JP2003342167A - Pharmaceutical preparation of camptothecin derivative and method for producing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a water-soluble preparation of a camptothecin derivative. <P>SOLUTION: The pharmaceutical composition contains a drug-containing polymer micelle produced by sealing a camptothecin derivative in a polymer micelle containing a hydrophilic segment and a hydrophobic segment and having a carboxy group on the side chain of a part of repeating units in the hydrophobia segment. The invention further provides a method for producing the composition. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a pharmaceutical preparation containing a derivative of a natural alkaloid, camptothecin, as an active ingredient and a method for producing the same. More specifically, this pharmaceutical formulation comprises the active ingredient in a form encapsulated in polymeric micelles.

[0002]

BACKGROUND OF THE INVENTION Camptothecin comprises a quinoline (A and B) ring, as shown in formula (I) below,
A pyrrolidine ring (C) is fused to this ring, and α-
It is an alkaloid having a condensed ring system in which a pyridone ring (D) is condensed and a lactone ring (E) is further condensed on the D ring.

[0003]

[Chemical 1]

(Note that the numbers in the above formulas are the position numbers of each atom usually attached, and the position numbers used in the present specification to indicate camptothecin derivatives are unless otherwise specified.
According to the above position number. 3.) Camptothecin is a topoisomerase I inhibitor and a potent antitumor agent, but is essentially insoluble in physiologically acceptable aqueous media. Therefore, parenteral administration (subcutaneous, intramuscular,
In order to apply camptothecin or a water-insoluble camptothecin derivative to administration of drugs other than oral administration such as intravascular and intraperitoneal administration, for example, the drug is encapsulated in liposomes (see Japanese Patent Publication No. 2001-524512) or Form a complex with phospholipids (see, for example, Japanese Patent Publication No. 10-5
No. 07454 (corresponding to WO 96/11669))
Alternatively, a derivative is proposed which is encapsulated in a polymer micelle (see, for example, JP-A No. 11-335267), or makes camptothecin itself water-soluble without opening the lactone ring (E). (For example, US Pat. Nos. 4,943,579 and 4,473,6).
No. 92, No. 4,545,880, European Patent Application Publication No. 321122, Japanese Unexamined Patent Publication No. 5-222048, and Japanese Patent Publication No.
No. 509740 (corresponding to WO 94/25466),
See Table 8-50221 (corresponding to WO 94/11377). For example, according to JP-A-11-335267, a hydrophobic segment containing a hydrophilic segment containing poly (alkylene oxide) and poly (β-benzyl aspartate-co-glutamic acid or -β-alkyl aspartate). There is described a drug-containing polymer micelle in which camptothecin is encapsulated in a polymer micelle formed by a block copolymer composed of a hydrophobic segment, and a particularly preferable block copolymer is a hydrophobic segment having a β-intermediate or higher alkyl aspartate. -Co-β-benzyl aspartate). It is also described that such drug-containing polymer micelles are solubilized in water.

[0005]

The above-mentioned composition having the phospholipid complex or the drug-containing polymer micelle, and the compound having the water-soluble derivative of camptothecin can be used in the preparation for parenteral administration. There would still be a need to provide formulations (or compositions) with enhanced drug stability and improved water solubility of drug-containing compositions. It is an object of the present invention to provide a composition that meets such needs and a convenient method of making the same.

[0006]

The present inventors have found that even a camptothecin derivative that is water-soluble in its free base form (not in the form of acid addition salt) contains a hydrophilic segment and a hydrophobic segment. The drug-containing polymer micelle obtained by encapsulating the camptothecin derivative in a polymer micelle derived from a block copolymer in which the hydrophobic segment has a carboxyl group in a side chain of a part of its repeating unit further promotes water solubilization of the derivative. , And found that the derivative can be stabilized. In addition, certain water-insoluble or sparingly water-soluble, low to moderately water-soluble camptothecin derivatives (including camptothecin) can be water-solubilized and stable similarly to the drug-containing polymer micelle encapsulating the water-soluble camptothecin derivative. It was also found that the property is enhanced.

Therefore, according to the present invention, there is provided a composition containing a polymer micelle encapsulating a camptothecin derivative, wherein the polymer micelle is derived from a block copolymer comprising a hydrophilic segment and a hydrophobic segment,
Then, a composition in which the hydrophobic segment has a carboxyl group in a side chain of a part of its repeating unit is provided. As a preferred embodiment of the composition, when the composition is reconstituted with an aqueous diluent, substantially all of the polymeric micelles present are in the form of lyophilizates which pass through a sterile filter with a pore size of 0.22 μm. Will be provided.

As another aspect of the present invention, there is provided a method for producing the above composition conveniently, specifically, comprising a hydrophilic segment and a hydrophobic segment, the hydrophobic segment being a repeating unit thereof. A block copolymer having a carboxyl group in a part of its side chain and a camptothecin derivative (in a free base form) are dispersed and dissolved in a volatile organic solvent to form a solution, and then the organic solvent is removed to obtain the thus obtained product. The residue is combined with water and then for a sufficient time to dissolve the residue in water at a suitable temperature (e.g.
Also provided is a method for producing a composition containing a polymer micelle encapsulating a camptothecin derivative, which comprises stirring at 30 ° C. or lower).

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION The camptothecin derivative which can be used in the present invention includes the camptothecin itself represented by the above-mentioned formula (I) and the object of the present invention (in particular, it enhances the stability of the drug and contains the drug. It includes all camptothecin derivatives that can achieve the water solubility of the composition or the solubilization of the drug in water). It does not matter whether such a derivative is publicly known in the literature. The camptothecin derivatives known in the literature include, but are not limited to, the above-mentioned US Pat. Nos. 4,943,579 and 4,
473,692, 4,545,880, European Patent Application Publication No. 321122, JP-A-5-222048,
Tokuyo H8-509740 (corresponding to WO 94/25466), Tokuhyo H8-50221 (WO 94/113)
(Corresponding to 77), and others, JP-A-4-13918
7, JP-A-4-139188, JP-A-5-2793.
No. 70, Tokuyo Hyodai 8-505626, Tokuyo Hyodai 8-509
No. 244, Japanese Patent Laid-Open No. 10-503525, Japanese Patent Laid-Open No. 11-
140085, No. 2001-506270, No. 2001-506282, etc., and the analogs thereof.

According to the present invention, among these derivatives and their analogs, 5-, 7-, 9 of the camptothecin skeleton
-Amino group, mono- or di-substituted amino group at one or more positions selected from the 10- and 11-positions (when the di-substituents are taken together to form a ring together with the nitrogen atom to which they are bonded) Derivatives having side chains carrying (including also) are conveniently used. Although not limited thereto, such a side chain is preferably a group which can be specifically represented by the following formula.

[0011]

[Chemical 2]

In the formula, L is a divalent group connecting the camptothecin skeleton and the amino group at the above-mentioned position, for example, C _1-4 alkylene, ester bond (-OCO-), carbonyl (-C).
O-), or iminocarbonyl (= C = NH),
Or a single bond, and R ¹ and R ² are each independently a hydrogen atom, C _1-4 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-4 alkyl, C _{3- 6} alkenyl, hydroxy C _1-6 alkyl, C _1-4 alkoxy C
_1-4 alkyl, or R ¹ and R ² , together with the nitrogen atom to which they are attached, are saturated alkyl groups which may contain one oxygen, nitrogen or sulfur atom as a ring atom. 5- to 8-membered carbocycles or heterocycles may be formed and consist of one or more identical or different C _1-4 alkyl, halogen, amino, hydroxy, piperidino and piperazino, etc. on these rings. It may have a substituent selected from the group.

At other positions not having such a side chain, C _1-4 alkyl, C _1-4 hydroxyalkyl, hydroxy, alkylenedioxy (-O (CH ₂ ) _m O
-; M represents the integer 1 or 2. ) Halogen (fluorine, chlorine, bromine) and the like may be substituted.

Camptothecin derivatives having such preferred substituents (many of which have antitumor activity equal to or higher than camptothecin exist).
When they are used in the substantially free base form, they generally have a high content of polymer micelles according to the invention (but not limited to about 5 per total weight of drug-containing polymer micelles).
% Or more, preferably about 10% by weight or more, and in some cases, more than 15% by weight), a drug-containing polymer micelle stably encapsulated can be provided. In addition, the above "substantial"
Ni means that the content of the acid addition salt is 5% by weight or less, preferably 0% by weight. Further, such a drug-containing polymer micelle strongly solubilizes the camptothecin derivative itself even if the camptothecin derivative itself is poorly soluble in water, and is apparently water-soluble. The term “apparently” is used to mean that the polymer micelles also include a dispersed state as if they were completely dissolved. Although details will be described later, according to the present invention, the above camptothecin derivative is water-soluble in the form of a free base (in the present invention, “water-soluble” means 25
Even when the drug is dissolved in 0.5 mg or more per 1 ml of water at 0 ° C.), it is possible to provide a stable drug-containing polymer micelle with a high content as described above.
The camptothecin derivative is further accelerated in water solubilization.

Especially, the camptothecin derivative which can be preferably used is not limited, but 9-N, N
-Dimethylethyl-10-hydroxycamptothecin (topotecan), N-desmethyltopotecan, 7-ethyl-10- [1- (4-piperidino) piperidino] carbonyloxycamptothecin, 7-ethyl-9- (N-
Methyl-N-phenyl) amidinocamptothecin, and the like.

The polymer that can be used to form the drug-containing polymer micelles as described above is a block copolymer comprising a hydrophilic segment and a hydrophobic segment, and the hydrophobic segment is a part of its repeating unit. Has a carboxyl group on its side chain.
Here, the term "a part of the side chain" means that 5 to 95%, preferably 10 to 90%, more preferably 30 to 70% of all repeating units constituting the hydrophobic segment are carboxyl groups as side chains. Means occupied by a repeating unit having a group. These block copolymers may contain any hydrophilic segment and any hydrophobic segment as long as they meet the object of the present invention, and specifically include the following. .

The hydrophilic segment includes, but is not limited to, those derived from poly (ethylene glycol) [or poly (ethylene oxide)], polysaccharides, poly (vinylpyrrolidone), poly (vinyl alcohol), and the like. To be Examples of the polysaccharides include starch, dextran, fructan, galactan and the like. Of these, poly (ethylene glycol) segments having various functional groups at one end are provided, and those having a controlled segment size are easily available, which is preferable. On the other hand, although not limited thereto, the hydrophobic segment may be poly [alkyl ((meth) acrylate-co- (meth)]
Acrylic acid], poly (β-alkylaspartate-co-aspartic acid), poly (β-aralkylaspartate-co-aspartic acid), poly (γ-alkylglutamate-co-glutamic acid), poly (γ-aralkylglutamate) -Co-glutamic acid), poly (β-alkylaspartamide-co-aspartic acid) and poly (γ-aralkylglutamide-co-glutamic acid). The block copolymer that can be used in the present invention is composed of the hydrophilic segment and the hydrophobic segment described above, and an aqueous medium (for example, water or buffered water or a water-miscible solvent, methanol, acetone,
(Aqueous solution containing dinaphthylacetamide, polyethylene glycol, saccharides, etc.) which can form polymer micelles, all of which consist of combinations of segments having respective molecular weights, preferably hydrophilic segments Is composed of poly (ethylene glycol), and the hydrophobic segment is composed of the above poly (amino acid derivative). The alkyl and aralkyl in each of the above segments have the following meanings. The alkyl is a C ₁ -C ₂₂ linear or branched alkyl, which is a lower alkyl such as methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-hexyl and the like, and further has a carbon number. There are many common intermediate alkyls, and also tetradecyl, hexadecyl, octodecyl, docosanyl and the like. These groups may optionally be substituted with one or more halogens (eg fluorine, base, bromine) and, in medium to higher alkyl, may be substituted with one hydroxyl group. Good. Aralkyl may include phenyl-C ₁ -C ₄ alkyl, such as benzyl, optionally substituted on the benzene ring by 1 to 3 halogens or lower alkyl.

The poly (amino acid derivative) segment having such a substituent is an alcohol or amine known per se, for example, corresponding to the benzyl group of poly (β-benzyl aspartate) or poly (γ-benzyl glutamate). Can be converted to an ester or amide, followed by partial hydrolysis to give a hydrophobic segment having a carboxyl group in a side chain at a desired ratio.
The degree of partial hydrolysis is such that the repeating unit having a carboxyl group in the side chain is occupied in the above-mentioned proportion. Aspartic acid and glutamic acid can be any optically active type or a mixture thereof. The hydrophilic segment and the hydrophobic segment described above can be linked via a linking group known per se, for example, an ester bond, an amide bond, an imino group, a carbon-carbon bond, an ether bond or the like.

Particularly, a block copolymer which is easy to manufacture and can be conveniently used in the present invention is represented by the following formula (I).
And (II) can be mentioned.

[0020]

[Chemical 3]

In the above formulas, R ₁ and R ₃ each independently represent a hydrogen atom or a lower alkyl group substituted or unsubstituted by an optionally protected functional group, and R ₂ is a hydrogen atom, saturated or R ₅ represents an unsaturated C ₁ -C ₂₉ aliphatic carbonyl group or arylcarbonyl group, R ₄ represents a hydroxyl group, a saturated or unsaturated C ₁ -C ₃₀ aliphatic oxy group or an aryl-lower alkyloxy group, R ₅ Represents phenyl, C ₁ -C ₄ alkyl or benzyl group, L
₁ and L ₂ each independently represent a linking group, and n is 1
Is an integer from 0 to 2500, x and y are the same or different and their sum is from 10 to 300, and x to y is in the range of 7: 3 to 1: 3, and x And y are randomly present. Examples of the functional group which may be protected include a hydroxyl group, an acetal, a ketal, an aldehyde and a sugar residue. When R ₁ and R ₃ represent a lower alkyl group substituted with an optionally protected functional group, the hydrophilic segment is
For example, WO96 / 33233, WO96 / 3243
4, the method described in WO 97/06202 can be followed.

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

According to the present invention, a hydrophilic segment and a hydrophobic segment (herein referred to as “hydrophobic” from the viewpoint of having a lower hydrophilicity than a segment such as poly (ethylene glycol)) are provided. The block copolymers comprising are those capable of forming polymeric micelles that are associated molecular assemblies in an aqueous medium. Such a block copolymer provides a drug-containing (or containing) polymer micelle mainly containing a drug in a core region composed of a hydrophobic segment in an aqueous medium in which a camptothecin derivative coexists, and surrounded by a shell composed of a hydrophilic segment. To do. Usually, when a drug-containing polymer micelle is formed in an aqueous medium using a parent-hydrophobic block copolymer, a hydrophobic-hydrophobic interaction (hydrophobic bond) between a poorly water-soluble drug and a hydrophobic segment, For the first time, it is understood by those skilled in the art that a drug is efficiently encapsulated in a polymer micelle, but according to the present invention, surprisingly, even if the camptothecin derivative is water-soluble, in particular as described above. Those having an amino group or a mono- or di-substituted amino group in the side chain of the camptothecin skeleton are efficiently encapsulated in the polymer micelle. Therefore,
As described above, the drug-containing polymer micelle of the present invention is
Even if the drug is a water-soluble camptothecin derivative as described above, 5 to 15 per total weight of the drug-containing polymer micelle
It is possible to provide a polymer micelle in which a drug is encapsulated at a weight percentage of 15% or more.

The particle size of such a drug-containing polymer micelle can be conveniently controlled by the method for producing the drug micelle according to another embodiment of the present invention described later. Therefore, according to the present invention, their average particle size is 0.22 μm.
It is possible to provide a drug-containing polymer micelle having a narrower particle size distribution and a very narrow particle size distribution if necessary. Such drug-containing polymer micelles are extremely efficient, for example, even when an aqueous solution containing them is filtered with a sterilization filter, almost none or none are unfiltered.
A liquid composition for parenteral preparation can be provided.

Such a liquid composition may optionally contain an auxiliary agent selected from the group consisting of sugars and polyethylene glycol. Such an auxiliary agent enhances the stability of drug-containing micelles, and in some cases, camptothecin derivative itself, and when it is made into a freeze-dried product, it also has an action of preventing aggregation between polymer micelles. Thus, the composition according to the invention is also provided in lyophilized form. The saccharides and polyethylene glycol are not particularly limited as long as they have the above-mentioned action, but maltose, trehalose, xylitol, glucose, sucrose, fructose, lactose, mannitol and dextrin are respectively used as the saccharides. And polyethylene glycol having a molecular weight of about 1000 to about 35,000, for example, various macrogol available for pharmaceutical preparations.

The composition of the present invention as described above can be efficiently produced by the following production method. Therefore, according to the present invention, a block copolymer comprising a hydrophilic segment and a hydrophobic segment and a camptothecin derivative are dispersed and dissolved in a volatile organic solvent to form a solution, and then the organic solvent is removed to obtain A process for the preparation of a composition containing polymeric micelles encapsulating a camptothecin derivative, characterized in that the retentate obtained is combined with water and then stirred at a suitable temperature for a time sufficient for the retentate to dissolve in water. Is also provided.

In the above method of the present invention, the block copolymer and the drug are dispersed and dissolved in a volatile organic solvent. Dispersion and dissolution means not only a state in which the solute block copolymer and the drug are completely dissolved but also a state in which the block copolymer and the drug are solubilized and are dispersed as, for example, polymer micelles. It should be noted that the term “solution” as used herein may include the dispersed state as described above. The solvent that can be used for such a purpose may be any solvent as long as it can achieve the purpose, and examples thereof include methyl alcohol, ethyl alcohol, isopropyl alcohol, acetone, acetonitrile and methyl acetate. , Ethyl acetate, tetrahydrofuran, etc., which have a certain degree of polarity and have volatility (that is, tendency to vaporize) at room temperature. Dispersion dissolution, if it can be heated by the characteristics of the drug,
It may be heated to the boiling point of the solvent, but it is carried out by homogeneously stirring the solute at a temperature below room temperature and above the freezing point of the solvent.

After forming the solution in this way, the solvent is evaporated off under reduced pressure, if necessary. In the present invention, the solvent does not necessarily have to be completely removed, but it is sufficient that the residue after removal of the solvent can maintain a paste or solid state. However, when the resulting drug-encapsulated polymer micelle-containing aqueous solution is directly used as an injection, it is preferable that the solvent be substantially completely removed.

Next, the paste-like or solid residue is combined with water (water may be added to the residue or the residue may be added to water), and the temperature is 30 ° C. or lower, preferably 25 ° C.
Hereafter, stirring is carried out at a temperature of 10 ° C. or 5 ° C. or less.

When the treatment temperature exceeds 60 ° C., drug-containing polymer micelles having an average particle size of more than 220 nm can be produced, and in the case where the above-mentioned sterilization filtration is not required, these polymers can be prepared. Compositions containing micelles are also useful. If necessary, ultrasonic waves may be applied during this stirring. This agitation is carried out for a time sufficient for the residue consisting of the block copolymer and the drug to be almost completely solubilized. The solubilization time varies depending on the type of polymer and the type of drug, and is not limited. However, stirring time of 5 hours or more and 24 hours or less is generally preferable. The ratio of the amount of the residue to the amount of water may be 1:10 to 1: 300.

Thus, in the aqueous solution, drug-encapsulating polymer micelles are formed and exist in a solubilized state. According to the method of the present invention, for example, according to Example 1 described below, the drug-encapsulated polymer micelle has an average particle diameter of about 48 when measured with a dynamic light scattering photometer (Otsuka Electronics Co., Ltd., DLS-7000DH type). It was 0.4 nm.

A filter having a pore size of 0.22 μm is usually
It is well known to be used in the preparation of parenteral agents (for intravenous injection, arterial injection, intramuscular injection, intraperitoneal injection, etc.). The above drug-encapsulating polymer micelle aqueous solution is 0.2
As described above, even if the sterilization filtration is performed using a 2 μm filter, the sterilized drug-encapsulated polymer micelle aqueous solution can be obtained in an extremely high yield when the lysis treatment is performed at a temperature of 30 ° C. or lower. . That is, according to the present invention, an injection can be efficiently provided. As one of the preferred embodiments of the present invention, such an injection is prepared by removing an auxiliary agent that can improve the stability of drug-encapsulated polymer micelles, various sugars, and various polyethylene glycols (trade name, Macrogol). It can be produced by a method further comprising a step of adding to the drug-encapsulated polymer micelle aqueous solution (or aqueous solution) before bacterial filtration. The sugars that can be used include, but are not limited to, maltose, trehalose, xylitol, glucose, sucrose, fructose, lactose, mannitol, and dextrin as described above, and the polyethylene glycol that can be used has a molecular weight of about 1,000 to. It is about 35,000, for example, Macrogol 1000, 1540, 4000, 6000, 2
0000 and 35000 and the like. These auxiliaries are added when the above residue and water are combined together, even if they are included in water, or after the drug-encapsulating polymer micelles from the residue are dispersed and dissolved in water, and then the whole is sterilized by filtration. You may. Thus, according to the present invention, an auxiliary agent capable of stabilizing the drug-encapsulating polymer micelle in the injection can be easily and safely added to the injection.

Not only can such injections be produced simply and safely, but when they are lyophilized,
Even when the dry preparation is redispersed (re-dissolved) or reconstituted in a drug-encapsulating polymer micelle-containing solution using water or an aqueous solution, an injection solution in which aggregation between micelle particles hardly occurs can be provided. For such freeze-drying treatment, a method known per se in which the solution is frozen and then the solvent is distilled off under reduced pressure can be used.

In order for the freeze-dried preparation to exert the above-mentioned effects, the saccharide in the solution before freeze-drying is added so that the final concentration thereof is 0.1 to 15% by weight, and polyethylene glycol is added at the final concentration. Is preferably added in an amount of 0.5 to 10% by weight. Usually, the ratio of block copolymer to sugar or polyethylene glycol is 1: 1 to 1:10 or 1: 0.5 to 1: 1 by weight, respectively.
It is 0.

[0035]

EXAMPLES In order to simplify the description, the present invention will be specifically described below with reference to an example using topotecan represented by the following formula as a camptothecin and a camptothecin derivative and a block copolymer represented by the following formula. explain.

[0036]

[Chemical 4]

[0037]

[Chemical 5]

Example 1: Desalting treatment Since commercially available topotecan is usually obtained as a hydrochloride, the following desalting treatment was carried out.

Topotecan (hereinafter abbreviated as TPT) hydrochloride was added to 5
mg was precisely weighed and dissolved in 0.5 ml of 1N hydrochloric acid. Separately, a cation-adsorptive ion-exchange resin (OASIS MC
X 6cc 150mg, Nippon Waters) 2.0ml
The solution was passed through methanol and 2.0 ml of pure water to stabilize it. After that, 1N of TPT hydrochloride was added to this ion exchange resin.
A hydrochloric acid solution was provided to adsorb TPT on the ion exchange resin. Add 2.0 ml of 1N hydrochloric acid and 2.0 to this ion exchange resin.
Chloride ions were removed by passing ml of methanol.
Further, TPT was extracted by passing a sufficient amount of basic methanol (20% aqueous ammonia: methanol = 5: 95, V / V). Ammonia was flowed off from the recovered basic methanol solution of TPT to give a final methanol solution of TPT. NMR
As a result of the analysis, it was observed that the chemical shift of 2.8336 ppm (TPT hydrochloride) derived from the dimethylaminomethyl group shifted to 2.3999 ppm (TPT). Further elemental analysis revealed that the chlorine content of TPT was 0.1%. When a chloride purity test was conducted according to the chloride test method described in the Japanese Pharmacopoeia, the precipitation of silver nitrate observed with TPT hydrochloride was not observed with TPT. Thus, the free base TPT was obtained from TPT hydrochloride. Preparation Examples 1 to 6: Preparation of drug-containing polymer micelle Polyethylene glycol-poly (β-benzyl-L-aspartic acid) block copolymer (PEG chain molecular weight 1
2000, PBLA chain length 50 amino acid residues) PBLA
Side chain benzyl group hydrolysis rate 50% (hereinafter, PEG-PB
LA12-50 (50% P.H.) or an unhydrolyzed product (hereinafter, PEG-PBLA12-50 (0% P.H.).
H.) is abbreviated to 50 mg, and the TPT methanol solution prepared in advance is used as TPT hydrochloric acid base.
Each amount of camptothecin, topotecan and topotecan hydrochloride corresponding to 0 mg was added. After stirring well, the solution became transparent and completely dissolved, then methanol was distilled off under a nitrogen stream, and further methanol was removed under reduced pressure. Each of the obtained drugs and PEG-PBLA12-50
5.0 mL of pure water was added to the mixture with (50% PH),
The mixture was stirred overnight at about 4 ° C while protected from light. After that, the liquid in the lower layer was collected and irradiated with ultrasonic waves for 10 minutes with a probe type ultrasonic generator, which was then injected with a syringe filter (Millex GS
0.22 μm pore size, Millipore) to obtain a polymer micelle inclusion body aqueous solution of each drug.

The aqueous solutions were subjected to ultrafiltration (Microcon YM 30, Millipore) using a centrifuge, and the amounts of the drug contained in the obtained filtrate and the residual liquid were measured. At this time, the drug that was not ultrafiltered was regarded as being encapsulated in the micelle, and the encapsulation efficiency was calculated. The results and the average particle diameter values of the polymer micelles obtained by the measurement with a dynamic light scattering photometer using an argon laser are summarized in Table 1 below.

[0041]

[Table 1]

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 35/00 A61P 35/00 43/00 111 43/00 111 F term (reference) 4C076 AA16 AA29 BB11 BB12 BB15 BB16 CC27 EE23E EE41E FF15 GG08 4C086 AA01 AA02 CB22 MA02 MA03 MA05 MA21 MA44 MA66 NA02 NA03 ZB26 ZC20

Claims (12)

[Claims] 1. A composition containing a polymer micelle encapsulating a camptothecin derivative, wherein the polymer micelle is a block copolymer comprising a hydrophilic segment and a hydrophobic segment, and the hydrophobic segment is one of its repeating units. A composition having a carboxyl group in a side chain of a part. 2. A block copolymer comprising a hydrophilic segment consisting of poly (ethylene glycol) and poly (β-alkylaspartate-co-aspartic acid), poly (β-aralkylaspartate-co-aspartic acid), poly ( γ-alkyl glutamate-co-glutamic acid), poly (γ-aralkyl glutamate-co-glutamic acid), poly (β-alkyl aspartamide-co-
The composition according to claim 1, which is selected from the group consisting of aspartic acid) and poly (γ-aralkylglutamide-co-glutamic acid). 3. A side in which a camptothecin derivative carries an amino group, a mono- or di-substituted amino group at one or more positions selected from the 5-, 7-, 9-, 10- and 11-positions of the camptothecin skeleton. The composition of claim 1 or 2 having a chain. 4. The composition according to claim 3, wherein the camptothecin derivative is water-soluble. 5. The composition according to claim 4, wherein the camptothecin derivative is topotecan. 6. When the composition is reconstituted with an aqueous diluent,
Substantially all of the existing polymeric micelles have a pore size of 0.2
The composition according to any one of claims 1 to 5, which is a lyophilized product that passes through a 2 µm sterilization filter. 7. The composition according to claim 6, further comprising an auxiliary agent selected from the group consisting of sugars and polyethylene glycol. 8. A block copolymer comprising a hydrophilic segment and a hydrophobic segment and a camptothecin derivative are dispersed and dissolved in a volatile organic solvent to form a solution, the organic solvent is removed, and the residue thus obtained is obtained. Is combined with water, and then the mixture is stirred at a suitable temperature for a time sufficient to dissolve the residue in water, and a method for producing a composition containing a polymer micelle encapsulating a camptothecin derivative. 9. A process according to claim 8 wherein the suitable temperature is above the freezing point of the organic solvent used and below 30 ° C. 10. The method according to claim 8 or 9, further comprising a step of sterilizing and filtering an aqueous solution obtained by stirring the residue for a time sufficient to dissolve it in water. 11. The method according to claim 10, further comprising the step of preparing an aqueous solution containing an auxiliary agent selected from the group consisting of sugars and polyethylene glycol, prior to sterilization filtration. 12. The method according to claim 8, further comprising a step of freeze-drying the aqueous solution.