JP4747256B2 - Composite stimulus response material - Google Patents

Description

  The present invention relates to a composite stimulus responsive material. More specifically, a biodegradable polymer in which a biodegradable cyclic molecule is bonded to 1/3 to 2/3 of the cationic group or anionic group of the biodegradable polycation or biodegradable polyanion, and the cyclic molecule A composition containing a guest component capable of inclusion, wherein the guest component is included in only one site of the cyclic molecule, and the biodegradable polymer is not included in a site (non-inclusion site). The biodegradable polymer and the guest component have two or more kinds of external stimuli to form a multi-point inclusion complex. The present invention relates to a composite stimulus responsive material.

  Conventionally, in the fields of cosmetics, pharmaceuticals and agrochemicals, paints, foods, etc., improved solubility and stability of various functional molecules such as drugs, fragrances, and pigments, improved emulsification characteristics, improved texture, sustained release For the purpose of imparting water, suppressing deliquescence and volatility, and pulverizing oil and fat base materials, an inclusion compound in which the functional molecule is included in a cyclic molecule having a cavity in the molecule is used. However, such an inclusion molecule lacks stability over time because the inclusion molecule starts desorption immediately after production, and cannot be desorbed under specific conditions that require the function of the inclusion molecule. There is a problem that the size of the entire inclusion molecule and the type of functional group that the inclusion molecule has are limited.

In order to solve these problems, the present inventors have disclosed in Patent Document 1 a biodegradable polymer to which a cyclic molecule is bonded, a third component having two or more sites that can be included in the cyclic molecule ( A multi-point inclusion complex formed by adding a guest component), specifically, a biodegradable polymer in which α-cyclodextrin is bonded to 41 mol% of an amino group of ε-polylysine; -A biodegradable inclusion complex, which is a multi-point inclusion complex formed from trimethylsilylpropionic acid, which is included at two sites by two cyclodextrins, was proposed as an example.
JP 2003-246882 A

  However, the multipoint inclusion complex proposed in Patent Document 1 does not require two or more types of external stimuli as the conditions for formation, and includes two or more sites of the third component (guest component). Because it is necessary, there are still problems such as a case where the reaction may occur under conditions other than the set conditions, a wide range of external stimuli to react, and a slow reaction speed.

  The present inventors have intensively studied to solve the problems of the background art described above. As a result, a biodegradable polymer in which a biodegradable cyclic molecule is bonded to 1/3 to 2/3 of the cation group or anion group of the biodegradable polycation or the biodegradable polyanion, and the cyclic molecule is encapsulated. A composition containing a guest component that can be contacted, wherein the guest component includes only one site of the cyclic molecule, and the biodegradable polymer is not included in the site (non-inclusion site). A composite that has a polar group with a sign opposite to the polarity of the cationic group or anionic group, and the biodegradable polymer and the guest component form a multipoint inclusion complex by applying two or more external stimuli It has been found that if the stimulus response material is used, the possibility of reacting under conditions other than the set conditions is reduced, the range of external stimuli to be reacted is narrowed, and the reaction speed is increased, and the present invention has been completed based on this finding.

  Specifically, a biodegradable polymer in which β-cyclodextrin is bonded to 48 mol% of the amino group of ε-polylysine, which is an example of the present invention, and trimethylsilyl which is the only one in the β-cyclodextrin A complex response stimuli consisting of a composition containing trimethylsilylpropionic acid having a carboxyl group with a polar group opposite to the amino group, and forming a multipoint inclusion complex by applying appropriate pH and temperature Materials can be mentioned.

This invention is shown by following (1)-(8).
(1) A biodegradable polymer in which a biodegradable cyclic molecule is bonded to 1/3 to 2/3 of the cationic group or anionic group of the biodegradable polycation or biodegradable polyanion, and the cyclic molecule A composition containing a guest component that can be contacted, wherein the guest component includes only one site of the cyclic molecule, and the biodegradable polymer is not included in the site (non-inclusion site). The biodegradable polymer and the guest component have two or more external stimuli to form a multipoint inclusion complex by having a polar group having a sign opposite to the polarity of the cationic group or anionic group possessed. A composite stimulus responsive material characterized by (In the case of the present invention, ε-polylysine having an amino group (cation group) is used as a biodegradable polycation, β-cyclodextrin is used as a biodegradable cyclic molecule, and an amino which is a cation group as a guest component. (Use a polar group having a polarity opposite to the polarity of the group.)

( 2 ) The polar group which the guest component has at the non-inclusion site is an amino group when the biodegradable polymer is composed of a biodegradable polycation, and is a carboxyl group when the biodegradable polymer is composed of a biodegradable polyanion. The composite stimulus responsive material according to item (1).

( 3 ) The composite stimulus responsive material according to (1) above, wherein the guest component is trimethylsilylpropionic acid and / or a derivative thereof.

( 4 ) The composite stimulus responsive material according to (1), wherein the polar group of the non-inclusion site of the guest component is a carboxyl group.

( 5 ) The composite stimulus responsive material according to item (1), wherein the guest component is trimethylsilylpropionic acid.

( 6 ) The above (1) to ( 5 ), wherein at least one of two or more external stimuli imparted to form a multipoint inclusion complex is pH, temperature, electromagnetic wave, light, enzyme, or chemical substance. The composite stimulus responsive material according to any one of Items.

( 7 ) A pharmaceutical comprising the composite stimulus responsive material according to any one of (1) to ( 6 ).

( 8 ) A medical material containing the composite stimulus responsive material according to any one of (1) to ( 6 ).

  The composite stimulus responsive material of the present invention has a structure similar to that of the biodegradable inclusion tissue proposed in Patent Document 1, but only a single site of the guest component is included in the cyclic molecule, and is not included. The site has a polar group with a sign opposite to the polarity of the cationic group or anionic group of the biodegradable polymer, and the number of bonds of the biodegradable cyclic molecule to the biodegradable polymer (polycation or polyanion) It is different in that it is limited. That is, in Patent Document 1, two cyclic molecules include one guest component, whereas in the present invention, one cyclic molecule includes one guest component.

  As a result, the above-described biodegradable clathrate assembly requires only one mechanical clathration for forming a multipoint clathrate complex, thereby improving the rate of clathrate complex formation. Multipoint inclusion complex by polar interaction of the biodegradable polycation or biodegradable polyanion and the polar group of the guest component at the non-inclusion site (ionic bond etc.) Since it is easy to make two or more external stimuli applied to form the multipoint inclusion complex, the possibility of reacting under conditions other than the set conditions is reduced. The range of external stimulation to be performed can be narrowed.

Hereinafter, the present invention will be described in detail.
In the present invention, biodegradability is a general term including biodegradability. The biodegradable polycation (or polyanion) used in the present invention is a cation group (or anion group) for binding with a biodegradable cyclic molecule and electrostatic interaction with a guest component described later, such as a hydroxyl group, an amino group. The group is not particularly limited as long as it has a group, a carboxyl group, a sulfonyl group, etc., and may be appropriately selected according to the intended use and purpose.
For example, a biodegradable polycation (or polyanion) can be selected when used as a drug for implantation in a diseased part, and in vivo excellent in migration to a diseased part when used as a drug delivery system. Degradable polycations (or polyanions) can be selected. When used in an external environment such as agricultural chemicals, biodegradable polycations (or polyanions) that can be degraded by microorganisms in the environment can be selected.

  Examples of such biodegradable polycations (or polyanions) include ε-polylysine, chitosan, hyaluronic acid, alginic acid, polyglutamic acid, carrageenan, chondroitin sulfate, dermatan sulfate, and derivatives thereof.

  The biodegradable cyclic molecule used in the present invention is a cation group (or anion group) for binding the biodegradable polycation (or polyanion) described above, such as a hydroxyl group, an amino group, a carboxyl group, a sulfonyl group, and the like. It is not particularly limited as long as it has a cavity capable of enclosing a guest component described later. For example, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, and the like are stable, safe, It can be preferably used from the viewpoint of easy availability.

  The guest component in the present invention has only one site included in one of the aforementioned biodegradable cyclic molecules, and has a sign opposite to the polarity of the aforementioned biodegradable polycation (or polyanion) in the non-inclusion site. It is not particularly limited as long as it has a polar group, and it is biodegradable such that the multipoint inclusion complex of the present invention is formed by two or more external stimuli added according to the use and purpose of use. What is necessary is just to select the combination with a cyclic molecule suitably.

  As the polar group that the guest component has at the non-inclusion site, the amino group is stable when the biodegradable polymer is composed of a biodegradable polycation, and the carboxyl group is stable when it is composed of a biodegradable polyanion. It can be preferably used in terms of biocompatibility and the like.

  In the present invention, the two or more external stimuli imparted to form a multi-point inclusion complex are not particularly limited, but pH, temperature, electromagnetic waves, light, enzymes, chemical substances, etc. are imparted. It can be preferably used from the viewpoint of ease.

  The pharmaceutical of the present invention is not particularly limited as long as it contains a composite stimulus responsive material, and can be suitably used for, for example, an implant drug for a diseased part or a drug delivery system.

  The medical material of the present invention is not particularly limited as long as it contains a composite stimulus responsive material, and can be suitably used for, for example, a hemostatic coating agent or an artificial biological tissue during surgery.

  In the present invention, the method for binding the biodegradable cyclic molecule to the biodegradable polycation (or polyanion) is not particularly limited, but the biodegradable cyclic molecule selected according to the intended use and purpose, and What is necessary is just to select suitably according to the cation group (or anion group) which biodegradable polycation (or polyanion) has, for example, a hydroxyl group, an amino group, a carboxyl group, a sulfonyl group, etc. For example, when β-cyclodextrin is bound to ε-polylysine, a method in which monoaldehyde-modified β-cyclodextrin and ε-polylysine are Schiff-basified and then reduced is preferably used.

  Furthermore, the number of biodegradable cyclic molecules to be bonded to the biodegradable polycation (or polyanion) is 1/3 to 2/3 of the cation group (or anion group) of the biodegradable polycation (or polyanion). Is more preferable, and 2/5 to 3/5 is more preferable. When this value is less than 1/3 or more than 2/3, the guest group included in the biodegradable cyclic molecule has a polar group in the non-inclusion site and the polar group in the biodegradable polymer described above Since the electrostatic interaction with the above becomes weak, the formation rate of the above-mentioned multipoint inclusion complex is slow, the response range to external stimuli is expanded, the strength is weak, etc. There is.

  In the present invention, the method for forming the multipoint inclusion complex is not particularly limited, but the biodegradable polycation (or polyanion) to which the biodegradable cyclic molecule as described above is bound is usually water-soluble. Therefore, a method of forming the multipoint inclusion complex by adding the guest component described above to an aqueous solution in which a factor of external stimulation necessary for forming the multipoint inclusion complex is previously provided can be exemplified. Further, even if only one necessary external stimulus factor is removed and given in advance, and the last removed stimulus is given, a multipoint inclusion complex can be formed quickly.

  For example, when sodium trimethylsilylpropionate is added as a guest component to ε-polylysine to which β-cyclodextrin is bound to form a multipoint inclusion complex, both aqueous solutions should be prepared in advance at pH 7 and 20 ° C. For example, the reaction is completed in about 0.1 seconds after mixing.

  Next, the present invention will be further described with reference to examples. However, the present examples are not intended to limit the present invention. In this example, α and β-cyclodextrin are α and β-cyclodextrin manufactured by Tokyo Chemical Industry Co., Ltd., trimethylsilylpropionic acid is sodium trimethylsilylpropionate manufactured by Kanto Chemical Co., and ε-polylysine is manufactured by Chisso Corporation. ε-polylysine 100% powder was used without purification. The molecular weight of the ε-polylysine was measured by gel permeation chromatography using a low-angle light scattering photometer as a detector, and had a weight average molecular weight of 4700 ± 470 and a number average molecular weight of 4090 ± 410. The average degree of polymerization was about 30.5 as measured by the graphic method.

Synthesis Example 1 Synthesis of mono-aldehyde product of β-cyclodextrin 11.7 g (10.3 mmol) of β-cyclodextrin was dissolved in 250 ml of dimethyl sulfoxide, and 8.7 g (20.6 mmol) of 2 equivalent of Dess-Martin periodinane was added. The mixture was further stirred at 25 ° C. for 1 hour. The solution was added to acetone, cooled at −20 ° C. for 2 hours, and the deposited precipitate was filtered to obtain a filtrate. The filtrate was redissolved in distilled water, and insoluble matters were removed by filtration. The filtrate was concentrated with an evaporator, added to acetone at 0 ° C. and recrystallized. The crystals were collected by filtration and then dried under reduced pressure at 60 ° C. to obtain monoaldehyde-ized β-cyclodextrin (Compound 1). The yield was 88%. The obtained compound 1 was confirmed by proton nuclear magnetic resonance spectroscopy (hereinafter referred to as ¹ H-NMR) and Fourier transform infrared absorption spectroscopy (hereinafter referred to as FT-IR). The results are shown below.
FT-IR (KBr): 3384 (s; OH), 2930 (s; C—H), 1731 (m; aldehyde C═O), 1500 to 1200 (m; C—H, CH ₂ , OH), 1200 ˜800 cm ⁻¹ (m; C—C, C—O)
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 9.68 (s; formyl H), 5.48 (m; 14H, secondary OH), 4.81 (s; 7H, H-1) 4.43 (m; 6H, primary OH), 4.00 to 3.00 ppm (4m; cyclodextrin H).

Synthesis Example 2 Synthesis of ε-polylysine bound with β-cyclodextrin 1.1 g (0.27 mmol) of ε-polylysine was dissolved in 1000 ml of 0.2 M acetic acid buffer (pH 4.4), and 11.33 g (10.0 mmol). ) Was added and stirred at 25 ° C. for 1 hour, and then 2 equivalents of sodium cyanoborohydride was added to compound 1 and stirred at 25 ° C. for 72 hours. After neutralization with a 2M aqueous sodium hydroxide solution and dialysis for 1 week with a dialysis membrane having a molecular weight cut off of 10,000, the dialysis internal solution was lyophilized to give β-cyclodextrin-bound ε-polylysine (compound 2). Obtained. The yield was 73%. The obtained compound 2 was confirmed by ¹ H-NMR and FT-IR. The results are shown below.
FT-IR (KBr): 3413 (s; OH), 2929 (s; C—H), 1637 (m; C═O), 1559 (m; N—H), 1458 (m; C—H), 1200 to 800 cm ⁻¹ (m; C—C, C—O)
¹ H-NMR (300 MHz, D ₂ O): δ = 4.96 (s; 7H, H-1, cyclodextrin), 4.00 to 3.35 (2 m; cyclodextrin H), 3.35-2 .90 (3 m; αH, εH, ε-polylysine), 1.78 to 1.00 ppm (3 m; βH, δH, γH, ε-polylysine).

The ratio of the amino group to which β-cyclodextrin is bonded to the total amino groups of ε-polylysine and the number average molecular weight of the obtained compound 2 are H-1 of glucose and β, γ of lysine in ¹ H-NMR spectrum. And calculated from the ratio of the peak areas of δ and the values were 48 mol% and 20270, respectively.

Synthesis Example 3 Synthesis of mono-aldehyde product of α-cyclodextrin 10.0 g (10.3 mmol) of α-cyclodextrin was dissolved in 250 ml of dimethyl sulfoxide, and 8.7 g (20.6 mmol) of 2 equivalent of Dess-Martin periodinane was added. In addition, the mixture was stirred at 25 ° C for 1.5 hours. The solution was added to acetone, cooled at −20 ° C. for 2 hours, and the deposited precipitate was filtered to obtain a filtrate. The filtrate was redissolved in distilled water, and insoluble matters were removed by filtration. The filtrate was concentrated with an evaporator, added to acetone at 0 ° C. and recrystallized. The crystals were collected by filtration and then dried under reduced pressure at 60 ° C. to obtain monoaldehyde-ized α-cyclodextrin (Compound 3). The yield was 88%. The obtained compound 3 was confirmed by ¹ H-NMR and FT-IR. The results are shown below.
FT-IR (KBr): 3384 (s; OH), 2930 (s; C—H), 1731 (m; aldehyde C═O), 1500 to 1200 (m; C—H, OH), 1154 (m; C—O), 1032 cm ⁻¹ (m; C—O)
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 9.68 (s; formyl H), 5.44 (m; 12H, secondary OH), 4.75 (s; 6H, H-1) 4.42 (m; 5H, primary OH), 4.00 to 3.00 ppm (4m; cyclodextrin H).

Synthesis Example 4 Synthesis of ε-polylysine bound with α-cyclodextrin 1.25 g (0.31 mmol) of ε-polylysine was dissolved in 1000 ml of 0.5 M acetate buffer (pH 4.5) to obtain 7.5 g (7.7 mmol). ) Was added and stirred at 25 ° C. for 1 hour, and then 3.07 g (48.85 mmol) of sodium cyanoborohydride was added and stirred at 25 ° C. for 96 hours. After neutralization with a 2M aqueous sodium hydroxide solution and dialysis with a dialysis membrane having a molecular weight cut off of 8000 for one week, the dialysis internal solution was lyophilized to obtain α-cyclodextrin-bound ε-polylysine (compound 4). Obtained. The yield was 32%. The obtained compound 4 was confirmed by ¹ H-NMR and FT-IR. The results are shown below.
FT-IR (KBr): 3413 (s; OH), 2929 (s; C—H), 1637 (m; C═O), 1559 (m; N—H), 1458 (m; C—H), 1154 (m; C—O), 1077 (m; C—O), 1031 cm ⁻¹ (m; C—O)
¹ H-NMR (300 MHz, D ₂ O): δ = 4.96 (s; 6H, H-1, cyclodextrin), 4.30 to 3.35 (2 m; cyclodextrin H), 3.35-2 .60 (3 m; αH, εH, ε-polylysine), 2.00 to 1.00 ppm (3 m; βH, γH, δH, ε-polylysine).

The ratio of the amino group to which α-cyclodextrin is bonded to the total amino groups of ε-polylysine and the number average molecular weight of the obtained compound 4 are H-1 of glucose and β, γ of lysine in ¹ H-NMR spectrum. And the ratio of the peak area of δ was 41 mol% and 15860.

Test Example 1: Confirmation of formation pH of multi-point inclusion complex (20 ° C.)
Β-cyclodextrin prepared by dissolving Compound 2 in 0.1 M phosphate buffer (pH 6) at 20 ° C. to prepare a 1 wt% aqueous solution and adding sodium trimethylsilylpropionate as a guest component to the dissolved Compound 2 Aqueous solution A was prepared by adding them so as to be stoichiometrically equal to each other. An α-cyclodextrin in which Compound 4 is dissolved in 0.1 M phosphate buffer (pH 7) at 20 ° C. to prepare a 1 wt% aqueous solution and sodium trimethylsilylpropionate is added as a guest component to the dissolved Compound 4 And an aqueous solution B was prepared so that the amount was stoichiometrically equal. 2M hydrochloric acid or 2M aqueous sodium hydroxide solution is added to the aqueous solution A, and the pH is 2, 3, 4.5, 5, 5.5, 6.5, 7, 7.5, 8, 9, 10, 11, Twelve aqueous solutions were prepared. Similarly, the aqueous solution B was prepared with pH 2,3,4,5,6,6.5,7.5,8,9,10,11,12.
The absorbance at 500 nm at 20 ° C. was measured with a visible ultraviolet spectrophotometer (V-550 manufactured by JASCO Corporation), and the results are shown in FIG.

  As is clear from FIG. 1, the composition comprising Compound 2 and sodium trimethylsilylpropionate, which is an example of the present invention, forms a multipoint inclusion complex at 20 ° C. in a narrow pH range of pH 6 to 6.5. I understand that. Further, it can be seen that the composition comprising the compound 4 and sodium trimethylsilylpropionate as a comparative example also forms a multipoint inclusion complex in a narrow pH range of pH 7 to 7.5, which is almost the same as the compound 2.

Test Example 2: Confirmation of formation temperature of multi-point inclusion complex (pH 6 and pH 7)
The aqueous solutions A and B were heated to about 50 ° C., and the change in transmittance at 500 nm during the cooling process was measured in the same manner as in Test Example 1, and the results are shown in FIG.

  As is clear from FIG. 2, the composition comprising Compound 2 and sodium trimethylsilylpropionate, which is an example of the present invention, rapidly exhibits a multipoint inclusion complex in a very narrow temperature range of about 34 to 32.5 ° C. It turns out that it forms. On the other hand, it can be seen that the composition comprising Compound 4 as a comparative example and sodium trimethylsilylpropionate gradually forms a multipoint inclusion complex over about 45 to 20 ° C., unlike the examples.

Test Example 3: Confirmation of formation time of multipoint inclusion complex (20 ° C.)
Compound 2 was dissolved in 0.1 M phosphate buffer (pH 6) at 20 ° C. to prepare 4.7 × 10 ⁻⁴ M aqueous solution C. Sodium trimethylsilylpropionate as a guest component dissolved in 0.1M phosphate buffer (pH 6) at 20 ° C. so as to be stoichiometrically equal to β-cyclodextrin added to Compound 2 dissolved in aqueous solution C Then, an aqueous solution D of 7.3 × 10 ⁻³ M was prepared. 2M hydrochloric acid or 2M sodium hydroxide aqueous solution was added to the aqueous solutions C and D to prepare aqueous solutions of pH 4, 7, and 9, respectively.
Absorbance at 500 nm at 20 ° C. was measured by the stopped-flow method. RA-2100HS manufactured by Otsuka Electronics Co., Ltd. was used as the visible ultraviolet spectrophotometer. 60 ms after the spectrophotometer started data collection, aqueous solutions C and D were simultaneously injected into the measurement cell and mixed for 100 ms. Therefore, the actual measurement start time is 60 ms. The same measurement was performed for each of the aqueous solutions at pH 4, 7, and 9, and the results are shown in FIG.

  As is clear from FIG. 3, at pH 6 and 7 where a multipoint inclusion complex can be formed, about 2 ms is obtained after mixing Compound 2 and sodium trimethylsilylpropionate, which is a combination of the embodiment of the present invention. It can be seen that the inclusion complex is formed in a very short time. On the other hand, although not measured as data, mixing of compound 4 and sodium trimethylsilylpropionate, which is a combination as a comparative example, takes about several seconds that can be visually confirmed to form a multipoint inclusion complex.

The composite stimulus responsive material of the present invention can be used for bioimplantation with a low in vivo persistence by appropriately selecting a biodegradable polycation (or polyanion), for example, by using a biodegradable polycation (or polyanion). By using biodegradable polycations (or polyanions) that are excellent in migration to the affected area as planting agents, biodegradable polycations (or polyanions) that are degraded by microorganisms in the environment are used as drug delivery systems. By using it, it can be suitably used as a functional material used in the external environment such as agricultural chemicals and paints with reduced environmental impact after use and disposal.
In addition, since the composite stimulus-responsive material of the present invention has a very short formation time due to a specific external stimulus, for example, by using a biodegradable polycation (or polyanion), a hemostatic coating or temporary agent during surgery can be used. In addition, it can be used as an artificial biological tissue such as artificial muscle that is used as an artificial muscle, and further, as formation and dissociation can be reversibly repeated.

It is the figure which showed the change of the light transmittance by pH change of the multipoint inclusion complex aqueous solution. It is the figure which showed the change of the light transmittance by the temperature change of the multipoint clathrate aqueous solution. It is the figure which showed the change of the light absorbency accompanying formation of a multipoint inclusion complex with time.

Explanation of symbols

1, 2, and 3, TPA represents sodium trimethylsilylpropionate.

Claims (8)

A composition comprising a biodegradable polymer in which a biodegradable cyclic molecule is bonded to 1/3 to 2/3 of the cationic group of the biodegradable polycation, and a guest component that can be included in the cyclic molecule. The biodegradable polycation is ε-polylysine having an amino group as a cationic group, the biodegradable cyclic molecule is β-cyclodextrin, and the guest component has only one site in the cyclic molecule. The site that is included and not included (non-inclusion site) has a polar group with a sign opposite to the polarity of the amino group that is a cationic group, and the biodegradable polymer and the guest component are two or more types A composite stimulus responsive material characterized in that a multipoint inclusion complex is formed by applying an external stimulus. The composite stimulus responsive material according to claim 1, wherein the polar group of the guest component in the non-inclusion site is a carboxyl group . The composite stimulus responsive material according to claim 1, wherein the guest component is trimethylsilylpropionic acid and / or a derivative thereof. The composite stimulus response material according to claim 1, wherein the polar group of the non-inclusion site of the guest component is a carboxyl group. The composite stimulus responsive material according to claim 1, wherein the guest component is trimethylsilylpropionic acid. The at least one of two or more kinds of external stimuli imparted to form a multipoint inclusion complex is pH, temperature, electromagnetic wave, light, enzyme, or chemical substance, according to any one of claims 1 to 5 . Composite stimulus response material. A pharmaceutical comprising the composite stimulus responsive material according to any one of claims 1 to 6 . The medical material containing the composite stimulus responsive material in any one of Claims 1-6 .

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