JP2017023374A - Medical device and manufacturing method therefor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a medical device where surfaces of not only a silicone hydrogel, but also hydrous or non-hydrous material other than silicone hydrogel are made into a hydrophilic state by once heat treatment at good cost efficiency.SOLUTION: There is provided a medical device having a polymer layer in at least a part on a substrate surface, the polymer layer has at least two kinds of acidic polymer and the content of a basic polymer in the polymer layer is 3 pts,mass or less based on total 100 pts,mass of the acidic polymer.SELECTED DRAWING: None

Description

  The present invention relates to a medical device and a manufacturing method thereof.

  Conventionally, resin-made soft materials such as silicone rubber and hydrogel (hydrogel), and hard materials such as metal and glass have been used in various fields in various fields. For example, soft materials can be used for medical devices that are introduced into the living body or cover the surface of a living body, biotechnology devices such as cell culture sheets and scaffolds for tissue regeneration, and cosmetics such as facial packs. Device. Uses of hard materials include electrical appliances such as personal computers, mobile phones, displays, etc., and use as diagnostic / analytical tools such as ampoules, capillaries, biosensing chips used for injections.

  For the purpose of improving biocompatibility, such as hydrophilicity and slipperiness, in order to make it easy to become familiar with the living body when using various materials, for example, as medical devices introduced into the living body or pasted on the surface of the living body. The surface modification of the material is important. If characteristics such as hydrophilicity, slipperiness, and biocompatibility better than before can be provided, the user (patient or the like) has a better feeling of use and can reduce pain.

  Various methods for modifying the surface of the material are known, and among them, a method of coating and laminating two or more layers of polymer materials one by one is known (for example, Patent Document 1). reference). Above all, the method of alternately coating two polymer materials with opposite charges one by one is called LbL method (Layer by Layer method), and each layer of material is not shared with other layers of different materials It is considered to be coupled together.

  However, the conventional LbL coating is performed in multiple layers such as about 3 to 20 layers, which may increase the manufacturing process and increase the manufacturing cost.

  Therefore, recently, as a method of improving the multi-layer LbL coating in order to improve cost efficiency, polyionic substances and hydrolyzed substances during autoclave are used, and the polyionic substances are adsorbed on the surface of the silicone hydrogel by one heat treatment. A method for hydrophilizing the surface of a silicone hydrogel is disclosed (see Patent Document 2).

  However, materials to which the invention can be applied have been limited to hydrous hydrogels.

  Patent Document 3 discloses a method of crosslinking two types of hydrophilic polymers on the surface of a silicone hydrogel by a single heat treatment.

  However, the material which can be applied in this respect is also limited to a hydrous hydrogel. Further, a step of cross-linking the carboxyl group-containing polymer to the surface of the silicone hydrogel is necessary before the heat treatment, and the epoxide between the cross-linkable hydrophilic polymer material having an epoxide group in an aqueous solution and the silicone hydrogel having a cross-linked carboxyl group. Since the hydrophilic polymer is cross-linked to the lens surface through a covalent bond between the group and the carboxyl group, the process becomes complicated, which may increase the manufacturing cost.

International Publication No. 2013/024800 Special table 2010-508563 Special table 2014-533381 gazette

  The present invention has been made in view of the above, and an object thereof is to provide a medical device whose surface can be hydrophilized by a simple method.

  In order to achieve the above object, the present invention has the following configuration.

  The present invention is a medical device having a polymer layer on at least a part of a substrate surface, wherein the polymer layer has at least two kinds of acidic polymers, and the content of the basic polymer in the polymer layer is such The present invention relates to a medical device that is 3 parts by mass or less with respect to 100 parts by mass of the acidic polymer in the polymer layer.

  In the present invention, unlike the above prior art, a polymer layer can be formed only with two or more kinds of acidic polymers, and the basic polymer may be substantially absent. Is hydrophilized. In addition, the polymer layer is not included in the base material surface itself, but the polymer layer is formed on the base material surface.

  In the above, it is preferable that at least one of the acidic polymers is a polymer having a group selected from a hydroxyl group and an amide group.

  In the above, at least one of the acidic polymers is preferably a polymer having a hydrophobic main chain and an ionic pendant group, and any of the acidic polymers has a hydrophobic main chain common to a part of the structure and It is preferred to have a polymer with an ionic pendant group.

  According to the present invention, a medical device imparted with hydrophilicity, water wettability, slipperiness and antifouling property can be obtained at a low cost by a simple process, and the applicable substrate is a hydrous hydrogel. Not limited.

  In the present invention, the substrate of the medical device is not particularly limited to water-containing or non-water-containing, and any known material that is known or that will be developed in the future may be adopted.

  Specifically, hydrogel or the like can be used as the hydrous substrate, and acrylic resin such as polymethyl methacrylate can be used as the non-hydrous substrate.

In the present invention, the polymer layer is formed as a layer on at least a part of the substrate surface, and a part of the polymer layer may enter the substrate. The presence of the polymer layer imparts hydrophilicity to the surface of the medical device. The polymer layer may be a material different from the substrate, and is usually a material different from the substrate. Moreover, it is preferable that the material which has hydrophilic property is included.
Here, the material having hydrophilicity refers to a material that is soluble in 0.0001 parts by mass or more in 100 parts by mass of water at room temperature (20 to 23 ° C.), or a material having a water content of 10% by mass or more.
The material constituting the polymer layer of the present invention is more preferably a material soluble in 0.01 parts by mass or more in 100 parts by mass of water, more preferably a material soluble in 0.1 parts by mass or more, and most preferably a material soluble in 1 part by mass or more. . Alternatively, the material constituting the polymer layer of the present invention is preferably a material having a water content of 15% by mass or more, more preferably 20% by mass or more, still more preferably 30% by mass or more, and more preferably 40% by mass or more. A material is even more preferred.
The example of the measuring method of the moisture content of the material which comprises a polymer layer is given. First, the mass of the polymer layer in a dry state is determined. The thickness of the polymer layer (dry state) is measured, for example, by observing a cross section with an optical microscope or an electron microscope. The mass (Wpd) of the polymer layer (dry state) is determined from the thickness and specific gravity of the polymer layer (1 may be substituted if unknown) and the area of the material surface covered with the polymer layer. The dry state means a state in which the sample was dried at 40 ° C. for 2 hours in a vacuum dryer to remove moisture. Next, the mass of moisture contained in the polymer layer is determined. The polymer layer is impregnated with water at 25 ° C. to obtain an equilibrium water content, and the excess moisture on the surface is gently wiped off with a wiping cloth (for example, “Kimwipe (registered trademark)” manufactured by Nippon Paper Crecia). Find the mass (Wwa) of. Examples of the method for obtaining the mass (Wwa) of water in the polymer layer include a method for obtaining a mass difference between a water-containing state and a dry state, a Karl Fischer method, a nuclear magnetic resonance method, and the like. The moisture content (%) of the material constituting the polymer layer is given by the following equation.

Moisture content of material composing polymer layer (%) = 100 × Wwa / (Wwa + Wpd)
The polymer layer according to the present invention may be bonded to the substrate by a covalent bond, but does not necessarily have a covalent bond. Since it is possible to produce in a simple process, it is preferable that there is no covalent bond with the base material.

  In the present invention, a polymer layer is present on at least a part of the substrate surface. Although it depends on the application, it is preferable that the polymer layer is present on the entire surface of one side of the substrate surface, and it is also preferable that the polymer layer is present on the entire surface of both surfaces of the substrate surface. Specific examples include those formed by coating the surface of a substrate with a polymer that forms a polymer layer, as will be described later. As such a polymer, at least two kinds of acidic polymers are used. It may be a polymer layer composed of a plurality of acidic polymers substantially free of basic polymer. The number of types of acidic polymer is preferably 2 to 10, and more preferably 2 to 6. Specifically, a polymer having a hydrophobic main chain and an ionic pendant group as at least one of the acidic polymers can be used. It is preferred that both of the at least two types of acidic polymers have a common hydrophobic main chain and ionic pendant group in a part of the structure.

  Here, in the present invention, one kind of acidic polymer means a polymer or a polymer group produced by one synthesis reaction. Even if the constituent monomer species are the same, the number of polymers synthesized by changing the compounding ratio is not one. On the other hand, when the constituent monomer species are the same, they are not counted as one species due to the difference in molecular weight.

  In the present invention, as the acidic polymer having a hydrophobic main chain and an ionic pendant group, a homopolymer or copolymer having a plurality of acidic groups along the hydrophobic main chain can be suitably used. As the group having acidity, a carboxyl group, a sulfonic acid group, and a salt thereof are preferable, and a carboxyl group and a salt thereof are most preferable.

  Suitable examples of the acidic polymer include polymethacrylic acid, polyacrylic acid, poly (vinylbenzoic acid), poly (thiophene-3-acetic acid), poly (4-styrenesulfonic acid), polyvinylsulfonic acid, poly (2- Acrylamido-2-methylpropanesulfonic acid) and salts thereof. The above are examples of homopolymers, but these copolymers (that is, copolymers of acidic monomers constituting the acidic polymer, or copolymers of acidic monomers and other monomers) can also be suitably used. .

  When the acidic polymer is a copolymer, the acidic monomer constituting the copolymer is preferably a monomer having an allyl group, a vinyl group, and a (meth) acryloyl group in terms of high polymerizability. ) Monomers having an acryloyl group are most preferred. Examples of suitable acidic monomers constituting the copolymer include (meth) acrylic acid, vinyl benzoic acid, styrene sulfonic acid, vinyl sulfonic acid, 2-acrylamido-2-methylpropane sulfonic acid, and these Salt. Among these, (meth) acrylic acid, 2-acrylamido-2-methylpropanesulfonic acid, and salts thereof are more preferable, and (meth) acrylic acid and salts thereof are most preferable.

  The acidic polymer is preferably a polymer having at least one group selected from an amide group and a hydroxyl group. When it has an amide group, it is preferable because a surface having not only water wettability but also easy slipperiness can be formed. When it has a hydroxyl group, it is preferable because it can form a surface excellent in antifouling properties against body fluids as well as water wettability.

  Examples of the acidic polymer having an amide group include a polyamide having a carboxyl group, a copolymer of an acidic monomer and a monomer having an amide group, and the like.

  Examples of the acidic polymer having a hydroxyl group include polysaccharides having acidic groups such as hyaluronic acid, chondroitin sulfate, carboxymethyl cellulose, and carboxypropyl cellulose, and copolymers of acidic monomers and monomers having amide groups.

  As the monomer having an amide group, a monomer having a (meth) acrylamide group and an N-vinylcarboxylic acid amide (including a cyclic one) are preferable from the viewpoint of ease of polymerization. Suitable examples of such monomers include N-vinylpyrrolidone, N-vinylcaprolactam, N-vinylacetamide, N-methyl-N-vinylacetamide, N-vinylformamide, N, N-dimethylacrylamide, N, N-diethyl. Mention may be made of acrylamide, N-isopropylacrylamide, N- (2-hydroxyethyl) acrylamide, acryloylmorpholine, and acrylamide. Among these, N-vinylpyrrolidone and N, N-dimethylacrylamide are preferable from the viewpoint of easy slipping, and N, N-dimethylacrylamide is most preferable.

  Preferable examples of the monomer having a hydroxyl group include hydroxyethyl (meth) acrylate, hydroxypropyl (meth) acrylate, hydroxybutyl (meth) acrylate, hydroxyethyl (meth) acrylamide, glycerol (meth) acrylate, caprolactone-modified 2-hydroxy Examples thereof include ethyl (meth) acrylate, N- (4-hydroxyphenyl) maleimide, hydroxystyrene, and vinyl alcohol (a carboxylic acid vinyl ester as a precursor). As the monomer having a hydroxyl group, a monomer having a (meth) acryloyl group is preferable from the viewpoint of ease of polymerization, and a (meth) acrylic acid ester monomer is more preferable. Among these, hydroxyethyl (meth) acrylate, hydroxypropyl (meth) acrylate, and glycerol (meth) acrylate are preferable in terms of antifouling properties against body fluids, and hydroxyethyl (meth) acrylate is most preferable. .

  Specific examples of preferred copolymers of the acidic monomer and the monomer having an amide group include (meth) acrylic acid / N-vinylpyrrolidone copolymer, (meth) acrylic acid / N, N-dimethylacrylamide copolymer, 2- Acrylamide-2-methylpropanesulfonic acid / N-vinylpyrrolidone copolymer and 2-acrylamido-2-methylpropanesulfonic acid / N, N-dimethylacrylamide copolymer. Most preferred is a (meth) acrylic acid / N, N-dimethylacrylamide copolymer.

Specific preferred examples of the copolymer of the acidic monomer and the monomer having a hydroxyl group include (meth) acrylic acid / hydroxyethyl (meth) acrylate copolymer, (meth) acrylic acid / glycerol (meth) acrylate copolymer, 2- Acrylamide-2-methylpropanesulfonic acid / hydroxyethyl (meth) acrylate copolymer and 2-acrylamido-2-methylpropanesulfonic acid / glycerol (meth) acrylate copolymer. Most preferred is a (meth) acrylic acid / hydroxyethyl (meth) acrylate copolymer.
When a copolymer of the above acidic monomer and another monomer is used, the copolymerization ratio of [mass of acidic monomer] / [mass of other monomer] is preferably 1/99 to 99/1, and 2/98 to 90/10 is more preferable, and 10/90 to 80/20 is more preferable. The range which combined any of the said upper limit and the minimum may be sufficient. When the copolymerization ratio is within this range, functions such as slipperiness and antifouling properties against body fluids are easily developed.

  Examples of combinations of acidic polymers having a common hydrophobic main chain and ionic pendant groups include polyacrylic acid and (meth) acrylic acid / N, N-dimethylacrylamide copolymer, etc. Mention may be made of all combinations of acidic polymers having an ionic main chain and ionic pendant groups. Preferred examples of the combination of two kinds of acidic polymers include polyacrylic acid and (meth) acrylic acid / N, N-dimethylacrylamide copolymer, polyacrylic acid and (meth) acrylic acid / N-vinylpyrrolidone copolymer Polyacrylic acid and (meth) acrylic acid / hydroxyethyl (meth) acrylate copolymer, which are easy to express functions such as slipperiness and antifouling properties against body fluids. Acid and (meth) acrylic acid / N, N-dimethylacrylamide copolymer.

  In the present invention, when the total mass of the acidic polymer in the polymer layer is 100 parts by mass, the usage ratio of the polymer of the most used amount among the acidic polymers is preferably 50-100 parts by mass, and 70-80 A mass part is more preferable, and 80-95 mass parts is further more preferable. The range which combined any of the said upper limit and the minimum may be sufficient.

  Of the acidic polymers, the ratio of the most used polymer to the second most polymer is greater than 50/50 and preferably 99/1 or less. The range which combined any of the said upper limit and the minimum may be sufficient. When the use ratio is within this range, functions such as easy slipping and antifouling against body fluids are easily developed.

  The medical device of the present invention is a medical device having a polymer layer on at least a part of a substrate surface, the polymer layer has at least two kinds of acidic polymers, and the content of the basic polymer is the above acidic It is 3 parts by mass or less with respect to 100 parts by mass of the total polymer.

  In the present invention, the content of the basic polymer in the polymer layer is 3 parts by mass or less when the total mass of the acidic polymer in the polymer layer is 100 parts by mass, preferably 0.1 parts by mass or less, and 0.0001 parts by mass or less. More preferred. When the use ratio is within this range, functions such as transparency and slipperiness and antifouling properties against body fluids are easily developed. When the content of the basic polymer is more than this range, a white salt may be precipitated due to the reaction between the acid and the base, causing a problem in transparency. Conventionally, when the amount of the basic polymer is within the above range, an electrostatic adsorption effect due to use with the acidic polymer cannot be expected. Therefore, a polymer layer having at least two types of acidic polymers is formed on the substrate surface as a single layer or multiple layers. However, according to the present invention, it has been found that such a polymer layer can be formed on the surface of the substrate even when the basic polymer is present in an amount in the above range. It was.

  In the present invention, the polymer layer has a layered structure that can be observed when a cross section of the medical device substrate is observed using a transmission electron microscope. The thickness of the polymer layer is preferably from 1 to 200 nm, more preferably from 10 to 150 nm, and even more preferably from 30 to 100 nm because functions such as water wettability and easy slipping are easily exhibited. Most preferably, the thickness is 30 to 100 nm because of excellent water wettability and easy slipperiness. The range which combined any of the said upper limit and the minimum may be sufficient. The polymer layer may have a multilayer structure or a single layer structure. In a state where two or more types of acidic polymers exist on the substrate surface in a multilayer structure (overlapping multiple layers with different compositions) or in a state where two or more types of acidic polymers are intertwined (single layer structure) Either is preferable.

  When two or more types of acidic polymers are present in a layer structure on the substrate surface, the molecular weight can be changed between the acidic polymers in order to change various properties as a layer, for example, the thickness. Specifically, increasing the molecular weight generally increases the thickness of the layer. However, if the molecular weight is too large, handling may increase due to increased viscosity. Therefore, the acidic polymer used in the present invention preferably has a molecular weight of 2000 to 150,000. More preferably, the molecular weight is 5000-1200000, and still more preferably 75000-10000000. Here, as the molecular weight, a mass average molecular weight in terms of polyethylene glycol measured by a gel permeation chromatography method (aqueous solvent) is used.

  In a preferred embodiment of the present invention, the medical device of the present invention may have a tube shape.

  As an example, the medical device can be preferably used as an infusion tube, gas transport tube, drainage tube, blood circuit, coating tube, catheter, stent, sheath, tube connector or access port.

  In another preferred embodiment of the present invention, the medical device may be in the form of a sheet or film.

  Specifically, the medical device can be preferably used also as a skin covering material, a wound covering material, a skin protecting material, a skin drug carrier, or an endoscope covering material.

  In still another preferred embodiment of the present invention, the medical device may have a storage container shape.

  Specifically, the medical device can be preferably used as a drug carrier, cuff, or drainage bag.

  In still another preferred embodiment of the present invention, the medical device may have a lens shape.

  Specifically, it can be preferably used as an ophthalmic lens such as an intraocular lens, an artificial cornea, a corneal inlay, a corneal onlay, and a spectacle lens.

  Next, the manufacturing method of the medical device of this invention is demonstrated. The medical device of the present invention can be obtained by a method of heating a medical device substrate in a state where the medical device substrate is placed in a solution containing at least two kinds of acidic polymers.

  Here, the inventors of the present invention adjust the initial pH of the solution containing the acidic polymer to 4.0 or more and 6.8 or less, place a medical device in the solution, and heat in that state. The above acidic polymer can be formed on the surface of a substrate by forming a single layer or a multilayer on the surface of the substrate without using the electrostatic adsorption action used together with the basic polymer. It discovered that lubricity etc. could be provided. This is very important industrially from the viewpoint of shortening the manufacturing process.

  The pH of the solution containing the acidic polymer can be measured using a pH meter (for example, pH meter KR5E (As One Corporation)). In this specification, the initial pH of a solution containing an acidic polymer was measured after all the acidic polymer was added to the solution and then stirred for 2 hours at room temperature (23-25 ° C.) using a rotor to make the solution uniform. Refers to the pH value. In the present invention, the second decimal place of the pH value is rounded off. In the present invention, the range of the initial pH of the solution containing the acidic polymer is preferably 4.0 to 6.8, and preferably 4.3 to 6.6, because the solution does not become turbid and the resulting medical device surface has good transparency. More preferably, 4.5 to 6.4 is most preferable. The range which combined any of the said upper limit and the minimum may be sufficient.

  The pH of the solution can be changed after the heating operation according to the present invention is performed, but the pH after the change is not treated as the initial pH according to the present invention.

  When the initial pH of the solution containing the acidic polymer is less than 4.0 or more than 6.8, the solution may become turbid. As a result, the transparency of the surface of the medical device is lowered, which is not preferable.

  In the present invention, a solution containing a buffering agent is preferably used as a solvent for the solution containing the acidic polymer.

The pH of the buffer is preferably maintained in the desired range, for example, approximately 6.3 to 7.8, preferably 6.5 to 7.6, more preferably 6.8 to 7.4, which is a physiologically acceptable range. Any physiologically compatible known buffer can be used. Suitable buffering agents in the present invention are known to those skilled in the art, and examples are as follows. Examples: boric acid, borates (eg, sodium borate), citric acid, citrates (eg, potassium citrate), bicarbonate (eg, sodium bicarbonate), phosphate buffer (eg, Na ₂ HPO ₄ , NaH ₂ PO ₄ , and KH ₂ PO ₄ ), TRIS (tris (hydroxymethyl) aminomethane), 2-bis (2-hydroxyethyl) amino-2- (hydroxymethyl) -1,3-propanediol , Bis-aminopolyol, triethanolamine, ACES (N- (2-hydroxyethyl) -2-aminoethanesulfonic acid), BES (N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid) , HEPES (4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid), MES (2- (N-morpholino) ethanesulfonic acid), MOPS 3- [N-morpholino] -propanesulfonic acid, PIPES (piperazine -N, N'-Bi (2-ethanesulfonic acid), TES (N- [tris (hydroxymethyl) methyl] -2-aminoethanesulfonic acid), and salts thereof. The amount of each buffer is to achieve the desired pH. The amount necessary to be effective is used, and usually 0.001% to 2% by weight, preferably 0.01% to 1% by weight in the above solution; most preferably 0.05% to 0.30% by weight. Amount exists.

  Examples of the heating method include a high-pressure steam sterilization method, a dry heat method, and a flame method, but the high-pressure steam sterilization method is most preferable from the viewpoint of water wettability, easy slipping, and shortening of the manufacturing process. As an apparatus, it is preferable to use an autoclave.

  When the heating temperature is too low, a medical device surface exhibiting good water wettability and slipperiness cannot be obtained. When the heating temperature is too high, the strength of the medical device itself is affected. C. to 140.degree. C. is more preferred, and 80.degree. C. to 130.degree. C. is most preferred.

  When the heating time is too short, a medical device surface showing good water wettability and slipperiness cannot be obtained, and when it is too long, the strength of the medical device itself is affected. -200 minutes are more preferable, and 15 minutes-100 minutes are more preferable.

  The range may be any combination of the upper limit and the lower limit of the heating temperature and time.

  After the heat treatment, the same heat treatment as that described above or radiation irradiation may be carried out successively in a solution containing at least two kinds of acidic polymers, or replaced with a solution containing no acidic polymer.

  As the radiation in the above case, various ion beams, electron beams, positron beams, X-rays, γ rays and neutron beams are preferable, electron beams and γ rays are more preferable, and γ rays are most preferable.

  Hereinafter, the present invention will be specifically described by way of examples, but the present invention is not limited thereto.

Analysis method and evaluation method <water wettability>
The medical device was immersed for more than 24 hours in phosphate buffer in a beaker at room temperature. The state of the surface when the medical device was pulled up from the phosphate buffer and held in the air was visually observed and judged according to the following criteria.

  A: The liquid film on the surface is held for 20 seconds or more.

  B: The liquid film on the surface breaks in 10 seconds or more and less than 20 seconds.

  C: The liquid film on the surface breaks in 5 seconds or more and less than 10 seconds.

  D: The liquid film on the surface breaks in 1 second or more and less than 5 seconds.

  E: The liquid film on the surface is cut instantly (less than 1 second).

<Easily slippery>
The medical device was immersed for more than 24 hours in phosphate buffer in a beaker at room temperature. The medical device was lifted from the phosphate buffer, and the sensitivity was evaluated when it was rubbed 5 times with a human finger.

  A: There is very good slipperiness.

  B: Easily slippery between A and C.

  C: Medium slipperiness.

  D: There is almost no slipperiness (about the middle of C and E).

  E: There is no slipperiness.

<Water content of substrate>
The substrate was immersed in a phosphate buffer and allowed to stand at room temperature for 24 hours or more, and then the surface moisture was wiped off with a wiping cloth (“Kimwipe (registered trademark)” manufactured by Nippon Paper Crecia) and the mass (Ww) was measured. Then, it dried at 40 degreeC for 2 hours with the vacuum dryer, and mass (Wd) was measured. From these masses, the water content was calculated by the following formula (1). When the obtained value was less than 1%, it was judged to be below the measurement limit, and was expressed as “less than 1%”.

Moisture content of substrate (%) = 100 × (Ww−Wd) / Ww formula (1)

<Atomic force microscope observation>
Under the following conditions, the surface of the medical device was observed with an atomic force microscope, and the root mean square roughness value (Rms value) was measured.
Observation device: WET-SPM9500J3 manufactured by Shimadzu Corporation
Tip: Silicon cantilever OMCL-AC160TS-C3
Scanning mode: Phase detection Scanning range: 5mm
Measurement environment: room temperature, air

<Molecular weight measurement>
The molecular weight of the acidic polymer used was measured under the following conditions.
(GPC measurement conditions)
Equipment: Prominence GPC system manufactured by Shimadzu Corporation Pump: LC-20AD
Autosampler: SIL-20AHT
Column oven: CTO-20A
Detector: RID-10A
Column: GMPWXL manufactured by Tosoh Corporation (inner diameter 7.8 mm x 30 cm, particle diameter 13 mm)
Solvent: water / methanol = 1/1 (0.1N lithium nitrate added)
Flow rate: 0.5 mL / min Measurement time: 30 minutes Sample concentration: 0.1% by mass
Injection volume: 100mL
Standard sample: Agilent polyethylene oxide standard sample (0.1kD ~ 1258kD)

<Transmission electron microscope>
The cross-sectional thickness of the medical device was measured under the following conditions.
Equipment: Transmission electron microscope (Hitachi H-7100FA)
Condition: Acceleration voltage 100kV
Sample preparation: RuO4 stained ultrathin section method

<PH measurement method>
The pH of the solution was measured using a pH meter KR5E (As One Corporation). The initial pH of the solution containing the acidic polymer was determined by adding the acidic polymer to the solution described in each example, etc., and stirring the mixture for 2 hours at room temperature (23 to 25 ° C.) to make the solution uniform. The measured “pre-autoclave pH”. The “pH after the first autoclave”, “pH after the second autoclave”, and “pH after the third autoclave” described in each example and the like were measured immediately after the solution was cooled to room temperature (23 to 25 ° C.) after autoclaving. pH. The initial pH according to claim 1 indicates “pH before autoclave”.
[Reference Example 1]
Polydimethylsiloxane having methacryloyl groups at both ends (FM7726, JNC Corporation, compound of formula (M1), Mw 30,000) (28 parts by mass), silicone monomer represented by formula (M2) (7 parts by mass), tri Fluoroethyl acrylate (Biscoat (registered trademark) 3F, Osaka Organic Chemical Industry Co., Ltd.) (57.9 parts by mass), 2-ethylhexyl acrylate (Tokyo Chemical Industry Co., Ltd.) (7 parts by mass), dimethylaminoethyl acrylate (Co., Ltd.) Kojin) (0.1 part by mass), photoinitiator Irgacure (registered trademark) 819 (Nagase Sangyo Co., Ltd.) (5000 ppm), UV absorber (RUVA-93, Otsuka Chemical) (5000 ppm), colorant (RB246, Arran chemical) (100 ppm) and t-amyl alcohol (10 parts by mass) were mixed and stirred. A monomer filter was obtained by filtering through a membrane filter (0.45 mm) to remove insoluble matter.

The above monomer mixture is injected into a contact lens mold made of transparent resin (base curve side polypropylene, front curve side polypropylene), and light irradiation (wavelength 405 nm (± 5 nm), illuminance: 0 to 0.7 mW / cm ² , 30 minutes) And polymerized.

  After polymerization, the mold with the front curve and the base curve released from each other was immersed in a 100% by mass isopropyl alcohol aqueous solution at 60 ° C. for 1.5 hours, and the contact lens-shaped molded product was peeled from the mold. The molded body thus obtained was immersed in a large excess amount of 100 mass% isopropyl alcohol aqueous solution kept at 60 ° C. for 2 hours to extract impurities such as residual monomers. Then, it was dried at room temperature (23 ° C.) for 12 hours.

[Reference Example 2]
Methacrylic acid-2-hydroxyethyl (98 parts by mass), triethylene glycol dimethacrylate (1.0 parts by mass), and photoinitiator Irgacure 819 (1.0 parts by mass) were mixed and stirred. A monomer filter was obtained by filtering through a membrane filter (0.45 mm) to remove insoluble matter. This monomer mixture was put into a test tube, deaerated under a reduced pressure of 20 Torr (27 hPa) while stirring with a touch mixer, and then returned to atmospheric pressure with argon gas. This operation was repeated three times. Inject a monomer mixture into a contact lens mold made of transparent resin (base curve side polypropylene, front curve side ZEONOR) in a nitrogen atmosphere glove box, and fluorescent lamps (Toshiba, FL-6D, daylight color, 6W, 4) And polymerized by light irradiation (1.01 mW / cm ² , 20 minutes). After the polymerization, the mold in which the front curve and the base curve were released was immersed in pure water at 90 ° C. for 1 hour to peel the contact lens-shaped molded body from the mold. The obtained molded body was immersed in a large excess amount of 100% by mass isopropyl alcohol aqueous solution maintained at 90 ° C. for 2 hours to extract impurities such as residual monomers. Then, it was immersed in the phosphate buffer.

[Example 1]
The molded body obtained in Reference Example 1 was prepared by using 0.18% by mass of polyacrylic acid (“Sokalan PA110S”, Mw 250000, manufactured by BASF) and 0.02% by mass of acrylic acid / N, N-dimethylacrylamide copolymer (copolymer). The mixture was placed in a phosphate buffer containing a polymerization ratio of 9/1, Mw 1040000, manufactured by Osaka Organic Chemical Industry Co., Ltd., and heated in an autoclave at 121 ° C for 30 minutes. The evaluation results are shown in Table 1.
[Example 2]
The molded body obtained in Example 1 was replaced with a phosphate buffer, and further heated in an autoclave at 121 ° C. for 30 minutes. The evaluation results are shown in Table 1.
[Example 3]
The same operation as in Example 1 was carried out except that 0.018% by mass of polyacrylic acid and 0.002% by mass of acrylic acid / N, N-dimethylacrylamide copolymer were carried out, and the same operation as in Example 2 was further carried out. The evaluation results are shown in Table 1.
[Example 4]
The same operation as in Example 1 was performed except that the autoclave time was 60 minutes, and the same operation as in Example 2 was further performed. The evaluation results are shown in Table 1.
[Example 5]
The same operation as in Example 1 was carried out except that 0.36% by mass of polyacrylic acid and 0.04% by mass of acrylic acid / N, N-dimethylacrylamide copolymer were carried out, and the same operation as in Example 2 was further carried out. The evaluation results are shown in Table 1.
[Example 6]
The same operation as in Example 5 was performed except that the autoclave time was 60 minutes. The evaluation results are shown in Table 1.
[Example 7]
The molded body obtained in Reference Example 1 was mixed with 0.36% by mass of polyacrylic acid (“Sokalan” (registered trademark) PA110S, Mw 250kD, manufactured by BASF) and 0.04% by mass of acrylic acid / N, N-dimethylacrylamide. The solution was placed in a phosphate buffer containing a polymer (copolymerization ratio 9/1, Mw 1040 kD, manufactured by Osaka Organic Chemical Industry Co., Ltd.), and autoclaved at 121 ° C. for 30 minutes. Thereafter, the obtained molded product was made into 0.18% by mass of polyacrylic acid (“Sokalan” (registered trademark) PA110S, Mw 250000, manufactured by BASF) and 0.02% by mass of acrylic acid / N, N-dimethylacrylamide copolymer ( The mixture was placed in a phosphate buffer containing a copolymerization ratio of 9/1, Mw 1040000, manufactured by Osaka Organic Chemical Industry Co., Ltd., and heated in an autoclave at 121 ° C for 30 minutes. Furthermore, the obtained molded body was replaced with a phosphate buffer and heated in an autoclave at 121 ° C. for 30 minutes. The evaluation results are shown in Table 1.
[Example 8]
The molded body obtained in Reference Example 1 was mixed with 0.36% by mass of polyacrylic acid (“Sokalan” (registered trademark) PA110S, Mw 250,000, manufactured by BASF) and 0.04% by mass of acrylic acid / N, N-dimethylacrylamide. The solution was placed in a phosphate buffer containing a polymer (copolymerization ratio 9/1, Mw 1040000, manufactured by Osaka Organic Chemical Industry Co., Ltd.), and autoclaved at 121 ° C. for 30 minutes. Thereafter, the obtained molded body was placed in a phosphate buffer containing 1.2% by mass of the polyacrylic acid, and heated in an autoclave at 121 ° C. for 30 minutes. Furthermore, the obtained molded body was replaced with a phosphate buffer and heated in an autoclave at 121 ° C. for 30 minutes. The evaluation results are shown in Table 1.
[Example 9]
The same operation as in Example 8 was performed except that the polyacrylic acid concentration in the phosphate buffer used in the second autoclave was 0.18% by mass. The evaluation results are shown in Table 1.
[Example 10]
The acidic polymer in the phosphate buffer used during the second autoclave was 1.0% by mass acrylic acid / N, N-dimethylacrylamide copolymer (copolymerization ratio 9/1, Mw 1040000, manufactured by Osaka Organic Chemical Co., Ltd.) The same operation as in Example 8 was carried out except that. The evaluation results are shown in Table 1.
[Example 11]
The same operation as in Example 8 was performed except that the acrylic acid / N, N-dimethylacrylamide copolymer concentration in the phosphate buffer used in the second autoclave was 0.02% by mass. The evaluation results are shown in Table 1.
[Example 12]
The molded body obtained in Reference Example 1 was mixed with 0.13% by mass of polyacrylic acid (“Sokalan” (registered trademark) PA110S, Mw 250,000, manufactured by BASF) and 0.067% by mass of acrylic acid / N, N-dimethylacrylamide. The solution was placed in a phosphate buffer containing a polymer (copolymerization ratio 9/1, Mw 1040000, manufactured by Osaka Organic Chemical Industry Co., Ltd.), and heated in an autoclave at 121 ° C. for 30 minutes. The evaluation results are shown in Table 1.
[Example 13]
The molded body obtained in Reference Example 1 was mixed with 0.065% by mass of polyacrylic acid (“Sokalan” (registered trademark) PA110S, Mw 250,000, manufactured by BASF) and 0.034% by mass of acrylic acid / N, N-dimethylacrylamide. The solution was placed in a phosphate buffer containing a polymer (copolymerization ratio 9/1, Mw 1040000, manufactured by Osaka Organic Chemical Industry Co., Ltd.), and heated in an autoclave at 121 ° C. for 30 minutes. The evaluation results are shown in Table 1.
[Example 14]
The same operation as in Example 1 was performed except that the molded body obtained in Reference Example 2 was used, and the same operation as in Example 2 was further performed. The evaluation results are shown in Table 1.
[Example 15]
The molded body obtained in Reference Example 1 was mixed with 0.198% by mass of polyacrylic acid (“Sokalan” (registered trademark) PA110S, Mw 250,000, manufactured by BASF) and 0.002% by mass of acrylic acid / N, N-dimethylacrylamide. The solution was placed in a phosphate buffer containing a polymer (copolymerization ratio 9/1, Mw 1040000, manufactured by Osaka Organic Chemical Industry Co., Ltd.), and heated in an autoclave at 121 ° C. for 30 minutes. The evaluation results are shown in Table 1.
[Example 16]
The molded body obtained in Reference Example 1 was mixed with 0.1998% by mass of polyacrylic acid (“Sokalan” (registered trademark) PA110S, Mw 250000, manufactured by BASF) and 0.0002% by mass of acrylic acid / N, N-dimethylacrylamide. The solution was placed in a phosphate buffer containing a polymer (copolymerization ratio 9/1, Mw 1040000, manufactured by Osaka Organic Chemical Industry Co., Ltd.), and heated in an autoclave at 121 ° C. for 30 minutes. The evaluation results are shown in Table 1.
[Example 17]
The molded body obtained in Reference Example 1 was mixed with 0.18% by mass of polyacrylic acid (“Sokalan” (registered trademark) PA110S, Mw 250000, manufactured by BASF) and 0.02% by mass of acrylic acid / N, N-dimethylacrylamide. The solution was placed in a phosphate buffer containing a polymer (copolymerization ratio 2/1, Mw 200,000, manufactured by Osaka Organic Chemical Industry Co., Ltd.), and heated in an autoclave at 121 ° C. for 30 minutes. The evaluation results are shown in Table 1.
[Comparative Example 1]
Phosphorus containing 0.2% by mass of acrylic acid / N, N-dimethylacrylamide copolymer (copolymerization ratio 2/1, Mw 200,000, manufactured by Osaka Organic Chemical Industry Co., Ltd.) was obtained from the molded product obtained in Reference Example 1. The solution was placed in an acid buffer and heated in an autoclave at 121 ° C. for 30 minutes. The evaluation results are shown in Table 1.
[Comparative Example 2]
The molded body obtained in Reference Example 1 was put in a phosphate buffer containing 0.2% by mass of polyacrylic acid (“Sokalan” (registered trademark) PA110S, Mw 250000, manufactured by BASF), and 121 ° C. for 30 minutes. Heated in an autoclave. The evaluation results are shown in Table 1.
[Comparative Example 3]
Phosphorus containing 0.2% by mass of acrylic acid / N, N-dimethylacrylamide copolymer (copolymerization ratio 9/1, Mw 1040000, manufactured by Osaka Organic Chemical Industry Co., Ltd.) was obtained from the molded product obtained in Reference Example 1. The solution was placed in an acid buffer and heated in an autoclave at 121 ° C. for 30 minutes. The evaluation results are shown in Table 1.
[Comparative Example 4]
The molded body obtained in Reference Example 1 was placed in a phosphate buffer and heated in an autoclave at 121 ° C. for 30 minutes. The evaluation results are shown in Table 1.
[Comparative Example 5]
The molded body obtained in Reference Example 1 was mixed with 0.18% by mass of polyacrylic acid (“Sokalan” (registered trademark) PA110S, Mw 250000, manufactured by BASF) and 0.02% by mass of acrylic acid / N, N-dimethylacrylamide. Add 0.1% by mass of disodium hydrogenphosphate to a phosphate buffer containing a polymer (copolymerization ratio 9/1, Mw 1040000, manufactured by Osaka Organic Chemical Industry Co., Ltd.), and place in a solution adjusted to pH 6.93. The mixture was heated in an autoclave at 121 ° C for 30 minutes. The evaluation results are shown in Table 1, but a polymer layer could not be formed on the surface of the molded body.
[Comparative Example 6]
The molded body obtained in Reference Example 1 was prepared by using 0.18% by mass of polyacrylic acid (“Sokalan” (registered trademark) PA110S, Mw 250000, manufactured by BASF) and 0.02% by mass of N, N-dimethylacrylamide / hydroxyethylacrylamide. The solution was placed in a phosphate buffer containing a copolymer (copolymerization ratio 9/1, Mw241000), and heated in an autoclave at 121 ° C. for 30 minutes. The obtained molded body was replaced with a phosphate buffer and heated in an autoclave at 121 ° C. for 30 minutes. The evaluation results are shown in Table 1, but a polymer layer could not be formed on the surface of the molded body.
[Comparative Example 7]
The molded body obtained in Reference Example 1 was placed in a phosphate buffer containing 0.2% by mass of polydimethylacrylamide (Mw 1000000, manufactured by Osaka Organic Chemical Industry Co., Ltd.), and heated in an autoclave at 121 ° C. for 30 minutes. The obtained molded body was replaced with a phosphate buffer and heated in an autoclave at 121 ° C. for 30 minutes. The evaluation results are shown in Table 1.

Claims (7)

A medical device having a polymer layer on at least a portion of a substrate surface,
The polymer layer has at least two kinds of acidic polymers;
In the polymer layer, the content of the basic polymer is 3 parts by mass or less with respect to a total of 100 parts by mass of the acidic polymer.   2. The medical device according to claim 1, wherein at least one of the acidic polymers has a group selected from a hydroxyl group and an amide group. The medical device according to claim 1 or 2, wherein at least one of the acidic polymers has a hydrophobic main chain and an ionic pendant group. The medical device according to any one of claims 1 to 3, wherein each of the at least two kinds of acidic polymers has a common hydrophobic main chain and an ionic pendant group in a part of the structure. Ophthalmic lens, skin covering material, wound covering material, skin protective material, skin drug carrier, infusion tube, gas transport tube, drainage tube, blood circuit, covering tube, catheter, stent, sheath, The medical device according to any one of claims 1 to 4, which is a tube connector, an access port, or an endoscope covering material.   A method for producing a medical device, comprising placing a medical device substrate in a solution containing at least two kinds of acidic polymers and adjusted to an initial pH of 4.0 or more and 6.8 or less, and heating the solution. 7. The method for producing a medical device according to claim 6, wherein the heating is performed in an autoclave.