Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,...
Reexamination Certificate
1997-09-11
2002-06-25
Caputa, Anthony C. (Department: 1642)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
C424S141100, C430S387000, C430S389000, C430S416000
Reexamination Certificate
active
06410019
ABSTRACT:
The present invention relates to a new therapeutic use of G class immunoglobulins, particularly immunoglobulins for intravenous use (IVIG) or for intramuscular use (IMIG). More particularly, the present invention relates to the topical use of G class immunoglobulins which are normally administered intravenously or intramuscularly for the therapeutic treatment of dermatitis, particularly acne, contact dermatitis, atopic dermatitis, eczema and ichthyosis, psoriasis, papulosquamous dermatopathies (seborrheic dermatitis, erythrodermia, etc.), as well as fungus, parasite, bacterium and virus infection dermatitis.
Therefore, this invention also relates to the pharmaceutical compositions suitable for topical application, which contain G class immunoglobulins, and particularly IVIG or IMIG, as the active ingredient.
As is well known, the term “immunoglobulins for intravenous use” indicates a human-protein-based product, at least 90% of which has the electrophoretic mobility of gammaglobulin (IgG), at least 90% of IgG being made up of monomer. Traces of IgA and IgM may also be present. The distribution of the IgG subclasses is similar to that encountered in normal serum.
Several commercial immunoglobulin preparations for intravenous use are currently available on the market, e.g. under the trade marks VENO-GLOBULIN®, GAMMIMUNE®, SANDOGLOBULIN®, GAMMAGARD®, GAMMAR® and IVEGAAM®.
The “immunoglobulins for intramuscular use” differ from the intravenous immunoglobulins in their lower degree of purity. Various commercial preparations of immunoglobulins for intramuscular use are currently available on the market, e.g. under the trade marks GLOBUMAN®, GAMMABULINE®, LIOGAMMA®, BOEHRIGAMMA® and UMANGAMMA®.
The skin interacts continuously and intimately with a vast range of environmental agents more than any other organ in the body. The environment comes into contact with the body in the form of substances or forces (physical, chemical, biological) and via different routes: irradiation, air, food, direct contact with the skin, injections, or psychosocial interactions. All these agents may lead to diseases of the skin (Ring, J:, “The skin and the environment”, Hautarzt, 44:625-35, 1993). Atopic dermatitis (AD) is a multifactorial skin disease with a chronic or chronic-recurrent course, which often sets in during infancy. The aetiology of this troublesome skin condition is still obscure, but an immunological disorder of the T cell immune response is likely involved in its pathogenesis (Wuthrich, B., Atopic dermatitis”,
Ther. Umsch
., 51:45-54, 1994).
Recent discoveries have revealed various key factors in maintaining the vicious circle of AD, associated with elevated activation of T lymphocytes, hyper-stimulating Langerhans cells, an abnormal cell-mediated immunity and an overproduction of IgEs by the B cells (Cooper, KID., “Atopic dermatitis: recent trends in pathogenesis and therapy”,
J. Invest. Dermatol
., 102:128-37, 1994). In-situ hybridization has revealed that, as compared to normal control skin or to the unaffected skin of AD sufferers, the acute and chronic lesions of the skin had a significantly greater numbers of cells which were positive for IL-4 and IL-5 mRNA (Hamid, Q., et al. “Differential in situ cytokine gene expression in acute versus chronic atopic dermatitis”,
J. Clin. Invest
., 94:870-6, 1994). These and other data suggest the activation of a selected population of T-helper cells which produce a type of Th2 cytokines related to IL-4 and IL-5 but not to IL-2 and interferon-&ggr; (IFN-&ggr;) in AD (Kagi, M.K., et al, “Differential cytokine profiles in peripheral blood lymphocyte supernatants and skin biopsies from patients with different forms of atopic dermatitis, psoriasis and normal individuals”,
Int. Arch. Allergy Immunol
., 103:332-40, 1994). The micro-organisms of the skin flora may also be a further stimulus for allergic reactions of the skin. Abnormal bacterial colonization of the skin is a typical characteristic of AD.
Staphylococcus aureus
(
Staph. aureus
) is the most common pathogen and in some cases an antimicrobial and antifungal treatment has proved useful (Ring, J., et al, “Atopic eczema: role of micro-organisms on the skin surface”,
Allergy
, 47:265-9, 1992).
Conventional therapy remains the mainstay of treatment of atopic dermatitis, but often proves unsatisfactory. New therapies based on the concepts outlined above are being tested in clinical trials, and for this purpose trials have been suggested with modifiers of the biological response such as interferon-&ggr;, cyclosporin A, or thymopentin, administered parenterally (Cooper, KD., “Atopic dermatitis: recent trends in pathogenesis and therapy”,
J. Invest. Dermatol
., 102:128-37, 1994).
To date, the accepted use of IVIG and IMIG has been as antibody replacement in states of immunodeficiency to treat and/or prevent infectious diseases (Newland A.C., “The use and mechanism of action of intravenous immunoglobulin”,
Br. J. Haematol
., 72:301-5, 1989). In addition, there is increasing evidence that intravenous infusion of large amounts of polymeric immunoglobulin causes more than simple antibody replacement and may have a profound effect on the reticulendothelial system. IVIG and IMIG can alter the function of B and T lymphocytes and cause short-term blockade of phagocyte function with down-regulation of immunological activity (Newland, A.C., Macey et al, “Intravenous immunoglobulin: mechanism of action and their clinical application” in “Immunotherapy with intravenous immunoglobulins”, edited by P. Imbrach, Academic Press, London, 1991, pp. 14-25). It is conceptually important to note that, in numerous diseases, more than one mechanism of action is possible and that the therapeutic effect may be due to several concomitant actions rather than to any single mechanism. Nevertheless, the IVIG and IMIG preparations have been developed to date so as to allow systemic administration.
As regards skin diseases, an improvement in AD has been observed in patients suffering both from AD and from Kawasaki's disease or from idiopathic thrombocytopenia, but the immunoglobulins were administered, as usual, by the intravenous route and at high doses (Kimata, H., “High dose gammaglobulin treatment for atopic dermatitis”,
Arch. Dis. Child
., 70:335-6, 1994).
Surprisingly, however, it has now been found that G class immunoglobulins, and in particular IVIGs or IMIGs, in solution or in the form of ointments or gels, or in liposomes (or other formulations) at concentrations of 0.1-25% are potentially effective for the prophylaxis and treatment of AD or of other skin diseases characterized by a poorly regulated immune response and/or by abnormal bacterial, viral or fungal colonization.
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Bruschi Pietro
De Simone Claudio
Canella Karen A.
Caputa Anthony C.
Mendes s.u.r.l.
Nixon & Vanderhye
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