JP6269111B2 - Microneedle and microneedle array - Google Patents

Description

  The present invention relates to a microneedle and a microneedle array used in a drug delivery system (DDS), in particular, a trans-dermal therapeutic system (TTS) for administering a drug or the like into the body through the skin. .

  The drug administration method using the transdermal absorption system has less pain and less invasiveness to the human body than injections, less burden on the digestive tract and liver than oral agents, and does not receive the first-pass effect, In addition, there are conveniences such as being able to transport a drug at a constant concentration into the body for a long period of time. Since the skin of the human body originally has a biological barrier function that protects against the invasion of foreign substances, even when a polymer drug (for example, insulin or vaccine antigen) is administered transdermally, it is hardly transported into the body.

  The microneedle method is one of transdermal absorption systems. A microneedle array used in the microneedle method is generally formed by arranging a plurality of microneedles having a cone or pyramid shape and a height of several hundred μm. The surface of the needle is coated with a drug, or the needle is impregnated with the drug. When the tip of the microneedle pierced through the skin penetrates the stratum corneum, the drug dissolved in the dermal tissue is transported into the body. The pain is hardly felt because the needle does not reach the nerve in the procedure.

  At the beginning of the development of the microneedle method in medicine, microneedles were manufactured from metal materials such as titanium. In recent years, the development of micro electro mechanical systems (MEMS) using ultraviolet light or electron beam photolithography, etc., and that it is possible to produce at low cost and in large quantities using such photolithography technology. For this reason, research on a method for producing a microneedle array using single crystal silicon as a material is underway (see, for example, Patent Document 1).

  On the other hand, microneedles also have a risk of remaining inside the skin due to breakage. Therefore, a percutaneous absorption agent made of an in-vivo soluble polymer that can be gradually released into the body by self-dissolution within the skin has been proposed (for example, see Patent Documents 2 and 3). Patent Document 2 discloses a percutaneous absorption preparation in which a needle-like base material holding a target substance is composed of a polymer such as sodium chondroitin sulfate and hyaluronic acid. Patent Document 3 discloses a microneedle array in which the needle material is made of low molecular collagen and hyaluronic acid. Each microneedle is in the shape of a cone, a truncated cone or a cone, and has a suitable mechanical strength that can be punctured without breaking into the stratum corneum. The frustoconical microneedle described in Patent Document 3 is filled with a biodegradable material aqueous solution in a mold (mold mold) having a recess corresponding to the frustoconical, and is peeled off from the mold after water is evaporated by heating. It is molded by

  The needle shape of the medical microneedle is generally a cone or pyramid as described above. However, for example, Patent Document 4 discloses a microdevice for transdermal delivery of a drug, called a microblade or a microknife, in which straight blades are arranged in parallel.

Patent No. 3521205 Japanese Patent No. 4913030 Japanese Patent No. 4276691 Special table 2010-502268 gazette

  Conventionally, an applicator is used when applying a microneedle to the skin. The applicator is a medical instrument for uniformly piercing the skin with microneedles. If the microneedles are punctured unevenly into the skin, a predetermined amount of drug cannot be sufficiently transdermally delivered, and in some cases, pain may be caused.

  The present invention provides a microneedle or a microneedle array that can puncture the skin uniformly and safely without using an applicator, for example, and supports simple transdermal delivery of a drug by the patient himself / herself. It is aimed.

The present invention relates to a microneedle for transdermal delivery of a medicine , comprising a skirt and a needle protruding from the skirt in the puncturing direction, and the needle has two inclined surfaces forming an acute angle with each other. The ridgeline of the blade where the two inclined surfaces of the needle portion intersect at an acute angle is a microneedle formed in a knife edge shape having the highest blade edge at the center of the ridgeline .

In the microneedle, it is preferable that the cutting edge is formed in a linear shape or a curved shape having a certain length .

In the microneedle, the dimensional ratio H: L between the height H in the puncture direction and the length L in the ridge line direction of the blade is preferably 2: 3 to 5: 6, and is 3: 4. More preferably. The dimensional ratio W: L between the width W in the direction perpendicular to the edge of the blade and the length L in the direction of the edge of the blade is preferably 1: 4 to 1: 3, and preferably 3:10. Is more preferable.

  The microneedles are preferably made of metal, silicon, a resin such as polyamide or polyester, or a biodegradable material. However, the microneedle is more preferably a biodegradable material because it may remain inside the skin due to breakage of the needle. More preferably, the microneedles are formed of a biodegradable material containing glycosaminoglycan as a main component and a water-soluble polymer other than glycosaminoglycan as a subcomponent.

  The glycosaminoglycan is chondroitin, chondroitin sulfate, dermatan sulfate, heparan sulfate, heparin, keratan sulfate or hyaluronic acid, preferably chondroitin, chondroitin sulfate or hyaluronic acid.

  The microneedle may be formed of a biodegradable material including the glycosaminoglycan and a water-soluble polymer containing at least one of dextran, gelatin, collagen, low molecular collagen, polyvinylpyrrolidone, or polyethylene glycol. preferable.

  Further, the present invention is a microneedle array in which a plurality of the microneedles are arranged.

  According to the present invention, it is possible to puncture the skin uniformly and safely without using, for example, an applicator, thereby supporting simple percutaneous delivery of a medicine by the patient himself / herself.

FIG. 1 is a plan view of a microneedle having a knife edge shape as viewed from the blade edge side. FIG. 2 is a side view of the microneedle as viewed from the direction A shown in FIG. FIG. 3 is a side view of the microneedle as viewed from the B direction shown in FIG. 1. FIG. 4 is a perspective view of the microneedle array. FIG. 5 is a diagram for explaining a process for producing a biodegradable microneedle array. FIG. 6 is a model diagram of a test apparatus for evaluating the puncture property of the microneedle array. FIG. 7 is a graph showing the relationship between displacement and load by the biodegradable microneedle array of the example. FIG. 8 is a graph showing, as a reference example, the relationship between displacement and load due to the Si microneedle array. FIG. 9 is a diagram showing an image of the surface of the porcine excision skin after the biodegradable microneedle array is punctured and stained in the porcine excision skin. FIG. 10 is a diagram showing an image of the surface of the porcine excision skin after puncturing the porcine excision skin with a truncated cone-shaped biodegradable microneedle array.

  The microneedle for transdermal delivery of a drug according to an embodiment of the present invention has a knife edge shape. FIG. 1 is a plan view of a microneedle 1 having a knife edge shape as viewed from the blade tip 4 side. FIG. 2 is a side view of the microneedle 1 when viewed from the direction A shown in FIG. FIG. 3 is a side view of the microneedle 1 when viewed from the B direction shown in FIG. 1. Here, the “knife edge shape” refers to a shape having a blade edge at the center of a ridge line of a sharp blade of a knife, and the ridge line bent to the left and right around the blade edge. That is, the knife-needle-shaped microneedle 1 forms a ridge line 5 of the blade at a position where the slopes 6 and 7 of the knife intersect each other at an acute angle, and has the highest cutting edge 4 at the center of the ridge line 5.

  The microneedle 1 according to this embodiment has a rhombus-shaped hem portion 2 at the bottom, and a knife edge-shaped needle portion 3 is formed so as to protrude from above the hem portion 2. When the height of the needle portion 3 in the puncture direction, that is, the direction in which the blade edge 4 protrudes, is H, and the length in the direction along the ridge line 5 of the blade is L, the dimension ratio H: L of the height H to the length L is 2. : It is preferable that it is 3-5: 6, and it is more preferable that it is 3: 4. Specifically, for example, when the length L is 200 to 800 μm, the height H is 150 to 600 μm. When the width in the direction perpendicular to the ridge line 5 of the blade of the needle portion 3 is W, the dimensional ratio W: L of the width W to the length L is preferably 1: 4 to 1: 3. 10 is more preferable. Specifically, for example, when the length L is 200 to 800 μm, the width W is 60 to 240 μm. Further, the diagonal width LW of the skirt 2 in the direction along the ridge line 5 of the blade at this time is 600 to 2400 μm, whereas the diagonal width TW of the skirt 2 in the direction orthogonal to the ridge line 5 of the blade is 370. ˜1480 μm.

  Further, as shown in FIG. 2, the microneedle 1 may have a certain diameter of the head due to the shape in which the blade edge 4 is headed. The head portion of the cutting edge 4 may have a rounded shape having a curve. The edge of the edge 5 of the blade is ideally sharp, but the radius of curvature of the blade molded from the biodegradable material is preferably 6 μm or less.

The microneedle 1 and the microneedle array 10 are preferably made of metal, silicon, a resin such as polyamide or polyester, or a biodegradable material. However, the microneedle 1 and the microneedle array 10 are also biodegradable materials because they may remain inside the skin due to breakage of the needle. More preferably.
The biodegradable material is not particularly limited, but for example, glycosaminoglycan, polylactic acid, polyglycolide, polylactic acid-CO-polyglycolide, pullulan, polycaprolactone, polyurethane, polyanhydride, etc. can be used, and the dissolution rate In view of metabolic rate in the body, it is particularly preferable to use glycosaminoglycan as a main component.

The microneedle 1 and the microneedle array 10 according to the present embodiment are formed of a biodegradable material containing a glycosaminoglycan as a main component and a water-soluble polymer other than the glycosaminoglycan as a subcomponent.
Specifically, as the glycosaminoglycan, chondroitin, chondroitin sulfate, dermatan sulfate, heparan sulfate, heparin, keratan sulfate or hyaluronic acid is preferable, and chondroitin, chondroitin sulfate or hyaluronic acid is more preferable.
Here, “chondroitin sulfate” refers to a compound in which chondroitin sulfate is desulfated, unlike chondroitin sulfate, and can be obtained by chemical treatment or culture method of chondroitin sulfate.

  The microneedle 1 and the microneedle array 10 are biodegradable materials in which glycosaminoglycan and a water-soluble polymer containing at least one of dextran, gelatin, collagen, low molecular collagen, polyvinylpyrrolidone, or polyethylene glycol are blended. It may be composed of FIG. 4 shows a perspective view of a biodegradable microneedle array 10 formed by arranging a plurality of microneedles 1 according to the present embodiment.

  Next, a method for manufacturing the biodegradable microneedle array 10 according to the present embodiment will be described. FIG. 5 is a diagram for explaining a process for manufacturing the biodegradable microneedle array 10.

  First, an array master 11 of a microneedle array is made of Si (FIG. 5A). The array master 11 is formed by arranging a plurality of knife-edge shaped microneedles 111 on a single crystal Si wafer and anisotropically etching the Si wafer. Note that anisotropic etching refers to a three-dimensional microfabrication method using a difference in etch rate depending on crystal orientation. The array master 11 according to the present embodiment is formed by wet etching using TMAH (tetramethylammonium hydroxide), but other alkaline aqueous solution such as KOH (potassium hydroxide) may be used as an etching solution. .

A single crystal Si wafer is prepared, and the surface is thermally oxidized to form a SiO ₂ oxide film. Then, a resist is applied to, for example, the (110) surface of the Si wafer. A photomask in which a large number of rhombus mask patterns corresponding to individual microneedles are arranged on the Si wafer surface is installed. The resist is patterned by irradiating the Si wafer on which the photomask is set with ultraviolet rays and developing the Si wafer. SiO ₂ is removed using a BHF solution, and a diamond-shaped oxide film pattern is formed on the wafer surface.

  Using TMAH, the portion of the wafer where Si is exposed is etched. Etching of the (110) plane in the thickness direction of the Si wafer proceeds fast, and undercut of the crystal plane with a relatively low etch rate proceeds slowly under the oxide film, and slopes 6 and 7 are formed. Furthermore, a knife edge-shaped microneedle having a ridge line is formed by the difference in the diagonal dimension of the oxide film patterned in a diamond shape. Then, the Si wafer on which a large number of microneedles are formed is diced into a predetermined size to obtain a microneedle array master 11 formed into chips.

  Next, a process of forming a PDMS mold 12 which is a mold mold using the Si array master 11, and a process of finally manufacturing the microneedle array 10 by filling the PDMS mold 12 with a biodegradable material, Will be explained.

  In the process of forming the PDMS mold 12 that is a mold mold, in order to prevent sticking between the Si array master 11 and the PDMS mold 12, first, a Cr layer and an Au layer are formed on the knife surface of the array master 11 by sputtering. Cover. The layer thickness is, for example, 10 nm for Cr and 250 nm for Au.

  Subsequently, PDMS (polydimethylsiloxane) which is a material of the PDMS mold 12 is prepared. A two-component room temperature curable PDMS main agent and a curing agent are mixed in a ratio of, for example, 10: 1 by weight, and then defoamed for a long time using a vacuum pump. The array master 11 is surrounded by a silicone rubber sheet, and degassed PDMS is injected into the enclosure (FIG. 5B). Hold at atmospheric temperature and normal temperature for about 1 day to cure PDMS. The PDMS mold 12 is obtained by peeling the array master 11 from the cured PDMS (FIG. 5C).

  In the process of molding the biodegradable microneedle array 10 using the PDMS mold 12, first, pure water and a biodegradable material are blended to prepare a material solution. The biodegradable material contains glycosaminoglycan as a main component and a water-soluble polymer other than glycosaminoglycan as a minor component. The glycosaminoglycan is chondroitin, chondroitin sulfate, dermatan sulfate, heparan sulfate, heparin, keratan sulfate or hyaluronic acid, and more preferably chondroitin, chondroitin sulfate or hyaluronic acid.

  The prepared biodegradable material solution is poured into the PDMS mold 12 (FIG. 5D) and left at room temperature for about 1 day so that the material solution is filled to the back of the knife edge groove (FIG. 5E). The biodegradable material solution immediately after blending may be defoamed using a vacuum pump so that air is not trapped in the grooves of the PDMS mold 12. The cured biodegradable material is peeled from the PDMS mold 12 to obtain a molded biodegradable microneedle array 10 (FIG. 5F).

  Next, examples of the biodegradable microneedle array will be described.

(1) Si Array Master Table 1 shows the dimensions and needle density of the Si array master created.

(2) Biodegradable material solution Table 2 shows the conditions and molding results of the biodegradable material solution used in the production of the microneedle array. The biodegradable material solution was obtained by mixing two components of low molecular weight collagen and hyaluronic acid and dissolving them in pure water.

Except for using a biodegradable material solution in which three components of hyaluronic acid (molecular weight 980,000), chondroitin (molecular weight 30,000) and polyvinylpyrrolidone (molecular weight 2,000) were mixed at a weight ratio of 6: 3: 1. Thus, a microneedle array was obtained.

(3) Evaluation of puncture property A load was applied to the microneedle array using a parallel plate cantilever, and the puncture property of the microneedle array was evaluated from the relationship between the load and the displacement. FIG. 6 shows a model of a test apparatus for evaluating the puncture property. The parallel plate cantilever 21 has a predetermined spring constant that elastically deforms in the vertical direction, and is provided so as to reciprocate in the vertical direction by a Z stage 20 having a stroke in the vertical direction. The displacement of the tip of the cantilever 21 is measured by a laser displacement meter 22.

  The calibration of the test apparatus is performed by measuring the spring constant of the parallel plate cantilever 21. That is, a substantially incompressible Si microneedle array (array master 11) is attached to the tip of the cantilever 21 and the Z stage 20 is lowered with the Si microneedle array in contact with a load meter (not shown). Let The calibration spring constant is measured from the relationship between the amount of deformation of the cantilever 21 (the difference in displacement of the tip of the cantilever 21 from the amount of movement of the i.e.Z stage 20) and the load value indicated by the load meter. In the experiment for evaluating the puncture property described below, the load applied to the tip of the cantilever 21 was calculated by multiplying the deformation amount of the cantilever 21 by the calibration spring constant.

  In the experiment for evaluating the puncture property, the prototype biodegradable microneedle array 10 is attached to the tip of the cantilever 21 and the cantilever 21 when the microneedle array 10 is pressed against the artificial skin 23 that is a silicone rubber sheet. The relationship between the tip displacement (displacement of the microneedle array 10) and the load was determined.

  FIG. 7 shows the relationship between displacement and load due to the prototype biodegradable microneedle array 10. For comparison, FIG. 8 shows a relationship between the displacement and the load by the substantially incompressible Si microneedle array as a reference example. Although the prototype biodegradable microneedle array 10 has a large displacement and slightly elastic characteristics compared to the microneedle array made of Si, the puncture performance and machine sufficient to withstand practical use in the percutaneous absorption system Strength characteristics were confirmed.

(4) Evaluation of puncture ability for pig-extracted skin The pig-extracted skin and the biodegradable microneedle array 10 were placed in a digital force cage at an angle of 30 degrees. The biodegradable microneedle array 10 was inserted into the pig-extracted skin with a constant load (1 kgf, 5 minutes). After the insertion, the skin surface was stained with Evans Blue and then evaluated by measuring the stained perforations. The microneedle array used for the evaluation was biodegradable in which three components of hyaluronic acid (molecular weight 980,000), chondroitin (molecular weight 30,000) and polyvinylpyrrolidone (molecular weight 2,000) were mixed at a weight ratio of 6: 3: 1. What was molded with the raw material solution was used.

FIG. 9 shows an image of the surface of the pig excised skin when the biodegradable microneedle array 10 according to this example is used. A perforation stained with Evans Blue is shown in the ellipse of FIG. According to the biodegradable microneedle array 10 of this example, a puncture performance of at least 60% was confirmed at a puncture angle of 30 degrees with respect to the porcine excised skin. Here, “puncture performance” was evaluated using the following formula.
Puncture performance (%) = [puncture hole (number of staining) / total number of needles] × 100

  For comparison, the same evaluation was performed using a conventional frustoconical biodegradable microneedle array. FIG. 10 shows an image of the surface of the pig removed after staining with Evans Blue using a truncated cone-shaped biodegradable microneedle array under the same conditions. As shown in FIG. 10, the biodegradable microneedle array having a truncated cone shape showed no puncture performance with respect to the pig-extracted skin.

  Thus, it was shown that the microneedle array and the skin contact surface do not necessarily have to be horizontally limited by confirming the puncture property in the insertion direction having an angle. Since the skin insertion direction of the microneedle array using the applicator is always limited to the horizontal direction, the biodegradable microneedle array 10 has been shown to be able to be administered to human skin with only finger pressure without using the applicator. .

According to the biodegradable microneedle array 10 of the present embodiment, the knife edge shape different from that of the conventional microneedles has the following advantageous effects.
(1) The microneedle 1 of the present embodiment can increase the surface area of the portion punctured into the skin as compared with a conventional needle shape such as a cone or pyramid, and thereby the diffusion efficiency of the drug Can be increased.
(2) In addition, the knife edge shape of the present embodiment can hold a larger amount of medicine in the tip portion of the needle than the needle shape having a sharp tip, so that the above-described synergistic effect with the surface area of the needle portion The amount of medicine transported per unit time can be further increased.
(3) When a conventional needle-shaped microneedle is molded using a biodegradable material, it is difficult to fill the material up to the deep part of the mold groove matched to the needle shape with a sharp tip. On the other hand, according to the knife edge shape of the present embodiment, the area corresponding to the needle root portion is wider than the conventional needle shape, so if it is a filling method using the same material under the same conditions, molding is easier than before. Become. In addition, before and after each knife edge groove formed in the mold die (PDMS die 12) becomes a passage for air accumulated during filling of the material, so that the biodegradable material is sufficiently filled to the back of the knife edge groove. Can do. Therefore, the microneedle array 10 of the present embodiment can easily mold the target knife edge shape, and thereby can produce a final product with a high yield. The knife edge shape of the present embodiment is particularly suitable for molding using a polymer material having viscosity such as hyaluronic acid as a biodegradable material.
(4) The microneedle 1 having a knife edge shape according to the present embodiment is less likely to break due to its shape than the conventional needle shape needle, and has high safety in drug administration.
(5) According to the microneedle array 10 of the present embodiment, it is possible to puncture the skin uniformly and safely without using an applicator, and the percutaneous delivery of the medicine by the patient himself / herself becomes easier.

DESCRIPTION OF SYMBOLS 1 Microneedle 2 Bottom part 3 Needle part 4 Cutting edge 5 Blade ridgeline 6, 7 Slope 10 Microneedle array 11 Array master 12 PDMS type 20 Z stage 21 Cantilever 22 Laser displacement meter 23 Artificial skin

Claims (8)

A microneedle for transdermal delivery of a drug,
A hem, and a needle portion protruding from the hem in the puncture direction,
The needle part has two inclined surfaces forming an acute angle with each other;
The ridge line of the blade where the two inclined surfaces of the needle part intersect at an acute angle is formed in a knife edge shape having the highest blade edge in the center part of the ridge line,
A microneedle in which the cutting edge is formed in a linear or curved shape having a certain length . The microneedle according to claim 1 , wherein a dimensional ratio H: L of a height H in the puncture direction and a length L in the ridge line direction of the blade is 2: 3 to 5: 6. The needle portion of the dimensional ratio between the length L in the ridge line direction of the width W in the direction perpendicular to the ridge of the blade the blade W: L of 1: 4 to 1: 3, to claim 1 or 2 The microneedle described. The microneedles is formed by a biodegradable material comprising a main component glycosaminoglycan water-soluble polymer other than the glycosaminoglycan as a sub-component, according to any one of claims 1 to 3 Microneedle. The microneedle according to claim 4 , wherein the glycosaminoglycan is chondroitin, chondroitin sulfate, dermatan sulfate, heparan sulfate, heparin, keratan sulfate, or hyaluronic acid. The microneedle according to claim 4 or 5 , wherein the water-soluble polymer contains at least one of dextran, gelatin, collagen, low molecular collagen, polyvinyl pyrrolidone, or polyethylene glycol. Microneedle array formed by arranging a plurality of microneedles according to any of claims 1-6. A method of manufacturing a microneedle array for transdermal delivery of a drug,
An array master in which a plurality of knife edge shapes having the highest cutting edge at the center of the ridge line are formed on the wafer by anisotropic etching of a single crystal wafer. The process of preparing and
A process of forming a mold for molding by injecting and curing a curable material into the array master; and
A process of obtaining a microneedle array in which a plurality of knife-edge shaped microneedles are arranged by molding a biodegradable material using the mold;
Including
The process of preparing the array master comprises
Forming a diamond-shaped oxide film pattern on the surface of the wafer;
A process of forming the knife edge shape portion having an edge corresponding to the diagonal dimension difference of the rhombus by anisotropic etching below the oxide film pattern;
A method of manufacturing a microneedle array, comprising: