JP6369992B2 - Dissolving microneedle formulation - Google Patents

Description

  The present invention relates to a dissolution type microneedle preparation.

  For example, a dissolved microneedle formulation is known as a method for administering physiologically active ingredients such as anti-inflammatory analgesics and blood flow promoters into the human body. The dissolution type microneedle preparation has a plurality of needle parts formed on one side of a sheet-like base material and has an adhesive part containing a physiologically active ingredient. When the dissolution type microneedle preparation is attached to the skin, the physiologically active ingredient is percutaneously absorbed while the base material and the needle part are dissolved.

As a dissolution type microneedle formulation, what is provided with the sticking part which has a base material containing a hyaluronic acid and a needle part, for example is mentioned (patent documents 1 and 2).
However, the dissolution type microneedle preparation has a lower injection amount of the active ingredient than that having a hollow type needle part, and the percutaneous absorption is possible because the active ingredient is uniformly present in the base material and the needle part. It tends to be lower.

  In addition, a dissolved microneedle preparation is usually produced by pouring a composition in which a component such as hyaluronic acid is dissolved or dispersed in water into a mold, drying it to a specific moisture content, and then removing it from the mold. However, a substrate containing hyaluronic acid is likely to bend and warp after drying. When the base material is curved, it is difficult to puncture all the needle portions into the skin, and the transdermal absorbability is lowered.

  Also, in dissolving microneedle preparations, the needle has sufficient height and stress, and the tip angle is controlled to 90 ° C or lower in order to ensure sufficient transdermal absorbability by puncturing the needle into the skin. It is also important that the substrate follows the curved surface of the skin well.

JP 2009-201956 A JP 2013-189432 A

  The present invention is a dissolution type having a height, tip angle and stress sufficient for the needle portion to puncture the skin, curving the substrate to be bent and being excellent in followability to the curved surface of the skin. It aims at providing a microneedle formulation.

  The dissolution type microneedle preparation of the present invention comprises an adhesive part comprising a base material and a plurality of needle parts protruding from one side of the base material, and the components contained in the adhesive part are dissolved while the adhesive part dissolves. It is a dissolved microneedle preparation that is absorbed into the skin, and the sticking part contains (A) component: one or more selected from the group consisting of hyaluronic acid and hyaluronic acid salt, and (B) component: glycerin. The mass ratio A / B of the component (A) to the component (B) is 1 to 5.

The sticking part may further contain (C) component: physiologically active component (however, excluding the component (A)).
The component (A) preferably contains one or more selected from the group consisting of hyaluronic acid having a mass average molecular weight of 50,000 or more and hyaluronic acid salt having a mass average molecular weight of 50,000 or more.
The component (C) is preferably a non-steroidal anti-inflammatory drug.
It is preferable that content of the said (A) component is 20-75 mass% in a sticking part (100 mass%).

  The dissolution type microneedle preparation of the present invention has a height, a tip angle and a stress sufficient for the needle portion to puncture the skin, the substrate is prevented from curving and warping, and the curved surface of the skin is curved. Excellent trackability.

It is sectional drawing which showed an example of the melt | dissolution type microneedle formulation of this invention. It is an enlarged front view which shows an example of the needle part of the melt | dissolution type microneedle formulation of this invention.

  In the present invention, the needle portion means a needle-shaped minute convex structure (microneedle) in a broad sense, and is not limited to a needle shape having a sharp tip, and has a shape with no point ( For example, a truncated cone shape is also included.

The dissolution type microneedle preparation of the present invention comprises an adhesive part comprising a base material and a plurality of needle parts protruding from one side of the base material, and the components contained in the adhesive part are dissolved while the adhesive part dissolves. It is a dissolved microneedle preparation that is absorbed through the skin.
An example of the dissolution type microneedle preparation of the present invention is shown in FIG. The dissolution type microneedle preparation 1 includes an adhesive portion 10. The sticking part 10 includes a sheet-like base material 12 and a plurality of needle parts 14 protruding from one side of the base material 12.

The shape of the needle part is preferably a conical shape. The shape of the needle portion is not limited to a conical shape, and may be a polygonal pyramid shape such as a quadrangular pyramid or other shapes such as a truncated cone shape.
50-1000 micrometers is preferable and, as for the height of a needle part, 100-700 micrometers is more preferable. If the height of the needle part is equal to or higher than the lower limit, the transdermal administration of the component (A) or the component (C) tends to be sufficient. If the height of the needle portion is less than or equal to the above upper limit value, the needle portion is less likely to come into contact with the nerve, so that it is easy to avoid pain and bleeding.

  10-1200 micrometers is preferable and, as for the thickness of the base end of a needle part, 25-600 micrometers is more preferable. In addition, when the shape of the cross section perpendicular to the height direction of the base end of the needle part is other than a circle, such as a polygonal pyramid needle part, the thickness of the base end of the needle part is the cross-sectional shape of the base end Means the diameter of the circle circumscribing.

The tip angle of the needle part is preferably 90 degrees or less, more preferably 10 to 60 degrees, and still more preferably 15 to 45 degrees. If the tip angle of the needle portion is equal to or greater than the lower limit value, the needle portion is unlikely to break during puncturing. If the tip angle of the needle part is less than or equal to the upper limit value, the puncture property is excellent.
In addition, in the case of a needle part with a pointed shape, the tip angle of the needle part means an angle at which the extension lines extending upward on both sides of the needle part in front view intersect each other. To do. For example, in the case of the truncated cone-shaped needle portion 14A illustrated in FIG. 2, the angle θ formed by the extension line p and the extension line q extending upward on the sides 14a and 14b on both sides of the needle portion 14A in the front view is defined as The tip angle.

It is preferable that the distance between adjacent needle portions is substantially equal, and it is preferable that approximately 1 to 10 needle portions are arranged per 1 mm.
The density of the needle part is preferably 100 to 10,000, more preferably 100 to 5,000, and still more preferably 100 to 2,000 per 1 cm ² . If the density of the needle part is equal to or higher than the lower limit, the skin can be efficiently perforated. If the density of the needle portion is less than or equal to the above upper limit value, the strength of the needle portion is easily maintained.

  The sticking part of the dissolution type microneedle preparation of the present invention contains the component (A) and the component (B).

[(A) component]
(A) A component is 1 or more types chosen from the group which consists of hyaluronic acid and hyaluronate. The component (A) is a polysaccharide and has a cosmetic effect. When the sticking part contains the component (A), the base material and the needle part can be formed without blending other bases.
Hereinafter, hyaluronic acid and hyaluronate may be collectively referred to as hyaluronic acid or the like.

Hyaluronic acid is a kind of glycosaminoglycan (mucopolysaccharide) and has a structure in which disaccharide units of N-acetylglucosamine and glucuronic acid are linked.
Examples of hyaluronic acid include hyaluronic acid derived from organisms isolated from chicken crowns, umbilical cords, and the like, and hyaluronic acid utilizing fermentation by microorganisms. Biologically-derived hyaluronic acid cannot completely remove the collagen of the organism from which it is derived, and the remaining collagen may adversely affect it, so hyaluronic acid derived from microbial fermentation is preferred.

  As hyaluronic acid salts, pharmaceutically and physiologically acceptable salts can be used, for example, alkali metal salts (sodium salts, potassium salts, etc.), alkaline earth metal salts (magnesium salts, calcium salts, etc.), ammonium salts, etc. And alkanolamine salts (monoethanolamine and the like). Of these, alkali metal salts are preferred as the hyaluronate.

The mass average molecular weight of hyaluronic acid or the like is preferably 5,000 to 1,000,000, and more preferably 10,000 to 200,000. If mass average molecular weights, such as a hyaluronic acid, are more than the said lower limit, it will be easy to suppress that the mechanical strength of a sticking part falls, and it will become difficult to break a needle | hook part at the time of a preservation | save or puncture. When the mass average molecular weight of hyaluronic acid or the like is less than or equal to the above upper limit value, the needle part is likely to pierce the skin, and the permeability of the sticking part to the skin is improved.
In addition, mass average molecular weights, such as a hyaluronic acid, are the values measured by gel permeation chromatography (GPC).

The following (A-1) component is preferably used as the component (A) from the viewpoint that the needle part does not break when it is inserted into the skin, and is easily dissolved in the body. It is more preferable to use a mixture of the component -1) and the component (A-2).
(A-1) One or more selected from the group consisting of hyaluronic acid having a mass average molecular weight of 50,000 or more and hyaluronic acid salt having a mass average molecular weight of 50,000 or more.
(A-2) One or more selected from the group consisting of hyaluronic acid having a mass average molecular weight of less than 50,000 and hyaluronate having a mass average molecular weight of less than 50,000.

[Component (B)]
(B) A component is glycerol. When the sticking part contains the component (B), the base material of the sticking part is curved and is hardly warped.
Glycerin is a trivalent alcohol represented by the formula C ₃ H ₅ (OH) ₃ or the molecular formula C ₃ H ₈ O ₃ . There are commercially available products such as 84 to 87% by mass of glycerin, and these commercially available products may be used.

[Component (C)]
In order to give an effect other than the moisturizing effect by the component (A) to the sticking part, the component (C): a physiologically active component (however, the component (A) is excluded) as necessary. It may be contained. In addition, the dissolution type microneedle preparation of the present invention does not contain the component (C) in the sticking part, and other effective effects due to the component (C) cannot be obtained except the moisturizing effect due to the component (A). It may be a thing.
The physiologically active component means a component that exerts some action on the living body.

(C) As a component, the well-known component normally used for a dissolution type microneedle formulation is employable. The component (C) may be a low molecular compound or a high molecular compound.
As the component (C), a nonsteroidal anti-inflammatory drug is preferable.

  Non-steroidal anti-inflammatory agents include, for example, ferbinac, butorphanol tartrate, perisoxal citrate, acetaminophen, mefenamic acid, diclofenac sodium, aspirin, alclofenac, ketoprofen, flurbiprofen, naproxen, piroxicam, pentazocine, indomethacin, ibuprofen , Flurpiprofen, glycol salicylate, aminopyrine, loxoprofen and the like.

Examples of the component (C) other than the non-steroidal anti-inflammatory agent include the following components.
Hypnotic sedative: flurazepam hydrochloride, rilmazafone hydrochloride, phenobarbital, amobarbital, etc.
Steroidal anti-inflammatory agents: hydrocortisone, prednisolone, dexamethasone, betamethasone, etc.
・ Exciting / stimulant: methamphetamine hydrochloride, methylphenidate hydrochloride, etc.
Psychiatric and neuropsychiatric agents: imiplan hydrochloride, diazepam, sertraline hydrochloride, fluvoxamine maleate, paroxetine hydrochloride, citalopram hydrobromide, fluoxetine hydrochloride, alprazolam, haloperidol, clomipramine, amitriptyline, desipramine, amoxapine, maprotiline, mianserin, cetipitrine, tolazidone Lohepramine, milnacipran, duloxetine, venlafexine, chlorpromazine hydrochloride, thioridazine, diazepam, meprobamate, etizolam and the like.

Hormonal agents: estradiol, estriol, progesterone, norethisterone acetate, metellonone acetate, testosterone, human chorionic gonadotropin, luteinizing hormone, human growth hormone and the like.
-Local anesthetics: lidocaine hydrochloride, procaine hydrochloride, tetracaine hydrochloride, dibucaine hydrochloride, propitocaine hydrochloride, etc.
・ Urological agents: oxybutynin hydrochloride, tamsulosin hydrochloride, propiverine hydrochloride, etc.
-Skeletal muscle relaxants: tizanidine hydrochloride, eperisone hydrochloride, pridinol mesylate, sisamethonium hydrochloride, etc.
Reproductive organ agents: ritodrine hydrochloride, meradrine tartrate, etc.
Antiepileptic agents: sodium valproate, clonazepam, carbamazepine, etc.

Autonomic nerve agents: carpronium chloride, neostigmine bromide, bethanechol chloride, etc.
Antiparkinsonian agents: pergolide mesylate, bromocriptine mesylate, trihexyphenidyl hydrochloride, amantadine hydrochloride, ropinirole hydrochloride, talipexol hydrochloride, cabergoline, droxidopa, piperidene, selegiline hydrochloride, etc.
・ Diuretics: hydroflumethiazide, furosemide, etc.
・ Respiratory agent: lobeline hydrochloride, dimorphoamine, naloxone hydrochloride, etc.
Anti-migraine agents: dihydroergotamine mesylate, sumatriptan, ergotamine tartrate, flunarizine hydrochloride, cyproheptadine hydrochloride, etc.

Antihistamines: clemastine fumarate, diphenhydramine tannate, chlorpheniramine maleate, diphenylpyralin hydrochloride, promethazine, etc.
Bronchodilators: tubuterol hydrochloride, procaterol hydrochloride, salbutamol sulfate, clenbuterol hydrochloride, phenoterol hydrobromide, terbutaline sulfate, isoprenaline sulfate, formoterol fumarate, etc.
-Cardiotonic agents: isoprenaline hydrochloride, dopamine hydrochloride, etc.
-Coronary vasodilators: diltiazem hydrochloride, verapamil hydrochloride, isosorbide nitrate, nitroglycerin, nicorandil and the like.
・ Peripheral vasodilators: Nicamethate citrate, trazoline hydrochloride, etc.

・ Smoking cessation aids: nicotine, etc.
-Cardiovascular agents: flunarizine hydrochloride, nicardipine hydrochloride, nitrendipine, nisoldipine, felodipine, amlodipine besylate, nifedipine, nilvadipine, manidipine hydrochloride, benidipine hydrochloride, enalapril maleate, democapril hydrochloride, alacepril, imidapril hydrochloride, cilazapril, caprypril, captopril Trandolapril, perindopril erbumine, atenolol, bisoprolol fumarate, bunitrolol hydrochloride, metoprolol tartrate, betaxolol hydrochloride, arotinolol hydrochloride, seriprolol hydrochloride, carvedilol, carteolol hydrochloride, bevantolol hydrochloride, valsartan, candesartan cilexetil, losartan potassium, Clonidine hydrochloride and the like.
Arrhythmic agents: propranolol hydrochloride, alprenolol hydrochloride, procainamide hydrochloride, mexitylene hydrochloride, nadolol, disopyramide, etc.

Anti-malignant ulcer agents: cyclophosphamide, fluorouracil, degafur, procarbazine hydrochloride, ranimustine, irinotecan hydrochloride, fluridine and the like.
Antilipemic agents: pravastatin, simvastatin, bezafibrate, probucol, etc.
-Hypoglycemic agents: glibenclamide, chlorpropamide, tolbutamide, glymidine sodium, glibutol, buformin hydrochloride, etc.
-Peptic ulcer treatment: proglumide, cetraxate hydrochloride, spizoflon, cimetidine, glycopyrronium bromide, etc.
・ Boldener: Ursodesoxycholic acid, osalmid, etc.
・ Gastrointestinal motility improving agent: domperidone, cisapride and the like.

-Liver disease agents: thiopronin and the like.
-Antiallergic agents: ketotifen fumarate, azelastine hydrochloride, etc.
-Antiviral agents: acyclovir and the like.
Antipruritics: betahistine mesylate, diphenidol hydrochloride, etc.
Antibiotics: cephaloridine, cefdinir, cefpodoxime proxetil, cefaclor, clarithromycin, erythromycin, methylerythromycin, kanamycin sulfate, cycloserine, tetracycline, benzylpenicillin potassium, propicillin potassium, cloxacin sodium, ampicillin sodium, Bacampicillin hydrochloride, carbenicillin sodium, chloramphenicol, etc.

・ Additives for addictive addiction: cyanamide, etc.
・ Appetite suppressant: mazindol, etc.
Chemotherapeutic agents: isoniaside, ethionamide, pyrazinamide, etc.
-Blood coagulation promoter: ticlopidine hydrochloride, warfarin potassium, etc.
-Anti-Alzheimer agents: physostigmine, donepezil hydrochloride, tacrine, arecoline, xanomeline, etc.
Serotonin receptor antagonist antiemetics: ondansetron hydrochloride, granisetron hydrochloride, ramosetron hydrochloride, azasetron hydrochloride, etc.
・ Gout treatment: colchicine, probenecid, sulfinpyrazone, etc.
Narcotic analgesics: fentanyl citrate, morphine sulfate, morphine hydrochloride, codeine phosphate, cocaine hydrochloride, pethidine hydrochloride, etc.

As the component (C), for example, vaccines having a molecular weight of about 1000, such as peptides, proteins and derivatives thereof, nucleic acids (DNA, RNA, etc.), sugars, etc. may be used.
As vaccines, for example, Japanese encephalitis vaccine, rotavirus vaccine, Alzheimer's disease vaccine, arteriosclerosis vaccine, cancer vaccine, nicotine vaccine, diphtheria vaccine, tetanus vaccine, whooping cough vaccine, Lyme disease vaccine, rabies vaccine, pneumococcal vaccine, Examples include yellow fever vaccine, cholera vaccine, seed urticaria vaccine, tuberculosis vaccine, rubella vaccine, measles vaccine, mumps vaccine, botulinum vaccine, herpes virus vaccine, other DNA vaccine, hepatitis B vaccine and the like.

  In addition, as the component (C), lixenatide, naltrexone, cetrorelix acetate, tartilellin, nafarelin acetate, prostaglandin A1, alprostadil, α-interferon, β-interferon for multiple sclerosis, erythropoietin, Also included are follitropin β, follitropin α, G-CSF, GM-CSF, salmon calcitonin, glucagon, GNRH antagonist, insulin, filgrastin, heparin, low molecular weight heparin, somatropin, incretin, GLP-1 derivative and the like.

In addition, as component (C), crotamiton, l-menthol, mint oil, limonene, diisopropyl adipate, etc., and as a medicinal aid, methyl salicylate, glycol salicylate, l-menthol, thymol, mint oil, nonyl acid vanillylamide, noryl Acid vanillylamide, capsicum extract, capsine, ascorbyl palmitate, kojic acid, lucinol, tranexamic acid, oily licorice extract, retinol, retinoic acid, retinol acetate, retinol palmitate, isopropylmethylphenol, vitamins (vitamin D2, vitamin D3 , Vitamin K, etc.).
The compound of component (C) includes pharmaceutically acceptable salts, and may be in the form of an inorganic salt or an organic salt.
As the component (C), one type may be used alone, or two or more types may be used in combination.

[(D) component]
In the sticking part, (D) component other than the components (A) to (C): an optional component may be contained as necessary.
Examples of the component (D) include additives such as a solubilizer, a transdermal absorption accelerator, a stabilizer, an antioxidant, an emulsifier, a surfactant, and a metal salt.

Examples of solubilizers include ethylene glycol, propylene glycol, 1,3-butylene glycol, and polyethylene glycol.
As the surfactant, any of a nonionic active agent, a cationic active agent, an anionic active agent, and an amphoteric active agent may be used, and a nonionic active agent usually used in pharmaceutical preparations is preferred.
Specifically, sugar alcohol fatty acid ester such as sucrose fatty acid ester, sorbitan fatty acid ester, glycerin fatty acid ester, polyglycerin fatty acid ester, propylene glycol fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene glycerin fatty acid ester, polyethylene glycol Examples include fatty acid esters, polyoxyethylene castor oil, and polyoxyethylene hydrogenated castor oil.

  Polymers that can be blended for the purpose of bases, solvents, stabilizers, plasticizing aids, etc. include polyethylene oxide, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, pullulan Carmellose sodium, croscarmellose sodium, gum arabic, heparin, chondroitin sulfate and salts thereof, trehalose, maltose and the like.

  Examples of metal salts that can be blended for the purpose of buffers, stabilizers, bases, solvents, suspending agents and the like include sodium chloride, potassium chloride, magnesium chloride, potassium chloride, aluminum chloride, and zinc chloride.

  The sticking part preferably contains water. Water is blended in order to ensure manufacturability when the preparation is filled in the mold, but it is preferably contained in the sticking part even after drying.

[Ratio of each component]
20-75 mass% is preferable, as for content of (A) component in an adhesion part (100 mass%), 20-70 mass% is more preferable, and 30-70 mass% is more preferable. If content of (A) component is more than the said lower limit, formation of a base material and a needle part will become easy. If content of (A) component is below the said upper limit, a base material will curve and it will become difficult to warp.

  When (A-1) component is used as (A) component, 20-75 mass% is preferable and, as for content of (A-1) component in a sticking part (100 mass%), 20-70 mass% is. More preferably, 30-70 mass% is further more preferable. If content of (A-1) component is more than the said lower limit, formation of a base material and a needle part will become easy. If content of (A-1) component is below the said upper limit, a base material will curve and it will become difficult to warp.

  0-30 mass% is preferable, as for content of the (A-2) component in an adhesion part (100 mass%), 0-25 mass% is more preferable, and 5-10 mass% is further more preferable. If content of (A-2) component is more than the said lower limit, the puncture property of a needle part will become more favorable. If content of (A-2) component is below the said upper limit, a needle | hook part will become harder to bend at the time of a preservation | save or puncture.

As (A) component, what consists of (A-1) component 60-100 mass% and (A-2) component 40-0 mass% (total 100 mass%) is preferable.
The mass ratio (A-2) / (A-1) of the component (A-2) to the component (A-1) varies depending on the mass average molecular weight of each hyaluronic acid or the like. The strength and hardness can be determined as appropriate. As mass ratio (A-2) / (A-1), 0-1.75 are preferable and 0.05-0.5 are more preferable. If mass ratio (A-2) / (A-1) is below the said upper limit, it will become difficult to break a needle part at the time of preservation | save or piercing into skin.

  15-45 mass% is preferable and, as for content of (B) component in a sticking part (100 mass%), 20-40 mass% is more preferable. If content of (B) component is more than the said lower limit, a base material will curve more and it will become difficult to warp. If the content of the component (B) is less than or equal to the above upper limit value, it is easy to suppress the sticking part from becoming too soft, the tip angle is small, and a needle part with sufficient hardness is easily formed. The needle part is easily punctured into the skin.

  The mass ratio A / B of the component (A) to the component (B) is 1 to 5, preferably 1 to 4.5, and more preferably 1 to 4. If the mass ratio A / B is equal to or greater than the lower limit, it is possible to prevent the sticking part from becoming too soft, and the needle part can be easily formed because the tip angle is small and a sufficiently hard needle part is formed. You can puncture the skin. If mass ratio A / B is below the said upper limit, the curvature of a base material can be suppressed.

  0.1-80 mass% is preferable and, as for content of (C) component in a sticking part (100 mass%), 1-50 mass% is more preferable.

  5-20 mass% is preferable and, as for content of the water in the sticking part (100 mass%) after drying, 10-15 mass% is more preferable. If the water content is at least the lower limit, the flexibility of the dissolved microneedle preparation will be good. If water content is below an upper limit, it will be easy to suppress a thin needle part at the time of manufacture, and the mass change after opening will also decrease.

[PH]
The pH of the sticking part varies depending on the blending of the physiologically active ingredient, but is preferably 3 to 9 from the viewpoint of irritation to the skin.

[Support]
The dissolution type microneedle preparation of the present invention may be provided with a support on the surface opposite to the side where the needle part is formed in the sticking part.
The support is not particularly limited, and a known support that is usually used as a support for patches can be used. Examples of the support include a resin film, a cloth, and a composite sheet in which the resin film and the cloth are integrated.

  Examples of the resin film include films made of resins such as polyethylene, polypropylene, polyester, rayon, polyamide, polyvinyl chloride, urethane / vinyl chloride copolymer, and polyurethane.

The fabric may be a non-woven fabric, a woven fabric, or a knitted fabric.
As a nonwoven fabric, what was manufactured by the needle punch method, the spunlace method, the spun bond method, the stitch bond method, the melt blown method etc. is mentioned, for example.
The weaving method of the woven fabric and the knitting method of the knitted fabric are not particularly limited. For example, warp knitting (tricot knitting, denby tricot knitting, satin knitting, atlas knitting, flat knitting, rim knitting, pearl knitting), circular knitting (both sides) Knitting, single-sided knitting, and milling knitting).

  Examples of the material of the fibers constituting the fabric include polyester, rayon, nylon, polypropylene, polyethylene, polyamide, and polyurethane.

  Examples of the composite sheet include a sheet in which a resin film and a fabric are bonded by thermal fusion, an adhesive, or the like, a sheet formed by extruding a molten resin on a fabric, and the like.

[Production method]
The production method of the dissolution type microneedle preparation of the present invention is not particularly limited, and any conventionally known method can be adopted except that the component (A) and the component (B) are blended in a specific ratio.
For example, a composition made by mixing water with a component (A) and a component (B) and other components to be used as necessary is cast on a silicon mold having a needle portion perforated and dried. And then peeling from the mold.

[Function and effect]
In the dissolution type microneedle formulation of the present invention described above, since the component (A) and the component (B) are contained in a specific ratio, the tip is sufficiently high to allow the needle portion to puncture the skin. In addition to having an angle and a stress, the base material is prevented from being bent and warped, and the followability to the curved surface of the skin is excellent. Therefore, the dissolution type microneedle preparation of the present invention can stably puncture the needle part when stuck to the skin, so that excellent transdermal absorbability can be secured stably.

EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, this invention is not limited by the following description.
[Raw materials]
The raw materials used in this example are shown below.

((A) component)
A-11: High molecular sodium hyaluronate (trade name “hyaluronic acid FCH-SU”, manufactured by Kikkoman Biochemifa Co., Ltd., mass average molecular weight: 50,000 to 110,000).
A-21: Low molecular hyaluronic acid (trade name “Halo-oligo”, manufactured by Kewpie Co., Ltd., mass average molecular weight: 1,000 to 10,000).

((B) component)
B-1: Glycerin ("concentrated glycerin (JP)", Sakamoto Pharmaceutical Co., Ltd.).

((B ′) component: comparison target)
B′-1: 1,3-butylene glycol (“1,3-butylene glycol (pharmaceutical additive standard)”, manufactured by Daicel Corporation).
B′-2: Propylene glycol (“Propylene glycol (Japan Pharmacopoeia)”, manufactured by ADEKA Corporation).
B′-3: Polyethylene glycol (“polyethylene glycol 600”, manufactured by Wako Pure Chemical Industries, Ltd.).

((C) component)
C-1: Felbinac (“Ferbinac (Japan)”, manufactured by HANSEO CHEMICAL).

(Optional component)
Water: “Purified water (JP)”, manufactured by Kyoei Pharmaceutical Co., Ltd.

[Examples 1-9, Comparative Examples 1-6]
As a mold for producing a dissolution type microneedle preparation, a pocket having a cone shape with a root diameter of 0.5 mm, a height of 0.65 mm, and a shape complementary to a needle portion having a tip angle of 33 degrees is 1 A total of 10 pockets, each having 10 pockets in the vertical and horizontal directions at intervals of 0 mm, were used. In addition, the tip angle of the needle part which is not pointed is an angle formed by extension lines extending upward from both sides of the needle part in a front view. The mold was entirely made of 100% silicone resin (two-component RTV rubber KE-17: Shin-Etsu Silicone).
As shown in Table 2 and Table 3, compositions in which each component was uniformly dissolved or dispersed were obtained. For the component (A), a 10% by mass aqueous solution was prepared and mixed. About 0.5 g of the composition was applied to a mold heated to 80 ° C. (amount such that the mass after drying was 0.05 g or more). After coating, the mold was cooled under conditions of 25 ° C. and 100% Rh. After the mold reached 25 ° C., it was naturally dried for about 8 hours to obtain a dissolved microneedle preparation.

[Evaluation of curvature and tracking]
For the dissolved microneedles obtained in each example, the degree of curvature of the base material when observed from the side in a state of being placed on a flat surface and the followability when placed on the skin surface of the arm were evaluated according to the following criteria: did.
(Evaluation criteria: Table 1)
(Double-circle): When it puts on a plane, a curvature is not recognized by a base material, but it follows a skin curved surface.
○: The substrate is not curved when placed on a flat surface, but does not follow the curved surface of the skin.
X: The part which a base material curves when it puts on a plane, and does not touch a plane is recognized. In this case, the substrate does not follow the curved surface of the skin.

[Evaluation of needle height]
The height of the needle part in the dissolution type microneedle obtained in each example was measured with a digital microscope and evaluated according to the following criteria.
(Evaluation criteria)
(Double-circle): The height of a needle part is 500 micrometers or more.
A: The height of the needle part is 400 μm or more and less than 500 μm.
X: The height of the needle part is less than 400 μm.
When the height of the needle portion is less than 400 μm, it is difficult to obtain the effect sufficiently even when puncturing.

[Needle angle evaluation]
The tip angle of the needle part in the dissolution type microneedle obtained in each example was measured with a digital microscope and evaluated according to the following criteria. The angle formed by the upward extension lines of both sides of the needle part in front view was defined as the tip angle.
(Evaluation criteria)
A: The tip angle is less than 50 degrees.
○: The tip angle is 50 degrees or more and less than 90 degrees.
X: The tip angle is 90 degrees or more.
When the tip angle of the needle part is 90 degrees or more, it is difficult to puncture the needle part.

[Evaluation of needle stress]
Using a texture analyzer, the stress when the needle part of the dissolution type microneedle obtained in each example was pressed by 0.01 mm from the tip side was measured and evaluated according to the following evaluation criteria. In addition, the material of the probe to press used the disk-shaped ground glass of diameter 1cm.
(Evaluation criteria)
○: Stress is 0.05 N or more.
X: Stress is less than 0.05N.
When the stress is less than 0.05N, it is difficult to puncture the needle portion.

Tables 2 and 3 show the composition of each component and the evaluation results in Examples and Comparative Examples.
In addition, the composition in Table 2 and Table 3 is a composition when the coating amount and the mass after drying are measured, and it is assumed that all the weight reductions were water. Moreover, content of (B) component is the mass% of solid content conversion of glycerol. Moreover, the column of the mass ratio A / B in Comparative Examples 4 to 6 shows the mass ratio of the component (A) to the component (B ′).

As shown in Table 2 and Table 3, in the dissolution type microneedle preparations of Examples 1 to 9 in which the components (A) and (B) are blended in the ratio defined in the present invention, the needle portion punctures the skin. It had sufficient height, tip angle and stress. In addition, the base material was suppressed from being curved, and was excellent in followability to the curved surface of the skin.
In the dissolution type microneedle formulation of the comparative example 1 which does not use the (B) component and the comparative example 2 in which the mass ratio A / B is more than 5, the substrate was curved. In the dissolution type microneedle preparations of Comparative Examples 4 to 6 using the component (B ′) instead of the component (B), the substrate was also curved.
In the dissolution type microneedle preparation of Comparative Example 3 having a mass ratio A / B of less than 1, the needle portion did not have a height, a tip angle, and a stress sufficient to puncture the skin.

DESCRIPTION OF SYMBOLS 1 Dissolving type microneedle formulation 10 Adhering part 12 Base material 14 Needle part

Claims (5)

A dissolution type microneedle formulation comprising a base and a plurality of needles protruding from one side of the base, wherein the adhesive is percutaneously absorbed while the adhesive is dissolved There,
In the sticking part, (A) component: one or more selected from the group consisting of hyaluronic acid and hyaluronate, and (B) component: glycerin,
The dissolution type microneedle formulation whose mass ratio A / B of the said (A) component with respect to the said (B) component is 1-5.   The dissolution type microneedle formulation according to claim 1, wherein component (C): a physiologically active component (excluding the component (A)) is further contained in the sticking part.   The component (A) contains at least one selected from the group consisting of hyaluronic acid having a mass average molecular weight of 50,000 or more and hyaluronic acid salt having a mass average molecular weight of 50,000 or more. The dissolution type microneedle formulation as described.   The dissolution type microneedle formulation as described in any one of Claims 1-3 whose said (C) component is a non-steroidal anti-inflammatory drug.   The dissolution type microneedle formulation as described in any one of Claims 1-4 whose content of the said (A) component in the said sticking part (100 mass%) is 20-75 mass%.

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