Liposomes have been proposed as carriers for the delivery of molecules to cells. They have been shown to enhance the efficacy of encapsulated drugs, prolonging the circulation time and reducing side effects. Moreover, the targeting of liposomes to desirable sites has been attempted. 1,2) In addition, a number of attempts have been made to develop functional liposomes, which can regulate the release of drugs responding to various stimuli, such as pH, [3][4][5][6] light 7,8) and temperature. 9-15)The liposomes injected into blood would be opsonized by serum components, and rapidly taken up by the reticuloendothelial system (RES) including the liver and spleen. [16][17][18][19][20] This is a major problem for researchers, because it is a significant disadvantage for the delivery of drugs to non-RES tissues. Moreover, some serum components have a destabilizing effect upon lipid vesicles and thereby cause leakage of liposomal contents. For example, high-density lipoprotein (HDL) is known to cause the disintegration of liposomes. 21,22) Yatvin et al. and Weinstein et al. reported an unique approach to controlling the release of drugs using temperaturesensitive liposomes in conjunction with local hyperthermia.9-11) The barrier efficiency of the membrane abruptly decreases near the gel-to-liquid crystalline phase transition temperature (T m ) of the phospholipid membrane. The temperature-sensitive liposomes have been designed to release a drug in response to local hyperthermia, during which a tumor was heated at temperatures of 41 to 45°C. Other strategies have been used for the production of temperature-sensitive liposomes. One example is the use of polymers, which are attached to the liposome to exhibit temperature-sensitivity and cause release of the internal content above a certain temperature. 14,15) In the development of the liposome, pharmaceutical scientists have been confronted with two difficulties. The first is how to prolong circulation time. Recently, the liposome surface has been modified with GM1 ganglioside 23) and polyoxyethylene derivatives, 24,25) which have some ability to escape the RES. The second is the problem regarding the stability of liposomes in systemic circulation after injection. In general, it is favorable for a drug delivery system (DDS) to have liposomes that are stable in the blood circulation, especially for chemotherapy and gene therapy. In addition, when trying to develop stimulus-sensitive liposomes, one should consider the influence of the serum components on the function of liposomes. Liu and Huang have observed that DOPEbased pH-sensitive liposomes lost their pH-sensitivity in the presence of serum. 26)Anionic lipids are frequently used in preparing liposomes for drug delivery. In the fluid state, negatively charged liposomes composed of phosphatidylglycerol (PG) interacted with serum components and caused an increase in the leakage of the encapsulated drug. 27) Therefore, it is necessary to investigate the effects of serum components on the temperature-dependent release propert...

Transdermal drug absorption includes several sequential processes, as follows: (1) drug absorption into the skin; (2) transfer from skin to cutaneous vein; (3) transport to systemic circulation by blood flow. In systemic therapy, it is necessary to transfer drug molecules from skin (application site) to cutaneous blood flow and to transport to the target organ through systemic circulation. [2][3][4][5][6][7] On the other hand, local therapy needs to accumulate drug molecules at the local site (skin, muscle and joint, etc.), but not to eliminate into the blood flow.2-7) Therefore, the evaluation of drug transfer properties into local blood flow would be expected to predict the systemic and local therapeutic effects.Previously, we have developed a method to investigate transdermal absorption processes in vivo, whereby the drug concentrations in skin, cutaneous vein and systemic vein are measured after iontophoretic delivery of drugs to rats. 8) Further, kinetic analysis of drug transfer from skin to cutaneous vein has been established by modifying a physiological pharmacokinetic model. 9) In the previous study, we investigated the effect of drug lipophilicity on the iontophoretic transdermal absorption of non-steroidal anti-inflammatory drugs (NSAIDs) such as salicylic acid, ketoprofen, naproxen and indomethacin.10) The transfer properties of these NSAIDs from skin to cutaneous vein decreased with an increase in their lipophilicity.The NSAIDs examined previously are acidic drugs with a carboxyl group. In the present study, b-blockers were selected as basic drugs having an amino group and included atenolol (AT), pindolol (PD), metoprolol (MP), acebutolol (AB), oxprenolol (OX) and propranolol (PP). The chemical structures and physicochemical properties are listed in Table 1. 11-13) These b-blockers are adequate for evaluating the effect of lipophilicity on transdermal absorption properties, because the molecular weights are of narrow range. As an indication of drug lipophilicity, we used the logarithm of n-octanol/buffer partition coefficient (Log P), which varied from Ϫ0.11 to 1.49 (pH 7.4, 37°C).12) The difference in the lipophilicity is a consequence of the difference in the aromatic substituents of the b-blockers.Beta-blockers are used in the treatment of hypertension, angina pectoris and cardiac arrhythmia.14) Because of their short elimination half-life (from several to less than 6 h), 15) sustained release formulations for oral administration have been developed to prolong the therapeutic effects.16-21) However, the oral absorption of b-blockers is influenced by hepatic first-pass metabolism. 15,22) Thus, the development of transdermal delivery systems may be expected to achieve good maintenance of optimal blood levels and the avoidance of first-pass effects. Anodal Iontophoresis Anodal iontophoresis was performed as described previously. 10) Briefly, male SpragueDawley rats (8-10 weeks old, Charles River Japan) were anesthetized with ether throughout the experiment, and their body temperature was maintained...

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