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

doi:10.5246/jcps.2025.03.021

Abstract

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:

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.

Figures/Tables 14

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

Table 2. Formulation of suspension.

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.

Table 7. Analysis of the orthogonal experiment.

Table 8. OP suspension under accelerated conditions.

References 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.