WO2013081399A1 - Hollow microneedle for intravitreal injection - Google Patents

Abstract

The present invention provides a preparation method of a hollow microneedle for intravitreal injection comprising the following steps: (a) coating a viscous material solution on the surface of a substrate; (b) bringing the viscous material solution into contact with a frame; (c) lifting the substrate, the frame, or the substrate and the frame in such a way that the contact frame and the substrate are spaced from each other, thereby preparing a solid microstructure; (d) depositing a metal on the solid microstructure; (e) plating a metal on the metal-deposited solid microstructure; (f) bevel cutting a tip portion of the metal-plated solid microstructure, wherein the bevel angle formed by the bevel cutting is 5-20 degrees; and (g) removing the solid microstructure to obtain a hollow microstructure. The hollow microneedle for intravitreal injection of the present invention comprises a metal, and thus has the strength or force capable of passing through the sclera and the retina. The hollow microneedle for intravitreal injection of the present invention has an ultrahigh aspect ratio, and thus can minimize damage of the retina. The hollow microneedle for intravitreal injection of the present invention has an effective length sufficient for delivery of a drug to the center of the eyeball, and thus can enhance the efficacy of a drug. The hollow microneedle for intravitreal injection of the present invention is compatible with a normal syringe, and thus can be easily used.

Description

 【Specification】

[Name of invention]

 Hollow Microneedle for Vitreous Steel Injection

Technical Field

 The present invention relates to a hollow microneedle for vitreous cavity injection and a method for producing the same. Background Art

 Many fatal eye diseases are caused by lesions of the inner retina of the eye, and there are physicochemical barriers in the retina, including the brain-retina-Barrier (BRB). Thus, topical medications in the form of eye drops or systemic administration via oral or intravenous injection do not effectively reach the retinal tissue.

 These eye diseases include age-related macular degeneration (AMD), diabetic retinopathy (DR), retinal vein occlusion (brvo), 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).

 In the treatment of eye diseases, generally, there are 27 gauges, 30 gauges and 31 gauges used in hospitals. If the outer diameter is larger than 27 gauge, it can cause bleeding and hypotony along with damage to the eye tissue, so it is safer if the outer diameter of the needle used to treat eye disease is small (Pulido JS, Pulido CM, Bakr i SJ, McCannel). CA, Cameron J D. The use of 31-gauge needles and syringes for intraocular injections.Eye. 2007; 21: 829-830.].

The minimum length of the drug delivery device for injecting drugs into the eye by puncturing the retina, including the eye sclera, is 3 醒. The required length is 8-10 隱. 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 μηι in diameter and 5,10 mm in length. Throughout this specification, many papers and patent documents are referenced and their citations are indicated. The disclosures of cited papers and patent documents are incorporated herein by reference in their entirety, and the level of the technical field to which the present invention belongs and the contents of the present invention are more clearly explained. [Content of invention]

 [Problem to solve]

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 μιτι, a length of 5-10 μs, 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.

 Accordingly, 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. Other objects and advantages of the present invention will become apparent from the following detailed description, claims and drawings.

[Measures of problem]

 According to one aspect of the present invention, the present invention provides a method for preparing hollow microneedle for intravitreal injection, comprising the following steps:

 (a) applying a solution of viscous material to the substrate surface;

(b) contacting the frame with the solution of viscous material; (c) manufacturing a solid microstructure by lifting the substrate, the frame or the substrate and the frame so that the contacted frame and the substrate are spaced apart;

 (d) depositing metal on the solid microstructure;

(e) metal plating the metal deposited solid microstructure; (f) beveling the tip portion of the metal plated solid microstructure; The bevel angle given by the bevel cutting is 5 ^ο -20 ^ο ,

(g) removing the solid microstructure to obtain a hollow microstructure. The inventors have sought to develop hollow microneedles for intravitreal injection that can deliver drugs into the eye. As a result, we developed a hollow microneedle with an ultra-high aspect ratio that satisfies 5-10 mm in length and several tens of um in diameter, which enables practical intraocular drug delivery by the hollow microneedle. Succeeded. The method of the present invention will be described in detail with each step as follows;

Step (a): applying a solution of viscous material to the substrate surface

 According to the method of the present invention, 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. As used herein, the term "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. Preferably, 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

It exhibits a viscosity of 200000 cSt (cent i stoke) or less.

 Fluidization of the viscous material can be carried out through various methods known in the art. For example, when the viscous material is a liquid polymer, no fluidization process is required, and in the case of the thermoplastic resin, the viscous material is viscous by heating at a temperature above the melting point and then lowering the temperature to approach the vitrification temperature. It is also possible to dissolve the polymer material in 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) Can be mad.

 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.

 According to a preferred embodiment of the invention, the coating thickness of the viscous solution of the invention is controlled in the range 10-500 μιη, more preferably in the range 50-200 urn, most preferably in the range 75-165 um Adjusted in

 According to a preferred embodiment of the present invention, the viscous material of step (a) is a high molecular compound removed by an organic solvent.

 As used herein, the term "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.

 More preferably, the high molecular compound used in the present invention is ASCacrylonitrile styrene), polyamide, polyethylene ᅳ polyester, polyacryl, polyacetyl, stylone, teflon, polyvinyl chloride, polyurethane, nylon, sulfone resin or epoxy polymer. . Most preferably 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. For example, when an epoxy polymer is used as the polymer compound, N-methyl pyrrol idine (NMP) may be used as a solvent. Step (b): contacting the frame with a solution of viscous material

 After the coating of the fluidized viscous material, preferably the polymer compound, the lifting frame is brought into contact with the interface of the viscous material. According to a preferred embodiment of the invention, 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.

 According to a preferred embodiment of the invention, the frame used herein is 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.

 As such, when the microstructure is attached to the needle for injection to produce an integrated body, there is an advantage that the drug delivery device for injection of the vitreous cavity is provided.

 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. Step (c): fabricating the solid microstructure by lifting the substrate, the frame or the substrate and the frame such that the contacted frame and the substrate are spaced apart.

 As used herein, the term "solid microstructure" refers to the mold of the micro pliers and hollow microneedle fabricated integrally without the formation of hollows. ,

In the present invention, by lowering the temperature of the fluidized viscous material (preferably high molecular material) to approach the vitrification temperature (Glass temperature) Increase.

 According to a preferred embodiment of the present invention, in order to provide a hollow microneedle suitable for intravitreal injection, a rapid speed of about 3000 after full contact of the hollow lifting frame with the fluidized (eg heated fluid) viscous material -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.

 According to a preferred embodiment of the present invention, 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.

 As used herein, 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. According to a preferred embodiment of the present invention, 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.

 As used herein, 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.

According to the present invention, by controlling the lifting speed of the viscous polymer, various external elements of the finally manufactured hollow microneedle can be adjusted, namely, effective length, inner diameter, outer diameter, sharpness and aspect ratio. In particular, the effective length of the solid microstructure, the effective length of the hollow microneedle can be adjusted. As the lifting speed is increased, the effective length of the hollow microneedle increases.

 As used herein, the term "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. Step (d): metal deposition on the solid microstructure

 According to 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.

 As used herein, 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. Say that. 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.

 According to a preferred embodiment of the present invention, 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.

According to one embodiment of the present invention, silver (Ag) precipitated through reduction reaction using a ᅳ lene reagent (Ag ₂ 0 + H ₄ 0H + ¾0) 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. Step (e): metal plating the surface of the metal deposited solid microphone structure

 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) essentially include masking the tip portion of the microneedle prior to metal plating. The present invention shortens the production time and increases the convenience of the process without carrying out such a process.

 Conventional techniques follow the process of "application-lifting ᅳ metal deposition-tip masking-plating-solid structure removal-bevel cutting", but the present invention is "application-lifting-metal deposition-plating ᅳ bevel cutting-solid structure removal" It provides a hollow microstructure for intravitreal injection by the process of.

 The plating thickness used in the present invention is preferably 5-100 μπι, more preferably 10-50 μηι.

 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.

 According to a preferred embodiment of the present invention, 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 tip portion of the metal plated solid microstructure is then beveled. Bevel angle imparted by the cutting bevel (Bevel angle) is 5 ⁰ - 20 ^ο a. The term "tip" as used herein to refer to a microstructure refers to the tip portion of the upper end of the microstructure to which the bevel hang is given (see Figure 3).

Although the bevel angle of the conventional hollow microneedle is 30-90 ⁰ , 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.

In intravitreal injectable hollow microstructures, the bevel angle is 5 coming 20ο, preferably 5 ° - a ^ο 15 °, preferably 10 ° -15 more. Step (g): removing the solid microphone structure to obtain a hollow microphone structure

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. According to a preferred embodiment of the present invention, 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.

According to a preferred embodiment of the invention, 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. The term "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.

 The term "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 term “tip tip rung” means the length across the tip tip at the middle of the tip tip (see FIG. 5). The term "tip tip angle" means the angle between the two blades at the tip tip (see Figure 5),

In order to minimize damage to the vitreous steel tissue into which the hollow microstructure of the present invention is injected, the tip tip is cut / polished. In the present invention, 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 μηι, 2-8 μιη). 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. . According to a preferred embodiment of the present invention, the effective length of the finally prepared hollow microstructure is 5-10 mm 3.

 The microneedle developed to date is only 2 隱 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. As used herein, the term "effective length" means the vertical length from the upper end of the microneedle to the lower substrate surface. As used herein, 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.

 According to a preferred embodiment of the present invention, the inner diameter of the upper end of the finally prepared hollow microstructure is 50-150 i.

As used herein, the term "top" refers to the microneedle having the smallest diameter. "End" means the lower end of the microneedle in contact with the substrate. According to another aspect of the present invention, 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 ^ο- 20 ^ο .

 According to a preferred embodiment of the present invention, the vacuum microneedle is formed on the syringe needle.

 According to a preferred embodiment of the invention, 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.

 According to a preferred embodiment of the present invention, 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.

According to a preferred embodiment of the present invention, the bevel angle of the hollow microneedle of the present invention is 5 ° -15 °, more preferably 10 ^o- 15 ^o .

 According to a preferred embodiment of the present invention, the effective length of the hollow microneedle of the present invention is 5-10 mm.

 According to a preferred embodiment of the present invention, the inner diameter of the upper end of the hollow microstructure of the present invention is 50-100 i.

 According to a preferred embodiment of the invention, the hollow microstructures of the invention are prepared by the process of the invention described above.

 According to a preferred embodiment of the invention, 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 醒 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. According to a preferred embodiment of the present invention, 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. As such, 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.

 According to a preferred embodiment of the present invention, the hollow microstructures of the present invention have the use of injecting drugs into eye augment through the sclera and retina.

According to a preferred embodiment of the present invention, 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 μπι (more preferably 2 -10 μι ^η , 5-10 μιτι, 2-8 μηι).

【Effects of the Invention】

 The features and advantages of the present invention are summarized as follows:

 (i) 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.

 (ii) The hollow microstructure for intravitreal injection of the present invention has an ultra-high aspect ratio, thereby minimizing damage to the retina.

(iii) intravitreal injectable hollow ^"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.

 (iv) The intravitreal injection-enhanced microstructure of the present invention is easily compatible with general syringes.

[Brief Description of Drawings]

1 is a schematic diagram of an intravitreal injection device including a hollow microstructure of the present invention. 1: 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. In the case of using the hollow microneedle for vitreous cavity injection of the present invention (Microneedle injection), the damage site was remarkably small. ^'

 7 is a result of analyzing the effect of the hollow microneedle for vitreous cavity injection of the present invention on the tissue or cell of the injection site.

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.

[Specific contents to carry out invention]

 Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention more specifically, it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples in accordance with the gist of the present invention. . EXAMPLE

Example 1 Fabrication of Hollow Microneedle for Vitreous Steel Injection I

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 μπι and a length of 5-10 mm.

Silver plating was performed on the produced solid structure using a Tollen'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 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 μm, an inner diameter of 50 μm, a diameter of 350 μm 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. Example 2 Fabrication of Hollow Microneedle for Vitreous Steel Injection

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. Next, a 27-gauge needle with a flat end was contacted and lifted vertically to produce a solid structure having a diameter of 20-60 μιη and a length of 5-10 mm. In this case, while lifting the cover glass, that is, lowering the temperature of the substrate to 90 ^° C (polymer adhesion strength: IN, viscosity: 100 Poise) and 60 ^° C (adhesion of polymer: 2N, viscosity: 6,500 Poise), the lifting frame ( Needles) were each lifted for 5 minutes at a rate of 10 um / s. Tolen's reagent on the fabricated solid structure After plating with silver using a reagent), nickel plating was performed. Nickel electroplating was performed at 0.206 / m / min per 1 A / dm ² for 75 minutes to make the plated metal thickness 20 μτη. 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 μιη 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. Example 3 Fabrication of Hollow Microneedle for Vitreous Steel Injection m

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. Subsequently, 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. Using 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 μπι, a lower diameter of 350 μηι, 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.

 In this embodiment, the hollow microneedle for vitreous steel injection having various dimension toks (inner diameter, diameter and length) was prepared by adjusting the temperature and lifting speed of the polymer.

 Preferred embodiments and advantages of the invention are best understood by reference to Figs. 1 and 2, wherein like reference numerals are used for corresponding and identical parts of the various figures.

 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 誦 and 8–10 隱. 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 隱 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.

4). 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.

 As can be seen in Figure 6, it can be seen that the damage site is significantly smaller when using the vitreous cavity injection microneedle of the present invention than when using a 30 gauge needle.

 On the other hand, the dead cells can be confirmed by fluorescence. NaF (Sodhim fluorescein), which is widely used as a method of identifying corneal damage in ophthalmology, was applied to the perforated area, washed with distilled water, and confirmed by fluorescence microscopy. Cells that die due to physical damage show fluorescence. Using this method, the degree of cell death was observed when the microneedle for vitreous cavity injection was injected. As can be seen in Figure 7, 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.

In addition, 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). 5 μΐ of phenylephrine solution was administered into rabbit ocular vitreous cavity using the vitreous cavity injection microneedle and 30 gauge needle of the present invention. Pupil dilation was measured using a microscope (SZ61, Olympus) at intervals of 0, 30, 100 and 300 seconds after drug administration. As a result, no pupil dilation occurred in PBS (control) (Panel a of FIG. 8), but the vitreous cavity injection microneedle (Panel b of FIG. 8) and 30 gauge of the present invention. In the case of injection of a dilator with a needle (panel c in FIG. 8), the pupil was similarly gradually enlarged. As can be seen in Figure 8, it can be seen that the drug was well delivered into the vitreous cavity by the vitreous cavity injection microneedle of the present invention by confirming that the pupil is expanded over time. 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. For comparison experiments, 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. As a result, 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. However, the microneedle without making bevel hangers increased the transmission intensity by 17 times (about 3.5 N) (FIG. 9). The external diameter of the hypodermic needles is almost no difference despite being 2-3 times thicker than the microneedle because the bevel angles are also introduced in the hypodermic needles. These results thus suggest that the introduction of the bevel angle is important for reducing the strength required for scleral penetration. Having described the specific part of the present invention in detail, it is apparent to those skilled in the art that such a specific technology is only a preferred embodiment, and the scope of the present invention is not limited thereto. Therefore, the substantial scope of the present invention will be defined by the appended claims and equivalents thereof.

Claims

[Patent Claims] [Claim 1]  Method for preparing hollow microneedle for intravitreal injection, comprising the following steps:  (a) applying a solution of viscous material to the substrate surface;  (b) contacting the frame with the solution of viscous material;  (c) fabricating a solid microstructure by lifting a substrate, frame or substrate and frame such that the contacted frame and substrate are spaced apart;  (d) depositing metal on the solid microstructure;  (e) metal plating the metal deposited solid microstructure; (f) beveling the tip portion of the metal plated solid microstructure; The bevel angle given by the bevel cutting is 5 ° -20 ^ο , (g) removing the solid microstructure to obtain a hollow microstructure. [Claim 2] ^"  The method of claim 1, wherein the frame is a syringe needle. [Claim 3]  The method of claim 2, wherein the syringe needle is a syringe needle of 23 gauge or more. [Claim 4] The method of claim 1, wherein the viscosity of the viscous material is controlled by adjusting the temperature of the viscous material higher than a glass temperature and lower than 130 ^° C. 6. O 2013/081399 [Claim 5]  The method of claim 1, wherein the plating metal is stainless steel, aluminum (A1), chromium (Cr), nickel (Ni), gold (Au), silver (Ag), copper (Cu), titanium (Ti), cobalt ( Co) or an alloy thereof. [Claim 6] The method of claim 1 wherein the bevel angle of the tip portion of the hollow microneedle is 5 ⁰ -15 ⁰ . [Claim 7]  The method of claim 1, wherein the effective length of the hollow microstructure is 5 ᅳ 10 麵. [Claim 8]  8. The method according to claim 7, wherein the effective length of the vaporized microstructure is 8-10 mm 3. [Claim 91]  The method of claim 1, wherein the inner diameter of the upper end of the hollow microstructure is 50-150. [Claim 10]  The method of claim 1, further comprising the step of cutting the tip tip of the hollow microneedle after step (g) to have a tip tip angle of 1-45 ° and a tip tip length of 2-30 μιτι. Characterized in the manufacturing method. [Claim 11] Hollow microneedle for intravitreai injection with effective length 5 ᅳ 10 闘, upper diameter 50-150 μιη and bevel angle 5 ^ο _20 ^ο . [Claim 12]  The intravitreal injection-enhanced microneedle of claim 11, wherein the hollow microneedle is formed on a syringe needle. [Claim 13]  13. The hollow microneedle for intravitreal injection according to claim 12, wherein the syringe needle is a syringe needle of 23 gauge or more. [Claim 14]  The method of claim 11, wherein the hollow microneedle is made of stainless steel, aluminum (A1), crumb (Cr), nickel (Ni), gold (Au), silver (Ag), copper (Cu), titanium (Ti), A hollow microneedle for intravitreal injection, characterized in that it has a material of cobalt (Co) or an alloy thereof. [Claim 15] 12. The hollow microneedle for intravitreal injection according to claim 11, wherein the bevel angle of the hollow microneedle is 5 ^{0-15 0} . [Claim 16]  12. The hollow microneedle for intravitreal injection according to claim 11, wherein the effective length of the hollow microstructure is 8-10 mm. [Claim 17]  12. The hollow microneedle for intravitreal injection according to claim 11, wherein the inner diameter of the upper end of the hollow microstructure is 50-100 urn. [Claim 18] 12. The hollow microneedle for intravitreal injection according to claim 11, wherein the hollow microstructure is produced by the method of any one of claims 1 to 10. [Claim 19]  12. The hollow microneedle for intravitreal injection according to claim 11, wherein the hollow microstructure has a strength of 0.1-2.0 N. [Claim 20]  12. The hollow microneedle for intravitreal injection according to claim 11, wherein the hollow microstructure has a purpose of injecting a drug into the center of the eye by penetrating the sclera and the retina. [Claim 21] 12. The hollow microneedle for intravitreal injection according to claim 11, wherein the hollow microstructure has a tip tip angle of 1-45 ⁰ and a tip tip cross section of 2-30 μηι.