WO2006080523A1 - 自己分解性を有する医療用2液反応型接着剤、及び医療用樹脂 - Google Patents
自己分解性を有する医療用2液反応型接着剤、及び医療用樹脂 Download PDFInfo
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- 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
-
- 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
- A61L24/10—Polypeptides; Proteins
-
- 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
- A61L24/08—Polysaccharides
-
- 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
- A61L24/10—Polypeptides; Proteins
- A61L24/108—Specific proteins or polypeptides not covered by groups A61L24/102 - A61L24/106
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
- C08B37/0021—Dextran, i.e. (alpha-1,4)-D-glucan; Derivatives thereof, e.g. Sephadex, i.e. crosslinked dextran
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08H—DERIVATIVES OF NATURAL MACROMOLECULAR COMPOUNDS
- C08H1/00—Macromolecular products derived from proteins
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09J—ADHESIVES; NON-MECHANICAL ASPECTS OF ADHESIVE PROCESSES IN GENERAL; ADHESIVE PROCESSES NOT PROVIDED FOR ELSEWHERE; USE OF MATERIALS AS ADHESIVES
- C09J103/00—Adhesives based on starch, amylose or amylopectin or on their derivatives or degradation products
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09J—ADHESIVES; NON-MECHANICAL ASPECTS OF ADHESIVE PROCESSES IN GENERAL; ADHESIVE PROCESSES NOT PROVIDED FOR ELSEWHERE; USE OF MATERIALS AS ADHESIVES
- C09J105/00—Adhesives based on polysaccharides or on their derivatives, not provided for in groups C09J101/00 or C09J103/00
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09J—ADHESIVES; NON-MECHANICAL ASPECTS OF ADHESIVE PROCESSES IN GENERAL; ADHESIVE PROCESSES NOT PROVIDED FOR ELSEWHERE; USE OF MATERIALS AS ADHESIVES
- C09J105/00—Adhesives based on polysaccharides or on their derivatives, not provided for in groups C09J101/00 or C09J103/00
- C09J105/02—Dextran; Derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09J—ADHESIVES; NON-MECHANICAL ASPECTS OF ADHESIVE PROCESSES IN GENERAL; ADHESIVE PROCESSES NOT PROVIDED FOR ELSEWHERE; USE OF MATERIALS AS ADHESIVES
- C09J189/00—Adhesives based on proteins; Adhesives based on derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L2666/00—Composition of polymers characterized by a further compound in the blend, being organic macromolecular compounds, natural resins, waxes or and bituminous materials, non-macromolecular organic substances, inorganic substances or characterized by their function in the composition
- C08L2666/02—Organic macromolecular compounds, natural resins, waxes or and bituminous materials
- C08L2666/26—Natural polymers, natural resins or derivatives thereof according to C08L1/00 - C08L5/00, C08L89/00, C08L93/00, C08L97/00 or C08L99/00
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
- C08L5/02—Dextran; Derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L89/00—Compositions of proteins; Compositions of derivatives thereof
Definitions
- the present invention relates to a medical adhesive used for adhesion, filling, and adhesion prevention of living tissue, and hemostasis at the time of surgical operation and others, and a medical grease.
- a medical adhesive particularly a surgical adhesive, (1) a cyanoacrylate adhesive, and
- Fibrin glue (fibrin 'glue) has been mainly used.
- This type of adhesive utilizes the fact that cyanoacrylate monomer is polymerized and solidified using a small amount of moisture as a polymerization initiator, and is fast in polymerization and solidification, and has high adhesion to living tissue.
- the solidified material is inflexible and hard, wound healing may be hindered, and since it is difficult to decompose in vivo, it is easily encapsulated and becomes a foreign substance.
- formaldehyde is produced in the process of decomposition, there are reports that it shows cytotoxicity and tissue damage.
- Fibrin glue is widely used for the purpose of preventing force bleeding such as a sutured part after a surgical operation, which is highly compatible and convenient for living bodies, and enhances tissue adhesion and closure.
- this adhesive has a rather low adhesive strength, the resulting fibrin clot may peel off the tissue strength.
- it is a blood product, there is a concern about virus infection.
- the molar ratio of the aldehyde group Z amino group was about 13.6 ("DA6" in Table 3), and the mixture A two-component reactive adhesive with a ratio of 1Z1 is said to be effective as a hemostatic agent for rat liver.
- the curing time for this adhesive is about 15 seconds according to Table 2.
- Polymer micelle aqueous solution having a structure of terminal aldehyde group (polyethylene glycol chain segment with molecular weight of 5500) (polylactic acid segment with molecular weight of 4000) is the first solution, and an aqueous solution of polyallylamine with a high molecular weight (over 60,000)
- a two-component reactive type “adhesive for animal tissue” is disclosed in which is used as the second solution.
- the second solution uses an aqueous solution of poly-L-lysine (Table 3, and RUN13-14, 16 in Table 1-5) or an aqueous chitosan solution (Table 1 4). It has been shown to be possible.
- acid starch can be used as the first liquid (paragraph number 0031).
- poly-L-lysine has a relatively molecular weight of 30,000. It is shown that it is necessary to use a high molecular weight compound with a molecular weight of 700,000 (RUN13-14, 16 in Table 1).
- the pH of the aqueous solution of poly-L-lysine as the second liquid should be 9.0 or higher (RUN12-16 in Table 3 and Table 5).
- the molecular weight of soluble starch is assumed to be “variable in the range of 1 to 200,000 daltons” (Example 1). Although there is no mention of the molecular weight of collagen, it is considered to be about 300,000, which is the same as the general case.
- This adhesive can be used as a biological tissue adhesive and has an anti-adhesion effect (Examples 3 to 6).
- a medical adhesive in which an aqueous solution containing gelatin obtained by heat denaturation of collagen is used as a first solution, and an aqueous solution containing succinimidized poly-L-glutamic acid is used as a second solution.
- Patent Document 6 an adhesive having an additional strength of polyol and polyisocyanate has been disclosed (see Patent Document 6).
- this adhesive has disadvantages such as being difficult to handle due to its high viscosity, having many blood and body fluids, and difficult to adhere at the site.
- Patent Document 1 WO 2003/035122 (corresponding to AESCULAP AG & CO KG (DE), US2005 / 0002893 Al and EP1438079 Bl)
- Patent Document 2 Japanese Patent Application Laid-Open No. 2005-21454 “Tissue adhesive containing polymer micelle as active ingredient” Hiroshi Nishida, Masayuki Yokoyama
- Patent Document 3 W098 / 15299 (“Macromolecular polyaldehyde-based adhesive composition and collagen cross-linking method”, corresponding to Japanese Patent 323871)
- Patent Document 4 Japanese Patent Laid-Open No. 9 (1997) -103479 “Medical Materials and Manufacturing Method Thereof”
- Patent Document 5 Japanese Patent Laid-Open No. 11 (1999) -239610 “Biomedical tissue-adhesive medical material and method for producing the same”
- Patent Document 6 Japanese Patent Application Laid-Open No. 2004-261590 “Medical Adhesive”
- the fibrin glue When the fibrin glue is used, the physical properties of the cured product cannot be changed or adjusted appropriately when it is made more flexible. In addition, the period of degradation in vivo (generally 1 to 3 days) can be extended. I can't. There is also a report that when cyanoacrylate resin is used, the time required to be completely decomposed and absorbed in the living body is considerably longer than one year. Therefore, for example, it is practically impossible to design such that it is completely decomposed and absorbed in 1 to 2 weeks.
- the obtained cured product maintains an adhesive force, etc., that does not proceed rapidly after a predetermined period of time when there is decomposition or disintegration in vivo. If a sufficient period of time is taken, an undesired resin layer or resin composition may remain for a very long time, which is a problem.
- the desired retention period or degradation start period varies depending on the type of disease and the type of treatment, but it was practically impossible to control the degradation period to meet such detailed requirements.
- the present invention has been made in view of the above. While sufficiently satisfying general properties required for medical adhesives, the present invention rapidly disintegrates after a design collapse time, and the design period is reduced. It provides a medical adhesive that can be adjusted and controlled relatively freely and a water-containing gel-like resin for medical use.
- the medical two-component reactive adhesive of the present invention comprises a first liquid consisting of an aqueous solution of an aldehyde ⁇ -glucan having a weight average molecular weight of 1,000 to 200,000 and a chain of amino group-containing units.
- ⁇ is 5.0 to 8.0.
- the water-containing gel-like medical resin of the present invention comprises a first liquid consisting of an aqueous solution of an aldehyde ⁇ -glucan having a weight average molecular weight of 1,000 to 200,000 and a chain of amino group-containing units.
- a water-containing gel-like medical resin obtained by mixing an aqueous solution of an amino group-containing polymer having a weight average molecular weight of 1000 to 20,000, which also has an aqueous solution power, and comprising a reaction mole of aldehyde group and amino group. If the ratio is 0.2 to 2.0 and stored in a water-containing state, after a gel state retention period that can be arbitrarily set between 1 day and 1 month, it is converted into a sol state by autolysis. It is characterized by changing.
- the system quickly collapses and the design period can be adjusted and controlled relatively freely.
- it has excellent adhesion to living tissues and the like that are free from toxicity and other adverse effects on the living body, and the hydrated gel-like greaves layer is flexible after solidification.
- the time required for the solidification reaction can be adjusted and controlled to some extent as desired.
- Aldehyde a-glucan forming the first liquid is an a-glucan oxidized to introduce an aldehyde group, and has a weight average molecular weight in the range of 1,000 to 200,000.
- A-glucan is a sugar chain in which glucose is dehydrated and condensed through an ⁇ bond, and the molecular weight of a sugar residue (anhydrous glucose 'unit) in glucan is 162.14.
- the a-glucan used in the present invention includes dextran, dextrin, and pullulan, and these can be used in combination. Starch and amylose can also be used if they are decomposed appropriately. High molecular weight pullulan products can also be used after being appropriately decomposed.
- the introduction of the aldehyde group can be carried out by a general periodate method, and it is preferable to provide appropriate self-degradability per anhydroglucose unit.
- 0.1 to 1.0 aldehyde groups more preferably 0.2 to 0.9, and even more preferably 0.3 to 0.8 aldehyde groups are introduced.
- the degree of aldehyde formation is relatively low.
- 0.2 to 0.4 aldehyde groups are introduced per anhydroglucose unit.
- aldehyde-modified dextran and aldehyde-modified dextrin are particularly preferable for reasons such as stability of adhesive performance.
- the weight average molecular weight of the dextran used to obtain the aldehyded dextran is preferably 2000 to 200,000, more preferably 2000 to 100,000.
- medical grade Dextran 40, Dextran 60, Dextran 70 and T-Dextran series Dextran T10 to Dextran T2000 commercially available from Pharmacosmos A / S can be used.
- dextrin used to obtain aldehyded dextrin dextrin sold by Wako Pure Chemicals can be used.
- the weight average molecular weight of dextrin is, for example, 1000 to 10,000.
- the optimal molecular weight of aldehyde ⁇ -glucan varies depending on the specific application, and by selecting a specific molecular weight or molecular weight distribution, it is possible to adjust the time period until the liquid is dissolved by autolysis. it can. If the molecular weight of the aldehyde ⁇ -dulcan is excessively large, the liquid due to self-decomposition is excessively delayed. Moreover, when the molecular weight of the aldehyde-ized ⁇ -dulcan is excessively small, the time for maintaining the gelled state becomes too short.
- the weight average molecular weight and molecular weight distribution of a-glucan can be easily determined by general aqueous GPC (gel filtration chromatography; formally size exclusion chromatography (SEC)) measurement. Specifically, cross-linked water-soluble polymer (TOSOH TSK gel The GPC column consisting of G3000PW, G5000PW, and TSK guard column (PWH) is warmed to 40 ° C, and the buffer (10 mM KH2PO4 + 10 mM K2HPO4) is used as the eluent.
- GPC gel filtration chromatography
- SEC formally size exclusion chromatography
- the amino group-containing polymer forming the second liquid is composed of a chain of amino group-containing units, and has a weight average molecular weight force S i000 to 20,000, preferably 1000 to 10,000, more preferably 1500 to 800,000. is there. Further, it preferably contains substantially no high molecular weight fraction having a molecular weight of 30,000 or more.
- a particularly preferred amino group-containing polymer has a molecular weight fraction of 1000 or more and less than 30,000, and more preferably 100000 to 250,000, when the molecular weight is measured by SDS gel electrophoresis. From the molecular weight fraction alone, more preferably, only the molecular weight fraction of 1000 to 20,000 is obtained.
- “substantially” means that the molecular weight fraction V-stained dyed dot pattern whose weight fraction is 5% or less is ignored!
- the molecular weight distribution (polymerization degree distribution) and average molecular weight of polylysine and other amino-containing polymers can be determined easily and with high accuracy by any of the following methods.
- Ion association chromatography Measured using a reversed-phase column (TSKgel ODS-80Ts) by high performance liquid chromatography (HPLC) ion association chromatography. At this time, measurement is performed while applying a gradient using acetonitrile as a non-aqueous solvent.
- GPC-LALLS low-angle laser light scattering method
- amino group-containing polymer used in the second liquid ⁇ -poly-L-lysine produced using a microorganism or an enzyme and having a molecular weight of 1000 to 20,000, particularly 1000 to 6000 is preferable. It may be mentioned. However, ⁇ -poly-L-lysine may also be used. Also suitable Chitosan oligomer or decomposed chitosan may be used if it has a proper molecular weight and molecular weight distribution. In some cases, polyglycerin or polybulualcohol into which a large number of amino group side chains are introduced may be used.
- ⁇ -poly-L-lysine may be obtained, for example, as follows.
- the strain described in Japanese Patent No. 3525190 or Japanese Patent No. 3653766 is Streptomyces albulus subspecies' lysinopolymeras.
- the amino group-containing polymer in a predetermined molecular weight range can be partially replaced by a higher molecular weight or lower molecular weight amino group-containing polymer.
- chitosan having a high molecular weight for example, a molecular weight of 200,000
- polylysine having only a molecular weight fraction of 1000 to 20,000 up to an equal weight can be blended with polylysine having only a molecular weight fraction of 1000 to 20,000 up to an equal weight.
- PEG-NH aminated polyethylene glycol
- LOOO aminated polyethylene glycol
- a particularly large functional number starting from sucrose or the like is preferable for blending.
- the second liquid is added with an acid or an acid salt as a rhodium regulator.
- ⁇ is a value in the range of 5.0 to 8.0, preferably a value in the range of 5.5 to 7.5. More preferably, the value is in the range of 6.5 to 7.5.
- the ⁇ of the second liquid is preferably 7.0 to 9.0.
- carboxylic acid or anhydride thereof is preferably added.
- carboxylic acid include naturally occurring carboxylic acids such as acetic acid, succinic acid, succinic acid, glutaric acid, malic acid, fumaric acid, and maleic acid. Can be mentioned. Such carboxylic acids are not harmful to the living body because of their large pH control ability due to buffering action. However, it is possible to use inorganic acids or inorganic salts such as hydrochloric acid and sulfuric acid as long as the pH reaches an appropriate value of 5.0 to 8.0, and use in combination with the carboxylic acid or anhydride thereof. You can also. It is also possible to use phosphate buffer salts.
- the gel strength after curing until liquidity is obtained by autolysis under water-containing conditions.
- the period can be adjusted. This is thought to be due to the formation of pseudo-crosslinks in polylysine and other amino group-containing polymers when polyvalent carboxylic acids are used, thereby delaying liquids due to autolysis.
- the molar ratio of the aldehyde group Z amino group in the mixed state of the first liquid and the second liquid is 0.1 or more and less than 3, preferably 0.2 to 2.0, more preferably 0.5 to 1. .5. Closer to the molar ratio power s l of aldehyde group Z an amino group, eliminating the residual aldehyde group or Amino groups small, in further reducing the toxicity, is meaningful.
- the concentration of aldehyde ⁇ -glucan in the first liquid is usually 5 to 50% by weight, and preferably 15 to 25% by weight.
- the concentration of the amino group-containing polymer in the second liquid is usually 0.5 to 60% by weight, preferably 5 to 50% by weight, more preferably 5 to 20% by weight. If the concentration of the first liquid or the second liquid is too low, there is a problem that the curing reaction becomes insufficient. If it is too high, the viscosity of the adhesive liquid becomes high, which leads to handling.
- the first liquid and the second liquid can be easily sterilized by radiation sterilization, and are preferably sterilized by irradiation with an electron beam of 10 to 50KGy, more preferably an electron beam of 20 to 30KGy.
- Such a sterilization treatment can be performed by setting conditions so that the curing time and other adhesive performance are not adversely affected.
- the mixing and application of the first liquid and the second liquid can be performed by various methods. For example, mixing can be performed by applying one of the first and second adhesive stock solutions to the adherend surface and then applying the other. Alternatively, after the first liquid and the second liquid are mixed in the mixing chamber of the coating apparatus, spraying may be performed by spraying from the nozzle cover. It may be done. In some cases, in addition to use as an adhesive, It can also be used for the purpose of preventing adhesions, etc.
- the mixing ratio (volume ratio) between the first liquid and the second liquid is usually set to 0.5 to 2.0, preferably about 1.0 (that is, about the same amount).
- a Schiff bond is formed between the aldehyde group of the aldehyde a-glucan and the amino group of the amino group-containing polymer, which serves as a crosslinking point.
- a hide-mouthed gel having a network structure is formed.
- curing occurs between 2 and 150 seconds, preferably 3 to 100 seconds, more preferably 5 to 50 seconds after mixing.
- the preferred time from mixing to curing varies slightly depending on the application, and in order to penetrate into living tissue and exert a high degree of adhesion, the curing time should be 10 seconds or more, especially 15 seconds or more. preferable.
- the hydrated gel-like cured adhesive layer or the hydrated gel-like resin produced by such a curing reaction changes to a liquid state by self-decomposition after the design liquid period.
- the design disassembly period is arbitrarily set within a range of several hours to 4 power months, usually 1 day to 1 power month, particularly 2 days to 2 weeks.
- the decomposition period by self-decomposition is the selection or adjustment of the molecular weight or distribution of the aldehyde a-glucan and Z- or amino group-containing polymer, the use or non-selection of polyvalent carboxylic acid, and two-component mixing. It can be adjusted and set arbitrarily by adjusting the pH of the hour. In other words, the period of decomposition and absorption can be arbitrarily designed by adjusting the configuration of the two-component adhesive.
- Patent Documents 1 to 3 Conventionally, as seen in the description of Patent Documents 1 to 3, it is necessary to use a high molecular weight aldehyde group-containing polymer in terms of the performance of the adhesive resin. It is thought that preconception prevails.
- the medical adhesive and medical coagulant of the present invention include a bioadhesive, a tissue filler, a hemostatic agent, a vascular embolic agent, an aneurysm sealant, an antiadhesive material, and a drug delivery system (DDS). It can be suitably applied as a carrier for use.
- DDS drug delivery system
- the amount of aldehyde group introduced was measured by the oxidation-reduction titration method. Specifically, 20 ml of 0.05 molZl aqueous iodine solution, 10 ml of lOmgZml aqueous aldehyde dextran solution and 20 ml of ImolZl sodium hydroxide aqueous solution were placed in a 100 ml Meyer flask and stirred at 25 ° C. for 15 minutes. Then add 15ml of 6vZv% sulfuric acid aqueous solution, 0.1ml Titrated with an aqueous solution of sodium thiosulfate in Zi. The end point was when the reaction system became colorless and transparent, and the indicator was an aqueous starch solution.
- the amount of aldehyde groups introduced increased linearly with respect to the amount of sodium periodate added!].
- the amount of sodium periodate relative to the amount of sugar residues was 0.05 to: L
- the amount of aldehyde groups was 0.1 to 2. Therefore, it was found that when an amount of sodium periodate equal to the sugar residue was added, two aldehyde groups were introduced per sugar residue, and the oxidation reaction proceeded efficiently. .
- Aldehyde dextran was obtained according to the method of Section 2 by reacting 20 g of dextran having a molecular weight of 75000 (Wako Pure Chemical Industries, Ltd., Lot No. EWK3037) with 5 g of sodium periodate. Thereafter, a 20 wt% aqueous solution was prepared and used as the first solution.
- the cytotoxicity test was performed using the mouse isolated cell line L929 according to the method described in J. Biomed. Mater. Res., 29, 829-835 (1995). Specifically, first, 0.1 ml of the cell suspension prepared to 10000 cellsZml was seeded on a 96-well culture plate and cultured at 37 ° C. for 3 days. Next, the above-mentioned various aqueous solutions were diluted to various concentrations with a medium, added with 0.1 ml each, and further cultured for 2 days. Subsequently, 0.1 ml each of the -eutralar red medium solution prepared to 150 / z gZml was added and cultured at 37 ° C for 3 hours.
- the medium was removed, and finely fixed with a 1 wt% aqueous solution of dartalaldehyde and air-dried.
- 0.1 ml each of water Z ethanol solution (same volume mixture) containing 1% by weight acetic acid was added to extract -eutralar red molecules taken up by viable cells.
- the absorbance at 541 nm was measured, and the NR50 value was determined based on the measured value.
- the NR50 value is the solution concentration required to kill 50% of the cells. The lower the value, the stronger the toxicity.
- Table 3 summarizes the NR50 values of various compounds.
- the NR50 value of aldehyde dextran is> 6000 ⁇ gZml, which is 1/3500, 1/1500 or less, respectively, compared with formaldehyde and glutaraldehyde.
- the toxicity was found to be very slight.
- polylysine has extremely low toxicity, and each component of the adhesive is considered extremely safe.
- Section (added sodium periodate 10g against dextran in 20 g) obtained 20 weight 0/0 aldehyde dextran solution at 2 and 20 wt% of the neutral polylysine aqueous solution, the first and second, respectively Two liquids were used. That is, the two-part adhesive of Example 1 was employed. Then, about 0.5 ml (0.25 + 0.25 ml) of these adhesive stock solutions were applied to a laboratory rubber glove using a dedicated mixing device, and thinly stretched. After being allowed to cure for about 1 minute, air was put into the gloves using an air pump to expand the cured product.
- Figure 2 shows the state of the cured adhesive before expansion (a) and after expansion (b). In the figure, the colored adhesive (Blue No. 1, Wako Pure Chemical Industries, Ltd., Lot No. KLN3789) is the cured adhesive gel.
- the adhesive cured product was expanded about three times in diameter by the air injection. From this result, it was found that the adhesive of this example (Example 1) was very flexible even after curing. Although photos and data are omitted, when the molecular weight of dextran is 40000, the amount of sodium periodate added to 20 g of dextran is 3 g or 5 g, or when dextrin is used, Similarly, a flexible and tough gel-like resin layer was obtained. [0066] 5. Evaluation of Adhesive Strength Using Usagi Skin
- 20 weight 0/0 aldehyde dextran aqueous solution obtained in Section 4 was first liquid. Also, 20% by weight neutral polylysine aqueous solution obtained in Section 2, 30% by weight and 50% by weight bifunctional PEG-NH aqueous solution, and 50% by weight tetrafunctional PEG-NH aqueous solution,
- Second liquid Only the 20% by weight neutral polylysine aqueous solution in the second liquid is the adhesive of the example (Example 1).
- Adhesive strength (gf / cm 2 ) A liquid 2nd liquid
- the 75,000 molecular weight aldehyde dextran aqueous solution (20% by weight) used in Section 3 was used.
- the same 10% by weight neutral polylysine solution as in Section 3 was prepared and used as the second solution. That is, the adhesive of Example 1 was employed.
- the following experiment was conducted using rabbits (body weight 2.5-3.0 kg, female).
- Fig. 4 shows the state of decomposition of the cured adhesive. It was confirmed that the degradation gradually started 3 days after implantation, and about 90% after 4 weeks. The tissue reaction also showed no adverse effects that were of particular concern from the tissue section images, indicating that safety was high. Furthermore, during the decomposition experiment, there was no particular decrease in the appetite of the rabbits, and no adverse effects due to the placement of the adhesive were confirmed.
- the degradation rate of the cured adhesive was evaluated by the method described in Section 6.
- the results are summarized in Figure 5.
- the notation in the figure means the weight ratio of acetic acid to citrate, and the leftmost is the case where ⁇ is adjusted with acetic acid only on the left and chenic acid only on the right.
- the acid species used for ⁇ adjustment of the polylysine aqueous solution was only acetic acid, it was completely decomposed after 4 days, whereas as the amount of citrate increased, the decomposition of the cured product was delayed.
- the original shape was retained after 2 weeks, and complete disassembly took more than 2 months. From this, it was shown that the decomposition rate of the cured adhesive can be easily controlled by the type and amount of ⁇ adjuster.
- ⁇ -poly-L-lysine powder having a molecular weight of 4000 (Chisso Corporation, Lot No. 20211023F) was subjected to vacuum drying (heat treatment) at 180 ° C.
- the molecular weight of the obtained heat-treated ⁇ -poly-L-lysine was evaluated by gel electrophoresis. Here, 15% SDS is used as the electrophoresis gel, and the electrophoresis gel is used.
- the running buffer solution (Nacalai Testa Co., 0.25 mol / KTris, 1.92 mol / kg glycine, 10 g / g SDS) was used as the moving fluid, and the measurement was performed at a current of 50 mA using a device from Nippon Aidichi Co.
- the obtained heat-treated polylysine powder was dissolved in distilled water to 10 wt%, and 4 wt% acetic acid was contained to prepare a second liquid.
- the first liquid used was an aldehyde-dextran aqueous solution (20 wt%) having a molecular weight of 75000 used in Section 3.
- the first and second liquids were mixed and the decomposition rate of the cured adhesive was evaluated according to the method described in Section 6. The result is shown in FIG.
- the degradation period increases with the treatment time (molecular weight), and degradation takes 2 days at treatment time 0, compared to 2 weeks at treatment time 1.5 hours, and more than 1 month when treated for another 6 hours. It cost.
- the degradation time of the cured product can be easily delayed by the choice of ⁇ modifier (such as acetic acid or citrate), so low molecular weight ⁇ -poly-L-
- ⁇ modifier such as acetic acid or citrate
- the period of degradation can be freely adjusted from early to long, whereas when using polylysine after heat treatment for a long time, this adjustment will be difficult.
- heat treatment at 180 ° C for about 0.5 hours or less can be used as a treatment for adjusting the decomposition period.
- the molecular weight of the aldehyde group-containing polymer is tens of thousands or less, which is necessary for fully exhibiting the self-degradability of the present invention. Judgment can be made.
- Each solution was filtered using a syringe filter (Dismic 25-AS020AS, manufactured by Advante c) having a pore size of 0.2 ⁇ m, and each solution was packed in a 5 ml glass ampule and sealed.
- a syringe filter (Dismic 25-AS020AS, manufactured by Advante c) having a pore size of 0.2 ⁇ m, and each solution was packed in a 5 ml glass ampule and sealed.
- the first and second liquids were used as a set, and sterilization was performed at 25 ° C under the conditions shown in Table 5, left end.
- the 75,000 molecular weight aldehyde dextran aqueous solution (20% by weight) used in Section 3 was used.
- the same 10% by weight neutral polylysine aqueous solution as in Section 3 was prepared and used as the second solution.
- These were mixed using a dedicated mixing device, and 2 ml was poured into a cell culture 24-well plate (bottom area 2 cm 2 ). After 2 minutes at 25 ° C, tensile tester (Shimadzu Corporation The hardness of the cured product was evaluated by pressing a 6.6 mm diameter hemisphere against the cured adhesive product at a speed of lOmm / min using ADS-5D) and measuring the compressive stress.
- fibrin glue Bolheel, Institute of Chemo- and Serum Therapy
- the stress value (mN) at that time is plotted against the penetration amount (mm) of the hemisphere into the cured product.
- the slope of the adhesive was about half that of the fibrin glue, while the penetration was about 1 mm. From this, it was shown that the hardened
- the adhesive of the present invention has a strain-tail stress curve by a compression test by setting the amount of sodium periodate added to 20 g of dextran to 3 g and 10 g. I was able to change it. That is, by changing the degree of aldehyde formation of a-glucan and changing the molar ratio of aldehyde group and Z amino group, the crosslink density during curing can be freely changed, and the flexibility of the gel-like resin layer after curing can be changed. Can be adjusted freely.
- the 75,000 molecular weight aldehyde dextran aqueous solution (20% by weight) used in Section 3 was used.
- the same 10% by weight neutral polylysine solution as in Section 3 was prepared and used as the second solution. That is, the two-part adhesive of Reference Example 3 was used.
- an adhesion test was conducted using cowhide as an adherend. Cut cowhide (TRUSCO's JT-5L, work floor leather sleeve long gloves) into 1 x 5cm strips, bond 2 skins with 1 x 1cm bonding area, 5 minutes under 100g load Allowed to cure.
- fibrin glue Bolheel, Institute of Chemotherapy and Serum Therapy
- the adhesive strength of this adhesive was 2024 ⁇ 563 gf / cm 2
- that of fibrin glue was 519 ⁇ 136 gf / cm 2
- the average value showed adhesive strength nearly four times that of fibrin glue, and many samples showed lkg / cm 2 or more, whereas fibrin glue was too short to cure, making it difficult to produce an adhesive.
- the bond strength was also very large.
- the method in section 2 The curing time measured with the adhesive was about 10 seconds for this adhesive, whereas it was less than 1 second for fibrin glue.
- the second liquid corresponds to the adhesive of Example 1 (Section 2).
- a midline incision was made on the abdomen of the sacrificed rabbit to expose the liver. Then, using a scalpel, the incision force was continuously bleeded by making a wound (cut) of about 2 cm in length and about 5 mm in depth. Subsequently, using a dedicated mixing device, equal volumes of the first and second adhesive stock solutions were mixed and applied to the incision.
- FIG. 9 shows the liver before and after hemostasis when polylysine aqueous solution was used as the second solution, indicating that hemostasis was effectively achieved.
- the adhesive film was firmly fixed to the liver. From this, it was found that the adhesive of this example exerted an excellent effect as a hemostatic agent in the digestive surgery field.
- the 75,000 molecular weight aldehyde dextran aqueous solution (20%) used in Section 3 was used.
- the same 10% by weight neutral polylysine aqueous solution as in Section 3 was prepared and used as the second solution. That is, the same two-component adhesive as in Reference Example 3 (Section 3) was prepared.
- the scores were 2.4 ⁇ 0.5, 1.2 ⁇ 0.4, 3.2 ⁇ 0.4, 1.2 in the order of untreated, fibrin glue, adhesive of Reference Example 3 (section 3), and dextrin-type example, respectively. ⁇ 0.4 for the first time.
- FIG. 10 shows a tissue section image of the affected area after 4 weeks of surgical force (Masson-Trichrome staining).
- the remaining cured product can be confirmed on the core surface.
- the epicardium on the surface of the heart is scratched with gauze to create an adhesion-inducing site.
- the epicardium is almost peeled off due to abrasion, and the myocardial tissue is exposed and applied to the site.
- the tissue surrounding the adhesive is the tissue that was created later.
- the amount of adhesive applied is the same.
- the amount of the cured product remaining was very small compared to the case of Reference Example 3 because it decomposed quickly. For this reason, it is thought that adhesion was also slight. From the above, it was shown that the adhesive of this example is effective as an anti-adhesion agent in the cardiovascular surgical field because the degradation rate can be easily controlled.
- the 20% by weight aldehyde dextran aqueous solution used in Section 8 was prepared and used as the first solution.
- the 20% by weight neutral A lysine aqueous solution was prepared and used as the second solution (taenoic acid content 4%). That is, a two-component adhesive corresponding to Reference Example 3 (Section 3) was prepared.
- the adhesive of Reference Example 3 exhibits the same properties and performance as the adhesive of each Example, except that the decomposition is somewhat slow.
- Anesthesia was performed by inhalation of isoflurane by intubation after leaving in an ether atmosphere for about 30 seconds. Blood flow was stopped by suturing the left ventricular free wall of the rat, and puncture was made by puncturing with a 19 gauge needle. After confirming that the suture was temporarily loosened and bleeding in a pulsatile manner, it was sutured again to completely stop blood flow. The surrounding blood was removed, and a paper with a hole slightly larger than 19 gauges was placed on the heart to prevent the adhesive and blood from leaking out.
- the 75,000 molecular weight aldehyde dextran aqueous solution (20% by weight) used in Section 3 was used.
- the same 10% by weight neutral polylysine aqueous solution as in Section 3 was prepared and used as the second solution. That is, a two-component adhesive corresponding to Reference Example 3 (Section 3) was prepared.
- Fig. 11 shows the lung surface before and after application of the adhesive, and it can be seen that the defect site is coated with the cured adhesive by application. The post-operative course was good with both the adhesive and fibrin glue, and no dogs were allowed to leak again. From this result, it was shown that this adhesive is highly effective for embolizing lung air leakage in the field of respiratory surgery.
- the second component bifunctional PEG-NH, has a molecular weight of 3000 but has amino groups only at both ends, so it reacts only at the ends.
- reaction force was the same as in Reference Example 1.
- the force did not cure even after 7 hours.
- 1 ml of the first solution was added to the test tube, and lOO mg of Y.H. chitosan oligosaccharide powder was added and mixed in place of the second solution.
- 3 ml of phosphate buffer solution (PBS) was added, and after sealing the tube, the adhesive cured product was observed over time. As a result, it completely liquidated in 6 hours.
- PBS phosphate buffer solution
- YH chitosan oligosaccharide has one amino group per sugar residue, but its molecular weight is too low so that no gel is formed at 50% by weight, and an effective gel network structure even when powder is used. Is not formed, so it is considered that it was quickly decomposed
- FIG. 1 is a graph showing the relationship between the amount of sodium periodate added and the amount of aldehyde groups introduced. (Section 1)
- FIG. 2-1 Photo (1) showing the appearance of the cured adhesive when the glove is expanded after applying the adhesive to rubber gloves.
- FIG. 2-2 Photo (2) showing the appearance of the cured adhesive when the gloves are expanded after the adhesive is applied to rubber gloves. (Section 4)
- FIG. 4-1 Photograph (1) showing how the cured adhesive is broken down on the rabbit liver.
- FIG. 4-2 Photograph (2) showing how the cured adhesive is broken down on the rabbit liver. (Section 7)
- Photograph (5) showing the state of decomposition of the cured adhesive prepared using polylysine whose pH was adjusted with a mixture of acetic acid and citrate.
- Photograph (6) showing the state of decomposition of a cured product of an adhesive prepared using polylysine adjusted to pH with a mixture of acetic acid and citrate.
- FIG. 6-1 is an electrophoresis pattern (1) of heat-treated polylysine. (Section 9)
- FIG. 7-1 A photograph (1) showing the state of degradation over time of a cured adhesive prepared using heat-treated polylysine. (Section 9)
- FIG. 7-2 is a photograph (2) showing the state of degradation over time of a cured adhesive prepared using heat-treated polylysine. (Section 9)
- FIG. 7-3 is a photograph (3) showing the state of degradation over time of a cured adhesive prepared using heat-treated polylysine. (Section 9)
- FIG. 7-4 is a photograph (4) showing the state of degradation over time of the cured adhesive prepared using heat-treated polylysine. (Section 9)
- FIG. 7-5 is a photograph (5) showing the state of degradation over time of the cured adhesive prepared using heat-treated polylysine. (Section 9)
- FIG. 7-6 is a photograph (6) showing the state of degradation over time of the cured adhesive prepared using heat-treated polylysine. (Section 9)
- FIG. 10-1 A tissue section image (1) of the affected area 4 weeks after application to the adhesion-inducing site. (Section 14)
- FIG. 10-2 A tissue section image (2) of the affected area 4 weeks after application to the adhesion-inducing site. (Section 14)
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Abstract
Description
Claims
Priority Applications (5)
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CN2006800036346A CN101111272B (zh) | 2005-01-31 | 2006-01-31 | 具有自分解性的医疗用2液反应型粘合剂及医疗用树脂 |
JP2007500647A JP4092512B2 (ja) | 2005-01-31 | 2006-01-31 | 自己分解性を有する医療用2液反応型接着剤、及び医療用樹脂 |
EP06712686.2A EP1849486B1 (en) | 2005-01-31 | 2006-01-31 | Self-degradable two-component reactive adhesive for medical use and resin for medical use |
KR1020077019753A KR101201056B1 (ko) | 2005-01-31 | 2006-01-31 | 자기 분해성을 갖는 의료용 2액 반응형 접착제 및 의료용수지 |
US11/881,941 US7834065B2 (en) | 2005-01-31 | 2007-07-30 | Medical-use two part reactive adhesive and medical-use resin having self-degradation property |
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JP2005-054577 | 2005-01-31 | ||
JP2005054577 | 2005-01-31 | ||
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JP2005-128610 | 2005-03-29 |
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US11/881,941 Continuation-In-Part US7834065B2 (en) | 2005-01-31 | 2007-07-30 | Medical-use two part reactive adhesive and medical-use resin having self-degradation property |
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EP (1) | EP1849486B1 (ja) |
JP (1) | JP4092512B2 (ja) |
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WO (1) | WO2006080523A1 (ja) |
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Also Published As
Publication number | Publication date |
---|---|
JPWO2006080523A1 (ja) | 2008-06-19 |
KR101201056B1 (ko) | 2012-11-14 |
EP1849486A1 (en) | 2007-10-31 |
EP1849486B1 (en) | 2015-04-08 |
KR20070104446A (ko) | 2007-10-25 |
JP4092512B2 (ja) | 2008-05-28 |
CN101111272A (zh) | 2008-01-23 |
CN101111272B (zh) | 2010-09-29 |
EP1849486A4 (en) | 2011-12-28 |
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