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WO2013081399A1 - Micro-aiguille creuse pour une injection intravitréenne - Google Patents

Micro-aiguille creuse pour une injection intravitréenne Download PDF

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Publication number
WO2013081399A1
WO2013081399A1 PCT/KR2012/010254 KR2012010254W WO2013081399A1 WO 2013081399 A1 WO2013081399 A1 WO 2013081399A1 KR 2012010254 W KR2012010254 W KR 2012010254W WO 2013081399 A1 WO2013081399 A1 WO 2013081399A1
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WO
WIPO (PCT)
Prior art keywords
hollow
microstructure
microneedle
hollow microneedle
tip
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/KR2012/010254
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English (en)
Korean (ko)
Inventor
정형일
이창열
이광
유용성
이성호
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Industry Academic Cooperation Foundation of Yonsei University
Original Assignee
Industry Academic Cooperation Foundation of Yonsei University
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Publication date
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Publication of WO2013081399A1 publication Critical patent/WO2013081399A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14—Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • A61M5/158—Needles for infusions; Accessories therefor, e.g. for inserting infusion needles, or for holding them on the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F9/00—Methods or devices for treatment of the eyes; Devices for putting in contact-lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
    • A61F9/0008—Introducing ophthalmic products into the ocular cavity or retaining products therein
    • A61F9/0017—Introducing ophthalmic products into the ocular cavity or retaining products therein implantable in, or in contact with, the eye, e.g. ocular inserts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F9/00—Methods or devices for treatment of the eyes; Devices for putting in contact-lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
    • A61F9/007—Methods or devices for eye surgery
    • 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
    • A61M31/00—Devices for introducing or retaining media, e.g. remedies, in cavities of the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0053—Methods for producing microneedles
    • 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
    • A61M2207/00—Methods of manufacture, assembly or production
    • 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
    • A61M2210/00—Anatomical parts of the body
    • A61M2210/06—Head
    • A61M2210/0612—Eyes
    • 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

Definitions

  • the present invention relates to a hollow microneedle for vitreous cavity injection and a method for producing the same.
  • AMD age-related macular degeneration
  • DR diabetic retinopathy
  • Brvo retinal vein occlusion
  • uveit is, and endoothalmitis.
  • Drug delivery to the retina challenges and opportunities, Sridhar Duwur i et. Al., Expert Opin. Biol. Ther., (2003) 3 ( 1) 45-56).
  • the minimum length of the drug delivery device for injecting drugs into the eye by puncturing the retina, including the eye sclera, is 3 ⁇ .
  • the required length is 8-10 ⁇ . Therefore, the solid structure needed to manufacture hollow microneedle having a diameter of 8 150 um and a length of 5-10 mm should satisfy several tens of ⁇ in diameter and 5,10 mm in length.
  • the inventors have sought to develop hollow microneedles for intravitreal injection that can deliver drugs into the eye.
  • the result is an ultra-high aspect ratio that satisfies a diameter of tens of ⁇ , a length of 5-10 ⁇ s, which enables practical intraocular drug delivery by hollow microneedle .
  • the success of the development of the hollow microneedle has led to the completion of the present invention.
  • an object of the present invention is to provide a method for manufacturing hollow microneedle for intravitreal injection.
  • Another object of the present invention is to provide a hollow microneedle for intravitreal injection.
  • the present invention provides a method for preparing hollow microneedle for intravitreal injection, comprising the following steps:
  • a solution of a viscous material is first applied to a surface of a substrate to prepare a solid microstructure, which is a mold of hollow microneedle.
  • the material used to make the solid microstructure which is a mold of the hollow microneedle, is a viscous material.
  • viscosity refers to a material having a low viscosity fluid form above a certain temperature but having a high viscosity when approaching the vitrification temperature by lowering the temperature.
  • Viscous materials used in the present invention include, but are not limited to, acrylic polymers, amide polymers, acetyl polymers, vinyl polymers, epoxy polymers, silicone polymers, sulfone resins, polycarbonate polymers or copolymers thereof. Any viscous material conventionally used in the art can be used.
  • the viscous material used in the present invention is viscous when fluidized. This viscosity is the type of viscosity, concentration and temperature, organic solvent It can be changed in various ways, etc., it can be adjusted to suit the purpose of the present invention. More preferably, the viscous material of the present invention is fluidized
  • Fluidization of the viscous material can be carried out through various methods known in the art.
  • the viscous material is a liquid polymer
  • no fluidization process is required
  • the viscous material is viscous by heating at a temperature above the melting point and then lowering the temperature to approach the vitrification temperature.
  • a suitable organic solvent e.g. anhydrous or hydrous lower alcohol having 1 to 4 carbon atoms, acetone, ethyl acetate, chloroform, 1,3-butylene glycol, nucleic acid, diethyl ether and butyl acetate
  • a suitable organic solvent e.g. anhydrous or hydrous lower alcohol having 1 to 4 carbon atoms, acetone, ethyl acetate, chloroform, 1,3-butylene glycol, nucleic acid, diethyl ether and butyl acetate
  • the term "application” as used herein means to make a layer of a certain thickness of a certain material on the object surface.
  • the substrate providing the surface is made of a material such as a polymer, an organic chemical, a metal, a ceramic, a semiconductor, or the like.
  • the coating thickness of the viscous solution of the invention is controlled in the range 10-500 ⁇ , more preferably in the range 50-200 urn, most preferably in the range 75-165 um Adjusted in
  • the viscous material of step (a) is a high molecular compound removed by an organic solvent.
  • high molecular compound removed by an organic solvent refers to a compound having a solubility in an organic solvent as a natural or synthetic compound having a molecular weight of 5,000 or more.
  • the polymer compound used in the present invention should be easily removed after metal deposition and plating for fabricating the hollow microneedle, and the present inventors removed the polymer compound by dissolving the polymer compound, which is a metal plated solid microstructure component, in an organic solvent.
  • the high molecular compound used in the present invention is ASCacrylonitrile styrene), polyamide, polyethylene ⁇ polyester, polyacryl, polyacetyl, stylone, teflon, polyvinyl chloride, polyurethane, nylon, sulfone resin or epoxy polymer.
  • the polymer compound of the present invention is an epoxy polymer.
  • the organic solvent used in the present invention is preferably benzene, toluene, All polar or nonpolar solvents can be used, including, but not limited to, xylene (xylene), nucleic acids, ethers, acetone, alcohols and amines, typically used for dissolving each polymer compound.
  • xylene xylene
  • NMP N-methyl pyrrol idine
  • the lifting frame is brought into contact with the interface of the viscous material.
  • the diameter of the lifting frame used at this time is variable and can be adjusted in the range of 1-1,000 um in diameter, most preferably 10-500 ⁇ m.
  • Preferred examples of the lifting frame used in the present invention include a cannulated stainless frame and a tubular frame with passages.
  • the frame used herein is a syringe needle.
  • a syringe needle for example, in a syringe consisting of a syringe and a syringe needle, the formation of a vacuum microneedle on the syringe needle can provide a highly efficient intravitreal drug delivery device.
  • the syringe needle as the frame is preferably at least 23 gauge, more preferably 23-34 gauge, even more preferably 23-30 gauge or 23-27 gauge syringe needle.
  • solid microstructure refers to the mold of the micro pliers and hollow microneedle fabricated integrally without the formation of hollows.
  • the fluidized viscous material preferably high molecular material
  • the vitrification temperature Glass temperature
  • the solid structure is made by lifting up to 5000um / s, and the solid structure is rapidly vitrified at room temperature.
  • Viscosity in step (c) affects various external factors of the evaporated microneedles finally produced, namely effective length, inner diameter, outer diameter, sharpness and aspect ratio, and especially effective lengths of solid and hollow microstructures. It acts as a variable to change. The greater the viscosity of the viscous material in step (C), the greater the effective length of the hollow microstructure.
  • the viscosity of the viscous material is controlled by adjusting the temperature in the range higher than the glass transition temperature (Tg) and lower than 130 ° C.
  • the term "glass transition temperature” refers to the temperature at which the solidification of a material in the form of a viscous fluid occurs. Therefore, the lifting process for the already solidified material is possible at a temperature lower than the vitrification temperature, and if the temperature is too high, the viscosity is low and the lifting process is also impossible, so that a solid microstructure cannot be manufactured.
  • the viscosity of the viscous material controlled in step (c) is 5, 000 Poise, more preferably 80-8, 000 Poise, even more preferably 100-6,500 Poise to be.
  • the term “separation” refers to increasing the distance between the substrates in contact with each other and opening them apart.
  • the inventors have fabricated a solid microstructure by lifting (upward) the frame in contact with the viscous material, but the method of spaced apart by fixing the frame and moving the substrate down or moving the frame and the substrate up and down simultaneously. All is possible.
  • various external elements of the finally manufactured hollow microneedle can be adjusted, namely, effective length, inner diameter, outer diameter, sharpness and aspect ratio.
  • the effective length of the solid microstructure the effective length of the hollow microneedle can be adjusted.
  • the lifting speed is increased, the effective length of the hollow microneedle increases.
  • lifting speed is meant to include not only the upward or downward movement speed of the frame or the substrate, but also the relative speed that moves away between them when the frame and the substrate simultaneously move upward and downward.
  • the lifting speed used herein has 0.1-2,000 i / s, most preferably 1-1,000 i / s.
  • the correlation (lift) between the lifting speed and the lifting time can be used to control the length of the final solid microstructure.
  • the present invention by depositing the fabricated solid microstructure with a metal (deposit ion) to facilitate the metal plating reaction for the subsequent hollow microneedle fabrication.
  • the term "deposition” refers to forming a film by vaporizing or subliming a material to be coated in a physical or chemical manner so as to be deposited on the surface of a substrate in atomic or molecular units in order to increase the mechanical strength of the material.
  • Deposition of the present invention may be used for all physical vapor deposition (Physical Vapor Deposition) and chemical vapor deposition (Chemical Vapor Deposit ion) commonly used in the art.
  • the deposition metal of the present invention is stainless steel, aluminum (A1), chromium (Cr), nickel (Ni), gold (Au), silver (Ag), copper (Cu), titanium (Ti), cobalt (Co) or alloys thereof. More preferably, silver (Ag) is chemically deposited using a tolens reaction.
  • silver (Ag) precipitated through reduction reaction using a ⁇ lene reagent (Ag 2 0 + H 4 0H + 3 ⁇ 40) was deposited on the solid microstructure.
  • the silver mirror reaction is more advantageous for metal deposition on the target surface because it does not require heating, pressurization, and a separate cooling process, compared to physical deposition using a sputter or the like.
  • Plating the metal-deposited solid microstructure may provide a foundation for the hollow microneedle.
  • One of the features of the present invention is to perform metal plating without the process of masking the tip portion of the microneedle after the metal deposition.
  • Conventional evaporative microneedle manufacturing techniques eg, Korean Patent No. 781702 and Patent Application No. 2010-0066940
  • the present invention shortens the production time and increases the convenience of the process without carrying out such a process.
  • the plating thickness used in the present invention is preferably 5-100 ⁇ , more preferably 10-50 ⁇ .
  • Plating materials used in the present invention include, for example, nickel, stainless steel, aluminum, crucible, cobalt-based alloys, titanium and alloys thereof, but is not limited to these as a bio-applicable metal is not toxic or carcinogenic, There is no objection rejection, good mechanical properties such as tensile strength, elastic modulus, abrasion resistance, and all metals known in the art as a metal having corrosion resistance to withstand the corrosive environment in the human body can be used.
  • the plating metal of the present invention is made of stainless steel, aluminum (A1), chromium (Cr), nickel (Ni), gold (Au), silver (Ag), copper (Cu), titanium ( Ti), cobalt (Co) or alloys thereof. More preferably, the plating metal of this invention is nickel (Ni). Step (f): Bevel Cutting of the Metal Plated Solid Microphone Structure
  • the bevel hang of the ocular disease customized microstructure of the present invention has a bevel angle value similar to that of a normal syringe.
  • Bevel cutting can be used with all precision cutting methods commonly used in the art, preferably using laser or dipping saw. Adjustment of the bevel angle provides sharpness suitable for intravitreal injection applications.
  • the bevel angle is 5 coming 20 ⁇ , preferably 5 ° - a ⁇ 15 °, preferably 10 ° -15 more.
  • the hollow microneedle is fabricated by removing the solid microneedle. Removal of the solid microneedles can be dissolved, burned, or physically removed black using an appropriate organic solvent. Preferably it is removed using the appropriate organic solvents listed above.
  • the method of the present invention comprises the step of cutting the tip tip of the hollow microneedle after step (g) such that the tip tip angle is 1-45 0 and the tip tip length 2-30 urn. It further includes.
  • Polishing of the tip tip can be carried out through various methods known in the art, for example, using laser cutting or a dicing saw.
  • the tip tip of the hollow microstructure for intravitreal injection of the present invention in two directions, in three directions (eg, in the bevel face direction and in the bi-blade direction of the tip bevel face) or in four directions, More preferably, it may be formed by cutting in three directions. This cutting further improves the sharpness of the tip tip.
  • tip as used herein referring to a hollow microstructure refers to the tip portion of the upper end of the microstructure given the bevel angle.
  • tip tip refers to the portion from the hollow upper end to the extreme end of the microstructure which is endowed with a bevel angle to the tip of the upper end of the microstructure (see Figure 4).
  • the tip tip is cut / polished.
  • the tip tip of the microneedle was polished so that the tip tip cross section became 2-30 urn (preferably 2-10 urn, 5-10 ⁇ , 2-8 ⁇ ).
  • the tip tip angle was also 1-45 0 (preferably 30-45 0 ).
  • the hollow microneedle for intravitreal injection prepared through the above process has structural and physical properties for injecting drugs into the eye by penetrating the sclera and retina. .
  • the effective length of the finally prepared hollow microstructure is 5-10 mm 3.
  • the microneedle developed to date is only 2 ⁇ at maximum.
  • the present invention overcomes this limitation and provides an effective length suitable for intravitreal injection.
  • the present invention can penetrate the most intense sclera of the outer wall of the eye, and has a length that can be treated by injecting drugs into the eye center.
  • the term "effective length” means the vertical length from the upper end of the microneedle to the lower substrate surface.
  • the term “aspect ratio” means the ratio of the height to the vertical length from the top to the bottom substrate surface to the maximum diameter of the microneedle.
  • the inner diameter of the upper end of the finally prepared hollow microstructure is 50-150 i.
  • the term “top” refers to the microneedle having the smallest diameter.
  • “End” means the lower end of the microneedle in contact with the substrate.
  • the present invention provides hollow microneedle for intravitreal injection having an effective length of 5-10 mm, a top diameter of 50-150 urn and a bevel angle of 5 ⁇ - 20 ⁇ .
  • the vacuum microneedle is formed on the syringe needle.
  • the syringe needle is at least 23 gauge, more preferably 23-34 gauge, even more preferably 23-30 gauge or 23-27 gauge syringe needle.
  • the hollow microneedle of the present invention is made of stainless steel, aluminum (A1), chromium (Cr), nickel (Ni), gold (Au), silver (Ag), copper (Cu titanium) Ti;), cobalt (Co) or an alloy thereof.
  • the bevel angle of the hollow microneedle of the present invention is 5 ° -15 °, more preferably 10 o- 15 o .
  • the effective length of the hollow microneedle of the present invention is 5-10 mm.
  • the inner diameter of the upper end of the hollow microstructure of the present invention is 50-100 i.
  • the hollow microstructures of the invention are prepared by the process of the invention described above.
  • the hollow microstructures of the invention have a strength of 0.1-2.0 N, more preferably of 0.5-2.0 N, even more preferably of 1.0-2.0 N.
  • the minimum force required to penetrate the sclera of the eye is known to be less than 1 N (JS Pulido et al., Scleral penetrat ion force requirements for co ⁇ only used intravitreal needles, EYE, 21: 1210-1211 (2007)),
  • the strength of the hollow microstructures of the present invention can readily penetrate the sclera and retina to deliver the drug in the vitreous cavity, ie the eye.
  • the force required for permeation of the human sclera of the hollow g microstructure of the present invention is 0.1-1 N, preferably 0.2-0.8 N, more preferably 0.2-0.6 N, even more preferably Is 0.2-0.4 N, even more preferably 0.2-0.35 N.
  • the small force required for the hollow microstructure of the present invention to penetrate the human sclera is achieved by the structural features of the hollow microstructure of the present invention, and particularly by the suitable bevel angle.
  • the hollow microstructures of the present invention have the use of injecting drugs into eye augment through the sclera and retina.
  • the hollow microstructure of the present invention has a tip tip angle of 1-45 0 (more preferably 30-45 0 ) and a tip tip cross-section 2-30 ⁇ (more preferably 2 -10 ⁇ ⁇ , 5-10 ⁇ , 2-8 ⁇ ).
  • the hollow microstructure for intravitreal injection of the present invention is made of metal and has a strength or force that can pass through the sclera and the retina.
  • the hollow microstructure for intravitreal injection of the present invention has an ultra-high aspect ratio, thereby minimizing damage to the retina.
  • the microstructures of the present invention may be sufficient to have an effective length be delivering drugs to the eye center to improve the effectiveness of the drug.
  • the intravitreal injection-enhanced microstructure of the present invention is easily compatible with general syringes.
  • FIG. 1 is a schematic diagram of an intravitreal injection device including a hollow microstructure of the present invention.
  • microstructure 2 syringe needle, 3.
  • syringe connection 2 is a schematic diagram of a hollow microstructure of the present invention.
  • 3 is an image showing a tip portion in the microstructure of the present invention.
  • Figure 4 is an image of a hollow microneedle made in accordance with the present invention.
  • FIG. 5 is a conceptual diagram of a bevel angle, a tip tip angle and a tip tip length in the intravitreal injection hollow microneedle according to the present invention.
  • Figure 6 is a mouse scleral permeation experiment results using the hollow microneedle for vitreous cavity injection of the present invention.
  • the damage site was remarkably small.
  • 8 is a test result of whether the intravitreal administration was successfully performed by the hollow microneedle for vitreous cavity injection of the present invention.
  • 9 is a comparative analysis of the strength required when the hollow microneedle for vitreous cavity injection of the present invention, the microneedle without the barbell angle, and the 30 gauge hypodermic needle made with the barbell angle of 15 0 penetrate the sclera of the human eye. The result is.
  • Solid microstructures were fabricated using SU-8 2050 photoresist (purchased from Microchem) with a viscosity of 14,000 cSt. Apply SU-8 8 50 at 1000 RPM on a 1.5 x 1.5 cm cover glass The thickness was maintained at about 160 u. The cover glass was heated on a hot plate at 120 ° C. for about 1 hour to maintain SU-8 2050 fluidity. Subsequently, a 27 gauge needle with a flat end was contacted and lifted vertically to produce a solid structure having a diameter of 50 ⁇ and a length of 5-10 mm.
  • a hollow microneedle was fabricated by cutting a plated structure with a bevel of 0 0 0 0 0 using a fiber laser and removing solid structures using SU-8 remover (purchased from Microchem) or acetone. Then, the tip of the hollow microneedle is cut in three directions so that the tip tip side length is 10 um or 8 um and the tip tip angle is 30-45 0.
  • An ophthalmic drug delivery device including a needle was manufactured (FIG. 1).
  • the manufactured hollow microneedle for vitreous steel injection was a hollow microneedle having an outer diameter of 120 ⁇ m, an inner diameter of 50 ⁇ m, a diameter of 350 ⁇ m of a lower end, and a length of 9.02 mm.
  • the hardness of the manufactured hollow microneedle shows a value of 1-2 N, which is greater than the minimum strength that can penetrate the sclera.
  • Solid microstructures were fabricated using SU-8 2050 photoresist (purchased from Microchem) with a viscosity of 14,000 cSt.
  • the SU-8 8 5050 was applied on a 1.5 1.5 cm cover glass at 1000 RPM to maintain a thickness of about 160 um.
  • the cover glass was heated on a hot plate at 120 ° C. for about 1 hour to maintain SU-8 2050 fluidity.
  • a 27-gauge needle with a flat end was contacted and lifted vertically to produce a solid structure having a diameter of 20-60 ⁇ and a length of 5-10 mm.
  • a hollow microneedle was fabricated by cutting a plated structure with a bevel of 0 0 0 0 0 0 using a fiber laser and removing the solid structure using SU-8 remover (purchased from Microchem) or acetone. The tip of the hollow microneedle is then cut in three directions, with a tip tip length of 10 ⁇ or 8 um and a tip tip angle of 30-45 0. An ophthalmic drug delivery device including a needle was produced.
  • the manufactured hollow microneedle for vitreous steel injection is a hollow microneedle having an outer diameter of 110 urn, an inner diameter of 40 urn, a lower diameter of 350 urn, and a length of 3-6 mm.
  • the hardness of the manufactured hollow microneedle shows a value of 1-2 N, which is greater than the minimum strength that can penetrate the sclera.
  • Solid microstructures were fabricated using SU-8 2050 photoresist (purchased from Microchem) with a viscosity of 14,000 cSt.
  • SU-8 2050 was applied at 1000 RPM on a 1.5 ⁇ 1.5 cm cover glass to maintain a thickness of about 160 pm.
  • the cover glass was heated on a hot plate at 120 ° C. for about 1 hour to maintain SU-82050 fluidity.
  • a 27-gauge needle with a flat end was contacted and lifted vertically to produce a solid structure having a diameter of 20 to 60 um and a length of 5 to 10 mm.
  • the lifting frame (needle) was lifted for 5 minutes at a rate of 5 ⁇ m / s and 10 pi / s while slowly lowering to ° C.
  • Silver plating was performed on the produced solid structure using a Rollens reagent (To 11 en's reagent), followed by nickel electroplating.
  • Nickel electroplating was performed at 0.206 um / min per 1 A / dm 2 for 75 minutes to give a plated metal thickness of 20 um.
  • a fiber laser cut the plated structure by giving a bevel of 15 0 and then remove the solid structure using a SU-8 remover (purchased from Microchem) or acetone.
  • Microneedle was produced. Then, the tip of the hollow microneedle is cut in three directions so that the tip tip horizontality is 10 um or 8 and the tip tip angle is 30-45 °.
  • An ophthalmic drug delivery device was prepared.
  • the manufactured hollow microneedle for vitreous steel injection is a hollow microneedle having an outer diameter of 120 urn, an inner diameter of 50 ⁇ , a lower diameter of 350 ⁇ , and a length of 5_8 mm.
  • the hardness of the manufactured hollow microneedle shows a value of 1-2 N, which is greater than the minimum strength that can penetrate the sclera.
  • the hollow microneedle for vitreous steel injection having various dimension toks was prepared by adjusting the temperature and lifting speed of the polymer.
  • Ophthalmic microneedles generally include syringe connections, needles, and microstructures.
  • the syringe connector is the part connecting the syringe and the needle.
  • the needle is in fluid communication between the syringe and the microstructure.
  • the microstructure is connected in fluid communication with the tip of the needle.
  • Ophthalmic microstructures have an optimal length of at least 3 ⁇ and 8–10 ⁇ .
  • the diameter of the tip of the microstructure is up to 150 um and usually 90 urn.
  • the components of the microstructures are metals and include titanium, nickel and stainless steel.
  • SU-8 2050 is applied on a 1.5 X 1.5 cm cover glass at 1000 RPM to maintain a thickness of about 160 um. Heat to 120 ° C on the hotplate for about an hour. Contact the needle with a flat end and lift it vertically to make a solid structure of 50 um in diameter and 5 to 10 ⁇ in length.
  • the plated solid structure was silver plated using Elens reagent, and then electroplated to a thickness of 20-30 m with nickel.
  • An ophthalmic drug delivery device was fabricated by cutting a bevel of 15 0 at the end of the plated structure using a fiber laser and removing the solid structure using a SU-8 remover or acetone.
  • Example 4 Animal experiment Mouse scleral permeation experiment was performed using hollow microneedle for vitreous cavity injection. The efficacy of the vitreous cavity injectable microneedle of the present invention was verified through perforation of the ocular surface of mice with a small surface area. The microneedle produced in Example 1 was used in this experiment.
  • the dead cells can be confirmed by fluorescence.
  • NaF Sodhim fluorescein
  • the degree of cell death was observed when the microneedle for vitreous cavity injection was injected.
  • the experimental results show that the damage site is significantly smaller because the fluorescent site is much smaller in the case of using the vitreous cavity injection microneedle of the present invention than when using the 30 gauge needle.
  • the intravitreal dilator (pharmaceutical name: Mydrin-P ophthalmic solution, manufacturer name: SANTEN PHARMACEUTICAL CO) is administered into the rabbit eye vitreous cavity using the vitreous cavity injection microneedle of the present invention, and the vitreous cavity injection micrograph of the present invention.
  • the efficiency of intravitreal drug delivery by needle was confirmed.
  • New Zealand rabbits (1-1.5 kg) were used for this experiment. All experiments were conducted in compliance with the ARV0 Statement for the Use of Animals in Ophthalmic and Vision Research and approved by the Animal Experimentation Committee of Nune Eye Hospital (South Korea). Anesthesia was performed by intramuscular injection of 3 mg of Uletamine HCl and 3 mg of Zolazepam HCKZoletil 50, France).
  • Example 5 Penetration force experiment of human sclera using hollow microneedle for vitreous cavity injection
  • the human carcass sclera (2 X 2 cm 2 ) was provided by Nune Eye Hospital (Seoul, Korea) with the approval of the Nune Eye Hospital Committee and stored in a humidifier at 1 ° C for 1-2 days before use.
  • the scleral tissue was fixed on a model zwicki-line testing machines Z0.5TN of Zwick, and individual microneedles were forced at 100 um s— 1 loading speed on the fixed human carcass sclera surface. The penetration intensity at the moment when the microneedle penetrated the sclera tissue was measured.
  • the vitreous cavity injection microneedle of the present invention (the microneedle produced in Example 1), the microneedle without the bevel angle, and the 30 gauge hypodermic needle with the barbell angle of 15 0 were used.
  • the vitreous cavity injection microneedles (0.28 ⁇ 0.03 N) and 30 gauge hypodermic needles (0.29 ⁇ 0.02 N) of the present invention showed no significant difference in the maximum strength required in penetrating the human sclera.
  • the microneedle without making bevel hangers increased the transmission intensity by 17 times (about 3.5 N) (FIG. 9).

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Abstract

La présente invention concerne un procédé de préparation d'une micro-aiguille creuse pour une injection intravitréenne, lequel procédé de préparation comprend les étapes suivantes consistant à : (a) revêtir la surface d'un substrat d'une solution de matière visqueuse ; (b) à amener la solution de matière visqueuse en contact avec un cadre ; (c) à soulever le substrat, le cadre, ou le substrat et le cadre d'une manière telle que le cadre de contact et le substrat sont espacés l'un de l'autre, permettant ainsi de préparer une microstructure solide ; (d) à déposer un métal sur la microstructure solide ; (e) à plaquer un métal sur la microstructure solide à métal déposé ; (f) à couper en biseau une partie de pointe de la microstructure solide à métal plaqué, l'angle de biseau formé par la coupe en biseau étant de 5-20 degrés ; et (g) à retirer la microstructure solide pour obtenir une microstructure creuse. La micro-aiguille creuse pour une injection intravitréenne de la présente invention comprend un métal, et a ainsi la puissance ou la force d'être apte à passer à travers la sclérotique et la rétine. La micro-aiguille creuse pour une injection intravitréenne de la présente invention a un rapport d'aspect ultra-élevé, et peut ainsi réduire au minimum l'endommagement de la rétine. La micro-aiguille creuse pour une injection intravitréenne de la présente invention a une longueur effective suffisante pour l'administration d'un médicament au centre du globe oculaire, et peut ainsi améliorer l'efficacité d'un médicament. La micro-aiguille creuse pour une injection intravitréenne de la présente invention est compatible avec une seringue normale, et peut ainsi être utilisée facilement.
PCT/KR2012/010254 2011-11-29 2012-11-29 Micro-aiguille creuse pour une injection intravitréenne Ceased WO2013081399A1 (fr)

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Cited By (2)

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Publication number Priority date Publication date Assignee Title
US20180056053A1 (en) * 2016-08-26 2018-03-01 Juvic Inc. Protruding microstructure for transdermal delivery
CN117339063A (zh) * 2023-12-06 2024-01-05 杭州迪视医疗生物科技有限公司 一种微针管及显微注射针的制造方法

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20210095385A (ko) 2020-01-23 2021-08-02 주식회사 씨엠랩 안구용 주사 장치 및 물질 전달 장치

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005503194A (ja) * 2001-06-13 2005-02-03 アボット・ラボラトリーズ 低侵襲的薬物供給のためのマイクロニードルおよびマイクロニードルの製造方法
US20090043279A1 (en) * 2007-08-06 2009-02-12 Kaspar Roger L Microneedle arrays formed from polymer films
KR20090059971A (ko) * 2007-12-07 2009-06-11 인싸이토 주식회사 중공형 마이크로 니들

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Publication number Priority date Publication date Assignee Title
JP2005503194A (ja) * 2001-06-13 2005-02-03 アボット・ラボラトリーズ 低侵襲的薬物供給のためのマイクロニードルおよびマイクロニードルの製造方法
US20090043279A1 (en) * 2007-08-06 2009-02-12 Kaspar Roger L Microneedle arrays formed from polymer films
KR20090059971A (ko) * 2007-12-07 2009-06-11 인싸이토 주식회사 중공형 마이크로 니들

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180056053A1 (en) * 2016-08-26 2018-03-01 Juvic Inc. Protruding microstructure for transdermal delivery
CN117339063A (zh) * 2023-12-06 2024-01-05 杭州迪视医疗生物科技有限公司 一种微针管及显微注射针的制造方法

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