Investigating the prilling/vibration technique to produce gastric-directed drug delivery systems for misoprostol.

Prilling/vibration technique to produce oral microcapsules was explored to achieve local delivery of misoprostol (MIS), a prostaglandin E1 analogue indicated for the treatment of gastric-duodenal ulcers, at the gastric mucosa. To improve MIS chemical stability and reduce its associated systemic side effects, drug delivery systems were designed and developed as microcapsules consisting of a core of sunflower oil and MIS (Fs6 and Fs14) or a MIS complex with hydroxypropyl-beta-cyclodextrin (HP-ß-CD) (Fs18), confirmed by specific studies, and a polymeric shell. The produced microcapsules showed high encapsulation efficiencies for those with MIS solubilized in sunflower oil (>59.86 %) and for the microcapsules with MIS/HP-ß-CD (97.61 %). To demonstrate the ability of these systems to deliver MIS into the stomach, swelling and drug release experiments were also conducted in simulated gastric fluid. Among the three formulations, FS18 showed gastric release within 30 min and was the most advantageous formulation because the presence of the MIS/HP-ß-CD inclusion complex ensured a greater ability to stabilise MIS in the simulated gastric environment. In addition, these new systems have a small size (<540 µm), and good flow properties and the dose of the drug could be easily adapted using different amounts of microcapsules (flexibility), making them a passepartout for different age population groups.

Magnetic implants in vivo guiding sorafenib liver delivery by superparamagnetic solid lipid nanoparticles.

HYPOTHESIS: Solid lipid nanoparticles (SLNs), co-encapsulating superparamagnetic iron oxide nanoparticles and sorafenib, have been exploited for magnetic-guided drug delivery to the liver. Two different magnetic configurations, both comprising two small magnets, were under-skin implanted to investigate the effect of the magnetic field topology on the magnetic SLNP accumulation in liver tissues. A preliminary simulation analysis was performed to predict the magnetic field topography for each tested configuration. EXPERIMENTS: SLNs were prepared using a hot homogenization approach and characterized using complementary techniques. Their in vitro biological behavior was assessed in HepG-2 liver cancer cells; wild-type mice were used for the in vivo study. The magnet configuration that resulted in a higher magnetic targeting efficiency was investigated by evaluating the iron content in homogenated murine liver tissues. FINDINGS: SLNs, characterized by an average size smaller than 200 nm, retained their superparamagnetic behavior and relevant molecular resonance imaging properties as negative contrast agents. The evaluation of iron accumulation in the liver tissues was consistent with the magnetic induction profile of each magnet configuration, concurring with the results predicted by simulation analysis and obtained by measurements in living mice.

Stability of Diazepam Enema Extemporaneous Formulation in Manzoni Base.

The authors provide a report on the preparation of an extemporaneous liquid formulation of diazepam enema using an alcohol-free base solution for use by both pediatric and adult patients. A solubility study using this base and the chemical stability of the drug in this formulation was performed by using a high-pressure liquid chromatography analytical method. Results of this study showed that the intrinsic solubility of the drug in this liquid base was 6.03 mg/mL ± 0.06 mg/mL and that diazepam was chemically stable when the formulation was stored at 25°C over a period of 3 months.

Frog intestinal sac as an in vitro method for the assessment of intestinal permeability in humans: Application to carrier transported drugs.

The aim of this study was to investigate the presence of pharmaceutically relevant drug transporters in frog intestine which has been proposed as model for intestinal permeability screening assays of passively absorbed drugs in humans [Trapani, G., Franco, M., Trapani, A., Lopedota, A., Latrofa, A., Gallucci, E., Micelli, S., Liso, G., 2004. Frog intestinal sac: a new in vitro method for the assessment of intestinal permeability. J. Pharm. Sci. 93, 2909-2919]. The expression of transporters in frog intestine was supported by the following observations: (i) the involvement of purine nucleobase transport system was deduced by inhibition of acyclovir transport in the presence of adenine; (ii) baclofen or l-dopa transport was inhibited by the digitalis steroid ouabain and it may be related to the Na(+) electrochemical potential difference, presumably involving amino acid transporters; (iii) the presence of proton-dependent peptide transporters was argued evaluating the effect of the pH change (from pH 5.9 to pH 7.4) on the transport of glutathione; (iv) the possible expression in the frog intestine of an efflux system distinct from P-glycoprotein (Pgp) in the benzylpenicillin transport was deduced using a glucose enriched frog Ringer with or without the known Pgp inhibitor verapamil; (v) the contribution of Pgp-mediated efflux system in determining the frog intestinal absorption of drugs was supported by the specific inhibition of cimetidine or nadolol transport in the presence of verapamil. These results indicate that pharmaceutically relevant drug transporters should be also expressed in frog intestine. In this work, an attempt was also made to compare the measured P(app) values in the frog intestinal model for the aforementioned series of actively/effluxed transported drugs in humans to the corresponding literature values for the fraction absorbed. The P(app) values used in these comparisons were obtained at high concentrations of drugs at which probably saturation of the carrier occurs. Interestingly, it was found that drugs that are completely absorbed had P(app) values >3 x 10(-6)cm/s, while drugs absorbed <90% had P(app) values lower than 1 x 10(-6)cm/s. In these cases, indeed, a borderline region characterized by the apparent permeability coefficient P(app) value between 1 x 10(-6) and 3 x 10(-6)cm/s should be considered for which the prediction of the absorbed fraction after oral administration in humans become more uncertain by the frog intestinal sac system.

Structure-activity relationships and effects on neuroactive steroid synthesis in a series of 2-phenylimidazo[1,2-a]pyridineacetamide peripheral benzodiazepine receptors ligands.

A series of 36 imidazopyridineacetamides (2-37) were designed and synthesized to evaluate the effects of structural changes on the amide nitrogen at both central (CBRs) and peripheral benzodiazepine receptors (PBRs). These changes include variations in the length and number of the alkyl groups as well as introduction of different aromatic, heteroaromatic, and conformationally constrained groups. The affinities of these compounds for CBRs and PBRs were determined, and the results indicate that bulkiness of the substituents, their branching, and length beyond an optimal value may cause hindrance to the ligand in its interaction with the receptor. The presence of aromatic or conformationally constrained substituents on the carboxamide nitrogen can be conducive to high affinity and selectivity. Furthermore, the ability of a subset of the most active ligands to stimulate synthesis of neuroactive steroids in plasma and brain was evaluated in vivo and in vitro. Compound 3 exhibited very marked effects on the peripheral and central synthesis of neuroactive steroids, while 36 (potent at subnanomolar level) showed a slight ability to affect neuroactive steroid content in the cerebral cortex.

Evaluation of new propofol aqueous solutions for intravenous anesthesia.

The aim of this study was to evaluate the potential of using three new aqueous formulations of propofol for intravenous (i.v.) anesthesia. The first formulation can be prepared by using hydroxypropyl-gamma-cyclodextrin (HP-gamma-CD) as a solubilizer. Phase-solubility analysis showed a linear increase in the solubility of propofol to a maximum of 16.6 mg/ml in 30% (w/v) HP-gamma-CD. Moreover, phase-solubility studies demonstrated that 18% (w/v) HP-beta-CD or SBE-beta-CD and 24% HP-gamma-CD solutions, respectively, are required to dissolve 10mg of propofol in 1 ml of the vehicle; the corresponding solutions, however, are slightly hypertonic. Autoclaving the 10 mg/ml CD-based formulations for 15 min at 121 degrees C caused a change in pH which was more evident for the HP-beta-CD-based formulation while, in any case, no detectable fall in propofol concentration was observed. The second formulation herein evaluated is a co-solvent mixture (i.e., propylene glycol:water (1:1), v/v) which is able to dissolve 10 mg/ml of the anesthetic agent. However, although it is simple to prepare, the stability of this formulation is limited. The third aqueous formulation can be prepared by using the prolinate ester of propofol and its water-soluble derivative dissolved in water at equimolar concentration. The efficacy of all these formulations as i.v. anesthetic agents was assessed using a pharmacodynamic measure (onset and duration of loss of the righting reflex, LORR), and compared with that of the commercial propofol formulation (Diprivan, 10 mg/ml) in rats. It was found that minimizing the amount of cyclodextrin in all CD-based formulations, anesthetic effects comparable to those of propofol in Diprivan were still observed. Moreover, the prolinate ester constituted an effective i.v. anesthetic formulation with the same duration of action but with a longer induction time than Diprivan.