CN109096910A - A kind of medical composite coating agent, preparation method and application - Google Patents
A kind of medical composite coating agent, preparation method and application Download PDFInfo
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- C08J7/00—Chemical treatment or coating of shaped articles made of macromolecular substances
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- C08J7/0427—Coating with only one layer of a composition containing a polymer binder
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- C09D105/00—Coating compositions based on polysaccharides or on their derivatives, not provided for in groups C09D101/00 or C09D103/00
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- C09D105/00—Coating compositions based on polysaccharides or on their derivatives, not provided for in groups C09D101/00 or C09D103/00
- C09D105/10—Heparin; Derivatives thereof
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- C09D7/00—Features of coating compositions, not provided for in group C09D5/00; Processes for incorporating ingredients in coating compositions
- C09D7/40—Additives
- C09D7/60—Additives non-macromolecular
- C09D7/63—Additives non-macromolecular organic
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- C08J2323/00—Characterised by the use of homopolymers or copolymers of unsaturated aliphatic hydrocarbons having only one carbon-to-carbon double bond; Derivatives of such polymers
- C08J2323/02—Characterised by the use of homopolymers or copolymers of unsaturated aliphatic hydrocarbons having only one carbon-to-carbon double bond; Derivatives of such polymers not modified by chemical after treatment
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- C08J2405/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2401/00 or C08J2403/00
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- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
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- C08J2405/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2401/00 or C08J2403/00
- C08J2405/10—Heparin; Derivatives thereof
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- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
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Abstract
The present invention relates to the anticoagulations of medical instrument and antimicrobial coating technical field, more particularly to a kind of medical composite coating agent, preparation method and application, medical composite coating agent provided by the invention is by including that the raw material of biology base ionomer and biology base ionic surface active agent is prepared；The biology base ionic surface active agent is selected from one of triacetyl cholic acid choline chloride ester, three butyryl cholic acid choline chloride esters, stearic acid choline chloride ester, N- deoxycholic acid -2-aminoethanesulfonic acid sodium, N- stearyl-Taurine sodium and the mono- cholesterol succinic acid acyl group -2-aminoethanesulfonic acid sodium of N-.Specific biology base ionic surface active agent and biology base ionomer act synergistically, and the safety for the medical composite coating being prepared is higher, and medical coating toxic side effect is small, are easy katabolism.
Description
Technical field
The present invention relates to the anticoagulation of medical instrument and antimicrobial coating technical fields more particularly to a kind of medical compound to apply
Layer agent, preparation method and application.
Background technique
Interposing catheter is in use often with the blood coagulation of hospital-acquired infection and intervention position.According to report
Road, the ratio infected in the catheter of Preserving time is up to 50%, Catheter-related bloodstream infections incidence
Increased with the speed in 0.44%/day, this dramatically increases the survival risk of patient and medical burdens.In most cases, germ
Enter human body via the catheter outer surface of wound location, then adhere to and breed in catheter surface, causes nosocomial infection.In addition, leading
Pipe inevitably leads to the generation of blood coagulation as guest materials when with contacting blood, and the blood coagulation of catheter surface further promotees
Into the adherency and breeding of germ.
Ontology blending method, surface grafting method, infusion process and surface physics cladding process are four kinds common anti-infective and anticoagulant
The preparation means of blood interposing catheter, wherein surface physics cladding process has the characteristics of simple process and is widely used.It is a kind of normal
The mode seen is to utilize the electricity formed between biology base ionomer and corresponding yin-yang biology base ionic surface active agent
Lotus compound prepares medical coating, and the hydrophobicity by adjusting yin, yang biology base ionic surface active agent can make this charge
Compound is dissolved in organic solvent and not soluble in water, relatively stable so as to be prepared by the easy means of " dipping-drying "
Anti-infective and anticoagulant coatings, such as being led using heparin/benzalkonium chloride charge recombination object coating central vein for Edwards company
Pipe surface, to achieve the purpose that anticoagulation and antibacterial are difunctional.But quaternary surfactant used in this method
Toxic side effect it is big, it is difficult to katabolism, in large dosage in use, for example as central venous catheter and electricity through peripheral vein
When antibacterial/anticoagulant coatings of the large specific surface areas medical catheter such as pole ablation catheter, this type coating is easy to cause musculature
Damage, leucocyte membranolysis and hepar damnification (such as United States Patent (USP) of Publication No. 4510135).Using cation
Polymer and biological vaginal base ionic surface active agent can also be formed similar to heparin/quaternary ammonium salt charge recombination object coating.Such as
Biomacromolecules, 2017,18 (4), 1387, which report the polylysine with antibacterial properties/docusate sodium charge, answers
Object coating is closed, similarly, the biological vaginal base ionic surface active agent docusate sodium that this coating uses also has certain poison secondary
Effect should not have hepatotoxic drug to use simultaneously with other.And docusate sodium is used usually as oral drugs, is passed through
The mode of catheter coatings is equivalent to intravenously administrable into intravascular, and application security needs more comprehensive assessment.
Summary of the invention
In view of this, the technical problem to be solved in the present invention is that providing a kind of medical composite coating agent, its preparation side
Method and application, for solving the problems, such as existing medical coating toxic side effect greatly and being difficult to katabolism, safety is higher.
The present invention provides a kind of medical composite coating agent, by including biology base ionomer and biology base ion table
The raw material of face activating agent is prepared；
The biology base ionic surface active agent is selected from triacetyl cholic acid choline chloride ester, three butyryl gallbladders
Sour choline chloride ester, stearic acid choline chloride ester, N- deoxycholic acid -2- amino second
One of sodium sulfonate, N- stearyl-Taurine sodium and the mono- cholesterol succinic acid acyl group -2-aminoethanesulfonic acid sodium of N-.
Preferably, the biology base ionomer includes polylysine hydrochloride, poly- L-arginine hydrochloride, heparin
One or more of sodium, chitosan, Sodium Hyaluronate, dextran sulfate and chondroitin sulfate.
Preferably, the polylysine hydrochloride be selected from poly-l-lysine hydrochloride, poly ε-lysine hydrochloride, its
One or more of its amino acid and the hydrochloride of copolymer of lysine.
Preferably, in the medical composite coating agent, the biology base ionic surface active agent of charge recombination does not occur
Content is 0.1~5wt%.
The present invention also provides a kind of preparation methods of medical composite coating agent described above, comprising the following steps:
The aqueous solution of biology base ionic surface active agent is mixed with the aqueous solution of biology base ionomer, 10~80
At DEG C reaction 0.5~for 24 hours, obtain medical composite coating agent.
Preferably, the biology base ionic surface active agent is prepared in accordance with the following methods:
Material a is reacted with material b, obtains biology base ionic surface active agent；
The material a is quaternary ammonium salt or sulfonate；
The material b is the derivative of hydrophobic bionic acid.
Preferably, the material a is 2-aminoethanesulfonic acid sodium or choline chloride；
One in derivative, the derivative of cholic acid and the derivative of succinic acid sterol ester of the material b selected from fatty acid
Kind is several.
Preferably, the material b is selected from stearyl chloride, monocholesterylsuccinate acyl chlorides, triacetyl cholic acid acyl chlorides and three
One of butyryl cholic acid acyl chlorides.
Preferably, the concentration of the aqueous solution of the biology base ionic surface active agent is 0.1~10wt%；The biology base
The concentration of the aqueous solution of ionomer is 0.1~10wt%；
The charge ratio of the biology base ionic surface active agent and biology base ionomer is 0.9~3:1.
The present invention also provides a kind of application methods of medical composite coating agent, comprising the following steps:
A medical composite coating agent is mixed with organic solvent), obtains the organic solution of medical composite coating agent；
The medical composite coating agent includes medical composite coating agent described above or preparation side described above
The medical composite coating agent of method preparation；
B the organic solution of the medical composite coating agent) is passed through into dipping, the dry table for being coated on object to be coated
Face.
The present invention provides a kind of medical composite coating agent, by including biology base ionomer and biology base ion table
The raw material of face activating agent is prepared；The biology base ionic surface active agent is selected from triacetyl cholic acid 2- ethoxy trimethyl chlorine
Change ammonium ester, three butyryl cholic acid choline chloride esters, stearic acid choline chloride ester, N- deoxidation gallbladder
Sour acyl group -2-aminoethanesulfonic acid sodium, N- stearyl-Taurine sodium and the mono- cholesterol succinic acid acyl group -2- amino second of N-
One of sodium sulfonate.Specific biology base ionic surface active agent and biology base ionomer act synergistically, and are prepared
Medical composite coating safety it is higher, medical coating toxic side effect is small, be easy katabolism.
The present invention also provides a kind of preparation methods of medical composite coating agent, comprising the following steps: by biology base from
The aqueous solution of sub- surfactant is mixed with the aqueous solution of biology base ionomer, at 10~80 DEG C react 0.5~for 24 hours,
Obtain medical composite coating agent.With benzalkonium chloride in the prior art, three (octadecyl) ammonium chlorides and docusate sodium two
The property of class surfactant is dramatically different, and biology base ionic surface active agent provided by the invention occurs slowly to hydrolyze in vivo
And it or can be decomposed by lipase and protein digestibility enzyme with the bionic acid and 2- ethoxy for determining biological safety
Trimethyl ammonium chloride and/or 2-aminoethanesulfonic acid sodium.By the aqueous solution and biology base of above-mentioned biology base ionic surface active agent
The safety of the reactant aqueous solution of ionomer, obtained medical composite coating is higher, and medical coating toxic side effect is small, holds
Degradable metabolism.
Detailed description of the invention
Fig. 1 is the pattern for the medical catheter coating that embodiment 12 is prepared；
Fig. 2 is the pattern for the medical catheter coating that embodiment 1 is prepared according to the method for embodiment 10.
Specific embodiment
Below in conjunction with the embodiment of the present invention, technical solution of the present invention is clearly and completely described, it is clear that institute
The embodiment of description is only a part of the embodiment of the present invention, instead of all the embodiments.Based on the embodiments of the present invention,
Every other embodiment obtained by those of ordinary skill in the art without making creative efforts, belongs to this hair
The range of bright protection.
The present invention provides a kind of medical composite coating agent, by including biology base ionomer and biology base ion table
The raw material of face activating agent is prepared；
The biology base ionic surface active agent is selected from triacetyl cholic acid choline chloride ester (TACC), three
Butyryl cholic acid choline chloride ester (TBCC), stearic acid choline chloride ester (SC), N- deoxidation
Cholic acid -2-aminoethanesulfonic acid sodium (TCA), N- stearyl-Taurine sodium (STA) and the mono- cholesterol succinic acid acyl of N-
One of base -2-aminoethanesulfonic acid sodium (SCTA).
Specific biology base ionic surface active agent and biology base ionomer act synergistically, and what is be prepared is medical multiple
The safety for closing object coating is higher, and medical coating toxic side effect is small, is easy katabolism.
In the present invention, the biology base ionomer preferably includes polylysine hydrochloride, poly- L-arginine hydrochloric acid
One or more of salt, heparin sodium, chitosan, Sodium Hyaluronate, dextran sulfate and chondroitin sulfate.It is described poly-
Lysine hydrochloride is preferably poly-l-lysine hydrochloride, poly ε-lysine hydrochloride, other amino acid and lysine
One or more of hydrochloride of copolymer；More preferably poly-l-lysine hydrochloride, poly ε-lysine hydrochloride, rely
One or more of hydrochloride, lysine and hydrochloride of arginic copolymer of the copolymer of propylhomoserin and alanine.Institute
Biology base ionomer is stated with distinctive bioactivity, the physical strength and planarization of coating can also be increased.
Since during synthesis of medical composite coating agent, biology base ionomer and biology base ion surface are living
Property agent be according to positive and negative charge ratio 1:1 formed complex precipitate, i.e., medical composite coating agent, this charge is than invariable.
More flat and smooth medical coating in order to obtain, the present invention add additional life on the basis of meeting positive and negative charge ratio 1:1
The content of the biology base ionic surface active agent of charge recombination does not occur for the content of object base ionic surface active agent.The doctor
Content with the biology base ionic surface active agent that charge recombination in composite coating agent, does not occur is preferably 0.1~5wt%；
More preferably 1~3wt%.In certain embodiments of the present invention, in the medical composite coating agent, charge recombination does not occur
Biology base ionic surface active agent content be 3wt%.
The present invention also provides a kind of preparation methods of medical composite coating agent described above, comprising the following steps:
The aqueous solution of biology base ionic surface active agent is mixed with the aqueous solution of biology base ionomer, 10~80
At DEG C reaction 0.5~for 24 hours, obtain medical composite coating agent.
The biology base ionic surface active agent is selected from triacetyl cholic acid choline chloride ester, three butyryl gallbladders
Sour choline chloride ester, stearic acid choline chloride ester, N- deoxycholic acid -2- amino second
One of sodium sulfonate, N- stearyl-Taurine sodium and the mono- cholesterol succinic acid acyl group -2-aminoethanesulfonic acid sodium of N-.
The biology base ionic surface active agent can be made by oneself, can also be using general commercially available.In certain realities of the invention
It applies in example, the biology base ionic surface active agent is commercially available N- deoxycholic acid -2-aminoethanesulfonic acid sodium (TCA).?
In certain embodiments of the present invention, the biology base ionic surface active agent is prepared in accordance with the following methods:
Material a is reacted with material b, obtains biology base ionic surface active agent；
The material a is quaternary ammonium salt or sulfonate；
The material b is the derivative of hydrophobic bionic acid.
The material a is quaternary ammonium salt or sulfonate.In certain embodiments of the present invention, the material a is 2- amino second
Sulfonic acid or choline chloride.
The material b is the derivative of hydrophobic bionic acid.The derivative of the hydrophobic bionic acid preferably includes
One or more of the derivative of fatty acid, the derivative of cholic acid and derivative of succinic acid sterol ester.The fatty acid
Derivative is preferably fat acyl chloride one or more.The fatty acid used in the fat acyl chloride is preferably erucic acid, stearic acid, oil
The one or more of acid, linolenic acid, palmitinic acid, lauric acid and pungent capric acid.In certain embodiments of the present invention, the fatty acid
Derivative be stearyl chloride.In certain embodiments of the present invention, the derivative of the cholic acid is triacetyl cholic acid acyl chlorides, three
One or more of butyryl cholic acid acyl chlorides and three hexanoyl cholic acid acyl chlorides.The succinic acid sterol ester is preferably succinic acid cholesterol
One or more of ester, succinic acid stigmasterol ester and succinic acid ergosterol ester.In certain embodiments of the present invention, described
The derivative of succinic acid sterol ester is mono succinate cholesteryl ester acyl chlorides (i.e. monocholesterylsuccinate acyl chlorides), mono succinate beans
Sterol ester acyl chlorides and mono succinate ergosterol ester acyl chlorides.
Bionic acid in the derivative of above-mentioned hydrophobic bionic acid can be found in human body, and have unique physiology living
Sexual function can provide energy if fatty acid is the main component of cell membrane for human body；Cholic acid be human bile main component it
One, play a significant role to absorption of human body fat；Cholesterol and phytosterol are that institute of human tissue cell is indispensable important
Substance, therefore they have biological safety known and that verified evidence.
In the present invention, the derivative of the hydrophobic bionic acid can be made by oneself, can also be using general commercially available.
In certain embodiments of the present invention, the derivative of the hydrophobic bionic acid is commercially available stearyl chloride.
In certain embodiments of the present invention, the derivative of the hydrophobic bionic acid is by corresponding hydrophobic biology
Acid is made.Such as: triacetyl cholic acid acyl chlorides is made of triacetyl cholic acid；Three butyryl cholic acid acyl chlorides are made of three butyryl cholic acid；Three
Acetyl cholic acid acyl chlorides is made of triacetyl cholic acid.The present invention is made hydrophobic bionic acid to the hydrophobic bionic acid and spreads out
The preparation method of biology has no special limitation, and hydrophobicity is made using hydrophobic bionic acid well known to those skilled in the art
Bionic acid derivative preparation method.The hydrophobic bionic acid can be made by oneself, can also be using general commercially available.
The present invention has no special limitation to the preparation method of the hydrophobic bionic acid, is dredged using well known to those skilled in the art
The preparation method of aqueous bionic acid.
Preferably, the preparation method of the hydrophobic bionic acid specifically:
Cholic acid solution and fatty acid anhydride are subjected to back flow reaction in organic solvent, are diluted with water, after cooling, is obtained by filtration
Fatty acyl cholic acid.
The solvent of the cholic acid solution is preferably tetrahydrofuran.The concentration of the cholic acid solution is preferably 5wt%.The acid
Acid anhydride is preferably acetic anhydride or butyric anhydride.The molar ratio of the cholic acid and acid anhydrides is preferably 1:5.
The temperature of the back flow reaction is preferably 60~70 DEG C.The time of the back flow reaction is preferably 12h.The reflux
After reaction, it is also preferable to include excessive water is added.
Preferably, the preparation method of the derivative of the hydrophobic bionic acid specifically:
The solution for preparing hydrophobic bionic acid, after cooling in ice-water bath, is added thionyl chloride, react 1 at room temperature~
2h, then be warming up to boiling temperature and react 5~12h, obtain the derivative of hydrophobic bionic acid.
Solvent in the solution of the hydrophobic bionic acid is preferably anhydrous tetrahydro furan.The hydrophobic bionic acid
The mass concentration of solution be preferably 4~5wt%.The molar ratio of the hydrophobic bionic acid and thionyl chloride is preferably 1:1
~2.
The time of the addition is preferably 20~120min.
In certain embodiments of the present invention, the boiling temperature is 50 DEG C.
After the reaction, it is also preferable to include: vacuum distillation.The vacuum distillation is for removing solvent and by-product.This hair
Bright equipment and parameter to the vacuum distillation has no special limitation, is needed according to experiment using known to those skilled in the art
Vacuum distillation equipment and parameter.
In certain embodiments of the present invention, the present invention is made using a kind of derivative of commercially available hydrophobic bionic acid
The derivative of required hydrophobic bionic acid.Such as: the monocholesterylsuccinate acyl chlorides is by commercially available succinic acid list gallbladder
Sterol ester is made.Spreading out for required hydrophobic bionic acid is made to a kind of derivative of the hydrophobic bionic acid in the present invention
The preparation method of biology has no special limitation, using a kind of derivative of hydrophobic bionic acid well known to those skilled in the art
The preparation method of the derivative of required hydrophobic bionic acid is made in object.
Preferably, specifically:
The solution for preparing monocholesterylsuccinate is added thionyl chloride, reacts 1 at room temperature after cooling in ice-water bath
~2h, then be warming up to boiling temperature and react 5~12h, obtain monocholesterylsuccinate acyl chlorides.
Solvent in the solution of the monocholesterylsuccinate is preferably anhydrous tetrahydro furan.The succinic acid list gallbladder is solid
The mass concentration of the solution of alcohol ester is preferably 4~5wt%.The molar ratio of the monocholesterylsuccinate and thionyl chloride is preferred
For 1:1~2.
The time of the addition is preferably 20~120min.
In certain embodiments of the present invention, the boiling temperature is 65 DEG C.
After the reaction, it is also preferable to include: vacuum distillation.The vacuum distillation is for removing solvent and by-product.This hair
Bright equipment and parameter to the vacuum distillation has no special limitation, is needed according to experiment using known to those skilled in the art
Vacuum distillation equipment and parameter.
The hydrophobic bionic acid can increase the hydrophobicity of coating, characteristic that is not soluble in water and being dissolved in organic solvent
Facilitate and the medical composite coating agent is homogeneously applied to medical catheter surface.Meanwhile hydrophobic bionic acid has
Know and verified evidence biological safety.
After obtaining material a and material b, material a is reacted with material b, obtains biology base ionic surface active agent.
Preferably, specifically:
When material a is sulfonate:
The solution of material a is mixed with NaOH solid, at room temperature, the solution of material b is added, reacts 2~12h,
Obtain biology base sulfosalt surfactant.
The solvent of the solution of the material a is preferably the mixed solution of tetrahydrofuran and deionized water.The present invention is to described
The proportion of tetrahydrofuran and deionized water has no special limitation, in certain embodiments of the present invention, the tetrahydrofuran and
The volume ratio of deionized water is 80:20 or 19:1.The concentration of the solution of the material a is preferably 2~10wt%.Of the invention
In some embodiments, the concentration of the solution of the material a is 5wt%.
The molar ratio of the material a and the NaOH solid is preferably 0.25~1:1.In certain embodiments of the present invention
In, the molar ratio of the material a and the NaOH solid is 1:1 or 0.5:1.
The solvent of the solution of the material b is preferably tetrahydrofuran.The concentration of the solution of the material b is preferably 5~
15wt%.In certain embodiments of the present invention, the concentration of the solution of the material b is 3wt% or 5wt%.
The molar ratio of the material a and material b is preferably 1~3:1.In certain embodiments of the present invention, the material a
Molar ratio with material b is 2:1.
The time that the material b solution is added is preferably 0.25~1h.In certain embodiments of the present invention, the material
The time that b solution is added is 0.5h or 0.25h.
The temperature of the reaction is preferably room temperature.The time of the reaction is 2~12h.In certain embodiments of the present invention
In, the time of the reaction is 12h.
After the reaction, it is also preferable to include removing solvent and dryings.The present invention is to the removing solvent and dry method
Special limitation is had no, using removing solvent well known to those skilled in the art and dry method.
In certain embodiments of the present invention, before the removing solvent further include: hydrochloric acid neutralization reaction pH value is added extremely
7.0。
When material a is quaternary ammonium salt:
Material a, material b and anhydrous triethylamine are reacted in a solvent, obtain biology base quaternary surfactant.
Before the reaction, it is also preferable to include material b is dried.
The solvent is preferably anhydrous methylene chloride.
The molar ratio of the material a, material b and anhydrous triethylamine is preferably 1:1:1.Dosage of the present invention to the solvent
Special limitation is had no, material a and material b can be completely dissolved.
The temperature of the reaction is preferably room temperature.The time of the reaction be 2~for 24 hours.In certain embodiments of the present invention
In, the time of the reaction is for 12h or for 24 hours.
After the reaction, it is also preferable to include: filtering and removing solvent.The filtering is for removing precipitating.The present invention is to institute
The method stated filtering and remove solvent has no special limitation, using filtering well known to those skilled in the art and removes solvent
Method.
In the present invention, the biology base ionomer preferably includes polylysine hydrochloride, poly- L-arginine hydrochloric acid
One or more of salt, heparin sodium, chitosan, Sodium Hyaluronate, dextran sulfate and chondroitin sulfate.It is described poly-
Lysine hydrochloride is preferably poly-l-lysine hydrochloride, poly ε-lysine hydrochloride, other amino acid and lysine
One or more of hydrochloride of copolymer；More preferably poly-l-lysine hydrochloride, poly ε-lysine hydrochloride, rely
One or more of hydrochloride, lysine and hydrochloride of arginic copolymer of the copolymer of propylhomoserin and alanine.Institute
Biology base ionomer is stated with distinctive bioactivity, the physical strength and planarization of coating can also be increased.
After obtaining biology base ionic surface active agent, by the aqueous solution of biology base ionic surface active agent and biology base ion
The aqueous solution of polymer mixes, react 0.5 at 10~80 DEG C~for 24 hours, obtain medical composite coating agent.
Preferably, the aqueous solution of biology base ionic surface active agent is mixed into tool with the aqueous solution of biology base ionomer
Body are as follows:
The aqueous solution of biology base ionic surface active agent is added dropwise in the aqueous solution of biology base ionomer.
The concentration of the aqueous solution of the biology base ionic surface active agent is preferably 0.1~10wt%.In certain of the invention
In a little embodiments, the concentration of the aqueous solution of the biology base ionic surface active agent is 2wt%, 2.5wt%, 4wt%, 5wt%,
6wt% or 7.82wt%.The concentration of the aqueous solution of the biology base ionomer is preferably 0.1~10wt%.In the present invention
Some embodiments in, the concentration of the aqueous solution of the biology base ionomer be 1.64wt%, 2wt%, 2.66wt% or
3wt%.The present invention matches to the aqueous solution of the biology base ionic surface active agent and the aqueous solution of biology base ionomer
Method processed has no special limitation, using the method for solution well known to those skilled in the art.
The charge of the biology base ionic surface active agent and biology base ionomer is than being preferably 0.9~3:1；It is more excellent
It is selected as 1~2:1.In certain embodiments of the present invention, the biology base ionic surface active agent and biology base ionomer
Charge ratio be 0.9:1,1:1,1.08:1,1.15:1,2:1 or 2.03:1.
The time of the dropwise addition is preferably 10~30min, and in certain embodiments of the present invention, the time for adding is
30min。
The temperature of the reaction is 10~80 DEG C.In certain embodiments of the present invention, the temperature of the reaction is 80 DEG C.
The time of the reaction be 0.5~for 24 hours.In certain embodiments of the present invention, the time of the reaction is 4h.Of the invention
In some embodiments, the reaction is stirred for reaction 12h first to react 3h at 80 DEG C after being cooled to room temperature.
After the reaction, it is also preferable to include: the precipitating after the reaction is washed.
The washing is preferably washed with hot water.The temperature of the hot water is preferably 50~90 DEG C.The water is preferably gone
Ionized water.The present invention has no special limitation to the number of the washing, can be selected according to the actual situation, in the present invention
Some embodiments in, the number of the washing is 3~5 times.
It in certain embodiments of the present invention, further include drying after the washing.The drying is preferably dried in vacuo.This
Invention has no special limitation to the parameter of the drying, using the parameter of drying well known to those skilled in the art.
The present invention also provides a kind of application methods of medical composite coating agent, comprising the following steps:
A medical composite coating agent is mixed with organic solvent), obtains the organic solution of medical composite coating agent；
The medical composite coating agent is medical composite coating agent or preparation method described above described above
The medical composite coating agent of preparation；
B the organic solution of the medical composite coating agent) is passed through into dipping, the dry table for being coated on object to be coated
Face.
The organic solvent is preferably ethyl alcohol and/or isopropanol.
Generally, has medical composite coating prepared by the bionic acid of more carbon atom numbers with higher stabilization
Property, to be more difficult to be washed away by blood and medical fluid in the blood vessels.But carbon atom number is too high, it will gained coating is caused to be difficult to
It is dissolved in ethyl alcohol and isopropanol, to be unfavorable for preparing medical coating on conduit, it is therefore preferable that carbon atom number is within 16~36
Bionic acid derivative, it is hereby achieved that the medical composite coating of best performance.
The present invention has no special limitation to the proportion of the medical composite coating agent and organic solvent, using this field
The proportion of medical composite coating agent and organic solvent known to technical staff.
The present invention has no special limitation to the dipping and dry method and parameter, ripe using those skilled in the art
The medical coating agent solution dipping known and dry method and parameter.
The present invention has no special limitation to the source of above-mentioned used raw material, can be general commercially available.
The present invention provides a kind of medical composite coating agent, by including biology base ionomer and biology base ion table
The raw material of face activating agent is prepared；The biology base ionic surface active agent is selected from triacetyl cholic acid 2- ethoxy trimethyl chlorine
Change ammonium ester, three butyryl cholic acid choline chloride esters, stearic acid choline chloride ester, N- deoxidation gallbladder
Sour acyl group -2-aminoethanesulfonic acid sodium, N- stearyl-Taurine sodium and the mono- cholesterol succinic acid acyl group -2- amino second of N-
One of sodium sulfonate.Specific biology base ionic surface active agent and biology base ionomer act synergistically, and are prepared
Medical composite coating safety it is higher, medical coating toxic side effect is small, be easy katabolism.
The present invention also provides a kind of preparation methods of medical composite coating agent, comprising the following steps: by biology base from
The solution of sub- surfactant is mixed with the solution of biology base ionomer, at 10~80 DEG C react 0.5~for 24 hours, obtain
Medical composite coating agent.With two class table of benzalkonium chloride in the prior art, three (octadecyl) ammonium chlorides and docusate sodium
The property of face activating agent is dramatically different, biology base ionic surface active agent provided by the invention occur in vivo slowly hydrolyze and
Or it can be decomposed by lipase and protein digestibility enzyme with the bionic acid and 2- ethoxy front three for determining biological safety
Ammonium chloride and/or 2-aminoethanesulfonic acid.By the solution of above-mentioned biology base ionic surface active agent and biology base ionic polymerization
The safety of the solution reaction of object, obtained medical composite coating is higher, and medical coating toxic side effect is small, is easy degradation generation
It thanks.
In order to further illustrate the present invention, with reference to embodiments to a kind of medical composite coating provided by the invention
Agent, preparation method and application are described in detail, but cannot be understood as limiting the scope of the present invention.
Raw material used in following embodiment is general commercially available.
Embodiment 1
Biology base ionic surface active agent is used as using commercially available N- deoxycholic acid -2-aminoethanesulfonic acid sodium (TCA).
6.00g TCA (0.0115mol anion) is dissolved in 100mL deionized water, the TCA aqueous solution that concentration is 6wt% is obtained, it will
The poly-l-lysine hydrochloride (PLS, 0.01mol cation) that 1.64g molecular weight is 15000~30000g/mol is dissolved in 82mL
In deionized water, obtains the PLS aqueous solution that concentration is 2wt% and TCA aqueous solution is added dropwise to PLS water in 80 DEG C of water-bath
In solution, 4h is sufficiently stirred, the time of the dropwise addition is 30min.Later collect bottom white precipitate, and with 50 DEG C go from
Sub- water sufficiently washs 5 times, and the medical composite coating agent of PLS/TCA is obtained after vacuum drying.The biology being related in the coating agent
The carbon atom number of acid is 24, and solubility of the coating agent in ethyl alcohol, isopropanol is greater than 5%.
Embodiment 2
First prepare biology base ionic surface active agent N- stearyl-Taurine sodium (STA):
0.05mol 2-aminoethanesulfonic acid is dissolved in tetrahydrofuran/aqueous solution (volume ratio of tetrahydrofuran and water is 80:
20) the 2-aminoethanesulfonic acid solution that concentration is 5wt%, is obtained, 0.025mol stearyl chloride is dissolved in tetrahydrofuran, is obtained dense
Degree is the stearyl chloride solution of 5wt%.0.05mol NaOH solid is added in the 2-aminoethanesulfonic acid sodium solution, to NaOH
After solid dissolution, under room temperature, stearyl chloride solution is added dropwise, controls rate of addition, guarantee to be added dropwise in 0.5h, later
N- stearyl-Taurine sodium (STA) is prepared after removing solvent seasoning in the reaction was continued 12h.
7.82g N- stearyl-Taurine sodium (STA, 0.02mol) is dissolved in 100mL deionized water, is obtained
Concentration is the STA aqueous solution of 7.82wt%, and 1.64g PLS (0.01mol anion) is dissolved in 100mL deionized water, is obtained
Concentration is that STA aqueous solution is added dropwise in PLS aqueous solution, sufficiently by the PLS aqueous solution of 1.64wt% in 80 DEG C of water-bath
4h is stirred, the time of the dropwise addition is 30min.The white precipitate of bottom is collected later, and sufficiently washs 5 with the deionized water of heat
It is secondary, the medical composite coating agent of PLS/STA is obtained after vacuum drying.The carbon atom number for the bionic acid being related in the coating agent is
18, solubility of the coating agent in ethyl alcohol, isopropanol is greater than 5%.
Embodiment 3
First prepare the derivative of hydrophobic bionic acid: monocholesterylsuccinate acyl chlorides
9.73g (0.02mol) monocholesterylsuccinate is dissolved in 200mL anhydrous tetrahydro furan, being configured to concentration is
The monocholesterylsuccinate solution of 4.86wt% then in ice-water bath after cooling, is added dropwise thionyl chloride (0.025mol),
It is added dropwise in 30min, reacts 2h at room temperature later, then be warming up to 65 DEG C of reaction 12h, finally vacuum distillation removing solvent obtains
To monocholesterylsuccinate acyl chlorides.
The mono- cholesterol succinic acid acyl group of biology base ionic surface active agent N- -2-aminoethanesulfonic acid sodium (SCTA) is prepared again:
0.01mol 2-aminoethanesulfonic acid is dissolved in tetrahydrofuran/aqueous solution (volume ratio of tetrahydrofuran and water is 19:
1) the 2-aminoethanesulfonic acid sodium solution that concentration is 5wt% is obtained, 0.005mol monocholesterylsuccinate acyl chlorides is dissolved in tetrahydro
In furans, the monocholesterylsuccinate solution of acid chloride that concentration is 3wt% is obtained.It is added in the 2-aminoethanesulfonic acid solution
After the dissolution of NaOH solid under room temperature, monocholesterylsuccinate solution of acid chloride, control is added dropwise in 0.02mol NaOH solid
It is added dropwise in 15min in rate of addition processed, the reaction was continued later 12h, and hydrochloric acid neutralization reaction pH value is added to 7.0, takes off
Except the mono- cholesterol succinic acid acyl group of N- -2-aminoethanesulfonic acid sodium (SCTA) is prepared after solvent seasoning.
By the mono- cholesterol succinic acid acyl group -2-aminoethanesulfonic acid sodium (SCTA, 0.00325mol anion) of 2.00g N-
It 615.7g/mol) is dissolved in 80mL deionized water, obtains the SCTA aqueous solution that concentration is 2.5wt%, 0.533g poly L- is relied
Propylhomoserin hydrochloride (PLS, 0.00325mol anion) is dissolved in 20mL deionized water, obtains the PLS water that concentration is 2.66wt%
SCTA aqueous solution is added dropwise in PLS aqueous solution by solution in 80 DEG C of water-bath, and 4h, the time of the dropwise addition is sufficiently stirred
For 30min.The white precipitate of bottom is collected later, and is sufficiently washed 5 times with the deionized water of heat, and PLS/ is obtained after vacuum drying
The medical composite coating agent of SCTA.The carbon atom number for the bionic acid being related in the coating agent is 31, and coating agent is in ethyl alcohol, isopropyl
Solubility in alcohol is greater than 2%.
Embodiment 4
The mono- cholesterol succinic acid acyl group of N- -2-aminoethanesulfonic acid sodium (SCTA) is prepared according to the preparation method of embodiment 3.
The mono- cholesterol succinic acid acyl group -2-aminoethanesulfonic acid sodium (SCTA, 0.00325mol anion) of 2.00g N- is molten
In 50mL deionized water, the SCTA aqueous solution that concentration is 4wt% is obtained, is 10000~20000g/ by 0.578g molecular weight
The poly- L-arginine hydrochloride (PLA, 0.003mol) of mol is dissolved in 28.9mL deionized water, and obtaining concentration is the poly- of 2.0wt%
SCTA aqueous solution is added dropwise in PLS aqueous solution, is sufficiently stirred in 80 DEG C of water-bath by L-arginine salt acid salt aqueous solution
4h, the time of the dropwise addition are 30min.The white precipitate of bottom is collected later, and is sufficiently washed 5 times with the deionized water of heat,
The poly- medical composite coating agent of L-arginine hydrochloride/SCTA is obtained after vacuum drying.The bionic acid being related in the coating agent
Carbon atom number be 31, solubility of the coating agent in ethyl alcohol, isopropanol be greater than 2%.
Embodiment 5
First prepare hydrophobic bionic acid: triacetyl cholic acid
0.02mol cholic acid is dissolved in tetrahydrofuran, the cholic acid solution that concentration is 5wt% is configured to, 0.1mol vinegar is added
Acid anhydrides, the back flow reaction 12h at 70 DEG C are added excessive water and triacetyl cholic acid are obtained by filtration after refrigerator is cooling.
The derivative of hydrophobic bionic acid: triacetyl cholic acid acyl chlorides is prepared again
0.02mol triacetyl cholic acid is dissolved in anhydrous tetrahydro furan, the solution that concentration is 5wt% is configured to, then exists
In ice-water bath after cooling, thionyl chloride (0.025mol) is slowly added dropwise, is added dropwise in 30min, reacts 2h at room temperature later,
It is warming up to 50 DEG C of reaction 12h again, finally vacuum distillation removing solvent obtains triacetyl cholic acid acyl chlorides.
Triacetyl cholic acid choline chloride ester (TACC) is prepared again:
By 0.01mol triacetyl cholic acid acyl chlorides, equimolar drying choline chloride with it is equimolar
Anhydrous triethylamine reacts in anhydrous methylene chloride, and the temperature for controlling reaction is room temperature, and the time of reaction is for 24 hours.Reaction terminates
After filter out solid precipitating, solution obtains triacetyl cholic acid choline chloride ester (TACC) after mutually removing solvent.
2.00g TACC (0.00305mol cation) is dissolved in 50mL deionized water, obtaining concentration is 4wt%'s
1.362g heparin sodium (HP, 0.0015mol anion) is dissolved in deionized water by TACC aqueous solution, and obtaining concentration is 3wt%'s
TACC aqueous solution is added dropwise in HP aqueous solution by HP aqueous solution at 80 DEG C, after reacting 3h, is stirred for after being cooled to room temperature anti-
12h is answered, the time of the dropwise addition is 30min.The white precipitate of bottom is collected later, and is sufficiently washed with 60 DEG C of deionized water
3 times, obtain the medical composite coating agent of HP/TACC.The carbon atom number for the bionic acid being related in the coating agent is 30, coating agent
Solubility in ethyl alcohol, isopropanol is greater than 2%.
Embodiment 6
First prepare hydrophobic bionic acid: three butyryl cholic acid
0.02mol cholic acid is dissolved in tetrahydrofuran, the cholic acid solution that concentration is 5wt% is configured to, 0.10mol fourth is added
Acid anhydrides, the back flow reaction 12h at 70 DEG C add 500mL water and three butyryl cholic acid are obtained by filtration after refrigerator is cooling.
The derivative of hydrophobic bionic acid: three butyryl cholic acid acyl chlorides is prepared again
Tri- butyryl cholic acid of 0.02mol is dissolved in anhydrous tetrahydro furan, the solution that concentration is 5wt% is configured to, then exists
In ice-water bath after cooling, thionyl chloride (0.02mol) is slowly added dropwise, is added dropwise in 30min, reacts 2h at room temperature later,
It is warming up to 50 DEG C of reaction 12h again, finally vacuum distillation removing solvent obtains three butyryl cholic acid acyl chlorides.
Three butyryl cholic acid choline chloride esters (TBCC) are prepared again:
By tri- butyryl cholic acid acyl chlorides of 0.01mol, the choline chloride of equimolar drying and equimolar
Anhydrous triethylamine reacts in anhydrous methylene chloride, and the temperature for controlling reaction is room temperature, and the time of reaction is for 24 hours that reaction terminates
Filtering removal triethylamine hydrochloride precipitating afterwards, removing solvent obtain three butyryl cholic acid choline chloride esters
(TBCC)。
2.00g TBCC (0.00270mol cation) is dissolved in 100mL deionized water, obtaining concentration is 2wt%'s
1.65g heparin sodium (HP, 0.0024mol anion) is dissolved in deionized water by TBCC aqueous solution, and obtaining concentration is 2wt%'s
TBCC aqueous solution is added dropwise in HP aqueous solution by HP aqueous solution at 80 DEG C, after reacting 3h, is stirred for after being cooled to room temperature anti-
12h is answered, the time of the dropwise addition is 30min.The white precipitate of bottom is collected later, and sufficiently washs 3 with the deionized water of heat
It is secondary, obtain the medical composite coating agent of HP/TBCC.The carbon atom number for the bionic acid being related in the coating agent is 36, coating agent
Solubility in ethyl alcohol, isopropanol is greater than 1%.
Embodiment 7
First prepare stearic acid choline chloride ester (SC):
0.05mol stearyl chloride, equimolar choline chloride and equimolar anhydrous triethylamine are existed
It is reacted in anhydrous methylene chloride, the temperature of the reaction is room temperature, and the time of the reaction is 12h, filtering removal triethylamine salt
Hydrochlorate precipitating, removing solvent obtain stearic acid choline chloride ester (SC).
2.00g SC (0.0049mol cation) is dissolved in 40mL deionized water, it is water-soluble to obtain the SC that concentration is 5wt%
3.17g heparin sodium (HP, 0.0046mol anion) is dissolved in deionized water by liquid, obtains the HP aqueous solution that concentration is 2wt%,
At 80 DEG C, SC aqueous solution is added dropwise in HP aqueous solution, after reacting 3h, reaction 12h, the drop are stirred for after being cooled to room temperature
The time added is 30min.The white precipitate of bottom is collected later, and is sufficiently washed 3 times with the deionized water of heat, and HP/SC is obtained
Medical composite coating agent.The carbon atom number for the bionic acid being related in the coating agent is 18, and coating agent is in ethyl alcohol, isopropanol
Solubility be greater than 5%.
Embodiment 8
Three butyryl cholic acid choline chloride esters (TBCC) are prepared according to the preparation method of embodiment 6
2.00g TBCC (0.0027mol cation) is dissolved in deionized water, it is water-soluble to obtain the TBCC that concentration is 5wt%
0.961g Sodium Hyaluronate (HA, 0.0024mol anion) is dissolved in deionized water by liquid, obtains the HA water that concentration is 2wt%
TBCC aqueous solution is added dropwise in HA aqueous solution by solution at 80 DEG C, after reacting 3h, is stirred for reacting after being cooled to room temperature
12h, the time of the dropwise addition are 30min.The white precipitate of bottom is collected later, and is sufficiently washed 3 times with the deionized water of heat,
Obtain the medical composite coating agent of HA/TBCC.The carbon atom number for the bionic acid being related in the coating agent is 36, and coating agent is in second
Solubility in alcohol, isopropanol is greater than 1%.
Comparative example 1
Using docusate sodium as biology base ionic surface active agent.By 3.00g docusate sodium (0.0067mol anion)
It is dissolved in 60mL deionized water, the benzalkonium chloride in water that concentration is 5wt% is obtained, by 1.0g poly-l-lysine hydrochloride
(PLS, 0.0061mol cation) is dissolved in 50mL deionized water, the PLS aqueous solution that concentration is 2wt% is obtained, in 80 DEG C of water
In bath, docusate sodium aqueous solution is added dropwise in PLS aqueous solution, 4h is sufficiently stirred.The white precipitate of bottom is collected later, and
It is sufficiently washed 5 times with the deionized water of heat, the medical composite coating agent of PLS/ docusate sodium is obtained after vacuum drying.The present embodiment
The carbon atom number of middle biology base ionic surface active agent docusate sodium is 20.
Comparative example 2
Using benzalkonium chloride as biology base ionic surface active agent.3.00g benzene is pricked into chlorine ammonia (0.0085mol cation)
It is dissolved in 60mL deionized water, obtains the benzene that concentration is 5wt% and prick chlorine ammonia spirit, by 5.45g heparin sodium (HP, 0.0080mol
Anion) it is dissolved in 100mL deionized water, the HP aqueous solution that concentration is 5.45wt% is obtained, in 80 DEG C of water-bath, by benzene
It pricks chlorine ammonia spirit to be added dropwise in HP aqueous solution, 4h is sufficiently stirred.Collect the white precipitate of bottom later, and with hot deionization
Water sufficiently washs 5 times, and HP/ benzene is obtained after vacuum drying and pricks the medical composite coating agent of chlorine ammonia.Biology base ion in the present embodiment
The carbon atom number of surfactant benzalkonium chloride is 22.
Comparative example 3
First prepare hydrophobic bionic acid: three hexanoyl cholic acid
0.02mol cholic acid is dissolved in tetrahydrofuran, be configured to concentration be 5wt% cholic acid solution, be added 0.10mol oneself
Acid anhydrides, the back flow reaction 12h at 70 DEG C add excessive water and three hexanoyl cholic acid are obtained by filtration after refrigerator is cooling.
The derivative of hydrophobic bionic acid: three hexanoyl cholic acid acyl chlorides is prepared again
Tri- hexanoyl cholic acid of 0.02mol is dissolved in anhydrous tetrahydro furan, the solution that concentration is 5wt% is configured to, then exists
In ice-water bath after cooling, thionyl chloride (0.02mol) is slowly added dropwise, is added dropwise in 30min, reacts 2h at room temperature later,
It is warming up to 50 DEG C of reaction 12h again, finally vacuum distillation removing solvent obtains three caproic acid cholic acid acyl chlorides.
Three hexanoyl cholic acid choline chloride esters (THCC) are prepared again:
By tri- hexanoyl cholic acid acyl chlorides of 0.01mol, the choline chloride of equimolar drying and equimolar
Anhydrous triethylamine reacts in anhydrous methylene chloride, and the temperature of the reaction is room temperature, and the time of the reaction is filtering for 24 hours
Triethylamine hydrochloride precipitating is removed, removing solvent obtains three hexanoyl cholic acid choline chloride esters (THCC).
2.00gTHCC (0.00243mol cation) is dissolved in 100mL deionized water, obtaining concentration is 2wt%'s
1.65g heparin sodium (HP, 0.0024mol anion) is dissolved in deionized water by THCC aqueous solution, and obtaining concentration is 2wt%'s
THCC aqueous solution is added dropwise in HP aqueous solution by HP aqueous solution at 80 DEG C, after reacting 3h, is stirred for after being cooled to room temperature anti-
12h is answered, the time of the dropwise addition is 30min.The white precipitate of bottom is collected later, and sufficiently washs 3 with the deionized water of heat
It is secondary, obtain the medical composite coating agent of HP/THCC.The carbon atom number for the bionic acid being related in the coating agent is 42, coating agent
It is slightly soluble in ethyl alcohol, in isopropanol.
Embodiment 9
The degradability of biology base ionic surface active agent is analyzed
Method: the ionic surface active agent of the embodiment of the present invention 1~8 and comparative example 1~3, which is dissolved in pH, is
In 7.0 phosphate buffer solution (0.05mol/L), it is configured to the solution of 1% (w/v), is placed in 37 DEG C of constant-temperature table, with
The revolving speed of 100rpm carries out shake culture, reaction is terminated after 48h, and be freeze-dried and obtain freeze-dried powder.It is extracted later using chloroform
Product hydrolyzes generated bionic acid, and the percent hydrolysis of biology base ionic surface active agent is determined by nuclear magnetic resonance.Corresponding knot
Fruit is listed in table 1.Meanwhile using the percent hydrolysis of identical method test benzalkonium chloride and docusate sodium, accordingly result is listed in table 1.
The hydrolytic stability of the ionic surface active agent of 1 Examples 1 to 8 of table and comparative example 1~3
As it can be seen from table 1 biology base ionic surface active agent provided by the present invention has faster relative to comparative example
Hydrolysis rate, and theoretically presumable, biology base ionic surface active agent hydrolysate provided by the present invention is
Bionic acid and 2- hydroxyl trimethyl ammonium chloride or 2-aminoethanesulfonic acid, these three substances all have and can be specific and need not set
Doubtful safety.
Embodiment 10: the stability assessment of coating agent
The preparation of coated catheters: medical composite coating agent prepared by Examples 1 to 8 and comparative example 1~3 is matched respectively
The ethanol solution that mass concentration is 1% is made, it will be having a size of 30s in 6F polyethylene catheter dipping solution, then with 60cm/min's
Speed is taken out, hot blast drying under the conditions of 60 DEG C, then is dried in vacuo to obtain the polyethylene catheter of medical composite coating agent coating.
Coating stability assessment: polyethylene catheter is soaked in physiological saline, washing is shaken under the conditions of 37 DEG C, after 2 days
Conduit is taken out, deionized water is dried in vacuo after sufficiently washing, and the loss late of coating is assessed by weight method.Accordingly result is listed in table
2。
Medical coating loss late prepared by the medical composite coating agent of 2 Examples 1 to 8 of table, comparative example 1~3
From table 2 it can be seen that the stability raising of coating increases with the increase of the carbon atom number of hydrophobic bionic acid
Add, but when the carbon atom number of hydrophobic bionic acid is too big, such as THCC (carbon atom number 42), prepared compound doctor
It will be difficult to be dissolved in organic solvent with coating agent and coating can not be prepared.Simultaneously relative to comparative example 1 and 2, the present invention is mentioned
The method of confession has higher stability.
Embodiment 11
The vitro cytotoxicity of coating is assessed: according to " the 5th part of BiologicalEvaluationofMedicalDevice: body GB/T 16886.5
Outer cell toxicity test " described in method to coated catheters carry out vitro Cytotoxicity Evaluation.Specifically:
(1) preparation of coated catheters: medical composite coating agent point prepared by Examples 1 to 8 and comparative example 1~3
It is not configured to the ethanol solution that mass concentration is 1%, it will be having a size of 30s in 6F polyurethane catheter dipping solution, then with 60cm/
The speed of min is taken out, hot blast drying under the conditions of 60 DEG C, then is dried in vacuo to obtain the polyurethane of medical composite coating agent coating
Conduit.
(2) polyurethane catheter: being cut into the small fragment of 1cm long by the preparation of leaching liquor to be detected, after ethylene oxide sterilizing,
It is 6cm according to the ratio of external surface area summation in conduit and physiological saline leaching liquor volume2: the mode of 1mL is in 37 DEG C of conditions
Lower isothermal vibration extracts.It after 48h, is separated by solid-liquid separation, liquid portion is liquid to be detected.Physiological saline under the same terms is as negative
Control.Positive control is with the preparation of 5vol% dimethyl sulfoxide.
(3) it cytotoxicity analysis: freezes l cell and is containing 10vol% cow's serum and 1vol% penicillin-
Subculture 48h in the dual anti-DMEM culture medium of streptomysin is desorbed using 0.25% trypsin-EDTA solutions later, centrifugation
It is dispersed in DMEM culture medium again after separation, adjustment cell concentration is 105/mL.Pipetting 100 μ L cell liquid, to be inoculated into 96 holes thin
In born of the same parents' culture plate, in carbon dioxide incubator after 37 DEG C of cultures for 24 hours, original fluid is removed, 100 μ L leaching liquors are added to training
It supports in plate, continues to cultivate cell 72h.20 μ LMTT (5g/L) are added in each micropore, continues after cultivating 4h, removes in orifice plate
Liquid, be added 150 μ LDMSO, shaking table shake 10min after, extinction is measured under 570nm and 630nm wavelength by microplate reader
Degree.Opposite appreciation rate is finally calculated by absorbance and determines cytotoxicity, accordingly result is listed in table 3.
3 Examples 1 to 8 of table, comparative example 1~3 medical composite coating agent cytotoxicity (mtt assay)
From table 3 it can be seen that biology base charge recombination object medical coating provided by the present invention is disclosed relative to document
Method there is lower cytotoxicity, and cytotoxicity can be reduced by increasing the carbon atom number of bionic acid.In addition,
More significantly, biology base ionic surface active agent provided by the present invention, which pricks chlorine ammonia relative to benzene, has lower cell toxicant
Property, this is because biology base ionic surface active agent provided by the present invention has hydrolyzable chemical characteristic.
Embodiment 12
The medical composite coating agent 2.000g of the PLS/TCA that embodiment 1 is obtained and 0.060g TCA co-dissolve in
In 100mL dehydrated alcohol, the medical composite coating agent of PLS/ (TCA+) is obtained, the biology of charge recombination does not occur in the coating agent
The content of base ionic surface active agent is 3wt%.Medical catheter coating is prepared according to the method for embodiment 10.Pass through electricity after drying
The pattern of sub- flying-spot microscope observation catheter surface coating.Accordingly result is as shown in Figure 1.Fig. 1 is what embodiment 12 was prepared
The pattern of medical catheter coating.The present embodiment has also observed the shape for the catheter surface coating being made by embodiment 1 in embodiment 10
Looks, as shown in Figure 2.Fig. 2 is the pattern for the medical catheter coating that embodiment 1 is prepared according to the method for embodiment 10.From Fig. 1
It can see in Fig. 2, the medical catheter coating in Fig. 1 is more uniform.
Embodiment 13
The medical composite coating agent 2.000g life corresponding with 0.060g respectively that the application also obtains embodiment 2~8
Object base ionic surface active agent is dissolved in 100mL dehydrated alcohol, obtains corresponding medical composite coating agent, resulting coating
The content that the biology base ionic surface active agent of charge recombination does not occur in agent is 3wt%.It is prepared according to the method for embodiment 10
Medical catheter coating.The pattern of catheter surface coating is observed after drying by electronic scanner microscope.Meanwhile comparative example 10
The pattern of catheter surface coating made from middle corresponding embodiment.The experimental results showed that charge does not occur containing 3wt% in coating agent
The medical catheter coating of compound biology base ionic surface active agent is more uniform.
The foregoing description of the disclosed embodiments enables those skilled in the art to implement or use the present invention.
Various modifications to these embodiments will be readily apparent to those skilled in the art, as defined herein
General Principle can be realized in other embodiments without departing from the spirit or scope of the present invention.Therefore, of the invention
It is not intended to be limited to the embodiments shown herein, and is to fit to and the principles and novel features disclosed herein phase one
The widest scope of cause.
Claims (10)
1. a kind of medical composite coating agent, by the raw material including biology base ionomer and biology base ionic surface active agent
It is prepared；
The biology base ionic surface active agent is selected from triacetyl cholic acid choline chloride ester, three butyryl cholic acid 2-
Ethoxy trimethyl ammonium chloride ester, stearic acid choline chloride ester, N- deoxycholic acid -2-aminoethanesulfonic acid
One of sodium, N- stearyl-Taurine sodium and the mono- cholesterol succinic acid acyl group -2-aminoethanesulfonic acid sodium of N-.
2. medical composite coating agent according to claim 1, which is characterized in that the biology base ionomer includes
Polylysine hydrochloride, poly- L-arginine hydrochloride, heparin sodium, chitosan, Sodium Hyaluronate, dextran sulfate and sulphur
One or more of aching and limp ossein.
3. medical composite coating agent according to claim 2, which is characterized in that the polylysine hydrochloride is selected from more
Polylysine hydrochloride, poly ε-lysine hydrochloride, other amino acid and lysine copolymer hydrochloride in one
Kind is several.
4. medical composite coating agent according to claim 1, which is characterized in that in the medical composite coating agent,
The content that the biology base ionic surface active agent of charge recombination does not occur is 0.1~5wt%.
5. the preparation method of medical composite coating agent described in claim 1, comprising the following steps:
The aqueous solution of biology base ionic surface active agent is mixed with the aqueous solution of biology base ionomer, at 10~80 DEG C
Reaction 0.5~for 24 hours, obtain medical composite coating agent.
6. preparation method according to claim 5, which is characterized in that the biology base ionic surface active agent is according to following
It is prepared by method:
Material a is reacted with material b, obtains biology base ionic surface active agent；
The material a is quaternary ammonium salt or sulfonate；
The material b is the derivative of hydrophobic bionic acid.
7. preparation method according to claim 5, which is characterized in that the material a is 2-aminoethanesulfonic acid sodium or 2- hydroxyl
Ethyl-trimethyl salmiac；
The material b be selected from one of derivative of the derivative of fatty acid, the derivative of cholic acid and succinic acid sterol ester or
It is several.
8. preparation method according to claim 7, which is characterized in that the material b is selected from stearyl chloride, succinic acid list gallbladder
One of sterol ester acyl chlorides, triacetyl cholic acid acyl chlorides and three butyryl cholic acid acyl chlorides.
9. preparation method according to claim 5, which is characterized in that the aqueous solution of the biology base ionic surface active agent
Concentration be 0.1~10wt%；The concentration of the aqueous solution of the biology base ionomer is 0.1~10wt%；
The charge ratio of the biology base ionic surface active agent and biology base ionomer is 0.9~3:1.
10. the application method of medical composite coating agent, comprising the following steps:
A medical composite coating agent is mixed with organic solvent), obtains the organic solution of medical composite coating agent；
The medical composite coating agent includes that the described in any item medical composite coating agent of Claims 1 to 4 or right are wanted
Ask the medical composite coating agent of 5~9 described in any item preparation method preparations；
B the organic solution of the medical composite coating agent) is passed through into dipping, the dry surface for being coated on object to be coated.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112772709A (en) * | 2021-01-06 | 2021-05-11 | 南京工业大学 | Preservative film antibacterial spray and preparation method and application thereof |
| CN114657778A (en) * | 2022-05-18 | 2022-06-24 | 广东洪兴实业股份有限公司 | Cooling agent composition containing plant sugar alcohol and application of cooling agent composition in preparation of cool pure cotton fabric |
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| JP4691745B2 (en) * | 1999-06-21 | 2011-06-01 | 東洋紡績株式会社 | Method for coating antibacterial antithrombotic material |
| CN102432477A (en) * | 2011-11-04 | 2012-05-02 | 江南大学 | Synthetic process of double-long-chain diester quaternary ammonium salt |
| CN102698648A (en) * | 2012-06-27 | 2012-10-03 | 东北石油大学 | Dendritic sulfonate-type tetramer surfactant and preparation method thereof |
| CN102757723A (en) * | 2012-07-19 | 2012-10-31 | 黄斌 | Coating liquid and coating method for improving biocompatibility of surfaces of biomedical materials by one-step method |
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| JP4691745B2 (en) * | 1999-06-21 | 2011-06-01 | 東洋紡績株式会社 | Method for coating antibacterial antithrombotic material |
| CN102432477A (en) * | 2011-11-04 | 2012-05-02 | 江南大学 | Synthetic process of double-long-chain diester quaternary ammonium salt |
| CN102698648A (en) * | 2012-06-27 | 2012-10-03 | 东北石油大学 | Dendritic sulfonate-type tetramer surfactant and preparation method thereof |
| CN102757723A (en) * | 2012-07-19 | 2012-10-31 | 黄斌 | Coating liquid and coating method for improving biocompatibility of surfaces of biomedical materials by one-step method |
Cited By (2)
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| CN112772709A (en) * | 2021-01-06 | 2021-05-11 | 南京工业大学 | Preservative film antibacterial spray and preparation method and application thereof |
| CN114657778A (en) * | 2022-05-18 | 2022-06-24 | 广东洪兴实业股份有限公司 | Cooling agent composition containing plant sugar alcohol and application of cooling agent composition in preparation of cool pure cotton fabric |
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