JP3040551B2 - Polymer solution for artificial emboli formation - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a polymer solution which is injected into a site of vascular injury for the purpose of treatment to form an artificial embolus.

[0002]

2. Description of the Related Art At present, as a method for treating vascular disorders in the human body,
There has been an attempt to lead a catheter to a vascular disorder site, inject a resin piece or the like into this portion, and inhibit blood flow to the vascular disorder site to perform treatment. In this method, a resin piece is injected using a catheter having a relatively large diameter.
However, in this method, it is not possible to reliably inject into a desired site because sufficient selectivity of the resin pieces into the blood vessel cannot be obtained. Can not form an embolus having, or so-called postoperative damage occurs after embolization procedure, and collateral circulation is formed early,
There are various disadvantages.

[0003] Under the circumstances described above, recently, an attempt has been made to form an embolus by injecting and solidifying an infusion solution made of a resin-forming agent into a vascular lesion using a minute balloon catheter. Here, as the resin forming agent, a cyanoacrylate-based monomer which is polymerized when injected into a blood vessel to form an embolus made of a high molecular weight resin is used. For this purpose, various cyanoacrylate-based monomers have been experimentally produced, but there are still the following problems at present.

(1) Cyanoacrylate monomers are
When it comes into contact with water or amines, it rapidly polymerizes and hardens, so that injection into a target site in a blood vessel may not be sufficiently achieved. (2) Since the cyanoacrylate-based monomer has a strong adhesive property, when injected into a blood vessel, the balloon or the catheter and the blood vessel wall are strongly adhered, and as a result, the catheter is removed. It may cause a serious situation that it is not possible. (3) Since the resin formed by the cyanoacrylate-based monomer injected into the blood vessel has extremely high hardness, it is inconvenient when performing an operation for removing a vascular lesion site later. (4) The cyanoacrylate polymer decomposes in a living body to form formaldehyde which has a bad influence on the living body. (5) In order to perform the intended injection, it is actually necessary that the injection liquid be X-ray transparent, but a suitable contrast agent that can be mixed with the cyanoacrylate-based monomer is known. In fact, X-ray fluoroscopy is practically impossible.

[0005]

SUMMARY OF THE INVENTION The present invention has been made in view of the above circumstances, and has a relatively low viscosity suitable for injection into a blood vessel and facilitates X-ray imaging. Can be applied, and thus can be easily injected into a desired part of a blood vessel by a catheter, and after being injected into the blood vessel, it quickly solidifies to form an embolus for surely closing the blood vessel. An object of the present invention is to provide a polymer solution for forming an artificial embolus, which does not have a harmful effect on a living body.

[0006]

In the polymer solution for forming an artificial embolus according to the present invention, a solute composed of a methyl methacrylate-butyl methacrylate-dimethylaminoethyl methacrylate copolymer has a pH of 3. Dissolved in a solvent consisting of water adjusted to 0 to 5.0 or an aqueous ethanol solution containing 50 to 70% by weight of ethanol;
Alternatively, a solute composed of a methacrylic acid-methyl methacrylate copolymer is dissolved in water whose pH is adjusted to 8.0 to 10.0 or a solvent composed of an aqueous ethanol solution containing 50 to 70% by weight of ethanol. It is characterized by being done.

In the present invention, a terpolymer obtained by polymerizing three kinds of monomers of methyl methacrylate, butyl methacrylate and dimethylaminoethyl methacrylate (hereinafter referred to as a "first specific copolymer") ")
Or 2 of methacrylic acid and methyl methacrylate
Binary copolymer (hereinafter referred to as “the second specific copolymer”) obtained by polymerizing various kinds of monomers as a solute, and water adjusted to pH in a specific range according to the type of the solute, or water. Using an aqueous ethanol solution containing ethanol at a concentration of 1 as a solvent, a polymer solution obtained by dissolving the solute in this solvent is used for forming an artificial embolus.

[0008] The first specific copolymer used as a solute in the present invention has a methyl methacrylate component content of 40%.
It is preferable that the content of the butyl methacrylate component is 20 to 30% by weight, and the remainder is a dimethylaminoethyl methacrylate component, and the average molecular weight is 50,000 to 500,000. Those in the range are preferred.

[0009] The first specific copolymer has a pH of 3.0.
Water adjusted to -5.0, preferably pH 4.0-5.0.
It is dissolved in a solvent consisting of water adjusted to zero. Alternatively, an aqueous ethanol solution having an ethanol content of 50 to 70% by weight, preferably having an ethanol content of 50 to 60% by weight.
Is dissolved in a solvent consisting of an aqueous ethanol solution.

In the case where water is used as a solvent, the first specific copolymer cannot be dissolved unless the pH of the water is 5.0 or less, and water having a pH lower than 3.0 is used. The blood pH is between 7.2 and 7.3,
Physiological disorders may occur.

When the aqueous ethanol solution is used as a solvent, the first specific copolymer cannot be dissolved unless the content of ethanol in the aqueous ethanol solution is 50% by weight or more. If the content of ethanol exceeds 70% by weight, a physiological disorder may occur when released into the blood.

The second specific copolymer which is used as a solute in the present invention has a methacrylic acid component content of 38.0 to 38.0.
52.0% by weight, the balance being preferably a methyl methacrylate component, and having an average molecular weight of 50,0
Those having a range of 00 to 500,000 are preferred.

This second specific copolymer has a pH of 8.0.
Water adjusted to ~ 10.0, preferably with a pH of 8.0
It is dissolved in a solvent consisting of water adjusted to 9.0. Alternatively, it is dissolved in a solvent composed of an aqueous ethanol solution having an ethanol content of 50 to 70% by weight, preferably an aqueous ethanol solution having an ethanol content of 50 to 60% by weight.

When water is used as the solvent, the second specific copolymer is dissolved in water having a pH of 8.0 or more. Although the second specific copolymer can be dissolved in water as long as the pH is less than 8.0 and the pH is 6 or more,
The solution obtained in this case has a blood pH of 7.2-7.
Since it is 3, it does not sufficiently precipitate even when released into the blood, so that a good effect cannot be obtained as a polymer solution for forming an artificial embolus. The pH of the water is 1
If it exceeds 0.0, physiological disorders may occur.

In the case where an aqueous ethanol solution is used as a solvent, the second specific copolymer cannot be dissolved unless the content of ethanol in the aqueous ethanol solution is 50% by weight or more. If the content of ethanol in the aqueous ethanol solution exceeds 70% by weight, physiological disorders may occur when released into the blood.

In the polymer solution for forming an artificial embolus of the present invention, the concentration of the solute composed of the first specific copolymer or the second specific copolymer with respect to the solvent is in any case:
0.5 to 30% by weight, particularly preferably 1.0 to 10% by weight.
% By weight.

In the above description, “pH-adjusted water” refers to, for example, an acid, alkali or buffer solution.
Means water in a state where is adjusted, and specific examples of the pH adjuster include acetic acid, sodium hydroxide, and an aqueous solution of acetic acid-sodium acetate.

The first solute used as a solute in the present invention
The specific copolymer or the second specific copolymer is generally used as a coating agent or a matrix agent for tablets and granules provided as pharmaceuticals, and has sufficient safety and non-toxicity for living bodies. It is a well-known fact that it has. In addition, since the solvent in the present invention is also water adjusted to a specific pH or a relatively low-concentration aqueous ethanol solution, the polymer solution for forming an artificial embolus of the present invention has a possibility of causing toxic or harmful effects on a living body. Not at all.

The polymer solution for forming an artificial embolus of the present invention includes:
If desired or necessary, appropriate additives can be blended as long as the purpose is not hindered. Specific examples of the additive include a contrast agent such as an X-ray contrast agent. And, X-ray contrast agents are practically useful in most cases.

As the X-ray contrast agent for making the polymer solution for forming an artificial embolus of the present invention X-ray transparent, those which are uniformly dissolved or dispersed in the solvent of the polymer solution are preferably used. As such X-ray contrast agents, those currently used clinically as angiographic agents or spinal contrast agents for such purposes, such as sodium iotalamate, iopamidol, metrizamide, sodium iodamide meglumine or tantalum powder And the like can be mentioned as preferable ones. The addition ratio of this X-ray contrast agent is
50 per milliliter of polymer solution for artificial embolization
４００400 mg, preferably 100-250 mg.

[0021]

In the present invention, when water is used as the solvent, when water is the first specific copolymer, p
H is dissolved in water of 5.0 or less, and when the solute is the second specific copolymer, it is dissolved in water of pH 8.0 or more. However, since the pH of the blood is 7.2-7.3,
When the polymer solution for forming an artificial embolus is released into blood, the solute in the polymer solution precipitates as a solid,
As a result, an artificial embolic material is immediately formed.

Further, the polymer solution for forming an artificial embolus of the present invention when an aqueous ethanol solution is used as a solvent,
Regardless of whether the solute is the first specific copolymer or the second specific copolymer, when released into the blood, the concentration of ethanol in the solution decreases, so that the solute in the polymer solution decreases. Precipitates as a solid, resulting in immediate formation of an artificial embolic material.

In the polymer solution for forming an artificial embolus of the present invention, when the solute is the first specific copolymer or the second specific copolymer, water used as a solvent is Since the pH is not less than 3.0 and not more than 10.0 and is not strongly acidic or strongly alkaline, or the content of ethanol in an aqueous ethanol solution used as a solvent is low, a physiological disorder is caused to a living body. There is no fear.

[0024]

The polymer solution for forming an artificial embolus according to the present invention can be quickly solidified when it is injected into blood and can reliably form a suitable artificial embolus. It has a low viscosity, is easy to inject with a catheter, has high safety, has no harmful effect on the living body, and can easily impart good X-ray imaging ability. Moreover, the formed artificial embolus is a sponge-like solid material, and is not inconvenient even after the embolization treatment.

[0025]

【Example】

Example 1 [Preparation Example] 10 g of the following solute in 55 g of the following solvent
Was mixed and dispersed with 35 g of an X-ray contrast agent, iopamidol, to prepare a polymer solution 1 for forming an artificial embolus of the present invention. Solvent: Ethanol aqueous solution with 60 parts by weight of ethanol and 40 parts by weight of ion-exchanged water Solute: Obtained by polymerizing 50 parts by weight of methyl methacrylate, 25 parts by weight of butyl methacrylate, and 25 parts by weight of dimethylaminoethyl methacrylate. First specific copolymer having an average molecular weight of about 150,000 The viscosity of this polymer solution 1 at 25 ° C. was 21 centipoise. [Experimental Example] Heparin was added to 100 ml of blood collected from an adult dog, and 0.3% of the polymer solution 1 was added.
When the milliliter was injected with a syringe, the polymer solution 1 immediately formed a sponge-like precipitate upon contact with blood.

[Application Example] A mongrel dog is anesthetized with an anesthetic Nembutal, a balloon catheter having a pinhole at the tip is introduced into the blood vessel from the femoral artery, and the polymer solution 1 for forming an artificial embolus is removed under fluoroscopy. 0.3 ml was injected. At this time, the injection site and the injection amount could be monitored and confirmed with sufficiently high accuracy under X-ray fluoroscopy.
Five minutes after the completion of the infusion of the polymer solution 1, the balloon catheter was removed, and then angiography of the infusion site of the polymer solution 1 showed no blood flow at the infusion site. It was confirmed that the blood vessel was completely embolized. From this, it is clear that the polymer solution for forming an artificial embolus of the present invention forms an artificial embolus exhibiting a sufficiently good embolizing effect.

Example 2 [Preparation Example] 10 g of the following solute in 55 g of the following solvent
Was mixed and dispersed with 35 g of an X-ray contrast agent, iopamidol, to prepare a polymer solution 2 for forming an artificial embolus of the present invention. Solvent: Aqueous ethanol solution with 60 parts by weight of ethanol and 40 parts by weight of ion-exchanged water Solute: Second polymer having an average molecular weight of about 150,000, obtained by polymerizing 45 parts by weight of methacrylic acid and 55 parts by weight of methyl methacrylate. This polymer solution 1 had a viscosity at 25 ° C. of 73 centipoise. [Experimental Example] Heparin was added to 100 ml of blood collected from adult mongrel dogs.
When the milliliter was injected with a syringe, the polymer solution 2 immediately formed a sponge-like precipitate upon contact with blood.

Example 3 Preparation Example 10 g of the following solute in 55 g of the following solvent
Was mixed with 35 g of an X-ray contrast agent, iopamidol, to prepare a polymer solution 3 for forming an artificial embolus of the present invention. Solvent: Aqueous solution whose pH was adjusted to 3.6 with an acetic acid-sodium acetate buffer solution: First specific copolymer similar to that in Example 1 The viscosity of this polymer solution 1 at 25 ° C. was 380 centipoise. . [Experimental example] Heparin was added to 100 ml of blood collected from a mongrel dog, and 0.3% of the polymer solution 3 was added.
When milliliters were injected with a syringe, the polymer solution 3 immediately formed a sponge-like precipitate upon contact with blood.

Example 4 Preparation Example 10 g of the following solute in 55 g of the following solvent
Was mixed with 35 g of an X-ray contrast agent, iopamidol, to prepare a polymer solution 4 for forming an artificial embolus of the present invention. Solvent: p with 1N aqueous sodium hydroxide solution
Water solute with H adjusted to 9.9: Second specific copolymer similar to that in Example 2 The viscosity of this polymer solution 1 at 25 ° C. was 1,400 centipoise. [Experimental Example] Heparin was added to 100 ml of blood collected from a mongrel dog, and 0.3% of the polymer solution 4 was added.
When milliliters were injected with a syringe, the polymer solution 4 immediately formed a sponge-like precipitate upon contact with blood.

──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-5-253283 (JP, A) JP-A-4-197359 (JP, A) JP-A-62-97558 (JP, A) (58) Field (Int.Cl. ⁷ , DB name) A61L 27/00 A61K 9/08

Claims (2)

(57) [Claims] 1. A solute consisting of a methyl methacrylate-butyl methacrylate-dimethylaminoethyl methacrylate copolymer is water having a pH adjusted to 3.0 to 5.0, or 50 to 7
A polymer solution for forming an artificial embolus, which is dissolved in a solvent comprising an aqueous ethanol solution containing 0% by weight of ethanol. 2. A solute comprising a methacrylic acid-methyl methacrylate copolymer, wherein water whose pH is adjusted to 8.0 to 10.0, or
A polymer solution for forming an artificial embolus, which is dissolved in a solvent composed of an aqueous ethanol solution containing 70% by weight of ethanol.