JP2017095427A - Dissolution type microneedle pharmaceutical preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To reduce discomfort at the time of attachment and during attachment, in dissolution type microneedle pharmaceutical preparations.SOLUTION: An attachment part 10 which is provided with a substrate 12 and a plurality of needle parts 14 protruded from one face of the substrate 12 is provided. The needle parts 14 contains component (A): 20-90 mass% of one or more selected from the group consisting of hyaluronic acid, hyaluronate and pullulan; and component (B): 0.5-50 mass% of a cyclic terpene compound. Preferably, the needle part contains component (C): polyhydric alcohol.SELECTED DRAWING: Figure 1

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 needle part is punctured into the keratin or dermis of the skin, the base material and the needle part are dissolved, and the physiologically active ingredient is absorbed percutaneously.

  As a dissolution type microneedle preparation, for example, an invention has been proposed in which a mixture of a water-soluble polymer and at least one saccharide selected from monosaccharides and disaccharides is used as a microneedle material (Patent Document 1). . According to the invention of Patent Document 1, it is intended to quickly dissolve the microneedles after sticking.

JP 2013-189432 A

However, when the dissolved microneedle preparation is attached to the skin, the needle portion of the microneedle preparation is punctured into the skin, which may cause discomfort such as pain. In addition, since the dissolution type microneedle preparation is adhered to the skin until the needle portion or the base material is dissolved, there may be a case where the adhered portion is uncomfortable. That is, the conventional dissolution type microneedle preparation may cause a sense of incongruity when attached to the skin or during application.
In the invention of Patent Document 1, although the dissolution rate of the needle portion can be promoted, the relaxation of the uncomfortable feeling is not considered.
Then, this invention aims at the melt | dissolution type microneedle formulation which can reduce the discomfort at the time of sticking and during sticking.

The present invention has the following aspects.
[1] A sticking portion including a base material and a plurality of needle portions protruding from one side of the base material,
As for the said sticking part, 20-90 mass% of 1 or more types chosen from the group which consists of (A) component: hyaluronic acid, hyaluronic acid salt, and pullulan, and (B) component: cyclic terpene compound are 0.5-50. Dissolving type microneedle formulation containing the mass%.
[2] The dissolution type microneedle preparation according to [1], wherein the sticking part further contains (C) component: a polyhydric alcohol.
[3] The dissolution type microneedle preparation according to [1] or [2], wherein the sticking part further contains (D) component: physiologically active component (excluding the component (A)).
[4] The component (A) is selected from the group consisting of component (A-1): 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. And (A-2) component: one or more selected from the group consisting of hyaluronic acid having a weight average molecular weight of less than 50,000 and hyaluronate having a weight average molecular weight of less than 50,000, 1]-[3] The dissolution type microneedle formulation in any one of.
[5] The dissolution type microneedle preparation according to [4], wherein the mass ratio represented by (A-2) component / (A-1) component is 0 to 1.75.
[6] The dissolution according to any one of [1] to [5], wherein the sticking part contains water, and the content of water in 100% by weight of the sticking part is 5 to 20% by weight. Type microneedle formulation.

  According to the dissolution type microneedle formulation of the present invention, it is possible to reduce a sense of incongruity during and during sticking.

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

(Dissolved microneedle formulation)
The dissolution type microneedle preparation of the present invention includes a sticking portion including a base material and a plurality of needle portions protruding from one surface of the base material.
In this paper, the term “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, but has a shape with no sharp point (for example, Including a truncated cone).
The dissolution type microneedle preparation is a patch that, when attached to an adherent part (for example, an affected part), allows the components contained therein to be absorbed transdermally while dissolving the attached part.

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.
In the present embodiment, the base material 12 and the plurality of needle portions 14 are integrally formed.

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 above lower limit, transdermal administration of the active ingredient contained in the needle part or the base material is likely 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 cone shaped 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 part is equal to or greater than the lower limit value, the needle part is unlikely to break during puncturing. If the tip angle of the needle part is not more than the above 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 not less than the above lower limit value, the skin can be efficiently perforated. If the density of the needle portion is not more than the above upper limit value, the mechanical strength of the needle portion is easily maintained.

  The thickness of the base material 12 is not specifically limited, For example, 30 micrometers-3 mm are preferable, and 30 micrometers-1.5 mm are more preferable. If the thickness of the base material 12 is not less than the above lower limit value, the mechanical strength of the dissolved microneedle formulation 1 can be easily increased. If the thickness of the base material 12 is less than or equal to the above upper limit value, it is easy to impart flexibility to the dissolved microneedle formulation 1.

The size (area in plan view) of the dissolved microneedle formulation 1 is not particularly limited, and is appropriately determined in consideration of the application.
The planar view shape of the dissolution type microneedle preparation 1 is not particularly limited, and may be a polygon such as a quadrangle, or a circle such as a perfect circle or an ellipse.

  Sticking part 10 of dissolution type microneedle formulation 1 contains (A) ingredient and (B) ingredient. In this embodiment, the needle part 14 and the base material 12 are integrally molded to form the sticking part 10. For this reason, the needle part 14 and the base material 12 are the same compositions. That is, the needle part 14 contains (A) component and (B) component.

<(A) component>
(A) A component is 1 or more types chosen from the group which consists of hyaluronic acid, a hyaluronic acid salt, and a pullulan. 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 the mass average molecular weight of hyaluronic acid or the like is equal to or higher than the lower limit, it is easy to prevent the mechanical strength of the sticking part 10 from being lowered, and the needle part 14 is difficult to break when stored or inserted into the skin. . If mass average molecular weights, such as a hyaluronic acid, are below the said upper limit, the needle part 14 will pierce skin easily and the permeability to the skin of an adhesion part will improve.
In addition, mass average molecular weights, such as a hyaluronic acid, are the values measured by gel permeation chromatography (GPC).

Pullulan is a kind of polysaccharide consisting of glucose, and has a structure in which maltotriose in which three molecules of glucose are α1-4 linked are linked by α1-6 bonds.
Pullulan is represented by the formula (C ₁₈ H ₃₀ O ₁₅ ) _n . Examples of the pullulan include neutral simple polysaccharides produced outside the cells when Aureobasidium pullulans is cultured.

The mass average molecular weight of pullulan is preferably 20,000 to 2,000,000. If the mass average molecular weight of pullulan is not less than the above lower limit value, it is easy to suppress the mechanical strength of the sticking part 10 from being lowered, and the needle part 14 is not easily broken during storage or when it is inserted into the skin. When the mass average molecular weight of pullulan is not more than the above upper limit value, the needle part 14 is easy to pierce the skin, and the permeability of the sticking part to the skin is improved.
The mass average molecular weight of pullulan is a value measured by gel permeation chromatography (GPC).

Said (A) component may be used individually by 1 type, and may be used in combination of 2 or more type.
As the component (A), hyaluronic acid and the like are preferable. By using hyaluronic acid or the like, it is easy to increase the mechanical strength of the needle portion.

The following (A-1) component is preferably used as the component (A) from the viewpoint that the needle part 14 is not broken 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 (A-1) and the component (A-2).
Component (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.
Component (A-2): One or more selected from the group consisting of hyaluronic acid having a weight average molecular weight of less than 50,000 and hyaluronic acid salt having a weight average molecular weight of less than 50,000.

  Content of the (A) component in the sticking part 10 (100 mass%) is 20-90 mass%, 20-75 mass% is preferable and 30-70 mass% is more preferable. If content of (A) component is more than the said lower limit, the needle part 14 of the intensity | strength calculated | required can be formed. If content of (A) component is below the said upper limit, the compounding quantity of another component can be made into sufficient quantity.

  When (A-1) component is used as (A) component, 20-90 mass% is preferable and, as for content of (A-1) component in the adhesion part 10 (100 mass%), 20-75 mass%. Is more preferable, 20-70 mass% is further more preferable, and 30-70 mass% is especially 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 the sticking part 10 (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 the needle part 14 will become more favorable. If content of (A-2) component is below the said upper limit, a needle | hook part will become more difficult to bend at the time of preservation | save or puncture.

As (A) component, what consists of (A-1) component 60-100 mass% and (A-2) component 40-0 mass% in (A) component 100 mass% is preferable.
Although 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 machine where the sticking part 10 is preferable. It can be suitably determined so as to achieve the desired strength and hardness. The upper limit of the mass ratio (A-2) / (A-1) is preferably 1.5 or less, and more preferably 0.5 or less. If it is below the said upper limit, the needle part 14 becomes difficult to break at the time of preservation | save or when inserting in skin. The lower limit of the mass ratio (A-2) / (A-1) may be 0 (that is, does not contain the component (A-2)) or more, more preferably more than 0, and even more preferably 0.05 or more. preferable. (A-2) If a component is more than the said lower limit, the needle part 14 will become easy to melt | dissolve in a body.

<(B) component>
The component (B) is a cyclic terpene compound. Dissolution type microneedle formulation 1 can reduce the uncomfortable feeling at the time of sticking and during sticking by containing (B) component.

Examples of component (B) include menthols. Menthols are a kind of alcohol represented by the molecular formula C ₁₀ H ₂₀ O. Menthols is a general term for substances having structures such as menthol compounds and camphor compounds (a kind of bicyclic monoterpene ketones represented by the molecular formula C ₁₀ H ₁₆ O).
Examples of menthol include l-menthol, dl-menthol, d-camphor, and dl-camphor.
l-menthol is (1R, 2S, 5R) -5-methyl-2- (1-methylethyl) cyclohexanol. dl-Menthol is (1RS, 2SR, 5RS) -5-methyl-2- (1-methylethyl) cyclohexanol. d-Camphor is (1R, 4R) -1,7,7-Trimethylbicyclo [2.2.1] heptan-2-one. dl-camphor is (1RS, 4RS) -1,7,7-Trimethylbiccyclo [2.2.1] heptan-2-one.
These (B) components may be used individually by 1 type, and may be used in combination of 2 or more type.

  Content of the (B) component in the sticking part 10 (100 mass%) is 0.5-50 mass%, and 0.5-25 mass% is preferable. If content of (B) component is more than the said lower limit, the discomfort at the time of sticking and during sticking can be relieved. If the content of the component (B) is not more than the above upper limit value, the needle part is not too soft, and a needle part having a strength that can puncture the skin can be obtained.

  In addition, in the sticking part 10, the total amount of (A) component and (B) component does not exceed 100 mass%.

<(C) component>
The sticking part 10 may contain (C) component: a polyhydric alcohol. Dissolving type microneedle formulation 1 can suppress bending of sticking part 10 by containing (C) component.

Examples of the polyhydric alcohol include ethylene glycol, 1,3-butanediol, propylene glycol, butylene glycol, isoprene glycol, amylene glycol, glycerin, diglycerin, triglycerin, polyglycerin, diethylene glycol, dipropylene glycol, and diethylene glycol mono. Examples include alkyl ether and sorbitol. Among these, glycerin, diglycerin, triglycerin, and polyglycerin are preferable, and glycerin is more preferable.
Said (C) component may be used individually by 1 type, and may be used in combination of 2 or more type.
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.

  10-45 mass% is preferable and, as for content of (C) component in the sticking part 10 (100 mass%), 17-40 mass% is more preferable. If content of (C) component is more than the said lower limit, it will be easy to suppress dissolution type microneedle formulation 1 curving. If content of (C) component is below the said upper limit, the needle part 14 will not become too soft, and the needle part of the intensity | strength which can puncture skin can be obtained.

  1-8 are preferable, as for the mass ratio (mass ratio A / C) represented by (A) component / (C) component in the sticking part 10, 1-4 are more preferable, and 1-4 are further. preferable. If the mass ratio A / C is equal to or greater than the lower limit value, the sticking portion is suppressed from becoming too soft, and the needle portion 14 having a small tip angle and sufficient hardness is formed. You can puncture the skin. If mass ratio A / C is below the said upper limit, the curvature of a base material can be suppressed.

<(D) component>
The sticking part 10 may contain (D) component: physiologically active component (however, except (A) component) as needed. In addition, dissolution type microneedle formulation 1 does not mix | blend (D) component in the sticking part 10, and the other effectiveness effect by (D) component is not acquired except the moisturizing effect by (A) component It may be.
The physiologically active component means a component that exerts some action on the living body.

(D) As a component, the well-known component normally used for a dissolution type microneedle formulation is employable. The component (D) may be a low molecular compound or a high molecular compound.
As the component (D), 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 and the like.
Excitement / stimulant: methamphetamine hydrochloride, methylphenidate hydrochloride, etc.
Psychiatric and neurological agents: imiplan hydrochloride, diazepam, sertraline hydrochloride, fluvoxamine maleate, paroxetine hydrochloride, citalopram hydrobromide, fluoxetine hydrochloride, alprazolam, haloperidol, clomipramine, amitriptyline, desipramine, amoxapine, maprotiline, mianserin, cetipiroline, tolazipramine , 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, meladrin 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 and the like.
Diuretics: hydroflumethiazide, furosemide, etc.
Respiratory agent: lobeline hydrochloride, dimorphoamine, naloxone hydrochloride, etc.
Antimigraine agents: dihydroergotamine mesylate, sumatriptan, ergotamine tartrate, flunarizine hydrochloride, cyproheptadine hydrochloride, and the like.

Antihistamines: clemastine fumarate, diphenhydramine tannate, chlorpheniramine maleate, diphenylpyralin hydrochloride, promethazine, etc.
Bronchodilators: tulobuterol hydrochloride, procaterol hydrochloride, salbutamol sulfate, clenbuterol hydrochloride, phenolate hydrobromide, terbutaline sulfate, isoprenaline sulfate, formoterol fumarate and the like.
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, capripril, capripril Drapril, perindopril erbumine, atenolol, bisoprolol fumarate, butnitrolol hydrochloride, metoprolol tartrate, betaxolol hydrochloride, arotinolol hydrochloride, seriprolol hydrochloride, carvedilol, carteolol hydrochloride, bevantolol hydrochloride, valsartan, candesartan cilexetil, losartan potassium hydrochloride Clonidine etc.
Arrhythmic agents: propranolol hydrochloride, alprenolol hydrochloride, procainamide hydrochloride, mexitylene hydrochloride, nadolol, disopyramide and the like.

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

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

Addictive addiction: cyanamide, etc.
Appetite suppressant: mazindol and the like.
Chemotherapeutic agents: isoniaside, ethionamide, pyrazinamide and the like.
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 and the like.

As the component (D), for example, vaccines having a molecular weight of about 1000, such as peptides, proteins and derivatives thereof, nucleic acids (DNA, RNA, etc.), sugars and the like 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 component (D), lixenatide, naltrexone, cetrorelix acetate, tartilelin, 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.
Said (D) component may be used individually by 1 type, and may be used in combination of 2 or more type.

  0.1-75 mass% is preferable and, as for content of (D) component in the sticking part 10 (100 mass%), 1-50 mass% is more preferable.

<Optional component>
The sticking part 10 may contain arbitrary components other than (A)-(D) component as needed. Examples of the optional component include additives such as a transdermal absorption enhancer, a stabilizer, an antioxidant, an emulsifier, a surfactant, and a metal salt.

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, carme Examples include sodium loose, 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.

It is preferable that the sticking part 10 contains water. Water is blended in order to ensure manufacturability when filling a mold with a liquid composition containing the component (A) and the component (B), but is contained in the sticking part 10 even after drying. Preferably it is.
5-20 mass% is preferable and, as for content of water in the sticking part 10 (100 mass%), 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.

Other optional ingredients include crotamiton, limonene, diisopropyl adipate, etc .; methyl salicylate, glycol salicylate, thymol, peppermint oil, nonyl acid vanillyl amide, noryl acid vanillyl amide, capsicum extract, capsine, ascorbyl palmitate, kojic acid, lucinol, tranexamic acid , Edible licorice extract, retinol, retinoic acid, retinol acetate, retinol palmitate, isopropylmethylphenol, vitamins (vitamin D2, vitamin D3, vitamin K, etc.) and the like;
Optional ingredients include pharmaceutically acceptable salts and may be in the form of inorganic or organic salts.
An arbitrary component may be used individually by 1 type, and 2 or more types may be used in combination.

<PH>
The pH of the sticking part 10 varies depending on the blending of the physiologically active ingredients, but is preferably 3 to 9 from the viewpoint of irritation to the skin.

<Support>
The dissolution type microneedle preparation 1 may include a support on the surface of the sticking portion 10 opposite to the side where the needle portion 14 is formed.
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. 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.

(Method for producing melt-type microneedle formulation)
It does not specifically limit as a manufacturing method of a melt | dissolution type microneedle formulation, Conventionally well-known arbitrary methods are employable except mix | blending (A) component and (B) component by a specific ratio.
The dissolution type microneedle formulation 1 is manufactured by the following method, for example.
First, components (A) to (B) and other components as necessary are dispersed in water to prepare a liquid composition. A silicon mold in which the shape of the needle portion 14 is perforated is filled with the liquid composition, and the filled liquid composition is dried to obtain a dissolved microneedle preparation 1. Thereafter, the dissolved microneedle preparation 1 is peeled from the mold.
The temperature at the time of drying a liquid composition shall be 15-50 degreeC, for example.

As described above, the melt-type microneedle formulation of the present embodiment contains the component (A), and thus has a height, a tip angle, and a stress sufficient for the needle portion to puncture the skin.
In addition, since the dissolution type microneedle formulation of the present embodiment contains the component (B), it is possible to reduce a sense of incongruity during and during sticking.

  EXAMPLES Hereinafter, although an Example is shown and this invention is demonstrated in detail, this invention is not limited by the following description.

(Raw materials used)
<(A) component>
A-11: High molecular hyaluronic acid Na (trade name “hyaluronic acid FCH-SU”, manufactured by Kikkoman Biochemifa Co., Ltd., mass average molecular weight: 50,000 to 110,000), equivalent to component (A-1).
-A-21: Low molecular weight hyaluronic acid (trade name “Harooligo”, manufactured by Kewpie Co., Ltd., mass average molecular weight: 1000 or more and 10,000 or less), corresponding to the component (A-2).
A-3: Pullulan (trade name “Pullulan (Japan Pharmacopoeia)”, manufactured by Hayashibara Co., Ltd.)
<(B) component>
B-1: l-menthol (trade name “l-menthol (JP)”, manufactured by Simrise Co., Ltd.)
-B-2: dl-camphor (trade name “dl-camphor (JP)”, manufactured by Ogi Pharmaceutical Co., Ltd.).
<(B ′) Component> Comparative product of component (B) B′-1: Orange oil (manufactured by Takasago International Corporation).
<(C) component>
C-1: Glycerin (trade name “concentrated glycerin (Japan Pharmacopoeia)”, Sakamoto Pharmaceutical Co., Ltd.).
<(D) component>
D-1: Felbinac (trade name “Felbinac (Japan)”, manufactured by HANSEO CHEMICAL).
D-2: Loxoprofen Na (trade name “loxoprofen sodium hydrate (Nippon)”, manufactured by HUBEY XUNDA PHAMMACUTICAL CO., LTD).
D-3: Lidocaine (trade name “Lidocaine (JP)”, manufactured by Iwaki Pharmaceutical Co., Ltd.)
D-4: Crotamiton (trade name “Crotamiton (External Code)”, manufactured by Fujimoto Chemical Products Co., Ltd.
D-5: Diphenhydramine (trade name “Diphenhydramine (JP)”, manufactured by Kongo Chemical Co., Ltd.
D-6: Isopropylmethylphenol (trade name “Biosol (Kotohara)”, manufactured by Osaka Chemical Industry Co., Ltd.)
D-7: Tocopherol acetate (trade name “acetic acid dl-α-tocopherol (JP)”, manufactured by DSM Nutrition Japan Co., Ltd.)
<Other optional components>
・ Water: “Purified water (JP)”, manufactured by Kyoei Pharmaceutical Co., Ltd.

(Examples 1-14, Comparative Examples 1-4)
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 material of the mold as a whole was 100% by mass of silicone resin (two-component RTV rubber KE-17: Shin-Etsu Silicone).
A liquid composition in which each component was dissolved or dispersed in water was obtained so that the composition of the adhered part after drying would be the composition shown in Tables 1 to 3. For the component (A), a 10% by mass aqueous solution was prepared and mixed. A mold heated to 80 ° C. was filled with approximately 0.5 g of the liquid composition (an amount that would cause the mass of the dissolved microneedle preparation after drying to be 0.05 g or more). After filling, 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.
In Comparative Examples 2 and 3, since the base material was not formed in a flat shape and the needle portion was hardly formed, the evaluations of discomfort 1 and 2 were not performed.

(Evaluation method)
<Discomfort 1> Discomfort at the time of application The dissolved microneedle preparation of each example was applied to the inner side of the forearm of 10 subjects (5 adult men and 5 adult women). The uncomfortable feeling (pain) at the time of sticking was evaluated according to the following evaluation criteria 1 (6-step evaluation). The average score of 10 subjects was calculated. If the average score was less than 6, it was judged that the uncomfortable feeling at the time of sticking could be reduced.
In addition, the following evaluation criteria were created with reference to the description of references (Takumi Nagamine, “Pain Clinic and Oriental Medicine”, Shinko Trading Medical Book Publishing Department, 2004, pp. 29-34).
≪Evaluation criteria 1≫
10 points: Painful for non-work.
8 points: Very painful.
6 points: It hurts.
4 points: A little painful.
2 points: Just a little painful.
0 points: no pain.

<Discomfort 2> Discomfort during application 10 subjects were evaluated for the discomfort 4 hours after the dissolution type microneedle preparation of each example was applied in the evaluation of “<discomfort 1>”, based on the following evaluation criteria 2 (6-level evaluation) ). “Uncomfortable feeling” during application is a skin sensation with respect to the dissolved microneedle preparation being applied. When the subject recognized the sensation that the dissolved microneedle preparation was adhered to the skin, or felt that the sensation was uncomfortable, the subject evaluated that there was a sense of discomfort. The average score of 10 subjects was calculated. If the average score was less than 6, it was judged that the uncomfortable feeling during sticking could be reduced.
In addition, the following evaluation criteria were created with reference to the description of references (Takumi Nagamine, “Pain Clinic and Oriental Medicine”, Shinko Trading Medical Book Publishing Department, 2004, pp. 29-34).
≪Evaluation criteria 2≫
10 points: Discomfort in non-business.
8 points: There is a sense of incongruity.
6 points: There is a sense of incongruity.
4 points: A little uncomfortable.
2 points: It feels a little uncomfortable.
0 points: No discomfort.

As shown in Tables 1 to 3, Examples 1 to 14 were less than 6 in the evaluation of discomfort 1 and 2.
In comparison between Example 2 and Example 7, Example 7 containing the component (D) had lower discomfort points 1 and 2 than Example 2 (that is, the discomfort was reduced more favorably). )
In Examples 1 to 7, 9 and 10 containing the component (C), the number of subjects who scored 8 points or more with discomfort 1 and 2 was 0.
Comparative Example 1 containing no component (B) and Comparative Example 4 containing a component (B ′) instead of the component (B) both had a discomfort 1 of 6 or more.
From the above results, it was confirmed that by applying the present invention, the uncomfortable feeling at the time of sticking and during sticking can be reduced.

Claims (3)

A sticking part comprising a base material and a plurality of needle parts protruding from one side of the base material,
As for the said sticking part, 20-90 mass% of 1 or more types chosen from the group which consists of (A) component: hyaluronic acid, hyaluronic acid salt, and pullulan, and (B) component: cyclic terpene compound are 0.5-50. Dissolving type microneedle formulation containing the mass%.   The dissolution type microneedle preparation according to claim 1, wherein the sticking part further contains (C) component: a polyhydric alcohol.   The dissolution type microneedle preparation according to claim 1 or 2, wherein the sticking part further contains (D) component: physiologically active component (however, excluding the component (A)).

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