KR102822252B1 - Composition for wound dressing using chitosan and method for fabricating the same - Google Patents

Abstract

The present invention relates to a chitosan wound dressing and a method for manufacturing the same. The present invention relates to a chitosan wound dressing which has the effect of maintaining excellent adhesiveness even after attachment to the skin, despite the user's activities and changes in the external environment, and being able to be removed from the skin without irritation.

Description

{COMPOSITION FOR WOUND DRESSING USING CHITOSAN AND METHOD FOR FABRICATING THE SAME}

The present invention relates to a gel composition for wound dressing, which maintains excellent adhesiveness even after attachment to the skin, despite the user's activities and changes in the external environment, and in particular, has excellent durability in a low-temperature environment, and is maintained without being destroyed or damaged even with repeated temperature changes, and a method for producing the same.

A wound is an injury related to a rupture of the injured tissue or cell membrane caused by an external attack or unconscious activity. External infectious agents can enter the body through the wound. If the wound is open for a long time, secondary complications such as infection can occur, and pain and inconvenience in daily life can occur during the healing period.

Accordingly, wounds should be closed as soon as possible after they occur to prevent external sources of infection, moisture, and physical stimulation, and to prevent inflammatory reactions caused by these.

Wound dressings are medical devices designed to prevent contamination of the wound area, protect the skin, and prevent bleeding or body fluid loss. They must prevent the wound and the dressing contact surface from drying out so that the wound can maintain appropriate moisture, absorb excessive exudate, and protect the wound from external bacterial invasion while preventing trauma to the wound when changing the dressing.

Depending on the intended use of the wound dressing, there are various types, including foam dressing, hydrocolloid dressing, hydrofiber dressing, film dressing, alginate dressing, wound contact layer dressing, collagen dressing, hydrogel dressing, and superabsorbent dressing.

Korean Patent No. 1511405 discloses a hydrogel wound dressing, which is manufactured by widely spreading a hydrogel containing a water-soluble synthetic or semi-synthetic polymer, glycerin, and water on a two-layer laminate film composed of a polyurethane film and hydrophobic fibers.

Korean Patent No. 2130119 discloses a method for producing a wound dressing, comprising the steps of: (a) producing a nanofiber sheet by electrospinning a solution containing an acrylic polymer and a crosslinking agent; (b) heat-treating the sheet; and (c) neutralizing the sheet.

Korean Patent No. 2350526 relates to a method for producing a wound dressing composition with improved cohesion, and discloses a method for producing a wound dressing composition, comprising the step of (a) mixing an aqueous solution of hyaluronic acid or a salt thereof at a concentration of 5.85 to 7.15 mg/ml and an aqueous solution of collagen at a concentration of 8.1 to 9.9 mg/ml, characterized in that the mixing is performed at a stirring speed of 80 to 300 rpm under vacuum for 24 to 120 hours.

Wound dressings are attached to the skin to help the wound heal while preventing external infectious agents from entering the body through the wound. Therefore, it is necessary to maintain adhesiveness even when attached to the skin and subject to changes in the patient's movement, external temperature, humidity, etc. In addition, they must be easy to attach and detach without irritating the skin. Research is ongoing into wound dressings with better usability and durability.

(0001) Republic of Korea Patent No. 2226810 (0002) Republic of Korea Patent No. 2130119 (0003) Republic of Korea Patent No. 2350526

The purpose of the present invention is to provide a chitosan wound dressing having excellent adhesive strength and maintaining adhesive strength for a long period of time, and also not causing irritation to the skin when removed from the skin.

In particular, the present invention aims to provide a chitosan wound dressing that maintains its quality without being deformed even when exposed to rapid external environmental changes, such as changes in humidity or temperature.

The purpose of the present invention is to provide a chitosan wound dressing that maintains excellent adhesiveness even when a patient moves after attachment to the skin and has an improved wearing comfort for the user.

In order to solve the above-mentioned problems, a wound dressing composition using chitosan according to the present invention comprises 100 parts by weight of a chitosan derivative, 50 to 100 parts by weight of gelatin, 100 to 500 parts by weight of glycerol, 80 to 120 parts by weight of gelatin methacrylate, 10 to 30 parts by weight of cocamidopropyl betaine, and 1 to 10 parts by weight of a thermodegradable coated crosslinking agent capsule.

In the present invention, the thermally decomposable coating may include paraffin wax having a thickness of 50 to 100 ㎛ (micrometers).

In the present invention, the cross-linking agent includes glutaraldehyde, and the thermally decomposable coated cross-linking agent capsule may be capable of expelling the cross-linking agent inside when exposed to a temperature of 30 to 37° C. for 1 to 5 minutes.

The present invention also provides a method for producing a wound dressing composition containing chitosan, comprising the steps of: a) preparing a chitosan solution and a gelatin solution and mixing them;

b) a step of adding a cross-linking agent to the mixture to react the chitosan and gelatin;

c) a step of separating the cross-linked complex from the above mixture and then grinding it to produce a hydrogel; and

d) a step of manufacturing a thermodegradable coated cross-linking agent capsule; and

g) a step of mixing the hydrogel manufactured in step c), the crosslinking agent capsule manufactured in step d), glycerol and gelatin methacrylate;

A method for producing a wound dressing composition containing chitosan including .

In the manufacturing method according to the present invention, the step d) may include: d1) a step of mixing a cross-linking agent and cocamidopropyl betaine and then compressing them to manufacture spherical particles; d2) a step of putting the spherical particles into double-boiled paraffin wax and applying ultrasonic waves for 5 to 6 minutes; and d3) a step of taking out the spherical particles in the step d2) and cooling them.

The chitosan wound dressing according to the present invention has adhesive strength and long-term adhesive strength, while not causing skin irritation when removed from the skin.

The chitosan wound dressing according to the present invention has the effect of maintaining quality even when exposed to changes in external temperature and humidity.

The chitosan wound dressing according to the present invention has the effect of improving the user's wearing comfort and usability.

Hereinafter, each component of the present invention will be described in more detail so that a person with ordinary skill in the art can easily implement the present invention. However, this is only an example, and the scope of the rights of the present invention is not limited by the following contents.

As used herein, "preferred" or "preferably" refers to an embodiment of the invention that has a particular advantage under certain conditions. However, other embodiments may also be preferred under the same or different conditions. Furthermore, the fact that one or more preferred embodiments is not intended to imply that other embodiments are not useful, nor does it exclude other embodiments that are within the scope of the invention.

The term "including" as used herein is used to list materials, compositions, devices, and methods useful in the present invention, but is not limited to the listed examples.

The present invention relates to a hydrogel wound dressing, which is composed of a gel-like formulation and has a film layer that hardens when applied to a wound site and functions as a wound dressing.

Specifically, it comprises 100 parts by weight of a chitosan derivative, 50 to 100 parts by weight of gelatin, 100 to 500 parts by weight of glycerol, 80 to 120 parts by weight of gelatin methacrylate, and 1 to 10 parts by weight of a thermodegradable coated cross-linking agent capsule.

The wound dressing composition is formed into a film and has adhesive properties when in direct contact with the skin, and is an area that has a wound healing function.

It is preferable that the composition for wound dressing is composed of a material that is harmless to the human body, and the present invention is characterized in that it contains chitosan.

More specifically, a complex of chitosan and gelatin can be formed, and this can be obtained and used as a hydrogel.

The above chitosan and gelatin complex can be formed by cross-linking using a cross-linking agent, preferably by mixing in a ratio of 50 to 100 parts by weight based on 100 parts by weight, and more preferably by mixing in a ratio of 100 parts by weight based on 100 parts by weight to form a complex manufactured by the method.

If the ratio of gelatin is lower than the above ratio, adhesiveness may decrease, and if the ratio of gelatin is higher than the above ratio, waterproofing and moisture permeability may decrease.

In the present invention, the content of chitosan in the skin contact layer may be added in an amount of 1 to 10 wt% based on the total weight of the layer, and more preferably, 3 to 8 wt%.

The above chitosan derivative may include any derivative derived from chitosan.

Meanwhile, the cross-linking agent for forming the complex is not particularly limited, and any agent capable of forming a cross-linking bond between chitosan and gelatin may be used, but may include, for example, one or more selected from the group consisting of epichlorohydrine, glutaraldehyde, chloromethyloxirane, acrylic acid, and methacrylamide.

The cross-linking agent is added in the form of a thermodegradable coated capsule, and the cross-linking agent capsule can be added in an amount of 1 to 10 parts by weight based on 100 parts by weight of the chitosan derivative.

Meanwhile, the cross-linking agent capsule may further contain cocamidopropyl betaine in a weight ratio of 1:0.2 to 0.5 based on the weight of the cross-linking agent. This is to facilitate forming spherical particles by compression without the cross-linking agent reacting.

The above-mentioned thermally decomposed coating may include paraffin wax having a thickness of 50 to 100 ㎛ (micrometers). If it is thicker than the above-mentioned thickness, there is a problem in that the thermally decomposable coating is not destroyed by body temperature, and thus, after application of the composition for wound dressing, it is not formed into a film layer forming a barrier, and thus, the wound healing effect is not obtained, and thus, there is a problem in that it is difficult for the effect itself to appear.

Ultimately, the above thickness range is intended to ensure that the internal cross-linking agent is discharged when exposed to a temperature of 30 to 37°C for 1 to 5 minutes, so that the gel is formed into a solid film, thereby helping wound healing smoothly.

Meanwhile, the wound dressing according to the present invention has the advantage of being able to be used in extreme environments or stored in extreme environments, as its quality does not deteriorate even when exposed to extremely low-temperature environments or extremely dry environments for a certain period of time or for long periods of time.

Manufacturing method

The present invention also provides a method for producing a wound dressing composition containing chitosan:

a) A step of preparing a chitosan solution and a gelatin solution and mixing them;

b) a step of adding a cross-linking agent to the mixture to react the chitosan and gelatin;

c) a step of separating the cross-linked complex from the above mixture and then grinding it to produce a hydrogel; and

d) a step of manufacturing a thermodegradable coated cross-linking agent capsule; and

e) a step of mixing the hydrogel manufactured in step c), the crosslinking agent capsule manufactured in step d), glycerol and gelatin methacrylate.

Below, the composition of each step is described in detail, but the description of the composition of the wound dressing described above can be referenced.

The above step a) is a step of preparing a chitosan solution and a gelatin solution, and more specifically, it is a step of adding gelatin to water and dispersing it at a temperature of 50°C for 5 hours to prepare a gelatin solution, adding a chitosan derivative to an acidic aqueous solution and dispersing it at room temperature to prepare a chitosan solution, and then mixing them. The solvent is not limited to water and an aqueous solvent can be used.

b) Step is to mix a chitosan solution and a gelatin solution, and add a small amount of a cross-linking agent thereto to form a cross-linked complex. This complex is not completely solidified or film-formed, and is a step to form a blocked complex so that, in the future, when the cross-linking agent inside the cross-linking agent capsule is extracted, it can quickly form a film.

Next, step c) separates and pulverizes the formed complex, then washes the obtained hydrogel to adjust the pH to a neutral range, and then refrigerates for 24 to 36 hours.

Step d) is the manufacturing step of the cross-linking agent capsule, and the detailed process is as follows:

d1) A step of mixing a cross-linking agent and cocamidopropyl betaine and then compressing them to produce spherical particles;

d2) a step of placing the spherical particles in double-boiled paraffin wax and applying ultrasonic waves for 5 to 6 minutes; and

d3) A step of taking out the spherical particles from step d2) and cooling them.

If the time for applying the above ultrasonic waves becomes long, there is a problem that a thermally decomposable coating layer cannot be formed due to the heat from the ultrasonic waves, and if the time for applying the above ultrasonic waves becomes short, there is a problem that the thickness of the coating layer becomes thick, making it difficult for the process of causing the crosslinking agent to be ejected due to the destruction of the crosslinking agent capsule by body temperature to proceed.

A step of completing the final composition by mixing the hydrogel manufactured in step c), the crosslinking capsule manufactured in step d), glycerol, and gelatin methacrylate, and storing the mixture in containers to prevent self-solidification due to external heat changes.

Hereinafter, the present invention will be described in more detail based on examples, but this is only an exemplary description for understanding the present invention, and the scope of the present invention is not limited or restricted to the following examples.

[Example 1]

100 parts by weight of gelatin (MW100,000~120,000) was added to 1 L of water and dispersed at 50°C for 5 hours to prepare a gelatin solution, and 100 parts by weight of chitosan was added to an acidic aqueous solution (pH 4.5) and dispersed at room temperature for 12 hours to prepare a chitosan solution.

The above chitosan solution and the above gelatin solution were mixed, 1 part by weight of glutaraldehyde was added thereto to proceed with the reaction, the formed complex was separated, uniformly mixed so that no lumps were present, and pulverized to prepare a hydrogel. The chitosan content in the obtained hydrogel was confirmed to be 6 wt% of the total weight.

Separately, 5 parts by weight of a cross-linking agent (glutaraldehyde) and 10 parts by weight of cocamidopropyl betaine were uniformly mixed, pressed to form spherical particles having a diameter of 100 to 200 ㎛ (micrometers), placed in double-boiled paraffin wax, and applied ultrasonic waves of 50 Hz for 5 minutes, then taken out and cooled. At this time, the thickness of the obtained coating layer was confirmed to be 60 to 70 ㎛.

The manufactured hydrogel was washed with distilled water and the pH was adjusted to 6.8. Then, the manufactured cross-linking capsule and 100 parts by weight of glycerol and 80 parts by weight of gelatin methacrylate were mixed and stirred sufficiently. The mixture was stored at a temperature of 5°C or lower for 24 hours.

[Reference example]

Use of commercially available hydrogel wound dressings

[Comparative Example 1]

In the above example, the same method was used for manufacturing the product, except that 5 parts by weight of the crosslinking agent was added as is instead of the crosslinking agent capsule.

[Comparative Example 2]

In the above example, the crosslinking agent capsule was manufactured using the same method except that the diameter of the spherical particles inside the capsule was manufactured to be 250 μm.

[Comparative Example 3]

In the above example, the crosslinking agent capsule was manufactured in the same manner except that 20 Hz ultrasonic waves were applied instead of 50 Hz ultrasonic waves during the manufacturing process.

[Experimental method]

1. Wound healing assessment

Using the wound dressing gel of Example 1 and the wound dressing gel of Reference Example, wound healing was evaluated on mice. A commercially available sterilized film was included as a control group.

Ten males were selected per sample, and each specimen had a wound area measuring approximately 1 cm x 1 cm. The examples and reference examples were applied to cover the entire wound area and an area 1 cm away from the wound area.

The existing wound dressing was removed at 8:00 AM every day, and the size and repair of the wound area were checked each time a new wound dressing was attached, and wound healing was observed for 14 days.

The success or failure of a wound was assessed by comparing the initial wound condition with the final condition after 14 days, taking into account the size and depth of the wound, and the average score was calculated by evaluating the results by experts (three specialists at a university hospital), and this is shown in the table below. (5 points: excellent ~ 1 point: poor).

Evaluation items Example 1 Control group For reference Wound shrinkage rate (%) 4 days 48 34 44 9 days 79 42 69 14 days 86 61 74 Whether the wound site is repaired* 5 3 4

*Rounding off the first decimal place of the average value Referring to Table 1 above, it was confirmed that the wound dressing of Example 1 had a high wound shrinkage rate over time compared to the control group and the reference example, and it was also confirmed that the final wound site repair effect was excellent.

2. Wound dressing test evaluation

Test evaluations were conducted on wound dressings of examples and comparative examples according to the test items in Table 2 below. Tests were conducted according to the standards specified for each test item, and the results of the pass/fail evaluation of the test are shown in Table 3.

Test items standard Test purpose applied area Waterproofing Test EN 13726-3 Check the product's waterproofness Applicable to products in the form of attachments with waterproof performance Permeability test EN 13726-2 A test to check whether an appropriate moist environment is created by blocking moisture from the surrounding environment and allowing moisture from the wound surface to escape. This is a standard applied to products that can be applied for long periods of time, more than 24 hours. It blocks surrounding moisture and allows moisture from the wound surface to escape, creating an appropriate moist environment. Adhesion test ASTM D3330 A test to determine whether a wound dressing can adhere well to the wound without damaging the wounded skin when applied to the wound. Wound dressings in the form of foam and sheet types that adhere to the skin

Example 1 Comparative Example 1 Comparative Example 2 Comparative Example 3 For reference Waterproofing Test fitness fitness fitness Inappropriate fitness Permeability test fitness fitness Inappropriate Inappropriate fitness Adhesion test fitness fitness Inappropriate fitness fitness

* Comparative Example 1 was manufactured into a film form by hardening, and was tested by applying it onto a release film and manufacturing it into a film form.

3. Adhesion test and usability evaluation

A panel test was conducted by recruiting 50 panelists aged 20 to 60. Five adult men and five adult women were selected for each age group, and the panelists were selected as those who had not suffered from any skin disease in the past 3 years and were evaluated to have healthy skin without any chronic skin disease.

Each specimen was cut to a size of 1cm*1cm and all specimens were attached in a row to the user's forearm. The attachment site for each specimen was marked so that only the tester could see it, and the panel and specialists were not aware of it.

When selecting the panel, only those panelists who were deemed suitable for conducting this test were selected based on evaluations by three dermatologists and the test was conducted.

The panel visited the designated hospital every two days and changed the wound dressing with a new one every day (48 hours) at designated times (10:00 AM, 1:00 PM, and 3:00 PM) and submitted an evaluation report immediately after the change.

The test was conducted over a total of 8 days, and the panel and experts evaluated the following items. The average score of the evaluation results was calculated, and the relative evaluation results are shown in Table 4 below.

For the psalms with a difference in average scores of less than 0.5 points, the evaluation was conducted by comparing the most frequent score values, and if the scores were confirmed to be the same despite the comparison of the most frequent score values, they were displayed in the same rank.

i) Initial adhesion (Adhesion when removing the release film and first attaching to the skin, as assessed by a specialist)

ii) Long-term adhesion (whether adhesion is maintained when the existing film is removed, expert evaluation)

iii) Adhesion during activity (assessment by panel evaluation after riding an indoor bicycle for 30 minutes 3 hours after attaching a new wound dressing on the same day)

iv) Skin irritation evaluation (evaluation of the attachment site for pain, itchiness, skin rash, etc. after removal from the skin, panel and specialist evaluation)

v) Comprehensive usability evaluation (1 point (not recommended) to 10 points (strongly recommended), panel evaluation)

Example 1 Comparative Example 1 Comparative Example 2 Comparative Example 3 For reference Initial adhesion 2 5 7 4 3 Long-term adhesion 1 2 4 3 5 Adhesion during activity 1 2 4 3 5 Skin irritation assessment 2 3 1 5 5 Overall usability 1 2 4 3 5

4. Quality assessment according to changes in external environment

When each specimen was rapidly cooled to a cryogenic temperature and then naturally cooled to room temperature (25℃), the quality change was confirmed when it was maintained in an extremely dry environment (relative humidity 10%, 25℃) for 5 hours. The evaluation was focused on adhesion and the occurrence of cracks (no deformation: X, partially deformed: △, greatly deformed: O).

Whether or not it is deformed Example 1 Comparative Example 1 Comparative Example 2 Comparative Example 3 For reference After cryogenic cooling X O O X O After exposure to extremely dry conditions X O O △ O

Referring to Tables 1 to 5 above, it can be confirmed that the wound dressing of Example 1 has excellent usability, and in particular, not only has excellent adhesiveness, but also does not cause skin irritation when removed.

In addition, since there is no significant deterioration in quality after cryogenic cooling and exposure to extremely dry environments, it can be confirmed that it is suitable for use in various climates and environments.

Claims (5)

A composition for wound dressing comprising 100 parts by weight of a chitosan derivative, 50 to 100 parts by weight of gelatin, 100 to 500 parts by weight of glycerol, 80 to 120 parts by weight of gelatin methacrylate, 10 to 30 parts by weight of cocamidopropyl betaine, and 1 to 10 parts by weight of a thermodegradable coated cross-linking agent capsule.
In the first paragraph,
A composition for wound dressing, wherein the thermally decomposable coating comprises paraffin wax having a thickness of 50 to 100 ㎛ (micrometers).
In the first paragraph,
The above cross-linking agent comprises glutaraldehyde,
A composition for wound dressing, wherein the thermally decomposable coated crosslinking agent capsules release the crosslinking agent inside when exposed to a temperature of 30 to 37°C for 1 to 5 minutes.
A method for producing a wound dressing composition containing chitosan according to Article 1,
a) A step of preparing a chitosan solution and a gelatin solution and mixing them;
b) a step of adding a cross-linking agent to the mixture to react the chitosan and gelatin;
c) a step of separating the cross-linked complex from the above mixture and then grinding it to produce a hydrogel; and
d) a step of manufacturing a thermodegradable coated cross-linking agent capsule; and
g) a step of mixing the hydrogel manufactured in step c), the crosslinking agent capsule manufactured in step d), glycerol and gelatin methacrylate;
A method for producing a wound dressing composition comprising:
In paragraph 4,
The above step d is,
d1) A step of mixing a cross-linking agent and cocamidopropyl betaine and then compressing them to produce spherical particles;
d2) a step of placing the spherical particles in double-boiled paraffin wax and applying ultrasonic waves for 5 to 6 minutes; and
d3) A step of taking out the spherical particles in step d2) and cooling them;
A method for producing a wound dressing composition comprising: