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WO2017010813A1 - Microstructure using fluidization of solid, and manufacturing method therefor - Google Patents

Microstructure using fluidization of solid, and manufacturing method therefor Download PDF

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Publication number
WO2017010813A1
WO2017010813A1 PCT/KR2016/007634 KR2016007634W WO2017010813A1 WO 2017010813 A1 WO2017010813 A1 WO 2017010813A1 KR 2016007634 W KR2016007634 W KR 2016007634W WO 2017010813 A1 WO2017010813 A1 WO 2017010813A1
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WO
WIPO (PCT)
Prior art keywords
microstructure
solid
drug
solvent
fluidization
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PCT/KR2016/007634
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French (fr)
Korean (ko)
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WO2017010813A9 (en
Inventor
정형일
양휘석
Original Assignee
주식회사 주빅
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Priority claimed from KR1020160088235A external-priority patent/KR101808066B1/en
Application filed by 주식회사 주빅 filed Critical 주식회사 주빅
Priority to US15/744,768 priority Critical patent/US11382841B2/en
Publication of WO2017010813A1 publication Critical patent/WO2017010813A1/en
Publication of WO2017010813A9 publication Critical patent/WO2017010813A9/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B81—MICROSTRUCTURAL TECHNOLOGY
    • B81B—MICROSTRUCTURAL DEVICES OR SYSTEMS, e.g. MICROMECHANICAL DEVICES
    • B81B1/00—Devices without movable or flexible elements, e.g. microcapillary devices
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B81—MICROSTRUCTURAL TECHNOLOGY
    • B81C—PROCESSES OR APPARATUS SPECIALLY ADAPTED FOR THE MANUFACTURE OR TREATMENT OF MICROSTRUCTURAL DEVICES OR SYSTEMS
    • B81C1/00—Manufacture or treatment of devices or systems in or on a substrate

Definitions

  • the present invention relates to a microstructure using the fluidization of solids and a method for producing the same.
  • Injection is delivered to the body by inserting a needle to deliver the drug, the drug appears quickly and the drug is immediately delivered to the body tissues, such as blood or muscle is used in various fields as an effective drug delivery method. Injections, however, cause strong irritation and damage to the skin, which is accompanied by pain. In addition, there is a problem that the additional infection occurs due to the wound, which can be performed only by a specialist.
  • Microneedle is a drug delivery system designed to solve these problems is a system for delivering drugs to the body with minimal invasion using a fine needle.
  • the biodegradable microneedle refers to a microneedle skeleton composed of a biodegradable material.
  • the biodegradable material formed into microneedles penetrates the stratum corneum and is dissolved by body fluid and body temperature in the skin.
  • the biodegradable microneedles formed by mixing the biodegradable substance and the drug and formed into microneedles have a principle that the mounted drugs are melted together and delivered to the body.
  • Biodegradable microneedles are currently manufactured by molding viscous compositions into microneedles.
  • the viscosity composition is easily changed by the surrounding environment such as humidity and temperature, it is difficult to produce a microneedle of a certain form in mass production.
  • the degree of drying by the surrounding environment varies depending on the discharge sequence, so the viscosity of each droplet Since it is different, it was difficult to manufacture a uniform biodegradable microneedle in large quantities. This complicates the process for precise control and has a problem of lowering the productivity, uniformity and quality of the microneedle.
  • the drug loading in the biodegradable microneedle uses a method of preparing a viscous composition mixed with a biodegradable substance and a drug first and then using the microneedle.
  • the drug may be denatured or destroyed by the biodegradable substance or solvent in the process of mixing the biodegradable substance and the drug or in the state of the biodegradable substance-drug mixture solution. It is therefore essential to minimize the interaction of drugs with solvents or biodegradable materials.
  • the mixed solution can be formed only by adding a separate surfactant. This limits the types of drugs that can be loaded into biodegradable materials.
  • the mixed solution of the drug and the biodegradable material has a problem that it is difficult to accurately quantify the drug in the form having a high viscosity. This is because the heterogeneity of the biodegradable material causes the drug in the mixed solution to be heterogeneous together.
  • the above problems can be seen as a problem that occurs because the formulation and molding in the form of a microneedle only a mixed solution of a biodegradable material and drug.
  • the present invention comprises the steps of (a) preparing a solid on a substrate; (b) fluidizing by adding a solvent onto the solid; And (c) to provide a method for producing a microstructure comprising the step of forming the fluidized solid.
  • the present invention comprises the steps of (a) preparing a solid on a substrate; (b) fluidizing by adding a solvent onto the solid; And (c) provides a method for producing a microstructure comprising the step of forming the fluidized solid.
  • Solid in the (a) may be 70% or more solid content.
  • a separate drug or a separate additive may be added in advance.
  • the addition of the solvent in step (b) may be performed by one or more methods selected from the group consisting of contacting, discharging, spraying, depositing and immersion.
  • the degree of fluidization of the solid may be adjusted according to the type of solvent, the affinity of the solvent and the solid, the amount of the solvent or the fluidization conditions.
  • the solvent may be added in an amount of 10 parts by volume to 200 parts by weight based on 100 parts by weight of the solid in step (b).
  • the degree of fluidization of the solid upper layer compared to the degree of fluidization of the solid lower layer It can be characterized by a large one.
  • step (b) it may be further loaded with the drug in the solvent.
  • step (b) after re-solidifying the fluidized solid, it may further comprise the step of refluidizing by adding a second solvent on the solid.
  • Molding in step (c) may be performed by one or more methods selected from the group consisting of molding, drawing, blowing, suction, centrifugal force application and magnetic field application.
  • Molding in the step (c) may be performed so that curing occurs at the same time.
  • Aspect ratio of the microstructure formed in step (c) can be adjusted according to the degree of fluidization.
  • the loading distribution of the drug in the microstructure formed in step (c) may be adjusted according to the degree of fluidization.
  • the distribution of the drug in the microstructure formed in step (c) may be adjusted according to the degree of refluidization.
  • a microstructure manufactured according to the above method is provided.
  • the drug loading distribution in the microstructure provides a microstructure that forms a gradual concentration gradient.
  • the drug loading distribution in the microstructure upper layer is the drug loading distribution in the microstructure lower layer. It may be characterized by a large relative to the degree.
  • the degree of drug loading in the microstructure intermediate layer It can be characterized in that the large compared to the degree of drug loading in the microstructure upper layer and the microstructure lower layer.
  • Microstructure manufacturing method using the fluidization of the solid according to the present invention can solve the difficulty of adjusting the viscosity of the conventional viscous composition, while ensuring the productivity, uniformity and quality of the microstructure, can facilitate mass production, Various aspects of the aspect ratio of the microstructure can be adjusted.
  • the drug is a microstructure upper layer Or it may be concentrated in the microstructure interlayer, there is an advantage that can effectively penetrate the drug deep into the skin.
  • FIG. 1 is a flow chart showing a method of manufacturing a microstructure using the fluidization of a solid according to an embodiment of the present invention.
  • FIG. 2 is a diagram illustrating a method of manufacturing a microstructure using the fluidization of a solid according to an embodiment of the present invention.
  • FIG. 3 is a drawing illustrating the manufacture of solids on a substrate having various surface shapes.
  • 5 is a diagram illustrating solids of various shapes.
  • FIG. 6 is a diagram illustrating the addition and fluidization of solvents on various solids by various methods.
  • FIG. 7 is a diagram illustrating the addition and fluidization of a solvent using a separate substrate on a solid.
  • FIG. 8 shows the degree of fluidization controlled by (a) affinity of the solvent and solids, (b) amount of solvent, and (c) fluidization time.
  • FIG. 9 is a diagram illustrating the addition and fluidization of solvents loaded with drugs in various ways on solids.
  • Figure 10 is a diagram showing the distribution of drug in the solid according to (a) the solubility of the solvent and the solid loaded with the drug and (b) the degree of fluidization controlled by the fluidization time.
  • FIG. 11 is a diagram showing the degree of refluidization and the distribution of drug in the stock form adjusted according to the refluidization time.
  • FIG. 12 is a diagram showing the degree of refluidization and the distribution of drug in the stock that is controlled by the difference in solubility between the drug loaded solvent, the solid and the second solvent.
  • FIG. 13 is a diagram showing the payload distribution of drugs in the microstructure controlled by the aspect ratio of (a) the degree of fluidization and (b) the degree of refluidization.
  • Example 14 is an optical micrograph showing the (a) solids and (b) microstructures in Example 1, respectively.
  • FIG. 15 is an optical micrograph showing the microstructures according to the amount of solvent in Example 2 ((a) 10 ⁇ l, (b) 15 ⁇ l and (c) 20 ⁇ l, respectively).
  • Figure 16 is an optical micrograph showing (a) the microstructures in Example 3 and (b) the microstructures in Example 4, respectively.
  • the present inventors have completed the present invention by confirming that the microstructures can be successfully produced by adding a solvent on a solid, fluidizing the upper part, and molding without using a viscous composition directly on a substrate as in the prior art. .
  • any configuration is formed on (or under) the substrate, not only means that any configuration is formed in contact with (or below) the substrate, but also formed on (or below) the substrate and the substrate. It does not limit to not including another structure between arbitrary structures.
  • the present invention comprises the steps of (a) preparing a solid on a substrate; (b) fluidizing by adding a solvent onto the solid; And (c) provides a method for producing a microstructure comprising the step of forming the fluidized solid.
  • 1 and 2 are a flow chart and a figure showing a method for producing a microstructure using the fluidization of a solid according to an embodiment of the present invention, respectively.
  • the method for producing a microstructure according to an embodiment of the present invention is to prepare a solid on a substrate [(a)], and then by adding a solvent on the solid to fluidize [ step (b)], by shaping the fluidized solid [step (c)].
  • the method for producing a microstructure according to the present invention includes the step of preparing a solid on a substrate (step (a)).
  • the substrate is used to finally manufacture the microstructure, and is used for supporting the manufactured solid.
  • FIG. 3 is a drawing illustrating the manufacture of solids on a substrate having various surface shapes.
  • the substrate may have various surface shapes.
  • the substrate is for forming one microstructure, and may support one solid directly on the substrate without forming pillars, and a cylinder, truncated cone, and cone for supporting one solid on the substrate. It is also possible to control the degree of skin delivery of the microstructure, preferably the microneedle by forming one pillar having various shapes such as hemispherical shape (see FIG. 3 (a)).
  • the substrate is for forming a plurality of microstructures or integral microstructures, and may support a plurality of solids or a single solid directly on the substrate without forming a pillar, a plurality of solids or It is also possible to adjust the degree of skin delivery of the microneedle by forming a certain pattern of bends or irregularities for supporting the solids (see Fig. 3 (b)).
  • the surface shape of such a substrate can be variously selected depending on the purpose of use and the application form of the microstructure.
  • the solid material is a concept that is distinguished from the conventional viscous composition.
  • the solid content is preferably 70% or more, more preferably 90% or more, but is not limited thereto.
  • the solids can be used to solve the problems caused by the difficulty of controlling the viscosity of the conventional viscous composition by maintaining the solid content in the above range, while ensuring the productivity, uniformity and quality of the microstructure, can facilitate mass production There is an advantage to that.
  • the production of the solid is a solid precursor, which naturally dries the viscous droplets discharged on the substrate, or adjusts pressure, temperature, blowing, magnetic field, electricity, etc. to the viscous droplets discharged on the substrate.
  • Solids may be prepared by heat or freeze drying, molding, drawing, blowing, centrifugal force, suction, magnetic field, injection, and electrospinning.
  • the preparation of the solid may be prepared by applying a solid powder on the substrate or by moving the solid already formed on another substrate onto the substrate. In this case, it is preferable that the substrate has a higher affinity with the solids than the other substrates.
  • the solid material may be a polymer material and may include a biocompatible or biodegradable material.
  • the biocompatible material in the present specification means a material that is substantially nontoxic to the human body, chemically inert and immunogenic, and the biodegradable material in the present specification means a material that can be decomposed by body fluids or microorganisms in a living body. .
  • biocompatible or biodegradable materials include hyaluronic acid, polyesters, polyhydroxyalkanoates (PHAs), poly ( ⁇ -hydroxyacid), poly ( ⁇ -hydroxyacid), poly (3 -Hydrobutyrate-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, polyglycolide, poly ( Lactide-co-glycolide; PLGA), polydioxanone, polyorthoester, polyetherester, polyanhydride, poly (glycolic acid-co-trimethylene carbonate), polyphosphoester, polyphosphoester Urethane, Poly (Amino Acid), Polycyanoacrylate , Poly (trimethylene carbonate), poly (iminocarbonate), poly (PH
  • the solid may be previously added with a separate drug or separate additive.
  • the separate drug added in advance as described above is characterized in that it is distributed in the solid as a whole, there is a limit in drug loading due to the interaction between the separate drug or separate additives and the polymer or solvent in the solid precursor.
  • the separate drugs include chemical drugs, protein drugs, peptide drugs, nucleic acid molecules for gene therapy, and nanoparticles.
  • Separate drugs that can be used in the present invention are, 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, hormone, coronary, cerebrovascular or peripheral vasodilator, contraceptive, antithrombotic, diuretic, Antihypertensives, cardiovascular disease agents, cosmetic ingredients (eg, anti-wrinkle agents, skin aging inhibitors and skin lightening agents) and the like, but are not limited thereto.
  • ascorbic acid 2-glucoside (AA2G) corresponding to a cosmetic ingredient, specifically, a whitening ingredient, was used as a separate drug.
  • the separate drug used in the present invention is a protein drug, a peptide drug, a nucleic acid molecule for gene therapy, a vitamin (preferably, Even if the drug is weak to heat, such as vitamin C), according to the present invention, it is possible to prepare a microstructure including the separate drug.
  • the protein / peptide medicament may be a hormone, a hormone analog, an enzyme, an inhibitor, a signaling protein or part thereof, an antibody or part thereof, a short chain antibody, a binding protein or a binding domain thereof, an antigen, an adhesion protein, a structural protein, a regulatory protein, a toxin Proteins, cytokines, transcriptional regulators, blood clotting factors, vaccines, and the like.
  • the protein / peptide medicament is insulin, insulin-like growth factor 1 (IGF-1), growth hormone, erythropoietin, granulocytecolony stimulating factors (G-CSFs), GM-CSFs (granulocyte / 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, Dynorphin A (1-13), elcatonin, eleidosin, eptifibatide, growth hormone releasing hormone-II (GHRH-II), gonadorerin ( gonadorelin, gose
  • the separate additive mainly refers to a variety of substances to increase the effect or stability of the separate drug, a known immune inducing agent to increase the efficacy of the drug or sugars such as trehalose (trehalose) to increase the stability of the drug And the like can be used.
  • trehalose trehalose
  • energy can also be used.
  • the microstructure may be used for transmitting or transmitting energy forms such as thermal energy, light energy, and electrical energy.
  • microstructures can be used to direct light to specific areas within the body, such that light can act directly on tissues or light can act on mediators such as light-sensitive molecules. Can be used to derive.
  • the separate drug or separate additive is preferably 0.1 parts by weight to 10 parts by weight with respect to 100 parts by weight of the biocompatible or biodegradable material, but is not limited thereto.
  • the solids can be produced sequentially through natural drying, molding, spraying and electrospinning of viscous droplets on the substrate, as shown in FIG. 4 (b). As such, it can be made sequentially through application of solid powder on the substrate and transfer from solids already formed on another substrate.
  • the solid may not be added to a separate drug or additive in advance, a separate drug may be added to the solid in advance by adding a separate drug to the solid precursor, the solid A separate additive may be added to the solid in advance by adding a separate additive to the precursor in advance.
  • 5 is a diagram illustrating solids of various shapes.
  • the solids may be manufactured by various methods mentioned above, and may have various shapes, and finally, the microstructures having various shapes may be manufactured from solids having various shapes, and thus, drug loading. There is an advantage to control the distribution, degree of drug delivery, and the like.
  • the method for producing a microstructure according to the present invention includes the step of fluidizing by adding a solvent on the solid.
  • solvent used for the fluidization various known solvents can be used. Specifically, a polar solvent such as water, a lower alcohol having 1 to 4 carbon atoms, or the like may be used as the solvent, or a nonpolar solvent such as hexane, acetone, chloroform, dichloromethane, ethyl acetate, or the like may be used.
  • a polar solvent such as water, a lower alcohol having 1 to 4 carbon atoms, or the like
  • nonpolar solvent such as hexane, acetone, chloroform, dichloromethane, ethyl acetate, or the like may be used.
  • the addition of the solvent may be carried out by a method known in the art, and is preferably performed by one or more methods selected from the group consisting of contacting, discharging, spraying, depositing and immersion, but are not limited thereto.
  • a contact method if a plurality of solids are produced on the substrate, a plurality of solids can be fluidized by using a separate substrate in which the solvent is applied in whole or in part have.
  • an integral solid is produced on the substrate, it is possible to partially fluidize the integral solid by using a separate substrate partially coated with a solvent or by using a separate substrate having a plurality of pillars coated with a solvent. Can be.
  • FIG. 6 is a diagram illustrating the addition and fluidization of solvents on various solids by various methods.
  • the addition of the solvent may be performed through a method of discharge-contacting, ejection by a jet nozzle, spraying by a jet nozzle, and deposition.
  • FIG. 7 is a diagram illustrating the addition and fluidization of a solvent using a separate substrate on a solid.
  • the addition of the solvent may be performed using a separate substrate having a solvent applied thereon and a separate substrate having a plurality of pillars having a solvent applied thereon.
  • the degree of fluidization of the solid may be controlled according to the type of solvent, the affinity of the solvent and the solid, the amount of the solvent or the fluidization conditions.
  • the degree of fluidization in the present specification means the solvent content in the solids, and the degree of fluidization is increased as the solids content in the solids decreases and the solvent content increases.
  • the solvent may penetrate relatively deeply into the solid even if the other conditions are kept the same, while the degree of fluidization increases, whereas when the affinity between the solvent and the solid is low, the other conditions are the same. Even so, the solvent may penetrate relatively shallowly into the solids and the degree of fluidization may be reduced.
  • the fluid when a polar solvent is used as the solvent, the fluid easily penetrates into the solid containing the hydrophilic polymer to increase the degree of fluidization, but the fluid does not easily penetrate into the solid including the hydrophobic polymer, thereby decreasing the degree of fluidization.
  • a nonpolar solvent when a nonpolar solvent is used as the solvent, it tends to be the opposite.
  • the degree of fluidization may be adjusted in detail according to the dielectric constant of the polar solvent or the nonpolar solvent.
  • the higher the affinity between the solvent and the solid the deeper the solvent can penetrate into the solid, and the greater the degree of fluidization.
  • a microstructure having a high aspect ratio can be finally manufactured.
  • the lower the affinity between the solvent and the solid the more the solvent penetrates into the solid, and thus the degree of fluidization becomes smaller.
  • a microstructure having a small aspect ratio can be finally manufactured.
  • the solvent can penetrate deeply into the solid material, and thus the degree of fluidization increases. Accordingly, a microstructure having a large aspect ratio can be manufactured.
  • the solvent may penetrate shallowly into the solid material, thereby reducing the degree of fluidization, and thus, a microstructure having a small aspect ratio may be manufactured.
  • the solvent is added to 10 parts by volume to 200 parts by volume, preferably 30 parts by volume to 200 parts by volume, by adjusting the degree of fluidization, the appropriate aspect ratio ( Microstructures having aspect ratios can be prepared.
  • the degree of fluidization can be controlled by adjusting fluidization conditions such as fluidization temperature, fluidization humidity, fluidization time and the like.
  • Figure 8 shows the degree of fluidization controlled by (a) affinity of the solvent and solids, (b) amount of solvent and (c) fluidization time.
  • the degree of fluidization is relatively high when the affinity of the solvent and the solid is high (first picture), and the degree of fluidization is relatively low when the affinity of the solvent and solid solid is low (second picture). .
  • the microstructure having a sharp upper end can be finally manufactured, thereby having a shape suitable as a microneedle.
  • the half point of the solid in the present specification refers to the middle point of the upper end of the solid from the lowest point of the substrate surface that is in contact with the lower end of the solid with respect to the vertical direction of the substrate.
  • a solvent may be added on the solid, but may be added by adding a drug to the solvent.
  • a solvent By additionally mounting the drug in a solvent for fluidization of the solid apart from the solid, it is easy to quantitatively mount the drug and to mount the drug in various formulations, and has the advantage of minimizing drug activity loss and improving stability.
  • the drug may be of the same kind as the aforementioned separate drug, and may be irrespective of the kind, dosage, dosage form, and the like. Of course, additives may also be added to the solvent.
  • ascorbic acid 2-glucoside (AA2G) corresponding to a cosmetic ingredient, specifically, a whitening ingredient, was used as a drug.
  • the drug is preferably 0.1 parts by weight to 10 parts by weight based on 100 parts by weight of a solution [drug (additive) and a solvent], but is not limited thereto.
  • FIG. 9 is a diagram illustrating the addition and fluidization of solvents loaded with drugs in various ways on solids.
  • the addition and fluidization of the solvent-loaded solvent on the solids can be achieved by discharging and spontaneous drying, discharging and freeze drying, solids omnidirectional deposition, solids top deposition, solids omnidirectional and support surface deposition, and solids top. And support surface deposition.
  • Figure 10 is a diagram showing the distribution of drug in the solid according to (a) the solubility of the solvent and the solid loaded with the drug and (b) the degree of fluidization controlled by the fluidization time.
  • the second solvent may be added to the solid to reflow to form the mold.
  • the distribution of the drug can be more freely controlled.
  • the drug distribution may be concentrated in the microstructure intermediate layer.
  • the second solvent may be the same as or different from the aforementioned solvent. It is also possible to add additional drugs or additional additives to the second solvent.
  • FIG. 11 is a diagram showing the degree of refluidization and the distribution of drug in the stock form adjusted according to the refluidization time.
  • FIG. 12 is a diagram showing the degree of refluidization and the distribution of drug in stocks, controlled by the difference in solubility between the drug loaded solvent, solids and the second solvent.
  • the method for producing a microstructure according to the present invention may include the step of forming the fluidized solids (step (c)).
  • the molding may be performed by a molding method, or may be performed by one or more methods selected from the group consisting of drawing, blowing, suction, centrifugal force application, and magnetic field application by applying an outward force to the fluidized solid material. At this time, the molding may be performed so that curing occurs at the same time.
  • the aspect ratio of the molded microstructure may be adjusted according to the degree of fluidization.
  • the aspect ratio of the microstructures in this specification is the micro-to-top of the microstructure from the lowest point of the substrate surface that abuts the bottom of the solid in the vertical direction of the substrate to the maximum diameter when cutting the microstructure in the horizontal direction of the substrate.
  • the ratio of the height of the structure is the micro-to-top of the microstructure from the lowest point of the substrate surface that abuts the bottom of the solid in the vertical direction of the substrate to the maximum diameter when cutting the microstructure in the horizontal direction of the substrate.
  • the aspect ratio of the microstructure refers to the ratio of the maximum diameter to the height of the microstructure. As the degree of fluidization increases, the shrinkage rate increases during molding, so that the aspect ratio of the microstructure tends to increase. Seems.
  • the payload distribution of the drug in the molded microstructure can be adjusted according to the degree of fluidization or refluidization.
  • FIG. 13 shows (a) aspect ratio of microstructures controlled by degree of fluidization and (b) payload distribution of drugs controlled by degree of refluidization.
  • the degree of fluidization increases, so the shrinkage ratio during molding increases, so the aspect ratio of the microstructure tends to increase.
  • the drug when the degree of refluidization is small as shown in the first or second picture of FIG. 11, the drug may be concentrated in the microstructure upper layer without distributing the drug in the microstructure lower layer.
  • the degree of refluidization when the degree of refluidization is large, the drug may be distributed throughout the microstructure.
  • the aspect ratio of the microstructure may be adjusted according to the degree of fluidization of the solid, and the payload distribution of the drug in the microstructure may be adjusted according to the degree of refluidization of the inventory.
  • the present invention also provides a microstructure manufactured according to the above method.
  • the present invention provides a microstructure formed on a substrate and drug-mounted microstructure, wherein the drug loading distribution in the microstructure forms a gradual concentration gradient.
  • the drug loading distribution in such a microstructure can form a gradual concentration gradient due to the degree of fluidization.
  • the drug loading distribution in the microstructure upper layer is the drug loading distribution in the microstructure lower layer. It may be characterized by a large relative to the degree.
  • microstructures can be prepared by directly molding after drug-loaded solvent addition, fluidization, or by molding after drug-loaded solvent addition, fluidization, stocking, and refluidization,
  • the structure has the advantage that the drug can be effectively penetrated deep into the skin by distributing the drug in the microstructure upper layer.
  • the drug is loaded in the microstructure intermediate layer.
  • the degree of distribution may be greater than the degree of drug loading in the microstructure upper layer and the microstructure lower layer.
  • microstructures can be prepared by addition of drug-loaded solvents, fluidization, re-shaping, and re-fluidization with a second solvent comprising a polymeric material followed by shaping, and the microstructures thus prepared can be used to convert drugs into microstructures.
  • a second solvent comprising a polymeric material followed by shaping
  • microstructure according to the present invention can be used as microblades, microblades, microknifes, microfibers, microspikes, microprobes, microbarbs, microarrays or microelectrodes.
  • the manufacturing method of the microstructure using the fluidization of the solid according to the present invention can solve the difficulty of adjusting the viscosity of the conventional high viscosity composition, while ensuring the productivity, uniformity and quality of the microstructure, and facilitate mass production
  • the aspect ratio of the microstructures may be adjusted in various ways.
  • the drug is a microstructure upper layer It can also be concentrated in the distribution, so that the drug can effectively penetrate deep into the skin.
  • the substrate was mounted in a centrifuge (Combi-514R), the centrifuge was accelerated to 11.6 g / sec, and then operated at 900 g of gravity acceleration for 3 minutes. Then, the centrifuge was decelerated at a speed of 14.3 g / sec to finally prepare the microstructure. At this time, curing occurred simultaneously in the molding process.
  • Example 14 is an optical micrograph showing the (a) solids and (b) microstructures in Example 1, respectively.
  • the substrate was mounted in a centrifuge (Combi-514R), and the centrifuge was rotated at 2700 rpm for 1 minute to finally prepare the microstructure. At this time, curing occurred simultaneously in the molding process.
  • FIG. 15 is an optical micrograph showing the microstructures according to the amount of solvent in Example 2 ((a) 10 ⁇ l, (b) 15 ⁇ l and (c) 20 ⁇ l, respectively).
  • the solvent can be adjusted to an appropriate degree of fluidization by adding 10 to 40 parts by volume, preferably 15 to 40 parts by volume, based on 100 parts by weight of the solids.
  • Ascorbic acid 2-glucoside (AA2G) 2 (w / v)%, hyaluronic acid (30kDa) 60 as a whitening component by applying a pressure of 200 kPa for 0.110 seconds through a dispenser (Musashi, ML-5000X-mini) on an aluminum substrate. (w / v)% and a red pigment, a solution containing Rhodamine B (0.1% (w / v)%) was discharged, and then naturally dried to obtain a solid (solid content) in which most of the water was evaporated. 99.9%). 20 ⁇ l of distilled water was discharged through a jet nozzle onto 50 ⁇ g of the prepared solid, followed by fluidization at 23 ° C. and 50% humidity for 30 seconds.
  • the substrate was mounted in a centrifuge (Combi-514R), and the centrifuge was rotated at 2700 rpm for 1 minute to finally prepare the microstructure. At this time, curing occurred simultaneously in the molding process.
  • Figure 16 (a) is an optical micrograph showing the microstructure in Example 3, it was confirmed that the microstructure can be successfully prepared by fluidizing and then molding the solid to which the additional drug is added in advance.
  • the substrate was mounted in a centrifuge (Combi-514R), and the centrifuge was rotated at 2700 rpm for 1 minute to finally prepare the microstructure. At this time, curing occurred simultaneously in the molding process.
  • Figure 16 (b) is an optical micrograph showing the microstructure in Example 4, it was confirmed that the microstructure can be successfully prepared by fluidizing the solid with a solvent in which the drug is additionally loaded.

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Abstract

The present invention relates to a microstructure, and a manufacturing method therefor, the manufacturing method comprising the steps of: (a) manufacturing a solid on a substrate; (b) adding a solvent onto the solid so as to fluidize the same; and (c) molding the fluidized solid.

Description

고형물의 유동화를 이용한 마이크로구조체 및 이의 제조방법Microstructures Using Fluidization of Solids and Manufacturing Method Thereof
본 발명은 고형물의 유동화를 이용한 마이크로구조체 및 이의 제조방법에 관한 것이다.The present invention relates to a microstructure using the fluidization of solids and a method for producing the same.
현재 약물을 체내로 전달하기 위하여 여러 가지 기술이 개발되어 왔다. 그 중 피부를 통한 약물전달은 주사, 연고, 패치 등의 형태가 있다.Currently, several techniques have been developed to deliver drugs into the body. Among them, drug delivery through the skin is in the form of injections, ointments, patches.
주사는 체내에 바늘을 삽입하여 약물을 전달하므로 약효가 신속하게 나타나며 약물이 바로 혈액 또는 근육과 같이 체내 조직으로 전달되어 효과적인 약물전달방법으로 다양한 분야에 사용되고 있다. 하지만 주사는 피부에 강한 자극과 조직 손상을 야기하며 이로 인하여 고통이 동반된다. 또한 상처로 인해 추가감염이 발생하기도 하여 전문가에 의해서만 시술이 가능하다는 문제점이 있다.Injection is delivered to the body by inserting a needle to deliver the drug, the drug appears quickly and the drug is immediately delivered to the body tissues, such as blood or muscle is used in various fields as an effective drug delivery method. Injections, however, cause strong irritation and damage to the skin, which is accompanied by pain. In addition, there is a problem that the additional infection occurs due to the wound, which can be performed only by a specialist.
연고나 패치의 경우, 각질층을 투과하는 것이 어려워 적용가능약물에 한계가 있으며 약물의 전달시간이 오래 걸리고 정확한 양을 전달하기 어렵다는 문제가 있다.In the case of ointments or patches, it is difficult to penetrate the stratum corneum, there is a limit to the applicable drug, there is a problem that the delivery time of the drug is long and difficult to deliver the correct amount.
마이크로니들은 이러한 문제점들을 해결하기 위하여 고안된 약물전달시스템으로 미세한 바늘을 이용하여 최소의 침습만으로 체내에 약물을 전달하는 시스템이다.Microneedle is a drug delivery system designed to solve these problems is a system for delivering drugs to the body with minimal invasion using a fine needle.
이 중 생분해성 마이크로니들의 경우, 생분해성 물질로 마이크로니들 골격을 구성한 것을 말한다. 마이크로니들로 성형된 생분해성 물질은 피부각질층을 투과한 후 피부 내 체액과 체온에 의하여 용해된다. 이때에 생분해성 물질과 약물을 혼합하여 마이크로니들로 성형된 생분해성 마이크로니들의 경우 탑재된 약물들이 함께 녹아나오면서 체내로 전달되는 원리를 갖는다.Among these, the biodegradable microneedle refers to a microneedle skeleton composed of a biodegradable material. The biodegradable material formed into microneedles penetrates the stratum corneum and is dissolved by body fluid and body temperature in the skin. In this case, the biodegradable microneedles formed by mixing the biodegradable substance and the drug and formed into microneedles have a principle that the mounted drugs are melted together and delivered to the body.
현재 생분해성 마이크로니들은 점성 조성물을 마이크로니들로 성형하는 방법으로 제조되고 있다. 그러나, 점성 조성물은 습도와 온도와 같은 주변 환경에 의해 점도가 쉽게 변하므로, 대량 생산시 일정한 형태의 마이크로니들로 제작하기 어려움이 있다. 특히, 점성 조성물이 토출되어 방울(droplet)을 형성한 후 생분해성 마이크로니들을 제조하는 경우에는 일정한 양이 토출된 것이라 하더라도, 토출 순서에 따라 주변 환경에 의해 건조되는 정도가 다르므로 각 방울의 점도가 달라지므로 균일한 생분해성 마이크로니들을 대량으로 제조하기 어려움이 있었다. 이는 정밀 제어를 위한 공정을 복잡하게 만들어 마이크로니들의 생산성, 균일성 및 품질을 저하시키는 문제점이 있었다.Biodegradable microneedles are currently manufactured by molding viscous compositions into microneedles. However, since the viscosity composition is easily changed by the surrounding environment such as humidity and temperature, it is difficult to produce a microneedle of a certain form in mass production. In particular, in the case of manufacturing a biodegradable microneedle after the viscous composition is discharged to form droplets, even if a certain amount is discharged, the degree of drying by the surrounding environment varies depending on the discharge sequence, so the viscosity of each droplet Since it is different, it was difficult to manufacture a uniform biodegradable microneedle in large quantities. This complicates the process for precise control and has a problem of lowering the productivity, uniformity and quality of the microneedle.
또한, 생분해성 마이크로니들 내 약물 탑재는 생분해성 물질과 약물을 혼합한 점성 조성물을 먼저 제조한 후 이를 사용하여 마이크로니들로 제조하는 방법을 사용하고 있다. 하지만 생분해성 물질과 약물의 혼합 과정이나 생분해성 물질-약물 혼합용액 상태에서 약물은 생분해성 물질 또는 용매에 의해 변성되거나 파괴될 수 있다. 따라서 약물과 용매 또는 생분해성 물질과의 상호작용을 최소화하는 것이 필수적이다. 생분해성 물질과 약물의 용매가 서로 다른 경우는 별도의 계면활성제 첨가를 통해서만 혼합용액이 형성 가능하다. 이로 인해 생분해성 물질 내 탑재가능 약물의 종류에 한계가 생긴다. 또한, 약물과 생분해성 물질의 혼합용액은 높은 점도를 갖는 형태로 약물의 정확한 정량이 어렵다는 문제가 있다. 생분해성 물질의 불균일성으로 인하여 혼합용액 상의 약물도 함께 불균일해지기 때문이다. 위와 같은 문제점들은 생분해성 물질과 약물을 혼합한 혼합용액으로만 마이크로니들의 형태로 제형, 성형하기 때문에 발생하는 문제점으로 볼 수 있다. In addition, the drug loading in the biodegradable microneedle uses a method of preparing a viscous composition mixed with a biodegradable substance and a drug first and then using the microneedle. However, the drug may be denatured or destroyed by the biodegradable substance or solvent in the process of mixing the biodegradable substance and the drug or in the state of the biodegradable substance-drug mixture solution. It is therefore essential to minimize the interaction of drugs with solvents or biodegradable materials. When the biodegradable substance and the solvent of the drug are different from each other, the mixed solution can be formed only by adding a separate surfactant. This limits the types of drugs that can be loaded into biodegradable materials. In addition, the mixed solution of the drug and the biodegradable material has a problem that it is difficult to accurately quantify the drug in the form having a high viscosity. This is because the heterogeneity of the biodegradable material causes the drug in the mixed solution to be heterogeneous together. The above problems can be seen as a problem that occurs because the formulation and molding in the form of a microneedle only a mixed solution of a biodegradable material and drug.
본 발명은 (a) 기판 상에 고형물을 제조하는 단계; (b) 상기 고형물 상에 용매를 첨가하여 유동화시키는 단계; 및 (c) 상기 유동화된 고형물을 성형하는 단계를 포함하는 마이크로구조체의 제조방법 등을 제공하고자 한다. The present invention comprises the steps of (a) preparing a solid on a substrate; (b) fluidizing by adding a solvent onto the solid; And (c) to provide a method for producing a microstructure comprising the step of forming the fluidized solid.
그러나, 본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 과제에 제한되지 않으며, 언급되지 않은 또 다른 과제들은 아래의 기재로부터 당업자에게 명확하게 이해될 수 있을 것이다.However, the technical problem to be achieved by the present invention is not limited to the above-mentioned problem, another task that is not mentioned will be clearly understood by those skilled in the art from the following description.
본 발명은 (a) 기판 상에 고형물을 제조하는 단계; (b) 상기 고형물 상에 용매를 첨가하여 유동화시키는 단계; 및 (c) 상기 유동화된 고형물을 성형하는 단계를 포함하는 마이크로구조체의 제조방법을 제공한다.The present invention comprises the steps of (a) preparing a solid on a substrate; (b) fluidizing by adding a solvent onto the solid; And (c) provides a method for producing a microstructure comprising the step of forming the fluidized solid.
상기 (a)에서 고형물은 고형분 함량이 70% 이상일 수 있다.Solid in the (a) may be 70% or more solid content.
상기 (a)에서 고형물은 별도 약물 또는 별도 첨가제가 미리 첨가될 수 있다. 상기 (b) 단계에서 용매의 첨가는 접촉, 토출, 분사, 증착 및 담금으로 이루어진 군으로부터 선택된 하나 이상의 방법으로 수행될 수 있다.In the solid (a), a separate drug or a separate additive may be added in advance. The addition of the solvent in step (b) may be performed by one or more methods selected from the group consisting of contacting, discharging, spraying, depositing and immersion.
상기 (b) 단계에서 고형물의 유동화 정도는 용매의 종류, 용매와 고형물의 친화도, 용매의 양 또는 유동화 조건에 따라 조절될 수 있다.In the step (b), the degree of fluidization of the solid may be adjusted according to the type of solvent, the affinity of the solvent and the solid, the amount of the solvent or the fluidization conditions.
상기 (b) 단계에서 고형물 100 중량부 대비, 용매는 10 부피부 내지 200 부피부로 첨가될 수 있다.The solvent may be added in an amount of 10 parts by volume to 200 parts by weight based on 100 parts by weight of the solid in step (b).
상기 기판의 수직 방향을 기준으로 할 때, 상기 고형물의 1/2 지점을 경계로 고형물 상부층 및 고형물 하부층으로 구분하는 경우, 상기 (b) 단계에서 고형물 상부층의 유동화 정도가 고형물 하부층의 유동화 정도에 비해 큰 것을 특징으로 할 수 있다.Based on the vertical direction of the substrate, in the case of dividing the solid upper layer and the solid lower layer on the basis of the half point of the solid, in the step (b) the degree of fluidization of the solid upper layer compared to the degree of fluidization of the solid lower layer It can be characterized by a large one.
상기 (b) 단계에서 용매에 약물을 추가로 탑재할 수 있다.In step (b) it may be further loaded with the drug in the solvent.
상기 (b) 단계 후, 상기 유동화된 고형물을 재고형화시킨 후, 상기 고형물 상에 제2 용매를 첨가하여 재유동화시키는 단계를 추가로 포함할 수 있다.After the step (b), after re-solidifying the fluidized solid, it may further comprise the step of refluidizing by adding a second solvent on the solid.
상기 (c) 단계에서 성형은 몰딩, 드로잉, 송풍, 흡입, 원심력 인가 및 자기장 인가로 이루어진 군으로부터 선택된 하나 이상의 방법으로 수행될 수 있다.Molding in step (c) may be performed by one or more methods selected from the group consisting of molding, drawing, blowing, suction, centrifugal force application and magnetic field application.
상기 (c) 단계에서 성형은 경화가 동시에 일어나도록 수행될 수 있다.Molding in the step (c) may be performed so that curing occurs at the same time.
상기 (c) 단계에서 성형되는 마이크로구조체의 종횡비(aspect ratio)는 유동화 정도에 따라 조절될 수 있다.Aspect ratio of the microstructure formed in step (c) can be adjusted according to the degree of fluidization.
상기 (c) 단계에서 성형되는 마이크로 구조체 내 약물의 탑재 분포는 유동화 정도에 따라 조절될 수 있다. The loading distribution of the drug in the microstructure formed in step (c) may be adjusted according to the degree of fluidization.
상기 (c) 단계에서 성형되는 마이크로 구조체 내 약물의 탑재 분포는 재유동화 정도에 따라 조절될 수 있다.The distribution of the drug in the microstructure formed in step (c) may be adjusted according to the degree of refluidization.
본 발명의 일 구현예로, 상기 방법에 따라 제조된 마이크로구조체를 제공한다.In one embodiment of the present invention, a microstructure manufactured according to the above method is provided.
본 발명의 다른 구현예로, 기판 상에 형성되고, 약물이 탑재된 마이크로구조체에 있어서, 상기 마이크로구조체 내 약물 탑재 분포는 점진적 농도 구배를 형성하는 것인 마이크로구조체를 제공한다.In another embodiment of the present invention, in a microstructure formed on a substrate and loaded with drugs, the drug loading distribution in the microstructure provides a microstructure that forms a gradual concentration gradient.
상기 기판의 수직 방향을 기준으로 할 때, 상기 마이크로구조체의 1/2 지점을 경계로 마이크로구조체 상부층 및 마이크로구조체 하부층으로 구분하는 경우, 마이크로구조체 상부층 내 약물 탑재 분포 정도가 마이크로구조체 하부층 내 약물 탑재 분포 정도에 비해 큰 것을 특징으로 할 수 있다.Based on the vertical direction of the substrate, when the half point of the microstructure is divided into the microstructure upper layer and the microstructure lower layer, the drug loading distribution in the microstructure upper layer is the drug loading distribution in the microstructure lower layer. It may be characterized by a large relative to the degree.
상기 기판의 수직 방향을 기준으로 할 때, 상기 마이크로구조체의 1/3 및 2/3 지점을 경계로 마이크로구조체 상부층, 마이크로구조체 중간층, 마이크로구조체 하부층으로 구분하는 경우, 마이크로구조체 중간층 내 약물 탑재 분포 정도가 마이크로구조체 상부층 및 마이크로구조체 하부층 내 약물 탑재 분포 정도에 비해 큰 것을 특징으로 할 수 있다.Based on the vertical direction of the substrate, when the microstructure is divided into a top layer, a microstructure middle layer, and a microstructure lower layer at the 1/3 and 2/3 points of the microstructure, the degree of drug loading in the microstructure intermediate layer It can be characterized in that the large compared to the degree of drug loading in the microstructure upper layer and the microstructure lower layer.
본 발명에 따른 고형물의 유동화를 이용한 마이크로구조체의 제조방법은 종래 점성 조성물의 점도 조절의 어려움을 해결할 수 있고, 마이크로구조체의 생산성, 균일성 및 품질을 확보하면서, 대량 생산을 용이하게 할 수 있으며, 마이크로구조체의 종횡비(aspect ratio)를 다양하게 조절할 수 있다. Microstructure manufacturing method using the fluidization of the solid according to the present invention can solve the difficulty of adjusting the viscosity of the conventional viscous composition, while ensuring the productivity, uniformity and quality of the microstructure, can facilitate mass production, Various aspects of the aspect ratio of the microstructure can be adjusted.
또한, 고형물과는 별도로 고형물의 유동화를 위한 용매에 약물을 추가 탑재함으로써, 약물의 정량 탑재 및 다양한 제형의 약물 탑재가 용이하고, 약물 활성 손실 최소화 및 안정성 향상을 가져올 수 있으며, 약물을 마이크로구조체 상부층 또는 마이크로구조체 중간층에 집중 분포시킬 수도 있어, 약물을 피부 깊숙히 효과적으로 침투시킬 수 있는 이점이 있다. In addition, by additionally mounting the drug in a solvent for fluidization of the solid separately from the solid, it is easy to quantitatively mount the drug and to mount the drug in a variety of formulations, it is possible to minimize the loss of drug activity and to improve the stability, the drug is a microstructure upper layer Or it may be concentrated in the microstructure interlayer, there is an advantage that can effectively penetrate the drug deep into the skin.
도 1은 본 발명의 일 구현예에 따른 고형물의 유동화를 이용한 마이크로구조체의 제조방법을 나타낸 순서도이다.1 is a flow chart showing a method of manufacturing a microstructure using the fluidization of a solid according to an embodiment of the present invention.
도 2는 본 발명의 일 구현예에 따른 고형물의 유동화를 이용한 마이크로구조체의 제조방법을 도시한 그림이다. 2 is a diagram illustrating a method of manufacturing a microstructure using the fluidization of a solid according to an embodiment of the present invention.
도 3은 다양한 표면 형상을 가지는 기판 상에 고형물의 제조를 도시한 그림이다.3 is a drawing illustrating the manufacture of solids on a substrate having various surface shapes.
도 4는 다양한 방법에 의한 고형물의 제조를 도시한 그림이다.4 is a drawing illustrating the production of solids by various methods.
도 5는 다양한 형상의 고형물을 도시한 그림이다.5 is a diagram illustrating solids of various shapes.
도 6은 고형물 상에 다양한 방법에 의한 용매의 첨가 및 유동화를 도시한 그림이다.6 is a diagram illustrating the addition and fluidization of solvents on various solids by various methods.
도 7은 고형물 상에 별도 기판을 이용한 용매의 첨가 및 유동화를 도시한 그림이다.7 is a diagram illustrating the addition and fluidization of a solvent using a separate substrate on a solid.
도 8은 (a) 용매와 고형물의 친화도, (b) 용매의 양 및 (c) 유동화 시간에 따라 조절되는 유동화 정도를 보여주는 그림이다.FIG. 8 shows the degree of fluidization controlled by (a) affinity of the solvent and solids, (b) amount of solvent, and (c) fluidization time.
도 9는 고형물 상에 다양한 방법으로 약물이 탑재된 용매의 첨가 및 유동화를 도시한 그림이다.9 is a diagram illustrating the addition and fluidization of solvents loaded with drugs in various ways on solids.
도 10은 (a) 약물이 탑재된 용매와 고형물의 용해도 및 (b) 유동화 시간에 따라 조절되는 유동화 정도에 따라 고형물 내 약물의 탑재 분포를 보여주는 그림이다.Figure 10 is a diagram showing the distribution of drug in the solid according to (a) the solubility of the solvent and the solid loaded with the drug and (b) the degree of fluidization controlled by the fluidization time.
도 11은 재유동화 시간에 따라 조절되는 재유동화 정도 및 재고형물 내 약물의 탑재 분포를 보여주는 그림이다.FIG. 11 is a diagram showing the degree of refluidization and the distribution of drug in the stock form adjusted according to the refluidization time.
도 12는 약물이 탑재된 용매, 고형물 및 제2 용매 사이의 용해도 차이에 따라 조절되는 재유동화 정도 및 재고형물 내 약물의 탑재 분포를 보여주는 그림이다.FIG. 12 is a diagram showing the degree of refluidization and the distribution of drug in the stock that is controlled by the difference in solubility between the drug loaded solvent, the solid and the second solvent.
도 13은 (a) 유동화 정도에 따라 조절되는 마이크로구조체의 종횡비(aspect ratio) 및 (b) 재유동화 정도에 따라 조절되는 마이크로구조체 내 약물의 탑재 분포를 보여주는 그림이다.FIG. 13 is a diagram showing the payload distribution of drugs in the microstructure controlled by the aspect ratio of (a) the degree of fluidization and (b) the degree of refluidization.
도 14는 실시예 1에서 (a) 고형물 및 (b) 마이크로구조체를 각각 보여주는 광학 현미경 사진이다.14 is an optical micrograph showing the (a) solids and (b) microstructures in Example 1, respectively.
도 15는 실시예 2에서 용매의 양[(a) 10㎕, (b) 15㎕ 및 (c) 20㎕]에 따른 마이크로구조체를 각각 보여주는 광학 현미경 사진이다. FIG. 15 is an optical micrograph showing the microstructures according to the amount of solvent in Example 2 ((a) 10 µl, (b) 15 µl and (c) 20 µl, respectively).
도 16은 (a) 실시예 3에서 마이크로구조체 및 (b) 실시예 4에서 마이크로구조체를 각각 보여주는 광학 현미경 사진이다.Figure 16 is an optical micrograph showing (a) the microstructures in Example 3 and (b) the microstructures in Example 4, respectively.
본 발명자들은 종래와 같이 기판 상에 점성 조성물을 바로 사용하지 않고, 고형물 상에 용매를 첨가하여 상부를 유동화시킨 후, 성형하여 마이크로구조체를 성공적으로 제조할 수 있음을 확인하고, 본 발명을 완성하였다.The present inventors have completed the present invention by confirming that the microstructures can be successfully produced by adding a solvent on a solid, fluidizing the upper part, and molding without using a viscous composition directly on a substrate as in the prior art. .
이하, 첨부한 도면을 참고로 하여 본 발명의 실시예에 대하여 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자가 용이하게 실시할 수 있도록 상세히 설명한다. 본 발명은 여러 가지 상이한 형태로 구현될 수 있으며 여기에서 설명하는 실시예에 한정되지 않는다.Hereinafter, exemplary embodiments of the present invention will be described in detail with reference to the accompanying drawings so that those skilled in the art may easily implement the present invention. As those skilled in the art would realize, the described embodiments may be modified in various different ways, all without departing from the spirit or scope of the present invention.
도면에서 여러 층 및 영역을 명확하게 표현하기 위하여 두께를 확대하여 나타내었다. 그리고 도면에서, 설명의 편의를 위해, 일부 층 및 영역의 두께를 과장되게 나타내었다.In the drawings, the thickness of layers, films, panels, regions, etc., are exaggerated for clarity. In the drawings, the thicknesses of layers and regions are exaggerated for clarity.
이하에서 기재의 상 (또는 하)에 임의의 구성이 형성된다는 것은, 임의의 구성이 상기 기재의 상 (또는 하)에 접하여 형성되는 것을 의미할 뿐만 아니라, 상기 기재와 기재 상 (또는 하) 형성된 임의의 구성 사이에 다른 구성을 포함하지 않는 것으로 한정하는 것은 아니다.In the following, any configuration is formed on (or under) the substrate, not only means that any configuration is formed in contact with (or below) the substrate, but also formed on (or below) the substrate and the substrate. It does not limit to not including another structure between arbitrary structures.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명은 (a) 기판 상에 고형물을 제조하는 단계; (b) 상기 고형물 상에 용매를 첨가하여 유동화시키는 단계; 및 (c) 상기 유동화된 고형물을 성형하는 단계를 포함하는 마이크로구조체의 제조방법을 제공한다.The present invention comprises the steps of (a) preparing a solid on a substrate; (b) fluidizing by adding a solvent onto the solid; And (c) provides a method for producing a microstructure comprising the step of forming the fluidized solid.
도 1 및 도 2는 본 발명의 일 구현예에 따른 고형물의 유동화를 이용한 마이크로구조체의 제조방법을 각각 나타낸 순서도 및 그림이다. 1 and 2 are a flow chart and a figure showing a method for producing a microstructure using the fluidization of a solid according to an embodiment of the present invention, respectively.
도 1 및 도 2에 나타난 바와 같이, 본 발명의 일 구현예에 따른 마이크로구조체의 제조방법은 기판 상에 고형물을 제조하고[(a) 단계], 상기 고형물 상에 용매를 첨가하여 유동화시킨 후[(b) 단계], 상기 유동화된 고형물을 성형함으로써[(c) 단계] 이루어진다. As shown in Figures 1 and 2, the method for producing a microstructure according to an embodiment of the present invention is to prepare a solid on a substrate [(a)], and then by adding a solvent on the solid to fluidize [ step (b)], by shaping the fluidized solid [step (c)].
먼저, 본 발명에 따른 마이크로구조체의 제조방법은 기판 상에 고형물을 제조하는 단계[(a) 단계]를 포함한다.First, the method for producing a microstructure according to the present invention includes the step of preparing a solid on a substrate (step (a)).
상기 기판은 마이크로구조체를 최종적으로 제조하기 위한 것으로, 상기 제조된 고형물을 지지하기 위한 용도로 사용된다. The substrate is used to finally manufacture the microstructure, and is used for supporting the manufactured solid.
도 3은 다양한 표면 형상을 가지는 기판 상에 고형물의 제조를 도시한 그림이다.3 is a drawing illustrating the manufacture of solids on a substrate having various surface shapes.
도 3에 도시한 바와 같이, 상기 기판은 다양한 표면 형상을 가질 수 있다. 구체적으로, 상기 기판은 하나의 마이크로구조체를 형성하기 위한 것으로, 필라의 형성 없이 상기 기판 상에 바로 하나의 고형물을 지지할 수도 있고, 상기 기판 상에 하나의 고형물을 지지하기 위한 원기둥, 원뿔대, 원뿔, 반구형 등 다양한 형상을 가진 하나의 필라를 형성함으로써 마이크로구조체, 바람직하게 마이크로니들의 피부 전달 정도를 조절할 수도 있다(도 3(a) 참고). 또한, 상기 기판은 다수의 마이크로구조체 또는 일체의 마이크로구조체를 형성하기 위한 것으로, 필라의 형성 없이 상기 기판 상에 바로 다수의 고형물 또는 일체의 고형물을 지지할 수도 있고, 상기 기판 상에 다수의 고형물 또는 일체의 고형물을 지지하기 위한 일정한 패턴의 굴곡 또는 요철 등을 형성함으로써 마이크로니들의 피부 전달 정도를 조절할 수도 있다(도 3(b) 참고). 이와 같은 기판의 표면 형상은 사용목적 및 마이크로구조체의 적용 형태에 따라 다양하게 선택 가능하다.As shown in FIG. 3, the substrate may have various surface shapes. Specifically, the substrate is for forming one microstructure, and may support one solid directly on the substrate without forming pillars, and a cylinder, truncated cone, and cone for supporting one solid on the substrate. It is also possible to control the degree of skin delivery of the microstructure, preferably the microneedle by forming one pillar having various shapes such as hemispherical shape (see FIG. 3 (a)). In addition, the substrate is for forming a plurality of microstructures or integral microstructures, and may support a plurality of solids or a single solid directly on the substrate without forming a pillar, a plurality of solids or It is also possible to adjust the degree of skin delivery of the microneedle by forming a certain pattern of bends or irregularities for supporting the solids (see Fig. 3 (b)). The surface shape of such a substrate can be variously selected depending on the purpose of use and the application form of the microstructure.
상기 고형물은 종래 점성 조성물과는 구별되는 개념으로, 수분이 증발된 상태로 고형분 함량이 70% 이상인 것이 바람직하고, 90% 이상인 것이 더욱 바람직하나, 이에 한정되지 않는다. 상기 고형물은 상기 범위의 고형분 함량을 유지함으로써 종래 점성 조성물의 점도 조절의 어려움에 따른 문제점을 해결하기 위해 사용될 수 있어, 마이크로구조체의 생산성, 균일성 및 품질을 확보하면서, 대량 생산을 용이하게 할 수 있는 이점이 있다.The solid material is a concept that is distinguished from the conventional viscous composition. The solid content is preferably 70% or more, more preferably 90% or more, but is not limited thereto. The solids can be used to solve the problems caused by the difficulty of controlling the viscosity of the conventional viscous composition by maintaining the solid content in the above range, while ensuring the productivity, uniformity and quality of the microstructure, can facilitate mass production There is an advantage to that.
상기 고형물의 제조는 고형물 전구체로, 상기 기판 상에 토출된 점성 방울(droplet)을 자연 건조시키거나, 상기 기판 상에 토출된 점성 방울(droplet)에 압력, 온도, 송풍, 자기장, 전기 등을 조절하는 등 열 또는 동결 건조, 몰딩, 드로잉, 송풍, 원심력, 흡입, 자기장, 분사 및 전기방사 등을 통해 고형물을 제조할 수 있다. 그 밖에, 상기 고형물의 제조는 상기 기판 상에 고형 분말을 도포하거나, 다른 기판 상에 이미 형성된 고형물을 상기 기판 상으로 이동시킴으로써 제조할 수 있다. 이러한 경우 기판은 다른 기판 보다 상기 고형분과 친화도가 높은 것이 바람직하다.The production of the solid is a solid precursor, which naturally dries the viscous droplets discharged on the substrate, or adjusts pressure, temperature, blowing, magnetic field, electricity, etc. to the viscous droplets discharged on the substrate. Solids may be prepared by heat or freeze drying, molding, drawing, blowing, centrifugal force, suction, magnetic field, injection, and electrospinning. In addition, the preparation of the solid may be prepared by applying a solid powder on the substrate or by moving the solid already formed on another substrate onto the substrate. In this case, it is preferable that the substrate has a higher affinity with the solids than the other substrates.
상기 고형물은 고분자 물질로, 생체적합성 또는 생분해성 물질을 포함할 수 있다. The solid material may be a polymer material and may include a biocompatible or biodegradable material.
본 명세서 내 생체적합성 물질은 실질적으로 인체에 독성이 없고 화학적으로 불활성이며 면역원성이 없는 물질을 의미하고, 본 명세서 내 생분해성 물질은 생체 내에서 체액 또는 미생물 등에 의해서 분해될 수 있는 물질을 의미한다.The biocompatible material in the present specification means a material that is substantially nontoxic to the human body, chemically inert and immunogenic, and the biodegradable material in the present specification means a material that can be decomposed by body fluids or microorganisms in a living body. .
구체적으로, 생체적합성 또는 생분해성 물질로는 히알루론산, 폴리에스테르, 폴리하이드록시알카노에이트(PHAs), 폴리(α-하이드록시액시드), 폴리(β-하이드록시액시드), 폴리(3-하이드로식부티레이트-co-발러레이트; PHBV), 폴리(3-하이드록시프로프리오네이트; PHP), 폴리(3-하이드록시헥사노에이트; PHH), 폴리(4-하이드록시액시드), 폴리(4-하이드록시부티레이트), 폴리(4-하이드록시발러레이트), 폴리(4-하이드록시헥사노에이트), 폴리(에스테르아마이드), 폴리카프로락톤, 폴리락타이드, 폴리글리코라이드, 폴리(락타이드-co-글리코라이드; PLGA), 폴리디옥사논, 폴리오르토에스테르, 폴리에테르에스테르, 폴리언하이드라이드, 폴리(글리콜산-co-트리메틸렌 카보네이트), 폴리포스포에스테르, 폴리포스포에스테르 우레탄, 폴리(아미노산), 폴리사이아노아크릴레이트, 폴리(트리메틸렌 카보네이트), 폴리(이미노카보네이트), 폴리(타이로신 카보네이트), 폴리카보네이트, 폴리(타이로신 아릴레이트), 폴리알킬렌 옥살레이트, 폴리포스파젠스, PHA-PEG, 에틸렌 비닐 알코올 코폴리머(EVOH), 폴리우레탄, 실리콘, 폴리에스테르, 폴리올레핀, 폴리이소부틸렌과 에틸렌-알파올레핀 공중합체, 스틸렌-이소브틸렌-스틸렌 트리블록 공중합체, 아크릴 중합체 및 공중합체, 비닐 할라이드 중합체 및 공중합체, 폴리비닐 클로라이드, 폴리비닐 에테르, 폴리비닐 메틸 에테르, 폴리비닐리덴 할라이드, 폴리비닐리덴 플루오라이드, 폴리비닐리덴 클로라이드, 폴리플루오로알켄, 폴리퍼플루오로알켄, 폴리아크릴로니트릴, 폴리비닐 케톤, 폴리비닐 아로마틱스, 폴리스틸렌, 폴리비닐 에스테르, 폴리비닐 아세테이트, 에틸렌-메틸 메타크릴레이트 공중합체, 아크릴로니트릴-스틸렌 공중합체, ABS 수지와 에틸렌-비닐 아세테이트 공중합체, 폴리아마이드, 알키드 수지, 폴리옥시메틸렌, 폴리이미드, 폴리에테르, 폴리아크릴레이트, 폴리메타크릴레이트, 폴리아크릴산-co-말레산, 키토산, 덱스트란, 셀룰로오스, 헤파린, 알기네이트, 이눌린, 녹말 또는 글리코겐을 사용할 수 있고, 히알루론산, 폴리에스테르, 폴리하이드록시알카노에이트(PHAs), 폴리(α-하이드록시액시드), 폴리(β-하이드록시액시드), 폴리(3-하이드로식부티레이트-co-발러레이트; PHBV), 폴리(3-하이드록시프로프리오네이트; PHP), 폴리(3-하이드록시헥사노에이트; PHH), 폴리(4-하이드록시액시드), 폴리(4-하이드록시부티레이트), 폴리(4-하이드록시발러레이트), 폴리(4-하이드록시헥사노에이트), 폴리(에스테르아마이드), 폴리카프로락톤, 폴리락타이드, 폴리글리코라이드, 폴리(락타이드-co-글리코라이드; PLGA), 폴리디옥사논, 폴리오르토에스테르, 폴리에테르에스테르, 폴리언하이드라이드, 폴리(글리콜산-co-트리메틸렌 카보네이트), 폴리포스포에스테르, 폴리포스포에스테르우레탄, 폴리(아미노산), 폴리사이아노아크릴레이트, 폴리(트리메틸렌 카보네이트), 폴리(이미노카보네이트), 폴리(타이로신 카보네이트), 폴리카보네이트, 폴리(타이로신 아릴레이트), 폴리알킬렌 옥살레이트, 폴리포스파젠스, PHA-PEG, 키토산, 덱스트란, 셀룰로오스, 헤파린, 알기네이트, 이눌린, 녹말 또는 글리코겐을 사용하는 것이 바람직하나, 이에 한정되지 않는다. Specifically, biocompatible or biodegradable materials include hyaluronic acid, 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-hydroxyvalorate), poly (4-hydroxyhexanoate), poly (esteramide), polycaprolactone, polylactide, polyglycolide, poly ( Lactide-co-glycolide; PLGA), polydioxanone, polyorthoester, polyetherester, polyanhydride, poly (glycolic acid-co-trimethylene carbonate), polyphosphoester, polyphosphoester Urethane, Poly (Amino Acid), Polycyanoacrylate , Poly (trimethylene carbonate), poly (iminocarbonate), poly (tyrosine carbonate), polycarbonate, poly (tyrosine arylate), polyalkylene oxalate, polyphosphazene, PHA-PEG, ethylene vinyl alcohol Copolymers (EVOH), polyurethanes, silicones, polyesters, polyolefins, polyisobutylene and ethylene-alphaolefin copolymers, styrene-isobutylene-styrene triblock copolymers, acrylic polymers and copolymers, vinyl halide polymers and Copolymer, polyvinyl chloride, polyvinyl ether, polyvinyl methyl ether, polyvinylidene halide, polyvinylidene fluoride, polyvinylidene chloride, polyfluoroalkene, polyperfluoroalkene, polyacrylonitrile, polyvinyl Ketones, polyvinyl aromatics, polystyrene, polyvinyl esters, polyvinyl acetate, ethylene-methyl meth Relate copolymers, acrylonitrile-styrene copolymers, ABS resins and ethylene-vinyl acetate copolymers, polyamides, alkyd resins, polyoxymethylenes, polyimides, polyethers, polyacrylates, polymethacrylates, polyacrylic acids co-maleic acid, chitosan, dextran, cellulose, heparin, alginate, inulin, starch or glycogen can be used, hyaluronic acid, polyester, polyhydroxyalkanoate (PHAs), poly (α-hydroxy Acid), poly (β-hydroxyacid), poly (3-hydrosuccinate-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, polyglycolide, poly (lactide-co-glycolide; PLGA) , Polydioxanone, polyorthoester, polyether ester, polyanhydride, poly (glycolic acid-co-trimethylene carbonate), polyphosphoester, polyphosphoesterurethane, poly (amino acid), polycyano Acrylate, poly (trimethylene carbonate), poly (iminocarbonate), poly (tyrosine carbonate), polycarbonate, poly (tyrosine arylate), polyalkylene oxalate, polyphosphazene, PHA-PEG, chitosan, Dextran, cellulose , Heparin, alginate, one desirable to use inulin, starch or glycogen, and the like.
선택적으로, 상기 고형물은 별도 약물 또는 별도 첨가제가 미리 첨가될 수 있다. 이와 같이 미리 첨가된 별도 약물은 고형물 내 전체적으로 분포하는 것을 특징으로 하나, 별도 약물 또는 별도 첨가제와, 상기 고형물 전구체 내 고분자 물질 또는 용매 간의 상호작용에 의해 약물 탑재에 한계가 있다. Optionally, the solid may be previously added with a separate drug or separate additive. The separate drug added in advance as described above is characterized in that it is distributed in the solid as a whole, there is a limit in drug loading due to the interaction between the separate drug or separate additives and the polymer or solvent in the solid precursor.
상기 별도 약물로는 공지의 약물이 사용가능하고, 예를 들어, 상기 별도 약물은 화학약물, 단백질 의약, 펩타이드 의약, 유전자 치료용 핵산 분자 및 나노입자 등을 포함한다. 본 발명에 이용될 수 있는 별도 약물은 예를 들어, 항염증제, 진통제, 항관절염제, 진경제, 항우울증제, 항정신병약물, 신경안정제, 항불안제, 마약길항제, 항파킨스질환 약물, 콜린성 아고니스트, 항암제, 항혈관신생억제제, 면역억제제, 항바이러스제, 항생제, 식욕억제제, 진통제, 항콜린제, 항히스타민제, 항편두통제, 호르몬제, 관상혈관, 뇌혈관 또는 말초혈관 확장제, 피임약, 항혈전제, 이뇨제, 항고혈압제, 심혈관질환 치료제, 미용성분(예컨대, 주름개선제, 피부노화 억제제 및 피부미백제) 등을 포함하나, 이에 한정되지 않는다.As the separate drugs, known drugs can be used. For example, the separate drugs include chemical drugs, protein drugs, peptide drugs, nucleic acid molecules for gene therapy, and nanoparticles. Separate drugs that can be used in the present invention are, 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, hormone, coronary, cerebrovascular or peripheral vasodilator, contraceptive, antithrombotic, diuretic, Antihypertensives, cardiovascular disease agents, cosmetic ingredients (eg, anti-wrinkle agents, skin aging inhibitors and skin lightening agents) and the like, but are not limited thereto.
본 발명에서는 별도 약물로서 미용성분, 구체적으로, 미백성분에 해당하는 아스코르브산2-글루코사이드(AA2G)를 사용하였다.In the present invention, ascorbic acid 2-glucoside (AA2G) corresponding to a cosmetic ingredient, specifically, a whitening ingredient, was used as a separate drug.
본 발명에 따른 마이크로구조체의 제조는 비가열 조건(non-heating treatment) 하에서 실시될 수 있으므로, 본 발명에 이용되는 별도 약물이 단백질 의약, 펩타이드 의약, 유전자 치료용 핵산 분자, 비타민(바람직하게는, 비타민 C) 등과 같이 열에 약한 약물이더라도 본 발명에 따르게 되면 상기 별도 약물을 포함하는 마이크로구조체의 제조가 가능하다.Since the preparation of the microstructures according to the present invention can be carried out under non-heating treatment, the separate drug used in the present invention is a protein drug, a peptide drug, a nucleic acid molecule for gene therapy, a vitamin (preferably, Even if the drug is weak to heat, such as vitamin C), according to the present invention, it is possible to prepare a microstructure including the separate drug.
상기 단백질/펩타이드 의약은 호르몬, 호르몬 유사체, 효소, 효소저해제, 신호전달단백질 또는 그 일부분, 항체 또는 그 일부분, 단쇄항체, 결합단백질 또는 그 결합도메인, 항원, 부착단백질, 구조단백질, 조절단백질, 독소단백질, 사이토카인, 전사조절 인자, 혈액 응고 인자 및 백신 등을 포함하나, 이에 한정되지 않는다. 보다 상세하게는, 상기 단백질/펩타이드 의약은 인슐린, IGF-1(insulin-like growth factor 1), 성장호르몬, 에리쓰로포이에틴, G-CSFs (granulocytecolony stimulating factors), GM-CSFs (granulocyte/macrophage-colony stimulating factors), 인터페론 알파, 인터페론 베타, 인터페론 감마, 인터루킨-1 알파 및 베타, 인터루킨-3, 인터루킨-4, 인터루킨-6, 인터루킨-2, EGFs (epidermal growth factors), 칼시토닌(calcitonin), ACTH (adrenocorticotropic hormone), TNF(tumor necrosis factor), 아토비스반(atobisban), 부세레린(buserelin), 세트로렉릭스(cetrorelix), 데스로레린(deslorelin), 데스모프레신(desmopressin), 디노르핀 A (dynorphin A) (1-13), 엘카토닌(elcatonin), 엘레이도신(eleidosin), 엡티피바타이드(eptifibatide), GHRH-II(growth hormone releasing hormone-II), 고나도레린(gonadorelin), 고세레린(goserelin), 히스트레린(histrelin), 류프로레린(leuprorelin), 라이프레신(lypressin), 옥트레오타이드(octreotide), 옥시토신(oxytocin), 피트레신(pitressin), 세크레틴(secretin), 신칼라이드(sincalide), 테르리프레신(terlipressin), 티모펜틴(thymopentin), 티모신(thymosine) α1, 트리프토레린(triptorelin), 바이발리루딘(bivalirudin), 카르베토신(carbetocin), 사이클로스포린, 엑세딘(exedine), 란레오타이드(lanreotide), LHRH (luteinizing hormone-releasing hormone), 나파레린(nafarelin), 부갑상선 호르몬, 프람린타이드(pramlintide), T-20 (enfuvirtide), 타이말파신(thymalfasin) 및 지코노타이드를 포함할 수 있다.The protein / peptide medicament may be a hormone, a hormone analog, an enzyme, an inhibitor, a signaling protein or part thereof, an antibody or part thereof, a short chain antibody, a binding protein or a binding domain thereof, an antigen, an adhesion protein, a structural protein, a regulatory protein, a toxin Proteins, cytokines, transcriptional regulators, blood clotting factors, vaccines, and the like. More specifically, the protein / peptide medicament is insulin, insulin-like growth factor 1 (IGF-1), growth hormone, erythropoietin, granulocytecolony stimulating factors (G-CSFs), GM-CSFs (granulocyte / 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, Dynorphin A (1-13), elcatonin, eleidosin, eptifibatide, growth hormone releasing hormone-II (GHRH-II), gonadorerin ( gonadorelin, goserelin, hystrelin, leuprorelin, life lesin pressin, octreotide, oxytocin, phytosin, pitressin, secretin, sincalide, terlipressin, thymopentin, thymosine ) α1, triptorelin, bivalirudin, carbetocin, cyclosporin, exedine, lanreotide, LHRH (luteinizing hormone-releasing hormone), na And parenin, parathyroid hormone, pramlintide, T-20 (enfuvirtide), thymalfasin and ziconotide.
상기 별도 첨가제는 주로 상기 별도 약물의 효과나 안정성을 높이기 위한 다양한 물질을 의미하는 것으로, 약물의 효능을 증가시키기 위한 공지의 면역 유도제 또는 약물의 안정성을 높이기 위한 트레할로오스(trehalose)와 같은 당류 등이 사용될 수 있다. 그밖에, 에너지 역시 사용될 수 있다. 이 경우 마이크로구조체는 열에너지, 빛에너지, 전기에너지 등과 같은 에너지 형태를 전송 또는 전달하기 위한 용도로 이용될 수 있다.The separate additive mainly refers to a variety of substances to increase the effect or stability of the separate drug, a known immune inducing agent to increase the efficacy of the drug or sugars such as trehalose (trehalose) to increase the stability of the drug And the like can be used. In addition, energy can also be used. In this case, the microstructure may be used for transmitting or transmitting energy forms such as thermal energy, light energy, and electrical energy.
예를 들어, 광역동 치료(photodynamic therapy)에 있어서 마이크로구조체는 광이 직접적으로 조직에 작용할 수 있도록 하거나 또는 광감응성(light-sensitive) 분자와 같은 매개체에 광이 작용하도록, 신체 내의 특정부위에 광을 유도하는 데 이용될 수 있다.For example, in photodynamic therapy, microstructures can be used to direct light to specific areas within the body, such that light can act directly on tissues or light can act on mediators such as light-sensitive molecules. Can be used to derive.
구체적으로, 상기 별도 약물 또는 별도 첨가제는 생체적합성 또는 생분해성 물질 100 중량부 대비, 0.1 중량부 내지 10 중량부인 것이 바람직하나, 이에 한정되지 않는다.Specifically, the separate drug or separate additive is preferably 0.1 parts by weight to 10 parts by weight with respect to 100 parts by weight of the biocompatible or biodegradable material, but is not limited thereto.
도 4는 다양한 방법에 의한 고형물의 제조를 도시한 그림이다.4 is a drawing illustrating the production of solids by various methods.
도 4(a)에 도시한 바와 같이, 상기 고형물은 상기 기판 상에 점성 방울(droplet)의 자연 건조, 몰딩, 분사 및 전기방사를 통해 순차적으로 제조될 수 있고, 도 4(b)에 도시한 바와 같이, 상기 기판 상에 고형 분말의 도포 및 다른 기판 상에 이미 형성된 고형분으로부터 이동을 통해 순차적으로 제조될 수 있다. As shown in FIG. 4 (a), the solids can be produced sequentially through natural drying, molding, spraying and electrospinning of viscous droplets on the substrate, as shown in FIG. 4 (b). As such, it can be made sequentially through application of solid powder on the substrate and transfer from solids already formed on another substrate.
또한, 도 4(c)에 나타난 바와 같이, 상기 고형물은 별도 약물 또는 첨가제가 미리 첨가되지 않을 수도 있고, 상기 고형물 전구체에 별도 약물을 첨가함으로써 상기 고형물에 별도 약물이 미리 첨가될 수도 있으며, 상기 고형물 전구체에 별도 첨가제를 미리 첨가함으로써 상기 고형물에 별도 첨가제가 미리 첨가될 수도 있다. In addition, as shown in Figure 4 (c), the solid may not be added to a separate drug or additive in advance, a separate drug may be added to the solid in advance by adding a separate drug to the solid precursor, the solid A separate additive may be added to the solid in advance by adding a separate additive to the precursor in advance.
도 5는 다양한 형상의 고형물을 도시한 그림이다.5 is a diagram illustrating solids of various shapes.
도 5에 도시한 바와 같이, 상기 고형물은 앞서 언급한 다양한 방법에 의해 제조되어 다양한 형상을 가질 수 있고, 이와 같은 다양한 형상을 가지는 고형물로부터 다양한 형상을 가지는 마이크로구조체를 최종 제조할 수 있어, 약물 탑재 분포, 약물 전달 정도 등을 조절할 수 있는 이점이 있다.As shown in FIG. 5, the solids may be manufactured by various methods mentioned above, and may have various shapes, and finally, the microstructures having various shapes may be manufactured from solids having various shapes, and thus, drug loading. There is an advantage to control the distribution, degree of drug delivery, and the like.
다음으로, 본 발명에 따른 마이크로구조체의 제조방법은 상기 고형물 상에 용매를 첨가하여 유동화시키는 단계[(b) 단계]를 포함한다.Next, the method for producing a microstructure according to the present invention includes the step of fluidizing by adding a solvent on the solid.
상기 유동화에 사용되는 용매로 공지의 다양한 용매를 사용할 수 있다. 구체적으로, 상기 용매로 물, 탄소수 1 내지 4의 저급 알코올 등과 같은 극성 용매를 사용하거나, 헥산, 아세톤, 클로로포름, 디클로로메탄, 에틸아세테이트 등과 같은 비극성 용매를 사용할 수 있다. As the solvent used for the fluidization, various known solvents can be used. Specifically, a polar solvent such as water, a lower alcohol having 1 to 4 carbon atoms, or the like may be used as the solvent, or a nonpolar solvent such as hexane, acetone, chloroform, dichloromethane, ethyl acetate, or the like may be used.
상기 용매의 첨가는 당업계 공지된 방법으로 수행될 수 있고, 접촉, 토출, 분사, 증착 및 담금으로 이루어진 군으로부터 선택된 하나 이상의 방법으로 수행되는 것이 바람직하나, 이에 한정되지 않는다. 이때, 상기 용매의 첨가가 접촉에 의한 방법으로 수행되는 경우, 상기 기판 상에 다수의 고형물이 제조된 경우라면, 용매가 전체적으로 또는 부분적으로 도포된 별도 기판을 이용하여, 다수의 고형물을 유동화시킬 수 있다. 한편, 상기 기판 상에 일체의 고형물이 제조된 경우라면, 용매가 부분적으로 도포된 별도 기판을 이용하거나, 용매가 도포된 다수의 필라를 가지는 별도 기판을 이용하여, 일체의 고형물을 부분적으로 유동화시킬 수 있다.The addition of the solvent may be carried out by a method known in the art, and is preferably performed by one or more methods selected from the group consisting of contacting, discharging, spraying, depositing and immersion, but are not limited thereto. At this time, when the addition of the solvent is carried out by a contact method, if a plurality of solids are produced on the substrate, a plurality of solids can be fluidized by using a separate substrate in which the solvent is applied in whole or in part have. On the other hand, if an integral solid is produced on the substrate, it is possible to partially fluidize the integral solid by using a separate substrate partially coated with a solvent or by using a separate substrate having a plurality of pillars coated with a solvent. Can be.
도 6은 고형물 상에 다양한 방법에 의한 용매의 첨가 및 유동화를 도시한 그림이다.6 is a diagram illustrating the addition and fluidization of solvents on various solids by various methods.
도 6에 도시한 바와 같이, 용매의 첨가는 토출-접촉, 제트 노즐에 의한 토출, 제트 노즐에 의한 분사, 증착의 방법을 통해 수행될 수 있다. As shown in FIG. 6, the addition of the solvent may be performed through a method of discharge-contacting, ejection by a jet nozzle, spraying by a jet nozzle, and deposition.
도 7은 고형물 상에 별도 기판을 이용한 용매의 첨가 및 유동화를 도시한 그림이다.7 is a diagram illustrating the addition and fluidization of a solvent using a separate substrate on a solid.
도 7에 도시한 바와 같이, 용매의 첨가는 용매가 도포된 별도 기판, 용매가 도포된 다수의 필라를 가지는 별도 기판을 이용하여 수행될 수 있다. As shown in FIG. 7, the addition of the solvent may be performed using a separate substrate having a solvent applied thereon and a separate substrate having a plurality of pillars having a solvent applied thereon.
또한, 상기 고형물의 유동화 정도는 용매의 종류, 용매와 고형물의 친화도, 용매의 양 또는 유동화 조건에 따라 조절될 수 있다.In addition, the degree of fluidization of the solid may be controlled according to the type of solvent, the affinity of the solvent and the solid, the amount of the solvent or the fluidization conditions.
본 명세서 내 유동화 정도는 고형물 내 용매 함량을 의미하는 것으로, 고형물 내 고형분 함량을 감소시키고 용매 함량이 증가시킬수록 유동화 정도가 크다고 볼 수 있다.The degree of fluidization in the present specification means the solvent content in the solids, and the degree of fluidization is increased as the solids content in the solids decreases and the solvent content increases.
구체적으로, 용매와 고형물의 친화도가 높은 경우에는 다른 조건을 동일하게 유지하더라도 용매가 고형물에 비교적 깊게 침투할 수 있어 유동화 정도가 커지는 반면, 용매와 고형물의 친화도가 낮은 경우에는 다른 조건을 동일하게 유지하더라도 용매가 고형물에 비교적 얕게 침투하게 되어 유동화 정도가 작아질 수 있다.Specifically, in the case where the affinity between the solvent and the solid is high, the solvent may penetrate relatively deeply into the solid even if the other conditions are kept the same, while the degree of fluidization increases, whereas when the affinity between the solvent and the solid is low, the other conditions are the same. Even so, the solvent may penetrate relatively shallowly into the solids and the degree of fluidization may be reduced.
예를 들어, 용매로 극성 용매가 사용된 경우에는 친수성 고분자를 포함하는 고형물에는 용이하게 침투하여 유동화 정도가 커지게 되나, 소수성 고분자를 포함하는 고형물에는 용이하게 침투하지 못하여 유동화 정도가 작아진다. 반면, 용매로 비극성 용매가 사용된 경우에는 위 경우와 반대되는 경향을 보인다. For example, when a polar solvent is used as the solvent, the fluid easily penetrates into the solid containing the hydrophilic polymer to increase the degree of fluidization, but the fluid does not easily penetrate into the solid including the hydrophobic polymer, thereby decreasing the degree of fluidization. On the other hand, when a nonpolar solvent is used as the solvent, it tends to be the opposite.
이때, 극성 용매 또는 비극성 용매의 유전율 크기에 따라 유동화 정도를 세부적으로 조절할 수 있다. In this case, the degree of fluidization may be adjusted in detail according to the dielectric constant of the polar solvent or the nonpolar solvent.
즉, 용매와 고형물의 친화도가 높을수록 용매가 고형물에 깊게 침투할 수 있어 유동화 정도가 커지게 되는바, 종횡비(aspect ratio)가 큰 마이크로구조체를 최종 제조할 수 있다. 반면, 용매와 고형물의 친화도가 낮을수록 용매가 고형물에 얕게 침투할 수 있어 유동화 정도가 작아지게 되는바, 종횡비(aspect ratio)가 작은 마이크로구조체를 최종 제조할 수 있다.That is, the higher the affinity between the solvent and the solid, the deeper the solvent can penetrate into the solid, and the greater the degree of fluidization. Thus, a microstructure having a high aspect ratio can be finally manufactured. On the other hand, the lower the affinity between the solvent and the solid, the more the solvent penetrates into the solid, and thus the degree of fluidization becomes smaller. Thus, a microstructure having a small aspect ratio can be finally manufactured.
또한, 용매의 양이 많아질수록 용매가 고형물에 깊게 침투할 수 있어 유동화 정도가 커지게 되는바, 종횡비(aspect ratio)가 큰 마이크로구조체를 제조할 수 있다. 반면, 용매의 양이 적어질수록 용매가 고형물에 얕게 침투할 수 있어 유동화 정도가 작아지게 되는바, 종횡비(aspect ratio)가 작은 마이크로구조체를 제조할 수 있다.In addition, as the amount of the solvent increases, the solvent can penetrate deeply into the solid material, and thus the degree of fluidization increases. Accordingly, a microstructure having a large aspect ratio can be manufactured. On the other hand, as the amount of the solvent decreases, the solvent may penetrate shallowly into the solid material, thereby reducing the degree of fluidization, and thus, a microstructure having a small aspect ratio may be manufactured.
구체적으로, 상기 (b) 단계에서 고형물 100 중량부 대비, 용매는 10 부피부 내지 200 부피부로, 바람직하게, 30 부피부 내지 200 부피부로 첨가됨으로써, 적절한 유동화 정도를 조절하여, 적절한 종횡비(aspect ratio)를 가지는 마이크로구조체를 제조할 수 있다.Specifically, compared to 100 parts by weight of the solids in the step (b), the solvent is added to 10 parts by volume to 200 parts by volume, preferably 30 parts by volume to 200 parts by volume, by adjusting the degree of fluidization, the appropriate aspect ratio ( Microstructures having aspect ratios can be prepared.
그밖에, 용매의 첨가 후, 유동화 온도, 유동화 습도, 유동화 시간 등 유동화 조건을 조절함으로써 유동화 정도를 조절할 수 있다.In addition, after the addition of the solvent, the degree of fluidization can be controlled by adjusting fluidization conditions such as fluidization temperature, fluidization humidity, fluidization time and the like.
도 8은 (a) 용매와 고형물의 친화도, (b)용매의 양 및 (c) 유동화 시간에 따라 조절되는 유동화 정도를 보여주는 그림이다.Figure 8 shows the degree of fluidization controlled by (a) affinity of the solvent and solids, (b) amount of solvent and (c) fluidization time.
도 8(a)에 나타난 바와 같이, 용매와 고형물의 친화도가 높은 경우(첫번째 그림)에는 유동화 정도가 비교적 크고, 용매와 고형 고성물의 친화도가 낮은 경우(두번째 그림)에는 유동화 정도가 비교적 작다. As shown in Fig. 8 (a), the degree of fluidization is relatively high when the affinity of the solvent and the solid is high (first picture), and the degree of fluidization is relatively low when the affinity of the solvent and solid solid is low (second picture). .
도 8(b)에 나타난 바와 같이, 용매의 양이 많아질수록, 유동화 정도가 커지고, 도 8(c)에 나타난 바와 같이, 유동화 시간이 길어질수록, 유동화 정도가 커진다. As shown in Fig. 8 (b), the greater the amount of solvent, the greater the degree of fluidization, and as shown in Fig. 8 (c), the longer the fluidization time, the greater the degree of fluidization.
상기 기판의 수직 방향을 기준으로 할 때, 상기 고형물의 1/2 지점을 경계로 고형물 상부층 및 고형물 하부층으로 구분하는 경우, 상기 고형물 상부층의 유동화 정도가 고형물 하부층의 유동화 정도에 비해 큰 것을 특징으로 함으로써, 성형을 용이하게 하여 상단부가 뾰죡한 마이크로구조체를 최종 제조함으로써, 마이크로니들로서 적합한 형태를 가질 수 있다.Based on the vertical direction of the substrate, when the solid is divided into a solid upper layer and a solid lower layer on the half point of the solid, characterized in that the degree of fluidization of the solid upper layer compared to the degree of fluidization of the solid lower layer By facilitating the molding, the microstructure having a sharp upper end can be finally manufactured, thereby having a shape suitable as a microneedle.
본 명세서 내 고형물의 1/2 지점이라 함은 기판의 수직 방향을 기준으로, 고형물의 하단부와 맞닿는 기판 표면 최저점으로부터 고형물 상단부의 중간 지점을 말한다.The half point of the solid in the present specification refers to the middle point of the upper end of the solid from the lowest point of the substrate surface that is in contact with the lower end of the solid with respect to the vertical direction of the substrate.
한편, 상기 용매에 생체적합성 또는 생분해성 물질과 같은 고분자 물질을 첨가하여 점성 조성물을 형성함으로써, 마이크로구조체의 종횡비(aspect ratio)를 세부적으로 조절할 수도 있다.On the other hand, by adding a polymer material such as a biocompatible or biodegradable material to the solvent to form a viscous composition, it is also possible to adjust the aspect ratio of the microstructure in detail.
앞서 언급한 바와 같이, 상기 고형물 상에 용매를 첨가할 수도 있으나, 용매에 약물을 추가로 탑재하여 첨가할 수도 있다. 고형물과는 별도로 고형물의 유동화를 위한 용매에 약물을 추가 탑재함으로써, 약물의 정량 탑재 및 다양한 제형의 약물 탑재가 용이하고, 약물 활성 손실 최소화 및 안정성 향상을 가져올 수 있는 이점이 있다.As mentioned above, a solvent may be added on the solid, but may be added by adding a drug to the solvent. By additionally mounting the drug in a solvent for fluidization of the solid apart from the solid, it is easy to quantitatively mount the drug and to mount the drug in various formulations, and has the advantage of minimizing drug activity loss and improving stability.
상기 약물은 앞서 언급한 별도 약물과 동일한 종류를 사용할 수 있고, 종류, 용량, 제형 등에 구애받지 않을 수 있다. 물론, 상기 용매에 첨가제 역시 추가로 탑재가능하다. 본 발명에서는 약물로서 미용성분, 구체적으로, 미백성분에 해당하는 아스코르브산2-글루코사이드(AA2G)를 사용하였다.The drug may be of the same kind as the aforementioned separate drug, and may be irrespective of the kind, dosage, dosage form, and the like. Of course, additives may also be added to the solvent. In the present invention, ascorbic acid 2-glucoside (AA2G) corresponding to a cosmetic ingredient, specifically, a whitening ingredient, was used as a drug.
구체적으로, 상기 약물은 용액[약물(첨가제) 및 용매] 100 부피부 대비, 0.1 중량부 내지 10 중량부인 것이 바람직하나, 이에 한정되지 않는다.Specifically, the drug is preferably 0.1 parts by weight to 10 parts by weight based on 100 parts by weight of a solution [drug (additive) and a solvent], but is not limited thereto.
도 9는 고형물 상에 다양한 방법으로 약물이 탑재된 용매의 첨가 및 유동화를 도시한 그림이다.9 is a diagram illustrating the addition and fluidization of solvents loaded with drugs in various ways on solids.
도 9에 도시한 바와 같이, 고형물 상에 약물이 탑재된 용매의 첨가 및 유동화는 토출 및 자연 건조, 토출 및 동결 건조, 고형물 전방향 증착, 고형물 상단 증착, 고형물 전방향 및 지지체 표면 증착, 고형물 상단 및 지지체 표면 증착을 통해 수행될 수 있다.As shown in Fig. 9, the addition and fluidization of the solvent-loaded solvent on the solids can be achieved by discharging and spontaneous drying, discharging and freeze drying, solids omnidirectional deposition, solids top deposition, solids omnidirectional and support surface deposition, and solids top. And support surface deposition.
도 10은 (a) 약물이 탑재된 용매와 고형물의 용해도 및 (b) 유동화 시간에 따라 조절되는 유동화 정도에 따라 고형물 내 약물의 탑재 분포를 보여주는 그림이다.Figure 10 is a diagram showing the distribution of drug in the solid according to (a) the solubility of the solvent and the solid loaded with the drug and (b) the degree of fluidization controlled by the fluidization time.
도 10(a)에 도시한 바와 같이, 약물이 탑재된 용매와 고형물의 용해도가 높은 경우(첫번째 그림)에는 유동화 정도가 비교적 크고, 약물이 탑재된 용매와 고형물의 용해도가 낮은 경우(두번째 그림)에는 유동화 정도가 비교적 작다. As shown in Fig. 10 (a), when the solubility of the solvent and the solid on which the drug is loaded is high (first picture), the degree of fluidization is relatively high, and the solubility of the solvent and the solid on which the drug is loaded is low (second picture). The degree of fluidization is relatively small.
도 10(b)에 도시한 바와 같이, 유동화 시간이 길어질 수록, 유동화 정도가 커지고, 고형물 내 약물의 탑재 분포가 광범위해진다.As shown in Fig. 10 (b), the longer the fluidization time, the greater the degree of fluidization and the wider the payload distribution of the drug in the solid.
또한, 상기 고형물 상에 약물을 추가로 탑재한 용매를 첨가하고 유동화시켜, 이를 바로 성형할 수도 있으나, 상기 고형물 상에 약물을 추가로 탑재한 용매를 첨가하고 유동화시키고, 상기 유동화된 고형물을 재고형화시킨 후, 상기 고형물 상에 제2 용매를 첨가하여 재유동화시켜, 이를 성형할 수도 있다. 상기와 같이 재고형화 및 재유동화 과정을 추가로 거치는 경우에는 약물의 탑재 분포를 보다 자유롭게 조절가능하다.In addition, by adding and fluidizing a solvent further loaded with the drug on the solid, it may be molded immediately, but by adding and fluidizing the solvent further loaded with the drug on the solid, and re-solidified the fluidized solid After the addition, the second solvent may be added to the solid to reflow to form the mold. As described above, in addition to the inventory and refluidization process, the distribution of the drug can be more freely controlled.
이때, 상기 제2 용매에 생체적합성 또는 생분해성 물질과 같은 고분자 물질을 첨가하여 점성 조성물을 형성함으로써, 약물의 탑재 분포를 마이크로구조체 중간층에 집중 분포시킬 수도 있다.In this case, by adding a polymer material such as a biocompatible or biodegradable material to the second solvent to form a viscous composition, the drug distribution may be concentrated in the microstructure intermediate layer.
상기 제2 용매는 앞서 언급한 용매와 동일하거나, 상이할 수 있다. 상기 제2 용매에 추가 약물 또는 추가 첨가제를 추가로 탑재하는 것 역시 가능하다. The second solvent may be the same as or different from the aforementioned solvent. It is also possible to add additional drugs or additional additives to the second solvent.
도 11은 재유동화 시간에 따라 조절되는 재유동화 정도 및 재고형물 내 약물의 탑재 분포를 보여주는 그림이다.FIG. 11 is a diagram showing the degree of refluidization and the distribution of drug in the stock form adjusted according to the refluidization time.
도 11에 도시한 바와 같이, 재유동화 시간이 길어질수록 제2 용매에 의한 재유동화 정도가 커지게 되고, 재고형물 내 약물의 탑재 분포가 점점 광범위해진다. As shown in FIG. 11, the longer the refluidization time is, the greater the degree of refluidization by the second solvent is, and the loading distribution of the drug in the stock form becomes wider.
도 12은 약물이 탑재된 용매, 고형물 및 제2 용매 사이의 용해도 차이에 따라 조절되는 재유동화 정도 및 재고형물 내 약물의 탑재 분포를 보여주는 그림이다.FIG. 12 is a diagram showing the degree of refluidization and the distribution of drug in stocks, controlled by the difference in solubility between the drug loaded solvent, solids and the second solvent.
도 121에 도시한 바와 같이, 약물이 탑재된 용매와 고형물의 용해도가 높은 경우로서, 약물에 대한 용해도가 높은 제2 용매가 첨가되면(첫번째 그림), 제2 용매에 의해 고형물 내 약물의 탑재 분포가 광범위해진다. 또한, 약물이 탑재된 용매와 고형물의 용해도가 낮은 경우로서, 약물에 대한 용해도가 낮은 제2 용매가 첨가되면(두번째 그림), 재고형물 내 약물의 탑재 분포가 비교적 좁아진다.As shown in FIG. 121, when the solubility of the drug and the solid loaded with the drug is high, when a second solvent having high solubility in the drug is added (first picture), the distribution of the drug in the solid by the second solvent is added. Becomes wider. In addition, when the solubility of the drug and the solid on which the drug is loaded is added, when the second solvent having a low solubility in the drug is added (second picture), the distribution of the drug in the stock is relatively narrow.
또한, 약물이 탑재된 용매와 고형물의 용해도가 낮은 경우로서, 고분자 물질이 첨가된 제2 용매가 첨가되면(세번째 그림), 재고형물 내 약물 탑재 분포층 상에 고분자 물질층을 형성하게 되어, 약물 탑재 분포는 최종 제조되는 마이크로구조체 중간층에 위치하게 된다. In addition, when the drug-loaded solvent and the solubility of the solids are low, when the second solvent with the polymer material is added (third picture), a polymer material layer is formed on the drug loading distribution layer in the inventory. The payload distribution is located in the microstructured intermediate layer that is finally manufactured.
마지막으로, 본 발명에 따른 마이크로구조체의 제조방법은 상기 유동화된 고형물을 성형하는 단계[(c) 단계]를 포함할 수 있다.Finally, the method for producing a microstructure according to the present invention may include the step of forming the fluidized solids (step (c)).
상기 (c) 단계에서 성형은 몰딩 방법으로 수행될 수도 있고, 유동화된 고형물에 외향력을 인가함으로써 드로잉, 송풍, 흡입, 원심력 인가 및 자기장 인가로 이루어진 군으로부터 선택된 하나 이상의 방법으로 수행될 수 있다. 이때, 상기 성형은 경화가 동시에 일어나도록 수행될 수 있다.In the step (c), the molding may be performed by a molding method, or may be performed by one or more methods selected from the group consisting of drawing, blowing, suction, centrifugal force application, and magnetic field application by applying an outward force to the fluidized solid material. At this time, the molding may be performed so that curing occurs at the same time.
상기 성형되는 마이크로구조체의 종횡비(aspect ratio)는 유동화 정도에 따라 조절될 수 있다. The aspect ratio of the molded microstructure may be adjusted according to the degree of fluidization.
본 명세서 내 마이크로구조체의 종횡비(aspect ratio)는 상기 기판의 수평 방향으로 마이크로구조체를 절단하는 경우 최대 직경에 대한 상기 기판의 수직 방향으로 고형물의 하단부와 맞닿는 기판 표면 최저점으로부터 마이크로구조체의 상단부까지의 마이크로구조체의 높이의 비를 말한다. The aspect ratio of the microstructures in this specification is the micro-to-top of the microstructure from the lowest point of the substrate surface that abuts the bottom of the solid in the vertical direction of the substrate to the maximum diameter when cutting the microstructure in the horizontal direction of the substrate. The ratio of the height of the structure.
즉, 상기 마이크로구조체의 종횡비(aspect ratio)는 마이크로구조체의 최대 직경 대 높이의 비를 의미하는 것으로, 유동화 정도가 클수록 성형시 수축률이 증가하게 되므로, 상기 마이크로구조체의 종횡비(aspect ratio)는 커지는 경향을 보인다. That is, the aspect ratio of the microstructure refers to the ratio of the maximum diameter to the height of the microstructure. As the degree of fluidization increases, the shrinkage rate increases during molding, so that the aspect ratio of the microstructure tends to increase. Seems.
한편, 상기 고형물 상에 약물이 탑재된 용매를 첨가하여 유동화 또는 재유동화시킨 경우, 상기 성형되는 마이크로 구조체 내 약물의 탑재 분포는 유동화 또는 재유동화 정도에 따라 조절될 수 있다.On the other hand, when fluidized or refluidized by adding a solvent loaded with the drug on the solid, the payload distribution of the drug in the molded microstructure can be adjusted according to the degree of fluidization or refluidization.
도 13은 (a) 유동화 정도에 따라 조절되는 마이크로구조체의 종횡비(aspect ratio) 및 (b) 재유동화 정도에 따라 조절되는 약물의 탑재 분포를 보여주는 그림이다.FIG. 13 shows (a) aspect ratio of microstructures controlled by degree of fluidization and (b) payload distribution of drugs controlled by degree of refluidization.
도 13(a)에서 보듯이, 유동화 정도가 커질수록 성형시 수축률이 증가하게 되므로, 상기 마이크로구조체의 종횡비(aspect ratio)는 커지는 경향을 보인다. 또한, 도 13(b)에서 보듯이, 도 11의 첫번째 그림 또는 두번째 그림과 같이 재유동화 정도가 작은 경우에는 마이크로구조체 하부층에는 약물을 분포시키지 않고, 약물을 마이크로구조체 상부층에 집중 분포시킬 수 있는 반면, 도 11의 세번째 그림과 같이 재유동화 정도가 큰 경우에는 약물을 마이크로구조체 전체적으로 분포시킬 수 있다.As shown in FIG. 13 (a), as the degree of fluidization increases, the shrinkage ratio during molding increases, so the aspect ratio of the microstructure tends to increase. In addition, as shown in FIG. 13 (b), when the degree of refluidization is small as shown in the first or second picture of FIG. 11, the drug may be concentrated in the microstructure upper layer without distributing the drug in the microstructure lower layer. As shown in the third figure of FIG. 11, when the degree of refluidization is large, the drug may be distributed throughout the microstructure.
즉, 고형물의 유동화 정도에 따라 마이크로구조체의 종횡비(aspect ratio)를 조절할 수 있고, 재고형물의 재유동화 정도에 따라 마이크로구조체 내 약물의 탑재 분포를 조절할 수 있다.That is, the aspect ratio of the microstructure may be adjusted according to the degree of fluidization of the solid, and the payload distribution of the drug in the microstructure may be adjusted according to the degree of refluidization of the inventory.
또한, 본 발명은 상기 방법에 따라 제조된 마이크로구조체를 제공한다.The present invention also provides a microstructure manufactured according to the above method.
또한, 본 발명은 기판 상에 형성되고, 약물이 탑재된 마이크로구조체에 있어서, 상기 마이크로구조체 내 약물 탑재 분포는 점진적 농도 구배를 형성하는 것인 마이크로구조체를 제공한다.In addition, the present invention provides a microstructure formed on a substrate and drug-mounted microstructure, wherein the drug loading distribution in the microstructure forms a gradual concentration gradient.
상기와 같은 마이크로구조체 내 약물 탑재 분포는 유동화 정도로 인하여 점진적 농도 구배를 형성할 수 있다.The drug loading distribution in such a microstructure can form a gradual concentration gradient due to the degree of fluidization.
상기 기판의 수직 방향을 기준으로 할 때, 상기 마이크로구조체의 1/2 지점을 경계로 마이크로구조체 상부층 및 마이크로구조체 하부층으로 구분하는 경우, 마이크로구조체 상부층 내 약물 탑재 분포 정도가 마이크로구조체 하부층 내 약물 탑재 분포 정도에 비해 큰 것을 특징으로 할 수 있다.Based on the vertical direction of the substrate, when the half point of the microstructure is divided into the microstructure upper layer and the microstructure lower layer, the drug loading distribution in the microstructure upper layer is the drug loading distribution in the microstructure lower layer. It may be characterized by a large relative to the degree.
이러한 마이크로구조체는 약물 탑재된 용매 첨가, 유동화한 후에 성형을 바로 진행하거나, 약물 탑재된 용매 첨가, 유동화, 재고형화, 및 재유동화한 후에 성형을 진행함으로써 제조될 수 있는 것이고, 이와 같이 제조된 마이크로구조체는 약물을 마이크로구조체 상부층에 집중 분포시킴으로써, 약물을 피부 깊숙히 효과적으로 침투시킬 수 있는 이점이 있다.Such microstructures can be prepared by directly molding after drug-loaded solvent addition, fluidization, or by molding after drug-loaded solvent addition, fluidization, stocking, and refluidization, The structure has the advantage that the drug can be effectively penetrated deep into the skin by distributing the drug in the microstructure upper layer.
또한, 상기 기판의 수직 방향을 기준으로 할 때, 상기 마이크로구조체의 1/3 및 2/3 지점을 경계로 마이크로구조체 상부층, 마이크로구조체 중간층, 마이크로구조체 하부층으로 구분하는 경우, 마이크로구조체 중간층 내 약물 탑재 분포 정도가 마이크로구조체 상부층 및 마이크로구조체 하부층 내 약물 탑재 분포 정도에 비해 큰 것을 특징으로 할 수 있다.In addition, when the substrate is divided into a microstructure upper layer, a microstructure intermediate layer, and a microstructure underlayer based on the 1/3 and 2/3 points of the microstructure based on the vertical direction of the substrate, the drug is loaded in the microstructure intermediate layer. The degree of distribution may be greater than the degree of drug loading in the microstructure upper layer and the microstructure lower layer.
이러한 마이크로구조체는 약물 탑재된 용매 첨가, 유동화, 재고형화, 및 고분자 물질을 포함하는 제2용매로 재유동화한 후에 성형을 진행함으로써 제조될 수 있는 것이고, 이와 같이 제조된 마이크로구조체는 약물을 마이크로구조체 중간층에 집중 분포시킴으로써, 약물을 피부 적절한 위치에 효과적으로 침투시킬 수 있는 이점이 있다.Such microstructures can be prepared by addition of drug-loaded solvents, fluidization, re-shaping, and re-fluidization with a second solvent comprising a polymeric material followed by shaping, and the microstructures thus prepared can be used to convert drugs into microstructures. By concentrated distribution in the middle layer, there is an advantage that can effectively penetrate the drug into the skin proper position.
본 발명에 따른 마이크로구조체는 마이크로니들 외에, 마이크로블레이드, 마이크로나이프, 마이크로파이버, 마이크로스파이크, 마이크로프로브, 마이크로발브(microbarb), 마이크로어레이 또는 마이크로전극 등으로 사용 가능하다.The microstructure according to the present invention can be used as microblades, microblades, microknifes, microfibers, microspikes, microprobes, microbarbs, microarrays or microelectrodes.
따라서, 본 발명에 따른 고형물의 유동화를 이용한 마이크로구조체의 제조방법은 종래 고점성 조성물의 점도 조절의 어려움을 해결할 수 있고, 마이크로구조체의 생산성, 균일성 및 품질을 확보하면서, 대량 생산을 용이하게 할 수 있으며, 마이크로구조체의 종횡비(aspect ratio)를 다양하게 조절할 수 있다. Therefore, the manufacturing method of the microstructure using the fluidization of the solid according to the present invention can solve the difficulty of adjusting the viscosity of the conventional high viscosity composition, while ensuring the productivity, uniformity and quality of the microstructure, and facilitate mass production In addition, the aspect ratio of the microstructures may be adjusted in various ways.
또한, 고형물과는 별도로 고형물의 유동화를 위한 용매에 약물을 추가 탑재함으로써, 약물의 정량 탑재 및 다양한 제형의 약물 탑재가 용이하고, 약물 활성 손실 최소화 및 안정성 향상을 가져올 수 있으며, 약물을 마이크로구조체 상부층에 집중 분포시킬 수도 있어, 약물을 피부 깊숙히 효과적으로 침투시킬 수 있는 이점이 있다.In addition, by additionally mounting the drug in a solvent for fluidization of the solid separately from the solid, it is easy to quantitatively mount the drug and to mount the drug in a variety of formulations, it is possible to minimize the loss of drug activity and to improve the stability, the drug is a microstructure upper layer It can also be concentrated in the distribution, so that the drug can effectively penetrate deep into the skin.
이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예를 제시한다. 그러나 하기의 실시예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐, 하기 실시예에 의해 본 발명의 내용이 한정되는 것은 아니다.Hereinafter, preferred examples are provided to aid in understanding the present invention. However, the following examples are merely provided to more easily understand the present invention, and the contents of the present invention are not limited by the following examples.
[[ 실시예Example ]]
실시예Example 1 One
스테인레스 스틸 기판 상에 디스펜서(Musashi, ML-5000X-mini)를 통해 200kPa의 압력을 0.110초 인가하여 히알루론산(29kDa) 55(w/v)% 및 붉은 색소로서, 로다민 B(Rhodamine B) 0.1(w/v)%를 포함하는 용액을 토출한 후, 이를 자연건조시켜 대부분의 수분이 증발된 상태의 고형물(고형분 함량 = 98%)을 제조하였다. 제조된 고형물 50㎍ 상에 증류수 60㎕를 제트 노즐로 토출한 후, 23℃ 및 50% 습도 조건에서 30초 동안 유동화시켰다. 이후, 유동화된 고형물을 성형하기 위해, 기판을 원심분리기(Combi-514R)에 장착하고, 원심분리기를 11.6 g/sec로 가속한 후, 900g의 중력가속도에서 3분 동안 운행하였다. 그런 다음, 원심분리기를 14.3 g/sec의 속도로 감속하여 마이크로구조체를 최종 제조하였다. 이때, 성형 과정에서 경화가 동시에 일어났다.Hyaluronic acid (29 kDa) 55% (w / v)% and red pigment, Rhodamine B 0.1, by applying a pressure of 200 kPa 0.110 seconds through a dispenser (Musashi, ML-5000X-mini) on a stainless steel substrate After discharging the solution containing (w / v)%, it was naturally dried to prepare a solid (solid content = 98%) in which most of the water was evaporated. 60 μl of distilled water was discharged through a jet nozzle onto 50 μg of the prepared solid, followed by fluidization at 23 ° C. and 50% humidity for 30 seconds. Subsequently, in order to mold the fluidized solid, the substrate was mounted in a centrifuge (Combi-514R), the centrifuge was accelerated to 11.6 g / sec, and then operated at 900 g of gravity acceleration for 3 minutes. Then, the centrifuge was decelerated at a speed of 14.3 g / sec to finally prepare the microstructure. At this time, curing occurred simultaneously in the molding process.
도 14는 실시예 1에서 (a) 고형물 및 (b) 마이크로구조체를 각각 보여주는 광학 현미경 사진이다.14 is an optical micrograph showing the (a) solids and (b) microstructures in Example 1, respectively.
도 14에 나타난 바와 같이, 광학 현미경(SC-150, Samwon, Korea)을 통해 (a) 고형물 및 (b) 마이크로구조체를 각각 관찰한 결과, 고형물을 유동화시킨 후, 성형하여 마이크로구조체를 성공적으로 제조할 수 있음을 확인할 수 있었다.As shown in FIG. 14, (a) solids and (b) microstructures were observed through an optical microscope (SC-150, Samwon, Korea), respectively. As a result, the solids were fluidized and then molded to successfully manufacture the microstructures. It could be confirmed.
실시예Example 2 2
알루미늄 기판 상에 디스펜서(Musashi, ML-5000X-mini)를 통해 200kPa의 압력을 0.110초 인가하여 히알루론산(30kDa) 60(w/v)% 및 붉은 색소로서, 로다민 B(Rhodamine B) 0.1(w/v)%를 포함하는 용액을 토출한 후, 이를 자연건조시켜 대부분의 수분이 증발된 상태의 고형물(고형분 함량 = 99.9%)을 제조하였다. 제조된 고형물 50㎍ 상에 증류수 10㎕, 15㎕ 및 20㎕을 제트 노즐로 각각 토출한 후, 23℃ 및 50% 습도 조건에서 30초 동안 유동화시켰다. 이후, 유동화된 고형물을 성형하기 위해, 기판을 원심분리기(Combi-514R)에 장착하고, 원심분리기를 2700rpm으로 1분 동안 회전시켜 마이크로구조체를 최종 제조하였다. 이때, 성형 과정에서 경화가 동시에 일어났다.Applying a pressure of 200 kPa for 0.110 seconds through a dispenser (Musashi, ML-5000X-mini) on an aluminum substrate, 60 (w / v)% of hyaluronic acid (30kDa) and red pigment, Rhodamine B 0.1 ( After discharging the solution containing w / v)%, it was naturally dried to prepare a solid (solid content = 99.9%) of the evaporated state of most moisture. 10 μl, 15 μl, and 20 μl of distilled water were respectively discharged onto the 50 μg of the prepared solid with a jet nozzle, followed by fluidization at 23 ° C. and 50% humidity for 30 seconds. Then, to form the fluidized solid, the substrate was mounted in a centrifuge (Combi-514R), and the centrifuge was rotated at 2700 rpm for 1 minute to finally prepare the microstructure. At this time, curing occurred simultaneously in the molding process.
도 15는 실시예 2에서 용매의 양[(a) 10㎕, (b) 15㎕ 및 (c) 20㎕]에 따른 마이크로구조체를 각각 보여주는 광학 현미경 사진이다. FIG. 15 is an optical micrograph showing the microstructures according to the amount of solvent in Example 2 ((a) 10 µl, (b) 15 µl and (c) 20 µl, respectively).
도 15에 나타난 바와 같이, 용매의 양이 많아질수록 용매가 고형물에 깊게 침투할 수 있어 유동화 정도가 커지게 되는바, 종횡비(aspect ratio)가 큰 마이크로구조체를 제조할 수 있는 반면, 용매의 양이 적어질수록 용매가 고형물에 얕게 침투할 수 있어 유동화 정도가 작아지게 되는바, 종횡비(aspect ratio)가 작은 마이크로구조체를 제조할 수 있음을 확인할 수 있었다. 따라서, 용매는 고형물 100 중량부 대비, 10 부피부 내지 40 부피부, 바람직하게, 15 부피부 내지 40 부피부로 첨가됨으로써, 적절한 유동화 정도를 조절할 수 있다고 본다.As shown in FIG. 15, as the amount of the solvent increases, the solvent can penetrate deeply into the solids, and thus the degree of fluidization increases, so that the microstructure having a large aspect ratio can be prepared, while the amount of solvent As the amount decreased, the solvent was able to penetrate shallowly into the solid material, and thus the degree of fluidization was reduced. Therefore, it was confirmed that the microstructure having a small aspect ratio could be manufactured. Therefore, it is believed that the solvent can be adjusted to an appropriate degree of fluidization by adding 10 to 40 parts by volume, preferably 15 to 40 parts by volume, based on 100 parts by weight of the solids.
실시예Example 3 3
알루미늄 기판 상에 디스펜서(Musashi, ML-5000X-mini)를 통해 200kPa의 압력을 0.110초 인가하여 미백성분으로서, 아스코르브산2-글루코사이드(AA2G) 2(w/v)%, 히알루론산(30kDa) 60(w/v)% 및 붉은 색소로서, 로다민 B(Rhodamine B) 0.1(w/v)%를 포함하는 용액을 토출한 후, 이를 자연건조시켜 대부분의 수분이 증발된 상태의 고형물(고형분 함량 = 99.9%)을 제조하였다. 제조된 고형물 50㎍ 상에 증류수 20㎕을 제트 노즐로 토출한 후, 23℃ 및 50% 습도 조건에서 30초 동안 유동화시켰다. 이후, 유동화된 고형물을 성형하기 위해, 기판을 원심분리기(Combi-514R)에 장착하고, 원심분리기를 2700rpm으로 1분 동안 회전시켜 마이크로구조체를 최종 제조하였다. 이때, 성형 과정에서 경화가 동시에 일어났다.Ascorbic acid 2-glucoside (AA2G) 2 (w / v)%, hyaluronic acid (30kDa) 60 as a whitening component by applying a pressure of 200 kPa for 0.110 seconds through a dispenser (Musashi, ML-5000X-mini) on an aluminum substrate. (w / v)% and a red pigment, a solution containing Rhodamine B (0.1% (w / v)%) was discharged, and then naturally dried to obtain a solid (solid content) in which most of the water was evaporated. = 99.9%). 20 μl of distilled water was discharged through a jet nozzle onto 50 μg of the prepared solid, followed by fluidization at 23 ° C. and 50% humidity for 30 seconds. Then, to form the fluidized solid, the substrate was mounted in a centrifuge (Combi-514R), and the centrifuge was rotated at 2700 rpm for 1 minute to finally prepare the microstructure. At this time, curing occurred simultaneously in the molding process.
도 16(a)는 실시예 3에서 마이크로구조체를 보여주는 광학 현미경 사진으로, 별도 약물이 미리 첨가된 고형물을 유동화시킨 후, 성형하여 마이크로구조체를 성공적으로 제조할 수 있음을 확인할 수 있었다.Figure 16 (a) is an optical micrograph showing the microstructure in Example 3, it was confirmed that the microstructure can be successfully prepared by fluidizing and then molding the solid to which the additional drug is added in advance.
실시예Example 4 4
알루미늄 기판 상에 디스펜서(Musashi, ML-5000X-mini)를 통해 200kPa의 압력을 0.110초 인가하여 히알루론산(30kDa) 60(w/v)% 및 붉은 색소로서, 로다민 B(Rhodamine B) 0.1(w/v)%를 포함하는 용액을 토출한 후, 이를 자연건조시켜 대부분의 수분이 증발된 상태의 고형물(고형분 함량 = 99.9%)을 제조하였다. 제조된 고형물 50㎍ 상에 미백성분으로서, 아스코르브산2-글루코사이드(AA2G) 2(w/v)% 및 증류수를 포함하는 용액 20㎕을 제트 노즐로 토출한 후, 23℃ 및 50% 습도 조건에서 30초 동안 유동화시켰다. 이후, 유동화된 고형물을 성형하기 위해, 기판을 원심분리기(Combi-514R)에 장착하고, 원심분리기를 2700rpm으로 1분 동안 회전시켜 마이크로구조체를 최종 제조하였다. 이때, 성형 과정에서 경화가 동시에 일어났다.Applying a pressure of 200 kPa for 0.110 seconds through a dispenser (Musashi, ML-5000X-mini) on an aluminum substrate, 60 (w / v)% of hyaluronic acid (30kDa) and red pigment, Rhodamine B 0.1 ( After discharging the solution containing w / v)%, it was naturally dried to prepare a solid (solid content = 99.9%) of the evaporated state of most moisture. After discharging 20 µl of a solution containing 2 (w / v)% ascorbic acid 2-glucoside (AA2G) and distilled water as a whitening ingredient on 50 µg of the prepared solid material, a jet nozzle was used. Fluidized for 30 seconds. Then, to form the fluidized solid, the substrate was mounted in a centrifuge (Combi-514R), and the centrifuge was rotated at 2700 rpm for 1 minute to finally prepare the microstructure. At this time, curing occurred simultaneously in the molding process.
도 16(b)는 실시예 4에서 마이크로구조체를 보여주는 광학 현미경 사진으로, 고형물을 약물이 추가로 탑재된 용매로 유동화시킨 후, 성형하여 마이크로구조체를 성공적으로 제조할 수 있음을 확인할 수 있었다.Figure 16 (b) is an optical micrograph showing the microstructure in Example 4, it was confirmed that the microstructure can be successfully prepared by fluidizing the solid with a solvent in which the drug is additionally loaded.
전술한 본 발명의 설명은 예시를 위한 것이며, 본 발명이 속하는 기술분야의 통상의 지식을 가진 자는 본 발명의 기술적 사상이나 필수적인 특징을 변경하지 않고서 다른 구체적인 형태로 쉽게 변형이 가능하다는 것을 이해할 수 있을 것이다. 그러므로 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적이 아닌 것으로 이해해야만 한다.The foregoing description of the present invention is intended for illustration, and it will be understood by those skilled in the art that the present invention may be easily modified in other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, it should be understood that the embodiments described above are exemplary in all respects and not restrictive.

Claims (18)

  1. (a) 기판 상에 고형물을 제조하는 단계; (a) preparing a solid on a substrate;
    (b) 상기 고형물 상에 용매를 첨가하여 유동화시키는 단계; 및 (b) fluidizing by adding a solvent onto the solid; And
    (c) 상기 유동화된 고형물을 성형하는 단계를 포함하는(c) forming the fluidized solid;
    마이크로구조체의 제조방법.Method for producing a microstructure.
  2. 제1항에 있어서,The method of claim 1,
    상기 (a)에서 고형물은 고형분 함량이 70 % 이상인 In the solid (a) is a solid content of more than 70%
    마이크로구조체의 제조방법.Method for producing a microstructure.
  3. 제1항에 있어서,The method of claim 1,
    상기 (a)에서 고형물은 별도 약물 또는 별도 첨가제가 미리 첨가된 Solid (a) in the (a) is a separate drug or a separate additive is added in advance
    마이크로구조체의 제조방법.Method for producing a microstructure.
  4. 제1항에 있어서,The method of claim 1,
    상기 (b) 단계에서 용매의 첨가는 접촉, 토출, 분사, 증착 및 담금으로 이루어진 군으로부터 선택된 하나 이상의 방법으로 수행되는The addition of the solvent in the step (b) is carried out by at least one method selected from the group consisting of contacting, discharging, spraying, deposition and immersion
    마이크로구조체의 제조방법.Method for producing a microstructure.
  5. 제1항에 있어서,The method of claim 1,
    상기 (b) 단계에서 고형물의 유동화 정도는 용매의 종류, 용매와 고형물의 친화도, 용매의 양 또는 유동화 조건에 따라 조절되는The degree of fluidization of the solid in step (b) is controlled according to the type of solvent, the affinity of the solvent and solids, the amount of solvent or fluidization conditions
    마이크로구조체의 제조방법.Method for producing a microstructure.
  6. 제1항에 있어서,The method of claim 1,
    상기 (b) 단계에서 고형물 100 중량부 대비, 용매는 10 부피부 내지 200 부피부로 첨가되는Compared to 100 parts by weight of the solid in step (b), the solvent is added in 10 parts by volume to 200 parts by volume
    마이크로구조체의 제조방법Manufacturing method of microstructure
  7. 제1항에 있어서,The method of claim 1,
    상기 기판의 수직 방향을 기준으로 할 때, 상기 고형물의 1/2 지점을 경계로 고형물 상부층 및 고형물 하부층으로 구분하는 경우, Based on the vertical direction of the substrate, when divided into a solid upper layer and a solid lower layer on the basis of the half point of the solid,
    상기 (b) 단계에서 고형물 상부층의 유동화 정도가 고형물 하부층의 유동화 정도에 비해 큰 것을 특징으로 하는In the step (b) characterized in that the degree of fluidization of the solid upper layer is larger than the degree of fluidization of the solid lower layer
    마이크로구조체의 제조방법.  Method for producing a microstructure.
  8. 제1항에 있어서,The method of claim 1,
    상기 (b) 단계에서 용매에 약물을 추가로 탑재하는Mounting the drug in the solvent in the step (b)
    마이크로구조체의 제조방법.Method for producing a microstructure.
  9. 제8항에 있어서,The method of claim 8,
    상기 (b) 단계 후, 상기 유동화된 고형물을 재고형화시킨 후, 상기 고형물 상에 제2 용매를 첨가하여 재유동화시키는 단계를 추가로 포함하는After the step (b), after re-solidifying the fluidized solid, further comprising adding and reflowing a second solvent on the solid
    마이크로구조체의 제조방법.Method for producing a microstructure.
  10. 제1항에 있어서,The method of claim 1,
    상기 (c) 단계에서 성형은 몰딩, 드로잉, 송풍, 흡입, 원심력 인가 및 자기장 인가로 이루어진 군으로부터 선택된 하나 이상의 방법으로 수행되는The molding in step (c) is performed by one or more methods selected from the group consisting of molding, drawing, blowing, suction, centrifugal force application and magnetic field application.
    마이크로구조체의 제조방법.Method for producing a microstructure.
  11. 제1항에 있어서,The method of claim 1,
    상기 (c) 단계에서 성형은 경화가 동시에 일어나도록 수행되는 Molding in the step (c) is performed so that curing occurs at the same time
    마이크로구조체의 제조방법.Method for producing a microstructure.
  12. 제1항에 있어서,The method of claim 1,
    상기 (c) 단계에서 성형되는 마이크로구조체의 종횡비(aspect ratio)는 유동화 정도에 따라 조절되는 Aspect ratio of the microstructure formed in step (c) is adjusted according to the degree of fluidization
    마이크로구조체의 제조방법. Method for producing a microstructure.
  13. 제8항 또는 제9항에 있어서,The method according to claim 8 or 9,
    상기 (c) 단계에서 성형되는 마이크로 구조체 내 약물의 탑재 분포는 유동화 정도에 따라 조절되는 The loading distribution of the drug in the microstructure formed in step (c) is adjusted according to the degree of fluidization
    마이크로구조체의 제조방법. Method for producing a microstructure.
  14. 제9항에 있어서,The method of claim 9,
    상기 (c) 단계에서 성형되는 마이크로 구조체 내 약물의 탑재 분포는 재유동화 정도에 따라 조절되는 The loading distribution of the drug in the microstructure formed in step (c) is controlled according to the degree of refluidization
    마이크로구조체의 제조방법. Method for producing a microstructure.
  15. 제1항의 방법에 따라 제조된 마이크로구조체.Microstructures prepared according to the method of claim 1.
  16. 기판 상에 형성되고, 약물이 탑재된 마이크로구조체에 있어서,In a microstructure formed on a substrate, the drug is mounted,
    상기 마이크로구조체 내 약물 탑재 분포는 점진적 농도 구배를 형성하는 것인The drug loading distribution in the microstructures forms a gradual concentration gradient.
    마이크로구조체.Microstructures.
  17. 제16항에 있어서,The method of claim 16,
    상기 기판의 수직 방향을 기준으로 할 때, 상기 마이크로구조체의 1/2 지점을 경계로 마이크로구조체 상부층 및 마이크로구조체 하부층으로 구분하는 경우, When the substrate is divided into a microstructure upper layer and a microstructure lower layer based on a half point of the microstructure based on the vertical direction of the substrate,
    마이크로구조체 상부층 내 약물 탑재 분포 정도가 마이크로구조체 하부층 내 약물 탑재 분포 정도에 비해 큰 것을 특징으로 하는The drug loading distribution in the microstructure upper layer is larger than the drug loading distribution in the microstructure lower layer.
    마이크로구조체.Microstructures.
  18. 제16항에 있어서,The method of claim 16,
    상기 기판의 수직 방향을 기준으로 할 때, 상기 마이크로구조체의 1/3 및 2/3 지점을 경계로 마이크로구조체 상부층, 마이크로구조체 중간층, 마이크로구조체 하부층으로 구분하는 경우, When the substrate is divided into a microstructure upper layer, a microstructure intermediate layer, and a microstructure lower layer based on 1/3 and 2/3 points of the microstructure based on the vertical direction of the substrate,
    마이크로구조체 중간층 내 약물 탑재 분포 정도가 마이크로구조체 상부층 및 마이크로구조체 하부층 내 약물 탑재 분포 정도에 비해 큰 것을 특징으로 하는The degree of drug loading in the microstructure intermediate layer is greater than the degree of drug loading in the microstructure upper layer and the microstructure lower layer.
    마이크로구조체.Microstructures.
PCT/KR2016/007634 2015-07-13 2016-07-13 Microstructure using fluidization of solid, and manufacturing method therefor WO2017010813A1 (en)

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