CN105982842A - Microneedle preparation and method for producing the microneedle preparation - Google Patents
Microneedle preparation and method for producing the microneedle preparation Download PDFInfo
- Publication number
- CN105982842A CN105982842A CN201610158044.6A CN201610158044A CN105982842A CN 105982842 A CN105982842 A CN 105982842A CN 201610158044 A CN201610158044 A CN 201610158044A CN 105982842 A CN105982842 A CN 105982842A
- Authority
- CN
- China
- Prior art keywords
- composition
- preparation
- pin
- micropin
- sticking part
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- 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
-
- 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
-
- 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
-
- 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
- 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
-
- 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
A microneedle preparation having a substrate difficult to bend and good compliance for skin curve surfaces, and allowing easy needle puncturing into skin, and a method of preparing the microneedle preparation capable of stably forming needles are provided. The microneedle preparation (11) provided with the substrate (112) and a plurality of needles (114) protruding from one side surface of the substrate (112), and comprising an (A) component and a (B) component is provided, wherein the (A) component is more than one selected from a group consisting of hyaluronic acid and hyaluronates, the (B) component is a glycerol adhering part (110), and the mass ratio A/B of the (A) component to the (B) component is 1-5. In addition, the method of preparing the microneedle preparation by dissolving a preparation into a water soluble solvent to form a liquid composition, filling a mold the temperature TA of which meets a conditions that the TA is not less than 50 DEG C with the composition, and drying in an environment the temperature TB of which is lower than the TA to form the adhering part is also provided.
Description
Technical field
The present invention relates to the manufacture method of a kind of micropin preparation and micropin preparation.
Background technology
Micropin preparation (also referred to as lysotype micropin preparation.), give and such as anti-inflammation analgesic or increase as in human body
The preparation of the physiologically active ingredient of CBF medicine etc., known.Micropin preparation, possesses the single side face shape of base material in sheet
Cheng Duogen pin, and the sticking part containing physiologically active ingredient.When micropin preparation fits in skin, base material and pin dissolve
Meanwhile, the physiologically active ingredient wherein comprising is absorbed transdermally.
As micropin preparation, for example, the base material possessing containing hyaluronic acid can be enumerated and there is the micropin system of sticking part of pin
Agent (patent document the 1st, 2).
But, micropin preparation, and possess compared with hollow type pin, owing to the injection rate of active ingredient is few, and active ingredient
Being evenly present in base material and pin, percutaneous absorbability is in reduction trend.
Additionally, in micropin preparation, pin punctures into after skin in order to ensure sufficient percutaneous absorbability, and needle set has sufficient height
Degree and stress, top Angle ambiguity is below 90 degree, and base material chases after from skin curved surface also critically important well.
As the manufacture method of micropin preparation, for example, can enumerate the composition (preparation) containing hyaluronic acid or gelatin etc.
Dissolve or be dispersed in the water-soluble solvent of water etc. the fluid composition being formed and pour into mould and fill, and be dried to becoming special
Fixed amount of moisture so that it is the method being removed from the molds after solidification.But, in this manufacture method, due to according to liquid group
The composition of compound or the material of mould, the formation easness of pin changes very greatly, is stably formed pin and is difficult to.Once can not stablize
Ground forms pin, and the Transdermal absorption of physiologically active ingredient just becomes insufficient.
Therefore, it is proposed to following methods: the fluid composition that formulation dissolution is formed in the aqueous medium of water etc., pressurization
Be infused on the mould being put in pressure vessel for being formed in the container of pin (patent document 3).But, even if
In the method, when being removed from the molds micropin preparation, also have the top defect of pin, pin form insufficient situation.
It additionally, the base material containing hyaluronic acid, is easily bent generation after being dried and tilts.It is just difficult to make pin once base material bending
All puncturing into skin, percutaneous absorbability reduces.
Prior art literature
Patent document
[patent document 1] Japanese Patent Laid-Open 2009-201956 publication
[patent document 2] Japanese Patent Laid-Open 2013-189432 publication
[patent document 3] Japanese Patent Laid-Open 2013-162982 publication
Content of the invention
Problem to be addressed by invention
1st purpose of the present invention is to provide and makes pin puncture into skin hour hands to have sufficient height, top angle and stress,
Suppression base material bending tilts, and to the excellent micropin preparation of the following of skin curved surface.
2nd purpose of the present invention is to provide the fluid composition using formulation dissolution to be formed in water-soluble solvent, Neng Gouwen
Surely the manufacture method of the micropin preparation of pin is formed.
The means of solution problem
Solve the micropin preparation of the 1st mode of the 1st purpose of the present invention, be to possess there is base material and the single side face from this base material
The sticking part of many prominent pins, the micropin preparation that the composition that above-mentioned sticking part wherein comprises while dissolving is absorbed transdermally,
In above-mentioned sticking part, contain (A) composition: the one in the group that is made up of hyaluronic acid and hyaluronate with
On, and (B) composition: glycerine, above-mentioned (A) composition is 1～5 relative to the mass ratio A/B of above-mentioned (B) composition.
In the micropin preparation of the 1st mode, above-mentioned sticking part, it is also possible to contain (C) composition further: physiologically active becomes
Point (but, in addition to above-mentioned (A) composition.).
Above-mentioned (A) composition, preferably comprises the one in the group being made up of (A-1) composition and (A-2) composition
Above, described (A-1) composition is selected from by the hyaluronic acid of matter average molecular weight 50, more than 000 and matter average molecular weight 50,000
More than one in the group that above hyaluronate is constituted, described (A-2) composition selected from by matter average molecular weight less than 50,000
Hyaluronic acid and the group that constitutes of the hyaluronate less than 50,000 for the matter average molecular weight in more than one.
Above-mentioned (C) composition, preferably non-steroid anti-inflammatory drug.
20～75 mass % in the content of above-mentioned (A) composition, preferably sticking part (100 mass %).
Above-mentioned (A-2) composition relative to mass ratio (A-2)/(A-1) of above-mentioned (A-1) composition, preferably 0～1.75.
Solve the manufacture method of the micropin preparation of the 2nd mode of the 2nd purpose of the present invention, be the base material possessing and there is sheet,
The manufacture method of the micropin preparation of the sticking part of the many piece pins prominent with the single side face from this base material, it is characterised in that by preparation
It is dissolved in water-soluble solvent the fluid composition being formed, be filled in temperature TAMeet in the mould of following formula (1) condition,
In temperature TBThe environment meeting following formula (2) condition makes it be dried and form above-mentioned sticking part.
50(℃)≦TA···(1)
TB＜ TA···(2)
In the manufacture method of the micropin preparation of the 2nd mode, the material of the part contacting with above-mentioned sticking part in above-mentioned mould
Matter, preferably polysiloxanes.This situation, can be the whole of the part contacting with above-mentioned sticking part in above-mentioned mould
For polysiloxanes, it is also possible to be a part of for polysiloxanes.Especially, preferred contacting with above-mentioned sticking part in above-mentioned mould
All polysiloxanes of part.
Above-mentioned preparation, preferably comprises composition (X): in the group being made up of water soluble polymer and carbohydrate at least
A kind of.
The content of the water-soluble solvent in above-mentioned sticking part, below preferably 35 mass %.
Above-mentioned preparation, preferably comprises composition (Y): physiologically active ingredient.
In the present invention, it is also preferred that utilize the micropin preparation of manufacture method manufacture the 1st mode of the micropin preparation of the 2nd mode.Tool
(A) and (B) composition and (C) composition using as required and (D) composition are preferably dissolved in by body ground
The fluid composition being formed in water-soluble solvent, is filled in temperature TAMeet in the mould of above-mentioned formula (1) condition, in temperature
Degree TBThe environment meeting above-mentioned formula (2) condition makes it be dried and form sticking part, obtain the micropin preparation of the 1st mode.
The effect of invention
The micropin preparation of the 1st mode of the present invention, makes pin puncture into skin hour hands and has a sufficient height, top angle and
Stress, suppression base material bending tilts, and excellent to the following of skin curved surface.
The manufacture method of the micropin preparation of the 2nd mode according to the present invention, uses formulation dissolution to be formed in water-soluble solvent
Fluid composition, can be stably formed pin.
Brief description
[Fig. 1] is the sectional view of an example of the micropin preparation of the 1st mode illustrating the present invention.
[Fig. 2] is the front enlarged drawing of an example of the pin of the micropin preparation of the 1st mode illustrating the present invention.
[Fig. 3] is cutting of an example of the micropin preparation of the manufacture method manufacture illustrating the 2nd mode using the present invention
Face figure.
[Fig. 4] is the example illustrating the operation in the manufacture method of the micropin preparation of the 2nd mode of the present invention
Sectional view.
[Fig. 5] is the base illustrating when the micropin preparation obtaining in each example is observed from its side in the state of being positioned over plane
The degree of crook of material and the chart of following when being placed on the skin curved surface of wrist.
[explanation of symbol]
11 micropin preparations
110 sticking parts
112 base materials
114 pins
21 micropin preparations
210 sticking parts
212 base materials
214 pins
2100 moulds
2110 depressed parts
2112 containers
Detailed description of the invention
In the present invention, so-called " pin ", the meaning is the small convex shape works (micropin) of needle-like in a broad sense,
It is not limited to the spicule with pointed end, also comprise the not sharp-pointed shape in top (for example coniform).
" the bottom rugosity of pin ", such as how pyramidal pin etc. in this wise, the vertical cross section of the short transverse of the bottom with pin
In the case of shape is beyond circle, represent the diameter of a circle external with the cross sectional shape of the bottom of pin.
[the 1st mode]
The micropin preparation of the 1st mode of the present invention, is to possess to have base material and the many prominent pins from this base material
Sticking part, the micropin preparation that the composition that above-mentioned sticking part wherein comprises while dissolving is absorbed transdermally.
Fig. 1 illustrates an example of the micropin preparation of the 1st mode of the present invention.Micropin preparation 11, possesses sticking part
110.Sticking part 110, possesses the base material 112 of sheet and the many pins 114 that the single side face from base material 112 is prominent.
The shape of pin, preferably coniform.It additionally, the shape of pin, is not limited to coniform, it is also possible to quadrangular pyramid etc. are many
Shape beyond pyramidal or coniform etc. these.
The height of pin, preferably 50～1000 μm, more preferably 100～700 μm.If the height of pin is in above-mentioned lower limit
Above, the cutaneous penetration of (A) composition or (C) composition is easy for becoming abundant.If the height of pin is in above-mentioned higher limit
Hereinafter, it owing to pin is difficult to and nerve contact, is easy for evading pain or bleeding.Further, the height of above-mentioned pin, represent to
10 pins that machine selects measure the mean value of ground level.
The bottom rugosity of pin, preferably 10～1200 μm, more preferably 25～600 μm.Further, the end of so-called above-mentioned pin
End rugosity, represents the mean value measuring ground bottom rugosity to 10 pins randomly choosing.
The top angle of pin, preferably less than 90 degree, more preferably 10～60 degree, more preferably 15～45 degree.
If the top angle of pin is more than above-mentioned lower limit, puncturing hour hands just becomes to be difficult to fracture.If the top angle of pin is upper
Stating below higher limit, puncture is just excellent.
Further, the top angle of pin, represents the angle of pin in front view, in the case of being the pin of not sharp shape on top,
Represent the angle that the extended line of the side gained of the both sides extending this pin in front view upward intersects.For example, Fig. 2 arranges
In the case of the cone shape pin 114A lifting, in front view each upward the both sides of extension pin 114A side 114a,
The extended line p of 114b gained and extended line q angulation θ is top angle.
The distance of adjacent needles is preferably substantially equal, and preferably every 1mm about arranges 1～10 pin.As adjacent needles away from
From the allowed band of error, for example, it is of about 0.01～0.5mm.
The density of pin, preferably every 1cm2100～10000, more preferably 100～5000, further preferred 100～2000
Root.If the density of pin is more than above-mentioned lower limit, it becomes possible to pass through skin efficiently.If the density of pin is in the above-mentioned upper limit
Below value, thus it is easily ensured that the intensity of pin.
In the sticking part of the micropin preparation of the 1st mode of the present invention, contain (A) composition and (B) composition.
((A) composition)
(A) composition, is more than one in the group that is made up of hyaluronic acid and hyaluronate.(A) composition,
It is polysaccharide, there is modification effect.Owing to sticking part contains (A) composition, even if mismatching other matrix, base material with
And the formation of pin is also possibly realized.
Hereinafter, also have hyaluronic acid and hyaluronate are referred to as hyaluronic acid etc..
Hyaluronic acid, is the one of glycosaminoglycan (mucopolysaccharide), has the disaccharide list of N-acetyl-glucosamine and glucuronic acid
The structure that unit connects.
As hyaluronic acid, for example, the hyaluronic acid of the biogenetic derivation separating from cockscomb, umbilical cord etc. can be enumerated, utilize micro-life
Hyaluronic acid etc. obtained by thing fermentation.The hyaluronic acid of biogenetic derivation, owing to can not completely remove the biological tool originated as it
Some collagen, remaining collagen be possible to bad influence, it is advantageous to microbe fermentation method source hyaluronic acid.
As hyaluronate, the salt that pharmacy, physiology aspect can be used to allow, for example, alkali metal salt (sodium can be enumerated
Salt, sylvite etc.), alkali salt (magnesium salts, calcium salt etc.), ammonium salt, alcohol amine salt (MEA etc.) etc..Wherein,
As hyaluronate, preferred as alkali salt.
The matter average molecular weight of hyaluronic acid etc., preferably 5,000～1,000,000, more preferably 10,000～200,000.If thoroughly
Bright matter acid etc. matter average molecular weight more than above-mentioned lower limit, be easy for suppress sticking part mechanical strength reduce, during preservation or
Person thrusts skin hour hands to be become to be difficult to fracture.If the matter average molecular weight of hyaluronic acid etc. is below above-mentioned higher limit, pin just holds
Easily thrust skin, and the permeability of sticking part skin is improved.
Further, the matter average molecular weight of hyaluronic acid etc., is the value being measured by gel permeation chromatography (GPC).
Do not easily penetrate with not fractureing from thrusting skin hour hands, and from the viewpoint of easily dissolving in vivo, as (A)
Composition, is preferably used following (A-1) composition, more preferably uses the mixing of following (A-1) composition and (A-2) composition
Thing.
(A-1) saturating selected from by the hyaluronic acid of matter average molecular weight more than 50,000 and matter average molecular weight more than 50,000
Bright matter hydrochlorate constitute group in more than one.
(A-2) selected from by saturating less than 50,000 of the hyaluronic acid less than 50,000 for the matter average molecular weight and matter average molecular weight
Bright matter hydrochlorate constitute group in more than one.
((B) composition)
(B) composition is glycerine.Because sticking part contains (B) composition, tilt so the base material of sticking part becomes to be difficult to bending.
Glycerine (glycerin), is with skeleton symbol C3H5(OH)3Or molecular formula C3H8O3The trivalent alcohol representing.Sweet
In You, there is the commercially available product of the aqueous solution etc. of 84～87 mass %, it is possible to use this commercially available product.
((C) composition)
In the sticking part of the micropin preparation of the 1st mode of the present invention, in order to give with the moistening effect of (A) composition beyond
Other validity effect, as required, it is also possible to containing (C) composition: physiologically active ingredient (but, except (A)
Beyond composition.).Further, the micropin preparation of the present invention, it is also possible to be not mix (C) composition in sticking part, removes (A)
Beyond the moistening effect of composition, it is impossible to access the micropin preparation of other the validity effect of (C) composition.
Additionally, physiologically active ingredient, represent the composition producing some effect to organism.
As (C) composition, the known composition generally using in micropin preparation can be used.As (C) composition, can
To be low molecular compound, it is also possible to be macromolecular compound.
As (C) composition, preferably non-steroid anti-inflammatory drug.
As non-steroid anti-inflammatory drug, for example, can enumerate felbinac, butorphanol tartrate, Perisoxal Citrate,
Paracetamol, mefenamic acid, C14H10Cl2NNaO2, aspirin, alclofenac (Alclofenac), Ketoprofen, fluorine
Than ibuprofen, naproxen, piroxicam, pentazocine, Indomethacin, brufen, Flurbiprofen (Flurbiprofen),
Salicylic acid ethylene glycol, aminopyrine, loxoprofen etc..
As (C) composition beyond non-steroid anti-inflammatory drug, for example, following composition can be enumerated.
Hypnotic sedative agent: flurazepam hydrochloride, hydrochloric acid Rilmazafone, phenobarbital, amytal etc..
Steroidal anti-inflammatory drugs: hydrocortisone, prednisone, dexamethasone, betamethasone etc..
Excitant: Methamphetaminium Chloride, methylphenidate hydrochloride etc..
Spirit and nervous system medication: imipramine hydrochloride (Imipramine hydrochloride), stable, hydrochloric acid sertraline
Woods, fluvoxamine maleate, paroxetine hydrochloride, citalopram hydrobromate, Fluoxetine hydrochloride, alprazolam, fluorine resources
Alcohol, clomipramine, amitriptyline, desipramine, amoxapine (Amoxapine), luxazone, Mianserin,
Setiptiline, Trazodone, Luo Feipaming, Milnacipran, Duloxetine, Venlafaxine, chlorpromazine hydrochloride, thioridazine,
Stable, miltown, Etizolam etc..
Hormone drug: estradiol, estriol, progesterone, norethindrone acetate, Methenolone Acetate (Metenolone Acetate),
Testosterone, human chorionic's glandular hormone, rush corpus luteum (leutinizing) generate hormone, human growth hormone (HGH) etc..
Local anesthetic: lidocaine hydrochloride, procaine hydrochloride, tetracaine hydrochloride, quinocaine, hydrochloric acid third
Amine cacaine etc..
Drug for urinary system: ditropan XL, tamsulosin hydrochloride, propiverine hydrochloride etc..
Skeletal muscle relaxant: Tizanidine, E-0646, methylsulfonic acid pridinol, hydrochloric acid Scoline etc..
Reproductive system medication: ritodrine hydrochloride, tartaric acid meluadrine etc..
Antiepileptic: sodium vedproate, Clonazepam, carbamazepine etc..
Autonomic nerves system medication: Kapp chloramines, Neostigmine, Bethanechol Chloride etc..
Antiparkinsonism drugs: pergolide mesylate, bromocriptine methanesulfonate, benzhexol hydrochloride, amantadine hydrochloride, salt
Acid Ropinirole, talipexole hydrochloride, Cabergoline, Droxidopa, Biperiden, SelegilineHydrochloride etc..
Diuretics: Hydroflumethiazide, frusemide etc..
Respiration stimulant: lobeline hydrochloride, Dimorpholamine, naloxone hydrochloride etc..
Antimigraine: agit, sumatriptan, gynergen, flunarizine hydrochloride, hydrochloric acid
Cyproheptadine etc..
Antihistamine: the double benzene ratio of clemastine fumarate, diphenhydramine tannate, chlorphenamine maleate, hydrochloric acid draw woods,
Fenazil etc..
Tracheaectasy medicine: Tulobuterol, Procaterol Hydrochloride, salbutamol sulfate, Clenizole Hydrochloride, hydrogen bromine
Acid fenoterol, bricalin, isoprenaline sulfate, formoterol fumarate etc..
Cardiotonic drug: isoprenaline hydrochloride, Dopamine hydrochloride etc..
Coronary vasodilator: diltiazem hydrochloride, verapamil hydrochloride, ISDN, monobel, Buddhist nun can
Ground that etc..
Peripheral vasodilator: Nicametate Citrate, Tolazoline etc..
Smoking cessation adjuvant: nicotine etc..
Circulatory system medication: flunarizine hydrochloride, Licardipine Hydrochloride, nitrendipine, Nisoldipine, felodipine,
Amlodipine Besylate Tablet, nifedipine, Nilvadipine, CV-4093, KW-3049, enalapril maleate,
Temocapril hydrochloride (Temocapril Hydrochloride), alacepril, hydrochloric acid Imidapril, Cilazapril, Lai Nuo
Puli, captopril, Trandolapril, Perindopril, atenolol, bisoprolol fumarate, Betriol (Boehringer,Ing.) (bunitrolol
Hydrochloride), metoprolol tartrate, betaxolol hydrochloride, Arotinolol Hydrochlorid, Celiprolol Hydrochorid, card dimension
Lip river, ground, carteolol hydrochloride, bevantolol hydrochloride, Valsartan, candesartan Cilexetil, Losartan Potassium, clonidine hydrochloride etc..
Cardiac arrhythmia medication: Propranolol Hydrochloride, hydrochloric acid alprenolol, procamide, mexiletine hydrochloride, receive
Many Luo Er, norpace (disopyramide) etc..
Anti-malignant ulcer medicine: endoxan, fluorouracil, Tegafur, procarbazine hydrochloride, Ranimustine, hydrochloric acid she
Vertical for health, fluridine (Fluridine) etc..
Hypolipidemic: general Liprevil, simvastatin, Bezafibrate, probucol etc..
Hypoglycemic agent: glibenclamide, chlorpropamide, orinase, glymidine sodium, glybuzole, hydrochloric acid fourth good fortune
Bright etc..
Drug for peptic ulcer: paddy propylamine, cetraxate hydrochloride, Spizofurone, Cimetidine, glycopyrronium bromide etc..
Cholagogic: urso, oxaphenamide etc..
Improve gastrointestinal motor medicine: Domperidone, Cisapride etc..
Liver diseases medication: Tiopronin etc..
Antiallergic: Ketotifen Fumarate, azelastine hydrochloride etc..
Antiviral agent: ACV etc..
Antidinic: Betahistine Mesylate, difenidol hydrochloride etc..
Antibiotic: cefaloridine, Cefdinir, Cefpodoxime ester, Cefaclor, CLA, erythromycin, methyl
Erythromycin, kanamycin sulfate, seromycin, tetracycline, potassium phenylacetamidopenicillanate, propicillin potaszium, Cloxacillin Sodium (Cloxacillin
Sodium), ampicillin sodium, bacampicillin hydrochloride, carbenicillin sodium, chloramphenicol etc..
Habitual poisoning medication: cyanamide etc..
Appetite-suppressing medicine: 5-(4-chlorophenyl)-2,5-dihydro-3H-imadazo[2,1-a etc..
Chemotherapeutic: isoniazid, 2-ethylisonicotinthionamide, pyrazinamide etc..
Promotion blood clotting medicine: ticlopidine hydrochloride, potassium warfarin etc..
Anti-Alzheimer disease medicine: eserine, Doneppezil Hydrochloride, tacrine, arecaline, xanomeline etc..
Serotonin receptor antagonism antiemetic: muriatic ondansetron, Granisetron Hydrochloride, Ramosetron HCl, azasetron hydrochloride
Department's fine jade etc..
Gout therapertics: colchicin, probenecid, sulfinpyrazone etc..
The antalgesic of anaesthetic class: fentanyl citrate, morphine sulfate, morphine hydrochloride, codeine phosphate, cocainehydrochloride,
Pethidine hydrochloride etc..
As (C) composition, for example, it is also possible to use peptide, protein and its derivative etc.；Molecular weight about 1000
Vaccine, nucleic acid (DNA, RNA etc.), sugar etc..
As vaccine, for example, JE vaccine, Rotavirus Vaccine, Alzheimer disease vaccine, artery can be enumerated
Hardening vaccine, cancer vaccine, nicotine vaccine, diphtheria vaccine, tetanus vaccine, pertussis vaccine, ImuLyme,
Rabies vacciness, polyvalent pneumococcal vaccine, yellow fever vaccine, cholera vaccine, varicella vaccine, Vaccinum Calmette-Guerini, nettle rash vaccine,
Measles vaccine, mumps vaccine, clostridium botulinum vaccine, herpesvirus vaccine, other DNA vaccination, viral hepatitis type b epidemic disease
Seedling etc..
Further, as (C) composition, it is possible to enumerate lixisenatide (Lixisenatide), naltrexone, cetrorelix acetate,
Taltirelin, nafarelin acetate, PGA1, Alprostadil, alpha-interferon, for multiple sclerosis β-
Interferon, hematopoietin, follitropin beta, follitropin alfa, G-CSF, GM-CSF, salmon calcitonin, height
Blood sugar element, GNRH antagonistic, insulin, Filgrastim (Filgrastim), heparin, LMWHs, growth hormone,
Incretin, GLP-1 derivative etc..
Additionally, as (C) composition, Crotamiton, Menthol, peppermint oil, citrene, adipic acid two can be enumerated different
Propyl ester etc., or as drug effect adjuvant, gaultherolin, ethylene glycol salicylate, Menthol, thymol, peppermint
Oil, Vanillyl pelargonic amide (Nonanoic acid Vanillylamide), vanilla Capsaicin (Noroyl Nanillylamide),
Pepper extract, capsicim, ascorbyl palmitate, kojic acid, Rucinol (Rucinol), tranexamic acid, oil
Licorice (oil with property Radix Glycyrrhizae エ キ ス), retinol, retinoic acid, retinyl acetate, retinyl palmitate,
Isopropyl methyl phenol, vitamins (calciferol, vitamine D3, vitamin K etc.) etc..
(C) compound of composition, also comprises the salt that pharmacy aspect can allow for, any form of inorganic salts or organic salt
All may be used.
(C) composition, can be used alone one, it is also possible to be applied in combination two or more.
((D) composition)
In the sticking part of the micropin preparation of the 1st mode of the present invention, as required, it is also possible to become containing (A)～(C)
(D) composition beyond Fen: any composition.
As (D) composition, for example, cosolvent, skin penetration enhancer, stabilizer, antioxidant, emulsification can be enumerated
The additive of agent, surfactant, slaine etc..
As cosolvent, ethylene glycol, propane diols and 1,3-BDO, polyethylene glycol etc. can be enumerated.
As surfactant, nonionic surface active agent, cationic surface active agent, anionic surface activity,
Any one in amphoteric surfactant all can, the nonionic surface active agent using in preferably usual pharmaceutical preparations.
Specifically, the sugar alcohol fatty acid ester of sucrose fatty ester etc., sorbitan fatty acid ester, glycerine fatty acid can be enumerated
Ester, polyglyceryl fatty acid ester, methyl glycol fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene glycerides
Fat acid esters, cithrol, Emulsifier EL-60, Crodaret etc..
As the macromolecule that can mix with matrix, solvent, stabilizer, the purpose of auxiliary etc. of plasticizing, polyethylene can be enumerated
Oxide, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methylcellulose, glucan, poly-second
Enol, polyvinylpyrrolidone, pulullan, sodium carboxymethylcellulose, Ac-Di-Sol, Arabic gum,
Heparin, chondroitin sulfate and its salt, trehalose, maltose etc..
The slaine that can mix as the purpose with buffer, stabilizer, matrix, solvent, supensoid agent etc., can enumerate chlorine
Change sodium, potassium chloride, magnesium chloride, potassium chloride, aluminium chloride, zinc chloride etc..
In the sticking part of the micropin preparation of the 1st mode of the present invention, preferably comprise water.Although water is present to ensure that at mould
Manufacturability during middle filling preparation and mix, but after being preferably dried, sticking part also contains water.
(ratio of each composition)
The ratio of each composition in the sticking part of the micropin preparation of the 1st mode of the present invention shown below.
The content of (A) composition in sticking part (100 mass %), preferably 20～75 mass %, more preferably 20～70 matter
Amount %, further preferred 30～70 mass %.If (A) content of composition is more than above-mentioned lower limit, base material and pin
Formation become easy.If (A) content of composition is below above-mentioned higher limit, base material becomes to be difficult to bending and tilts.
When using (A-1) composition as (A) composition, the content of (A-1) composition in sticking part (100 mass %),
Preferably 20～75 mass %, more preferably 20～70 mass %, further preferred 30～70 mass %.If (A-1) become
The content dividing is more than above-mentioned lower limit, and the formation of base material and pin becomes easy.If (A-1) content of composition is upper
Stating below higher limit, base material becomes to be difficult to bending and tilts.
The content of (A-2) composition in sticking part (100 mass %), preferably 0～30 mass %, more preferably 0～25 matter
Amount %, further preferred 5～10 mass %.If (A-2) content of composition is more than above-mentioned lower limit, the puncture of pin
Become more preferable.If (A-2) content of composition is below above-mentioned higher limit, during preservation or thrust skin hour hands and become more
It is difficult to fracture.
As (A) composition, preferably by (A-1) composition 60～100 mass % and (A-2) composition 40～0 mass % ((A-1)
Composition adds up to 100 mass % with (A-2) composition) constitute.
(A-2) composition is relative to mass ratio (A-2)/(A-1) of (A-1) composition, although because of each hyaluronic acid etc.
Matter average molecular weight different and different, but can suitably determine so that sticking part has gratifying mechanical strength and firmly
Degree.As mass ratio (A-2)/(A-1), preferably 0～1.75, more preferably 0.05～0.5.If mass ratio (A-2)/
(A-1) below above-mentioned higher limit, during preservation or thrust skin hour hands and become to be difficult to fracture.
The content of (B) composition in sticking part (100 mass %), preferably 15～45 mass %, more preferably 20～40 matter
Amount %.If (B) content of composition is more than above-mentioned lower limit, base material just becomes more difficult to bending and tilts.If (B)
The content of composition, below above-mentioned higher limit, is easy for suppression sticking part and becomes over softness, and owing to top angle is little,
In addition being easily formed with the pin of abundant hardness, pin becomes easily to puncture into skin.
(A) composition is relative to the mass ratio A/B of (B) composition, is 1～5, and preferably 1～4.5, more preferably 1～4.As
Really mass ratio A/B is more than above-mentioned lower limit, it becomes possible to suppression sticking part becomes over softness, and owing to top angle is little,
In addition can be formed with the pin of abundant hardness, pin becomes able to easily puncture into skin.If mass ratio A/B is on above-mentioned
Below limit value, it becomes possible to the bending of suppression base material.
The content of (C) composition in sticking part (100 mass %), preferably 0.1～80 mass %, more preferably 1～50 matter
Amount %.
The content of the water in sticking part (100 mass %), preferably 5～20 mass %, more preferably 10～15 mass %.As
Really the content of water is more than lower limit, and the flexibility of micropin preparation just improves.If the content of water is below higher limit, just hold
Easily suppression manufacture hour hands are shrivelled, and the mass change behind Kaifeng also tails off.
Further, the total content of (A) composition, (B) composition, (C) composition and water, is less than 100 mass %.
It is distributed in sticking part to preferably each uniform component.Therefore, the content of above-mentioned each composition, is preferably relative to sticking part
Load per unit of mass.
[pH]
Although according to physiologically active ingredient mixing, the pH of sticking part can repeatedly, but irritating to skin
Viewpoint considers, preferably 3～9.
[supporter]
The micropin preparation of the 1st mode of the present invention, it is also possible to possess support in the one side forming pin and opposing face of sticking part
Body.
It as supporter, is not particularly limited, the known supporter that the supporter of patch generally uses can be employed as.
As supporter, for example, the composite sheet etc. of resin film, cloth, resin film and cloth package integral can be enumerated.
As resin film, for example, can enumerate by polyethylene, polypropylene, polyester, artificial silk, polyamide, polyvinyl chloride,
The film that the resin of urethanes vinyl chloride copolymer, polyurethane etc. is constituted.
Cloth, can be non-woven fabrics, can be to spin cloth, it is also possible to be to compile cloth.
As non-woven fabrics, for example, the non-woven fabrics manufacturing by needle point method, spun lacing method, spun-bond process, loop bonding method, meltblown etc..
Spin Weaving method or the weaving method of cloth, be not particularly limited, for example, warp knit (rib warp knit (tricot can be enumerated
Knitting), sley bar warp knit (denbigh tricot knitting), satin weave warp knit (satin knitting), Atlas satin weave
Warp knit (atlas knitting), flat sennit (flat knitting), rib-loop warp knit (rib stitch), double reverse side warp knit (purl
Knitting)), circle compiles (two-sided circle volume, one-side circular knitting, rib-loop circle compile (circular rib knitting)) etc..
As the material of fiber constituting cloth, for example, can enumerate polyester, artificial silk, nylon, polypropylene, polyethylene,
Polyamide, polyurethane etc..
As composite sheet, resin film and the cloth sheet material by the heat bonding such as fusion, adhesive can be enumerated；In cloth
The sheet material etc. that the melted resin of extrusion is formed.
(manufacture method)
As the manufacture method of the micropin preparation of the present invention, be not particularly limited, except will (A) composition and (B) composition according to
Beyond specific ratio allotment, known any means before can using.
For example, can be set forth in the mould of polysiloxanes of the shape having worn pin, curtain coating (A) composition and (B) become
The fluid composition that other the composition dividing and using as required is mixed in water, the method peeled off from mould after being dried.
(action effect)
In the micropin preparation of the 1st mode of present invention mentioned above, owing to containing (A) composition according to specific ratio
(B) composition, makes pin puncture into skin hour hands and has sufficient height, top angle and stress, and suppression base material is curved
Warped rises, and excellent to the following of skin curved surface.Therefore, the micropin preparation of the 1st mode of the present invention, due to laminating
Pin can be stably made to puncture into skin during skin, therefore, it is possible to stably guarantee excellent percutaneous absorbability.
[the 2nd mode]
The manufacture method of the micropin preparation of the 2nd mode of the present invention, is the liquid using formulation dissolution to be formed in water-soluble solvent
Body composition, possess the micropin preparation of the sticking part with the base material of sheet and the prominent many pins of single side face from this base material
Manufacture method.
(construction of micropin preparation)
The structure of the micropin preparation that the manufacture method of the 2nd mode according to the present invention manufactures, if possessing the base with sheet
The sticking part of the many pins that material and the single side face from this base material highlight, is just not particularly limited.
As an example of the micropin preparation that the manufacture method of the 2nd mode according to the present invention manufactures, illustrate in figure 3
Micropin preparation 21.Micropin preparation 21 possesses sticking part 210.Sticking part 210 has the base material 212 of sheet and from base material 212
The prominent many pins 214 of single side face.
The shape of pin, is not particularly limited, and can enumerate coniform, how pyramidal (quadrangular pyramid etc.), coniform etc., preferably
Coniform.
The height of pin, identical with the 1st mode, preferably 50～1000 μm, more preferably 100～700 μm.If the height of pin
More than above-mentioned lower limit, the cutaneous penetration of active ingredient is easy for becoming abundant.
That shows in the preferred scope of the bottom rugosity of pin, the distance of adjacent needles, and the density of pin, with the 1st mode is preferred
Scope is identical.
When pin is coniform, the rugosity on the top of pin, preferably 5～500 μm, more preferably 5～300 μm.
In the micropin preparation that the manufacture method of the 2nd mode according to the present invention manufactures, it is also possible to the pin at sticking part is formed
One side surface and opposite side surfaces arrange supporter.It as supporter, is not particularly limited, be employed as the supporter of patch
The known supporter of generally use can be used.
As supporter, can enumerate identical with the supporter enumerated in the 1st mode, for example, resin film can be enumerated (poly-
Vinyl film, polypropylene film etc.), cloth (non-woven fabrics that is made up of polyester fiber etc., spin cloth, compile cloth etc.), resin
Film and the composite sheet etc. of cloth package integral.
(manufacture method)
In the manufacture method of the micropin preparation of the 2nd mode of the present invention, the liquid that formulation dissolution is formed in water-soluble solvent
Body composition, is filled in temperature TAMeet in the mould of following formula (1) condition, in temperature TBMeet following formula (2)
The environment of condition makes it be dried and form sticking part.Hereby it is possible to obtain being stably formed pin, the Transdermal absorption of active ingredient
The excellent micropin preparation of property.
50(℃)≦TA···(1)
TB＜ TA···(2)
For example, when manufacturing micropin preparation 21, as shown in Figure 4, use is provided with the shape of the base material 212 with micropin preparation 21
The mould 2100 of the container 2112 of the shape of the recess 2110 of the complementary shape of shape and the shape complementarity with pin 214.Adding
Heat is to temperature TAThe recess 2110 of mould 2100 and container 2112 in fill fluid composition X.Then, in deficiency
Temperature TATemperature TBEnvironment in, place and be filled with the mould 2100 of fluid composition X, make fluid composition X do
Form micropin preparation 21 after dry.Afterwards, micropin preparation 21 is peeled off from mould 2100.
Temperature T of mould during filling fluid compositionA, it is more than 50 DEG C, preferably more than 80 DEG C.If temperature TA
More than above-mentioned lower limit, owing to when being dried, fluid composition becomes the easily container bottom well into mould, it becomes possible to
To the micropin preparation being stably formed pin.Further, temperature TAAs long as less than the water-soluble solvent using in fluid composition
Boiling point, preferably below the heat resisting temperature of mould.Specifically, for example, temperature TA100 DEG C can be less than.
The temperature of fluid composition when filling in a mold, there is no particular limitation, preferably 0～80 DEG C, more preferably
10～70 DEG C, more preferably 20～60 DEG C.If the temperature of fluid composition is below higher limit, the stability of medicament
Just promote.If the temperature of fluid composition is more than lower limit, filling fluid composition in a mold just becomes easy.
Temperature T when being driedBThe temperature of the environment placed when representing the mould drying being filled with fluid composition.Mould when being dried
Tool and the temperature of fluid composition, be reduced to temperature TB。
Temperature TBNot enough temperature TA, become to be difficult to from the viewpoint of bending tilts from the micropin preparation obtaining, preferably 25 DEG C with
Under.Further, from the viewpoint of shortening from drying time, temperature TB, preferably more than 5 DEG C.
Temperature T of mould during filling fluid compositionAWith temperature T when being driedBDifference (TA-TB), more than 0 DEG C,
Preferably more than 10 DEG C, more preferably more than 25 DEG C, further preferred more than 30 DEG C.If difference (TA-TB) under above-mentioned
It more than limit value, owing to fluid composition becomes the easily container bottom well into mould, is easy for obtaining being stably formed pin
Micropin preparation.
Being dried, so that the content of the aqueous solvent in fluid composition becomes desired ratio, fluid composition solidifies shape
Become sticking part just.Drying time is according to temperature T when being driedBSuitably determine.
<fluid composition>
Fluid composition is at the composition of aqueous solvent by formulation dissolution.
As preparation, the known preparation using in the manufacture of the micropin preparation in being dissolved in aqueous solvent can be used.Make
For preparation, preferably comprise composition (X): be selected from least one in the group being made up of water soluble polymer and carbohydrate,
Preferably with composition (X) as principal component.Further, the total amount (100 relative to preparation is represented with composition based on composition (X)
Quality) containing more than composition (X) 50 mass %.
The meaning of so-called water soluble polymer be the solubility to water (100g) when 20 DEG C be more than 0.01g, molecular weight 1000
Above compound (but, remove carbohydrate.).
As composition (X), for example, can enumerate hyaluronic acid, Sodium Hyaluronate, gelatin, maltose, pulullan polysaccharide,
Pre-gelatinized starch, glucan, sodium carboxymethylcellulose, avicel cellulose, lactose etc..Wherein, as composition (X),
From the viewpoint of the formation transfiguration of pin easily, preferably clear matter acid sodium, gelatin, maltose.
(X) composition can be a kind of or two or more.
The content of (X) composition in preparation (100 mass %), preferably 10～95 mass %, more preferably 20～90
Quality %, most preferably 50～90 mass %.If the content of water soluble polymer is within the above range, the formation of pin just becomes
Obtain easily, and become easy from mould stripping micropin preparation.
When using water soluble polymer as (X) composition, the content of the water soluble polymer in preparation (100 mass %),
It is preferably 15～90 mass %, more preferably 30～70 mass %, most preferably 55～90 mass %.If it is water-soluble high
Within the above range, the formation of pin just becomes easy to the content of molecule, and becomes easy from mould stripping micropin preparation.
When using carbohydrate as (X) composition, the content of the carbohydrate in preparation (100 mass %), preferably 15～80 matter
Amount %, more preferably 30～70 mass %, most preferably 50～70 mass %.If the content of carbohydrate is within the above range,
The formation of pin just becomes easy, and becomes easy from mould stripping micropin preparation.
Preparation, it is also possible to containing (Y) composition: physiologically active ingredient (also referred to as medicine.).
As physiologically active ingredient, if the physiologically active ingredient of the form can being dispersed in sticking part does not just limit especially
Fixed, for example, felbinac, C14H10Cl2NNaO2, loxoprofen sodium, salicylic acid ethylene glycol, Ketoprofen, indoles U.S. can be enumerated
Pungent etc..
(Y) composition, can be a kind of or two or more.
When using (Y) composition, the content of (Y) composition in preparation (100 mass %), preferably 1～10 mass %,
More preferably 2～6 mass %.It if (Y) content of composition is more than above-mentioned lower limit, is easy for playing physiologically active and becomes
The validity divided.If (Y) content of composition is below above-mentioned higher limit, the formative of pin just improves.
Preparation, it is also possible to containing (Z) composition: alkanolamine.
Alkanolamine, can be monoalkanolamine, it is also possible to be dialkanol amine, it is also possible to be three alkanolamines.
The carbon number of the hydroxyalkyl that alkanolamine has, preferably 1～10, more preferably 2 or 3.
As the concrete example of alkanolamine, for example, can enumerate MEA, diethanol amine, triethanolamine, single Propanolamine, two
Propanolamine, tripropanol amine, monoisopropanolamine, diisopropanolamine (DIPA), triisopropanolamine etc..
(Z) composition, can be a kind of or two or more.
When using (Z) composition, the content of (Z) composition in preparation (100 mass %), preferably 1～20 mass %,
More preferably 2～15 mass %.If (Z) content of composition is more than above-mentioned lower limit, the formative of pin just improves.As
Really the content of (Z) composition is below above-mentioned higher limit, and the puncture of pin just improves.
Further, the total content of (X) composition～(Z) composition, is less than 100 mass %.
In the formulation, as required, it is also possible to other the composition beyond allotment (X)～(Z) composition.As other
Composition, can enumerate the plasticizer of glycerine etc., surfactant, the cosolvent of medicine, tackifier, stabilizer, colouring agent,
Spices etc..
As water-soluble solvent, the organic solvent that water mixes can be enumerated with water.Water-soluble solvent can be only water, it is possible to
With the organic solvent only mixing with water, it is also possible to be water and the mixture of the organic solvent mixing with water.
Further, the organic solvent mixing with water, represents the organic solvent dissolving more than 0.01g in the water 100g of 20 DEG C.
As the organic solvent mixing with water, for example, ethanol, methyl alcohol, isopropanol, oxolane, acetone etc. can be enumerated.
As water-soluble solvent, it is necessary to use boiling point in temperature T of mouldAAbove water-soluble solvent.As water solubility
Solvent, from the viewpoint of the difficulty of volatilization, preferably water, ethanol.
The content of the water in water-soluble solvent (100 mass %) is preferably more than 50 mass %, more preferably 70 mass % with
On.
The mass ratio (water: organic solvent) of water and organic solvent, preferably 1:0～1:1 in water-soluble solvent.If
Within the above range, the formation of pin becomes easier for above-mentioned mass ratio.
The content of the water-soluble solvent in fluid composition (100 mass %) when being packed in mould, preferably 30～90 matter
Amount %, more preferably 50～90 mass %.If the content of above-mentioned water-soluble solvent is more than lower limit, the formation of pin just becomes
It is more prone to.If the content of above-mentioned water-soluble solvent is below higher limit, the puncture of the pin of formation is all right.
The viscosity of 20 DEG C of fluid composition when being packed in mould, as long as have the mobility that can be packed into mould
In the range of, from the viewpoint of the formation transfiguration of pin easily, preferably 1～20,000mPa s, more preferably 1～
10,000mPa·s。
Further, above-mentioned viscosity represents the numerical value measuring according to Brookfield viscometer.
<content of the aqueous media in sticking part>
Water-soluble solvent in the sticking part (100 mass %) of the micropin preparation obtaining according to the manufacture method of the 2nd mode
Content, below preferably 35 mass %, below more preferably 25 mass %, below further preferred 20 mass %.If patch
The content of the water-soluble solvent in conjunction portion is below above-mentioned higher limit, and the hardness of pin is easy for fully becoming strong, just becomes easily to wear
Thrust skin.Further, more than content preferably 5 mass % of the water-soluble solvent in sticking part (100 mass %).If patch
The content of the water-soluble solvent in conjunction portion, more than above-mentioned lower limit, is peeled off micropin preparation hour hands from mould and is just difficult to fracture.Patch
The content of the water-soluble solvent in conjunction portion (100 mass %) is preferably 5～20 mass %.In sticking part (100 mass %)
The content of water-soluble solvent also can be 0 mass %.
<mould>
As mould, it is possible to use with the matching form of micropin preparation manufacturing, possess shape complementarity with base material recess and
Mould with the container of the shape complementarity of pin.As mould, can unrestrictedly use known mould.
The material of mould, is not particularly limited, can be resin, metal, wooden etc. any one.Wherein, as mould
Material, from the viewpoint of processability, preferred resin.
As formed mould resin, for example, can enumerate polysiloxanes, polyethylene, polypropylene, polyvinyl chloride, acrylic acid,
Polyethylene terephthalate, polystyrene, acrylonitrile-butadiene-styrene copolymer, Merlon, polyamide,
Fluororesin, polybutylene terephthalate (PBT) etc..
As the material of the part contacting with sticking part in mould, from easy from the viewpoint of micropin preparation peeled off by mould,
Preferably polysiloxanes.At this point it is possible to be only mould to be polysiloxanes system with sticking part contact portion, it is also possible to be that mould is whole
Body is polysiloxanes system.The part of polysiloxanes in mould, can be complete in the part contacting with sticking part in mould
Portion, it is also possible to be a part.What in mould, the part of polysiloxanes was preferably in mould with sticking part contact portion is whole.
(action effect)
In the manufacture method of the micropin preparation of the 2nd mode of present invention mentioned above, during by making filling fluid composition
Temperature T of mouldAIt it is more than 50 DEG C, at ratio temperature TALower temperature TBEnvironment in make its be dried formed sticking part,
Thus it is stably formed pin.By control temperature T as noted aboveAAnd temperature TB, just can be stably formed the main of pin
Reason, as described below.
When filling fluid composition in a mold, especially in the case of the viscosity height of fluid composition, in the container bottom of mould
The easy air pocket in portion or steam.It is thus impossible to be sufficient filling with fluid composition to the container bottom of mould, the top of pin
End defect etc. thus be difficult to be stably formed pin.In this regard, in the 2nd mode of the present invention, by the temperature more than 50 DEG C
TAMould in fill fluid composition, the mould being filled with this fluid composition is placed on not enough temperature TATemperature TB
Environment in make fluid composition be dried, in the container of mould remaining air and steam shrink, become negative pressure in container.
Accordingly, it is fully filled owing to fluid composition is attracted to the container bottom of mould, pin can be stably formed.
As described above, in the micropin preparation of the manufacture method manufacture of the 2nd mode according to the present invention, owing to being stably formed
Pin, the percutaneous absorbability of active ingredient is excellent.In the micropin preparation manufacturing according to the manufacture method of the 2nd mode, relative to
At 100 containers of mould, the quantity of the pin of formation is preferably more than 90, more preferably more than 95.
Hereinafter, explained the 1st mode of the present invention by embodiment, but the 1st mode of the present invention is not limited to following institute
State.
[use raw material]
The raw material using in the present embodiment is as follows.
((A) composition)
A-11: polymer hyaluronic acid sodium (trade name " hyaluronic acid FCH-SU " (ヒ ア Le ロ Application acid FCH-SU),
Kikkoman biochemistry manufactures Co., Ltd. (キ ッ U マ Application バ イ オ ケ ミ Off ァ Co., Ltd.) system, matter average molecular weight: 5
Ten thousand～110,000).
A-21: low molecular weight hyaluronic acid (trade name " Hiaroorigo " (ヒ ア ロ オ リ go), Q. P. Corp. (キ ュ
ピ Co., Ltd.) system, matter average molecular weight: less than more than 1,000 1 ten thousand).
((B) composition)
B-1: glycerine (" concentrated glycerin (Japanese Pharmacopoeia) " (グ リ セ リ Application (day office)), slope this pharmaceutical industries Co., Ltd.
System).
((B ') composition: comparison other)
B '-1:1,3-butanediol (" 1,3-BDO (pharmaceuticals additive specification) ", (strain of Daicel Co., Ltd.
Formula commercial firm ダ イ セ Le) system).
B '-2: propane diols (" propane diols (Japanese Pharmacopoeia) ", ADEKA Corp.'s system).
B '-3: polyethylene glycol (" Macrogol 600 ", Wako Pure Chemical Industries, Ltd.'s system).
((C) composition)
C-1: felbinac (" felbinac (Japanese Pharmacopoeia) ", HANSEO CHEMICAL Co., Ltd. system).
(any composition)
Water: " purified water (Japanese Pharmacopoeia) ", common prosperity Pharmaceutical Co., Ltd system.
[embodiment A1～A9, Comparative examples A 1～A6]
As the mould for manufacturing micropin preparation, using base diameter 0.5mm, highly 0.65mm's is coniform, as
The container of the shape complementary with the pin of top angle 33 degree, every 1.0mm is spaced each 10 containers of transverse and longitudinal, amounts to formation 100
The mould of individual container.Further, the top angle of the not sharp-pointed pin in top, is prolonging above the dual-side of pin in front view
The angle that long line intersects.The material of above-mentioned mould, all 100% polyorganosiloxane resins (two-liquid type RTV rubber KE-17:
SHIN-ETSU HANTOTAI's polysiloxanes (SHIN-ETSU HANTOTAI's シ リ U Application)).
As shown in table 2 and table 3, dissolve with obtaining each uniform component or scattered composition.With regard to (A) composition,
Modulate the 10 mass % aqueous solution and mix.In being heated to the mould of 80 DEG C, smear above-mentioned composition about 0.5g and (be dried
After quality become the amount of more than 0.05g).At 25 DEG C, cooling down mould under conditions of 100%Rh, mould is becoming 25 DEG C
After, natural drying obtains micropin preparation in about 8 hours.
[bending following evaluation]
With regard to the micropin preparation obtaining in each example, observe from its side in the state of being positioned over plane according to following benchmark evaluation
When the degree of crook of base material and following when being placed on the skin curved surface of wrist.
(metewand: Fig. 5)
◎: be positioned over during plane unconfirmed to base material bending, and chase after from skin curved surface.
Zero: be positioned over during plane unconfirmed to base material bending, but do not chase after from skin curved surface.
×: confirm base material bending when being positioned over plane, have the discontiguous part with plane.Now, base material does not chase after from skin
Curved surface.
[high evaluation of pin]
Measured the height of the pin of the micropin preparation obtaining in each case by digit microscope, according to following benchmark evaluation.
(metewand)
The height of ◎: pin is more than 500 μm.
Zero: the height of pin be more than 400 μm less than 500 μm.
×: the height of pin is less than 400 μm.
If the height of pin is less than 400 μm, also become to be difficult to obtain sufficient effect even if puncturing.
[the angle evaluation of pin]
The top angle of the pin of the micropin preparation being obtained in each case by determination of electron microscopy, is commented according to following benchmark
Valency.Further, the angle extended line above the dual-side of pin in front view intersected is as top angle.
(metewand)
◎: top angle is less than 50 degree.
Zero: top angle be more than 50 degree less than 90 degree.
×: top angle is more than 90 degree.
Once the top angle of pin is more than 90 degree, and pin just becomes to be difficult to puncture.
[stress appraisal of pin]
Use stress when tip side presses the pin 0.01mm of the micropin preparation obtaining in each case for the instrumental test, according to
Following metewand evaluation.Further, the material pressing probe uses the discoideus frosted glass of diameter 1cm.
(metewand)
Zero: stress is more than 0.05N.
×: understrressing 0.05N.
Once understrressing 0.05N, pin just becomes to be difficult to puncture.
The composition of each composition being illustrated in table 2 and table 3 in embodiment and comparative example and evaluation result.
Additionally, the composition in table 2 and table 3 be measure applying amount and be dried after quality when supposing all water of amount reducing
Composition.Further, the content of (B) composition is quality % of the solid constituent conversion of glycerine.Further, Comparative examples A 4～
In mass ratio A/B hurdle in A6, represent the mass ratio relative to composition (B ') for the composition (A).
[table 2]
[table 3]
As shown in table 2 and table 3, in the reality according to ratio mixing (A) composition and (B) composition specified in the present invention
Execute in the micropin preparation of example A1～A9, make pin puncture into skin hour hands and there is sufficient height, top angle and stress.
And it is possible to suppression base material bending, also excellent to the following of skin curved surface.
In the Comparative examples A 1 not using (B) composition and mass ratio A/B the Comparative examples A 2 more than 5 micropin preparation in,
Visible base material bends.Even if use (B ') composition replace (B) composition Comparative examples A 4～A6 micropin preparation in,
Also show base material bending.
In the micropin preparation of the Comparative examples A 3 less than 1 for the mass ratio A/B, make pin puncture into skin hour hands and do not have sufficiently
Highly, top angle and stress.
Hereinafter, it is described in detail according to the 2nd mode to the present invention for the embodiment, but the 2nd mode of the present invention is not limited to
The following stated.
[use raw material]
Raw material for using in the present embodiment as follows.
HA-1: Sodium Hyaluronate (matter average molecular weight: 50,000～110,000, trade name " FCH-SU ", Kikkoman is raw
Materialization length of schooling makes Co., Ltd.'s system).
HA-2: hyaluronic acid (matter average molecular weight: 1,000～10,000, trade name " Hiaroorigo ", mound is than the meeting of strain formula
Society's system).
GEN: gelatin (Rousselot Co., Ltd. system).
MAL: maltose (trade name " Sanmaruto " (サ Application マ Le ト), Lin Yuan Co., Ltd. system).
GL: concentrated glycerin (trade name " Japanese Pharmacopoeia concentrated glycerin " (office side's グ リ セ リ Application), slope this pharmaceutical industries strain formula meeting
Society's system).
DIPA: diisopropanolamine (DIPA) (the fine Co., Ltd. of Mitsui Chemicals (Mitsui Chemicals ファイン Co., Ltd.) system).
LOX: loxoprofen sodium (Daidoh Limited (ダ イ ト Co., Ltd.) system).
DCF: C14H10Cl2NNaO2 (big and pharmaceutical industries Co., Ltd. system).
FEL: felbinac (HANSEO CHEMICAL Co., Ltd. system).
Water: " purified water (Japanese Pharmacopoeia) ", common prosperity Pharmaceutical Co., Ltd system.
EtOH: ethanol (Junsei Chemical Co., Ltd.'s system).
Matter average molecular weight represents the numerical value measuring according to gel permeation chromatography.
[embodiment B1]
As the mould for manufacturing micropin preparation, use base diameter 0.5mm height 0.65mm, have and top end diameter
The container of the complementary shape of the cone shape pin of 0.04mm, every 1.0mm is spaced each 10 containers of transverse and longitudinal, amounts to formation 100
The mould of individual container.The material of above-mentioned mould, also comprises base material and the face contacting with pin, all 100% polysiloxanes
(two-liquid type RTV rubber KE-17: SHIN-ETSU HANTOTAI's polysiloxanes).
Modulation makes the lysigenous fluid composition in water of composition (beyond water) shown in table 4.Then, thermostat is used
Heating mould is to 80 DEG C of (temperature TAAfter), from thermostat, take out mould, this mould is filled rapidly above-mentioned liquid
Composition about 1g.Fluid composition before filling is normal temperature (25 DEG C).
25 DEG C of (temperature TBMould and fluid composition is stood under), after dry liquid composition to constant mass, from
Mould takes out micropin preparation.
[embodiment B2～B27, comparative example B1～B15]
Except according to composition, temperature T of mould changing the fluid composition being packed into mould shown in table 4～8AAnd be dried
When temperature TBIn addition, micropin preparation is manufactured in the same manner as embodiment B1.
[mensuration of medicine transit dose]
Hairless mouse is used to carry out skin permeation test in vitro.Summary is as follows.
Place mouse skin in vertical Franz diffusion cell (Off ラ Application Star セ Le), stick patch.Afterwards, gather 8 hours
After acceptable solution, measured the transit dose of medicine according to following treatment conditions by HPLC.For containing loxoprofen sodium
Embodiment B10～B17 and comparative example B6～B10 and the embodiment B20～B27 containing felbinac and comparative example
B11～B15 implements the mensuration of medicine transit dose.
(treatment conditions)
Mensuration environment: 25 DEG C, 50%RH,
Mouse skin: take out from the back of the public mouse of HR-1 7 week old,
Acceptable solution: phosphate buffer (pH7.4),
Stick area: 5cm2,
Patch: 1 (about 0.5g),
Franz diffusion cell outer sheath temperature: 37 DEG C.
Additionally, according to following benchmark evaluation medicine permeability.
(metewand when medicine is loxoprofen sodium)
◎: medicine transit dose is 200 μ g/cm2Above.
Zero: medicine transit dose is 150 μ g/cm2Above, less than 200 μ g/cm2。
△: medicine transit dose is 100 μ g/cm2Above, less than 150 μ g/cm2。
×: medicine transit dose is less than 100 μ g/cm2。
(metewand when medicine is felbinac)
◎: medicine transit dose is 450 μ g/cm2Above.
Zero: medicine transit dose is 350 μ g/cm2Above, less than 450 μ g/cm2。
△: medicine transit dose is 250 μ g/cm2Above, less than 350 μ g/cm2。
×: medicine transit dose is less than 250 μ g/cm2。
[aciculiform becomes second nature]
(Keyemce (キ エ Application ス) is made: VHX-1000), observes micropin preparation, and confirmation defines several to use microscope
Root, corresponding to the pin of 100 containers of mould, becomes second nature according to following benchmark evaluation aciculiform.
(metewand)
The formation radical of ◎: pin is more than 95.
Zero: the formation radical of pin is more than 90, less than 95.
The formation radical of △: pin is more than 80, less than 90.
×: the formation radical of pin is less than 80.
Manufacturing condition and the evaluation result of embodiment B1～B27 and comparative example B1～B15 is shown in table 4～8.
In addition, " the dried amount of composition " in table 4～8 represents the fluid composition just filled before being dried in a mold
Quality when being 100, the mass ratio of dried composition.
[table 4]
[table 5]
[table 6]
[table 7]
[table 8]
As shown in table 4～8, in using the embodiment B1～B27 of manufacture method of the present invention, define more than 90
Pin, the formation of pin is stable.Further, the micropin preparation of embodiment B10～B17, B20～B27, medicine permeability is excellent.
On the other hand, temperature T at mouldAAnd temperature T when being driedBIt is unsatisfactory for formula (1) and the condition of formula (2)
In the comparative example of any one B1～B15 in, the radical of the pin of formation is less than 90, and the formation of pin is unstable.Further,
The micropin preparation of comparative example B6～B15, medicine permeability difference.
Claims (11)
1. a micropin preparation, it possesses the sticking part with many prominent pins of base material and the single side face from this base material, described
While sticking part dissolves, the composition that wherein comprises is absorbed transdermally, and in described sticking part, contains (A) composition: selected from by
More than one in the group that hyaluronic acid and hyaluronate are constituted, and (B) composition: glycerine, wherein, described
(A) composition is 1～5 relative to the mass ratio A/B of described (B) composition.
2. micropin preparation as claimed in claim 1, wherein, in described sticking part, contains (C) composition physiology further and lives
Property composition, but, described (C) composition be in addition to described (A) composition beyond material.
3. micropin preparation as claimed in claim 1 or 2, wherein, described (A) composition, comprise to become selected from by (A-1)
Point and (A-2) composition constitute group in more than one,
Described (A-1) composition is selected from by the hyaluronic acid of matter average molecular weight more than 50,000 and matter average molecular weight 50,000
More than one in the group that above hyaluronate is constituted,
Described (A-2) composition selected from by the hyaluronic acid less than 50,000 for the matter average molecular weight and matter average molecular weight less than 50,000
Hyaluronate constitute group in more than one.
4. micropin preparation as claimed in claim 2, wherein, described (C) composition, is non-steroid anti-inflammatory drug.
5. micropin preparation as claimed in claim 1 or 2, wherein, described (A) in described sticking part 100 mass % becomes
The content dividing is 20～75 mass %.
6. micropin preparation as claimed in claim 3, wherein, described (A-2) composition is relative to described (A-1) composition
Mass ratio (A-2)/(A-1) is 0～1.75.
7. a manufacture method for micropin preparation, is the base material possessing and having sheet, and the single side face from this base material is prominent many
The manufacture method of the micropin preparation of the sticking part of root pin, it is characterised in that the liquid that formulation dissolution is formed in water-soluble solvent
Body composition, is filled in temperature TAMeet in the mould of following formula (1) condition, in temperature TBMeet following formula (2)
The environment of condition makes it be dried and forms described sticking part,
50(℃)≦TA···(1)
TB＜ TA···(2)。
8. the manufacture method of micropin preparation as claimed in claim 7, wherein, in the mold with described fluid composition
The material on the surface of contact is polysiloxanes.
9. the manufacture method of micropin preparation as claimed in claim 7, wherein, described preparation, comprise composition (X) selected from by
At least one in the group that water soluble polymer and carbohydrate are constituted.
10. the manufacture method of the micropin preparation as described in claim 7 or 9, wherein, water-soluble solvent in described sticking part
Content be below 35 mass %.
The manufacture method of the 11. micropin preparations as described in claim 7 or 9, wherein, it is raw that described preparation comprises composition (Y)
Reason active component.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2015-056033 | 2015-03-19 | ||
| JP2015-056111 | 2015-03-19 | ||
| JP2015056111A JP6369992B2 (en) | 2015-03-19 | 2015-03-19 | Dissolving microneedle formulation |
| JP2015056033A JP6369991B2 (en) | 2015-03-19 | 2015-03-19 | Method for producing microneedle preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105982842A true CN105982842A (en) | 2016-10-05 |
| CN105982842B CN105982842B (en) | 2021-05-28 |
Family
ID=57044219
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610158044.6A Active CN105982842B (en) | 2015-03-19 | 2016-03-18 | Microneedle preparation and method for producing microneedle preparation |
Country Status (2)
| Country | Link |
|---|---|
| KR (1) | KR102497984B1 (en) |
| CN (1) | CN105982842B (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN110505896A (en) * | 2017-05-22 | 2019-11-26 | 考司美德制药株式会社 | Water solubility makeup patch supporter |
| 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 |
| CN112957607A (en) * | 2021-01-30 | 2021-06-15 | 上海应用技术大学 | Microneedle transdermal patch and preparation method thereof |
| TWI820135B (en) * | 2018-05-23 | 2023-11-01 | 日商富士軟片股份有限公司 | Microneedle array containing Japanese encephalitis vaccine |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR102033686B1 (en) | 2017-05-19 | 2019-10-18 | 보령제약 주식회사 | Microneedle transdermal patch comprising donepezil |
| 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 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102770176A (en) * | 2010-02-24 | 2012-11-07 | 久光制药株式会社 | Micro-needle device and preparation method |
| CN104095761A (en) * | 2013-04-08 | 2014-10-15 | 上海汇林医药科技有限公司 | Polymer microneedle patch and application thereof |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP5267910B2 (en) | 2008-02-28 | 2013-08-21 | コスメディ製薬株式会社 | Microneedle array |
| KR101386442B1 (en) * | 2010-04-01 | 2014-04-18 | 주식회사 라파스 | Process for Preparing Solid Microstructures by Blowing and Solid Microstructures Prepared by the Same |
| JP2013162982A (en) | 2012-02-13 | 2013-08-22 | Fujifilm Corp | Method of manufacturing microneedle sheet |
| WO2013122160A1 (en) | 2012-02-17 | 2013-08-22 | コスメディ製薬株式会社 | Microneedle of short-time dissolution type |
-
2016
- 2016-03-14 KR KR1020160030327A patent/KR102497984B1/en active IP Right Grant
- 2016-03-18 CN CN201610158044.6A patent/CN105982842B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102770176A (en) * | 2010-02-24 | 2012-11-07 | 久光制药株式会社 | Micro-needle device and preparation method |
| CN104095761A (en) * | 2013-04-08 | 2014-10-15 | 上海汇林医药科技有限公司 | Polymer microneedle patch and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| HARVINDER S. GILL等: "Coating Formulations for Microneedles", 《PHARMACEUTICAL RESEARCH》 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110505896A (en) * | 2017-05-22 | 2019-11-26 | 考司美德制药株式会社 | Water solubility makeup patch supporter |
| 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 |
| TWI820135B (en) * | 2018-05-23 | 2023-11-01 | 日商富士軟片股份有限公司 | Microneedle array containing Japanese encephalitis vaccine |
| 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 |
| CN112957607A (en) * | 2021-01-30 | 2021-06-15 | 上海应用技术大学 | Microneedle transdermal patch and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20160112975A (en) | 2016-09-28 |
| CN105982842B (en) | 2021-05-28 |
| KR102497984B1 (en) | 2023-02-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105982842A (en) | Microneedle preparation and method for producing the microneedle preparation | |
| JP6894455B2 (en) | Microarrays, usage and manufacturing methods for delivery of therapeutic agents | |
| CN102770176B (en) | Microneedle devices and manufacture method thereof | |
| US8911422B2 (en) | Micro-needle device | |
| KR101747099B1 (en) | Method of Preparing Micro-Needle Using Biocompatible Polymer | |
| JP6323975B2 (en) | Manufacturing method of needle-shaped body | |
| Pettis et al. | Microneedle delivery: clinical studies and emerging medical applications | |
| Kang et al. | Microneedles for drug delivery: recent advances in materials and geometry for preclinical and clinical studies | |
| JP2016512754A5 (en) | ||
| KR20150100807A (en) | Microarray for delivery of therapeutic agent and methods of use | |
| US20120101457A1 (en) | Needle device | |
| JP2010082401A (en) | Microneedle array | |
| JP6020771B2 (en) | Transdermal administration device and method for producing transdermal administration device | |
| TW201309331A (en) | Biologically active nonaqueous composition for microneedle devices, and biologically active nonaqueous composition adhering to microneedle | |
| Yuzhakov | The AdminPen™ microneedle device for painless & convenient drug delivery | |
| JP5928661B2 (en) | Acicular body | |
| JP2013032324A (en) | Rapid-acting microneedle array patch preparation including local anesthetic | |
| TW201828920A (en) | Microneedle device | |
| Liu et al. | Fabrication of rapidly separable microneedles for transdermal delivery of metformin on diabetic rats | |
| CN108367142A (en) | Microneedle sheet | |
| JP2023528622A (en) | Heat-resistant embedded polymer microneedle, its fabrication method and use | |
| Alshammari et al. | An update on microneedle in insulin delivery: quality attributes, clinical status and challenges for clinical translation | |
| Li et al. | Multifunctional Microneedle Patches via Direct Ink Drawing of Nanocomposite Inks for Personalized Transdermal Drug Delivery | |
| JP2017023511A (en) | Stylet | |
| JP2014151122A (en) | Coating, and microneedle device |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |