Relationships between skin permeability and physicochemical properties of drugs were examined to establish a predictive method for the steady-state permeation rate of drugs through human skin. Human skin permeation properties fell into two categories: one in which the permeability coefficient is correlated to the partition coefficient, revealed with lipophilic drugs; and the other in which the permeability coefficients are almost constant, shown with hydrophilic drugs. The stratum corneum, the main barrier in skin, could be considered as a membrane with two parallel permeation pathways: lipid and pore pathways, and an equation for predicting the steady-state permeation rate of drugs was derived. The skin permeabilities of drugs for man were compared with those for hairless rat. The species difference in skin permeability found was suggested to be due to the difference in skin permeation pathways, since lipid content and water uptake of the stratum corneum varied between human and hairless rat skin.
Pravastatin, one of the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) widely used in the management of hypercholesterolaemia, has unique pharmacokinetic characteristics among the members of this class. Many in vivo and in vitro human and animal studies suggest that active transport mechanisms are involved in the pharmacokinetics of pravastatin. The oral bioavailability of pravastatin is low because of incomplete absorption and a first-pass effect. The drug is rapidly absorbed from the upper part of the small intestine, probably via proton-coupled carrier-mediated transport, and then taken up by the liver by a sodium-independent bile acid transporter. About half of the pravastatin that reaches the liver via the portal vein is extracted by the liver, and this hepatic extraction is mainly attributed to biliary excretion which is performed by a primary active transport mechanism. The major metabolites are produced by chemical degradation in the stomach rather than by cytochrome P450-dependent metabolism in the liver. The intact drug and its metabolites are cleared through both hepatic and renal routes, and tubular secretion is a predominant mechanism in renal excretion. The dual routes of pravastatin elimination reduce the need for dosage adjustment if the function of either the liver or kidney is impaired, and also reduce the possibility of drug interactions compared with other statins. which are largely eliminated by metabolism. The lower protein binding than other statins weakens the tendency for displacement of highly protein-bound drugs. Although all statins show a hepatoselective disposition, the mechanism for pravastatin is different from that of the others. There is high uptake of pravastatin by the liver via an active transport mechanism, but not by other tissues because of its hydrophilicity, whereas the disposition characteristics of other statins result from high hepatic extraction because of high lipophilicity. These pharmacokinetic properties of pravastatin may be the result of the drug being given in the pharmacologically active open hydroxy acid form and the fact that its hydrophilicity is markedly higher than that of other statins. The nature of the pravastatin transporters, particularly in humans, remains unknown at present. Further mechanistic studies are required to establish the pharmacokinetic-pharmacodynamic relationships of pravastatin and to provide the optimal therapeutic efficacy for various types of patients with hypercholesterolaemia.
Skin age is one of the biological factors affecting percutaneous absorption. 1,2) To regulate the therapeutic efficacy of transdermal drug delivery, the difference in skin permeability at various ages is a subject of considerable importance. We previously reported that the permeability through the skin decreases with aging, 3,4) and that the extent of this decrease is higher for lipophilic permeants than for hydrophilic permeants. 4) We clarified that the thickness of skin strata is an important factor for limited percutaneous absorption in aging. However, other physiological changes in the skin with age, e.g., moisture content in the skin, lipid composition, lipid content, dermis thickness, and density of skin appendages, have been also reported. [5][6][7][8] Therefore the age-related differences in the skin barrier function must be further investigated based on physiological alterations in the skin to elucidate the mechanisms of the age dependency of transdermal absorption of drugs.There have been many reports on age-related changes in the transdermal permeation of drugs, 3,4,[6][7][8][9] however, age-related changes in skin permeability have not been fully interpreted because of large interindividual variance and the limited number of model permeants. Recently, it was reported that impedance parameters can sensitively reflect the properties of skin permeation pathways. [10][11][12] The impedance technique enables us to determine rapidly changes in skin physical properties, and one measurement provides information on pathways for both hydrophilic and lipophilic permeants. Therefore skin impedance analysis may be a useful method to elucidate the skin barrier function at different ages.In the present study, we attempted to apply impedance analysis to investigate age-dependent changes in permeation pathways of rat skin. In vitro skin impedance data of rats at various ages were compared. Physiological characteristics of the skin, e.g., the water and lipid content of the stratum corneum and the thickness of the skin strata, were also evaluated. Finally, we demonstrated the age dependency of relations between these electrical and physiological properties. MATERIALS AND METHODS AnimalsMale STD: Wistar rats at the age of 5, 10, 21, 90, and 180 d (Japan SLC Inc., Hamamatsu, Japan) were used. Rats were fed commercial food pellets and tap water ad libitum. Under sodium pentobarbital anesthesia (50 mg/kg, i.p.), a round section of the abdominal skin was excised, and then the subcutaneous fat and other extraneous tissue were trimmed off carefully. The skin sample was immediately used in the following skin impedance experiments.Skin Impedance Measurement and Analysis A sideby-side, two-chamber electrochemical cell with four electrodes, two for supplying current and two for recording signals, was designed according to the procedure of Burnett and Bagniefski.11) The rat skin was mounted in an O-ring seal between the two chambers, each having 23 ml volume and 1 cm 2 exposed area. The current-supplying electrode consisted of 0....
The aim of the present study was to assess the potential of biocompatible polymeric nanosheets as topical and transdermal drug-delivery devices. Nanosheets are two-dimensional nanostructures with a thickness in the nanometer order, and their extremely large aspect ratios result in unique properties, including high transparency, flexibility, and adhesiveness. Nanosheet formulations containing betamethasone valerate (BV) as a model drug and consisting of poly (L-lactic acid) or poly (lactic-co-glycolic) acid were fabricated through a spin-coating-assisted layer-by-layer method using a water-soluble sacrificial membrane. The fabricated formulations could incorporate and release higher amounts of BV compared with a commercial ointment, and the amounts could be controlled by the polymers used, the amount of BV added, and the use of controlled-release membranes. The presence of BV had a minimal effect on thickness, transparency, adhesiveness, and moisture permeability of nanosheets, permitting their application to any area of skin for a long period of time. Therefore, this biocompatible polymeric nanosheet formulation represents a novel and promising topical and transdermal drug delivery device, which has potential to deliver drugs regardless of the area of skin.
Polycationic compounds, such as poly-L-arginine and poly-L-ornithine (PLO), enhance the nasal absorption of hydrophilic macromolecular drugs. However, the bio availability corresponding to the dose of these enhancers has not been obtained in an open system study, where an administered solution is transferred to the pharynx because they do not exhibit mucoadhesion/retention in the nasal cavity. In this study, we prepared PEGylated-poly-L-ornithine (PEG-PLO) and investigated the effects of PEGylation on in vitro adhesion/retention properties, permeation enhancement efficiency, and cytotoxicity. PEG-PLO bearing 3-4 polyethylene glycol (PEG) chains per PLO molecule was more retentive than unmodified PLO on an inclined plate. The permeability of a model drug, FD-4, across Caco-2 cell sheets was enhanced by PEG-PLO as well as by PLO. PLO showed cytotoxicity at high concentrations, whereas PEG-PLO did not decrease cell viability, even above the concentration giving a sufficient enhancement effect. These findings suggest that PEGylation of polycationic absorption enhancers improves their adhesion/retention and decreases their cytotoxicity, which may lead to enhancers with greater utility.Key words poly-L-ornithine (PLO); polyethylene glycol (PEG); permeation enhancer Bioactive peptides, such as insulin, teriparatide, liraglutide, and somatropin, have been used widely as therapeutic drugs because of their intrinsic and effective activities, however, they have poor permeability across the epithelium because they are hydrophilic macromolecules. Orally administered peptides are often inactivated in the gastrointestinal tract, and thus peptides are usually administered as injectable formulations. However, injection can result in poor compliance because it is painful and burdensome. 1) Therefore, alternative routes of administration are required.The nasal mucosa has a large surface area for absorption because of its villus structure. Drugs absorbed across the nasal mucosa avoid the hepatic first pass effect because of the abundant vasculature under the nasal mucosa.2) The intranasal route is effective for absorbing high molecular weight drugs 3) and is usually not painful. Therefore, intranasal administration is an important alternative route to injection for peptides and proteins.Polycationic compounds, such as poly-L-arginine (PLA), poly-L-lysine, and poly-L-ornithine (PLO), enhance the transmucosal absorption of hydrophilic macromolecules.4,5) PLA enhances the paracellular permeability of rabbit nasal mucosa and Caco-2 cell sheets reversibly.6,7) The absorption of hydrophilic macromolecules across the nasal mucosa in rats is also increased by co-administration with PLA. 8) PLA enhances the permeability by altering the localization of tight junction proteins from the cell-cell junction to the intracellular space without causing cytotoxicity. 9) Therefore, polycationic absorption enhancers are useful in developing efficient transmucosal drug delivery systems.Nevertheless, it is difficult to increase the bioavailability of dr...
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