No abstract

The stress distribution of tablets after compression was simulated using a finite element method, where the powder was defined by the Drucker-Prager cap model. The effect of tablet shape, identified by the surface curvature, on the residual stress distribution was investigated. In flat-faced tablets, weak positive shear stress remained from the top and bottom die walls toward the center of the tablet. In the case of the convexly curved tablet, strong positive shear stress remained on the upper side and in the intermediate part between the die wall and the center of the tablet. In the case of x-axial stress, negative values were observed for all tablets, suggesting that the x-axial force always acts from the die wall toward the center of the tablet. In the flat tablet, negative x-axial stress remained from the upper edge to the center bottom. The x-axial stress distribution differed between the flat and convexly curved tablets. Weak stress remained in the y-axial direction of the flat tablet, whereas an upward force remained at the center of the convexly curved tablet. By employing multiple linear regression analysis, the mechanical properties of the tablets were predicted accurately as functions of their residual stress distribution. However, the multiple linear regression prediction of the dissolution parameters of acetaminophen, used here as a model drug, was limited, suggesting that the dissolution of active ingredients is not a simple process; further investigation is needed to enable accurate predictions of dissolution parameters. Key words tablet shape; simulation; mathematical model; residual stress; finite element method; multiple linear regression Tablets are the most common and popular dosage form of drug administration. Tablets are generally manufactured by compressing a mixture of dry powders or granules using metal dies and punches. Various stresses remain on the surface and in the interior of tablets after the compression. The effect of the residual stress distributions of tablets on tablet hardenss [1][2][3][4][5][6][7][8] and tableting failures such as capping and lamination 9,10) have been numerically investigated. The finite element method (FEM), in which the powder is modeled using the Drucker-Prager cap (DPC) model, [9][10][11][12][13][14] can be applied to modeling the deformation of pharmaceutical powders 11,15) and thus to simulate the residual stress distribution of tablets. Powders are modeled as continuum media in the FEM and the compaction process is identified by boundary-value analysis. The DPC model is often applied to the analysis of the stress distribution and relative-density changes of the tablets during the tableting process. In examples of the use of the DPC model, Han et al. 12) reported that the density distributions of the tablets were affected by the punch geometry while Wu et al. 9,10) described how tablet failure is more likely to be associated with a band of intensive shear stress generated during the decompression of tablets. Additionally, the density distribution pa...

Permeation enhancers are required to deliver drugs through the skin efficiently and maintain effective blood concentrations. Studies of the barrier function of the stratum corneum using l-menthol, a monocyclic monoterpene widely used in medicines and foods, have revealed an interaction between characteristic intercellular lipid structures in the stratum corneum and permeation enhancers. The variety of permeation enhancers that can be used to contribute to transdermal delivery systems beyond l-menthol is increasing. In this study, we focused on nerolidol and levulinic acid and investigated their influence on stratum corneum lipid structures. Nerolidol, a sesquiterpene, has been reported to enhance the permeation of various drugs. Levulinic acid is reported to enhance the permeability of buprenorphine and is used as a component of the buprenorphine ® patch. Synchrotron X-ray diffraction and attenuated total reflectance Fourier transform IR spectroscopy measurements revealed that nerolidol disturbs the rigidly arranged lipid structure and increases lipid fluidity. Levulinic acid had a smaller effect on stratum corneum lipid structures, but did increase lipid fluidity when co-administered with nerolidol or heat. We found that nerolidol has an effect on stratum corneum lipids similar to that of l-menthol, and levulinic acid had an effect similar to that of oleic acid.Key words nerolidol; levulinic acid; stratum corneum; synchrotron X-ray diffraction; attenuated total reflectance Fourier transform IR spectroscopy Chemical penetration enhancers are useful in transdermal delivery systems. These enhancers act on intercellular lipid structures in the stratum corneum, reversibly decreasing its barrier function and increasing drug permeability. Many types of enhancers have been investigated, including alcohols, [1][2][3] pyrrolidones, 4,5) surfactants, 6,7) fatty acids, 8,9) and terpenes.10,11)The modes of action of penetration enhancers include increasing lipid partitioning or diffusion, disturbing lipid structure, and extracting lipids. 11) Chemical absorption enhancers must not only have high permeation effects but also a margin of safety for administration to live organisms, and thus many compounds are restricted from practical use. Based on their safety and efficacy, terpenes 10-12) and fatty acids 8,9) have been studied extensively as permeation enhancers. Terpenes increase the diffusion of drugs in the intercellular lipids of the stratum corneum, and fatty acids increase the distribution of drugs to the surface. 11) Combining enhancers with different actions can have a synergistic effect on drug permeability.13) The compatibility of the principal agent and the effect of permeation enhancers on drug permeability has been investigated. 14) Intercellular lipid structures in the stratum corneum of skin act as a barrier to drug permeability.15) These lipids have been shown to form hexagonal and orthorhombic structures. [15][16][17] The observation of hydrocarbon chain packing by wide-angle X-ray diffraction has revealed h...

l-Menthol increases drug partitioning on the surface of skin, diffusion of drugs in the skin, and lipid fluidity in the stratum corneum and alters the rigidly arranged lipid structure of intercellular lipids. However, l-menthol is a solid at room temperature, and it is difficult to determine the effects of l-menthol alone. In this study, we vaporized l-menthol in order to avoid the effects of solvents. The vaporized l-menthol was applied to the stratum corneum or lipid models comprising composed of ceramides (CER) [EOS], the longest lipid acyl chain of the ceramides in the stratum corneum lipids that is associated with the barrier function of the skin; CER [NS], the shorter lipid acyl chain of the ceramides, and the most components in the stratum corneum of the intercellular lipids that is associated with water retention in the intercellular lipid structure of the stratum corneum; cholesterol; and palmitic acid. Synchrotron X-ray diffraction, differential scanning calorimetry, and attenuated total reflection Fourier transform infrared spectroscopy analyses revealed that the lipid models were composed of hexagonal packing and orthorhombic packing structures of different lamellar periods. Taken together, our results revealed that l-menthol strongly affected the lipid model composed of CER [EOS]. Therefore, l-menthol facilitated the permeation of drugs through the skin by liquid crystallization of the longer lamellar structure. Importantly, these simple lipid models are useful for investigating microstructure of the intercellular lipids in the stratum corneum.Key words intercellular lipid; stratum corneum; synchrotron X-ray diffraction; lipid model; vaporized lmenthol The stratum corneum, as the outer skin layer, plays an important role in biological defense mechanisms, such as protection from bacteria and foreign matter intrusion and maintenance of moisture. The rigid arrangement of intercellular lipids, composed of ceramides (CERs), cholesterol (CHOL), free fatty acids (FFAs), and their derivatives, plays a major role in the barrier function of the tissue.1-3) Recent reports have shown that CER [EOS] is associated with the barrier function of the skin, while CER [NS] is related to water retention in the intercellular lipid structure of the stratum corneum. 4,5) CERs, CHOL, and FFAs, components of intercellular lipids, form the lipid bilayer, in which the hydrophobic groups face each other. 6)Small-angle X-ray diffraction has shown that there are two types of lamellar structures: a short lamellar structure with a repeat distance of about 6 nm, and a long lamellar structure with a repeat distance of about 13 nm.7-9) The observation of hydrocarbon chain packing by wide-angle X-ray diffraction has reveal hexagonal packing with a lattice distance of about 0.42 nm and orthorhombic packing with lattice distances of about 0.42 and 0.37 nm. [9][10][11] Although the majority of water is held in the stratum corneum of corneocytes, a portion of the water is taken into the intercellular lipid structure of the stratum corneum....