CZ20002664A3 - Medicament for treating shank ulcers and bedsores - 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

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 ulcers).

Dos_v_stav_techniky

The diagnosis of leg ulcers / Ulcus cruris / ⁴ is a collective term referring 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 the knowledge of the possible causes of the defect. In general, it is a disturbed blood supply 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 attack the affected areas of the skin and contribute 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 the 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.

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For topical treatment of leg ulcers, two methods of treatment are currently acceptable, in particular phase-adjusted and wound-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, epithelization 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. Both therapeutic procedures are comparable with each other by their therapeutic effect.

The 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. In particular, any ointment and crusts and, if necessary, necrosis 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 such substances as trypsin, chymotrypsin, collagenase, fibrolysin, streptokinase and the like. 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 \

The use of topical antibiotics should not be envisaged because it is

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Not only is the development of resistance high, but also a 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, crystal, sugar or powdered dextran. Sodium 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 variety of preparations, such as hydrogels, hydrocolloids, foam compresses, and lattice gauze, are suitable as wound dressings that support epithelization. Skin graft transplantation can also be performed.

In the treatment of wounds that extend beyond 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 growth of 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, along with impaired micro-circulation, is the most important factor that causes pressure sores (National Pressure Ulcer Advisory Panel, 1989). The shear forces acting on the skin and the tissues below it, as well as the friction, also play an important role. , ····· * · ♦ · ♦ · * and humidity. The less movable the patient, the longer the skin is stressed at the same spot. In the supine position it is primarily the area of the skin above the sacrum. Thus, the elderly who are immobile, their blood supply is disturbed, or those suffering from neurological disorders, and relieving the affected areas of the skin, are essentially at risk for local pressure sores as well as for the treatment of leg ulcers.

Substance_of the invention

It has now been found that hydroxypyridone derivative powder formulations are suitable for simple and inexpensive, cross-phase, topical ulcer and pressure sore therapy. This finding is so surprising since preparations 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

in which it means:

3

R, R, and R, which are the same or different, are hydrogen or al-. (1-4C) keel;

R 6 is a C 6 -C 6 saturated hydrocarbon radical or a radical of formula II

Ar-Z

/ 11 /, in which it indicates:

9 9999 9 9 99 9 9 9 9 9 9 9 9 9 9

99 99 99

9 9 9

9 99 99

X a sulfur atom or an oxygen atom,

Y a hydrogen atom or up to 2 halogen atoms such as chlorine and / or bromine, ‘

Z is a single bond or divalent radicals -C-, -3-, wherein R represents a hydrogen atom or a C1-C4 alkyl group, or other divalent radicals having 2 to 10 chain-linked carbon atoms and optionally oxygen and / or sulfur atoms wherein, when the radicals 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 carbon atoms are saturated with hydrogen atoms and / or (C1-C4) 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 group, for the manufacture of a medicament for treating 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 @ 1 are hexyl, heptyl, octyl, cyclonexyl or cycloheptyl.

In formula I represents a hydrocarbyl radical R ^- preferably an alkyl radical with 6-8 carbon atoms or cyclohexyl, which may also be via a methylene or ethylene group bonded to pyridonovájádro or may contain endomethyl group. R 6 may also be an aromatic radical, but is preferably attached to the pyridone radical via at least one aliphatic carbon atom *

In the moieties of the linen moiety, the carbon chain links are preferably methyl-CH ₂ '. When methylene groups are substituted

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- C 1 -C 4 alkyl groups, methyl and ethyl are preferred substituents.

Examples of residues z 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-, -CH ₂ -,

-SCH (C ₂ H _s) -, -CH = CH-CH ₂ -O-. -OCH ₂ CH = CHCH ₂ O- -OCH ₂ CH ₂ O-,

-CH 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 remainder s denotes a sulfur atom, the remainder o denotes an oxygen atom. The term Ar means phenyl and fused systems such as naphthyl, tetrahydronaphthyl and indenyl, as well as such isolated systems which are derived from diphenyl, diphenyl alkanes, diphenyl ethers and diphenylthioethers. The term (C 1 -C 4) -alkyl means radicals such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl or tert-butyl.

Important representatives of the group of compounds which are characterized by the general 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- (4- (2,4-dichlorobenzyl) -phenoxymethyl] -1-hydroxy-5,4-dimethyl-2-pyridone,

6- (4- (cinnamyloxy) -phenoxymethyl] -1-hydroxy-4-methyl-2-pyridone, 1-hydroxy-4-methyl-6- [4- (4-trifluoromethylphenoxy) -phenoxymethyl] -2-pyridone ,

9 9999 • 9

9 9 »

99999 9

9 9 9

999 99 ··

99

9

9 9 9 «

9 9 9 9 ·

9

9 9 99 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, -β-iso-hexyl-, 6-n-heptyl- or 6-iso-heptyl-2-pyridone, 1-hydroxy-4-methyl-6-octyl- or -6-iso -octyl-2-pyridone, in particular 1-hydroxy-4-methyl-6-cyclohexylmethyl or -6-cyclohexylethyl-2-pyridone, wherein the cyclohexyl radical may also carry a methyl radical, 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- T-3-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.

The active compounds, i.e. the compounds of the formula I which can be used in the formulations, can be prepared, for example, according to the methods 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. up to 1 wt.

With the medicaments according to the invention, a topical improvement can be achieved by topical application 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 amounts of from 95.0 to 99.4% by weight. parts, based on ICO wt. parts of the final product.

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Highly disperse silica is useful as an additional excipient for the pharmaceutical formulation of the invention to improve flowability and spreadability.

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.

Examples_of_your_convention_of_the invention

Example 1

The composition according to the invention has the following composition:

6-Cyclohexyl-1-hydroxy-4-methyl-2 H -pyridone salt 1.00 g with 2-aminoethanol

Highly dispersed 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 (1H) pyridone

Saoharosis

0.01 g 98.99 g

0.50 g

99,50 g

Example 3

The composition according to the invention has the following composition:

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 compared to the wound size after standard therapy. hydrogen peroxide, potassium permanganate, sodium chloride solution / decreased only by 30

l.íí®2Sloyá_yyUŽIVNOST

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 significantly more effective than standard therapy.

Claims (8)

Use of a powder and at least one 1-hydroxy-2-pyridone of the general formula I R OH where: R '', Ή2 and R ^, which are the same or different, a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, R @ 6 is a saturated hydrocarbyl radical having 6 to C atoms or a radical of formula II I / 11 /, 'X-CH, Y in which denotes: 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 -C-, -S-, -CRg-, wherein R represents a hydrogen atom or a (C1-C4) alkyl group, or other divalent radicals, having 2 to 10 chain-linked carbon atoms and optionally atoms oxygen and / or sulfur, wherein when the radicals contain 2 or more oxygen and / or sulfur atoms, these atoms must be separated by at least 2 carbon atoms and 2 adjacent carbon atoms; they may also be linked to each other by a double bond and the free valences of the carbon atoms are saturated with hydrogen atoms and / or alkyl groups of 1 to 4 carbon atoms, Ar system of aromatic nuclei up to two nuclei, which may be substituted by up to three residues selected from the group consisting of atom - 11 f f ef ef ef ef ef f f ef f f ef f,,,,,,,, a chlorine atom, a bromine atom, a methoxy group, a C1-C4 alkyl group, a trifluoromethyl group and a trifluoromethoxy group, for the manufacture of a medicament for the treatment of leg ulcers and / or pressure ulcers. 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 1 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 R 1 position contains an octyl radical of the formula ₉ CH CH / CH -CH J _q -C / CE,. Use according to claim 1, characterized in that 1-hydroxy-4-methyl-6- [4- (4-chlorophenoxy) -phenoxymethyl] -2- (1Ξ) -pyridone, 1-hydroxy-4 is used. methyl-6-cyclohexyl-2- (12) -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 0.05% by weight. up to about 5 wt.%, preferably from 0.1 to ⁶ wt. up to 1 wt.