DE2840684A1 - Anti-inflammatory agent - Google Patents

Description

Anti-inflammatory agent

The invention relates to a new method of treating Inflammation in mammals from administration of bis (2-pyridyl-1-oxide) disulfide alone or in combination with non-steroidal anti-inflammatory drugs or corticosteroids as well as new agents containing such compounds.

Bis- (2-pyridyl-n-oxide) disulfide and its adducts have been proven proven effective for the relief and suppression of inflammatory symptoms by topical administration.

It has also been found that even stronger pharmacological Properties for the relief and suppression of inflammation by topical administration of the combination a non-steroid anti-inflammatory agent or a corticosteroid containing a bis (2-pyridylnoxide) disulfide compound, i.e. bis (2-pyridy1-1-oxide) disulfide and / or the adducts of bis (2-pyridy1-1-oxide) disulfide can be obtained according to the invention. More specifically, these adducts have the general formula

(C ₅ H ₄ NOS) ₂ MY _t (I)

where M is zinc, iron, magnesium, tin, cadmium, zirconium, an alkali or alkaline earth metal, Y is the anion of an inorganic one or organic acid and t is either 1 or 2. The anion Y from the group of Halides, sulfates, nitrates, chlorates and acetates are selected, with the chlorides and sulfates being most preferred.

609814/0705

The water-soluble adducts, especially calcium chloride (CaCl ₂ ) or magnesium sulfate (MgSO.), Are particularly preferred. Also included in the adducts according to the invention are the hydrates of the above-mentioned compounds, ie adducts which contain η KUO groups, where η is an integer from 0 to 10. In addition, the adducts (I) can contain one or more substituents on one or both of the pyridine rings, such as alkyl groups, halogen atoms and alkoxy groups. It should also be noted that (C ₅ H ₄ NOS) ₂ , as used in the formula (I) above and in the description, means bis (2-pyridyl-1-oxide) disulfide with the following structural formula:

Θ O

Among the adducts that combine with the anti-inflammatory Non-steroids or corticosteroids can be used according to the invention, the following are mentioned:

Bis (2-pyridyl-1-oxide) disulfide magnesium sulfate, bis (2-pyridyl-1-oxide) disulfide magnesium acetate. Bis (2-pyridy1-1-oxide) disulfide magnesium chloride, Bis (2-pyridy1-1-oxide) disulfide magnesium bromide, Bis (2-pyridyl-1-oxide) disulfide calcium chloride, Bis- (2-pyridy1-1-oxide) -disulphide calcium sulphate, bis- (2-pyridy1-1-oxide) -disulphide calcium nitrate, Bis (2-pyridyl-1-oxide) disulfide calcium acetate, Bis (2-pyridy1-1-oxide) disulfide calcium chlorate, Bis- (2-pyridyl-1-oxide) -disulfidbarium chloride, bis- (2-pyridyl-1-oxide) -disulfidbariumulfat, Bis (2-pyridy1-1-oxide) disulfide barium nitrate, Bis (2-pyridy1-1-oxide) -disulfide-

barium acetate, bis (2-pyridy1-1-oxide) disulfide barium chlorate, Bis (2-pyridyl-1-oxide) -disulfidstrontium chloride, bis- (2-pyridyl-1-oxide) -disulfidstrontium sulfate, Bis (2-pyridyl-1-oxide) disulfide strontium nitrate, Bis (2-pyridy1-1-oxide) -disulfidstrontium acetate, Bis (2-pyridy1-1-oxide) disulfide strontium chlorate, Bis- (2-pyridyl-1-oxide) disulfide potassium chloride, bis (2-pyridyl-1-oxide) disulfide potassium sulfate, Bis (2-pyridyl-1-oxide) disulfide potassium nitrate, Bis (2-pyridy1-1-oxide) disulfide potassium acetate. Bis (2-pyridyl-1-oxide) disulfide potassium chlorate. Bis (2-pyridy1-1-oxide) disulfide sodium chloride, Bis (2-pyridyl-1-oxide) disulfide sodium sulfate, Bis (2-pyridyl-1-oxide) disulfide sodium nitrate, Bis (2-pyridy1-1-oxide) disulfide sodium acetate. Bis (2-pyridy1-1-oxide) disulfide sodium chlorate, Bis (2-pyridy1-1-oxide) disulfide zinc chloride, Bis (2-pyridyl-1-oxide) disulfide zinc sulfate, Bis (2-pyridyl-1-oxide) disulfide zinc nitrate, bis (2-pyridyl-1-oxide) disulfide zinc acetate, Bis (2-pyridyl-1-oxide) disulfide zinc chlorate, Bis (2-pyridy1-1-oxide) disulfide tin (II) chloride, Bis (2-pyridyl-1-oxide) disulfide tin (II) sulfate, bis (2-pyridyl- 1-oxide) disulfide tin (II) nitrate, bis (2-pyridyl-1-oxide) disulfide tin (II) acetate, Bis (2-pyridy1-1-oxide) disulfide tin (II) chlorate, Bis (2-pyridy1-1-oxide) disulfide zirconium chloride, Bis (2-pyridy1-1-oxide) disulfide zirconium sulfate. Bis (2-pyridy1-1-oxide) disulfide zirconium nitrate, Bis (2-pyridyl-1-oxide) disulfide zirconium acetate, Bis (2-pyridyl-1-oxide) disulfide zirconium chlorate, Bis- (2-pyridy1-1-oxide) disulfide iron (II) chloride. Bis- (2-pyridy 1-1 -oxide) -disulphideiron (II) -sulphate, bis- (2-pyridy1-1-oxide) -disulphideiron (II) -nitrate, Bis (2-pyridyl-1-oxide) -disulfideiron (II) -acetate, bis- (2-pyridyl-1-oxide) -disulfideisen (II) -

-. 7 -

chlorate, bis (2-pyridyl-1-oxide) -disulphide lithium sulphate, bis (2-pyridyl-1-oxide) -disulphide lithium nitrate, Bis (2-pyridyl-1-oxide) disulfide lithium acetate and bis (2-pyridyl-1-oxide) disulfide lithium chlorate.

Any of the known effective anti-inflammatory corticosteroids can be used in the invention. Under the suitable corticosteroids are hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone valerate, Traiamcinolone acetonide, fluocinolone acetonide, 16d-hydroxyprednisolone-16 0.17M ~ acetonide, fluorohydrocortisone, 1-dehydrocortisone and similar connections. Preferably the hydrocortisone compounds are used in conjunction with the active adducts I used.

A number of known effective anti-inflammatory nonsteroids can be used in accordance with the invention. Among these suitable non-steroids, 1- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid, d-2- (6-methoxy-2-naphthyl) propionic acid, 1-methyl-5- (4- methylbenzoyl-i-Η-pyrrole) -2-acetic acid, o (-Methyl-4- (2-methylpropyl) benzene acetic acid, 4- (2-methylpropyl) benzene acetic acid, o (-Methyl-3-phenoxybenzenoacetic _{acid r} iA, 3 -Dichloro-4-cyclohexyl phenylacetic acid, 2 ', 4'-difluoro-4-hydroxy-3-biphenyl carboxylic acid and similar compounds may be mentioned.

It has surprisingly been found that the anti-inflammatory Activity of corticosteroids or anti-inflammatory nonsteroids is improved when treated with bis- (2-pyridy1-2-oxide) disulfide and / or its adducts combined.

In accordance with the present invention, there is provided a method for the treatment of inflammation in warm-blooded animals, which consists in giving warm-blooded animals such treatment when necessary an effective amount of bis (2-pyridyl-i-oxide) disulfide and / or the adducts of the formula I alone or in combination with a corticosteroid or an anti-inflammatory Topically administered nonsteroid. When the term "treatment" is used here, it means both curative and curative also prophylactic or preventive treatment.

In addition, it was found that the active compounds used according to the invention have the property on the skin and maintain their anti-inflammatory activity even after washing and rinsing the skin.

The invention also relates to agents for treating mammals, who need anti-inflammatory curative or prophylactic treatment, such as for skin conditions, such as e.g. contact dermatitis, seborrheic dermatitis, non-local Dermatitis, neurodermatitis and the like as well as against other mammalian diseases where symptoms of inflammation and associated pain and fever occur such as rheumatic diseases including arthritis, tendonitis, erythema, sciatic pain and similar human or veterinary conditions wherein treatment with 0.1 to 5% by weight of at least one active compound, preferably takes place with 0.2 to 1.5% by weight of the same. These funds can be in the form of a solution, a cream, a Powder, gel, ointment, lotion or milk. For the treatment of the skin, the active

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These compounds can also be supplements or dermatological cakes, the standard ingredients for compositions of such a type.

The invention also relates to agents or compositions for the treatment of the skin where an anti-inflammatory Treatment of a prophylactic or curative nature is required, such as contact dermatitis, seborrhoeic dermatitis, non-local dermatitis, neurodermatitis and the like as well as in a variety of mammalian diseases and - discomfort where the symptoms of inflammation as well as associated fever and pain occur, such as for rheumatic diseases including arthritis, tendinitis, erythema, sciatic pain and similar symptoms, wherein a composition comprising a combination of a corticosteroid with bis (2-pyridyl-1-oxide) disulfide and / or at least one adduct of formula I in an amount of about 0.05 to 5.0% by weight of the composition, preferably in in an amount of 0.1 to 1.0% by weight of the composition is used. The corticostaroids are in the composition in an amount of 0.01 to 2.5% by weight of the bis (2-pyridyl-1-oxide) disulfide compound in the composition, preferably used in an amount of 0.1 to 1.0% by weight of the bis (2-pyridyl-1-oxide) disulfide compound. These Compositions can be in the form of a solution, cream, powder, gel, ointment, lotion or a milk. For the treatment of the skin, they can also be complementary products or dermatological cakes, which contain the usual constituents for this type of composition.

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The invention also relates to agents for the treatment of Warm-blooded animals that require anti-inflammatory treatment of the skin, such as contact dermatitis, seborrhoeic dermatitis, non-local dermatitis, neurodermatitis and the like as well as in various other mammalian diseases where the symptoms of inflammation and associated fever and pain occurs as in rheumatic diseases including arthritis, tendonitis, sciatic pain, erythema and similar conditions employing a composition comprising the combination of a non-steroid with anti-inflammatory activity and at least bis (2-pyridyl-1-oxide) disulfide or one of the adducts of the formula I in an amount of about 0.05 to 10% by weight of the composition, preferably from about 0.25 to 5.0% by weight of the composition. - The non-steroids are in the composition in an amount of 1 to 40% by weight of the bis (2-pyridyl-1-oxide) disulfide compound in the composition, preferably in an amount of 5 to 25% by weight of this compound used. These compositions can be in the form of solutions, creams, powders, gels, ointments, lotions or one Milk present. For the treatment of the skin, they can also be part of supplement products or dermatological cakes otherwise the same for this type of composition the usual ingredients.

The corticosteroids are used in the composition in an amount of 0.01 to 2.5% by weight of the bis (2-pyridy1-1-oxide) disulfide compound in the composition, preferably in an amount of 0.1 to 1% by weight of the bis (2-

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pyridy1-1-oxide) disulfide compound is used. These compositions can also be in the form of a solution, a cream, a powder, a gel, an ointment, a lotion or a milk. For the treatment of the skin they can also be part of supplements or dermatological products Be cakes that otherwise contain the usual ingredients of these compositions.

The following examples serve to illustrate agents which contain bis (2-pyridyl-1-oxide) disulfide compounds according to the invention contain.

example 1

A cream was made as follows:

Bis (2-pyridy1-1-oxide) disulfide calcium chloride

Hydrocortisone Titanium Dioxide Red Iron Oxide Yellow. Iron oxide Brown iron oxide Chestnut colored iron oxide

Various oxyethylene stearyl alcohols with 33 moles of ethylene oxide

Plyglycol stearate Propyl parahydroxybenzoate water to 100 g

Example 2

The synergistic effect of the combination of hydrocortisone and the adducts of the formula I using bis- (2-pyridyl-

2 G 0.05 G 10 G 0.3 G 0.2 G O, 4 G 0.2 G 7th G 6th G 0.2 G 100 G

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1-oxide) disulfide magnesium sulfate as a representative compound was tested using a modification of the experimental method developed by G. Tonelli, L. Thibault and L. Ringler in "A Bioassay for the Concomitant Assessment of the Anti-phlogistic and Thymolytic Activities of Topically Applied Corticoids "in" Endocrinology ", 77, p. 625 (1965) and by A.P. Roszkowski, W.H. Rooks, A.J. Tomolohis and L.M. Miller in "Anti-inflammatory and Analgetic Properties of d-2- (6'-methoxy-2 * -naphthyl) Propionic Acid (Naproxen) "in" J. Pharm. Exp. Ther. ", 179, page 114 (1971). The mathematical Determination of the synergistic effects of the combinations of bis (2-pyridy1-1-oxide) disulfide magnesium sulfate and Hydrocortisone was done using a modification of the method developed by CG. Van Arman, G.W. Nuss and E.A. Risley in "Interactions of Aspirin, Indomethacin and Other Drugs in Adjuvant-Induced Arthritis In The Rat (appendix)", "J. Pharmacol. Exp. Therap. ", 187, p. 400 (1973).

Hydrocortisone and bis (2-pyridy1-1-oxide) disulfide magnesium sulfate in Ethanol U.S.P. (200 proof) in concentrations of 20, 40 and 80 mg / ml bis (2-pyridyl-1-oxide) disulfide magnesium sulfate and 0.01, 1 "and 10 mg hydrocortisone suspended or solved. In the experiments where the interaction of hydrocortisone and bis (2-pyridyl-1-oxide) disulfide magnesium sulfate To be determined, equal doses of each agent were administered simultaneously after mixing in the alcohol vehicle. Bis (2-pyridyl-1-oxide) disulfide magnesium sulfate formed a fine suspension, while hydrocortisone was in the alcohol was completely soluble.

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The therapeutic effects of bis (2-pyridy1-1-oxide) disulfide magnesium sulfate in local doses of 2, 4 and 8 mg per ear (O _f O1 ml) and hydrocortisone in doses of 0.01, 0.1 and 1 mg per ear (0.1 ml) were measured after application to the left ear of a mouse one hour after the induction of inflammation by local application of an irritating solution, the latter containing 2% croton oil (Amend Drug and Chemical Co., Irvington, NJ Lot 710034) , 73% Diethyl Ether USP (Corco Chemical Corp., Fairless Hills, PA), 20% pyridine (JT Baker Chemical Co., Phillipsburg, PA, Lot 3348) and 5% distilled water. Groups of mice treated with only the croton oil as the irritant solution served as control animals. The right ear of the mouse in each group was not treated.

Four hours after application of the irritating solution (three hours after administration of the agent) both ears were amputated, and a circular section was cut out of each ear using a No. 4 cork drill bit (7 mm inside diameter). The ear sections were then weighed. The increase in weight as a result of the formation of edema caused by the croton oil caused in the treated ear and the reduction in edema caused by treatment with bis (2-pyridy1-1-oxide) disulfide magnesium sulfate, Hydrocortisone or combinations thereof were caused by subtraction the weight of the untreated right ear section is determined by that of the treated left ear section.

The anti-inflammatory effects of bis (2-pyridy1-1-oxide) disulfide magnesium sulfate or hydrocortisone or simultaneously administered equally strong doses as combinations of the two

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the means in terms of percent inhibition were as follows calculated:

Edema weight (control animals) - Edema dedicated (treated animals) _1on edema weight (control ^{animals) x}

The immediate anti-inflammatory effects of bis (2-pyridyl-1-oxide) disulfide magnesium sulfate were through direct

of applying the in a 2% solution / croton oil in 95% Ethanol suspended agent measured. Ethanol was used as the vehicle. In the usual irritating vehicle as above described, contained pyridine gives an alkaline reaction. Control animals were treated with the croton oil vehicle only.

The potential synergistic effects produced by topical co-application of doses of hydrocortisone and Bis (2-pyridyl-2-oxide) disulfide magnesium sulfate were produced, were determined by immediate application (Table I) and by delayed application to an existing inflammation (Table II) determined.

A _i _S2ner2ismus_nach_unmittelbaren_Aufgabe A fixed dose of 4 mg per ear of bis (2-pyridy1-1-oxide) -disulphide magnesium sulphate was applied together with 0.01, 01 and 1 mg of hydrocortisone per ear. Such co-application at the time of initiation of the inflammatory process (Table I) resulted in effects that were less than those expected with simple addition, that is, there was some antagonism of therapeutic effects under these conditions. At the dose of 0.01 mg per ear, hydrocortisone gave 53.3 % inhibition. If the same dose of Hydrocor-

. Away-

tison applied together with 4 mg of bis- (2-pyridy1-1-oxide) disulfide magnesium sulfate (24.9% own inhibition) per ear
only an effect of 39.6% was obtained, while an effect of 58.5% inhibition was expected. This reduction in the effect when combinations of bis (2-pyridyl-1-oxide) disulfide magnesium sulfate and hydrocortisone were applied at the same time was evident at all dosages.

_after_ delayed "application
When an equal dose pair of combinations of bis (2-pyridyl-1-oxide) disulfide magnesium sulfate and hydrocortisone were co-administered to an existing inflammation in the mouse ear, the results listed in Table II were obtained. The observed effects at each dose of the combinations were compared to the expected effect calculated from simple addition. the
The type of interaction between bis (2-pyridy1-1-oxide) disulfide magnesium sulfate and hydrocortisone was dose-dependent and
varied from exponentiation to simple addition.

Doses of bis (2-pyridy1-1-oxide) disulfide magnesium sulfate (0.87 mg per ear) and hydrocortisone (0.00125 mg per ear) would be expected for the compounds as such by extrapolating their respective dose-response curves, that they have little, if any, anti-inflammatory effect.
When the expected effect resulting from a simple addition was calculated from the dose pair combination, a value of 10.6% inhibition was obtained. The observed effect was 46.3%. To get a similar effect from either
Hydrocortisone or bis (2-pyridy1-1-oxide) disulfide magnesium

To get sulfate alone, it would be necessary to give 0.25 mg per ear or 17.7 mg per ear.

A similar potentiation was made with combinations of bis- (2-pyridy1-1-oxide) disulfide magnesium sulfate (1/5 mg per ear) and hydrocortisone (0.004 mg per ear) or bis (2-pyridy1-1-oxide) disulfide magnesium sulfate (1.9 mg per ear) and hydrocortisone (0.005 mg per ear) were observed. Higher dosages of bis (2-pyridyl-1-oxide) disulfide magnesium sulfate in combination with equally strong doses of hydrocortisone resulted in a simple one Addition.

Table I.

Interaction of bis (2-pyridy1-1-oxide) disulfide magnesium sulfate with hydrocortisone after immediate co-administration with that induced by croton oil Inflammation of the mouse ear

Treatment ^a
Control attempt

Bis (2-pyridy1-1-oxide) disulfide magnesium sulfate

Hydrocortisone

Bis (2-pyridy1-1-oxide) disulfide magnes iumsulf at

Hydrocortisone

Bis (2-pyridy1-1-oxide) disulfide magnesium sulfate

Hydrocortisone

percent

Local dose edema weight inhibition of (mg / ear) mg + S .D. ^b. ear edema

16.9 + 3.0

12.7 + 3.0 24.9

13.0 + 3.8 23.1

7.9 + 2.3 53.3

5.5 + 2.6 67.5

14.3 + 2.2 15.4

10.2 + 2.6 39.6

0.01 0.1 1.0

4 0.01

4 0.1

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Yl -

Bis (2-pyridy1-1-oxide) disulfide magnesium sulfate

Hydrocortisone

4th
1.0

8.4 + 2.1

50.3

a) 2% croton oil in 95% ethanol as an irritant; Bis (2-pyridy1-1-oxide) disulfide magnesium sulfate alone or Bis (2-pyridy1-1-oxide) disulfide magnesium sulfate and hydrocortisone, suspended in the same vehicle.

b) standard deviation.

Table II

Interaction of bis (2-pyridy1-1-oxide) disulfide magnesium sulfate with hydrocortisone after delayed co-application to croton oil induced inflammation of the mouse ear

treatment
Control attempts

Bis (2-pyridyl-1-oxide) disulfide magnesium sulfate

Hydrocortisone
(non-alcoholic)

Bis (2-pyridy1-1-oxide) disulfide magnesium sulfate

Hydrocortisone

Bis (2-pyridy1-1-oxide) disulfide magnesium sulfate

Hydrocortisone

percent

local dose edema weight inhibition of (mg / ear) mg + SDb ear edema

14.9 + 3.8

2 12.7 + 2.4 14.8 4th 11.4 + 2.8 23.5 8th 9.6 + 2.2 35.6 0.01 12.3 + 3.3 17.5 0.1 8.9 + 2.3 40.3 1.0 6.2 + 2.4 58.4 0.87 7.9 + 2.5 47.3 0.00125 1.5 9.2 + 2.7 38.1 0.004

90981

Bis (2-pyridyl-1-oxide) -

disulfide magnesia sulfate 1.9 9.5 + 2.4 36.4

Hydrocortisone 0.005

Bis (2-pyridyl-1-oxide) -

disulfide magnesia sulfate 3.7 9.87 + 2.7 34.0

Hydrocortisone 0.02

Bis (2-pyridyl-1-oxide) -

disulfide magnesium sulfate 7.0 8.7 + 2.4 41.6

Hydrocortisone 0.08

a) Agent suspended or dissolved in 95% ethanol and applied one hour after 2% croton oil.

b) standard deviation.

Example 3

A dermatological cleansing cake was made by mixing the following components:

Esters of sodium isothionate and copra fatty acids (under the trade name "IGEPON A" of the formula R-COO-CH ₂ -CH ₂ -SO ₃ Na, where R is fatty acid derivatives with 12 to 15 carbon atoms) 75 g

Lanolin derivatives 22.75 g

(C ₅ H ₄ NOS) ₂ • MgCl ₂ 2 g

Hydrocortisone acetate 0.02 g

Other dermatological cleansing cakes, identical to the above, were made by using the magnesium chloride salt of Bis (2-pyridyl-1-oxide) disulfide by any of the above active connections has been replaced. Any of the corticosteroids mentioned can also be used.

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86 85 g 3 G 7th G 1 G 1 G 2 ecm

Example 4

A powder was made from the following mixture:

talc

Glycerol oleate Isopropylmyri s tat

Bis (2-pyridyl-1-oxide) disulfide magnesium sulfate

1 -Methyl 1-5- (4-methylbenzoy1-1-Η-pyrrole) -2-acetic acid

Perfume (about 1.9 g)

About equally effective powder compositions, identical to that above, is prepared with the exception that the active component bis (2-pyridy1-1-oxide) -disulfidemagnesiumsulfat by any the other active compounds mentioned above.

Example 5

A tincture is made as follows:

Bis (2-pyridy1-1-oxide) disulfide barium acetate 1%

Ethanol 20%

Propylene glycol 10%

Water 69%

Example 6

Bis (2-pyridy1-1-oxide) -disulphide magnesium chloride 1%

Vitamin E 2%

Propylene glycol 20%

Ethanol 20%

Water 57%

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Example 7

The following ointment base was used as a vehicle for the active ingredients according to the invention:

Components Quantity in grams
Polyoxyethylene stearyl ether 5.0

White Vaseline 5.0

Steary alcohol 15.0

Distilled water 63.5

The ointment containing the above active ingredients was prepared as follows: 3.0 g of bis (2-pyridy1-1-oxide) disulfide magnesium sulfate were added to a heated mixture of
Dissolved 59 ml of distilled water and 11.50 g of propylene glycol. This solution was heated to a temperature of 75 ° C and added to a mixture at the same temperature, which consists of
15.0 g of stearyl alcohol, 5.0 g of white petrolatum, 1.0 ml of concentrated ammonia solution and 5.0 g of polyoxyethylene stearyl ether with a molecular weight of about 700. While the resulting mixture was still hot, lactic acid was added to adjust the pH of the mixture to about 5.5, that is, about the pH of the skin. The resulting mixture was then cooled to form a cream which was processed using a three-roll device and placed in tubes
was filled.

In an analogous manner, using the following ingredients for the formation of the initial solutions ointments are made:

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a) 2.27 g of bis (2-pyridy1-1-oxide) disulfide iron (II) chloride in 53.23 ml of distilled water and .11.5 g of propylene glycol,

b) 2.51 g of bis (2-pyridy1-1-oxide) disulfide lithium acetate in 56.19 ml of distilled water and 11.5 g of propylene glycol,

c) 2.62 g of bis (2-pyridy1-1-oxide) disulfide zirconium chloride in 56.35 ml of distilled water and 11.5 g of propylene glycol,

d) 1.0g bis (2-pyridy1-1-oxide) -disulfidstrontium chloride in 60.7 ml of distilled water and 11.5 g of propylene glycol and 0.80 g of sodium hydroxide. In this example, the Solution heated to 75 C and added to a mixture at the same temperature, the 1.0g bis (2-pyridy1-1-oxide) disulfide magnesium sulfate, 13.0 g of stearyl alcohol, 5.0 g of polyoxyethylene stearyl ether with a molecular weight of about 700 and 5.0 grams of white petrolatum. The pH was adjusted with lactic acid and the mixture was cooled to form a cream which was worked up as above.

Example 8

2.5 g bis (2-pyridy1-1-oxide) disulfide magnesium sulfate and 0.05 g hydrocortisone was predispersed in 30.0 g propylene glycol. The mixture was then finished in 97.4 g cream, ointment or lotion homogenized after a modification of one of the methods of Examples 2, 6 and 7, or according to the method, that of F.W. Martin et al in "Remington's Pharmaceutical Sciences" 14th Edition, Mack Publishing Co., Easton, Pa., 1965 has been described.

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Other agents with medical or therapeutic value can also be incorporated into the compositions of the invention.

Example 9

An anti-inflammatory agent in the form of a milk was made from the following ingredients:

Components Weight in grams

Hydrogenated Ethoxylated (10 moles)

Lanolin 1.8

Coconut fatty acid triglyceride 7.0

Cetyl alcohol O, 6

S te aryl alcohol 0.6

Paraffin oil (light) 5.0

Hydrocortisone 0.05

Tearic acid 3.0

Bis (2-pyridy1-1-oxide) -disulfide-

magnesium sulfate, 2.0

Demineralized water 72.2

Triethanolamine 0.8

Perfume 0.5

Carboxy vinyl polymer 2.0

Preservative 2.0

The preparation was carried out as follows: A mixture of 1.8 g of hydrogenated, ethoxylated (10 mol) lanolin and 7.0 g of triglyceride of coconut fatty acid, 0.6 g cetyl alcohol, 0.6 g stearyl alcohol, 5.0 g of paraffin oil, 0.05 g of hydrocortisone and 3.0 g of stearic acid were prepared at 70 ° C. After adding

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Add 2.0 g of bis (2-pyridy1-1-oxide) disulfide magnesium sulfate 2.0 grams of carboxyvinyl polymer in 72.2 grams of demineralized water added to the resulting suspension at 70 ° C. with stirring. The mixture was stirred for 15 minutes and then cooled. 0.8 g of triethanolamine and 0.5 g of perfume were heated at 60 C and 45 ° C added. The resulting mixture was stirred until it was cold and at 3000 rpm for one hour get stable milk. Viscosity 6000 cp (Brockfield, spindle 5, 10 rpm).

9098U / 0785

Claims (9)

Dr. Hans-Heinrich Willrath for Dr. Dieter Weber Diploma in Phys. Klaus Seiflfert PATENTANWÄLTE D - 6200 WIESBADEN 1 15.9.1978 PO Box 6145 GusUY-fteytag-StraSe 25 Dr .We / Wh <g "(0 61 21) 37 2720 P Λ Π RPA Telegram address: WILLPATENT fm W -t UVV * t Telex: 4-186 247 William H. Rorer, Inc., Fort Washington, Pennsylvania, USA Anti-Inflammatory Agent Priorities: Serial Nos. 835 594, 835 595 and 835 596 dated September 22, 1977 in USA Claims File 11221-78 1. Anti-inflammatory agent for topical treatment of Inflammations in warm-blooded animals containing bis (2-pyridyl-1-oxide) disulfide or at least one adduct of bis (2-pyridy1-1-oxide) disulfide the general formula (I) Postal check: Frankfurt / Main 67 6J-402 Buk: Dresdner Btnk AG, Wiesbaden, account no. 276107 ORIGINAL INSPECTED wherein M is zinc, iron, magnesium, tin, cadmium, zirconium Denotes alkali or alkaline earth metal, Y denotes an anion of an inorganic or organic acid and t is 1 or 2, in a customary pharmaceutical carrier material and optionally additionally containing at least one anti-inflammatory Non-steroidal compound and / or at least one corticosteroid. 2. Means according to claim 1, characterized in that M magnesium, Y is sulfate and t is 1. 3. Composition according to claim 1, characterized in that M is calcium, Y is chloride and t 2 is. 4. Composition according to claim 1, characterized in that M is calcium, magnesium or barium. 5. Composition according to claim 1 to 4, characterized in that it is an adduct of bis (2-pyridy1-1-oxide) disulfide (C ₅ H ₄ NOS) ₂ CaCl ₂ , (C ₅ H ₄ NOS) ₂ MgSO ₄ , (C ₅ H ₄ NOS) ₂ SrCl ₂ , (C ₅ H ₄ NOS) ₂ SrBr ₂ , (C ₅ H ₄ NOS) ₂ Ca- (NO ₃ ) ₂ and / or (C ₅ H ₄ NOS) ₂ Contains Ba- (ClO ₃ ) ₂ . 6. Composition according to claim 1 to 5, characterized in that it is a water-soluble adduct of bis (2-pyridy1-1-oxide) disulfide contains. 7. Composition according to claim 1 to 6, characterized in that Y is a halide, sulfate, nitrate or acetate anion. 8. Composition according to claim 1 to 7, characterized in that it is the corticosteroid hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, Hydrocortisone valerate, triamcinolone acetonide, 9098H / 0785 Sorer Oct. 30 1978 ¹ NACHQEREIOHI Contains fluocinolone acetonide, 1 6oC -llydroxyprednisolone-1 6 <X , McC -acetonic fluorohydroccrtisone or 1-dehydrocortisone. 9. Composition according to claim 1 to 8, characterized in that it is the important steroid compound 1- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid, d-2- (6-methoxy-2-naphthyl) - propionic acid, 1-methyl-5- (4-methylbenzoyl) -IH-pyrrole-2-acetic acid, £? C-methyl-4- (2-methylpropyl) benzene acetic acid, 4- (2-methylpropyl) benzene acetic acid, o6- Methyl-3-phenoxybenzeneacetic acid, oil, 3-dichloro-4-cyclohexy! Phenylacetic acid and / or 2 ', 4'-difluoro-4-hydroxyl-3-bipheny! Carboxylic acid. 9098U / 07SS