CN105982842B - Microneedle preparation and method for producing microneedle preparation - Google Patents
Microneedle preparation and method for producing microneedle preparation Download PDFInfo
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- CN105982842B CN105982842B CN201610158044.6A CN201610158044A CN105982842B CN 105982842 B CN105982842 B CN 105982842B CN 201610158044 A CN201610158044 A CN 201610158044A CN 105982842 B CN105982842 B CN 105982842B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0046—Solid microneedles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0053—Methods for producing microneedles
Abstract
The invention provides a microneedle preparation which is difficult to bend a substrate, has excellent adaptability to a curved surface of the skin and is easy to pierce a needle into the skin, and a method for manufacturing the microneedle preparation capable of stably forming the needle. The needle assembly comprises a base material (112) and a plurality of needles (114) protruding from one side surface of the base material (112), and comprises a component (A): one or more selected from the group consisting of hyaluronic acid and a hyaluronate salt, and (B) component: a bonding part (110) of glycerin, wherein the mass ratio A/B of the component (A) to the component (B) is 1-5. The liquid composition obtained by dissolving the preparation in a water-soluble solvent is filled at a temperature TASatisfies 50 (DEG C) ≦ TAIn conditioned mold at temperature TBSatisfy TB＜TAA method for producing a microneedle preparation in which a bonding part is formed by drying the microneedle preparation under a conditioned environment.
Description
Technical Field
The present invention relates to a microneedle preparation and a method for producing the microneedle preparation.
Background
Microneedle preparations (also referred to as dissolving microneedle preparations) are known as preparations for administering physiologically active ingredients such as anti-inflammatory analgesics and blood flow-increasing drugs into the human body. A microneedle preparation comprises a sheet-like base material, a plurality of needles formed on one side surface of the base material, and a bonding section containing a physiologically active ingredient. When the microneedle preparation is applied to the skin, the base material and the needles are dissolved, and the physiologically active ingredients contained therein are transdermally absorbed.
Examples of microneedle preparations include microneedle preparations having a substrate containing hyaluronic acid and a needle-attached portion (patent documents 1 and 2).
However, in the microneedle preparation, the injection amount of the active ingredient is smaller than that of the hollow type needles, and the active ingredient is uniformly present in the base material and the needles, so that the transdermal absorbability tends to be lower.
In the microneedle preparation, in order to ensure sufficient transdermal absorbability after the needle has penetrated into the skin, the needle has sufficient height and stress, the tip angle is controlled to 90 degrees or less, and it is also important that the base material favorably follows the curved surface of the skin.
As a method for producing a microneedle preparation, for example, a method in which a liquid composition in which a component (preparation) containing hyaluronic acid, gelatin, or the like is dissolved or dispersed in a water-soluble solvent such as water is poured into a mold and filled, dried until a specific water content is obtained, and then solidified and taken out from the mold is exemplified. However, in this production method, the ease of forming the needles varies greatly depending on the composition of the liquid composition and the material of the mold, and it is difficult to form the needles stably. If the needle is not stably formed, transdermal absorption of the physiologically active ingredient becomes insufficient.
Therefore, the following methods are proposed: a liquid composition obtained by dissolving the preparation in a water-soluble medium such as water is injected under pressure into a needle-forming container placed on a mold in a pressure-resistant container (patent document 3). However, even in this method, when the microneedle preparation is taken out from the mold, the tip of the needle may be broken, and the formation of the needle may be insufficient.
In addition, a substrate containing hyaluronic acid is easily bent after drying to cause warpage. Once the substrate is bent, it is difficult to pierce the entire needle into the skin, and the transdermal absorbability is lowered.
Documents of the prior art
Patent document
[ patent document 1] Japanese patent application laid-open No. 2009-201956
[ patent document 2 ] Japanese patent laid-open publication No. 2013-189432
[ patent document 3 ] Japanese patent laid-open No. 2013-162982
Disclosure of Invention
Problems to be solved by the invention
The present invention has as its 1 st object the provision of a microneedle preparation which has a sufficient height, tip angle and stress when the needle is inserted into the skin, suppresses the warp and lift of the base material, and has excellent followability to the curved surface of the skin.
The 2 nd object of the present invention is to provide a method for producing a microneedle preparation, which can stably form a needle using a liquid composition in which a preparation is dissolved in a water-soluble solvent.
Means for solving the problems
A microneedle preparation according to the 1 st aspect for solving the 1 st object of the present invention is a microneedle preparation comprising a base material and a bonded portion having a plurality of needles protruding from one side of the base material, wherein the bonded portion dissolves and at the same time transdermally absorbs a component contained therein, and the bonded portion contains a component (a): one or more selected from the group consisting of hyaluronic acid and a hyaluronate salt, and (B) component: glycerin, wherein the mass ratio A/B of the component (A) to the component (B) is 1 to 5.
In the microneedle preparation according to embodiment 1, the bonded portion may further contain a component (C): a physiologically active ingredient (however, in addition to the above-mentioned (a) ingredient).
The component (A) preferably contains at least one selected from the group consisting of a component (A-1) and a component (A-2), the component (A-1) being selected from the group consisting of hyaluronic acid having a mass average molecular weight of 50,000 or more and a hyaluronate salt having a mass average molecular weight of 50,000 or more, and the component (A-2) being selected from the group consisting of hyaluronic acid having a mass average molecular weight of less than 50,000 and a hyaluronate salt having a mass average molecular weight of less than 50,000.
The component (C) is preferably a non-steroidal anti-inflammatory drug.
The content of the component (A) is preferably 20 to 75% by mass in the bonded portion (100% by mass).
The mass ratio (A-2)/(A-1) of the component (A-2) to the component (A-1) is preferably 0 to 1.75.
The method for producing a microneedle preparation according to claim 2 for solving the object 2 of the present invention is a method for producing a microneedle preparation comprising a sheet-like base material and a bonded part of a plurality of needles protruding from one side of the base material, characterized in that a liquid composition obtained by dissolving the preparation in a water-soluble solvent is filled at a temperature TAIn a mold satisfying the condition of the following formula (1), at a temperature TBThe bonded portion is formed by drying in an environment satisfying the following formula (2).
50(℃)≦TA···(1)
TB＜TA···(2)
In the method for producing a microneedle preparation according to mode 2, a material of a portion of the mold that contacts the bonding portion is preferably polysiloxane. In this case, the entire portion of the mold that contacts the bonded portion may be a polysiloxane, or a part thereof may be a polysiloxane. In particular, it is preferable that the entire portion of the mold that contacts the bonded portion be polysiloxane.
The above preparation preferably contains component (X): at least one selected from the group consisting of water-soluble polymers and saccharides.
The content of the water-soluble solvent in the bonded portion is preferably 35% by mass or less.
The above preparation preferably contains component (Y): a physiologically active ingredient.
In the present invention, it is also preferable to produce the microneedle preparation of embodiment 1 by the method for producing a microneedle preparation of embodiment 2. Specifically, it is preferable that the temperature T is filled with a liquid composition obtained by dissolving the components (A) and (B) and, if necessary, (C) and (D) in a water-soluble solventAIn the mold satisfying the condition of the above formula (1), at the temperature TBDrying the microneedle preparation in an environment satisfying the condition of the above formula (2) to form a bonded portion, thereby obtaining the microneedle preparation of the 1 st aspect.
ADVANTAGEOUS EFFECTS OF INVENTION
The microneedle preparation according to embodiment 1 of the present invention has a sufficient height, tip angle and stress when the needle is inserted into the skin, suppresses the warp and lift of the base material, and has excellent conformability to the curved surface of the skin.
According to the method for producing a microneedle preparation of embodiment 2 of the present invention, a needle can be stably formed using a liquid composition in which the preparation is dissolved in a water-soluble solvent.
Drawings
Fig. 1 is a sectional view showing an example of a microneedle preparation according to embodiment 1 of the present invention.
Fig. 2 is an enlarged front view showing an example of a needle of the microneedle preparation according to the first embodiment of the present invention.
Fig. 3 is a sectional view showing an example of a microneedle preparation manufactured by the manufacturing method of embodiment 2 of the present invention.
Fig. 4 is a sectional view showing an example of a process in the method for producing a microneedle preparation according to embodiment 2 of the present invention.
Fig. 5 is a graph showing the degree of curvature of the base material when the microneedle preparation obtained in each example was observed from the side surface thereof in a state of being placed on a flat surface, and the followability when the microneedle preparation was placed on a curved surface of the skin of the wrist.
[ description of symbols ]
11 microneedle formulations
110 bonding part
112 base material
114 needle
21 microneedle formulations
210 bonding part
212 base material
214 needles
2100 die
2110 recess
2112 Container
Detailed Description
In the present invention, the term "needle" means a needle-like minute projection-like structure (microneedle) in a broad sense, and includes not only a needle having a sharp tip but also a shape having a non-sharp tip (for example, a conical shape).
The "needle base end thickness" indicates the diameter of a circle circumscribing the cross-sectional shape of the needle base end when the cross-sectional shape perpendicular to the height direction of the needle base end is other than a circle, such as a polygonal-cone-shaped needle.
[ means 1]
The microneedle preparation according to claim 1 of the present invention is a microneedle preparation comprising a base material and a bonded portion having a plurality of needles protruding from one side of the base material, wherein the bonded portion is dissolved and a component contained therein is transdermally absorbed.
Fig. 1 shows an example of a microneedle preparation according to mode 1 of the present invention. The microneedle preparation 11 includes a bonding section 110. The bonding section 110 includes a sheet-like base material 112 and a plurality of needles 114 protruding from one side surface of the base material 112.
The shape of the needle is preferably conical. The shape of the needle is not limited to a conical shape, and may be a polygonal cone shape such as a quadrangular cone or a conical shape.
The height of the needle is preferably 50 to 1000 μm, and more preferably 100 to 700 μm. If the needle height is not less than the lower limit, transdermal administration of the component (a) or the component (C) is likely to be sufficient. If the height of the needle is less than the upper limit value, the needle is hard to contact with the nerve, and pain or bleeding is easily avoided. The height of the needles represents an average value of the heights measured for 10 randomly selected needles.
The thickness of the bottom end of the needle is preferably 10 to 1200 μm, and more preferably 25 to 600 μm. The bottom end thickness of the needle means an average value of the bottom end thicknesses measured for 10 randomly selected needles.
The angle of the tip of the needle is preferably 90 degrees or less, more preferably 10 to 60 degrees, and still more preferably 15 to 45 degrees. If the angle of the tip of the needle is greater than the lower limit value, the needle is less likely to break during puncture. If the angle of the tip of the needle is equal to or less than the upper limit value, the puncture performance is excellent.
The needle tip angle indicates an angle at which an extension line obtained by extending the side edges on both sides of the needle upward in the front view intersects, in the case of a needle having a non-sharp tip. For example, in the case of the conical needle 114A illustrated in fig. 2, an angle θ formed by an extension line p and an extension line q extending upward from both side edges 114A and 114b of the needle 114A in a front view is a tip angle.
The distance between adjacent needles is preferably substantially equal, preferably about 1 to 10 needles per 1 mm. The allowable range of the distance error between adjacent needles is, for example, about 0.01 to 0.5 mm.
The density of the needles is preferably per 1cm2100 to 10000, preferably 100 to 5000, and more preferably 100 to 2000. If the density of the needles is not less than the lower limit, the needles can efficiently penetrate the skin. If the density of the needles is less than the upper limit value, the strength of the needles can be easily ensured.
The bonded portion of the microneedle preparation according to embodiment 1 of the present invention contains the component (a) and the component (B).
(component (A))
(A) Component (b) is at least one selected from the group consisting of hyaluronic acid and a hyaluronic acid salt. (A) The component (B) is polysaccharide and has modification effect. Since the bonded portion contains the component (a), the formation of the substrate and the needle becomes possible without blending other matrix.
Hereinafter, hyaluronic acid and hyaluronate may be collectively referred to as hyaluronic acid and the like.
Hyaluronic acid, a kind of glycosaminoglycan (mucopolysaccharide), has a structure in which disaccharide units of N-acetylglucosamine and glucuronic acid are linked.
Examples of the hyaluronic acid include hyaluronic acid derived from a living organism isolated from cockscomb, umbilical cord, or the like, hyaluronic acid obtained by fermentation with a microorganism, and the like. Hyaluronic acid derived from a living organism is preferably one derived from a microbial fermentation method because collagen existing in the living organism from which hyaluronic acid is derived cannot be completely removed and residual collagen may exert a bad influence.
As the hyaluronic acid salt, pharmaceutically and physiologically acceptable salts can be used, and examples thereof include alkali metal salts (e.g., sodium salt and potassium salt), alkaline earth metal salts (e.g., magnesium salt and calcium salt), ammonium salts, and ethanolamine salts (e.g., monoethanolamine). Among them, as the hyaluronic acid salt, an alkali metal salt is preferable.
The mass average molecular weight of hyaluronic acid and the like is preferably 5,000 to 1,000,000, more preferably 10,000 to 200,000. When the mass average molecular weight of hyaluronic acid or the like is not less than the above lower limit, the mechanical strength of the bonded portion is easily suppressed from being lowered, and the bonded portion is hardly broken during storage or when the skin is pierced. When the mass average molecular weight of hyaluronic acid or the like is not more than the above upper limit, the needle is easily penetrated into the skin, and the permeability into the skin of the bonded portion is improved.
The mass average molecular weight of hyaluronic acid and the like is a value measured by Gel Permeation Chromatography (GPC).
From the viewpoint of allowing the needle to easily penetrate the skin without breaking and to be easily dissolved in the body, the following component (A-1) is preferably used as the component (A), and a mixture of the following component (A-1) and component (A-2) is more preferably used.
(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 a hyaluronic acid salt having a mass average molecular weight of 50,000 or more.
(A-2) at least one member selected from the group consisting of hyaluronic acid having a mass average molecular weight of less than 50,000 and a hyaluronic acid salt having a mass average molecular weight of less than 50,000.
(component (B))
(B) The ingredient is glycerin. Since the bonded portion contains the component (B), the substrate of the bonded portion becomes difficult to bend and lift.
Glycerol (glycerol), in the structural formula C3H5(OH)3Or formula C3H8O3The 3-valent alcohol is shown. Among glycerin, there are commercially available products such as 84 to 87 mass% aqueous solutions, and such commercially available products can be used.
(component (C))
In the bonding portion of the microneedle preparation according to the 1 st aspect of the present invention, in order to impart other effect than the moisturizing effect with the component (a), the microneedle preparation may contain, as necessary, the component (C): a physiologically active ingredient (but, in addition to the (a) ingredient). Further, the microneedle preparation of the present invention may be one in which the component (C) is not mixed in the bonding portion, and the effectiveness of the component (C) is not obtained in addition to the moisture retention effect of the component (a).
In addition, a physiologically active ingredient means an ingredient that exerts some action on an organism.
As the component (C), known components generally used in microneedle preparations can be used. The component (C) may be a low molecular weight compound or a high molecular weight compound.
The component (C) is preferably a non-steroidal anti-inflammatory drug.
Examples of the non-steroidal anti-inflammatory drug include felbinac, butorphanol tartrate, perisoxazole citrate, acetaminophen, mefenamic acid, diclofenac sodium, aspirin, Alclofenac (Alclofenac), ketoprofen, Flurbiprofen, naproxen, piroxicam, pentazocine, indomethacin, ibuprofen, Flurbiprofen (Flurbiprofen), ethylene glycol salicylate, aminopyrine, and loxoprofen.
Examples of the component (C) other than the nsaid include the following components.
Sedative hypnotics: flurazepam hydrochloride, limazan hydrochloride, phenobarbital, amobarbital and the like.
Steroidal anti-inflammatory drugs: hydrocortisone, prednisone, dexamethasone, betamethasone, and the like.
Agonists: methamphetamine hydrochloride, methylphenidate hydrochloride, and the like.
Psycho-and nervous system medications: imipramine hydrochloride (Imipramine hydrochloride), diazepam, sertraline hydrochloride, fluvoxamine maleate, paroxetine hydrochloride, citalopram hydrobromide, fluoxetine hydrochloride, alprazolam, haloperidol, clomipramine, amitriptyline, desipramine, Amoxapine (Amoxapine), mepriptyline, mianserin, sipriptyline, trazodone, rofecopramine, milnacipran, duloxetine, venlafaxine, chlorpromazine hydrochloride, thiopyridazine, diazepam, milnacipran, etizolam, and the like.
Hormonal drugs: estradiol, estriol, progesterone, norethindrone Acetate, Metenolone Acetate, testosterone, human chorionic gonadotropin, luteinizing hormone, human growth hormone, etc.
Local anesthetics: lidocaine hydrochloride, procaine hydrochloride, tetracaine hydrochloride, dibucaine hydrochloride, prilocaine hydrochloride, and the like.
Urinary system drug use: oxybutynin hydrochloride, tamsulosin hydrochloride, propiverine hydrochloride and the like.
Skeletal muscle relaxants: tizanidine hydrochloride, eperisone hydrochloride, pridinol mesylate, succincholine hydrochloride and the like.
Reproductive system medication: ritodrine hydrochloride, meluadrine tartrate and the like.
Antiepileptic drugs: sodium valproate, clonazepam, carbamazepine, and the like.
Autonomic nervous system medication: carproamines, neostigmine bromide, clobecholine, and the like.
Antiparkinsonian drugs: pergolide mesylate, bromocriptine mesylate, diphenhydramine hydrochloride, amantadine hydrochloride, ropinirole hydrochloride, talipexole hydrochloride, cabergoline, droxidopa, biperiden, selegiline hydrochloride, and the like.
Diuretic: hydroflumethiazide, furosemide and the like.
Respiratory stimulants: lobeline hydrochloride, dimolomine hydrochloride, naloxone hydrochloride and the like.
Antimigraine drugs: dihydroergotamine mesylate, sumatriptan, ergotamine tartrate, flunarizine hydrochloride, cyproheptadine hydrochloride and the like.
Antihistamines: clemastine fumarate, diphenhydramine tannate, chlorpheniramine maleate, dibenzepin hydrochloride, promethazine, and the like.
Bronchodilators: tulobuterol hydrochloride, procaterol hydrochloride, salbutamol sulfate, clenbuterol hydrochloride, fenoterol hydrobromide, terbutaline sulfate, isoproterenol sulfate, formoterol fumarate, and the like.
Cardiotonic agents: isoproterenol hydrochloride, dopamine hydrochloride, and the like.
Coronary vasodilators: diltiazem hydrochloride, verapamil hydrochloride, isosorbide dinitrate, nitroglycerin, nicorandil and the like.
Peripheral vasodilators: ethyl nicotinate citrate, tolazan hydrochloride, etc.
Smoking cessation adjuvant: nicotine, and the like.
Drug administration to the circulatory system: flunarizine Hydrochloride, nicardipine Hydrochloride, nitrendipine, nisoldipine, felodipine, amlodipine besylate, nifedipine, nilvadipine, manidipine Hydrochloride, benidipine Hydrochloride, enalapril maleate, Temocapril Hydrochloride (Temocapril Hydrochloride), alacepril, imidapril Hydrochloride, cilazapril, lisinopril, captopril, trandolapril, perindopril, atenolol, bisoprolol fumarate, bunolol Hydrochloride (bunitrolol Hydrochloride), metoprolol tartrate, betaxolol Hydrochloride, arolol Hydrochloride, celiprolol Hydrochloride, carvedilol Hydrochloride, carteolol Hydrochloride, bevantolol Hydrochloride, valsartan, candesartan cilexetil, losartan potassium, cola Hydrochloride, and the like.
Arrhythmia medication: propranolol hydrochloride, allylolol hydrochloride, procainamide hydrochloride, mexiletine hydrochloride, nadolol, disopropylamine and the like.
Anti-malignant ulcer agent: cyclophosphamide, fluorouracil, tegafur, procarbazine hydrochloride, ranimustine, irinotecan hydrochloride, fluorouracil (Fluridine), and the like.
Hypolipidemic agents: pravastatin, simvastatin, bezafibrate, probucol and the like.
Hypoglycemic agents: glibenclamide, chlorpropamide, tolbutamide, glimepiride, glibutrazole, buformin hydrochloride and the like.
Peptic ulcer therapeutic agent: glufosamine, cetrimide hydrochloride, spirozofurone, cimetidine, glycopyrrolate and the like.
Cholagogue: ursodeoxycholic acid, choleretic phenol, etc.
Drugs for improving gastrointestinal motility: morpholine, cisapride, and the like.
Liver disease drug: tiopronin, and the like.
Anti-allergic agents: ketotifen fumarate, azelastine hydrochloride, and the like.
Antiviral agents: acyclovir and the like.
Anti-dizziness drugs: betahistine mesylate, difenidol hydrochloride and the like.
Antibiotics: ceftazidime, cefdinir, cefpodoxime proxetil, cefaclor, clarithromycin, erythromycin, clarithromycin, kanamycin sulfate, cycloserine, tetracycline, benzylpenicillin potassium, propicillin potassium, Cloxacillin sodium (Cloxacillin sodium), ampicillin sodium, bacampicillin hydrochloride, carbenicillin sodium, chloramphenicol, and the like.
Habitual intoxication medication: cyanamide, and the like.
Appetite suppressants: mazindol, and the like.
Chemotherapeutic agents: isoniazid, ethionamide, pyrazinamide, and the like.
Blood-clotting-promoting drugs: ticlopidine hydrochloride, warfarin potassium, and the like.
Anti-alzheimer agents: physostigmine, donepezil hydrochloride, tacrine, arecoline, pennomycin, etc.
Serotonin receptor antagonist antiemetic agents: ondansetron hydrochloride, granisetron hydrochloride, ramosetron hydrochloride, azasetron hydrochloride and the like.
Gout therapy: colchicine, probenecid, and benzsulazolone.
Analgesics of the narcotic type: fentanyl citrate, morphine sulfate, morphine hydrochloride, codeine phosphate, cocaine hydrochloride, meperidine hydrochloride, and the like.
As the component (C), for example, peptides, proteins, derivatives thereof, and the like; vaccines with a molecular weight of about 1000, nucleic acids (DNA, RNA, etc.), sugars, etc.
Examples of vaccines include japanese encephalitis vaccines, rotavirus vaccines, alzheimer vaccines, arteriosclerosis vaccines, cancer vaccines, nicotine vaccines, diphtheria vaccines, tetanus vaccines, pertussis vaccines, lyme disease vaccines, rabies vaccines, pneumococcal vaccines, yellow fever vaccines, cholera vaccines, vaccinia vaccines, tuberculosis vaccines, rubella vaccines, measles vaccines, mumps vaccines, botulinum vaccines, herpes viruses, other DNA vaccines, and hepatitis B vaccines.
Further, examples of the component (C) include Lixisenatide, naltrexone, cetrorelix acetate, taltirelin, nafarelin acetate, prostaglandin A1, alprostadil, alpha-interferon, beta-interferon for multiple sclerosis, erythropoietin, follitropin beta, follitropin alpha, G-CSF, GM-CSF, salmon calcitonin, glucagon, GNRH antagonists, insulin, Filgrastim (Filgrastim), heparin, low-molecular heparin, growth hormone, incretin, GLP-1 derivatives, and the like.
Examples of the component (C) include crotamiton, 1-menthol, peppermint oil, limonene, diisopropyl adipate, methyl salicylate, ethylene glycol salicylate, 1-menthol, thymol, peppermint oil, nonanic acid Vanillylamide, vanillyl capsaicin (Noroyl namide), capsicum extract, capsaicin, ascorbyl palmitate, kojic acid, Rucinol (Rucinol), tranexamic acid, glycyrrhiza extract for oil (glycyrrhiza uralensis エキス), retinol, retinoic acid, retinol acetate, retinol palmitate, isopropylmethylphenol, and vitamins (e.g., vitamin D2, vitamin D3, and vitamin K).
(C) The compound of component (a) may also contain any pharmaceutically acceptable salt, inorganic salt or organic salt.
(C) One kind of the component may be used alone, or two or more kinds may be used in combination.
(component (D))
The bonded portion of the microneedle preparation according to embodiment 1 of the present invention may contain, as necessary, a component (D) other than the components (a) to (C): any component.
Examples of the component (D) include additives such as a cosolvent, a percutaneous absorption enhancer, a stabilizer, an antioxidant, an emulsifier, a surfactant, and a metal salt.
Examples of the cosolvent include ethylene glycol, propylene glycol, 1, 3-butanediol, and polyethylene glycol.
The surfactant may be any of nonionic surfactants, cationic surfactants, anionic surfactants and amphoteric surfactants, and is preferably a nonionic surfactant used in general pharmaceutical preparations.
Specific examples thereof include 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 esters, polyoxyethylene castor oils, and polyoxyethylene hydrogenated castor oils.
Examples of polymers that can be mixed for the purpose of, for example, a substrate, a solvent, a stabilizer, and an aid to plasticization include polyethylene oxide, hydroxymethyl cellulose, hydroxypropyl methylcellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone, pullulan, sodium carboxymethyl cellulose, croscarmellose sodium, gum arabic, heparin, chondroitin sulfate and salts thereof, trehalose, and maltose.
Examples of the metal salt that can be mixed for the purpose of a buffer, a stabilizer, a base, a solvent, a suspension, and the like include sodium chloride, potassium chloride, magnesium chloride, potassium chloride, aluminum chloride, zinc chloride, and the like.
The bonded portion of the microneedle preparation according to embodiment 1 of the present invention preferably contains water. Water is mixed for ensuring the manufacturability when filling the formulation in the mold, but it is preferable that water is also contained in the bonded portion after drying.
(proportions of the respective components)
The proportions of the respective components in the bonded portion of the microneedle preparation according to embodiment 1 of the present invention are shown below.
The content of the component (a) in the bonded portion (100 mass%) is preferably 20 to 75 mass%, more preferably 20 to 70 mass%, and still more preferably 30 to 70 mass%. If the content of the component (A) is not less than the lower limit, the formation of the base material and the needles becomes easy. If the content of the component (A) is not more than the above upper limit, the substrate becomes less likely to be warped.
When the component (A-1) is used as the component (A), the content of the component (A-1) in the bonded part (100 mass%) is preferably 20 to 75 mass%, more preferably 20 to 70 mass%, and still more preferably 30 to 70 mass%. If the content of the component (A-1) is not less than the lower limit, the formation of the base material and the needles becomes easy. If the content of the component (A-1) is not more than the above upper limit, the substrate is less likely to be warped.
The content of the component (a-2) in the bonded portion (100 mass%) is preferably 0 to 30 mass%, more preferably 0 to 25 mass%, and still more preferably 5 to 10 mass%. If the content of the component (A-2) is not less than the lower limit value, the needle penetrability is improved. If the content of the component (A-2) is less than the above upper limit, the composition is less likely to break during storage or when the skin is pierced.
The component (A) is preferably composed of 60 to 100% by mass of the component (A-1) and 40 to 0% by mass of the component (A-2) (the total of the component (A-1) and the component (A-2) is 100% by mass).
The mass ratio (A-2)/(A-1) of the component (A-2) to the component (A-1) may be determined appropriately so that the bonded portion has satisfactory mechanical strength and hardness, although it varies depending on the mass average molecular weight of hyaluronic acid or the like. The mass ratio (A-2)/(A-1) is preferably 0 to 1.75, more preferably 0.05 to 0.5. If the mass ratio (A-2)/(A-1) is not more than the above upper limit, it becomes difficult to break the skin during storage or when the skin is pierced.
The content of the component (B) in the bonded portion (100 mass%) is preferably 15 to 45 mass%, more preferably 20 to 40 mass%. If the content of the component (B) is not less than the lower limit, the substrate becomes more difficult to bend and lift. If the content of component (B) is less than the above upper limit, the bonded part is easily prevented from becoming excessively soft, and since the tip angle is small, a needle having sufficient hardness is easily formed, and the needle easily penetrates into the skin.
(A) The mass ratio of component (A) to component (B), A/B, is 1 to 5, preferably 1 to 4.5, more preferably 1 to 4. If the mass ratio a/B is not less than the lower limit value, the bonded portion can be prevented from becoming excessively soft, and since the tip angle is small, a needle having sufficient hardness can be formed, and the needle can be easily inserted into the skin. If the mass ratio A/B is not more than the above upper limit, the warpage of the base material can be suppressed.
The content of the component (C) in the bonded portion (100 mass%) is preferably 0.1 to 80 mass%, more preferably 1 to 50 mass%.
The content of water in the bonded portion (100 mass%) is preferably 5 to 20 mass%, more preferably 10 to 15 mass%. If the water content is not less than the lower limit, the microneedle preparation has good flexibility. If the water content is not more than the upper limit, the occurrence of shriveling during production can be easily suppressed, and the quality change after opening is reduced.
The total content of the component (A), the component (B), the component (C) and water is not more than 100% by mass. The components are preferably uniformly distributed in the bonded portion. Therefore, the content of each component is preferably a content per unit mass of the bonded portion.
[pH]
The pH of the bonded part may be repeated depending on the mixture of the physiologically active ingredients, but is preferably 3 to 9 from the viewpoint of skin irritation.
[ support ]
The microneedle preparation according to embodiment 1 of the present invention may be provided with a support on one surface of the bonding portion on which the needles are formed and on the opposite surface.
The support is not particularly limited, and a known support generally used as a support for an adhesive patch can be used. Examples of the support include a resin film, a cloth, and a composite sheet in which a resin film and a cloth are integrated.
Examples of the resin film include films made of resins such as polyethylene, polypropylene, polyester, rayon, polyamide, polyvinyl chloride, urethane-vinyl chloride copolymer, and polyurethane.
The cloth can be non-woven fabric, woven fabric or knitted fabric.
Examples of the nonwoven fabric include those produced by needle punching, spunlacing, spunbonding, stitch-bonding, melt-blowing, and the like.
The method of weaving or Knitting the fabric is not particularly limited, and examples thereof include warp Knitting (rib Knitting, comb Knitting, satin Knitting, atlas Knitting, flat Knitting, rib Knitting, links Knitting, and purl Knitting), circular Knitting (double-sided circular Knitting, single-sided circular Knitting, and link Knitting).
Examples of the material of the fibers constituting the fabric include polyester, rayon, nylon, polypropylene, polyethylene, polyamide, and polyurethane.
Examples of the composite sheet include a sheet in which a resin film and a cloth are bonded by heat fusion, an adhesive, or the like; a sheet formed of a molten resin is extruded into a cloth.
(production method)
The method for producing the microneedle preparation of the present invention is not particularly limited, and any known method can be employed except that the component (a) and the component (B) are blended in a specific ratio.
For example, a method of casting a liquid composition prepared by mixing the component (a) and the component (B) with other components used as needed in water in a silicone mold having a needle-like shape, drying the liquid composition, and then peeling the liquid composition from the mold can be mentioned.
(Effect)
In the microneedle preparation according to the above-described aspect 1 of the present invention, since the component (a) and the component (B) are contained in a specific ratio, the height, tip angle and stress at the time of inserting the needle into the skin are sufficient, the warp and lift of the base material are suppressed, and the microneedle preparation is excellent in the following property to the curved surface of the skin. Therefore, the microneedle preparation according to embodiment 1 of the present invention can stably pierce a needle into the skin when it is attached to the skin, and thus can stably ensure excellent transdermal absorbability.
[ means 2 ]
A method for producing a microneedle preparation according to claim 2 of the present invention is a method for producing a microneedle preparation using a liquid composition in which a preparation is dissolved in a water-soluble solvent, the microneedle preparation including a sheet-like base material and a bonded portion having a plurality of needles protruding from one side of the base material.
(construction of microneedle preparation)
The configuration of the microneedle preparation produced by the production method of the 2 nd aspect of the present invention is not particularly limited as long as it has a bonding portion having a sheet-like base material and a plurality of needles protruding from one side of the base material.
Fig. 3 shows a microneedle preparation 21 as an example of a microneedle preparation produced by the production method according to mode 2 of the present invention. The microneedle preparation 21 includes a bonding portion 210. Bonding portion 210 includes a sheet-like base material 212 and a plurality of needles 214 protruding from one side surface of base material 212.
The shape of the needle is not particularly limited, and examples thereof include a conical shape, a polygonal conical shape (e.g., a quadrangular pyramid), and a conical shape is preferable.
The height of the needles is preferably 50 to 1000 μm, more preferably 100 to 700 μm, as in the case of embodiment 1. If the height of the needle is not less than the lower limit, transdermal administration of the active ingredient is likely to be sufficient.
The preferred ranges for the thickness of the base end of the needles, the distance between adjacent needles, and the density of the needles are the same as those set forth in mode 1.
When the needle is conical, the thickness of the tip of the needle is preferably 5 to 500 μm, more preferably 5 to 300 μm.
In the microneedle preparation manufactured by the manufacturing method according to mode 2 of the present invention, a support may be provided on one surface and the opposite surface of the bonding portion where the needles are formed. The support is not particularly limited, and a generally used known support can be used as the support for the adhesive patch.
Examples of the support include the same ones as those listed in embodiment 1, and examples thereof include a resin film (e.g., polyethylene film and polypropylene film), a cloth (e.g., nonwoven fabric, woven fabric and knitted fabric made of polyester fiber), and a composite sheet in which a resin film and a cloth are integrated.
(production method)
In the method for producing a microneedle preparation according to embodiment 2 of the present invention, a liquid composition in which the preparation is dissolved in a water-soluble solvent is filled at a temperature TAIn a mold satisfying the condition of the following formula (1), at a temperature TBThe bonded portion is formed by drying in an environment satisfying the following formula (2). Thus, a microneedle preparation having a stable needle formation and excellent percutaneous absorbability of the active ingredient can be obtained.
50(℃)≦TA···(1)
TB＜TA···(2)
For example, in manufacturing the microneedle preparation 21, as shown in fig. 4, a mold 2100 provided with a recess 2110 having a shape complementary to the shape of the base material 212 of the microneedle preparation 21 and a reservoir 2112 having a shape complementary to the shape of the needle 214 is used. After heating to a temperature TAThe recess 2110 and the container 2112 of the mold 2100 are filled with the liquid composition X. Then, at a temperature TATemperature T ofBThe mold 2100 filled with the liquid composition X is placed in the environment of (a), and the liquid composition X is dried to form the microneedle preparation 21. Thereafter, the microneedle preparation 21 is peeled off from the mold 2100.
Temperature T of the mold at the time of filling the liquid compositionAIt is 50 ℃ or higher, preferably 80 ℃ or higher. If the temperature T isAAbove the lower limit, the liquid composition can easily enter the bottom of the container of the mold sufficiently during drying, and thus a microneedle preparation in which needles are stably formed can be obtained. And, the temperature TAThe temperature is preferably not higher than the heat-resistant temperature of the mold, as long as it is lower than the boiling point of the water-soluble solvent used in the liquid composition. In particular, for example, the temperature TAMay be below 100 deg.c.
The temperature of the liquid composition when filling the mold is not particularly limited, but is preferably 0 to 80 ℃, more preferably 10 to 70 ℃, and still more preferably 20 to 60 ℃. If the temperature of the liquid composition is below the upper limit, the stability of the medicament is improved. If the temperature of the liquid composition is not lower than the lower limit, the liquid composition can be easily filled into the mold.
Temperature T at dryingBThe temperature of the environment in which the mold filled with the liquid composition is left to dry is indicated. The temperature of the mold and the liquid composition during drying is lowered to a temperature TB。
Temperature TBInsufficient temperature TAFrom the viewpoint that the microneedle preparation obtained is less likely to bend and lift, it is preferably 25 ℃ or lower. And, from the viewpoint of shortening the drying time, the temperature TBPreferably 5 ℃ or higher.
Temperature T of the mold at the time of filling the liquid compositionAAnd temperature T at the time of dryingBDifference (T) ofA－TB) The temperature is preferably 10 ℃ or higher, more preferably 25 ℃ or higher, and still more preferably 30 ℃ or higher, exceeding 0 ℃. If the difference (T)A－TB) Above the lower limit, the liquid composition can easily enter the bottom of the container of the mold sufficiently, and thus a microneedle preparation in which needles are stably formed can be easily obtained.
Drying the adhesive layer to set the content of the aqueous solvent in the liquid composition to a desired ratio, and curing the liquid composition to form the bonded portion. The drying time is determined by the temperature T during dryingBIt is determined appropriately.
< liquid composition >
The liquid composition is a composition in which the preparation is dissolved in an aqueous solvent.
As the formulation, a known formulation used for producing a microneedle formulation dissolved in an aqueous solvent can be used. As the formulation, it preferably contains component (X): at least one selected from the group consisting of water-soluble polymers and saccharides, preferably containing the component (X) as a main component. The component (X) is a main component, and is contained in an amount of 50% by mass or more based on the total amount (100% by mass) of the preparation.
The term "water-soluble polymer" means a compound having a solubility in water (100g) at 20 ℃ of 0.01g or more and a molecular weight of 1000 or more (excluding saccharides).
Examples of the component (X) include hyaluronic acid, sodium hyaluronate, gelatin, maltose, pullulan, pregelatinized starch, dextran, sodium carboxymethylcellulose, crystalline cellulose, lactose, and the like. Among them, sodium hyaluronate, gelatin and maltose are preferable as the component (X) from the viewpoint of facilitating the formation of needles.
The component (X) may be one kind or two or more kinds.
The content of the component (X) in the preparation (100 mass%) is preferably 10 to 95 mass%, more preferably 20 to 90 mass%, and most preferably 50 to 90 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.
When a water-soluble polymer is used as the component (X), the content of the water-soluble polymer in the preparation (100 mass%) is preferably 15 to 90 mass%, more preferably 30 to 70 mass%, and most preferably 55 to 90 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.
When a saccharide is used as the component (X), the content of the saccharide in the preparation (100 mass%) is preferably 15 to 80 mass%, more preferably 30 to 70 mass%, and most preferably 50 to 70 mass%. If the content of the saccharide is within the above range, formation of needles becomes easy, and peeling of the microneedle preparation from the mold becomes easy.
The preparation may also contain (Y) component: a physiologically active ingredient (also known as a drug).
The physiologically active ingredient is not particularly limited as long as it is in a form that can be dispersed in the adhesive portion, and examples thereof include felbinac, diclofenac sodium, loxoprofen sodium, salicylic acid glycol, ketoprofen, indomethacin, and the like.
The component (Y) may be one kind or two or more kinds.
When the component (Y) is used, the content of the component (Y) in the preparation (100 mass%) is preferably 1 to 10 mass%, more preferably 2 to 6 mass%. If the content of the component (Y) is not less than the lower limit, the effectiveness of the physiologically active ingredient can be easily exerted. If the content of the component (Y) is not more than the above upper limit, the needle formability is improved.
The preparation may also contain (Z) component: an alkanolamine.
The alkanolamine may be monoalkanolamine, dialkanolamine or trialkanolamine.
The number of carbon atoms of the hydroxyalkyl group contained in the alkanolamine is preferably 1 to 10, more preferably 2 or 3.
Specific examples of the alkanolamines include monoethanolamine, diethanolamine, triethanolamine, monopropanolamine, dipropanolamine, tripropanolamine, monoisopropanolamine, diisopropanolamine, triisopropanolamine, and the like.
The component (Z) may be one or two or more.
When the component (Z) is used, the content of the component (Z) in the preparation (100 mass%) is preferably 1 to 20 mass%, more preferably 2 to 15 mass%. If the content of the component (Z) is not less than the lower limit, the needle formability is improved. If the content of the component (Z) is less than the above upper limit, the needle penetrability is improved.
The total content of the components (X) to (Z) is not more than 100% by mass.
In the preparation, other components than the components (X) to (Z) may be blended as necessary. Examples of the other components include plasticizers such as glycerin, surfactants, cosolvents for medicines, tackifiers, stabilizers, colorants, and perfumes.
Examples of the water-soluble solvent include water and an organic solvent mixed with water. The water-soluble solvent may be water alone, an organic solvent mixed with water alone, or a mixture of water and an organic solvent mixed with water.
The organic solvent mixed with water means that 0.01g or more of the organic solvent is dissolved in 100g of water at 20 ℃.
Examples of the organic solvent to be mixed with water include ethanol, methanol, isopropanol, tetrahydrofuran, and acetone.
As the water-soluble solvent, it is necessary to use a solvent having a boiling point at the temperature T of the moldAThe above water-soluble solvent. As the water-soluble solvent, water and ethanol are preferable from the viewpoint of difficulty in volatilization.
The content of water in the water-soluble solvent (100 mass%) is preferably 50 mass% or more, and more preferably 70 mass% or more.
The mass ratio of water to organic solvent in the water-soluble solvent (water: organic solvent) is preferably 1: 0-1: 1. if the above mass ratio is within the above range, the formation of the needle becomes easier.
The content of the water-soluble solvent in the liquid composition (100 mass%) when filled into the mold is preferably 30 to 90 mass%, more preferably 50 to 90 mass%. If the content of the water-soluble solvent is not less than the lower limit, the formation of needles becomes easier. If the content of the water-soluble solvent is less than the upper limit, the needle can be formed with good penetration.
The viscosity at 20 ℃ of the liquid composition when filled into a mold may be within a range that allows the liquid composition to have fluidity enough to be filled into a mold, and is preferably 1 to 20,000 mPas, more preferably 1 to 10,000 mPas, from the viewpoint of facilitating the formation of needles.
The viscosity is a value measured by a B-type viscometer.
< content of aqueous Medium in bonded portion >
The content of the water-soluble solvent in the bonded portion (100 mass%) of the microneedle preparation obtained by the production method according to embodiment 2 is preferably 35 mass% or less, more preferably 25 mass% or less, and still more preferably 20 mass% or less. If the content of the water-soluble solvent in the bonded portion is not more than the upper limit value, the hardness of the needle tends to be sufficiently increased, and the needle tends to easily penetrate into the skin. The content of the water-soluble solvent in the bonded portion (100 mass%) is preferably 5 mass% or more. If the content of the water-soluble solvent in the bonded portion is not less than the lower limit value, the microneedle preparation is less likely to break when peeled from the mold. The content of the water-soluble solvent in the bonded portion (100 mass%) is preferably 5 to 20 mass%. The content of the water-soluble solvent in the bonded portion (100 mass%) may be 0 mass%.
< mold >
As the mold, a mold having a recess complementary to the shape of the base material and a container complementary to the shape of the needle, which is adapted to the shape of the produced microneedle preparation, can be used. As the mold, a known mold can be used without limitation.
The material of the mold is not particularly limited, and may be any of resin, metal, wood, and the like. Among them, as a material of the mold, a resin is preferable from the viewpoint of processability.
Examples of the resin for forming the mold include polysiloxane, polyethylene, polypropylene, polyvinyl chloride, acrylic acid, polyethylene terephthalate, polystyrene, acrylonitrile-butadiene-styrene copolymer, polycarbonate, polyamide, fluororesin, polybutylene terephthalate, and the like.
The material of the portion of the mold that contacts the bonded portion is preferably polysiloxane, from the viewpoint of easy release of the microneedle preparation from the mold. In this case, only the portion of the mold that contacts the bonded portion may be made of silicone, or the entire mold may be made of silicone. The silicone part of the mold may be all or part of the mold that contacts the bonded part. The silicone part of the mold is preferably all of the part of the mold that contacts the bonded part.
(Effect)
In the method for producing a microneedle preparation according to embodiment 2 of the present invention described above, the temperature T of the mold at the time of filling the liquid composition is controlledAAt a specific temperature T of 50 ℃ or higherALower temperature TBThe needle is dried in the environment of (1) to form a bonded portion, thereby stably forming the needle. By controlling the temperature T as indicated aboveAAnd temperature TBThe main reason why the needle can be stably formed is as follows.
When the liquid composition is filled in the mold, particularly when the viscosity of the liquid composition is high, air or water vapor tends to remain in the bottom of the container of the mold. Therefore, the liquid composition cannot be sufficiently filled into the bottom of the container of the mold, and the needle is difficult to be stably formed because the tip of the needle is broken. In contrast, in the 2 nd aspect of the present invention, the temperature T is 50 ℃ or higherAThe mold (2) is filled with the liquid composition, and the mold filled with the liquid composition is placed at the deficiency temperature TATemperature T ofBThe liquid composition is dried in the atmosphere of (2), and the air and water vapor remaining in the container of the mold shrink to make the inside of the container negative pressure. Accordingly, since the liquid composition is sufficiently filled by being drawn to the bottom of the container of the mold, the needle can be stably formed.
As described above, in the microneedle preparation manufactured by the manufacturing method of the 2 nd aspect of the present invention, since the needles are stably formed, the percutaneous absorbability of the active ingredient is excellent. In the microneedle preparation produced by the production method according to aspect 2, the number of needles to be formed is preferably 90 or more, more preferably 95 or more, per 100 containers in the mold.
Hereinafter, the 1 st aspect of the present invention will be described in detail by way of examples, but the 1 st aspect of the present invention is not limited to the following.
[ materials used ]
The raw materials used in this example are as follows.
(component (A))
A-11: polymer sodium hyaluronate (trade name "hyaluronic acid FCH-SU" (ヒアルロン acid FCH-SU), manufactured by Tortoise Shell Wan Biochemical Co., Ltd. (キッコーマンバイオケミファ Co., Ltd.), mass average molecular weight: 5 to 11 ten thousand).
A-21: low-molecular hyaluronic acid (trade name "Hiaroogeno" (ヒアロオリゴ), manufactured by Kyobo Co., Ltd. (キューピー Co., Ltd.) has a mass-average molecular weight of 1000 to 1 ten thousand).
(component (B))
B-1: glycerin ("concentrated glycerin (japanese pharmacopoeia)" ( グリセリン (japan), manufactured by saka pharmaceutical industry co.
(B') component: comparison object)
B' -1: 1, 3-butanediol ("1, 3-butanediol (pharmaceutical additives standard)", manufactured by Dailuo Kagaku K.K. (ダイセル)).
B' -2: propylene glycol ("propylene glycol (japanese pharmacopoeia)", manufactured by ADEKA corporation).
B' -3: polyethylene glycol ("polyethylene glycol 600", manufactured by Wako pure chemical industries, Ltd.).
(component (C))
C-1: felbinac ("felbinac (japanese pharmacopoeia)", manufactured by haneo CHEMICAL co.
(optional Components)
Water: "purified water (Japanese pharmacopoeia)" manufactured by Kyoho pharmaceutical Co., Ltd.
Examples A1 to A9 and comparative examples A1 to A6
As a mold for manufacturing a microneedle preparation, a mold was used in which a conical shape having a bottom diameter of 0.5mm and a height of 0.65mm was used, and 10 containers were used at intervals of 1.0mm as containers having a shape complementary to a needle having a tip angle of 33 degrees, thereby forming 100 containers in total. The needle tip angle with a non-sharp tip is an angle at which the extension lines above the two side edges of the needle intersect in the front view. The material of the above-mentioned mold was 100% silicone resin (two-pack type RTV rubber KE-17: fumed silica (fumed シリコーン)).
As shown in table 2 and table 3, compositions in which each component was uniformly dissolved or dispersed were obtained. Component (a) was mixed by preparing a 10 mass% aqueous solution. In a mold heated to 80 ℃, approximately 0.5g of the above composition was applied (the mass after drying became an amount of 0.05g or more). The mold was cooled at 25 ℃ with 100% Rh, and after the mold was changed to 25 ℃, it was naturally dried for about 8 hours to obtain a microneedle preparation.
[ evaluation of bending and tracking Property ]
The microneedle preparations obtained in the respective examples were evaluated for the degree of bending of the base material when viewed from the side in a flat state and the followability when placed on the curved surface of the skin of the wrist, according to the following criteria.
(evaluation criteria: FIG. 5)
Very good: no bending of the substrate was confirmed when placed on a flat surface and followed the curved surface of the skin.
O: no bending of the substrate was confirmed when placed on a flat surface, but no tracking of the curved surface of the skin was observed.
X: when the substrate was placed on a flat surface, it was confirmed that the substrate was bent and had a portion not in contact with the flat surface. At this time, the substrate does not follow the curved surface of the skin.
[ evaluation of height of needle ]
The height of the microneedle preparation obtained in each example was measured by a digital microscope, and evaluated according to the following criteria.
(evaluation criteria)
Very good: the height of the needle is 500 μm or more.
O: the height of the needle is 400 μm or more and less than 500 μm.
X: the height of the needles is less than 400 μm.
If the height of the needle is less than 400 μm, it becomes difficult to obtain a sufficient effect even by puncturing.
[ evaluation of needle Angle ]
The angle of the tip of the needle of the microneedle preparation obtained in each example was measured by an electron microscope, and evaluated according to the following criteria. In addition, the angle of intersection of the extension lines above the two side edges of the needle in the front view is taken as the top angle.
(evaluation criteria)
Very good: the tip angle is less than 50 degrees.
O: the top angle is more than 50 degrees and less than 90 degrees.
X: the top angle is more than 90 degrees.
If the tip angle of the needle is 90 degrees or more, the needle becomes difficult to pierce.
[ evaluation of stress of needle ]
The stress at 0.01mm pressing the microneedle preparation obtained in each example from the tip side was measured using a texture analyzer, and evaluated according to the following evaluation criteria. The pressing probe was made of disk-shaped ground glass having a diameter of 1 cm.
(evaluation criteria)
O: the stress is 0.05N or more.
X: the stress is less than 0.05N.
If the stress is less than 0.05N, the needle becomes difficult to pierce.
The compositions of the respective components and the evaluation results in examples and comparative examples are shown in tables 2 and 3.
The compositions in tables 2 and 3 are compositions obtained by measuring the applied amount and the dried mass and assuming that the total amount of decrease is water. The content of the component (B) is mass% in terms of the solid content of glycerin. In columns 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 the component (a) and the component (B) were mixed at the ratio specified in the present invention, the needle had sufficient height, tip angle and stress when the needle was inserted into the skin. Further, the substrate can be prevented from being bent, and the flexibility to the curved surface of the skin is also excellent.
In the microneedle preparations of comparative example a1 in which component (B) was not used and comparative example a2 in which the mass ratio a/B exceeded 5, the substrate was seen to be bent. Even in the microneedle preparations of comparative examples a4 to a6 in which component (B') was used instead of component (B), the base material was seen to be bent.
In the microneedle preparation of comparative example a3 in which the mass ratio a/B was less than 1, the needle was not provided with sufficient height, tip angle and stress when it was inserted into the skin.
Hereinafter, the 2 nd embodiment of the present invention will be described in detail with reference to examples, but the 2 nd embodiment of the present invention is not limited to the following.
[ materials used ]
The raw materials used in this example are as follows.
HA-1: sodium hyaluronate (mass average molecular weight: 50,000 to 110,000, trade name "FCH-SU", manufactured by Tortoise Shell Wan Biochemical Co., Ltd.).
HA-2: hyaluronic acid (mass average molecular weight: 1,000-10,000, trade name "Hiaroorigo", manufactured by Kyobi Co., Ltd.).
GEN: gelatin (manufactured by Rousselot corporation).
MAL: maltose (trade name "Sanmarto" (サンマルト), manufactured by Lin Yuan corporation).
GL: concentrated glycerin (trade name "concentrated glycerin from japanese pharmacopoeia" (office グリセリン), manufactured by saka pharmaceutical industry co., ltd.).
DIPA: diisopropanolamine (manufactured by Mitsui chemical Co., Ltd. (Mitsui chemical ファイン Co., Ltd.)).
LOX: loxoprofen sodium (manufactured by Kyowa Kaisha (ダイト Co., Ltd.)).
DCF: diclofenac sodium (manufactured by Daohu pharmaceutical industries, Ltd.).
FEL: felbinac (manufactured by HANSEO CHEMICAL Co., Ltd.).
Water: "purified water (Japanese pharmacopoeia)" manufactured by Kyoho pharmaceutical Co., Ltd.
EtOH: ethanol (pure chemical Co., Ltd.).
The mass average molecular weight represents a value determined according to gel permeation chromatography.
Example B1
As a mold for producing a microneedle preparation, a mold was used in which a bottom diameter of 0.5mm and a height of 0.65mm were provided, and containers having a shape complementary to a conical needle having a tip diameter of 0.04mm were used, and 10 containers were arranged at intervals of 1.0mm, and 100 containers were formed in total. The material of the mold, including the base material and the surface in contact with the needles, was 100% polysiloxane (two-part RTV rubber KE-17: fumed silica).
A liquid composition was prepared by dissolving the components (except water) shown in table 4 in water. Then, the mold was heated to 80 ℃: (using a thermostatic bath)Temperature TA) Thereafter, the mold was taken out of the thermostatic bath, and about 1g of the above-mentioned liquid composition was rapidly filled in the mold. The liquid composition before filling was at room temperature (25 ℃).
At 25 deg.C (temperature T)B) The mold and the liquid composition are left standing, and after the liquid composition is dried to a constant mass, the microneedle preparation is taken out from the mold.
Examples B2 to B27 and comparative examples B1 to B15
Except that the composition of the liquid composition filled into the mold and the temperature T of the mold were changed as shown in tables 4 to 8AAnd temperature T at the time of dryingBExcept for this, microneedle preparations were produced in the same manner as in example B1.
[ measurement of drug permeation quantity ]
Transdermal absorption experiments were performed using hairless mice. The outline is as follows.
The skin of the mice was placed in a vertical Franz diffusion cell (フランツセル) and the patch was applied. After that, the receiving solution was collected after 8 hours, and the permeation amount of the drug was measured by HPLC under the following processing conditions. Drug permeation was measured for loxoprofen sodium-containing examples B10 to B17 and comparative examples B6 to B10, and felbinac-containing examples B20 to B27 and comparative examples B11 to B15.
(treatment conditions)
And (3) measuring environment: at 25 ℃ and 50% RH,
mouse skin: taking out from the back of a male mouse with the age of HR-17 weeks,
receiving liquid: a phosphate buffer (pH7.4),
the application area is as follows: 5cm2，
Patch preparation: 1 tablet (about 0.5g),
franz diffusion cell jacket temperature: 37 ℃ is carried out.
The drug permeability was evaluated according to the following criteria.
(evaluation criteria for loxoprofen sodium drug)
Very good: the drug permeability is 200 mug/cm2The above.
O: the drug permeability is 150 mug/cm2Above and below 200μg/cm2。
And (delta): the drug permeability is 100 mu g/cm2Above and below 150 mu g/cm2。
X: the drug permeability is less than 100 mu g/cm2。
(evaluation criteria when felbinac is used as the drug)
Very good: the drug permeability is 450 mu g/cm2The above.
O: the drug permeability is 350 mug/cm2Above and below 450 mu g/cm2。
And (delta): the drug permeability is 250 mug/cm2Above and below 350 mu g/cm2。
X: the medicine penetration is less than 250 mu g/cm2。
[ needle formability ]
The microneedle preparation was observed using a microscope (VHX-1000 manufactured by Kenyx (キーエンス)) to confirm that several needles corresponding to 100 wells of the mold were formed, and needle formability was evaluated according to the following criteria.
(evaluation criteria)
Very good: the number of needles is 95 or more.
O: the number of needles formed is 90 or more, less than 95.
And (delta): the number of needles formed is 80 or more and less than 90.
X: the number of needles formed is less than 80.
The production conditions and evaluation results of examples B1 to B27 and comparative examples B1 to B15 are shown in tables 4 to 8.
In tables 4 to 8, "amount of composition after drying" indicates a mass ratio of the composition after drying when the mass of the liquid composition immediately before filling in the mold and drying is 100.
[ TABLE 4 ]
[ TABLE 5]
[ TABLE 6]
[ TABLE 7 ]
[ TABLE 8 ]
As shown in tables 4 to 8, in examples B1 to B27 in which the production method of the present invention was used, 90 or more needles were formed, and the formation of needles was stable. The microneedle preparations of examples B10 to B17 and B20 to B27 were excellent in drug permeability.
On the other hand, at the temperature T of the moldAAnd temperature T at the time of dryingBIn comparative examples B1 to B15 that did not satisfy any of the conditions of formula (1) and formula (2), the number of needles formed was less than 90, and the formation of needles was unstable. The microneedle preparations of comparative examples B6 to B15 were poor in drug permeability.
Claims (8)
1. A microneedle preparation comprising a bonded part having a base material and a plurality of needles protruding from one side of the base material, wherein the bonded part dissolves and at the same time transdermally absorbs a component contained therein, and the bonded part contains a component (A): one or more selected from the group consisting of hyaluronic acid and a hyaluronate salt, and (B) component: glycerin, wherein the mass ratio A/B of the component (A) to the component (B) is 1 to 5, and the content of the component (A) in 100 mass% of the bonded portion is 20 to 75 mass%.
2. The microneedle preparation according to claim 1, wherein the component (A) contains one or more selected from the group consisting of the component (A-1) and the component (A-2),
the component (A-1) is selected from at least one of the group consisting of hyaluronic acid having a mass average molecular weight of 50,000 or more and a hyaluronic acid salt having a mass average molecular weight of 50,000 or more,
the component (A-2) is at least one selected from the group consisting of hyaluronic acid having a mass average molecular weight of less than 50,000 and a hyaluronic acid salt having a mass average molecular weight of less than 50,000.
3. The microneedle preparation according to claim 1, wherein the fitting portion further contains (C) component: non-steroidal anti-inflammatory drugs.
4. The microneedle preparation according to claim 2, wherein the mass ratio (a-2)/(a-1) of the component (a-2) to the component (a-1) is 0 to 1.75.
5. A method for producing a microneedle preparation according to claim 1, wherein a liquid composition obtained by dissolving the preparation in a water-soluble solvent is filled at a temperature TAIn a mold satisfying the condition of the following formula (1), at a temperature TBDrying the bonded part in an environment satisfying the following formula (2),
50(℃)≦TA···(1)
TB＜TA···(2)。
6. the method for manufacturing a microneedle preparation according to claim 5, wherein a material of a surface in contact with the liquid composition in the mold is polysiloxane.
7. The method for producing a microneedle preparation according to claim 5, wherein the preparation contains at least one component (X) selected from the group consisting of water-soluble polymers and saccharides.
8. The method for producing a microneedle preparation according to claim 5 or 7, wherein a content of the water-soluble solvent in the bonded portion is 35% by mass or less.
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| KR102033686B1 (en) * | 2017-05-19 | 2019-10-18 | 보령제약 주식회사 | Microneedle transdermal patch comprising donepezil |
| JP2018192177A (en) * | 2017-05-22 | 2018-12-06 | コスメディ製薬株式会社 | Water soluble cosmetic sheet-holding film |
| CN109200012A (en) * | 2017-07-06 | 2019-01-15 | 中科微针（北京）科技有限公司 | A kind of layering dissolution micropin containing inorganic salts |
| CN109646673A (en) * | 2017-10-12 | 2019-04-19 | 秀杰股份公司 | The micro-structure preparation technique of botulin toxin |
| WO2019225650A1 (en) * | 2018-05-23 | 2019-11-28 | 富士フイルム株式会社 | Japanese-encephalitis-vaccine-containing microneedle array |
| CN110947085A (en) * | 2018-09-27 | 2020-04-03 | 中科微针（北京）科技有限公司 | Method for accelerating forming and instant drug delivery of polyvinyl alcohol soluble microneedle and prepared microneedle |
| CN112957607B (en) * | 2021-01-30 | 2023-08-04 | 上海应用技术大学 | Microneedle transdermal patch and preparation method thereof |
| CN114903843B (en) * | 2022-06-02 | 2023-01-13 | 优微（珠海）生物科技有限公司 | Microneedle preparation, microneedle patch and preparation method thereof |
| CN116548205B (en) * | 2023-04-24 | 2024-02-13 | 南京师范大学 | Microneedle preparation, microneedle patch, and preparation methods and applications thereof |
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