WO2017043627A1 - Préparation de micro-aiguilles - Google Patents

Préparation de micro-aiguilles 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
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English (en)
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
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Publication date
Priority claimed from JP2015179295A external-priority patent/JP2018193300A/ja
Priority claimed from JP2016013266A external-priority patent/JP2018193301A/ja
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/fr

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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

La présente invention aborde le problème de la fourniture d'une préparation de micro-aiguilles, permettant qu'une substance souhaitée puisse être libérée de façon prolongée depuis une micro-aiguille, et une partie de micro-aiguilles insérée dans la peau puisse être séparée d'un support sans qu'il soit nécessaire d'appliquer une force de traction au support. Afin de résoudre ce problème, la présente invention concerne une préparation de micro-aiguilles comportant une première partie qui est pourvue d'une partie supérieure et comprend une substance polymère biodégradable insoluble dans l'eau et une substance souhaitée dissoute ou dispersée dans la substance polymère, et une deuxième partie qui est pourvue d'une partie de base et comprend une substance soluble dans l'eau dissoute dans un solvant capable de dissoudre la substance polymère biodégradable insoluble dans l'eau.
PCT/JP2016/076619 2015-09-11 2016-09-09 Préparation de micro-aiguilles WO2017043627A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP2015-179295 2015-09-11
JP2015179295A JP2018193300A (ja) 2015-09-11 2015-09-11 基盤、シートから切り離し可能な徐放性多層マイクロニードル
JP2016-013266 2016-01-27
JP2016013266A JP2018193301A (ja) 2016-01-27 2016-01-27 基盤、シートから切り離し可能な徐放性多層マイクロニードル

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Cited By (10)

* Cited by examiner, † Cited by third party
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CN108158843A (zh) * 2017-12-25 2018-06-15 陕西佰傲再生医学有限公司 一种可微针导入的玻尿酸原液及其制备方法
CN109884223A (zh) * 2019-02-23 2019-06-14 贵阳中医学院 一种马钱子碱可溶性微针、制备方法及检测方法和应用
WO2020043167A1 (fr) * 2018-08-31 2020-03-05 中科微针（北京）科技有限公司 Timbre à micro-aiguilles à libération prolongée implantable rapide et son procédé de préparation
CN110897997A (zh) * 2019-12-31 2020-03-24 广州贝奥吉因生物科技股份有限公司 一种葡聚糖接枝甲基丙烯酸水凝胶微针及其制备方法
CN112023033A (zh) * 2020-04-29 2020-12-04 中山大学·深圳 一种同时实现卡介苗接种及其诊断的两段式微针阵列药贴及其制备方法
WO2021081260A1 (fr) 2019-10-22 2021-04-29 Georgia Tech Research Corporation Procédés de fabrication de micro-aiguilles par ajustement de la solubilité de composant dans des formulations de coulage
CN113426004A (zh) * 2021-07-06 2021-09-24 尹忠 强亲水型微针基材与载药微针及其在治疗疾病中的应用
CN114376569A (zh) * 2022-01-19 2022-04-22 浙江大学 用于救治低血糖的载胰高血糖素可穿戴设备
CN115300783A (zh) * 2022-07-03 2022-11-08 湖北迈科泰克生物医药有限公司 一种可提高给药效率的双相微针贴片及制备方法
CN116549827A (zh) * 2023-06-13 2023-08-08 中日友好医院(中日友好临床医学研究所) 用于向胃壁递送药物的微针及其制备方法和药物递送系统

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WO2014142135A1 (fr) * 2013-03-12 2014-09-18 武田薬品工業株式会社 Timbre à microaiguilles

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WO2002064193A2 (fr) * 2000-12-14 2002-08-22 Georgia Tech Research Corporation Appareils a microaiguilles et fabrication
JP2008194288A (ja) * 2007-02-14 2008-08-28 Toppan Printing Co Ltd 針状体および針状体の製造方法
JP2010233674A (ja) * 2009-03-30 2010-10-21 Fujifilm Corp マイクロニードルシート及びその使用方法並びに製造方法
JP2011224332A (ja) * 2010-03-29 2011-11-10 Fujifilm Corp 経皮吸収シート及びその製造方法
WO2014142135A1 (fr) * 2013-03-12 2014-09-18 武田薬品工業株式会社 Timbre à microaiguilles

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108158843A (zh) * 2017-12-25 2018-06-15 陕西佰傲再生医学有限公司 一种可微针导入的玻尿酸原液及其制备方法
WO2020043167A1 (fr) * 2018-08-31 2020-03-05 中科微针（北京）科技有限公司 Timbre à micro-aiguilles à libération prolongée implantable rapide et son procédé de préparation
CN109884223A (zh) * 2019-02-23 2019-06-14 贵阳中医学院 一种马钱子碱可溶性微针、制备方法及检测方法和应用
WO2021081260A1 (fr) 2019-10-22 2021-04-29 Georgia Tech Research Corporation Procédés de fabrication de micro-aiguilles par ajustement de la solubilité de composant dans des formulations de coulage
EP4048347A4 (fr) * 2019-10-22 2024-01-10 Georgia Tech Research Corporation Procédés de fabrication de micro-aiguilles par ajustement de la solubilité de composant dans des formulations de coulage
CN110897997A (zh) * 2019-12-31 2020-03-24 广州贝奥吉因生物科技股份有限公司 一种葡聚糖接枝甲基丙烯酸水凝胶微针及其制备方法
CN112023033B (zh) * 2020-04-29 2023-08-25 中山大学·深圳 一种同时实现卡介苗接种及其诊断的两段式微针阵列药贴及其制备方法
CN112023033A (zh) * 2020-04-29 2020-12-04 中山大学·深圳 一种同时实现卡介苗接种及其诊断的两段式微针阵列药贴及其制备方法
CN113426004A (zh) * 2021-07-06 2021-09-24 尹忠 强亲水型微针基材与载药微针及其在治疗疾病中的应用
CN114376569B (zh) * 2022-01-19 2023-10-13 浙江大学 用于救治低血糖的载胰高血糖素可穿戴设备
CN114376569A (zh) * 2022-01-19 2022-04-22 浙江大学 用于救治低血糖的载胰高血糖素可穿戴设备
CN115300783A (zh) * 2022-07-03 2022-11-08 湖北迈科泰克生物医药有限公司 一种可提高给药效率的双相微针贴片及制备方法
CN116549827A (zh) * 2023-06-13 2023-08-08 中日友好医院(中日友好临床医学研究所) 用于向胃壁递送药物的微针及其制备方法和药物递送系统
CN116549827B (zh) * 2023-06-13 2024-08-02 中日友好医院(中日友好临床医学研究所) 用于向胃壁递送药物的微针及其制备方法和药物递送系统

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