A low absorption in the gastrointestinal tract of hydrophobic pharmaceutical compounds in use today considerably limits their bioavailability and therefore they are taken in large doses in order to reach the therapeutic plasma concentration, which inevitably results in undesired side effects. In this study, we demonstrate a new nanoparticle approach to overcome this problem and our experimental results show that this approach has a high efficiency of drug loading and is easily adaptable to industrial scale. Characterization of nanoparticles containing a cholesterol-lowering hydrophobic drug, probucol, using a variety of biophysical techniques revealed higher homogeneity of these particles compared to those prepared using other approaches. Intermolecular interactions of these nanoparticles are probed at a high-resolution by magic angle spinning solid-state NMR experiments.
Pentazocine (PTZ), a narcotic-antagonist analgesic, has been widely used in the management of patients with postoperative pain or initial carcinogenic pain. However, PTZ has a number of severe drawbacks, such as a short half-life of 2 to 3 h, 1) and low oral bioavailability of about 20% due to an extensive first-pass effect, thus leading to wastage of the dose. 2)A transdermal drug delivery system (TDDS) has many advantages over conventional modes of drug administration, in particular the avoidance of hepatic fast-pass metabolism, a reduction in the frequency of drug administration, and an improvement of patient compliance.3) Thus, transdermal administration is a potential approach to overcoming these problems with PTZ treatment. A TDDS consists of several components, including the active ingredient, a pressure-sensitive adhesive (PSA), a permeation enhancer, backing membrane and so on. A PSA fulfills the adhesion-to-skin function and serves as the formulation foundation. Because the physicochemical properties of PSA significantly affect the permeation rate of a drug across the skin, the selection of an appropriate PSA matrix is of importance in designing a TDDS. 4,5) Permeation enhancers can overcome the intrinsic resistance of the stratum corneum, which results in an increase in the flux of the active ingredient. 6)We have previously reported the effects of glyceryl monocaprylate (GEFA-C 8 ) as an enhancer of skin permeation of PTZ from isopropyl myristate (IPM) solution across excised hairless mouse skins. 7,8) The PTZ flux was about four times greater with a combination of both GEFA-C 8 and IPM, than with IPM alone.In the present study, therefore, we tried to design a monolithic adhesive matrix-type patch, which is the simplest among the various patches used in the present study. PTZ patches were prepared using different polyacrylate copolymers, and both IPM and GEFA-C 8 were incorporated in the patch. First, the effect of different PSAs on the release rate of PTZ from TDDS patches was investigated using a shaking method. We also evaluated the effect of IPM and GEFA-C 8 on the PTZ flux from TDDS patches using Franz diffusion cells fitted with excised hairless mouse skin. MATERIALS AND METHODSMaterials PTZ was purchased from Kobayashi Kako Co., Ltd. (Fukui, Japan). Isopropyl myristate (IPM) was purchased from Wako Pure Chemical Industries, Ltd. (Osaka, Japan). Glyceryl monocaprylate (GEFA-C 8 , Sunsoft ® 700P-2) was gifted from Taiyo Kagaku Co., Ltd. (Mie, Japan). Acrylic PSA solutions in organic solvents, Duro-Tak ® 87-9301, 87-2677, 87-201A, 87-2196 and 87-2852 were kindly gifted from the National Starch and Chemical Company (Bridgewater, NJ, U.S.A.). All other solvents and reagents were commercial products of analytical grade and were used without further purification.Preparation of Patches Preparation of patches was carried out by a minor modification of the method of Buchi et al.9) Appropriate amounts of the adhesive PTZ and enhancers were mixed and sonicated. The mixed PSA solution was cast at a thickne...
High cholesterol levels (or hypercholesterolemia) are linked with many diseases, particularly with the risk of coronary heart diseases. Probucol is commonly used to reduce cholesterol in blood. While the effectiveness of this drug highly depends on its solubility, unfortunately, it is nearly insoluble (solubility is 5 ng/mL in water). Therefore, it is essential to develop approaches to increase its solubility and bioavailability and to enhance the efficiency of the drug. Here we show that a new method increases the solubility of probucol in water and its ability to permeate cell membranes. This new method of processing the drug in a nanoparticle utilizes the grinding of PBC probucol together with sodium dodecylsulfate and methacrylic copolymer. Solid-state NMR experiments reveal the polymorphic state of probucol and the conversion of this drug from crystalline to the amorphous state, and determine its nearness to the copolymer due to the grinding process that enables the formation of nanoparticles.
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