QbD-driven development of dissolving microneedle patch loaded with ultradeformable liposomes encapsulated Noopept: Exploring a patient friendly, once-daily option to manage dementia.

Noopept (NPT), a potent neuroprotective agent, suffers the problem of poor oral bioavailability (~10%) and thus demands exploration of ways of bioavailability improvement. Present work focuses on confronting this issue via development of NPT loaded ultradeformable liposomes (UDL) and its further incorporation in fast dissolving microneedle patch (MNP) for transdermal route. A combination of Phospholipon 90 G and Phospholipon 90H was used as bilayer forming lipids while sodium deoxycholate was used as edge activator to formulate NPT UDL by ethanol injection method. QbD approach was adapted to optimize NPT UDL considering vesicle size and entrapment efficiency as critical quality attributes (CQA). Fractional factorial design established amount of lipids, surfactant and NPT as critical material attributes and their optimum levels were statistically derived using combined D-optimal design. These optimized NPT UDL were fabricated as fast dissolving MNP and exhaustively evaluated to establish their safety, efficacy and stability. NPT UDL MNP possessed axial needle fracture force of 0.688 N which was sufficient enough to breach stratum corneum. Physical stability evaluation revealed that NPT UDL re-dispersion obtained from MNP matrix dissolution possessed identical vesicle shape and size while retaining > 99% NPT when compared to optimized NPT UDL. In vitro viability of HaCaT cells after exposure to NPT UDL MNP matrix was found to be 89.74% supporting the formulation as safe for transdermal application. NPT UDL MNP showed a 6.5-fold increase in steady state flux across full thickness pig ear skin as compared to NPT suspension. A 3-fold increase in relative bioavailability with similar pharmacological response as compared to oral NPT suspension was also observed during PK-PD studies in Sprague Dawley rats. Results were found fairly encouraging and created a scope of reducing both dose and dosing frequency to eventually improve the associated patient compliance.

Vinpocetine loaded ultradeformable liposomes as fast dissolving microneedle patch: Tackling treatment challenges of dementia.

Vinpocetine (VPN) displays poor bioavailability (~7%) and short half-life (2-3 h) justifying the frequent dosing requirement of currently marketed oral tablets (thrice daily) and thus, posing a great challenge to patient compliance. Present work envisaged to achieve an infusion like delivery through transdermal route so as to tackle aforesaid challenges. With this aim, ultradeformable liposomes (UDL) incorporated fast dissolving microneedle patch (MNP) of VPN was developed and optimized for vesicle size and percent drug entrapment (critical quality attributes, CQA) utilizing the quality by design tool. Fractional factorial design followed by combined D-optimal design were applied to identify critical material attributes and obtain their statistically verified optimum levels (Phospholipon 90G, 15.17 mM; Phospholipon 90H, 4.83 mM; sodium deoxycholate, 15 mol% and Vinpocetine, 5 mol%) showing mean vesicle size of 75.65 nm and mean drug entrapment of 87.44%. An insignificant change in CQA of optimized UDL after incorporation in MNP further represented their physical compatibility with MNP components. In vitro characterization of these microneedles revealed rapid dissolution (~2 min) and good skin penetrability with around 0.684 N axial needle fracture force (ANFF). The safety was ascertained in vitro by exposing HaCaT cells to VPN UDL MNP components. A 94.27% cell viability advocated the safe nature of excipients used in formulation. Ex vivo permeation across full thickness pig ear skin revealed a steady state flux of 11.091 µg/cm2/h via VPN UDL MNP with around 9-fold enhancement when compared to flux value achieved through VPN suspension. In vivo pharmacokinetic and pharmacodynamic study in Sprague Dawley rats showed a 3-fold rise in relative bioavailability and a comparable mean escape latency via UDL MNP as compared to its oral suspension. In addition, half-life of 14 h and MRT of 21 h further confirmed the controlled release behavior of UDL MNP for prolonged period of time. In nutshell, the developed fast dissolving microneedle patch of VPN showed promising results with the prospect of lowering dose as well as dosing frequency for improved patient compliance.

Formulation and evaluation of liquisolid compacts of itraconazole to enhance its oral bioavailability.

Aim: Formulate and evaluate liquisolid compacts of Itraconazole, a biopharmaceutical classification system class II drug, which has poor bioavailability. Materials & methods: PEG 600 was used as a nonvolatile solvent, Alfacel PH 200 as a carrier and Aerosil 200 as a coating material. The Itraconazole solution upon mixing with a carrier and coating material resulted in a dry powder, which was compressed into tablets. Results & conclusion: The optimized formulation exhibited a significantly higher drug dissolution (90.73% in 90 min) compared with conventional tablets and marketed capsules. The antifungal activity was retained in the formulation. Higher values of Cmax and AUC0-24 of the formulation compared with the plain drug indicated enhancement in oral bioavailability. The formulation was stable at room temperature as well as in accelerated conditions.

Statistically optimized fast dissolving microneedle transdermal patch of meloxicam: A patient friendly approach to manage arthritis.

INTRODUCTION: The long term administration of Meloxicam for the management of arthritis, a chronic disorder, results in gastrointestinal disturbances leading to poor patient compliance. Considering the favorable molecular weight, therapeutic dose, biological half-life and log P value of meloxicam for transdermal delivery, its fast dissolving microneedle patch, with an ability to breach the stratum corneum and efficiently deliver the cargo to deeper skin layers, were developed. METHODS: Microneedle patch of low molecular weight polyvinyl alcohol and polyvinylpyrrolidone was prepared using Polydimethylsiloxane micromolds. The ratio of polyvinyl alcohol to polyvinyl pyrrolidone and solid content of matrix solution was optimized to achieve maximum needle strength. The optimized batch was extensively evaluated for in vitro dissolution, drug release, stability, ex vivo skin permeation/deposition, histopathology and in vivo pharmacodynamic study. RESULTS: The patch containing 9:1 polyvinyl alcohol to polyvinylpyrrolidone ratio with 50% solid content had shown maximum axial needle fracture force (0.9N) suitable for penetrating the skin. The optimized batch was found to be fast dissolving and released almost 100% drug in 60min following dissolution controlled kinetics. The formulation showed a significant drug deposition within skin (63.37%) and an improved transdermal flux (1.60µg/cm2/h) with a 2.58 fold enhancement in permeation as compared to plain drug solution. The formulation showed a comparable anti-inflammatory activity in rats when compared to its existing approved marketed oral tablet. Histopathology and stability evaluations demonstrated acceptable safety and shelf-life of the developed formulation. CONCLUSION: The successful verification of safety, efficacy and stability of microneedle patch advocated the suitability of the formulation for transdermal use.

Ethosomal Hydrogel of Raloxifene HCl: Statistical Optimization & Ex Vivo Permeability Evaluation Across Microporated Pig Ear Skin.

BACKGROUND: The oral bioavailability of Raloxifene hydrochloride, an FDA approved selective estrogen receptor modulator, is severely limited due to its poor aqueous solubility and extensive first pass metabolism. The Present work focuses on the development of ethosomal hydrogel for transdermal delivery of Raloxifene HCl as an alternate way to solve aforementioned problem. The physical breaching of stratum corneum, the principal barrier, by microneedle treatment was also employed to potentiate its transdermal permeation. METHODS: The influence of lipid and ethanol concentration on vesicle size and entrapment efficiency was extensively investigated using response surface methodology based on central composite design. The software based optimization was done and validated using check point analysis. Optimized batch was extensively evaluated for its safety, efficacy and stability. RESULTS: The optimized ethosomal batch possessed 403 nm size and 74.25% drug entrapment. Its zeta potential and in vitro drug release were also found favorable for transdermal permeation. The ex vivo skin permeation study revealed a transdermal flux of 4.621 µg/cm2/h through the intact pig ear skin which was further enhanced through the microporated skin (transdermal flux, 6.194 µg/cm2/h) with a 3.87 fold rise when compared to drug permeation from plain solution applied over intact skin (transdermal flux, 1.6 µg/cm2/h). Histopathological skin sections showed the non-irritant nature of the ethosomal hydrogel and microneedle treatment. The formulation was found stable under both refrigeration and room temperature conditions for 6 weeks. CONCLUSION: In a nutshell, the developed system was found efficient, safe and stable and seems promising for transdermal use.

Development and Evaluation of a Once-Daily Controlled Porosity Osmotic Pump of Tapentadol Hydrochloride.

The present study aimed to prepare, optimize, and evaluate Tapentadol hydrochloride controlled porosity osmotic pump (CPOP) and to achieve the drug release at nearly zero-order. The CPOP was prepared by the coating of polymers (Eudragit RSPO and RLPO) on a directly compressed core tablet. A Box-behnken experimental design was applied to optimize the parameters for CPOP. The optimized batch was characterized for in vitro drug release study, effect of pH, osmolarity and agitation intensity, and surface morphology and stability study. In vivo pharmacokinetic studies were performed on New Zealand white rabbits for CPOP and marketed tablet. All the batches showed a drug release ranging from 29.87 to 56.92% after 12 h; and from 59.64 to 99.96% after 24 h. There was no change in the drug release pattern at different pH and agitation intensities. The drug release was found to decrease with increasing osmolarity of dissolution media.An in vivo study showed a higher mean residence time, area under the curve, and biological half-life (T 1/2) than the marketed tablet with low rate of elimination (Ke) and a 2.35-fold increase in relative bioavailability. The result showed that the amounts of sodium chloride and PEG 400 were contributing positively while the number of coats was negatively affecting the drug release. The drug release was found to be independent of physiological conditions. The stability testing showed that the prepared CPOP was stable for 3 months at accelerated conditions. The prepared CPOP was found to deliver Tapentadol hydrochloride at zero-order for up to 24 h.

Formulation and evaluation of Itraconazole nanoemulsion for enhanced oral bioavailability.

Itraconazole (ITR), an antifungal agent has poor bioavailability due to low aqueous solubility. The present investigation aimed at development of ITR nanoemulsion to enhance its oral bioavailability. ITR nanoemulsion was prepared using Capmul MCM C8 as oil, Pluronic F68 as co-surfactant and Cremophore EL as surfactant using high speed stirring, followed by probe sonication. Nanoemulsion with average globule size of 100.9 nm and zeta potential of -35.9 ± 1.2 mV was able to penetrate well into the intestinal membrane as confirmed by the laser confocal scanning microscopy and ex vivo intestinal permeability study. Antimycotic study confirmed the efficacy of ITR nanoemulsion. Significantly higher values of pharmacokinetic parameters the formulation than the plain drug and marketed formulation indicated an increase in the bioavailability of ITR. The prepared nanoemulsion was stable at both, refrigerated and room temperature conditions. Nanoemulsion of ITR seems to be a promising formulation for enhancement of its oral bioavailability.

Formulation and evaluation of Itraconazole nanoemulsion for enhanced oral bioavailability.

Itraconazole (ITR), an antifungal agent has poor bioavailability due to low aqueous solubility. The present investigation aimed at development of ITR nanoemulsion to enhance its oral bioavailability. ITR nanoemulsion was prepared using Capmul MCM C8 as oil, Pluronic F68 as co-surfactant and Cremophore EL as surfactant using high speed stirring, followed by probe sonication. Nanoemulsion with average globule size of 100.9 nm and zeta potential of -35.9 ± 1.2 mV was able to penetrate well into the intestinal membrane as confirmed by the laser confocal scanning microscopy and ex vivo intestinal permeability study. Antimycotic study confirmed the efficacy of ITR nanoemulsion. Significantly higher values of pharmacokinetic parameters the formulation than the plain drug and marketed formulation indicated an increase in the bioavailability of ITR. The prepared nanoemulsion was stable at both, refrigerated and room temperature conditions. Nanoemulsion of ITR seems to be a promising formulation for enhancement of its oral bioavailability.

Formulation and evaluation of tacrolimus-loaded galactosylated Poly(lactic-co-glycolic acid) nanoparticles for liver targeting.

OBJECTIVE: The aim of this investigation was to formulate liver targeted tacrolimus-loaded nanoparticles for reducing renal distribution and thereby decreasing nephrotoxicity. METHOD: Poly lactic-co-glycolic acid (PLGA) was galactosylated, and confirmation of galactosylation was performed by Fourier transform infrared spectroscopy and nuclear magnetic resonance spectroscopy. Tacrolimus-loaded PLGA nanoparticles (Tac-PLGA NP) and galactosylated PLGA nanoparticles (Tac-Gal-PLGA NPs) were prepared by ultrasonic emulsification solvent evaporation technique and characterized. KEY FINDINGS: The size of both the formulations was below 150 nm and negative zeta potential indicated the stability and reticuloendothelial system targeting efficiency. The in-vitro release and pharmacokinetics showed sustained release of tacrolimus from nanoparticles in comparison to plain drug solution. The biodistribution studies revealed the potential of both the nanoparticulate systems to target tacrolimus to the liver for prolonged periods of time compared with the plain drug solution. However, significantly higher liver and spleen targeting efficiency of Tac-Gal-PLGA NPs compared with Tac-PLGA NPs was evident indicating its active targeting. Significantly lower distribution in the kidney from nanoparticles indicated the possibility of reduced nephrotoxicity - the principal reason for patient non-compliance. Both nanoparticles showed stability at refrigerated condition (5°C ± 3°C) upon storage for 1 month. CONCLUSION: Galactosylated PLGA nanoparticles seem to be a promising carrier for liver targeting of tacrolimus.

Gemcitabine hydrochloride-loaded functionalised carbon nanotubes as potential carriers for tumour targeting.

The objective of the present work was to formulate gemcitabine hydrochloride loaded functionalised carbon nanotubes to achieve tumour targeted drug release and thereby reducing gemcitabine hydrochloride toxicity. Multiwalled carbon nanotubes were functionalised using 1,2-distearoylphosphatidyl ethanolamine-methyl polyethylene glycol conjugate 2000. Optimised ratio 1:2 of carbon nanotubes:1,2-distearoylphosphatidyl ethanolamine-methyl polyethylene glycol conjugate 2000 was taken for loading of gemcitabine hydrochloride. The formulation was evaluated for different parameters. The results showed that maximum drug loading efficiency achieved was 41.59% with an average particle size of 188.7 nm and zeta potential of -10-1 mV. Scanning electron microscopy and transmission electron microscopy images confirmed the tubular structure of the formulation. The carbon nanotubes were able to release gemcitabine hydrochloride faster in acidic pH than at neutral pH indicating its potential for tumour targeting. Gemcitabine hydrochloride release from carbon nanotubes was found to follow Korsmeyer-Peppas kinetic model with non-Fickian diffusion pattern. Cytotoxic activity of formulation on A549 cells was found to be higher in comparison to free gemcitabine hydrochloride. Stability studies indicated that lyophilised samples of the formulation were more stable for 3 months under refrigerated condition than at room temperature. Thus carbon nanotubes can be promising carrier for the anticancer drug gemcitabine hydrochloride.

Formulation of niosomal gel for enhanced transdermal lopinavir delivery and its comparative evaluation with ethosomal gel.

The aim was to develop niosomal gel as a transdermal nanocarrier for improved systemic availability of lopinavir. Niosomes were prepared using thin-film hydration method and optimized for molar quantities of Span 40 and cholesterol to impart desirable characteristics. Comparative evaluation with ethosomes was performed using ex vivo skin permeation, fluorescence microscopy, and histopathology studies. Clinical utility via transdermal route was acknowledged using in vivo bioavailability study in male Wistar rats. The niosomal formulation containing lopinavir, Span 40, and cholesterol in a molar ratio of 1:0.9:0.6 possessed optimally high percentage of drug entrapment with minimum mean vesicular diameter. Ex vivo skin permeation studies of lopinavir as well as fluorescent probe coumarin revealed a better deposition of ethosomal carriers but a better release with niosomal carriers. Histopathological studies indicated the better safety profile of niosomes over ethosomes. In vivo bioavailability study in male Wistar rats showed a significantly higher extent of absorption (AUC(0→∞), 72.87 h × µg/ml) of lopinavir via transdermally applied niosomal gel as compared with its oral suspension. Taken together, these findings suggested that niosomal gel holds a great potential of being utilized as novel, nanosized drug delivery vehicle for transdermal lopinavir delivery.