Abstract
BCS class II drugs usually suffer inadequate bioavailability as dissolution step is the absorption rate limiting step. In this work, the effect of solubility increase at the main absorption site for these drugs was investigated using risperidone as a drug model. Liquisolid technique was applied to prepare risperidone per-oral tablets of high dissolution rate at intestinal pH (6.8) using versatile nonionic surfactants of high solubilizing ability [Transcutol HP, Labrasol and Labrasol/Labrafil (1:1) mixture] as liquid vehicles at different drug concentrations (10–30%) and fixed (R). The prepared liquisolid tablets were fully evaluated and the dissolution rate at pH 6.8 was investigated. The formulae that showed significantly different release rate were selected and subjected to mathematical modeling using DE25, MDT and similarity factor (f2). Depending on mathematical modeling results, formula of higher dissolution rate was subjected to solid state characterization using differential scanning calorimetric (DSC), infrared spectroscopy (IR) and X-ray diffraction (XRD). Finally, the drug bioavailability was studied in comparison to conventional tablets in rabbits. Results showed that liquisolid tablet prepared using Labrasol/Labrafil (1:1) mixture as liquid vehicle containing 10% risperidone is a compatible formula with law drug crystallinity and higher dissolution rate (100% in 25 min). The drug bioavailability was significantly increased in comparison to the conventional tablets (1441.711 μg h/mL and 137.518 μg/mL in comparison to 321.011 μg h/mL and 38.673 μg/mL for AUC and Cpmax, respectively). This led to the conclusion that liquisolid technique was efficiently improved drug solubility and solubility increase of BCS class II drugs at their main absorption site significantly increases their bioavailability.
Highlights
In order to achieve a desired pharmacological response, the drug must reach a reasonable significant concentration in plasma which is mainly correlated to its solubility in GIT fluids (Vemula et al, 2010), except pinocytosis, all other drug absorption mechanisms from GIT require the presence of drug in solution form (Paradkar & Bakliwal, 2008).For poorly water soluble drugs, mainly categorized as class II in biopharmaceutical classification system (BCS) classification system, the dissolution is the rate determining step in the absorption process (Takano et al, 2008)
Results showed that liquisolid tablet prepared using Labrasol/ Labrafil (1:1) mixture as liquid vehicle containing 10% risperidone is a compatible formula with law drug crystallinity and higher dissolution rate (100% in 25 min)
The prepared liquisolid mixtures were directly compressed into tablets without any additional processing steps, this gives the advantage of avoiding the wet granulation problems and save equipment
Summary
In order to achieve a desired pharmacological response, the drug must reach a reasonable significant concentration in plasma which is mainly correlated to its solubility in GIT fluids (Vemula et al, 2010), except pinocytosis, all other drug absorption mechanisms from GIT require the presence of drug in solution form (Paradkar & Bakliwal, 2008). Risperidone is categorized by biopharmaceutical classification system (BCS), as a class II drug of low solubility and high permeability, its absorption from GIT and bioavailability is mainly controlled by its dissolution rate (Silva et al, 2011). It is mainly absorbed (82.2% of the dose) in the upper part of the gastrointestinal tract, i.e. duodenum and jejunum of mild alkalinity, in vitro/in vivo correlation with level A (a point-topoint correlation) was proved in different dissolution media for Cpmax and AUC with low prediction error (510%) (Saibi et al, 2012). Investigation of the effect of solubility 329 expected negative effect on its bioavailability) to increase the drug concentration at the absorption site in GIT and maximize the absorption process with consequent expected higher bioavailability
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