Manufacturing methods for pharmaceutical products with shorter production times and improved 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 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. [Background technology]

[0002] There have been many studies on wet chemical synthesis methods to synthesize nanomaterials. The basic parameters that affect the properties of nanomaterials are the reactant concentration, precursor pH, heating temperature, and reaction time.

[0003] The variables for synthesizing high-quality nanoparticles as products include narrow particle size distribution, crystal quality, the desired morphology of the product nanomaterial, sufficient supersaturation, careful selection of precursors, and concentration of stabilizer species, and these synthesis parameters play a key role in maintaining nanoparticles in a stable state for a long time. By successfully mixing each precursor on an atomic scale, the method based on this route can prepare materials with relatively good stoichiometry and sizes ranging from 1 nm to several microns, which can be easily stabilized using capping agents.

[0004] Below, we explain each category of wet chemical synthesis method that has been developed to date.

[0005] First, there is Chemical Bath Deposition Synthesis, where the reaction solution becomes supersaturated as a result of the chemical reaction, and solid precipitation occurs. There is 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 expensive and complicated technical equipment because it does not require a vacuum and is performed at low temperatures. There is also Chemical Co-precipitation Method, where precursors are dissolved and mixed separately, and then a precipitation reagent is mixed to grow nanoparticles. There is also Electrochemical Synthesis, where a nanocrystal thin film is deposited on a substrate in the presence of a substrate, two or three electrodes, a container electrolyte solution, and a current source, using an electric current as a driving force. There are also Solvothermal Synthesis, where physicochemical reactions are performed at high pressure and high temperature to synthesize nanoparticles in an organic solvent, and Hydrothermal Synthesis, where physicochemical reactions are performed in an aqueous solution. Then there is the Sol-Gel Synthesis, where a liquid (sol) is chemically transformed into a gel state and then condensed in the form of solid nanostructures, and still another synthesis method is the Microemulsion Synthesis, which is carried out using a homogeneous solution containing water, oil, surfactant, and amine-based or alcohol co-surfactant. This technique consists of a set of processes in a thermodynamically set colloidal system, which contains an isotropic mixture of a hydrophilic liquid (water), a lipophilic liquid (oil) and an amphiphilic surfactant (hydrophilic and hydrophobic groups).

[0006] Among these synthesis strategies, Berlin blue nanoparticles and its analogues have been reported to have a narrow size distribution, stabilized dispersion in the solution, and uniform morphology through double-precursor synthesis and hydrothermal synthesis. However, the double-precursor synthesis method has the disadvantages of being difficult to produce a uniform morphology and difficult to control the growth rate compared to hydrothermal synthesis, while hydrothermal synthesis has problems such as long synthesis time, needing an excessive amount of stabilizer, making it difficult to dissolve, and producing toxic substances as by-products. Gold nanoparticles are also synthesized by hydrothermal synthesis, which is produced at high temperatures using sodium citrate (Na3C6H5O7) as a reducing agent and surfactant. However, since it relies only on sodium citrate, it has the disadvantage that the reduced gold atoms are easily aggregated together. In addition, it is not easy to produce each particle in a uniform size quickly, so a method to finely adjust the nanoparticles needs to be devised.

[0007] Existing nanoparticle synthesis methods require expensive equipment, and it is difficult to produce nanoparticles with a relatively low production rate per hour and uniform size distribution. In addition, there are disadvantages in that harmful reactive gases such as chlorine gas and by-products are generated during particle generation, and it is difficult to produce nanoparticles composed of various materials due to the characteristics of producing particles in a molecular state, and there are disadvantages in that the manufacturing conditions and processes are complicated. In particular, during the transportation and final application of nanoparticles, there is a problem that aggregation occurs between each particle due to the surface effect of the nanoparticles, so additional processes are required to reprocess the nanoparticles by methods such as dispersion in a solution, re-grinding, or ultrasonic treatment, and in the case of metals, there is a problem of oxidation due to exposure. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] Korean Patent No. 10-1329646 Summary of the Invention [Problem to be solved by the invention]

[0009] The present invention has been 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 the particles are uniform in size, accumulation phenomena and oxidation reactions are minimized, the synthesis time is shortened, the yield within the same reaction time is improved, synthesis can be performed even at high temperatures, and various types of particles can be easily produced, as well as a method for producing synthetic drugs and biopharmaceuticals with an increased yield of the finished product.

[0010] The object of the present invention is not limited to the object mentioned above. The object of the present invention will become apparent from the following description and will be realized by the means and combinations thereof set forth in the claims. [Means for solving the problem]

[0011] The present invention provides a synthesis method in cutting liquid to solve the problem of heat transfer that takes a long time during synthesis, and has the effect of shortening the overall synthesis time;

[0012] One aspect of the present invention provides a method for producing nanoparticles or nanomedicines, comprising: (a) introducing synthesis materials and a solvent into a precursor mixing chamber connected to an injection pipe and swirling them; (b-1) transferring the solution produced in (a) to a reaction chamber 30 connected to the mixing chamber; and (b-2) allowing gas to flow at high speed between the interface of the reaction chamber 30 and a liquid cutting tube 31, which are separated by a gap of 10 nm to 1000 μm.

[0013] In one aspect of the present invention, a method for producing nanoparticles or nanomedicines is provided, the method further comprising the step of (c) collecting the solution cut at the interface of the reaction chamber 30 and the liquid cutting tube 31 and allowing it to re-collect at the interface of the reaction chamber in a certain amount.

[0014] In one aspect of the present invention, a method for producing nanoparticles or nanomedicines is provided, the method further comprising the step of (d) separating or extracting the reactants synthesized at the interface and circulating them to bind to the target substance in a separate binding chamber.

[0015] In one aspect of the present invention, there is provided a method for producing nanoparticles or nanomedicine, 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, there is provided a method for producing nanoparticles or nanomedicines, wherein in step (b-2), the gas is designed to flow at a high speed by voltage, and the gas flows at a high speed at an applied voltage of 5 kV to 60 kV.

[0017] In one aspect of the present invention, there is provided a method for producing nanoparticles or nanomedicines, wherein the boundary surface of the reaction chamber and the liquid cutting tube are 0.25 rad to 0.85 rad.

[0018] In one aspect of the present invention, there is provided a method for producing nanoparticles or nanomedicine, wherein in step (b-2), the gap is 500 nm to 1500 nm.

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

[0020] Another aspect of the present invention provides a nanoparticle or nanomedicine produced according to any one of the above aspects of the present invention. Effect of the Invention

[0021] The synthesis method of the present invention provides a method designed to allow for rapid synthesis of drugs by continuously breaking down bulk liquid into smaller cut liquids, accelerating the transfer of heat, thereby facilitating dissolution of poorly soluble materials and increasing the rate of synthesis of the compound.

[0022] According to the synthesis method in a cutting liquid depending on the gas flow rate of the present invention, the particle size is uniform, the accumulation phenomenon and oxidation reaction are minimized, the synthesis time is shortened, the yield is improved within the same reaction time, synthesis is possible even at high temperatures, and it is easy to produce various types of particles with a simple manufacturing process, so that it is possible to economically produce and provide high-quality nanoparticles and chemical drugs.

[0023] The production method according to one aspect of the present invention can improve the water solubility of the produced poorly water-soluble substance compared to existing methods.

[0024] The method according to one aspect of the present invention can improve the stability of the produced material compared to existing methods.

[0025] The effects of the present invention are not limited to those mentioned above, and should be understood to include all effects that can be inferred from the following description. [Brief description of the drawings]

[0026] [Figure 1] FIG. 1 illustrates the concept of the present invention and the structure of a synthesis device.

[0027] [Diagram 2] FIG. 1 shows the structure of the synthesized final product.

[0028] [Figure 3a-3c] FIG. 13 shows the temperature rotation results of the device and the time it takes for the mixed solution to reach the target temperature.

[0029] [Figure 4a-4i] FIG. 1 shows the results of analyzing the effect of killing cancer cells.

[0030] [Diagram 5] FIG. 1 is a diagram showing an image of cancer cells subjected to phototherapy (Photomedicine).

[0031] [Figure 6a-6b] FIG. 13 is a graph showing the results of the time it takes for a cerium mixed solution to reach a target temperature.

[0032] [Figure 7a-7b] FIG. 13 is a graph showing the results of the time it takes for a gold ion mixed solution to reach a target temperature.

[0033] [Figure 8a-8b] FIG. 13 is a graph showing the results of the time it takes for a palladium mixed solution to reach a target temperature.

[0034] [Figure 9a-9b] FIG. 1 shows the purity and UV-Vis spectrum of MPPa synthesized by the manufacturing method of this patent.

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

[0036] [Figure 11a-11b] FIG. 1 shows the results of the time it takes for a mixed solution of methyl pheophorbide a to reach a target temperature.

[0037] [Fig. 12a-12c] FIG. 13 shows the results of the time it takes for a docetaxel mixed solution to reach a target temperature.

[0038] [Figure 13a-13b] FIG. 1 shows the results of the time it takes for a hypromellose mixed solution to reach a target temperature.

[0039] [Figure 14a-14b] FIG. 1 shows UV-Vis spectra and dot blot analysis results of antibody-drug conjugates.

[0040] [Figure 15a-15b] FIG. 1 is a graph showing the time required for a 6-maleimidocaproic acid mixed solution to reach a target temperature. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0041] The above objects, other objects, features, and advantages of the present invention can be easily 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 described herein are provided so that the disclosed content is thorough and complete, and to fully convey the concept of the present invention to those skilled in the art.

[0042] In this specification, terms such as "comprise" or "have" are intended to specify the presence of features, numbers, steps, operations, components, parts, or combinations thereof described in the specification, but should be understood as not precluding the presence or additional possibility of one or more other features, numbers, steps, operations, components, parts, or combinations thereof.

[0043] Unless otherwise indicated, all numbers, values ​​and / or expressions expressing amounts of ingredients, reaction conditions, polymer compositions and formulations used herein should be understood in all cases as being modified by the term "about" since these numbers, among other things, are approximations that reflect the various uncertainties of measurement that occur in obtaining such values. Also, when ranges of values ​​are disclosed in this description, such ranges are continuous and include all values ​​included from the minimum value to the maximum value of such range, unless otherwise indicated. Furthermore, when such ranges refer to integers, they include all integers included from the minimum value to the maximum value, unless otherwise indicated.

[0044] When a range is recited herein for a variable, the variable may be understood to include all values ​​within the recited range, including each of the endpoints of the range recited. 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, etc., and any value between each of the reasonable integers within the recited range, such as 5.5, 6.5, 7.5, 5.5 to 8.5, and 6.5 to 9. Also, for example, the range "10% to 30%" may be understood to include not only values ​​such as 10%, 11%, 12%, 13%, etc., and all integers up to and including 30%, but also any subranges such as 10% to 15%, 12% to 18%, 20% to 30%, and any value between each reasonable integer within the stated range, such as 10.5%, 15.5%, 25.5%, etc.

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

[0046] In the synthesis of compounds, heat is an important factor that facilitates the melting and dissolution of chemical substances and determines the synthesis rate. In addition, in the synthesis of drugs, the yield, amount of by-products, uniformity, etc. change depending on the heat transfer rate. For this reason, manufacturers are trying to control heat in the synthesis process. One fact is that heat flows faster in a liquid with a smaller volume than in a bulk liquid (solution or mixture). Treatments needed for pandemic diseases such as COVID-19 need to be synthesized in bulk units, but as the volume increases, problems arise in synthesis time, yield, and uniformity. Furthermore, producing a large amount of products in small units increases purification time and installation costs. As a method to solve such problems, the synthesis method of the present invention is a method designed to enable fast synthesis of drugs by continuously making the bulk liquid into small cut liquids, accelerating heat transfer and increasing the synthesis rate.

[0047] In addition, the present invention has been devised by improving the synthesis method in a cutting liquid that depends on gas flow rate in order to solve the problems in the production, storage and application of the above-mentioned organic or inorganic nanoparticles and chemical drugs, and aims to provide a method for producing organic or inorganic nanoparticles and nanopharmaceuticals in which the particles are uniform in size, accumulation phenomena and oxidation reactions are minimized, the synthesis time 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 with an increased yield of the finished product.

[0048] The present invention relates to a method for shortening the production time of chemical substances and for uniformly producing pharmaceuticals. In addition, the present invention relates to a nano-drug carrier and a method for producing the same, which enhances the water solubility of drugs and helps drugs to exert their intended efficacy. Metal-organic framework (MOF) nanoparticles that can be stabilized for a long period of time in various sterilized aqueous solutions frequently used in biological experiments and medicine have been produced by a synthesis method in a cutting liquid that depends on a gas flow rate, which has not been used in wet chemical synthesis methods. Compared with the existing method for producing MOF nanoparticles, the nanoparticles produced by the production method of the present invention can increase the water solubility of pyropheophorbide-a methyl ester, a poorly soluble photosensitizer, and the phototherapy effect on cancer cells has also increased. In addition, the synthesis method of the present invention can provide the effect of shortening the production time of drugs produced by existing chemical synthesis and biopharmaceuticals produced by binding.

[0049] The method for producing nanoparticles or pharmaceuticals according to the present invention may include: (a) a step of vortexing synthesis materials and a solvent in a precursor mixing chamber connected to an injection pipe; (b) a step of transferring the prepared solution to a reaction chamber connected to the mixing chamber; and a step of allowing a gas to flow at high speed between the boundary surface of the chamber and a liquid cutting tube, which are separated by a gap of tens of nanometers to hundreds of micrometers.

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

[0051] In one embodiment, the liquid cutting tube has an inlet with a side angle of 5° to 60° and a front angle of 5° to 60°.

[0052] In one embodiment, the reaction chamber has a structure with an inlet and an outlet or a simple structure that can be opened and closed to facilitate smooth air flow.

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

[0054] In one embodiment, the nanoparticles produced by the above manufacturing method are diagnostic or therapeutic nanomedicines characterized in that they are combined in one or more configurations of a photosensitizer, a first generation anticancer drug, a second generation anticancer drug, a third generation anticancer drug, a nuclear medicine therapeutic drug, a metabolic anticancer drug, an enzyme, a gene therapy drug, 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 that does not cause the solvent to completely evaporate; the drug is characterized by being synthesized in a smaller volume and in a shorter time than a drug produced without the above apparatus.

[0056] In one embodiment, the biopharmaceutical has a structure in which one or more of a drug, a nucleic acid-based molecule, an amino acid-based antibody, a specific binding protein, and an enzyme group with high biological safety are bound together by the above manufacturing method.

[0057] Various aspects of the invention will now be described.

[0058] One aspect of the present invention provides a method for producing nanoparticles or nanomedicines, comprising: (a) introducing synthesis materials and a solvent into a precursor mixing chamber connected to an injection pipe and swirling them; (b-1) transferring the solution produced in (a) to a reaction chamber 30 connected to the mixing chamber; and (b-2) allowing gas to flow at high speed between the interface of the reaction chamber 30 and a liquid cutting tube 31, which are separated by a gap of 10 nm to 1000 μm.

[0059] In one aspect of the present invention, a method for producing nanoparticles or nanomedicines is provided, the method further comprising the step of (c) collecting the solution cut at the interface of the reaction chamber 30 and the liquid cutting tube 31 and allowing it to re-collect at the interface of the reaction chamber in a certain amount.

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

[0061] In one aspect of the present invention, there is provided a method for producing nanoparticles or nanomedicine, 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, there is provided a method for producing nanoparticles or nanomedicines, wherein in step (b-2), the gas is designed to flow at a high speed by voltage, and the gas flows at a high speed at an applied voltage of 5 kV to 60 kV.

[0063] In one aspect of the present invention, there is provided a method for producing nanoparticles or nanomedicines, wherein the boundary surface of the reaction chamber and the liquid cutting tube are 0.25 rad to 0.85 rad.

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

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

[0066] Another aspect of the present invention provides a nanoparticle or nanomedicine produced according to any one of the above aspects of the present invention. EXAMPLES

[0067] The present invention will be described in more detail with reference to the following specific examples. The following examples are merely illustrative for the purpose of facilitating understanding of the present invention, and are not intended to limit the scope of the present invention.

[0068] Example 1. Preparation of Berlin Blue Nanoparticles and Nanomedicine

[0069] Polyvinylpyrrolidone (PVP, Sigma-Aldrich) 1 g was dissolved in 20 g of ultrapure water and stirred at 1500 RPM for 30 min in a mixing chamber to obtain an aqueous PVP solution. Potassium hexacyanoferrate(III) trihydrate was then added. 131.7 mg of trihydrate (K3Fe(CN)6·3H2O, Sigma-aldrich) was dissolved in 20 g of ultrapure water and mixed with the PVP aqueous solution. 400 μL of 1 M HCl (Sigma-aldrich) was then added to the mixing chamber and vortexed at 60 J / s. The solution was subjected to a step of making gas flow at high speed at the boundary surface inside the chamber and the liquid cutting tube at 140 °C, with an applied voltage of 30 kV through the injection tube, a distance of 25 cm between the reaction chamber and the end of the injection tube, and an applied voltage of 30 kV through the injection tube. As shown by the green arrow in Figure 1, the gas moves to the upper layer of the reaction chamber while passing through a structure in which the boundary surface of the reaction chamber and the liquid cutting tube are 0.29 rad and the boundary gap is 900 nm. The gas The solution produced by passing through the tube was cut into small pieces. The cut liquid was heated in the reaction chamber, and the movement of heat within the liquid caused a faster temperature rise than the bulk liquid of the same total volume (40 mL) (Figure 3). As the solution reaction took place in the reaction chamber, the cut solution was collected at the interface of the reaction chamber and the liquid cutting tube, and a certain amount of it re-gathered at the interface of the reaction chamber. After the reaction was completed after 3 hours, the reactants synthesized at the interface were extracted through centrifugation and washed with water. The washed resultant was then pumped and moved to the binding chamber, where it was circulated to bind 2 mg of docetaxel (DTX) or pyropheophorbide-a methyl ester (MPPa). The completed sample was washed three times with methanol and distilled water, dried, and produced into a nanomedicine with a diameter of 200 nm. To confirm the cancer cell killing efficiency, cells cultured for 24 hours in a 96-well plate were treated with various concentrations of nanomedicines.The photothermal effect of the drug was confirmed by irradiating the subject with a 808nm laser at a voltage of 9.26V (corresponding to 1W / cm^2), a distance of 8.54cm between the subject and the laser, and a spot area (optical fiber itself) diameter of 3.5cm for 2 minutes, and was performed with a CCK8 assay. The broad-spectrum therapeutic effect of the drug was confirmed by irradiating the subject with a 660nm laser (ThorLabs, ED1-C50-MD, θ1.0” 50°circle, TOP_HAT diffuser attached) at a voltage of 0.44V (corresponding to 1~2.3mW / cm^2), a distance of 16cm between the subject and the laser, and a spot diameter of 24cm for 10 minutes, and was performed with a CCK8 assay. The results of the CCK8 assay confirmed the effect of the anticancer drug in the nanodrug, and the effects of photothermal therapy (PTT) and photodynamic therapy (PDT) were also observed (Figure 4).

[0070] In Figure 2, the morphology of Berlin blue nanoparticles (a) produced by the manufacturing method of the present invention and the nanomedicine of Berlin blue nanoparticles bound to MPPa (b) can be seen, and in Figure 3, the time taken for the mixed solution to reach the boiling point can be seen; and in Figure 4, the killing effect on cancer cells (PANC-1) can be seen (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 PDT treatment after PTT). In addition, Figure 5 confirms that the nano-drug is taken up into cancer cells (cellular uptake) (a, b), that cancer cells are killed by Berlin Blue nanoparticles combined with an anti-cancer drug (DTX) (c, d), that the PDT effect of cancer cell death by Berlin Blue nanoparticles combined with MPPa (e, f), and that the PTT effect is also confirmed (g, h) (scale bar = 50 nm). These results prove that the manufacturing method of this patent can produce Berlin Blue nanoparticles; it takes less time to reach high temperatures compared to producing nanoparticles from the same weight of bulk liquid; and it is a method for producing a finished product with the function of a nanomedicine.

[0071] Example 2. Preparation of ceria nanoparticles

[0072] A 0.3 mol / L solution of diammonium cerium (IV) nitrate and a 0.6 mol / L solution of ammonium sulfate were added to the mixing chamber and swirled at 40 J / s. The solution was then subjected to a high-speed gas flow at the boundary surface inside the chamber and the liquid cutting tube at 230°C, with an applied voltage of 30 kV and a distance of 25 cm between the reaction chamber and the end of the injection tube through the injection tube. As the reaction of the solution took place in the reaction chamber, the solution cut at the boundary surface of the reaction chamber and the liquid cutting tube was collected and re-collected at the boundary surface of the reaction chamber in a certain amount. After one hour, when the reaction was completed, the reactants synthesized at the boundary were extracted through centrifugation and washed with water.

[0073] The morphology of ceria nanoparticles can be seen in Figure 2 (c). In the previously developed method of reacting at 91°C for 3 hours, small particles of 50 nm had to be dried at a high temperature and then heat-treated at 800°C. This method also has the problem that it is difficult to obtain uniform and independent particles. In contrast, in the manufacturing method of the present invention, the nanoparticles have a uniform average size of 160 nm and the reaction time is shorter based on a total volume of 100 mL (Figure 6).

[0074] Example 3. Preparation of gold nanoparticles

[0075] 20 mL of 1 mM HAuCl4 aqueous solution was transferred to the mixing chamber, and then transferred to the reaction chamber through the injection tube, and a step of making gas flow at high speed at the boundary surface inside the chamber and the liquid cutting tube was performed at 110 °C with an applied voltage of 30 kV, a distance of 5 cm between the reaction chamber and the end of the injection tube, and 2 mL of 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. While the reaction of the mixed solution was taking place in the reaction chamber, the solution cut at the boundary surface of the reaction chamber and the liquid cutting tube was collected and re-collected at the boundary surface of the reaction chamber in a certain amount. After 10 minutes, when the reaction was completed, the gold nanoparticles synthesized at the boundary were separated and purified.

[0076] The morphology of gold nanoparticles can be seen in Figure 2 (d). With existing wet chemical synthesis methods, it was difficult to obtain uniform and independent gold nanoparticles of around 200 nm, but the nanoparticles produced by the manufacturing method of the present invention were uniform, with an average size of 180 nm. This makes it possible to omit the separation process. Also, when comparing the rate of temperature increase, it can be seen that the reaction time is shortened with the manufacturing method of this patent (Figure 7).

[0077] Example 4. Preparation of palladium metal nanoparticles

[0078] 5g of polymethyl methacrylate (PMMA, Sigma-aldrich) was dissolved in 40g of DMF to obtain a PMMA solution. The solution was then added to 0.5g of palladium dichloride (PdCl2) in a mixing chamber, which was stirred at 600 RPM for 30 minutes. The solution was subjected to a step of flowing gas at high speed at the boundary surface inside the chamber and the liquid cutting tube at 80°C, with an applied voltage of 30kV through the injection tube, a distance of 25cm between the reaction chamber and the end of the injection tube, and an applied voltage of 30kV through the injection tube. While the reaction of the solution was taking place in the reaction chamber, the solution cut by the boundary surface of the reaction chamber and the liquid cutting tube was collected and re-collected at the boundary surface of the reaction chamber in a certain 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 distributed very uniformly with an average size of 205 nm. In addition, by comparing the rate of temperature increase, 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-a methylester (MPPa)

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

[0082] The synthesis method of MPPa using the manufacturing method of this patent was carried out as follows. 1g of MPa and 100ml of 2,4,6-trimethylpyridine were added to a mixing chamber, and this was swirled at 20 J / s. The solution produced was subjected to a step of flowing gas at a high speed at the boundary surface inside the chamber and the liquid cutting tube at 175°C, with an applied voltage of 30 kV through the injection tube, a distance of 25 cm between the reaction chamber and the end of the injection tube, and an injection tube. While the reaction of the solution was carried out in the reaction chamber, the solution cut by the boundary surface of the reaction chamber and the liquid cutting tube was collected and re-collected at the boundary surface of the reaction chamber in a certain amount. Then, after 1 hour, when the reaction was completed, the reactant synthesized at the boundary was washed with the same amount of 2N hydrochloric acid and dichloromethane, and the organic solvent layer was collected and distilled under reduced pressure. Then, column chromatography for purification was carried out in the same manner as above. The purified MPPa was analyzed using tetramethylsilane (TMS), which is inactive to the sample and organic solvent, as a reference substance. 1 The absorbance was confirmed by dissolving the powder in dichloromethane, which is a good solubility for the powder, using H-NMR. In addition, the HPLC analysis of MPPa showed that it had 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). λmax(CH2Cl2) / nm 667 (rel.intensity 0.457), 610 (0.078), 540 (0.092), 508.5 (0.106), 413.5 (1.108); five main peaks are clearly visible, and the positions of the NMR peaks indicate that MPPa has been synthesized (Figure 10). 1 H-NMR (500MHz, 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). In addition, when comparing the case where it is produced by the existing bulk method with the case where it is produced by the cutting liquid method, it can be seen that the reaction starts faster with the production method of this patent (Figure 11).

[0084] Example 6. Preparation of Paclitaxel Analogues

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

[0086] [Structural formula 1]

[0087] TIFF2024546440000002.tif3259

[0088] [Structural formula 2]

[0089] TIFF2024546440000003.tif5174

[0090] The reaction mixture was then stirred at room temperature for 16 hours. DCM was removed by distillation under reduced pressure, 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 solution was subjected to a step of flowing gas at high speed at the interface inside the chamber and the liquid cutting tube at 50°C, with an applied voltage of 30 kV through the injection tube, a distance of 25 cm between the reaction chamber and the end of the injection tube, and an injection tube. The reaction of the solution was carried out in the reaction chamber for 10 minutes, and 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 certain amount, which was then left at room temperature for an additional 2 hours. The precipitate was filtered through a sintered glass filter, transferred into a vacuum oven, and maintained at 40° C. under vacuum for 16 hours to obtain 16.75 g of semi-purified Docetaxel.

[0091] Then, the semi-purified docetaxel was dissolved in 95% ethanol (160 ml) at 50°C, and acetic acid (0.39 ml) was added. After adding ultrapure water (320 ml), the solution was subjected to a step of flowing gas at high speed at the boundary surface inside the chamber and the liquid cutting tube at 50°C, with an applied voltage of 30 kV through the injection tube, a distance of 25 cm between the reaction chamber and the end of the injection tube, and the reaction chamber. The reaction of the solution was carried out in the reaction chamber for 10 minutes, and the solution cut at the boundary surface of the reaction chamber and the liquid cutting tube was collected and allowed to re-collect at the boundary surface of the reaction chamber in a certain amount, and then left at room temperature for an additional 2 hours. The precipitate was filtered through a sintered glass filter and maintained at 40°C under vacuum for 16 hours to obtain 15.25 g of docetaxel. The second crystallization was carried out by mixing the product dissolved in acetone (150 ml) at 30° C. with 150 ml of heptane. The mixture was left at room temperature for 3 hours, filtered through a sintered glass filter, and 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 through UV spectrum (FIG. 12c).

[0092] [Structural formula 3]

[0093] TIFF2024546440000004.tif5479

[0094] As can be seen from Figure 4a, docetaxel synthesized by the patented manufacturing method increased the death rate of cancer cells as the treatment concentration increased. This is the result of docetaxel binding to β-tubulin of microtubules. In addition, when comparing the synthesis method produced by the existing bulk method with the cutting liquid method, it can be seen that the reaction starts faster with the patented manufacturing method (Figure 12).

[0095] Example 7. Melt testing of hypromellose for tablet dosage form

[0096] 1 g of hydroxypropyl methylcellulose (H8384, SA) was placed in a mixing chamber alone or with 100 mg of MPPa prepared by the manufacturing method of this patent, and vortexed with 20 g of 50% DMSO solution at 90 J / s. The mixed solution was subjected to a step of flowing gas at high speed at the boundary surface inside the chamber and the liquid cutting tube at 178.9 °C with an applied voltage of 10 kV through the injection tube, a distance of 25 cm between the reaction chamber and the end of the injection tube, and a temperature of 178.9 °C. While the reaction of the solution was taking place in the reaction chamber, the solution cut by the boundary surface of the reaction chamber and the liquid cutting tube was collected and re-collected at the boundary surface of the reaction chamber in a certain amount. After 1 hour, when the reaction was completed, the reactant melted at the boundary was taken out and filtered with ultrapure water. It was then dried for 24 hours to obtain a paste and stored. Some of the hydroxypropyl methylcellulose granules or MPPa mixed granules stored were extruded at 50 °C and tableted (Fig. 2 f).

[0097] Also, to prepare 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°C) (lit.), SA) (or the MPPa mixed granules) was mixed in a high shear mixer granulator for 5 minutes. Then, 213 mg of ultrapure water was added and mixed for 15 minutes. The reaction mixture was left to dry at 40°C for 24 hours and sieved through a 2 mm sieve. The dried granules were then transferred to a servolift bin blender, where 15 mg of colloidal silica (anhydrous) and 4 mg of stearic acid were added. The mixer was set at 6 RPM, and mixing was stopped after 20 minutes. The granules were then transferred to a tablet press (Korsch EKO tablet press) for compression. The resulting slugs were then sieved through a 1.6 mm screen. The sieved slugs were transferred to a blender (servolift bin blender), 4 mg of stearic acid was added to the blender, the blender was set at 6 RPM, and the blending was stopped after 20 minutes. The slugs were then transferred to a tablet press (Korsch PH 106 tablet press) and made into rifaximin tablets under a pressure of 20 kN. Additionally, the rifaximin tablets were placed in a coating machine (BYC-400) and coated for 70 minutes after adding 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, and setting the inlet air to 50° C. (FIG. 2 g).

[0098] The melting point of hydroxypropyl methylcellulose (viscosity of 40-60cP, 2% in H2O (20℃) (lit.), H8384, SA) is 178.9℃. As the concentration of hydroxypropyl methylcellulose in a mixture containing hydroxypropyl methylcellulose increases, the viscosity also increases, making it difficult to melt. In this case, melting becomes easier when the temperature is increased. As shown in FIG. 13, it can be seen that there is a difference between the melting speed in the bulk solution and the melting speed in the cutting liquid due to the difference in temperature increase. In this case, it can be seen that the cutting liquid reaches the target temperature more quickly due to the difference in surface area, and this is a result that shows that when hydroxypropyl methylcellulose is melted by the method of the present invention, the time can be reduced compared to the control group.

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

[0100] First, antibody reduction-alkylation was performed as follows. Panitumumab (from Vectibix) was buffer exchanged with 25 mM sodium borate pH 8, 25 mM NaCl, 5 mM EDTA, 10 mM TCEP to a concentration of 10 mg / mL, and 10 mM TCEP was added to make 8 moles of TCEP per mole of antibody. 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, 1 mM EDTA (Tris / DMSO buffer). The antibody was then concentrated 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 and stirred for 1 hour. Then, for the solvent removal reaction, the solution was subjected to a step of flowing gas at a high speed at the boundary surface inside the chamber and the liquid cutoff tube at 70°C, with an applied voltage of 30 kV, a distance of 25 cm between the reaction chamber and the end of the injection tube, and an applied voltage of 30 kV. Then, after 20 minutes, the solid was collected from the reaction chamber and dried for 2 hours. 2.11g of dried 6-maleimidohexanoic acid was dissolved in 200mL of tetrahydrofuran, and 1g of N-methylmorpholine was added and stirred in a mixing chamber. The mixture was then transferred to a reaction chamber, and 1.36g of isobutyl chloroformate solution was added dropwise. Additionally, 1.32g of tert-butyl carbazate was added dropwise, reacted at 4°C for 30 minutes, and then left to stand at room temperature for 1 hour. The organic layer was washed, dried over anhydrous sodium sulfate, and removed. 545mg of the finished product was dissolved in 10mL of cold trifluoroacetic acid, stirred in an ice bath for 8 minutes, and the acid generated was removed. Then, the mixture was dried by column chromatography using a solvent of methylene chloride-methanol-ammonium hydroxide (100:5:0.5).9.2g of dried 6-Maleimidocaproylhydrazide and 5.2g of Doxorubicin hydrochloride were mixed in 1750mL of methanol, and then 0.5mL of trifluoroacetic acid was added and stirred at room temperature for 24 hours. Then, at 31℃, 1250mL of acetonitrile was added after leaving only 250mL. After waiting for 48 hours at 4℃, it was separated by centrifugation, washed with methanol-acetonitrile, and dried.

[0102] The antibody and linker-anticancer drug (MC-DOXHZN) prepared as above were conjugated by the following process. 10 mg of antibody was mixed with 23 mL of 10 mM DTT and reacted for 3 hours. Residual DTT was removed by centrifugal dialysis, and then reacted with the same amount of 1 mol of MC-DOXHZN at 4°C for 30 minutes. Then, it was filtered through a cellulose acetate membrane and washed using Bio-Rad's BioBeads SM-2 resin column. Finally, 9.2 mg / mL of the conjugate was obtained.

[0103] Figure 14 shows the UV-Vis spectrum and dot blot analysis results of the antibody-drug conjugate (ADC) synthesized by the manufacturing method of this patent. The sample was subjected to non-reducing blotting without DTT or beta-mercaptoethanol to confirm the presence or absence of conjugation. As a result, DOX fluorescence 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 created (ADC=antibody-drug conjugate, DOX=Doxorubicin, mAb=Panitumumab). In terms of synthesis time, it can be seen that the reaction starts faster with the manufacturing method of this patent when compared with the existing bulk method and the cutting liquid method (Figure 15).

[0104] Although the embodiments of the present invention have been described above with reference to the accompanying drawings, those skilled in the art will understand that the present invention can be embodied in other specific forms without changing the technical concept or essential features of the present invention. Therefore, it should be understood that the embodiments described above are illustrative in all respects and are not limiting. [Explanation of symbols]

[0105] 10 Mixture intake section

[0106] 11 Injection pipe

[0107] 12 Mixing chamber connection

[0108] 20 Air Circulation Device

[0109] 21 Air inlet

[0110] 22 Air outlet

[0111] 30 Reaction Chamber

[0112] 31 Liquid cutting tube

[0113] 40 Product discharge section

[0114] 41 Discharge pipe

[0115] 42 Combined chamber connection

Claims

1. In the manufacturing method of a pharmaceutical product, (a) adding synthesis materials and a solvent to a precursor mixing chamber connected to an injection pipe and swirling them; (b-1) transferring the solution prepared in (a) to a reaction chamber (30) connected to a mixing chamber; and (b-2) A step of making a gas flow at a high speed at the boundary surface of the reaction chamber (30) and the liquid cutting tube (31) that sandwich a gap of 10 nm to 1000 μm.

2. The method for producing a pharmaceutical product according to claim 1, further comprising the step of: (c) collecting the solution cut at the boundary surface of the reaction chamber (30) and the liquid cutting tube (31) and allowing it to re-gather at the boundary surface of the reaction chamber in a certain amount.

3. The method for producing a pharmaceutical product according to claim 2, further comprising the step of: (d) separating or extracting the reactants synthesized at the interface and circulating them to bind the target substance in a separate binding chamber.

4. The method for producing pharmaceutical products according to claim 1, wherein the inlet side angle of the liquid cutting tube (31) is between 5° and 60° and the front angle is between 5° and 60°.

5. The method for producing a pharmaceutical product according to claim 1, wherein in step (b-2), the gas is designed to flow at a high speed by a voltage, and the gas flows at a high speed with an applied voltage of 5 kV to 60 kV.

6. The method for producing a diagnostic or therapeutic pharmaceutical according to claim 1, wherein the pharmaceutical is a nanoparticle, an organic compound, an inorganic compound or a nanomedicine, and the nanoparticle or nanomedicine is bound to one or more of a photosensitizer, a first generation anticancer drug, a second generation anticancer drug, a third generation anticancer drug, a nuclear medicine treatment drug, a metabolic anticancer drug, an enzyme, a gene therapy agent or a near-infrared fluorescent dye in one or more configurations.

7. The method for producing a pharmaceutical product according to claim 1, wherein the reaction chamber has a structure with an inlet and an outlet or a structure that is simple to open and close so as to facilitate smooth air flow.

8. The method for producing a pharmaceutical product according to claim 3, wherein the binding chamber is connected to a circulation device through a tube having a circular structure or a continuous zigzag structure so as to enable circulation of the reactant (nanoparticle or drug) produced in step (c).

9. A pharmaceutical product produced by the method of any one of claims 1 to 8.

10. The pharmaceutical product according to claim 9, wherein the pharmaceutical product produced by said manufacturing method is synthesized at a low temperature that is not the freezing point of the solvent used or at a high temperature at which the solvent does not completely evaporate; and is synthesized in a smaller volume and in a shorter time than a drug produced by a manufacturing method different from said manufacturing method.

11. A biopharmaceutical having a structure comprising a pharmaceutical agent according to claim 9 and at least one selected from the group consisting of a nucleic acid-based molecule, an amino acid-based antibody, a specific binding protein, and an enzyme having high biological safety.

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