JP5843086B2 - Use of polymerized cyclic nitroxide radical compounds to enhance the action of therapeutically active substances - Google Patents

Description

The present invention relates to a pharmaceutical preparation for enhancing the action of a therapeutically active substance containing a polymerized cyclic nitroxide radical compound as an active ingredient.

  In recent years, research and development of drug delivery systems that can eliminate or reduce side effects by encapsulating anticancer drugs in nanocapsules and increase the treatment efficiency have attracted attention. In fact, there are cases where drugs using polymer micelles have progressed to clinical trials.

  On the other hand, other measures for improving the efficacy of anticancer agents are known to affect, for example, anti-inflammatory effects, antiallergic effects, metabolism of sugars, proteins, qualities, etc., and immune responses of living bodies. It has been reported that the effects of anticancer agents such as carboplatin, gemcitabine and adriamycin can be improved by subcutaneous administration of dexamethasone to the tumor (Non-patent Document 1, Non-patent Document 2, Non-patent Document 3). However, low molecular weight compounds such as dexamethasone have a problem of poor accumulation efficiency in the vicinity of the tumor.

  Against this background, not only the above-mentioned drugs, but also the efficiency of delivery of a wide variety of therapeutically active substances, including anticancer drugs themselves, to the target in vivo or the desired activity at the target is enhanced. If the means for doing so can be developed, it will have extremely important significance for the technical field.

Leggas M.M. Cancer Chemother Pharmacol. 2009; 63 (4): 731-743 Wang H. Clin Cancer Res. 2004; 10 (5): 1633-16445 Wang H. Int J Oncol. 2007; 30 (4): 947-953

  Accordingly, an object of the present invention is to provide a means for enhancing the delivery efficiency of a wide variety of therapeutically active substances to in vivo targets or the activity inherent in the active substance at the target.

As a means for solving the above problems, the present inventors have found that the polymerized cyclic nitroxide radical compound previously proposed by the present inventors can be effectively used, and have completed the present invention. Specifically, the polymerized cyclic nitroxide radical compound is formed by covalently bonding a low molecular weight, for example, 2,2,6,6-tetramethylpiperidinooxy radical (TEMPO) to a specific block copolymer. And a compound capable of forming a polymer micelle having a diameter on the order of nm in an aqueous medium. TEMPO encapsulated in such nanoparticles showed an overwhelming stability of several hours or more, whereas the low-molecular-weight TEMPO has a blood half-life of about 2 minutes (Yoshitomi, et al.). Biomacromolecules: 10 (3), 596 (2009)). And the compound itself is a disease or condition involving active oxygen or free radicals, such as cerebral infarction, myocardial infarction, cerebral edema, neuronal loss, inflammation, hypertension, hyperlipidemia, obesity, cerebrovascular injury and It is confirmed or presumed to be effective for nerve cell damage or the like (see WO2009 / 133647 A1).

  These nanoparticles containing cyclic nitroxide radical compounds (hereinafter sometimes abbreviated as “RNP”) can not only encapsulate a poorly water-soluble drug in a hydrophobic core layer, but also can be complexed with genes using electrostatic interactions. Can be formed. It has also been clarified that such RNPs accumulate in the vicinity of tumors or in inflamed tissues by their enhanced permeability and retention (EPR) effect. When such an RNP was used to examine the interaction with an anticancer agent, it was confirmed in animal experiments that the antitumor activity of the anticancer agent was improved. Furthermore, it has been revealed that the RNP has an effect of enhancing gene delivery.

  Therefore, according to the present invention, the following are provided as main aspects of the invention.

  A pharmaceutical preparation for increasing the delivery efficiency of a therapeutically active substance to a target tissue or cell in vivo, or enhancing the activity of the therapeutically active substance in the target, comprising a polymerized cyclic nitroxide as an active ingredient The pharmaceutical preparation comprising a radical compound.

  As a specific embodiment, the pharmaceutical preparation wherein the therapeutically active substance is an antitumor agent or a nucleic acid molecule.

  A pharmaceutical preparation for preventing or treating a disease requiring treatment with an antitumor agent or nucleic acid molecule, which comprises a combination of a polymerized cyclic nitroxide radical compound and an antitumor agent or nucleic acid molecule.

  A method for treating a mammal in need of treatment with an antitumor agent or a nucleic acid molecule, wherein the polymerized cyclic nitroxide radical compound and the antitumor agent or nucleic acid molecule are administered before, after or simultaneously with the mammal. The method of treatment comprising the step of:

  The polymerized cyclic nitroxide radical compound is not limited, but preferably has the general formula (II)

In which A represents unsubstituted or substituted C ₁ -C ₁₂ alkoxy, and when substituted, the substituent represents a formyl group or a group of formula R ¹ R ² CH—, wherein R ¹ and R ² is _{independently,} C 1 -C ₄ alkoxy or ^{R 1} and ^{R 2} are -OCH ₂ CH ₂ O together _{-, - O (CH 2)} 3 O- or -O _{(CH 2)} 4 O -
L ₁ represents a linking group selected from the group consisting of an atomized bond, — (CH ₂ ) _c S—, —CO (CH ₂ ) _c S—, wherein c is 1 to 5, preferably 2. An integer,
L ₂ represents a linking group selected from the group consisting of methylimino, methyliminomethyl, methyloxy, methyloxymethyl, methyl ester and methyl ester methyl,
In R, at least 50% of the total number n of R is 2,2,6,6-tetramethylpiperidin-1-oxyl-4-yl, 2,2,5,5-tetramethylpyrrolidine-1-oxyl-3- Yl, 2,2,5,5-tetramethylpyrrolin-1-oxyl-3-yl and 2,4,4-trimethyl-1,3-oxazolidine-3-oxyl-2-yl, 2,4,4- Represents a residue of a cyclic nitroxide radical compound selected from the group consisting of trimethyl-1,3-thiazolidine-3-oxyl-2-yl and 2,4,4-trimethyl-imidazolindin-3-oxyl-2-yl; When present, the remaining R is a hydrogen atom, a halogen atom or a hydroxy group;
m represents an integer of 20 to 5,000, and n represents an integer of 3 to 1,000.
The compound represented by these can be mentioned.

  As described above, the RNP according to the present invention accumulates in the vicinity of a tumor due to the enhanced permeability and retention (EPR) effect and effectively suppresses the inflammatory reaction of the cell, thereby efficiently exerting the original activity of the therapeutically active substance in the target tissue or cell. Therefore, the activity can be enhanced. In the case where the therapeutically active substance is a nucleic acid molecule, its expression efficiency can be increased in the vicinity of a tumor or inflamed tissue.

Detailed Description of the Invention

  The terms that define the present invention will be described in more detail below.

  In vivo target tissue or cell means a mammal, preferably a human, organ or tissue of a living body or cells thereof for delivering a therapeutically active substance, and the former includes brain, blood, lung, heart, Examples include liver, kidney, pancreas, spleen, gastrointestinal tract, skin, bladder and other organ tumors, and inflamed tissues.

  The polymerized cyclic nitroxide radical compound is a compound stabilized according to the method for stabilizing a cyclic nitroxide radical compound described in WO2009 / 133647 A1, and refers to all of the objects in accordance with the object of the present invention (WO2009 / 133647). A1 is hereby incorporated by reference herein in its entirety). Briefly, the stabilization method involves the conversion of a cyclic nitroxide radical compound into a block copolymer comprising a poly (ethylene glycol) chain segment and a hydrophobic chain segment bearing a reactive group. A group (for example, an amino group, an aminomethyl group, a hydroxy group, a hydroxymethyl group, a carboxyl group or a carbomethyl group, and the reactive group is a halogen atom, a carboxyl group, an isocyanate residue, an isothiocyanate residue, an ester residue) A group, an acid anhydride residue, a boronic acid residue, a maleimide residue or an epoxy group) and a covalent bond with a reactive group of the copolymer.

The polymerized nitroxide radical compound obtainable by such a stabilization method is, for example, preferably a poly (ethylene glycol) chain segment having 15 to 10,000 ethylene glycol repeating units and 3 repeating units of styrene. Comprising 3,000 poly (styrene) chain segments and at least 10%, preferably 30%, more preferably 50%, even more preferably of styrene repeating units in the poly (styrene) chain segments. 80%, particularly preferably _-CH 2 _NH 100% in the 4-position of the phenyl group _{-, - CH 2 NHCH 2 -} , - CH 2 O -, - CH 2 OCH 2 -, - CH 2 OCO- and -CH ₂ OCOCH 2 _- residues of cyclic nitroxide radical compound via a linking group selected from the group consisting of When present, the remainder of the 4-position is a halogen atom, a hydrogen atom or a hydroxyl group, and the residue of the cyclic nitroxide radical compound is 2,2,6,6-tetramethyl Piperidin-1-oxyl-4-yl, 2,2,5,5-tetramethylpyrrolidin-1-oxyl-3-yl, 2,2,5,5-tetramethylpyrrolin-1-oxyl-3-yl and 2,4,4-trimethyl-1,3-oxazolidine-3-oxyl-2-yl, 2,4,4-trimethyl-1,3-thiazolidin-3-oxyl-2-yl and 2,4,4- A compound selected from the group consisting of trimethyl-imidazolindin-3-oxyl-2-yl can be mentioned. More specifically, the general formula (II)

In which A represents unsubstituted or substituted C ₁ -C ₁₂ alkoxy, and when substituted, the substituent represents a formyl group or a group of formula R ¹ R ² CH—, wherein R ¹ and R ² is _{independently,} C 1 -C ₄ alkoxy or ^{R 1} and ^{R 2} are -OCH ₂ CH ₂ O together _{-, - O (CH 2)} 3 O- or -O _{(CH 2)} 4 O -
L ₁ represents a linking group selected from the group consisting of an atomized bond, — (CH ₂ ) _c S—, —CO (CH ₂ ) _c S—, wherein c is 1 to 5, preferably 2. An integer,
L ₂ represents a linking group selected from the group consisting of methylimino, methyliminomethyl, methyloxy, methyloxymethyl, methyl ester and methyl ester methyl,
In R, at least 50% of the total number n of R is 2,2,6,6-tetramethylpiperidin-1-oxyl-4-yl, 2,2,5,5-tetramethylpyrrolidine-1-oxyl-3- Yl, 2,2,5,5-tetramethylpyrrolin-1-oxyl-3-yl and 2,4,4-trimethyl-1,3-oxazolidine-3-oxyl-2-yl, 2,4,4- Represents a residue of a cyclic nitroxide radical compound selected from the group consisting of trimethyl-1,3-thiazolidine-3-oxyl-2-yl and 2,4,4-trimethyl-imidazolindin-3-oxyl-2-yl; When present, the remaining R is a hydrogen atom, a halogen atom or a hydroxy group;
m represents an integer of 20 to 5,000, and n represents an integer of 3 to 1,000.
The polymeric nitroxide radical compound represented by these can be mentioned. As preferred examples of the compound, in general formula (II), L ₁ is an atomized bond or —CH ₂ CH ₂ S—, L ₂ is methylimino or methyliminomethyl, and all of R are formula

Wherein R ′ is a methyl group,
The compound represented by either of these can be mentioned.

  The therapeutically active substance is any active substance mainly used for chemotherapeutic purposes, and may be any kind of compound having any activity as long as it meets the purpose of the present invention. However, although not limited thereto, considering that the polymerized cyclic nitroxide radical compound tends to accumulate in the vicinity of the tumor due to the EPR effect and that the expression efficiency of the nucleic acid molecule is increased, an antitumor agent and Nucleic acid molecules can be mentioned as specific examples of preferred therapeutically active substances.

The antitumor agent is not limited, but for example,
・ Antineoplastic drugs (alkylating drugs):
Ifosfamide,
Cyclophosphamide hydrate,
Busulfan,
Melphalan,
Nimustine hydrochloride,
Ranimustine,
Dacarbazine,
Temozolomide, and procarbazine hydrochloride,
・ Antimetabolite:
Pemetrexed sodium hydrate,
Methotrexate,
Enocitabine,
Capecitabine,
Gemcitabine hydrochloride,
Cytarabine,
Cytarabine ocfosphate hydrate,
Tegafur,
Tegafur uracil,
Tegafur / gimeracil oteracil potassium,
Doxifluridine,
Fluorouracil,
Cladribine,
Nelarabine,
Fludarabine phosphate,
Mercaptopurine hydrate, and hydroxycarbamide,
Anticancer antibiotics:
Aclarubicin hydrochloride,
Amrubicin hydrochloride,
Idarubicin hydrochloride,
Epirubicin hydrochloride,
Daunorubicin hydrochloride,
Doxorubicin hydrochloride,
Pirarubicin hydrochloride,
Mitoxantrone hydrochloride,
Bleomycin hydrochloride,
Peplomycine sulfate,
Actinomycine D,
Zinostatin stimalamer, and mitomycin C,
DNA topoisomerase inhibitors:
Irinotecan hydrochloride hydrate,
Etoposide,
Sobuzoxane and nogitecan hydrochloride,
・ Platinum preparation:
Oxaliplatin,
Carboplatin,
Cisplatin,
Nedaplatin and diaminocyclohexane platinum (II),
・ Taxo rings:
Docetaxel hydrate, and paclitaxel,
・ Vinca Alkaloid:
Vinorelbine ditartrate,
Vincristine sulfate (vincristine sufate),
Vindesine sulfate, and vinblastine sulfate,
・ Multiple myeloma treatment:
Thalidomide,
・ Molecular targeted drugs:
Gemtuzumab ozogamicin,
Cetuximab,
Trastuzumab,
Rituximab,
Imatinib mesilate,
Erlotinib hydrochloride,
Gefitinib,
Dasatinib hydrate,
Nilotinib hydrochloride hydrate,
Sunitinib malate,
Sorafenib tosirate,
Lapatinib tosilate hydrate,
Bevacizumab and bortezomib,
・ Acute promyelocytic leukemia treatment:
Tamibarotene,
Tretinoin and arsenic trioxide,
・ Aromatase inhibitors:
Anastrozole,
Exemestane, and letrozole,
・ Antiestrogen:
Tamoxifen citrate, and toremifene citrate,
・ Antiandrogens:
Bicalutamide, and flutamide,
・ Estrogen:
Estramustine phosphate sodium hydrate,
・ Progesterone:
Medroxyprogesterone acetate
・ LH-RH agonist:
Goserelin acetate and leuprorelin acetate,
・ Anti-breast tumor drug:
Mepitiostane
・ Interferon gamma preparation:
Interferon gamma-1a (innterferon gamma-1a),
・ Interleukin-2 preparation:
Celmoleukin, teceleukin,
・ Anti-malignant tumor effective enzyme:
L-asparaginase,
・ Other tumor drugs:
Aceglatone,
Ubenimex,
Strontium chloride (strontium (89Sr) chloride),
Kawaratake polysaccharide preparation (obtained from coriolus versicolor),
Sizofiran,
Pentostatin, calcium folinate, and streptococcal extract:
Levofolinate calcium,
Lentinan,
Talaporfin sodium and porfimer sodium
Can be mentioned. Of these, preferred are doxorubicin hydrochloride, idarubicin hydrochloride), epirubicin hydrochloride, pirarubicin hydrochloride, irinotecan hydrochloride hydrate, etoposide, sobuzoxan, nogitecan hydrochloride, carboplatin, cisplatin, nedaplatin, diaminocyclohexaneplatinum (II) , Docetaxel hydrate, and paclitaxel. In addition, these antitumor agents can be encapsulated in liposomes or conjugates with block copolymers. For example, examples of doxorubicin block copolymer conjugates can be found in EP 0 397 307 B1,
Examples of diaminocyclohexaneplatinum (II) and block copolymer conjugates are EP1
695 991B1, the contents of which are hereby incorporated herein by reference.

  On the other hand, the nucleic acid molecule is a so-called nucleic acid molecule that can be used for gene therapy, DNA and RNA, and encodes a gene protein that expresses or enhances a protein having a function effective for imaging and treatment of a delivery site, or It can be a regulatory factor that suppresses the expression of a gene causing symptoms by an antisense strand or siRNA, and these nucleic acid molecules can have about 80,000 to 100,000 nucleobases, and a viral vector: A retroviral vector, adenoviral vector, adeno-associated virus, baculovirus, human herpes simplex virus, lentivirus (retroviridae), barbovirus, foamy virus, syn-S dopis virus or alphavirus, or Viral vector: Polyplex (cationic polymer: polyethyleneimine, chitosan, etc.) Lipoplex (cationic lipid: liposome, lipofectamine, etc.) Complex with cationic peptide, immunoporter, calcium phosphate, erythrocyte ghost, etc. .

  The polymerized nitroxide radical compound and the therapeutically active substance can be used for the patient at the same time or in a mode of administration in which one is administered and then the other is preferably administered. It is preferred to administer the therapeutically active substance after administration.

  Each route of administration can be the same or different and can be oral or parenteral. Parenteral administration can be intravenous, intraarterial, subcutaneous, intramuscular, intraperitoneal, rectal infusion, or can be implanted within a lesion. Thus, each of these components can be the compound itself or, if present, a physiologically acceptable salt thereof, and further, powders, tablets, capsules, gels, drops, It can be in the form of suppositories, suspensions, solutions, and the like. In preparing such dosage forms, carriers, excipients, or other inert ingredients can be included. The carrier or excipient can be a pharmaceutically acceptable solvent, suspending medium or any other pharmaceutically inert vehicle. Excipients may be liquid or solid so as to provide the desired bulk, consistency, etc. when combined with the polymerized nitroxide radical compound or therapeutically active substance, keeping in mind the planned mode of administration. Selected. Typical pharmaceutical carriers include, but are not limited to, binders (eg, gelatinized starch, polyvinyl pyrrolidone, polyethylene glycol,) bulking agents (eg, lactose and other commonly used in the art) Sugar, crystalline cellulose, gelatin, ethyl cellulose), lubricants (eg, magnesium stearate, talc, silica, corn starch) and the like.

The formulation or dosage of the polymerized nitroxide radical compound and the therapeutically active agent can be determined based on the experience of those skilled in the art and will vary depending on the severity and responsiveness of the condition of the patient being treated, respectively. In general, it can be estimated based on an EC ₅₀ that has been confirmed to be effective in in vitro and in vivo animal models. In general, it can be 0.0 μg to 100 g, preferably 0.1 μg to 1 g, more preferably 10 μg to 100 mg per kg body weight, respectively. The dosing schedule is typically to administer the therapeutically active substance a few minutes to several days (eg, 4-8 days) after administering the polymerized nitroxide radical compound. When both are administered simultaneously, a therapeutically active substance that is a poorly water-soluble drug and not a polymer compound is a polymer of a polymerized nitroxide radical compound in an aqueous solvent (eg, pure water or buffered physiological saline). When forming a micelle, it may be encapsulated in the core region of the polymeric micelle and administered as a composition in which they are integrated.

2 is a graph display of the results of cell experiments in Example 1. 2 is a graphical representation of the results of animal experiments in Example 1. 3 is a graph display of expression efficiency of Example 2.

  Hereinafter, the present invention will be specifically described with reference to specific examples of the present invention, but the present invention is not intended to be limited to these specific examples.

Production example:
<Production of N-RNP>
PEG-b-PCMS was prepared by radical telomerization of chloromethylstyrene (CMS) using thiol-terminated polyethylene glycol (PEG) as the telogen. (PEG having a molecular weight of 5,000 was used.) 4-Amino-TEMPO was introduced into this side chain chloromethyl group. The block copolymer (PEG-b-PCTEMPO (N), molecular weight 5,000 of PCTEMPO (N)) having TEMPO thus obtained in the side chain self-associates in water, and has an average diameter of about 40 nm. Form particles.

<Production of O-RNP>
PEG-b-PCMS was prepared by radical telomerization of chloromethylstyrene (CMS) using thiol-terminated polyethylene glycol (PEG) as the telogen. (PEG having a molecular weight of 5,000 was used.) 4-Hydroxy-TEMPO was introduced into this side chain chloromethyl group. The thus obtained block copolymer having TEMPO in the side chain (molecular weight of PEG-b-PCTEMPO (O), PCTEMPO (O) 5,000) self-associates in water and has an average diameter of about 40 nm. Form particles.

Example 1: Interaction of doxorubicin (DOX) and O-RNP <Cell experiment>
1 × 10 ⁵ colon 26 cells were seeded on a 96-well plate. After 48 hours, DOX (2 μg / ml) was added, and the concentration was varied 24, 12, 6, and 0 hours before addition of O-RNP. Cell viability was measured using WST-assay 24 hours after adding doxorubicin. As a control, the cell viability when O-RNP was added alone for 48 hours was measured.

<Experimental result>
The results are shown in FIG. When O-RNP alone was exposed for 48 hours, no toxicity was observed at any concentration. Moreover, it was revealed that pre-administration of O-RNP before addition of DOX increased cell viability depending on the TEMPO concentration in O-RNP.

<Experimental animals>
BALB / c mice 6 weeks old and weighing 30 ± 2 g were purchased and used for experiments after 2-3 days of acclimatization. Tumor-bearing mice were prepared by subcutaneously administering colon cancer-derived Colon-26 (1 × 10 ⁶ cells / 100 L) to BALB / c mice. First, O-RNP (30 mg / ml, TEMPO concentration 40 mM, 50 μL) obtained in the above production example was locally administered to tumor-bearing mice for 4 days, and stage DOX (10 mg / kg) on day 4 was administered via the tail vein. Thereafter, the size of the tumor was measured.

<Experimental result>
The results are shown in FIG.

In the cell experiment, when O-RNP was administered before the addition of DOX, the cytotoxicity of DOX was reduced. However, when O-RNP was locally administered to the cancer tissue in advance, the tumor after the administration of DOX was observed. It became clear that it restrained growth.
Each display in the figure corresponds to the following experimental system.
-RNP group: Only O-RNP was administered.
-DOX + O-RNP group: O-RNP alone was administered (4 days), and DOX was administered.
DOX group: PBS was administered for 4 days and DOX was administered. S. Group: PBS for 4 days only.

Example 2: Interaction between gene delivery using polyethyleneimine and RNP This experiment is for confirming improvement in expression efficiency in gene delivery using N-RNP.

  pGL3 (luciferase gene) was used as the pDNA, and polyethyleneimine (PEI: branched, Mw = 25000) was used as the vector. pDNA and PEI were mixed so that (amino group in PEI) / (phosphate group in pDNA) = N / P = 10 to form a complex (pDNA / PEI).

HeLa cells were seeded on a 24 well plate at 5 × 10 ⁵ cells / well, and 24 hours later, pDNA / PEI and N-RNP were added. 0.2 μg / well of pDNA was added. The medium was changed after 24 hours, and further luciferase assay (measurement of luminescence) and BCA assay (quantification of protein) were performed after 24 hours.

  The results are shown in FIG.

The vertical axis in FIG. 3 is obtained by normalizing the value obtained by dividing the amount of luminescence by the amount of protein with the value of pDNA / PEI alone as 1. The amount of N-RNP added is R1 = 3.3 × 10 ⁻⁵ mM.
N-RNP, R2 = 3.3 × 10 ⁻⁴ mM N-RNP, R3 = 3.3 × 10 ⁻³ mM
N-RNP, R4 = 3.3 × 10 ⁻² mM RNP. From the above figure, it was found that the amount of luciferase expressed increased as the amount of N-RNP added increased.

  From the above results, it was shown that N-RNP has higher gene expression efficiency than that of pDNA / PEI alone in gene delivery.

Claims (4)

A pharmaceutical preparation for enhancing the activity of a therapeutically active substance on a target tissue or cell in vivo, as an active ingredient,
Formula (II)

Wherein A represents unsubstituted or substituted C ₁ -C ₁₂ alkoxy, and when substituted, the substituent represents a formyl group or a group of formula R ¹ R ² CH—, wherein R ¹ and R ² is independently, C ₁ -C ₄ alkoxy or R ¹ and R ² are -OCH ₂ CH ₂ O together _{-, - O (CH 2)} 3 O- or -O (CH _{2) 4} O -
L ₁ is an atom _{binding, - (CH 2) c S} -, - CO (CH 2) represents a linking group selected from the group consisting of _c S-, where c is 1 to 5 integer,
L ₂ represents a linking group selected from the group consisting of methylimino, methyliminomethyl, methyloxy, methyloxymethyl, methyl ester and methyl ester methyl,
In R, at least 50% of the total number n of R is 2,2,6,6-tetramethylpiperidin-1-oxyl-4-yl, 2,2,5,5-tetramethylpyrrolidine-1-oxyl-3- Yl, 2,2,5,5-tetramethylpyrrolin-1-oxyl-3-yl and 2,4,4-trimethyl-1,3-oxazolidine-3-oxyl-2-yl, 2,4,4- Represents a residue of a cyclic nitroxide radical compound selected from the group consisting of trimethyl-1,3-thiazolidine-3-oxyl-2-yl and 2,4,4-trimethyl-imidazolindin-3-oxyl-2-yl; When present, the remaining R is a hydrogen atom, a halogen atom or a hydroxy group;
m represents an integer of 20 to 5,000, and n represents an integer of 3 to 1,000.
Comprising a polymerized cyclic nitroxide radical compound represented by
An antitumor agent The therapeutically active agent is doxorubicin, idarubicin, selected from epirubicin and Pirarubishi down or Ranaru group, and,
A pharmaceutical preparation, wherein an antitumor agent is administered after a polymerized cyclic nitroxide radical compound is administered. A pharmaceutical preparation for preventing or treating cancer, characterized by combining a polymerized cyclic nitroxide radical compound and an antitumor agent,
The polymerized cyclic nitroxide radical compound has the general formula (II)

Wherein A represents unsubstituted or substituted C ₁ -C ₁₂ alkoxy, and when substituted, the substituent represents a formyl group or a group of formula R ¹ R ² CH—, wherein R ¹ and R ² is independently, C ₁ -C ₄ alkoxy or R ¹ and R ² are -OCH ₂ CH ₂ O together _{-, - O (CH 2)} 3 O- or -O (CH _{2) 4} O -
L ₁ is an atom _{binding, - (CH 2) c S} -, - CO (CH 2) represents a linking group selected from the group consisting of _c S-, where c is 1 to 5 integer,
L ₂ represents a linking group selected from the group consisting of methylimino, methyliminomethyl, methyloxy, methyloxymethyl, methyl ester and methyl ester methyl,
In R, at least 50% of the total number n of R is 2,2,6,6-tetramethylpiperidin-1-oxyl-4-yl, 2,2,5,5-tetramethylpyrrolidine-1-oxyl-3- Yl, 2,2,5,5-tetramethylpyrrolin-1-oxyl-3-yl and 2,4,4-trimethyl-1,3-oxazolidine-3-oxyl-2-yl, 2,4,4- Represents a residue of a cyclic nitroxide radical compound selected from the group consisting of trimethyl-1,3-thiazolidine-3-oxyl-2-yl and 2,4,4-trimethyl-imidazolindin-3-oxyl-2-yl; When present, the remaining R is a hydrogen atom, a halogen atom or a hydroxy group;
m represents an integer of 20 to 5,000, and n represents an integer of 3 to 1,000.
Represented by
Antitumor agents, doxorubicin, idarubicin, selected from epirubicin and Pirarubishi down or Ranaru group, and,
A pharmaceutical preparation, wherein an antitumor agent is administered after a polymerized cyclic nitroxide radical compound is administered. L ₁ is an atomized bond or —CH ₂ CH ₂ S—, L ₂ is selected from the group consisting of methylimino, methyliminomethyl, methyloxy, methyloxymethyl, and R is

Wherein R ′ is a methyl group,
The pharmaceutical formulation of Claim 1 or 2 represented by either. The pharmaceutical preparation according to claim 3, wherein L ₂ is methylimino or methyloxy.

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