JPH0728912B2 - Biomedical materials - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a biomedical material, and more particularly to a biomedical material composed of a polymer capable of gelating with time to form a hydrogel.

[Conventional technology]

Hydrogel is used as a biomedical material because of its water-leaking property and water-containing property, it is excellent in compatibility with living organisms, has less foreign body sensation and discomfort, and is less likely to cause inflammation and thrombus formation.

Conventionally, hydrogel materials used as biomedical materials include, for example, hydroxyalkyl (meth) acrylate-based polymers, acrylamide-based polymers, polyvinyl alcohol, polyvinylpyrrolidone, synthetic polymers such as polyethylene glycol, cellulose, collagen, and gelatin. , Natural polymers such as alginic acid, chitin, chitosan and dextran, or semi-synthetic polymers obtained by mixing or reacting a synthetic gel with a natural gel are known.
It is appropriately selected and used depending on the application site, application, etc.
These materials are prepared by previously polymerizing a hydrophilic monomer together with a crosslinking agent, or by gelling a hydrophilic polymer with a chemical crosslinking agent or radiation and hydrating it to give a hydrogel.

[Problems to be Solved by the Invention] However, the conventional hydrogel has some problems. That is, when performing a prosthesis of a minute portion of the human body or a prosthesis of a deep tissue in the body, for example, when it is used to perform replacement of the vitreous body or lens in the eye, in order to replace the conventional hydrogel with the desired site. Had a problem in that it required a large incision, complicated and difficult surgery, and associated great danger.

[Means for Solving the Problems]

In such an actual situation, as a result of intensive studies conducted by the present inventors, a water-soluble copolymer having components derived from a specific silane compound and a hydrophilic compound is used as a biomedical material that solves the above problems. The inventors have found that they are suitable and completed the present invention.

That is, the present invention provides (A) a silane compound having at least one hydrolyzable group and at least one reactive unsaturated group (hereinafter simply referred to as "silane compound"), and (B) a hydrophilic compound having a reactive unsaturated group. (Less than,
Water-soluble copolymer (hereinafter simply referred to as "polymer") having constituent components derived from "hydrophilic compound")
The present invention provides a biomedical material characterized by comprising:

In the present invention, the biomedical material is a material used in the fields of biology and medicine, and particularly means a material that comes into direct contact with a living body such as a human being or an animal in some way.

The polymer in the present invention is a hydrophobic compound (hereinafter, simply referred to as "hydrophobic compound") which is obtained by copolymerizing a silane compound and a hydrophilic compound or has a silane compound and a reactive unsaturated group and can be hydrophilized. And a) to obtain a precursor of a water-soluble copolymer, and by saponifying the precursor, for example, a component derived from a hydrophobic compound is converted into a constituent component derived from a hydrophilic compound. Obtainable.

The silane compound used in the present invention has at least one hydrolyzable group and at least one reactive unsaturated group, and is a silane derivative capable of forming silanol in the presence of water, for example, represented by the following general formula (I). Compounds that can be mentioned.

[In the formula, R ¹ represents a hydrolyzable group, R ² represents a non-hydrolyzable group, X represents a reactive unsaturated group, m and n each represent a number of 1 to 3, and r represents 0. Indicates the number of ~ 2, m + n + r
= 4. The hydrolyzable group represented by R ¹ in the formula (I) is an alkoxy group having about 1 to 10 carbon atoms, for example, a methoxy group, an ethoxy group, a propoxy group, a butyloxy group, a hexyloxy group, a nonyloxy group; Atoms, for example, chlorine atom, bromine atom, iodine atom and the like; acyloxy group having about 1 to 10 carbon atoms, such as acetoxy group, propionyloxy group, valeryloxy group and the like, as the non-hydrolyzable group represented by R ² , An alkyl group having about 1 to 10 carbon atoms, for example, a methyl group, an ethyl group, a propyl group, a butyl group, a hexyl group, etc .; an aryl group, for example, a phenyl group,
Examples of the reactive unsaturated group represented by X include a xylyl group and a tolyl group. Or base Etc. [where R ″ is a hydrogen atom or a methyl group, and p is 0 to
And a vinyl group, an acryloyl group, a methacryloyl group, and the like.

Incidentally, in the general formula (I), when R ^1, R ² or X there are a plurality, the plurality of R ^1, R ² or X may contain a different group.

As the silane compound, trimethoxyvinylsilane, triethoxyvinylsilane, tripropoxyvinylsilane, diethoxymethylvinylsilane, diethoxyethylvinylsilane, diethoxypropylvinylsilane,
Diethoxyphenylvinylsilane, dimethylethoxyvinylsilane, diethylethoxyvinylsilane, dipropylethoxyvinylsilane, diphenylethoxyvinylsilane, triethoxyallylsilane, 3-butenyltriethoxysilane, 4-pentenyltriethoxysilane, 5
Unsaturated silanes such as hexenyltriethoxysilane, 6-heptenyltriethoxysilane, 7-octenyltriethoxysilane, trichlorovinylsilane, tribromovinylsilane, triiodovinylsilane, dichloromethylvinylsilane, dichloroethylvinylsilane, dichloropropylvinylsilane , Dichlorophenylvinylsilane, dimethylchlorovinylsilane, diethylchlorovinylsilane, dipropylchlorovinylsilane, diphenylchlorovinylsilane, trichloroallylsilane, 3-butenyltrichlorosilane, 4-pentenyltrichlorosilane, 5-hexenyltrichlorosilane, 6-heptenyl Unsaturated halogenated silanes such as trichlorosilane and 7-octenyltrichlorosilane, triacetoxy vinyl sila , Tripropoxyvinylsilane, tributyroxyvinylsilane, trivaleroxyvinylsilane, diacetoxymethylvinylsilane, diacetoxyethylvinylsilane, diacetoxypropylvinylsilane, diacetoxyphenylvinylsilane, dimethylacetoxyvinylsilane, diethylacetoxyvinylsilane, dipropylacetoxyvinylsilane, dif Unsaturated esters such as enylacetoxyvinylsilane, triacetoxyallylsilane, 3-butenyltriacetoxysilane, 4-pentenyltriacetoxysilane, 5-hexenyltriacetoxysilane, 6-heptenyltriacetylsilane, 7-octenyltriacetylsilane. Silanes may be mentioned. Furthermore, as the silane compound, 3-methacryloxypropyltrimethoxysilane,
3-methacryloxypropyltris (methoxyethoxy) silane, N- (3-acryloxy-2-hydroxypropyl) -3-aminopropyltriethoxysilane,
3-methacryloxypropyltrichlorosilane, methacryloxypropyldimethylethoxysilane and the like can also be used. Examples of these silane compounds include triethoxyvinylsilane, triethoxyallylsilane, dimethylethoxyvinylsilane, phenylethoxyvinylsilane, 7-octenyltriethoxysilane, N- (3-acryloxy-2-hydroxypropyl) -3-aminopropyltrisilane. Ethoxysilane and the like are preferably used.

These silane compounds may be used alone or in combination of two or more.

Further, the hydrophilic compound used in the present invention may be any one as long as the polymer is water-soluble, and examples thereof include those represented by the following general formula (II) or (III).

[In the formula, R ₁ represents a hydrogen atom or a methyl group, and R ₂ is an alkylene group or group which may have a polar group as a substituent. (N is an integer of 1 or more, R ₃ is a hydrogen atom or a methyl group), and q is 0 or 1.] [In the formula, R ₁ represents a hydrogen atom or a methyl group, and R ₄ and R ₅ are a hydrogen atom, a methyl group, an ethyl group or Examples of the compound represented by the general formula (II) include acrylic acid, methacrylic acid, hydroxyethyl methacrylate, diethylene glycol methacrylate, dimethylaminoethyl methacrylate, glycidyl methacrylate, hydroxyethyl acrylate, polyethylene glycol methacrylate, polyethylene glycol acrylate, polypropylene. Examples thereof include acrylic acid such as glycol methacrylate, polypropylene glycol acrylate, 2-aminohydroxypropyl methacrylate and 2-aminohydroxypropyl acrylate, methacrylic acid or their esters. Examples of the compound represented by the general formula (III) include acrylamides such as acrylamide, dimethylacrylamide, diethylacrylamide, isopropylacrylamide, N-propyloxymethylacrylamide, dimethylmethacrylamide, and diacetoneacrylamide, or methacrylamides or derivatives thereof. And so on.

Further, examples of the hydrophilic compound include N-vinylpyrrolidone, N-vinylpiperidone, N-vinylcaprolactam, vinylpyridine, and styrenesulfonic acid, in addition to the compound represented by the general formula (II) or (III).

These hydrophilic compounds can be used alone or in combination of two or more.

Examples of the hydrophobic compound include vinyl esters such as vinyl acetate, vinyl propionate and vinyl butyrate, and these hydrophobic compounds may be used alone or in combination of two or more.

The polymer used in the present invention is another unsaturated monomer copolymerizable with the silane compound and a component derived from a hydrophilic compound or a hydrophobic compound, such as ethylene, propylene, vinyl chloride, vinylidene chloride, acrylonitrile. ,
Copolymerization of methacrylonitrile, methyl acrylate, methyl methacrylate, styrene, methyl vinyl ketone, phenyl vinyl ketone, methyl vinyl ether, phenyl vinyl ether, phenyl vinyl sulfide, methacrolein, acrolein, etc. The constituent component derived from the saturated monomer may be present in the polymer in an amount of about 10 mol% or less.

In the present invention, a water-soluble polymer or a precursor of a water-soluble polymer is obtained by copolymerizing at least one silane compound and at least one hydrophilic compound or at least one hydrophobic compound. The charging amount of the silane compound and the hydrophilic compound or the hydrophobic compound is 0.1
~ 25% by weight (hereinafter, "% by weight" is simply indicated by "%"),
The proportion of the hydrophilic compound or the hydrophobic compound is 75 to 99.9%, particularly preferably 0.5 to 10% of the silane compound and 90 to 99.5% of the hydrophilic compound or the hydrophobic compound. If the silane compound content is less than 0.1%, the obtained polymer cannot be gelated with time, and if it exceeds 25%, the polymer becomes difficult to dissolve in water.

In the present invention, it is preferable to use radical polymerization as the polymerization mode. The polymerization initiator includes a thermal polymerization initiator and a photopolymerization initiator, and examples thereof include peroxides such as t-butyl peroxide, benzoyl peroxide, 2,4-dichlorobenzoyl peroxide and t-butyl hydroperoxide; peracetic acid. Persulfates such as ammonium persulfate; azo compounds such as azobisisobutyronitrile, azobiscyclohexanecarbonitrile, phenylazoisobutyronitrile, naphthylazoisobutyronitrile and azobisvaleronitrile Or a redox catalyst or the like can be used.

The polymerization method of the silane compound and the hydrophilic compound or the hydrophobic compound can be carried out by any of bulk polymerization, solution polymerization, suspension polymerization and emulsion polymerization, but solution polymerization is preferable. When using a photopolymerization initiator, acetophenone, propiophenone, xanthone,
Fluorenone, benzaldehyde, fluorene, anthraquinone, p-diacetylbenzene, carbazole, 3
It is also possible to include a photosensitizer such as -or 4-methylbenzopheno, benzoin, benzoin ethyl ether. As an example of the polymerization method, a raw material such as a silane compound and a hydrophilic compound or a hydrophobic compound and a solvent such as methanol and ethyl acetate in a flask equipped with a stirrer, a cooling pipe, a temperature sensor, etc. %, Preferably 1 to 50%, and heat with stirring to 30
After setting to ~ 100 ℃, 0.01 ~ 5
%, Preferably 0.1 to 1%, polymerized by heating or irradiating with light while stirring, and after completion of the polymerization, refined,
The method of drying is mentioned.

When a hydrophobic compound is used, it is rendered water-soluble by saponifying the obtained water-soluble polymer precursor with an alkali compound such as sodium hydroxide or potassium hydroxide.

Here, as an example of the saponification method, the obtained water-soluble polymer precursor is contacted with an alcohol solution of an alkali compound of about 0.5 to 5% and reacted at 30 to 60 ° C. for about 0.5 to 5 hours. The method to do is mentioned.

The polymer used in the present invention usually contains 0.1 to 10 mol% of constituent components derived from a silane compound, preferably 1 to 5 mol%.

The molecular weight of the polymer used in the present invention is usually 5,000 to 200,000 in terms of polystyrene equivalent weight average molecular weight. When the weight average molecular weight is less than 5,000, the mechanical strength of the obtained hydrogel becomes weak, and when the weight average molecular weight exceeds 200,000, the solution has a high viscosity and becomes difficult to handle.

The biomedical material of the present invention is usually applied to a living body as a solution of water, physiological saline or physiological buffer having a concentration of 1 to 50%, preferably 5 to 40%. If the concentration of this biomedical material is less than 1%, gelation takes too long, and if it exceeds 50%, the viscosity of the solution is too high, which makes handling inconvenient.

To the solution of the biomedical material of the present invention, an acid such as acetic acid, phosphoric acid or lactic acid may be added in an amount of 0.01 to 1 mol per 1 mol of the polymer in order to control the time required for gelation. Good.

The biomedical material of the present invention is, for example, for prostheses such as skin and tissue defects, prostheses in mammoplasty, lubricants and cushioning materials in joints, constituents of defects in blood vessels and organs, artificial livers and artificial prostheses. It can be used as a base material for artificial organs of the pancreas, an artificial lens, an artificial vitreous body, and the like.

Hereinafter, the method of using the biomedical material of the present invention will be described by taking as an example the case of using it as an artificial lens (intraocular lens).

First, a crystalline lens that becomes cloudy due to a cataract or the like is removed by an ultrasonic suction method while leaving a crystalline lens capsule. Next, the solution of the biomedical material of the present invention prepared in the above concentration range is filled in a lens capsule with a syringe. Then, after several hours to several days, the biomedical material of the present invention is hydrolyzed by water in the living body and cross-linked to complete gelation, thereby forming an intraocular lens.

〔Example〕

Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

Examples 1 to 9 A solvent and a monomer having the composition shown in Table 1 were charged in a flask equipped with a reflux condenser, a stirrer, a temperature sensor and a nitrogen inlet, and heated to 70 ° C in the presence of nitrogen, and then azobis. 0.125 g of isobutyronitrile (AIBN) was added. Continue the reaction with stirring, and after 2 hours and 5 hours, 0.125 g of AIBN
Each of them was added and finally reacted for 7.5 hours. After the reaction,
Further, in Examples 1 to 6, the reaction product was saponified at 50 ° C. for 1 hour by dropping the reaction product into 100 ml of a 1% sodium hydroxide methanol solution at a speed of 200 ml / 30 minutes. Next, each of the obtained polymers was purified by Soxhlet extraction with methanol for 5 hours or more, and dried under reduced pressure to obtain a desired polymer, which was used as a sample.

The polystyrene-reduced weight average molecular weight of the sample was measured by gel permeation chromatography (GPC). The results are shown in Table 1.

The conversion rate in each example was about 50%.

Test Example 1 Gelability Test Each sample synthesized in Examples 1 to 9 was made into an aqueous solution having a concentration of 5%, and allowed to stand at 37 ° C. under saturated humidity for the time required for gelation to rotate by BM type. It was measured with a viscometer and the time when it reached 100,000 cps was taken as the end point of gelation. The results are shown in Table 2.

Test Example 2 Biocompatibility test The samples synthesized in Examples 1 to 9 were sterilized and dissolved in physiological saline to prepare a 5% solution. Next, the backs of three Nembutal anesthetized rabbits (Japanese white) are depilated to create 1.5 × 1.5 × 1.5 cm ³ defect wounds at each of the three back muscles, and the surface of the defect wounds is treated with a medical silicone sheet. Covered with (thickness 0.5 mm).
Each sample was injected with a syringe through the silicone sheet, the back skin was sutured, and then raised as usual.

On the 3rd day, 1st week, 4th week, and 3rd month after the operation, the tissue in contact with each sample was taken out and observed.

On the 3rd day after the operation, neutrophil infiltration was observed in all the sample parts, but at 1 week, the neutrophil infiltration was decreased in all the sample parts, and instead, macrophages and histiocytes appeared. It was Furthermore, in the samples other than Example 7, gelation was completed in the first week.

By the fourth week, gelation of the sample of Example 7 was completed, fibroblasts appeared in each sample part, and thin fibrous tissue encapsulation was observed around each sample part. Even at the third month, no thickening of these encapsulations was observed, and no foreign body giant cells were observed, showing a stable histology. Further, all the samples were in close contact with each other, corresponding to the fine shape of the tissue.

Test Example 3 Biocompatibility test The samples synthesized in Examples 1 to 6 and 8 to 9 were sterilized and dissolved in physiological saline to prepare a 5% solution. Then, 9 right eyeballs of Nembutal anesthetized rabbits (Japanese white) were paralyzed by instilling lidocaine, and then the conjunctiva and the connection between the cornea and the sclera were incised by about 1 mm, and an ultrasonic vibrating needle was inserted. The contents were emulsified, aspirated through the needle, and residual lens material was aspirated off, leaving the lens capsule intact, inserting the syringe through the incision and injecting 0.3 cc of sample.

The intraocular pressure, changes in corneal endothelial cells, and changes in retinal image were observed 1 day, 1 week, 1 month, and 3 months after surgery, respectively. In all the samples, the high intraocular pressure (20 to 26 mmHg) continued until 1 week after the operation as compared with that before the operation, but thereafter returned to normal. Almost no other tissue changes were seen, and the retinal image was unchanged from before surgery.

〔The invention's effect〕

The present invention is a silane compound having a hydrolyzable group, and a water-soluble polymer having a constituent derived from a hydrophilic compound, and a solution of the polymer in water, physiological saline or a physiological buffer solution. It provides a biomedical material that hydrolyzes with time, crosslinks and gels to form a hydrogel, which is significantly easier to use and more compatible with living organisms than conventional hydrogels. And its scope of application has been greatly expanded. That is, in the biomedical material of the present invention, since the solution gels with time to become a hydrogel, it is easy to inject into deep parts or minute parts of the body, and it is possible to sufficiently cope with minute shape changes, and It is a very useful biomedical material because it requires only a small incision upon injection and gels over time, resulting in excellent postoperative stability.

Claims (1)

[Claims] 1. A water-soluble compound having a constituent derived from (A) a silane compound having at least one hydrolyzable group and at least one reactive unsaturated group, and (B) a hydrophilic compound having a reactive unsaturated group. A biomedical material characterized by comprising a copolymer.