JPH05253283A - Artificial-embolism forming polymer solution - Google Patents

Abstract

PURPOSE:To provide an artificial-embolism forming polymer solution having relatively low viscosity, capable of being quickly clotted after being injected into a blood vessel so as to obstruct the blood vessel without directly damaging the endothelia of the blood vessel, and usable in combination with an X-ray shading agent without adversely affecting the human body. CONSTITUTION:An artificial-embolism forming polymer solution in which a random copolymer of 2-hydroxyethyl methacrylate and N-isopropylacrylamide is dissolved in an aqueous solution or an ethanol aqueous solution isotonic with the blood.

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 used to form an artificial embolus for therapeutic purposes by injecting it into a vascular lesion site.

[0002]

2. Description of the Related Art Currently, as a method for treating a vascular injury site in a human body, a catheter is introduced to the vascular injury site and a platinum coil or a resin piece is injected from the catheter to the vascular injury site to form an embolus. Attempts have been made to block the flow of blood to the site of injury. In such a method, conventionally, a catheter having a relatively large diameter has been used, and the resin piece or the like has been injected from the catheter. However, in the above method, it is not possible to give sufficient selectivity to the migration of the resin piece to the vascular injury site, or the formation of an embolus at the vascular injury site is incomplete, resulting in postoperative injury or early Problems such as the formation of collateral circulation were likely to occur.

As a treatment method which does not cause the above-mentioned drawbacks, a catheter having a small diameter or a micro balloon catheter having a pinhole at the tip is used to guide the catheter to the vascular lesion site and inject the monomer to solidify the polymer. Attempts have been made to create an embolus by allowing it to do so. In this method, a cyanoacrylate-based monomer is used as the intravascular injection resin. The cyanoacrylate-based monomer is polymerized immediately after being injected into the blood vessel to form a high molecular weight resin, so that an embolus is formed. For the above purpose, various cyanoacrylate-based monomers have been experimentally produced and used. However, there are various problems as described below.

When contacted with water or amines, the cyanoacrylate-based monomer rapidly undergoes polymerization and hardening, and therefore it may not be able to be sufficiently injected into the vascular injury site. The cyanoacrylate-based monomer has a strong adhesive property, so that when it is injected into a vascular injury site, the balloon catheter or a normal catheter and the blood vessel wall are strongly adhered to each other, and as a result, the catheter is There was a danger of causing a serious situation in which it could not be removed. The resin formed from the cyanoacrylate-based monomer injected into the vascular lesion site has extremely high hardness, and thus it tends to be difficult to perform an operation to remove the vascular lesion site later.

The cyanoacrylate polymer decomposes in vivo to release formaldehyde, but this formaldehyde has a problem that it has an adverse effect on the body. The cyanoacrylate-based monomer does not have a suitable angiographic agent that can be mixed for X-ray visualization. In addition to the cyanoacrylate-based monomer, a polymer solution obtained by dissolving a polymer material in dimethyl sulfoxide or an aqueous solution containing 40% by volume or more of ethanol has also been used as a liquid artificial embolic material. However, these polymer solutions have a problem of damaging vascular endothelial cells when injected into blood vessels.

[0006]

SUMMARY OF THE INVENTION The present invention has been made in view of the above-mentioned drawbacks of the conventional artificial embolization-forming materials, and does not directly damage vascular endothelial cells. It has a relatively low viscosity suitable for injection into a blood vessel by a catheter, can be used in combination with an X-ray contrast agent, and can immediately embolize a vascular lesion site after injection into a blood vessel, and It is an object of the present invention to provide a polymer solution for artificial embolism formation that does not have a harmful effect on the human body.

[0007]

The invention according to claim 1 of the present application provides 2-hydroxyethyl methacrylate (hereinafter abbreviated as HEMA) and N-isopropylacrylamide (hereinafter abbreviated as IPAAm). A polymer solution for artificial embolization, characterized in that a random copolymer of the above is dissolved in an aqueous solution isotonic with blood or a mixed solvent of an aqueous solution isotonic with blood and ethanol. The invention according to claim 2 is characterized in that the random copolymer is dissolved in an aqueous solution of a blood vessel contrast agent or a mixed solution of a blood vessel contrast agent and an aqueous ethanol solution, which is a polymer solution for artificial embolization. Is. Hereinafter, the details of the polymer solution for forming an artificial embolus according to the inventions of claims 1 and 2 will be described.

In the polymer solution for forming an artificial embolus of the present invention,
HEMA-IPAAm random copolymer is used as the solute. The molecular structure of this HEMA-IPAAm random copolymer is shown in the chemical formula below.

[0009]

[Chemical 1]

The content ratio of the HEMA component in the above random copolymer is 30 to 90% by weight, and the balance is IPAAm.
Must be an ingredient. When the copolymerization ratio of HEMA is less than 30% by weight or more than 90% by weight, ethanol containing 40% by volume or less of ethanol is used.
It cannot be dissolved in a water mixed solvent or an ethanol-vascular contrast agent mixed solution. The average molecular weight of the random copolymer is preferably in the range of 10,000 to 500,000. If the average molecular weight is less than 10,000, an embolus having sufficient strength cannot be formed in the blood vessel, and
When it exceeds 00000, the viscosity of the polymer solution for artificial embolization becomes too high, and it cannot be injected into a vascular injury site using a catheter.

The above random copolymer is satisfactorily dissolved in an aqueous solution isotonic with blood and an aqueous solution of an angiographic agent. Also,
It dissolves well in a physiological saline-ethanol mixed solvent having an ethanol content of less than 40% by volume or a mixed solution of the ethanol-containing mixed solvent and an angiographic agent regardless of temperature.

The above random copolymer obtained from a monomer solution having a charged HEMA content of 70 mol% is dissolved in an ethanol-free blood vessel contrast agent Iopamidol 75 w / v% aqueous solution at a temperature of 37 ° C. In ion-exchanged water, the low temperature critical solution temperature (LC) of the random copolymer is
ST) is 0 ° C or lower and does not dissolve at a temperature of 0 ° C or higher. However, Iopamidol 75w / v% aqueous solution
It is considered that the solvent power of the ion-exchanged water was changed because it contained 75 w / v% of iopamidol, and the copolymer could be dissolved even at 37 ° C. This is the preparation H
A copolymer obtained from a monomer solution having an EMA content of 70 mol% was dissolved in a 75 w / v% aqueous solution of iopamidol at body temperature, and when this was injected into a blood vessel, iopamidol was diffused into blood and the copolymer was precipitated. It suggests that it may precipitate and embolize blood vessels.

In the polymer solution for forming an artificial embolus of the present invention,
An aqueous solution isotonic with blood, for example, a mixed solvent of physiological saline and ethanol is used, and further, an aqueous solution of a blood vessel contrast agent or a mixture of a blood vessel contrast agent and a low ethanol aqueous solution as described in claim 2. A solution can be used. Iopamidol with Iopamidol as angiographic agent 75
When a mixed solution of w / v% and ethanol is used as a solvent, the content ratio of ethanol in the ethanol mixed solution containing 75% w / v of iopamidol is 40 v / v.
Must be less than or equal to%. Iopamidor 75w / v
This is because, when the content ratio of ethanol in the ethanol-containing mixed solution containing 40% exceeds 40 v / v%, there is a possibility of causing a physiological disorder such as damage to the vascular endothelium when injected into a blood vessel.

In the polymer solution for forming an artificial embolus of the present invention, the concentration of the solute composed of the HEMA-IPAAm random copolymer in the solvent is 0.5 to 30% by weight / volume%, particularly preferably 5 to 20%. It is defined as weight / volume%. This is because if it is less than 0.5% by weight / volume, a sufficient embolism cannot be formed, and if it exceeds 30% by weight / volume, the viscosity of the polymer solution for artificial embolization becomes too high,
Injection through a catheter is difficult.

In the polymer solution for forming an artificial embolus according to the present invention, the HEMA-IPAAm random copolymer is used as a solute as described above. HEMA constituting this random copolymer has been generally used for a long time as a medical material such as a contact lens, while IPAAm has been developed as a controlled release sustained-release base material for drugs. It is well known that both have sufficient safety and no toxicity to living bodies. Further, the solvent in the present invention is also an aqueous solution, an ethanol aqueous solution, an aqueous solution of a blood vessel contrast agent, or a mixed solution of a blood vessel contrast agent and an aqueous ethanol solution having a relatively low concentration. Therefore, the polymer solution for artificial embolization according to the present invention Has no toxic or harmful effects on the living body.

The solution for a polymer for forming an artificial embolus according to the present invention may optionally or optionally contain a blood vessel contrast agent other than iopamidol, such as sodium iothalamate, metrizamide, sodium iodamide meglumine or tantalum. Powder or the like can be used. The proportion of X-ray contrast agent added is 50 to 800 mg, preferably 100 to 800, per milliliter of the polymer solution for artificial embolization.
It is 750 mg. If it is less than 50 mg, it is difficult to perform visualization by X-ray sufficiently, and if it exceeds 750 mg, it is difficult to prepare it due to the solubility of the vascular contrast agent. In addition, claim 1
As described above, the random copolymer may be dissolved in an aqueous solution in which an angiographic agent is not mixed, or an ethanol aqueous solution consisting of ethanol-physiological saline, and in that case also, it is used as a polymer solution for artificial embolization. be able to.

[0017]

In the polymer solution for forming an artificial embolus according to claims 1 and 2, the above HEMA-IPAA is used.
Since the m random copolymer is used as a solute, when it is injected into blood, it rapidly cures and reliably forms an artificial embolus. Moreover, since the random copolymer is satisfactorily dissolved in a mixed solvent of ethanol and an isotonic aqueous solution such as physiological saline, it can be configured to have a relatively low viscosity and therefore a catheter. Is easy to inject. Moreover, the random copolymer is excellent in safety and does not have a harmful effect on the living body.

Further, since the artificial embolic material formed is a sponge-like solid substance and has a relatively low hardness, it is possible to easily perform an operation for removing a vascular injury site after embolization. Further, as described in claim 2, since the random copolymer is satisfactorily dissolved in the blood vessel contrast agent aqueous solution or the mixed solution of the blood vessel contrast agent and the ethanol aqueous solution, it is possible to easily impart an X-ray contrast function. You can

[0019]

[Examples] Hereinafter, by giving specific examples,
The present invention will be specifically described, but the present invention is not limited to these examples. Example 1: Synthesis of HEMA-IPAAm random copolymer
And Iopamidol 75 w / v% (ethanol content 0
˜40 v / v%) Soluble HEMA in mixed solution , dioxane, and 2,2-azobisisobutyroamide dihydrate (hereinafter, AIBA) which is a radical polymerization initiator are all manufactured by Wako Pure Chemical Industries, Ltd. I prepared one. IPAAm used was manufactured by Eastman Kodak Company.

The mixing ratio of HEMA and IPAAm is 0%, 20%, 40%, 50%, 60%, 70%, when the mixing ratio of HEMA is mol%.
Eight kinds of mixed monomers of 80 and 100 were prepared, and 10 g of each mixed monomer and 71 mg of AIBA were mixed with dioxane 2
It was dissolved in 0 ml, charged into a polymerization tube made of glass, deaerated, and sealed. The polymerization was carried out at 70 ° C. for 2 hours. Recovery of the HEMA-IPAAm random copolymer from the polymerization solution
The polymerization was carried out by dropping the polymerization solution in ion-exchanged water at 60 to 70 ° C. to cause precipitation. Furthermore, the above HEMA-IP
Dissolve the AAm random copolymer in ethanol and repeat 6
The precipitate was recovered by dropping it in ion-exchanged water at 0 to 70 ° C., and the unreacted monomer was removed from the HEMA-IPAAm random copolymer by repeating this operation several times. The obtained HEMA-IPAAm random copolymer aqueous solution was freeze-dried and used in the subsequent experiments.

The solubility of various HEMA-IPAAm random copolymers is 100 mg of each copolymer and 1 part of ion-exchanged water.
0 ml was added and the mixture was dissolved in ice water, then kept at a predetermined temperature and visually judged. Possibility as a liquid embolic agent: 100 mg of each copolymer and 75 contrast agent Iopamidol
Add 1 ml of ethanol-water mixed solvent containing w / v% (containing 100 g of iopamidol in 100 ml of solution), and add 3
It was kept at 7 ° C. and judged from its solubility. First, in Table 1 below, Iopamidol 75 w / v at a body temperature of 37 ° C.
% And ethanol aqueous solution (ethanol content 0-40 v / v
%) Shows the solubility of the HEMA-IPAAm random copolymer obtained in the mixed solution. S in Table 1 is dissolved (So
w), SW represents swelling, and I represents insoluble.

[0022]

[Table 1]

Charged HEMA content is 50 to 70 mole
%, The copolymer obtained had an ethanol content of the mixed solvent of 2
It dissolved at 0 v / v%. Charged HEMA content is 7
The copolymer obtained from the 0 mole% monomer solution is
It was also dissolved in Iopamidol aqueous solution containing no ethanol.

Example 2 Animal Experiments Monomer 1 of HEMA and IPAAm in a molar ratio of 1: 1
0 g and AIBA 71 mg were melt | dissolved in dioxane 20 ml, it polymerized like Example 1, HEMA-IPAAm random copolymer was collect | recovered, and it dried. Obtained H
0.5 g of EMA-IPAAm random copolymer was dissolved in 10 ml of a mixed solution of 75 w / v% iopamidol and an aqueous ethanol solution (ethanol content 30 v / v%) to prepare a polymer solution for forming an artificial embolus. I did.

Wistar rats were anesthetized with the anesthetic Nembutal, a catheter was introduced into the renal artery, and 0.1 ml of a polymer solution for forming an artificial embolus under fluoroscopy was injected into the renal artery. At this time, the injection site and injection amount could be monitored and confirmed with high accuracy under fluoroscopy. Although the viscosity of the polymer solution was high and it was difficult to inject it, the catheter was removed after the injection of the polymer solution was completed, and then an angiography of the injection site of the polymer solution was performed. No blood flow was observed, and it was confirmed that the blood vessels were completely embolized. Therefore, it was clear that the polymer solution forming an artificial embolus of this example forms an artificial embolus that exhibits a sufficiently good embolic effect. Since the viscosity of the polymer solution can be controlled by adjusting the polymerization degree of the copolymer, it was found that the polymer solution is effective as an intravascular embolization material.

Example 3: Animal experiment Mixed monomer 5 of HEMA and IPAAm in a molar ratio of 7: 3
g, a polymerization initiator 2-2 ′ azobisisobutyronitrile (AIBN) 10 mg, and further obtained HEMA-IPA
1.0 ml of benzyl alcohol as a radical linear transfer agent for controlling the molecular weight of the Am random copolymer was added, and these were dissolved in 4 ml of dioxane. It was charged in a glass polymerization tube, degassed and sealed, and then polymerization was carried out at 60 ° C. for 40 minutes. HEMA-IPAAm from polymerization liquid
The random copolymer was recovered in the same manner as in Example 1.

The effect as an artificial embolic agent is HEMA-I.
1.0 g of PAAm random copolymer was added to Iopamidol 7
It was dissolved in 10 ml of 5 w / v% and introduced into a Wistar rat renal artery through a catheter in the same manner as in Example 2, and X
It was judged by forming an artificial embolus under fluoroscopy.
The embolization effect was sufficient, and the blood flow to the kidney was blocked only by injecting 0.1 ml of the polymer solution. It was clear that the polymer solutions for forming artificial embolisms of the examples exhibited sufficiently good embolic effect.

Claims (2)

[Claims] 1. A random copolymer of 2-hydroxyethyl methacrylate and N-isopropylacrylamide is dissolved in an aqueous solution isotonic with blood or a mixed solvent of the aqueous solution isotonic with blood and ethanol. A polymer solution for forming an artificial embolus, which comprises: 2. The artificial embolization-forming plate according to claim 1, wherein the random copolymer is dissolved in an aqueous solution of an angiographic contrast agent or a mixed solution of an angiographic agent and an aqueous ethanol solution. Molecular solution.