Assessment of Dose Proportionality of Rivaroxaban Nanocrystals
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Research Article Assessment of Dose Proportionality of Rivaroxaban Nanocrystals Huriye Demir,1 Tugba Gulsun,1 Melike Hacer Ozkan,2 Emirhan Nemutlu,3 Selma Sahin,1 and Levent Öner1,4
Received 2 May 2020; accepted 27 July 2020 Abstract. Rivaroxaban (RXB) is a class II drug, according to the Biopharmaceutics Classification System. Since its bioavailability is low at high doses, dose proportionality is not achieved for pharmacokinetic parameters. However, when taken with food, its bioavailability increases at high doses. In this study, nanocrystal technology was used to increase the solubility and, hence, the bioavailability of RXB. Pluronic F127, pharmacoat 603, and PVP K-30 were used as stabilizers to prepare RXB nanosuspension, combining ball mill and high pressure homogenization methods. Particle sizes of RXB in nanosuspension (formulation A:348 nm; formulation B:403 nm) and nanocrystal formulations (formulation A:1167 nm; formulation B:606 nm) were significantly reduced (p < 0.05) compared to those of bulk RXB. In both formulations, 80% of the drug dissolved in 30 min. For dose proportionality evaluation, 3, 10, and 15 mg/kg of RXB nanosuspensions (formulation B) were administered to rabbits. The dose proportionality for AUC and Cmax of RXB nanocrystals was assessed by the power model, variance analysis of pharmacokinetic parameters, linear regression, and equivalence criterion methods. Dose proportionality for AUC was achieved at doses between 10–15 and 3–15 mg/kg. In conclusion, the preparation of a nanocrystal formulation of RXB improved its dissolution rate and pharmacokinetic profile. KEY WORDS: rivaroxaban; nanocrystals; pharmacokinetics; dose proportionality; dissolution rate.
INTRODUCTION Venous thromboembolism (VTE) is a disease that causes morbidity and mortality in newly admitted or hospitalized patients. There are two types of VTE: deep vein thrombosis (DVT) and pulmonary embolism (PE) (1,2). The reported incidence rates for PE (with or without DVT) are between 29 and 78 per 100,000 person-year, respectively, and that for DVT alone (without PE) are between 45 and 117 per 100,000 person-year, respectively (3). In patients with symptomatic VTE, especially in those currently affected by it, the risk of recurrence (including non-fatal and fatal PE) continues for many years (4). In addition, complications such as chronic pulmonary hypertension post-PE and post-thrombotic syndrome after DVT may occur in the long term (1). Therefore,
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Department of Pharmaceutical Technology, Faculty of Pharmacy, Hacettepe University, 06100, Ankara, Turkey. 2 Department of Pharmacology, Faculty of Pharmacy, Hacettepe University, 06100, Ankara, Turkey. 3 Department of Analytical Chemistry, Faculty of Pharmacy, Hacettepe University, 06100, Ankara, Turkey. 4 To whom correspondence should be addressed. (e–mail: [email protected]) Abbreviations: RXB, Rivaroxaban; P127, Pluronic F127; P 603, Pharmacoat 603; PS, Particle size (nm); PDI, Polydispersity index; ZP, Zeta potential (mV); AL, After lyophilization; CI, Confidence inte
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