CZ295316B6 - Medicament for treating leg ulcers and decubital ulcers - Google Patents

Abstract

In the present invention, there are disclosed powder preparations containing at least one compound of the general formula I, and being useful in the treatment of leg ulcers or decubital ulcers.

Description

Technical field

The present invention relates to the use of a powder formulation containing hydroxypyridones for the treatment of leg ulcers (Ulcus cruris) and pressure sores (pressure sores).

BACKGROUND OF THE INVENTION

The diagnosis of leg ulcers (Ulcus cruris) is a collective term that refers to ulcers of various origins [Phlebologie (1996); 25; 254-258],

In Germany, about 1.6 million people are affected by poorly healing leg ulcers. A prerequisite for the effective treatment of damage resulting from a leg ulcer is to recognize the possible causes of the defect. In general, this is a disturbed blood flow to the lower leg vessels. The resulting limited oxygen supply induces lesions, tissue loss and then necrotization and spreading of the defect. Bacterial and fungal infections affect the affected areas of the skin, thus contributing to the formation of a stinking secretion in addition to wound enlargement.

Therapy of leg ulcer consists of a dual strategy, namely local treatment of the wound and at the same time eliminating the causes of ulceration. Compression therapy in ulcer, which is caused by chronic venous hypertonia, can be used for this purpose, as well as rehabilitation of the arterial bloodstream in arterial leg ulcer.

As a matter of principle, local ulcer therapy for venous ulcer should be used to avoid as much as possible polypragmazia when using medicines, as it often causes multivalent contact allergy to patients with venous ulcer, especially drug substances, during long-term local therapy. Topical therapeutics should therefore be as simple as possible and the number of substances used should be as low as possible.

For topical treatment of leg ulcers, two methods of treatment are currently acceptable, in particular wound-adapted and phase-wound treatment. These therapeutic concepts refer to the three phases of wound healing, which proceed as follows:

exudation phase, (often caused by ulcer superinfection), granulation phase, epithelialization phase.

Treatment of wounds, which is adapted to the phases, corresponds to conventional, long-known therapy, has to be constantly changed and is demanding but financially advantageous. Transbound therapy using wound dressings that can be treated in the same way during all three phases is considerably simpler, but also more expensive to apply. The two therapeutic procedures are comparable in their therapeutic effect.

Wound healing, which is adapted to the phases, intervenes in the three phases of wound healing as follows:

purification, granulation support, drying epithelization support.

The aim of cleaning is to prepare a clean wound base. Above all, grease and crust and possibly necrosis residues, if any, must be removed. This is best done with a sharp spoon and tweezers

And scissors. In addition, ointments containing enzymes that preferably degrade denatured protein may be used. They contain substances such as trypsin, chymotrypsin, collagenase, fibrolysin, streptokinase, etc. The ulcer area should be protected by applying a hard zinc paste. At the same time, regular disinfection is performed with baths with potassium permanganate or Rivanol ^R.

The use of topical antibiotics should not be envisaged, since not only the development of resistance is high, but also the considerable amount of sensitization.

The granulation is stimulated by mechanical irritation. Therefore, even nowadays curettage with a sharp spoon is a very successful intervention. A little more finely, the wound base can be irritated by sea sand, granulated sugar or powdered dextran. Also hypertonic solutions of grape sugar and sodium chloride promote granulation. Previously common treatments with ointments, dyes and refined mineral oils are currently not recommended, as they often cause contact allergies when used for extended periods.

In the epithelialization phase, sensitive, newly formed tissue should be protected and epithelialization promoted. Epithelization begins when the granulating tissue reaches the skin level. A wide variety of preparations, such as hydrogels, hydrocolloids, foam compresses, and lattice gauze, are suitable for wound coverage that promote epithelization. Skin graft transplantation can also be performed.

In the treatment of wounds that exceed the phase, for example, dry wound dressing or gel (dry dressing and xerogel) as well as hydrocolloid wound dressing (hydrocolloid dressings) are applied. At each stage they develop their effect and can be used as monotherapy to treat leg ulcer. Their properties include exudate retention, ulcer cleansing, as well as support for granulation and epithelization.

According to publications from England, Denmark, Canada, Switzerland, South Africa and the USA, 1 to 11% of all patients in the hospital had bedsores. This is due to rising life expectancy, the increase in patients at risk, and the fact that more and more severely ill and severely injured patients survive. This is accompanied by an increasing shortage of nursing staff and their constant overloading.

Prolonged skin pressure, together with impaired microcirculation, is the most important factor causing bed sores (National Pressure Ulcer Advisory Panel (1989)). The shear forces acting on the skin and the underlying tissues as well as friction and moisture also play an important role. The less movable the patient, the further the skin is stressed at the same place. In the supine position it is primarily the area of the skin above the sacrum. Thus, elderly patients who are immobile, their blood supply is impaired, or those suffering from neurological disorders are particularly at risk of pressure sores. In addition to relieving the affected areas of the skin, the local treatment of pressure sores is essentially the same as the treatment of leg ulcers.

SUMMARY OF THE INVENTION

It has now been found that powder formulations of hydroxypyridone derivatives are suitable for a simple and inexpensive, transversal phase therapy of leg ulcers and pressure sores. This finding is so surprising since preparations containing hydroxypyridone have hitherto been used exclusively as antimicrobial agents.

-2GB 295316 B6

The invention therefore relates to the use of a powder base and at least one compound of the formula I

OH (I), in which:

R ¹ , R ² and R ³ which are the same or different, a hydrogen atom or a C 1 -C 4 alkyl group,

R ^{4 is a} saturated hydrocarbon radical having 6 to 9 carbon atoms or a radical of formula II

Ar-Z

(Π) indicating:

X a sulfur atom or an oxygen atom,

Y is hydrogen or up to 2 halogen atoms such as chlorine and / or bromine,

Z is a single bond or bivalent radicals -O-, -S-, -CR ₂ -, where R represents a hydrogen atom or a C 1 -C 4 alkyl group, or other bivalent radicals of 2 to 10 chain-linked carbon atoms and optionally with atoms oxygen and / or sulfur, where the residues contain 2 or more oxygen and / or sulfur atoms - these atoms must be separated by at least 2 carbon atoms, and the 2 adjacent carbon atoms can also be linked to each other by a double bond and the free valencies of the carbon atoms are saturated with hydrogen atoms and / or C 1 -C 4 alkyl groups,

Ar system of aromatic nuclei of up to two nuclei, which may be substituted by up to three radicals selected from the group consisting of fluorine atom, chlorine atom, bromine atom, methoxy group, C 1 -C 4 alkyl group, trifluoromethyl group and trifluoromethoxy group, to produce medicines for the treatment of leg ulcers and / or pressure sores.

The term "saturated hydrocarbon radical" means that the radical may be straight, branched or cyclic and that it contains no aliphatic multiple bonds. Examples of the radical R ⁴ are hexyl, heptyl, octyl, cyclohexyl or cycloheptyl.

In the compound of formula (I), the hydrocarbon radical R ^{@ 4} is preferably an alkyl group having 6 to 8 carbon atoms or a cyclohexyl group which may also be bonded to the pyridone ring via a methylene or ethylene group or may contain an endomethyl group. R ⁴ may also represent an aromatic radical, but is preferably attached to the pyridone radical via at least one aliphatic carbon atom.

In the radicals "Z" are carbon chains articles preferably methylene group -CH ₂ -. When methylene groups are substituted with C 1 -C 4 alkyl groups, methyl and ethyl are preferred substituents.

Examples of "Z" residues are as follows:

-O- -S-, -CH ₂ - - (CH ₂ ) _m - (m = 2-10), -C (CH ₃ ) ₂ - -CH ₂ O- -OCH ₂ -, -CH ₂ S- - SCH ₂ -SCH (C ₂ H ₅ ) -, -ch = ch-ch ₂ o -OCH ₂ CH = CHCH ₂ O- -OCH ₂ CH ₂ O-,

-och ₂ ch ₂ ch ₂ o-, -sch ₂ ch ₂ ch ₂ s- -sch ₂ ch ₂ ch ₂ ch ₂ o-,

-SCH ₂ CH ₂ OCH ₂ CH ₂ O-, -SCH ₂ CH ₂ OCH ₂ CH ₂ OCH ₂ CH ₂ S- or -SCH ₂ C (CH ₃ ) ₂ CH ₂ S-.

The rest of the "S" indicates a sulfur atom, the rest of the "O" indicates an oxygen atom. The term "Ar" refers to phenyl and fused systems such as naphthyl, tetrahydronaphthyl and indenyl, as well as such isolated systems derived from diphenyl, diphenyl alkanes, diphenyl ethers and diphenylthioethers. The term "C 1 -C 4 alkyl" means radicals such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl or tert-butyl.

Important representatives of the group of compounds that are characterized by formula (I) are: 6- [4- (4-chlorophenoxy) -phenoxymethyl] -1-hydroxy-4-methyl-2-pyridone, 6- [4- (2,4 -dichlorophenoxy) -phenoxymethyl] -1-hydroxy-4-methyl-2-pyridone, 6- (diphenylyl-4-oxymethyl) -1-hydroxy-4-methyl-2-pyridone, 6- (4-benzylphenoxymethyl) -1 -hydroxy-4-methyl-2-pyridone, 6- [4- (2,4-dichlorobenzyloxy) -phenoxymethyl] -1-hydroxy-4-methyl-2-pyridone, 6- [4- (4-chlorophenoxy) - phenoxymethyl] -1-hydroxy-3,4-dimethyl-2-pyridone, 6 - [(2,4-dichlorobenzyl) -phenoxymethyl] -1-hydroxy-3,4-dimethyl-2-pyridone, 6- [4- (Cinnamyloxy) -phenoxymethyl] -1-hydroxy-4-methyl-2-pyridone, 1-hydroxy-4-methyl-6- [4- (4-trifluoromethylphenoxy) phenoxymethyl] -2-pyridone, 1-hydroxy-4 - methyl-6-cyclohexyl-2-pyridone, 1-hydroxy-4-methyl-6- (2,4,4-trimethylpentyl) -2-pyridone, 1-hydroxy-4-methyl-6-n-hexyl, - 6-iso-hexyl-, 6-n-heptyl- or 6-iso-heptyl-2-pyridone, 1-hydroxy-4-methyl-6-octyl- or -6-isooctyl-2-pyridone, especially 1-hydroxy -4-methyl-6-cyclohexylmethyl- or -6-cycl ohexylethyl-2-pyridone, wherein the cyclohexyl radical may also carry a methyl radical,

-hydroxy-4-methyl-6- (2-bicyclo [2.2.1] heptyl) -2-pyridone, 1-hydroxy-3,4-dimethyl-6-benzyl- or -6-dimethylbenzyl-2-pyridone or 1-hydroxy-4-methyl-6- (P-phenylethyl) -2-pyridone.

The above compounds of formula (I) may be used both in free form and in salt form, with the free form being preferred.

-4GB 295316 B6

The active compounds, i.e. the compounds of the formula I which can be used in the preparations, can be prepared, for example, by the method of U.S. Pat. Nos. 2,540,218 or 4,797,409.

Powder formulations are particularly suitable for the use of the compounds according to the invention.

In the compositions of the invention, the active ingredient is incorporated in amounts which are usually in the range of about 0.05% by weight. about 15 wt.%, preferably in the range of 0.1 wt.%, to about 1 wt.

By the medicaments according to the invention, a topical improvement can be achieved when topically applied to the leg ulcers and bedsores.

Suitable powder bases are native substances such as sucrose, lactose, gelatin, pectin, carrageenan, agar, tragacanth and alginates, semisynthetic powder bases such as cellulose ethers, starch derivatives, dextran and pectin, as well as synthetic compounds such as polyvinylpyrrolidone. Modified types of starches are extremely aqueous. They are used in an amount of from 95.0 to 99.4 wt. parts, based on 100 wt. parts of the final product.

Highly disperse silica to improve flowability and spreadability is suitable as another excipient for the pharmaceutical formulation of the invention.

The preparation of the preparations can be carried out in a known manner by mixing the individual components and, if necessary, further processing adapted to the particular preparation.

The invention is illustrated by the following examples without being limited thereto. Unless otherwise noted, quantity data refer to weight.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

The composition according to the invention has the following composition:

6-Cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone salt with 2-aminoethanol

Highly disperse silica

Modified maize starch, phosphatized

Example 2

The composition according to the invention has the following composition:

1-hydroxy-4-methyl-6- (2,4,4-trimethylpentyl-2 (1 H) -pyridone Sucrose

1,00 g

0.01 g

98.99 g

0.50 g

99,50 g

Example 3

The composition according to the invention has the following composition:

6- [4- (4-Chloro-phenoxy) -phenoxymethyl] -1-hydroxy-4-methyl-2 (1H) -pyridone

Lactose

0.25 g

99.75 g

Example 4

Efficacy test

In a clinical study in patients suffering from poorly healing leg ulcers, it was shown that after 6 weeks of treatment with the composition of the invention of Example 1, the ulcer area decreased by 80%. In comparison, the wound size after standard therapy (hydrogen peroxide, potassium permanganate, sodium chloride solution) decreased by only 30%.

Industrial applicability

The medicament for the treatment of leg ulcers and pressure sores, which has been formulated as a powder and which contains the active ingredient 1-hydroxy-4-pyridone in admixture with a suitable powder component, is both simple to manufacture and has shown significantly higher efficacy compared to standard therapy.

Claims (8)

PATENT CLAIMS Use of a powder base and at least one 1-hydroxy-2-pyridone of the general formula I (i), in which: R ^1, R ² and R ³ are the same or different, are hydrogen or alkyl having 1 to 4 carbon atoms, R ^{4 is a} saturated hydrocarbon radical having 6 to 9 carbon atoms or a radical of formula II -6GB 295316 B6 where: X a sulfur atom or an oxygen atom, Y is hydrogen or up to 2 halogen atoms such as chlorine and / or bromine, Z is a single bond or divalent radicals -O-, -S-, -CR ₂ -, wherein R represents a hydrogen atom or a C 1 -C 4 alkyl group, or other divalent radicals of 2 to 10 chain-linked carbon atoms and optionally with oxygen and / or sulfur atoms, where, when the residues contain 2 or more oxygen and / or sulfur atoms, these atoms must be separated by at least 2 carbon atoms, and the 2 adjacent carbon atoms may also be linked to each other by a double bond and the free valences of the atoms carbon are saturated with hydrogen atoms and / or C 1 -C 4 alkyl groups, Ar system of aromatic nuclei of up to two nuclei, which may be substituted with up to three radicals selected from the group consisting of fluorine atom, chlorine atom, bromine atom, methoxy group, C 1 -C 4 alkyl group, trifluoromethyl group and trifluoromethoxy group, to produce medicines for the treatment of leg ulcers and / or pressure sores. Use according to claim 1, characterized in that a compound of the formula I is used in which Ar represents a bicyclic system which is derived from diphenyl, diphenyl alkane or diphenyl ether. Use according to claim 1 or 2, characterized in that the compound of the formula I in the position of the substituent R ⁴ contains a cyclohexyl radical. Use according to one or more of claims 1 to 3, characterized in that the compound of the formula I in the position of the substituent R ⁴ contains an octyl radical of the formula -CH ₂ -CH (CH ₃ ) -CH ₂ -C (CH ₃ ) ₃ . Use according to claim 1, characterized in that 1-hydroxy-4-methyl-6- [4- (4-chlorophenoxy) -phenoxymethyl] -2- (1H) -pyridone, 1-hydroxy-4-methyl is used. 1-6-cyclohexy-1-2 (1H-pyridone or 1-hydroxy-4-methyl-6- (2,4,4-trimethylphenyl) -2- (1H) -pyridone). Use according to one or more of claims 1 to 5, characterized in that a modified maize starch, sucrose, lactose or a mixture thereof is used as the powder base. Use according to one or more of Claims 1 to 6, characterized in that a highly dispersed silica is additionally used. Use according to one or more of claims 1 to 7, characterized in that 1-hydroxy-2-pyridone of the formula I is used in an amount of from 0.05% by weight. % to about 5 wt.%, preferably from 0.1 wt. % to 1 wt.