KR102497984B1 - Microneedle preparation and method for producing microneedle preparation - Google Patents

Abstract

Provided are a microneedle preparation in which the substrate is difficult to curve, excellent in following the curve of the skin, and the needle is easy to puncture the skin, and a method for producing a microneedle preparation capable of stably forming the needle. Equipped with a substrate 112 and a plurality of needles 114 protruding from one side of the substrate 112, component (A): at least one selected from the group consisting of hyaluronic acid and a salt thereof, and (B) Component: A microneedle preparation (11) comprising an adhesive portion (110) containing glycerin and having a mass ratio (A/B) of component (A) to component (B) of 1 to 5. Further, the liquid composition in which the formulation is dissolved in an aqueous solvent is filled into a mold at a temperature (T _A ) that satisfies the condition of 50 (° C.) ≤ T _A , and the temperature (T _B ) that satisfies the condition of T _B <T _A A method for producing a microneedle preparation comprising drying in an environment to form an adhesive portion.

Description

Microneedle preparation and method for preparing microneedle preparation {MICRONEEDLE PREPARATION AND METHOD FOR PRODUCING MICRONEEDLE PREPARATION}

The present invention relates to a microneedle preparation and a method for producing the microneedle preparation.

For example, microneedle preparations (also referred to as dissolving type microneedle preparations) are known as those for administering physiologically active ingredients such as anti-inflammatory analgesics and blood flow promoters into the human body. The microneedle preparation has a plurality of needles formed on one side of a sheet-like base material and an adhesive part containing a physiologically active ingredient. When the microneedle preparation is adhered to the skin, the physiologically active ingredient contained therein is percutaneously absorbed while the substrate and the needle dissolve.

Examples of microneedle preparations include those provided with a substrate containing hyaluronic acid and an adhesive portion having needles (Patent Documents 1 and 2). However, microneedle preparations tend to have low transdermal absorption compared to those provided with hollow needles because the injection amount of the active ingredient is low and the active ingredient is uniformly present in the substrate and the needle.

In addition, in the microneedle preparation, in order to ensure sufficient percutaneous absorption by piercing the skin with the needle, the needle has a sufficient height and stress, the tip angle is controlled to 90 degrees or less, and the substrate is good for the curved surface of the skin. It is also important to follow closely.

As a method for producing a microneedle preparation, for example, a liquid composition obtained by dissolving or dispersing a component (preparation) containing hyaluronic acid, gelatin, etc. in an aqueous solvent such as water is poured into a mold and filled, and a specific A method of taking out from a mold after drying and solidifying until it becomes a moisture content is mentioned. However, in the manufacturing method, it is difficult to form the needle stably because the ease of formation of the needle varies greatly depending on the composition of the liquid composition and the material of the mold. If needles are not stably formed, transdermal absorption of physiologically active ingredients becomes insufficient.

Therefore, a method of pressurizing and injecting a liquid composition in which an agent is dissolved in an aqueous medium such as water is injected into a pocket for forming a needle in a mold placed in a pressure-resistant container has been proposed (Patent Document 3). However, even in this method, when the microneedle preparation is taken out from the mold, the tips of the needles may become brittle or the needles may be insufficiently formed.

In addition, the base material containing hyaluronic acid tends to curve and warp after drying. If the substrate is curved, it is difficult to puncture the entire needle into the skin, and percutaneous absorption is lowered.

Japanese Unexamined Patent Publication No. 2009-201956 Japanese Unexamined Patent Publication No. 2013-189432 Japanese Patent Laid-Open No. 2013-162982

A first object of the present invention is to provide a microneedle preparation that has a sufficient height, tip angle, and stress to pierce the skin with a needle, suppresses bending of the base material, and has excellent followability to the curved surface of the skin. is to do

A second object of the present invention is to provide a method for producing a microneedle preparation capable of stably forming needles using a liquid composition in which the preparation is dissolved in an aqueous solvent.

A microneedle preparation of a first aspect to solve the first object of the present invention includes a substrate and an adhesive portion having a plurality of needles protruding from one side of the substrate, and while the adhesive portion is dissolved, they A microneedle preparation in which the components included in are percutaneously absorbed, wherein the adhesive portion contains (A) component: at least one selected from the group consisting of hyaluronic acid and hyaluronic acid salts, and (B) component: glycerin; The mass ratio (A/B) of the component (A) to the component (B) is 1 to 5.

In the microneedle preparation of the first aspect, the sticking portion may further contain (C) component: a physiologically active component (except for the component (A)).

Component (A) includes at least one selected from the group consisting of component (A-1): hyaluronic acid having a mass average molecular weight of 50,000 or more, and component (A-2): hyaluronic acid salt having a mass average molecular weight of 50,000 or more. It is preferable to include

It is preferable that said (C)component is a non-steroidal anti-inflammatory drug.

It is preferable that content of the said (A) component is 20-75 mass % in the sticking part (100 mass %).

It is preferable that mass ratio (A-2)/(A-1) of the said (A-2) component with respect to the said (A-1) component is 0-1.75.

A method for producing a microneedle preparation of a second aspect to solve the second object of the present invention is a microneedle preparation comprising a sheet-shaped substrate and an adhesive portion having a plurality of needles protruding from one surface of the substrate As a manufacturing method, a liquid composition in which an agent is dissolved in an aqueous solvent is filled into a mold at a temperature (T _A ) that satisfies the condition of the following formula (1), and a temperature (T _B that satisfies the condition of the following formula (2)) It is characterized in that the adhesive portion is formed by drying in an environment of.

50(℃)≤T _A ... (One)

T _B < T _A . . . (2)

In the microneedle formulation manufacturing method of the second aspect, the material of the part in contact with the sticking part in the mold is preferably silicon. In this case, all of the parts of the mold in contact with the sticking portion may be made of silicone, or part of them may be made of silicone. Among these, it is preferable that all of the portions in contact with the adhesive portion in the mold are made of silicone.

The formulation preferably contains component (X): at least one selected from the group consisting of water-soluble polymers and sugars.

It is preferable that content of the aqueous solvent in the said sticking part is 35 mass % or less. The formulation preferably contains component (Y): a physiologically active component.

In the present invention, it is also preferable to manufacture the microneedle preparation of the first aspect using the method for producing the microneedle preparation of the second aspect. Specifically, the temperature (T It is preferable to obtain the microneedle formulation of the first aspect by filling the mold of _A ) and drying in an environment at a temperature (T _B ) that satisfies the condition of the above formula (2) to form an adhesive portion.

The microneedle preparation of the first aspect of the present invention has a height, tip angle, and stress sufficient for the needle to pierce the skin, suppresses bending of the base material, and has excellent followability to the curved surface of the skin.

According to the microneedle preparation method of the second aspect of the present invention, needles can be stably formed using a liquid composition in which the preparation is dissolved in an aqueous solvent.

1 is a cross-sectional view showing an example of a microneedle preparation of a first aspect of the present invention.
Fig. 2 is an enlarged front view showing an example of the needle of the microneedle preparation of the first embodiment of the present invention.
3 is a cross-sectional view showing an example of a microneedle preparation prepared by the manufacturing method of the second aspect of the present invention.
Fig. 4 is a cross-sectional view showing an example of a step in the method for producing a microneedle preparation according to the second aspect of the present invention.

In the present invention, "needle" means a needle-shaped microconvex structure (micro-needle) in a broad sense, and is not limited to a needle-shaped one having a sharp tip, and the tip is not sharp. A shape (for example, a truncated conical shape) is also included.

"Thickness of the base end of the needle" refers to a circle circumscribed to the cross-sectional shape of the base end of the needle when the shape of the cross section perpendicular to the height direction of the base end of the needle is other than a circle, such as a polygonal cone-shaped needle. to mean the diameter.

[First aspect]

The microneedle preparation of the first aspect of the present invention includes a substrate and an adhesive portion having a plurality of needles protruding from one surface of the substrate, and the components contained in the adhesive portion dissolve while dissolving the skin. It is an absorbable microneedle preparation.

One example of the microneedle preparation of the first aspect of the present invention is shown in FIG. The microneedle formulation 11 includes an adhesive portion 110 . The sticking portion 110 includes a sheet-shaped substrate 112 and a plurality of needles 114 protruding from one side of the substrate 112 .

The shape of the needle is preferably conical. In addition, the shape of the needle 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. The height of the needle is preferably 50 to 1000 μm, and more preferably 100 to 700 μm. When the height of the needle is equal to or greater than the lower limit, transdermal administration of component (A) or component (C) is likely to be sufficient. When the height of the needle is equal to or less than the above upper limit, it is difficult for the needle to come into contact with the nerve, so pain and bleeding can be easily avoided. In addition, the height of the needle means an average value of heights measured for 10 randomly selected needles.

The thickness of the base end of the needle is preferably 10 to 1200 μm, and more preferably 25 to 600 μm. In addition, the thickness of the base of the needle means the average value of the thickness of the base measured for 10 randomly selected needles.

The tip angle of the needle is preferably 90 degrees or less, more preferably 10 to 60 degrees, and still more preferably 15 to 45 degrees. When the tip angle of the needle is equal to or greater than the lower limit, the needle is difficult to break during puncture. When the tip angle of the needle is equal to or less than the above upper limit, the puncture property is excellent.

In addition, the angle of the tip of the needle means the angle of the needle in the front view, and in the case of a needle with a sharp tip, the extension lines extending upward on both sides of the needle in the front view. is the angle at which it intersects. For example, in the case of the truncated cone-shaped needle 114A illustrated in FIG. 2, the extension line p and the extension line q extending upwardly the side edges 114a and 114b on both sides of the needle 114A in the front view, respectively. ) is defined as the tip angle.

It is preferable that the distance between adjacent needles is substantially equal, and it is preferable that about 1 to 10 needles are arranged per 1 mm. An allowable range of error in the distance of adjacent needles is, for example, about 0.01 to 0.5 mm.

The density of the needles is preferably 100 to 10000, more preferably 100 to 5000, and even more preferably 100 to 2000 per 1 cm2. When the density of the needle is equal to or greater than the lower limit, the skin can be punctured efficiently. When the density of the needle is equal to or less than the above upper limit, it is easy to maintain the strength of the needle.

The adhesive portion of the microneedle preparation of the first aspect of the present invention contains component (A) and component (B).

(Component (A))

(A) component is 1 or more types chosen from the group which consists of hyaluronic acid and a salt of a hyaluronic acid. Component (A) is a polysaccharide and has a cosmetic effect. When the sticking portion contains the component (A), it is possible to form the base material and the needle portion without blending other base materials.

Hereinafter, hyaluronic acid and a salt of hyaluronic acid may be collectively referred to as hyaluronic acid or the like.

Hyaluronic acid is a type of glycosaminoglycan (mucopolysaccharide), and has a structure in which disaccharide units of N-acetylglucosamine and glucuronic acid are connected.

Examples of the hyaluronic acid include hyaluronic acid derived from living organisms isolated from a crown, an umbilical cord, and the like, hyaluronic acid using fermentation by microorganisms, and the like. Since biologically derived hyaluronic acid cannot completely remove the collagen of the organism from which it was derived, and there is a possibility that the remaining collagen may adversely affect, hyaluronic acid derived from microbial fermentation is preferred.

As the hyaluronic acid salt, pharmaceutically and physiologically acceptable salts can be employed, and examples thereof include alkali metal salts (sodium salts, potassium salts, etc.), alkaline earth metal salts (magnesium salts, calcium salts, etc.), ammonium salts, and alkanes. Olamine salts (monoethanolamine etc.) etc. are mentioned. Especially, as a hyaluronic acid salt, an alkali metal salt is preferable.

5,000-1,000,000 are preferable and, as for the mass average molecular weight of hyaluronic acid etc., 10,000-200,000 are more preferable. When the mass average molecular weight of hyaluronic acid or the like is equal to or greater than the lower limit above, it is easy to suppress a decrease in the mechanical strength of the sticking portion, and it becomes difficult for the needle to break during storage or when inserting into the skin. When the mass average molecular weight of hyaluronic acid or the like is less than or equal to the above upper limit, the needles are easily pierced into the skin, and the permeability of the sticking portion into the skin is improved.

In addition, the mass average molecular weight of hyaluronic acid or the like is a value measured by gel permeation chromatography (GPC).

When penetrating into the skin, the needle does not break and is easily pierced and is easily dissolved in the body. As the component (A), it is preferable to use the component (A-1) described below, ) It is more preferable to use a mixture of the component and the (A-2) component.

(A-1) 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 salts having a mass average molecular weight of 50,000 or more.

(A-2) At least one selected from the group consisting of hyaluronic acid having a mass average molecular weight of less than 50,000 and hyaluronic acid salts having a mass average molecular weight of less than 50,000.

((B) component)

(B) Component is glycerin. When the sticking part contains the component (B), the base material of the sticking part curves and becomes difficult to bend.

Glycerin is a trivalent compound represented by the chemical formula C ₃ H ₅ (OH) ₃ or the molecular formula C ₃ H ₈ O ₃

It is alcohol. There are commercial items, such as an 84-87 mass % aqueous solution, in glycerol, You may use the commercial item.

((C) component)

In order to give other effective effects other than the moisturizing effect by component (A) to the adhered portion of the microneedle preparation of the first aspect of the present invention, if necessary, component (C): physiologically active component (provided that (A ) component) may be contained. In the microneedle preparation of the present invention, component (C) is not added to the adhesive portion, and other than the moisturizing effect by component (A), other effective effects due to component (C) may not be obtained.

In addition, a physiologically active component means a component that exerts some kind of action on a living body.

As component (C), known components commonly used in microneedle formulations can be employed. (C) As a component, a low molecular compound may be sufficient and a high molecular compound may be sufficient. (C) As a component, a non-steroidal anti-inflammatory drug is preferable.

Non-steroidal anti-inflammatory drugs include, for example, felbinac, butorphanol tartrate, ferrisoxal citrate, acetaminophen, mefenamic acid, diclofenac sodium, aspirin, alclofenac, ketoprofen, flurbiprofen, naproxen, blood Roxicam, indomethacin, indomethacin, ibuprofen, flurbiprofen, salicylic acid glycol, aminopyrine, loxoprofen and the like.

As (C)component other than a non-steroidal anti-inflammatory agent, the following components are mentioned, for example.

Hypnotic sedatives: flurazepam hydrochloride, rillamazapon hydrochloride, phenobarbital, amobarbital.

Steroid anti-inflammatory drugs: hydrocortisone, prednisolone, dexamethasone, betamethasone, etc.

· Stimulants/stimulants: methamphetamine hydrochloride, methylphenidate hydrochloride, etc.

Psychotropic agents: Imifuran hydrochloride, diakepam, sertraline hydrochloride, fluvoxamine maleate, paroxetine hydrochloride, talopram hydrogen bromide, fluoxetine hydrochloride, alprazolam, haloperidol, clomipramine, amitriptyline, desi pramin, amoxapine, maprotiline, mianserin, cetiptyline, trazodone, lopepramine, milnacipran, duloxetine, venlafaxine, chlorpromazine hydrochloride, thioridazine, diazepam, meprobamate, etizolam etc.

Hormonal agents: estradiol, estriol, progesterone, norethisterone acetate, methenolone acetate, testosterone, human chorionic gonadotropin, leutiniing hormone, human growth hormone, etc.

·Local anesthetic: lidocaine hydrochloride, procaine hydrochloride, tetracaine hydrochloride, dibucaine hydrochloride, propitocaine hydrochloride, etc.

· Urinary system agents: oxybutynin hydrochloride, tamusulosin hydrochloride, propiverine hydrochloride, etc.

Skeletal muscle relaxants: tizanidine hydrochloride, eperisone hydrochloride, pridinol mesylate, succimethonium hydrochloride, etc.

·Agents for reproductive organs: lithodrine hydrochloride, meluadrine tartrate, etc.

Antiepileptic drugs: sodium valproate, clonazepam, carbamazepine, etc.

· Autonomic nervous agents: carpronium chloride, bromide neostigmine, betanecol chloride.

Anti-Parkinson's disease: pergolide mesylate, bromocriptine mesylate,

Trihexyphenidyl hydrochloride, amantadine hydrochloride, ropinirole hydrochloride, taripexole hydrochloride, cabergoline, droxydopa, piperidene, selegiline hydrochloride, etc.

Diuretics: Hydroflumethiazide, Furosemide, etc.

Respiratory enhancers: lobeline hydrochloride, dimorpholamine, naloxone hydrochloride, etc.

· Antimigraine: Dihydroergotamine mesylate, smartriptan, ergotamine tartrate, flunarizine hydrochloride, cyproheptadine hydrochloride, etc.

Antihistamines: Clemastine fumarate, diphenhydramine tannate, chlorpheniramine maleate, diphenylpyralline hydrochloride, promethazine, etc.

Bronchodilators: Tolobuterol hydrochloride, furocaterol hydrochloride, salbutamol sulfate, clenbuterol hydrochloride, penoterol hydrobromide, terbutaline sulfate, isoprenaline sulfate,

Formoterol fumarate.

Cardiac drugs: Isoprenaline hydrochloride, dopamine hydrochloride, etc.

Vascular dilators: diltiazem hydrochloride, verapamil hydrochloride, isosorbide nitrate, nitroglycerin, nicorandil, etc.

·Peripheral vasodilators: nicametate citrate, thorazoline hydrochloride, etc.

· Smoking cessation aids: nicotine, etc.

Agents for circulatory organs: flunarizine hydrochloride, nicardipine hydrochloride, nitrendipine, nisoldipine, felodipine, amlodipine besylate, nifedipine, nilvadipine, manidipine hydrochloride, benidipine hydrochloride, enalapril maleate, te hydrochloride Mocapril, alacepril, imidapril hydrochloride, cilazapril, lisinopril, captopril, trandolapril, perindoprilerbumin, atenolol, bisoprolol fumarate, bunitrol hydrochloride, bunitrol tartrate , Betaxolol hydrochloride, Arotinolol hydrochloride, Celiprolol hydrochloride, Carvedilol, Carteolol hydrochloride, Bevantolol hydrochloride, Valsartan, Candesartan cilexetil, Losartan potassium, Clonidine hydrochloride, etc.

· Arrhythmia agents: Propranolol hydrochloride, alprenolol hydrochloride, procainamide hydrochloride, maxiletin hydrochloride, nadolol, disopyramide, etc.

Anti-malignant ulcer drugs: cyclophosphamide, fluorouracil, tegafur, procarbazine hydrochloride, ranimustine, irinotecan hydrochloride, fluridine, etc.

Antilipidemic drugs: pravastatin, simvastatin, bezafibrate, probucol.

Hypoglycemic agents: glibenclamide, chlorpropamide, tolbutamide, glimidine sodium, glybuzol, buformin hydrochloride, etc.

Peptic ulcer treatment: proglumid, cetraxate hydrochloride, spizofuron, cimetidine, bromide glycopyrronium, etc.

Hypoallergenic agents: Ursodesoxycholic acid, osalmid, etc.

Gastrointestinal motility improvers: domperidone, cisapride, etc.

・Agents for liver disease: Thiopronin, etc.

Anti-allergic agents: Ketotifen fumarate, azelastine hydrochloride, etc.

Antiviral agents: Acyclovir, etc.

Concentrates: betahistine mesylate, dipheidol hydrochloride, etc.

Antibiotics: Cepharolidin, cefdinir, cefpodoxime proxetil, cefaclo, clarithromycin, erythromycin, methylerythromycin, kanamycin sulfate, cycloserine, tetracycline, benzylpenicillin potassium, propicillin potassium, closacin Sodium, ampicillin sodium, bacampicillin hydrochloride, carbenicillin sodium, chloramphenicol, etc.

· Habitual poisoning agents: cyanamide, etc.

Appetite suppressant: Majindol, etc.

· Chemotherapeutic agents: Isoniazid, ethionamide, pyrazinamide, etc.

·Blood clotting promoters: ticlopidine hydrochloride, warfarin potassium, etc.

Anti-Alzheimer's drugs: physostigmine, donepezil hydrochloride, tacrine, arecoline, xanomerin, etc.

Serotonin receptor antagonist antiemetics: ondansetron hydrochloride, granisetron hydrochloride, ramosetron hydrochloride, azasetron hydrochloride, etc.

· Gout medications: colchicine, probenecid, sulfinpyrazone, etc.

Narcotic analgesics: pentanyl citrate, morphine sulfate, morphine hydrochloride, codeine phosphate, cocaine hydrochloride, petidine 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, 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, pertussis vaccine, Lyme disease vaccine, rabies vaccine, pneumonia These include diplococcus vaccine, yellow fever vaccine, cholera vaccine, vaccinia vaccine, tuberculosis vaccine, rubella vaccine, measles vaccine, mumps vaccine, botulinum vaccine, herpes virus vaccine, other DNA vaccines, and hepatitis B vaccine.

Further, as component (C), lixisenatide, naltrexone, acetorelix acetate, tartirelin, nafarelin acetate, prostaglandin A1, alprostadil, α-interferon, β-interferon for multiple sclerosis, and erythropoietin , Follitropin β, Follitropin α, G-CSF, GM-CSF, Salmoncalcitonin, Glucagon, GNRH antagonist, Insulin, Filgurascin, Heparin, Low-molecular-weight heparin, Somatropin, Incretin, GLP-1 derivatives, etc. can be heard

In addition, as component (C), crotamiton, l-menthol, mentha oil, limonene, diisopropyl adipate, etc., and as medicinal supplements, methyl salicylate, glycol salicylate, l-menthol, thymol, mentha oil, vanillyl nonylate Amide, vanillylamide norylate, red pepper extract, capsine, ascorbine palmitate, kojic acid, lucinol, tranexamic acid, oil-soluble licorice extract, retinol, retinoic acid, retinol acetate, retinol palmitate, isopropylmethylphenol, vitamins (vitamins D2, vitamin D3, vitamin K, etc.) and the like.

The compound of component (C) includes a pharmaceutically acceptable salt, and may be in any form of an inorganic salt or an organic salt.

(C) Component may be used individually by 1 type, and may be used in combination of 2 or more type.

((D)component)

The adhered portion of the microneedle preparation according to the first aspect of the present invention may contain optional components other than components (A) to (C): component (D) as needed.

As component (D), additives, such as solubility aids, percutaneous absorption accelerators, stabilizers, antioxidants, emulsifiers, surfactants and metal salts, are exemplified.

Examples of the solubilizer include ethylene glycol, propylene glycol, 1,3-butylene glycol, and polyethylene glycol.

As the surfactant, any of nonionic active agents, cationic active agents, anionic active agents, and amphoteric active agents may be used, and nonionic active agents commonly used in pharmaceutical preparations are preferable.

Specifically, sugar alcohol fatty acid esters such as sucrose fatty acid esters, sorbitan fatty acid esters, glycerin fatty acid esters, polyglycerin fatty acid esters, propylene glycol fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene glycerin fatty acid esters, polyethylene glycol Fatty acid ester, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, etc. are mentioned.

Polymers that can be formulated for the purpose of a base, solvent, stabilizer, plasticization aid, etc. include polyethylene oxide, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, dextran, poly vinyl 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 purposes such as buffers, stabilizers, bases, solvents, and suspending agents include sodium chloride, potassium chloride, magnesium chloride, potassium chloride, aluminum chloride, and zinc chloride.

It is preferable that water is contained in the adhered portion of the microneedle preparation of the first aspect of the present invention. Water is blended to ensure productivity when filling the mold with the formulation, but it is preferably contained in the adhesive portion even after drying.

(Ratio of each ingredient)

The ratio of each component in the adhered part in the microneedle preparation of the first embodiment of the present invention is shown below.

20-75 mass % is preferable, as for content of (A) component in an adhesive part (100 mass %), 20-70 mass % is more preferable, and its 30-70 mass % is still more preferable. When the content of component (A) is equal to or greater than the lower limit, formation of the substrate and the needle becomes easy. (A) When content of component is below the said upper limit, a base material curves and it becomes difficult to bend.

(A) In the case of using the component (A-1) as the component, the content of the component (A-1) in the adhesive portion (100% by mass) is preferably 20 to 75% by mass, and more preferably 20 to 70% by mass. It is preferable, and 30-70 mass % is more preferable. When the content of component (A-1) is equal to or greater than the lower limit, formation of the substrate and the needle becomes easy. (A-1) When content of component is below the said upper limit, a base material curves and it becomes difficult to bend.

0-30 mass % is preferable, as for content of the component (A-2) in an adhesive part (100 mass %), 0-25 mass % is more preferable, and its 5-10 mass % is still more preferable. (A-2) When the content of the component is equal to or greater than the lower limit, the puncture of the needle becomes better. (A-2) When content of component is below the said upper limit, a needle part becomes more difficult to break at the time of preservation or when it inserts into skin.

As component (A), 60 to 100% by mass of component (A-1) and 40 to 0% by mass of component (A-2) (the total of component (A-1) and component (A-2) is 100% by mass ) is preferably made of.

The mass ratio (A-2)/(A-1) of the component (A-2) to the component (A-1) (A-2)/(A-1) varies depending on the mass average molecular weight of each hyaluronic acid or the like. can be determined appropriately. As mass ratio (A-2)/(A-1), 0-1.75 are preferable and 0.05-0.5 are more preferable. When the mass ratio (A-2)/(A-1) is equal to or less than the above upper limit, it becomes difficult for the needle to break when stored or inserted into the skin.

15-45 mass % is preferable and, as for content of the (B) component in an adhering part (100 mass %), 20-40 mass % is more preferable. (B) When content of component is more than the said lower limit, a base material curves more and becomes difficult to bend. If the content of component (B) is less than the above upper limit, it is easy to suppress the sticking portion from being too soft, and it is easy to form a needle with a small tip angle and sufficient hardness, so that the needle is easy to puncture 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. When the mass ratio (A/B) is equal to or greater than the above lower limit, excessive softness of the sticking portion is suppressed, and a needle having a small tip angle and sufficient hardness is formed, so that the needle can be easily punctured into the skin. Curvature of a base material can be suppressed as mass ratio (A/B) is below the said upper limit.

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

5-20 mass % is preferable and, as for content of the water in an adhering part (100 mass %), 10-15 mass % is more preferable. When the water content is equal to or greater than the lower limit, the microneedle formulation has good flexibility. When the water content is below the upper limit, it is easy to suppress drying of the needle during production, and the change in mass after opening is also reduced.

Moreover, the total content of (A) component, (B) component, (C) component, and water does not exceed 100 mass %. It is preferable that each component is uniformly distributed in the sticking part. Therefore, it is preferable that content of each component mentioned above is content with respect to the unit mass of an adhesive part.

[pH]

Although the pH of the adhesive part varies depending on the blending of the physiologically active ingredient, from the viewpoint of irritation to the skin, 3 to 9 are preferable.

[support body]

In the microneedle preparation of the first aspect of the present invention, a support may be provided on the side of the sticking portion opposite to the side on which the needle is formed.

It does not specifically limit as a support body, A well-known support body normally used as a support body of an adhesive agent can be employ|adopted. Examples of the support include a resin film, a fabric, and a composite sheet in which a resin film and fabric 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 nonwoven fabric, a woven fabric, or a knitted fabric. Examples of the nonwoven fabric include those manufactured by the needle punch method, the spunlace method, the spunbond method, the stitch bond method, and the melt blown method.

The method of weaving the woven fabric or the knitting method of the knitted fabric is not particularly limited, and, for example, warp knitting (tricot knitting, denbitric knitting, satin knitting, atlas knitting, flat knitting, rim knitting, pearl knitting) ), circle knitting (double-sided knitting, single-sided knitting, price knitting), etc.

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 or an adhesive, a sheet formed by extruding a resin melted into a fabric, and the like.

(Manufacturing method)

The method for producing the microneedle preparation of the present invention is not particularly limited, and any conventionally known method can be employed except for blending component (A) and component (B) in a specific ratio.

For example, a liquid composition obtained by mixing components (A) and (B) and other components used as necessary with water is poured into a silicone mold having a perforated needle shape, dried, and then peeled from the mold. way can be

(action effect)

In the microneedle preparation of the first aspect of the present invention described above, since component (A) and component (B) are contained in a specific ratio, the needle has a sufficient height, tip angle and stress to puncture the skin, Curvature of the base material is suppressed, and the followability to the curved surface of the skin is excellent. Therefore, since the microneedle preparation of the first aspect of the present invention can stably puncture the needle when applied to the skin, excellent percutaneous absorption can be stably secured.

[Second aspect]

The method for producing a microneedle preparation according to the second aspect of the present invention uses a liquid composition in which the preparation is dissolved in an aqueous solvent, and includes a sheet-shaped substrate and an adhesive portion having a plurality of needles protruding from one side of the substrate. A method for preparing a microneedle preparation.

(Structure of microneedle preparation)

The structure of the microneedle preparation produced by the production method of the second aspect of the present invention is not particularly limited as long as it includes a sheet-shaped substrate and an adhesive portion having a plurality of needles protruding from one side of the substrate. .

As an example of a microneedle preparation prepared by the production method of the second aspect of the present invention, a microneedle preparation 21 is shown in FIG. 3 . The microneedle formulation 21 includes an adhesive portion 210 . The sticking portion 210 includes a sheet-shaped substrate 212 and a plurality of needle portions 214 protruding from one side of the substrate 212 .

The shape of the needle is not particularly limited, and examples thereof include a conical shape, a polygonal pyramidal shape (such as a quadrangular pyramidal shape), and a truncated cone shape, with a conical shape being preferable.

As in the first aspect, the height of the needle is preferably 50 to 1000 μm, and more preferably 100 to 700 μm. When the height of the needle is equal to or greater than the lower limit, transdermal administration of the active ingredient is likely to be sufficient.

The preferred ranges of the thickness of the base end of the needle, the distance between adjacent needles, and the density of the needle are the same as the preferred ranges shown in the first embodiment.

When the needle has a truncated conical shape, the thickness of the tip of the needle is preferably 5 to 500 µm, and more preferably 5 to 300 µm.

In the microneedle preparation produced by the production method of the second aspect of the present invention, a support may be provided on the side opposite to the side on which the needles are formed in the sticking portion. It does not specifically limit as a support body, A well-known support body normally used as a support body of an adhesive agent can be employ|adopted.

Examples of the support include those mentioned in the first aspect, such as resin films (polyethylene films, polypropylene films, etc.), fabrics (nonwoven fabrics made of polyester fibers, etc., woven fabrics, knitted fabrics, etc.), resin films and a composite sheet in which a fabric and a fabric are integrated.

(Manufacturing method)

In the method for producing a microneedle formulation of the second aspect of the present invention, a liquid composition in which the formulation is dissolved in an aqueous solvent is filled into a mold at a temperature (T _A ) that satisfies the condition of the following formula (1), and the following formula ( It is dried in an environment of temperature (T _B ) that satisfies the condition of 2) to form an adhesive part. As a result, a microneedle preparation with stable formation of needles and excellent percutaneous absorption of active ingredients can be obtained.

50(℃)≤T _A ... (One)

T _B < T _A . . . (2)

For example, when the microneedle preparation 21 is manufactured, as shown in FIG. 4 , a concave portion 2110 having a shape complementary to the shape of the substrate 212 of the microneedle preparation 21, and a needle ( A mold 2100 in which a pocket 2112 having a shape complementary to that of 214 is installed is used. The liquid composition (X) is filled into the concave portion 2110 and the pocket 2112 of the mold 2100 heated to the temperature T _A . Then, the mold 2100 filled with the liquid composition (X) is placed in an environment at a temperature (T _B ) less than the temperature (T _A ), and the liquid composition (X) is dried to form the microneedle preparation 21. . After that, the microneedle preparation 21 is peeled from the mold 2100 .

The temperature (T _A ) of the mold when filling the liquid composition is 50°C or higher, preferably 80°C or higher. When the temperature (T _A ) is equal to or greater than the above lower limit, the liquid composition easily enters the bottom of the pocket of the mold during drying, so that a microneedle preparation with stably formed needles can be obtained. In addition, the temperature (T _A ) may be less than the boiling point of the aqueous solvent used for the liquid composition, and is preferably equal to or less than the heat resistance temperature of the mold. Specifically, for example, the temperature T _A can be less than 100°C.

The temperature of the liquid composition when filling the mold is not particularly limited, and is preferably 0 to 80°C, more preferably 10 to 70°C, and even more preferably 20 to 60°C. When the temperature of the liquid composition is below the upper limit, the stability of the drug is improved. When the temperature of the liquid composition is equal to or higher than the lower limit, it becomes easy to fill the mold with the liquid composition.

The temperature during drying (T _B ) means the temperature of the environment in which the mold filled with the liquid composition is placed during drying. The temperatures of the mold and the liquid composition during drying are lowered to the temperature (T _B ). The temperature (T _B ) is less than the temperature (T _A ), and is preferably 25°C or lower from the viewpoint that the obtained microneedle preparation becomes difficult to bend due to curvature. In addition, since the drying time is shortened, the temperature (T _B ) is preferably 5°C or higher.

The difference (T _A -T _B ) between the temperature of the mold when filling the liquid composition (T _A ) and the temperature during drying (T _B ) is greater than 0°C, preferably 10°C or higher, and 25°C or higher. It is more preferable, and 30 degreeC or more is still more preferable. When the difference (T _A -T _B ) is equal to or greater than the lower limit, the liquid composition can easily enter the bottom of the pocket of the mold, so that a microneedle preparation with stably formed needles can be easily obtained.

Drying may be performed until the content of the aqueous solvent in the liquid composition reaches a desired ratio and the liquid composition solidifies to form an adhesive portion. What is necessary is just to determine drying time suitably according to the temperature (T _B ) at the time of drying.

<Liquid composition>

A liquid composition is a composition in which a formulation is dissolved in an aqueous solvent.

As the formulation, a known formulation dissolved in an aqueous solvent and used for the production of a microneedle formulation can be employed. As a preparation, component (X): It is preferable to contain at least 1 sort(s) selected from the group which consists of water-soluble polymers and sugars, and it is preferable to use component (X) as a main component. In addition, having component (X) as a main component means containing 50 mass % or more of component (X) with respect to the total amount (100 mass) of a formulation.

A water-soluble polymer means a compound having a solubility in water (100 g) at 20°C of 0.01 g or more and a molecular weight of 1000 or more (however, saccharides are excluded).

Examples of the component (X) include hyaluronic acid, sodium hyaluronate, gelatin, maltose, pullulan, pregelatinized starch, dextrin, carmellose sodium, crystalline cellulose, and lactose. Especially, as component (X), sodium hyaluronate, gelatin, and maltose are preferable from the viewpoint of facilitating the formation of needles.

1 type may be sufficient as (X) component, and 2 or more types may be sufficient as it.

The content of component (X) in the formulation (100% by mass) is preferably 10 to 95% by mass, more preferably 20 to 90% by mass, and most preferably 50 to 90% by mass. If the content of the water-soluble polymer is within the above range, formation of needles becomes easy and peeling of the microneedle preparation from the mold becomes easy.

(X) When using a water-soluble polymer as component, the content of the water-soluble polymer in the formulation (100% by mass) is preferably 15 to 90% by mass, more preferably 30 to 70% by mass, and 55 to 90% by mass. most desirable If the content of the water-soluble polymer is within the above range, formation of needles becomes easy and peeling of the microneedle preparation from the mold becomes easy.

(X) In the case of using saccharides as component, the content of saccharides in the formulation (100% by mass) is preferably 15 to 80% by mass, more preferably 30 to 70% by mass, and most preferably 50 to 70% by mass. do. If the content of the saccharide is within the above range, the formation of the needle becomes easy, and it becomes easy to peel the microneedle preparation from the mold.

The formulation may contain (Y) component: a physiologically active component (also referred to as a drug).

The physiologically active component is not particularly limited as long as it can be dispersed in the adhesive portion, and examples thereof include felbinac, diclofenac sodium, loxoprofen sodium, salicylic acid glycol, ketoprofen, and indomethacin. (Y) 1 type may be sufficient as a component, and 2 or more types may be sufficient as it.

When using component (Y), 1-10 mass % is preferable and, as for content of component (Y) in a formulation (100 mass %), 2-6 mass % is more preferable. (Y) When the content of the component is equal to or greater than the lower limit, the effectiveness of the physiologically active ingredient is easily exhibited. When the content of component (Y) is below the upper limit above, formability of needles is improved.

The formulation may contain (Z) component: alkanolamine.

The alkanolamine may be a monoalkanolamine, a dialkanolamine, or a trialkanolamine.

1-10 are preferable and, as for carbon number of the hydroxyalkyl group which an alkanolamine has, 2 or 3 are more preferable.

Specific examples of the alkanolamine include monoethanolamine, diethanolamine, triethanolamine, monopropanolamine, dipropanolamine, tripropanolamine, monoisopropanolamine, diisopropanolamine, and triisopropanolamine. there is.

(Z) 1 type may be sufficient as a component, and 2 or more types may be sufficient as it.

When using the component (Z), the content of the component (Z) in the formulation (100% by mass) is preferably 1 to 20% by mass, and more preferably 2 to 15% by mass. When the content of the component (Z) is equal to or greater than the lower limit, the formability of the needle improves. When the content of component (Z) is less than the upper limit above, needle puncture properties are improved. also,

(X) The total content of component - (Z) component does not exceed 100 mass %.

You may mix|blend other components other than components (X) - (Z) with a formulation as needed. Examples of other components include plasticizers such as glycerin, surfactants, drug solubilizers, tackifiers, stabilizers, colorants, perfumes, and the like.

Examples of the aqueous solvent include water and water-miscible organic solvents. The aqueous solvent may be only water, an organic solvent miscible with water, or a mixture of water and an organic solvent miscible with water.

In addition, the organic solvent miscible with water means an organic solvent that dissolves 0.01 g or more in 100 g of water at 20°C.

As an organic solvent miscible with water, ethanol, methanol, isopropanol, tetrahydrofuran, acetone etc. are mentioned, for example.

As the aqueous solvent, it is necessary to use one having a boiling point equal to or higher than the temperature of the mold (T _A ). As an aqueous solvent, water and ethanol are preferable from the viewpoint of being difficult to volatilize.

50 mass % or more is preferable and, as for content of the water in an aqueous solvent (100 mass %), 70 mass % or more is more preferable.

The mass ratio (water: organic solvent) of water and the organic solvent in the aqueous solvent is preferably from 1:0 to 1:1. If the mass ratio is within the above range, formation of the needle becomes easier.

The content of the aqueous solvent in the liquid composition (100% by mass) when filling the mold is preferably 30 to 90% by mass, and more preferably 50 to 90% by mass. When the content of the physical solvent is equal to or greater than the lower limit, formation of needles becomes easier. When the content of the physical solvent is below the upper limit, the puncture properties of the needle formed are good.

The viscosity of the liquid composition at 20° C. when filling a mold may be within a range having fluidity capable of filling a mold, and is preferably 1 to 20,000 mPa·s, and 1 to 10,000 mPa·s from the viewpoint of facilitating needle formation. mPa·s is more preferable. In addition, the said viscosity means the value measured by the B-type clay meter.

<Content of Aqueous Medium in Attached Area>

The content of the aqueous solvent in the adhesive portion (100% by mass) of the microneedle preparation obtained by the production method of the second aspect is preferably 35% by mass or less, more preferably 25% by mass or less, and 20% by mass or less. more preferable When the content of the aqueous solvent in the sticking portion is equal to or less than the above upper limit, the hardness of the needle portion becomes sufficiently high, and puncture into the skin becomes easy. Moreover, as for content of the aqueous solvent in an adhesive part (100 mass %), 5 mass % or more is preferable. When the content of the aqueous solvent in the adhered portion is equal to or greater than the lower limit, the needle portion is less likely to break when peeling the microneedle preparation from the mold. It is preferable that content of the aqueous solvent in an adhesive part (100 mass %) is 5-20 mass %. The content of the aqueous solvent in the sticking portion (100% by mass) may be 0% by mass.

<template>

As the mold, a mold having a concave portion complementary to the shape of the base material and a pocket complementary to the shape of the needle portion can be used according to the shape of the microneedle preparation to be produced. As the template, a known template can be used without limitation.

The material of the mold is not particularly limited, and any of resin, metal, wood, and the like may be used. Among them, as the material of the mold, resin is preferable from the viewpoint of workability. Examples of the resin forming the mold include silicone, polyethylene, polypropylene, polyvinyl chloride, acrylic, polyethylene terephthalate, polystyrene, acrylonitrile/butadiene/styrene copolymer, polycarbonate, polyamide, fluororesin, and polystyrene. Butylene terephthalate etc. are mentioned.

As the material of the portion in contact with the sticking portion in the mold, silicone is preferable because it is easy to peel the microneedle formulation from the mold. In this case, only the portion of the mold in contact with the sticking portion may be made of silicone, or the entire mold may be made of silicone. The portion made of silicone in the mold may be all or part of the portion in contact with the sticking portion in the mold. It is preferable that the part made of silicone in the mold is all of the parts in contact with the sticking part in the mold.

(action effect)

In the method for producing a microneedle preparation of the second aspect of the present invention described above, the temperature (T _A ) of the mold when filling the liquid composition is set to 50°C or higher, and the temperature (T _B ) lower than the temperature (T _A ) ) by drying in an environment to form an adhesive portion, the needle portion is stably formed. Factors for stably forming the needle by controlling the temperature T _A and the temperature T _B as described above are considered as follows.

When the mold is filled with the liquid composition, especially when the liquid composition has a high viscosity, air or water vapor tends to remain at the bottom of the pocket of the mold. Therefore, the liquid composition is not sufficiently filled to the bottom of the pocket of the mold, and the tips of the needles become brittle, making it difficult for the needles to be stably formed. In contrast, in the second aspect of the present invention, a mold is filled with a liquid composition at a temperature (T _A ) of 50°C or higher, and the mold filled with the liquid composition is placed at a temperature (T _B ) lower than the temperature (T _A ). By drying the liquid composition in an environment of the mold, the air and water vapor remaining in the pockets of the mold are contracted, and the inside of the pockets becomes negative pressure. As a result, it is thought that the needle is stably formed because the liquid composition is introduced to the bottom of the pocket of the mold and is sufficiently filled.

As described above, since needles are stably formed in the microneedle preparation produced by the production method of the second aspect of the present invention, the percutaneous absorption of the active ingredient is excellent. In the microneedle preparation produced by the production method of the second aspect, the number of needles formed is preferably 90 or more, more preferably 95 or more, for 100 pockets in the mold.

Hereinafter, the first aspect of the present invention will be described in detail with examples, but the first aspect of the present invention is not limited by the following description.

[Ingredients used]

The raw materials used in this Example are shown below.

((A) component) A-11: High molecular weight sodium hyaluronate (Brand name "Hyaluronic acid FCH-SU", the Kikoman Biochemical Co., Ltd. make, mass average molecular weight: 50,000-110,000).

A-21: Low molecular weight hyaluronic acid (trade name "Hyaroorigo", manufactured by QP Co., Ltd., mass average molecular weight: 1000 or more and 10,000 or less).

((B) component)

B-1: Glycerin (“Agricultural Glycerin (Japan)”, manufactured by Sakamoto Chemical Industry Co., Ltd.).

((B') component: comparison target)

B'-1: 1,3-butylene glycol (“1,3-butylene glycol (pharmaceutical additives standard)”, manufactured by Daicel Co., Ltd.).

B'-2: Propylene glycol ("Propylene glycol (Japan)", made by Adeka Corporation).

B'-3: Polyethylene glycol ("Polyethylene glycol 600", manufactured by Wako Pure Chemical Industries, Ltd.).

((C) component)

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

(optional ingredients)

Water: 「Purified water (Ilguk)」, manufactured by Kogyong Pharmaceutical Co., Ltd.

[Examples A1 to A9, Comparative Examples A1 to A6]

As a mold for producing microneedle formulations, pockets in the shape of a conical shape with a root diameter of 0.5 mm and a height of 0.65 mm and a tip angle of 33 degrees complementary to the needle are formed at intervals of 1.0 mm in length and width of 10 For each pocket, a total of 100 pockets were used. In addition, the angle of the tip of the needle with no sharp tip is the angle formed by the upwardly extending lines of the side edges of both sides of the needle in a frontal view. The material of the mold was 100% silicone resin (two-component RTV rubber KE-17: Shin-Etsu Silicone) as a whole.

As shown in Tables 2 and 3, compositions in which each component was uniformly dissolved or dispersed were obtained. Regarding the component (A), a 10% by mass aqueous solution was prepared and mixed. Approximately 0.5 g of the composition (an amount of 0.05 g or more in mass after drying) was applied to a mold heated to 80°C. After application, the mold was cooled under conditions of 25°C and 100% Rh, and after the mold reached 25°C, it was naturally dried for about 8 hours to obtain a microneedle formulation.

[Curvature/followability evaluation]

Regarding the microneedle preparations obtained in each case, the degree of curvature of the substrate when viewed from the side in a state of being placed on a flat surface and the followability when placed on the curved skin surface of the arm were evaluated according to the following criteria.

(Evaluation criteria: Table 1)

(double-circle): When placed on a flat surface, no curvature is observed in the base material, and it follows the curved surface of the skin.

○: When placed on a flat surface, no curvature is observed in the base material, but it does not follow the curved surface of the skin.

×: When placed on a flat surface, the base material is curved, and a portion not in contact with the flat surface is recognized. In this case, the substrate does not follow the curved surface of the skin.

[Table 1]

[Evaluation of the height of the bed]

The height of the needle in the microneedle preparation obtained in each case was measured with a digital microscope, and evaluated according to the following criteria.

(Evaluation standard)

◎: The height of the needle is 500 μm or more.

○: The height of the needle is 400 μm or more and less than 500 μm.

×: The height of the needle is less than 400 µm.

If the height of the needle is less than 400 µm, it becomes difficult to sufficiently obtain the effect even when pierced.

[Evaluation of the angle of the needle]

The tip angle of the needle in the microneedle preparation obtained in each case was measured with a digital microscope and evaluated according to the following criteria. In addition, the angle formed by the extension lines to the upper side of the side of both sides of the needle in the front view was made into the tip angle.

(Evaluation standard)

◎: 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.

If the tip angle of the needle is 90 degrees or more, it becomes difficult to puncture the needle.

[Evaluation of stress in the needle]

Using a texture analyzer, the stress when the needle of the microneedle formulation obtained in each example was pressed 0.01 mm from the tip side was measured, and the following evaluation criteria were evaluated. In addition, as the material of the probe to be pressed, disc-shaped opaque glass with a diameter of 1 cm was used.

(Evaluation standard)

○: Stress is 0.05 N or more.

x: The stress is less than 0.05 N.

If the stress is less than 0.05 N, it becomes difficult to puncture the needle.

Table 2 and Table 3 show the composition and evaluation results of each component in Examples and Comparative Examples.

In addition, the composition in Table 2 and Table 3 is a composition at the time of assuming that the coating amount and the mass after drying were measured and all the weight loss was water. In addition, content of (B) component is mass % of solid content conversion of glycerol. In addition, in the column of mass ratio (A/B) in Comparative Examples A4 to A6, the mass ratio of component (A) to component (B') is shown.

[Table 2]

[Table 3]

As shown in Tables 2 and 3, in the microneedle preparations of Examples A1 to A9 in which components (A) and (B) were blended in the proportions stipulated in the present invention, the needles had a height sufficient to puncture the skin, It has tip angle and stress. In addition, the base material is suppressed in curvature and has excellent followability to the curved surface of the skin.

In the microneedle preparations of Comparative Example A1 in which the component (B) was not used, and Comparative Example A2 in which the mass ratio (A/B) was greater than 5, curvature was observed in the base material. Also in the microneedle preparations of Comparative Examples A4 to A6 in which component (B') was used instead of component (B), curvature was observed in the base material.

In the microneedle formulation of Comparative Example A3 having a mass ratio (A/B) of less than 1, the needle did not have sufficient height, tip angle, and stress to puncture the skin.

The second aspect of the present invention will be described in detail below with examples, but the second aspect of the present invention is not limited by the description below.

[Ingredients used]

The raw materials used in this Example are shown below.

HA-1: Sodium hyaluronate (mass average molecular weight: 50,000 to 110,000, trade name "FCH-SU", manufactured by Kikoman Biochemifa Co., Ltd.).

HA-2: Hyaluronic acid (mass average molecular weight: 1,000 to 10,000, trade name "Hyaroorigo", manufactured by QP Co., Ltd.).

GEN: Gelatin (manufactured by Rousselot Co., Ltd.).

MAL: Maltose (trade name "Sunmalto", manufactured by Hayashibara Co., Ltd.).

GL: Agricultural glycerin (trade name "Defense Agricultural Glycerin", manufactured by Sakamoto Chemical Industry Co., Ltd.). DIPA: Diisopropanolamine (made by Mitsui Chemical Fine Co., Ltd.).

LOX: Sodium loxoprofen (manufactured by Daito Co., Ltd.).

DCF: Diclofenac sodium (manufactured by Yamato Chemical Industry Co., Ltd.).

FEL: Felvinac (manufactured by HANSEO CHEMICAL Co., Ltd.).

Water: 「Purified water (Ilguk)」, manufactured by Kogyong Pharmaceutical Co., Ltd.

EtOH: Ethanol (manufactured by Junsei Chemical Co., Ltd.).

The mass average molecular weight means a value measured by a gel permeation chromatography method.

[Example B1]

As a mold for preparing a microneedle preparation, pockets of a shape complementary to a conical needle having a root diameter of 0.5 mm, a height of 0.65 mm, and a tip diameter of 0.04 mm, 10 pockets each vertically and horizontally at intervals of 1.0 mm, in total, 100 pockets were used. The material of the mold was 100% silicone (two-component RTV rubber KE-17: Shin-Etsu Silicone), including the surface in contact with the substrate and the needle.

Components (other than water) shown in Table 4 were dissolved in water to prepare a liquid composition. Subsequently, after heating the mold to 80°C (temperature (T _A )) using a thermostat, the mold was taken out of the thermostat, and about 1 g of the liquid composition was quickly filled into the mold. The liquid composition before filling was at room temperature (25°C).

The mold and the liquid composition were left still at 25°C (temperature (T _B )) and the liquid composition was dried until the mass reached a constant weight, and then the microneedle preparation was taken out from the mold.

[Examples B2 to B27, Comparative Examples B1 to B15]

Microneedle preparation in the same manner as in Example B1, except that the composition of the liquid composition filled in the mold, the temperature of the mold (T _A ), and the temperature (T _B ) at the time of drying were changed as shown in Tables 4 to 8. was produced.

[Measurement of drug permeation amount]

A percutaneous absorption test was conducted using hairless mice. An outline is shown below.

A mouse skin was placed on a bell-type Franz cell, and a patch was applied. Thereafter, the receiver solution after 8 hours was collected, and the permeation amount of the drug was measured by HPLC under the following treatment conditions. Measurement of the permeation amount of the drug was performed on Examples B10 to B17 and Comparative Examples B6 to B10 containing loxoprofen sodium, and Examples B20 to B27 and Comparative Examples B11 to B15 containing felbinac.

(processing conditions)

Measurement environment: 25℃, 50%RH,

Mouse skin: HR-1 excised from the back of a 7-week-old male,

Receiver solution: Phosphate buffer (pH 7.4),

Attached area: 5cm2,

Patch: 1 sheet (about 0.5g),

Franz cell jacket temperature: 37°C.

In addition, drug permeability was evaluated according to the following criteria.

(Evaluation criteria when the drug is loxoprofen sodium)

◎: The permeation amount of the drug is 200 μg/cm 2 or more.

○: The amount of permeation of the drug is 150 μg/cm 2 or more and less than 200 μg/cm 2 .

Δ: The amount of permeation of the drug is 100 μg/cm 2 or more and less than 150 μg/cm 2 .

×: The amount of permeation of the drug is less than 100 μg/cm 2 .

(Evaluation criteria when the drug is felbinac)

◎: The permeation amount of the drug is 450 μg/cm 2 or more.

○: The drug permeation amount is 350 μg/cm 2 or more and less than 450 μg/cm 2 .

Δ: The amount of permeation of the drug is 250 μg/cm 2 or more and less than 350 μg/cm 2 .

×: The amount of permeation of the drug is less than 250 μg/cm 2 .

[Acupuncture formation]

Using a microscope (Keyence: VHX-1000), the microneedle formulation was observed, the number of needles corresponding to 100 pockets of the mold was confirmed, and the needle formation was evaluated according to the following criteria. did

(Evaluation standard)

◎: The number of needles formed is 95 or more.

○: The number of needles formed is 90 or more and less than 95.

Δ: The number of needles formed is 80 or more and less than 90.

×: The number of needles formed is less than 80.

The manufacturing conditions and evaluation results in Examples B1 to B27 and Comparative Examples B1 to B15 are shown in Tables 4 to 8. In addition, "amount of composition after drying" in Tables 4 to 8 means the ratio of the mass of the composition after drying when the mass of the liquid composition immediately after filling the mold before drying is set to 100.

[Table 4]

[Table 5]

[Table 6]

[Table 7]

[Table 8]

As shown in Tables 4 to 8, in Examples B1 to B27 using the production method of the present invention, 90 or more needles were formed, and the formation of the needles was stable. In addition, the microneedle preparations of Examples B10 to B17 and B20 to B27 had excellent drug permeability.

On the other hand, in Comparative Examples B1 to B15 in which the temperature of the mold (T _A ) and the temperature (T _B ) at the time of drying do not satisfy either of the conditions of equations (1) and (2), the number of needles formed is less than 90, and the formation of needles was unstable. In addition, the microneedle preparations of Comparative Examples B6 to B15 were inferior in drug permeability.

11: Microneedle preparation
110: adhesive part
112: description
114: sleep
21: microneedle preparation
210: adhesive part
212: materials
214: sleep
2100: mold
2110: recess
2112: Pocket

Claims (11)

A microneedle preparation comprising a substrate and an adhesive portion having a plurality of needles protruding from one side of the substrate, wherein components contained in the adhesive portion are percutaneously absorbed while dissolving in the adhesive portion, comprising:
The adhesive portion contains (A) at least one selected from the group consisting of hyaluronic acid and a salt thereof, and (B) glycerin;
The mass ratio (A/B) of the component (A) to the component (B) is 1 to 5,
A microneedle preparation characterized in that the content of the component (A) in the sticking portion (100% by mass) is 30 to 70% by mass. According to claim 1,
The microneedle preparation characterized in that the attachment portion further contains (C) a physiologically active component (except for the component (A)). According to claim 1 or 2,
Component (A) comprises one selected from the group consisting of (A-1) hyaluronic acid having a mass average molecular weight of 50,000 or more and (A-2) a hyaluronic acid salt having a mass average molecular weight of 50,000 or more. needle formulation. According to claim 2,
A microneedle preparation characterized in that the component (C) is a non-steroidal anti-inflammatory drug. According to claim 1 or 2,
A microneedle preparation, wherein the component (A) comprises (A-1) hyaluronic acid having a mass average molecular weight of 50,000 or more and (A-2) a hyaluronic acid salt having a mass average molecular weight of 50,000 or more. According to claim 5,
A microneedle preparation characterized in that the mass ratio (A-2)/(A-1) of the component (A-2) to the component (A-1) is 0.05 to 0.5. A method for producing the microneedle preparation according to claim 1, comprising a sheet-like substrate and an adhesive portion having a plurality of needles protruding from one side of the substrate,
A liquid composition in which a formulation is dissolved in an aqueous solvent is filled into a mold at a temperature (T _A ) that satisfies the condition of the following formula (1), and dried in an environment of a temperature (T _B ) that satisfies the condition of the following formula (2) A method for producing a microneedle preparation, characterized in that by forming the adhesive portion by
50(℃)≤T _A ... (One)
T _B < T _A . . . (2) According to claim 7,
Method for producing a microneedle formulation, characterized in that the material of the surface in contact with the liquid composition in the mold is silicone. According to claim 7,
A method for producing a microneedle formulation, wherein the formulation comprises (X) at least one selected from the group consisting of water-soluble polymers and sugars. The method of claim 7 or 9,
A method for producing a microneedle preparation, characterized in that the content of the aqueous solvent in the sticking portion is 35% by mass or less. The method of claim 7 or 9,
A method for producing a microneedle preparation, characterized in that the preparation contains (Y) a physiologically active ingredient.

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