Mina Ibrahim Tadros

Controlled-release effervescent floating matrix tablets of ciprofloxacin hydrochloride: Development, optimization and in vitro–in vivo evaluation in healthy human volunteers

Ciprofloxacin hydrochloride has a short elimination half-life, a narrow absorption window and is mainly absorbed in proximal areas of GIT. The purpose of this study was to develop a gastroretentive controlled-release drug delivery system with swelling, floating, and adhesive properties. Ten tablet formulations were designed using hydroxypropylmethylcellulose (HPMC K15M) and/or sodium alginate (Na alginate) as release-retarding polymer(s) and sodium bicarbonate (NaHCO(3)) or calcium carbonate (CaCO(3)) as a gas former. Swelling ability, floating behaviour, adhesion period and drug release studies were conducted in 0.1 N HCl (pH 1.2) at 37+/-0.5 degrees C. The tablets showed acceptable physicochemical properties. Drug release profiles of all formulae followed non-Fickian diffusion. Statistical analyses of data revealed that tablets containing HPMC K15M (21.42%, w/w), Na alginate (7.14%, w/w) and NaHCO(3) (20%, w/w) (formula F7) or CaCO(3) (20%, w/w) (formula F10) were promising systems exhibiting excellent floating properties, extended adhesion periods and sustained drug release characteristics. Both formulae were stored at 40 degrees C/75% RH for 3months according to ICH guidelines. Formula F10 showed better physical stability. Abdominal X-ray imaging of formula F10, loaded with barium sulfate, in six healthy volunteers revealed a mean gastric retention period of 5.50+/-0.77h.

Sucrose stearate-based proniosome-derived niosomes for the nebulisable delivery of cromolyn sodium.

A Novel approach was developed for the preparation of controlled release proniosome-derived niosomes, using sucrose stearates as non-ionic biocompatible surfactants for the nebulisable delivery of cromolyn sodium. Conventional niosomes were prepared by a reverse phase evaporation method followed by the preparation of proniosomes by spraying the optimized surfactant-lipid mixture of sucrose stearate, cholesterol and stearylamine in 7:3:0.3 molar ratio onto the surface of spray dried lactose powder. Proniosome-derived niosomes were obtained by hydrating proniosomes with 0.9% saline at 50 degrees C and mixing for approximately 2 min. All vesicles were evaluated for their particle size, morphological characteristics, entrapment efficiency, in vitro drug release, nebulisation efficiency and physical stability at 2-8 degrees C. In addition, coating carrier surface with the surfactant-lipid mixture, during preparation of proniosomes, resulted in smaller, free flowing, homogenous and smooth vesicles with high drug entrapment efficiency. Compared to a standard drug solution, a successful retardation of the drug release rate was achieved with the proniosome-derived niosomes, where the t50% value of the release profile was 18.1h compared to 1.8h. Moreover, high nebulisation efficiency percentage and good physical stability were also achieved. The results are very encouraging and offer an alternative approach to minimize the problems associated with conventional niosomes like degradation, sedimentation, aggregation and fusion.

Enhanced transdermal delivery of salbutamol sulfate via ethosomes

The main objective of the present work was to compare the transdermal delivery of salbutamol sulfate (SS), a hydrophilic drug used as a bronchodilator, from ethosomes and classic liposomes containing different cholesterol and dicetylphosphate concentrations. All the systems were characterized for shape, particle size, and entrapment efficiency percentage, by image analysis optical microscopy or transmission electron microscopy, laser diffraction, and ultracentrifugation, respectively. In vitro drug permeation via a synthetic semipermeable membrane or skin from newborn mice was studied in Franz diffusion cells. The selected systems were incorporated into Pluronic F 127 gels and evaluated for both drug permeation and mice skin deposition. In all systems, the presence of spherical-shaped vesicles was predominant. The vesicle size was significantly decreased (P<.05) by decreasing cholesterol concentration and increasing dicetylphosphate and ethanol concentrations. The entrapment efficiency percentage was significantly increased (P<.05) by increasing cholesterol, dicetylphosphate, and ethanol concentrations. In vitro permeation studies of the prepared gels containing the selected vesicles showed that ethosomal systems were much more efficient at delivering SS into mice skin (in terms of quantity and depth) than were liposomes or aqueous or hydroalcoholic solutions.

Brain targeting of olanzapine via intranasal delivery of core–shell difunctional block copolymer mixed nanomicellar carriers: In vitro characterization, ex vivo estimation of nasal toxicity and in vivo biodistribution studies

Olanzapine (OZ) is atypical antipsychotic drug that suffers from low brain permeability due to efflux by P-glycoproteins and hepatic first-pass metabolism. The current work aimed to develop OZ-loaded micellar nanocarriers and investigate their nose-to-brain targeting potential. OZ-loaded (5mg/ml) micelles (F1-F12) were prepared, using a Pluronic(®) mixture of L121 and P123, adopting thin-film hydration method. The micelles were evaluated for turbidity, particle size, morphology, drug-entrapment efficiency (EE%), drug-loading characteristics, in vitro drug release and ex vivo nasal toxicity in sheep. The in vivo biodistribution and pharmacokinetic studies in the brain/blood following intravenous (i.v.) and intranasal (i.n.) administrations of technetium-labeled OZ-loaded micelles and OZ-solution were evaluated in rats. Spherical micelles ranging in size from 18.97 to 380.70 nm were successfully developed. (1)H NMR studies confirmed OZ incorporation into micelle core. At a drug:Pluronic(®) L121:Pluronic(®) P123 ratio of 1:8:32 (F11), the micelles achieved a conciliation between kinetic and thermodynamic stability, high drug-EE%, controlled drug-release characteristics and evoked minor histopathological changes in sheep nasal mucosa. The significantly (P<0.05) higher values for F11 micelles (i.n.); brain/blood ratio (0.92), drug targeting index (5.20), drug targeting efficiency (520.26%) and direct transport percentage (80.76%) confirm the development of a promising non-invasive OZ-loaded nose-to-brain delivery system.

Promising ion-sensitive in situ ocular nanoemulsion gels of terbinafine hydrochloride: Design, in vitro characterization and in vivo estimation of the ocular irritation and drug pharmacokinetics in the aqueous humor of rabbits

Terbinafine hydrochloride (T-HCl) is recommended for the management of fungal keratitis. To maintain effective aqueous humor concentrations, frequent instillation of T-HCl drops is necessary. This work aimed to develop alternative controlled-release in situ ocular drug-loaded nanoemulsion (NE) gels. Twelve pseudoternary-phase diagrams were constructed using oils (isopropyl myristate/Miglyol 812), surfactants (Tween 80/Cremophor EL), a co-surfactant (polyethylene glycol 400) and water. Eight drug-loaded (0.5%, w/v) NEs were evaluated for thermodynamic stability, morphology, droplet size and drug release in simulated tear fluid (pH 7.4). Following dispersion in gellan gum solution (0.2%, w/w), the in situ NE gels were characterized for transparency, rheological behavior, mucoadhesive force, drug release and histopathological assessment of ocular irritation. Drug pharmacokinetics of sterilized F31 [Miglyol 812, Cremophor EL: polyethylene glycol 400 (1:2) and water (5, 55 and 40%, w/w, respectively)] in situ NE gel and oily drug solution were evaluated in rabbit aqueous humor. The NEs were thermodynamically stable and have spherical droplets (<30 nm). The gels were transparent, pseudoplastic, mucoadhesive and showed more retarded zero-order drug release rates. F31 in situ NE gel showed the least ocular irritation potential and significantly (P<0.01) higher C(max), delayed T(max), prolonged mean residence time and increased bioavailability.

Design and in vitro/in vivo evaluation of novel nicorandil extended release matrix tablets based on hydrophilic interpolymer complexes and a hydrophobic waxy polymer

The purpose of this work was to develop an extended release matrix tablet of nicorandil; a freely water soluble drug used in cardiovascular diseases. Chitosan (CH)/hyaluronate sodium (HA), pectin (PE) or alginate sodium (AL) interpolymer complexes (IPCs) were prepared. The optimum IPCs (CH:HA, 40:60), (CH:PE, 30:70) and (CH:AL, 20:80) were characterized by Fourier transform infrared spectroscopy. The IPCs were based on electrostatic interactions between protonated amine groups of CH and carboxylate groups of HA, PE or AL. Nicorandil matrix tablets were prepared using the optimum IPCs, alone or in combination with Imwitor 900 K. Evaluations such as weight variation, thickness, content uniformity, friability, disintegration and in vitro release studies were performed. The tablets showed acceptable pharmacotechnical properties and complied with compendial requirements. Results of the dissolution studies revealed that formula F11 (CH:AL, 20:80) IPC:Imwitor 900 K, 3:1) could extend drug release > 8h. Most formulae exhibited non-Fickian diffusion drug release profiles. When compared to the immediate release Ikorel tablet, the duration of effective nicorandil therapeutic concentration from formula F11, in healthy human volunteers, was significantly (P<0.05) extended from 4 to 8 h with expected lowering in side effects potential.

Implantable Biodegradable Sponges: Effect of Interpolymer Complex Formation of Chitosan With Gelatin on the Release Behavior of Tramadol Hydrochloride

ABSTRACT The effect of interpolymer complex formation between positively charged chitosan and negatively charged gelatin (Type B) on the release behavior of tramadol hydrochloride from biodegradable chitosan-gelatin sponges was studied. Mixed sponges were prepared by freeze-drying the cross-linked homogenous stable foams produced from chitosan and gelatin solutions where gelatin acts as a foam builder. Generation of stable foams was optimized where concentration, pH of gelatin solution, temperature, speed and duration of whipping process, and, chitosan-gelatin ratio drastically affect the properties and the stability of the produced foams. The prepared sponges were evaluated for their morphology, drug content, and microstructure using scanning electron microscopy, mechanical properties, uptake capacity, drug release profile, and their pharmacodynamic activity in terms of the analgesic effect after implantation in Wistar rats. It was revealed that whipping 7% (w/w) gelatin solution, of pH 5.5, for 15 min at 25°C with a stirring speed of 1000 rpm was the optimum conditions for stable gelatin foam generation. Moreover, homogenous, uniform chitosan-gelatin foam with small air bubbles were produced by mixing 2.5% w/w chitosan solution with 7% w/w gelatinsolution in 1:5 ratio. Indeed, polyionic complexation between chitosan and gelatin overcame the drawbacks of chitosan sponge mechanical properties where, pliable, soft, and compressible sponge with high fluid uptake capacity was produced at 25°Cand 65% relative humidity without any added plasticizer. Drugreleasestudies showed a successful retardation of the incorporated drug where the t50% values of the dissolution profiles were 0.55, 3.03, and 4.73 hr for cross-linked gelatin, un-cross-linked chitosan-gelatin, and cross-linked chitosan-gelatin sponges, respectively. All the release experiments followed Higuchis diffusion mechanism over 12 hr. The achieved drug prolongation was a result of a combined effect of both cross-linking and polyelectrolyte complexation between chitosan and gelatin. The analgesic activity of the implanted tramadol hydrochloride mixed chitosan-gelatin sponge showed reasonable analgesic effect that was maintained for more than 8 hr. Therefore, the use of chitosan and gelatin together appears to allow the formulator to manipulate both the drug release profiles and the mechanical properties of the sponge that could be effectively implanted.

Colon-targeted celecoxib-loaded Eudragit® S100-coated poly-ϵ-caprolactone microparticles: Preparation, characterization and in vivo evaluation in rats

Context: Celecoxib suffers from low and variable bioavailability following oral administration of solutions or capsules. Recent studies proved that chemoprevention of colorectal cancer is possible with celecoxib. Objective: This work aimed to tailor colon-targeted celecoxib-loaded microparticles using time-dependant and pH-dependant coats. Estimation of drug pharmacokinetics following oral administration to fasted rats was another goal. Methods: A 23 factorial design was adopted to develop poly-ϵ-caprolactone (PCL) celecoxib-loaded microparticles (F1–F8). To minimize drug-percentages released before colon, another coat of Eudragit® S100 was applied. In vitro characterization of microparticles involved topography, determination of particle size and entrapment efficiency (EE %). Time for 50% drug release (t50%) and drug-percentages released after 2 hours (Q2h) and 4 hours (Q4h) were statistically compared. Estimation of drug pharmacokinetics following oral administration of double-coat microparticles (F10) was studied in rats. Results: PCL-single-coat microparticles were spherical, discrete with a size range of 60.66 ± 4.21–277.20 ± 6.10 μm. Direct correlations were observed between surfactant concentration and EE%, Q2h and Q4h. The PCL M.wt. and drug: PCL ratio had positive influences on EE% and negative impacts on Q2h and Q4h. When compared to the best achieved PCL-single-coat microparticles (F2), the double-coat microparticles (F10) showed satisfactory drug protection; Q2h and Q4h were significantly (P < 0.01) decreased from 31.84 ± 1.98% and 54.72 ± 2.10% to 15.92 ± 1.78% and 26.93 ± 2.76%, respectively. When compared to celecoxib powder, F10 microparticles enhanced the bioavailability and extended the duration of drug-plasma concentration in rats. Conclusion: The developed double-coat microparticles could be considered as a promising celecoxib extended-release colon-targeting system.

Optimization of Biodegradable Sponges as Controlled Release Drug Matrices. I. Effect of Moisture Level on Chitosan Sponge Mechanical Properties

Cross‐linked chitosan sponges as controlled release drug carrier systems were developed. Tramadol hydrochloride, a centrally acting analgesic, was used as a model drug. The sponges were prepared by freeze‐drying 1.25% and 2.5% (w/w) high and low M.wt. chitosan solutions, respectively, using glutaraldehyde as a cross‐linking agent. The hardness of the prepared sponges was a function of glutaraldehyde concentration and volume where the optimum concentration that offered accepted sponge consistency was 5%. Below or above 5%, very soft or very hard and brittle sponges were obtained, respectively. The determined drug content in the prepared sponges was uniform and did not deviate markedly from the calculated amount. Scanning electron microscopy (SEM) was used to characterize the internal structures of the sponges. The SEM photos revealed that cross‐linked high M.wt. chitosan sponges have larger size surface pores that form connections (channels) with the interior of the sponge than cross‐linked low M.wt. ones. Moreover, crystals of the incorporated Tramadol hydrochloride were detected on the lamellae and within pores in both chitosan sponges. Differences in pore size and dissolution medium uptake capacity were crucial factors for the more delayed drug release from cross‐linked low M.wt. chitosan sponges over high M.wt. ones at pH 7.4. Kinetic analysis of the release data using linear regression followed the Higuchi diffusion model over 12 hours. Setting storage conditions at room temperature under 80–92% relative humidity resulted in soft, elastic, and compressible sponges.

Controlled-release triple anti-inflammatory therapy based on novel gastroretentive sponges: Characterization and magnetic resonance imaging in healthy volunteers

The current work aimed to develop novel composite sponges of chitosan (CH)-chondroitin sulfate (CS) as a low-density gastroretentive delivery system for lornoxicam (LOR). This triple anti-inflammatory therapy-loaded matrices are expected to expand and float upon contact with gastric fluids for prolonged times. CH and CS solutions (3%, w/w) were prepared, mixed in different ratios, lyophilized, coated with magnesium stearate and compressed. The CH:CS interpolymer complex (IPC) was evaluated via FT-IR, DSC, and XRD. The compressed-sponges were evaluated for appearance, structure, porosity, pore diameter, density, wetting-time, floating characteristics, adhesion-retention, and LOR-release. The gastroretentivity of the best achieved magnetite-loaded sponges was monitored in healthy volunteers via MRI. The interaction between CH (protonated amino groups) and CS (anionic carboxylate/sulfate groups) proved IPC formation. DSC and XRD studies confirmed loss of LOR crystallinity. The sponges possessed interconnecting porous-network structures. The porosity, mean pore diameter, and bulk density of CH:CS (10:3) IPC sponges were 11.779%, 25.4 nm, and 0.670 g/mL, respectively. They showed complete wetting within seconds, gradual size-expansion within minutes and prolonged adhesion for hours. Controlled LOR-release profiles were tailored over 12h to satisfy individual patient needs. Monitoring of sponges via MRI proved their gastroretentivity for at least 5h.