Eudragit E PO as a complementary material for designing oral drug delivery systems with controlled release properties: comparative evaluation of new interpolyelectrolyte complexes with countercharged eudragit L100 copolymers.

The design of new interpolyelectrolyte complexes (IPEC) between countercharged polymers (Eudragit EPO (EPO) and Eudragit L100 (L100)) was investigated. The formation and chemical composition of three new IPECs between EPO and L100 was established by elemental analysis. The structure and solid state properties of the synthesized IPEC were investigated using Fourier transform infrared (FTIR) spectroscopy and modulated temperatre differential scanning calorimetry (MTDSC). The binding ratio of a unit molecule of EPO with L100 was found to range between 1:0.98 (Z = 1.02) and 1:0.50 (Z = 2.00) while increasing the pH from 6.0 to 7.0. As a result of electrostatic interaction between the copolymer chains, the glass transition temperature of the IPEC increased significantly. Considerable pH-sensitive swelling in acidic and neutral media was observed for different type of IPECs. Through evaluation of diffusion-transportation properties of the IPECs, basic mechanisms controlling the delivery of chemically different drugs (diclofenac sodium and theophylline) were obtained. The results of swelling and release of the model drugs from the polycomplex matrices confirm that they have potential to be used in oral controlled drug delivery.

PLGA nanoparticles and nanosuspensions with amphotericin B: Potent in vitro and in vivo alternatives to Fungizone and AmBisome.

This paper describes the development of poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles (NPs) and nanosuspensions with the polyene antibiotic amphotericin B (AmB). The nanoformulations were prepared using nanoprecipitation and were characterised with respect to size, zeta potential, morphology, drug crystallinity and content. Standard in vitro sensitivity tests were performed on MRC-5 cells, red blood cells, Leishmania infantum promastigotes and intracellular amastigotes and the fungal species Candida albicans, Aspergillus fumigatus and Trichophyton rubrum. The in vivo efficacy was assessed and compared to that of Fungizone and AmBisome in the acute A. fumigatus mouse model at a dose of 2.5 and 5.0mg/kg AmB equivalents. The developed AmB nanoformulations were equivalently or more effective against the different Leishmania stages and axenic fungi in comparison with the free drug. The in vitro biological activity, and especially hemolytic activity, clearly depended on the preparation parameters of the different nanoformulations. Further, we demonstrated that the superior in vitro antifungal activity could be extrapolated to the in vivo situation. At equivalent dose, the optimal AmB-loaded PLGA NP was about two times and the AmB nanosuspension about four times more efficacious in reducing the total burden than AmBisome. The developed AmB nanomedicines could represent potent and cost-effective alternatives to Fungizone and AmBisome.

Solution calorimetry as an alternative approach for dissolution testing of nanosuspensions.

The formulation of poorly soluble drugs as nanocrystals/nanosuspensions has rapidly evolved during the past decade into a mature drug-delivery strategy. The major characteristic of these systems is the high drug dissolution rate, enabling bioavailability enhancement after oral administration. It is therefore of great importance to have access to analytical methodology that is able to accurately monitor the extreme fast dissolution process of such formulations. The aim of the present study was to evaluate solution calorimetry as a novel approach to measure the dissolution rate of nanosuspensions by recording the temperature change in the dissolution vessel during the dissolution process of the nanocrystals. The applicability was tested on different nanosuspensions made up of three model drugs: naproxen, cinnarizine and an investigational API, i.e. compound A. The dissolution process of all nanosuspensions investigated was completed within less than 1 min. During this period, sufficient data points were collected to transform temperature offset data to cumulative heat of solution pointing to the potential of this technique. However, of significant concern is the fact that this technique measures the total heat produced or consumed by all processes that occur during the dissolution, e.g. the heat of mixing when the nanosuspension comes in contact with the dissolution medium. Erroneous conclusions will result if phenomena other than dissolution are not accounted for.

Comparison of external radiotherapy, laser microsurgery and partial laryngectomy for the treatment of T1N0M0 glottic carcinomas: a retrospective evaluation.

PURPOSE: The aim of this study was to retrospectively compare the efficacy and functional results of three treatment options for T1N0M0 glottic carcinomas applied in a single institution. MATERIALS AND METHODS: One hundred six charts of patients with biopsy-proven T1N0M0 glottic carcinomas treated between 1979 and 1995 were reviewed. There were 81 T1a and 25 T1b tumors. Forty-one patients were treated by radiotherapy (RT) (median dose of 64 Gy), 34 patients were treated by partial laryngectomy (PL) and 31 patients were treated by laser microsurgery (L) of which 10 received postoperative RT for positive margins. In 18 patients, a perceptual voice rating on a visual scale was performed by the patients themselves, three non-speech specialists and two speech therapists. RESULTS: With a median follow-up time of 63.5 months, the 5- and 10-year loco-regional control probabilities reached 91 and 87%, respectively, without any difference between the treatment groups. After salvage laryngectomy, the 5- and 10-year loco-regional control probabilities reached 97% without any difference between the treatment groups. For the whole population, overall survival reached 78 and 62.4% at 5 and 10 years, respectively. The actuarial incidence of second primary reached 19% at 10 years. Regarding the quality of voice, overall there was a trend towards a worse satisfaction index, more hoarseness and more breathiness after PL than after L or RT. CONCLUSIONS: Our data suggested that assuming proper selection of patients, RT and L yielded similar outcomes and functional results. Local recurrence can be adequately salvaged by surgery. On the other hand, PL appeared to yield similar loco-regional control probability but with a worse quality of voice.

The release mechanism of an oral controlled-release delivery system for indomethacin.

This study was carried out to fully characterize the release kinetics of an oral controlled-release tablet formulation of indomethacin with xanthan gum. Matrix swelling, matrix erosion, and drug diffusion studies were performed to elucidate the operative release mechanisms of a tablet compressed from a ternary mixture of indomethacin-xanthan gum-lactose. Drug release tests were performed according to the USP paddle method in phosphate buffer pH 7.4, concurrently with the dissolution of the gum. Mean dissolution time (MDT) of the drug was calculated from the release profile and it was used as a parameter to evaluate the influence of (a) polymer content in the dosage form, (b) ionic strength of the medium, and (c) the rotation speed of the paddle on the release characteristics of the drug. There is a linear relationship between MDT and the inverse of polymer content. Within the range of ionic strength of the gastrointestinal tract, the salt concentration of the dissolution medium has a negative (inhibitory) effect on release rate of the drug and on matrix swelling. A positive (enhancing) influence of the salt concentration on drug diffusion in the hydrated matrices was noted. The polymer dissolution follows almost immediately the dissolution of the drug. A linear relationship between MDT and the inverse of paddle rotation speed has been observed. Swelling-controlled erosional process is the operative mechanism for indomethacin release from xanthan gum matrices.

Estimation of the amount of water removed by gap and atomization air streams during pelletization in a rotary processor.

The purpose of this study was to estimate the amount of water removed by the gap and atomization air streams during pelletization by the wet granulation technique in a rotary processor and to test the hypothesis that the influence of the water addition rate on the pellet size (1,7) mainly originates from differences in the amount of water removed by these air streams. Estimations from flow, temperature, and relative humidity measurements of the air streams, and estimations from moisture content measurements, indicated that approximately 3.6 g of water/min was removed during spheronization. The estimations from the air streams' characteristics obtained for the water loss during the water addition phase (2.6 g/min) reflected the water removal during the later stages and did not reflect the overall rate of water removal during the total water addition phase as estimated from moisture content measurements (2.0 g/min). This was attributed to the fact that estimations from the air streams' characteristics could not take into account the early stages of the water addition phase. In these early stages, the amount of water removed was very limited. Using the foregoing estimations, differences in amount of water removed by the air streams could be compensated by adding more water when the water addition rate was decreased. This resulted in similar pellet sizes (geometric mean diameter of 800-850 microns) using different water addition rates. Thus, the hypothesis that the major influence of the water addition rate on the pellet size mainly originates from differences in the amount of water removed by the gap and atomization air streams was confirmed.

Improvement of the material motion in a rotary processor.

The purpose of this paper is to reject or to confirm the hypothesis that the influence of the water addition rate on the size and size distribution of pellets is caused by insufficient spreading of the added water at higher water addition rates. To overcome insufficient spreading of the added water, the agitation in the rotary processor is intensified by improving the spiral, rope-like movement by means of two baffles and a permanent PTFE coating, and by installing a chopper. Improvement of the spiral, rope-like movement moderates the influence of the water addition rate on the pellet size. The chopper has no significant influence on pellet size, pellet size distribution, or percentage of agglomerates for the pellets, which are investigated in this study. Furthermore, the implementation of the technical modifications does not influence the dissolution characteristics of the pellets directly. It is therefore concluded that the water added is well spread over the mass by ensuring an optimal spiral, rope-like movement, so that incorporation of a chopper is superfluous. The remaining influence of the water addition rate on the pellet size can most probably be explained by differences in processing time, resulting in different volumes of air capable of extracting water from the powder mass.

Congenital malformations caused by psychotropic drugs in pregnancy.

After a description of the harmful effects of psychotropic drugs as well as of the moments of vulnerability to any teratogenic effect, this paper reviews prospective, retrospective and epidemiological studies of the teratogenic effects of anticonvulsants (phenytoin, valproic acid, carbamazepine and barbiturates), lithium, anti-psychotics, benzodiazepines and anti-depressive agents. It is found that the results of these studies are not unequivocal. Only lithium and valproic acid are shown to be teratogenic. In cases where malformations of the fetus are observed, the treatment often consisted in a combination of various psychotropic drugs. The review is completed with data on the psychopharmacological problems during delivery and their side-effects on the newborn.