Mohammed M. Mehanna

In sight into tadalafil – block copolymer binary solid dispersion: Mechanistic investigation of dissolution enhancement

Tadalafil is a phosphodiesterase-5 inhibitor that is characterized by low solubility and high permeability. Solid dispersion approach represents a promising carrier system for effective enhancement of dissolution and oral bioavailability of poorly soluble drugs. In the present work, novel tadalafil-loaded solid dispersions employing various block copolymers (Pluronics(®)) were prepared through fusion technique. Their solubility and dissolution properties were compared to the drug alone. In order to elucidate the mechanism of dissolution enhancement, solid state characteristics were investigated using scanning electron microscopy, Fourier transform infrared spectroscopy, differential scanning calorimetry and powder X-ray diffraction. Furthermore, contact angle measurements were carried out. The sign and magnitude of the thermodynamic parameters indicated spontaneity of solubilization process. The phase solubility studies revealed A(L) type of curves for the carriers. Unlike traditional solid dispersion systems, the crystal form of drug in the formulated systems could not be converted to amorphous form. Most of the studied grades showed dissolution improvement vis-à-vis pure drug, with Pluronic F-127 as the most promising carrier. Mathematical modeling of in vitro dissolution data indicated the best fitting with Korsemeyer-Peppas model. Thus, the results demonstrated that tadalafil/Pluronic F-127 solid dispersion system is a direct and feasible technology which represents a potential candidate for delivering a poorly water-soluble drug with enhanced solubility and dissolution.

Respirable nanocarriers as a promising strategy for antitubercular drug delivery

Tuberculosis is considered a fatal respiratory infectious disease that represents a global threat, which must be faced. Despite the availability of oral conventional anti-tuberculosis therapy, the disease is characterized by high progression. The leading causes are poor patient compliance and failure to adhere to the drug regimen primarily due to systemic toxicity. In this context, inhalation therapy as a non-invasive route of administration is capable of increasing local drug concentrations in lung tissues, the primary infection side, by passive targeting as well as reducing the risk of systemic toxicity and hence improving the patient compliance. Nanotechnology represents a promising strategy in the development of inhaled drug delivery systems. Nanocarriers can improve the drug effectiveness and decrease the expected side effects as consequences of their ability to target the drug to the infected area as well as sustain its release in a prolonged manner. The current review summarizes the state-of-the-art in the development of inhaled nanotechnological carriers confined currently available anti-tuberculosis drugs (anti TB) for local and targeting drug delivery specifically, polymeric nanoparticles, solid lipid nanoparticles, nanoliposomes and nanomicelles. Moreover, complexes and ion pairs are also reported. The impact and progress of nanotechnology on the therapeutic effectiveness and patient adherence to anti TB regimen are addressed.

Tadalafil Inclusion in Microporous Silica as Effective Dissolution Enhancer: Optimization of Loading Procedure and Molecular State Characterization

Tadalafil is an efficient drug used to treat erectile dysfunction characterized by poor water solubility, which has a negative influence on its bioavailability. Utilization of microporous silica represents an effective and facile technology to increase the dissolution rate of poorly soluble drugs. Our strategy involved directly introducing tadalafil as guest molecule into microporous silica as host material by incipient wetness impregnation method. To optimize tadalafil inclusion, response surface methodology (RSM) using 3(3) factorial design was utilized. Furthermore, to investigate the molecular state of tadalafil, Fourier-transform infrared spectroscopy, differential scanning calorimetery, thermal gravimetrical analysis, nitrogen adsorption, and powder X-ray diffraction (PXRD) were carried out. The results obtained pointed out that the quantity of microporous silica was the predominant factor that increased the loading efficiency. For the optimized formula, the loading efficiency was 42.50 wt %. Adsorption-desorption experiments indicated that tadalafil has been introduced into the micropores. Powder XRD and differential scanning calorimetry analyses revealed that tadalafil is arranged in amorphous form. In addition, the dissolution rate of tadalafil from the microporous silica was faster than that of free drug. Amorphous tadalafil occluded in microporous silica did not crystallize over 3 months. These findings contributed in opening a new strategy concerning the utilization of porous silica for the dissolution rate enhancement.

Ciprofloxacin Liposomes as Vesicular Reservoirs for Ocular Delivery: Formulation, Optimization, and In Vitro Characterization

Management of extraocular diseases is mainly limited by the inability to provide long-term drug delivery without avoiding the systemic drug exposure and/or affecting the intraocular structures and poor availability of drugs, which may be overcome by prolonging the contact time with the ocular system, for instance with liposomes. Development and optimization of reverse phase evaporation ciprofloxacin (CPF) HCl liposomes for ocular drug delivery was carried out using a 25 full factorial design based on five independent variables. The effects of the studied parameters on drug entrapment efficiency (EE), particle size, and percentage of drug released after 1 and 10 h were investigated. The results obtained pointed out that the molar concentration of cholesterol was the predominant factor that increased the EE% of the drug and the particle size responses. The percentage of drug released after 1 h was significantly controlled by the initial CPF concentration while that after 10 h was controlled by molar cholesterol concentration. The designed liposomes had average particle sizes that ranged from 2.5 to 7.23 μm. In addition, liposomes revealed a fast release during the first hour followed by a more gradual drug release during the 24-h period according to Higuchi diffusion model.

Self-assembled nano-architecture liquid crystalline particles as a promising carrier for progesterone transdermal delivery.

The study aims to elaborate novel self-assembled liquid crystalline nanoparticles (LCNPs) for management of hormonal disturbances following non-invasive progesterone transdermal delivery. Fabrication and optimization of progesteroneloaded LCNPs for transdermal delivery were assessed via a quality by design approach based on 2(3) full factorial design. The design includes the functional relationships between independent processing variables and dependent responses of particle size, polydispersity index, zeta potential, cumulative drug released after 24h and ex-vivo transdermal steady flux. The developed nanocarrier was subjected to TEM (transmission electron microscope) for morphological elucidation and stability study within a period of three months at different storage temperatures. The cubic phase of LCNPs was successfully prepared using glyceryl monooleate (GMO) via the emulsification technique. Based on the factorial design, the independent operating variables significantly affected the five dependent responses. The cubosomes hydrodynamic diameters were in the nanometric range (101-386 nm) with narrow particle size distribution, high negative zeta potential ≥-30 mV and entrapment efficiency ≥94%. The LCNPs succeeded in sustaining progesterone release for almost 24h, following a non-fickian transport of drug diffusion mechanism. Ex-vivo study revealed a significant enhancement up to 6 folds in the transdermal permeation of progesterone-loaded LCNPs compared to its aqueous suspension. The optimized LCNPs exhibited a high physical stability while retaining the cubic structure for at least three months. Quality by design approach successfully accomplished a predictable mathematical model permitting the development of novel LCNPs for transdermal delivery of progesterone with the benefit of reducing its oral route side effects.

Nanovesicular carrier-mediated transdermal delivery of tadalafil: i-formulation and physicsochemical characterization.

Abstract The limited permeability of stratum corneum, the main skin barrier, towards pharmaceutical active ingredients represents the main obstacle encounter the transdermal drug delivery system. In the current study, penetration enhancer-containing nanoliposomes, that is, penetrosomes were formulated incorporating tadalafil to enhance its transdermal permeability. Hydration-sonication method was used to prepared penetrosomes bearing tadalafil. The prepared nanocarriers were characterized in terms of vesicles shape and surface morphology, size and size distribution, zeta potential, entrapment efficiency, and elasticity. Results pointed to that penetrosomes were spherical in shape with a unilamellar-closed structure in the nanometric narrow size range proved by their law span index. Penetrosomes formulations elaborated deformable vesicles more than the conventional liposomes, with the Penetrosomes-based Labrasol® being the most deformable formulation. Penetrosomes-ultraelastic nanoliposomes represent an attractive vehicle for transdermal delivery of tadalafil to treat erectile dysfunction.

Formulation, physicochemical characterization and in-vivo evaluation of ion-sensitive metformin loaded-biopolymeric beads

Abstract The demand on the controlled release of short acting antidiabetic drug, metformin (MT), has been increased dramatically. Thus, boosting the development of new sustained release formulations with contents of multi-micro-scaled particles. This paved the way for the preparation of MT-loaded Gellan gum (GG) microbeads through inotropic gelation technique. The prepared beads were characterized for the following parameters; yield and loading efficiency particle size, particles morphology and topography, swelling behavior, and in-vitro release studies. In view of any possible interactions, differential scanning calorimetry and infrared spectroscopy were performed. As an ultimate evaluation, the relative bioavailability of the sustained release beads was studied in healthy volunteers after oral administration in a fasted state compared to commercially available immediate and extended release tablets using a new validated HPTLC method for MT assay in urine. Results obtained revealed that the formulated Gellan beads were spherical in shape with less smooth surface in the micron range with high yield and entrapment efficiency. In-vitro release studies of the prepared beads were achieved up to 8 h. The prolonged release of MT can be explained through various factors among them; the swelling of the biopolymer and the ionic interaction between the drug and the GG. After oral administration, the AUC0−24, t1/2 and tmax of the prepared beads were of 246.74 ± 26.81 mg, 11.84 ± 2.79 and 7.17 ± 1.75 h, respectively, demonstrating its bioequivalence to the marketed products. In conclusion, the formulated GG microbeads exhibit potentials as an oral sustained release MT system.

Optimization, physicochemical characterization and in vivo assessment of spray dried emulsion: A step toward bioavailability augmentation and gastric toxicity minimization.

The limited solubility of BCS class II drugs diminishes their dissolution and thus reduces their bioavailability. Our aim in this study was to develop and optimize a spray dried emulsion containing indomethacin as a model for Class II drugs, Labrasol®/Transuctol® mixture as the oily phase, and maltodextrin as a solid carrier. The optimization was carried out using a 2(3) full factorial design based on two independent variables, the percentage of carrier and concentration of Poloxamer® 188. The effect of the studied parameters on the spray dried yield, loading efficiency and in vitro release were thoroughly investigated. Furthermore, physicochemical characterization of the optimized formulation was performed. In vivo bioavailability, ulcerogenic capability and histopathological features were assessed. The results obtained pointed out that poloxamer 188 concentration in the formulation was the predominant factor affecting the dissolution release, whereas the drug loading was driven by the carrier concentration added. Moreover, the yield demonstrated a drawback by increasing both independent variables studied. The optimized formulation presented a complete release within two minutes thus suggesting an immediate release pattern as well, the formulation revealed to be uniform spherical particles with an average size of 7.5μm entrapping the drug in its molecular state as demonstrated by the DSC and FTIR studies. The in vivo evaluation, demonstrated a 10-fold enhancement in bioavailability of the optimized formulation, with absence of ulcerogenic side effect compared to the marketed product. The results provided an evidence for the significance of spray dried emulsion as a leading strategy for improving the solubility and enhancing the bioavailability of class II drugs.

The relevancy of controlled nanocrystallization on rifampicin characteristics and cytotoxicity.

Purpose This article investigated the influence of novel rifampicin nanosuspension (RIF NS) for enhancing drug delivery properties. Methods RIF NS was fabricated using the antisolvent precipitation technique. The impact of solvent type and flow rate, stabilizer type and concentration, and stirring time and apparatus together with the solvent–antisolvent volume ratio on its controlled nanocrystallization has been evaluated. NSs were characterized by transmission electron microscopy, particle size and zeta potential analysis, solubility, and dissolution profiles. The compatibility between RIF and the stabilizer was investigated via Fourier transform infrared spectroscopy and the differential scanning calorimetry techniques. The shelf-life stability of the RIF NS was assessed within a period of 3 months at different storage temperatures. Cell cytotoxicity was evaluated using 3(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay on lung epithelial cells. Results Polyvinyl alcohol at 0.4% w/v, 1:15 methanol to deionized water volume ratio and 30-minutes sonication were the optimal parameters for RIF NS preparation. Nanocrystals were obtained with a nanometeric particle size (101 nm) and a negative zeta potential (−26 mV). NS exhibited a 50-fold enhancement in RIF solubility and 97% of RIF was dissolved after 10 minutes. The RIF NS was stable at 4±0.5°C with no significant change in particle size or zeta potential. The MTT cytotoxicity assay of RIF NS demonstrated a good safety profile and reduction in cell cytotoxicity with half maximal inhibitory concentration values of 0.5 and 0.8 mg/mL for free RIF and RIF NS, respectively. Conclusion A novel RIF NS could be followed as an approach for enhancing RIF physicochemical characteristics with a prominence of a safer and better drug delivery.

Superiority of liquid crystalline cubic nanocarriers as hormonal transdermal vehicle: comparative human skin permeation-supported evidence

ABSTRACT Objectives: The aim of this investigation was to explore the feasibility of various nanocarriers to enhance progesterone penetration via the human abdominal skin. Methods: Four progesterone-loaded nanocarriers; cubosomes, nanoliposomes, nanoemulsions and nanomicelles were formulated and characterized regarding particle size, zeta potential, % drug encapsulation and in vitro release. Structural elucidation of each nanoplatform was performed using transmission electron microscopy. Ex vivo skin permeation, deposition ability and histopathological examination were evaluated using Franz diffusion cells. Results: Each nanocarrier was fabricated with a negative surface, nanometric size (≤ 270 nm), narrow size distribution and reasonable encapsulation efficiency. In vitro progesterone release showed a sustained release pattern for 24 h following a non-Fickian transport diffusion mechanism. All nanocarriers exhibited higher transdermal flux relative to free progesterone. Cubosomes revealed a higher skin penetration with transdermal steady flux of 48.57.10–2 ± 0.7 µg/cm2 h. Nanoliposomes offered a higher percentage of skin progesterone deposition compared to other nanocarriers. Based on the histopathological examination, cubosomes and nanoliposomes were found to be biocompatible for transdermal application. Confocal laser scanning microscopy confirmed the ability of fluoro-labeled cubosomes to penetrate through the whole skin layers. Conclusion: The elaborated cubosomes proved to be a promising non-invasive nanocarrier for transdermal hormonal delivery.