Method for manufacturing nanobubble-based drug carrier using focused ultrasound technology and nanobubble-based drug carrier manufactured thereby

Abstract

The present disclosure relates to a method for manufacturing a nanobubble-based drug carrier using focused ultrasound technology and a nanobubble-based drug carrier manufactured thereby and, more specifically, to a method for manufacturing a drug carrier containing a shell, with drugs and nanobubbles encapsulated inside the shell, using focused ultrasound technology, and a nanobubble-based drug carrier manufactured thereby.

Description

Method for manufacturing a nanobubble-based drug delivery system using focused ultrasound technology and a nanobubble-based drug delivery system manufactured thereby

[0001] The present disclosure relates to a method for manufacturing a nanobubble-based drug delivery system using focused ultrasound technology and a nanobubble-based drug delivery system manufactured thereby, and more specifically, to a method for manufacturing a drug delivery system containing a shell and a drug and nanobubbles inside the shell using focused ultrasound technology and a nanobubble-based drug delivery system manufactured thereby.

[0002] Drug delivery systems are one of the important technologies in the field of nanomedicine, and drug delivery technologies based on nanomaterials have been steadily increasing since 1997, and active technology development is observed in China, Korea, the United States, Japan, and Europe in that order, centered on patent applications from research institutes such as universities. Recently, development is actively underway in various fields such as Lipid Nanoparticle (LNP) technology, nanoemulsion technology, and nanoliposomes.

[0003] In particular, as the field of nanomedicine with high human absorption rate is gaining attention, there is a persistent need for technology that can deliver a certain amount of nano-sized drugs to the location of the lesion. In this regard, technology for manufacturing microbubbles currently exists, but the problem is that the micro-sized bubbles have a low human absorption rate due to their relatively large size. In addition, the micro-sized bubbles manufactured with the current technology are not uniform in size, so the content of the drug delivered through the bubbles is not constant. In addition, there is no technology yet to deliver nano-sized drugs to the area around the lesion, so this need has not been resolved.

[0004] In addition, reducing agents, surfactants, and organic solvents used to control the size of substances used in current drug delivery systems are toxic, making it difficult to use them in objects applied in vivo as drug delivery vehicles. In addition, even when surfactants and organic solvents are used, the size of the manufactured substances is not uniform, resulting in poor bioavailability. In order to overcome these shortcomings, encapsulated drug delivery vehicles using proteins and phospholipids with excellent reducing power have been proposed. However, their types and concentrations are limited, and their therapeutic efficacy is very low due to the protein corona phenomenon in which numerous proteins existing in the body stick to these drug delivery vehicles. In addition, side effects that cause toxicity have been confirmed as they affect organs other than the target.

[0005] Against this backdrop, there is a continuing need for a method for manufacturing a nanobubble-based drug delivery system that can selectively treat by directing drugs to the lesion site, thereby minimizing drug side effects, delivering a uniform content of nanodrugs, and maximizing therapeutic efficacy with high human absorption rate, as well as a nanobubble-based drug delivery system.

[0006] The problem that the present disclosure seeks to solve is to provide a method for manufacturing a drug delivery system using focused ultrasound.

[0007] Another problem that the present disclosure seeks to solve is to provide a method for manufacturing a drug delivery system with maximized bioavailability by delivering a uniform content of nanodrug.

[0008] Another problem that the present disclosure seeks to solve is to provide a method for manufacturing a drug delivery system that can maximize therapeutic effects and minimize drug-induced side effects by using nano-sized drugs with high human absorption rates.

[0009] Another problem that the present disclosure seeks to solve is to provide a drug delivery vehicle comprising a shell and a drug and a first nanobubble.

[0010] Another problem that the present disclosure seeks to solve is to provide a drug delivery vehicle manufactured using a focused ultrasound device.

[0011] The problems to be solved by the present disclosure are not limited to the problems mentioned above, and problems to be solved by the present disclosure that are not mentioned can be clearly understood by a person having ordinary knowledge in the technical field to which the present disclosure belongs (“ordinary skilled person”) from the description below.

[0012] In order to solve the technical problem as described above, a method for manufacturing a drug delivery system using focused ultrasound provided according to the present disclosure may be a method for manufacturing a drug delivery system using focused ultrasound, comprising: a step of manufacturing a first solution; a step of manufacturing a second solution; and a step of mixing the first solution and the second solution and irradiating focused ultrasound to manufacture a third solution including a shell and a drug delivery system containing a drug and first nanobubbles inside the shell.

[0013] For example, the uniformity of the drug delivery system may be such that the Poly-Dispersity Index (PDI) is greater than 0 and less than or equal to 0.3.

[0014] For example, the size of the drug delivery vehicle may be determined by at least one of size control factors including focused ultrasound frequency, ultrasound irradiation time, ultrasound intensity, phase transition temperature of the material, and mixing speed of the solution.

[0015] For example, the irradiation conditions of the above focused ultrasound may be 10 to 100 W and 200 to 800 kHz.

[0016] For example, the first solution may be characterized by being heated to about 25 to 80 degrees Celsius.

[0017] For example, the first solution may be characterized by being heated to about 25 to 80 degrees Celsius.

[0018] For example, the second solution may be characterized by being heated to about 50 to 110 degrees Celsius.

[0019] For example, the first solution may be characterized by being heated to about 60 to 80 degrees Celsius.

[0020] For example, the first solution may be characterized in that it is mixed by injection at a rate of 0.3 to 5.0 mL / min.

[0021] For example, the second solution may be characterized in that it is injected at a rate of 10 to 100 mL / min.

[0022] For example, the drug delivery system may have second nanobubbles formed on the surface of the shell.

[0023] For example, the drug delivery system may have a decrease in absolute zeta potential as second nanobubbles are formed on the surface of the shell.

[0024] In addition, in order to solve the technical problem as described above, the drug delivery system provided according to the present disclosure is: a shell; and a drug delivery system having a predetermined range of uniformity including a drug and first nanobubbles contained inside the shell, wherein the uniformity of the drug delivery system may be a poly-dispersity index (PDI) of greater than 0 and less than or equal to 0.3.

[0025] For example, the drug delivery system may be characterized by being at least one selected from the group consisting of lecithin, cholesterol, PEG-PCL (poly(ethylene glycol)-poly(ε-caprolactone)), DSPC (Distearoylphosphatidylcholine), DODMA (1,2-Dioleyloxy-3-(dimethylamino)propane, N,N-Dimethyl-2,3-bis[(9Z)-9-octadecen-1-yloxy]-1-propanamine), PLGA (poly(lactic-co-glycolic acid)), PLA (polylactic acid), and PVA (polyvinyl alcohol).

[0026] According to the present disclosure, a method for manufacturing a nanobubble-based drug delivery system with maximized bioavailability through delivery of a uniform content of nanodrugs and a nanobubble-based drug delivery system manufactured thereby can be provided.

[0027] According to the present disclosure, a method for manufacturing a nanobubble-based drug delivery system capable of maximizing therapeutic effects and minimizing side effects caused by drugs by using nano-sized drugs with high human absorption rates, and a nanobubble-based drug delivery system manufactured thereby can be provided.

[0028] According to the present disclosure, a method for manufacturing a nanobubble-based drug delivery system capable of maximizing therapeutic effects and minimizing side effects of drugs by selectively delivering drugs to the location of a lesion using magnetic nanoparticles, and a nanobubble-based drug delivery system manufactured thereby can be provided.

[0029] According to the present disclosure, a method for manufacturing a nanobubble-based drug delivery system capable of imaging by using light emitted from the bubble surface to identify the location of a therapeutic agent contained in a nanobubble, and a nanobubble-based drug delivery system manufactured thereby can be provided.

[0030] According to the present disclosure, a drug delivery system having excellent functionality can be provided efficiently using a focused ultrasound device.

[0031] The excellent and / or useful effects according to the present disclosure are not limited to the effects of the present disclosure described above, and it should be understood that those skilled in the art will also be able to clearly recognize excellent and / or useful effects of the present disclosure that are not explicitly disclosed in the present disclosure based on the disclosure of the present specification, and that these are intentionally disclosed by the present specification and are clearly included in the scope of the present disclosure.

[0032] Figure 1 is a schematic diagram illustrating a method for manufacturing a drug delivery system using focused ultrasound according to the present disclosure.

[0033] Figure 2 is a schematic diagram showing the structure of a drug delivery system according to the present disclosure.

[0034] Figure 3 is a schematic diagram illustrating a process for manufacturing a drug delivery system according to the present disclosure using a focused ultrasound device.

[0035] Figure 4 is a diagram showing the results of visual observation of a drug delivery system according to the present disclosure.

[0036] Figure 5 is a diagram showing the results of particle size and size distribution measured using DLS for a drug delivery vehicle according to the present disclosure.

[0037] Figure 6 is a diagram showing the results of turboscan for a drug delivery system according to the present disclosure.

[0038] FIG. 7 is a diagram showing a Cryo-EM image of a liposome included in a drug delivery vehicle according to the present disclosure.

[0039] FIG. 8 is a diagram showing a Cryo-EM image of a liposome included in a drug delivery vehicle according to the present disclosure.

[0040] Hereinafter, the present disclosure will be described in detail.

[0041] The terms or words used in this specification and claims are not intended to be interpreted as limited to their commonly used dictionary meanings, and a person of ordinary skill in the art to which this disclosure pertains will clearly understand that the terms or words are used in the sense intended to convey the meaning of this disclosure within the scope of expressing the concepts that this specification and claims clearly intend to convey.

[0042] In addition, it will be clearly understood by those skilled in the art that the embodiments described in this specification and the configurations described in the embodiments are merely preferred embodiments presented as examples to enable those skilled in the art to understand and reproduce the present disclosure, and that the present disclosure is not intended to be limited thereto.

[0043] Furthermore, the descriptions and specific embodiments of each configuration described in this specification can be readily applied to other descriptions and embodiments. That is, all combinations of the various configurations and specific embodiments disclosed in this specification fall within the scope of this disclosure, as will be readily apparent to those skilled in the art.

[0044] The term "and / or" as used herein is a term that includes each and every combination of one or more of the items mentioned. In addition, singular terms also include plural terms unless otherwise stated.

[0045] The terms 'comprising' and / or 'comprising' used in this specification are terms that do not exclude the presence or addition of items other than those mentioned.

[0046] The numerical range indicated by the term "to" in this specification refers to a numerical range that includes the values ​​described before and after the term as the lower limit and the upper limit, respectively. When a plurality of numerical values ​​are disclosed as the upper limit and the lower limit of an arbitrary numerical range, the numerical range disclosed in this specification can be understood as an arbitrary numerical range that includes any one of the plurality of lower limit values ​​and any one of the plurality of upper limit values ​​as the lower limit and the upper limit, respectively.

[0047] The terms 'about' or 'approximately' as used herein, when used, mean a value or numerical range within 10% of the value or numerical range stated after the term.

[0048] The terms or words used in this specification and claims should not be interpreted based on their conventional dictionary meanings, but rather should be interpreted with meanings and concepts consistent with the technical concept of the present invention, based on the principle that the inventor can appropriately define the concept of the term to best explain his or her invention. Therefore, the configurations described in the embodiments described in this specification are merely the most preferred embodiments of the present invention and do not represent the entire technical concept of the present invention. Therefore, it should be understood that various equivalents and modified examples may exist as of the time of this application.

[0049] Meanwhile, each description and embodiment disclosed in this specification may also be applied to each other description and implementation. That is, all combinations of the various elements disclosed in this specification fall within the scope of the present invention, and descriptions omitted in one embodiment may be interpreted in the same manner as described in other embodiments. Furthermore, the scope of the present disclosure is not limited by the specific descriptions described below.

[0050] According to one aspect of the present disclosure, a method for manufacturing a drug delivery system using focused ultrasound can be provided.

[0051] For example, the method for manufacturing a drug delivery system using focused ultrasound may include: a step of manufacturing a first solution; a step of manufacturing a second solution; and a step of mixing the first solution and the second solution and irradiating focused ultrasound to manufacture a third solution including a shell and a drug delivery system containing a drug and first nanobubbles inside the shell.

[0052] For example, the first solution may be a solution in which one or more materials selected from the group consisting of lecithin, cholesterol, PEG-PCL (poly(ethylene glycol)-poly(ε-caprolactone)), DSPC (Distearoylphosphatidylcholine), DODMA (1,2-Dioleyloxy-3-(dimethylamino)propane, N,N-Dimethyl-2,3-bis[(9Z)-9-octadecen-1-yloxy]-1-propanamine), PLGA (poly(lactic-co-glycolic acid)), PLA (polylactic acid), and PVA (polyvinyl alcohol) are dissolved in a solvent.

[0053] For example, the material of the first solution may be 0.5 to 1.0 parts by weight based on 100 parts by weight of the entire first solution. If the material of the first solution is included in less than 0.5 parts by weight based on 100 parts by weight of the entire first solution, there is a problem that nanobubbles are not formed well, and if the material of the first solution is included in more than 1.0 parts by weight based on 100 parts by weight of the entire first solution, there is a problem that the size of the formed nanobubbles is not uniform and they are formed in a form in which cavities are not formed inside. Therefore, it is preferable that the content of the material of the first solution satisfies the above numerical range. Preferably, the material of the first solution may be 0.6 to 0.9 parts by weight based on 100 parts by weight of the entire first solution, more preferably 0.7 to 0.8 parts by weight, and most preferably 0.75 parts by weight.

[0054] For example, in the first step, the solvent may be an organic solvent, and the organic solvent may be an organic solvent including tetrahydrofuran (THF).

[0055] For example, in the first step, the volume of the solvent may be 1.5 to 2.5 parts by volume based on 100 parts by volume of the entire first solution.

[0056] For example, the second solution may be a solution in which the drug is dissolved in a solvent. For example, the solvent may be at least one selected from among a lipophilic solvent and a hydrophilic solvent.

[0057] For example, the irradiation conditions of the focused ultrasound may be 10 to 100 W and 200 to 800 kHz.

[0058] For example, the first nanobubbles of the third step may have an average diameter of 10 nm or more and 200 nm or less. By satisfying the above numerical range for the average diameter of the first nanobubbles, the drug delivery system may have excellent in vivo membrane permeability based on its small size. For example, the drug delivery system may be designed to penetrate intracellular barriers with different permeabilities, such as cell membranes and the blood-brain barrier, by appropriately adjusting the average diameter of the first nanobubbles within the above numerical range.

[0059] For example, the uniformity of the drug delivery system may be such that the Poly-Dispersity Index (PDI) is greater than 0 and less than or equal to 0.3.

[0060] For example, the size of the drug delivery vehicle may be determined by at least one of size control factors including focused ultrasound frequency, ultrasound irradiation time, ultrasound intensity, phase transition temperature of the material, and mixing speed of the solution. For example, the first solution may be characterized in that it is heated to about 25 to 80 degrees Celsius.

[0061] For example, the first solution may be characterized by being heated to about 25 to 80 degrees Celsius.

[0062] For example, the second solution may be characterized by being heated to about 50 to 110 degrees Celsius.

[0063] For example, the first solution may be characterized by being heated to about 60 to 80 degrees Celsius.

[0064] For example, the first solution may be characterized in that it is mixed by injection at a rate of 0.3 to 5.0 mL / min.

[0065] For example, the second solution may be characterized in that it is injected at a rate of 10 to 100 mL / min.

[0066] For example, the drug delivery vehicle may have second nanobubbles formed on the surface of the shell.

[0067] For example, the drug delivery system may have a decrease in absolute zeta potential as second nanobubbles are formed on the surface of the shell.

[0068] In addition, in order to solve the technical problem as described above, the drug delivery system provided according to the present disclosure is: a shell; and a drug delivery system having a predetermined range of uniformity including a drug and first nanobubbles contained inside the shell, wherein the uniformity of the drug delivery system may be a poly-dispersity index (PDI) of greater than 0 and less than or equal to 0.3.

[0069] For example, the material used in the drug delivery system may be at least one selected from the group consisting of lecithin, PEG-PCL (poly(ethylene glycol)-poly(ε-caprolactone)), DSPC (Distearoylphosphatidylcholine), DODMA (1,2-Dioleyloxy-3-(dimethylamino)propane, N,N-Dimethyl-2,3-bis[(9Z)-9-octadecen-1-yloxy]-1-propanamine), PLGA (poly(lactic-co-glycolic acid)), PLA (polylactic acid), and PVA (polyvinyl alcohol).

[0070] For example, the first nanobubble may have an average diameter of 10 nm or more and 200 nm or less. By satisfying the above numerical range for the average diameter of the first nanobubble, the drug delivery system may have excellent in vivo membrane permeability based on its small size. For example, the drug delivery system may be designed to penetrate intracellular barriers with different permeabilities, such as cell membranes and the blood-brain barrier, by appropriately adjusting the average diameter of the first nanobubble within the above numerical range.

[0071] For example, the uniformity of the drug delivery system may be such that the Poly-Dispersity Index (PDI) is greater than 0 and less than or equal to 0.3.

[0072] For example, the size of the drug delivery vehicle may be determined by at least one of size control factors including focused ultrasound frequency, ultrasound irradiation time, ultrasound intensity, phase transition temperature of the material, and mixing speed of the solution.

[0073] For example, the drug delivery vehicle may further include second nanobubbles formed on the surface of the shell.

[0074] For example, the drug delivery system may have a decrease in absolute zeta potential as second nanobubbles are formed on the surface of the shell.

[0075] For example, the drug delivery system may be characterized by using at least one material selected from the group consisting of lecithin, cholesterol, PEG-PCL (poly(ethylene glycol)-poly(ε-caprolactone)), DSPC (Distearoylphosphatidylcholine), DODMA (1,2-Dioleyloxy-3-(dimethylamino)propane, N,N-Dimethyl-2,3-bis[(9Z)-9-octadecen-1-yloxy]-1-propanamine), PLGA (poly(lactic-co-glycolic acid)), PLA (polylactic acid), and PVA (polyvinyl alcohol).

[0076] Hereinafter, the present disclosure will be described in more detail using the following examples. Process conditions and preparation steps not specified in the examples may be process conditions or preparation steps that are self-evident in the technical field to which the present disclosure pertains, and those skilled in the art will be able to select these conditions and reproduce the problem-solving principles of the present disclosure without much difficulty based on the present disclosure.

[0077] In addition, in the manufacturing method according to the present disclosure, unless otherwise specified, each step constituting the manufacturing method is performed at room temperature (25°C), and it should be understood that each step is performed by means and tools that can be derived without much difficulty by a person skilled in the art.

[0078] Manufacturing Preparation Example: Preparation of ingredients used in this disclosure

[0079] Hydrogenated soy lecithin (GL-SPC 75 H) was commercially obtained from Goshen Biotech (Namyangju, South Korea). Cholesterol reagent, an auxiliary material to reinforce the liposome structure, was commercially obtained from Nippon Fine Chemical (Osaka, Japan). 95% ethanol reagent was commercially obtained from Duksan. Distilled water was prepared to a standard of 18.2 mΩ. The ultrasonic processor used was a FUST Lab FS-R01K1.

[0080] Example 1: Preparation of drug delivery system according to the present disclosure

[0081] Lecithin and cholesterol were mixed in amounts of 1.0 g and 0.3 g, respectively, and dissolved in 70 mL of ethanol to prepare a liposome precursor solution as the first solution. Subsequently, the solution was mixed with 100 mL of DI water to prepare a second solution as an aqueous solution. The first solution was prepared by heating to approximately 78°C, and the second solution was prepared by heating to approximately 70°C.

[0082] The focused ultrasound method used a high-intensity focused ultrasound device (FS-R01K1, FUST Lab, Daejeon, South Korea). The focused ultrasound device consists of a cylindrical piezoelectric ceramic that focuses ultrasound onto the sample at its center. This allows the sample to absorb strong mechanical energy evenly, resulting in more uniform dispersion than other ultrasound devices.

[0083] To maximize the sonication effect, two lead zirconate titanate (PZT) electrodes were used. The frequencies of both PZT electrodes were set to 380 kHz, and the output of the first PZT electrode was set to 100 W and the output of the second PZT electrode was set to 150 W. Using the first and second solutions maintained at the above temperatures, the oily first solution was injected at a rate of 1.0 mL / min, and the water-phase second solution was injected at a rate of 17.79 mL / min. It took approximately 1 hour and 40 minutes to completely inject the first solution, after which the mixed solution was circulated for an additional 2 hours. The concentration of lecithin in the mixed solution was confirmed to be 5.88 g / L.

[0084] Successful liposome particle fabrication was confirmed through particle size and uniformity (PDI) analysis, as well as cryo-EM imaging. The average size of the liposomes was confirmed to be 120 nm, and the uniformity value was confirmed to be less than 0.17.

[0085] Experimental Example 1: Visual observation of drug delivery system according to the present disclosure

[0086] FIG. 4 is a diagram illustrating the results of visual observation of Example 1, a drug delivery vehicle according to the present disclosure. Referring to FIG. 4, it can be confirmed that the drug delivery vehicle was successfully and uniformly formed on a dark background. Furthermore, in the case of the liposome solution prepared using focused ultrasound, there were no air bubbles in the upper layer of the solution, and the solution had excellent transparency. While not intending to be bound by a particular theory, it is known that transparency is a correlation between particle size and light scattering, with larger particles scattering more light and smaller particles scattering less light.

[0087] Experimental Example 2: Confirmation of particle size distribution of drug delivery system according to the present disclosure

[0088] The Zetasizer Nano ZSP (Malvern Panalytical, Malvern, UK) is an analytical instrument capable of measuring particle size and particle density index (PDI) in solution. Particle size was analyzed by measuring the scattering intensity over time in a solution under Brownian motion. Measurements were performed after diluting the liposome solution of Example 1 100-fold in deionized water. The liposome solution was measured daily for four days from the day of preparation to assess changes in liposome size and PDI. The results are shown in Table 1.

[0089] Day 0 Day 1 Day 2 Day 3 Size (nm) (SD value) 113.6 (0.3055) 123.8 (0.3055) 113.7 (0.8327) 116.5 (2.371) PDI (SD value) 0.124 (0.011) 0.165 (0.018) 0.083 (0.007) 0.060 (0.024)

[0090] Figure 5 shows the particle size and size distribution results measured using DLS for Example 1, a drug delivery vehicle according to the present disclosure. In the case of the liposome solution prepared using focused ultrasound (indicated as "Focused"), the liposome size measured on the day of the experiment was the smallest (113.6 nm), and the solution was confirmed to be quite stable when measured after a total of 4 days, and the PDI was measured to be approximately 0.1, confirming that the size distribution was very uniform. The results are shown in Table 1 below. Experimental Example 3: Stability Evaluation of the Drug Delivery Vehicle According to the Present Disclosure

[0091] The Turbiscan AGS (Formulation, Toulouse, France) is a device that measures the permeability of a solution at regular time intervals, allowing analysis of solution stability through changes in aggregation or phase separation. The stability of the liposome solution of Example 1 was analyzed by measuring it every six hours for one week.

[0092] Figure 6 is a diagram showing the results of turboscan, which is an important result showing the stability of the liposome solution of Example 1. Referring to Figure 6, the results of measuring the degree of delta transmission every 6 hours for one week are shown, and the X-axis represents the height of the bottle containing the sample, and the Y-axis represents the change in delta transmission (%). Referring to Figure 6, it was confirmed that the liposome solution of Example 1 was quite stable, showing a significantly low data transmission rate, and that there was not much aggregation or phase separation.

[0093] Experimental Example 4: Cryo-EM Evaluation of Drug Delivery Systems According to the Present Invention

[0094] Frozen biological samples were observed by transmission electron microscopy using a cryo-EM (Talos L 120C, FEI, Oregon, USA). Unlike other electron microscopes, cryo-EM has the advantage of easily preventing sample deterioration. In this experimental example, the acceleration voltage was set to 120 kV, and the ice growth rate was set to less than 0.7 nm / h.

[0095] Figures 7 and 8 show Cryo-EM images of liposomes included in the liposome solution of Example 1. The circular shapes shown in the image of Figure 7 are grids appearing on the Cryo-EM measurement plate. In the liposome solution of Example 1, liposomes with a size of 100 nm, which is smaller than 200 nm, were observed, and liposomes with a very uniform size distribution were confirmed as unilamellar liposomes with a uniform shape and size distribution.

[0096] In summary, it was found that the focused ultrasound method can obtain the smallest and most uniformly sized liposomes compared to similar technologies such as homogenization, high-pressure emulsification, and existing ultrasonic treatment methods such as bath-type and hybrid-type methods. It is expected that this is due to the ability of the focused ultrasound method according to the present invention to apply an appropriate frequency and energy to the liposome solution while simultaneously delivering focused energy to the circulating solution. Therefore, the focused ultrasound method can be used to create nano-sized liposomes with a uniform structure, increase stability, and significantly improve encapsulation efficiency, and such liposomes are expected to be applied in various fields such as drug delivery and cosmetics.

[0097] Although the preferred embodiments of the present invention have been described in detail above, the scope of the present invention is not limited thereto, and various modifications and improvements made by those skilled in the art using the basic concept of the present invention defined in the following claims also fall within the scope of the present invention.

Claims

1. Step of preparing the first solution; a step of preparing a second solution; and A step of mixing the first solution and the second solution and irradiating focused ultrasound to produce a third solution including a shell and a drug delivery vehicle containing first nanobubbles inside the shell, Method for manufacturing a drug delivery vehicle using focused ultrasound.

2. A method for manufacturing a drug delivery system using focused ultrasound, characterized in that in the first paragraph, the uniformity of the drug delivery system has a PDI (Poly-Dispersity Index) of greater than 0 and less than or equal to 0.

3.

3. A method for manufacturing a drug delivery system using focused ultrasound, characterized in that in the first paragraph, the size of the drug delivery system is determined according to at least one of size control factors including focused ultrasound frequency, ultrasound irradiation time, ultrasound intensity, phase transition temperature of the material, and mixing speed of the solution.

4. A method for producing a drug delivery vehicle using focused ultrasound, characterized in that in the third paragraph, the first solution contains lecithin and cholesterol.

5. A method for producing a drug delivery vehicle using focused ultrasound, characterized in that in the third paragraph, the first solution is heated to about 25 to 80 degrees Celsius.

6. A method for producing a drug delivery vehicle using focused ultrasound, characterized in that in paragraph 5, the first solution is heated to about 25 to 80 degrees Celsius.

7. A method for producing a drug delivery vehicle using focused ultrasound, characterized in that in the third paragraph, the second solution is heated to about 50 to 110 degrees Celsius.

8. A method for producing a drug delivery vehicle using focused ultrasound, characterized in that in paragraph 7, the first solution is heated to about 60 to 80 degrees Celsius.

9. A method for producing a drug delivery vehicle using focused ultrasound, characterized in that in paragraph 1, the irradiation conditions of the focused ultrasound are 10 to 100 W and 200 to 800 kHz.

10. A method for producing a drug delivery vehicle using focused ultrasound, characterized in that in the first paragraph, the first solution is mixed by injection at a speed of 0.3 to 5.0 mL / min.

11. A method for producing a drug delivery vehicle using focused ultrasound, characterized in that in the first paragraph, the second solution is injected at a speed of 10 to 100 mL / min.

12. A method for manufacturing a drug delivery system using focused ultrasound, characterized in that in the first paragraph, the drug delivery system has second nanobubbles formed on the surface of the shell.

13. A method for manufacturing a drug delivery system using focused ultrasound, wherein in the fourth paragraph, the drug delivery system is characterized in that the absolute value of the zeta potential decreases as the second nanobubbles are formed on the surface of the shell.

14. Shell; and A drug delivery vehicle having a predetermined range of uniformity comprising first nanobubbles contained within the shell, The uniformity of the above drug delivery system is characterized by a PDI (Poly-Dispersity Index) of greater than 0 and less than or equal to 0.

3. Drug delivery vehicle.

15. A drug delivery system according to claim 14, characterized in that it comprises at least one selected from the group consisting of lecithin, cholesterol, PEG-PCL (poly(ethylene glycol)-poly(ε-caprolactone)), DSPC (Distearoylphosphatidylcholine), DODMA (1,2-Dioleyloxy-3-(dimethylamino)propane, N,N-Dimethyl-2,3-bis[(9Z)-9-octadecen-1-yloxy]-1-propanamine), PLGA (poly(lactic-co-glycolic acid)), PLA (polylactic acid), and PVA (polyvinyl alcohol).

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