Water-containing hydrogels for dressing wounds

Abstract

The invention relates to water-containing hydrogels for dressing wounds, comprising a polyurethane-polyurea copolymer having a polyvalent alcohol, except propylene glycol.

Claims

1. A wound dressing comprising a backing layer and a layer comprising an aqueous hydrogel for the treatment of wounds obtainable by reacting an a) amine-terminated prepolymer containing polyalkylene oxide units with an b) isocyanate-terminated prepolymer containing polyalkylene oxide units, the reaction taking place in the presence of a polyhydric alcohol, except propylene glycol, and in the presence of water and, based on the total mass of all reactants, the sum total of the masses of amine-terminated prepolymer and isocyanate-terminated prepolymer being 10-30% by weight of the total mass of all reactants and the mass of the polyhydric alcohol, except propylene glycol, being 5-35% by weight of the total mass of all reactants and the mass of the water used being at least 40% by weight of the total mass of all reactants, and the molar ratio of reactive isocyanate end groups to reactive amine end groups being 1.0 to 2.0.

2. The wound dressing of claim 1, wherein the polyhydric alcohol is glycerol.

3. The wound dressing of claim 2, wherein the glycerol is used in an amount of 15-25% by weight.

4. The wound dressing of claim 1 wherein the layer comprising the aqueous hydrogel is a wound contact layer.

5. The wound dressing of claim 4, wherein the wound dressing further comprises one or more distributor layers.

6. The wound dressing of claim 1, wherein the hydrogel is obtainable by reacting an a) amine-terminated prepolymer containing polyethylene oxide units and/or polypropylene oxide units with an b) at least three-armedly branched isocyanate-terminated prepolymer containing polyethylene oxide units and/or polypropylene oxide units.

7. The wound dressing of claim 1, wherein the polyalkylene oxide units in (a) and (b) are both polyethylene oxide and polypropylene oxide units in a weight ratio of polyethylene oxide units to polypropylene oxide units of from 3:1 to 7:1.

8. The The wound dressing aqueous hydrogel of claim 1, wherein the polyhydric alcohol is selected from the group consisting of ethylene glycol, glycerol, sorbitol, PEG300, PEG2000 and sucrose.

9. The wound dressing of claim 1, wherein the polyhydric alcohol is used in a proportion of 10-25% by weight, based on the total mass of all reactants.

10. The wound dressing of claim 1, wherein the glycerol is used in an amount of 10-25% by weight.

11. The wound dressing of claim 1, wherein the reaction further takes place in the presence of 0.5-1.5% by weight of a salt selected from the group consisting of sodium chloride, potassium chloride, magnesium chloride, calcium chloride and combinations thereof.

12. The wound dressing of claim 1, wherein the wound dressing additionally comprises an absorbent layer which is arranged between the backing layer and the layer comprising the aqueous hydrogel.

13. The wound dressing of claim 1, wherein the layer comprising an aqueous hydrogel is continuous.

14. The wound dressing of claim 1, wherein the layer comprising an aqueous hydrogel comprises holes, openings or channels.

15. A method of treating chronic wounds comprising applying the wound dressing of claim 1 to a chronic wound.

16. A method of concentrating would healing-promoting growth factors comprising applying the wound dressing of claim 1 to wound healing-promoting growth factors in a wound.

17. A method of treating a wound in a granulation and/or epithelialization phase comprising applying the wound dressing of claim 1 to a wound in the granulation and/or epithelialization phase.

18. The wound dressing of claim 1, wherein the molar ratio of reactive isocyanate end groups to reactive amine end groups is 1.0 to 1.5.

Description

DESCRIPTION OF THE FIGURES

(1) FIG. 1: A first wound dressing according to the invention

(2) FIG. 2: A second wound dressing according to the invention in cross section

(3) FIG. 3: A third wound dressing according to the invention in cross section

(4) FIG. 3a: A subsection of the third wound dressing according to the invention in cross section

(5) FIG. 4: A fourth wound dressing according to the invention in cross section

(6) FIG. 1 shows a first wound dressing (10) according to the invention with a view of the wound contact layer. The wound dressing (10) is manufactured as a so-called island dressing and consists of a support layer (11) composed of a water-impermeable and water vapor-permeable polyurethane film coated with an acrylic adhesive (12) over its entire surface. By means of the acrylic adhesive (12), what is applied in the center of the support layer is an absorbent hydrophilic polyurethane foam layer (not depicted here), to which a hydrogel (15) according to the invention is applied as wound contact layer. The hydrophilic polyurethane foam layer comprises a proportion of water of 40% by weight of water. Thus, 100 g of a polyurethane foam used in this example comprise 40 g of water and 60 g of polyurethane matrix. The hydrogel wound contact layer (15) is connected adhesively to the absorbent polyurethane foam layer (not depicted here). Introduced into the hydrogel wound contact layer are a multiplicity of circular holes (16) to allow the flow of wound exudate from the wound into the absorbent layer. The hydrogel wound contact layer prevents an inward growth of newly formed cells into the pores of the polyurethane foam.

(7) FIG. 2 shows a further embodiment of a wound dressing according to the invention. The wound dressing (20) comprises a support layer (21) congruent with an absorbent layer (23) and composed of a water-impermeable and water vapor-permeable polyurethane foam, which support layer (21) is connected to the absorbent layer (23) by means of a discontinuous adhesive layer (22) composed of an acrylic adhesive. The discontinuous application means that regions (27) of the absorbent layer and of the support layer remain unconnected. The wound dressing comprises an absorbent layer (23) having a layer thickness of 4 mm and a support layer (21) having a layer thickness of 1.5 mm. The absorbent layer (23) is formed from an open-pore hydrophilic polyurethane foam having a pore size of on average 220 μm. The polyurethane foam comprises, at the same time, a proportion of water of 70% by weight. Applied to the first side of the polyurethane foam is a hydrogel according to the invention as wound contact layer (25). With a basis weight of 75 g/m.sup.2, the hydrogel is not applied continuously on the polyurethane foam, with the result that circular holes (26) are provided in the hydrogel wound contact layer (25) for the improved passage of wound exudate. The polyurethane foam comprises a first side having an area of 25 cm.sup.2, with the holes (26) occupying altogether an area of 5 cm.sup.2.

(8) FIG. 3 shows a third embodiment of a wound dressing according to the invention. The wound dressing (30) comprises a support layer (31) composed of a water-impermeable and water vapor-permeable polyurethane film, an absorbent layer (33) composed of an open-pore hydrophilic polyurethane foam having a proportion of water of 52.8% by weight (based on the polyurethane foam) and a wound contact layer (35) composed of a hydrogel according to the invention having a proportion of water of approx. 57.9% by weight (based on the hydrogel). The entire surface of the support layer (31) is laminated onto the hydrophilic polymer foam by means of an acrylic adhesive (32) applied to the polymer film. An aqueous hydrogel (35) according to the invention, comprising a polyurethane-polyurea copolymer, is applied on the first side of the absorbent layer that faces the wound during use. The hydrogel wound contact layer is provided with conical channels (36) which are circular in cross section (in parallel to the wound), with the result that an improved flow of wound exudate from the wound into the absorbent hydrophilic foam can occur (cf. FIG. 3a). When preparing the wound dressing, the still viscous hydrogel has slightly penetrated into the polyurethane foam, and what is formed between the hydrogel wound contact layer and the hydrophilic polyurethane foam is therefore a transition layer (34) consisting of the hydrogel and the hydrophilic polyurethane foam. The transition layer on its part comprises channels (37) which are filled only with polyurethane foam and which are arranged congruently to the channels in the hydrogel wound contact layer.

(9) FIG. 4 shows a fourth embodiment of a wound dressing according to the invention. The wound dressing (40) comprises a support layer (41) composed of a water-impermeable and water vapor-permeable polyurethane film, a layer (42) composed of aqueous hydrogel according to the invention, and a two-part cover layer (43) composed of siliconized paper. The hydrogel layer has a thickness of 3 mm.

EXAMPLES

Examples 1-13

Preparation of the Gels

(10) Mixtures of alcohol, demineralized water and sodium chloride are prepared according to Table 1 below.

(11) TABLE-US-00001 TABLE 1 Mixtures of alcohol, water and sodium chloride Example Designation Demin. No. of gel Alcohol water NaCl  1 Glycerol 5%  70.4 g of glycerol 916.0 g 13.6 g  2 Glycerol 10% 140.8 g of glycerol 845.6 g 13.6 g  3 Glycerol 15% 211.3 g of glycerol 775.1 g 13.6 g  4 Glycerol 20% 281.7 g of glycerol 704.7 g 13.6 g  5 Glycerol 25% 352.1 g of glycerol 634.3 g 13.6 g  6 Glycerol 30% 422.5 g of glycerol 563.9 g 13.6 g  7 Ethylene 281.7 g of ethylene 704.7 g 13.6 g glycol 20% glycol  8 Sorbitol 20% 281.7 g of sorbitol 704.7 g 13.6 g  9 Sucrose 20% 281.7 g of sucrose 704.7 g 13.6 g 10 PEG300 20% 281.7 g of PEG 300 704.7 g 13.6 g 11 PEG2000 20% 281.7 g of PEG 2000 704.7 g 13.6 g 12 H.sub.2O — 986.4 g 13.6 g 13 Propylene 281.7 g of propylene 704.7 g 13.6 g glycol glycol

(12) In a second step, 3.465 g of Jeffamin are melted at 50° C. and mixed with 3.135 g of demineralized water. This amount of Jeffamin contains 3.31 mmol of reactive amine end groups. The mixture obtained is mixed with 28.4 g of an alcohol mixture prepared according to the table and 5.0 g of Aquapol with vigorous stirring and ice-cold water cooling. This amount of Aquapol contains 3.84 mmol of reactive isocyanate end groups. In this connection, the molar ratio of reactive isocyanate end groups to reactive amine groups is in each case 1.16. The mixture obtained is poured out and is spread out to form a gel having a thickness of 3 mm.

(13) The masses of the constituents used in the reaction to prepare the gels have the proportions indicated in Table 2, based on the total mass of the reactants used:

(14) TABLE-US-00002 TABLE 2 Proportions by mass of the reactants used Example Jeffamin Aquapol Demin. No. ED-2003 PL-13000-3 Alcohol Wasser NaCl  1 8.7% 12.5%  5.0% 72.9% 1.0%  2 8.7% 12.5% 10.0% 67.9% 1.0%  3 8.7% 12.5% 15.0% 62.9% 1.0%  4 8.7% 12.5% 20.0% 57.9% 1.0%  5 8.7% 12.5% 25.0% 52.9% 1.0%  6 8.7% 12.5% 30.0% 47.9% 1.0%  7 8.7% 12.5% 20.0% 57.9% 1.0%  8 8.7% 12.5% 20.0% 57.9% 1.0%  9 8.7% 12.5% 20.0% 57.9% 1.0% 10 8.7% 12.5% 20.0% 57.9% 1.0% 11 8.7% 12.5% 20.0% 57.9% 1.0% 12 8.7% 12.5%  0.0% 77.9% 1.0% 13 8.7% 12.5% 20.0% 57.9% 1.0%

(15) Example No. 12 is a comparative example without polyhydric alcohol.

(16) Example No. 13 is a comparative example according to WO2010/000451.

Example 14

Measurement of Moisture Loss

(17) Moisture loss describes the loss of weight over a certain period at a defined temperature.

(18) Moisture loss is calculated according to the following equation and is specified in the unit g/g:

(19) $\mathrm{Moisture}\mathrm{loss}=\frac{\mathrm{Final}\mathrm{weight}}{\mathrm{Starting}\mathrm{weight}}$

(20) For the gels of the exemplary embodiments, the moisture losses indicated in Table 3 were ascertained:

(21) TABLE-US-00003 TABLE 3 Moisture loss in g/g gel Example Moisture loss [g/g] No. Sample 2 h 4 h 6 h 8 h 24 h  1 Glycerol 5% 0.857 0.763 0.716 0.682 0.583  2 Glycerol 10% 0.861 0.779 0.724 0.702 0.641  3 Glycerol 15% 0.865 0.791 0.747 0.734 0.726  4 Glycerol 20% 0.884 0.827 0.785 0.756 0.688  5 Glycerol 25% 0.927 0.874 0.840 0.824 0.802  6 Glycerol 30% 0.951 0.914 0.894 0.883 0.864  7 Ethylene glycol 20% 0.943 0.910 0.887 0.874 0.819  8 Sorbitol 20% 0.804 0.698 0.637 0.596 0.510  9 Sucrose 20% 0.795 0.672 0.631 0.611 0.582 10 PEG300 20% 0.828 0.708 0.663 0.646 0.638 11 PEG2000 % 0.806 0.710 0.645 0.604 0.516 12 H2O 0.781 0.641 0.560 0.505 0.299 13 Propylene glycol 20% 0.832 0.720 0.655 0.617 0.529

(22) Example 15

Measurement of Absorption Capacity

(23) To measure absorption capacity, gel samples having a diameter Ø of 5 cm are punched out. Thereafter, they are placed in a beaker containing V=300 ml of deionized water. Subsequently, they are reweighed at certain intervals. Absorption capacity is calculated according to the following equation and is specified in the unit g/g:

(24) $\mathrm{Absorption}\mathrm{capacity}=\frac{\mathrm{Final}\mathrm{weight}-\mathrm{Starting}}{\mathrm{Starting}\mathrm{weight}}$

(25) For the gels of the exemplary embodiments, the absorption capacities indicated in Table 4 were ascertained:

(26) TABLE-US-00004 TABLE 4 Absorption capacity in g/g gel Example Absorption capacity [g/g] No. Sample 2 h 4 h 6 h 8 h 24 h  1 Glycerol 5% 1.195 1.574 1.844 2.027 2.511  2 Glycerol 10% 1.209 1.581 1.859 2.061 2.707  3 Glycerol 15% 1.635 2.237 2.654 3.043 3.894  4 Glycerol 20% 1.647 2.171 2.514 2.815 3.706  5 Glycerol 25% 1.743 2.337 2.806 3.096 4.111  6 Glycerol 30% 1.845 2.463 2.855 3.157 4.183  7 Ethylene glycol 20% 2.200 3.026 3.663 3.945 5.331  8 Sorbitol 20% 1.997 2.734 3.377 3.965 5.994  9 Sucrose 20% 2.704 3.498 4.124 4.587 5.877 10 PEG300 20% 2.759 3.641 4.245 4.785 6.820 11 PEG2000 20% 1.527 2.276 2.597 2.819 3.044 12 H2O 1.230 1.703 2.022 2.141 2.670 13 Propylene glycol 20% 1.694 2.313 2.655 2.958 3.836

Example 16

Measurement of Adhesive Force

(27) The term adhesive force describes the ability of an adhesive to adhere to a surface. It corresponds to the force required to detach a body which has come into contact with the gel surface from said surface, and is ascertained with the aid of a Zwick 010 static materials testing machine. The tests are carried out at a standard temperature of T=23° C. and a relative humidity of 50% rh. The gels must be conditioned under the test conditions for 24 hours before the test. For each measurement, three samples, each having a size of 5 cm×5 cm, are punched out from the gels in each case. The samples are affixed on a horizontally movable slide, via the side which faces away from the wound, with a double-sided adhesive tape. The approach speed of the slide is 100 mm/min, the contact time with the gel surface is 2 s and the withdrawal speed of the slide is 400 mm/min. The test body (weight=0.245 N) moves downward until it comes into contact with the surface of the gel, where it resides for a period of t=2 s. After this contact time, the test body moves upward and measures the force required for the detachment of the body from the gel surface.

Example 17

Test for Cell Compatibility

(28) The tests for cell compatibility were carried out in accordance with DIN EN ISO 10993-5 and the procedural instructions from the Abteilung für Funktionswerkstoffe der Medizin and der Zahnheilkunde [department of functional materials in medicine and dentistry]: BioLab 973302, 042901, 964702 and 964805, and comprise measurements of cell growth, metabolic activity and protein content.

(29) The hydrogels were delivered in a sterile state in Petri dishes. For the test, what were weighed out were, in each case, 0.1 g/ml culture medium of the samples.

(30) For each sample, cellular activity, cell count and protein concentration were each tested in quadruplicate three times. The elution time was 48 h, and the incubation of the cells with the eluates was also 48 h.

(31) The cell line used was L 929 CC1 mouse fibroblasts, American Type Culture Collection, Rockville, Md., USA.

(32) The culture medium used for preliminary culture and elution was DMEM (Dulbecco's Mod. Eagle Medium) according to procedural instructions BioLab 042901.

(33) The negative control used was polystyrene from Nunc GmbH & Co KG, Wiesbaden. The positive control used was Vekoplan KT PVC plates from Konig GmbH, Wendelstein.

(34) For each sample, three eluates, each from one hydrogel, which were prepared on different test days were tested. To this end, the hydrogels in the Petri dishes were halved in the middle using a sterile scalpel and transferred into a sterile 50 ml reaction vessel. For each 0.1 g of sample, 1 ml of elution medium was added to the hydrogels and this was then eluted for 48 h at 37° C. and 5% CO2 in an incubator. To remove any suspended solids from the eluates, the samples were centrifuged for 5 min at 4000 rpm after the incubation and filtered through a filter (pore size 0.2 μm).

(35) The cells were seeded at a concentration of 50 000 cells/ml, and the preliminary culture was carried out at 37° C. and 5% CO2 for 24 h. Thereafter, the DMEM medium added in the seeding was removed and the cells were each covered with 1 ml of eluate at a concentration of 100%. As negative control, DMEM medium was incubated for 48 h in a 50 ml Falcon tube like the samples and, as positive control, what was used was the eluate of the plastic disks at a concentration of 100%. After incubation for 48 hours, cellular activity, cell count and total protein content were determined.

(36) Cell Growth

(37) After enzymatic detachment of the cells using Accutase, the cells were counted with the aid of a cell counter.

(38) Viability Test via Metabolic Activity

(39) Viability is tested using tetrazolium salt, WST 1, Roche Diagnostics GmbH Mannheim, according to the information from the manufacturer. WST 1 is converted by succinate dehydrogenase (citric acid cycle enzyme) in the mitochondria of the metabolically active cells to form the colored formazan and is measured photometrically. The absorption values (OD), determined at 450 nm and 620 nm, correlate with the respiratory activity of the cultured cells.

(40) Protein Content

(41) Protein content is tested using the DC Protein Assay, BIO-RAD GmbH Munich, according to the information from the manufacturer. Lowry protein determination is based on the reduction of Cu(II) to form Cu(I) by the aromatic tyrosine/tryptophan residues of proteins. In a further step, the copper-protein complex reduces a phosphomolybdic acid/phosphotungstate reagent to form molybdenum and tungsten blue. The absorbance of this intense blue color is measured photometrically at 750 nm. By running a standard series at the same time, it is possible to determine the protein concentration.

(42) Acceptance and Evaluation

(43) The classification of the score ranges for acceptance and evaluation was done in accordance with DIN EN ISO 7405 and the term inhibitory dose (ID 50: dose at which 50% of cells are inhibited in terms of growth) (literature: Allgemeine Pharmakologie and Toxikologie [general pharmacology and toxicology], Henschler, editor: Forth Wolfgang; Spektrum akad. Verl. Heidelberg; 7th edition 1996). Severe growth inhibition, moderate inhibition and slight inhibition are characterized by a cell growth of 0-29%, a cell growth of 30-59% and a cell growth of 60-79%, respectively, in comparison with the control. Cell growth rates between 80% and 100% indicate noninhibited cell growth.

(44) Severely reduced metabolic activity, moderately reduced metabolic activity and slightly reduced metabolic activity are characterized by a cellular activity of 0-29%, a cellular activity of 30-59% and a cellular activity of 60-79%, respectively, in comparison with the control. Cellular activity rates between 80% and 100% indicate a nonreduced metabolic activity.

(45) Severe reduced protein content and moderately reduced protein content are characterized by a protein concentration of 0-34% and a protein concentration of 35-69%, respectively, in comparison with the control. Protein concentrations between 70% and 100% indicate a nonreduced protein content.

(46) For the gels of the exemplary embodiments, the cell compatibilities indicated in Table 5 were ascertained:

(47) TABLE-US-00005 TABLE 5 Cell compatibility Reduction Inhibition of Reduction Example of cell metabolic of protein No. Sample growth activity content  1 Glycerol 5% Slight Moderate Moderate  2 Glycerol 10% Slight Slight None  3 Glycerol 15% Slight Slight None  4 Glycerol 20% Slight Slight None  5 Glycerol 25% Slight Slight None  6 Glycerol 30% Moderate Slight None  7 Ethylene Moderate Moderate Moderate glycol 20%  8 Sorbitol 20% Moderate Severe Moderate  9 Sucrose 20% Slight Moderate None 10 PEG300 20% Severe Severe Moderate 11 PEG2000 20% Moderate Moderate Moderate 12 H2O Slight Slight Moderate 13 Propylene Severe Severe Moderate glycol 20%