Ahmed N. Allam

Optimization of acyclovir oral tablets based on gastroretention technology: Factorial design analysis and physicochemical characterization studies

The purpose of this research was to prepare a floating drug delivery system of acyclovir. Floating matrix tablets of acyclovir were developed to prolong gastric residence time and increase its bioavailability. The tablets were prepared by direct compression technique, using polymers such as hydroxypropylmethylcellulose 4000, Compritol 888. Sodium bicarbonate was used as a gas-generating agent. A 32 factorial design using the Design Expert Software (version 7.1.6) was applied to optimize the drug release profile systematically. The amounts of hydroxypropylmethylcellulose 4000 (X1) and Compritol 888 (X2) were selected as independent variables and the percentage drug released in 1 (Q1), 6 (Q6), and 12 (Q12) h as dependent variables. The results of factorial design indicated that a high level of both hydroxypropylmethylcellulose 4000 (X1) and Compritol 888 (X2) favors the preparation of floating controlled-release of acyclovir tablets. Also, a good correlation was observed between predicted and actual values of the dependent variables chosen for the study. By fitting the data into zero-order, first-order, and Higuchi models, we concluded that the release followed Higuchi diffusion kinetics. Storage of the prepared formulations at 40°C/75% relative humidity for 3 months showed no significant change in drug release profiles and buoyancy of the floating tablets. We can conclude that a combination of hydroxypropylmethylcellulose 4000, Compritol 888, and sodium bicarbonate can be used to increase the gastric residence time of the dosage form up to 12 h. These floating tablets seem to be a promising gastroretentive drug delivery system.

Preparation, characterization and in vivo evaluation of curcumin self-nano phospholipid dispersion as an approach to enhance oral bioavailability

The aim of this study was to examine the efficacy of self-nano phospholipid dispersions (SNPDs) based on Phosal(®) to improve the oral bioavailability of curcumin (CUR). SNPDs were prepared with Phosal(®) 53 and Miglyol 812 at different surfactant ratio. Formulations were evaluated for particle size, polydispersity index, zeta potential, and robustness toward dilution, TEM as well as in vitro drug release. The in vivo oral absorption of selected formulations in comparison to drug suspension was evaluated in rats. Moreover, formulations were assessed for in vitro characteristic changes before and after storage. The SNPDs were miscible with water in any ratio and did not show any phase separation or drug precipitation. All the formulas were monodisperse with nano range size from 158±2.6 nm to 610±6.24 nm. They passed the pharmacopeial tolerance for CUR dissolution. No change in dissolution profile and physicochemical characteristics was detected after storage. CUR-SNPDs are found to be more bioavailable compared with suspension during an in vivo study in rats and in vitro release studies failed to imitate the in vivo conditions. These formulations might be new alternative carriers that enhance the oral bioavailability of poorly water-soluble molecules, such as CUR.

Ethyl cellulose nanoparticles as a platform to decrease ulcerogenic potential of piroxicam: formulation and in vitro/in vivo evaluation

Nanoparticles (NPs) have long gained significant interest for their use in various drug formulations in order to increase bioavailability, prolong drug release, and decrease side effects of highly toxic drugs. The objective of this investigation was to evaluate the potential of ethyl cellulose-based NPs (EC-NPs) to modulate the release and reduce ulcerogenicity of piroxicam (PX) after oral administration. PX-loaded EC-NPs were prepared by solvent evaporation technique using different stabilizers at three concentration levels. Morphological examination of selected formulas confirmed the formation of spherical NPs with slightly porous surface. Formulation containing poloxamer-stabilized EC-NPs (P188/0.2), having a particle size of 240.26±29.24 nm, polydispersity index of 0.562±0.030, entrapment efficiency of 85.29%±1.57%, and modulated release of PX (88% after 12 hours), was selected as the optimum formulation. Differential scanning calorimetry demonstrated the presence of PX in an amorphous form in the NPs. Fourier-transform infrared spectroscopy revealed the possible formation of hydrogen bond and the absence of chemical interaction. In vivo study, evaluation of pharmacokinetic parameters, evaluation of gastric irritation potential, and histological examination were conducted after administration of the selected formulation. Time to reach maximum plasma concentration, tmax, of poloxamer-stabilized EC-NPs was significantly higher than that of Feldene® 20 mg capsules (P≤0.001). Encapsulation of the acidic, gastric offender PX into NPs managed to significantly suppress gastric ulceration potential in rats (P≤0.05) as compared to that of PX suspension. A reduction of 66% in mean ulcer index was observed. In conclusion, poloxamer-stabilized EC-NPs (P188/0.2) had a significant potential of offsetting deleterious side effects common in PX use.

Formulation and physicochemical characterization of chitosan/acyclovir co-crystals.

In the current study, the influence of chitosan on the dissolution rate and bioavailability of acyclovir has been illustrated through the preparation of co-crystals by simple solvent change method. Chitosan was precipitated on acyclovir crystals using sodium citrate as the salting out agent. The pure drug and the prepared co-crystals using different concentrations and molecular weights of chitosan were characterized in terms of drug content, particle size, thermal behavior, IR analysis, surface morphology, in vitro drug release and physical stability. The results obtained showed that the practical yield of the prepared co-crystals was found to be inversely proportional to chitosan concentration. The drug content of the co-crystals was uniform among the different batches. The prepared co-crystals showed a slower drug release when compared to that of pure drug. The considerable change in the dissolution rate of acyclovir from optimized crystal formulation was attributed to the wetting effect of chitosan, the reduction in drug crystallinity and the altered surface morphology. The thermograms showed a decrease in the melting enthalpy of acyclovir indicating a disorder in the crystalline content whereas IR spectroscopy studies revealed an interaction between acyclovir and chitosan. The optimized co-crystals were stable for three months at 40°C and 75 ± 5% RH.

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.

Curcumin phytosomal softgel formulation: Development, optimization and physicochemical characterization.

Abstract Curcumin, a naturally occurring lipophilic molecule can exert multiple and diverse bioactivities. However, its limited aqueous solubility and extensive presystemic metabolism restrict its bioavailability. Curcumin phytosomes were prepared by a simple solvent evaporation method where free flowing powder was obtained in addition to a newly developed semisolid formulation to increase curcumin content in softgels. Phytosomal powder was characterized in terms of drug content and zeta potential. Thirteen different softgel formulations were developed using oils such as Miglyol 812, castor oil and oleic acid, a hydrophilic vehicle such as PEG 400 and bioactive surfactants such as Cremophor EL and KLS P 124. Selected formulations were characterized in terms of curcumin in vitro dissolution. TEM analysis revealed good stability and a spherical, self-closed structure of curcumin phytosomes in complex formulations. Stability studies of chosen formulations prepared using the hydrophilic vehicle revealed a stable curcumin dissolution pattern. In contrast, a dramatic decrease in curcumin dissolution was observed in case of phytosomes formulated in oily vehicles.

Mucoadhesive buccal tablets containing silymarin Eudragit-loaded nanoparticles: formulation, characterisation and ex vivo permeation

Abstract Eudragit-loaded silymarin nanoparticles (SNPs) and their formulation into buccal mucoadhesive tablets were investigated to improve the low bioavailability of silymarin through buccal delivery. Characterisation of SNPs and silymarin buccal tablets (SBTs) containing the optimised NPs were performed. Ex vivo permeability of nominated SBTs were assessed using chicken pouch mucosa compared to SNPs and drug suspension followed by histopathological examination. Selected SNPs had a small size (<150 nm), encapsulation effciency (>77%) with drug release of about 90% after 6 h. For STBs, all physicochemical parameters were satisfactory for different polymers used. DSC and FT-IR studies suggested the presence of silymarin in an amorphous state. Ex vivo permeation significantly emphasised the great enhancement of silymarin permeation after NPs formation and much more increase after formulating into BTs relative to the corresponding drug dispersion with confirmed membrane integrity. Incorporation of SNPs into BTs could be an efficient vehicle for delivery of silymarin.

Chitosan-coated diacerein nanosuspensions as a platform for enhancing bioavailability and lowering side effects: preparation, characterization, and ex vivo/in vivo evaluation

Nanodrug delivery systems have been widely reviewed for their use in several drug formulations to improve bioavailability, sustain effect, and decrease side effects of many candidate drugs. The objective of this study was to evaluate the potential of chitosan (CS)-coated nanosuspensions to enhance bioavailability and reduce the diarrheal side effect of diacerein (DCN) after oral administration. DCN nanosuspensions (DNS) were prepared by sonoprecipitation technique using different stabilizers at three different concentrations. The selected DNS with optimum particle size (PS), polydispersity index (PDI), and Zeta potential (ZP) was coated with three different concentrations of CS-coated DNS (CS-DNS) and screened. In vitro dissolution was performed for the selected lyophilized formulae and compared with DCN powder in addition to the assessment of drug crystallinity via scanning electron microscopy, X-ray powder diffraction, and differential scanning calorimetry. Ex vivo drug permeability using noneverted rat intestine, intraluminal content, and mucoadhesion evaluation was studied for nominated formulae in comparison to DCN suspension. Moreover, in vivo study, pharmacokinetic parameters, and evaluation of diarrheal potential were conducted after oral administration of selected formulae. Polyvinyl pyrrolidone (PVP)-stabilized DNS showed a significant increase (P≤0.05) in PS and PDI as the stabilizer concentration increased. PVP-stabilized DNS with the lowest CS concentration was protected from aggregation by lyophilization with mannitol. A remarked enhancement in dissolution parameters was observed in the nanocrystals’ formulae. Morphological examination and X-ray diffraction confirmed drug crystallinity. The intermediate permeation parameters of CS-DNS-F10, lowest rhein-to-DCN ratio in intraluminal content along with the highest percentage of mucoadhesive, could serve as a sustaining profile of coated formula. CS-DNS-F10 showed a significantly higher Cmax of 0.74±0.15 µg/mL at a delayed Tmax of 3.60±0.55 hours with a relative bioavailability of 172.1% compared to DCN suspension. CS-coated nanosuspensions could serve as promising revenue to enhance bioavailability and reduce the diarrheal side effect of DCN after oral administration.