Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-04-06
2001-01-16
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S912000
Reexamination Certificate
active
06174859
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a method of treating eye and ear infections resulting from parasites and/or infections characterized by the presence of pseudomonas, increased kallikrein and kinin activity. More particularly, there is provided compositions containing a protease inhibitor selected from the group consisting of alpha 1-antitrypsin (AAT), secretory leucocyte protease inhibitor (SLPI) and anti-plasmin inhibitor.
BACKGROUND OF THE INVENTION
Arachidic acid is liberated in damaged, wounded, or inflamed tissues from phospholipids of cytoplasmatic membranes by the action of phospholipase enzyme and may be then metabolized by the cyclooxygenase cycle (by lipoxygenase enzyme) to prostanoids and eicosanoids. Antiphlogistics of both the steroid and nonsteroid nature, antibiotics, and sulfonamides are often used for therapeutic purposes. The antibiotics which specifically suppress pathogenic microbes and are often used in ophthalmology, are tetracycline, chloramphenicol, bacitracin, and neomycin. Therapeutics which prevent the development of inflammation (antiphlogistics) are both steroid and nonsteroid. The steroid antiphlogistics (e.g., dexamethasone block phospholipase. The anti-inflammatory drugs of nonsteroid nature (e.g., indomethacin, flurbiprofen, pirprofen) block cyclooxygenase and others. The blockage of these enzymes is important, because the products formed in metabolic cycles have a strong chemotactic effect (they cause accumulation of leukocytes in the sites of origin), (e.g., some leucotrienes) and increase the vascular permeability. This contributes to an excess development of the inflammation. Inflammations, (both of infectious and noninfectious origin) are very dangerous for the anterior and posterior segments of the eye. Thus, scars formed in the cornea during the final stage of the healing process cause the loss of an exceptional function of this tissue, i.e. transparency. The loss of transparency of optical media of the eye (cornea, lens) then leads to a reduction or even loss of sight.
A disadvantage of locally applied antiphlogistics is the relatively low efficiency, retarded healing, and contribution to the development of infection. The local effect of antibiotics is limited.
One of the very prospective possibilities of treatment is the inhibition of plasmin and other destruction proteases (e.g., collagenase or elastase) with specific inhibitors. These enzymes either directly develop the destruction processes (e.g., plasmin) or enable these processes by their own activity (e.g., collagenase, elastase). However, plasmin is effective not only as an initiator developing the degeneration processes proceeding in cascades, but also contributes to an excessive development of inflammation by several other mechanisms of which at least chemotaxis should be mentioned. U.S. Pat. Nos. 5,217,951; 5,290,762, and 5,190,917 which are herein incorporated by reference disclose the treatment of inflammation with serine protease inhibitors alone or in combination with a corticosteroid. None of the references teach or suggest eye and ear infections caused by parasites or relating to pseudomonas infection.
What is needed then is a medicamentous form for external use as an ophthalmologic or otolaryngologic drug.
This medicamentous form must have strong antiexudative, antiphlogistic, and antimicrobial effect. This medicamentous form is presenting lacking in the prior art.
SUMMARY OF THE INVENTION
The medicamentous form or composition of the present invention is delivered in an aqueous or ointment base particularly suited for ophthalmologic and otolaryngologic application. This medicamentous form contains inhibitors of proteases such as alpha1-antitrypsin, secretory leucocyte protease inhibitor, and anti-plasmin inhibitor trypsin and elastin. These can also be delivered with antiphlogistics and antibiotics.
Accordingly, an object of the present invention is to provide a medicamentous form having strong antiexudative, antiphlogistic and antimicrobial effects.
Still another object of the present invention is to provide a medicamentous form having therapeutic effects including the inhibition of plasmin, leucolytic elastase, and other serine proteases.
Another object of the present invention is to provide a medicamentous form that inhibits the activation of latent forms of some endoproteases and several further subsequent reactions of chemotaxis and vascularization of the cornea.
Yet another object of the present invention is to treat ear and eye infections characterized by the presence of pseudomonas, excess Kallikerin and Kinin activity.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
The composition of the present invention is a medicamentous form or composition in an aqueous or ointment base particularly suitable for ophthalmologic and otolaryngologic application. The medicamentous form contains inhibitors of proteases such as alpha1-antitrypsin, secretory protease inhibitor and anti-plasmin inhibitor having a concentration of substantially 0.1 to 20 mg. per 1 ml of solution or per 1 g. of ointment base. These inhibitors are applied either individually or in combination after being dissolved in physiological saline or buffer solution with a pH of 6.5 to 7.5, which is advantageously ionically balanced (e.g., phosphate or borax buffer) or present in the ointment base.
The ionically balanced buffer solution means that sodium chloride is added to the buffer solution in such a way that the resulting solution is ionically balanced. For example, the precise performance for borax buffer with pH 7.4 is as follows:
Solution A—1.9 g. Na2P4O7 per 100 ml H2O pro injection.
Solution B—1.25 g. H3BO3+) 0.3 g. NaCl per 100 ml H2) pro injection. Anti-plasmin inhibitor provides a mix of—10 ml of solution A+90 ml of solution B.
The medicamentous form according to the preferred embodiment in the liquid state may further advantageously contain 0.05 to 15 percent by weight of thickeners selected from the group comprising hydroxypropylmethyl cellulose, methyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, poly (alkaline glycols), poly/-hydroxyalkyl, (meth)acrylates or poly(meth)acrylamides.
High concentrations of alpha1-antitrypsin or another inhibitor, when locally applied, act not only curably in the advanced stage of disease but also prospectively by the prevention of the formation of destructive processes if timely administered. The vehicles or thickeners with protracted effect then enable a longer contact of the remedy (e.g. AAT) with the tissues. The medicamentous form according to the preferred embodiment may contain 0.05 to 1.5 percent by weight of steroidal antiphlogistics such as indomethacin or 0.2 to 1 percent by weight of antibiotics such as bacitracin, meomycin, tetracycline, or chloramphenicol and/or hyaluronic acid. Preferred is an antibiotic which is anti-pseudomonas.
The combination of protease inhibitors with antiphlogistics or antibiotics, or all substances together, increases the antiinflammatory and anti-microbial effect because the inhibitors block some products of microbes such as elastase or other proteases. This enables ont to use the antibiotics only locally and in smaller doses. The concentration of antiphlogistics may be reduced and, at the same time, the therapeutic effect is higher and the time of treatment shorter which is of great value in healing of tissue.
Ear infections are generally characterized by the presence of pseudomonas and increased tissue kallikrein and kinin activity. The more serious the infection, the greater the levels of pseudomoas, kallikrein activity and elastase. The reduction of kallikrein and kinin activity also results in reduction of pain.
Parasitic infestation of the eyes and ears has resulted in increased kallikrein activity and proteases which are released by the parasites. The common parasites which invade the eyes and ears usually through contaminated water generally express serine proteases. The protozoan parasite Cryptosporidium parvum, for example, expresses a protease-like component which is rec
Lezdey Darren
Lezdey John
Fay Zohreh
J & D Sciences, Inc.
John Lezdey & Assoc
LandOfFree
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