JPS649294B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a therapeutic agent for hyperkalemia. Renal failure is a state in which renal function is severely impaired and the internal environment of the body cannot be maintained normally.
In cases of acute or chronic renal failure, urinary potassium excretion decreases and serum potassium levels increase, resulting in hyperkalemia and cardiac arrest. It has been recognized that polystyrene sulfonic acid resins are effective against hyperkalemia, and two types of resins have been mainly used as therapeutic agents for hyperkalemia.

these are or It has a molecular structure like this.

In the above-mentioned hyperkalemia therapeutic agent, a styrene/divinylbenzene copolymer with a particle size of about 0.5 to 1 mm is synthesized, and after sulfonation, a styrene/divinylbenzene copolymer with a particle size of 10 to 100 mm, which is suitable for use, is synthesized. The material used was ground to micron size. However, since sulfonation is carried out from the surface of the copolymer particles, an incompletely sulfonated portion remains near the center of the copolymer particle, and this portion may be exposed to the surface by pulverization.

On the other hand, when such a hyperkalemia therapeutic agent is administered into the body, it passes through the intestinal tract without being digested or absorbed, and is exchanged with cations such as potassium. This effect is especially greatest near the colon. However, in vivo it does not show the same ion exchange ability as in vitro. This is partly due to ion exchange with cations other than potassium, but on the other hand, proteins etc. are adsorbed to the non-sulfonated portions of the resin surface due to so-called hydrophobic interactions, resulting in steric hindrance. Therefore, it is presumed that this is to prevent potassium ions from approaching.

As mentioned above, conventional hyperkalemia therapeutic agents have a fairly good potassium excretion ability in vitro, but have a fatal defect in that their potassium excretion ability rapidly decreases in vivo.

In addition, conventional hyperkalemia therapeutic agents have the disadvantage that they are difficult to excrete from the body because the particles have irregular irregularities obtained by pulverization.

The present invention provides a method for producing a therapeutic agent for hyperkalemia without such drawbacks, and the gist thereof is to copolymerize styrene and divinylbenzene by aqueous suspension polymerization to reduce the particle size. 10～
A substantially spherical styrene/divinylbenzene copolymer of 100 microns is made, and the copolymer is sulfonated,
The present invention provides a method for producing a therapeutic agent for hyperkalemia, which comprises then performing ion exchange using a sodium compound or a calcium compound.

Next, the method for producing the therapeutic agent for hyperkalemia of the present invention will be explained in more detail.

In the present invention, styrene and divinylbenzene are copolymerized by aqueous suspension polymerization to obtain a styrene/divinylbenzene copolymer, and styrene and divinylbenzene are used as monomers.
At this time, vinylbenzenesulfonic acid or a salt thereof may be present in an amount of 5% by weight or less based on the total amount of styrene and divinylbenzene monomers.

Ion-exchanged water is suitable as a medium for aqueous suspension polymerization, and is preferably used in a weight ratio of 1.5 times or more based on the total amount of monomers.As a catalyst, for example, benzoyl peroxide, methyl ethyl ketone peroxide, etc. Peroxide, azobisisobutyronitrile, etc. are preferably used in a proportion of 0.1 to 0.5% by weight based on the total amount of monomers.

In order to uniformly disperse the monomer in the medium,
It is preferable to use a dispersant, for example, a water-soluble polymer substance such as polyvinyl alcohol, polyacrylic acid, carboxymethyl cellulose, etc., or a combination of this and a surfactant. It is preferable to use 1% by weight or more based on the total amount of polymers.

During polymerization, in a medium in which a dispersant is dissolved,
Disperse the monomer mixed with the catalyst in a nitrogen stream.
A styrene/divinylbenzene copolymer can be synthesized by heating to 60 to 80°C.

At this time, aqueous suspension polymerization can be carried out in the coexistence of vinylbenzenesulfonic acid or a salt thereof. The amount of vinylbenzenesulfonic acid or its salt used is 5% by weight or less based on the total amount of styrene and divinylbenzene monomers. And in this case,
The amount of vinylbenzenesulfonic acid or its salt is 0.5
It is preferable to set it as % by weight or more. By coexisting vinylbenzenesulfonic acid or its salt, it is possible to obtain a copolymer whose particle size is uniform within a certain range, and when sulfonation is carried out in the later step, A product is obtained in which sulfonation is uniformly carried out throughout the interior.

When aqueous suspension polymerization is carried out in the coexistence of vinylbenzenesulfonic acid or its salt, styrene
A terpolymer of divinylbenzene/vinylbenzesulfonic acid or a salt thereof is obtained.

By obtaining a copolymer by aqueous suspension polymerization, it can be made to have a substantially spherical shape.

In addition, the particle size of the copolymer is adjusted within the range of 10 to 100 microns, and for this purpose, the stirring speed during aqueous suspension polymerization, the amount of dispersant, and the amount of vinylbenzenesulfonic acid or its salt are adjusted. This can be done by appropriately selecting the amount, etc.

Since the copolymer has a substantially spherical shape, the hyperkalemia therapeutic agent produced by the present invention has the advantage that it can be easily taken orally with a small amount of water and is quickly excreted from the body. occurs. Furthermore, since the particle size of the copolymer is 10 to 100 microns, the entire particle is uniformly sulfonated, resulting in excellent ion exchange ability.

The thus obtained styrene/divinylbenzene copolymer and styrene/divinylbenzene sulfonic acid or salt thereof copolymer are further sulfonated.

To carry out sulfonation, a styrene/divinylbenzene copolymer, a styrene/divinylbenzene/vinylbenzene sulfonic acid or a salt thereof copolymer is heated, for example, in concentrated sulfuric acid at 95 to 100°C for 5 to 10 minutes.
This can be carried out by heating for 10 hours or by contacting with a mixed gas of air and sulfuric anhydride at 80 to 100°C.

After ion-exchanging the sulfonated copolymer thus obtained with calcium in an aqueous solution of a calcium salt such as calcium chloride, or with sodium in an aqueous solution of caustic soda,
Wash with water and dry. The sulfonated copolymer is ion-exchanged with sodium or calcium because these have excellent exchangeability with potassium.

According to the present invention, since the copolymer particles are reliably sulfonated, they not only have a higher potassium excretion ability in vitro than conventional pulverized hyperkalemia treatment agents, but also have the above-mentioned hydrophobicity in vivo. Since there is no adsorption of proteins and the like due to sexual interactions, a hyperkalemia therapeutic agent having a higher potassium excretion ability than conventional pulverized hyperkalemia therapeutic agents can be obtained.

Example 1 Styrene 89 parts by weight Divinylbenzene 20 parts by weight Sodium vinylbenzenesulfonate 1 part by weight Benzoyl peroxide 0.5 parts by weight A mixture of the above components was dispersed in 200 parts by weight of a 0.5% aqueous solution of polyvinyl alcohol, and nitrogen Aqueous suspension polymerization was carried out at 80° C. for 10 hours while stirring in an air stream. Through this aqueous suspension polymerization, the fine particles of styrene/divinylbenzene/sodium vinylbenzenesulfonate copolymer are approximately spherical and have a particle size of 30 mm.
They were all in the range of 60 to 60 microns. After dehydration, washing with water, and drying, the fine particles were dispersed in 200 parts by weight of 98% concentrated sulfuric acid, and a sulfonation reaction was carried out at 95 to 100°C. After reacting for 5 hours, fine particles of the sulfonated copolymer were collected by filtration.

Next, ion exchange was performed in 200 parts by weight of a 1.0N calcium chloride aqueous solution at 60°C for 5 hours, followed by dehydration, washing with water, and drying to obtain a therapeutic agent for hyperkalemia.

One gram of the tablet was exchanged with 1.5 mEq of potassium in vitro.

In addition, this drug was orally administered to male rats in an amount of 2 g/Kg. 85% in feces after 24 hours, and after 100 hours
It was found that 100% was excreted. Furthermore, as a result of measuring the potassium content of this drug in this excrement, it was confirmed that it was exchanged with 0.7 mEq of potassium in vivo.

Example 2 A mixture of the same components as in Example 1 was subjected to aqueous suspension polymerization under the same conditions as in Example 1, and further sulfonated.

Then, in 200 parts by weight of 1.0 normal caustic soda, 30
Ion exchange was carried out at ℃ for 2 hours, followed by dehydration, washing with water, and drying to obtain a therapeutic agent for hyperkalemia having a particle size of 30 to 60 microns and a substantially spherical shape.

1 g of this drug was replaced with 3.2 mEq of potassium in vitro.

In addition, the tablet was orally administered to male rats in an amount of 2 g/Kg. It was found that 83% was excreted within 24 hours and 98% after 100 hours. Furthermore, as a result of measuring the potassium content of this book in this excrement, it was confirmed that it was exchanged with 1.8 mEq of potassium in vivo.

Comparative Example 1 Polystyrene sulfonic acid resin was crushed and the particle size was
Example 1: Particles of 10 to 100 microns
Ion exchanged with calcium in the same manner as above.

This was exchanged in vitro with 1.3 mEp/g of potassium. A dose of 2 g/Kg was also administered orally to male rats. 72% in feces after 24 hours, 100
Although 86% was excreted after 100 hours, it was found that 14% still remained in the body even after 100 hours. Furthermore, the results of measurements using excreta showed that only 0.4 mEp of potassium was exchanged in vivo.

Claims (1)

[Claims] 1. Styrene and divinylbenzene are copolymerized by aqueous suspension polymerization to form a substantially spherical copolymer with a particle size of 10 to 100 microns, and the copolymer is sulfonated, and then a sodium compound or calcium A method for producing a therapeutic agent for hyperkalemia, which comprises performing ion exchange using a compound. 2. Aqueous suspension polymerization of styrene and divinylbenzene in the coexistence of vinylbenzene sulfonic acid or its salt to form a substantially spherical copolymer with a particle size of 10 to 100 microns, and sulfonation of the copolymer;
A method for producing a therapeutic agent for hyperkalemia, which comprises then performing ion exchange using a sodium compound or a calcium compound. 3. 5% by weight of vinylbenzenesulfonic acid or its salt based on the total amount of styrene and divinylbenzene.
A method for producing a therapeutic agent for hyperkalemia according to claim 2, which is used as follows.