Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-08-05
2001-09-11
Davenport, Avis M. (Department: 1654)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S012200, C530S300000, C424S185100
Reexamination Certificate
active
06288025
ABSTRACT:
BACKGROUND OF THE INVENTION
Psoriasis is a chronic skin disease characterized by erythematous plaques of thickened, reddening, and scaling skin. Psoriasis affects about 2% of the population. Onset occurs most often in early adult life, but also may begin in childhood or in aged people. Severity of the disease varies and is usually characterized by alternating periods of remission and flare-up. In more serious cases, psoriasis can affect up to 90% of the skin and can be life threatening
At the cellular level, psoriasis is characterized by a hyper proliferation of epidermal keratinocytes, accompanied by infiltration of T lymphocytes and other immune system cells, the latter giving rise to inflammation similar to that in autoimmnune diseases. The epidermal turnover time for a keratinocyte to travel from the basal cell layer to the stratum corneum normally is 14 days, during which the keratinocyte undergoes a complex series of changes in gene expression resulting in cell death—“terminal differentiation.” In a psoriasis patient, the epidermal turnover time is 2 days, with marked increase in proliferation of keratinocytes, which are subsequently shed in a relative immature, or less differentiated, form.
Currently, there is no long-term cure for psoriasis. Treatments include coal tar preparations (natural coal tar or the distillate anthralin), topical corticosteroids, mechanical treatments to remove scale, and antimetabolites such as methotrexate. The photosensitizing drug, psoralen, combined with long wavelength ultraviolet light (PUVA), and synthetic retinoids also are used. While mild to moderate cases can be treated somewhat effectively, more extensive cases are difficult and tend to be resistant to either topical therapy or ultraviolet phototherapy. Moreover, systemic use of traditional antipsoriatic drugs, or prolonged use of topical steroids, can lead to undesirable side effects or rebound worsening of psoriasis.
Genetic analysis indicates that at least some forms of psoriasis include an inherited component, and intense efforts are underway to locate “psoriasis susceptibility genes.” The similarity to autoimmune diseases, and the increased incidence of HLA-13, HLA-17, HLA-Cw6, and HLA-DRw7 in affected individuals has focused attention on on immunomodulatory strategies and the development of new drugs which decrease T-cell activation or deplete activated T-cell pools. Research has been severely impeded, however, by the lack of an animal model which reflects all the diverse clinical and cellular changes present in psoriatic plaques.
An alternative approach to immune modulation that may avoid potential side effects from drugs of this type is to focus on the abnormal keratinocyte differentiation in psoriasis. Keratinocyte maturation is associated with the production of proteinases, which can degrade the surrounding extracellular matrix to allow cell migration to the superficial layers and activate cells to divide, either directly, or indirectly by activating cytokines precursors. At terminal differentiation, the formation of a stable stratum corneum would require that the activity of such proteinases be down-regulated. Several proteinases, such as plasminogen activator and cathepsin B, have been shown to be present in normal skin, and it is possible that the cellular pathophysiology in psoriasis may result from excessive and unregulated levels of proteinases.
In psoriasis, abnormalities in the expression of both urokinase plasminogen activator (u-PA) and tissue plasminogen activator (t-PA) expression have been observed. The most dramatic change is the greatly enhanced t-PA expression in suprabasal epidermis. Jensen et al.,
J. Invest. Dermatol.
90(6):777-782 (1988). Baird et al.,
J. Invest. Dermatol.
95(5):548-552 (November 1990). Biopsies from 40 patients with psoriasis before and after topical (anthralin, corticosteroid) and systemic (PUVA) treatments by the autohistographic fibrin film method showed that both u-PA and t-PA immunoreactivity were present in psoriatic patches but absent from normal and treated, clear skin. Lotti et al., Int.
J. Dermatol.
29(7):528-530 (1990). Moreover, increase in PAI-2 in psoriatic epidermis, in the same suprabasal areas as t-PA suggests that PAI-2 has a protective role in cutaneous pathologies that elicit abnormal wound healing patterns. Lyons-Giordano et al., “Expression of plasminogen activator inhibitor type 2 in normal and psoriatic epidermis,”
Histoclemistry
101(2):105-112 (February 1994).
It is apparent, therefore, that new methods and compositions for treating psoriasis are greatly to be desired. In particular, it would be desirable to develop new methods and compositions for treating psoriasis that regulate the plasminogen activator/inhibitor system and in particular that utilize plasminogen activator inhibitors.
SUMMARY OF THE INVENTION
The present invention relates to the use of a urokinase inhibitor for treating psoriasis. Thus, the present invention provides a method of treating psoriasis comprising administering to a patient in need thereof an effective amount of a urokinase inhibitor, wherein said inhibitor is topically administered to the affected area of the skin. In one embodiment of the invention, the urokinase inhibitor is selected from the group consisting of PAI-2, a variant thereof having plasminogen activating inhibitory properties, a derivative of PAI-2, and a variant of said derivative.
According to one aspect of the invention, the derivative is obtained by biochemical modification of PAI-2, wherein said modification is selected from the group consisting of chemical linking with polyethylene glycol, phosphate group attachment, sulfate group attachment, peptidase treatment, treatment with a sugar chain-modifying enzyme, and treatment with a sugar attachment enzyme. In one embodiment, the variant is obtained by deletion or addition of amino acid residues from the amino terminal end of PAI-2. In another embodiment, the variant is obtained by deletion or addition of amino acid residues from the carboxy terminal end of PAI-2.
According to another aspect of the invention, the urokinase inhibitor is administered in a gel formulation. In one embodiment, the gel is a cellulose gel further comprising a detergent. In another embodiment of the invention, the detergent is Tween-80.
According to yet another aspect of the invention, the PAI-2 is administered in a range of 0.1-2000 &mgr;g/cm
2
of wound. According to yet another aspect of the invention, the PAI-2 is administered at least once a day for at least five days.
The present invention also provides a method of treating psoriasis comprising administering to a patient in need thereof an effective amount of a therapeutic agent comprising PAI-2 and at least one other serine protease inhibitor, wherein said therapeutic agent is topically administered to the affected area of the skin. In one embodiment, the other serine protease inhibitor is a uPA inhibitor.
According to one aspect of the invention, the therapeutic agent further comprises a protease inhibitor selected from the group consisting of thiol protease inhibitors, acid protease inhibitors, and metalloproteinase inhibitors. In one embodiment, these protease inhibitors are co-administered with PAI-2.
The present invention further relates to a pharmaceutical composition comprising PAI-2 in a gel containing a detergent. According to one aspect of the invention, the pharmaceutical composition comprises PAI-2 and at least one other serine protease inhibitor. According to another aspect of the invention, the pharmaceutical composition further comprising a protease inhibitor selected from the group consisting of thiol protease inhibitors, acid protease inhibitors, and metalloproteinase inhibitors. In one embodiment, the detergent is Tween-80. In another embodiment, the gel is a cellulose gel. In another embodiment, the gel contains at least one further component that reduces the formation of aggregates, enhances the stability of PAI-2, and that may act as a penetration enhancer. In a preferred embodiment, that component is p
Bunn Clive Leighton
Sharp Phillip John
Biotech Australia Pty Limited
Davenport Avis M.
Foley & Lardner
LandOfFree
Protease inhibitors for use in the treatment of psoriasis does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Protease inhibitors for use in the treatment of psoriasis, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Protease inhibitors for use in the treatment of psoriasis will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2465993