Mahmoud M. Ghorab

Inclusion complexes of tadalafil with natural and chemically modified β-cyclodextrins. I: Preparation and in-vitro evaluation

The aim of this work was to investigate the inclusion complexation between tadalafil, a practically insoluble selective phosphodiesterase-5 inhibitor (PDE5), and two chemically modified beta-cyclodextrins: hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and heptakis-[2,6-di-O-methyl]-beta-cyclodextrin (DM-beta-CD), in comparison with the natural beta-cyclodextrin (beta-CD) in order to improve the solubility and the dissolution rate of the drug in an attempt to enhance its bioavailability. Inclusion complexation was investigated in both the solution and the solid state. The UV spectral shift method indicated guest-host complex formation between tadalafil and the three cyclodextrins (CDs). The phase solubility profiles with all the used CDs were classified as A(p)-type, indicating the formation of higher order complexes. The complexation efficiency values (CE), which reflect the solubilizing power of the CDs towards the drug, could be arranged in the following order: DM-beta-CD>HP-beta-CD>beta-CD. Solid binary systems of tadalafil with CDs were prepared by kneading and freeze-drying techniques at molar ratios of 1:1, 1:3 and 1:5 (drug to CD). Physical mixtures were prepared in the same molar ratios for comparison. Physicochemical characterization of the prepared systems at molar ratio of 1:5 was studied using differential scanning calorimetry (DSC), X-ray diffractometry (XRD), and Fourier-transform infrared spectroscopy (FTIR). The results showed the formation of true inclusion complexes between the drug and both HP-beta-CD and DM-beta-CD using the freeze-drying method at molar ratio of 1:5. In contrast, crystalline drug was detectable in all other products. The dissolution of tadalafil from all the prepared binary systems was carried out to determine the most appropriate CD type, molar ratio, and preparation technique to prepare inclusion complexes to be used in the development of tablet formulation for oral delivery of tadalafil. The dissolution enhancement was increased on increasing the CD proportion in all the prepared systems. Both the CD type and the preparation technique played an important role in the performance of the system. Irrespective of the preparation technique, the systems prepared using HP-beta-CD and DM-beta-CD yielded better performance than the corresponding ones prepared using beta-CD. In addition, the freeze-drying technique showed superior dissolution enhancement than other methods especially when combined with the beta-CD derivatives.

Characterization and bioavailability of danazol-hydroxypropyl β-cyclodextrin coprecipitates

Danazol, a steroid with very low aqueous solubility and poor bioavailability, and its coprecipitates were characterized for solubility, dissolution rate and bioavailability. Solubility diagrams of danazol in aqueous hydrox-ypropyl β-cyclodextrin (HPCD) solutions and isopropanol/water solutions were constructed with concentration of HPCD solutions ranging between 0.65 and 65.0 mM. Coprecipitates of danazol and HPCD at ratios ranging from 1:1 to 1:10 were prepared by solvent evaporation method using ethanol and by freeze drying method. Solubility diagrams indicated the existence of a complex between danazol and HPCD, and showed a remarkable increase in danazol solubility. Stability constants of the complex and thermodynamic parameters of complexation were calculated in both aqueous and aqueous / organic solvents; the presence of isopropanol appeared to have negative effect on the stability of the complex. Dissolution profiles of the coprecipitates demonstrated higher dissolution rates than pure danazol.Characterization of coprecipitates by DSC and X-ray diffraction techniques showed that danazol existed almost exclusively in crystalline form in coprecipitates at low danazol to HPCD ratios; while at high ratios, danazol appeared to exist in a non-crystalline form. No distinct differences in the product characteristics could be attributed to the method of preparation. Oral bioavailability of the coprecipitate (danazol: HPCD, 1:10) and a marketed danazol were tested in Wistar rats in a two-way, randomized cross-over study. The area under the curve (AUC) of plasma concentration versus time was significantly higher (P < 0.05) for the complex than the commercial formulation, with mean AUC value more than two-fold higher for the complex. The bioavailability of the coprecipitate relative to the commercial formulation was calculated to be 237%. The peak plasma concentration (Cmax) of the coprecipitate was higher and the time to reach the peak (Tmax) was lower for the complex. The greater rate and extent of absorption of danazol from the complex makes it a formulation with the potential to decrease the oral dose of danazol. Absolute bioavailability of the coprecipitate and commercial formulation was 14.2% and 6.2%, respectively.

Bioavailability of danazol-hydroxypropyl-β-cylodextrin complex by different routes of administration

Abstract Bioavailability of danazol-hydroxypropyl-β-cyclodextrin complex was investigated in rats and dogs using different routes of administration. The complex was administered buccally in an aqueous solution form to rats in which the esophagus had been ligated to prevent swallowing of the complex, while oral administration was by gastric gavage. In dogs, the complex was administered buccally in the form of rapidly dissolving adhesive patch formulation, and orally in the form of hard gelatin capsules. Buccal absorption of the complex was evaluated in an attempt to bypass presystemic elimination. Buccal absorption of danazol in rats was slow and mean plasma concentration exhibited a plateau for 5 h. However, the extent of absorption was higher than the oral route, and bioavailability was 186% relative to oral administration. The absolute bioavailability was 26.4% indicating incomplete absorption of the complex after buccal administration. Plasma profiles and pharmacokinetic parameters obtained in dogs were similar in the orally and buccally administered doses, suggesting that drug release from the buccal patch was not slow enough and the drug was consequently swallowed rather than absorbed across the buccal mucosa.

A Study of the Complexation Between Danazol and Hydrophilic Cyclodextrin Derivatives

AbstractComplexation between danazol, a steroid used for endometriosis, and both hydroxypropyl- β-cyclodextrin (HPCD) and sulfobutyl ether-β-cyclodextrin (SBE) was studied in solution and solid state. Complexation was evaluated in solution using solubility studies and proton magnetic resonance (1H NMR) spectroscopy, and in the solid state using x-ray diffraction, Fourier-transform infrared spectroscopy (FTIR)), and dissolution studies. Solubility studies suggested the existence of a 1:1 complex between danazol and either HPCD or SBE. 1H NMR showed that complexation occurs by inclusion of the isoxazole ring of danazol into the cyclodextrin cavity in both cases. Powder x-ray diffraction indicated that danazol existed in a crystalline noncomplexed form at low danazol-to-cyclodextrin ratios in the coprecipitates prepared by solvent evaporation method, while at higher ratios danazol existed in an amorphous complexed form. This ratio was 1:10 w/w for HPCD and 1:20 for SBE; the higher ratio in the case of SBE is...

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.

Nano Spray Drying Technique as a Novel Approach To Formulate Stable Econazole Nitrate Nanosuspension Formulations for Ocular Use.

The effect of using methyl-β-cyclodextrin and hydroxypropyl-β-cyclodextrin as carriers for econazole nitrate nanoparticles prepared by nano spray dryer was explored in this work. Stabilizers, namely, poly(ethylene oxide), polyvinylpyrrolidone k30, poloxamer 407, Tween 80, and Cremophor EL, were used. The nano spray dried formulations revealed almost spherical particles with an average particle size values ranging from 121 to 1565 nm and zeta potential values ranging from -0.8 to -2.5 mV. The yield values for the obtained formulations reached 80%. The presence of the drug in the amorphous state within the nanosuspension matrix system significantly improved drug release compared to that for pure drug. Combination of hydroxypropyl-β-cyclodextrin with Tween 80 achieved an important role for preserving the econazole nanosuspension from aggregation during storage for one year at room temperature as well as improving drug release from the nanosuspension. This selected formulation was suspended in chitosan HCl to increase drug release and bioavailability. The in vivo evaluation on albino rabbits eyes demonstrated distinctly superior bioavailability of the selected formulation suspended in chitosan compared to its counterpart formulation suspended in buffer and crude drug suspension due to its mucoadhesive properties and nanosize. The nano spray dryer could serve as a one step technique toward formulating stable and effective nanosuspensions.

Lamotrigine loaded poly-ɛ-(d,l-lactide-co-caprolactone) nanoparticles as brain delivery system

Abstract Management of epilepsy requires brain delivery therapy, therefore, this study was aimed to prepare lamotrigine loaded poly‐&egr;‐(d,l‐lactide‐co‐caprolactone) (PLCL) nanoparticles using spontaneous emulsification solvent diffusion method. Nanoparticles for brain delivery required to have a particle size <200 nm, polydispesity index <0.2 and a sustained drug release properties. For such aim different factors were considered in preparing the nanoparticles as PLCL monomers’ ratio, type of organic solvent used to prepare the nanoparticles, amount of PLCL and Pluronic®F127 in the nanoparticles. Prepared nanoparticles were characterized for their shape, particle size, polydispersity index, zeta potential, encapsulation efficiency, drug loading capacity, process yield and in‐vitro drug release pattern. The in‐vivo investigation for brain delivery of selected nanoparticles delivered by intravenous route was investigated in rats and compared to that for oral tablet. The obtained nanoparticles were spherical in shape. The amount of surfactant and PLCL affected the properties of the obtained nanoparticles. Using a mixture of organic solvent in preparing the nanoparticles improved its properties. The nanoparticles prepared using PLCL with monomers’ ratio of 25:75, had particle size value of 125 nm, polydispersity index value of 0.184, zeta potential value of −39 mV and encapsulation efficiency value of 99%, was selected to study their efficacy to deliver the drug to the brain. The tested nanoparticles showed higher values of Tmax, Cmax, AUC, and MRT in homogenized rat brain, compared to oral lamotrigine tablet, while the bioavailability of the oral tablet was higher in rat plasma compared to that for the nanoparticles. This reflects that brain was the main distribution site for tested nanoparticles, and plasma was the main distribution site for oral tablets. This confirms the goal of the selected formulation as brain delivery nanoparticles. Graphical abstract Figure. No caption available.

Hydroxypropyl-Beta-Cyclodextrin as Cryoprotectant in Nanoparticles Prepared By Nano-Spray Drying Technique

Nano-spray dryer is advanced instrument to produce a stable and spherical nanoparticles with high yield. In this study, econazole nitrate nanoparticles were formulated by nano-spray dryer using 1:1, 1:2 and 1:3 weight ratios of drug to hydroxypropyl-betacyclodextrin and stabilizer. The prepared samples were sprayed through nozzle size of 7.0 μm using 95oC and 45oC as inlet temperature and outlet temperatures, respectively. The prepared nanoparticles were evaluated for process yield and percent drug loading. Furthermore, the drug nanoparticles were dispersed in isotonic buffer solution and examined for drug release and their stability at room temperature. The spray dried particles were in the nano-range (148 to 294 nm) and their yield values ranged between 79.1 and 84.9 %. Increasing weight ratio of drug to hydroxypropylbeta- cyclodextrin to 1:2 and 1:3 showed increases in percent drug release compared to formulation containing 1:1 weight ratio of drug to hydroxypropyl-beta-cyclodextrin. On the other hand, the prepared econazole nitrate nanosuspension containing 1:1 weight ratio of drug to hydroxypropyl-beta-cyclodextrin revealed best stability study during storage period at room temperature compared to other formulations. As a result of in-vitro drug release and stability studies, the optimum weight ratio of 1:1, drug to hydroxylpropylbeta- cyclodextrin was chosen as a best weight ratio duo to its good balance between drug release and stability of drug loaded nanoparticles.

Effervescent tablet formulation for enhanced patient compliance and the therapeutic effect of risperidone

Abstract Risperidone is a poorly water soluble atypical antipsychotic drug. This work investigated the potential of developing risperidone effervescent tablets to facilitate drug administration and mask drug taste. The solid dispersion technique was selected to improve drug solubility due to its ease of scaling up, reproducibility and affordable cost. Thirty formulas were prepared adopting a 51.21.31 full factorial design. Trehalose, Inulin, pregelatinized starch, carboxymethylcellulose sodium and Eudragit E100 were used as hydrophilic carriers at different ratios. Rotovap, lyophilization and the kneading-oven were applied as solvent evaporation techniques. Differential scanning calorimetry, X-ray powder diffraction, Fourier transform infrared spectroscopy and scanning electron microscopy showed that the drug was present as amorphous material entrapped within the carrier matrix. Eight tablet blends were prepared using different effervescent mixture ratios with or without binder and lubricant/glidant mixture. All of the blends had acceptable flowability, acceptable effervescence times and immediate drug release that could not be achieved by any of the control formulas. The formula of choice contained 40% effervescent mixture, 5% starch, 1% boric acid, 1% aspartame and sufficient lactose. The relative bioavailability (RB) of risperidone from this formula was 161.41% with a significantly higher extent of absorption compared to the market conventional tablets. This formula may be promising in improving patient compliance and drug efficiency.