Biodegradable medical adhesive

Abstract

The present invention relates to a biodegradable medical adhesive, which is obtained by mixing 97-99.9 wt% of n-butyl cyanoacrylate, 0.06-2 wt% of cellulose nanofibrils (CNFs), and 0.04-1 wt% of iodine, wherein the n-butyl cyanoacrylate has a structure of chemical formula 1.

Description

Biodegradable medical adhesives

[0001] The present invention relates to a biodegradable medical adhesive, and more particularly, to a biodegradable medical adhesive capable of providing excellent biocompatibility and adhesiveness, and reducing the risk of infection by providing a hemostatic effect and a strong antibacterial effect.

[0002] Typically, when the skin is incised due to surgery or an accident, mechanical sutures such as sutures, staplers, and wires are used to close the wound. However, these methods can leave behind inflammation or scars, and are difficult to use on relatively weak tissues.

[0003] Accordingly, the use of medical adhesives instead of sutures or staplers has recently been demanded.

[0004] Medical adhesives are classified into natural adhesives using natural materials and synthetic or semi-synthetic adhesives using chemicals. Natural adhesives have the advantage of excellent biocompatibility, but are expensive due to limited supply and may also cause allergic reactions in some patients. Synthetic or semi-synthetic adhesives are inexpensive and have strong adhesive strength, but have relatively high cytotoxicity, which reduces biocompatibility and causes low adhesion on moist surfaces.

[0005] In addition, synthetic or semi-synthetic adhesives have strong adhesive strength but low elasticity, which can cause discomfort and rejection in flexible areas due to differences in physical properties, and also have problems such as leakage or whitening as impact strength is weakened.

[0006] Accordingly, there is a need to develop medical adhesives that can provide sufficient elasticity while providing excellent biocompatibility and bonding strength.

[0007] Accordingly, the present invention is intended to solve the above-described problems, and an object of the present invention is to provide a biodegradable medical adhesive that can provide excellent biocompatibility and adhesiveness, and reduce the risk of infection by providing a hemostatic effect and a strong antibacterial effect.

[0008] In order to achieve the above purpose, the present invention is characterized in that it is mixed with 97 to 99.9 wt% of n-butyl cyanoacrylate, 0.06 to 2 wt% of cellulose nanofibrils (CNF), and 0.04 to 1 wt% of iodine (iodine), and the n-butyl cyanoacrylate has a structure represented by the following chemical formula 1.

[0009] [Chemical Formula 1]

[0010]

[0011] In the present invention, the cellulose nanofiber is characterized by having a structure represented by the following chemical formula 2.

[0012] [Chemical Formula 2]

[0013]

[0014] In the present invention, the cellulose nanofibers are characterized by having a diameter of 5 to 20 nm, a length of 500 to 2,000 nm, and being divided into an amorphous region and a crystalline region.

[0015] According to the present invention, by adding cellulose nanofibers to n-butyl cyanoacrylate, not only can adhesive strength and flexibility be improved, but also biodegradability and biocompatibility can be improved, and by adding iodine, a strong antibacterial effect can be achieved, thereby reducing the risk of infection and enabling rapid healing of wounds.

[0016] Figure 1 shows the results of mortality and general symptom experiments according to an acute systemic toxicity test of a biodegradable medical adhesive according to an embodiment of the present invention.

[0017] Figure 2 shows the results of a weight change experiment according to an acute systemic toxicity test of a biodegradable medical adhesive according to an embodiment of the present invention.

[0018] Figure 3 shows the autopsy findings from an acute systemic toxicity test of a biodegradable medical adhesive according to an embodiment of the present invention.

[0019] FIG. 4 is a drawing for explaining the intradermal administration site in the intradermal reaction test of a biodegradable medical adhesive according to an embodiment of the present invention.

[0020] Figure 5 shows the results of mortality and general symptom experiments according to an intradermal reaction test of a biodegradable medical adhesive according to an embodiment of the present invention.

[0021] Figure 6 shows the results of a weight change experiment according to an intradermal reaction test of a biodegradable medical adhesive according to an embodiment of the present invention.

[0022] Figure 7 shows the results of an intradermal reaction test according to the site of administration of sterile saline solution in an intradermal reaction test of a biodegradable medical adhesive according to an embodiment of the present invention.

[0023] Figure 8 shows the results of an intradermal reaction test according to the site of application of cottonseed oil in an intradermal reaction test of a biodegradable medical adhesive according to an embodiment of the present invention.

[0024] Figure 9 shows the results of a general symptom experiment according to a material-mediated exothermicity test of a biodegradable medical adhesive according to an embodiment of the present invention.

[0025] Figure 10 shows the results of a heat generation experiment according to a material-mediated heat generation test of a biodegradable medical adhesive according to an embodiment of the present invention.

[0026] Figure 11 shows the results of chemical tests on a biodegradable medical adhesive according to an embodiment of the present invention.

[0027] Figure 12 shows the results of a cytotoxicity test of a biodegradable medical adhesive according to an embodiment of the present invention.

[0028] Figure 13 shows the results of a microbial limit test of the contents of a biodegradable medical adhesive before accelerated aging according to an embodiment of the present invention.

[0029] Figure 14 is a drawing for explaining the intradermal administration site in a skin sensitivity test of a biodegradable medical adhesive according to an embodiment of the present invention.

[0030] Figures 15 and 16 show the results of mortality and general symptom experiments according to skin sensitivity tests of biodegradable medical adhesives according to embodiments of the present invention.

[0031] Figures 17 and 18 show the results of a weight change experiment according to a skin sensitivity test of a biodegradable medical adhesive according to an embodiment of the present invention.

[0032] Figure 19 shows the results of a skin reaction experiment after the induction stage according to a skin sensitivity test of a biodegradable medical adhesive according to an embodiment of the present invention.

[0033] Hereinafter, with reference to the attached drawings, preferred embodiments of the present invention will be described in detail, so that those skilled in the art can easily implement the present invention. However, when describing the operating principles of preferred embodiments of the present invention in detail, if a detailed description of a related known function or configuration is judged to unnecessarily obscure the gist of the present invention, such detailed description will be omitted.

[0034] Additionally, the same drawing symbols are used for parts that have similar functions and actions throughout the drawing.

[0035] Additionally, when a part of a specification is said to be "connected" to another part, this includes not only direct connections but also indirect connections through intervening components. Furthermore, unless otherwise specifically stated, "including" a component does not exclude other components, but rather implies the inclusion of additional components.

[0036] The biodegradable medical adhesive according to an embodiment of the present invention is preferably mixed with 97 to 99.9 wt% of n-butyl cyanoacrylate, 0.06 to 2 wt% of cellulose nanofibrils (CNF), and 0.04 to 1 wt% of iodine (iodine). If the above mixing range is exceeded, problems such as reduced adhesive strength, shortened shelf life, and toxicity may occur.

[0037] In other words, when only n-butyl cyanoacrylate monomer is used as an adhesive, it tends to break easily after curing and has low viscosity, so it easily flows down around the wound during suturing. To prevent this, a biodegradable polymer material (i.e., cellulose nanofibers) is added to increase the viscosity of the adhesive, provide flexibility, and alleviate toxicity. However, when the content of cellulose nanofibers is less than 0.06 wt%, it is difficult to maintain the viscosity of the adhesive, and it is difficult to expect biodegradability and biocompatibility of the adhesive. In addition, when the content of cellulose nanofibers exceeds 2 wt%, the flexibility of the adhesive is reduced, which causes the adhesive to break easily.

[0038] In addition, if the iodine content is less than 0.04 wt%, it is difficult to expect an antibacterial effect, and if the iodine content exceeds 1 wt%, toxicity occurs, so it is preferable to mix at the above mixing ratio.

[0039] n-Butyl cyanoacrylate is a liquid alkyl-2 cyanoacrylate monomer that forms a flexible polymer with a strong adhesive bond to soft tissue when in contact with an ionic medium (e.g., water or blood), and has a structural formula as shown in Chemical Formula 1 below, and its properties are as shown in Table 1 below.

[0040] [Chemical Formula 1]

[0041]

[0042] CAS No.6606-65-1Chemical Formula C8H 11 NO2 Molar Mass 153.181g / mol Density 0.986g / cm3 at 20℃ Boiling Point 69~72℃ at 1.6mmHg Flash Point 80℃ or higher

[0043] Cellulose nanofibers (CNFs) are natural polymers obtained from bio-based materials such as wood, fibers, and bacteria. They are natural linear polymers of anhydroglucose units, in which one carbon atom and four carbon atoms are linked by b-glycosidic bonds. These cellulose nanofibers are usually fibrils composed of 36 cellulose chains, and have a structure as shown in chemical formula 2 below. They have a diameter of 5–20 nm and a length of 500–2,000 nm, and are divided into amorphous and crystalline regions.

[0044] [Chemical Formula 2]

[0045]

[0046] Meanwhile, cellulose nanofibers, in addition to their characteristics of light weight, high strength, high elastic modulus, and low coefficient of linear expansion, also possess the characteristics of cellulose itself, such as being a renewable resource, biodegradability, biocompatibility, and organic solvent resistance. Compared to microfibrils, their specific surface area is approximately 1,000 times larger, which greatly improves their adsorption properties. Since they are nano-sized, the pressure loss when they come into contact with fluids such as gases is considerably small, and since the fiber diameter is shorter than the wavelength of visible light, they do not diffusely reflect light.

[0047] Furthermore, cellulose nanofibers exhibit excellent electrical, mechanical, and thermal properties due to the linear arrangement of the fiber polymers. Table 2 below shows the key properties of cellulose nanofibers.

[0048] Classification Main characteristics Mechanical characteristics Light weight, high strength, high elastic modulus, friction and wear resistance, elastic modulus stability (-200~200℃), surface smoothness, thixotropy Chemical / physical characteristics Adsorption, gas barrier properties, water retention, water repellency, permeability (fluid dynamic properties with very low pressure loss), biodegradability, low environmental toxicity, biocompatibility Other (optical / thermal / electrical properties) Transparency, UV absorption, dimensional stability (low coefficient of linear expansion), high thermal conductivity, electrical insulation

[0049] Iodine not only promotes wound healing but also possesses powerful antibacterial properties, reducing the risk of infection. Iodine has atomic number 53, CAS number 7553-56-2, an atomic radius of 140 pm, an average atomic mass of 126.90, a melting point of 114°C, a boiling point of 184°C, a density of 4.94 g / cm³, and oxidation states of -1, +1, +3, +5, and +7.

[0050] <Example: Preparation of biodegradable medical adhesive>

[0051] A biodegradable medical adhesive was manufactured by mixing 99 wt% of n-butyl cyanoacrylate, 0.7 wt% of cellulose nanofiber, and 0.3 wt% of iodine based on the total weight of the biodegradable medical adhesive in a sterilized container and mixing until well mixed.

[0052] At this time, in order to increase the storage properties of the manufactured biodegradable medical adhesive (i.e., long-term storage), it is preferable that the manufacturing process be carried out at a humidity of “0”.

[0053] The tensile shear bond strength (ASTM D1003) of the biodegradable medical adhesive manufactured in this way was tested five times as shown in Table 3 below, and the average time taken for each tensile shear bond strength to be developed (i.e., drying time) was 20 seconds.

[0054] Number of experiments Tensile shear bond strength (N / ㎟) 112.72 12.13 12.54 14.45 13.2 Standard deviation (SD) 0.9 Coefficient of variation (%) 6.65 Average 13.0

[0055] This was compared with a competitor's product, and the results of the comparison are shown in Table 4 below. Here, Comparative Example 1 is a 3M product (product name: Vet bond), and Comparative Example 2 is a Johnson & Johnson product (product name: Dermabond). Tensile shear bond strength and drying time were measured five times for each, and the average value was extracted.

[0056] Test Items Comparative Example 1 Comparative Example 2 Example Adhesive strength (N / ㎟) 61113 Drying time (dry time, sec) 1206020

[0057] In Comparative Examples 1 and 2, it took more than 1 minute to develop adhesive strength, but in the biodegradable medical adhesive of the present invention, adhesion was completely completed within 20 seconds, which was measured to be 3 to 6 times faster than in Comparative Examples 1 and 2, and the adhesive strength was also improved by 1.2 to 2.2 times, confirming that the adhesive strength was significantly increased.

[0058] <Experimental Example 1: Acute Systemic Toxicity Test of Biodegradable Medical Adhesives>

[0059] In this experiment, we conducted an acute systemic toxicity test of the biodegradable medical adhesive manufactured in the above example. This test was conducted in accordance with Good Laboratory Practice (GLP) regulations, No. 2022-93 (December 27, 2022), "Good Laboratory Practice," OECD "Principles of Good Laboratory Practice, ENV / MC / CHEM (98)17 (as revised in 1997)," and ISO 10993-11:2017, "Tests for Systemic Toxicity." The specific experimental conditions are as follows.

[0060] 1. Extraction solvent

[0061] - Polar solvent: Sterile saline (Lot No. D2Z7B58)

[0062] - Nonpolar solvent: Cottonseed oil (Lot No. 050323)

[0063] 2. Extraction

[0064] Dissolution area: Entire specimen

[0065] Dissolution rate: 6㎠ / mL (total surface area per specimen: 59.72㎠)

[0066] Dissolution conditions: (50±2)℃, (72±2) hours, stirring in a shaking water bath

[0067] Solvent control group: Dissolution under the same conditions excluding the test substance

[0068] 3. Dissolution conditions

[0069] The dissolution conditions are as shown in Table 5 below.

[0070] GroupExtraction vehicleSurface area(㎠)Volume of extraction vehicle(mL)G1Sterile saline-10.0G2Sterile saline1493.0248.8G3Cottonseed oil-10.0G4Cottonseed oil1493.0248.8

[0071] In Table 5, G1 represents the polar vehicle control group, G2 represents the polar vehicle test group, G3 represents the non-polar vehicle control group, and G4 represents the non-polar vehicle test group. "-" represents not applicable.

[0072] 4. Properties of the extract immediately before use

[0073] The properties of the extract immediately before use are as shown in Table 6 below.

[0074] Group Extraction medium Condition of extracts Color Clarity Particulate G1 Sterile saline Colorless Clear None G2 Sterile saline Colorless Clear None G3 Cottonseed oil Pale yellow Clear None G4 Cottonseed oil Pale yellow Clear None

[0075] 5. Test system

[0076] Strains and Species: ICR Mouse (CrlOri:CD1(ICR)), SPF

[0077] Gender, age, number of individuals, and weight range at introduction: Male, 3 weeks old, 22 individuals, 9.83–11.86 g

[0078] Gender, age, number of animals, and weight range at the time of administration: Male, 4 weeks old, 22 animals, 18.47~22.61g

[0079] 6. Test method

[0080] 6-1. Military composition

[0081] The composition of each group is as shown in Table 7 below.

[0082] Group Extraction Medium Animal Number Number of Animals Dose (mL / kg BW) Route of Administration G1 Sterile saline 1101-1105 550 Intravenous G2 Sterile saline 1201-120 55 G3 Cottonseed oil 1301-130 55 Intraperitoneal G4 Cottonseed oil 1401-140 55

[0083] 6-2. Administration method

[0084] Five mice per group were injected intraperitoneally and intravenously with the extract at a dose of 50 mL / kg BW using a disposable syringe (26 Gauge).

[0085] All animals were observed for symptoms 4, 24, 48, and 72 hours after administration. Body weight was measured at the time of introduction, group separation, and administration, and at 24, 48, and 72 hours after administration. After 72 hours after administration, all surviving animals were examined visually, and then sacrificed by exsanguination under isoflurane (Hana Pharmaceutical) anesthesia, and their organs were examined visually. No abnormalities were found in the organs, so histopathological examination was not performed.

[0086] 7. Evaluation Method

[0087] The evaluation of acute systemic toxicity tests was conducted by applying the following four criteria.

[0088] (1) If, during the observation period of the acute systemic toxicity test, no animals administered the test substance show a significantly greater biological response than the control group, the test substance satisfies the requirements of this test.

[0089] (2) If two or more animals in a test group using five animals die, two or more animals exhibit behaviors such as convulsions or weakness, or three or more animals show a weight loss of 10% or more of their body weight at the end of the experiment, the test substance does not meet the requirements of this test.

[0090] (3) If one animal treated with the test substance shows a mild biological reaction and one animal shows a serious biological reaction or dies, the test is repeated using a test group of 10 animals.

[0091] (4) If 10 animals treated with the test substance in a repeated test do not show a scientifically significant biological response compared to the control group during the observation period, the test substance satisfies the requirements of this test.

[0092] 8. Test results

[0093] As shown in Fig. 1, no dead animals or abnormal findings were observed in any administration group during the experimental period, and as shown in Fig. 2, weight loss was observed in two animals in the non-polar solvent test group (G4) 24 hours after administration. However, the animals in question gained weight again after 48 hours and during the experimental period, indicating that a temporary weight loss occurred due to the administration of the test substance. As shown in Fig. 3, visual observations of major organs revealed no abnormal findings related to the administration of the test substance extract in any administration group.

[0094] Accordingly, it was confirmed that the biodegradable medical adhesive of the present invention satisfies the requirements of the acute systemic toxicity test.

[0095] <Experimental Example 2: Intradermal Reaction Test of Biodegradable Medical Adhesive>

[0096] In this experiment, we conducted an intradermal reaction test of the biodegradable medical adhesive manufactured in the above example. This test was conducted in accordance with GLP regulations, No. 2022-93 (December 27, 2022), "Good Laboratory Practice," OECD "Principles of Good Laboratory Practice, ENV / MC / CHEM (98)17 (as revised in 1997)," and ISO 10993-23:2021, "Tests for Irritation." The specific experimental conditions are as follows.

[0097] 1. Extraction solvent

[0098] - Polar solvent: Sterile saline (Lot No. D2Z7B58)

[0099] - Nonpolar solvent: Cottonseed oil (Lot No. 050323)

[0100] 2. Extraction

[0101] Dissolution area: Entire specimen

[0102] Dissolution rate: 6㎠ / mL (total surface area per specimen: 59.72㎠)

[0103] Dissolution conditions: (50±2)℃, (72±2) hours, stirring in a shaking water bath

[0104] Solvent control group: Dissolution under the same conditions excluding the test substance

[0105] 3. Dissolution conditions

[0106] The dissolution conditions are as shown in Table 8 below.

[0107] Group Test material Surface area (㎠) Medium extraction amount (mL) G1 Control group (Sterile saline blank) - 10.0 G2 Test group (Sterile saline blank) 895.81 49.3 G3 Control group (Cottonseed oil blank) - 10.0 G4 Test group (Cottonseed oil blank) 895.81 49.3

[0108] 4. Properties of the extract immediately before use

[0109] The properties of the extract immediately before use are as shown in Table 9 below.

[0110] Group Test Material Extraction Medium Extract State Color Transparency Particulate G1 Control (Sterile saline blank) Sterile saline Color None Transparent None G2 Test Group (Sterile saline blank) Sterile saline Color None Transparent None G3 Control (Cottonseed oil blank) Cottonseed oil Light yellow Transparent None G4 Test Group (Cottonseed oil blank) Cottonseed oil Light yellow Transparent None

[0111] 5. Test system

[0112] Strains and Species: Pdb:NZWnl, Rabbit, SPF

[0113] Sex, age, and number of individuals at introduction: male, 3 months old, 4 individuals

[0114] Sex, age, number of animals, and weight at the time of administration: 3 males, 3 months old, 3 animals, (2283.38-2698.70) g

[0115] 6. Test method

[0116] 6-1. Military composition

[0117] The composition of each group is as shown in Table 10 below.

[0118] Subject numberSexTest materialNumber of sites(per animal)Dosage(μL per site)1101-1103MaleControl group(Sterile saline blank)5200Test group(Sterile saline blank)5200Control group(Cottonseed oil blank)5200Test group(Cottonseed oil blank)5200

[0119] 6-2. Administration method

[0120] After body weight measurement, the back area was shaved about 4 hours before administering the test substance, and 3 animals with clean skin were selected for the test. Using a 1 mL syringe (KOVAX-SYRINGE 1 mL, KOREA VACCINE CO, LTD, Korea), sterile saline and cottonseed oil extracts were intradermally administered to the left side of the rabbit spine, and each solvent control group was administered to the right side, as shown in Fig. 4. The injection site was set to 5 sites / extract or blank, and the administration amount was set to 200 μL / site.

[0121] All animals were observed once a day until the 72-hour observation period, and the body weight of each animal was measured when the experimental animals were introduced, when the groups were separated, and on the 72-hour observation period. In addition, the injection site was checked for abnormalities immediately after administration, and the degree of erythema, crust formation, and edema formation was observed according to Table 11 below at (24±2) hours, (48±2) hours, and (72±2) hours after administration, and the results were recorded. In addition, photographs were taken of the shape of the injection site immediately after intradermal administration and every (24±2) hours, (48±2) hours, and (72±2) hours.

[0122] Reaction Grade Erythema and Crust Formation No Erythema 0 Very slight erythema (barely perceptible) 1 Well-defined erythema 2 Moderately detailed erythema 3 Severe erythema (dark red) - Crust formation with difficult erythema grading 4 Edema Formation No edema 0 Very slight edema (barely perceptible) 1 Well-defined edema (clearly raised with well-defined borders) 2 Moderate edema (raised approximately 1 mm) 3 Severe edema (raised more than 1 mm and extending beyond the exposed area) 4 Maximum possible irritation score 8 Record and report any other unusual changes that occur on the skin area.

[0123] 7. Evaluation Method

[0124] For the evaluation of intradermal reactions, the erythema and edema grades observed at (24±2) hours, (48±2) hours, and (72±2) hours after administration were added together, and then divided by the total number of observations (15) (3 scoring time points × 5 test injection sites). After calculating all values ​​for each animal, the values ​​were added together and divided by 3. In addition, the same method was used for calculating the site where the control substance was administered, and if the difference in scores between the test substance and the control substance was 1.0 or less, the necessary conditions of the test were determined to be met.

[0125] 8. Evaluation of positive contrast

[0126] As a result of conducting a positive control test using 0.5% SDS (sodium dodecyl sulfate) according to ISO 10993-23 (KTR test number: TNK-2023-000696), the score difference between the test substance administration site and the control substance administration site was calculated as "6.25", which was confirmed as a positive result of "1.0" or higher.

[0127] 9. Test results

[0128] As shown in Fig. 5, no animals were observed to die or exhibit abnormal symptoms related to the administration of the test substance during the experimental period, and as a result of body weight measurement, normal weight gain was observed in all animals as shown in Fig. 6. As shown in Fig. 7, as a result of observing local irritation at the site of sterile saline solution administration, no intradermal reaction was observed at the site of the extract (test substance) and control substance administration in any animal. In addition, as shown in Fig. 8, as a result of observing local irritation at the site of cottonseed oil administration, very slight erythema and swelling were observed at the site of the extract (test substance) and control substance administration, and the score difference between the test substance and the control substance was calculated as "0.00" for sterile saline solution and "0.00" for cottonseed oil.

[0129] Accordingly, it was confirmed that the biodegradable medical adhesive of the present invention does not cause an intradermal reaction.

[0130] <Experimental Example 3: Material-mediated pyrogenicity test of biodegradable medical adhesives>

[0131] In this experiment, a material-mediated pyrogenicity test was conducted on the biodegradable medical adhesive manufactured in the above example. This test was conducted in accordance with GLP regulations, No. 2022-93 (December 27, 2022), "Good Laboratory Practice," OECD "Principles of Good Laboratory Practice, ENV / MC / CHEM (98)17 (as revised in 1997)," and ISO 10993-11:2017, "Tests for Systemic Toxicity." The specific experimental conditions are as follows.

[0132] 1. Extraction solvent

[0133] Polar solvent: Sterile saline (Lot No. D2Z7B58)

[0134] 2. Extraction

[0135] Dissolution area: Entire specimen

[0136] Dissolution rate: 6㎠ / mL (total surface area per specimen: 59.72㎠)

[0137] Dissolution conditions: (50±2)℃, (72±2) hours, stirring in a shaking water bath

[0138] 3. Dissolution conditions

[0139] The dissolution conditions are as shown in Table 12 below.

[0140] Extract surface area (㎠) Medium extraction amount (mL) Test group 2986.0497.6

[0141] 4. Properties of the extract immediately before use

[0142] The properties of the extract immediately before use are as shown in Table 13 below.

[0143] ExtractionExtraction mediumExtract stateColorTransparencyParticulate Test groupSterile salineColorlessTransparencyNone

[0144] 5. Test system

[0145] Strains and Species: Pdb:NZWnl, Rabbit, SPF

[0146] Sex, age, and number of individuals at introduction: male, 3 months old, 4 individuals

[0147] Sex, age, number of animals, and weight at the time of administration: 3 males, 3 months old, 3 animals, (2327.01-2617.62) g

[0148] 6. Test method

[0149] 6-1. Military composition

[0150] The composition of the military is as shown in Table 14 below.

[0151] Group Subject Number Subject Number Dosage (mL / kg BW) Administration Route G11101-1103310 Ear marginal vein

[0152] In Table 14, G1 is the first test and BW represents body weight.

[0153] 6-2. Administration method

[0154] When the body temperature of all animals was 38.5℃ or higher but lower than 39.8℃ and the difference in body temperature between animals was 1.0℃ or lower, the animals were considered stable. When the animals were stable for more than 15 minutes, administration of the test substance was started. The body temperature at the start of administration was used as the control body temperature. The test substance was warmed to (37±2)℃ in a constant temperature water bath and injected into the intravenous vein. In addition, the injection time per experimental animal was limited to 10 minutes.

[0155] All animals were observed daily for changes in general symptoms and deaths, and body temperature was measured at the start and end of administration and at 15-minute intervals for 3 hours after the end of administration.

[0156] 7. Evaluation Method

[0157] For the febrile evaluation, body temperature is measured at 15-minute intervals for 3 hours after injection of the test substance extract, and the difference between the control body temperature and the highest body temperature is considered the body temperature rise. Three experimental animals are used for the first test, and if no animal has a body temperature rise of 0.5℃ or more after injection, the test is judged as “negative” for the febrile substance.

[0158] In addition, when there are experimental animals with a body temperature of 0.5℃ or higher, a second test is conducted, and 5 animals are used in the second test. Among the 8 experimental animals used in the 1st and 2nd tests, if there are 3 or fewer experimental animals with a body temperature increase of 0.5℃ or higher, and the total body temperature increase of the 8 animals is 3.3℃ or lower, it is judged as "negative" for fever.

[0159] However, if the body temperature of all three animals rises by more than 0.5℃ in the first test and the total body temperature rise exceeds 3.3℃, ​​the second test will not be conducted and the animals will be judged as “positive” for the pyrogen.

[0160] 8. Test results

[0161] As shown in Fig. 9, no abnormal symptoms were observed in any animals during the experimental period as a result of general symptom observation, and as a result of body temperature measurement as shown in Fig. 10, no animal was observed with a body temperature increase of more than 0.5℃, and the sum of the body temperature increases was measured to be 0.64℃.

[0162] Accordingly, the biodegradable medical adhesive of the present invention was judged to be “negative” for pyrogens.

[0163] Experimental Example 4: Chemical Testing of Biodegradable Medical Adhesives

[0164] In this experiment, we conducted a chemical analysis of the biodegradable medical adhesive manufactured in the above example. This analysis was conducted in accordance with the "Designation of Household Chemical Products Subject to Safety Confirmation and Safety / Labeling Standards (Ministry of Environment Notice No. 2023-163 (July 6, 2023))" and the "Regulations on Testing and Inspection Standards and Methods for Household Chemical Products Subject to Safety Confirmation (National Institute of Environmental Research Notice No. 2022-26 (June 15, 2022))".

[0165] As shown in Fig. 11, the results of the chemical substance test for the biodegradable medical adhesive of the present invention show that not only were almost no toxic substances detected, but all detected substances were also detected below the standard value.

[0166] <Experimental Example 5: Cytotoxicity Test of Biodegradable Medical Adhesives>

[0167] In this experiment, a cytotoxicity test was conducted on the biodegradable medical adhesive manufactured in the above example. This test was conducted in accordance with GLP regulations, No. 2022-93 (December 27, 2022), "Non-clinical Laboratory Management Standards," OECD "Principles of Good Laboratory Practice, ENV / MC / CHEM (98)17 (as revised in 1997)," and ISO 10993-5:2009, "Tests for in vitro cytotoxicity." The specific experimental conditions are as follows.

[0168] 1. Control material

[0169] The control substances are as shown in Table 15 below.

[0170] Solvent control material: Minimum essential medium with horse serum 10% (v / v), penicillin-streptomycin 1% (v / v) Negative control material: High Density Polyethylene Film Positive control material: ZDEC Polyurethane Film

[0171] 2. Dissolution of test substances and control substances

[0172] Elution site: 1 mL of MEM medium supplemented with 10% serum per 6 cm2 of the entire test substance in the specimen was dissolved by stirring in a (5±1)% CO2 incubator at (37±1)℃ for (24±2) hours. For the reagent control, the MEM medium excluding the test substance was dissolved under the same dissolution conditions as the test substance. For the negative control and positive control, 1 mL of 1X MEM medium per 0.1 g was dissolved by stirring in a (5±1)% CO2 incubator at (37±1)℃ for (24±2) hours based on the cytotoxicity test method of the manufacturer (Hatano Research Institute). All elutions were not pH adjusted, stored at room temperature after elution, and used within 4 hours. No other treatments such as centrifugation or filtration were applied to the elution.

[0173] 3. Dissolution conditions

[0174] The dissolution conditions are as shown in Table 16 below.

[0175] Group Extraction ratio Amount of medium extraction Reagent control--20 mL Negative control 0.1 g: 1 mL 0.72 g 7.2 mL Positive control 0.1 g: 1 mL 0.69 g 6.9 mL Test group 6 cm2: 1 mL 2 98.6 cm2 49.7 mL

[0176] 4. Properties of the extract

[0177] The properties of the extract are as shown in Table 17 below.

[0178] Extraction mediumObservation time (Time Observed)GroupExtract statusColorTransparencyParticulateAggregate (Aggregate)MEM with serumBefore extractionSolvent controlReddish orangeTransparentNoneNoneNegative controlReddish orangeTransparentNoneNonePositive controlReddish orangeTransparentNoneNoneTest groupReddish orangeTransparentNoneNoneAfter extractionSolvent controlReddish orangeTransparentNoneNoneNegative controlReddish orangeTransparentNoneNonePositive controlReddish orangeTransparentNoneNoneTest groupReddish orangeTransparentNoneNoneAggregation

[0179] 5. Test system

[0180] Test cells: NCTC Clone 929 (L-929)

[0181] 6. Badge

[0182] 6-1. MEM

[0183] Minimum essential medium [MEM, Liquid (gibco)]

[0184] 6-2. 1X MEM

[0185] Add 10% (v / v) of horse serum (gibco) and 1% (v / v) of penicillin-streptomycin (gibco) to MEM.

[0186] 7. Test method

[0187] Monolayer cultured cells were treated with trypsin (trypsin / EDTA, Gibco) to obtain a cell concentration of 10 per mL. 5 The cells were adjusted to be a dog, and 2 mL was inoculated into a well of approximately 10 cm2 (6-well tissue culture plate, Φ35 mm / well). The cells were cultured for more than 24 hours in a (37±1)℃, (5±1)% CO2 incubator, and the wells that had become monolayer cultures were selected, marked as each test substance treatment group and control group, and the medium was removed.

[0188] The test substance treatment group, solvent control group, negative control group, and positive control group were dispensed into three selected wells at 2 mL each and cultured in a (37±1)℃, (5±1)% CO2 incubator for (48±1) hours. After culture, cell lysis and morphology were observed under a microscope (100×).

[0189] 8. Determination of cytotoxicity

[0190] When a uniform monolayer of cells existed, it was expressed as (+), and when it did not exist, it was expressed as (-). The cell solubility and the degree of morphological change of the cells in each cultured well were recorded. When the color of the medium turned yellow after dissolution, it was judged that the medium had become acidic due to the dissolved substance, and when it turned crimson or purple, it was judged that the medium had become basic.

[0191] The final interpretation of the cytotoxicity test results was conducted according to ISO 10993-5, 8.5 Determination of cytotoxicity shown in Table 18 below. To verify the validity of the test, the solvent control and negative control groups should not show cytotoxicity (i.e., grade 0), and the positive control group should show cytotoxicity of intermediate or higher (i.e., grade 2 or higher). If each control group did not show the expected results or different results were observed in the three test substance treatment groups, a retest was conducted.

[0192] Grade Reaction Status of cultured cells 0 None No intracytoplasmic granule separation, no cell lysis, no inhibition of cell growth 1 Slight Rounded, loosely attached cells, no more than 20% of cells with loss of intracytoplasmic granules or changes in shape. Occasionally lysed cells are present, and slight growth inhibition is observed. 2 Mild Rounded, no more than 50% of cells with loss of intracytoplasmic granules, no extensive cell lysis. No more than 50% growth inhibition. 3 Moderate Rounded, lysed cells in no more than 70%. Cell layers are not completely destroyed, but growth inhibition of more than 50% is observed. 4 Severe Cell layers are largely or completely destroyed.

[0193] 9. Test results

[0194] The biodegradable medical adhesive of the present invention maintained a uniform monolayer cultured in cells treated with the extract of the test substance, but as shown in Fig. 12, about 10% of proliferation inhibition was observed, which can be seen to indicate that the test substance has very weak reactivity to cultured cells in this test environment.

[0195] Additionally, the solvent control group and the negative control group did not show any toxicity to cultured cells, while the positive control group caused cytotoxicity in more than 75% of all cells.

[0196] As can be seen from this, the biodegradable medical adhesive of the present invention is thought to have very weak cytotoxicity, but is judged to be Class 1 according to the cytotoxicity judgment criteria of ISO 10993-5, so it can be seen that it meets the cytotoxicity test criteria for general medical devices that must be Class 2 or lower, and it can be confirmed that the results of this test are very valid through the test results of the solvent control group, negative control group, and positive control group.

[0197] That is, it was confirmed that the biodegradable medical adhesive of the present invention is suitable as it has a cytotoxicity reaction grade of grade 1.

[0198] <Experimental Example 6: Accelerated Aging Test of Biodegradable Medical Adhesives>

[0199] In this experiment, we conducted an accelerated aging test on the biodegradable medical adhesive manufactured in the above example. This test is conducted at a constant temperature (50±2)℃ according to the Stability Test Standards for Medical Devices (Ministry of Food and Drug Safety Notice No. 2023-34) and the ASTM F1980-21 Standard Guide for Accelerated Aging of Sterile Barrier Systems and Medical Devices test method. The test compares and tests changes in packaging and performance of the product before and after accelerated aging to determine the product's shelf life. The specific test conditions are as follows.

[0200] 1. Test method

[0201] After placing it in the center of a temperature and humidity chamber set to (50±2)℃ in advance, it was subjected to accelerated aging for the “accelerated aging environmental conditions” and “accelerated aging period” below.

[0202] 1-1. Estimation of accelerated aging environmental conditions

[0203] - Accelerated Aging Time (AAT) = 365 days / AAF

[0204] - Accelerated Aging Factor (AAF) = Q10(Taa-Trt) / 10

[0205] - Q10 = 2.0 or 1.8

[0206] Here, Q10 is the aging coefficient when the aging temperature increases or decreases by 10℃. In this test, 2.0, which is generally used in industrial standards, was adopted and used. Taa is the accelerated aging temperature, and Trt is the actual storage temperature or room temperature, which is usually specified as 20℃ to 25℃, and was set to 20℃ in this test.

[0207] 1-2. Accelerated aging period

[0208] According to the “Accelerated Aging Environmental Conditions Calculation,” the accelerated aging period corresponding to a validity period of one year is calculated as follows.

[0209] AAF = 2.0 (50-20)10 =(2.0) 3.0 = 8.0000

[0210] AAT = 365 days / 8.0000 = 45.6250 days

[0211] As above, if the accelerated aging time is 45.6250 days or more under the temperature condition of (50±2)℃, it means that the real-time corresponding validity period is 1 year or more. Therefore, in this test, the accelerated period was set to 46 days to evaluate the validity period of 1 year, and in order to evaluate the test at two time points, the test was conducted on the first day (day 0) and on day 46, which is the accelerated aging period corresponding to the validity period of 1 year.

[0212] 1-3. Accelerated aging equipment and testing equipment

[0213] The equipment for accelerated aging testing is as shown in Table 19 below.

[0214] Equipment name Model name Management number Waterproof tester Membrane Factory / Waterproof tester 120-C70-0583 Clean bench JEIOTECH / BC-21B120-H14-0031 High-pressure sterilizer Daihan-sci / MaXterile-100120-H14-0024 Electromagnetic incubator OHAUS / AX4202KR120-F41-0298 Constant temperature incubator Hanbaeksci / HB-101L120-B22-0017 Low temperature incubator Hanbaeksci / HB-103M120-B22-0018 Constant temperature water bath Labtech / LSB-030S120-H17-0076

[0215] 2. Test results

[0216] 2-1. Results of appearance test of product packaging

[0217] As shown in Table 20 below, the appearance of the product packaging before and after 46 days of accelerated aging met the test criteria, so it can be inferred that there is no problem with the product packaging even for a period equivalent to one year in real time.

[0218] Accelerated aging before classification test standard result 46 days After accelerated aging: equivalent to 1 year in real time S1 No damage, foreign matter or contamination when visually inspected Suitable Suitable S2 Suitable Suitable S3 Suitable Suitable

[0219] 2-2. Product appearance test results

[0220] As shown in Table 21 below, the appearance of the product before and after 46 days of accelerated aging met the test criteria, so it can be inferred that there is no problem with the product even for a period equivalent to one year in real time.

[0221] Accelerated aging before classification test standard result 46 days After accelerated aging: equivalent to 1 year in real time S1 No damage, foreign matter or contamination when visually inspected Suitable Suitable S2 Suitable Suitable S3 Suitable Suitable

[0222] 2-3. Product waterproofing test results

[0223] As shown in Table 22 below, the results of the waterproofing test on the products before and after 46 days of accelerated aging showed that all products met the test standards, so it can be inferred that there is no problem with the product performance even for a period equivalent to one year in real time.

[0224] Accelerated aging before classification test standard result 46 days After accelerated aging: equivalent to 1 year in real time S1 No damage, foreign matter or contamination when visually inspected Suitable Suitable S2 Suitable Suitable S3 Suitable Suitable

[0225] 2-4. Microbial limit test results

[0226] As shown in Figure 13, in the microbial limit test before accelerated aging, the number of colonies in the sample was below the standard, which was suitable, and in the microbial limit test on the product aged for 46 days, the number of colonies in the sample was below the standard, as shown in Figure 13. This can be inferred that the microbiological quality of the product is well maintained within the standard even for a period equivalent to one year in real time.

[0227] <Experimental Example 7: Container Extraction Test for Biodegradable Medical Adhesives>

[0228] In this experiment, a test was conducted on the container extract of the biodegradable medical adhesive manufactured in the above example. In this test, the usability of the biodegradable medical adhesive container of the present invention was tested using the test method as shown in Table 24 under the test solution manufacturing conditions as shown in Table 23 below.

[0229] Sample thickness and shape Surface area and weight Extraction solvent amount Elution conditions Amorphous 4g 20ml 70±2℃, 24±2 hours

[0230] Test item Test standard Test method Extraction Test property Colorless and transparent, free of foreign matter. Observe with the naked eye. pH pH difference ≤ 1.5 Test according to the pH section of the Korean Pharmacopoeia Plastic Pharmaceutical Container Test Method. Potassium permanganate reducing substance Difference in potassium permanganate consumption ≤ 2.0 ml Take 20 ml of the test solution and blank test solution and test according to the potassium permanganate reducing substance section of the Korean Pharmacopoeia Plastic Pharmaceutical Container Test Method. Ultraviolet absorption spectrum Maximum absorbance value ≤ 0.1 Measure the absorbance at a wavelength of 250 to 350 nm according to the absorbance measurement method in the general test methods of the Korean Pharmacopoeia, using the blank test as a control. Evaporation residue Difference in residual amount ≤ 1.0 mg Take 20 ml of the test solution and blank test solution and test according to the evaporation residue section of the Korean Pharmacopoeia Plastic Pharmaceutical Container Test Method. Heavy metal Should not be darker than the comparison solution. Take 10 ml of the test solution and Test according to Method 1 of the General Test Methods for Heavy Metals in the Korean Pharmacopoeia. Add 2.0 ml of lead standard solution to the comparison solution.

[0231] As shown in Table 25 below, the biodegradable medical adhesive container according to an embodiment of the present invention satisfies all of the test criteria shown in Table 24, and thus can be seen as a usable container.

[0232] Test / Inspection Item Unit Test / Inspection Standard Result Judgment (Container + Nozzle + Cap) - Extraction Test: Appearance - Colorless and transparent, free of foreign substances Colorless and transparent, free of foreign substances Suitable (Container + Nozzle + Cap) - Extraction Test: pH - ≤ 1.5 0.5 Suitable (Container + Nozzle + Cap) - Extraction Test: Heavy Metal - Not more concentrated than the reference solution Not more concentrated than the reference solution Suitable (Container + Nozzle + Cap) - Extraction Test: Potassium Permanganate Reducing Substance mL ≤ 2.0 0.2 Suitable (Container + Nozzle + Cap) - Extraction Test: Evaporation Residue mg ≤ 1.0 0.0 Suitable (Container + Nozzle + Cap) - Extraction Test: UV Absorption Spectrum - ≤ 0.1 0.0 Suitable

[0233] <Experimental Example 8: Skin Sensitivity Test of Biodegradable Medical Adhesive>

[0234] In this experiment, a skin sensitization test was conducted on the biodegradable medical adhesive manufactured in the above example. This test was conducted in accordance with GLP regulations, No. 2022-93 (December 27, 2022), "Non-clinical Laboratory Management Standards," OECD "Principles of Good Laboratory Practice, ENV / MC / CHEM (98)17 (as revised in 1997)," and ISO 10993-10:2021, "Tests for Skin Sensitization." The specific experimental conditions are as follows.

[0235] 1. Extraction solvent

[0236] - Polar solvent: Sterile saline (Lot No. 742DB58, 872DB58)

[0237] - Nonpolar solvent: Cottonseed oil (Lot No. 050323, 070423)

[0238] 2. Other substances

[0239] - Freund's Complete Adjuvant (FCA) (Lot No. SLCQ9227)

[0240] - 10% Sodium Dodecly Sulfate (10% SDS) (Lot No. 22040F)

[0241] 3. Extraction

[0242] Dissolution area: Entire specimen

[0243] Dissolution rate: 6㎠ / mL (total surface area per specimen: 59.72㎠)

[0244] Dissolution conditions: (50±2)℃, (72±2) hours, stirring in a shaking water bath

[0245] Solvent control group: Dissolution under the same conditions excluding the test substance

[0246] 4. Discharge amount

[0247] The yield is as shown in Table 26 below.

[0248] GroupIntradermal inductionTopical inductionChallengeSurfacearea(㎠)Volume of extractionvehicle(mL)Surfacearea(㎠)Volume of extractionvehicle(mL)Surfacearea(㎠)Volume of extractionvehicle(mL)G1-10.0-10.0-10.0G2179.1629.8179.1629.8179.1629.8G3-10.0-10.0-10.0G4179.1629.8179.1629.8179.1629.8

[0249] In Table 26, G1 represents the vehicle control (Sterile saline), G2 represents the test sample (Sterile saline extraction), G3 represents the vehicle control (Cottonseed oil), and G4 represents the test sample (Cottonseed oil extraction). "-" represents not applicable.

[0250] 5. Properties of the extract before use

[0251] The properties of the extract before use are as shown in Table 27 below.

[0252] Group Extraction vehicle Condition of extracts Color Clarity Particulate G1 (Negative control) Sterile saline Colorless Clear None G2 (Test sample) Sterile saline Colorless Clear None G3 (Negative control) Cottonseed oil Pale yellow Clear None G4 (Test sample) Cottonseed oil Pale yellow Clear None

[0253] 6. Test system

[0254] Lineage and Species: Dunkin Hartley Guinea Pig (ElmSam:HA), SPF

[0255] Gender, age, and number of animals at introduction: 32 males, 5 weeks old

[0256] Gender, age, number of animals, and body weight at the time of administration: Male, 6 weeks old, 30 animals, 363.06~407.12g

[0257] 7. Test method

[0258] 7-1. Military composition

[0259] The composition of each group is as shown in Table 28 below.

[0260] Group Sex Extraction vehicle Animal number G1 (Control) Male Sterile Saline 1101~1105 G2 (Test) Male Sterile Saline 1201~1210 G3 (Control) Male Cottonseed oil 1301~1305 G4 (Test) Male Cottonseed oil 1401~1410

[0261] 7-2. Hair removal

[0262] Hair removal was performed at least 3 hours before each stage. Hair was removed from the inner part of the scapula during the intradermal and local induction stages, and hair was removed from the upper part of the flank 24 and 48 hours before the induction stage and skin reaction evaluation.

[0263] 7-3. Intradermal induction stage

[0264] Three types of test substances prepared according to Table 29 below were injected intradermally into the skin of the scapula area at 0.1 mL each according to Figure 14.

[0265] Group Animal No. Test materials Dose (mL) Injection site G11101~1105 Sterile Saline: * FCA(1:1)0.1①Blank(Sterile Saline)0.1②Blank(Sterile Saline): ** FCA emulsion(1:1)0.1③G21201~1210Sterile Saline: * FCA(1:1)0.1①Sterile Saline extract0.1②Sterile Saline extract: ** FCA emulsion(1:1)0.1③G31301~1305Cottonseed oil: * FCA(1:1)0.1①Blank(Cottonseed oil)0.1②Blank(Cottonseed oil): ** FCA emulsion(1:1)0.1③G41401~1410Cottonseed oil: * FCA(1:1)0.1①Cottonseed oil extract0.1②Cottonseed oil extract: ** FCA emulsion(1:1)0.1③

[0266] 7-4. Local induction stage

[0267] Five days after the completion of the intradermal induction phase, 0.5 mL of 10% Sodium Dodesyl Sulfate (SDS) was applied, and after (24 ± 2) hours, the test substance (0.4 mL) was soaked on a non-irritating tape (Tegarderm™, 3M) with a filter paper (2 cm × 4 cm) attached and applied to the intradermal injection site. After application, the patch was maintained for (48 ± 2) hours using Coban™, and then removed. The control substance (0.4 mL) was applied to the control animals using the same method.

[0268] 7-5. Induction stage

[0269] Thirteen days after completion of the local induction phase, the test substance (left, 0.2 mL) and the control substance (right, 0.2 mL) were soaked on non-irritating tape (Tegarderm™, 3M) with filter paper (2 cm × 2 cm) attached and applied to the upper flanks on both sides. After application, the patch was maintained for (24 ± 2) hours using Coban™ (3M) and then removed.

[0270] 8. Evaluation Method

[0271] Skin reactions were evaluated according to Table 30 below and the average skin reaction score was calculated. If the control group's Magnusson and Kligman scale was less than grade 1 and the test group's was grade 1 or higher, it was generally considered to indicate sensitization. If the control group showed grade 1 or higher, the reaction in the test group showing a more severe reaction was considered to be due to sensitization. In cases where the reaction was unclear, a re-provocation was performed to confirm the result of the first provocation test, but if sensitization was not observed, a re-provocation was not performed. The test results were expressed as the frequency of positive provocation results in the experimental and control animals, and a positive control test was performed once every 6 months according to ISO 10993-10.

[0272] Patch test reactionGrading scaleNo visible change0Discrete or patchy erythema1Moderate and confluent erythema2Intense erythema and / or swelling3

[0273] 9. Test results

[0274] As shown in Figures 15 and 16, no deaths (moribundity) or abnormal animals were observed in any test group during the experimental period due to test substance administration, and as shown in Figures 17 and 18, no weight loss was observed in any animals in the test group or control group due to test substance administration. As a result of evaluating the skin reaction 24 hours and 48 hours after the induction phase and the trigger phase using the test substance, as shown in Figure 19, no skin reactions such as erythema and edema were observed in the test group or control group, and the sensitization index and sensitization rate of the polar solvent test group (G2) were calculated as 0.0% and 0.0%, and the sensitization index and sensitization rate of the non-polar solvent test group (G4) were calculated as 0.0% and 0.0%.

[0275] From the above results, when the skin sensitization of the biodegradable medical adhesive of the present invention on guinea pigs was evaluated using the Guinea Pig Maximization Test (GPMT) method, no skin reaction was observed, so it is considered to be a non-sensitizing substance.

[0276] In this way, the biodegradable medical adhesive according to an embodiment of the present invention can improve adhesive strength and flexibility as well as biodegradability and biocompatibility by adding cellulose nanofibers to n-butyl cyanoacrylate, and the addition of iodine can reduce the risk of infection due to a strong antibacterial effect and enable rapid healing of the wound area.

[0277] As described above, the detailed description of the present invention has described preferred embodiments of the present invention. However, this has been described as an example of the most preferred embodiment of the present invention and is not intended to limit the present invention. Furthermore, it goes without saying that anyone with ordinary skill in the art to which the present invention pertains can make various modifications and imitations without departing from the scope of the technical idea of ​​the present invention. Therefore, the scope of the present invention should not be limited to the described embodiments, but should be defined not only by the claims described below but also by equivalents thereof.

[0278] The biodegradable medical adhesive of the present invention can be applied to suturing skin cuts resulting from surgical operations or accidents.

Claims

1. Mixed with 97 to 99.9 wt% of n-butyl cyanoacrylate, 0.06 to 2 wt% of cellulose nanofibrils (CNF), and 0.04 to 1 wt% of iodine. A biodegradable medical adhesive characterized in that the above n-butyl cyanoacrylate has a structure represented by the following chemical formula 1. [Chemical Formula 1] 2. In claim 1, A biodegradable medical adhesive characterized in that the above cellulose nanofibers have a structure represented by the chemical formula 2 below. [Chemical Formula 2] 3. In claim 1, A biodegradable medical adhesive characterized in that the above cellulose nanofibers have a diameter of 5 to 20 nm, a length of 500 to 2,000 nm, and are divided into an amorphous region and a crystalline region.

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