Enhanced Dissolution and Bioavailability of Raloxifene Hydrochloride by Co-grinding with Different Superdisintegrants

Abstract

The present study investigated the effect of co-grinding raloxifene HCL (RHCL) with different superdisintegrants, namely crospovidone (CP), croscarmellose sodium (CCS) and sodium starch glycolate (SSG), using a ball mill, in order to determine the potential effect on dissolution rate and bioavailability of raloxifene hydrochloride (RHCL). The dissolution studies of the co-ground compositions and the corresponding physical mixtures were carried out in U.S. Pharmacopeia (USP) Type II apparatus. The solid state interactions of the co-ground and the physical mixtures were evaluated by differential scanning calorimetry (DSC) and X-ray diffraction (XRD). The pharmacokinetics of co-ground mixture (1 : 5 RHCL : CP) and milled RHCL was evaluated following oral administration (25 mg/kg) in healthy female Sprague-Dawley rats. DSC studies showed that the crystalline nature of RHCL was reduced after co-grinding with superdisintegrants, while co-grinding with CP resulted in significant particle-size reduction of the mixture. Significant enhancement in dissolution rate was observed with coground mixture of RHCL with CP (1 : 5). The extent of the mean plasma exposures of RHCL was 7-fold higher in animals treated with co-ground mixture of RHCL, CP (1 : 5) compared to animals treated with milled RHCL. Co-grinding of RHCL with CP, reduced drug crystallinity, increased the rate and extent of dissolution, and improved bioavailability.

Nanoemulsion liquid preconcentrates for raloxifene hydrochloride: optimization and in vivo appraisal

“…5 Lipid-based formulations were recognized to decrease or eliminate the high-fat-meal effect, therefore increasing the solubility of class II compounds. 45 These results are in accordance with those obtained by Wempe et al 8 and Jagadish et al 10 who reported bioavailability studies on RLX in the fasted state. It was reported that administration of RLX with a standardized, high-fat meal insignificantly increased the systemic exposure of RLX.…”

“…RLX suspension in water (0.4% w/v) was added into the dissolution cup in 5 mL volume to contain the same drug amount as nanocarriers (20 mg). At selected time intervals (10,20,30,45,60,90, and 120 minutes), aliquots (5 mL) were withdrawn from the dissolution medium, filtered through a Millipore filter (0.45 µ) and replaced with an equivalent amount of the fresh dissolution medium. Concentrations of RLX were determined spectrophotometrically at 287 nm.…”

“…15,27 Preparation of RLX-loaded SNEDDS Preparation of nonalkalinized nanocarriers (NA-SNEDDS) RLX was added to the selected formulations based on the aforementioned optimization steps. The drug was added in incremental amounts (2,5,10,20,30,40,50, 60 mg/g), and dispersion was gently shaken at 60°C for 30 minutes. Shaking was aided by sonication and vortex mixing.…”

“…RLX in incremental amounts (2,5,10,20,30,40,50, 60 mg/g) was added to SNEDDS alkalinized with triethanolamine (TEA) (10% weight/weight [w/w]). Dispersion was gently shaken at 60°C for 30 minutes.…”

“…7 So far, formulation attempts to improve RLX characteristics and oral bioavailability have focused only on solubility or permeability enhancement of the drug, regardless of drug metabolism. Trials encompassed use of hydrophilic binders, 9 cogrinding technique, 10 cyclodextrin complexation, 8 and use of mucoadhesive microspheres of the complex to give a controlled release pattern. 11 Although the reported permeability of RLX as class II drug is high, one attempt has adopted enhancing in vitro intestinal permeability of drug via microemulsion technique and a water titration method.…”