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Melperone is an atypical antipsychotic agent that has shown a wide spectrum of neuroleptic properties, particularly effective in the treatment of senile dementia and Parkinson's-associated psychosis, and is marketed in Europe as an immediate-release (IR) tablet and syrup. An orally disintegrating tablet (ODT) dosage form would be advantageous for patients who experience difficulty in swallowing large tablets or capsules or those who experience dysphagia. Controlled-release (CR) capsule and ODT formulations containing melperone HCl were developed with target in vitro release profiles suitable for a once-daily dosing regimen. Both dosage forms allow for the convenient production of dose-proportional multiple strengths. Two ODT formulations exhibiting fast and medium release profiles and one medium release profile capsule formulation (each 50 mg) were tested in vivo using IR syrup as the reference. The two medium release formulations were shown to be bioequivalent to each other and are suitable for once-daily dosing. Based on the analytical and organoleptic test results, as well as the blend uniformity and in-process compression data at various compression forces using coated beads produced at one-tenth (1/10) commercial scale, both formulations in the form of CR capsules and CR ODTs have shown suitability for progression into further clinical development.

Rabies continues to be a major public health problem in India. Nearly 17 million people are getting exposed to this disease every year. Therefore the need for effective post-exposure prophylaxis with safe and potent modern rabies vaccines continues to exist. Purified Duck Embryo Vaccine (PDEV) was introduced in this country to meet the ever increasing need for modern rabies vaccines. In this study we have assessed the safety, imunogenicity and tolerance of an indigenously manufactured PDEV in people exposed to dog and other animal bites. One hundred and fifty people (5-59 years) who were having WHO category II or III animal bites were vaccinated with PDEV using the Essen Intramuscular regimen and rabies immunoglobluin (RIG) was administered to category III exposures. Their blood samples were analyzed for rabies virus neutralizing antibody response (RVNA) by Rapid Fluorescent Focus Inhibition Test (RFFIT) on day 0, 14, 30, 90, 180 and 365. Adverse effects to vaccines were monitored during the course of vaccination. There was 100% sero-conversion from day 14 onwards with adequate RVNA titers (>=0.5 IU/mL) up to day 365. The incidence of side effects was minimal and self limiting. Hence it can be concluded that indigenously manufactured PDEV (Vaxirab) is a safe and immunogenic vaccine and can safely be used for post-exposure prophylaxis.

Purified duck embryo vaccine (PDEV, Vaxirab) for rabies prophylaxis is now indigenously manufactured in India under technology transfer from Berna Biotech who made the original PDEV (Lyssavac). In the present study we have compared the two vaccines in terms of safety, immunogenicity and tolerance. The study was conducted in 220 adult healthy volunteers. It was observed that both vaccines produced neutralizing antibody titers (as determined by rapid fluorescent focus inhibition test, RFFIT) more than 0.5 IU/mL (minimum level for seroconversion) on all days tested but the titers on days 90 and 180 were significantly higher with Lyssavac. The adverse reactions produced were slightly more with Lysssavac but both vaccines were well tolerated. In conclusion, the indigenously produced PDEV (Vaxirab) was found to be equally safe and immunogenic as the original PDEV (Lyssavac) manufactured at Switzerland.

Fourteen pregnant women who received rabies post-exposure prophylaxis (PEP) at the anti-rabies clinic (ARC) of Kempegowda Institute of Medical Sciences (KIMS) were followed up for assessing the safety of modern rabies vaccines and equine rabies immunoglobulin (ERIG) in pregnancy. The women were in the age range of 18-28 years, mostly from urban area (64%) and exposed to suspect rabid dogs (86%). They had received purified vero cell rabies vaccine (Verorab = 8 and Abhayrab = 4), purified chick embryo cell vaccine (Rabipur = 2) by Essen regimen; and equine rabies immunoglobulin (Equirab = 7 and Pasteur anti-rabies serum = 1). None of the pregnant women reported any adverse events to either vaccine or equine rabies immunoglobulin. All had safe vaginal deliveries and in all cases both the mother and the child were found to be healthy and normal.

Objectives: The present study was undertaken to standardize skin testing and to develop a safe and effective premedication protocol for administration of ERIG in those with skin test positivity/hypersensitivity., Methods: A method of grading of skin testing was developed using injection histamine as a positive control. This was evaluated by using it on 517 subjects who had severe (WHO category III) exposure to rabies. A premedication protocol consisting of injections pheniramine, ranitidine, hydrocortisone and adrenaline was evaluated by using it on fifty one subjects who were skin test positive/hypersensitive to ERIG., Results: The premedication protocol was safe and effective as all the S1 subjects could be administered the full dose of ERIG despite being skin test positive/hypersensitive to ERIG. Besides the premedication drugs/protocol did not affect the immune response to vaccine and ERIG therapy.

Background: At present, in the event of re-exposure to rabies, 2 booster doses are recommended for people who have been previously vaccinated with cell culture rabies vaccines by the conventional intramuscular route. As the intradermal route of vaccination is likely to be introduced in the future, we investigated the immune response to a cell culture rabies vaccine after crossing over from the intramuscular to the intradermal route and vice versa., Methods: Twenty healthy adult volunteers who had received a primary course of rabies vaccination with purified chick embryo cell rabies vaccine by either the intramuscular (n = 10) or intradermal (n = 10) route received booster vaccination with the same vaccine by the alternative route. The regimen used was 0.1 ml of vaccine by the intradermal route at two sites (deltoid area) for the intramuscular group, or 1 ml of vaccine by the intramuscular route (deltoid muscle) to the intradermal group on days 0 and 3., Results: There was a 15-fold rise in the rabies virus neutralizing antibody response both by the intradermal and intramuscular routes of booster vaccination (p < 0.0001). Thus, the change of route of purified chick embryo cell booster vaccination did not alter the anamnestic immune response to the vaccine. No side-effects were observed after vaccination with either of the routes., Conclusion: Purified chick embryo cell vaccine was found to be safe and immunologically efficacious following booster vaccination after cross-over from the intradermal to the intramuscular route and vice versa.

Purpose: To demonstrate the applicability of thermally stimulated current (TSC) spectrometry for the detection of low levels of the amorphous phase in crystalline pharmaceutical materials., Methods: A crystalline drug substance was melt quenched to produce an amorphous material. Blends of the crystalline and amorphous phases in different ratios (from 75:25 to 99:01) were prepared by serial dilution. TSC studies were performed by applying an electric field at a temperature above the glass transition temperature (Tg) to orient the dipoles, rapidly cooling to 0 degrees C, short circuiting for 1 min, and scanning at 7 degrees C/min to measure the depolarization current. The temperature of the peak in the spectrum corresponds to the Tg of the amorphous phase. Modulated differential scanning calorimtery (DSC) studies were performed using three different test protocols (varying linear heating rate, modulation amplitude, and time period). Powder X-ray diffraction (XRD) studies were performed using a Siemens D500 diffractometer., Results: The ability to detect the amorphous phase by powder XRD is beset with problems due to indirect inference, orientation effects, and instrument-related intensity variations. Even using a consistent sampling procedure and an internal standard, the XRD could quantify the amorphous phase at a level of 5%. In the conventional or modulated DSC, the amorphous phase manifests itself as a shift in the baseline. Using modulated DSC it was possible to detect the amorphous phase at a level of 5% when tested at a heating rate of 2 degrees C/min and an amplitude of +/-1.0 degrees C with a period of 30 s. The moisture sorption method appears to have a similar detection capability. In TSC scans, the glass transition event due to molecular/segmental mobility in the amorphous phase was manifested as a peak/shoulder on the low-temperature side of the depolarization peak of the crystalline phase. The amorphous phase was unambiguously detected at 2% with a lower detection limit of approximately 1%., Conclusions: On the basis of the results of this preliminary investigation, TSC appears to be capable of detecting the amorphous phase at as low as approximately 1% in crystalline pharmaceuticals, thus offering a much needed capability in discerning factors.

The effects of the amounts of lubricants (magnesium stearate 0-5% and talc 0-3%) and changes in compaction rate and tablet porosity on the mechanism of drug release from high drug-load controlled-release theophylline tablets have been examined. Drug release was satisfactorily described by a surface-erosion model that takes into account the geometry of the tablet, differential radial and axial erosion rates, and the initial burst effect (r2 > 0.99 for all formulations). The axial and radial erosion rate constants were inversely proportional to the amount of magnesium stearate in the formulation (P < 0.0001). The most dramatic reductions in erosion rate occurred between 0 and 1% magnesium stearate content. For magnesium stearate concentrations > or =2.5% the ratio of radial to axial erosion rate constants was essentially constant at 3 (approx.); however, for formulations with magnesium stearate < or =1% the ratio tended toward unity. Reducing matrix porosity over the range 26 to 14% resulted in reduced erosion rates. However, a threshold of 17% (approx.) porosity was identified below which further reductions in porosity resulted in only incremental changes in release rates. The rate of erosion and drug release was insensitive to changes in machine speed over the range 20 to 100 rev min(-1). For highly loaded matrix tablets containing sparingly soluble drugs, such as theophylline, magnesium stearate at appropriate levels can modulate the erosion rate constants and act as an effective release-controlling excipient. Drug-release profiles are predictable and relatively robust in terms of changes in compaction rate and applied force routinely encountered in large-scale tablet manufacturing.

Eprosartan mesylate (SKF 108566-J; EM) is an antihypertensive agent approved for marketing in the USA. EM dihydrate was prepared by three methods, one of which included suspending the anhydrous drug in an aqueous solution of 1.0 M methanesulfonic acid to form a slurry, followed by filtration. The dehydration kinetics of EM dihydrate were derived by analyzing the fit of the isothermal thermogravimetric analytical (TGA) data to numerous kinetic models. EM dihydrate undergoes dehydration in two distinct steps, each involving the loss of 1 mol of water at 25-70 degrees C and 70-120 degrees C, respectively. Recrystallization of EM occurs at approximately 120-140 degrees C after dehydration to the anhydrous phase. This explanation is supported by variable temperature powder X-ray diffractometry. The mechanism of the dehydration reaction is complex, the dependence of the reaction rate on temperature varying as a function of the particles size. For the dihydrate of sieve fraction <125 microm, the kinetics of the first and second dehydration steps are consistent with the Avrami-Erofeev equation (A3, n = 1/3) over the temperature range studied, corresponding to three-dimensional growth of nuclei. In contrast, for the 125-180-microm and 180-250-microm sieve fractions, the kinetics are best described by the two-dimensional phase boundary reaction (R2) at a lower dehydration temperature (i.e., 28.3 degrees C), and by the Avrami-Erofeev equation (A3, n = 1/3) at a higher dehydration temperature (i.e., 93.7 degrees C). The activation energies (15-40 kcal/mol) and frequency factors of the dehydration of EM dihydrate were determined both by Arrhenius plots of the isothermal rates determined by TGA and by Kissinger plots of the nonisothermal differential scanning calorimetric data. Hot stage microscopy of single crystals of EM dihydrate showed random nucleation at the surface and dehydration with the growth of microcrystals along the needle a axis. Cerius(2) molecular modeling software showed the existence of water channels along the a axis and enabled the observed dehydration behavior of EM dihydrate crystals to be explained in terms of the bonding environment of water molecules in the crystal structure.

The purpose of this research was to design and develop a novel controlled-release bead formulation for oral administration with buffer crystals as a carrier for loading of fenoldopam mesylate, an intravenous antihypertensive agent, which provides an in vitro release rate of 30-50 mg/hr for 6-8 hr. Buffer crystals were coated in a fluid-bed granulator with a blend of gastrointestinal (GI) insoluble/enteric Eudragit polymers (such as RSPM/S100 polymer blend), drug was layered on these polymer-subcoated buffer beads by a slurry coating process, and the drug-layered beads were subsequently overcoated using a blend of GI insoluble/enteric polymers. The release of fenoldopam and tartaric acid was monitored by a two-stage dissolution procedure using USP Apparatus 2 (paddles at 50 rpm) and HPLC methodologies. The overcoating of drug-layered tartaric acid crystals with Eudragit polymers with different permeabilities significantly affected the release of fenoldopam. However, even the least permeable polymer, Eudragit RS, could not sustain the release of tartaric acid beyond 2 hr, suggesting the need to subcoat freely water-soluble tartaric acid crystals prior to drug layering. By varying the type/ratios of the GI insoluble/enteric polymers for subcoat and overcoat, capsule formulations were developed, which released fenoldopam and tartaric acid at different rates. The use of Eudragit polymer blends at the optimized ratios for both subcoat and overcoat resulted in a significant retardation in the release of tartaric acid; still, the tartaric acid release was faster than that of fenoldopam, suggesting the need to use a less water-soluble fumaric or succinic acid crystals as the buffer. However, the technology described using tartaric acid crystals as the buffer will be highly useful for weakly basic drug substances with less stringent pH-dependent solubility profiles.