WO2015133828A1

WO2015133828A1 - Micelle containing bubbles for drug delivery and method for manufacturing same

Info

Publication number: WO2015133828A1
Application number: PCT/KR2015/002111
Authority: WO
Inventors: 서종범; 박진감; 원종호; 김성배; 신운철; 손정우; 송길수; 차오름; 김진호
Original assignee: 주식회사 퍼시픽시스템; 연세대학교 원주산학협력단
Priority date: 2014-03-07
Filing date: 2015-03-05
Publication date: 2015-09-11

Abstract

Disclosed are a micelle containing bubbles for drug delivery and a method for manufacturing the same. The micelle formed according to the present invention includes micro-bubbles formed by evaporating the liquefied inert gas due to the irradiation of ultrasonic waves to a solution in which the liquefied inert gas is mixed with a drug for disease treatment, and the micelle is formed as a unit structure in which the micro-bubbles are contained in a cavity and the cavity is enclosed in a shell, and delivers the drug to the human body. Therefore, the micelle can protect a material of the drug, which is delivered to the human body, as well as deliver a larger amount of the drug than the existing technique, and can be easily applied to the treatment of various diseases.

Description

Micelles containing air bubbles for drug delivery and methods of manufacturing the same

The present invention relates to a drug delivery technology, and more particularly, to a micelle comprising a bubble and a method for manufacturing the same so that the drug can be effectively delivered to the human body using cavitation by ultrasonic waves.

A microbubble of the general form consists of the gas inside and the membrane which protects it. Recent studies have shown that microbubbles have an excellent effect of improving the contrast of ultrasound images, and thus research into the use of microbubbles as an ultrasound contrast agent is being actively conducted.

1 is an exemplary view illustrating micro bubbles utilized as a conventional ultrasound contrast agent.

Referring to FIG. 1, the micro bubbles used as the ultrasound contrast agent may have an engineered shape as shown in FIG. 1A.

More specifically, looking at the Cryo-TEM image, it can be seen that the micro-bubbles used as the ultrasound contrast agent is composed of the gas 11 and the thin film 13 to protect the gas as shown in Figure 1 (b). have.

Here, as the gas 11 contained in the microbubbles, an inert gas having high stability is generally adopted. The membrane 13 for protecting the gas may increase the stability of the microbubbles 10 and may be made of various materials such as lipids, phospholipids, or proteins that are not bio-compatible.

Recently, however, studies are being actively conducted to introduce microbubbles as ultrasound contrast agents into drug delivery systems for efficiently delivering drugs to the human body.

According to the results of the study that the microcavity caused by the ultrasonic wave is effectively induced in the microbubbles used as an ultrasound contrast agent, a desired drug or a ligand binding material is uniformly attached to the microbubble membrane 13 to have a thickness of several tens of nm or less. The drug was intended to be delivered to the human body by forming a thin film.

However, since the conventional method binds the drug to the membrane surface, there is a limitation that the loss of the drug may occur while the microbubbles move to the target position, and thus cannot fully function as a drug carrier. In addition, there is a limitation in that a large amount of drug cannot be loaded.

SUMMARY OF THE INVENTION An object of the present invention for solving the above problems is to provide a micelle containing bubbles for drug delivery that can safely deliver the substance of the drug to the human body to optimize the efficacy and effect of the drug.

In addition, another object of the present invention is to provide a method for manufacturing a micelle that can be easily applied to the treatment of all diseases because the drug to be loaded (loading) can be changed according to the type of disease.

In order to achieve the above object, micelles containing bubbles for drug delivery according to an aspect of the present invention are liquefied inert liquid by irradiating ultrasonic waves to a solution in which a liquefied inert gas and a drug for treating a disease are mixed. It contains microbubble formed by vaporization of gas, contains microbubbles inside the cavity, has a unit structure surrounded by a shell, and delivers drugs contained in micelles to the human body. .

Here, the unit structure may have the form of a capsule.

Here, the micro-bubble may refer to a space in which the inert gas liquefied in the solution is formed by cavitation by ultrasonic waves.

Here, liquefied inert gas may mean perflouorobutane.

Here, the solution is a mixture of a liquefied inert gas perfluorobutane and at least one of saline, glycerol, propylene glycol and phospholipids in the form of powder is mixed at a temperature of -15 ℃ to 5 ℃ It can be prepared by mixing a drug for treating a disease.

Here, the membrane can maintain a space in which the liquefied inert gas is vaporized and the remaining drug is in the liquid state.

Here, micelles may be capable of altering the drug loaded into the unit structure so that it can be applied to the treatment of at least one disease.

In addition, the micelle manufacturing method comprising a bubble for drug delivery according to another aspect of the present invention for achieving the above object, the step of preparing a first solution by mixing a liquefied inert gas and a pre-prepared liquid mixture, the first Mixing a drug for treating a disease into a solution to prepare a second solution, and irradiating ultrasound to cause cavitation to the second solution to form micelles containing microbubbles.

Here, the pre-prepared mixed solution may be prepared by mixing at least one of saline, glycerol, propylene glycol and phospholipid in the form of a powder.

Here, the preparing of the first solution may mix perflouorobutane, a liquefied inert gas, and a previously prepared mixed solution at a temperature of -15 ° C to 5 ° C.

Here, the step of preparing the second solution may be applied to the treatment of at least one disease by changing the drug to be mixed into the first solution.

Here, in the forming of the micelles containing the micro bubbles, when ultrasonic waves are irradiated on the second solution, the inert gas liquefied in the second solution is vaporized by ultrasonic cavitation to form micro bubbles. The micelle may be formed in the form of a capsule enclosed in a cavity and surrounded by a shell that maintains a space in which the liquefied inert gas is vaporized and the remaining drug is in a liquid state.

According to the micelle including the bubble for the drug delivery according to an embodiment of the present invention as described above and a method for manufacturing the same, it is possible to optimize the efficacy and effect of the drug by safely delivering the substance of the drug to the human body.

In addition, since the drug to be loaded (loading) can be changed according to the type of disease, it can be easily applied to the treatment of all diseases.

Figure 2 is an exemplary view illustrating the configuration of a micelle containing bubbles for drug delivery according to an embodiment of the present invention.

Figure 3 is an exemplary view illustrating the form of micelles containing bubbles for drug delivery according to an embodiment of the present invention.

4 is an exemplary view illustrating a composition ratio of micelles including bubbles for drug delivery according to an embodiment of the present invention.

5 is an exemplary view illustrating components of micelles including bubbles for drug delivery according to an embodiment of the present invention.

6 is an exemplary view illustrating a method for identifying a drug loaded into a micelle containing bubbles for drug delivery according to an embodiment of the present invention.

7 is an exemplary view of confirming via a confocal image a drug loaded into a micelle containing bubbles for drug delivery according to an embodiment of the present invention.

8 is an exemplary view confirming a drug loaded in a micelle containing bubbles for drug delivery according to an embodiment of the present invention through a microscope image.

9 is an exemplary view for confirming the drug loaded in the micelles containing the bubbles through electrophoresis for drug delivery according to an embodiment of the present invention.

10 is a graph showing the results confirmed through electrophoresis according to an embodiment of the present invention.

11 is a flow chart illustrating a method of manufacturing a micelle comprising bubbles for drug delivery according to an embodiment of the present invention.

As the invention allows for various changes and numerous embodiments, particular embodiments will be illustrated in the drawings and described in detail in the written description. However, this is not intended to limit the present invention to specific embodiments, it should be understood to include all modifications, equivalents, and substitutes included in the spirit and scope of the present invention. In describing the drawings, similar reference numerals are used for similar elements.

Terms such as first, second, A, and B may be used to describe various components, but the components should not be limited by the terms. The terms are used only for the purpose of distinguishing one component from another. For example, without departing from the scope of the present invention, the first component may be referred to as the second component, and similarly, the second component may also be referred to as the first component. The term and / or includes a combination of a plurality of related items or any item of a plurality of related items.

When a component is referred to as being "connected" or "connected" to another component, it may be directly connected to or connected to that other component, but it may be understood that other components may be present in between. Should be. On the other hand, when a component is said to be "directly connected" or "directly connected" to another component, it should be understood that there is no other component in between.

The terminology used herein is for the purpose of describing particular example embodiments only and is not intended to be limiting of the present invention. Singular expressions include plural expressions unless the context clearly indicates otherwise. In this application, the terms "comprise" or "have" are intended to indicate that there is a feature, number, step, operation, component, part, or combination thereof described in the specification, and one or more other features. It is to be understood that the present invention does not exclude the possibility of the presence or the addition of numbers, steps, operations, components, components, or a combination thereof.

Unless defined otherwise, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art. Terms such as those defined in the commonly used dictionaries should be construed as having meanings consistent with the meanings in the context of the related art and shall not be construed in ideal or excessively formal meanings unless expressly defined in this application. Do not.

Hereinafter, exemplary embodiments of the present invention will be described in detail with reference to the accompanying drawings.

Figure 2 is an exemplary view illustrating the configuration of micelles containing bubbles for drug delivery according to an embodiment of the present invention, Figure 3 is a form of micelles including bubbles for drug delivery according to an embodiment of the present invention. It is an illustrative view explaining.

In addition, Figure 4 is an exemplary view for explaining the composition ratio of micelles containing bubbles for drug delivery according to an embodiment of the present invention, Figure 5 is a micelle containing bubbles for drug delivery according to an embodiment of the present invention It is an illustration explaining the component of.

2 to 5, the shape of the micelle 20 including micro bubbles for use in drug delivery may be described.

Conventionally, micro bubbles are used as an ultrasound contrast agent, but recently, as a result of introducing micro bubbles into a drug delivery system, studies for actively performing drug delivery roles using micro bubbles used as ultrasound contrast agents have been actively conducted.

Thus, the microbubbles used in the ultrasonic contrast agent were shaken strongly in the state where the gas and the film were mixed or exposed to strong ultrasonic waves to form bubbles. This allows the membrane to be present between the gas and the liquid, which is a polar fluid, so that most of the phospholipid or hydrophilic and hydrophilic forms of the membrane are in contact with the gas and the hydrophilic portion is in solution. In contact with the phosphorus to form a monolayer (monolayer).

In this case, in order to construct a thick film, a method of attaching the material of the membrane to the shell formed in the form of a membrane after removing all moisture by rapid freezing at low pressure to form a thick membrane. However, there is a limit that it is difficult to include the fluid inside the membrane if not repeated several processes.

Thus, a rapid mixing of a liquid mixed with a lipid (typically phospholipid) containing a liquid and a polar tail, such as forming a cell, or rapidly irradiating the fluid with ultrasonic waves to form a micelle By rapid cooling at very low pressure to saturate, the remaining film form can be reused after the liquid inside is vaporized. However, although bilayer shells of phospholipids can be formed, it is difficult to control them to contain a sufficient amount of drug inside the micelle.

Therefore, in the present invention, the micelles in which the drug is loaded between the microbubble, the shell and the microbubble and the membrane by mixing the gas of the liquid state with a relatively high boiling temperature of the liquid and then raising the temperature through ultrasonic waves. We propose a method of forming a micelle.

Here, the micelle 20 may have a form in which a fluid portion including micro bubbles is present to perform a drug delivery role. This type of micelle 20 is efficient in that it can load a larger amount of drug than the conventional method of binding the drug to the membrane surface through cavitation by ultrasound.

The micelle 20 may comprise microbubbles 21, a membrane 23 and a drug 25.

In this case, the micelle 20 includes a micro bubble 21 in a cavity to allow the drug to be delivered to the human body, and has a form of a capsule surrounded by the membrane 23. A drug 25 for treating a disease may be loaded between 21 and the membrane 23.

First, the micro-bubble 21 is formed by vaporizing the inert gas liquefied in the solution by cavitation by the ultrasonic wave to the ultrasonic solution in the solution (liquid) mixed with the liquefied inert gas and the drug for the treatment of diseases. It can mean a space to be.

Here, the perfluorobutane (perflouorobutane) may be used in that the inert gas can be easily mixed in the pre-prepared liquid mixture at a break point of −2.56 ° C., but is not limited thereto.

In addition, the solution is a mixture of the liquefied inert gas perflouorobutane and at least one of saline, glycerol, propylene glycol and phospholipid in the form of powder is mixed with a pre-prepared mixture of -15 ℃ to 5 ℃ After mixing at temperature, it can be prepared by mixing the drug for treating the disease.

At this time, the reason for mixing the perfluorobutane and the pre-prepared mixture at a temperature of -15 ° C to 5 ° C is because it can be easily mixed with the pre-prepared mixture.

The drug 25 for treating a disease may be included in the liquid remaining after the inert gas liquefied in the solution and may be loaded between the micro bubbles 21 and the membrane 23. Accordingly, by changing the drug mixed in the solution to form the micelle 20, the drug contained in the micelle 20 can be easily changed. Thus, it can be applied to the treatment of various kinds of diseases.

The membrane 23 may maintain a space in which the liquefied inert gas is vaporized and the drug is loaded so that the drug can safely reach the human body.

Looking at the micelle 20 having the above-described shape in detail, as shown in FIG. 3, the brightest part is the microbubble 21, and the dark part surrounding the microbubble 21 is used to treat the disease. The drug 25 is loaded, and the membrane 23 may be formed on the outermost side so as to maintain the space in which the drug 25 is loaded. Thus, the micelle 20 may take the form of a capsule.

For example, the micelle 20 may refer to an echogenic liposome generated by echo. The liposomes mostly take the form of capsules, such as spherical or ellipsoidal, as shown in FIG. 4, microbubbles 21 composed of 45.20% gas core, 47.34% liquid drug 25. , A film 23 forming a 7.46% layer.

More specifically, as shown in FIG. 5, the Echogenic liposome is hydrophilic when irradiated with a transducer of a ultrasonic device (Ultrasound Equipment) to a mixture of phospholipids such as DPPC and DPPA. The part which shows is going to approach the liquid and the part which shows hydrophobic avoids the liquid and aggregates the components which are hydrophobic. As a result, a bilayer structure of about 7 nm can form the film 23.

In this case, the inside of the membrane may include a micro bubble 21 formed by perflouorobutane and a drug 25 containing siRNA effective for gene therapy. Thus, when the Echogenic liposome is destroyed, the siRNA, a protected drug inside the membrane, can be delivered to the human body.

As described above, the micelle 20 including bubbles for drug delivery may be loaded with a drug 25 for treating a disease and delivered to the human body. Hereinafter, a detailed method of identifying a drug loaded into micelles in FIGS. 6 to 10 will be described.

In addition, Figure 7 is an exemplary view for confirming the drug loaded in the micelles containing bubbles for drug delivery according to an embodiment of the present invention through a confocal image, Figure 8 is for drug delivery according to an embodiment of the present invention It is an exemplary view for confirming the drug loaded in the micelle containing bubbles through a microscope image, Figure 9 is a drug loaded in the micelle containing bubbles for drug delivery according to an embodiment of the present invention through electrophoresis It is an illustration.

In addition, Figure 10 is a graph showing the results confirmed through electrophoresis according to an embodiment of the present invention.

Referring to FIG. 6, since the drug is loaded into micelles containing bubbles for drug delivery and cannot be visually identified, micelles and perflouorobutane are added at a ratio of 1: 100 and then 3 μm of disease. The drug loaded into micelles can be identified by removing siRNA using a 3-way stopcock, a syringe filter, and RNase, an enzyme that cuts RNA, using a vialmixer mixed with siRNA, a drug for treatment. have.

For example, if a 100 μm size micelle is prepared and loaded with a drug, the syringe filter is compressed by installing a syringe filter with a size of 10 μm. Then, the siRNA size is smaller than the size of the filter, so as to filter the vial as shown in Figure 6 (a) and only the micelles remain. At this time, RNase is added to remove siRNA that may remain on the membrane of the micelle, and extracted with a 3-way stopcock as shown in FIG. This not only shows that the drug is loaded into the micelle, but also checks what kind of drug is loaded.

As described above, micelles containing bubbles and loaded drugs for drug delivery can be visually identified using various methods.

First, it can be confirmed through an image sharing a focus as shown in FIG. 7.

More specifically, FIG. 7 (a) is an original image including a plurality of micelles A, each having a different size and shape, and FIG. 7 (b) is an image confirmed by fluorescence staining of the wavelength of siRNA B at 488 nm. Looking at the image of Fig. 7 (a) and the image of Fig. 7 (b) combined as shown in Fig. 7 (c), even though RNA was removed with RNase, the position of siRNA B shown in the fluorescence image is the position of micelle A You can see that it is very similar. This shows that the drug siRNA is protected by micelles.

In addition, the micelle and the drug loaded with bubbles for drug delivery can be confirmed through an image by a microscope as shown in FIG.

More specifically, FIG. 8 (a) is an original image including a plurality of micelles each having a different size and shape, and FIG. 8 (b) is an image visualized by fluorescence staining of a lipid constituting the membrane of the micelle at wavelength 534 nm. In addition, Figure 8 (c) is an image visualized by fluorescent staining the drug siRNA contained in the micelle at wavelength 488nm. When the image of FIG. 8 (b) and the image of FIG. 8 (c) are combined as shown in FIG. 8 (d), the image of the drug siRNA included in the micelle of FIG. 8 (b) and the micelle is shown. It can be seen that Figure 8 (c) overlaps about 88%. Through this, it can be seen that the drug contained in the micelle can be encapsulated and protected by the liposome membrane.

Finally, micelles and bubbles loaded with bubbles for drug delivery can be identified through electrophoresis as shown in FIG. 9.

More specifically, in FIG. 9, I is an image showing pure siRNA, and II is an image showing irradiation of pure siRNA with ultrasound. In addition, III is an image which shows pure micelles, and IV is an image which shows that siRNA was mixed with micelles. V is an image showing the ultrasonic irradiation after mixing the siRNA in micelles, VI represents the control of the membrane using a filter in the micelles mixed with siRNA, and VII is a membrane using the filter in micelles mixed with siRNA. It is an image showing that the ultrasonic irradiation. In addition, VIII shows the addition of RNase after mixing siRNA in micelles, and Ⅸ shows the image of ultrasonic irradiation after using RNase inhibitor to control the remaining RNase after RNase treatment by mixing siRNA in micelles.

As described above, each result of the electrophoresis in FIG. 9 may be confirmed through a graph representing a percentage according to a band line as shown in FIG. 10. Among these, when comparing the bar graph f showing the VI process of FIG. 9 with the bar graph g showing the Ⅶ process, the micelles were protected by destruction of the micelles after controlling the membrane using a filter in micelles mixed with siRNA. As siRNA affects the band signal, it can be seen that the band line is increased by about 20%, through which the siRNA is protected by the micelle.

In addition, since the bar graph h showing the process of FIG. 9 adds RNase after mixing siRNAs to micelles, it can be confirmed that siRNA is disappeared by RNase and thus almost no band signal appears. Furthermore, bar graph i illustrating the process of FIG. 9 shows that a band signal of about 20% is formed due to residual siRNA in micelles.

This makes it easy to recognize that micelles can load drugs for treating diseases.

Referring to FIG. 11, in the method of preparing a micelle, a first solution is prepared by mixing a liquefied inert gas and a pre-prepared mixed solution (S100), and a step of preparing a second solution by mixing drugs with the first solution (S200). ) And forming a micelle containing micro bubbles by irradiating ultrasonic waves to the second solution (S300).

More specifically, in order to manufacture a micelle containing bubbles for drug delivery, a first solution may be prepared by mixing a liquefied inert gas and a previously prepared mixed solution (S100).

For example, to prepare the first solution, first, 50 ml of saline and 2.5 ml of glycerol are mixed and then 52.5 ml of propylene glycol. Here, 0.1 g of Dipalmitoyl Phosphatidyl Choline (DPPC) and 0.01 g of Diphenoxy Phosphoryl Azide (DPPA) are mixed and heated at 60 ° C. for 30 minutes with a hot plate to prepare a mixed solution in advance. At this time, since DPPC and DPPA are in the form of powder, the heating time of the hot plate may mean the time point at which both DPPC and DPPA are melted, but the present invention is not limited thereto.

Then use a micro pipette to remove 2000μl of the mixed solution and place in 2ml vial. Mix 20 μl of the inert gas liquefied into 2000 μl of the mixed solution in 2 ml vial using a micropipette and shake for 45 seconds using the Vialmix.

At this time, perfluorobutane is used in that the inert gas can be easily mixed with the previously prepared mixed liquid at a break point of -2.56 占 폚. Therefore, the liquefied perfluorobutane (perflouorobutane) and the mixed liquid can be mixed at a temperature of -15 ° C to 5 ° C, which is a suitable temperature that can be easily mixed.

Thus, the first solution can be prepared by filtering the mixed solution using a 100 μm membrane filter selected according to the bubble size.

Here, perflouorobutane was used as the inert gas, but is not limited thereto.

The second solution may be prepared by mixing a drug for treating a disease with the first solution prepared as described above (S200).

Accordingly, by changing the drug to be mixed in the first solution, the drug applicable to the treatment of at least one disease, such as cancer treatment, skin disease, brain disease, gene therapy, etc., may be loaded into the micelle.

Thus, ultrasonic waves may be irradiated to cause cavitation to the second solution in which the drug is mixed to form micelles containing micro bubbles (S300).

At this time, the cavity phenomenon by the ultrasonic wave means a phenomenon in which the gas contained in the liquid is released from the liquid by the ultrasonic wave and the empty space composed of the gas is gathered at a low pressure.

That is, when the second solution is irradiated with ultrasonic waves, the inert gas liquefied in the second solution may be vaporized by cavitation by the ultrasonic waves to form micro bubbles.

At this time, the inert gas liquefied in the second solution is vaporized and the remaining drug is loaded in the liquid state between the microbubbles and the shell, and the membrane maintains the space in the liquid state so that the drug in the liquid state is safe for the human body. The drug may be enclosed to be delivered.

As a result, micelles can be formed to have the form of capsules that collectively contain microbubbles inside and are surrounded by a membrane, and the human body to treat the drug by loading a drug for treating a disease between the microbubbles and the membrane. Can be delivered safely.

Although described above with reference to a preferred embodiment of the present invention, those skilled in the art will be variously modified and changed within the scope of the invention without departing from the spirit and scope of the invention described in the claims below I can understand that you can.

Claims

Micelle (microelle) containing a microbubble formed by vaporizing the liquefied inert gas as a solution of a mixture of liquefied inert gas and drugs for the treatment of diseases,

The micelle,

The microbubble is contained inside the cavity in a cavity, and has a unit structure surrounded by a shell.

A micelle containing bubbles for drug delivery, characterized in that for delivering the drug contained in the micelle to the human body.
The method according to claim 1,

The unit structure,

A micelle containing air bubbles for drug delivery, characterized in that it has the form of a capsule (capsule).
The method according to claim 1,

The micro bubble is,

The micelle comprising bubbles for drug delivery, characterized in that the space is formed by the vaporization of the liquefied inert gas in the solution by the cavitation by the ultrasonic wave.
The method according to claim 3,

The liquefied inert gas,

A micelle comprising air bubbles for drug delivery, characterized in that perfluorobutane (perflouorobutane).
The method according to claim 4,

The solution,

After perflouorobutane, the liquefied inert gas, and at least one of saline, glycerol, propylene glycol, and phospholipid in the form of powder are mixed, a mixed solution prepared in advance is mixed at a temperature of -15 ° C to 5 ° C, A micelle containing bubbles for drug delivery, characterized in that it is prepared by mixing the drug for the treatment of the disease.
The method according to claim 3,

The membrane,

The micelle containing bubbles for drug delivery, characterized in that to maintain a space in which the liquefied inert gas is vaporized and the drug remains in the liquid state.
The method according to claim 6,

The micelle,

A micelle containing bubbles for drug delivery, characterized in that the drug loaded into the unit structure can be modified to be applied to the treatment of at least one disease.
In the method of manufacturing a micelle to deliver the drug,

Mixing the liquefied inert gas with a pre-prepared liquid mixture to prepare a first solution;

Preparing a second solution by mixing a drug for treating a disease with the first solution; And

And forming ultrasonic micelles containing micro bubbles by irradiating ultrasonic waves to cause cavitation in the second solution.
The method according to claim 8,

The prepared liquid mixture is,

Method for producing micelles characterized in that at least one of saline, glycerol, propylene glycol and phospholipids in powder form is mixed and prepared.
The method according to claim 8,

Preparing the first solution,

A method for producing a micelle, wherein the liquefied inert gas, perflouorobutane, and the previously prepared mixed solution are mixed at a temperature of -15 ° C to 5 ° C.
The method according to claim 8,

Preparing the second solution,

The method of manufacturing a micelle, characterized in that applicable to the treatment of at least one disease by changing the drug to be mixed in the first solution.
The method according to claim 8,

Forming the micelles containing the micro-bubbles,

When the ultrasonic wave is irradiated to the second solution, the liquefied inert gas is vaporized in the second solution by the cavity phenomenon by the ultrasonic wave to form micro bubbles.

It has a form of a capsule containing the formed micro bubbles in a cavity and surrounded by a shell for maintaining a space in which the liquefied inert gas is vaporized and the remaining drug remains in a liquid state. A micelle manufacturing method, characterized in that micelles are formed.