WO2004096367A1

WO2004096367A1 - A wound-cover material containing radical scavengers

Info

Publication number: WO2004096367A1
Application number: PCT/CZ2004/000022
Authority: WO
Inventors: Jiri Michalek; Pavel Novak; Ilja Straskraba; Jiri Vacik; Eva Wirthova
Original assignee: Ustav Makromolekularni Chemie Akademie Ved Ceske Republiky; Wilens, Spol.S.R.O.
Priority date: 2003-04-28
Filing date: 2004-04-22
Publication date: 2004-11-11
Also published as: CZ295826B6; CZ20031187A3

Abstract

A material for wound covers consisting of a polymer carrier based on lightly crosslinked hydrophilic polymers or copolymers formed from one or more monomers, a crosslinker and a physiological biologically active substance with radical scavenger properties. The monomers are selected from the group including 2-hydroxyethyl methacrylate, diethylene glycol methacrylate, triethylene glycol methacrylate, poly(ethylene glycol methacrylate), glycerol methacrylate, alkyl methacrylates, acrylic or methacrylic acid and its salts. The crosslinkers are diacrylate or dimethacrylate esters (preferably ethylene dimethacrylate, diethylene glycol dimethacrylate, triethylene glycol dimethacrylate) in amounts up to 5 wt.% in the polymerization mixture. A physiological biologically active substance with radical scavenging properties is selected from the group of vitamins A, carotenoids, vitamins E, ubiquinones, flavonoids, nicotinamide, uric acid, bilirubin, lipoic acid, glutathione, and melatonin.

Description

A wound-cover material containing radical scavengers

Technical field The invention deals with a wound-cover material containing radical scavengers and method of its preparation.

Background art

A number of hydrophilic materials are known for covers of wounds, which are based on alginates (Sorbalgon®, Paul Hartman, Heywood, Lanes., UK), polyurethanes (Cutifilm,

Beiersdorf AG, Hamburg, Germany), cellulose derivatives (Comfeel®, Coloplast Co.,

Marietta, Georgia, USA), poly(vinylpyrrolidone) (Aqua-gel, KIK-GEL, Ujazd, Poland).

Their action consists in that they form a damp medium on the wound, which aids healing and, at the same time, hinders penetration of infection into the wound from outside. Some of them, in particular materials based on alginates, possess the ability to absorb great amounts of exsudate from the wound.

It is well known that in the healing process, large amounts of various free radicals are formed at the site of lesion by a physiological process and at a considerable rate, known under the designation RONS (reactive oxygen and nitrogen species), which serve for disinfection of the wound. The production of radicals is often excessive and the radicals destroy, in addition to alien microorganisms, also the own cells of the organism. The process is especially perceptible with chronic inflammations, when the production of free radicals hinders wound healing. (Stipek S.,- Antioxidants and free radicals in health and illness (in Czech), Grada Publishing, Praha 2000).

It is also known that sterically hindered amines chemically bonded to polymer carriers aid wound healing by RONS deactivation (Labsky L, Vacik I, Hosek P. CZ PV 1997-3867, Preparation for prevention and healing of inflammatory diseases).

Disclosure of the invention

The subject of the present invention is a material for wound healing, containing radical scavengers, the essence of which is that the material consists of a polymer carrier based on lightly crosslinked hydrophilic polymers or copolymers from one or more monomers, a crosslinker and a physiological, biologically active substance . with radical- scavenging properties selected from the group of vitamins A, carotenoids, vitamins E, ubiquinones, flavonoids, nicotinamide, uric acid, bilirubin, lipoic acid, glutathione, melatonin.

According to the invention, hydrophilic polymers and copolymers are formed from the monomers selected from the group including 2-hydroxyethyl methacrylate, diethylene glycol methacrylate, triethylene glycol methacrylate, poly(ethylene glycol methacrylate), glycerol methacrylate, alkyl methacrylates, 2,3-dihydroxypropyl methacrylate, acrylic or methacrylic acid and their; salts, and containing, at the same time, up to 5 wt.% of crosslinker.

Diacrylate or dimethacrylate esters, to advantage ethylene dimethacrylate, diethylene glycol dimethacrylate and triethylene glycol dimethacrylate, are used as crosslinkers.

Another feature of the invention is that the polymer carrier has the form of a flexible film, powder or gel with a dispersed or dissolved substance having properties of radical scavenger in amounts 0.0001-50 wt. %.

A unique property of the material for wound covers according to the invention is that it consists of well-known components, which underwent long-term clinical tests and which in the combination according to the invention show useful properties. The properties have not yet been utilized, according to the background art.

The material for wound covers according to the invention can have different forms depending on the method of preparation; each of the forms is suitable for a different wound type. Elastic films are prepared by block or solution polymerization in the presence of a radical scavenger. In the block polymerization, the radical scavenger is incorporated in the film by swelling with a solvent containing the dissolved scavenger. The solvent acts in the film as plastifier and enables its good adherence to the wound. The film protects the wound from external contamination, provides a damp medium and deactivates radicals. It can be easily removed without pain.

The material for wound covers according to the invention in the powder form is prepared by precipitation polymerization. The radical scavenger is dissolved in a suspension of the powder in a solvent and the solvent is then evaporated. The powder has the same functions as the film but, in addition, absorbs the wound exsudate up to a multiple of its original weight. The swollen powder is easily separated from the wound in the form of gel. If the material contains methacrylic acid or its salts, it acts also as an ion exchanger. The change of ion medium in the wound affects favourably its healing (Resl V., Healing of Chronic Wounds, in Czech, Grada Publishing, Praha 1997).

The material for wound covers according to the invention in the gel form is obtained from the powder prepared by precipitation polymerization by mixing with a thermodynamically good solvent and a radical scavenger, possibly with addition of an emulgator. As solvents, in particular poly(oxyethylene)s of different molecular weights can be used and their aqueous solutions. The outstanding feature of the gel is its ability to adhere to the wound also in skin folds, where the application of film is not appropriate. The application form is very advantageous in veterinary applications.

In all application forms, the effect of the material for wound covers consists in a synergistic effect of the damp cover of the wound and the ability to deactivate RONS. The wounds treated with the material according to the invention heal without complications, without secondary infections and with successfully proceeding epithelization.

The material for wound covers according to the invention is suitable for the application in traumatic, surgical and chronic wounds. In dependence on the intensity of exsudation, the powder is applied to strongly weeping wounds and film or gel for weakly weeping wounds. The effect of the material for wound covers can be supported by admixing other additives, in particular substances with antibacterial properties, such as antibiotics, corticoids or disinfection agents.

All application forms of the materials for wound covers can be sterilized by some well-known methods. For powders, sterilization by γ-radiation is suitable, for gels and films thermal sterilization in a steam autoclave.

The invention is elucidated in detail in the following examples of embodiment. The examples have only an illustration character and by no means limit the scope of the invention. Examples

All percentages and ratios in the examples are based on weight.

Example 1

A mixture of 5.00 g 2-hydroxyethyl methacrylate, 0.10 g ethylene dimethacrylate, 0.50 g benzoin ethyl ether, 4.83 g poly(ethylene glycol) 300 and 0.10 g retinol acetate was stirred for 10 min. After short bubbling with nitrogen, the polymerization mixture was transferred into a polymerization device consisting of two parallel polypropylene plates of the size 120x120x1 mm separated with a spacer of 0:8 mm thickness. The device was placed under a source of UV light for 30 min. The obtained film was swollen in distilled water and then in an emulsion of the composition 47.5 % distilled water, 48 % poly(ethylene glycol) 300, 4 % tocopherol acetate and 0.5 % surfactant Polysorbate 80. The film dimensions were adjusted to the 10x10 cm size, the film was sealed into an aluminium foil lined with polypropylene and sterilized with steam at 121 °C for 20 min.

Example 2

A mixture of 4.95 g 2-hydroxyethyl methacrylate, 0.10 g ethylene dimethacrylate, 2.97 g poly(ethylene glycol) 300, 1.98 g distilled water, 0.40 g tocopherol acetate and 0.05 g benzoin ethyl ether was stirred until all components dissolved and then polymerized by the method described in Example 1. A homogeneous opaque and elastic film was obtained with drawability of 250 %. The film was packed up and sterilized by the method described in Example 1.

Example 3

A mixture of 2.76 g 2-hydroxyethyl methacrylate, 1.18 g 2,3-dihydroxypropyl methacrylate, 0.05 g ethylene dimethacrylate, 1.00 g glycerol, 0.025 g photoinitiator Darocure 1173 and 0.05 g β-carotene was stirred until all components dissolved and then polymerized by the method described in Example 1. A homogeneous yellowish and elastic film was obtained, which was packed up and sterilized by the method described in Example 1.

Example 4

9.90 g 2-hydroxyethyl methacrylate, 0.10 g ethylene dimethacrylate and 0.10 g 2,2'- azobisisobutyronitrile were dissolved in 100 ml of toluene in a reaction vessel. After short bubbling with nitrogen, the reaction mixture was heated at 80 °C under constant stirring for 120 min. The product was filtered off, washed three times with a small amount of toluene and once with a small amount of w-hexanc and dried in air for 48 h. Then it was dried at the pressure 5 Pa at room temperature for 4 h. The residual content of toluene was 0.009 %. 9.4 g of the thus obtained product was mixed with 30 g of a 1.5% solution of tocopherol acetate in petroleum ether. The petroleum ether was evaporated in air and the product subsequently dried for 4 h at the pressure 5 Pa at room temperature. The resulting product, a white fluffy and loose powder, was stored in polyethylene bottles, 2.5 g in each, and sterilized with a 24 kGy dose of γ-radiation. On equilibrium swelling, the powder absorbed 1.15 g of physiological saline of pH 7.3 per 1 g of dry matter.

Example 5

A powdery polymer was prepared by the method described in Example 4 from 9.40 g 2-hydroxyethyl methacrylate, 0.10 g ethylene dimethacrylate, 0.50 g sodium methacrylate and 0.10 g 2,2'-azobisisobutyronitrile in 100 g of toluene. The polymer was further worked up by the procedure described in Example 4. On equilibrium swelling, the powder absorbed 3.2 g of physiological saline of pH 7.3 per 1 g of dry matter.

Example 6 , . . A powdery polymer was prepared by the method described in Example 4 from a solution of 9.40 g 2-hydroxyethyl methacrylate, 0.10 g ethylene dimethacrylate, 0.20 g methacrylic acid and 0.01 g 2,2'-azobisisobutyronitrile in 100 g of toluene. The polymer was further worked up by the procedure described in Example 4. On equilibrium swelling, the powder absorbed 1.0 g of physiological saline of pH 7.3 per 1 g of dry matter.

Example 7

Into 50 g of the emulsion prepared from 24.5 g distilled water, 25.0 g poly(ethylene glycol) 300, 0.4 g tocopherol acetate, and 0.10 g Polysorbate 80 was successively added, under stirring, 10.0 g of powdery polymer prepared by the method given in Example 4. The mixture was left standing for 24 h until a homogeneous opalescent gel formed. The gel was filled into glass vials, 15 g in each, and into polypropylene blisters, 2.0 g in each and sterilized in a steam autoclave at 121 °C for 20 min.

Example 8 into 50 g of the emulsion prepared from 24.5 g distilled water, 25.0 g poly(clhylcne glycol) 300, 0.4 g retinol acetate, and 0.10 g Polysorbate 80 was successively added, under stirring, 10.0 g of powdery polymer prepared by the method given in Example 4. The mixture was left standing for 24 h until a homogeneous opalescent gel formed. The gel was filled into glass vials, 15 g in each, and into polypropylene blisters, 2.0 g in each and sterilized in a steam autoclave at 121 °C for 20 min.

Example 9

A mixture of 6.92 g 2-hydroxyethyl methacrylate, 2.96 g 2,3-dihydroxypropyl methacrylate, 0.12 g ethylene dimethacrylate, 2.00 g anhydrous glycerol, O.lOg retinol acetate and 0.50 g benzoin ethyl ether was stirred for 10 min and then polymerized by the method described in Example 1. A homogeneous yellowish elastic film was obtained, which was packed and sterilized by the method described in Example 1. The film absorbed 52 % of water.

Example 10

A mixture of 9.5 g 2-hydroxyethyl methacrylate, 0.4 g ethyl methacrylate, 0.1 g triethylene glycol dimethacrylate, 2.00 g anhydrous glycerol, 0.10 g retinol acetate and 0.50 g benzoin ethyl ether was stirred for 10 min and then polymerized by the method described in Example 1. The obtained film was packed and sterilized by the method described in Example 1. The film absorbed 38 % of water.

Example 11

A powdery polymer was prepared by the method described in Example 4 from a solution of 4.90 g 2-hydroxyethyl methacrylate, 5.00 g 2,3-dihydroxypropyl methacrylate, 0.10 g ethylene dimethacrylate, and 0.10 g 2,2'-azobisisobutyronitrile in 100 g of toluene. The polymer was further worked up by the procedure described in Example 4. On equilibrium swelling, the powder absorbed 1.5 g of physiological saline of pH 7.3 per 1 g of dry matter.

Example 12 Into the solution prepared by mixing 25.0 g 0.4% aqueous solution of amoxicillin and 25.0 g poly(ethylene glycol) 300 was successively added, under stirring, 10.0 g of the powdery polymer prepared by the method given in Example 4. The mixture was left standing for 24 h until a homogeneous opalescent gel formed. The gel was filled into glass vials, 15 g in each, and into polypropylene blisters, 2.0 g in each. Example 13

0.2 g sodium hydroxide and 0.2 g uric acid were successively dissolved in 24.6 g of distilled water and 25.0 g of poly(ethylene glycol) 300 was added, into the formed solution of pH 8.1 was successively added, under stirring, 10.0 g of the powdery polymer prepared by the method given in Example 4. The mixture was left standing for 24 h until a homogeneous opalescent gel formed. The gel was filled into glass vials, 15 g in each, and into polypropylene blisters, 2.0 g in each and sterilized in a steam autoclave at 121 °C for 20 min.

Example 14

A bruised laceration on the ear auricle of a three-year tomcat was cleaned and irrigated with physiological saline. After a Shotrapen injection the wound was treated with the powder prepared according to Example 6. The powder was applied three times in 24-h intervals and - then the gel prepared by the method described in Example 8 was applied twice. A week after starting the treatment, the wound healed forming a scar with a small central focus of pure granulation tissue.

Example 15

A wound of forearm and autopodium of the the upper left limb, with deep alterations of periosteum and articular capsule of a six-month German shepherd was cleaned, irrigated with hydrogen peroxide, physiological saline and generally repaired. The wound was treated with the gel prepared according to Example 8. The gel was applied twice in a 24-h interval; the next dressing was after 48 h. On day five of the treatment, the wound was without inflammation and with pure granulations. Three weeks after starting the treatment, the wound was healed forming a scar, with no pain on palpation. The dog normally loaded the limb.

Claims

1. A material for wound covers containing radical scavengers, characteristic in that it consists of a polymer carrier based on lightly crosslinked hydrophilic polymers or copolymers and a physiological biologically active substance with radical scavenger properties, selected from the group of vitamins A, carotenoids, vitamins E, ubiquinones, flavonoids, nicotinamide, uric acid, bilirubin, lipoic acid, glutathione, and melatonin.

2. A material for wound covers according to Claim 1, characteristic in that the hydrophilic polymers or copolymers are formed from monomers selected from the group including 2- hydroxyethyl methacrylate, diethylene glycol methacrylate, triethylene glycol methacrylate, poly(ethylene glycol) methacrylate, glycerol methacrylate, alkyl methacrylates, 2,3-dihydroxypropyl methacrylate, acrylic or methacrylic acid and their salts and, at the same time, a crosslinker in an amount up to 5 wt.% .

3. A material for wound covers according to Claims 1 and 2, characteristic in that the crosslinkers are diacrylate or dimethacrylate esters, preferably ethylene dimethacrylate, diethylene glycol dimethacrylate, triethylene glycol dimethacrylate.

4. A material for wound covers according to Claims 1 - 3, characteristic in that the polymer carrier in the form of an elastic film, powder or gel contains a dispersed or dissolved substance with radical scavenger properties in amounts 0.0001 - 50 wt.%.

5. A material for wound covers according to Claims 1 - 4, characteristic in that the polymer carrier contains, in addition to a substance with radical scavenging properties, one or more substances selected from the groups of substances with disinfection properties, antibiotics or corticoids.