Method of treatment

The present invention provides a method and composition for treating eye and ear infections from parasites and eye and ear infections, characterized by the presence of pseudomonas and increased kallikrein and kinin activity. The compositions contain a protease inhibitor selected from the group consisting of alpha 1-antitrypsin, secretory leucocyte protease inhibitor and antiplasmin inhibitor, a steroidal antiphlogistic compound, and a non-steroidal antiphlogistic compound and optionally hyaluronic acid.

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 recognized by alpha 1-antitrypsin.
 Shistosomiasis infections are easily started by Shistosoma mansoni entering
 the eyes and ears of swimmers.
 Hyaluronic acid promotes healing and is especially advantageous in treating
 injury to the cornea.
 The medicamentous form is most often applied by instillation or as an
 ointment into the conjunctival sac. However, it can also be used for
 irrigation or lubrication of the eye, facial sinuses, and external
 auditory meatus. It may also be injected into the anterior eye chamber and
 other places. The medicamentous form in the liquid state may be also
 present in a hydrophilic three-dimensional polymer matrix in the form of a
 strip, contact lens, and the like from which the active components are
 released. The incorporation of medicamentous form into a hydrophilic
 matrix can be performed according to the invention by conditioning of the
 matrix in the solution of medicamentous form in order to obtain the
 required concentration of inhibitors and also for the antiphlogistics and
 antibiotics in polymer matrix.
 The invention is illustrated in the examples of performance and the
 examples are provided without the intention of limiting the scope of the
 present invention.
 The preparation of medicamentous form in liquid state is begun by
 separately dissolving each substance in a small amount (10 to 40 ml) of
 buffer or physiological saline.
 The ointment base is prepared by melting 10 g. lanolin, 10 g. liquid
 paraffin, and 80 g. white vaseline in bath water. The mixture is then
 strained through a hydrophilic gauze and sterilized. If the applicable
 therapeutic is easily soluble in water, it is dissolved in the necessary
 amount of distilled water for the preparation of injections, mixed with
 the ointment base in part melted in a water bath and stirred until
 completely cooled. If the therapeutic is insoluble in water, it is used
 for the preparation in the finest powdered form. However, it is first
 titrated in a smaller amount of liquid paraffin and then mixed with the
 ointment base.

EXAMPLE 1
 A mixture is provided by combining alpha 1-antitrypsin hydroxypropyl methyl
 cellulose 1 g.; and ionically balanced borax buffer of pH 7.4 up to 100 g.
 Drops of this composition dosed into the conjunctival sac of a patient at
 intervals of 3 hours heals allergic conjunctivitis within 3 to 5 days.
 EXAMPLE 2
 A mixture is provided by combining alpha 1-antitrypsin 0.005 g.;
 hydroxypropyl methyl cellulose 2.5 g.; and ionically balanced phosphate
 buffer of pH 7.4 up to 100 g. The drops were dosed into the ear of a
 patient with swimmer's ear three times a day. Pain was reduced with the
 initial dose.
 EXAMPLE 3
 A mixture is prepared by combining alpha 1-antitrypsin 0.005 g.;
 polyvinylalcohol a g.; 0.001 g of hyaluronic acid and ionically balanced
 borax buffer of pH 7.4 up to 100 g. Drops of the mixture were applied into
 the conjunctival sac of the patient at intervals of 2 hours. This heals
 minute wounds of the conjunctive, cornea, and eyelids within 2 to 4 days.
 EXAMPLE 4
 A mixture is prepared by combining 0.2 g.; hydroxypropyl methyl cellulose
 2.5 g.; and physiological saline up to 100 g. An etched and burnt cornea
 can be healed during 4 days by application of the drops four times a day.
 The transparency of the cornea can be recovered either completely or at
 least in the periphery of the cornea.
 EXAMPLE 5
 A mixture is prepared combining SLPI 0.01 g.; dexamethasone sodium
 phosphate 0.1 g.; hydroxypropyl methyl cellulose 2.5 g.; and ionically
 balanced borax buffer up to 100 g. The eye drops can be used to heal
 severe allergic conjunctivitis by instillation three times a day.
 EXAMPLE 6
 A mixture is prepared by combining alpha 1-antitrypsin 0.1 g.;
 dexamethasone sodium phosphate 0.5 g.; hydroxypropyl methyl cellulose 2
 g.; 0.58 hyaluronic acid and ionically balanced phosphate buffer up to 100
 g. The drops can be administered into an infected ear 3 times a day. Pain
 and inflammation will be reduced immediately.
 EXAMPLE 7
 A mixture is prepared by combining 0.1 g. of alpha 1-antitrypsin 0.05 g. of
 hyduronic acid 0.05 g.; dexamethasone sodium phosphate 0.1 g.;
 chloramphenicol 0.5 g. and physiological saline up to 100 g. The solution
 can be used in the treatment of rhinal allergoses and allergoses of meatus
 acusticus externus.
 EXAMPLE 8
 Ten patients from India suffering from parasitic infestation of the eyes
 resulting from exposure in the Ganges river and exhibiting red inflamed
 eyes were treated with a 5% solution of alpha 1-antitrypsin in saline
 solution. Immediately after the application of three drops to each of the
 eyes of the patients, the redness of the inflammation disappeared.