WO2009154411A1

WO2009154411A1 - Process for preparing solid microstructures

Info

Publication number: WO2009154411A1
Application number: PCT/KR2009/003272
Authority: WO
Inventors: 정형일; 이광
Original assignee: 연세대학교 산학협력단
Priority date: 2008-06-18
Filing date: 2009-06-18
Publication date: 2009-12-23
Also published as: KR20090131540A; KR100938631B1

Abstract

The present invention relates to a process for preparing a solid microstructure and the solid microstructure prepared thereby. The process for preparing the solid microstructure comprises: (a) preparing fluidized biocompatible materials; (b) inducing three-dimensional downward flow of the fluidized biocompatible materials wherein all surfaces in the downward flow are in contact with air; and (c) solidifying the downward flow of the fluidized biocompatible materials to form the solid microstructure.

Description

【Specification】

[Name of invention]

Manufacturing method of solid microstructure

[Technical field]

The present invention relates to a method for producing a microstructure and a microstructure produced thereby. [Background technology]

The microneedle developed to date has been mainly used for drug delivery, blood collection, and analyte detection in vivo.

Unlike the conventional needle, the microneedle is characterized by painless skin penetration and no trauma, and the painless skin penetration is important for the top diameter for minimal aggression. In addition, microneedles must penetrate the stratum corneum of 10-20, which is the most powerful obstacle in the skin, so it is required to have a sufficient physical hardness. In addition, the proper length to increase the efficiency of drug delivery by reaching the capillaries should also be considered.

After In- lane type of micro-needle ( "Si 1 icon-processed Microneedles ", Journal of microelectrochemical systems 8, 1999) is the first ^"eyes, and ⁰ t ᄋ a type of micro-needle has been developed. The fabrication method of the solid microneedle of the out-of-plane type using the etching method (US Patent Application Publication No. 2002138049 "Microneedle devices and methods of manufacture and use thereof") is a 50-100 diameter, 500 jum length solid silicon microneedle It was impossible to realize painless skin penetration by making needles, and it was difficult to deliver drugs and cosmetic ingredients to the target site. Meanwhile, Prausnitz of the University of Georgia, U.S., has proposed a method of making biodegradable polymer microneedles by etching glass or making a photolithography mold (Biodegradable polymer microneedles: Fabrication, mechanics and transdermal drug delivery). , Journal of Controlled Release 104, 2005, 5166). In 2006,

1 Alternative paper (Article 26) A method of fabricating a biodegradable solid microneedle by mounting a capsular material at the end of a mold made by a photolithography method has been proposed (Polymer Microneedles for Control led-Re lease Drug Delivery, Pharmaceutical Research 23, 2006, 1008). ). This method has the advantage of free loading of drugs that can be produced in the form of capsule, but as the drug loading increases, the hardness of the microneedles is weakened.

In 2005, absorbent microneedles were proposed by Nano Devices and Systems (Japanese Patent Application Laid-Open No. 2005154321; and "Sugar Micro Needles as Transdermic Drug Delivery System Biomedical Microdevices 7, 2005, 185). The needle is intended for use in drug delivery or cosmetics without removing the microneedle inserted into the skin In this method, a microneedle was prepared by adding a maltose and drug to the mold and coagulating the same. The Japanese patent proposes a transdermal absorption of the drug by making the microneedle absorbent, but it is accompanied by pain when penetrating the skin, and due to the technical limitation of mold making, it has an effective upper diameter with painlessness and is effective. Microphones with lengths of 1 顏 or more, which are required for drug delivery To fabricate the needle impossible.

Recently, biodegradable microneedle manufactured by Prausnitz of the University of Georgia, USA, polyvinylpyrrolidone (PVP) and methacrylic acid in polydimethylsiloxane (PDMS) template acid: MAA) was prepared using a material mixed with (Minimally Invasive Protein Delivery with Rapidly Dissolving Polymer Microneedles, Advanced Materials 2008, 1). In addition, carboxymethylcell was added to a pyramidal template to prepare microneedles (Dissolving microneedles for transdermal drug delivery, Bi materials 2007, 1). The method using the mold does not solve the limitation that it is difficult to manufacture by adjusting the diameter and length of the microneedle despite the advantage that it can be quickly and easily manufactured.

The skin is cut from the epidermis to the stratum corneum (<20 im), the epidermis (<100), And dermis (300-2, 500). Therefore, in order to deliver drugs and skin care ingredients without pain to a specific skin layer, it is recommended to produce the microneedle upper diameter within 30, effective length 1, 000-2, 000, and have sufficient hardness for skin penetration. Effective for the delivery of skin and beauty ingredients.

Conventional solid microneedles have been limited to materials such as silicon, polymer, metal, glass, etc. due to the limitations of the manufacturing method, and the upper end diameter of 50-100 / 500 urn in length was not easy to achieve the desired effect. Therefore, a method of manufacturing microneedles and a microneedle having a narrow diameter enough to realize painlessness when penetrating the skin and a long enough length to penetrate deeply into the skin without any particular limitation on the material and the microneedles The demand for it continues. 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.

[Detailed Description of the Invention]

The inventors have sought to develop an improved process for producing solid microstructures. As a result, the inventors have found that when fluidizing a biocompatible material and solidifying the three-dimensional flow of the fluid, the solid has the desired properties (e.g. effective length, top diameter and hardness) at a simpler, faster and lower cost of production. By confirming that a microstructure can be produced, the present invention has been completed.

Accordingly, it is an object of the present invention to provide a method for producing a solid microstructure.

Another object of the present invention is to provide a solid microstructure. Other objects and advantages of the present invention will become apparent from the following detailed description of the claims and drawings. According to one aspect of the present invention, the present invention provides a method for producing a solid microstructure, comprising the following steps:

(a) preparing a fluidized biocompatible material;

(b) inducing a three-dimensional downward f lowing of the fluidized biocompatible material such that all sides of the downward flow are in contact with air; And,

(c) solidifying (sol idi fying) the descent of the fluidized biocompatible material to form a solid microstructure. According to another aspect of the present invention, the present invention provides a solid microstructure produced by the method of the present invention described above. The inventors have sought to develop an improved process for producing solid microstructures. As a result, the inventors have found that when fluidizing a biocompatible material and solidifying the three-dimensional flow of the fluid, the solid has the desired properties (e.g. effective length, top diameter and hardness) at a simpler, faster and lower cost of production. It was confirmed that microstructures can be prepared. The method of the present invention is described in detail according to each step as follows;

Step (a): Preparation of a f luidized biocompatible material

The material used in the present invention for preparing the microstructures is a biocompatible material. As used herein, the term "biocompatible material" means a material that is substantially nontoxic to the human body, chemically inert and immunogenic.

According to a preferred embodiment of the present invention, the material used in the present invention has both biocompatible and biodegradable properties. As used herein, the term "biodegradable substance" refers to a substance that can be degraded by body fluids or microorganisms in vivo. Materials that can be used in the present invention include all materials that are biocompatible and can be fluidized.

Preferably, the biocompatible material used in the present invention is a carbohydrate, more preferably a tan sugar, peat sugar, tritan sugar, loli sugar, polysaccharide or an alcohol derivative thereof. Even more preferably, the biocompatible material used in the present invention is glucose, lactose, fructose galactose, mannose, maltose, lactose, maltose, sucrose, trehalose, raffinose, meljitose, melibiose, xyl lobby _OSU: cellobiose, stachyose (stachyose), of a sorbitan non manni, the erythritol (erythritol), the chairs come, the Lashio (lacitol), Mali (maltitol); such as gluconic acid and gluconic lactone aldonic Aldaric acid and its lactone derivatives such as aldonic acid and its lactone derivatives, ribaraic acid, arabinaric acid (& ^ 1 11 £ 11 ^" acid) and galactaric acid Uronic acids such as glucuronic acid, galaccuronic acid and mannuronic acid; starch, vegetable gums, substituted cellulose (e.g. Tilcelose, hydroxyethylcellose and alkylcellose), crystalline cellose, heparin, hyaluronic acid, chitosan, dextran, alginate, tragacanta, agar and carrageenan.

According to a preferred embodiment of the present invention, the biocompatible material used in the present invention has viscosity when fluidized. Such viscosity can be variously changed according to the type, concentration and temperature of the biocompatible material, and can be adjusted to suit the purpose of the present invention. Preferably, the biocompatible materials used in the present invention exhibit viscosities up to 200000 cSt when fluidized.

Fluidization of biocompatible materials can be carried out through various methods known in the art. According to a preferred embodiment of the present invention, the fluidization may be carried out by heating at a temperature above the melting point of the biocompatible material or by using a suitable solvent (eg water, anhydrous or hydrous lower alcohol, acetone). , Ethyl acetate, chloroform, 1,3-butylene glycol, nucleic acid, diethyl ether and butyl acetate) Is carried out.

According to a preferred embodiment of the invention, the biocompatible material used in the present invention is ^at least 50 ^° C, more preferably at least 60 ^° C, even more preferably at least 70 ^° C, most preferably at least 80 ^° C Has a point. When referring to the melting point, the upper limit is not particularly limited, but is preferably 500 ^° C., more preferably 400 ^° C., even more preferably 300 ^° C. and most preferably 200 ^° C. .

Plates containing biocompatible material fluids are not particularly limited and may be made, for example, of materials such as polymers, organic chemicals, metals, ceramics, semiconductors and the like.

The fluidized biocompatible material exhibits flowability. The present invention manufactures a solid microstructure using the flowability, that is, the fluid. According to a preferred embodiment of the invention, the biocompatible material further comprises a drug. One of the main uses of the microstructures of the present invention is microneedle, which is intended for transdermal administration. Therefore, in the process of preparing a fluidized biocompatible material, a drug is mixed with the biocompatible material and prepared.

Drugs that can be used in the present invention are not particularly limited. For example, the drug includes a chemical drug, a protein drug, a peptide drug, nucleic acid molecules and nanoparticles for gene therapy, and the like.

Drugs that can be used in the present invention are, for example, anti-inflammatory drugs, analgesics, anti-arthritis agents, antispasmodics, anti-inflammatory drugs, antipsychotics, neurostabilizers, anti-anxiety drugs, antagonists, anti-Parkin's disease drugs, cholinergic agonists, anticancer agents, Antiangiogenic, immunosuppressive, antiviral, antibiotic, appetite suppressant, analgesic, anticholinergic, antihistamine, antimigraine, hormone, coronary, cerebrovascular or peripheral vasodilator contraceptive, antithrombotic, diuretic, antihypertensive , Cardiovascular diseases treatment agents, cosmetic ingredients (eg, wrinkle improvement, skin aging inhibitors and skin lightening agents) and the like, but are not limited thereto.

The drug used in the present invention is preferably one having thermal stability. The reason for this is that when fluidizing a biocompatible material, it is generally heated at a high temperature, and thus the silver of the fluidized biocompatible material is high. Step (b): Three-Dimensional Downflow Derivation of Fluidized Biocompatible Material One of the greatest features of the present invention is the preparation of the microstructure by inducing a three-dimensional downflow of the fluidized biocompatible material.

Terms used herein to refer to fluidized biocompatible materials

"Three-dimensional descending flow" means that fluids of the biocompatible material flow downward without contacting the support or the substrate in all parts except the base part. That is, all sides of the descending flow of the biocompatible fluid flow in contact with air only, without contacting a solid substrate or the like.

Three-dimensional downflow of fluidized biocompatible materials can be induced in a variety of ways. Two representative preferred embodiments are described as follows:

According to the first embodiment, the three-dimensional descending flow of the fluidized biocompatible material is made by a support having a contacting protrusion, and the fluidized biocompatible material is attached to the contacting protrusion. And the fluidized biocompatible material has a three-dimensional descending flow from the contact protrusion by gravity.

The first embodiment is illustrated in FIG. 3. In FIG. 3, when the support mounted in the elevator contacts the fluid of the biocompatible material on the plate through the contact protrusion, the fluid is attached to the contact protrusion. Subsequently, moving the support upwards at a constant speed by an elevator to separate the contact protrusions from the biocompatible fluid induces the flow of falling of the fluid and creates the shape of the microstructure. Subsequently, solidifying at a constant temperature (eg, room temperature) produces a microstructure having a constant hardness, effective length and diameter. In this case, the solidification may be completed in the process of moving the contact projection upward, or may be completed after a predetermined time elapses after moving the contact projection upward.

According to a second embodiment, the three-dimensional descending flow of the fluidized biocompatible material is achieved by a support having a hole at the bottom, wherein the fluidized biocompatible material is formed on the bottom surface of the support. And said Fluidized biocompatible materials undergo three-dimensional down flow through the opening by gravity, atmospheric pressure, or external pressure.

The second embodiment is illustrated in FIGS. 4 and 5.

Referring to FIG. 4, a support having an opening, not a contact protrusion, is used. The support mounted in the elevator is impregnated with a fluid of biocompatible material. Subsequently, moving the support upwards at a constant speed by the elevator induces a flow of descent of the fluid and creates the shape of the microstructure. Subsequently, solidifying at a constant temperature (eg, in reality) produces a microstructure having a constant hardness, effective length and diameter. In this case, the solidification may be completed in the process of moving the support upwards, or may be completed after a predetermined time after the support is moved upwards.

Alternatively, the rapid introduction of a fluid of biocompatible material into a support with an opening located at a certain space height induces a descent flow of the fluid and allows the microstructure to be produced.

Referring to FIG. 5, when heat is applied to a support having a solid biocompatible material, the biocompatible material is fluidized and a downward flow is induced, thereby forming the shape of the microstructure. Heating can be carried out by various methods known in the art. For example, there is a method of using a laser heating or an electric conductor plate. Subsequently, solidifying at a constant temperature (eg room temperature) produces a microstructure having a constant hardness, effective length and diameter. In this case, the solidification may be completed in the course of descending flow is induced to form the microstructure, or may be completed after a certain time.

4 and 5, the opening is located at the bottom of the plate. Referring to FIG. 2, the inlet of the opening may be inclined so that fluids are introduced well. In addition, the inside of the opening is also inclined, so that the opening of the opening has a nozzle shape having a smaller diameter than the opening of the opening.

In a second embodiment the descent of the fluid of the biocompatible material may be by gravity, atmospheric pressure and / or negative pressure.

According to a preferred embodiment of the present invention, the contact projections or The opening is patterned (see FIG. 1). Such patterning is advantageous when fabricating the microneedle of the present invention as a patch (£ & 1 ^ 011). Step (c): solidification of the descent of the biocompatible material

Finally, the downflow of the biocompatible material is solidified to obtain a microstructure having a certain hardness.

Solidification occurs when the fluid of the biocompatible material is at a temperature below the melting point. Therefore, the solidification may be generated and completed in the falling flow process of step (b), or may be completed after the predetermined time elapses.

According to a preferred embodiment of the present invention, the solidification can be in the manner of natural solidification, dry solidification or blowing solidification in the atmosphere, and most preferably natural solidification, that is, natural solidification by standing at room temperature.

One of the advantages of the present invention is that it can produce microstructures very quickly. According to a preferred embodiment of the invention, the steps (b) and (c) are 1-2000 seconds, more preferably 1-1000 seconds, even more preferably 1-400 seconds, most preferably 1-200 In seconds.

The present invention can provide a variety of microstructures, preferably the microstructures provided by the present invention are microneedle, microspike, microblade, microknife, microfiber, microprobe, microbarb, microarray Or a microelectrode, more preferably, a microneedle, microspike, microblade, microknife, microfiber, microprobe or microvalve, most preferably solid microneedle.

According to a preferred embodiment of the invention, the microstructures of the invention are of top diameter 1-500 urn, more preferably 2-300 β «, most preferably of 5-100 /, preferably It has an effective length of 100-10,000 im, more preferably 200-10,000 im, even more preferably 300-8,000 im and most preferably 500-2,000. As used herein, the term "top" of a microstructure is one of the microstructures having the smallest diameter. Means a distal end. As used herein, the term “effective length” means the vertical length from the top of the microstructure to the support surface. As used herein, the term "solid microneedles" refers to microneedles made integrally without forming hollows. The features and advantages of the present invention are summarized as follows:

(i) The present invention is a method for producing a microstructure through the flow of falling of the fluid, this strategy has not been conventionally adopted.

(ii) According to the present invention, solid microstructures can be produced more simply, quickly and at lower production costs.

(iii) According to the present invention, it is possible to provide a solid microstructure having various characteristics by adjusting various elements of the manufacturing process (for example, the type of biocompatible material, the falling flow rate). [Brief Description of Drawings]

Figure 1 schematically shows a specific embodiment of the support used in the present invention.

2 diagrammatically shows an embodiment of an opening in a plate (support) for use in the present invention.

3 shows one specific embodiment of the method of the present invention.

4 illustrates another specific embodiment of the method of the present invention.

5 shows another specific embodiment of the method of the present invention. Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention in more detail, and the scope of the present invention is not limited by these examples according to the gist of the present invention to those skilled in the art to which the present invention pertains. Will be self explanatory. [Example]

Example 1 Fabrication of Maltose Microstructures I Biodegradable microneedles, a kind of microstructures, were prepared using maltose (Maltose monohydrate, Sigma), a type of natural sugar. The maltose powder was made into maltose candy by maintaining 140 ^° C. in a petri dish, and a small amount of water was added to prevent the maltose candy interface from hardening by contact with air. A contact protrusion of diameter 200 contacted the 3 × 3 patterned support (see FIG. 1) to the maltose candy solution interface, and then the support was lifted at 25 im / s for 1 minute to produce maltose microneedle of length 1500. After 30 seconds, the maltose microneedles solidified naturally and the maltose candy interface did not solidify until then. As a result, an effective length of 1, 500 and a diameter of 10 urn maltose microneedles of the top were prepared on the patterned support. The hardness of the fabricated microneedle represents 1-2 N value, which is much larger than 0.06 N. Example 2: Fabrication of Maltose Microstructures

Biodegradable microneedles, a kind of microstructures, were prepared using maltose (Maltose monohydrate, Sigma), a type of natural sugar. The maltose powder was added to the petri dish to maintain maltose candy at 140 ^° C., and a small amount of water was added to prevent the maltose candy interface from hardening by contact with air. Into the maltose candy solution was placed a support (see Fig. 1) having a diameter of 3 x 3 200 iM holes, lifted the support, and hardened as maltose candy flowed down from the patterned holes, ultimately producing maltose microneedle. It was. As a result, a maltose microneedle having a patterned effective length of 1,500 iM and a diameter of 10 at the top was obtained. The hardness of the fabricated microneedle represents 1-2 N value, which is much greater than 0.06 N. Example 3: Preparation of Maltose Microstructures m

Maltose in powder form, a type of natural sugar

Biodegradable microneedle, a type of microstructure, Produced. The maltose powder is made into maltose candy by maintaining the state of 14CTC, and the maltose candy solution is hardened by placing the maltose candy solution on a metal support having a diameter of 200 ji hole pattern of 3 X 3 (see FIG. 1), or according to the metal support pattern. Harden by dripping. As the metal support was temporarily raised to 140 ^° C., the maltose candy melted down from the patterned holes and flowed downward, ultimately producing maltose microneedles. As a result, a maltose microneedle having a patterned effective length of 1, 500 prn and a diameter of 10; The hardness of the fabricated microneedle represents 1-2 N value, which is much larger than 0.06 N. Example 4 Fabrication of Sucrose Microneedle I

Biodegradable microneedles, a kind of microstructures, were prepared using sucrose standard (Sigma), a powder form of natural sugars. Sucrose powder was dissolved in a small amount of water in Patridish and water was evaporated at ioo ° C to make sucrose candy. After the contact protrusion of diameter 200 contacted the 3 × 3 patterned support at the sucrose candy solution interface, the support was lifted at a rate of 25 pm / s for 1 minute to prepare a 1,500 micron sucrose microneedle. After 30 seconds, the sucrose microstructures solidified naturally and the sucrose candy interface did not solidify until then. As a result, a sucrose microneedle having an effective length of 1, 500! M and a diameter of 10 of the top was fabricated on the patterned support. The hardness of the fabricated microneedle represents 1-2 N value, which is much greater than 0.06 N. Example 5 Fabrication of Sucrose Microneedle

Biodegradable microneedles, a kind of microstructures, were prepared using sucrose standard (Sigma), a powder form of natural sugars. Sucrose powder was dissolved in a small amount of water in a petri dish and water was evaporated from the locrc into sucrose candy. Into the sucrose candy solution was placed a support having a diameter of 200 × M hole pattern of 3 × 3, By lifting, the sucrose candy flows down from the patterned lines and hardens, ultimately producing sucrose microneedles. As a result, a sucrose microneedle having a patterned effective length of 1,500 urn and a top diameter of 10 was produced. The hardness of the fabricated microneedle represents 1-2 N value, which is much larger than 0.06 N. Example 6 Preparation of Sucrose Microneedle

Biodegradable microneedles, a kind of microstructures, were prepared using sucrose standard (Sigma), a form of natural sugar. Dissolve sucrose powder in a small amount of water

Water is evaporated at 100 ^° C to make sucrose candy, and the sucrose candy solution is hardened by placing the sucrose candy solution on a metal support having a diameter of 200 m hole pattern of 3 x 3, or hardened by sucrose candy solution according to the metal support pattern. . As the silver support was temporarily raised to ioo ° C, sucrose candy melted downward from the patterned holes to harden, ultimately producing sucrose microneedles. As a result, the patterned effective length

Sucrose microneedle having a diameter of 1,500 iffli and a top 10 was made. The hardness of the fabricated microneedle represents 1-2 N value, which is much greater than 0.06 N. Example 7 Preparation of Cellulose Microstructures

Biodegradable microneedles, a kind of microstructures, were fabricated using powdered cellulose (Carboxymethylcel lulose sodium solt MC, Sigma). A 10% (W / V) cell was made into a solution of solution and coated on the substrate with 200. Then, a contact with a diameter of 200 contact projections with a 3 X 3 patterned contact (see FIG. 1) was brought into contact with the cell-coated interface and a -50 kPa vacuum. Stayed and dried for 5 minutes on 20% humidity. Subsequently, the support is lifted at a speed of 25 m / s for 20 seconds to fabricate a 500 μm length cell initial microstructure, and dried at humidity 17-18% for 2 minutes while maintaining a vacuum of −70 kPa. I was. Cells attached to the contact protrusion The microstructure was solidified because the amount of cells coated on the substrate was less than that of the Rhodes interface. The microstructure was separated from the Rhodes interface by continuous lifting at 25 / s. Finally, the resultant was dried at a humidity of 17-18% for 5 minutes while maintaining a vacuum of -70 kPa. Thus, a patterned support was fabricated with an effective length of 500 [M and a diameter of 10! The hardness of the fabricated microneedle represents 1-2 N value, which is much higher than 0.06 N. Having described the specific part of the present invention in detail, it is apparent to those skilled in the art that the specific technology is merely a preferred embodiment, and the scope of the present invention is not limited thereto. Thus, the substantial scope of the present invention will be defined by the appended claims and equivalents thereof.

Claims

[Range of request]

[Claim 1]

Method for producing a solid microstructure comprising the following steps:

(a) preparing a fluidized biocompatible material;

(b) inducing a three-dimensional downward flow of the fluidized biocompatible material, wherein all sides of the downflow are in contact with air; And,

(c) solidifying the descent of the fluidized biocompatible material to form a solid microstructure.

[Claim 2]

The method of claim 1, wherein the biocompatible material is viscous when fluidized. [Claim 3]

The method of claim 1, wherein the fluidization is accomplished by heating at a temperature above the melting point of the biocompatible material or by dissolving the biocompatible material. [Claim 4]

The method of claim 1, wherein the biocompatible material has a melting point of 50 ^° C. or higher.

[Claim 5]

The method of claim 1 wherein the biocompatible material is a carbohydrate.

[Claim 6]

6. The method of claim 5, wherein the carbohydrate is peat sugar tritan sugar, oligosaccharide, polysaccharide or alcohol derivatives thereof. [Claim 71

The fluidized biocompatible material of claim 1, wherein the three-dimensional descending flow of the fluidized biocompatible material is made by a support having a contact protrusion, and the fluidized biocompatible material is attached to the contact protrusion. And the fluidized biocompatible material undergoes a three-dimensional descending flow from the contact protrusion by gravity.

[Claim 8]

The fluidized biocompatible material of claim 1, wherein the three-dimensional descending flow of the fluidized biocompatible material is formed by a support having a hole at the bottom thereof, and the fluidized biocompatible material is formed on a lower surface of the support. And the fluidized biocompatible material undergoes a three-dimensional down flow through the opening by gravity, air pressure or external pressure. [Claim 9]

9. A method according to claim 7 or 8, wherein the contact protrusion or opening is patterned.

[Claim 10]

The method of claim 1, wherein steps (b) and (C) are performed simultaneously in time.

[Claim 11]

The method of claim 1, wherein steps (b) and (c) occur within 1-400 seconds.

[Claim 12]

The method according to claim 1, wherein the solidification is natural solidification, dry solidification, or blowing solidification in the atmosphere.

[Claim 13] The method of claim 1, wherein the biocompatible material of step (a) further comprises a drug.

[Claim 14]

The method of claim 1, wherein the microstructures are microneedles, microspikes, microblades, microknifes, microfibers, microprobes, microbarbs, microarrays or microelectrodes.

[Claim 15]

A solid microstructure produced by the method of claim 1.