Development of immediate-release formulation with reliable absorption of rivaroxaban in various meal regimes

The bioavailability of rivaroxaban at the higher doses (15 and 20 mg) is considerably reduced when the drug is administered on an empty stomach. This can lead to inadequate anticoagulant effect, and therefore, it is recommended to use the higher doses at fed state. However, proper posology may represent a barrier for some patients. Therefore, the aim of this study was to evaluate innovative rivaroxaban-containing formulations designed to eliminate the food effect to ensure reliable absorption and thus to improve patient adherence with the treatment.

Study Highlights

 

WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

The bioavailability of rivaroxaban at the higher doses is considerably reduced when the drug is administered on an empty stomach. This can lead to inadequate anticoagulant effect, and therefore, it is recommended to use the higher doses at fed state. However, proper posology may represent a barrier for some patients.

WHAT QUESTION DID THIS STUDY ADDRESS?

The clinical program was focused on the development of innovative rivaroxaban-containing formulations with diminished food effect to ensure reliable absorption and thus to improve patients’ adherence with the treatment.

WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

An innovative immediate release form of rivaroxaban with eliminated effect of food on drug bioavailability has been developed and bioequivalence irrespective of food administration with reference formulation under fed conditions has been documented in healthy human subjects.

HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Improved drug bioavailability may represent an important step toward increasing adherence to therapy and subsequently improving treatment outcomes and reducing health care costs spent for cardiovascular complications related to inadequate anticoagulation.

Three prototypes (Cocrystal, HPMCP and Kollidon) with rivaroxaban were developed and their bioavailability and food effect in comparison to the reference product was tested in open label, randomized, single oral dose, crossover studies, where test products were administered under fasting and fed conditions and the reference product was administered under fed conditions. Comparable bioavailability for all tested prototypes both under fed and fasting conditions was demonstrated as the 90% confidence intervals of the geometric mean ratios for area under the concentration–time curve remained within the standard acceptance range of 80.00%–125.00%.

An innovative immediate release form of rivaroxaban with no food effect on drug bioavailability has been developed, which may represent an important step toward increasing adherence, improving treatment outcome and reducing health care costs.

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Prepapration of formulation

Cocrystal prototype

Rivaroxaban Cocrystal was homogenized with lactose monohydrate, croscarmellose sodium, sodium lauryl sulfate, silicified cellulose, and sodium stearyl fumarate. The homogenized mixture was compacted to obtain a granulate. More detailed information regarding preparation and characterization of this prototype has been published.¹⁰

HPMCP prototype

The solid solution of rivaroxaban and HPMCP was prepared by spray-drying process. The weight ratio of the prepared solid solution was 1:3 (rivaroxaban:HPMCP). The rivaroxaban and the polymer in the mentioned weight ratio were dissolved in organic solvent/s (e.g., 2,2,2-trifluoroethanol). The prepared solution was spray dried using lab scale spray dryer Büchi B 290 with the following process parameters: inlet temperature of 90–100°C, feed rate of 1 kg/h, air atomization pressure of 40 m³/h and aspiration 85%. The product was then dried in vacuum oven at 45°C. The dried material was homogenized with lactose monohydrate, sodium cross carmellose, sodium lauryl sulfate, silicified cellulose, and sodium stearyl fumarate. The homogenized mixture was compacted to obtain a granulate.

Kollidon prototype

The solid solution of rivaroxaban, Kollidon VA64, and Polysorbate 80 was prepared by hot melt extrusion process. The weight ratio of the prepared solid solution was 1:4.5:0.055 (rivaroxaban:Kollidon VA64:Polysorbate 80). All the components of solid solution were homogenized in high-shear mixer. The homogenized mixture was then extruded using lab scale hot melt extruder Three-Tec, 12 mm with the following process parameters: temperature of heating segments of 140–200°C, screws speed of 50 rpm and feed rate of 200 g/h. The extrudate was then milled and homogenized with lactose monohydrate, sodium cross carmellose, sodium lauryl sulfate, silicified cellulose, and sodium stearyl fumarate. The homogenized mixture was compacted to obtain a granulate.

Jan Bosák, Martin Šíma, Tereza Krejčí, Iva Obadalová, Jaroslava Šmardová, Petr Kozlík, Tomáš Křížek, Josef Beránek, Tomáš Hauser, Ondřej Slanař, Development of immediate-release formulation with reliable absorption of rivaroxaban in various meal regimes, First published: 13 May 2024 https://doi.org/10.1111/cts.13820

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