JP2007325824A - Chemotherapy material for local administration - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To improve chemotherapy materials for local administration with an excellent biological tissue affinity and biodegradable absorbency and strong tissue adhesion. <P>SOLUTION: The chemotherapy material is used for low-invasive administration of liquid or sol therapeutic agents to specified sites in vivo and gelatinization and it is characterized in that the chemotherapy materials are formed by crosslinking an aqueous solution of biodegradable polymer or buffer solution of the salts including the therapeutic agent with organic acid derivatives. It has an excellent biological tissue affinity and biodegradable absorbency and strong tissue adhesion and the administration can be easily performed to the specified site with a syringe, and then it can be applied to drug administration to low-invasive focus, medical adhesive agents containing therapeutic agents, hemostatic agents, vascular embolic agents, sealants, or sealants of aneurysm. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

The present invention is a material for administering a therapeutic agent to a local region in an individual, and a locally administered chemotherapeutic material that gels by administering the therapeutic agent to a specific site in a living body in a minimally invasive state in a liquid or sol state. About.

Research and development of various locally administered chemotherapeutic materials has been carried out, but the invention relating to materials that are easy to operate and that have excellent biological tissue affinity, biodegradability and strong biological tissue adhesion not exist.

As an example in which a drug is contained in a polymer material for the purpose of application to local chemotherapy, JP-A-2002
No. -102331 discloses a complex composed of particles containing an anticancer agent and a temperature-responsive polymer (N-isopropylacrylamide). In the invention disclosed herein, particles containing an anticancer agent are combined with a copolymer that responds to changes in temperature and pH, which is synthesized using N-isopropylacrylamide, which is known as a temperature-responsive polymer, as a basic substance. This is intended to cure as the temperature rises due to body temperature, and to gradually release the drug locally.

In the present invention, it is necessary to control physical properties by external stimulation, and the problem is that the carrier is non-biodegradable and absorbable. In addition, since the present invention forms a crosslinked structure using aggregation due to hydrophobic interaction accompanying a temperature rise, the crosslinked body is extremely soft, and it is difficult to spread over a wide range after administration and for a long-term sustained release of a drug. There is a problem. Furthermore, since the base material does not have biological tissue adhesiveness, it may move from the local area after administration (Patent Document 1).
).

Similarly, ML Veyries (1999) et al.
We are conducting research on drug release from hydrogels in which a drug is combined with ronic F-127 (registered trademark). The invention disclosed herein is for Pluron for application to local cancer chemotherapy
The drug release behavior was investigated by combining vancomycin with ic F-127. The invention disclosed here is also non-bioabsorbable because it uses a temperature-responsive synthetic polymer, the crosslinked body is soft, and it is difficult to slowly release the drug for a long time (release the drug in several hours). There is a problem that it does not have biological tissue adhesion (Non-Patent Document 1).

Furthermore, as another example of the polymer material for local chemotherapy, JP-T-2004-52
No. 8278 discloses a hydrogel for topical administration. The invention disclosed herein is a complex in which a drug is contained in a carrier using a polyanion as a base material and a divalent salt as a crosslinking agent.
In the invention disclosed herein, since the carrier forms a cross-linked structure by ionic bonding, it is unstable in the body after administration, and there are restrictions on the drugs that can be used (Patent Document 2).

The present inventors have an excellent biodegradable polymer and an organic acid derivative in which two carboxyl groups of dicarboxylic acid and two or three carboxyl groups of tricarboxylic acid are modified with an electron-withdrawing group. Developed two-component biodegradable and absorbable adhesive biomedical materials that have both biotissue affinity and biodegradable absorbability and strong biotissue adhesion (Patent Documents 3 to 9, Non-patent Documents 2 to 3) .

JP 2002-102331 A Special Table 2004-528278 JP 2004-99562 A JP 2004-261222 A JP 2005-168949 A JP 2005-187670 A JP 2006-52158 A JP 2006-52158 A International Publication 2006/016600 A1 Int. J. Pharm. 192 (1999) 183-193. T Taguchi et al. Materials Science and Engineering C24 (2004) 775-780 H Saito et al. Materials Science and Engineering C24 (2004) 787-790

An object of the present invention is to develop a locally administered chemotherapeutic material to which the biodegradable absorbable adhesive medical material developed by the present inventors is applied in order to solve the above-mentioned problems.

In order to solve the above-described problems, the present invention has excellent biotissue affinity and biodegradable absorption by mixing a therapeutic agent with the biodegradable absorbable adhesive medical material developed by the present inventors. A locally administered chemotherapeutic material that combines high tissue adhesion and strong tissue adhesion has been developed.

That is, the present invention is based on an aqueous solution or salt buffer solution in which a biodegradable polymer is dissolved for administering a therapeutic agent to a local region in an individual, and an organic acid derivative mixed in the substrate is used as a crosslinking agent. A locally administered chemotherapeutic material comprising a complex in which a drug is mixed in a carrier.

The strong tissue adhesion in the present invention means an adhesive strength of 30 kPa or more in an adhesion test using a biological tissue or a test piece similar thereto.

The biodegradable absorbability in the present invention refers to degradation, absorption within one year after injection in vivo,
Indicates metabolized properties.

  Although there is no limitation in particular in the chemical | medical agent used for this invention, an anticancer agent is mentioned as an example.

The locally administered chemotherapeutic material of the present invention combines excellent biotissue affinity and biodegradability and strong tissue adhesion, and can be easily administered to a specific site with a syringe. Therefore, it is possible to administer a drug to a lesion site with minimal invasiveness and to apply as a medical adhesive, a hemostatic agent, a vascular embolization agent, a sealant, or an aneurysm sealing agent containing a therapeutic agent.

The locally administered sustained-release biodegradable and absorbable medical material in the present invention is a mixture of a biodegradable polymer, an organic acid derivative and a bioactive agent, and has a property of curing after a certain time. It is characterized by having.

Curing in the present invention means that it is cured by a chemical reaction between a biodegradable polymer and an organic acid derivative and loses fluidity.

The biodegradable polymer in the present invention is at least one selected from the group consisting of collagen, gelatin, serum albumin, elastin, actin, keratin, chitin, chitosan, polyamino acid, depsipeptide and the like, and a recombinant protein. Or 2 or more types are preferable.

The biodegradable polymer has an amino group in the molecule and is a drug carrier base material suitable for reaction with an organic acid derivative crosslinking agent.

Examples of the organic acid derivative used as the crosslinking agent of the present invention include those obtained by modifying at least one carboxyl group of di- or tricarboxylic acid with an electron-withdrawing group.

Moreover, the weight average molecular weight of these biodegradable polymers is preferably about 500 to 100,000 from the viewpoint of not impairing the strong tissue adhesion.

Examples of the solvent that dissolves the biodegradable polymer include one kind or a combination of two or more kinds of distilled water or a salt buffer solution. The concentration of the biodegradable polymer in the solution at the time of preparing the biodegradable polymer solution is preferably 0.1% by weight or more from the viewpoint of not impairing the strong tissue adhesion. Weight percent is more preferred.

The salt buffer solution for preparing the biodegradable polymer solution is not particularly limited, and examples thereof include phosphate, borate, Tris hydrochloride, and aminoethanesulfonate. The concentration of the salt buffer is 0.01M to 10M, more preferably 0.1 to 1.0M.

The organic acid derivative used as the crosslinking agent of the present invention is a carboxyl group of dicarboxylic acid.
And two or three of the carboxyl groups of the tricarboxylic acid are modified with electron withdrawing groups. Examples of the di- or tricarboxylic acid include citric acid, malic acid, oxalacetic acid, cis-aconitic acid, succinic acid, fumaric acid, α-ketoglutaric acid, tartaric acid, and derivatives thereof. The electron-withdrawing group includes succinimidyl, At least one of sulfosuccinimidyl, maleimidyl, imidazolyl, nitrophenyl, and trezyl groups is used.

The organic acid derivative uses 0.001 to 10% by weight of N-hydroxysuccinimide and 0.001 to 10% by weight of carbodiimide derivative with respect to 0.001 to 10% by weight of dicarboxylic acid and tricarboxylic acid, and the reaction time is 1 to 48 hours. It can be obtained by appropriately selecting the reaction temperature of 0-100 ° C. The obtained organic acid derivative is purified by recrystallization using alcohol to obtain a powder.

Examples of the carbodiimide derivative include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide / hydrochloride (EDC), 1-cyclohexyl-3- (2-monophorinoethyl) carbodiimide / meth-p-toluenesulfonate, Dicyclohexylcarbodiimide (DCC) can be used. Further, N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), or tetrahydrofuran (THF) can be used as the reaction solvent.

Examples of alcohols used for purification by recrystallization of organic acid derivatives include methyl alcohol, ethyl alcohol, 1-propyl alcohol, 2-propyl alcohol,
1-butyl alcohol, 2-butyl alcohol, isobutyl alcohol, and tert-butyl alcohol can be used.

The concentration of the aqueous solution, organic solvent solution or powder of the organic acid derivative used for curing is from 0.01 to 1 g of the biodegradable polymer solution from the viewpoint of not damaging strong tissue adhesion.
1000 mmol is preferable, and 0.1 to 100 mmol is more preferable. For example, biodegradable polymer solution 1
When 0.1 mmol of organic acid derivative is added to g, the curing time is about 20 to 180 seconds, and the mixed solution before curing is a property suitable for injection by a syringe, that is, a liquid or sol state having fluidity. .

The property suitable for local administration by a syringe in the present invention means a liquid or sol state that passes through any of 17G to 27G injection needles without resistance.

Preferred injection methods for injection with a syringe in the present invention include subcutaneous injection, intraperitoneal injection, and local injection with a catheter.

The mixing method of the biodegradable polymer solution and the organic acid derivative aqueous solution or organic solvent solution or powder is not particularly limited. For example, a small mixer or the like can be used immediately before use.

Although there is no limitation in particular in the drug used for this invention, an anticancer agent is mentioned as an example. Anticancer drugs include doxorubicin hydrochloride, pepromycin hydrochloride, nitrogen mustard-N-oxide, cyclofasfamide, thiodepa, carbocon, nimustine hydrochloride, bleomycin hydrochloride, bleomycin sulfate, pepromycin sulfate, aclarubicin hydrochloride, idarubicin hydrochloride, epirubicin hydrochloride, hydrochloric acid Daunorubicin, pirarubicin hydrochloride, dinostatin stymalamar, neocartinostatin, etoposide, teniposide, irinotecan hydrochloride,
Vincristine sulfate, vindesine sulfate, vinblastine sulfate, L-asparaginase, mitoxantrone hydrochloride, cisplatin, carboplatin, nedaplatin, pentostatin,
Examples include dizofilan, porfimer sodium, ifasfamide, catalbazine, mercaptopurine, thioinosine, cytarabine, inositabine, fluorouracil, tegafur, ancitabine hydrochloride, methotrexate, carmofur, mitomycin C, actinomycin, bleomycin hydrochloride, taxol.

As described above, the present invention uses a salt buffer solution in which a biodegradable polymer is dissolved and an aqueous solution or organic solvent solution or powder of an organic acid derivative as a mixed solution or sol. By injecting into the local region using a syringe, the organic acid derivative acts as a cross-linking agent, and the biodegradable polymer is cured and adhered to the tissue in the local region.

Since the curing reaction of the present invention is based on a covalent crosslinking reaction between a substrate and a crosslinking agent, a wide variety of drugs can be used. For example, proteins, gene therapy drugs, radionuclides and the like can be mentioned, and the characteristics of the drugs can be used in both cases of hydrophilicity and hydrophobicity.

Furthermore, the present invention has the property of decomposing in vivo after being applied to the use, and absorbing and disappearing within 6 months, and does not remain as a foreign substance in the body.

EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in more detail, this invention is not limited to this Example at all. The adhesive strength of the material of the present invention was measured in advance for Test Example 1 below.

Human serum albumin (HSA) was used as the biodegradable polymer, and tartaric acid derivative (TAD) whose carboxyl group was modified with N-hydroxysuccinimide was used as an organic acid derivative modified with an electron withdrawing group as a crosslinking agent.

[Test Example 1]
0.25 mg of doxorubicin hydrochloride is added to 0.19 g of a 0.1 M phosphate buffer solution (pH 7.4) of 33% by weight of HSA, and further 0.1 mmol (0.01 g) of TAD is added, followed by stirring for 5 seconds. A mixed solution was prepared.

Control Example 1 was prepared under the following conditions.
[Control Example 1]
0.2g of 25w% aqueous solution of temperature-responsive polymer material (Pluronic F-127, AnaSpec, Inc)
Was added with 0.25 mg of doxorubicin hydrochloride.

The tensile shear bond strength was measured using Test Example 1 and Control Example 1 as test substances. That is, 1.0 cm × 1.0 cm on one end of a PET film having a thickness of 1.0 cm × 4.0 cm and a thickness of 1.0 mm.
A sample having a collagen casing of cm was used as a test piece, and the collagen casing portion was used as a bonding surface and bonded using Test Example 1 and Control Example 1, and then the tensile shear bond strength was measured using a tensile tester (TA -XT2i, Eihiro Seiki Co., Ltd.)

The results of the adhesive strength measurement are shown in Table 1.

From the results shown in Table 1, it is clear that Test Example 1 has much stronger adhesive strength than Control Example 1. That is, it was shown that the locally administered chemotherapeutic material used in the present invention clearly has stronger adhesive strength than Pluronic F-127, which is a temperature-responsive synthetic polymer.

33% by weight of HSA in 0.1 M phosphate buffer (pH 7.4) 0.3 at room temperature
Add 8 mg of doxorubicin hydrochloride to 8 g and add 0.2 mmol of TAD (0.02 g
) Was added and stirred for 5 seconds to prepare a mixed solution. The mixed solution obtained here was a fluid liquid, and its curing time was 67.5 seconds at 37 ° C.
0.2 g of the prepared mixed solution was administered using a syringe equipped with a 24 G needle at the bottom of the tumor,
Changes in tumor volume were measured.

[Comparative Example 1]
0.4g of 25w% aqueous solution of temperature-responsive polymer material (Pluronic F-127, AnaSpec, Inc)
A mixed solution was prepared by adding 0.5 mg of doxorubicin hydrochloride. Prepared mixed solution 0.2
g was administered to the bottom of the tumor and changes in tumor volume were measured.

[Comparative Example 2]
33% by weight of HSA in 0.1 M phosphate buffer (pH 7.4) 0.38 g and TAD 0.2
mmol (0.02 g) was added and stirred for several seconds to prepare a mixed solution. 0.2 g of the prepared mixed solution was administered to the bottom of the tumor, and the change in the tumor volume was measured.

[Comparative Example 3]
An aqueous solution in which 0.25 mg of doxorubicin was dissolved in 0.2 mL of sterile water was prepared. 0.2 mL of the prepared aqueous solution was administered to the bottom of the tumor, and the change in the tumor volume was measured.

[Comparative Example 4]
Changes in tumor volume were measured without administration of carriers, drugs, etc.

The antitumor effect was examined using Example 1 and Comparative Examples 1 to 4 as test substances. First, 5
1 × 10 ⁷ human colon cancer cell lines (WiDr) were transplanted subcutaneously in the back of a week-old immunodeficient mouse (BALB / cAnNCrj-nu / nu, Charles River Japan Co., Ltd.) to prepare a tumor bearing mouse. After engrafting the prepared tumor-bearing mice with a tumor having a diameter of about 1 cm, a predetermined amount of Example 1 and Comparative Examples 1 to 4 were injected into the bottom of the tumor using an injection syringe equipped with a 24G needle. Thereafter, the major axis and minor axis of the tumor were measured over time using calipers, the converted tumor volume was calculated, and the rate of change from the converted tumor volume before administration of Example 1 and Comparative Examples 1 to 4 was measured as the antitumor effect. Evaluation was performed. The converted tumor volume was calculated from 1/2 × major axis × minor axis ² .

Table 2 shows the change rate of the converted tumor volume 24 hours after administration.

From the results of Table 2, Example 1 showed an excellent antitumor effect as compared with Comparative Example 1. Comparative Example 1 releases the drug in a few hours in order to form a non-covalent soft crosslinked body.
In Example 1, since the drug can be sustainedly released over a long period of time in order to form a covalently crosslinked product, an excellent antitumor effect was obtained. In addition, Example 1 clearly showed an excellent antitumor effect even when compared with Comparative Examples 2-4. From these results, it can be said that Example 1 showed an excellent antitumor effect due to a synergistic effect of the adhesion of living tissue and the sustained release of the anticancer agent.

The present invention is a locally administered chemotherapeutic material that can be used to administer a therapeutic agent to a local region in a minimally invasive manner and has excellent biotissue compatibility, biodegradability and strong tissue adhesion. Yes, it can also be used for minimally invasive local administration chemotherapy, hemostasis, vascular embolization, sealant or aneurysm sealing.

Claims (6)

A locally administered chemotherapeutic material that is administered in a liquid or sol state in a minimally invasive manner to a specific site in the body and gels, and an aqueous solution or salt buffer of a biodegradable polymer mixed with the therapeutic agent A locally administered chemotherapeutic material characterized by cross-linking a solution with an organic acid derivative. The organic acid derivative according to claim 1 is a carboxyl group of dicarboxylic acid or tricarboxylic acid.
A locally administered chemotherapeutic material characterized in that one or three are modified with an electron-withdrawing group. 2. A locally administered chemotherapy, wherein the concentration of the aqueous solution of organic acid derivative or organic solvent solution or powder is 0.01 to 1000 mmol per 1 g of the biodegradable polymer solution according to claim 1. Materials. The locally administered chemotherapeutic material according to claim 1, wherein the locally administered chemotherapeutic material has biological tissue adhesion. 2. The topical administration characterized in that the therapeutic agent according to claim 1 is a drug, an anticancer drug, a protein, a gene therapy drug, a radionuclide, a hydrophilic drug, or a combination of two or more hydrophobic drugs. Type chemotherapy material. 6. The locally administered chemotherapeutic material, wherein the anticancer agent according to claim 5 is doxorubicin.