Zhenjiang College, Zhenjiang 212028, Jiangsu, China
⁴ Department of Pharmaceutics, Shen yang Pharmaceutical University, Shen yang 110016, Liaoning, China
⁵ Jiangsu Haizhihong Biomedical Co., Ltd, Nantong 226001, Jiangsu, China
⁶ Yangtze River Pharmaceutical Group Nanjing Hailing Pharmaceutical Company, Nanjing 210046, Jiangsu, China

Received:2024-06-17 Revised:2024-07-21 Accepted:2024-10-23 Online:2025-03-31 Published:2025-04-01
Contact: Hongfei Liu, Haibing He
Supported by:
2023 Nantong Jianghai Talents Project, 2023 Nantong Social Livelihood Science and Technology Plan, 2021 Jurong Social Development Science&Technology Program (Grant No. ZA42109), 2022 New Drugs and Platform Enhancement Project of the Yangtze Delta Drug Advanced Research Institute, China Postdoctoral Science Foundation (Grant No. 2020M681532), and Jiangsu Planned Projects for Postdoctoral Research Funds (Grant No. 2020Z209). Natural Science Research Projects of Universities in Jiangsu Province (Grant No. 20KJD350001).

摘要/Abstract

摘要：

磷酸奥司他韦(OP)是治疗流感最有效的药物之一, 面临着稳定性差、吞咽困难和苦味等挑战, 制约着儿童用药的依从性。因此, 本研究使用离子交换树脂作为载体来补救这种情况, 旨在开发一种新型的OP缓释混悬液。我们通过离子交换技术制备OP-药物树脂复合物(OP-DRC), 之后采用乳化蒸发法制备OP-包衣微囊(OP-CM)。利用单因素法结合正交试验设计确定OP缓释混悬剂的最佳配方, 研究缓释混悬液的体外/体内释放行为和药代动力学活性。SEM、XRD和ATR-FTIR结果表明, 药物-树脂复合物是通过离子键形成的。缓释混悬液的体外累积释放率分别为16% (1 h)、53% (6 h)和84% (24 h)。自制缓释混悬液与市售颗粒剂(t_1/2 = 8.466 h; T_max = 2 h; C_max = 0.631 μg/mL)相比, t_1/2 (21.518 h)增加, T_max (6 h)延迟, C_max (0.397 μg/mL)降低。AUC显示, 自制OP混悬剂的相对生物利用度为101%,高于市售OP颗粒剂。因此, 成功研制的口服磷酸奥司他韦缓释混悬液具有稳定、无味、易吞咽、灵活方便、缓释等特点, 可提高儿童的用药依从性。

关键词: 磷酸奥司他韦, 缓释, 离子交换树脂, 混悬液

Abstract:

Oseltamivir phosphate (OP), renowned as one of the most effective drugs for influenza treatment, encounters several challenges, including poor stability, difficulty in swallowing, and a bitter taste, thereby limiting its compliance, particularly among children. Consequently, this study aimed to devise a novel sustained-release suspension of OP employing an ion exchange resin as a carrier to address these challenges. The OP-drug resin complex (OP-DRC) was synthesized utilizing ion exchange technology, while OP-coated microcapsules (OP-CM) were fabricated via the emulsion-evaporation method. The optimization of the formulation process for the OP sustained-release suspension was achieved through a combination of single-factor experimentation and orthogonal experimental design. Furthermore, the drug release kinetics and pharmacokinetic properties of the sustained-release suspension were thoroughly evaluated both in vitro and in vivo. Scanning electron microscopy (SEM), X-ray diffraction (XRD), and attenuated total reflectance Fourier-transform infrared spectroscopy (ATR-FTIR) analyses confirmed the formation of drug-resin complexes via ionic bonding. The in vitro cumulative release rates were found to be 16% (1 h), 53% (6 h), and 84% (24 h), respectively. Notably, the self-made sustained-release suspension exhibited an extended half-life (21.518 h), delayed time to peak concentration (T_max) (6 h), and reduced maximum plasma concentration (C_max) (0.397 μg/mL) in comparison to commercial granules (half-life = 8.466 h; T_max = 2 h; C_max = 0.631 μg/mL). Additionally, the area under the curve (AUC) indicated that the bioavailability of the self-made OP suspension surpassed that of the commercial OP granules by 101%. These findings underscored the successful development of an oral OP sustained-release suspension characterized by stability, tastelessness, ease of swallowing, convenient administration, and sustained-release properties, thereby potentially enhancing drug compliance among children.

Key words: Oseltamivir phosphate, Sustained-release, Ion exchange resin, Suspension

Supporting:

辛渊蓉, 窦玉甜, 陈晓琳, 冯颖淑, 刘学盛, Caleb Kesse Firempong, 杨丹, 刘宏飞, 何海冰. 口服磷酸奥司他韦缓释混悬液的制备及其体内外评价[J]. 中国药学(英文版), 2025, 34(3): 269-283.

Yuanrong Xin, Yutian Dou, Xiaolin Chen, Yingshu Feng, Xuesheng Liu, Caleb Kesse Firempong, Dan Yang, Hongfei Liu, Haibing He. Synthesis and in vitro/in vivo assessment of sustained-release oral oseltamivir phosphate suspension[J]. Journal of Chinese Pharmaceutical Sciences, 2025, 34(3): 269-283.

图/表 14

Figure 1. Schematic diagram of static drug loading.

Table 1. The factor and level in the orthogonal experiment.

Table 2. Formulation of suspension.

Figure 2. (a) The SEM images of Amberlite® IRP69 blank resin; (b) The SEM images of OP-DRC; (c) XRD patterns of resin and OP samples; (d) IR spectra of OP (A), Amberlite® IRP 69 (B), OP drug-resin (C) and physical mixture (D).

Table 3. The dynamic profile patterns of OP loading at 37 °C.

Table 4. The k1, r and Q∞ at different temperatures.

Table 5. Equilibrium constant (Ke) of at different temperatures.

Table 6. Thermodynamic constants of OP at different temperatures.

Figure 3. Effect of coating time (a), coalescence temperature (b), coating materials (c), amount of coating materials (d), plasticizer amount to coating material (e) and concentration of material (f) on in vitro drug release of OP-CM.

Table 7. Analysis of the orthogonal experiment.

Figure 4. The in vitro release curves of three batches of OP-CM.

Table 8. OP suspension under accelerated conditions.

Figure 5. (a) Representative chromatogram of in vivo specificity investigations in rats. A: Blank plasma, B: OC + plasma, and C: OC+ IS + plasma at 12.5 μg/mL; (b) Calibration curve of OC; (c) Intra-day precision of OC; (d) Inter-day precision of OC.

Figure 6. (a) OC plasma concentration-time profiles after single oral administration of OP granules and sustained release suspension; (b) Pharmacokinetic parameters of CAM solution and CAM sustained suspension (n = 6).

参考文献 30

[1]	Roche, T. Capsules and for Oral Suspension. Complete Production Information. F. Hoffmann-La Roche Ltd, Basel, Switzerland. 2006.
[2]	Dutkowski, R. Oseltamivir in seasonal influenza: cumulative experience in low- and high-risk patients. J. Antimicrob. Chemother. 2010, 65, ii11–ii24.
[3]	Laver, W.G.; Bischofberger, N.; Webster, R.G. The origin and control of pandemic influenza. Perspect. Biol. Med. 2000, 43, 173–192.
[4]	Davies, B.E. Pharmacokinetics of oseltamivir: an oral antiviral for the treatment and prophylaxis of influenza in diverse populations. J. Antimicrob. Chemother. 2010, 65, ii5–ii10.
[5]	Chen, X.; Lu, A.; Wang, X.Y.; Wang, X.L.; Zheng, A.P.; Wang, J.C. Analysis of technical difficulties and new strategies of oral liquid pharmaceutical preparation for children. Acta Pharm. Sin. 2021, 56, 130–137.
[6]	Gupta, S.; Benien, P.; Sahoo, P.K. Ion exchange resins transforming drug delivery systems. Curr. Drug Deliv. 2010, 7, 252–262.
[7]	Alayoubi, A.; Daihom, B.; Adhikari, H.; Mishra, S.; Helms, R.; Almoazen, H. Development of a taste-masked oral suspension of clindamycin HCl using ion exchange resin Amberlite IRP 69 for use in pediatrics. Drug Dev. Ind. Pharm. 2016, 42, 1579–1589.
[8]	Rajesh, A.M.; Popat, K.M. Taste masking of azithromycin by resin complex and sustained release through interpenetrating polymer network with functionalized biopolymers. Drug Dev. Ind. Pharm. 2017, 43, 732–741.
[9]	van Riet-Nales, D.A.; Römkens, E.G.A.W.; Saint-Raymond, A.; Kozarewicz, P.; Schobben, A.F.A.M.; Egberts, T.C.G.; Rademaker, C.M.A. Oral medicines for children in the European paediatric investigation plans. PLoS One. 2014, 9, e98348.
[10]	Guo, X.D.; Chang, R.K.; Hussain, M.A. Ion-exchange resins as drug delivery carriers. J. Pharm. Sci. 2009, 98, 3886–3902.
[11]	Su, Q.X.; Huang, B.J. Study on clinical curative effect and adverse reactions of memantine hydrochloride in treatment of senile patients with parkinson disease with dementia. China Foreign Med. Treat. 2018, 37, 129–131.
[12]	Zhu, F.Q. Construction and in vivo/In vitro evaluation of levodopa/benserazide hydrochloride oral liquid controlled drug release system. Jiangsu Univ. 2018.
[13]	National Research Council (US) Committee for the Update of the Guide for the Care and Use of Laboratory Animals. Guide for the Care and Use of Laboratory Animals. 8th ed. Washington (DC): National Academies Press (US). 2011.
[14]	Boyd, G.E.; Adamson, A.W.; Myers, L.S. Jr. The exchange adsorption of ions from aqueous solutions by organic zeolites. II. Kinetics¹. J. Am. Chem. Soc. 1947, 69, 2836–2848.
[15]	Swarbrick, J. Encyclopedia of Pharmaceutical Technology: Volume 6. CRC press. 2013.
[16]	Choi, M.; Cho, H.S.; Srivastava, R.; Venkatesan, C.; Choi, D.H.; Ryoo, R. Amphiphilic organosilane-directed synthesis of crystalline zeolite with tunable mesoporosity. Nat. Mater. 2006, 5, 718–723.
[17]	Cuña, M.; Vila Jato, J.L.; Torres, D. Controlled-release liquid suspensions based on ion-exchange particles entrapped within acrylic microcapsules. Int. J. Pharm. 2000, 199, 151–158.
[18]	Gu, B.C.; Chen, R.; Cai, D.M.; Tang, W.; Liu, S.B.; Miao, L.Y. Determination of the dissolution of Oseltamivir phosphate capsule from three manufacturers by HPLC. West China J. Pharm. Sci. 2016, 31, 61–63.
[19]	Wei, Y.D.; Li, C.H.; Zhu, Q.; Zhang, X.; Guan, J.; Mao, S.R. Comparison of thermosensitive in situ gels and drug-resin complex for ocular drug delivery: in vitro drug release and in vivo tissue distribution. Int. J. Pharm. 2020, 578, 119184.
[20]	Liu, H.F. Investigation of the pharmacokinetics of a novel sustained release metformin hydrochloride suspension with ion exchange resin as carriers in beagle dogs. Afr. J. Pharm. Pharmacol. 2012, 6, 502–504.
[21]	Babu, B.; Meyyanathan, S.N.; Gowramma, B.; Muralidharan, S. Pharmacokinetic evaluation of newly developed oral immediate release and sustained release dosage forms of losartan potassium. J. Bioequivalence Bioavailab. 2013, 4, 121–127.
[22]	Qu, Y.; Lai, W.L.; Xin, Y.R.; Zhu, F.Q.; Zhu, Y.; Wang, L.; Ding, Y.P.; Xu, Y.; Liu, H.F. Development, optimization, and evaluation in vitro/in vivo of oral liquid system for synchronized sustained release of levodopa/benserazide. AAPS PharmSciTech. 2019, 20, 312.
[23]	Yang, Y.J.; Du, Y.; He, H.B.; Yu, Y.; Li, D.L.; Liu, H.F. Fabrication and evaluation for the novel ranitidine hydrochloride resinates and calculation of the kinetics and thermodynamics parameter for the ion exchange process. Pak. J. Pharm. Sci. 2021, 34, 1715–1722.
[24]	Fu, S.J. Determination of oseltamivir, itraconazole and their metabolites in plasma by liquid chromatographic-tandem mass spectrometry. Shenyang Pharmaceutical. Univ. 2007.
[25]	Kaushik, D.; Dureja, H. Ion exchange resin complexation technique for pharmaceutical taste masking: An overview. World J. Prep. Sch. 2015, 4, 600–614.
[26]	Liu, H.F.; Wang, M.Z.; Pan, W.S. Application of ion-exchange resin in the pharmaceutical preparation. Chin. J. Pharm. Online Ed. 2007, 5, 218–222.
[27]	Shang, R.; Liu, C.; Quan, P.; Zhao, H.Q.; Fang, L. Effect of drug-ion exchange resin complex in betahistine hydrochloride orodispersible film on sustained release, taste masking and hygroscopicity reduction. Int. J. Pharm. 2018, 545, 163–169.
[28]	Rahul, B.; Rahul, R.; Senthil, A.; Uday, M.S.; Byruppa, N.V. Formulation and evaluation of ion exchange resin matrix tablets of propranolol. Int. Res. J. Pharmacy. 2012, 3, 132–154.
[29]	Li, H.J.; Zhang, X.R.; Liu, H.Z.; Chen, C.X.; Li, S.M. Oral osmotic pump tablet of famotidine coated with Eudragit RS100 and Eudragit RL100. J. Shenyang Pharm. Univ. 2007, 24, 398–401.
[30]	Liu, H.F.; Xie, X.Y.; Chen, C.; Firempong, C.K.; Feng, Y.S.; Zhao, L.M.; Yin, X.Z. Preparation and in vitro/in vivo evaluation of a clonidine hydrochloride drug-resin suspension as a sustained-release formulation. Drug Dev. Ind. Pharm. 2021, 47, 394–402.

口服磷酸奥司他韦缓释混悬液的制备及其体内外评价

Synthesis and in vitro/in vivo assessment of sustained-release oral oseltamivir phosphate suspension

RichHTML

可视化

摘要/Abstract

引用本文

使用本文

图/表 14

参考文献 30

相关文章 15

编辑推荐

Metrics

本文评价

[1]	殷站暖, 孟祥欢, 冯颖淑, 李可, 唐欣怡, 刘宏飞, 何海冰, 米伟. 一种新型药用辅料阴离子交换树脂的合成[J]. 中国药学(英文版), 2025, 34(2): 109-125.
[2]	涂颖秋, 赖敏芳, 钟楠, 曹洪晓, 黄正刚. 13岁以下儿童使用泊沙康唑口服混悬液的真实世界安全性研究[J]. 中国药学(英文版), 2024, 33(4): 352-357.
[3]	高美琪, 吴佳丽, 朱文静, 张晓彤, 樊文玲. 利用热熔挤出技术制备和表征白藜芦醇缓释固体分散体[J]. 中国药学(英文版), 2023, 32(3): 165-179.
[4]	饶欣, 王长连, 许雄伟, 黄品芳, 王航, 林璐. 盐酸羟考酮缓释片与硫酸吗啡缓释片的临床疗效安全性对比[J]. 中国药学(英文版), 2016, 25(5): 387-394.
[5]	陈中芬, 刘文, 陈大业, 施晓伟, 王群. 戊己胃漂浮缓释片HPLC指纹图谱定性及定量分析[J]. 中国药学(英文版), 2015, 24(5): 310-317.
[6]	赵子明, 李佳林, 杨勇杰, 崔代超, 卢晓静, 范田园. 载舒尼替尼栓塞微球的制备及体外性质研究[J]. 中国药学(英文版), 2014, 23(8): 558-564.
[7]	单利, 范云周, 王玉丽, 陈红鸽, 高春生, 杨美燕. 效应面法优化尼美舒利双层缓释片处方[J]. 中国药学(英文版), 2014, 23(2): 89-93.
[8]	王金萍, 祝侠丽, 席延伟, 王德凤, 黄桂华^*. 洛莫司汀脂质体的制备及药代动力学和组织分布学研究[J]. , 2010, 19(5): 353-362.
[9]	崔保松, 马晓庆, 杨东辉*, 胡学桥, 蔡少青. 红果樫木树皮中罗希吐碱的纯化方法 [J]. , 2008, 17(2): 153-157.
[10]	武静, 王本杰, 魏春敏, 卜凡龙, 郭瑞臣^*. 硝苯地平缓释片人体药代动力学研究[J]. , 2007, 16(3): 192-196.
[11]	胡连栋^*, 王成伟. 头孢克洛缓释胶囊的研制及生物利用度研究[J]. , 2007, 16(1): 57-60.
[12]	吴静, 杨丽, 刘宏飞, 王超, 曹国良, 潘卫三^*. 阴离子交换树脂与双氯芬酸钠的交换反应特性[J]. , 2006, 15(4): 228-232.
[13]	刘宏飞, 苏显英, 李想, 赵欣, 臧蕾, 潘卫三^*. 盐酸二甲双胍缓释微囊的制备[J]. , 2006, 15(3): 155-161.
[14]	胡容峰^*, 朱家壁, 马凤余, 许向阳, 孙玉亮, 梅康康, 李师. 球晶制粒技术制备水飞蓟宾缓释微球[J]. , 2006, 15(2): 83-91.
[15]	欧阳德方, 聂淑芳, 孟晋, 杨星钢, 宋志全, 潘卫三^*. 复方二甲双胍/格列吡嗪双层缓释片: 设计与体外释放[J]. , 2005, 14(3): 169-172.