JPH0812597A - Topically administered radiotherapy - Google Patents

Abstract

PURPOSE:To provide the subject therapeutic agent composed of a giant molecular compound in which radioactive metal ions are bonded to a biodegradable hydrophilic polymer containing monomer units having an amino group, a hydroxyl group, COOH group, etc., and exhibiting suitable retention and rapid discharge to the outside of the body. CONSTITUTION:This is a pharmaceutically permissible radiotherapeutic agent for local administration, capable of gelation at physiological pH and temperature, exhibiting suitable retention and rapid discharge to the outside of the body in combination, free from a problem related to its production and suppliable at low cost. Production of this agent is carried out by chemically bonding one or more kinds of radioactive metal ions (e.g. yttrium 90 ion) through a complexing agent (e.g. diethylenetriaminepentaacetic acid) to a biodegradable hydrophilic polymer composed of a polysaccharide containing hydrophilic repeating monomer units having an amino group, a hydroxyl group, a carboxyl group or their derivative and having 1X10<3> to 1X10<6> average molecular weight, e.g. chitin, chitosan or their derivative.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a radiotherapy agent for local administration. More specifically, the present invention relates to a novel locally administered radiotherapeutic agent having characteristics that enable control of in-vivo drug behavior useful for the treatment of tumors and inflammatory diseases by the radiation effect of α rays and β rays.

[0002]

BACKGROUND ART Various studies have already been conducted on the effects of radiation on living organisms, and the essence is to suppress the metabolic activity of cells, suppress growth by inhibiting cell division, and lethal effects.
The mechanism of action of the locally administered radiotherapeutic agent also depends on the action of this radiation, but the target diseases are local inflammation sites of inflammatory diseases such as rheumatoid arthritis and lung cancer, liver cancer, gastric cancer, colon cancer,
It is the primary and metastatic focus of most solid tumors usually found clinically, including breast, uterine, and epithelial cancers.

A locally administered radiotherapeutic agent is directly administered to an affected area where a therapeutic effect is to be obtained, and then remains at the affected area until radioactivity is attenuated, and radioactive metal ions are emitted to the affected area.
It irradiates with rays or β rays. Therefore, if it is excreted from the target site in the meantime, other normal tissues are irradiated with radiation and an undesirable action occurs.

From the viewpoint of safety, the locally administered radiotherapy agent exhibits a therapeutic effect by irradiation by staying at the administration site only for a limited period of time after administration to the affected area, which corresponds to the physical attenuation of the radionuclide, After that, it is required to have the characteristic of being excreted and not remaining in the living body for a long time.

Conventionally, a locally administered radiotherapeutic agent has been devised in the therapeutic study of tumors and inflammatory diseases.

As one of the methods for locally retaining the administered drug, there is a method in which the administered substance is made into particles and the excretion rate is physically slowed. Radioisotopes, especially radioactive metal ions, can rapidly move in the body by themselves, and therefore must be bound to some particles or macromolecules in order to be locally retained. In order to satisfy this purpose, conventionally, radiation metal ions have been processed so as to be contained in colloidal particles (particles of several to several tens μm) made of hydroxide of stable isotope metal ions.

[0007] A typical example is a radioactive metal colloid preparation which replaces synovectomy, which is a surgical treatment method for synovitis caused by rheumatoid arthritis, or a radioactive metal colloid preparation which is directly injected into a tumor site. To be For example,
These are Y-90 colloid and Au-198 colloid. The radioactive metal colloid preparation exhibits a therapeutic effect by irradiating the affected area with α-rays or β-rays, which remains at the site after administration. However, since this type of preparation has some drawbacks, it has not been industrialized as an official drug in Japan.
The drawbacks can be pointed out in three points: manufacturing operation, in vivo pharmacokinetic control, and safety.

[0008] Pharmaceutical products to be administered to living bodies are required to have certain quality conditions such as sterility. The active ingredient of the metal colloid preparation is particles of about several to several tens of μm, so that aseptic filtration cannot be performed in the final manufacturing process even though it is an injection.
This is a fatal defect when it is premised on biological administration. In addition, it is required that the metal colloid is inexpensive and stably supplied, but the condition is not necessarily satisfied by the metal colloid. Metal colloid formulations often remain at the site of administration for extended periods of time and are not excreted and develop chemical toxicity as a metal (eg Jean, PH et al: Therapie 41, p. 357, (198
6)). And it is almost impossible to control the residence time by the metal element. Thus, it has been recognized that the metal colloid preparation has a safety problem because it remains at the administration site for a considerably long period of time, and that it must be excreted from the body.

[0009] On the other hand, typical examples of chemical preparations to be directly injected into the tumor site or inflammatory site include acetic acid injection preparation, ethanol injection preparation, cisplatin injection preparation, osmic acid injection preparation, etc. The shortcomings can be pointed out in two points, that is, there is a transient effect from a short-term residue due to being a solution of molecules and side effects of various sizes. Most of the dosage forms of chemicals directly injected into a tumor site or an inflammation site are low-molecular-weight solutions, so that they cannot be localized and are scattered throughout the body. For this reason, the effect is not sustainable, and a large amount is administered over several times, resulting in poor economic efficiency for treatment. Further, in the administration method of this preparation, for liver cancer and the like, a method in which an acetic acid injection preparation or the like is administered several times while incising an artery and inserting a catheter into the blood vessel is used, which imposes a heavy burden on the doctor and the patient.

For this reason, the emergence of a local radiotherapy agent, which has both appropriate retention and rapid excretion outside the body and which can be supplied inexpensively without any problems in production, has been awaited.

[0011]

SUMMARY OF THE INVENTION In order to overcome the above-mentioned drawbacks of conventional metal colloid preparations and chemical preparations, we have attempted to invent a novel locally administered radiotherapy agent. INDUSTRIAL APPLICABILITY The present invention makes it possible to avoid difficulties during the manufacturing process, to enable pharmacokinetic control in vivo, and thus to use a biodegradable hydrophilic polymer as a carrier, which realizes higher safety, and complex it. It is an object of the present invention to provide a therapeutic agent chemically bound with a radioactive metal ion having a therapeutic effect via the agent.

[0012]

[Means for Solving the Problems] As a result of various studies to achieve the above object, as a result, a radioactive metal was bound to a biodegradable hydrophilic polymer typified by a chitin derivative through a complexing agent. We have succeeded in finding the fact that the macromolecular compounds that have fulfilled such demands have safety and therapeutic effects that are considered to be clinically effective.

For example, a macromolecular compound in which diethylenetriaminepentaacetic acid (abbreviated as DTPA) is chemically bonded as a complexing agent to chitosan having a molecular weight of about 500,000 and indium 111 (abbreviated as In-111) is coordinated as a radioactive metal ion. Was investigated in rats. Where In-1
The reason for using 11 is to avoid the unnecessary use of β-ray emitting radioactive metal ions, and in place of indium 114m (abbreviated as In-114m), which has similar chemical and physical properties to the extent that it does not pose a problem, and Yttrium 90 (Y with similar chemical properties
(Abbreviated as -90).

As a result, the half-life of elimination of the macromolecular compound according to the present invention in the intra-articular administration of the rat was In-11.
1 Compared with metal colloids, it was 1/17 times faster, and it was confirmed that most of the administered radioactivity of the present invention was distributed to the administration site within a certain period. Moreover, it was confirmed that most of them were excreted in urine after that, and no accumulation in the body was observed.

The present invention is based on these findings and has an average molecular weight of 1 × 10 ³ to 1 × 10 ^{3 including} hydrophilic repeating monomer units containing an amino group, a hydroxyl group or a carboxyl group, or a derivative thereof. ^6. A biodegradable hydrophilic polymer, to which at least one radioactive metal is chemically bound via a complexing agent, is physiologically tolerable, and gels at physiological pH and temperature. It has been completed as a locally administered radiotherapeutic agent comprising a characteristic macromolecular compound or a salt thereof.

Since the non-radioactive labeling carrier of the present invention uses a biodegradable hydrophilic polymer having an average molecular weight of 1 × 10 ³ to 1 × 10 ⁶ , it can be sterilized by filtration, and aseptic operation in the production of a preparation. It is possible and easy.

Furthermore, local administration radiotherapeutic agents of the present invention, for example, the target region by performing local administration to a tumor and inflammatory disease site, longer than the low-molecular compound having a molecular weight of less than 1 × 10 ^3, a metal colloid It is characterized by having a short retention property and having expected therapeutic effect and safety that is considered clinically effective due to its rapid elimination from the body, and is a complexing agent for polysaccharides represented by chitosan derivatives. By using the synthetic polymer bound to the above as a carrier for radioactive metal ions, the locally administered radiotherapeutic agent of the present invention can be inexpensively supplied.

The biodegradable hydrophilic polymer used in the present invention has a physiological pH and a elimination half-life which is about 1 to 3 times the physical half-life of radioactive metal at the locally-administered specific disease site. The average molecular weight of gelling at temperature is 1 x 1
It is a macromolecular compound and its salt that are decomposed and metabolized in the body from 0 ³ to 1 × 10 ⁶ . In particular, considering the concept and practicality of the present invention, a polysaccharide or polyamino acid having a chargeable functional group as a repeating unit, a complex sugar having an amino acid side chain,
The usefulness is suitably exhibited in synthetic polymers having various organic compounds artificially synthesized as constitutional units, and also in a mixture thereof which gels under neutral conditions. Examples of the macromolecules include polyglucosamine (= chitosan), polygalactosamine, and polymannosamine in polysaccharides having an amino group as a repeating unit; hyaluronic acid in polysaccharides having a carboxyl group in a repeating unit; and polylysine and polyamino acid as polyamino acids. Examples thereof include glutamic acid and the like, and complex sugars, complex lipids and polynucleotides having them in the molecule.

It can be said that the synthetic polymer is highly useful in that it can be produced with any molecular weight depending on the constitutional unit and can obtain biocompatibility and degradability arbitrarily. On the other hand, polysaccharides with various molecular weights are known and often have low antigenicity. From the viewpoint of application to pharmaceuticals, hydrophilic polysaccharides that are decomposed in vivo have excellent utility value as a carrier of radioactive metal ions among various macromolecules.

Many naturally occurring polysaccharides such as starch are known. Chitin present in the shell of the cellulose and crustaceans constituting the plant cell wall, chitosan etc. are inexhaustible is estimated that each year ^{1 × 10 11 t, 1 ×} 10 9 ~1 × 10 11 t to produce. In addition, the amount of chitin available as a raw material is estimated to be 1.5 × 10 ⁵ t, and the isolation method is relatively simple, so it is supplied at an extremely low cost (Saburo Fukui,
Hinata Saito: Biotechnology Encyclopedia, CMC, p.645, (1986). Tracey, MV: Chitin; Rev.Pure App
l. Chem. 7, p. 1, (1957)).

Among them, a polysaccharide having a chargeable functional group as a repeating unit, for example, a polysaccharide having an amino group, dissolves in an aqueous solvent under acidic conditions and forms a hydrophilic gel under neutral to alkaline conditions. Have. On the contrary, a polysaccharide having a carboxyl group is dissolved in an aqueous solvent under alkaline conditions and forms a hydrophilic gel under acidic conditions. It can be said that such a property is extremely advantageous in manufacturing a drug. That is, in the dissolved state, chemical modification reactions and industrial operations such as purification / filtration / dispensing / sterilization can be easily carried out, and weak acidic to
In a neutral living body, gelation makes it possible to control the pharmacokinetics such as an increase in retention.

A chitin derivative, which is a polysaccharide having an amino group as a repeating unit, has excellent properties in terms of biocompatibility and safety. For example, chitin is gradually hydrolyzed by lysozyme (BC.3.2.1.17), which is incorporated in the body's defense mechanism, and causes almost no foreign body reaction in the body (N.Ni.
shi, S.Nishimura, O.Somorin: Lysozyme-accessible Fi
bers from Chitin and its Derivatives, Edt. S. Tokur
a, Sen-i Gakkaishi.39, p.45-49 (1983)). On the other hand, chitosan is also less toxic than sucrose, has no antigenicity, has no anticoagulant action, and is rapidly digested and excreted in the body (chitin, application of chitosan: chitin,
Chitosan Kenkyukai, pp.221 (1988)).

It can be said that the polysaccharide having a chargeable functional group as a repeating unit as described above, especially the chitin derivative, has the property of being easily used as a medical substance, which is advantageous for solving the problems in the present invention. .

As an application example of a chitin derivative to a drug, a sustained release drug carrier using a chitosan bead or a carboxymethyl chitin gel has been devised, but all of them physically act as a chemical substance having a medicinal effect. It utilizes the property of chitin derivatives that it is adsorbed. And the carrier used is designed to gradually release the adsorbed components. On the other hand, the feature of the macromolecular compound in the present invention is that it is not sustained-released and utilizes a stable chemical bond that is not released until the carrier itself is decomposed and metabolized. The concept of the present invention is different from the sustained release drug carrier and has not been devised yet.

In order to obtain a therapeutic effect on a tumor or an inflammatory disease, it is necessary to coexist with a substance having some therapeutic effect on a polysaccharide represented by a chitin derivative, for example, a radioactive metal ion emitting α-ray or β-ray. There is.

Radioactive metal ions that emit β-rays are typical examples of substances having a therapeutic action, and generally, a carrier metal ion-free (that is, a state in which the same type of metal ion is not contained as a stable isotope) has a therapeutic effect. Even with a sufficient amount of radioactivity, the chemical amount as an element is extremely small. This is an excellent property when considering persistence and safety in topical administration.

Considering the characteristics of the locally administered radiotherapeutic agent, the radioactive metal ion to be used, specifically, the radioactive metal ion must satisfy some conditions. Listed below are α nuclides and β nuclides, decay half-life (T (1/2)) of 5 to 400 hours, α or β emission efficiency of 90% or more, α Line or β
The line energy must be 0.1 MeV or more.

Any radioactive metal ion satisfying these conditions can be used in the present invention, but Y-90,
Rh-105, Pd-109, In-114m, Sn-117m, Sn-121, Pm-149,
Sm-153, Gd-159, Tb-161, Dy-165, Ho-166, Er-169, Y
b-175, Lu-177, Re-186, Re-188, Os-193, and more preferably Y-90, Ho-166, Lu-177, Re-186.

Some macromolecules, such as polysaccharides, have been shown to have the ability to bind metal ions directly on their own. For example, carboxymethyl chitin is used as an ion exchange resin, and chitosan is also said to coordinate with divalent transition metal ions. However, these coordination bonds are not strong enough to exist stably in vivo. This can be experimentally proved also by the fact that when the chitin derivative and the radioactive metal ion are mixed in a neutral buffer and then analyzed by electrophoresis or thin layer chromatography, the two are easily separated. If macromolecules such as polysaccharides are used as it is, it is difficult to obtain a stable metal conjugate in vivo and it cannot be used as a carrier for radioactive metal ions.

Then, a complexing agent for strongly coordinating a metal ion to a macromolecule such as a polysaccharide and the radioactive metal ion is bound to the complexing agent, and the object can be achieved. The complexing agent used in the present invention satisfying this condition is ethylenediaminetetraacetic acid (EDTA), diaminopropanoltetraacetic acid (DPTA), glycol etherdiaminetetraacetic acid (GEDTA), hexamethylenediaminetetraacetic acid (HDT).
A), diethylenetriaminepentaacetic acid (DTPA), triethylenetetraminepentaacetic acid (TTHA), 1,4,7,10-tetracarboxymethyl-1,4,7,10-tetraazacyclododecane (DOTA),
1,4,7,10- Tetraazacyclododecane-1-aminoethylcarbamoylmethyl-4,7,10-tris [(R, S) methylacetic acid] (DO3MA), triethylenetetramine polystyrene (TE
TA), or cyclohexanediaminetetraacetic acid (CyDTA), hydroxyethylethylenediaminetriacetic acid (EDTA-OH), ethylenediaminetetrakis (methylenephosphonic acid) (ED
Polyaminopolycarboxylic acids such as TPO), diaminopropanetetraacetic acid (Methyl-EDTA), nitrilotriacetic acid (NTA), polyaminopolyphosphonic acid, polyaminopolysulfonic acid, etc.

As a result of repeated preparations and preparation of macromolecular compounds in which the above-mentioned complexing agents were bound to polysaccharides by a chemical bond in an appropriate manner, they were found to be useful as carriers for radioactive metal ions. It was

The production method is as follows. The biodegradable hydrophilic polymer is dissolved in a suitable solvent at a suitable concentration, and then a suitable amount of a complexing agent is added, followed by reacting at room temperature to form a complex. A macromolecular compound to which an agent is bound can be obtained. The appropriate concentration as used herein refers to that which can bind a sufficient amount of radioactive metal ion to exert a therapeutic effect, and which is within the range of solubility without exceeding the bioavailable limit. In addition, the suitable solvent here refers to sterile water, physiological saline, various buffers, and if necessary, an organic solvent for increasing the solubility of the non-radioactive carrier, an acid for adjusting the pH, and a base. , A reducing agent or an oxidizing agent for adjusting the valence state of the radioactive metal ion, and a stabilizer, an isotonic agent, and a preservative may be added.

The resulting non-radioactive composition may be directly subjected to labeling with a radioactive metal ion in the form of a solution,
Alternatively, the solvent may be removed by a method such as a freeze-drying method or a low temperature pressure evaporation method to obtain a dried product, which may be then subjected to labeling with a radioactive metal ion.

In this way, DTPA- cellulose, DTPA-
Chitin, DTPA- Chitosan, DTPA- Glycol Chitosan,
DO3MA-cellulose, DO3MA-chitin, DO3MA-chitosan and
Complexing agent-bound polymeric polysaccharides can be obtained, as shown in the example of DO3MA-glycol chitosan.

Further, the solution of the radioactive metal ion dissolved in the ionic state is mixed with the solution or suspension of the macromolecular compound to which the complexing agent which is the non-radioactive carrier is bound, and the mixture is heated to 20 to 50 ° C. By heating, a macromolecular compound labeled with a radiometal can be obtained by an extremely simple operation.

A solution or suspension prepared by dissolving the above-mentioned biodegradable hydrophilic polymer in a suitable solvent at a suitable concentration is mixed with a complexing agent solution to which radioactive metal ions are bound, By heating to 50 ° C., a macromolecule compound labeled with a radiometal can be obtained by an extremely simple operation.

In this way, ⁹⁰ Y-DTPA-cellulose, ⁹⁰
Y-DTPA- chitin, ⁹⁰ Y-DTPA- chitosan, ⁹⁰ Y-DTPA- glycol chitosan, ⁹⁰ Y-DO3MA-cellulose, ⁹⁰ Y-DO3MA-chitin, ⁹⁰ Y-DO3MA-chitosan, ¹⁵³ Sm-DO3MA- chitin,
It is possible to obtain the macromolecular compound to which the β-ray emitting radioactive metal ion shown in the examples such as ¹⁵³ Sm-DO3MA-chitosan and ¹⁸⁶ Re-DTPA-glycol chitosan is stably bound.

In the case of application to an inflammatory site, the present invention 37MBq-3.
Direct treatment of 7GBq (1-100mCi) to the affected area is expected to have therapeutic effect by suppressing metabolic activity of inflammatory cells. When applied to solid cancer, the size and spread of the cancer to be administered are affected, but administration of 37MBq to 18.5GBq (1 to 500mCi) of the present invention is expected to kill cancer cells due to the lethal effect of radiation. The intensity of action is easily achieved by controlling the amount of radioactivity administered. Since the effect of radiation is limited to the range of β-ray range of a few millimeters, the systemic side effects of radiation can be minimized, and it is safer than the usual treatment methods of external radiation. There is expected.

Various methods can be applied to the administration of the present invention. For example, administration methods such as percutaneous direct injection into the affected area using a syringe equipped with an injection needle having an appropriate thickness and length, administration methods using an endoscope, intraarterial administration using a catheter, and the like. Intra-arterial administration with a catheter is effective for liver cancer, percutaneous injection is effective for skin cancer, and gastric cancer, lung cancer,
For bile duct cancer, colorectal cancer, and uterine cancer, as described above, direct administration by endoscope is effective, and various administration methods are possible depending on the characteristics of the disease. This is a variety that is possible only if it has the property of staying locally.

According to the present invention, a complexing agent is bound to a biodegradable hydrophilic polymer by exhibiting contradictory retention properties such as residence time in vivo and rapid excretion in vitro, which are in proportion to physical decay of radioactive metal ions. It is characterized in that it is achieved by the pharmacokinetics of the macromolecular compound. In the case of a chitin derivative, this pharmacokinetic control is determined by its gel forming ability in a neutral aqueous solution and its enzymatic degradability. This is shown from the experimental results that, as shown in Examples described later, the difference in the molecular weight of the polysaccharides does not greatly affect the in vivo elimination half-life, the half-life differs depending on the type of the monosaccharide as the structural unit, etc. Be done. It can be said that the usefulness of the present therapeutic agent is determined by the presence state of the complexing agent-bound polysaccharide in the neutral aqueous solution.

[0041]

EXAMPLES Examples of the present invention will be shown below, but the present invention is not limited to the description of these examples.

In the examples, abbreviations were used instead of Japanese names in some cases. That is, chitin is CHN, chitosan is CHT, especially chitosan with a molecular weight of about 500,000 is CHT (PSH), especially molecular weight is about
CHT (LL) for 50,000 chitosan and Gly for glycol chitosan
CHT. Bifunctional complexing agents include diethylenetriaminepentaacetic acid anhydride DTPA, tetraazacyclododecaneaminoethylcarbamoylmethyltris (methylacetic acid)
DO3MA. Metal elements, indium-111 to ¹¹¹ I
n, yttrium 90 is abbreviated as ⁹⁰ Y, samarium is abbreviated as Sm, and gadolinium is abbreviated as Gd.

In order to avoid unnecessary use of β-ray emitting radioactive metal ions, ⁹⁰ Y and
^An experimental study was carried out using ¹¹¹ In instead of ^114m In, Sm stable isotope instead of ¹⁵³ Sm, and Gd stable isotope instead of ¹⁵⁹ Gd. This is similar to the chemical behavior of In and Y,
It is a reasonable measure based on the identity of the chemical behavior of radioisotopes and stable isotopes.

[0044]

Example 1 Synthesis of complexing agent-bound polysaccharide

1-1. Preparation of DTPA-CHT conjugate Chitosan PSH (molecular weight: about 500,000) and chitosan LL (molecular weight: about 50,000) were each added at a concentration of 4 to 5 mg / ml in methanol / 10%.
It was dissolved in acetic acid (volume ratio 5/1) or methanol / 0.1N hydrochloric acid (volume ratio 4/1). Where 8N sodium hydroxide
One-tenth volume was added to make a gel state under alkaline conditions, and a solution that remained in a dissolved state under acidic conditions without adding 8N sodium hydroxide was prepared. That is, eight kinds of solutions were prepared. Then add an excess amount of DTPA anhydride (1 to 20 mg / CHT 1 m
g) was added and reacted at room temperature for 10 minutes while sonicating in an ultrasonic generator.

Here, a small amount was taken out from the reaction solution, labeled with ¹¹¹ In, and DTPA per 100 repeating units constituting the polysaccharide
The number of bonds (DTPA binding ratio) was determined by TLC analysis using the following formula. (1) Peak area of TLC analysis (2) Molar amount added to reaction solution (3) Number of moles of polysaccharide constitutional repeating unit (glucosamine) The calculated binding ratio is CHT (PSH) under acetic acid / acidic reaction conditions.
It was 6.9 and 2.4 under alkaline reaction conditions. CHT (LL) was 3.1 under acetic acid / acid reaction conditions and less than 1 under alkaline reaction conditions.

0.2M citrate buffer pH 5.5 for each reaction
Was added to about 4 times the amount of the solution to gelate chitosan, and the precipitate was collected by centrifugation. The above buffer solution was added to the precipitate to resuspend it, and the operation of collecting the precipitate by centrifugation was repeated twice to remove impurities such as unbound DTPA to obtain the desired DTPA-CHT.

This was subjected to infrared absorption spectrum analysis. And the amide I band at 1655 cm ^{-1 in} the infrared absorption spectrum
The degree of deacetylation was examined from the ratio of absorption with the band due to the hydroxyl group stretching vibration at 3450 cm ^-1 . When determining the ratio of the 1655 cm ^-1 and 3450 cm ^-1 CHT-PSH _{is, A 1655 / A 3450 = 0.711} , CHT-
LL: A ₁₆₅₅ / A _{3450 =} 0.53. Also, in the DTPA conjugate
Although the peaks around 1655 cm ^-1 overlap, the height of the peaks increased, and it was confirmed that DTPA was bound to CHT. To determine the degree of purification of the target substance, a small amount of the target substance was extracted and suspended in 0.2M citrate buffer pH 5.5 (1-2 mg / ml) to the target substance solution 9 at 740 MBq / ml.
¹¹¹ InCl ₃ (0.1N hydrochloric acid dissolved state) of 1 was added to label ¹¹¹ In and determined by TLC analysis. Labeling rate (= purity)
Both CHT (PSH) and CHT (LL) were 98%. By this method, chitosan PSH and chitosan LL were added to methanol / 10%
Dissolved in acetic acid (volume ratio 5/1), added with alkali, and reacted with DTPA acid anhydride as it is,
Almost similar results were obtained. Also, when chitosan PSH and chitosan LL were dissolved in methanol / 0.1N hydrochloric acid (volume ratio 4/1), almost the same results as when acetic acid was used were obtained. In addition, for the detection of chitosan, ninhydrin color reaction that specifically reacts with an amino group and iodine color reaction that reacts with an organic compound were each performed, and both color developments were observed corresponding to the radioactivity peak position. It was clarified that the DTPA-CHT conjugate was certainly obtained by.

1-2. Preparation of DTPA-GlyCHT conjugate 0.1 M citric acid / 0.2 M sodium dihydrogen phosphate (volume ratio
3/5) pH 6.0 and 0.4M sodium phosphate buffer pH 8.
GlyCHT was dissolved in each of the two buffer solutions of 0, and DTP was equimolar to glycol glucosamine, which is a constituent unit of GlyCHT.
Acid A was added with stirring. To obtain the DTPA binding ratio, remove a small amount from the reaction solution and label it with ¹¹¹ In.
Determined by C. The DTPA binding ratios were 11 and 1 for the two solvents, citrate phosphate buffer and phosphate buffer, respectively.
Met. Purification was performed by electrolytic dialysis using 5 mM sodium citrate buffer (pH 8.0) as a running buffer. In order to determine the degree of purification, a small amount of the target substance was taken out, labeled with ¹¹¹ In, and determined by TLC. It was clarified that the method carried out provided a product with a purity of 100% and a DTPA-CHT conjugate could be obtained with certainty.

1-3. Preparation of DTPA-CHN Conjugate Chitin was dissolved in methanol / 10% acetic acid (volume ratio 5/1) at a concentration of 10 mg / ml. Then add excess DTPA anhydride.
(1 to 20 mg or more / CHN 1 mg) was added, and the mixture was subjected to ultrasonic waves in an ultrasonic cleaner to react. To determine the DTPA binding ratio, a small amount was taken out from the reaction solution, labeled with ¹¹¹ In, and determined by TLC, and it was less than 1%.

To each reaction solution, 1.5 volumes of phosphate / citrate buffer pH 7.4 was added, and the precipitates were collected by centrifugation and collected.
Suspended in 0.1N sodium hydroxide and sonicated. This operation was repeated 2-3 times, and then the precipitate was collected by centrifugation to obtain the desired product. In order to determine the degree of purification, a small amount of the target substance was extracted, labeled with ¹¹¹ In, and determined by TLC analysis. It was revealed that the DTPA-CHN conjugate could be reliably obtained by the method used.

1-4. Preparation of DO3MA-GlyCHT Conjugate To 3 ml of dimethylformamide solution of DO3MA dissolved at a concentration of 0.1M, triethylamine was added to a concentration of 0.2M, and then the mixture was stirred at room temperature for 10 minutes. . Next, after adding 0.5 mmol of chloroacetyl chloride, the mixture was stirred at room temperature, and DO3MA was added.
A hydrochloride (DO3MA-Cl) in which an acetyl chloride group was introduced was prepared. Next, dissolve each of the glycol chitosan, which is a constituent unit of glycol chitosan, in pure water so that equimolar amount of DO3MA-Cl 2 is present in the reaction solution to a concentration of 50 mM. The pH of this solution is adjusted to 8-9 with 0.1N sodium hydroxide.
Was prepared. After stirring at 60 ° C for 1 hour, the mixture was neutralized with 0.1N hydrochloric acid and dialyzed against citrate buffer solution pH6 to obtain high-purity DO3MA-GlyCHT. The degree of purification was determined by TLC analysis with a small amount of the reaction solution labeled with ¹¹¹ In. This revealed that the DO3MA-GlyCHT conjugate could be reliably obtained.

[0053]

Example 2 Binding of radioactive / non-radioactive metal ions to complexing agent-bound polysaccharides

2-1. Preparation of ¹¹¹ In-DTPA-CHT conjugate DTPA-CHT conjugate was added to 0.2 M citrate buffer at pH 5.5 for 1-2 m.
Suspend g / ml, add 370MBq / ml of ¹¹¹ InCl ₃ (0.1N hydrochloric acid dissolved state) in 1/9 volume, and stir at room temperature for 5 minutes.
A labeling reaction for chelating ¹¹¹ In was performed. TL after labeling
C analysis was performed to confirm that ¹¹¹ In was stably bound to the DTPA-CHT conjugate. The labeling rate was 98%.

2-2. Preparation of ¹¹¹ In-DTPA-GlyCHT Conjugate DTPA-GlyCHT was suspended in 0.4 ml of 0.1 M citric acid / 0.2 M sodium dihydrogen phosphate (volume ratio 3/5) pH 6.0 buffer, 3
After adding an equal volume of 70 MBq / ml of ¹¹¹ InCl ₃ (in a state of dissolving 0.1 N hydrochloric acid), the mixture was stirred at room temperature for 5 minutes to perform a labeling reaction for chelating ¹¹¹ In. After labeling, TLC analysis was performed, and ¹¹¹ In was DTP
It was confirmed that the protein was stably bound to the A-GlyCHT conjugate. The labeling rate was 100%.

2-3. Preparation of ¹¹¹ In-DTPA-CHN conjugate DTPA-CHN was dissolved in phosphate / citric acid / borate buffer pH 8.5 and 370 MBq / ml of ¹¹¹ InCl ₃ (0.1N hydrochloric acid dissolved state) was prepared.
After adding an equal volume of the above, the mixture was stirred at room temperature for 5 minutes to perform a labeling reaction for chelating ¹¹¹ In. After labeling, perform TLC analysis,
It was confirmed that ¹¹¹ In was stably bound to the DTPA-CHN conjugate.

2-4. Preparation of ¹¹¹ In-DO3MA-GlyCHT conjugate A small amount of DO3MA-GlyCHT conjugate was added to 0.2M citrate buffer pH6.
Suspended in 370MBq / ml of ¹¹¹ InCl ₃ (0.1N hydrochloric acid dissolved state)
Was stirred 60 ° C. 1 hour after the addition 1 volume of 9 minutes, ¹¹¹ an In
A labeling reaction for chelating was carried out. After labeling, TLC analysis was performed to confirm that ¹¹¹ In was stably bound to the DO3MA-GlyCHT conjugate.

2-5. Preparation of Sm-DTPA-GlyCHT conjugate DTPA-GlyCHT dissolved in 0.2M citrate buffer pH 5
Samarium chloride (abbreviated as SmCl ₃ ) was dissolved in 0.4 ml of the solution so that the concentration thereof was 0.07 mmol. This solution was stirred at room temperature for 4 to 5 hours, and the reaction solution was centrifuged to obtain a supernatant. After concentration, dialysis was performed against pure water to obtain the desired product. Sm DTPA-Gl
For coupling with yCHT, an inductively coupled high frequency plasma analyzer (I
CP). 108 ppm of Sm was bound to the amount of DTPA bound to GlyCHT of 27.4 ppm.

2-6. Preparation of Y-DTPA-GlyCHT conjugate 0.4 ml of DTPA-GlyCHT solution dissolved in 0.2M citrate buffer pH 5 was added with yttrium chloride (abbreviated as YCl ₃ ) concentration.
Dissolved to 0.07 mmol. This solution at room temperature
After stirring for 4 to 5 hours, the reaction solution was dialyzed against pure water.
Next, the cloudy reaction solution was centrifuged to collect the precipitate, which was washed with pure water to obtain the desired product. The bond of Y with DTPA-GlyCHT is
Confirmed by ICP. For every 10 ppm of DTPA bound to GlyCHT, 46.2 ppm of Y was bound.

2-7. Preparation of ⁹⁰ Y-DTPA-GlyCHT Conjugate DTPA-GlyCHT was added to phosphoric acid / citric acid / borate buffer pH 8.5.
The mixture was dissolved in 100 μg / ml, ⁹⁰ YCl _{3 of} 94 MBq / ml (0.1 N hydrochloric acid dissolved state) was added thereto, and the mixture was stirred at room temperature for 1 hour to perform a labeling reaction for chelating ⁹⁰ Y. After labeling, perform TLC analysis, ⁹⁰ Y
Was confirmed to be stably bound to the DTPA-GlyCHT conjugate. The labeling rate was 100%.

[0061]

Example 3 Production of Macromolecular Compound Injection for Administration

⁹⁰ Y-DTPA-GlyCHT Injection Solution DTPA-GlyCHT suspension prepared according to the method of Example 1
It was dialyzed against a physiological saline solution adjusted to pH 3 or less with 0.1N hydrochloric acid. After dialysis, DTPA-GlyCHT was aseptically filtered with a 0.2 μm pore size membrane filter and dispensed and sealed in a glass vial. Yttrium chloride ( ⁹⁰ YCl ₃ ) has a pH of 5 to 7
It was dissolved in the citrate buffer solution or the phosphate buffer solution, and aseptically filtered with a 0.2 μm membrane filter, and then the tube was dispensed and sealed in a glass vial. The labeling was performed by extracting the DTPA-GlyCHT solution from the vial with an appropriate syringe, adding it to a ⁹⁰ YCl ₃ vial, and shaking / standing at room temperature for 30 minutes. DT
PA-GlyCHT is mixed with a neutral buffer solution in a ⁹⁰ YCl ₃ vial to change into a colloidal state, and the target macromolecular compound is produced at the same time as the labeling reaction proceeds.

[0063]

[Example 4] Pharmacokinetics of ¹¹¹ In-labeled complexing agent-bound polysaccharide

4-1. Biodistribution by subcutaneous administration ¹¹¹ In-DTPA-CHT (PSH) sample solution (37MBq / ml) was subcutaneously injected under anesthesia in the vicinity of the knee joint of normal SD rats (female: body weight 230 to 280g). 25 μl was administered. The distribution in the body is 1, 3, 6, after administration.
After dissection for 24 hours, the radioactivity distribution for each organ was calculated using a single channel counter. After 24 hours,
Eighty-one percent remained in the rest of the body including the joints where it was administered, and the amount of radioactivity excreted in the urine was 17%, and the remaining 2% was transferred to organs.

[0065] ¹¹¹ In-DTPA-CHT (PSH) is characterized by its subcutaneous distribution in the body, and is characterized by being gradually metabolized while remaining at the administration site, showing almost no transition to the abdominal organs, and its main elimination route. Is the renal / urinary system, etc. Based on these findings, it was revealed that ¹¹¹ In-DTPA-CHT (PSH) has a retention property at the administration site and is immediately metabolized and excreted outside the body after being excreted from the administration site.

4-2. Distribution in the body by joint cavity administration [0066] The knee skin of a normal SD rat (female: body weight 230-280g) was incised under Ronald's anesthesia, and the sample solution prepared in the joint cavity was 2μ.
l was administered. The sample solution is ¹¹¹ In-DT with a molecular weight of approximately 500,000.
PA-CHT (PSH) suspension (37MBq / ml), ¹¹¹ In- with a molecular weight of about 50,000
DTPA-CHT (LL) suspension (37 MBq / ml) and ¹¹¹ In-DTPA-GlyCHT suspension (185 MBq / ml) were used, and the samples shown in the examples were used. The incised skin was adhered with a cyanoacrylate-based instant adhesive after administration. Distribution in the body is 3,
Two mice were dissected at each time point after 6, 24, and 48 hours, and the radioactivity distribution was calculated for each organ. ¹¹¹ In-DTPA-CHT (PSH),
^{111 In-DTPA-CHT (LL} ), 111 In-DTPA- body features of dynamics of GlyCHT was the result of either similar. That is, almost no transfer to other normal organs was observed, and the main excretion route was the renal / urinary system.

The radioactivity administered into the joint cavity was excreted from the joint cavity over time, and the excretion of radioactivity was exponential from the graph (FIG. 1) in which the ratio of radioactivity in the joint was plotted against time. It became clear. The slope of the straight line in Fig. 1 was calculated by the method of least squares, and the elimination half-life from the joint cavity (time when the residual amount in the joint cavity reaches 50%: T1 / 2) was calculated.
¹¹¹ In-DTPA-CHT (PSH) is 53.6 hours, ¹¹¹ In-DTPA-CHT
(LL) was 52.7 hours and ¹¹¹ In-DTPA-GlyCHT was 208 hours. A half-life of 4 for chitosan and glycol chitosan
About twice as different. Furthermore, chitosan (LL) and chitosan (PSH
It was clarified that the difference in the molecular weight of) does not reflect the elimination half-life. From these findings, it was clarified that pharmacokinetics can be controlled by selecting a carrier represented by chitosan.

4-3. Biodistribution by administration to subcutaneously transplanted tumor Using a lyophilized product of DTPA-GlyCHT with a DTPA binding ratio of 11,
Dissolve 0.1M citric acid 0.2M sodium dihydrogen phosphate (volume ratio 3: 5) in pH 6.0 buffer to a concentration of 2mg / ml, add 0.2 ml of ¹¹¹ InCl ₃ hydrochloric acid solution to O.5ml, It was used as a sample solution for administration test.

¹¹¹ In-DTPA-GlyCHT 5 was added to the tumor site of WKA male rats (body weight 270 to 310 g) transplanted with hepatocellular carcinoma on the back.
0 μl (5.3 MBq) was injected. Imaging was performed with a gamma camera after 3 hours and 48 hours (Fig. 2). After 5 days, autopsy was performed to determine the distribution in the body (n = 3).

From the imaging with the gamma camera, 90% of the tumor remained after 3 hours, 81% after 24 hours, and 75% after 48 hours. After dissection 5 days later, approximately 23% of the tumor remained.

From the results of imaging and dissection, ¹¹¹ In-DTP
The elimination half-life (T1 / 2) of A-GlyCHT from the tumor was calculated to be about 74 hours (Fig. 3). The retention property in the tumor site was sufficiently long, suggesting its usefulness as an embolic local administration therapeutic agent which is directly administered to the tumor or directly administered to the tumor through the feeding blood vessels.

[0072]

[Reference example] ¹¹¹ In, ¹¹¹ In-DTPA, ¹¹¹ In colloid and ¹¹¹ In-DTPA
Distribution comparison of intra-articular administration of GlyCHT

Similar to the procedure shown in the fourth embodiment, the normal SD
The knee skin of a rat (female: body weight 230 to 280 g) was incised under rabonal anesthesia, and 2 μl of the prepared sample solution was administered into the joint cavity. Each of the prepared sample solutions was ¹¹¹ In-DTPA solution (74 MBq / m
l), ¹¹¹ In solution (185MBq / ml), ¹¹¹ In colloidal solution (37MB
q / ml). ¹¹¹ In-DTPA solution is 1 mM DTPA solution,
0.4M boric acid: 0.1M citric acid-0.2M trisodium phosphate buffer (volume ratio 39: 100) Add 4 volumes of pH 8.5 and add 0.2mM DT
After adjusting the concentration of PA, 1/5 of ¹¹¹ InCl ₃ was added, shaken well, and allowed to stand for 1 hour. ¹¹¹
The In solution was prepared by mixing ¹¹¹ InCl ₃ in 0.1N hydrochloric acid and 0.4M boric acid: 0.1M citric acid-0.2M trisodium phosphate buffer (volume ratio 39: 100) pH 8.5 in equal amounts, and the pH was 6.5. It is the one. ¹¹¹ In colloidal solution has a concentration of 1 OmM
l ₃ of 0.1N hydrochloric acid solution was added with 1/9 volume of ¹¹¹ InCl ₃ 0.1N hydrochloric acid solution, and then sodium hydroxide was used.
The pH was adjusted to 6-8. The incised skin was adhered with an instant adhesive after administration. The distribution in the body was determined as the radioactivity distribution for each organ by dissecting two animals at each time point 3, 6, 24, and 48 hours after administration.

FIG. 4 shows the time-dependent changes in the biodistribution of each sample due to the administration of the joint cavity. The distribution characteristics of the three samples were as follows. Clearance of ¹¹¹ In-DTPA from the joint cavity is very fast, transfer to the liver, blood, and the rest of the body is observed, and excretion into the body as urine is slightly slow. ¹¹¹ In is excreted from the kidney / urinary system, and is also observed to be transferred to the liver and large intestine and accumulated in the rest of the body.
There is excretion by the liver / biliary system.

The characteristic of ¹¹¹ In colloid distribution in the body is that it stays in the joint cavity for a long time and hardly migrates out of the joint cavity. The results showed the time course of the joint cavity remaining of these samples in Figure 4, it obtains a gradient of the straight line of each sample by the least square method to calculate the elimination half-life from the joint cavity the (T1 / 2), ¹¹¹ In-D
TPA was 3 hours or less, ¹¹¹ In was 3.95 hours, and ¹¹¹ In colloid was 923 hours. The results are shown in Table 1.

This experimental result shows that ¹¹¹ In ions or ¹¹¹ In-DTPA that has just been complexed are rapidly excreted and are unlikely to show a drug effect, but that long-term persistence becomes a problem in the colloidal state. . As shown in Example 4 above, the elimination half-life of ¹¹¹ In bound to a polysaccharide is
Approximately 53 hours for chitosan and 208 hours for glycol chitosan, which is more retentive than ¹¹¹ In-DTPA, ¹¹¹ In,
¹¹¹ In Easier to be discharged than colloid. From the above results, it can be expected that the drug efficacy and safety can be achieved at the same time by using a polysaccharide as a carrier for radioactive metal ions, and further, by appropriately selecting the polysaccharide to be used as a carrier, It was shown that it is also possible to control the excretion rate of.

[Table 1]

[0077]

[Example 5] Examination of safety

[0078] 5-1. ¹¹¹ In-DTPA-GlyCHT analysis ¹¹¹ In-DTPA-GlyCHT sample solution metabolites ^{(185MBq / ml), 111 In} -DTPA solution (74MBq / ml), ¹¹¹ In solution (185 MBq / ml ) Each sample solution 2
Metabolites contained in rat urine at 3, 6, 24, and 48 hours after intra-articular administration of μl were analyzed by TLC system. It was suggested that, in the sample to which a carrier such as ¹¹¹ In-DTPA-GlyCHT was bound, the molecule was digested in vivo to become a low molecule.

[0079]

Example 6 Therapeutic effect of ⁹⁰ Y-labeled chelating agent-bound polysaccharide

[0080] 6-1. Tumors of C57BL therapeutic efficacy Lewis lung cancer cells of the tumor portion topical by tumor-bearing mice were transplanted into the back / 6 strain male mice (body weight 12 ~14g), shown in Example 4 ⁹⁰ Y-DTPA
-GlyCHT 375 μl (0.3 MBq) was injected in 4 portions. The results are shown in Table 2. Tumor degeneration was observed on day 2 after the start of administration, and the difference widened on day 5 compared to untreated tumors, and growth suppression and lethal effects on tumor cells were observed.

Further, in order to confirm the state of the tumor tissue, the collected tumor tissue was fixed with formalin. After fixation, a paraffin section sliced into about 4 μm was prepared according to a standard method (paraffin embedding method), stained with hematoxylin and eosin, and subjected to histopathological examination. The obtained tissue images are shown in FIGS.
It was shown to. ⁹⁰ Y-DTPA-GlyCHT-treated tumor tissue was
The tissue is generally small microscopically, and the necrotic area occupies most of the mass of tissue (Fig. 5). Connective tissue grew around the necrotic area, and a large number of cell nests and nuclear collapse were observed in the center. The cells characteristic of Lewis lung cancer cells were not found on the tissue specimen (FIGS. 6 and 7). On the other hand, in the control tumor tissue, cells having large and small nuclei were densely present, and the cell sizes were various. A mitotic figure was observed in many of these cells (Figs. 8 and 9). There are hemorrhagic foci, mononuclear cell infiltration, and small necrotic foci around the tumor tissue,
It was bounded by connective tissue with adjacent muscle tissue. From these findings, it was revealed that tumor cells were injured by administration of ⁹⁰ Y-DTPA-GlyCHT. In addition, no significant change was observed in the muscle tissue around the microscopic examination, and the cells were necrotic throughout the tumor tissue, so the therapeutic effect of this drug administration is expected.

[Table 2]

6-2. Intra-articular administration pharmacokinetics and therapeutic effect in a pathological model Ovalbumin (10 mg / ml) was intradermally administered to several tens of the skin of a rabbit with Freund's complete adjuvant four times at intervals of one month, 0.1 ml. Each was injected to sensitize rabbits. Then, 50 μl of an adjuvant suspension of ovalbumin was administered into the knee joint cavity of the right hind limb to induce an immune reaction, which was used as an adjuvant arthritis model. ¹¹¹ In-D labeled with ¹¹¹ In instead of ⁹⁰ Y to obtain a clear biodistribution image
50 μl (6.2 MBq) of TPA-GlyCHT sample solution was administered into the cavity of the knee joint of the right hind leg of the diseased state. The distribution of the administered drug in the body is
Gamma cameras were used at 3, 24 and 48 hours, and dissection was performed 5 days later, and the results were obtained (n = 3). Figure 10 shows the image taken by the gamma camera. Fig. 11 shows the ratio of radioactivity to the whole body of joints and urine. 85.6% after 3 hours and 83.8% after 6 hours from the gamma camera image.
%, 63.1% after 24 hours and 49% after 48 hours remained, and decreased exponentially with time. The joint cavity elimination half-life (T1 / 2) of the administered radioactivity was calculated by the least squares method, and it was 54.6 hours.

[0083]

Since the present invention is configured as described above, it has the following effects.

In the locally administered radiotherapeutic agent of the present invention characterized by the use of a polymeric polysaccharide carrier, the use of a polysaccharide as a carrier makes it physiologically tolerable and decomposed in vivo to be in vitro. It is possible to provide a locally administered radiotherapeutic agent which facilitates excretion and has no negative effects such as a toxic disorder resulting from long-term residue.

By using it as a naturally occurring polysaccharide carrier such as a chitin derivative, which is naturally present in a large amount, the preparation can be stably and inexpensively supplied. Further, when a chitin derivative is used, the dissolution state changes depending on the difference in pH, so that sterilization operation and production are easy.

Furthermore, by utilizing the property that in vivo digestibility differs depending on the type of polysaccharide and selecting an appropriate polysaccharide, it is possible to obtain the desired local retention and facilitate pharmacokinetic control. Become.

By binding a complexing agent to the polysaccharide serving as a carrier, it is possible to stably bind many kinds of radioactive metal ions to many kinds of polysaccharides regardless of the binding ability of the polysaccharide itself to metal ions. It is possible and many types of polysaccharides can be used as carriers.

[Brief description of drawings]

FIG. 1 is a diagram comparing the residual rates of radioactivity in joint cavities of chitin derivatives.

FIG. 2. Tumor image at 3,48 hours after administration.

FIG. 3 is a view showing a change over time in the residual radioactivity in the tumor part.

FIG. 4 is a diagram comparing the residual rates of radioactivity in joint cavities of respective samples.

FIG. 5 is an image showing the therapeutic effect of cancer-bearing mice.

FIG. 6 is an image showing the therapeutic effect of cancer-bearing mice.

FIG. 7 is an image showing the therapeutic effect of cancer-bearing mice.

FIG. 8 is an image showing the therapeutic effect of cancer-bearing mice.

FIG. 9 is an image showing the therapeutic effect of cancer-bearing mice.

FIG. 10 shows changes over time in a joint model image of a pathological model.

FIG. 11 is a diagram showing changes over time in the distribution of disease state model in the body.

[Explanation of symbols]

 N: Necrotic area M: Muscle tissue F: Cell clusters (including nuclear collapse image) C: Cells that make up cell clusters L: Tumor cells S: Nuclear division image

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[Procedure amendment]

[Submission date] May 23, 1995

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be corrected] Brief description of the drawing

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[Brief description of drawings]

FIG. 1 is a diagram comparing the residual rates of radioactivity in joint cavities of chitin derivatives.

FIG. 2 is a photograph of tumor image (form of organism) at 3,48 hours after administration.

FIG. 3 is a view showing a change over time in the residual radioactivity in the tumor part.

FIG. 4 is a diagram comparing the residual rates of radioactivity in joint cavities of respective samples.

FIG. 5 is a histopathological photograph showing the therapeutic effect of a tumor-bearing mouse (morphology of organism).

FIG. 6 is a histopathological photograph showing the therapeutic effect of cancer-bearing mice (morphology of organism).

FIG. 7 is a histopathological photograph showing the therapeutic effect of tumor-bearing mice (morphology of organism).

FIG. 8 is a histopathological photograph showing the therapeutic effect of tumor-bearing mice (morphology of organism).

FIG. 9 is a histopathological photograph showing the therapeutic effect of tumor-bearing mice (morphology of organism).

FIG. 10: Time-dependent change of pathological model image photograph (morphology of organism).

FIG. 11 is a diagram showing changes over time in the distribution of disease state model in the body.

[Explanation of Codes] N: Necrosis area M: Muscle tissue F: Cell aggregates (including nuclear collapse image) C: Cells constituting cell aggregates L: Tumor cells S: Nuclear division image

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Front Page Continuation (72) Inventor Hiroaki Washino 3 Kita-sode, Sodegaura-shi, Chiba 1 Central Research Institute, Japan Medi-Physics Co., Ltd.

Claims (5)

[Claims] 1. An average molecular weight of 1 × 10 comprising a hydrophilic repeating monomer unit containing an amino group, a hydroxyl group or a carboxyl group, or a derivative thereof.
³ to 1 × 10 ⁶ biodegradable hydrophilic polymers chemically bound to at least one radiometal ion via a complexing agent, physiologically tolerable, at physiological pH and temperature A radiotherapy agent for local administration comprising a macromolecular compound or a salt thereof, which gels in 2. The therapeutic agent according to claim 1, wherein the biodegradable hydrophilic polymer is a polysaccharide or a derivative thereof. 3. A general formula: (In the formula, R ₁ and R ₂ are different from each other and each represents an amino group, a hydroxyl group or a hydrogen atom, R ₃ is a hydrogen atom, a glycol group or a carboxymethyl group, and R ₄ and R ₅ are different from each other. A hydrophilic repeating monomer unit represented by 1 or 4 represents an atom or a hydroxyl group.
A macromolecule in which at least one radioactive metal ion is chemically bound to a biodegradable polymer formed by binding and / or 1 → 6 binding via a complexing agent bound to R ₁ or R _2. The therapeutic agent according to claim 1, which comprises a compound. 4. The therapeutic agent according to claim 1, wherein the biodegradable hydrophilic polymer is chitin, chitosan or a derivative thereof. 5. The therapeutic agent according to claim 1, wherein the radioactive metal ion is an α-ray or β-ray emitting nuclide.