Development and Evaluation of Lorazepam Microemulsions for Parenteral Delivery

The objective of this investigation was to develop lorazepam (LZM) microemulsions as an alternative to the conventional cosolvent based formulation. Solubility of LZM in various oils and Tween 80 was determined. The ternary diagram was plotted to identify area of microemulsion existence and a suitable composition was identified to achieve desired LZM concentration. The LZM microemulsions were evaluated for compatibility with parenteral fluids, globule size, in vitro hemolysis and stability of LZM. Capmul MCM demonstrated highest solubilizing potential for LZM and was used as an oily phase. LZM microemulsions were compatible with parenteral dilution fluids and exhibited mean globule size less than 200 nm. The in vitro hemolysis studies indicated that microemulsions were well tolerated by erythrocytes. The LZM microemulsions containing amino acids exhibited good physical and chemical stability when subjected to refrigeration for 6 months

Intranasal Microemulsion of Sildenafil Citrate: In Vitro Evaluation and In Vivo Pharmacokinetic Study in Rabbits

The purpose of the present study was to prepare intranasal delivery system of sildenafil citrate and estimate its relative bioavailability after nasal administration in rabbits to attain rapid onset of action with good efficacy at lower doses. Sildenafil citrate saturated solubility was determined in different solvents, cosolvents, and microemulsion systems. For nasal application, sildenafil citrate was formulated in two different systems: the first was a cosolvent system (S3) of benzyl alcohol/ethanol/water/Transcutol/taurodeoxy cholate/Tween 20 (0.5:16.8:47.7:15.9:1:18.1% w/w). The second was a microemulsion system (ME6) containing Oleic acid: Labrasol/Transcutol/water (8.33:33.3:16.66:41.66% w/w). The prepared systems were characterized in relation to their clarity, particle size, viscosity, pH, and nasal ciliotoxicity. In vivo pharmacokinetic performance of the selected system ME6 (with no nasal ciliotoxicity) was evaluated in a group of six rabbits in a randomized crossover study and compared to the marketed oral tablets. The targeted solubility (>20 mg/ml) of sildenafil citrate was achieved with cosolvent systems S1, S3, and S5 and with microemulsion systems ME3–ME6. The saturated solubility of sildenafil citrate in cosolvent system S3 and microemulsion system ME6 were 22.98 ± 1.26 and 23.79 ± 1.16 mg/ml, respectively. Microemulsion formulation ME6 showed shorter tmax (0.75 h) and higher AUC(0-∞) (1,412.42 ng h/ml) compared to the oral tablets which showed tmax equals 1.25 h and AUC(0-∞) of 1,251.14 ng h/ml after administration to rabbits at dose level of 5 mg/kg. The relative bioavailability was 112.89%. In conclusion, the nasal absorption of sildenafil citrate microemulsion was found to be fast, indicating the potential of nasal delivery instead of the conventional oral administration of such drug

Transdermal Delivery of an Anti-Cancer Drug via W/O Emulsions Based on Alkyl Polyglycosides and Lecithin: Design, Characterization, and In Vivo Evaluation of the Possible Irritation Potential in Rats

The purpose of this work was to develop w/o emulsions that could be safely used to promote transdermal delivery of 5-fluorouracil (5-FU). Two pseudo-ternary phase diagrams comprising oleoyl-macrogol glycerides, water, and a surfactant/co-surfactant (S/CoS) mixture of lecithin, ethanol, and either coco glucoside or decyl glucoside were investigated for their potential to develop promising 5-FU emulsions. Six systems were selected and subjected to thermodynamic stability tests; heat–cool cycles, centrifugation, and finally freeze–thaw cycles. All systems passed the challenges and were characterized for transmission electron microscopy, droplet size, rheological behavior, pH, and transdermal permeation through newly born mice skin in Franz diffusion cells. The systems had spherical droplets ranging in diameter from 1.81 to 2.97 μm, pH values ranging from 7.50 to 8.49 and possessed Newtonian flow. A significant (P < 0.05) increase in 5-FU permeability parameters as steady-state flux, permeability coefficient was achieved with formula B5 comprising water (5% w/w), S/CoS mixture of lecithin/ethanol/decyl glucoside (14.67:12.15:18.18% w/w, respectively) and oleoyl-macrogol glycerides (50% w/w). When applied to shaved rat skin, this system was well tolerated with only moderate skin irritation that was recovered within 12 h. Indeed, minor histopathologic changes were observed after 5-day treatment. Further studies should be carried out, in the future, to investigate the potentiality of this promising system to promote transdermal delivery of 5-FU through human skin

Preparation and Solid-State Characterization of Inclusion Complexes Formed Between Miconazole and Methyl-β-Cyclodextrin

The aim of this study is to confirm the formation of inclusion complexes between miconazole (MCZ) and two derivatives of beta-cyclodextrin, methyl-beta-cyclodextrin (MβCD) and 2-hydroxypropyl-beta-cyclodextrin (HPβCD) in aqueous solution by phase solubility studies. Inclusion complexes with MβCD in the solid state were then prepared by different methods, i.e., kneading, coevaporation (COE), spray-drying (SD), and lyophilization (LPh). The physicochemical properties of these complexes were subsequently studied by means of differential scanning calorimetry, Fourier transform infrared spectroscopy, scanning electron microscopy, and X-ray diffraction techniques. Phase solubility diagrams with MβCD and HPβCD were classified as AP type, indicating the formation of 1:1 and 1:2 stoichiometric inclusion complexes. The apparent stability constants (KS) calculated from the phase solubility diagram were 145.69 M−1 (K1:1) and 11.11 M−1 (K1:2) for MβCD and 126.94 M−1 (K1:1) and 2.20 M−1 (K1:2) for HPβCD. The method of preparation of the inclusion complexes in the solid state was shown to greatly affect the properties of the formed complex. Hence, the LPh, SD, and COE methods produce true inclusion complexes between MCZ and MβCD. In contrast, crystalline drug was still clearly detectable in the kneaded (KN) product