M. El-Mahdy

The formulation-performance relationship of multiple emulsions and ocular activity

Abstract Multiple emulsions containing prednisolone were prepared using a two step emulsification technique. The effect of various concentrations of hydrophilic and lipophilic emulsifiers (Tween-20 and Span-60) in multiple emulsions based on liquid paraffin on the drug bioavailability and duration of action as a controlled release formulation was studied following instillation in the rabbits eye. The parameter of ocular activity such as area under the intraocular pressure/time curve (AUC); time for maximum response (TMR) and half value duration (HVD) were assessed for the o/w/o and w/o/w multiple emulsions. It was found that the hydrophilic emulsifier reduced the bioavailability but increased the concentration of lipophilic emulsifier to bring about the reverse effect. Therefore the bioavailability of the drug can be controlled by the proper choice and concentration of the emulsifier in the preparation of emulsions. The hydrophile-lipophile balance (HLB) values calculated for a surfactant mixture in a multiple emulsion was found to be highly negatively correlated to the values of the parameters of ocular activity. Decreasing the HLB value of the surfactant mixture in a w/o/w emulsion favours the bioavailability; the intensity and duration of drug action.

Safety and efficacy of amine-containing methacrylate polymers as nonviral gene delivery vectors

Abstract Background: Nonviral polymeric delivery systems are explored to enhance clinical development of nucleic acids as therapeutic entities for effective management of debilitating conditions such as cancer. This

Microemulsion for ocular delivery: ocular irritancy test and in vivo studies of anti-inflammatory action

Microemulsions are promising drug delivery systems for ocular delivery of drugs, especially water insoluble drugs such as diclofenac in its acid undissociated form. Microemulsions are characterized with high surfactant content (> 10 % w/w) in order to lower the interfacial tension which facilitates dispersion process during the preparation of microemulsion and provides a flexible film around the droplets. However, there are a few researches that have studied the possible irritation effect of microemulsion on the eye. Therefore, evaluation of the ocular irritancy is an important requirement in the development of ocular delivery vehicles such as microemulsions. Draize test using rabbits was used for evaluation of the ocular irritation potential of the prepared microemulsions. The efficacy of the anti-inflammatory action of the formulation showing the least Draize score was then evaluated using 3 % croton oil in 2-ethoxyethanol to induce corneal inflammation in rabbits. Results showed that the tested formulations, M5 and M6, were non irritant (NI) where they showed a Draize score of 8 and 14 respectively. When M5 was studied for its anti-inflammatory action and compared with marketed eye drops, Epifenac, it showed a significantly shorter recovery time compared to Epifenac eye drops.

Formulation and evaluation of quercetin in certain dermatological preparations

Quercetin is a bioactive flavonoid widely used as a health supplement. Quercetin was formulated in different dermatological preparations as gel, emulgel and microemulsion gel. Different gel bases were used for the preparation of quercetin gel as sodium carboxymethylcellulose (NaCMC), Carbopol 934 and Pluronic F-127. Also different formulae of both emulgel and microemulsion gel were prepared using different gel bases and surfactants. These formulations were evaluated for their drug content, in vitro release of the drug from cellophane membrane and skin permeability through hairless mouse skin. The antibacterial activity against Gram positive and Gram negative organisms was also studied. The results of the drug release indicated that the highest release was obtained from the microemulsion gel followed by gel and emulgel, respectively. The same results were obtained for drug penetration through hairless mouse skin. Analysis of the data according to different kinetic mechanisms revealed that the release pattern of the drug from the tested bases followed zero-order and the Higuchi diffusion model. Results also indicated an excellent activity against all tested organisms and the inhibition zone was dependent on the type of formulation used.

Solubilization and Enhancement of Ex Vivo Vaginal Delivery of Progesterone Using Solid Dispersions, Inclusion Complexes and Micellar Solubilization

BACKGROUND Progesterone (PG), a natural female sex hormone is used clinically in menopausal hormone replacement therapy and to control reproductive functions. Its very limited aqueous solubility results in reduced oral bioavailability and low patient compliance when administered in high doses. The aim of this study was to enhance PG aqueous solubility and vaginal delivery using solid dispersion, inclusion complex and micellar solubilization techniques. METHODS PG solid dispersions and inclusion complexes were prepared by solvent evaporation method using different polymers, such as cyclodextrins, polyvinyl pyrrolidone (PVP), poly (ethylene glycol) 6000, Pluronic® F-127 and Pluronic® F-68. PG was also incorporated into polymeric micelles of Pluronic® F-127, Pluronic® F- 68, Brij®35 and Myrj®52. The prepared solid dispersions, inclusion complexes and micelles were characterized using different techniques. Drug permeability across rabbit vaginal mucosa was also studied. RESULTS Dissolution studies of PG solid dispersions showed that the highest drug dissolution rate was achieved at PG/polymer weight ratio of 5:5. Further, complete drug dissolution was obtained for PG/Pluronic® F-127 solid dispersion after 15 min compared to 42% dissolution for the drug alone. Brij®35 micelles had a drug loading capacity ~15%, which increased the drug aqueous solubility by more than 20 folds. PG permeability coefficients through rabbit vaginal mucosa for PG/Brij®35 micelles and PG/Pluronic® F-127 micelles were ~ two times higher than that of the drug alone. CONCLUSION These results confirm that Brij®35 and Pluronic® F-127 micelles are promising carriers to overcome PG shortcomings through enhancing its aqueous solubility and vaginal permeability.

NF-κB decoy polyplexes decrease P-glycoprotein-mediated multidrug resistance in colorectal cancer cells.

Multidrug resistance (MDR), a major cause for chemotherapy failure, has been linked to upregulation of ATP-dependent membrane efflux systems that limit intracellular accumulation of cytotoxic anticancer agents. P-glycoprotein (P-gp) encoded by the human ABCB1 gene was the first efflux transporter identified to contribute to MDR. ABCB1 gene expression is correlated with constitutive activation of the NF-κB signaling pathway in tumor cells. The objective of this research is to modulate P-gp activity in colon cancer cells using NF-κB decoy oligodeoxynucleotides (ODNs) that are effectively delivered into the nucleus of colorectal cancer cells by self-assembling nonviral nanoparticles comprising the novel poly[N-(2-hydroxypropyl)methacrylamide]-poly(N,N-dimethylaminoethylmethacrylate) diblock copolymer (pHPMA-b-pDMAEMA). Ethidium bromide intercalation and gel retardation assays demonstrated high DNA condensation capacity of pHPMA-b-pDMAEMA. Nanoparticles prepared with and without decoy ODNs did not significantly compromise cellular safety at N/P ratios ⩽4. Transfection efficiency of pHPMA-b-pDMAEMA polyplexes (N/P=4) in Caco-2 cells was comparable to TurboFect transfection standard, resulting in a 98% reduction in P-gp protein levels. As a pharmacodynamic consequence, intracellular accumulation of the P-gp substrate Rhodamine123 significantly increased by almost twofold. In conclusion, NF-κB ODN polyplexes fabricated with pHPMA-b-pDMAEMA polymer effectively reduced P-gp-mediated efflux activity in Caco-2 cells, suggesting successful interference with NF-κB-binding sites in the promoter region of the ABCB1 gene.

Mucoadhesive tablets for the vaginal delivery of progesterone: in vitro evaluation and pharmacokinetics/pharmacodynamics in female rabbits

Abstract Objective: To develop mucoadhesive tablets for the vaginal delivery of progesterone (P4) to overcome its low oral bioavailability resulting from drug hydrophobicity and extensive hepatic metabolism. Methods: The tablets were prepared using mixtures of P4/Pluronic® F-127 solid dispersion and different mucoadhesive polymers. The tablets physical properties, swelling index, mucoadhesion and drug release kinetics were evaluated. P4 pharmacokinetic and pharmacodynamic properties were evaluated in female rabbits and compared with vaginal micronized P4 tablets and intramuscular (IM) P4 injection, respectively. Results: The tablets had satisfactory physical properties and their swelling, in vitro mucoadhesion force and ex vivo mucoadhesion time were dependent on tablet composition. Highest swelling index and mucoadhesion time were detected for tablets containing 20% chitosan-10% alginate mixture. Most tablets exhibited burst release (∼25%) during the first 2 h but sustained the drug release for ∼48 h. In vivo study showed that chitosan-alginate mucoadhesive tablets had ∼2-fold higher P4 mean residence time (MRT) in the blood and 5-fold higher bioavailability compared with oral P4. Further, same tablets showed 2-fold higher myometrium thickness in rabbit uterus compared with IM P4 injection. Conclusion: These results confirm the potential of these mucoadhesive vaginal tablets to enhance P4 efficacy and avoid the side effects associated with IM injection.

Oil-entrapped ranitidine HCl beads heal peptic ulcers via local and systemic mechanisms

Abstract Objective: Oral gastroretentive system is one of the site-specific drug delivery system, which is designed to be retained in upper GIT for a prolonged time. Ranitidine hydrochloride (RHCl), which is used frequently in treatment of peptic ulcer, is a suitable candidate for gastroretentive delivery systems. Dependently, floating oil-entrapped alginate beads of RHCl were developed and evaluated as an approach to site-specific delivery avoiding colonic degradation and enhancing both bioavailability and the proposed local effect. Methods: Different formulations of floating beads were suggested and randomized using 24 full factorial design. Optimized formulation was subjected for in vivo studies to measure the oral bioavailability and the healing effect of induced peptic ulcers. Results: Beads size ranged from 1.32 to 2.3 mm. All beads revealed excellent floating capabilities. Optimum formulation (F12) has entrapment efficiency of 70%, drug loading of 7% and 71% RHCl released after 6 h. SEM of F12 shows a grossly spherical structure with presence of oil droplets distributed throughout structure. AUC obtained from F12 was nonsignificantly higher than that of a commercial tablet. Signs of ulcer healing appeared clearly with F12 through appearance of granulation tissue, collagen fibers and newly formed blood vessels. Healing rate and extent obtained with a commercial tablet were less than F12. Quantitative analysis confirmed histopathological findings. Conclusion: Floating oil-entrapped beads are a promising approach for RHCl delivery to remain in stomach for a longer time ensuring site-specific delivery and consequently, enhancing local healing effect of peptic ulcers.