JP3220069B2 - Drug-containing polymer micelle and pharmaceutical preparation thereof - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a polymer micelle containing a drug and a pharmaceutical preparation thereof, and more particularly to a polymer micelle capable of reducing the toxicity of a polyene antibiotic.

[0002]

BACKGROUND OF THE INVENTION It has been known that polyene antibiotics (or polyene macrolides) bind to cell membrane sterols of fungi and other eukaryotic cells to change membrane fluidity, thereby having a function of damaging the membrane. ing. Those having a high selectivity for fungi-specific ergosterol are used as antifungal agents. Above all,
An overview of amphotericin B (hereinafter also referred to as AmB), which is the most selective toxicity and is a typical compound of polyene antibiotics, will be given below.

[0003] AmB is a broad spectrum antifungal drug used in the treatment of systemic fungal diseases. In immunocompromised (compromised) hosts, these diseases are the leading cause of death and are also diseases that have increased with AIDS and aggressive chemotherapy, such as in cancer treatment and organ transplantation. AmB has been used for over 30 years, and despite the development of new antifungal agents,
It is still the drug of choice for systemic fungal disease.
For example, an aqueous solution of a complex of AmB and deoxycholate [eg, Fungizone ™, Bristol-Myers
Squibb] has been used as an injection for treating deep mycosis.

[0004] However, although specific preparations of AmB have been widely used as therapeutic agents for systemic fungal diseases, they have toxicity,
It is especially known to be highly renal toxic and cause general malaise, anemia and phlebitis. Also, AmB
Is water-insoluble and its precipitation in diluents and infusions may be associated with acute toxicity. From this perspective,
Attempts have been made to increase the water solubility of AmB by chemical modification, but has not succeeded in reducing toxicity.

Therefore, AmB is wrapped in a drug carrier.
As a result, vigorous research has been conducted to improve the efficacy of AmB
Is being done. In particular, for the last decade, lipid-based
AmB carriers have been extensively studied and some of them
Is to reduce the toxicity of AmB while maintaining its antibacterial activity.
Some success in reducing. In such formulations
It is unknown why AmB toxicity is reduced in
AmB concentration in kidney is found to be low
[J. Brajtburg, et al., Clin. Microbiol. Rev.9
(1996) pp. 512-531]. Other offers
The proposed formulation of AmB may be an oil-in-water emulsion or a wash.
The micellar system of the agent. For example, C. Tasset, et al.,
J. Pharm. Pharmacol.43(1991) pp. 297-
302 is a polyoxyethylene glycol (POE)
An example using mixed micelles of a derivative as a carrier is described.
You. According to this report, POE derivatives of cholesterol
Solubilizes AmB,in in vitro Antifungal of AmB
Without changing the activityin in vitro and in vivo 
Can reduce the toxicity of AmB in
OE derivative also solubilizes AmB and reduces hemolytic activity
Is taught. J. Barwicz, et a
l., Antimicrob. Agents Chemother.,36(199
2), pp. 2310-2315, as a carrier,
Fungizone using sodium deoxycholate
The high toxicity of (marker) is caused by aggregation (or self-association) of AmB.
Lauryl sucrose (LS)
Is used as a carrier, and the mixture molar ratio of LS to AmB is selected.
(Eg, LS / AmB about 50)
Exists in monomeric form and reduces AmB toxicity
Has been suggested.

[0006] As described above, some of the AmB preparations contain A
Although it has succeeded in reducing the toxicity of mB, it has not always succeeded in providing a physically stable AmB preparation which can contain AmB at a high level.

On the other hand, among the carriers used in the preparation of other drugs, an interesting one will be outlined.

[0008] The present inventors have developed a method for solubilizing and delivering drugs.
Research on the use of polymer micelles as a carrier
[K. Kataoka, et al., J. Controlled Release24
(1993) pp. 119-132; G. S. Kwon, et a.
l., Adv. Drug Delivery Rev. 16 (1995) pp.
259-309, etc.]. According to these papers, Shell
Formable poly (ethylene oxide) (hereinafter also referred to as PEO)
Block) and a core-forming polymer that is a biodegradable polymer.
Diblock copolymer consisting of L (amino acid) blocks
Polymer-derived micelles from nano-sized core / shell
A hydrophobic drug, pyrene, doxorubicin
[Also called adriamycin (ADM)] and
And solubilization of indomethacin.
In addition, those papers show that core forming blocks
Constructing a poly (L-amino acid) with L-aspartic acid,
ADM is covalently linked via its β-carboxyl group.
Conjugate type polymer micelle
Is the absorption, excretion, and tissue (or
Exhibit very interesting properties in the selectivity of organs)
Are also described. G. S. Kwon, et al., Pharmaceuti
cal Research,12(1995) pp. 192-195
Are different from micelles to which drugs such as
The block derived from L-aspartic acid is poly (β-beta)
Nil L-partate) (hereinafter also referred to as PBLA)
The polymer micelle of PEO-PBLA constructed in
DM can be physically stably confined in micelles.
And can significantly affect the pharmacokinetics of ADM
It is also described. In addition, this document includes ADM
Have also been suggested to self-associate within micelles.

[0009]

As described above, there is provided an AmB preparation using a lipid liposome or a mixed micelle of a detergent,
It has been reported that the toxicity of AmB itself can be reduced, some of which have been used clinically. However, there is still a strong demand for providing a physically stable AmB formulation that increases the drug content in the formulation while reducing toxicity.

In order to satisfy such demands, the present inventors have intensively studied whether the above-mentioned polymer micelle system can be used as a carrier. As a result, structural AmB is clearly distinguished from anthracycline antibiotic ADM, in particular, despite having a specific object of <br/> shown amphipathic, consisting of PEO-PBLA It was confirmed that the drug-containing polymer micelles were stably confined in the polymer micelles derived from the block copolymer and exhibited sustained drug release.

By the way, ADM is a PEO-PBLA
It is known that self-assemblies will take place in the
et al., Pharmaceutical Research,12(1995)
pp. 192-195), but AmB
Filled PEO-PBLA micelles convert AmB to monomeric
Can be supported and released in micelles in a form,
In addition, the fact that the toxicity of AmB can be significantly reduced
Was found. This reduction in toxicity is due to the high toxicity of AmB
There is a suggestion that this is due to self-association of mB (see above,
 Barwicz, et al., Antimicrob.Agents Chemother.,
36(1992) pp.2310-2315)
Can be understood by taking into account Furthermore, such as
The behavior of the mixed micelle system of AmB and PEO-PBLA is Am
B and other polyene antibiotics and PEO-Po
Li (β-alkyl or aralkyl L-aspartate
G) or PEO-poly (γ-alkyl or arral)
(L-glutamate) can also be reproduced.

Thus, according to the present invention, there is provided a polymeric micelle containing a drug, wherein the drug is a polyene antibiotic and the polymer is poly (ethylene oxide) -block-poly (β-alkyl or aralkyl L-aspartate). ) And poly (ethylene oxide) -block-poly (γ-alkyl or aralkyl L-glutamate), and a polyene antibiotic, preferably in the form of a monomer, of said block copolymer. A polymer micelle is provided, wherein the polymer micelle is confined within the polymer micelle. Such polymer micelles are stable enough to be filter sterilizable in aqueous solutions, slowly release the drug from the polymer micelle core over a long period of time while retaining its activity, and also have a very narrow size distribution of nano-sized Aqueous solutions or dispersions of these polymeric micelles can be used directly as pharmaceutical preparations, as they can be provided as granules.

Further, the drug-containing polymer micelle according to the present invention is stable even in a lyophilized form, and can be mixed with other pharmaceutical ingredients as it is, and by returning this lyophilized product to an aqueous medium. It can also be reconstituted into a polymer micelle solution (or dispersion) that behaves similarly to the starting polymer micelle. The solution thus reconstituted can also be kept stable at high drug content.

Therefore, in another aspect of the present invention,
There is provided a pharmaceutical preparation containing the drug-containing polymer micelle as an active ingredient in a lyophilized state.

According to a further aspect of the present invention, there is provided a pharmaceutical preparation containing the drug-containing polymer micelle as an active ingredient in a state of being dissolved or dispersed in an aqueous medium.

[0016]

DETAILED DESCRIPTION OF THE INVENTION Drugs entrapped in polymeric micelles according to the present invention include any compound belonging to the polyene class of antibiotics, as long as it is for the purpose of the present invention. Specific examples of polyene antibiotics include:
The following formula

[0017]

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Amphotericin B (AmB) represented by
The following formula

[0019]

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Nystatin represented by the following formula:

[0021]

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Pimaridine represented by the following formula:

[0023]

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Pentamycin and the like. In particular, polymer micelles relating to AmB, which have the best selective toxicity, are preferred.

The polymer which can be used in the present invention is
It belongs to the AB type block copolymer, and the polymer block is composed of poly (ethylene oxide) and poly (β-alkyl or aralkyl L-aspartate) or poly (γ-alkyl or aralkyl L-glutamate). The alkyl or aralkyl group in L-aspartate or L-glutamate may be any group that can trap the above drugs and release them slowly. Specific examples of such alkyl groups include linear or branched C _1-20 alkyl, such as methyl, ethyl, propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, hexyl,
Octyl, decanyl, undecanyl, tetradecanyl,
Hexadecanyl, octadecanyl and eicosanil can be mentioned, and among these, tert-butyl, octyltetradecanyl and hexadecanyl having a certain bulkiness can be mentioned as preferred. An aralkyl group has _{1 to 3} hydrogen atoms of a C _1-3 alkyl group.
Among the above-mentioned groups substituted with an aryl group, benzyl and benzhydryl can be particularly mentioned. Of these alkyl and aralkyl groups,
Particularly preferred is a benzyl group. On the other hand, blocks derived from amino acids are preferred because poly (L-aspartate) provides a more stable polymer.

Accordingly, in the present invention, poly (ethylene oxide) -block-poly (β-alkyl or aralkyl L-aspartate) or -poly (γ-
Preferred alkyl or aralkyl L-glutamate) are the block copolymers of PEO-PBLA described above. Hereinafter, the AB type block copolymer used in the present invention will be described with reference to a block copolymer composed of PEO-PBLA. In addition, "PEO-PB
“Consisting of” in “consisting of LA” means the following general formula:

[0027]

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In other words, at both ends or one end of PEO-PBLA, or between PEO and PBLA, any group which does not adversely affect the formation of the polymer micelle according to the present invention is shared. It means that they may be combined. Specifically, a group derived from an initiator or a protecting group for a hydroxyl group (corresponding to X in the above formula) used for polymerizing ethylene oxide, for example, an acetal may be bound to the terminal of PEO. In addition, a PEO block is formed between the PEO and the PBLA, and, for example, an imino group (—NH—) (corresponding to Y in the above formula) so as to act as an initiator for forming the PBLA block. May be present. Further, the amino group of β-benzyl aspartate at the end of PBLA may be protected by any amino protecting group (corresponding to Z in the above formula) as used in the field of peptide synthesis. In addition, when it does not have such a protecting group, Z represents a hydrogen atom.

P in each block of PEO-PBLA
The molecular weights of EO and PBLA may be in any range as long as they can form polymer micelles. Thus, without limitation, m is 2
It is an integer of any of 10 to 10,000, preferably 20 to 1,000, and more preferably 40 to 400. On the other hand, n
Is an integer of 2 to 10,000, preferably 20 to 1,000, more preferably 10 to 100.

For example, formula (I):

[0031]

Embedded image

The PEO block of PEO-PBLA represented by the formula is about 12,000 g / mol (m = about 270), and the PEB block is about 3,000 g / mol (n =
When n and m are constant integers such that about 12), such block copolymer drug-containing polymer micelles have an average particle size of about 20 nm to about 30 nm. According to the present invention, the average particle size of the polymeric micelles will vary depending on the type and amount of block copolymer making up the micelles, and will average from about 5 nm to about 1000 nm, preferably from about 10 nm to about 500 nm, more preferably about 10 nm. 2
0 nm to about 100 nm.

Such a drug-containing polymer micelle comprises A
The molar ratio of mB / PEO-PBLA can be set to 1.0 or less, and it is desirable that the drug content density in the preparation is as high as possible.
Attention should be paid to the fact that it may show hemolytic activity like (trademark).

As described above, the drug-containing polymer micelle according to the present invention has a nano-sized core / shell structure and has physical stability that enables filtration sterilization. Also, without being bound by theory, the drug-containing polymeric micelles of the present invention have a drug-filled (or confined) core, preferably in monomeric form, masked by a hydrophilic shell. There is a feature in the point. Furthermore, although these micelles are extremely stable, they can gradually be cleaved into individual polymers and even monomers [see K. Kataoka, et al., GS Kwon, et.
al., see].

In addition, the drug-containing polymeric micelles according to the present invention are capable of slowly releasing the drug from its core in monomeric form when placed in an aqueous environment.

A further feature of the drug-containing polymeric micelles according to the invention is that they have the property that the lyophilized one can be easily dissolved in an aqueous solution in a few seconds. For example, P
Given that both EO-PBLA and AmB are poorly soluble in water when placed individually in aqueous solution, the lyophilized drug-containing polymeric micelles according to the present invention exhibit extremely unique properties. I can say. Thus, the use of lyophilized polymer micelles makes it possible to obtain a high-concentration AmB solution. For example, the concentration of AmB in an aqueous solution is 5.0 mg / ml (approximately 10,000 of the solubility of AmB itself).
Times).

As described above, the drug-containing polymer micelle according to the present invention is freeze-dried and then dissolved again in an aqueous solution (reconstitution).
Even in this case, the morphology of the polymer micelles is maintained in an intact state, and the drug release behavior from the core is not substantially changed from that before freeze-drying. Further, such micelles do not show a hemolytic effect on erythrocytes even at a concentration of 10 μg / ml.

The block copolymer used in the present invention can be produced according to a method known per se [for example, M. Yokoyama, et al., Bioconjugate Ch.
em. 3 (1992) pp. 291-301]. Specifically, α-methyl-ω-amino-PE prepared in advance
O:

[0039]

Embedded image

Is used as an initiator, and the corresponding aspartic acid β-ester N-carboxyanhydride (NC
A):

[0041]

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(R represents an alkyl or aralkyl group).

On the other hand, poly (γ-
Block copolymers with alkyl or aralkyl L-glutamate) are described, for example, in Z. Hruska et al., Poly.
mer 34 (1993) p. 1333-1335 or an improved method thereof.

The drug-containing polymer micelles provided above can be prepared into pharmaceutical preparations containing them as active ingredients. For example, when preparing for parenteral administration,
The drug-containing polymer micelles may be dissolved or dispersed in saccharides or physiological saline to which a physiologically acceptable buffer has been added, if necessary, in order to adjust isotonicity and pH. Further, if necessary, when vegetable oil (olive oil, castor oil, sesame oil, etc.) is intravenously injected into such a solution preparation, the total dose may be adjusted by a doctor or other expert according to the patient's age, weight, and disease state. As determined, it is usually administered as a solution at 50-100 μg / ml at the AmB level.
In addition, such a solution preparation may be one in which a lyophilized drug-containing polymer micelle is reconstituted into a solution at the time of use. The orally administered drug can be prepared by mixing the lyophilized drug-containing polymer micelle with a diluent or excipient commonly used for the preparation of an orally administered drug, if necessary. Such oral administration preparations can be prepared into tablets, capsules, granules and the like, and excipients that can be used in this case include, for example, starch, lactose, sucrose, glucose, mannitol and silica as fillers and bulking agents. Acids, such as carboxymethylcellulose, alginate, gelatin and polyvinylpyrrolidone as binders, wetting agents such as glycerol, disintegrants such as agar-agar, calcium carbonate and sodium carbonate, kaolin and bentonite as absorbents, and lubrication. As an agent, talc,
Mention may be made of calcium stearate, magnesium stearate and solid polyethylene glycol.

[0045]

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to specific examples of polymer micelles prepared using AmB as a drug and PEO-PBLA as a polymer.
The present invention is not limited to these.

Example 1: Preparation of PEB-PBLA micelle containing AmB (1) PE represented by the above formula (I) used in this example
O-PBLA is available from M.P. Yokoyama, et al., Bioconjugate
Chem. 3 (1992) pp. 291-301, each of which had a PEO block of 12,000 g / mol and a PBLA block of 3,000 g / mol.

PEO-PBLA (20 mg) was 4.0 m
of dimethylformamide (DMF) under heating (40
C) for 5 minutes to obtain a polymer solution. A predetermined amount of AmB (Dumex, Denmark) was added to the polymer solution and dissolved by stirring. This solution was distilled water (pH = 1).
Dialyzed 3 times against 2 L (adjusted to 1.3) (Spectra-po)
r, MWCO 12,000 to 14,000 g / mol). The dialysis time was 40 hours. Thereafter, the dialysis medium was neutralized to pH 5.6 with 1.0 N HCl. The isotonicity in the dialysis bag was adjusted with dextrose. The solution in the dialysis bag is taken out, filtered through a 0.22 μm filter, and filtered.
Stored at ° C.

(2) Preparation of freeze-dried polymer micelle Instead of the dialysis described in (1) above, dialysis was performed without adjusting isotonicity, followed by filtration through a 0.22 μm filter and lyophilization. The procedure of Example 1 was repeated.

FIG. 1 shows a conceptual diagram of the dialysis step.

During this process, the solubilization of AmB occurs during the self-assembly of the PEO-PBLA micelles, and DMF is exchanged with an alkaline aqueous solution through dialysis. PH of aqueous solution
AmB, which is incompletely incorporated by holding at 11.3, is ionized and removed by dialysis. When the initial amount of AmB used was 2.0 mg and 4.0 mg, the PEO-PBLA micelles added AmB to 5 mg each.
Solubilized at a level of 7 μg / ml and 141 μg / ml. The yield and other data are summarized in Table I below.

[0051]

[Table 1]

Example 2: Absorption of UV / VIS spectrum of AmB-containing PEO-PBLA micelle solution AmB-containing PEO-PBLA prepared in Example 1 (1) above
Micellar aqueous solution (0.024% w / w) and Fung
izone ™ (0.002155% w / w) with Spectr
onic 3000 ultraviolet-visible spectrophotometer spectrograms measured at (Milton Ray) shown in FIG. Fungizone has major absorption on the low wavelength side, whereas AmB-containing PEO
The -PBLA micelle solution still has major absorption on the high wavelength side, and it can be confirmed that AmB is not self-associated.

Example 3: Examination of PEO-PBLA micelles by transmission electron microscope (TEM) The method of reverse staining PEO-PBLA micelles is as follows. PEO-PBLA micelle solution (about 1.0
mg / ml in water) was placed on the membrane-coated grid. Remove excess liquid from the grid surface with filter paper (Whatma
n, No. 1). Immediately, a drop of 1% phosphotungstic acid was added to the surface. After one minute, excess liquid was removed, the surface was air dried, and the grid was loaded on a transmission electron microscope (Hitachi H7000). Pictures were taken at 18,000 times magnification (75 kV). TEM can resolve nano-range colloids as polymer micelles. The above photograph is shown in FIG. The photograph clearly shows a spherical PEO-PBLA, consistent with the results of early dynamic light scattering on polymer micelles. The average diameter of PEO-PBLA micelles is the average value of the results of direct measurement of 100 polymer micelles in a TEM photograph. The average diameters of drug-free micelles and drug-containing micelles were 20.0 ± 3.9 nm and 25.8 ± 4.2 nm, respectively. The size distribution of these PEO-PBLA micelles is
It turns out that it is very narrow. Independently of the polymer micelles, micelles of AmB itself (without using PEO-PBLA) were obtained by the above dialysis method, and the average diameter of these micelles was 12.9 ± 2.4 nm. Example 4: Hemolysis by AmB Blood was collected from male Sprague-Dawley rats by cardiac puncture using a syringe previously filled with acidic dextrose acid citrate. Whole blood was centrifuged (2000 rpm) and the supernatant was removed with a pipette. Red blood cells (RBC) were diluted in isotonic PBS. This shows an absorbance at 576 nm of 0.40 in the presence of 20 μg / ml Fungizone ™.

At 37 ° C., the AmB and RBC solutions (5.
0 ml) was incubated and tested for hemolysis. Hemolysis was stopped by lowering the temperature (° C.) and then unlysed RBC was removed by centrifugation for 20 seconds. The supernatant was collected and analyzed for hemoglobin by UV / VIS spectroscopy at 576 nm. The percentage of hemolyzed RBC is
Hemolysis (%) = 100 × (Abs−Abs ₀ ) / (Abs ₁₀₀ −
Abs ₀ ) In the above equation, Abs, Abs ₀ and Abs ₁₀₀ are the sample, AmB-free control and 20 μg / ml Fungi, respectively.
Control in the presence of zone ™.

Result: A confined in PEO-PBLA
mB was measured for AmB even at an AmB level of 10 μg / ml.
It dramatically reduces the hemolytic action of B. When AmB was solubilized with sodium deoxycholate [Fungizone ™], AmB showed strong hemolysis, about 3.0 μg / m 2.
At 1 level 100% hemolysis is reached (see FIG. 4). AmB
Micelles have slightly less hemolysis than Fungizone ™ due to the absence of sodium deoxycholate. PEO
AmB entrapped in the PBLA micelles did not cause any hemolysis at the level of 3.0 μg / ml, even after 5.5 hours, even at 5.5 hours. This means that PEO-PBL
The slow release of AmB from A micelles is shown (FIG. 5). PEO-PBLA micelles confined with AmB show no hemolytic effect at both AmB / PEO-PBLA molar ratios of 0.40 and 1.0 (FIG. 5).

The slow release of AmB from PEO-PBLA micelles may be due to their core exhibiting solid-like properties. In addition, the lack of hemolysis is due to the lack of monomeric AmB from PEO-PBLA micelles.
May reflect the release of Monomeric AmB
Is known to be less hemolytic than AmB in the aggregated state (see J. Brajtburg et. Al., Supra). In addition, when the molar ratio of AmB / PEO-PBLA exceeds 1.0, it exhibits hemolysis like Fungizone (trademark). On the other hand, PEO-PBLA micelle used for the carrier is 0.70
Even at the mg / ml level, it does not cause any hemolysis (FIG. 6).

<Freeze-dried PEB-PB containing AmB
Characteristics of LA micelles> AmB-containing P obtained in Example 1 (2)
EO-PBLA micelles (in addition, "contain" and "fill"
Is used interchangeably with "trapped")
Dissolves in aqueous solution within seconds. Along with the solubility of PEO-PBLA and AmB are summarized in Table II.

[0058]

[Table 2]

High AmB levels in solution (5.0 mg / m
1) indicates 10,000 times the solubility of AmB, so that the micelle has a solubility in an aqueous solution of AmB
It is 10,000 times or more of B itself. FIG. 7 shows TEM photographs of these micelles. These size distributions also indicate that no secondary aggregation of the AmB-containing PEO-PBLA micelles has occurred.

Example 5: Antifungal activity of AmB AmB (comparative), Fungizone ™ (comparative), AmB-containing PEO-PBLA micelles and PEO-PBLA micelles (control) according to the broth dilution method as shown in Table III below. Was measured for antimicrobial activity. Results are shown as minimum inhibitory concentrations.

[0061]

[Table 3]

It can be seen that the AmB-containing PEO-PBLA micelle of the present invention does not adversely affect the antibacterial activity of AmB, but rather enhances its activity.

[Brief description of the drawings]

FIG. 1 is a conceptual diagram of a process for preparing AmB-containing PEO-PBLA micelles by dialysis.

FIG. 2 PEO-PB containing AmB prepared in Example 1 (1)
Aqueous LA micelles and UV / VIS from Fungizone
It is a figure showing a spectrum.

FIG. 3 is a photograph replacing a transmission electron microscope (TEM) of AmB-containing PEO-PBLA micelles (particles) (top). The lower part is PEO-PBLA micelle (open circle), Am
It is a graph which shows the size distribution of B containing PEO-PBLA micelle (square) and AmB micelle (black circle).

FIG. 4: Rat erythroid cells (R) at various AmB levels as Fungizone (black diamonds), AmB micelles (squares) and PEB-PBLA micelles containing AmB (circles).
It is a graph which shows the hemolytic property of BC). AmB-containing PEO
-AmB / PEO-PBLA of PBLA micelle is 0.4
0 (molar ratio).

FIG. 5: PEO-PBLA containing Fungizone and AmB
Figure 4 is a graph showing the hemolytic properties of rat RBC over time at the micelle AmB 3.0 μg / ml level. AmB of the latter
The molar ratio of / PEO-PBLA is 0.4 and 1.0.

FIG. 6: PEB-PBLA, AmB as Fungizone
FIG. 4 is a graph showing the hemolytic properties of rat RBC at various levels of sodium and sodium deoxycholate.

FIG. 7: AmB-containing PE after reconstitution of freeze-dried powder
It is a photograph which replaces a TEM figure of O-PBLA micelle (particle) (upper part). The lower part is the PEB containing AmB before freeze-drying.
-It is a graph which shows the size distribution (black circle) of the PBLA micelle, and those (white circle) of freeze-drying.

────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Bong Yo 53719, Wisconsin, USA Madison Moreinbeau Drive 305 1124 (56) References JP-A-6-107565 (JP, A) JP-A-6-206830 (JP) , A) J. Pharm. Pharmaco l. , Vol. 43, p. 297-302 (58) Field surveyed (Int. Cl. ⁷ , DB name) A61K 47/34, 9/107

Claims (9)

(57) [Claims] 1. A polymer micelle containing a drug, wherein the drug is amphotericin B, nystatin, pimalizine or the like.
And poly (ethylene oxide) -block-poly (β-alkyl or aralkyl L-aspartate) and poly (ethylene oxide) -block-poly (γ-alkyl). Or aralkyl L-glutamate)
A polymer micelle, wherein the polymer is a block copolymer selected from the group consisting of: and a polyene antibiotic is confined within a polymer micelle of the block copolymer. 2. The polymer micelle according to claim 1, wherein the polyene antibiotic is confined in the polymer micelle in a monomer form. 3. The polymer according to claim 1, wherein the polymer has the following general formula: (Where X is a group derived from an initiator for deriving a poly (ethylene oxide) block, and Y is poly (β-alkyl or aralkyl L-aspartate) or poly (γ-alkyl or aralkyl L
-Glutamate), Z is a hydrogen atom or an amino protecting group, R is an alkyl group or an aralkyl group,
m and n are independently an integer of any of 2 to 10,000, and p is an integer of 1 or 2). 4. The method of claim 1, wherein the polyene antibiotic is amphotericin B.
(AmB), and the polymer is poly (ethylene oxide) -block-poly (β-benzyl L-aspartate). 5. The polymer micelle having an average particle size of 5 nm to 1
The polymer micelle according to any one of claims 1 to 4, which has a molecular weight of 000 nm. 6. The molar ratio of drug to polymer is 0.4.
The polymer micelle according to any one of claims 1 to 5, which has a molecular weight of from 1.0 to 1.0 . 7. A pharmaceutical preparation containing the polymer micelle according to claim 1 as a lyophilized state as an active ingredient. 8. A pharmaceutical preparation comprising, as an active ingredient, the polymer micelle according to claim 1 dissolved or dispersed in an aqueous medium. 9. The method according to claim 1, wherein the drug is from 10 μg / ml to 5.0 mg / m.
The pharmaceutical preparation according to claim 8, which is in a concentration range of 1.