JP5353159B2 - Method for producing medical material and medical material - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a medical care material more excellent in antithrombogenicity, biocompatibility and safety than conventional medical care materials. <P>SOLUTION: A method of manufacturing the medical care material is characterized in that a solution A of polysaccharide except heparin and a solution B of phospholipid are prepared separately, and that then the solution A is added to the solution B while the latter is being agitated, so that the phospholipid is introduced into the polysaccharide molecular chains through ionic bonds. <P>COPYRIGHT: (C)2010,JPO&amp;INPIT

Description

  The present invention is a novel and highly safe composition used for medical use or cosmetics, in particular, an antithrombotic material excellent in biocompatibility and hydrophilicity, a lubricant, a wound dressing material, a mucosal protective material, an immunosuppressive material, The present invention relates to a composition in which a polysaccharide having a low anticoagulant activity and an phospholipid are ion-bonded, which can be suitably used for medical applications such as an adhesion prevention material and a drug sustained-release base.

  Biocompatible materials using naturally derived compounds are widely applied in the medical industry or the cosmetics industry, and are particularly suitably used in the medical industry due to the precise molecular design and excellent safety of naturally derived compounds. Among them, heparin typified by naturally derived compounds is widely used as a coating material for medical substrates as a material having excellent anticoagulant activity.

  Speaking of medical base materials requiring anticoagulant activity, blood such as artificial heart, artificial heart valve, artificial blood vessel, vascular catheter, cannula, artificial heart lung, vascular bypass tube, aortic balloon pumping, infusion device and extracorporeal circuit There are those that are used in direct contact, and many techniques for immobilizing an antithrombogenic material on these substrates have been disclosed.

  As a method for developing antithrombogenicity on the substrate surface, there is a method for improving biocompatibility by treating the substrate surface with a hydrophilic treatment. This is manifested by the water molecule barrier created by the hydrophilic surface inhibiting the contact between the blood component and the substrate. Among them, the polymer using 2-methacryloyloxyethylphosphocholine called MPC polymer has a structure similar to phospholipid, which is a main component of biological membranes, and therefore exhibits excellent hydrophilicity and biocompatibility. (See Patent Document 1 and Patent Document 2).

Also disclosed is a method for producing a biocompatible material by combining naturally-derived materials instead of a polymerizable polymer using a polymerization initiator. For example, a derivative by peptide bond can be produced by reacting a glycosaminoglycan, in particular, a carboxyl group of hyaluronic acid and an amino group of lipid in the presence of a catalyst in a mixed solvent of water and a cyclic ether (see Patent Document 3). However, since the catalyst used for production is toxic to the living body, a process for complete removal is required. Moreover, since the cyclic ether used for a solvent is also toxic, the process of removing completely is required. In addition, these natural materials are bound by covalent bonds. If they are eluted from the base material into the blood and the body, it is unlikely to be decomposed into individual natural materials. There is no denying the possibility that the safety will not be fully demonstrated.
Japanese Patent No. 3207210 Japanese Patent No. 3802656 JP 2006-348071 A

  It is an object of the present invention to provide a medical material that is superior in antithrombogenicity and, consequently, biocompatibility and high in safety compared to conventional medical materials.

  The inventor of the present invention is a complex composed of a combination of highly safe materials, and has an excellent antithrombogenicity, biocompatibility, hydrophilicity, and a material suitable for medical use having such durability. As a result of investigation, it was found that a material in which a polysaccharide and a phospholipid are complexed by ionic bonding can solve the above-mentioned problems, and the present invention has been completed.

That is, the present invention has the following configuration.
(1) A solution A in which a polysaccharide excluding heparin is dissolved and a solution B in which a phospholipid is dissolved are prepared separately, and the solution A is added to the solution B to be stirred, so that the phospholipid is ionized in the polysaccharide molecular chain. a method of manufacturing a to that physician Ryoyo material introduced by coupling,
(A) The solution A is polysaccharide / alcohol / water = 0.01 / 0 / 99.9 to 20/56/24
(B) The solution B is phospholipid / alcohol / water = 0.01 / 99.9 / 0 to 20/32/48
A method characterized by that.
(2) The method for producing a medical material according to (1), wherein the ionic bond is a bond between an anionic group in a polysaccharide molecular chain and a cationic group of a phospholipid.
(3) The method for producing a medical material according to (1) or (2), wherein the temperature when the solution A is added to the solution B is 80 ° C. or less.
( 4 ) The polysaccharide is an acid selected from fucoidan, alginic acid, hyaluronic acid, chondroitin sulfate, heparan sulfate, dermatan sulfate, keratan sulfate, dextran sulfate, carboxymethylcellulose, pectin, pectic acid, hexuronic acid, carrageenan, xanthan gum, rhamnan sulfate. It is at least 1 sort (s) of polysaccharide, The manufacturing method of the medical material in any one of (1)-( 3 ) characterized by the above-mentioned.
( 5 ) The method for producing a medical material according to any one of (1) to ( 4 ), wherein the polysaccharide has a molecular weight of 500 to 1,500,000.
( 6 ) The method for producing a medical material according to any one of (1) to ( 5 ), wherein the phospholipid is at least one selected from compounds represented by the following general formulas 1 to 5 .

(In the formula, R 1 and R 2 represent an alkyl group having 10 to 24 carbon atoms, and may be the same or different.)

(In the formula, R 3 and R 4 represent an alkyl group having 10 to 24 carbon atoms, and may be the same or different.)

(In the formula, R5 and R6 each represent an alkyl group having 10 to 24 carbon atoms, and may be the same or different.)

(In the formula, R7 represents an alkyl group having 10 to 24 carbon atoms.)

(In the formula, R8 and R9 each represent an alkyl group having 10 to 24 carbon atoms, and may be the same or different.)
( 7 ) The method for producing a medical material according to any one of (1) to ( 6 ), wherein monovalent or / and divalent ions are further added to the solution B.
( 8 ) A medical material comprising a complex in which a phospholipid is introduced into a polysaccharide molecular chain by ionic bonding by the method according to any one of (1) to ( 7 ).

  The composite obtained by the production method of the present invention is highly safe because it is insoluble in water, and has excellent biocompatibility because of a high balance between hydrophilicity and hydrophobicity. It can be suitably used as a treatment material. In addition, since the physical properties of the material are insoluble in water, the long-term surface treatment effect can be maintained. Furthermore, since polysaccharides and phospholipids are complexed by ionic bonds, they have harmful effects on the human body. Therefore, it can be used for human tissues such as skin. In addition, by applying the present invention, a composite can be produced with a high yield, so that the production cost can be kept low.

  In the present invention, it is preferable that the solution A in which the polysaccharide is dissolved and the solution B in which the phospholipid is dissolved are prepared separately, and the polysaccharide and the phospholipid are reacted by dropping the solution A while stirring the solution B. . In order to ion-bond the polysaccharide and the phospholipid, it is necessary to optimize the ion selectivity of the ionic group of each compound and the cohesive force when the compound changes from a dissolved state to an insoluble state. Here, when a hydrophilic polysaccharide and a hydrophobic phospholipid are dissolved in the same solution and reacted (ion-bonded), either compound becomes insoluble or non-uniform when the compound is dissolved. Or one of the compounds may not be ionized and ionic bonding may not be achieved. In addition, even if both can be dissolved using a strong co-soluble solvent, the complex itself also dissolves, and the aggregation effect due to insolubilization cannot be obtained, or the recovery rate cannot be increased. May occur. Therefore, it is the first point of the present invention to prepare a solution in which each compound is dissolved separately and to use them for the reaction.

  The medical material obtained by the production method of the present invention is preferably composed of a complex in which a phospholipid is introduced into a polysaccharide molecular chain by ionic bonding as described above. Other possible methods for introducing phospholipids into the polysaccharide molecular chain are covalent bonds. However, a catalyst, oxidizing agent, reducing agent, strong acid, strong alkali, etc. are used for the reaction. When used for applications, it is necessary to completely remove these in consideration of adverse effects on living bodies. In addition, since the molecular structure itself of the complex may change due to the covalent bond, the living body may recognize the complex as a foreign substance, which may impair the original safety of polysaccharides and phospholipids.

  In addition, ionic bonds are not as strong as covalent bonds, and therefore, the original safety of each molecule can be maintained. The ionic bond is that each compound is only attracted electrically, the structure itself is not changed, and in the presence of other ions, the bond is gradually released due to the selectivity of the ions, Eventually, it may be possible to return completely to individual molecules. This is a great merit as a biomaterial. In vivo, for example, in blood, there are many ions such as sodium ion, potassium ion, calcium ion, etc. Therefore, even when a complex consisting of ionic bonds is eluted and mixed in blood, It can be degraded and returned to the original highly safe individual molecules (compounds). Therefore, if it is a highly safe compound, for example, a compound of biological origin, plant origin, natural origin, etc., or an ionic conjugate of a synthetic product that has already been confirmed to be safe, absorption, metabolism and excretion in vivo There seems to be little risk in terms of surface.

  In the present invention, the solution A in which the polysaccharide is dissolved is preferably one in which the polysaccharide is dissolved in water alone or in a mixed solvent of alcohol and water. Since polysaccharides are mainly water-soluble and most of them are ionized in water, water is preferred as a solvent for polysaccharides, but this reduces the reactivity with hydrophobic phospholipids. Further, the reason for mixing the alcohol is to increase the hydrophobicity of the mixed solution of both liquids and promote the aggregation of the complex when mixed with a solution containing phospholipid. Other organic solvents can be considered to increase the hydrophobicity, but alcohol is preferable in consideration of safety to living bodies and miscibility with water. Examples of the alcohol include methanol, ethanol, isopropyl alcohol and the like, and ethanol is preferable.

  In the present invention, the solution B in which the phospholipid is dissolved is preferably alcohol alone or a mixed solvent of alcohol and water as a solvent. Since phospholipids are mainly insoluble in water and aggregate in water, it is preferable to use alcohol for dissolution or uniform dispersion. The reason for mixing water is that the ionic group of the phospholipid is not ionized by alcohol alone, so that water is mixed and ionized. Alcohol alone can be ionized and bonded instantaneously when the two solutions are mixed, but mixing water in advance is preferable because of its high bonding rate. The alcohol used for the solution B is preferably the same alcohol used for the solution A.

  The weight of the polysaccharide dissolved in water A or a mixed solvent of alcohol and water in the solution A is preferably 0.01 to 20% by weight with respect to 100 weight of the mixed solvent of water alone or alcohol and water. When it is 0.01% by weight or less, the yield of the composite becomes extremely small, which is disadvantageous in terms of cost. In addition, when the amount is 20% by weight or more, the viscosity is remarkably increased, so that even if the two liquids are mixed, they cannot be mixed sufficiently and non-uniform bonding may occur.

  The weight ratio of alcohol to water in the solution A is preferably alcohol / water = 0 to 70/30 to 100. When the alcohol content is 70% by weight or more or the water content is 30% by weight or less, the polysaccharide is insolubilized and a uniform complex may not be obtained. That is, in the solution A, the mixing ratio of polysaccharide / alcohol / water is preferably 0.01 / 0 / 99.9 to 20/56/24.

  The weight of the phospholipid dissolved in the solvent B in the solvent B alone or in the mixed solvent of alcohol and water is preferably 0.01 to 20% by weight with respect to 100 weight of the alcohol alone or the mixed solvent of alcohol and water. When the amount is 0.01% by weight or less, the yield of the combined complex is extremely small, which is disadvantageous in terms of cost. In addition, in the case of 20% by weight or more, the phospholipid is saturated and an insoluble matter is formed, and even if the two liquids are mixed, they may not be mixed sufficiently, resulting in uneven bonding. .

  The weight ratio of alcohol to water in the solution B is preferably alcohol / water = 40 to 100/0 to 60. If the weight ratio of alcohol / water is 40 to 100/0 to 60, the phospholipid can be uniformly dissolved or dispersed. When the alcohol content is 40% by weight or less or the water content is 60% by weight or more, the phospholipid is remarkably insolubilized and aggregated, and a uniform complex may not be obtained. That is, the solution B of the present invention is adjusted at a weight ratio of phospholipid / alcohol / water = 0.01-20 / 40-100 / 0-60. That is, in the solution B, the mixing ratio of phospholipid / alcohol / water is preferably 0.01 / 99.9 / 0 to 20/32/48.

  In the present invention, the number average molecular weight of the polysaccharide is preferably 500 to 1,500,000. If the number average molecular weight is 500 to 1,500,000, a sufficient amount of phospholipid can be introduced into the polysaccharide structure by ionic bonding. When the number average molecular weight is 500 or less, there are only 1 or 2 saccharide units, and the number of ionic groups is small, so that the binding is not performed sufficiently, or the absolute amount of phospholipid is small, which is for medical use. The effectiveness as a material may not be obtained. In addition, when the number average molecular weight is 1,500,000 or more, the complex bound to the phospholipid becomes an ultra-high molecular weight complex and becomes insoluble in a solvent, or even when dissolved, the viscosity is too high and the handleability is high. It may decrease and cannot be used for coating applications.

  Polysaccharides applied to the present invention include hyaluronic acid, fucoidan, alginic acid, chondroitin sulfate, heparan sulfate, dermatan sulfate, keratan sulfate, dextran sulfate, carboxymethylcellulose, pectin, pectic acid, hexuronic acid, carrageenan, xanthan gum, rhamnan sulfate, etc. Acidic polysaccharides are preferable, and among them, plant-derived fucoidan and alginic acid, which have no risk of viral infection and are considered to be highly safe, are preferable. More preferred is fucoidan having a highly hydrophilic sulfate group. However, heparin that strongly expresses a pharmacological anticoagulant action is not preferable for patients or patients affected by bleeding because of risk. If a patient has any bleeding problems, the fact that heparin has been used, even if it is a heparin-containing complex designed not to elute, can make it difficult to completely negate the causal relationship. Because there is.

  The polysaccharide applied to the present invention is composed of at least one selected from the above-mentioned polysaccharides, and these compounds are medically acceptable salts such as sodium salt, potassium salt, calcium salt, Also good.

  Fucoidan and alginic acid are plant-derived polysaccharides and are mainly contained in brown algae. The ionic group capable of binding to the phospholipid is a sulfate group for fucoidan and a carboxyl group for alginic acid. Hyaluronic acid and heparin are polysaccharides derived from living organisms. Hyaluronic acid is mainly contained in chicken caps, and heparin is mainly contained in pig intestines and cow lungs. Among ionic groups that can bind to phospholipids, hyaluronic acid is a carboxyl group and fucoidan is a sulfate group. Since these polysaccharides are widely used as pharmaceuticals, medical devices, or foods, they can be suitably used as medical materials.

In the present invention, the phospholipid is at least one selected from compounds represented by the following general formulas 1 to 5, and these phospholipids are all preferably phospholipids having an N + ionic group. The alkyl chain at the terminal of the phospholipid is preferably one having 1 to 2 alkyl chains and 10 to 24 carbon atoms. At this time, all the carbon-carbon bonds of the alkyl chain do not have to be single bonds, and may include one or more double bonds, that is, an unsaturated alkyl chain. The phospholipid of general formula 1 is phosphatidylcholine (PC), the phospholipid of general formula 2 is phosphatidylethanolamine (PE), the phospholipid of general formula 3 is sphingomyelin (SPM), and the phospholipid of general formula 4 is lysophosphatidylcholine (LysoPC). ), Phospholipids of general formula 5 are commonly referred to as phosphatidylserine (PS).
If R ₁ = 14 and R ₂ = 16 in the general formula 1, it is expressed as myristoyl palmitoyl phosphatidylcholine (MPPC). In addition, naturally-occurring phospholipids such as egg-derived, soybean-derived, and milk-derived lecithin are mixed with phospholipids represented by the general formulas 1 to 5, and the composition ratio varies depending on the origin. Thus, the phospholipid applied to the present invention contains at least one phospholipid represented by the general formulas 1 to 5 of natural origin or synthetic product, and may be a combination of several phospholipids such as lecithin. . The reason for selecting these phospholipids is that an ionic group of N + is contained, so that the production method of the present invention enables ionic bonds with polysaccharides.
(Wherein R ₁ and R ₂ represent an alkyl group having 10 to 24 carbon atoms, and may be the same or different from each other.)
(Wherein R ₃ and R ₄ represent an alkyl group having 10 to 24 carbon atoms, and may be the same or different from each other.)
(In the formula, R ₅ and R ₆ represent an alkyl group having 10 to 24 carbon atoms, and may be the same or different.)
(In the formula, R ₇ represents an alkyl group having 10 to 24 carbon atoms.)
(Wherein R ₈ and R ₉ represent an alkyl group having 10 to 24 carbon atoms, and may be the same or different from each other.)

The number of carbon atoms of _R 1 to R ₉ in the general formula 1-5 is preferably 10-24. When the number of carbon atoms is 9 or less, the hydrophobicity is lowered, and the performance that should originally be imparted to the polysaccharide may not be obtained. In addition, when the number of carbon atoms is 25 or more, when preparing the solution B, it becomes insoluble in alcohol and cannot be uniformly dissolved or dispersed, or when it becomes an ionic bond complex, it is too hydrophobic and becomes a solvent. It may become inconvenient for applications such as coating because it does not melt.

On the other hand, other phospholipids such as phosphatidylglycerol (PG) represented by the general formula 6 and phosphatidic acid (PA) represented by the general formula 7 do not have an N + ionic group. Ion bonding is not possible. In order to bind these to polysaccharides, it may be possible to covalently bond them, but depending on the type of catalyst or reducing agent used, it may be necessary to consider the harm to the living body, or the safety of the covalently bonded complex itself It is doubtful.
(In the formula, R ₁₀ and R ₁₁ represent an alkyl group having 10 to 24 carbon atoms.)
(Wherein R ₁₂ and R ₁₃ represent an alkyl group having 10 to 24 carbon atoms.)

  In the present invention, the binding rate between the polysaccharide and the phospholipid is 1 to 100%. The binding rate here means how many phospholipids are bound to the number of ionic groups of the polysaccharide, specifically the number of sulfate groups or carboxyl groups, in the complex. . That is, the binding rate = the number of phospholipids in the complex / the number of ionic groups of the polysaccharide in the complex × 100. When the binding rate is less than 1%, the amount of phospholipid bound is extremely small, so that the effects of imparting hydrophobicity, imparting dispersibility, imparting biocompatibility, etc. cannot be obtained sufficiently, which is different from a polysaccharide alone. There is a possibility of becoming a complex.

  One factor that determines the binding rate is the ratio of the weight of polysaccharide in solution A to the weight of phospholipid in solution B. In the present invention, the ratio of the weight of the polysaccharide in the solution A / the weight of the phospholipid in the solution B = 5 to 99/1 to 95 is preferable. When the weight ratio of the polysaccharide is 99 or more and the weight ratio of the phospholipid is 1 or less, the amount of phospholipid bound to the polysaccharide becomes extremely small, and the binding rate may not be increased. Further, when the weight ratio of the polysaccharide is 5 or less and the weight ratio of the phospholipid is 95 or more, the phospholipid is sufficiently bound in the polysaccharide and the binding rate is sufficiently high, but the unbound phospholipid is excessive. Therefore, purification becomes difficult and disadvantageous in terms of cost.

  In the production method of the present invention, the temperature at the time of mixing the solution A and the solution B may be a relatively low temperature such as room temperature or lower, but it is preferable to warm the solution A and the solution B, respectively. The temperature of the solution is preferably 40 to 100 ° C, more preferably 60 to 80 ° C. Reasons for warming the solution include increasing the solubility of the raw materials in the solution and decreasing the viscosity of the solution. By increasing the solubility, the ionization of the ionic compound can be promoted to make it easy to form an ionic bond. In addition, for the purpose of lowering the viscosity, it is necessary to mix the solutions A and B uniformly when mixing them. Therefore, a solution having a remarkably high viscosity cannot be mixed uniformly, and the binding rate between composites is poor. May be uniform.

  Particularly, since the viscosity of the high molecular weight polysaccharide contained in the solution A increases remarkably as the concentration in the solution increases, it is preferable to mix them in a state where the viscosity is lowered by heating. (For reference, temperature and viscosity data for fucoidan and alginic acid are shown in FIG. 1). The viscosity of the solution for making the bonding rate uniform between the composites is preferably 30,000 cP or less. By reducing the viscosity of the solution, the mobility of polysaccharide molecules and phospholipid molecules is increased, the collision probability is increased, and the binding rate between the complexes can be made uniform.

  In the production method of the present invention, the yield of the composite is preferably 15 to 90%, more preferably 50 to 90%. The yield (%) in the present invention is calculated by “weight of the obtained complex / (weight of polysaccharide contained in solution A + weight of phospholipid contained in solution B) × 100”. Factors affecting the yield include the content of polysaccharides and phospholipids in the solution. To increase the yield, many polysaccharides and phospholipids can be dissolved in the solution. However, as described above, when a large amount is dissolved, the viscosity of each solution increases or the solubility of the raw material decreases. As a result, the quality of the complex may be deteriorated. Therefore, it is preferable to prepare the composition so as to contain as much polysaccharide and phospholipid as possible by heating to lower the viscosity.

  Further, by adding monovalent or / and divalent cations to the solution B, the yield of the complex of the present invention can be increased. Since the phospholipid used in the present invention has both a cationic group of N + and an anionic group of a phosphate group, when the anionic group of the polysaccharide and N + are bonded, the anion of the phosphate group It is conceivable that the sex group inhibits the binding. However, by adding a monovalent or divalent cation to the solution B containing a phosphate group, it was found that the yield of the complex was dramatically increased by masking the anionic group of the phosphate group. It was. This masking effect promotes the formation of the complex and increases the yield. By using this method, the present inventor has succeeded in increasing the yield of the composite to a maximum of about 600%, that is, increasing the yield to a maximum of about 90%. .

  Examples of the monovalent or divalent cation added to the solution B include medically acceptable ions such as sodium ion, potassium ion, calcium ion, and magnesium ion. It is also conceivable to use silver ions in anticipation of effects such as imparting antibacterial properties. These ions may be medically acceptable salts with chloride ions, sulfate ions and the like. By adding these ions, the yield of the complex can be increased, but there are ions that are not suitable depending on the patient's health condition and application, so in such cases there is no need to add ions. good. For example, for patients with hyperkalemia or hypercalcemia, a complex synthesized without adding ions is used, or ions other than potassium are added when injecting the complex directly into the blood. It is preferable to use a composite with no added ions. Moreover, after forming a composite_body | complex, the method of removing an ion can also be taken.

  The complex obtained by the method of the present invention is preferably water-insoluble. Here, water-insoluble means that 0.1 g of the complex is added to a beaker containing 10 g of water and sufficiently stirred at room temperature for 24 hours or more, then centrifuged at 3000 rpm for 15 minutes in a centrifuge, and the supernatant is discarded. It means that the weight of the remaining precipitate after freeze-drying is 50% or more of the initial weight. It is preferable in that it is insoluble in water, so that even when a living tissue or medical substrate is coated and contacted with living tissue or blood, the complex is prevented from being eluted into blood or the like. Moreover, since it can stay on a biological tissue or a medical base material for a long time, a long-term effect can be expected.

  Furthermore, the composite obtained by the method of the present invention is preferably excellent in water dispersibility. Water dispersibility refers to the property of being insoluble and uniformly dispersible in water or a liquid containing a large amount of water, and is characterized by appearing white and cloudy. For example, generally well-known milk is in a state of being uniformly dispersed without precipitation or aggregation even though the components are water-insoluble. This is because the water-insoluble component holds the hydrophilic part and the hydrophobic part in a balanced manner. The complex obtained by the method of the present invention also has water dispersibility because it has both the hydrophilicity of the polysaccharide and the hydrophobicity of the phospholipid. The merit of the composite having water dispersibility is that water can be used as a solvent when the coating liquid is used. In general, alcohol and various organic solvents are used to coat a hydrophobic material on a substrate, but it is often inconvenient to damage the substrate or extract the additive in the substrate. . In addition, these organic solvent-based coating liquids can be coated only on the substrate for extracorporeal circulation. Cannot be used. Therefore, the composite having water dispersibility is not only advantageous when coating a substrate, but also has an advantage that it can be used for a living body. Of course, taking into account the efficiency of the drying time, etc., it is also an option to use it dissolved in an organic solvent.

  The present invention is a novel and highly safe composition used for medical use or cosmetics, in particular, an antithrombotic material excellent in biocompatibility and hydrophilicity, a lubricant, a wound dressing material, a mucosal protective material, an immunosuppressive material, The present invention relates to a composition in which a polysaccharide and a phospholipid are combined, which can be suitably used for medical applications such as an adhesion preventing material and a sustained-release drug base. In order to purify the obtained complex, a general method such as reprecipitation with a complex-insoluble solvent or dialysis of the complex dispersion is also possible.

  Since the solution obtained by mixing the solution A and the solution B contains unbound polysaccharides and phospholipids in addition to the complex obtained by ionic bonding, it is purified to obtain a highly pure complex. Is required. In order to purify the obtained complex, a general method such as reprecipitation with a complex-insoluble solvent or dialysis of the complex dispersion is also possible. In this invention, it is preferable to reprecipitate using water, alcohol, and another organic solvent. As the solvent used for reprecipitation, water, methanol, ethanol, isopropyl alcohol, tetrahydrofuran, and acetone, which have low solubility of the complex, are used, and may be mixed with other solvents.

  As an actual reprecipitation treatment method, for example, 5 to 10 parts by weight of water is added to 1 part by weight of the obtained composite and sufficiently stirred and dispersed. It implements by dripping at 10-20 weight part reprecipitation solvent with respect to 1 weight part of obtained dispersion solutions. If the complex cannot be sufficiently purified by one reprecipitation, the same operation may be performed twice or more. Further, when the precipitation is slow or does not sufficiently precipitate, it may be separated by an operation such as centrifugation.

  In order to use the purified composite as a material, it is necessary to remove the solvent by drying. Examples of the drying method include freeze drying, warm drying, and reduced pressure drying. When purification and drying are completed, the complex of the present invention becomes a white or slightly yellow white powder, and is easy to store, transport and weigh.

  The composite obtained by the above-described method of the present invention is insoluble in water and can be preferably used as a surface treatment agent for tissues and medical substrates. As a specific embodiment, a solution obtained by dissolving and dispersing the obtained complex in an organic solvent or water can be applied to the surface of a substrate such as a medical device, and then the solvent can be removed. As another method for supporting the composite obtained by the method of the present invention on the substrate surface, the composite can also be formed on the substrate surface. Specifically, the substrate is coated with a solution in which phospholipids and phospholipids and cations are dissolved and dispersed, and then a solution in which polysaccharides are dissolved is immersed. Then, a composite is formed on the base material, and the adhesion to the base material becomes strong. As described above, the method of supporting the composite on the base material does not necessarily require that the composite is manufactured in advance, and the composite can be formed on the base material.

  The complex obtained by the method of the present invention is a combination of highly safe materials of polysaccharide and phospholipid, and can be suitably used as a medical material.

  The complex obtained by the method of the present invention combines the hydrophilicity / water retention property of polysaccharides with the hydrophobicity / water resistance properties of the alkyl groups of phospholipids, improving biocompatibility due to hydrophilicity, and water retention properties. The structure and the substrate can be protected by the adhesion, the adhesion to the substrate by the hydrophobic property, and the long-term effect by the water resistance can be exhibited. On the other hand, since a polysaccharide alone can exhibit hydrophilicity and water retention properties, it easily dissolves in water, so that it cannot stay on a substrate or the like for a long time, and only a short-term effect can be obtained. In addition, phospholipid alone can adhere to a substrate or the like due to hydrophobicity, but cannot form a hydrophilic surface. Moreover, it is considered that the phospholipid adhering to the base material is easily peeled off by an external pressure such as a water pressure. This is considered to be because phospholipid alone has only one or two adhesion portions with the base material. However, since the complex of polysaccharide and phospholipid has multiple adhesion surfaces to the base material that one molecule has, the hydrophobic part of the phospholipid part adheres firmly to the base material, and the hydrophilicity of the polysaccharide. Sexual part covers the underwater surface. Furthermore, when a cation is contained in the complex of the present invention, phospholipids are also ionically bonded to each other by the cation, so that the adhesion to the substrate is further increased (FIGS. 2 to 4). Thus, the complex of the present invention has characteristics that could not be obtained with conventional polysaccharides and phospholipids alone.

  Although the composite obtained by the method of the present invention is insoluble in water, it also has excellent dispersibility in water. Dispersibility in water is a characteristic often found in amphiphilic molecules such as surfactants, and is used as an emulsifier and a cleaning agent. Although a water-insoluble compound can be dissolved in an organic solvent or the like, it is not preferable to use a water-insoluble compound because an organic solvent that is highly irritating to the skin cannot be used in cosmetics and the like. However, the composite of the present invention having excellent dispersibility in water can be easily mixed and dispersed in an aqueous cosmetic solution. Further, since micelles can be formed in water and the drug can be included in the micelle, application to a drug delivery system for the drug can also be considered.

  Since the medical material comprising the composite obtained by the present invention is excellent in blood compatibility such as antithrombotic properties, it can be used for the surface treatment of medical devices that come into contact with blood or body fluids. Examples of such medical devices include blood filters, blood storage containers, blood circuits, indwelling needles, catheters, guide wires, stents, artificial lung devices, dialysis devices, adhesion prevention materials, wound dressings, and biological tissue adhesive materials. And a repair material for living tissue regeneration. In particular, a medical device having an extracorporeal circuit and having a blood contact portion is a preferred embodiment.

  Here, all the materials normally used are included as a base material of a medical device. That is, polyvinyl chloride, polycarbonate, polyethylene terephthalate, polyethylene, polypropylene, polymethylpentene, thermoplastic polyether polyurethane, thermosetting polyurethane, silicone rubber such as polydimethylsiloxane having a crosslinked portion, polymethyl methacrylate, polyacetal, polystyrene, Examples thereof include ABS resins and mixtures of these resins, and metals such as stainless steel, titanium, and aluminum.

  EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, this invention is not limited by these.

(Measurement of coupling rate)
The measurement of the binding rate was carried out by analyzing the surface elemental composition of the sample by ESCA measurement (ESCA-5500MC manufactured by PERKIN ELMER PHI). Measurement conditions were such that the excitation source used was an Al-Kα ray, the output was 14 kV, 150 W, a monochromator was used, and the take-off angle was 65 degrees. The control element and functional group were the S element or COO group of the polysaccharide, and the phospholipid was the P element, and the binding rate was calculated from these ratios. If the S element or COO group and the P element have the same strength, the bonding rate is 100%.

(Measurement of weight composition ratio)
The weight composition ratio was measured by NMR (JEOL JNM-alpha400), and the obtained mole composition ratio was multiplied by the molecular weight of each composition to calculate the weight composition ratio.

(Measurement of yield)
The weight of the obtained complex was defined as the yield when the sum of the weight of the polysaccharide contained in solution A and the weight of the phospholipid contained in solution B was 100%. That is, “weight of the obtained complex / (weight of polysaccharide contained in solution A + weight of phospholipid contained in solution B) × 100” was calculated. The case where the yield was less than 15% was indicated by Δ, the case where the yield was 15 to 49% was indicated by ○, and the case where the yield was 50% or more was indicated by ◎.

(Water insolubility test)
After adding 0.1 g of the complex to a beaker containing 10 g of water and stirring well for at least 24 hours at room temperature, centrifuge at 3000 rpm for 15 minutes, discard the supernatant and freeze-dry the remaining precipitate. When the weight was 50% or more of the initial weight, it was judged to be water-insoluble and evaluated as ◯.

(Water dispersibility test)
Add 0.1 g of sample and 10 g of distilled water to a 20 ml vial, stir well for about 1 hour, cap the vial, and let stand at room temperature (25 ° C.) for 24 hours. Thereafter, the solution was measured with a spectrophotometer at a wavelength of 600 nm, and a sample having an absorbance of 1.000 or more was marked as ◯. In addition, the supernatant was measured when precipitation had arisen after standing still. As an example, a photograph of a solution having an absorbance of 2.313 is shown (FIG. 5).

(Aging process)
A composite was coated on a 25 × 25 × 1 mm PVC sheet to prepare a sample. This sample was aged in physiological saline at 37 ° C. for 30 days to obtain an aging sample for blood compatibility and hydrophilicity test.

(Blood compatibility test)
0.2 mL of fresh blood removed from the rabbit was dropped onto the upper surface of the aging sample for blood compatibility test in a 60 x 15 mm petri dish (Corning, polystyrene), then covered and incubated at 37 ° C for 24 hours . Thereafter, 5 mL of a 2.5% by weight aqueous glutaraldehyde solution was added, and the mixture was allowed to stand at room temperature for 24 hours. After replacing the solution in the petri dish with water three times, water was removed. The PVC sheet washed with water was frozen at −5 ° C. for 24 hours and then dried at 0.1 Torr for 24 hours. A 10 × 10 mm piece was cut from the blood-attached portion and attached to a scanning electron microscope (SEM) sample stage with double-sided tape to obtain a measurement sample. Using a measurement sample subjected to ion vapor deposition, the state of adhesion of blood components (platelets, red blood cells, white blood cells) was photographed by SEM. Compare the observed SEM photographs (× 1000 magnification) by visual observation. ◎ When the number of adhering blood components (platelets, red blood cells, white blood cells) is 10 or less, ◎, when 10 or less and less than 50, ○, 50 or more The case was marked △.

(Hydrophilic surface test)
0.5 ml of a colored aqueous solution of 0.1% by weight of Orange II reagent (manufactured by Wako) is dropped on the center of an aging sample for hydrophilicity test in a 60 × 15 mm petri dish (Corning, polystyrene), and the shape is a circle after standing for 1 minute. The diameter of the water drop area was measured. Since polystyrene as a base material is hydrophobic, when a coloring reagent is dropped on the base material itself, the diameter of the circular water droplet region becomes small due to the hydrophobicity. If the surface of the base material is subjected to hydrophilic treatment, the surface of the base material becomes hydrophilic and the diameter of the circular water droplet region increases. If the diameter exceeds 20 mm, the surface is considered to be a sufficient hydrophilic surface. A case where the diameter is 25 mm or more is rated as ◎, a case where the diameter is 20 mm or more and less than 25 mm is given as ◯, and a case where it is less than 20 mm is given as △. In the case of an untreated petri dish, it was 10.9 mm.

(Risk assessment)
Determine whether there is a possible risk when coating a medical substrate that comes into contact with blood or injecting it into the body, and (1) is likely to elute in the blood, or (2) Judge whether there is a risk that the complex contains harmful substances.If both (1) and (2) are not considered, ○, either (1) and (2) or The case where both possibilities were considered was evaluated as Δ.

Example 1
2 g of fucoidan (Sigma Aldrich) having a number average molecular weight of 50,000 was dissolved in 80 g of distilled water, and 20 g of ethanol was further added and stirred well. Next, 8 g of egg-derived phosphatidylcholine (Egg-PC, product name: COATSOME NC-50, Nippon Oil & Fats) dissolved in 80 g of ethanol, and further stirred with distilled water of 0.2 g of calcium chloride (Wako) 20g was added. These solutions were heated to 70 ° C., and the solution containing fucoidan was added little by little to the solution containing Egg-PC while stirring. After all the solutions were mixed and stirred for 1 hour, a solid precipitate was collected. The solution contained in the precipitate was sufficiently removed, 50 g of distilled water was added, and the mixture was sufficiently stirred and dispersed. This dispersion was added dropwise with stirring to 500 g of ethanol in a 1 L beaker for purification, and the same purification operation was performed twice. After sufficiently removing ethanol from the precipitate obtained after purification, lyophilization was performed to obtain Complex 1.

  Next, in order to coat the composite 1 on the base material, a PVC sheet of 25 × 25 × 1 mm is immersed in 100 g of a solution in which the composite 1 is dispersed in distilled water so as to be 1 wt%, and dried at a temperature of 60 ° C. The solvent was removed by drying in the apparatus for 24 hours. Using this coated PVC sheet, a water insolubility test, a water dispersibility test, a blood compatibility test, and a hydrophilic surface test were conducted.

(Example 2)
3.3 g of sodium hyaluronate (Sigma Aldrich) having a number average molecular weight of 300,000 was dissolved in 70 g of distilled water, and 30 g of ethanol was further added and stirred well. Next, 6.7 g of diel coil phosphatidylethanolamine (DEPE, product name: COATSOME ME2121-AL, Nippon Oil & Fats Co., Ltd.) was dissolved in 70 g of ethanol, and further 30 g of distilled water added with 0.3 g of sodium chloride was added with stirring. These solutions were heated to 60 ° C., and the solution containing sodium heparin was added little by little to the solution containing DEPE while stirring. After all the solutions were mixed and stirred for 1 hour, a solid precipitate was collected. The solution contained in the precipitate was sufficiently removed, 50 g of distilled water was added, and the mixture was sufficiently stirred and dispersed. This dispersion was added dropwise with stirring to 500 g of ethanol in a 1 L beaker for purification, and the same purification operation was performed twice. After sufficiently removing ethanol from the precipitate obtained after purification, lyophilization was performed to obtain Complex 2.

  Next, in order to coat the composite 2 on the substrate, a PVC sheet of 25 × 25 × 1 mm was immersed in 100 g of a solution in which the composite 2 was dispersed in distilled water so as to be 1 wt%. The solvent was removed by drying in a dryer for 24 hours. Using this coated PVC sheet, a water insolubility test, a water dispersibility test, a blood compatibility test, and a hydrophilic surface test were conducted.

(Example 3)
5.0 g of sodium alginate having a number average molecular weight of 600,000 (Sigma Aldrich) was dissolved in 90 g of distilled water, and 10 g of ethanol was further added and stirred well. Next, 5.0 g of didecanoylphosphatidylcholine (DDPC, product name: COATSOME MC1010, Nippon Oil & Fats Co., Ltd.) was dissolved in 90 g of ethanol, and further 10 g of distilled water added with 0.3 g of magnesium chloride was added with stirring. These solutions were heated to 60 ° C., and the solution containing fucoidan was added little by little to the solution containing Egg-PC while stirring. After all the solutions were mixed and stirred for 1 hour, a solid precipitate was collected. The solution contained in the precipitate was sufficiently removed, 50 g of distilled water was added, and the mixture was sufficiently stirred and dispersed. This dispersion was added dropwise with stirring to 500 g of ethanol in a 1 L beaker for purification, and the same purification operation was performed twice. After sufficiently removing ethanol from the precipitate obtained after purification, lyophilization was performed to obtain Complex 3.

  Next, in order to coat the composite 3 on the substrate, a PVC sheet of 25 × 25 × 1 mm was added to 100 g of a solution obtained by dissolving the composite 3 in DMF (N, N-dimethylformamide) so as to be 1 wt%. It was immersed and dried in a dryer at a temperature of 60 ° C. for 24 hours to remove the solvent. Using this coated PVC sheet, a water insolubility test, a water dispersibility test, a blood compatibility test, and a hydrophilic surface test were conducted.

Example 4
2.5 g of fucoidan (Sigma Aldrich) having a number average molecular weight of 1 million was dissolved in 50 g of distilled water, and 50 g of ethanol was further added and stirred well. Next, 7.5 g of egg-derived lecithin (Wako) was dissolved in 70 g of ethanol, and 30 g of distilled water was added while stirring. These solutions were heated to 40 ° C., and the solution containing fucoidan was added little by little to the solution containing egg-derived lecithin while stirring. After all the solutions were mixed and stirred for 1 hour, a solid precipitate was collected. The solution contained in the precipitate was sufficiently removed, 50 g of distilled water was added, and the mixture was sufficiently stirred and dispersed. This dispersion was added dropwise with stirring to 500 g of ethanol in a 1 L beaker for purification, and the same purification operation was performed twice. After sufficiently removing ethanol from the precipitate obtained after purification, lyophilization was performed to obtain Complex 4.

  Next, in order to coat the composite 4 on the substrate, a PVC sheet of 25 × 25 × 1 mm is immersed in 100 g of a solution in which the composite 4 is dissolved in cyclohexane so that the concentration of the composite 4 is 1 wt%, and drying is performed at a temperature of 60 ° C. The solvent was removed by drying in the apparatus for 24 hours. Using this coated PVC sheet, a water insolubility test, a water dispersibility test, a blood compatibility test, and a hydrophilic surface test were conducted.

(Example 5)
6.7 g of fucoidan (Sigma Aldrich) having a number average molecular weight of 1.5 million was dissolved in 100 g of distilled water and stirred well. Next, 3.3 g of milk-derived sphingomyelin (Milk-SPM, product name: COATSOME NM-70, Nippon Oil & Fats) is dissolved in 50 g of ethanol, and 50 g of distilled water in which 0.5 g of silver nitrate is dissolved is added while stirring. It was. These solutions were heated to 60 ° C., and the solution containing fucoidan was added little by little to the solution containing Milk-SPM while stirring. After all the solutions were mixed and stirred for 1 hour, a solid precipitate was collected. The solution contained in the precipitate was sufficiently removed, 50 g of distilled water was added, and the mixture was sufficiently stirred and dispersed. This dispersion was added dropwise with stirring to 500 g of ethanol in a 1 L beaker for purification, and the same purification operation was performed twice. After sufficiently removing ethanol from the precipitate obtained after purification, lyophilization was performed to obtain Complex 5.

  Next, in order to coat the composite 5 on the substrate, 25 × 25 × 1 mm in 100 g of a solution in which the composite 5 is dispersed in distilled water / ethanol mixed solvent (50 wt% vs. 50 wt%) so as to be 1 wt%. The PVC sheet was dipped and dried in a dryer at a temperature of 60 ° C. for 24 hours to remove the solvent. Using this coated PVC sheet, a water insolubility test, a water dispersibility test, a blood compatibility test, and a hydrophilic surface test were conducted.

(Example 6)
9.9 g of fucoidan having a number average molecular weight of 5000 (Sigma Aldrich) was dissolved in 40 g of distilled water, and 60 g of ethanol was further added and stirred well. Next, 0.1 g of myristoyl stearoyl phosphatidylcholine (MSPC, product name: COATSOME MC-4080, NOF Corporation) was dissolved in 40 g of ethanol, and 60 g of distilled water in which 0.6 g of calcium chloride was dissolved was further added with stirring. These solutions were heated to 60 ° C., and a solution containing fucoidan was added little by little to the MSPC solution while stirring. After all the solutions were mixed and stirred for 1 hour, a solid precipitate was collected. The solution contained in the precipitate was sufficiently removed, 50 g of distilled water was added, and the mixture was sufficiently stirred and dispersed. This dispersion was added dropwise with stirring to 500 g of ethanol in a 1 L beaker for purification, and the same purification operation was performed twice. After sufficiently removing ethanol from the precipitate obtained after purification, lyophilization was performed to obtain Complex 6.

  Next, in order to coat the composite 6 on the substrate, a PVC sheet of 25 × 25 × 1 mm was immersed in 100 g of a solution in which the composite 6 was dissolved in EDA (ethylenediamine) so as to be 1 wt%, and the temperature was 60 The solvent was removed by drying in a drier at 24 ° C. for 24 hours. Using this coated PVC sheet, a water insolubility test, a water dispersibility test, a blood compatibility test, and a hydrophilic surface test were conducted.

(Example 7)
8.9 g of sodium alginate having a number average molecular weight of 30,000 (Sigma Aldrich) was dissolved in 60 g of distilled water, and 40 g of ethanol was further added and stirred well. Dipalmitoylphosphatidylserine (DPPS, product name: COATSOME MS-6060LS, Nippon Oil & Fats) 1.1 g was dissolved in 80 g of ethanol, and further 20 g of distilled water in which 0.2 g of potassium chloride was dissolved was added with stirring. These solutions were heated to 60 ° C., and a solution containing sodium alginate was added little by little to the DPPS solution while stirring. After all the solutions were mixed and stirred for 1 hour, a solid precipitate was collected. The solution contained in the precipitate was sufficiently removed, 50 g of distilled water was added, and the mixture was sufficiently stirred and dispersed. This dispersion was added dropwise with stirring to 500 g of ethanol in a 1 L beaker for purification, and the same purification operation was performed twice. After sufficiently removing ethanol from the precipitate obtained after purification, lyophilization was performed to obtain Complex 7.

  Next, in order to coat the composite 7 on the base material, a PVC sheet of 25 × 25 × 1 mm is immersed in 100 g of a solution in which the composite 7 is dissolved in cyclohexane so that the concentration of the composite 7 is 1 wt%, and drying is performed at a temperature of 60 ° C. The solvent was removed by drying in the apparatus for 24 hours. Using this coated PVC sheet, a water insolubility test, a water dispersibility test, a blood compatibility test, and a hydrophilic surface test were conducted.

(Example 8)
0.5 g of sodium hyaluronate (Sigma Aldrich) having a number average molecular weight of 1 million was dissolved in 30 g of distilled water, and 70 g of ethanol was further added and stirred well. 9.5 g of stearoyl lysophosphatidylcholine (S-LysoPC, product name: COATSOME MC-80H, NOF Corporation) was dissolved in 100 g of ethanol. These solutions were heated to 60 ° C., and a solution containing sodium hyaluronate was added little by little to the S-LysoPC solution while stirring. After all the solutions were mixed and stirred for 1 hour, a solid precipitate was collected. The solution contained in the precipitate was sufficiently removed, 50 g of distilled water was added, and the mixture was sufficiently stirred and dispersed. This dispersion was added dropwise to 500 g of ethanol in a 1 L beaker with stirring to perform purification, and the same purification operation was performed twice. After sufficiently removing ethanol from the precipitate obtained after the purification, lyophilization was performed to obtain a complex 8.

  Next, in order to coat the composite 8 on the substrate, a PVC sheet of 25 × 25 × 1 mm is immersed in 100 g of a solution in which the composite 8 is dissolved in DMSO (dimethyl sulfoxide) so as to be 1 wt%. The solvent was removed by drying in a dryer at 60 ° C. for 24 hours. Using this coated PVC sheet, a water insolubility test, a water dispersibility test, a blood compatibility test, and a hydrophilic surface test were conducted.

(Comparative Example 1)
By using dioleoylphosphatidylethanolamine (DOPE, product name: COATSOME ME-8181, Nippon Oil & Fats Co., Ltd.), sodium hyaluronate, EDC, and HOBt, a complex 9 is obtained according to Example 1 described in JP-A-2006-348071. It was.

  Next, in order to coat the composite 9 on the substrate, a PVC sheet of 25 × 25 × 1 mm was added to 100 g of a solution in which the composite 9 was dissolved in DMF (N, N-dimethylformamide) so as to be 1 wt%. It was immersed and dried in a dryer at a temperature of 60 ° C. for 24 hours to remove the solvent. Using this coated PVC sheet, a water insolubility test, a water dispersibility test, a blood compatibility test, and a hydrophilic surface test were conducted.

(Comparative Example 2)
5.0 g of fucoidan (Sigma Aldrich) having a number average molecular weight of 2 million was dissolved in 20 g of distilled water, and 80 g of ethanol was further added and stirred well. Distearoyl phosphatidylglycerol sodium (DSPG-Na, product name: COATSOME MG-8080LS, Nippon Oil & Fats Co., Ltd.) 5.0 g was dissolved in 10 g of ethanol, and 90 g of distilled water in which 0.9 g of calcium chloride was dissolved was added and stirred well. These solutions were heated to 60 ° C., and the solution containing fucoidan was added little by little to the DSPG-Na solution while stirring. After all the solutions were mixed and stirred for 1 hour, a solid precipitate was collected. The solution contained in the precipitate was sufficiently removed, 50 g of distilled water was added, and the mixture was sufficiently stirred and dispersed. This dispersion was added dropwise with stirring to 500 g of ethanol in a 1 L beaker for purification, and the same purification operation was performed twice. After sufficiently removing ethanol from the precipitate obtained after purification, lyophilization was performed to obtain a mixture 1.

  Next, in order to coat the mixture 1 on the substrate, a PVC sheet of 25 × 25 × 1 mm was immersed in 100 g of a solution in which the mixture 1 was dissolved in EDA (ethylenediamine) so as to be 1 wt%, and the temperature was 60 ° C. The solvent was removed by drying in a dryer for 24 hours. Using this coated PVC sheet, a water insolubility test, a water dispersibility test, a blood compatibility test, and a hydrophilic surface test were conducted.

(Comparative Example 3)
100 g of ethanol was added to 0.5 g of heparin sodium (Sigma Aldrich) having a number average molecular weight of 100,000, and the mixture was stirred well. 9.5 g of sodium dipalmitoyl phosphatidylate (DPPA-Na, product name: COATSOME MA-6060LS, Nippon Oil & Fats) was added to 100 g of distilled water and stirred well. These solutions were heated to 60 ° C., and a solution containing sodium heparin was added little by little to the DPPA-Na solution while stirring. After all the solutions were mixed and stirred for 1 hour, a solid precipitate was collected. The solution contained in the precipitate was sufficiently removed, 50 g of distilled water was added, and the mixture was sufficiently stirred and dispersed. This dispersion was added dropwise with stirring to 500 g of ethanol in a 1 L beaker for purification, and the same purification operation was performed twice. After sufficiently removing ethanol from the precipitate obtained after purification, lyophilization was performed to obtain a mixture 2.

  Next, in order to coat the mixture 2 onto the substrate, a 25 × 25 × 1 mm PVC sheet was immersed in 100 g of a solution in which the mixture 2 was dissolved in distilled water so as to be 1 wt%. And dried for 24 hours to remove the solvent. Using this coated PVC sheet, a water insolubility test, a water dispersibility test, a blood compatibility test, and a hydrophilic surface test were conducted.

  In the blood compatibility test, as shown in Tables 1 and 2, Examples 1 to 8 show good blood compatibility even after aging treatment for 30 days. This is because the phospholipid part in the complex showed excellent water resistance and could remain on the substrate for a long time, and the polysaccharide part in the complex covered the blood contact part on the substrate surface. This is considered to be due to the excellent blood compatibility.

  On the other hand, in Comparative Examples 1 to 3 shown in Table 3, sufficient effects were not exhibited. In Comparative Example 1, it is not clear whether the effect is due to the remaining catalyst or the strong bond due to the covalent bond, but it is not preferable to use it for the blood contact portion. Moreover, in Comparative Examples 2-3, since ionic bond was not performed, it is thought that it flowed down rapidly in the aging process.

  The complex of the present invention is a complex composed of a highly safe material, is excellent in blood compatibility and biocompatibility, and can be used as a medical material for hydrophilic treatment. Moreover, since it is a substance insoluble in water, the effect can be maintained for a long time. Therefore, it is important to contribute to industrial development.

Relationship between temperature and viscosity of aqueous polysaccharide solution Schematic diagram of substrate adhesion of phospholipid alone Schematic diagram of substrate adhesion in the present invention 1 Schematic diagram of substrate adhesion in the present invention 2 Example of water-dispersible compound solution A photograph showing the results of the blood compatibility test of Example 1 A photograph showing the results of the blood compatibility test of Example 2 A photograph showing the results of the blood compatibility test of Example 3 A photograph showing the results of the blood compatibility test of Example 4 Photograph showing results of blood compatibility test of Example 5 Photograph showing results of blood compatibility test of Example 6 Photograph showing results of blood compatibility test of Example 7 Photograph showing results of blood compatibility test of Example 8 A photograph showing the results of the blood compatibility test of Comparative Example 1 A photograph showing the results of the blood compatibility test of Comparative Example 2 Photograph showing results of blood compatibility test of Comparative Example 3 A photograph showing the results of the hydrophilic surface test of Example 1 A photograph showing the results of the hydrophilic surface test of Example 2 Photograph showing results of hydrophilic surface test of Example 3 Photograph showing results of hydrophilic surface test of Example 4 A photograph showing the results of the hydrophilic surface test of Example 5 Photograph showing the results of the hydrophilic surface test of Example 6 Photograph showing the results of the hydrophilic surface test of Example 7 A photograph showing the results of the hydrophilic surface test of Example 8 Photo showing the results of the hydrophilic surface test of Comparative Example 1 Photograph showing results of hydrophilic surface test of Comparative Example 2 Photo showing the results of the hydrophilic surface test of Comparative Example 3

Claims (8)

A solution A in which polysaccharides other than heparin are dissolved and a solution B in which phospholipids are dissolved are prepared separately, and the solution A is added to the solution B to be stirred to introduce phospholipids into the polysaccharide molecular chains by ionic bonds. a method of manufacturing a be that physicians Ryoyo material,
(A) The solution A is polysaccharide / alcohol / water = 0.01 / 0 / 99.9 to 20/56/24
(B) The solution B is phospholipid / alcohol / water = 0.01 / 99.9 / 0 to 20/32/48
A method characterized by that.   The method for producing a medical material according to claim 1, wherein the ionic bond is a bond between an anionic group in the polysaccharide molecular chain and a cationic group of the phospholipid.   The method for producing a medical material according to claim 1 or 2, wherein the temperature when the solution A is added to the solution B is 80 ° C or lower. The polysaccharide is an acidic polysaccharide selected from fucoidan, alginic acid, hyaluronic acid, chondroitin sulfate, heparan sulfate, dermatan sulfate, keratan sulfate, dextran sulfate, carboxymethylcellulose, pectin, pectic acid, hexuronic acid, carrageenan, xanthan gum, rhamnan sulfate. It is at least 1 sort (s) or more, The manufacturing method of the medical material in any one of Claims 1-3 characterized by the above-mentioned. Method for producing a medical material according to any one of claims 1-4 in which the molecular weight of the polysaccharide is characterized in that it is a 500 to 1,500,000. The method for producing a medical material according to any one of claims 1 to 5 , wherein the phospholipid is at least one selected from compounds represented by the following general formulas 1 to 5 .

(In the formula, R 1 and R 2 represent an alkyl group having 10 to 24 carbon atoms, and may be the same or different.)

(In the formula, R 3 and R 4 represent an alkyl group having 10 to 24 carbon atoms, and may be the same or different.)

(In the formula, R5 and R6 each represent an alkyl group having 10 to 24 carbon atoms, and may be the same or different.)

(In the formula, R7 represents an alkyl group having 10 to 24 carbon atoms.)

(In the formula, R8 and R9 each represent an alkyl group having 10 to 24 carbon atoms, and may be the same or different.) The method for producing a medical material according to any one of claims 1 to 6, wherein monovalent or / and divalent ions are further added to the solution B. A medical material comprising a complex in which a phospholipid is introduced into a polysaccharide molecular chain by ionic bonding by the method according to any one of claims 1 to 7 .