WO2017065570A1 - Microstructure using gel-type polymer material, and method of manufacturing same - Google Patents

Microstructure using gel-type polymer material, and method of manufacturing same Download PDF

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Publication number
WO2017065570A1
WO2017065570A1 PCT/KR2016/011581 KR2016011581W WO2017065570A1 WO 2017065570 A1 WO2017065570 A1 WO 2017065570A1 KR 2016011581 W KR2016011581 W KR 2016011581W WO 2017065570 A1 WO2017065570 A1 WO 2017065570A1
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Prior art keywords
gel
microstructure
polymer material
region
base region
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PCT/KR2016/011581
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French (fr)
Korean (ko)
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정형일
장민규
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주식회사 주빅
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Priority claimed from KR1020160133482A external-priority patent/KR20170044049A/en
Publication of WO2017065570A1 publication Critical patent/WO2017065570A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin

Definitions

  • Subcutaneous drug injection methods are one of the methods commonly used in the treatment of various diseases and drug delivery.
  • Subcutaneous drug injection has advantages such as lower drug denaturation and degradation rate, higher efficiency of drug delivery in the body, and lower side effects through quantitative drug delivery compared to oral drug delivery methods absorbed through the digestive system.
  • hypodermic needles of various diameters are widely used as a subcutaneous drug injection method.
  • hypodermic needles are used in most drug delivery methods.
  • skin damage and pain are inevitable, and side effects such as allergic reaction due to metal material and injection phobia due to pain occur.
  • side effects such as allergic reaction due to metal material and injection phobia due to pain occur.
  • the same site injection due to the wound that occurs when using a conventional subcutaneous injection is impossible, there is a problem such as decreased patient convenience, drug injection efficiency.
  • Microneedles capable of subcutaneous drug injection in a micro size have been developed.
  • Microneedle is a micro-sized structure that can solve problems such as pain, trauma, and patient convenience of conventional hypodermic needles.
  • Biodegradable microneedle is a technology that enables painless drug delivery with minimal invasiveness. It is a field of research.
  • Existing biodegradable microneedles have been manufactured using mold molding method, tensile molding method, and tensile blow molding method. In the case of the molding method, the process of filling the viscous solution into the micro-sized mold is indispensable.
  • the limit of the length of the biodegradable microneedle that can be manufactured and the loss rate in the manufacturing process are high.
  • the microneedle structure is formed by stretching by using the viscosity of the viscous solution, and then, the biodegradable microneedle is formed through a drying process.
  • a high molecular weight polymer material is used, it is impossible to prepare a viscous solution.
  • a low molecular weight polymer material it is difficult to form a structure of the biodegradable microneedles and the strength is weakened.
  • the present invention comprises the steps of (a) forming a gelled base region comprising a polymeric material on a support; And (b) to provide a method of manufacturing a microstructure comprising the step of forming an outer region on the gel-based base region.
  • the present invention comprises the steps of (a) forming a gelled base region comprising a polymeric material on a support; And (b) forming an outer region on the gelled base region.
  • the weight average molecular weight of the polymer material in (a) may be 50kDa to 2,500kDa.
  • the viscosity of the gel-based region may be 5 Pa ⁇ s to 400 Pa ⁇ s at 25 ° C.
  • the gel strength of the gel-based base region may be 0.03N to 5N.
  • the gel base region may be divided into multiple base regions.
  • the drug may be further loaded into the gel-based base region in step (a) or the outer region in step (b).
  • the gel base region may be formed by discharging, attaching, punching, or molding.
  • a precoat layer may be formed on the support in advance.
  • the method may further include modifying the gel base region.
  • the formation of the outer region is performed by coating a coating region including a second polymer material on the gel-based base, and the second polymer material has a weight average molecular weight or a viscosity lower than that of the polymer material. It may be characterized by.
  • the formation of the outer region may be performed by attaching a second microstructure on the gel-based region.
  • the coating area may be divided into multiple coating areas.
  • the coating can be carried out by ejection, immersion or spraying.
  • the coating area may be molded or a separate microstructure may be attached onto the coating area.
  • the molding 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.
  • a microstructure manufactured according to the above method is provided.
  • the base layer comprising a polymer material; And an outer layer including a second polymer material formed on the base layer, wherein the second polymer material has a weight average molecular weight or a viscosity lower than that of the polymer material.
  • the weight average molecular weight of the polymer material may be 50kDa to 2,500kDa.
  • the viscosity of the polymer material may be 5 Pa.s to 400 Pa.s at 25 ° C.
  • the method of manufacturing a microstructure using the gel polymer material according to the present invention even when a high weight average molecular weight polymer material is used, not only the structure of the microstructure can be easily formed, but also the strength of the microstructure can be improved. In addition, when applied to the human body, it is possible to administer a high dose of a polymer substance or drug in the human body.
  • FIG. 1 is a view showing a method of manufacturing a microstructure using a gel polymer material according to various embodiments of the present invention.
  • FIG. 2 is a view showing a support of various materials and various forms.
  • 3 is a diagram showing gel-based base regions formed in various diameters, various heights, and various shapes.
  • FIG. 4 is a diagram showing the formation of a gelled base region by various methods.
  • 5 is a view showing a precoat layer of various materials.
  • FIG. 7 is a diagram illustrating coating regions formed in various shapes.
  • FIG. 9 is an electron micrograph showing a gel-based base region and a microstructure prepared according to Examples 1 to 3.
  • FIG. 10 is an electron micrograph showing the gelled base region and microstructures prepared according to Example 4.
  • FIG. 11 is an electron micrograph showing the gelled base region and microstructures prepared according to Example 5.
  • Example 12 is an electron micrograph showing a microstructure prepared according to Example 6.
  • the present inventors have found that by forming a gel-based base region containing a high weight average molecular weight polymer material, it is possible to successfully manufacture a microstructure having improved strength, and completed the present invention.
  • gel polymer material refers to a high weight average molecular weight polymer material for forming a gel-based base region, and the polymer material may be formed by crosslinking two or more of the same or different low molecular weight materials, and the polymer material. The same or different two or more high molecular materials may form a crosslink.
  • gel refers to a colloidal dispersion system in which the dispersed phase is a solid and the dispersion medium is a liquid, and maintains its form without flowing like a sol. That is, gel is a concept that is distinguished from a liquid (viscous solution) or a solid.
  • any configuration is formed on the "top (or bottom)" of the substrate not only means that any configuration is formed in contact with the top (or bottom) of the substrate, but also the above and the top (or bottom) of the substrate It does not limit to not including another structure between arbitrary structures formed).
  • the present invention comprises the steps of (a) forming a gelled base region comprising a polymeric material on a support; And (b) forming an outer region on the gelled base region.
  • FIG. 1 is a view showing a method of manufacturing a microstructure using a gel polymer material according to various embodiments of the present invention.
  • the gel base region 20 includes the second polymer material.
  • Step (c)
  • the method for producing a microstructure according to the present invention includes the step of forming a gel-based base region including a polymer material on a support [step (a)].
  • the support is used for supporting a gel-based base region containing a polymer material.
  • FIG. 2 is a view showing a support of various materials and various forms.
  • the support 10 may be formed of various materials such as a metal and a polymer material, and may have various shapes such as a substrate and a pillar. In this case, when the support is a substrate, it may have various surface shapes.
  • the present invention is characterized by using a gel-based base region containing a polymer material in order to overcome the limitation of the weight average molecular weight of the polymer material that can be included in the conventional viscous solution.
  • a gel-based base region containing a polymer material formed directly on the support without forming a separate viscous solution on the support, after forming a separate viscous solution on the support first, It may also include the case of using a gel base region comprising a polymer material formed thereon.
  • the weight average molecular weight of the polymer material is preferably 50 kDa to 2,500 kDa, and more preferably 1000 kDa to 2,500 kDa, but is not limited thereto.
  • the weight average molecular weight of the polymer material is less than the above range, there is a problem that gel formation is difficult, and when the weight average molecular weight of the polymer material exceeds the above range, there is a problem that molding is difficult after gel formation.
  • the concentration of the polymer material may be influenced by the weight average molecular weight, preferably 5% (w / v) to 95% (w / v), but is not limited thereto.
  • the concentration of the polymer material is less than 5% (w / v)
  • the concentration of the polymer material exceeds 95% (w / v)
  • the problem of deformation after gel formation is difficult There is this.
  • the polymer material may effectively form a gel-based base region by simultaneously maintaining a weight average molecular weight of 50 kDa to 2,500 kDa and a concentration of 5% (w / v) to 95% (w / v).
  • the polymer material may be a biocompatible or biodegradable material.
  • biocompatible material means a material that is substantially nontoxic to the human body, chemically inert, and not immunogenic, and “biodegradable material” in the present specification may be degraded by body fluids or microorganisms in a living body. Mean material.
  • hyaluronic acid polyester, polyhydroxyalkanoate (PHAs), poly ( ⁇ -hydroxyacid), poly ( ⁇ -hydroxyacid), poly (3- Hydrosulfitrate-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 (lac Tide-co-glycolide; PLGA), polydioxanone, polyorthoester, polyetherester, polyanhydride, poly (glycolic acid-co-trimethylene carbonate), polyphosphoester, polyphosphoester urethane , Poly (amino acid), polycyanoacrylate, Li (trimethylene carbonate), poly (iminocarbonate), poly (
  • Drugs may be further loaded inside the gelled base region.
  • the drug includes a chemical drug, a protein drug, a peptide drug, a nucleic acid molecule for gene therapy, and a nanoparticle.
  • Drugs that can be used in the present invention include, for example, anti-inflammatory drugs, analgesics, anti-arthritis agents, antispasmodics, antidepressants, antipsychotics, neurostabilizers, anti-anxiety agents, antagonists, antiparkin disease drugs, cholinergic agonists, anticancer agents, Antiangiogenic, immunosuppressive, antiviral, antibiotic, appetite suppressant, analgesic, anticholinergic, antihistamine, antimigraine, hormonal, coronary, cerebrovascular or peripheral vasodilator, contraceptive, antithrombotic, diuretic, anti Hypertension agents, cardiovascular diseases treatment agents, cosmetic ingredients (eg, wrinkle improvement agents, skin aging inhibitors and skin lightening agents) and the like, but are not limited thereto.
  • the viscosity of the gel-based region may be 5 Pa ⁇ s to 400 Pa ⁇ s at 25 ° C. and preferably 100 Pa ⁇ s to 400 Pa ⁇ s, but is not limited thereto. At this time, if the viscosity of the gel-based region is less than the above range, there is a problem that it is difficult to form a gel-shaped base region of a uniform form, and if the viscosity of the gel-based region exceeds the above range, the gel-based region is produced in a uniform length There is a difficult problem.
  • Gel strength of the gel-based base region is preferably 0.03N to 5N, but is not limited thereto. At this time, when the gel strength of the gel-based region (gel strength) is less than 0.03N, there is a problem that the gel-based base is broken during insertion, when the gel strength of the gel-based base region exceeds 5N, according to the increase in the diameter There is a problem of pain during insertion.
  • the gel base region may be divided into multiple base regions, which may be classified according to the polymer material (type, weight average molecular weight, concentration, etc.) included in the gel base region and the loaded drug (type, concentration, etc.). will be.
  • 3 is a diagram showing gel-based base regions formed in various diameters, various heights, and various shapes.
  • the diameter, height and shape of the gel-based base region can be variously adjusted according to the polymer material (type, weight average molecular weight, concentration, etc.), the formation method, and the like. Accordingly, the strength of the final prepared microstructure, the degree of administration of the polymeric material or drug (dose rate, dosage, depth of administration, etc.) can be variously controlled.
  • the gel-based base region may be a single base region, but the gel-based base region may be different depending on the polymer material (type, weight average molecular weight, concentration, etc.) and the loaded drug (type, concentration, etc.). By performing the formation repeatedly, it may be divided into multiple base regions.
  • Formation of the gel base region may be carried out by a method known in the art, it is preferably carried out by ejection, adhesion, punching or molding, but is not limited thereto.
  • FIG. 4 is a diagram showing the formation of a gelled base region by various methods.
  • the formation of the gel base region may be performed by discharging, attaching or punching. Along with this, curing can occur.
  • a precoat layer may be formed on the support in advance.
  • the precoating layer may be formed in advance before forming the gelled base region on the support, wherein the precoating layer not only serves to facilitate the separation of the gelled base region from the support. In addition, it can impart the ability to penetrate the skin due to the improved strength, and can also impart the drug loading function.
  • the precoating layer may be formed by a method known in the art, but is preferably formed by discharge, immersion and spraying, but is not limited thereto. Along with this, curing can occur.
  • 5 is a view showing a precoat layer of various materials.
  • the precoating layer may include the same polymer material as the polymer material included in the gel-based base region (see above), or may include a polymer material different from the polymer material included in the gel-based base region. You can also do it (pictured below).
  • the thickness of the precoat layer may be adjusted in various ways depending on the polymer material (type, weight average molecular weight, concentration, etc.), formation method, and the like included in the precoat layer.
  • the method may further include modifying the gelled base region.
  • the modification of the gelled base region can be carried out through cutting or drying. At this time, the concentration of the polymer material in the gel-based region may be further increased through drying.
  • the gel-based region can modify the shape of the gel-based region through cutting, and as shown in FIG. 6 (b), full drying, partial drying (internal drying, top) Drying) may be modified, and as shown in FIG. 6 (c), the gel base region may be modified by cutting after drying and drying after cutting.
  • the method for producing a microstructure according to the present invention includes the step of forming an outer region on the gel-based base region (step (b)).
  • the formation of the outer region may be carried out by coating a coating region comprising a second polymeric material on the gelled base region, or may be carried out through the attachment of a second microstructure on the gelled base region.
  • the coating region is formed on the gel-based region, it is viscous to facilitate molding May be present in solution. That is, the weight average molecular weight of the second polymer material included in the coating region may be lower than the weight average molecular weight of the polymer material included in the gel-based base region.
  • the viscosity of the outer region may be 0.15 Pa ⁇ s to 400 Pa ⁇ s at 25 ° C., preferably 0.15 Pa ⁇ s to 40 Pa ⁇ s, but is not limited thereto.
  • the second polymer material may be a biocompatible or biodegradable material, and specific types of the biocompatible or biodegradable material are as mentioned above.
  • the second polymer material may be the same as or different from the aforementioned polymer material.
  • the coating area may be further loaded with a drug, the specific type of the drug is also as mentioned above.
  • the coating area may be formed such that the gel-based area is coated entirely, or the gel-based area may be formed to be partially coated.
  • the coating area may be divided into multiple coating areas, which may be classified according to the material (type, weight average molecular weight, concentration, etc.) and the loaded drug (type, concentration, etc.) included in the coating area. .
  • FIG. 7 is a diagram illustrating coating regions formed in various shapes.
  • the shape of the coating area can be variously adjusted according to the material (type, weight average molecular weight, concentration, etc.), the formation method, Accordingly, the strength, penetration, etc. of the final microstructure can be adjusted in various ways.
  • the coating area may be a single coating area, but the formation of the coating area is repeated by varying the material (type, weight average molecular weight, concentration, etc.) and the loaded drug (type, concentration, etc.). May be divided into multiple coating areas.
  • the coating area may be molded or a separate microstructure may be attached onto the coating area.
  • the molding 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 by applying an outward force to the coating area or the viscous droplet. Along with this, curing can occur.
  • the molding of the coating area in (c-1) may have various arrangements of the coating layer 30 ′ depending on the molding method. According to various shapes and arrangements of the coating layer 30 ′, strength, penetrating force, and the like of the final microstructure may be adjusted.
  • the present invention also provides a microstructure manufactured according to the above method.
  • the strength is improved.
  • the present invention is a base layer comprising a polymer material; And an outer layer including a second polymer material formed on the base layer, wherein the second polymer material has a weight average molecular weight or a viscosity lower than that of the polymer material.
  • the weight average molecular weight of the polymer material may be 50kDa to 2,500kDa.
  • the viscosity of the polymer material may be 5 Pa.s to 400 Pa.s at 25 ° C.
  • the base layer is formed from a gel-based base region
  • the outer layer is formed from an outer region, and the gel-based base region, the outer region, and a manufacturing method thereof are as described above.
  • microstructure according to the present invention can be used as microblades, microblades, microknifes, microfibers, microspikes, microprobes, microbarbs, microarrays or microelectrodes.
  • Hyaluronic acid (1250 kDa) 25 (w / v)% gel was applied on an aluminum pillar having a diameter of 190 ⁇ m using a nozzle having a diameter of 190 ⁇ m (MUSASHI engineering, SN-27G-LF) at 100 ⁇ m / s for 4 seconds and Discharge and cure for 6.6 seconds to form a gelled base region which was then cut using a blade.
  • MUSASHI engineering, SN-27G-LF MUSASHI engineering, SN-27G-LF
  • the discharged gel-based region was measured under a condition of 25 ° C. and 30 mm Parallel Plate 1.0 mm Gap using a viscosity meter (Rheosys) before curing.
  • the viscosity was 203 Pa.s, and it was confirmed that the gel base region was successfully prepared.
  • FIG. 9 (a) is an electron micrograph showing a gel-based region formed according to Example 1, in which the diameter of the gel-based region in FIG. 9 (a) is about 62.02 ⁇ m and the height is about 394.12 ⁇ m and about 659.52 ⁇ m, respectively. It was confirmed that the gel base region was successfully prepared.
  • a hyaluronic acid (30 kDa) 40 (w / v)% solution was dispensed on a gel-based base region using a dispenser (MUSASHI engineering, ML-5000xII) at a pressure of 0.2 MPa for 0.22 seconds to form a coating region. Thereafter, the aluminum substrate on which the precoating layer was previously formed was brought into contact with the top of the coating area, and then vertically drawn for 3.3 seconds at a rate of 100 ⁇ m / s. Thereafter, after curing for 1 minute, the aluminum substrate on which the pre-coating layer was previously formed was vertically raised at a rate of 100 ⁇ m / s to finally manufacture the microstructure.
  • a dispenser MUSASHI engineering, ML-5000xII
  • the formed gel-based region was measured at a speed of 3.6 mm / min using a strength meter (Zwick / Roell, Z0.5). As a result, it was confirmed that the gel-based base region was successfully produced with an average strength of 1.3 N.
  • Hyaluronic acid (1250kDa) 25 (w / v)% gel was applied on aluminum pillars with a diameter of 190 ⁇ m using nozzles with internal diameters of 330 ⁇ m and 580 ⁇ m (MUSASHI engineering, SN-23G-LF and SN-20G-LF). Discharged and cured at 100 ⁇ m / s for 6 seconds and 6.5 seconds to form a gel base region, which was then cut using a blade. Thereafter, the microstructures were finally manufactured in the same manner as in Example 1.
  • the discharged gel-based region was measured under a condition of 25 ° C. and 30 mm Parallel Plate 1.0 mm Gap using a viscosity meter (Rheosys) before curing.
  • the viscosity was 203 Pa.s, and it was confirmed that the gel base region was successfully prepared.
  • FIG. 9 (b) is an electron micrograph showing the gel base region formed according to Example 2, in which the diameters of the gel base region in FIG. 9 (b) are about 341.37 ⁇ m and about 575.54 ⁇ m, respectively, and the heights are about 512.49 ⁇ m and At about 444.44 ⁇ m, it was confirmed that the gelled base region was successfully prepared.
  • the formed gel-based region was measured at a speed of 3.6 mm / min using a strength meter (Zwick / Roell, Z0.5). As a result, it was confirmed that the gel-based base region was successfully prepared with an average intensity of 2.2 N.
  • Carbosymethylcellulose (Sigma-Aldrich, Inc.) precoating layer 30 ⁇ m pre-formed on an aluminum substrate, and then hyaluronic acid (1250kDa) 25 (w / v)% gel was applied. Subsequently, the applied hyaluronic acid gel was vertically lowered at a nozzle having a diameter of 190 ⁇ m (MUSASHI engineering, SN-27G-LF) at a speed of 100 ⁇ m / s, and the applied hyaluronic acid gel was mounted inside the nozzle.
  • hyaluronic acid (1250kDa) 25 (w / v)% gel was applied.
  • the applied hyaluronic acid gel was vertically lowered at a nozzle having a diameter of 190 ⁇ m (MUSASHI engineering, SN-27G-LF) at a speed of 100 ⁇ m / s, and the applied hyaluronic acid gel was mounted inside the nozzle.
  • the nozzle on which the hyaluronic acid gel is mounted is placed at a height of 500 ⁇ m on an aluminum substrate on which a precoating layer is formed, and then discharged at a pressure of 0.5 MPa using a dispenser (MUSASHI engineering, ML-5000 ⁇ II) to obtain a gel-based base region. Formed. Thereafter, the microstructures were finally manufactured in the same manner as in Example 1.
  • the discharged gel-based region was measured under a condition of 25 ° C. and 30 mm Parallel Plate 1.0 mm Gap using a viscosity meter (Rheosys) before curing.
  • the viscosity was 203 Pa.s, and it was confirmed that the gel base region was successfully prepared.
  • the formed gel-based region was measured at a speed of 3.6 mm / min using a strength meter (Zwick / Roell, Z0.5). As a result, it was confirmed that the gel-based base region was successfully prepared with an average strength of 1.8 N.
  • FIG. 9 (c) is an electron micrograph showing the gel-based region formed according to Example 3, in which the diameters of the gel-based region in FIG. 9 (c) are about 218.64 ⁇ m and about 196.11 ⁇ m, respectively, and the heights are about 368.34 ⁇ m and At about 446.52 ⁇ m, it was confirmed that the gelled base region was successfully prepared.
  • Figure 9 (d) is an electron micrograph showing the final microstructure prepared according to Example 3, it was confirmed that the microstructure was successfully produced.
  • carboxymethyl cellulose precoat layer was attached to a height of 1.0 mm, dried for 5 minutes, and separated to prepare a gel-based base region.
  • a 55 (w / v)% solution of hyaluronic acid (39 kDa) on the gel-based area was dispensed for 0.22 seconds at a pressure of 0.2 MPa using a dispenser (MUSASHI engineering, ML-5000 II) to form a coating area.
  • a dispenser MUSASHI engineering, ML-5000 II
  • the gel-based base region in which the coating region was formed was mounted in a centrifuge (Hanil, Combi 514-R), and the aluminum substrate on which the pre-coating layer was previously formed was placed at 1.0 mm intervals from the gel-based base region in which the coating region was formed. After rotating for 60 seconds at a speed of 2000rpm, after curing for 1 minute, the microstructure was finally produced.
  • the formed gel-based region was measured at a speed of 3.6 mm / min using a strength meter (Zwick / Roell, Z0.5). As a result, it was confirmed that the gel-based base region was successfully prepared with an average strength of 1.5 N.
  • FIG. 10 (a) is an electron micrograph showing a gel-based region formed according to Example 4, in which the diameters of the gel-based regions in FIG. 10 (a) are each about 557.69 ⁇ m and the heights are about 365.38 ⁇ m, respectively. It was confirmed that this was successfully manufactured.
  • Figure 10 (b) and 10 (c) is an electron micrograph showing the final microstructure prepared according to Example 4, it was confirmed that the microstructure was successfully manufactured.
  • carboxymethyl cellulose precoat layer was attached to a height of 1.0 mm, dried for 5 minutes, and separated to prepare a gel-based base region.
  • the formed gel-based region was measured at a speed of 3.6 mm / min using a strength meter (Zwick / Roell, Z0.5). As a result, it was confirmed that the gel-based base region was successfully prepared with an average strength of 1.5 N.
  • FIG. 11 (a) is an electron micrograph showing a gel-based region formed according to Example 5, wherein the diameter of the gel-based region in FIG. 11 (a) is about 324.74 ⁇ m and the height is about 247.77 ⁇ m, respectively. It was confirmed that this was successfully manufactured.
  • Figure 11 (b) is an electron micrograph showing the final microstructure prepared according to Example 5, it was confirmed that the microstructure was successfully produced.
  • Gel-like base regions were prepared in the same manner as in Example 5. At this time, the discharged gel-based region was measured using a viscosity meter (Rheosys) before curing under conditions of 25 ° C. and 30 mm Parallel Plate 1.0 mm Gap. As a result, the viscosity was 193 Pa? S, and it was confirmed that the gel-based base region was successfully prepared.
  • a viscosity meter Heosys
  • a 55% w / v) solution of hyaluronic acid (39 kDa) was dispensed on the gel-based area using a dispenser (MUSASHI engineering, ML-5000 II) at a pressure of 0.2 MPa for 0.40 seconds to form a coating area.
  • a dispenser MUSASHI engineering, ML-5000 II
  • the gel-based base region in which the coating region was formed was mounted in a centrifuge (Hanil, Combi 514-R), and the aluminum substrate on which the pre-coating layer was previously formed was placed at 1.0 mm intervals from the gel-based base region in which the coating region was formed. After rotating for 60 seconds at a speed of 2000rpm, after curing for 1 minute, the microstructure was finally produced.
  • the formed gel-based region was measured at a speed of 3.6 mm / min using a strength meter (Zwick / Roell, Z0.5). As a result, it was confirmed that the gel-based base region was successfully prepared with an average strength of 1.5 N.
  • 12 (a) and 12 (b) are electron micrographs showing the microstructures finally prepared according to Example 6, wherein the gel-based base diameters were about 485 ⁇ m and about 610 ⁇ m, respectively, and the heights were about 466 ⁇ m and It was about 317 ⁇ m, and the heights of the microstructures were 461 ⁇ m and 495 ⁇ m, respectively.

Abstract

The present invention relates to a microstructure and a method of manufacturing same, the method comprising steps: (a) forming a gel-type base region including a polymer material on a support; and (b) forming an outer region on the gel-type base region.

Description

겔형 고분자 물질을 이용한 마이크로구조체 및 이의 제조방법Microstructure using gel polymer material and its manufacturing method
본 출원은 2015년 10월 14일 출원된 대한민국 특허출원 제10-2015-0143257 호 및 2016년 10월 14일 출원된 대한민국 특허출원 제10-2016-0133482호를 우선권으로 주장하고, 상기 명세서 전체는 본 출원의 참고문헌이다. This application claims the priority of Republic of Korea Patent Application No. 10-2015-0143257 filed October 14, 2015 and Republic of Korea Patent Application No. 10-2016-0133482 filed October 14, 2016, the entire specification It is a reference of the present application.
피하 약물 주사 방법은 다양한 질환 치료 및 약물 전달에 흔히 사용되는 방법 중 하나이다. 피하 약물 주사는 체내 소화기관을 통과하면서 흡수 되는 경구 약물 전달 방법에 비해 약물 변성 및 분해율이 낮고 체내 약물 전달 효율이 높으며, 정량의 약물 전달을 통한 부작용 감소 등의 장점을 가지고 있다. 현재 피하 약물 주사 방법으로는 다양한 직경의 피하 주사 바늘(Hypodermic Needle)이 널리 사용되고 있다.Subcutaneous drug injection methods are one of the methods commonly used in the treatment of various diseases and drug delivery. Subcutaneous drug injection has advantages such as lower drug denaturation and degradation rate, higher efficiency of drug delivery in the body, and lower side effects through quantitative drug delivery compared to oral drug delivery methods absorbed through the digestive system. Currently, hypodermic needles of various diameters are widely used as a subcutaneous drug injection method.
기존 피하 주사 바늘은 대부분의 약물 전달 방법에 이용되고 있다. 그러나, 피하 주사 바늘의 길이와 직경에 따른 피부 삽입시 피부손상과 통증 발생이 불가피하며, 금속 재질로 인한 알레르기 반응 발생, 통증으로 인한 주사 공포증(Needle Phobia) 발생 등의 부작용이 발생한다. 특히, 짧은 기간 동안 반복적인 약물 주사가 필요한 특정 질환의 경우, 기존 피하 주사 사용 시 발생하는 상처로 인한 동일 부위 주사가 불가능하며, 환자의 편의성 감소, 약물 주사 효율의 감소 등의 문제점이 있다. Existing hypodermic needles are used in most drug delivery methods. However, when the skin is inserted according to the length and diameter of the hypodermic needle, skin damage and pain are inevitable, and side effects such as allergic reaction due to metal material and injection phobia due to pain occur. In particular, in the case of a certain disease requiring repeated drug injection for a short period of time, the same site injection due to the wound that occurs when using a conventional subcutaneous injection is impossible, there is a problem such as decreased patient convenience, drug injection efficiency.
기존 피하 주사 바늘의 문제점을 해결하기 위해, 마이크로 사이즈로 피하 약물 주사가 가능한 마이크로니들이 개발되었다. 마이크로니들은 마이크로 크기의 구조체로, 기존 피하 주사 바늘의 통증, 외상, 환자 편의성 감소 등의 문제점을 해결 가능하며, 생분해성 마이크로니들은 최소 침습적으로 무통증 약물 전달이 가능한 기술로, 최근 각광받고 있는 연구 분야이다. 기존 생분해성 마이크로니들은 주형 성형 방법, 인장 성형 방법, 인장 송풍 성형 방법 등을 이용해 제작 되었다. 주형 성형 방법의 경우 점성 용액을 마이크로 크기의 주형에 채우는 과정이 필수적이며, 이에 따라 제작 가능한 생분해성 마이크로니들 길이의 한계 및 제작 과정에서 손실률이 높다는 단점이 있다. 인장 방법 및 인장 송풍 방법은 점성 용액의 점성을 이용해 인장하여 마이크로니들 구조체를 형성한 후, 건조과정을 통해 생분해성 마이크로니들을 성형한다. 그러나, 고분자량의 고분자 물질을 사용하면 점성 용액의 제조가 불가능한 반면, 저분자량의 고분자 물질을 사용하면 생분해성 마이크로니들의 구조 형성이 어렵고, 강도가 약해지는 문제점이 있어 왔다.In order to solve the problem of the conventional hypodermic needle, microneedles capable of subcutaneous drug injection in a micro size have been developed. Microneedle is a micro-sized structure that can solve problems such as pain, trauma, and patient convenience of conventional hypodermic needles. Biodegradable microneedle is a technology that enables painless drug delivery with minimal invasiveness. It is a field of research. Existing biodegradable microneedles have been manufactured using mold molding method, tensile molding method, and tensile blow molding method. In the case of the molding method, the process of filling the viscous solution into the micro-sized mold is indispensable. Thus, there is a disadvantage in that the limit of the length of the biodegradable microneedle that can be manufactured and the loss rate in the manufacturing process are high. In the tensile method and the tensile blowing method, the microneedle structure is formed by stretching by using the viscosity of the viscous solution, and then, the biodegradable microneedle is formed through a drying process. However, when a high molecular weight polymer material is used, it is impossible to prepare a viscous solution. However, when a low molecular weight polymer material is used, it is difficult to form a structure of the biodegradable microneedles and the strength is weakened.
본 발명은 (a) 지지체 상에 고분자 물질을 포함하는 겔형 베이스 영역을 형성하는 단계; 및 (b) 상기 겔형 베이스 영역 상에 외부 영역을 형성하는 단계를 포함하는 마이크로구조체의 제조방법 등을 제공하고자 한다.The present invention comprises the steps of (a) forming a gelled base region comprising a polymeric material on a support; And (b) to provide a method of manufacturing a microstructure comprising the step of forming an outer region on the gel-based base region.
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) 지지체 상에 고분자 물질을 포함하는 겔형 베이스 영역을 형성하는 단계; 및 (b) 상기 겔형 베이스 영역 상에 외부 영역을 형성하는 단계를 포함하는The present invention comprises the steps of (a) forming a gelled base region comprising a polymeric material on a support; And (b) forming an outer region on the gelled base region.
마이크로구조체의 제조방법을 제공한다.It provides a method for producing a microstructure.
상기 (a)에서 고분자 물질의 중량평균분자량은 50kDa 내지 2,500kDa일 수 있다. The weight average molecular weight of the polymer material in (a) may be 50kDa to 2,500kDa.
상기 (a)에서 겔형 베이스 영역의 점도는 25℃에서 5 Pa·s내지 400 Pa·s 일 수 있다. In (a), the viscosity of the gel-based region may be 5 Pa · s to 400 Pa · s at 25 ° C.
상기 (a) 단계에서 겔형 베이스 영역의 겔 강도(gel strength)는 0.03N 내지 5N 일 수 있다. In step (a), the gel strength of the gel-based base region may be 0.03N to 5N.
상기 (a) 단계에서 겔형 베이스 영역은 다중 베이스 영역으로 구분될 수 있다.In step (a), the gel base region may be divided into multiple base regions.
상기 (a) 단계에서 겔형 베이스 영역 또는 상기 (b) 단계에서 외부 영역 내부에 약물이 추가로 탑재될 수 있다.The drug may be further loaded into the gel-based base region in step (a) or the outer region in step (b).
상기 (a) 단계에서 겔형 베이스 영역의 형성은 토출, 부착, 펀칭 또는 몰딩에 의해 수행될 수 있다.In the step (a), the gel base region may be formed by discharging, attaching, punching, or molding.
상기 지지체 상에 프리코팅층이 미리 형성될 수 있다.A precoat layer may be formed on the support in advance.
상기 (a) 단계에서 겔형 베이스 영역의 형성과 동시에, 또는 상기 (a) 단계에서 겔형 베이스 영역의 형성 후에, 상기 겔형 베이스 영역을 변형하는 단계를 추가로 포함할 수 있다.Simultaneously with the formation of the gel base region in step (a) or after the formation of the gel base region in step (a), the method may further include modifying the gel base region.
상기 (b) 단계에서 외부 영역의 형성은 상기 겔형 베이스 영역 상에 제2 고분자 물질을 포함하는 코팅 영역의 코팅을 통해 수행되고, 상기 제2 고분자 물질은 상기 고분자 물질 보다 중량평균분자량 또는 점도가 작은 것을 특징으로 할 수 있다.In the step (b), the formation of the outer region is performed by coating a coating region including a second polymer material on the gel-based base, and the second polymer material has a weight average molecular weight or a viscosity lower than that of the polymer material. It may be characterized by.
상기 (b) 단계에서 외부 영역의 형성은 상기 겔형 베이스 영역 상에 제2 마이크로구조체의 부착을 통해 수행될 수 있다.In the step (b), the formation of the outer region may be performed by attaching a second microstructure on the gel-based region.
상기 코팅 영역은 다중 코팅 영역으로 구분될 수 있다.The coating area may be divided into multiple coating areas.
상기 코팅은 토출, 담금 또는 분사에 의해 수행될 수 있다. The coating can be carried out by ejection, immersion or spraying.
상기 코팅 후, 상기 코팅 영역을 성형하거나, 상기 코팅 영역 상에 별도의 마이크로구조체를 부착할 수 있다.After the coating, the coating area may be molded or a separate microstructure may be attached onto the coating area.
상기 성형은 몰딩, 드로잉, 송풍, 흡입, 원심력 인가 및 자기장 인가로 이루어진 군으로부터 선택된 하나 이상의 방법으로 수행될 수 있다.The molding 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.
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, 고분자 물질을 포함하는 베이스층; 및 상기 베이스층 상에 형성된 제2 고분자 물질을 포함하는 외부층을 포함하고, 상기 제2 고분자 물질은 상기 고분자 물질 보다 중량평균분자량 또는 점도가 작은 것을 특징으로 할 수 있다.In another embodiment of the invention, the base layer comprising a polymer material; And an outer layer including a second polymer material formed on the base layer, wherein the second polymer material has a weight average molecular weight or a viscosity lower than that of the polymer material.
상기 고분자 물질의 중량평균분자량은 50kDa 내지 2,500kDa일 수 있다.The weight average molecular weight of the polymer material may be 50kDa to 2,500kDa.
상기 고분자 물질의 점도는 25℃에서 5 Pa·s 내지 400 Pa·s일 수 있다.The viscosity of the polymer material may be 5 Pa.s to 400 Pa.s at 25 ° C.
본 발명에 따른 겔형 고분자 물질을 이용한 마이크로구조체의 제조방법의 경우, 높은 중량평균분자량의 고분자 물질을 사용한 경우에도 마이크로구조체의 구조 형성이 용이할 뿐만 아니라, 마이크로구조체의 강도를 향상시킬 수 있다. 또한, 인체에 적용시, 인체 내 고분자 물질 또는 약물의 고용량 투여가 가능하다.In the method of manufacturing a microstructure using the gel polymer material according to the present invention, even when a high weight average molecular weight polymer material is used, not only the structure of the microstructure can be easily formed, but also the strength of the microstructure can be improved. In addition, when applied to the human body, it is possible to administer a high dose of a polymer substance or drug in the human body.
도 1은 본 발명의 다양한 구현예에 따른 겔형 고분자 물질을 이용한 마이크로구조체의 제조방법을 나타낸 그림이다. 1 is a view showing a method of manufacturing a microstructure using a gel polymer material according to various embodiments of the present invention.
도 2는 다양한 재질 및 다양한 형태의 지지체를 보여주는 그림이다. 2 is a view showing a support of various materials and various forms.
도 3은 다양한 직경, 다양한 높이 및 다양한 형상으로 형성된 겔형 베이스 영역을 보여주는 그림이다.3 is a diagram showing gel-based base regions formed in various diameters, various heights, and various shapes.
도 4는 다양한 방법에 의한 겔형 베이스 영역의 형성을 보여주는 그림이다. 4 is a diagram showing the formation of a gelled base region by various methods.
도 5는 다양한 재질의 프리코팅층을 보여주는 그림이다. 5 is a view showing a precoat layer of various materials.
도 6은 겔형 베이스 영역의 다양한 변형을 보여주는 그림이다. 6 shows various modifications of the gelled base region.
도 7은 다양한 형상으로 형성된 코팅 영역을 보여주는 그림이다. 7 is a diagram illustrating coating regions formed in various shapes.
도 8은 코팅 영역의 성형을 보여주는 그림이다. 8 is a drawing showing the shaping of the coating area.
도 9는 실시예 1~3에 따라 제조된 겔형 베이스 영역 및 마이크로구조체를 보여주는 전자현미경 사진이다.9 is an electron micrograph showing a gel-based base region and a microstructure prepared according to Examples 1 to 3.
도 10은 실시예 4에 따라 제조된 겔형 베이스 영역 및 마이크로구조체를 보여주는 전자현미경 사진이다. FIG. 10 is an electron micrograph showing the gelled base region and microstructures prepared according to Example 4. FIG.
도 11은 실시예 5에 따라 제조된 겔형 베이스 영역 및 마이크로구조체를 보여주는 전자현미경 사진이다. FIG. 11 is an electron micrograph showing the gelled base region and microstructures prepared according to Example 5. FIG.
도 12는 실시예 6에 따라 제조된 마이크로구조체를 보여주는 전자현미경 사진이다. 12 is an electron micrograph showing a microstructure prepared according to Example 6.
본 발명자들은 높은 중량평균분자량의 고분자 물질을 포함하는 겔형 베이스 영역을 형성함으로써, 강도가 향상된 마이크로구조체를 성공적으로 제조할 수 있음을 확인하고, 본 발명을 완성하였다.The present inventors have found that by forming a gel-based base region containing a high weight average molecular weight polymer material, it is possible to successfully manufacture a microstructure having improved strength, and completed the present invention.
본 명세서 내 "겔형 고분자 물질"은 겔형 베이스 영역을 형성하기 위한 높은 중량평균분자량의 고분자 물질을 말하며, 상기 고분자 물질은 동일하거나 다른 2 이상의 저분자 물질이 가교결합함으로써 형성된 것일 수 있고, 또한 상기 고분자 물질은 동일하거나 다른 2 이상의 고분자 물질이 가교결합을 형성할 수 있다. As used herein, the term "gel polymer material" refers to a high weight average molecular weight polymer material for forming a gel-based base region, and the polymer material may be formed by crosslinking two or more of the same or different low molecular weight materials, and the polymer material. The same or different two or more high molecular materials may form a crosslink.
본 명세서 내 "겔형"은 분산상이 고체이고 분산매가 액체인 콜로이드 분산계로서 졸과 같이 유동하지 않고 형태를 유지하고 있는 상태를 말한다. 즉, 겔은 액체(점성 용액) 또는 고체와는 구별되는 개념이다.As used herein, "gel" refers to a colloidal dispersion system in which the dispersed phase is a solid and the dispersion medium is a liquid, and maintains its form without flowing like a sol. That is, gel is a concept that is distinguished from a liquid (viscous solution) or a solid.
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 the "top (or bottom)" of the substrate not only means that any configuration is formed in contact with the top (or bottom) of the substrate, but also the above and the top (or bottom) of the substrate It does not limit to not including another structure between arbitrary structures formed).
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명은 (a) 지지체 상에 고분자 물질을 포함하는 겔형 베이스 영역을 형성하는 단계; 및 (b) 상기 겔형 베이스 영역 상에 외부 영역을 형성하는 단계를 포함하는 마이크로구조체의 제조방법을 제공한다.The present invention comprises the steps of (a) forming a gelled base region comprising a polymeric material on a support; And (b) forming an outer region on the gelled base region.
도 1은 본 발명의 다양한 구현예에 따른 겔형 고분자 물질을 이용한 마이크로구조체의 제조방법을 나타낸 그림이다.1 is a view showing a method of manufacturing a microstructure using a gel polymer material according to various embodiments of the present invention.
도 1에 나타난 바와 같이, 지지체(10) 상에 고분자 물질을 포함하는 겔형 베이스 영역(20)을 형성한 후[(a) 단계], 겔형 베이스 영역(20) 상에 제2 고분자 물질을 포함하는 코팅 영역의 코팅(30) 및 성형(30')을 통해 외부 영역을 형성하거나, 겔형 베이스 영역(20) 상에 제2 고분자 물질을 포함하는 코팅 영역의 코팅(30) 및 별도의 마이크로구조체의 부착(31)을 통해 외부 영역을 형성하거나, 상기 겔형 베이스 영역 상에 제2 마이크로구조체의 부착(40)을 통해 외부 영역을 형성하여[(b) 단계], 다양한 구현예에 따른 마이크로구조체를 제조할 수 있다[(c) 단계]. As shown in FIG. 1, after the gel base region 20 including the polymer material is formed on the support 10 [step (a)], the gel base region 20 includes the second polymer material. Forming an external area through coating 30 and molding 30 'of the coating area, or attaching a separate microstructure and coating 30 of the coating area comprising a second polymeric material on the gelled base area 20 Forming an outer region through 31 or forming an outer region through attachment 40 of the second microstructure on the gel-based region [step (b)] to produce a microstructure according to various embodiments. [Step (c)].
먼저, 본 발명에 따른 마이크로구조체의 제조방법은 지지체 상에 고분자 물질을 포함하는 겔형 베이스 영역을 형성하는 단계[(a) 단계]를 포함한다. First, the method for producing a microstructure according to the present invention includes the step of forming a gel-based base region including a polymer material on a support [step (a)].
상기 지지체는 고분자 물질을 포함하는 겔형 베이스 영역을 지지하기 위한 용도로 사용된다. The support is used for supporting a gel-based base region containing a polymer material.
도 2는 다양한 재질 및 다양한 형태의 지지체를 보여주는 그림이다. 2 is a view showing a support of various materials and various forms.
도 2에 나타난 바와 같이, 상기 지지체(10)는 금속, 고분자 물질 등 다양한 재질로 형성될 수 있으며, 기판, 기둥 등 다양한 형태를 가질 수 있다. 이때, 상기 지지체가 기판인 경우에는 다양한 표면 형상을 가질 수 있다. As shown in FIG. 2, the support 10 may be formed of various materials such as a metal and a polymer material, and may have various shapes such as a substrate and a pillar. In this case, when the support is a substrate, it may have various surface shapes.
본 발명은 종래 점성 용액에 포함될 수 있는 고분자 물질의 중량평균분자량의 한계를 극복하기 위해, 고분자 물질을 포함하는 겔형 베이스 영역을 이용한 것을 특징으로 한다.The present invention is characterized by using a gel-based base region containing a polymer material in order to overcome the limitation of the weight average molecular weight of the polymer material that can be included in the conventional viscous solution.
본 발명에서는 상기 지지체 상에 별도의 점성 용액을 형성하지 않고, 상기 지지체 상에 바로 형성된 고분자 물질을 포함하는 겔형 베이스 영역을 이용하는 경우뿐만 아니라, 상기 지지체 상에 별도의 점성 용액을 먼저 형성한 후, 그 위에 형성된 고분자 물질을 포함하는 겔형 베이스 영역을 이용하는 경우도 포함할 수 있다.In the present invention, as well as using a gel-based base region containing a polymer material formed directly on the support, without forming a separate viscous solution on the support, after forming a separate viscous solution on the support first, It may also include the case of using a gel base region comprising a polymer material formed thereon.
상기 고분자 물질의 중량평균분자량은 50 kDa 내지 2,500 kDa인 것이 바람직하고, 1000 kDa 내지 2,500kDa인 것이 더욱 바람직하나, 이에 한정되지 않는다. 이때, 고분자 물질의 중량평균분자량이 상기 범위 미만인 경우, 겔 형성이 어려운 문제점이 있고, 고분자 물질의 중량평균분자량이 상기 범위를 초과하는 경우, 겔 형성 후 성형이 어렵다는 문제점이 있다.The weight average molecular weight of the polymer material is preferably 50 kDa to 2,500 kDa, and more preferably 1000 kDa to 2,500 kDa, but is not limited thereto. In this case, when the weight average molecular weight of the polymer material is less than the above range, there is a problem that gel formation is difficult, and when the weight average molecular weight of the polymer material exceeds the above range, there is a problem that molding is difficult after gel formation.
이때, 상기 고분자 물질의 농도는 중량평균분자량에 의해 좌우될 수 있는 것으로, 5% (w/v) 내지 95% (w/v) 인 것이 바람직하나, 이에 한정되지 않는다. 이때, 고분자 물질의 농도가 5% (w/v) 미만인 경우, 겔 형성 자체가 어려운 문제점이 있고, 고분자 물질의 농도가 95% (w/v) 를 초과하는 경우, 겔 형성 후 변형이 어렵다는 문제점이 있다.In this case, the concentration of the polymer material may be influenced by the weight average molecular weight, preferably 5% (w / v) to 95% (w / v), but is not limited thereto. In this case, when the concentration of the polymer material is less than 5% (w / v), there is a problem that the gel formation itself is difficult, and when the concentration of the polymer material exceeds 95% (w / v), the problem of deformation after gel formation is difficult There is this.
즉, 상기 고분자 물질은 50 kDa 내지 2,500 kDa의 중량평균분자량 및 5% (w/v) 내지 95% (w/v) 의 농도를 동시에 유지함으로써, 겔형 베이스 영역을 효과적으로 형성할 수 있다.That is, the polymer material may effectively form a gel-based base region by simultaneously maintaining a weight average molecular weight of 50 kDa to 2,500 kDa and a concentration of 5% (w / v) to 95% (w / v).
구체적으로, 상기 고분자 물질은 생체적합성 또는 생분해성 물질일 수 있다. Specifically, the polymer material may be a biocompatible or biodegradable material.
본 명세서 내 "생체적합성 물질"은 실질적으로 인체에 독성이 없고 화학적으로 불활성이며 면역원성이 없는 물질을 의미하고, 본 명세서 내 "생분해성 물질"은 생체 내에서 체액 또는 미생물 등에 의해서 분해될 수 있는 물질을 의미한다.As used herein, "biocompatible material" means a material that is substantially nontoxic to the human body, chemically inert, and not immunogenic, and "biodegradable material" in the present specification may be degraded by body fluids or microorganisms in a living body. Mean material.
이때, 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.In this case, as a biocompatible or biodegradable material, hyaluronic acid, polyester, polyhydroxyalkanoate (PHAs), poly (α-hydroxyacid), poly (β-hydroxyacid), poly (3- Hydrosulfitrate-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 (lac Tide-co-glycolide; PLGA), polydioxanone, polyorthoester, polyetherester, polyanhydride, poly (glycolic acid-co-trimethylene carbonate), polyphosphoester, polyphosphoester urethane , Poly (amino acid), polycyanoacrylate, Li (trimethylene carbonate), poly (iminocarbonate), poly (tyrosine carbonate), polycarbonate, poly (tyrosine arylate), polyalkylene oxalate, polyphosphazene, PHA-PEG, ethylene vinyl alcohol copolymer (EVOH), polyurethanes, silicones, polyesters, polyolefins, polyisobutylene and ethylene-alphaolefin copolymers, styrene-isobutylene-styrene triblock copolymers, acrylic polymers and copolymers, vinyl halide polymers and copolymers , Polyvinyl chloride, polyvinyl ether, polyvinyl methyl ether, polyvinylidene halide, polyvinylidene fluoride, polyvinylidene chloride, polyfluoroalkene, polyperfluoroalkene, polyacrylonitrile, polyvinyl ketone, Polyvinyl aromatics, polystyrene, polyvinyl ester, polyvinyl acetate, ethylene-methyl methacrylate Copolymer, acrylonitrile-styrene copolymer, ABS resin and ethylene-vinyl acetate copolymer, polyamide, alkyd resin, polyoxymethylene, polyimide, polyether, polyacrylate, polymethacrylate, polyacrylic acid- co-maleic acid, chitosan, dextran, cellulose, heparin, alginate, inulin, starch or glycogen can be used, hyaluronic acid, polyester, polyhydroxyalkanoate (PHAs), poly (α-hydroxyxe) Seeds), 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.
상기 겔형 베이스 영역 내부에 약물이 추가로 탑재될 수 있다.Drugs may be further loaded inside the gelled base region.
상기 약물로는 공지의 약물이 사용가능하고, 예를 들어, 상기 약물은 화학약물, 단백질 의약, 펩타이드 의약, 유전자 치료용 핵산 분자 및 나노입자 등을 포함한다. 본 발명에 이용될 수 있는 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 drug, a known drug can be used. For example, the drug includes a chemical drug, a protein drug, a peptide drug, a nucleic acid molecule for gene therapy, and a nanoparticle. Drugs that can be used in the present invention include, for example, anti-inflammatory drugs, analgesics, anti-arthritis agents, antispasmodics, antidepressants, antipsychotics, neurostabilizers, anti-anxiety agents, antagonists, antiparkin disease drugs, cholinergic agonists, anticancer agents, Antiangiogenic, immunosuppressive, antiviral, antibiotic, appetite suppressant, analgesic, anticholinergic, antihistamine, antimigraine, hormonal, coronary, cerebrovascular or peripheral vasodilator, contraceptive, antithrombotic, diuretic, anti Hypertension agents, cardiovascular diseases treatment agents, cosmetic ingredients (eg, wrinkle improvement agents, skin aging inhibitors and skin lightening agents) and the like, but are not limited thereto.
상기 겔형 베이스 영역의 점도는 25℃에서 5 Pa·s내지 400 Pa·s일 수 있고 100 Pa·s내지 400 Pa·s인 것이 바람직하나, 이에 한정되지 않는다. 이때, 겔형 베이스 영역의 점도가 상기 범위 미만인 경우, 균일한 형태의 겔형 베이스 영역 형성이 어려운 문제점이 있고, 겔형 베이스 영역의 점도가 상기 범위를 초과하는 경우, 겔형 베이스 영역을 균일한 길이로 제작이 어려운 문제점이 있다.The viscosity of the gel-based region may be 5 Pa · s to 400 Pa · s at 25 ° C. and preferably 100 Pa · s to 400 Pa · s, but is not limited thereto. At this time, if the viscosity of the gel-based region is less than the above range, there is a problem that it is difficult to form a gel-shaped base region of a uniform form, and if the viscosity of the gel-based region exceeds the above range, the gel-based region is produced in a uniform length There is a difficult problem.
상기 겔형 베이스 영역의 겔 강도(gel strength)는 0.03N 내지 5N 인 것이 바람직하나, 이에 한정되지 않는다. 이때, 겔형 베이스 영역의 겔 강도(gel strength) 0.03N 미만인 경우, 삽입 시 겔형 베이스가 부러지는 문제점이 있고, 겔형 베이스 영역의 겔 강도(gel strength)가 5N 을 초과하는 경우, 직경의 증가에 따른 삽입시 통증 발생 문제점이 있다. Gel strength of the gel-based base region is preferably 0.03N to 5N, but is not limited thereto. At this time, when the gel strength of the gel-based region (gel strength) is less than 0.03N, there is a problem that the gel-based base is broken during insertion, when the gel strength of the gel-based base region exceeds 5N, according to the increase in the diameter There is a problem of pain during insertion.
상기 겔형 베이스 영역은 다중 베이스 영역으로 구분될 수 있는데, 이는 상기 겔형 베이스 영역에 포함된 고분자 물질(종류, 중량평균분자량, 농도 등) 및 탑재된 약물(종류, 농도 등)에 따라 구분될 수 있는 것이다. The gel base region may be divided into multiple base regions, which may be classified according to the polymer material (type, weight average molecular weight, concentration, etc.) included in the gel base region and the loaded drug (type, concentration, etc.). will be.
도 3은 다양한 직경, 다양한 높이 및 다양한 형상으로 형성된 겔형 베이스 영역을 보여주는 그림이다. 3 is a diagram showing gel-based base regions formed in various diameters, various heights, and various shapes.
도 3(a)~(c)에 나타난 바와 같이, 상기 겔형 베이스 영역의 직경, 높이 및 형상은 고분자 물질(종류, 중량평균분자량, 농도 등), 형성 방법 등에 따라 다양하게 조절될 수 있고, 이에 따라 최종 제조된 마이크로구조체의 강도, 고분자 물질 또는 약물의 투여 정도(투여 속도, 투여량, 투여 깊이 등) 등을 다양하게 조절할 수 있다. 도 3(d)에 나타난 바와 같이, 겔형 베이스 영역은 단일 베이스 영역일 수도 있으나, 고분자 물질(종류, 중량평균분자량, 농도 등) 및 탑재된 약물(종류, 농도 등)을 달리하여 겔형 베이스 영역의 형성을 반복하여 수행함으로써 다중 베이스 영역으로 구분될 수도 있다. As shown in Figure 3 (a) ~ (c), the diameter, height and shape of the gel-based base region can be variously adjusted according to the polymer material (type, weight average molecular weight, concentration, etc.), the formation method, and the like. Accordingly, the strength of the final prepared microstructure, the degree of administration of the polymeric material or drug (dose rate, dosage, depth of administration, etc.) can be variously controlled. As shown in (d) of FIG. 3, the gel-based base region may be a single base region, but the gel-based base region may be different depending on the polymer material (type, weight average molecular weight, concentration, etc.) and the loaded drug (type, concentration, etc.). By performing the formation repeatedly, it may be divided into multiple base regions.
상기 겔형 베이스 영역의 형성은 당업계 공지된 방법으로 수행될 수 있고, 토출, 부착, 펀칭 또는 몰딩에 의해 수행되는 것이 바람직하나, 이에 한정되지 않는다.Formation of the gel base region may be carried out by a method known in the art, it is preferably carried out by ejection, adhesion, punching or molding, but is not limited thereto.
도 4는 다양한 방법에 의한 겔형 베이스 영역의 형성을 보여주는 그림이다. 4 is a diagram showing the formation of a gelled base region by various methods.
도 4에 나타난 바와 같이, 상기 겔형 베이스 영역의 형성은 토출, 부착 또는 펀칭에 의해 수행될 수 있다. 이와 함께, 경화가 일어날 수 있다.As shown in FIG. 4, the formation of the gel base region may be performed by discharging, attaching or punching. Along with this, curing can occur.
한편, 상기 지지체 상에 프리코팅층이 미리 형성될 수 있다. Meanwhile, a precoat layer may be formed on the support in advance.
상기 프리코팅층은 상기 지지체 상에 상기 겔형 베이스 영역을 형성하기 전에, 미리 형성될 수 있는데, 상기 프리코팅층은 상기 지지체로부터 상기 겔형 베이스 영역을 분리하고자 하는 경우, 이를 용이하게 하는 기능을 수행할 뿐만 아니라, 강도 향상으로 인한 피부 관통 능력을 부여할 수 있고, 약물 탑재 기능도 부여할 수 있다.The precoating layer may be formed in advance before forming the gelled base region on the support, wherein the precoating layer not only serves to facilitate the separation of the gelled base region from the support. In addition, it can impart the ability to penetrate the skin due to the improved strength, and can also impart the drug loading function.
상기 프리코팅층은 당업계 공지된 방법으로 형성될 수 있고, 토출, 담금 및 분사에 의해 형성되는 것이 바람직하나, 이에 한정되지 않는다. 이와 함께, 경화가 일어날 수 있다.The precoating layer may be formed by a method known in the art, but is preferably formed by discharge, immersion and spraying, but is not limited thereto. Along with this, curing can occur.
도 5는 다양한 재질의 프리코팅층을 보여주는 그림이다. 5 is a view showing a precoat layer of various materials.
도 5에 나타난 바와 같이, 상기 프리코팅층은 상기 겔형 베이스 영역에 포함되는 고분자 물질과 동일한 고분자 물질을 포함할 수도 있고(위 그림), 혹은상기 겔형 베이스 영역에 포함되는 고분자 물질과 상이한 고분자 물질을 포함할 수도 있다(아래 그림). As shown in FIG. 5, the precoating layer may include the same polymer material as the polymer material included in the gel-based base region (see above), or may include a polymer material different from the polymer material included in the gel-based base region. You can also do it (pictured below).
상기 프리코팅층의 두께는 상기 프리코팅층에 포함되는 고분자 물질(종류, 중량평균분자량, 농도 등), 형성 방법 등에 따라 다양하게 조절될 수 있다.The thickness of the precoat layer may be adjusted in various ways depending on the polymer material (type, weight average molecular weight, concentration, etc.), formation method, and the like included in the precoat layer.
상기 겔형 베이스 영역의 형성과 동시에, 또는 상기 겔형 베이스 영역의 형성 후에, 상기 겔형 베이스 영역을 변형하는 단계를 추가로 포함할 수 있다. At the same time as the formation of the gelled base region or after the formation of the gelled base region, the method may further include modifying the gelled base region.
상기 겔형 베이스 영역의 변형은 절단 또는 건조를 통해 수행될 수 있다. 이때, 건조를 통하여 상기 겔형 베이스 영역에서 고분자 물질의 농도를 더욱 높일 수 있다. The modification of the gelled base region can be carried out through cutting or drying. At this time, the concentration of the polymer material in the gel-based region may be further increased through drying.
도 6은 겔형 베이스 영역의 다양한 변형을 보여주는 그림이다.6 shows various modifications of the gelled base region.
도 6(a)에 나타난 바와 같이, 상기 겔형 베이스 영역은 절단을 통하여 상기 겔형 베이스 영역의 형상을 변형할 수 있고, 도 6(b)에 나타난 바와 같이, 전체 건조, 일부 건조(내부 건조, 상부 건조)를 통하여 상기 겔형 베이스 영역을 변형할 수도 있으며, 도 6(c)에 나타난 바와 같이, 건조 후 절단, 절단 후 건조를 통하여 상기 겔형 베이스 영역을 변형할 수도 있다.As shown in FIG. 6 (a), the gel-based region can modify the shape of the gel-based region through cutting, and as shown in FIG. 6 (b), full drying, partial drying (internal drying, top) Drying) may be modified, and as shown in FIG. 6 (c), the gel base region may be modified by cutting after drying and drying after cutting.
다음으로, 본 발명에 따른 마이크로구조체의 제조방법은 상기 겔형 베이스 영역 상에 외부 영역을 형성하는 단계[(b) 단계]를 포함한다.Next, the method for producing a microstructure according to the present invention includes the step of forming an outer region on the gel-based base region (step (b)).
상기 외부 영역의 형성은 상기 겔형 베이스 영역 상에 제2 고분자 물질을 포함하는 코팅 영역의 코팅을 통해 수행될 수도 있고, 상기 겔형 베이스 영역 상에 제2 마이크로구조체의 부착을 통해 수행될 수도 있다.The formation of the outer region may be carried out by coating a coating region comprising a second polymeric material on the gelled base region, or may be carried out through the attachment of a second microstructure on the gelled base region.
먼저, 상기 외부 영역의 형성이 상기 겔형 베이스 영역 상에 제2 고분자 물질을 포함하는 코팅 영역의 코팅을 통해 수행되는 경우, 상기 코팅 영역은 상기 겔형 베이스 영역 상에 형성되는 것으로, 성형이 용이하도록 점성 용액 상태로 존재할 수 있다. 즉, 상기 코팅 영역에 포함되는 제2 고분자 물질의 중량평균분자량은 상기 겔형 베이스 영역에 포함되는 고분자 물질의 중량평균분자량 보다 낮은 것을 특징으로 할 수 있다.First, when the formation of the outer region is carried out through the coating of the coating region containing the second polymer material on the gel-based region, the coating region is formed on the gel-based region, it is viscous to facilitate molding May be present in solution. That is, the weight average molecular weight of the second polymer material included in the coating region may be lower than the weight average molecular weight of the polymer material included in the gel-based base region.
또한, 상기 외부 영역의 점도는 25℃에서 0.15 Pa·s 내지 400 Pa·s일 수 있고, 0.15 Pa·s 내지 40 Pa·s 인 것이 바람직하나, 이에 한정되지 않는다. In addition, the viscosity of the outer region may be 0.15 Pa · s to 400 Pa · s at 25 ° C., preferably 0.15 Pa · s to 40 Pa · s, but is not limited thereto.
상기 제2 고분자 물질은 생체적합성 또는 생분해성 물질일 수 있고, 생체적합성 또는 생분해성 물질의 구체적인 종류는 앞서 언급한 바와 같다. The second polymer material may be a biocompatible or biodegradable material, and specific types of the biocompatible or biodegradable material are as mentioned above.
즉, 상기 제2 고분자 물질은 앞서 언급한 고분자 물질과 동일하거나 상이할 수 있다.That is, the second polymer material may be the same as or different from the aforementioned polymer material.
또한, 상기 코팅 영역은 약물을 추가로 탑재할 수 있는데, 상기 약물의 구체적인 종류 역시 앞서 언급한 바와 같다. 상기 코팅 영역은 상기 겔형 베이스 영역이 전체적으로 코팅되도록 형성될 수도 있고, 상기 겔형 베이스 영역이 부분적으로 코팅되도록 형성될 수도 있다.In addition, the coating area may be further loaded with a drug, the specific type of the drug is also as mentioned above. The coating area may be formed such that the gel-based area is coated entirely, or the gel-based area may be formed to be partially coated.
또한, 상기 코팅 영역은 다중 코팅 영역으로 구분될 수 있는데, 이는 상기 코팅 영역에 포함된 물질(종류, 중량평균분자량, 농도 등) 및 탑재된 약물(종류, 농도 등)에 따라 구분될 수 있는 것이다.In addition, the coating area may be divided into multiple coating areas, which may be classified according to the material (type, weight average molecular weight, concentration, etc.) and the loaded drug (type, concentration, etc.) included in the coating area. .
도 7은 다양한 형상으로 형성된 코팅 영역을 보여주는 그림이다. 7 is a diagram illustrating coating regions formed in various shapes.
도 7에 나타난 바와 같이, 도 7(a) 및 (b)에 나타난 바와 같이, 상기 코팅 영역의 형상은 물질(종류, 중량평균분자량, 농도 등), 형성 방법 등에 따라 다양하게 조절될 수 있고, 이에 따라 최종 제조된 마이크로구조체의 강도, 관통력 등을 다양하게 조절할 수 있다. 도 7(c)에 나타난 바와 같이, 코팅 영역은 단일 코팅 영역일 수도 있으나, 물질(종류, 중량평균분자량, 농도 등) 및 탑재된 약물(종류, 농도 등)을 달리하여 코팅 영역의 형성을 반복하여 수행함으로써 다중 코팅 영역으로 구분될 수도 있다.As shown in Figure 7, as shown in Figure 7 (a) and (b), the shape of the coating area can be variously adjusted according to the material (type, weight average molecular weight, concentration, etc.), the formation method, Accordingly, the strength, penetration, etc. of the final microstructure can be adjusted in various ways. As shown in FIG. 7C, the coating area may be a single coating area, but the formation of the coating area is repeated by varying the material (type, weight average molecular weight, concentration, etc.) and the loaded drug (type, concentration, etc.). May be divided into multiple coating areas.
상기 코팅 후, 상기 코팅 영역을 성형하거나, 상기 코팅 영역 상에 별도의 마이크로구조체를 부착할 수 있다. After the coating, the coating area may be molded or a separate microstructure may be attached onto the coating area.
이때, 상기 성형은 코팅 영역 또는 점성 방울에 외향력을 인가함으로써 몰딩, 드로잉, 송풍, 흡입, 원심력 인가 및 자기장 인가로 이루어진 군으로부터 선택된 하나 이상의 방법으로 수행될 수 있다. 이와 함께, 경화가 일어날 수 있다.In this case, the molding 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 by applying an outward force to the coating area or the viscous droplet. Along with this, curing can occur.
도 8는 코팅 영역의 성형을 보여주는 그림이다. 8 is a drawing showing the shaping of the coating area.
도 8에 나타난 바와 같이, (c-1)에서 코팅 영역의 성형은 성형 방법에 따라 다양한 배열의 코팅층(30')을 가질 수 있다. 이와 같은 코팅층(30')의 다양한 형상 및 배열에 따라 최종 제조되는 마이크로구조체의 강도, 관통력 등을 조절할 수 있다.As shown in FIG. 8, the molding of the coating area in (c-1) may have various arrangements of the coating layer 30 ′ depending on the molding method. According to various shapes and arrangements of the coating layer 30 ′, strength, penetrating force, and the like of the final microstructure may be adjusted.
또한, 본 발명은 상기 방법에 따라 제조된 마이크로구조체를 제공한다. The present invention also provides a microstructure manufactured according to the above method.
상기 방법에 따라 제조된 마이크로구조체의 경우, 강도가 향상된 특징을 갖는다. 또한, 인체에 적용시, 인체 내 고분자 물질 또는 약물의 고용량 투여가 가능하다.In the case of the microstructure manufactured according to the above method, the strength is improved. In addition, when applied to the human body, it is possible to administer a high dose of a polymer substance or drug in the human body.
또한, 본 발명은 고분자 물질을 포함하는 베이스층; 및 상기 베이스층 상에 형성된 제2 고분자 물질을 포함하는 외부층을 포함하고, 상기 제2 고분자 물질은 상기 고분자 물질 보다 중량평균분자량 또는 점도가 작은 것을 특징으로 하는 마이크로구조체를 제공한다.In addition, the present invention is a base layer comprising a polymer material; And an outer layer including a second polymer material formed on the base layer, wherein the second polymer material has a weight average molecular weight or a viscosity lower than that of the polymer material.
상기 고분자 물질의 중량평균분자량은 50kDa 내지 2,500kDa일 수 있다. The weight average molecular weight of the polymer material may be 50kDa to 2,500kDa.
상기 고분자 물질의 점도는 25℃에서 5 Pa·s 내지 400 Pa·s일 수 있다. The viscosity of the polymer material may be 5 Pa.s to 400 Pa.s at 25 ° C.
상기 베이스층은 겔형 베이스 영역으로부터 형성된 것이고, 상기 외부층은 외부 영역으로부터 형성된 것으로, 겔형 베이스 영역, 외부 영역 및 이들의 제조 방법에 대해서는 전술한 바와 같다.The base layer is formed from a gel-based base region, and the outer layer is formed from an outer region, and the gel-based base region, the outer region, and a manufacturing method thereof are as described above.
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 겔형 고분자 물질을 이용한 마이크로구조체의 제조방법의 경우, 높은 중량평균분자량의 고분자 물질의 사용으로 인하여, 마이크로구조체의 구조 형성이 용이할 뿐만 아니라, 마이크로구조체의 강도를 향상시킬 수 있다. 또한, 인체에 적용시, 인체 내 고분자 물질 또는 약물의 고용량 투여가 가능하다.Therefore, in the method of manufacturing a microstructure using the gel polymer material according to the present invention, due to the use of a high weight average molecular weight polymer material, not only the structure of the microstructure can be easily formed, but also the strength of the microstructure can be improved. have. In addition, when applied to the human body, it is possible to administer a high dose of a polymer substance or drug in the human body.
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
직경이 190㎛의 알루미늄 기둥 상에 히알루론산(1250kDa) 25(w/v)% 겔을 내경 190㎛의 노즐(MUSASHI engineering, SN-27G-LF)을 이용하여 100㎛/s 속도로 4초 및 6.6초 동안 토출 및 경화시켜 겔형 베이스 영역을 형성하였고, 이후 칼날을 이용하여 절단하였다. Hyaluronic acid (1250 kDa) 25 (w / v)% gel was applied on an aluminum pillar having a diameter of 190 µm using a nozzle having a diameter of 190 µm (MUSASHI engineering, SN-27G-LF) at 100 µm / s for 4 seconds and Discharge and cure for 6.6 seconds to form a gelled base region which was then cut using a blade.
이후, 토출한 겔형 베이스 영역을 경화 전 점도측정기(Rheosys)을 이용하여 25℃, 30mm Parallel Plate 1.0mm Gap의 조건으로 점도를 측정하였다. 그 결과 점도는 203 Pa·s 로, 겔형 베이스 영역이 성공적으로 제조되었음을 확인할 수 있었다.Subsequently, the discharged gel-based region was measured under a condition of 25 ° C. and 30 mm Parallel Plate 1.0 mm Gap using a viscosity meter (Rheosys) before curing. As a result, the viscosity was 203 Pa.s, and it was confirmed that the gel base region was successfully prepared.
도 9(a)은 실시예 1에 따라 형성된 겔형 베이스 영역을 보여주는 전자 현미경 사진으로, 도 9(a)에서 겔형 베이스 영역의 직경은 약 62.02㎛이고, 높이는 각각 약 394.12㎛ 및 약 659.52㎛로, 겔형 베이스 영역이 성공적으로 제조되었음을 확인할 수 있었다.9 (a) is an electron micrograph showing a gel-based region formed according to Example 1, in which the diameter of the gel-based region in FIG. 9 (a) is about 62.02 μm and the height is about 394.12 μm and about 659.52 μm, respectively. It was confirmed that the gel base region was successfully prepared.
겔형 베이스 영역 상에 히알루론산(30kDa) 40(w/v)% 용액을 디스펜서(MUSASHI engineering, ML-5000ⅩⅡ)를 이용하여 0.2MPa의 압력으로 0.22초 동안 토출하여 코팅 영역을 형성하였다. 이후, 프리코팅층이 미리 형성된 알루미늄 기판을 코팅 영역 상단에 접촉시킨 후, 100㎛/s의 속도로 3.3초 동안 수직으로 드로잉하였다. 이후, 1분 동안 경화시킨 후, 프리코팅층이 미리 형성된 알루미늄 기판을 100㎛/s의 속도로 수직 상승시켜 마이크로구조체를 최종 제조하였다.A hyaluronic acid (30 kDa) 40 (w / v)% solution was dispensed on a gel-based base region using a dispenser (MUSASHI engineering, ML-5000xII) at a pressure of 0.2 MPa for 0.22 seconds to form a coating region. Thereafter, the aluminum substrate on which the precoating layer was previously formed was brought into contact with the top of the coating area, and then vertically drawn for 3.3 seconds at a rate of 100 μm / s. Thereafter, after curing for 1 minute, the aluminum substrate on which the pre-coating layer was previously formed was vertically raised at a rate of 100 μm / s to finally manufacture the microstructure.
이후, 형성된 겔형 베이스 영역을 강도측정기(Zwick/Roell, Z0.5)을 이용하여 3.6mm/min 속도로 강도를 측정하였다. 그 결과 평균 강도 1.3 N로, 겔형 베이스 영역이 성공적으로 제조되었음을 확인할 수 있었다.Thereafter, the formed gel-based region was measured at a speed of 3.6 mm / min using a strength meter (Zwick / Roell, Z0.5). As a result, it was confirmed that the gel-based base region was successfully produced with an average strength of 1.3 N.
실시예Example 2 2
직경이 190㎛의 알루미늄 기둥 상에 히알루론산(1250kDa) 25(w/v)% 겔을 내경 330㎛ 및 580㎛의 노즐(MUSASHI engineering, SN-23G-LF 및 SN-20G-LF)을 이용하여 100㎛/s 속도로 6초 및 6.5초 동안 토출 및 경화시켜 겔형 베이스 영역을 형성하였고, 이후 칼날을 이용하여 절단하였다. 이후, 실시예 1과 동일한 방법으로 마이크로구조체를 최종 제조하였다.Hyaluronic acid (1250kDa) 25 (w / v)% gel was applied on aluminum pillars with a diameter of 190 µm using nozzles with internal diameters of 330 µm and 580 µm (MUSASHI engineering, SN-23G-LF and SN-20G-LF). Discharged and cured at 100 μm / s for 6 seconds and 6.5 seconds to form a gel base region, which was then cut using a blade. Thereafter, the microstructures were finally manufactured in the same manner as in Example 1.
이후, 토출한 겔형 베이스 영역을 경화 전 점도측정기(Rheosys)을 이용하여 25℃, 30mm Parallel Plate 1.0mm Gap의 조건으로 점도를 측정하였다. 그 결과 점도는 203 Pa·s 로, 겔형 베이스 영역이 성공적으로 제조되었음을 확인할 수 있었다. Subsequently, the discharged gel-based region was measured under a condition of 25 ° C. and 30 mm Parallel Plate 1.0 mm Gap using a viscosity meter (Rheosys) before curing. As a result, the viscosity was 203 Pa.s, and it was confirmed that the gel base region was successfully prepared.
도 9(b)은 실시예 2에 따라 형성된 겔형 베이스 영역을 보여주는 전자 현미경 사진으로, 도 9(b)에서 겔형 베이스 영역의 직경은 각각 약 341.37㎛ 및 약 575.54㎛이고, 높이는 각각 약 512.49㎛ 및 약 444.44㎛로, 겔형 베이스 영역이 성공적으로 제조되었음을 확인할 수 있었다.FIG. 9 (b) is an electron micrograph showing the gel base region formed according to Example 2, in which the diameters of the gel base region in FIG. 9 (b) are about 341.37 μm and about 575.54 μm, respectively, and the heights are about 512.49 μm and At about 444.44 μm, it was confirmed that the gelled base region was successfully prepared.
이후, 형성된 겔형 베이스 영역을 강도측정기(Zwick/Roell, Z0.5)을 이용하여 3.6mm/min 속도로 강도를 측정하였다. 그 결과 평균 강도 2.2 N로, 겔형 베이스 영역이 성공적으로 제조되었음을 확인할 수 있었다.Thereafter, the formed gel-based region was measured at a speed of 3.6 mm / min using a strength meter (Zwick / Roell, Z0.5). As a result, it was confirmed that the gel-based base region was successfully prepared with an average intensity of 2.2 N.
실시예Example 3 3
알루미늄 기판 상에 카르복시메틸셀룰로오스(Carbosymethylcellulose, Sigma-Aldrich, Inc.) 프리코팅층 30㎛을 미리 형성한 후, 히알루론산(1250kDa) 25(w/v)% 겔을 도포하였다. 이어서, 도포된 히알루론산 겔에 내경 190㎛의 노즐(MUSASHI engineering, SN-27G-LF)을 100㎛/s 속도로 수직으로 하강시켜 도포된 히알루론산 겔을 노즐 내부에 탑재시켰다. 이어서, 히알루론산 겔이 탑재된 노즐을 프리코팅층이 미리 형성된 알루미늄 기판 상에 500㎛ 높이에 위치시킨 후, 디스펜서(MUSASHI engineering, ML-5000ⅩⅡ)를 이용하여 0.5MPa의 압력으로 토출하여 겔형 베이스 영역을 형성하였다. 이후, 실시예 1과 동일한 방법으로 마이크로구조체를 최종 제조하였다.Carbosymethylcellulose (Sigma-Aldrich, Inc.) precoating layer 30㎛ pre-formed on an aluminum substrate, and then hyaluronic acid (1250kDa) 25 (w / v)% gel was applied. Subsequently, the applied hyaluronic acid gel was vertically lowered at a nozzle having a diameter of 190 μm (MUSASHI engineering, SN-27G-LF) at a speed of 100 μm / s, and the applied hyaluronic acid gel was mounted inside the nozzle. Subsequently, the nozzle on which the hyaluronic acid gel is mounted is placed at a height of 500 μm on an aluminum substrate on which a precoating layer is formed, and then discharged at a pressure of 0.5 MPa using a dispenser (MUSASHI engineering, ML-5000 × II) to obtain a gel-based base region. Formed. Thereafter, the microstructures were finally manufactured in the same manner as in Example 1.
이후, 토출한 겔형 베이스 영역을 경화 전 점도측정기(Rheosys)을 이용하여 25℃, 30mm Parallel Plate 1.0mm Gap의 조건으로 점도를 측정하였다. 그 결과 점도는 203 Pa·s 로, 겔형 베이스 영역이 성공적으로 제조되었음을 확인할 수 있었다. Subsequently, the discharged gel-based region was measured under a condition of 25 ° C. and 30 mm Parallel Plate 1.0 mm Gap using a viscosity meter (Rheosys) before curing. As a result, the viscosity was 203 Pa.s, and it was confirmed that the gel base region was successfully prepared.
이후, 형성된 겔형 베이스 영역을 강도측정기(Zwick/Roell, Z0.5)을 이용하여 3.6mm/min 속도로 강도를 측정하였다. 그 결과 평균 강도 1.8 N로, 겔형 베이스 영역이 성공적으로 제조되었음을 확인할 수 있었다.Thereafter, the formed gel-based region was measured at a speed of 3.6 mm / min using a strength meter (Zwick / Roell, Z0.5). As a result, it was confirmed that the gel-based base region was successfully prepared with an average strength of 1.8 N.
도 9(c)는 실시예 3에 따라 형성된 겔형 베이스 영역을 보여주는 전자 현미경 사진으로, 도 9(c)에서 겔형 베이스 영역의 직경은 각각 약 218.64㎛ 및 약 196.11㎛이고, 높이는 각각 약 368.34㎛ 및 약 446.52㎛로, 겔형 베이스 영역이 성공적으로 제조되었음을 확인할 수 있었다.9 (c) is an electron micrograph showing the gel-based region formed according to Example 3, in which the diameters of the gel-based region in FIG. 9 (c) are about 218.64 μm and about 196.11 μm, respectively, and the heights are about 368.34 μm and At about 446.52 μm, it was confirmed that the gelled base region was successfully prepared.
또한, 도 9(d)는 실시예 3에 따라 최종 제조된 마이크로구조체를 보여주는 전자현미경 사진으로, 마이크로구조체가 성공적으로 제조되었음을 확인할 수 있었다.In addition, Figure 9 (d) is an electron micrograph showing the final microstructure prepared according to Example 3, it was confirmed that the microstructure was successfully produced.
실시예Example 4 4
알루미늄 기판 상에 카르복시메틸셀룰로오스(Carbosymethylcellulose, Sigma-Aldrich, Inc.) 프리코팅층 30㎛을 미리 형성한 후, 히알루론산(800kDa) 10(w/v)% 겔을 내경 250㎛의 노즐(MUSASHI engineering, TPND-25G)에 탑재시켰다. 이어서 히알루론산 겔이 탑재된 노즐을 프리코팅층이 미리 형성된 알루미늄 기판 상에 100㎛ 높이에 위치시킨 후, 디스펜서(MUSASHI engineering, ML-5000ⅩⅡ)를 이용하여 0.2MPa의 압력으로 토출하였다. 이후, 토출한 겔형 베이스 영역을 경화 전 점도측정기(Rheosys)을 이용하여 25℃, 30mm Parallel Plate 1.0mm Gap의 조건으로 점도를 측정하였다. 그 결과 점도는 180 Pa?s 로, 겔형 베이스 영역이 성공적으로 제조되었음을 확인할 수 있었다.Carbosymethylcellulose (Sigma-Aldrich, Inc.) pre-coating layer 30㎛ pre-formed on an aluminum substrate, hyaluronic acid (800kDa) 10 (w / v)% gel with an internal diameter of 250㎛ nozzle (MUSASHI engineering, TPND-25G). Subsequently, the nozzle on which the hyaluronic acid gel was mounted was placed at a height of 100 μm on an aluminum substrate on which a precoating layer was previously formed, and then discharged at a pressure of 0.2 MPa using a dispenser (MUSASHI engineering, ML-5000 Pa II). Subsequently, the discharged gel-based region was measured under a condition of 25 ° C. and 30 mm Parallel Plate 1.0 mm Gap using a viscosity meter (Rheosys) before curing. As a result, the viscosity was 180 Pa · s, and it was confirmed that the gel-based base region was successfully prepared.
이후, 1.0mm 높이에 카르복시메틸셀룰로오스 프리코팅층을 부착하여 5분 건조 후 분리하여 겔형 베이스 영역을 제조하였다.Thereafter, the carboxymethyl cellulose precoat layer was attached to a height of 1.0 mm, dried for 5 minutes, and separated to prepare a gel-based base region.
겔형 베이스 영역 상에 히알루론산(39kDa) 55(w/v)% 용액을 디스펜서(MUSASHI engineering, ML-5000Ⅱ)를 이용하여 0.2MPa의 압력으로 0.22초 동안 토출하여 코팅 영역을 형성하였다. 이후, 코팅 영역이 형성된 겔형 베이스 영역을 원심분리기(Hanil, Combi 514-R)에 탑재 후, 코팅 영역이 형성된 겔형 베이스 영역과 1.0mm 간격으로 프리코팅층이 미리 형성된 알루미늄 기판을 위치시켰다. 이후 2000rpm의 속도로 60초 동안 회전시킨 이후, 1분 동안 경화시킨 후, 마이크로구조체를 최종 제조하였다.A 55 (w / v)% solution of hyaluronic acid (39 kDa) on the gel-based area was dispensed for 0.22 seconds at a pressure of 0.2 MPa using a dispenser (MUSASHI engineering, ML-5000 II) to form a coating area. Subsequently, the gel-based base region in which the coating region was formed was mounted in a centrifuge (Hanil, Combi 514-R), and the aluminum substrate on which the pre-coating layer was previously formed was placed at 1.0 mm intervals from the gel-based base region in which the coating region was formed. After rotating for 60 seconds at a speed of 2000rpm, after curing for 1 minute, the microstructure was finally produced.
이후, 형성된 겔형 베이스 영역을 강도측정기(Zwick/Roell, Z0.5)을 이용하여 3.6mm/min 속도로 강도를 측정하였다. 그 결과 평균 강도 1.5 N로, 겔형 베이스 영역이 성공적으로 제조되었음을 확인할 수 있었다.Thereafter, the formed gel-based region was measured at a speed of 3.6 mm / min using a strength meter (Zwick / Roell, Z0.5). As a result, it was confirmed that the gel-based base region was successfully prepared with an average strength of 1.5 N.
도 10(a)는 실시예 4에 따라 형성된 겔형 베이스 영역을 보여주는 전자 현미경 사진으로, 도 10(a)에서 겔형 베이스 영역의 직경은 각각 약 557.69㎛이고, 높이는 각각 약 365.38㎛로, 겔형 베이스 영역이 성공적으로 제조되었음을 확인할 수 있었다.10 (a) is an electron micrograph showing a gel-based region formed according to Example 4, in which the diameters of the gel-based regions in FIG. 10 (a) are each about 557.69 μm and the heights are about 365.38 μm, respectively. It was confirmed that this was successfully manufactured.
또한, 도 10(b)와 10(c)는 실시예 4에 따라 최종 제조된 마이크로구조체를 보여주는 전자현미경 사진으로, 마이크로구조체가 성공적으로 제조되었음을 확인할 수 있었다.In addition, Figure 10 (b) and 10 (c) is an electron micrograph showing the final microstructure prepared according to Example 4, it was confirmed that the microstructure was successfully manufactured.
실시예Example 5 5
알루미늄 기판 상에 카르복시메틸셀룰로오스(Carbosymethylcellulose, Sigma-Aldrich, Inc.) 프리코팅층 30㎛을 미리 형성한 후, 히알루론산(1400kDa) 10(w/v)% 겔을 내경 250㎛의 노즐(MUSASHI engineering, TPND-25G)에 탑재시켰다. 이어서 히알루론산 겔이 탑재된 노즐을 프리코팅층이 미리 형성된 알루미늄 기판 상에 100㎛ 높이에 위치시킨 후, 디스펜서(MUSASHI engineering, ML-5000ⅩⅡ)를 이용하여 0.2MPa의 압력으로 토출하였다. 이후, 토출한 겔형 베이스 영역을 경화 전 점도측정기(Rheosys)을 이용하여 25℃, 30mm Parallel Plate 1.0mm Gap의 조건으로 점도를 측정하였다. 그 결과 점도는 193 Pa?s 로, 겔형 베이스 영역이 성공적으로 제조되었음을 확인할 수 있었다.Carbosymethylcellulose (Sigma-Aldrich, Inc.) pre-coating layer 30㎛ pre-formed on an aluminum substrate, hyaluronic acid (1400kDa) 10 (w / v)% gel was 250㎛ nozzle (MUSASHI engineering, TPND-25G). Subsequently, the nozzle on which the hyaluronic acid gel was mounted was placed at a height of 100 μm on an aluminum substrate on which a precoating layer was previously formed, and then discharged at a pressure of 0.2 MPa using a dispenser (MUSASHI engineering, ML-5000 Pa II). Subsequently, the discharged gel-based region was measured under a condition of 25 ° C. and 30 mm Parallel Plate 1.0 mm Gap using a viscosity meter (Rheosys) before curing. As a result, the viscosity was 193 Pa? S, and it was confirmed that the gel-based base region was successfully prepared.
이후, 1.0mm 높이에 카르복시메틸셀룰로오스 프리코팅층을 부착하여 5분 건조 후 분리하여 겔형 베이스 영역을 제조하였다.Thereafter, the carboxymethyl cellulose precoat layer was attached to a height of 1.0 mm, dried for 5 minutes, and separated to prepare a gel-based base region.
이후, 실시예 4와 동일한 방법으로 마이크로구조체를 최종 제조하였다. Thereafter, the microstructures were finally manufactured in the same manner as in Example 4.
이후, 형성된 겔형 베이스 영역을 강도측정기(Zwick/Roell, Z0.5)을 이용하여 3.6mm/min 속도로 강도를 측정하였다. 그 결과 평균 강도 1.5 N로, 겔형 베이스 영역이 성공적으로 제조되었음을 확인할 수 있었다.Thereafter, the formed gel-based region was measured at a speed of 3.6 mm / min using a strength meter (Zwick / Roell, Z0.5). As a result, it was confirmed that the gel-based base region was successfully prepared with an average strength of 1.5 N.
도 11(a)는 실시예 5에 따라 형성된 겔형 베이스 영역을 보여주는 전자 현미경 사진으로, 도 11(a)에서 겔형 베이스 영역의 직경은 각각 약 324.74㎛이고, 높이는 각각 약 247.77㎛로, 겔형 베이스 영역이 성공적으로 제조되었음을 확인할 수 있었다.FIG. 11 (a) is an electron micrograph showing a gel-based region formed according to Example 5, wherein the diameter of the gel-based region in FIG. 11 (a) is about 324.74 µm and the height is about 247.77 µm, respectively. It was confirmed that this was successfully manufactured.
또한, 도 11(b) 는 실시예 5에 따라 최종 제조된 마이크로구조체를 보여주는 전자현미경 사진으로, 마이크로구조체가 성공적으로 제조되었음을 확인할 수 있었다.In addition, Figure 11 (b) is an electron micrograph showing the final microstructure prepared according to Example 5, it was confirmed that the microstructure was successfully produced.
실시예Example 6 6
실시예 5와 동일한 방법으로 겔형 베이스 영역을 제조하였다. 이 때, 토출한 겔형 베이스 영역을 경화 전 점도측정기(Rheosys)을 이용하여 25℃, 30mm Parallel Plate 1.0mm Gap의 조건으로 점도를 측정하였다. 그 결과 점도는 193 Pa?s 로, 겔형 베이스 영역이 성공적으로 제조되었음을 확인할 수 있었다.Gel-like base regions were prepared in the same manner as in Example 5. At this time, the discharged gel-based region was measured using a viscosity meter (Rheosys) before curing under conditions of 25 ° C. and 30 mm Parallel Plate 1.0 mm Gap. As a result, the viscosity was 193 Pa? S, and it was confirmed that the gel-based base region was successfully prepared.
겔형 베이스 영역 상에 히알루론산(39kDa) 55(w/v)% 용액을 디스펜서(MUSASHI engineering, ML-5000Ⅱ)를 이용하여 0.2MPa의 압력으로 0.40초 동안 토출하여 코팅 영역을 형성하였다. 이후, 코팅 영역이 형성된 겔형 베이스 영역을 원심분리기(Hanil, Combi 514-R)에 탑재 후, 코팅 영역이 형성된 겔형 베이스 영역과 1.0mm 간격으로 프리코팅층이 미리 형성된 알루미늄 기판을 위치시켰다. 이후 2000rpm의 속도로 60초 동안 회전시킨 이후, 1분 동안 경화시킨 후, 마이크로구조체를 최종 제조하였다.A 55% w / v) solution of hyaluronic acid (39 kDa) was dispensed on the gel-based area using a dispenser (MUSASHI engineering, ML-5000 II) at a pressure of 0.2 MPa for 0.40 seconds to form a coating area. Subsequently, the gel-based base region in which the coating region was formed was mounted in a centrifuge (Hanil, Combi 514-R), and the aluminum substrate on which the pre-coating layer was previously formed was placed at 1.0 mm intervals from the gel-based base region in which the coating region was formed. After rotating for 60 seconds at a speed of 2000rpm, after curing for 1 minute, the microstructure was finally produced.
이후, 형성된 겔형 베이스 영역을 강도측정기(Zwick/Roell, Z0.5)을 이용하여 3.6mm/min 속도로 강도를 측정하였다. 그 결과 평균 강도 1.5 N로, 겔형 베이스 영역이 성공적으로 제조되었음을 확인할 수 있었다.Thereafter, the formed gel-based region was measured at a speed of 3.6 mm / min using a strength meter (Zwick / Roell, Z0.5). As a result, it was confirmed that the gel-based base region was successfully prepared with an average strength of 1.5 N.
도 12(a)와 12(b)는 실시예 6에 따라 최종 제조된 마이크로구조체를 보여주는 전자현미경 사진으로, 겔형 베이스 영역의 직경은 각각 약 485㎛ 및 약 610㎛이고, 높이는 각각 약 466㎛ 및 약 317㎛이고, 마이크로구조체의 높이는 각각 461㎛ 및 약 495㎛로 마이크로구조체가 성공적으로 제조되었음을 확인할 수 있었다.12 (a) and 12 (b) are electron micrographs showing the microstructures finally prepared according to Example 6, wherein the gel-based base diameters were about 485 μm and about 610 μm, respectively, and the heights were about 466 μm and It was about 317 μm, and the heights of the microstructures were 461 μm and 495 μm, respectively.
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 (19)

  1. (a) 지지체 상에 고분자 물질을 포함하는 겔형 베이스 영역을 형성하는 단계; 및 (a) forming a gelled base region comprising a polymeric material on a support; And
    (b) 상기 겔형 베이스 영역 상에 외부 영역을 형성하는 단계를 포함하는 (b) forming an outer region on the gelled base region;
    마이크로구조체의 제조방법.Method for producing a microstructure.
  2. 제1항에 있어서, The method of claim 1,
    상기 (a)에서 고분자 물질의 중량평균분자량은 50kDa 내지 2,500kDa인 The weight average molecular weight of the polymer material in (a) is 50kDa to 2,500kDa
    마이크로구조체의 제조방법.Method for producing a microstructure.
  3. 제1항에 있어서, The method of claim 1,
    상기 (a)에서 겔형 베이스 영역의 점도는 25℃에서 5 Pa·s내지 400 Pa·s 인 In (a), the viscosity of the gel-based region is 5 Pa.s to 400 Pa.s at 25 ° C.
    마이크로구조체의 제조방법.Method for producing a microstructure.
  4. 제1항에 있어서, The method of claim 1,
    상기 (a) 단계에서 겔형 베이스 영역의 겔 강도(gel strength)는 0.03N 내지 5N 인 In step (a), the gel strength of the gel-based base region is 0.03N to 5N.
    마이크로구조체의 제조방법.Method for producing a microstructure.
  5. 제1항에 있어서, The method of claim 1,
    상기 (a) 단계에서 겔형 베이스 영역은 다중 베이스 영역으로 구분되는 In step (a), the gel base region is divided into multiple base regions.
    마이크로구조체의 제조방법.Method for producing a microstructure.
  6. 제1항에 있어서, The method of claim 1,
    상기 (a) 단계에서 겔형 베이스 영역 또는 상기 (b) 단계에서 외부 영역 내부에 약물이 추가로 탑재된 In the step (a) the gel-based region or in step (b) the drug is further mounted inside the outer region
    마이크로구조체의 제조방법.Method for producing a microstructure.
  7. 제1항에 있어서, The method of claim 1,
    상기 (a) 단계에서 겔형 베이스 영역의 형성은 토출, 부착, 펀칭 또는 몰딩에 의해 수행되는 In the step (a), the formation of the gel-based base region is performed by discharging, attaching, punching or molding.
    마이크로구조체의 제조방법.Method for producing a microstructure.
  8. 제1항에 있어서, The method of claim 1,
    상기 지지체 상에 프리코팅층이 미리 형성된 Pre-coating layer is formed on the support in advance
    마이크로구조체의 제조방법.Method for producing a microstructure.
  9. 제1항에 있어서, The method of claim 1,
    상기 (a) 단계에서 겔형 베이스 영역의 형성과 동시에, 또는 상기 (a) 단계에서 겔형 베이스 영역의 형성 후에, 상기 겔형 베이스 영역을 변형하는 단계를 추가로 포함하는 Simultaneously deforming the gel base region in step (a) or after forming the gel base region in step (a), further comprising deforming the gel base region.
    마이크로구조체의 제조방법.Method for producing a microstructure.
  10. 제1항에 있어서, The method of claim 1,
    상기 (b) 단계에서 외부 영역의 형성은 상기 겔형 베이스 영역 상에 제2 고분자 물질을 포함하는 코팅 영역의 코팅을 통해 수행되고, In the step (b), the formation of the outer region is performed by coating a coating region including a second polymer material on the gel-based base region.
    상기 제2 고분자 물질은 상기 고분자 물질 보다 중량평균분자량 또는 점도가 작은 것을 특징으로 하는 The second polymer material is characterized in that the weight average molecular weight or viscosity is less than the polymer material
    마이크로구조체의 제조방법.Method for producing a microstructure.
  11. 제1항에 있어서, The method of claim 1,
    상기 (b) 단계에서 외부 영역의 형성은 상기 겔형 베이스 영역 상에 제2 마이크로구조체의 부착을 통해 수행되는 Formation of the outer region in step (b) is carried out through the attachment of a second microstructure on the gel-based base region
    마이크로구조체의 제조방법.Method for producing a microstructure.
  12. 제10항에 있어서, The method of claim 10,
    상기 코팅 영역은 다중 코팅 영역으로 구분되는 The coating area is divided into multiple coating areas
    마이크로구조체의 제조방법.Method for producing a microstructure.
  13. 제10항에 있어서, The method of claim 10,
    상기 코팅은 토출, 담금 또는 분사에 의해 수행되는 The coating is carried out by discharging, immersing or spraying
    마이크로구조체의 제조방법.Method for producing a microstructure.
  14. 제10항에 있어서, The method of claim 10,
    상기 코팅 후, 상기 코팅 영역을 성형하거나, 상기 코팅 영역 상에 별도의 마이크로구조체를 부착하는After the coating, forming the coating area, or attach a separate microstructure on the coating area
    마이크로구조체의 제조방법.Method for producing a microstructure.
  15. 제14항에 있어서, The method of claim 14,
    상기 성형은 몰딩, 드로잉, 송풍, 흡입, 원심력 인가 및 자기장 인가로 이루어진 군으로부터 선택된 하나 이상의 방법으로 수행되는 The molding 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.
  16. 제1항의 방법에 따라 제조된 마이크로구조체.Microstructures prepared according to the method of claim 1.
  17. 고분자 물질을 포함하는 베이스층; 및 A base layer comprising a polymer material; And
    상기 베이스층 상에 형성된 제2 고분자 물질을 포함하는 외부층을 포함하고, An outer layer including a second polymer material formed on the base layer,
    상기 제2 고분자 물질은 상기 고분자 물질 보다 중량평균분자량 또는 점도가 작은 것을 특징으로 하는 The second polymer material is characterized in that the weight average molecular weight or viscosity is less than the polymer material
    마이크로구조체.Microstructures.
  18. 제17항에 있어서,The method of claim 17,
    상기 고분자 물질의 중량평균분자량은 50kDa 내지 2,500kDa인 The weight average molecular weight of the polymer material is 50kDa to 2,500kDa
    마이크로구조체.Microstructures.
  19. 제17항에 있어서, The method of claim 17,
    상기 고분자 물질의 점도는 25℃에서 5 Pa·s 내지 400 Pa·s 인The viscosity of the polymeric material is 5 Pa.s to 400 Pa.s at 25 ° C.
    마이크로구조체. Microstructures.
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