Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Liposomes
Reexamination Certificate
1999-06-07
2001-11-06
Slobodyansky, Elizabeth (Department: 1652)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Liposomes
C424S094400, C435S189000
Reexamination Certificate
active
06312720
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to the use of superoxide dismutase (SOD), preferably of recombinant human SOD, in liposomes, for the preparation of pharmaceutical compositions, optionally mixed with hyaluronic acid and/or at least one physiologically acceptable carrier and/or other optional additives, for therapeutic and/or prophylactic use against increased concentration of superoxide radicals and/or damage caused thereby. More in particular, the present invention relates to the use of human SOD packed within liposomes in the treatment of human fibrotic tissue degeneration diseases, including induratio penis plastica (IPP), also commonly known as Peyronie's Disease.
2. Discussion of Related Art
Superoxide radicals are extremely reactive intermediate forms of the natural oxygen molecule and, as a result of this property, can irreversibly damage organic compounds in the cells of the human body. As protection from the dangerous effect of these superoxide radicals, the cells have an enzyme which is capable of rapidly converting such superoxide radicals into the more rapidly metabolizable and less toxic hydrogen peroxide (H
2
O
2
).
Thereafter, the hydrogen peroxide, which is still toxic, is usually decomposed by the enzyme catalese into the harmless components water and oxygen.
The enzyme superoxide dismutase (SOD) occurs both in the human and animal body and in plants and presumably in all microorganisms which come directly into contact with atmospheric oxygen (aerobic bacteria and fungi). In the cells of higher organisms (eucaryotes), there are mainly two types of this SOD: a manganece-containing SOD which is localized in the mitochondria and is very similar to the bacterial SOD, and a second one which is present freely in the cytosol and contains copper and zinc atoms.
Unless stated otherwise, the term SOD is to be understood below as meaning mainly Cu,Zn-SOD except for that from bovine blood erthrocytes, and bacterial or mitochondrial Mn-SOD and/or Fe-SOD, and recombinant human Cu,Zn-SOD (rhSOD).
Superoxide dismutase has been known under the name Orgotein since 1939, but the dismatuse activity was not discovered and described until 1969, by McCord and Fridovich. Its practical use was limited in the past in particular by the short life or short biological availability of the protein under natural conditions, which of course has an adverse effect on the frequency of the dosage intervals, the therapeutic doses to be chosen and the associated costs.
The most investigated and used SOD to date was the Cu,Zn-SOD from bovine blood erythrocytes. Following severe and in some cases even fatal adverse reactions in the clinical-therapeutic use of bovine blood SOD, especially against arthritic diseases, preparations containing bovine blood SOD were prohibited, for example, in Austria. The preparation of recombinant human SOD, as described, for example, in AT 397 812 (Polymun Scientific, 1994), offers a way out of this situation.
Inter alia, the incorporation of SOD molecules in liposomes is a possible method for controlling the short life or short biological availability of the active substance SOD (Senga et al. 1990, Transplant. Proc. 22:2025).
The very first trial applications related to the treatment of inflammations and inflammatory processes of the skin. However, uses in osteoarthritis and rheumatic arthritis are now also reported in the literature (Hartmann et al. 1986, Proc. Natl. Acad. Sci. U.S.A. 83:7142; Bannister et al. 1987, Critical Rev. Biochem 22:111). Especially in the area of medicine, it is also reported that SOD improves the storability of organs for the purpose of a subsequent transplantation (Olson et al. 1988, Transplant. Proc. 20:961), and a use for food preservation has already been mentioned (WO 85/01503).
SUMMARY OF THE INVENTION
The primary object of the present invention is to provide pharmaceutical compositions for transporting SOD, preferably rhSOD enclosed in protective liposomes, in a gentle, effective manner and with better bioavailability, to those parts of the body which are to be treated. In spite of a continuing general prejudice on the part of those skilled in the art, the inventors have been able in particular to use liposomally packaged SOD successfully for human fibrotic tissue degeneration diseases such as Peyronie's Disease, for bums and scalds and for radiation damage, caused, for example, by UV radiation or ionizing radiation, in particular by external application. In the case of exposure to radiation, prophylactic use, for example together with a radiation-filtering or radiation-absorbing screening agent, is also possible in addition to therapeutic use.
A further object is to provide a pharmaceutical composition based on SOD in liposomes, which overcomes the stated disadvantages of the prior art and thus opens up additional fields of use, in particular in the area of cosmetics.
It is a further object of the present invention to transport SOD, preferably rhSOD enclosed in protective liposomes, in a gentle, effective manner and with better stability and a longer lasting effect, to the organic materials to be treated, for example vegetable or animal tissues, organs, organ or tissue transplants, cosmetic preparations based on organic substances and/or foods.
A particular object of the present invention is use of the synergistic effect of a mixture of hyaluronic acid and SOD. Hyaluronic acid has also recently become known to those skilled in the art for its “free radical acceptor properties”, and its use in wound treatment has repeatedly been described (Amgen, WO 214480, 1992). The use of hyaluronic acid together with Colony Stimulating Factor (CSF) or Platelet Derived Growth Factor (PDGF) for accelerating wound healing has also been described in the literature (Zymogenetics, U.S. Pat. No. 5,128,321, 1992), and hyaluronic acid has also been described as an additive in cosmetics and pharmaceutical preparations (Shiseido, WO 9104279, 1991).
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
Surprisingly—a combination of hyaluronic acid and SOD, in particular a mixture of hyaluronic acid and liposomally incorporated SOD, has not been described to date. To what extent this represents or represented a prejudice on the part of se skilled in the art cannot be adequately assessed at the present time. In any case, it was surprisingly found, in the course of the experiments which have finally led to the present invention, that hyaluronic acid supports and reinforces the effect of SOD, also of liposomally incorporated SOD, in an almost ideal manner.
In the course of the experiments which have finally led to the present invention, it was also surprisingly found that, thanks to the inclusion of the SOD molecules in liposomes, not only was their stability and bioavailability increased but also the concentration of SOD required to achieve the desired effect could be reduced by a factor of 10 compared with SOD compositions without liposomes, without having to accept lower activity. Moreover, because of the liposomal dosage form, a physiologically more advantageous dosage of the active substance at the place of demand is also achieved, which of course has a very advantageous effect on the amount and/or frequency of the doses and the associated costs. This advantageous effect of the physiologically more advantageous dosage of liposomally incorporated SOD on site also plays a role in inflammations and inflammatory processes at the body surface and in the interior of the body and in processes for improving the stability of organic materials.
It is however also presumed that the direct enzymatic action of the SOD protein may not be the only decisive factor for the success of healing. It is known that other enzymes, e.g., cytochrome A, histone, lysozyme and ribonuclease, for example in dimerized form, have additional properties which considerably extend those of the monomer, the action spectrum and the respective field of use of the dimeric proteins thus being advantageously extended in comparison with the monom
Katinger Hermann
Riedl Claus
Vorauer-Uhl Karola
Oliff & Berridg,e PLC
Polymun Scientific Immunbiogische Forschung GmbH
Slobodyansky Elizabeth
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