Lipid Microspheres and Lecithinized-Polymer Drug Delivery Systems

Chapter 23

Lipid Microspheres and Lecithinized-Polymer Drug Delivery Systems Y. Mizushima and R. Igarashi

Downloaded by PRINCETON UNIV on July 2, 2013 | http://pubs.acs.org Publication Date: August 15, 1991 | doi: 10.1021/bk-1991-0469.ch023

Institute of Medical Science, St. Marianna University, Kawasaki 216, Japan

Prostaglandins and some bioactive polypeptides are autacoids which are produced and act locally in the body as needed. The use of drug delivery systems in the treatment of diseases by these drugs may become necessary to achieve the needed pharmacokinetics. Lipid microspheres with an average diameter of 0.2μ resemble liposomes in terms of tissue distribution. They accumulate in the reticuloendothelial organs, inflamed tissues and particularly vascular lesions. In our studies, we have determined the distribution of the lipid microspheres in the vascular lesions. They accumulate in subendothelial space through the gaps of endothelial cells of arteriosclerotic and inflamed vessels. The lipid microspheres are much more stable than liposomes and can be mass produced for commercial use. Moreover, there is no toxicity associated with the use of a large amount of lipid microspheres. Prostaglandin E , the methyl ester of isocarbacyclin, and some anti-inflammatory drugs were incorporated in lipid microspheres, and it was found that these lipo preparations were significantly superior to each free drug in term of efficacy and safety not only in basic studies but also in clinical trials. Bioactive peptides which could not be incorporated into lipid microspheres were conjugated with a modified lecithin. It was found that the tissue distribution of these lecithinized peptides was somewhat similar to lipo preparations. It is considered therefore that lecithinization of bioactive proteins may be one approach to developing drug delivery systems for these peptides. 1

When we use a hormone as a drug, we can give it systemically. It enters into the blood stream and acts physiologically and pharmacologically as it is acting in the body. Contrary, autacoids such as prostaglandins and superoxide dismutase are 0097-6156/91/0469-0266$06.00/0 © 1991 American Chemical Society

In Polymeric Drugs and Drug Delivery Systems; Dunn, R., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1991.


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produced locally in the body and act also locally for their own purposes, and they are rapidly inactivated when they enter systemic circulation to avoid side effects. Therefore, when they are injected systemically, accumulation of these active substances into a diseased site is not satisfactory, and systemic side effects may occur. Therefore, a certain type of drug delivery system is needed for systemic administration of these drugs. Prostaglandin E j (PGEj) and prostacyclin ( P G I 2 ) are known to be very valuable for the treatment of many arteriosclerotic diseases if they can be free from adverse reactions. 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 P G E j and a P G I derivative into l i p i d microspheres, and the tissue distribution and clinical effectiveness of these lipopreparations were studied. Bioactive peptides such as superoxide dismutase and interferon are 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. 2

Experimental and Results Preparation of lipid microspheres. The lipid microspheres (lipo-PGEi) with a diameter of 0.2 to 0.3 μ m are 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 P G E j . Glycerol was added to make the water phase isotonic. Isocarbacyclin, a prostacyclin derivative (TEI9090), was incorporated into the lipid microspheres (lipo-PGI ) in a similar composition except for the use of oleic acid. 2

Tissue distribution of lipo-preparations. The tissue distribution of l i p i d 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 l i p i d


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POLYMERIC DRUGS AND DRUG DELIVERY SYSTEMS


Prostaglandin

Soybean oil

0.2/im

Figure 1. A model of lipo-PGE . 1

Table I. Composition of Lipo-PGE}

Prostaglandin E 2 Soybean oil Egg yolk phospholipids Oleic acid Glycerol Water for injection

5 μg 100 mg 18 mg 2.4 mg 22.1 mg q.s. Total volume

1 mL

pH: 4.5-6.0 Osmolality: 280-300 mOsm Particle size: 200-300 nm in diameter Shelf life: 12 months at cold room



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microspheres by incorporating a radiolabeled compound. The third is scintigraphic clinical assessment of technetium-labelled lipid microspheres. We injected lipid microspheres intravenously into SHR (spontaneously hypertensive rats), and then examined them by electron microscope (3). Many lipid microspheres accumulated below the vascular endothelium in the arterial lesions of SHR which had lesions similar to arteriosclerosis. In contrast, lipid microspheres did not accumulate in subendothelial spaces in normal rats or SHR before the development of vascular lesions. We investigated the delivery of lipid microspheres to atherosclerotic lesions induced by cannulation in rabbits. Many lipid microspheres, which passed through the gaps between the endothelial cells, accumulated below the endothelium at the site of atherosclerotic lesions (3). When lipid microspheres incorporating radiolabelled palmitate ester were injected, radioactivity in the atherosclerotic vascular wall was about double the level in normal sites (3). Nakura et al. similarly studied the distribution of radioactivity in SHR, and found that lipo-PGEj accumulated at the site of pathologic lesions at higher concentrations than free PGEj (4). Technetium-labelled lipid microspheres were given to patients with A S O (arteriosclerosis obliterans) by intravenous injection, followed by scintigraphy. Technetium accumulated at the sites corresponding to the atherosclerotic lesions (5). Clinical studies on l i p o - P G E . After several phase 2 clinical studies were completed (6,7), controlled multicentered trials of lipo-PGEj were conducted (Table II). In all diseases tested, lipo-PGEj was significantly more useful than P G E j CD (cyclodextrin) or other reference standard. A cold feeling in the extremities, numbness, paresthesia, and pain were very responsive to lipo-PGEj. The size of the ulcers which could be assessed objectively was measured in a blind manner. Ulcer lesions associated with collagen diseases regressed significantly within a week of daily treatment with lipo-PGEi. After 4 weeks of treatment, the difference from the control group was significant (8). One double-blind study demonstrated a better safety profile for lipo-PGEj than for placebo. There have been many sporadic reports that lipo-PGEj is effective in fulminant hepatitis, neuralgia associated with herpes zoster, multiple spinal canal stenosis, cerebral infarction, myocardial infarction, chronic renal failure, and bed sores as well as for its registered indications. Lipo-PGEj was reported to be 10 to 20 times more effective than P G E j in the treatment of ductus dependent congenital heart diseases. It can be used at much lower doses, and accordingly, adverse reactions are reduced (9). The drug is approved for this indication, and has already been used safely in many patients. 1

L i p o - P G I . Prostacyclin (PGI ) is more potent than P G E j in antiplatelet and antithrombotic effects, and is expected to be very useful in the treatment of various thrombotic diseases (10,11). However, it causes more adverse reactions, such as hypotension and facial flushes, because of its vasodilation and possible suppression of feed-back mechanisms. Many attempts at clinical applications have failed. We have conducted studies on methylated TEI9090 (Figure 2), a chemically stable and 2

2


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POLYMERIC DRUGS AND DRUG DELIVERY SYSTEMS

Table Π. Summary of Clinical Results on Lipo-PGEj 1.

Arterial-duct-dependent congenital heart disease

Lipo-PGEj PGE CD r


2.

No. of Patients

Efficacy

83 (historical)

94.0% 50-70%

Dose 5 ng/kg/min 50-100 ng/kg/min

30.1% 70-80%

Buerger's disease plus arteriosclerosis obliterans (double blind trial) No. of Patients

Lipo-PGE! IHN

62 62

Adverse Reaction**

Improvement* Dose 59.7% 40.3%

10 μ g/day/4 weeks iv 9.4% 1200 mg/day/4 weeks po 6.3% *p

Lipid Microspheres and Lecithinized-Polymer Drug Delivery Systems

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