JP2005239641A - Diethylenetriaminepentaacetic acid complex polymer composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a diethylenetriaminepentaacetic acid complex polymer composition suitable as a contrast medium material having a prolonged serum half-life useful as a reagent for treatment or diagnosis, low in toxicity and immunogenicity and capable of visually checking as a label in medical image diagnosis techneque, e.g. Magnetic Resonance Imaging (MRI) method. <P>SOLUTION: This diethylenetriaminepentaacetic acid complex polymer composition comprises a paramagnetic metal complex of a compound derived from diethylenetriaminepentaacetic acid which is chemically modified into a matrix of a water-absorbing polymer. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

The present invention has prolonged blood half-life, low toxicity and low immunogenicity useful as therapeutic or diagnostic reagents, as well as medical diagnostic imaging techniques such as magnetic resonance imaging (MRI). The present invention relates to a diethylenetriaminepentaacetic acid complex polymer composition suitable for a contrast agent material that can be visually recognized as a label in a method.

Recent advances in clinical diagnostic imaging have been remarkable, and various diagnostic imaging methods such as X-ray CT (computed tomography), ultrasonic imaging diagnosis, MRI diagnosis, scintigraphy, etc. are used in almost all fields of the whole body. Furthermore, various contrast agents suitable for these diagnostic imaging methods have been developed and their usefulness has been reported. In particular, MRI diagnostic methods have recently attracted significant attention not only from the field of radiological diagnosis but also from the entire medical community, and are spreading. Compared with other contrast agents, MRI contrast agents have superior contrast resolution between tissues, are highly safe without exposure to γ-rays, etc. Further, indication of lesions, normal and anatomy of lesion sites It is well known that it is clinically useful for grasping the scientific and functional images.

Engineering technology plays a wide variety of roles in the medical and welfare fields, but one of the most important is technological innovation for the realization of minimally invasive and non-constrained medicine. Catheter procedures including the vascular system are representative of minimally invasive treatments.
However, in clinical practice, X-ray imaging is frequently performed to guide the catheter to the affected part, and in some cases, a contrast medium is introduced from the guided catheter to further perform X-ray CT imaging.
The exposure dose received by the patient and the operator by these X-ray imaging, etc. reaches a skin surface dose rate of about 50 mGy / min at the maximum by X-ray irradiation of about 10 to 50 minutes in the anticancer agent arterial injection / vascular embolization. This value is well above the IAEA (International Atomic Energy Commission) fluoroscopy guidance level (normal level 25 mGy / min).

By replacing part of the catheter guidance and imaging process using X-rays with MRI, it becomes possible to reduce the exposure dose of the patient and the operator. For this purpose, it is clearly recognized in MRI imaging. The development of possible catheters and contrast agents that make them possible is essential. If such MR visibility of the catheter can be realized by application of a contrast agent, an MRI catheter that is easier to use than a technique of active visualization by an electromagnetic mechanism can be manufactured. However, no practical product of such a contrast agent has yet been made, and this development is urgent.

At present, diethylenetriaminepentaacetic acid-Gd complex is well known as a contrast agent for nuclear magnetic resonance diagnosis (see, for example, Patent Document 1), and this complex compound is a spin-lattice relaxation of water protons by paramagnetic metal ions. Time (T1) change is the mechanism of action. The contrast agent for MRI comprising such a complex compound has a high effect of reducing the relaxation time of water protons by the contained Gd ions. As a result, the MR signal from the surrounding water protons is increased, resulting in a contrast enhancement effect. It has been known.
However, this complex compound has an extremely short half-life in blood, and simply applying the complex compound or a mixture of the complex compound to an aqueous binder resin onto the catheter causes the complex compound to elute into the blood during use. There is a problem that the MR visibility of the catheter is lost in a short time.

JP 58-29718 A

In view of the above-described situation, the present invention has a prolonged blood half-life, low toxicity and low immunogenicity useful as therapeutic or diagnostic reagents, and medical diagnostic imaging techniques such as magnetic resonance imaging (Magnetic). It is an object of the present invention to provide a diethylenetriaminepentaacetic acid complex polymer composition suitable for a contrast agent material that can be visually recognized as a label in the Resonance Imaging (MRI) method.

The present invention is a diethylenetriaminepentaacetic acid complex polymer composition in which a paramagnetic metal complex of a compound derived from diethylenetriaminepentaacetic acid is chemically modified and contained in a water-absorbing polymer matrix.
The present invention is described in detail below.

The diethylenetriaminepentaacetic acid complex polymer composition of the present invention (hereinafter also referred to as DTPA complex polymer composition of the present invention) is a paramagnetic substance of a compound derived from diethylenetriaminepentaacetic acid (hereinafter also referred to as DTPA) in a matrix of a water-absorbing polymer. A metal complex (hereinafter also referred to as a DTPA complex) is contained by chemical modification.

In the DTPA complex polymer composition of the present invention, the DTPA complex acts on the protons of water absorbed in the water-absorbing polymer, so that the MR signal contrast in MRI imaging is improved and the MR visibility is excellent. . Therefore, the water-absorbing polymer needs to have a function of retaining water therein, and examples of such a water-absorbing polymer include polyacrylic acid copolymers, polymethacrylic acid copolymers, and gelatin. , Agar, starch, cellulose, hyaluronic acid, polyvinyl alcohol and the like.

The DTPA complex is a compound in which a compound derived from DTPA is coordinated as a ligand to a paramagnetic metal ion. Such a DTPA complex is known to have low toxicity and low immunogenicity. Therefore, the DTPA complex polymer composition of the present invention containing the DTPA complex is used as a contrast agent material in MRI imaging. It can be preferably used.

Examples of the ligand of the compound derived from DTPA include N, N, N ′, N ″, N ″ -diethylenetriaminepentaacetic acid (DTPA) and ethylenediamine-N, N, N ′, N′—. Bifunctional ligands such as tetraacetic acid (EDTA), 1,4,7,10-tetraazacyclododecane-N, N ′, N ″, N ′ ″-tetraacetic acid (DOTA) .

Examples of the paramagnetic metal ions include divalent or trivalent metal ions of the elements having atomic numbers 21 to 29, 42, 44, and 58 to 70. Specifically, for example, Cr ³⁺ , Mn ²⁺ , Fe ²⁺ , Co ²⁺ , Ni ²⁺ , Cu ²⁺ , Pr ³⁺ , Nd ³⁺ , Sm ³⁺ , Yb ³⁺ , Gd ³⁺ , Tb ³⁺ , Dy ³⁺ , Ho ³⁺ , Er ³⁺ and Fe ³⁺ . Among these, Gd ³⁺ , Tb ³⁺ , Dy ³⁺ , Ho ³⁺ , Er ³⁺ and Fe ³⁺ are preferable because they have a very strong magnetic moment.

In such a DTPA complex, when one or more carboxyl groups that are not coordinated to the paramagnetic metal ion are present, the hydrogen atoms in these carboxyl groups are, as necessary, an inorganic base, an organic base May be substituted by a cation of an amino acid and / or an amino acid amide. This is because a neutral complex compound makes it easier to obtain crystals to be purified.

The cation of the inorganic base is not particularly limited, and examples thereof include calcium ion, sodium ion, lithium ion, potassium ion, magnesium ion, and the like, among which calcium ion and sodium ion are preferable.

The cation of the organic base is not particularly limited, and examples thereof include primary, secondary, and tertiary amine cations. Examples of such primary, secondary or tertiary amine cations include ethanolamine, diethanolamine, morpholine, glucamine, N, N-dimethylglucamine and N-methylglucamine cations, and the like. Of these, a cation of N-methylglucamine is preferable.

The cation of the amino acid is not particularly limited, and examples thereof include lysine, arginine, ornithine cation, and the like.

The cation of the amino acid amide is not particularly limited, and examples thereof include lysine methylamide, glycine ethylamide, and serine methylamide cations.

In the DTPA complex polymer composition of the present invention, the DTPA complex is chemically modified in the matrix of the water-absorbing polymer. In the present specification, “chemical modification” refers to a state where the polymer is fixed to the polymer by a chemical bond such as copolymerization or chemical affinity.

The method for chemically modifying the DTPA complex into the matrix of the water-absorbing polymer is not particularly limited, and a conventionally known general method can be used. For example, the carboxylic acid in the DTPA can be combined with the water-absorbing polymer. Examples thereof include a method of esterification or amidation, a method of esterification with the water-absorbing polymer using the anhydride of the DTPA.

Thus, in the DTPA complex polymer composition of the present invention, since the DTPA complex is chemically modified in the matrix of the water absorbent polymer, the DTPA complex is firmly fixed in the matrix of the water absorbent polymer. Accordingly, when the DTPA complex polymer composition of the present invention is immersed in blood using, for example, a contrast agent in MRI imaging, a contrast medium comprising a conventional complex compound or a mixture obtained by mixing the complex compound with an aqueous binder resin. Compared with the agent, the DTPA complex is less likely to elute in the blood, and the blood half-life is prolonged.

A method for producing such a DTPA complex polymer composition of the present invention is not particularly limited. For example, the monomer of the water-absorbing polymer and DTPA which is a ligand of the DTPA complex are chemically modified, and the DTPA Is coordinated to the paramagnetic metal ion, and then the monomer is polymerized to form a polymer. The absorbent polymer is chemically modified with DTPA, which is a ligand of the DTPA complex, and then the DTPA is converted to the paramagnetic metal ion. Examples thereof include a method of coordinating with magnetic metal ions.

Specifically, the monomer of the water-absorbing polymer and the DTPA which is a ligand of the DTPA complex are chemically modified, the DTPA is coordinated to the paramagnetic metal ion, and then the monomer is polymerized to be polymerized. For example, 2-hydroxyethyl methacrylate and DTPA anhydride are reacted to esterify, and the esterified product is reacted with a metal hydrate and an organic base cation to form a complex. Examples thereof include a method of subjecting a monomer to suspension polymerization with methacrylic acid.

A molar ratio of the monomer to be copolymerized with the complex monomer is preferably 1:20 to 1: 500. When the molar ratio of the monomer to be copolymerized with respect to the complex monomer is less than 20, the polymer after polymerization may not be dissolved in the solvent, and when it exceeds 500, sufficient MR visibility may not be obtained.
Moreover, it does not specifically limit as a monomer chemically modified with the said DTPA, For example, 2-hydroxyethyl acrylate, 2-hydroxypropyl acrylate, 4-hydroxybutyl acrylate, 2-hydroxypropyl methacrylate, etc. are mentioned.

As a specific method of coordinating the DTPA to the paramagnetic metal ion after chemically modifying DTPA, which is a ligand of the DTPA complex, to the absorbent polymer, for example, a hydroxyl group of polyvinyl alcohol and DTPA Examples include a method in which an anhydride is reacted and esterified, and a metal hydrate and an organic base cation are reacted to form a complex.

In the DTPA complex polymer composition of the present invention, since the DTPA, which is a ligand of the DTPA complex, is chemically modified and contained in the matrix of the water-absorbing polymer, the DTPA complex is firmly fixed to the water-absorbing polymer. . Therefore, even when the DTPA complex polymer composition of the present invention is immersed in blood, the DTPA complex does not elute from the water-absorbing polymer in the blood in a short time. Further, in MRI imaging, the DTPA complex acts on the protons of water absorbed and retained by the water-absorbing polymer, whereby the contrast of the MR signal can be improved and the MR visibility is excellent.
Accordingly, the DTPA complex polymer composition of the present invention has a prolonged blood half-life, low toxicity and low immunogenicity useful as a therapeutic or diagnostic reagent, and a medical diagnostic imaging technique such as MRI method. It is suitable for a contrast medium material that can be visually recognized as a label. In addition, by applying such a DTPA complex polymer composition of the present invention onto an in-vivo minimally invasive medical device such as a catheter, the DTPA complex does not elute from the catheter into the blood in a short time, Because the MR visibility of the catheter is excellent for a long period of time, part of the catheter guidance and imaging process using X-rays can be replaced with MRI, and the exposure dose of patients and operators can be reduced. It becomes.
An in-vivo minimally invasive medical device having the DTPA complex polymer composition of the present invention as such a contrast agent is also one aspect of the present invention.

Hereinafter, the present invention will be described in more detail with reference to examples. However, the present invention is not limited to these examples.

(Example 1)
(Esterification of DTPA anhydride with HEMA)
In 12.5 g (0.035 mol) of diethylenetriaminepentaacetic acid dianhydride, 1.84 g (0.014 mol) of 2-hydroxyethyl methacrylate (HEMA), 4.29 g (0.042 mol) of triethylamine, 0.54 g of pyridine ( 0.0068 mol) was dissolved dropwise at room temperature. After completion of the dropwise addition, the mixture was refluxed and stirred for 5 hours for reaction.
After completion of the reaction, dimethylformamide (DMF) was added and dissolved, and the mixture was washed with 2M hydrochloric acid and then with an aqueous sodium hydrogen carbonate solution. The washed washing liquid was distilled off to obtain an esterified product of DTPA anhydride and HEMA (esterified product of DTPA / HEMA monomer). The obtained compound was identified by mass spectrum: 504.4.

(Complex formation of esterified product)
Water was added to 17.4 g (0.034 mol) of the obtained DTPA / HEMA monomer esterified product so that the total concentration was 15% by weight, and the mixture was stirred at 95 to 100 ° C. for 1 hour.
Next, 14.0 g (0.034 mol) of gadolinium acetate tetrahydrate was added and reacted at the same temperature for 2 hours.
Furthermore, 13.4 g (0.069 mol) of meglumine was added and reacted at the same temperature for 1.5 hours.
Ethanol, methanol and acetone were added to the resulting reaction solution, and the mixture was ice-cooled and reprecipitated. Thereafter, the precipitate was recovered to obtain a DTPA / HEMA monomer complex in which Gd ions were coordinated to the esterified product of the DTPA / HEMA monomer.
Whether or not Gd ions are coordinated to the esterified product of the DTPA / HEMA monomer is confirmed by measuring an infrared absorption spectrum (IR): 1599 cm ⁻¹ (OH out-of-plane vibration of carboxy ions). I was able to.

(Polymerization)
First, 1.974 g of sorbitan monostearate was added to n-hexane, and dissolved oxygen was removed by blowing nitrogen.
Next, 30.0 g (0.348 mol) of methacrylic acid and 3.0 g (0.0035 mol) of the esterified product of DTPA / HEMA monomer were dissolved in water so that the monomer concentration became 45%, and potassium persulfate ( KPS) After adding 0.117 g and dissolving, nitrogen gas was blown to remove dissolved oxygen, added and dispersed in n-hexane, and maintained at a temperature of 60 to 65 ° C. while introducing nitrogen gas. Stir for 6 hours.
After completion of the stirring, suction filtration was performed with a glass filter, and the material on the filter was dissolved in methanol and dropped into chloroform for reprecipitation. Further, reprecipitation was performed twice and dried under reduced pressure to obtain a copolymer of methacrylic acid and an esterified product of DTPA / HEMA monomer (DTPA complex polymer composition (1)).
In addition, Gd was detected from the obtained DTPA complex polymer composition (1) by XRF (fluorescence X-ray analyzer: Rigaku Denki Kogyo Co., Ltd.) measurement.
The molar ratio of methacrylic acid and complex monomer was 100: 1.

(Comparative Example 1)
Water was added to 1.0 g (1 mol) of DTPA so that the total concentration was 10% by weight, and the mixture was stirred for 1 hour while stirring at 95 to 100 ° C.
Next, 1.0 g (1 mol) of gadolinium acetate tetrahydrate was added and reacted at the same temperature for 2 hours.
Furthermore, 1.0 g (2 mol) of meglumine was added and reacted at the same temperature for 1.5 hours.
Ethanol, methanol and acetone were added to the resulting reaction solution, and the mixture was ice-cooled and reprecipitated. Thereafter, the precipitate was recovered to obtain a DTPA complex (2).

In addition, Gd was detected from the obtained DTPA complex (2) by XRF (fluorescence X-ray analyzer: Rigaku Denki Kogyo Co., Ltd.) measurement.

(Comparative Example 2)
25 phr of the DTPA complex (2) synthesized in Comparative Example 1 was added to an aqueous binder resin (urethane-based, solid content: 30%) and mixed and dissolved to obtain a mixed liquid (3) containing the DTPA complex. .
The obtained mixed solution (3) containing the DTPA complex was dried to obtain a mixture (4) of the binder resin and the DTPA complex.

(Evaluation)
(1) Confirmation of Gadolinium Outflow The composition synthesized and mixed in Example 1 and Comparative Examples 1 and 2 was immersed in distilled water for 1 hour and 10 hours, and the presence or absence of Gd was confirmed by fluorescent X-rays. The results are shown in Table 1.

(2) MR imaging test The DTPA complex polymer composition (1) obtained in Example 1 was dissolved in methanol, applied onto the slide glass 10 and dried as shown in FIG. A film 11 was formed.
This slide glass (line drawing coating film formation) was immersed in distilled water in a petri dish 21 placed on a table 20 (see FIG. 2), and MRI imaging was performed to confirm MR visibility. As a reference example, MR visibility was also confirmed for the DTPA complex polymer composition produced in the same manner as in Example 1 except that the molar ratio of methacrylic acid to the complex monomer was 50: 1. The results are shown in FIG. 3 and FIG.
3 and 4, the DTPA complex polymer composition (1) according to Example 1 is denoted as “GdP1”, the DTPA complex polymer composition according to the reference example is denoted as “GdP2”, and FIG. 3 and FIG. In FIG. 4, the case where neither “GdP1” nor “GdP2” is described indicates the result of MRI imaging in a state of being arranged on the table 20 shown in FIG.

As shown in Table 1, in Example 1 in which DTPA, which is a ligand of the DTPA complex, was chemically modified in the matrix of the water-absorbing polymer, Gd was detected even after being immersed in distilled water for 10 hours. The DTPA complex was not flowing out into the water. On the other hand, in Comparative Example 1, it was dissolved in distilled water, and in Comparative Example 2, Gd was not detected when immersed in distilled water for 1 hour, and the DTPA complex complex flowed out into water.

Moreover, as shown in FIG.3 and FIG.4, the visibility of the DTPA complex polymer composition (1) which concerns on Example 1 was confirmed after 10-minute progress after being immersed in distilled water. Moreover, although visibility was confirmed also about the DTPA complex polymer composition which concerns on a reference example, the direction of the DTPA complex polymer composition (1) which concerns on Example 1 was excellent in visibility.

In accordance with the present invention, it has prolonged blood half-life, low toxicity and low immunogenicity useful as a therapeutic or diagnostic reagent, as well as medical imaging techniques such as magnetic resonance imaging (Magnetic Resonance Imaging). A diethylenetriaminepentaacetic acid complex polymer composition suitable for a contrast agent material that can be visually recognized as a label in the (MRI) method can be provided.

3 is a plan view schematically showing the line drawing coating film produced in Example 1. FIG. It is a perspective view which shows typically the mode of the MR imaging test of the DTPA complex polymer composition which concerns on Example 1 and a reference example. It is MRI which shows the result of MR imaging test of the DTPA complex polymer composition which concerns on Example 1 and a reference example. It is MRI which shows the result of MR imaging test of the DTPA complex polymer composition which concerns on Example 1 and a reference example.

Explanation of symbols

10 slide glass 11 line drawing film 20 stand 21 petri dish

Claims (4)

A diethylenetriaminepentaacetic acid complex polymer composition, wherein a paramagnetic metal complex of a compound derived from diethylenetriaminepentaacetic acid is chemically modified and contained in a water-absorbing polymer matrix. 2. The diethylenetriaminepentaacetic acid complex polymer composition according to claim 1, wherein the water-absorbing polymer is a polyacrylic acid copolymer, a polymethacrylic acid copolymer, gelatin, agar, starch, cellulose, hyaluronic acid or polyvinyl alcohol. Stuff. The paramagnetic metal complex of the compound derived from diethylenetriaminepentaacetic acid contains at least one paramagnetic metal ion selected from the group consisting of Gd ³⁺ , Tb ³⁺ , Dy ³⁺ , Ho ³⁺ , Er ³⁺ and Fe ^3+. 3. The diethylenetriaminepentaacetic acid complex polymer composition according to claim 1 or 2. An in-vivo minimally invasive medical device comprising the diethylenetriaminepentaacetic acid complex polymer composition according to claim 1, 2 or 3 as a contrast agent.