阅读说明：本技术 一种医用粘合剂及其制备方法和应用 (Medical adhesive and preparation method and application thereof ) 是由 杜宇聪 谢剑波 曾仑 欧达欣 于 2021-06-28 设计创作，主要内容包括：本发明提供了一种医用粘合剂及其制备方法和应用,所述医用粘合剂以重量份数计包括α-氰基丙烯酸酯90-99份、增粘剂1-10份和增韧剂1-10份。本发明提供的医用粘合剂粘合速度快、粘合强度高、伸长率高、持久性好,具有良好的生物相容性、能够快速止血、促组织再生和抑菌功能。(The invention provides a medical adhesive and a preparation method and application thereof, wherein the medical adhesive comprises 90-99 parts of alpha-cyanoacrylate, 1-10 parts of tackifier and 1-10 parts of toughening agent by weight. The medical adhesive provided by the invention has the advantages of high adhesion speed, high adhesion strength, high elongation, good durability, good biocompatibility, quick hemostasis, tissue regeneration promotion and bacteriostasis functions.)

1. The medical adhesive is characterized by comprising 90-99 parts of alpha-cyanoacrylate, 1-10 parts of tackifier and 1-10 parts of toughening agent in parts by weight.

2. The medical adhesive according to claim 1, wherein the medical adhesive comprises 93-97 parts by weight of alpha-cyanoacrylate, 3-7 parts by weight of tackifier and 3-7 parts by weight of toughening agent.

3. The medical adhesive according to claim 1 or 2, wherein the α -cyanoacrylate comprises any one of α -cyanoacrylate, α -cyanoacrylate propyl, α -cyanoacrylate butyl, α -cyanoacrylate octyl or α -cyanoacrylate methoxyethyl, or a combination of at least two thereof.

4. The medical adhesive of claim 3, wherein the α -cyanoacrylate comprises a combination of butyl α -cyanoacrylate and octyl α -cyanoacrylate.

5. The medical adhesive according to any one of claims 1 to 4, wherein the tackifier comprises dextran including any one or a combination of at least two of dextran 100, dextran 200, dextran 500 or ethyl methacrylate dextran, preferably a combination of dextran 200 and dextran 500.

6. The medical adhesive according to any one of claims 1 to 5, wherein the toughening agent comprises any one of or a combination of at least two of poly n-butyl cyanoacrylate, poly ethyl cyanoacrylate, polylactic acid or polyethylene glycol.

7. A method of preparing a medical adhesive according to any one of claims 1-6, comprising the steps of: and mixing and stirring the alpha-cyanoacrylate, the tackifier and the toughening agent to obtain the medical adhesive.

8. The method for preparing a medical adhesive according to claim 8, wherein the stirring temperature is 25-80 ℃, the speed is 100-120r/min, and the time is 0.5-3 h.

9. The method for preparing a medical adhesive according to claim 7 or 8, comprising the steps of: mixing alpha-cyanoacrylate, tackifier and toughener, stirring for 0.5-3h at 25-80 ℃ and 120r/min, and obtaining the medical adhesive.

10. Use of a medical adhesive according to any one of claims 1-6 for the preparation of a medical material.

Technical Field

The invention belongs to the field of medical materials, particularly relates to a medical adhesive and a preparation method and application thereof, and particularly relates to a medical adhesive with good toughness and a preparation method and application thereof.

Background

Medical adhesives are novel medical materials used for bonding tissue sites of living organisms during surgical operations. In the twentieth and forty years, Ardis first synthesizing cyanoacrylate, and ten years later, a company in the united states first discovered that cyanoacrylate had better adhesive properties, and later, kupffer et al discovered that this adhesive could be used for the bonding of biological tissues, and thus used as a new type of medical adhesive. Cyanoacrylate adhesives were popular in the early sixties of the twentieth century, but in use, biotoxicity limited the development of such adhesives. After seventy years, researchers found that modified monomers of cyanoacrylate, such as isobutyl cyanoacrylate, n-butyl cyanoacrylate and n-octyl cyanoacrylate, can be used for reducing the biological toxicity of the cyanoacrylate adhesive, and the discovery promoted the further development of medical adhesives. At present, medical adhesives are widely applied in various disciplines in the medical field, and have particularly remarkable clinical effects.

The common adhesive on the market, namely alpha-n-butyl cyanoacrylate or alpha-2-octyl cyanoacrylate, has the defects of high hardness, poor toughness and poor fit with human skin. Since the adhered part is too hard, the elasticity of the surface tension of the organ is insufficient, and repeated abrasion causes damage to the tissue, and also causes a series of problems including premature detachment or rupture of the adhesive film, and even a reactive inflammatory reaction. Moreover, the adhesive has short storage time, poor water resistance, easy solidification, pungent smell and lacrimation; moreover, the operation of the adhesive is not easy to master, so that the actual bonding effect is greatly influenced by human factors

CN106519995A discloses a toughened alpha-cyanoacrylate adhesive, which comprises the following components in percentage by weight: 85-99% of alpha-ethyl cyanoacrylate monomer; 0.001-10% of anionic polymerization inhibitor; 0.01-4% of free radical polymerization inhibitor; 0.01-5% of micro-nano core-shell particles. According to the invention, micro-nano core-shell particles are introduced into alpha-cyanoacrylate adhesive, and the toughness and the impact resistance of the alpha-cyanoacrylate adhesive are enhanced by the micro-nano core-shell particles. The adhesive has good toughness and high viscosity, is beneficial to bonding porous materials and is suitable for wide-gap scenes. However, the core-shell particles added thereto are a rubber which is hardly decomposed in the body and may exist in the body for a long time.

CN104368030B discloses a medical adhesive and a preparation method thereof, wherein the adhesive comprises: polyacrylate, tragacanth, polymethacrylate, squalane, benzoyl peroxide, glycerol triabietate, dimethyl sebacate, hydroquinone, p-toluenesulfonic acid, dioctyl phthalate, tricalcium phosphate and sodium alginate. The preparation method comprises mixing polyacrylate, tragacanth, polymethacrylate and squalane, adding benzoyl peroxide and glycerol trirosin acid ester, and stirring to obtain mixture I; then mixing dimethyl sebacate, hydroquinone, p-toluenesulfonic acid, dioctyl phthalate, tricalcium phosphate and sodium alginate to obtain a mixture II; and then mixing the mixture I and the mixture II, heating, preserving heat, and cooling to room temperature to obtain the compound. The medical adhesive has moderate curing speed, long stabilization time and strong bonding strength. However, the method disclosed in the patent has complicated steps, complicated components and high preparation cost.

The medical adhesive has high hardness, poor toughness and low elasticity, so a series of use problems are caused. Therefore, how to provide a medical adhesive with high bonding strength, good ductility and good durability becomes a problem to be solved urgently.

Disclosure of Invention

Aiming at the defects of the prior art, the invention aims to provide a medical adhesive and a preparation method and application thereof, in particular to a medical adhesive with good toughness and a preparation method and application thereof. The medical adhesive provided by the invention has the advantages of high adhesion speed, high adhesion strength, high elongation, good durability, good biocompatibility, quick hemostasis, tissue regeneration promotion and bacteriostasis functions.

In order to achieve the purpose, the invention adopts the following technical scheme:

in a first aspect, the invention provides a medical adhesive, which comprises 90-99 parts of alpha-cyanoacrylate, 1-10 parts of tackifier and 1-10 parts of toughening agent by weight.

The amount of the α -cyanoacrylate may be 90 parts, 91 parts, 92 parts, 93 parts, 94 parts, 95 parts, 96 parts, 97 parts, 98 parts or 99 parts, the amount of the tackifier may be 1 part, 2 parts, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts, 9 parts or 10 parts, the amount of the toughening agent may be 1 part, 2 parts, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts, 9 parts or 10 parts, but is not limited to the above-mentioned values, and other values not listed in the above-mentioned numerical range are also applicable.

The medical adhesive with the specific components and the proportion has the advantages that the specific raw materials, the tackifier and the toughening agent are compounded, and the alpha-cyanoacrylate, the tackifier and the toughening agent are used in a combined manner, so that the adhesive strength and the elongation are obviously improved, and meanwhile, the medical adhesive has good biocompatibility, can quickly stop bleeding, promote tissue regeneration and inhibit bacteria, has no toxic or side effect on a human body, and is low in cost.

Preferably, the medical adhesive comprises 93-97 parts of alpha-cyanoacrylate, 3-7 parts of tackifier and 3-7 parts of toughening agent by weight.

The proportion of the components further improves the bonding strength and the elongation of the medical adhesive.

Preferably, the α -cyanoacrylate includes any one or a combination of at least two of α -cyanoacrylate, octyl ester, or methoxyethyl ester, such as a combination of α -cyanoacrylate and octyl ester, α -cyanoacrylate, propyl ester, or octyl ester and methoxyethyl ester, but is not limited to the above-listed combinations, and other combinations not listed within the above-listed combinations are also applicable.

The selection of the specific alpha-cyanoacrylate can improve the bonding strength and the elongation of the medical adhesive, and simultaneously has the functions of quickly stopping bleeding, promoting tissue regeneration and inhibiting bacteria; meanwhile, the adhesive strength and the elongation of the medical adhesive are improved through the synergistic effect of the adhesive, the tackifier and the toughening agent.

Preferably, the α -cyanoacrylate comprises a combination of butyl α -cyanoacrylate and octyl α -cyanoacrylate.

The specific alpha-cyanoacrylate further improves the bonding strength and the elongation of the medical adhesive.

Preferably, the viscosity enhancer comprises dextran, and the modified dextran comprises any one of or a combination of at least two of dextran 100, dextran 200, dextran 500 or ethyl methacrylate dextran, such as dextran 100 and ethyl methacrylate dextran, dextran 200 and dextran 500, or dextran 100 and dextran 500, but is not limited to the above-listed combinations, and other combinations not listed within the above-listed combinations are equally applicable, preferably dextran 200 and dextran 500.

The specific tackifier and the toughening agent are compounded and have a synergistic effect, so that the bonding strength, viscosity and elongation of the medical adhesive are improved, and the curing time is shortened; meanwhile, within the preferable range of the tackifier of the invention, the bonding strength and the elongation of the medical adhesive are further improved.

Preferably, the toughening agent comprises any one or a combination of at least two of poly n-butyl cyanoacrylate, poly ethyl cyanoacrylate, polylactic acid or polyethylene glycol, such as a combination of poly n-butyl cyanoacrylate and poly ethyl cyanoacrylate, a combination of poly ethyl cyanoacrylate and polylactic acid or a combination of polylactic acid and polyethylene glycol, and the like, but is not limited to the above-listed combinations, and other combinations not listed within the above-mentioned combination range are also applicable.

The toughening agent can be compounded with the tackifier to achieve a synergistic effect, so that the bonding strength and the elongation of the medical adhesive are improved.

In a second aspect, the present invention provides a method for preparing a medical adhesive as described above, comprising the steps of: and mixing and stirring the alpha-cyanoacrylate, the tackifier and the toughening agent to obtain the medical adhesive.

The preparation method can quickly and conveniently prepare the medical adhesive.

Preferably, the stirring temperature is 25-80 ℃, the speed is 100-120r/min, and the time is 0.5-3 h.

Wherein the stirring temperature can be 25 deg.C, 30 deg.C, 35 deg.C, 40 deg.C, 45 deg.C, 50 deg.C, 55 deg.C, 60 deg.C, 65 deg.C, 70 deg.C, 75 deg.C or 80 deg.C, the speed can be 100r/min, 105r/min, 110r/min, 115r/min or 120r/min, the time can be 0.5h, 1h, 1.5h, 2h, 2.5h or 3h, but not limited to the above-mentioned values, and other values not listed in the above-mentioned value range can be applied similarly.

As a preferred technical scheme of the invention, the preparation method comprises the following steps: mixing alpha-cyanoacrylate, tackifier and toughener, stirring for 0.5-3h at 25-80 ℃ and 120r/min, and obtaining the medical adhesive.

In a third aspect, the present invention also provides the use of a medical adhesive as described above for the preparation of a medical material.

Compared with the prior art, the invention has the following beneficial effects:

the invention provides a medical adhesive, which is prepared by selecting characteristic raw materials, compounding a tackifier and a toughening agent and using alpha-cyanoacrylate and the tackifier and the toughening agent together, so that the adhesive strength and the elongation are obviously improved, and the adhesive has good biocompatibility, can quickly stop bleeding, promote tissue regeneration and inhibit bacteria, has no toxic or side effect on a human body, and is low in cost; the adhesive strength and the elongation of the medical adhesive are further improved by selecting the specific alpha-cyanoacrylate and the tackifier, and the compounding and synergistic action of the toughening agent and the tackifier, and the synergistic action of the alpha-cyanoacrylate, the tackifier and the toughening agent.

Detailed Description

To further illustrate the technical means and effects of the present invention, the following further describes the technical solution of the present invention with reference to the preferred embodiments of the present invention, but the present invention is not limited to the scope of the embodiments.

In the following examples, dextran 100 is available from Shanghai Michelin Biochemical technology, Inc. under model number D872032;

dextran 200 was purchased from Shanghai Michelin Biochemical technology, Inc. under model number D872030;

dextran 500 was purchased from Shanghai Michelin Biochemical technology, Inc. model No. D872024;

poly (n-butyl cyanoacrylate) was purchased from Shanghai Michelin Biochemical technology, Inc. under model number B895525;

polylactic acid was purchased from Sigma-Aldrich, model 900293;

polyethylene glycol was purchased from the national pharmaceutical group with model number 30150628.

Example 1

The embodiment provides a medical adhesive which comprises the following components in parts by weight:

45 parts of alpha-butyl cyanoacrylate, 40 parts of alpha-octyl cyanoacrylate, 2002.5 parts of glucan, 5002.5 parts of glucan and 5 parts of poly n-butyl cyanoacrylate.

The preparation method comprises the following steps: alpha-butyl cyanoacrylate, alpha-octyl cyanoacrylate, dextran 200, dextran 500 and poly n-butyl cyanoacrylate are mixed and stirred at 55 ℃ and 110r/min for 1.5h to obtain the medical adhesive.

Example 2

The embodiment provides a medical adhesive which comprises the following components in parts by weight:

95 parts of alpha-butyl cyanoacrylate, 2002.5 parts of glucan, 5002.5 parts of glucan and 5 parts of poly n-butyl cyanoacrylate.

The preparation method comprises the following steps: mixing alpha-butyl cyanoacrylate, dextran 200, dextran 500 and poly n-butyl cyanoacrylate, and stirring at 55 ℃ and 110r/min for 1.5h to obtain the medical adhesive.

Example 3

The embodiment provides a medical adhesive which comprises the following components in parts by weight:

93 parts of alpha-cyanoacrylate, 5007 parts of glucan and 3 parts of polylactic acid.

The preparation method comprises the following steps: mixing alpha-octyl cyanoacrylate, glucan 500 and polylactic acid, and stirring for 3 hours at 25 ℃ and 120r/min to obtain the medical adhesive.

Example 4

The embodiment provides a medical adhesive which comprises the following components in parts by weight:

97 parts of alpha-cyanoacrylate, 2003 parts of dextran and 7 parts of polyethylene glycol.

The preparation method comprises the following steps: mixing alpha-ethyl cyanoacrylate, dextran 200 and polyethylene glycol, and stirring at 80 ℃ and 100r/min for 0.5h to obtain the medical adhesive.

Example 5

The embodiment provides a medical adhesive which comprises the following components in parts by weight:

90 parts of alpha-butyl cyanoacrylate, 2005 parts of glucan, 5005 parts of glucan and 1 part of poly n-butyl cyanoacrylate.

The preparation method was identical to example 2.

Example 6

The embodiment provides a medical adhesive which comprises the following components in parts by weight:

99 parts of alpha-butyl cyanoacrylate, 2000.5 parts of glucan, 5000.5 parts of glucan and 10 parts of poly n-butyl cyanoacrylate.

The preparation method was identical to example 2.

Example 7

The embodiment provides a medical adhesive which comprises the following components in parts by weight:

45 parts of alpha-ethyl cyanoacrylate, 40 parts of alpha-octyl cyanoacrylate, 2002.5 parts of glucan, 5002.5 parts of glucan and 5 parts of poly n-butyl cyanoacrylate.

The preparation process is referred to example 1.

Example 8

The embodiment provides a medical adhesive which comprises the following components in parts by weight:

45 parts of alpha-propyl cyanoacrylate, 40 parts of octyl alpha-cyanoacrylate, 2002.5 parts of glucan, 5002.5 parts of glucan and 5 parts of poly n-butyl cyanoacrylate.

The preparation process is referred to example 1.

Example 9

The embodiment provides a medical adhesive which comprises the following components in parts by weight:

45 parts of alpha-cyano acrylic acid methoxyl ester, 40 parts of alpha-cyano acrylic acid ethyl ester, 2002.5 parts of glucan, 5002.5 parts of glucan and 5 parts of poly n-butyl cyanoacrylate.

The preparation process is referred to example 1.

Example 10

The embodiment provides a medical adhesive which comprises the following components in parts by weight:

95 parts of alpha-butyl cyanoacrylate, 2002.5 parts of glucan, 1002.5 parts of glucan and 5 parts of poly n-butyl cyanoacrylate.

The preparation method was identical to example 2.

Example 11

The embodiment provides a medical adhesive which comprises the following components in parts by weight:

95 parts of alpha-butyl cyanoacrylate, 1002.5 parts of glucan, 5002.5 parts of glucan and 5 parts of poly n-butyl cyanoacrylate.

The preparation method was identical to example 2.

Comparative example 1

The comparative example provides a medical adhesive, which comprises the following components in parts by weight:

80 parts of alpha-butyl cyanoacrylate, 2006.5 parts of glucan, 5006.5 parts of glucan and 0.1 part of poly n-butyl cyanoacrylate.

The preparation method was identical to example 2.

Comparative example 2

The comparative example provides a medical adhesive, which comprises the following components in parts by weight:

110 parts of alpha-butyl cyanoacrylate, 2000.05 parts of glucan, 5000.05 parts of glucan and 13 parts of poly n-butyl cyanoacrylate.

The preparation method was identical to example 2.

Comparative example 3

The comparative example provides a medical adhesive, which comprises the following components in parts by weight:

95 parts of alpha-butyl cyanoacrylate, 2005 parts of glucan and 5005 parts of glucan.

The preparation method refers to example 2.

Comparative example 4

The comparative example provides a medical adhesive, which comprises the following components in parts by weight:

95 parts of alpha-butyl cyanoacrylate and 10 parts of poly (n-butyl cyanoacrylate).

The preparation method refers to example 2.

Comparative example 5

The comparative example provides a medical adhesive, which comprises the following components in parts by weight:

105 parts of alpha-butyl cyanoacrylate.

The preparation method refers to example 2.

Comparative example 6

A commercially available medical adhesive.

And (3) toxicity testing:

toxicity tests were carried out on the medical adhesives provided in examples 1 to 11 and comparative examples 1 to 5, with reference to GB/T16886.11. The test result shows that the sample has no systemic toxicity to the SD rat, and the product provided by the invention has no toxic or side effect on human body and has good biocompatibility.

Physical property test:

the following tests were carried out on the medical adhesives provided in examples 1 to 11 and comparative examples 1 to 6, with the following test criteria:

viscosity: GB/T2794;

bonding strength: YY/T0729;

curing time: Q/ZQ-101-2021;

elongation percentage: ASTM D638;

the results are as follows:

group of	Viscosity (pa.m)	Bonding Strength (Mpa)	Curing time(s)	Elongation (%)
					Example 1	8	6.2	22	260
Example 2	8	6.0	22	250
					Example 3	6	5.9	17	220
Example 4	7	5.6	13	200
					Example 5	9	5.3	19	210
Example 6	9	5.3	22	210
					Example 7	10	4.3	24	230
Example 8	12	4.6	27	220
					Example 9	6	5.9	17	220
Example 10	9	5.1	21	230
					Example 11	9	5.4	18	220
Comparative example 1	10	5.5	23	180
					Comparative example 2	14	5	21	170
Comparative example 3	9	5.1	23	160
					Comparative example 4	10	5	26	150
Comparative example 5	15	4.5	27	150
					Comparative example 6	11	4.8	26	140

The data show that the medical adhesive provided by the invention has high bonding strength and large elongation; comparing examples 1, 2, and 7 to 9, it was found that the medical adhesive further improved the adhesive strength and elongation in the range of the combination of α -cyanoacrylate preferred in the present invention; comparing examples 2 and 10 to 11, it was found that the medical adhesive further improved the adhesive strength and elongation in the preferable tackifier range of the present invention; comparing example 2 with comparative examples 3-5, it can be found that the adhesive strength and the elongation of the medical adhesive are improved by compounding the tackifier and the toughening agent, performing synergistic action, and combining the tackifier and the toughening agent with the alpha-cyanoacrylate.

The applicant states that the present invention is illustrated by the above examples of the medical adhesive of the present invention and the preparation method and application thereof, but the present invention is not limited to the above examples, i.e. it does not mean that the present invention must be implemented by the above examples. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.

The preferred embodiments of the present invention have been described in detail, however, the present invention is not limited to the specific details of the above embodiments, and various simple modifications may be made to the technical solution of the present invention within the technical idea of the present invention, and these simple modifications are within the protective scope of the present invention.

It should be noted that the various technical features described in the above embodiments can be combined in any suitable manner without contradiction, and the invention is not described in any way for the possible combinations in order to avoid unnecessary repetition.