Needle assembly for transdermal administration and method of producing the same

A needle assembly for transdermal administration including a substrate having a first surface and a second surface opposite to the first surface, and fine needles projecting perpendicularly from the first surface. The substrate has grooves on at least one of the first surface and the second surface, and the grooves are formed such that the substrate is deformable following a surface shape of a skin to allow axes of the fine needles to extend in a direction normal to the surface of the skin.

BACKGROUND OF THE INVENTION

Field of the Invention

The present invention relates to a needle assembly for transdermal administration and a method of producing the same. In particular, the invention relates to a needle assembly for transdermal administration, in which a plurality of fine needles are integrally formed in the front surface of a substrate, and a method of producing the same.

Discussion of the Background

Percutaneous absorption is a method of delivering medicines into the body by osmosis through the skin. Percutaneous absorption is used as a convenient method for painless medication administration; however, percutaneous absorption is difficult for some types of medicines. Recent attention has focused on a method of allowing the body to absorb such medicines efficiently. This method involves piercing the skin with a micron-size fine needle body (i.e., a microneedle) and directly administering medicines into the skin. This method eliminates the need for using conventional syringes, thus simplifying the administration of medicines into the skin (see PTL 1). Such a fine needle body is required to have a thinness and a tip angle sufficient to pierce the skin, and a length sufficient for subcutaneous delivery of a liquid medicine. The needle body preferably has a conical shape whose diameter ranges from several micrometers to some hundreds of micrometers, and whose length ranges from some tens of micrometers to some hundreds of micrometers for the needle body to penetrate the horny layer, which is the outermost layer of the skin, but not to reach nerve cells.

Specifically, the needle body is required to penetrate the horny layer, which is the outermost skin layer having a thickness of about 20 μm, although the thickness of the horny layer depends on parts of the skin. Beneath the horny layer is the epidermis having a thickness ranging from about 200 μm to 350 μm, and beneath the epidermis is the dermis housing an extensive network of capillaries. This structure requires a needle to have a length of at least 20 μm to penetrate the horny layer so that a liquid medicine is permeated. In producing a needle body for blood sampling, the needle body is required to be designed with a length of at least 350 μm, considering the above-described skin structure.

The material for the needle body needs to be harmless to the human body even if a broken piece of the needle body remains in the human body. As such materials, biocompatible resins such as a medical silicone resin, maltose, polylactic acid, and dextran are considered to be suitable (see PTL 2).

Some mechanisms for administering medicines into the body have been proposed. In one mechanism, a medicine is applied to the surface of a needle and the skin is pierced with this needle to thereby administer the medicine. In another mechanism, a hollow needle or a needle body having fine holes for passage of a liquid medicine is used to administer a liquid medicine from a substrate surface attached to the body (see PTL 3).

A method of improving the performance of a needle body in the administration of medicines is described in PTL 4. According to this method, grooves are formed in a side surface of the needle portion to assist delivery of compounds.PTL 1: U.S. Pat. No. 6,183,434 B1PTL 2: JP-A-2005-021677PTL 3: JP-A-2001-309977PTL 4: JP-A-2004-516868

SUMMARY OF THE INVENTION

According to an aspect of the present invention, a needle assembly for transdermal administration including a substrate having a first surface and a second surface opposite to the first surface, and fine needles projecting perpendicularly from the first surface. The substrate has grooves on at least one of the first surface and the second surface, and the grooves are formed such that the substrate is deformable following a surface shape of a skin to allow axes of the fine needles to extend in a direction normal to the surface of the skin.

According to another aspect of the present invention, a method of producing a needle assembly for transdermal administration, includes producing an original plate which includes a substrate-forming part and has, on a surface of the substrate-forming part, a needle-forming part and a groove-forming part, forming a reproduction plate based on the original plate such that the reproduction plate includes a flat part corresponding to the substrate-forming part, a recess corresponding to the needle-forming part, and a linear projection corresponding to the groove, placing a polymer material on a surface of the reproduction plate having the flat part, the recess, and the linear projection, heating the polymer material such that the polymer material is melted, pressing melted polymer material by a press including a flat surface portion facing the flat part and a projecting portion formed in the flat surface portion which extends in a direction parallel to or perpendicular to a direction in which the groove-forming part extends, curing the polymer material such that a needle assembly is formed, and releasing the needle assembly from the reproduction plate to obtain the needle assembly including fine needles and a substrate having a groove formed such that the substrate is deformable following a surface shape of a skin.

DESCRIPTION OF THE EMBODIMENTS

Embodiment

With reference toFIGS. 1-2(b), an embodiment of a needle assembly for transdermal administration101will now be described.

As illustrated inFIG. 1, the needle assembly101of the present embodiment includes a substrate102. One surface of the substrate102in a thickness direction is a front surface102a, and the other surface of the substrate102in the thickness direction is a rear surface102b. The front surface102ais an example of the first surface, and the rear surface102bis an example of the second surface. The needle assembly101includes a plurality of fine needles103projecting perpendicularly from the front surface102aand arranged in a matrix at regular intervals along longitudinal and lateral directions of the front surface102a.

The fine needles103of the needle assembly101according to the present embodiment have a height H which preferably ranges from 50 μm to 2000 μm, inclusive. More preferably, the height H of the fine needles103in the needle assembly101according to the present embodiment preferably ranges from 50 μm to 1000 μm, inclusive. The height H of each fine needle103is defined as a distance from the front surface102aof the substrate102to the tip of the fine needle103.

As illustrated inFIG. 2 (a), a group of fine needles103disposed in the longitudinal direction of the front surface102ais defined as one column, and a group of fine needles103disposed in the lateral direction of the front surface102ais defined as one row. The front surface102aof the substrate102includes a plurality of first linear grooves104aeach formed along the column direction of fine needles103and located between adjacent columns of fine needles103so as to extend along the entire length of the substrate102in the longitudinal direction. That is, the first grooves104aeach extend in the longitudinal direction, which is an example of the first direction, and are arranged in the lateral direction, which is an example of the second direction perpendicular to the longitudinal direction.

The front surface102aof the substrate102further includes a plurality of second grooves104beach formed along the row direction of fine needles103and located between adjacent rows of fine needles103so as to extend along the entire length of the substrate102in the lateral direction and thus to cross the first grooves104a. That is, the second grooves104bextend in the lateral direction, which is an example of the first direction, and are arranged in the longitudinal direction, which is an example of the second direction that intersects the lateral direction.

As illustrated inFIG. 2 (b), the rear surface102bof the substrate102includes a plurality of linear third grooves105aeach formed along the column direction of fine needles103so as to extend along the entire length of the rear surface102bin the longitudinal direction. That is, the third grooves105aextend in the longitudinal direction, which is an example of the third direction, and are arranged in the lateral direction, which is an example of the fourth direction perpendicular to the longitudinal direction.

The rear surface102bof the substrate102includes a plurality of linear fourth grooves105beach formed along the row direction of fine needles103so as to extend along the entire length of the substrate102in the lateral direction and thus to cross the third grooves105a. That is, the fourth grooves105bextend in the lateral direction, which is an example of the fourth direction, and are arranged in the longitudinal direction, which is an example of the fourth direction that intersects the lateral direction.

The positions of the grooves105aand105bin the rear surface102bare offset from those of the grooves104aand104bin the front surface102aas seen perpendicular to the front surface102a.

In the above-configured needle assembly101, the front surface102aof the substrate102has fine needles103each positioned in a surface portion surrounded by the first and second grooves104aand104bextending, respectively, along the column direction and row direction. In the rear surface102bof the substrate102, the third grooves105aextending along the column direction intersect the fourth grooves105bextending along the row direction. The fine needles103in the front surface102aare located at positions corresponding to the respective intersections of the third and fourth grooves105aand105bin the rear surface102b.

The first, second, third, and fourth grooves104a,104b,105a, and105beach have a trapezoidal cross section perpendicular to the directions in which the grooves extend. The cross-sectional shape of the first grooves104and the second grooves105is not limited to the trapezoidal shape illustrated inFIG. 14 (a), but may be rectangular, triangular, semicircular, semielliptical as illustrated inFIGS. 14 (b)to14(d), respectively, or any combination thereof. That is, the plurality of grooves in each surface of the substrate102may include at least one type of grooves selected from among rectangular cross section grooves, triangular cross section grooves, semicircular cross section grooves, and semielliptical cross section grooves.

The grooves may have any dimensions, but their width W preferably ranges from 50 μm to 1000 μm, inclusive, and more preferably, from 100 μm to 300 μm, inclusive. The grooves have a depth D which preferably ranges from 50 μm to 1000 μm, inclusive, and more preferably, from 100 μm to 300 μm, inclusive.

The first grooves104are constituted by the first grooves104aand the second grooves104b, while the second grooves105are constituted by the third grooves105aand the fourth grooves105b.

In the above-configured needle assembly101, the first and second grooves104aand104bare formed in the front surface102aof the substrate102, and the third and fourth grooves105aand105bare formed in the rear surface102bof the substrate102. This structure allows the needle assembly101to bend following a curved surface shape assumed by a skin106aof a body106, as illustrated inFIG. 3. This, in turn, allows a vertical axis L1of each of the fine needles103to be displaced in a direction coinciding with the line normal to the curved surface of the skin106aof the body106.

The line normal to the curved surface of the skin of the body106is a straight line perpendicular to a tangent plane to the curved surface at a given point of the curved surface of the skin.

In the above-configured needle assembly101according to the embodiment, the front surface portion of the substrate102, that is, the front surface102a, has the first grooves104aand the second grooves104bextending, respectively, along the column direction and row direction, so as to form grooves in a matrix. The rear surface portion of the substrate102, that is, the rear surface102b, has the third grooves105aand the fourth grooves105bextending, respectively, along the column direction and row direction, so as to form grooves in a matrix. The substrate102is thus thinner at the groove segments formed in a matrix than in the remaining portions, allowing the substrate102to be easily deformed for bending.

This structure allows the substrate102to deform following a surface shape of the skin of the body, thus improving the ability of the needle assembly for transdermal administration to follow the skin. This, in turn, allows the vertical axis of the fine needles103to be displaced in a direction coinciding with the line normal to the surface of the skin of the body, thus allowing the needle assembly for transdermal administration to be highly flexible. The flexible substrate enables all the fine needles to pierce the skin uniformly, thus increasing the amount of a substance containing a medicine to be delivered into the skin.

The embodiment may be modified as appropriate in the following way. The plurality of grooves in the front surface102amay extend in the diagonal direction of the front surface102a, that is, a direction crossing the longitudinal and lateral directions of the front surface102a.

The plurality of grooves in the front surface102amay include at least two types of grooves selected from among grooves extending in the longitudinal direction, grooves extending in the lateral direction, and grooves extending in the diagonal direction.

The plurality of grooves in the rear surface102bmay extend in the diagonal direction of the rear surface102b, that is, a direction crossing the longitudinal and lateral directions of the rear surface102b.

The plurality of grooves in the rear surface102bmay include at least two types of grooves selected from among grooves extending in the longitudinal direction, grooves extending in the lateral direction, and grooves extending in the diagonal direction.

With reference to the accompanying drawings, description will now be given of modifications in the arrangements of the grooves formed in the substrate of the needle assembly for transdermal administration according to the present embodiment.

First Modification

A needle assembly301according to a modification illustrated inFIG. 4includes a substrate302and a plurality of fine needles303projecting perpendicularly from a front surface302a, which is one surface of the substrate302in a thickness direction, and arranged in a matrix at regular intervals along longitudinal and lateral directions of the front surface302a. A group of fine needles303disposed in the longitudinal direction of the front surface302ais defined as one column, and a group of fine needles303disposed in the lateral direction of the front surface302ais defined as one row.

The front surface302aincludes a plurality of linear grooves304aeach formed along the column direction of fine needles303and located between adjacent columns of fine needles303so as to extend along less than the entire length of the front surface302ain the longitudinal direction. The front surface302afurther includes a plurality of linear grooves304beach formed along the row direction of fine needles303and located between adjacent rows of fine needles303so as to extend along less than the entire length of the front surface302ain the lateral direction and thus to cross the grooves304a.

The grooves304aand304ballow the substrate302to easily deform following a surface shape of the skin of the body. The lengths of the grooves304aand304bare designed to be less than the lengths of the front surface302ain the longitudinal and lateral directions, respectively, so that the lengths of the grooves304aand304bare less than the lengths of the front surface302aof the substrate302in the longitudinal and lateral directions, respectively. This configuration makes the substrate302suitable for a needle assembly for transdermal administration, which is used for a three-dimensionally curved skin surface of the body.

In the modification illustrated inFIG. 4, the grooves in the rear surface of the substrate302, which is the other surface of the substrate302in the thickness direction, may be omitted. Alternatively, grooves similar to those in the front surface302aof the substrate302may be formed such that the positions of the grooves in the front surface302aand the rear surface are offset from each other along the row and column direction.

In other words, the positions of the grooves in the rear surface may be offset from those of the grooves in the front surface302aas seen perpendicular to the front surface302a. For example, the rear surface of the substrate302may be formed with grooves described below. Specifically, the rear surface may include a plurality of grooves extending along less than the entire length of the rear surface in the longitudinal direction, and are offset from the grooves304ain the lateral direction, as seen perpendicular to the front surface302aof the substrate302. The rear surface may further include a plurality of grooves extending along less than the entire length of the rear surface in the lateral direction, and are offset from the grooves304bin the longitudinal direction, as seen perpendicular to the front surface302aof the substrate302.

Second Modification

The needle assembly401according to a modification illustrated inFIG. 5includes a substrate402and a plurality of fine needles403projecting perpendicularly from a front surface402a, which is one surface of the substrate402in a thickness direction, and arranged in a matrix at regular intervals along longitudinal and lateral directions of the front surface402a. A group of fine needles403disposed in the longitudinal direction of the front surface402ais defined as one column, and a group of fine needles403disposed in the lateral direction of the front surface402ais defined as one row.

The front surface402ahas a plurality of discontinuous grooves404aeach formed along the column direction of fine needles403and located between adjacent columns of fine needles403so as to extend along the entire length of the front surface402ain the longitudinal direction, with the discontinuous grooves404aeach separated at positions each facing fine needles403. The front surface402afurther has a plurality of discontinuous grooves404beach formed along the row direction of fine needles403and located between adjacent rows of fine needles403so as to extend along the entire length of the front surface402ain the lateral direction, with the discontinuous grooves404beach separated at positions each facing fine needles403. The positions facing fine needles403refers to positions at each of which a first groove104aofFIG. 2(a)extending in the longitudinal direction crosses a second groove104bofFIG. 2(a)extending in the lateral direction.

The discontinuous grooves404aand404ballow the substrate402to easily deform following a surface shape of the skin of the body. The needle assembly401including the discontinuous grooves404aand404bachieves an advantageous effect similar to that exerted by the grooves illustrated inFIGS. 1-2(b).

The discontinuous grooves404aand404bare constituted by a plurality of groove segments. Preferably, each groove segment has a maximum length L of 200 μm or more in the front surface402aof the substrate402.

In the modification illustrated inFIG. 5, the grooves in the rear surface of the substrate402, which is the other surface of the substrate402in the thickness direction, may be omitted. Alternatively, grooves similar to those in the front surface402aof the substrate402may be formed in the rear surface, such that the positions of the grooves in the front surface402aand the rear surface are offset from each other along the row and column direction.

For example, the rear surface of the substrate402may be formed with grooves described below. The rear surface of the substrate402may include a plurality of discontinuous grooves extending in the longitudinal direction of the rear surface and being offset from the discontinuous grooves404ain the lateral direction, and include a plurality of discontinuous grooves extending in the lateral direction and being offset from the discontinuous grooves404bin the longitudinal direction, as seen perpendicular to the front surface402aof the substrate402.

Third Modification

The needle assembly501according to a modification illustrated inFIG. 6includes a substrate502and a plurality of fine needles503projecting perpendicularly from a front surface502a, which is one surface of the substrate502in a thickness direction, and arranged in a matrix at regular intervals along longitudinal and lateral directions of the front surface502a. With a group of fine needles503disposed in the longitudinal direction of the front surface502abeing defined as one column, the front surface502aincludes a plurality of grooves504each formed along the column direction of fine needles503and located between adjacent columns of fine needles503so as to extend along the entire length of the front surface502ain the longitudinal direction.

The grooves504allow the substrate502to easily deform following a surface shape of the skin of the body. The needle assembly501including the grooves504achieves an advantageous effect similar to that exerted by the grooves illustrated inFIGS. 1-2(b).

In the modification illustrated inFIG. 6, the grooves in the rear surface of the substrate502, which is the other surface of the substrate502in the thickness direction, may be omitted. Alternatively, grooves similar to those in the front surface502aof the substrate502may be formed such that the positions of the grooves in the front surface502aand the rear surface are offset from each other along the row direction.

For example, the rear surface of the substrate502may include a plurality of grooves extending in the longitudinal direction of the rear surface and being offset from the grooves504in the lateral direction, as seen perpendicular to the front surface502aof the substrate502.

Fourth Modification

The needle assembly601according to a modification illustrated inFIG. 7includes a substrate602and a plurality of fine needles603projecting perpendicularly from the front surface602a, which is one surface of the substrate602in a thickness direction, and arranged in a matrix at regular intervals along longitudinal and lateral directions of the front surface602a. A group of fine needles603disposed in the longitudinal direction of the front surface602ais defined as one column, and a group of fine needles603disposed in the lateral direction of the front surface602ais defined as one row.

The front surface602aincludes a plurality of linear grooves604aeach formed along the column direction of fine needles603and located between adjacent columns of fine needles603so as to extend in the longitudinal direction of the front surface602a, so that adjacent linear grooves604aare spaced apart from each other by a distance corresponding to 2 spaces, which corresponds to a length along the row direction of two adjacent columns of fine needles603. The front surface602afurther includes a plurality of linear grooves604beach formed along the row direction of fine needles603and located between adjacent rows of fine needles603so as to extend in the lateral direction of the front surface602a, so that adjacent linear grooves604bare spaced apart from each other by a distance corresponding to 2 spaces, which corresponds to a length along the column direction of two adjacent rows of fine needles603.

That is, in the front surface602aof the substrate602, each groove604aextending in the longitudinal direction of the substrate602is disposed in a gap between two columns of fine needles603adjacent along the row, so that one groove604ais disposed every two columns. Each groove604bextending in the lateral direction of the substrate602is disposed in a gap between two rows of fine needles603adjacent along the column direction, so that one groove604bis disposed every two rows.

The grooves604aand604ballow the substrate602to easily deform following a surface shape of the skin of the body. The needle assembly601including the grooves604aand604bachieves an advantageous effect similar to that exerted by the grooves illustrated inFIGS. 1-2(b).

In the modification illustrated inFIG. 7, the grooves in the rear surface of the substrate602, which is the other surface of the substrate602in the thickness direction, may be omitted. Alternatively, grooves similar to those in the front surface602aof the substrate602may be formed in the rear surface, such that the positions of the grooves in the front surface602aand the rear surface are offset from each other along the row and column direction.

For example, the rear surface of the substrate602may be formed with grooves described below. Specifically, the rear surface of the substrate602may include a plurality of grooves extending in the longitudinal direction of the rear surface and being offset from the grooves604ain the lateral direction, and include a plurality of grooves extending in the lateral direction and being offset from the grooves604bin the longitudinal direction, as seen perpendicular to the front surface602aof the substrate602.

Fifth Modification

A needle assembly701according to a modification illustrated inFIG. 8includes a substrate702and a plurality of fine needles703projecting perpendicularly from a front surface702a, which is one surface of the substrate702in a thickness direction, and arranged in a matrix at regular intervals along longitudinal and lateral directions of the front surface702a. A group of fine needles703disposed in the longitudinal direction of the front surface702ais defined as one column, and a group of fine needles703disposed in the lateral direction of the front surface702ais defined as one row.

The front surface702aincludes a plurality of linear grooves704aeach formed along the column direction of fine needles703and located between adjacent columns of fine needles703so as to extend in the longitudinal direction of the front surface702a, so that adjacent linear grooves704aare spaced apart from each other by a distance corresponding to 3 spaces, which corresponds to a length along the row direction of three adjacent columns of fine needles703. The front surface702afurther includes a plurality of linear grooves704beach formed along the row direction of fine needles703and located between adjacent rows of fine needles703so as to extend in the lateral direction of the front surface702a, so that adjacent linear grooves704bare spaced apart from each other by a distance corresponding to 3 spaces, which corresponds to a length along the column direction of three adjacent rows of fine needles603.

That is, in the front surface702aof the substrate702, each groove704aextending in the longitudinal direction of the substrate702is disposed in a gap between two columns of fine needles703adjacent along the row direction, so that one groove704ais disposed every three columns. Each groove704bextending in the lateral direction of the substrate702is disposed in a gap between two rows of fine needles703adjacent along the column direction, so that one groove704bis disposed every three rows.

The fifth modification in the arrangement of the grooves achieves an effect similar to that exerted by the grooves illustrated inFIGS. 1-2(b).

In the modification illustrated inFIG. 8, the grooves in the rear surface of the substrate702, which is the other surface of the substrate702in the thickness direction, may be omitted. Alternatively, grooves similar to those in the front surface702aof the substrate702may be formed such that the positions of the grooves in the front surface702aand the rear surface are offset from each other along the row and column direction.

For example, the rear surface of the substrate702may be formed with grooves described below. Specifically, the rear surface of the substrate702may include a plurality of grooves extending in the longitudinal direction of the rear surface and being offset from the grooves704ain the lateral direction, and include a plurality of grooves extending in the lateral direction and being offset from the grooves704bin the longitudinal direction, as seen perpendicular to the front surface702aof the substrate702.

With reference to the accompanying drawings, description will now be given of other exemplary arrangements of the grooves in the needle assembly for transdermal administration according to the present embodiment.

Second Exemplary Arrangement

As with the exemplary arrangement ofFIG. 2 (a), a needle assembly901according to an exemplary arrangement ofFIG. 9includes, as illustrated inFIG. 9 (a), a substrate902and a plurality of fine needles903projecting perpendicularly from a front surface902aof the substrate902and arranged in a matrix at regular intervals along longitudinal and lateral directions of the front surface902a. The front surface902aincludes a plurality of linear grooves904aeach formed along the column direction of fine needles903and located between adjacent columns of fine needles903disposed in the longitudinal direction so as to extend along the entire length of the substrate902in the longitudinal direction. The front surface902afurther includes a plurality of linear grooves904beach formed along the row direction of fine needles903and located between adjacent rows of fine needles903disposed in the lateral direction so as to extend along the entire length of the front surface902ain the lateral direction and thus to cross the grooves904a.

As illustrated inFIG. 9 (b), the rear surface902bof the substrate902is not formed with grooves that allow the substrate902to easily deform following a surface shape of the skin of the body, unlikeFIG. 2 (b).

The needle assembly according to the second exemplary arrangement achieves an effect similar to that exerted by the grooves illustrated inFIGS. 1-2(b).

Third Exemplary Arrangement

As illustrated inFIG. 10 (a), a needle assembly1001according to an exemplary arrangement ofFIG. 10includes a substrate1002and a plurality of fine needles1003projecting perpendicularly from a front surface1002aof the substrate1002and arranged in a matrix at regular intervals along longitudinal and lateral directions of the front surface1002a.

As illustrated inFIG. 10 (b)and as with the exemplary arrangement ofFIG. 2 (b), a rear surface1002bof the substrate1002includes a plurality of linear third grooves1005aeach formed along the column direction of fine needles1003and extending along the entire length of the rear surface1002bin the longitudinal direction. The rear surface1002bof the substrate1002further includes a plurality of linear third grooves1005beach formed along the row direction of fine needles1003and extending along the entire length of the substrate1002in the lateral direction so as to cross the grooves1005a.

The needle assembly according to the third exemplary arrangement achieves an effect similar to that exerted by the grooves illustrated inFIGS. 1-2(b).

Fourth Exemplary Arrangement

As illustrated inFIG. 11 (a), a needle assembly1101according to an exemplary arrangement ofFIG. 11includes a substrate1102and a plurality of fine needles1103projecting perpendicularly from a front surface1102aof the substrate1102and arranged in a matrix at regular intervals along longitudinal and lateral directions of the front surface1102a. The front surface1102aincludes a plurality of linear grooves1104aeach formed along the column direction of fine needles1103and located between adjacent columns of fine needles1103disposed in the longitudinal direction so as to extend along the entire length of the substrate1102in the longitudinal direction. The front surface1102afurther includes a plurality of linear grooves1104beach formed along the row direction of fine needles1103and located between adjacent rows of fine needles1103disposed in the lateral direction so as to extend along the entire length of the front surface1102ain the lateral direction and thus to cross the grooves1104a.

As illustrated inFIG. 11 (b), a rear surface1102bof the substrate1102includes a plurality of first grooves1105aeach extending in a diagonal direction at an angle of 45° from upper left to lower right relative to the grooves1104ain the row direction and the grooves1104bin the column direction, and disposed parallel to each other at regular intervals in a direction perpendicular to the diagonal direction. The rear surface1102bincludes a plurality of second grooves1105beach extending in a direction perpendicular to the first grooves1105aand disposed parallel to each other at regular intervals in the perpendicular direction. Thus, the rear surface1102bof the substrate1102includes grooves formed in a matrix.

That is, the rear surface1102bincludes a plurality of first grooves1105aeach extending in the diagonal direction at an angle of 45° relative to the longitudinal and lateral directions and formed at regular intervals in the direction perpendicular to the diagonal direction as seen perpendicular to the front surface1102aof the substrate1102. The rear surface1102bincludes a plurality of second grooves1105beach extending in the direction perpendicular to the first grooves1105aand formed at regular intervals along the first grooves1105a.

The needle assembly according to the fourth exemplary arrangement achieves an effect similar to that exerted by the grooves illustrated inFIGS. 1-2(b).

Fifth Exemplary Arrangement

As illustrated inFIG. 12 (a), a needle assembly1201according to an exemplary arrangement ofFIG. 12includes a substrate1202and a plurality of fine needles1203projecting perpendicularly from a front surface1202aof the substrate1202and arranged in a matrix at regular intervals along longitudinal and lateral directions of the front surface1202a. With a group of fine needles1203disposed in the longitudinal direction of the front surface1202abeing defined as one column, the front surface1202aincludes a plurality of grooves1204each formed along the column direction of fine needles1203and located between adjacent columns of fine needles1203so as to extend in the longitudinal direction of the front surface1202a.

As illustrated inFIG. 12 (b), the rear surface1202bof the substrate1202includes a plurality of grooves1205each formed at a portion corresponding to a column of fine needles1203and each extending in the longitudinal direction of the rear surface1202balong the column direction of fine needles1203. That is, the rear surface1202bof the substrate1202includes the grooves1205each formed at a position corresponding to a column of fine needles1203and extending in the longitudinal direction as seen perpendicular to the front surface1202aof the substrate1202.

The needle assembly according to the fifth exemplary arrangement achieves an effect similar to that exerted by the grooves illustrated inFIGS. 1-2(b).

Sixth Exemplary Arrangement

As illustrated inFIG. 13 (a), a needle assembly1301according to an exemplary arrangement ofFIGS. 13(a) and 13(b)includes a substrate1302and a plurality of fine needles1303projecting perpendicularly from a front surface1302aof the substrate1302and arranged in a matrix at regular intervals along longitudinal and lateral directions of the front surface1302a. With a group of fine needles1303disposed in the longitudinal direction of the front surface1302abeing defined as one column, the front surface1302aincludes a plurality of grooves1304each formed along the column direction of fine needles1303and located between adjacent columns of fine needles1303so as to extend in the longitudinal direction of the front surface1302a.

As illustrated inFIG. 13 (b), a rear surface1302bof the substrate1302includes a plurality of grooves1305each formed at a portion corresponding to a row of fine needles1303and each extending in the lateral direction of the rear surface1302balong the row direction of fine needles1303so as to be perpendicular to the fine needles1304in the front surface. That is, the rear surface1302bof the substrate1302includes grooves1305each formed at a position corresponding to a row of fine needles1303and extending in the lateral direction as seen perpendicular to the front surface1302aof the substrate1302.

The needle assembly according to the sixth exemplary arrangement achieves an effect similar to that exerted by the grooves illustrated inFIGS. 1-2(b).

With reference toFIGS. 15(a)-15(d), description will now be given of a method of producing the needle assembly for transdermal administration according to the present embodiment.

The method of producing the needle assembly according to the present embodiment includes a step of preparing an original plate, a step of preparing a reproduction plate having a reversed pattern of the original plate, a step of forming a needle assembly, using the reproduction plate, and a step of releasing the needle assembly from the reproduction plate after the needle assembly has been cured.

<Step of Preparing Original Plate>

An original plate can be formed using an appropriate, known micromachining technique. For example, an original plate of the needle assembly for transdermal administration may be produced by (1) using micromachining such as grinding or cutting to a substrate, or (2) using micromachining such as lithography or etching.

The material used for the original plate can be selected according to the adopted processing method. For example, a silicon substrate can be used when the original plate is produced by grinding, and a brass substrate can be used when the original plate is produced by cutting.

As illustrated inFIG. 15 (a), an original plate201includes a substrate-forming portion201afor forming a substrate of a needle assembly for transdermal administration, and, in the upper surface of the forming substrate portion201a, a needle-forming portion201bfor forming a fine needle of the needle assembly for transdermal administration. The original plate201further includes a groove-forming portion201cfor forming a groove that allows the substrate of the needle assembly for transdermal administration to deform following a surface shape of the skin of the body, in the upper surface of the substrate-forming portion201a.

The groove-forming portion201cextends linearly in at least one direction between adjacent needle-forming portions201b. The groove-forming portions201ccan be formed using the method of producing the original plate. Each groove-forming portion201cformed between needle-forming portions201bmay have any width. However, considering workability, for example, the width of the groove-forming portion201cpreferably ranges from 50 μm to 1000 μm, inclusive, and more preferably, from 100 μm to 300 μm, inclusive. Each groove-forming portion201cformed in a substrate-forming portion201amay have any depth. However, considering workability, for example, the depth of the groove-forming portion201cpreferably ranges from 50 μm to 1000 μm, inclusive, and more preferably, from 100 μm to 300 μm, inclusive.

<Step of Preparing Reproduction Plate>

A reproduction plate can be formed using an appropriate, known micromachining technique. Specifically, after the original plate201has been formed, the upper surface of the original plate201is filled with a filling material for forming a reproduction plate, and then the filling material is released from the original plate201, to form a reproduction plate202illustrated inFIG. 15 (b). As illustrated inFIG. 15 (b), the upper surface of the reproduction plate202includes a flat portion202acorresponding to the substrate-forming portion201aof the original plate201, a recess202bcorresponding to the needle-forming portion201bof the original plate201, and a linear projection202ccorresponding to the groove-forming portion201cof the original plate201.

Any filling material can be selected for use in the formation of the reproduction plate202as long as it allows the reproduction plate202to have shape followability, durability, and releasability, and thus to function as a reproduction plate. For example, nickel and a thermosetting silicone resin may be used. When nickel is selected, plating, physical vapor deposition (PVD), or chemical vapor deposition (CVD) can be used as a method of forming the filling material.

<Step of Forming Needle Assembly using Reproduction Plate>

As illustrated inFIG. 15 (c), a polymer material203is placed on the surface of the reproduction plate202, the surface including the flat portion202a, recess202b, and projection202c. Then, the polymer material203is melted by heating, and the melted polymer material203is pressed with a press204, followed by curing to form a needle assembly as a molded product.

As illustrated inFIG. 15 (c), the press204includes a flat surface portion204afacing the flat portion202aof the reproduction plate202, and a projection204bformed on the flat surface portion204aso as to extend in a direction coinciding with or perpendicular to a direction in which the recess202bof the reproduction plate202extends. As illustrated inFIG. 15 (d), the projection204bis used for forming grooves207aand207bon, respectively, a front surface205aof a needle assembly205as a molded product and a rear surface205b, which is opposite to the front surface205a. The forming grooves207aand207ballow a substrate to deform following a surface shape of the skin of the body.

Nonlimiting examples of the polymer material203for forming a needle assembly as a molded product include biocompatible materials such as a medical silicone resin, and thermoplastic polymer materials such as polyglycolic acid, polylactic acid, and polycarbonate. These materials may be used to form a needle assembly applicable to the body. The use of a biocompatible material allows the needle assembly to be harmless even if a needle portion breaks off and remains in the body. The polymer material203may be a thermoplastic polymer material such as polyethylene resin, polypropylene resin, cyclic polyolefin resin, epoxy resin, polyamide resin, phenol resin, polystyrene resin, polycaprolactone resin, acrylic resin, urethane resin, aromatic polyether ketone, and epoxy resin. Such a thermoplastic polymer material is preferably used as the material for the needle assembly of the present embodiment.

Preferable methods of filling the reproduction plate202with the polymer material203include, but are not limited to, imprinting, hot embossing, and injection molding.

Preferably, the reproduction plate202is filled with a polymer material through pressing using a press or a mold. The material of the press can be selected as appropriate considering durability or workability. For example, when durability is considered, SUS303 can be used; when workability is considered, A5052 can be used.

Although the press204ofFIG. 15(c)is flat, a roller-shaped press can be used. In the present embodiment, the needle assembly can be produced through roll-to-roll processing, using a roller-shaped reproduction plate and a roller-shaped press.

The polymer material filled in the reproduction plate is cured by cooling. The polymer material can be cured using any method. For example, the reproduction plate may be blown with air and cooled, so that the polymer material is indirectly cured.

The material for forming the needle assembly of the present embodiment may be a water-soluble material. Examples of the water-soluble material include water-soluble polymer materials and polysaccharides. Nonlimiting examples of the water-soluble polymer materials and polysaccharides include chitosan, chitosan succinamide, hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), sodium chondroitin sulfate, dextran, curdlan, trehalose, sucrose, gelatin, collagen, pullulan, pectin, alginates, starch, methyl cellulose, hydroxypropylmethyl cellulose (HPMC), polyvinyl alcohol (PVA), polyacrylic acid polymer, polyacrylamide (PAM), and polyethylene oxide (PEO).

When a water-soluble material is used as the material for forming the needle assembly of the present embodiment, a method of producing the needle assembly may involve dissolving or dispersing the material for forming the needle assembly in a solvent such as water, to prepare a liquid material, and filling the liquid material in a reproduction plate. In that case, after the liquid material has been filled in the reproduction plate, the liquid material may be heated to dry and remove the solvent, followed by curing. Thus, the needle assembly can be produced.

<Step of Removing Cured Needle Assembly>

The needle assembly formed of the polymer material that has been cured by cooling is released from the reproduction plate to obtain a needle body. The needle assembly can be released by peeling using physical peeling force, or selective etching, for example.

To improve releasability of the needle assembly as a molded product from the reproduction plate, a release layer for enhancing the effect of releasing may be formed on a surface of the reproduction plate before a polymer material is filled in the reproduction plate. The release layer may be made of a fluoride resin.

The release layer can be preferably formed using a method of forming a thin film, such as PVD, CVD, spin coating, or dip coating.

The outline of the method of producing the needle body of the present embodiment has been described. However, other methods applicable to the respective steps may be used instead.

EXAMPLE

With reference toFIGS. 15 (a) to (d), a method of producing the needle assembly of the present embodiment will be described by way of an example. A ceramics substrate having a thickness of 5 mm was used as a substrate for forming an original plate.

The substrate was machined with a two-lip ball end mill having a 0.01 mm radius ball. The ball end mill as a cutting tool was mounted to an NC controlled XYZ-axis milling machine. The cutting depth of the cutting tool was increased to deeply carve a needle body as the cutting tool was revolved from the center of the needle body toward its perimeter, so that the needle body had a conical portion.

The number of revolutions of the ball end mill was set to 50000 rpm, and a feed rate was set to 0.1 mm/s. The cones formed by the machining were designed to have a bottom surface diameter of 280 μm, a pitch of 500 μm, and a depth of 450 μm. Portions with no fine needles were each uniformly cut to have a depth of 450 μm, so that vertexes of the fine needles had the greatest height on the substrate-forming portion201a. Likewise, as with the exemplary arrangement ofFIG. 2 (a), groove-forming portions201ceach having a width of 150 μm and a depth of 100 μm were formed in a longitudinal direction and a lateral direction, perpendicular to the longitudinal direction, of a front surface201dof the substrate-forming portion201a, with the front surface201dbeing exposed between adjacent needle-forming portions201b. As a result of the process, an original plate201was produced (FIG. 15 (a)).

The original plate201produced as described above was observed using a scanning electron microscope (SEM). As a result of the observation, the formation of needle-forming portions201band groove-forming portions201cwere confirmed. The needle-forming portions201beach were a conical projection having a width of 280 μm at its base, a height of 445 μm, and a tip angle of 35°. The groove-forming portions201ceach had a width of 150 μm and a depth of 100 μm. Further, it was confirmed that 25 needle-forming portions201bwere formed in a square lattice with a pitch of 500 μm.

Then a silicone resin as a filling material was filled in the original plate201, and the filling material was subjected to thermosetting treatment at 100° C. for 1 hour in a clean oven. Then, the filling material was released from the original plate to produce the reproduction plate202formed of the silicone resin (FIG. 15 (b)).

Then, a needle assembly for transdermal administration was produced by imprinting. Polyglycolic acid as the polymer material203was placed on the reproduction plate202, and then the polymer material was heated and melted using a hot plate set to 250° C. Then, the polymer material203was pressed with the press204so as to be filled in the reproduction plate202. The material of the press204was SUS303. The projection202cof the reproduction plate202allows the front surface of the polymer material203, which was polyglycolic acid, to be formed with grooves203ahaving a width of 150 μm and a depth of 100 μm in a longitudinal direction and a lateral direction, perpendicular to the longitudinal direction, of the front surface (FIG. 15(c)).

Lastly, the polymer material203was released from the reproduction plate202. As a result of the SEM observation, the formation of a needle assembly for transdermal administration205was confirmed. The needle assembly205included conical fine needles206made of polyglycolic acid and having a diameter of 280 μm at its base, a height of 445 μm, and a tip angle of 35°. It was confirmed that the front surface205aof the needle assembly205was formed with grooves207aeach positioned between adjacent fine needles206and having a width of 150 μm and a depth of 100 μm. The grooves207awere formed in a longitudinal direction and a lateral direction, perpendicular to the longitudinal direction, of the front surface205a. The rear surface205bof the needle assembly205was also confirmed to be formed with grooves207beach having a width of 150 μm and a depth of 100 μm in a longitudinal direction and a lateral direction, perpendicular to the longitudinal direction, of the front surface205a. The fine needles206, which were 25 in all, were arranged in a square lattice with a pitch of 495 μm (FIG. 15 (d)). The size of the substrate of the needle assembly205was 5 cm×5 cm, and its thickness was 500 μm.

To confirm that the needle assembly for transdermal administration according to the present embodiment increases the amount of medicines delivered, a needle assembly for transdermal administration was additionally prepared which was of the same design except that it had no grooves, and the two types of needle assemblies for transdermal administration were pierced into a swine skin, to compare the number of piercing scars. To observe the piercing of fine needles into the swine skin, these fine needles were stained with a blue ink in advance. The test showed that 25 piercing scars equal in number to the fine needles were formed in the swine skin into which the needle assembly with grooves was pierced, whereas 18 piercing scars were formed in a swine skin into which the needle assembly without grooves was pierced. These results confirmed that the present embodiment increases the amount of medicines delivered.

The needle assembly for transdermal administration according to the present embodiment achieves greater effects as the substrate of the needle assembly increases in size. This is because as the substrate of the needle assembly increases in size, greater flexibility is required for the needle assembly to allow the substrate to follow the skin. The needle assembly according to the present embodiment is preferably applied to a needle assembly having a substrate which is 4 cm2or more.

The needle assembly for transdermal administration according to the present embodiment achieves greater effects as the substrate of the needle assembly increases in thickness. This is because as the substrate of the needle assembly increases in thickness, flexibility decreases in the needle assembly. The needle assembly according to the present embodiment is preferably applied to a needle assembly having a substrate with a thickness of 200 μm or more.

The needle assembly for transdermal administration according to the present embodiment achieves greater effects when the substrate and fine needles of the needle assembly are made of a thermoplastic polymer material. This is because as the size of the substrate increases, flexibility decreases in the needle assembly formed of a thermoplastic polymer material.

When a needle body having grooved needle portions is used as described in PTL 4, it is difficult for all the needles of the needle body to pierce the skin uniformly, rendering such a needle body inappropriate for assisting the delivery of medicines into the body. This difficulty comes from the fact that the skin has an uneven surface, and a substrate of the needle body is insufficiently flexible for the needle body to pierce the skin.

An aspect of the present invention is to provide a needle assembly for transdermal administration, in which a substrate having a plurality of fine needles capable of piercing the skin is formed to flexibly deform following a surface shape of the skin of the body, and a method of producing the same.

To overcome the problem, the needle assembly for transdermal administration includes a substrate having a first surface and a second surface opposite to the first surface, and a plurality of fine needles projecting perpendicularly from the first surface. The substrate has a plurality of grooves formed in at least one of the first surface and the second surface. The plurality of grooves are formed to allow the substrate to deform following a surface shape of the skin of the body, such that axes of the fine needles are each displaced in a direction coinciding with a direction of the line normal to the surface of the skin of the body.

In the needle assembly for transdermal administration, the fine needles are arranged in a matrix at regular intervals along longitudinal and lateral directions of the first surface. The plurality of grooves include a plurality of grooves formed in the first surface so as to extend in a first direction between adjacent ones of the fine needles, and to be arranged in a second direction perpendicular to the first direction. The first direction preferably includes at least one of the longitudinal direction, the lateral direction, and a diagonal direction of the first surface.

In the needle assembly for transdermal administration, the plurality of grooves include a plurality of grooves formed in the second surface so as to extend in a third direction, and to be arranged in a fourth direction perpendicular to the third direction. The third direction includes at least one of a longitudinal direction, a lateral direction, and a diagonal direction of the second surface. The positions of the plurality of grooves in the second surface may be offset from the positions of the grooves in the first surface as seen perpendicular to the first surface.

In the needle assembly for transdermal administration, the plurality of grooves may include one type of grooves selected from among grooves each having a trapezoidal cross section, grooves each having a rectangular cross section, grooves each having a triangular cross section, grooves each having a semicircular cross section, and grooves each having a semielliptical cross section, the cross sections being perpendicular to a direction in which the grooves extend.

To overcome the problem, a method of producing the needle assembly for transdermal administration according to an embodiment of the present invention includes a substrate and a plurality of fine needles formed in one surface of the substrate so as to project perpendicularly from the one surface. This method includes a step of producing an original plate of the needle assembly for transdermal administration, such that the original plate includes a substrate-forming portion for forming the substrate, and includes, in the upper surface of the substrate-forming portion, a needle-forming portion for forming the fine needles and a groove-forming portion for forming a groove that allows the substrate to deform following a surface shape of the skin of the body, and a step of forming a reproduction plate that includes a flat portion corresponding to the substrate-forming portion, a recess corresponding to the needle-forming portion, and a linear projection corresponding to the groove, based on the original plate. The method of producing the needle assembly for transdermal administration includes a step of heating a polymer material to melt the polymer material after the polymer material has been placed on a surface of the reproduction plate, the surface including the flat portion, the recess, and the projection, a step of pressing the polymer material melted in the heating step, using a press including both a flat surface portion facing the flat portion and a projection formed in the flat surface portion so as to extend in a direction coinciding with or perpendicular to a direction in which the groove-forming portion extends, followed by curing to form a needle assembly, and a step of releasing the cured needle assembly from the reproduction plate.

According to the method of producing the needle assembly for transdermal administration, the polymer material is preferably a biocompatible, thermoplastic resin.

According to the needle body of the present invention and a method of producing the same, a substrate having a plurality of fine needles capable of piercing the skin flexibly deforms following a surface shape of the skin of the body.

INDUSTRIAL APPLICABILITY

Besides medical fields, the method of producing the needle assembly for transdermal administration can be applied in a variety of fields in which a needle assembly for transdermal administration is used. For example, the method is useful in producing a needle assembly for transdermal administration for use in drug development, cosmetics, and beauty applications.

REFERENCE SIGNS LIST

101: Needle assembly for transdermal administration,102: Substrate,103: Fine needle,104: First groove,105: Second groove,104a: First groove,104b: Second groove,105a: Third groove,105b: Fourth groove,201: Original plate,202: Reproduction plate,203: Polymer material,204: Press,205: Needle assembly for transdermal administration
Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein.