JPH04124144A - Polymeric complex material of sugar-responsive type - Google Patents

Abstract

PURPOSE:To obtain a polymeric complex material of sugar-responsive type utilizable as a diabetes-treating system or a sugar sensor, etc., controlling the release of drug according to the concentration of sugar, comprising a crosslinked polymer having boric acid group. CONSTITUTION:Boric acid group-containing monomer, e.g. (meth) acryloylaminobenzene boric acid is copolymerized with polyfunctional monomer and impregnated with polyfunctional monomer and polyfunctional hydroxyl group-containing monomer, then copolymerized, or a functional group-containing polymer is crosslinked with a suitable crosslinking agent (e.g. diisocyanate or diamine) and impregnated with boric acid group-containing monomer and polyfunctional monomer, then copolymerized to afford the objective crosslinked polymer having boric acid group. In said complex material, crosslinked polymer itself is deformed in swelling according to the concentration of sugar and diffusion or permeation of a substance into the complex material becomes ready, then contraction of the complex material is generated by the reduction of sugar concentration, thus suppressing diffusion of the substance in the complex material.

Description

[Detailed description of the invention] (Industrial application field) The present invention relates to a sugar-responsive polymer complex.

The sugar-responsive polymer complex can be used as a diabetes treatment system, a sugar sensor, etc. that controls the release of drugs depending on the concentration of sugar.

(Prior Art) It has been known that adding boric acid to an aqueous solution of polyvinyl alcohol causes gelation of polyvinyl alcohol.

In addition, there is Matrex (registered trademark) PBA-30 (benzene boronic acid-crosslinked agarose gel) manufactured by Amicon, which has a boronic acid group introduced into the agarose gel. It is used as a gel carrier for affinity chromatography by taking advantage of the fact that the #I group and Ws containing a cis-diol group form a complex.

- In a living body, in a healthy state, the in-vivo regulatory mechanism (homeostasis) functions sufficiently, and for example, various altitudes are maintained so that the concentration of various ions in the blood, blood sugar level, etc. are always kept constant. tightly regulated by a comprehensive feedbank system. However, if a problem arises in this regulatory mechanism for some reason, for example if you suffer from a chronic disease such as diabetes or hypertension, insulin or other drugs may be administered periodically depending on the symptoms. need to be administered. Careful consideration should be given to the placement and timing of the drug to be administered.

In particular, significant changes in the balance of regulatory mechanisms within the body will have serious consequences, so special care must be taken.

So far, the main treatments for diabetes have been dietary therapy and self-injection of insulin, even in this day and age of advances in medicine and the proliferation of various medical devices.

From this point of view, drug release is performed only when necessary,
There is an increasing need for a treatment system for glycosylation that has a built-in autofeedback mechanism that immediately stops release when normal.

Eliot et al. reported a small, portable device that detects blood sugar levels with a glucose detector and injects the corresponding amount of insulin into a vein using a pump (J, A
11. Med, As5oc,, 241223(1
979)).

In addition, the need for measuring glucose, a type of sugar, is increasing in other fields, and glucose sensors are being actively developed in fields such as medicine, food, and fermentation processes.

(Problem to be solved by the invention) However, the method of adding boric acid into an aqueous polyvinyl alcohol solution is difficult because the added boric acid has a low molecular weight, so it easily diffuses or permeates into the substance, and is also toxic. However, it was not suitable for medical applications.

The method of self-injection of insulin is: ■ The amount of insulin injected does not match the required amount, ■ The operation is cumbersome, ■ There is a risk of accidents such as hypoglycemic coma, and ■ It requires strong self-control on the part of the patient. Due to these drawbacks, the development of a more convenient and safe insulin release control device (artificial elbow K) is eagerly awaited.

Eliot et al.'s method also connects the glucose sensor into the patient's bloodstream through the cortical layer over a long period of time.
There are problems such as bacterial infection from the connection port and the formation of blood clots, and furthermore, troubles such as clogging of the injection needle due to crystallization of insulin and failure of mechanical or electronic circuits are expected. It is not sufficient in terms of safety and reliability. Furthermore, since conventional glucose sensors use enzymes, they have the disadvantage of a lifespan of about one week.

Up to now, there have been no reports of methods that utilize the phenomenon in which a boronic acid group is introduced into a synthetic polymer to cause a swelling change in a crosslinkable polymer due to complex nox formation with sugar.

The present invention aims to provide a sugar-responsive polymer complex with low toxicity and easy moldability.

(Means for Solving the Problems) The present invention is a tong-responsive polymer composite characterized by comprising a crosslinked polymer having a boronic acid group.

The crosslinked polymer contains a boronic acid group-containing monomer and a polyfunctional heptamer as essential components, and is obtained by copolymerizing with other copolymerizable heptamers as necessary.

Examples of monomers containing a boronic acid group include acryloylaminobenzene boronic acid, methacryloylaminobenzene boronic acid, and 4-vinylhenzene boronic acid.

Examples of polyfunctional monomers include polyethylene glycol diacrylate, 1,6-hexanediol diacrylate, neopentyl glycol diacrylate, tripropylene glycol diacrylate, polypropylene glycol diacrylate, 2.2-bis[4-(acryloxy) jetoxy)phenyl]propane, 2,2-
Bis[4-(acryloxypolyethoxy)phenyl]furopane, 2-hydroxy-1-acryloxy3-methacryloxypropane, 2,2-bis[4(acryloxypolypropoxy)phenyl]propane, ethylene glycol dimethacrylate, diethylene glycol Dimethacrylate, triethylene glycol dimethacrylate, polyethylene glycol dimethacrylate, 1,3-butylene gelicol dimethacrylate, 1,6-hexanediol diacrylate, neopentyl glycol dimethacrylate, polypropylene glyconyl dimethacrylate, 2 -Hydroxy-1,3-dimethacryloxypropane, 2,2-bis[4-(methacryloxyethoxy)]
Phenyl]propane, 2,2-bis[4-(methacryloxyethoxyjethoxy)phenyl]propane, 2,2
-bis[4-(methacrylicoxyethoxyboriethoxy)
phenyl]propane, trimethylolpropane trimethacrylate, tetramethylolmethane trimethacrylate, trimethylolpropane triacrylate, tetramethylolmethane triacrylate, tetramethylolmethanetetraacrylate, dipentaerythritol hexaacrylate, N,N'-methylenebisacrylamide, N,N'-methylenebismethacrylamide F,
Examples include diethylene glycol diallyl ether and divinylhenzen.

Monomers copolymerizable with the poronic acid group-containing monomer or polyfunctional monomer that can be used in the present invention include:
For example, acrylamide, N-methylacrylamide,
N,N-dimethylacrylamide, N,N-dimethylaminopropylacrylamide, various quaternary salts of N,N-dimethylaminopropylacrylamide, acryloylmorpholine, various quaternary salts of N,N-dimethylaminoethyl acrylate, acrylic acid, various alkyl These include acrylate, methacrylic acid, various alkyl methacrylates, 2hydroxyethyl methacrylate, glycerol monomethacrylate, N-vinylpyrrolidone, acrylonitrile, and styrene.

Examples of crosslinked polymers that can be used in the present invention include those obtained by reacting functional group-containing polymers having hydroxyl groups, amino groups, carboxyl groups, etc. with crosslinking agents such as diisocyanates, dialdehydes, diamines, dicarboxylic acid chlorides, etc. It is.

Examples of polymers having hydroxyl groups include polyvinyl alcohol, galactomannan, pullulan, dextran, and amylose.

Polymers having amino groups include polyallylamine and proteinaceous compounds.

The polymer having a carboxyl group is one obtained by polymerizing acrylic acid, maleic acid, fumaric acid, itaconic acid, or the like.

The method for producing the polymer composite of the present invention can be exemplified below.

For example, it can be obtained by copolymerizing the above-mentioned boronic acid group-containing monomer, polyfunctional Kitakami-zuma, and a monomer copolymerizable with these in one step.

In addition, after copolymerizing the boronic acid group-containing monomer and the polyfunctional Kitakami monomer in the second stage, the polyfunctional Kitakami monomer and the polyvalent hydroxyl group-containing monomer are impregnated in the second stage, and then copolymerized. It can be synthesized.

In addition, after copolymerizing the polyfunctional Kitakami compound and the polyvalent hydroxyl compound compound in the second stage, the boronic acid group-containing monomer and the polyfunctional Kitakami compound are impregnated in the second stage, and then copolymerized. It can also be synthesized.

On the other hand, it can also be synthesized by crosslinking a functional group-containing polymer with a suitable crosslinking agent, impregnating it with a boronic acid group-containing monomer and a polyfunctional monomer, and then copolymerizing it.

Furthermore, the crosslinked polymer that can be used in the present invention is
A polymer obtained by copolymerizing a polyfunctional monomer and an unsaturated carboxylic acid can also be synthesized by a condensation reaction with a polyhydric hydroxyl compound having a primary amino group, such as tris(hydroxymethyl)aminomethane.

In addition, polymerizable heptamers containing -grade amino groups, for example,
The amino group in the polymer obtained by polymerizing or copolymerizing aminostyrene, vinylbenzylamine, etc., is replaced with a polyhydric hydroxyl group compound having a carboxylic acid group, such as brotocatechuic acid, gallic acid, tricine, 2,2-(dihydroxymethyl ) It may also be a polymer obtained by an amide reaction with propionic acid or the like.

The amount of heptamine having a poronic acid group used is in the range of 0.1 to 90 mol%, preferably 0.5 to 30 mol%, based on the total monomers.

The amount of polyfunctional Kitakami Tsuma used is 0.0 in all monomers.
It is used in a range of 1 to 50 mol%.

The amount of copolymerizable heptamer used in all monomers is
It is used in a range of 0.1 to 98 mol%.

The polymer of the present invention can be produced by known solution, bulk, emulsion, or reverse phase suspension polymerization using radical polymerization at a polymerization temperature of 0 to 100°C.
, can be obtained in a polymerization time of 10 minutes to 48 hours. Examples of the polymerization initiator used here include benzoyl peroxide, diisopropyl peroxydicarbonate, tert-butyl peroxy-2-ethylhexanoate, tert-butyl peroxy bihalt, tert-butyl peroxy diisobutyrate, and lauroyl peroxide. , abbis isobutyronitrile, 2,2'-azobis(2,4-dimethylvaleronitrile), or various redonx initiator systems. 01 to 5.0% by weight.

In the polymer complex of the present invention, the sugar binds to the boron eIR group in the complex depending on the sugar concentration, so that the boron in the complex has a negative charge and swells due to the repulsive force, and I!
It is a sugar-responsive polymer complex that causes contraction when the concentration decreases.

In addition, after the complex is formed between the boronic acid group and the polyvalent hydroxyl group formed in the complex, the sugar is bonded to the boronic acid group in the complex by adding sugar, and the polyvalent hydroxyl group in the complex becomes boron. It is a strain-responsive polymer complex that dissociates from acid groups, swells due to repulsive force, and when the sugar concentration decreases, complex formation between boronic acid groups and polyvalent hydroxyl groups is promoted again, causing contraction.

In other words, in the complex of the present invention, the crosslinked polymer itself undergoes a swelling change depending on the sugar concentration, facilitating the diffusion or permeation of substances within the complex, and shrinks due to the decrease in sugar concentration, causing swelling within the complex. It becomes a sugar-responsive polymer complex that suppresses material diffusion.

The complex of the present invention is used in an aqueous medium or an aqueous medium containing 50% or less of an organic solvent, preferably using a buffer. As the buffer, sodium phosphate buffer, sodium acetate buffer, O-chlorophenol buffer, sodium arsenate buffer, sodium carbonate buffer, Heves buffer, Chess buffer, etc. can be used.

Further, the pl (value in this case is particularly preferably 6.0 or more). The present composite is used at a temperature of 1 to 50°C.

Sugars to which the polymer complex of the present invention responds include, for example, glucose, galactose, fructose, and mannose.

The complex of the invention is I! It responds at a sugar concentration of 0.1 .mu./a or more, but it is preferably used at a sugar concentration of 1 to 1 oooo .mu./a.

By using this complex as a permeable membrane to control drug release, it can also be used as a sugar-responsive drug releaser.For example, when insulin is used as the drug, it can be used for insulin administration in diabetes, etc. Drugs that can be made into aqueous solutions are applicable to various preparations used for administration of drugs that are desired to be taken in response to increases in blood sugar levels after meals, or to 0-bond complexes used as diabetes treatment systems. All soluble drugs can be used, and insulin, glucagon, somatostatin, corticosteroids, etc. are particularly effective. Moreover, two or more of these drugs can also be used in combination.

Furthermore, by using the polymer complex of the present invention with a substance that can be measured spectroscopically, such as a staining agent, it can also be used as a sugar sensor. In this case, preferably 1 to 10
It is preferable to use a sugar concentration of 000 μ/d1.

(Effects of the Invention) The complex of the present invention has an autofeedback mechanism in which it swells and changes in response to the m concentration of glucose, etc., and controls the release of the drug held inside, and is useful for diabetes treatment. It can be used as a device or a sugar sensor.

Also, since it uses polymerized boron, its toxicity is extremely low.

(Examples) Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited to these Examples.

Example 1 2.05 g of 3-methacryloylaminobenzene boronic acid
(10+*mol) and 11.7 g (90 mn+ol) of 2-hydroxyethyl methacrylate and 0.099 g of ethyl L/7 glycol dimethacrylate (
0.5 mmol) and 0.07 g of tert-butylperoxy-2-ethylhexanoate as an initiator.
was added, and the mixture was replaced with nitrogen for 20 minutes, and then poured into a film forming container to form a film.

For film formation, a polyethylene terephthalate film (thickness: 10,100p is pasted on two glass plates, and a frame (Teflon, thickness: 20.1 mm
After pouring in the monomer solution, it was sandwiched between glass plates covered with polyethylene terephthalate film and placed in an oven (60°C, 12 hours, under a nitrogen stream).
This was carried out by polymerizing with As for whether the phenylboronic acid group is released from the obtained complex,
As confirmed by UV (254nap) measurement,
It was not detected even after immersion in distilled water or buffer solution for 10 days.

The obtained complex was examined for swelling changes in the presence and absence of sugar in a buffer solution at 37°C.

The results are shown in Table 1.

Example 2 2.05 g of 3-methacryloylaminobenzene boronic acid
(10n+mol), 10.4 g (80 mmol) of 2-hydroxyethyl methacrylate, and 1.85 g (10 mmol) of diethylaminoethyl methacrylate.
1), 0.099 g (0.5 mmol) of ethylene glycol dimethacrylate was added as a crosslinking agent, 0.072 g of tert-butyl peroxy-2-ethylhexanoate was added as an initiator, and the film was formed after purging with nitrogen for 20 minutes. A film was formed by pouring it into a container.

The film forming method was the same as in Example 1.

Release of boronic acid groups from the composite after synthesis was confirmed in the same manner as in Example 1, and no release was detected even after immersion in distilled water or buffer solution for 10 days.

The resulting composite was examined for swelling changes in the presence and absence of scale in a buffer solution at 37°C.

The results are shown in Table 1.

Example 3 0.82 g of 3-methacryloylaminobenzene boronic acid
(4mlol) and N,N-dimethylacrylamide 3
．． 569 g (36 mmol) was added to 14.355 g of dimethylformamide, and 0.396 g (2 mmol) of ethylene glycol dimethacrylate was added as a frame 41Jf.
) and tert-butylperoxy as an initiator.
Add 0.096 g of 2-ethylhexanoate and add 20
After purging with nitrogen for a minute, the mixture was poured into a film forming container to form a film.

The film forming method was the same as in Example 1.

Release of boronic acid groups from the composite after synthesis was confirmed in the same manner as in Example 1, and no release was detected even after immersion in distilled water or buffer solution for 10 days.

The obtained complex was examined for swelling changes in the presence and absence of sugar in a buffer solution at 37°C.

The results are shown in Table 1.

Example 4 0.41 g of 3-methacryloylaminobenzene boronic acid
(2ml mol) and N,N-dimethylacrylamide 3
, 569 g (36 fimol) and 0.32 g (2 mmol) of glycerol monomethacrylate were added to 14.085 g of dimethylformamide, and 0.396 g (2 mmol) of ethylene glycol dimethacrylate was added as a crosslinking agent.
+*mol) was added thereto, 0.094 g of tert-butyl peroxy-2-ethylhexanoate was added as an initiator, the mixture was purged with nitrogen for 20 minutes, and then poured into a film forming container to form a film.

The film forming method was the same as in Example 1.

Release of boronic acid groups from the composite after synthesis was confirmed in the same manner as in Example 1, and no release was detected even after immersion in distilled water or buffer solution for 10 days.

The obtained complex was examined for swelling changes in the presence and absence of sugar in a buffer solution at 37°C.

The results are shown in Table 1.

Example 5 Among the monomers in Example 4, 3-methacryloylaminobenzene boronic acid was replaced with 0.764 g (4 mmol) of 3-acryloylaminobenzene boronic acid,
Polymerization was carried out under the same conditions except for the above. Release of boronic acid groups from the composite after synthesis was confirmed in the same manner as in Example 1, and no release was detected even after immersion in distilled water or buffer solution for 10 days.

The obtained complex was examined for swelling changes in the presence and absence of sugar in a buffer solution at 37°C.

The results are shown in Table 1.

Example 6 As the first stage, add 2 (ld) of a 5 wt% aqueous solution of polyvinyl alcohol with a degree of polymerization of 500, 0.95 m of a 2.5% aqueous glutaraldehyde solution, and 1.0 m of a 10% aqueous sulfuric acid solution, place in a flat petri dish, and stir at room temperature for 24 hours. After leaving it for a while to crosslink, it was poured into distilled water, and after removing unreacted substances by changing the distilled water three times, in the second stage, 0.41 g of 3-methacryloyl aminohensenboronic acid (1 mol at 2°C), NN-dimethyl Acrylamide 9.72g (98n+11+ol),
NN'-methylenebisacrylamide 0.385g (2
, 5 mmol) and distilled water, and 0.5 g of ammonium persulfate as an initiator, the mixture was immersed for 48 hours in an aqueous solution containing 0.5 g of ammonium persulfate as an initiator, and then replaced with nitrogen for 2 to 3 hours. The polymerization was carried out by polymerization under air flow).

The obtained complex was placed in distilled water and used after changing the triple distilled water to remove unreacted substances. The release of boronic acid groups from the synthesized complex was confirmed in the same manner as in Example 1, and the obtained complex was not detected even after being immersed in distilled water or buffer solution for 10 days. Changes in swelling were investigated in the presence and absence of scale in a buffer solution at ℃.

The results are shown in Table 1.

Example 7 As the first stage, add 20% dimethyl sulfoxide solution of 5% by weight of polyhinyl alcohol with a degree of polymerization of 500, and add 0.2 g of triisocyanate Coronate HL (manufactured by Nippon Polyurethane Industries Co., Ltd.) to a petri dish. The mixture was placed in an oven at 80°C for 72 hours for crosslinking, then placed in dimethyl sulfoxide, and the dimethyl sulfoxide was changed three times to remove unreacted materials. 025g (5mna
o1. ), N, N-dimethylacrylamide9.
Add 418 g (95 mmol), 0.495 g (2.5 mmol) of ethylene glycol dimethacrylate, and 98.4 g (2.5 mmol) of ethylene glycol dimethacrylate, and add tert-butylperoxy-2-ethylhexanony as an initiator.
After soaking for 48 hours in a solution containing 0.55 g,
After purging with nitrogen for 3 hours, polymerization was carried out in an oven (60° C., 12 hours, under a nitrogen stream).

The obtained complex was placed in dimethyl sulfoxide, and the dimethyl sulfoxide was changed three times to remove unreacted substances.
The water was gradually replaced with distilled water and then completely replaced with distilled water. Release of boronic acid groups from the composite after synthesis was confirmed in the same manner as in Example 1, and no release was detected even after immersion in distilled water or buffer solution for 10 days.

The obtained complex was examined for swelling changes in the presence and absence of sugar in a buffer solution at 37°C.

The results are shown in Table 1.

Example 8 Distilled water 121R1 contains 33 µm (0.16 mmol) of 3-methacryloylaminohensenboronic acid, 1.14 g (16, On+mol) acrylamide, 26 µm (0,16+u+ol) glycerol monomethacrylate, and N and N as crosslinking agents. '-Methylenebisacrylamide 90■
(0.58+u+ol), ammonium persulfate (0°6g/W11) aqueous solution 0.2-1N as an initiator,
N,N',N'-tetramethylethylenediamine 0.1
- is added to a solution of 0.4 - of Aracel C (manufactured by Kanto Kasei) in a toluene chloroform solvent.
Obtained by. Release of boronic acid groups from the composite after synthesis was confirmed in the same manner as in Example 1, and no release was detected even after immersion in distilled water or buffer solution for 10 days.

The obtained complex was examined for swelling changes in the presence and absence of sugar in a buffer solution at 37°C.

The results are shown in Table 1.

Comparative example 1 2-hydroxyethyl methacrylate 13.0g (10
011+101) was added with 0.099 g (0.5 gmol) of ethylene glycol dimethacrylate as a crosslinking agent, and polymerization was carried out in the same manner as in Example 1.

The obtained complex was examined for swelling changes in the presence and absence of sugar in a buffer solution at 37°C.

The results are shown in Table 1.

Comparative Example 2 Among the monomers in Example 3, 3-methacryloylaminobenzene boronic acid was not added, and the amount of N7N-dimethylacrylamide was changed to 3.965 g (40 Jr1 m
o1. ), add the amount of dimethylformamide to 13.084
Polymerization was carried out under the same conditions except for different g.

The obtained complex was examined for swelling changes in the presence and absence of sugar in a buffer solution at 37°C.

The results are shown in Table 1.

Comparative Example 3 Polymerization was carried out in the same manner as in Example 3, except that 0.64 g (4 mmol) of glycerol monomethacrylate was used instead of 3-methacryloylaminobenzene boronic acid.

The obtained complex was examined for swelling changes in the presence and absence of sugar in a buffer solution at 37°C.

The results are shown in Table 1.

Examples 1 to 8 and Comparative Examples 1 to 3 are summarized in Table 1 regarding the degree of swelling.

The degree of swelling is expressed as the amount of solvent contained per gram of the composite.

The solutions used for the measurements in Table 1 were: A: IJ acid physiological buffer (pH = 7.4), B: Hebbes buffer e, (p) I =
8.5), C: Hebes buffer (pH = 8.5), glucose 100 IIIg/dl, l): Hebes buffer (
pH=8.5), glucose 1ooo■/d! , E: Heves buffer (pH=8.5), galactose 1000■
/d1 was used, respectively.

Table 1 From the results in Table 1, it can be seen that the degree of swelling of the Examples increases depending on the sugar concentration, but the degree of swelling of all the Comparative Examples is constant.

Example 9 The complex of Example 3 was subjected to insulin permeation through a membrane (diameter 20D) in a thermostatic bath at 37°C using a permeation device consisting of two layers (the capacity of the negative layer was 20.ff). I looked into it. As a buffer solution, Heves buffer (pl+ = 8.
5), one side is Hepes buffer containing 0.5 ■/d of insulin, and the other side is Hepes buffer or glucose concentration 1000 ■/d! The measurement was performed by adding Heves buffer. Note that raw insulin manufactured by Sigma was used as the insulin, and the insulin was quantified by UV measurement (274 nm). As a result, the insulin concentration on the side where insulin permeates after 6 hours is 32 n/d when Hepes buffer is added to the permeate side, and 32 n/d when Hepes buffer with a glucose concentration of 1000/d1 is added to the permeate side. When added, it was 63n/dl.

Claims (2)

[Claims] (1) A sugar-responsive polymer complex comprising a crosslinked polymer having a boronic acid group. (2) A sugar-responsive polymer complex consisting of a crosslinked polymer having a boronic acid group and a drug.