Microenvironmental pH-modified Amisulpride-Labrasol matrix tablets: development, optimization and in vivo pharmacokineti
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ORIGINAL ARTICLE
Microenvironmental pH-modified Amisulpride-Labrasol matrix tablets: development, optimization and in vivo pharmacokinetic study Nihal Farid Younes 1 & Abd El-Halim I. El Assasy 1 & Amal I.A. Makhlouf 1
# Controlled Release Society 2020
Abstract Amisulpride (AMS) is atypical antipsychotic with a weak basic nature (pKa 9.37), which results in low solubility in the high pH of the intestine. It is also recognized as a substrate of P-glycoprotein efflux pump. Both factors lead to its low oral bioavailability (48%). The daily dose of AMS is between 200 and 1200 mg to be taken in divided doses which compromise patient compliance. Therefore, controlled release formulation of AMS is of clinical significance. AMS was formulated into matrix tablets containing Labrasol, P-glycoprotein efflux inhibitor, and a penetration enhancer, using direct compression technique. The tablets were prepared according to 21·41 factorial design using two polymers, namely, HPMC and Carbopol 934 at four concentrations (20%, 30%, 40%, 50%). Percentage AMS released after 2 h (Q2hr%) and 8 h (Q8hr%) were chosen as dependent variables. Two acidic pH modifiers (fumaric acid and tartaric acid) at two levels (15% and 30%) were incorporated in the tablet according to 22 factorial design. All formulae with acidic pH modifier had similarity factor (f2) ≥ 50 proving the pH independent release of AMS. The pharmacokinetic study in rabbits revealed 30% enhancement of the oral absorption AMS imparted by the pHmodified matrix tablet containing Labrasol.
Keywords Matrix tablet . Amisulpride . pH-independent . Labrasol . Controlled release Abbreviations AMS Amisulpride HPMC Hydroxypropyl methyl cellulose pHM Microenvironmental pH GIT Gastrointestinal tract ALPE Amisulpride-Labrasol penetration enhanced DSC Differential scanning calorimetry FTIR Fourier transform infra-red spectroscopy f2 Similarity factor LC/MS/MS Liquid chromatography-tandem mass spectrometry SD Standard deviation ANOVA Analysis of variance AUC Area under the curve RB Relative bioavailability
* Amal I.A. Makhlouf [email protected]; [email protected] 1
Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Kasr El Aini, Cairo 11562, Egypt
Introduction Amisulpride (4-amino-N-[(1-ethylpyrrolidin-2-yl) methyl]5ethylsulfonyl-2-methoxy-benzamide), a second-generation antipsychotic, is a substituted benzamide acting primarily as a D2 and D3 receptor antagonist [1, 2]. Its weak basic nature (pKa 9.37) causes incomplete dissolution in the high pH of the intestine [3]. In addition, it is recognized as a substrate of Pglycoprotein efflux pump which expels most of the absorbed drug back into the gut lumen [4]. These factors caused the oral bioavailability of the drug to be approximately 48% [5, 6]. The dose of AMS ranges from 200 to 1200 mg in divided doses, which results in compliance problems [7]. In addition, it was reported that controlled release formulation might increase the bioavailability of drugs that undergo exten
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