Lipid microspheres

Figure 1. Structure of liposomes and lipid microsphere a), multilamellar vesicle b). unilamellar vesicle c). lipid microsphere. Symbols inside the microsphere indicate di- and tri-acyl glycerol.

Lipid Microspheres and Lecithinized-Polymer Drug Delivery Systems... 

MIZUSHIMA IGARASHI Lipid Microspheres and Lecithinized Peptides 267... 

An excellent carrier is needed to deliver a sufficient amount of prostaglandins to the diseased site. Liposomes have been studied for a long time as possible drug carriers. However, the clinical use of liposomes has delayed because of some difficulties in mass production, sterilization, stability and safety. Since 1980 we have attempted to use lipid microspheres (lipid emulsions) instead of liposomes as a better carrier for lipophilic drugs (7). 

In this study we incorporated PGEj and a PGI2 derivative into lipid microspheres, and the tissue distribution and clinical effectiveness of these lipo-preparations were studied. 

Bioactive peptides such as superoxide dismutase and interferon arc also hoped to be accumulated in the inflamed and vascular lesions. However, these active peptides cannot be incorporated in lipid microspheres. Instead of incorporating them into lipid microspheres, we devised a method to combine the bioactive peptides with a chemically modified lecithin. In this study, we also examined the tissue distribution of lecithinized IgG. 

Preparation of lipid microspheres. The lipid microspheres (lipo-PGEj) with a diameter of 0.2 to 0.3 p m arc prepared from the drug, soybean oil and lecithin (Figure 1). The drug to be enclosed in the microspheres is first dissolved in soybean oil, and then emulsified with lecithin by a Manton-Gaulin homogenizer (7,2). 

Table I shows the composition of lipo-PGEj. Oleic acid was used to improve the stability of PGEj. Glycerol was added to make the water phase isotonic. Isocarbacyclin, a prostacyclin derivative (TEI9090), was incorporated into the lipid microspheres (lipo-PGI2) in a similar composition except for the use of oleic acid.

Tissue distribution of lipo-preparations. The tissue distribution of lipid microspheres in normal and pathologic animals was studied. Research into liposomes of similar size suggested that lipid microspheres accumulated preferentially in the reticuloendothelial system, inflammatory sites, or certain tumors. The distribution of lipid microspheres to these tissues has been found in our studies (7,2). Interestingly, our study showed that lipid microspheres accumulated, particularly at high concentrations, in damaged vascular walls such as atherosclerotic vascular walls. 

Accumulation of lipid microspheres at the site of vascular lesions can be evaluated by three methods. First, electron microscopy can be used to examine the site of tissue damage. The second method is to follow the delivery of lipid... 

Technetium-labelled lipid microspheres were given to patients with ASO (arteriosclerosis obliterans) by intravenous injection, followed by scintigraphy. Technetium accumulated at the sites corresponding to the atherosclerotic lesions (5). 

Lipid microspheres were used instead of liposomes as a carrier of lipophilic drugs in this study. Because the outside layer of liposomes and lipid microspheres is lecithin the distribution into the body was expected to be similar. 

A large amount of lipid microspheres has been used under the name of Intralipid for almost 50 years and we used only 1 mL of it for DDS. Therefore, there was no problem with regard to safety, stability, sterilization and mass production. 

It was found in animal and clinical studies that lipid microspheres accumulated particularly in arteriosclerotic and damaged vessel walls. Earlier studies (16,17) of lipid emulsions demonstrated also that lipid microspheres had an affinity to vascular walls, including capillaries, like chylomicrons. Shaw et al. reported that they had... 

Of the various pharmacological actions of PGEj and PGI2, one action which has not yet been studied intensively, but seems to be important for the treatment of arteriosclerotic diseases, is their effect on vascularization. This suggests the need to determine if lipid microspheres accumulate at the site of vascularization. We are now conducting a study to investigate this possibility. Since the space between endothelial cells in new blood vessels is as big as that of vessels with sclerosis or inflammation, lipid microspheres are very likely to accumulate in new blood vessels. Figure 4 shows a schema of the distribution and accumulation of lipid microspheres at the site of vascular lesions. 

Takenaga, M., Application of lipid microspheres for the treatment of cancer, Advanced Drug Delivery Review, 1996, 20, 209-219. 

Inoue, K., Aoki, Y., Hayashi, M., Kitahara, S., Tanabe, H., Kiyoki, M., and Araki, H., Ex vivo anti-platelet effects of isocarbacyclin methyl ester incorporated in lipid microspheres in rabbits, Arzneim-Forsch/Drug Research, 1995, 45, 980-984. 

Yamaguchi, T. and Mizushima, Y. (1994) Lipid microspheres for drug delivery from the pharmaceutical viewpoint. Crit. Rev. Drug Carrier Systems, 114 215-229. 

Emulsions and suspensions are colloidal dispersions of two or more immiscible phases in which one phase (disperse or internal phase) is dispersed as droplets or particles into another phase (continuous or dispersant phase). Therefore, various types of colloidal systems can be obtained. For example, oil/water and water /oil single emulsions can be prepared, as well as so-called multiple emulsions, which involve the preliminary emulsification of two phases (e.g., w/o or o/w), followed by secondary emulsification into a third phase leading to a three-phase mixture, such as w/o/w or o/w/o. Suspensions where a solid phase is dispersed into a liquid phase can also be obtained. In this case, solid particles can be (i) microspheres, for example, spherical particles composed of various natural and synthetic materials with diameters in the micrometer range solid lipid microspheres, albumin microspheres, polymer microspheres and (ii) capsules, for example, small, coated particles loaded with a solid, a liquid, a solid-liquid dispersion or solid-gas dispersion. Aerosols, where the internal phase is constituted by a solid or a liquid phase dispersed in air as a continuous phase, represent another type of colloidal system. 

Emulsions (lipid microspheres) Colloid-sized emulsion droplets are used in drug delivery to solubilize... 

Murthy TH, Weissman NJ. The advanced echocardiographic contrast agent Definity (perflutren lipid microspheres). Today s Ther Trends 2002 20 233 1. 

QF14 Preparation of lipid microspheres Imaging agent Injectable 355-42-0 May 2002/ Imcor PH... 

Definity (perflutren lipid microsphere) by Bristol-Myers Squibb ... 

Yui, N., Okano, T., and Sakurai, Y. (1993) Photo-responsive degradation of heterogeneous hydrogels comprising crosslinked hyaluronic acid and lipid microspheres for term-poral drug delivery, J. Contr. Rel., 26, 141-145. 

Recently, EHEC and other hydrocolloids were used for the stabilization of lipid microspheres. The coating reduced the zeta potential of the liposomes to a neutral value and decreased their surface fluidity, as measured by fluorescence... 

T. Yamaguchi, Lipid microspheres as drug carriers A pharmaceutical point of view, Adv. Drug Deliv. Rev., 20(2-3), 117-130(1996). 

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