JP2001131092A - Laminar structure for controlling passage of medicine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a laminar structure for controlling passage (or permeation) of medicine. SOLUTION: This laminar structure for controlling passage (or permeation) of a medicine contains at least one layer of polymer micelle layer forming a covalent bond on the surface of a porous polymer membrane or a hydrophilic polymer matrix.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a layered structure for controlling the passage of a drug. More specifically, the present invention relates primarily to membranes for controlling the passage or release of hydrophilic drugs or layered structures in a form capable of encapsulating or loading the drug in a polymer matrix.

[0002]

2. Description of the Related Art At present, many studies have been made on utilizing hydrogels composed of water-soluble polymer compounds for medical treatment. Enzyme is confined in the gel and the surrounding environment (temperature, p
H, a solvent), and is used to create a system that maintains the activity while suppressing denaturation, and to construct a system that allows only small molecules to pass through without attracting biological substances. Also, studies are being conducted on gels that release protein-based drugs while controlling them. Since the proposed gel generally has high drug permeability, the drug was immobilized by a degradable functional group on the polymer compound forming the gel, or was confined in a gel with high biodegradable crosslink density Although reported, it has not always been successful in releasing a zero-order (linear) drug. This is because it is difficult to suppress the diffusion from the inside of the gel or the decomposition rate of the gel. [Harris, JM, Zalipsky, S, eds., Poly (ethylen
e glycol) Chemistry. etc.] More specifically, biodegradable polymers such as polylactide and poly (lactide-coglycolide) are generally used as sustained-release carriers for low-molecular-weight drugs, and their biodegradation rates It has been proposed to release the drug into the body by adjusting the concentration of the drug (eg, US Pat. No. 3,887,699).
However, these carriers are not necessarily suitable for sustained release of peptides, polysaccharides, nucleic acids and the like having a certain molecular weight or more. Further, as a carrier for achieving sustained release of polypeptides, a hydrogel made of a copolymer which can be dispersed in water itself has been proposed. Such a gel is suitable for sustained release of bovine serum albumin (BSA). (For example, Japanese Patent Publication No. 7-106)
987 or U.S. Pat. No. 5,410,016).

[0003]

However, drugs, especially,
There remains a need for means by which polypeptides, polysaccharides, nucleic acids, etc., can be controlled more strictly or to a desired release rate. Accordingly, the object of the present invention is to provide controlled release of drugs belonging mainly to the group of compounds as described above,
In particular, it is to provide a means which allows a sustained release over a long period.

[0004]

The present inventors have previously developed polymer micelles and reported that the surface of various articles can be stably coated with such polymer micelles (Emoto, e).
t al., Langmuir, 1999, 15, 5212). It is also known that such a layer composed of polymer micelles exists as a hydrogel in an aqueous medium and has high biocompatibility.

[0005] It has now been found that when a layer comprising such polymer micelles is carried on a given porous membrane or hydrophilic polymer matrix surface, the rate at which a drug passes through or permeates the layer can be controlled. It has also been found that by making the layers a desired number (or layer thickness), the rate at which the drug passes or permeates these layers can be strictly controlled.

The present invention is based on such findings.

Accordingly, the present invention is directed to a layered structure for controlling the passage of a drug, which comprises a layer of polymer micelle having one functional group capable of forming a covalent bond with each other on the surface and another functional group. A layer of polymer micelles formed by covalent bonding of both functional groups with a porous polymer membrane or a hydrophilic polymer matrix having on the surface thereof, and the polymer micelles are essentially poly (ethylene glycol) The present invention relates to the above-mentioned layered structure, which is formed from a block copolymer having a hydrophilic polymer segment and a hydrophobic polymer segment. Further, as a preferred embodiment of the present invention, the polymer micelle layer is further formed of a polymer compound having a plurality of the other functional groups or a polyfunctional low-molecular compound having two or more other functional groups via a polymer compound. Said layered structure, wherein said layered structure is alternately covalently bonded to a layer.

[0008]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The polymer micelles used in the present invention are essentially poly (ethylene glycol) (hereinafter referred to as "poly (ethylene glycol)").
(Sometimes abbreviated as PEG) and a block copolymer having a hydrophilic polymer segment and a hydrophobic polymer segment. "Essentially ..." means that PEG occupies a major part of the hydrophilic polymer segment, and any linking group or the like that does not essentially affect the hydrophilicity of the segment is included in the PEG chain or hydrophobic group. It means that it may be slightly contained between the polymer segments. However, it is preferred that the PEG chain consist only of PEG.

On the other hand, for the hydrophobic polymer segment, for example, the corresponding block copolymer is dissolved or dispersed in a selective solvent having the solubility of the PEG segment but not the solubility of the hydrophobic segment to form a stable polymer micelle. It may be derived from any polymer as long as it forms. However, preferred hydrophobic polymer segments are poly (α-hydroxycarboxylic acids) derived from glycolide or lactide, or γ-lactone, δ-lactone or ε-lactone.
Examples thereof include poly (ω-hydroxycarboxylic acid) derived from lactone or the like, or those derived from copolymers thereof. Further, these hydrophobic polymer segments may have an ethylenically unsaturated polymerizable group at the terminal opposite to the terminal bonded to the hydrophilic polymer segment.

[0010] Such a copolymer is prepared in an aqueous medium (eg, water containing a buffer, water containing a water-miscible organic solvent (eg, water, methanol, ethanol, acetone, dimethylformamide, etc.)) in a surfactant. It is sufficient if it is dispersible itself without depending on the action of or other additives.
Thus, these copolymers can form polymer micelles, for example, in the manner described below. In addition, the polymerizable group can be introduced from, for example, meth (acrylic) acid or vinylbenzyl chloride, and can be in a polymerized (crosslinked) state by being subjected to a polymerization reaction after polymer micelle formation. When in such a state, the polymeric micelles themselves will become more stable.

On the other hand, the hydrophilic polymer segment has a functional group at the terminal opposite to the terminal bonded to the hydrophobic polymer segment. When the block copolymer forms polymer micelles, the functional groups will generally be at or near the polymer micelle surface. The functional group includes a functional group (another functional group) on the surface of a porous polymer membrane or a hydrophilic polymer matrix, which will be described in detail later, and a polymer compound existing or interposed between polymer micelle layers, if necessary. It becomes a functional group (one functional group) that forms a covalent bond with a functional group (the other functional group) of the polyfunctional low molecular compound. Although not limited, the functional groups of the block copolymer include an aldehyde group, a carboxyl group, a hydroxyl group, a mercapto group, and an amino group.

The block copolymers usable in the present invention include the above-mentioned WO 96/32434 and WO 96/3.
3233 or WO 97/06203, or a block copolymer described in U.S. Pat. No. 5,410,016 or an appropriate functional group thereof (an ethylenically unsaturated polymerizable group at a hydrophobic polymer segment terminal, a hydrophilic polymer Those modified by introducing an aldehyde group or the like at the end of the segment may be mentioned. Preferable are those described in the above three international publication pamphlets, and in the case of a block copolymer having a sugar residue at a terminal of a hydrophilic polymer segment, for example, WO 96/32434, a sugar residue is used. Mention may be made of the formation of the corresponding aldehyde group by Malaprade oxidation of the group.

Specific examples of these block copolymers include those represented by the following formulas (I), (II) and (III). Formula (I):

[0014]

Embedded image Where L is the formula

[0015]

Embedded image Wherein R ¹ and R ² independently represent a hydrogen atom, C _1-10 alkyl, aryl or aryl-C _1-3 alkyl;
r is an integer of 2 to 5, m is an integer of 2 to 10,000, n is an integer of 2 to 10,000, and p is 1 to 5.
5, q is 0 or an integer of 1 to 20,
And Z is acetyl, acryloyl, methacryloyl, cinnamoyl, allyl or vinylbenzyl; Formula (II):

[0016]

Embedded image In the formula, X is an alkyl group having 1 to 10 carbon atoms having an amino group, a carboxyl group or a mercapto group;
Is the expression

[0017]

Embedded image Here, R ¹ and R ² independently represent a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, R ³ represents a hydrogen atom or a methyl group, and R ⁴ is an optionally protected, Represents an alkyl group of 1 to 5 carbon atoms substituted with a hydroxyl group, and q is an integer of 2 to 5, Z is acryloyl, methacryloyl, cinnamoyl, allyl or vinylbenzyl, and m is 2 to 5 Is an integer of 10,000 and n is an integer of 2 to 10,000. Formula (III):

[0018]

Embedded image Where A is the formula

[0019]

Embedded image Here, a dashed line (---) indicates that a sugar residue of one of which represents a single bond, the other represents a hydrogen atom, and a and b are each independently an integer of 0 or 1 is a malaprad ( Malaprade) is a group derived by oxidation,
Is the expression

[0020]

Embedded image Wherein R ¹ and R ² are independently a hydrogen atom C _1-6 alkyl, aryl or C _1-3 alkylaryl, and m is an integer of 2 to 10,000. , N is an integer from 2 to 10,000 and Z is acryloyl, methacryloyl, cinnamoyl, allyl,
Or vinyl benzyl.

The polymer micelle formed from the above block copolymer usually has a form in which the functional group at the terminal of the hydrophilic polymer segment is protected (for example, an aldehyde group is in an acetal or ketalized form, or an amino group is in a form in which the functional group is protected). Etc. are protected by amino protection)
And then subjected to a deprotection grouping reaction. On the other hand, when an ethylenically unsaturated polymerizable group is present at the terminal of the hydrophobic polymer segment, each block copolymer may be polymerized and crosslinked via the polymerizable group after polymer micelle formation.

The porous or hydrophilic polymer matrix according to the invention may be an ultrafiltration membrane or a dialysis membrane, or a microcapsule capable of encapsulating or encapsulating a drug or a drug in a polymer matrix. It may be in any form of the hydrogel surface layer carried on the substrate. Thus, but not by way of limitation, particular contemplated uses of the present invention are ultrafiltration membranes, dialysis membranes, drug carriers for oral or parenteral administration or for implantation in vivo.

The material constituting the film or the microcapsule may be one of the functional groups (for example,
(Aldehyde group, carboxyl group, hydroxyl group, mercapto group, amino group) and another functional group capable of forming a covalent bond, such as an amino group, a mercapto group, a carboxyl group, a plurality of aldehyde groups in the molecule, preferably It can be chosen from film-forming polymers. Examples of the polymer include, but are not limited to, a polymer derived from (meth) acrylic acid or a derivative thereof containing an amino group, a hydroxyl group or a mercapto group, a polypropylene modified with an amino group or a hydroxyl group, and polystyrene. Or organic silicone, poly-α-
Amino acids (eg, polylysine, polyaspartic acid, etc.),
Polysaccharides (eg, carboxymethylcellulose, hydroxypropylcellulose, alginic acid, chitoic acid, etc.) can be mentioned.

The hydrophilic polymer matrix may be formed of any of the above-mentioned polymers capable of forming a hydrogel in an aqueous medium. Polymers (including copolymers) that are themselves dispersible can also be included.

In the polymer micelle layer of the present invention, one of the functional groups present on the surface of the polymer micelle is covalently bonded to the other functional group in the polymer molecule constituting the membrane or the hydrophilic polymer matrix. A layered structure having a form in which a polymer micelle layer is laminated on the surface of a polymer matrix is formed. FIG. 1 shows a conceptual diagram of such a layered structure. The polymer micelle layer formed in this manner utilizes one functional group remaining without being used for bonding the polymer micelle to the surface of the membrane or the hydrophilic polymer matrix, and has a plurality of other functional groups. A molecular compound or a polyfunctional low-molecular compound having two or more (preferably 2 or 3) other functional groups is covalently bonded to the surface of the layer, and the high-molecular compound or the polyfunctional low-molecular compound is Utilizing the other functional group remaining without being used for covalent bonding, a further polymer micelle layer is alternately laminated with the layer composed of the high molecular compound or the polyfunctional low molecular compound. There can be.

Thus, the layered structure according to the present invention has 1
The thickness of the hydrogel layer composed of polymer micelles can be in the form of laminated polymer micelle layers, including, but not limited to, several tens nanometers to several hundred nanometers, depending on the number of layers. Can be provided. Thus, adjusting the thickness of the polymer micelle layer and the nature of the membrane or polymer matrix to which the layer is covalently bonded, can control the rate of passage through a layered structure such as a drug. it can.

The drug intended to be used in the layered structure according to the present invention is not particularly limited as long as it can control the rate of passage or release of the drug. ,
Oligodeoxynucleotides or polydeoxynucleotides, oligonucleotides or polynucleotides, oligosaccharides or polysaccharides can be mentioned. These peptides, nucleotides and sugars include any derivatives thereof as long as they do not substantially alter their solubility in water. It can also be a complex thereof, for example, a glycopeptide, glycoprotein, peptidized nucleotide, or judo peptide. For the purpose of providing an indication of the drug that can be used in the present invention, peptides or polypeptides (including proteins) include, for example, vasopressin, oxidosine, somatostatin, insulin, calcitonin, albumin, bacitracin, polymyxin, gramicidin, immunoglobulin, Cytokines and the like.

The layered structure of the present invention can be conveniently prepared as follows. Preparation of polymer micelles: When the above block copolymer is dispersed in an aqueous solvent and stirred by mechanical stirring or ultrasonic treatment, polymer micelles having a size of several tens of nanometers are usually formed. Next, this stirred liquid was subjected to the fractionation molecular weight 12-
By dialysis against water for several hours using 14000 dialysis membrane, polymer micelles can be separated. As the aqueous solvent, a solvent that solubilizes the hydrophilic polymer segment of the block copolymer but cannot solubilize the hydrophobic polymer segment, for example, water, dimethylacetamide, or a mixture thereof is used. Regarding the method for preparing polymer micelles, see WO 97/06202 and Emoto et.
See al., Lamination on membrane or polymer matrix (drug-loaded hydrogel) surface:

A film or a polymer matrix having on its surface a functional group capable of forming a covalent bond with the functional group carried on the block copolymer is prepared. The polymer micelle is brought into contact with the membrane or polymer matrix surface in an aqueous solvent and deposited on the surface, and then, if necessary, in the presence of a basic substance, an oxidizing agent, a condensing agent, and further a reducing agent. A covalent bond is formed between the functional groups by an addition reaction or condensation known per se.

Next, after the unreacted polymer micelles are washed away, the unreacted functional groups of the polymer micelles covalently bonded to the membrane or polymer matrix in the same aqueous solvent as described above are utilized. A covalent bond formation reaction is performed with a polymer compound having a plurality of functional groups capable of forming a covalent bond with a low molecular compound (eg, ethylenediamine, dicarboxylic acid compound, polyol compound, or the like) having two or more such functional groups. This reaction can be carried out by the above addition reaction or condensation reaction.

Furthermore, after the unreacted high molecular compound or polyfunctional low molecular compound is washed away, it is not used for the formation of the covalent bond of the high molecular compound or multifunctional low molecular compound covalently bonded on the polymer micelle. The remaining functional groups are used to covalently bond additional polymer micelles. This covalent bond can be carried out in the same manner as in the covalent bond formation reaction described above. When the functional group of the polymer micelle is an aldehyde group and the functional group on the membrane surface is an amino group, an example of the formation of a covalent bond will be described with reference to the following specific examples. It will be obvious to those skilled in the art how to carry out the reaction between other functional groups known per se as well as the reaction between them.

Thus, a layered structure according to the present invention can be manufactured.

[0033]

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to specific examples using specific block copolymers, polymer compounds, and membrane surfaces, but it is not intended to limit the present invention thereto. .

Example 1 (Reference): Acetal-terminated polyethylene glycol-polylactide block copolymer (Ac
Production of et-PEG-PLA) Under an argon atmosphere, 30 ml of THF, 0.147 g of 3,3-diethoxypropanol and 3.0 m of 0.34 mol / l of potassium naphthalene-THF solution were placed in a reaction vessel.
was added and the mixture was stirred at room temperature for 10 minutes to produce potassium chloride of 3,3-diethoxypropanol. 7.04 g of ethylene oxide was added to this solution, and the mixture was stirred at 1 atm and room temperature. After the reaction for 2 days, 26.0 ml of a DL-lactide 1.92 mol / l-THF solution was added to the solution, followed by addition of 2 ml.
Stirred for hours. Further, 3.1 g of methacrylic anhydride was added, followed by stirring at room temperature for 2 days. The solution was poured into cooled 2-propanol to precipitate the resulting polymer. The precipitate obtained by centrifugation was purified by freeze-drying from benzene. The yield was 11.48 g (79.4%). Polyethylene glycol (PEG) segment, polylactide (PL) determined by GPC and ¹ H-NMR
A) The molecular weights (number average molecular weight: the same applies hereinafter) of the segment and block copolymers were 5,800, 4000 and 9800, respectively.

Example 2 (Reference): Acet-PEG-PLA
Preparation of micelles and conversion to aldehyde PEG-PLA micelles 280 mg of the block copolymer obtained according to Example 1 was dissolved in 40 ml of dimethylacetamide (DMAc) and dialyzed against water using a dialysis membrane having a molecular weight cut-off of 12-14000 (2 l). 2 hours, 5 hours and 8 hours). The dialysate was adjusted to pH 2 by adding 1N-HCl and stirred at room temperature for 2 hours. A 0.1N aqueous solution of NaOH was added to the solution to adjust the pH to 7. Thereafter, the molecular weight cutoff is 12-14.
Dialysis against water using a dialysis membrane of 2,000 for 24 hours. This dialysate was transferred to a flask under an argon atmosphere, and 1.8 (w / w)% potassium persulfate was added to the micelles.
After degassing, the reaction was carried out at 50 ° C. for 24 hours. According to the dynamic light scattering (DLS) measurement, the particle size and the polydispersity index μ / Γ2 of the polymer micelle before and after the polymerization reaction were 35.5 n each.
m, 0.094 and 41.0 nm, 0.125.
The particle size was hardly changed before and after the polymerization.

A 2 g aqueous solution (20 g / l) of sodium dodecyl sulfate (SDS) was added to each 2 ml of the solution before and after the polymerization reaction.
Was added in 1 ml portions, followed by stirring for 24 hours, and DLS measurement.
As a result, although the polymer micelles before the reaction had almost completely disappeared, the polymer micelles after the reaction maintained particles having a particle size and polydispersity of 47.2 nm and 0.106. Thus, it can be seen that the polymer micelle after the reaction is a stable micelle that does not decompose at all even when treated with a surfactant. Was freeze dried before and after the reaction micelles, ¹ in deuterochloroform
When H-NMR measurement was performed, peaks (5.6 and 6.2 ppm) derived from terminal olefins observed before the reaction were observed.
Completely disappeared, indicating that the polymerization proceeded efficiently. As described above, polymerization of the methacryloyl group at the terminal of polylactide resulted in extremely stable polymer micelles.

Example 3: Coating of polymer micelle Polypropylene porous membrane (Daicel Chemical, Celgard 25)
00) The surface was immersed in a 10% polyhydroxyethyl methacrylate (PHEMA) / methanol solution for 1 hour and dried at normal temperature and pressure for 1 day. Both sides of this film are plasma (SAMCO INTER INTERNATIONAL, model BP-1) by a mixed gas of nitrogen and hydrogen (N ₂ : H ₂ = 1: 2).
75 W, 30 minutes) to introduce an amino group on the surface [Em
oto, et, al., Langmuir, 1999, 15, 5212]. Polymer micelles prepared according to Example 2 in PHEMA / Celgard film with amino groups introduced, followed by polyallylamine (Nitto Boseki, PAA-L, molecular weight 10,
000) (other amines such as polyvinylamine, polylysine, etc., and ammonia, diamine, etc. are also possible) in the presence of a reducing agent (see FIG. 1). The above membrane sample was added to a 1 mg / ml micelle solution (0.04M HEPES,
(0.0032 w / v% NaCNBH ₃ ) at room temperature for 2 hours. The sample is washed with pure water and 0.6 w / v%
Polyallylamine solution (0.04M HEPES, 0.2
5% w / v NaCNBH ₃ ) for 2 hours. By repeating these steps, a laminated polymer micelle gel thin film was constructed. However, the last micelle coat was 0.04 M HEPES, 0.25 w / v% Na
CNBH ₃ was used.

For comparison, a polyethylene glycol (PEG) coat was a 1 mg / mL solution of PEG (molecular weight 5000) having an aldehyde group at one end (0.04 M HEPES, 0.25 (w / v)). )% NaC
NBH ₃ ) at room temperature for 2 hours.

Example 4: Permeation of dextran (test) A membrane sample was set in a two-chamber cell as shown in FIG. 2, and a buffer (physiological phosphate buffer; pH 7.4, 0.02M, 0.2 M) was placed in one chamber. 05% NaN ₃ containing) the other side to 0.2 g / L of FITC (fluorescently labeled) dextran (SIGMA FD-10S, molecular weight 9500) / buffer solution (0.2 g / L) placed,
The transmission of dextran to the buffer side was determined by the fluorescence intensity of FITC (emission 495 nm, excitation 520 n).
It was examined from the change in m). The solution on the buffer side was sampled, and the concentration of dextran transmitted to the buffer was measured by a fluorescence spectrometer to determine the transmittance. Figure 3 shows PHEMA
The transmittance of dextran of coated Celgard, one layer of micelle coat, three layers of micelle coat, and PEG-coated sample is shown. Compared to a sample simply coated with PHEMA, PEG was coated by plasma treatment but dextran permeation increased, but when PEG was coated on PHEMA whose surface was eroded by the plasma treatment, the molecules themselves were small (Rg 〜１０10 nm), PHEM
It is considered that the increase in the surface hydrophilicity of A and the expansion of the inside promoted the penetration of dextran. Micelle 1
The layer-coated one recovers to the same level as the original film,
Further, in the case of coating with three layers, transmission was greatly suppressed.
It is considered that when micelles are coated on the surface eroded by the plasma, PHEMA on the surface is cross-linked, and transmission is suppressed because of high-density coating.

[0040]

According to the present invention, when a polymer micelle layer is multi-layer coated on a membrane surface, a network of polymer micelles can be formed on the surface, and therefore, the drug permeation speed can be greatly suppressed. It can be understood that this action and effect can be similarly achieved in oligosaccharides, oligopeptides or polypeptides (proteins), oligodeoxynucleotides or polydeoxynucleotides, oligonucleotides or polynucleotides, and the like. It is also understood that the effect of the polymer micelle layer bound to the membrane to permeate the drug can also suppress the rate of permeation and release of the drug encapsulated by such a layer through the layer. . Therefore, the present invention can be used as a means for achieving ultrafiltration or permeation of a drug as described above, and sustained release of the drug.

[Brief description of the drawings]

FIG. 1 shows a conceptual diagram of a layered structure in which polymer micelle layers are laminated according to the present invention.

FIG. 2 is a schematic diagram of a two-chamber cell used in the dextran permeation test of Example 4.

FIG. 3 is a graphical representation of transmittance by a dextran permeation test using various membranes of Example 4. The white corner is a PHEMA coat film, the black corner is a PEG coat film, the white circle is a polymer micelle once coat film, the black circle is a polymer micelle three coat film,
These are the results used.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C08J 7/12 CES C08J 7/12 CESC // C08F 299/00 C08F 299/00 299/02 299/02 299 / 04 299/04 C08L 101: 00 C08L 101: 00 (72) Inventor Michihiro Iijima 2-1 Akebono, Yokkaichi-shi, Mie Prefecture Mitsubishi Chemical Akebono House, Building 3, Room 23 F-term (reference) 4C076 AA09 AA67 EE23M EE49M FF31 GG50 4F073 AA11 BA08 BB04 BB09 EA02 EA11 EA62 EA63 EA64 EA65 FA01 4F100 AK01A AK31C AK41B AK41J AK54B AK54J AL02B BA02 BA03 BA07 BA10A BA10B BA10C BA15 DJ01A GB15 GB66 JB05A JD16 JM08A4A0 AC02 A01 A02 AC02 EG00 EH01 FA17 FA18 FB03 GA31 GA32 GA41 GA42 GA43 JE182

Claims (10)

[Claims] 1. A layered structure for controlling the passage of a drug, comprising a layer of polymer micelle having one functional group capable of forming a covalent bond with each other on the surface and another functional group on the surface. A layer of polymer micelles formed by a porous polymer membrane or a hydrophilic polymer matrix formed through the covalent bonding of both functional groups, and wherein the polymer micelles consist essentially of poly (ethylene glycol). The above layer structure, which is formed from a block copolymer having a polymer segment and a hydrophobic polymer segment. 2. The polymer micelle layer alternates with a further polymer micelle layer via the high molecular compound having a plurality of the other functional groups or the polyfunctional low molecular compound having two or more other functional groups. The layered structure according to claim 1, which is covalently bonded. 3. The layered structure according to claim 1, which is in the form of a film or a form capable of encapsulating a drug. 4. The method according to claim 1, wherein the hydrophobic polymer segment is poly (α-
The layered structure according to any one of claims 1 to 3, wherein the layered structure is selected from the group consisting of (hydroxycarboxylic acids) and poly (ω-hydroxycarboxylic acids). 5. The layered structure according to claim 1, wherein the hydrophobic polymer segment has an ethylenically unsaturated polymerizable group at its terminal, and the polymerizable group is polymerized in a polymer micelle. Structure. 6. The layered structure according to claim 1, wherein the functional group of the polymer micelle is selected from the group consisting of an aldehyde group, a carboxyl group, a hydroxyl group, a mercapto group and an amino group. 7. The layered structure according to claim 6, wherein the high molecular compound or low molecular compound and the functional group of the support are independently selected from the group consisting of an amino group, a mercapto group, a carboxyl group and a sulfo group. . 8. The polymer micelle of the formula (I) Where L is the formula Here, R ¹ and R ² independently represent a hydrogen atom, C _1-10 alkyl, aryl or aryl-C _1-3 alkyl, r is an integer of 2 to 5, m is 2 to 10,000. N is an integer from 2 to 10,000, p is an integer from 1 to 5, q is an integer from 0 or 1 to 20, and Z is acetyl, acryloyl, methacryloyl, cinnamoyl,
A block copolymer represented by allyl or vinylbenzyl, or a compound represented by the formula (II): In the formula, X is an alkyl group having 1 to 10 carbon atoms having an amino group, a carboxyl group or a mercapto group, and Y is a group represented by the formula: Here, R ¹ and R ² independently represent a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, R ³ represents a hydrogen atom or a methyl group, and R ⁴ is optionally protected. Represents an alkyl group of 1 to 5 carbon atoms substituted with a hydroxyl group, and q is an integer of 2 to 5, Z is acryloyl, methacryloyl, cinnamoyl, allyl or vinylbenzyl, and m is 2 to 5 1
A block copolymer of the formula (III), wherein n is an integer from 0,000 and n is an integer from 2 to 10,000, or Wherein A is of the formula Here, the dashed line (---) is a group in which either one represents a single bond, the other represents a hydrogen atom, and a and b are independently an integer of 0 or 1, and L is , The formula Wherein R ¹ and R ² are independently a hydrogen atom C _1-6 alkyl, aryl or C _1-3 alkylaryl, and m is an integer of 2 to 10,000. And n is an integer of 2 to 10,000, and Z is a block copolymer represented by acryloyl, methacryloyl, cinnamoyl, allyl, or vinylbenzyl. Structure. 9. The layered structure according to claim 2, wherein the polymer compound is at least one compound selected from the group consisting of polyallylamine, polyvinylamine, polylysine and polyethyleneimine. 10. The drug according to claim 1, wherein the drug is selected from the group consisting of oligosaccharides or polysaccharides, oligopeptides or polypeptides, oligodeoxynucleotides or polydeoxynucleotides, and oligonucleotides or polynucleotides. Layered structure.