Formulation and evaluation of Fluconazole Nanosuspensions: In vitro characterization and transcorneal permeability studies.

The aim in this study was to develop and evaluate a nanofluconazole (FLZ) formulation with increased solubility and permeation rate using nanosuspensions. The FLZ nanosuspensions were stabilized using a variety of stabilizing agents and surfactants in various concentrations. The FLZ nanosuspension was characterized in vitro using particle size, zeta potential, X-ray powder diffraction (XRPD), and solubility. In addition, the ex vivo ocular permeation of FLZ through a goat cornea was analyzed. The results showed that the particle size of all nanosuspension formulations was in the nanometer range from 174.5 ± 1.9 to 720.2 ± 4.77 nm; that of the untreated drug was 18.34 µm. The zeta potential values were acceptable, which indicated suitable stability for formulations. The solubility of the nanosuspensions was up to 5.7-fold higher compared with that of the untreated drug. The results of the ex vivo ocular diffusion of the FLZ nanosuspensions showed the percentage of FLZ penetrating via the goat cornea increased after using Kollicoat to stabilize the nanosuspension formulation. Consequently, when using a nanosuspension formulation of Kollicoat, the antifungal activity of the drug strengthens.

Novel Metoprolol-Loaded Chitosan-Coated Deformable Liposomes in Thermosensitive In Situ Gels for the Management of Glaucoma: A Repurposing Approach.

Glaucoma is a long-term eye disease associated with high intraocular pressure (IOP), which seriously damages the eyes, causing blindness. For successful therapy, potent drugs and delivery systems are required. Metoprolol (MT) is believed to help reduce elevated IOP. The paradigm of ocular therapeutics may be changed by the integration of chitosan-coated liposomes (CLPs) with thermosensitive in situ gel (ISG). Therefore, MT-CLPs were developed and characterized and compared to uncoated ones (MT-LPs). Furthermore, MT-LP- and MT-CLP-loaded ISGs were prepared and characterized in in vitro, ex vivo, and in vivo studies. MT-LPs and MT-CLPs displayed spherical shapes with nanosize range, reasonable EE%, and significant bioadhesion. The zeta potential changed from negative to positive after CS coating. The extended in vitro drug release of MT-CLPs showed significant mucin mucoadhesion. The formed ISGs were homogeneous with a pH range of 7.34 to 7.08 and a rapid sol-gel transition at physiological temperature. MT-ISG1 (MT-LP) and MT-ISG2 (MT-CLPs-0.5) could increase ocular permeability by 2-fold and 4.4-fold compared to MT-ISG (pure MT). MT-ISG2 demonstrated significantly reduced IOP in rabbits without causing any irritation. In conclusion, MT-ISG2 markedly enhanced corneal permeability and reduced IOP. They would be promising carriers for MT for glaucoma management.

Transdermal Glipizide Delivery System Based on Chitosan-Coated Deformable Liposomes: Development, Ex Vivo, and In Vivo Studies.

The current study aimed to develop and evaluate a sustained-release transdermal Glipizide (GLP) film to overcome its oral administration problems. Chitosan (CS)-coated deformable liposomes (DLs) were utilized to enhance the drug transdermal delivery. The formulations were characterized in terms of particle size, zeta potential, entrapment efficiency (EE%), vesicle deformability, morphology, stability, and in vitro release. Transdermal films of chosen formulations were prepared by the solvent casting technique, and an ex vivo study throughout rat skin was also performed. Moreover, a pharmacokinetics (PK) study was carried out and blood glucose levels were estimated. All the liposomes were in the nanometer range and a high EE% was obtained from DLs compared to conventional liposomes (CL). The prepared formulations showed a high stability and the DLs exhibited a high deformability compared to CL. The in vitro release study confirmed the sustained release of GLP from both CL and DL and a more pronounced sustained release of GLP was detected after coating with CS. Moreover, GLP was shown to efficiently permeate through the rat skin from transdermal films by an ex vivo permeation test. The transdermal films showed a promising PK profile in the rat as compared with oral GLP. Most importantly, GLP-CS-DL1 demonstrated a higher hypoglycemic effect, confirming the possibility of systemic action by the local topical delivery of GLP.

Co-stabilization of pioglitazone HCL nanoparticles prepared by planetary ball milling: in-vitro and in-vivo evaluation.

Pioglitazone (PGZ) is an oral antidiabetic agent that increases cell resistance to insulin, thereby decreasing blood glucose levels. PGZ is a class II drug. Because of its pH-dependent solubility, it precipitates at the intestinal pH, resulting in an erratic and incomplete absorption following oral administration, which causes fluctuations in its plasma concentration. A nanoparticle drug delivery system offers a solution to enhance the dissolution rate of this poorly water-soluble drug. PGZ nanoparticles were formulated by the wet milling technique using a planetary ball mill. The effects of the steric stabilizer (Pluronic F-127, PL F-127), electrostatic stabilizer (sodium deoxycholate, SDC), and number of milling cycles were optimized using a Box-Behnken factorial design. The results showed that the ratio of PL F-127: SDC significantly affected the zeta potential and the dissolution efficiency (DE%) of PGZ. The optimized PGZ nanoparticle formulation enhanced the dissolution to reach 100% after 5 min. The in-vivo results showed significant enhancement in Cmax (1.3-fold) compared to that of the raw powder, and both AUC0-24 and AUC0-∞ were significantly (p < 0.05) enhanced. In conclusion, PGZ nanoparticle formulation had enhanced dissolution rate in the alkaline media, which improved its drug bioavailability relative to that of the untreated drug.

Physicochemical and pharmacodynamic evaluation of pioglitazone binary systems with hydrophilic carriers.

Pioglitazone (PGZ) is an antidiabetic agent belongs to thiazolidinediones. Binary systems of PGZ in the matrices of kollicoat IR (KL) and gelucire (GL) at different weight ratios were prepared by kneading and co-evaporation methods, respectively. The drug solid dispersions were characterized in terms of in vitro dissolution studies, differential scanning calorimetry (DSC), and X-ray powder diffraction (XRPD). The effects of PGZ-KL (1:4) solid dispersion on the body weight, blood glucose, renal and hepatic functions of the diabetic rats were evaluated. Enhanced drug dissolution was observed in the case of PGZ-KL binary systems depending on the drug to polymer weight ratio. A reduction of 39.7, 32.7 and 26.6% for diabetic control, PGZ untreated and PGZ-KL (1:4), respectively, was recorded after 2 weeks. PGZ-KL (1:4) solid dispersion also showed significantly lower glucose blood level (p < 0.05) compared to the diabetic control group along the period of experiment. The level of ALT was highly significantly decreased in the animal group treated with PGZ-KL solid dispersion (p < 0.001). However, treatment of diabetic rats with either PGZ-KL or PGZ untreated significantly reduced the level of creatinine compared to the diabetic control and the difference between them was non-significant.

Optimized furosemide taste masked orally disintegrating tablets.

Optimized orally disintegrating tablets (ODTs) containing furosemide (FUR) were prepared by direct compression method. Two factors, three levels (32) full factorial design was used to optimize the effect of taste masking agent (Eudragit E100; X1) and superdisintegarant; croscarmellose sodium (CCS; X2) on tablet properties. A composite was prepared by mixing ethanolic solution of FUR and Eudragit E100 with mannitol prior to mixing with other tablet ingredients. The prepared ODTs were characterized for their FUR content, hardness, friability and wetting time. The optimized ODT formulation (F1) was evaluated in term of palatability parameters and the in vivo disintegration. The manufactured ODTs were complying with the pharmacopeia guidelines regarding hardness, friability, weight variation and content. Eudragit E100 had a very slightly enhancing effect on tablets disintegration. However, the effects of both Eudragit E100 (X1) and CCS (X2) on ODTs disintegration time (Y1) were insignificant (p > 0.05). Moreover, X1 exhibited antagonistic effect on the dissolution after 5 and 30 min (D5 and D30, respectively), but only its effect on D30 is significant (p = 0.0004). Furthermore, the optimized ODTs formula showed good to acceptable taste in term of palatability, and in vivo disintegration time of this formula was about 10 s.

Pharmacokinetics and anti-hypertensive effect of metoprolol tartrate rectal delivery system.

The main aim of this work was to develop rectal suppositories for better delivery of metoprolol tartrate (MT). The various bases used were fatty, water soluble and emulsion bases. The physical properties of the prepared suppositories were characterized such as weight variation, hardness, disintegration time, melting range and the drug content uniformity. The in vitro release of MT from the prepared suppositories was carried out. The evaluation of the pharmacological effects of MT on the blood pressure and heart rate of the healthy rabbits after the rectal administration compared to the oral tablets was studied. Moreover, the formulation with the highest in vitro release and the highest pharmacological effects would be selected for a further pharmacokinetics study compared to the oral tablets. The results revealed that the emulsion bases gave the highest rate of the drug release than the other bases used. The reduction effect of the emulsion MT suppository base on the blood pressure and heart rate was found to be faster and greater than that administered orally. The selected emulsion suppository base (F11) showed a significant increase in the AUC (1.88-fold) in rabbits as compared to the oral tablets. From the above results we can conclude that rectal route can serve as an efficient alternative route to the oral one for systemic delivery of MT which may be due to the avoidance of first-pass effect in the liver.

Pharmacokinetics and analgesic effect of ketorolac floating delivery system.

OBJECTIVES: The efficacy of ketorolac tromethamine (KT) floating alginate beads as a drug delivery system for better control of KT release was investigated. The formulation with the highest drug loading, entrapment efficiency, swelling, buoyancy, and in vitro release would be selected for further in vivo analgesic effect in the mice and pharmacokinetics study in rats compared to the tablet dosage form. METHODS: KT floating alginate beads were prepared by extrusion congealing technique. KT in plasma samples was analyzed using a UPLC MS/MS assay. RESULTS: The percentage yield, drug loading and encapsulation efficiency were increased proportionally with the hydroxypropylmethyl cellulose (HPMC) polymer amount in the KT floating beads. A reverse relationship was observed between HPMC amount in the beads and the KT in vitro release rate. F3-floating beads were selected, due to its better in vitro results (continued floating for >8 h) than others. A longer analgesic effect was observed for F3 in fed mice as compared to the tablets. After F3 administration to rats, the Cmax (2.2 ± 0.3 µg/ml) was achieved at ∼2 h and the decline in KT concentration was slower. F3 showed a significant increase in the AUC (1.89 fold) in rats as compared to the tablets. CONCLUSION: KT was successfully formulated as floating beads with prolonged in vitro release extended to a better in vivo characteristic with higher bioavailability in rats. KT in floating beads shows a superior analgesic effect over tablets, especially in fed mice.

Ketorolac tromethamine floating beads for oral application: Characterization and in vitro/in vivo evaluation.

The floating beads have been employed to make a sustained release of the drug in the stomach and to decrease the dose of the drug and hence overcome its side effects. The common benefits of the floating beads were it is easy preparation, without the need of a high temperature, and high percentage of the drug entrapment. In the present work, the Ketorolac tromethamine (KT) floating beads were prepared by extrusion congealing method utilizing calcium carbonate as a gas forming agent. The physical characters of the produced beads were investigated such as KT yield, KT loading, and entrapment efficiency of the drug. In addition, floating behavior, swelling, particle size, morphology and KT stability were also evaluated. In vitro drug release study was carried out, and the kinetics of the release was evaluated using the linear regression method. Furthermore, the in vivo analgesic effect of KT after oral administration of the selected formula of floating beads (F10) was carried out using hot plate and tail flick methods. Oral commercial KT tablets and KT solution were used for the comparison. The prepared beads remained floated for more than 8 h. The optimized formulation (F10) exhibited prolonged drug release (more than 8 h) and the drug release follows the Higuchi kinetic model, with a Fickian diffusion mechanism according to Korsmeyer-Peppas (n = 0.466). Moreover, F10 showed a sustained analgesic effect as compared to the commercial tablet.

Formulation and evaluation of new long acting metoprolol tartrate ophthalmic gels.

The rationale of the present work is to formulate and evaluate metoprolol tartrate (MT), which is a beta-1 selective adrenergic blocking agent in a new ocular gel delivery system; this is our way and method to increase its contact to the cornea, giving a longer time of drug contact to the eye and slow possible release from the preparation. Metoprolol tartrate is chosen as a candidate for gel formulation because although it has been available for a few years as ophthalmic solutions, it has not been marketed as an ocular gel yet. Two polymers; Carbopol 934 and Pluronic F127 (PF127) were used in two different concentrations in this study. Metoprolol tartrate was used in two concentrations, 0.5% and 1% (w/w). All formulations were exposed to visual examinations, pH measurement, in vitro release, rheological study and differential scanning calorimetry (DSC). Results showed that all formulations were clear, showed pH within the acceptable range suitable to be administered in the eye, and exhibited pseudoplastic flow behavior. DSC results concluded that, MT was compatible with different polymers used. In vitro release results showed that the release rate of metoprolol tartrate from gel preparations decreased as an inverse function of polymer concentration, and the release rate of the drug increased as the initial concentration increased. Intra-ocular pressure (IOP) measurements of rabbit's eye treated with 1% (w/w) metoprolol tartrate in gel formulations with different concentrations of the polymer were determined. Carbopol 934 gel formulations showed that this polymer extended the duration of pressure reducing effect of MT to more than 5hr when compared with Pluronic F127 gel formulations. The area above the curve (AAC), maximum response, time of maximum response (t max), and the duration of the drug action were also calculated.