Risk assessment and QbD based optimization of an Eprosartan mesylate nanosuspension: In-vitro characterization, PAMPA and in-vivo assessment.

Quality by design (QbD) principles were implemented to understand the product and process variables of sonoprecipitation technique, for preparation of eprosartan mesylate (EM) nanosuspension. Quality risk management approach was utilized to identify and assess high-risk attributes affecting critical quality attributes (CQA's), prioritizing the number of experiments. The effect of critical material attributes (CMA's) and critical process parameters (CPP's) (soluplus concentration, drug concentration ultrasonication amplitude) on z-average particle size and PDI were investigated using a central composite face-centered design (CCF). Further, design space with criteria set of CMA's and CPP's was established to offer assurance of quality. The optimal formulation, identified using numerical optimization method, was further lyophilized and evaluated for redispersibility, solubility saturation, dissolution kinetic and in-vitro dissolution behavior. The EM nanoparticles were in an amorphous state as confirmed by differential scanning calorimetry (DSC) and X-ray diffraction (XRD) studies. The stability study conducted for a span of 6 months attests physical and chemical stability of EM dry nanosuspension in an amorphous state when stored at 4 °C. The enhanced solubility and in-vitro dissolution of EM nanosuspension may be attributed to the reduced particle size and alteration of the physical state from a crystalline to an amorphous state. Further, the optimized formulation was subjected to in-vitro and ex-vivo transport study using parallel artificial membrane permeability assay (PAMPA) and rat everted gut sac model respectively. The transport studies revealed successful permeation enhancement of EM nanoparticle when compared with EM API and physical mixture (PM). The absolute bioavailability of EM API was 7.1% and improved to 39.9% for EM nanosuspension, suggesting that nanoformulation had overcome solubility and permeability limited bioavailability which was observed with EM API.

Enhanced dissolution/caco-2 permeability, pharmacokinetic and pharmacodynamic performance of re-dispersible eprosartan mesylate nanopowder.

Eprosartan mesylate is an angiotensin receptor blocker which suffers from extremely poor bioavailability owing to its poor solubility and poor permeability. The rationale of the present work was to design the drug delivery system capable of overcoming these constraints. Nanoformulation of eprosartan mesylate was developed using ultrasonic wave-assisted liquid-antisolvent technique. Nanoformulation was further freeze dried with the addition of 1% of mannitol resulting in formation of re-dispersible EPM nanopowder. To prove our proof of principle, the re-dispersed nanopowder with z-average particle size 165.2 ±â€¯1.8 nm was evaluated enormously for in-vitro dissolution behaviour and permeability assay through Caco-2 cell model. In-vitro dissolution study was performed at pH 1.2, pH 4.5 and pH 6.8. Result demonstrates enhanced dissolution from EPM nanopowder with negligible pH dependence. Transport studies accomplished using validated Caco-2 based cell model showed 11-fold enhanced apparent permeability of redispersed nanopowder when compared to pure EPM and corresponding physical mixture (p < 0.0001). In-vivo study reveals, exceptionally strong variations in plasma concentration of EPM through nanopowder (62 mg/kg) formulation when compared with physical mixture and pure EPM (62 mg/kg) group. Moreover, study manifests that 5-fold lower dose (12.4 mg/kg) of developed formulation yields higher exposure (4600 ±â€¯36 ng·mL-1·h) than pure EPM (2349 ±â€¯34 ng·mL-1·h) and corresponding physical mixture (2456 ±â€¯49 ng·mL-1·h) at therapeutic dose (62 mg/kg). Further, L-NAME induced hypertensive model was undertaken to investigate effect of reduced dose of EPM nanopowder on systolic blood pressure, biochemical analysis and histopathology of heart. Results revealed pronounced antihypertensive potential of re-dispersed EPM nanopowder at 5-fold lower dose (12.4 mg/kg). In conclusion, our study indicates that nanopowder delivery might be the promising approach for providing enhanced oral bioavailability at lower dose.

Understanding peroral absorption: regulatory aspects and contemporary approaches to tackling solubility and permeability hurdles.

Oral drug absorption is a process influenced by the physicochemical and biopharmaceutical properties of the drug and its inter-relationship with the gastrointestinal tract. Drug solubility, dissolution and permeability across intestinal barrier are the key parameters controlling absorption. This review provides an overview of the factors that affect drug absorption and the classification of a drug on the basis of solubility and permeability. The biopharmaceutical classification system (BCS) was introduced in early 90׳s and is a regulatory tool used to predict bioavailability problems associated with a new entity, thereby helping in the development of a drug product. Strategies to combat solubility and permeability issues are also discussed.