WO2017010813A1 - Microstructure basée sur la fluidisation d'un solide, et son procédé de fabrication - Google Patents

Microstructure basée sur la fluidisation d'un solide, et son procédé de fabrication 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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Prior art keywords
microstructure
solid
drug
solvent
fluidization
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PCT/KR2016/007634
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English (en)
Korean (ko)
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WO2017010813A9 (fr
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정형일
양휘석
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주식회사 주빅
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Priority claimed from KR1020160088235A external-priority patent/KR101808066B1/ko
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/fr
Publication of WO2017010813A9 publication Critical patent/WO2017010813A9/fr

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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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  • Microelectronics & Electronic Packaging (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Manufacturing & Machinery (AREA)
  • Chemical & Material Sciences (AREA)
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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne une microstructure, et son procédé de fabrication, le procédé de fabrication comprenant les étapes suivantes : (a) fabrication d'un solide sur un substrat ; (b) ajout d'un solvant sur le solide pour le fluidiser ; et c) moulage du solide fluidisé.
PCT/KR2016/007634 2015-07-13 2016-07-13 Microstructure basée sur la fluidisation d'un solide, et son procédé de fabrication WO2017010813A1 (fr)

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US15/744,768 US11382841B2 (en) 2015-07-13 2016-07-13 Microstructure using fluidization of solid, and manufacturing method therefor

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KR20150099056 2015-07-13
KR10-2015-0099056 2015-07-13
KR1020160088235A KR101808066B1 (ko) 2015-07-13 2016-07-12 고형물의 유동화를 이용한 마이크로구조체 및 이의 제조방법
KR10-2016-0088235 2016-07-12

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180056053A1 (en) * 2016-08-26 2018-03-01 Juvic Inc. Protruding microstructure for transdermal delivery

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0884484A (ja) * 1994-09-09 1996-03-26 Canon Inc マイクロ構造体の形成法
JP2009233170A (ja) * 2008-03-27 2009-10-15 Fujifilm Corp 高アスペクト比構造シートの製造方法
KR101180032B1 (ko) * 2010-07-12 2012-09-05 인싸이토(주) 외형 조절이 가능한 중공형 마이크로니들의 제조방법
KR20140006167A (ko) * 2012-06-27 2014-01-16 연세대학교 산학협력단 저온 드로잉 기법을 이용한 나노/마이크로 니들 및 그 제조방법
KR20140051648A (ko) * 2012-10-23 2014-05-02 연세대학교 산학협력단 히알루론산을 이용한 생분해성 마이크로니들 제조방법

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0884484A (ja) * 1994-09-09 1996-03-26 Canon Inc マイクロ構造体の形成法
JP2009233170A (ja) * 2008-03-27 2009-10-15 Fujifilm Corp 高アスペクト比構造シートの製造方法
KR101180032B1 (ko) * 2010-07-12 2012-09-05 인싸이토(주) 외형 조절이 가능한 중공형 마이크로니들의 제조방법
KR20140006167A (ko) * 2012-06-27 2014-01-16 연세대학교 산학협력단 저온 드로잉 기법을 이용한 나노/마이크로 니들 및 그 제조방법
KR20140051648A (ko) * 2012-10-23 2014-05-02 연세대학교 산학협력단 히알루론산을 이용한 생분해성 마이크로니들 제조방법

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180056053A1 (en) * 2016-08-26 2018-03-01 Juvic Inc. Protruding microstructure for transdermal delivery

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