Howida Kamal Ibrahim

Mucoadhesive Nanoparticles as Carrier Systems for Prolonged Ocular Delivery of Gatifloxacin/Prednisolone Bitherapy

A fluoroquinolone/glucocorticoid combination for the treatment of bacterial keratitis in the form of mucoadhesive nanoparticle suspensions was developed to prolong the release and improve patient compliance. Gatifloxacin/prednisolone loaded nanoparticles were prepared using Eudragit RS 100 and RL 100 and coated with the bioadhesive polymer, hyaluronic acid. FT-IR and DSC studies revealed no interaction between gatifloxacin and prednisolone. The effects of the drug:polymer ratio (D:P) and the RS/RL ratio were studied. The obtained nanoparticles were distinct and spherical with a solid dense structure. They have average particle size range of 315.2 to 973.65 nm. Increasing the D:P ratio significantly lowered the entrapment efficiency for both drugs (p < 0.05). The nanoparticle suspensions revealed significantly prolonged drug release comparing to the free drugs (p < 0.05) with no burst effect. Increasing the polymer concentration and the Eudragit RS ratio significantly decreased the release efficiency values. Gatifloxacin showed anomalous release (n = 0.4943) from 1:1 D:P ratio nanoparticle suspension and Fickian diffusion mechanism (n < 0.45) from formulas prepared at higher D:P ratios. Gatifloxacin showed better bioavailability and sustained action in aqueous humor and corneal tissue from the nanoparticles compared to the commercial eye drops. The resulting nanoparticle suspension is promising in reducing dose frequency and improving patient compliance.

Microemulsions as vehicles for topical administration of voriconazole: formulation and in vitro evaluation

This work was undertaken to investigate microemulsion (ME) as a topical delivery system for the poorly water-soluble voriconazole. Different ME components were selected for the preparation of plain ME systems with suitable rheological properties for topical use. Two permeation enhancers were incorporated, namely sodium deoxycholate or oleic acid. Drug-loaded MEs were evaluated for their physical appearance, pH, rheological properties and in vitro permeation studies using guinea pig skin. MEs based on polyoxyethylene(10)oleyl ether (Brij 97) as the surfactant showed pseudoplastic flow with thixotropic behavior and were loaded with voriconazole. Jojoba oil-based MEs successfully prolonged voriconazole release up to 4 h. No significant changes in physical or rheological properties were recorded on storage for 12 months at ambient conditions. The presence of permeation enhancers favored transdermal rather than dermal delivery. Sodium deoxycholate was more effective than oleic acid for enhancing the voriconazole permeation. Voriconazole-loaded MEs, with and without enhancers, showed significantly better antifungal activity against Candida albicans than voriconazole supersaturated solution. In conclusion, the studied ME formulae could be promising vehicles for topical delivery of voriconazole.

Fast-dissolving sublingual films of terbutaline sulfate: formulation and in vitro/in vivo evaluation.

Terbutaline sulfate fast dissolving sublingual films were prepared using seven drug compatible film formers in different combinations and proportions. The film polymers are maltodextrin, Na alginate, Carpabol 430, xanthan gum, HPMC E5, PVP K-25, and Na CMC. Propylene glycol and sorbitol were used as plasticizers and mannitol as filler. The optimum polymer concentrations and the plasticizer amount were selected on the basis of flexibility, tensile strength, and stickiness of the films. The prepared films were evaluated for their tensile strength, thickness uniformity, disintegration time (in vitro and in vivo), in vitro dissolution, and moisture content. Polymer type rather than total polymer concentration or plasticizer amount showed a significant effect on the tested film properties. A randomized, single dose, crossover study was conducted in four healthy volunteers to compare the pharmacokinetic profile of terbutaline sulfate from the prepared films and the conventional oral tablets. The film formula of choice gave a significantly faster drug absorption rate and recorded a relative bioavailability of 204.08%. Sublingual films could be promising as a convenient delivery system for terbutaline sulfate in patients with swallowing problems. The improved extent of absorption (higher AUC(0-24)) indicates success in improving drug bioavailability, and the faster absorption rate could be promising for the management of acute episodes of asthma.

In vitro and in vivo evaluation of indomethacin nanoemulsion as a transdermal delivery system

Abstract Nanoemulsions were investigated as transdermal delivery systems for indomethacin. Six formulae were prepared using Triacetin, capryol 90 and labrafil as oils; Tween 80 and pluronic F127 as surfactants and transcutol and propylene glycol as co-surfactants. The continuous phase was that one with the larger volume fraction regardless of the hydrophile–lipophile balance of the surfactant/co-surfactant mixture. Surfactant type had significant effects on particle size and rheological properties of the nanoemulsions. Pluronic-based formulae recorded the lowest particle sizes and the highest viscosities. The prepared nanoemulsions increased drug solubility up to 610-fold compared with water. Refractive index measurements proved the compatibility between indomethacin and the used nanoemulsion components. Indomethacin was almost completely ionized at the pH values of the prepared nanoemulsions, suggesting drug absorption via the hydrophilic pathway of the skin upon topical application. Nanoemulsions controlled indomethacin release through semipermeable membrane and enhanced its permeation through excised newly born albino rat skin. The formulae were stable for six months at ambient conditions. Transdermal single application of selected formulae resulted in effective plasma levels up to 32 h in rats. Nanoemulsions were significantly superior to other investigated transdermal approaches at solubilizing indomethacin and achieving higher plasma levels.

Formulation of avanafil in a solid self-nanoemulsifying drug delivery system for enhanced oral delivery ☆

Avanafil was incorporated into solid self-nanoemulsifying systems with the aim of improving its oral bioavailability. Labrafil, Labrafac, and Miglyol 812 N were investigated as oils, Tween 80 and Cremophor EL as surfactants, and Transcutol HP as a co-surfactant. Nine formulations produced clear solutions of 13.89-38.09nm globules after aqueous dilution. Adsorption of preconcentrate onto Aeroperl 300 Pharma at a 2:1 ratio had no effect on nanoemulsion particle size. Differential scanning calorimetry, X-ray diffraction, and scanning electron microscopy indicated that avanafil was molecularly dispersed within the solid nanosystems. A formulation containing 10% Labrafil, 60% Tween 80, and 30% Transcutol HP had the highest drug loading (44.48mg/g) and an acceptable in vitro dissolution profile (96.42% within 30min). This formulation was chemically and physically stable for 6months under accelerated storage conditions and it produced a 3.2-fold increase in bioavailability in rabbits, as compared to conventional commercially available avanafil tablets (Spedra(®)).

Effects of different combinations of nanocrystallization technologies on avanafil nanoparticles: in vitro, in vivo and stability evaluation.

The study investigated the effects of different combined top-down and bottom-up nanocrystallization technologies on particle size and solid state of avanafil nanoparticles. Combined antisolvent precipitation-ultrasonication (sonoprecipitation) technique was adopted to prepare 18 formulas according to 32.21 factorial design using 3 stabilizers; Tween 80, polyvinyl alcohol (PVA) and Pluronic F68 at different concentrations with different cryoprotectants. Particle size analysis of the lyophilized formulas showed that Tween 80 was an effective nanoparticles stabilizer in contrast to Pluronic F68 and PVA which failed to prevent nanoparticles flocculation when they were used at high concentration. The combined effects of nanonization and amorphism contributed to the improvement in solubility. Further processing of the sonoprecipitated formulas by high pressure homogenization (HPH) (modified NANOEDGE™ technology) resulted in further size reduction of PVA-stabilized particles, while it stimulated flocculation of Tween-stabilized nanoparticles. Nevertheless, all of the homogenized formulas partially retrieved their crystallinity which reduced their solubility. Non-homogenized formula 2E composed of 1:2 (avanafil: Tween) with glucose as cryoprotectant, exhibited 13.68- and 2.59-fold improvement in solubility and in vitro dissolution, respectively. This formula had oral bioavailability of 137.02% relative to Spedra® tablets and it maintained its nanosize, amorphism and dissolution behavior over 6 months of storage under stress conditions.

Formulation of Convenient, Easily Scalable, and Efficient Granisetron HCl Intranasal Droppable Gels

Deacetylated gellan gum and two sodium alginate polymer types were used each at three concentrations in the suitable range for their sol-gel transition. The prepared nine droppable gels were evaluated in vitro, ex vivo through sheep nasal mucosa, as well as in vivo in comparison to drug solution given intravenously and orally at the same dose. The prepared formulas gelled instantaneously in simulated nasal fluid and the obtained gels sustained their shear thinning and thixotropic behavior up to 48 h. Polymer type and concentration had significant effects on the apparent viscosities and the in vitro release profile of granisetron from the prepared gels. The drug release data best fitted a modified Higuchi equation with initial burst and followed Fickian diffusion mechanism. A 0.5% gellan-gum-based formula sustained the in vitro drug release up to 3 h and enhanced the drug permeation without need for an enhancer. The histopatholgical study revealed the safety of the tested formula. Intranasal delivery recorded double the drug bioavailabilty in comparison to the oral route. It had an absolute bioavailability of 0.6539 and the maximum plasma drug concentration reached after 1.5 h. The developed formula could be promising for the management of chemotherapy-induced nausea and vomiting regarding its improved bioavailability, patient acceptability, and ease of production.

Localized rosuvastatin via implantable bioerodible sponge and its potential role in augmenting bone healing and regeneration

Abstract Objective: Statins proved potential bone healing properties. Rosuvastatin is a synthetic, hydrophilic, potent and highly efficacious statin. In the current work, an attempt was investigated to develop, evaluate various bioerodible composite sponges enclosing rosuvastatin and explore their potential in augmenting bone healing and regeneration. Method: Twelve lyophilized sponge formulae were prepared adapting a 41.31 full factorial design. Xanthan gum, polycarbophil, Carbopol® and sodium alginate were investigated as anionic polymers, each at three chitosan:anionic polymer ratios (1:3, 1:1, 3:1). The formula of choice was implanted in fractured rat femora. Results: Visual and microscopic examination showed flexible homogenous porous structures with considerable bending ability. Polyelectrolyte complex formation was proved by DSC and FT-IR for all chitosan/anionic combinations except with xanthan gum where chitosan probably bound to the drug rather than xanthan gum. Statistical analysis proved that anionic polymer type and chitosan: polymer ratio, as well as, their interactions, exhibited significant effects on the release parameters at p ≤ 0.05. The optimum chitosan/anionic polymer complexation ratios were 3:1 for polycarbophil and 1:1 for Carbopol and alginate. The release at these ratios followed Fiction diffusion while other ratios had anomalous diffusion. Imwitor® 900K and HPMC K100M were added as release retarardants for further release optimization. The formula of choice was implanted in fractured rat femora. Histopathological examination revealed advanced stages of healing in treated femora compared to control ones. Conclusion: Biodegradable sponges for local rosuvastatin delivery proved significantly enhanced wound healing and regeneration properties to fractured bones.

Formulation of Risperidone as Self-Nanoemulsifying Drug Delivery System in Form of Effervescent Tablets

Risperidone is an atypical antipsychotic drug used to treat schizophrenia. This study aims to formulate risperidone as effervescent tablets to improve patient compliance. Different nanoemulsion combinations were loaded with risperidone to improve its poor water solubility then adsorbed on Aeroperl. The formula showing highest drug dissolution was formulated as effervescent tablets. Factorial design was applied for different tablet formulation variables and the prepared formulae were tested for different criteria in comparison with their corresponding formulae containing drug without nanoemulsion formulation. Statistical analysis was used to determine the most desirable tablet formula considering its Carr index, effervescence time, and drug release.

Enhancement of the intranasal delivery of insulin via a novel mucoadhesive Carbopol gel

Objectives  The objectives of this study were to develop an intranasal insulin gel using Carbopol homogenization rather than neutralization and to examine the effectiveness of the gel compared with a subcutaneous injection.