Powder-dissolving apparatus and powder-dissolving method

Abstract

This powder-dissolving apparatus comprises: a powder supply mechanism that supplies powder; a liquid supply mechanism that continuously supplies liquid; a mixing mechanism that mixes the powder supplied from the powder supply mechanism and the liquid supplied from the liquid supply mechanism to generate a mixed liquid; and a dissolution promoting mechanism that supplies a pH adjuster to the mixed liquid discharged from the mixing mechanism to promote dissolution of the powder in the mixed liquid and thereby generate a solution. Also provided is a powder dissolving method.

Description

Powder dissolving apparatus and powder dissolving method

[0001] This disclosure relates to a powder dissolving apparatus and a powder dissolving method.

[0002] Powders are used in solution form, dissolved in a solvent, depending on their application. Traditionally, the dissolution of powders into solvents has often been carried out in batches due to the ease of manufacturing control. However, from the perspective of mass production, reduced production time, and ensuring product homogeneity, continuous dissolution of powders into solvents is desirable.

[0003] For example, Patent Document 1 discloses a system and method for continuously dissolving solid materials.

[0004] Patent Document 1: U.S. Patent Application Publication No. 2022 / 0380718

[0005] However, certain substances may not dissolve completely simply by mixing them with a solvent. Undissolved substances in a solution can be a quality issue. One reason for this problem is that certain substances only dissolve within a specific pH range. Furthermore, while Patent Document 1 discloses a method for continuously dissolving solid materials, it does not consider adjusting the pH as well.

[0006] This disclosure has been made in view of the foregoing, and one embodiment of this disclosure relates to a powder dissolving apparatus and a powder dissolving method that can adjust the pH and continuously produce a dissolved solution.

[0007] This disclosure includes the following embodiments: <1> A powder dissolving apparatus comprising: a powder supply mechanism for supplying powder; a liquid supply mechanism for continuously supplying liquid; a mixing mechanism for mixing the powder supplied from the powder supply mechanism and the liquid supplied from the liquid supply mechanism to produce a mixed liquid; and a dissolution promoting mechanism for supplying a pH adjusting agent to the mixed liquid discharged from the mixing mechanism to promote the dissolution of the powder in the mixed liquid and produce a dissolved solution. <2> The powder dissolving apparatus according to <1>, wherein the amount of the pH adjusting agent supplied is predetermined so that the pH of the mixed liquid and the dissolved solution reaches a desired value. <3> The powder dissolving apparatus according to <1> or <2>, wherein in the dissolution promoting mechanism, the mixed liquid undergoes one or more pH fluctuations of ±1.0 or more at 25°C. <4> The powder dissolving apparatus according to any one of <1> to <3>, which produces the dissolved solution exhibiting a pH within ±0.2 of a desired pH at 25°C. <5> The powder dissolving apparatus according to any one of <1> to <4>, wherein the pH adjusting agent is at least one selected from the group consisting of buffers, bases, and acids. <6> The powder dissolving apparatus according to <5>, wherein the dissolution promoting mechanism starts a continuous supply of at least one of the acid and base after the start of a continuous supply of the buffer. <7> The powder dissolving apparatus according to any one of <1> to <6>, wherein the powder comprises at least one selected from the group consisting of cystine, tyrosine, arginine, and lysine. <8> The powder dissolving apparatus according to any one of <1> to <7>, wherein the powder is a powder culture medium for cell culture. <9> The powder dissolving apparatus according to any one of <1> to <8>, wherein the liquid is water. <10> A method for dissolving powder using the powder dissolving apparatus according to any one of <1> to <9>.

[0008] According to one embodiment of the present disclosure, a powder dissolving apparatus and a powder dissolving method are provided that can adjust the pH and continuously produce a dissolved solution.

[0009] Figure 1 is a schematic diagram showing one embodiment of the powder dissolving apparatus of the present disclosure. Figure 2 is a block diagram showing the configuration of the control unit. Figure 3 is a schematic diagram showing the powder dissolving apparatus used in Example 1.

[0010] One embodiment of this disclosure is described in detail below. However, this disclosure is not limited to the embodiment described below. In the following disclosure, the components (including elemental steps, etc.) are not essential unless otherwise explicitly stated. The same applies to numerical values ​​and their ranges, and they do not limit this disclosure.

[0011] In this disclosure, numerical ranges indicated using "~" include the numbers before and after "~" as the lower and upper limits, respectively. In numerical ranges described in stages in this disclosure, the upper or lower limit stated in one numerical range may be replaced with the upper or lower limit of another numerical range described in stages. Also, in numerical ranges described in this disclosure, the upper or lower limit of that numerical range may be replaced with the values ​​shown in the examples. In this disclosure, the content of each component in a composition means the total content of the multiple substances present in the composition, unless otherwise specified, if multiple substances corresponding to each component exist in the composition. In this disclosure, where multiple elements are listed using "or" or "or," the selection of multiple elements in combination is not excluded unless otherwise explicitly stated, as long as it does not result in a technical inconsistency. Even when an element is expressed in the singular form in this disclosure, the existence of multiple elements is not excluded unless otherwise explicitly stated, as long as it does not result in a technical inconsistency. In this disclosure, multiple exemplary embodiments described separately may be combined to form new embodiments, as long as they do not contradict each other. When embodiments are described in this disclosure with reference to the drawings, the configuration of the embodiments is not limited to the configuration shown in the drawings. Furthermore, the sizes of the components in each figure are conceptual, and the relative relationships between the sizes of the components are not limited thereto. In this disclosure, pH is measured at 25°C using a pH meter with a glass electrode.

[0012] ≪Powder Dissolving Apparatus≫ The powder dissolving apparatus of this disclosure comprises: a powder supply mechanism for supplying powder; a liquid supply mechanism for continuously supplying liquid; a mixing mechanism for mixing the powder supplied from the powder supply mechanism and the liquid supplied from the liquid supply mechanism to produce a mixed liquid; and a dissolution promoting mechanism for supplying a pH adjusting agent to the mixed liquid discharged from the mixing mechanism to promote the dissolution of the powder in the mixed liquid and produce a dissolved solution.

[0013] The powder dissolving apparatus of this disclosure allows for pH adjustment and continuous production of the dissolved solution. Hereinafter, an embodiment of the powder dissolving apparatus of this disclosure will be described with reference to Figure 1. Note that Figure 1 is an illustrative diagram and does not limit the embodiments of this disclosure. As shown in Figure 1, the powder dissolving apparatus 1 comprises a powder supply mechanism 2, a liquid supply mechanism 3, a mixing mechanism 4, and a dissolution acceleration mechanism 5. The powder supply mechanism 2 supplies powder 21 to the mixing mechanism 4. The liquid supply mechanism 3 continuously supplies liquid 31 to the mixing mechanism 4. Next, the mixing mechanism 4 mixes the powder 21 supplied from the powder supply mechanism 2 and the liquid 31 supplied from the liquid supply mechanism 3 to produce a mixed solution 41. Then, the dissolution acceleration mechanism 5 supplies a pH adjusting agent 51 to the mixed solution 41 discharged from the mixing mechanism 4, thereby promoting the dissolution of the powder 21 in the mixed solution 41 and producing a dissolved solution 61.

[0014] As described above, the powder dissolving apparatus of this disclosure can continuously generate a dissolving solution while adjusting the pH in-line, thus achieving high productivity.

[0015] The powder dissolving apparatus of this disclosure can continuously produce a dissolving solution for, for example, 1 minute to 12 months. The powder dissolving apparatus of this disclosure may continuously produce a dissolving solution for 10 minutes or more, 1 hour or more, 12 hours or more, 24 hours or more, 1 week or more, or 1 month or more, or it may continuously produce a dissolving solution for 6 months or less or 3 months or less.

[0016] The materials used for each component in each mechanism of the powder dissolving apparatus of this disclosure may be metal, alloys such as stainless steel, plastic, glass, ceramic, polytetrafluoroethylene (PTFE), polyvinylidene fluoride (PVDF), polypropylene (PP), polyethylene (PE), silicone, ethylene vinyl acetate copolymer (EVA), or other disposable materials. Disposable materials are preferred from the viewpoint of eliminating the need for sterilization, cleaning, and maintenance steps.

[0017] <Powder Supply Mechanism> A powder dissolving apparatus 1, which is one embodiment of the present disclosure, includes a powder supply mechanism 2 for supplying powder 21. The powder supply mechanism 2 may supply the powder 21 continuously or discontinuously (for example, intermittently), and from the viewpoint of continuous production, continuous supply is preferable. The powder supply mechanism 2 is preferably connected to a mixing mechanism 4, which will be described later.

[0018] The powder supply mechanism 2 may consist of a cartridge 22 containing powder 21 and a feeder 24 that discharges the powder 21 from a powder discharge port 23. The cartridge 22 is connected to the feeder 24, and the powder 21 is introduced into the feeder 24 aseptically from the cartridge 22 without being exposed to the outside air. An agitator may be introduced inside the cartridge 22 to break up rat holes that occur due to prolonged use. The cartridge 22 and the feeder 24 may have a sliding surface on their inner walls to improve the discharge of the powder 21. The feeder 24 is connected to the cartridge 22, and the powder discharge port 23 of the feeder 24 is connected to a mixing mechanism 4 (more specifically, a mixing tank 42), which will be described later. The feeder 24 is driven and controlled by the control unit 7, and supplies powder 21 to the mixing mechanism 4 by discharging a predetermined amount of powder, for example, continuously from the powder discharge port 23.

[0019] The powder supply mechanism 2 may consist of a hopper (not shown) for storing powder 21 and a feeder 24 for discharging the powder from the hopper through a powder discharge port 23. The hopper is connected to the feeder 24, and a bag containing the powder 21 is set in the upper opening of the hopper. The powder 21 is introduced into the feeder 24 aseptically from the hopper without being exposed to the outside air. An agitator may be introduced into the hopper to break up rat holes that occur due to prolonged use. The inner walls of the hopper and feeder 24 may be treated with a sliding surface to improve the discharge of the powder 21. The powder discharge port 23 may have a valve that can control the flow of powder 21. The valve may be a solenoid valve or a pinch valve.

[0020] Examples of feeders 24 include dispensers, screw conveyors, extruders, apron conveyors, pneumatic conveyors, roller conveyors, belt conveyors, pelletizers, compounders, weight feeders, acoustic and ultrasonic vibration conveyors, rotary conveyors, electromagnetic conveyors, and vertical conveyors. The feeder can move the powder 21 by any combination of mechanisms selected from gravity, acoustic vibration, ultrasonic vibration, pulsed inertial force, acoustic radiation force, electromagnetic force, vacuum force, weights, aprons, belts, rollers, rotation, and vertical movement.

[0021] The powder 21 may be supplied in a predetermined amount. The amount of powder 21 to be supplied is predetermined based on the type of powder 21 to be supplied, the type of liquid 31, and the amount of dissolving solution 61 produced, etc.

[0022] The supply rate of powder 21 is, for example, 0.10 g / min to 100.00 g / min. The supply rate of powder may be 0.50 g / min or more, 1.00 g / min or more, or 2.00 g / min or more, and may be 50.00 g / min or less, 10.00 g / min or less, or 5.00 g / min or less. The supply rate of powder 21 is adjusted by the feeder 24.

[0023] (Powder) The type of powder 21 supplied by the powder supply mechanism 2 is not particularly limited. The powder 21 may contain at least one selected from the group consisting of amino acids, carbon sources, vitamins, fatty acids, lipids, salts, trace metals, polymers, proteins, peptides, nucleic acid components, organic acids, natural extracts, growth factors, buffers, and other additives.

[0024] Examples of amino acids include alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, and cystine. The solubility of amino acids is pH-dependent. From the viewpoint that even amino acids that are difficult to dissolve in neutral water can be dissolved using the powder dissolving apparatus of this disclosure, it is preferable that the amino acids include at least one selected from the group consisting of cystine, tyrosine, arginine, and lysine.

[0025] Examples of carbon sources include monosaccharides such as glucose, galactose, ribose, and fructose; disaccharides such as sucrose, lactose, and maltose; sugar derivatives such as sugar alcohols; polysaccharides such as oligosaccharides; and starch. Examples of vitamins include vitamin A (retinol, retinal, retinoids, and carotenoids), vitamin B1 (thiamine), vitamin B2 (riboflavin), vitamin B3 (niacin and niacinamide), vitamin B5 (pantothenic acid), vitamin B6 (pyridoxine, pyridoxamine, and pyridoxal), vitamin B7 (biotin), vitamin B9 (folic acid and folinic acid), vitamin B12 (cyanocobalamin, hydroxycobalamin, and methylcobalamin), vitamin C (ascorbic acid), vitamin D (ergocalciferol and cholecalciferol), vitamin E (tocopherol and tocotrienol), vitamin K (phylloquinone and menaquinone), as well as vitamin precursors and analogs. Examples of fatty acids and lipids include triglycerides, cholesterol, steroids, sphingomyelin, and phosphatidylcholine (lecithin). Examples of salts include sodium salts, potassium salts, magnesium salts, calcium salts, bicarbonates, and phosphates, such as sodium chloride (NaCl), calcium chloride (CaCl ２ ·2H ２ O), potassium chloride (KCl), monosodium hydrogen phosphate (anhydrous) (NaH ２ PO ４ ), and disodium hydrogen phosphate (anhydrous) (Na ２ HPO ４ ). Examples of trace metals include zinc, copper, cobalt, iron, manganese, nickel, molybdenum, silicon, and selenium, such as copper(II) sulfate pentahydrate, iron(II) sulfate, magnesium sulfate (anhydrous) (MgSO ４ ), magnesium chloride hexahydrate (MgCl ２ ·6H ２ O), and zinc sulfate heptahydrate (ZnSO ４ ·7H ２O) is the polymer. Examples of polymers include polyethylene glycol (PEG), polypropylene glycol, and carboxymethylcellulose. Examples of proteins and peptides include albumin, transferrin, fibronectin, and fetuin. Examples of nucleic acid components include nucleic acid bases such as cytosine, guanine, adenine, thymine, uracil, xanthine, and hypoxanthine; nucleosides such as cytidine, uridine, adenosine, xanthosine, inosine, guanosine, and thymidine; nucleotides having monophosphate, diphosphate, or triphosphate; and nucleic acids such as RNA and DNA. Examples of organic acids include ascorbic acid, tranexamic acid, citric acid, salicylic acid, lactic acid, tartaric acid, malic acid, succinic acid, oxalic acid, gluconic acid, fumaric acid, aspartic acid, pyrrolidone carboxylic acid, ε-aminocaproic acid, glutamic acid, and aminoethylsulfonic acid. Examples of natural extracts include coconut milk, yeast extract, and peptone. Growth factors include fibroblast growth factor (FGF), epidermal growth factor (EGF), hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), bone morphogenetic factor (BMP), transforming growth factor (TGF), and insulin-like growth factor (IGF-1). Buffering agents include borate buffers, phosphate buffers, Tris buffers, citrate buffers, tartaric acid buffers, acetate buffers, amino acid buffers, and sulfonic acid buffers. Other additives include pH indicators (e.g., phenol red), surfactants, chelating agents (e.g., EDTA), antioxidants, detergents, emulsifiers (e.g., polysorbate), neutralizing agents, micelle-forming agents, and micelle inhibitors.

[0026] The powder 21 may be in the form of powder, granules, pellets, or crystals. The powder is an aggregate of multiple fine solid particles. The particle size of the powder 21 may be between 1 μm and 10,000 μm. The powder 21 may also be a molded product formed by crushing and granulation or the like to achieve the particle size of the powder. In this disclosure, the particle size is measured as the volume-average particle size (D50) using a laser diffraction scattering particle size distribution analyzer.

[0027] From the viewpoint that the solution 61 obtained by dissolving the powder 21 can be used for cell culture, the powder 21 is preferably a powder medium for cell culture, and more preferably a powder medium for culturing cells that produce antibody drugs. In cell culture, during culture, the old medium consumed by cell growth is removed and new medium is supplied to the cells. Therefore, the powder dissolution apparatus of this disclosure can dissolve a powder medium for cell culture to continuously produce a liquid medium for cell culture, and the obtained new liquid medium can be continuously supplied to the cells.

[0028] Powdered culture media for cell culture are powdered media containing nutrients for maintaining cell survival, growth, and proliferation. Powdered culture media for cell culture may contain at least one selected from the group consisting of, for example, amino acids, carbon sources, vitamins, fatty acids, lipids, salts, trace metals, polymers, proteins, peptides, nucleic acid components, organic acids, natural extracts, growth factors, buffers, and other additives.

[0029] <Liquid Supply Mechanism> One embodiment of the powder dissolving apparatus 1 of the present disclosure includes a liquid supply mechanism 3 for continuously supplying liquid 31. The liquid supply mechanism 3 is preferably connected to a mixing mechanism 4, which will be described later.

[0030] The liquid supply mechanism 3 may consist of a liquid supply passage 32 and a first pump 33 provided in the liquid supply passage 32. The liquid supply passage 32 is connected to the mixing tank 42, and the first pump 33 drives the liquid 31 through it to supply the liquid 31 to the mixing mechanism 4 (more specifically, the mixing tank 42). The first pump 33 is driven and controlled by the control unit 7, and supplies the liquid 31 to the mixing mechanism 4 at a predetermined flow rate.

[0031] The liquid supply passage 32 may have a valve that can control the flow of the liquid 31. The valve may be a solenoid valve or a pinch valve.

[0032] The first pump 33 can be a peristaltic pump, piston pump, vacuum pump, screw pump, gear pump, or eccentric screw pump. The pump may be provided with a pump head.

[0033] Liquid 31 may be supplied in a predetermined amount. The amount of liquid 31 supplied is predetermined based on the type of powder 21 to be supplied, the type of liquid 31, and the amount of dissolving solution 61 produced.

[0034] The supply rate of liquid 31 is, for example, 0.1 ml / min to 1000 ml / min. The supply rate of liquid 31 may be 1 ml / min or more, 10 ml / min or more, or 50 ml / min or more, and may be 500 ml / min or less, 200 ml / min or less, or 100 ml / min or less. The supply rate of liquid 31 is adjusted by the first pump.

[0035] (Liquid) The type of liquid 31 supplied by the liquid supply mechanism 3 is not particularly limited. Liquid 31 may be water, a buffer solution, or physiological saline, and water is preferred from the viewpoint of ease of handling during manufacturing. Examples of buffer solutions include borate buffer, phosphate buffer, Tris buffer, citrate buffer, tartaric acid buffer, acetate buffer, amino acid buffer, and sulfonic acid buffer. The pH of liquid 31 is not particularly limited and may be, for example, pH 2.0 to pH 13.0 at 25°C. The pH of liquid 31 may be pH 3.0 or higher, pH 4.0 or higher, pH 5.0 or higher, pH 6.0 or higher, pH 6.5 or higher, or pH 6.8 or higher, and may be pH 12.0 or lower, pH 11.0 or lower, pH 10.0 or lower, pH 9.0 or lower, pH 8.0 or lower, pH 7.5 or lower, or pH 7.3 or lower.

[0036] <Mixing Mechanism> A powder dissolving apparatus 1, which is one embodiment of the present disclosure, includes a mixing mechanism 4 that mixes powder 21 supplied from the powder supply mechanism 2 and liquid 31 supplied from the liquid supply mechanism 3 to produce a mixed liquid 41. The mixing mechanism 4 preferably continuously produces the mixed liquid 41 by mixing the powder 21 supplied from the powder supply mechanism 2 and liquid 31 supplied from the liquid supply mechanism 3. The mixing mechanism 4 is preferably connected to the aforementioned powder supply mechanism 2 and liquid supply mechanism 3, and further preferably connected to a dissolution acceleration mechanism 5, which will be described later.

[0037] The mixing mechanism 4 may be composed of a mixing tank 42 that mixes the powder 21 and the liquid 31, a stirrer 43 for stirring the powder 21 and the liquid 31, a mixed liquid discharge passage 44 that discharges the generated mixed liquid 41, and a second pump 45 provided in the mixed liquid discharge passage 44. The mixing tank 42 is connected to the powder discharge port 23 of the liquid supply passage 32 and the feeder 24, and mixes the powder 21 and the liquid 31 in the tank. The stirrer 43 is provided in the mixing tank 42 and mixes the powder 21 and the liquid 31. The mixed liquid discharge passage 44 is connected to the mixing tank 42, circulates the mixed liquid 41 by driving the second pump 45, and supplies the mixed liquid 41 to the dissolution promotion mechanism 5. The second pump 45 is driven and controlled by the control unit 7, and supplies the mixed liquid 41 to the dissolution promotion mechanism 5 at a predetermined flow rate.

[0038] The mixing tank 42 has, for example, a wide-diameter cylindrical shape with an open upper part, and the upper part of the mixing tank 42 may be sealed with a lid. It is preferable that the powder discharge port 23 of the powder supply mechanism 2, the liquid supply passage 32 of the liquid supply mechanism 3, and the mixed liquid discharge passage 44 are aseptically connected to the mixing tank 42. The mixing tank 42 may further be connected with one or more inlets for introducing additives (for example, pH adjusters or antifoaming agents).

[0039] The volume of the mixing tank 42 is, for example, 0.1 L to 10000 L. The volume of the mixing tank 42 may be 0.1 L or more, 1 L or more, 10 L or more, 50 L or more, 100 L or more, 500 L or more, or 1000 L or more, and may also be 5000 L or less or 2000 L or less.

[0040] The stirrer 43 may stir at a predetermined stirring speed. The stirring speed of the stirrer 43 is determined in advance based on the type of the powder 21 to be supplied, the type of the liquid 31, and the production amount of the dissolved solution 61.

[0041] The stirring speed of the stirrer 43 is, for example, 1 rpm to 10000 rpm. The stirring speed of the stirrer 43 may be 10 rpm or more, 50 rpm or more, or 100 rpm or more, and may also be 1000 rpm or less, 500 rpm or less, or 300 rpm or less. In the present disclosure, rpm represents revolutions per minute. The stirring speed of the stirrer 43 is adjusted by the control unit 7.

[0042] The mixed liquid discharge path 44 may have a valve that can control the flow of the mixed liquid 41. The valve may be a solenoid valve or a pinch valve.

[0043] Examples of the second pump 45 include a peristaltic pump, a piston pump, a vacuum pump, a screw pump, a gear pump, and an eccentric screw pump. The pump may be provided with a pump head.

[0044] The mixed liquid 41 may be discharged at a predetermined discharge amount. The discharge amount of the mixed liquid 41 is predetermined based on factors such as the type of powder to be supplied, the type of liquid, and the production amount of the dissolved solution.

[0045] The discharge amount of the mixed liquid 41 is, for example, 0.1 ml / min to 1000 ml / min. The supply amount of the mixed liquid 41 may be 1 ml / min or more, 10 ml / min or more, or 50 ml / min or more, and may also be 500 ml / min or less, 200 ml / min or less, or 100 ml / min or less. The discharge amount of the mixed liquid 41 is adjusted by the second pump 45.

[0046] (Mixed Liquid) The mixed liquid 41 may not have the powder 21 completely dissolved, and there may be undissolved residue of the powder 21. Even when there is undissolved residue of the powder 21, the powder 21 is dissolved by the dissolution promotion mechanism 5 described later.

[0047] The pH of the mixed liquid 41 is not particularly limited, and may be, for example, pH 2.0 to pH 13.0 at 25°C. The pH of the mixed liquid may be pH 3.0 or more, pH 4.0 or more, pH 5.0 or more, pH 6.0 or more, pH 6.5 or more, or pH 6.8 or more, and may also be pH 12.0 or less, pH 11.0 or less, pH 10.0 or less, pH 9.0 or less, pH 8.0 or less, pH 7.5 or less, or pH 7.3 or less.

[0048] <Dissolution Acceleration Mechanism> A powder dissolution apparatus 1, which is one embodiment of the present disclosure, includes a dissolution acceleration mechanism 5 that promotes the dissolution of the powder 21 in the mixed liquid 41 by supplying a pH adjusting agent 51 to the mixed liquid 41 discharged from the mixing mechanism 4, thereby generating a dissolved solution 61. The dissolution acceleration mechanism 5 does not supply the pH adjusting agent 51 to the mixing mechanism 4, but rather supplies the pH adjusting agent 51 to the mixed liquid 41 discharged from the mixing mechanism 4. This is preferable to continuously generate the dissolved solution 61 by promoting the dissolution of the powder 21 in the mixed liquid 41, and more preferable to continuously generate the dissolved solution 61 by continuously supplying the pH adjusting agent 51 to the mixed liquid 41 discharged from the mixing mechanism 4. The dissolution acceleration mechanism 5 is preferably connected to the mixing mechanism 4 and further preferably to a culture tank or storage tank 6, which will be described later.

[0049] The dissolution promotion mechanism 5 may consist of a mixed liquid discharge channel 44 and a pH adjusting agent supply channel 52 connected to the mixed liquid discharge channel 44. The mixed liquid 41 discharged from the mixing mechanism 4 (specifically, the mixing tank 42) flows through the mixed liquid discharge channel 44. The pH adjusting agent supply channel 52 may be provided with a pH adjusting agent supply pump 53, and the pH adjusting agent supply channel 52 supplies the pH adjusting agent 51 to the mixed liquid discharge channel 44. At the connection between the mixed liquid discharge channel 44 and the pH adjusting agent supply channel 52, an inline mixer (not shown; for example, a micro mixer, static mixer, or T-mixer) or a sub-tank may be provided to promote the mixing of the mixed liquid 41 and the pH adjusting agent 51 and the dissolution of the powder 21 in the mixed liquid 41. The inline mixer promotes the mixing of the mixed liquid 41 and the pH adjusting agent 51 and the dissolution of the powder 21 in the mixed liquid 41 by stirring the mixed liquid 41 and the pH adjusting agent 51. The sub-tank stores the mixed liquid 41 and the pH adjusting agent 51, thereby promoting the mixing of the mixed liquid 41 and the pH adjusting agent 51, and the dissolution of the powder 21 in the mixed liquid 41. The volume of the sub-tank is preferably smaller than the volume of the mixing tank 42, for example, 0.01 L to 100 L. The volume of the sub-tank may be 0.01 L or more, 0.1 L or more, 1 L or more, or 10 L or more, and may be 50 L or less, or 20 L or less.

[0050] From the viewpoint of adjusting the pH to an arbitrary value, the pH adjusting agent 51 is preferably at least one selected from the group consisting of a buffer 51A, a base 51B, and an acid 51C. The dissolution promoting mechanism 5 may consist of a mixed liquid discharge channel 44, a buffer supply channel 52A connected to the mixed liquid discharge channel 44, and a base supply channel 52B connected to the mixed liquid discharge channel, or it may consist of a mixed liquid discharge channel 44, a buffer supply channel 52A connected to the mixed liquid discharge channel 44, a base supply channel 52B connected to the mixed liquid discharge channel, and an acid supply channel 52C connected to the mixed liquid discharge channel. A third pump 53A is provided in the buffer supply channel 52A, and it is preferable that the buffer 51A is circulated by driving the third pump 53A and supplied to the mixed liquid discharge channel 44. A fourth pump 53B is provided in the base supply channel 52B, and it is preferable that the base 51B is circulated by driving the fourth pump 53B and supplied to the mixed liquid discharge channel 44. Preferably, a fifth pump 53C is provided in the acid supply passage 52C, and the acid 51C is circulated by driving the fifth pump 53C and supplied to the mixed liquid discharge passage 44. The pump may be provided with a pump head.

[0051] In the mixed liquid discharge channel 44, it is preferable that the buffer supply channel 52A is connected upstream of the base supply channel 52B and the acid supply channel 52C. That is, it is preferable that the dissolution promotion mechanism 5 starts supplying at least one of the base 51B and the acid 51C after starting to supply the buffer 51A. By supplying the buffer 51A before supplying the base 51B or the acid 51C to the mixed liquid 41, a rapid change in the pH of the mixed liquid 41 can be suppressed, and changes in the components in the mixed liquid 41 can be suppressed. From the viewpoint of continuous production, it is preferable that the dissolution promotion mechanism 5 starts the continuous supply of at least one of the base 51B and the acid 51C after starting the continuous supply of the buffer 51A.

[0052] The pH adjusting agent 51 supplied to the mixed liquid discharge channel 44 may be a solid or a liquid, or it may be in the form of a solvate such as a hydrate.

[0053] (Buffering agent) Buffering agent 51A may be used alone or in combination of two or more types. Examples of buffering agent 51A include boric acid buffering agent, phosphate buffering agent, Tris buffering agent, citrate buffering agent, tartaric acid buffering agent, acetate buffering agent, amino acid buffering agent, and sulfonic acid buffering agent.

[0054] Examples of boric acid buffers include orthoboric acid, metaboric acid, and tetraboric acid, as well as their salts (alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; aluminum salts; organic amine salts such as triethylamine, triethanolamine, morpholine, piperazine, and pyrrolidine).

[0055] Examples of phosphate buffering agents include phosphoric acid; dialkali metal salts of hydrogen phosphate such as disodium hydrogen phosphate and dipotassium hydrogen phosphate; dialkali metal salts of hydrogen phosphate such as sodium dihydrogen phosphate and potassium dihydrogen phosphate; and trialkali metal salts of phosphate such as trisodium phosphate and tripotassium phosphate.

[0056] Examples of Tris buffering agents include trometamol and its salts (organic acid salts such as acetate; organic acid salts such as hydrochloride and sulfonate).

[0057] Examples of citrate buffers include citric acid and its salts (alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt, etc.).

[0058] Examples of tartaric acid buffers include tartaric acid and its salts (alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt, etc.).

[0059] Examples of acetic acid buffers include acetic acid and its salts (alkali metal salts such as sodium and potassium salts; alkaline earth metal salts such as calcium and magnesium salts; ammonium salts, etc.).

[0060] Examples of amino acid buffers include acidic amino acids and their salts (such as alkali metal salts like sodium and potassium salts).

[0061] Examples of sulfonic acid buffers include 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), 2-morpholinoethanesulfonic acid (MES), 3-morpholinopropanesulfonic acid (MOPS), piperazine-1,4-bis(2-ethanesulfonic acid) (PIPES), N-(2-acetamide)-2-aminoethanesulfonic acid (ACES), N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES), and N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid (TES).

[0062] The concentration of the buffer 51A supplied to the mixed liquid discharge channel 44 is not particularly limited, and is, for example, 0.1 g / L to 100 g / L. The concentration of the buffer 51A may be 0.5 g / L or more, or 1.0 g / L or more, or 50 g / L or less, 10 g / L or less, or 5 g / L or less. The concentration of the buffer 51A is predetermined based on the type of powder 21 supplied, the type of liquid 31, and the amount of dissolving solution 61 produced.

[0063] The supply rate of the buffer 51A is, for example, 0 ml / min to 1000 ml / min. The supply rate of the buffer 51A may be 0.1 ml / min or more, 0.5 ml / min or more, 1 ml / min or more, or 3 ml / min or more, and may be 500 ml / min or less, 100 ml / min or less, or 10 ml / min or less. The supply rate of the buffer 51A is adjusted by the third pump 53A.

[0064] (Base) Base 51B may be used alone or in combination of two or more types. Examples of base 51B include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; and lithium hydroxide monohydrate (LiOH·H). ２ Examples include hydrates of metal hydroxides such as O); alkali metal carbonates such as sodium carbonate, potassium carbonate, and cesium carbonate; alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkaline earth metal carbonates such as calcium carbonate and barium carbonate; and alkaline earth metal hydroxides such as calcium hydroxide and barium hydroxide.

[0065] The concentration of base 51B supplied to the mixed liquid discharge channel 44 is not particularly limited, and is, for example, 0.010 mol / L to 10 mol / L. The concentration of base 51B may be 0.050 mol / L or more, or 0.100 mol / L or more, and may be 5.000 mol / L or less, 1.000 mol / L or less, or 0.500 mol / L or less. The concentration of base 51B is predetermined based on the type of powder 21 supplied, the type of liquid 31, and the amount of dissolving solution 61 produced.

[0066] The supply rate of base 51B is, for example, 0 ml / min to 1000 ml / min. The supply rate of base 51B may be 0.1 ml / min or more, 0.5 ml / min or more, 1 ml / min or more, or 5 ml / min or more, and may be 500 ml / min or less, 100 ml / min or less, or 20 ml / min or less. The supply rate of base 51B is adjusted by the fourth pump 53B.

[0067] (Acids) Acid 51C may be used alone or in combination of two or more types. Examples of Acid 51C include organic acids such as formic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, and trifluoromethanesulfonic acid; and inorganic acids such as hydrochloric acid, sulfuric acid, and hydrogen bromide.

[0068] The concentration of acid 51C supplied to the mixed liquid discharge channel 44 is not particularly limited, and is, for example, 0.1 mol / L to 100 mol / L. The concentration of acid 51C may be 1 mol / L or more, 3 mol / L or more, 50 mol / L or less, 30 mol / L or less, or 10 mol / L or less. The concentration of acid 51C is predetermined based on the type of powder 21 supplied, the type of liquid 31, and the amount of dissolving solution 61 produced.

[0069] The supply rate of acid 51C is, for example, 0 ml / min to 1000 ml / min. The supply rate of acid 51C may be 0.1 ml / min or more, 0.5 ml / min or more, 1 ml / min or more, or 5 ml / min or more, and may be 500 ml / min or less, 100 ml / min or less, or 20 ml / min or less. The supply rate of acid 51C is adjusted by the fifth pump 53C.

[0070] (pH) The pH is adjusted by a pH adjusting agent 51 in the mixed liquid discharge channel 44. Preferably, the amount of pH adjusting agent 51 supplied is predetermined so that the pH of the mixed liquid 41 and the dissolving solution 61 reaches a desired value.

[0071] In the dissolution-promoting mechanism 5, the mixed solution 41 preferably undergoes one or more pH fluctuations of ±1.0 or more at 25°C, more preferably one or more pH fluctuations of ±2.0 or more at 25°C, and may undergo one or more pH fluctuations of ±3.0 or more at 25°C. In the dissolution-promoting mechanism 5, the mixed solution 41 may undergo pH fluctuations of ±5.0 or less, ±4.0 or less, or ±3.0 or less at 25°C. The mixed solution 41 may also undergo pH fluctuations of ±1.0 to ±5.0 at 25°C. In the dissolution-promoting mechanism 5, the mixed solution 41 preferably undergoes one or more pH fluctuations of ±1.0 or more at 25°C, and may undergo two or more pH fluctuations of ±1.0 or more at 25°C. In the dissolution-promoting mechanism 5, the mixed solution 41 may undergo pH fluctuations of four or fewer times, three or fewer times, or two or fewer times. The mixed solution 41 may also undergo pH fluctuations of one to four times. In the dissolution promotion mechanism 5, the mixed solution 41 undergoes a pH fluctuation of ±1.0 or more at 25°C at least once, causing the mixed solution 41 to become acidic or basic at least once, making any undissolved powder 21 in the mixed solution 41 more easily dissolved by the acidity or basicity. In the dissolution promotion mechanism 5, the mixed solution 41 may also undergo a pH fluctuation of ±3.0 or more at 25°C at two or more times to produce the dissolving solution 61.

[0072] As described above, the pH adjusting agent 51 may be a buffer 51A and a base 51B, that is, the pH may be adjusted using the buffer 51A and the base 51B to dissolve any undissolved powder 21 that may remain in the mixture 41. Alternatively, the pH adjusting agent 51 may be a buffer 51A, a base 51B and an acid 51C, that is, the pH may be adjusted using the buffer 51A, a base 51B and an acid 51C to dissolve any undissolved powder 21 that may remain in the mixture 41. The pH at which any undissolved powder 21 that may remain in the mixture 41 dissolves easily depends on the undissolved components, so it is preferable to adjust the pH of the mixture 41 to be strongly acidic or basic, respectively. For example, after starting to supply buffer 51A to the mixed solution 41, the supply of base 51B may be started to cause a pH fluctuation of ±3.0 or more once, and then, after starting to supply base 51B, the supply of acid 51C may be started to cause another pH fluctuation of ±3.0 or more once.

[0073] The pH of the solution 61 obtained via the dissolution promotion mechanism 5 is not particularly limited and may be, for example, pH 2.0 to pH 13.0 at 25°C. The pH of the solution 61 may be pH 3.0 or higher, pH 4.0 or higher, pH 5.0 or higher, pH 6.0 or higher, pH 6.5 or higher, or pH 6.8 or higher, and may be pH 12.0 or lower, pH 11.0 or lower, pH 10.0 or lower, pH 9.0 or lower, pH 8.0 or lower, pH 7.5 or lower, or pH 7.3 or lower.

[0074] From the viewpoint of obtaining a dissolution 61 with a desired pH, it is preferable to produce a dissolution 61 having a pH within ±0.2 of the desired pH at 25°C, and more preferable to produce a dissolution 61 having a pH within ±0.1 of the desired pH at 25°C. By producing a dissolution 61 having a pH within ±0.2 of the desired pH at 25°C, the dissolution 61 can be easily used for the desired application (for example, cell culture where the efficiency may change depending on the pH).

[0075] (Culture tank) The dissolution 61 is obtained by passing the mixed solution 41 through the dissolution-promoting mechanism 5 of this disclosure. The dissolution-promoting mechanism 5 may be connected to the culture tank 6. That is, the mixed solution discharge channel 44 may be connected to the culture tank 6 via the dissolution-promoting mechanism 5. It is preferable that the dissolution-promoting mechanism 5 continuously supplies the dissolution 61 to the culture tank 6.

[0076] The most common culture methods used in biomanufacturing are batch culture, fed-batch culture, and perfusion culture. From the viewpoint of being able to continuously produce the lysate 61, the powder dissolution apparatus 1 of this disclosure preferably uses a culture medium for perfusion culture. In perfusion culture, fresh culture medium is continuously perfused into the culture vessel while maintaining a high number of viable cells. This perfusion supplies fresh culture medium to the cells, and by further removing the consumed medium, and optionally dead cells and desired products, continuous culture is possible for long periods ranging from several hours to several months. The advantages of perfusion culture are that a higher yield per culture vessel volume can be obtained and a more consistent quality of product can be obtained. Unlike batch culture, perfusion culture does not accumulate waste in the culture vessel. Products produced by cell culture can be quickly removed and purified. Perfusion culture has advantages when the desired product is an unstable substance. Removing consumed culture medium while retaining cells in culture can be achieved by filtration (e.g., alternating tangential flow filtration (ATF) and standard tangential flow filtration (TFF)), sedimentation devices, centrifugation, acoustic devices, or attachment to the surface of the cell culture vessel (e.g., capillary fibers, membranes, and microcarriers).

[0077] (Storage Tank) The dissolution acceleration mechanism 5 is connected to the storage tank 6, and a culture tank (not shown) may be connected further downstream thereof. That is, the mixed liquid discharge passage 44 is connected to the storage tank 6 via the dissolution acceleration mechanism 5, and a culture tank may be connected further downstream thereof. It is preferable that the dissolution acceleration mechanism 5 continuously supplies the dissolution solution 61 to the culture tank. The storage tank 6 stores the dissolution solution 61 of this disclosure.

[0078] <Uses of the lysate> The culture vessel uses the lysate 61 of this disclosure and cells, microorganisms, or enzymes to perform culturing, synthesis, or degradation of substances. Examples of cells include mammalian cells, bacterial cells, insect cells, fungal cells, algae, and yeast. Examples of substances obtained from cells, microorganisms, or enzymes using the lysate 61 of this disclosure include peptides, proteins, oligonucleotides, polynucleotides, protein complexes, cellular metabolites, viruses, virus-like particles, exosomes, microorganisms, cells, and tissues. In one embodiment, the culture vessel includes any of mammalian cells, bacterial cells, insect cells, fungal cells, algae, or yeast, and the mammalian cells, bacterial cells, insect cells, algae, or yeast produce at least one substance selected from the group consisting of peptides, proteins, oligonucleotides, polynucleotides, protein complexes, and cellular metabolites. In one embodiment, the product is a protein, for example, an antibody or a monoclonal antibody. The antibody serves as the active pharmaceutical ingredient for an antibody drug. In another embodiment, the culture vessel contains any of mammalian cells, bacterial cells, insect cells, fungal cells, algae, or yeast, which are used, for example, as cell products for cell therapy.

[0079] When using the dissolving solution 61 of this disclosure as a culture medium, it is preferable that the components used in each mechanism of the powder dissolving apparatus 1 of this disclosure are sterile-connected, from the viewpoint of avoiding contamination.

[0080] <Control Unit> The powder dissolving apparatus of the present disclosure may include a control unit 7. One embodiment of the control unit 7 is further shown in Figure 2. As shown in Figure 2, the control unit 7 includes, for example, a processor such as a CPU (Central Processing Unit) 71, a memory 72, and a storage 73, and comprehensively controls each mechanism of the powder dissolving apparatus 1 of the present disclosure. The CPU 71, memory 72, and storage 73 are interconnected via a bus line 74.

[0081] The processor may be a programmable logic device (PLD), such as an FPGA (Field Programmable Gate Array), which is a processor whose circuit configuration can be changed after manufacturing; or a dedicated electrical circuit, such as an ASIC (Application Specific Integrated Circuit), which has a circuit configuration specifically designed to perform a particular process.

[0082] Memory 72 is work memory for the CPU 71 to execute processing. The CPU 71 loads programs stored in storage 73 into memory 72 and executes processing according to the programs. In this way, the CPU 71 comprehensively controls all parts of the computer. Memory 72 may be built into the CPU 71.

[0083] The storage 73 is a hard disk drive or a solid-state drive. The storage 73 stores control programs such as the operating system, various application programs, and various data associated with these programs.

[0084] (Operation Unit) The powder dissolving apparatus of the present disclosure may include an operation unit 8. The operation unit 8 is, for example, a touch panel and receives various operation instructions from the operator of the powder dissolving apparatus 1 of the present disclosure. These operation instructions include instructions to start and stop the supply of powder 21 to the mixing tank 42, instructions to start and stop the continuous supply of liquid 31, instructions to start and stop the operation of the first pump 33 to the fifth pump 53C, and instructions to start and stop the operation of the agitator 43.

[0085] <Other Mechanisms> In addition to the mechanisms described above, the powder dissolving apparatus 1, which is one embodiment of the present disclosure, may also include at least one of an adjustment mechanism and a measuring instrument. The adjustment mechanism and the measuring instrument may be provided in any part of any mechanism of the powder dissolving apparatus 1 of the present disclosure.

[0086] (Adjustment Mechanism) An adjustment mechanism is a mechanism for adjusting the state of the powder 21, liquid 31, mixture 41, and dissolving solution 61 of this disclosure, and may be at least one selected from the group consisting of an additive supply mechanism, a sterilization mechanism, and a temperature control mechanism. The additive supply mechanism further supplies additives to the powder 21, liquid 31, mixture 41, or dissolving solution 61. Examples of additives include whole blood, serum such as fetal bovine serum (FBS), plasma, bovine serum albumin (BSA), antibiotics, cytokines, and growth factors. The sterilization mechanism sterilizes the powder 21, liquid 31, mixture 41, or dissolving solution 61. The sterilization method may be heat sterilization, pressure sterilization, filter sterilization, or a combination thereof. The temperature control mechanism heats or cools the powder 21, liquid 31, mixture 41, or dissolving solution 61. The temperature control mechanism may heat to 25°C to 100°C or cool to 0 to 20°C. Furthermore, from the viewpoint of eliminating the need for a temperature control mechanism, the powder dissolving apparatus 1 of this disclosure is preferably used at 20°C to 25°C.

[0087] (Measuring instrument) The measuring instrument is an instrument for measuring and monitoring the state of the powder 21, liquid 31, mixed solution 41 and dissolving solution 61 of the present disclosure, and may be at least one selected from the group consisting of a pH meter, thermometer, conductivity meter, flow meter, concentration meter, spectrophotometer, dissolved oxygen meter and viscometer.

[0088] ≪Powder Dissolution Method≫ The powder dissolution method of this disclosure dissolves powder using the powder dissolution apparatus of this disclosure. According to the powder dissolution method of this disclosure, pH adjustment is possible and the dissolved solution can be continuously produced. The powder dissolution apparatus and powder used in the powder dissolution method of this disclosure are described above.

[0089] The present disclosure will be further described below with reference to examples, but the present disclosure is not limited to the following examples unless it exceeds the spirit of the disclosure.

[0090] <Example 1> The following powder and liquid were used. The following powder is a cell culture medium containing cystine, tyrosine, arginine, and lysine. Powder: BalanCD CHO GROWTH A, manufactured by FUJIFILM Irvine Scientific Liquid: Water

[0091] The following powder dissolving apparatus was used, equipped with a feeder, pump, pump head, and agitator: Feeder: Aisin Nanotechnologies TF-70-AD Pump: Masterflex 07522-30 Pump head: Masterflex 77201-60 Agitator: ASONE TORNADO SMT-104

[0092] The configuration of the powder dissolving apparatus 1 of Example 1 is as shown in Figure 3, and comprises a powder supply mechanism 2, a liquid supply mechanism 3, a mixing mechanism 4, and a dissolution promotion mechanism 5. The powder dissolving apparatus 1 of Example 1 includes a 1L volume mixing tank 42 equipped with a stirrer 43 for generating a mixed liquid 41. The mixing tank 42 is connected to a feeder 24 for supplying powder 21 to the mixing tank 42 and a liquid supply passage 32 equipped with a first pump 33 for supplying liquid 31. The mixing tank 42 is connected to a mixed liquid discharge passage 44 equipped with a second pump 45 for discharging the mixed liquid 41. Downstream of the second pump 45, the mixed liquid discharge passage 44 is connected to two inline mixers for pH adjustment to promote the dissolution of the powder 21. Each inline mixer is connected, in order from upstream, to a buffer supply channel 52A equipped with a third pump 53A that supplies an aqueous sodium bicarbonate solution, and to a base supply channel 52B equipped with a fourth pump 53B that supplies an aqueous sodium hydroxide solution. Further downstream of the inline mixers, a 10L storage tank 6 is connected for storing the resulting solution 61.

[0093] The powder dissolving apparatus 1 of Example 1 was operated according to the following procedure: (1) The first pump 33 was driven and 850 ml of water was stored in the mixing tank 42. (2) Powder 21 was added to the mixing tank 42 from the feeder 24 to a concentration of 23.7 g / L. (3) The stirrer 43 was driven and stirred at 200 rpm for 30 minutes (initial stirring). (4) Sodium bicarbonate was dissolved in water to obtain a 2.2 g / L sodium bicarbonate aqueous solution, and the container holding this sodium bicarbonate aqueous solution was connected to the buffer supply channel 52A equipped with the third pump 53A. (5) A 5 mol / L sodium hydroxide aqueous solution was diluted 40 times to obtain a 0.125 mol / L diluted solution, and the container holding this diluted solution was connected to the base supply channel 52B equipped with the fourth pump 53B. (6) The supply rates from the first pump 33 and the second pump 45 were set to 85 ml / min, the supply rate from the third pump 53A was set to 5 ml / min, and the supply rate from the fourth pump 53B was set to 10 ml / min. (7) The powder supply rate from the feeder 24 was set to 2.37 g / min. (8) The first pump 33, the second pump 45, the feeder 24, and the third pump 53A were driven, followed by the fourth pump 53B. (9) The dissolution solution 61 was generated continuously for 10 minutes until the 10 L storage tank 6 was filled.

[0094] In step (8) of Example 1, the dissolution acceleration mechanism involved the mixture undergoing a pH fluctuation of +2.3 at 25°C once. In step (9), a solution with a pH of 7.1 was produced relative to the desired pH of 7.0 at 25°C.

[0095] <Comparative Example 1> The following powder and liquid were used. The following powder is a powdered culture medium for cell culture and contains cystine, tyrosine, arginine, and lysine. Powder: BalanCD CHO GROWTH A, manufactured by FUJIFILM Irvine Scientific Liquid: Water

[0096] The following apparatus, consisting of a feeder, pump, pump head, and agitator, was used: Feeder: Aisin Nanotechnologies TF-70-AD Pump: Masterflex 07522-30 Pump head: Masterflex 77201-60 Agitator: ASONE TORNADO SMT-104

[0097] The configuration of the apparatus in Comparative Example 1 differs from that of Example 1 (i.e., Figure 3) in that it does not have the dissolution acceleration mechanism 5 of the present disclosure, but it does have a dissolution tank in which pH adjustment is performed. In other words, the apparatus of Comparative Example 1 sends the mixed liquid from the mixing tank 42 to the dissolution tank in a batch manner using a sixth pump (not shown), and after sending the liquid, the pH is adjusted to produce a pH-adjusted dissolution discontinuously. The details of the apparatus of Comparative Example 1 are as follows. The apparatus of Comparative Example 1 has a 1 L volume mixing tank equipped with a stirrer for producing the mixed liquid, and the mixing tank is connected to a feeder for supplying powder to the mixing tank and a liquid supply passage equipped with a first pump for supplying liquid. The mixing tank is connected to a mixed liquid discharge passage equipped with a second pump for discharging the mixed liquid. The mixed liquid discharge passage equipped with the second pump is connected to a dissolution tank for pH adjustment. The dissolution tank is equipped with a stirrer for producing the dissolution. The dissolution tank is connected to a buffer supply passage equipped with a third pump for supplying an aqueous sodium bicarbonate solution and a base supply passage equipped with a fourth pump for supplying an aqueous sodium hydroxide solution. The dissolution tank is further connected to a discharge channel equipped with a sixth pump for discharging the resulting solution. Downstream of the discharge channel equipped with the sixth pump, a 10L storage tank for storing the resulting solution is connected.

[0098] The apparatus of Comparative Example 1 was operated according to the following procedure: (1) The first pump was driven and 850 ml of water was stored in the mixing tank. (2) Powder was added from the feeder to the mixing tank to a concentration of 23.7 g / L. (3) The stirrer was driven and stirred at 200 rpm for 30 minutes (initial stirring). (4) Sodium bicarbonate was dissolved in water to obtain a 2.2 g / L sodium bicarbonate aqueous solution, and the container holding this sodium bicarbonate aqueous solution was connected to the buffer supply line equipped with the third pump. (5) A 5 mol / L sodium hydroxide aqueous solution was diluted 40 times to obtain a 0.125 mol / L diluted solution, and the container holding this diluted solution was connected to the base supply line equipped with the fourth pump. (6) The supply rates from the first and second pumps were set to 75 ml / min, the supply rate from the third pump to 5 ml / min, and the supply rate from the fourth pump to 10 ml / min. (7) The second pump was activated to discharge the mixture from the mixing tank to the dissolution tank. (8) The third pump was activated to supply sodium bicarbonate aqueous solution to the dissolution tank for 1 minute. (9) The stirrer in the dissolution tank was activated and stirred at 200 rpm for 30 minutes. (10) The fourth pump was activated to supply sodium hydroxide aqueous solution to the dissolution tank for 1 minute. (11) The stirrer in the dissolution tank was activated and stirred at 200 rpm for 10 minutes. (12) The sixth pump was set to 100 mL / min and the dissolution solution was sent to the storage tank for 10 minutes. (13) Steps (1) to (12) of Comparative Example 1 were repeated 10 times until 10 L of dissolution solution accumulated in the storage tank. Note that in steps (1) to (11), the sixth pump was stopped, so pH adjustment was performed discontinuously in the dissolution tank.

[0099] In steps (10) to (11) of Comparative Example 1, the mixture underwent one pH fluctuation of +2.3 at 25°C. In step (13), a solution with a pH of 7.1 was produced relative to the desired pH of 7.0 at 25°C of the original solution.

[0100] As in Example 1, when pH adjustment was performed continuously in-line, it took a total of 40 minutes to produce 10 L of dissolution, consisting of 30 minutes of initial stirring in the mixing tank and 10 minutes of continuous dissolution. On the other hand, as in Comparative Example 1, when pH adjustment was performed in a batch manner, it took a total of approximately 700 minutes, consisting of (30 minutes of initial stirring in the mixing tank + 30 minutes of stirring after adding sodium bicarbonate + 10 minutes of stirring after adding sodium hydroxide) x 10 times. Even if the scale of the apparatus were increased in a batch-type system like Comparative Example 1, and steps (1) to (12) of Comparative Example 1 were not repeated, it would still take at least 70 minutes in total, consisting of 30 minutes of initial stirring in the mixing tank + 30 minutes of stirring after adding sodium bicarbonate + 10 minutes of stirring after adding sodium hydroxide. Therefore, the powder dissolution apparatus of this disclosure is capable of pH adjustment and can continuously produce dissolution, and is highly productive.

[0101] Furthermore, the disclosure of Japanese Patent Application No. 2024-169447, filed on 27 September 2024, is incorporated herein by reference in its entirety. In addition, all documents, patent applications, and technical standards described herein are incorporated herein by reference to the same extent as if each individual document, patent application, and technical standard were specifically and individually noted to be incorporated by reference.

[0102] (Explanation of symbols in the drawing) 1: Powder dissolving device 2: Powder supply mechanism 3: Liquid supply mechanism 4: Mixing mechanism 5: Dissolution acceleration mechanism 6: Culture tank or storage tank 7: Control unit 8: Operation unit 21: Powder 22: Cartridge 23: Powder outlet 24: Feeder 31: Liquid 32: Liquid supply channel 33: First pump 41: Mixed liquid 42: Mixing tank 43: Agitator 44: Mixed liquid discharge channel 45: Second pump 51: pH adjuster 51A: Buffer 51B: Base 51C: Acid 52: pH adjuster supply channel 52A: Buffer supply channel 52B: Base supply channel 52C: Acid supply channel 53: pH adjuster supply pump 53A: Third pump 53B: Fourth pump 53C: Fifth pump 61: Dissolving liquid 71: CPU 72: Memory 73: Storage 74: Bus Line

Claims

1. A powder dissolving apparatus comprising: a powder supply mechanism for supplying powder; a liquid supply mechanism for continuously supplying liquid; a mixing mechanism for mixing the powder supplied from the powder supply mechanism and the liquid supplied from the liquid supply mechanism to produce a mixed liquid; and a dissolution promoting mechanism for supplying a pH adjusting agent to the mixed liquid discharged from the mixing mechanism to promote the dissolution of the powder in the mixed liquid and produce a dissolved solution.

2. The amount of pH adjusting agent supplied is predetermined so that the pH of the mixed liquid and the dissolving liquid reaches a desired value, as described in claim 1.

3. The powder dissolving apparatus according to claim 1 or claim 2, wherein the dissolution promoting mechanism involves the mixed liquid undergoing one or more pH fluctuations of ±1.0 or more at 25°C.

4. The powder dissolving apparatus according to claim 1 or claim 2, which produces the dissolving solution having a pH within ±0.2 of a desired pH at 25°C.

5. The powder dissolving apparatus according to claim 1 or claim 2, wherein the pH adjusting agent is at least one selected from the group consisting of buffers, bases, and acids.

6. The powder dissolving apparatus according to claim 5, wherein the dissolution promoting mechanism starts a continuous supply of at least one of the acid and the base after the start of the continuous supply of the buffering agent.

7. The powder dissolving apparatus according to claim 1 or claim 2, wherein the powder comprises at least one selected from the group consisting of cystine, tyrosine, arginine, and lysine.

8. The powder dissolving apparatus according to claim 1 or claim 2, wherein the powder is a powder culture medium for cell culture.

9. The powder dissolving apparatus according to claim 1 or claim 2, wherein the liquid is water.

10. A method for dissolving powder using the powder dissolving apparatus described in claim 1 or claim 2.

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