Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Patent
1997-01-07
1999-04-27
Page, Thurman K.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
424472, 424491, A61K 964
Patent
active
058978798
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The invention relates to sustained-release pharmaceutical delivery system comprising a low molecular weight antioxidant drug in combination with a polymeric matrix, in various dosage forms.
BACKGROUND OF THE INVENTION
In the last decade the role of oxygen free radicals as well as other oxygen reactive metabolites has been at least somewhat elucidated. These reactive metabolites are today considered to be responsible for oxidative toxicity Gutteridge, J. M. C. (1989) Free Rad. Biol. Med. (2nd ed.) Clarendon Press, Oxford; Halliwell, B. (1989) Br. J. Exp. Path. 70: 737-752!.
Free radicals are defined as an atom, group of atoms or molecule which contain at least one unpaired electron in their outer shell. The oxygen molecule itself, containing two unpaired electrons is, by definition, a free radical (.sup.3 .SIGMA..sub.g O.sub.2 --biradical), although it is not a reactive one due to the arrangement of its spins it its outer shell. Reduction of the oxygen molecule is a process which does not require changes in the spin direction of movement and therefore can be easily performed.
The complete reduction of the oxygen molecule results, at the first stage, in the production of the ion radical superoxide (O.sub.2.sup.-), followed by the production of hydrogen perxide (H.sub.2 O.sub.2) which is not a free radical, although a reactive species. Addition of another electron to the hydrogen peroxide leads to the production of the hydroxyl radical (1989) ibid.!. In this system which contains cytochrome oxidase, the oxygen is reduced in stages. During the reduction of the oxygen molecule, active metabolites are produced. These active oxygen species can leak to the immediate surroundings and may cause biological damage.
The production of oxygen reactive metabolites is not unique to the mitochondria organ, but occurs also in many other systems. Phagocytes, for example, are known for their ability to produce the superoxide radical and other species which participate in the defence mechanism against invaders although necessary, can also lead to biological damage in the surrounding environment. Production of the superoxide radical has been identified in liver Kupffer cells, in monocytes, basophyls, eosinofils and mast cells. In some genetic disorders, such as chronic granulomatosus disease (CGD), the phagocytes are incapable of producing the oxygen radicals and consequently the patients suffer from recurring infections which can lead Another source for free radicals are enzymes. During their catalytic activity many enzymes such as prolyl hydroxylase, lipoxygenase and (1989) ibid.!.
Amongst the diseases in which free radicals have been shown to play an important role in the initiation and pathogenesis, one can find chronic inflammation, autoimmune diseases such as Hashimoto's thyroiditis, systemic lupus erythematosus, myasthenia gravis, chronic autoimmune Res. Comms. 19: 141-158!. Release of a free radicals efflux by the phagocytes can increase the severity of these diseases. This is the case, for example, in rheumatoid arthritis which is characterized by chronic inflammation of the joints. In this disease, the production of the inter-joint fluid is normal, but its viscosity is changed. The major constitutent of the inter-joint fluid, hyaluronic acid, is broken down Gutteridge (1989) ibid.!.
It has been proposed that free radicals are involved in the damage caused to the brain in brain degenerative diseases such as epilepsy, Parkinson's disease, Wilson's disease (the excess of copper in this disorder causes the transformation of the superoxide radical into a more reactive species, the hydroxyl radical, in the metal-mediated Haber-Weiss reaction) has also been suggest that free radicals are involved in eye diseases such Rad. Biol. Med. 3: 371-377!.
It has recently been demonstrated that oxygen driven free radicals play an important role in the post-ischemic damage to various biological tissues such as heart and brain. It has further been suggested that these metabolites take part in the aging process a
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Friedman Michael
Kohen Ron
Page Thurman K.
Shelborne Kathryne E.
Yissum Research Development Co. of the Hebrew University of Jeru
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