WO2017043627A1 - Microneedle preparation - Google Patents

Microneedle preparation Download PDF

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Publication number
WO2017043627A1
WO2017043627A1 PCT/JP2016/076619 JP2016076619W WO2017043627A1 WO 2017043627 A1 WO2017043627 A1 WO 2017043627A1 JP 2016076619 W JP2016076619 W JP 2016076619W WO 2017043627 A1 WO2017043627 A1 WO 2017043627A1
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WO
WIPO (PCT)
Prior art keywords
water
raw material
microneedle
material mixture
substance
Prior art date
Application number
PCT/JP2016/076619
Other languages
French (fr)
Japanese (ja)
Inventor
高田　寛治
友規 矢野
Original Assignee
株式会社バイオセレンタック
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from JP2015179295A external-priority patent/JP2018193300A/en
Priority claimed from JP2016013266A external-priority patent/JP2018193301A/en
Application filed by 株式会社バイオセレンタック filed Critical 株式会社バイオセレンタック
Publication of WO2017043627A1 publication Critical patent/WO2017043627A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • 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
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/84—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
    • A61K8/85—Polyesters
    • 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
    • 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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • 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
    • 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

Definitions

  • the present invention relates to a microneedle preparation that contains a drug in a biodegradable substance and delivers the drug into the body when inserted or placed in a body surface or the like.
  • Microneedle As a preparation technique for improving the absorption rate of a drug having extremely low permeability through the stratum corneum of the skin into the skin. Microneedles are miniaturized needles.
  • the microneedle has a hollow structure similar to that of an injection needle, and is a type for injecting a chemical solution or a microneedle made of a biodegradable polymer. Furthermore, a dissolution type microneedle based on a water-soluble polymer substance has also been developed.
  • Patent Document 1 a target substance is held in a base of a water-soluble polymer substance, and after the substance is inserted into the skin, the base substance is dissolved by moisture in the skin, so that the target substance is absorbed into the skin.
  • Microneedle formulations that can be described are described.
  • the efficacy of the microneedle formulation is sustained.
  • the target substance is a water-soluble (polar) substance typified by insulin
  • the clearance from the body is fast, it cannot be expected to have a long-term medicinal effect and a hypoglycemic action.
  • a fat-soluble substance typified by paclitaxel high drug efficacy and anticancer effect may be expected by exposing it to cancer cells for a longer period of time.
  • the microneedle preparation is required to have a function of gradually releasing the target substance.
  • Patent Document 1 describes a microneedle formulation that contains a porous substance that retains a target substance and that allows the target substance to be released slowly.
  • the content of the porous substance is limited, and it is difficult to sufficiently increase the dose of the target substance.
  • Patent Document 2 describes a microneedle array provided with microneedles containing amorphous polylactic acid.
  • the microneedle disclosed in Patent Document 2 is configured such that a physiologically active ingredient is mixed into a resin so that the physiologically active ingredient is released into the body at the same time as the microneedle is released in the body. Since polylactic acid is a biodegradable resin, such microneedles can have the effect of gradually releasing the physiologically active component.
  • the drug is made into a sustained-release microcapsule or sustained-release microsphere using a biodegradable resin, it is dispersed in a base for a soluble microneedle and suspended to provide a sustained-release function as a microneedle.
  • the amount of the biodegradable resin base increases to some extent, there is a drawback that the drug content in the microneedle preparation is reduced.
  • the skin, body after puncture to the skin, body surface, or cancer tissue is possible. If the sustained-release microneedle portion inserted into the surface or the cancer tissue can be separated from the support such as the base or the base sheet, the perforation generated in the skin, the body surface, or the cancer tissue It is considered to be effective in preventing infection because it is blocked.
  • Patent Document 3 discloses a microneedle sheet that is used by inserting a biodegradable needle supported on the surface of the sheet into the skin, and the root of the microneedle is formed more brittle than the tip. Are listed.
  • the microneedle sheet of Patent Document 3 breaks the root portion with a force that pulls the sheet along the skin surface while the needle is stabbed in the skin, so that the microneedle part inserted into the skin is removed from the support. To separate.
  • the sheet after puncturing the skin, the sheet must be shifted parallel to the skin and peeled off. Since the sheet is soft, it is difficult to shift the entire surface in the lateral direction, and the microneedle that receives the shifting force may damage the skin or come off. Furthermore, when the separable microneedle is applied to a narrow portion, it is difficult to separate the sheet in the lateral direction and peel it off.
  • the present invention comprises a top part, a first part containing a water-insoluble biodegradable polymer substance and a target substance dissolved or dispersed in the polymer substance, and a base part, and the water-insoluble biodegradable substance
  • a second part containing a water-soluble substance that dissolves in a solvent capable of dissolving the soluble polymer substance;
  • a microneedle formulation having
  • the said microneedle formulation has a 3rd part which is located between a 2nd part and a support body, and contains a water-soluble substance.
  • the biodegradable polymer substance contained in the said 1st part is from the group which consists of polylactic acid (PLA), polyglycolic acid (PGA), a lactic acid-glycolic acid copolymer, and polycaprolactone (PCL). At least one kind selected.
  • the water-soluble substance contained in the second part and the third part is a polymer substance.
  • the water-soluble substance contained in the second part is selected from the group consisting of hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, methacrylic acid copolymer S, methacrylic acid copolymer LD, and aminoalkyl methacrylate copolymer RS. Is at least one kind.
  • the water-soluble substance contained in the third part is at least one selected from the group consisting of sodium chondroitin sulfate, dextran, dextran sulfate, hydroxypropyl ⁇ cyclodextrin and sodium hyaluronate,
  • an alkalizing agent typified by sodium hydride
  • the substance constituting the second portion can be dissolved and firmly bonded.
  • the present invention also provides a microneedle preparation administration member having a support and a plurality of any of the above microneedle preparations.
  • the present invention places a first raw material mixture obtained by mixing a water-insoluble biodegradable polymer substance, a target substance and a solvent on a mold having a hole with a shape in which the microneedle preparation is reversed, Drying and filling the dried first raw material mixture to a predetermined height of the hole;
  • a water-soluble substance that dissolves in a solvent capable of dissolving a water-insoluble biodegradable polymer substance and the water-insoluble biodegradable polymer substance can be dissolved in a mold filled with the dried first raw material mixture
  • Placing the second raw material mixture obtained by mixing the solvent and filling the second raw material mixture into the holes Overlaying the support on the mold so as to contact the second raw material mixture; Drying the second raw material mixture filled in the mold holes; and peeling the support from the mold;
  • the manufacturing method of the microneedle formulation administration member containing this is provided.
  • the present invention places a first raw material mixture obtained by mixing a water-insoluble biodegradable polymer substance, a target substance and a solvent on a mold having a hole with a shape in which the microneedle preparation is reversed, Drying and filling the dried first raw material mixture to a predetermined height of the hole;
  • a water-soluble substance that dissolves in a solvent capable of dissolving a water-insoluble biodegradable polymer substance and the water-insoluble biodegradable polymer substance can be dissolved in a mold filled with the dried first raw material mixture
  • the surface of a support body has an area substantially in a sheet
  • the front surface of the support means the surface on the side facing the application site when the microneedle preparation is administered.
  • the rear surface of the support means the surface on the side facing the pressing means when the microneedle preparation is administered.
  • the target substance can be released slowly from the microneedle, and after administration, the microneedle portion inserted into the skin is separated from the support by dissolution without the need to apply a tensile force to the support.
  • a microneedle formulation is provided.
  • microneedle formulation administration member which is one Embodiment of this invention. It is sectional drawing of the two-layer microneedle formulation which is one Embodiment of this invention. It is sectional drawing of the three-layer microneedle formulation which is other embodiment of this invention.
  • FIG. 1 is a partial cross-sectional view of a microneedle preparation administration member according to an embodiment of the present invention.
  • the microneedle preparation administration member 11 has a support 13 and a plurality of needle-shaped microneedle preparations 12 formed on the front surface of the support.
  • the support is composed of a material capable of fixing the microneedle preparation.
  • the support is water insoluble.
  • the support may be a flexible film, sheet, or hard chip. Further, the support is preferably porous and does not hinder the drying of the components in the course of forming the microneedles.
  • the shape of the surface of the support (that is, the front surface or the rear surface) is circular or polygonal.
  • the shape of the surface of the support is preferably a shape that can be arranged without gaps at the location where the microneedle preparation is applied.
  • An example of a preferred support shape is a quadrangle, such as a rectangle or a square.
  • the dimensions of the support are, for example, a surface diameter or diagonal of about 8.5 cm or less, preferably about 0.42 cm to about 4.2 cm, and more preferably about 1.4 cm to about 3.5 cm.
  • the thickness of the support is about 0.01 to 10 mm, preferably about 0.05 to 5 mm, more preferably about 0.1 to 3 mm.
  • the length of the longest side is 6 cm or less, preferably 0.3 cm to 3 cm, more preferably 1 cm to 2.5 cm. If the size of the surface of the support is too small, the number of administrations increases and labor is increased, and if it is too large, the unevenness of the application site cannot be dealt with, and many microneedle insertion defects occur.
  • the support may be a tape.
  • the width of the tape-like support is, for example, about 0.05 to 15 cm, preferably about 0.3 to 7 cm, and more preferably 0.5 to 3 cm.
  • the tape-like support is convenient for use, for example, by being wound around the side surface of a cylinder or a rod.
  • the length of the tape-like support can be appropriately determined when used.
  • the microneedle preparation is present on the support at a density of about 1 to 300 / cm 2 , preferably about 2 to 250 / cm 2 , more preferably about 4 to 100 / cm 2 .
  • the density of the microneedle preparation exceeds 300 / cm 2 , the resistance at the time of insertion of the microneedle preparation increases, and the insertion depth may become shallow.
  • FIG. 2 is a cross-sectional view of a two-layer microneedle preparation that is one embodiment of the present invention.
  • the microneedle formulation 12 has a top that is shaped to penetrate skin, body surface, or cancer tissue.
  • the microneedle preparation is wide and has a base that can be fixed to a support.
  • the shape of the microneedle preparation may be substantially conical or may be substantially pyramidal.
  • the microneedle preparation has a base diameter D of 50 to 3000 ⁇ m, preferably 100 to 2000 ⁇ m, more preferably 200 to 1500 ⁇ m.
  • the microneedle preparation has a length H in the insertion direction of 50 to 5000 ⁇ m, preferably 100 to 4000 ⁇ m, more preferably 150 to 3000 ⁇ m.
  • the length H in the insertion direction of the microneedle preparation is 400 to 4000 ⁇ m, preferably 800 to 3000 ⁇ m, more preferably 1500 to 2500 ⁇ m.
  • the microneedle preparation may have a conical shape with a length in the insertion direction of 2000 ⁇ m and a base diameter of 800 ⁇ m.
  • the microneedle preparation 12 has two layers of a first portion 12A and a second portion 12B.
  • the first part has a top and the second part has a base. Further, the first portion and the second portion form a boundary surface. The interface between the first part and the second part is substantially parallel or substantially parallel to the bottom surface of the microneedle formulation.
  • the first portion 12A includes a water-insoluble biodegradable polymer substance and a target substance dissolved or dispersed in the polymer substance. Since the biodegradable polymer substance of the first part is water-insoluble, the first part does not dissolve quickly in the body, and the biodegradable polymer substance is hydrolyzed over time, resulting in the target substance Is slowly released into the body.
  • the target substance is dissolved or dispersed in the biodegradable polymer substance.
  • a third component such as a porous material that retains and slowly releases the target substance is not used as a component of the first part. Therefore, even when the strength of the microneedle preparation is taken into consideration, the content of the target substance can be sufficiently increased.
  • the target substance is dispersed in the biodegradable polymer substance in a state where the target substance is substantially uniformly dispersed in the biodegradable polymer substance or in the biodegradable polymer substance. It means a state in which the target substance is suspended substantially uniformly.
  • the first portion is composed of a water-insoluble biodegradable polymer substance and a target substance dissolved or dispersed in the polymer substance.
  • the water-insoluble biodegradable polymeric material forms a first part matrix and the target material forms a domain.
  • the concentration of the water-insoluble biodegradable polymer substance contained in the first part is preferably 50% by weight or more. When the concentration of the polymer substance is less than 50% by weight, the strength of the microneedle preparation is lowered, and puncture failure or breakage may occur during administration.
  • the concentration of the water-insoluble biodegradable polymer substance contained in the first part is preferably 60 to 99.99% by weight, more preferably 70 to 99.9% by weight.
  • the concentration of the target substance contained in the first part is preferably less than 50% by weight. When the concentration of the target substance is 50% by weight or more, the strength of the microneedle preparation decreases, and puncture failure or breakage may occur during administration.
  • the concentration of the target substance contained in the first part is preferably 0.001 to 40% by weight, more preferably 0.1 to 30% by weight.
  • the length in the insertion direction of the first portion is about 50% or more of the length H in the insertion direction of the microneedle preparation in order to contain the target substance in a sufficient amount.
  • the length of the first portion in the insertion direction is preferably about 60 to 98% of the length H, more preferably about 70 to 90%.
  • the length of the first portion in the insertion direction is 10 to 5000 ⁇ m. If the length of the first portion in the insertion direction is less than 10 ⁇ m, the dose and sustained release of the target substance are insufficient, and if it exceeds 5000 ⁇ m, the blood vessel may be damaged, which is not preferable.
  • the length of the first portion in the insertion direction is preferably 200 to 4000 ⁇ m, more preferably 250 to 3000 ⁇ m. In one embodiment, the length of the first portion in the insertion direction is 500 to 2500 ⁇ m, preferably 1000 to 2300 ⁇ m.
  • the region may be divided into a plurality of portions in the length direction to form a multilayer structure, and the target substance may be held only in a certain layer.
  • the administration position of the target substance can be adjusted in the vertical direction, that is, in the depth direction of the skin.
  • the second portion 12B includes a water-soluble substance that dissolves in a solvent that can dissolve the water-insoluble biodegradable polymer substance. Since the substance of the second part is water-soluble, the second part dissolves in the body and the first part is separated from the support. By dissolving the substance in the second part in a solvent capable of dissolving the water-insoluble biodegradable polymer substance, the second part binds to the first part with sufficient strength to function as a microneedle formulation. .
  • the substance of a 2nd part is a water-soluble polymer substance which melt
  • a 2nd part consists of a water-soluble substance which melt
  • the length of the second portion in the insertion direction is 10 to 2000 ⁇ m.
  • the insertion length of the second part is less than 10 ⁇ m, the bonding strength between the first part and the support becomes insufficient, and puncture failure or breakage may occur during administration.
  • the length of the second portion in the insertion direction exceeds 2000 ⁇ m, the amount of the target substance contained in the first portion is reduced.
  • the length of the second portion in the insertion direction is preferably 50 to 500 ⁇ m, more preferably 100 to 300 ⁇ m.
  • FIG. 3 is a cross-sectional view of a three-layer microneedle preparation that is another embodiment of the present invention.
  • the microneedle formulation 12 has a third portion 12C between the second portion 12B and a support (not shown).
  • the third part 12C contains a water-soluble substance. Since the substance of the third part is water-soluble, the third part is firmly bonded to the second part, while rapidly dissolving in the body, and the first part is separated from the support.
  • the third part material is a water-soluble polymer material. By including the water-soluble polymer substance in the third portion, the bond strength to the second portion is improved.
  • a 3rd part consists of water-soluble substances. The water-soluble substance of the third part must be able to bind tightly with the water-soluble substance of the second part.
  • the length of the third portion in the insertion direction is 10 to 2000 ⁇ m.
  • the insertion length of the third part is less than 10 ⁇ m, the bonding strength to the second part becomes insufficient, and puncture failure or breakage may occur during administration.
  • the length of the third portion in the insertion direction is preferably 50 to 500 ⁇ m, more preferably 100 to 300 ⁇ m.
  • microneedles based on biodegradable polymer materials In order to mold microneedles based on biodegradable polymer materials, methods such as injection molding after heating and melting have been put into practical use. However, since many drugs decompose when exposed to high temperatures, they are versatile. Low. To form a microneedle shape using a biodegradable polymer substance as a base under low temperature conditions, dissolve the biodegradable polymer substance once in a solvent using a solvent, dry it after drying it, etc. It is preferable to mold by taking out. Further, a micro dispenser may be used for filling the female mold. A biodegradable polymer material solution containing the target substance may be directly shaped on the support with a 3D printer.
  • the microneedle preparation administration member of the present invention is formed by, for example, forming a microneedle preparation using a template having a hole with a shape reverse to that of the microneedle preparation, and then fixing the formed microneedle preparation to a support. Manufactured.
  • a mold a plate-like material provided with holes corresponding to the shape and arrangement of the microneedle preparation is used.
  • a metal such as stainless steel or aluminum, a fluororesin, a silicon resin, or the like is used.
  • a water-insoluble biodegradable polymer substance, a target substance and a solvent which are raw materials for the first part of the microneedle preparation, are mixed to prepare a first raw material mixture.
  • the biodegradable polymer substance is dissolved in the solvent, and the target substance is dissolved in the solvent or dispersed substantially uniformly.
  • preferable biodegradable polymer materials include polylactic acid (PLA), polyglycolic acid (PGA), lactic acid / glycolic acid copolymer, polycaprolactone (PCL), and a copolymer of PLA, PGA and PCL.
  • PLA polylactic acid
  • PGA polyglycolic acid
  • PCL polycaprolactone
  • the solvent a solvent that dissolves the biodegradable polymer substance and does not deteriorate and alter the target substance may be used.
  • Specific examples of the solvent include dichloromethane, ethanol, ethyl acetate, and mixtures thereof. Only one type of biodegradable polymer substance and solvent may be used, or a plurality of types may be used in combination.
  • the target substance is a substance that is administered to the human body to obtain efficacy.
  • biocompatible substances such as high molecular weight substances, low molecular weight substances, chemical substances, physiologically active substances, proteins (recombinant or natural type), peptides, polysaccharides, etc. can be adopted as target substances. . It can be applied to a wide range of target substances from fat-soluble (water-insoluble) substances to polar (water-soluble) substances, and coexists in a dissolved or dispersed state in a biodegradable polymer substance that is a sustained release base. Preferably, they are anticancer drugs, immunosuppressive drugs, peptides, proteins, nucleic acids, or polysaccharides.
  • the target substance may be a drug, vaccine antigen, nutrient, or cosmetic ingredient.
  • preferable target substances include diabetes drugs, anticancer drugs, immunosuppressive drugs, hormone drugs, vaccines and the like.
  • the first raw material mixture is placed on a mold, and if necessary, coating pressure is applied using a coating tool such as squeegee or a coating apparatus or a filling apparatus, and this is filled into a hole formed in the mold.
  • a centrifugal force may be applied to the mold using a centrifuge or the like.
  • the first raw material mixture filled in the holes is dried. Drying is performed at a temperature of 50 ° C. or lower, preferably room temperature (about 25 ° C.) or lower in order to prevent the target substance from being altered. After drying, the volume of the first raw material mixture decreases.
  • This length can be used to adjust the length of the first portion of the microneedle formulation in the insertion direction. That is, when preparing the first raw material mixture, the solid content concentration of the first raw material mixture is high corresponding to the length in the insertion direction of the first portion of the microneedle preparation after the first raw material mixture is dried in the mold. Then, the concentration is adjusted to an appropriate concentration so that the solid content of the first raw material mixture remains.
  • the water-soluble substance and the water-insoluble biodegradable polymer substance that can be dissolved in the solvent that can dissolve the water-insoluble biodegradable polymer substance that is the raw material of the second part of the microneedle preparation can be dissolved.
  • a solvent is mixed to prepare a second raw material mixture.
  • the water-soluble substance is dissolved in a solvent capable of dissolving the water-insoluble biodegradable polymer substance.
  • the second raw material mixture is placed on the mold filled with the dried first raw material mixture and filled into the mold holes, or the second raw material mixture is applied to the surface of the support, or as required. Do both.
  • the water-soluble substance as the raw material of the second part is converted into the water-insoluble biodegradable part of the first part. Bonds firmly to the conductive polymer layer.
  • the water-soluble substance that dissolves in the solvent capable of dissolving the water-insoluble biodegradable polymer substance is a water-soluble substance, but a substance that can adhere to the biodegradable polymer substance is used.
  • the substances include hydroxypropyl methylcellulose phthalate (trade name HPMCP HP-55, manufactured by Shin-Etsu Chemical Co., Ltd.), hydroxypropyl methylcellulose acetate succinate (trade name AQOAT, manufactured by Shin-Etsu Chemical Co., Ltd.), methacrylic acid copolymer S (Eudragit S, Rohm Pharma), methacrylic acid copolymer LD (Eudragit L, Rohm Pharma), and aminoalkyl methacrylate copolymer RS (Eudragit RS, RohmRPharma) are suitable. This is because these polymer substances are dissolved in the solvent used for dissolving the biodegradable polymer substance, so that they can be adhered to the layer of the first part when used as a solution
  • these polymer substances are dissolved in water at neutral to alkaline pH.
  • HP-55 dissolves in water at a pH of 5.5 or higher, so when puncturing the skin, it dissolves in body fluid (pH 7.4), and the first part based on a biodegradable polymer substance can be separated. it can.
  • alkalizing agents such as sodium hydrogencarbonate, as needed.
  • the material for creating the second portion need not be limited to these polymer materials. Even a water-soluble low-molecular substance can be used as long as it is a substance that dissolves in a solvent that dissolves a biodegradable substance that is a main component of the upper microneedle.
  • a support is stacked on the mold so as to come into contact with the second raw material mixture.
  • the support is a sheet, a film, and is in contact with the second mixture, and preferably, the components of the second mixture are firmly joined by intruding into the pores inside the support by the anchor effect and are bonded to the second mixture. It can absorb and release the contained solvent.
  • a centrifugal force may be applied to the mold using a centrifuge or the like.
  • Preferred supports are polyurethane, polyimide, polyethylene, polypropylene, polymethylmethacrylate, polyvinyl chloride, chlorinated polyethylene-styrene resin and silicone resin films or porous plates, and water-insoluble tablet excipients. Or a sheet made of fiber such as cloth, paper, or non-woven fabric.
  • the support may be a resin film or an elastomer film exhibiting stretchability or stretchability. Specific examples of the resin film exhibiting stretchability or stretchability include polyurethane film, polyethylene film, polypropylene film, and silicone resin film.
  • fiber sheet cloth, paper, non-woven fabric and film used as a base material for medical tape such as adhesive bandage are preferable.
  • Tablet excipients include cellulose acetate, crystalline cellulose, cellulose derivatives, chitin and chitin derivatives. What is necessary is just to manufacture the molded object which consists of an excipient
  • a tablet excipient is put into a mortar of a tableting machine and tableted with a suitable tableting pressure using a punch. The dimensions of the support are appropriately adjusted by increasing or decreasing the diameter of the mortar, the filling amount of the tablet excipient, and the tableting pressure.
  • the disclosures of US Patent Publication No. 2011/0152792 and Japanese Patent Application Laid-Open No. 2011-12050 are inserted here.
  • a magnetic responsive substance such as iron powder may be mixed into the tablet excipient.
  • a magnetically responsive component is mixed with a tablet excipient and placed in a mortar of a tableting machine, and tableted with an appropriate tableting pressure using a punch. It is preferable that the magnetic-responsive chip has a two-layer tablet structure so that a magnetic-responsive substance is not blended in the first layer constituting the microneedle.
  • the disclosure content of JP2013-169432A is inserted here.
  • the second raw material mixture filled in the mold holes is dried. Drying is performed under the same conditions as the first raw material mixture in order to prevent deterioration of the target substance. Thereafter, the support body is peeled off from the mold to obtain the microneedle preparation administration member of the present invention.
  • a third material mixture is prepared by mixing a water-soluble substance as a raw material of the third part of the microneedle formulation and water as a solvent. At that time, the water-soluble substance is dissolved in water. In consideration of the binding property with the water-soluble substance constituting the second part layer, the water may be adjusted from neutral to alkaline pH.
  • the third raw material mixture is placed on the mold filled with the dried second raw material mixture and filled into the mold holes, or the third raw material mixture is applied to the surface of the support, or as required. Do both.
  • water As the solvent of the third raw material mixture, the water-soluble substance that is the raw material of the third part is mixed with the water-soluble substance of the second part. As a result, the third part is bonded to the second part.
  • a support is stacked on the mold so as to come into contact with the third raw material mixture.
  • water-soluble substance examples include at least one substance selected from the group consisting of polysaccharides, proteins, polyvinyl alcohol, carboxyvinyl polymers, and sodium polyacrylate.
  • the polysaccharide is chondroitin sulfate and salts thereof (such as sodium chondroitin sulfate), dextran, dextran sulfate, hyaluronic acid and salts thereof (such as sodium hyaluronate), cyclodextrin, hydroxypropyl ⁇ cyclodextrin, hydroxypropyl cellulose, At least one substance selected from alginic acid, agarose, pullulan, and glycogen and derivatives thereof.
  • chondroitin sulfate and salts thereof such as sodium chondroitin sulfate
  • dextran dextran sulfate
  • hyaluronic acid and salts thereof such as sodium hyaluronate
  • cyclodextrin hydroxypropyl ⁇ cyclodextrin
  • hydroxypropyl cellulose At least one substance selected from alginic acid, agarose, pullulan, and glycogen and derivatives thereof.
  • the protein is at least one substance selected from serum albumin, serum ⁇ -acid glycoprotein, collagen, low molecular collagen, gelatin, and derivatives thereof.
  • Particularly preferred water-soluble substances include sodium chondroitin sulfate, dextran, dextran sulfate, hydroxypropyl ⁇ cyclodextrin and hyaluronic acid. Since these substances have been used as pharmaceuticals, their safety is guaranteed. Only one type of water-soluble substance may be used, or a plurality of types may be used in combination.
  • the third raw material mixture is dried. Drying is performed under the same conditions as the first raw material mixture in order to prevent deterioration of the target substance. Thereafter, the support body is peeled off from the mold to obtain the microneedle preparation administration member of the present invention.
  • the obtained microneedle preparation administration member is useful for treating diseases of human or animal body surfaces such as skin diseases.
  • the body surface broadly refers to a part of a living body that can come into contact with a substance existing outside the living body.
  • inner surfaces such as skin, nails, eye surface, inner surface of nose, inner surface of oral cavity, trachea, esophagus, stomach, intestine, anus, bile duct are included in the body surface.
  • the resulting microneedle formulation administration member is also useful for drug delivery applications across human or animal body tissue.
  • the microneedle preparation administration member of the present invention is applied to the mucous membrane or tube wall of the oral cavity, eye, nasal cavity, vagina, esophagus, upper digestive tract, lower digestive tract and bile duct, blood vessels, etc.
  • drugs such as insulin and anticancer drugs, vaccine antigens and the like are gradually released into the body.
  • Example 1 To 200 mg of polylactic acid, 1.2 mL of a mixed solution of dichloromethane and ethyl alcohol was added and dissolved. Further, 2 mg of tacrolimus was added and mixed well to obtain a viscous liquid. The viscous liquid is applied to a 5 mm-thick resin female mold in which 10 conical holes with a diameter of 800 ⁇ m and a depth of 2000 ⁇ m are formed per 10 mm ⁇ 50 mm, and a centrifugal separator is applied at about 10 ° C. The holes were filled and dried by centrifuging at 2000 rpm for 5 minutes.
  • HP-55 hydroxypropylmethylcellulose phthalate
  • Example 2 To 200 mg of polylactic acid, 2.0 mL of a mixed solution of dichloromethane and ethyl alcohol was added and dissolved. Furthermore, 20 mg of cyclosporine was added and mixed well to obtain a viscous liquid. The viscous liquid was applied to the female mold produced in Example 1, and filled in the hole by centrifuging at 2000 rpm with a centrifuge at about 10 ° C. for 5 minutes and dried.
  • a solution obtained by dissolving 8 mL of a mixed solution of dichloromethane and ethyl alcohol was applied to 0.3 g of hydroxypropylmethylcellulose phthalate (trade name HP-55, manufactured by Shin-Etsu Chemical Co., Ltd.), and filled into a female mold under pressure.
  • a viscous liquid prepared by adding 1 ml of 0.05N sodium hydroxide to 500 mg of dextran was applied to a nonwoven fabric for a base sheet, covered on a female mold, and dried under pressure. After 8 hours, the nonwoven fabric was separated from the female mold to obtain a sustained-release three-layer microneedle sheet.
  • Example 3 To 200 mg of polylactic acid, 1.2 mL of a mixed solution of dichloromethane and ethyl alcohol was added and dissolved. Furthermore, 10 mg of insulin was added and mixed well to obtain a viscous liquid. The viscous liquid was applied to the female mold produced in Example 1, and filled in the hole by centrifuging at 2000 rpm with a centrifuge at about 10 ° C. for 5 minutes and dried.
  • HP-55 hydroxypropylmethylcellulose phthalate
  • the viscous liquid containing tacrolimus was applied to the nonwoven fabric for the base sheet, applied to a female mold, and dried under pressure. After 2 hours, the nonwoven fabric was peeled to obtain a sustained-release single-layer microneedle sheet.
  • Example 4 To 200 mg of polylactic acid, 1.2 mL of a mixed solution of dichloromethane and ethyl alcohol was added and dissolved. Further, 50 mg of paclitaxel was added and mixed well to obtain a viscous liquid. Viscous liquid is sequentially filled with a dispenser into a 5 mm thick resin female hole formed with 10 conical holes of diameter 800 ⁇ m and depth 2000 ⁇ m per 10 mm ⁇ 50 mm, and dried. did.
  • HP-55 hydroxypropylmethylcellulose phthalate
  • Example 5 To 200 mg of polylactic acid, 1.2 mL of a mixed solution of dichloromethane and ethyl alcohol was added and dissolved. Further, 50 mg of 5-fluorouracil was added and mixed well to obtain a viscous liquid. The viscous liquid was applied to the female mold produced in Example 4, and filled in the hole by centrifuging at 2000 rpm with a centrifuge at about 10 ° C. for 1 minute.
  • a solution obtained by adding 8 mL of a mixed solution of dichloromethane and ethyl alcohol to 0.5 g of hydroxypropylmethylcellulose phthalate (trade name HP-55, manufactured by Shin-Etsu Chemical Co., Ltd.) was applied onto a female mold and filled. After drying, the base sheet non-woven fabric coated with the HP-55 solution was applied to a knife under pressure. After 3 hours, the nonwoven fabric was peeled to obtain a sustained-release two-layer microneedle sheet.
  • Example 6 To 200 mg of polylactic acid, 1.2 mL of a mixed solution of dichloromethane and ethyl alcohol was added and dissolved. Further, 50 mg of paclitaxel was added and mixed well to obtain a viscous liquid. This viscous liquid was put into a dispenser and filled into the female mold produced in Example 4.
  • a viscous liquid obtained by adding 8 mL of a mixed solution of dichloromethane and ethyl alcohol to 0.5 g of hydroxypropylmethylcellulose phthalate (trade name HP-55, manufactured by Shin-Etsu Chemical Co., Ltd.) was placed in a dispenser and filled into a female mold.
  • the polyurethane film was quickly applied to the female mold and pressurized.
  • the film was peeled after 3 hours to obtain a sustained-release two-layer microneedle sheet.
  • the obtained microneedle sheet could be stretched by pulling by hand, and even in that case, the microneedle was kept upright.
  • Example 7 The microneedle sheets prepared in Examples 1 to 6 and the comparative example were immersed in a buffer solution having a pH of 7.4 for 10 minutes, and then placed in an ultrasonic cleaning machine and subjected to vibration for 30 seconds. The microneedle sheet of the comparative example remained standing on the sheet even when vibration was applied. On the other hand, in the microneedles of Examples 1, 2, 3, 4, 5 and 6, the root part was dissolved and separated from the sheet and fell down.
  • microneedle preparation member 12
  • Microneedle formulation 12A ... 1st part, 12B ... the second part, 12C ... the third part, 13: Support.

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Abstract

The present invention addresses the problem of providing a microneedle preparation whereby an object substance can be released in sustained fashion from a microneedle, and a microneedle portion inserted into skin can be separated from a support without the need for applying a pulling force to the support. In order to solve this problem, the present invention is a microneedle preparation having a first portion which is provided with a top part and includes a water-insoluble biodegradable polymer substance and an object substance dissolved or dispersed in the polymer substance, and a second portion which is provided with a base part and includes a water-soluble substance dissolved in a solvent capable of dissolving the water-insoluble biodegradable polymer substance.

Description

マイクロニードル製剤Microneedle formulation
　本発明は、薬物を生分解性物質に含有させ、体表等に挿入又は留置された場合に、体内に薬物を送達させるマイクロニードル製剤に関する。 The present invention relates to a microneedle preparation that contains a drug in a biodegradable substance and delivers the drug into the body when inserted or placed in a body surface or the like.
　皮膚の角質層の透過性が極めて低い薬物の皮膚内への吸収率を改善する製剤技術として、マイクロニードルがある。マイクロニードルは微細化された針状物である。 There is a microneedle as a preparation technique for improving the absorption rate of a drug having extremely low permeability through the stratum corneum of the skin into the skin. Microneedles are miniaturized needles.
　マイクロニードルは、注射針と同様の中空構造を有し、薬液を注入するタイプであったり、生分解性高分子製のマイクロニードルであったりする。さらに、水溶性高分子物質を基剤とする溶解型のマイクロニードルも開発されている。 The microneedle has a hollow structure similar to that of an injection needle, and is a type for injecting a chemical solution or a microneedle made of a biodegradable polymer. Furthermore, a dissolution type microneedle based on a water-soluble polymer substance has also been developed.
　特許文献１には、水溶性高分子物質の基剤に目的物質を保持させておき、皮膚に挿入した後、基剤が皮膚内の水分により溶解することにより、目的物質を皮膚内に吸収させることができるマイクロニードル製剤が記載されている。 In Patent Document 1, a target substance is held in a base of a water-soluble polymer substance, and after the substance is inserted into the skin, the base substance is dissolved by moisture in the skin, so that the target substance is absorbed into the skin. Microneedle formulations that can be described are described.
　マイクロニードル製剤の薬効が持続することが好ましい場合がある。例えば、目的物質がインスリンに代表される水溶性（極性）物質である場合には、体内からのクリアランスが速いために、長時間にわたる薬効、血糖降下作用、を期待することができない。また、パクリタキセルに代表される脂溶性物質である場合には、より長期間、癌細胞へ曝露させることにより高い薬効、抗癌効果、が期待される場合もある。マイクロニードル製剤の薬効を持続させるためには、マイクロニードル製剤に目的物質を徐放する機能が求められる。 It may be preferable that the efficacy of the microneedle formulation is sustained. For example, when the target substance is a water-soluble (polar) substance typified by insulin, since the clearance from the body is fast, it cannot be expected to have a long-term medicinal effect and a hypoglycemic action. In addition, in the case of a fat-soluble substance typified by paclitaxel, high drug efficacy and anticancer effect may be expected by exposing it to cancer cells for a longer period of time. In order to maintain the drug efficacy of the microneedle preparation, the microneedle preparation is required to have a function of gradually releasing the target substance.
　特許文献１には、目的物質を保持する多孔性物質を含有し、目的物質が徐放されるマイクロニードル製剤が記載されている。しかしながら、マイクロニードル製剤の強度を考慮すると多孔性物質の含有量には限界があり、目的物質の投与量を十分に増大させることが困難である。 Patent Document 1 describes a microneedle formulation that contains a porous substance that retains a target substance and that allows the target substance to be released slowly. However, considering the strength of the microneedle preparation, the content of the porous substance is limited, and it is difficult to sufficiently increase the dose of the target substance.
　特許文献２には、非晶質のポリ乳酸を含むマイクロニードルを備えたマイクロニードルアレイが記載されている。特許文献２のマイクロニードルは、生理活性成分を樹脂の中に混ぜ込んで、体内でマイクロニードルが解けると同時に生理活性成分が体内に放出されるように構成している。ポリ乳酸は生分解性樹脂であるためかかるマイクロニードルは、生理活性成分を徐放させる作用を有しうる。 Patent Document 2 describes a microneedle array provided with microneedles containing amorphous polylactic acid. The microneedle disclosed in Patent Document 2 is configured such that a physiologically active ingredient is mixed into a resin so that the physiologically active ingredient is released into the body at the same time as the microneedle is released in the body. Since polylactic acid is a biodegradable resin, such microneedles can have the effect of gradually releasing the physiologically active component.
　しかしながら、生分解性樹脂を基剤としてその中に薬物を含有させたマイクロニードルを使用して薬物を徐放させる場合、そのようなマイクロニードルは速やかに溶解しないので長期にわたりマイクロニードルを皮膚に穿刺しておく必要がある。かかる場合、皮膚の穿刺部分から感染が起こり、炎症などの副作用が生じる危険性がある。この欠点は、生分解性樹脂製の徐放性マイクロニードルを臨床応用する際の障害になっている。また、薬物を生分解性樹脂を用いていったん徐放性マイクロカプセルあるいは徐放性マイクロスフェアとした後、溶解性マイクロニードル用基剤に分散、縣濁させてマイクロニードルとしても徐放性の機能をもたせることはできるが、何分にも生分解性樹脂基剤の量が多くなるために、マイクロニードル製剤中の薬物含量が低下してしまうという欠点がある。 However, when using a microneedle containing a biodegradable resin as a base and containing a drug therein, the drug is slowly released, and such a microneedle does not dissolve quickly, so that the microneedle is punctured into the skin over a long period of time. It is necessary to keep it. In such a case, there is a risk that infection will occur from the puncture portion of the skin, causing side effects such as inflammation. This drawback is an obstacle to clinical application of sustained-release microneedles made of biodegradable resin. Also, once the drug is made into a sustained-release microcapsule or sustained-release microsphere using a biodegradable resin, it is dispersed in a base for a soluble microneedle and suspended to provide a sustained-release function as a microneedle. However, since the amount of the biodegradable resin base increases to some extent, there is a drawback that the drug content in the microneedle preparation is reduced.
　徐放性マイクロニードルについて皮膚、体表、あるいは癌組織への穿刺部分から感染が起こる欠点を解決する手段としては、投与後、すなわち皮膚、体表、あるいは癌組織へ穿刺した後に、皮膚、体表、あるいは癌組織に挿入された徐放性マイクロニードル部分を、基盤、基盤シート等の支持体から分離することができれば、皮膚、体表、あるいは癌組織に生じた穿孔が生体の修復作用により塞がれるので感染防止に有効であると考えられる。 As a means of solving the disadvantage that infection occurs from the puncture portion of the skin, body surface, or cancer tissue with respect to the sustained release microneedle, the skin, body after puncture to the skin, body surface, or cancer tissue is possible. If the sustained-release microneedle portion inserted into the surface or the cancer tissue can be separated from the support such as the base or the base sheet, the perforation generated in the skin, the body surface, or the cancer tissue It is considered to be effective in preventing infection because it is blocked.
　特許文献３には、シートの面に支持された生分解性のニードルを皮膚内に刺して使用するマイクロニードルシートであって、マイクロニードルの根元部は先端部よりも脆く形成されているものが記載されている。特許文献３のマイクロニードルシートは、皮膚内にニードルを刺した状態で前記シートを前記皮膚表面に沿って引っ張る力で根元部を破壊することで、皮膚に挿入されたマイクロニードル部分を支持体から分離する。 Patent Document 3 discloses a microneedle sheet that is used by inserting a biodegradable needle supported on the surface of the sheet into the skin, and the root of the microneedle is formed more brittle than the tip. Are listed. The microneedle sheet of Patent Document 3 breaks the root portion with a force that pulls the sheet along the skin surface while the needle is stabbed in the skin, so that the microneedle part inserted into the skin is removed from the support. To separate.
　しかしながら、上記分離性マイクロニードルシートでは、皮膚に穿刺した後にシートを皮膚に平行にずらして剥離しなければならない。シートは柔らかいので、面の全体を横方向にずらすことは困難であり、また、ずらす力を受けたマイクロニードルが皮膚を傷つけたり、抜ける可能性がある。更に、上記分離性マイクロニードルを狭い箇所に適用した場合には、シートを横方向にずらして剥離することが困難である。 However, in the above-described separable microneedle sheet, after puncturing the skin, the sheet must be shifted parallel to the skin and peeled off. Since the sheet is soft, it is difficult to shift the entire surface in the lateral direction, and the microneedle that receives the shifting force may damage the skin or come off. Furthermore, when the separable microneedle is applied to a narrow portion, it is difficult to separate the sheet in the lateral direction and peel it off.
国際公開第２００６／０８０５０８号International Publication No. 2006/080508 国際公開第２０１１／０１０６０５号International Publication No. 2011/010605 特開２０１０－２３３６７４号JP 2010-233694 A
　本発明は上記に記載した従来の問題を解決するものであり、その目的とするところは、マイクロニードルから目的物質を徐放することができ、投与後に、支持体に引っ張り力を適用する必要なく、皮膚、体表、あるいは癌組織に挿入された徐放性マイクロニードル部分を支持体から溶解により分離することができるマイクロニードル製剤を提供することにある。 The present invention solves the above-described conventional problems, and the object of the present invention is to be able to release the target substance from the microneedle without the need to apply a tensile force to the support after administration. Another object of the present invention is to provide a microneedle preparation capable of separating a sustained-release microneedle portion inserted into the skin, body surface, or cancer tissue from a support by dissolution.
　本発明は、頂上部を備え、非水溶性の生分解性高分子物質と該高分子物質に溶解又は分散した目的物質とを含む第１部分、及び
　基底部を備え、該非水溶性の生分解性高分子物質を溶解し得る溶媒に溶解する水溶性物質を含む第２部分、
を有するマイクロニードル製剤を提供する。 The present invention comprises a top part, a first part containing a water-insoluble biodegradable polymer substance and a target substance dissolved or dispersed in the polymer substance, and a base part, and the water-insoluble biodegradable substance A second part containing a water-soluble substance that dissolves in a solvent capable of dissolving the soluble polymer substance;
A microneedle formulation having
　ある一形態においては、上記マイクロニードル製剤は、第２部分と支持体の間に位置し、水溶性物質を含む第３部分を更に有する。 In one certain form, the said microneedle formulation has a 3rd part which is located between a 2nd part and a support body, and contains a water-soluble substance.
　ある一形態においては、上記第１部分に含まれる生分解性高分子物質がポリ乳酸（PLA）、ポリグリコール酸（PGA）、乳酸・グリコール酸共重合体及びポリカプロラクトン（PCL）から成る群から選択される少なくとも一種である。 In one certain form, the biodegradable polymer substance contained in the said 1st part is from the group which consists of polylactic acid (PLA), polyglycolic acid (PGA), a lactic acid-glycolic acid copolymer, and polycaprolactone (PCL). At least one kind selected.
　ある一形態においては、上記第２部分及び第３部分に含まれる水溶性物質が高分子物質である。 In one embodiment, the water-soluble substance contained in the second part and the third part is a polymer substance.
　ある一形態においては、上記第２部分に含まれる水溶性物質がヒドロキシプロピルメチルセルロースフタレート、ヒドロキシプロピルメチルセルロースアセテートサクシネート、メタクリル酸コポリマーS、メタクリル酸コポリマーLD及びアミノアルキルメタクリレートコポリマーRSから成る群から選択される少なくとも一種である。 In one embodiment, the water-soluble substance contained in the second part is selected from the group consisting of hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, methacrylic acid copolymer S, methacrylic acid copolymer LD, and aminoalkyl methacrylate copolymer RS. Is at least one kind.
　ある一形態においては、上記第３部分に含まれる水溶性物質がコンドロイチン硫酸ナトリウム、デキストラン、デキストラン硫酸及びヒドロキシプロピルβシクロデキストリン及びヒアルロン酸ナトリウムから成る群から選択される少なくとも一種あるいは混合物であり、炭酸水素ナトリウムに代表されるアルカリ化剤を添加して濃厚水溶液（ヒドロゲル）とするとき上記第2部分を構成する物質を溶解して強固に接着し得る。 In one embodiment, the water-soluble substance contained in the third part is at least one selected from the group consisting of sodium chondroitin sulfate, dextran, dextran sulfate, hydroxypropyl β cyclodextrin and sodium hyaluronate, When an alkalizing agent typified by sodium hydride is added to make a concentrated aqueous solution (hydrogel), the substance constituting the second portion can be dissolved and firmly bonded.
　また、本発明は、支持体と複数の上記いずれかのマイクロニードル製剤とを有するマイクロニードル製剤投与部材を提供する。 The present invention also provides a microneedle preparation administration member having a support and a plurality of any of the above microneedle preparations.
　また、本発明は、マイクロニードル製剤が逆転した形状の穴を有する鋳型に、非水溶性の生分解性高分子物質、目的物質及び溶媒を混合することにより得られた第１原料混合物を載せ、乾燥させて、乾燥した第１原料混合物を穴の所定の高さまで充填する工程；
　乾燥した第１原料混合物が充填されている鋳型に、非水溶性の生分解性高分子物質を溶解し得る溶媒に溶解する水溶性物質及び該非水溶性の生分解性高分子物質を溶解し得る溶媒を混合することにより得られた第２原料混合物を載せて、第２原料混合物を穴に充填する工程；
　第２原料混合物に接触するように鋳型の上に支持体を重ねる工程；
　鋳型の穴に充填された第２原料混合物を乾燥させる工程；及び
　支持体を鋳型から剥がす工程；
を包含するマイクロニードル製剤投与部材の製造方法を提供する。 In addition, the present invention places a first raw material mixture obtained by mixing a water-insoluble biodegradable polymer substance, a target substance and a solvent on a mold having a hole with a shape in which the microneedle preparation is reversed, Drying and filling the dried first raw material mixture to a predetermined height of the hole;
A water-soluble substance that dissolves in a solvent capable of dissolving a water-insoluble biodegradable polymer substance and the water-insoluble biodegradable polymer substance can be dissolved in a mold filled with the dried first raw material mixture Placing the second raw material mixture obtained by mixing the solvent and filling the second raw material mixture into the holes;
Overlaying the support on the mold so as to contact the second raw material mixture;
Drying the second raw material mixture filled in the mold holes; and peeling the support from the mold;
The manufacturing method of the microneedle formulation administration member containing this is provided.
　また、本発明は、マイクロニードル製剤が逆転した形状の穴を有する鋳型に、非水溶性の生分解性高分子物質、目的物質及び溶媒を混合することにより得られた第１原料混合物を載せ、乾燥させて、乾燥した第１原料混合物を穴の所定の高さまで充填する工程；
　乾燥した第１原料混合物が充填されている鋳型に、非水溶性の生分解性高分子物質を溶解し得る溶媒に溶解する水溶性物質及び該非水溶性の生分解性高分子物質を溶解し得る溶媒を混合することにより得られた第２原料混合物を載せ、乾燥させて、乾燥した第２原料混合物を穴の所定の高さまで充填する工程；
　乾燥した第２原料混合物が充填されている鋳型に、水溶性物質及び水を混合することにより得られた第３原料混合物を載せて、第３原料混合物を穴に充填する工程；
　第３原料混合物に接触するように鋳型の上に支持体を重ねる工程；
　鋳型の穴に充填された第３原料混合物を乾燥させる工程；及び
　支持体を鋳型から剥がす工程；
を包含するマイクロニードル製剤投与部材の製造方法を提供する。 In addition, the present invention places a first raw material mixture obtained by mixing a water-insoluble biodegradable polymer substance, a target substance and a solvent on a mold having a hole with a shape in which the microneedle preparation is reversed, Drying and filling the dried first raw material mixture to a predetermined height of the hole;
A water-soluble substance that dissolves in a solvent capable of dissolving a water-insoluble biodegradable polymer substance and the water-insoluble biodegradable polymer substance can be dissolved in a mold filled with the dried first raw material mixture Placing the second raw material mixture obtained by mixing the solvent, drying, and filling the dried second raw material mixture to a predetermined height of the hole;
Placing the third raw material mixture obtained by mixing the water-soluble substance and water on the mold filled with the dried second raw material mixture, and filling the third raw material mixture into the holes;
Stacking a support on the mold in contact with the third raw material mixture;
Drying the third raw material mixture filled in the mold holes; and peeling the support from the mold;
The manufacturing method of the microneedle formulation administration member containing this is provided.
　尚、本明細書において支持体の表面とは、シート形状において実質的に面積を有し、相対する二面をいう。支持体の前面とはマイクロニードル製剤を投与する際に、その適用部位に対向する側の表面をいう。支持体の後面とはマイクロニードル製剤を投与する際に、その押圧手段に対向する側の表面をいう。 In addition, in this specification, the surface of a support body has an area substantially in a sheet | seat shape, and means two opposing surfaces. The front surface of the support means the surface on the side facing the application site when the microneedle preparation is administered. The rear surface of the support means the surface on the side facing the pressing means when the microneedle preparation is administered.
　本発明によれば、マイクロニードルから目的物質を徐放することができ、投与後に、支持体に引っ張り力を適用する必要なく、皮膚に挿入されたマイクロニードル部分が支持体から溶解により分離されるマイクロニードル製剤が提供される。 According to the present invention, the target substance can be released slowly from the microneedle, and after administration, the microneedle portion inserted into the skin is separated from the support by dissolution without the need to apply a tensile force to the support. A microneedle formulation is provided.
本発明の一実施形態であるマイクロニードル製剤投与部材の一部断面図である。It is a partial cross section figure of the microneedle formulation administration member which is one Embodiment of this invention. 本発明の一実施形態である２層マイクロニードル製剤の断面図である。It is sectional drawing of the two-layer microneedle formulation which is one Embodiment of this invention. 本発明の他の実施形態である３層マイクロニードル製剤の断面図である。It is sectional drawing of the three-layer microneedle formulation which is other embodiment of this invention.
　図１は、本発明の一実施形態であるマイクロニードル製剤投与部材の一部断面図である。このマイクロニードル製剤投与部材１１は、支持体１３と、該支持体の前面上に複数形成された針状のマイクロニードル製剤１２を有している。 FIG. 1 is a partial cross-sectional view of a microneedle preparation administration member according to an embodiment of the present invention. The microneedle preparation administration member 11 has a support 13 and a plurality of needle-shaped microneedle preparations 12 formed on the front surface of the support.
　支持体はマイクロニードル製剤を固定することが可能な材料で構成される。支持体は非水溶性である。支持体は柔軟性を有するフィルム、シートでも、硬質のチップでもよい。また、支持体は、好ましくは多孔性であり、マイクロニードルを成形する課程において、成分の乾燥を妨げない。 The support is composed of a material capable of fixing the microneedle preparation. The support is water insoluble. The support may be a flexible film, sheet, or hard chip. Further, the support is preferably porous and does not hinder the drying of the components in the course of forming the microneedles.
　支持体の表面（即ち前面又は後面）の形状は円形又は多角形である。支持体の表面の形状はマイクロニードル製剤を適用する箇所に隙間無く並べることができる形状が好ましい。好ましい支持体の形状の一例は四角形、例えば長方形又は正方形である。 The shape of the surface of the support (that is, the front surface or the rear surface) is circular or polygonal. The shape of the surface of the support is preferably a shape that can be arranged without gaps at the location where the microneedle preparation is applied. An example of a preferred support shape is a quadrangle, such as a rectangle or a square.
　支持体の寸法は、例えば、表面の直径又は対角線が約８．５ｃｍ以下、好ましくは約０．４２ｃｍ～約４．２ｃｍ、より好ましくは約１．４ｃｍ～約３．５ｃｍである。支持体の厚さは約０．０１～１０ｍｍ、好ましくは約０．０５～５ｍｍ、さらに好ましくは約０．１～3ｍｍである。 The dimensions of the support are, for example, a surface diameter or diagonal of about 8.5 cm or less, preferably about 0.42 cm to about 4.2 cm, and more preferably about 1.4 cm to about 3.5 cm. The thickness of the support is about 0.01 to 10 mm, preferably about 0.05 to 5 mm, more preferably about 0.1 to 3 mm.
　支持体の寸法は、支持体の表面の形状が四角形又は正方形である場合は、最も長い一辺の長さが６ｃｍ以下、好ましくは０．３ｃｍ～３ｃｍ、より好ましくは１ｃｍ～２．５ｃｍである。支持体の表面の寸法が小さすぎると投与回数が増加して労力が大きくなり、大きすぎると適用部位の凹凸に対応できず、マイクロニードルの挿入不良が多く発生する。 When the surface shape of the support is quadrangular or square, the length of the longest side is 6 cm or less, preferably 0.3 cm to 3 cm, more preferably 1 cm to 2.5 cm. If the size of the surface of the support is too small, the number of administrations increases and labor is increased, and if it is too large, the unevenness of the application site cannot be dealt with, and many microneedle insertion defects occur.
　支持体はテープ状であってもよい。テープ状の支持体の幅は、例えば、約０．０５～１５ｃｍ、好ましくは、約０．３～７ｃｍ、より好ましくは、０．５～３ｃｍである。テープ状の支持体は、例えば、円筒又は棒の側面に巻き付けて使用するのに便利である。テープ状の支持体の長さは、使用する際に適宜決定することができる。 The support may be a tape. The width of the tape-like support is, for example, about 0.05 to 15 cm, preferably about 0.3 to 7 cm, and more preferably 0.5 to 3 cm. The tape-like support is convenient for use, for example, by being wound around the side surface of a cylinder or a rod. The length of the tape-like support can be appropriately determined when used.
　また、マイクロニードル製剤は、約１～３００本／ｃｍ２、好ましくは約２～２５０本／ｃｍ２、より好ましくは約４～１００本／ｃｍ２の密度で支持体上に存在する。マイクロニードル製剤の密度が３００本／ｃｍ２を超えるとマイクロニードル製剤の刺入時における抵抗が増大し、刺入深度が浅くなることがある。 Further, the microneedle preparation is present on the support at a density of about 1 to 300 / cm 2 , preferably about 2 to 250 / cm 2 , more preferably about 4 to 100 / cm 2 . When the density of the microneedle preparation exceeds 300 / cm 2 , the resistance at the time of insertion of the microneedle preparation increases, and the insertion depth may become shallow.
　図２は、本発明の一実施形態である２層マイクロニードル製剤の断面図である。マイクロニードル製剤１２は皮膚、体表、あるいは癌組織を貫くことができる形状の頂上部を有する。また、マイクロニードル製剤は、幅広であり、支持体に固定されうる基底部を有する。マイクロニードル製剤の形状は略円錐状であってよく、略角錐状であってもよい。 FIG. 2 is a cross-sectional view of a two-layer microneedle preparation that is one embodiment of the present invention. The microneedle formulation 12 has a top that is shaped to penetrate skin, body surface, or cancer tissue. In addition, the microneedle preparation is wide and has a base that can be fixed to a support. The shape of the microneedle preparation may be substantially conical or may be substantially pyramidal.
　マイクロニードル製剤は、５０～３０００μｍ、好ましくは１００～２０００μｍ、より好ましくは２００～１５００μｍの基底部直径Ｄを有する。また、マイクロニードル製剤は、５０～５０００μｍ、好ましくは１００～４０００μｍ、より好ましくは１５０～３０００μｍの挿入方向長さＨを有する。ある一形態においては、マイクロニードル製剤の挿入方向長さＨは、４００～４０００μｍ、好ましくは８００～３０００μｍ、より好ましくは１５００～２５００μｍである。 The microneedle preparation has a base diameter D of 50 to 3000 μm, preferably 100 to 2000 μm, more preferably 200 to 1500 μm. The microneedle preparation has a length H in the insertion direction of 50 to 5000 μm, preferably 100 to 4000 μm, more preferably 150 to 3000 μm. In one certain form, the length H in the insertion direction of the microneedle preparation is 400 to 4000 μm, preferably 800 to 3000 μm, more preferably 1500 to 2500 μm.
　マイクロニードル製剤の寸法がこの範囲外であると、強度が不足したり、刺入性が低下したりする。より具体的には、マイクロニードル製剤は挿入方向長さ２０００μｍ、基底部直径８００μｍの円錐状でありうる。 If the size of the microneedle preparation is outside this range, the strength will be insufficient or the penetration will be reduced. More specifically, the microneedle preparation may have a conical shape with a length in the insertion direction of 2000 μm and a base diameter of 800 μm.
　マイクロニードル製剤１２は、第１部分１２Ａと第２部分１２Ｂの２層を有する。第１部分は頂上部を有し、第２部分は基底部を有する。また、第１部分と第２部分は境界面を形成する。第１部分と第２部分の境界面はマイクロニードル製剤の底面と略平行、又は実質的に平行である。 The microneedle preparation 12 has two layers of a first portion 12A and a second portion 12B. The first part has a top and the second part has a base. Further, the first portion and the second portion form a boundary surface. The interface between the first part and the second part is substantially parallel or substantially parallel to the bottom surface of the microneedle formulation.
　第１部分１２Ａは非水溶性の生分解性高分子物質と該高分子物質に溶解又は分散した目的物質とを含む。第１部分の生分解性高分子物質が非水溶性であることで、第１部分は体内で速やかに溶解せず、生分解性高分子物質が時間をかけて加水分解される結果、目的物質が体内に徐放される。 The first portion 12A includes a water-insoluble biodegradable polymer substance and a target substance dissolved or dispersed in the polymer substance. Since the biodegradable polymer substance of the first part is water-insoluble, the first part does not dissolve quickly in the body, and the biodegradable polymer substance is hydrolyzed over time, resulting in the target substance Is slowly released into the body.
　目的物質は生分解性高分子物質に溶解又は分散される。目的物質を保持し徐放する多孔性物質等の第三成分は、第１部分の成分として使用しない。そのため、マイクロニードル製剤の強度を考慮した場合でも、目的物質の含有量を十分に増大させることができる。 The target substance is dissolved or dispersed in the biodegradable polymer substance. A third component such as a porous material that retains and slowly releases the target substance is not used as a component of the first part. Therefore, even when the strength of the microneedle preparation is taken into consideration, the content of the target substance can be sufficiently increased.
　本明細書において、生分解性高分子物質に目的物質が分散するとは、生分解性高分子物質の内部に目的物質が実質的に均一に分散した状態、又は生分解性高分子物質の内部に目的物質が実質的に均一に懸濁した状態を意味する。 In the present specification, the target substance is dispersed in the biodegradable polymer substance in a state where the target substance is substantially uniformly dispersed in the biodegradable polymer substance or in the biodegradable polymer substance. It means a state in which the target substance is suspended substantially uniformly.
　ある一形態においては、第１部分は、非水溶性の生分解性高分子物質と該高分子物質に溶解又は分散した目的物質とからなる。典型的には、非水溶性の生分解性高分子物質は第１部分のマトリックスを形成し、目的物質はドメインを形成する。 In one embodiment, the first portion is composed of a water-insoluble biodegradable polymer substance and a target substance dissolved or dispersed in the polymer substance. Typically, the water-insoluble biodegradable polymeric material forms a first part matrix and the target material forms a domain.
　第１部分に含まれる非水溶性の生分解性高分子物質の濃度は、好ましくは、５０重量％以上である。該高分子物質の濃度が５０重量％未満であるとマイクロニードル製剤の強度が低下して、投与時に突刺不良又は破損が発生しうる。第１部分に含まれる非水溶性の生分解性高分子物質の濃度は、好ましくは６０～９９．９９重量％、より好ましくは７０～９９．９重量％である。 The concentration of the water-insoluble biodegradable polymer substance contained in the first part is preferably 50% by weight or more. When the concentration of the polymer substance is less than 50% by weight, the strength of the microneedle preparation is lowered, and puncture failure or breakage may occur during administration. The concentration of the water-insoluble biodegradable polymer substance contained in the first part is preferably 60 to 99.99% by weight, more preferably 70 to 99.9% by weight.
　第１部分に含まれる目的物質の濃度は、好ましくは、５０重量％未満である。目的物質の濃度が５０重量％以上であるとマイクロニードル製剤の強度が低下して、投与時に突刺不良又は破損が発生しうる。第１部分に含まれる目的物質の濃度は、好ましくは０．００１～４０重量％、より好ましくは０．１～３０重量％である。 The concentration of the target substance contained in the first part is preferably less than 50% by weight. When the concentration of the target substance is 50% by weight or more, the strength of the microneedle preparation decreases, and puncture failure or breakage may occur during administration. The concentration of the target substance contained in the first part is preferably 0.001 to 40% by weight, more preferably 0.1 to 30% by weight.
　一般に、第１部分の挿入方向長さは、目的物質を十分な量で含有させるために、マイクロニードル製剤の挿入方向長さＨの約５０％以上である。第１部分の挿入方向長さは、好ましくは長さＨの約６０～９８％、より好ましくは、約７０～９０％である。 Generally, the length in the insertion direction of the first portion is about 50% or more of the length H in the insertion direction of the microneedle preparation in order to contain the target substance in a sufficient amount. The length of the first portion in the insertion direction is preferably about 60 to 98% of the length H, more preferably about 70 to 90%.
　典型的には、第１部分の挿入方向長さは１０～５０００μｍである。第１部分の挿入方向長さが１０μｍ未満であると、目的物質の投与量及び徐放性が不十分になり、５０００μｍを超えると、血管を傷つける恐れが生じるので好ましくない。第１部分の挿入方向長さは、好ましくは２００～４０００μｍ、より好ましくは２５０～３０００μｍである。ある一形態においては、第１部分の挿入方向長さは、５００～２５００μｍ、好ましくは１０００～２３００μｍである。 Typically, the length of the first portion in the insertion direction is 10 to 5000 μm. If the length of the first portion in the insertion direction is less than 10 μm, the dose and sustained release of the target substance are insufficient, and if it exceeds 5000 μm, the blood vessel may be damaged, which is not preferable. The length of the first portion in the insertion direction is preferably 200 to 4000 μm, more preferably 250 to 3000 μm. In one embodiment, the length of the first portion in the insertion direction is 500 to 2500 μm, preferably 1000 to 2300 μm.
　第１部分は、長さ方向に領域が複数に分割されて、多層構造を形成し、ある層にのみ目的物質を保持しているものであってよい。そのことで、目的物質の投与位置を垂直方向、すなわち、皮膚の深さ方向に調節できる。 In the first portion, the region may be divided into a plurality of portions in the length direction to form a multilayer structure, and the target substance may be held only in a certain layer. Thereby, the administration position of the target substance can be adjusted in the vertical direction, that is, in the depth direction of the skin.
　第２部分１２Ｂは非水溶性の生分解性高分子物質を溶解し得る溶媒に溶解する水溶性物質を含む。第２部分の物質が水溶性であることで、第２部分は体内で溶解し、第１部分が支持体から分離される。第２部分の物質が非水溶性の生分解性高分子物質を溶解し得る溶媒に溶解することで、第２部分は第１部分に対しマイクロニードル製剤として機能するのに十分な強度で結合する。ある一形態においては第２部分の物質は非水溶性の生分解性高分子物質を溶解し得る溶媒に溶解する水溶性高分子物質である。第２部分に水溶性高分子物質を含ませることで、第１部分に対する結合強度が向上する。ある一形態においては、第２部分は非水溶性の生分解性高分子物質を溶解し得る溶媒に溶解する水溶性物質からなる。 The second portion 12B includes a water-soluble substance that dissolves in a solvent that can dissolve the water-insoluble biodegradable polymer substance. Since the substance of the second part is water-soluble, the second part dissolves in the body and the first part is separated from the support. By dissolving the substance in the second part in a solvent capable of dissolving the water-insoluble biodegradable polymer substance, the second part binds to the first part with sufficient strength to function as a microneedle formulation. . In one certain form, the substance of a 2nd part is a water-soluble polymer substance which melt | dissolves in the solvent which can melt | dissolve a water-insoluble biodegradable polymer substance. By including a water-soluble polymer substance in the second part, the bond strength to the first part is improved. In one certain form, a 2nd part consists of a water-soluble substance which melt | dissolves in the solvent which can melt | dissolve a water-insoluble biodegradable polymer substance.
　典型的には、第２部分の挿入方向長さは１０～２０００μｍである。第２部分の挿入方向長さが１０μｍ未満であると、第１部分と支持体の結合強度が不十分になり、投与時に突刺不良又は破損が発生しうる。第２部分の挿入方向長さが２０００μｍを超えると、第１部分に含有される目的物質の量が少なくなってしまう。第２部分の挿入方向長さは、好ましくは５０～５００μｍ、より好ましくは１００～３００μｍである。 Typically, the length of the second portion in the insertion direction is 10 to 2000 μm. When the insertion length of the second part is less than 10 μm, the bonding strength between the first part and the support becomes insufficient, and puncture failure or breakage may occur during administration. If the length of the second portion in the insertion direction exceeds 2000 μm, the amount of the target substance contained in the first portion is reduced. The length of the second portion in the insertion direction is preferably 50 to 500 μm, more preferably 100 to 300 μm.
　図３は、本発明の他の実施形態である３層マイクロニードル製剤の断面図である。マイクロニードル製剤１２は、第２部分１２Ｂと支持体（非表示）の間に、第３部分１２Ｃを有する。 FIG. 3 is a cross-sectional view of a three-layer microneedle preparation that is another embodiment of the present invention. The microneedle formulation 12 has a third portion 12C between the second portion 12B and a support (not shown).
　第３部分１２Ｃは水溶性物質を含む。第３部分の物質が水溶性であることで、第３部分は第２部分に強固に結合し、一方、体内では速やかに溶解して、第１部分が支持体から分離される。ある一形態においては第３部分の物質は水溶性高分子物質である。第３部分に水溶性高分子物質を含ませることで、第２部分に対する結合強度が向上する。ある一形態においては、第３部分は水溶性物質からなる。第３部分の水溶性物質は第２部分の水溶性物質と強固に結合できるようにしなければならない。 The third part 12C contains a water-soluble substance. Since the substance of the third part is water-soluble, the third part is firmly bonded to the second part, while rapidly dissolving in the body, and the first part is separated from the support. In one embodiment, the third part material is a water-soluble polymer material. By including the water-soluble polymer substance in the third portion, the bond strength to the second portion is improved. In one certain form, a 3rd part consists of water-soluble substances. The water-soluble substance of the third part must be able to bind tightly with the water-soluble substance of the second part.
　典型的には、第３部分の挿入方向長さは１０～２０００μｍである。第３部分の挿入方向長さが１０μｍ未満であると、第２部分に対する結合強度が不十分になり、投与時に突刺不良又は破損が発生しうる。第３部分の挿入方向長さは、好ましくは５０～５００μｍ、より好ましくは１００～３００μｍである。 Typically, the length of the third portion in the insertion direction is 10 to 2000 μm. When the insertion length of the third part is less than 10 μm, the bonding strength to the second part becomes insufficient, and puncture failure or breakage may occur during administration. The length of the third portion in the insertion direction is preferably 50 to 500 μm, more preferably 100 to 300 μm.
　生分解性高分子物質を基剤としてマイクロニードルに成形するには加熱して溶融した後に射出成形する方法などが実用化されているが、高温に晒されると分解する薬物が多いので汎用性が低い。低温条件下で生分解性高分子物質を基剤としてマイクロニードル形状に成形するには、溶媒を用いて生分解性高分子物質をいったん溶解してメス型などに充填し、乾燥した後に剥離して取り出すことにより成形することが好ましい。また、メス型への充填にはマイクロディスペンサーを用いても良い。目的物質を含む生分解性高分子物質溶液を３Dプリンターで支持体上に直接造形しても良い。 In order to mold microneedles based on biodegradable polymer materials, methods such as injection molding after heating and melting have been put into practical use. However, since many drugs decompose when exposed to high temperatures, they are versatile. Low. To form a microneedle shape using a biodegradable polymer substance as a base under low temperature conditions, dissolve the biodegradable polymer substance once in a solvent using a solvent, dry it after drying it, etc. It is preferable to mold by taking out. Further, a micro dispenser may be used for filling the female mold. A biodegradable polymer material solution containing the target substance may be directly shaped on the support with a 3D printer.
　本発明のマイクロニードル製剤投与部材は、例えば、マイクロニードル製剤が逆転した形状の穴を有する鋳型を用いてマイクロニードル製剤を形成し、次いで、形成されたマイクロニードル製剤を支持体に固定することにより製造される。鋳型としては、マイクロニードル製剤の形状及び配置に対応する穴が設けられた板状材料を用いる。板状材料の材質には、ステンレス、アルミなどの金属やフッ素樹脂、シリコン樹脂等が用いられる。 The microneedle preparation administration member of the present invention is formed by, for example, forming a microneedle preparation using a template having a hole with a shape reverse to that of the microneedle preparation, and then fixing the formed microneedle preparation to a support. Manufactured. As the mold, a plate-like material provided with holes corresponding to the shape and arrangement of the microneedle preparation is used. As the material of the plate-like material, a metal such as stainless steel or aluminum, a fluororesin, a silicon resin, or the like is used.
　まず、マイクロニードル製剤の第１部分の原料である非水溶性の生分解性高分子物質、目的物質及び溶媒を混合して、第１原料混合物を調製する。その際、生分解性高分子物質は溶媒に溶解し、目的物質は溶媒に溶解するか実質的に均一に分散する。 First, a water-insoluble biodegradable polymer substance, a target substance and a solvent, which are raw materials for the first part of the microneedle preparation, are mixed to prepare a first raw material mixture. At that time, the biodegradable polymer substance is dissolved in the solvent, and the target substance is dissolved in the solvent or dispersed substantially uniformly.
　好ましい生分解性高分子物質の具体例としては、ポリ乳酸（PLA）、ポリグリコール酸（PGA）、乳酸・グリコール酸共重合体、ポリカプロラクトン（PCL）、PLAとPGAとPCLとの共重合体、ポリジオキサノン、キトサン、乳酸デプシペプチドランダム共重合体、乳酸デプシペプチドボロック共重合体、トリメチレンカーボネート、ポリエチレングリコールとPGA、PCL及び／又はPLAとのブロック共重合体、ポリ乳酸グラフト化多糖が挙げられる。大矢裕一、「ドラッグデリバリーシステム」　２３－６、６１８～６２６頁、２００８年の記載をここに援用する。 Specific examples of preferable biodegradable polymer materials include polylactic acid (PLA), polyglycolic acid (PGA), lactic acid / glycolic acid copolymer, polycaprolactone (PCL), and a copolymer of PLA, PGA and PCL. , Polydioxanone, chitosan, lactic acid depsipeptide random copolymer, lactic acid depsipeptide boron block copolymer, trimethylene carbonate, block copolymer of polyethylene glycol and PGA, PCL and / or PLA, and polylactic acid grafted polysaccharide. Yuichi Oya, “Drug Delivery System” 23-6, pages 618 to 626, 2008, is incorporated herein by reference.
　溶媒は生分解性高分子物質を溶解し、目的物質を劣化変質させないものを使用すればよい。溶媒の具体例としては、ジクロロメタン、エタノール、酢酸エチルおよびそれらの混和物等が挙げられる。生分解性高分子物質及び溶媒は１種類だけを用いてもよいし、複数種を組み合わせて用いてもよい。 As the solvent, a solvent that dissolves the biodegradable polymer substance and does not deteriorate and alter the target substance may be used. Specific examples of the solvent include dichloromethane, ethanol, ethyl acetate, and mixtures thereof. Only one type of biodegradable polymer substance and solvent may be used, or a plurality of types may be used in combination.
　目的物質は、効能を得るために人体に投与する物質である。目的物質としては、高分子物質、低分子物質、化学物質、生理活性物質、タンパク質（組換え型または天然型）、ペプチド、多糖類など、生体適合性を示す物質が目的物質として採用可能である。脂溶性（非水溶性）物質から極性（水溶性）物質までの広範な目的物質に適用でき、徐放性基剤である生分解性高分子物質内に溶解あるいは分散した状態で共存する。好ましくは、抗癌薬、免疫抑制薬、ペプチド、タンパク質、核酸、又は多糖類である。目的物質は、薬物、ワクチン抗原、栄養素、又は化粧品用成分であってもよい。 The target substance is a substance that is administered to the human body to obtain efficacy. As the target substance, biocompatible substances such as high molecular weight substances, low molecular weight substances, chemical substances, physiologically active substances, proteins (recombinant or natural type), peptides, polysaccharides, etc. can be adopted as target substances. . It can be applied to a wide range of target substances from fat-soluble (water-insoluble) substances to polar (water-soluble) substances, and coexists in a dissolved or dispersed state in a biodegradable polymer substance that is a sustained release base. Preferably, they are anticancer drugs, immunosuppressive drugs, peptides, proteins, nucleic acids, or polysaccharides. The target substance may be a drug, vaccine antigen, nutrient, or cosmetic ingredient.
　本発明のマイクロニードル製剤の徐放性を考慮した場合に、好ましい目的物質としては、糖尿病薬、抗がん薬、免疫抑制薬、ホルモン薬、ワクチンなどが挙げられる。 Considering the sustained release of the microneedle preparation of the present invention, preferable target substances include diabetes drugs, anticancer drugs, immunosuppressive drugs, hormone drugs, vaccines and the like.
　次いで、第１原料混合物を鋳型に載せ、要すれば、スキジー等の塗布用具又は塗布装置、充填装置を用いて塗布圧をかけて、これを鋳型に形成された穴の中に充填する。充填を確実に行うために、遠心分離機等を用いて鋳型に遠心力を印加してもよい。 Next, the first raw material mixture is placed on a mold, and if necessary, coating pressure is applied using a coating tool such as squeegee or a coating apparatus or a filling apparatus, and this is filled into a hole formed in the mold. In order to ensure filling, a centrifugal force may be applied to the mold using a centrifuge or the like.
　余分な第１原料混合物を除去した後、穴に充填された第１原料混合物を乾燥させる。乾燥は、目的物質の変質等を防止するために、５０℃以下、好ましくは室温（約２５℃）以下の温度で行われる。乾燥後、第１原料混合物の体積は減少する。 After removing the excess first raw material mixture, the first raw material mixture filled in the holes is dried. Drying is performed at a temperature of 50 ° C. or lower, preferably room temperature (about 25 ° C.) or lower in order to prevent the target substance from being altered. After drying, the volume of the first raw material mixture decreases.
　この現象を利用して、マイクロニードル製剤の第１部分の挿入方向長さを調節することができる。すなわち、第１原料混合物を調製する際、第１原料混合物の固形分濃度は、第１原料混合物が鋳型の中で乾燥した後に、マイクロニードル製剤の第１部分の挿入方向長さに対応する高さまで第１原料混合物の固形分が残存するのに適当な濃度に調節する。 This length can be used to adjust the length of the first portion of the microneedle formulation in the insertion direction. That is, when preparing the first raw material mixture, the solid content concentration of the first raw material mixture is high corresponding to the length in the insertion direction of the first portion of the microneedle preparation after the first raw material mixture is dried in the mold. Then, the concentration is adjusted to an appropriate concentration so that the solid content of the first raw material mixture remains.
　次に、マイクロニードル製剤の第２部分の原料である非水溶性の生分解性高分子物質を溶解し得る溶媒に溶解する水溶性物質及び非水溶性の生分解性高分子物質を溶解し得る溶媒を混合して、第２原料混合物を調製する。その際、上記水溶性物質は非水溶性の生分解性高分子物質を溶解し得る溶媒に溶解する。次いで、乾燥した第１原料混合物が充填されている鋳型に第２原料混合物を載せて鋳型の穴の中に充填するか、第２原料混合物を支持体の表面に塗布するか、又は必要に応じてその両方を行う。第２原料混合物の溶媒として非水溶性の生分解性高分子物質を溶解し得る溶媒を使用することで、第２部分の原料である上記水溶性物質は第１部分の非水溶性の生分解性高分子物質層にしっかり結合する。 Next, the water-soluble substance and the water-insoluble biodegradable polymer substance that can be dissolved in the solvent that can dissolve the water-insoluble biodegradable polymer substance that is the raw material of the second part of the microneedle preparation can be dissolved. A solvent is mixed to prepare a second raw material mixture. At this time, the water-soluble substance is dissolved in a solvent capable of dissolving the water-insoluble biodegradable polymer substance. Then, the second raw material mixture is placed on the mold filled with the dried first raw material mixture and filled into the mold holes, or the second raw material mixture is applied to the surface of the support, or as required. Do both. By using a solvent capable of dissolving the water-insoluble biodegradable polymer substance as the solvent of the second raw material mixture, the water-soluble substance as the raw material of the second part is converted into the water-insoluble biodegradable part of the first part. Bonds firmly to the conductive polymer layer.
　非水溶性の生分解性高分子物質を溶解し得る溶媒に溶解する水溶性物質は、水溶性物質ではあるが生分解性高分子物質と接着可能な物質を使用する。その物質としては、ヒドロキシプロピルメチルセルロースフタレート（商品名HPMCPのHP-55、信越化学社製）、ヒドロキシプロピルメチルセルロースアセテートサクシネート（商品名AQOAT、信越化学社製）、メタクリル酸コポリマーS（オイドラギットS、Rohm Pharma社製）、メタクリル酸コポリマーLD（オイドラギットL、Rohm Pharma社製）、アミノアルキルメタクリレートコポリマーRS（オイドラギットRS、Rohm Pharma社製）などが適している。何故ならば、これらの高分子物質は生分解性高分子物質の溶解に用いる溶媒に溶解するので、溶液としてマイクロニードルの第２部分の調製に用いると第１部分の層に接着させることができるからである。 The water-soluble substance that dissolves in the solvent capable of dissolving the water-insoluble biodegradable polymer substance is a water-soluble substance, but a substance that can adhere to the biodegradable polymer substance is used. The substances include hydroxypropyl methylcellulose phthalate (trade name HPMCP HP-55, manufactured by Shin-Etsu Chemical Co., Ltd.), hydroxypropyl methylcellulose acetate succinate (trade name AQOAT, manufactured by Shin-Etsu Chemical Co., Ltd.), methacrylic acid copolymer S (Eudragit S, Rohm Pharma), methacrylic acid copolymer LD (Eudragit L, Rohm Pharma), and aminoalkyl methacrylate copolymer RS (Eudragit RS, RohmRPharma) are suitable. This is because these polymer substances are dissolved in the solvent used for dissolving the biodegradable polymer substance, so that they can be adhered to the layer of the first part when used as a solution for the preparation of the second part of the microneedle. Because.
　一方、これらの高分子物質は腸溶性コーティングに用いられているので、中性からアルカリ側のpHにて水に溶解する。例えば、HP-55は5.5以上のpHで水に溶解するので、皮膚に穿刺すると体液（pH7.4）にて溶解し、生分解性高分子物質を基剤とする第１部分を切り離すことができる。また、必要に応じて炭酸水素ナトリウムなどのアルカリ化剤を混合しても良い。 On the other hand, since these polymer substances are used for enteric coatings, they are dissolved in water at neutral to alkaline pH. For example, HP-55 dissolves in water at a pH of 5.5 or higher, so when puncturing the skin, it dissolves in body fluid (pH 7.4), and the first part based on a biodegradable polymer substance can be separated. it can. Moreover, you may mix alkalizing agents, such as sodium hydrogencarbonate, as needed.
　但し、第２部分を作成するための物質としてはこれらの高分子物質に限定される必要はない。水溶性の低分子物質であっても上部マイクロニードルの主構成物である生分解性物質を溶解する溶媒に溶解する物質であれば使用することができる。 However, the material for creating the second portion need not be limited to these polymer materials. Even a water-soluble low-molecular substance can be used as long as it is a substance that dissolves in a solvent that dissolves a biodegradable substance that is a main component of the upper microneedle.
　次いで、第２原料混合物に接触するように鋳型の上に支持体を重ねる。第２部分との結合を確実に行うために、支持体の前面に第２原料混合物を塗布しておいてもよい。 Next, a support is stacked on the mold so as to come into contact with the second raw material mixture. In order to perform the coupling | bonding with a 2nd part reliably, you may apply | coat the 2nd raw material mixture to the front surface of a support body.
　支持体は、シート、フィルムであり、第２混合物と接触して、好ましくは、第２混合物の成分がアンカー効果で支持体内部の細孔へ侵入することにより強固に接合するとともに第２混合物に含まれる溶媒を吸収し、放出することができる。充填を確実に行うために、遠心分離機等を用いて鋳型に遠心力を印加してもよい。 The support is a sheet, a film, and is in contact with the second mixture, and preferably, the components of the second mixture are firmly joined by intruding into the pores inside the support by the anchor effect and are bonded to the second mixture. It can absorb and release the contained solvent. In order to ensure filling, a centrifugal force may be applied to the mold using a centrifuge or the like.
　好ましい支持体は、ポリウレタン、ポリイミド、ポリエチレン、ポリプロピレン、ポリメチルメタクリレート、ポリ塩化ビニル、塩素化ポリエチレン－スチレン樹脂及びシリコーン樹脂等の樹脂製のフィルム又は多孔性板、非水溶性の錠剤用賦形剤から成る板状成形体、又は布、紙、不織布等の繊維製シートである。支持体は、伸張性又は伸縮性を示す樹脂製フィルム、エラストマーフィルムであってよい。伸張性又は伸縮性を示す樹脂製フィルムの具体例には、ポリウレタンフィルム、ポリエチレンフィルム、ポリプロピレンフィルム、シリコーン樹脂フィルムが挙げられる。 Preferred supports are polyurethane, polyimide, polyethylene, polypropylene, polymethylmethacrylate, polyvinyl chloride, chlorinated polyethylene-styrene resin and silicone resin films or porous plates, and water-insoluble tablet excipients. Or a sheet made of fiber such as cloth, paper, or non-woven fabric. The support may be a resin film or an elastomer film exhibiting stretchability or stretchability. Specific examples of the resin film exhibiting stretchability or stretchability include polyurethane film, polyethylene film, polypropylene film, and silicone resin film.
　繊維製シートとしては、絆創膏のような医療用テープの基材に使用されている布、紙、不織布及びフィルムが好ましい。 As the fiber sheet, cloth, paper, non-woven fabric and film used as a base material for medical tape such as adhesive bandage are preferable.
　錠剤用賦形剤としては、酢酸セルロース、結晶セルロース、セルロース誘導体、キチン及びキチン誘導体などが挙げられる。錠剤用賦形剤から成る成形体は錠剤と同様にして製造すればよい。例えば、錠剤用賦形剤を打錠機の臼に入れ、杵を用いて適当な打錠圧で打錠する。支持体の寸法は、臼の直径、錠剤用賦形剤の充填量及び打錠圧を増減することにより、適宜調節される。錠剤基盤に関しては、米国特許公開第２０１１／０１５２７９２号及び特開２０１１－１２０５０号の開示内容をここに挿入する。 Tablet excipients include cellulose acetate, crystalline cellulose, cellulose derivatives, chitin and chitin derivatives. What is necessary is just to manufacture the molded object which consists of an excipient | filler for tablets similarly to a tablet. For example, a tablet excipient is put into a mortar of a tableting machine and tableted with a suitable tableting pressure using a punch. The dimensions of the support are appropriately adjusted by increasing or decreasing the diameter of the mortar, the filling amount of the tablet excipient, and the tableting pressure. Regarding the tablet base, the disclosures of US Patent Publication No. 2011/0152792 and Japanese Patent Application Laid-Open No. 2011-12050 are inserted here.
　チップに磁力応答性を付与する場合は、錠剤用賦形剤に鉄粉等の磁力応答性物質を混入すればよい。例えば、錠剤用賦形剤に磁力応答性成分を混和して打錠機の臼の中に入れ、杵を用いて適当な打錠圧で打錠する。磁力応答性チップは２層錠構造にして、マイクロニードルを構築する第一層には磁力応答性物質を配合しないようにすることが好ましい。磁力応答性を付与した錠剤基盤に関しては、特開２０１３－１６９４３２号の開示内容をここに挿入する。 When magnetic responsiveness is imparted to the chip, a magnetic responsive substance such as iron powder may be mixed into the tablet excipient. For example, a magnetically responsive component is mixed with a tablet excipient and placed in a mortar of a tableting machine, and tableted with an appropriate tableting pressure using a punch. It is preferable that the magnetic-responsive chip has a two-layer tablet structure so that a magnetic-responsive substance is not blended in the first layer constituting the microneedle. Regarding the tablet base to which magnetic responsiveness is imparted, the disclosure content of JP2013-169432A is inserted here.
　次いで、鋳型の穴に充填された第２原料混合物を乾燥させる。乾燥は、目的物質の変質等を防止するために、第１原料混合物と同様の条件で行われる。その後、支持体を鋳型から剥がすことにより、本発明のマイクロニードル製剤投与部材が得られる。 Next, the second raw material mixture filled in the mold holes is dried. Drying is performed under the same conditions as the first raw material mixture in order to prevent deterioration of the target substance. Thereafter, the support body is peeled off from the mold to obtain the microneedle preparation administration member of the present invention.
　３層マイクロニードル製剤投与部材を製造する場合は、マイクロニードル製剤の第３部分の原料である水溶性物質及び溶媒である水を混合して、第３原料混合物を調製する。その際、上記水溶性物質は水に溶解する。第２部の層を構成する水溶性物質との結合性を考慮して、水は中性からアルカリ側のpHに調節してもよい。 In the case of producing a three-layer microneedle formulation administration member, a third material mixture is prepared by mixing a water-soluble substance as a raw material of the third part of the microneedle formulation and water as a solvent. At that time, the water-soluble substance is dissolved in water. In consideration of the binding property with the water-soluble substance constituting the second part layer, the water may be adjusted from neutral to alkaline pH.
　次いで、乾燥した第２原料混合物が充填されている鋳型に第３原料混合物を載せて鋳型の穴の中に充填するか、第３原料混合物を支持体の表面に塗布するか、又は必要に応じてその両方を行う。第３原料混合物の溶媒として水を使用することで、第３部分の原料である上記水溶性物質は第２部分の水溶性物質と混和する。その結果、第３部分は第２部分に結合する。 Next, the third raw material mixture is placed on the mold filled with the dried second raw material mixture and filled into the mold holes, or the third raw material mixture is applied to the surface of the support, or as required. Do both. By using water as the solvent of the third raw material mixture, the water-soluble substance that is the raw material of the third part is mixed with the water-soluble substance of the second part. As a result, the third part is bonded to the second part.
　次いで、第３原料混合物に接触するように鋳型の上に支持体を重ねる。第３部分との結合を確実に行うために、支持体の前面に第３原料混合物を塗布しておいてもよい。 Next, a support is stacked on the mold so as to come into contact with the third raw material mixture. In order to perform the coupling | bonding with a 3rd part reliably, you may apply | coat the 3rd raw material mixture to the front surface of a support body.
　水溶性物質の具体例としては、多糖類、タンパク質、ポリビニルアルコール、カルボキシビニルポリマー、及びポリアクリル酸ナトリウムからなる群より選ばれた少なくとも１つの物質が挙げられる。 Specific examples of the water-soluble substance include at least one substance selected from the group consisting of polysaccharides, proteins, polyvinyl alcohol, carboxyvinyl polymers, and sodium polyacrylate.
　好ましくは、前記多糖類は、コンドロイチン硫酸及びその塩類（コンドロイチン硫酸ナトリウム等）、デキストラン、デキストラン硫酸、ヒアルロン酸及びその塩類（ヒアルロン酸ナトリウム等）、シクロデキストリン、ヒドロキシプロピルβシクロデキストリン、ヒドロキシプロピルセルロース、アルギン酸、アガロース、プルラン、及びグリコーゲンおよびそれらの誘導体より選ばれた少なくとも１つの物質である。 Preferably, the polysaccharide is chondroitin sulfate and salts thereof (such as sodium chondroitin sulfate), dextran, dextran sulfate, hyaluronic acid and salts thereof (such as sodium hyaluronate), cyclodextrin, hydroxypropyl β cyclodextrin, hydroxypropyl cellulose, At least one substance selected from alginic acid, agarose, pullulan, and glycogen and derivatives thereof.
　好ましくは、前記タンパク質は、血清アルブミン、血清α酸性糖タンパク質、コラーゲン、低分子コラーゲン及びゼラチンおよびそれらの誘導体より選ばれた少なくとも１つの物質である。 Preferably, the protein is at least one substance selected from serum albumin, serum α-acid glycoprotein, collagen, low molecular collagen, gelatin, and derivatives thereof.
　特に好ましい水溶性物質としては、コンドロイチン硫酸ナトリウム、デキストラン、デキストラン硫酸、ヒドロキシプロピルβシクロデキストリン及びヒアルロン酸等が挙げられる。これらの物質は医薬品としての使用実績があるため、安全性が担保されている。水溶性物質は１種類だけを用いてもよいし、複数種を組み合わせて用いてもよい。 Particularly preferred water-soluble substances include sodium chondroitin sulfate, dextran, dextran sulfate, hydroxypropyl β cyclodextrin and hyaluronic acid. Since these substances have been used as pharmaceuticals, their safety is guaranteed. Only one type of water-soluble substance may be used, or a plurality of types may be used in combination.
　次いで、第３原料混合物を乾燥させる。乾燥は、目的物質の変質等を防止するために、第１原料混合物と同様の条件で行われる。その後、支持体を鋳型から剥がすことにより、本発明のマイクロニードル製剤投与部材が得られる。 Next, the third raw material mixture is dried. Drying is performed under the same conditions as the first raw material mixture in order to prevent deterioration of the target substance. Thereafter, the support body is peeled off from the mold to obtain the microneedle preparation administration member of the present invention.
　得られたマイクロニードル製剤投与部材は皮膚病等のヒト又は動物の体表の疾患を治療するために有用である。体表とは、生体の外部に存在する物質と接触しうる生体の部分を広くいう。例えば、皮膚、爪、目の表面、鼻の内面、口腔内面、気管、食道、胃、腸、肛門、胆管などの内面は体表に含まれる。得られたマイクロニードル製剤投与部材は、加えて、ヒト又は動物の体内の組織を横切る薬物送達の用途にも有用である。 The obtained microneedle preparation administration member is useful for treating diseases of human or animal body surfaces such as skin diseases. The body surface broadly refers to a part of a living body that can come into contact with a substance existing outside the living body. For example, inner surfaces such as skin, nails, eye surface, inner surface of nose, inner surface of oral cavity, trachea, esophagus, stomach, intestine, anus, bile duct are included in the body surface. The resulting microneedle formulation administration member is also useful for drug delivery applications across human or animal body tissue.
　適用例としては、本発明のマイクロニードル製剤投与部材を口腔、眼、鼻腔、膣部、食道、上部消化管、下部消化管及び胆管、血管等の粘膜又は管壁へ適用して、免疫抑制薬、インシュリン及び抗がん薬等の薬物、ワクチン抗原などを体内に徐放させる用途が挙げられる。 As an application example, the microneedle preparation administration member of the present invention is applied to the mucous membrane or tube wall of the oral cavity, eye, nasal cavity, vagina, esophagus, upper digestive tract, lower digestive tract and bile duct, blood vessels, etc. In addition, there are applications in which drugs such as insulin and anticancer drugs, vaccine antigens and the like are gradually released into the body.
　以下に実施例を挙げて具体的な実施形態を説明する。もちろん、本発明は以下の実施例に限定されるものではない。 Hereinafter, specific embodiments will be described with reference to examples. Of course, the present invention is not limited to the following examples.
（実施例１）
　ポリ乳酸２００ｍｇにジクロロメタンとエチルアルコールの混液１．２ｍＬを加えて溶解した。さらにタクロリムス２ｍｇを加えてよく混和して粘調液とした。入り口の直径８００マイクロメートル、深さ２０００マイクロメートルの円錐状の穴を、１０ｍｍ×５０ｍｍ当たり１０個形成した厚さ５ｍｍの樹脂製メス型に粘調液を塗布し、約１０℃で遠心分離機で５分間２０００ｒｐｍで遠心することにより穴に充填、乾燥した。 Example 1
To 200 mg of polylactic acid, 1.2 mL of a mixed solution of dichloromethane and ethyl alcohol was added and dissolved. Further, 2 mg of tacrolimus was added and mixed well to obtain a viscous liquid. The viscous liquid is applied to a 5 mm-thick resin female mold in which 10 conical holes with a diameter of 800 μm and a depth of 2000 μm are formed per 10 mm × 50 mm, and a centrifugal separator is applied at about 10 ° C. The holes were filled and dried by centrifuging at 2000 rpm for 5 minutes.
　ヒドロキシプロピルメチルセルロースフタレート（商品名ＨＰ－５５、信越化学社製）０．５ｇにジクロロメタンとエチルアルコールの混液８ｍＬを加えて溶解した液をメス型の上に塗布して充填した。乾燥した後、ＨＰ－５５の液を塗布した基盤シート用不織布を加圧下メス型に貼付した。２時間後に不織布を剥離することにより徐放性の２層マイクロニードル・シートを得た。 A solution obtained by adding 8 mL of a mixed solution of dichloromethane and ethyl alcohol to 0.5 g of hydroxypropylmethylcellulose phthalate (trade name HP-55, manufactured by Shin-Etsu Chemical Co., Ltd.) was applied onto a female mold and filled. After drying, the base sheet non-woven fabric coated with the HP-55 solution was applied to a knife under pressure. After 2 hours, the nonwoven fabric was peeled to obtain a sustained-release two-layer microneedle sheet.
（実施例２）
　ポリ乳酸２００ｍｇにジクロロメタンとエチルアルコールの混液２．０ｍＬを加えて溶解した。さらにシクロスポリン２０ｍｇを加えてよく混和して粘調液とした。実施例１で作製したメス型に粘調液を塗布し、約１０℃で遠心分離機で５分間２０００ｒｐｍで遠心することにより穴に充填、乾燥した。 (Example 2)
To 200 mg of polylactic acid, 2.0 mL of a mixed solution of dichloromethane and ethyl alcohol was added and dissolved. Furthermore, 20 mg of cyclosporine was added and mixed well to obtain a viscous liquid. The viscous liquid was applied to the female mold produced in Example 1, and filled in the hole by centrifuging at 2000 rpm with a centrifuge at about 10 ° C. for 5 minutes and dried.
　ヒドロキシプロピルメチルセルロースフタレート（商品名ＨＰ－５５、信越化学社製）０．３ｇにジクロロメタンとエチルアルコールの混液８ｍＬで溶解した液を塗布し、加圧条件下でメス型に充填した。乾燥した後、デキストランの５００ｍｇに０．０５規定の水酸化ナトリウムの１ミリリットルを加えて作成した粘調液を基盤シート用不織布に塗り、メス型の上に被せ、加圧下で乾燥を行った。８時間後に不織布をメス型から引き離すことにより徐放性の３層マイクロニードル・シートを得た。 A solution obtained by dissolving 8 mL of a mixed solution of dichloromethane and ethyl alcohol was applied to 0.3 g of hydroxypropylmethylcellulose phthalate (trade name HP-55, manufactured by Shin-Etsu Chemical Co., Ltd.), and filled into a female mold under pressure. After drying, a viscous liquid prepared by adding 1 ml of 0.05N sodium hydroxide to 500 mg of dextran was applied to a nonwoven fabric for a base sheet, covered on a female mold, and dried under pressure. After 8 hours, the nonwoven fabric was separated from the female mold to obtain a sustained-release three-layer microneedle sheet.
（実施例３）
　ポリ乳酸２００ｍｇにジクロロメタンとエチルアルコールの混液１．２ｍＬを加えて溶解した。さらにインスリン１０ｍｇを加えてよく混和して粘調液とした。実施例１で作製したメス型に粘調液を塗布し、約１０℃で遠心分離機で５分間２０００ｒｐｍで遠心することにより穴に充填、乾燥した。 (Example 3)
To 200 mg of polylactic acid, 1.2 mL of a mixed solution of dichloromethane and ethyl alcohol was added and dissolved. Furthermore, 10 mg of insulin was added and mixed well to obtain a viscous liquid. The viscous liquid was applied to the female mold produced in Example 1, and filled in the hole by centrifuging at 2000 rpm with a centrifuge at about 10 ° C. for 5 minutes and dried.
　ヒドロキシプロピルメチルセルロースフタレート（商品名ＨＰ－５５、信越化学社製）０．５ｇにジクロロメタンとエチルアルコールの混液８ｍＬを加えて溶解した液をメス型の上に塗布して充填した。乾燥した後、ＨＰ－５５の液を塗布した基盤シート用不織布を加圧下メス型に貼付した。３時間後に不織布を剥離することにより徐放性の２層マイクロニードル・シートを得た。 A solution obtained by adding 8 mL of a mixed solution of dichloromethane and ethyl alcohol to 0.5 g of hydroxypropylmethylcellulose phthalate (trade name HP-55, manufactured by Shin-Etsu Chemical Co., Ltd.) was applied onto a female mold and filled. After drying, the base sheet non-woven fabric coated with the HP-55 solution was applied to a knife under pressure. After 3 hours, the nonwoven fabric was peeled to obtain a sustained-release two-layer microneedle sheet.
（比較例）
　ポリ乳酸２００ｍｇにジクロロメタンとエチルアルコールの混液１．２ｍＬを加えて溶解した。さらにタクロリムス２ｍｇを加えてよく混和して粘調液とした。実施例１で作製したメス型に粘調液を塗布し、約１０℃で遠心分離機で１分間２０００ｒｐｍで遠心することにより穴に充填した。 (Comparative example)
To 200 mg of polylactic acid, 1.2 mL of a mixed solution of dichloromethane and ethyl alcohol was added and dissolved. Further, 2 mg of tacrolimus was added and mixed well to obtain a viscous liquid. The viscous liquid was applied to the female mold produced in Example 1, and filled in the hole by centrifuging at 2000 rpm with a centrifuge at about 10 ° C. for 1 minute.
　タクロリムスを含有する粘調液を基盤シート用不織布に塗布してメス型に貼付し、加圧下で乾燥した。２時間後に不織布を剥離することにより徐放性の単層マイクロニードル・シートを得た。 The viscous liquid containing tacrolimus was applied to the nonwoven fabric for the base sheet, applied to a female mold, and dried under pressure. After 2 hours, the nonwoven fabric was peeled to obtain a sustained-release single-layer microneedle sheet.
（実施例４）
　ポリ乳酸２００ｍｇにジクロロメタンとエチルアルコールの混液１．２ｍＬを加えて溶解した。さらにパクリタキセル５０ｍｇを加えてよく混和して粘調液とした。入り口の直径８００マイクロメートル、深さ２０００マイクロメートルの円錐状の穴を、１０ｍｍ×５０ｍｍ当たり１０個形成した厚さ５ｍｍの樹脂製メス型の穴に粘調液をディスペンサーにて順次充填し、乾燥した。 Example 4
To 200 mg of polylactic acid, 1.2 mL of a mixed solution of dichloromethane and ethyl alcohol was added and dissolved. Further, 50 mg of paclitaxel was added and mixed well to obtain a viscous liquid. Viscous liquid is sequentially filled with a dispenser into a 5 mm thick resin female hole formed with 10 conical holes of diameter 800 μm and depth 2000 μm per 10 mm × 50 mm, and dried. did.
　ヒドロキシプロピルメチルセルロースフタレート（商品名ＨＰ－５５、信越化学社製）０．５ｇにジクロロメタンとエチルアルコールの混液８ｍＬを加えて溶解した液をメス型の上に塗布して穴に充填した。乾燥した後、ＨＰ－５５の液を塗布した基盤シート用不織布を加圧下メス型に貼付した。３時間後に不織布を剥離することにより徐放性の２層マイクロニードル・シートを得た。 A solution obtained by adding 8 mL of a mixed solution of dichloromethane and ethyl alcohol to 0.5 g of hydroxypropylmethylcellulose phthalate (trade name HP-55, manufactured by Shin-Etsu Chemical Co., Ltd.) was applied onto a female mold and filled in a hole. After drying, the base sheet non-woven fabric coated with the HP-55 solution was applied to a knife under pressure. After 3 hours, the nonwoven fabric was peeled to obtain a sustained-release two-layer microneedle sheet.
（実施例５）
　ポリ乳酸２００ｍｇにジクロロメタンとエチルアルコールの混液１．２ｍＬを加えて溶解した。さらに５－フルオロウラシル５０ｍｇを加えてよく混和して粘調液とした。実施例４で作製したメス型に粘調液を塗布し、約１０℃で遠心分離機で１分間２０００ｒｐｍで遠心することにより穴に充填した。 (Example 5)
To 200 mg of polylactic acid, 1.2 mL of a mixed solution of dichloromethane and ethyl alcohol was added and dissolved. Further, 50 mg of 5-fluorouracil was added and mixed well to obtain a viscous liquid. The viscous liquid was applied to the female mold produced in Example 4, and filled in the hole by centrifuging at 2000 rpm with a centrifuge at about 10 ° C. for 1 minute.
　乾燥後、ヒドロキシプロピルメチルセルロースフタレート（商品名ＨＰ－５５、信越化学社製）０．５ｇにジクロロメタンとエチルアルコールの混液８ｍＬを加えて溶解した液をメス型の上に塗布して充填した。乾燥した後、ＨＰ－５５の液を塗布した基盤シート用不織布を加圧下メス型に貼付した。３時間後に不織布を剥離することにより徐放性の２層マイクロニードル・シートを得た。 After drying, a solution obtained by adding 8 mL of a mixed solution of dichloromethane and ethyl alcohol to 0.5 g of hydroxypropylmethylcellulose phthalate (trade name HP-55, manufactured by Shin-Etsu Chemical Co., Ltd.) was applied onto a female mold and filled. After drying, the base sheet non-woven fabric coated with the HP-55 solution was applied to a knife under pressure. After 3 hours, the nonwoven fabric was peeled to obtain a sustained-release two-layer microneedle sheet.
（実施例６）
　ポリ乳酸２００ｍｇにジクロロメタンとエチルアルコールの混液１．２ｍＬを加えて溶解した。さらにパクリタキセル５０ｍｇを加えてよく混和して粘調液とした。この粘調液をディスペンサーに入れて実施例４で作製したメス型に充填した。 (Example 6)
To 200 mg of polylactic acid, 1.2 mL of a mixed solution of dichloromethane and ethyl alcohol was added and dissolved. Further, 50 mg of paclitaxel was added and mixed well to obtain a viscous liquid. This viscous liquid was put into a dispenser and filled into the female mold produced in Example 4.
　乾燥後、ヒドロキシプロピルメチルセルロースフタレート（商品名ＨＰ－５５、信越化学社製）０．５ｇにジクロロメタンとエチルアルコールの混液８ｍＬを加えて溶解した粘調液液をディスペンサーに入れてメス型に充填した。素早くポリウレタンフィルムをメス型に貼付して、加圧した。３時間後にフィルムを剥離することにより徐放性の２層マイクロニードル・シートを得た。得られたマイクロニードルシートは手で引っ張ることで伸張することができ、その場合でもマイクロニードルは直立を維持していた。 After drying, a viscous liquid obtained by adding 8 mL of a mixed solution of dichloromethane and ethyl alcohol to 0.5 g of hydroxypropylmethylcellulose phthalate (trade name HP-55, manufactured by Shin-Etsu Chemical Co., Ltd.) was placed in a dispenser and filled into a female mold. The polyurethane film was quickly applied to the female mold and pressurized. The film was peeled after 3 hours to obtain a sustained-release two-layer microneedle sheet. The obtained microneedle sheet could be stretched by pulling by hand, and even in that case, the microneedle was kept upright.
（実施例７）
　実施例１から６、及び比較例で作成したマイクロニードル・シートをｐＨ７．４の緩衝液に１０分間浸した後、超音波洗浄機に入れて３０秒間振動を加えた。比較例のマイクロニードル・シートは、振動を加えてもマイクロニードルはシート上に立ったままであった。一方、実施例１、２、３、４、５及び６のマイクロニードルは根元部が溶解してシートから切り離されて倒れた。 (Example 7)
The microneedle sheets prepared in Examples 1 to 6 and the comparative example were immersed in a buffer solution having a pH of 7.4 for 10 minutes, and then placed in an ultrasonic cleaning machine and subjected to vibration for 30 seconds. The microneedle sheet of the comparative example remained standing on the sheet even when vibration was applied. On the other hand, in the microneedles of Examples 1, 2, 3, 4, 5 and 6, the root part was dissolved and separated from the sheet and fell down.
１１…マイクロニードル製剤投与部材、
１２…マイクロニードル製剤、
１２Ａ…第１部分、
１２Ｂ…第２部分、
１２Ｃ…第３部分、
１３…支持体。 11 ... microneedle preparation member,
12 ... Microneedle formulation,
12A ... 1st part,
12B ... the second part,
12C ... the third part,
13: Support.

Claims (9)

  1. 　頂上部を備え、非水溶性の生分解性高分子物質と該高分子物質に溶解又は分散した目的物質とを含む第１部分、及び
    　基底部を備え、該非水溶性の生分解性高分子物質を溶解し得る溶媒に溶解する水溶性物質を含む第２部分、
    を有するマイクロニードル製剤。     A water-insoluble biodegradable polymer material comprising a top portion, a first portion containing a water-insoluble biodegradable polymer material and a target material dissolved or dispersed in the polymer material, and a base portion A second part comprising a water-soluble substance that dissolves in a solvent capable of dissolving
    A microneedle formulation comprising:
  2. 　第２部分と支持体の間に位置し、水溶性物質を含む第３部分、
    を更に有する請求項１に記載のマイクロニードル製剤。     A third part located between the second part and the support and comprising a water-soluble substance;
    The microneedle preparation according to claim 1, further comprising:
  3. 　前記第１部分に含まれる生分解性高分子物質がポリ乳酸（ＰＬＡ）、ポリグリコール酸（ＰＧＡ）、乳酸・グリコール酸共重合体、ポリカプロラクトン（ＰＣＬ）、ＰＬＡとＰＧＡとＰＣＬとの共重合体、ポリジオキサノン、キトサン、乳酸デプシペプチドランダム共重合体、乳酸デプシペプチドボロック共重合体、トリメチレンカーボネート、ポリエチレングリコールとＰＧＡ、ＰＣＬ及び／又はＰＬＡとのブロック共重合体及びポリ乳酸グラフト化多糖から成る群から選択される少なくとも一種である請求項１又は２に記載のマイクロニードル製剤。 The biodegradable polymer substance contained in the first part is polylactic acid (PLA), polyglycolic acid (PGA), lactic acid / glycolic acid copolymer, polycaprolactone (PCL), co-polymerization of PLA, PGA and PCL. From the group consisting of polydioxanone, chitosan, lactate depsipeptide random copolymer, lactate depsipeptide bolock copolymer, trimethylene carbonate, block copolymer of polyethylene glycol and PGA, PCL and / or PLA, and polylactic acid grafted polysaccharide The microneedle preparation according to claim 1 or 2, which is at least one selected.
  4. 　前記第２部分及び第３部分に含まれる水溶性物質が高分子物質である請求項１～３のいずれか一項に記載のマイクロニードル製剤。 4. The microneedle preparation according to claim 1, wherein the water-soluble substance contained in the second part and the third part is a polymer substance.
  5. 　前記第２部分に含まれる水溶性物質がヒドロキシプロピルメチルセルロースフタレート、ヒドロキシプロピルメチルセルロースアセテートサクシネート、メタクリル酸コポリマーＳ、メタクリル酸コポリマーＬＤ及びアミノアルキルメタクリレートコポリマーＲＳから成る群から選択される少なくとも一種である請求項１～４のいずれか一項に記載のマイクロニードル製剤。 The water-soluble substance contained in the second part is at least one selected from the group consisting of hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, methacrylic acid copolymer S, methacrylic acid copolymer LD, and aminoalkyl methacrylate copolymer RS. Item 5. The microneedle preparation according to any one of Items 1 to 4.
  6. 　前記第３部分に含まれる水溶性物質がコンドロイチン硫酸ナトリウム、デキストラン、デキストラン硫酸及びヒドロキシプロピルβシクロデキストリン及びヒアルロン酸ナトリウムから成る群から選択される少なくとも一種である請求項１～５のいずれか一項に記載のマイクロニードル製剤。 The water-soluble substance contained in the third part is at least one selected from the group consisting of sodium chondroitin sulfate, dextran, dextran sulfate, hydroxypropyl β cyclodextrin, and sodium hyaluronate. The microneedle formulation described in 1.
  7. 　支持体と複数の請求項１～６のいずれか一項に記載のマイクロニードル製剤とを有するマイクロニードル製剤投与部材。 A microneedle preparation administration member comprising a support and a plurality of microneedle preparations according to any one of claims 1 to 6.
  8. 　マイクロニードル製剤が逆転した形状の穴を有する鋳型に、非水溶性の生分解性高分子物質、目的物質及び溶媒を混合することにより得られた第１原料混合物を載せ、乾燥させて、乾燥した第１原料混合物を穴の所定の高さまで充填する工程；
    　乾燥した第１原料混合物が充填されている鋳型に、非水溶性の生分解性高分子物質を溶解し得る溶媒に溶解する水溶性物質及び該非水溶性の生分解性高分子物質を溶解し得る溶媒を混合することにより得られた第２原料混合物を載せて、第２原料混合物を穴に充填する工程；
    　第２原料混合物に接触するように鋳型の上に支持体を重ねる工程；
    　鋳型の穴に充填された第２原料混合物を乾燥させる工程；及び
    　支持体を鋳型から剥がす工程；
    を包含するマイクロニードル製剤投与部材の製造方法。     A first raw material mixture obtained by mixing a water-insoluble biodegradable polymer substance, a target substance and a solvent was placed on a mold having a hole having a shape in which the microneedle preparation was reversed, dried and dried. Filling the first raw material mixture to a predetermined height of the hole;
    A water-soluble substance that dissolves in a solvent capable of dissolving a water-insoluble biodegradable polymer substance and the water-insoluble biodegradable polymer substance can be dissolved in a mold filled with the dried first raw material mixture Placing the second raw material mixture obtained by mixing the solvent and filling the second raw material mixture into the holes;
    Overlaying the support on the mold so as to contact the second raw material mixture;
    Drying the second raw material mixture filled in the mold holes; and peeling the support from the mold;
    A method for producing a microneedle preparation dosing member.
  9. 　マイクロニードル製剤が逆転した形状の穴を有する鋳型に、非水溶性の生分解性高分子物質、目的物質及び溶媒を混合することにより得られた第１原料混合物を載せ、乾燥させて、乾燥した第１原料混合物を穴の所定の高さまで充填する工程；
    　乾燥した第１原料混合物が充填されている鋳型に、非水溶性の生分解性高分子物質を溶解し得る溶媒に溶解する水溶性物質及び該非水溶性の生分解性高分子物質を溶解し得る溶媒を混合することにより得られた第２原料混合物を載せ、乾燥させて、乾燥した第２原料混合物を穴の所定の高さまで充填する工程；
    　乾燥した第２原料混合物が充填されている鋳型に、水溶性物質及び水を混合することにより得られた第３原料混合物を載せて、第３原料混合物を穴に充填する工程；
    　第３原料混合物に接触するように鋳型の上に支持体を重ねる工程；
    　鋳型の穴に充填された第３原料混合物を乾燥させる工程；及び
    　支持体を鋳型から剥がす工程；
    を包含するマイクロニードル製剤投与部材の製造方法。     A first raw material mixture obtained by mixing a water-insoluble biodegradable polymer substance, a target substance and a solvent was placed on a mold having a hole having a shape in which the microneedle preparation was reversed, dried and dried. Filling the first raw material mixture to a predetermined height of the hole;
    A water-soluble substance that dissolves in a solvent capable of dissolving a water-insoluble biodegradable polymer substance and the water-insoluble biodegradable polymer substance can be dissolved in a mold filled with the dried first raw material mixture Placing the second raw material mixture obtained by mixing the solvent, drying, and filling the dried second raw material mixture to a predetermined height of the hole;
    Placing the third raw material mixture obtained by mixing the water-soluble substance and water on the mold filled with the dried second raw material mixture, and filling the third raw material mixture into the holes;
    Stacking a support on the mold in contact with the third raw material mixture;
    Drying the third raw material mixture filled in the mold holes; and peeling the support from the mold;
    A method for producing a microneedle preparation dosing member.
PCT/JP2016/076619 2015-09-11 2016-09-09 Microneedle preparation WO2017043627A1 (en)

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CN114376569A (en) * 2022-01-19 2022-04-22 浙江大学 Glucagon-carrying wearable device for treating hypoglycemia
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CN108158843A (en) * 2017-12-25 2018-06-15 陕西佰傲再生医学有限公司 It is a kind of can the sodium hyaluronate stoste and preparation method thereof that imports of micropin
WO2020043167A1 (en) * 2018-08-31 2020-03-05 中科微针（北京）科技有限公司 Quick implantable slow-release microneedle patch and preparation method therefor
CN109884223A (en) * 2019-02-23 2019-06-14 贵阳中医学院 A kind of strychnia solubility micropin, preparation method and detection method and application
EP4048347A4 (en) * 2019-10-22 2024-01-10 Georgia Tech Res Inst Methods for making microneedles using adjustment of component solubility in casting formulations
CN110897997A (en) * 2019-12-31 2020-03-24 广州贝奥吉因生物科技股份有限公司 Dextran grafted methacrylic acid hydrogel microneedle and preparation method thereof
CN112023033A (en) * 2020-04-29 2020-12-04 中山大学·深圳 Two-section type micro-needle array medicine patch capable of simultaneously realizing BCG vaccine inoculation and diagnosis and preparation method thereof
CN112023033B (en) * 2020-04-29 2023-08-25 中山大学·深圳 Two-section micro-needle array patch for simultaneously realizing BCG vaccine inoculation and diagnosis and preparation method thereof
CN113426004A (en) * 2021-07-06 2021-09-24 尹忠 Strong hydrophilic microneedle substrate, drug-loaded microneedle and application of strong hydrophilic microneedle substrate and drug-loaded microneedle in treatment of diseases
CN114376569A (en) * 2022-01-19 2022-04-22 浙江大学 Glucagon-carrying wearable device for treating hypoglycemia
CN114376569B (en) * 2022-01-19 2023-10-13 浙江大学 Glucagon-carrying wearable device for treating hypoglycemia
CN115300783A (en) * 2022-07-03 2022-11-08 湖北迈科泰克生物医药有限公司 Double-phase microneedle patch capable of improving drug delivery efficiency and preparation method
CN116549827A (en) * 2023-06-13 2023-08-08 中日友好医院(中日友好临床医学研究所) Microneedle for delivering drug to stomach wall, preparation method thereof and drug delivery system

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