WO2011105508A1 - マイクロニードルデバイス及びその製造方法 - Google Patents
マイクロニードルデバイス及びその製造方法 Download PDFInfo
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- WO2011105508A1 WO2011105508A1 PCT/JP2011/054177 JP2011054177W WO2011105508A1 WO 2011105508 A1 WO2011105508 A1 WO 2011105508A1 JP 2011054177 W JP2011054177 W JP 2011054177W WO 2011105508 A1 WO2011105508 A1 WO 2011105508A1
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- microneedle
- physiologically active
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- bioactive
- bioactive composition
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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
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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
-
- 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
-
- 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
- A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
- A61M5/14—Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
- A61M5/158—Needles for infusions; Accessories therefor, e.g. for inserting infusion needles, or for holding them on the body
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
- B05D—PROCESSES FOR APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
- B05D5/00—Processes for applying liquids or other fluent materials to surfaces to obtain special surface effects, finishes or structures
-
- 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
- A61M2037/0023—Drug applicators using 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
- A61M2037/0046—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
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the present invention relates to a microneedle device and a manufacturing method thereof.
- a microneedle device is known as a device for improving transdermal absorption of a drug.
- Microneedles provided in a microneedle device are intended to puncture the stratum corneum, which is the outermost layer of the skin, and various sizes and shapes have been proposed, and are expected as non-invasive administration methods (for example, patents) Reference 1).
- various methods have been proposed for applying drugs when using a microneedle device.
- a microneedle device it is known to coat the surface of the microneedle with a drug, to provide a groove or a hollow part for allowing the drug or a biological component to permeate the microneedle, and to mix the drug with the microneedle itself.
- the substance to be mixed together when coating the drug preferably contains a saccharide, and in particular, a stabilizing saccharide such as lactose, raffinose, trehalose or sucrose that forms glass (amorphous solid substance).
- a stabilizing saccharide such as lactose, raffinose, trehalose or sucrose that forms glass.
- Patent Document 3 discloses a device and method for transdermal delivery of a biologically active agent, including a delivery system having a microprojection member.
- the biocompatible coating formulation applied to the microprojection member is at least one non-aqueous solvent such as ethanol, isopropanol, methanol, propanol, butanol, propylene glycol, dimethyl sulfoxide, glycerin, N , N-dimethylformamide, and polyethylene glycol 400, preferably the non-aqueous solvent is disclosed in the coating formulation in a range of about 1% to 50% by weight of the coating formulation. ing. It is also disclosed that the viscosity of the coating formulation is from 3 to about 500 centipoise (cps).
- the bioactive composition is used as a solvent.
- the manufacturing method of adhering onto the microneedles after being accommodated in a container where volatilization may occur is employed, there may be a problem when the bioactive composition is adhered onto a large number of microneedle arrays (on the microneedles). found. That is, when trying to manufacture a microneedle device continuously by such a method, the amount of the bioactive composition applied on the microneedle greatly varies, and a microneedle device with a stable application amount is manufactured. It turns out that the problem of not being able to occur. Changing the amount of drug depending on the individual microneedle device being manufactured is undesirable both medically (therapeutically) and economically, especially when using highly active or expensive bioactive substances. .
- the object of the present invention is to reduce the variation in the amount of the physiologically active substance adhered to the microneedles to a practically sufficient level even when the above continuous production method using a mask plate is employed. It is providing the manufacturing method of a microneedle device. Another object of the present invention is to provide a microneedle device that can be obtained by such a manufacturing method.
- the present invention relates to a method for producing a microneedle device in which a bioactive composition containing a bioactive substance and a solvent capable of dispersing or dissolving the bioactive substance is attached to the microneedle,
- a production method in which at least one polyhydric alcohol selected from glycerin, ethylene glycol, propylene glycol and 1,3-butylene glycol is used as the solvent, and water is not used.
- the change in viscosity of the bioactive composition with time during production is small and uniform on the microneedle.
- a microneedle device to which a physiologically active composition containing a small amount of a physiologically active substance is attached can be stably obtained. It can be considered that the microneedle device in which the amount of the physiologically active substance adhered is obtained by such a production method is largely due to the fact that water is not contained in the solvent.
- Stabilization of the amount of bioactive substance attached is that the container is a mask plate having an opening formed therein, and the microneedle is inserted into the opening after the opening is filled with the bioactive composition.
- the manufacturing method for attaching the physiologically active composition on the microneedles is applied, it becomes particularly remarkable.
- a physiologically active composition containing a physiologically active substance and a solvent capable of dispersing or dissolving the physiologically active substance is contained in a liquid reservoir having an open top.
- a method of applying a pump or the like and moving it to the periphery of the microneedle, for example, and applying it by spraying can be used.
- the mass ratio of the bioactive substance and the polyhydric alcohol is preferably 20:80 to 80:20, and the bioactive composition at room temperature (25 ° C.) has a viscosity of 600 to 45000 cps. Preferably there is.
- a physiologically active composition containing a physiologically active substance and a solvent capable of dispersing or dissolving the physiologically active substance is placed in a container that can cause volatilization of the solvent, and then deposited on the microneedle.
- at least one polyhydric alcohol selected from glycerin, ethylene glycol, propylene glycol and 1,3-butylene glycol is used as the solvent, and water is not used. It can also be grasped as a method for stabilizing the adhesion amount of the composition.
- a microneedle device comprising a substrate, a microneedle provided on the substrate, and a bioactive composition attached to the microneedle and / or the substrate.
- the bioactive composition includes a microbe containing at least one polyhydric alcohol selected from glycerin, ethylene glycol, propylene glycol and 1,3-butylene glycol, and a bioactive substance, and does not substantially contain water.
- a needle device is provided.
- substantially not containing water means that the bioactive composition is contained by moisture absorption from the atmosphere after the attachment. This means that the water content does not exceed the water content, and typically the water content is 7% by mass or less, preferably 5% by mass or less, based on the total amount of the bioactive composition adhered thereto, 3% by mass or less.
- the bioactive composition attached to the microneedle and / or the substrate is selected from hydroxypropylcellulose, polyethylene glycol, chondroitin sulfate, hyaluronic acid, dextran, croscarmellose sodium and magnesium chloride. It is preferable to further contain at least one compound.
- the microneedle device When the microneedle device has such a configuration, the viscosity of the bioactive composition is improved, and the height of the bioactive composition adhering to the microneedle and / or the substrate and the content of the bioactive substance can be adjusted. It can be controlled to a higher degree.
- the bioactive composition adhering to the microneedles and / or the substrate is dried and fixed after being applied onto the microneedles and / or the substrate.
- a method for manufacturing a microneedle device in which variation in the amount of physiologically active substance to be attached to the microneedle is reduced to a practically sufficient level is provided.
- FIG. 2 is a sectional view taken along line II-II in FIG. (A)-(c) is a figure which shows an example of the manufacturing method of a microneedle device. It is a graph which shows a time-dependent change of the content of the bioactive substance in the bioactive composition adhering on the microneedle at the time of manufacturing the microneedle device by repeating the filling and attachment process of the bioactive composition. It is a graph which shows the time-dependent change of the blood lixenatide density
- 3 is a graph showing changes over time in blood ⁇ -interferon concentration when ⁇ -interferon is administered by administration with a microneedle device and subcutaneous administration.
- FIG. 1 is a perspective view showing an embodiment of a microneedle device according to the present invention.
- the microneedle device 1 includes a microneedle substrate 2 and a plurality of microneedles 3 arranged two-dimensionally on the microneedle substrate 2.
- the microneedle substrate 2 is a base for supporting the microneedles 3.
- the form of the microneedle substrate 2 is not particularly limited.
- the microneedle substrate 2 may be formed so that a plurality of through holes 4 are two-dimensionally arranged.
- the microneedles 3 and the through holes 4 are alternately arranged in the diagonal direction of the microneedle substrate 2.
- the through-hole 4 it becomes possible to administer the physiologically active composition from the back surface of the microneedle substrate 2. But you may use the board
- the area of the microneedle substrate 2 is 0.5 to 10 cm 2 , preferably 1 to 5 cm 2 , more preferably 1 to 3 cm 2 .
- a plurality of microneedle substrates 2 may be connected to form a substrate having a desired size.
- the microneedle 3 has a fine structure, and its height (length) is preferably 50 to 600 ⁇ m.
- the length of the microneedle 3 is set to 50 ⁇ m or more in order to ensure the transdermal administration of the physiologically active substance, and the length of 600 ⁇ m or less avoids the microneedle from contacting the nerve. This is to reduce the possibility of pain and to avoid the possibility of bleeding.
- the length of the microneedle 3 is 500 ⁇ m or less, an amount of a physiologically active substance that should enter the skin can be efficiently administered, and in some cases, it can be administered without perforating the skin. is there.
- the length of the microneedle 3 is particularly preferably 300 to 500 ⁇ m.
- the microneedle means a convex structure and a needle shape in a broad sense or a structure including a needle shape.
- the microneedle is not limited to a needle shape having a sharp tip, and includes a shape having a sharp tip.
- the diameter at the base is about 50 to 200 ⁇ m.
- the microneedle 3 has a conical shape, but a polygonal pyramid such as a quadrangular pyramid or a microneedle having another shape may be used.
- the microneedles 3 are typically spaced apart to provide a density of about 1 to 10 per millimeter (mm) for a row of needles. In general, adjacent rows are separated from each other by a substantially equal distance with respect to the space of the needles in the row and have a density of 100-10000 needles per cm 2 . When there is a needle density of 100 or more, the skin can be efficiently perforated. On the other hand, when the needle density exceeds 10,000, it is difficult to maintain the strength of the microneedles 3.
- the density of the microneedles 3 is preferably 200 to 5000, more preferably 300 to 2000, and most preferably 400 to 850.
- Examples of the material of the microneedle substrate 2 or the microneedle 3 include silicon, silicon dioxide, ceramic, metal (stainless steel, titanium, nickel, molybdenum, chromium, cobalt, etc.) and synthetic or natural resin materials.
- biodegradable polymers such as polylactic acid, polyglycolide, polylactic acid-co-polyglycolide, pullulan, capronolactone, polyurethane, polyanhydride, polycarbonate which is a non-degradable polymer, Synthetic or natural resin materials such as polymethacrylic acid, ethylene vinyl acetate, polytetrafluoroethylene, and polyoxymethylene are particularly preferred.
- polysaccharides such as hyaluronic acid, sodium hyaluronate, pullulan, dextran, dextrin or chondroitin sulfate.
- Microneedle substrate 2 or microneedle 3 can be produced by wet etching or dry etching using a silicon substrate, precision machining using metal or resin (electric discharge machining, laser machining, dicing machining, hot embossing, injection, etc. Molding processing, etc.), machine cutting, and the like.
- the needle portion and the support portion are integrally molded.
- Examples of the method for hollowing the needle part include a method of performing secondary processing by laser processing or the like after the needle part is manufactured.
- FIGS. 3A to 3C are diagrams showing an example of a manufacturing method of the microneedle device 1.
- the physiologically active composition 10 is swept in the direction of arrow A with a spatula 12 on a mask plate 11.
- the opening 13 is filled with the physiologically active composition.
- the microneedle 3 is inserted into the opening 13 of the mask plate 11.
- the microneedle 3 is pulled out from the opening 13 of the mask plate 11.
- the bioactive composition 10 is adhered (in this case, applied) to the microneedle 3.
- the bioactive composition on the microneedles is dried by a known method of air drying, vacuum drying, freeze drying, or a combination thereof.
- the solid bioactive composition 10 is fixed to the microneedle 3 as the bioactive composition 5 attached on the microneedle 3.
- the microneedle device is manufactured. “Fixed” refers to maintaining a state in which the physiologically active composition adheres almost uniformly to the object.
- the height H of the bioactive composition adhering on the microneedle 3 is adjusted by a clearance (gap) C shown in FIG.
- This clearance C is defined by the distance from the base of the microneedle to the mask surface (the substrate thickness is not involved), and is set according to the tension of the mask plate 11 and the length of the microneedle 3.
- the distance range of the clearance C is preferably 0 to 500 ⁇ m. When the distance of the clearance C is 0, it means that the bioactive composition is attached to the entire microneedle 3.
- the height H of the bioactive composition 5 adhering to the microneedles 3 varies depending on the height h of the microneedles 3, but can be 0 to 500 ⁇ m, usually 10 to 500 ⁇ m, and preferably 30 About 300 ⁇ m.
- the thickness of the physiologically active composition 5 adhered on the microneedle 3 is less than 50 ⁇ m, preferably less than 40 ⁇ m, more preferably 1 to 30 ⁇ m.
- the thickness of the bioactive composition attached on the microneedle 3 is an average thickness measured over the surface of the microneedle 3 after drying.
- the thickness of the bioactive composition attached on the microneedle 3 is generally increased by applying a plurality of coatings of the bioactive composition, that is, the bioactive composition is attached on the microneedle 3. It can be increased by repeating the process.
- the temperature and humidity of the installation environment of the apparatus are controlled to be constant.
- the component (B) described later which is used in the physiologically active composition as necessary, is “at least one polyhydric alcohol selected from the group consisting of glycerin, ethylene glycol, propylene glycol and 1,3-butylene glycol. It can also be filled with a “solvent consisting of”. Thereby, the evaporation of the solvent in the physiologically active composition can be prevented as much as possible.
- the bioactive composition comprises (A) a “bioactive substance” and (B) a solvent comprising at least one polyhydric alcohol selected from the group consisting of “glycerin, ethylene glycol, propylene glycol, and 1,3-butylene glycol”. And containing.
- the physiologically active composition contains substantially no water.
- “substantially not containing water” means that the bioactive composition does not contain water exceeding the water content that would be contained by moisture absorption from the atmosphere. Specifically, the water content is 20% by mass or less, preferably 10% by mass or less, and further 5% by mass or less based on the total amount of the physiologically active composition.
- the component (B) is preferably “a solvent comprising only at least one polyhydric alcohol selected from the group consisting of glycerin, ethylene glycol, propylene glycol and 1,3-butylene glycol”.
- Biologically active substances are those that have some effect on the living body, and include low molecular compounds, peptides, proteins, derivatives thereof, and the like.
- the “solvent” is a compound capable of dispersing or dissolving the physiologically active substance.
- the physiologically active substance (drug) may be a high molecular compound such as peptide, protein, DNA, RNA or the like, but is not particularly limited. If the molecular weight is about 1000, vaccine, low molecular peptide, sugar, nucleic acid Etc.
- physiologically active substance examples include lixenatide, naltrexone, cetrorelix acetate, tartilelin, nafarelin acetate, prostaglandin A1, alprostadil, ⁇ -interferon, ⁇ -interferon for multiple sclerosis, erythropoietin, folliculin Tropine ⁇ , follitropin ⁇ , G-CSF, GM-CSF, human chorionic gonadotropin, luteinizing hormone, salmon calcitonin, glucagon, GNRH antagonist, insulin, human growth hormone, filgrastin, heparin, small molecule Examples include heparin, somatropin, incretin, and GLP-1 derivatives.
- vaccines include Japanese encephalitis vaccine, rotavirus vaccine, Alzheimer's disease vaccine, arteriosclerosis vaccine, cancer vaccine, nicotine vaccine, diphtheria vaccine, tetanus vaccine, pertussis vaccine, Lyme disease vaccine, rabies vaccine, pneumococcus pneumoniae Vaccines, yellow fever vaccines, cholera vaccines, seed urticaria vaccines, tuberculosis vaccines, rubella vaccines, measles vaccines, mumps vaccines, botulinum vaccines, herpes virus vaccines, other DNA vaccines, hepatitis B vaccines and the like.
- hypnotic / sedative flurazepam hydrochloride, rilmazaphone hydrochloride, phenobarbital, amobarbital, etc.
- antipyretic analgesics butorphanol tartrate, perisoxal citrate, acetaminophen, mefenamic acid, diclofenac sodium, aspirin, alclofenac, ketoprofen , Flurbiprofen, naproxen, piroxicam, pentazocine, indomethacin, glycol salicylate, aminopyrine, loxoprofen, etc.), steroidal anti-inflammatory agents (hydrocortisone, prednisolone, dexamethasone, betamethasone, etc.), stimulants / stimulants (methamphetamine hydrochloride, methylphenidate hydrochloride) Etc.), neuropsychiatric agents (imiplan, hydrochloride, diazepam, sertraline
- the content of the (A) physiologically active substance in the physiologically active composition is 0.1 to 80% by mass, preferably 1 to 70% by mass, particularly preferably 5 to 60% by mass.
- a solvent composed of at least one polyhydric alcohol selected from the group consisting of glycerin, ethylene glycol, propylene glycol, and 1,3-butylene glycol has a high boiling point and little volatilization in the filling and attaching steps. Even when the microneedle device is continuously manufactured, the change in viscosity of the bioactive composition is small, and the bioactive substance has high solubility or dispersibility. A microneedle device having a uniform content of the active composition can be obtained.
- the blending ratio (A: B) of the component (A) and the component (B) in the physiologically active composition is preferably 20:80 to 80:20, more preferably 40:60 to 80:20, based on mass. Most preferably, it is 50:50 to 70:30.
- the bioactive composition comprises (A) a “bioactive substance”, and (B) a solvent comprising at least one polyhydric alcohol selected from the group consisting of glycerin, ethylene glycol, propylene glycol and 1,3-butylene glycol.
- a compound such as a polymer compound or metal chloride may be included.
- the physiologically active composition contains a compound such as the polymer compound or metal chloride, the viscosity of the physiologically active composition can be improved.
- the drug has a large molecular weight and high solubility in a solvent, the drug itself may function as a thickener.
- a polymer compound or metal chloride different from the physiologically active substance is further added to the physiologically active composition to improve the viscosity of the physiologically active composition.
- the polymer compound include polyethylene oxide, polyhydroxymethylcellulose, hydroxypropylcellulose, polyhydroxypropylmethylcellulose, polymethylcellulose, dextran, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, pullulan, carmellose sodium, chondroitin sulfate, and hyaluronic acid. Dextran, gum arabic and the like.
- the polymer compound is preferably hydroxypropylcellulose, polyethylene glycol, chondroitin sulfate, hyaluronic acid, dextran or croscarmellose sodium.
- the polymer compound when propylene glycol is used as a solvent for a physiologically active composition, is preferably hydroxypropyl cellulose, polyethylene glycol, chondroitin sulfate or hyaluronic acid, and when glycerin is used as a solvent,
- the molecular compound is preferably dextran, croscarmellose sodium or chondroitin sulfate.
- metal chlorides include sodium chloride, potassium chloride, magnesium chloride, potassium chloride, aluminum chloride, and zinc chloride.
- the metal chloride is preferably magnesium chloride.
- the bioactive composition contains the metal chloride, it is possible to suppress a decrease in the content of the drug on the microneedle and / or the substrate when the microneedle device is stored for a long time.
- the metal chloride is preferably magnesium chloride. Therefore, when propylene glycol is used as the solvent for the bioactive composition, the bioactive composition attached on the microneedles is selected from hydroxypropylcellulose, polyethylene glycol, chondroitin sulfate, hyaluronic acid and magnesium chloride. It is preferable to contain at least one compound.
- the bioactive composition attached to the microneedles is at least one selected from dextran, croscarmellose sodium, chondroitin sulfate, and magnesium chloride. It is preferable that the compound is included.
- the physiologically active composition includes, as necessary, a solubilizing agent or absorption promoter, such as propylene carbonate, crotamiton, l-menthol, mint oil, limonene, diisopropyl adipate, and the like, as a medicinal aid, methyl salicylate, Salicylic acid glycol, l-menthol, thymol, mint oil, nonylic acid vanillylamide, pepper extract, etc. may be added.
- a solubilizing agent or absorption promoter such as propylene carbonate, crotamiton, l-menthol, mint oil, limonene, diisopropyl adipate, and the like
- a solubilizing agent or absorption promoter such as propylene carbonate, crotamiton, l-menthol, mint oil, limonene, diisopropyl adipate, and the like
- methyl salicylate Salicylic acid glycol, l-ment
- the surfactant may be any of a nonionic active agent and an ionic active agent (cation, anion, amphoteric). From the viewpoint of safety, a nonionic active agent usually used for a pharmaceutical base is used. desirable.
- sugar alcohol fatty acid esters such as sucrose fatty acid ester, sorbitan fatty acid ester, glycerin fatty acid ester, polyglycerin fatty acid ester, propylene glycol fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene glycerin fatty acid ester, polyethylene glycol fatty acid Examples thereof include esters, polyoxyethylene castor oil, and polyoxyethylene hydrogenated castor oil.
- Physiologically active composition needs to have a certain degree of viscosity so as not to drip. Specifically, it needs a viscosity of about 100 to 100,000 cps at room temperature (25 ° C.). A more preferable viscosity of the bioactive composition is 100 to 60000 cps, and the viscosity in this range allows a desired amount of the bioactive composition to be attached at a time without depending on the material of the microneedle 3. It becomes possible. In general, the higher the viscosity, the more the amount of the bioactive composition to be attached tends to increase. When the viscosity is less than 600 cps, it becomes difficult to attach the minimum physiologically active substance to the microneedle 3. .
- the bioactive substance content in the bioactive composition 5 adhering to the microneedles starts to decrease. From these characteristics, when the viscosity of the bioactive composition is 45000 cps or more, the content of the bioactive substance in the attached bioactive composition 5 according to the amount of the bioactive substance used cannot be expected.
- the viscosity of the physiologically active composition is particularly preferably 600 to 45000 cps because it is not economically preferable.
- FIG. 2 is a sectional view taken along line II-II in FIG.
- the microneedle device 1 of the present invention includes a microneedle substrate 2, a microneedle 3 provided on the microneedle substrate 2, the microneedle 3 and / or the substrate. And a bioactive composition 5 attached thereto.
- the attached physiologically active composition 5 is at least one selected from the group consisting of (A) “physiologically active substance” and (B) “glycerin, ethylene glycol, propylene glycol and 1,3-butylene glycol”. For example, and is manufactured through the steps shown in FIGS. 3 (a) to 3 (c).
- the bioactive composition immediately after production of the microneedle device is at least one polyvalent selected from the group consisting of the above-mentioned “glycerin, ethylene glycol, propylene glycol, and 1,3-butylene glycol contained in the bioactive composition.
- glycerin ethylene glycol, propylene glycol, and 1,3-butylene glycol contained in the bioactive composition.
- a solvent such as moisture may be retained depending on the surrounding atmosphere.
- the water content in this case is as described above.
- Example 2 The composition of a physiologically active composition comprising a model physiologically active substance (octreotide acetate) and propylene glycol or glycene, the viscosity, and the physiologically active substance content in the physiologically active composition adhering to the microneedles ⁇ Setting conditions>
- Microneedle material polylactic acid, height: 500 ⁇ m, density: 625 / cm 2 , preparation area of microneedle substrate: 1 cm 2 / patch
- B Metal mask plate, pitch: 400 ⁇ m, mask thickness: 100 ⁇ m, opening: square shape (side 250 ⁇ m)
- C Environmental setting: Room temperature (25 ° C)
- ⁇ Viscosity measurement> As shown in Tables 3 and 4, octreotide acetate concentration and propylene glycol or glycerin concentration were set to prepare a physiologically active composition. The viscosity of the obtained bioactive composition was measured 10 times with a micro sample viscometer (RHEOSENSE INC. Micron Sample-Viscometer / Rheometer-on-a-chip VLOCTM), and the calculated average values are shown in Table 2 and Table 3. It was.
- the bioactive composition on the attached microneedle is extracted with purified water, and the microneedle device 1 patch (octreotide standard) is extracted by the BCA method (octreotide standard).
- the octreotide acetate content (adhesion amount) per sheet was measured 10 times, and the calculated average values are shown in Tables 3 and 4.
- the viscosity of the bioactive composition increases with the increase in the content of octreotide acetate in the bioactive composition, but in the bioactive composition 5 attached on the microneedles It has been found that the octreotide acetate content increases with increasing viscosity up to a certain viscosity, but then starts decreasing after exceeding a certain viscosity.
- the octreotide acetate content started to decrease from 21000 cps to 27000 cps, so the optimum viscosity is 2000 cps to 25000 cps, and a viscosity higher than this is not preferable from the viewpoint of administration efficiency.
- Example 3 Test for measuring change in content of bioactive substance in bioactive composition adhering to microneedle when manufacturing process of microneedle device is repeatedly performed
- a PP polypropylene
- human plasma 40 parts by mass of albumin (HSA) and 60 parts by mass of glycerin were added and dissolved to obtain a physiologically active composition having a non-aqueous formulation.
- a bioactive composition of an aqueous prescription used as a control a mixed solution of 40 parts by mass of human plasma albumin (HSA), 30 parts by mass of glycerin and 30 parts by mass of water was prepared and dissolved to obtain a bioactive composition.
- Example 2 In order to produce a plurality of microneedle devices, the steps of filling and attaching these bioactive compositions were repeated under the same conditions as in Example 2. Immediately after the start of the attachment step, the content of human plasma albumin (HSA) in the bioactive composition attached on the microneedle of the microneedle device obtained after 20 minutes, 40 minutes, and 60 minutes was Measurement was performed in the same manner as in Example 2. The obtained measurement results are shown as a graph in FIG.
- HSA human plasma albumin
- the viscosity was stable over time, and there was almost no variation in the content of the physiologically active substance in the physiologically active composition adhering to the microneedles.
- the water-based formulation an increase in viscosity with the evaporation of water over time was confirmed, and the content of the physiologically active substance in the physiologically active composition tended to decrease significantly with the passage of time.
- Example 4 Viscosity imparting test to physiologically active composition in non-aqueous formulation
- Polymer compounds shown in Tables 5 and 6 were added to propylene glycol and glycerin solvents, respectively, to prepare mixed solutions.
- the concentration of the polymer compound is set in consideration of the molecular weight and the like.
- the prepared mixed solution was stirred with a stirrer (1500 rpm, 12 hours, 25 ° C.), and the solubility of the polymer compound was visually evaluated according to the following criteria.
- the viscosity of the liquid mixture or solution after stirring was measured at 25 ° C. using a micro sample viscometer.
- the evaluation results of viscosity and solubility are shown in Tables 5 and 6. a: completely dissolved b: partially dissolved c: not dissolved
- the measurement result of the viscosity and solubility in the example which added Dx40 and Dx70 by using glycerol as a solvent was obtained by setting the temperature at the time of stirring to 80 ° C.
- PEG4000 in the table is a polyethylene glycol having a weight average molecular weight of 4,000
- Dx40 and Dx70 are dextrans having a weight average molecular weight of about 40,000 and about 70,000, respectively.
- PVA117, PVA220, and PVA617 are all weights.
- HPC-H, HPC-M and HPC-L have weight average molecular weights of 250,000 to 400,000, 110,000 to 150,000, and 55,000, respectively.
- ⁇ 70,000 hydroxypropylcellulose, HA is hyaluronic acid.
- hydroxypropylcellulose has high solubility in propylene glycol, and the viscosity of the solution is greatly improved as compared to before addition of hydroxypropylcellulose.
- HPC-H is expected to have a viscosity improving effect even with a small addition amount (low concentration).
- HPC-H is considered the most suitable thickener for propylene glycol.
- dextran was highly soluble in glycerin, and the viscosity of the solution was greatly improved as compared to before dextran was added. Further, there was a tendency that the viscosity of the solution was improved by increasing the molecular weight of dextran or increasing the concentration of dextran. Although croscarmellose sodium (Na) and chondroitin sulfate were not completely dissolved in glycerin, an effect of improving the viscosity of the solution or the mixed solution was observed.
- Viscosity imparting test to physiologically active composition in non-aqueous formulation (Example 5) 7.3 parts by mass of propylene glycol, 0.7 parts by mass of sodium hydroxide and 2.0 parts by mass of magnesium chloride were stirred and mixed with a stirrer. Further, the obtained mixed solution and octreotide acetate were mixed at a mass ratio of 1: 1 to obtain a bioactive composition (50.0% by mass octreotide acetate / 3.5% by mass sodium hydroxide / 10.0% by mass magnesium chloride / 36.5 mass% propylene glycol) was obtained. Sodium hydroxide was added in the same number of moles as the acetic acid portion of octreotide acetate.
- the bioactive composition was applied to the tip of a microneedle similar to that in Example 2, dried, and the height H of the bioactive composition adhering to the microneedle was measured by microscopic observation. Table 7 shows the evaluation results.
- Example 1 A physiologically active composition (50.0% by mass octreotide acetate / 3.5% by mass sodium hydroxide / non-magnesium chloride was added in the same manner as in Example 5 except that the same mass of propylene glycol was added instead. 46.5 mass% propylene glycol) was obtained.
- the bioactive composition was applied onto the microneedles in the same manner as in Example 5, and the height H of the bioactive composition adhering to the microneedles was measured. Table 7 shows the evaluation results.
- Example 6 8.434 parts by mass of glycerin, 0.233 parts by mass of sodium hydroxide and 1.333 parts by mass of magnesium chloride were mixed with stirring with a stirrer. Further, the obtained mixed solution and LHRH (Luteinizing Hormone Releasing Hormone Acetate) were mixed at a mass ratio of 3: 1 to obtain a bioactive composition (25.0% by mass LHRH / 1.75% by mass sodium hydroxide / 10 0.0 mass% magnesium chloride / 63.25 mass% glycerin). Sodium hydroxide was added in the same number of moles as the acetic acid portion of LHRH. The bioactive composition was applied onto the microneedles in the same manner as in Example 5, and the height H of the bioactive composition adhering to the microneedles was measured. Table 7 shows the evaluation results.
- Example 2 A physiologically active composition (25.0% by mass LHRH / 1.75% by mass sodium hydroxide / 73. 7% by mass) was added in the same manner as in Example 6 except that magnesium chloride was not added and instead the same mass of glycerin was added. 25 mass% glycerin) was obtained.
- the bioactive composition was deposited on the microneedles in the same manner as in Example 5, and the height H of the bioactive composition deposited on the microneedles was measured. Table 7 shows the evaluation results.
- Example 5 and Example 6 by adding magnesium chloride to the bioactive composition, the bioactive composition adhering to the microneedles is controlled to be thin (height H is reduced). We were able to. This is because the viscosity of the physiologically active composition is improved and dripping can be improved.
- Test of stability of drug content of bioactive composition adhering to microneedle (Example 7) 9.444 parts by mass of propylene glycol and 0.556 parts by mass of magnesium chloride were mixed with stirring with a stirrer. Furthermore, the obtained mixed solution and octreotide acetate were mixed at a mass ratio of 9: 1 to obtain a physiologically active composition (10% by mass octreotide acetate / 5.0% by mass magnesium chloride / 85% by mass propylene glycol).
- Example 2 10 mg of the above physiologically active composition was applied to the entire surface of the same microneedle as in Example 2, and dried at 50 ° C. for 30 minutes to obtain a microneedle device. Thereafter, the obtained microneedle device was enclosed in a packing material together with a preservative (Pharmace Keep KD; manufactured by Mitsubishi Gas Chemical), and the enclosed microneedle device was stored under conditions of 60 ° C. for 1 week. Furthermore, another encapsulated microneedle device was stored under conditions of 5 ° C. for 1 week.
- a preservative Pharmace Keep KD
- the content of the physiologically active substance on the microneedle device after storage was measured by high performance liquid chromatography (HPLC). And the residual rate of the bioactive substance on the microneedle preserve
- Example 3 A physiologically active composition (10% by mass octreotide acetate / 90% by mass propylene glycol) was obtained in the same manner as in Example 7 except that magnesium chloride was not added and the same mass of propylene glycol was added instead.
- a microneedle device was obtained in the same manner as in Example 7 using the bioactive composition. The obtained microneedle device was stored in the same manner as in Example 7, and the residual ratio of the physiologically active substance was calculated. Table 8 shows the calculation results.
- Example 8 A microneedle device was obtained in the same manner as in Example 7 except that the type of drug was LHRH, and the residual ratio of the physiologically active substance was calculated. Table 8 shows the calculation results.
- Comparative Example 4 A microneedle device was obtained in the same manner as in Comparative Example 3 except that the type of drug was LHRH, and the residual ratio of the physiologically active substance was calculated. Table 8 shows the calculation results.
- the residual rate of the physiologically active substance could be maintained high by adding magnesium chloride to the physiologically active composition.
- Hairless rat in vivo absorption test of lixenatide (Example 9) Lixenatide and propylene glycol were added to the tube in a mass ratio of 50:50 and mixed with a mixer, and the resulting mixture was used as a physiologically active composition.
- the physiologically active composition was applied to the microneedles using a mask plate having a thickness of 50 ⁇ m. The content of the applied physiologically active substance was 12.2 ⁇ g / patch / head. Using a 0.4J applicator with a coated microneedle array, the physiologically active substance was administered to hairless rats (3 repeats).
- the concentration of lixenatide in the blood was measured using Exendin-4 EIA Kit.
- the measurement results are shown in FIG. Table 9 shows the AUC values (area under the content concentration-time curve) and the BA values (bioavailability) obtained from the graph of FIG.
- the AUC value refers to the area under the blood concentration-time curve in the range from 0 minutes to 720 minutes after administration in the graph of FIG.
- the BA value refers to the relative bioavailability value for subcutaneous administration.
- Example 5 Lixenatide and physiological saline were added to the tube in a mass ratio of 50:50 and mixed with a mixer, and the resulting mixture was used as a physiologically active composition.
- the physiologically active composition was subcutaneously administered to hairless rats under the conditions of 15.1 ⁇ g / 300 ⁇ L / head. Thereafter, the lixenatide concentration in the blood was measured in the same manner as in Example 9. The measurement results are shown in FIG. Table 9 shows the AUC value and BA value.
- Hairless rat in vivo absorption test of ⁇ -interferon (Example 10) ⁇ -interferon and glycerin were added to the tube at a mass ratio of 30:70 and mixed with a mixer, and the resulting mixture was used as a physiologically active composition.
- the bioactive composition was applied to the microneedles using a mask plate having a thickness of 100 ⁇ m.
- the content of the applied physiologically active substance was 10.3 ⁇ g / patch / head.
- the physiologically active substance was administered to hairless rats (3 repeats).
- Example 6 (Comparative Example 6) ⁇ -interferon and physiological saline were added to the tube in a mass ratio of 50:50 and mixed with a mixer, and the resulting mixture was used as a physiologically active composition.
- the physiologically active composition was subcutaneously administered to hairless rats under the conditions of 10 ⁇ g / 300 ⁇ L / head (3 repetitions). Thereafter, the ⁇ -interferon concentration in blood was measured in the same manner as in Example 10. The measurement results are shown in FIG.
- the present invention it becomes possible to obtain a microneedle device in which the content change of the physiologically active substance in the physiologically active composition adhering to the microneedle over time is significantly reduced. It can be remarkably improved, and its industrial applicability is great.
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Abstract
Description
表1に示す各種生理活性物質10質量部とプロピレングリコール又はグリセリン90質量部とを、約1時間混合して、混合液を得た。また表2に示すように生理活性物質OVA(オブアルブミン)43質量部とトリエタノールアミン、ジエタノールアミン、又はマクロゴール400 57質量部とを、上記と同様に混合して、混合液を得た。そして、得られた混合液について、生理活性物質の溶媒に対する溶解性又は分散性の評価を、以下の指標により目視にて行った。評価結果をそれぞれ表1、表2に示す。
a:生理活性物質は溶媒に溶解した(均一な液性)。
b:生理活性物質は溶媒に分散した(分散された液性)。
c:生理活性物質は溶媒に溶解せず、混合液には明らかな凝集物が認められた(不均一な液性)。
<設定条件>
(a)マイクロニードル
・材質:ポリ乳酸、高さ:500μm、密度:625本/cm2、マイクロニードル基板の製剤面積:1cm2/patch
(b)メタルマスク版
・ピッチ:400μm、マスク厚:100μm、開口部:四角形状(一辺250μm)
(c)環境設定:室温(25℃)
表3及び表4に示すとおり、オクトレオチド酢酸塩濃度とプロピレングリコール又はグリセリン濃度を設定し、生理活性組成物を調製した。得られた生理活性組成物の粘度を微量サンプル粘度計(RHEOSENSE INC. Micron Sample-Viscometer/Rheometer-on-a-chip VROCTM)で10回測定し、算出した平均値を表2及び表3に示した。
表3及び表4に示すとおり、オクトレオチド酢酸塩濃度とプロピレングリコール又はグリセリン濃度を設定し、生理活性組成物を調製した。マイクロニードルへの生理活性組成物の付着を、上述の図3(a)~(c)に示す方法で行った。生理活性組成物をヘラにより掃引し、メタルマスク開口部に充填した。充填した開口部にマイクロニードル(針)を挿入させた後引き出すことにより、付着されたマイクロニードル上の生理活性組成物を精製水で抽出し、BCA法(オクトレオチド標準)により、マイクロニードルデバイス1patch(枚)当たりのオクトレオチド酢酸塩含量(付着量)を10回測定し、算出した平均値を表3及び表4に示した。
PP(ポリプロピレン)製マイクロチューブに、ヒト血漿アルブミン(HSA)40質量部、グリセリンを60質量部添加し、溶解したものを非水系処方の生理活性組成物とした。対照となる水系処方の生理活性組成物には、ヒト血漿アルブミン(HSA)40質量部、グリセリン30質量部及び水30質量部の混合液を調製し、溶解したもの生理活性組成物とした。複数のマイクロニードルデバイスの製造を行うため、実施例2と同様の条件でこれらの生理活性組成物の充填、付着の工程を繰り返し行った。上記付着工程の開始直後、20分、40分、及び60分経過後に得られたマイクロニードルデバイスのマイクロニードル上に付着している生理活性組成物中のヒト血漿アルブミン(HSA)の含量を、実施例2と同様に測定した。得られた測定結果をグラフとして図4に示す。
プロピレングリコール及びグリセリンの溶媒に対し、それぞれ表5及び表6に示す高分子化合物を加え、混合液を作製した。高分子化合物の濃度は分子量等を考慮して設定されたものである。作製した混合液をスターラーにより撹拌(1500rpm、12時間、25℃)し、高分子化合物の溶解性を目視にて以下の基準にしたがって評価した。また、撹拌後の混合液又は溶液の粘度を、微量サンプル粘度計を用いて25℃にて測定した。粘度及び溶解性の評価結果を表5及び6に示す。
a:完全に溶解している
b:一部溶解している
c:溶解していない
(実施例5)
プロピレングリコール7.3質量部、水酸化ナトリウム0.7質量部及び塩化マグネシウム2.0質量部をスターラーにより撹拌混合した。さらに得られた混合液と酢酸オクトレオチドを1:1の質量比で混合し、生理活性組成物(50.0質量%酢酸オクトレオチド/3.5質量%水酸化ナトリウム/10.0質量%塩化マグネシウム/36.5質量%プロピレングリコール)を得た。なお、水酸化ナトリウムは酢酸オクトレオチドの酢酸部分と同じモル数分、添加された。
塩化マグネシウムを加えず、代わりに同じ質量分のプロピレングリコールを加えたこと以外は実施例5と同様にして、生理活性組成物(50.0質量%酢酸オクトレオチド/3.5質量%水酸化ナトリウム/46.5質量%プロピレングリコール)を得た。上記生理活性組成物を実施例5と同様にマイクロニードル上に塗布し、マイクロニードル上に付着している生理活性組成物の高さHを測定した。評価結果を表7に示す。
グリセリン8.434質量部、水酸化ナトリウム0.233質量部及び塩化マグネシウム1.333質量部をスターラーにて撹拌混合した。さらに得られた混合液とLHRH(黄体形成ホルモン放出ホルモン酢酸塩)を3:1の質量比で混合し、生理活性組成物(25.0質量%LHRH/1.75質量%水酸化ナトリウム/10.0質量%塩化マグネシウム/63.25質量%グリセリン)を得た。なお、水酸化ナトリウムはLHRHの酢酸部分と同じモル数分、添加された。上記生理活性組成物を実施例5と同様にマイクロニードル上に塗布し、マイクロニードル上に付着している生理活性組成物の高さHを測定した。評価結果を表7に示す。
塩化マグネシウムを加えず、代わりに同じ質量分のグリセリンを加えたこと以外は実施例6と同様にして、生理活性組成物(25.0質量%LHRH/1.75質量%水酸化ナトリウム/73.25質量%グリセリン)を得た。上記生理活性組成物を実施例5と同様にマイクロニードル上に付着させ、マイクロニードル上に付着している生理活性組成物の高さHを測定した。評価結果を表7に示す。
(実施例7)
プロピレングリコール9.444質量部、塩化マグネシウム0.556質量部をスターラーにて撹拌混合した。さらに得られた混合液と酢酸オクトレオチドを9:1の質量比で混合し、生理活性組成物(10質量%酢酸オクトレオチド/5.0質量%塩化マグネシウム/85質量%プロピレングリコール)を得た。
塩化マグネシウムを加えず、代わりに同じ質量分のプロピレングリコールを加えたこと以外は実施例7と同様にして、生理活性組成物(10質量%酢酸オクトレオチド/90質量%プロピレングリコール)を得た。上記生理活性組成物を用いて実施例7と同様に、マイクロニードルデバイスを得た。得られたマイクロニードルデバイスを実施例7と同様に保存し、生理活性物質の残存率を算出した。算出結果を表8に示す。
薬物の種類をLHRHとした以外は実施例7と同様にして、マイクロニードルデバイスを得、生理活性物質の残存率を算出した。算出結果を表8に示す。
薬物の種類をLHRHとした以外は比較例3と同様にして、マイクロニードルデバイスを得、生理活性物質の残存率を算出した。算出結果を表8に示す。
(実施例9)
チューブに、リキセナチドとプロピレングリコールを、50:50の質量比となるように加え、ミキサーで混合し、得られた混合物を生理活性組成物とした。生理活性組成物を、厚さ50μmのマスク版を用いて、マイクロニードルに塗布した。塗布された生理活性物質の含量は、12.2μg/patch/headであった。コーティングされたマイクロニードルアレイを有する0.4Jのアプリケータを用いて、生理活性物質をヘアレスラットに投与した(繰り返し試験数3回)。
チューブに、リキセナチドと生理食塩水を、50:50の質量比となるように加え、ミキサーで混合し、得られた混合物を生理活性組成物とした。生理活性組成物を15.1μg/300μL/headの条件で、ヘアレスラットに皮下投与した。その後、実施例9と同様に血中のリキセナチド濃度を測定した。測定結果を図5に示す。また、AUC値及びBA値を表9に示す。
(実施例10)
チューブに、β-インターフェロンとグリセリンを、30:70の質量比となるように加え、ミキサーで混合し、得られた混合物を生理活性組成物とした。生理活性組成物を、厚さ100μmのマスク版を用いて、マイクロニードルに塗布した。塗布された生理活性物質の含量は、10.3μg/patch/headであった。コーティングされたマイクロニードルアレイを有する0.4Jのアプリケータを用いて、生理活性物質をヘアレスラットに投与した(繰り返し試験数3回)。
チューブに、β-インターフェロンと生理食塩水を、50:50の質量比となるように加え、ミキサーで混合し、得られた混合物を生理活性組成物とした。生理活性組成物を10μg/300μL/headの条件で、ヘアレスラットに皮下投与した(繰り返し試験数3回)。その後、実施例10と同様に血中のβ-インターフェロン濃度を測定した。測定結果を図6に示す。
Claims (9)
- 基板と、
前記基板上に設けられた、マイクロニードルと、
前記マイクロニードル上及び/又は基板上に付着している生理活性組成物と、を備えるマイクロニードルデバイスであって、
前記生理活性組成物は、
グリセリン、エチレングリコール、プロピレングリコール及び1,3-ブチレングリコールから選ばれる少なくとも1種の多価アルコールと、生理活性物質とを含み、実質的に水を含有しないマイクロニードルデバイス。 - 前記生理活性組成物は、ヒドロキシプロピルセルロース、ポリエチレングリコール、コンドロイチン硫酸、ヒアルロン酸、デキストラン、クロスカルメロースナトリウム及び塩化マグネシウムから選ばれる少なくとも1種の化合物をさらに含む、請求項1に記載のマイクロニードルデバイス。
- 前記生理活性組成物は前記マイクロニードル上及び/又は基板上に固着化されている請求項1又は2に記載のマイクロニードルデバイス。
- 生理活性物質と当該生理活性物質を分散又は溶解可能な溶媒とを含有する生理活性組成物を、マイクロニードル上に付着させるマイクロニードルデバイスの製造方法であって、
前記溶媒として、グリセリン、エチレングリコール、プロピレングリコール及び1,3-ブチレングリコールから選ばれる少なくとも1種の多価アルコールを用い、水を用いない、製造方法。 - 前記容器は開口部が形成されたマスク版であり、
前記開口部に前記生理活性組成物を充填させた後に、前記開口部に前記マイクロニードルを挿入して引き出すことにより、当該マイクロニードル上に前記生理活性組成物を付着させる、請求項4記載の製造方法。 - 前記生理活性組成物を充填させるマスク版として、
前記マイクロニードルを引き出した後のマスク版を再利用する、請求項4又は5記載の製造方法。 - 生理活性物質と多価アルコールの質量比率が、20:80~80:20である、請求項4~6のいずれか一項に記載の製造方法。
- 前記生理活性組成物は、粘度が600~45000cpsである、請求項4~7のいずれか一項に記載の製造方法。
- 生理活性物質と当該生理活性物質を分散又は溶解可能な溶媒とを含有する生理活性組成物を、前記溶媒の揮発が生じ得る容器に収容させた後に、マイクロニードル上に付着させマイクロニードルデバイスを製造するに当り、
前記溶媒として、グリセリン、エチレングリコール、プロピレングリコール及び1,3-ブチレングリコールから選ばれる少なくとも1種の多価アルコールを用い、水を用いない、生理活性組成物の付着量安定化方法。
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JP2012501859A JP5715617B2 (ja) | 2010-02-24 | 2011-02-24 | マイクロニードルデバイス及びその製造方法 |
SG2012061743A SG183421A1 (en) | 2010-02-24 | 2011-02-24 | Micro-needle device and preparation method |
KR1020127024166A KR101728194B1 (ko) | 2010-02-24 | 2011-02-24 | 마이크로 니들 디바이스 및 그 제조 방법 |
CA2790923A CA2790923C (en) | 2010-02-24 | 2011-02-24 | Micro-needle device and preparation method |
CN201180010839.8A CN102770176B (zh) | 2010-02-24 | 2011-02-24 | 微针装置及其制造方法 |
EP11747468.4A EP2540337B1 (en) | 2010-02-24 | 2011-02-24 | Micro-needle device and preparation method |
US13/580,300 US20130041330A1 (en) | 2010-02-24 | 2011-02-24 | Micro-needle device and preparation method |
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WO2012115207A1 (ja) * | 2011-02-24 | 2012-08-30 | 久光製薬株式会社 | マイクロニードルデバイス用生理活性非水組成物及びマイクロニードル上に付着している生理活性非水組成物 |
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Also Published As
Publication number | Publication date |
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CA2790923C (en) | 2017-10-31 |
JP5715617B2 (ja) | 2015-05-07 |
SG183421A1 (en) | 2012-09-27 |
CA2790923A1 (en) | 2011-09-01 |
JPWO2011105508A1 (ja) | 2013-06-20 |
EP2540337A4 (en) | 2014-04-30 |
EP2540337B1 (en) | 2019-04-03 |
US20130041330A1 (en) | 2013-02-14 |
CN102770176B (zh) | 2015-11-25 |
KR20120138235A (ko) | 2012-12-24 |
KR101728194B1 (ko) | 2017-05-02 |
EP2540337A1 (en) | 2013-01-02 |
CN102770176A (zh) | 2012-11-07 |
MY158687A (en) | 2016-10-31 |
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