DE2634908C2 - - Google Patents

Description

The present invention relates to the external Treatment of skin diseases using 1,3-bis- (2-carboxychromon-5-yloxy) -2-hydroxypropane (salts). Compounds of the general formula:

and their therapeutically acceptable salts, esters and amides, in which R¹, R², R³, R⁴, R⁵ and R⁶, the same or different can be low, each for H or halogen Alkyl, hydroxy, low alkoxy, low alkenyl, benzyloxy, Nitro, substituted low alkyl or substituted are lower alkoxy and X is a saturated or unsaturated, substituted or unsubstituted, straight or branched polymethylene chain stands by one or several carbocyclic rings or oxygen-containing heterocyclic Rings, oxygen atoms or carbonyl groups are interrupted, are allergic to treatment Diseases, especially allergic asthma Administration by inhalation of a powder formulation or a mist-like aqueous formulation been.

Surprisingly, it has now been found that the 1,3-bis (2-carboxychromon-5-yloxy) -2-hydroxypropane or their Salts when administered externally to the skin of a Mammal or human pharmacological activity show and so for the treatment of chronic skin diseases displayed in humans and animals (e.g. cats and dogs) are.

So prove u. a. Letters from medical professionals in the "Medical Journal of Australia ", 1978, 2, page 32 and in" Medical News ", 1978, 10, page 6 and in" Family Practitioner ", 3 (3), 1978, Page 10 published the effectiveness of sodium cromoglycate  in the treatment of skin ulcers where others recognized good means failed. The corresponding goes from the Abstract of the article in the "Journal of Skin Diseases", 57, No. 14, 1982, where also pointed out is that by treating sodium cromoglycate z. B. complete in 3 patients within 6 to 8 weeks Healing of the ulcers that previously met occurred six months of local treatment proved resistant had.

The present invention therefore creates one possibility for the treatment of chronic skin diseases in which allergic or immune reactions play a role.

The invention relates to the use of 1,3-bis (2-carboxychromon-5-yloxy) -2-hydroxypropane or one pharmaceutically acceptable salt thereof for external Treatment of skin diseases.

Suitable pharmaceutically acceptable salts of said compound include e.g. B. ammonium salts, alkali metal salts (such as sodium, potassium and lithium), alkaline earth metal salts (such as magnesium and calcium) and salts with organic amines, (eg. Mono-, di- or trialkyl-C _1-6 amines, piperidine and trialkanol -C _1-6 amine salts).

According to the invention, particularly preferred compounds of formula I and derivatives thereof are e.g. B. this:
Disodium salt of 1,3-bis (2-carboxychromon-5-yloxy) -2-hydroxypropane,
1,3-bis (2-carboxychromon-5-yloxy) -2-hydroxypropane,
Calcium salt of 1,3-bis (2-carboxychromon-5-yloxy) -2-hydroxypropane,
Magnesium salt of 1,3-bis (2-carboxychromon-5-yloxy) -2-hydroxypropane
and the
Dipiperidine salt of 1,3-bis (2-carboxychromon-5-yloxy) -2-hydroxypropane.

The 1,3-bis (2-carboxychromon-5-yloxy) -2-hydroxypropane or a pharmaceutically acceptable salt thereof (hereinafter Chromon compound called) can locally on the skin tissue of humans or animals (e.g. cat or dog) in any suitable formulation can be applied. The Chromon compound is preferably formulated as an ointment, in which the finely ground chromon compound in one Wax, fat, protein or paraffin base, in particular a soft paraffin base is dispersed. The ointment base can be liquid paraffin, hard paraffin and Include wool fat.

According to the invention, a preparation is preferably used which is a major proportion (e.g. 70-90% w / w) of a white or yellow soft paraffins and a lower percentage a liquid paraffin 5-15% w / w) and one hard paraffins (0-12% w / w).

The ointment can also contain other liquid components, such as water or contain a polyethylene glycol for consistency based to improve a solvent for the active To create component so that this by filtration can be sterilized and / or at the release rate of the active ingredient from the foundation to change.

The chromone compound can also be used as an oil-in-water type cream or water-in-oil type. Suitable Emulsifiers of the former type include sodium, potassium, Ammonium and triethanolamine soaps, polysorbates and cationic, anionic and non-ionic emulsifying waxes. Suitable emulsifiers for the latter type include Calcium soaps, wool fat, wool alcohols, beeswax and certain Sorbitan esters.

The ointment and cream preparations can optionally be one effective portion of a pharmaceutically acceptable preservative or sterilizing agent included for  an ointment or cream is suitable; Preservative are z. B .:

• (i) chlorobutol (2,2,2-trichloro-1,1-dimethylethanol hemihydrate), that in the preparation in about 0.5% w / w. present can be;
• (ii) Chlorcresol, which is in the preparation in about 0.05-0.2% w / w. can be present; and
• (iii) methyl p-hydroxybenzoate, alone or in combination with propyl p-hydroxybenzoate. The total concentration of Hydroxybenzoate ester in the preparation can be between about 0.08-0.2% W / w. lie.

Other suitable preservatives include thiomersal. The chromon compound can also be used as a lotion or liniment Dissolve or disperse them in an aqueous or oily basis. In the wording can a suitable preservative can also be used. Ethanol and / or glycerin can be found in the aqueous base be used. Suitable oil bases are arachis oil (peanut oil), Castor oil and other vegetable oils. Where pastes or gels if desired, thickeners can be added to an aqueous Basis to be incorporated. These components can also serve as stabilizing agents for emulsions. Suitable Agents include "carbopol", bentonite, soluble cellulose derivatives (such as sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose), "Veegum" and polyvinyl alcohol.

If necessary, other components such as humectants, Antioxidants, perfumes and pigments, to be present.

The chromon compound can also be formulated as a dust formulation in which two or more components in fine powder form are intimately mixed. The chromon compound can continue as a solution or suspension in a liquid carrier applied to the surface of a solid support and the coated particles are dried. Solid supports that normally sterilized are talc, starch, lactose, Zinc oxide, light kaolin and calcium carbonate.  

A particularly suitable semi-solid foundation is based on a Fatty alcohol / glycol mixture. Suitable fatty alcohols include saturated alkanols with 16-24 C atoms, and suitable Glycols are u. a. 1,2-propylene glycol, 1,3-propylene glycol, Polyethylene glycols with molecular weights of 100-800 and Dipropylene glycol. Fatty alcohol and glycol are between 15-45: 45-85 parts by weight, preferably 20-35: 55-80 parts, present. Optionally, a plasticizer, e.g. B. a polyethylene glycol with a molecular weight of 800-20,000 or 1,2,6-hexanetriol, and / or an agent for better penetration to be present.

The chromon compound (possibly in the form of its salt) can be found in the corresponding pharmaceutical preparations in an amount of 0.5-20% by weight.

Typical formulations of the chromon compound for application on the skin are shown in the following examples:

example 1

Ointment% w / v Chromon compound 10 liquid paraffin BP10 Wool fat BP10 white soft paraffin BP70

Example 2

water-miscible ointment
Chromon compound10 polyethylene glycol 40040 polyethylene glycol 400050

Example 3

aqueous cream
Chromon compound 5 emulsifying ointment BP30 chlorcresol 1 purified water64

Example 4

oily cream
Chromon compound 10

Wool alcohols BP 3

hard paraffin BP12

white soft paraffin BP10

liquid paraffin BP30

purified water 35

Example 5

aqueous lotion
Chromone compound 10 glycerol 20 alcohol (96%) 20 sodium carboxymethyl cellulose 1 purified water 49

Example 6

oily lotion
Chromon compound 15

Arachis Oil85

Example 7

Dust powder
Chromon compound10 Zinc oxide25 Purified talc 10 Sterilizable. Cornstarch55

Example 8

Fatty alcohol / glycol base
Chromone compound10 stearyl alcohol27 propylene glycol63

The chromone compound is common in the above formulations between 5-20% by weight, in particular 10-15% by weight, present. Where solid particles of the chromone compound are present, e.g. B. in a suspension or dispersion or powder formulation this preferably an average particle size between 0.01-10 microns.  

The corresponding pharmaceutical preparations can according to any suitable method, e.g. B. by dry mixing the solid components or grinding them together or by emulsifying an aqueous solution of the chromon compound with an appropriate oil base will.

The chromon compound is preferred on the patient's skin simply by rubbing in an ointment, cream or Paste applied over the affected skin area. The Chromon compound can also be impregnated in gauze or a gauze pad and applied it to the infested surface will; or one which contains the active ingredient Dust powder on the affected area.

The amount of the chromon compound used depends on the Severity and the surface area of the disease to be treated starting, the application repeated at intervals during the day, e.g. B. 1-6 times a day. Of course, a more frequent dose can be used.

The chromon compounds or their pharmaceutically acceptable ones Salts are used in the treatment of various diseases in humans and animals. The dermatoses to be treated include those of the skin mast cells and / or antibody / antigen reactions including eczema, drug fever, Psoriasis, dermatitis herpetiformis, pemphigus and chronic skin ulcers, especially those of humans in tropical climates. The chromon compounds or theirs Salts are particularly useful in the treatment of atopic Eczema in humans.

Example 9

By mixing the disodium salt of 1,3-bis (2-carboxychromon-5-yloxy) -2-hydroxypropane with a petroleum jelly foundation Ointment formulations prepared with 5 or 10 wt .-% disodium salt. These ointments have been used to treat eczema, especially atopic  Eczema, suffering patients by greasing the ointments used on the diseased skin areas 2-4 times a day.

In 16 treated patients there was an improvement after 7-10 days of the itching sensation, and within the 4 months Test duration with the ointment, the skin improved continuously. In In some cases, the improvement was at least as good as it was was expected by using a steroid ointment.

The compound used in the invention and its preparation are described in GB-PS 11 44 905.

Claims (3)

1. Use of 1,3-bis (2-carboxychromon-5-yloxy) -2-hydroxypropane or a pharmaceutically acceptable one Salt of the same for the external treatment of skin diseases. 2. Use according to claim 1, characterized in that the pharmaceutically acceptable salt is the disodium salt is. 3. Use according to claim 1 and 2 in the form of an ointment or cream, with 0.5-20% by weight of the active ingredient are available.