HK1034447B - Utilization of powder preparations containing hydroxypyridones for treating leg ulcers and decubitus ulcers - Google Patents

Description

Use of powder formulations containing hydroxypyridones for the treatment of leg ulcers and pressure ulcers

The invention relates to the use of powder preparations containing hydroxypyridones for treating leg ulcers (leg ulcers) and pressure ulcers (decubitus ulcers).

Diagnosis of leg ulcers (ulcers of the lower extremities) is a collective term, including ulcers of different origins (Phlebologie (1996); 25: 254-. In germany, about one hundred and sixty thousand people do not have a complete cure for leg ulcers. A prerequisite for effective treatment of ulcer wounds of the lower limbs is the determination of the likely cause of the development of the defect. It is generally considered that blood flow disturbance in the blood vessel of the lower limb exists. The resulting insufficient oxygen supply to the tissue causes damage, tissue loss, and ultimately necrosis and dilation of the defect. Bacterial and fungal infections invade the skin at the affected site, causing malodour to be emitted in addition to enlarging the wound.

The treatment of lower limb ulcers consists of a dual strategy of topical wound treatment and elimination of the cause of the ulcer. The latter may include compression therapy for ulcers caused by chronic venous hypertension and restoration of the arterial system for ulcers of the arterial lower limb.

In the course of topical treatment of ulcers, it must always be considered in principle that the use of compound medicaments is avoided, if possible, since patients often have multiple contact allergies, in particular for topical treatment sometimes several years of composition are applied. The topical therapeutic composition should therefore be as simple as possible and the amount of substance used should be kept as small as possible.

Currently, two treatment methods are accepted for topical ulcer therapy, namely stage-adaptive and stage-overlapping wound treatment. These treatment strategies involve 3 phases of wound healing as follows:

exudation stage

(frequently triggered by repeated infection with ulcers)

Granulation stage

Stage of epithelialization

Staged adaptive wound healing is equivalent to conventional, traditional therapies, which must be constantly changing, complex and low cost. Phase-overlapping therapy makes use of modern wound dressings, making it possible to treat all 3 phases in the same way, with a very simple operation, but at a very high cost. These two treatments are comparable in therapeutic effect to each other.

Phase-adaptive wound therapy intervenes in the 3 phases of wound healing as follows:

cleaning

Promoting granulation

Promotion of epithelialization by desiccation

The purpose of the cleaning is to create a clean wound bed. For this purpose, it is necessary to first remove the residual ointment and scab and cut away any necrotic sites. The most important operation of excisionThis is done with a sharp spoon, forceps and scissors. It is also possible to use enzyme ointments which preferably degrade denatured proteins. They contain trypsin, chymotrypsin, collagenase, plasmin, streptokinase and other substances. During this process, the environment surrounding the ulcer should always be protected by the application of a hard zinc paste. With simultaneous timed sterilisation, e.g. with potassium permanganate or rivanol^And (4) bathing.

The use of local antibiotics should be avoided because on the one hand resistance is created and on the other hand the speed of sensitization is high.

Granulation is promoted by mechanical stimulation. This is why curettage with a sharp spoon is still a very successful treatment. The use of sea sand, crystalline sugar or dextran powder may be milder in the irritation of the wound bed. Hypertonic glucose and sodium chloride solutions also promote granulation. These treatments, which were previously often used in combination with ointments, dyes and refined mineral oils, are no longer recommended because they frequently cause contact allergies over long periods of use.

Sensitive neogenetic tissue should be protected during the epithelialization phase, promoting epithelialization. Epithelialization begins with granulation tissue reaching the upper plane of the skin. There are many products suitable as wound dressings that promote epithelialization, such as hydrogels, hydrocolloids, foam compresses, and gauze meshes. Also, transplantation of separated skin can be performed.

In stage-overlapping wound therapy, for example, dry wound dressings and gels (dry dressings and xerogels) and hydrocolloid wound dressings (hydrocolloid dressings) are used. They act at all stages and can be used as monotherapy for the treatment of lower limb ulcers. Their properties include trapping exudate, cleansing ulcers, and promoting granulation and epithelialization.

According to publications from england, danish, canada, sweden, south africa and the us, 1 to 11% of all hospitalized patients suffer from decubitus ulcers: the reasons for this relate to the increasing life expectancy, the increase in patients at risk, and the fact that increasing numbers of critically ill and severely injured patients survive. Other factors are the ever increasing shortage of caregivers and their continued work.

Long-term pressure on the skin makes microcirculation impaired, the most important factor causing pressure ulcers (national pressure ulcer counselor (1989)). Shear forces acting on the skin and underlying tissue, as well as friction and moisture, also play an important role. A reduction in patient activity means that the stress on the skin at the same point lasts longer. In the supine position, this is particularly the sacral region of the skin. Patients susceptible to pressure ulcers, therefore, are particularly elderly, and have difficulty moving, disturbed blood flow, or neurological disorders. The topical treatment of decubitus ulcers is in principle the same as for leg ulcers, except for relieving pressure on the skin of the affected area.

It has now been found that powder formulations of hydroxypyridone derivatives are very suitable for simple and low cost, phase-overlapping topical treatment of leg ulcers and pressure ulcers. This finding is surprising, since formulations containing hydroxypyridone have hitherto been used exclusively as antimicrobial agents.

The invention therefore relates to the use of a powder and at least one compound of the formula I for the production of a medicament for the treatment of leg ulcers and/or decubitus ulcers,

wherein R is¹、R²And R³Are identical or different and are a hydrogen atom or an alkyl radical having 1 to 4 carbon atoms, R⁴Is a saturated hydrocarbon radical having from 6 to 9 carbon atoms or a radical of the formula II,

wherein

X is S or O, and X is S or O,

y is a hydrogen atom or up to 2 halogen atoms, for example chlorine and/or bromine,

z is a single bond or a divalent group O, S, -CR₂-, wherein R is hydrogen or C₁-C₄-alkyl, or Z is another divalent radical having 2 to 10 chain-connected C and optionally O and/or S atoms, wherein it is necessary if the radical contains 2 or more O and/or S atoms-the latter being separated from one another by at least 2C atoms when connected, and wherein 2 adjacent C atoms may be connected to one another by a double bond and the free valences of the C atoms are replaced by H and/or C₁-C₄-the saturation of the alkyl groups,

ar is an aromatic ring system having up to two rings which may be substituted with up to three groups selected from fluorine, chlorine, bromine, methoxy, C₁-C₄-alkyl, trifluoromethyl and trifluoromethoxy.

The term "saturated hydrocarbon group" means that the hydrocarbon group may be linear, branched or cyclic, and does not contain aliphatic multiple bonds. R⁴Examples of radicals are hexyl, heptyl, octyl, cyclohexyl or cycloheptyl.

Hydrocarbyl radicals R in the Compounds of formula I⁴Preferably C₆-C₈Alkyl or cyclohexyl, which may also be linked to the pyridone ring via a methylene or ethylene group, or may contain a bridged methyl group. R⁴It may also be an aryl group, although it is preferably attached to the pyridonyl group through at least one aliphatic C atom.

The C chain unit in the "Z" group is preferably CH₂And (4) a base. If the CH is₂Radical quilt C₁-C₄Alkyl substitution, then the preferred substituent is CH₃And C₂H₅。

Examples of "Z" groups are: -O-, -S-, -CH₂-，-(CH₂)_m-(m＝2-10)，-C(CH₃)₂-，-CH₂O-，OCH₂-，-CH₂S-，-SCH₂-，-SCH(C₂H₅)-，-CH＝CH-CH₂O-，-OCH₂CH＝CHCH₂O-，-OCH₂CH₂O-，-OCH₂CH₂CH₂O-，-SCH₂CH₂CH₂S-，-SCH₂CH₂CH₂CH₂O-，-SCH₂CH₂OCH₂CH₂O-，-SCH₂CH₂OCH₂CH₂OCH₂CH₂S-, or-SCH₂C(CH₃)₂CH₂S-.

The "S" group refers to a sulfur atom and the "O" group refers to an oxygen atom. The term "Ar" refers to phenyl and fused systems such as naphthyl, tetrahydronaphthyl and indenyl, as well as to isolated systems such as those derived from biphenyl, diphenylalkane, diphenyl ether and diphenyl sulfide. The term "alkyl group having 1 to 4 carbon atoms" means a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group or a tert-butyl group, and the like.

Important representatives of this class of compounds 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- (biphenyl-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- [4- (2, 4-dichlorobenzyl) phenoxymethyl ] -1-hydroxy-3, 4-dimethyl-2-pyridone;

6- [4- (cinnamoyloxy) 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-isohexyl-, -6-n-heptyl-or-6-isoheptyl-2-pyridone, 1-hydroxy-4-methyl-6-octyl-or-6-isooctyl-2-pyridone, in particular 1-hydroxy-4-methyl-6-cyclohexylmethyl-or-6-cyclohexylethyl-2-pyridone, it being possible for the cyclohexyl group in each case to carry a further methyl group;

1-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- (. beta. -phenethyl-2-pyridone.

The compounds of the formula I mentioned above can be used both in free form and in the form of salts; use in free form is preferred.

The active ingredients of the compounds of formula I for use in the formulations may be prepared, for example, by the methods disclosed in US 2540218 or US 4797409.

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

According to the present invention, the amount of active ingredient added to the formulation is normally between about 0.05 and about 5%, preferably between 0.1 and 1%.

It is entirely possible for the medicament according to the invention to achieve a complete cure for the topical treatment of leg ulcers and decubitus ulcers.

Suitable as powder bases are natural substances, such as sucrose, lactose, gelatin, pectin, carrageenan, agar, tragacanth and alginate; semi-synthetic powder matrices, such as cellulose ethers, starch, dextran and pectin derivatives; fully synthetic substances, such as polyvinylpyrrolidone. Modified starches are particularly suitable. They are used in amounts of 95.0 to 99.4 parts by weight per 100 parts by weight of the final product.

Further auxiliaries which are suitable for the pharmaceutical preparations according to the invention are highly dispersible silicas in order to improve flowability and dustiness.

The formulations are prepared in a manner known per se by mixing the components and, if appropriate, suitable further processing of the respective formulations.

The present invention is illustrated in detail by the following examples, but is not limited thereto. Unless otherwise noted, amounts are by weight.

Example 1

The formulation according to the invention has the following composition: 6-cyclohexyl-1-hydroxy-4-methyl-2 (1H) -pyridone, 1.00g of 2-aminoethanol satz, 0.01g of highly dispersible silicon, 98.99g of phosphated corn starch

Example 2

The formulation according to the invention has the following composition: 1-hydroxy-4-methyl-6- (2, 4, 4-trimethylpentyl) -2(1H) -pyridinone 0.50g sucrose 99.50g

Example 3

The formulation according to the invention has the following composition: 6- [4- (4-chlorophenoxy) phenoxymethyl ] -1-hydroxy-4-methyl-2 (1H) -0.25 g pyridone lactose 99.75g

Example 4

Activity assay

Clinical studies carried out on patients who did not have a complete healing of the leg ulcers showed that the ulcer sites were reduced by 80% after 6 weeks of treatment with the formulation according to example 1 of the present invention. In contrast, the size of the wound was reduced only by about 30% after standard therapy (hydrogen peroxide, potassium permanganate, sodium chloride solution).

Claims (9)

1. Use of a powder base and at least one 1-hydroxy-2-pyridone of formula I for producing a medicament for treating leg ulcers and/or decubitus ulcers

Wherein R is¹、R²And R³Are identical or different and are a hydrogen atom or an alkyl radical having 1 to 4 carbon atoms, R⁴Is a saturated hydrocarbon radical having from 6 to 9 carbon atoms or a radical of the formula II,

wherein

X is S or O, and X is S or O,

y is a hydrogen atom or up to 2 halogen atoms, for example chlorine and/or bromine,

z is a single bond or a divalent group O, S, -CR₂-, wherein R is hydrogen or C₁-C₄-alkyl, or Z is another divalent radical having 2 to 10 chain-connected C and optionally O and/or S-atoms, wherein it is necessary if the radical contains 2 or more O and/or S atoms-the latter being separated from one another by at least 2C atoms when connected, and where 2 adjacent C atoms can be connected to one another by a double bond, and the free valences of the C atoms are replaced by H and/or C₁-C₄-the saturation of the alkyl groups,

ar is an aromatic ring system having up to two rings which may be substituted with up to three groups selected from fluorine, chlorine, bromine, methoxy, C₁-C₄-alkyl, trifluoromethyl and trifluoromethoxy.

2. The use as claimed in claim 1, wherein compounds of the formula I are used in which Ar is a bicyclic ring system derived from biphenyl, diphenylalkane or diphenyl ether.

3. The use as claimed in claim 1 or 2, wherein the compound of formula I is at R⁴A position contains one cyclohexyl group.

4. The use as claimed in claim 1 or 2, wherein the compound of formula I is at R⁴The position containing a radical of formula-CH₂-CH(CH₃)-CH₂-C(CH₃)₃(iii) octyl group (c).

5. The use as claimed in claim 1, wherein 1-hydroxy-4-methyl-6- [4- (4-chlorophenoxy) phenoxymethyl ] -2(1H) -pyridinone, 1-hydroxy-4-methyl-6-cyclohexyl-2 (1H) -pyridinone or 1-hydroxy-4-methyl-6- (2, 4, 4-trimethylpentyl) -2(1H) -pyridinone is used.

6. The use as claimed in claim 1 or 2, wherein modified corn starch, sucrose, lactose or mixtures thereof are used as powder base.

7. The use as claimed in claim 1 or 2, wherein highly dispersible silicas are additionally used.

8. The use as claimed in claim 1 or 2, wherein the 1-hydroxy-2-pyridone of the formula I is used in an amount of from 0.05% to about 5%.

9. The use as claimed in claim 8, wherein the 1-hydroxy-2-pyridone of the formula I is used in an amount of from 0.1% to 1%.