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    • 专利摘要:
    microneedle, microneedle array and device, and, method for administering a drug. The aim of the present invention is to provide a microneedle and microneedle arrangement capable of supporting not only a drug but also a stabilizer or thickener in large quantities and offering favorable piercing properties. the present invention is a microneedle for administering a drug transdermally, the microneedle comprises a distal end section, a stem section and a base section; (i) the distal end apex angle (a) being in the range of 15 to 60°; (ii) the distal end diameter (d0) being in the range from 1 to 20 (mi)m; (iii) the area (a3) of the upper surface of the base section being greater than the area (a2) of the lower surface of the shank section; (iv) formulas (1) and (2) being satisfied: h/d4 (greater than or equal to) 3 (1) (h is the total height and d4 is the diameter of the bottom surface of the base section) and (beta) ( greater than or equal to) 90 - 0.5(alpha) (2) (beta is the angle formed by a lateral surface of the shank section and the upper surface of the base section, and (alpha) is the apex angle of the distal end ); and (v) a solid drug-containing composition being attached to the lateral surface of the shank section and satisfying the formula (5): 10° (less than or equal) y (less than or equal) 60° (5) (y is the angle formed by tangent lines connecting the apex point of the distal end section and points on the surface of the solid composition attached to the lateral surface of the shank section on the same side).
    公开号:BR112014026570B1
    申请号:R112014026570-4
    申请日:2013-04-24
    公开日:2021-06-29
    发明作者:Kiyotsuna Toyohara；Taishi Tanaka；Kazuki Kohno；Takashi Oda；Koichi Masaoka；Katsunori Kobayashi；Masaki Ishibashi；Hidetoshi Hamamoto
    申请人:Medrx Co., Ltd；
    IPC主号:
    专利说明:

    TECHNICAL FIELD
    [0001] The present invention relates to a microneedle and a microneedle arrangement. More specifically, it refers to a microneedle and microneedle array capable of injecting a drug into the surface layer or stratum corneum of the skin easily, safely and efficiently. PRIOR TECHNIQUE
    [0002] Until now, to administer a drug or the like to the biological surface of a patient, that is, to the surface of the skin or mucous membrane, a method of applying a liquid substance or a powdery substance has been employed in most cases. However, since the area to which a drug can be applied is limited to the surface of the skin, a patient suffers on a daily basis from the drug applied by perspiration or contact with foreign matter, thus making it difficult to administer an appropriate amount of a drug effectively.
    [0003] As an alternative to the application of a drug to the biological surface, it is proposed to administer a drug in a living body through a microneedle. Also, proposals have been made to improve the proper piercing of the microneedle.
    [0004] For example, in the methods of Patent Document 1 and Patent Document 2, a microneedle and a microneedle arrangement are proposed, both of which are hardly broken and bent. However, the piercing properties of the microneedle and microneedle array are not satisfactory.
    [0005] Patent Document 3 proposes a method of facilitating the perforation by bending a conical surface or a pyramidal surface towards the interior of a microneedle. However, since the method set forth by Patent Document 3 makes use of volumetric shrinkage when a polymer solution is applied to a matrix to be gelled and dried, it is not suitable for a thermoplastic resin.
    [0006] Patent document 4 describes a microneedle that is formed from a water-soluble or water-swellable resin, shaped as a spindle, a truncated pyramid or a conical pyramid and coated with a lubricant component.
    [0007] Patent document 5 describes a method of administering a drug under the epidermis by loading a microneedle with a drug efficiently. This is a technology that can be applied to a liquid drug, but it is not satisfactory as a technology that can properly achieve perforation, drug loaded quantity, and medication property for a solid drug.
    [0008] (Patent Document 1) JP-A 2007-130030
    [0009] (Patent Document 2) JP-A 2007-190112
    [00010] (Patent Document 3) JP-A 2008-142183
    [00011] (Patent Document 4) JP-A 2010-029634
    [00012] (Patent Document 5) JP-A 2007-260351 DESCRIPTION OF THE INVENTION
    [00013] It is an objective of the present invention to provide a microneedle and a microneedle arrangement that can be introduced into the epidermis layer of a patient smoothly, have safety and simplicity and are capable of administering a predetermined drug without pain. It is another object of the present invention to provide a microneedle and microneedle array that can support not only a drug, but also a stabilizer or thickener in large amounts and have excellent suitability for piercing. It is another object of the present invention to provide a microneedle device including a microneedle array.
    [00014] The present invention is a microneedle for administering a drug transdermally, comprising an upper section, a stem section and a base section, wherein: the apex angle of the tip (α) is 15 to 60°; tip diameter (Do) is 1 to 20 µm; the area (A3) of the upper surface of the base section is greater than the area (A2) of the lower surface of the shank section; the following expressions (1) and (2) are satisfied;
    (H is the total height, and D4 is the diameter of the bottom surface of the base section).
    (β is the angle between the lateral surface of the shank section and the upper surface of the base section, and α is the apex angle of the tip); and a solid drug-containing composition is attached to the side surface of the rod section and the following expression (5) is satisfied.
    (y is the angle formed by tangent lines connecting the apex of the upper surface and the surface of the solid composition attached to the lateral surface of the shank section).
    [00015] The present invention is also a microneedle arrangement including a plurality of the above microneedles. BRIEF DESCRIPTION OF THE DRAWINGS
    [00016] Fig. 1 is a schematic diagram of the microneedle of the present invention; Fig. 2 is a schematic diagram of the upper section of the microneedle of the present invention; Fig. 3 is a schematic diagram of the microneedle carrying a drug; Fig. 4 shows a microneedle before immersion in Example 4; Fig. 5 shows the microneedle after the first immersion time in Example 4; Fig. 6 shows the microneedle after the second immersion time in Example 4; shows the microneedle after the third immersion time in Example 4; Fig. 8 shows the microneedle after the fourth immersion time in Example 4; Fig. 9 shows the microneedle after the fifth immersion time in Example 4; 10 shows the microneedle after the sixth immersion time in Example 4; Fig. 11 shows the microneedle after the seventh immersion time in Example 4; Fig. 12 is a schematic diagram showing a method of evaluating drilling performance in the Examples 5 to 7 and Comparative Examples 1 to 3; Fig. 1 3 shows the evaluation results of Examples 5 to 7 and Comparative Examples 1 to 3; Fig. 14 is a schematic diagram showing a method of evaluating drilling performance in Examples 8 and 9 and Comparative Examples 4 to 6; and Fig. 15 shows the evaluation results of Examples 8 and 9 and Comparative Examples 4 to 6.Explanation of symbolsDo: tip diameterDi: diameter of lower surface of upper sectionD : diameter of lower surface of shank section D3: diameter of top surface of base section D4: diameter of bottom surface of base section H: total heightHi: height of top sectionH2: height of shank sectionH3: height of base section a: tip apex angle β: angle between side surface of shank section and upper surface of basey section: angle formed by apex of upper section and uppermost layer of solid composition attached to lateral surface of shank sectionδ: angle formed by lines connecting apex of upper section and surface of composition solid piece attached to the upper section BEST MODE FOR CARRYING OUT THE INVENTION
    [00017] The microneedle of the present invention is a drug-bearing microneedle, in which a solid composition comprising a drug is attached to the lateral surface of the rod section. The microneedle supporting a drug may be referred to as a "supporting microneedle". The microneedle, before drug support, can simply be referred to as a “microneedle”. The same can be said of the microneedle arrangement.<microneedle>
    [00018] The microneedle will be explained with reference to Fig. 1. Fig. 1 is an overall view of the microneedle. The microneedle has a base section, a rod section for holding a drug, which is formed over the base section, and an upper skin piercing section, which is formed over the rod section, and all of the three sections are unified. (base section)
    [00019] The base section may be shaped as a polygonal truncated pyramid, such as a triangular, quadrangular or hexagonal truncated pyramid, or conical truncated pyramid. The diameter (D4) of the bottom surface of the base section is preferably 30 to 500 µm, more preferably 100 to 250 µm. The diameter (D3) of the top surface of the base section is preferably 30 to 500 µm, more preferably 90 to 240 µm. The height (H3) of the base section is preferably 35 to 600 µm, more preferably 100 to 500 µm. The diameter (D4) of the bottom surface of the base section is a diameter when the bottom surface of the base section is approximated to a circular surface. The diameter (D3) of the top surface of the base section is a diameter when the top surface of the base section is approximated to a circular surface. (shank section)
    [00020] The stem section can be shaped as a polygonal truncated pyramid, such as a triangular, square or hexagonal truncated pyramid, or conical truncated pyramid. The rod section has a pedestal shape so that the top surface can be mounted on top of it. The diameter (D2) of the lower surface of the shank section is preferably 25 to 450 µm, more preferably 25 to 235 µm. The diameter (D ) of the lower surface of the shank section is a diameter when the lower surface of the shank section is approximated to a circular surface. The diameter (Di) of the upper surface of the shank section is the same as the diameter (DJ of the lower surface of the upper section. The height (H ) of the shank section is preferably 50 to 600 μm, more preferably 50 to 500 μm , much more preferably 50 to 240 µm. The stem section serves the function of fixing a drug to the wall thereof and transporting the drug to a predetermined delivery position.(upper section)
    [00021] The top surface may be shaped as a polygonal truncated pyramid, such as a triangular, square or hexagonal truncated pyramid, or conical truncated pyramid. The diameter (Di) of the lower surface of the upper section is preferably 1 to 170 µm, more preferably 10 to 80 µm. The diameter (Di) of the lower surface of the upper section is a diameter when the lower surface of the upper section is approximated to a circular surface. The height (Hi) of the top section is preferably 1 to 640 µm, more preferably 10 to 150 µm.
    [00022] The tip diameter (Do) is 1 to 20 µm, from the point of view of improving the effect of perforating the epidermis layer of a patient gently, the tip diameter (Do) is preferably 1 to 10 µm. When the tip diameter (Do) is greater than 20 μm, the resistance at the time of skin piercing becomes great, so it is difficult to pierce the skin and the tip tends to deform disadvantageously.
    [00023] The tip apex angle (α) is 15 to 60°, preferably 30 to 60°. When the tip apex angle (α) falls within the range of 30 to 45°, a more excellent effect is obtained. When the apex angle of the tip (α) is outside the range of 15 to 60°, the resistance at the time of skin piercing becomes great, so it is difficult to pierce the skin and the tip tends to deform disadvantageously.( total height)
    [00024] The total height (H) is the sum of the thickness (X) of the skin when the effect of a drug is efficiently developed and the length (Y) of the space in consideration of sagging skin when the microneedle is slowly inserted into the skin painless. X is preferably 15 to 800 µm, more preferably 100 to 500 µm. Y is preferably 30 to 500 µm, more preferably 50 to 300 µm. The total height (H) is preferably 120 to 800 µm, more preferably 150 to 500 µm. (expressions (1) and (2))
    [00025] The microneedle satisfies the following expression (1).
    (H: total height, Dμ diameter of base section bottom surface)
    [00026] The upper limit of H/D4 is preferably not greater than 20, from the viewpoints of the object of the present invention and moldability. When H/D4 is less than 3, the resistance at the time of skin piercing becomes great, so it is difficult to pierce the skin and the microneedle tip tends to deform, which is inconvenient in terms of purpose and effect. H/D4 is preferably 3 to 10, more preferably 3 to 6.
    [00027] The microneedle satisfies the following expression (2).

    [00028] In expression (2), β is the angle between the lateral surface of the shank section and the upper surface of the base section, as shown in Fig. 1. ot is the tip apex angle. In the microneedle, the area (A3) of the upper surface of the base section is greater than the area (A2) of the lower surface of the shank section. (A3/A2)
    [00029] As described previously, the microneedle has the base section, the rod section for holding most of a drug, which is mounted over the base section, and the upper surface for skin piercing, which is formed about the stem section, and all of the three sections are unified.
    [00030] The microneedle preferably satisfies the following expression (6).
    (A3: upper surface area of base section, A2: lower surface area of shank section)
    [00031] Since the area (A3) of the upper surface of the base section is greater than the area (A2) of the lower surface of the rod section, when a drug is loaded, it can be closely adhered to the upper surface of the section. base to be fixed, thus making it possible to reduce the amount of drug fixed near the upper section. Thus, the amount of drug to be loaded can be increased without impairing suitability for piercing. A3/A2 is more preferably 1.2 to 3. When this value is too small, a sufficient amount of drug fixed on the base section cannot be assured and when the value is too large, the amount of drug loaded on the section of rod is reduced, so that even when the microneedle is pierced, the amount of the drug capable of being directly injected into the body is reduced, (support microneedle)
    [00032] The present invention is a microneedle in which a solid composition comprising a drug is attached to the lateral surface of the rod section. The drug content in the solid composition is preferably 5 to 90 parts by weight, more preferably 10 to 80 parts by weight based on 100 parts by weight of the solid composition.
    [00033] The solid composition preferably comprises a water-soluble polymer as a binder component. Although the water soluble polymer is not particularly limited, a water soluble polymer which has a low skin irritation capacity is preferably used.
    [00034] When the drug is fixed to the microneedle, the microneedle has another shape according to the fixed state of the drug. The microneedle of the present invention can assume the shape shown in Fig. 3. When the drug is attached to the stem section and rarely to the upper section, the microneedle can ensure almost the same level of corneal piercing property as that of a microneedle not supported with any drugs. After the drug is supported, desirably the fixed drug does not protrude from the angle of the upper section after coating.
    [00035] The microneedle carrying a drug of the present invention satisfies the following expression (5), preferably the following expression (5-i), more preferably the following expression (5-ii). When the angle of the microneedle carrying a drug of the present invention falls within the range of the following expression (5), the drug can be loaded without impairing suitability for piercing.
    [00036] The microneedle carrying a drug of the present invention preferably satisfies the following expression (6), from the point of view of piercing property and the amount of drug loaded. Furthermore, the drug-carrying microneedle of the present invention preferably satisfies the following expression (7), from the viewpoints of piercing property and the amount of drug loaded.
    Y is the angle formed by tangent lines connecting the apex of the upper surface and the surface of the solid composition attached to the lateral surface of the shank section.
    δ is the angle formed by lines connecting the apex of the upper surface and the surface of the solid composition attached to the upper section.
    (damn it)
    [00037] Biologically active agents, such as hormones and vaccines, are used as the drug. Specific drug examples include growth hormone releasing hormone (GHRH), growth hormone releasing factor (GHRF), insulin, insultropin, calcitonin, octreotide, endorphin, TRN, NT-36 (chemical name: N-[[ (s)-4-oxo-2-azetidinyl]carbonyl]-L-histidyl-L-prolinamide), liprecin, pituitary gland hormones (eg, HGH, HMG, desmopressin acetate, etc.), follicle luteoids, aANF, growth factors such as growth factor releasing factor (GFRF), bMSH, GH, somatostatin, bradykinin, somatotropin, platelet-derived growth factor releasing factor, asparaginase, bleomycin sulfate, chemopapain, cholecystokinin, chorionic gonadotrophin, erythropoietin, epoprostenol (platelet aggregation inhibitor), glucagon, HCG, hirulog, hyaluronidase, interferon α, interferon β, interferon y, interleukins, interleukin-10 (IL-10), erythropoietin (EPO), stimulating factor of granulocyte macrophage colony (GM-CSF), granulocyte colony-stimulating factor (G-CSF), glucagon, leutinizing hormone-releasing hormone (LFLRH), LHR.H analogues (such as goserelin, leuprolide, buserelin, triptorelin, gonadorelin, and nafarelin, menotropins (urofolitropin (FSH) and LH)), oxytocin, streptokinase, tissue plasminogen activator, urokinase, vasopressin, deamino [Val4, D-Arg8] arginine vasopressin, desmopressin, corticotropin (ACTH), ACTH analogues such as ACTH (1- 24), ANP, ANP clearance inhibitors, angiotensin II antagonists, antidiuretic hormone agonists, bradykinin antagonists, ceredase, CSI's, calcitonin gene-related peptide (CGRP), enkephalins, FAB fragments, IgE peptide suppressors , IGF-1, neurotrophic factors, colony stimulating factors, parathyroid hormone and agonists, parathyroid hormone antagonists, parathyroid hormone (PTH), PTH analogues such as PTH (1-34), pros antagonists taglandin, pentigotide, protein C, protein S, renin inhibitors, thymosin cc-1, thrombolytics, TNF, vasopressin antagonist analogues, α-1 antitrypsin (recombinant), and TGF-β.
    [00038] The drug is also selected from the group consisting of antigens in the form of proteins, polysaccharide conjugates, oligosaccharides and lipoproteins. These subunit vaccines include Bordetella pertussis (acellular-recombinant PT accince), Clostridium tetani (purified, recombinant), Corynebacterium diptheriae (purified, recombinant), Cytomegalovirus (glycoprotein subunit), group A streptococcus (glycoprotein subunit, polysaccharide glycoconjugate of group A with tetanus toxoid, Protein M/peptides linked to toxing subunit carriers, Protein M, multivalent type-specific epitopes, cysteine protease, C5a peptidase), hepatitis B virus (Pre SI, Pre-S2, S, recombinant core protein), hepatitis C virus (recombinant expressed surface proteins and epitopes), human papilloma virus (Capsid Protein, recombinant L2 and E7 Protein TA-GN [from HPV-6], MEDI-501 recombinant VLP LI of HPV-11, quadrivalent recombinant BLP L1 [from HPV-6], HPV-11, HPV-16, and HPV-18, LAMP-E7 [from HPV-16]), Legionella pneumophila (purified bacteriological surface protein), Neisseria meningitis (glycoconjugate with tetanus toxoid), Pseudomonas aeruginosa (synthetic peptides), rubella virus (synthetic peptide), Streptococcus pneumoniae (glycoconjugate [1, 4, 5, 6B, 9N, 14, 18C, 19V, 23F] conjugated to meningococcal B OMP, glycoconjugate [4, 6B, 9V, 14, 18C, 19F, 23F] conjugated to CR.M197, glycoconjugate [1, 4, 5, 6B, 9V, 14, 18C, 19F, 23F] conjugated to CRM1970, Treponema pallidum (surface lipoproteins), Varicella-zoster virus (subunit, glycoproteins) and Vibrio cholerae (lipopolysaccharide conjugate).
    [00039] Adrenaline, nicotine, biophosphonates and fentanyl are also included as the drug.(surface roughness)
    [00040] The surface roughness of the microneedle shank section preferably satisfies 5 nm < Rz < 10 µm, more preferably 50 nm < Rz < 5 µm. When the surface roughness of the rod section is high at the time of supporting a drug solution, the amount of drug to be supported advantageously increases. When the surface roughness is high, the rod section has the effect of preventing spheroidization by the surface tension of the drug solution at the time of supporting the drug. The surface roughness threshold is a value just before the occurrence of deformation, breakage and production reduction, as it becomes resistant to release at the time of molding. Irregularities can be produced through the use of machining traces intentionally. Rz is a measured value according to JIS B0601 -2001.(thermoplastic resin)
    [00041] The microneedle and microneedle array preferably contain a thermoplastic resin as the main component. The content of thermoplastic resin in the microneedle and microneedle array is preferably not less than 50% by weight, more preferably not less than 90% by weight, most preferably 100% by weight.
    [00042] The thermoplastic resin is preferably at least one selected from the group consisting of polycarbonates, polypropylene, cycloolefin polymers, cycloolefin copolymers, polyethylene terephthalate, acrylic resin, polyphenylene sulfide, polyether ether ketone, terephthalate of polybutylene, polybutylene naphthalate and polyethylene naphthalate.
    [00043] The microneedle and microneedle array preferably contain a biodegradable resin as the main component.
    [00044] The biodegradable resin is preferably at least one selected from the group consisting of polyglycolic acid, polylactic acid, stereocomplex polylactic acid, plant-derived polycarbonate resin and polybutylene succinate.
    [00045] The plant-derived polycarbonate resin is a resin comprising a plant-derived raw material as the main component, preferably a polycarbonate resin containing a carbonate constituting unit represented by the following formula (a).

    [00046] The polyglycolic acid resin used in the present invention is preferably a glycolic acid homopolymer consisting of a recurrent glycolic acid unit, i.e. a glycolic acid homopolymer (PGA, including a glycolide ring opening polymer (GL ) which is a bimolecular cyclic ester of glycolic acid). More specifically, it may be a copolymer of another comonomer, i.e. a glycolic acid copolymer, as long as it does not contain less than 90% by weight of the above recurring unit. Polyglycolic acid has a molecular weight (Mw (weight average molecular weight) in terms of polymethyl methacrylate) measured by GPC using a hexafluoroisopropanol solvent of preferably 100,000 to 800,000, particularly preferably 130,000 to 750,000. When the molecular weight is too low, the molded product obtained tends to be unsatisfactory in terms of strength. When the molecular weight is too high, extrusion or molding of the molten mass can be difficult.
    [00047] The thermoplastic resin used in the present invention may contain additives such as a stabilizer, reinforcing agent and plasticizer. Examples of the stabilizer include an antioxidant, heat stabilizer, hydrolysis resistance agent, electron beam stabilizer and ultraviolet stabilizer. Examples of the reinforcing agent include inorganic fillers and organic fillers. Additives that do not harm a living body are preferably used.<microneedle production process>
    [00048] The microneedle and microneedle array can be manufactured by the following steps. An apparatus described in JP-A 2008-49646 can be used as the molding machine. (merging step)
    [00049] This is the step of heating the resin at a temperature of 200 to 300°C to melt it.(coating step)
    [00050] This is the step of applying the molten resin to a mold kept at 100 to 250°C.
    [00051] The mold temperature is preferably raised at a rate of 5°C/sec. at 10°C/sec. In the process of the present invention, after resin is applied to the mold held at 100 to 250°C and molded, the mold temperature is reduced to remove a molded product from the mold. That is, when molding is carried out continuously, the mold temperature is repeatedly raised and lowered. Therefore, when the temperature rise rate and the temperature fall rate are high, the cycle time is advantageously reduced. To obtain the above temperature rise time, electromagnetic induction heating is preferably employed. Since electromagnetic induction heating does not increase the temperature of the entire mold, but allows the local temperature to rise, the energy required for molding can be reduced, (molding step)
    [00052] This is the molding step by applying a pressure of 0.1 to 30 MPa for 5 to 200 seconds. (demolding step)
    [00053] The molded product is removed from the mold by reducing the temperature to 50 to 100°C at a rate of 5°C/sec. at 10°C/sec.
    [00054] In the above process, the resin temperature rise time is reduced and the molding time is short through the use of the cast resin compared to a process where a film is printed. The internal temperature of the resin is uniform and predetermined, thus making transfer with high precision possible. For example, as for producing a mold for molding, a method of manufacturing a mold by cutting a metal to produce a pattern and inverting it by electrocasting is employed. The method of making a mold is not limited to this one. (drug support step)
    [00055] The solid composition containing a drug can be attached to the lateral surface of the rod section by immersing the microneedle or microneedle array in a solution containing the drug, pulling it up and drying it. Therefore, dipping and drying are preferably repeated to obtain a desired amount of the supported drug.<microneedle array>
    [00056] In the present invention, a microneedle array including a plurality of the above microneedles can be used. The microneedle arrangement has both safety and simplicity and a microneedle density of preferably 1 to 1000/cm2 per needle, more preferably 100 to 1000/cm2 per needle because it can deliver a predetermined drug without pain. Although the amount of drug to be supported can be increased as the density becomes higher, greater force is required to push the microneedle and the microneedle array as the density becomes higher. Density is preferably a value at which a painless pressing force is obtained.
    [00057] Pressure force is the force required to pierce the skin with the microneedle and microneedle array. If it is too big, a patient feels pain at the time of application. Therefore, the pressing force is preferably 1 to 10 N, more preferably 1 to 5 N. Since the pressing force is limited, a microneedle with which the piercing is done smoothly with a small load is required.
    [00058] The microneedle array preferably has a piercing ratio of not less than 80% when it is pushed to a depth of 10 mm from the skin surface. When the microneedle array is pressed against the skin with a force of 5 Newtons (N) applied to a substrate having a diameter of 10mm, it preferably has a piercing ratio of not less than 80%.<microneedle device>
    [00059] The present invention includes a microneedle device containing a microneedle or microneedle array carrying a drug and an applicator for administering the drug to a living body. Like the applicator, a known applicator that pushes the microneedle array manually or mechanically can be used.<method of administering a drug>
    [00060] According to the present invention, there is provided a method of administering a drug by piercing the skin surface with the microneedle or microneedle array carrying the drug. The drug is selected from biologically active agents, vaccines and the like as described above. The administration method of the present invention can be applied to living bodies such as mammals, including cows, pigs and humans. According to the administration method of the present invention, the microneedle or microneedle array can be introduced into a living body painlessly with small force.EXAMPLESExamples of the present invention will be given below.Example 1 (two-stage needle: PGA, fixation normal)
    [00061] The microneedle was manufactured as follows. A mold was fabricated by cutting a metal to produce a pattern that is the base of the mold and inverting the pattern by nickel electrosmelting. As for the microneedle shape, the tip diameter (Do) was 7 μm, the diameter (Di) of the lower surface of the upper section was 60 μm, the diameter (D2) of the lower surface of the shank section was 100 μm, the diameter (D4) of the bottom surface of the base section was 150 μm, the total height (H) was 600 μm, the height (Hi) of the upper section was 65 μm, the height (H2) of the shank section was 240 μm, the tip apex angle (α) was 45°, and 120 needles were used.
    [00062] For microneedle molding, the Micro-Nano Melt Transcription molding machine (trademark) of The Japan Steel Works, Ltd. was used. Polyglycolic acid (PGA) was used as the resin, melted at 260°C and applied to a mold at 200°C. Then, the resin was pressed at a pressure of 20 MPa for about 30 seconds, the mold obtained was cooled to 80°C, and a microneedle array was removed from the mold. The obtained microneedle array was observed using a laser microscope to confirm that the mold shape was accurately transferred without breakage and deformation of the microneedle array. (drug support)
    [00063] 1.5 g of polyvinyl pyrrolidone (K20) and 0.1 g of Blue No. 1 as a drug were dissolved in 8.4 g of water. The resulting solution was applied to a metal plate to form a liquid film. The molded microneedle was fixed to an XYZ stage, the upper section of the microneedle was immersed in the liquid film above to a height of the base section or to a depth of about 0.3 mm while being observed through a microscope, and the microneedle was pulled up immediately and dried for 1 minute. This operation was repeated 5 times to fix the drug. (evaluation)
    [00064] As for the obtained microneedle arrangement, (1) the amount of fixed drug, (2) the angle (y) between the fixed material and the tip, (3) surface roughness and (4) perforation property were evaluated. As for the measurement of y, when the adhered drug projected above the slanted extension line of the upper section of the microneedle, the angle formed by tangent lines connecting the apex of the upper surface and the fixed material was measured. When the amount of drug adhered was small and the fixed drug material was existing below the sloping extension line of the upper section of the microneedle, the angle formed by lines connecting the upper surface and most projecting part of the fixed material was measured.
    [00065] The evaluation of the angle (y) between the fixed material and the tip is 45° or less as shown in Table 1 and does not differ from the value (45°) of the apex angle of the tip (a) before coating. This makes it clear that a portion, except for the upper section of the microneedle, can carry drug adhered to the upper surface based on the shape of each of the two-stage needles of the microneedle array of the present invention when the microneedle is immersed in the solution of drug and pulled up, whereby the drug is rigidly attached to the upper surface, with the result that the tip of the microneedle is exposed and the pointed upper section can be maintained even after application of the drug solution.
    [00066] After the microneedle was pressed against the abdomen of a rat, whose fur was shaved, for 10 seconds, the needle was observed to check whether a pigment had peeled or not, to evaluate the perforation property based on the following criteria.O: pigment peeling is observed in 70% or more of needles Δ: pigment peeling is observed in 20% or more of needles X : pigment peeling is observed in less than 20% of needles Example 2 (two-stage needle: SUS, normal fixation)
    [00067] A microneedle having the same shape as that of Example 1 was manufactured by cutting stainless steel, and a drug was closed to the microneedle by the same method as in Example 1 to make the above evaluations in the same manner as in Example 1.Example 3 (two-stage needle: PGA, fixation of a small amount)
    [00068] The microneedle manufactured in Example 1 was used to fix a drug by the same method as in Example 1, but the number of times of dipping was 3. The above evaluations were done in the same way as in Example 1.
    [00069] The results are shown in Table 1. In Table 1, a description method for specifying the shape of the two-stage needle of the present invention is employed and does not correspond to a method for a one-stage needle. For example, when the one-stage needle is described by the method for the two-stage needle, D2=D3. In the case of the two-stage needle, Ü2<D3.Example 4The microneedle was manufactured as follows.
    [00070] A mold was fabricated by cutting a metal to produce a pattern that is the base of the mold and inverting the pattern by nickel electrosmelting. As for the microneedle shape, the tip diameter (D(>) was 7 µm, the diameter (D|) of the lower surface of the upper section was 60 µm, the diameter (D2) of the lower surface of the shank section was 75 μm, the diameter (D4) of the bottom surface of the base section was 150 μm, the total height (H) was 600 μm, the height (Hi) of the upper section was 65 μm, the height (EE) of the shank section was 235 µm, the apex tip angle (ot) was 45°, and 120 needles were used.
    [00071] For microneedle molding, the Micro-Nano Melt Transcription molding machine (trademark) (trademark) of The Japan Steel Works, Ltd. was used. Polyglycolic acid (PGA) was used as the resin, melted at 260°C and applied to a mold at 200°C. Then, the resin was pressed at a pressure of 20 MPa for about 30 seconds, the mold was cooled to 80°C, and a microneedle array was removed from the mold. The obtained microneedle array was observed using a laser microscope to confirm that the mold shape was accurately transferred without breakage and deformation of the microneedle array.
    [00072] 15 g of polyvinyl pyrrolidone (K90), 1 g of Blue No. 1 and 10•g of lidocaine hydrochloride salt were dissolved in 74 g of purified water to prepare a sample solution.
    [00073] The prepared sample solution was filled into a slit having a depth of 400 µm and a width of 400 µm, and the microneedle manufactured as described above was immersed in the sample solution until the drug solution was fixed to the base section and dried for 1 minute. Dipping and drying was repeated 7 times to observe the microneedle after drug fixation through a microscope (Figs. 4 to 11). The angle (y(°)) between the fixed material and the tip was evaluated in the same way as in Example 1.
    [00074] The amount of lidocaine hydrochloride was determined from the microneedle after 7 times of immersion.
    [00075] It was confirmed from the shape of the microneedle, after drug fixation, that most of the drug was first supported by the base section and then by the shank section, when the dip was repeated multiple times.
    [00076] Since the drug tends to be supported by a stepped portion and rarely supported by the upper surface of the needle, it is understood that the stepped portion can be used as a location for drug storage and this shape hardly harms the shape of the needle tip.

    Examples 5 to 7, Comparative Examples 1 to 3
    [00077] 20 g of polyvinyl pyrrolidone (K90), 1 g of Blue No. 1 and 10 g of lidocaine hydrochloride were dissolved in 69 g of purified water to prepare a sample solution.
    [00078] The prepared sample solution was filled into a slit having a depth of 500 μm and a width of 400 μm, and a stainless steel microneedle shown in Table 3 was immersed in the sample solution in the slit to its base section or to a depth of about 0.3 mm and dried for 2 minutes. Dipping and drying were repeated several times (4 times in Example 5, 4 times in Example 6, 4 times in Example 7, 10 times in Comparative Example 1 and 5 times in Comparative Examples 2 and 3). In comparative example 3, a slit having a depth of 500 µm and a width of 700 µm was used to apply the drug.

    [00079] The microneedle, after drug fixation, was observed through a microscope to assess the angle (y(°)) between the fixed material and the tip in the same way as in Example 1. The amount of drug supported was measured from the microneedle.
    [00080] Furthermore, the microneedle piercing performance was evaluated by the following method (see Fig. 12).1. The abdominal skin of Wistar 5w tf was placed and fixed onto a silicone sheet (thickness 5 mm, hardness 50°).2. The microneedle was inserted into the skin at a rate of 1 mm/min. and stopped when voltage reached 0.05N.3. The microneedle was removed, and 2% gentian violet was placed over the perforated site.4. The drug was left to rest for a few minutes.5. The perforated site was cleaned with ethanol.6. The existence or absence of a perforation mark was verified by a stereoscopic microscope. The indicates the perforated spot has been stained and x indicates the perforated location has not been stained.
    [00081] The above evaluation results are shown in Fig. 13. That is, as shown in Fig. 13, the perforation property is satisfactory until the value of y is up to 60°. It was found that the amount of drug capable of being supported differs by the shape of the microneedle even when the number of times of application is the same. That is, when H/D4 is 3 to 5, about 1 µg of the drug can be supported while, when H/D4 is 7.5, the amount of drug is greatly reduced to about 0.1 µg. and 9 (two-stage needle)
    [00082] A microneedle array molded by the same molding method as in Example 1 was used, except that the tip diameter (Do) was 7 µm, the diameter (D|) of the lower surface of the upper section was 60 µm, the diameter (D2) of the lower surface of the shank section was 75 µm, the diameter (D4) of the lower surface of the base section was 150 µm, the total height (H) was 6OO µm, the height (Hi) of the upper section was 65 μm, the height (H2) of the shank section was 235 μm, the apex angle of the tip (α) was 45°, and 120 microneedles were arranged in a 12 x 10 matrix at 800 μm intervals, as for the shape of the microneedle array. The shape of the microneedle is shown in Table 4.
    [00083] Coating was carried out by the following method.
    [00084] 1.0 g of polyvinyl pyrrolidone (K90), 1.0 g of OVA and 0.1 g of Blue No. 1 were dissolved in 7.9 g of purified water to prepare a sample solution. The prepared sample solution was filled into a slit having a depth of 400 µm and a width of 400 µm, and the microneedle was immersed in the sample solution in the slit to its base section or to a depth of about 0.3 mm and dried for 1 minute. Dipping and drying were repeated a number of times, shown in Table 4, to manufacture microneedles that differed in the amount of drug supported.
    [00085] Furthermore, the drilling performance was evaluated by the following method (Fig. 14).1. The abdominal skin of Wistar 5w tf was placed and fixed onto a silicone sheet (thickness 5 mm, hardness 50°).2. The microneedle was inserted into the skin at a rate of 1 mm/min. and stopped when tension reached 0.03N per needle.3. The microneedle was removed, and 2% gentian violet was placed over the perforated site.4. The drug was left to rest for a few minutes.5. The perforated site was cleaned with ethanol.6. The existence or absence of a perforation mark was verified by a stereoscopic microscope. The indicates that the perforated spot has been stained and X indicates that the perforated location has not been stained. Comparative Examples 4, 5 and 6 (one-stage needle)
    [00086] Microneedles were manufactured in the same way as in Example 1. As for the shape of each of the microneedles, the tip diameter (Do) was 7 µm, the diameter (D4) of the bottom surface of the base section was 150 µm , the total height (H) was 600 µm, the height (Hi) of the upper section was 65 µm, the apex angle of tip (oc) was 45°, and 97 needles were used. The shape of the microneedle is shown in Table 4.
    [00087] The drug was fixed by the same method as in Example 1 and evaluated in the same way as in Example 1. Evaluation of application and perforation property was carried out in the same manner as in Examples 8 and 9.
    [00088] The above evaluation results are shown in Table 5 and Fig. 15. As shown by these results, even when 230 μg of drug is supported by the microneedle array, as shown in Fig. 13 and Fig. 15, y tends to get big with a one-stage needle and hardly big with a two-stage needle, δ (angle formed by lines connecting the apex of the upper surface and the surface of a solid composition attached to the upper section) tends to become big with a one-stage needle and hardly become equally big with a two-stage needle. When y is 60° or higher, it is difficult to apply the microneedle and when y is 70°, the piercing property degrades. When δ is 60°, the perforation property is satisfactory, while when δ is 70°, the perforation property degrades. That is, when the drug is supported by the microneedle, both y and δ tend to become large with a single-stage needle whereas the sharpness of the upper section of a microneedle tends to be maintained and the piercing property is satisfactory with the two-stage needle even when the amount of drug supported is the same.
    [00089] Thus, it was found that even when the amount of drug applied is large, the tip angle is easily maintained in the two-stage needle. As a result, it has been shown that when the tip angle is within a predetermined range, if a sufficient amount of a drug is loaded, the piercing property is not impaired.

    Effect of the Invention
    [00090] Since the microneedle and microneedle array constituting the present invention have a two-stage needle shape, when the microneedle is immersed in a drug solution and pulled up, a staggered part may carry the drug solution adhered to the upper section. As a result, the stepped portion can be used as a place for drug storage and even when a large amount of drug is supported, the microneedle tip can be exposed and a sharp upper section can be maintained after application of the drug solution. damn it.
    [00091] The two-stage shape of the microneedle shown in Fig. 1 is a needle shape that makes it difficult to attach the drug to the upper section of the microneedle. As a result, the microneedle and microneedle array of the present invention can be inserted into a patient's epidermis layer smoothly when an acute upper section is maintained, has both safety and simplicity, and can deliver a predetermined drug without pain. Since the microneedle and microneedle arrangement constituting the present invention are excellent in carrying a drug, it is possible to administer the drug efficiently. Industrial Applicability
    [00092] The microneedle and microneedle array of the present invention can be used not only for medicinal purposes, but also in MEMS devices that require a fine needle structure, drug research and cosmetics.
    权利要求:
    Claims (9)
    [0001]
    1. Microneedle for administering a drug transdermally, characterized by the fact that it comprises a base section in the form of a truncated polygonal or conical pyramid, a rod section, formed in the base section, having the shape of a truncated polygonal or conical pyramid and an upper section formed in the shank section, wherein (i) a tip apex angle (α) at the upper section is from 15 to 60°; (ii) a tip diameter (OD) is from 1 to 20 μm;(iii) the area (A3) of the upper surface of the base section is greater than the area (A2) of the lower surface of the shank section;(iv) the following expressions (1) and (2) are satisfied;H /D4 > 3 (1)(H is the total height, and D4 is the diameter of the bottom surface of the base section).β > 90 - 0.5α (2)(β is the angle between the side surface of the base section). stem and the upper surface of the base section, and α is the apex angle of the tip); (v) and a solid composition containing the drug is attached to the lateral surface of the stem section and the following expression (5) is sati sfeita.10° < Y < 60° (5)(Y is the angle formed by tangent lines connecting the apex of the upper surface and the surface of the solid composition attached to the lateral surface of the shank section).
    [0002]
    2. Microneedle according to claim 1, characterized in that the solid composition contains a water-soluble polymer as a binding component.
    [0003]
    3. Microneedle according to claim 1, characterized in that it has a total height (H) of 120 to 800 μm.
    [0004]
    4. Microneedle according to claim 1, characterized in that it satisfies the following expression (6).1,2 < A3/A2 < 10 (6) (A3 is the upper surface area of the base section, and A2 is the lower surface area of the rod section).
    [0005]
    5. Microneedle according to claim 1, characterized in that the height (H3) of the base section is 100 to 500 μm.
    [0006]
    6. Microneedle according to claim 1, characterized in that it contains a biodegradable resin as the main component.
    [0007]
    7. Microneedle according to claim 6, characterized in that a biodegradable resin is at least one selected from the group consisting of polyglycolic acid, polylactic acid, stereocomplex polylactic acid, plant-derived polycarbonate resin and polybutylene succinate.
    [0008]
    8. Microneedle arrangement, characterized in that it includes the microneedles defined in any one of claims 1 to 7 at a density of 100 to 1,000 needle/cm2.
    [0009]
    9. Microneedle device, characterized in that it includes the microneedle arrangement as defined in claim 8 and an applicator for administration to a living body.
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    同族专利:
    公开号 | 公开日
    CN104321105B|2016-11-23|
    CN104321105A|2015-01-28|
    ES2730735T3|2019-11-12|
    KR20150003745A|2015-01-09|
    US20150094648A1|2015-04-02|
    US9974935B2|2018-05-22|
    CA2871575A1|2013-10-31|
    EP2842595B1|2019-03-20|
    JP5439633B1|2014-03-12|
    EP2842595A1|2015-03-04|
    AU2013253306A1|2014-11-13|
    WO2013162053A1|2013-10-31|
    RU2014147308A|2016-06-10|
    BR112014026570A2|2018-09-18|
    JPWO2013162053A1|2015-12-24|
    HK1205024A1|2015-12-11|
    MX2014012957A|2015-02-05|
    EP2842595A4|2015-12-09|
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    法律状态:
    2018-10-16| B25A| Requested transfer of rights approved|Owner name: MEDRX CO., LTD. (JP) |
    2018-12-04| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2019-12-03| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2021-05-04| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2021-06-29| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 24/04/2013, OBSERVADAS AS CONDICOES LEGAIS. |
    优先权:
    申请号 | 申请日 | 专利标题
    JP2012-099489|2012-04-25|
    JP2012099489|2012-04-25|
    PCT/JP2013/062735|WO2013162053A1|2012-04-25|2013-04-24|Microneedle and microneedle array|
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