AAPS pharmSci最新文献

The development of new direct compression excipients should include a comprehensive and rapid determination of deformation properties. The aim of this study was to characterize StarLac, a new coprocessed compound for direct compression based on lactose and maize starch. For this purpose, the effects of the base materials (maize starch and spray-dried lactose) were considered and the influence of the spray-drying process was investigated. This was performed by comparing the physical mixture of starch and spray-dried lactose at the same ratio as for StarLac. For analysis of the deformation behavior, the 3-D model and the Walker equation were applied; for verification, the Heckel equation and the pressure time function (a modified Weibull equation) were used. The advantages of StarLac are its good flowability depending on the spray-drying process, an acceptable crushing force due to its lactose content, its rapid disintegration depending on starch, and a brilliant fast release of an active ingredient, such as theophylline monohydrate. The volume-pressure deformation properties of StarLac were dependent on the lactose properties. Only at high maximum relative density (rho(rel, max)) did the influence of starch cause a change in these properties. A network-like structure can be observed using scanning electron microscopy pictures. Overall, StarLac deformed plastically with a low portion of elasticity. The physical mixture exhibited a more elastic behavior than StarLac. However, the part of the powder that was irreversibly compressed was much lower than was observed for the single substances. This behavior is caused by an interaction between the components, which in StarLac is prevented by spray drying.

The purpose of this study was to assess the potential use of poly(ethylene oxide) (PEO) as matrix-forming material for tablets and extrudates. Raw materials were characterized for size, size distribution, and shape. Tablets with 2- and 10-mm diameter were prepared by direct compression at both 13 and 38 MPa from mixtures with poly(ethylene oxide)s, a model drug (propranolol hydrochloride), and lactose. To these mixtures water was added (16%-43%) prior to extrusion in a ram extruder fit with different dies (1-, 3-, 6-, and 9-mm diameter and 4-mm length). Tablets and extrudates were characterized for work of compression or extrusion, respectively, relaxation, tensile strength, friability, and drug release. Both PEOs produced tablets easily and with different properties. Some relaxation was observed, particularly for tablets with higher amounts of PEOs. Release of the drug occurred after swelling of the matrix, and between 10% and 70% drug released, a quasi zero-order release was observed for large tablets. Extrusion was possible for formulations with PEO only with amounts of water between 16% and 50%. Both radial and axial relaxation of both plugs and extrudates were observed. Moreover, different extrusion profiles reflected the different behaviors of the different formulations. The model drug was released in the same fashion as observed for the tablets. It was possible to produce tablets by direct compression and extrudates or pellets from those extrudates from different formulations with PEO. Tablets and pellets have shown distinct properties depending upon the PEO considered. Extrusion was particularly complex with different formulations with PEO.

This study was undertaken to categorize representative fluoroquinolone drug substance permeability based on the methods outlined in the Food and Drug Administration's biopharmaceutic classification system (BCS) Guidance for Industry. The permeability of ciprofloxacin, levofloxacin, lomefloxacin, and ofloxacin was measured in an in vitro Caco-2 assay with previously demonstrated method suitability. The permeability class and efflux potential were ascertained by comparing test drug results with standard compounds (metoprolol, atenolol, labetalol, and rhodamine-123). All 4 quinolones drugs demonstrated concentration-dependent permeability, indicating active drug transport. In comparing absorptive versus secretive in vitro transport, the tested fluoroquinolones were found to be subject to efflux in varying degrees (ciprofloxacin > lomefloxacin > rhodamine 123 > levofloxacin > ofloxacin). Based on comparison to labetalol, the high permeability internal standard, ciprofloxacin was classified as a low permeability drug, whereas lomefloxacin, levofloxacin, and ofloxacin were classified as high permeability drugs. The in vitro permeability results matched human in vivo data based on absolute bioavailabilities. This laboratory exercise demonstrated the applicability of an in vitro permeability method for classifying drugs as outlined in the BCS Guidance.

The aim of the current study was to compare the predictive performance of a mechanistically based model and an empirical artificial neural network (ANN) model to describe the relationship between the tissue-to-unbound plasma concentration ratios (Kpu's) of 14 rat tissues and the lipophilicity (LogP) of a series of nine 5-n-alkyl-5-ethyl barbituric acids. The mechanistic model comprised the water content, binding capacity, number of the binding sites, and binding association constant of each tissue. A backpropagation ANN with 2 hidden layers (33 neurons in the first layer, 9 neurons in the second) was used for the comparison. The network was trained by an algorithm with adaptive momentum and learning rate, programmed using the ANN Toolbox of MATLAB. The predictive performance of both models was evaluated using a leave-one-out procedure and computation of both the mean prediction error (ME, showing the prediction bias) and the mean squared prediction error (MSE, showing the prediction accuracy). The ME of the mechanistic model was 18% (range, 20 to 57%), indicating a tendency for overprediction; the MSE is 32% (range, 6 to 104%). The ANN had almost no bias: the ME was 2% (range, 36 to 64%) and had greater precision than the mechanistic model, MSE 18% (range, 4 to 70%). Generally, neither model appeared to be a significantly better predictor of the Kpu's in the rat.