Dosage form having identification information, method for manufacturing same, pestle for use in manufacturing dosage form, and method for manufacturing same

Abstract

In one embodiment, the present invention provides a dosage form having identification information, a method for manufacturing the dosage form having identification information, or a pestle for use in manufacturing the dosage form having identification information. One embodiment of the present invention provides a dosage form that is provided with a first part in which a plurality of uneven shape structures are arranged on a surface of the dosage form, and a second part in which a plurality of uneven shape structures are not arranged on the surface of the dosage form, wherein the first part is arranged adjacent to the second part, and the first part or the second part constitutes at least one pattern having identification information.

Description

Formulation having identification information, manufacturing method thereof, pestle used for manufacturing thereof, and manufacturing method thereof

[0001] One embodiment of the present invention relates to a preparation having identification information, or to a method for producing a preparation having identification information, or to a punch used for producing a preparation having identification information.

[0002] In order to prevent accidental ingestion of medicines or mix-up of medicines during dispensing, identification information is attached to medicines, and such identification information is generally attached not only to the medicine packaging but also to the surfaces of tablets and capsules. Methods for attaching identification information to medicines themselves, such as tablets and capsules, include, for example, engraving during tableting and printing techniques such as gravure printing and inkjet printing (Patent Document 1).

[0003] Japanese Patent Application Laid-Open No. 2019-194335

[0004] While the markings used in the past were highly recognizable, they had the problem of only being able to display a few simple characters. In addition, the printing method had problems with the print bleeding and rubbing off.

[0005] The present invention aims to solve the above problems and has as its object to provide a preparation, particularly a tablet, having novel identification information. Alternatively, in one embodiment, it has as its object to provide a method for producing a preparation having identification information. Alternatively, in one embodiment, it has as its object to provide a punch used for producing a preparation having identification information.

[0006] According to one embodiment of the present invention, there is provided a pharmaceutical preparation comprising a first portion having a textured structure disposed on the surface of the preparation and a second portion having no textured structure disposed on the surface of the preparation, the first portion being disposed adjacent to the second portion, and the first portion or the second portion comprising at least one pattern having identification information.

[0007] The uneven structure may have a maximum peak height (Rp) of 1.0 μm to 13.2 μm.

[0008] The arithmetic mean height Sa of the first portion may be 0.80 μm or more and 10.00 μm or less, and the ratio of the arithmetic mean height Sa of the first portion to the arithmetic mean height Sa of the second portion may be 1.05 or more.

[0009] The contrast ratio of the arithmetic mean height Sa between a portion of the surface of the preparation on which the identification information is arranged and another portion of the surface of the preparation may be 1.05 or more.

[0010] The contrast ratio of relative luminance between a portion of the surface of the preparation on which the identification information is arranged and another portion of the surface of the preparation may be 1.05 or more.

[0011] According to one embodiment of the present invention, there is provided a tableting punch comprising a first portion having an indentation and a second portion having no indentation on the tablet surface, the first portion being disposed adjacent to the second portion, the first portion or the second portion including at least one first pattern having identification information, the at least one first pattern corresponding to a second pattern constituting identification information for the formulation.

[0012] In the tableting punch, the at least one first pattern may be composed of at least one linear pattern including a concave-convex portion.

[0013] In the tableting punch, the arithmetic mean height Sa of the second portion may be less than 0.20 μm, and the arithmetic mean height Sa of the first portion may be 0.20 μm or more and 10.00 μm or less.

[0014] According to one embodiment of the present invention, there is provided a method for manufacturing a tableting punch, which includes forming a first portion by irradiating only a portion of the tableting surface with a laser to arrange a concave-convex portion, wherein the first portion or a second portion adjacent to the first portion that is not irradiated with the laser forms at least one first pattern having identification information, and the at least one first pattern corresponds to a second pattern that constitutes the identification information of the formulation.

[0015] In the method for manufacturing a tableting punch, forming at least one first pattern may include irradiating a laser to form at least one uneven portion on the tableting surface.

[0016] In the method for manufacturing a tableting punch, forming at least one uneven portion may include continuously or intermittently irradiating the tableting surface with a laser to form at least one irradiation mark.

[0017] According to one embodiment of the present invention, there is provided a method for producing a formulation, which comprises tableting a pharmaceutical composition using the above-mentioned tableting punch or a tableting punch produced by the above-mentioned production method.

[0018] According to one embodiment of the present invention, a formulation having identification information is provided. Alternatively, according to one embodiment, a method for producing a formulation having identification information is provided. Alternatively, according to one embodiment, a punch for use in producing a formulation having identification information is provided.

[0019] 6A is a perspective view of formulation 10 according to one embodiment of the present invention. FIG. 6B is a top view of formulation 10 according to one embodiment of the present invention. FIG. 6C is an enlarged view of pattern 15a according to one embodiment of the present invention. FIG. 6D is an enlarged view of the left end of concave-convex pattern 15a-1 according to one embodiment of the present invention. FIG. 6E is an enlarged view of a cross section of formulation 10 taken along line AA' in FIG. 2B. FIG. 6F is a perspective view of upper punch 600 according to one embodiment of the present invention. FIG. 6G is an enlarged view of a cross section of tip 630 of upper punch 600 according to one embodiment of the present invention. FIG. 6H is an enlarged view of a cross section of tip 730 of lower punch 700 according to one embodiment of the present invention. FIG. 6H is an enlarged view of a pattern 615a according to one embodiment of the present invention. FIG. 6I is an enlarged view of the right end of concave pattern 615a-1 according to one embodiment of the present invention. FIG. 6I is an enlarged view of a cross section of tip 630 according to one embodiment of the present invention taken along line AA' in FIG. 6A. FIG. 6I is an optical microscope image showing concave pattern 115a-1 of one example. FIG. 6I is an optical microscope image showing pattern 15a formed on the surface of a tablet of one example. Photographs of tablets of each example are shown. 1 is a photograph of a tablet having identification information in a 1.0 mm square checkered pattern illuminated from above with fluorescent light. FIG. 2 is a photograph of a tablet having identification information in a 0.5 mm square checkered pattern illuminated from above with fluorescent light. FIG. 3 is a photograph of a tablet having identification information in a 1.0 mm square checkered pattern illuminated from the side with fluorescent light. FIG. 4 is a photograph of a tablet having identification information in a 0.5 mm square checkered pattern illuminated from the side with fluorescent light. FIG. 5 is a photograph of an enlarged tablet having identification information in a 1.0 mm square checkered pattern. FIG. 6 is a photograph of an enlarged tablet having identification information in a 0.5 mm square checkered pattern, shown in a concavo-convex emphasis mode. FIG. 7 is a photograph of an enlarged tablet having identification information in a 0.5 mm square checkered pattern, shown in a concavo-convex emphasis mode. FIG. 8 is a schematic diagram showing the tableting surface 731A of a lower punch 700A of one embodiment. FIG. 9 is an optical microscope image of a gold-deposited lactose hydrate tablet of one embodiment. 1 is an optical microscope image of a gold-deposited tadalafil tablet CI 20 mg tablet of one example. 2 is an optical microscope image of a gold-deposited crystalline cellulose tablet of one example. 3 is an image showing the top surface of test piece 830 of one example. 4 is a schematic diagram showing the top surface of test piece 830 of one example. 5 is a photograph showing a tablet of a reference example.Photographs showing the patterns, engraved areas, or plain areas arranged on the tableting surfaces of punches A to D. An optical microscope image of the pattern arranged on the surface of tablet 1 photographed at 20x magnification is shown. For tablets 1 to 4 compressed at 5 kN, 3D images are shown showing the pattern portion of punch A irradiated with a laser three times, plain areas, and the engraved "S" on the tablet compressed with punch D of the reference example.

[0020] The formulation having identification information according to the present invention, its manufacturing method, and the punch used for the manufacturing method are described in detail below. However, the formulation having identification information according to the present invention, its manufacturing method, and the punch used for the manufacturing method are not to be construed as being limited to the description of the following embodiments and examples.

[0021] [Preparation] FIG. 1A is a perspective view of a preparation 10 according to one embodiment of the present invention. FIG. 1B is a top view of the preparation 10 according to one embodiment of the present invention. The preparation 10 has identification information on its surface. In this embodiment, the identification information includes at least one pattern arranged on the surface of the uncoated tablet 11. The at least one pattern comprises an uneven structure 17 (first portion) in which a plurality of convex portions 17a, which will be described later, is arranged, and a region 13 (second portion) on the surface of the uncoated tablet 11 where no pattern is arranged. The first portion is arranged adjacent to the second portion. In this embodiment, the first portion or the second portion has the identification information. That is, the first portion may have a shape that is visually recognized as the identification information, or the second portion may have a shape that is visually recognized as the identification information. The identification information has an area of ​​1% to 99% of the entire surface of the preparation (100%). Alternatively, the identification information may be arranged within a range of 0.04 mm ２ It has an area of ​​more than 100m2.

[0022] In this specification, the term "plain tablet" refers to a dosage form obtained by compressing the pharmaceutical composition constituting Formulation 10, and is not a film-coated formulation. On the other hand, bilayer tablets (including multilayer tablets) and dry-coated tablets, which have different additives in their internal portions (or layers), are considered to be plain tablets unless they are film-coated.

[0023] 1A and 1B show patterns 15a, 15b, and 15c as examples of patterns, but the patterns included in the identification information of the formulation 10 according to the present invention are not limited to these. Any identifiable design or character may be used. Furthermore, it is sufficient that at least one pattern constituting the identification information is disposed, and the number of patterns constituting the identification information is not particularly limited.

[0024] FIG. 2A shows an enlarged view of a pattern 15a according to one embodiment of the present invention. The pattern 15a includes at least one uneven pattern 15a-1. FIG. 2A shows, as an example, a rectangular pattern 15a composed of multiple uneven patterns 15a-1. The uneven pattern 15a-1 has an uneven structure including convex portions 17a that slightly protrude (or are raised) from the surface of the plain tablet 11. FIG. 2A shows, as an example, a pattern 15a composed of multiple linear uneven patterns 15a-1 arranged in parallel or approximately parallel, but the convex pattern according to this embodiment is not limited to this. For example, instead of or in addition to a linear pattern, one or more convex structures selected from dots, circles, triangles, rectangles, polygons, etc. may be included. Furthermore, the number of uneven patterns constituting the pattern according to this embodiment is not particularly limited. The uneven pattern according to this embodiment is composed of uneven structures 17 arranged on the surface of the plain tablet 11, unlike structures composed of deep grooves like conventionally used markings.

[0025] FIG. 2B is an enlarged view of the left end of the uneven pattern 15a-1 (the portion surrounded by the dashed line in FIG. 2A) according to one embodiment of the present invention. FIG. 2C is an enlarged view of a cross section of the formulation 10 according to one embodiment of the present invention taken along line AA' in FIG. 2B. The uneven pattern 15a-1 is composed of an uneven structure 17 arranged on the surface of the uncoated tablet 11, and the uneven structure 17 is composed of a plurality of roughly circular convex portions 17a. The convex portions 17a have a structure that slightly protrudes (or rises) from the surface of the uncoated tablet 11 (or from a region 13 on the surface of the uncoated tablet 11 where no pattern is arranged). One convex portion 17a may be arranged so as to be in contact with an adjacent convex portion 17a, or may be arranged so as to be slightly spaced apart. In one embodiment, one convex portion 17a may be arranged so that a portion thereof overlaps an adjacent convex portion 17a. Note that while FIG. 2B shows a schematic diagram in which a plurality of roughly circular convex portions 17a are regularly arranged, the plurality of convex portions 17a may also be arranged irregularly.

[0026] In one embodiment, the convex portions 17a may have a shape of a circle having a diameter of 10 μm to 100 μm in a plan view, or a shape where the circle is arranged so that the circle overlaps with an adjacent circle. Note that the convex portions 17a are formed using the concave portions 617 of the punch 600 described below as a mold, and therefore adjacent convex portions 17a are not necessarily clearly distinguishable from each other in images observed with, for example, a scanning electron microscope (SEM) or an atomic force microscope (AFM). For example, the convex portions 17a may have a structure such that the concave-convex structure 17 is observed on the surface of the concave-convex pattern 15a-1.

[0027] In one embodiment, the average height of the concave-convex pattern included in one pattern and the average height of the concave-convex pattern included in the other pattern may be changed so that the contrast between one pattern and the other pattern is visible. A method for changing the average height of the concave-convex pattern will be described later.

[0028] In one embodiment, the identification information of the formulation 10 can be configured from countless pattern combinations by combining the shape of the pattern included in the identification information, the shape of the concave-convex pattern included in the pattern, and the average height of the concave-convex pattern. Therefore, by having the identification information, the formulation 10 can be improved in distinguishability from other formulations. Furthermore, the formulation 10 may have barcode-like identification information or two-dimensional barcode-like identification information configured from a pattern, and the formulation 10 can be identified by reading the identification information with a barcode reader.

[0029] In one embodiment, the arithmetic mean height Sa of region 13 on the surface of the formulation is less than 2.00 μm, and the arithmetic mean height Sa of the uneven structure 17 may be 0.80 μm or more and 10.00 μm or less. Also, in one embodiment, the ratio of the arithmetic mean height Sa of the uneven structure 17 on the surface of the uncoated tablet 11 to region 13 may be 1.05 or more. In this embodiment, the uneven structure 17 has an arithmetic mean height Sa greater than that of region 13 on the surface of the uncoated tablet 11, thereby making the identification information visible as pattern 15a. On the other hand, the identification information of this embodiment does not have an arithmetic mean height Sa as large as that of the region where the conventional formulation name stamp is located.

[0030] In one embodiment, the protrusions 17a may have an average height of 3 μm to 5 μm. When the protrusions 17a have an average height in this range, the visibility of the identification information can be improved.

[0031] [Maximum Peak Height (Rp) of Convex Pattern] In one embodiment, the textured structure 17 may be evaluated by the maximum peak height (Rp) of the convex portions 17a. The maximum peak height (Rp) represents the height of the highest peak among the contour curves in the reference length. As used herein, "peak" refers to the portion of the convex portion 17a above the mean line. The maximum peak height (Rp) described herein conforms to the definition set forth in JIS B 0601. In one embodiment, the maximum peak height (Rp) of the convex portions 17a can be obtained by measuring the tablet surface using a laser microscope. In the textured structure 17, the convex portions 17a have a maximum peak height (Rp) of 1.0 μm to 13.2 μm. The maximum peak height (Rp) shows an excellent correlation with the visibility of the identification information, and by having the convex portions 17a have a maximum peak height (Rp) in this range, the visibility of the identification information can be improved.

[0032] In one embodiment, formulation 10 may include colored drug substances or excipients to enhance the contrast of the pattern and improve the discernibility of the identifying information.

[0033] In one embodiment, the contrast ratio of the relative brightness between the region 13 on the surface of the uncoated tablet 11 and the pattern 15a is preferably 1.05 or more. Such a contrast ratio makes the pattern 15a visible. The upper limit of the contrast ratio between the region 13 on the surface of the uncoated tablet 11 and the pattern 15a is not particularly limited, but may be 6.00 or less.

[0034] In this specification, the contrast ratio between the surface region 13 of the uncoated tablet 11 and the pattern 15a is evaluated by depositing gold on the uncoated tablet 11 and analyzing an image captured with an optical microscope. Specifically, the captured image is decomposed into three color components, RGB, to generate an 8-bit monochrome image. The brightness statistics for the image of each color component are output, and the contrast ratio is calculated using the output brightness values ​​according to the following formula: s = (V / 255) (V is the value of R, G, or B at a certain position in 8-bit representation) t = s / 12.92 (if s < 0.003928) or t = ((s + 0.055) / 1.055)^2.4 (if s ≥ 0.003928) Relative luminance L = 0.2126 × t(R) + 0.7152 × t(G) + 0.0722 × tB Contrast ratio = (L1 + 0.05) / (L2 + 0.05) (L1 is the relative luminance of pattern 15a, L2 is the relative luminance of region 13 on the surface of plain tablet 11)

[0035] As described above, the formulation 10 according to the present invention has novel identification information on its surface, which has not been available in the past, thereby improving the identifiability of the formulation. Furthermore, the identification information according to the present invention can also make the formulation distinguishable from counterfeit medicines.

[0036] [Punch] The above-described identification information can be imparted to the formulation 10 by the punch used during tableting. Fig. 3A is a perspective view of an upper punch 600 according to one embodiment of the present invention. The upper punch 600 includes, for example, but is not limited to, a tip portion 630, a body 650, and a head 670. The tip portion 630 is connected to the body 650 and supported by the body 650. The head 670 is connected to the body 650 and is a member that is pressed by the rollers of the tablet press. Fig. 3B is an enlarged view of a cross section of the tip portion 630. A concave tableting surface 631 is arranged on the tip portion 630.

[0037] Fig. 4A is a perspective view of a lower punch 700 according to one embodiment of the present invention. The lower punch 700 includes, for example, but is not limited to, a tip portion 730, a body 750, and a head 770. The tip portion 730 is connected to the body 750 and supported by the body 750. The head 770 is connected to the body 750 and is a member that receives pressure from the rollers of the tablet press. Fig. 4B is an enlarged cross-section of the tip portion 730. A concave tableting surface 731 is disposed on the tip portion 730. In Fig. 4A, the tip portion 730 of the lower punch 700 is longer than the tip portion 630 of the upper punch 600. In this embodiment, the tip portion 730 of the lower punch 700 enters deeper below the die than the tip portion 630 of the upper punch 600 during tableting, but is not limited to these configurations.

[0038] Formulation 10 can be compressed into tablets by inserting tip 630 of upper punch 600 and tip 730 of lower punch 700 into a die and pressing the pharmaceutical composition (also referred to as pre-tabletting powder) that constitutes Formulation 10 within the die. When tableting surfaces 631 and 731 come into contact with the pharmaceutical composition, the pharmaceutical composition can be compressed into a shape that conforms to (or corresponds to) tableting surfaces 631 and 731.

[0039] 5A is a top view of the tableting surface 631. The tableting surface 631 has a shape on its surface that is the left-right reverse of the identification information of the formulation 10 (hereinafter also referred to as the identification information-corresponding shape). In this embodiment, the identification information-corresponding shape includes at least one pattern (hereinafter also referred to as the first pattern) arranged on only a portion of the tableting surface 631. In one embodiment, the tableting surface 631 includes a portion (first portion) 616 where an uneven portion is arranged and a region (second portion) 613 of the tableting surface 631 where an uneven portion is not arranged. The first portion is arranged adjacent to the second portion. In this embodiment, either the first portion or the second portion has the identification information. That is, the first portion may be configured as a shape that is visually recognized as the identification information, or the second portion may be configured as a shape that is visually recognized as the identification information. The identification information has an area of ​​1% to 99% of the entire tableting surface 631, which is 100%. Alternatively, the identification information corresponding shape is 0.04 mm on the tableting surface 631. ２ It has an area of ​​more than 100m2.

[0040] 5A shows patterns 615a, 615b, and 615c as examples of patterns, but the patterns included in the identification information-corresponding shape of the upper punch 600 according to the present invention are not limited to these. A pattern that becomes an identifiable design or character in the formulation 10 tableted using the upper punch 600 can be used. Furthermore, the number of patterns that constitute the identification information-corresponding shape is not particularly limited, as long as at least one pattern is disposed. Patterns 615a, 615b, and 615c are patterns for forming patterns 15a, 15b, and 15c (hereinafter also referred to as second patterns) in the tableted formulation 10, and have shapes that are left-right reversed from patterns 15a, 15b, and 15c (or shapes that correspond to them when tableted).

[0041] FIG. 5B shows an enlarged view of pattern 615a according to one embodiment of the present invention. Pattern 615a includes at least one concave-convex pattern 615a-1. FIG. 5B shows, as an example, a rectangular pattern 615a composed of multiple concave-convex patterns 615a-1. The concave-convex pattern 615a-1 has a structure (recess) 617 that is slightly recessed (or sunken) from the tableting surface 631. FIG. 5B shows, as an example, pattern 615a composed of multiple linear concave-convex patterns 615a-1 arranged in parallel or approximately parallel, but the concave-convex pattern according to this embodiment is not limited to this. For example, instead of or in addition to a linear pattern, one or more concave-shaped structures selected from dots, circles, triangles, rectangles, polygons, etc. may be included. Furthermore, the number of concave patterns constituting the pattern according to this embodiment is not particularly limited. The uneven pattern according to this embodiment is composed of uneven structures 616 arranged on the tableting surface 631, unlike the conventionally used markings which are composed of large protruding convex shapes.

[0042] Figure 6A is an enlarged view of the right end portion (the portion surrounded by the dashed line in Figure 5B) of the uneven pattern 615a-1 according to one embodiment of the present invention. Figure 6B is an enlarged view of the cross section of the tip portion 630 according to one embodiment of the present invention taken along line AA' in Figure 6A. The uneven pattern 615a-1 is composed of an uneven structure 616 arranged on the tableting surface 631, and the uneven structure 616 is composed of a plurality of roughly circular recesses 617. The recesses 617 have a structure surrounded by ridges 619. The recesses 617 have a structure that is slightly recessed (or sunken) from the tableting surface 631 (or the region 613 of the tableting surface 631 where no pattern is arranged). On the other hand, the ridges 619 have a structure that slightly protrudes from the tableting surface 631 (or the region 613 of the tableting surface 631 where no pattern is arranged). One recess 617 may be arranged so as to be in contact with an adjacent recess 617, or may be arranged so as to be slightly spaced apart. In one embodiment, one recess 617 may be arranged so that a portion of it overlaps an adjacent recess 617. In this case, two adjacent recesses 617 (first recess 617a and first recess 617b) partially overlap, and therefore a portion of the ridge 619 surrounding the first recess 617a does not overlap with the first recess 617b. Note that although Fig. 6A shows a schematic diagram in which a plurality of roughly circular recesses 617 are regularly arranged, a plurality of recesses 617 may also be irregularly arranged.

[0043] In one embodiment, the recesses 617 may have a shape of a circle having a diameter of 10 μm to 100 μm in a plan view, or a shape of a circle arranged so that the circle overlaps with an adjacent circle. Note that, as will be described later, the recesses 617 are structures formed by irradiating with a laser, and therefore, adjacent recesses 617 are not necessarily clearly distinguishable from each other in images observed with, for example, a scanning electron microscope (SEM) or an atomic force microscope (AFM). For example, the recesses 617 may have a structure such that a recessed and raised structure 616 is observed on the surface of the recessed and raised pattern 615a-1.

[0044] In one embodiment, when the recess 617 is set to 70 μm, the visibility of the pattern is improved by setting the interval P between two adjacent recesses 617 (first recess 617a and first recess 617b) to 50 μm.

[0045] In one embodiment, the length of one side of the pattern 615a is 0.2 mm or more, and the area is 0.04 mm ２ By doing so, the visibility of the pattern is improved.

[0046] In one embodiment, the depth of the recessed pattern included in one pattern and the depth of the recessed pattern included in the other pattern may be changed so that the contrast between one pattern and the other pattern is visible. A method for changing the depth of the recessed pattern will be described later.

[0047] In one embodiment, the arithmetic mean height Sa of the second portion 613 of the tableting surface 631 may be less than 0.20 μm, and the arithmetic mean height Sa of the first portion 616 where the uneven portion is arranged may be 0.20 μm or more and 10.00 μm or less.

[0048] In one embodiment, the identification information of the formulation 10 can be configured by countless combinations of patterns by combining the shape of the pattern included in the identification information-corresponding shape of the upper punch 600, the shape of the recessed pattern included in the pattern, and the depth of the recessed pattern. Therefore, by imparting identification information to the formulation 10, the upper punch 600 can improve the distinguishability of the formulation from other formulations.

[0049] As described above, the upper punch 600 according to the present invention can improve the identifiability of the formulation by providing novel, previously unavailable identification information on the surface of the formulation 10. Furthermore, the identification information according to the present invention can also provide the formulation with the ability to be distinguished from counterfeit medicines.

[0050] In the above-described embodiment, an example has been described in which a pattern constituting an identification information corresponding shape is arranged on the tableting surface 631 of the upper punch 600, but the present invention is not limited to this, and a pattern constituting an identification information corresponding shape may also be arranged on the tableting surface 731 of the lower punch 700. That is, a pattern constituting an identification information corresponding shape may be arranged only on the tableting surface 731 of the lower punch 700, or patterns constituting an identification information corresponding shape may be arranged on the tableting surface 631 of the upper punch 600 and the tableting surface 731 of the lower punch 700. In this case, the pattern constituting the identification information corresponding shape arranged on the tableting surface 631 of the upper punch 600 and the pattern constituting the identification information corresponding shape arranged on the tableting surface 731 of the lower punch 700 may be the same as or different from each other.

[0051] [Method of Manufacturing Pestle] In one embodiment, the upper punch 600 according to the present invention can be manufactured by irradiating the tableting surface 631 with a laser to form at least one pattern composed of recesses. Specifically, the first portion 616 is formed by irradiating only a portion of the tableting surface 631 with a laser to arrange recesses and protrusions on the tableting surface 631. At this time, the laser has a circular irradiation area with a diameter of 10 μm to 100 μm. By irradiating the laser, circular irradiation marks are formed on the tableting surface 631, thereby forming recesses 617. At least one first pattern having identification information can be formed in the first portion 616 or in an area of ​​the tableting surface 631 adjacent to the first portion 616 that is not irradiated with the laser (second portion). The at least one first pattern corresponds to a second pattern constituting the identification information of the formulation 10. The recess and protrusion pattern 615a-1 can be formed by continuously or intermittently irradiating the tableting surface 631 with a laser.

[0052] In one embodiment, the first uneven pattern 615a-1 is formed by irradiating the tableting surface 631 with a laser while moving the laser or tableting surface 631 in a first direction. Next, the laser or tableting surface 631 is moved at a predetermined interval in a second direction parallel or approximately parallel to the first direction. Then, the laser or tableting surface 631 is moved in a third direction opposite to the first direction while irradiating the tableting surface 631 with a laser, thereby forming a second uneven pattern 615a-1 on the tableting surface 631. By repeating this operation, the pattern 615a can be formed. After forming one uneven pattern 615a-1, the laser or tableting surface 631 may be moved at a predetermined interval in the second direction, the laser or tableting surface 631 may be moved in a third direction, and then the laser or tableting surface 631 may be moved in the first direction while irradiating the tableting surface 631 with a laser, thereby forming a second uneven pattern 615a-1 on the tableting surface 631.

[0053] When the tableting surface 131 is irradiated with a laser, the laser may be irradiated so that one recess 617 is in contact with an adjacent recess 617, or the laser may be irradiated so that the recesses are slightly spaced apart. In one embodiment, the laser may be irradiated so that one recess 617 partially overlaps with an adjacent recess 617.

[0054] Furthermore, when forming one concave-convex pattern 615a-1, the above-described laser irradiation step may be performed multiple times on the region where the concave-convex pattern 615a-1 is to be formed. That is, after performing laser irradiation to form the concave-convex pattern 615a-1, the same region may be irradiated with laser again to form the concave-convex pattern 615a-1. By performing laser irradiation multiple times, the recesses 617 are formed deeper from the tableting surface 631 (or the region 613 of the tableting surface 631 where no pattern is arranged), and the contrast of the pattern or concave-convex pattern formed on the surface of the formulation 10 can be enhanced.

[0055] [Method for manufacturing the formulation] Formulation 10 according to the present invention can be manufactured by tableting a pharmaceutical composition using tableting punches (upper punch 600 and lower punch 700). The pharmaceutical composition contained in Formulation 10 is not particularly limited, and is composed of any combination of drug substances and pharmaceutically acceptable additives that provide stability and dissolution properties of the drug substances as tablets. Formulation 10 can be manufactured by a known tableting method, except for using the tableting punch according to this embodiment.

[0056] A laser was irradiated onto the tableting surface of a punch having a diameter of 8 mm to form a concave pattern with a maximum length of 1.5 mm in a first direction, and then the laser was translated in a second direction perpendicular to the first direction to form multiple concave-convex patterns. Pattern 615a (square), pattern 615b (circle with a diameter of 1.5 mm), and pattern 615c (triangle with a base and height of 1.5 mm) each having a side length of 1.5 mm were arranged in this order from left to right (second direction). Furthermore, translation in the first direction formed a total of three sets of these patterns. The laser used was a Yb fiber laser with an output of 2.5 W to 50 W and a circular irradiation range of 10 μm to 100 μm in diameter. In this example, the three patterns in the first row were formed with two laser irradiations, the three patterns in the second row were formed with three laser irradiations, and the three patterns in the third row were formed with four laser irradiations.

[0057] 7 is an optical microscope image showing the uneven pattern 615a-1. The pattern 615a was formed by arranging nine uneven patterns 615a-1 in parallel. It was confirmed that a plurality of recesses 617 recessed deeper than the region 613 of the tabletting surface 631 where no pattern was arranged were formed by laser irradiation on the tabletting surface 631, forming the uneven pattern 615a-1.

[0058] Various additives were tableted using a patterned upper punch. 200 mg of each of the following pre-tabletting powders was prepared as additives: lactose hydrate (Pharmatose 200M, DMV), lactose hydrate (Dilactose S, Freund Corporation), crystalline cellulose (PH-101, Asahi Kasei Corporation), additive granules (Sawai Pharmaceutical Co., Ltd.), and tadalafil tablets CI 20 mg (Sawai Pharmaceutical Co., Ltd.), and these were tableted at a compression pressure of 2 kN, 5 kN, or 9 kN. The additive granules contained D-mannitol, crystalline cellulose, crospovidone, and low-substituted hydroxypropyl cellulose.

[0059] 8 is an optical microscope image showing the square pattern 15a formed on the surface of the tablet. In the pattern 15a, a structure in which nine concave-convex patterns 15a-1 are arranged in parallel was confirmed.

[0060] Gold vapor deposition was performed on each compressed tablet, and the identification information was observed. Figure 9 shows a photograph of each tablet. It was revealed that the pattern formed with three laser irradiations was easier to see than the pattern formed with two laser irradiations. Furthermore, no difference in visibility was observed between the pattern formed with three laser irradiations and the pattern formed with four laser irradiations. It was revealed that the visibility of the pattern improved as the impact pressure was increased. It was also revealed that a rectangular pattern with a large area had higher visibility than a triangular pattern with a small area.

[0061] In another example, a laser was irradiated onto the tableting surfaces of upper and lower punches having a diameter of 9 mm to form a 1.0 mm long concave-convex pattern in a first direction, and the laser was translated in a second direction perpendicular to the first direction to form multiple concave-convex patterns, and square patterns 615a with sides of 1.0 mm were arranged in a checkerboard pattern on the tableting surface of the upper punch. Also, a 0.5 mm long concave-convex pattern was formed in the first direction, and the laser was translated in a second direction perpendicular to the first direction to form multiple concave-convex patterns, and square patterns with sides of 0.5 mm were arranged in a checkerboard pattern on the tableting surface of the lower punch.

[0062] Using the patterned punch, 250 mg of powder before tableting of tadalafil tablets CI 20 mg (Sawai Pharmaceutical Co., Ltd.) was prepared and tableted at a hitting pressure of 11 kN.

[0063] Figure 10A is a photograph of a tablet having identification information in a 1.0 mm square checkerboard pattern illuminated from above by fluorescent light. Figure 10B is a photograph of a tablet having identification information in a 0.5 mm square checkerboard pattern illuminated from above by fluorescent light. Figure 11A is a photograph of a tablet having identification information in a 1.0 mm square checkerboard pattern illuminated from the side by fluorescent light. Figure 11B is a photograph of a tablet having identification information in a 0.5 mm square checkerboard pattern illuminated from the side by fluorescent light.

[0064] FIG. 12A is a photograph of an enlarged tablet having identification information of a 1.0 mm square checkerboard pattern. FIG. 12B is a photograph of an enlarged tablet having identification information of a 0.5 mm square checkerboard pattern. FIG. 13A is a photograph of an enlarged tablet having identification information of a 1.0 mm square checkerboard pattern, shown in unevenness emphasis mode. FIG. 13B is a photograph of an enlarged tablet having identification information of a 0.5 mm square checkerboard pattern, shown in unevenness emphasis mode. Here, the unevenness emphasis mode was observed using a digital microscope (VHX-7000, Keyence Corporation) with an observation tilt of 0 degrees, an observation magnification of 50x, and Optical-Shadow-Effect Mode (ring illumination, shadow direction is upper left, unevenness emphasis 70, standard (monochrome)).

[0065] 10A to 11B and 12A to 13B, it was revealed that the identification information with a pattern arranged over the entire surface of the tablet has excellent visibility. Furthermore, it was revealed that when the pattern is observed in the unevenness enhancement mode, it is possible to observe even the convex portions (corresponding to the concave portions formed by laser irradiation) that make up the unevenness pattern. Therefore, it was suggested that the convex portions observed in the unevenness enhancement mode could be used to prevent counterfeit drugs.

[0066] [Height of the Convex Pattern] To evaluate the height of the convex pattern placed on the tablet surface, a laser was irradiated onto the tableting surface of the punch two, three, or four times using the method described above to form a pattern. Using these punches, pre-tabletting powder of lactose hydrate (Dilactose S, Freund Corporation) or tadalafil tablets CI 20 mg (Sawai Pharmaceutical Co., Ltd.) was tableted at 2 kN or 5 kN to obtain tablets. The height of the convex pattern formed on the tablet surface was measured using a scanning electron microscope (TM3030Plus Miniscope, Hitachi High-Tech Corporation). Measurements were performed four times, and the average height was calculated. The average height of the convex pattern is shown in Table 1.

[0067]

[0068] The results in Table 1 clearly show that the height of the raised pattern tends to increase with increasing number of laser irradiations. In particular, a significant difference in the height of the raised pattern was observed between two and three laser irradiations. In this example, it was revealed that visibility improved when the height of the raised pattern was 3 μm to 5 μm.

[0069] [Maximum Peak Height (Rp) of Convex Pattern] The height of the convex pattern placed on the tablet surface was evaluated using the maximum peak height (Rp) as an index. To evaluate the height of the convex pattern placed on the tablet surface, a pattern was formed by irradiating the tableting surface of the punch with a laser 2 to 5 times or 10 times using the method described above. Using these punches, pre-tabletting powders of lactose hydrate (Dilactose S, Freund Corporation), lactose hydrate (Dilactose R, Freund Corporation), additive granules (Sawai Pharmaceutical Co., Ltd.), or tadalafil tablets CI 20 mg (Sawai Pharmaceutical Co., Ltd.) were tableted at 2 kN or 5 kN to obtain tablets. The maximum peak height (Rp) of the convex pattern formed on the tablet surface was measured using a laser microscope (laser microscope VK-X3000, Keyence Corporation). Measurements were performed 2 to 6 times, and the minimum and maximum values ​​of the maximum peak height (Rp) were calculated from the measured values. The minimum and maximum values ​​of the maximum peak height (Rp) of the convex pattern are shown in Table 2.

[0070]

[0071] The results in Table 2 clearly show that the height of the raised pattern tends to increase with increasing number of laser irradiations. In this example, it was revealed that visibility is improved when the maximum peak height (Rp) of the raised pattern is 1.0 μm to 13.2 μm. In particular, on the surface of tablets compressed with a punch whose tableting surface was irradiated twice with a laser to form a pattern, the additive granules were compressed at a punching pressure of 5 kN, and although the minimum value of the maximum peak height (Rp) of the raised pattern was 1.05 μm, visibility was good. These results demonstrate a better correlation between the maximum peak height (Rp) of the raised pattern on the tablet surface and the visibility of the pattern.

[0072] [Contrast ratio of identification information] A lower punch 700A was prepared to evaluate the contrast ratio between the surface area of ​​the uncoated tablet and the pattern contained in the identification information. Figure 14 is a schematic diagram showing the tableting surface 731A of the lower punch 700A. A 0.1 mm x 0.1 mm (0.01 mm) area was placed on a circle concentric with the circular tableting surface 731A. ２ ) pattern 715a, 0.2 mm × 0.2 mm (0.04 mm ２ ) pattern 715b, 0.3 mm × 0.3 mm (0.09 mm ２ ) pattern 715c, 0.4 mm × 0.4 mm (0.16 mm ２ ) pattern 715d, and 0.5 mm × 0.5 mm (0.25 mm ２ In this example, for patterns 715a to 715e, four lower punches 700A were prepared in which the intervals P between two adjacent recesses shown in FIG. 6A were set to 0.01 mm, 0.03 mm, 0.05 mm, and 0.07 mm. Each pattern was formed by irradiating the laser three times.

[0073] 200 mg of the aforementioned lactose hydrate (Dilactose S, Freund Corporation), tadalafil tablet CI 20 mg (Sawai Pharmaceutical Co., Ltd.) pre-tabletting powder, and crystalline cellulose (PH-101, Asahi Kasei Corporation) were prepared and compressed using four 700A lower punches at a compression pressure of 2 kN, 3 kN, or 5 kN. The resulting tablets were gold-deposited using a sputtering device (MSP-mini, Vacuum Devices Co., Ltd.). The gold-deposited surface of each tablet was observed under an optical microscope (digital microscope VHX-7000, Keyence Corporation). Figure 15 shows a lactose hydrate tablet, Figure 16 shows a tadalafil tablet CI 20 mg tablet, and Figure 17 shows a crystalline cellulose tablet.

[0074] The tablet images in Figures 15 to 17 were converted into three monochrome 8-bit images of red (R), green (G), and blue (B) using image processing software ImageJ. For each converted image, brightness statistics were output and the contrast ratio was calculated using the following formula: s = (V / 255) (V is the 8-bit value of R, G, or B) t = s / 12.92 (if s < 0.003928), or t = ((s + 0.055) / 1.055)^2.4 (otherwise) Relative luminance L = 0.2126 * t(R) + 0.7152 * t(G) + 0.0722 * t(B) Contrast ratio = (L1 + 0.05) / (L2 + 0.05) (L1 is the relative luminance of the pattern, and L2 is the relative luminance of the portion of the tablet surface where the pattern is not placed).

[0075] The relationship between the pitch, pattern size, and impact force and the contrast ratio for each tablet is shown in Tables 2 to 4. Table 3 shows the contrast ratio of the pattern placed on the surface of a lactose hydrate tablet, Table 4 shows the contrast ratio of the pattern placed on the surface of a tadalafil tablet CI 20 mg tablet, and Table 5 shows the contrast ratio of the pattern placed on the surface of a microcrystalline cellulose tablet.

[0076]

[0077]

[0078]

[0079] 0.1mm x 0.1mm (0.01mm ２ Although some of the patterns 715a of 0.2 mm × 0.2 mm (0.04 mm) were visible, the area was small and the contrast ratio could not be calculated. ２ ) or more gives good visibility to the identification information. From the results of Figures 15 to 17 and Tables 3 to 5, it is clear that patterns with a contrast ratio of 1.05 or more are visible as identification information. Patterns with a contrast ratio of 1.04 or less are not visible as identification information. It is also clear that the contrast ratio has a positive correlation with the striking pressure. By setting the striking pressure to 3 kN, the area of ​​0.2 mm x 0.2 mm (0.04 mm ２ It was also revealed that the pattern 715b of the tablet 100 shown in FIG. 1 is sufficiently visible. It was also revealed that the contrast ratio tends to increase as the distance P between two adjacent recesses increases. It is estimated that when the distance P decreases, the overlapping area between the two adjacent recesses increases, making the convex shape of the pattern on the tablet surface unclear and reducing the contrast ratio. This example revealed that arranging two adjacent recesses at an interval of 0.05 mm further improves the visibility of the identification information.

[0080] [Arithmetic mean height of pattern] Test pieces were prepared to evaluate the arithmetic mean height (Sa) of the pattern placed on the tableting surface of the punch and the Sa of the pattern formed on the tablet surface. Fig. 18A is an image showing the top surface of test piece 830, and Fig. 18B is a schematic diagram showing the top surface of test piece 830. On the top surface of test piece 830, there were patterns 815a, 815b, 815c, 815d, 815a, 815b, 815c, 815cb, 815d, 815dc, 815bb, 815bc ... ２ Each pattern was formed by irradiating the laser three times.

[0081] Further, as punch A, punch 600 having the tableting surface 631 shown in FIG. 5A was used. For punch A, a pattern was formed by irradiating the laser three times. For punches B-1 to B-4, punches arranged in the same pattern as the punches shown in FIG. 14A (with changed spacing P) were used. As punch C, a punch for tableting tablets having identification information in the form of a 1.0 mm square checkerboard pattern shown in FIG. 10A or a 0.5 mm square checkerboard pattern shown in FIG. 10B was used. As a reference example, punch D was prepared for tableting tablets having the markings shown in FIG. 19.

[0082] FIG. 20 shows optical microscope images of the patterns arranged on punches A to D photographed at 20x magnification. In FIG. 20, punch B-1 shows pattern 815a in which the spacing P is set to 0.01 mm, punch B-2 shows pattern 815b in which the spacing P is set to 0.03 mm, punch B-3 shows pattern 815c in which the spacing P is set to 0.05 mm, and punch B-4 shows pattern 815d in which the spacing P is set to 0.07 mm. Punch C shows a punch pattern for tableting tablets having identification information in the form of a 1.0 mm square checkerboard pattern. Punch D shows a protruding portion of the punch corresponding to the letter "S" engraved on the tablet shown in FIG. 19. The plain portion indicates the portion of the punch shown in FIG. 5A in which no protruding portion corresponding to the pattern or engraving is arranged.

[0083] In addition, using a laser microscope (color 3D laser microscope VK-X3000, Keyence Corporation), the arithmetic mean height (Sa) was measured for punches A to D. The measurement results are shown in Table 6.

[0084]

[0085] For punch A, which has different numbers of laser irradiations shown in Table 6, Sa was 0.62 μm to 0.83 μm when the number of irradiations was two, and Sa was 1.07 μm when the number of irradiations was three. Sa was 1.03 μm when the number of irradiations was four, and it was confirmed that there was no difference in pattern transferability when the number of laser irradiations was three or more. Because Sa in the plain area of ​​punch A was 0.1 μm or less, a difference of 10 to 20 times was confirmed compared to the area where the multiple recesses that make up the pattern were arranged.

[0086] In punch B with different laser irradiation intervals P, as shown in Figure 20, the smaller the interval P, the more the shape of the laser-induced irradiation marks disappeared. However, in the patterns with intervals P of 0.03 μm to 0.07 μm, Sa was approximately 1.9 μm, while in the pattern with intervals P of 0.01 μm, Sa was approximately 2.1 μm, and no significant difference was observed.

[0087] The same laser irradiation conditions were used for the three-time irradiation of punch 1, in which the laser was irradiated three times, and the pattern in which the interval P of punch B was set to 0.05 mm, but the values ​​of Sa were significantly different. This is thought to be because punch A had a chromium nitride coating on its surface, while punch B had not been surface treated.

[0088] For punch C, Sa was measured due to the difference in punch shape (Φ9.0, Sumikaku R). Sa was about 1.5 μm to 1.6 μm, and the difference from the uncoated area was about 20 times, similar to punches A and B.

[0089] Pestle D, which is used for engraving, is subjected to an uneven surface treatment, as in the above examples. The (engraved portion) of Pestle D has an Sa of 18 μm or more, which is a larger value than the above examples of Pestles A to C. These results suggest that the pattern of the pestle in this example has an Sa in the range of 0.2 μm to 2.5 μm, which is distinct from the Sa of the plain portion and the engraving.

[0090] Using Pestles A to D, tablets 1 to 5 having the compositions shown in Table 7 were produced.

[0091]

[0092] Figure 21 shows an optical microscope image of the pattern arranged on the surface of tablet 1 photographed at 20x magnification. Figure 21 shows optical microscope images of punches B-1 to B-4, punch C, and the plain area. Figure 22 is a 3D image showing the pattern portion of punch A irradiated with a laser three times, the plain area, and the engraved "S" on the tablet compressed with punch D of the reference example for tablets 1 to 4 compressed at 5 kN. The arithmetic mean height (Sa) was measured for punches A to D using a laser microscope (color 3D laser microscope VK-X3000, Keyence Corporation). The contrast ratio of the arithmetic mean height (Sa) of the pattern relative to the plain area in the patterned tablets is also shown. The measurement results are shown in Tables 8 to 11.

[0093]

[0094]

[0095]

[0096]

[0097] For tablet 1, Sa was evaluated for each punch. As shown in Table 8, the surface pattern of the punch was transferred to tablet 1, so the laser irradiation marks disappeared more as the spacing P became smaller, but no significant difference in Sa was observed due to differences in the shape of the punch and the spacing P. Also, as shown in Figure 22, the unevenness that constitutes the pattern can be clearly seen on all tablets, and the difference from the plain area is clear. Furthermore, in the engraving of punch D of the reference example, the height of the corresponding part is significantly lower, so the engraving was distinguishable from the patterns of the above examples.

[0098] When examining the effects of differences in the compositions of tablets 1 to 4, it was confirmed that when tablets were compressed under low pressure conditions (3 kN), the Sa of tablet 3 tended to be larger than that of tablets 1, 2, and 4. This tendency was thought to be due to the difference in moldability of each component, since the composition of tablet 3 is a mixture of a stirred kneaded product and a post-additive such as crystalline cellulose, which have significantly different properties. However, at a hammering pressure of 5 kN or more, the effect of differences in components became smaller, and almost no difference was observed in the Sa of tablets compressed using a punch irradiated with the laser of this example three or more times. From these results, it was inferred that the impact of the hammering pressure during tableting has a greater effect on Sa than differences in the components of the composition constituting the tablet. Generally, because a hammering pressure of 5 kN (100 MPa) or more is often used, it is thought that the impact of differences in the components of the composition constituting the tablet on Sa is minor.

[0099] When tableted under low pressure conditions (2 kN and 3 kN), Sa of the pattern on the tablet surface was about 0.9 μm to 3.1 μm, while Sa of the plain area was about 0.7 μm to 1.8 μm, and Sa varied greatly depending on the compression pressure and the components of the tablet composition. However, in the present invention, just as contrast is generated by the coexistence of areas with different surface conditions on the same surface of the tablet, making the pattern visible, the contrast ratio between the concave-convex pattern and the plain area present on the same surface of the tablet (Sa of the concave-convex pattern / Sa of the plain area) was almost always 1.00 or more.

[0100] The Sa of the stamped portion of the punch and the Sa of the tablet were similar values, regardless of the components of the composition that constitutes the tablet. This is thought to be because the depth (height) of the stamp is much larger than the unevenness caused by the components and the impact pressure, which cancels out the differences. The Sa of the stamped portion of the punch used in the reference example was approximately 18 μm to 27 μm, which was significantly different from the Sa of the pattern (0.9 μm to 3.1 μm). Therefore, it became clear that by using Sa as an index of unevenness, it is possible to distinguish between the pattern and the stamp on the tablet surface.

[0101] 10 Preparation, 11 Uncoated tablet, 13 Region, 15a Pattern, 15a-1 Uneven pattern, 15b Pattern, 15c Pattern, 17 Uneven structure, 17a Convex portion, 600 Upper punch, 613 Region, 615a Pattern, 615a-1 Uneven pattern, 615b Pattern, 615c Pattern, 617 Concave portion, 619 Convex rib, 630 Tip portion, 631 Tableting surface, 650 Main body, 670 Head, 700 Lower punch, 715a Pattern, 715b Pattern, 715c Pattern, 715d Pattern, 715e Pattern, 720 Mark, 730 Tip portion, 731 Tableting surface, 750 Main body, 770 Head, 815a Pattern, 815b Pattern, 815c Pattern, 815d Pattern, 830 Test piece

Claims

1. A pharmaceutical preparation comprising: a first portion having a plurality of textured structures arranged on the surface of the preparation; and a second portion having no textured structures arranged on the surface of the preparation, wherein the first portion is arranged adjacent to the second portion, and the first portion or the second portion constitutes at least one pattern having identification information.

2. The formulation of claim 1, wherein the plurality of concave-convex structures have a maximum peak height (Rp) of 1.0 μm to 13.2 μm.

3. The formulation according to claim 1, wherein the arithmetic mean height Sa of the first portion is 0.80 μm or more and 10.00 μm or less, and the ratio of the arithmetic mean height Sa of the first portion to the arithmetic mean height Sa of the second portion is 1.05 or more.

4. The preparation according to claim 1, wherein the contrast ratio of the arithmetic mean height Sa between the first portion and the second portion is 1.05 or more.

5. The formulation of claim 1, wherein the relative luminance contrast ratio between said first portion and said second portion is 1.05 or greater.

6. A tableting punch comprising a first portion having an uneven portion arranged on its tableting surface and a second portion having no uneven portion arranged on its tableting surface, wherein the first portion is arranged adjacent to the second portion, and the first portion or the second portion includes at least one first pattern having identification information, and the at least one first pattern corresponds to a second pattern constituting identification information for a formulation.

7. A tableting punch according to claim 6, wherein said at least one first pattern is composed of at least one linear pattern including said concave and convex portions.

8. A tableting punch as described in claim 6, wherein the arithmetic mean height Sa of the second portion is less than 0.20 μm, and the arithmetic mean height Sa of the first portion is 0.20 μm or more and 10.00 μm or less.

9. A method for manufacturing a tableting punch, comprising forming a first portion by irradiating only a portion of the tableting surface with a laser to form an uneven portion, wherein the first portion or a second portion adjacent to the first portion that is not irradiated with the laser forms at least one first pattern having identification information, and the at least one first pattern corresponds to a second pattern that constitutes the identification information of a formulation.

10. The method for manufacturing a tableting punch according to claim 9, wherein forming the at least one first pattern comprises irradiating the laser to form at least one uneven portion on the tableting surface.

11. The method for manufacturing a tableting punch according to claim 10, wherein forming the at least one uneven portion includes irradiating the tableting surface with the laser continuously or intermittently to form at least one irradiation mark.

12. A method for producing a formulation, comprising tableting a pharmaceutical composition using a tableting punch according to any one of claims 6 to 8 or a tableting punch produced by the production method according to any one of claims 9 to 11.

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