AT521126A2 - Sprühpflasterzusammensetzung - Google Patents

Abstract

The invention relates to a liquid spray plaster composition for application to a surface, in particular to the skin or to a wound, comprising at least one film polymer dissolved in a solvent, and at least one polymeric guanidine as biocidal active ingredient.

Description

The invention relates to a liquid spray plaster composition for application to a surface, in particular to the skin or to a wound.

Spray patches are used to treat superficial scratches, scrapes and cuts. They allow a quick and easy use and are suitable for all wound sizes and skin areas. Especially on difficult to reach body parts or on the face is an application possible. In this case, a spray plaster composition must meet some requirements.

So the composition should not burn when applied and cause no allergic reactions. It should dry quickly after application and allow a waterproof and breathable wound closure. The spray plaster composition should be low in odor. In addition, a sunscreen may be included to protect the resulting delicate scar tissue. At the same time, the spray patch should be transparent to allow control of wound healing.

Common spray plasters are based on film-forming polymers which are stored in dissolved form and, after application, serve for the production of wound coverings. The solutions can be sprayed in thin layers on a cut or abrasion to be treated. After evaporation of the solvent, a thin, coherent film forms on the wound, covering the site of injury and protecting the wound area against external influences.

/ 23

Spray plaster compositions often consist essentially of an acrylate-based film-forming polymer dissolved in a mixture of solvents, e.g. Ethyl acetate and propellants, e.g. n-pentane or CO2. In addition, additives such as essential oils are often included, which improve odor and may also slightly disinfect. Against many pathogens, however, so that no sufficient effect can be achieved.

Wound disinfection is particularly important to reduce the risk of infection. This is necessary even for small injuries, for example, if the blood circulation of the affected areas is reduced, because then the body's defenses can only be inadequate. So even the smallest injuries can lead to wound infections. These complications are described, for example, in diabetic patients.

To achieve effective wound disinfection, various active ingredients are currently available. Octenidine, povidone-iodine and polihexanide are often used. These disinfectants have various disadvantages. Either the agents do not act against spores and viruses, some show a protein defect, others cause more allergic reactions or are colored.

The requirements for a disinfectant are manifold. First, a broad spectrum of action is desirable, which advantageously also detects multi-resistant germs. Inactivation by blood and proteins should not occur. There should also be no inhibition of wound healing and the disinfectant should have little, if any, toxic effects on the tissue. In general, the disinfectant should have a good compatibility and only a low risk of allergic reactions. Burning when applying to the skin should be avoided. Also, a transparent compound to / 23 is preferred because it allows the control of wound healing and so prevents soiling of clothing and other items.

The object of the invention is therefore to provide a spray plaster composition which enables effective wound disinfection with good compatibility.

The object is achieved by a spray plaster composition according to claim 1 comprising at least one dissolved in a solvent film polymer, as well as at least one polymeric guanidine as a biocidal active ingredient.

It has surprisingly been found that the spray plaster composition according to the invention can meet the high requirements of spray plaster and wound disinfection at the same time. A spray plaster composition according to the invention can be applied to all wound sizes and to all skin sites, as it can be variably sized and flexibly applied.

The spray plaster composition of the present invention forms a well-adherent, non-tacky, sheet, water-insoluble, breathable and transparent film which additionally enables long-lasting disinfection against a variety of different germs, even against multi-resistant germs. The spray plaster composition also has a fungicidal effect. Since the polymeric guanidine is anchored in the matrix, there is no systemic effect. However, despite being anchored in the matrix, the polymeric guanidine may exert its disinfecting effect and will not be inactivated.

The film-forming polymer is particularly suitable for a spray plaster composition when it rapidly dries in the air by evaporation of the solvent, thereby rapidly forming a film or ensuring wound closure / 23.

In particular, after spraying and drying, the film polymer forms a thin, coherent polymer film so that abrasion upon movement and contact with clothing and other articles can be reduced and permanent wound closure achieved. Particularly suitable is a spray plaster composition which has a low viscosity, whereby a thinner plaster layer can be obtained. In addition, a gluing of the applicator can be avoided with a lower viscosity.

To avoid burning, it is advantageous to use an alcohol-free composition.

Siloxane-based film polymers are particularly suitable for the composition according to the invention. Particularly suitable are siloxanes having the general formula

R _{3 is} -Si- [O-SiR ₂ ] _n -O-SiR ₃ where RA is H.

Among these, particularly oligomeric or polymeric organosiloxanes are suitable in connection with the present invention, in particular silicone or silicone oil. A particularly advantageous feature of such a composition is that it is odorless. In addition, such a composition is particularly durable in its disinfecting effect. The polymeric guanidine is bound by the matrix and can act long term on the affected skin site. Despite the anchoring in the matrix it does not come to a reduced effectiveness.

Particularly good film-forming properties can be achieved if different compounds are used in the composition.

/ 23

For example, the spray plaster composition may include trimethylsiloxysilicate and trimethylsiloxyphenyl dimethicone. Such a composition has particularly good film-forming properties. In addition, it dries quickly. This effect can be achieved, for example, by the addition of an organic solvent.

Advantageously, disiloxanes, in particular hexamethyldisiloxane, may also be present. Hexamethyldisiloxane counteracts irritation of the skin.

Trimethylsiloxysilicate is a film-forming polymer that regulates the water loss of the skin, creating a good wound healing environment. In addition, it reduces foaming when the composition is shaken. Since spray patches are mainly used on the way, this feature is particularly advantageous. The spray plaster composition may thus be provided, for example, in a pump spray container.

Trimethylsiloxyphenyl dimethicone is a phenyl-modified polydimethylsiloxane. It has a good skin tolerance and a pleasant skin feel, in particular it moisturizes the skin without producing a sticky feeling. In addition, it gives the composition water-repellent properties. It is compatible with many components. Therefore, it is particularly suitable for use in a spray plaster composition containing a polymeric guanidine as a biocidic agent. The composition therefore forms a stable emulsion together with the polymeric guanidine in solution. After drying, a homogeneous wound closure is formed in which the polymeric guanidine derivative is dispersedly distributed in the matrix.

The polymeric guanidine may be incorporated into the composition as an aqueous solution. Thus, for example, water can be used as the solvent for the polymeric guanidine in the composition. By the use of water, a harmless to health can be used. Water is also

By using water, the applicator can be further avoided. Water evaporates without leaving residue and thus helps to form the protective layer. In addition, water has good dissolving properties for polymeric guanidines.

Solvent odorless. a bonding

Different polymeric guanidines can be used for the composition. The preparation of polymeric guanidines is described, for example, in WO 01/85676 A1 and in patents AT 408302 B and AT 411060 B. For example, polymeric guanidines include or are referred to as Akacid, or X-cid, and are e.g. in Kratzer et al., Antibiotika Monitor 1/2/2006; Buxbaum et al., Journal of Antimicrobial Chemotherapy (2006) 58, 193-197; US 2,325,586;

GB 1095902 A; WHERE 1999/054291 A1; WO 01/85676 A1; WHERE 2002/030877 A1; WHERE 2006/047800 A1; WO 2008/080184 A2; WHERE 2009/092123 A2; EP 2520605 A1; WO 2013/064161 A1; WHERE

2014/113835 A1; WO 2016/015081 A1 described (all by

Incorporated herein by reference). The polymeric guanidine may also be used as a complex, e.g. with gelatin or a polysaccharide (e.g., as described in WO 2010/106007 A1). WO 2008/080184 describes the use of polymeric guanidines for controlling microorganisms in non-therapeutic applications, e.g. by nebulization for room disinfection. A composition referred to therein is Akacid, poly [2- (2-ethoxy) -ethoxy-ethyl-guanidinium chloride, and Akacid Plus, a 3: 1 mixture of poly (hexamethyleneguanidinium chloride) and poly [2- (2-ethoxy) ethoxyethyl] - guanidinium chloride].

Herein the term "polymeric guanidines" in particular for "polymeric guanidine derivatives based on an alkylenediamine and / or an oxyalkylenediamine" (WO 2009/009815 A1), especially for "polymeric guanidine derivatives based on / 23

Diamines containing alkyl chains and / or oxyalkylene chains between two amino groups, wherein the guanidine derivatives a product of the polycondensation of a guanidine acid addition salt with diamines, which

Polyalkylene chains and / or polyoxyalkylene containing between two amino groups, represent (EP 1 280 766 B1, claim 1) used. Particularly preferred are a poly (hexamethyleneguanidinium) salt ethoxy) ethoxyethyl) guanidinium salt.

are preferred polymeric guanidines according to the present invention.

and / or poly [2- (2Akacid and Akacid Plus

A preferred embodiment of the composition according to the invention is characterized in that a polymeric guanidine is provided which contains an alkylenediamine and the oxyalkylenediamine in a molar ratio between 4: 1 and 1: 4. The amino groups of the alkylenediamine and / or the oxyalkylenediamine are preferably terminal, wherein for the preparation of the polymeric guanidine as alkylenediamine primarily a compound of the general formula NH ₂ (CH ₂ ) _n NH _{2 is} provided, in which an integer between 2 and 10 , in particular 6, is. For the preparation of the polymeric guanidine, a compound of the general formula NH ₂ [(CH ₂ ) ₂ O)] _m (CH ₂ ) ₂ NH ₂ may be provided as oxyalkylenediamine, in which an integer between 2 and 5, in particular 2.

Preferred polymeric guanidines may be selected from polyhexamethyleneguanidine; Poly [2- (2-ethoxy) -ethoxyethyl] guanidine (Akacid, [374572-91-5]); Polytriethylenglykolguanidin; Polyethylenglykolguanidin; Polyoxypropylenguanidin; Polyoxyethylene guanidine or mixture of poly (hexamethylene guanidinium chloride) and poly [2- (2-ethoxy) ethoxyethyl) guanidinium chloride] (Akacid Plus), in particular a 3: 1 mixture. These polymeric guanidines are low odor and therefore particularly well suited for use in a spray plaster composition.

/ 23

Most preferably, the polymeric guanidine is a polyalkylene guanidine, especially a polyoxyalkylene guanidine. "Alkylene may be a C1-C8 alkyl, preferably a C2-C6 alkyl such as ethyl, propyl, butyl, methylpropyl, pentyl, branched or unbranched. This is preferred in all uses of the term "alkylene or" alkyl herein.

Other preferred polymeric guanidines which are well suited for the present invention are described in WO 2014/113835 A1 and WO 2016/015081 A1. Such polymeric guanidines (also called "polyguanidine") may correspond to the formula (I), (II) or (III)

(I)

H

.N

-CHa-RvCH / (II)

23.9

η (III) wherein Ri is either an aromatic ring system having at least one aromatic ring optionally containing one or more heteroatoms selected from O, N and S and which is optionally substituted with one or two vinyl groups, or is ethylene, or the like has a cyclic structure obtained by ring closure with the elimination of a guanidine. Examples of R 1 are benzenes (preferably para- or meta-digit embedded), pyridine (preferably attached to the two carbon atoms adjacent to the N), divinylbenzene, biphenyl (preferably both benzene linked in a para-position), 1,3-bis ((E) -2-vinyl) benzene, furan, pyrrole, thiophene, fluorene, ethylene (preferably cis-linked). Such polymeric guanidines are described in WO 2016/015081 A1.

Polymeric guanidines may also contain the compound of formula (IV)

rn

R.

H

N ·

Y (IV) wherein

X from -NH ₂ , aminoguanidino and 1, 3-diaminoguanidino

10/23 is selected;

Y is selected from -H and -R ₁ -NH ₂ ; or X and Y together represent a chemical bond to give a cyclic structure;

R1 is selected from divalent organic radicals having from 2 to 20 carbon atoms in which one or more carbon atoms are optionally replaced by O or N; a and b are each 0 or 1, where a + b is other than 2 when no 1,3-diaminoguanidine units are included;

R2 is selected from -H and -NH2 where R _{2 is} -NH ₂ when a + b = 0,

R _{2 is} -H or -NH ₂ when a + b = 1 and

R _{2 is} -H when a + b = 2; and n is greater than or equal to 2;

or a salt of it. Such polymeric guanidines are in WO

2014/113835 A1.

In the formulas (I) to (IV), n corresponds to a plurality, e.g. to achieve the above molar masses of the polymer. For example, n can be 3 to 200.

Preferably, the guanidine is a guanidinium salt, preferably selected from a halide, preferably a chloride; Phosphate, preferably one

dihydrogen phosphate; Carbonate; Nitrate; sorbate; Acetate, preferably hydroacetate; gluconate; Citrate; Silicate; etc. This also applies to the polymeric guanidines. The polymeric guanidine of the present invention may be a polyguanidine salt. These compounds with salting partners (counterions), e.g. Halide, phosphate, etc. are e.g. described in AT 411060 B.

Preferably, the average molecular weight of the polymeric guanidine is 200 Da to 10,000 Da, preferably 500 Da to 3,000 Da. For example, For example, the polymeric guanidine may be provided with at least 3 guanidine residues. The polymers of these sizes can be obtained by nanofiltration through membranes. For nanofiltration, filters with corresponding pore sizes can be used for the permeability of the desired molecular weights. Filtrates (to remove larger polymers) or the residue (to remove the smaller polymers) can be further used to obtain the desired polymer. The desired preferred polymeric guanidines have improved toxicology. In particular, the elimination of short-chain oligomers and monomers, as well as the elimination of the entrained by the synthesis residues of the diamines comes here to a main focus. Accordingly, monomeric starting materials (guanidines) and oligomers or polymers of guanidine having a molecular weight of 250 Da or smaller, or even 400 Da or smaller, are advantageously removed. In this way, it can be avoided that poorly anchored low molecular weight substances in the matrix can be released from the spray plaster composition, which is particularly important when applying the spray plaster composition on the non-intact skin in the area of a wound.

The spray plaster composition described above also serves for use in the prophylaxis of wound infections, in particular for the application of a thin film to a wound area, preferably by spraying. The application can be done for example by means of a spray container.

The invention is illustrated by way of example with reference to the following examples and figures, without limiting the general inventive idea:

Fig. 1: Filming of a spray plaster composition before adding a 2% Akacid Plus solution

FIG. 2: Film formation of a spray plaster composition after addition of a 2% Akacid Plus solution / 23. FIG

Fig. 3: action on Gram-negative bacteria

Fig. 4: Evaluation effect on Gram-negative bacteria

Fig. 5: action on Gram-positive bacteria

Fig. 6: Evaluation effect on Gram-positive bacteria

Fig. 7: effect on pathogenic fungi

Fig. 8: Evaluation effect on pathogenic fungi

Example 1: Preparation of a polymeric guanidine (e.g., Akacid Plus)

The formulations are based on active ingredients of the group of polyguanidines (Akacid, described in Kratzer et al., Antibiotika Monitor 1/2/2006, Buxbaum et al., Journal of Antimicrobial Chemotherapy (2006) 58, 193-197, WO 01/85676

A1; WO 2006/047800 A1; WO 2008/080184 A2; WO 2013/064161 A1), The preparation of Akacid Plus is described in particular in WO 2006/047800 (incorporated herein by reference). The starting substances triethylene glycol diamine, hexamethylene diamine and guanidine hydrochloride were reacted together in one process. In the present case, a 3: 1 mixture of polyhexamethylene guanidinium chloride and poly [2 - (- ethoxy) ethoxyethyl] guanidinium chloride was used. These polymeric guianidine compounds exhibit an excellent antimicrobial profile and are also able to impart stable formulations with difficult-to-mix substances without solubilizers from the group of polyethoxylated nonionic compounds.

Example 2: Preparation and Examination of a

composition

To prepare an exemplary composition, / 23

Hexamethyldisiloxane, trimethylsiloxysilicate and trimethylsiloxyphenyl dimethicone provided as a mixture. An addition of sun protection factors, for example ethylhexyl methoxy cinnamate and diethylamino hydroxybenzoylhexyl benzoate, may be provided. An aqueous 2% Akacid Plus solution was then incorporated into this starting mixture.

The film-forming properties were investigated with this composition. For this purpose, the composition was analyzed microscopically. For example, a microscopic examination can be made by spraying the composition onto a slide and looking at it after drying.

Fig. 1 shows the structure of the composition before the 2% Akacid Plus solution was incorporated. It was found that a fine-structured film layer was formed.

Fig. 2 shows the structure of the composition after the 2% Akacid Plus solution has been incorporated. It could be achieved a homogeneous, uniform distribution. The dried composition formed a laminar film layer, with a slightly coarser texture. Thus, the composition has very good spray plaster properties.

Example 3: Action against bacteria

The activity of the composition was tested. The antibacterial activity was examined by MIC test. MIC stands for the minimum inhibitory concentration (MIC for minimal inhibitory concentration) and denotes the lowest concentration of a substance in which no increase of microorganisms can be perceived with the naked eye. The MIC is determined by a so-called titer method in which the substance is diluted out and / or the pathogen is subsequently added.

As a rule, this determines the concentration that just barely inhibits the growth of a bacterial strain. MIC is expressed in micrograms per milliliter (pg / ml) or in vol.%, And dilutions are usually in log2 increments. Here, a starting concentration of 2% was each doubled, thus giving test concentrations of 1%, 0.5%, 0.25%, and so on.

Lower values therefore reflect better activity as an anti-infective agent.

In a first experiment, the activity against gram-negative bacteria was investigated using the example of Escherichia coli (EC13). E. coli was used at 10 ⁴ CFU / ml. FIGS. 3 and 4 show the test results. The MIC of Gram-negative bacteria was therefore 0.02%.

In a second experiment, the activity against gram-positive bacteria was investigated using the example of Multi resistant Staphylococcus aureus (MRSA 1). MRSA 1 at 10 ⁴ CFU / ml was used for this purpose. FIGS. 5 and 6 show the test results. The MIC for gram-positive bacteria was therefore 0.03%.

/ 23

Example 4: Action against fungal infections

The activity of the composition was tested. The fungicidal activity was also tested by MIC test. The procedure corresponded to that which was also used for the investigations on the antibacterial effect.

In an experiment, the activity against pathogenic fungi was investigated using the example of Candida albicans. Candida albicans was used at 10 ⁴ CFU / ml. FIGS. 7 and 8 show the test results. The MIC was therefore 0.03% for Candida albicans.

An overview of the test results from Examples 3 and 4 is shown in the following table:

composition MRSA (1) E.coli (13) Candida albicans Starting composition + Akacid Plus (in%) <0.03 <0.02 <0.03 Basic composition No inhibition No inhibition No inhibition

/ 23

Claims (17)

Claims: 1. Liquid spray plaster composition for application to a surface, in particular to the skin or to a wound, comprising at least one film polymer dissolved in a solvent, and at least one polymeric guanidine as a biocidal active ingredient. 2. Composition according to claim 1, characterized in that the film polymer is a film-forming polymer which, after being applied to a surface, dries in air, in particular by evaporation of the solvent, and forms a polymer film, in particular a wound closure. 3. Composition according to one of claims 1 to 2, characterized in that the film polymer is a siloxane-based polymer. 4. Composition according to one of claims 1 to 3, characterized in that the film polymer is a siloxane with the general formula R _{3 is} Si [O-SiR ₂ ] _n -O-SiR ₃ , where R Ψ H and / or that the film polymer is an oligomeric or polymeric organosiloxane, in particular a silicone or a silicone oil. 5. Composition according to one of claims 1 to 4, characterized in that at least two different film polymers according to one of claims 2 to 4 are included. 6. Composition according to one of claims 1 to 5, 17/23 containing: - at least one disiloxane - At least one trimethylsiloxy silicate - At least one trimethylsiloxyphenyl dimethicone 7. Composition according to one of the Claims 1 to 6 including: polymeric guanidine - hexamethyldisiloxane Trimethylsiloxysilicate Trimethylsiloxyphenyl dimethicone - If necessary, a UV solvent preservative 8. Composition according to one of the Claims 1 to 7, characterized in that the polymeric guanidine and the Film polymer in the composition as a stable emulsion available. 9. Composition according to one of the Claims 1 to 8th, characterized in that an organic solvent and / or an inorganic solvent, in particular water, is contained as a solvent for the film polymer and / or that an inorganic solvent, in particular water, is contained as a solvent for the polymeric guanidine. 10. Composition according to one of claims 1 to 9, characterized in that the polymeric guanidine is a polyalkylene guanidine or a polyoxyalkylene guanidine. 11. The composition according to any one of claims 1 to 10, characterized in that the polymeric guanidine is a polymeric condensation product, obtainable by reacting guanidine or a salt thereof, with an alkylenediamine and / or an oxyalkylenediamine, in particular with an alkylenediamine and / or With oxyalkylenediamine 18/23 terminal amino groups. 12. The composition according to any one of claims 1 to 11, characterized in that the polymeric guanidine is obtainable by reacting guanidine or a salt thereof with an alkylene diamine and an oxyalkylene diamine, in which the alkylene diamine and the oxyalkylene diamine in a molar ratio between 4: 1 and 1: 4 can be used. 13. Composition according to one of claims 1 to 12, characterized in that triethylene glycol diamine (relative molecular mass: 148), polyoxypropylene diamine (relative molecular mass: 230) and / or polyoxyethylene diamine (relative molecular mass: 600) is provided as the oxyalkylene diamine. 14. Composition according to one of claims 1 to 13, characterized in that the polymeric guanidine is obtainable by reacting guanidine hydrochloride with triethylene glycol diamine or is obtainable by reacting guanidine hydrochloride with hexamethylene diamine and with triethylene glycol diamine. 15. The composition according to any one of claims 1 to 14, characterized in that the polymeric guanidine is selected from polyhexamethylene guanidine; Poly [2- (2-ethoxy) ethoxyethyl) guanidine (Akacid, [374572-91-5]); Polytriethylenglykolguanidin; Polyethylenglykolguanidin; Polyoxypropylenguanidin; Polyoxyethylene guanidine or a mixture, in particular a 3: 1 mixture, of poly (hexamethylene guanidinium chloride) and poly [2- (2ethoxy) ethoxyethyl) guanidinium chloride] (Akacid Plus, [905929-86-4]). 16. The composition according to any one of claims 1 to 15, characterized in that the guanidine is a guanidinium salt, preferably selected from a halide, 19/23 preferably a chloride; Phosphate, preferably a dihydrogen phosphate; Carbonate; Nitrate; sorbate; Acetate, preferably hydroacetate; gluconate; Citrate; Silicate. 17. The composition according to any one of claims 1 to 16, characterized in that the average molecular weight of the polymeric guanidine is 200 Da to 10000 Da, preferably 500 Da to 3000 Da. 18. Composition according to one of claims 1 to 17, characterized in that the composition contains 0.4 to 2% by weight of polymeric guanidine, based on the total amount of the composition. 19. Use of the composition according to one of claims 1 to 18, as a spray plaster composition for application to the skin, in particular to a wound. 20. The composition according to any one of claims 1 to 18 for use in the prophylaxis of wound infections, in particular for the flat application of a thin film to a wound area, preferably by spraying.