JP4929567B2 - Method for producing preparation containing polymer micelle - Google Patents

Description

The present invention relates to a method for producing a polymer micelle-containing preparation containing polymer micelles encapsulating a water-soluble drug.

  Research has been conducted in which polymer micelles (polymer micelles) formed from block copolymers are used as drug carriers, and drugs are encapsulated in the polymer micelles and applied to drug delivery systems (DDS). Polymer micelles are fine particles in which a large number of block copolymers having a hydrophobic segment and a hydrophilic segment are associated. This copolymer is a synthetic polymer composed of a polyamino acid in the hydrophobic part and polyethylene glycol in the hydrophilic part. is there. Therefore, by changing the length and structure of these segments, the stability of polymer micelles and the drug release rate can be controlled, and therefore, development as a drug carrier is expected.

  Examples of the method for producing a polymer micelle encapsulating a drug include a method in which a poorly water-soluble drug is dissolved in an organic solvent, this solution is mixed with a dispersed aqueous solution of a block copolymer, and then the organic solvent is volatilized ( For example, see Patent Documents 1 and 2). Also proposed is a method in which a poorly water-soluble drug and a block copolymer are dissolved in an organic solvent, these are uniformly mixed, the solvent is distilled off, and then the residue is dissolved in water (for example, Patent Document 3). See).

  However, in such a method, it is unavoidable to use an organic solvent when dissolving a poorly water-soluble drug. Therefore, the resulting polymer micelle-containing preparation has a problem that not a few organic solvents remain and is administered to the human body. In some cases, there were problems that caused side effects.

Further, as far as the description of these documents is concerned, no investigation has been made to encapsulate a water-soluble drug in a drug carrier such as polymer micelle. That is, the block copolymer has a structure composed of a hydrophobic segment and a hydrophilic segment. In an aqueous solution, the hydrophobic portion is inwardly entangled to form a central portion, and the hydrophilic portion is outward. A micelle is formed facing (aqueous solution side). Therefore, when polymer micelle is used as a drug carrier, a poorly water-soluble drug that is easily encapsulated in a hydrophobic portion is used, and no research using a water-soluble drug has been conducted.
Japanese Patent No. 2777530 JP 2001-226294 A JP 2003-342168 A

  The present invention solves the problems of the prior art, and provides a polymer micelle-containing preparation having a polymer micelle that can be produced without using an organic solvent and further contains a water-soluble drug, and a method for producing the same The purpose is to do.

The polymer micelle-containing preparation according to the present invention is a preparation containing a polymer micelle of a block copolymer encapsulating a water-soluble drug,
The block copolymer is formed of a hydrophilic polymer segment and a hydrophobic polymer segment.

In the method for producing a polymer micelle-containing preparation according to the present invention, the liquid temperature is raised to 40 to 70 ° C. while stirring and mixing an aqueous solution of a water-soluble drug and a block copolymer, and then the obtained suspension is used. It is characterized by vigorously stirring and cooling the liquid temperature to 15 to 35 ° C. to encapsulate the water-soluble drug in the polymer micelle formed from the block copolymer.

After cooling the suspension, it is preferable to irradiate the suspension with ultrasonic waves for at least 5 minutes, and it is also preferable that the frequency of the ultrasonic waves is 10 to 100 kHz.
The block copolymer is preferably represented by the following formula (I) or (II).

[In the above formulas, R ₁ and R ₃ represent a hydrogen atom or a C ₁ -C ₄ lower alkyl group substituted or unsubstituted by an optionally protected functional group,
R ₂ represents a hydrogen atom, a saturated or unsaturated C ₁ -C ₂₉ aliphatic carbonyl group, or an arylcarbonyl group,
R ₄ represents a hydroxyl group, a saturated or unsaturated C _{1 to} C ₃₀ aliphatic oxy group, or an aryl-lower alkyloxy group,
R ₅ represents a benzyl group, an alkylbenzyl group, or an allyl group,
L ₁ and L ₂ represent a linking group,
n is an integer from 10 to 2500, x and y are the same or different, and their sum is 10 to 300, and x: y is in the range of 8: 2 to 0: 1; and -COC (CH ₂ COOH) HNH- and -COC (CH ₂ COOR ₅₎ HNH- repeating units are present at random, respectively. ]
L _{1 in the} formula (I) is —NH—, —O—, —CO—, —CH ₂ —, —O—Z—S—Z—, —O—Z—NH— or —OCO—Z—. NH- (Z is C ₁ -C a ₄ alkylene group) represent a group selected from the group consisting of,
L _{2 in the} formula (II) represents —OCO—Z—CO— and —NHCO—Z—CO—, —O—.
It is preferable to represent a group selected from the group consisting of Z—NH— (where Z is a C ₁ -C ₄ alkylene group).

  It is also preferred that the water-soluble drug is a contrast compound or an anticancer substance.

  The polymer micelle-containing preparation of the present invention has polymer micelles in which an organic solvent does not remain and encapsulates a water-soluble drug. Therefore, there is no side effect on the human body due to the organic solvent, and even a water-soluble drug can be applied to a drug delivery system using polymer micelles.

  Furthermore, according to the method for producing a polymer micelle-containing preparation of the present invention, it is not necessary to use an organic solvent, and a water-soluble drug can be efficiently encapsulated in the polymer micelle.

The polymer micelle-containing preparation according to the present invention contains a block copolymer polymer micelle encapsulating a water-soluble drug, and the block copolymer is formed from a hydrophilic polymer segment and a hydrophobic polymer segment. Yes.

As used herein, the “polymer segment” is a concept including an oligomer as long as the object of the present invention is met.
Each of the above components will be described.

(Block copolymer)
The block copolymer used in the present invention can be used without particular limitation as long as it has a hydrophilic polymer segment and a hydrophobic polymer segment and can form a polymer micelle. Specific examples of the hydrophilic polymer segment and the hydrophobic polymer segment of the block copolymer include the following.

  Examples of the hydrophilic polymer segment include poly (ethylene glycol) [or poly (ethylene oxide)], poly (malic acid), poly (saccharide), poly (acrylic acid), poly (vinyl alcohol) and the like. It is done.

  The hydrophobic segments include poly (β-alkyl aspartate), poly (β-alkyl aspartate-co-aspartate), poly (β-aralkyl aspartate), poly (β-aralkyl aspartate-co- Aspartic acid), poly (β-alkylaspartamide), poly (β-alkylaspartamide-co-aspartic acid), poly (β-aralkylaspartamide), poly (β-aralkylaspartamide-co-) Aspartic acid), poly (γ-alkyl glutamate), poly (γ-alkyl glutamate-co-glutamic acid), poly (γ-aralkyl glutamate), poly (γ-aralkyl glutamate-co-glutamic acid), poly (γ-alkyl glutamate) ), Poly (γ-alkylglutamide-co-glutamic acid), poly (γ- Aralkylglutamide), poly (γ-aralkylglutamide-co-glutamic acid), poly (lactide), poly (lactide-co-glycolide), poly (ε-caprolactone), poly (δ-valerolactone) and poly ( γ-butyrolactone).

In the above segments, alkyl is a C ₁ -C ₂₂ linear or branched alkyl, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-hexyl, etc. Lower alkyl, intermediate alkyl having more carbon atoms, tetradecyl, hexadecyl, octodecyl, docosanyl and the like. These groups may optionally be substituted with one or more halogens (eg, fluorine, base, bromine), and may be substituted with one hydroxyl group in medium to higher alkyl. Aralkyl in the above segment may include phenyl-C ₁ -C ₄ alkyl, such as benzyl, optionally having 1 to 3 hydrogens on the benzene ring substituted by halogen or lower alkyl. .

  Such polymer segments can be obtained by transesterification known per se, for example poly (β-benzylaspartate) or poly (γ-benzylglutamate) with the corresponding alcohol or amine. it can. The display of the hydrophobic polymer segment as a copolymer is obtained by partial esterification or partial hydrolysis of the corresponding alkyl- or aralkyl-ester or amide. The degree of partial esterification is generally 20-80%. In addition, aspartic acid, glutamic acid, and lactide are either optically active type or a mixture thereof.

As long as the hydrophilic segment and the hydrophobic segment as described above can form polymer micelles in an aqueous solution (or an aqueous medium), the size of each segment is not limited. The hydrophilic segment as described above has a repeating unit of 10 to 2500, while the hydrophobic segment has a repeating unit of 10 to 300.

  In the present invention, it is preferable to use a block copolymer represented by the following formula (I) or (II).

In the above formulas (I) and (II), R ₁ and R ₃ represent a hydrogen atom or a C ₁ -C ₄ lower alkyl group substituted or unsubstituted by an optionally protected functional group,
R ₂ represents a hydrogen atom, a saturated or unsaturated C ₁ -C ₂₉ aliphatic carbonyl group, or an arylcarbonyl group,
R ₄ represents a hydroxyl group, a saturated or unsaturated C _{1 to} C ₃₀ aliphatic oxy group, or an aryl-lower alkyloxy group,
R ₅ represents a benzyl group, an alkylbenzyl group, or an allyl group,
L ₁ and L ₂ represent a linking group,
n is an integer from 10 to 2500, x and y are the same or different, and their sum is 10 to 300, and x: y is in the range of 8: 2 to 0: 1; and -COC (CH ₂ COOH) HNH- and -COC (CH ₂ COOR ₅₎ HNH- repeating units are present at random, respectively.

Examples of the functional group that may be protected in R ₁ and R ₃ include a hydroxyl group, an acetal, a ketal, an aldehyde, and a sugar residue. The hydrophilic segment in the case where R ₁ and R ₃ represent a lower alkyl group substituted with a functional group which may be protected is produced, for example, according to the method described in WO96 / 33233, WO96 / 32434, WO97 / 06202. Can do.

The linking group represented by L ₁ and L ₂ is not limited because it can be changed mainly by the production method of the block copolymer. As specific examples, L ₁ is —NH—,
—O—, —CO—, —CH ₂ —, —O—Z—S—Z— and —OCO—Z—NH—, —O
-Z-NH (Z is C ₁ -C ₄ alkylene group.) Selected from the group consisting of, L ₂ is -OC
Examples include a group selected from the group consisting of O—Z—CO—, —NHCO—Z—CO—, and —O—Z—NH (wherein Z is a C _{1 to} C ₄ alkylene group). .

  In the present invention, the block copolymer represented by the formula (I) or (II) can freely change the shape and length of the hydrophobic polymer segment and the hydrophilic polymer segment, The structure of the block copolymer can be designed in consideration of the release rate, polymer particle size, storage stability, and the like.

(Water-soluble drug)
The water-soluble drug used in the present invention is a drug encapsulated in a polymer micelle of a block copolymer, specifically, a contrast substance, an anticancer substance, a photosensitizing compound for photodynamic therapy, Antioxidants, antibacterial substances, anti-inflammatory substances, blood circulation promoting substances, whitening substances, skin roughening substances, anti-aging substances, hair growth promoting substances, moisturizing substances, hormones, vitamins, pigments, and proteins Water-soluble drugs such as The polymer micelle-containing preparation of the present invention preferably uses a contrast-enhancing substance or an anticancer substance as a water-soluble drug.

  A water-soluble iodine compound can be used as the contrast material. The water-soluble iodine compound is not particularly defined as long as it has contrast properties, regardless of whether it is ionic or nonionic. In general, a nonionic iodine compound is more desirable because it has a lower osmotic pressure than an ionic iodine compound and a smaller burden on the administered human body. As the water-soluble nonionic iodide compound, a nonionic iodide compound containing phenyl iodide, for example, having at least one 2,4,6-triiodophenyl group is preferable.

As such a nonionic iodine compound, specifically, iopamidol (Iopamidol)
), Iomeprol, Iohexol, Iopentol
, Iopromide, Iosimide, Ioversol, Iotrolan, Iotasul, Iodixanol, Iodecimol, (1,3-bis- (N-3,5-) Bis- [2,3-dihydroxypropylaminocarbonyl] -2,4,6-triiodophenyl) -N-hydroxyacetylamino) propane. These compounds may be used alone or in combination of two or more.

  When the polymer micelle-containing preparation of the present invention is used as a contrast medium for X-ray examination, preferred iodo compounds are iomeprol, iopamidol, iotrolan and iodixanol which are highly hydrophilic and do not increase osmotic pressure even at high concentrations. . In particular, dimer nonionic iodine compounds such as iotrane and iodixanol have the advantage of further reducing the osmotic pressure because the total number of moles is low even when a contrast agent having the same iodine concentration is prepared.

  The concentration of the water-soluble iodine compound in the polymer micelle-containing preparation of the present invention can be arbitrarily set based on factors such as the nature of the contrast compound, the intended route of administration of the preparation, and clinical indicators. The amount of the iodine compound encapsulated in the polymer micelle is typically 5 to 40% by weight, preferably 5 to 35% by weight, more preferably 10 to 25% by weight of the total iodine compound in the polymer micelle-containing preparation. It is desirable.

  Specific examples of the anticancer compound include methotrexate, ebirubicin, daunorubicin, vincristine, vinblastine, and the like. These compounds may be used alone or in combination of two or more.

In addition, in this specification, the said compound may be mentioned including the salt, hydrate, etc. other than a free form.
The polymer micelle-containing preparation according to the present invention can be produced as follows using each component as described above.

Specifically, first, a liquid temperature is raised to 40 to 70 ° C. while stirring and mixing an aqueous solution of a water-soluble drug and a block copolymer to prepare a suspension.
An aqueous solution of a water-soluble drug can be prepared according to a conventionally known method. The aqueous drug solution is preferably in a supersaturated state at room temperature (15 to 25 ° C.). If supersaturated, it is made of a block copolymer by cooling with strong stirring after heating as described below. A part of the water-soluble drug can be encapsulated in the polymer micelle.

As an aqueous medium in which the water-soluble drug is dissolved, water such as distilled water, pharmacopoeia water, and pure water, physiological saline, and an aqueous solution containing a formulation aid are used. As formulation aids, specifically, various physiologically acceptable buffers, chelating agents, osmotic pressure regulators, stabilizers, viscosity regulators, pH regulators, antioxidants such as α-tocopherol And preservatives such as methyl paraoxybenzoate.

  The stirring conditions for stirring and mixing the aqueous solution of the water-soluble drug and the block copolymer are not particularly limited as long as the block copolymer can be dispersed in the aqueous solution. It is desirable to prepare a suspension by increasing the liquid temperature to 40 to 70 ° C., preferably 40 to 60 ° C. over about 30 minutes while stirring and mixing. By raising the temperature to such a temperature range, it is preferable because the block copolymer can be efficiently dispersed and dissolved in the aqueous solution, and the formation of the polymer micelle made of the block copolymer is facilitated.

  A suspension having polymer micelles is prepared in this way, and then the suspension is vigorously stirred and the liquid temperature is cooled to 15 to 35 ° C., preferably 15 to 30 ° C., to form the block copolymer. A water-soluble drug is encapsulated in the formed polymer micelle.

  The preferred range of strong stirring varies depending on the volume of the suspension and the stirring means. For example, when the volume of the suspension is about 100 to 500 ml, the rotation speed is 5000 to 25000 rpm using a homomixer type stirrer, preferably Means stirring at 8000-20000 rpm. Furthermore, it is desirable that the time for the strong stirring is 10 to 60 minutes, preferably 10 to 40 minutes. Even if the volume of the suspension and the stirring means are different from the above, it is preferable to appropriately determine the stirring conditions in consideration of the shearing force applied to the suspension under the stirring conditions.

  By cooling the suspension under such conditions and stirring vigorously, the water-soluble drug dissolved in the suspension is encapsulated in the polymer micelle. That is, the polymer micelles are reconstructed by vigorous stirring under the above conditions, and at this time, the water-soluble drug dissolved in the suspension is encapsulated in the polymer micelles by cooling to the above temperature. It is done.

Unlike PEGylated liposomes, polymer micelles are not hollow inside, and are thought to encapsulate water-soluble drugs in hydrophobic segments entangled inside the micelles.
Therefore, since water-soluble drugs are not encapsulated in a complete capsule structure and the drug is relatively easily released, the stability of the polymer micelles and the drug release rate are controlled by changing the segment length and structure. This is very important.

  In the production method of the present invention, it is preferable that the suspension of polymer micelles is further irradiated with ultrasonic waves. This ultrasonic irradiation may be performed when the suspension is cooled with strong stirring, or may be performed while continuing strong stirring after cooling with strong stirring. Ultrasound irradiation conditions are appropriately selected depending on the volume of the preparation, stirring conditions, etc., and ultrasonic waves with a frequency of 10 to 100 kHz, preferably 15 to 45 kHz, are irradiated for at least 5 minutes, preferably about 5 to 20 minutes. Is desirable. The irradiation amount can be calculated from the rated output of the ultrasonic disperser to be used, the amount of the dispersion liquid to be irradiated, and the irradiation time.

  By irradiating with ultrasonic waves under such conditions, it is possible to promote the rearrangement of the block copolymer in the polymer micelle, and to incorporate the water-soluble drug more efficiently in the polymer micelle, and further miniaturize the polymer micelle. You can also.

Moreover, it is preferable that after irradiating the polymer micelle suspension with ultrasonic waves under the above-described conditions, the suspension is further filtered through a filtration membrane or the like. Filtration is performed by passing through a hydrostatic extruder equipped with a filter having a pore size of 0.05 to 0.45 μm, preferably 0.1 to 0.4 μm, more preferably 0.15 to 0.2 μm. Specifically, various types of hydrostatic extrusion equipment, such as “Extruder” (trade name, manufactured by NOF Liposome), “Liponizer” (trade name, manufactured by Nomura Microscience), etc. are used to force the filter. Let it pass. As the filter, a polycarbonate type, a cellulose type or the like can be used as appropriate. The extrusion filtration method is described in, for example, Biochim. Biophys. Acta 557, 9 (1979).

  By incorporating such an “extrusion” operation step, there is an advantage that in addition to the above sizing, the exchange of the polymer micelle dispersion, the removal of undesirable substances, and the filter sterilization can be performed together.

  The polymer micelle-containing preparation of the present invention is not retained in the polymer micelle by filtering the polymer micelle suspension through a filtration membrane as described above and, if necessary, by centrifugation, ultrafiltration, gel filtration, or the like. It may be purified by removing the above-mentioned drug, or it can be prepared by concentrating to a predetermined concentration and further appropriately mixing formulation adjuvants such as a commonly used diluent.

  In addition, the polymer micelle-containing preparation of the present invention can also be obtained by lyophilizing polymer micelles from a suspension of polymer micelles according to a conventional method. When polymer micelles are lyophilized, they are resuspended in an aqueous medium or the like immediately before use.

According to such a method for producing a polymer micelle-containing preparation of the present invention, it is not necessary to use an organic solvent, and a water-soluble drug can be efficiently encapsulated in the polymer micelle.
The polymer micelle-containing preparation of the present invention produced as described above has a polymer micelle formed from a block copolymer having a hydrophilic polymer segment and a hydrophobic polymer segment, and the polymer micelle is a water-soluble drug. Is included.

  The average particle size of the polymer micelle is usually 0.05 to 0.30 μm, preferably 0.05 to 0.20 μm, and more preferably 0.05 to 0.13 μm. The average particle size is preferably set appropriately according to the purpose of treatment, diagnosis, and X-ray imaging. For example, in order to selectively deliver to the tumor part, the particle size of the polymer micelle is 0.10 to 0.20 μm. More preferably, the thickness is 0.11 to 0.13 μm nm. This makes it possible to concentrate the drug substance or contrast agent selectively on the cancer tissue. In other words, the pores of the new blood vessel wall in the solid cancer tissue are abnormally large compared to the pore size (about 0.03 to 0.08 μm) of the capillary wall window (fenestra) of the normal tissue, 0.1 to 0. Even molecules having a size of about 2 μm leak from the blood vessel wall, so that polymer micelles in the above range can be selectively concentrated on the cancer tissue. This is known as the “EPR effect” and utilizes the fact that the neovascular wall in cancer tissue is more permeable than the microvascular wall in normal tissue.

  When a drug such as a contrast agent or an anticancer compound is encapsulated in the polymer micelle as in the polymer micelle-containing preparation of the present invention, the polymer micelle is added to the delivery efficiency and retention stability of the anticancer compound. It is also necessary to consider the weight of the block copolymer. Specifically, the amount of the drug enclosed in the polymer micelle is 1 to 8, preferably 3 to 8, more preferably 5 to 8 with respect to the block copolymer. Is desirable.

  If the weight ratio of the drug encapsulated in the polymer micelle is less than 1, it is necessary to introduce a relatively large amount of the preparation, resulting in poor drug delivery efficiency. Moreover, since the viscosity of a formulation increases and the force added at the time of injection increases, the pain given to a patient becomes large. On the other hand, when the weight ratio of the drug contained in the polymer micelle exceeds 8, the polymer micelle becomes structurally unstable, and the drug diffuses and leaks out from the polymer micelle during storage or after being injected into the living body. .

  The polymer micelle-containing preparation of the present invention can contain various drugs in the polymer micelle as described above, and the preparation form is determined in consideration of the action effect and storage stability of the drug. . When drugs such as contrast agents and anticancer compounds are encapsulated in polymer micelles, the polymer micelle-containing preparations are used as injections or infusions. Is administered intravascularly in the patient.

The polymer micelle-containing preparation of the present invention has polymer micelles in which an organic solvent does not remain and encapsulates a water-soluble drug. Therefore, there is no side effect on the human body due to the organic solvent, and even a water-soluble drug can be applied to a drug delivery system using polymer micelles.
[Example]
EXAMPLES Hereinafter, although this invention is demonstrated further more concretely based on an Example, this invention is not limited to these Examples.

In this example, the following block copolymer was used.
Block copolymer: Polyethyleneglycol (molecular weight 12000) 50% hydrolyzed polyaspartic acid benzyl ester represented by the following formula

[N: number such that the molecular weight of poly (ethylene glycol) is about 12000, x + y: about 50x / (x + y)]
[Example 1]
Contrast agent solution [Japan iopamidol solution 306.2 mg / mL (iodine content 150 mg / mL), trometamol 1 mg / mL, calcium edetate disodium (EDTANa ₂ -Ca) 0.1 mg / mL, containing appropriate amount of hydrochloric acid and The pH was adjusted to around 7 with sodium hydroxide] To 100 mL, 0.3 g of the block copolymer was added, and the temperature was raised to 50 ° C. over about 30 minutes with gentle stirring. Next, using a homomixer (product name: Omnimixer GLH, manufactured by Omni Corporation), the liquid temperature was cooled to 25 ° C. with vigorous stirring for 30 minutes at a rotational speed of 15000 rpm. Furthermore, the obtained suspension was treated with an ultrasonic disperser (trade name: UH-600-SR (manufactured by SSM Corporation) output 600 W, frequency 20 kHz) for 10 minutes,
A polymer micelle-containing preparation was obtained. When the particle size of the polymer micelle was measured with a light scattering particle size measuring apparatus (Malvern, Zetasizer 1000), the average particle size was 110 nm.

  Place 0.5 g of polymer micelle-containing preparation in a dialysis membrane, dialyze 3 times in physiological saline, and then put it in ethanol / water, 3/1 to break the polymer micelle and determine the concentration of the contrast agent contained. When measured with a spectrophotometer, it was found that 12% of the drug was contained.

Claims (5)

While stirring and mixing the aqueous solution of the water-soluble drug and the block copolymer, the liquid temperature is raised to 40 to 70 ° C, and then the resulting suspension is vigorously stirred and the liquid temperature is cooled to 15 to 35 ° C. A method for producing a polymer micelle-containing preparation comprising encapsulating a water-soluble drug in a polymer micelle formed from the block copolymer,
The block copolymer is represented by the following formula (I) or (II): A method for producing a polymer micelle-containing preparation.

[In the above formulas, R ₁ and R ₃ represent a hydrogen atom or a C ₁ -C ₄ lower alkyl group substituted or unsubstituted by an optionally protected functional group ,
R ₂ represents a hydrogen atom, a saturated or unsaturated C ₁ -C ₂₉ aliphatic carbonyl group, or an arylcarbonyl group,
R ₄ represents a hydroxyl group, a saturated or unsaturated C _{1 to} C ₃₀ aliphatic oxy group, or an aryl-lower alkyloxy group,
R ₅ represents a benzyl group, an alkylbenzyl group, or an allyl group,
L ₁ and L ₂ represent a linking group,
n is an integer from 10 to 2500, x and y are the same or different, and their sum is 10 to 300, and x: y is in the range of 8: 2 to 0: 1; and -COC (CH ₂ COOH) HNH- and -COC (CH ₂ COOR ₅₎ HNH- repeating units are present at random, respectively. ].   The method for producing a polymer micelle-containing preparation according to claim 1, wherein the suspension is cooled and then irradiated with ultrasonic waves for at least 5 minutes.   The method for producing a polymer micelle-containing preparation according to claim 2, wherein the ultrasonic frequency is 10 to 100 kHz. L _{1 in the} formula (I) is —NH—, —O—, —CO—, —CH ₂ —, —O—Z—S—Z—, —O—Z—NH— or —OCO—Z—. NH- (Z is C ₁ -C a ₄ alkylene group) represent a group selected from the group consisting of,
From the formula (II), L ₂ represents —OCO—Z—CO—, —NHCO—Z—CO—, —O—Z—NH— (wherein Z is a C ₁ -C ₄ alkylene group). The method for producing a polymer micelle-containing preparation according to any one of claims 1 to 3, which represents a group selected from the group consisting of: The method for producing a polymer micelle-containing preparation according to any one of claims 1 to 4 , wherein the water-soluble drug is a contrast compound or an anticancer substance.