CN117085168A - Medical adhesive and preparation method thereof - Google Patents
Medical adhesive and preparation method thereof Download PDFInfo
- Publication number
- CN117085168A CN117085168A CN202210514377.3A CN202210514377A CN117085168A CN 117085168 A CN117085168 A CN 117085168A CN 202210514377 A CN202210514377 A CN 202210514377A CN 117085168 A CN117085168 A CN 117085168A
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- China
- Prior art keywords
- polyethylene glycol
- arm polyethylene
- star
- capped
- medical
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims description 21
- 239000000853 adhesive Substances 0.000 title abstract description 37
- 230000001070 adhesive effect Effects 0.000 title abstract description 37
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 119
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 115
- 239000007788 liquid Substances 0.000 claims abstract description 32
- 239000002270 dispersing agent Substances 0.000 claims abstract description 30
- 125000003396 thiol group Chemical class [H]S* 0.000 claims abstract description 30
- 150000002148 esters Chemical class 0.000 claims abstract description 27
- 230000023597 hemostasis Effects 0.000 claims abstract description 10
- 208000031737 Tissue Adhesions Diseases 0.000 claims abstract description 8
- 230000002265 prevention Effects 0.000 claims abstract description 7
- 230000002980 postoperative effect Effects 0.000 claims abstract description 6
- 238000011049 filling Methods 0.000 claims abstract description 4
- 230000017423 tissue regeneration Effects 0.000 claims abstract description 4
- 239000000843 powder Substances 0.000 claims description 19
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 14
- 239000003292 glue Substances 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 238000000227 grinding Methods 0.000 claims description 9
- NWAGXLBTAPTCPR-UHFFFAOYSA-N 5-(2,5-dioxopyrrolidin-1-yl)oxy-5-oxopentanoic acid Chemical compound OC(=O)CCCC(=O)ON1C(=O)CCC1=O NWAGXLBTAPTCPR-UHFFFAOYSA-N 0.000 claims description 7
- QXZGLTYKKZKGLN-UHFFFAOYSA-N 4-(2,5-dioxopyrrolidin-1-yl)oxy-4-oxobutanoic acid Chemical compound OC(=O)CCC(=O)ON1C(=O)CCC1=O QXZGLTYKKZKGLN-UHFFFAOYSA-N 0.000 claims description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 4
- 239000003349 gelling agent Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- RZRNAYUHWVFMIP-KTKRTIGZSA-N 1-oleoylglycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-KTKRTIGZSA-N 0.000 claims description 3
- RZRNAYUHWVFMIP-HXUWFJFHSA-N glycerol monolinoleate Natural products CCCCCCCCC=CCCCCCCCC(=O)OC[C@H](O)CO RZRNAYUHWVFMIP-HXUWFJFHSA-N 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- 239000011736 potassium bicarbonate Substances 0.000 claims description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 3
- QMMJWQMCMRUYTG-UHFFFAOYSA-N 1,2,4,5-tetrachloro-3-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=C(Cl)C(Cl)=CC(Cl)=C1Cl QMMJWQMCMRUYTG-UHFFFAOYSA-N 0.000 claims description 2
- AFSHUZFNMVJNKX-UHFFFAOYSA-N 1,2-di-(9Z-octadecenoyl)glycerol Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC(CO)OC(=O)CCCCCCCC=CCCCCCCCC AFSHUZFNMVJNKX-UHFFFAOYSA-N 0.000 claims description 2
- AFSHUZFNMVJNKX-LLWMBOQKSA-N 1,2-dioleoyl-sn-glycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](CO)OC(=O)CCCCCCC\C=C/CCCCCCCC AFSHUZFNMVJNKX-LLWMBOQKSA-N 0.000 claims description 2
- SHFFGFYVCNSAPR-UHFFFAOYSA-N 10-(2,5-dioxopyrrolidin-1-yl)oxy-10-oxodecanoic acid Chemical compound OC(=O)CCCCCCCCC(=O)ON1C(=O)CCC1=O SHFFGFYVCNSAPR-UHFFFAOYSA-N 0.000 claims description 2
- JWUFSYXQWPXFIL-UHFFFAOYSA-N 6-(2,5-dioxopyrrolidin-1-yl)oxy-6-oxohexanoic acid Chemical compound OC(=O)CCCCC(=O)ON1C(=O)CCC1=O JWUFSYXQWPXFIL-UHFFFAOYSA-N 0.000 claims description 2
- NVWKYNBWYYJZTK-UHFFFAOYSA-N 8-(2,5-dioxopyrrolidin-1-yl)oxy-8-oxooctanoic acid Chemical compound OC(=O)CCCCCCC(=O)ON1C(=O)CCC1=O NVWKYNBWYYJZTK-UHFFFAOYSA-N 0.000 claims description 2
- BAECOWNUKCLBPZ-HIUWNOOHSA-N Triolein Natural products O([C@H](OCC(=O)CCCCCCC/C=C\CCCCCCCC)COC(=O)CCCCCCC/C=C\CCCCCCCC)C(=O)CCCCCCC/C=C\CCCCCCCC BAECOWNUKCLBPZ-HIUWNOOHSA-N 0.000 claims description 2
- PHYFQTYBJUILEZ-UHFFFAOYSA-N Trioleoylglycerol Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC(OC(=O)CCCCCCCC=CCCCCCCCC)COC(=O)CCCCCCCC=CCCCCCCCC PHYFQTYBJUILEZ-UHFFFAOYSA-N 0.000 claims description 2
- 239000006185 dispersion Substances 0.000 claims description 2
- IIGMITQLXAGZTL-UHFFFAOYSA-N octyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCC IIGMITQLXAGZTL-UHFFFAOYSA-N 0.000 claims description 2
- NMHMNPHRMNGLLB-UHFFFAOYSA-N phloretic acid Chemical compound OC(=O)CCC1=CC=C(O)C=C1 NMHMNPHRMNGLLB-UHFFFAOYSA-N 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- 229920002545 silicone oil Polymers 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 2
- PHYFQTYBJUILEZ-IUPFWZBJSA-N triolein Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CCCCCCCC)COC(=O)CCCCCCC\C=C/CCCCCCCC PHYFQTYBJUILEZ-IUPFWZBJSA-N 0.000 claims description 2
- PHALYIWLKRSLME-UHFFFAOYSA-N decanoic acid;2,3-dihydroxypropyl octanoate Chemical compound CCCCCCCCCC(O)=O.CCCCCCCC(=O)OCC(O)CO PHALYIWLKRSLME-UHFFFAOYSA-N 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 20
- 238000007789 sealing Methods 0.000 abstract description 13
- 239000008280 blood Substances 0.000 abstract description 12
- 210000004369 blood Anatomy 0.000 abstract description 12
- 239000007787 solid Substances 0.000 abstract description 11
- 239000011248 coating agent Substances 0.000 abstract description 3
- 238000000576 coating method Methods 0.000 abstract description 3
- 238000002347 injection Methods 0.000 abstract description 3
- 239000007924 injection Substances 0.000 abstract description 3
- 239000003431 cross linking reagent Substances 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 238000002156 mixing Methods 0.000 description 9
- 239000004480 active ingredient Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 230000015556 catabolic process Effects 0.000 description 7
- 238000000354 decomposition reaction Methods 0.000 description 7
- 238000006731 degradation reaction Methods 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- 206010052428 Wound Diseases 0.000 description 6
- 208000027418 Wounds and injury Diseases 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- CXMXRPHRNRROMY-UHFFFAOYSA-N sebacic acid Chemical compound OC(=O)CCCCCCCCC(O)=O CXMXRPHRNRROMY-UHFFFAOYSA-N 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 5
- 239000012530 fluid Substances 0.000 description 5
- 235000011187 glycerol Nutrition 0.000 description 5
- 239000003106 tissue adhesive Substances 0.000 description 5
- 230000000740 bleeding effect Effects 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 235000015277 pork Nutrition 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- ZJIFDEVVTPEXDL-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) hydrogen carbonate Chemical compound OC(=O)ON1C(=O)CCC1=O ZJIFDEVVTPEXDL-UHFFFAOYSA-N 0.000 description 3
- LFIKKCLFUXSIMK-UHFFFAOYSA-N C(CCCCCCCCC(=O)O)(=O)O.C1(CCC(N1)=O)=O Chemical compound C(CCCCCCCCC(=O)O)(=O)O.C1(CCC(N1)=O)=O LFIKKCLFUXSIMK-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- VANNPISTIUFMLH-UHFFFAOYSA-N glutaric anhydride Chemical compound O=C1CCCC(=O)O1 VANNPISTIUFMLH-UHFFFAOYSA-N 0.000 description 3
- 230000002209 hydrophobic effect Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- RTBFRGCFXZNCOE-UHFFFAOYSA-N 1-methylsulfonylpiperidin-4-one Chemical compound CS(=O)(=O)N1CCC(=O)CC1 RTBFRGCFXZNCOE-UHFFFAOYSA-N 0.000 description 2
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 description 2
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 2
- JFCQEDHGNNZCLN-UHFFFAOYSA-N anhydrous glutaric acid Natural products OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- 238000007654 immersion Methods 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000012064 sodium phosphate buffer Substances 0.000 description 2
- 229940014800 succinic anhydride Drugs 0.000 description 2
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 229940087068 glyceryl caprylate Drugs 0.000 description 1
- 230000002439 hemostatic effect Effects 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- -1 m.w.20000 Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012567 medical material Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- GHBFNMLVSPCDGN-UHFFFAOYSA-N rac-1-monooctanoylglycerol Chemical compound CCCCCCCC(=O)OCC(O)CO GHBFNMLVSPCDGN-UHFFFAOYSA-N 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical class O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 1
- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/046—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
- A61L24/0015—Medicaments; Biocides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/04—Materials for stopping bleeding
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/06—Flowable or injectable implant compositions
Abstract
The invention provides a medical adhesive which is free from the interference of liquid such as blood and has high adhesive forming speed and high strength, and is characterized by comprising the following components: active ester end-capped star multi-arm polyethylene glycol, mercapto end-capped star multi-arm polyethylene glycol, and liquid dispersant. The medical gel provided by the invention has good fluidity when not contacted with water, can be subjected to injection coating and other operations, can be quickly solidified to form solid gel after being contacted with water, and has high gel forming speed. In addition, the medical adhesive can be successfully formed in a large amount of liquid environment, plays roles in corresponding adhesion, sealing, hemostasis and the like, and is suitable for being applied to various scenes, such as wound surface sealing, first-aid hemostasis, intraoperative hemostasis, postoperative tissue sealing and leakage prevention, postoperative tissue adhesion, tissue adhesion prevention, tissue filling, tissue repair and the like, or is used as a skin dressing.
Description
Technical Field
The invention belongs to the field of medical materials, and particularly relates to medical adhesive and a preparation method thereof.
Background
The medical adhesive mainly comprises a tissue adhesive and a tissue sealing agent, and can play roles in adhering tissues, sealing wounds and stopping bleeding in clinical operations, so that the medical adhesive is widely applied. The tissue adhesive is prepared from substances with in-situ polymerization characteristics, can adhere tissues or surfaces of the tissues and the non-tissues, can control bleeding to play a role in stopping bleeding, and can also form a barrier at a wound to block gas or liquid so as to prevent the wound from being influenced by the outside or leakage of wound liquid.
At present, the common medical adhesive is generally prepared by subpackaging an active ingredient and a crosslinking agent, respectively dissolving the active ingredient and the crosslinking agent to prepare solutions when in use, then mixing the active ingredient and the crosslinking agent through a blending injection head, injecting and coating the mixture on a bleeding part, and performing an adhesive sealing function after the mixture is crosslinked and solidified. The medical adhesive has the defect that the medical adhesive is easy to wash away by a large amount of blood or tissue fluid on the surface of a tissue during the gel forming, so that the hemostatic effect is not ideal, and the medical adhesive can only be applied to the situation that a small amount of blood seeps but cannot be applied to a larger amount of blood.
In order to avoid the above-mentioned problem of flushing, there are some medical adhesives to which a dispersing agent is added in the prior art. For example, CN201910049714.4 uses a hydrophobic organic solvent such as castor oil, which is not miscible with water, as a dispersant, and this dispersant can drain blood through a hydrophobic effect, avoid the blood from washing away the active ingredient, thereby increasing the contact of the active ingredient with the tissue surface, and thus achieving the purpose of being able to solidify and adhere to the tissue surface where a large amount of blood is present. However, because the addition amount of the hydrophobic dispersant is large, the active ingredients and the crosslinking agent are easy to dilute, and the water in blood or tissue fluid which is difficult to contact is dissolved and crosslinked, so that the problems of low gel forming speed and poor gel forming strength are caused.
Disclosure of Invention
Based on the above problems, the present invention provides a medical gel which is free from interference of liquid such as blood, has a high gel forming speed and a high strength, and is characterized by comprising: active ester end-capped star multi-arm polyethylene glycol, mercapto end-capped star multi-arm polyethylene glycol, and liquid dispersant.
Furthermore, the medical adhesive provided by the invention can also have the technical characteristics that the active ester in the active ester end-capped star-shaped multi-arm polyethylene glycol is one or more of succinimidyl succinate, succinimidyl glutarate, succinimidyl adipate, succinimidyl suberate, succinimidyl sebacate and N-hydroxysuccinimide ester.
Furthermore, the medical adhesive provided by the invention can also have the technical characteristics that the star-shaped multi-arm polyethylene glycol in the star-shaped multi-arm polyethylene glycol capped by the active ester is one or more of multi-arm polyethylene glycols with the number of arms of 2-8 and the molecular weight of not less than 400.
Furthermore, the medical adhesive provided by the invention can also have the technical characteristics that the star-shaped multi-arm polyethylene glycol in the sulfhydryl end-capped star-shaped multi-arm polyethylene glycol is one or more of multi-arm polyethylene glycols with the number of arms of 2-8 and the molecular weight of not less than 400.
Furthermore, the medical adhesive provided by the invention can also have the technical characteristics that the molar ratio of the mercapto group in the mercapto-terminated star multi-arm polyethylene glycol to the active ester in the active ester-terminated star multi-arm polyethylene glycol is 0.3:1-6:1.
Furthermore, the medical adhesive provided by the invention can also have the technical characteristics that the liquid dispersing agent is one or a combination of a plurality of liquids such as glycerol, glycerol monooleate, glycerol dioleate, glycerol trioleate, butyl stearate, octyl stearate, glyceryl caprylate, propylene glycol, liquid polyethylene glycol, silicone oil and the like.
Further, the medical adhesive provided by the invention can further comprise: the auxiliary gelling agent is one or a combination of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate and sodium hydroxide.
In addition, the invention also provides a preparation method of the medical adhesive, which comprises the following steps: grinding the active ester end-capped star multi-arm polyethylene glycol and the sulfhydryl end-capped star multi-arm polyethylene glycol into powder, and adding the powder and the auxiliary gelling agent into a liquid dispersing agent for uniform dispersion.
In addition, the invention also provides application of the medical adhesive in preparing a medicinal preparation, wherein the medicinal preparation can be used for wound surface sealing, first-aid hemostasis, intraoperative hemostasis, postoperative tissue sealing and leakage prevention, postoperative tissue adhesion, tissue filling, tissue repair or used as a skin dressing.
The actions and effects of the invention
The medical adhesive provided by the invention has good fluidity when not contacted with water because the medical adhesive contains the active ester end-capped star-shaped multi-arm polyethylene glycol, the sulfhydryl end-capped star-shaped multi-arm polyethylene glycol powder and the dispersing agent, and can be injected, coated and other operations through an injector and other devices; when the medical tissue adhesive contacts the wet tissue surface containing tissue fluid or blood, the dispersing agent in the medical tissue adhesive is firstly absorbed and dissolved, and the dissolved dispersing agent is used for removing the tissue fluid or blood on the tissue surface, so that the active ingredient and the auxiliary crosslinking agent can fully contact the tissue surface. Subsequently, molecules with tissue adhesion such as star-shaped multi-arm polyethylene glycol succinimide esters in the active ingredient are gradually dissolved by water, and a strong tissue adhesion force is formed by chemical bonds with amino groups and sulfhydryl groups on the surface of the tissue. At the same time, the medical tissue adhesive further absorbs tissue fluid and water in blood, the absorbed water is gradually mixed with the dispersing agent, and the active ester end-capped star-shaped multi-arm polyethylene glycol, the sulfhydryl end-capped star-shaped multi-arm polyethylene glycol and the auxiliary crosslinking agent are gradually infiltrated, so that the active ester end-capped star-shaped multi-arm polyethylene glycol, the sulfhydryl end-capped star-shaped multi-arm polyethylene glycol and the auxiliary crosslinking agent are fully dissolved, thereby triggering the reaction between the active ester group and the sulfhydryl to form a chemical bond, and further rapidly curing to form solid gel. Due to the characteristics, the medical adhesive can be adhered and solidified into adhesive rapidly in an environment with a large amount of liquid, and plays roles of corresponding adhesion, sealing, tissue and body fluid exudation and the like, so that the medical adhesive is suitable for being applied to various scenes, such as wound surface sealing, first-aid hemostasis, hemostasis in operation, tissue sealing and leakage prevention after operation, tissue adhesion prevention, tissue filling, tissue repair and the like, or used as a skin dressing.
Drawings
FIG. 1 is a photograph of a medical gel prepared in example 1 of the present invention.
Fig. 2 is a photograph of a cured medical gel prepared in example 1 of the present invention.
Detailed Description
The medical gel of the present invention and the preparation method thereof are illustrated in the following examples. In the following examples, the underwater adhesive strength of the gel was determined by measuring the lap shear strength, which was measured as follows: pork tissue was cut into pieces of 2cm x 2cm and placed in 0.2mol/L sodium phosphate buffer for adequate wetting. One of the pieces was taken, placed in a Petri dish containing 0.2mol/L sodium phosphate buffer, a syringe containing the present medical gel was inserted into a dish, and 0.2mL of the medical gel was extruded onto pork tissue, immediately pressed against the above medical gel with another piece of wet pork tissue, pressed with a 200g weight for 3 minutes, and the two pieces of pork adhered together were taken out of the water, and the lap shear strength of the present medical gel was determined according to ASTM F2255 test specification.
In addition, in each example, all reagent materials are commercially available in general, and the methods of operation for the specific process are not described with reference to the conventional methods of operation of the prior art.
Example 1 ]
The preparation method of the medical adhesive of the embodiment comprises the following steps: grinding 1g of active ester end-capped star-shaped multi-arm polyethylene glycol and 1g of sulfhydryl end-capped star-shaped multi-arm polyethylene glycol into powder, and then mixing the obtained two powders with 5mL of liquid dispersing agent, stirring and dispersing uniformly to obtain the product.
Specifically, the active ester end-capped star-shaped multi-arm polyethylene glycol adopted in the embodiment is four-arm polyethylene glycol succinimidyl glutarate (M.W.20000), namely, star-shaped multi-arm polyethylene glycol with 4 arms and end capped by succinimidyl glutarate, and the preparation process is as follows: the m.w.20000 quadrifilar polyethylene glycol, glutaric anhydride and catalyst were dissolved in dichloromethane and stirred overnight at room temperature. And then washing and drying to obtain the M.W.20000 glutaric acid end-capped four-arm polyethylene glycol. Then dissolving the glutaric acid end capped four-arm polyethylene glycol, N-hydroxysuccinimide, condensing agent and catalyst in methylene dichloride, and stirring overnight at normal temperature. Washing, drying, purifying and vacuum drying to obtain M.W.20000 quadrifilar polyethylene glycol succinimidyl glutarate.
The thiol-terminated star-shaped multi-arm polyethylene glycol of the embodiment is four-arm polyethylene glycol thiol (M.W.10000), and the preparation process is as follows: the four-arm polyethylene glycol of M.W.10000, thioglycollic acid, condensing agent and catalyst are dissolved in methylene dichloride, and the reaction is stirred at room temperature for overnight. Washing, drying, purifying and vacuum drying to obtain M.W.10000 four-arm polyethylene glycol mercaptan solid.
In addition, the liquid dispersant of this example is glycerin.
FIG. 1 is a photograph of a medical gel prepared in example 1 of the present invention.
As shown in fig. 1, the medical gel of this example was opaque after preparation, and had good fluidity, and it could be injected into a syringe or the like for injection coating.
Fig. 2 is a photograph of a cured medical gel prepared in example 1 of the present invention.
As shown in fig. 2, the medical gel of this example was injected into a centrifuge tube using a syringe and added with a certain amount of water, and solidified to form a transparent bar-shaped solid gel after about 60 seconds, the gel shape of which was complete, indicating that the immersion in water did not affect the gel shape. The gel is placed in 0.01M PBS buffer solution with pH of 7.4, and after the gel is placed in an environment of 37 ℃ for 14 days, no obvious degradation or decomposition phenomenon is observed, which indicates that the gel is not easy to degrade in an environment similar to the physiological condition of a human body, and is suitable for long-term adhesion or long-term sealing of human tissues.
Example 2 ]
The preparation method of the medical adhesive of the embodiment comprises the following steps: grinding 1g of active ester end-capped star-shaped multi-arm polyethylene glycol and 600mg of sulfhydryl end-capped star-shaped multi-arm polyethylene glycol into powder, and then mixing the obtained two powders with 4mL of liquid dispersing agent, stirring and dispersing uniformly to obtain the product.
Specifically, the active ester-terminated star-shaped multi-arm polyethylene glycol used in this example was linear polyethylene glycol succinimidyl succinate (m.w.10000), i.e., polyethylene glycol terminated with succinimidyl succinate and having a terminal group number of 2, which was prepared in a similar manner to example 1, except that linear polyethylene glycol of m.w.10000 was used in place of the four-arm polyethylene glycol of m.w.20000, and succinic anhydride was used in place of glutaric anhydride.
The thiol-terminated star-shaped multi-arm polyethylene glycol of this example was eight-arm polyethylene glycol thiol (m.w.10000), and the preparation process was similar to example 1, except that eight-arm polyethylene glycol of m.w.10000 was used instead of four-arm polyethylene glycol of m.w.10000.
In addition, the liquid dispersant of this example is glycerin.
Injecting the medical gel of the embodiment into a centrifuge tube by adopting an injector, adding water, and curing after about 53 seconds to form transparent strip-shaped solid gel; the gel was placed in 0.01M PBS buffer at pH 7.4 and after 7 days at 37℃no significant degradation or decomposition was observed.
In addition, the gel of this example was found to have an underwater adhesion strength of 132kPa.
Example 3 ]
The preparation method of the medical adhesive of the embodiment comprises the following steps: grinding 1g of active ester end-capped star-shaped multi-arm polyethylene glycol and 300mg of sulfhydryl end-capped star-shaped multi-arm polyethylene glycol into powder, and then mixing the obtained two powders with 14mg of auxiliary cross-linking agent and 6mL of liquid dispersing agent, and uniformly stirring and dispersing to obtain the modified polyethylene glycol.
Specifically, the active ester end capped star multi-arm polyethylene glycol adopted in the present example is eight-arm polyethylene glycol succinimide sebacate (m.w. 20000), that is, star multi-arm polyethylene glycol end capped by succinimide sebacate and having 8 arms, and the preparation process thereof is as follows: eight-arm polyethylene glycol, sebacic acid, m.w.20000, and catalyst were heated and stirred in xylene overnight. And washing and drying to obtain the eight-arm polyethylene glycol capped by sebacic acid of M.W.20000. Then, the eight-arm polyethylene glycol capped by sebacic acid of M.W.20000, N-hydroxysuccinimide, condensing agent and catalyst are dissolved in methylene dichloride and stirred at normal temperature overnight. Washing, drying, purifying and vacuum drying to obtain M.W.20000 eight-arm polyethylene glycol succinimide sebacate
The thiol-terminated star-shaped multi-arm polyethylene glycol of this example was a four-arm polyethylene glycol thiol (m.w. 20000), which was prepared in a similar manner to example 1, except that m.w.10000 of four-arm polyethylene glycol was replaced with m.w.20000 of four-arm polyethylene glycol.
In addition, the auxiliary crosslinking agent of this example was sodium bicarbonate, and the liquid dispersant was glycerol monooleate.
The medical gel of this example was injected into water using a syringe and cured to form a transparent bar-like solid gel after about 6.2 seconds. The gel was placed in 0.01M PBS buffer at a pH of 7.4 and after 5 days at 37℃no significant degradation or decomposition was observed.
In addition, the gel of this example was found to have an underwater adhesion strength of 101kPa.
Example 4 ]
The preparation method of the medical adhesive of the embodiment comprises the following steps: grinding 1g of active ester end-capped star-shaped multi-arm polyethylene glycol and 1g of mercapto end-capped star-shaped multi-arm polyethylene glycol into powder, and then mixing the obtained two powders with 43mg of auxiliary cross-linking agent and 7mL of liquid dispersing agent, and uniformly stirring and dispersing to obtain the modified polyethylene glycol.
Specifically, the active ester end capped star multi-arm polyethylene glycol adopted in the present example is hexa-arm polyethylene glycol succinimidyl carbonate (m.w. 15000), that is, star multi-arm polyethylene glycol end capped by succinimidyl carbonate and having 6 arms, the preparation process is as follows: six-arm polyethylene glycol, N, N' -disuccinimide carbonate and an acid binding agent of M.W.15000 were dissolved in methylene chloride and stirred overnight at room temperature. And then washing, drying, purifying and vacuum drying to obtain the M.W.15000 six-arm polyethylene glycol succinimidyl carbonate.
The thiol-terminated star-shaped multi-arm polyethylene glycol of this example was linear polyethylene glycol thiol (m.w.5000), which was prepared similarly to example 1, except that m.w.5000 linear polyethylene glycol was used instead of m.w.10000 four-arm polyethylene glycol.
In addition, the auxiliary crosslinking agent of this example was potassium bicarbonate, and the liquid dispersant was polyethylene glycol dioleate (m.w.600).
The medical gel of this example was injected into water using a syringe and cured to form a transparent bar-like solid gel after about 2.9 seconds. The gel was placed in 0.01M PBS buffer at a pH of 7.4 and after 20 days at 37℃no significant degradation or decomposition was observed.
In addition, the gel of this example was found to have an underwater adhesion strength of 99.3kPa.
Example 5 ]
The preparation method of the medical adhesive of the embodiment comprises the following steps: grinding 1g of active ester end-capped star-shaped multi-arm polyethylene glycol and 400mg of mercapto end-capped star-shaped multi-arm polyethylene glycol into powder, and then mixing the obtained two powders with 4mL of liquid dispersing agent, stirring and dispersing uniformly to obtain the modified polyethylene glycol.
Specifically, the active ester-terminated star-shaped multi-arm polyethylene glycol used in this example was hexa-arm polyethylene glycol succinimidyl succinate (m.w.15000), i.e., a star-shaped multi-arm polyethylene glycol terminated with succinimidyl succinate and having 6 arms, which was prepared in a similar manner to example 1, except that the hexa-arm polyethylene glycol of m.w.15000 was substituted for the tetra-arm polyethylene glycol of m.w.20000 and succinic anhydride was substituted for glutaric anhydride.
The thiol-terminated star-shaped multi-arm polyethylene glycol of this example is the same as that of example 3, namely, a four-arm polyethylene glycol thiol (m.w.20000). In addition, the liquid dispersant of this example was polyethylene glycol dioleate (m.w. 1500).
The medical gel of this example was injected into water using a syringe and cured to form a transparent bar-like solid gel after about 10.7 seconds. The gel was placed in 0.01M PBS buffer at a pH of 7.4 and after 12 days at 37℃no significant degradation or decomposition was observed.
In addition, the gel of this example was determined to have an underwater adhesion strength of 105kPa.
Example 6 ]
The preparation method of the medical adhesive of the embodiment comprises the following steps: grinding 1g of active ester end-capped star-shaped multi-arm polyethylene glycol and 700mg of sulfhydryl end-capped star-shaped multi-arm polyethylene glycol into powder, and then mixing the obtained two powders with 10mg of auxiliary cross-linking agent and 5mL of liquid dispersing agent, and uniformly stirring and dispersing to obtain the modified polyethylene glycol.
Specifically, the active ester-terminated star-shaped multi-arm polyethylene glycol used in this example was the same as in example 1, i.e., a four-arm polyethylene glycol succinimidyl glutarate (m.w.20000). The thiol-terminated star-shaped multi-arm polyethylene glycol was linear polyethylene glycol thiol (m.w.2000) and was prepared similarly to example 1, except that m.w.2000 linear polyethylene glycol was used instead of m.w.10000 four-arm polyethylene glycol. In addition, the auxiliary crosslinking agent in this example is sodium hydroxide, and the liquid dispersant is glycerin.
The medical gel of this example was injected into water using a syringe and cured to form a transparent bar-like solid gel after about 3.7 seconds. The gel was placed in 0.01M PBS buffer at a pH of 7.4 and after 10 days at 37℃no significant degradation or decomposition was observed.
In addition, the gel of this example was determined to have an underwater adhesion strength of 109kPa.
Example 7 ]
The preparation method of the medical adhesive of the embodiment comprises the following steps: grinding 1g of active ester end-capped star-shaped multi-arm polyethylene glycol and 300mg of sulfhydryl end-capped star-shaped multi-arm polyethylene glycol into powder, and then mixing the obtained two powders with 23mg of auxiliary cross-linking agent and 4mL of liquid dispersing agent, and uniformly stirring and dispersing to obtain the modified polyethylene glycol.
Specifically, the active ester-terminated star-shaped multi-arm polyethylene glycol employed in this example was the same as in example 1, i.e., a tetra-arm polyethylene glycol succinimidyl glutarate (m.w.20000); the thiol-terminated star-shaped multi-arm polyethylene glycol was a four-arm polyethylene glycol thiol (m.w.5000), which was prepared similarly to example 1, except that m.w.5000 four-arm polyethylene glycol was used instead of m.w.10000 four-arm polyethylene glycol. In addition, the auxiliary crosslinking agent of this example was sodium bicarbonate, and the liquid dispersant was glycerin.
The medical gel of this example was injected into water using a syringe and cured to form a transparent bar-like solid gel after about 4.4 seconds. The gel was placed in 0.01M PBS buffer at a pH of 7.4 and after 8 days at 37℃no significant degradation or decomposition was observed.
In addition, the gel of this example was found to have an underwater adhesion strength of 133kPa.
Effects and effects of the examples
As described above, the medical glue of each example contains the active ester-terminated star-shaped multi-arm polyethylene glycol, the mercapto-terminated star-shaped multi-arm polyethylene glycol, and the dispersing agent, and thus has good fluidity when not contacted with water, and can be injected, coated, and the like by means of a syringe and the like; after contacting water, the active ester groups and the sulfhydryl groups can react to form chemical bonds, so that the medical gel can be quickly solidified to form solid gel. In addition, the glue forming shape of the medical glue of each embodiment is not easily affected by water immersion, which indicates that the medical glue can be successfully formed even in a large amount of liquid environment, and the medical glue has the corresponding functions of adhesion, sealing, hemostasis and the like.
Further, the auxiliary crosslinking agent in the invention is used for adjusting the pH value of the reaction environment of the active substances in the medical adhesive, and the optimal reaction pH value is different under different ratios of active ester to sulfhydryl. Examples 3, 4, 6 and 7, in which the amount of auxiliary crosslinking agent is such that the reactivity is higher and the reaction product is more stable, are all preferred formulations for the active material ratios. The increase or decrease of the amount of the auxiliary crosslinking agent is not more than 20% based on the given amount, and the glue forming speed and the adhesive strength are not significantly affected.
Claims (9)
1. A medical gel, comprising:
active ester end-capped star multi-arm polyethylene glycol, mercapto end-capped star multi-arm polyethylene glycol, and liquid dispersant.
2. The medical glue of claim 1, wherein:
wherein the active ester in the active ester end-capped star-shaped multi-arm polyethylene glycol is one or more of succinimidyl succinate, succinimidyl glutarate, succinimidyl adipate, succinimidyl suberate, succinimidyl sebacate and N-hydroxysuccinimide ester.
3. The medical glue of claim 1, wherein:
wherein the star-shaped multi-arm polyethylene glycol in the star-shaped multi-arm polyethylene glycol capped by the active ester is one or more of multi-arm polyethylene glycols with the number of arms of 2-8 and the molecular weight of not less than 400.
4. The medical glue of claim 1, wherein:
wherein the star-shaped multi-arm polyethylene glycol in the sulfhydryl end-capped star-shaped multi-arm polyethylene glycol is one or more of multi-arm polyethylene glycols with the number of arms of 2-8 and the molecular weight of not less than 400.
5. The medical glue of claim 1, wherein:
wherein the molar ratio of the mercapto group in the mercapto-terminated star multi-arm polyethylene glycol to the active ester in the active ester-terminated star multi-arm polyethylene glycol is 0.3:1-6:1.
6. The medical glue of claim 1, wherein:
wherein the liquid dispersing agent is one or more of glycerol, glycerol monooleate, glycerol dioleate, glycerol trioleate, butyl stearate, octyl stearate, glyceryl caprylate decanoate, propylene glycol, liquid polyethylene glycol, silicone oil and other liquids.
7. The medical glue of claim 1, further comprising:
the auxiliary gelling agent is one or a combination of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate and sodium hydroxide.
8. The method for preparing the medical gel according to claim 7, comprising:
grinding the active ester end-capped multi-arm polyethylene glycol and the sulfhydryl end-capped star-shaped multi-arm polyethylene glycol into powder, and adding the powder and the auxiliary gelling agent into the liquid dispersing agent together for uniform dispersion.
9. Use of a medical gel according to any one of claims 1-7 for the preparation of a pharmaceutical formulation for wound closure, emergency hemostasis, intraoperative hemostasis, postoperative tissue closure and leakage prevention, postoperative tissue adhesion, tissue adhesion prevention, tissue filling, tissue repair, or as a skin dressing.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202210514377.3A CN117085168A (en) | 2022-05-12 | 2022-05-12 | Medical adhesive and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210514377.3A CN117085168A (en) | 2022-05-12 | 2022-05-12 | Medical adhesive and preparation method thereof |
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| CN117085168A true CN117085168A (en) | 2023-11-21 |
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| CN202210514377.3A Pending CN117085168A (en) | 2022-05-12 | 2022-05-12 | Medical adhesive and preparation method thereof |
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| CN (1) | CN117085168A (en) |
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- 2022-05-12 CN CN202210514377.3A patent/CN117085168A/en active Pending
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