Wound dressing composition with excellent hemostatic and Anti-adhesion effects and use thereof

Abstract

The present invention relates to a wound dressing composition with excellent hemostatic and anti-adhesion effects and use thereof. More specifically, the present invention relates to a wound dressing composition and use thereof in a medical device, the wound dressing composition comprising hyaluronic acid, collagen, and sodium carboxymethylcellulose in a weight ratio of 1: 1-5: 3-10.

Description

Wound dressing composition with excellent hemostatic and anti-adhesion effects and use thereof

[0001] The present invention relates to a wound dressing composition having excellent hemostatic and anti-adhesion effects and its use. More specifically, the present invention relates to a wound dressing composition comprising hyaluronic acid, collagen, and sodium carboxymethylcellulose in a weight ratio of 1:1 to 5:3 to 10, and its use in a medical device.

[0002]

[0003] A wound is a condition in which the continuity of tissue is disrupted by external pressure. The wound healing process is generally divided into three stages: inflammation, proliferation, and maturation. For wound healing, an ideal dressing should block the wound from exposure to the external environment, prevent infection, and suppress the inflammatory response. Many biological dressings for wound healing are being developed based on collagen and elastin, components of the dermis, which are essential components of human skin. Collagen is a key protein that forms tissues such as bone and skin, and 70% of skin is composed of collagen, which plays a crucial physiological role in tissue remodeling and wound healing. Furthermore, numerous studies have demonstrated the effectiveness of collagen in wound healing. As an example of such biological dressing materials, Korean Patent Application Publication No. 10-2010-0009305 discloses a chitosan sponge with enhanced cell adhesion protein adhesion by binding hydrophobic fatty acid groups to chitosan, and a wound dressing using the same.

[0004]

[0005] Meanwhile, hyaluronic acid (HA) is a biopolymer composed of N-acetyl-D-glucosamine and D-glucuronic acid, and the repeating units are linearly linked. It is abundantly found in the vitreous humor of the eye, synovial fluid of joints, and rooster combs. Due to its excellent biocompatibility and viscoelasticity, hyaluronic acid is being developed for various purposes, such as post-surgical adhesion prevention, wrinkle improvement, cosmetic aid, joint function improvement, drug delivery vehicle, and cell culture scaffold (F. Manna, M. Dentini, P. Desider, O. De Pita, E. Mortilla, B. Maras, Journal of European Academy of Dermatology and Venereology, 13(1999) 183-192).

[0006]

[0007] The present inventors have made great efforts to develop a wound dressing that not only has excellent exudate absorption capacity and suitability for use after wetting, but also can shorten the wound recovery time and has an adhesion-preventing effect, and as a result, when hyaluronic acid, collagen, and carboxymethylcellulose sodium are mixed in a weight ratio of 1:1 to 5:3 to 10 to prepare a wound dressing, it has a hard texture and excellent suitability for use and absorbency after wetting (Examples 1 to 3), and exhibits a hemostatic effect in a significantly shorter time than commercially available products (Experimental Example 1), and has a nasal adhesion-preventing effect (Experimental Example 2) and a nasal wound healing effect (Experimental Example 3), and as a result, the present invention has been completed.

[0008]

[0009] However, the problems that the present invention seeks to solve are not limited to the problems mentioned above, and other problems not mentioned will be clearly understood by those skilled in the art from the description below.

[0010]

[0011] The present invention aims to provide a wound dressing composition comprising hyaluronic acid, collagen and carboxymethylcellulose sodium in a weight ratio of 1:1 to 5:3 to 10 and its use in a medical device.

[0012]

[0013] According to the first implementation example,

[0014] A wound dressing composition comprising hyaluronic acid, collagen, and sodium carboxymethylcellulose in a weight ratio of 1:1 to 5:3 to 10 is disclosed.

[0015] In the present invention, the weight ratio of hyaluronic acid, collagen and sodium carboxymethylcellulose may be 1:1.5 to 3:4 to 8.

[0016] In the present invention, the weight ratio of hyaluronic acid, collagen and sodium carboxymethylcellulose may be 1:3:8.

[0017] In the present invention, the sodium carboxymethyl cellulose may be high viscosity sodium carboxymethyl cellulose of 5.0 to 7.0 Pa·s.

[0018] In the present invention, the wound dressing composition may additionally include one or more drugs selected from the group consisting of sterilizing and disinfecting agents, hemostatic agents, opioid analgesics, sulfa drugs, and antibiotics.

[0019]

[0020] According to the second implementation example,

[0021] A medical device is disclosed, wherein a wound dressing composition comprising hyaluronic acid, collagen, and sodium carboxymethylcellulose in a weight ratio of 1:1 to 5:3 to 10 is applied to at least one surface.

[0022] In the present invention, the medical device may be a medical dressing, fiber, mesh, powder, microsphere, sheet, sponge, foam, suture anchoring device, conduit, stent, surgical tack, plate and screw, drug delivery device, anti-adhesion membrane or tissue adhesive.

[0023]

[0024] The wound dressing composition according to the present invention has a firm texture and excellent usability and absorbency after wetting, and can also exhibit excellent hemostatic effects, excellent nasal adhesion prevention effects, and excellent nasal wound healing effects. Therefore, the wound dressing composition according to the present invention is expected to be useful in medical devices such as hemostatic agents and anti-adhesion agents.

[0025]

[0026] Meanwhile, the scope of the present invention is not limited by the effects described above.

[0027]

[0028] Figure 1 shows the results of an evaluation of the adhesion prevention effect of a wound dressing according to the present invention.

[0029] Figure 2 shows the results of evaluating the nasal wound healing effect of the wound dressing according to the present invention.

[0030]

[0031] Hereinafter, a wound dressing composition with excellent hemostasis and adhesion prevention effects and its use according to specific embodiments of the invention will be described in detail. However, this is presented as one example of the invention, and the scope of the invention is not limited thereby, and it is obvious to those skilled in the art that various modifications to the embodiments are possible within the scope of the invention. Unless otherwise specified, throughout this specification, "include" or "containing" refers to including a certain component (or component) without any particular limitation, and cannot be interpreted as excluding the addition of other components (or components).

[0032] The term "wound dressing composition" as used herein means a composition that can be used to prepare various wound dressings, unless otherwise specified.

[0033] The term "hyaluronic acid" used herein is used to mean both hyaluronic acid itself and hyaluronic acid salts. Therefore, the term "hyaluronic acid aqueous solution" used hereinafter is a concept that includes all of an aqueous solution of hyaluronic acid, an aqueous solution of a hyaluronic acid salt, and a mixed aqueous solution of hyaluronic acid and a hyaluronic acid salt. The hyaluronic acid salts include inorganic salts such as sodium hyaluronate, potassium hyaluronate, calcium hyaluronate, magnesium hyaluronate, zinc hyaluronate, and cobalt hyaluronate, and organic salts such as tetrabutylammonium hyaluronate. In some cases, two or more of them may be used in combination.

[0034]

[0035] 1. Wound dressing composition

[0036] The present invention

[0037] The present invention provides a wound dressing composition comprising hyaluronic acid, collagen, and sodium carboxymethylcellulose in a weight ratio of 1:1 to 5:3 to 10.

[0038] In the wound dressing composition according to the present invention, the weight ratio of hyaluronic acid, collagen, and sodium carboxymethylcellulose may be 1:1.5 to 3:4 to 8.

[0039] In the wound dressing composition according to the present invention, the weight ratio of hyaluronic acid, collagen, and sodium carboxymethylcellulose may be 1:3:8.

[0040] In the wound dressing composition according to the present invention, the carboxymethylcellulose sodium may be a high viscosity carboxymethylcellulose sodium of 5.0 to 7.0 Pa·s.

[0041] In the wound dressing composition according to the present invention, the wound dressing composition is characterized in that it can additionally contain one or more drugs selected from the group consisting of a bactericidal disinfectant, a hemostatic agent, an opioid analgesic, a sulfa agent, and an antibiotic. For example, the bactericidal disinfectant includes acrinols, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, iodine, iodine tincture, iodoform, or povidone iodine. The hemostatic agent may include thrombin, sodium alginate, ε-aminocaproic acid, monoethanolamine oleate, sodium carbazochrome sulfonate, or tranexamic acid. The opioid analgesic may include morphine hydrochloride or morphine sulfate. The above sulfa agent may include salazosulfapyridine, sulfadiazine, silver sulfadiazine, sulfadimethoxine, sulfamethizole, sulfamethoxazole, sulfamonomethoxine, sulfisomidine or sulfisomidine sodium. The above antibiotics are vancomycin hydrochloride, lincomycin hydrochloride, clindamycin, teicoplanin, phenethicillin potassium, benzylpenicillin potassium, benzylpenicillin benzathine, mupirocin calcium hydrate, arbekacin sulfate, aztreonam, spectinomycin hydrochloride, pibmesirinam hydrochloride, carmonam sodium, coristine sodium methanesulfonate, cefsulodin sodium, ceftibuten, tobramycin, amikacin sulfate, isepamycin sulfate, kanamycin sulfate, pradiomycin sulfate, polymyxin B sulfate, aspoxycillin, amoxicillin, ampicillin, ampicillin sodium, ceftamet pivoxil hydrochloride, cefepime hydrochloride, cefozopran hydrochloride, cefotiam hydrochloride, cefotiamhexetyl hydrochloride, cefcapene pivoxil hydrochloride. Cefmenoxime hydrochloride, talampicirin hydrochloride, bacampicirin hydrochloride, lenampicirin hydrochloride, cyclacillin, sulfenicillin sodium, cephacrole, cefazolin sodium, cephatrizine propylene glycol, cefadroxil, cephapirin sodium, cefamandole sodium, cephalexin, cephalothin sodium, cephaloridine, cefixime, cefoxitin sodium, ceftazidime sodium, cefotaxime sodium, cefotetan sodium, cefoperazone sodium, cefditoren pivoxil, cefudinir, ceftazidime, ceftizoxime sodium,Ceftezole sodium, cefteram pivoxil, ceftriakisone sodium, cefpyramid sodium, cefbuperazone sodium, cefpodoxime proxetil, cefminox sodium, cefmetazole sodium, cefrazine, cefroxadine, cefroxime axetil, cefuroxime sodium, ticarcirine sodium, sultamicin tosylate, piperacirin sodium, faropenem sodium, flomoxcef sodium, fosfomycin, meropenem trihydrate, ratamoxef sodium, astromycin sulfate, gentamicin sulfate, sisomicin sulfate, dibekacin sulfate, cefoselis sulfate, cefpirome sulfate, netilmycin sulfate, becanamycin sulfate, micronomicin sulfate, ribostamycin sulfate, acetylkitasamycin, acetylspiramycin, Ethylsuccinyl erythromycin, erythromycin, erythromycin estolate, kitasamycin, clarithromycin, midecamycin acetate, kitasamycin tartrate, josamycin, erythromycin stearate, josamycin propionate, midecamycin, erythromycin lactobionate, roxithromycin, rokitamicin, tetracycline hydrochloride, demethylchlortetracycline hydrochloride, doxycycline hydrochloride, minocycline hydrochloride, chloramphenicol, chloramphenicol sodium succinate, chloramphenicol palmitate, cycloserine, rifampicin, enviomycin sulfate, streptomycin sulfate, oxytetracycline hydrochloride, gramicidin S hydrochloride, tetracycline, nadifloxacin, bacitracin, sodium fusidic acid or sulfate May contain curlistin.

[0042]

[0043] 2. Medical devices

[0044] The present invention

[0045] The present invention provides a medical device having a wound dressing composition comprising hyaluronic acid, collagen, and sodium carboxymethylcellulose in a weight ratio of 1:1 to 5:3 to 10 applied to at least one surface.

[0046] In the medical device according to the present invention, the weight ratio of hyaluronic acid, collagen, and sodium carboxymethylcellulose may be 1:1.5 to 3:4 to 8.

[0047] In the medical device according to the present invention, the weight ratio of hyaluronic acid, collagen, and sodium carboxymethylcellulose may be 1:3:8.

[0048] In the medical device according to the present invention, the sodium carboxymethylcellulose may be high viscosity sodium carboxymethylcellulose of 5.0 to 7.0 Pa·s.

[0049] In the medical device according to the present invention, the wound dressing is characterized in that it can additionally contain at least one drug selected from the group consisting of a sterilizing disinfectant, a hemostatic agent, an opioid analgesic, a sulfa agent, and an antibiotic.

[0050] In the medical device according to the present invention, the medical device may be a medical dressing, fiber, mesh, powder, microsphere, sheet, sponge, foam, suture anchoring device, conduit, stent, surgical tack, plate and screw, drug delivery device, anti-adhesion membrane or tissue adhesive.

[0051]

[0052] Below, various examples are presented to aid understanding of the invention. These examples are provided solely to facilitate understanding of the invention and are not intended to limit the scope of protection of the invention.

[0053]

[0054] <Example>

[0055] 1. Manufacturing of wound dressings

[0056] Hyaluronic acid, collagen, and sodium carboxymethylcellulose were mixed in the mixing ratio shown in Table 1 below and stirred at a speed of 100 to 300 rpm for 24 to 120 hours under vacuum to produce a wound dressing.

[0057] Prescription Raw material solid content (mg / ml) Sodium hyaluronate Collagen CMC (low viscosity 0.659 Pa·s) CMC (high viscosity 5.96 Pa·s) Example 12308 Example 21308 Example 32380 Example 41380 Comparative Example 142100 Comparative Example 244100 Comparative Example 32150 Comparative Example 42250 Comparative Example 52350 Comparative Example 642150 Comparative Example 744150

[0058] 2. Characteristic evaluation

[0059] (1) Evaluation of texture, usability after wetting, and shape resilience

[0060] In order to evaluate the texture, usability after wetting, and shape recovery of wound dressings, wound dressings manufactured according to Examples 1 to 4 and Comparative Examples 1 to 7 were hydrated, pressure was applied to remove moisture, and then rehydrated to measure the extent to which the dimensions (thickness) were recovered.

[0061] Prescription Texture After wetting, usability Shape Restoration (%) Example 1 Hardness Large fragments > 100 Example 2 Hardness Maintains shape > 100 Example 3 Hardness Small fragments > 100 Example 4 Hardness Large fragments > 100 Comparative Example 1 Softness Small fragments 95 Comparative Example 2 Softness Small fragments 95 Comparative Example 3 Softness Small fragments 95 Comparative Example 4 Softness Small fragments > 100 Comparative Example 5 Softness Small fragments 84 Comparative Example 6 Very hardness Small fragments > 100 Comparative Example 7 Very hardness Small fragments > 100 Commercial Product 1 Softness Maintains shape > 100 Commercial Product 2 Very hardness Maintains shape > 100

[0062] As a result, as shown in Table 2 above, the wound dressings manufactured according to Examples 1 to 4 were found to have a hard texture and a shape resilience of 100% or more, and among them, it was confirmed that the wound dressing manufactured according to Example 2 could maintain its shape even after wetting.

[0063] (2) Evaluation of suction availability after wetting

[0064] In order to determine the days after application of a wound dressing, the wound dressings manufactured according to Examples 1 to 4 and Comparative Examples 1 to 7 were prepared in a size of 2 cm X 2 cm X 0.5 cm, placed in a 6-well plate, hydrated by adding 10 ml of saline solution, and then left at a temperature of 37°C±2°C. Then, whether or not they could be removed by suction was determined for 0-7 days of the test.

[0065] Suction possible days after prescription wetting (days) Example 12 Example 23 Example 31 Example 41 Comparative Example 11 Comparative Example 21 Comparative Example 31 Comparative Example 41 Comparative Example 51 Comparative Example 61 Comparative Example 71 Commercial product 11 Commercial product 21

[0066] As a result, as shown in Table 3 above, it was confirmed that the wound dressings according to Examples 1 and 2 were suction-capable for 3 to 3 days after wetting.

[0067] (3) Absorption capacity evaluation

[0068] In order to determine the absorbency of the wound dressing, the wound dressings manufactured according to Examples 1 to 4 and Comparative Examples 1 to 7 were cut into appropriate sizes, weighed (W1), and the sample was immersed in distilled water to ensure sufficient absorption. Then, the sample was hung using tweezers for 30 seconds and the weight was measured (W2). However, in the case of a product that could not be hung with tweezers, the sample was placed in a petri dish to ensure sufficient absorption. Then, the petri dish was tilted to remove any unabsorbed moisture, and the weight was measured. Then, the absorbency was calculated according to the following mathematical equation 1.

[0069] [Mathematical Formula 1]

[0070] Absorbency (%) = (W2-W1) / W2 x 100

[0071] Sample W1 (g) W2 (g) Absorption (%) Example 10.25 2 1 4.99 5 5 8 4 1 Example 20.23 8 14.25 2 5 9 8 8 Example 30.25 1 1 6 5 5 4 5 4 2 Example 40.24 0 14.70 0 6 0 3 0 Comparative Example 10.04 9 14.73 0 4 3 1 5 Comparative Example 20.08 0 2 3.91 0 3 4 2 4 Comparative Example 30.03 3 9.96 0 4 0 5 4 Comparative Example 40.04 0 12.06 0 3 4 8 8 Comparative Example 50.20 8 8.63 4 4 0 5 1 Comparative Example 60.08 6 2 5.83 0 4 4 2 2 Comparative Example 70.10 5 3 1 5 6 0 3 5 1 6 Commercially available product 10.0710.8551103 Commercial product 20.0752.3303006

[0072] As a result, as shown in Table 4 above, the absorbency of the wound dressings manufactured according to Examples 1 to 4 was about 5500 to 6500%, which was not only superior to Comparative Examples 1 to 7, but also significantly increased compared to commercial product 1 (1103%) and commercial product 2 (3006%).

[0073]

[0074] <Experimental Example>

[0075] Experimental Example 1. Evaluation of the hemostatic effect of the wound dressing according to the present invention.

[0076] The wound dressing manufactured according to Example 2 was prepared as 1.5 mm X 2 mm X 0.5 mm. Anesthetized Spragure Dawley (SD) responsive SPF 7-week-old rats by intramuscular injection of a mixture of zoletil and xylazine in a 1:3 ratio, and the abdomen was incised, exposing the left lobe of the liver to gauze. Then, a 5 mm biopsy punch was used to make a wound 3 to 4 mm deep on the left lobe of the liver, and the area was cut into a cylinder to induce bleeding. The fixation plate on which the SD rat was placed was tilted at an angle of approximately 45 degrees, and the blood was wiped clean with gauze, and the test substance was immediately attached. A gauze whose weight was measured was placed below the attached area of ​​the test substance. Hemostasis was checked for the first 30 seconds. If hemostasis was not achieved, each substance was attached again, and hemostasis was checked at 30-second intervals. The time of hemostasis was checked, and the total bleeding time (seconds) was measured.

[0077] ControlCommercial product 1Commercial product 2Example 2Average time197.52180.22156.74113.81

[0078] As a result, as shown in Table 5 above, it was confirmed that the wound dressing according to Example 2 exhibited a hemostatic effect in a significantly faster time than the negative control group and even the commercially available products 1 and 2.

[0079] Experimental Example 2. Evaluation of the adhesion prevention effect of the wound dressing according to the present invention.

[0080] The wound dressing manufactured according to Example 2 was prepared as 2 mm X 2 mm X 0.5 mm. Anesthesia was induced in 7-week-old SD rats by injecting 1 μl / g of an anesthetic mixed with zoletil and rompun, and the surgical site was raised, washed with 70% ethanol, and disinfected with povidone iodine. Next, a 1-2 cm long incision was made in the central part of the nasal cavity to expose the skull tissue, and a hole was created in the nasal cavity using a 3 mm spherical drill. Through the created hole, a 1.5 mm spherical drill was used to induce adhesion by repeatedly drilling 5 times between the nasal septum and the lateral wall of the nasal cavity. After inducing adhesion, the test substance was inserted into the nasal cavity and treated, followed by suturing with 5-0 suture and disinfection with povidone iodine. On the 7th day of the test, the experimental animals were euthanized using a CO2 chamber, and the skin was removed centered on the nasal cavity, and the tissue was extracted, immersed in formalin, and stored.

[0081] Formalin-fixed tissues were immersed in a 5% nitric acid solution for 1 day to remove calcium, then paraffin-embedded and sectioned into 6-μm-thick tissue slides using a microtome. The tissue slides were deparaffinized, stained with hematoxylin and eosin (H&E), dehydrated, and mounted. In addition, the tissue slides were deparaffinized and stored in BOUIN solution for 1 hour, and then stained with Weigert iron hematoxylin, Biebrich scarlet acid fuchsin solution, and phosphomolybdic-phosphotungstic acid solution to evaluate the degree of fibrosis. The degree of fibrosis was scored from 0 to 4 points according to the following criteria.

[0082] 0: No fibrosis and no nasal epithelial damage

[0083] 1: Mild fibrotic response observed, but no nasal epithelial damage

[0084] 2: There is a thick, fibrous band and implant material inserted. There is also damage to the nasal epithelium.

[0085] 3: Densely fibrous tissue is present, along with implant material. There is also severe nasal epithelial damage.

[0086] 4: Severe fibrotic reaction over a large area, with tissue forming between the nasal walls.

[0087] Sham Commercial Product 1 Example 27 days 4 / 2 / 4 / 4 / 3 / 23 / 3 / 3 / 3 / 2 / 41 / 2 / 2 / 0 / 2 / 0 Total 19187 Average 3.231.2

[0088] As a result, as shown in Fig. 1, the wound dressing according to Example 2 was found to have a nasal adhesion prevention effect similar to that of commercial product 1, and as shown in Table 6 above, the degree of fibrosis was lower than that of commercial product 1, confirming that it had the best adhesion prevention effect.

[0089]

[0090] Experimental Example 3. Evaluation of the nasal wound healing effect of the wound dressing according to the present invention.

[0091] The wound dressing manufactured according to the above Example 2 was subjected to H&E staining in the same manner as in the above Experimental Example 2, and the Epithelial Thickness was measured to compare the Index (wounded / control).

[0092]

[0093] As a result, as shown in Fig. 2, in the negative control group, the epithelial thickness remained at only about 60% of the area where no wound was induced, whereas when the wound dressing according to Example 2 was applied, it was confirmed that the epithelial thickness recovered to more than 80%.

[0094]

[0095] While specific aspects of the present invention have been described in detail above, it should be apparent to those skilled in the art that these specific descriptions are merely preferred implementation examples and are not intended to limit the scope of the present invention. Therefore, the substantial scope of the present invention is defined by the appended claims and their equivalents.

[0096]

[0097] It is expected that the wound dressing according to the present invention can be usefully used in medical devices such as hemostatic agents and anti-adhesion agents.

Claims

1. A wound dressing composition comprising hyaluronic acid, collagen and sodium carboxymethyl cellulose in a weight ratio of 1:1 to 5:3 to 10.

2. In paragraph 1, A wound dressing composition, characterized in that the weight ratio of hyaluronic acid, collagen, and sodium carboxymethyl cellulose is 1:1.5 to 3:4 to 8.

3. In paragraph 1, A wound dressing composition, characterized in that the weight ratio of hyaluronic acid, collagen and sodium carboxymethyl cellulose is 1:3:

8.

4. In paragraph 1, A wound dressing composition, characterized in that the above-mentioned sodium carboxymethyl cellulose is a high viscosity sodium carboxymethyl cellulose having a viscosity of 5.0 to 7.0 Pa·s.

5. In paragraph 1, A wound dressing composition, characterized in that the above wound dressing composition additionally contains at least one drug selected from the group consisting of a sterilizing disinfectant, a hemostatic agent, an opioid analgesic, a sulfa agent, and an antibiotic.

6. A medical device having a wound dressing composition according to any one of claims 1 to 5 applied to at least one surface.

7. In paragraph 6, A medical device characterized in that the medical device is a medical dressing, fiber, mesh, powder, microsphere, sheet, sponge, foam, suture anchoring device, conduit, stent, surgical tack, plate and screw, drug delivery device, anti-adhesion membrane or tissue adhesive.

Images