KR101412535B1 - Hollow Microneedle for Intravitreal Drug Delivery - Google Patents

Abstract

(A) applying a solution of a viscous material to a substrate surface; (b) contacting a solution of the viscous material with a syringe needle as a frame; (c) lifting the substrate, the syringe needle or the substrate and the syringe needle such that the contacted syringe needle and the substrate are spaced apart to produce a solid microstructure; (d) depositing a metal on the solid microstructure; (e) metal plating the metal deposited solid microstructure; (f) beveling the tip portion of the metal plated solid microstructure; Bevel angle imparted by the bevel cutting is 5 ^o -20 ^o, and, (g) intravitreal (intravitreal) for injection of hollow micro-needles comprises the step of obtaining a hollow fiber type micro-structure by removing the solid microstructures And a manufacturing method thereof. The hollow microstructure for intravitreal injection of the present invention is made of metal and has strength or force to pass through the sclera and the retina. The hollow microstructure for intravitreal injection of the present invention has a very high aspect ratio and can minimize damage to the retina. The hollow microstructure for intravitreal injection of the present invention has an effective length sufficient to transfer the drug to the center of the eyeball, thereby enhancing the effect of the drug. The hollow microstructure for intra-vitreous injection of the present invention is compatible with general syringes and is easily usable.

Description

Hollow microneedle for Intravitreal Drug Delivery Background < RTI ID = 0.0 > [0001] <

The present invention relates to a hollow microneedle for glass body cavity injection and a method for producing the same.

Many fatal eye diseases are caused by lesions of the inner retina of the eye, and physiochemical barriers including BRB (blood-retina-barrier) similar to the cranial nervous system exist in the retina. Therefore, the drug can not effectively reach the retinal tissue by using topical medicines in the form of eye drops or by systemic administration through the oral or vascular injections.

These eye diseases include age-related macular degeneration (AMD), diabetic retinopathy (DR), retinal vein occlusion, brvo, uveitis, endothalmitis, etc. This is the most effective treatment method of injecting direct intra-ocular drug (Sridhar Duvvuri et al., Expert Opin . Biol . Ther . , (2003) 3 (1) 45-56 ).

 There are 27 gauge, 30 gauge and 31 gauge needle types commonly used in hospitals in the treatment of eye diseases. The larger the outer diameter of the 27-gauge needle, the smaller the outer diameter of the needle used for ophthalmic treatment is, the more safe it is (Pulido JS, Pulido CM, Bakri SJ, McCannelce , Cameron JD. 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 perforating the retina including the sclera and injecting the drug into the eyeball is 3 mm, and the length required to deliver the drug to the center of the eye is 8-10 mm. Therefore, in order to fabricate a hollow micro needle having a diameter of 80-150 μm and a length of 5-10 mm, the solid structure required to have a diameter of several tens of μm and a length of 5-10 mm should be satisfied.

Numerous papers and patent documents are referenced and cited throughout this specification. The disclosures of the cited papers and patent documents are incorporated herein by reference in their entirety to better understand the state of the art to which the present invention pertains and the content of the present invention.

The present inventors have made efforts to develop a hollow microneedle for intravenous intravitreal injection which can deliver drugs into the eyeball. As a result, it has succeeded in developing a hollow micro needle having an ultra-high aspect ratio that can practically perform intra-ocular drug delivery by a hollow micro needle in a diameter of several tens of micrometers and a length of 5-10 millimeters Thereby completing the present invention.

Accordingly, it is an object of the present invention to provide a method for producing hollow microneedles for intravitreal injection.

It is another object of the present invention to provide hollow microneedles for intravitreal injection.

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

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

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

(b) contacting the frame with a solution of the viscous material;

(c) lifting the substrate, the frame or the substrate and the frame such that the contacted frame and the substrate are spaced apart to manufacture a solid microstructure;

(d) depositing a metal on the solid microstructure;

(e) metal plating the metal deposited solid microstructure;

(f) beveling the tip portion of the metal plated solid microstructure; And the bevel angle imparted by the bevel cutting is 5 ^o -20 ^o,

(g) removing the solid microstructure to obtain a hollow microstructure.

The present inventors have made efforts to develop a hollow microneedle for intravenous intravitreal injection which can deliver drugs into the eyeball. As a result, it has succeeded in developing a hollow micro needle having an ultra-high aspect ratio that can practically perform intra-ocular drug delivery by a hollow micro needle in a diameter of several tens of micrometers and a length of 5-10 millimeters Respectively.

The method of the present invention will be described in detail in accordance with the respective steps.

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

According to the method of the present invention, a solution of a viscous substance is first applied to the surface of a substrate to produce a solid microstructure that is a mold of a hollow micro needle.

The material used to make the solid microstructures, which are molds of hollow micro needles, is a viscous material. The term " viscous material " as used herein means a material having a low viscosity at a certain temperature or higher, but having a high viscosity when the temperature is lowered to approach the vitrification temperature. The viscous material used in the present invention includes, but not limited to, an acrylic polymer, an amide polymer, an acetyl polymer, a vinyl polymer, an epoxy polymer, a silicone polymer, a sulfone resin, a polycarbonate polymer, Any viscous material conventionally used in the industry may be used.

Preferably, the viscous material used in the present invention is viscous when fluidized. Such a viscosity can be variously changed depending on the kind, concentration and temperature of the viscous substance, organic solvent, etc., and can be appropriately adjusted for the purpose of the present invention. More preferably, the viscous material of the present invention exhibits a viscosity of less than 200000 cSt (centistoke) when fluidized.

Fluidization of viscous materials can be accomplished through a variety of methods known in the art. For example, when a viscous material is a liquid polymer, a fluidization process is not required. In the case of a thermoplastic resin, the thermoplastic resin 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 (such as anhydrous or a lower alcohol with 1-4 carbon atoms, acetone, ethyl acetate, chloroform, 1,3-butylene glycol, hexane, diethyl ether and butyl acetate, .

As used herein, the term " application " means making the object surface a layer of constant thickness of a certain material. The substrate providing the surface is made of materials such as polymers, organic chemicals, metals, ceramics, and semiconductors.

According to a preferred embodiment of the present invention, the coating thickness of the viscous material solution of the present invention is adjusted in the range of 10-500 mu m, more preferably in the range of 50-200 mu m, and most preferably in the range of 75-165 mu m Lt; / RTI >

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

As used herein, the term " polymer compound removed by 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 easy to remove after metal deposition and plating for the production of a hollow micro needle, and the present inventors have removed the polymer compound as a metal-coated solid micro structure component by dissolving it as an organic solvent.

The polymer compound used in the present invention is more preferably an acrylonitrile styrene (AS), a polyamide, a polyethylene, a polyester, a polyacrylic, a polyacetyl, a styrene, a teflon, a polyvinyl chloride, a polyurethane, a nylon, Polymer. Most preferably, the polymeric compound of the present invention is an epoxy polymer.

The organic solvent used in the present invention preferably includes but is not limited to benzene, toluene, xylene (xylene), hexane, ether, acetone, alcohol and amine. Polar or nonpolar solvents may be used. For example, when an epoxy polymer is used as the polymer compound, NMP (N-methyl pyrrolidine) can be used as a solvent.

Step (b): contacting the frame with a solution of viscous material

In this specification, the lifting frame is brought into contact with the interface of the fluidized viscous material, preferably the viscous material after the coating of the polymeric compound. According to a preferred embodiment of the present invention, the diameter of the lifting frame used is variable and is adjusted in the range of 1-1,000 mu m diameter, most preferably 10-500 mu m.

A preferred example of a lifting frame used in the present invention includes a stainless steel frame in the form of a cannula and a tubular frame with a passage.

According to a preferred embodiment of the present invention, the frame used herein is a syringe needle. For example, in a syringe made of a syringe and a syringe needle, if a hollow micro needle is formed on the syringe needle, a highly efficient intra-vitreous drug delivery device can be provided.

As described above, when the microstructure is attached to a needle for injection to produce a single body, there is an advantage that a drug delivery device for glass body cavity injection is provided.

The syringe needle as the frame is preferably a syringe needle of 23 gage or more, more preferably 23-34 gage, even more preferably of 23-30 gauge or 23-27 gauge.

Step (c): The contacted frame and the substrate To be spaced  The substrate, frame or substrate and frame lifting  So Solid  Step of preparing microstructure

 As used herein, the term " solid microstructure " refers to a mold of microstructures and hollow micro-needles integrally fabricated without the formation of hollows.

In the present invention, the temperature of the fluidized viscous material (preferably, the polymeric material) is lowered to increase the viscosity while approaching the glass temperature.

According to a preferred embodiment of the present invention, in order to provide a hollow micro needle suitable for intravitreal injection, the hollow lifting frame is fully contacted with the fluidized (e.g., heated fluid) viscous material, -5000 ㎛ / s to make a solid structure, and the solid structure to be manufactured rapidly vitrifies at room temperature.

The viscosity in step (c) affects various external factors of the finally produced hollow micro needle, namely effective length, inner diameter, outer diameter, sharpness and aspect ratio, and in particular, the effective length of the solid microstructure and the hollow microstructure As a function of time. As the viscosity of the viscous material increases in step (c), the effective length of the hollow microstructure increases.

According to a preferred embodiment, the temperature of the viscous material is a glass transition temperature: the viscosity of the viscous material is adjusted by being adjusted in the high and low range below 130 ℃ than (glass transition temperature T _g).

As used herein, the term " glass transition temperature " refers to the temperature at which solidification of a viscous fluid-like material occurs. Therefore, a lifting process for a solidified material is impossible at a temperature lower than the vitrification temperature, and when the temperature is too high, a solid microstructure can not be fabricated because the lifting process can not be performed because the viscosity is low.

According to a preferred embodiment of the present invention, the viscosity of the viscous material controlled in step (c) is 50-10,000 Poise, more preferably 80-8,000 Poise, even more preferably 100-6,500 Poise.

As used herein, the term " spacing " refers to increasing the distance between the substrates that are in contact with each other so that they are spaced apart. The present inventors have fabricated a solid microstructure by lifting (lifting) a frame in contact with a viscous material, but a method of fixing the frame and moving the substrate downward, or moving the frame and the substrate simultaneously by moving them upward and downward Everything is possible.

According to the present invention, by adjusting the lifting speed of the polymer having viscosity, it is possible to control various external factors such as effective length, inner diameter, outer diameter, sharpness and aspect ratio of the hollow micro needle manufactured finally, The effective length of the hollow micro needle can be adjusted. As the lifting speed is increased, the effective length of the hollow micro needle increases.

As used herein, the term " lifting speed " is meant to include not only the upward or downward movement speed of a frame or substrate, but also the relative speed at which the frame and substrate move away from each other when they move up and down.

Lifting speeds used herein have a lifting speed of 0.1-2,000 μm / s, most preferably 1-1,000 μm / s. The length of the final solid microstructure can be adjusted by the product (product) of the lifting speed and the lifting time.

Step (d): Solid  Step of metal deposition on the microstructure

According to the present invention, metal solid deposition of the fabricated solid microstructure results in better metal plating reactions for subsequent hollow microneedle fabrication.

As used herein, the term " deposition " refers to a method of vaporizing or sublimating a material to be coated in a physical or manganese way so as to increase the mechanical strength of the material, It says. The physical vapor deposition and the chemical vapor deposition commonly used in the art can be used for the deposition of the present invention.

According to a preferred embodiment of the present invention, the vapor deposition metal of the present invention is at least one selected from the group consisting of stainless steel, aluminum (Al), chromium (Cr), nickel (Ni), gold (Au), silver (Ag) (Ti), cobalt (Co), or an alloy thereof. More preferably, silver is deposited chemically using a tollens reaction.

According to one embodiment of the present invention, silver (Ag) precipitated through a reduction reaction using a toluene reagent (Ag ₂ O + NH ₄ OH + H ₂ O) was deposited on a solid microstructure. The immersion reaction is more advantageous for the metal deposition on the object surface than the physical vapor deposition using a sputter or the like, since heating, pressurization and separate cooling are not necessary.

Step (e): The metal- Solid  Metal plating the surface of the microphone structure

The metallized solid microstructure may be plated to provide the basis for hollow micro-needles.

One of the features of the present invention is to perform metal plating without masking the tips of the microneedles after the metal deposition. Conventional hollow micro needle manufacturing techniques (e.g., Korean Patent No. 781702 and Patent Application No. 2010-0066940) essentially include a process of masking the tip portion of the micro needle prior to metal plating. The present invention can shorten the production time and convenience of the process without performing such a process.

Conventional techniques follow the process of "application-lifting-metal deposition-tip portion masking-plating-solid structure removal-bevel cutting", but the present invention is applicable to "removal-lifting-metal deposition- plating- Thereby providing a hollow microstructure for intravitreal injection.

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

The plating material used in the present invention includes, but is not limited to, nickel, stainless steel, aluminum, chromium, cobalt-based alloys, titanium, and alloys thereof, and is not toxic or carcinogenic as a bio- Any metal known in the art can be used as a metal having no human body rejection, good mechanical properties such as tensile strength, elastic modulus, abrasion resistance and the like, and having corrosion resistance capable of withstanding the corrosion environment in human body.

According to a preferred embodiment of the present invention, the plating metal of the present invention is formed of a metal such as stainless steel, aluminum (Al), chromium (Cr), nickel (Ni), gold (Au), silver (Ag), copper (Cu) Ti), cobalt (Co), or an alloy thereof. More preferably, the plating metal of the present invention is nickel (Ni).

Step (f): Metal-plated Solid  Microphone structure Bevel  Step of cutting

Then, the tip portion of the metal-plated solid microstructure is beveled. The bevel angle imparted by the bevel cutting is 5 ^o -20 ^o .

The term " tip " used in referring to the microstructure in the present specification means a tip end portion of the upper end of the microstructure imparted with a bevel angle (see FIG. 3).

The bevel angle of the conventional hollow micro needle is 30-90 ^o, but the bevel angle of the eye disease customized micro structure of the present invention has a bevel angle value similar to that of the silver syringe.

The bevel cutting can be performed using all precision cutting methods commonly used in the art, and preferably using a laser or a dicing saw. Adjustment of the bevel angle provides a sharpness for intravitreal injection applications.

For a hollow microstructure for intravitreal injection, the bevel angle is 5 ^o -20 ^o , preferably 5 ^o- 15 ^o , more preferably 10 ^o- 15 ^o .

Step (g): Solid  Removing the microphone structure to obtain a hollow microphone structure

A hollow micro needle is manufactured by removing the solid micro needle. Removal of solid micro-needles can be dissolved, burned, or physically removed using an appropriate organic solvent. Preferably by using the appropriate organic solvents listed above.

According to a preferred embodiment of the present invention, the method further comprises the step of cutting the tip tip of the hollow micro needle to a tip tip angle of 1-45 [deg.] And a tip tip lateral extent of 2-30 [mu] m after step (g) .

The tip tip polishing may be carried out through a variety of methods known in the art and may be performed, for example, using a laser or a dicing saw.

According to a preferred embodiment of the present invention, the tip tip portion of the hollow fiber micro-structure for intra-vitrectomy use of the present invention is provided in two directions, in three directions (for example, in both directions of the bevel surface direction and tip tip bevel surface) More preferably, cut in three directions. This cutting further improves the sharpness of the tip tip.

The term " tip " used in referring to the hollow microstructure in this specification means the tip end portion of the upper end of the microstructure to which the bevel angle is imparted.

The term " tip tip portion " means a portion from the upper end of the hollow portion to the end portion of the microstructure which can be observed from the outside, which is given a bevel angle at the tip portion of the upper end of the microstructure.

The term " tip-tip sub-lateral " means the length across the tip-tip at the mid-point of the tip-tip end (see FIG. 5). The term " tip tip angle " means the angle between the two edges at the tip of the tip (see Fig. 5).

The tip of the tip is cut / polished to minimize damage to the glass body tissue to which the hollow microstructure of the present invention is injected. The present invention polishes the tips of the tips of the microneedles so that the tip-tip lateral length is 2-30 占 퐉 (preferably 2-10 占 퐉, 5-10 占 퐉, 2-8 占 퐉). Also, tip tip angle was set to be 1-45 (preferably 30-45).

The hollow microneedles used for intravitreal injection prepared through the above procedure have structural and physical characteristics to penetrate the sclera and the retina and inject drugs into the eye.

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

The length of microneedles developed to date is only up to 2 mm. The present invention overcomes these limitations and provides an effective length suitable for intravitreal injection. The present invention can penetrate the sclera having the highest strength among the outer walls of the eyeball, and has a length that can be treated by injecting drugs into the center of the eyeball.

As used herein, the term " effective length " means the vertical length from the top of the micro needle to the bottom substrate surface. As used herein, the term " aspect ratio " refers to the height to diameter at base to the maximum diameter of the microneedles from the top to the bottom substrate surface.

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

As used herein, the term " upper end " refers to one end of a micro needle having a minimum diameter, and " lower end " refers to a lower end of a micro needle that abuts a substrate.

According to another aspect of the present invention, there is provided an intravitreal injectable hollow microneedle having an effective length of 5-10 mm, an upper end inner diameter of 50-150 μm and a bevel angle of 5 ^° -20 ^° .

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

According to a preferred embodiment of the invention, the syringe needle is a syringe needle of 23 gauge or more, more preferably 23-34 gauge, even more preferably 23-30 gauge or 23-27 gauge.

According to a preferred embodiment of the present invention, the hollow microneedle of the present invention is made of stainless steel, Al, Cr, Ni, Au, Ag, Cu, Titanium (Ti), cobalt (Co), or an alloy thereof.

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

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

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

According to a preferred embodiment of the present invention, the hollow microstructure of the present invention is produced by the method of the present invention described above.

According to a preferred embodiment of the present invention, the hollow microstructure of the present invention has a strength of 0.1-2.0 N, more preferably 0.5-2.0 N, even more preferably 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 penetration force requirements for commonly used intravitreal needles, EYE , 21: 1210-1211 (2007) The strength of the hollow microstructure can easily penetrate the sclera and the retina to transfer the drug into the vitreous cavity, that is, the eyeball.

According to a preferred embodiment of the present invention, the hollow microstructure of the present invention has a purpose of penetrating the sclera and the retina and injecting the drug into the center of the eye.

According to a preferred embodiment of the present invention, the hollow microstructure of the present invention has a tip tip angle of 1-45 [deg.] (More preferably 30-45 [deg.]) And a tip tip lateral extent of 2-30 [ -10 占 퐉, 5-10 占 퐉, 2-8 占 퐉).

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 strength or force capable of passing through the sclera and the retina.

(Ii) The hollow microstructure for intravitreal injection of the present invention has a very high aspect ratio and can minimize damage to the retina.

(Iii) The hollow microstructure for intra-vitreous intramuscular injection of the present invention has an effective length sufficient to deliver drugs at the center of the eye, thereby enhancing the effect of the drug.

(Iv) The hollow microstructure for intra-vitreous injection of the present invention is compatible with common syringes and is easily usable.

1 is a schematic view of an intravitreal injection device including a hollow microstructure of the present invention. 1: Microstructure, 2: Syringe needle, 3. Sulled delayed attachment
2 is a schematic view of the hollow microstructure of the present invention.
3 is an image showing a tip portion in the microstructure of the present invention.
4 is an image of a hollow micro needle manufactured according to the present invention.
5 is a conceptual view of a bevel angle, a tip apex angle, and a tip apex of a hollow microneedle for intra-vitrectomy use of the present invention.
6 is a graph showing the results of a mouse scleral permeation experiment using a hollow microneedle using glass body steel according to the present invention. In the microneedle injection using the hollow micro needle for glass body cavity of the present invention, the damage area was significantly small.
FIG. 7 shows the results of analysis of the effects of hollow micro-needles using glass body cavity according to the present invention on injection site tissues or cells (upper panel). FIG. 7 is a graph showing the results of an experiment in which the intraocular cavity administration was successfully performed by the hollow micro needle for injecting the vitreous cavity of the present invention (lower panel).

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .

Example

Example  One: Glass body cavity  Hollow used Micro needle  Production I

Solid microstructures were prepared using SU-8 2050 photoresist (purchased from Microchem) having a viscosity of 14,000 cSt. SU-8 2050 was applied on a 1.5 x 1.5 cm cover glass at 1000 RPM to maintain a thickness of about 160 μm. The cover glass was heated on a hot plate at 120 캜 for about 1 hour to maintain the SU-8 2050 fluidity. Then, a 27-gauge needle having a flat end was contacted and lifted vertically to prepare a solid structure having a diameter of 50 탆 and a length of 5 to 10 mm.

The prepared solid structure was subjected to silver plating using Tollen's reagent, followed by nickel electroplating. The nickel electroplating was performed for 75 minutes at 0.206 μm / min per 1 A / dm ² , so that the thickness of the plated metal was 20 μm. A hollow microneedle was prepared by cutting a solid bead with a 15 ^° bevel at the end of the plated structure using a fiber laser and removing the solid structure using an SU-8 remover (purchased from Microchem) or acetone. Then, the end portion of the tip of the hollow micro needle was cut in three directions so that the tip tip end transverse length was 10 占 퐉 or 8 占 퐉 and the tip tip angle was 30-45 占 Finally, the hollow micro- An ophthalmic drug delivery device containing needles was prepared (Fig. 1).

The prepared hollow micro needle for hollow fiberglass casting was a hollow micro needle having an upper end outer diameter of 120 mu m, an inner diameter of 50 mu m, a lower end diameter of 350 mu m, and a length of 9.02 mm. The hardness of the fabricated hollow micro needle is 1-2 N, which is higher than the minimum strength that can penetrate the sclera.

Example  2: Glass body cavity  Hollow used Micro needle  Production II

Solid microstructures were prepared using SU-8 2050 photoresist (purchased from Microchem) having a viscosity of 14,000 cSt. SU-8 2050 was applied on a 1.5 x 1.5 cm cover glass at 1000 RPM to maintain a thickness of about 160 μm. The cover glass was heated on a hot plate at 120 캜 for about 1 hour to maintain the SU-8 2050 fluidity. Then, a 27-gauge needle having a flat end was contacted and lifted vertically to prepare a solid structure having a diameter of 20-60 mu m and a length of 5-10 mm. In this case, while the temperature of the cover glass or substrate is slowly lowered to 90 ° C (adhesion of polymer: 1N, viscosity: 100 Poise) to 60 ° C (adhesion of polymer: 2N, viscosity: 6,500 Poise) Injection needles) were each lifted for 5 minutes at a rate of 10 占 퐉 / s. The prepared solid structure was subjected to silver plating using Tollen's reagent, followed by nickel electroplating. The nickel electroplating was performed for 75 minutes at 0.206 μm / min per 1 A / dm ² , so that the thickness of the plated metal was 20 μm. A hollow microneedle was prepared by cutting a solid bead with a 15 ^° bevel at the end of the plated structure using a fiber laser and removing the solid structure using an SU-8 remover (purchased from Microchem) or acetone. Then, the end portion of the tip of the hollow micro needle was cut in three directions so that the tip tip end transverse length was 10 占 퐉 or 8 占 퐉 and the tip tip angle was 30-45 占 Finally, the hollow micro- An ophthalmic drug delivery device including needles was prepared.

The prepared hollow micro-needle for hollow fiberglass is a hollow micro needle having an upper end outer diameter of 110 mu m, an inner diameter of 40 mu m, a lower end diameter of 350 mu m, and a length of 3-6 mm. The hardness of the fabricated hollow micro needle is 1-2 N, which is higher than the minimum strength that can penetrate the sclera.

Example  3: Glass body cavity  Hollow used Micro needle  Production Ⅲ

Solid microstructures were prepared using SU-8 2050 photoresist (purchased from Microchem) having a viscosity of 14,000 cSt. SU-8 2050 was applied on a 1.5 x 1.5 cm cover glass at 1000 RPM to maintain a thickness of about 160 μm. The cover glass was heated on a hot plate at 120 캜 for about 1 hour to maintain the SU-8 2050 fluidity. Then, a 27-gauge needle having a flat end was contacted and lifted vertically to prepare a solid structure having a diameter of 20-60 mu m and a length of 5-10 mm. In this case, the lifting frame (injection needle) was lifted at a rate of 5 탆 / s and 10 탆 / s for 5 minutes, respectively, while slowly lowering the temperature of the cover glass or the substrate to 70 to 60 ° C.

The prepared solid structure was subjected to silver plating using Tollen's reagent, followed by nickel electroplating. The nickel electroplating was performed for 75 minutes at 0.206 μm / min per 1 A / dm ² , so that the thickness of the plated metal was 20 μm. A hollow microneedle was prepared by cutting a solid bead with a 15 ^° bevel at the end of the plated structure using a fiber laser and removing the solid structure using an SU-8 remover (purchased from Microchem) or acetone. Then, the end portion of the tip of the hollow micro needle was cut in three directions so that the tip tip end transverse length was 10 占 퐉 or 8 占 퐉 and the tip tip angle was 30-45 占 Finally, the hollow micro- An ophthalmic drug delivery device including needles was prepared.

The prepared hollow micro-needle for hollow fiberglass is a hollow micro needle having an upper end outer diameter of 120 mu m, an inner diameter of 50 mu m, a lower end diameter of 350 mu m, and a length of 5-8 mm. The hardness of the fabricated hollow micro needle is 1-2 N, which is higher than the minimum strength that can penetrate the sclera.

In the above examples, the hollow micro needle for glass body cavity having various dimensions characteristics (inner diameter, diameter and length) was prepared by adjusting the temperature and lifting speed of the polymer.

The preferred embodiments and advantages of the present invention are best understood by reference to Figures 1 and 2, and the same reference numerals are used for corresponding parts and the same parts of the various figures.

Ophthalmic microneedles generally include an incorporated delayed ligature, needles, and microstructures. The delayed coupling is the part that connects the syringe to the needle. The needles are in fluid communication connecting the syringes and the microstructure. The microstructure is connected to the tip of the needle for fluid communication.

Ophthalmic microstructures have an optimal length of at least 3 millimeters and 8 to 10 millimeters in length. The diameter of the tip of the microstructure is up to 150 micrometers and is usually 90 micrometers. The components of the microstructure include metal, titanium, nickel, stainless steel, and the like.

The SU-8 2050 is applied on a 1.5 x 1.5 centimeter cover glass at 1000 RPM to maintain a thickness of about 160 micrometers. Heat on a hot plate at 120 ° C for about one hour. A solid needle with a diameter of 50 micrometers and a length of 5 to 10 millimeters is prepared by vertically lifting the contact needle with a flat tip. The prepared solid structure was silver plated using toluene reagent and then electroplated with nickel to a thickness of 20 to 30 micrometers. A fiber laser was used to cut a 15-degree bevel at the end of the plated structure, and the solid structure was removed using SU-8 remover or acetone to prepare an ophthalmic drug delivery device [Fig. 4].

Example  4: Glass body cavity  Hollow used Micro needles  Used animal experiment

Mouse sclera permeation experiment was performed. The efficacy of the micro-needle of the present invention was verified through perforation of the ocular surface of a small surface area mouse. In this experiment, the microneedles prepared in Example 1 were used.

As can be seen from FIG. 6, it can be seen that the damage site is significantly smaller when the micro-needle according to the present invention is used than the 30 gauge needle.

On the other hand, dead cells can be confirmed by fluorescence. Sodium fluorescein (NaF), which is widely used as a method to identify corneal damage in ophthalmology, was applied to the perforated area and washed with distilled water and confirmed by fluorescence microscopy. Cells that are damaged by physical damage show fluorescence. In this method, the degree of apoptosis was observed when injecting the micro - needle into the vitreous cavity. As can be seen from the upper panel of FIG. 7, it can be seen that the fluorescence sites are much smaller in the case of using the micro-needle according to the present invention than in the case of using the 30 gauge needle.

In addition, a pupil dilator (drug name: Mydrin-P ophthalmic solution, manufactured by SANTEN PHARMACEUTICAL CO) was injected into the rabbit eyeball cavity using the glass needle of the present invention. As can be seen from the lower panel of FIG. 7, it can be seen that the drug was successfully delivered into the glass body cavity by the glass needle injector microneedles of the present invention, confirming that the pupil expanded over time.

Claims (21)

1. An intravitreal injectable hollow microneedle comprising the steps of:
(a) applying a solution of a viscous material to a substrate surface;
(b) contacting a solution of the viscous material with a syringe needle as a frame;
(c) lifting the substrate, the syringe needle or the substrate and the syringe needle such that the contacted syringe needle and the substrate are spaced apart to produce a solid microstructure;
(d) depositing a metal on the solid microstructure;
(e) metal plating the metal deposited solid microstructure;
(f) beveling the tip portion of the metal plated solid microstructure; And the bevel angle imparted by the bevel cutting is 5 ^o -20 ^o,
(g) removing the solid microstructure to obtain a hollow microstructure.
delete 2. The method of claim 1, wherein the syringe needle is a needle of at least 23 gauge.
The method of claim 1, wherein the viscosity of the viscous material is controlled by adjusting the viscosity of the viscous material to be higher than a glass temperature and lower than 130 ° C.
The method of claim 1, wherein the plating metal is selected from the group consisting of stainless steel, aluminum (Al), chromium (Cr), nickel (Ni), gold (Au), silver (Ag), copper (Cu), titanium (Ti), cobalt Co) or an alloy thereof.
The method of claim 1, wherein the bevel angle of the tip portion of the hollow micro-needle fabrication method, characterized in that 5 ^o -15 ^o.
The method according to claim 1, wherein the effective length of the hollow microstructure is 5-10 mm.
8. The method according to claim 7, wherein the effective length of the hollow microstructure is 8 to 10 mm.
The manufacturing method according to claim 1, wherein an upper end inner diameter of the hollow microstructure is 50-150 탆.
2. The method of claim 1, wherein the method further comprises cutting the tip tip of the hollow micro needle to a tip tip angle of 1-45 [deg.] And a tip tip lateral extent of 2-30 [mu] m after step (g) .
Intravitreal injectable hollow microneedles with an effective length of 5-10 mm, an upper end diameter of 50-150 μm and a bevel angle of 5 ^° -20 ^° and formed on the needle of a syringe.
delete 12. The hollow micro needle according to claim 11, wherein the syringe needle is a syringe needle of 23 gauge or more.
The hollow micro needle according to claim 11, wherein the hollow micro needle is made of stainless steel, aluminum, chromium, nickel, gold, silver, copper, Cobalt (Co), or an alloy thereof.
The method of claim 11, wherein the bevel angle of the hollow micro-needle 5 ^o -15 ^o the intravitreal injectable hollow microneedle, characterized in that.
The hollow micro needle according to claim 11, wherein the effective length of the hollow micro needle is 8 to 10 mm.
[12] The hollow micro needle according to claim 11, wherein an inner diameter of the upper end of the hollow micro needle is 50-100 [mu] m.
12. The hollow micro needle according to claim 11, wherein the hollow micro needle is manufactured by the method according to any one of claims 1 to 10.
12. The hollow micro needle according to claim 11, wherein the hollow micro needle has a strength of 0.1-2.0 N.
[12] The hollow micro needle according to claim 11, wherein the hollow micro needle has a function of injecting a drug into the center of the eye through the sclera and the retina.
12. The hollow microneedle of claim 11, wherein the hollow microneedle has a tip tip angle of 1-45 [deg.] And a tip tip lateral dimension of 2-30 [mu] m.

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