TWI631965B - Microneedle device and its manufacturing method - Google Patents

Abstract

The present invention is a microneedle device comprising a substrate, a microneedle provided on the substrate, a microneedle device attached to the microneedle and / or a physiologically active composition on the substrate, the physiologically active composition At least one polyol from glycerin, ethylene glycol, propylene glycol, and 1,3-butanediol, and physiologically active substances, and is substantially free of water.

Description

Microneedle device and its manufacturing method

The invention relates to a microneedle device and a manufacturing method thereof.

In the past, it has been known that a microneedle device can be used as a device to promote the transdermal absorption of medicines. The microneedles provided in the microneedle device are aimed at puncturing the outermost stratum corneum of the skin, and various documents have proposed various sizes or shapes, and can be expected as a non-invasive administration method (for example, Patent Document 1) .

In addition, in the case of using a microneedle device, various methods have been proposed in the literature regarding the method of supplying drugs. For example, it is known to apply a medicament on the surface of a microneedle; to provide a groove or a hollow part for passing a medicament or a biological component on the microneedle; and to mix the microneedle itself with the medicament. It has been disclosed in the literature that the substance mixed together when applying the drug at this time should contain the gist of sugar, especially the lactose, raffinose, trehalose or sucrose-like glass-like (amorphous solid substance) Sugar for stabilization (Patent Document 2).

In addition, Patent Document 3 discloses a transdermal delivery device and method for a bioactive drug, which includes a delivery system having minute protrusion members. In one form, a biocompatible coating formulation suitable for microprotrusion members is disclosed, which contains at least one non-aqueous solvent, such as ethanol, isopropanol, methanol, propanol, butanol, propylene glycol, dimethyl sulfoxide Rocket, glycerin, N, N-dimethylformamide, and polyethylene glycol 400, preferably non-aqueous solvents, in the range of about 1% to 50% by weight of the coating formulation, stored in the coating formulation . In addition, the viscosity of the coating formulation is 3 to about 500 centipoise (cps).

Prior technical literature

Patent Literature

Patent Document 1: Japanese Special Publication No. 2001-506904

Patent Document 2: Japanese Special Publication No. 2004-504120

Patent Document 3: Japanese Special Publication No. 2007-536988

However, it was found that when a microneedle device is manufactured using a composition (physiologically active composition) containing a physiologically active substance and a solvent as disclosed in Patent Documents 1 to 3, if the physiologically active composition is contained in the microneedle device, the solvent can be volatilized. After the container is made, the manufacturing method of attaching it to the microneedles may cause problems when the physiologically active composition is attached to a plurality of microneedle arrays (on the microneedles). That is to say, if the microneedle device is to be continuously manufactured by this method, the amount of the physiologically active composition coated on the microneedle will be greatly different, and the problem that the stable application amount of the microneedle device cannot be manufactured occur. The amount of the medicament varies with each microneedle device manufactured, and it is not suitable in the case of using highly effective or expensive physiologically active substances, especially in terms of medicine (treatment) or economy.

Therefore, an object of the present invention is to provide a method of manufacturing a microneedle device, even in the case of using the continuous manufacturing method as described above using a mask plate, the difference in the amount of adhesion of the physiologically active substance attached to the microneedle is reduced Small enough to be practical. Another object of the present invention is to provide a microneedle device obtainable by such a manufacturing method.

The invention provides a method for manufacturing a microneedle device for attaching a physiologically active composition to a microneedle. The physiologically active composition contains a physiologically active substance and a solvent that can disperse or dissolve the physiologically active substance. At least one polyol selected from glycerin, ethylene glycol, propylene glycol, and 1,3-butanediol is used, and water is not used.

According to the manufacturing method of the microneedle device of such a configuration, even in the case of continuous manufacturing, it is still possible to stably obtain that the viscosity of the physiologically active composition changes little with time during manufacturing, and the microneedles adhere to and contain a uniform amount ( The micro-needle device of the physiologically active composition of the physiologically active substance with a small difference). It is believed that the microneedle device in which the adhesion amount of the physiologically active substance can be stabilized by this manufacturing method is greatly assisted by the setting of not containing water in the solvent.

After a container is used as a mask plate with an opening formed and the physiologically active composition is filled into the opening, the physiologically active composition is attached to the microneedle by inserting and extracting the microneedle into the opening In the case of the above manufacturing method, the stabilization of the adhesion amount of physiologically active substances is particularly remarkable.

As described above, since the stabilization of the amount of the physiologically active substance is particularly remarkable in the above-mentioned manufacturing method, one microneedle can be extracted from the mask plate filled with the physiologically active composition, and then the same can be used for the other microneedle Mask plate. In addition to this method of using a mask plate, a physiologically active composition containing a physiologically active substance and a solvent that can disperse or dissolve the physiologically active substance is accommodated in a liquid storage part that is open at the top, and a pump is used. For example, the method of moving to the periphery of a microneedle and spray coating.

In the physiologically active composition, the mass ratio of the physiologically active substance to the polyol is preferably 20:80 to 80:20, and the viscosity of the physiologically active composition at room temperature (25 ° C) is preferably 600 to 45000 cps. By adopting such conditions, the physiologically active substance in the content corresponding to the amount of the physiologically active substance used in the physiologically active composition is easily included in the physiologically active composition adhering to the microneedles, so physiological activity can be obtained Microneedle device with high material administration efficiency.

In addition, the above manufacturing method can also be understood as a method for stabilizing the adhesion amount of a physiologically active composition, which is a method in which a physiologically active composition containing a physiologically active substance and a solvent that can disperse or dissolve the physiologically active substance is contained in After the container in which the solvent is volatilized is adhered to the microneedle to manufacture a microneedle device, the solvent uses at least one polyol selected from glycerin, ethylene glycol, propylene glycol, and 1,3-butanediol, And no water is used.

Therefore, according to the present invention, there can be provided a microneedle device comprising: a substrate; a microneedle provided on the substrate; and a microneedle device attached to the microneedle and / or the physiologically active composition on the substrate, and The physiologically active composition contains at least one polyol selected from glycerin, ethylene glycol, propylene glycol, and 1,3-butanediol; and a physiologically active substance, and does not substantially contain water.

Here, the physiologically active composition attached to the microneedles and / or the substrate does not substantially contain water, which means that the moisture content does not exceed the moisture contained after the physiologically active composition is attached because it absorbs moisture from the atmosphere, Typically, the moisture content is 7 mass% or less, preferably 5 mass% or less, or even 3 mass% or less, based on the total amount of the attached physiologically active composition.

In the above-mentioned microneedle device, the physiologically active composition attached to the microneedle and / or the substrate further contains hydroxypropyl cellulose, polyethylene glycol, chondroitin sulfate, hyaluronic acid, polydextrose, At least one compound of croscarmellose sodium and magnesium chloride is preferred.

Since the microneedle device has such a structure, the viscosity of the physiologically active composition can be increased, and the height of the physiologically active composition attached to the microneedles and / or the substrate or the content of the physiologically active substance can be more reliably controlled.

In addition, the physiologically active composition attached to the microneedles and / or the substrate is preferably applied to the microneedles and / or the substrate, and then dried and fixed.

According to the present invention, a method for manufacturing a microneedle device can be provided. Even in the case of a continuous manufacturing method using a mask plate, the difference in the amount of the physiologically active substance attached to the microneedle is reduced to a practically sufficient level, and The microneedle device obtained by this manufacturing method.

Hereinafter, suitable embodiments will be described with reference to the drawings. In the description of the drawings, the same reference numerals are used for the same elements, and repeated explanations are omitted. In addition, in order to make the drawing easy to understand, a part is exaggeratedly drawn, and the size ratio does not necessarily coincide with the description.

FIG. 1 is a perspective view showing one embodiment of the microneedle device related to the present invention. As shown in FIG. 1, the microneedle device 1 includes a microneedle substrate 2 and a plurality of microneedles 3 arranged on the microneedle substrate 2 in a planar shape.

The microneedle substrate 2 is a pedestal for supporting the microneedle 3. The form of the microneedle substrate 2 is not particularly limited. For example, in the microneedle substrate 2, a plurality of through holes 4 can be formed in a planar arrangement. The microneedles 3 and the through holes 4 may be alternately arranged in the diagonal direction of the microneedle substrate 2. Through the through hole 4, the physiologically active composition can be administered from the back of the microneedle substrate 2. Nevertheless, a substrate without such a through hole can also be used. The area of the microneedle substrate 2 is 0.5 to 10 cm ² , preferably 1 to 5 cm ² , and preferably 1 to 3 cm ² . It is also possible to connect the plurality of microneedle substrates 2 to make the formed substrate a desired size.

The microneedle 3 has a micro structure, and its height (length) is preferably 50 to 600 μm. Here, the length of the microneedles 3 is set to 50 μm or more to ensure the transdermal administration of physiologically active substances, and 600 μm or less to avoid the contact between the microneedles and nerves to reduce the possibility of pain and avoid Possible bleeding. In addition, if the length of the microneedles 3 is 500 μm or less, the physiologically active substance can be effectively administered in an amount that can enter the skin, and it may be administered without perforating the skin as the case may be. The length of the microneedle 3 is particularly preferably 300 to 500 μm.

Here, the microneedle means a convex structure and is a needle-shaped structure in a broad sense, or a structure including a needle-shaped structure. Even so, the microneedles are not limited by the sharp needle shape at the tip, and objects with a non-sharp tip shape are also included. When the microneedle 3 has a conical structure, the diameter of the base portion is about 50 to 200 μm. In the present embodiment, the microneedles 3 have a conical shape. However, microneedles such as a polygonal pyramid such as a quadrangular pyramid or other shapes can also be used.

The microneedles 3 are typically provided at intervals with a density of about 1 to 10 per millimeter (mm) in the horizontal direction of the needles. Generally speaking, adjacent horizontal rows are substantially separated from each other by an equal distance with respect to the space of the needles in the horizontal row, and have a needle density of 100 to 10,000 needles per 1 cm ² . If the needle density is above 100, the skin can be effectively perforated. On the other hand, when the needle density exceeds 10,000, it becomes difficult to maintain the strength of the microneedles 3. The density of the microneedles 3 is preferably 200 to 5000, more preferably 300 to 2000, and most preferably 400 to 850.

The material of the microneedle substrate 2 or the microneedle 3 may include silicon, silicon dioxide, ceramics, metals (stainless steel, titanium, nickel, molybdenum, chromium, cobalt, etc.) and synthetic or natural resin materials, etc. However, the antigen of the microneedle is considered Properties and the unit price of materials, biodegradable polymers such as polylactic acid, polyglycolide, polylactic acid polyglycolide copolymer, polytriglucose, caprolactone, polyurethane, polyanhydride, etc., or Synthetic or natural resin materials such as polycarbonate, polymethacrylic acid, ethylene vinyl acetate, polytetrafluoroethylene, polyoxymethylene, etc. of non-degradable polymers are particularly preferred. In addition, polysaccharides such as hyaluronic acid, sodium hyaluronate, polytriglucose, polydextrose, dextrin or chondroitin sulfate are also suitable.

The manufacturing method of the microneedle substrate 2 or the microneedle 3 includes wet etching processing or dry etching processing using a silicon substrate, precision mechanical processing using metal or resin (discharge processing, laser processing, dicing processing, hot pressing processing, injection) Molding, etc.), mechanical cutting, etc. By these processing methods, the needle part and the support part can be integrally formed. The method of making the needle part hollow may include a method of performing secondary processing such as laser processing after the needle part is produced.

3 (a) to (c) are diagrams showing an example of a method of manufacturing the microneedle device 1. FIG. In this method, first, as shown in FIG. 3 (a), the physiologically active composition 10 is swept in the arrow A direction on the mask plate 11 by the spatula 12. As a result, the opening 13 can be filled with the physiologically active composition. Next, as shown in FIG. 3 (b), the microneedle 3 is inserted into the opening 13 of the mask plate 11. Thereafter, as shown in FIG. 3 (c), the microneedle 3 is drawn out from the opening 13 of the mask plate 11. As a result, the physiologically active composition 10 will adhere (in this case, coating) to the microneedles 3. Thereafter, the physiologically active composition on the microneedles is dried by a well-known method of air drying, vacuum drying, freeze drying, or a combination of these. As a result, the solid physiologically active composition 10 is fixed to the microneedles 3 and becomes the physiologically active composition 5 attached to the microneedles 3. In this way, a microneedle device can be manufactured. "Immobilization" refers to keeping the physiologically active composition attached to the object substantially uniformly.

The height H of the physiologically active composition attached to the microneedles 3 (on the microneedles 3 and / or the substrate) can be adjusted by the clearance area (gap) C shown in FIG. 3 (b). This clearance area C is defined as the distance from the base of the microneedles to the mask surface (regardless of the thickness of the substrate), and can be set according to the tension of the mask plate 11 and the length of the microneedles 3. The distance of the clearance zone C should preferably range from 0 to 500 μm. When the distance of the clearance area C is 0, it means that the physiologically active composition adheres to the entire microneedles 3. The height H of the physiologically active composition 5 attached to the microneedles 3 will vary with the height h of the microneedles 3, and can be set to 0 to 500 μm, usually 10 to 500 μm, and preferably about 30 to 300 μm.

The thickness of the physiologically active composition 5 attached to the microneedles 3 is less than 50 μm, preferably less than 40 μm, and more preferably 1 to 30 μm. In general, the thickness of the physiologically active composition attached to the microneedles 3 is the average thickness measured over the entire surface of the microneedles 3 after drying. The thickness of the physiologically active composition attached to the microneedle 3 can generally be increased by applying a plurality of physiologically active composition coatings, that is, the physiologically active composition can be attached to the microneedle 3 by repeating Steps to increase the thickness.

When attaching the physiologically active composition to the microneedles 3 and / or the substrate 2, the temperature and humidity of the installation environment of the device are preferably controlled to be constant. In addition, if necessary, it can be filled with physiologically active composition by using at least one kind of multicomponent selected from the group consisting of glycerin, ethylene glycol, propylene glycol and 1,3-butanediol, which is used in the component (B) described later Alcohol solvent ". This can prevent evaporation of the solvent in the physiologically active composition as much as possible.

The physiologically active composition contains (A) "physiologically active substance"; and (B) "consisting of at least one polyol selected from the group consisting of glycerin, ethylene glycol, propylene glycol and 1,3-butanediol Solvent ". In addition, the physiologically active composition does not substantially contain water. Here, the above-mentioned physiologically active composition does not substantially contain water, meaning that the moisture content of the physiologically active composition does not exceed the moisture contained due to moisture absorption from the atmosphere. Typically, the moisture content is The total amount is based on 20 mass% or less, preferably 10 mass% or less, or even 5 mass% or less. The above component (B) is preferably "a solvent composed of at least one polyhydric alcohol selected from the group consisting of glycerin, ethylene glycol, propylene glycol, and 1,3-butanediol". "Physiologically active substances" refer to substances that have any effect on organisms, including low-molecular compounds, peptides, proteins, and derivatives thereof. "Solvent" means a compound that can disperse or dissolve the aforementioned physiologically active substance. Polymer compounds such as peptides, proteins, DNA, and RNA may be considered as (A) physiologically active substances (drugs), but are not particularly limited, as long as the molecular weight is around 1,000, they can also be vaccines or low-molecular peptides , Sugar, nucleic acid, etc. Examples of physiologically active substances include lixisenatide, nalquixone, cetrorelix acetate, tatirelin, nafarelin acetate, prostaglandin A1, alprostadil, α-interferon, and multiple sclerosis Β-interferon, erythropoietin, follicle-stimulating hormone β, follicle-stimulating hormone α, G-CSF, GM-CSF, human chorionic gonadotropin, leutinizing hormone, salmon calcitonin, Glucagon, GNRH antagonist, insulin, human growth hormone, Whirlpool blood, heparin, low molecular weight heparin, growth hormone, incretin, GLP-1 derivatives, etc. In addition, examples of vaccines include Japanese encephalitis vaccine, viral virus vaccine, Alzheimer's disease vaccine, arteriosclerosis vaccine, cancer vaccine, nicotine vaccine, diphtheria vaccine, tetanus vaccine, pertussis vaccine, Lyme disease vaccine, rabies vaccine , Pneumococcal vaccine, yellow fever vaccine, cholera vaccine, vaccinia vaccine, tuberculosis vaccine, rubella vaccine, measles vaccine, mumps vaccine, botulinum vaccine, herpes virus vaccine, other DNA vaccines, hepatitis B vaccine, etc.

Others include, for example, sleeping sedatives (flulurol hydrochloride, limazalazine hydrochloride, phenobarbital, amobarbital, etc.), antipyretic and anti-inflammatory analgesics (butorphanol tartrate, piperizol citrate, vinegar Paracetamol, mefenamic acid, diclofenac sodium, aspirin, aclofenac, ketoprofen, fluproxen, naproxen, piroxicam, analgesic, indomethacin, salicylic acid Ethylene glycol esters, aminopyrine, loxoprofen, etc.), steroid-based anti-inflammatory agents (hydrocorticosterone, prasulone, dexamethasone, betamethasone, etc.), excitatory-awakening agents (hydrochloride Kiamphetamine, methylphenidate hydrochloride, etc.), psychiatric agents (imipramine hydrochloride, diazepam, sertraline hydrochloride, fluvoxamine maleate, paroxetine hydrochloride, citalopram hydrobromide, hydrochloric acid Fluoxetine, alprazolam, haloperidol, chlorpromazine, amitriptyline, norimipramine, amoxapine, maprotiline, miterin, sptriptyline, trimethoprim Azolidinone, lofepyramine, milnacipran, duloxetine, venlafaxine, chlorpromazine hydrochloride, thioridazine, diazepam, meprobazone, etazolam, etc.), hormones (Estradiol, estriol, progesterone, norethisterone acetate, metenolone acetate, testosterone, etc.), local anesthetics (lidocaine hydrochloride, procaine hydrochloride, tetracaine hydrochloride, dibutyl hydrochloride Caine, prilocaine hydrochloride, etc.) Agents for urinary organs (oxybutynin hydrochloride, chlorpheniramine hydrochloride, propiverine hydrochloride, etc.), skeletal muscle relaxants (tizanidine hydrochloride, eperisone hydrochloride, mesylate Acid predino, succinylcholine hydrochloride, etc.), agents for reproductive organs (litojun hydrochloride, melujun tartrate), antiepileptic agents (sodium valproate, clonazepam, carbamazepine, etc.), autonomic nerves Agents (carpium chloride, neostigmine bromide, cholesteryl chloride, etc.), anti-Parkinson's disease agents (pergolide mesylate, bromocriptine mesylate, diphenhydroxide hydrochloride, adamantine hydrochloride) Alkylamine, ropinirole hydrochloride, talixor hydrochloride, cabergoline, tricodopa, biperidin, selegiline hydrochloride, etc.), diuretics (hydrofluorothiazide, furosemide, etc.) , Respiratory promoters (colobine hydrochloride, bismorpholinamine, naloxone hydrochloride, etc.), anti-migraine agents (dihydroergotamine mesylate, sumatriptan, ergotamine tartrate, flurazine hydrochloride Lizine, Sepuridine hydrochloride, etc.), antihistamines (Cremantine fumarate, diphenhydramine tannic acid, chlorpheniramine maleate, diphenhydramine hydrochloride, promethidine Nearly etc.), bronchodilators (toluoterol hydrochloride, procadilu hydrochloride, salbutamol sulfate, clenbuterol hydrochloride, fenoterol hydrobromide, terbutaline sulfate, isoproterenol sulfate, Formoterol fumarate, etc.), cardiotonics (isoproterenol hydrochloride, dopamine hydrochloride, etc.), coronary dilators (diltiazem hydrochloride, verapamil hydrochloride, isosorbide dinitrate, nitroglycerin, nicorandil Etc.), peripheral vasodilators (nicotinic acid ethyl citrate, tolazoline hydrochloride, etc.), smoking cessation aids (nicotine, etc.), agents for circulating organs (flunarizine hydrochloride, nicardipine hydrochloride, nitrendipine hydrochloride) , Nisoldipine, felodipine, amlodipine besylate, nifedipine, nilvadipine, manidipine hydrochloride, benidipine hydrochloride, maleate Napril, temopril hydrochloride, arapride, midapril hydrochloride, cilazapril, lisinopril, captopril, trandolapril, perindopril tert-butylamine salt, atenolol , Bisoprolol fumarate, metoprolol tartrate, betaxolol hydrochloride, alorolol hydrochloride, celirolol hydrochloride, carvirolol, carteolol hydrochloride, befanolol hydrochloride , Valsartan, candesartan, celecoxib, losartan, clonidine hydrochloride, etc.), drugs for incomplete pulse (propranolol hydrochloride, apollorol hydrochloride, procainamide hydrochloride, meclizine hydrochloride) (Xilute, naduro, diisopropylpyramine, etc.), antitumor drugs (cyclic amide amide phosphate, fluorouracil, pyrfluridine, benzylhydrazine hydrochloride, ramustine, irinotecan hydrochloride, fluorouridine, etc.) , Hypolipidemic agents (pravastatin, simvastatin, bezafibrate, proloco, etc.), hypoglycemic agents (glibenclamide, chlorpropamide, tolbutamide, glipizide sodium, glitazone Tebuconazole, bufomin hydrochloride), therapeutic agent for peptic ulcer (proglumide, cetrimonate hydrochloride, spirozofurone, cimetidine, glycopyrrolate), choleretic agent (ursodeoxycholic acid, salix (Aminophenol, etc.), gastrointestinal motility improvers (domperidone, cisapride, etc.), liver disease agents (tiopronin, etc.), antiallergic agents (ketotifen fumarate, azelastine hydrochloride, etc.), anti Viral agents (aciclovir, etc.), sedatives (betahistine mesylate, difenidol hydrochloride, etc.), antibiotics (cephalosporin, cefdinir, cefpodoxime, cefaclor, clavulanate) Amycin, erythromycin, methylerythromycin, concamycin sulfate, cycloserine, tetracycline, benzylpenicillin potassium, propicillin potassium, o-cloxillin sodium, ampicillin sodium, baxicillin hydrochloride, card Bicillin sodium, chloramphenicol, etc.), habitual poisoning agents (cyanamide, etc.), appetite suppressants (marindole, etc.), chemotherapeutic agents (isonicotinamide, ethionamide, pyrazinamide) Amines, etc.), blood coagulation promoters (thiclopyridine hydrochloride, triflumuron), anti-Alzheimer's drugs (toxin lentil, donepezil hydrochloride, tacrine, arecoline, xomeprine, etc.), serum Anti-emetic anti-emetic agents (ondansetron hydrochloride, granisetron hydrochloride, ramosetron hydrochloride, atazosetron hydrochloride, etc.), gout therapeutic agents (colchicine, promethazine, benzenesulfazolone, etc.) ), Anesthetics analgesics (fentanyl citrate, morphine sulfate, morphine hydrochloride, codeine phosphate, cocaine hydrochloride, coxetine hydrochloride, etc.).

In addition, these drugs may be used alone or in combination of two or more. As long as they are pharmaceutically acceptable salts, of course, they may contain drugs in any form of inorganic salts or organic salts. The content of (A) physiologically active substance in the physiologically active composition is 0.1 to 80% by mass, preferably 1 to 70% by mass, particularly preferably 5 to 60% by mass.

(B) "A solvent composed of at least one polyol selected from the group consisting of glycerin, ethylene glycol, propylene glycol, and 1,3-butanediol" has a high boiling point and little volatility during the filling and adhesion steps, Therefore, even in the case of continuous production of the microneedle device, the viscosity change of the physiologically active composition is small, and in addition, it has high solubility or dispersibility to the physiologically active substance, so that the physiologically active composition attached to the microneedle can be obtained Micro needle device with uniform content. The blending ratio (A: B) of the (A) component and (B) component in the physiologically active composition is preferably 20: 80-80: 20, preferably 40: 60-80: 20, based on the mass basis. The best is 50:50 ~ 70:30.

The physiologically active composition contains, in addition to: (A) "Physiologically active substance"; and (B) "At least one polyol selected from the group consisting of glycerin, ethylene glycol, propylene glycol and 1,3-butanediol In addition to the "constituent solvent", it may contain compounds different from the above-mentioned physiologically active substances, such as polymer compounds or metal chlorides. The physiologically active composition can increase the viscosity of the physiologically active composition by containing the above-mentioned polymer compound or metal chloride and other compounds. When the molecular weight of the drug is large and the solubility in the solvent is high, the drug itself may function as a thickener. However, when the solubility of the drug in the solvent is low or the molecular weight of the drug is small, in order to increase the viscosity of the physiologically active composition, it may be necessary to further contain a polymer compound or a polymer compound different from the physiologically active substance in the physiologically active composition In the case of compounds such as metal chlorides. Examples of the polymer compound include polyethylene oxide, polyhydroxymethyl cellulose, hydroxypropyl cellulose, polyhydroxypropyl methyl cellulose, polymethyl cellulose, polydextrose, polyethylene glycol, and poly Vinyl alcohol, polyvinylpyrrolidone, polytriglucose, sodium carboxymethyl cellulose, chondroitin sulfate, hyaluronic acid, polydextrose, gum arabic, etc.

The polymer compound is preferably hydroxypropyl cellulose, polyethylene glycol, chondroitin sulfate, hyaluronic acid, polydextrose, or croscarmellose sodium. Especially when propylene glycol is used as the solvent of the physiologically active composition, the polymer compound is preferably hydroxypropyl cellulose, polyethylene glycol, chondroitin sulfate, or hyaluronic acid, and when the solvent is glycerin, the polymer compound is Polydextrose, croscarmellose sodium or chondroitin sulfate are preferred.

Examples of metal chlorides include sodium chloride, potassium chloride, magnesium chloride, potassium chloride, aluminum chloride, and zinc chloride. In particular, when glycerin and / or propylene glycol is used as the solvent of the physiologically active composition, the metal chloride is preferably magnesium chloride.

In addition, when the physiologically active composition contains the above-mentioned metal chloride, when the microneedle device is stored for a long period of time, it is possible to suppress the decrease in the drug content on the microneedle and / or the substrate. Especially when propylene glycol is used as the solvent of the physiologically active composition, the metal chloride is preferably magnesium chloride. Therefore, when propylene glycol is used as the solvent of the physiologically active composition, the physiologically active composition attached to the microneedles contains at least 1 selected from the group consisting of hydroxypropyl cellulose, polyethylene glycol, chondroitin sulfate, hyaluronic acid, and magnesium chloride. This compound is preferred. In addition, when glycerin is used as the solvent of the physiologically active composition, the physiologically active composition attached to the microneedle contains at least one selected from polydextrose, croscarmellose sodium, chondroitin sulfate, and magnesium chloride. The compound is preferred.

In addition, in the physiologically active composition, propylene carbonate, crotamiton, 1-menthol, peppermint oil, Tulene, diisopropyl adipate, etc. may be added as a dissolution aid or absorption enhancer as necessary Or, add methyl salicylate, ethylene glycol salicylate, 1-menthol, thymol, peppermint oil, vanillyl nonanoic acid amide, chili extract, etc. as pharmaceutical supplements.

Further, in the physiologically active composition, stabilizers, antioxidants, emulsifiers, surfactants, salts, etc. may be added as necessary. In the present invention, the surfactant may be any of nonionic surfactants and ionic surfactants (cationic, anionic, amphoteric), and from the viewpoint of safety, it is expected to be a general pharmaceutical base Non-ionic surfactant used. In more detail, 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 fats Ester, polyoxyethylene glycol fatty acid ester, polyethylene glycol fatty acid ester, polyoxyethylene castor oil, polyoxyethylene hardened castor oil, etc.

Other known supplementary substances for preparations can be added as long as they do not have a harmful effect on the solubility and viscosity characteristics necessary for the application of the physiologically active composition and the properties and physical properties of the physiologically active composition after drying Into physiologically active compositions.

For a physiologically active composition, a certain degree of viscosity is required so that dripping does not occur. Specifically, it must have a viscosity of about 100 to 100,000 cps at room temperature (25 ° C). The preferred viscosity of the physiologically active composition is 100 to 60,000 cps. By setting the viscosity in this range, it will not be limited by the material of the microneedles 3, but the desired amount of the physiologically active composition can be temporarily attached. In addition, in general, the higher the viscosity, the more the amount of the physiologically active composition attached tends to increase. When the viscosity is less than 600 cps, it is difficult to attach the minimum physiologically active substance to the microneedles 3. However, surprisingly, if it is 45,000 cps or more, the content of the physiologically active substance in the physiologically active composition 5 attached to the microneedles instead decreases. Due to such characteristics, if the viscosity of the physiologically active composition is set to be 45,000 cps or more, the content of the physiologically active substance in the attached physiologically active composition 5 corresponding to the amount of the physiologically active substance becomes inferior. The economic level is not suitable, so the viscosity of the physiologically active composition is particularly suitable for 600 ~ 45000cps.

FIG. 2 is a cross-sectional view taken along line II-II of FIG. 1. FIG. As shown in FIG. 2, the microneedle device 1 of the present invention includes: a microneedle substrate 2; a microneedle 3 provided on the microneedle substrate 2; and a physiology attached to the microneedle 3 and / or the substrate Active composition 5. The attached physiologically active composition 5 contains (A) "physiologically active substance"; and (B) "at least one multicomponent selected from the group consisting of glycerin, ethylene glycol, propylene glycol and 1,3-butanediol "Solvent composed of alcohol" can be produced through the steps shown in, for example, Figs. 3 (a) to (c). In addition, the physiologically active composition immediately after the manufacture of the microneedle device contains the above-mentioned “consisting of at least one selected from the group consisting of glycerin, ethylene glycol, propylene glycol, and 1,3-butanediol” contained in the physiologically active composition. A kind of solvent composed of polyhydric alcohol ", and it does not contain water substantially. However, in the storage of the manufactured microneedle device, the solvent such as moisture may be kept under the influence of the environment. The moisture content in this case is as described above.

[Example]

The embodiments of the present invention are disclosed below, and the present invention is further described in detail, but the present invention is not limited by these embodiments, and various changes can be made without departing from the technical idea of the present invention.

(Example 1) Solubility or dispersibility test of solvent

10 parts by mass of various physiologically active substances shown in Table 1 and 90 parts by mass of propylene glycol or glycerin were mixed for about 1 hour to obtain a mixed solution. In addition, as shown in Table 2, 43 parts by mass of the physiologically active substance OVA (ovalbumin) was mixed with 57 parts by mass of triethanolamine, diethanolamine, or polyethylene glycol 400 in the same manner as described above to obtain a mixed solution. Then, with respect to the obtained mixed liquid, the solubility or dispersibility of the physiologically active substance in the solvent was visually evaluated by the following indicators. The evaluation results are disclosed in Table 1 and Table 2, respectively.

a: The physiologically active substance is dissolved in the solvent (uniform liquidity).

b: The physiologically active substance is dispersed in the solvent (dispersed liquidity).

c: The physiologically active substance is insoluble in the solvent, and obvious agglomerates (uneven liquidity) are observed in the mixed solution.

(Example 2) The relationship between the composition of a physiologically active composition composed of a model physiologically active substance (octreotide acetate), propylene glycol or glycerin and the viscosity and the content of the physiologically active substance in the physiologically active composition attached to the microneedle

<Setting conditions>

(a) Microneedle

‧Material: Polylactic acid, height: 500μm, density; 625 pieces / cm ² , preparation area of microneedle substrate: 1cm ² / patch

(b) Metal shield plate

‧Pitch: 400μm, mask thickness: 100μm, opening: quadrilateral (side length 250μm)

(c) Environment setting: room temperature (25 ℃)

＜ Viscosity measurement ＞

As shown in Table 3 and Table 4, the concentration of octreotide acetate and the concentration of propylene glycol or glycerin were set to prepare a physiologically active composition. The viscosity of the obtained physiologically active composition was measured 10 times with a micro sample viscometer (RHEOSENSE INC. Micron Sample-Viscometer / Rheometer-on-a-chip VROCTM), and the calculated average value is disclosed in Table 2 and table 3.

<Determination of the content of octreotide acetate in the physiologically active composition attached to the microneedles>

As shown in Table 3 and Table 4, the concentration of octreotide acetate and the concentration of propylene glycol or glycerin were set to prepare a physiologically active composition. The attachment of the physiologically active composition to the microneedles is performed by the method shown in Figs. 3 (a) to (c) above. The physiologically active composition is swept by a spatula and filled into the opening of the metal shield. By inserting the microneedle (needle) into the filled opening and then withdrawing it, the physiologically active composition attached to the microneedle is extracted with purified water, and then the microneedle device is measured per patch by the BCA method (octreotide as a standard) The octreotide acetate content (adhesion amount) was 10 times, and the calculated average values are shown in Table 3 and Table 4.

As shown in Table 3 and Table 4, it is clear that as the content of octreotide acetate in the physiologically active composition increases, the viscosity of the physiologically active composition will increase, and regarding the physiologically active composition 5 attached to the microneedle The content of octreotide acetate will increase as the viscosity increases until a certain viscosity value. However, if it exceeds a certain viscosity value, it will then decrease.

In the results of propylene glycol in Table 3, the content of octreotide acetate was reduced at a viscosity of 15,000 cps to 45,000 cps, which shows that the most suitable viscosity is 200 cps to 45,000 cps. From the perspective of administration efficiency, viscosities outside this range are not suitable.

In addition, among the glycerin in Table 4, the content of octreotide acetate was reduced from 21000 cps to 27000 cps, which shows that the most suitable viscosity is 2000 cps to 25000 cps. From the perspective of administration efficiency, viscosities outside this range and Not suitable.

(Example 3) When the manufacturing steps of the microneedle device are repeatedly performed, the measurement test for the change of the content of the physiologically active substance in the physiologically active composition attached to the microneedle

To PP (polypropylene) microtubes, 40 parts by mass of human plasma proteinin (HSA) and 60 parts by mass of glycerin were added, and the resulting substance was determined as a physiologically active composition of non-aqueous formula. For the physiologically active composition of the water-based formulation as a control group, a mixture of 40 parts by mass of human plasma protein (HSA), 30 parts by mass of glycerin, and 30 parts by mass of water was prepared, and the dissolved substance was determined as the physiologically active composition Thing. In order to manufacture a plurality of microneedle devices, the steps of filling and attaching these physiologically active compositions were repeated under the same conditions as in Example 2. Immediately after the above attachment step, after 20 minutes, 40 minutes, and 60 minutes, the human plasma protein in the physiologically active composition attached to the microneedles of the obtained microneedle device was measured in the same manner as in Example 2. (HSA) content. The obtained measurement result is shown graphically in FIG. 4.

Even though the non-aqueous formulation has a stable viscosity over time, the content of physiologically active substances in the physiologically active composition attached to the microneedles is hardly observed to change. On the other hand, it was confirmed that the water content of the water-based formulation will evaporate with the passage of time, and with such a viscosity increase, it shows that the content of the physiologically active substance in the physiologically active composition tends to decrease significantly with the passage of time.

(Example 4) Test for imparting viscosity to physiologically active compositions in non-aqueous formulations

The polymer compounds shown in Table 5 and Table 6 were added to the solvents of propylene glycol and glycerin, respectively, to prepare a mixed liquid. The concentration of the polymer compound is set in consideration of molecular weight and the like. The prepared mixed liquid was stirred by a magnetic stirrer (1500 rpm, 12 hours, 25 ° C.), and the solubility of the polymer compound was visually evaluated according to the following criteria. In addition, using a micro sample viscometer, the viscosity of the mixed liquid or solution after stirring was measured at 25 ° C. The evaluation results of viscosity and solubility are disclosed in Tables 5 and 6.

a: completely dissolved

b: partly dissolved

c: not dissolved

In addition, in the case where D × 40 and D × 70 were added using glycerin as a solvent, the measurement results of the viscosity and solubility were the values measured by setting the temperature during stirring to 80 ° C.

In the table, PEG4000 has a weight average molecular weight of 4,000 polyethylene glycol, D × 40 and D × 70 have a weight average molecular weight of about 40,000 and about 70,000 polyglucose, and any of PVA117, PVA220 and PVA617 have a weight average molecular weight of About 75,000 polyvinyl alcohol, HPC-H, HPC-M and HPC-L have a weight average molecular weight of 250,000 to 400,000, 110,000 to 150,000, and 55,000 to 70,000 hydroxypropyl cellulose, HA is hyaluronic acid.

If a small amount of polymer compound is used to increase the viscosity of the solution, the physiologically active composition after coating and drying can be controlled to be thin. Therefore, this polymer compound is particularly suitable as a component of a physiologically active composition attached to a microneedle. As shown in Table 5, the solubility of hydroxypropyl cellulose in propylene glycol is high, and the viscosity of the solution is greatly improved compared to before the addition of hydroxypropyl cellulose. In addition, by increasing the molecular weight of hydroxypropyl cellulose, the viscosity of the solution will tend to increase. From these results, even in the case where the amount of HPC-H added is small (low concentration), the effect of viscosity improvement can be expected. By reducing the amount of HPC-H added and further adding a physiologically active substance to the above solution to produce a physiologically active composition, the content of the physiologically active substance on the microneedles can be relatively increased. Therefore, in Table 5, HPC-H is considered to be the most suitable tackifier for propylene glycol.

In addition, although PEG4000, chondroitin sulfate, and HA were not completely dissolved in propylene glycol, the viscosity-increasing effect of the solution or mixed solution was observed.

As shown in Table 6, the solubility of polydextrose in glycerol is high, and the viscosity of the solution will increase significantly compared to before the addition of polydextrose. In addition, by increasing the molecular weight of polydextrose or increasing the concentration of polydextrose, the viscosity of the solution tends to increase. Although croscarmellose sodium (Na) and chondroitin sulfate were not completely soluble in glycerin, the viscosity-increasing effect of the solution or mixed solution was observed.

From the results shown in Tables 5 and 6, it can be seen that polymer compounds suitable for increasing viscosity can be found for propylene glycol and glycerin, respectively.

Test for imparting viscosity to physiologically active compositions in non-aqueous formulations

(Example 5)

7.3 parts by mass of propylene glycol, 0.7 parts by mass of sodium hydroxide, and 2.0 parts by mass of magnesium chloride were stirred and mixed with a magnetic stirrer. Further, the obtained mixed solution and octreotide acetate were mixed in a mass ratio of 1: 1 to obtain a physiologically active composition (50.0 mass% octreotide acetate / 3.5 mass% sodium hydroxide / 10.0 mass% magnesium chloride / 36.5 mass% propylene glycol). In addition, sodium hydroxide was added in the same molar amount as the acetic acid portion of octreotide acetate.

The above-mentioned physiologically active composition was applied to the tip of the microneedle similar to Example 2 and dried, and the height H of the physiologically active composition adhering to the microneedle was measured by observation with a microscope. The evaluation results are disclosed in Table 7.

(Comparative example 1)

A physiologically active composition (50.0% by mass of octreotide acetate / 3.5% by mass of sodium hydroxide / 46.5% by mass of propylene glycol) was obtained in the same manner as in Example 5, except that magnesium chloride was not added and propylene glycol of the same mass was added instead. The above physiologically active composition was applied to the microneedles in the same manner as in Example 5, and the height H of the physiologically active composition attached to the microneedles was measured. The evaluation results are disclosed in Table 7.

(Example 6)

8.434 parts by mass of glycerin, 0.233 parts by mass of sodium hydroxide, and 1.333 parts by mass of magnesium chloride were stirred and mixed with a magnetic stirrer. Further, the obtained mixed solution was mixed with LHRH (Lutein Forming Hormone Release Hormone Acetate) at a mass ratio of 3: 1 to obtain a physiologically active composition (25.0 mass% LHRH / 1.75 mass% sodium hydroxide / 10.0 mass% magnesium chloride /63.25 mass% glycerin). In addition, sodium hydroxide was added in the same molar amount as the acetic acid portion of LHRH. The above physiologically active composition was applied to the microneedles in the same manner as in Example 5, and the height H of the physiologically active composition attached to the microneedles was measured. The evaluation results are disclosed in Table 7.

(Comparative example 2)

A physiologically active composition (25.0% by mass LHRH / 1.75% by mass sodium hydroxide / 73.25% by mass glycerol) was obtained in the same manner as in Example 6 except that magnesium chloride was not added and the same mass of glycerin was added instead. The physiologically active composition was attached to the microneedles in the same manner as in Example 5, and the height H of the physiologically active composition attached to the microneedles was measured. The evaluation results are disclosed in Table 7.

As shown in Table 7, in Example 5 and Example 6, by adding magnesium chloride to the physiologically active composition, it is possible to control the thickness of the physiologically active composition attached to the microneedles to be thin (decrease the height H) . Increasing the viscosity of the physiologically active composition is to improve the dripping phenomenon.

Stability test of the drug content of the physiologically active composition attached to the microneedle

(Example 7)

9.444 parts by mass of propylene glycol and 0.556 parts by mass of magnesium chloride were stirred and mixed with a magnetic stirrer. Further, the obtained mixed solution and octreotide acetate were mixed at a mass ratio of 9: 1 to obtain a physiologically active composition (10% by mass octreotide acetate / 5.0% by mass magnesium chloride / 85% by mass propylene glycol).

10 mg of the above physiologically active composition was applied to the entire surface of the same microneedle as in Example 2, and dried at 50 ° C. for 30 minutes to obtain a microneedle device. Thereafter, the obtained microneedle device was sealed in a packing material together with a preservative (PharmaKeep KD; manufactured by Mitsubishi Gas Chemical Co., Ltd.), and the sealed microneedle device was stored at 60 ° C. for 1 week. The sealed microneedle device was further stored at 5 ° C for 1 week.

The content of the physiologically active substance on the microneedle device after storage was measured by high performance liquid chromatography (HPLC). Then, the residual rate of the physiologically active substance content stored on the microneedle at 60 ° C relative to the physiologically active substance content stored on the microneedle at 5 ° C was calculated as a percentage. Table 8 shows the results of the calculation.

(Comparative example 3)

A physiologically active composition (10% by mass of octreotide acetate / 90% by mass of propylene glycol) was obtained in the same manner as in Example 7 except that magnesium chloride was not added and propylene glycol of the same mass was added instead. Using the physiologically active composition described above, a microneedle device was obtained in the same manner as in Example 7. The obtained microneedle device was stored in the same manner as in Example 7, and the residual rate of the physiologically active substance was calculated. The calculated results are shown in Table 8.

(Example 8)

A microneedle device was obtained in the same manner as in Example 7 except that the type of medicine was LHRH, and the residual rate of physiologically active substances was calculated. The calculated results are shown in Table 8.

(Comparative example 4)

The microneedle device was obtained in the same manner as in Comparative Example 3 except that the type of drug was set to LHRH, and the residual rate of physiologically active substances was calculated. The calculated results are shown in Table 8.

As shown in Table 8, in Example 7 and Example 8, by adding magnesium chloride to the physiologically active composition, the physiologically active substance can be maintained at a high residual rate.

In Vitro Absorption Test of Hairless Rats from Lisila

(Example 9)

In a test tube, lixisenatide and propylene glycol were added at a mass ratio of 50:50 and mixed with a blender, and the resulting mixture was determined as a physiologically active composition. The physiologically active composition was applied to the microneedles using a mask plate with a thickness of 50 μm. The content of the coated physiologically active substance was 12.2 μg / patch / head. Using a 0.4 J applicator with a microneedle array after coating, the physiologically active substance was administered to hairless rats (the number of repeated tests was 3).

At 10 minutes, 30 minutes, 60 minutes, 120 minutes, 240 minutes, 480 minutes, and 720 minutes after administration, 300 μL of blood was collected from the jugular vein. The Exendin-4 EIA Kit was used to determine the lixisenatide concentration in the blood. The measurement results are shown in Fig. 5. In addition, Table 9 shows AUC values (area under the blood concentration-time curve) and BA values (bioavailability) obtained from the graph of FIG. 5. In addition, the AUC value refers to the area under the blood concentration-time curve in the range of 0 minutes to 720 minutes after administration in the graph of FIG. 5. The BA value refers to the relative bioavailability value relative to subcutaneous administration.

(Comparative example 5)

In a test tube, add lixisenat to physiological saline at a mass ratio of 50:50, and mix with a stirrer to determine the resulting mixture as a physiologically active composition. The physiologically active composition was subcutaneously administered to hairless rats under the condition of 15.1 μg / 300 μL / head. Thereafter, the lixisenatide concentration in blood was measured in the same manner as in Example 9. The measurement results are shown in Fig. 5. In addition, AUC values and BA values are shown in Table 9.

In vivo absorption test of hairless rats with β-interferon

(Example 10)

Β-interferon and glycerin were added to the test tube at a mass ratio of 30:70, and mixed with a blender, and the resulting mixture was designated as a physiologically active composition. The physiologically active composition was applied to the microneedles using a mask plate with a thickness of 100 μm. The content of the coated physiologically active substance was 10.3 μg / patch / head. Using a 0.4 J applicator with a microneedle array after coating, the physiologically active substance was administered to hairless rats (the number of repeated tests was 3).

At 30 minutes, 60 minutes, 90 minutes, 180 minutes, 300 minutes, 420 minutes, and 1440 minutes after administration, 300 μL of blood was collected from the jugular vein. The Exendin-4 EIA Kit was used to determine the β-interferon concentration in the blood. The measurement results are shown in Fig. 6.

(Comparative example 6)

Β-interferon and physiological saline were added to the test tube at a mass ratio of 50:50, and mixed with a stirrer, and the resulting mixture was determined as a physiologically active composition. The physiologically active composition was subcutaneously administered to hairless rats under the condition of 10 μg / 300 μL / head (the number of repeated tests was 3 times). Thereafter, the β-interferon concentration in blood was measured in the same manner as in Example 10. The measurement results are shown in Fig. 6.

Industrial availability

According to the present invention, a microneedle device can be obtained, and the content of physiologically active substances in the physiologically active composition attached to the microneedle is significantly reduced with time, so the usability of the microneedle can be further improved, and the industrial usability is great.

1. . . Microneedle device

2. . . Microneedle substrate

3. . . Microneedles

5. . . Physiologically active composition attached to microneedles

10. . . Physiologically active composition

11. . . Mask Board

12. . . spatula

13. . . Opening

H. . . Height of physiologically active composition

C. . . Headroom

FIG. 1 is a perspective view showing one embodiment of the microneedle device related to the embodiment of the present invention.

FIG. 2 is a sectional view taken along line II-II of FIG. 1.

3 (a) to (c) are diagrams showing an example of a method of manufacturing a microneedle device.

4 is a graph showing the time-dependent changes in the content of the physiologically active substance in the physiologically active composition attached to the microneedles when the microneedle device is manufactured by repeating the steps of filling and attaching the physiologically active composition.

Fig. 5 is a graph showing the time-dependent changes in the concentration of lixisenatide in blood when administered with a microneedle device and administered with lixisenatide by subcutaneous administration.

Fig. 6 is a graph showing the time-dependent change in the concentration of β-interferon in blood when administration is performed by a microneedle device and administration of β-interferon by subcutaneous administration.

Claims (8)

A microneedle device comprising: a substrate, a microneedle provided on the substrate, and a microneedle device attached to the microneedle and / or the physiologically active composition on the substrate, characterized in that: the physiologically active composition The substance is: contains glycerin and magnesium chloride and physiologically active substances, and does not substantially contain water, or contains propylene glycol and magnesium chloride and physiologically active substances, and does not substantially contain water. For example, in the microneedle device of claim 1, the physiologically active composition is fixed on the microneedle and / or the substrate. A method for manufacturing a microneedle device is a method for manufacturing a microneedle device in which a physiologically active composition containing a physiologically active substance and a solvent capable of dispersing or dissolving the physiologically active substance is attached to a microneedle, characterized in that: The physiologically active composition further contains magnesium chloride, and the solvent system uses glycerin without water, or the physiologically active composition further contains magnesium chloride, and the solvent system uses propylene glycol without water. A method for manufacturing a microneedle device according to claim 3, wherein after filling the physiologically active composition into the opening of the mask plate having the opening, the microneedle is inserted into the opening Then, it is extracted and the physiologically active composition is attached to the microneedle. For example, the method for manufacturing a microneedle device according to claim 3 or 4, wherein the mask plate filled with the physiologically active composition is the mask plate after the microneedles are extracted and reused. For example, in the method of manufacturing a microneedle device according to item 3 or 4 of the patent application, the mass ratio of the physiologically active substance to glycerin or propylene glycol is 20: 80 ~ 80: 20. For example, in the method of manufacturing a microneedle device according to claim 3 or 4, the viscosity of the aforementioned physiologically active composition is 600-45000 cps. A method for stabilizing the amount of adhesion of a physiologically active composition, after containing a physiologically active composition containing a physiologically active substance and a solvent that can disperse or dissolve the physiologically active substance in a container that can volatilize the aforementioned solvent, When it is attached to a microneedle to manufacture a microneedle device, the physiologically active composition further contains magnesium chloride, and the solvent system uses glycerin, and no water is used, or the physiologically active composition further contains magnesium chloride, and the solvent system is used Propylene glycol, and no water is used.