Gulam Mustafa

Bromocriptine loaded chitosan nanoparticles intended for direct nose to brain delivery: pharmacodynamic, pharmacokinetic and scintigraphy study in mice model.

The primary aim of this study was to investigate the potential use of chitosan nanoparticles as a delivery system to enhance the brain targeting efficiency of bromocriptine (BRC) following intranasal (i.n.) administration. The BRC loaded chitosan nanoparticles (CS NPs) were prepared by ionic gelation of CS with tripolyphosphate anions. These NPs had a mean size (161.3 ± 4. 7 nm), zeta potential (+40.3 ± 2.7 mV), loading capacity (37.8% ± 1.8%) and entrapment efficiency (84.2% ± 3.5%). The oral administration of haloperidol (2mg/kg) to mice produced typical Parkinson (PD) symptoms. Catalepsy and akinesia outcomes in animals receiving BRC either in solution or within CS NPs showed a reversal in catalepsy and akinesia behavior when compared to haloperidol treated mice, this reversal being specially pronounced in mice receiving BRC loaded CS NPs. Biodistribution of BRC formulations in the brain and blood of mice following i.n. and intravenous (i.v.) administration was performed using optimized technetium labeled (99mTc-labeled) BRC formulations. The brain/blood ratio of 0.47 ± 0.04, 0.69 ± 0.031, and 0.05 ± 0.01 for BRC solution (i.n.), BRC loaded CS NPs (i.n.) and (i.v.) respectively, at 0.5h are suggestive of direct nose to brain transport bypassing the blood-brain barrier. Gamma scintigraphy imaging of mice brain following i.v. and i.n. administrations were performed to determine the localization of drug in brain. The drug targeting index and direct transport percentage for BRC loaded CS NPs following i.n. route were 6.3 ± 0.8 and 84.2% ± 1.9%. These encouraging results confirmed the development of a novel non-invasive nose to brain delivery system of BRC for the treatment of PD.

Development and evaluation of thymoquinone-encapsulated chitosan nanoparticles for nose-to-brain targeting: a pharmacoscintigraphic study

Chitosan (CS) nanoparticles of thymoquinone (TQ) were prepared by the ionic gelation method and are characterized on the basis of surface morphology, in vitro or ex vivo release, dynamic light scattering, and X-ray diffractometry (XRD) studies. Dynamic laser light scattering and transmission electron microscopy confirmed the particle diameter was between 150 to 200 nm. The results showed that the particle size of the formulation was significantly affected by the drug:CS ratio, whereas it was least significantly affected by the tripolyphosphate:CS ratio. The entrapment efficiency and loading capacity of TQ was found to be 63.3% ± 3.5% and 31.23% ± 3.14%, respectively. The drug-entrapment efficiency and drug-loading capacity of the nanoparticles appears to be inversely proportional to the drug:CS ratio. An XRD study proves that TQ dispersed in the nanoparticles changes its form from crystalline to amorphous. This was further confirmed by differential scanning calorimetry thermography. The flat thermogram of the nanoparticle data indicated that TQ formed a molecular dispersion within the nanoparticles. Optimized nanoparticles were evaluated further with the help of scintigraphy imaging, which ascertains the uptake of drug into the brain. Based on maximum concentration, time-to-maximum concentration, area-under-curve over 24 hours, and elimination rate constant, intranasal TQ-loaded nanoparticles (TQ-NP1) proved more effective in brain targeting compared to intravenous and intranasal TQ solution. The high drug-targeting potential and efficiency demonstrates the significant role of the mucoadhesive properties of TQ-NP1.

Vitamin E loaded resveratrol nanoemulsion for brain targeting for the treatment of Parkinson’s disease by reducing oxidative stress

Resveratrol, a potent natural antioxidant, possesses a wide range of pharmacological activities, but its oral bioavailability is very low due to its extensive hepatic and presystemic metabolism. The aim of the present study was to formulate a kinetically stable nanoemulsion (o/w) using vitamin E:sefsol (1:1) as the oil phase, Tween 80 as the surfactant and Transcutol P as the co-surfactant for the better management of Parkinsons disease. The nanoemulsion was prepared by a spontaneous emulsification method, followed by high-pressure homogenization. Ternary phase diagrams were constructed to locate the area of nanoemulsion. The prepared formulations were studied for globule size, zeta potential, refractive index, viscosity, surface morphology and in vitro and ex vivo release. The homogenized formulation, which contained 150 mg ml(-1) of resveratrol, showed spherical globules with an average globule diameter of 102xa0±xa01.46 nm, a least poly dispersity index of 0.158xa0±xa00.02 and optimal zeta potential values of -35xa0±xa00.02. The cumulative percentage drug release for the pre-homogenized resveratrol suspension, pre-homogenized nanoemulsion and post-homogenized nanoemulsion were 24.18xa0±xa02.30%, 54.32xa0±xa00.95% and 88.57xa0±xa01.92%, respectively, after 24 h. The ex vivo release also showed the cumulative percentage drug release of 85.48xa0±xa01.34% at 24 h. The antioxidant activity determined by using a DPPH assay showed high scavenging efficiency for the optimized formulation. Pharmacokinetic studies showed the higher concentration of the drug in the brain (brain/blood ratio: 2.86xa0±xa00.70) following intranasal administration of the optimized nanoemulsion. Histopathological studies showed decreased degenerative changes in the resveratrol nanoemulsion administered groups. The levels of GSH and SOD were significantly higher, and the level of MDA was significantly lower in the resveratrol nanoemulsion treated group.

Transdermal and Topical Delivery of Anti-inflammatory Agents Using Nanoemulsion/Microemulsion: An Updated Review

Nanoemulsions/microemulsions are thermodynamically stable transparent (translucent) isotropic dispersions of oil and water stabilized by an interfacial film of surfactant and cosurfactant molecules having the droplet size of less than 100 nm. Because of their thermodynamic stability, they can be manufactured without utilizing high input of energy. In an attempt to enhance transdermal/topical drug delivery of anti-inflammatory agents (AIs), nanoemulsions/microemulsions have been more frequently employed over the recent years. Nanoemulsions/microemulsions have been shown to be superior for transdermal/topical delivery of particularly lipophilic compounds as compared to conventional vehicles such as emulsions, suspensions, gels and liposomes. Nanoemulsions/microemulsions exhibit excellent solubility properties. These vehicles also act as transdermal permeation enhancers without utilizing additional permeation enhancers. In this review transdermal and topical delivery of AIs both in vitro as well as in vivo has been summarized and reviewed.

Nanosizing of valsartan by high pressure homogenization to produce dissolution enhanced nanosuspension: pharmacokinetics and pharmacodyanamic study

Abstract Purpose: The purpose of the present study was to formulate and evaluate nanosuspension of Valsartan (VAL), a poorly water soluble and low bioavailable drug (solubility of 0.18u2009mgu2009mL−1; 23% of oral bioavailability) with the aim of improving the aqueous solubility thus the bioavailability and consequently better anti-hypertensive activity. Methods: Valsartan nanosuspension (VAL-NS) was prepared using high-pressure homogenization followed by lyophilisation. The screening of homogenization factors influencing nanosuspension was done by 3-factorial, 3-level Box-Behnken statistical design. Model suggested the influential role of homogenization pressure and cycles on drug nanosizing. The optimized formulation containing Poloxamer−188 (PXM 188) was homogenized for 2 cycles at 500 and 1000u2009bar, followed by 5 cycles at 1500 bars. Results: The size analysis and transmission electron microscopy showed nanometric size range and uniform shape of the nanosuspension. The in vitro dissolution showed an enhanced release of VAL from nanosuspension (VAL-NS) compared to physical mixture with PXM 188. Pharmacodynamic results showed that, oral administration of VAL-NS significantly lowered (pu2009≤u20090.001) blood pressure in comparison to non-homogenized VAL (VAL-Susp) in Wistar rat. The level of VAL in rat plasma treated with VAL-NS showed significant difference (pu2009≤u20090.005) in Cmax (1627.47u2009±u2009112.05u2009ngu2009mL−1), Tmax (2.00u2009h) and AUC0→24 (13279.2u2009±u2009589.426u2009ngu2009hu2009mL−1) compared to VAL-Susp that was found to be 1384.73u2009±u200998.76u2009ngu2009mL−1, 3.00u2009h and 9416.24u2009±u2009218.48u2009ngu2009hu2009mL−1 respectively. The lower Tmax value, proved the enhanced dissolution rate of VAL. Conclusion: The overall results proved that newly developed VAL-NS increased the plasma bioavailability and pharmacodyanamic potential over the reference formulation containing crude VAL.

Box-Behnken supported validation of stability-indicating high performance thin-layer chromatography (HPTLC) method: An application in degradation kinetic profiling of ropinirole

Stability-indicating high-performance thin-layer chromatographic (HPTLC) method for the analysis of ropinirole HCl was developed and validated as per the ICH guidelines. The method employed the mobile phase and toluene-ethyl acetate-6xa0M ammonia solution (5:6:0.5, v/v/v) was optimized with the help of a design expert. Densitometric analysis of ropinirole HCl was carried out in the absorbance mode at 250 and 254xa0nm. Compact spots for ropinirole HCl were found at R f value of 0.58xa0±xa00.02. The linear regression analysis data for the calibration plots showed R (2)xa0=xa00.9989xa0±xa00.0053 with a concentration range of 100-3000xa0ngxa0spot(-1). The method was validated for precision, accuracy, ruggedness, robustness, specificity, recovery, limit of detection (LOD) and limit of quantitation (LOQ). The LOD and LOQ were 12.95 and 39.25xa0ngxa0spot(-1) respectively. Drug was subjected to acidic, alkaline, oxidative, dry heat, wet heat and photo degradation stress. All the peaks of degradation products were well resolved from the standard drug peak with significant difference of R f. The acidic and alkaline stress degradation kinetics of ropinirole, were found to be in first order, showing high stability (t 1/2, 146.37xa0h(-1); t 0.9, 39.11xa0h(-1)) in the acidic medium and low stability (t 1/2, 97.67xa0h(-1); t 0.9, 14.87xa0h(-1)) in the alkaline environment.

STABILITY-INDICATING RP-HPLC METHOD FOR ANALYSIS OF ATORVASTATIN IN BULK DRUG, MARKETED TABLET AND NANOEMULSION FORMULATION

ABSTRACT A simple, highly sensitive, isocratic stability indicating reversed phase-high performance liquid chromatography (RP-HPLC) method with UV detection at 247 nm was developed and validated for analysis of atorvastatin (AT). Retention time of the AT was found to be 4.02 min. A mobile phase consisting of 0.05 M sodium phosphate buffer and methanol (3:7 v/v) pH 4.1 at flow rate of 1mL/min was employed in this study. The calibration curves were linear with regression coefficient (r 2 ) of 0.9997 ± 0.0014. The limits of detection (LOD) and the limits of quantification (LOQ) were found to be 0.20 and 0.60 μg/mL, respectively. The method was statistically validated in accordance with International conference on harmonization (ICH) guidelines. The proposed method was found sensitive, specific and was successfully applied for the estimation of atorvastatin in pharmaceutical formulations (bulk drug, tablet, nanoemulsion). Keywords: RP-HPLC; atorvastatin; nanoemulsion; tablets; ICH guidelines.

Brain targeting by intranasal drug delivery (INDD): a combined effect of trans-neural and para-neuronal pathway

Abstract The effectiveness of intranasal drug delivery for brain targeting has emerged as a hope of remedy for various CNS disorders. The nose to brain absorption of therapeutic molecules claims two effective pathways, which include trans-neuronal for immediate action and para-neuronal for delayed action. To evaluate the contribution of both the pathways in absorption of therapeutic molecules and nanocarriers, lidocaine, a nerve-blocking agent, was used to impair the action potential of olfactory nerve. An anti-Parkinson drug ropinirole was covalently complexes with 99mTc in presence of SnCl2 using in-house developed reduction technology. The radiolabeled formulations were administered intranasally in lidocaine challenged rabbit and rat. The qualitative and quantitative outcomes of neural and non-neural pathways were estimated using gamma scintigraphy and UHPLC-MS/MS, respectively. The results showed a significant (pu2009≤u20090.005) increase in radioactivity counts and drug concentration in the brain of rabbit and rat compared to the animal groups challenged with lidocaine. This concludes the significant contribution (pu2009≤u20090.005) of trans-neuronal and para-neuronal pathway in nose to brain drug delivery. Therefore, results proved that it is an art of a formulator scientist to make the drug carriers to exploit the choice of absorption pathway for their instant and extent of action.

UHPLC/ESI-Q-TOF-MS method for the measurement of dopamine in rodent striatal tissue: A comparative effects of intranasal administration of ropinirole solution over nanoemulsion

An ultra high performance liquid chromatography-electrospray ionization-tandem mass spectrometric method (UHPLC/ESI-Q-TOF-MS) for the analysis of dopamine (DA) in Wistar rat brain homogenate has been developed and validated. The chromatographic separation was achieved on a Waters ACQUITY UPLC™ BEH C18 (100.0u2009mmu2009×u20092.1u2009mm; 1.7u2009µm) column using isocratic mobile phase, consisting of acetonitrile and Formic acid (0.1% w/v) (10: 90; v/v), at a flow rate of 0.15u2009mlu2009min(-1) . The transitions occurred at m/z 154.04u2009→u2009137.006 for DA, and m/z 184.204u2009→u2009166.08 for the internal standard. The recovery of the analytes from Wistar rat brain homogenate was optimized using liquid-liquid extraction technique (LLE) in ethyl acetate. The total run time was 3.5u2009min and the elution of DA occurred at 1.44u2009±u20090.05u2009min. The linear dynamic range was established over the concentration range 75-750u2009ngu2009mL(-1) (r(2) ; 0.9921u2009±u20090.0005) for DA. The intra-assay and inter-assay accuracy in terms of % CV was in the range 0.73-2.80. The lower limit of detection (LOD) and quantitation (LOQ) for DA was 0.278 and 0.844u2009ngu2009mL(-1) , respectively. Analytes were stable under various conditions (in autosampler, during freeze-thaw, at room temperature, and under deep-freeze conditions). The developed method was successfully applied for in vivo profiling in rodents.

Design Expert-Supported Development and Validation of High-Performance Thin-Layer Chromatographic Stability-Indicating (HPTLC) Method: an Application in Quantitative Analysis of Ropinirole in the Bulk Drug and in Marketed Dosage Forms

A simple, precise and stability-indicating thin-layer chromatographic method for estimation of ropinirole HCl was developed and validated as per ICH guidelines. The mobile phase consisted of acetone–cyclohexane–6 M ammonia solution (8:5.5:0.5, v/v/v). Scanning the drug was done at 250 nm. Compact spots for ropinirole HCl were found at an Rf value of 0.51u2009±u20090.002. The linear regression analysis data for the calibration plots showed good linear relationship with R2 0.9976u2009±u20090.0011 in the working concentration range of 100–3,000 ng spot−1. The method was validated for precision, accuracy, ruggedness, robustness, specificity, recovery, limit of detection (LOD), and limit of quantitation (LOQ). The LOD and LOQ were 12.89 and 42.53 ng spot−1, respectively. The drug was subjected to degradation; the peaks of degradation products were well resolved from the standard with significantly different Rf values. Hence, this method can be used for quality control assay of ropinirole.