Process for producing a cationic polymer

Details Process for producing a cationic polymer Process for producing a cationic polymer

2000-04-05

2001-07-17

Boykin, Terressa M. (Department: 1711)

Synthetic resins or natural rubbers -- part of the class 520 ser

Synthetic resins

Treating polymer containing material or treating a solid...

Reexamination Certificate

active

06262227

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a process f or producing a specific cationic polymer having a marked activity as a cholesterol-lowering drug and relates to a production process capable of achieving both properties of the safety as a drug and a satisfactory production efficiency.
2. Description of the Prior Art
Cationic polymers have cationic groups that can be ionized in water to yield cation. Typical examples of such cationic polymers include a polymer having quaternary ammonium salt groups or amino groups, which are used in the fields of, for example, ion-exchange resins, adsorbents, and flocculants. Cationic polymers having ef ficacy as drugs have been f ound in recent years, and expectations are made for developing new applications of these polymers. Especially, a cationic polymer having a unit shown by the following formula (III) has been found to lower a blood cholesterol level (PCT International Publication No. WO93/13781).
(wherein R
1
is H or a methyl group; R
2
, R
3
, and R
4
are each independently H, an alkyl group, or an aralkyl group; A is an alkylene group; X
−
is a counter anion; and p is an average polymerization degree.)
When such cationic polymers and other polymers are used as drugs, the most problematic matter is the existence of impurities such as low molecular weight polymer, unreacted monomer, and the like. This is because such low molecular weight polymer and unreacted monomers act as toxic substances or foreign substances in vivo and may cause adverse drug reactions, even though the polymers themselves have efficacies as drugs. A principle in the formation of such polymers does not allow them to have a single molecular weight but always render them polydisperse, and low molecular weight polymer and unreacted monomers are therefore inevitably formed. Accordingly, these low molecular weight polymer and unreacted monomers must be removed.
Incidentally, illustrative techniques for producing cationic polymers and other water-soluble polymers include bulk polymerization, suspension polymerization, emulsion polymerization, slurry polymerization, and aqueous polymerization. Among them, the aqueous polymerization technique is in wide use, because it requires no step for removing a solvent and does not invite a toxic solvent or emulsifier to be contaminated in product polymers.
According to the aqueous polymerization technique, water-soluble polymers can be obtained as hydrous polymers having viscosity by adding a radical initiator to an aqueous solution of a radical-polymerizable monomer, and where necessary heating to an adequate temperature to perform a polymerization reaction. If necessary, the hydrous polymers are pulverized after vacuum drying or hot-air drying, or are subjected to spray drying or freeze-drying to yield powdered polymers.
The water-soluble polymers obtained by such a technique contain residual low molecular weight polymer and unreacted monomers and cannot be used as intact as drugs with safety. Therefore, the water-soluble polymers must be purified in a purification step. Such purification techniques for polymers include fractionation, reprecipitation, and ultrafiltration, as well as adsorptive removal, and filtration with a permselective membrane as special techniques. Each of these techniques is, however, complicated and time-consuming.
The present inventors attempted to purify the cationic polymer (III) by ultrafiltration, but this purification was disadvantageous in that it required a long time to perform an ultrafiltration step and a drying step to thereby increase required energy and costs. In addition, during these steps, the cationic polymer (III) was hydrolyzed to form a hydrolysis product or quaternarizing agent moeity (R
3
X) was eliminated from the quaternary ammonium salt moiety. When the time required for drying was prolonged, an undesirable necessary crosslinking reaction occurred to make it difficult to redissolve the dried polymer, and the polymer could not be significantly prepared into a drug in some cases. When polymers were obtained by ultrafiltration under the same condition and were tabletted, the resulting tablets might show variations in disintegratability.
The present invention has been accomplished under these circumstances. Accordingly, it is an object of the invention to provide a process for producing a cationic polymer capable of ensuring the safety as a drug and capable of producing and purifying the object polymer with high efficiency, in the production of a specific cationic polymer having a marked cholesterol-lowering activity.
SUMMARY OF THE INVENTION
The invention provides a process for producing a cationic polymer having a cholesterol-lowering activity to reduce the amount of a low molecular weight polymer having a weight average molecular weight of 10,000 or less, an unreacted monomer, and a degradation product, and the process including the steps of:
(1) subjecting a water-soluble monomer component essentially containing a cationic monomer represented by the following formula (I) to aqueous polymerization in such a manner that the viscosity of a polymerization reaction solution is equal to or more than 1,000 cps and less than 300,000 cps at the point of time when a polymerization rate reaches 90%;
(wherein R
1
is H or a methyl group; R
2
, R
3
, and R
4
are each independently H, an alkyl group, or an aralkyl group; A is an alkylene group; X
−
is a counter anion)
(2) continuing the polymerization until the polymerization rate exceeds 95%;
(3) subjecting the obtained aqueous polymer to ultrafiltration;
(4) subjecting the obtained ultrafiltrated residue to concentration under depressurization at a temperature of the solution lower than 100° C.; and
(5) drying a product after the depressurized concentration at a temperature D
1
(° C.) for a time T
1
(second), both parameters satisfying the following mathematical relational expression, until the water content of a resulting cationic polymer reaches 10% by weight or less:
350≧
D
1
×Log
10
T
1
where
100≦D
1
≦180
T
1
>1
When the drying step is performed at a temperature lower than 100° C., the product is dried at a temperature D
2
(° C.) for a time T
2
(min.) both satisfying the following mathematical relational expressions, until the water content of a resulting cationic polymer reaches 10% by weight or less:
300
≧D
2
×Log
10
T
2
where
10≦D
2
<100
T
2
>1
DETAILED DESCRIPTION OF THE PREFFERRED EMBODYMENTS OF THE INVENTION
The present inventors made investigations to pursue the causes of the above problems, and found, for example, that a specific polymerization technique can reduce unreacted monomers and low molecular weight polymer which adversely affect the safety, that harmful effects such as deteriorated efficiencies of the ultrafiltration step and drying step are caused by an ultra high molecular weight polymer in the polymerization product, that these unreacted monomers and low molecular weight polymer can be further reduced and removed by ultrafiltration, and that if the condition in the drying step is not selected appropriately, a quaternarizing agent which may have safety problem is eliminated from the polymer, which is liable to contaminate the product cationic polymer above the allowable amount.
Specifically, the inventors found that when a polymerization reaction solution has a viscosity of 300,000 cps or more, the end product polymer, as a result, contains large amount of ultra high molecular weight cationic polymers, which causes the following disadvantages.
(1) An ultrafiltration rate becomes extremely low to invite the ultrafiltration step to require a long time. In contrast, if the viscosity of a solution to be filtreated is reduced to yield a dilute solution in order to increase the filtration rate, concentration and drying of a residual solution require enormous amount of energy and increased costs.
(2) Ester groups in the cationic polymer are liable to be hydrolyzed, and if a dilute solution is subjected to ultrafiltration

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