JPH06293632A - Temperature response type medicinal composition - Google Patents

Abstract

PURPOSE:To obtain a temperature response type medicinal composition capable of responding a given change in temperature and controlling release of a medicine. CONSTITUTION:This temperature response type medicine composition comprises an aqueous solution of one or more kinds of temperature response type polymers selected from a group consisting of a polymer and a copolymer of one or more kinds of N-substituted (meth)acrylamide derivatives and another vinyl-based monomer as an arbitrary component, hydroxypropyl cellulose, partially acetated substance of polyvinyl alcohol, etc., and a medicine.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a temperature-responsive drug composition capable of delivering a required amount of a drug to a required place only when needed by changing temperature.

[0002]

2. Description of the Related Art Conventionally, in the administration of drugs to animals including humans, the administration of pesticides to plants and pests, the supply of catalysts for chemical reactions, the release of fragrances, etc. into malodorous environments, There is a problem that it is difficult to control the dosage of a drug having a high decomposition rate, a drug having poor stability, a drug having a short drug onset period, and the like.

On the other hand, in recent years, basic and practical studies have been actively carried out on so-called drug delivery systems (DDS), which are drugs that act in a required amount at a required place only when needed. Practical applications include scopolamine for motion sickness, nitrite drugs such as nitroglycerin for the treatment of angina, transdermal preparations such as nicotine for smoking cessation, and diazinon. Examples of the pesticide include microcapsule type preparations.

However, most of these are merely intended for sustained release of the drug and do not fulfill all the concept of DDS.

Recently, studies aiming at realization of an ideal DDS in which a stimulus-responsive polymer is used to release a necessary amount of a drug to a necessary place only when a stimulus is added to a preparation have been started. There is. In particular, temperature-responsive DDS represented by N-alkyl-substituted (meth) acrylamide polymers has attracted attention.

The conventional controlled release method using a temperature-responsive polymer uses a water-insoluble polymer formed into a membrane, microsphere, microcapsule, hollow fiber, etc.
The release of the drug is controlled by changing the temperature at the phase transition temperature.

That is, at a temperature below the phase transition temperature, the water-insoluble temperature-responsive polymer hydrates and swells, and the drug is easily diffused through water existing in the polymer and released to the external environment. It At a temperature above the phase transition temperature, water that had been hydrated to a water-insoluble temperature-responsive polymer is dehydrated and de-swelled, and the drug is suppressed from diffusing in the water-deficient polymer to the external environment. Emission stops. By utilizing such a property, the drug release is membrane-controlled.

[0008]

However, such a method by controlling the membrane has a practical problem that the structure of the preparation becomes complicated and the application range is limited, or it is industrially disadvantageous. is there.

[0009]

The inventors of the present invention have conducted extensive studies to solve the above-mentioned problems, and as a result, a composition obtained by dispersing or dissolving a drug in an aqueous solution of a temperature-responsive polymer was found to be external. The inventors have found that the composition is an industrially and practically advantageous drug composition in which the drug release can be controlled by reversibly adsorbing / desorbing the drug to / from the polymer in response to a temperature change, and completed the present invention. .

That is, the present invention is as follows: 1. A temperature-responsive drug composition comprising an aqueous solution of a temperature-responsive polymer having a phase transition temperature of 4 to 90 ° C. and a drug,

2. The temperature responsive polymer is a polymer or copolymer of one or more N-substituted (meth) acrylamide derivatives or a vinyl monomer, polyoxyethylene derivatives, hydroxypropyl cellulose and polyvinyl alcohol. 1. The temperature-responsive pharmaceutical composition according to the above item 1, which is one or more kinds selected from the group consisting of partial acetic acid.

3. It consists of an aqueous solution of a temperature-responsive polymer and a drug. At temperatures above the phase transition temperature, the drug is adsorbed to the polymer and its release to the external environment is suppressed, and at temperatures below the phase transition temperature. The present invention also relates to a temperature-responsive drug composition for release control, wherein the drug is desorbed from the polymer and released to the external environment.

The "temperature-responsive polymer" in the present invention refers to a polymer having a phase transition temperature, and more specifically, the polymer and water molecules are hydrogen-bonded (hydrated) at a temperature lower than the phase transition temperature. A polymer that becomes hydrophilic, dissociates (dehydrates) water molecules at a temperature higher than the phase transition temperature, becomes hydrophobic, and interacts among the polymers to cause aggregation, which is reversible.

As typical examples of the temperature-responsive polymer in the present invention, specifically, hydroxypropyl cellulose, polyvinyl alcohol partial acetic acid having a saponification degree of 70 to 90 mol%, polyoxyethylene nonylphenyl ether, poly Polyoxyethylene alkylphenyl ether derivatives such as oxyethylene octyl phenyl ether, polyoxyethylene lauryl ether, polyoxyethylene oleyl ether, polyoxyethylene tridecyl ether and other polyoxyethylene alkyl ether derivatives, and polyoxyethylene lauryl amine Oxyethylene alkylamine derivatives, polyoxyethylene sorbitan laurate and other polyoxyethylene sorbitan ester derivatives, polyoxyethylene phenyl ether, polyoxyethylene Ren styrenated phenol, polyoxyethylene castor oil derivatives, (polyoxyethylene - polyoxypropylene) block copolymer derivatives,
Polyoxyethylene derivatives such as

N-n-propyl acrylamide, N-isopropyl acrylamide, N-ethyl acrylamide, N, N-dimethyl acrylamide, N-acryloyl pyrrolidine, N-acryloyl piperidine, N-acryloyl morpholine, N-n-propyl methacrylamide, N-isopropyl methacrylamide, N-ethyl methacrylamide, N, N-dimethyl methacrylamide,
Examples thereof include polymers of N-substituted (meth) acrylamide derivatives such as N-methacryloylpyrrolidine, N-methacryloylpiperidine, N-methacryloylmorpholine and the like, whose polymers are temperature-responsive polymers.

The above N-substituted (meth) acrylamide derivatives can also be used by copolymerizing two or more thereof. Further, a copolymer of one or more of the above N-substituted (meth) acrylamide derivatives and another vinyl monomer copolymerizable therewith can also be used. Examples of the copolymerizable vinyl monomer include a hydrophilic monomer and a hydrophobic monomer, and one or more kinds of these monomers can be used.

Specific examples of the vinyl monomer copolymerizable with the above N-substituted (meth) acrylamide derivative include hydrophilic monomers such as acrylamide, methacrylamide, and N.
-Methyl acrylamide, diacetone acrylamide,
Hydroxyethyl methacrylate, hydroxyethyl acrylate, hydroxypropyl acrylate, hydroxypropyl methacrylate, N-vinyl-2-pyrrolidone, acrylic acid, methacrylic acid, vinyl sulfonic acid,
Acids such as allylsulfonic acid, methacrylsulfonic acid, styrenesulfonic acid, 2-acrylamido-2-phenylpropanesulfonic acid, 2-acrylamido-2-methyl-propanesulfonic acid and salts thereof,

N, N-dimethylaminoethyl methacrylate, N, N-dimethylaminoethyl acrylate,
N, N-dimethylaminopropyl methacrylamide,
Examples include amines such as N, N-dimethylaminopropyl acrylamide and salts thereof, various polyoxyethylene acrylates, various polyoxyethylene methacrylates, various polyoxymethylethylene acrylates, various polyoxymethylethylene methacrylates, and the like.

As the hydrophobic monomer, for example, N-
n-butyl acrylamide, Nt-butyl acrylamide, Nn-hexyl acrylamide, Nn-octyl acrylamide, Nt-octyl acrylamide, Nn-dodecyl acrylamide, Nn-butyl methacrylamide, N- t-butyl methacrylamide,
N-alkyl (meth) acrylamide derivatives such as Nn-hexyl methacrylamide, Nn-octyl methacrylamide, Nt-octyl methacrylamide, and Nn-dodecyl methacrylamide.

N, N-diglycidyl acrylamide, N
-(4-glycidoxybutyl) acrylamide, N-
(5-glycidoxypentyl) acrylamide, N-
(6-glycidoxyhexyl) acrylamide, N, N
N- (ω such as diglycidyl methacrylamide, N- (4-glycidoxybutyl) methacrylamide, N- (5-glycidoxypentyl) methacrylamide, and N- (6-glycidoxyhexyl) methacrylamide. -Glycidoxyalkyl) (meth) acrylamide derivatives,

(Meth) acrylate derivatives such as ethyl acrylate, methyl methacrylate, butyl methacrylate, butyl acrylate, lauryl acrylate, 2-ethylhexyl methacrylate, glycidyl methacrylate, acrylonitrile, methacrylonitrile, vinyl acetate, vinyl chloride, ethylene, propylene, butene. Olefins such as

Styrene, α-methylstyrene, butadiene, isoprene, etc., dimethylvinylmethoxysilane, dimethylvinylethoxysilane, methylvinyldimethoxysilane, methylvinyldiethoxysilane, vinyltriethoxysilane, vinyltrimethoxysilane, vinyltris (trimethylsiloxy). ) Silane, 3-methacryloxypropyltrimethoxysilane, 3-methacryloxypropylmethyldimethoxysilane, 3-methacryloxypropyltris (trimethoxy) silane, 1- (3-methacryloxypropyl) -1,1,3,3,3 Examples thereof include silane derivatives such as 3-pentamethyldisiloxane and N, N-bis (3- (trimethoxysilyl) propyl) methacrylamide.

When a hydrophobic monomer is used, it is copolymerized with an N-substituted (meth) acrylamide derivative and, if necessary, the hydrophobic monomer-derived structural portion in the copolymer is hydrolyzed, Hydrophilicity can also be imparted to the copolymer.

The above-mentioned N-substituted (meth) acrylamide derivative whose polymer is a temperature-responsive polymer is preferably used in an amount of 30 mol% or more, and particularly preferably 50 mol% or more, based on all monomers to be polymerized. Is good.

At that time, as a method for initiating the polymerization,
Well-known methods such as radiation and heating can be adopted, but normally, a better result is obtained by using a polymerization initiator. The polymerization initiator is not limited as long as it has the ability to initiate radical polymerization, and examples thereof include inorganic peroxides, organic peroxides, combinations of those peroxides and reducing agents, and azo compounds. Can be mentioned.

Specifically, hydrogen peroxide, potassium persulfate, ammonium persulfate, benzoyl peroxide, t
There are peroxides such as -butyl peroxide, t-butyl peroxy-2-ethylhexanoate and butyl perbenzoate, and sulfites are used as reducing agents in combination with them.
Examples thereof include bisulfite, salts of iron, cobalt, copper and the like, organic acids such as ascorbic acid, and organic amines such as aniline.

Examples of the azo compound include azobisisobutyronitrile, 2,2'-azobis-2-amidinopropane hydrochloride and 2,2'-azobis-2,4-dimethylvaleronitrile.

The addition amount of these polymerization initiators is sufficient within the range employed in ordinary radical polymerization, and is, for example, 0.01 to 5% by weight, preferably 0.05 to 5% with respect to the monomer.
It is in the range of 2% by weight. The polymerization temperature and the polymerization time vary depending on the type of the initiator used, but are usually 4 to 4 respectively.
90 ° C, preferably 40 to 80 ° C, usually 1 to 72
The time is preferably 12 to 48 hours.

The temperature-responsive polymer thus obtained is obtained by removing unreacted substances by a known method such as a reprecipitation method, an ultrafiltration method, a gel filtration method and the like, followed by drying to obtain a purified product. You can The method for obtaining the temperature-responsive polymer that can be used in the present invention is not particularly limited to the above method as long as the polymer is finally obtained. Specifically, a method of polymerizing the monomer as it is without diluting it with a solvent, a method of diluting the monomer with a solvent to polymerize, and the like can be mentioned.

The structure of the temperature-responsive polymer of the present invention may be a homopolymer or a random copolymer, but if necessary, it may be a block copolymer, a graft (co) polymer, a starburst (co) polymer or the like. It can also be used as a structure.

The phase transition temperature of the temperature-responsive polymer of the present invention is determined by the type of polyoxyethylene derivative or the degree of polymerization of oxyethylene, the molecular weight of hydroxypropyl cellulose, the degree of saponification or molecular weight of polyvinyl alcohol partial acetic acid, and the N substitution ( Types of (meth) acrylamide derivatives,
It can be freely changed depending on the kind or composition ratio of the monomers to be copolymerized.

Specifically, in the case of a polyoxyethylene derivative, for example, the larger the number of carbon atoms in the alkyl group of the polyoxyethylene alkyl ether or the smaller the degree of polymerization of oxyethylene, the lower the phase transition temperature. In the case of hydroxypropyl cellulose, the phase transition temperature tends to decrease as the molecular weight increases, and in the case of polyvinyl alcohol partial acetic acid, the phase transition temperature tends to decrease as the saponification degree decreases or the molecular weight increases. .

In the case of a (co) polymer of an N-substituted (meth) acrylamide derivative, the higher the hydrophobicity of the substituent of the derivative, the more the copolymerization of a hydrophobic monomer, or the hydrophobic homopolymer. The higher the composition ratio of the monomer, the lower the phase transition temperature tends to be. Further, the phase transition temperature tends to increase as the hydrophobicity of the substituent decreases, or the hydrophilic monomer is copolymerized, or the composition ratio of the hydrophilic monomer increases.

The phase transition temperature of the temperature-responsive polymer used in the present invention may be set at the temperature at the time of controlled release, and this temperature is generally determined by the drug used or the environment to which it is applied. However, since the temperature-responsive polymer of the present invention can be designed with a phase transition temperature in the range of 4 ° C to 90 ° C, it can be applied in a wide range.

In the present invention, the "temperature-responsive drug composition" refers to a composition in which a drug is dispersed or dissolved in an aqueous solution of a temperature-responsive polymer. The drug can be used by being dissolved or dispersed at a concentration equal to or lower than the maximum adsorption amount that can be adsorbed when the temperature-responsive polymer is hydrophobic at a temperature above the phase transition temperature. The form of the pharmaceutical composition may be any conventional form,
For example, it can be used as a capsule, ointment, lotion, injection or the like in medicine, and as a microcapsule or dusting agent in agrochemicals.

Here, the medium in the "aqueous solution" does not have to be only water, but a water-containing polymer capable of dissolving the temperature-responsive polymer and allowing the polymer to behave as hydrophilic-hydrophobic. Any medium may be used. For example, 10% or less of various surfactants and / or 5 other than water may be used.
Examples thereof include a water-containing medium containing 0% or less of an organic solvent and various aqueous electrolyte solutions. The concentration of the temperature-responsive polymer in the aqueous solution varies depending on the type of polymer, etc., but is usually 0.01-
It is selected in the range of 50% by weight, preferably 0.1 to 20% by weight.

The drug whose release is controlled from the temperature-responsive drug composition of the present invention is not particularly limited as long as it is soluble in an aqueous solution. For example, in the case of medicine, anti-inflammatory analgesics such as indomethacin, ketoprofen, salicylic acid, tetracycline and the like. , Antibiotics such as chloramphenicol, penicillin,
Antibacterial agents such as benzacorconium chloride, clotrimazole, pyrrolenitrin, anesthetics such as lidocaine and pentobarbital, cold agents such as aminoacetophenone, etenzamid, aspirin,

Antihistamines such as diphenhydramine hydrochloride, promethazine hydrochloride and clemastine fumarate, antianginal agents such as nitroglycerin, isosorbide nitrate and nitromannitol, antihypertensive agents such as clonidine, hydralazine and methyldopa, testosterone, estradiol,
Hormonal agents such as, thiamine, riboflavin, pyridoxine, vitamin agents such as ascorbic acid, bleomycin,
Anticancer agents such as cisplatin, bestatin, etoposide and the like can be mentioned.

In addition, as agricultural chemicals, sodium pentachlorophenol, zinc ethylene bisdithiocarbamate,
O, O-diisopropyl-S-benzylthiophosphate, 5-methyl-1,2,4-triazolo (3,4-
b) Bactericidal agents such as benzothiazole, nicotine sulfate, dimethyl (3-methyl-4-nitrophenyl) thiophosphate, (2-isopropyl-4-methylpyrimidyl-)
6) -insecticides such as diethylthiophosphate,

Weeding of 2,4-dichlorophenoxyacetic acid sodium salt, 2,4-dinitroortho-sec-butylphenolisopropanolamine, 3- (5-tert-butyl-3-isooxazolyl) -1,1-dimethylurea and the like. Agents, plant growth regulators such as indole butyric acid, nicotinic acid amide, maleic acid hydrazide potassium salt, 2-
Preservatives such as (4-thiazolyl) benzimidazole may be mentioned.

Examples of catalysts in chemical reactions include:
Reducing agents such as sodium borohydride, lithium borohydride, ascorbic acid, methylamine, hydrogen peroxide, N-bromosuccinimide, oxidizing agents such as sodium metaperiodate, 2-methylimidazole, 2, 4, 6
An epoxy curing accelerator such as tris (diethylaminomethyl) phenol,

Ammonium peroxide, 2,2'-
Polymerization initiators such as azobis (2-methylpropionamidine) dihadrochloride and 2,2'-azobis (2- (2-imidazolin-2-yl) propane) dihydrochloride, alpha-amylase, papain, chymopapain, lipase Enzymes such as cellulase, pectinase, glucose oxidase, catalase, lactase, lysozyme, pepsin, L-asparaginase and protease.

Further, as an example of the fragrance for the bad smell environment,
Muscon, civetone, cinnamic acid, benzoic acid, castoramine, lithrol, linalool, camphene, santalol, d-limonene, citral, 1-menthol, cinnamic alkyd, vanillin, heliotropin, lilial and the like can be mentioned. .

The amount of the drug dispersed or dissolved in the temperature responsive drug composition of the present invention is not particularly limited, but it is generally determined by the drug used, the temperature responsive polymer used, and the environment to which it is applied. Specifically, the range of 0.1 μg to the maximum adsorption amount per 1 g of the polymer is preferable.

Here, the maximum amount of drug adsorbed on the temperature-responsive polymer is a value determined as follows. A temperature-responsive polymer that has become hydrophobic due to the precipitation of a specific amount of a drug at a temperature below the phase transition temperature in an aqueous solution of the temperature-responsive polymer at a predetermined concentration, and then becomes hydrophobic and precipitates. Ultrafilter. The amount of the drug in the filtrate is measured, and the value obtained by subtracting the amount of the drug in the filtrate from the amount of the drug initially added is the maximum adsorption amount.

For example, the maximum adsorption of nitroglycerin on a (polyoxyethylene-polyoxypropylene) block copolymer having a phase transition temperature of 37 ° C. (Sanmor I-906, Nika Kagaku Co., Ltd., phase transition temperature 37 ° C.) The amount is 7.524 m per 1 g of Sunmol at 39 ° C.
It was g.

In the present invention, the "temperature-controlled drug composition for controlled release" means that the temperature-responsive polymer reversibly changes its hydrophilicity and hydrophobicity with the phase transition temperature as a boundary depending on the external environment temperature. In doing so, the drug reversibly adsorbs and desorbs on the polymer,
As a result, the composition enables controlled release of the drug.

That is, at a temperature equal to or higher than the phase transition temperature, the drug is distributed or adsorbed on the hydrophobic polymer, and the release of the drug to the external environment is suppressed. At a temperature below the phase transition temperature, the drug is desorbed from the hydrophilic polymer and the drug is released to the external environment. These behaviors can be reversibly performed. Therefore, the temperature-responsive drug composition can be used as it is as the temperature-controlled drug composition for controlling release.

Efficient controlled release of a drug from the composition of the present invention can be achieved by selecting the type and concentration of the temperature-responsive polymer and the type and concentration of the drug according to the controlled environment. You can

For example, when the composition of the present invention is applied to a rabbit as a percutaneous absorption preparation of nitroglycerin,
Controlled release environment (Rabbit surface temperature: average 38.5
℃), the phase transition temperature of the polymer is generally determined. Specifically, when the release is controlled by heating, the polymer having a phase transition temperature of 38.5 ° C or higher, and when controlled by cooling The polymer having a phase transition temperature of 38.5 ° C. or lower may be designed.

Further, the optimum concentration of the polymer selected as described above can be determined according to the following method by specifying the kind and concentration of the drug to be used.
Specifically, in an environment where controlled release is desired, the drug is at a temperature below the phase transition temperature (adsorption / desorption temperature) of the polymer and above the phase transition temperature (adsorption / desorption temperature) of the polymer. Can be determined by finding the distribution coefficient of

That is, at temperatures below and above the phase transition temperature, various concentrations of the polymer were added to an aqueous solution of a drug having a constant concentration, and the respective partition coefficients were measured. Is higher than the partition coefficient above the phase transition temperature (in other words, the drug is adsorbed above the phase transition temperature, and the drug is desorbed below the phase transition temperature). The molecular concentration can be determined.

For example, when the composition of the present invention is applied to a rabbit as a percutaneous absorption preparation of nitroglycerin,
The concentration when Sanmol I-906 is used as the temperature-responsive polymer can be determined by measuring the partition coefficient of nitroglycerin to rabbit skin at the temperature at which the phase transition temperature is the boundary.

Specifically, 0.1% Sanmor I-90
The partition coefficients of nitroglycerin for the skin of rabbits at 32 ° C. and 39 ° C. in 6 aqueous solutions are 256.5 and 665 (Example 1), respectively, and the partition coefficients in 0.5% Sanmol I-906 aqueous solution are: 485 and 227 (Example 2), 1
The respective partition coefficients for the% Sanmor I-906 aqueous solution were 161.9 and 46 (Example 3). That is,
It is difficult to control the release of nitroglycerin in Example 1, and it is possible to control the release of nitroglycerin in Examples 2 and 3.

Here, the distribution coefficient was calculated by the following formula. Cpre: initial concentration of nitroglycerin in 1% sammol aqueous solution Cpost: concentration of nitroglycerin in 1% sanmol aqueous solution after 24 hours V: volume of 1% sanmol / nitroglycerin aqueous solution Vs: volume of rabbit skin piece

By changing the concentration of Sanmol I-906 and measuring the distribution coefficient as described above, the optimum concentration of Sanmol I-906 can be determined. It can be seen that when applied as a percutaneous absorption preparation of nitroglycerin for rabbits, a concentration of 0.5% or more of sanmol is suitable. The composition of the present invention can be used as it is, or in a conventional manner in a dosage form (eg, capsule) capable of releasing a drug through a drug-permeable membrane, or a drug-permeable membrane or pellet. It can be used by impregnating the carrier. The composition of the present invention can deliver a drug to a required place in a required amount and only in a required time in response to a change in environmental temperature.

[0057]

EXAMPLES Next, the contents of the present invention will be specifically described by way of examples, but the present invention is not limited to these examples.

Example 1 A rabbit skin piece was immersed in an aqueous solution of 0.1% Sanmol I-906 (manufactured by Nichika Chemical Co., Ltd.) in which a predetermined amount of nitroglycerin was dissolved, and the temperature was set at 32 ° C and 39 ° C. Table 1 shows the results of measuring the partition coefficient of nitroglycerin to the skin of rabbits after keeping it for 24 hours.

Examples 2 to 5 Table 1 shows the results of partition coefficient measurement performed in the same manner as in Example 1 except that the concentration of Sanmol was changed as shown in Table 1.

Comparative Example 1 Rabbit skin pieces were immersed in an aqueous solution in which a predetermined amount of nitroglycerin was dissolved, and the distribution coefficient of nitroglycerin to rabbit skin was measured after keeping the temperature at 32 ° C. and 39 ° C. for 24 hours. The results obtained are shown in Table 1.

[0061]

[Table 1]

Example 6 10 g of N-isopropylacrylamide was added to 100 ml of water.
The monomer solution dissolved in is stirred, thermometer, cooler,
After charging a 300 ml four-necked round bottom separable flask equipped with a nitrogen introduction tube and replacing the atmosphere with nitrogen, 1% of ammonium persulfate as a polymerization initiator was added to the monomer.
Polymerization was carried out at 0 ° C. for 4 hours. From this mixed solution, water was distilled off under reduced pressure, dissolved in 10 ml of toluene, and reprecipitated in 500 ml of petroleum ether for purification.

The poly N-isopropylacrylamide obtained was adjusted to a 1% by weight aqueous solution, and then the transmittance with respect to a temperature change at 700 nm was measured with a spectrophotometer with a temperature controller (U-3210, manufactured by Hitachi, Ltd.). Was measured. The cloudy temperature is defined as the phase transition temperature, and the results are shown in Table 2.

Example 7 A monomer solution prepared by dissolving 10 g of N-isopropylacrylamide and 0.526 g of 2-hydroxyethyl methacrylate in 100 ml of water was copolymerized and purified in the same manner as in Example 6 to obtain N-isopropylacrylamide. A copolymer containing 95% by weight and 5% by weight of 2-hydroxyethyl methacrylate was obtained. The results of measuring the phase transition temperature in the same manner as in Example 6 are shown in Table 2.

Examples 8 to 12 Copolymerization was carried out in the same manner as in Example 7 except that the monomers shown in Table 2 were used in the proportions shown in Table 2, and the phase transition temperature was measured. The results are summarized in Table 2.

[0066]

[Table 2] Explanation of abbreviations N-IPAAm: N-isopropyl acrylic amide VP: N-vinyl propylidene HEMA: 2-human hydroxyethyl methacrylate DMAA: N, N-dimethyl acrylic amide AA: acrylic acid AAm: acrylic amide

Examples 13 to 16 The results of measuring the distribution coefficient of nitroglycerin to rabbit skin in the same manner as in Example 1 except that the concentration of the aqueous solution of the copolymer of Example 12 was changed as shown in Table 3 Are summarized in Table 3.

[0068]

[Table 3]

Example 17 A dialysis membrane (SPE
CTRUM MEDICAL IND--USTRIES, INC CUTOFF Molecular weight: 1
000) sandwiched between the cells and 1% Sanmor I-906
Add the maximum adsorbed amount of nitroglycerin to the aqueous solution, add the pH 7.4 0.2M phosphate buffer solution to the other cell, and gradually increase the temperature to 32 ° C and 39 ° C every 4.5 hours. , And the accumulated permeation amount of nitroglycerin was measured by sampling from the cell containing phosphate buffer over time.
Table 4 shows the results of the measurement of C and the determination of the transmission coefficient.

Examples 18 to 19 Table 4 shows the results of determining the transmission coefficient in the same manner as in Example 17, except that the concentration of Sanmol I-906 was changed as shown in Table 4.

[0071]

[Table 4]

Example 20 Rabbit skin was sandwiched between two chamber cells made of glass with a jacket, and 0.5% Sanmol I-906 was placed in one cell.
Table 5 shows the results of a permeation experiment conducted by the same method as in Example 17 except that the aqueous solution added with the maximum adsorption amount of nitroglycerin was added.

Examples 21 to 22 Table 5 shows the results of a permeation experiment conducted in the same manner as in Example 20 except that the concentration of Sanmol was changed as shown in Table 5.

[0074]

[Table 5]

Example 23 Rabbit skin was sandwiched between jacketed glass two-chamber cells, and the temperature-responsive type obtained from 95% by weight of N-isopropylacrylamide and 5% by weight of N-vinylpyrrolidone of Example 9 in one cell. Example 1 was prepared by adding a maximum adsorbed amount of nitroglycerin to a 1% aqueous solution of polymer.
Table 6 shows the results of determining the transmission coefficient by the same method as in 7.

Example 24 Except that the temperature responsive polymer was changed as shown in Table 6,
Table 6 shows the results of the transmission coefficient obtained by the same method as in Example 23.
Are shown together.

[0077]

[Table 6]

[0078]

INDUSTRIAL APPLICABILITY The composition of the present invention can achieve a reversible controlled release in which a drug is supplied to a required place in a required amount in a required amount only when necessary in response to a change in temperature of an environment It is possible to provide a dispenser capable of automating a drug administration period and making intelligent in response to an external stimulus.

Claims (3)

[Claims] 1. A temperature-responsive drug composition comprising an aqueous solution of a temperature-responsive polymer having a phase transition temperature of 4 to 90 ° C. and a drug. 2. A polymer or copolymer of at least one N-substituted (meth) acrylamide derivative or a vinyl monomer, wherein the temperature-responsive polymer is a polyoxyethylene derivative, hydroxypropyl cellulose, and polyvinyl. The temperature-responsive pharmaceutical composition according to claim 1, which is one or more kinds selected from the group consisting of alcohol partial acetyl chlorides. 3. An aqueous solution of a temperature-responsive polymer and a drug. The drug is adsorbed to the polymer at a temperature higher than the phase transition temperature and its release to the external environment is suppressed, and at a temperature lower than the phase transition temperature. The drug is desorbed from the polymer and is released to the external environment, which is a temperature-responsive drug composition for controlling release.