Evaluation of VCH-759 monotherapy in hepatitis C infection.

BACKGROUND/AIMS: VCH-759 is a non-nucleoside inhibitor of HCV RNA-dependent polymerase with sub-micromolar IC(50) values versus genotype 1a/1b replicons. METHODS: The antiviral activity, pharmacokinetics and tolerability of VCH-759 administered as monotherapy for 10 days with a 14 day follow-up period were evaluated in 31 treatment-nai ve genotype 1 participants. Three cohorts received: 400mg thrice (t.i.d.), 800 mg twice (b.i.d.), 800 mg t.i.d or placebo. RESULTS: VCH-759 was well tolerated with the most frequent adverse event being gastrointestinal upset in both the active and placebo groups attributable, in part, to the dosing vehicle. VCH-759 was rapidly absorbed and trough plasma levels were at or above the IC(90) (non protein-adjusted) for all dosing regimens. The mean maximal decrease in HCV RNA log(10) (IU/mL) was 1.97, 2.30 and 2.46 for 400mg t.i.d., 800 mg b.i.d. and 800 mg t.i.d. doses. Viral polymerase genotypic sequencing revealed emergence of HCV variants in a majority of participants that coincided with on-treatment viral rebound. CONCLUSIONS: VCH-759 was well tolerated and achieved a> or =2 log(10) decline in HCV RNA with 800 mg b.i.d. and t.i.d doses. In a subset of participants, viral rebound was observed and associated with resistant variants. This data supports further evaluation of VCH-759 in combination with interferon-ribavirin treatment.

Development of a discriminating in vitro dissolution method for a poorly soluble NO-donating selective cyclooxygenase-2 inhibitor.

A discriminating dissolution method using a USP apparatus 2 dissolution tester was developed for a nitric oxide donating selective COX-2 inhibitor to support phase I and II formulation development, clinical supplies release and stability testing of an immediate release oral tablet. The BCS class II compound showed very low aqueous solubility and required the use of surfactant-containing (sodium lauryl sulfate (SLS)) dissolution medium in order to achieve an appropriate release profile. The dissolution method utilized 900 mL of 2% SLS (w/v). Samples were withdrawn at five specified time-points over 60 min, at a paddle speed of 75 rpm. Analysis of samples was performed using a validated HPLC method. Despite the use of high levels of SLS, the ability to discriminate variations in physical properties such as drug particle size, granule particle size and tablet compression force was demonstrated. In order to confirm the relationship between these physical parameters and the tablet in vivo release profile, oral dosing of the formulations in fasted beagle dogs was performed to determine if the changes observed in the dissolution profiles were biorelevant. The results of the dissolution and corresponding in vivo experiments helped identify the critical processing parameters likely to influence product bioavailability.

Clickhaler dry powder inhaler: focussed in vitro proof of principle evaluation of a new chemical entity for asthma.

A new chemical entity (NCE) was evaluated in the Clickhaler (Innovata Biomed Ltd.) dry powder inhaler, a reservoir-based multidose delivery system. The standard device metering system was modified to handle higher doses (nominally 20 mm(3) of lactose based blend). The micronized drug was formulated at 12.5% w/w in lactose monohydrate (Pharmatose 325M, DMV) equivalent to a nominal dose of approximately 1 mg. Delivered shot weight (mg of blend) and emitted dose (microg drug) averaged 7.4 mg and 905 microg, respectively, and were consistent (within +/-20 to 25% of mean) through the life of the inhaler. The fine particle fraction (FPF) (Andersen cascade impactor) was typically 60%. A short stability study (i.e. 3 months at room temperature, 53 or 75% RH, unpacked) showed that the in vitro performance was maintained. The results of these studies provide in vitro proof of principle for this novel drug/device combination.

New methods characterizing avalanche behavior to determine powder flow.

PURPOSE: To characterize the avalanche behavior of different powders and to compare the results of the strange-attractor and novel characterization approaches. METHODS: The following nine different materials were tested: three lactoses, maltodextrin, two microcrystalline celluloses, sodium chloride, sucrose, and glass beads. Morphology, size, and size distribution, true density, bulk and tap density, angle of repose, flow index, and avalanching behavior were quantified for each excipient by scanning electron microscopy, laser time-of-flight analysis, helium pycnometer, graduated cylinder, fixed-height funnel, Flodex (Hanson Research Corp., Chatsworth, California) method, and AeroFlow (TSI, Inc., St. Paul, Minnesota), respectively. Environmental factors were controlled, and the avalanches were studied at various speeds. RESULTS: The strange-attractor graph obtained at 1 rotation per 120 s showed that it was difficult to appreciate the flowability differences among 3-mm glass beads, lactose 100, and lactose 325. However, plotting the raw data as a relationship of the time between each avalanche and the inverse of speed revealed a characteristic linear slope for each sample. Furthermore, a new flowability index based on the SD calculated from the raw data gave results that were consistent with Carr's index. A cohesive index also can be determined by avalanche behavior, and it reflects the stability of the rapid particular rearrangements of powder. CONCLUSION: A novel method of evaluating avalanche measurements makes it possible to better characterize powder flowability and to predict powder behavior under working conditions.

Physicochemical evaluation of carbamazepine microparticles produced by the rapid expansion of supercritical solutions and by spray-drying.

PURPOSE: To compare the physical and physicochemical characteristics of carbamazepine microparticles prepared using two different methods: (1) the rapid expansion of supercritical solutions (RESS) and (2) the spray-drying process. METHODS: For both processes, microparticles were produced over a range of different temperatures (35 to 100 degrees C). For the RESS method, carbon dioxide was the solvent used over a pressure range of 2500 to 3500 psi. As for the spray-drying method, different organic solvents were used at atmospheric pressure. Comparison was based on morphology, crystalline structure, mean particle size, and size distribution of processed particles. The influence of process parameters on microparticles' characteristics was also investigated. Particles were analyzed using scanning electron microscopy (SEM), X-ray powder diffraction (XRPD), thermogravimetric analyzer (TGA), and differential scanning calorimetry (DSC). RESULTS: The carbamazepine particles used as unprocessed starting material had a mean diameter of approximately 85 microm with a size distribution range between 15 and 336 microm. Microparticles produced by either the RESS or spray-drying method had a mean diameter smaller than 2 microm and a narrower size distribution range between 0.25 and 2.5 microm. SEM photomicrographs, X-ray diffractograms, and DSC spectra revealed that modification of crystal morphology was dependent on the operating conditions. CONCLUSIONS: Significant reduction in mean particle size and size distribution range of carbamazepine particles was observed by RESS and spray-drying methods. The results also demonstrate that the crystalline nature of carbamazepine particles depends on the method of production and on the operating parameters of pressure and temperature.