WO2022173227A1 - Method for preparing solid drug formulation on basis of ultraviolet printing - Google Patents

Method for preparing solid drug formulation on basis of ultraviolet printing Download PDF

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Publication number
WO2022173227A1
WO2022173227A1 PCT/KR2022/001995 KR2022001995W WO2022173227A1 WO 2022173227 A1 WO2022173227 A1 WO 2022173227A1 KR 2022001995 W KR2022001995 W KR 2022001995W WO 2022173227 A1 WO2022173227 A1 WO 2022173227A1
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Prior art keywords
drug
present
solid
biocompatible ink
ink
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PCT/KR2022/001995
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French (fr)
Korean (ko)
Inventor
최은표
박종오
김창세
강병전
방도연
다르마완 바비아디티아
이상봉
Original Assignee
전남대학교 산학협력단
재단법인 한국마이크로의료로봇연구원
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Priority claimed from KR1020220016536A external-priority patent/KR20220115527A/en
Application filed by 전남대학교 산학협력단, 재단법인 한국마이크로의료로봇연구원 filed Critical 전남대학교 산학협력단
Publication of WO2022173227A1 publication Critical patent/WO2022173227A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction

Definitions

  • the present invention was made by project number 9991006801 under the support of the Ministry of Science and ICT, the Ministry of Trade, Industry and Energy, the Ministry of Health and Welfare, and the Ministry of Food and Drug Safety.
  • the research project name is "Pan-ministerial cycle medical device R&D project”
  • the research project name is "Development of a biodegradable porous micromedibot with an optimally designed shape according to the disease environment and treatment”
  • the host organization is Chonnam National University Industry-Academic Cooperation Foundation
  • the research period is 2021.03.01 ⁇ 2022.02.28.
  • the present invention relates to a method for manufacturing a solid drug based on ultraviolet printing, and more particularly, the method for manufacturing a solid drug according to the present invention can produce a uniform and constant number of drug solids, and the preparation process for the preparation of drug solids and
  • the advantage is that the production process is simple.
  • Drug delivery technology is known as a technology designed to effectively deliver a required amount of a drug by maximizing the efficacy and therapeutic effect of the drug while reducing the side effects of the drug.
  • Effective and economical treatment for various diseases is required, and it is expected that customized medical care that appropriately administers the necessary amount to the necessary place according to the patient's condition will arrive.
  • the need for drug delivery technology is increasing, and a technology capable of simultaneously performing diagnosis as well as existing therapeutic purposes is being developed.
  • a solid dosage form is a solid dosage form of a drug, usually administered orally to a patient, and is usually formulated with suitable excipients and coated with a variety of colors, fragrances, and the like.
  • Solid formulations differ in size, shape, weight, hardness, thickness, and disintegration characteristics depending on the purpose of use and manufacturing method. These solids are mainly prepared by compression, and it is common to produce the solids by mold molding. Types of solid preparations include compressed tablets, multi-compressed tablets, dragees, film-coated tablets, enteric-coated tablets, thin or sublingual tablets, chewed tablets, effervescent tablets, acid tablets, subcutaneous injection solids, and solid preparations. The most common compressed tablets are punches and dies of various shapes, and are manufactured by applying strong pressure to powders and granules.
  • the existing solid preparation technology had a problem in that it was difficult to produce a solid preparation in a uniform size and in a constant number, and the preparation process and production process for the solid preparation were excessively complicated.
  • the present inventors have devised a method for manufacturing a drug solid drug based on ultraviolet printing that compensates for the disadvantages of the existing drug solid preparation method, and the manufacturing method according to the present invention can produce a drug solid drug in a uniform size and in a constant number. , there is an advantage in that the solid preparation preparation process and the production process are simple.
  • the present invention relates to a method for manufacturing a solid drug based on ultraviolet printing, and the method for manufacturing a solid drug according to the present invention can produce a uniform and constant number of drug solids, and has the advantage of simple preparation and production of solid preparations. And, the drug solid produced through the manufacturing method according to the present invention exhibits high uniformity, can carry more drug than the drug-coated formulation only on the outer surface, and can release the drug within a faster time.
  • One aspect of the present invention is a method for preparing a UV-based solid drug formulation comprising the steps of:
  • the chamber may be a microchamber, but is not limited thereto.
  • microchamber refers to a chamber having a size small enough to contain a photocrosslinkable and biocompatible ink and a drug, that is, a chamber having a sufficiently small compartment (well) to contain the biocompatible ink and a drug. it means
  • the diameter of the well is 0.2 to 8.0 mm, 0.4 to 8.0 mm, 0.6 to 8.0 mm, 0.8 to 8.0 mm, 1.0 to 8.0 mm, 1.2 to 8.0 mm, 1.4 to 8.0 mm, 1.6 to 8.0 mm.
  • the height of the well is 0.1 to 3.0 mm, 0.1 to 2.5 mm, 0.1 to 2.0 mm, 0.1 to 1.5 mm, 0.1 to 1.0 mm, 0.1 to 0.8 mm, 0.1 to 0.6 mm, 0.1 to 0.4 mm, 0.2 to 3.0 mm, 0.2-2.5 mm, 0.2-2.0 mm, 0.2-1.5 mm, 0.2-1.0 mm, 0.2-0.8 mm, 0.2-0.6 mm, 0.2-0.4 mm, 0.3-3.0 mm, 0.3-2.5 mm, 0.3-2.0 mm, 0.3 to 1.5 mm, 0.3 to 1.0 mm, 0.3 to 0.8 mm, 0.3 to 0.6 mm, or 0.3 to 0.4 mm, for example, 0.36 mm.
  • the microchamber may have various shapes such as a circle, a rectangle, a triangle, a square, a rhombus, a pentagon, and a hexagon, for example, it may be a square, but is not limited thereto.
  • the well may have various shapes such as a circle, a rectangle, a triangle, a square, a rhombus, a pentagon, and a hexagon, for example, it may be a circle, but is not limited thereto.
  • the method may further include an ink production step of producing a biocompatible ink.
  • the biocompatible ink may be cured by a photocrosslinking reaction.
  • the biocompatible ink is fucoidan, alginate, chitosan, hyaluronic acid, silk, polyethylene glycol (Poly Ethylene Glycol; PEG), polyimides, polyamic acid (polyamix acid), polycaprolactone (polycarprolactone), Polyetherimide, nylon, polyaramid, polyvinyl alcohol, polyvinylpyrrolidone, poly-benzyl-glutamate, polyphenylene terephthalate Amide (polyphenyleneterephthalamide), polyaniline (polyaniline), polyacrylonitrile (polyacrylonitrile), polyethylene oxide (polyethylene oxide), polystyrene (polystyrene), cellulose (cellulose), polyacrylate (polyacrylate), polymethylmethacrylate (polymethylmethacrylate) ), polylactic acid (PLA), polyglycolic acid (PGA), copolymer of polylactic acid and polyglycolic acid (PLGA), polylactic acid (PLA
  • the biocompatible ink may include a crosslinking agent or an optical initiator (photoinitiator).
  • the crosslinking agent may be a compound containing a polyvalent metal ion used in a conventional hydrogel composition, but is not limited thereto.
  • the polyvalent metal ion compound may be one selected from the group consisting of an aluminum compound, a calcium compound, and a magnesium compound, for example, aluminum hydroxide, hydrous aluminum silicate, calcium chloride, magnesium chloride, aluminum chloride, aluminum metasilicate acid It may be at least one selected from the group consisting of magnesium, aluminum acetate, and magnesium alumina silicate, but is not limited thereto.
  • photoinitiator refers to a substance that causes rapid crosslinking upon exposure to light.
  • an optical initiator in which a crosslinking reaction occurs by irradiation of ultraviolet (UV) or an optical initiator in which a crosslinking reaction occurs by irradiation of visible light may be used, for example, acetophenone, methyl benzoin It may be ethyr, diethoxyacetophenone, benzoyl phosphine oxide, 1-hydroxycyclohexyl phenyl ketone or eosin, and the like, but is not limited thereto, and the amount of the optical initiator added may vary depending on the wavelength and time of the exposed light. have.
  • the biocompatible ink may further include a viscosity enhancer to control the mechanical properties or printing tendency of the biocompatible ink, for example, may further include hyaluronic acid or dextran, but this It is not limited.
  • the biocompatible ink may further include an antioxidant.
  • the antioxidant is erythorbic acid, dibutylhydroxytoluene, butylhydroxyanisole, ⁇ -tocopherol, tocopherol acetate, L-ascorbic acid and its salts, L-ascorbic acid palmitate, L-ascorbic acid stearate Rate, sodium hydrogen sulfite, sodium sulfite, triamyl gallic acid, propyl gallate, sodium ethylenediamine tetraacetate (EDTA), sodium pyrophosphate, and sodium metaphosphate may be at least one selected from the group consisting of, but limited thereto it's not going to be
  • the UV-based drug solid preparation method may further include a washing step of washing the drug solid.
  • the washing solution in the washing step may be isopropyl alcohol (IPA), ethanol, distilled water or deionized water, but is not limited thereto.
  • IPA isopropyl alcohol
  • ethanol distilled water or deionized water
  • UV irradiation time of the manufacturing step in the present invention is 60 to 240 seconds, 80 to 240 seconds, 100 to 240 seconds, 60 to 220 seconds, 80 to 220 seconds, 100 to 220 seconds, 60 to 200 seconds, 80 to 200 seconds , 100 to 200 seconds, 60 to 180 seconds, 80 to 180 seconds, 100 to 180 seconds, 60 to 160 seconds, 80 to 160 seconds, 100 to 160 seconds, 60 to 140 seconds, 80 to 140 seconds, 100 to 140 seconds , for example, may be 120 seconds.
  • irradiating UV within the above range there is a remarkable effect of maximally loading the drug.
  • the UV of the manufacturing step may be to use a UV laser, but is not limited thereto.
  • the wavelength of UV in the present invention is 340 to 390nm, 340 to 385nm, 340 to 380nm, 340 to 375nm, 340 to 370nm, 345 to 390nm, 345 to 385nm, 345 to 380nm, 345 to 375nm, 345 to 370nm, 350 to 390 nm, 350-385 nm, 350-380 nm, 350-375 nm, 350-370 nm, 355-390 nm, 355-385 nm, 355-380 nm, 355-375 nm, 355-370 nm, 360-390 nm, 360-385 nm, 360-380 nm, 360 to 375 nm, or 360 to 370 nm, for example, may be 365 nm, but is not limited thereto.
  • the UV-based drug solid preparation method may be performed by a UV-printer (UV-printer).
  • UV-printer UV-printer
  • the drug may be an antibiotic, statin, stimulant, antiseptic, antipyretic, chemotherapeutic, anti-inflammatory, antifungal, hormonal drug, diuretic, contraceptive, antipsychotic (antidepressant, antipsychotic, etc.) or anticancer agent, for example,
  • it may be doxorubicin (Doxorubicin), Cy5.5, cisplatin (Cisplatin) or oxaliplatin (oxaliplatin), but is not limited thereto.
  • the biocompatible ink contains 1 to 25 mg/mL, 3 to 25 mg/mL, 5 to 25 mg/mL, 1 to 20 mg/mL, 3 to 20 mg/mL, 5 to 20 mg/mL of the drug.
  • mL, 1 to 15 mg/mL, 3 to 15 mg/mL, for example, 5 to 15 mg/mL may be included.
  • the drug loading amount is maximized, and there is a remarkable effect that the economical cost is the best during production.
  • the solid drug may include a pharmaceutically acceptable carrier in addition to the drug as an active ingredient.
  • pharmaceutically acceptable carriers are those commonly used in formulation, and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose. , polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil.
  • the drug solid agent may further include a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, etc. in addition to the above components.
  • the diameter of the drug solid in the present invention is 0.2 to 8.0 mm, 0.4 to 8.0 mm, 0.6 to 8.0 mm, 0.8 to 8.0 mm, 1.0 to 8.0 mm, 1.2 to 8.0 mm, 1.4 to 8.0 mm, 1.6 to 8.0 mm, 0.2 to 7.0 mm, 0.4 to 7.0 mm, 0.6 to 7.0 mm, 0.8 to 7.0 mm, 1.0 to 7.0 mm, 1.2 to 7.0 mm, 1.4 to 7.0 mm, 1.6 to 7.0 mm, 0.2 to 6.0 mm, 0.4 to 6.0 mm, 0.6 to 6.0 mm, 0.8 to 6.0 mm, 1.0 to 6.0 mm, 1.2 to 6.0 mm, 1.4 to 6.0 mm, 1.6 to 6.0 mm, 0.2 to 5.0 mm, 0.4 to 5.0 mm, 0.6 to 5.0 mm, 0.8 to 5.0 mm, 1.0-5.0 mm, 1.2-5.0 mm, 1.4-5.0
  • the height of the drug solid in the present invention is 0.1 to 3.0 mm, 0.1 to 2.5 mm, 0.1 to 2.0 mm, 0.1 to 1.5 mm, 0.1 to 1.0 mm, 0.1 to 0.8 mm, 0.1 to 0.6 mm, 0.1 to 0.4 mm , 0.2 to 3.0 mm, 0.2 to 2.5 mm, 0.2 to 2.0 mm, 0.2 to 1.5 mm, 0.2 to 1.0 mm, 0.2 to 0.8 mm, 0.2 to 0.6 mm, 0.2 to 0.4 mm, 0.3 to 3.0 mm, 0.3 to 2.5 mm , 0.3 to 2.0 mm, 0.3 to 1.5 mm, 0.3 to 1.0 mm, 0.3 to 0.8 mm, 0.3 to 0.6 mm, or 0.3 to 0.4 mm, for example, may be 0.36 mm.
  • the present invention relates to a method for manufacturing a solid drug based on ultraviolet printing, and the method for manufacturing a solid drug according to the present invention can produce a uniform and constant number of drug solids, and has the advantage of simple preparation and production of solid preparations. And, the drug solid produced through the manufacturing method according to the present invention exhibits high uniformity, can carry more drug than the drug-coated formulation only on the outer surface, and can release the drug within a faster time.
  • FIG. 1 is a schematic diagram of a method for manufacturing a solid drug in various shapes and sizes using a UV-printing system according to an embodiment of the present invention.
  • SEM scanning electron microscope
  • FIG 3 is a photograph taken through a confocal microscope (Confocal Micro Scope) of a drug solid prepared using a UV-printing system according to an embodiment of the present invention.
  • 5 is an analysis result of drug loading efficiency in the UV-printing drug loading formulation according to the diameter of the formulation and the drug loading concentration in the ink used for manufacturing according to an embodiment of the present invention.
  • FIG. 6 is a comparison analysis result of (a) drug loading and (b) drug release between a UV-printing drug loading formulation (drug encapsulation, the present invention) and a formulation coated with a drug on the outer surface according to an embodiment of the present invention; .
  • a method for preparing a UV-based solid drug formulation comprising the steps of:
  • polyethylene glycol diacrylate poly(ethylene glycol) diacrylate; Chemical reagents including PEG-DA] and photocuring agent [phenylbis(2,4,6-trimethyl benzoyl)phospine oxide] were purchased from Sigma-Aldrich (St. Louis, MO, USA). Doxorubicin hydrochloride was purchased from Jinhe Biotechnology (China).
  • the UV-printing drug loading system was fabricated through direct patterning and optical system visualization.
  • the microchamber was prepared as follows. First, two transparent slide glasses with an area of 24 x 24 mm and 20 x 20 mm were prepared, and then, using double-sided tape, a microchamber (Nitto, Inc) containing wells having various heights and structures was attached. .
  • biocompatible ink PEG-DA+Dox
  • a microchamber containing biocompatible ink PEG-DA+Dox was placed in a UV-printing sample holder and polymerized with UV (365 nm) for 120 seconds.
  • the sample was filled in a Petri dish with isopropyl alcohol (IPA), the slide glass and tape were removed, and washed directly with additional isopropyl alcohol to remove unpolymerized ink, and finally, the polymerized UV-printing drug-carrying formulation was applied. extracted.
  • IPA isopropyl alcohol
  • Example 3 one prepared sample is taken in 500 uL of DI water, the sample is crushed through ultrasound, and 100 uL of this solution is taken in a 96 well-plate to measure the amount of drug loaded through a microplate reader. Quantitatively analyzed.
  • the maximum amount of doxorubicin that can be loaded when irradiated with UV for 60 seconds, 120 seconds, and 240 seconds is that when irradiated with UV for 120 seconds, up to about 19 ug of doxorubicin drug is loaded. Confirmed. At this time, there is no difference in the amount of drug loaded in the biocompatible ink containing 5 mg/mL and 15 mg/mL doxorubicin. It is judged that it is advisable to use compatible inks.
  • the UV-printing drug-carrying formulation of the present invention is a form in which the drug is contained in the formulation, which can carry more drugs compared to the formulation in which the drug is coated on the outer surface of the formulation.
  • the shape of the sample was fixed in a cylindrical shape with a diameter of 1.8 mm and a thickness of 0.36 mm, and UV was irradiated with doxorubicin-free biocompatible ink for 120 seconds (365 nm wavelength, 12 uW power fixed).
  • the prepared sample was taken in Tris buffer solution in which 10 mg/mL PDA was dissolved for 30 minutes, and then in 15 mg/mL doxorubicin solution for 1 hour, and the drug was coated on the outer surface.
  • the prepared sample is irradiated with UV light of the same shape and time with a biocompatible ink containing 5 mg/mL doxorubicin as in the present invention, and the drug loading concentration is compared with the preparation, and the results are shown in FIGS. 6 and 3 to 4 are shown.
  • the formulation of the present invention can carry the drug 4 times or more when compared with the coating of the drug only on the outer surface with the present invention.
  • the present invention has a doxorubicin concentration of three times or less, it can carry a larger amount of drug, and it is more economically advantageous because additional materials such as PDA are not required. confirmed that there is.
  • the present invention can confirm that the drug release occurs in a faster time than the sample coated with only the outer surface of the drug in the pH 5, pH 7 environment.
  • the present invention can carry more drugs than a drug-coated formulation only on the outer surface and release the drug within a faster time.
  • the present invention relates to a method for manufacturing a solid drug drug based on ultraviolet printing, and more particularly, the method for manufacturing a drug solid drug according to the present invention can produce a uniform and constant number of drug solids, the preparation process for the drug solid preparation and
  • the advantage is that the production process is simple.

Abstract

The present invention relates to a method for preparing a solid drug formulation on the basis of ultraviolet printing. By the method for preparing a solid drug formulation according to the present invention, a solid drug formulation may be produced uniformly and in a certain number, and there are advantages in that a production preparation step and a production step for the solid formulation are simple.

Description

자외선 프린트 기반 약물 고형제 제조 방법Ultraviolet print-based drug solid preparation method
본 발명은 과학기술정보통신부, 산업통상자원부, 보건복지부, 식품의약품안전처의 지원 하에서 과제번호 9991006801에 의해 이루어진 것으로서, 상기 과제의 연구관리전문기관은 (재)범부처전주기의료기기연구개발사업단, 연구사업명은 " 범부처전주기의료기기연구개발사업", 연구과제명은 "질환환경 및 치료제에 따라 형상을 최적설계한 생분해 다공성 마이크로메디봇 개발", 주관기관은 전남대학교산학협력단, 연구기간은 2021.03.01 ~ 2022.02.28이다.The present invention was made by project number 9991006801 under the support of the Ministry of Science and ICT, the Ministry of Trade, Industry and Energy, the Ministry of Health and Welfare, and the Ministry of Food and Drug Safety. , The research project name is "Pan-ministerial cycle medical device R&D project", the research project name is "Development of a biodegradable porous micromedibot with an optimally designed shape according to the disease environment and treatment", the host organization is Chonnam National University Industry-Academic Cooperation Foundation, the research period is 2021.03.01 ~ 2022.02.28.
본 특허출원은 2021년 02월 21일에 대한민국 특허청에 제출된 대한민국 특허출원 제10-2021-0019321호에 대하여 우선권을 주장하며, 상기 특허출원의 개시 사항은 본 명세서에 참조로서 삽입된다.This patent application claims priority to Korean Patent Application No. 10-2021-0019321 filed with the Korean Intellectual Property Office on February 21, 2021, the disclosure of which is incorporated herein by reference.
본 특허출원은 2022년 02월 08일에 대한민국 특허청에 제출된 대한민국 특허출원 제10-2022-0016536호에 대하여 우선권을 주장하며, 상기 특허출원의 개시 사항은 본 명세서에 참조로서 삽입된다.This patent application claims priority to Korean Patent Application No. 10-2022-0016536 filed with the Korean Intellectual Property Office on February 08, 2022, the disclosure of which is incorporated herein by reference.
본 발명은 자외선 프린트 기반 약물 고형제 제조 방법에 관한 것으로, 더욱 상세하게는, 본 발명에 따른 약물 고형제 제조 방법은 약물 고형제를 균일하고 일정한 개수로 생산할 수 있으며, 약물 고형제 생산 준비과정 및 생산과정이 단순한 장점이 있다.The present invention relates to a method for manufacturing a solid drug based on ultraviolet printing, and more particularly, the method for manufacturing a solid drug according to the present invention can produce a uniform and constant number of drug solids, and the preparation process for the preparation of drug solids and The advantage is that the production process is simple.
약물전달 기술은 약물의 부작용을 감소시키는 동시에, 약물의 효능 및 치료 효과를 극대화시켜 필요한 양의 약물을 효과적으로 전달할 수 있도록 설계하는 기술로 알려져 있다. 최근, 고령화 복지 사회로의 진입에 따라 각종 질병에 효과적이고 경제적인 치료가 요구되고 있고, 환자의 상태에 따라 필요한 양을 필요한 곳에 적절하게 투여하는 맞춤형 의료가 도래할 것으로 전망되고 있다. 이러한 배경에서, 약물전달 기술의 필요성이 높아지고 있으며, 기존 치료목적뿐만 아니라 진단까지 동시에 수행될 수 있는 기술이 개발되고 있는 추세이다. Drug delivery technology is known as a technology designed to effectively deliver a required amount of a drug by maximizing the efficacy and therapeutic effect of the drug while reducing the side effects of the drug. Recently, with the entry into an aging welfare society, effective and economical treatment for various diseases is required, and it is expected that customized medical care that appropriately administers the necessary amount to the necessary place according to the patient's condition will arrive. Against this background, the need for drug delivery technology is increasing, and a technology capable of simultaneously performing diagnosis as well as existing therapeutic purposes is being developed.
고형제는 약물의 고형 투여 형태이며, 보통 환자의 경구로 투여되고 일반적으로 적당한 첨가제와 함께 조제되고 착색, 방향 등의 다양한 코팅이 이루어진다. 고형제는 사용목적 및 제조 방법에 따라서 크기, 모양 중량, 경도, 두께 및 붕해특성 등이 다르다. 이러한 고형제는 주로 압축에 의해서 조제되며, 주형 몰딩에 의해서 고형제를 생산하는 것이 일반적이다. 고형제의 종류로는 압축정, 다중압축정, 당의정, 필름피복정, 장용피정, 박칼정 또는 설하정, 저작정, 발포정, 산약정제, 피하주사용 고형제, 조제용 고형제가 있으며, 그 중 가장 일반적인 압축정은 다양한 모양을 한 펀치와 다이 로서 분말, 과립에 강한 압력을 가하여 제조한다. A solid dosage form is a solid dosage form of a drug, usually administered orally to a patient, and is usually formulated with suitable excipients and coated with a variety of colors, fragrances, and the like. Solid formulations differ in size, shape, weight, hardness, thickness, and disintegration characteristics depending on the purpose of use and manufacturing method. These solids are mainly prepared by compression, and it is common to produce the solids by mold molding. Types of solid preparations include compressed tablets, multi-compressed tablets, dragees, film-coated tablets, enteric-coated tablets, thin or sublingual tablets, chewed tablets, effervescent tablets, acid tablets, subcutaneous injection solids, and solid preparations. The most common compressed tablets are punches and dies of various shapes, and are manufactured by applying strong pressure to powders and granules.
다만, 기존의 고형제 제조기술은 고형제를 균일한 크기 및 일정한 개수로 생산하기 어려웠으며, 고형제 생산 준비과정 및 생산과정이 과도하게 복잡하다는 문제가 있었다. However, the existing solid preparation technology had a problem in that it was difficult to produce a solid preparation in a uniform size and in a constant number, and the preparation process and production process for the solid preparation were excessively complicated.
이에, 최근에는 제약회사들에서 스프레이 분무 방법이나 플라스크 교반 방법 또는 마이크로 플로이드 방법을 주로 약물의 제어방출, 독성감소, 복용 및 투여의 편의성 증대를 위한 고형제 기술을 개발 중이다. 하지만, 이러한 노력에도 불구하고 기존의 고형제 생산기술의 단점을 완벽하게 보완할 수 있는 고형제 기술의 개발은 요원한 실정이다.Accordingly, recently, pharmaceutical companies are developing solid formulation technologies for controlled release of drugs, reduced toxicity, and increased convenience of dosing and administration using the spray spray method, flask stirring method, or microfluid method. However, despite these efforts, the development of a solid preparation technology that can completely compensate for the shortcomings of the existing solid preparation technology is far from being developed.
이에 본 발명자들은 기존의 약물 고형제 제조 방법의 단점을 보완한 자외선 프린트 기반의 약물 고형제 제조 방법을 고안해냈으며, 본 발명에 따른 제조 방법은 약물 고형제를 균일한 크기 및 일정한 개수로 생산할 수 있고, 고형제 생산준비 과정 및 생산 과정이 단순하다는 장점이 존재한다. Accordingly, the present inventors have devised a method for manufacturing a drug solid drug based on ultraviolet printing that compensates for the disadvantages of the existing drug solid preparation method, and the manufacturing method according to the present invention can produce a drug solid drug in a uniform size and in a constant number. , there is an advantage in that the solid preparation preparation process and the production process are simple.
이에, 본 발명의 목적은 자외선 프린트 기반 약물 고형제 제조 방법을 제공하는 것이다.Accordingly, it is an object of the present invention to provide a method for manufacturing a solid drug based on ultraviolet printing.
본 발명은 자외선 프린트 기반 약물 고형제 제조 방법에 관한 것으로, 본 발명에 따른 약물 고형제 제조 방법은 약물 고형제를 균일하고 일정한 개수로 생산할 수 있으며, 고형제 생산 준비과정 및 생산과정이 단순한 장점이 있으며, 본 발명에 따른 제조 방법을 통해 생산된 약물 고형제는 높은 균일성을 나타내며, 겉 표면에만 약물이 코팅된 제제보다 더 많은 약물 담지 할 수 있으며, 더 빠른 시간 내에 약물을 방출 할 수 있다. The present invention relates to a method for manufacturing a solid drug based on ultraviolet printing, and the method for manufacturing a solid drug according to the present invention can produce a uniform and constant number of drug solids, and has the advantage of simple preparation and production of solid preparations. And, the drug solid produced through the manufacturing method according to the present invention exhibits high uniformity, can carry more drug than the drug-coated formulation only on the outer surface, and can release the drug within a faster time.
이하 본 발명을 더욱 자세히 설명하고자 한다.Hereinafter, the present invention will be described in more detail.
본 발명의 일 양태는 다음의 단계를 포함하는 UV 기반 약물 고형제 제조 방법이다:One aspect of the present invention is a method for preparing a UV-based solid drug formulation comprising the steps of:
챔버에 광가교성인 생체적합성 잉크 및 약물을 주입하는 주입 단계; 및an injection step of injecting a photocrosslinkable biocompatible ink and a drug into the chamber; and
UV를 조사하여 생체적합성 잉크를 경화하여 약물 고형제를 제조하는 제조 단계.A manufacturing step of curing the biocompatible ink by irradiating UV to prepare a drug solid.
본 발명에 있어서 챔버는 마이크로챔버인 것일 수 있으나, 이에 한정되는 것은 아니다. In the present invention, the chamber may be a microchamber, but is not limited thereto.
본 명세서 상의 용어 "마이크로챔버"는 광가교성 및 생체적합성 잉크와, 약물을 함유할 정도의 작은 크기를 가진 챔버, 즉, 생체적합성 잉크와 약물을 함유할 정도의 충분히 작은 구획(웰)을 가진 챔버를 의미하는 것이다.As used herein, the term “microchamber” refers to a chamber having a size small enough to contain a photocrosslinkable and biocompatible ink and a drug, that is, a chamber having a sufficiently small compartment (well) to contain the biocompatible ink and a drug. it means
본 발명에 있어서 웰 (well)의 직경은 0.2 내지 8.0 mm, 0.4 내지 8.0 mm, 0.6 내지 8.0 mm, 0.8 내지 8.0 mm, 1.0 내지 8.0 mm, 1.2 내지 8.0 mm, 1.4 내지 8.0 mm, 1.6 내지 8.0 mm, 0.2 내지 7.0 mm, 0.4 내지 7.0 mm, 0.6 내지 7.0 mm, 0.8 내지 7.0 mm, 1.0 내지 7.0 mm, 1.2 내지 7.0 mm, 1.4 내지 7.0 mm, 1.6 내지 7.0 mm, 0.2 내지 6.0 mm, 0.4 내지 6.0 mm, 0.6 내지 6.0 mm, 0.8 내지 6.0 mm, 1.0 내지 6.0 mm, 1.2 내지 6.0 mm, 1.4 내지 6.0 mm, 1.6 내지 6.0 mm, 0.2 내지 5.0 mm, 0.4 내지 5.0 mm, 0.6 내지 5.0 mm, 0.8 내지 5.0 mm, 1.0 내지 5.0 mm, 1.2 내지 5.0 mm, 1.4 내지 5.0 mm, 1.6 내지 5.0 mm, 0.2 내지 4.0 mm, 0.4 내지 4.0 mm, 0.6 내지 4.0 mm, 0.8 내지 4.0 mm, 1.0 내지 4.0 mm, 1.2 내지 4.0 mm, 1.4 내지 4.0 mm, 1.6 내지 4.0 mm, 0.2 내지 3.0 mm, 0.4 내지 3.0 mm, 0.6 내지 3.0 mm, 0.8 내지 3.0 mm, 1.0 내지 3.0 mm, 1.2 내지 3.0 mm, 1.4 내지 3.0 mm, 1.6 내지 3.0 mm, 0.2 내지 2.0 mm, 0.4 내지 2.0 mm, 0.6 내지 2.0 mm, 0.8 내지 2.0 mm, 1.0 내지 2.0 mm, 1.2 내지 2.0 mm, 1.4 내지 2.0 mm 또는 1.6 내지 2.0 mm인 것일 수 있으며, 예를 들어, 1.8 mm인 것일 수 있다.In the present invention, the diameter of the well is 0.2 to 8.0 mm, 0.4 to 8.0 mm, 0.6 to 8.0 mm, 0.8 to 8.0 mm, 1.0 to 8.0 mm, 1.2 to 8.0 mm, 1.4 to 8.0 mm, 1.6 to 8.0 mm. , 0.2 to 7.0 mm, 0.4 to 7.0 mm, 0.6 to 7.0 mm, 0.8 to 7.0 mm, 1.0 to 7.0 mm, 1.2 to 7.0 mm, 1.4 to 7.0 mm, 1.6 to 7.0 mm, 0.2 to 6.0 mm, 0.4 to 6.0 mm , 0.6 to 6.0 mm, 0.8 to 6.0 mm, 1.0 to 6.0 mm, 1.2 to 6.0 mm, 1.4 to 6.0 mm, 1.6 to 6.0 mm, 0.2 to 5.0 mm, 0.4 to 5.0 mm, 0.6 to 5.0 mm, 0.8 to 5.0 mm , 1.0-5.0 mm, 1.2-5.0 mm, 1.4-5.0 mm, 1.6-5.0 mm, 0.2-4.0 mm, 0.4-4.0 mm, 0.6-4.0 mm, 0.8-4.0 mm, 1.0-4.0 mm, 1.2-4.0 mm , 1.4-4.0 mm, 1.6-4.0 mm, 0.2-3.0 mm, 0.4-3.0 mm, 0.6-3.0 mm, 0.8-3.0 mm, 1.0-3.0 mm, 1.2-3.0 mm, 1.4-3.0 mm, 1.6-3.0 mm , 0.2 to 2.0 mm, 0.4 to 2.0 mm, 0.6 to 2.0 mm, 0.8 to 2.0 mm, 1.0 to 2.0 mm, 1.2 to 2.0 mm, 1.4 to 2.0 mm, or 1.6 to 2.0 mm, for example, 1.8 mm may be.
본 발명에 있어서 웰의 높이는 0.1 내지 3.0 mm, 0.1 내지 2.5 mm, 0.1 내지 2.0 mm, 0.1 내지 1.5 mm, 0.1 내지 1.0 mm, 0.1 내지 0.8 mm, 0.1 내지 0.6 mm, 0.1 내지 0.4 mm, 0.2 내지 3.0 mm, 0.2 내지 2.5 mm, 0.2 내지 2.0 mm, 0.2 내지 1.5 mm, 0.2 내지 1.0 mm, 0.2 내지 0.8 mm, 0.2 내지 0.6 mm, 0.2 내지 0.4 mm, 0.3 내지 3.0 mm, 0.3 내지 2.5 mm, 0.3 내지 2.0 mm, 0.3 내지 1.5 mm, 0.3 내지 1.0 mm, 0.3 내지 0.8 mm, 0.3 내지 0.6 mm, 또는 0.3 내지 0.4 mm인 것일 수 있으며, 예를 들어, 0.36 mm인 것일 수 있다.In the present invention, the height of the well is 0.1 to 3.0 mm, 0.1 to 2.5 mm, 0.1 to 2.0 mm, 0.1 to 1.5 mm, 0.1 to 1.0 mm, 0.1 to 0.8 mm, 0.1 to 0.6 mm, 0.1 to 0.4 mm, 0.2 to 3.0 mm, 0.2-2.5 mm, 0.2-2.0 mm, 0.2-1.5 mm, 0.2-1.0 mm, 0.2-0.8 mm, 0.2-0.6 mm, 0.2-0.4 mm, 0.3-3.0 mm, 0.3-2.5 mm, 0.3-2.0 mm, 0.3 to 1.5 mm, 0.3 to 1.0 mm, 0.3 to 0.8 mm, 0.3 to 0.6 mm, or 0.3 to 0.4 mm, for example, 0.36 mm.
본 발명에 있어서 마이크로챔버는 원형, 직사각형, 삼각형, 사각형, 마름모형, 오각형, 및 육각형 등의 다양한 형태인 것일 수 있으며, 예를 들어, 사각형인 것일 수 있으나, 이에 한정되는 것은 아니다.In the present invention, the microchamber may have various shapes such as a circle, a rectangle, a triangle, a square, a rhombus, a pentagon, and a hexagon, for example, it may be a square, but is not limited thereto.
본 발명에 있어서 웰은 원형, 직사각형, 삼각형, 사각형, 마름모형, 오각형, 및 육각형 등의 다양한 형태인 것일 수 있으며, 예를 들어, 원형인 것일 수 있으나, 이에 한정되는 것은 아니다.In the present invention, the well may have various shapes such as a circle, a rectangle, a triangle, a square, a rhombus, a pentagon, and a hexagon, for example, it may be a circle, but is not limited thereto.
본 발명의 일 구현예에서, 방법은 생체적합성 잉크를 제작하는 잉크 제작 단계를 더 포함하는 것일 수 있다. In one embodiment of the present invention, the method may further include an ink production step of producing a biocompatible ink.
본 발명에 있어서 생체적합성 잉크는 광가교 반응에 의해서 경화되는 것일 수 있다.In the present invention, the biocompatible ink may be cured by a photocrosslinking reaction.
본 발명에 있어서 생체적합성 잉크는 푸코이단, 알지네이트, 키토산, 히알루론산, 실크, 폴리에틸렌 글리콜 (Poly Ethylene Glycol; PEG), 폴리이미드 (polyimides), 폴리아믹스산 (polyamix acid), 폴리카프로락톤 (polycarprolactone), 폴리에테르이미드 (polyetherimide), 나일론 (nylon), 폴리아라미드 (polyaramid), 폴리비닐알콜 (polyvinyl alcohol), 폴리비닐피롤리돈 (polyvinylpyrrolidone), 폴리벤질글루타메이트 (poly-benzyl-glutamate), 폴리페닐렌테레프탈아마이드 (polyphenyleneterephthalamide), 폴리아닐린 (polyaniline), 폴리아크릴로나이트릴 (polyacrylonitrile), 폴리에틸렌옥사이드 (polyethylene oxide), 폴리스티렌 (polystyrene), 셀룰로오스 (cellulose), 폴리아크릴레이트 (polyacrylate), 폴리메틸메타크릴레이트 (polymethylmethacrylate), 폴리락산 (polylactic acid; PLA), 폴리글리콜산 (polyglycolic acid; PGA), 폴리락산과 폴리글리콜산의 공중합체 (PLGA), 폴리 {폴리(에틸렌옥사이드)테레프탈레이트-co-부틸렌테레프탈레이트} (PEOT/PBT), 폴리포스포에스터 (polyphosphoester; PPE), 폴리포스파젠 (PPA), 폴리안하이드라이드 (Polyanhydride; PA), 폴리오르쏘에스터 {poly(ortho ester;POE}, 폴리 (프로필렌푸마레이트)-디아크릴레이트 {poly(propylene fumarate)-diacrylate; PPF-DA} 및 폴리에틸렌글라이콜디아크릴레이트 {poly(ethylene glycol) diacrylate; PEG-DA}로 이루어진 그룹 중에서 선택된 1종 이상을 포함할 수 있으며, 예를 들어, 폴리에틸렌 글리콜, 폴리락산과 폴리글리콜산의 공중합체 및 PCA로 이루어진 그룹에서 선택된 1종 이상을 포함하는 것일 수 있다.In the present invention, the biocompatible ink is fucoidan, alginate, chitosan, hyaluronic acid, silk, polyethylene glycol (Poly Ethylene Glycol; PEG), polyimides, polyamic acid (polyamix acid), polycaprolactone (polycarprolactone), Polyetherimide, nylon, polyaramid, polyvinyl alcohol, polyvinylpyrrolidone, poly-benzyl-glutamate, polyphenylene terephthalate Amide (polyphenyleneterephthalamide), polyaniline (polyaniline), polyacrylonitrile (polyacrylonitrile), polyethylene oxide (polyethylene oxide), polystyrene (polystyrene), cellulose (cellulose), polyacrylate (polyacrylate), polymethylmethacrylate (polymethylmethacrylate) ), polylactic acid (PLA), polyglycolic acid (PGA), copolymer of polylactic acid and polyglycolic acid (PLGA), poly {poly (ethylene oxide) terephthalate-co-butylene terephthalate } (PEOT/PBT), polyphosphoester (PPE), polyphosphazene (PPA), polyanhydride (PA), polyorthoester {poly(ortho ester;POE}, poly(propylene) fumarate)-diacrylate {poly(propylene fumarate)-diacrylate; PPF-DA} and polyethylene glycol diacrylate {poly(ethylene glycol) diacrylate; PEG-DA} can be, for example, polyethylene glycol, polylactic acid and polyglycolic acid It may include one or more selected from the group consisting of a copolymer and PCA.
본 발명에 있어서 생체적합성 잉크는 가교제 또는 광학개시제 (photoinitiator)를 포함할 수 있다.In the present invention, the biocompatible ink may include a crosslinking agent or an optical initiator (photoinitiator).
본 발명에 있어서 가교제는 통상적인 하이드로겔 조성물에 사용되는 다가 금속이온을 포함하는 화합물일 수 있으나, 이에 한정되는 것은 아니다.In the present invention, the crosslinking agent may be a compound containing a polyvalent metal ion used in a conventional hydrogel composition, but is not limited thereto.
본 발명에 있어서 다가 금속이온 화합물은 알루미늄 화합물, 칼슘 화합물 및 마그네슘 화합물로 이루어진 그룹으로부터 선택되는 것일 수 있고, 예를 들어, 수산화알루미늄, 함수규산알루미늄, 염화칼슘, 염화마그네슘, 염화알루미늄, 메타규산알루미늄산마그네슘, 아세트산알루미늄 및 규산알루미늄산마그네슘으로 구성되는 그룹으로부터 선택되는 1종 이상인 것일 수 있으나, 이에 한정되는 것은 아니다. In the present invention, the polyvalent metal ion compound may be one selected from the group consisting of an aluminum compound, a calcium compound, and a magnesium compound, for example, aluminum hydroxide, hydrous aluminum silicate, calcium chloride, magnesium chloride, aluminum chloride, aluminum metasilicate acid It may be at least one selected from the group consisting of magnesium, aluminum acetate, and magnesium alumina silicate, but is not limited thereto.
본 명세서 상의 용어 "광학개시제"는 빛에 노출됨에 따라 신속한 가교결합을 유발하는 물질을 의미한다. As used herein, the term “photoinitiator” refers to a substance that causes rapid crosslinking upon exposure to light.
본 발명에 있어서 광학개시제는 자외선(UV)의 조사에 의해 가교반응이 일어나는 광학개시제 또는 가시광선의 조사에 의해 가교반응이 일어나는 광학개시제가 사용이 될 수 있으며, 예를 들어, 아세토페논, 벤조인 메틸 에티르, 디에톡시아세토페논, 벤조일 포스핀 옥사이드, 1-히드록시사이클로헥실 페닐 케톤 또는 에오신 등일 수 있으며, 이에 한정되는 것은 아니고, 첨가되는 광학개시제의 양은 노출되는 빛의 파장 및 시간에 따라 달라질 수 있다.In the present invention, as the optical initiator, an optical initiator in which a crosslinking reaction occurs by irradiation of ultraviolet (UV) or an optical initiator in which a crosslinking reaction occurs by irradiation of visible light may be used, for example, acetophenone, methyl benzoin It may be ethyr, diethoxyacetophenone, benzoyl phosphine oxide, 1-hydroxycyclohexyl phenyl ketone or eosin, and the like, but is not limited thereto, and the amount of the optical initiator added may vary depending on the wavelength and time of the exposed light. have.
본 발명에 있어서 생체적합성 잉크는 생체적합성 잉크의 기계적 물성 또는 프린팅 경향성을 조절하기 위해 점성 증강제를 더 포함할 수 있고, 예를 들어, 히알루론산 또는 덱스트란 (dextran)을 더 포함할 수 있으나, 이에 한정되는 것은 아니다.In the present invention, the biocompatible ink may further include a viscosity enhancer to control the mechanical properties or printing tendency of the biocompatible ink, for example, may further include hyaluronic acid or dextran, but this It is not limited.
본 발명에 있어서 생체적합성 잉크는 산화방지제를 더 포함할 수 있다.In the present invention, the biocompatible ink may further include an antioxidant.
본 발명에 있어서 산화방지제는 에리소르브산, 디부틸히드록시톨루엔, 부틸히드록시아니솔, α -토코페롤, 아세트산토코페롤, L-아스코르브산 및 그 염, L-아스코르브산팔미테이트, L-아스코르브산스테아레이트, 아황산수소나트륨, 아황산나트륨, 갈릭산트리아밀, 갈릭산프로필, 에틸렌디아민4아세트산나트륨 (EDTA), 피로인산나트륨, 및 메타인산나트륨으로 이루어지는 그룹에서 선택되는 1종 이상인 것일 수 있으나, 이에 한정되는 것은 아니다.In the present invention, the antioxidant is erythorbic acid, dibutylhydroxytoluene, butylhydroxyanisole, α-tocopherol, tocopherol acetate, L-ascorbic acid and its salts, L-ascorbic acid palmitate, L-ascorbic acid stearate Rate, sodium hydrogen sulfite, sodium sulfite, triamyl gallic acid, propyl gallate, sodium ethylenediamine tetraacetate (EDTA), sodium pyrophosphate, and sodium metaphosphate may be at least one selected from the group consisting of, but limited thereto it's not going to be
본 발명에 있어서 UV 기반 약물 고형제 제조 방법은 약물 고형제를 세척하는 세척 단계를 더 포함하는 것일 수 있다.In the present invention, the UV-based drug solid preparation method may further include a washing step of washing the drug solid.
본 발명에 있어서 세척 단계의 세척액은 아이소프로필알코올 (isopropyl alcohol; IPA), 에탄올 (ethanol), 증류수 또는 초순수(deionized water)인 것일 수 있으나, 이에 한정되는 것은 아니다.In the present invention, the washing solution in the washing step may be isopropyl alcohol (IPA), ethanol, distilled water or deionized water, but is not limited thereto.
본 발명에 있어서 제조 단계의 UV 조사 시간은 60 내지 240 초, 80 내지 240 초, 100 내지 240 초, 60 내지 220 초, 80 내지 220 초, 100 내지 220 초, 60 내지 200 초, 80 내지 200 초, 100 내지 200 초, 60 내지 180 초, 80 내지 180 초, 100 내지 180 초, 60 내지 160 초, 80 내지 160 초, 100 내지 160 초, 60 내지 140 초, 80 내지 140 초, 100 내지 140 초, 예를 들어, 120초인 것일 수 있다. 상기 범위 내에서 UV를 조사하는 경우 약물이 최대로 담지되는 현저한 효과가 있다.UV irradiation time of the manufacturing step in the present invention is 60 to 240 seconds, 80 to 240 seconds, 100 to 240 seconds, 60 to 220 seconds, 80 to 220 seconds, 100 to 220 seconds, 60 to 200 seconds, 80 to 200 seconds , 100 to 200 seconds, 60 to 180 seconds, 80 to 180 seconds, 100 to 180 seconds, 60 to 160 seconds, 80 to 160 seconds, 100 to 160 seconds, 60 to 140 seconds, 80 to 140 seconds, 100 to 140 seconds , for example, may be 120 seconds. When irradiating UV within the above range, there is a remarkable effect of maximally loading the drug.
본 발명에 있어서 제조 단계의 UV는 UV 레이저를 사용하는 것일 수 있으나, 이에 한정되는 것은 아니다.In the present invention, the UV of the manufacturing step may be to use a UV laser, but is not limited thereto.
본 발명에 있어서 UV의 파장은 340 내지 390nm, 340 내지 385nm, 340 내지 380nm, 340 내지 375nm, 340 내지 370nm, 345 내지 390nm, 345 내지 385nm, 345 내지 380nm, 345 내지 375nm, 345 내지 370nm, 350 내지 390nm, 350 내지 385nm, 350 내지 380nm, 350 내지 375nm, 350 내지 370nm, 355 내지 390nm, 355 내지 385nm, 355 내지 380nm, 355 내지 375nm, 355 내지 370nm, 360 내지 390nm, 360 내지 385nm, 360 내지 380nm, 360 내지 375nm, 또는 360 내지 370nm, 예를 들어, 365 nm인 것일 수 있으나, 이에 한정되는 것은 아니다.The wavelength of UV in the present invention is 340 to 390nm, 340 to 385nm, 340 to 380nm, 340 to 375nm, 340 to 370nm, 345 to 390nm, 345 to 385nm, 345 to 380nm, 345 to 375nm, 345 to 370nm, 350 to 390 nm, 350-385 nm, 350-380 nm, 350-375 nm, 350-370 nm, 355-390 nm, 355-385 nm, 355-380 nm, 355-375 nm, 355-370 nm, 360-390 nm, 360-385 nm, 360-380 nm, 360 to 375 nm, or 360 to 370 nm, for example, may be 365 nm, but is not limited thereto.
본 발명의 일 구현예에서, UV 기반 약물 고형제 제조 방법은 UV-프린터 (UV-printer)에 의해서 수행되는 것일 수 있다.In one embodiment of the present invention, the UV-based drug solid preparation method may be performed by a UV-printer (UV-printer).
본 발명에 있어서 약물은 항생제, 스타틴, 자극제, 방부제, 해열제, 화학 요법제, 항염증제, 항진균제, 호르몬 약제 물질, 이뇨제, 피임약, 항정신약(항우울제, 항정신병제 등) 또는 항암제일 수 있으며, 예를 들어, 독소루비신 (Doxorubicin), Cy5.5, 시스플라틴 (Cisplatin) 또는 옥살리플라틴 (oxaliplatin)인 것일 수 있으나, 이에 한정되는 것은 아니다.In the present invention, the drug may be an antibiotic, statin, stimulant, antiseptic, antipyretic, chemotherapeutic, anti-inflammatory, antifungal, hormonal drug, diuretic, contraceptive, antipsychotic (antidepressant, antipsychotic, etc.) or anticancer agent, for example, For example, it may be doxorubicin (Doxorubicin), Cy5.5, cisplatin (Cisplatin) or oxaliplatin (oxaliplatin), but is not limited thereto.
본 발명에 있어서 생체적합성 잉크는 약물을 1 내지 25 mg/mL, 3 내지 25 mg/mL, 5 내지 25 mg/mL, 1 내지 20 mg/mL, 3 내지 20 mg/mL, 5 내지 20 mg/mL, 1 내지 15 mg/mL, 3 내지 15 mg/mL, 예를 들어, 5 내지 15 mg/mL 포함하는 것일 수 있다. 상기 범위 내로 포함하는 경우 약물 담지량이 최대가 되며, 제작 시 경제적 비용이 가장 좋은 현저한 효과가 있다.In the present invention, the biocompatible ink contains 1 to 25 mg/mL, 3 to 25 mg/mL, 5 to 25 mg/mL, 1 to 20 mg/mL, 3 to 20 mg/mL, 5 to 20 mg/mL of the drug. mL, 1 to 15 mg/mL, 3 to 15 mg/mL, for example, 5 to 15 mg/mL may be included. When included within the above range, the drug loading amount is maximized, and there is a remarkable effect that the economical cost is the best during production.
본 발명에 있어서 약물 고형제는 유효성분으로 약물 이외에 약제학적으로 허용되는 담체를 포함할 수 있다. 이때, 약제학적으로 허용되는 담체는 제제 시에 통상적으로 이용되는 것으로서, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 전분, 아카시아고무, 인산 칼슘, 알기네이트, 젤라틴, 규산 칼슘, 미세 결정성 셀룰로스, 폴리비닐피로리돈, 셀룰로스, 물, 시럽, 메틸 셀룰로스, 메틸히드록시벤조에이트, 프로필 히드록시벤조에이트, 활석, 스테아르산 마그네슘 및 미네랄 오일 등을 포함하나, 이에 한정되는 것은 아니다. In the present invention, the solid drug may include a pharmaceutically acceptable carrier in addition to the drug as an active ingredient. In this case, pharmaceutically acceptable carriers are those commonly used in formulation, and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose. , polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil.
또한, 본 발명에 있어서 약물 고형제는 상기 성분들 이외에 윤활제, 습윤제, 감미제, 향미제, 유화제, 현탁제, 보존제 등을 추가로 포함할 수 있다.In addition, in the present invention, the drug solid agent may further include a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, etc. in addition to the above components.
본 발명에 있어서 약물 고형제의 직경은 0.2 내지 8.0 mm, 0.4 내지 8.0 mm, 0.6 내지 8.0 mm, 0.8 내지 8.0 mm, 1.0 내지 8.0 mm, 1.2 내지 8.0 mm, 1.4 내지 8.0 mm, 1.6 내지 8.0 mm, 0.2 내지 7.0 mm, 0.4 내지 7.0 mm, 0.6 내지 7.0 mm, 0.8 내지 7.0 mm, 1.0 내지 7.0 mm, 1.2 내지 7.0 mm, 1.4 내지 7.0 mm, 1.6 내지 7.0 mm, 0.2 내지 6.0 mm, 0.4 내지 6.0 mm, 0.6 내지 6.0 mm, 0.8 내지 6.0 mm, 1.0 내지 6.0 mm, 1.2 내지 6.0 mm, 1.4 내지 6.0 mm, 1.6 내지 6.0 mm, 0.2 내지 5.0 mm, 0.4 내지 5.0 mm, 0.6 내지 5.0 mm, 0.8 내지 5.0 mm, 1.0 내지 5.0 mm, 1.2 내지 5.0 mm, 1.4 내지 5.0 mm, 1.6 내지 5.0 mm, 0.2 내지 4.0 mm, 0.4 내지 4.0 mm, 0.6 내지 4.0 mm, 0.8 내지 4.0 mm, 1.0 내지 4.0 mm, 1.2 내지 4.0 mm, 1.4 내지 4.0 mm, 1.6 내지 4.0 mm, 0.2 내지 3.0 mm, 0.4 내지 3.0 mm, 0.6 내지 3.0 mm, 0.8 내지 3.0 mm, 1.0 내지 3.0 mm, 1.2 내지 3.0 mm, 1.4 내지 3.0 mm, 1.6 내지 3.0 mm, 0.2 내지 2.0 mm, 0.4 내지 2.0 mm, 0.6 내지 2.0 mm, 0.8 내지 2.0 mm, 1.0 내지 2.0 mm, 1.2 내지 2.0 mm, 1.4 내지 2.0 mm 또는 1.6 내지 2.0 mm인 것일 수 있으며, 예를 들어, 1.8 mm인 것일 수 있다.The diameter of the drug solid in the present invention is 0.2 to 8.0 mm, 0.4 to 8.0 mm, 0.6 to 8.0 mm, 0.8 to 8.0 mm, 1.0 to 8.0 mm, 1.2 to 8.0 mm, 1.4 to 8.0 mm, 1.6 to 8.0 mm, 0.2 to 7.0 mm, 0.4 to 7.0 mm, 0.6 to 7.0 mm, 0.8 to 7.0 mm, 1.0 to 7.0 mm, 1.2 to 7.0 mm, 1.4 to 7.0 mm, 1.6 to 7.0 mm, 0.2 to 6.0 mm, 0.4 to 6.0 mm, 0.6 to 6.0 mm, 0.8 to 6.0 mm, 1.0 to 6.0 mm, 1.2 to 6.0 mm, 1.4 to 6.0 mm, 1.6 to 6.0 mm, 0.2 to 5.0 mm, 0.4 to 5.0 mm, 0.6 to 5.0 mm, 0.8 to 5.0 mm, 1.0-5.0 mm, 1.2-5.0 mm, 1.4-5.0 mm, 1.6-5.0 mm, 0.2-4.0 mm, 0.4-4.0 mm, 0.6-4.0 mm, 0.8-4.0 mm, 1.0-4.0 mm, 1.2-4.0 mm, 1.4-4.0 mm, 1.6-4.0 mm, 0.2-3.0 mm, 0.4-3.0 mm, 0.6-3.0 mm, 0.8-3.0 mm, 1.0-3.0 mm, 1.2-3.0 mm, 1.4-3.0 mm, 1.6-3.0 mm, 0.2 to 2.0 mm, 0.4 to 2.0 mm, 0.6 to 2.0 mm, 0.8 to 2.0 mm, 1.0 to 2.0 mm, 1.2 to 2.0 mm, 1.4 to 2.0 mm, or 1.6 to 2.0 mm, for example, 1.8 mm may be
또한, 본 발명에 있어서 약물 고형제의 높이는 0.1 내지 3.0 mm, 0.1 내지 2.5 mm, 0.1 내지 2.0 mm, 0.1 내지 1.5 mm, 0.1 내지 1.0 mm, 0.1 내지 0.8 mm, 0.1 내지 0.6 mm, 0.1 내지 0.4 mm, 0.2 내지 3.0 mm, 0.2 내지 2.5 mm, 0.2 내지 2.0 mm, 0.2 내지 1.5 mm, 0.2 내지 1.0 mm, 0.2 내지 0.8 mm, 0.2 내지 0.6 mm, 0.2 내지 0.4 mm, 0.3 내지 3.0 mm, 0.3 내지 2.5 mm, 0.3 내지 2.0 mm, 0.3 내지 1.5 mm, 0.3 내지 1.0 mm, 0.3 내지 0.8 mm, 0.3 내지 0.6 mm, 또는 0.3 내지 0.4 mm인 것일 수 있으며, 예를 들어, 0.36 mm인 것일 수 있다.In addition, the height of the drug solid in the present invention is 0.1 to 3.0 mm, 0.1 to 2.5 mm, 0.1 to 2.0 mm, 0.1 to 1.5 mm, 0.1 to 1.0 mm, 0.1 to 0.8 mm, 0.1 to 0.6 mm, 0.1 to 0.4 mm , 0.2 to 3.0 mm, 0.2 to 2.5 mm, 0.2 to 2.0 mm, 0.2 to 1.5 mm, 0.2 to 1.0 mm, 0.2 to 0.8 mm, 0.2 to 0.6 mm, 0.2 to 0.4 mm, 0.3 to 3.0 mm, 0.3 to 2.5 mm , 0.3 to 2.0 mm, 0.3 to 1.5 mm, 0.3 to 1.0 mm, 0.3 to 0.8 mm, 0.3 to 0.6 mm, or 0.3 to 0.4 mm, for example, may be 0.36 mm.
본 발명의 약물 고형제의 직경 및 높이가 상기 범위 내인 경우에 약물 고형제의 부피 대비 약물의 담지 능력이 최대가 되는 현저한 효과가 있다.When the diameter and height of the drug solid agent of the present invention are within the above ranges, there is a remarkable effect of maximizing the drug loading capacity relative to the volume of the drug solid agent.
본 발명은 자외선 프린트 기반 약물 고형제 제조 방법에 관한 것으로, 본 발명에 따른 약물 고형제 제조 방법은 약물 고형제를 균일하고 일정한 개수로 생산할 수 있으며, 고형제 생산 준비과정 및 생산과정이 단순한 장점이 있으며, 본 발명에 따른 제조 방법을 통해 생산된 약물 고형제는 높은 균일성을 나타내며, 겉 표면에만 약물이 코팅된 제제보다 더 많은 약물 담지 할 수 있으며, 더 빠른 시간 내에 약물을 방출 할 수 있다.The present invention relates to a method for manufacturing a solid drug based on ultraviolet printing, and the method for manufacturing a solid drug according to the present invention can produce a uniform and constant number of drug solids, and has the advantage of simple preparation and production of solid preparations. And, the drug solid produced through the manufacturing method according to the present invention exhibits high uniformity, can carry more drug than the drug-coated formulation only on the outer surface, and can release the drug within a faster time.
도 1은 본 발명의 일 실시예에 따른 UV-프린팅 시스템을 이용하여 다양한 모양 및 크기로 약물 고형제를 제조하는 방법에 대한 모식도이다.1 is a schematic diagram of a method for manufacturing a solid drug in various shapes and sizes using a UV-printing system according to an embodiment of the present invention.
도 2은 본 발명의 일 실시예에 따른 UV-프린팅 시스템을 이용하여 제조한 약물 고형제를 주사 전자 현미경 (Scanning Electron Microscope; SEM)을 통해 촬영한 사진이다. 2 is a photograph taken through a scanning electron microscope (SEM) of a drug solid prepared using a UV-printing system according to an embodiment of the present invention.
도 3는 본 발명의 일 실시예에 따른 UV-프린팅 시스템을 이용하여 제조한 약물 고형제를 공초점 현미경 (Confocal Micro Scope)을 통해 촬영한 사진이다.3 is a photograph taken through a confocal microscope (Confocal Micro Scope) of a drug solid prepared using a UV-printing system according to an embodiment of the present invention.
도 4는 본 발명의 일 실시예에 따라 UV 조사 시간 및 제작에 사용된 잉크내 약물담지 농도에 따른 UV-프린팅 약물 담지 제제내 약물 담지 효율 분석 결과 이다.4 is an analysis result of drug loading efficiency in UV-printing drug loading formulation according to UV irradiation time and drug loading concentration in ink used for production according to an embodiment of the present invention.
도 5는 본 발명의 일 실시예에 따라 제제의 직경 및 제작에 사용된 잉크내 약물담지 농도에 따른 UV-프린팅 약물 담지 제제내 약물 담지 효율 분석 결과이다.5 is an analysis result of drug loading efficiency in the UV-printing drug loading formulation according to the diameter of the formulation and the drug loading concentration in the ink used for manufacturing according to an embodiment of the present invention.
도 6은 본 발명의 일 실시예에 따라 UV-프린팅 약물 담지 제제(약물 내포, 본원발명)와 겉 표면에 약물이 코팅된 제제와의 (a) 약물 담지량 및 (b) 약물 방출량 비교 분석 결과이다.6 is a comparison analysis result of (a) drug loading and (b) drug release between a UV-printing drug loading formulation (drug encapsulation, the present invention) and a formulation coated with a drug on the outer surface according to an embodiment of the present invention; .
다음의 단계를 포함하는 UV 기반 약물 고형제 제조 방법:A method for preparing a UV-based solid drug formulation comprising the steps of:
챔버에 광가교성인 생체적합성 잉크 및 약물을 주입하는 주입 단계; 및an injection step of injecting a photocrosslinkable biocompatible ink and a drug into the chamber; and
UV를 조사하여 상기 생체적합성 잉크를 경화하여 약물 고형제를 제조하는 제조 단계.A manufacturing step of curing the biocompatible ink by irradiating UV to prepare a drug solid.
이하, 본 발명을 하기의 실시예에 의하여 더욱 상세히 설명한다. 그러나 이들 실시예는 본 발명을 예시하기 위한 것일 뿐이며, 본 발명의 범위가 이들 실시예에 의하여 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to the following examples. However, these examples are only for illustrating the present invention, and the scope of the present invention is not limited by these examples.
실시예 1: UV-프린팅을 이용한 약물 고형제의 제조Example 1: Preparation of drug solids using UV-printing
1-1. 재료의 준비1-1. preparation of materials
폴리에틸렌글라이콜디아크릴레이트 [poly(ethylene glycol) diacrylate; PEG-DA] 및 광경화제 [phenylbis(2,4,6-trimethyl benzoyl)phospine oxide]를 비롯한 화학 시약은 Sigma-Aldrich (St. Louis, MO, USA)로부터 구매하였다. 독소루비신염산염 (Doxorubicin hydrochloride)은 Jinhe Biotechnology (중국)에서 구매하였다.polyethylene glycol diacrylate [poly(ethylene glycol) diacrylate; Chemical reagents including PEG-DA] and photocuring agent [phenylbis(2,4,6-trimethyl benzoyl)phospine oxide] were purchased from Sigma-Aldrich (St. Louis, MO, USA). Doxorubicin hydrochloride was purchased from Jinhe Biotechnology (China).
1-2. 생체적합성 잉크 (PEG-DA+Dox) 준비1-2. Biocompatible ink (PEG-DA+Dox) preparation
폴리에틸렌글라이콜디아크릴레이트(MW 575) 1 ml, 1 mL의 DI water 및 광경화제(Lithium phenyl-2,4,6-trimethyl benzoyl phosphinate)를 10 mg를 볼텍스믹서로 30분 혼합하여, UV경화성 PED-DA 용액을 준비하였다. 그 다음, UV경화성 PED-DA 용액 1 mL에 다양한 농도의 독소루비신염산염을 첨가한 후 볼텍스믹서로 10분 혼합하여 생체적합성잉크 (PEG-DA+Dox)를 제작하였다.1 ml of polyethylene glycol diacrylate (MW 575), 1 ml of DI water and 10 mg of a photocuring agent (Lithium phenyl-2,4,6-trimethyl benzoyl phosphinate) were mixed with a vortex mixer for 30 minutes, followed by UV-curable PED -DA solution was prepared. Then, doxorubicin hydrochloride of various concentrations was added to 1 mL of UV-curable PED-DA solution and mixed for 10 minutes with a vortex mixer to prepare biocompatible ink (PEG-DA+Dox).
1-3. UV-프린팅1-3. UV-printing
UV-프린팅 약물 담지 시스템은 직접 패터닝 및 광학 시스템 시각화를 통해 제작하였다. 마이크로 챔버는 다음과 같이 준비되었다. 우선, 24 x 24 mm와 20 x 20 mm 면적의 투명한 슬라이드 글라스 2 개를 준비한 다음 양면 테이프를 이용하여, 다양한 높이 및 구조를 가진 웰 (well)을 포함하는 마이크로 챔버 (Nitto, Inc)를 부착하였다. The UV-printing drug loading system was fabricated through direct patterning and optical system visualization. The microchamber was prepared as follows. First, two transparent slide glasses with an area of 24 x 24 mm and 20 x 20 mm were prepared, and then, using double-sided tape, a microchamber (Nitto, Inc) containing wells having various heights and structures was attached. .
그 다음, 주사기를 사용하여 생체적합성 잉크 (PEG-DA+Dox)를 마이크로 챔버에 주입하였다. 주입 후, 생체적합성 잉크 (PEG-DA+Dox)가 들어있는 마이크로 챔버를 UV-프린팅 샘플 홀더의 넣고 120초 동안 UV (365 nm)로 중합 했다. Then, using a syringe, biocompatible ink (PEG-DA+Dox) was injected into the microchamber. After injection, a microchamber containing biocompatible ink (PEG-DA+Dox) was placed in a UV-printing sample holder and polymerized with UV (365 nm) for 120 seconds.
그 다음, 샘플을 아이소프로필알코올(IPA)을 페트리 접시에 채우고 슬라이드 글라스와 테이프를 제거하고 추가 아이소프로필알코올로 직접 세척하여 중합되지 않은 잉크를 제거한 후, 마지막으로 중합된 UV-프린팅 약물 담지 제제를 추출하였다.Then, the sample was filled in a Petri dish with isopropyl alcohol (IPA), the slide glass and tape were removed, and washed directly with additional isopropyl alcohol to remove unpolymerized ink, and finally, the polymerized UV-printing drug-carrying formulation was applied. extracted.
실시예 2: UV-프린팅 약물 고형제의 분석Example 2: Analysis of UV-printed drug solids
여러 가지 모양의 UV-프린팅 약물 담지 제제를 주사전자현미경 (Scanning Electron Microscope; SEM)을 이용하여 형태학적 분석법을 통해 모양 및 크기를 확인하는 분석을 한 후, 공초점 현미경 (Confocal Micro Scope)을 이용하여 상기 실시예 1에서 제조한 약물 고형제를 분석하였다.Various shapes of UV-printing drug-loaded formulations were analyzed using a scanning electron microscope (SEM) to confirm the shape and size through morphological analysis, and then using a confocal microscope. Thus, the drug solid preparation prepared in Example 1 was analyzed.
분석결과, 도 2 내지 3에 나타난 바와 같이, 다양한 형태를 가진 약물 고형제가 제작된 것을 확인하였고, 각 약물 고형제가 견고한 구조를 가져 안정적으로 고형제로 존재하는 것을 확인하였다.As a result of the analysis, as shown in FIGS. 2 to 3 , it was confirmed that drug solids having various shapes were prepared, and it was confirmed that each drug solid had a solid structure and was stably present as a solid.
이하 실시예 3 내지 5에서는 제작된 샘플 1개를 500 uL의 DI water에 취한 후 초음파를 통해 샘플을 부수고, 이 용액에서 100 uL를 96 well-plate에 취하여 마이크로플레이트 리더기를 통해 담지된 약물 양을 정량적으로 분석하였다.Hereinafter, in Examples 3 to 5, one prepared sample is taken in 500 uL of DI water, the sample is crushed through ultrasound, and 100 uL of this solution is taken in a 96 well-plate to measure the amount of drug loaded through a microplate reader. Quantitatively analyzed.
실시예 3. UV 조사 시간에 따른 약물 담지 농도 분석Example 3. Analysis of drug loading concentration according to UV irradiation time
5 mg/mL, 15 mg/mL, 25 mg/mL의 독소루비신이 함유된 생체적합성 잉크에 대하여, UV 조사 시간 (365 nm wavelength, 12 uW power 고정)에 따른 약물 담지 농도 분석을 진행하였다. 이 때, 샘플의 모양은 직경 1.8 mm, 높이 0.36 mm의 원통형 모양으로 고정하였다. 그 결과는 도 4 및 표 1에 나타내었다.For biocompatible inks containing 5 mg/mL, 15 mg/mL, and 25 mg/mL doxorubicin, drug loading concentration analysis was performed according to UV irradiation time (365 nm wavelength, 12 uW power fixed). At this time, the shape of the sample was fixed to a cylindrical shape with a diameter of 1.8 mm and a height of 0.36 mm. The results are shown in FIG. 4 and Table 1.
60 sec60 sec 120 sec120 sec 240 sec240 sec
5 mg/ml5 mg/ml 12.52±2.83 ug12.52±2.83 ug 19.75±2.27 ug19.75±2.27 ug 18.20±2.50 ug18.20±2.50 ug
15 mg/ml15 mg/ml 9.67 ± 0.74 ug9.67 ± 0.74 ug 19.77 ± 1.99 ug19.77 ± 1.99 ug 19.08 ± 2.12 ug19.08 ± 2.12 ug
25 mg/ml25 mg/ml 5.75±1.03 ug5.75±1.03 ug 16.58±2.06 ug16.58±2.06 ug 15.58±1.02 ug15.58±1.02 ug
도 4 및 표 1에서 확인할 수 있듯이, 60초, 120초, 240초 동안 UV를 조사 했을 때 최대 담지 될 수 있는 독소루비신의 양은, 120초 동안 UV 조사 시 최대 약 19 ug의 독소루비신의 약물이 담지 됨을 확인하였다. 이 때, 5 mg/mL과 15 mg/mL의 독소루비신이 함유된 생체적합성 잉크에서 약물의 담지 양에서 차이가 없기 때문에 제작 시 경제적 비용을 고려 했을 때 5 내지 15 mg/mL의 약물이 포함된 생체적합성 잉크를 사용하는 것이 좋다고 판단 된다.As can be seen in FIG. 4 and Table 1, the maximum amount of doxorubicin that can be loaded when irradiated with UV for 60 seconds, 120 seconds, and 240 seconds is that when irradiated with UV for 120 seconds, up to about 19 ug of doxorubicin drug is loaded. Confirmed. At this time, there is no difference in the amount of drug loaded in the biocompatible ink containing 5 mg/mL and 15 mg/mL doxorubicin. It is judged that it is advisable to use compatible inks.
실시예 4. UV-프린팅 약물 담지 제제 직경에 따른 약물 담지 효율 분석Example 4. Analysis of drug loading efficiency according to the diameter of UV-printing drug loading formulation
제제의 크기에 따른 약물 담지 효율 분석을 위해 8.0, 1.8, 0.2 mm 직경의 샘플을 제작 하여 약물 담지 농도를 비교하였다. 이 때, 샘플의 높이는 0.36 mm, UV 조사 시간(365 nm wavelength, 12 uW power 고정)은 120초로 고정하였다. 그 결과는 도 5 및 표 2에 나타내었다.To analyze the drug loading efficiency according to the size of the formulation, samples of 8.0, 1.8, and 0.2 mm diameter were prepared and the drug loading concentrations were compared. At this time, the height of the sample was 0.36 mm, and the UV irradiation time (365 nm wavelength, 12 uW power fixed) was fixed to 120 seconds. The results are shown in FIG. 5 and Table 2.
8 mm8 mm 1.8 mm1.8 mm 0.2 mm0.2 mm
5 mg/ml5 mg/ml 32.37±3.69 ug32.37±3.69 ug 19.75±2.27 ug19.75±2.27 ug 0.68±0.09 ug0.68±0.09 ug
15 mg/ml15 mg/ml 34.31±2.90 ug34.31±2.90 ug 19.77 ± 1.99 ug19.77 ± 1.99 ug 0.22±0.01 ug0.22±0.01 ug
25 mg/ml25 mg/ml 26.93±0.96 ug26.93±0.96 ug 16.58±2.06 ug16.58±2.06 ug 0.01±0.005 ug0.01±0.005 ug
도 5 및 표 2에서 확인할 수 있듯이, 5 mg/mL, 15 mg/mL, 25 mg/mL의 독소루비신이 함유된 생체적합성 잉크로 UV 경화시 직경 8 mm의 경우 15 mg/mL 에서 최대 약 35 ug, 1.8 mm의 경우 5 mg/mL에서 최대 9 ug, 0.2 mm의 경우 5 mg/mL에서 최대 약 1 ug이 담지됨을 알 수 있다.As can be seen in FIG. 5 and Table 2, when UV cured with biocompatible ink containing 5 mg/mL, 15 mg/mL, and 25 mg/mL doxorubicin, for a diameter of 8 mm, up to about 35 ug at 15 mg/mL , it can be seen that, in the case of 1.8 mm, up to 9 ug at 5 mg/mL and at most about 1 ug at 5 mg/mL in the case of 0.2 mm are loaded.
실시예 5. 약물 담지량 및 약물 방출량 비교 분석Example 5. Comparative analysis of drug loading and drug release
본원 발명의 UV-프린팅 약물 담지 제제는 제제 안에 약물이 내포되어 있는 형태이며, 이는 제제 겉 표면에 약물이 코팅된 제제와 비교하여 더 많은 약물을 담지 할 수 있다. The UV-printing drug-carrying formulation of the present invention is a form in which the drug is contained in the formulation, which can carry more drugs compared to the formulation in which the drug is coated on the outer surface of the formulation.
이를 확인하기 위하여, 약물이 들어있지 않은 생체적합성 잉크를 UV-프린팅 한 후, 겉 표면에 폴리도파민 (PDA, polydopaine)을 이용하여 약물을 코팅한 샘플과 약물 담지량을 본원 발명과 비교하였다. 겉 표면 약물 코팅을 위한 자세한 방법은 다음과 같다: To confirm this, after UV-printing a drug-free biocompatible ink, a drug coated sample using polydopamine (PDA, polydopaine) on the outer surface and the drug loading amount were compared with the present invention. The detailed method for surface drug coating is as follows:
샘플의 모양은 직경 1.8 mm, 두께 0.36 mm의 원통형 모양으로 고정, 독소루비신이 비포함된 생체적합성 잉크를 120초 동안 UV를 조사하였다 (365 nm wavelength, 12 uW power 고정). 제작된 샘플을 10 mg/mL의 PDA가 녹아있는 Tris buffer용액에 30 분 동안 취한 후, 15 mg/mL의 독소루비신 용액에 1시간 동안 취하여 겉 표면에 약물을 코팅하였다. The shape of the sample was fixed in a cylindrical shape with a diameter of 1.8 mm and a thickness of 0.36 mm, and UV was irradiated with doxorubicin-free biocompatible ink for 120 seconds (365 nm wavelength, 12 uW power fixed). The prepared sample was taken in Tris buffer solution in which 10 mg/mL PDA was dissolved for 30 minutes, and then in 15 mg/mL doxorubicin solution for 1 hour, and the drug was coated on the outer surface.
이렇게 준비된 샘플을 본원발명과 같이 5 mg/mL의 독소루비신이 포함된 생체적합성 잉크로 같은 모양과 같은 시간의 UV를 조사하여 제작된 제제와 약물 담지 농도를 비교하여, 그 결과를 도 6 및 표 3 내지 4에 나타내었다.As in the present invention, the prepared sample is irradiated with UV light of the same shape and time with a biocompatible ink containing 5 mg/mL doxorubicin as in the present invention, and the drug loading concentration is compared with the preparation, and the results are shown in FIGS. 6 and 3 to 4 are shown.
표면코팅surface coating 본원발명the present invention
약물농도drug concentration 5.06±0.56 ug5.06±0.56 ug 19.75±2.27 ug19.75±2.27 ug
시간(h)time (h) 표면코팅surface coating 본원발명the present invention
pH 5pH 5 pH 7 pH 7 pH 5 pH 5 pH 7 pH 7
0.50.5 27.38%27.38% 15.26%15.26% 51.6%51.6% 44.58%44.58%
1One 32.09%32.09% 20.66%20.66% 54.40%54.40% 45.51%45.51%
22 38.39%38.39% 26.99%26.99% 63.69%63.69% 45.61%45.61%
88 46.93%46.93% 35.07%35.07% 64.21%64.21% 46.26%46.26%
2424 73.05%73.05% 57.64%57.64% 68.77%68.77% 49.24%49.24%
도 6a에서 확인할 수 있듯이, 본원발명과 겉 표면에만 약물을 코팅한 것과 비교 했을 때, 본원발명의 제제가 4배 이상 약물을 담지 할 수 있음을 알 수 있었다. 또한, 경제적으로 봤을 때, 본원 발명이 3배 이하의 독소루비신 농도를 취했음에도 불구하고, 더 많은 양의 약물을 담지 할 수 있음을 알 수 있으며, PDA와 같이 추가적인 재료가 불필요 함으로 경제적으로 더 이익이 있음을 확인하였다.As can be seen in FIG. 6a, it was found that the formulation of the present invention can carry the drug 4 times or more when compared with the coating of the drug only on the outer surface with the present invention. In addition, from an economic point of view, it can be seen that, despite the fact that the present invention has a doxorubicin concentration of three times or less, it can carry a larger amount of drug, and it is more economically advantageous because additional materials such as PDA are not required. confirmed that there is.
도 6b에서 확인할 수 있듯이, 두 샘플간의 약물 방출 거동의 경우, 본원발명은 pH 5, pH 7 환경에서 겉 표면에만 약물이 코팅된 샘플보다 더 빠른 시간 내에 약물 방출이 일어남을 확인 할 수 있다. As can be seen in Figure 6b, in the case of the drug release behavior between the two samples, the present invention can confirm that the drug release occurs in a faster time than the sample coated with only the outer surface of the drug in the pH 5, pH 7 environment.
결론적으로, 본원발명은 겉 표면에만 약물이 코팅된 제제보다 더 많은 약물 담지 할 수 있으며, 더 빠른 시간 내에 약물을 방출 할 수 있음을 확인하였다.In conclusion, it was confirmed that the present invention can carry more drugs than a drug-coated formulation only on the outer surface and release the drug within a faster time.
본 발명은 자외선 프린트 기반 약물 고형제 제조 방법에 관한 것으로, 더욱 상세하게는, 본 발명에 따른 약물 고형제 제조 방법은 약물 고형제를 균일하고 일정한 개수로 생산할 수 있으며, 약물 고형제 생산 준비과정 및 생산과정이 단순한 장점이 있다.The present invention relates to a method for manufacturing a solid drug drug based on ultraviolet printing, and more particularly, the method for manufacturing a drug solid drug according to the present invention can produce a uniform and constant number of drug solids, the preparation process for the drug solid preparation and The advantage is that the production process is simple.

Claims (15)

  1. 다음의 단계를 포함하는 UV 기반 약물 고형제 제조 방법:A method for preparing a UV-based solid drug formulation comprising the steps of:
    챔버에 광가교성인 생체적합성 잉크 및 약물을 주입하는 주입 단계; 및an injection step of injecting a photocrosslinkable biocompatible ink and a drug into the chamber; and
    UV를 조사하여 상기 생체적합성 잉크를 경화하여 약물 고형제를 제조하는 제조 단계.A manufacturing step of curing the biocompatible ink by irradiating UV to prepare a drug solid.
  2. 제1항에 있어서, 상기 방법은 생체적합성 잉크를 제작하는 잉크 제작 단계를 더 포함하는 것인, 방법.The method of claim 1 , further comprising an ink manufacturing step of manufacturing a biocompatible ink.
  3. 제1항에 있어서, 상기 생체접합성 잉크는 폴리에틸렌 글리콜 (Poly Ethylene Glycol; PEG), 폴리락산과 폴리글리콜산의 공중합체 (PLGA) 및 PCA (Phosphino-Carboxylic Acid)로 이루어진 그룹에서 선택된 1종 이상을 포함하는 것인, 방법.According to claim 1, wherein the biocompatible ink is polyethylene glycol (Poly Ethylene Glycol; PEG), a copolymer of polylactic acid and polyglycolic acid (PLGA) and PCA (Phosphino-Carboxylic Acid) at least one selected from the group consisting of comprising the method.
  4. 제1항에 있어서, 상기 생체적합성 잉크는 가교제 또는 광학개시제 (photoinitiator)를 포함하는 것인, 방법.The method of claim 1 , wherein the biocompatible ink comprises a crosslinking agent or a photoinitiator.
  5. 제1항에 있어서, 상기 생체적합성 잉크는 점성 증강제를 포함하는 것인, 방법.The method of claim 1 , wherein the biocompatible ink comprises a viscosity enhancing agent.
  6. 제1항에 있어서, 상기 생체적합성 잉크는 산화방지제를 포함하는 것인, 방법.The method of claim 1 , wherein the biocompatible ink comprises an antioxidant.
  7. 제1항에 있어서, 상기 방법은 경화된 상기 약물 고형제를 세척하는 세척 단계를 더 포함하는 것인, 방법.The method of claim 1, wherein the method further comprises a washing step of washing the cured drug solid agent.
  8. 제7항에 있어서, 상기 세척 단계의 세척액은 아이소프로필알코올 (isopropyl alcohol; IPA), 에탄올 (ethanol), 증류수 또는 초순수(deionized water)인 것인, 방법.The method of claim 7, wherein the washing solution of the washing step is isopropyl alcohol (IPA), ethanol, distilled water or deionized water.
  9. 제1항에 있어서, 상기 제조 단계의 UV 조사 시간은 60 내지 240 초인 것인, 방법.The method according to claim 1, wherein the UV irradiation time of the manufacturing step is 60 to 240 seconds.
  10. 제1항에 있어서, 상기 제조 단계의 UV의 파장은 340 내지 390 nm인 것인, 방법.The method according to claim 1, wherein the wavelength of UV in the manufacturing step is 340 to 390 nm.
  11. 제1항에 있어서, 상기 방법은 UV-프린터 (UV-printer)에 의해서 수행되는 것인, 방법.The method according to claim 1, wherein the method is performed by a UV-printer.
  12. 제1항에 있어서, 상기 약물은 독소루비신 (Doxorubicin), Cy5.5, 시스플라틴 (Cisplatin) 또는 옥살리플라틴 (oxaliplatin)인 것인, 방법.The method of claim 1, wherein the drug is doxorubicin, Cy5.5, cisplatin, or oxaliplatin.
  13. 제1항에 있어서, 상기 생체적합성 잉크는 약물을 1 내지 25 mg/mL 포함하는 것인, 방법.The method of claim 1 , wherein the biocompatible ink contains 1 to 25 mg/mL of drug.
  14. 제1항에 있어서, 상기 약물 고형제의 직경은 0.2 내지 8.0 mm인 것인, 방법.The method of claim 1, wherein the diameter of the drug solid agent is 0.2 to 8.0 mm.
  15. 제1항에 있어서, 상기 약물 고형제의 높이는 0.1 내지 3.0 mm인 것인, 방법.The method of claim 1, wherein the height of the drug solid agent is 0.1 to 3.0 mm.
PCT/KR2022/001995 2021-02-10 2022-02-09 Method for preparing solid drug formulation on basis of ultraviolet printing WO2022173227A1 (en)

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CN106109245A (en) * 2016-08-16 2016-11-16 华南农业大学 Cancer therapy drug that a kind of 3D of employing printing technique prepares and method
US20180214383A1 (en) * 2015-07-16 2018-08-02 National University Of Singapore Printing drug tablets with fully customizable release profiles for personalized medicine
KR20190022777A (en) * 2016-06-30 2019-03-06 쓰리엠 이노베이티브 프로퍼티즈 컴파니 Printable compositions comprising high viscosity components and methods for producing 3D articles therefrom
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US20180214383A1 (en) * 2015-07-16 2018-08-02 National University Of Singapore Printing drug tablets with fully customizable release profiles for personalized medicine
KR20190022777A (en) * 2016-06-30 2019-03-06 쓰리엠 이노베이티브 프로퍼티즈 컴파니 Printable compositions comprising high viscosity components and methods for producing 3D articles therefrom
CN106109245A (en) * 2016-08-16 2016-11-16 华南农业大学 Cancer therapy drug that a kind of 3D of employing printing technique prepares and method
KR20190062067A (en) * 2017-11-28 2019-06-05 재단법인 대구경북첨단의료산업진흥재단 Method for fabricating biocompatible porous structured block and biocompatible porous structured block fabricated thereby

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