Method for producing nanobubble-based drug delivery bodies using focused ultrasound technology and nanobubble-based drug delivery bodies produced thereby

Abstract

The present disclosure relates to a method for producing a nanobubble-based drug delivery device using focused ultrasound technology and the nanobubble-based drug delivery device produced thereby, and more specifically to a method for producing a drug delivery device using focused ultrasound technology, the drug delivery device including a shell and containing a drug and nanobubbles inside the shell, and the nanobubble-based drug delivery device produced thereby.

Description

[Technical Field]

[0001] The present disclosure relates to a method for producing a nanobubble-based drug delivery device using focused ultrasound technology and the nanobubble-based drug delivery device produced thereby, and more specifically to a method for producing a drug delivery device using focused ultrasound technology, the drug delivery device including a shell and containing a drug and nanobubbles inside the shell, and the nanobubble-based drug delivery device produced thereby. [Background technology]

[0002] Drug delivery systems are one of the key technologies in the field of nanomedicine, and nanomaterial-based drug delivery technologies have shown a continuous increase since 1997. Active technological development has been observed in China, Korea, the United States, Japan, and Europe, primarily through patent applications from universities and other research institutions. Recently, development has been active in various fields, including lipid nanoparticle (LNP) technology, nanoemulsion technology, and nanoliposomes.

[0003] In particular, the field of nanomedicines, which have a high rate of absorption by the human body, has been attracting attention, and there has been a continuous demand for a technology that can deliver a constant amount of nano-sized drugs to the location of a lesion. In this regard, although there is currently a technology for producing microbubbles, there is a problem that the micro-sized bubbles have a low rate of absorption by the human body due to their relatively large size, and there is a problem that the micro-sized bubbles produced by the current technology are not uniform in size, so the content of the drug delivered through the bubbles is not constant. Therefore, there has been no technology to deliver nano-sized drugs to the area around the lesion, and this demand has not been met.

[0004] In addition, reducing agents, surfactants, and organic solvents used to adjust the size of substances in current drug delivery systems are toxic, making them difficult to use as drug delivery vehicles for in vivo applications. Even when surfactants and organic solvents are used, the size of the resulting substances is not uniform, resulting in poor bioavailability. To overcome these drawbacks, drug delivery vehicles encapsulated using proteins and phospholipids with excellent reducing power have been proposed. However, these vehicles are limited in type and concentration, and many proteins present in the body attach to these drug delivery vehicles, resulting in very low therapeutic efficiency and side effects such as toxicity due to the protein corona phenomenon, which occurs when these vehicles affect non-target organs.

[0005] Under these circumstances, there is an ongoing demand for a manufacturing method of a nanobubble-based drug delivery system and a nanobubble-based drug delivery system that can deliver a drug to the location of a lesion for selective treatment, thereby minimizing drug side effects, delivering a uniform amount of nanodrug, and maximizing therapeutic efficacy through high absorption by the human body. Summary of the Invention [Problem to be solved by the invention]

[0006] The problem to be solved by the present disclosure is to provide a method for producing a drug delivery device using focused ultrasound.

[0007] Another problem to be solved by the present disclosure is to provide a method for producing a drug delivery system that maximizes bioavailability by delivering a uniform content of nano-drug.

[0008] Another problem to be solved by the present disclosure is to provide a method for manufacturing a drug delivery system that can maximize therapeutic effects and minimize side effects caused by drugs by using nano-sized drugs that have a high absorption rate in the human body.

[0009] Another problem to be solved by the present disclosure is to provide a drug delivery body comprising a shell, a drug, and first nanobubbles.

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

[0011] The problems that the present disclosure aims to solve are not limited to the problems mentioned above, and problems that the present disclosure aims to solve that are not mentioned can be clearly understood by a person having ordinary knowledge in the technical field to which the present disclosure pertains ("ordinary engineer") from the following description. [Means for solving the problem]

[0012] In order to solve the above-mentioned technical problems, the method for producing a drug delivery body using focused ultrasound provided by the present disclosure may be a method for producing a drug delivery body using focused ultrasound, comprising the steps of: producing a first solution; producing a second solution; and mixing the first solution and the second solution and irradiating the mixture with focused ultrasound to produce a third solution containing a drug delivery body having a shell and a drug and first nanobubbles contained inside the shell.

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

[0014] For example, the size of the drug delivery body may be determined by at least one of size-regulating 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 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 injected and mixed at a rate of 0.3 to 5.0 mL / min.

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

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

[0023] For example, the absolute value of the zeta potential of the drug delivery product may be reduced by forming second nanobubbles on the surface of the shell.

[0024] In addition, in order to solve the technical problems described above, the drug delivery body provided by the present disclosure is a drug delivery body having a predetermined range of uniformity, which includes: a shell; and a drug and first nanobubbles contained inside the shell, and the uniformity of the drug delivery body may have a PDI (Poly-Dispersity Index) greater than 0 and less than or equal to 0.3.

[0025] For example, the drug delivery vehicle may be characterized as being one or more 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). [Effects of the Invention]

[0026] According to the present disclosure, it is possible to provide a method for producing a nanobubble-based drug delivery device that maximizes bioavailability by delivering a uniform content of nanodrug, and the nanobubble-based drug delivery device produced thereby.

[0027] According to the present disclosure, it is possible to provide a method for producing a nanobubble-based drug delivery device that can maximize therapeutic effects and minimize drug-related side effects by utilizing nano-sized drugs that have a high rate of absorption by the human body, and the nanobubble-based drug delivery device produced thereby.

[0028] According to the present disclosure, there are provided a method for producing a nanobubble-based drug delivery device, which can maximize therapeutic effects and minimize drug-related side effects by selectively delivering drugs to the location of a lesion using magnetic nanoparticles, and the nanobubble-based drug delivery device produced thereby.

[0029] According to the present disclosure, it is possible to provide a method for producing an imageable nanobubble-based drug delivery device that can determine the location of a therapeutic agent carried in the nanobubble by utilizing light emanating from the bubble surface, and the nanobubble-based drug delivery device produced thereby.

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

[0031] The excellent and / or useful effects of the present disclosure are not limited to the effects of the present disclosure described above, and a person of ordinary skill in the art can clearly recognize excellent and / or useful effects of the present disclosure that are not explicitly disclosed herein based on the disclosure of the present specification, which are intentionally disclosed by the present specification and should be understood to be obviously included in the scope of the present disclosure. [Brief explanation of the drawings]

[0032] [Figure 1] 1 is a diagram illustrating a method for manufacturing a drug delivery device using focused ultrasound according to the present disclosure. [Figure 2] 1 is a diagram showing a schematic structure of a drug delivery device according to the present disclosure. [Figure 3] 1 is a diagram illustrating a process for manufacturing a drug delivery body according to the present disclosure using a focused ultrasound device. [Figure 4] FIG. 1 shows the results of visual observation of a drug delivery article according to the present disclosure. [Figure 5] FIG. 1 shows the particle size and size distribution measurement results for a drug delivery device according to the present disclosure, measured using DLS. [Figure 6] FIG. 1 shows the results of a Turbiscan for a drug delivery device according to the present disclosure. [Figure 7] FIG. 1 shows a Cryo-EM image of a liposome contained in a drug delivery vehicle according to the present disclosure. [Figure 8] FIG. 1 shows a Cryo-EM image of a liposome contained in a drug delivery vehicle according to the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0033] The present disclosure will be described in detail below.

[0034] The terms or words used in this specification and the claims are not intended to be interpreted limitedly to their common dictionary meanings, and a person having ordinary skill in the art to which this disclosure pertains can clearly understand that the terms or words are used in a sense intended to convey the meaning of this disclosure within the scope of expressing the idea that this specification and the claims are intended to convey obviously.

[0035] Furthermore, it can 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 so that those skilled in the art can understand and reproduce the present disclosure, and that they are not intended to limit the present disclosure.

[0036] Furthermore, the description of each configuration and specific embodiment described herein can be obviously applied to each different description and embodiment, that is, all combinations of the various configurations and specific embodiments disclosed herein belong to the scope of the present disclosure and can be clearly understood by a person of ordinary skill in the art.

[0037] As used herein, the term "and / or" is an inclusive term of each and every combination of one or more of the referenced items, and singular terms also include pluralities unless otherwise indicated.

[0038] As used herein, the terms "comprising" and / or "comprising" are terms that do not exclude the presence or addition of other items other than the stated items.

[0039] In this specification, a range of values ​​expressed using the term "to" indicates a range of values ​​that includes the values ​​before and after the term as the lower and upper limits, respectively. When multiple values ​​are disclosed as the upper and lower limits of a given range of values, the range of values ​​disclosed in this specification can be understood as any range of values ​​whose lower and upper limits are any of the multiple lower limits and any of the multiple upper limits, respectively.

[0040] As used herein, the term "about" or "approximately," when used, means a value or range of values ​​within 10% of the value or range of values ​​listed after said term.

[0041] The terms and words used in this specification and claims should not be interpreted limitedly to their ordinary dictionary meanings, but should be interpreted in a meaning and concept that is consistent with the technical idea of ​​the present invention, based on the principle that the inventor can appropriately define the concept of the term to best describe his / her invention. Therefore, it should be understood that 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 idea of ​​the present invention, and that there may be various equivalents and modifications that can be substituted for them at the time of filing this application.

[0042] Meanwhile, each description and embodiment disclosed in this specification may also be applied to each other description and embodiment. In other words, all combinations of various elements disclosed in this specification belong to the scope of the present invention, and a description omitted in one embodiment may be interpreted in the manner described in another embodiment. In addition, the specific description described below should not be considered to limit the scope of the present disclosure.

[0043] According to one aspect of the present disclosure, a method for producing a drug delivery agent using focused ultrasound can be provided.

[0044] As an example, the method for producing a drug delivery body using focused ultrasound may include: a step of producing a first solution; a step of producing a second solution; and a step of mixing the first solution and the second solution and irradiating the solution with focused ultrasound to produce a third solution containing a drug delivery body having a shell and a drug and first nanobubbles inside the shell.

[0045] As an example, the first solution may be a solution in which 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) is dissolved in a solvent.

[0046] For example, the content of the material for the first solution may be 0.5 to 1.0 parts by weight, based on 100 parts by weight of the total first solution. If the content of the material for the first solution is less than 0.5 parts by weight, based on 100 parts by weight of the total first solution, nanobubbles may not be formed properly. If the content of the material for the first solution is more than 1.0 parts by weight, based on 100 parts by weight of the total first solution, nanobubbles may be formed with uneven sizes and without internal cavities. Therefore, it is preferable that the content of the material for the first solution be within the above numerical range. Preferably, the content of the material for the first solution may be 0.6 to 0.9 parts by weight, more preferably 0.7 to 0.8 parts by weight, and most preferably 0.75 parts by weight, based on 100 parts by weight of the total first solution.

[0047] For example, in the first step, the solvent may be an organic solvent, and the organic solvent may be an organic solvent containing tetrahydrofuran (THF).

[0048] 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.

[0049] For example, the second solution may be a solution in which a drug is dissolved in a solvent, and the solvent may be at least one selected from the group consisting of a lipophilic solvent and a hydrophilic solvent.

[0050] For example, the irradiation conditions of the focused ultrasound may be 10 to 100 W and 200 to 800 kHz.

[0051] For example, the first nanobubbles of the third stage may have an average diameter of 10 nm to 200 nm. When the average diameter of the first nanobubbles falls within this range, the drug delivery vehicle can have excellent membrane permeability due to its small size. For example, when the average diameter of the first nanobubbles is appropriately adjusted within this range, the drug delivery vehicle can be designed to penetrate biological barriers with different permeabilities, such as cell membranes and the blood-brain barrier.

[0052] For example, the uniformity of the drug delivery formulation may be such that the PDI (Poly-Dispersity Index) is greater than 0 and equal to or less than 0.3.

[0053] For example, the size of the drug delivery body 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 by being heated to about 25 to 80 degrees Celsius.

[0054] As an example, the first solution may be characterized by being heated to about 25 to 80 degrees Celsius.

[0055] As an example, the second solution may be characterized by being heated to about 50 to 110 degrees Celsius.

[0056] As an example, the first solution may be characterized by being heated to about 60 to 80 degrees Celsius.

[0057] As an example, the first solution may be injected and mixed at a rate of 0.3 to 5.0 mL / min.

[0058] As an example, the second solution may be injected at a rate of 10 to 100 mL / min.

[0059] As an example, the drug delivery article may have second nanobubbles formed on the surface of the shell.

[0060] For example, the absolute value of the zeta potential of the drug delivery article may be reduced by forming second nanobubbles on the surface of the shell.

[0061] Furthermore, in order to solve the technical problems described above, the drug delivery body provided by the present disclosure is a drug delivery body having a predetermined range of uniformity, which includes: a shell; and a drug and first nanobubbles contained inside the shell, and the uniformity of the drug delivery body may have a PDI (Poly-Dispersity Index) greater than 0 and less than or equal to 0.3.

[0062] For example, the material used in the drug delivery body may be one or more 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).

[0063] For example, the first nanobubbles may have an average diameter of 10 nm to 200 nm. When the average diameter of the first nanobubbles falls within this range, the drug delivery vehicle can have excellent membrane permeability due to its small size. For example, when the average diameter of the first nanobubbles is appropriately adjusted within this range, the drug delivery vehicle can be designed to penetrate biological barriers with different permeabilities, such as cell membranes and the blood-brain barrier.

[0064] For example, the uniformity of the drug delivery formulation may be such that the PDI (Poly-Dispersity Index) is greater than 0 and equal to or less than 0.3.

[0065] As an example, the size of the drug delivery body may be determined by at least one of size-regulating factors including focused ultrasound frequency, ultrasound irradiation time, ultrasound intensity, phase transition temperature of the material, and mixing speed of the solution.

[0066] As an example, the drug delivery device may further include second nanobubbles formed on the surface of the shell.

[0067] For example, the absolute value of the zeta potential of the drug delivery article may be reduced by forming second nanobubbles on the surface of the shell.

[0068] As an example, the drug delivery vehicle 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).

[0069] The present disclosure will be described in more detail below with reference to the following examples. Process conditions and preparation steps not specified in the following examples may be obvious process conditions or preparation steps in the technical field to which the present disclosure pertains, and a person skilled in the art can easily select them based on the present disclosure to reproduce the problem-solving principle of the present disclosure.

[0070] Furthermore, in the manufacturing method according to the present disclosure, unless otherwise specified, it should be understood that each step constituting the manufacturing method is carried out at room temperature (25°C), and that each step is carried out using means and tools that a person of ordinary skill in the art can derive without any particular difficulty.

[0071] Manufacturing Preparation Example: Preparation of ingredients used in this disclosure Hydrogenated soybean lecithin (GL-SPC 75 H) was commercially obtained from Goshen Biotech (Namyangju, South Korea). Cholesterol reagent, an auxiliary material for strengthening 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 ultrasonicator used was the FS-R01K1 from FUST Lab.

[0072] Example 1: Production of drug delivery bodies according to the present disclosure Lecithin and cholesterol (1.0 g and 0.3 g, respectively) were mixed and dissolved in 70 mL of ethanol to prepare an oily phase liposome precursor solution (Solution 1). This solution was then mixed with 100 mL of DI water to prepare an aqueous phase solution (Solution 2). Solution 1 was heated to approximately 78°C, and solution 2 was heated to approximately 70°C.

[0073] For the focused ultrasound method, a high-intensity focused ultrasound device (FS-R01K1, FUST Lab, Daejeon, South Korea) was used. The focused ultrasound device consists of a cylindrical piezoelectric ceramic that concentrates ultrasound waves on the sample located in the center. Therefore, this device allows the sample to uniformly absorb strong mechanical energy and provides a more uniform dispersion force than other ultrasonic devices.

[0074] To maximize the ultrasonic treatment effect, two lead zirconate titanate (PZT) sensors were used. Both PZT frequencies were set to 380 kHz, with the first PZT set to 100 W and the second PZT set to 150 W. The first and second solutions were maintained at the temperatures described above. The oil phase of the first solution was injected at a rate of 1.0 mL / min, and the aqueous phase of the second solution was injected at a rate of 17.79 mL / min. It took approximately 1 hour and 40 minutes to inject all of the first solution, after which the mixed solution was circulated for another 2 hours. The lecithin concentration in the mixed solution was confirmed to be 5.88 g / L.

[0075] The successful preparation of liposome particles was confirmed through particle size and uniformity (PDI) analysis and cryo-EM images. The average liposome size was 120 nm, and the uniformity value was 0.17 or less.

[0076] Experimental Example 1: Visual Observation of Drug Delivery Forms According to the Present Disclosure Figure 4 shows the results of visual observation of Example 1, a drug delivery vehicle according to the present disclosure. Referring to Figure 4, it can be seen that the drug delivery vehicle was successfully and uniformly formed against a dark background. Furthermore, in the case of the liposome solution prepared using focused ultrasound, there were no bubbles in the upper layer of the solution, and the solution had excellent transparency. Without intending to be bound by any 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.

[0077] Experimental Example 2: Confirmation of particle size distribution of drug delivery bodies according to the present disclosure The Zetasizer® Nano ZSP (Malvern Panalytical, Malvern, UK) is an analytical instrument capable of measuring particle size and PDI in a solution. Particle size was analyzed by measuring the scattering intensity over time from the solution under Brownian motion. Measurements were performed after diluting the liposome solution of Example 1 100 times with DI water. The liposome solution was measured daily for four days from the date of production to evaluate changes in liposome size and PDI. The results are shown in Table 1 below.

[0078] [Table 1]

[0079] Figure 5 shows the particle size and size distribution 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 (labeled "Focused"), the liposome size measured on the day of the experiment was the smallest (113.6 nm). Measurements after a total of four days confirmed that the solution was fairly stable, with a PDI of approximately 0.1, confirming a very uniform size distribution. The results are shown in Table 1 below.

[0080] Experimental Example 3: Evaluation of the stability of the drug delivery formulation according to the present disclosure The Turbiscan® AGS (Formulation, Toulouse, France) is an instrument that measures the permeability of a solution at regular intervals and analyzes the stability of the solution through changes in aggregation or phase separation. The stability of the liposome solution of Example 1 was analyzed by measuring it every 6 hours for one week.

[0081] Figure 6 shows the results of Turbiscan, an important result demonstrating the stability of the liposome solution of Example 1. Referring to Figure 6, the results of measuring the degree of delta permeation every six hours for one week are shown, with the X axis representing the height of the bottle containing the sample and the Y axis representing the change in delta permeation (%). Referring to Figure 6, the liposome solution of Example 1 exhibited a significantly low data transfer rate, confirming that it was very stable and exhibited little aggregation or phase separation.

[0082] Experimental Example 4: Cryo-EM evaluation of the drug delivery form according to the present disclosure Frozen biological samples were observed using a transmission electron microscope (Cryo-EM) (Talos L 120C, FEI, Oregon, USA). Unlike other electron microscopes, Cryo-EM has the advantage of easily preventing sample deterioration. In this experiment, the accelerating voltage was set to 120 kV and the ice growth rate to less than 0.7 nm / h.

[0083] 7 and 8 show cryo-EM images of liposomes contained in the liposome solution of Example 1. The circular shapes shown in the image of Figure 7 are the lattice that appears on the cryo-EM measurement plate. Liposomes with a size of 100 nm, smaller than 200 nm, were observed in the liposome solution of Example 1, confirming that the liposomes had a very uniform size distribution as unilamellar liposomes with uniform shape and size distribution.

[0084] Overall, it was found that the focused ultrasound method can produce liposomes with the smallest and most uniform size compared to similar techniques such as homogenization and high-pressure hydrolysis, as well as conventional ultrasonic treatment methods such as bath and horn methods. This is expected to be due to the ability of the focused ultrasound method of the present invention to apply the appropriate frequency and energy to the liposome solution while simultaneously transferring the concentrated energy to the circulating solution. Therefore, the use of the focused ultrasound method can produce nano-sized liposomes with a uniform structure, which can significantly improve stability and encapsulation efficiency. Such liposomes are expected to be applicable in various fields such as drug delivery and cosmetics.

[0085] 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. preparing a first solution; preparing a second solution; and mixing the first solution with the second solution and irradiating the mixture with focused ultrasound to prepare a third solution containing a drug delivery device having a shell and first nanobubbles inside the shell; A method for producing a drug delivery device using focused ultrasound, comprising:

2. 2. The method of claim 1, wherein the drug delivery agent has a degree of uniformity such that a PDI (Poly-Dispersity Index) is greater than 0 and less than or equal to 0.

3.

3. 2. The method for manufacturing a drug delivery body using focused ultrasound according to claim 1, wherein the size of the drug delivery body is 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.

4. The method for preparing a drug delivery system using focused ultrasound according to claim 3, wherein the first solution contains lecithin and cholesterol.

5. The method for manufacturing a drug delivery system using focused ultrasound according to claim 3, wherein the first solution is heated to about 25 to 80 degrees Celsius.

6. The method for manufacturing a drug delivery system using focused ultrasound according to claim 5, wherein the first solution is heated to about 25 to 80 degrees Celsius.

7. The method for manufacturing a drug delivery system using focused ultrasound according to claim 3, wherein the second solution is heated to about 50 to 110 degrees Celsius.

8. The method for manufacturing a drug delivery system using focused ultrasound according to claim 7, wherein the first solution is heated to about 60 to 80 degrees Celsius.

9. 2. The method for producing a drug delivery agent using focused ultrasound according to claim 1, wherein the focused ultrasound is irradiated under conditions of 10 to 100 W and 200 to 800 kHz.

10. 2. The method of claim 1, wherein the first solution is injected and mixed at a rate of 0.3 to 5.0 mL / min.

11. 2. The method of claim 1, wherein the second solution is injected at a rate of 10 to 100 mL / min.

12. The method for manufacturing a drug delivery device using focused ultrasound according to claim 1 , wherein the drug delivery device has second nanobubbles formed on the surface of the shell.

13. The method for manufacturing a drug delivery device using focused ultrasound according to claim 4, wherein the absolute value of the zeta potential of the drug delivery device is reduced by forming second nanobubbles on the surface of the shell.

14. shell; and A drug delivery device having a predetermined range of uniformity, the drug delivery device including first nanobubbles contained inside the shell, The uniformity of the drug delivery formulation is characterized by a PDI (Poly-Dispersity Index) of more than 0 and not more than 0.

3. Drug delivery vehicles.

15. The drug delivery vehicle may be lecithin, cholesterol, PEG-PCL (poly(ethylene glycol)-poly(ε-caprolactone)), DSPC (distearoylphosphotidylcholine), 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). The drug delivery product according to claim 14, comprising at least one selected from the group consisting of:

Images