DE102020211389A1 - Wound closure preparation containing active ingredients - Google Patents

Abstract

The present invention relates to a wound closure preparation containing an active ingredient, in particular a sprayable wound closure preparation containing an active ingredient.

Description

The present invention relates to a wound closure preparation containing an active ingredient, in particular a sprayable wound closure preparation containing an active ingredient.

Wound closure preparations are mostly liquid agents that are applied to a wound and close it.

The application is usually done with a spatula or brush (wound balms, wound cream, 'healing ointment') or contactless by spraying. The contactless application has the advantage that no additional germs get into the wound through the applicator and large wounds, such as abrasions or burns, can be treated more quickly.

A flexible film (wound closure film) is formed from the liquid wound closure preparation after application and evaporation of the solvent contained in the wound closure preparation.

Wound closure preparations and the wound closure films formed from them cover the wound without the use of other agents and promote healing. However, wound closure films are usually not particularly resistant to mechanical stress, so that abrasion of the wound closure film can occur, for example, in connection with clothing.

In order to prevent abrasion or the formation of tears in the wound closure film, it can therefore be advantageous to protect the wound covered with the wound closure preparation by additional measures. Wound coverings such as bandages or plasters, which offer 'mechanical' protection, are often used for this purpose.

Furthermore, wound closure preparations can contain dispersed or crosslinkable polymers or hydrogels that form a stable film on the wound that cannot be rubbed off so easily and offers reliable protection against the ingress of dirt or microorganisms. In addition, such polymer films can be 'adjusted' in such a way that water (vapour) or wound secretion can pass through. This has a positive effect on the healing success.

the end DE 2343923 A1 film-forming, sprayable polymer solutions for the production of a wound dressing (wound dressing spray) are known. It is a film-forming polymer solution that can be sprayed in particular from aerosol containers, which is sprayed in thin layers onto a cut, abrasion or surgical wound to be bandaged or otherwise applied after the solvent has evaporated, forming a thin, coherent film that covers the injury site.

Antimicrobial agents have long been known to those skilled in the art. Basically, all substances above a certain concentration have a cell-damaging effect and thus also against microbes (e.g. bacteria, fungi), i.e. antimicrobial. Antimicrobial agents are characterized by the fact that the cell-damaging effect on microbes is higher than on the cells of higher organisms (humans, mammals, fish, etc.).

A relatively new group of antimicrobial agents are antimicrobial peptides, so-called AMP (antimicrobial peptides). These are short amino acid chains with 3 to 5 amino acids. Such AMPs are already used in agriculture because, in contrast to classic fungicides/bactericides, they are easily degradable and do not remain persistent in the environment.

the end SE1751277A1 , SE541313C2 , US9085608B2 and US9556223B2 are known to those skilled in the art of AMP for use as an antimicrobial agent or for inhibiting biofilm formation.

Within the scope of the invention, the terms antimicrobial, antibiotic and antibacterial are used synonymously. The specific effect against microorganisms, in particular fungi, yeasts and bacteria, is always meant.

Liquid dressing materials or liquid plasters are marketed filled with a propellant in aerosol containers, the so-called wound dressing sprays, from which they can be sprayed onto the wound as required by actuating the valve button.

However, it is also known to apply wound closure preparations with a pump sprayer, but this method of application is less uniform due to the pump strokes than when applying as an aerosol.

However, the known sprayable wound closure agents only have a covering task/effect. If the wound is contaminated with microorganisms or even an inflamed wound, a separate antiseptic treatment is required beforehand.

The invention circumvents this disadvantage.

• - mindestens ein synthetisches Polymer,
• - mindestens ein natürliches Polymer,
• - mindestes ein antiseptischer Wirkstoff,

wobei der Antiseptische Wirkstoff kovalent an das synthetische Polymer gebunden ist und wobei die Zubereitungsbestandteile in einem körperverträglichen Lösungsmittel gelöst sind, so dass die Lösung niederviskos genug ist, um sie zu versprühen, dem oben aufgeführten Problemen abhilft.It was not foreseeable for the person skilled in the art - and this represents the invention - that a preparation containing

• - at least one synthetic polymer,
• - at least one natural polymer,
• - at least one antiseptic agent,

wherein the antiseptic agent is covalently bonded to the synthetic polymer and wherein the formulation ingredients are dissolved in a biocompatible solvent such that the solution is low in viscosity enough to be sprayed, alleviates the problems set forth above.

According to the invention is also a wound closure film that is produced from the preparation and remains on the wound after the solvent has evaporated/evaporated.

The main task of the preparation according to the invention and the wound closure film formed from it is reliable wound closure and antiseptic properties which 'clean' the wound, ie kill wound germs, ie have a disinfecting effect and thereby promote wound healing.

The synthetic polymer can have a different structure (backbone), for example a linear, branched, hyper-branched or dendritic backbone, as well as different monomers, for example vinylpyrrolidone, acrylates, siloxanes, terpenes, maleic acid, vinyl ethers. In addition to the acid- or amine-containing polymers, other film-forming polymers can be formulated into a polymer system, for example cellulose derivatives, polylactic-co-glycolide, polyurethanes.

According to the invention, copolymers of acrylic acid, methyl methacrylate, hexamethyldisiloxane, phenylmethylsiloxane, isobutene, vinylpyrrolidone, ethyleneimine, ethylene oxide, glycerol/glycidol, levodopa, lactic acid, hydroxyacetic acid, glycolic acid, maleic acid, caprolactone and the respective derivatives can be used as synthetic polymers.

Polymers with a molar mass of 50,000 to 200,000 g/mol are advantageous.

A prerequisite according to the invention is that the polymer has at least one monomer which has free reactive groups, such as, for example, carboxyl groups or amino groups. These free reactive groups serve as a point of attachment for the antiseptic agent, for example through an esterification reaction or amide formation.

Polymers with a molar mass of 50,000 to 200,000 g/mol are advantageous.

According to the invention, a maleic acid-containing copolymer such as, for example, maleic acid isopropyl half ester copolymer (copolymer of maleic acid/maleic acid ester, isobutene and methyl acrylate) or a methyl vinyl ether/maleic acid copolymer is preferably used as the synthetic polymer. Particularly preferred are copolymers in which the monomers occur in the same accumulation, in particular in the sequence [-ABAB-] _n /[-AB-CA-BC-] _n (alternating copolymer). In addition, random copolymers or gradient copolymers can also be used to influence the properties of the polymer. On the other hand, the proportion of maleic acid or maleic acid derivative in the copolymer can be 10 to 30 percent by weight.

If acrylates are used as the comonomer, such as methyl acrylate, it is advantageous to use a ratio of 5 to 10 percent by weight of the maleic acid or the maleic acid derivative.

Celluloses, starches, natural rubber (gums), tannins, alginate, dextran, lignin are particularly suitable as natural polymers.

According to the invention, cellulose is preferably used as the natural polymer. Celluloses with a molar mass of 20,000 to 1,200,000 g/mol are particularly advantageous.

Surprisingly, the natural polymer ensures that the adhesive strength of the synthetic polymer increases in a moist environment. In addition, it can increase the passage of wound fluid through the wound closure film, i.e. through the polymer.

The adhesive strength and stability of the wound closure film is increased by the addition of natural polymer compared to films without the addition of a natural polymer. In addition, the wound secretion is absorbed by the natural polymer ('hydration' of the wound closure film) and can thus 'diffuse' through the wound closure film. The 'hydrated' wound closure film can thus keep the wound moist, which can support wound healing.

The polymer system also serves as a carrier for antimicrobial agents. As described above, the antiseptic active is covalently bound to the synthetic polymer.

According to the invention, active substances which have a reactive group “complementary” to the polymer are suitable as antiseptic active substances. This means that the antiseptic agent has a reactive group that allows covalent attachment to the synthetic polymer, such as a hydroxyl group (ester bond possible with the carboxyl group of the synthetic polymer), carboxyl group (amide bond possible with the amino group of the synthetic polymer).

The coupling of antimicrobial agents (e.g. AMP systems, proteins, enzymes and biguanide systems) and the synthetic polymer can advantageously take place via an amide bond. Similar bonds, such as via the formation of an ester, alkene, thioamide, triazole, imine, are also within the meaning of the invention.

Due to the covalent binding of the antiseptic active substance to the synthetic polymer, there is no migration/absorption of the antiseptic active substance into the wound, the antiseptic active substance is not absorbed by the body and only acts locally in the wound.

This has the advantage that the antiseptic active substance does not interact with the body, for example damaging body cells or organs.

However, the active substance can also be released in a controlled manner by means of degradable segments in the synthetic polymer. This results in a continuous release, i.e. the slow release and constant concentration of the active ingredient. The degradation can be controlled by the environment that forms in the wound. For example, certain microorganisms form an acidic environment, which can lead to degradation and the cleavage of ester bonds.

For example, biodegradable active ingredients, AMP systems (antimicrobial peptides), proteins and enzymes are preferably used as covalently bonded antiseptic active ingredients.

AMPs are particularly preferred as antimicrobial agents.

These antimicrobial agents can then be used for the antiseptic treatment of wounds as well as the preservation of the preparation.

Biodegradable active ingredients are mostly characterized by their positive charges. These can interact with the membrane of microorganisms by different mechanisms and often destroy these microorganisms. The length of the active ingredients and their flexibility play an important role here. AMPs are particularly interesting. These are sometimes more stable than proteins and enzymes to solvent and pH of the medium. In addition, AMPs are characterized by their rapid effect. In research, combinations of positively charged amino acids, such as lysine or arginine, and long, lipophilic amino acids, such as phenylalanine or tryptophan, have proven to be very effective. There is also a large number of different AMPs that consist of either short peptide sequences (2-8 amino acids) or long peptide sequences (10 to 40) and show different effectiveness.

The shorter the AMP, the more important it is that it has a cationic and sterically demanding structure. Tripeptides which have shown antimicrobial activity preferably consist of a combination of arginine, tryptophan and/or phenylalanine and preferably have a structure with the following sequence: positively charged amino acid - hydrophobic and sterically demanding amino acid - positively charged amino acid. It is also known that modifications, for example by the attachment of protective groups, even at unusual sites, such as multiple tert-butylations on the aromatic ring of tryptophan, have a positive effect on the antimicrobial properties of such AMPs.

According to the invention, it is also conceivable to use longer peptides than AMP for this invention. An example of this could be the Palmitoyl Tripeptide-3/5, which, in addition to a low antimicrobial effect, also simulates the naturally occurring thrombospondin-1 (TSP-1 sequence: Pal-Lys-Val-Lys; SYN®-COLL), which in turn Promotes the formation of collagen, which also supports wound healing. Longer peptides such as the RRP9W4N from Red Glead Discovery AB also showed good antimicrobial properties and can also be used for this invention, as well as AMPs of the LL-37 families, defensin peptides and bacterial permeabilizing proteins (BPI). Longer peptides from the same amino acid can also be used for this invention, such as ε-poly-L-lysine.

The preparation according to the invention contains the classic organic solvents such as ethyl acetate, alcohols and/or alkanes, which are highly volatile. These solvents generally do not pose a hazard to the human body as long as they are applied topically. When choosing solvents, there is a balance between the benefit of wound closure and the harm that a solvent may cause. Some solvents - such as ethyl alcohol or isopropyl alcohol - already have an antiseptic effect themselves, which can further increase the benefit of wound closure preparation.

QUOTES INCLUDED IN DESCRIPTION

This list of documents cited by the applicant was generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Patent Literature Cited

• DE 2343923 A1 [0008]
• SE 1751277 A1 [0011]
• SE 541313 C2 [0011]
• US 9085608 B2 [0011]
• US 9556223 B2 [0011]

Claims (22)

preparation containing - at least one synthetic polymer, - at least one natural polymer, - at least one antiseptic active ingredient, wherein the antiseptic active ingredient is covalently bound to the synthetic polymer and the preparation components are dissolved in a biocompatible solvent, so that the solution is of low viscosity enough to be sprayed. preparation after claim 1 , characterized in that the synthetic polymer has at least one monomer from the group of maleic acid, a maleic acid derivative or a maleic anhydride. Preparation according to at least one of the preceding claims, characterized in that the synthetic polymer is a maleic acid isopropyl half ester copolymer. Preparation according to at least one of the preceding claims, characterized in that the synthetic polymer consists of the following monomers: a substituted vinyl ether and a maleic acid derivative, in particular a methyl vinyl ether/maleic acid copolymer. Preparation according to at least one of the preceding claims, characterized in that the maleic acid derivative is a maleic acid ester. Preparation according to at least one of the preceding claims, characterized in that the natural polymer is chosen from the group of polysaccharides or the group of polyhydroxyphenols. Preparation according to at least one of the preceding claims, characterized in that the natural polymer is cellulose and/or nanocellulose. Preparation according to at least one of the preceding claims, characterized in that the antiseptic agent is selected from the bisguanidine group or from the polyamide group. Preparation according to at least one of the preceding claims, characterized in that the antiseptic agent is at least one polyhexanide. Preparation according to at least one of the preceding claims, characterized in that the antiseptic agent is at least one AMP. preparation after claim 10 , characterized in that the AMP identifies at least one of the amino acids from the group arginine, tryptophan and phenylalanine. Preparation according to at least one of the preceding claims, characterized in that the antiseptic agent is chosen from the group of bacteria-permeabilizing proteins (BPI). Preparation according to at least one of the preceding claims, characterized in that the antiseptic agent is a peptide. preparation after Claim 13 , characterized in that the antiseptic agent comes for example from the family of LL-37 or defensin peptides. preparation after Claim 13 , characterized in that the peptide consists of arginine, lysine or histidine as the cationic amino acid and phenylalanine and/or tryptophan as the demanding amino acid. preparation after Claim 13 until 15 , characterized in that the peptide is made up of three to thirty amino acid units, in particular three to 5 amino acid units. Preparation according to at least one of the preceding claims, characterized in that the solvent is chosen from the group of alcohols. preparation after Claim 17 , characterized in that the solvent is ethanol. Preparation according to at least one of the preceding claims, characterized in that the synthetic polymer has at least one monomer which has free reactive groups, such as carboxyl groups or amino groups, which serve to covalently bond the antimicrobial agent. Preparation according to at least one of the preceding claims, characterized in that the antimicrobial active substance is attached to the synthetic polymer via the formation of an ester, alkene, thioamide, triazole, imine or amide, in particular with the formation of an amide. Preparation according to at least one of the preceding claims, characterized in that the synthetic polymer has a molar mass of 50,000 to 200,000 g/mol. Wound closure film formed from a preparation according to at least one of the preceding claims, characterized in that the preparation is applied to a wound and the substance contained in the preparation has largely evaporated.