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WO2025071365A1 - Réacteur à écoulement et système de synthèse de polymère biologique le comprenant - Google Patents

Réacteur à écoulement et système de synthèse de polymère biologique le comprenant Download PDF

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Publication number
WO2025071365A1
WO2025071365A1 PCT/KR2024/014797 KR2024014797W WO2025071365A1 WO 2025071365 A1 WO2025071365 A1 WO 2025071365A1 KR 2024014797 W KR2024014797 W KR 2024014797W WO 2025071365 A1 WO2025071365 A1 WO 2025071365A1
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WIPO (PCT)
Prior art keywords
reactor
biological polymer
fluid
solid support
synthesis system
Prior art date
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PCT/KR2024/014797
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English (en)
Korean (ko)
Inventor
장명훈
최재순
최민혁
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Biosensor Laboratories Inc
Sp2 Tx Inc
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Biosensor Laboratories Inc
Sp2 Tx Inc
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Priority claimed from KR1020240131849A external-priority patent/KR20250047637A/ko
Publication of WO2025071365A1 publication Critical patent/WO2025071365A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • 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
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/04—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers

Definitions

  • the present invention relates to a flow reactor and a biological polymer synthesis system.
  • Peptide drugs generate billions of dollars in sales annually in the fields of diabetes, obesity, and oncology, and are expanding into the development of new drugs for emerging diseases such as cardiovascular and neurodegenerative diseases.
  • peptides which is a shortcoming of short half-life in the body, has been solved by methods such as the introduction of unnatural amino acids.
  • Various peptide drugs with a dosing cycle of more than one week are already on the market, and many candidates for oral administration are undergoing clinical trials with the U.S. Food and Drug Administration. Accordingly, the production demand for peptide drugs is increasing by nearly 10% every year, and there is an urgent need for a new synthesis platform to respond to increased productivity and ESG issues such as regulations on the use of DMF used in traditional chemical synthesis methods.
  • Peptide drugs are largely manufactured using biological or chemical methods. Biological methods using genetically modified plants or animals have the disadvantage that it is difficult to produce peptide drugs with extended half-lives using non-natural amino acids or PEGylation, which are recent trends, and that it is difficult to remove various endogenous contaminants derived from organisms or exogenous contaminants generated during the process.
  • SPPS Solid Phase Peptide Synthesis
  • reactors In order to increase the production capacity of various biological polymers including peptides, various types of reactors are being studied in the SPPS field. Representative reactors include batch type reactors and flow type reactors. For mass synthesis, batch type reactors have been gradually scaled up from 10-50 mL to 100-500 L units, and various solutions have been improved for transfer, stirring, pressure control, and filtering methods. In laboratory scale, flow reactors have recently been introduced, and it has been shown that rapid peptide synthesis with high purity and yield is possible.
  • batch reactors have problems such as differences in temperature transfer and time until uniform mixing between the center and surface of the reaction solution because the reactor size varies depending on the reaction scale, and low reproducibility of reaction temperature/mixing, making it difficult to control yield and quality due to reproducibility.
  • a general flow reactor has the advantage of excellent reaction reproducibility as it passes through a tubular reactor and is mixed at high speed to increase the reaction surface area, thereby inducing uniform temperature transfer and chemical reaction, and easy quality control and yield control due to high reaction reproducibility.
  • the currently developed flow reactor has the advantage of rapid synthetic reaction, but has the problem of a back pressure of 30-50 bar when using 200 mg PS/DVB. This high back pressure clearly shows that the synthetic scale cannot be significantly increased.
  • the flow reactor developed by Vapourtek in the UK solved the high back pressure, which is a disadvantage of packed bead-type resin, by using an adjustable syringe, but has a very small usable flow rate, and it has limitations in that it is difficult to significantly increase the synthetic scale due to the nature of pressure control using a syringe.
  • the present invention aims to provide a SPPS type flow reactor having improved synthesis efficiency and yield and high durability and stability, and a biological polymer synthesis system including the same.
  • One embodiment of the present invention provides a biological polymer synthesis system, comprising: a mixing tank in which at least one of an amino acid, a reagent, and an additive is mixed; a reactor into which a fluid discharged from the mixing tank is introduced; a temperature controller disposed between the mixing tank and the reactor to control a temperature of the fluid introduced into the reactor; and a pump providing a driving force so that the fluid flows from the mixing tank to the reactor, wherein the reactor comprises a column having an inlet through which the fluid is introduced and an outlet through which the fluid is discharged; and a composite solid support disposed inside the column.
  • the flow reactor of the present invention and the biological polymer synthesis system including the same can provide a biological polymer synthesis process with improved efficiency and yield.
  • the biological polymer synthesis system has the characteristics of using a flow reactor loaded with a composite solid support, exhibiting a low pressure drop even at a high flow rate, and maintaining excellent efficiency and yield even in a variety of fluid temperature ranges.
  • the flow reactor of the present invention and the biological polymer synthesis system including the same have improved overall durability and stability of the equipment and can precisely control the process.
  • FIG. 1 is a diagram illustrating a biological polymer synthesis system according to one embodiment of the present invention.
  • Figure 2 is a drawing illustrating the reactor of Figure 1.
  • Figure 3 is a graph measuring pressure drop according to flow rate to compare the reactor of the present invention with a comparative example.
  • Figure 4 is a graph measuring the pressure drop according to the size of the reactor of the present invention.
  • Figures 5 and 6 are graphs measuring the pressure drop according to temperature in the reactor of the present invention and a comparative example.
  • Figure 7 shows the appearance of the core substrate before coating
  • Figure 8 shows the appearance of the composite solid support.
  • Figures 9 to 11 show HPLC graphs for ACP synthesized according to flow rate using a composite solid support according to one specific example.
  • One embodiment of the present invention provides a biological polymer synthesis system, comprising: a mixing tank in which at least one of an amino acid, a reagent, and an additive is mixed; a reactor into which a fluid discharged from the mixing tank is introduced; a temperature controller disposed between the mixing tank and the reactor to control a temperature of the fluid introduced into the reactor; and a pump providing a driving force so that the fluid flows from the mixing tank to the reactor, wherein the reactor comprises a column having an inlet through which the fluid is introduced and an outlet through which the fluid is discharged; and a composite solid support disposed inside the column.
  • the composite solid support may include a core substrate and a functional coating positioned on the core substrate.
  • the composite solid support can be self-standing when the fluid passes through the column.
  • the composite solid support may have a loading density of the functional coating of 0.01 mmol/g to 2 mmol/g.
  • the pressure drop between the inlet and the outlet may be 10 bar or less at a flow rate of 40 C.V/min or less.
  • the pressure drop may be measured based on the pressure difference generated at the inlet and outlet of an empty column.
  • the flow rate can be expressed in C.V (Column Volume) per minute, and the reactor has a flow rate of 40 C.V/min or less, specifically 40 C.V/min or less, 30 C.V/min or less, 20 C.V/min or less, 0.1 C.V/min to 40 C.V/min, 1 C.V/min to 40 C.V/min, 5 C.V/min to 40 C.V/min, 10 C.V/min to 40 C.V/min, 15 C.V/min to 40 C.V/min, 20 C.V/min to 40 C.V/min, 25 C.V/min to 40 C.V/min, 30 C.V/min to 40 C.V/min, 35 C.V/min to 40 C.V/min, 0.1 C.V/min to 30 C.V/min, 1 C.V/min to 30 C.V/min, 5 C.V/min to 30 C.V/min, 10 C.V/min to 30 C.V/min, 15 C.
  • the pressure drop is 10 bar or less, specifically, 10 bar or less, 5 bar or less, 3 bar or less, 1 bar or less, 0.5 bar or less, 0.1 bar or less, 0.05 bar or less, 0.01 bar to 10 bar, 0.05 bar to 10 bar, 0.1 bar to 10 bar, 0.5 bar to 10 bar, 1 bar to 10 bar, 3 bar to 10 bar, 5 bar to 10 bar, 0.01 bar to 5 bar, 0.05 bar to 5 bar, 0.1 bar to 5 bar, 0.5 bar to 5 bar, 1 bar to 5 bar, 3 bar to 5 bar, 0.01 bar to 3 bar, 0.05 bar to 3 bar, 0.1 bar to 3 bar, 0.5 bar to 3 bar, 1 bar to 3 bar, It can represent 0.01 bar to 1 bar, 0.05 bar to 1 bar, 0.1 bar to 1 bar, 0.5 bar to 1 bar, 0.01 bar to 0.5 bar, 0.05 bar to 0.5 bar, 0.1 bar to 0.5 bar, 0.01 bar to 0.1 bar or 0.05 bar to 0.1 bar.
  • the temperature of the fluid flowing into the reactor after passing through the temperature controller may be 120°C or lower.
  • the biological polymer system of the present invention can synthesize a biological polymer with excellent purity and efficiency even in a variety of fluid temperature ranges, and the temperature of the fluid may be 120°C or lower, specifically, 120°C or lower, 100°C or lower, 80°C or lower, 60°C or lower, 25°C to 120°C, 50°C to 120°C, 70°C to 120°C, 100°C to 120°C, 25°C to 100°C, 50°C to 100°C, 70°C to 100°C, 25°C to 70°C, 50°C to 70°C, 25°C to 50°C, but is not limited thereto, and any temperature of the fluid used for biological polymer synthesis may be set without limitation.
  • a valve may be further included between the reactor and the mixing tank to discharge waste.
  • the method may further include a main line connecting the mixing tank, the pump, the temperature controller and the reactor, and a first branch line branched from the main line between the mixing tank and the reactor and connected to the mixing tank.
  • the fluid can have a circulating flow through the main line.
  • it may further include a solvent storage tank disposed on the first branch line.
  • the solvent storage tank can be connected to the valve and the mixing storage tank through the first branch line.
  • system may further include a sensor disposed on the main line to sense at least one of temperature, pressure, and flow rate of the fluid flowing along the main line.
  • the main line may further include a detector that detects the progress of synthesis of the biological polymer.
  • a second branch line branching from the valve and discharging the waste may be further included.
  • first, second, etc. are not used in a limiting sense but are used for the purpose of distinguishing one component from another.
  • a film, a region, a component, etc. when it is said that a film, a region, a component, etc. are connected, it includes not only the cases where the films, regions, and components are directly connected, but also the cases where other films, regions, and components are interposed between the films, regions, and components and are indirectly connected.
  • a film, a region, and a component, etc. are electrically connected, it includes not only the cases where the films, regions, and components, etc. are directly electrically connected, but also the cases where other films, regions, and components are interposed between them and are indirectly electrically connected.
  • loading density in this specification means “the number of moles of functional groups provided per unit mass of the composite solid support”, and may refer to a synthetic reaction site of a biological polymer according to the composition ratio of the polymer for biological polymer synthesis according to one embodiment.
  • the composite solid support comprises a core substrate having a length of 1 mm or more and a shape of one or more dimensions; and a functional coating surrounding the core substrate, wherein a biological polymer may be synthesized in the functional coating.
  • the functional coating may have a property of swelling in a solvent.
  • the functional coating may include a functional group on the surface and inside.
  • the functional coating includes a functional group, and due to the swelling characteristic in a solvent, it is easy for a reactant to penetrate into the functional coating due to a concentration gradient. Accordingly, the functional groups on the surface and inside of the functional coating are easily exposed to the reactant, so that high synthesis efficiency can be exhibited even at a low loading density.
  • the functional group may include at least one selected from an amine group, a carboxyl group, a hydroxyl group, a carbonyl group, an amino group, a thiol group, and a phosphoric acid group.
  • the loading density of the reaction site of the functional coating may be 0.01 mmol/g to 2 mmol/g.
  • the loading density of the reaction site of the functional coating is 0.01 mmol/g to 2 mmol/g, 0.05 mmol/g to 2 mmol/g, 0.1 mmol/g to 2 mmol/g, 0.3 mmol/g to 2 mmol/g, 0.5 mmol/g to 2 mmol/g, 0.7 mmol/g to 2 mmol/g, 1 mmol/g to 2 mmol/g, 0.01 mmol/g to 1.7 mmol/g, 0.05 mmol/g to 1.7 mmol/g, 0.1 mmol/g to 1.7 mmol/g, 0.3 mmol/g to 1.7 mmol/g, 0.5 mmol/g to 1.7 mmol/g, 0.7 mmol/g to 1.7 mmol/g, 1.0 mmol/g to
  • the functional coating may have an expansion rate per unit mass of 2 mL/g to 8 mL/g in water.
  • the functional coating may have an expansion rate per unit mass of 2 mL/g to 8 mL/g, 2 mL/g to 7 mL/g, 2 mL/g to 6 mL/g, 2 mL/g to 5 mL/g, 3 mL/g to 8 mL/g, 3 mL/g to 7 mL/g, 3 mL/g to 6 mL/g or 3 mL/g to 5 mL/g in water, but is not limited thereto.
  • the functional coating causes swelling in a solvent other than water and may have different expansion rates per unit mass depending on the type of solvent.
  • the core substrate may have solvent resistant, thermal resistant, or both properties. Unlike the functional coating, the core substrate does not have swelling properties and solvent-soluble properties, and thus can be self-standing even at high flow rates and can act as a support for a composite solid support. In addition, the core substrate has thermal resistance, and thus can act as a support without being changed even when the synthesis of a biological polymer is carried out at a high temperature.
  • the component of the core substrate may include at least one selected from a polymer, a metal, and a ceramic.
  • the polymer may include at least one selected from, but is not limited to, high-density polyethylene (HDPE), low-density polyethylene (LDPE), linear low-density polyethylene (LLDPE), ultra-high molecular weight polyethylene (UHMWPE), polypropylene (PP), polyethylene terephthalate (PET), polybutylene terephthalate (PBT), polyethylene naphthalate (PEN), polyamide (PA), polyvinyl chloride (PVC), polyvinyl difluoride (PVDF), polyacetal, polycarbonate (PC), polyimide (PI), polyether ether ketone (PEEK), polyether sulfone (PES), polyphenylene oxide (PPO), and polyphenylene sulfide (PPS).
  • HDPE high-density polyethylene
  • LDPE low-density polyethylene
  • the metal may include at least one selected from, but is not limited to, stainless steel, titanium, nickel, tantalum, zirconium, and alloys thereof.
  • the ceramic may include at least one selected from, but is not limited to, fused silica, alumina, zirconia, silicon carbide, silicon nitride, boron nitride, and titanium diboride.
  • the core substrate may have at least one shape selected from a one-dimensional shape, a two-dimensional shape, and a three-dimensional shape.
  • the one-dimensional shape may include at least one selected from a staple fiber, a filament fiber, and a rod.
  • the one-dimensional shape of the core substrate may include a fiber shape, in which case the core substrate is configured to have a length sufficient for biological polymer synthesis to occur, and the composite solid support is loaded into a reactor in an entangled form so as to be utilized in a biological polymer synthesis reaction.
  • the two-dimensional shape may include at least one selected from a spunbond non-woven fabric, a meltblown non-woven fabric, a needle-punched non-woven fabric, a hydroentangled non-woven fabric, a woven fabric, a knitted fabric, a porous membrane, a polymeric film, and a mesh.
  • the two-dimensional shape of the core substrate may include a form in which a plurality of the one-dimensionally shaped core substrates are randomly arranged.
  • the two-dimensional shape may exhibit random porosity.
  • the three-dimensional shape may include an open cell foam, a macropored sphere, or both.
  • the length of one cross-section of the core substrate may be 1 mm or more, and may have a size sufficient for the functional coating to participate in the synthesis of the intended biological polymer.
  • the core substrate when the core substrate has a one-dimensional shape, it may be implemented so that a core substrate having a shape such as a fiber or the like can act as a support for a composite solid support through entanglement.
  • the core substrate when the core substrate has a two-dimensional or three-dimensional shape, it may act as a support in itself, such as a nonwoven fabric (two-dimensional) and a foam (three-dimensional). Therefore, the length of one cross-section of the core substrate may be 1 mm or more, and theoretically, a one-dimensional core substrate having an infinite length can also serve as a support.
  • the functional coating may include a polymer of one or more main monomers and an active monomer.
  • the functional coating may include a polymer of the first monomer and the active monomer, or a polymer of the first monomer, the second monomer, and the active monomer.
  • the functional coating of the present invention may be a polymer formed through a polymerization reaction of one or more main monomers with an active monomer providing a reaction site as a main component.
  • the first monomer may include at least one selected from a bisacrylamide-based crosslinking agent, a methacryloyl group, an alkenyl group-substituted triazine, and an acrylate-based crosslinking agent, and specifically, the first monomer may include a polyethylene glycol-based agent, for example, polyethylene glycol diacrylate.
  • the first monomer may be used without limitation as long as it is a material that can react or bind with an active monomer for exposing a functional group to the interior and/or surface in a functional coating.
  • the first monomer may include at least one selected from polyethylene glycol diacrylate, N,N'-methylenebisacrylamide (MBA), ethylene glycol dimethacrylate (EGDMA), poly(ethylene glycol) dimethacrylate (PEGDMA), glycidyl methacrylate (GMA), divinyl sulfone (DVS), triethylene glycol divinyl ether (TEGDVE), and diallyl phthalate (DAP).
  • MSA polyethylene glycol diacrylate
  • MSA ethylene glycol dimethacrylate
  • PGDMA poly(ethylene glycol) dimethacrylate
  • GMA glycidyl methacrylate
  • DFS triethylene glycol divinyl ether
  • DAP diallyl phthalate
  • the second monomer may include at least one selected from 2-hydroxyethyl acrylate, It may include at least one selected from 2-hydroxyethyl methacrylate (HEMA), acrylic acid (AA), methyl methacrylate (MMA), ethyl acrylate (EA), butyl acrylate (BA), glycidyl methacrylate (GMA), and vinyl acetate (VAc).
  • HEMA 2-hydroxyethyl methacrylate
  • AA acrylic acid
  • MMA methyl methacrylate
  • EA ethyl acrylate
  • BA butyl acrylate
  • GMA glycidyl methacrylate
  • VAc vinyl acetate
  • the active monomer may include at least one selected from among acrylate-based, acrylamide-based, and methacrylamide-based materials to provide a functional group to the interior and/or surface of the functional coating.
  • the active monomers include N-(2-aminopropyl) methacrylamide hydrochloride, Aminoethyl Methacrylate Hydrochloride (AEMA.HCl), 2-Aminoethyl Methacrylate (2-AEMA), N-(3-Aminopropyl) methacrylamide Hydrochloride (APMA), 4-Aminostyrene, N-(4-Aminophenyl)methacrylamide, N,N-Dimethylaminoethyl Methacrylate (DMAEMA), N,N-Dimethylaminopropyl Acrylamide (DMAPAA). and may include at least one selected from N-(2-aminoethyl)acrylamide hydrochloride.
  • the composite solid support may include a homogeneous composite solid support, a heterogeneous composite solid support, or both.
  • the functional coating may be formed as a polymer of the one or more main monomers and the active monomer.
  • the functional coating including the pulverized conventional solid support may be in a form coated on the core substrate.
  • the above conventional solid support may include at least one selected from, but is not limited to, polystyrene/divinylbenzene copolymer (PS/DVB), crosslinked polyethyleneglycol, poly- ⁇ -lysine/sebacic acid, controlled pore glass, amino-polyacrylamide resin fiber, cellulose, and hydroxylated polypropylene.
  • PS/DVB polystyrene/divinylbenzene copolymer
  • crosslinked polyethyleneglycol poly- ⁇ -lysine/sebacic acid
  • controlled pore glass controlled pore glass
  • amino-polyacrylamide resin fiber cellulose
  • hydroxylated polypropylene hydroxylated polypropylene
  • the one-dimensional core substrate may have a diameter (cross-section) of 10 ⁇ m to 100 ⁇ m. Specifically, it may be, but is not limited to, 10 ⁇ m to 100 ⁇ m, 20 ⁇ m to 100 ⁇ m, 30 ⁇ m to 100 ⁇ m, 40 ⁇ m to 100 ⁇ m, 10 ⁇ m to 80 ⁇ m, 20 ⁇ m to 80 ⁇ m, 30 ⁇ m to 80 ⁇ m, 40 ⁇ m to 80 ⁇ m, 10 ⁇ m to 60 ⁇ m, 20 ⁇ m to 60 ⁇ m, 30 ⁇ m to 60 ⁇ m, 40 ⁇ m to 60 ⁇ m, 10 ⁇ m to 50 ⁇ m, 20 ⁇ m to 50 ⁇ m, 30 ⁇ m to 50 ⁇ m or 40 ⁇ m to 50 ⁇ m.
  • the diameter of the above one-dimensional core substrate is less than 10 ⁇ m, it may become too thin, causing the core substrate to clump together and resulting in poor mechanical properties. If it exceeds 100 ⁇ m, the loading density of the functional coating may become excessively low.
  • the two-dimensional core substrate may have a thickness (layer thickness) of 10 ⁇ m to 10 mm.
  • the two-dimensional core substrate has a thickness of 10 ⁇ m to 10 mm, 50 ⁇ m to 10 mm, 100 ⁇ m to 10 mm, 150 ⁇ m to 10 mm, 200 ⁇ m to 10 mm, 250 ⁇ m to 10 mm, 300 ⁇ m to 10 mm, 350 ⁇ m to 10 mm, 400 ⁇ m to 10 mm, 10 ⁇ m to 5 mm, 50 ⁇ m to 5 mm, 100 ⁇ m to 5 mm, 150 ⁇ m to 5 mm, 200 ⁇ m to 5 mm, 250 ⁇ m to 5 mm, 300 ⁇ m to 5 mm, 350 ⁇ m to 5 mm, 400 ⁇ m to 5 mm, 10 ⁇ m to 3 mm, 50 ⁇ m to 3 mm, 100 ⁇ m to 3 mm, 150 ⁇ m to 3 mm, 200 ⁇ m to 3 mm, 250 ⁇ m to
  • the porosity of the core substrate may be 50% to 95%.
  • core substrates having a shape such as fibers may form pores through entanglement, and when the core substrate is two-dimensional or three-dimensional, it may include pores inside, such as nonwoven fabrics or foams.
  • the porosity of the core substrate may be, but is not limited to, 50% to 95%, 60% to 95%, 70% to 95%, 80% to 95%, 90% to 95%, 50% to 90%, 60% to 90%, 70% to 90%, or 80% to 90%.
  • the pore size of the porous membrane substrate there is no particular limitation on the pore size of the porous membrane substrate, and if the porosity is less than 50%, the pores may be blocked even after the functional coating swells, preventing the synthesis of biological polymers into the interior of the functional coating. In addition, if the porosity exceeds 95%, it may be difficult to maintain mechanical properties.
  • the thickness of the functional coating may be from 0.1 ⁇ m to 1000 ⁇ m.
  • the thickness of the functional coating may be selected to an appropriate thickness depending on the type of the desired biological polymer and whether the core substrate has a one-dimensional, two-dimensional, or three-dimensional shape.
  • the thickness of the functional coating is 0.1 ⁇ m to 1000 ⁇ m, 0.5 ⁇ m to 1000 ⁇ m, 1 ⁇ m to 1000 ⁇ m, 5 ⁇ m to 1000 ⁇ m, 10 ⁇ m to 1000 ⁇ m, 50 ⁇ m to 1000 ⁇ m, 100 ⁇ m to 1000 ⁇ m, 0.1 ⁇ m to 500 ⁇ m, 0.5 ⁇ m to 500 ⁇ m, 1 ⁇ m to 500 ⁇ m, 5 ⁇ m to 500 ⁇ m, 10 ⁇ m to 500 ⁇ m, 50 ⁇ m to 500 ⁇ m, 100 ⁇ m to 500 ⁇ m, 0.1 ⁇ m to 200 ⁇ m, 0.5 ⁇ m to 200 ⁇ m, 1 ⁇ m to 200 ⁇ m, 5 ⁇ m to 200 ⁇ m, 10 ⁇ m to 200 ⁇ m, 50 ⁇ m to 200 ⁇ m, 100 ⁇ m to 200 ⁇ m, 0.1 ⁇ m to 100 ⁇ m, 0.5 ⁇ m to 100 ⁇ m, 1 ⁇ m to 200 ⁇ m
  • the thickness of the functional coating is excessively small, such as less than 0.1 ⁇ m, a problem occurs in that the loading density of the functional coating becomes very low.
  • the thickness of the functional coating is excessively large, such as exceeding 1000 ⁇ m, the functional coating itself may be manufactured through a non-uniform polymerization reaction, and a problem in that the purity decreases during the biological polymer synthesis process may occur.
  • the above composite solid support may not have a shell-core structure or a bead structure. Additionally, the solid support may not include a core in the shell-core structure.
  • the core substrate may have a surface that is hydrophilically treated.
  • the surface hydrophilic treatment may be performed by a method selected from a chemical method using a surfactant or an acidic solution and a physical method including plasma treatment or UV irradiation, but is not limited thereto.
  • the functional coating may be formed on the core substrate having a surface that is hydrophilically treated.
  • the functional coating may further include a linker.
  • the linker may include at least one selected from a Rink amide linker, a Wang linker, a 2-Chlorotrityl (CTC) linker, a Sieber linker, a BAL linker, a 4-sulfamylbutyryl linker, and a HMBA (TFA stabilized) linker.
  • a Rink amide linker a Wang linker, a 2-Chlorotrityl (CTC) linker, a Sieber linker, a BAL linker, a 4-sulfamylbutyryl linker, and a HMBA (TFA stabilized) linker.
  • the functional coating has a functional group exposed on the inside and/or surface, and the linker can be bonded to the functional group.
  • the linker can be bonded to the functional group.
  • the biological polymer may include, but is not limited to, one or more selected from a peptide, an oligonucleotide, and a peptide nucleic acid (PNA).
  • PNA peptide nucleic acid
  • FIG. 1 is a diagram illustrating a biological polymer synthesis system according to one embodiment of the present invention.
  • a biological polymer synthesis system (1) can synthesize a biological polymer by forming a circulating flow in a fluid including at least one of an amino acid, a reagent, and an additive.
  • the 'amino acid mixture' as used herein is a liquid comprising amino acid(s) as well as reagent(s), wherein the 'amino acids' may be modified or non-modified and optionally may be pre-activated, and the amino acid mixture may also comprise peptides.
  • 'SPPS' is an abbreviation for Solid Phase Peptide Synthesis, and is used to mean producing peptides by adding amino acid residues to peptides or amino acids fixed on a solid support (resin).
  • 'reagent' is used to mean coupling reagent, deprotecting reagent, additive, base, and other reagents used in the synthesis.
  • 'fluid' is defined as a substance discharged from a storage tank and moving along the piping of a biological polymer synthesis system, and may be a single substance or a mixed substance of various types depending on the process.
  • the biological polymer synthesis system (1) can be applied with a flow-through process for solid phase peptide synthesis (SPPS) that enables sequential synthesis of at least one amino acid.
  • SPPS solid phase peptide synthesis
  • the biological polymer synthesis system (1) may include a mixing tank (100), a pump (200), a temperature controller (300), and a reactor (400).
  • the biological polymer synthesis system (1) may further include a valve (500), a solvent tank (500), a sensor (SE), and a detector (DE).
  • the main line (ML) can provide a circulation pipeline by connecting a mixing tank (100), a pump (200), a temperature controller (300), and a reactor (400).
  • a valve (500) is arranged in the main line (ML), and the valve (500) can be connected to a first branch line (SL1) and a second branch line (SL2).
  • the mixing storage tank (100) can provide a space where a fluid containing at least one of an amino acid, a reagent, and an additive stays.
  • the mixing storage tank (100) has an on-off valve (not shown) arranged at the outlet end to control the type and flow rate of the fluid flowing into the main line (ML).
  • the mixing tank (100) can mix amino acids, reagents, and additives that are introduced from one or more reagent tanks (not shown) and solvent tanks.
  • the operator can precisely control the type and flow rate of the fluid discharged from the mixing tank (100) according to each synthesis step by controlling the opening amount of each chamber.
  • the corresponding fluid can be introduced into the mixing tank, mixed and suspended, and then introduced into the reactor.
  • the pump (200) provides a driving force to the fluid so that the fluid can move along the main line (ML).
  • the pump (200) can provide a driving force so that the fluid flows from the mixing storage tank (100) to the reactor (400).
  • the pump (200) is positioned between the mixing storage tank (100) and the reactor (400) in the flow of the fluid, but since the fluid forms a circulating flow, it is not necessarily required to be positioned between the mixing storage tank (100) and the reactor (400).
  • the pump (200) may be any type of device that provides suction and discharge to the fluid.
  • the pump (200) may be a gear pump, a screw pump, a vane pump, a cap pump, a piston pump, a plunger pump, a diaphragm pump, a centrifugal pump, etc.
  • the pump (200) may be any type of pump, such as a mechanical displacement micropump and an electromagnetic motion micropump.
  • a mechanical displacement micropump is a pump that uses the movement of a solid or fluid, such as a gear or diagram, to generate a pressure difference to induce a fluid flow, and includes a diaphragm displacement pump, a fluid displacement pump, a rotary pump, etc.
  • An electromagnetic motion micropump is a pump that uses electric or magnetic energy to directly move a fluid, and includes an electrohydrodynamic pump (EHD), an electroosmotic pump, a magnetohydrodynamic pump, an electrowetting pump, etc.
  • EHD electrohydrodynamic pump
  • the temperature controller (300) can set the temperature of the fluid flowing into the reactor (400) to a target temperature.
  • the temperature controller (300) is arranged downstream of the mixing storage tank (100) and upstream of the reactor (400) to cool or heat the fluid including at least one selected from amino acids, reagents, and additives.
  • the temperature controller (300) is positioned between the mixing storage tank (100) and the reactor (400) in the flow of the fluid, but since the fluid forms a circulating flow, it does not necessarily have to be positioned between the mixing storage tank (100) and the reactor (400).
  • the temperature controller (300) may be a variety of devices that transfer heat to a fluid or receive heat from a fluid through heat exchange.
  • the temperature controller (300) may be an electric heating device, an induction heater, or a microwave cavity.
  • the temperature controller (300) can maintain the temperature of the fluid flowing into the reactor (400) at room temperature.
  • the temperature controller (300) can control the temperature of the fluid to 120° C. or lower, specifically, to 25° C. to 100° C.
  • the temperature controller (300) can control the temperature of the fluid to 50° C. to 80° C.
  • Figure 2 is a drawing illustrating the reactor of Figure 1.
  • the reactor (400) can circulate and flow the fluid discharged from the mixing tank (100).
  • the reactor (400) may have a column (410) and a composite solid support (420).
  • the column (410) may have an inlet (411) through which a fluid is introduced and an outlet (412) through which a fluid is discharged.
  • the column (410) has an internal space, and a composite solid support (420) may be arranged therein.
  • the column (410) may have various sizes depending on the type of biological polymer being synthesized, the amount of biological polymer being synthesized, the flow rate of the fluid, the velocity of the fluid, the type of the composite solid support, etc.
  • the inlet (411) and outlet (412) of the column (410) are arranged on the main line (ML), so that the fluid entering the inlet (411) can pass through the internal space of the column (410) and be discharged through the outlet (412). At this time, the fluid can pass through the composite solid support (420) arranged in the internal space of the column (410).
  • a composite solid support (420) can be placed inside the column (410).
  • the solid support (420) can be filled inside the column (410).
  • the composite solid support (420) can be arranged in various positions and shapes in the internal space of the column (410).
  • the composite solid support (420) can be filled in a preset position in the internal space of the column (410).
  • a composite solid support (420) can be loaded into the internal space of the column (410).
  • the fluid can pass between the filaments (FM).
  • the flow path of the fluid can vary depending on the method of loading the composite solid support (420). For example, if a composite solid support in a spirally rolled form is loaded, the fluid can flow between each layer of the spiral composite solid support and in the porous space generated by the entanglement.
  • the composite solid support (420) may have a core substrate (BM) and a functional coating (CO).
  • the core substrate (BM) may be formed by entangling multiple filaments to form random porosity.
  • the functional coating (CO) may be a polymer for synthesizing biological polymers coated on the core substrate so that functional groups such as amine groups and carboxyl groups are exposed.
  • the core substrate (BM) may have a length of 1 mm or more and a shape of one or more dimensions.
  • the core substrate (FM) may have one or more shapes selected from a one-dimensional shape, a two-dimensional shape, and a three-dimensional shape.
  • the core substrate (BM) may have solvent resistant, thermal resistant, or both of the above properties. Unlike the functional coating (CO), the core substrate (BM) does not have swelling properties or solvent-soluble properties, and thus is capable of self-standing and can act as a support for a composite solid support. In addition, the core substrate (FM) has thermal resistance, and thus can act as a support without being changed even when the synthesis of a biological polymer is carried out at a high temperature.
  • a functional coating can surround a core substrate (FM) and provide an area where biological polymers can be synthesized.
  • the functional coating (CO) may have the property of swelling in a solvent.
  • the functional coating (CO) may include functional groups on the surface and inside.
  • the functional coating includes a functional group, and due to the swelling characteristic in a solvent, it is easy for a reactant to penetrate into the functional coating due to a concentration gradient. As a result, the functional groups on the surface and inside of the functional coating are easily exposed to the reactant, so that high synthesis efficiency can be exhibited even at a low loading density.
  • the valve (500) is arranged between the reactor (400) and the storage tank (100) to set a path for discharging waste.
  • the valve (500) can control the flow direction of the fluid so that the waste generated after the reaction of the reactor (400) is discharged to the second branch line (SL2).
  • the valve (500) can be a four-channel valve, and the four-channel valve can be connected to the mixing tank (100), the reactor (400), the solvent storage tank (600), and the second branch line (SL2).
  • the valve (500) can control the circulation of the fluid and the discharge of waste.
  • the valve (500) can set the circulation flow of the reactant fluid during each stage of SPPS synthesis to increase the synthesis rate of the biological polymer, and can discharge the remaining material of each stage to the second branch line (SL2) to enable the process to proceed to the next stage.
  • the solvent storage tank (600) can store solvents used for biological polymer synthesis and cleaning.
  • the solvent can be selected in various ways depending on the synthesis process.
  • the solvent storage tank (600) may be placed on the first branch line (SL1).
  • the solvent storage tank (600) is connected to the first branch line (SL1), so that the solvent may be moved to the valve (500) or the mixing storage tank (100) according to each stage of the SPPS synthesis.
  • the solvent discharged from the solvent storage tank (600) is discharged to the first branch line (SL1), so that the main line (ML) can be washed.
  • the sensor (SE) is arranged on the main line (ML) and can sense at least one of temperature, pressure, and flow rate of the fluid flowing along the main line (ML).
  • the detector (DE) is arranged on the main line (ML) and can detect the progress of the biological polymer synthesis.
  • the detector can be arranged at least one of the inlet and the outlet of the reactor (400) and can detect the circulating fluid.
  • the detector (DE) is arranged between the reactor (400) and the mixing reservoir (100) in the fluid flow, but since the fluid forms a circulating flow, it does not necessarily have to be arranged between the reactor (400) and the mixing reservoir (100).
  • the main line (ML) can connect a mixing tank (100), a pump (200), a temperature controller (300), and a reactor (400), and can provide a circulation path for the fluid.
  • the first branch line (SL1) branches from the main line (ML) between the mixing storage tank (100) and the reactor (400) and can be connected to the mixing storage tank (100).
  • the first branch line (SL1) connects the valve (500) and the mixing storage tank (100) to supply the solvent in the solvent storage tank (600) to the main line (ML), thereby removing the substances remaining in the main line (ML).
  • the second branch line (SL2) can be branched from the valve (500) to discharge waste.
  • Figure 3 is a graph measuring pressure drop according to flow rate to compare the reactor of the present invention with a comparative example.
  • DMF Dimethylformaminde, SAMJHUN
  • Rink-Amide-MBHA-Resin GL Biochme, 0.5mmole/g
  • a composite solid support As an example, 5.0 g (0.5 mmol, loading density: 0.1 mmol/g) of a composite solid support was placed in the column, and as a comparative example, 1.0 g (0.5 mmol, loading density: 0.5 mmol/g) of a particle-type solid support (PS/DVB) was placed in the column, and then 20 mL of DMF solvent was added and the composite solid support was swollen for 30 minutes.
  • PS/DVB particle-type solid support
  • the discharge tube of the pump was connected to the column, pressure sensors were installed at the inlet and outlet of the column, and each pressure sensor was connected to the controller.
  • DMF was flowed at a flow rate of 40 mL/min (1.48 C.V/min) through an empty column, a composite solid support column (Example), and a particle type solid support column (Comparative Example), and the pressures at the inlet and outlet were measured. Thereafter, the pressures at the inlet and outlet of the columns were measured while changing the flow rates to 50 ml/min (1.85 C.V/min), 100 ml/min (3.7 C.V/min), 200 ml/min (7.4 C.V/min), 300 ml/min (11.11 C.V/min), 400 ml/min (14.81 C.V/min), and 500 ml/min (18.52 C.V/min).
  • the pressure drop values that occurred at the inlet and outlet of the empty column were set as the reference value (Zero).
  • the additional pressure drop values that occurred were calculated by comparing them with the reference values at the inlet and outlet of the column containing the composite solid support, and the additional pressure drop values that occurred were calculated by comparing them with the reference values at the inlet and outlet of the column containing the particle-type solid support.
  • the composite solid support of the present invention exhibits a small pressure drop even when the flow rate increases. This is because the fluid can pass through the empty space of the composite solid support, so even when the flow rate increases, the pressure drop occurs small and the fluid flowability increases.
  • the conventional particle-type solid support (bead-type solid-phase synthetic resin polymer (PS/DVB)) exhibits a large pressure drop when the flow rate increases and the fluid is not discharged at 300 ml/min. This is because the conventional particle-type solid support clumps together when the flow rate increases to fill the space within the column, reducing the space through which the fluid can pass, significantly reducing the pressure measured at the outlet, and decreasing the fluid flowability.
  • Figure 4 is a graph measuring the pressure drop according to the size of the reactor of the present invention.
  • DMF Dimethylformaminde, SAMJHUN
  • Rink-Amide-MBHA-Resin GL Biochme, 0.5mmole/g
  • the discharge tube of the pump was connected to each column, a pressure sensor was installed at the inlet and outlet of each column, and each pressure sensor was connected to a controller.
  • DMF was flowed at a flow rate of 0.5 column volume (mL)/min through columns A, B, and C, respectively, and the pressures at the inlet and outlet were measured. After that, the flow rates were changed to 1 C.V/min, 2 C.V/min, 3 C.V/min, 4 C.V/min, and 5 C.V/min, and the pressures at the inlet and outlet of the columns were measured.
  • the pressure drop values that occurred at the inlet and outlet of each empty column were set as the reference value (Zero).
  • the additional pressure drop values that occurred at the inlet and outlet of columns A, B, and C containing composite solid supports were calculated by comparing them with the reference values.
  • the composite solid support of the present invention exhibits a small pressure drop in the fluid at various flow rates even when the volume of the column is varied. This is because the fluid can pass through the empty space of the composite solid support, so that the pressure drop is small and the fluidity of the fluid increases even when the flow rate increases. Accordingly, the composite solid support of the present invention exhibits a consistently small degree of pressure drop regardless of the volume of the column.
  • Figures 5 and 6 are graphs measuring the pressure drop according to temperature in the reactor of the present invention and a comparative example.
  • the RPM values of the pump were recorded when the flow rates were 50, 100, 150, 200, 250, 300, 350, and 400 ml/min using DMF solvent at 50°C.
  • the viscosity of the solution decreased, which reduced the back pressure.
  • the pump stopped operating at 350 ml/min due to the high back pressure.
  • the RPM values of the pump were recorded when the flow rates were 50, 100, 150, 200, 250, 300, 350, and 400 ml/min using DMF solvent at 70°C.
  • the viscosity of the solution decreased, which reduced the back pressure.
  • the pump stopped operating at 350 ml/min due to the high back pressure.
  • the rotation speed of the pump was measured at room temperature using Piperidine 20% in DMF (0.1 M Oxymapure), which is widely used in solid-phase peptide synthesis reactions.
  • the particle-type solid support stopped operating due to high back pressure at 250 ml/min. That is, it was confirmed that the composite solid support of the present invention was subjected to less back pressure than the conventional particle-type solid support.
  • the composite solid support of the present invention can enhance the synthetic performance of a flow reactor by increasing the fluid flowability, unlike the conventional particle-type solid support.
  • a flow reactor according to one embodiment of the present invention and a biological polymer synthesis system including the same can increase the efficiency of a synthesis reaction.
  • a flow reactor and a biological polymer synthesis system including the same have increased flowability of the reactor by a composite solid support. Accordingly, the reactor has a low pressure drop and thus achieves a low back pressure, so that an increase in the synthesis scale is possible.
  • the rate of decrease (loss) in the flow rate is small, so mixing and diffusion between the reactants and the reaction solution within the column are promoted.
  • the biological polymer synthesis system has improved flow dynamics as the flow rate increases, and the reaction efficiency and yield are improved.
  • reducing back pressure reduces the risk of damage to pipes and connections through which the fluid flows, thereby reducing fluid leakage and improving the durability of the system and the stability and reliability of the process.
  • the fluid passing through the reactor can be precisely controlled when the back pressure is reduced, the reproducibility of the reaction process is improved, and consistent quality and high-quality biological polymers can be synthesized.
  • the functional coating solution (before curing) of (1) of the above Example 4 and 20 g of a core substrate (polypropylene, spunbond nonwoven fabric, 40 g/m 2 ) were prepared.
  • the core substrate was sufficiently impregnated in the functional coating solution, and after the core substrate was taken out of the functional coating solution, it was sufficiently irradiated with ultraviolet energy of 10 mJ/cm 2 to 1,000 mJ/cm 2 in an ultraviolet curing chamber.
  • the coated core substrate was subjected to a process of removing reaction residues using ethanol and drying.
  • a composite solid support in which a functional coating polymer was coated on a core substrate was obtained (solid support 30.4 g, 60.8 g/m 2 ).
  • the appearance of the core substrate before coating is as shown in Fig. 7, and the appearance of the composite solid support is as shown in Fig. 8.
  • Reaction stage reagent (Solvent: DMF) Volume (mL) Temperature (°C) Time (minutes) Deprotection 20% piperidine,0.1M Oxyma pure 15 70 2 purifying DMF 10 (3 times) - - Coupling Fmoc-Ile(0.2M) 6 70 4 DIC (0.5M) 2 Oxyma pure(1.0M) 1 purifying DMF 10 (2 times) - -
  • the particle-type solid support and the composite solid support were each sufficiently washed with ethanol and dried, and a cleavage reaction was performed for 2 hours using a stripping solution (95% TFA, 2.5% TSI, 2.5% DW). After that, the solid was precipitated using cold ether and centrifuged to obtain a solid, which was washed twice more using 15 ml of cold ether, and then sufficiently dried using reduced pressure drying. The purity and yield of the dried peptide were measured using high-performance liquid chromatography (HPLC). The results of measuring the purity and yield of the dried peptide are shown in Table 8.
  • Reaction stage reagent (Solvent: DMF) Volume (mL) temperature (°C) hour (minute) flux (mL/min) Deprotection 20% piperidine, 0.1M Oxyma pure 25 70 2 100 purifying DMF 125 - - Coupling Fmoc-Amino acid(0.2M) 15 70 4 DIC (0.5M) 6 Oxyma pure(1.0M) 3 purifying DMF 20 - -
  • the composite solid support is suitable for both batch and flow-type synthesis systems compared to the existing particulate solid support, and in particular, when applied to a flow-type synthesis system, the yield and purity of the ACP peptide were over 90%, showing significantly superior efficacy in the synthesis of biological polymers.
  • Example 6 Analysis and evaluation of changes in yield and purity of synthesized peptides according to the flow rate of biological polymers in a flow reactor
  • Example 5 the yield and purity of the synthesized peptide according to the flow rate were confirmed using a composite solid support.
  • ACP was synthesized using the same method as in Example 5, and the results of the purity and yield of the synthesized ACP peptide are shown in Table 10 and Figures 9 to 11 below.
  • Figures 9 to 11 are composite solids for synthesizing biological polymers according to one specific example.

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Abstract

La présente invention concerne un réacteur à écoulement et un système de synthèse de polymère biologique le comprenant, le système comprenant : un réservoir de mélange dans lequel au moins l'un parmi un acide aminé, un réactif et un additif est mélangé ; un réacteur dans lequel s'écoule un fluide évacué du réservoir de mélange ; un régulateur de température disposé entre le réservoir de mélange et le réacteur de façon à réguler la température du fluide s'écoulant dans le réacteur ; et une pompe servant à produire une force d'entraînement de telle sorte que le fluide s'écoule du réservoir de mélange vers le réacteur, le réacteur comprenant : une colonne ayant une entrée à travers laquelle le fluide s'écoule et une sortie à travers laquelle le fluide est évacué ; et un support solide composite disposé dans la colonne.
PCT/KR2024/014797 2023-09-27 2024-09-27 Réacteur à écoulement et système de synthèse de polymère biologique le comprenant Pending WO2025071365A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4362699A (en) * 1981-03-10 1982-12-07 Bio Research, Inc. Apparatus for high pressure peptide synthesis
KR20090046857A (ko) * 2006-07-25 2009-05-11 크로마티드 엘티디 고체 지지체
WO2014149387A2 (fr) * 2013-03-15 2014-09-25 Massachusetts Institute Of Technology Méthodes de synthèse de peptide en phase solide et systèmes associés
KR20220154222A (ko) * 2020-03-17 2022-11-21 펩티시스템스 에이비 펩타이드 합성 및 이의 시스템

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4362699A (en) * 1981-03-10 1982-12-07 Bio Research, Inc. Apparatus for high pressure peptide synthesis
KR20090046857A (ko) * 2006-07-25 2009-05-11 크로마티드 엘티디 고체 지지체
WO2014149387A2 (fr) * 2013-03-15 2014-09-25 Massachusetts Institute Of Technology Méthodes de synthèse de peptide en phase solide et systèmes associés
KR20220154222A (ko) * 2020-03-17 2022-11-21 펩티시스템스 에이비 펩타이드 합성 및 이의 시스템

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHO, J. K. ET AL.: "A novel core-shell type polymer support for solid-phase peptide synthesis", TETRAHEDRON LETTERS, vol. 41, 2000, pages 7481 - 7485, XP004217334, DOI: 10.1016/S0040-4039(00)01279-X *

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