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This work describes the crystal structures of phenylbutazone 2:1 solvates with benzene, cyclohexane, 1,4-dioxane, tetrahydrofuran, tetrachloromethane, and chloroform. These solvates are isostructural, with the exception of the chloroform solvate. The solvent molecules are located in channels from which they can escape. Solvent incorporation causes an increase in volume of the unit cell to an extent that depends on the volume of the solvent molecule and the strength of the phenylbutazone-solvent interactions. The van der Waals interactions contribute most to the lattice energy in all these solvates. The volume available to the solvent correlates with the increase of the unit cell parameters. The quality of the crystallographic data of the chloroform solvate is poor as a result of twinning. Crystallographic differences of the chloroform solvate may result from hydrogen bonding between the chloroform molecules and the carbonyl oxygens of the phenylbutazone molecules.

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...

The in vivo elimination and tissue distribution (2 h after administration) of various types of formulations of alpha-tocopherol as a model drug were examined in rats. An organic cosolvents formulation of alpha-tocopherol (alpha-tocopherol/EtOH/polyethylene glycol 400) was rapidly removed from the blood circulation, the ratio of the distributed alpha-tocopherol was 20% in the lungs, about 70% in the liver and about 10% in the spleen. The main reason for this was considered to be the appearance of droplets more than 10 microns in diameter in the blood. Elimination of the micelle formulation using Brij58 from the blood was the most rapid, followed by Tween80 and HCO60. This order is thought to be due to the difference in the polyoxyethylene group among these surfactants. In liposome formulations, liposomes having a diameter of about 80 nm were the most stable in the blood circulation, and alpha-tocopherol was distributed in the reticuloendothelial system (RES) in the smallest ratio. The uptake of liposomes by the spleen and lungs depended on the liposome size. The uptake by the liver was in the decreasing order of 28 nm >> 42 nm, 151 nm, 195 nm, 3656 nm > 106 nm > 75 nm. The 100 nm lipid emulsion was eliminated from the blood more rapidly than the 100 nm liposome formulation.

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Several approaches to obtaining parenteral formulations for water-insoluble or poorly soluble drugs have been reported and dispersed systems for drug delivery such as emulsions, liposomes and nanospheres are improving all the time.1-12) For instance, diazepam recently became commercially available in a lipid emulsion form, 13,14) which was developed to reduce the incidence of local side effects after intravenous injection of conventional preparations of diazepam containing organic solvents. 7 ]nonyl)-3,7-dihydro-1H-purine-2,6-dione, see Fig. 1) is a newly synthesized adenosine A 1 -receptor antagonist. 15,16) Recently, it was reported that KW-3902 has potent diuretic and renal protective activities in rats and dogs. [17][18][19] Additionally, KW-3902 induces a diuretic effect in various models of acute renal failure in rats 20,21) and would be expected to have therapeutic value. In a previous study, 22) we developed a lipid emulsion of KW-3902 as an injectable formulation, because KW-3902 has a solubility of less than 1 mg/ml in water.However, intravenously injected emulsions and liposomes are rapidly captured by the reticuloendothelial system (RES) in organs such as the liver and spleen. [23][24][25][26][27] This is a major barrier to the delivery of drugs to non-RES tissues, and raises the specter that lipid emulsion formulations may affect the intrinsic therapeutic profiles of agents such as KW-3902 that targets the kidney.28) However, KW-3902 shows potent diuretic and renal protective activities even as a lipid emulsion. 21,29) In the present study, we have examined the influence of dispersed systems such as lipid emulsion or liposome on the pharmacokinetic profiles of KW-3902 and its main metabolite, M1 (Fig. 1). Moreover, to define the role of the lipid emulsion on the formulation of KW-3902, we investigated in vitro the binding to blood components of KW-3902 in each formulation. MATERIALS AND METHODSMaterials KW-3902 was synthesized at Kyowa Hakko Kogyo Co., Ltd. Egg yolk lecithin (containing 99% of phosphatidylcholine), oleic acid and concentrated glycerin were purchased from NOF Corporation (Tokyo, Japan). Soybean oil was purchased from the Nisshin Oil Mills, Ltd. (Tokyo, Japan). All other chemicals were of reagent grade and obtained from Kanto Chemical Co. (Tokyo, Japan).Lipid Emulsion Table 1 shows the formulation of the lipid emulsion of KW-3902 (Em-KW-3902). The preparation was described before.22) Briefly, KW-3902 was dissolved in soybean oil and mixed with egg yolk lecithin, oleic acid, concentrated glycerin and water for injection using a high-shear homogenizer (Model PVQS-1(3), Mizuho Industrial Co., Ltd., Osaka, Japan) at 8000 rpm for 15 min at 50°C. After adjustment of the pH to 7 with 1 N NaOH, the primary emulsion was passed through a microfluidizer (Model M-110EH, Microfluidics Corp., Newton, MA, U.S.A.) 5 times at 120 MPa. The emulsion was filtrated through a 0.22 mm Ultipor filter (Pall Corp., East Hills, NY, U.S.A.), then packaged in 10 ml ampules (Type 1 glass) and sealed after nitrogen...