Patent Application
20130066264
This invention relates to a sugar-responsive gel and a medicine administering device.
Methacrylamide phenylboronic acid (e.g., refer to patent document 1), 3-acrylamide-6-hexafluoropropyl phenylboronic acid (e.g., refer to patent document 2), N-(4′-vinylbenzyl)-4-phenylboronic acid carboxyamide (e.g., refer to patent document 3), 4-(1′,6′-dioxo-2′,5′-diaza-7′-octenyl)phenylboronic acid and the like are known as conventional phenylboronic acid derivatives (hereinafter referred to as PBAs) having a polymerizable unsaturated bond.
Any of these conventional phenylboronic acid derivatives, however, has not ever simultaneously satisfied all of the following three properties: (1) having high hydrophilicity; (2) having low pKa (a value represented by −log10 Ka, herein Ka denotes an acid dissociation constant); and (3) having a polimerizable unsaturated bond. Accordingly, when they are polymerized in water as a solvent, these conventional phenylboronic acid derivatives cannot be borne in a polymer in a sufficient amount, or cannot work fully as a sugar-responsive gel capitalizing on the Lower Critical Solution Temperature (LCST), because the polymerized polymer and the aqueous gel have a high hydrophobicity.
While, since a phenylboronic acid compound has a capability of reversible covalent binding to sugar molecules such as glucose, there has been developed a sugar-responsive gel that releases insulin autonomously in response to a glucose concentration, utilizing such properties of the phenylboronic acid compound.
Accordingly, the present invention has been accomplished, considering the properties described above, and an object of the present invention is to propose a sugar-responsive gel and a medicine administering device having pKa more suitable than conventional ones for the use in a body environment and capable of releasing a medicine autonomously.
A first aspect of the present invention for solving the problems is characterized by a gel composition comprising a phenylboronic acids monomer represented by the following formula (3):
(wherein R is H or CH3, F is independently present, n is 1, 2, 3 or 4, and R1 is a divalent linking group).
In addition, a second aspect of the present invention is characterized in that the formula (3) is represented by the following formula (4):
(wherein m is an integer of 0, or 1 or more).
Additionally, a third aspect of the present invention is characterized in that m is one or more.
Also, a fourth aspect of the present invention is characterized by the gel composition comprising the phenylboronic acids monomer, a gelling agent and a crosslinking agent.
Additionally, a fifth aspect of the present invention is characterized by comprising a gel body formed by the gel composition and a dehydrated shrunken layer enclosing the gel body, wherein a medicine is contained in the gel body enclosed by the dehydrated shrunken layer.
Also, a sixth aspect of the present invention is characterized by a medicine administering device in response to a blood-sugar level in a subject to be administered with the medicine, wherein the medicine administering device comprises the sugar-responsive gel formed by the gel composition described in any one of the first to the fourth aspects, an introducing unit for introducing the blood of the subject to be administered with the medicine into the sugar-responsive gel, and a releasing unit for releasing the medicine into the subject to be administered with the medicine based on a change in the sugar-responsive gel in response to a blood-sugar level of the blood.
Additionally, a seventh aspect of the present invention is characterized in that the sugar-responsive gel comprises a gel body formed by the gel composition and containing the medicine; and the dehydrated shrunken layer enclosing the gel body, and further the introducing unit and the releasing unit are comprised of a biocompatible material, so that the sugar-responsive gel is enclosed with the biocompatible material and implanted into an administration site.
Also, an eighth aspect of the present invention is characterized in that the introducing unit and the releasing unit are units of an indwelling needle whose tip is inserted into the administration site to be held therein, wherein the sugar-responsive gel comprises the gel body formed by the gel composition and containing the medicine; and the dehydrated shrunken layer enclosing the gel body, and the sugar-responsive gel is filled into the indwelling needle.
Additionally, a ninth aspect of the present invention is characterized by comprising an indwelling needle with a backflow prevention valve whose tip is inserted into the administration site to be held therein and a filling unit filled with the medicine and communicated with the indwelling needle with the backflow prevention valve, wherein the releasing unit releases the medicine into the administration site from the indwelling needle with backflow prevention valve in such a manner that the medicine in the filling unit is pushed out to the indwelling needle with backflow prevention valve by an expansion pressure generated in response to the blood-sugar level of the blood introduced by the introducing unit.
Also, a tenth aspect of the present invention is characterized by a supplying unit for supplying the medicine to the sugar-responsive gel.
According to the first to tenth aspects of the present invention, the present invention can work under the condition of pKa 7.4 or less, comprising a component that can release a medicine depending on an elevation of the sugar concentration, and, having pKa more suitable than conventional ones for the use in a body environment and capable of administering a medicine autonomously.
Embodiments of the invention are described in details hereinbelow with reference to the drawings.
(1) A phenylboronic acids monomer to be contained in a sugar-responsive gel of the present invention:
A phenylboronic acids monomer to be contained in a sugar-responsive gel of the present invention is represented by the following formula (5):
(wherein R is H or CH3, F is independently present, n is 1, 2, 3 or 4, and R1 is a divalent linking group).
The divalent linking group represented by R1 comprises one or more bonds selected from the group consisting of carbamoyl bond, amide bond, alkyl bond, ether bond, ester bond, thioester bond, thioether bond, sulfonamide bond, urethane bond, sulfonyl bond, imine bond, urea bond, thiourea bond and the like.
As described above, the phenylboronic acids monomer has a structure wherein one or more of fluorines are substituted for hydrogens on the phenyl ring of phenylboric acid group. Also, the phenylboronic acids monomer has a structure wherein the linking group R1 is bound to the phenyl ring and a carbon in unsaturated bond is bound to the linking group R1.
The phenylboronic acids monomer has a high hydrophilicity, and its pKa can be controlled to the values of 7.4 or less in the physiological level by fluorination of the phenyl ring. Further, this phenylboronic acids monomer can acquire the abilities not only to recognize a sugar in the physiological environments, but also to copolymerize with a gelling agent and a linking agent described below by an unsaturated bond, and thus can form a sugar-responsive gel.
As an embodiment, in phenylboronic acid monomer represented by the formula (5), if n is 1 and one fluorine is substituted for a hydrogen on the phenyl ring, F and B(OH)2 to be substituted may be in any of ortho, metha and para positions.
Under this condition, if carbamoyl group is applied to the linking group R1, the above formula (5) is represented by the following formula (6):
(wherein m is an integer of 0, or 1 or more).
As described above, a phenylboronic acids monomer has the structure comprising a fluorophenyl boronic acid group wherein one or a plurality of fluorines are substituted for hydrogens on the phenyl ring, and the carbon of amide group is bound to the phenyl ring.
In addition, if m is 0, the phenylboronic acids monomer has the structure wherein nitrogen of the amide group directly binds to nitrogen of other amide group to contain therein an acrylamide or methacrylamide structure comprising the part of this other amide group. While, if m is one or more, the phenylboronic acids monomer has the structure wherein nitrogen of the amide group binds to nitrogen of other amide group via one or a plurality of carbons to contain therein the acrylamide or methacrylamide structure comprising the part of this other amide group. Additionally, if m is one or more, the pKa of the phenylboronic acids monomer can be controlled to a lower value compared with the value obtained if m is 0. Further, even such phenylboronic acids monomer can achieve similar effect to that of the phenylboronic acids monomer represented by the above formula (5).
One embodiment of the formula (6) described above is a phenylboronic acids monomer, wherein n is 1, a fluorine is substituted for one hydrogen on the ring of phenylboronic acid group, m is 2 (spacer carbons are two), and its formula is represented by the following formula (7) (wherein R is H or CH3):
Here, a phenylboronic acids polymer polymerized among the phenylboronic acids monomer, represented by the formula (5) mentioned above, is represented by the following formula (8):
(R is H or CH3, F is independently present, n is 1, 2, 3 or 4, 1 is an integer of two or more, and R1 is a divalent linking group).
In addition, as one embodiment of the divalent linking group, if a linking group comprising carbamoyl bond is applied, the above formula (8) is represented by the following formula (9) (wherein m is an integer of 0, or 1 or more):
In addition, by polymerization among the phenylboronic acids monomers represented by the above-described formula (7), a phenylboronic acids polymer represented by the following formula (10) can be obtained (wherein R is H or CH3, 1 is an integer of two or more):
Here, the phenylboronic acids monomer represented by the above formula (7) is produced according to the synthetic scheme as shown in
Next, the acid chloride compound represented by the above formula (12) is dissolved in tetrahydrofuran (THF), triethylamine (TEA) is added thereto as a base catalyst, and reacted by addition of the compound represented by the following formula (13), then an intermediate represented by the formula (14) (
Subsequently, in the presence of hydrogen gas, an intermediate represented by the formula (15) (
Subsequently, according to the synthetic scheme shown in
At first, 27 mmol of carboxyfluorophenylboronic acid (formula (11)) was added with 50 mL of thionyl chloride, and refluxed at 90° C. (degrees Celsius) in an oil bath, and then a solution was produced. Subsequently, the redundant thionyl chloride was removed from the reaction mixture, which was then dissolved in 90 mL of tetrahydrofurane (THF), added with mmol of the compound represented by the above formula (13), further added with triethylamine (TEA) 200 mmol in an ice water bath, and then the mixture was stirred at room temperature for one day.
The product solution obtained in this manner was added with a diluted hydrochloric acid solution saturated with sodium chloride salt, and subjected to the procedures for washing and separating the solution, and then THF was removed. The residue was dissolved in 400 mL of ethanol, and added with 1 g of 10% palladium carbon catalyst, and subjected to hydrogen reduction reaction under the condition of 40° C. (degrees Celsius). Then, the palladium carbon catalyst was filtered out therefrom, and the intermediate represented by the formula (15) (
Subsequently, as a first comparative example, 3-acrylamidephenyl boronic acid (Wako Pure Chem. Ltd., hereinafter referred to as comparative sample 1) represented by the formula (17) shown in
Subsequently, as a second comparative example, 4-(2-acrylamideethylcarbamoyl)phenylboronic acid (hereinafter referred to as comparative sample 2) represented by the formula (18) shown in
Next, for the sample 1, the comparative sample 1 and the comparative sample 2, the relationships between glucose concentrations and apparent changes in pKa were derived by acid-base titration in the conditions of various glucose concentrations (0 g/L, 1 g/L, 3 g/L, 5 g/L and g/L).
The results were shown in
Next is a description of the sugar-responsive gel of the present invention containing the phenylboronic acids monomer described in “(1) A phenylboronic acids monomer to be contained in a sugar-responsive gel of the present invention”, and the phenylboronic acids polymer described in “(2) Phenylboronic acids polymer”. Such sugar-responsive gel can be produced from a gel composition comprising a gelling agent having a property (biocompatibility) that does not cause a toxic effect or an adverse effect to an in vivo biological function, the above-described phenylboronic acids polymer represented by the formula (5), and a cross-linking agent.
Then, the sugar-responsive gel can be produced by the procedures shown as follows: At first, a gel composition is prepared so as to comprise a gelling agent which is to form a main chain of the gel, the phenylboronic acids monomer represented by the above-described formula (5), and a cross-linking agent in a certain molar ratio described later. Subsequently, they are mixed and reacted with one another, thus producing a gel body in a gel state. Then, a medicine is diffused into the gel body by immersion of the gel body in a phosphate buffer containing a certain concentration of insulin, etc. Next, the gel body picked up from the phosphate buffer is immersed in hydrochloric acid for a certain period of time, thus forming a thin dehydrated shrunken layer on the surface of the gel body (hereinafter referred to as a skin layer), and thus the sugar-responsive gel loading the medicine can be produced.
In that case, the gel composition can be prepared so as to comprise the gelling agent, the above-described phenylboronic acids monomer represented by the formula (5), and the cross-linking agent, in a molar mixing ratio of reaction materials (gelling agent/phenylboronic acids monomer/cross-linking agent) being, for example, 92.5/7.5/1. According to the embodiment of the present invention, the description was given about the preparation in the molar mixing ratio of reaction materials (gelling agent/phenylboronic acids monomer/cross-linking agent) being 92.5/7.5/1. The present invention, however, is not limited thereto. Other molar ratios may be applicable, provided that a gel body formed by a gel composition comprising the gelling agent, the phenylboronic acids monomer and the cross-linking agent can be expanded or shrunk according to the glucose concentration, and maintain the properties in the condition of pH 7.4 or less, and can form a gel state.
In the conditions, the gelling agent may be applicable, provided that the gelling agent is a biocompatible material which has biocompatibility and can cause gelatinization, which, for example, may be exemplified by biocompatible acrylamides. Specifically, they may include N-isopropylacrylamide (NIPAAm), N-isoprpylacrylamide, N,N-diethylacrylamide and N-isopropylmethacrylamide, etc.
In addition, as a cross-linking agent, similarly, biocompatible materials that can cause cross-link with a monomer may be applicable, which, for example, may be exemplified by N,N′-methylenebisacrylamide, ethyleneglycol dimethacrylate, N,N′-methylenebismethacrylamide and others.
Additionally, as a medicine, a peptide hormone such as insulin, a protein, an antibody, a nucleic acid and a variety of synthetic drugs may be used.
Next, as shown in
Next, the gel body was picked up from the phosphate buffer solution, immersed in 0.01 M hydrochloric acid for one hour at 37° C. (degrees Celsius), so that a thin dehydrated shrunken layer (skin layer) was formed on the surface of the gel body, and thus a sugar-responsive gel with FITC modified insulin loaded in the gel body was produced.
Subsequently, the sugar-responsive gel was immersed in phosphate buffer solutions (155 mM NaCl) of pH 7.4, ion strength 0.15, prepared at 0.5 g/L, 1 g/L, 3 g/L, 5 g/L or 10 g/L of glucose concentrations, and then the temperatures of the phosphate buffer solutions with the respective glucose concentrations were adjusted at 34-45° C. (degrees Celsius). Then, the swelling degree (d/d0)3 of each sugar-responsive gel at certain temperature and at each glucose concentration was measured. Thus, the results of the measurement shown in
It should be noted that, the swelling degree referred to here, means a value obtained by calculating the ratio of d to d0 at each temperature and then cubing the ratio, wherein d0 is the diameter of the sugar-responsive gel in 0 g/L of glucose concentration in a phosphate buffer solution at each temperature, and d is the diameter of the sugar-responsive gel in the phosphate buffer solution at each temperature in a given glucose concentration. When the value of swelling degree is higher than 1, the value means that the sugar-responsive gel has caused swelling. When the value of swelling degree is lower than 1, the value means that the sugar-responsive gel has caused shrinking.
In the example, an image was taken by an optical microscope for each of the sugar-responsive gels immersed in the phosphate buffer solution prepared at 1 g/L of glucose concentration, and in the phosphate buffer solution prepared at 5 g/L of glucose concentration, at 37° C. (degrees Celsius), respectively, and thus there could be obtained photographs showing that the swelling degree becomes larger as the glucose concentration increases, as shown in
Additionally, it could be observed, from the graphs shown in
A verification test was conducted on controlled release of insulin responsive to changes in glucose concentration by use of the sugar-responsive gel produced according to the procedures described in the above-described section: “(6-1) Change in state of sugar-responsive gel in response to the concentration of glucose”, wherein the sugar-responsive gel comprised the thin dehydrated layer (skin layer) formed on the surface of the gel body with FITC modified insulin loaded therein.
The verification test on the controlled release of insulin was conducted by high-performance liquid chromatography (HPLC). Specifically, phosphate buffer solution of pH 7.4 (155 mM NaCl) was used as a mobile phase (solvent), and the pump 1 was filled with the phosphate buffer solution prepared at 1 g/L concentration of glucose, while a pump 2 was filled with the phosphate buffer solution prepared at 5 g/L of glucose concentration, then the glucose concentration in the HPLC column was adjusted by successively changing or maintaining the mixing ratio thereof at 1 mL/min of flow speed.
Next, the sugar-responsive gel with FITC modified insulin loaded in the dehydrated shrunken layer was enclosed in the HPLC column filled with the phosphate buffer solution prepared at 1 g/L of glucose concentration, then placed in the HPLC flow path, and stabilized at the flow rate described above (1 mL/min) for 24 hours at 37° C. (degrees Celsius).
Subsequently, as shown in
In this manner, the glucose concentration was changed in the phosphate buffer solution at pH 7.4 and 37° C. (degrees Celsius), and the amounts of the FITC modified insulin released from the sugar-responsive gel were observed based on the changes in fluorescence intensity. Then, it was observed that the fluorescence intensity was weak for 1 g/L of glucose concentration referred to as a normal blood-sugar level, and hence, it could be confirmed that the release of the FITC modified insulin from the sugar-responsive gel was suppressed. While, when the glucose concentration was 5 g/L, it was observed that the fluorescence intensity was sharply raised, and hence, it could be confirmed that the FITC modified insulin was released from the sugar-responsive gel.
Additionally, the relationships between the timing of rising of glucose concentration and fluorescence intensity, and the timing of dropping of glucose concentration and fluorescence intensity were investigated in further details, and thus, the results shown in
From these results, it was found that: the sugar-responsive gel begins to release the FITC modified insulin sharply at substantially the same time as the rise in glucose concentration in the phosphate buffer solution; when the increased glucose concentration is maintained at the constant enhanced level, the release of the FITC modified insulin is allowed to continue; upon the start of dropping of the glucose concentration, the amount of the FITC modified insulin release reaches a maximum; and then followed by the gradual decrease in release of the FITC modified insulin as the glucose concentration decreases. It was also found that the FITC modified insulin loaded in the sugar-responsive gel was gradually decreased, from the fact that the peaks of fluorescence intensity became lower and lower with the repetition of the changes in glucose concentration between high-low levels.
Next, the phosphate buffer solution prepared at 2 g/L of glucose concentration was freshly filled into the pump 2, and the glucose concentration in the HPLC column was adjusted by sequentially changing or maintaining the mixing ratio at 1 mL/min of flow rate. Practically, as shown in
In that case as well, it was observed from the level of the fluorescence intensity that the sugar-responsive gel began to release the FITC modified insulin, following the increase in the glucose concentration in the phosphate buffer solution, and that the amount of the released FITC modified insulin decreased gradually, following the decrease in the glucose concentration. Additionally, from the peaks of fluorescence intensity shown in
From these results, it was observed that the sugar-responsive gel did not release insulin at all when the glucose concentration was 1 g/L that is the normal blood-sugar level, and insulin was released when the glucose concentration was 2 g/L that is the diagnostic criteria level of diabetes mellitus, thus it is understood that the autonomous administration of insulin can be accomplished in response to the glucose concentration.
Next, as shown in
In addition, the phosphate buffer solution of 3 g/L glucose concentration was freshly filled into the pump 2, the glucose concentration in the HPLC column was adjusted while changing or maintaining the mixing ratio sequentially at 1 mL/min of flow rate. Practically, as shown in
Also in that case, it could be observed that the release of FITC modified insulin was increased following the sharp rising of glucose concentration, while the release of FITC modified insulin was decreased following the sharp dropping of the glucose concentration. Additionally, when the glucose concentration was increased to 3 g/L that is the condition of the high blood-sugar level, compared with 2 g/L of the glucose concentration, the release of insulin per hour was increased from 2 μg (microgram) to 20 μg (microgram) that was about 10 times increase.
As described above, in the controlled release of insulin by utilizing on the gel, it has been considered that a reversible formation of skin layer has an important role. For ascertaining this consideration directly, the experiment described below was conducted. The sugar-responsive gel formed in a cylindrical shape was immersed in the phosphate buffer solution prepared at 2 g/L of glucose concentration, pH 7.4 and 37° C. (degrees Celsius), and the glucose concentration was decreased from 2 g/L to 1 g/L, then the states were observed at 5 min, 10 min, 30 min, 3 hours, 24 hours after (the step SP 1 and step SP 2).
In that case, 8-anilino-1-naphtalene-sulfonic acid was used as a fluorescence probe molecule for the FITC modified insulin diffused to the gel body of the sugar-responsive gel. This reagent has a property to change a fluorescence intensity remarkably in response to change in electric permittivity at a local environment. That means, it is possible to visualize the environment of low electric permittivity as the increase in fluorescence intensity following the formation of the skin layer.
As the results shown in
Additionally, as another example, the sugar-responsive gel 5 formed in a cylindrical shape was immersed in the phosphate buffer solution at pH 7.4 and 37° C. (degrees Celsius) prepared at 2 g/L of glucose concentration, and as shown in
As the results shown in
In the above embodiments, since the sugar-responsive gel contains a phenylboronic acids having fluorophenylboronic acids group wherein a single of or a plurality of fluorine is substituted for hydrogens on the phenyl ring as represented by the above formula (5), pKa can be controlled to pH 7.4 or less of physiological level.
Additionally, for the sugar-responsive gel, a gel body has been configured to be formed according to copolymerization with a gelling agent via unsaturated bond of phenylboronic acids, and insulin is diffused to the gel body, the surface of the gel body is enclosed with a dehydrated shrunken layer. According to this configuration, the sugar-responsive gel can release insulin from inner part to outer part of the gel body, when the glucose concentration is increased at pKa 7.4 or less and 35-40° C. (degrees Celsius) of the physiological condition, then the dehydrated layer is disappeared according to the swelling of gel body.
While, the sugar-responsive gel, when the glucose concentration decreases from the condition again, can be suppressed releasing insulin from inner part to outer part of the gel body by reformation of the dehydrated layer (skin layer) on all of the surface by shrinking of the expanded state of the gel body.
Accordingly, the sugar-responsive gel of the present invention can release insulin autonomously in response to the glucose concentration, thus, the sugar-responsive gel has pKa more suitable for utilization in the physiological environment than convention, and can be applied for autonomous administration of insulin.
Next is a description of an insulin administering device utilizing the sugar-responsive gel described above. In
Insulin administering control unit 11 comprises the sugar-responsive gel 13, and the enclosing unit 14 which is formed to cover all of the surface of the sugar-responsive gel 13, further, a supplying unit 12 in a tube state is connected to the sugar-responsive gel 13, and insulin can be supplied from out to the sugar-responsive gel 13 as the occasion demands. The sugar-responsive gel 13 is the described above “(4) a sugar-responsive gel comprising phenylboronic acids monomer”, comprising a gel body wherein insulin is diffused, and a dehydrated shrunken layer enclosing the gel body. By this configuration, when the glucose concentration is increased in a patient and the blood sugar level become high, the sugar-responsive gel 13 can release insulin in the gel body by reacting with glucose in response to the increase in glucose concentration and elevation of the blood-sugar level.
The enclosing unit 14 that covers all of the surface of the sugar-responsive gel 13 as a releasing unit, has biocompatibility such as polyethylene glycol and the like, and is made of a biocompatible material through which glucose and insulin can pass. The enclosing unit 14 encloses the sugar-responsive gel 13, so as to protect the sugar-responsive gel 13 not to cause a diffusion via disruption by outer pressure.
In the configuration described above, the insulin administering device 10 is implanted, wherein the insulin administering control unit 11 having the sugar-responsive gel 13 containing phenylboronic acids monomer represented by the formula (5) described above is embedded into the body of a patient, and the supplying unit 12 is drawn out to out of the body.
In this manner, in the insulin administering device 10, when the glucose concentration level of a patient to be administered with the medicine is increased, insulin can be released from the inner sugar-responsive gel 13 in response to increase in the glucose concentration, while, when the glucose concentration is decreased, the release of insulin from the sugar-responsive gel 13 can be suppressed in response to the decrease in the glucose concentration. Then, autonomous administration of insulin in response to the glucose concentration can be carried out.
Additionally, in the insulin administering device 10, a supplying unit 12 is connected to the sugar-responsive gel 13 in the insulin administering control unit 11, insulin can be supplied to the sugar-responsive gel 13 embedded in the body from the supplying unit 12. In this manner, in the insulin administering device 10, if insulin causes deficiency in the sugar-responsive gel 13, the complement of insulin can be conducted from the out of the body without picking out the insulin administering control unit 11 from the body, thus the insulin administering device 10 can be used for a long time.
In the
The indwelling needle 22 is formed whose tip is a shape of needle in a conical shape, and by insertion of the tip into the skin of a patient, the sugar-responsive gel 23 can be contacted with the patient blood with the sugar-responsive gel 23 in the inner space. By this configuration, the sugar-responsive gel 23 can release insulin from the gel body in response to the blood glucose concentration, and it is formed so that the insulin is administered into the patient body from the inner part of indwelling needle 22.
Furthermore, in this embodiment, the embodiment of the small inner part in a conical shape in the indwelling needle 22 is described as the sugar-responsive gel 23 is filled therein, however, the present invention is not limited to the embodiment. The sugar-responsive gel 23 may be filled into the other area, provided that the sugar-responsive gel 23 in the indwelling needle 22 is certainly contacted with the blood by insertion of the indwelling needle 22 into the patient skin and that insulin can be released from the gel body in response to the blood glucose concentration.
Additionally, the indwelling needle 22 is formed so that the inner part of the body side thereof has a connection with the inner part of the insulin filling unit 21 to supply insulin in the insulin filling unit 21 to the sugar-responsive gel 23. By this configuration, the sugar-responsive gel 23 can maintain the state of containing insulin, even if it is filled into the micro-region of the indwelling needle 22.
While, the insulin filling unit 21, whose inner space is filled with insulin via the supplying unit 12, can supply insulin to the sugar-responsive gel 23 in the indwelling needle 22. By this way, the insulin administering device 20 can always supply insulin complementarily to the sugar-responsive gel 23 from the insulin filling unit 21, even if insulin is released from the sugar-responsive gel 23.
In the above configuration, the insulin administering device 20 is configured to comprise the sugar-responsive gel 23 containing phenylboronic acids monomer represented by the above formula (5) in the indwelling needle 22, the tip of the indwelling needle 22 is hold with insertion through the skin of a patient, then the patient blood is contacted with the sugar-responsive gel 23.
By this way, in the insulin administering device 20, insulin can be released from the sugar-responsive gel 23 in response to the increase in patient glucose concentration, while insulin release from the sugar-responsive gel 23 in the indwelling needle 22 can be suppressed in response to the decrease in the glucose concentration. Thus, the autonomous administration of insulin in response to the glucose concentration can be carried out.
In
The indwelling needle with backflow prevention valve 32 leads a flow of insulin in the insulin filling unit 31a to the front side, only when a pressure from insulin fulfilling unit with pumping function 31 in the body side to the front side is elevated over a predetermined level, while the flow from the front side to the body side is prevented by the backflow prevention valve 34 placed in the inner part of the conical-shaped indwelling needle 33.
The inner part of the insulin filling unit with pumping function 31 is separated into an insulin filling region 31a where insulin is filled and a pumping region 31b where blood is supplied, by a plate-like separator part 40. Insulin can be filled into the insulin filling region 31a in the insulin filling unit with pumping function 31 via a supplying unit 12 comprising a tube. While, in the pumping region 31b of the insulin filling unit with pumping function 31, a cylindrically-shaped sugar-responsive gel 41 is disposed so as to be contacted with the edge part and the separator part 40, and thus, the patient blood is supplied by an introducing unit 36, and the blood can make a contact with the sugar-responsive gel 41.
Here, the sugar-responsive gel 41 comprises a gel body containing a phenylboronic acids monomer represented by the formula (5) in a similar manner with the described above “(4) sugar-responsive gel containing phenylboronic acids monomer”. However, in the sugar-responsive gel 41 in this embodiment, insulin has not been diffused in the gel body and a dehydrated and shrunken layer has not been formed on the surface of the gel body unlike in the one described above. That is, the sugar-responsive gel 41 does not release insulin in response to the glucose concentration, and has a configuration wherein swelling and shrinking can merely occur.
As for the introducing unit 36 connected to the pumping region 31b, the tip of the needle disposed in the front of the indwelling needle 37 is inserted into the patient skin, and the blood is introduced to the pumping region 31b of the insulin filing unit with pumping function 31 from the indwelling needle 37 through the tube 38.
By this way, the insulin filling unit with pumping function 31 is configured so that the sugar-responsive gel 41 can cause swelling or shrinking in response to the blood glucose concentration by contacting the sugar-responsive gel 41 with the blood. By this configuration, regarding the insulin filling part with pumping function 31, for example, when blood glucose concentration is increased, the sugar-responsive gel 41 causes expansion in response to the glucose concentration, and the separator part is moved by a pressure from the sugar-responsive gel 41, then the insulin filling region 41a can be made smaller. According to the way, the insulin filling region with pumping function 31 can supply insulin in the insulin filling region 31a to the indwelling needle with backflow prevention valve 32, and insulin can be administered from the indwelling needle with backflow prevention valve 32 into the patient body.
While, as for the insulin filling unit with pumping function 31, for example, when the blood glucose concentration is decreased, the sugar-responsive gel 41 causes shrinking in response to the glucose concentration, the pressure caused by the separator part 40 due to the sugar-responsive gel 41 is stopped, then the administration of insulin in the insulin filling region 31a from the indwelling needle with backflow prevention valve 32 to the patient body can be discontinued.
As for the configuration described above, the insulin administering device 30 comprises the sugar-responsive gel 41 containing phenylboronic acids monomer represented by the described above formula (5) in the pumping region 31b of the insulin filling unit with pumping function 31, the tip of the indwelling needle with backflow prevention valve 32 and the tip of the indwelling needle 37 are inserted through the skin of the patient and held. While, in the insulin administering device 30, the patient blood is introduced into the pumping region 31b of the insulin filling unit with pumping function 31 by the introducing unit 36, and blood is contacted with the sugar-responsive gel 41.
By this way, in the insulin administering device 30, when the patient glucose concentration is increased, the sugar-responsive gel 41 in the pumping region 31b responds to this and causes expansion of the sugar-responsive gel 41 in the pumping region 31b, and the separator part is moved to the insulin filling region 31a side by the expansion pressure, thus insulin in the insulin filling region 31a can be released into the body from the indwelling unit with backflow prevention valve 32. Additionally, in the insulin administering device 30, when the glucose concentration is decreased, the sugar-responsive gel 41 responds and causes shrinking, then the separator part 40 stops moving to the filling region 31a side, and thus the insulin release into the body can be suppressed. Thus, in the insulin administering device 30, insulin can be autonomously administered in response to the glucose concentration.
While, the present invention should not be limited to the foregoing embodiments, a variety of modifications can be applied within a range of the scope of the present invention. For example, as any ratio of the polymerization between N-isopropylmethacrylamide (NIPMAAm) and the example sample 1 phenylboronic acids monomer of the present invention (FPBA), a variety of the molar ratios may be prepared within a range of 90/10 to 70/30 and the like, further any other variety of ratios can be applied. In these embodiments, around the normal physiological temperature (35° C.-37° C.), the prominent swelling can be caused in response to the glucose concentration, thus, the remarkable effects can be achieved sufficiently for a sugar-responsive gel which can be utilized for administering insulin autonomously.
Additionally, in the embodiments described above, glucose is applied as a sugar, however, in the present invention, not limited to this, other sugars that have a structure of 1,2-diol, or 1,3-diol such as galactose, mannose or fructose may be applied.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2010-208796 | Sep 2010 | JP | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/JP2011/061869 | 5/24/2011 | WO | 00 | 11/21/2012 |
| Number | Date | Country | |
|---|---|---|---|
| 61348334 | May 2010 | US |
