Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ortho-hydroxybenzoic acid or derivative doai
Patent
1998-01-27
1999-02-23
Henley, III, Raymond
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ortho-hydroxybenzoic acid or derivative doai
514570, A61K 3160, A61K 3119
Patent
active
058744223
DESCRIPTION:
BRIEF SUMMARY
This is a 371 of PCT/EP96/01936 filed May 9, 1996.
SUBJECT OF THE INVENTION
The invention relates to the subjects that are characterized in the claims, i.e., the use of nonsteroidal anti-inflammatory agents to improve the physiological compatibility of particulate pharmaceutical agent preparations.
PRIOR ART
Particulate pharmaceutical preparations, such as, e.g., liposomes, magnetites, cavisomes, nanoparticles, etc., have in recent years gained increasing importance in both diagnosis and therapy. Some of these particulate systems, especially liposomes and cavisomes, can in turn be suitable as vehicle systems for transporting diagnostically significant compounds, such as, e.g., contrast media or therapeutically usable substances, such as, e.g., gentamicin (INN). (Seltzer, S.: Liposomes in Diagnostic Imaging, in: Gregoriadis, G. (ed.), Liposomes as Drug Carriers, J. Wiley & Sons, Ltd., Chichester, New York, Brisbane, Toronto, Singapore, 1988).
After intravenous administration, such particulate vehicle systems are concentrated preferably in the organs of the mononuclear phagocyte system (RES), whereby the highest concentrations were reached in the liver and spleen (Krause, W. et al., J. Liposome Research 1995; 5:1-26).
WO88/09165 describes injectable aqueous liposome preparations with iodine-containing x-ray contrast media, as well as a process for the production of corresponding formulations. Owing to the sizes (0.15-0.3 .mu.m), as well as the high contrast medium inclusions (iodine/lipid quotient 1.5-6), these formulations are especially suitable for visualizing the liver.
Very high dosages, which may very well be in the order of magnitude of 10 g of lipid and more, are necessary especially for the particulate formulations that are used in diagnosis, and here again mainly for the preparations that are used in diagnostic radiology (standard x-ray, but also computer tomography). The result is strong activation of the reticuloendothelial system (RES) and other defense mechanisms. This can result in, i.a., the reactions described below: a drop in the mean and arterial blood pressure and peripheral resistance, and an increase in heart rate, contractility, cardiac output, and pressure in the pulmonary circulation.
Waddel et al. (J. Lab. Clin. Med. 1955; 45:697-710) describe these side-effects in patients after injection of lipid emulsions as follows: reddening of the skin, sensation of warmth in the face and on the neck, agitation, sensation of stenosis or pressure in the chest area, cyanosis, and strong back pains. The administration of antihistamines is not able to eliminate or mitigate these side-effects.
Behan et al. (AJR 1993; 160:399-405) observed a similar side-effect spectrum after an emulsion of perfluorooctylbromide was infused. Although it was possible to alleviate these effects with hydrocortisone, this compound is not used for computer tomography because of the high risk of side-effects. Similar results were described by Vercelloti et al. (Blood 1982; 59:1299-1304).
Rabinovici et al. (Circ. Shock 1990; 31:431-445) speculate that the undesirable effects of liposomes with encapsulated hemoglobin are attributable to the release of PAF (platelet-activating factor), and they attempted--successfully--to inhibit them by administering a PAF antagonist.
After administration of diatrizoate-containing liposomes to patients with Hodgkins lymphoma, cirrhosis of the liver, or liver tumors, Rosenberg et al. (Vestn. Rontgenol. Radiol. 5:35-8, 1993) describe side-effects such as elevated temperature and fever in 30% of the patients. It was possible to reduce or eliminate these effects by pretreatment with prednisolone (INN) and pipolphen.
It has now been found, surprisingly enough, that a direct addition of nonsteroidal anti-inflammatory agents to particulate formulations not only can reduce the undesirable effects on the cardiovascular system, but can even completely prevent them.
This is especially surprising because the side-effects without addition of nonsteroidal anti-inflammatory agents begin immediately
REFERENCES:
Cancer Immunol. Immunother. vol. 36, No. 1 pp. 45-51, 1993.
Krause Werner
Muschick Peter
Henley III Raymond
Schering Aktiengesellschaft
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