Microneedle and method for producing same

Abstract

Provided are a microneedle with excellent performance and a method for manufacturing the microneedle. A microneedle array in which a polyglycolic acid is used as a material, crystallinity of the polyglycolic acid is 21% or more and axial contraction rate of tips is 99% or more, and a manufacturing method in which a polyglycolic acid are injection-molded at a cylinder temperature of 230-280 C., a metal mold temperature of 60-130 C., and an injection pressure of 1000-1500 KPa so as to manufacture a microneedle array in which crystallinity of the polyglycolic acid is 21% or more and an axial contraction rate of tips is 99% or more.

Claims

1. A microneedle array, wherein: polyglycolic acid is used as a material; crystallinity of the polyglycolic acid is 21% or more; and an axial contraction rate of tips is 99% or more.

2. The microneedle array according to claim 1, characterized in that the microneedle array has a yield point in compressive strength measurement.

3. The microneedle array according to claim 1, characterized in that: the microneedle has a conical, or circular truncated cone, or konide-like shape; the microneedle takes one stage structure or two stage structure; the needle height of the microneedle is 0.1-1.5 mm; and intervals between the microneedles are 0.2-1.5 mm.

4. The microneedle array according to claim 1, characterized in that an upper part of a substrate has a substrate base stand part, and/or a lower part of the substrate has unevenness.

5. The microneedle array according to claim 1, characterized in that: a concave part in the lower part of the substrate has a depth of 0.2 mm or more; and the concave parts occupy 10-90% of the entire substrate area.

6. The microneedle array according to claim 1, characterized in that a drug is held in the tips of the microneedles.

7. A manufacturing method of a microneedle array, wherein polyglycolic acid is injection-molded at a cylinder temperature of 230-280 C., a metal mold temperature of 60-130 C., and an injection pressure of 1000-1500 KPa, so as to manufacture the microneedle array in which crystallinity of the polyglycolic acid is 21% or more, and an axial contraction rate of tips is 99% or more.

8. A percutaneous absorption preparation, wherein a drug is held on a range of 500 m from tips of a microneedle array in which polyglycolic acid, whose crystallinity is 21% or more and an axial contraction rate of tips is 99% or more, is used as a material.

9. The microneedle array according to claim 1, wherein the crystallinity of the polyglycol acid is 26.9% or more.

10. The manufacturing method of a microneedle array according to claim 7, wherein said metal mold temperature is 85 C. to 130 C. and the crystallinity of the polyglycol acid is 26.9% or more.

Description

BRIEF DESCRIPTION OF DRAWINGS

(1) FIG. 1 is a schematic view of a cross-section of a microneedle array.

(2) FIG. 2 is a microscope photograph of microneedles of a microneedle array according to Example 1.

(3) FIG. 3 is a photograph of a front side (right) and a rear side (left) of the microneedle array according to Example 1.

(4) FIG. 4 is a microscope photograph of microneedles of a microneedle array according to Comparative Example 1.

(5) FIG. 5 is a microscope photograph of the microneedle array according to Example 1 after being left at 60 C. for 24 hours.

(6) FIG. 6 is a microscope photograph of the microneedle array according to Comparative Example 1 after being left at 60 C. for 24 hours.

(7) FIG. 7 is a graph showing compressionstrain curves of microneedle patches according to Example 1 and Comparative Example 1.

(8) FIG. 8 is a microscope photograph of the microneedles according to Example 1 after skin administration.

(9) FIG. 9 is a microscope photograph of the microneedles according to Comparative Example 1 after skin administration.

(10) FIG. 10 is a microscope photograph of microneedles according to Example 9.

(11) FIG. 11 is a microscope photograph from a transverse direction of the microneedle array according to Example 1 after being left at 40 C. for three months.

(12) FIG. 12 is a microscope photograph from a transverse direction of the microneedle array according to Example 9 after being left at 40 C. for three months.

DESCRIPTION OF EMBODIMENTS

(13) Hereinafter, the embodiments of the present invention will be described in accordance with examples. However, the present invention is not limited to contents of the examples. FIG. 1 schematically shows a cross-sectional view of a microneedle array having typical two stage structure. The microneedles have a tip 11 and a bottom base 12. A substrate 14 has a substrate base stand part 13 and is provided with unevenness.

(14) Polyglycolic acid with (a) melt viscosity * of 500-1000 Pa.Math.s as measured at a temperature of 250 C. and a shear rate of 100/sec; (b) a melting point Tm of more than 220 C.; and (c) density of approximately 1.5 g/cm.sup.3; can be suitably used. For example, polyglycolic acid resin made by KUREHA CORPORATION is suitable. In the following examples and comparative examples, polyglycolic acid (high purity Kuredux: made by KUREHA CORPORATION) was used.

(15) 1. Manufacture of Highly Crystallized Microneedles by an Injection Molding Method

(16) A metal mold was attached to an injection molding machine (Fanuc Ltd.), and polyglycolic acid was melted to injection-mold. The polyglycolic acid was injection-molded at a cylinder temperature of 235 C., an injection pressure of 1350 KPa, and a metal mold temperature of 120 C., and then a milk-white microneedle array with the cross-sectional shape as shown in FIG. 1 was taken out. FIG. 2 shows a microscope photograph of the microneedles portion of the obtained microneedle array, and FIG. 3 shows a photograph of a front side and a back side of this microneedle array. The total number of the microneedles in the array is 458, and the microneedles have a circular truncated cone shape. This microneedle array is referred to as Example 1.

(17) The microneedles according to Example 1 have the two stage structure as shown in FIG. 1. The microneedles had a bottom base diameter of 0.13 mm, a bottom base height of 0.1 mm, a tip apex diameter of 0.034 mm, a tip base diameter of 0.062 mm, and a tip height of 0.3 mm. Distances between the microneedles were 0.4 mm. A substrate has an oval shape with a major axis of 1.4 mm, a minor axis of 1.2 mm, and a thickness of 1.0 mm, and a substrate base stand part with a thickness of 1.0 mm is provided on the upper part of the substrate. A lower part of the substrate does not have a flat surface but uneven structure and thus has grid-like holes with a depth of 0.5 mm. A total of the bottom base height and the tip height is a needle height of the microneedle.

(18) By variously changing the metal mold temperature, microneedle arrays referred to as Examples 2 to 8 were made in a similar manner to Example 1. Results are summarized in Table 2. However, the microneedles according to Example 8 have one stage structure. One stage structure means structure in which microneedles do not have the bottom base and are constituted only with the tip.

(19) 2. Manufacture of Lowly Crystallized Microneedles by the Injection Molding Method

(20) The metal mold temperature was set to 40-50 C. and then a microneedle array was injection-molded in an almost similar condition to Example 1. FIG. 4 shows a microscope photograph of the obtained microneedles. A tip apex diameter of the obtained microneedles is approximately 0.038 mm, and an almost transparent microneedle array having circular truncated cone shaped microneedles with a tip height of approximately 0.25 mm could be made. This microneedle array is referred to as Comparative Example 1.

(21) By variously changing the cylinder temperature and the metal mold temperature, microneedle arrays referred to as Comparative Example 2 to Comparative Example 4 were made in a similar manner. Results are summarized in Table 2. However, the microneedles according to Comparative Example 4 are not the two stage type but the one stage type.

(22) 3. Heat-holding Stability of the Microneedles

(23) If a microneedle array made of polyglycolic acid is put in 1,2-dichloroethane, the array sinks to a bottom. If carbon tetrachloride is added and mixed with 1,2-dichloroethane, then the microneedle array floats up. Density of a mixture of 1,2-dichloroethane and carbon tetrachloride in a state where the microneedle array did not float up nor become deposited was measured with a set of 7 densimeters (SOGO LABORATORY GLASS WORKS CO., LTD), and thereby the density was determined as density of the microneedle array.

(24) Crystallinity X (%) was calculated by the following formula using the density (g/cm.sup.3) of the microneedle array made of polyglycolic acid.
X=(1/.sub.a1/) /(1/.sub.a1/.sub.c)*100
wherein, .sub.a is density of polyglycolic acid with a crystallinity of 0% (=1.500 g/cm.sup.3), and .sub.c is density of polyglycolic acid with a crystallinity of 100% (=1.700 g/cm.sup.3).

(25) Changes of density and size after being held at 60 C. for 24 hours were measured to examine temporal stability of the microneedle array. FIG. 5 and FIG. 6 show photographs of the microneedle arrays according to Example 1 and Comparative Example lafter being left at 60 C. for 24 hours. Furthermore, the density and the crystallinity thereof are shown in Table 1. In Comparative Example 1 with low crystallinity, crystallization progressed and the density rose while being left, so it is understood that the microneedle array was accordingly abnormally deformed.

(26) TABLE-US-00001 TABLE 1 Physical properties of microneedle arrays of Example 1 and Comparative Example 1 before and after heating density (g/cm.sup.3) crystallinity (%) sample before after before after name heating heating heating heating Example 1 1.578 1.580 42.0 43.0 Comparative 1.504 1.560 2.3 32.7 Example 1

(27) In Example 1 in which crystallization has progressed, the changes of density and crystallinity by heat-holding are both extremely low. In contrast, in Comparative Example 1 in which the crystallinity in molding is low, rises in density and crystallinity by heat-holding are remarkable. When the microscope photographs are compared, it is found that the shape does not almost change in Example 1 while contraction of the needles is remarkable in Comparative Example 1.

(28) For each Example and Comparative Example, a tip height after the manufacture (A) and a tip height after being held at 60 C. for 24 hours (B) were compared. In Examples with high crystallinity, A and B are nearly same values (the needles do not contract). However, in Examples with low crystallinity, B is smaller than A, and thus the tips greatly contract. Table 2 shows the results.

(29) 4. Strength of the Microneedles

(30) The microneedles should have sufficient strength to allow for insertion into skin. Since it is conceivable that microneedles with high compressive strength can be easily inserted into skin, the compressive strength of the microneedles was measured with a compact desk testing machine (Shimazu Corporation, EZTest). A sample was sandwiched by two stainless steel plates and compressed at rate of 1.0 mm/min to determine yield point stress. Yield point stress per one microneedle was determined as the compressive strength (Compressive strength=Yield point stress/Number of needles). FIG. 7 shows the results. The reference character 20 is the result of the microneedle array according to Example 1, 21 is the result of the microneedle array according to Comparative Example 1. The compressive strength is 0.07 N in Example 1 while a clear yield point is not shown in Comparative Example. Table 2 shows values of the compressive strength in all Examples and Comparative Examples. Since the yield point was not shown in Comparative Examples, the values are shown by ().

(31) The microneedles according to Example 3 and Comparative Example 3 were attached to substrate rear sides with adhesive tape and administered to an upper arm skin of a volunteer using an applicator. The microneedles just after the administration were collected and measured whether each microneedle had been bent by the skin administration. The number of the needles in one microneedle array was 458. A ratio of the bent needles was 1.1% in Example 3 while 80% of needles had been bent in Comparative Example 3. Microscope photographs are shown in FIG. 8 (Example 3) and FIG. 9 (Comparative Example 3).

(32) When the needle tips to which model pigment had been applied were inserted into isolated human skin and then pulled out 30 minutes after administration, the pigment almost disappeared from the entire microneedles, so it was confirmed that the microneedles according to Example 3 were almost surely administered into the skin. Furthermore, the microneedles according to Example 3 were administered to an upper arm skin of a volunteer using the applicator, and then it was directly confirmed with OCT that the microneedles were inserted into deep parts of the skin.

(33) A substrate rear side of the microneedle array according to Example 1 has unevenness. A depth of the concave parts is 0.3 mm, and the concave parts occupy 60% of the rear side (see FIG. 3). In order to confirm effect of the unevenness of the substrate, a microneedle array referred to as Example 9 which did not have the concave parts was made in a similar injection molding condition to Example 1. The microneedle arrays according to Example 1 and Example 9 were held at 40 C. for three months, and FIG. 11 and FIG. 12 show microscope photographs from a horizontal direction of the both arrays after being held. Warpage of the rear side of the microneedle array was not almost observed in Example 1 while warpage up to 0.32 mm was observed in Example 9 (distance between the arrowheads in FIG. 12=0.32 mm). Although a skin insertion property can be ensured even if the flatness of the microneedle array is somewhat disordered, it is desirable to be plane.

(34) 5. Conclusion

(35) As described above, it is confirmed that the crystallization of the polyglycolic acid microneedles exerts serious influence on physical properties of the microneedle. A method in which degree of the crystallization can be most sensitively reflected and easily measured is to measure change of needle height of the microneedle array after being heated at 60 C. for 24 hours. Ratios (B/A) of a tip needle height (A) and a needle height (B) after being heated at 60 C. for 24 hours of the microneedle arrays made under various conditions are summarized as contraction rates (%) in Table 2. Although the microneedle arrays according to Example 8 and Comparative Example 4 were not the two step type but the one step type, there was little difference concerning the manufacturing conditions and the contraction rate between the two step type and the one step type.

(36) TABLE-US-00002 TABLE 2 Contraction rate of microneedles injection-molded under various conditions Examples cylinder metal mold tip height tip height contraction compressive Comparative temperature temperature crystallinity of needle (A) of needle (B) rate (B/A) strength Examples ( C.) ( C.) (%) (m) (m) (%) (N/microneedle) Ex. 1 235 120 42 294 292 99.3 0.070 Ex. 2 235 105 36.3 292 291 99.7 0.077 Ex. 3 235 95 33.7 293 292 99.7 0.076 Ex. 4 235 85 26.9 289 289 100 0.069 Ex. 5 235 80 21 291 289 99.3 0.071 Ex. 6 235 70 283 285 100.7 0.066 Ex. 7 235 60 265 270 101.9 0.066 Ex. 8 235 120 296 296 100 0.075 Comp. Ex. 1 260 40 2.3 251 148 59 Comp. Ex. 2 260 40 264 154 58.3 Comp. Ex. 3 235 50 18 237 212 89.5 Comp. Ex. 4 235 40 16.1 231 148 64.1 Comp. Ex. 5 260 40 270 179 66.3