KR20230006149A - Apparatus for homogenizing the emulsion and Method for manufacturing sustained-release microspheres with improved loading efficiency of the active substance - Google Patents

Apparatus for homogenizing the emulsion and Method for manufacturing sustained-release microspheres with improved loading efficiency of the active substance Download PDF

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KR20230006149A
KR20230006149A KR1020210086988A KR20210086988A KR20230006149A KR 20230006149 A KR20230006149 A KR 20230006149A KR 1020210086988 A KR1020210086988 A KR 1020210086988A KR 20210086988 A KR20210086988 A KR 20210086988A KR 20230006149 A KR20230006149 A KR 20230006149A
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stirring
emulsion
solution
aqueous solution
polymer
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이태호
백혜정
김진호
배병찬
김준식
김관영
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주식회사 대웅제약
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F27/00—Mixers with rotary stirring devices in fixed receptacles; Kneaders
    • B01F27/80—Mixers with rotary stirring devices in fixed receptacles; Kneaders with stirrers rotating about a substantially vertical axis
    • B01F27/91—Mixers with rotary stirring devices in fixed receptacles; Kneaders with stirrers rotating about a substantially vertical axis with propellers
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
    • 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
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
    • 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
    • A61K9/1682—Processes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F23/00—Mixing according to the phases to be mixed, e.g. dispersing or emulsifying
    • B01F23/40—Mixing liquids with liquids; Emulsifying
    • B01F23/41—Emulsifying
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F25/00—Flow mixers; Mixers for falling materials, e.g. solid particles
    • B01F25/10—Mixing by creating a vortex flow, e.g. by tangential introduction of flow components
    • B01F25/101—Mixing by creating a vortex flow, e.g. by tangential introduction of flow components wherein the vortex flows in a spherical shaped receptacle or chamber
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F27/00—Mixers with rotary stirring devices in fixed receptacles; Kneaders
    • B01F27/80—Mixers with rotary stirring devices in fixed receptacles; Kneaders with stirrers rotating about a substantially vertical axis
    • B01F27/805—Mixers with rotary stirring devices in fixed receptacles; Kneaders with stirrers rotating about a substantially vertical axis wherein the stirrers or the receptacles are moved in order to bring them into operative position; Means for fixing the receptacle
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F27/00—Mixers with rotary stirring devices in fixed receptacles; Kneaders
    • B01F27/80—Mixers with rotary stirring devices in fixed receptacles; Kneaders with stirrers rotating about a substantially vertical axis
    • B01F27/88—Mixers with rotary stirring devices in fixed receptacles; Kneaders with stirrers rotating about a substantially vertical axis with a separate receptacle-stirrer unit that is adapted to be coupled to a drive mechanism
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
    • B01F35/71—Feed mechanisms
    • B01F35/712—Feed mechanisms for feeding fluids
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F2101/00—Mixing characterised by the nature of the mixed materials or by the application field
    • B01F2101/2202—Mixing compositions or mixers in the medical or veterinary field

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Abstract

According to one embodiment of the present invention, an emulsion homogenizing device comprises: a mixing container; a mixing rod having a mixing shaft and a mixing blade and rotatably installed in the mixing container; and a medicinal liquid providing unit having an outlet through which a main component aqueous solution containing a drug is discharged in a form of a droplet and installed in the mixing container to enable the outlet to be oriented toward the mixing blade between a floor surface of the mixing container and the mixing blade.

Description

에멀젼 균질화 장치 및 약물봉입율이 향상된 서방성 미립구 제조 방법{Apparatus for homogenizing the emulsion and Method for manufacturing sustained-release microspheres with improved loading efficiency of the active substance}Apparatus for homogenizing the emulsion and Method for manufacturing sustained-release microspheres with improved loading efficiency of the active substance}

본 발명은 에멀젼 균질화 장치 및 약물봉입율이 향상된 서방성 미립구 제조 방법에 관한 것이며, 상세하게는 Ｗ1/Ｏ 에멀젼의 균질화를 통해, 미립구에 대한 약물의 봉입율을 증가시킬 수 있는 에멀젼 균질화 장치 및 약물봉입율이 향상된 서방성 미립구 제조 방법에 관한 것이다. The present invention relates to an emulsion homogenization device and a method for producing sustained-release microspheres with improved drug encapsulation rate, and more particularly, to an emulsion homogenization device capable of increasing the drug encapsulation rate to microspheres through homogenization of W1/O emulsion and a drug It relates to a method for producing sustained-release microspheres with improved encapsulation rate.

서방형 주사 제형이란 피하 또는 근육주사 시 체내에서 약물이 생물학적 활성을 유지하면서 지속적이고 균일하게 방출될 수 있도록 제제화된 주사 제형을 말한다.Sustained-release injectable formulation refers to an injectable formulation formulated to continuously and uniformly release a drug while maintaining biological activity in the body upon subcutaneous or intramuscular injection.

종래에 이와 같은 서방형 주사제제들의 일반적인 제조방법은 코아세르베이션법, 용융 사출법, 분무 건조법 및 용매 증발법 등이 알려져 있다. 이러한 방법 중 이중 유화 증발법(Ｗ/Ｏ/Ｗ emulsion)과 단일 유화 증발법(Ｏ/Ｗ emulsion)으로 분류되는 용매 증발법이 가장 많이 사용되고 있다. Conventionally, general methods for preparing such sustained-release injectable preparations include coacervation, melt injection, spray drying, and solvent evaporation. Among these methods, a solvent evaporation method classified into a double emulsion evaporation method (W/O/W emulsion) and a single emulsion evaporation method (O/W emulsion) is most commonly used.

종래의 미립구 제조 공정은, Ｗ1/Ｏ 에멀젼 형성시, 교반장치(20)에 의해, 약물이 포함된 주성분 수상용액(Ｗ1)과 고분자 유상용액(Ｏ)이 교반용기(10)에서 교반되면서 균질화된다. 여기서, 주성분 수상용액(Ｗ1)은 수상(water phase)이고, 고분자 유상용액(Ｏ)은 오일상(oil phase)이다. In the conventional microsphere manufacturing process, when forming the W1/O emulsion, the main component aqueous solution (W1) containing the drug and the polymer oil phase solution (O) are homogenized while being stirred in the stirring container 10 by the stirring device 20 . Here, the main component aqueous solution (W1) is a water phase, and the polymer oil phase solution (O) is an oil phase.

도 1을 참조하면, 종래에는 교반용기(10)에 고분자 유상용액(Ｏ)을 넣은 후에 주성분 수상용액(Ｗ1)을 교반용기(10)에 넣는다. Referring to FIG. 1, conventionally, after putting a polymer oil phase solution (O) into a stirring vessel (10), the main component aqueous solution (W1) is put into the stirring vessel (10).

그러나, 고분자 유상용액(Ｏ)의 용매인 염화메틸렌(MC, methylene chloride)와 주성분 수상용액의 용매인 물의 비중차이로 인해 주성분 수상용액이 상단에 위치하게 되면 층분리가 일어나게 되어, 주성분 수상용액(Ｗ1)이 고분자 유상용액(Ｏ)의 상단 표면에 위치하게 된다. However, due to the difference in specific gravity between methylene chloride (MC, methylene chloride), the solvent of the polymer oil phase solution (O), and water, the solvent of the main component aqueous solution, when the main component aqueous solution is located at the top, layer separation occurs, and the main component aqueous solution ( W1) is located on the upper surface of the polymer oil phase solution (O).

이후, 교반장치(20)가 회전되면서 주성분 수상용액(Ｗ1)과 고분자 유상용액(Ｏ)을 교반하여 주성분 수상용액(Ｗ1)과 고분자 유상용액(Ｏ)의 혼합액을 균질화시키는 과정이 진행된다.Thereafter, while the stirring device 20 rotates, the main component aqueous solution (W1) and the polymer oil phase solution (O) are stirred to homogenize the mixture of the main component aqueous solution (W1) and the polymer oil phase solution (O). The process proceeds.

교반장치(20)를 이용한 균질화시, 고분자 유상용액(oil phase, Ｏ)과 주성분 수상용액(W1)(water phase)간의 혼합액의 용량이 적은 경우에는 혼합하는 방법에 따른 봉입효율은 차이가 크지 않으나, 혼합액의 용량이 증가되면서 고분자 유상용액(Ｏ)의 고점도로 인해 주성분 수상용액(W1)의 혼합균질성이 떨어지게 된다. At the time of homogenization using the stirring device 20, when the capacity of the mixed solution between the polymer oil phase (O) and the main component aqueous solution (W1) (water phase) is small, the difference in encapsulation efficiency according to the mixing method is not large. , As the volume of the mixed solution increases, the mixing homogeneity of the main component aqueous solution (W1) deteriorates due to the high viscosity of the polymer oil phase solution (O).

고분자 유상용액(Ｏ)의 고점도로 인해 상단에 위치한 주성분 수상용액(W1)과 균질하게 혼합되기 위해서, 교반장치(20)의 높은 회전수(RPM)와 교반시간이 증가되어야 하며, 이때 열이 발생하게 되어 고분자 유상용액(Ｏ)의 용매인 염화메틸렌(b.p.: 39℃ 내지 40℃)이 끓게 되어 휘발되기에 고분자 유상용액(Ｏ)의 농도가 변화게 되는 문제가 발생한다. In order to homogeneously mix with the main component aqueous solution (W1) located at the top due to the high viscosity of the polymer oil phase solution (O), the high rotation speed (RPM) and stirring time of the stirring device 20 must be increased, at which time heat is generated As a result, methylene chloride (b.p.: 39 ℃ to 40 ℃), which is a solvent of the polymer oil phase solution (O), boils and volatilizes, causing a problem that the concentration of the polymer oil phase solution (O) changes.

결과적으로, 혼합액의 용량이 증가하게 되면 균질하게 교반되지 않게 되고, 혼합액이 균질하게 교반되지 않으면 혼합액에 대한 에멀젼화가 용이하지 않고, 이에 따라, 약물의 봉입 효율이 낮아지는 문제점이 있다.As a result, when the volume of the mixture is increased, it is not stirred homogeneously, and if the mixture is not stirred homogeneously, it is not easy to emulsify the mixture, and accordingly, there is a problem that the encapsulation efficiency of the drug is lowered.

한국공개특허 제10-2014-0135337호에는 1차 에멀젼과 2차 에멀젼을 동시에 주입하여 순간적으로 미립구를 형성하고 상기 형성된 미립구에 고압을 가한 후 교반기로 주입하는 과정이 연속적으로 이루어질 수 있는 미립구의 제조방법 및 이로부터 제조된 미립구가 개시되어 있다.Korean Patent Publication No. 10-2014-0135337 discloses that the process of injecting the first emulsion and the second emulsion at the same time to instantaneously form microspheres, applying high pressure to the formed microspheres, and then injecting the formed microspheres with a stirrer is continuously performed. Manufacturing of microspheres A method and microspheres made therefrom are disclosed.

따라서, 본 발명은 상기와 같은 문제점을 해결하기 위하여 안출된 것으로서, 교반용기에서 오일 상인 고분자 유상용액(Ｏ)이 선행 교반되는 중에, 주성분 수상용액(Ｗ1)이 드롭렛 형태로 교반용기의 하부로 주입되어, 고분자 유상용액(Ｏ)의 와류에 의해 분산되면서 고분자 유상용액(Ｏ)과 혼합되면서 교반됨에 따라 Ｗ1/Ｏ 에멀젼을 균질화시킬 수 있는 에멀젼 균질화 장치를 제공하는 것을 목적으로 한다. Therefore, the present invention has been made to solve the above problems, and while the polymer oil phase solution (O) in the oil phase is pre-stirred in the stirring vessel, the main component aqueous solution (W1) is poured into the lower part of the stirring vessel in the form of droplets. It is an object to provide an emulsion homogenization device capable of homogenizing the W1/O emulsion as it is injected and mixed with the polymer oil phase solution (O) while being stirred while being dispersed by the vortex of the polymer oil phase solution (O).

본 발명은 Ｗ1/Ｏ 에멀젼의 균질화를 통해, 미립구에 대한 약물의 봉입율을 증가시킬 수 있는 에멀젼 균질화 장치 및 약물봉입율이 향상된 서방성 미립구 제조 방법을 제공하는 것을 목적으로 한다. An object of the present invention is to provide an emulsion homogenizer capable of increasing the encapsulation rate of a drug into microspheres through homogenization of W1/O emulsion, and a method for producing sustained-release microspheres with improved drug encapsulation rate.

상기한 과제를 해결하기 위하여, 본 발명의 일 실시예에 따른 에멀젼 균질화 장치는 교반용기; 교반축과 교반날개가 구비되고, 교반용기에 회전가능하게 설치된 교반봉; 및 약물이 포함된 주성분 수상용액이 드롭렛 형태로 토출되는 토출구가 마련되고, 토출구가 교반용기의 바닥면과 교반날개 사이에서 교반날개를 향하게 교반용기에 설치된 약액 제공부를 포함하는 것이 바람직하다.In order to solve the above problems, the emulsion homogenization apparatus according to an embodiment of the present invention is a stirring vessel; An agitation bar having an agitation shaft and an agitation blade and rotatably installed in the agitation container; And a discharge port through which the main component aqueous solution containing the drug is discharged in the form of a droplet, and the discharge port is disposed between the bottom surface of the stirring vessel and the stirring blade toward the stirring blade.

일 예로, 약액 제공부는 갈고리 형태로 교반용기에 설치된 것이 바람직하다.For example, it is preferable that the chemical solution supply unit is installed in the stirring container in the form of a hook.

다른 예로, 교반용기의 바닥면에는 교반날개와 마주보는 위치에 본체관통홀이 마련되고, 약액 제공부는 본체관통홀을 관통하여 교반용기로 삽입되어, 토출구가 교반날개와 마주보게 설치된 것이 바람직하다.As another example, it is preferable that a body through-hole is provided on the bottom surface of the stirring vessel at a position facing the stirring blades, and the liquid supply unit is inserted into the stirring vessel through the body through-hole, and the discharge port is installed facing the stirring blades.

또 다른 예로, 교반봉은 교반축과 교반날개를 관통하는 교반관통홀이 마련되고, 약액 제공부는 토출구가 교반날개의 하부로 노출되게, 교반관통홀을 따라 교반봉에 설치된 것이 바람직하다.As another example, the stirring rod is preferably provided with a stirring through-hole penetrating the stirring shaft and the stirring blade, and the liquid supply unit is installed in the stirring rod along the stirring through-hole so that the discharge port is exposed to the lower part of the stirring blade.

본 발명의 일 실시예에서, 약액 제공부는 주입관 형태인 것이 바람직하다.In one embodiment of the present invention, it is preferable that the liquid supply unit is in the form of an injection tube.

한편, 본 발명의 일 실시예에 따른 약물봉입율이 향상된 서방성 미립구 제조 방법은, S1) 제1항의 에멀젼 균질화 장치를 이용하여, 오일상인 고분자 유상용액(Ｏ)이 교반되는 단계; S2) 교반 중인 고분자 유상용액(Ｏ)에, 주성분 수상용액(Ｗ1)이 드롭렛 형태로 주입되는 단계; S3) 주성분 수상용액(Ｗ1)과 고분자 유상용액(Ｏ)의 제1 균질화 공정에 의해, Ｗ1/Ｏ 에멀젼이 형성되는 단계; S4) 고분자 수상용액(Ｗ2)의 교반 중에, Ｗ1/Ｏ 에멀젼이 드롭렛 형태로 고분자 수상용액(Ｗ2)에 주입되는 단계; S5) 고분자 수상용액(Ｗ2)과 Ｗ1/Ｏ 에멀젼의 제2 균질화 공정에 의해, Ｗ1/Ｏ/Ｗ2 에멀젼이 형성되는 단계; 및 S6) Ｗ1/Ｏ/Ｗ2 에멀젼의 수중건조공정에 의해, 미립구가 형성되는 단계를 포함하는 것이 바람직하다. On the other hand, the method for producing sustained-release microspheres with improved drug encapsulation rate according to an embodiment of the present invention includes: S1) using the emulsion homogenizer of claim 1 to stir the polymer oil phase solution (O), which is an oil phase; S2) injecting the main component aqueous solution (W1) in the form of droplets into the polymer oil phase solution (O) being stirred; S3) forming a W1/O emulsion by first homogenizing the main component aqueous solution (W1) and the polymer oil phase solution (O); S4) injecting the W1/O emulsion into the polymer aqueous solution (W2) in the form of droplets while stirring the polymer aqueous solution (W2); S5) forming a W1/O/W2 emulsion by a second homogenization process of the polymer aqueous solution (W2) and the W1/O emulsion; and S6) forming microspheres by drying the W1/O/W2 emulsion in water.

S2단계에서, 주성분 수상용액(Ｗ1)의 드롭렛들은 에멀젼 균질화 장치의 교반봉의 하부로 주입되고, 고분자 유상용액(Ｏ)의 와류에 의해 분산되면서 고분자 유상용액(Ｏ)에 혼합되는 것이 바람직하다.In step S2, the droplets of the main component aqueous solution (W1) are injected into the lower part of the stirring rod of the emulsion homogenization device, and mixed with the polymer oil phase solution (O) while being dispersed by the vortex of the polymer oil phase solution (O) It is preferable.

S2단계에서, 고분자 유상용액(Ｏ)은 S1단계보다 1.5배 빠른 속도로 교반되는 것이 바람직하다. In step S2, the polymer oil phase solution (O) is preferably stirred 1.5 times faster than in step S1.

S4단계에서, Ｗ1/Ｏ 에멀젼은 고분자 수상용액(Ｗ2)가 교반용기로 흘러가고 있는 상태에서, 고분자 수상용액(Ｗ2)의 주입속도보다 1/100 범위 내에서 느린 속도로 기설정된 시간동안 주입되는 것이 바람직하다. In step S4, the W1/O emulsion is injected for a predetermined time at a slow rate within the range of 1/100 of the injection rate of the polymer aqueous solution (W2) while the polymer aqueous solution (W2) is flowing into the stirring container. it is desirable

고분자 유상용액(Ｏ)은 염화메틸렌(MC, Methylene Chloride)에 고분자물질인 폴리락트산(PLA, Poly Lactic Acid) 또는 락타이드·글리콜라이드 공중합체(PLGA, poly lactic-co-glycolic acid)가 용해된 용액인 것이 바람직하다.The polymer oil solution (O) is a mixture of polylactic acid (PLA, poly lactic acid) or lactide-glycolide copolymer (PLGA, poly lactic-co-glycolic acid) dissolved in methylene chloride (MC). Preferably it is a solution.

고분자 수상용액(Ｗ2)은 주사용수에 고분자물질인 폴리비닐알코올(PVA, polyvinyl alcohol)이 용해된 용액인 것이 바람직하다.The polymer aqueous solution (W2) is preferably a solution in which polyvinyl alcohol (PVA), a polymer material, is dissolved in water for injection.

주성분 수상용액(Ｗ1)은 주사용수(WFI, water for injection)에 약물이 용해된 용액인 것이 바람직하다. The main component aqueous solution (W1) is preferably a solution in which a drug is dissolved in water for injection (WFI).

여기서, 약물은 류프로라이드 아세트산염(Leuprolide Acetate)이고, 류프로라이드 아세트산염의 화학식은 (2S)-N-[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-5-(diaminomethylideneamino)-1-[(2S)-2-(ethylcarbamoyl)pyrrolidin-1-yl]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]-5-oxopyrrolidine-2-carboxamide;[(8R,9S,10R,13S,14S,17R)-17-ethynyl-13-methyl-3-oxo-1,2,6,7,8,9,10,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-yl] acetate 인 것이 바람직하다. Here, the drug is Leuprolide Acetate, and the chemical formula of Leuprolide Acetate is (2S)-N-[(2S)-1-[[(2S)-1-[[(2S)-1 -[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-5-(diaminomethylideneamino)-1-[(2S)-2-(ethylcarbamoyl)pyrrolidin -1-yl]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-( 4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl ]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]-5-oxopyrrolidine-2-carboxamide;[(8R,9S,10R,13S,14S,17R)-17- It is preferably ethynyl-13-methyl-3-oxo-1,2,6,7,8,9,10,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-yl]acetate.

이상에서 살펴본 바와 같이, 본 발명의 적어도 일 실시예와 관련된 에멀젼 균질화 장치는, 고분자 유상용액(Ｏ)의 교반 중에, 교반용기의 하부로 주성분 수상용액을 드롭렛 형태로 제공하여, 주성분 수상용액의 드롭렛이 고분자 유상용액(Ｏ)의 와류에 의해 분산되면서 고분자 유상용액(Ｏ)에 혼합되면서 교반되어, 주성분 수상용액(Ｗ1)과 고분자 유상용액(Ｏ)이 균질하게 교반되어, Ｗ1/Ｏ 에멀젼을 균질화할 수 있다. As described above, the emulsion homogenization device related to at least one embodiment of the present invention, while stirring the polymer oil phase solution (O), provides the main component aqueous solution in the form of a droplet to the lower part of the stirring vessel, so that the main component aqueous solution While the droplet is dispersed by the vortex of the polymer oil phase solution (O), it is stirred while being mixed with the polymer oil phase solution (O), and the main component aqueous solution (W1) and the polymer oil phase solution (O) are homogeneously stirred, resulting in a W1/O emulsion can be homogenized.

이에 따라, 에멀젼 균질화 장치를 이용한 약물봉입율이 향상된 서방성 미립구 제조 방법은, Ｗ1/Ｏ 에멀젼의 균질화를 통해, 약물의 봉입율을 종래와 비교하여 대략 2배 정도 향상시킬 수 있다. Accordingly, the method for producing sustained-release microspheres with improved drug encapsulation rate using the emulsion homogenizer can improve the drug encapsulation rate by about two times compared to the conventional method through homogenization of the W1/O emulsion.

도 1은 종래기술에 따른 교반장치에 대한 모식도이다.
도 2는 본 발명의 일 실시예에 따른 에멀젼 균질화 장치의 작동 상태도를 설명하기 위한 도면이다.
도 3 내지 도 5는 서로 다른 실시예에 따른 에멀젼 균질화 장치의 구성도를 개략적으로 도시한 것이다.
도 6은 본 발명의 일 실시예 따른 약물봉입율이 향상된 서방성 미립구 제조 방법을 설명하기 위한 순서도이다. 1 is a schematic diagram of a stirring device according to the prior art.
Figure 2 is a diagram for explaining the operating state of the emulsion homogenization device according to an embodiment of the present invention.
3 to 5 schematically show the configuration of the emulsion homogenization device according to different embodiments.
6 is a flow chart illustrating a method for manufacturing sustained-release microspheres with improved drug encapsulation rate according to an embodiment of the present invention.

이하에서는 첨부도면을 참조하여, 본 발명의 바람직한 실시예에 따른 에멀젼 균질화 장치 및 약물봉입율이 향상된 서방성 미립구 제조 방법에 대해 설명하기로 한다. Hereinafter, with reference to the accompanying drawings, an emulsion homogenization device and a method for manufacturing sustained-release microspheres with improved drug encapsulation rate according to a preferred embodiment of the present invention will be described.

도 2를 참조하면, 본 발명의 일 실시예에 따른 에멀젼 균질화 장치(100)는 교반용기(110), 교반봉(120) 및 약액 제공부(130)를 포함한다. Referring to Figure 2, the emulsion homogenization device 100 according to an embodiment of the present invention includes a stirring vessel 110, a stirring rod 120 and a chemical solution supply unit 130.

교반봉(120)은 교반축(121)과 교반날개(122)가 구비된다. 교반봉(120)은 교반용기(110)에 회전가능하게 설치된다. 교반용기(110)와 교반봉(120)은 공지된 구성요소로, 본 실시예에서는 이에 대해 구체적인 설명은 생략하기로 한다. The stirring bar 120 is provided with a stirring shaft 121 and a stirring wing 122 . The stirring rod 120 is rotatably installed in the stirring container 110 . The stirring vessel 110 and the stirring rod 120 are known components, and detailed description thereof will be omitted in the present embodiment.

약액 제공부(130)는 교반용기(110)로 주성분 수상용액(Ｗ1)을 제공한다. 여기서, 주성분 수상용액(Ｗ1)은 주사용수에 약물이 용해된 용액이다. 여기서, 약물은 제조하고자 하는 주사제의 종류에 따라, 다양한 종류의 약물이 적용될 수 있다. The chemical solution supply unit 130 provides the main component aqueous solution W1 to the stirring container 110 . Here, the main component aqueous solution (W1) is a solution in which a drug is dissolved in water for injection. Here, various types of drugs may be applied according to the type of injection to be prepared.

약액 제공부(130)는 주입관 형태로 마련된다. 본 실시예에, 약액 제공부(130)는 한 자리수의 mm단위(예컨대, 3mm 내지 5mm)의 직경을 가진 주입관이 사용될 수 있다. 약액 제공부(130)의 토출구(131)는 주성분 수상용액을 드롭렛 형태로 토출한다. 약액 제공부(130)는 토출구(131)가 교반용기(110)의 바닥면과 교반날개(122) 사이에서, 교반날개(122)를 향하게 교반용기(110)에 설치된다.The chemical solution supply unit 130 is provided in the form of an injection tube. In this embodiment, an injection tube having a diameter of a single digit mm unit (eg, 3 mm to 5 mm) may be used as the liquid medicine supply unit 130 . The discharge port 131 of the chemical solution supply unit 130 discharges the main component aqueous solution in the form of droplets. The chemical liquid supply unit 130 is installed in the stirring vessel 110 so that the discharge port 131 is between the bottom surface of the stirring vessel 110 and the stirring blades 122 toward the stirring blades 122.

일 예로, 도 3을 참조하면, 약액 제공부(130)는 갈고리 형태로 교반용기(110)에 설치된다. 이때, 약액 제공부(130)는 토출구(131)가 교반용기(110)의 바닥면에서 상부를 향해, 구체적으로는, 교반날개(122)의 하부로 이격되게 설치된다. For example, referring to FIG. 3 , the liquid medicine supply unit 130 is installed in the stirring vessel 110 in the form of a hook. At this time, the chemical solution supply unit 130 is installed so that the discharge port 131 is spaced apart from the bottom surface of the stirring container 110 toward the top, specifically, to the lower part of the stirring blades 122.

약액 제공부(130)의 토출방향은 교반용기(110)의 바닥면에서 상부를 향하도록 마련된다. 약액 제공부(130)의 토출방향이라 함은, 약액이 토출되는 압력이 제공되는 방향을 의미한다. 토출구(131)는 그 중심이 교반날개(122)의 회전반경 내에 위치하도록 배치될 수 있고, 예를 들어, 교반봉(121)과 동축이 되도록 배열될 수 있다. The discharge direction of the chemical liquid supply unit 130 is provided from the bottom surface of the stirring vessel 110 toward the top. The discharge direction of the chemical solution supply unit 130 means a direction in which pressure for discharging the chemical solution is provided. The discharge port 131 may be arranged so that its center is located within the rotation radius of the stirring blades 122, and may be arranged coaxially with the stirring bar 121, for example.

다른 예로, 도 4를 참조하면, 약액 제공부(130a)는 교반용기(110a)의 바닥면에 마련된 본체관통홀(111a)을 관통하여 교반용기(110a)로 삽입되어, 토출구가 교반날개의 하부로 이격된 위치에서, 교반날개(122)를 마주보게 설치된다. As another example, referring to FIG. 4 , the chemical liquid supply unit 130a is inserted into the stirring vessel 110a through the body through-hole 111a provided on the bottom surface of the stirring vessel 110a, and the discharge port is located at the bottom of the stirring blade. At a position spaced apart from, it is installed facing the stirring blades 122.

본체관통홀(111a)은 약액 제공부(130a)가 관통가능한 크기로 마련된다. 약액 제공부(130)가 교반용기(110)에 설치된 후, 약액 제공부(130a)와 본체관통홀(111a) 사이의 틈새는 실링처리되어, 교반용기(110)에 수용된 내용물의 누설을 방지한다. The main body through-hole 111a is provided with a size that allows the chemical solution supply unit 130a to pass through. After the chemical solution supply unit 130 is installed in the stirring container 110, the gap between the chemical solution supply unit 130a and the body through hole 111a is sealed to prevent leakage of contents contained in the stirring container 110. .

또 다른 예로, 도 5를 참조하면, 약액 제공부(130b)는 교반봉(120b)과 일체형으로 마련된다. 본 예에서, 교반봉(120b)은 교반축(121)과 교반날개(122)를 관통하는 교반관통홀(123b)이 마련된다. 약액 제공부(130b)는 토출구(131)가 교반날개(122)의 하부로 노출되게, 교반관통홀(123b)을 따라 교반봉(120b)에 설치된다. As another example, referring to FIG. 5 , the liquid medicine supply unit 130b is integrally provided with the stirring bar 120b. In this example, the stirring rod 120b is provided with a stirring through-hole 123b penetrating the stirring shaft 121 and the stirring blades 122 . The liquid chemical supply unit 130b is installed on the stirring rod 120b along the stirring through-hole 123b so that the discharge port 131 is exposed to the lower part of the stirring blade 122.

상기와 같은 구조를 가진 에멀젼 균질화 장치(100, 100a, 100b)는, 교반용기(110, 110a, 110b)에서 오일 상인 고분자 유상용액(Ｏ)이 선행 교반되는 중에, 주성분 수상용액(Ｗ1)이 드롭렛 형태로 교반용기(110, 110a, 110b)의 하부로 주입되고, 교반봉(120, 120a, 120b)의 회전에 의한 고분자 유상용액(Ｏ)의 와류에 의해 분산되면서 고분자 유상용액(Ｏ)에 혼합되면서 교반됨에 따라 Ｗ1/Ｏ 에멀젼을 균질화시킬 수 있다. In the emulsion homogenization apparatus (100, 100a, 100b) having the above structure, the main component aqueous solution (W1) is dropped while the polymer oil phase solution (O) in the oil phase is pre-stirred in the stirring container (110, 110a, 110b) It is injected into the lower part of the stirring vessel (110, 110a, 110b) in the form of a let, and dispersed by the vortex of the polymer oil phase solution (O) by the rotation of the stirring bar (120, 120a, 120b) to the polymer oil phase solution (O) As it is stirred while mixing, the W1/O emulsion can be homogenized.

이하에서는, 종래의 교반장치(10)를 이용한 경우와, 본 발명인 에멀젼 균질화 장치(100)를 이용하여 Ｗ1/Ｏ 에멀젼을 제조하는 약물봉입율이 향상된 서방성 미립구 제조 방법에 의한 실험예를 통해, 본 발명의 효과를 설명하기로 한다. Hereinafter, through an experimental example using a method for producing sustained-release microspheres with improved drug encapsulation rate, in which a W1/O emulsion is prepared using the conventional agitator 10 and the emulsion homogenizer 100 of the present invention, Effects of the present invention will be described.

약물봉입율(%)Drug encapsulation rate (%) 평균입도(um)Average particle size (um) 제 1실험1st experiment 42.842.8 35.135.1 제2실험2nd experiment 91.791.7 20.320.3 제3실험3rd experiment 85.985.9 17.817.8 제4실험4th experiment 98.098.0 20.920.9 제5실험Experiment 5 95.595.5 20.420.4

표 1은 종래의 교반장치(10)를 이용하여 Ｗ1/Ｏ 에멀젼 제조한 경우(제1실험)와, 본 발명인 에멀젼 균질화 장치(100)를 이용하여 Ｗ1/Ｏ 에멀젼 제조한 경우(제2실험 내지 제5실험)의 약물의 봉입율과 미립자의 평균입도를 비교한 것이다. 제1실험 내지 제5실험은 동일 조건에서 실험이 수행된 것을 전제로 한다. Table 1 shows the case of preparing a W1/O emulsion using a conventional agitator 10 (first experiment) and the case of preparing a W1/O emulsion using an emulsion homogenizer 100 of the present invention (second experiment to Experiment 5) compared the encapsulation rate of the drug and the average particle size of the particles. It is assumed that experiments 1 to 5 were conducted under the same conditions.

제1실험은 주성분 수상용액(Ｗ1)이 고분자 유상용액(Ｏ) 위로 주입하여, 고분자 유상용액(Ｏ)과 주성분 수상용액(Ｗ1)을 균질화시키는 실험으로서, 제1실험 결과, 미립구의 평균입도가 35.1um이고, 약물 봉입효율이 42.8%로 나타난다. The first experiment is an experiment in which the main component aqueous solution (W1) is injected onto the polymer oil phase solution (O) to homogenize the polymer oil phase solution (O) and the main component aqueous solution (W1). As a result of the first experiment, the average particle size of the microspheres is 35.1um, and the drug encapsulation efficiency is 42.8%.

본 발명인 에멀젼 균질화 장치(100)를 이용한 제2실험 내지 제5실험은 주성분 수상용액(Ｗ1)이 약액 제공부(130)에 의해 교반 중인 고분자 유상용액(Ｏ)의 하부로 드롭렛 형태로 주입하여, 고분자 유상용액(Ｏ)과 주성분 수상용액(Ｗ1)을 균질화시키는 실험이다. In the second to fifth experiments using the emulsion homogenization apparatus 100 of the present invention, the main component aqueous solution (W1) is injected in the form of droplets into the lower part of the polymer oil phase solution (O) being stirred by the chemical solution supply unit 130 , It is an experiment to homogenize the polymer oil phase solution (O) and the main component aqueous solution (W1).

제2실험 결과, 미립구의 평균입도가 20.3um이고, 약물 봉입효율이 91.7%로 나타난다. 제3실험 결과, 미립구의 평균입도가 17.8um이고, 약물 봉입효율이 85.9%로 나타난다. 제4실험 결과, 미립구의 평균입도가 20.9um이고, 약물 봉입효율이 98.0%로 나타난다. 제5실험 결과, 미립구의 평균입도가 20.4um이고, 약물 봉입효율이 95.5%로 나타난다. As a result of the second experiment, the average particle size of microspheres was 20.3um, and the drug encapsulation efficiency was 91.7%. As a result of the third experiment, the average particle size of microspheres was 17.8um, and the drug encapsulation efficiency was 85.9%. As a result of the fourth experiment, the average particle size of the microspheres was 20.9um, and the drug encapsulation efficiency was 98.0%. As a result of the fifth experiment, the average particle size of the microspheres was 20.4 μm, and the drug encapsulation efficiency was 95.5%.

제2 실험결과 내지 제5 실험 결과, 미립구의 평균입도는 17.8um 내지 20.9um 범위이고, 약물의 봉입율은 85.9% 내지 98% 범위로서, 제1실험결과와 비교하면, 약액 제공부(130)를 사용한 경우(제2실험 내지 제5실험)의 약물 봉입율(평균 92.78%)은 약액 제공부(130)를 사용하지 않은 경우(제1실험)의 약물봉입율(42.8%)보다 2.16배 증가함을 알 수 있고, 평균입도는 대략 1/2 사이즈로 줄어듦을 알 수 있다. As a result of the second to fifth experiments, the average particle size of the microspheres is in the range of 17.8 um to 20.9 um, and the encapsulation rate of the drug is in the range of 85.9% to 98%, compared to the first experimental results. The drug encapsulation rate (average of 92.78%) in the case of using (second to fifth experiment) increased by 2.16 times compared to the drug encapsulation rate (42.8%) in the case of not using the liquid supply unit 130 (first experiment). It can be seen that, and the average particle size is reduced to about 1/2 size.

이하에서는, 도 6을 참조하여, 본 발명의 바람직한 실시예에 따른 약물봉입율이 향상된 서방성 미립구 제조 방법에 대해 설명하기로 한다. Hereinafter, with reference to FIG. 6, a method for preparing sustained-release microspheres with improved drug encapsulation rate according to a preferred embodiment of the present invention will be described.

종래에는 고분자 유상용액(Ｏ)과 주성분 수상용액(Ｗ1)을 혼합한 상태에서 혼합액을 교반하여 Ｗ1/Ｏ 에멀젼을 만드는데 것과 비교하여, 본 발명의 일 실시예에 따른 약물봉입율이 향상된 서방성 미립구 제조 방법은 고분자 유상용액(Ｏ)이 먼저 교반되고, 주성분 수상용액(Ｗ1)이 교반 중인 고분자 유상용액(Ｏ)에 주입된다. Compared to conventionally, in a state where a polymer oil phase solution (O) and a main component aqueous solution (W1) are mixed and the mixed solution is stirred to form a W1/O emulsion, sustained-release microspheres with improved drug encapsulation rate according to an embodiment of the present invention In the manufacturing method, the polymer oil phase solution (O) is first stirred, and the main component aqueous solution (W1) is injected into the polymer oil phase solution (O) being stirred.

주성분 수상용액(Ｗ1)은 약액 제공부(130)에 의해 드롭렛 형태로, 교반용기(110)의 바닥에서 교반날개(122)를 향해 토출된다. 주성분 수상용액(Ｗ1)의 드롭렛들은 교반날개(122)의 회전력에 의한 고분자 유상용액(Ｏ)의 와류를 타고 분산되면서, 고분자 유상용액(Ｏ)에 혼합된다. 제1 균질화 공정을 통해, 주성분 수상용액(Ｗ1)과 고분자 유상용액(Ｏ)의 혼합액은 교반봉(120)에 의해 교반되면서 균질화되어, Ｗ1/Ｏ 에멀젼을 형성한다. The main component aqueous solution (W1) is discharged from the bottom of the stirring vessel 110 toward the stirring blades 122 in the form of droplets by the chemical solution supply unit 130. The droplets of the main component aqueous solution (W1) are mixed with the polymer oil phase solution (O) while being dispersed in the vortex of the polymer oil phase solution (O) by the rotational force of the stirring blades 122. Through the first homogenization process, the mixture of the main component aqueous solution (W1) and the polymer oil phase solution (O) is homogenized while being stirred by the stirring bar 120 to form a W1/O emulsion.

Ｗ1/Ｏ 에멀젼을 제조하는 과정에 대해, 실험예로 설명하면 다음과 같다. The process of preparing the W1/O emulsion is described as an experimental example as follows.

우선, Ｗ1/Ｏ 에멀젼을 제조하는데 사용되는 고분자 유상용액(Ｏ)과 주성분 수상용액(Ｗ1)의 성분 및 용량에 대해 설명하기로 한다. First, components and capacities of the polymer oil phase solution (O) and the main component aqueous solution (W1) used to prepare the W1/O emulsion will be described.

용액solution 주입량 (g)Injection amount (g) 고분자 유상용액(Ｏ)Polymer oily solution (O) 1397.28g1397.28g 주성분 수상용액(Ｗ1)Main ingredient aqueous solution (W1) 158.72g158.72g

표 2는 제1 균질화 공정에서, Ｗ1/Ｏ 에멀젼을 제조하는데 사용되는 고분자 유상용액(Ｏ) 및 주성분 수상용액(Ｗ1)의 용량이다. Table 2 is the capacity of the polymer oil phase solution (O) and the main component aqueous solution (W1) used to prepare the W1/O emulsion in the first homogenization step.

고분자 유상용액(Ｏ)이 1397.28g 주입될 때, 주성분 수상용액(Ｗ1)은 158.72g 주입된다. 고분자 유상용액(Ｏ)은 S1 단계에서 주입되고, 주성분 수상용액(Ｗ1)은 S2 단계에서 교반용기(110)의 바닥면에서 교반날개(122)를 향해 드롭렛 형태로 주입된다. When 1397.28 g of the polymer oil phase solution (O) is injected, 158.72 g of the main component aqueous solution (W1) is injected. The polymer oil phase solution (O) is injected in step S1, and the main component aqueous solution (W1) is injected in the form of droplets from the bottom surface of the stirring vessel 110 toward the stirring blades 122 in step S2.

고분자 유상용액(Ｏ)은 염화메틸렌(MC, Methylene Chloride)에 고분자물질인 폴리락트산(PLA, Poly Lactic Acid) 또는 락타이드·글리콜라이드 공중합체(PLGA, poly lactic-co-glycolic acid)가 용해된 용액이다. The polymer oil solution (O) is a mixture of polylactic acid (PLA, poly lactic acid) or lactide-glycolide copolymer (PLGA, poly lactic-co-glycolic acid) dissolved in methylene chloride (MC). it is a solution

그리고, 주성분 수상용액(Ｗ1)은 주사용수(ＷFI, Ｗater for injection)에 약물이 용해된 용액이다. 주사용수에 용해되는 약물은 제조하고자 하는 주사제의 종류에 따라 가변될 수 있다. And, the main component aqueous solution (W1) is a solution in which a drug is dissolved in water for injection (WFI, Water for injection). The drug dissolved in the water for injection may vary depending on the type of injection to be prepared.

일 예로, 자궁내막증, 자궁근종, 전립선암, 폐경전 유방암, 중추성 사춘기조발증을 치료하는데 사용되는 류프로라이드 데포 주사제를 제조하는 경우에, 주성분 수상용액(Ｗ1)에 포함된 약물은 류프로라이드 아세트산염(Leuprolide Acetate)이 사용될 수 있다. For example, in the case of preparing a leuprolide depot injection used to treat endometriosis, uterine fibroids, prostate cancer, premenopausal breast cancer, and central premature onset of puberty, the drug contained in the aqueous solution (W1) of the active ingredient is leuprolide Leuprolide Acetate may be used.

류프로라이드 아세트산염의 화학식은 (2S)-N-[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-5-(diaminomethylideneamino)-1-[(2S)-2-(ethylcarbamoyl)pyrrolidin-1-yl]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]-5-oxopyrrolidine-2-carboxamide;[(8R,9S,10R,13S,14S,17R)-17-ethynyl-13-methyl-3-oxo-1,2,6,7,8,9,10,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-yl]acetate 이다. The chemical formula of leuprolide acetate is (2S)-N-[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2R)- 1-[[(2S)-1-[[(2S)-5-(diaminomethylideneamino)-1-[(2S)-2-(ethylcarbamoyl)pyrrolidin-1-yl]-1-oxopentan-2-yl]amino ]-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino] -3-hydroxy-1-oxopropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-3-(1H-imidazol-5-yl) -1-oxopropan-2-yl]-5-oxopyrrolidine-2-carboxamide;[(8R,9S,10R,13S,14S,17R)-17-ethynyl-13-methyl-3-oxo-1,2,6 ,7,8,9,10,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-yl]acetate.

Ｗ1/Ｏ 에멀젼 제조 단계W1/O emulsion preparation step 교반 속도stirring speed 교반 시간stirring time S1- 고분자 유상용액(Ｏ) 선행 교반S1- polymer oil phase solution (O) pre-stirring 4000 rpm4000rpm 1분1 minute S2- 주성분 수상용액(Ｗ1)을 주입하면서 교반S2- stirring while injecting the main component aqueous solution (W1) 6000 rpm6000rpm 3분3 minutes S3- S2종료후, 추가 교반S3- After the end of S2, additional stirring 6000 rpm6000rpm 2분2 minutes

표3은 Ｗ1/Ｏ 에멀젼 제조시 각 단계별, 교반 속도 및 교반시간이다.Table 3 shows the stirring speed and stirring time for each step in preparing the W1/O emulsion.

표 3 및 도 6을 참조하면, S1 단계에서, 교반봉(120)은 4000rpm으로 1분간 회전하면서, 고분자 유상용액(Ｏ)을 교반한다. 이후, 교반 중인 고분자 유상용액(Ｏ)으로, 주성분 수상용액(Ｗ1)이 드롭렛 형태로 주입된다(S2). S2 단계에서, 교반봉(120)은 6000rpm으로 3분간 회전된다. Referring to Table 3 and FIG. 6, in step S1, the stirring bar 120 is stirred at 4000 rpm for 1 minute while stirring the polymer oil phase solution (O). Thereafter, the main component aqueous solution (W1) is injected in the form of droplets into the polymer oil phase solution (O) being stirred (S2). In step S2, the stirring bar 120 is rotated at 6000 rpm for 3 minutes.

주성분 수상용액(Ｗ1)의 주입이 완료된 후에도, 교반봉(120)은 6000rpm으로 2분간 더 회전되면서, 주성분 수상용액(Ｗ1)과 고분자 유상용액(Ｏ)을 교반하면서 균질화시킨다. S2 및 S3 단계를 거치면서, 주성분 수상용액(Ｗ1)과 고분자 유상용액(Ｏ)은 균질화되면서, Ｗ1/Ｏ 에멀젼을 형성한다. Even after the injection of the main component aqueous solution (W1) is completed, the stirring rod 120 is further rotated at 6000 rpm for 2 minutes to homogenize the main component aqueous solution (W1) and the polymer oil phase solution (O) while stirring. Through steps S2 and S3, the main component aqueous solution (W1) and the polymer oil phase solution (O) are homogenized to form a W1/O emulsion.

상기와 같은 과정을 통해 Ｗ1/Ｏ 에멀젼이 제조되면, Ｗ1/Ｏ/Ｗ2 에멀젼 제조공정이 진행된다. S4단계는 S1 내지 S3단계에서 사용된 에멀젼 균질화 장치(100)가 아닌 별개의 교반장치(미도시)에서 진행된다. When the W1/O emulsion is prepared through the above process, the W1/O/W2 emulsion manufacturing process proceeds. Step S4 is carried out in a separate stirring device (not shown) rather than the emulsion homogenizer 100 used in steps S1 to S3.

S4 단계에서, 고분자 수상용액(Ｗ2)의 교반 중에, Ｗ1/Ｏ 에멀젼이 드롭렛 형태로 고분자 수상용액(Ｗ2)에 주입된다. 여기서, 고분자 수상용액(Ｗ2)은 주사용수에 고분자물질인 폴리비닐알코올(PVA, polyvinyl alcohol)이 용해된 용액이다. 고분자 수상용액(Ｗ2)은 수상(Ｗater phase)이다. In step S4, while stirring the polymer aqueous solution (W2), the W1/O emulsion is injected into the polymer aqueous solution (W2) in the form of droplets. Here, the polymer aqueous solution (W2) is a solution in which polyvinyl alcohol (PVA), a polymer material, is dissolved in water for injection. The polymer aqueous solution (W2) is a water phase (Water phase).

S4단계에서, 고분자 수상용액(Ｗ2)이 주입되어 흘러 들어가고 있는 상태에서, 별도의 교반장치(미도시)의 교반봉이 7200RPM으로 회전되면서 교반한다. 고분자 수상용액(Ｗ2)은 1.5L/min의 주입속도로 교반용기로 주입된다. 그리고, Ｗ1/Ｏ 에멀젼은 14.6mL/min의 주입속도로 80분 동안 주입된다. 이때, 고분자 수상용액(Ｗ2)이 교반장치(미도시)의 교반용기로 흘러 들어가고 있는 상태에서, Ｗ1/Ｏ 에멀젼은 드롭렛 형태로 고분자 수상용액(Ｗ2)으로 주입된다. In step S4, while the polymer aqueous solution (W2) is being injected and flowing, the stirring bar of a separate stirring device (not shown) is rotated at 7200 RPM and stirred. The polymer aqueous solution (W2) is injected into the stirring vessel at an injection rate of 1.5 L/min. Then, the W1/O emulsion was injected for 80 minutes at an injection rate of 14.6 mL/min. At this time, in a state where the polymer aqueous solution (W2) flows into the stirring container of the stirring device (not shown), the W1/O emulsion is injected into the polymer aqueous solution (W2) in the form of droplets.

S5 단계에서, 고분자 수상용액(Ｗ2)과 Ｗ1/Ｏ 에멀젼의 제2 균질화 공정에 의해, Ｗ1/Ｏ/Ｗ2 에멀젼이 형성된다. S5 단계의 교반속도는 S4 단계의 교반속도와 동일한 7200RPM이다. In step S5, a W1/O/W2 emulsion is formed by a second homogenization process of the polymer aqueous solution (W2) and the W1/O emulsion. The stirring speed of step S5 is 7200 RPM, which is the same as the stirring speed of step S4.

S4 및 S5 단계를 통해 Ｗ1/Ｏ/Ｗ2 에멀젼이 제조되면, 미립구 제조단계가 수행된다. When the W1/O/W2 emulsion is prepared through steps S4 and S5, a microsphere preparation step is performed.

S6단계에서, Ｗ1/Ｏ/Ｗ2 에멀젼은 수중건조공정에 의해, 유기 용매가 휘발되면서 미립구를 형성한다. Ｗ1/Ｏ/Ｗ2 에멀젼을 원심분리시켜, Ｗ1/Ｏ/Ｗ2 에멀젼의 상등액을 버린 후에 증류수로 미립구를 세척 후 동결 건조시킨다. In step S6, the W1/O/W2 emulsion is dried in water to form microspheres as the organic solvent is volatilized. The W1/O/W2 emulsion is centrifuged, the supernatant of the W1/O/W2 emulsion is discarded, and the microspheres are washed with distilled water and freeze-dried.

S6 단계는 미립구를 제조하는 방법으로 공지된 기술로서, 수중 건조 공정, 세척 공정, 동결 건조 공정 및 미립구 분쇄 공정에 대해서는 구체적인 설명을 생략하기로 한다. Step S6 is a known technique for producing microspheres, and detailed descriptions of the underwater drying process, the washing process, the freeze drying process, and the microsphere grinding process will be omitted.

본 발명의 일 실시예에 따른 약물봉입율이 향상된 서방성 미립구 제조 방법은 미립구를 대량 생산하더라도 Ｗ1/Ｏ 에멀젼 및 Ｗ1/Ｏ/Ｗ2 에멀젼의 균질화를 통해 약물 봉입율을 종래보다 대략 2배 정도 증가시켜, 효과가 안정적인 서방성 미립구를 대량으로 생산가능하다.In the method for manufacturing sustained-release microspheres with improved drug encapsulation rate according to an embodiment of the present invention, even if microspheres are mass-produced, the drug encapsulation rate is increased by about two times compared to the conventional method through homogenization of W1/O emulsion and W1/O/W2 emulsion. By doing so, it is possible to mass-produce sustained-release microspheres with stable effects.

위에서 설명된 본 발명의 바람직한 실시예는 예시의 목적을 위해 개시된 것이고, 본 발명에 대한 통상의 지식을 가지는 당업자라면 본 발명의 사상과 범위 안에서 다양한 수정, 변경, 부가가 가능할 것이며, 이러한 수정, 변경 및 부가는 하기의 청구범위에 속하는 것으로 보아야 할 것이다.Preferred embodiments of the present invention described above have been disclosed for illustrative purposes, and those skilled in the art having ordinary knowledge of the present invention will be able to make various modifications, changes, and additions within the spirit and scope of the present invention, and such modifications and changes and additions are intended to fall within the scope of the following claims.

100, 110a, 110b: 에멀젼 균질화 장치
110, 110a, 110b: 교반용기
120, 120a, 120b : 교반봉
130, 130a, 130b: 약액 제공부100, 110a, 110b: emulsion homogenizer
110, 110a, 110b: stirring vessel
120, 120a, 120b: stirring bar
130, 130a, 130b: liquid medicine supply unit

Claims (13)

교반용기;
교반축과 교반날개가 구비되고, 상기 교반용기에 회전가능하게 설치된 교반봉; 및
약물이 포함된 주성분 수상용액이 드롭렛 형태로 토출되는 토출구가 마련되고, 상기 토출구가 상기 교반용기의 바닥면과 상기 교반날개 사이에서 상기 교반날개를 향하게 상기 교반용기에 설치된 약액 제공부를 포함하는 것을 특징으로 하는 에멀젼 균질화 장치. stirring vessel;
an agitation rod having an agitation shaft and an agitation wing and rotatably installed in the agitation container; and
A discharge port through which the main component aqueous solution containing the drug is discharged in the form of a droplet, and the discharge port includes a drug solution supply unit installed in the stirring vessel between the bottom surface of the stirring vessel and the stirring blades toward the stirring blades. Emulsion homogenizer characterized by. 제 1 항에 있어서,
상기 약액 제공부는 갈고리 형태로 상기 교반용기에 설치된 것을 특징으로 하는 에멀젼 균질화 장치. According to claim 1,
Emulsion homogenization device, characterized in that the chemical liquid supply unit is installed in the stirring container in the form of a hook. 제 1 항에 있어서,
상기 교반용기의 바닥면에는 상기 교반날개와 마주보는 위치에 본체관통홀이 마련되고,
상기 약액 제공부는 상기 본체관통홀을 관통하여 상기 교반용기로 삽입되어, 상기 토출구가 상기 교반날개와 마주보게 설치된 것을 특징으로 하는 에멀젼 균질화 장치. According to claim 1,
A body through-hole is provided on the bottom surface of the stirring container at a position facing the stirring blades,
Emulsion homogenization apparatus, characterized in that the chemical solution supply unit is inserted into the stirring container through the main body through-hole, and the discharge port is installed to face the stirring blades. 제 1 항에 있어서,
상기 교반봉은 상기 교반축과 상기 교반날개를 관통하는 교반관통홀이 마련되고,
상기 약액 제공부는 상기 토출구가 상기 교반날개의 하부로 노출되게, 상기 교반관통홀을 따라 상기 교반봉에 설치된 것을 특징으로 하는 에멀젼 균질화 장치. According to claim 1,
The stirring rod is provided with a stirring through-hole penetrating the stirring shaft and the stirring blades,
Emulsion homogenization apparatus, characterized in that the chemical liquid supply unit is installed on the stirring bar along the stirring through-hole so that the discharge port is exposed to the lower part of the stirring blade. 제 1 항에 있어서,
상기 약액 제공부는 주입관 형태인 것을 특징으로 하는 에멀젼 균질화 장치. According to claim 1,
Emulsion homogenization device, characterized in that the chemical solution supply unit is in the form of an injection tube. S1) 제1항의 에멀젼 균질화 장치를 이용하여, 오일상인 고분자 유상용액(Ｏ)이 교반되는 단계;
S2) 교반 중인 상기 고분자 유상용액(Ｏ)에, 주성분 수상용액(Ｗ1)이 드롭렛 형태로 주입되는 단계;
S3) 상기 주성분 수상용액(Ｗ1)과 상기 고분자 유상용액(Ｏ)의 제1 균질화 공정에 의해, Ｗ1/Ｏ 에멀젼이 형성되는 단계;
S4) 고분자 수상용액(Ｗ2)의 교반 중에, 상기 Ｗ1/Ｏ 에멀젼이 드롭렛 형태로 상기 고분자 수상용액(Ｗ2)에 주입되는 단계;
S5) 상기 고분자 수상용액(Ｗ2)과 상기 Ｗ1/Ｏ 에멀젼의 제2 균질화 공정에 의해, Ｗ1/Ｏ/Ｗ2 에멀젼이 형성되는 단계; 및
S6) 상기 Ｗ1/Ｏ/Ｗ2 에멀젼의 수중건조공정에 의해, 미립구가 형성되는 단계를 포함하는 것을 특징으로 하는 약물봉입율이 향상된 서방성 미립구 제조 방법.S1) using the emulsion homogenization device of claim 1, the step of stirring the oil phase polymer oil phase solution (O);
S2) injecting the main component aqueous solution (W1) in the form of droplets into the polymer oil phase solution (O) being stirred;
S3) forming a W1/O emulsion by a first homogenization process of the main component aqueous solution (W1) and the polymer oil phase solution (O);
S4) injecting the W1/O emulsion into the polymer aqueous solution (W2) in the form of droplets while stirring the polymer aqueous solution (W2);
S5) forming a W1/O/W2 emulsion by a second homogenization process of the polymer aqueous solution (W2) and the W1/O emulsion; and
S6) A method for producing sustained-release microspheres with improved drug encapsulation, characterized in that it comprises a step of forming microspheres by the water drying process of the W1/O/W2 emulsion. 제 6 항에 있어서,
상기 S2 단계에서, 상기 주성분 수상용액(Ｗ1)의 드롭렛들은 상기 에멀젼 균질화 장치의 교반봉의 하부로 주입되고, 상기 고분자 유상용액(Ｏ)의 와류에 의해 분산되면서 상기 고분자 유상용액(Ｏ)에 혼합되는 것을 특징으로 하는 약물봉입율이 향상된 서방성 미립구 제조 방법.According to claim 6,
In the step S2, the droplets of the main component aqueous solution (W1) are injected into the lower part of the stirring rod of the emulsion homogenization device, and mixed with the polymer oil phase solution (O) while being dispersed by the vortex of the polymer oil phase solution (O) Method for producing sustained-release microspheres with improved drug encapsulation rate, characterized in that. 제 6 항에 있어서,
상기 S2 단계에서, 상기 고분자 유상용액(Ｏ)은 상기 S1 단계보다 1.5배 빠른 속도로 교반되는 것을 특징으로 하는 약물봉입율이 향상된 서방성 미립구 제조 방법. According to claim 6,
In step S2, the polymer oil phase solution (O) is stirred 1.5 times faster than in step S1. 제 6 항에 있어서,
상기 S4 단계에서, 상기 Ｗ1/Ｏ 에멀젼은 상기 고분자 수상용액(Ｗ2)가 교반기로 흘러가고 있는 상태에서, 상기 고분자 수상용액(Ｗ2)의 주입속도보다 1/100 범위 내에서 느린 속도로 기설정된 시간동안 주입되는 것을 특징으로 하는 약물봉입율이 향상된 서방성 미립구 제조 방법.According to claim 6,
In the step S4, the W1/O emulsion is prepared at a slow rate within the range of 1/100 of the injection rate of the polymer aqueous solution (W2) while the polymer aqueous solution (W2) is flowing into the stirrer for a predetermined time Method for producing sustained-release microspheres with improved drug encapsulation rate, characterized in that injected during. 제 6항에 있어서,
상기 고분자 유상용액(Ｏ)은 염화메틸렌(MC, Methylene Chloride)에 고분자물질인 폴리락트산(PLA, Poly Lactic Acid) 또는 락타이드·글리콜라이드 공중합체(PLGA, poly lactic-co-glycolic acid)가 용해된 용액인 것을 특징으로 하는 약물봉입율이 향상된 서방성 미립구 제조 방법.According to claim 6,
The polymer oil solution (O) is a polymer material, polylactic acid (PLA, poly lactic acid) or lactide-glycolide copolymer (PLGA, poly lactic-co-glycolic acid) dissolved in methylene chloride (MC, Methylene Chloride). Method for producing sustained-release microspheres with improved drug encapsulation rate, characterized in that the solution. 제 6항에 있어서,
상기 고분자 수상용액(Ｗ2)은 주사용수에 고분자물질인 폴리비닐알코올(PVA, polyvinyl alcohol)이 용해된 용액인 것을 특징으로 하는 약물봉입율이 향상된 서방성 미립구 제조 방법. According to claim 6,
The polymer aqueous solution (W2) is a method for producing sustained-release microspheres with improved drug encapsulation rate, characterized in that a solution in which polyvinyl alcohol (PVA), a polymer material, is dissolved in water for injection. 제 6항에 있어서,
상기 주성분 수상용액(Ｗ1)은 주사용수(ＷFI, Ｗater for injection)에 약물이 용해된 용액인 것을 특징으로 하는 약물봉입율이 향상된 서방성 미립구 제조 방법. According to claim 6,
The method for producing sustained-release microspheres with improved drug encapsulation rate, characterized in that the main component aqueous solution (W1) is a solution in which the drug is dissolved in water for injection (WFI, Wate for injection). 제 12항에 있어서,
상기 약물은 류프로라이드 아세트산염(Leuprolide Acetate)이고,
상기 류프로라이드 아세트산염의 화학식은 (2S)-N-[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-5-(diaminomethylideneamino)-1-[(2S)-2-(ethylcarbamoyl)pyrrolidin-1-yl]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]-5-oxopyrrolidine-2-carboxamide;[(8R,9S,10R,13S,14S,17R)-17-ethynyl-13-methyl-3-oxo-1,2,6,7,8,9,10,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-yl] acetate인 것을 특징으로 하는 약물봉입율이 향상된 서방성 미립구 제조 방법. According to claim 12,
The drug is Leuprolide Acetate,
The chemical formula of the leuprolide acetate is (2S)-N-[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2R) -1-[[(2S)-1-[[(2S)-5-(diaminomethylideneamino)-1-[(2S)-2-(ethylcarbamoyl)pyrrolidin-1-yl]-1-oxopentan-2-yl] amino]-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino ]-3-hydroxy-1-oxopropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-3-(1H-imidazol-5-yl )-1-oxopropan-2-yl]-5-oxopyrrolidine-2-carboxamide;[(8R,9S,10R,13S,14S,17R)-17-ethynyl-13-methyl-3-oxo-1,2, A method for producing sustained-release microspheres with improved drug encapsulation, characterized in that 6,7,8,9,10,11,12,14,15,16-dodecahydrocyclopenta [a] phenanthren-17-yl] acetate.
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