Treatment of psoriasis

A method for the prophylaxis or direct treatment of dermatitis including psoriasis which comprises administering to the site of the disease an effective amount of a corticosteroid and a company which inhibits mast cells or binds with their mediators.

FIELD OF THE INVENTION 
The present invention relates to a method and composition for treating a 
patient afflicted with psoriasis. More particularly, the present invention 
relates to the direct or prophylaxis treatment of psoriasis by topically 
administering synergistic amount of the combination of a compound which 
can inhibit mast cell proliferation or degranulation or bind with 
neutrophils, T-cells and their mediators, and a corticosteroid. The 
composition can also be used to treat chronic dermatitis, pruritis, 
contact dermatitis and palmoplentar eruptions. 
BACKGROUND OF THE INVENTION 
Psoriasis is an inflammatory skin condition whose cause is unknown. The 
condition involves thick scaling due to epidermal cell proliferation, 
cracking and bleeding. Mast cells have recently noted as being involved in 
psoriasis. 
Inflammation is a non-specific response of tissues to diverse stimuli or 
insults and results in release of a variety of materials at the site of 
inflammation that induce pain. It is now recognized that mast cells, 
neutrophils and T-cells are implicated in the pathophysiology of 
inflammatory skin conditions as well as in other physiological disorders. 
Mast cells provide the greatest source of histamines in acute 
inflammation, as well as chymases, after degranulation by IgE. 
Neutrophils are prominent in psoriatic lesions due to the potent 
chemoattractants released by mast cells. 
Neutrophils are a main source of serine elastase and cathepsin G which are 
important in the tissue damage of inflammation. 
The most direct approach to therapy of psoriasis skin appears to be a 
direct attack at the site of inflammation of the mediators of inflammation 
and pain and the reduction of those neutrophilic derivatives which can 
cause damage to the growth of new tissue during the healing process. 
Disodium cromoglycate has been shown to inhibit the immediate and 
late-phase inflammatory reactions effectively by decreasing mast cell 
degranulation. Corticosteroids prevent late-phase inflammatory reactions 
partly by diminishing the neutrophilic infiltration triggered by mast cell 
degranulation. Serine protease inhibitors such as .alpha..sub.1 
-antitrypsin and .alpha..sub.1 -antichymotrypsin have been found to be 
useful in the treatment of atopic dermatitis by inhibiting and/or binding 
with elastase, cathepsin G and human mast cell chymase. However, each of 
the prior art methods of treatment for psoriases has involved long periods 
of treatment without success in its long term management. It is recognized 
that prolong treatment with steroids can cause many side effects. Yet when 
a psoriasis patient is removed from steroids there is almost immediate 
relapse to the prior condition. 
Alpha 1-antichymotrypsin is a plasma protease inhibitor synthesized in the 
liver. It is a single glycopeptide chain of approximately 68,000 daltons 
and belongs to a class of serine protease inhibitors with an apparent 
affinity toward chymotrypsin-like enzymes. Alpha 1-antichymotrypsin is 
structurally related to alpha 1-antitrypsin. 
Alpha 2-macroglobulin is a glycoprotein containing 8-11% carbohydrate which 
can be isolated from plasma by gel filtration chromatography. 
Alpha 1-proteinase inhibitor (alpha 1-antitrypsin) is a glycoprotein having 
a molecular weight of 53,000 determined by sedimentation equilibrium 
centrifugation. The glycoprotein consists of a single polypeptide chain to 
which several oligosaccharide units are covalently bonded. Human alpha 
1-proteinase inhibitor has a role in controlling tissue destruction by 
endogenous serine proteinases. A genetic deficiency of alpha-1-proteinase 
inhibitor, which accounts for 90% of the trypsin inhibitory capacity in 
blood plasma, has been shown to be associated with the development of 
asthma and pulmonary emphysema. The degradation of elastin associated with 
certain inflammatory diseases probably results from a local imbalance of 
elastolytic enzymes and the naturally occurring tissue and plasma 
proteinase inhibitors. Alpha-1-proteinase inhibitor inhibits human 
pancreatic and leukocyte elastases. See Pannell et al, Biochemistry. 13, 
5339 (1974); Johnson et al, Biochem. Biophys. Res. Commun., 72 33 (1976); 
Del Mar et al, Biochem. Biophys. Res. Commun., 88, 346 (1979); and 
Heimburger et al, Proc. Int. Res. Conf. Proteinase Inhibitors. 1st, 1-21 
(1970). 
The article of Groutas entitled "Inhibitors of Leukocyte Elastase and 
Leukocyte Cathepsin G Agents for the Treatment of Emphysema and Related 
Ailments" Medical Research Reviews, Vol. 7, No. 7, 227-241 (1987), 
discloses the role of eglin, elastinal 1 and elastin in emphysema. 
Lezdey et al U.S. Pat. No. 4,916,117 discloses the treatment of pulmonary 
inflammation where mast cells are involved with microcrystalline 
alpha-1-antichymotrypsin alone or with other serine protease inhibitors. 
SUMMARY OF THE INVENTION 
The present invention relates to a method for treating psoriasis in 
patients by the topical administration of an effective amount of a 
corticosteroid and a compound capable of inhibiting the degranulation of 
mast cells and/or binding with mast cell mediators. The corticosteroid can 
be administered separately or in combination with the serine protease 
inhibiting compound. Preferably, the site is first treated with the serine 
protease inhibitor. Among the inhibitors of mast cell degranulation are 
cromylyn, serine protease inhibitors, their analogs, salts or derivatives 
and recombinant products. Preferable are the serine protease inhibitors 
which have a specific inhibiting activity of mast cells and binding with 
the proteases derived therefrom such as cathepsin-G, elastase, human mast 
cell chymase, kinins, and the like. 
Among the topical corticosteroids which may be used in the present 
invention are triamcinolone acetonide, flurandrenolide, prednisone, 
amcinonide, dexamethasone, betamethasone valerate, halocinonide, 
clocortolone, hydrocortisone valerate, and the like. 
Serine protease inhibitors have been found to play a major role in the 
direct inactivation of the mediators of inflammation so that the normal 
wound healing process can be accelerated without interference from the 
excess of materials released at the site of inflammation. The almost 
immediate disappearance of pain and itch indicates that there can be a 
control of the kinins as well. A cocktail of serine protease inhibitors 
their analogs, salts or derivatives, appears to provide the quickest 
healing of psoriatic lesions when used in combination with a 
corticosteroid. 
As presently found, serine protease inhibitors are useful in the treatment 
of chronic psoriasis patients which not only experience pain and itch but 
have a problem in controlling the laydown of organized collagen because of 
elastase and cathepsin G; serine protease inhibitors permit healing and 
the growth of normal skin. The presence of the steroids enhance the 
healing and promote a more rapid skin growth which is initiated by the 
serine protease inhibitors. 
It has now been found that controlling the amount of mast cells and their 
mediators inherently controls the amount of the destructive enzymes at the 
site of inflammation and prevents proliferation of the disease, prevents 
associated tissue damage and promotes healing. Serine protease inhibitors, 
for example, alpha 2-macroglobulin, alpha 1-antichymotrypsin and 
C-reactive protein (CRP) or cromolyn, when administered to the site of 
inflammation provides a reduction in swelling, pain and stiffness. 
For chronic cases of dermatitis including psoriasis, a cocktail of protease 
inhibitors, which may include cromolyn, is preferably first administered 
at the site of inflammation. The treatment is then followed with the 
addition of a steroid. 
The serine protease inhibitors which are contemplated in the present 
invention are any of the inhibitors, their analogs, derivatives or salts 
and glycosylated or monoglycosylated recombinant compounds which can 
inhibit mast cells or bind with any one or more of the protease derived 
from eosinophils, basophils and/or neutrophils such as elastase, 
cathepsin-G, tryptase, chymase, kinin, kallikrein, chymotrypsin, 
collagenase, and the like. 
The serine protease inhibitors included in the present invention are alpha 
1-antichymotrypsin, alpha 1-antitrypsin, alpha 2-macroglobulin, eglin, 
elastinal 1, elasnin 3, C-reactive protein, beta 1-antigellagenase, serine 
amyloid A protein, alpha cysteine protease inhibitors, inter-alpha-trypsin 
inhibitor, secretory leucocyte protease inhibitor, bronchial mucous 
inhibitor, and C-1-inhibitor. The inhibitors of the invention may be 
natural or prepared by recombinant means. 
Eglin is particularly effective in binding with trypsin. 
Alpha 1-antitrypsin has also been found especially useful in the treatment 
of topical inflammatory conditions because of its association with 
elastase and kinins. However, it is preferably used in combination with 
alpha 1-antichymotrypsin. 
The serine protease inhibitors of the invention may be prepared by cloning, 
by conventional techniques utilizing an oligonucleotide probe or antibody 
probe, and the like. Analogs may be prepared using site specific 
mutagenesis. The recombinant gene product of the invention is especially 
useful since it is free of contaminating viruses when produced. 
The analogs, salts and derivatives may be formed utilizing conventional 
techniques associated with other proteins without effecting the utility of 
the compound. There may be prepared the alkali metal salts, acid-addition 
salts, and esters similar to other proteins or peptides. 
It is desirable to administer in some case a combination or cocktail of the 
serine protease inhibitors to provide a broad spectrum of drugs which can 
provide rapid relief of the different symptoms of psoriasis or other skin 
conditions. The most effective combination is alpha 1-antichymotrypsin and 
alpha 1-antitrypsin and/or alpha 2-macroglobulin. Preferably, the 
combination is administered in a ratio of 1:1:1: to 3:2:1: either in a 
single unit or in separate dosage form. The treatment may be simultaneous 
with a corticosteroid or the corticosteroid can be applied thereafter. 
It is therefore an object of the invention to provide a composition which 
can relieve the itching and redness associated with psoriasis or 
dermatitis. 
It is believed that the unique combination of the steroid and the serine 
protease inhibitor provides a two phase reaction. The steroid decreases 
the production of cytokines, leukotrines and interleukins which trigger 
mast cell secretion and a family of histamine releasing factors. The 
serine protease inhibitors complex with the mast cell mediators which are 
recognized as foreign molecules and cleared from circulation by 
heptocytes, macrophages and fibroblasts. 
It is a yet still further object of the invention to provide a method and a 
composition for treating chronic skin conditions.

DETAILED DESCRIPTION OF THE PRESENT INVENTION 
The objects of the present invention can be achieved by the topical 
administration of an affective amount of a serine protease inhibiting 
compound and a corticosteroid in a suitable pharmaceutical form to 
patients suffering from psoriasis or other skin conditions requiring 
steroids or other anti-inflammatory drugs. 
The present invention provides a pharmaceutical composition which comprises 
a corticosteroid and a mast cell inhibiting compound of this invention and 
a pharmaceutically acceptable carrier. The mast cell inhibiting compound 
may be used alone or in combination with other serine protease inhibitors 
to provide a broad spectrum of treatment. 
In accordance with one method of treatment, a 20% solution of a mast cell 
inhibitor such as a serine protease inhibitor, particularly .alpha. 
1-antitrypsin, alone or in combination with other serine protease 
inhibitors such as .alpha..sub.1 -antichymotrypsin, in a sterile water or 
saline solution, may be sprayed on the patient at the site of the 
psoriatic sores or skin lesions or the area can be wrapped in soaked 
bandages or an occlusive dressing may be used. A corticosteroid may be 
included in the initial treatment. The treatment provides immediate relief 
of pain. The patient can then be treated with the solution daily followed 
by the application of a corticosteroid until the healing process is normal 
and the psoriasis sores or skin lesions are under control. The length of 
time of treatment depends upon the severity of the disease. 
The pharmaceutical compositions of the present invention can be prepared 
utilizing conventional carriers for preparing skin creams, gels, 
ointments, lotions, sprays, liquids and the like. The mast cell inhibitors 
can be merely added to the new formulations or to topical steroidal 
formulations which are already prepared. The steroid and mast cell 
inhibitor can be formulated separately or combined in a single 
formulation. The amount of active ingredients is dependent upon the 
severity of the disease and whether or not the patient is merely on 
maintenance. An antioxidant may be used in the formulations to provide a 
longer shelf life for the mast cell inhibitor. 
Initial treatment preferably begins by applying a 10-20% aqueous solution 
of the mast cell inhibitor to the afflicted area in chronic cases followed 
by a topical formulation of the steroid alone or with a mast cell 
inhibitor. The treatment is continued daily until the condition is under 
control. The amount of steroid in the formulation can be about 0.1 to 10% 
depending upon the condition of the patient and the steroid utilized. 
Maintenance may be with a 1-10% by weight formulation of a serine protease 
inhibitor alone or combined with a steroid. 
Among the skin disease which may be treated with the compositions of the 
invention are bullous skin diseases, eczema, acne, nummular dermatitis, 
herpes, contact dermatitis, and the like. 
The following examples further illustrate the practice of this invention, 
but are not intended to be limiting thereof. It will be appreciated that 
the selection of actual amounts of mast cell inhibitors and 
corticosteroids to be administered to any individual patient (human or 
animal) will fall within the discretion of the attending physician and 
will be prescribed in a manner commensurate with the appropriate dosages 
will depend on the stage of the disease and like factors uniquely within 
the purview of the attending physician. 
EXAMPLE I 
A topical cream was prepared as follows: 
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A. The following mixture was prepared: 
Triamcinolone acetonide 2.0 g 
.alpha., -antitrypsin 1.0 g 
Olive oil 5.0 g 
Cetanol 2.0 g 
Stearic acid 5.0 g 
Glycerin aliphatic acid 12.0 g 
ester 
Tween 60 0.5 g 
B. The following mixture was also prepared: 
Propylene glycol 0.5 g 
Methyl paraben 0.1 g 
Propyl paraben 0.02 g 
Purified water to 100 g in total 
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The mixture of parts A and B were blended together by conventional means to 
give a total of 100 g. of 100% by weight topical cream which could be 
utilized for treatment of mild cases of psoriasis, or other inflammatory 
dermatological conditions. If desired secretory leucocyte protease 
inhibitor and/or alpha 2-macroglobulin may be added in an amount of 2.0 g 
to part A. 
EXAMPLE II 
An oleaginous anhydrous ointment was prepared with the following 
composition: 
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Composition % 
______________________________________ 
Dexamethasone 2.0 
.alpha., -antitrypsin 
5.0 
Soy phosphatide 4.0 
Plastibase 50W 85.950 
Butylated hydroxytoluene 
0.025 
Vitamin E 0.025 
100.00 
______________________________________ 
If desired, in lieu of alpha 1-antitrypsin as the active principal, there 
may utilized the combination of alpha 1-antichymotrypsin and alpha 
1-antitrypsin. Other non-aqueous lipid miscible carriers may also be 
utilized. The composition can be used on a maintenance program to prevent 
the recurrence of any cell proliferation upon the first indication of 
inflammation. 
EXAMPLE III 
1000 mg of PROLASTIN, a composition sold by Cutter Biological, Miles Inc., 
comprising about 70% .alpha..sub.1 -antitrypsin and about 10-18% 
.alpha..sub.1 -antichymotrypsin was dissolved in 50 ml of saline solution. 
A patient suffering from psoriasis with swelling and open lesions of the 
hand was treated by immersing the hand in the solution. The patient was 
previously treated only with steroids for 3 years without success. Pain 
disappeared within 6-10 minutes of treatment. Treatment was continued for 
1 hour. After treatment with PROLASTIN, 0.1% mometasone furoate was 
applied. The treatment was continued with alternate day application of 
PROLASTIN and daily applications of mometasone furoate. 
After three weeks all of the symptoms of psoriasis disappeared and 90% of 
the skin rash disappeared. 
The same procedure is effective in treating the symptoms of psoriatic 
arthritis. 
Example IV 
A suitable cream for topical use was prepared by admixing 43 g of PROLASTIN 
from Cutter Biological Laboratories, with 6 ml of water and 1000 g of a 
balm available under the trademark AQUAPHOR, sold by Beiesdorf Inc., 
Norwalk, Conn. AQUAPHOR comprises a mixture of petrolatum, mineral oil, 
wax and, wool wax alcohol. 
The cream is useful for the prophylaxis treatment of psoriasis.