WO2015060592A1 - Appareil de fabrication de liposomes - Google Patents

Appareil de fabrication de liposomes Download PDF

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Publication number
WO2015060592A1
WO2015060592A1 PCT/KR2014/009814 KR2014009814W WO2015060592A1 WO 2015060592 A1 WO2015060592 A1 WO 2015060592A1 KR 2014009814 W KR2014009814 W KR 2014009814W WO 2015060592 A1 WO2015060592 A1 WO 2015060592A1
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WO
WIPO (PCT)
Prior art keywords
channel
solution
vesicle
discharge
main channel
Prior art date
Application number
PCT/KR2014/009814
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English (en)
Korean (ko)
Inventor
정호섭
조혜성
김기성
김준수
Original Assignee
서울대학교산학협력단
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Application filed by 서울대학교산학협력단 filed Critical 서울대학교산학협력단
Publication of WO2015060592A1 publication Critical patent/WO2015060592A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
    • A61J3/07—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of capsules or similar small containers for oral use
    • A61J3/078—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of capsules or similar small containers for oral use into the form of wafers or cachets
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
    • B01J13/02—Making microcapsules or microballoons
    • B01J13/04—Making microcapsules or microballoons by physical processes, e.g. drying, spraying
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/03—Containers specially adapted for medical or pharmaceutical purposes for pills or tablets
    • A61J1/035—Blister-type containers

Definitions

  • the present invention relates to a vesicle manufacturing apparatus, and in particular, a vesicle (vesicle), which is a drug carrier, can be manufactured quickly in a uniform size, but a large amount of vesicles can be easily produced at a time with a simple configuration. It relates to a vesicle manufacturing apparatus capable of mass production.
  • a vesicle vesicle
  • drug carrier vesicle
  • vesicles which are drug delivery agents, to deliver drugs to specific sites in small amounts.
  • Ultrasonic grinding is generally prepared in the form of a film by volatilizing a solution of lipid or block copolymer dissolved in an organic solvent, and then spontaneously forming a single or double membrane by adding an aqueous phase, and then uniformly sized by ultrasonic grinding.
  • the permeation method is a method of dispersing a lipid or copolymer in the form of a film in an aqueous solution, and then uniformizing the size by using a polycarbonate membrane.
  • the vesicles it is difficult to manufacture the vesicles in the above-described manner quickly, when necessary, since it takes a lot of time of about 6 to 24 hours or more depending on the manufacturing method, including the time for stabilizing the vesicles.
  • the cycle should be manufactured and stored, the storage period is also limited, so that problems such as manufacturing and storing and discarding and remanufacturing after a certain period of time occur.
  • the above method uses ultrasonic waves to produce vesicles of uniform and fine size, so that enzymes, genes, proteins, and drugs are destroyed by heat and ultrasonic waves.
  • FIG. 1 is a view schematically showing a vesicle manufacturing method using a conventional microfluidic chip.
  • a vesicle manufacturing method using a microfluidic chip has two microfluidic chips configured to cross each other in a cross shape, and each microfluidic chip simultaneously has an aqueous fluid and hydrophobic and hydrophilic blocks.
  • the vesicle is uniformly and quickly generated by the self-assembly phenomenon of the fluid generated when the two fluids contact each other at the cross-region interface. It becomes possible to manufacture.
  • the vesicle manufacturing method using the microfluidic chip has the advantage that the vesicles can be produced uniformly and quickly, but the amount of vesicles that can be manufactured at one time is limited in that the microfluidic chip is used.
  • the microfluidic chip is used.
  • the present invention is to solve the above problems, to provide a vesicle manufacturing apparatus that can be easily and mass-produced vesicles can be mass produced easily.
  • a vesicle manufacturing apparatus for solving the technical problem is a platform; A main channel provided in the platform to provide a vesicle forming space; A first inflow channel into which one of a first solution and a second solution to form the vesicle flows into the main channel; A discharge part through which the vesicle formed in the main channel is discharged; A second inflow channel positioned between the first inflow channel and the discharge portion, and the other of the first solution and the second solution flows into the main channel; And a microhole array unit provided at an outlet of the second inflow channel and having a plurality of micropores through which the solution supplied to the second inflow channel passes.
  • the micropore array may be made of a polymer membrane having a plurality of micropores at predetermined intervals, or a tube having a plurality of microchannels.
  • the main channel may be formed of one closed straight line
  • the first inflow channel may be connected to the start of the straight line
  • the discharge channel may be formed at the end of the straight line
  • the discharge unit may include an discharge channel through which the vesicle formed in the main channel is discharged, and the first inflow channel, the second inflow channel, and the discharge channel may protrude to an upper portion of the platform.
  • the vesicle manufacturing apparatus is connected to the first inlet channel to supply a solution of any one of the first solution and the second solution to the main channel; First supply means for supplying a solution supplied to the first supply pipe at a predetermined pressure; A second supply pipe connected to the second inflow channel to supply the other solution of the first solution and the second solution to the main channel; And second supply means for supplying a fluid supplied to the second supply pipe at a predetermined pressure.
  • the vesicle manufacturing apparatus in another aspect is a main channel provided therein, a first inlet channel connected to one side of the main channel, the discharge channel provided on the other side of the main channel, the first inlet A platform having a second inlet channel connected to said main channel so as to be located between a channel and said outlet channel; A first supply pipe connected to the first inlet channel; A second supply pipe connected to the second inflow channel; A discharge pipe connected to the discharge channel; And a polymer membrane provided at an outlet of the second inflow channel and having a plurality of micropores.
  • a vesicle manufacturing apparatus in another aspect, includes a main channel provided therein, a first inflow channel connected to one side of the main channel, an exhaust channel provided on the other side of the main channel, and the first inflow channel.
  • a platform having a second inlet channel connected to the main channel so as to be positioned between the outlet channel and the outlet channel; A first supply pipe connected to the first inlet channel; A second supply pipe connected to the second inflow channel; A discharge pipe connected to the discharge channel; And a tube provided at an outlet of the second inflow channel and having a plurality of microchannels.
  • the vesicle manufacturing apparatus is provided with a micropore array having a micropore array of approximately 5 ⁇ m in a channel having a width of about 100 to 200 times wider than that of a conventional microfluidic chip.
  • the vesicle manufacturing apparatus can manufacture a large number of vesicles uniformly and quickly at a time by a simple configuration having a micro-hole array in the channel, thereby reducing the cost of manufacturing equipment for mass production It can be effective.
  • the vesicle manufacturing apparatus can manufacture a large amount of vesicles at once and uniformly, there is an effect that it is not necessary to prepare and store a predetermined amount of vesicles in advance.
  • the vesicle manufacturing apparatus can uniformly manufacture a vesicle having a fine size by providing a microhole array having a plurality of micropores inside the channel without using ultrasonic waves, a conventional method using ultrasonic waves Heat and ultrasound generated during the manufacture of vesicles have the effect of preventing phenomena such as destruction of enzymes, genes, proteins and drugs.
  • FIG. 1 is a view schematically showing a vesicle manufacturing method using a conventional microfluidic chip
  • FIG. 2 is a perspective view showing a vesicle manufacturing apparatus according to an embodiment of the present invention
  • FIG. 3 is a cross-sectional view taken along line 'D-D' of FIG.
  • FIG. 5 is a perspective view showing a polymer membrane which is one form of a micropore array portion
  • FIG. 6 is a cross-sectional view showing a state in which a tube, which is another form of the micropore array portion, is provided at the outlet of the second inflow channel.
  • Figure 2 is a perspective view showing a vesicle manufacturing apparatus according to an embodiment of the present invention
  • Figure 3 is a cross-sectional view 'D-D' of Figure 2
  • Figure 4 is an enlarged view of the 'E' portion of FIG.
  • the vesicle manufacturing apparatus 10 is a platform (platform) 20, the main channel 21, the first inlet channel 22, the second inlet It includes a channel 23, a fine hole array portion 30, the discharge portion.
  • the main channel 21 is a channel provided in the platform 20 to provide a space for forming a vesicle, and the first inflow channel 22 is a first solution A to form a vesicle; Any one solution of the second solution (B) is connected to one side of the main channel 21 as a channel into the main channel 21, the second inflow channel 23 is the first solution (A) and the second The other solution of the solution B is connected to the main channel 21 so as to be positioned between the first inlet channel 22 and the outlet as a channel into the main channel 21.
  • the discharge part is a configuration in which the vesicle formed in the main channel 21 is discharged, and may be composed of the discharge channel 24 and the discharge pipe 16.
  • the first solution (A) and the second solution (B), as in the conventional method for manufacturing a vesicle using a cross-shaped microfluidic chip, the vesicles by the self-assembly of the fluid generated when the two fluids contact As a solution which can be manufactured uniformly and quickly, this invention is not limited by the specific structure of a 1st solution (A) and a 2nd solution (B).
  • the second solution (B) is a fluid in which a predetermined drug is mixed. If the drug is poorly soluble, the second solution (B) may be an aqueous fluid in which the drug is dissolved in a lipid solution.
  • the first solution (A) has hydrophobic and hydrophilic properties. It may be a block copolymer having a simultaneously or a fluid mixed with a phospholipid to capture a predetermined drug.
  • the fine hole array unit 30 is provided at the outlet 25 of the second inlet channel 23 positioned between the first inlet channel 22 and the outlet, and the solution supplied to the second inlet channel 23 is It is the structure which has many microholes 32 which pass.
  • the micropore array unit 30 is a configuration for generating the same effect as that of the thousands of conventional microfluidic chips, for example, of the second inflow channel 23 If the width is approximately 1000 ⁇ m and the size of each of the plurality of micro holes 32 formed in the micro hole array unit 30 is approximately 5 ⁇ m, the size of the conventional microfluidic chip, the conventional microfluid The same effect that there are thousands of chips, that is, the vesicles can be made uniformly and quickly in a fine size, but a large number of vesicles can be produced at once.
  • the present invention is not limited to the specific size of the second inflow channel 23 and the micro-holes 32, the second inflow channel 23 and the micro-holes 32 in the vesicle manufacturing apparatus 10 according to the present invention. ) May vary depending on the amount and size of the vesicle to be manufactured.
  • the first inflow channel in the main channel 21 is caused by the inflow of the first solution A.
  • a flow of fluid from 22 to the outlet channel 24 occurs.
  • the second solution B is introduced into the main channel 21 through the second inlet channel 23 positioned between the first inlet channel 22 and the outlet channel 24, the second solution B is The micro hole 32 passes through the micro holes 32 and enters the main channel 21.
  • the second solution B passing through any one of the micro holes 32 is the main channel 21.
  • the vesicle C having the same fine size as the conventional microfluidic chip is uniform and rapid due to the self-assembly phenomenon of the fluid generated when contacting at the interface 26 that meets the first solution A flowing therein.
  • the uniform and rapid formation of the vesicle (C) is the same in the number of micro holes 32 forming an array in the micro hole array portion 30, the vesicle manufacturing apparatus according to the present invention (10) is the same effect that there are thousands of conventional microfluidic chips, that is, the vesicle (C) While being able to manufacture uniformly and quickly in a fine size, it is possible to manufacture a large number of vesicles (C) at once.
  • the vesicle (C) formed in a large amount at this time can be discharged to the outside through the discharge channel 24 in accordance with the flow of the fluid in the main channel 21, and thus not shown in the drawing, discharge pipe If the end of the (16) provided with a separate storage portion it is possible to manufacture and store a large number of vesicles (C) formed quickly and uniformly.
  • the aforementioned formation of the vesicle C causes the second solution B to flow into the main channel 21 through the first inflow channel 22, and the first solution A is introduced into the second inflow channel 23. The same effect can be obtained even when flowing into the main channel 21 through.
  • the vesicle manufacturing apparatus 10 introduces one of the first solution (A) and the second solution (B) into the first inlet channel 22, and the other into the second inlet channel 23. It is sufficient to flow into), and the present invention is not limited thereto.
  • the cross-sectional shape of the main channel 21, the first inlet channel 22, the second inlet channel 23 and the discharge channel 24 may be formed in the shape of a circle, a square, etc., the present invention is not limited thereto. .
  • the vesicle manufacturing apparatus 10 is connected to the first inlet channel 22 to supply a solution of any one of the first solution A and the second solution B to the first inlet channel 22.
  • a second supply pipe 14 connected to the first supply pipe 12 and the second inflow channel 23 to supply another solution to the second inflow channel 23.
  • the main channel 21 is composed of one straight line (straight line) closed inside the platform 20, the first inlet channel 22 is connected to the start of the straight line, the discharge channel 24 Is formed at the end of the straight line, the second inlet channel 23 may be connected between the first inlet channel 22 and the discharge channel 24, that is, one side of the straight line.
  • first inlet channel 22, the second inlet channel 23, and the outlet channel 24 may protrude upward from the platform 20. That is, one side of each of the first inlet channel 22, the second inlet channel 23, and the outlet channel 24 protrudes to the top of the platform 20, and the other side of the top surface 27 of the main channel 21. ) Can be connected. Then, the solution (A, B) can be easily supplied, especially in the discharge channel 24 in which the first solution (A) and the second solution (B) in the main channel 21 protrudes upward. As a result, the vesicle may be effectively formed by the flow of the fluid flowing from the first inlet channel 22 to the outlet channel 24 while remaining longer in the main channel 21.
  • the vesicle manufacturing apparatus 10 supplies the solution supplied to the first supply pipe 22 at a predetermined pressure to more effectively control the flow velocity of the fluid in the main channel 21.
  • the micro hole 32 of the micro hole array unit 30 is formed by supplying a first supply means to be formed and a solution supplied to the second supply pipe 14 at a predetermined pressure to flow into the second inflow channel 23.
  • the second supply means for generating the self-assembly of the fluid at the interface 26 of the main channel 21 more effectively may be further included.
  • microhole array unit 30 According to the present invention, various aspects of the microhole array unit 30 according to the present invention will be described in detail.
  • the micropore array unit 30 may be formed of a polymer membrane 34 having a thin film form in which a plurality of micropores 32 are formed.
  • FIG. 3 shows an embodiment in which the micropore array portion 30 is formed of a polymer membrane having a thin film form according to FIG. 5.
  • the micropore array portion 30 is formed of a polymer membrane having a thin film form.
  • the polymer membrane 34 In order to position the polymer membrane 34 in the outlet 25 of the second inlet channel 23, the polymer membrane 34 in the form of a thin film having a size larger than the cross section of the outlet 25 of the second inlet channel 23.
  • micropore array unit 30 may be formed of a tube in which a plurality of microchannels (or nozzles) are formed at predetermined intervals.
  • FIG. 6 is a cross-sectional view showing a state in which a tube 36 having a plurality of microchannels 35 formed at predetermined intervals is provided at the outlet 25 of the second inflow channel 23.
  • the method of positioning the tube 36 at the outlet 25 of the second inlet channel 23 may be performed by the outlet 25 of the second inlet channel 23.
  • a tube 26 having a size and shape corresponding to the size and shape is inserted into the outlet 25 in a manner such as an interference fit or a plurality of outlets 25 are formed on the outlet 25 side when the second inlet channel 23 is manufactured. It may be provided by a method of integrally forming the tube 36 on which the microchannels 35 are formed.
  • the present invention provides a micropore array having a plurality of micropores having a level of about 5 ⁇ m in a channel having a width of about 100 to 200 times wider than that of a conventional microfluidic chip.
  • a large number of vesicles can be produced at one time, while being able to produce vesicles of a small size uniformly and quickly, as in the vesicle manufacturing method using a conventional microfluidic chip.
  • the embodiment will be able to be changed in various forms. Therefore, the present invention is not limited to the embodiments disclosed in the present specification, and all forms changeable by those skilled in the art to which the present invention pertains will belong to the scope of the present invention.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Dispersion Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Manufacturing Of Micro-Capsules (AREA)

Abstract

La présente invention concerne un appareil de fabrication de liposomes permettant de fabriquer rapidement un liposome, qui consiste en un vecteur d'administration de médicament, présentant une taille uniforme et pouvant produire une grande quantité de liposomes uniquement au moyen d'une configuration simple une seule fois, ce qui permet de produire facilement et à grande échelle ledit liposome. L'appareil de fabrication de liposomes selon la présente invention comprend : une plate-forme ; un canal principal formé à l'intérieur de la plate-forme et conçu pour fournir un espace de formation de liposome ; un premier canal d'introduction à travers lequel une première solution ou une seconde solution destinées à former le liposome est introduite dans le canal principal ; une partie d'évacuation à travers laquelle est évacué un liposome formé dans le canal principal ; un second canal d'introduction situé entre le premier canal d'introduction et la partie d'évacuation et à travers lequel l'autre solution parmi la première solution et la seconde solution est introduite dans le canal principal ; et une partie réseau de trous fins agencée au niveau d'une sortie du second canal d'introduction et comportant une pluralité de trous fins à travers lesquels circule une solution fournie vers le second canal d'introduction.
PCT/KR2014/009814 2013-10-21 2014-10-18 Appareil de fabrication de liposomes WO2015060592A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2013-0125463 2013-10-21
KR20130125463A KR101492035B1 (ko) 2013-10-21 2013-10-21 베시클 제조장치

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WO2015060592A1 true WO2015060592A1 (fr) 2015-04-30

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Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101718514B1 (ko) * 2015-05-06 2017-03-22 한국해양과학기술원 방오 도료용 양친매성 하이드로젤 입자 및 그 제조방법
KR101809022B1 (ko) * 2015-11-20 2017-12-15 한국해양과학기술원 다기능성 하이드로젤 입자 및 그 제조 방법

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20090112826A (ko) * 2008-04-25 2009-10-29 한국과학기술연구원 마이크로 캡슐 제조장치 및 방법
JP2012513991A (ja) * 2008-12-29 2012-06-21 ペトロヴィッチ グレベンニコヴ，イヴゲニー リポソーム医薬の製造方法及びリポソーム製造装置
JP2012213738A (ja) * 2011-04-01 2012-11-08 Seiko Epson Corp マイクロカプセルの製造方法、マイクロカプセル塗布膜の形成方法及びマイクロカプセルの製造装置
KR101306264B1 (ko) * 2011-07-07 2013-09-09 한국기계연구원 하이드로젤 플로팅 장치

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20090112826A (ko) * 2008-04-25 2009-10-29 한국과학기술연구원 마이크로 캡슐 제조장치 및 방법
JP2012513991A (ja) * 2008-12-29 2012-06-21 ペトロヴィッチ グレベンニコヴ，イヴゲニー リポソーム医薬の製造方法及びリポソーム製造装置
JP2012213738A (ja) * 2011-04-01 2012-11-08 Seiko Epson Corp マイクロカプセルの製造方法、マイクロカプセル塗布膜の形成方法及びマイクロカプセルの製造装置
KR101306264B1 (ko) * 2011-07-07 2013-09-09 한국기계연구원 하이드로젤 플로팅 장치

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