Oral bioavailability enhancement of flubendazole by developing nanofibrous solid dosage forms.

The bioavailability of the anthelminthic flubendazole was remarkably enhanced in comparison with the pure crystalline drug by developing completely amorphous electrospun nanofibres with a matrix consisting of hydroxypropyl-ß-cyclodextrin and polyvinylpyrrolidone. The thus produced formulations can potentially be active against macrofilariae parasites causing tropical diseases, for example, river blindness and elephantiasis, which affect altogether more than a hundred million people worldwide. The bioavailability enhancement was based on the considerably improved dissolution. The release of a dose of 40 mg could be achieved within 15 min. Accordingly, administration of the nanofibrous system ensured an increased plasma concentration profile in rats in contrast to the practically non-absorbable crystalline flubendazole. Furthermore, easy-to-grind fibers could be developed, which enabled compression of easily administrable immediate release tablets.

Stability of doripenem in vitro in representative infusion solutions and infusion bags.

BACKGROUND: Doripenem, a new parenteral carbapenem with broad-spectrum antibacterial activity, is indicated for the treatment of complicated intra-abdominal infections and complicated urinary tract infections, including pyelonephritis. According to the US prescribing information, the carbapenems imipenem and meropenem are stable in sodium chloride for 4 hours. OBJECTIVE: The aim of this study was to assess the stability of doripenem following constitution (50 mg/mL) and in injection solutions in vitro (0.9% sodium chloride and 5% dextrose) at a concentration of 5 mg/mL in room and refrigerated conditions. METHODS: The stability of doripenem was assessed (1) under room-temperature conditions (25 degrees C +/- 2 degrees C, 60% +/- 5% relative humidity, under fluorescent light) immediately after constitution in vials with sterile water; (2) under room conditions and refrigerated conditions (5 degrees C +/- 3 degrees C, 60% relative humidity, protected from light) immediately after constitution with sodium chloride or dextrose in 3 different infusion bags (polyvinyl chloride [PVC], PVC with vial adapter, and polyethylene); and (3) under room and refrigerated conditions using 500-mg doripenem vials that had been stored for 12 months in room temperature and protected from light before constitution with water and dilution in sodium chloride or dextrose injection. Doripenem 5 mg/mL and related substances (degradation products and impurities related to doripenem) were measured using a validated high-performance liquid chromatography method. Doripenem was considered stable if its concentration remained within 90% to 110% of the initial concentration and the total concentration of degradation products and impurities related to doripenem was < or = 5%. Appearance of the solutions was assessed using clarity and comparison to color standards; pH, using standard methodologies; and particulate matter, using light-obscuration and microscopy. RESULTS: Three lots of doripenem were assessed. Doripenem potency in constituted suspension (50 mg/mL) remained unchanged (means, 99.2% and 99.3%, respectively, of initial doripenem amount) for up to 60 minutes in room or refrigerated conditions prior to transfer to infusion bags. The doripenem 5-mg/mL infusion solution retained its potency for 12 and 72 hours under room and refrigerated conditions, respectively, in 0.9% sodium chloride injection, and for 4 and 48 hours under room and refrigerated conditions, respectively, in 5% dextrose injection (mean percentages of initial doripenem concentration, 95.5% and 96.6% under room and refrigerated conditions, respectively). Comparable results were obtained with vials of doripenem that had been stored for 12 months at room temperature and protected from light and then constituted (50 mg/mL). Doripenem 5 mg/mL in 0.9% sodium chloride injection or 5% dextrose injection retained its potency in room conditions at the end of a 4-hour drip period when used with conventional infusion sets (mean, 96.6%) or Di(2-ethylhexyl)phthalate-free infusion sets (mean, 99.3%). CONCLUSIONS: Doripenem 5 mg/mL was stable for up to 12 hours in vitro in 0.9% sodium chloride at room temperature. Therefore, doripenem can be constituted, mixed with infusion fluids in the pharmacy, stored, delivered, and infused into a patient within a time frame suitable for 4-hour extended infusions.

Evaluation of Three Amorphous Drug Delivery Technologies to Improve the Oral Absorption of Flubendazole.

This study investigates 3 amorphous technologies to improve the dissolution rate and oral bioavailability of flubendazole (FLU). The selected approaches are (1) a standard spray-dried dispersion with hydroxypropylmethylcellulose (HPMC) E5 or polyvinylpyrrolidone-vinyl acetate 64, both with Vitamin E d-α-tocopheryl polyethylene glycol succinate; (2) a modified process spray-dried dispersion (MPSDD) with either HPMC E3 or hydroxypropylmethylcellulose acetate succinate (HPMCAS-M); and (3) confining FLU in ordered mesoporous silica (OMS). The physicochemical stability and in vitro release of optimized formulations were evaluated following 2 weeks of open conditions at 25°C/60% relative humidity (RH) and 40°C/75% RH. All formulations remained amorphous at 25°C/60% RH. Only the MPSDD formulation containing HPMCAS-M and 3/7 (wt./wt.) FLU/OMS did not crystallize following 40°C/75% RH exposure. The OMS and MPSDD formulations contained the lowest and highest amount of hydrolyzed degradant, respectively. All formulations were dosed to rats at 20 mg/kg in suspension. One FLU/OMS formulation was also dosed as a capsule blend. Plasma concentration profiles were determined following a single dose. In vivo findings show that the OMS capsule and suspension resulted in the overall highest area under the curve and Cmax values, respectively. These results cross-evaluate various amorphous formulations and provide a link to enhanced biopharmaceutical performance.

Compatibility of doripenem with other drugs during simulated Y-site administration.

PURPOSE: The compatibility of doripenem diluted for infusion with 82 other drugs during simulated Y-site administration was studied. METHODS: Five-milliliter samples of doripenem 5 mg/mL in 5% dextrose injection and separately in 0.9% sodium chloride injection were combined with 5 mL of 82 other drugs, undiluted or diluted in 5% dextrose injection or 0.9% sodium chloride injection. Visual examinations were performed with the unaided eye in fluorescent light and using a Tyndall beam to enhance visualization of small particles and low-level turbidity. The turbidity of each sample was measured, and particulate content was evaluated. Samples were inspected initially and one and four hours after preparation. RESULTS: Of the drugs tested, doripenem 5 mg/mL in 5% dextrose injection and in 0.9% sodium chloride injection was incompatible with diazepam, potassium phosphates, and undiluted propofol. Doripenem 5 mg/mL in 0.9% sodium chloride injection but not in 5% dextrose injection was incompatible with amphotericin B-containing drugs due to the diluent. Doripenem was found to be compatible when combined with the other 75 drugs for at least four hours. CONCLUSION: Doripenem 5 mg/mL in 5% dextrose injection or in 0.9% sodium chloride injection was physically compatible for four hours at room temperature with 75 drugs during simulated Y-site administration. Three drugs combined with doripenem in 5% dextrose injection or 0.9% sodium chloride injection and 7 drugs combined with doripenem in 0.9% sodium chloride injection resulted in unacceptable precipitation or an increase in measured haze and should not be simultaneously administered with doripenem admixtures.

Concentrated CO(2)-in-Water Emulsions with Nonionic Polymeric Surfactants.

Concentrated CO(2)-in-water (C/W) emulsions are reported for amphiphiles containing alkylene oxide-, siloxane-, and fluorocarbon-based tails as a function of temperature and salinity. Poly(ethylene oxide)-b-poly(butylene oxide) (EO(15)-b-BO(12)) can emulsify up to 70% CO(2) with droplet sizes from 2 to 4 &mgr;m in diameter, as determined by video-enhanced microscopy. This emulsion is stable over 48 h against both flocculation and coalescence. In contrast, it is extremely difficult to form concentrated water-in-CO(2) (W/C) emulsions with surfactants containing alkylene oxide moieties due to limited solvation of such tails by CO(2). In several cases, C/W emulsions are formed even when the surfactant prefers CO(2). This violation of Bancroft's rule may be attributed in part to the low viscosity of the compressed CO(2), which governs several mass and momentum transport mechanisms relevant to emulsion formation and stabilization. For the first time, W/C microemulsions are observed in a system with a nonionic amphiphile, namely F(CF(2)CF(2))(3-8)CH(2)CH(2)O(CH(2)CH(2)O)(10-15)H. For the same system, the emulsion morphology changes from C/W to W/C as the temperature increases. The electrical conductivity of C/W emulsions is predicted successfully as a function of the dispersed phase volume fraction of CO(2) with Maxwell's theory for inhomogeneous systems. Copyright 2001 Academic Press.