KR-20260068135-A - IMPROVED WOUND CARE DEVICE

Abstract

An antimicrobial amphiphilic hydrogel composition for hemostasis of a wound comprising, as a first crosslinkable amphiphilic component, a first amphiphilic component having a lyotropic liquid crystal in a chemically crosslinked state and an aligned nanostructure of hydrophobic and hydrophilic domains, wherein the hydrogel comprises an antimicrobial agent covalently attached to the hydrophilic and/or hydrophobic domains.

Inventors

• 쿠마르 라예스크하란 아난드
• 아테픽타 사바
• 안데르센 마르틴
• 블롬스트란드 에드빈

Assignees

• 암페리아 아베

Dates

Publication Date

20260513

Application Date

20201216

Priority Date

20191218

Claims (14)

1. An antimicrobial peptide derived from PRELP (proline arginine-rich end leucine-rich repeat protein) for inducing hemostasis in bleeding wounds, wherein the antimicrobial peptide is RRP9W4N.
2. The antimicrobial peptide of claim 1, wherein the antimicrobial peptide reduces the number of platelets in the blood of a bleeding wound.
3. The antimicrobial peptide of claim 1, wherein the antimicrobial peptide is covalently attached to amphiphilic hydrogel particles, the amphiphilic hydrogel particles are cross-linked polymerized lyotropic liquid crystals having an aligned nanostructure of hydrophobic and hydrophilic domains, the lyotropic liquid crystals are formed by an aqueous solution as aggregates and continuous domains of polymerizable polyethylene oxide-polypropylene oxide-polyethylene oxide (PEOx-PPOy-PEOx, where x and y represent the number of PEO and PPO groups present, respectively), and the antimicrobial peptide is covalently bonded to at least the hydrophilic domains of the hydrogel.
4. The antimicrobial peptide of claim 3, wherein the polymerized lyotropic liquid crystal is diacrylate-modified polyethylene oxide-polypropylene oxide-polyethylene oxide (DA-PEOx-PPOy-PEOx-DA, where x and y represent the number of PEO and PPO groups present, respectively).
5. The antimicrobial peptide according to claim 3, wherein the C-terminus of the antimicrobial peptide is covalently attached to the hydrophilic domain of the amphiphilic hydrogel through the activation of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)-N-hydroxysuccinimide (NHS) of a carboxyl group present in the hydrophilic domain of the hydrogel.
6. The antimicrobial peptide of claim 3, wherein the blood clot is physically bound to the amphiphilic hydrogel particle to which the antimicrobial peptide is attached.
7. The antimicrobial peptide of claim 3, wherein the hydrogel particles are solid cross-linked hydrogel particles separated from each other and separated from the continuous domain.
8. In claim 7, the antimicrobial peptide is an antimicrobial peptide in which the solid cross-linked hydrogel particles to which the antimicrobial peptide is attached are suspended in an aqueous solution.
9. The antimicrobial peptide of claim 3, wherein the lyotropic liquid crystal is a micelle cubic liquid crystal formed by mixing 20% to 65% (wt/wt) of polyethylene oxide (100)-polypropylene oxide (70)-polyethylene oxide (100) and 80% to 35% (wt/wt) of water.
10. In claim 9, the micelle cubic liquid crystal is an antimicrobial peptide formed by a mixture of 30% (wt/wt) polyethylene oxide (100)-polypropylene oxide (70)-polyethylene oxide (100) and 70% (wt/wt) water.
11. A method for preparing a suspension of hydrogel particles in solution for inducing hemostasis in wounds, comprising the following: - A step of forming a lyotropic liquid crystal hydrogel having an aligned nanostructure of hydrophobic and hydrophilic domains by providing a composition of polymerizable polyethylene oxide-polypropylene oxide-polyethylene oxide (PEOx-PPOy-PEOx, where x and y represent the number of present PEO and PPO groups, respectively) as an aggregate of lyotropic liquid crystals and an aqueous solution as a continuous domain of lyotropic liquid crystals; - A step of forming a chemically crosslinked solid lyotropic liquid crystal hydrogel by crosslinking the above lyotropic liquid crystal hydrogel composition; - A step of grinding the chemically crosslinked solid lyotropic liquid crystal hydrogel to form crosslinked solid hydrogel particles; - A step of suspending the above-mentioned cross-linked solid hydrogel particles in an aqueous solution; and - A step of covalently attaching an antimicrobial peptide RRP9W4N to at least a hydrophilic domain of the above lyotropic liquid crystal.
12. A method according to claim 11, wherein the polymerized lyotropic liquid crystal is diacrylate-modified polyethylene oxide-polypropylene oxide-polyethylene oxide.
13. A method according to claim 11, wherein the C-terminus of the antimicrobial peptide is covalently attached to the hydrophilic domain of an amphiphilic hydrogel through the activation of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)-N-hydroxysuccinimide (NHS) of a carboxyl group present in the hydrophilic domain of the hydrogel.
14. The method of claim 11 comprises the step of providing a photoinitiator to the composition, wherein the crosslinking is performed through ultraviolet (UV) crosslinking.

Description

Improved Wound Care Device The present invention relates to an antimicrobial hydrogel. Specifically, it relates to an antimicrobial amphiphilic hydrogel composition for wound hemostasis. The antimicrobial hydrogel may be provided as a dispersion. Wound infections involving the skin or tissues surrounding a wound can interfere with the healing process and lead to systemic diseases. Today, antibiotic therapy is the most common treatment for wound infections. Over the years, however, this antibiotic therapy has not only caused systemic side effects in patients but has also led to a rapid increase in severe infections caused by antibiotic-resistant bacteria. Hemostasis is the body's process of preventing and stopping bleeding. Hemostasis involves blood clotting and the formation of blood clots to stop bleeding. Microfibrillar collagen hemostatic agents are known to be used in wound healing to promote blood clot formation. Microfibrillar collagen is available in sheet, powder, and sponge forms. Commercially available wound dressings, such as Mepilex® or Mepilex-Ag® (sold by Molnlycke Health Care), contain a soft, superabsorbent dressing layer that includes silver as an antimicrobial agent. Silver is released into the wound to kill microorganisms by damaging cell walls or inhibiting their proliferation. Many other wound dressings contain antimicrobial molecules such as chlorhexidine, or conventional antibiotics such as penicillin are used to prevent bacterial adhesion or infection at the wound site. However, the use of these compounds is limited due to their limited active spectrum, cytotoxicity to human cells, and the potential for antimicrobial resistance to develop within a short period. Additionally, the release of silver into water systems has harmful effects on the environment. Alternative drinking-water disinfectants: bromine, iodine, and silver . According to the World Health Organization (WHO) 2018, "based on the lowest median L(E)C 50 value of major environmental organisms, silver salts and silver nanoparticles are both classified as "highly toxic to aquatic organisms" under EU Directive 93/67/EEC (CEC, 1996). Generally, wound healing devices such as the one mentioned above that may have antibacterial properties simply collect or absorb blood. WO 2019/074422 A1 (AMFERIA AB) dated April 18, 2019 describes an antimicrobial amphiphilic hydrogel. The hydrogel of WO 2019/074422 A1 is disclosed as a solid monomaterial suitable for use as an antimicrobial wound care device, particularly in antibiotic-resistant infections. This document is not related to hemostasis or bleeding wounds. Improved compositions of the material and new applications can improve wound care alternatives for healthcare workers and patients. A device combining antibacterial and hemostatic effects would be advantageous. These and other aspects, features, and advantages of the invention that are feasible will be apparent and explained from the following description of embodiments of the invention with reference to the accompanying drawings. Figure 1 is the synthesis scheme of a diacrylate-modified Pluronic® triblock copolymer, where X and Y represent the number of PEO and PPO groups. Figure 2 shows the covalent attachment reaction scheme of an antimicrobial peptide to diacrylate-modified Pluronic triblock copolymer F-127 by EDC/NHS activation. Figure 3 shows a zone inhibition test of antimicrobial hydrogels versus control samples. Figure 3A shows a negative control amphiphilic hydrogel without AMP; Figure 3B shows an amphiphilic hydrogel with only physically absorbed AMP; and Figure 3C shows an amphiphilic antimicrobial hydrogel according to the pattern of covalent attachment of AMP to the amphiphilic hydrogel. The inhibition zone is a darker area and can be seen extending beyond the hydrogel area (central circular element), but in Figure 3C, the inhibition zone is located directly beneath the hydrogel, indicating that AMP was not leached from the hydrogel. Figure 4 shows a schematic diagram of AMP covalently bonded to a chemically crosslinked amphiphilic hydrogel with repeating 3D printed and aligned general hexagonal array nanostructures. Figures 5a and 5b show the results of storage stability tests in phosphate-buffered saline (PBS). In Figure 5a, the ratio of dead cells ( S. aureus ) to the control amphiphilic hydrogel and the antimicrobial amphiphilic hydrogel can be seen. Figure 5b shows the total surface coverage found in the hydrogels. An asterisk (*) indicates a significant difference compared to the control at a 95% confidence level. Figure 6 shows the results of a serum stability test in which the hydrogel was exposed to 20% human serum. The hydrogel was withdrawn from the serum at the time indicated on the x-axis. The proportion of dead cells ( S. aureus ) on the hydrogel surface was determined by viability/death staining and is found on the y-axis. At each time point, except for day 5, there was a significant difference between