A Combined Utilization of Plasdone-S630 and HPMCAS-HF in Ziprasidone Hydrochloride Solid Dispersion by Hot-Melt Extrusion to Enhance the Oral Bioavailability and No Food Effect.

The purpose of this study was to research a novel combination of Plasdone-S630 and HPMCAS-HF as hot-melt carrier used in ziprasidone hydrochloride for enhanced oral bioavailability and dismissed food effect. Ziprasidone hydrochloride solid dispersion (ZH-SD) was prepared by hot-melt extrusion technique, and its optimized formulation was selected by the central composite design (CCD), which was characterized for powder X-ray diffraction (PXRD), fourier transform infrared spectroscopy (FTIR), in vitro dissolution study, and stability study. Finally, the in vivo study in fasted/fed state was carried out in beagle dogs. Based on PXRD analysis, HME technique successfully dispersed ziprasidone with a low crystallinity hydrochloride form in the polymers. According to the analysis of FTIR, hydrogen bonds were formed between drug and polymers during the process of HME. Without any noticeable bulk, crystalline could be found from the micrograph of ZH-SD when analyzed the result of scanning electron microscope (SEM). Pharmacokinetics studies indicated that the bioavailability of ZH-SD formulation had no significant difference in fasted and fed state, and the Cmax and AUC of ZH-SD were two fold higher than Zeldox® in fasted state. This result indicated that ziprasidone has achieved a desired oral bioavailability in fasted state and no food effect.

Dissolving polyvinylpyrrolidone-based microneedle systems for in-vitro delivery of sumatriptan succinate.

In-vitro permeation studies were conducted to assess the feasibility of fabricating dissolving-microneedle-array systems to release sumatriptan succinate. The formulations consisted mainly of the encapsulated active ingredient and a water-soluble biologically compatible polymer, polyvinylpyrrolidone (PVP), approved by the U.S. Food and Drug Administration (FDA). Tests with Franz-type diffusion cells and Göttingen minipig skins showed an increase of the transdermal flux compared to passive diffusion. A preparation, containing 30% by mass of PVP and 8.7mg sumatriptan, produced a delivery rate of 395±31µg/cm2h over a 7-hour period after a negligible lag time of approximately 39min. Theoretically, a 10.7cm2 microneedle-array patch loaded with 118.8mg of the drug would provide the required plasma concentration, 72ng/mL, for nearly 7h.

Localized cutaneous polyvinylpyrrolidone storage disease mimicking cheilitis granulomatosa.

Polyvinylpyrrolidone (PVP), a polymer of the monomer N-vinylpyrrolidone with various molecular weights, was originally developed as a plasma expander. Currently, it is widely used in hair sprays, skin care products, fruit juices, and as a retarding agent in drugs such as procaine and hormones. PVP polymers with a molecular weight greater than 20,000 cannot be excreted by the kidneys and therefore are phagocytosed and permanently stored in the reticular endothelial system, leading to the so-called PVP storage disease. We report a case of localized cutaneous PVP storage disease presenting with persistent upper lip swelling and mimicking cheilitis granulomatosa, which has never been reported before.

Comparison of the formulation requirements of dosator and dosing disc automatic capsule filling machines.

The overall objective of this study was to provide 'semi-quantitative' or 'rigorous' definitions of the fluidity, lubricity and compactibility requirements of formulation for representative dosator and dosing disc capsule filling machines. To that end, model formulations were developed for those properties using Carr's compressibility index, ejection force, and plug breaking force at a specified compression force to gauge fluidity, lubricity, and compactibility, respectively. These formulations were each encapsulated on an Hofliger-Karg GKF-400 dosing disc machine and a Zanasi LZ-64 dosator machine. Each machine was instrumented to measure plug compression and ejection forces. The encapsulation process was evaluated for %CV of fill-weight, ejection force, plug breaking force and the dissolution of marker drugs incorporated in the formulations. The f2 metric was used to compare dissolution profiles. The results suggest: (1) formulations should meet different flow criteria for successful encapsulation on the two machines, (2) a relatively lower level of lubricant may be sufficient for the dosing disc machine, (3) a higher degree of formulation compactibility is needed for the dosator machine, and (4) transferring formulations between these machine types (same class, different subclass per FDA's SUPAC-IR/MR Manufacturing Equipment Addendum) could be challenging. In certain cases dissolution profiles for the same formulation filled on the two machines with equivalent compression force were different based on f2 < 50. Overall, the results of this study suggest a range of formulation characteristics appropriate for transferring formulations between these two types of machines.

Coumarin-based prodrugs. Part 3: Structural effects on the release kinetics of esterase-sensitive prodrugs of amines.

To study the structural effects on the release kinetics of a coumarin-based esterase-sensitive prodrug system, two series of compounds with varying structural features of the ester 'trigger' part and the amine 'drug' part were synthesized. The half-lives of the nine model prodrugs in the presence of porcine liver esterase ranged from about 2 min to 190 min. The steric bulkiness of the acyl group seems to have only a very minor effect on the half-lives of the esterase-triggered release of amines from the model prodrugs. The rate of the lactonization depends on the steric and electronic properties of the amine moiety.

Production of useful chemicals from sunflower oil by microbial biotransformation with rhizopus stolonifer NRRL 1478.

A number of microorganisms has been screened for growth on sunflower oil as a sole carbon source for production of useful chemicals. Rhizopus stolonifer NRRL 1478 was found to transform the lipid contents of sunflower oil into dodecyl b-D-glucopyranoside and dodecanedioic acid in 15 and 25% yields respectively. The produced compounds were isolated and purified by column chromatography and their chemical identities were established using MS, IR, 1H and 13C NMR spectroscopy.

Choice of an optimal diluent for intravesical bacillus Calmette-Guerin administration.

The physical conditions, including diluent pH, salt concentration and duration of bacillus Calmette-Guerin attachment, were determined in in vitro binding assays for soluble and matrix fibronectin. Since soluble fibronectin may block attachment of bacillus Calmette-Guerin to matrix fibronectin in the bladder, the optimal conditions were determined under which matrix fibronectin-bacillus Calmette-Guerin binding was maximal and soluble fibronectin-bacillus Calmette-Guerin binding was minimal. These conditions, which were confirmed in vivo in the murine bladder model, included use of normal saline, pH 7 as diluent for bacillus Calmette-Guerin organisms, with retention of the bacillus Calmette-Guerin suspension for 2 hours.

Theophylline pharmacokinetics after intravenous infusion with ethylenediamine or sodium glycinate.

Six healthy volunteers received two theophylline preparations by short intravenous infusion, at weekly intervals in a randomized cross-over design. The solubilizer was ethylenediamine or sodium glycinate. Plasma concentrations of theophylline and ethylenediamine were measured by h.p.l.c. for up to 24 h after dosing. The pharmacokinetics of theophylline did not show any significant intra-subject variation associated with the solubilizing agent used.

The effect of some ointment bases on the systemic absorption of tobramycin from various wound surfaces of burned patients.

Three kinds of 0.2 per cent tobramycin ointment were prepared with tobramycin and 3 ointment bases (cream, polyethylene glycol and hydrophilic petrolatum), and applied to the various wound surfaces of 5 burned patients. The systemic absorptions of tobramycin were compared with the values of the tentative AUC (area under the curve of tobramycin blood level, micrograms.h/ml.g) until 12 hours after the applications, by determining tobramycin level in blood. Similar values of AUC from the cream and polyethylene glycol ointments were obtained, while that of hydrophilic petrolatum ointment was very low. The systemic absorption of tobramycin from the polyethylene glycol ointment was studied when the ointment was applied to the wound surfaces of 7 patients with partial-thickness burn, 9 patients with full-thickness burn and 6 patients with burn ulcer. The mean values of the tentative AUC of patients with partial-thickness burn, full-thickness burn and burn ulcer were found to be 0.06, 0.03 and 0.15, respectively. These results showed that cream and polyethylene glycol bases should be used carefully as a vehicle of tobramycin ointments because of the rapid systemic absorption of tobramycin from human burn wounds, especially burn ulcer.

The biotransformation and disposition of bronopol following topical and intravenous administration to rats.

Approx. 40% of the topically applied dose of antibacterial agent [14C] bronopol([14C]BP) was absorbed through the rat skin within 24 h. Of the applied radioactivity, about 19% was excreted in the urine, feces and expired air. The 24 h recoveries of 14C in the urine and expired air were 15 and 2%, respectively, of the dose applied to the skin, and 74 and 9%, respectively, of the dose given intravenously. The TLC of the urines showed three metabolites, but no unchanged [14C]BP in both groups. The results suggest that rat skin is quite permeable to bronopol.