Wound healing materials, wound gels and cosmetics

Abstract

The present invention relates to a synthetic particulate wound healing material (10) in the form of a bulk material (12) comprising particles (14) with a maximum dimension (d) of 5 millimeters, the particles (14) each having a porosity of more than 80% and each comprising a polyhydroxycarboxylic acid, i.e. a copolymer and / or terpolymer based on the monomers lactide, trimethylene carbonate, caprolactone and / or 1,4-dioxane-2-one. The present invention further relates to synthetic wound gels and cosmetics.

Description

[Technical field]

[0001] The present invention relates to wound healing materials, wound gels and cosmetics, especially skin care cosmetics.

[0002] When external tissue defects are relatively large, the risk of infection is often very high or bacterial (mixed) infection of the damaged tissue area is often already well underway. Such wounds are often accompanied by significant scarring during healing. In clinical practice, tissue defects often have to be covered with skin substitutes in the form of synthetic or biological surfaces to support secondary wound healing and combat infection. However, the effectiveness of such surfaces in supporting wound healing is often rather limited, especially when tissue defects are deep or irregular. Even when using, for example, vacuum foaming systems or artificial skin coverings that promote granulation formation in deep tissue layers, wound healing is often unsatisfactory and can be excessively delayed, which necessitates repeated surgical interventions and wound regeneration.

[0003] It is therefore an object of the present invention to provide a synthetic wound healing material and a synthetic wound gel suitable for application over large areas and supporting wound healing, especially in the case of deep tissue defects, and further to provide a synthetic cosmetic product having a skin-neutral anti-inflammatory effect, which is particularly suitable for the aftercare of healed skin wounds.

[0004] This problem with respect to wound-healing materials is solved by a wound-healing material having the features defined in claim 1. A gel or cosmetic product for wounds according to the invention has the features defined in claim 11. Preferred developments of the invention are set out in the dependent claims and in the present description.

[0005] The wound-healing material according to the invention is in the form of a bulk material comprising absorbent particles with a maximum dimension, i.e. maximum longitudinal extension, of 5 millimeters. The particles each have a porosity of more than 80% and each comprise a polyhydroxycarboxylic acid, i.e. a copolymer and / or terpolymer based on the monomers lactide, trimethylene carbonate (TMC), caprolactone and / or 1,4-dioxane-2-one or polyhydroxybutyrate (PHB). Particularly preferably, the particles each comprise a copolymer based on lactide and TMC, or a copolymer based on lactide and caprolactone, or a terpolymer of lactide and TMC, or lactide and caprolactone, and further, respectively, with 1,4-dioxane-2-one or polyhydroxybutyrate (PHB).

[0006] Due to its particle structure, the synthetic wound healing material can also be introduced as a bulk material into deep wound areas that are only partially or completely inaccessible to sheet materials, for example by blowing into these wound areas and exerting its wound healing support effect there. The bulk material is suitable for both large and small tissue defects and can be easily introduced into particularly deep wounds. Overall, the tissue defect can be completely blocked or filled with the wound healing material. Due to the very high porosity of the particles, the wound healing material can effectively absorb and adsorb wound secretions, inflammatory exudates and blood. Due to the lactate released during absorption by the wound healing material, the pH value can be kept in the (slightly) acidic range in the entire area of ​​the tissue defect, i.e. in the wound bed which is difficult to reach, thereby providing a bactericidal effect and promoting wound healing overall. Overall, the wound healing material can exert an anti-infective and pain-relieving effect, whereby it is completely hydrolytically and enzymatically degradable. Considering the complete absorption of the wound healing material, subsequent removal of the wound healing material is not necessary at all. This is also favorable for the formation of granulation tissue as part of secondary wound closure. The wound healing material can be easily provided in a sterile state. According to the invention, the bulk material particles can in particular have a maximum dimension of 2 mm. This allows the wound healing material to be introduced even into fine wounds with very small dimensions.

[0007] According to a particularly preferred development of the invention, the bulk material particles of the wound healing material can be at least partially or entirely powder-like, i.e. formed as fine particles. The particles in this case have a maximum dimension of 700 μm or 150 μm, very particularly preferably only 100 μm. This allows the powdered wound healing material to be introduced even into very small wound cavities and exert its effect there. The wound healing material can be easily provided in a sterile state. Furthermore, such a particle size allows the wound volume to be filled without or essentially without cavities, i.e. without large cavities between the particles of the wound healing material. As a result, a wound healing-promoting microenvironment can thus be set up throughout the defect volume of the damaged tissue and can counteract undesirable infections. The powdered bulk material can in particular be blown into the wound with a maximum particle dimension of 250 μm or 100 μm, both outside the wound and into the abdominal cavity for the prevention of adhesions.

[0008] The maximum dimension of the bulk material particles can be determined by optical microscopy of the individual particles in the case of relatively large particles. In the case of powdered bulk materials having particles with a maximum dimension of 250 μm, or even only 100 μm, the maximum dimension of each of the particles of the bulk material can also be determined experimentally by scanning electron microscopy.

[0009] The determination of the respective maximum particle dimensions by optical microscopy and scanning electron microscopy can in particular be carried out in a partially or fully automated manner by computer-based optical analysis software, which is advantageous for rapid and low-error inspection of particle size.

[0010] Advantageously, most or all of the particles of the bulk material / wound healing material have a random, i.e. irregular, basic shape. Thus, the particles are not designed to be spherical or rounded. This allows the wound healing material to have a mechanical stabilization function for the tissue surrounding the wound after application to the wound. This also allows the wound healing to be further promoted until complete absorption by the wound healing material occurs.

[0011] The particles of the wound-healing material according to the invention preferably have an average pore size in the range of 0.1 μm to 50 μm, in particular in the range of 0.5 μm to 30 μm. Such an average pore size, in combination with the very high porosity of the particles, which is more than 90%, ensures a particularly reliable absorption of the liquid, which allows the inner surface of the particles to be rapidly and comprehensively wetted with the liquid, which the particles can absorb reliably for this reason in particular.

[0012] The wound-healing material, in the form of the powdered bulk material described above, i.e. in the form of a fine powder, preferably has a bulk density, i.e. the ratio of the mass of the bulk material to the collected bulk volume, of 0.08 g / ml to 0.25 g / ml, in particular 0.12 to 0.14 g / ml, according to the measurement method defined in DIN EN ISO 60:2000-01.

[0013] When the particles in the sense of micrografts have a maximum dimension of 1 mm to 5 mm, the bulk material or wound healing material may advantageously have a density of 0.03 g / ml to 0.06 g / ml, in particular about 0.04 g / ml.

[0014] The particles of the wound-healing material in bulk form preferably have a bimodal pore structure or pore size distribution according to the invention, with a first pore size in the range of 0.1 μm to 50 μm, in particular in the range of 0.5 to 30 μm, and a second pore size in the range of 80 μm to 600 μm, in particular in the range of 100 μm to 500 μm. As a result, a particularly rapid and effective liquid absorption by the particles can be achieved when the wound-healing material is applied to the wound. Such a bimodal pore structure can be achieved on the one hand by the below-described drying process of the polymer solution used for the production of the particles, and on the other hand by additionally supplying sugars to the polymer solution before the start of the drying process and removing the sugars in a time-delayed manner.

[0015] The particles according to the invention may comprise a polyhydroxycarboxylic acid, in particular a terpolymer of 65-90% by weight of lactide (especially D,L-lactide), 5-20% by weight of trimethylene carbonate and 5-20% by weight of ε-caprolactone. The monomers lactide, trimethylene carbonate and ε-caprolactone may be present in the terpolymer in a range of, in particular, 85 / 10 / 5 to 70 / 20 / 10% by weight or may be mixtures thereof.

[0016] The wound-healing material according to the invention can have a glass transition temperature Tg of 22°C to 45°C. This ensures that the wound-healing material remains dimensionally stable at normal ambient temperatures during transport and storage and does not exhibit undesirable agglomeration. This ensures the flowability of the wound-healing material. The wound-healing material only softens on application due to the local thermal action of the respective surrounding (wound) tissue and can thus be optimally applied to the (wound) tissue. The glass transition temperature of the wound-healing material is determined in a manner known per se by dynamic differential thermal analysis in accordance with DIN EN ISO 11357-1.

[0017] According to the invention, the particles may each have a content of free monomer of 0 to 12% by weight, in particular 0.1 to 12% by weight, advantageously 1 to 10% by weight, relative to the weight of the copolymer and / or terpolymer.

[0018] According to an advantageous development of the invention, the copolymers and / or terpolymers can be doped with fillers, in particular synthetic polymers, preferably polyvinyl alcohol (PVA), the emulsifying effect of which facilitates the production of the particles.

[0019] Advantageously most or all of the particles of bulk material / wound healing material have a discrete basic shape, which allows the particles of wound healing material to interlock after application to the wound, so that their relative position and state to the wound surface, and thus the wound surface itself, are stable relative to each other, which is advantageous for wound healing.

[0020] The wound gel comprises the wound healing material described above and can be used in particular as a wound dressing or for the prevention of intraperitoneal adhesions in human and / or veterinary medicine, the wound gel can be injected or sprayed into the abdominal cavity for this purpose.

[0021] The wound gel according to the invention may contain, in addition to the wound healing material (and water), one or more further medicinal substances and / or additives. Suitable additives may be used, for example, to adjust the consistency, shelf life, cooling effect, etc. of the wound gel. For example, the wound gel may in particular contain a biocompatible thickening agent, such as a water-soluble and / or swellable non-ionic polymer, in particular poloxamer, polyvinyl alcohol, polyethylene glycol, hyaluronic acid, collagen, gelatin, alginate, or a cellulose derivative, such as hydroxypropylmethylcellulose, or an emulsifier, such as polyglyceryl-2-triisostearate, or another carrier, such as saline or petrolatum.

[0022] The wound-healing material can also be used according to the invention as a filler or auxiliary or active substance in cosmetic products, in particular in skin care cosmetic products.

[0023] The wound-healing material according to the present invention can be produced, for example, by the method described below: In a first step, a polymer solution is prepared from copolymers and / or terpolymers based on the monomers lactide, trimethylene carbonate, caprolactone and / or 1,4-dioxane-2-one or polyhydroxybutyrate in a suitable solvent, such as dimethylsulfoxide (DMSO). For example, a 10% polymer solution containing 4% PVA (polyvinyl alcohol) in DMSO is prepared.

[0024] The polymer solution is preferably applied to a flat support. For example, this can be done by discharging the polymer solution through a sieve with a certain opening, for example 0.042 mm. The support can be, for example, a glass plate. The polymer solution can be stretched on the support to form a film using a doctor blade or a film stretching device, and an excess of sugar, preferably sucrose, can be added.

[0025] The solvent is removed in a subsequent step by drying, in particular freeze-drying, to form a polymer cake, which can be carried out, for example, as follows: In the case of freeze-drying, the polymer solution is advantageously kept in a first partial step at −60° C. and at a vacuum below 0.5 mbar (ie below atmospheric ambient pressure) for at least 12 hours.

[0026] If necessary, the polymer cake can then be incubated for about 40 to 70 minutes in a bath filled with demineralized water (fully demineralized water) with circulation and temperature control (about 21°C) and then removed from the support in a convenient manner.

[0027] The polymer cake is then washed in double distilled water for 2 h each and then freeze-dried at -60°C and a vacuum of less than 0.5 mbar for at least 12 h.

[0028] In a subsequent optional step, the polymer cake 58 is further dried under clean room conditions at about +21° C. and 30% relative humidity for at least 12 hours.

[0029] The polymer cake thus obtained is then broken down, in particular by single or multi-stage coarse or comminuted grinding or other known processes, to form the bulk material or wound healing material having a respective predetermined maximum dimension d of the particles.

[0030] For example, the polymer cake can be pre-crushed to polymer cake pieces of about 2x2 cm size, which can be advantageously cooled with liquid nitrogen. The liquid nitrogen can pre-embrittle the polymer cake, thus achieving improved processability. These polymer cake pieces can be further crushed by a cryomill (e.g., equipped with a 12-tooth rotor at 18,000 rpm and a ring screen of 1.0-0.5 mm) with a sufficient amount of liquid nitrogen for cooling / embrittlement to form the wound healing material 10 / bulk material 12. As the cryomill, for example, an ultracentrifuge mill ZM 200 from RETSCH GmbH (Retsch-Allee 1-5, 42781 Haan, Germany) can be used. Excessively large particles possibly still contained in the bulk material can, if necessary, be detected and removed from the bulk material by optional preliminary sieving of the bulk material (according to DIN 66165) and subsequently based on optical (by optical microscope or scanning electron microscope) size measurements of the particles of the bulk material.

[0031] The bulk material / wound healing material thus obtained is then dried in vacuum, preferably at ambient atmospheric pressure below 2 mbar for at least 12 hours, which makes it possible to provide a bulk material with a degree of dryness suitable for packaging, storage and transport purposes, thus ensuring the flowability of the wound healing material upon application.

[0032] Furthermore, the bulk material according to the invention can be used as a matrix for nutrient media for culturing animal or plant cells, i.e. for cell culture.

[0033] The invention will now be described with reference to examples shown in the drawings, in which: the shown and described embodiments are not to be understood as an exhaustive list, but rather have an exemplary character for the explanation of the invention. [Brief description of the drawings]

[0034] [Figure 1]FIG. 1A shows an overall view (FIG. 1A) and a detailed view (FIG. 1B) of SEM images of a wound-healing material in the form of a bulk material composed of absorbent particles, which particles here have, exemplarily, a maximum particle size of 500 μm to 1 mm. [Diagram 2] Overall (Figure 2A) and detailed (Figure 2B) SEM images of a wound-healing material in the form of a bulk material composed of absorbent particles with a maximum particle size of 250 μm to 500 μm. [Diagram 3] FIG. 3A shows an overall view (FIG. 3A) and a detailed view (FIG. 3B) of SEM images of a wound-healing material in the form of a bulk material composed of absorbent particles with maximum particle sizes of 63 μm to 250 μm. [Figure 4] Overall (FIG. 4A) and high magnification detail (FIG. 4B) SEM images of individual particles of the wound healing material in bulk form. [Diagram 5] 5 is an SEM image of a particle of wound healing material similar to the particle shown in FIG. 4, showing a flat or substantially flat underside. [Figure 6] FIG. 2 is a block diagram showing the individual method steps of a method for producing a wound healing material in the form of a bulk material. [Figure 7] FIG. 1 is a schematic diagram of a wound gel or cosmetic product.

[0035] 1 to 3 each show a scanning electron microscope (SEM) image of the wound-healing material 10. The scales shown in Fig. 1A, Fig. 2A, and Fig. 3A without detailed description correspond to a length of 2 mm, and the scales shown in Fig. 1B, Fig. 2B, and Fig. 3B without detailed description correspond to a length of 200 µm.

[0036] The illustrated wound-healing materials 10 are each designed in the form of a bulk material 12 consisting of a plurality of particles 14. For example, the wound-healing material 12 according to FIG. 1 has particles 14 with a maximum dimension d (= maximum longitudinal extension) of 500 μm to 1 mm. The wound-healing material 12 shown in FIG. 2 has particles with a maximum dimension of 250 μm to 500 μm, the wound-healing material 12 shown in FIG. 3 has particles 14 with a maximum dimension of 63 μm to 250 μm. The bulk-material wound-healing materials 12 according to FIGS. 1A, 1B, 2A and 2B here have a density of 0.08 g / ml to 0.16 g / ml, in particular 0.12 to 0.14 g / ml.

[0037] The porous structure of the particles 14 can be clearly seen. The porosity of the particles 14 is more than 90%. The pores 16 can be differentiated into relatively large primary pores or macropores 16a and relatively small secondary pores or micropores 16b. Most or all of the particles 14 have a random, i.e. irregular, basic shape, respectively. This allows the particles to interlock with each other in the wound. In this way, the edges of the wound can be mechanically stabilized relative to each other by the wound healing powder introduced into the wound.

[0038] The different fineness of the wound healing material 10 in bulk form allows a particularly wide field of application of the wound healing material 10. The finer it is, i.e. the smaller the particle size, the better the applicability of the wound healing material 10 for small and very small wounds.

[0039] In Fig. 4A and Fig. 4B, SEM images of individual particles 14 of the wound-healing material 10 are shown at different magnifications. The particles 14 here have a maximum dimension d of 3 millimeters. The particles 14 can be called micrografts in this respect and are ideally suited to the treatment of large-area, irregularly defined wounds. The porous structure of the particles 14 can be seen well in Fig. 4B. The pores 16 can again be differentiated into relatively large primary pores or macropores 16a and relatively small secondary pores or micropores 16b. The particles 14 likewise have a discrete basic shape with irregularly defined side surfaces 18. The discrete basic shape of the particles 14 results from the mechanical disruption of the bulk material or large polymer cakes during the production of the particles 14. The underside 22 of the particles 14 shows a mainly closed, slightly wavy topography with individual pores 16b. According to a SEM image of a further particle 14 shown in Figure 5, the lower surface 22 can be designed relatively flat and can have only a small number of macropores 16a and a large number of micropores 16b. The scales shown in Figures 4 and 5 each correspond to 1 mm.

[0040] FIG. 6 shows a block diagram illustrating the individual method steps of the method 100 for manufacturing the wound healing material 10 described above in relation to FIGS.

[0041] The first step 102 is the preparation of a polymer solution 50 from copolymers and / or terpolymers based on the monomers lactide, trimethylene carbonate, caprolactone and / or 1,4-dioxane-2-one or polyhydroxybutyrate (PHB) (which of course have already been provided) and a suitable solvent. For example, a 10% polymer solution 50 can be prepared containing 4% PVA (polyvinyl alcohol) in DMSO.

[0042] The polymer solution 50 is applied in step 104, for example by discharging the polymer solution (e.g. through a sieve 51 with 0.042 mm openings) onto a support 52. The support 52 can in particular be a glass plate. The polymer solution 50 is stretched onto the support 52 using a doctor blade 54 or a film stretching device to form a film, and an excess of sugar 56 can be added in order to form the macropores 16a as described above.

[0043] In a further step 106, the solvent is removed by drying, in particular freeze-drying, to form a polymer cake 58.

[0044] For this purpose, the polymer solution 50 is freeze-dried in a partial step 106A at −60° C. and in a vacuum below 0.5 mbar for at least 12 hours.

[0045] The polymer precake 58a thus produced can be incubated in an optional intermediate step 106B for about 40 to 70 minutes in a bath filled with demineralized water (fully demineralized water) in a circulation and temperature control section (about 21°C), and then removed from the support in a convenient manner.

[0046] The polymer precake 58a is washed in double distilled water in the next step 106C for 2 hours each and then freeze dried in step 106D at least -60°C and at a vacuum of 0.5 mbar or less for at least 12 hours.

[0047] In a next step 106E, the polymer pre-cake 58a can be dried further for at least 12 hours under clean room conditions at about +21° C. and 30% relative humidity.

[0048] The polymer cake 58 thus obtained is mechanically crushed in a next step 108 to form the wound-healing material 10 in the form of a bulk material 12 having a predetermined maximum particle size / dimension d (see Figures 1 to 4) of each of the particles 14. This can in particular be done by single or multi-stage coarse or comminuting or by other techniques corresponding to the prior art.

[0049] For example, the polymer cake 58 may be pre-crushed in step 108 into polymer cake pieces 58b, particularly of a size of about 2×2 cm, and then cooled with liquid nitrogen 60. These polymer cake pieces 58a may then be further crushed by a cryomill (e.g., equipped with a 12-tooth rotor at 18,000 rpm and a 1.0-0.5 mm ring screen) with a sufficient amount of liquid nitrogen for cooling to form the wound healing material 10 / bulk material 12.

[0050] The (powdered) wound healing material 10 / bulk material 12 thus obtained is advantageously vacuum dried in step 110 at ambient atmospheric pressure below 2 mbar for at least 12 hours.

[0051] Excessively large particles possibly still contained in the wound healing material 10 / bulk material 12 can, if necessary, be removed from the wound healing material 10 / bulk material 12 by an optional preliminary sieving of the bulk material (in accordance with DIN 66165) before or after step 110 and based on optical (by optical microscope or scanning electron microscope) size measurements 112 of the particles of the wound healing material 10 / bulk material 12.

[0052] The mechanical disruption is preferably carried out at low humidity or at ambient atmospheric humidity of less than 40%, in particular less than 20%. Likewise, the wound healing material 10 is preferably vacuum-packed under the same conditions and thus presented for human / animal use or further processing.

[0053] The wound healing material 10 can also be used as a component of a wound gel 200 according to FIG. 7. That is, the wound gel 200 comprises the (preferably fine) granular wound healing material 10. The wound gel 200 can also comprise water and a water-soluble non-ionic polymer 400, in particular a cellulose derivative, such as hydroxypropylmethylcellulose or polyglyceryl-2-triisostearate, as emulsifiers and film-forming agents. The wound gel is particularly suitable for intracavitary application, in particular intraperitoneal application, for example for preventing adhesions after abdominal surgery. The wound gel 200 can be conveniently applied, in particular injected, in the operating room, even for minimally invasive surgical approaches. The wound gel 200 can further comprise a coloring agent, if necessary, which allows easy visual confirmation of the areal application.

[0054] 7, the wound-healing material 10 can also be used as a filler and active ingredient, in particular in cosmetic products 300 for external use, whereby the wound-healing material 10 can prevent skin irritation and skin microinflammation as precursors to acne and promote faster skin regeneration.

[0055] Furthermore, the bulk material 12 described above can also serve as a carrier system for medicinal substances. The carrier system, due to its biocompatibility and complete resorbability, can allow for sustained release of the drug and thus a long-term effect of the drug. Advantageously, the bulk material 12 is non-toxic for either external or internal surface application and can be readily provided in a sterile form.

Claims

1. A wound-healing material (10) in the form of a bulk material (12) comprising particles (14) with a maximum dimension d of 5 mm, said particles (14) each having a porosity of more than 80% and each comprising a polyhydroxycarboxylic acid, i.e. a copolymer and / or terpolymer based on the monomers lactide, trimethylene carbonate, caprolactone and / or 1,4-dioxane-2-one or polyhydroxybutyrate (PHB).

2. 2. Wound healing material (10) according to claim 1, characterized in that at least some or all of the particles (14) have a maximum dimension (d) of 2 mm, in particular 700 μm or 150 μm.

3. Wound healing material (10) according to claim 1 or 2, characterized in that the particles (14) have an average pore size in the range of 0.1 μm to 50 μm, in particular in the range of 0.5 to 30 μm.

4. Wound healing material (10) according to claim 2 or 3, characterized in that the particles (14) have a bulk density of 0.08 g / ml to 0.16 g / ml, in particular 0.12 to 0.14 g / ml.

5. 2. Wound healing material (10) according to claim 1, characterized in that the particles (14) have a maximum dimension d of 1 mm to 5 mm and a density of 0.03 g / ml to 0.06 g / ml, in particular about 0.04 g / ml.

6. 6. The wound healing material (10) according to claim 1 or 5, characterized in that the particles (14) have a bimodal pore structure with pore sizes in the range of 0.1 μm to 50 μm, in particular in the range of 0.5 to 30 μm and in the range of 80 μm to 600 μm, in particular in the range of 100 μm to 500 μm.

7. 7. The wound-healing material (10) according to any one of claims 1 to 6, characterized in that the particles (14) each have a content of free monomer of 0 to 12% by weight, in particular 0.1 to 10% by weight, preferably 1 to 9% by weight, based on the weight of the copolymer and / or terpolymer.

8. 8. The wound-healing material (10) according to any one of claims 1 to 7, characterized in that the copolymers and / or terpolymers are doped with a filler, in particular a synthetic polymer, preferably polyvinyl alcohol (PVA).

9. 9. Wound healing material (10) according to any one of claims 1 to 8, characterized in that most or all of the particles (14) have a random basic shape.

10. A wound gel (200) or cosmetic (300), characterized in that said wound gel (200) / said cosmetic (300) comprises an absorbent wound healing material (10) according to any one of claims 1 to 9.

11. The wound gel (200) or cosmetic (300) of claim 10, characterized in that the wound gel (200) / cosmetic (300) comprises a water-soluble non-ionic polymer (400), in particular a cellulose derivative, in particular hydroxypropylmethylcellulose and / or polyglyceryl-2-triisostearate.

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