HUT75736A - Agent and preparation for external application, practically useful to cure dermatological and immunological diseases - Google Patents

Abstract

Field of the Invention The present invention relates to an external therapeutic, therapeutic or cosmetic composition for the treatment or reduction of symptoms of skin diseases, particularly vitiligo or immunological diseases. The compositions are characterized in that they contain from 0.1 to 100,000 E of myeloperoxidase and 100% by weight of liquid or solid carrier, buffer and other known additives. The invention also relates to the use of myeloperoxidase in pure form or in the form of a cell extract for the treatment of skin diseases or immunological diseases, using the active ingredient as an external agent.

Description

ACTIVE SUBSTANCE AND PREPARATION FOR EXPERIMENTAL USE IN DEROGATION AND IMMUNOLOGICAL DISEASES

Dr. Tamás Pulay, Budapest

Date of filing: 05.04.1995

FIELD OF THE INVENTION The present invention relates to an agent and composition for external application, preferably dermatological and immunological, for the treatment of diseases.

Skin disease is characterized by spotty hypopigmentation, which has no peripheral phenomena such as hyperpigmentation or other epithelial phenomena and does not fluoresce under Wood light. Its appearance is symmetrical and bilateral. Histologically, the basal layer of the skin lacks melanocytes, although epithelial cells are found in normal numbers

The cause is unknown. There is a hypothesis that it is caused by a specific autoimmune process affecting melanocytes.

Disease course: extremely variable, unpredictable.

There is currently no clear specific or effective management.

Can be treated symptomatically with a topping cream (cosmetic cover only) or applying other ointments or painting the area in question; in rare cases, strong topical corticosteroids; PUVA treatment, supplemented internally or locally with methoxypsoralen.

The above attempts, however, have little effect on the patient.

(Judit Bíró - György Soós: Dermatological Diseases, Springer Verlag Budapest, [1994], Moschella S.L. Hurley H.J.: Dermatology 2nd Edition, W.B. Saunders Compl. London)

German Patent Publication No. A3413052 discloses an ointment containing acetylsalicylic acid as active ingredient for the treatment of vitiligo.

British Patent No. 1,194,912 also proposes an ointment for the treatment of vitiligo, which contains thiazolidene-4-carboxylic acid and calcium and lithium sulfosalicylate in addition to other conventional additives.

In our experiments we have found that the enzyme myeloperoxidase, in its pure form or in the form of cell extracts, as an external substance, is very effective in the treatment of vitiligo or other skin diseases or immunological diseases.

The invention further relates to compositions containing such an active ingredient.

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Myeloperoxidase (MPO) is a peroxidase-like enzyme found in the azurophilic granule of neutrophils, first isolated by Agner in 1941.

(Agner, K. Acta Physiol Scand., 2 [suppl. 8] 1-62, [1941])

The enzyme plays an important role in the killing of microorganisms (bacteria, fungi, viruses, protozoa, mycoplasmas) introduced into the cell during phagocytosis (Klebanoff, J. Bacteriol., 95: 2131-2138, [1968], and Klebanhoff, SJ Science, 169: 1095-1097 (1970)) and in neutrophil-mediated tumor cell cytotoxicity (Clarc, RA, Klebanoff, SJ, Einstein, AB, Fefer, A. Blood, 45: 161-170, [1975]).

Many immunological processes are also influenced by MPO by inactivating the following soluble mediators:

chemotactic factors: C5a, f-Met-Leu-Pha (Clark, RA, Klebanoff, SJ, J. Clin.Invest, 64: 913-920, [1979]), alpha-1 antitrypsin (Carp, H., Janoff). , A., J. Clin Invest, 66: 987-995 (1980)) and Klebanoff, SJ in Inflammation Eds .: Gallin, J.I., Goldstein, M.I., Snyderman, R. pp.391-444 Raven Press N.Y. [1988]) and, under appropriate conditions, can stimulate the secretion of biological mediators from certain cells (Clarc, R.A, Klebanoff,

S.J., J. Clin. Invest., 66: 987-995 (1979) and Henderson, W.R., Chi, E.Y., Klebanoff, S.J., J. Exp.Med., 152: 265-179 (1980)).

All these properties play an important role in the regulation of inflammatory processes (Clark, R.A., Klebanoff, S.J., J. Clin.Invest, 64: 913-920, [1979]).

There is little literature on the internal therapeutic use of the enzyme, but the presence and / or amount of MPO in certain tissues or cells is of diagnostic importance (Bhattacheijee, • * • · · * ·

P., Allén, G., Brook, C.D. J. Cardiovasc, Pharm., 7: 1154-1160, [1983] and Bendix-Hansen, K., Nielsen, H.K., ScandJ.Haematol. 30: 415-419 (1983). However, no myeloperoxidase active ingredient or a composition containing such active ingredient has been used as an external agent, especially for the treatment of skin diseases.

Surprisingly, our experiments have shown that myeloperoxidase and / or myeloperoxidase-containing pharmaceutical, cosmetic formulations, as external agents, are very effective in treating, alleviating or neglecting the symptoms of certain skin diseases, particularly vitiligo.

The present invention therefore relates to an external pharmaceutical, therapeutic or cosmetic composition for the treatment or amelioration of skin diseases, particularly vitiligo or immunological diseases, characterized in that it contains from 0.1 to 100,000 U of myeloperoxidase and 100 parts by weight of a liquid or solid carrier, buffer and other contains known additives.

The present invention also relates to the use of myoleperoxidase in pure form or in the form of a cell extract as an external agent for the treatment of skin or immunological diseases.

Liquid carriers, preferably water, physiological saline, vegetable or mineral oils are used.

Suitable solid carriers are preferably vegetable or animal fats, synthetic fats, natural or artificial waxes, carboxymethylcellulose and other polymers.

Suitable buffers are phosphate buffers of various compositions, or 0.01 M PBS buffer containing 0.15 moles of sodium chloride.

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Other additives include surfactants, inorganic and organic salts, emulsifiers, antimicrobial agents, antioxidants, colorants.

MBO is used in pure form or in the form of a cell concentrate containing peptides, lipo and glycoproteins in addition to MBO.

The MBO can also be used in encapsulated form.

The most preferred form of the composition is an ointment or gel, but may also be in the form of an aerosol composition or foam, or as a suppository.

The effect of the composition may be enhanced by the addition of certain adjuvants. The following examples illustrate the composition of the invention.

Example 1

Ointment (hydrophilic)

The formulation of the carrier and excipient of the preparation is as follows.

Polyoxyethylene 2-stearyl ether (Brij 72) 2.00 g Polyoxyethylene 21-stearyl ether (Brij 721) 2.00 g

Cetyl stearyl alcohol 4.00 g

Vaseline album 5.00 g

Paraffin oil 12.00 g methyl p-hydroxybenzoic acid methyl ester 0.10 g stearin 4.00 g distilled water 69.90 g

The mixture was thoroughly mixed and 0.1 E MBO per gram of mixture was added in 1 ml of 0.01 M PBS buffer containing 0.15 M NaCl pH 7.2.

Example 2

Ointment (lipoll type)

The composition of the additives is as follows.

Ceraalba 12.50 g

Lanolin 12.00 g

Vaseline album 12.00 g

Paraffin oil 30.00 g

Cholesterol 2.50 g

Distilled water 30.00 g

The additives were mixed and 0.01 U MBO was added to the homogenized mixture with 1 ml of the buffer of Example 1.

Example 3

Plastic based gel

The composition of the additives is as follows.

Polyethylene glycol monoalkyl ether (degree of polymerization 4000) 47.00 g

Polyethylene glycol monoalkyl ether (degree of polymerization 200) 26.50 g

Propylene glycol 25.50 g

The components are mixed and 1 ml of MBO-containing cell extract in physiological saline containing 0.1E MBO and 1 KD molecular weight peptide, 800 KD lipo and glycoproteins is added to the homogenized mixture.

Example 4 Hydrogel

The composition of the additives is as follows. Methyl p-hydroxybenzoic acid methyl ester of hydroxypropyl methylcellulose (HPMC 4000) (Nipagin M)

3.00 g

0.10 g * · »9 · · ·· * ·> · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·––––’ll regard

Distilled water 95.90 g

The HPMC is thawed in a water bath, and the Nipagin M is dissolved in distilled water at 50 ° C.

The Nipagin M solution is cooled and mixed with the melted HPMC. To 1 g of the homogenized mixture, 100 U of MBO was mixed with 1 ml of the buffer of Example 1.

Example 5: Cones

1000 Ε MBO was mixed with 1 ml of the buffer of Example 1 and then added to 99 g of cocoa butter heated to 30 ° C with vigorous stirring.

The mixture was poured into a suppository and frozen at -20 ° C.

Example 6: Vaginal foam

The composition of the additives is as follows.

Polyoxyethylene 23-lauryl ether (Brij 35) 6.50 g

Propylene glycol 5.87 g

Cetyl alcohol 0.07 g

Distilled water 86.50 g

The ingredients were emulsified at 60 ° C with stirring and then cooled to room temperature. 1000 U MBO was added with 1 ml of the buffer of Example 1. The mixture is filled into a glass aerosol can and filled with the appropriate quality LPG propellant.

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Example 7

Solution

The composition of the additives is as follows.

Polyvinylpyrrolidone C-30 (PVP) 1.00 g methyl p-hydroxybenzoate (Nipagin Μ) 0.10 g

PBS buffer (pH 6.7) 97.50 g

Nipagin M is dissolved in phosphate buffer at 20 ° C. PVP was swollen into the solution. At room temperature, 1 ml of the active ingredient, the composition of Example 3, was added. Fill it into a metering pump bottle.

EXAMPLE 8 Functional Example

The composition of Example 1 was used to treat 14 volunteers by applying a thin layer of vitiligo to the affected area of the body in the morning and evening.

The treatment was performed for 3 months.

The results were evaluated by visual inspection.

The patients included 6 men (18-54 years) and 8 women (21-63 years). their disease has been present for a period of 6 months to 20 years.

Periodic repigmentation of the depigmented area was observed in 4 patients during the three-month treatment period. For the others, repigmentation reached at least 50% of the bleached area, with healing partly in the form of protrusions from the edges, and partly in the form of islands and growing sharp-edged brown shapes on the bleached areas. Repigmentation developed after treatment was sustained and did not change after 6 months, so it did not decrease, nor did it increase.

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Some patients who developed vitiligo on the exposed skin surface had only one-sided treatment at the start of treatment, but in some cases, there was evidence of improvement on the untreated skin surface as well.

Claims (6)

An external pharmaceutical, therapeutic or cosmetic composition for the treatment or reduction of the symptoms of skin diseases, in particular vitiligo or immunological diseases, comprising 0.1 to 100,000 U of myeloperoxidase and 100 parts by weight of a liquid or solid carrier, buffer and other known contains additives. Composition according to Claim 1, characterized in that the liquid carrier comprises distilled water, vegetable or mineral oil. Composition according to claim 1, characterized in that the solid carrier is vegetable or animal fat, wax or polymer. 4. Composition according to claims 1 to 3, characterized in that it contains a phosphate buffer as a buffer. 5. Composition according to claims 1 to 3, characterized in that it contains myeloperoxidase in pure form or as an extract of cells. 6. The use of myoleperoxidase in pure form or as an extract of cells as an external agent, characterized in that it is used for the treatment of skin and immunological diseases.