DE202018004305U1 - PUR hydrogels and their use as wound dressings - Google Patents

Abstract

Polyurethane hydrogel formed from the reaction of at least the component a) of a hydrophilic aliphatic and / or cycloaliphatic polyisocyanate prepolymer containing less than 1% by weight of monomeric diisocyanates, b) a compound having at least one amino group in the presence of c) Water, characterized in that the compound b) has a primary amino group and a carboxyl group, wherein salts of weak acids and zwitterions of the compound b) are also included.

Description

The present invention relates to polyurethane hydrogels formed from the reaction of a) a nonionically hydrophilicized aliphatic and / or a nonionically hydrophilicized cycloaliphatic polyisocyanate prepolymer having a content of monomeric diisocyanates of less than 1 wt .-% with b) a compound having at least the amino group in the presence of c) water. The invention further relates to their use as medicaments, their use in the treatment of skin wounds and a wound dressing comprising such hydrogels.

As hydrogels are usually water-containing gels (dimensionally stable, easily deformable, rich in liquids and gases disperse systems of at least two components, which usually consist of a solid, Kolloidzerteilten substance with long or highly branched particles and a liquid (usually water) as a dispersant) based on hydrophilic but water-insoluble polymers, which are present as three-dimensional networks. In water, these networks swell up to an equilibrium volume while retaining their shape. The network formation occurs predominantly via chemical linkage of the individual polymer chains, but is also physically possible by electrostatic, hydrophobic or dipole / dipole interactions between individual segments of the polymer chains. On the choice of the monomers used for the polymer synthesis, the type of crosslinking u. the crosslink density can be adjusted to desired properties of the hydrogels targeted. Usually, hydrogels are based on poly (meth) acrylic acids, poly (meth) acrylates, polyurethanes, polyvinylpyrrolidone or polyvinyl alcohol. They are generally well tolerated by living tissues and are therefore often used as biomaterials, especially in the biomedical and pharmaceutical fields.

Polyurethane hydrogels prepared from hydrophilic NCO prepolymers are known per se ( EP 426 422 A1 . EP 455 324 A1 . WO 98/17215 A1 . WO 99/13923 A1 . WO 2002/060501 A1 ). They are used for the medical treatment of wounds and are used, for example, as wound dressings. They have the advantage of keeping (dry) wounds moist in a controlled manner, which has a favorable effect on wound healing. Polyurethane hydrogels generally have very good mechanical properties.

WO 2006/120454 A1 relates to a sterile film-forming composition for application to mammalian skin or injury to the skin, which is a liquid which can be obtained by mixing together a polyurethane-based polymer and an acrylate-based polymer and irradiating the resulting mixture using gamma radiation. According to one embodiment, the polyurethane-based polymer is selected either alone or in combination of the following: polyurethane, polyether polyurethane, polyurea-polyurethane, polyurethane copolymers, polyurethane / silicone copolymers, polyurethane / acrylic copolymers, polyurethane adhesives, polyurethane derivatives, polyurethane elastomers, polyurethane prepolymers , Polyurethane hydrogels. In another embodiment, the composition further comprises either alone or in combination: viscosity enhancing compounds, polyols, solvents, volatile solvents, antimicrobials, biofilm disrupters, adhesives, preservatives, saturants, growth factors, curatives, surfactants, moisturizers Agents, herbal extracts, amino acids, pH-altering twistings, cleansers, hemostasis agents, other skin adhesives and other film-forming compounds.

WO 2008/049527 A1 discloses a process for the preparation of polyurethane hydrogels in which a) non-ionically hydrophilicized, aliphatic and / or cycloaliphatic polyisocyanate prepolymers containing less than 1% by weight of monomeric diisocyanates, b) compounds containing at least one tertiary amino group and at least three Have hydroxy groups, c) water and d) if appropriate, antimicrobially active metal salts and / or metal particles are reacted.

The object of the present invention is to provide hydrogels with further improved biocompatibility. According to the invention, this object is achieved by hydrogels according to claim 1, their use as medicaments according to claim 12, their use in the treatment of skin wounds according to claim 13 and a wound dressing comprising such hydrogels according to claim 14.

Polyurethane hydrogels formed from the components a) a nonionically hydrophilicized aliphatic and / or a nonionically hydrophilicized cycloaliphatic polyisocyanate prepolymer, having a content of monomeric diisocyanates of less than 1 wt .-% with b) a compound having at least amino group, in the presence of c) water. The compound b) has a primary amino group and a carboxyl group, wherein salts and zwitterions of the compound b) are also included.

The amino acids used according to the invention are considered to be of little toxicological significance and therefore advantageous.

In a) it is possible to use all polyisocyanate prepolymers known per se to those skilled in the art, which have on average 2 or more free NCO groups and are furthermore based on aliphatic and / or cycloaliphatic mono-, di- and / or triisocyanates, and for nonionic hydrophilicization have one or more oxyethylene groups.

The polyisocyanate prepolymers used in a) preferably have polyoxyalkylene units bonded via urethane groups, with preferably 60% by weight, particularly preferably 70% by weight and very particularly preferably 80% by weight, of the oxyalkylene units bound therein being oxyethylene units.

Preferably, the oxyethylene units are contained therein in blocks. The polyisocyanate prepolymers can be obtained in a manner known per se by reacting polyetherdiols with mono-, di- and / or triisocyanates and / or their higher molecular weight secondary products with uretdione, isocyanurate, allophanate, biuret, iminooxadiazinedione and / or oxadiazinetrione structures. Optionally, even more mono-, di- or polyols can be used for the construction.

The underlying monomeric isocyanates can be any isocyanates accessible by phosgenation or by phosgene-free processes, for example by thermal urethane cleavage, with aliphatically, cycloaliphatically and / or araliphatically bonded isocyanate groups, such as 1,4-diisocyanatobutane, 1,6-diisocyanatohexane (HDI), 2- Methyl 1,5-diisocyanatopentane, 1,5-diisocyanato-2,2-dimethylpentane, 2,2,4- and 2,4,4-trimethyl-1,6-diisocyanatohexane, 1,10-diisocyanato-decane, 1,3- and 1,4-diisocyanatocyclohexane, 1,3- and 1,4-bis- (isocyanatomethyl) -cyclohexane, 1-isocyanato3,3,5-trimethyl-5-isocyanatomethylcyclohexane (isophorone diisocyanate, IPDI), 4,4 '-Diisocyanatodicyclohexylmethane, 1-isocyanato-1-methyl-4 (3) isocyanatomethylcyclohexane, bis (isocyanatomethyl) norbornane or any mixtures thereof.

The polyether diols are obtainable in a manner known per se using KOH or double metal cyanide (DMC) catalysis by adding cyclic ethers, such as alkylene oxides, to OH- or NH-functional starters. The addition may be blockwise or random, with blockwise addition being preferred.

Preferred cyclic ethers are alkylene oxides, more preferably ethylene oxide and optionally propylene oxide.

The NCO / OH ratio in the prepolymer preparation is preferably 1.6 to 30: 1, more preferably 4: 1 to 12: 1, very particularly preferably 4: 1 to 10: 1.

The prepolymers a) preferably have an NCO content (ISO 11909) of 1.5 to 3.5 wt .-%.

The prepolymer a) can be obtained, for example, from the reaction of aliphatic diisocyanates with dibis hexafunctional polyalkylene oxides having an ethylene oxide content of 50 to 100 mol%, based on the total amount of oxyalkylene groups contained.

It is possible that, for the polyurethane hydrogel according to the invention, the amino acid b) is dissolved in the water c) and the prepolymer a) is reacted with this solution.

The prepolymer a) and the aqueous solution of the amino acid b) can be used, for example, in a quantitative ratio (in parts by weight) of from 10:90 to 50:50, preferably from 15:85 to 30:70 and more preferably from 15:85 to 20:80 become.

In addition to component a) it is also possible to add further isocyanate-containing components based on aliphatic diisocyanates. These can then be mixed with a). Examples are oligomers or prepolymers of aliphatic diisocyanates; Optionally, these components are hydrophilized. In a preferred variant, the isocyanate-containing component consists exclusively of the prepolymer a).

The proportion of water c) in the hydrogel, based on the amount by weight of the compounds used in a) and b) (corresponding to 1 part by weight), for example, be ≥ 0.1 to ≤ 50 parts by weight.

The temperature at which the polyurethane hydrogel of the invention is formed is preferably 5 to 50 ° C, more preferably 10 to 45 ° C and most preferably 15 to 30 ° C.

In a preferred embodiment, the compound b) is an α-aminocarboxylic acid, a β-aminocarboxylic acid, a γ-aminocarboxylic acid or a mixture of at least two of the abovementioned amino acids. For compounds having a stereocenter or stereocenters, all stereoisomeric forms of compound b) are suitable. A preferred form is the racemate. At natural occurring compounds, a preferred form is the predominantly occurring in nature form.

Preferably, the α-aminocarboxylic acids alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine or a mixture of at least two of the aforementioned amino acids. Particularly preferred are lysine, glycine and arginine. Most preferred is lysine.

In addition to amino acids, it is also possible to use other amino-terminated compounds in component b). Particularly preferred here are hydrophilic, amine-terminated polymers such as e.g. the class of Jeffamine®.

In a further preferred embodiment, the reaction is also carried out in the presence of d) a pharmaceutical active substance. The active ingredient d) can already be dissolved or dispersed in the isocyanate prepolymer a) or in the water c) or in an aqueous solution of the amino acid b). In an alternative embodiment, the active ingredient d) can also be added after the formation of the hydrogel. In a further preferred embodiment, the pharmaceutically active substance d) is selected from wound healing accelerators, analgesics, antibiotics, antimycotics, bacteriostats, metal particles in the form of aqueous or alcoholic solutions, dispersions or sols added to at least one of the elements Ag, Cu , Zn or their alloys or a mixture of at least two of the aforementioned components. The proportion by weight of component d), based on the sum of components a) to d), is preferably up to 5, particularly preferably up to 1, very particularly preferably up to 0.2% by weight.

For example, for an antimicrobial finish of the hydrogels, metal salts and / or metal particles in the form of aqueous or alcoholic solutions, dispersions or sols can be used. Preferably, metal particles are added to the polyurethane hydrogels, e.g. from Ag, Cu, Zn or alloys containing these metals. In order to allow homogeneous incorporation, these metal particles are preferably nanoparticulate and have an average particle size, determined by means of laser correlation spectroscopy, of from 5 to 200 nm, preferably from 10 to 60 nm.

Preferred metal particles of the aforementioned type are silver particles. If these silver particles are used with an average particle size of 10 to 60 nm, although slightly yellow to orange, but still transparent hydrogels are obtained. Preferred silver particles in the form of aqueous sols contain from 0.05 to 5% by weight, preferably from 0.08 to 2% by weight, of silver. These are obtainable, for example, by initially charging a silver nitrate solution and adding the eqimolar amount of NaOH dissolved in water with the addition of a dispersing aid, such as polyvinylpyrrolidone. The subsequent reduction is carried out by reducing agents such as formaldehyde. These silver particles are preferably used on a carrier, for example a polymer or silica or borate glass particles.

In a further preferred embodiment, the prepolymer a) is obtainable from the reaction of an isocyanate component comprising hexamethylene diisocyanate, pentamethylene diisocyanate, isophorone diisocyanate or a mixture of at least two of the aforementioned isocyanates with a polyol component comprising a polyethylene oxide polyol, polypropylene oxide polyol or a mixture thereof. In a further preferred embodiment, additives for stabilization are added, for example an additive is a phosphoric acid ester. Particularly preferred is dibutyl phosphate.

In a further preferred embodiment, the prepolymer a) has urethane-bonded polyoxyalkylene units, where ≥ 60% of the oxyalkylene units bound therein are oxyethylene units.

In a further preferred embodiment, the prepolymer a) has a residual content of less than 0.5% by weight of monomeric diisocyanates (ISO 10283). This is usually achieved by prepolymer preparation in the presence of an excess of the isocyanate and subsequent removal by distillation of unreacted diisocyanates by means of thin film distillation.

In a further preferred embodiment, components a) and b) are used in a molar NCO: NH 2 ratio of ≥ 0.3: 1 to ≦ 10: 1, preferably of ≥ 0.7: 1 to ≦ 2: 1.

In a further preferred embodiment, the components a) to c) used are used in amounts such that the pH of the hydrogel is in a range from ≥ 3.8 to ≦ 8.2.

In a further preferred embodiment, the reaction is further carried out in the presence of e) a pH buffer. For example, a carbonate / bicarbonate buffer can be used.

In a further preferred embodiment, based on the amount by weight of the compounds used in a) and b) (corresponding to 1 part by weight) ≥ 0.1 to ≤ 20 (preferably> 1 to <8) parts by weight of water c).

In a further preferred embodiment, the proportion of water c) is selected so that the molar amount of the isocyanate-reactive amino groups from b) to the molar amount of isocyanate groups from a) (or the sum of a) and all other isocyanate-containing components) behaves such as 0.2 to 1 to 3 to 1, preferably 0.5 to 1 to 1 to 1.

A further aspect of the invention is a polyurethane hydrogel according to the invention, for use as a wound dressing, wound dressing, burn plaster or for another medical purpose.

Another aspect of the invention is a polyurethane hydrogel of the invention for use in the treatment of skin wounds.

Another aspect of the invention is a wound dressing which comprises a polyurethane hydrogel according to the invention. This wound dressing may have the usual structure - skin contact layer, outer adhesive layer and hydrogel arranged therebetween.

Examples

The present invention will be further illustrated by, but not limited to, the following examples.

Formation of a polyurethane prepolymer a)

1000 g of a polyalkylene oxide having a molecular weight of 4680 g / mol, started on glycerol, an ethylene oxide weight fraction of 72% and a propylene oxide weight fraction of 28%, were added to a mixture of 1000 g hexamethylene diisocyanate (HDI) and 1 g dibutyl phosphate at 80 ° C. over 3 h. , which was previously dried at 100 ° C for 6 h at a pressure of 0.1 mbar, added dropwise and stirred for 12 h. The excess HDI was removed by thin film distillation at 130 ° C and 0.1 mbar. This gave a prepolymer having an NCO content of about 2.8% and a viscosity of about 3500 mPas.

Formation of a hydrogel (according to the invention)

A mixture of 0.37 g lysine and 20.8 g water was mixed at room temperature with 8.57 g of the product from experiment 1). It immediately formed a solid, transparent, bubble-free hydrogel, which is permanently stable.

Formation of a hydrogel (according to the invention)

A mixture of 0.37 g lysine and 35.7 g water was mixed at room temperature with 8.57 g of the product from experiment 1). It formed within a few minutes a transparent, bubble-free hydrogel, which is permanently stable.

Formation of a hydrogel (according to the invention)

A mixture of 0.37 g lysine and 50.63 g water was mixed at room temperature with 8.57 g of the product from experiment 1). It formed within a few minutes a transparent, bubble-free hydrogel, which is permanently stable.

Formation of a hydrogel (according to the invention)

A mixture of 0.73 g lysine and 52.7 g water was mixed at room temperature with 8.57 g of the product from experiment 1). It immediately formed a transparent, bubble-free hydrogel, which is permanently stable.

Formation of a hydrogel (according to the invention)

A mixture of 0.18 g of lysine and 49.6 g of water was mixed at room temperature with 8.57 g of the product from Experiment 1). Within 60 minutes a transparent, bubble-free hydrogel was formed, which is permanently stable.

Formation of a hydrogel (according to the invention)

A mixture of 0.18 g lysine and 49.6 g water was mixed at room temperature with 8.57 g Baymedix FP505. It formed within a few minutes a transparent, bubble-free hydrogel, which is permanently stable.

Formation of a hydrogel (according to the invention)

A mixture of 7.64 g of an aqueous solution of lysine sodium salt (prepared from 11.8 g lysine, 3.22 g sodium hydroxide and 485 g water) and 42.1 g water was mixed at room temperature with 8.57 g of the product from experiment 1). It immediately formed a transparent, bubble-free hydrogel, which is permanently stable.

Formation of a hydrogel (according to the invention)

A mixture of 3.82 g of an aqueous solution of lysine sodium salt (prepared from 11.8 g lysine, 3.22 g sodium hydroxide and 485 g water) and 45.96 g water was mixed at room temperature with 8.57 g of the product from experiment 1). It formed within 10 minutes a transparent, bubble-free hydrogel, which is permanently stable.

Formation of a hydrogel (according to the invention)

A mixture of 4 g of Jeffamine ED2003 and 120 g of water was mixed at room temperature with 15 g of the product from experiment 1). It formed within 1 minute a transparent, bubble-free hydrogel, which is permanently stable.

Comparative test

50 g of water was mixed at room temperature with 8.57 g of the product from experiment 1). It only formed after a few hours a hydrogel, which is interspersed with bubbles.

The hydrogel in the comparative experiment is unusable for many applications because of the bubbles involved. Furthermore, the very long reaction time is not suitable to provide an economically useful hydrogel can.

Drying of the hydrogel

The hydrogel of example 5 was dried at room temperature until the water has largely evaporated. It shrinks to a transparent, colorless rubbery material.

QUOTES INCLUDE IN THE DESCRIPTION

This list of the documents listed by the applicant has been 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.

Cited patent literature

• EP 426422 A1 [0003]
• EP 455324 A1 [0003]
• WO 9817215 A1 [0003]
• WO 99/923 A1 [0003]
• WO 2002/060501 A1 [0003]
• WO 2006/120454 A1 [0004]
• WO 2008/049527 A1 [0005]

Claims (14)

A polyurethane hydrogel formed from the reaction of at least component a) a hydrophilic aliphatic and / or cycloaliphatic polyisocyanate prepolymer containing less than 1% by weight of monomeric diisocyanates with b) a compound having at least one amino group in the presence of c) water, characterized in that the compound b) has a primary amino group and a carboxyl group, wherein salts of weak acids and zwitterions of the compound b) are also included. Polyurethane hydrogel according to Claim 1 , characterized in that the compound b) is an α-aminocarboxylic acid, a β-aminocarboxylic acid, a γ-aminocarboxylic acid or a mixture of at least two of the aforementioned amino acids. Polyurethane hydrogel according to Claim 1 or 2 , characterized in that the reaction is further carried out in the presence of d) a pharmaceutical agent. Polyurethane hydrogel according to Claim 3 , characterized in that the pharmaceutical active ingredient d) is selected from: analgesics, antibiotics, antimycotics, bacteriostats, metal particles in the form of aqueous or alcoholic solutions or sols are added, based on at least one of the elements Ag, Cu, Zn or their alloys or a mixture of at least two of the aforementioned components. Polyurethane hydrogel according to one of Claims 1 to 4 , characterized in that the prepolymer a) is obtainable from the reaction of an isocyanate component comprising hexamethylene diisocyanate, pentamethylene diisocyanate, isophorone diisocyanate or a mixture of at least two of the aforementioned isocyanates with a polyol component comprising a polyethylene oxide, polypropylene oxide or their mixture in the presence of a metal-free catalyst. Polyurethane hydrogel according to one of Claims 1 to 5 , characterized in that the prepolymer a) has urethane-bonded polyoxyalkylene units, wherein ≥ 60% of the oxyalkylene units bound therein are oxyethylene units. Polyurethane hydrogel according to one of Claims 1 to 6 , characterized in that the prepolymer a) has a residual content of less than 0.1 wt .-% of monomeric diisocyanates. Polyurethane hydrogel according to one of Claims 1 to 7 , characterized in that the components a) and b) in a molar NCO: NH ₂ ratio of ≥ 0.7: 1 to ≤ 2: 1 are used. Polyurethane hydrogel according to one of Claims 1 to 8th , characterized in that the components used a) to c) are used in amounts such that the pH of the hydrogel in a range of ≥ 6 to ≤ 10, preferably ≥ 6.5 to ≤ 8.5. Polyurethane hydrogel according to one of Claims 1 to 9 , characterized in that the reaction is further carried out in the presence of e) a pH buffer. Polyurethane hydrogel according to one of Claims 1 to 10 , characterized in that based on the amount by weight of the compounds used in a) and b) (corresponding to 1 part by weight) ≥ 1 to ≤ 20 parts by weight of water c) are used. Polyurethane hydrogel, according to one of Claims 1 to 11 , for use as a medicine. Polyurethane hydrogel, according to one of Claims 1 to 11 , for use in the treatment of skin wounds. Wound dressing, characterized in that the wound dressing is a polyurethane hydrogel according to one of Claims 1 to 11 includes.