Ibrahim Elsayed

Transfersomal lyophilized gel of buspirone HCl: formulation, evaluation and statistical optimization

Abstract Context: Buspirone HCl has very low oral bioavailability (4%) due to deactivation by extensive first pass effect. It also has very limited transdermal permeation due to its high hydrophilicity. Objective: The aim of this study was to increase the transdermal permeation of buspirone HCl utilizing a stable dosage form. Methods: Transfersomes were prepared using Tween-80 as a flexibility imparting agent to the vesicular walls. Oleic acid and/or ethanol, with different percentages, were utilized as a permeation enhancer. Formulations were characterized by analyzing particle size, polydispersity index, zeta potential, entrapment efficiency, in vitro release and ex vivo drug permeation. Factorial design (32) was planned for the optimization of formulations using Design-Expert® software. Lyophilized transfersomal gel of the optimized formulation was prepared using hydroxypropyl methylcellulose (HPMC) K100, carboxymethyl cellulose or sodium alginate with or without mannitol as a cryoprotectant. Physical characterization of the transfersomes and the lyophilized gel were carried out using transmission and scanning electron microscopy, respectively. Results: The optimized formulation (T7), containing 35% oleic acid, had the highest desirability value (0.658) with high ex vivo drug flux (43.40 µg/h/cm2) through rat skin when compared with the aqueous drug solution and formula T1 (without oleic acid). The T7 transfersomal gel containing HPMC K100 (G2) had the highest desirability value (0.640) among the lyophilized gel formulations with decreased ex vivo drug flux (38.98 µg/h/cm2) in comparison with the original transfersomal formula (T7). Conclusions: Lyophilized transfersomal gel containing oleic acid was considered as a promising transdermal delivery system for hydrophilic drugs.

Nanosizing of a poorly soluble drug: technique optimization, factorial analysis, and pharmacokinetic study in healthy human volunteers

Context Diacerein (DCN) has low aqueous solubility (3.197 mg/L) and, consequently, low oral bioavailability (35%–56%). To increase both the solubility and dissolution rate of DCN while maintaining its crystalline nature, high pressure homogenization was used but with only a few homogenization cycles preceded by a simple bottom-up technique. Methods The nanosuspensions of DCN were prepared using a combined bottom-up/top-down technique. Different surfactants – polyvinyl alcohol, sodium deoxycholate, and sodium dodecyl sulfate – with different concentrations were used for the stabilization of the nanosuspensions. Full factorial experimental design was employed to investigate the influence of formulation variables on nanosuspension characteristics using Design-Expert® Software. Particle size (PS), zeta potential, saturation solubility, in vitro dissolution, and drug crystallinity were studied. Moreover, the in vivo performance of the optimized formula was assessed by bioavailability determination in healthy human volunteers. Results The concentration of surfactant had a significant effect on both the PS and polydispersity index values. The 1% surfactant concentration showed the lowest PS and polydispersity index values compared with other concentrations. Both type and concentration of surfactant had significant effects on the zeta potential. Formula F8 (containing 1% sodium deoxycholate) and Formula F12 (containing 1% sodium dodecyl sulfate) had the highest desirability values (0.952 and 0.927, respectively). Hence, they were selected for further characterization. The saturated solubility and mean dissolution time, in the case of F8 and F12, were significantly higher than the coarse drug powder. Techniques utilized in the nanocrystals’ preparation had no effect on DCN crystalline state. The selected formula (F12) showed a higher bioavailability compared to the reference market product with relative bioavailability of 131.4%. Conclusion The saturation solubility, in vitro dissolution rate and relative bioavailability of DCN were significantly increased after nanocrystallization. Less time and power consumption were applied by the combination of bottom-up and top-down techniques.

Optimization of long circulating mixed polymeric micelles containing vinpocetine using simple lattice mixture design, in vitro and in vivo characterization

The aim of this study was to increase the in vivo mean residence time of vinpocetine after IV injection utilizing long circulating mixed micellar systems. Mixed micelles were prepared using Pluronics L121, P123 and F127. The systems were characterized by testing their entrapment efficiency, particle size, polydispersity index, zeta potential, transmission electron microscopy and in vitro drug release. Simple lattice mixture design was planned for the optimization using Design-Expert(®) software. The optimized formula was lyophilized, sterilized and imaged by scanning electron microscope. Moreover, the in vivo behavior of the optimized formula was evaluated after IV injection in rabbits. The optimized formula, containing 68% w/w Pluronic L121 and 32% w/w Pluronic F127, had the highest desirability value (0.621). Entrapment efficiency, particle size, polydispersity index and zeta potential of the optimized formula were 50.74 ± 3.26%, 161.50 ± 7.39 nm, 0.21 ± 0.03 and -22.42 ± 1.72 mV, respectively. Lyophilization and sterilization did not affect the characteristics of the optimized formula. Upon in vivo investigation in rabbits, the optimized formula showed a significantly higher elimination half-life and mean residence time than the market product. Finally, mixed micelles could be considered as a promising long circulating nanocarrier for lipophilic drugs.

Investigating the cubosomal ability for transnasal brain targeting: In vitro optimization, ex vivo permeation and in vivo biodistribution.

The aim of this study was to enhance the risperidone delivery to the brain through the transnasal route via optimization of cubosomal gel. Cubosomes were prepared using glycerol mono-oleate (GMO), Pluronic F127 (PF127) and Tween 80 (T80). The prepared formulae were characterized by testing their particle size, polydispersity index, zeta potential, entrapment efficiency, in vitro drug release and transmission electron microscopy. Central composite design was planned for the formulae optimization and the selected formula (containing PF127 with concentration 15 mg/g GMO and T80 with concentration of 20mg/L) was re-prepared in presence of gelling polymer (gellan gum or polyox). The optimal cubosomal gel (containing 0.4% w/v polyox) had been subjected to ex-vivo permeation, histopathological evaluation and in vivo biodistribution studies. It showed significantly higher transnasal permeation and better distribution to the brain, when compared to the used control (drug solution and/or suspension). Finally, the cubosomal gel could be considered as a promising carrier for brain targeting of CNS acting drugs through the transnasal route.

Design of lipotomes as a novel dual functioning nanocarrier for bioavailability enhancement of lacidipine: in-vitro and in-vivo characterization.

Lipotomes were designed to enhance lacidipines oral bioavailability by improving its solubility and enhancing the oral lymphatic uptake. Lipotomes were prepared using cetyl alcohol and Tween(®) 80 using a thin film hydration technique. Cetyl alcohol was chosen for imparting a lipophilic environment that would enforce the lymphatic uptake while Tween(®) 80 would improve drug solubility within the lipotomes. Lipotomes were characterized by analyzing their particle size, solubilization efficiency and in-vitro drug release. Central composite design was applied to statistically optimize the formulations using Design-Expert(®) software. The optimum formula (OLT) was made up of excipients:drug ratio of 36.59:1 w/w and Tween(®) 80:cetyl alcohol ratio of 4:1 w/w. OLT was lyophilized and filled into Eudragit(®) L100 enteric coated capsules. Mannitol (10% w/v) was the ideal cryoprotectant to retain the physicochemical characteristics of the OLT formulation after lyophilization. In conclusion, the selected lyophilized formula (L3) succeeded in enhancing drugs oral bioavailability in human volunteers compared to the commercial product confirming the success of lipotomes as a novel oral nanocarrier for insoluble drugs having extensive first pass metabolism.

Biodegradable donepezil lipospheres for depot injection: optimization and in-vivo evaluation

Objectives  The purpose of this study was to develop an injectable depot liposphere delivery system with high loading capacity for controlled delivery of donepezil to decrease dosing frequency and increase patient compliance.

Pulsatile systems for colon targeting of budesonide: In vitro and in vivo evaluation

The purpose of this study is to increase the lag time and prevent release of budesonide, a corticosteroid drug used in Crohn’s disease for the first 5 h and efficiently deliver it to the colon. Eudragit S100 spray-coated capsules and pulsatile systems using tablet plugs of cellulose acetate butyrate (CAB), HPMC K4M, guar gum, and pectin were prepared. Eudragit S100-coated capsules released 80.62% after 5 h. In pulsatile systems, decreasing the ratio of the polymer significantly increased the rate and extent of drug release. Spray-coating with EUD S100 decreased the extent of drug release to 48.41%, 69.94%, 80.58%, and 45.23% in CAB, HPMC K4M, pectin, and guar gum, respectively; however, the entire amount was released in the target area. In the presence of bacterial enzymes, selected formulas showed nearly 100% release. X-ray imaging performed to monitor the capsules throughout the GIT in human volunteers of the capsules and spray-coated pulsatile systems with 25% guar gum in the plug showed bursting in the transverse and ascending colon, respectively. Both formulations showed marked reduction in induced rabbit colitis model.

A novel injectable in situ forming poly-DL-lactide and DL-lactide/glycolide implant containing lipospheres for controlled drug delivery

One of the greatest challenges in in situ forming implant (ISFI) systems by polymer precipitation is the large burst release during the first 1–24 hours after implant injection. The aim of this study was to decrease the burst-release effect of a water-soluble model drug, donepezil HCl, with a molecular weight of 415.96 Da, from in situ forming implants using a novel in situ implant containing lipospheres (ISILs). In situ implant suspensions were prepared by dispersing cetyl alcohol and glyceryl stearate lipospheres in a solution of poly-DL-lactide (PDL) or DL-lactide/glycolide copolymer (PDLG). Also, in situ implant solutions were prepared using different concentrations of PDL or PDLG solutions in N-methyl-2-pyrrolidone (NMP). Triacetin and Pluronic L121 were used to modify the release pattern of donepezil from the in situ implant solutions. In vitro release, rheological measurement, and injectability measurement were used to evaluate the prepared in situ implant formulae. It was found that ISIL decreased the burst effect as well as the rate and extent of drug release, compared to lipospheres, PDL, and PDLG in situ implant. The amount of drug released in the first day was 37.75, 34.99, 48.57, 76.3, and 84.82% for ISIL in 20% PDL (IL-1), ISIL in 20% PDLG (IL-2), lipospheres (L), 20% PDL ISFI (I5), and 20% PDLG ISFI (I8), respectively. The prepared systems showed Newtonian flow behavior. ISIL (IL-1 and IL-2) had a flow rate of 1.94 and 1.40 mL/min, respectively. This study shows the potential of using in situ implants containing lipospheres in controlling the burst effect of ISFI.

Response surface optimization, Ex vivo and In vivo investigation of nasal spanlastics for bioavailability enhancement and brain targeting of risperidone

Transnasal brain drug targeting could ensure better drug delivery to the brain through the olfactory pathway. Risperidone bioavailability is 66% in extensive metabolizers and 82% in slow metabolizers. The aim of this study is to investigate the ability of the nanovesicular spanlastics to effectively deliver risperidone through the nasal route to the brain and increase its bioavailability. Spanlastics formulae, composed of span and polyvinyl alcohol, were designed based on central composite statistical design. The planned formulae were prepared using ethanol injection method. The prepared formulae were characterized by testing their particle size, polydispersity index, zeta potential and encapsulation efficiency. The optimized formula having the lowest particle size, polydispersity index, the highest zeta potential and encapsulation efficiency was subjected to further investigations including characterization of its rheological properties, elasticity, transmission electron microscopy, in vitro diffusion, ex vivo permeation, histopathology and in vivo biodistribution. The optimized formula was composed of 5mg/mL span and 30mg/mL polyvinyl alcohol. It showed significantly higher transnasal permeation and better distribution to the brain, when compared to the used control regarding the brain targeting efficiency and the drug transport percentage (2.16 and 1.43 folds increase, respectively). The study introduced a successful and promising formula to directly and effectively carry the drug from nose to brain.

Design and development of novel lipid based gastroretentive delivery system: response surface analysis, in-vivo imaging and pharmacokinetic study.

Abstract Famotidine HCl has low bioavailability (40–45%) due to its narrow absorption window and low solubility in intestinal pH. Lipids were utilized in the formulation of novel gastroretentive dosage forms to increase the availability of famotidine HCl at its absorption site. Novel non-swellable gastroretentive lipid disks (D) and swellable compression coated tablets with a lipid core (T) were prepared. Formulae were characterized by friability testing, in-vitro buoyancy, in-vitro drug release and scanning electron microscopy (SEM). Factorial designs of 22 × 31 and 32 were planned for the optimization of disks and tablets, respectively, using Design-Expert® software. X-ray imaging was used for the in-vivo visualization of the selected formula in human gastrointestinal tract (GIT). Moreover, a bioavailability study was performed in healthy human volunteers using the optimized disk formula (D10). Results showed that formulae D10 (containing stearyl alcohol and polyethylene glycol in a ratio of 9:1 w/w) and T7 (containing polyethylene oxide only) had highest desirability values (0.684 and 0.842, respectively). Lipids achieved instantaneous floating and sustained the release of famotidine HCl over a prolonged period of time with significant bioavailability enhancement.