JP2017164308A - Puncture device and method for manufacturing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a technology that can inhibit adhesive force of drug and the like to a protrusion from changing over time.SOLUTION: A puncture device 1 includes: a support body 11; and the protrusion 12 supported by the support body 11. The protrusion 12 includes: a first polymer that is a thermoplastic resin; and a second polymer different from the first polymer. The second polymer includes at least one of an amino group and a peptide bond and mediates a bond between the first polymer and a drug or biological substance.SELECTED DRAWING: Figure 1

Description

  The present invention relates to a puncture device.

  The transdermal absorption method is a method in which a drug is administered into the body from the surface of a living body such as skin or mucous membrane. This method is non-invasive and can easily administer a drug without causing pain to the human body. However, in this method, the drug is easily removed from the surface of the living body due to sweating or external contact, etc., skin damage may occur during long-term use, or when a drug with a large molecular weight or a water-soluble drug is used. Has a problem that the stratum corneum of the epidermis becomes a barrier and the drug is hardly absorbed.

  A method using a puncture device called a microneedle or the like has attracted attention as a method for solving these problems and efficiently absorbing a drug into the body (Patent Document 1). In this method, a large number of needle-like convex portions having a length on the order of microns are punctured into the skin, and the drug is directly administered to the epidermis. In addition, a chemical | medical agent is previously made to adhere to a convex part, for example.

International Publication No. 2008/015782

The present inventor has found that there is room for improvement with respect to the adhesive force of a drug or the like on the convex portion, particularly the temporal change thereof.
An object of this invention is to provide the technique which can suppress the time-dependent change of the adhesive force of the chemical | medical agent etc. to a convex part.

  According to a first aspect of the present invention, a support and a convex portion supported by the support are provided, and the convex portion is different from the first polymer that is a thermoplastic resin and the first polymer. There is provided a puncture device that includes at least one of an amino group and a peptide bond, and mediates the bond between the first polymer and a drug or biological substance.

  According to a second aspect of the present invention, the method includes a step of forming a convex portion that is supported by a support and includes a first polymer that is a thermoplastic resin and a second polymer that is different from the first polymer, 2 Polymer has at least one of an amino group and a peptide bond, The manufacturing method of the puncture device which mediates the coupling | bonding of the said 1st polymer and a chemical | medical agent or a biological substance to the said 2nd polymer is provided.

  According to the present invention, there is provided a technique capable of suppressing a change with time of an adhesive force of a drug or the like.

1 is a cross-sectional view schematically showing a puncture device according to an embodiment of the present invention.

Hereinafter, embodiments of the present invention will be described.
FIG. 1 is a cross-sectional view schematically showing a puncture device according to an embodiment of the present invention.

This puncture device 1 includes a support 11, a convex portion 12, and a medicine 13.
The support 11 supports the convex portion 12. Here, the support 11 has a thin layer shape. The support 11 may have other shapes.

  For example, the entire support 11 is made of the same material as that of the protrusion 12. The support 11 is a composite in which a part is composed of a material different from the material included in the convex part 12 and at least a part of the surface is composed of the same material as the material included in the convex part 12. Also good. For example, the support 11 may have a multilayer structure including a layer different from the material included in the convex portion 12 and a layer made of the same material as the material included in the convex portion 12.

  The convex portion 12 is supported by the support body 11. Although many convex parts 12 are drawn in Drawing 1, the number of convex parts 12 should just be one or more.

  The convex portion 12 is a portion that pierces the skin when the puncture device 1 is pressed against the skin. The convex portion 12 may have any shape as long as it can puncture the skin. For example, the convex portion 12 has a needle shape or a blade shape. The convex portion 12 preferably has a tapered shape.

  When the puncture device 1 is applied to a human, the height of the convex portion 12 is preferably in the range of 50 μm to 1000 μm. In addition, when the puncture device 1 is applied to a human, a dimension perpendicular to the height direction of the convex portion 12, for example, a width or a diameter is preferably within a range of 10 μm to 1000 μm. When the puncture device 1 is applied to a living body other than a human, the dimensions of the convex portion 12 are appropriately set according to the thickness of the horny layer, epidermis, and dermis layer of the living body, and the hardness of the stratum corneum.

The convex part 12 contains the 1st and 2nd polymer.
As the first polymer, for example, a polymer having neither an amino group nor a peptide bond can be used. Examples of such polymers include polyethylene, polystyrene, polyethylene terephthalate, polycarbonate, polycaprolactone, polyethylene glycol, polylactic acid, polybutylene succinate, polyethylene succinate, trimethylene carbonate, polyhydroxybutyrate, cellulose, and starch. Can be mentioned. The first polymer may be a mixture of plural kinds of polymers or a copolymer. The first polymer is preferably biocompatible and / or biodegradable.

  The second polymer is different from the first polymer. The second polymer has at least one of an amino group and a peptide bond. Typically, the second polymer has at least one of an amino group and a peptide bond in the repeating unit. Typically, the second polymer is positively charged.

  The second polymer may be a single polymer, a mixture of a plurality of polymers, a copolymer, or a mixture of one or more polymers and one or more copolymers. May be. Examples of the second polymer include polylysine, polyhistidine, or polyethyleneimine; a mixture of two or more of these polymers; a copolymer containing two or more of these polymers; or one or more of these polymers and two or more of these polymers, respectively. Mixtures with one or more copolymers comprising can be used.

  When a copolymer is used as the second polymer, the copolymer may be a random copolymer or a block copolymer. By changing the types of monomers constituting the copolymer, their combinations, and their molar ratios, the binding strength of the second polymer to the first polymer, the binding strength of the second polymer to the drug 13, and their balance Etc. can be changed.

  The second polymer may be biodegradable or not biodegradable. In the latter case, the drug 13 can be dissociated from the convex portion 12 and diffused into the living body due to, for example, the pH in the living body or the action of the biological substance. In the former case, not only the dissociation of the drug 13 from the convex portion 12 but also the decomposition of the second polymer can contribute to the diffusion of the drug 13 in the living body.

  In the convex part 12, the 1st and 2nd polymer may be mixed. Or in the convex part 12, the 1st polymer may comprise a convex part main body, and the 2nd polymer may adhere to the surface of the convex part main body. When the ratio of the second polymer occupying the convex portion 12 is constant, the latter structure has a greater effect of suppressing the temporal change in the adhesive force of the drug 13 to the convex portion 12 compared to the former structure, Further, it is advantageous in terms of the mechanical strength of the convex portion 12. The convex body has the shape and dimensions described above for the convex portion 12.

  The drug 13 is bonded to the first polymer via the second polymer. The drug 13 is, for example, negatively charged. The drug 13 may be a medical substance or a cosmetic substance. The drug 13 may be a compound, a cell, or a part thereof. Examples of the drug 13 include drugs having a hydroxyl group, a carbonyl group, a carboxyl group, or the like in the molecule. A drug having a hydroxyl group, a carbonyl group, a carboxyl group or the like in the molecule has negative chargeability.

  This puncture device 1 is manufactured by the following method, for example. Here, as an example, it is assumed that the support 11 is made of a first polymer, and the convex portion 12 is made of a convex main body made of the first polymer and a second polymer attached thereto.

  First, a plate provided with concave portions corresponding to the convex portions 12 is prepared. Next, the melted first polymer is supplied to the plate and pressed as necessary. Subsequently, this is cooled to solidify the first polymer. Thereafter, the solidified first polymer is removed from the plate. Thereby, the molded article which consists of the support body 11 and a convex-part main body is obtained.

  Next, an oxygen plasma treatment is performed on the convex body. By performing the oxygen plasma treatment, the surface of the convex portion made of the first polymer is positively charged. Accordingly, the binding force of the second polymer to the first polymer is increased.

  The convex body may be subjected to corona treatment instead of oxygen plasma treatment. By applying the corona treatment, the convex surface of the first polymer is positively charged. Accordingly, the binding force of the second polymer to the first polymer is increased.

  Then, the 2nd polymer is supplied to a convex part main part, and the convex part 12 which consists of a convex part main body and the 2nd polymer adhering to this is obtained. For example, the solution in which the second polymer is dissolved is supplied to the convex body, and the second polymer in the solution is bonded to the first polymer. Thereafter, an excessive amount of the solution is removed from the convex body, and the convex body is dried. In this way, the second polymer is attached to the convex body. Next, the medicine 13 is supplied to the convex portion 12. For example, a liquid containing the drug 13 is supplied to the convex portion 12 to bond the drug 13 to the second polymer. Thereafter, an excessive amount of liquid is removed from the convex portion 12, and the convex portion 12 is dried. In this way, the medicine 13 is attached to the convex portion 12.

In addition, when the convex part 12 is comprised with the mixture of a 1st and 2nd polymer, the melt of this mixture is supplied to the said plate | board, and this is pressed as needed. Subsequently, it is cooled to solidify the mixture. Thereafter, the solidified product is removed from the plate. Thereby, the molded product which consists of the support body 11 and the convex part 12 is obtained. Next, the drug 13 is attached to the convex portion 12 by the same method as described above.
The puncture device 1 shown in FIG. 1 is obtained as described above.

  According to this embodiment, the period from the formation of the convex portion 12 to the supply of the drug 13 to the convex portion 12 has a small effect on the adhesive force of the drug 13 on the convex portion 12. That is, according to the present embodiment, it is possible to suppress a change with time of the adhesive force of the medicine 13 on the convex portion 12.

  The puncture device 1 described above is used for delivery of the medicine 13 into a living body. However, the techniques described herein can be used for other purposes. For example, the puncture device 1 in which the medicine 13 is omitted can be used for collecting biological substances. In this case, an effect is obtained that the period from the formation of the convex portion 12 to the puncture of the convex portion 12 into the living body has a small influence on the adhesion force of the biological material to the convex portion 12. That is, in this case, it is possible to suppress a change with time of the adhesion of the biological material to the convex portion 12.

  Specific examples of the present invention are described below.

[Example 1A]
Using precision machining, a regular quadrangular protrusion was formed on one main surface of the silicon substrate. The height of the convex portion was 150 μm, and the length of each side of the bottom surface was 60 μm. A total of 36 convex portions were arranged in a grid of 6 columns and 6 rows at intervals of 1 mm. The original plate was manufactured as described above.

  Next, a nickel film having a thickness of 500 μm was formed on the original plate by plating. Subsequently, silicon was removed by wet etching. As an etching solution, an aqueous solution containing potassium hydroxide at a concentration of 30% by mass and heated to 90 ° C. was used. In this way, an intaglio plate made of nickel and provided with a concave portion corresponding to the convex portion was manufactured.

  Next, a thermoplastic resin was placed on the intaglio, and the thermoplastic resin was heated by a hot plate to melt. Cyclic olefin copolymer (COC) was used as the thermoplastic resin. Subsequently, the melted thermoplastic resin was pressed with a metal plate, and the recesses of the intaglio were filled with the thermoplastic resin. In this state, the thermoplastic resin was cooled and solidified. Thereafter, the thermoplastic resin was peeled from the intaglio plate to obtain a molded product comprising a support and a convex body.

  Next, the surface of the molded article provided with the convex body was subjected to oxygen plasma treatment using a plasma treatment machine.

  The molded article subjected to the oxygen plasma treatment was immersed in an aqueous solution containing polylysine at a concentration of 1% by mass for 20 minutes. Thereafter, the molded product was taken out from the aqueous solution, and its surface was rinsed with water. Subsequently, it was dried at room temperature. As described above, polylysine was adhered to the convex body.

Within 3 hours after the polylysine coating on the convex body was completed, the molded article was immersed in an aqueous fluorescently labeled liposome solution containing sucrose for 20 minutes. This was then rinsed lightly with water and subsequently dried.
A puncture device was obtained as described above.

[Example 1B]
Example 1A, except that after the polylysine coating on the convex body was completed, the molded product was allowed to stand for 1 week at room temperature and normal pressure until it was immersed in a fluorescently labeled liposome aqueous solution containing sucrose. A puncture device was manufactured by the same method.

[Comparative Example 1A]
A puncture device was produced in the same manner as in Example 1A, except that the polylysine coating on the convex body was omitted.

[Comparative Example 1B]
Comparative Example 1A, except that after the polylysine coating on the convex body was completed, the molded product was allowed to stand for 1 week at room temperature and normal pressure until it was immersed in a fluorescently labeled liposome aqueous solution containing sucrose. A puncture device was manufactured by the same method.

[Evaluation 1]
The puncture devices according to Examples 1A and 1B and Comparative Examples 1A and 1B were observed with a fluorescence microscope. As a result, in the puncture device of Example 1A and the puncture device of Comparative Example 1A, Example 1A showed higher fluorescence emission intensity than Comparative Example 1B. Further, there was no significant difference in fluorescence emission intensity between the puncture device of Example 1A and the puncture device of Example 1B. On the other hand, the puncture device of Comparative Example 1B had significantly lower fluorescence emission intensity than the puncture device of Comparative Example 1A.

[Example 2A]
Polyethylene was used as the thermoplastic resin, and instead of an aqueous solution containing polylysine at a concentration of 1% by mass, an aqueous solution containing polyhistidine at a concentration of 1% by mass and adjusted to pH 4.5 with hydrochloric acid was used. Except for this, a puncture device was produced in the same manner as in Example 1A.

[Example 2B]
Example 2A, except that after the polyhistidine coating on the convex body was completed, the molded product was allowed to stand for 1 week at room temperature and normal pressure until it was immersed in an aqueous fluorescently labeled liposome solution containing sucrose. A puncture device was manufactured in the same manner as described above.

[Comparative Example 2A]
A puncture device was produced in the same manner as in Example 2A, except that the polyhistidine coating on the convex body was omitted.

[Comparative Example 2B]
Comparative Example 2A, except that after the polyhistidine coating on the convex body was completed, the molded product was allowed to stand for 1 week at room temperature and normal pressure until it was immersed in an aqueous solution of fluorescently labeled liposomes containing sucrose. A puncture device was manufactured in the same manner as described above.

[Evaluation 2]
The puncture devices according to Examples 2A and 2B and Comparative Examples 2A and 2B were observed with a fluorescence microscope. As a result, in the puncture device of Example 2A and the puncture device of Comparative Example 2A, Example 2A showed higher fluorescence emission intensity than Comparative Example 2B. In addition, there was no significant difference in fluorescence emission intensity between the puncture device of Example 2A and the puncture device of Example 2B. On the other hand, the puncture device of Comparative Example 2B had significantly lower fluorescence emission intensity than the puncture device of Comparative Example 2A.

[Example 3A]
A puncture device was produced in the same manner as in Example 1A, except that an aqueous solution containing polyethyleneimine at a concentration of 1% by mass was used instead of an aqueous solution containing polylysine at a concentration of 1% by mass.

[Example 3B]
Example 3A, except that after the polyethyleneimine coating on the convex body was completed, the molded product was allowed to stand at room temperature and normal pressure for 1 week until it was immersed in an aqueous fluorescently labeled liposome solution containing sucrose. A puncture device was manufactured in the same manner as described above.

[Comparative Example 3A]
A puncture device was produced in the same manner as in Example 3A, except that the polyethyleneimine coat on the convex body was omitted.

[Comparative Example 3B]
Comparative Example 3A, except that after the polyethyleneimine coating on the convex body was completed, the molded product was allowed to stand for 1 week at room temperature and normal pressure until it was immersed in an aqueous fluorescently labeled liposome solution containing sucrose. A puncture device was manufactured in the same manner as described above.

[Evaluation 3]
The puncture devices according to Examples 3A and 3B and Comparative Examples 3A and 3B were observed with a fluorescence microscope. As a result, in the puncture device of Example 3A and the puncture device of Comparative Example 3A, Example 3A showed higher fluorescence emission intensity than Comparative Example 3B. In addition, there was no significant difference in fluorescence emission intensity between the puncture device of Example 3A and the puncture device of Example 3B. On the other hand, the puncture device of Comparative Example 3B had significantly lower fluorescence emission intensity than the puncture device of Comparative Example 3A.

  DESCRIPTION OF SYMBOLS 1 ... Puncture device, 11 ... Support body, 12 ... Convex part, 13 ... Drug.

Claims (11)

  And a convex portion supported by the support, wherein the convex portion includes a first polymer that is a thermoplastic resin, and a second polymer that is different from the first polymer. The puncture device, wherein the polymer has at least one of an amino group and a peptide bond, and mediates a bond between the first polymer and a drug or a biological substance.   The puncture device according to claim 1, wherein the first polymer has neither an amino group nor a peptide bond.   The puncture device according to claim 1 or 2, wherein the second polymer includes one or more selected from the group consisting of polylysine, polyhistidine, and polyethyleneimine.   The puncture device according to any one of claims 1 to 3, wherein the convex portion includes a convex main body made of the first polymer, and the second polymer is supported on a surface of the convex main body.   The puncture device according to any one of claims 1 to 4, further comprising the drug, wherein the drug is bonded to the first polymer via the second polymer.   Forming a convex portion supported by a support and including a first polymer that is a thermoplastic resin and a second polymer different from the first polymer, wherein the second polymer has an amino group and a peptide bond A method for producing a puncture device, wherein the second polymer has at least one of the following: mediation of binding between the first polymer and a drug or biological substance.   The puncture device manufacturing method according to claim 6, wherein the first polymer has neither an amino group nor a peptide bond.   The puncture device manufacturing method according to claim 6 or 7, wherein the second polymer includes one or more selected from the group consisting of polylysine, polyhistidine, and polyethyleneimine.   The method of manufacturing a puncture device according to any one of claims 6 to 8, wherein the step of forming the protrusion includes attaching the second polymer to a protrusion main body made of the first polymer.   The method of manufacturing a puncture device according to claim 9, wherein the step of forming the convex portion further includes performing oxygen plasma treatment on the convex body before attaching the second polymer to the convex body. .   The puncture device according to any one of claims 6 to 10, further comprising a step of bonding the drug to the first polymer through the second polymer by supplying the drug to the convex portion. Production method.