KR101136739B1 - Multi-functional Hybrid Microstructure and Process for Preparing the Same - Google Patents

Abstract

The present invention provides a rapid release drug delivery method through a hollow microstructure, a sustained release drug delivery method through a biocompatible / biodegradable microstructure, and an electroporation method through a solid microstructure. The present invention relates to a multi-functional hybrid microstructure and a method for manufacturing the same, which integrate electroporation to simultaneously implement the functions of each microstructure and improve the transdermal administration efficiency of drugs.

Hybrid Microstructure, Biocompatibility, Biodegradable, Solid, Hollow, Microneedle, Microspike, Electroporation, Drug Delivery, Multifunctional

Description

Multi-functional Hybrid Microstructure and Process for Preparing the Same

The present invention relates to a multifunctional hybrid microstructure in which a solid microstructure, a hollow microstructure, and a biocompatible / biodegradable microstructure are mixed and a method of manufacturing the same.

In drug delivery for the treatment of diseases, problems such as biological barrier crossing and the efficiency of drug delivery are to be overcome. While effective over oral administration, the microneedle is an alternative device to the hypodermic needle that causes problems with pain at the injection site and local damage to the skin, bleeding and disease infection at the injection site. Microneedles and microstructures have been in the spotlight as a means of drug delivery. The microneedle is a solid microneedle (microspike) that can be used for skin channel generation and electroporation by simple physical skin penetration, and a hollow microneedle for immediate drug delivery after painless skin penetration. microneedle) and biodegradable microneedle capable of sustained-release drug delivery.

In general, solid microneedles can create channels of skin tissue to create drug delivery channels, and the purpose of delivering drugs to cell tissues within the tissues is to increase the efficiency of drug delivery by disturbing dense skin tissues by electroporation. It is done.

Although the solid microneedle of silicon material (US Patent Publication No. 2002/138049 “Microneedle devices and methods of manufacture and use thereof”) of the University of Georgia, USA, has been proposed, the solid microneedle structure can be used for drug delivery only by penetrating the skin. I could not.

Metal solid microneedles for electroporation have been proposed by The Procter & Gamble (US Patent No. 6,565,532 “Microneedle apparatus used for marking skin and for dispensing semi-permanent subcutaneous makeup”). The solid microneedle is intended to improve the efficiency of delivery of drugs and cosmetic ingredients in skin tissue by inducing the expansion of existing skin passages and the formation of new skin passages, and the solid micro needle that can deliver drugs to tissues by electroporation. Needle was proposed by Makoto Mad Systems, Inc. (US Pat. No. 7,127,284, “Electroporation microneedle and methods for its use”). Ultimately, however, electroporation solid microneedles are not devices that perform direct drug delivery, but only means to improve the delivery efficiency of patches and applied drugs. To this end, hollow microneedles and biodegradable microneedles capable of direct drug delivery have been proposed.

Hollow microneedles are intended for the delivery of transdermal drugs into the body by penetrating the skin directly without pain. University of Georgia (US Patent Publication No. 2002/138049, "Microneedle devices and methods of manufacture and use," US Patent Registration No. 7344499, "Microneedle device for extraction and sensing of bodily fluids") and Albert Lab. Publication No. 2002/0193754, “Microneedle for minimally invasive drug delivery”, and NanoPass Corporation (US Patent Publication No. 2005/0029223, “Microneedle sutructure and production method therefer”). Hollow microneedles have been proposed. The hollow microneedles perform direct fast-acting drug delivery, but have limitations that cannot control drug delivery rates and use only liquid drugs. In this way, biodegradable microneedles capable of drug delivery in the west and solidified have been proposed.

In general, drug delivery using biodegradable microneedles is intended for transdermal drug delivery through the skin rather than a bio circulatory system such as blood vessels or lymphatic vessels. Fabrication of biodegradable solid microneedle using the mold method is carried out by Nano Devices & Systems Co., Ltd. of Maltose microneedle (Japanese Patent Laid-Open No. 2005/154321) and Biodegradable polymer microneedles: Fabrication, mechanics and transdermal of biodegradable plastic microneedles. drug delivery, Journal of Controlled Biodegradable microneedles for sustained-release drug delivery have been proposed since publication in Release 104, 51-66, 2005, but ultimately the drug delivery efficiency of transdermal absorption has decreased.

Accordingly, solid microstructures, hollow microstructures, and biodegradable microstructures have different drug delivery methods and efficiency of drug delivery, but have disadvantages and limitations, respectively. This requires a new type of microstructure that can use all types of chemical and biological drugs, and also maximizes drug delivery efficiency, and a hybrid microstructure that integrates each type of microstructures to complement each other's shortcomings. Do. However, because each microstructure is made of a different material, and ultimately the manufacturing methods are different according to the type of microstructure, microstructures in which different types of microstructures are mixed cannot be implemented and manufactured on the same chip.

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 endeavor to develop an aggregate of drug delivery devices having a diameter of micro units, sufficient effective length and hardness, and which can improve water and water soluble drugs, liquid and solid drug delivery, drug delivery rate control and drug delivery efficiency. It was. As a result, integrating solid microstructures, hollow microstructures, and biocompatible / biodegradable microstructures onto a substrate allows simultaneous delivery of immediate and sustained release drugs with painlessness and electroporation in a single trial. By confirming that the efficiency of drug delivery can be improved through the method, the present invention has been completed.

Accordingly, an object of the present invention is a method for producing a hybrid microstructure in which a solid microstructure, a hollow microstructure, and a biocompatible / biodegradable microstructure are integrated into one to simultaneously implement the functions of all microstructures and to improve transdermal administration efficiency of drugs. To provide.

Another object of the present invention is to provide a hybrid microstructure.

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 invention, the invention includes a step of aggregating on one substrate at least two microstructures selected from the group consisting of solid microstructures, hollow microstructures and biocompatible / biodegradable microstructures. It provides a method for producing a microstructure.

According to another aspect of the present invention, the present invention provides one or more microstructures prepared by the method of the present invention described above and selected from the group consisting of solid microstructures, hollow microstructures and biocompatible / biodegradable microstructures. It provides a hybrid microstructure aggregated on a substrate.

According to another aspect of the invention, the invention is a solid microstructure, hollow microstructures and at least two microstructures selected from the group consisting of biocompatible / biodegradable microstructures are aggregated on one substrate, wherein 2 Drug delivery by the above microstructure provides a drug delivery device (drug delivery device) comprising the hybrid microstructure, characterized in that carried out simultaneously or sequentially.

The present inventors endeavor to develop an aggregate of drug delivery devices having a diameter of micro units, sufficient effective length and hardness, and which can improve water and water soluble drugs, liquid and solid drug delivery, drug delivery rate control and drug delivery efficiency. It was. As a result, integrating solid microstructures, hollow microstructures, and biocompatible / biodegradable microstructures onto a substrate allows simultaneous delivery of immediate and sustained release drugs with painlessness and electroporation in a single trial. It was confirmed that the method can improve the efficiency of drug delivery.

According to a preferred embodiment of the present invention, the solid or hollow microstructures used in the present invention are prepared by a process comprising the following steps:

(a) preparing a viscous material as a skeletal material of a micromolded structure for producing a solid microstructure or a hollow microstructure;

(b) fabricating the micromolded structure using the viscous material of (a);

(c) depositing metal on the micromolded structure of (b); And

(d) removing the micromolded structure of (c) to produce a solid microstructure or a hollow microstructure.

The method of the present invention will be described in detail with each step as follows:

Step (a): preparing a viscous material as the scaffold material of the micro-mold structure

First, a micro mold structure for manufacturing a solid microstructure or a hollow microstructure is manufactured. As used herein, the term “micromolded structure” refers to a microstructure made of a viscous material as a mold of a solid microstructure or a hollow microstructure, and solid micro-structured by metal deposition and / or metal plating on the micromolded structure. Construct a structure or hollow microstructure. As used herein, the term “solid microstructure” refers to a structure that performs electroporation with a metal microstructure that is not hollow. As used herein, the term “hollow microstructure” refers to a structure having a hollow hole and allowing rapid drug delivery to a metal hollow microstructure into which a liquid drug can be injected.

The material forming the backbone of the micromolded structure may include a material having a viscosity and a substance added with a viscosity modifying agent to have a viscosity, and the type, concentration, temperature, or addition of a thickener included in the viscosity material. Therefore, the viscosity can be changed in various ways, and can be adjusted to suit the purpose of the present invention. For example, SU-8 (epoxy negative photoresist) can be converted to a liquid state by heat, and can become viscous when cooled down and solidified in that state.

The viscous material constituting the framework of the micromolded structure is not particularly limited and may be polyhydroxyalkanoate (PHAs), poly (α-hydroxyacid), poly (β-hydroxyacid), poly (3 -Hydrobutyrate-co-valorate; PHBV), poly (3-hydroxypropionate; PHP), poly (3-hydroxyhexanoate; PHH), poly (4-hydroxyacid), Poly (4-hydroxybutyrate), poly (4-hydroxy valerate), poly (4-hydroxyhexanoate), poly (esteramide), polycaprolactone, polylactide (PLA), polyglyco Ride (PGA), poly (lactide-co-glycolide; PLGA), polydioxanone, polyorthoesters, polyanhydrides, poly (glycolic acid-co-trimethylene carbonate), polyphosphoesters, poly Phosphoester urethane, poly (amino acid), polycyanoacrylate, Li (trimethylene carbonate), poly (iminocarbonate), poly (tyrosine carbonate), polycarbonate, poly (tyrosine arylate), polyalkylene oxalate, polyphosphazene, PHA-PEG, polyvinylpyrrolidone , Polybutadiene, polyhydroxybutyric acid, polymethyl methacrylate, polymethacrylic acid ester, polypropylene, polystyrene, polyvinyl acetal diethylamino acetate, polyvinyl acetate, polyvinyl alcohol, polyvinylbutyral, polyvinyl foam , Polyester-carbonate, polyalkylene terephthalate, terpolymer elastomer, unsaturated polyester, polyolefin such as saturated polyester, polyethylene, polypropylene, polybutylene, alkyd resin, epoxy polymer, epoxy resin, polyamide, poly Mid, polyamideimide, polyesterimide, polyester Amideimide, polyurethane, polycarbonate, polyphenol, polyvinyl ester, polysilicon, polyacetal, cellulose acetate, polyvinylchloride, polysulfone, polyphenylsulfone, polyethersulfone, polyketone, polyetherketone, polybenzimine Dazoles, polybenzoxazoles, polybenzthiazoles, polyfluorocarbons, polyphenylethers, polyarylates, cyanate ester polymers, coumaronedene polymers, dibutylaminohydroxypropyl ethers, glycerol distearates, and Any copolymer of these polymers, vinyl chloride-propylene-vinylacetate copolymer, vinyl chloride-vinylacetate copolymer, ethylene-vinylacetate copolymer, 2-methyl-5-vinylpyridine methacrylate-methacrylic acid copolymer Copolymers of styrene and acrylonitrile, hyaluronic acid, myristic acid, palmitic acid, Tearic acid, behenic acids, cellulose or derivatives thereof, maltose, dextran, glucomannan, glucosamine, chitosan, heparin, alginate, inulin, starch, glycogen, chitin, chondroitin, dextrin, keratan sulfate ), Bee tallow, whale wax, beeswax, paraffin wax and castor wax.

On the other hand, the thickener that can control the viscosity of the material forming the skeleton of the micro-molded structure, thickeners commonly used in the art, such as hyaluronic acid and salts thereof, polyvinylpyrrolidone, cellulose polymer, dextran , Gelatin, glycerin, polyethylene glycol, polysorbate, propylene glycol, povidone, carbomer, gum ghatti, guar gum, glucomannan, glucosamine, dammer resin, rennet casein , Locust bean gum, microfibrillated cellulose, psyllium seed gum, xanthan gum, arabino galactan, arabic gum, alginic acid, gelatin, gellan gum gum, carrageenan, karaya gum, curdlan, chitosan, chitin, tara gum, tamarind gum, tragacanth gum, perselane ( furceller Viscosity agents, such as an), pectin or pullulan, may be added to the viscous material, which is the main component of the micromolded structure, to adjust the viscosity to suit the present invention.

According to a preferred embodiment of the present invention, the viscous material used in the present invention is dissolved in a suitable solvent to exhibit viscosity.

The solvent used to prepare the viscous material is not particularly limited and includes water, anhydrous or hydrous lower alcohol having 1 to 4 carbon atoms, acetone, ethyl acetate, chloroform, dichloromethane, 1,3-butylene glycol, hexane, Diethyl ether or butyl acetate can be used as the solvent.

Step (b): Fabrication of Micromolded Structure

The viscous material is then prepared on a substrate. The substrate containing the viscous material is not particularly limited and may be made of, for example, a polymer, an organic chemical, a metal, a ceramic, a semiconductor, or the like.

The manufacture of the micromolded structure using a viscous material on a substrate can be carried out using various methods known in the art.

Preferably, the preparation of the micromolded structure is carried out by a drawing method developed by the present inventors, which drawing method is disclosed in PCT / KR2007 / 003507 and PCT / KR2007 / 003506, which patent document is described herein. Inserted by reference.

When the micromolded structure is manufactured by a drawing method, while drawing a viscous material on a substrate, the viscous material is formed away from the substrate and forms a structure of decreasing diameter with coagulation. At this time, the drawing speed is accelerated to apply a tensile strength or more to the mixture, or a specific portion is cut using a laser to produce a micro-molded structure having a long and thin structure. Conditions to be adjusted during drawing and the drawing speed can be carried out according to conventional methods known in the art, for example, can be appropriately adjusted according to the viscosity change, adhesion, drawing speed, etc. through a thickener or temperature control. .

Finally, any portion drawn is cut off and finally a micromolded structure is obtained. Cutting may be carried out in a variety of ways, for example, by a variety of methods known in the art, such as physical cutting such as accelerating the drawing speed or applying a force greater than stress, or cutting with a laser.

Step (c): Deposition of Metals on the Micromolded Structure

After fabricating the micromolded structure, the metal deposition step is performed. Metal deposition may be performed using various methods known in the art, preferably physical metal deposition or chemical metal deposition, and most preferably sputtering, evaporation (physical metal deposition) Metal deposition may be performed using a Tollens' reaction by evaporation or chemical metal deposition.

According to a preferred embodiment of the present invention, the metal plating step may further include a metal plating step. The metal used for the deposition or plating is not particularly limited as long as it is a metal applicable to the living body, preferably cobalt, titanium, stainless steel, chromium, nickel, copper, silver, gold, aluminum or an alloy thereof, more preferably Is cobalt, titanium, stainless steel, chromium, nickel, copper, aluminum or alloys thereof, most preferably titanium, chromium, nickel, copper or alloys thereof.

The solid microstructure and the hollow microstructure are the same in the method of fabricating the micromolded structure, but the difference is that the metal deposition or metal plating is suppressed at the upper end during metal deposition or metal plating. Microneedles can be made, or solid microneedles without top protection.

Top protection can be performed, for example, by coating enamel or SU-8 on the top surface of the microstructure, but is not limited thereto. The hollow microstructure may be manufactured by removing the micro mold structure and the upper protective part after metal deposition or metal plating.

In addition, the hollow microstructure may be manufactured without the upper end protection step. In this case, a hollow microstructure may be manufactured by cutting the upper end of the manufactured solid microstructure with a laser or dicing saw and removing the inner micromolded structure.

Step (d): Preparation of Solid Microstructures or Hollow Microstructures by Removing Micromolded Structures

Finally, the micromoulded structure used as a template of the solid or hollow microstructure is removed to prepare a solid or hollow microstructure. The removal of the micromolded structure may be performed using a suitable solvent, burned or physically removed. For example, SU-8 remover or acetone may be used as a solvent for removing the micromolded structure, but is not limited thereto. The micromolded structure is removed and washed to complete the solid or hollow microstructure.

According to a preferred embodiment of the present invention, the biocompatible / biodegradable microstructures used in the present invention are prepared by a process comprising the following steps:

(a) preparing a biocompatible / biodegradable material as a backbone of the microstructures;

(b) mixing the biocompatible / biodegradable material and drug of (a), wherein the drug is incorporated into the drug carrier of the microparticle, nanoparticle or emulsion formulation; And,

(c) preparing a biocompatible / biodegradable microstructure comprising a drug carrier using the mixture of (b).

The method of the present invention will be described in detail with each step as follows:

Step (a): Preparation of biocompatible / biodegradable material as backbone material of the microstructures

The materials used in the present invention to prepare biocompatible / biodegradable microstructures are biocompatible / biodegradable materials. As used herein, the term “biocompatible material” means a material that is substantially nontoxic to the human body, chemically inert and immunogenic. As used herein, the term "biodegradable material" refers to a material that can be degraded by body fluids or microorganisms in a living body. As used herein, the term “biocompatible / biodegradable microstructure” refers to a microorganism that is made of a biocompatible / biodegradable material, unlike solid microstructures and hollow microstructures, that can be present or degraded in a non-toxic state within the skin. Refers to a structure.

Such biocompatible / biodegradable materials form the backbone of biocompatible / biodegradable microstructures, preferably polyhydroxyalkanoates (PHAs), poly (α-hydroxyacid), poly (β-hydroxy Acid), poly (3-hydrosuccibutyrate-co-valorate; PHBV), poly (3-hydroxyproprionate; PHP), poly (3-hydroxyhexanoate; PHH), poly (4 -Hydroxyacid), poly (4-hydroxybutyrate), poly (4-hydroxyvalorate), poly (4-hydroxyhexanoate), poly (esteramide), polycaprolactone, polylactide (PLA), polyglycolide (PGA), poly (lactide-co-glycolide; PLGA), polydioxanone, polyorthoesters, polyanhydrides, poly (glycolic acid-co-trimethylene carbonate), Polyphosphoester, polyphosphoester urethane, poly (amino acid), poly Lycyanoacrylate, poly (trimethylene carbonate), poly (iminocarbonate), poly (tyrosine carbonate), polycarbonate, poly (tyrosine arylate), polyalkylene oxalate, polyphosphazene, PHA-PEG, Polyvinylpyrrolidone, polybutadiene, polyhydroxybutyric acid, polymethyl methacrylate, polymethacrylic acid ester, polypropylene, polystyrene, polyvinyl acetal diethylamino acetate acetal dietylamino acetate, polyvinyl acetate, polyvinyl alcohol, polyvinyl butyral, polyvinyl formal, vinyl chloride-propylene-vinyl acetate vinylacetate copolymer, vinylchloride-vinylacetate copolymer, cumarone indene polymer neindene polymer, dibutylaminohydroxypropyl ether, ethylene-vinylacetate copolymer, glycerol distearate, 2-methyl-5-vinylpyridine methacrylate-metha 2-methyl-5-vinylpyridine methacrylate-methacrylic acid copolymer, hyaluronic acid, myristic acid, palmitic acid, stearic acid, behenic acids, cellulose or derivatives thereof, maltose, Dextran, glucomannan, glucosamine, chitosan, heparin, alginate, inulin, starch, glycogen, chitin, chondroitin, dextrin, keratan sulfate, bee tallow, whale wax, beeswax, paraffin Wax or castor wax, more preferably polylactide (PLA), polyglycolide (PGA), poly (lactide-co-glycolide); PLGA), cellulose or derivatives thereof, maltose, dextran, glucomannan, glucosamine, chitosan, heparin, alginate, inulin, starch or glycogen, most preferably polylactide (PLA), polyglycolide (PGA), poly (Lactide-co-glycolide; PLGA), cellulose or a derivative thereof, maltose or chitosan. When using a cellulose derivative as a biocompatible / biodegradable material, it is preferably a cellulose polymer, even more preferably hydroxypropyl methylcellulose, hydroxyalkyl cellulose (preferably hydroxyethyl cellulose or hydroxypropyl cellulose), Ethyl hydroxyethyl cellulose, alkyl cellulose and carboxymethyl cellulose, even more preferably hydroxypropyl methyl cellulose or carboxymethyl cellulose, most preferably carboxymethyl cellulose.

The biocompatible / biodegradable materials that make up the backbone of the biocompatible / biodegradable microstructures may themselves be viscous or include other viscosity modifying agents. The viscosity of such biocompatible / biodegradable materials can be varied in various ways depending on the type, concentration, temperature or addition of thickener, etc., and can be adjusted to suit the purposes of the present invention.

For example, thickeners commonly used in the art such as hyaluronic acid and salts thereof, polyvinylpyrrolidone, cellulose polymers, dextran, gelatin, glycerin, polyethyleneglycol, polysorbate, propylene glycol, Povidone, carbomer, gum ghatti, guar gum, glucomannan, glucosamine, dammer resin, rennet casein, locust bean gum, microfibrillated cellulose ), Psyllium seed gum, xanthan gum, arabino galactan, arabian gum, alginic acid, gelatin, gellan gum, carrageenan, karaya gum, curdlan (curdlan), chitosan, chitin, tara gum, tamarind gum, tragacanth gum, furcelleran, pectin or pullulan Same thickener for solid microstructures Viscosity can be adjusted to suit the present invention by addition to a main component such as a biocompatible / biodegradable material.

According to a preferred embodiment of the present invention, the biocompatible / biodegradable material used in the present invention is dissolved in a suitable solvent to exhibit viscosity.

The solvent used to prepare the biocompatible / biodegradable material is not particularly limited and includes water, anhydrous or hydrous lower alcohol having 1 to 4 carbon atoms, acetone, ethyl acetate, chloroform, dichloromethane, 1,3-butylene Glycol, hexane, diethyl ether or butyl acetate can be used as the solvent.

Step (b): mixing biocompatible / biodegradable materials and drugs

Next, as a step of mixing the biocompatible / biodegradable material and the drug, the drug is allowed to be incorporated into the microparticle, nanoparticle and emulsion formulations.

As used herein, the term "microparticle" refers to micro-sized microspheres in which the drug is encapsulated, and "nanoparticle" refers to nano-sized microspheres in which the drug is encapsulated. As used herein, the term “emulsion formulation” is a form in which a drug is emulsified in a biocompatible / biodegradable substance that is a framework of a biocompatible / biodegradable microstructure.

The biocompatible / biodegradable material as a backbone of the biocompatible / biodegradable microstructure and the drug incorporated into the formulation can be mixed in various ways.

Three exemplary preferred embodiments are described below:

According to a first embodiment, the biocompatible / biodegradable material may be mixed in emulsion formulation only. In the case of the emulsion formulation, the method of emulsifying the drug in a biocompatible / biodegradable substance that is a skeleton of the solid microstructure may be prepared using various methods known in the art. More specifically, it can be prepared in oil-in-water or water-in-oil emulsion type, multiple emulsion type and the like. The method of preparing the emulsion may preferably disperse the drug directly in a biocompatible / biodegradable material without an emulsifier to produce an emulsion containing the drug, or may include the drug using a variety of natural or synthetic emulsifiers. In the case of using an emulsifier, more preferably, it may be stabilized using a lecithin, borax, stearic acid, amisol soft, helio gel, beeswax, xanthan gum, emulsion wax or solubilizer as a natural emulsifier. PEG-8 dilaurate, PEG-150 distearate, PEG-8 stearate, PEG-40 distearate, PEG-100 disoem as an emulsifier for oil-in-water emulsions Consists of sorbitan stearate, sorbitan oleate, sorbitan sesquioleate, and sorbitan trioleate, emulsifiers for tearate and water-in-oil emulsions Selecting from the group or combining them to produce an emulsion containing a drug, most preferably an emulsion without an emulsifier. For example, a lipid-soluble drug may be emulsified in a water-in-oil (W / O) type with a homogenizer in a water-soluble biocompatible / biodegradable substance, or a water-soluble drug in a fat-soluble biocompatible / biodegradable substance such as chitosan or biodegradable plastics. The mixture may be prepared by emulsifying with a water-in-oil (O / W) type with a buffer. In addition, the water-in-oil-in-water (W / O / W) solution was prepared by a second emulsion of a water-in-oil (W / O) emulsion solution of a fat-soluble drug and a water-soluble drug in a mixture of a water-soluble biocompatible / biodegradable material and a water-soluble drug using a multi-emulsion method. Oil-in-water (O / W / O) by second emulsion of water-soluble (O / W) emulsion solution of water-soluble and fat-soluble drugs in a mixture of oil-soluble biocompatible / biodegradable and fat-soluble drugs The mixture can be prepared by emulsification to the type. The size of the emulsion of the drug to be produced depends on the homogeneity rate of the emulsion.

According to a second embodiment, only microparticles or nanoparticles may be mixed into the biocompatible / biodegradable material as a drug carrier. The method of mixing the particles with a biocompatible / biodegradable material can be made using a variety of methods known in the art. For example, microparticles or nanoparticles can be mixed with biocompatible / biodegradable materials by multiple emulsion methods, dispersion dry methods or particle precipitation methods.

According to a third embodiment, the biocompatible / biodegradable microstructures comprise both microparticles or nanoparticles and emulsions (including water-in-oil, oil-in-water or multiple emulsions) as drug carriers.

Drugs mixed with the biocompatible / biodegradable material 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.

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

Protein / peptide medicaments for use in the present invention are not particularly limited, and include hormones, hormone analogs, enzymes, inhibitors, signaling proteins or portions thereof, antibodies or portions thereof, short chain antibodies, binding proteins or binding domains thereof, antigens, Adhesion proteins, structural proteins, regulatory proteins, toxin proteins, cytokines, transcriptional regulators, blood coagulation factors and vaccines, and the like. More specifically, the protein / peptide medicament includes insulin, insulin-like growth factor 1 (IGF-1), growth hormone, erythropoietin, granulocyte-colony stimulating factors (G-CSFs), and GM-CSFs (granulocytes). / macrophage-colony stimulating factors, interferon alpha, interferon beta, interferon gamma, interleukin-1 alpha and beta, interleukin-3, interleukin-4, interleukin-6, interleukin-2, epidermal growth factors (EGGFs), calcitonin ), ACTH (adrenocorticotropic hormone), TNF (tumor necrosis factor), Atobisban, buserelin, cetrorelix, deslorelin, desmopressin ( desmopressin, dynorphin A (1-13), elcatonin, eleidosin, eptifibatide, growth hormone releasing hormone-II, Gona Gonadorelin, goserelin, hisstrin, leuprorelin, leiprenin (lypressin), octreotide, oxytocin, phytocin, pitressin, secretin, sincalide, terlipressin, thymopentin, thymosin ( thymosine α1, triptorelin, bivalirudin, carbetocin, cyclosporine, exedine, lanreotide, luteinizing hormone-releasing hormone, Nafarelin, parathyroid hormone, pramlintide, T-20 (enfuvirtide), thymalfasin and ziconotide.

Microparticles or nanoparticles comprising the drug are preferably polyesters, polyhydroxyalkanoates (PHAs), poly (α-hydroxyacid), poly (β-hydroxyacid), poly ( 3-hydrobutyrate-co-valorate; PHBV), poly (3-hydroxyproprionate; PHP), poly (3-hydroxyhexanoate; PHH), poly (4-hydroxyacid) , Poly (4-hydroxybutyrate), poly (4-hydroxy valerate), poly (4-hydroxyhexanoate), poly (esteramide), polycaprolactone, polylactide (PLA), polyglyco Ride (PGA), poly (lactide-co-glycolide; PLGA), polydioxanone, polyorthoester, polyanhydride, poly (glycolic acid-co-trimethylene carbonate), polyphosphoester, poly Phosphoester Urethane, Poly (Amino Acid), Polycyanoacrylic , Poly (trimethylene carbonate), poly (iminocarbonate), poly (tyrosine carbonate), polycarbonate, poly (tyrosine arylate), polyalkylene oxalate, polyphosphazene, PHA-PEG, polyvinylpyrroli Don, polybutadiene, polyhydroxybutyric acid, polymethyl methacrylate, polymethacrylic acid ester, polypropylene, polystyrene, polyvinyl acetal diethylamino acetate, polyvinyl acetate, polyvinyl alcohol, polyvinylbutyral, polyvinyl Foam, vinyl chloride-propylene-vinylacetate copolymer, vinyl chloride-vinylacetate copolymer, coumaronenate polymer, dibutylaminohydroxypropyl ether, ethylene-vinylacetate copolymer, glycerol distearate, 2-methyl- 5-vinylpyridine methacrylate-methacrylic acid copolymer, hyaluronic acid, myristic acid, palmitic acid, ste Leric acid, behenic acid, cellulose or derivatives thereof, maltose, dextran, glucomannan, glucosamine, chitosan, heparin, alginate, inulin, starch, glycogen, chitin, chondroitin, dextrin, keratan sulfate, tallow, whale wax, beeswax, paraffin Waxes or castor waxes, more preferably polylactide (PLA), polyglycolide (PGA), poly (lactide-co-glycolide); PLGA), cellulose or derivatives thereof, maltose, dextran, glucomannan, glucosamine, chitosan, heparin, alginate, inulin, starch or glycogen, most preferably polylactide (PLA), polyglycolide (PGA), poly (Lactide-co-glycolide; PLGA), cellulose or a derivative thereof, maltose or chitosan. When using a cellulose derivative as a biocompatible / biodegradable material, it is preferably a cellulose polymer, even more preferably hydroxypropyl methylcellulose, hydroxyalkyl cellulose (preferably hydroxyethyl cellulose or hydroxypropyl cellulose ), Ethyl hydroxyethyl cellulose, alkyl cellulose and carboxymethyl cellulose, even more preferably hydroxypropyl methyl cellulose or carboxymethyl cellulose, and most preferably carboxymethyl cellulose.

According to a preferred embodiment of the present invention, the biocompatible / biodegradable material as a backbone of the biocompatible / biodegradable microstructures used in the present invention is a material different from the microparticles or nanoparticles.

According to a preferred embodiment of the present invention, the biocompatible / biodegradable material as a backbone of the biocompatible / biodegradable microstructures used in the present invention further comprises a drug. The drug included is not limited, but more preferably the drug included in the biocompatible / biodegradable material is different from the microparticles or nanoparticles, or the drug included in the emulsion, and most preferably the backbone of the microstructure, microparticles. Or nanoparticles, and emulsions each contain a different kind of drug.

One of the biggest features of this biocompatible / biodegradable microstructure is to prepare a microstructure that can control multiple drug release by mounting various drugs on the microstructure. As used herein, the term “drug release control” refers to a drug delivery effect in vivo, whereby various drugs are used, using biocompatible / biodegradable substances and properties different in time and degree to which microparticles or nanoparticles are biodegraded in the body. This means that it can be adjusted differently.

Another feature of the present invention is the incorporation of one drug into the biocompatible / biodegradable microstructure in various ways. In this case, by using the property that the skeleton, microparticles or nanoparticles of the microstructures are decomposed at different rates, a microstructure that is controlled to allow drug release at a desired time can be prepared even with the same drug.

Drugs used in the present invention are not particularly limited, preferably the drug contained in the microparticles or nanoparticles and the drug contained in the emulsion is released at different rates, most preferably the skeleton of the microstructure Drugs contained in the substance and drugs contained in the microparticles, nanoparticles or emulsions are released at different rates.

Step (c): Preparation of biocompatible / biodegradable microstructures containing drug carriers

The drug carrier is mixed with a biocompatible / biodegradable material, with or without a drug, and finally a biocompatible / biodegradable microstructure is prepared. The method of manufacturing the microstructures can be produced using various methods known in the art. For example, mixtures produced by emulsions of drugs in biocompatible / biodegradable materials in water-in-oil (O / W) or water-in-oil (W / O) emulsions, microparticles or nanoparticles comprising drugs in biocompatible / biodegradable materials A mixture produced by mixing a microparticle or nanoparticle containing an oil-in-water (O / W) or water-in-oil (W / O) emulsion with another drug in a biocompatible / biodegradable substance containing a drug and another drug. The resulting mixture and the like are prepared on the surface of the substrate. In this case, a hybrid microstructure may be manufactured using a substrate including a solid microstructure, a hollow microstructure, or a microstructure in which the solid microstructure and the hollow microstructure are mixed.

Substrates containing a mixture of drug carriers and biocompatible / biodegradable materials are not particularly limited and may be made of, for example, materials such as polymers, organic chemicals, metals, ceramics, semiconductors and the like. Subsequently, the support prepared in the desired shape is brought into contact with the surface of the mixture, and then solidified while drawing, thereby forming a structure in which the diameter decreases from the substrate toward the support contact surface. At this time, the drawing speed is accelerated to apply a tensile strength or more to the mixture, or a specific portion is cut using a laser to produce a biocompatible / biodegradable microstructure having a thin and long structure. Conditions to be controlled during drawing and drawing speed may be carried out according to conventional methods known in the art, and include, for example, viscosity or adhesiveness of a solvent including a biocompatible / biodegradable substance, a drug carrier, a thickener or a mixture. Etc., it can adjust suitably.

Finally, any site of the drawn mixture is cut to finally obtain a biocompatible / biodegradable microstructure. Cutting may be carried out in a variety of ways, for example, by a variety of methods known in the art, such as physical cutting such as accelerating the drawing speed or applying a force greater than stress, or cutting with a laser.

The present invention can provide a variety of hybrid microstructures, for example, hybrid microstructures in which solid microstructures and hollow microstructures are concentrated, hybrid microstructures in which solid microstructures and biodegradable microstructures are integrated, hollow microstructures. Hybrid microstructures in which the structure and the biodegradable microstructures are integrated, or hybrid microstructures in which all of the solid microstructures, the hollow microstructures, and the biodegradable microstructures can all be provided.

According to the present invention, drug delivery is possible in different and desired ways by solid microstructures, hollow microstructures and biocompatible / biodegradable microstructures in one drug carrier. For example, if a drug is desired to be released slowly over a long period of time, the drug should be placed in a biocompatible / biodegradable microstructure and the drug that should exhibit efficacy in a short period of time is mounted in a hollow microstructure. In addition, in order to improve tissue permeability (eg, skin tissue permeability) of these drugs, a solid microstructure for electroporation is additionally applied. As a result, in one drug carrier, electroporation by solid microstructures, rapid drug delivery by hollow microstructures, and sustained release drug delivery by biocompatible / biodegradable microstructures are all possible. The most ideal device of drug delivery via can be provided.

As used herein, the term “aggregation” refers to a state in which two or more kinds of microstructures are gathered on one substrate. In the case of the present invention, the three microstructures can be fabricated and aggregated on a single substrate in various ways. Preferably, the solid microstructures and / or hollow microstructures are fabricated on the substrates, and then the substrates are used. Biocompatible / biodegradable microstructures can be prepared and aggregated.

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 microneedle, microspike, microblade, microknife, microfiber, microprobe or microvalve, most preferably microneedle.

It is important that each of the solid microstructures, hollow microstructures, and biodegradable microstructures in the hybrid microstructures have a sufficiently thin and long structure to minimize pain during penetration and foreign body sensation after insertion. Hybrid microstructures produced in accordance with the present invention can be produced without limitation to the desired shape diameter and length. According to a preferred embodiment of the invention, the hybrid microstructures of the invention have a top diameter of 1-100 μm, more preferably 2-50 μm and most preferably 5-20 μm.

The effective length of the hybrid microstructure is not particularly limited and may be manufactured in various lengths depending on the type of drug to be delivered, the drug delivery site, and the location for performing the electroporation method. The effective length of the hybrid microstructures of the present invention is preferably 100-10,000 μm, more preferably 200-10,000 μm, even more preferably 300-8,000 μm, most preferably 500-2,000 μm, all types being Also available as patch type and roller type. According to a preferred embodiment of the present invention, solid microstructures of hybrid microstructures are made longer than hollow microstructures and biodegradable microstructures for electroporation applications.

As used herein, the term "top" of a microstructure refers to one end of the microstructure having the smallest diameter. As used herein, the term “effective length” means the vertical length from the top of the microstructure to the support surface.

Electroporation method using a solid microstructure in the present invention can be carried out by a variety of methods known in the art, preferably using an electrical pulse effective voltage 100-1,500 V, the effective voltage acting intradermal 30-100 V, pulse interval 1-100 ms can be performed.

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

(Iii) The present invention is a hybrid microstructure in which a solid microstructure, a hollow microstructure, or a biocompatible / biodegradable microstructure is integrated on one substrate, and a method for producing the same, and this strategy has not been conventionally adopted.

(Ii) According to the present invention, solid microstructures of electroporation, hollow microstructures of immediate release liquid drug delivery and biocompatible / biodegradable microstructures of sustained release drug delivery can be integrated on one substrate in a convenient manner. Can be.

(Iii) According to the present invention, drug delivery is possible in different and desired ways by solid microstructures, hollow microstructures and biocompatible / biodegradable microstructures in one drug carrier. For example, if a drug is desired to be released slowly over a long period of time, the drug should be placed in a biocompatible / biodegradable microstructure and the drug that should exhibit efficacy in a short period of time is mounted in a hollow microstructure. In addition, in order to improve tissue permeability (eg, skin tissue permeability) of these drugs, a solid microstructure for electroporation is additionally applied. As a result, in one drug carrier, electroporation by solid microstructures, rapid drug delivery by hollow microstructures, and sustained release drug delivery by biocompatible / biodegradable microstructures are all possible. The most ideal device of drug delivery via can be provided.

(Iii) According to the present invention, drug delivery and electroporation can be improved by a painless immediate and / or sustained-release drug delivery and electroporation method in a single trial while having a diameter, sufficient effective length and hardness of micro units. .

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, 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  One: Micro mold  Structure creation

Micromolded structures were fabricated using SU-8 2050 photoresist (purchased from Microchem) with a viscosity of 14,000 cSt. After coating SU-8 2050 to a certain thickness on a metal substrate, it was maintained at 120 ° C for 5 minutes to maintain SU-8 fluidity, and then contacted with a 4 x 4 patterned frame having a diameter of 200 ㎛ in advance. The contact between the frame and SU-8 2050 was increased while curing the coated SU-8 2050 while slowly lowering the temperature of the substrate from 95 ° C. to 90 ° C. for about 5 minutes. The coated SU-8 2050 was drawn at a rate of 10 μm / s for 6 minutes using a frame in contact with the SU-8 2050 while slowly lowering the temperature from 65 ° C. to 60 ° C. again. Drawing was carried out for 6 minutes, and the 3,600 micrometer micro mold structure was produced. The formed micromolded structure may be accelerated to 700 μm / s or cut off from the frame. As a result, a micromolded structure having an inner diameter of 5 μm, an effective length of 1,500 μm, and a length of 2,000 μm was produced.

Example  2: Solid  Fabrication of Microstructures

Sputtering was used to deposit three layers of Ti-Cu-Ti (100 nm-300 nm-100 nm) onto the SU-8 micromolded structure fabricated in Example 1 above, or toxin reaction as a chemical metal deposition. (Tollens' reaction) The deposited micromolded structure is nickel electroplated (0.206 μm / min per 1 A / dm ² ) to produce a metal type solid microstructure which is electroporated.

Example  3: fabrication of hollow microstructures and Solid  Of microstructures and hollow microstructures Hybridization

Sputtering was used to deposit three layers of Ti-Cu-Ti (100 nm-300 nm-100 nm) onto the SU-8 micromolded structure fabricated in Example 1 above, or toxin reaction as a chemical metal deposition. (Tollens' reaction) The top of the optional micromolded structure for fabrication of the hollow microstructure was then protected with enamel or SU-8 2050. The deposited micromolded structure was nickel plated (1 A / dm ² 0.206 μm / min), and the plated structure is bathed in water at 60 ° C. and placed in an SU-8 remover (purchased from Microchem) for 1 hour to remove enamel of the first SU-8 2050 micromold and the upper part of the mold. At the same time, the hollow microstructure is completed. The fabricated hollow metal microstructure was found to have an outer diameter (OD) of 60 μm, an inner diameter (ID) of 20 μm, and an effective length of 1,500 μm and a length of 2,000 μm. In addition to the manufactured hollow microstructures, solid microstructures are hybridized to one array, and the liquid drug delivery to the body through the hollow microstructures is performed, followed by electroporation through the solid microstructures.

Example  4: Fabrication of biodegradable microstructures and biodegradable microstructures and hollow microstructures or biodegradable microstructures Solid  Microstructure Hybridization

Biodegradable microstructures are fabricated on solid microstructures or hollow microstructures known in Examples 2 and 3 or hybrid microstructures in which solid and hollow microstructures are integrated. Biodegradable microstructures were prepared using a cellulose derivative, Carboxymethyl cellulose (CMC: purchased from Sigma), on a chip on which other microstructures were made. CMC was used as water solvent to make 4% CMC solution, and the glass plate was coated with CMC solution to a certain thickness, and then contacted with a 3 × 3 patterned frame having a diameter of 200 μm in advance. For 10 seconds after contact, the coated CMC surface was dried to increase the contact between the frame and the CMC. The coated CMC was drawn for 60 seconds at a rate of 30 μm / s using a frame in contact with the CMC to produce a 1,800 μm biodegradable microstructure. Subsequently, it can be condensed with a strong dry for 5 minutes while solidifying or solidifying by removing the moisture as much as possible with a pump. The formed biodegradable microstructures can be speeded up, cut or separated from the frame. As a result, a biodegradable cellulose microstructure having a top diameter of 5 m and an effective length of 1,800 m was produced.

Biodegradable microstructures were prepared using maltose (Maltose monohydrate: purchased from Sigma) which is a natural sugar as another biodegradable material. The maltose was melted at 140 ° C. to form maltose candy, the maltose candy was coated on a glass plate to a certain thickness, and then contacted with a 3 × 3 patterned frame having a diameter of 200 μm in advance. The contact between the coated maltose candy and the frame was increased for 10 seconds after contact. The coated maltose candy was drawn for 6 seconds at a rate of 250 μm / s using a frame in contact with the maltose candy to produce a solid microstructure of 1,500 μm. Solid microstructures cured at room temperature may subsequently be separated from the frame by speeding up or cutting. As a result, a biodegradable maltose microstructure having a diameter of 5 μm of an upper end and an effective length of 1,500 μm was produced.

The fabricated biodegradable microstructures are hybrid structures concentrated in the same array as other microstructures (solid, hollow, solid and hollow), and electroporation using solid microstructures after sustained-release drug delivery of biodegradable microstructures, or Rapid drug delivery using hollow microstructures, or simultaneous treatment of solid and hollow microstructures, can serve as hybrid microstructures.

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the same is by way of illustration and example only and is not to be construed as limiting the scope of the present invention. Thus, the substantial scope of the present invention will be defined by the appended claims and equivalents thereof.

1 is a view showing a hybrid microstructure in which a hollow microstructure and a solid microstructure are integrated according to an embodiment of the present invention.

FIG. 2 is a diagram illustrating the immediate drug delivery of the hollow microstructure and the electroporation method of the solid microstructure according to an embodiment of the present invention.

3 illustrates a hybrid microstructure in which a biocompatible / biodegradable microstructure and a solid microstructure are integrated according to an embodiment of the present invention.

FIG. 4 is a diagram illustrating sustained-release drug delivery of a biocompatible / biodegradable microstructure and electroporation of a solid microstructure according to an embodiment of the present invention.

FIG. 5 illustrates a hybrid microstructure in which a hollow microstructure and a biocompatible / biodegradable microstructure are integrated according to an embodiment of the present invention.

FIG. 6 is a view showing immediate release drug delivery of a hollow microstructure and sustained release drug delivery of a biocompatible / biodegradable microstructure according to an embodiment of the present invention.

FIG. 7 illustrates a hybrid microstructure in which a solid microstructure, a hollow microstructure, and a biocompatible / biodegradable microstructure are integrated according to an embodiment of the present invention.

FIG. 8 is a diagram showing the application of electroporation of solid microstructures, immediate drug delivery of hollow microstructures, and sustained release drug delivery of biocompatible / biodegradable microstructures to the skin.

Claims (16)

At least one of the solid and hollow microstructures and the biocompatible / biodegradable microstructures are aggregated on one substrate, The biocompatible / biodegradable microstructure, (a) preparing a biocompatible / biodegradable material as a skeletal material of the microstructure, (b) mixing the drug with the biocompatible / biodegradable material of (a), wherein the drug is incorporated into the drug carrier of the microparticle, nanoparticle or emulsion formulation, (c) applying the mixture of (b) to the substrate, contacting the support to the applied mixture and then solidifying the mixture while drawing and then cutting the solidified mixture. Multifunctional hybrid microstructure. delete delete delete delete The method of claim 1, Biocompatible / biodegradable materials as skeletal materials of the microstructures include polyesters, polyhydroxyalkanoates (PHAs), poly (α-hydroxyacid), poly (β-hydroxyacid), poly (3 -Hydrobutyrate-co-valorate; PHBV), poly (3-hydroxypropionate; PHP), poly (3-hydroxyhexanoate; PHH), poly (4-hydroxyacid), Poly (4-hydroxybutyrate), poly (4-hydroxy valerate), poly (4-hydroxyhexanoate), poly (esteramide), polycaprolactone, polylactide (PLA), polyglycolide (PGA), poly (lactide-co-glycolide; PLGA), polydioxanone, polyorthoesters, polyanhydrides, poly (glycolic acid-co-trimethylene carbonate), polyphosphoesters, polyphos Polyester urethane, poly (amino acid), polycyanoacrylate, Li (trimethylene carbonate), poly (iminocarbonate), poly (tyrosine carbonate), polycarbonate, poly (tyrosine arylate), polyalkylene oxalate, polyphosphazene, PHA-PEG, polyvinylpyrrolidone , Polybutadiene, polyhydroxybutyric acid, polymethyl methacrylate, polymethacrylic acid ester, polypropylene, polystyrene, polyvinyl acetal dietylamino acetate, poly Polyvinyl acetate, polyvinyl alcohol, polyvinyl butyral, polyvinyl formal, vinyl chloride-propylene-vinylacetate copolymer, chloride Vinylchloride-vinylacetate copolymer, cumaroneindene polymer, dibutylamino Dibutylaminohydroxypropyl ether, ethylene-vinylacetate copolymer, glycerol distearate, 2-methyl-5-vinylpyridine methacrylate-methacrylic acid (2-methyl- 5-vinylpyridine methacrylate-methacrylic acid copolymer, hyaluronic acid, myristic acid, palmitic acid, stearic acid, behenic acids, cellulose or derivatives thereof, maltose, dextran, glucomannan, glucosamine, Chitosan, heparin, alginate, inulin, starch, glycogen, chitin, chondroitin, dextrin, keratan sulfate, bee tallow, whale wax, beeswax, paraffin wax and castor wax Multifunctional hybrid microstructure, characterized in that it is selected from the group consisting of. The method of claim 1, Microparticles or nanoparticles comprising the drug are polyester, polyhydroxyalkanoate (PHAs), poly (α-hydroxyacid), poly (β-hydroxyacid), poly (3-hydro Butyrate-co-valorate; PHBV), poly (3-hydroxypropionate; PHP), poly (3-hydroxyhexanoate; PHH), poly (4-hydroxyacid), poly (4 Hydroxybutyrate), poly (4-hydroxyvalorate), poly (4-hydroxyhexanoate), poly (esteramide), polycaprolactone, polylactide (PLA), polyglycolide (PGA) , Poly (lactide-co-glycolide; PLGA), polydioxanone, polyorthoester, polyanhydride, poly (glycolic acid-co-trimethylene carbonate), polyphosphoester, polyphosphoester urethane , Poly (amino acid), polycyanoacrylate, poly (trime Carbonate), poly (iminocarbonate), poly (tyrosine carbonate), polycarbonate, poly (tyrosine arylate), polyalkylene oxalate, polyphosphazenes, PHA-PEG, polyvinylpyrrolidone, polybutadiene , Polyhydroxybutyric acid, polymethyl methacrylate, polymethacrylic acid ester, polypropylene, polystyrene, polyvinyl acetal diethylamino acetate, polyvinyl acetate, polyvinyl alcohol, polyvinyl butyral, polyvinyl foam, vinyl chloride -Propylene-vinylacetate copolymer, vinyl chloride-vinylacetate copolymer, coumaronenate polymer, dibutylaminohydroxypropyl ether, ethylene-vinylacetate copolymer, glycerol distearate, 2-methyl-5-vinylpyridine Methacrylate-methacrylic acid copolymer, hyaluronic acid, myristic acid, palmitic acid, stearic acid, behene , Cellulose or derivatives thereof, maltose, dextran, glucomannan, glucosamine, chitosan, heparin, alginate, inulin, starch, glycogen, chitin, chondroitin, dextrin, keratan sulfate, tallow, whale wax, beeswax, paraffin wax and caster wax Multifunctional hybrid microstructure, characterized in that selected from the group consisting of. The method of claim 1, The biocompatible / biodegradable material as the skeletal material of the microstructure is a material different from the microparticles or nanoparticles. The multifunctional hybrid microstructure of claim 1, wherein the biocompatible / biodegradable material of the microstructure as a backbone material further comprises a drug. The method of claim 1, The biocompatible / biodegradable microstructure is a multifunctional hybrid microstructure, characterized in that it comprises both microparticles or nanoparticles and emulsions as drug carriers. The method of claim 10, Multi-functional hybrid microstructure, characterized in that the drug contained in the microparticles or nanoparticles and the drug contained in the emulsion is released at different rates. delete delete delete delete delete

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