CA2022426A1 - Electroresponsive hydrogel and physiologically active substance release control system - Google Patents
Electroresponsive hydrogel and physiologically active substance release control systemInfo
- Publication number
- CA2022426A1 CA2022426A1 CA002022426A CA2022426A CA2022426A1 CA 2022426 A1 CA2022426 A1 CA 2022426A1 CA 002022426 A CA002022426 A CA 002022426A CA 2022426 A CA2022426 A CA 2022426A CA 2022426 A1 CA2022426 A1 CA 2022426A1
- Authority
- CA
- Canada
- Prior art keywords
- hydrogel
- active substance
- control system
- physiologically active
- release control
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M35/00—Devices for applying media, e.g. remedies, on the human body
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/28—Insulins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0009—Galenical forms characterised by the drug release technique; Application systems commanded by energy involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
Abstract
ABSTRACT
An electroresponsive hydrogel produced by alkali hydro-lysis of a copolymer comprising N-isopropylacrylamide, an ionic monomer and a crosslinking agent; and a physiologically active substance release control system comprising a biosensor, an amplifier and an electroresponsive hydrogel containing physiologically active substance are disclosed. The hydrogel of the present invention is capable of releasing a physiolo-gically active substance alone in an amount corresponding to an applied voltage with excellent reproducibility by contracting and reswelling in good response to the loading and unloading of an external stimulation voltage, it can be advantageously used in a physiologically active substance release control system capable of releasing an essential physiologically active substance in a necessary amount accor-ding to changes in physiological conditions. Also, the phy-siologically active substance release control system of the present invention using this hydrogel is useful for the treatment of various diseases including diabetes mellitus.
An electroresponsive hydrogel produced by alkali hydro-lysis of a copolymer comprising N-isopropylacrylamide, an ionic monomer and a crosslinking agent; and a physiologically active substance release control system comprising a biosensor, an amplifier and an electroresponsive hydrogel containing physiologically active substance are disclosed. The hydrogel of the present invention is capable of releasing a physiolo-gically active substance alone in an amount corresponding to an applied voltage with excellent reproducibility by contracting and reswelling in good response to the loading and unloading of an external stimulation voltage, it can be advantageously used in a physiologically active substance release control system capable of releasing an essential physiologically active substance in a necessary amount accor-ding to changes in physiological conditions. Also, the phy-siologically active substance release control system of the present invention using this hydrogel is useful for the treatment of various diseases including diabetes mellitus.
Description
2~2~2~
ELECTRORESPONSI~E HYD~OGEL AND
PHYSIOLOGICALLY ACTIVE SUBSTANCE ~ELEASE CONTROL SYSTEM
[Background of the Invention]
The present invention relates to release control of a physiologically active substance, more specifically to an electroresponsive hydrogel and a physiologically active sub-stance release control system comprising a biosensor (parti-cularly a biosensor comprising an enzyme-immobili~ed ion sensitive field effect transistor), an amplifier and an elec-troresponsive hydrvgel containing a physiologically active substance.
For example, in the treatment of diabetes mellitus, it is considered desirable to release insulin into blood accor-ding to blood sugar level for maintenance of the level in a particular range, irrespective of food intake time and food consumption. In general, a mode for physiologically active substance administration capable of releasing an essential physiologically active component in a necessary amount accor-ding to changes in physiological conditions in vivo (herein-after referred to as "physiologically active substance re-lease control system") is useful for the treatment of various diseases.
As insulin pumps, there have been developed, for exam-pl.e, port~lble :infusion pumps such as the MI.I.IL.-ll-rLL injector (llarvard ~pparatus) and implantable admin:ist:rnt-ion systems such as the sophisticate(l, tele etry-modul.ated imp:Larltable ~.
' " ~, ~ ....... . :
~2~
infusion pump (John Hopkins University). However, these insulin pumps allow continuous release of a given amount of insulin at a constant rate, and cannot release an essential physiologically active substance in a necessary amount accor-ding to changes in physiological conditions in vivo.
Also, there are many reports on biosensors that convert chemical information in vivo to electric signals, but studies of carriers suitable to the controlled storage and release of the desired physiologically active substance shou]d be nlade for the realization of release control of a physiologically active substance by means of these biosensors.
With a potential for use in these applications, hydrogel, which shows expansion-contraction changes in response to external stimulation such as light, temperature, pH or electric field, has recently drawn much attention. For example, drug release could be reportedly controlled using a temperature-sensitive gel [You Han Bae et al.: Makromol~
Chem. Rapid Commun., 8, 481 (1982)]. Also, Tanaka et al.
[Science, 218, 467 (1982)] reported an electroresponsive hydrogel for the first time.
However, any configuration of release control system characterized by its temperature-based drug release control is considered as of little practical value because it is di~ficlllt to control the system due to temperature control, etc. when used Ln human boclies, etc. In addition, lt remains unknown what is an opt:imal configuration for practical use of " ~
' -, 2 ~
an electroresponsive hydrogel. With this background, there are demands for development of a release control system which can serve for practical use and a hydrogel which can serve as a component thereof.
[Summary of the Invention]
It is an object of the present invention to provide a system capable of releasing an essential physiologically active substance in a necessary amount according to changes in physiological conditions in vivo.
It is another object of the present inventlon to provide a hydrogel usable in such a system, i.e., a hydrogel capable `
of releasing or retaining an physiologically active substance in response to appropriate external stimulation.
With the aim of accomplishing these objects, the present inventors made intensive investigations and found that an electroresponsive hydrogel prepared with a given composition by a given process serves well for these objects, thus com-pleting a configuration of said hydrogel. Then, the present invento~s succeeded in configuring a release control system capable of controlling release of a physiologically active substance from hydrogel according to the concentration of an indicator chemical substance in vivo by combining said elec-troresponsive hydrogel with a particular biosensor and an voltage ampliEler, wh-ich resuLte(l -in completioll of the inven-tlon.
~ ccor(llngly, the present invent:ion comprises:
, ,~ ' ~ ,, :
.~ . .
:` .
2 ~ 2 ~
1) A physiologically active substance release control system wherein an electroresponsive hydrogel containing a physiologically active substance is contracted according to the concentration of an indicator chemical substance in vivo to cause it to release the physiologically active substance, by amplifying a voltage generated from a biosensor by means of an amplifier and introducing it into the electroresponsive hydrogel.
2) An electroresponsive hydrogel produced by alkali hydrolysis of a copolymer comprising N-isopropylacrylamide, an ionic monomer and a crosslinking agent.
[Brief Explanation of Drawings]
Fig. 1 shows contraction and reswelling of a hydrogel in response to voltage loading and unloading. Fig. 2 shows a pattern of insulin release from an insulin-containing hydrogel in response to voltage loading and unloading. Fig. 3 shows the configuration of a physiologically active substance re-lease control system. Fig. 4 shows the amount of insulin released from a hydrogel according to each concentration of glucose in contact with a biosensor. Fig. 5 shows a pattern of insulin release from a hydrogel obtained when glucose was added repeatedly to a biosensor.
[Detailed Description of the Invention]
Any biosensor can serve for the yresent :invent:Lon as long as it i8 capable oE detecting the ind:icator chemical sut)stallce in vivo, with preEerence given to an lon sensitive ' ~ , ,, ,. ~' . !j' . .
' ";
`
' " . ' ' ' ' ,~
2~ 27103-51 field effect transistor ~hereinafter reEerred to as ISFET) having an enzyme immobilized on its element. Such an IS~ET
is produced, for example, as follows: A photocuring resin mixed with a particular enzyme is coated on said element by dipping and immobilized thereon by near ultraviolet irradia-tion. The present inventors confirmPd that a potential dif-ference according to the indicator substance in solution can be produced by using such a biosensor.
In this case, any substance capable of reacti~g said en7yme to produce a hydrogen ion can be used as an indicator chemical substance in vivo. Therefore, glucose can be used as an indicator ~hen, for ins~ance, a biosensor produced by immobilizing glucose oxidase is used.
The voltage produced by a biosensor thus prepared is normaily of the order of mV. On the other hand, the voltage necessary to contract the electroresponsive hydrogel des-cribed below is normally of the order of V. Therefore, direct introduction of the voltage obtained using the biosensor into the hydrogel fails to cause efficient contract of the hydrogel. In cosideration of this fact, the present inven-tors placed an amplifier between the biosensor and the hydro~el, amplified the voltage obtained with the biosensor and introduced it into the hydrogel, thereby succeeded in e~flclent contracting of fl hydrogel according to the output erom a biosensor.
In this case, any ampllfier can be used as long as it S
2 ~
is capable of amplifying the voltage of the order of mV
generated from the biosensor into a voltage of the order of V at a constant rate of about 1000 folds.
The hydrogel used for the present invention should be a hydrogel obtained by the alkali hydrolysis of a copolymer coMprising N-isopropylacrylamide, an ionic monomer (preferably, an anionic monomer such as acrylic acid or methacrylic acid) and a crosslinking agent. In producing such a hydrogel, N-isopropylacrylamide and an ionic monomer are copolymerized in the presence of a crosslinking agent, and the resulting copolymer is hydrolyzed with alkali. In the reaction of N-isopropylacrylamide and an ionic monomer, it is preferable to carry out the reaction between 100 parts by weight of N-isopropylacrylamide and 5 to 50 parts by weight of an iOlliC
monomer. Exarnples of the crosslinking agent to be present in the reaction system include ethylene glycol dimethacrylate, diethylene glycol dimethacrylate, triethylene glycol dimetha-crylate and polyethylene glycol #200 dimethacrylate (produced by Shin Nakamura Kagaku Kogyo; number of ethylene units = 4).
It is preferable that these crosslinking agents be used in a ratio of 2 to lS parts by weight to 100 parts by weight of the above-mentioned N-isopropylacrylamide. It is still more preferable that the hydrogel for the present invention be a hydrogel producecl by hydrolyzing a copolymer compris-ing 100 par~s by weight of N-isopropylacry]am:ide, lO to 40 parts by we:ight of an anion:ic monomer described above and 5 to 10 ,,. , .:
:-.......... ,. -, . ,................................. ::
. : . , : -2 ~ :
parts by weight of a crosslinking agent described above.
In the performance of copolymerization, the above-mentioned components are each dissolved in dimethylsulfoxide (hereinafter referred to as DMSO) or distillecd water, after which the reaction is initiated by the addition of a polyme-rization initiator or by the irradiation of ionizing radia-tion. Any type of ionizing radiation such as X ray, y ray, ray, ~ ray and electron beam can serve well, with particular preference given to y ray. When using y ray for copolymeri-zation, it is ideal to irradiate the monomer mixture with 20 to 30 kGy of y ray at room temperature in a nitrogen atmos- ;
phere.
When using a polymerization initiator for copolymeriza-tion, the reaction can be carried out using in combination ordinary polymerization initiators such as benzoyl peroxide and N,N-dimethyl-p-toluidine in an ordinary ratio in the presence of DMSO, or using in combination ordinary polymeri-zation initiators such as ammonium persulfate and tetramethy-lethylenediamine in an ordinary ratio in the presence of distilled water.
~ Iydrolysis after completion of copolymerization can be carried out in an alkali. When using 1 N NaOH or 1 N KOH at room temperature to carry out the reaction, it is appropriate to carry out the reaction for ~ to 20 hours.
Into the hydrogeL thus obta~ ed, a phys-io:Logically ac-tive substance Ls incorporated. Any physio-Logically active :. `' ' :, .
,. . . . ..
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substance can be incorporated into the hydrogel as long as the corresponding indicator substance is detectable by the biosensor. Examples of such physiologically active substan-ces include insulin, antihypeIlipidemic agents, antiallergic agents and antipsychotic drugs. The indicator substances corresponding to these physiologically active substances are detected using an ISFET having glucose oxidase, lipase, anti-gen/antibody, acetylcholine receptor, as respectively immo-bilized thereon, and the generated voltage is introduced into the hydrogel, whereby the physiologically active subs~ance present in the hydrogel is released. In summary, when using ISFET as a biosensor, the indicator substance in vivo can easily be detected as a potential difference due to ions such as proton, sodium ion and potassium ion and positively or negatively charged polar substances, produced by the reaction of the substance immobilized on the sensor and the indicator substance. This mechanism makes it possible to release the physiologically active substance with appropriate timing.
In the present inven-tion, incorporation of a physiologi-cally active substance into the electroresponsive hydrogel can easily by achieved by immersing the hydrogel in a solu-tion containing said physiologically active substance after hydrogel lyophilization, or can also be achieved by copolyme-rLæation a~ter nlix-ing the phys:iologicaLLy active substance in thc monomer mixture constituting the hydrogeL.
The hydrogel containing a phys:iolog:ically active s~lbstance :~: ; .. : . .
' . . . : . :.: ............ , :....... ~-: . . : . : ~ .
2~2~
thus prepared is used as follows: The biosensor produced as above is brought into contact with an enzyme substrate indi-cator substance such as glucose in a solution; the resul.ting voltage is amplified with an amplifier and introduced i.nto the hydrogel containing the physiologically active substance, whereby the hydrogel contracts and, in response thereto, the physiologically active substance incorporated in the hydrogel is released. Thus, release of the physiologically active substance can take place according to the concentration of the indicator chemical substance.
Since the hydrogel according to the present invention is capable of releasing a physiologically active substance alone i.n an amount corresponding to the applied voltage with excel-lent reproducibility by contracting and reswelling in good response to the loading and unloading of an external stimula-tion voltage, it can be advantageous].y used in a physio].ogi-cally active substance release control system capable of releasing an essential physiologically active substance in a necessary amount according to changes in physiological concli~-tions. Also, the physiologically active substance release control system of the present invention using this hydrogel is useful for the treatment of various diseases including li.abetes mell:itus since it is capable of controlling the re].ease oE :i.nsulln, Eor :instance.
The hyclrogel oE the present :invent:ion call a:Lso serve we:Ll as art:iE:ic;.al. muscle, actuater Eor robots, sw:itch, : , . . , ~ , , . -. ~
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memory element, solvent pump, functional membrane, etc.
Since the hydrogel of the present invention is capable of sensoring, for i.nstanceS blood sugar level, etc. by means of a minute biosensor, it can serve well in an artificial organ type control system capable of controlling the release of a physiologically active substance such as insulin according to changes in physiological conditions in vivo (e.g. changes in indicator substance concentration) which comprises at least a biosensor, an amplifier and an electroresponsive hydrogel containing a physi.ologically active substance and implanted in vivo.
~ Example 1 : Preparation of hydrogel N-isopropylacrylamide (2.4 g), 0.45 g of acrylic acid and 0.15 g of diethylene glycol were dissolved in 4.8 ml of DMSO. This solution was packed in a glass ampule and irra-diated with ~ ray (25 kGy) generated from 60Co at room tempe-rature in a nitrogen atmosphere to initiate polymerization.
The resulting polymer was taken out from the ampule and immersed in deionized water. After removing the solvent and the unreacted portion of the monomer, the polymer was immersed in a 1 N NaOH solution at room temperature for l8 hours to hydrolyæe it, a~ter whi.ch it was w~shed w:ith water to y:ield a hyclro~el.
(Experi.ment 1-1) The hydrogel prep~red above was .i.nserted between plat-i-, .
, "~
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num electrodes and applied with a voltage of 2 or 5 V/cm2 in deioni~ed water for a given period, and its weight was mea-sured regularly to evaluate its electroresponsivity.
The hydrogel showed electroresponsivity in deionized water; it contracted quickly with time under voltage load.
At 5 V/cm , it contracted to about 5% of the initial weight to reach an equlibrium in about 5 hours. The contracted hydrogel reswelled quickly in response to voltage unloading;
it showed a recovery to about 83% its initial weight after about 48 hours.
Also, when voltage was applied for 2 hours, the hydrogel contracted to 46% of the initial weight at 2 V/cm2 and to about 10% of the initial weight at 5 V/cm2, and quick reswel-ling occurred in response to voltage unloading in both cases.
These results revealed that hydrogel contraction occured according to the intensity of the applied voltage.
(Experiment 1-2) The hydrogel prepared above was inserted between platinum electrodes and applied with a voltage at 5 V/cm2 in a 0.01 M phosphate buffer, pH 7.4, for a given period, and its weight was measured regularly to evaluate its electroresponsivity.
As shown :in Fig. l, the hydrogel contracted quickly in response to voltage loadlng and reswe:lled quickly in response to vol~.age unloading in the phosphate bu~ter.
~ 2 .
.
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2 ~
Preparation of hydrogel The same monomer components in the same aMounts as -those in Example 1 were dissolved in 8.6 ml of water, followed by the similar procedure as in Example 1 to yield a hydrogel.
This hydrogel showed an electroresponsivity equivalent to that of the hydrogel obtained in Example 1.
~xample 3 Preparation of insulin-containing hydrogel Bovine insulin (produced by Sigma) was dissolved in a 0.01 M phosphate buffer to reach a final concentration of 100 IU/ml, and pH was adjusted to 7.4. After lyophilization, the hydrogel prepared in Example 1 was immersed in the insulin solution described above and reswelled at 4C to yield an insulin-incorporated hydrogel.
(Experiment 3-1) The insulin-containing hydrogel prepared above was inserted between platinum electrodes and applied with a voltage at 5 V/cm2 in a 0.01 M phosphate buffer for a given period, and the amount of insulin released was measured.
As shown in Fig. 2, it was confirmed that insulin was released only when a voltage is applied to the hydrogel.
Rxample 4 Physiologically active substance release control system 1. Biosen~or An ISI~lET eLemellt was -immerse(l in a mixed solution (p~l 7) o~ (3-aminopropyl)tr:iethoxys-ilane and distilled water in a 1 .
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to 10 rati,o (50C, 2 hours) to treat the element's surface.
After the treatment, the element was washed with distilled water and dried.
A solution comprising 30 mg of glucose oxidase and O.l ml of distilled water was mixed with a solution of the fol-lowing composition, followed by vigorous agitation.
Photosetting resin ENTV-500..... 0.2 ml -LSS-3380 (3-methacryloxypropyltrimethoxysilane)..... 0.02 ml Benzoin ethyl ether..... 0.004 ml ' The solution prepared above was coated by dipping on the surface of the surface-treated ISFET element described above and set by irradiation with light at a main wavelength of 366 nm from a black light fluorescent lamp for 3 minutes to yield ~, a biosensor.
,' 2. Insulin-containing hydrogel An insulin-containing hydrogel as prepared in Example 3 was used.
~ 3. Amplifier ; A differential amplifier 5305 (produced by NF Kairo Sekkei Block) offering a maximum gain of lO00 against 50 ~
load with a frequency band of DC lO MHz and a maximum skew-ness of 0.02% was used at an amplification rate of 1000 folds.
4. Conflgllrat:ion of physiologicalLy flct-ive substance release eonkrol sys~,em The lnsulln-conta:in:ing hydrogel, the b:i,osensor and the *Trad~-mark l3 : .
, , .
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, amplifier described above were connected as illustrated in Fig. 3 to configure a physiologically active substance re-lease control system. The hydrogel was inserted between platinum electrodes and immersed in a 0.01 M phosphate buffer at pH 7.4. The biosensor was immersed in a 0.002 M phosphate buffer at pH 5 containing 25 to 100 mg/dl glucose, and the amount of insulin released was measured for each glucose concentration. Also, as for the response of the system to repeated addition of glucose, it was rated by repeatedly adding after a given time 0.1 ml of 2.5% glucose (dissolved in a phosphate buffer) to 4.9 ml of a 0.01 M phosphate buffer.
The insulin released from the hydrogel was assayed quantitatively by the HPLC method in accordance with the procedure of M. Ohta et al. [Chem. Pharm. Bull., 32, 4641 (1984)].
Fig. 4 shows the amount of insulin released from hydro-gel when the biosensor was immersed in a glucose solution at various concentrations. It was confirrned that insulin was released from hydrogel in an amount in proportion to the glucose concentration.
Fig. 5 shows the results with repeated addition of glucose. Reproducible insulin release from hydrogel occurred in response to glucose addition to the biosensor side.
,;: . . .: -~
. " , ~ . . , " ~ ~ :
:::
::
ELECTRORESPONSI~E HYD~OGEL AND
PHYSIOLOGICALLY ACTIVE SUBSTANCE ~ELEASE CONTROL SYSTEM
[Background of the Invention]
The present invention relates to release control of a physiologically active substance, more specifically to an electroresponsive hydrogel and a physiologically active sub-stance release control system comprising a biosensor (parti-cularly a biosensor comprising an enzyme-immobili~ed ion sensitive field effect transistor), an amplifier and an elec-troresponsive hydrvgel containing a physiologically active substance.
For example, in the treatment of diabetes mellitus, it is considered desirable to release insulin into blood accor-ding to blood sugar level for maintenance of the level in a particular range, irrespective of food intake time and food consumption. In general, a mode for physiologically active substance administration capable of releasing an essential physiologically active component in a necessary amount accor-ding to changes in physiological conditions in vivo (herein-after referred to as "physiologically active substance re-lease control system") is useful for the treatment of various diseases.
As insulin pumps, there have been developed, for exam-pl.e, port~lble :infusion pumps such as the MI.I.IL.-ll-rLL injector (llarvard ~pparatus) and implantable admin:ist:rnt-ion systems such as the sophisticate(l, tele etry-modul.ated imp:Larltable ~.
' " ~, ~ ....... . :
~2~
infusion pump (John Hopkins University). However, these insulin pumps allow continuous release of a given amount of insulin at a constant rate, and cannot release an essential physiologically active substance in a necessary amount accor-ding to changes in physiological conditions in vivo.
Also, there are many reports on biosensors that convert chemical information in vivo to electric signals, but studies of carriers suitable to the controlled storage and release of the desired physiologically active substance shou]d be nlade for the realization of release control of a physiologically active substance by means of these biosensors.
With a potential for use in these applications, hydrogel, which shows expansion-contraction changes in response to external stimulation such as light, temperature, pH or electric field, has recently drawn much attention. For example, drug release could be reportedly controlled using a temperature-sensitive gel [You Han Bae et al.: Makromol~
Chem. Rapid Commun., 8, 481 (1982)]. Also, Tanaka et al.
[Science, 218, 467 (1982)] reported an electroresponsive hydrogel for the first time.
However, any configuration of release control system characterized by its temperature-based drug release control is considered as of little practical value because it is di~ficlllt to control the system due to temperature control, etc. when used Ln human boclies, etc. In addition, lt remains unknown what is an opt:imal configuration for practical use of " ~
' -, 2 ~
an electroresponsive hydrogel. With this background, there are demands for development of a release control system which can serve for practical use and a hydrogel which can serve as a component thereof.
[Summary of the Invention]
It is an object of the present invention to provide a system capable of releasing an essential physiologically active substance in a necessary amount according to changes in physiological conditions in vivo.
It is another object of the present inventlon to provide a hydrogel usable in such a system, i.e., a hydrogel capable `
of releasing or retaining an physiologically active substance in response to appropriate external stimulation.
With the aim of accomplishing these objects, the present inventors made intensive investigations and found that an electroresponsive hydrogel prepared with a given composition by a given process serves well for these objects, thus com-pleting a configuration of said hydrogel. Then, the present invento~s succeeded in configuring a release control system capable of controlling release of a physiologically active substance from hydrogel according to the concentration of an indicator chemical substance in vivo by combining said elec-troresponsive hydrogel with a particular biosensor and an voltage ampliEler, wh-ich resuLte(l -in completioll of the inven-tlon.
~ ccor(llngly, the present invent:ion comprises:
, ,~ ' ~ ,, :
.~ . .
:` .
2 ~ 2 ~
1) A physiologically active substance release control system wherein an electroresponsive hydrogel containing a physiologically active substance is contracted according to the concentration of an indicator chemical substance in vivo to cause it to release the physiologically active substance, by amplifying a voltage generated from a biosensor by means of an amplifier and introducing it into the electroresponsive hydrogel.
2) An electroresponsive hydrogel produced by alkali hydrolysis of a copolymer comprising N-isopropylacrylamide, an ionic monomer and a crosslinking agent.
[Brief Explanation of Drawings]
Fig. 1 shows contraction and reswelling of a hydrogel in response to voltage loading and unloading. Fig. 2 shows a pattern of insulin release from an insulin-containing hydrogel in response to voltage loading and unloading. Fig. 3 shows the configuration of a physiologically active substance re-lease control system. Fig. 4 shows the amount of insulin released from a hydrogel according to each concentration of glucose in contact with a biosensor. Fig. 5 shows a pattern of insulin release from a hydrogel obtained when glucose was added repeatedly to a biosensor.
[Detailed Description of the Invention]
Any biosensor can serve for the yresent :invent:Lon as long as it i8 capable oE detecting the ind:icator chemical sut)stallce in vivo, with preEerence given to an lon sensitive ' ~ , ,, ,. ~' . !j' . .
' ";
`
' " . ' ' ' ' ,~
2~ 27103-51 field effect transistor ~hereinafter reEerred to as ISFET) having an enzyme immobilized on its element. Such an IS~ET
is produced, for example, as follows: A photocuring resin mixed with a particular enzyme is coated on said element by dipping and immobilized thereon by near ultraviolet irradia-tion. The present inventors confirmPd that a potential dif-ference according to the indicator substance in solution can be produced by using such a biosensor.
In this case, any substance capable of reacti~g said en7yme to produce a hydrogen ion can be used as an indicator chemical substance in vivo. Therefore, glucose can be used as an indicator ~hen, for ins~ance, a biosensor produced by immobilizing glucose oxidase is used.
The voltage produced by a biosensor thus prepared is normaily of the order of mV. On the other hand, the voltage necessary to contract the electroresponsive hydrogel des-cribed below is normally of the order of V. Therefore, direct introduction of the voltage obtained using the biosensor into the hydrogel fails to cause efficient contract of the hydrogel. In cosideration of this fact, the present inven-tors placed an amplifier between the biosensor and the hydro~el, amplified the voltage obtained with the biosensor and introduced it into the hydrogel, thereby succeeded in e~flclent contracting of fl hydrogel according to the output erom a biosensor.
In this case, any ampllfier can be used as long as it S
2 ~
is capable of amplifying the voltage of the order of mV
generated from the biosensor into a voltage of the order of V at a constant rate of about 1000 folds.
The hydrogel used for the present invention should be a hydrogel obtained by the alkali hydrolysis of a copolymer coMprising N-isopropylacrylamide, an ionic monomer (preferably, an anionic monomer such as acrylic acid or methacrylic acid) and a crosslinking agent. In producing such a hydrogel, N-isopropylacrylamide and an ionic monomer are copolymerized in the presence of a crosslinking agent, and the resulting copolymer is hydrolyzed with alkali. In the reaction of N-isopropylacrylamide and an ionic monomer, it is preferable to carry out the reaction between 100 parts by weight of N-isopropylacrylamide and 5 to 50 parts by weight of an iOlliC
monomer. Exarnples of the crosslinking agent to be present in the reaction system include ethylene glycol dimethacrylate, diethylene glycol dimethacrylate, triethylene glycol dimetha-crylate and polyethylene glycol #200 dimethacrylate (produced by Shin Nakamura Kagaku Kogyo; number of ethylene units = 4).
It is preferable that these crosslinking agents be used in a ratio of 2 to lS parts by weight to 100 parts by weight of the above-mentioned N-isopropylacrylamide. It is still more preferable that the hydrogel for the present invention be a hydrogel producecl by hydrolyzing a copolymer compris-ing 100 par~s by weight of N-isopropylacry]am:ide, lO to 40 parts by we:ight of an anion:ic monomer described above and 5 to 10 ,,. , .:
:-.......... ,. -, . ,................................. ::
. : . , : -2 ~ :
parts by weight of a crosslinking agent described above.
In the performance of copolymerization, the above-mentioned components are each dissolved in dimethylsulfoxide (hereinafter referred to as DMSO) or distillecd water, after which the reaction is initiated by the addition of a polyme-rization initiator or by the irradiation of ionizing radia-tion. Any type of ionizing radiation such as X ray, y ray, ray, ~ ray and electron beam can serve well, with particular preference given to y ray. When using y ray for copolymeri-zation, it is ideal to irradiate the monomer mixture with 20 to 30 kGy of y ray at room temperature in a nitrogen atmos- ;
phere.
When using a polymerization initiator for copolymeriza-tion, the reaction can be carried out using in combination ordinary polymerization initiators such as benzoyl peroxide and N,N-dimethyl-p-toluidine in an ordinary ratio in the presence of DMSO, or using in combination ordinary polymeri-zation initiators such as ammonium persulfate and tetramethy-lethylenediamine in an ordinary ratio in the presence of distilled water.
~ Iydrolysis after completion of copolymerization can be carried out in an alkali. When using 1 N NaOH or 1 N KOH at room temperature to carry out the reaction, it is appropriate to carry out the reaction for ~ to 20 hours.
Into the hydrogeL thus obta~ ed, a phys-io:Logically ac-tive substance Ls incorporated. Any physio-Logically active :. `' ' :, .
,. . . . ..
2~2~
substance can be incorporated into the hydrogel as long as the corresponding indicator substance is detectable by the biosensor. Examples of such physiologically active substan-ces include insulin, antihypeIlipidemic agents, antiallergic agents and antipsychotic drugs. The indicator substances corresponding to these physiologically active substances are detected using an ISFET having glucose oxidase, lipase, anti-gen/antibody, acetylcholine receptor, as respectively immo-bilized thereon, and the generated voltage is introduced into the hydrogel, whereby the physiologically active subs~ance present in the hydrogel is released. In summary, when using ISFET as a biosensor, the indicator substance in vivo can easily be detected as a potential difference due to ions such as proton, sodium ion and potassium ion and positively or negatively charged polar substances, produced by the reaction of the substance immobilized on the sensor and the indicator substance. This mechanism makes it possible to release the physiologically active substance with appropriate timing.
In the present inven-tion, incorporation of a physiologi-cally active substance into the electroresponsive hydrogel can easily by achieved by immersing the hydrogel in a solu-tion containing said physiologically active substance after hydrogel lyophilization, or can also be achieved by copolyme-rLæation a~ter nlix-ing the phys:iologicaLLy active substance in thc monomer mixture constituting the hydrogeL.
The hydrogel containing a phys:iolog:ically active s~lbstance :~: ; .. : . .
' . . . : . :.: ............ , :....... ~-: . . : . : ~ .
2~2~
thus prepared is used as follows: The biosensor produced as above is brought into contact with an enzyme substrate indi-cator substance such as glucose in a solution; the resul.ting voltage is amplified with an amplifier and introduced i.nto the hydrogel containing the physiologically active substance, whereby the hydrogel contracts and, in response thereto, the physiologically active substance incorporated in the hydrogel is released. Thus, release of the physiologically active substance can take place according to the concentration of the indicator chemical substance.
Since the hydrogel according to the present invention is capable of releasing a physiologically active substance alone i.n an amount corresponding to the applied voltage with excel-lent reproducibility by contracting and reswelling in good response to the loading and unloading of an external stimula-tion voltage, it can be advantageous].y used in a physio].ogi-cally active substance release control system capable of releasing an essential physiologically active substance in a necessary amount according to changes in physiological concli~-tions. Also, the physiologically active substance release control system of the present invention using this hydrogel is useful for the treatment of various diseases including li.abetes mell:itus since it is capable of controlling the re].ease oE :i.nsulln, Eor :instance.
The hyclrogel oE the present :invent:ion call a:Lso serve we:Ll as art:iE:ic;.al. muscle, actuater Eor robots, sw:itch, : , . . , ~ , , . -. ~
,, " , . .
:
' , , , ~, :, ,.' h~ ~
memory element, solvent pump, functional membrane, etc.
Since the hydrogel of the present invention is capable of sensoring, for i.nstanceS blood sugar level, etc. by means of a minute biosensor, it can serve well in an artificial organ type control system capable of controlling the release of a physiologically active substance such as insulin according to changes in physiological conditions in vivo (e.g. changes in indicator substance concentration) which comprises at least a biosensor, an amplifier and an electroresponsive hydrogel containing a physi.ologically active substance and implanted in vivo.
~ Example 1 : Preparation of hydrogel N-isopropylacrylamide (2.4 g), 0.45 g of acrylic acid and 0.15 g of diethylene glycol were dissolved in 4.8 ml of DMSO. This solution was packed in a glass ampule and irra-diated with ~ ray (25 kGy) generated from 60Co at room tempe-rature in a nitrogen atmosphere to initiate polymerization.
The resulting polymer was taken out from the ampule and immersed in deionized water. After removing the solvent and the unreacted portion of the monomer, the polymer was immersed in a 1 N NaOH solution at room temperature for l8 hours to hydrolyæe it, a~ter whi.ch it was w~shed w:ith water to y:ield a hyclro~el.
(Experi.ment 1-1) The hydrogel prep~red above was .i.nserted between plat-i-, .
, "~
~2~
num electrodes and applied with a voltage of 2 or 5 V/cm2 in deioni~ed water for a given period, and its weight was mea-sured regularly to evaluate its electroresponsivity.
The hydrogel showed electroresponsivity in deionized water; it contracted quickly with time under voltage load.
At 5 V/cm , it contracted to about 5% of the initial weight to reach an equlibrium in about 5 hours. The contracted hydrogel reswelled quickly in response to voltage unloading;
it showed a recovery to about 83% its initial weight after about 48 hours.
Also, when voltage was applied for 2 hours, the hydrogel contracted to 46% of the initial weight at 2 V/cm2 and to about 10% of the initial weight at 5 V/cm2, and quick reswel-ling occurred in response to voltage unloading in both cases.
These results revealed that hydrogel contraction occured according to the intensity of the applied voltage.
(Experiment 1-2) The hydrogel prepared above was inserted between platinum electrodes and applied with a voltage at 5 V/cm2 in a 0.01 M phosphate buffer, pH 7.4, for a given period, and its weight was measured regularly to evaluate its electroresponsivity.
As shown :in Fig. l, the hydrogel contracted quickly in response to voltage loadlng and reswe:lled quickly in response to vol~.age unloading in the phosphate bu~ter.
~ 2 .
.
:
2 ~
Preparation of hydrogel The same monomer components in the same aMounts as -those in Example 1 were dissolved in 8.6 ml of water, followed by the similar procedure as in Example 1 to yield a hydrogel.
This hydrogel showed an electroresponsivity equivalent to that of the hydrogel obtained in Example 1.
~xample 3 Preparation of insulin-containing hydrogel Bovine insulin (produced by Sigma) was dissolved in a 0.01 M phosphate buffer to reach a final concentration of 100 IU/ml, and pH was adjusted to 7.4. After lyophilization, the hydrogel prepared in Example 1 was immersed in the insulin solution described above and reswelled at 4C to yield an insulin-incorporated hydrogel.
(Experiment 3-1) The insulin-containing hydrogel prepared above was inserted between platinum electrodes and applied with a voltage at 5 V/cm2 in a 0.01 M phosphate buffer for a given period, and the amount of insulin released was measured.
As shown in Fig. 2, it was confirmed that insulin was released only when a voltage is applied to the hydrogel.
Rxample 4 Physiologically active substance release control system 1. Biosen~or An ISI~lET eLemellt was -immerse(l in a mixed solution (p~l 7) o~ (3-aminopropyl)tr:iethoxys-ilane and distilled water in a 1 .
:: . . : :.
.: . . :
2~2~
to 10 rati,o (50C, 2 hours) to treat the element's surface.
After the treatment, the element was washed with distilled water and dried.
A solution comprising 30 mg of glucose oxidase and O.l ml of distilled water was mixed with a solution of the fol-lowing composition, followed by vigorous agitation.
Photosetting resin ENTV-500..... 0.2 ml -LSS-3380 (3-methacryloxypropyltrimethoxysilane)..... 0.02 ml Benzoin ethyl ether..... 0.004 ml ' The solution prepared above was coated by dipping on the surface of the surface-treated ISFET element described above and set by irradiation with light at a main wavelength of 366 nm from a black light fluorescent lamp for 3 minutes to yield ~, a biosensor.
,' 2. Insulin-containing hydrogel An insulin-containing hydrogel as prepared in Example 3 was used.
~ 3. Amplifier ; A differential amplifier 5305 (produced by NF Kairo Sekkei Block) offering a maximum gain of lO00 against 50 ~
load with a frequency band of DC lO MHz and a maximum skew-ness of 0.02% was used at an amplification rate of 1000 folds.
4. Conflgllrat:ion of physiologicalLy flct-ive substance release eonkrol sys~,em The lnsulln-conta:in:ing hydrogel, the b:i,osensor and the *Trad~-mark l3 : .
, , .
' ,' ~ ::
, amplifier described above were connected as illustrated in Fig. 3 to configure a physiologically active substance re-lease control system. The hydrogel was inserted between platinum electrodes and immersed in a 0.01 M phosphate buffer at pH 7.4. The biosensor was immersed in a 0.002 M phosphate buffer at pH 5 containing 25 to 100 mg/dl glucose, and the amount of insulin released was measured for each glucose concentration. Also, as for the response of the system to repeated addition of glucose, it was rated by repeatedly adding after a given time 0.1 ml of 2.5% glucose (dissolved in a phosphate buffer) to 4.9 ml of a 0.01 M phosphate buffer.
The insulin released from the hydrogel was assayed quantitatively by the HPLC method in accordance with the procedure of M. Ohta et al. [Chem. Pharm. Bull., 32, 4641 (1984)].
Fig. 4 shows the amount of insulin released from hydro-gel when the biosensor was immersed in a glucose solution at various concentrations. It was confirrned that insulin was released from hydrogel in an amount in proportion to the glucose concentration.
Fig. 5 shows the results with repeated addition of glucose. Reproducible insulin release from hydrogel occurred in response to glucose addition to the biosensor side.
,;: . . .: -~
. " , ~ . . , " ~ ~ :
:::
::
Claims (16)
1. A physiologically active substance release control system comprising:
a biosensor for detecting a change in the concentration of an indicator chemical substance in vivo and for generating an electric voltage according to the change;
an amplifier for receiving and amplifying the electric voltage generated by the biosensor;
an electroresponsive hydrogel containing a physiologi-cally active substance;
means for electrically connecting the biosensor to the amplifier; and means for introducing the amplified electric voltage to the electroresponsive hydrogel;
the said electroresponsive hydrogel being capable of contracting upon receipt of the amplified electric voltage from the amplifier and thereby releasing the physiologically active substance.
a biosensor for detecting a change in the concentration of an indicator chemical substance in vivo and for generating an electric voltage according to the change;
an amplifier for receiving and amplifying the electric voltage generated by the biosensor;
an electroresponsive hydrogel containing a physiologi-cally active substance;
means for electrically connecting the biosensor to the amplifier; and means for introducing the amplified electric voltage to the electroresponsive hydrogel;
the said electroresponsive hydrogel being capable of contracting upon receipt of the amplified electric voltage from the amplifier and thereby releasing the physiologically active substance.
2. A physiologically active substance release control system as claimed in Claim 1 wherein the biosensor is an ion sen-sitive field effect transistor having an enzyme immobilized on its element.
3. A physiologically active substance release control system as claimed in Claim 2, wherein the biosensor is produced by coating a photocuring resin mixed with a particular enzyme on the element by dipping and immobilizing it by near ultraviolet irradiation.
4. A physiologically active substance release control system as claimed in Claim 2, wherein the indicator chemical substance is a substance capable of reacting with the enzyme to produce a hydrogen ion.
5. A physiologically active substance release control system as claimed in Claim 1, 2, 3 or 4, wherein the amplifier is capable of amplifying the voltage from the biosensor at a constant rate of about 1000 folds.
6. A physiologically active substance release control system as claimed in Claim 1, 2, 3 or 4, wherein the electro-responsive hydrogel is prepared by an alkali hydrolysis of a co-polymer comprising N-isopropylacrylamide, an ionic monomer and a crosslinking agent.
7. A physiologically active substance release control system as claimed in Claim 1, 2, 3 or 4, wherein the electro-responsive hydrogel is produced by alkali hydrolyzing a copolymer comprising 100 parts by weight of N-isopropylacrylamide, 5 to 50 parts by weight of an ionic monomer and 2 to 15 parts by weight of a crosslinking agent.
8. A physiologically active substance release control system as claimed in Claim 1, 2, 3 or 4, wherein the electro-responsive hydrogel is produced by alkali hydrolyzing a copolymer comprising 100 parts by weight of N-isopropylacrylamide, 10 to 40 parts by weight of an ionic monomer and 5 to 10 parts by weight of a crosslinking agent.
9. A physiologically active substance release control system as claimed in Claim 1, 2, 3 or 4, wherein the physiologi-cally active substance is insulin.
10. An insulin release control system, comprising:
an ion sensitive field effect transistor having an enzyme immobilized on an element thereof, the said enzyme being capable of reacting with an indicator chemical substance in vivo to produce a hydrogen ion, whereby the ion sensitive field effect transistor detects a change in the concentration of the indicator chemical substance and generates an electric voltage in the order of mV according to the change;
an amplifier for amplifying the electric voltage generated by the ion sensitive field effect transistor into a voltage in the order of V;
an electroresponsive hydrogel containing insulin; and means for introducing the amplified voltage to the electroresponsive hydrogel, wherein the electroresponsive hydrogel is an alkali hydrolysis product of a copolymer comprising N-isopropylacrylamide, an ionic monomer and a crosslinking agent and is capable of contracting upon receipt of the amplified voltage from the amplifier and thereby releasing insulin.
an ion sensitive field effect transistor having an enzyme immobilized on an element thereof, the said enzyme being capable of reacting with an indicator chemical substance in vivo to produce a hydrogen ion, whereby the ion sensitive field effect transistor detects a change in the concentration of the indicator chemical substance and generates an electric voltage in the order of mV according to the change;
an amplifier for amplifying the electric voltage generated by the ion sensitive field effect transistor into a voltage in the order of V;
an electroresponsive hydrogel containing insulin; and means for introducing the amplified voltage to the electroresponsive hydrogel, wherein the electroresponsive hydrogel is an alkali hydrolysis product of a copolymer comprising N-isopropylacrylamide, an ionic monomer and a crosslinking agent and is capable of contracting upon receipt of the amplified voltage from the amplifier and thereby releasing insulin.
11. An insulin release control system as claimed in Claim 10, wherein the enzyme is glucose oxidase and the indicator chemical substance is glucose.
12. An insulin release control system as claimed in Claim 11, wherein the copolymer is composed of 5 to 50 parts by weight of an anionic monomer and 2 to 15 parts by weight of a mono-, di-, tri- or tetra-ethylene glycol dimethacrylate as the crosslinking agent, each per 100 parts by weight of N isopropylacrylamide.
13. An electroresponsive hydrogel produced by alkali hydrolysis of a copolymer comprising N-isopropylacrylamide, an ionic monomer and a crosslinking agent.
14. A hydrogel as claimed in Claim 13 wherein the cross-linking agent is selected from the group consisting of ethylene glycol dimethacrylate, diethylene glycol dimethacrylate, tri-ethylene glycol dimethacrylate and polyethylene glycol #200 dimethacrylate.
15. A process for producing a hydrogel as claimed in Claim 13 or Claim 14, which comprises copolymerization of the monomers and the crosslinking agent by irradiation of ionizing radiation, and hydrolyzing the copolymerization product under alkaline conditions.
16. A process as claimed in Claim 15 wherein the ionizing radlatlon is .gamma. ray.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1203629A JPH0366384A (en) | 1989-08-04 | 1989-08-04 | System for controlling release of physiologically active material |
| JP203629 | 1989-08-04 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2022426A1 true CA2022426A1 (en) | 1991-02-05 |
Family
ID=16477207
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002022426A Abandoned CA2022426A1 (en) | 1989-08-04 | 1990-08-01 | Electroresponsive hydrogel and physiologically active substance release control system |
Country Status (5)
| Country | Link |
|---|---|
| US (1) | US5152758A (en) |
| EP (1) | EP0411621A3 (en) |
| JP (1) | JPH0366384A (en) |
| KR (1) | KR910004221A (en) |
| CA (1) | CA2022426A1 (en) |
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- 1989-08-04 JP JP1203629A patent/JPH0366384A/en active Pending
-
1990
- 1990-07-23 US US07/556,332 patent/US5152758A/en not_active Expired - Fee Related
- 1990-07-26 KR KR1019900011385A patent/KR910004221A/en not_active Application Discontinuation
- 1990-08-01 CA CA002022426A patent/CA2022426A1/en not_active Abandoned
- 1990-08-02 EP EP19900114805 patent/EP0411621A3/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| EP0411621A2 (en) | 1991-02-06 |
| US5152758A (en) | 1992-10-06 |
| KR910004221A (en) | 1991-03-28 |
| EP0411621A3 (en) | 1991-10-30 |
| JPH0366384A (en) | 1991-03-22 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |