In-situ Intestinal Absorption and Pharmacokinetic Investigations of Carvedilol Loaded Supersaturated Self-emulsifying Drug System

Background: Carvedilol (CD), a non-selective beta-blocker, is indicated for the management of mild to moderate congestive heart failure. After oral administration, CD is rapidly absorbed with an absolute bioavailability of 18-25% because of low solubility and extensive first-pass metabolism. Objective: The present investigation focused on enhanced oral delivery of CD using supersaturated self-emulsifying drug delivery (SEDDS) system. Methods: Optimized SEDDS consisted of a blend of Oleic acid and Labrafil-M2125 as an oil-phase, Cremophor-RH40, polyethylene glycol-400 and HPMC-E5 as a surfactant, co-surfactant and supersaturation promoter respectively. Formulations were characterized for physical characteristics, invitro release in simulated and biorelevant dissolution media, intestinal permeability and bioavailability studies in Wistar rats. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) analysis, scanning electron microscopy (SEM) studies were used to confirm the crystalline nature and shape of the optimized formulation. Results: DSC and XRD, SEM studies showed that the drug was in amorphous form, and droplets were spherical in shape. Dissolution studies clearly showed distinct CD release in compendial and biorelevant dissolution media. The results from permeability and in-vivo studies depicted 2.2-folds and 3.2-folds increase in permeability and bioavailability, respectively from supersaturated SEDDS in comparison with control. Conclusions: The results conclusively confirmed that the SEDDS formulation could be considered as a new alternative delivery vehicle for the oral supply of CD. Lay Summary: Carvedilol (CD) is a non-selective antihypertensive drug with poor oral bioavailability. Previously, various lipid delivery systems were reported with enhanced oral delivery. We developed suprsaturable SEDDS formulation with immediate onset of action. SEDDS formulation was developed and optimized as per the established protocols. The optimized SEDDS formulation was stable over three months and converted to solid and supersaturated SEDDS. The results from permeability and in-vivo studies demonstrated an enhancement in permeability and bioavailability from supersaturated SEDDS in comparison with control. The results conclusively confirmed that the SEDDS formulation could be considered as a new alternative delivery vehicle for the oral administration of CD.

METHOD DEVELOPMENT AND VALIDATION FOR THE SIMULTANEOUS DETERMINATION OF METOPROLOL AND ATORVASTATIN BY REVERSED-PHASE HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY IN ITS BULK AND PHARMACEUTICAL TABLET DOSAGE FORM USING BIORELEVANT DISSOLUTION MEDIA (FASTED STATE SMALL INTESTINAL FLUID)

Objective: A present investigation is based on method development and validation for the simultaneous determination of metoprolol and atorvastatin by reversed-phase high-performance liquid chromatography in its bulk and pharmaceutical dosage form using a biorelevant dissolution media (fasted state small intestinal fluid). Methods: The chromatographic separation technique performed by an isocratic method for this column used Inertsil ODS-3 (4.6×150 mm, 5 μm). The ratio of mobile phase used is phosphate buffer 4.8 pH: acetonitrile (35:65v/v), flow rate 1 ml/min, and analysis time 15.0 min, UV detection was at 244 nm. Results: According to the International Conference on Harmonisation Q2 (R1) guidelines, the method validation was done. Peaks were observed at 2.227 min and 5.819 min, concentration range of linearity was obtained at 50–250 μg/ml and 10–50 μg/ml, linearity correlation coefficients were 0.9997 and 0.9995, limit of detection was 0.33 mg/ml and 0.21 mg/ml, and limit of quantification was 1.08 mg/ml and 0.69 mg/ml for metoprolol and atorvastatin, respectively. Conclusion: The obtained results for this method validation are within acceptance criteria. This method was more economical and stable for routine analysis.

Development and Validation of a Robust and Efficient HPLC Method for the Simultaneous Quantification of Levodopa, Carbidopa, Benserazide and Entacapone in Complex Matrices

Purpose: A variety of fixed-dose combination products is used in the therapy of Parkinson Disease. However, to date a proper analytical method applicable for comparative screening of different antiparkinson products was not available. The objective of the present work was thus to develop and validate an analytical method for the simultaneous quantification of levodopa, carbidopa, benserazide and entacapone. The method should be applicable for quantifying samples from drug release experiments with marketed products and prototype formulations performed under compendial and biorelevant test conditions. Methods: A fast and robust method applicable for separation and quantification of the four compounds was developed and validated according to International Conference on Harmonization guidelines. Method validation covered applicability to a wide concentration range of all compounds and peak separation in complex sample matrices such as biorelevant dissolution media. Results: The compounds were successfully separated by using a gradient elution method on an endcapped LiChrospher 100 RP-18 (250 x 4.6 mm, 5 µm) column coupled with a LiChrospher 100 RP-18 precolumn (4 x 4 mm, 5 µm) at a column temperature of 35.0 °C and a flow rate of 1.50 mL/min. The injection volume was 30 µL and the detection wavelengths were 280 and 210 nm, respectively. For all drug/media combinations the method was linear (r2 > 0.999) for a concentration range corresponding to 1.25 - 125 % label claim (i.e. 200 mg levodopa/entacapone and 50 mg carbidopa/benserazide) released. All other validation parameters were in the specified limits over the same concentration range. Conclusion: The new method allows for robust and fast separation of levodopa, carbidopa, benserazide and entacapone without any interference caused by excipients or ingredients of compendial and biorelevant dissolution media and thus presents a valuable tool in both formulation development and in vitro drug release screening of numerous fixed-dose combinations of antiparkinson drugs. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.