Design and optimization of self-microemulsifying drug delivery system (SMEDDS) of felodipine for chronotherapeutic application

The objective of this research work was to design, develop and optimize the self micro-emulsifying drug delivery system (SMEDDS) of Felodipine (FL) filled in hard gelatine capsule coated with polymer in order to achieve rapid drug release after a desired time lag in the management of hypertension. Microemulsion is composed of a FL, Lauroglycol FCC, Transcutol P and Cremophor EL. The optimum surfactant to co-surfactant ratio was found to be 2:1. The resultant microemulsions have a particle size in the range of 65-85 nm and zeta potential value of -13.71 mV. FL release was adequately adjusted by using pH independent polymer i.e. ethyl cellulose along with dibutyl phthalate as plasticizer. Influence of formulation variables like viscosity of polymer, type of plasticizer and percent coating weight gain was investigated to characterize the time lag. The developed formulation of FL SMEDDS capsules coated with ethyl cellulose showed time lag of 5-7 h which is desirable for chronotherapeutic application

Respirable controlled release polymeric colloid (RCRPC) of bosentan for the management of pulmonary hypertension: in vitro aerosolization, histological examination and in vivo pulmonary absorption

Bosentan is an endothelin receptor antagonist (ERA) prescribed for patients with pulmonary arterial hypertension (PAH). The oral delivery of bosentan possesses several drawbacks such as low bioavailability (about 50%), short duration of action, frequent administration, hepatotoxicity and systemic hypotension. The pulmonary administration would circumvent the pre-systemic metabolism thus improving the bioavailability and avoids the systemic adverse effects of oral bosentan. However, the short duration of action and the frequent administration are the major drawbacks of inhalation therapy. Thus, the aim of this work is to explore the potential of respirable controlled release polymeric colloid (RCRPC) for effective, safe and sustained pulmonary delivery of bosentan. Central composite design was adopted to study the influence of formulation and process variables on nanoparticles properties. The particle size, polydispersity index (PDI), entrapment efficiency (EE) and in vitro bosentan released were selected as dependent variables. The optimized RCRPC showed particle size of 420 nm, PDI of 0.39, EE of 60.5% and sustained release pattern where only 31.0% was released after 16 h. The in vitro nebulization of RCRPC indicated that PLGA nanoparticles could be incorporated into respirable nebulized droplets better than drug solution. Pharmacokinetics and histopathological examination were determined after intratracheal administration of the developed RCRPC to male albino rats compared to the oral bosentan suspension. Results revealed the great improvement of bioavailability (12.71 folds) and sustained vasodilation effect on the pulmonary blood vessels (more than 12 h). Bosentan-loaded RCRPC administered via the pulmonary route may therefore constitute an advance in the management of PAH

Contribution of both olfactory and systemic pathways for brain targeting of nimodipine-loaded lipo-pluronics micelles: in vitro characterization and in vivo biodistribution study after intranasal and intravenous delivery

Nimodipine (NM) is the only FDA-approved drug for treating subarachnoid hemorrhage induced vasospasm. NM has poor oral bioavailability (5–13%) due to its low aqueous solubility, and extensive first pass metabolism. The objective of this study is to develop radiolabeled NM-loaded LPM and to test its ability prolong its circulation time, reduce its frequency of administration and eventually target it to the brain tissue. NM was radiolabeled with 99mTc by direct labeling method using sodium dithionite. Different reaction conditions that affect the radiolabeling yield were studied. The in vivo pharmacokinetic behavior of the optimum NM-loaded LPM formulation in blood, heart, and brain tissue was compared with NM solution, after intravenous and intranasal administration. Results show that the radioactivity percentage (%ID/g) in the heart of mice following administration of 99mTc-NM loaded LPM were lower compared with that following administration of 99mTc-NM solution, which is greatly beneficial to minimize the cardiovascular side effects. Results also show that the %ID/g in the blood, and brain following intravenous administration of 99mTc-NM-loaded LPM were higher at all sampling intervals compared with that following intravenous administration of 99mTc-NM solution. This would be greatly beneficial for the treatment of neurovascular diseases. The drug-targeting efficiency of NM to the brain after intranasal administration was calculated to be 1872.82%. The significant increase in drug solubility, enhanced drug absorption and the long circulation time of the NM-loaded LPM could be promising to improve nasal and parenteral delivery of NM

Effect of Different Meltable Binders on the Disintegration and Dissolution Behavior of Zolmitriptan Oromucosal Fast Melt Tablets

Objective: Fast melt tablets and sublingual route have been widely used for providing quick onset of action with the avoidance of first pass metabolism. The objective of this work was to compare the effect of different meltable binders namely; polyethylene glycol (PEG) 4000, pluronic F127 and pluronic F68 on the performance of fast release tablets of the model drug zolmitriptan prepared using the melt granulation technique regarding disintegration time (DT) and dissolution rate (DR) as criteria for rapid absorption and hence quick onset of action. Zolmitriptan is a potent antimigraine drug. Current oral zolmitriptan tablets suffer from slow onset of action, poor bioavailability and large inter-subject variability. Methods: 33 factorial design was adopted. The effect of binder type, binder concentration and croscarmellose sodium (disintegrant) concentration were studied on DT and DR. Results: The three factors were found to significantly affect the DR and the inverse square root of DT and significant interactions were elucidated. Conclusion: Although satisfactory results were obtained regarding DR, modifications using different excipients and or preparation methods should be considered to comply with pharmacopoeia requirement for DT

Effect of Different Meltable Binders on the Disintegration and Dissolution Behavior of Zolmitriptan Oromucosal Fast Melt Tablets

Objective: Fast melt tablets and sublingual route have been widely used for providing quick onset of action with the avoidance of first pass metabolism. The objective of this work was to compare the effect of different meltable binders namely; polyethylene glycol (PEG) 4000, pluronic F127 and pluronic F68 on the performance of fast release tablets of the model drug zolmitriptan prepared using the melt granulation technique regarding disintegration time (DT) and dissolution rate (DR) as criteria for rapid absorption and hence quick onset of action. Zolmitriptan is a potent antimigraine drug. Current oral zolmitriptan tablets suffer from slow onset of action, poor bioavailability and large inter-subject variability. Methods: 33 factorial design was adopted. The effect of binder type, binder concentration and croscarmellose sodium (disintegrant) concentration were studied on DT and DR. Results: The three factors were found to significantly affect the DR and the inverse square root of DT and significant interactions were elucidated. Conclusion: Although satisfactory results were obtained regarding DR, modifications using different excipients and or preparation methods should be considered to comply with pharmacopoeia requirement for DT

Quantification of sofosbuvir and ledipasvir in human plasma by UPLC–MS/MS method: Application to fasting and fed bioequivalence studies

A rapid and sensitive LC–MS/MS method was developed, optimized and validated for quantification of sofosbuvir (SF) and ledipasvir (LD) in human plasma using eplerenone as an internal standard (IS). Analytes and IS were extracted from plasma by simple liquid–liquid extraction technique using methyl tertiary butyl ether. The prepared samples were chromatographed on Acquity UPLC BEH C18 column. Separation was done using a mobile phase formed of 0.1% formic acid and acetonitrile (50:50, v/v) in an isocratic mode at a flow rate of 0.4 ml/min. The Xevo TQD LC–MS/MS was operated under the multiple-reaction monitoring mode using electrospray ionization. A full validation of the method was performed according to the FDA guidelines. Linearity was found to be in the range of 0.25–3500 ng/ml for SF and 5–2000 ng/ml for LD. The intra-day and inter-day precision and accuracy results were within the acceptable limits. A short run time of 2 min allows analysis of more than 400 plasma samples per day. The developed method was successfully applied to both fasting and fed bioequivalence studies in healthy human volunteers

Development and validation of sensitive and rapid UPLC–MS/MS method for quantitative determination of daclatasvir in human plasma: Application to a bioequivalence study

A rapid and sensitive UPLC–MS/MS method was developed and validated for determination of daclatasvir (DAC) in human plasma using sofosbuvir (SOF) as an internal standard (IS). The Xevo TQD LC–MS/MS was operated under the multiple-reaction monitoring mode using electrospray ionization. Precipitation with acetonitrile was used in sample preparation. The prepared samples were chromatographed on Acquity UPLC HSS C18 (50 × 2.1 mm, 1.8 μm) column by pumping 10 mM ammonium formate (pH 3.5) and acetonitrile in an isocratic mode at a flow rate of 0.30 ml/min. Method validation was performed as per the FDA guidelines and the standard curves were found to be linear in the range of 5–4000 ng/ml for DAC. The intra-day and inter-day precision and accuracy results were within the acceptable limits. A very short run time of 1.2 min made it possible to analyze more than 500 human plasma samples per day. The wider range of quantification of DAC allowed the applicability of the developed method for its determination in a bioequivalence study in human volunteers