A method for manufacturing pharmaceuticals that reduces production time and improves stability.

Abstract

The present invention relates to a novel method for producing a drug, a nano drug carrier, or a metal-organic framework, which can be produced by an existing wet chemical synthesis method, and a drug produced by the method.

Description

[Technical Field]

[0001] The present invention relates to a novel method for producing pharmaceuticals, nanodrug carriers, or metal-organic structures that can be manufactured by existing wet chemical synthesis methods, and to a drug produced by this method. [Background technology]

[0002] Various methods for synthesizing nanomaterials using wet chemical synthesis have been studied. The basic parameters that influence the properties of nanomaterials are the concentration of reactants, the pH of the precursor, the heating temperature, and the reaction time.

[0003] Variables for synthesizing high-quality nanoparticles as a product include a narrow particle size distribution, crystal quality, desired morphology of the product nanomaterial, sufficient supersaturation, careful selection of precursors, and concentration of stabilizing agents. These synthesis parameters play a crucial role in maintaining the nanoparticles in a stable state for extended periods. To effectively mix each precursor at the atomic level, this pathway-based method allows for the preparation of materials with relatively good stoichiometry and sizes ranging from 1 nm to several microns, which can then be easily stabilized using capping agents.

[0004] The following describes the various categories of wet chemical synthesis methods developed to date.

[0005] First, there is chemical bath deposition synthesis, in which a solid phase precipitate is generated as a result of a chemical reaction in the reaction solution. There is also successive ion layer adsorption and reaction (SILAR), which can be used to deposit a uniform film on all substrates with controlled deposition rate, composition, and thickness, and does not require a vacuum and the process is carried out at low temperatures, thus not requiring expensive and complex technical equipment. There is also the chemical co-precipitation method, in which nanoparticles are grown by dissolving and mixing a precursor separately and then mixing in a precipitation reagent. There is also electrochemical synthesis, in which a nanocrystalline thin film is deposited on a substrate using electric current as a driving force, with the substrate, two or three electrodes, an electrolyte solution in a container, and an electric current source. Furthermore, there is solvothermal synthesis, in which physicochemical reactions are carried out under high pressure and high temperature, and hydrothermal synthesis, in which physicochemical reactions are carried out in aqueous solution, for synthesizing nanoparticles in organic solvents. Furthermore, there is sol-gel synthesis, in which a liquid (sol) is chemically converted into a gel state and then condensed into the form of a solid nanostructure. Another synthesis method is microemulsion synthesis, which is carried out using a homogeneous solution containing water, oil, surfactant, and amine-based or alcohol-co-surfactants. This technique consists of a process set of thermodynamically configured colloidal systems and includes an isotropic mixture of hydrophilic liquid (water), lipophilic liquid (oil), and amphiphilic surfactant (hydrophilic and hydrophobic groups).

[0006] Among these synthesis strategies, Berlin blue nanoparticles and their analogues have been reported to have a narrow size distribution, stabilize dispersion in solution, and be produced in a uniform morphology through double-precursor synthesis and hydrothermal synthesis. However, double-precursor synthesis has disadvantages compared to hydrothermal synthesis, such as difficulty in producing a uniform morphology and difficulty in controlling the growth rate. Hydrothermal synthesis has problems such as a long synthesis time, the need for excessive stabilizers, difficulty in dissolution, and the production of toxic byproducts. Gold nanoparticles are also synthesized by hydrothermal synthesis, but this is done at high temperatures using sodium citrate (Na3C6H5O7) as a reducing agent and surfactant. However, because it relies solely on sodium citrate, it has the disadvantage that the reduced gold atoms tend to aggregate quickly. In addition, it is not easy to produce each particle in a uniform size in a short time, so there is a need to devise a method that can finely control the nanoparticles.

[0007] Existing nanoparticle synthesis methods require expensive equipment, have relatively low production rates per unit time, and make it difficult to produce nanoparticles with a uniform size distribution. Furthermore, the generation of particles has the disadvantage of producing harmful reactive gases such as chlorine gas and byproducts. Additionally, due to the nature of producing particles in a molecular state, it is difficult to manufacture nanoparticles composed of diverse materials, resulting in complex manufacturing conditions and processes. In particular, during nanoparticle transport and final application, the surface effect of the nanoparticles causes aggregation between particles, necessitating additional processes such as dispersion in solution, re-pulverization, or ultrasonic treatment. In the case of metals, this also presents problems such as oxidation due to exposure. [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] Korean Registered Patent No. 10-1329646 [Overview of the project] [Problems that the invention aims to solve]

[0009] The present invention was invented to solve the problems in the production, storage, and application of organic or inorganic nanoparticles and chemical drugs as described above, and aims to provide a method for producing organic or inorganic nanoparticles and nanopharmaceuticals in which particle size is uniform, aggregation phenomena and oxidation reactions are minimized, the time required for synthesis is shortened, the yield within the same reaction time is improved, synthesis is possible even at high temperatures, and it is easy to produce various types of particles, as well as a method for producing synthetic pharmaceuticals and biopharmaceuticals in which the yield of the finished product is increased.

[0010] The objects of the present invention are not limited to those mentioned above. The objects of the present invention will become clear from the following description and will be realized by the means and combinations thereof described in the claims. [Means for solving the problem]

[0011] This invention has the effect of shortening the overall synthesis time by devising a synthesis method in a cutting liquid to solve the problem of heat transfer, which takes a long time during the synthesis process;

[0012] One aspect of the present invention provides a method for producing nanoparticles or nanopharmaceuticals, comprising: (a) the step of introducing a synthesis material and a solvent into a precursor mixing chamber connected to an injection pipe and causing it to swirl; (b-1) the step of transferring the solution produced in (a) to a reaction chamber 30 connected to the mixing chamber; and (b-2) the step of causing a gas to flow at high speed between the interface of the reaction chamber 30 and the liquid cutting pipe 31, which has a gap of 10 nm to 1000 μm.

[0013] In one aspect of the present invention, the method provides a method for producing nanoparticles or nanopharmaceuticals, further comprising the step of (c) collecting the solution cut by the liquid cutting tube 31 and the interface of the reaction chamber 30, and collecting again at the interface of the reaction chamber in a certain amount.

[0014] In one aspect of the present invention, the method further includes: (d) separating or extracting the reactants synthesized at the interface and circulating them to bind the target substance in a separate binding chamber; and provides a method for manufacturing nanoparticles or nanopharmaceuticals.

[0015] In one aspect of the present invention, there is provided a method for manufacturing nanoparticles or nanopharmaceuticals, wherein the side angle of the inlet of the liquid cutting tube 31 is 5° to 60°, and the front angle is 5° to 60°.

[0016] In one aspect of the present invention, in step (b-2), the gas is designed to flow at high speed by voltage, and the gas flows at high speed with an applied voltage of 5 kV to 60 kV, and provides a method for manufacturing nanoparticles or nanopharmaceuticals.

[0017] In one aspect of the present invention, there is provided a method for manufacturing nanoparticles or nanopharmaceuticals, wherein the interface between the reaction chamber and the liquid cutting tube is 0.25 rad to 0.85 rad.

[0018] In one aspect of the present invention, in step (b-2), the gap is 500 nm to 1500 nm, and provides a method for manufacturing nanoparticles or nanopharmaceuticals.

[0019] In one aspect of the present invention, the nanoparticles or nanopharmaceuticals are photosensitizers, first-generation anticancer agents, second-generation anticancer agents, third-generation anticancer agents, nuclear medicine therapeutic drugs, metabolic anticancer agents, enzymes, gene therapy agents, or near-infrared fluorescent dyes, and provides a method for manufacturing nanoparticles or nanopharmaceuticals.

[0020] Another aspect of the present invention provides nanoparticles or nanopharmaceuticals manufactured by any one of the aspects of the present invention.

Effects of the Invention

[0021] The synthesis method of the present invention is designed to continuously break a bulk liquid into small cutting liquids, accelerate heat transfer, thereby facilitating the dissolution of poorly soluble substances and increasing the synthesis rate of compounds, enabling rapid synthesis of drugs.

[0022] According to the synthesis method in the cutting liquid depending on the gas flow rate of the present invention, the particle size is uniform, the aggregation phenomenon and oxidation reaction are minimized, the time required for synthesis is shortened, the yield within the same reaction time is improved, synthesis is possible even at high temperatures, and it is easy to manufacture various types of particles with a simple manufacturing process. Therefore, there is an effect that high-quality nanoparticles and chemical drugs can be economically manufactured and provided.

[0023] The manufacturing method according to one aspect of the present invention can enhance the water solubility of the manufactured poorly soluble substance compared to existing methods.

[0024] The manufacturing method according to one aspect of the present invention can enhance the stability of the manufactured substance compared to existing methods.

[0025] The effects of the present invention are not limited to the effects mentioned above. The effects of the present invention should be understood to include all effects inferable from the following description.

Brief Description of Drawings

[0026] [Figure 1] It is a diagram showing the concept of the present invention and the structure of the synthesis apparatus.

[0027] [Figure 2] It is a diagram showing the structure of the synthesized final product.

[0028] [Figure 3a-3c] It is a diagram showing the temperature rotation result of the apparatus and the time result for the mixed solution to reach the target temperature.

[0029] [Figure 4a-4i] It is a diagram showing the analysis result of the cancer cell killing effect.

[0030] [Figure 5] This is a diagram illustrating cancer cells treated with phototherapy (photomedicine).

[0031] [Figures 6a-6b] This figure shows the time it takes for a cerium mixture solution to reach the target temperature.

[0032] [Figures 7a-7b] This figure shows the time it takes for the gold ion mixture solution to reach the target temperature.

[0033] [Figures 8a-8b] This figure shows the time it takes for the palladium mixture solution to reach the target temperature.

[0034] [Figures 9a-9b] This figure shows the purity and UV-Vis spectrum of MPPa synthesized by the manufacturing method of this patent.

[0035] [Figure 10] This figure shows the 1H NMR analysis results of MPPa synthesized by the manufacturing method of this patent.

[0036] [Figures 11a-11b] This figure shows the time it takes for a methyl pheophorbide a mixed solution to reach the target temperature.

[0037] [Figures 12a-12c] This figure shows the time it takes for the docetaxel mixture solution to reach the target temperature.

[0038] [Figures 13a-13b] This figure shows the time it takes for the hypromellose mixture solution to reach the target temperature.

[0039] [Figures 14a-14b] This figure shows the UV-Vis spectrum and dot blot analysis results of the antibody-drug conjugate.

[0040] [Figures 15a-15b] This figure shows the time it takes for a 6-maleimidocaproic acid mixture solution to reach the target temperature. [Modes for carrying out the invention]

[0041] The above-described objects, other objects, features, and advantages of the present invention can be readily understood through the following preferred embodiments in conjunction with the accompanying drawings. However, the present invention is not limited to the embodiments described herein and may be embodied in other forms. Rather, the embodiments presented herein are provided to make the disclosed content thorough and complete and to fully convey the idea of ​​the invention to the ordinary person in the art.

[0042] In this specification, terms such as “includes” or “having” are intended to specify the presence of features, figures, stages, operations, components, parts, or combinations thereof as described in the specification, and should be understood not to preemptively exclude the presence or possibility of adding one or more other features, figures, stages, operations, components, parts, or combinations thereof.

[0043] Unless otherwise expressly stated, all numbers, values, and / or expressions used herein to express quantities of components, reaction conditions, polymer compositions, and formulations should be understood in all cases as being modified by the term "approximately," since these numbers are approximations that reflect the various uncertainties of measurement that arise in obtaining such values, among which they are essentially different. Furthermore, where a range of numbers is disclosed herein, such range is continuous and includes all values ​​from the minimum to the maximum of such range unless otherwise indicated. In addition, where such range refers to an integer, it includes all integers from the minimum to the maximum unless otherwise indicated.

[0044] In this specification, when a range is described for a variable, the variable may be understood to include all values ​​within the described range, including each endpoint to which the range is described. For example, the range "5 to 10" may be understood to include not only the values ​​5, 6, 7, 8, 9, and 10, but also any subranges such as 6 to 10, 7 to 10, 6 to 9, 7 to 9, and any values ​​between each reasonable integer within the described range, such as 5.5, 6.5, 7.5, 5.5 to 8.5, and 6.5 to 9. Furthermore, for example, the range "10% to 30%" can be understood to include not only all integers including values ​​such as 10%, 11%, 12%, 13% and up to 30%, but also any sub-ranges such as 10% to 15%, 12% to 18%, 20% to 30%, and any values ​​between each reasonable integer within the range described, such as 10.5%, 15.5%, 25.5%.

[0045] The present invention will be described in detail below.

[0046] In the synthesis of compounds, heat is a crucial factor in facilitating the melting and dissolution of chemicals and determining the synthesis rate. Furthermore, in drug synthesis, the rate of heat transfer affects yield, byproduct quantity, and homogeneity. Therefore, manufacturers strive to control heat in their synthesis processes. One fact is that heat flows more quickly through smaller volumes of liquids than through bulk liquids (solutions or mixtures). Therapeutic agents needed for epidemic diseases such as COVID-19 require synthesis in bulk units, but increasing volume leads to problems with synthesis time, yield, and homogeneity. Moreover, producing large quantities of products in small units increases purification time and installation costs. As a solution to these problems, the present invention's synthesis method is designed to enable rapid drug synthesis by continuously creating small, cleaved liquids from bulk liquids, thereby accelerating heat transfer and increasing the synthesis rate.

[0047] Furthermore, the present invention was devised to solve the problems in the production, storage, and application of organic or inorganic nanoparticles and chemical drugs described above by improving the synthesis method in a cutting liquid that depends on the gas flow rate, and aims to provide a method for producing organic or inorganic nanoparticles and nanopharmaceuticals in which particle size is uniform, aggregation phenomena and oxidation reactions are minimized, the time required for synthesis is shortened, the yield within the same reaction time is improved, synthesis is possible even at high temperatures, and it is easy to produce various types of particles, as well as a method for producing synthetic pharmaceuticals and biopharmaceuticals in which the yield of the finished product is increased.

[0048] This invention relates to a method for shortening the production time of chemical substances and uniformly manufacturing pharmaceuticals. It also relates to a nanodrug delivery body and a method for manufacturing the same, which enhances the water solubility of drugs and helps drugs exert their intended efficacy. Metal-organic framework (MOF) nanoparticles that can be stabilized for long periods in various sterile aqueous solutions frequently used in biological experiments and medicine were created using a synthesis method in a cutting liquid that depends on the gas flow rate, which has never been used in wet chemical synthesis methods. Compared to existing methods for manufacturing MOF nanoparticles, nanoparticles produced by the manufacturing method of this invention can increase the water solubility of pyropheophorbide-a methyl ester, a poorly soluble photosensitizer, and also increase the phototherapy effect on cancer cells. Furthermore, the synthesis method of this invention can shorten the production time of drugs produced by existing chemical synthesis methods and biopharmaceuticals produced by conjugation methods.

[0049] The present invention provides a method for producing nanoparticles or pharmaceuticals, which may include: (a) placing a synthesis material and a solvent into a precursor mixing chamber connected to an injection pipe and swirling it; (b) transferring the produced solution to a reaction chamber connected to the mixing chamber; and (b) ensuring that a gas flows at high speed between the chamber interface and a liquid cutting pipe, with a gap of several tens of nanometers to several hundred micrometers between them.

[0050] In one embodiment, the method may further include (c) the steps of collecting the solution cut by the liquid cutting tube and the interface of the reaction chamber and collecting a certain amount of it again at the interface of the reaction chamber, and separating and extracting the reactants synthesized at the interface and circulating them in a binding chamber to bind the target substance.

[0051] In one embodiment, the side angle of the inlet of the liquid cutting pipe is 5° to 60°, and the front angle is 5° to 60°.

[0052] In one embodiment, the reaction chamber has a structure that includes an inlet and an outlet, or a structure that is easy to open and close, in order to allow for smooth airflow.

[0053] In one embodiment, the binding chamber may be connected to a circulation device via a tube consisting of an annular structure or a continuous zigzag structure, so as to enable the circulation of the reactants (nanoparticles or drugs) produced in step (c).

[0054] In one embodiment, the nanoparticles produced by the manufacturing method are diagnostic or therapeutic nanopharmaceuticals characterized by being bound in one or more configurations of a photosensitizer, a first-generation anticancer agent, a second-generation anticancer agent, a third-generation anticancer agent, a nuclear medicine therapeutic drug, a metabolic anticancer agent, an enzyme, a gene therapy agent, and a near-infrared fluorescent dye.

[0055] In one embodiment, the drug produced by the above manufacturing method is synthesized at a low temperature that is not the freezing point of the solvent used, or at a high temperature in which the solvent does not completely evaporate; and is characterized by being synthesized in a smaller volume and in a shorter time compared to a drug produced without the above apparatus.

[0056] In one embodiment, the biopharmaceutical has a structure in which one or more components from the drugs, nucleic acid-based molecules, amino acid-based antibodies, specific-binding proteins, and enzymes with high biocompatibility, produced by the aforementioned manufacturing method, are linked together.

[0057] The following describes various aspects of the present invention.

[0058] One aspect of the present invention provides a method for producing nanoparticles or nanopharmaceuticals, comprising: (a) the step of introducing a synthesis material and a solvent into a precursor mixing chamber connected to an injection pipe and causing it to swirl; (b-1) the step of transferring the solution produced in (a) to a reaction chamber 30 connected to the mixing chamber; and (b-2) the step of causing a gas to flow at high speed between the interface of the reaction chamber 30 and the liquid cutting pipe 31, which has a gap of 10 nm to 1000 μm.

[0059] In one aspect of the present invention, the method provides a method for producing nanoparticles or nanopharmaceuticals, further comprising the step of (c) collecting the solution cut by the liquid cutting tube 31 and the interface of the reaction chamber 30, and collecting again at the interface of the reaction chamber in a certain amount.

[0060] In one aspect of the present invention, the method provides a method for producing nanoparticles or nanopharmaceuticals, further comprising the step of (d) separating or extracting the reactants synthesized at the interface and circulating them in a separate binding chamber to bind the target substance.

[0061] In one aspect of the present invention, a method for producing nanoparticles or nanopharmaceuticals is provided, wherein the side angle of the inlet of the liquid cutting tube 31 is 5° to 60° and the front angle is 5° to 60°.

[0062] In one aspect of the present invention, step (b-2) provides a method for producing nanoparticles or nanopharmaceuticals, wherein the gas is designed to flow at high speed by voltage, and the gas flows at high speed when an applied voltage of 5kV to 60kV is applied.

[0063] In one aspect of the present invention, a method for producing nanoparticles or nanopharmaceuticals is provided, wherein the interface between the reaction chamber and the liquid cutting tube is 0.25 rad to 0.85 rad.

[0064] In one aspect of the present invention, a method for producing nanoparticles or nanopharmaceuticals is provided, wherein in step (b-2) above, the gap is 500 nm to 1500 nm.

[0065] In one aspect of the present invention, the present invention provides a method for producing nanoparticles or nanopharmaceuticals, wherein the nanoparticles or nanopharmaceuticals are photosensitizers, first-generation anticancer agents, second-generation anticancer agents, third-generation anticancer agents, nuclear medicine therapeutic drugs, metabolic anticancer agents, enzymes, gene therapy agents, or near-infrared fluorescent dyes.

[0066] Another aspect of the present invention provides nanoparticles or nanopharmaceuticals manufactured by any one of the aforementioned aspects of the present invention. [Examples]

[0067] The present invention will be described in more detail below through specific examples. The following examples are merely illustrative to facilitate understanding of the present invention, and the scope of the present invention is not limited thereto.

[0068] Example 1. Production of Berlin Blue Nanoparticles and Nanopharmaceuticals

[0069] 1 g of polyvinylpyrrolidone (PVP, Sigma-aldrich) was dissolved in 20 g of ultrapure water, and the mixture was stirred in a mixing chamber at 1500 RPM for 30 minutes to obtain an aqueous PVP solution. Subsequently, potassium hexacyanoferrate(III) trihydrate was added. 131.7 mg of trihydrate (K3Fe(CN)6·3H2O, Sigma-aldrich) was dissolved in 20 g of ultrapure water and mixed with a PVP aqueous solution. Then, 400 μL of 1 M HCl (Sigma-aldrich) was added to the mixing chamber and vortexed at 60 J / s. The prepared solution was subjected to a procedure in which the gas flowed rapidly through the interface inside the chamber and the liquid cutting tube at a voltage of 30 kV via an injection tube, with a distance of 25 cm between the reaction chamber and the end of the injection tube, and at 140°C. As shown by the green arrows in Figure 1, the gas moves to the upper layer of the reaction chamber while passing through a structure where the interface between the reaction chamber and the liquid cutting tube is 0.29 rad and the boundary gap is 900 nm. The solution produced by passing through the liquid was cut into small pieces. The cut liquid was heated in the reaction chamber, and the transfer of heat within the liquid resulted in a faster temperature rise than that of the same total volume (40 mL) of bulk liquid (Figure 3). As the reaction of the solution took place in the reaction chamber, the cut solution was collected at the interface of the reaction chamber and in the liquid cutting tube, and a constant amount was collected again at the interface of the reaction chamber. After 3 hours, when the reaction was complete, the reactants synthesized at the interface were extracted by centrifugation and washed with water. The washed product was then pumped into a binding chamber and circulated to bind 2 mg of docetaxel (DTX) or pyropheophorbide-α methyl ester (MPPa) in the binding chamber. The finished sample was washed three times with methanol and distilled water, then dried to produce nanopharmaceuticals with a diameter of 200 nm. To confirm the cancer cell killing efficiency, cells cultured in a 96-well plate for 24 hours were treated with various concentrations of the nanopharmaceuticals.The photothermal effect of the drug was confirmed by irradiating the target with an 808nm laser at a voltage of 9.26V corresponding to 1W / cm², at a distance of 8.54cm from the laser, and with a spot area (optical fiber itself) diameter of 3.5cm for 2 minutes, and the results were obtained using the CCK8 assay. The broad-area therapeutic effect of the drug was confirmed by irradiating the target with a 660nm laser (ThorLabs, ED1-C50-MD, θ1.0” 50° circle, equipped with TOP_HAT diffuser) at a voltage of 0.44V corresponding to 1~2.3mW / cm², at a distance of 16cm from the laser, and with a spot diameter of 24cm for 10 minutes, and the results were obtained using the CCK8 assay. Through the results of the CCK8 assay, the effects observed with anticancer drugs could be confirmed with nanodrugs, and in addition, the effects of photothermal therapy (PTT) and broad-area dynamic therapy (PDT) were also observed (Figure 4).

[0070] Figure 2 shows the morphology of the berlin blue nanoparticles (a) and the nanopharmaceutical (b) of berlin blue nanoparticles bound to MPPa, produced by the manufacturing method of the present invention; Figure 3 shows the time taken for the mixed solution to reach its boiling point; and Figure 4 shows the effect of killing cancer cells (PANC-1) (a=docetaxel treatment; b=mPB-docetaxel treatment; c=mPB-docetaxel and PTT treatment; d=MPPa treatment; e=mPB-MPPa treatment; f=mPB-MPPa treatment and PDT treatment; g=mPB-MPPa treatment and PTT treatment; h=mPB-MPPa treatment and PTT treatment after PDT; i=mPB-MPPa treatment and PTT treatment after PTT). Furthermore, Figure 5 confirms that the nanodrug is taken up into cancer cells (Cellular uptake) (a, b), that cancer cells are killed by Berlin Blue nanoparticles bound to the anticancer drug (DTX) (c, d), that the PDT effect of killing cancer cells by Berlin Blue nanoparticles bound to MPPa is confirmed (e, f), and that the PTT effect can also be confirmed (g, h) (scale bar = 50 nm). Through these results, it is proven that the manufacturing method of this patent can produce Berlin Blue nanoparticles; the time to reach high temperatures is even shorter compared to manufacturing nanoparticles with the same weight of bulk liquid; and it is a method for manufacturing finished products with the function of nanopharmaceuticals.

[0071] Example 2. Production of ceria nanoparticles

[0072] A 0.3 mol / L solution of cerium(IV) diammonium nitrate and a 0.6 mol / L solution of ammonium sulfate were added to a mixing chamber and vortexed at 40 J / s. The prepared solution was then injected via an injection tube, with an applied voltage of 30 kV, a distance of 25 cm between the reaction chamber and the end of the injection tube, and a temperature of 230°C, to ensure that the gas flowed rapidly between the interface inside the chamber and the liquid cutting tube. As the reaction of the solution took place in the reaction chamber, the solution cut at the interface of the reaction chamber and the liquid cutting tube was collected and re-collected at the interface of the reaction chamber in a fixed amount. After 1 hour, when the reaction was complete, the reactants synthesized at the interface were extracted by centrifugation and washed with water.

[0073] Figure 2 shows the morphology of the ceria nanoparticles (c). In the previously developed method of reacting at 91°C for 3 hours, it was necessary to additionally dry the small 50 nm particles at a high temperature and then heat-treat them at 800°C. Furthermore, such methods have the problem of difficulty in obtaining uniform and independent particles. In contrast, the manufacturing method of the present invention produces nanoparticles with a uniform average size of 160 nm, and the reaction time is even shorter based on a total volume of 100 mL (Figure 6).

[0074] Example 3. Production of gold nanoparticles

[0075] 20 mL of a 1 mM HAuCl4 aqueous solution was transferred to a mixing chamber and then to a reaction chamber via an injection tube. The procedure was then carried out under conditions of a voltage of 30 kV, a distance of 5 cm between the reaction chamber and the end of the injection tube, and a temperature of 110°C, to ensure high-speed gas flow between the chamber interface and the liquid cutting tube. Subsequently, 2 mL of a 1% sodium citrate aqueous solution was added to the mixing chamber, and the aqueous solution was added to the 1 mM HAuCl4 solution in the reaction chamber while moving. As the reaction of the mixed solution took place in the reaction chamber, the solution cut by the liquid cutting tube at the reaction chamber interface was collected and re-collected at the reaction chamber interface in a fixed amount. After 10 minutes, when the reaction was complete, the gold nanoparticles synthesized at the interface were separated and purified.

[0076] Figure 2 shows the morphology of the gold nanoparticles (d). Existing wet chemical synthesis methods have the problem of difficulty in obtaining uniform and independent gold nanoparticles around 200 nm in size. However, the nanoparticles produced by the manufacturing method of the present invention were uniform despite having an average size of 180 nm. Therefore, the separation process can be omitted. Furthermore, comparing the rate of temperature transfer, it can be seen that the reaction time is shortened with the manufacturing method of this patent (Figure 7).

[0077] Example 4. Production of palladium metal nanoparticles

[0078] 5 g of polymethyl methacrylate (PMMA, Sigma-aldrich) was dissolved in 40 g of DMF to obtain a PMMA solution. Subsequently, this solution was added to 0.5 g of palladium dichloride (PdCl2) in a mixing chamber and stirred at 600 RPM for 30 minutes. The prepared solution was subjected to the following steps: an applied voltage of 30 kV was applied via an injection tube, the distance between the reaction chamber and the end of the injection tube was 25 cm, and the temperature was 80°C to ensure that gas flowed rapidly between the interface inside the chamber and the liquid cutting tube. As the reaction of the solution took place in the reaction chamber, the solution cut at the interface of the reaction chamber and the liquid cutting tube was collected and re-collected at the interface of the reaction chamber in a fixed amount. After 2 hours, the reaction was terminated, and the reactants were transferred to an alumina (Al2O3) crucible and treated at 400°C for 1 hour to obtain palladium metal nanoparticles.

[0079] Figure 2 shows a scanning electron microscope image of palladium metal nanoparticles (e). As shown in the figure, it was confirmed that the palladium metal nanoparticles were very uniformly distributed with an average size of 205 nm. Furthermore, comparing the rate of temperature transfer, it can be seen that the reaction time is shortened by the manufacturing method of this patent (Figure 8).

[0080] Example 5. Preparation of Pyropheophorbide-α methyl ester (MPPa)

[0081] All glassware was washed with acetone and then dried, or dried at 60°C, before use. First, the general synthesis method for pyropheophorbide a methyl ester (MPPa) as a control group was carried out as follows: 2N hydrochloric acid was prepared by adding DI water to 173 mL of 35% hydrochloric acid until the final volume was 1 L. Next, 1 g of methylpheophorbide a (MPPa) and 100 ml of 2,4,6-trimethylpyridine were mixed and stirred at 175°C for 3 hours. Then, the mixture was washed with the same amount of 2N hydrochloric acid and dichloromethane, and the mixture was subjected to vacuum distillation with an organic solvent layer. Subsequently, for purification, the inlet of the column tube was blocked with a small amount of cotton, and sea sand was poured onto the cotton until the curved surface of the lower end of the column was filled. Next, silica powder was placed in a 5L tall beaker, hexane was added, and the well-mixed liquid phase was packed into the column tube to a height of 2 / 3. When the hexane level reached the height of the silica, the compound dissolved in the solvent was slowly loaded along the wall. Then, sea sand was packed to the height of the compound layer, and after purification using a mobile phase solvent (acetone:dichloromethane = 2:98), the powder was obtained by vacuum distillation.

[0082] Next, the method for synthesizing MPPa using the manufacturing method of this patent was carried out as follows: 1 g of MPa and 100 ml of 2,4,6-trimethylpyridine were added to the mixing chamber and vortexed at 20 J / s. The prepared solution was subjected to a step in which gas flowed rapidly between the interface inside the chamber and the liquid cutting tube at a voltage of 30 kV, a distance of 25 cm between the reaction chamber and the end of the injection tube, and 175°C. While the reaction of the solution took place in the reaction chamber, the solution cut at the interface of the reaction chamber and the liquid cutting tube was collected and collected again at the interface of the reaction chamber in a fixed amount. After 1 hour, when the reaction was complete, the reactants synthesized at the interface were washed with equal amounts of 2N hydrochloric acid and dichloromethane, and then subjected to vacuum distillation with an organic solvent layer. Subsequently, column chromatography for purification was performed in the same manner as above. The purified MPPa was obtained using tetramethylsilane (TMS), which is inactive to the sample and organic solvent, as a reference substance. 1 The absorbance was confirmed by analyzing the 1H-NMR spectrum and dissolving the powder in dichloromethane, which dissolves the powder well. In addition, HPLC analysis of MPPa revealed a purity of 95.4% (Figure 9a).

[0083] Figure 9 shows the UV-Vis spectrum of MPPa synthesized by the manufacturing method of this patent (Figure 9b). Five major peaks are clearly visible at λmax(CH2Cl2) / nm 667 (rel.intensity 0.457), 610 (0.078), 540 (0.092), 508.5 (0.106), and 413.5 (1.108). The positions of these NMR peaks indicate that MPPa was synthesized (Figure 10). 1 H-NMR (500 MHz, DMSO, TMS) int )δ H , ppm 9.57(1H, s, 5-H), 9.39(1H, s, 10-H), 8.75(1H, s, 20-H), 8.10(1H, m, 3 1 -CH), 6.34 and 6.21 (each 1H, dd, 3 2 -CH2), 5.15(2H, q, 13 2-CH2), 4.56 (1H, m, 18-CH), 4.31 (1H, m, 17-CH), 3.63 (3H, s, 17 4 -OCH3), 3.56 (3H, s, 12 1 -CH3), 3.44 (3H, s, 2 1 -CH3), 3.23 (3H, s, 7 1 -CH3), 2.77 - 2.62 (2H, m, 17 1 -CH2), 2.47 - 2.31 (2H, m, 17 2 -CH2), 1.81 (3H, d, 18 1 -CH3), 1.67 (3H, t, 8 2 -CH3), 0.28 and -1.91 (each 1H, br, s, 2 X NH). Also, when comparing the case of manufacturing by the existing bulk method and the case of manufacturing by the cutting liquid method, it can be seen that the reaction starts faster with the manufacturing method of this patent (Figure 11).

[0084] Example 6. Production of Paclitaxel Analogs

[0085] Docetaxel (DTX) is a taxane-based anticancer agent used in the treatment of breast cancer, head and neck cancer, gastric cancer, prostate cancer, and non-small cell lung cancer, and can be used alone or in combination with other chemotherapeutic drugs. The inventors of the present invention referred to Patent No. 10-2007-0062533 and applied it to a new invention technology. Summarizing the manufacturing method, first, 16 g of compound (I) prepared in a mixing chamber was dissolved in a 1:1 mixture (320 ml) of anhydrous alcohol (EtOH) and methyl chloride (DCM), and 5.27 g (in 5 ml of DCM) of di-tert-butyl dicarbonate (Boc2O) was added, and this was vortexed at 20 J / s.

[0086] [Structural Formula 1]

[0087] TIFF0007832714000001.tif3259

[0088] [Structural Formula 2]

[0089] TIFF0007832714000002.tif5174

[0090] Subsequently, the reaction mixture was stirred at room temperature for 16 hours. DCM was removed by vacuum distillation, and 0.39 ml of acetic acid was added to the solution. The acidic ethanol solution was heated to 50°C, and 320 ml of ultrapure water was added dropwise. The prepared solution was subjected to the following steps: an applied voltage of 30 kV was applied through an injection tube, the distance between the reaction chamber and the end of the injection tube was 25 cm, and the gas flowed rapidly between the inner interface of the chamber and the liquid cutting tube at 50°C. While the reaction of the solution took place in the reaction chamber for 10 minutes, the solution cut at the interface of the reaction chamber and the liquid cutting tube was collected and allowed to re-collect at the interface of the reaction chamber in a certain amount, and this was left at room temperature for an additional 2 hours. The precipitate was filtered through a sintered glass filter, then transferred to a vacuum oven and maintained under vacuum at 40°C for 16 hours to obtain 16.75 g of semi-purified docetaxel.

[0091] Subsequently, the semi-purified docetaxel was dissolved in 95% ethanol (160 ml) at 50°C, and then acetic acid (0.39 ml) was added. After the addition of ultrapure water (320 ml), the prepared solution was subjected to the following steps: an applied voltage of 30 kV via an injection tube, a distance of 25 cm between the reaction chamber and the end of the injection tube, and a high-speed gas flow between the inner interface of the chamber and the liquid cutting tube at 50°C. While the solution reacted in the reaction chamber for 10 minutes, the solution cut at the interface of the reaction chamber and the liquid cutting tube was collected and allowed to re-collect at the interface of the reaction chamber in a fixed amount, and then left to stand for an additional 2 hours at room temperature. The precipitate was filtered through a sintered glass filter and maintained under vacuum at 40°C for 16 hours to obtain 15.25 g of docetaxel. The second crystallization was carried out by dissolving the product in acetone (150 ml) at 30°C and mixing it with 150 ml of heptane. The mixture was left at room temperature for 3 hours, filtered through a sintered glass filter, and then dried under vacuum at 40°C for 16 hours. Finally, 13.9 g of docetaxel was obtained (HPLC confirmation: purity higher than 99.4%, <0.1% 7-epi docetaxel, <0.1% 10-dehydrodocetaxel), and the synthesis was confirmed by UV spectroscopy (Figure 12c).

[0092] [Structural formula 3]

[0093] TIFF0007832714000003.tif5479

[0094] As can be seen in Figure 4a, docetaxel synthesized by the manufacturing method of this patent increased the cancer cell death rate as the treatment concentration increased. This is a result of docetaxel binding to β-tubulin on microtubules. Furthermore, comparing the synthesis method with the existing bulk method and the liquid cleavage method, it can be seen that the reaction starts faster with the manufacturing method of this patent (Figure 12).

[0095] Example 7. Melting test of hypromellose for tablet dosage form

[0096] 1 g of hydroxypropyl methylcellulose (H8384, SA) was placed in a mixing chamber either alone or together with 100 mg of MPPa prepared using the manufacturing method of this patent, and 20 g of 50% DMSO solution was added and vortexed at 90 J / s. The mixture was subjected to a procedure where a voltage of 10 kV was applied via an injection tube, the distance between the reaction chamber and the end of the injection tube was 25 cm, and the temperature was 178.9°C, ensuring that gas flowed rapidly between the interface inside the chamber and the liquid cutting tube. As the solution reaction took place in the reaction chamber, the solution cut at the interface of the reaction chamber and the liquid cutting tube was collected and re-collected at the interface of the reaction chamber in a fixed amount. After 1 hour, when the reaction was complete, the molten reactants at the interface were removed and filtered with ultrapure water. The mixture was then dried for 24 hours to obtain a paste, which was stored. Some of the hydroxypropyl methylcellulose granules or MPPa mixed granules during storage were extruded and tableted at 50°C (Figure 2f).

[0097] Furthermore, to manufacture rifaximin tablets, a mixture containing 200 mg of rifaximin, 30 mg of sodium starch glycolate (type A), 10 mg of disodium edetate hydrate, and 12 mg of hydroxypropyl methylcellulose 2910 (viscosity of about 4,000 cP, 2% in H2O (20℃) (lit.), SA) (or the aforementioned MPPa mixed granules) was placed in a high-shear mixing granulator and mixed for 5 minutes. Then, 213 mg of ultrapure water was added and mixed for 15 minutes. The reaction mixture was left at 40℃ for 24 hours to dry and then sieved through a 2 mm sieve. The dried granules were then transferred to a servolift bin blender, and 15 mg of colloidal silica (anhydrous) and 4 mg of stearic acid were added together. The blender was set to 6 RPM and mixing was terminated after 20 minutes. Subsequently, the granules were transferred to a tablet press (Korsch EK0 tablet press) for the compression stage. The resulting slag was then sieved through a 1.6 mm screen. The sieved slag was transferred to a mixer (Servolift bin blender), 4 mg of stearic acid was added to the mixer, the mixer was set to 6 RPM, and mixing was completed after 20 minutes. The slag was then transferred to a tablet press (Korsch Ph 106 tablet press) and rifaximin tablets were formed under a pressure of 20 kN. Additionally, the rifaximin tablets were placed in a coating machine (BYC-400), and 12 mg of hydroxypropyl methylcellulose (H8384, SA), 1.2 mg of polyethylene glycol 6000, 0.8 mg of titanium dioxide, 1 mg of talc, and 100 mg of ultrapure water were added. The inlet air was set to 50°C, and the tablets were coated for 70 minutes (Figure 2, g).

[0098] The melting point of hydroxypropyl methylcellulose (viscosity of 40-60 cP, 2% in H2O (20°C) (lit.), H8384, SA) is 178.9°C. In a mixture containing hydroxypropyl methylcellulose, the viscosity increases as the concentration of hydroxypropyl methylcellulose increases, making it more difficult to dissolve. In this case, increasing the temperature makes melting easier. As shown in Figure 13, it can be seen that there is a difference between the rate of dissolution in the bulk solution and the rate of dissolution in the cutting liquid, due to the difference in temperature rise. In this case, it can be seen that the cutting liquid reaches the target temperature even faster due to the difference in surface area, and this result shows that when melting hydroxypropyl methylcellulose by the method of the present invention, the time can be reduced compared to the control group.

[0099] Example 8. Production of antibody-drug conjugates

[0100] First, antibody reduction-alkylation was performed as follows: Panitumumab (from Vectibix) was added to a concentration of 10 mg / mL by exchanging the buffer with 25 mM sodium borate pH 8, 25 mM NaCl, 5 mM EDTA, and 10 mM TCEP, until the concentration was 8 moles of TCEP per mole of antibody, after which 10 mM TCEP was added. The mixture was then stirred at 40°C for 2 hours. To remove unreacted material, the mixture was filtered through a PD-10 column with ice-cold 40 / 60 (% v / v) DMSO / 0.1 M Tris-HCl pH 8 and 1 mM EDTA (Tris / DMSO buffer). Subsequently, the antibody was condensed using a 30 kDa MWCO Amicon filter.

[0101] Next, the linker-anticancer agent was prepared as follows: In the mixing chamber of the present invention, 29.4 g of maleic anhydride and 39.35 g of 6-aminocaproic acid were reacted in 900 mL of glacial acetic acid for 16 hours. Then, 30.6 g of acetic anhydride was added dropwise over 2 hours, followed by stirring for 1 hour. Subsequently, for the solvent removal reaction, the solution was subjected to the following steps: an applied voltage of 30 kV through an injection tube, a distance of 25 cm between the reaction chamber and the end of the injection tube, and a high-speed gas flow between the interface inside the chamber and the liquid cutting tube at 70°C. After 20 minutes, the solid was collected from the reaction chamber and dried for 2 hours. 2.11 g of dried 6-maleimidohexanoic acid was dissolved in 200 mL of tetrahydrofuran, and 1 g of N-methylmorpholine was added, followed by stirring in a mixing chamber. The mixture was then transferred to a reaction chamber, and 1.36 g of isobutyl chloroformate solution was added dropwise. Additionally, 1.32 g of tert-butyl carbadate was added dropwise, and the mixture was reacted at 4°C for 30 minutes, followed by standing at room temperature for 1 hour. The organic layer was washed and removed by drying on anhydrous sodium sulfate. 545 mg of the final product was dissolved in 10 mL of cold trifluoroacetic acid, stirred in an ice bath for 8 minutes, and the resulting acid was removed. Subsequently, the samples were dried by column chromatography using methylene chloride-methanol-ammonium hydroxide (100:5:0.5) solvent.9.2 g of dried 6-maleimidocaproylhydrazide and 5.2 g of doxorubicin hydrochloride were mixed in 1750 mL of methanol, then 0.5 mL of trifluoroacetic acid was added and the mixture was stirred at room temperature for 24 hours. After leaving 250 mL at 31°C, 1250 mL of acetonitrile was added. The mixture was then left to stand at 4°C for 48 hours, separated by centrifugation, washed with methanol-acetonitrile, and dried.

[0102] The antibody and linker-anticancer agent (MC-DOXHZN) prepared as described above were conjugated using the following procedure: 10 mg of antibody was mixed with 23 mL of 10 mM DTT and reacted for 3 hours. The remaining DTT was removed by centrifugal dialysis, and then the mixture was reacted with an equal amount of 1 mole of MC-DOXHZN at 4°C for 30 minutes. The mixture was then filtered through a cellulose acetate membrane and washed using a Bio-Rad BioBeads SM-2 resin column. Finally, a conjugate with a concentration of 9.2 mg / mL was obtained.

[0103] Figure 14 shows the UV-Vis spectrum and dot blot analysis results of antibody-drug conjugates (ADCs) synthesized by the manufacturing method of this patent. The samples were subjected to non-reducing blotting without DTT or beta-mercaptoethanol to confirm the presence or absence of conjugation. As a result, fluorescence of DOX appeared in the antibody-drug conjugate, and a change in the UV-Vis spectrum was confirmed, so it can be considered that an ADC was produced (ADC = antibody-drug conjugate, DOX = doxorubicin, mAb = panitumumab). In terms of synthesis time, when comparing the manufacturing method with the existing bulk method and the cleavage liquid method, it can be seen that the reaction starts faster with the manufacturing method of this patent (Figure 15).

[0104] Although embodiments of the present invention have been described above with reference to the attached drawings, a person with ordinary skill in the art to which the present invention pertains will understand that the present invention can be implemented in other specific forms without changing its technical idea or essential features. Therefore, it should be understood that the embodiments described above are illustrative in all respects and not limiting. [Explanation of symbols]

[0105] 10 Mixture intake section

[0106] 11 Injection pipe

[0107] 12 Mixing chamber connection

[0108] 20 Air circulation system

[0109] 21 Air Inlet

[0110] 22 Air outlet

[0111] 30 Reaction Chamber

[0112] 31 Liquid cutting tube

[0113] 40 Product extraction section

[0114] 41 Discharge pipe

[0115] 42 Connecting chamber connection

Claims

1. In the manufacturing method of pharmaceuticals, (a) The step of introducing the synthesis material and solvent into a precursor mixing chamber connected to an injection pipe and swirling it; (b-1) The step of transferring the solution produced in step (a) to a reaction chamber connected to the mixing chamber; and (b-2) A method for producing a pharmaceutical product, comprising the step of causing a gas to flow through the interface of the reaction chamber and the liquid cutting tube, having a gap of 10 nm to 1000 μm, wherein the side angle of the inlet of the liquid cutting tube is 5° to 60° and the front angle is 5° to 60°, and a voltage of 5 kV to 60 kV is applied to the gas.

2. In a method for manufacturing a pharmaceutical product, (a) The step of introducing the synthesis material and solvent into a precursor mixing chamber connected to an injection pipe and swirling it; (b-1) The step of transferring the solution produced in step (a) to a reaction chamber connected to the mixing chamber; and (b-2) A method for producing a pharmaceutical product, comprising the step of causing a gas to flow through a liquid cutting tube and the interface of the reaction chamber having a gap of 10 nm to 1000 μm, wherein the angle between the interface of the reaction chamber and the liquid cutting tube is 0.25 rad to 0.85 rad, and a voltage of 5 kV to 60 kV is applied to the gas.

3. The method for producing a pharmaceutical product according to claim 1 or 2, further comprising the step of (c) collecting the solution cut from the interface of the reaction chamber and the liquid cutting tube, and collecting a predetermined amount of the cut solution again at the interface of the reaction chamber.

4. The method for producing a pharmaceutical product according to claim 3, further comprising (d) separating or extracting the reactants synthesized from the interface of the reaction chamber and circulating them in a separate binding chamber to bind the target substance;

5. A method for producing a pharmaceutical product according to claim 1 or 2, wherein the pharmaceutical product is a nanoparticle, organic compound, inorganic compound, or nanopharmaceutical product for diagnostic or therapeutic purposes, and the nanoparticle or nanopharmaceutical product is characterized in that one or more selected from a photosensitizer, a first-generation anticancer agent, a second-generation anticancer agent, a third-generation anticancer agent, a nuclear medicine therapeutic drug, a metabolic anticancer agent, an enzyme, a gene therapy agent, and a near-infrared fluorescent dye are bound to the nanoparticle or nanopharmaceutical product.

6. The method for producing a pharmaceutical product according to claim 1 or 2, characterized in that the reaction chamber has a structure that includes an inlet and an outlet or a structure that is simple to open and close, so as to allow for smooth airflow.

7. The method for producing a pharmaceutical product according to claim 4, characterized in that the coupling chamber is connected to a circulation device by a tube having an annular structure or a continuous zigzag structure so as to enable circulation of the reactant obtained in step (c).

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