JP2841399B2 - Liquid separating agent - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a liquid separating agent. Specifically, the present invention, when separating each component having a different specific gravity coexisting in the liquid by utilizing the difference in specific gravity, by forming a partition between both components by having an intermediate specific gravity of both components And a liquid separating agent that can be used for the purpose of facilitating the operation of separating these two components.

[Conventional technology]

Conventionally, various compounds have been known as a separating agent used in such a separating operation. For example, silicone oil (Japanese Patent Application Laid-Open No. 54-2120), chlorinated polybutene oil (Japanese Patent Application Laid-Open
57-9718) or α-olefin-maleic acid diester copolymer (JP-A-62-199644)
It is known that these materials are used as a main component, and inorganic fine particles such as silica gel and clay are added thereto for adjusting specific gravity and viscosity or maintaining shape. On the other hand, in recent years, drug therapy has been actively performed in clinical settings, and thus it is necessary to accurately and quickly measure the blood concentration of a drug. Since blood separation can be performed easily and quickly, it is increasingly used as a separating agent for blood separation.

[Problems to be solved by the invention]

However, when a conventional liquid separating agent is used for blood separation, for example, hospital pharmacy vol. 12, No. 6, 401 (1986),
As already reported in Kyushu Pharmaceutical Society No. 40, 39 (1986) and the like, there is a problem that the drug component contained in the serum changes over time due to the influence of the liquid separating agent used. This is because the drug component to be measured is absorbed by the liquid separating agent due to the influence of the liquid separating agent used during the blood separating operation, and the blood concentration thereof decreases over time. Therefore, it is inappropriate to use a conventional liquid separating agent for the purpose of measuring the blood concentration of a certain drug, and there has been a strong demand for the development of a liquid separating agent that improves these points.

[Means for solving the problem]

In view of such circumstances, the present inventors have conducted intensive studies to provide a high-performance liquid separating agent such that the measurement target component does not decrease over time during the separation operation. The use of a liquid separating agent containing an α-olefin-maleic acid diester copolymer as an essential component and a maleic acid diester contained in the chain as a component of the copolymer can significantly reduce the decrease over time of the component to be measured. The inventors have found the present invention.

That is, the gist of the present invention is a copolymer of an α-olefin having 6 to 20 carbon atoms and a maleic diester, wherein at least a part of the maleic diester has a halogen atom in at least one of its ester chains. A liquid separating agent used for separating components having different specific gravities coexisting in a liquid containing α-olefin-maleic acid diester copolymer as an essential component.

 Hereinafter, the present invention will be described in detail.

The α-olefin used in the present invention has 6 to 20 carbon atoms and is a straight-chain or low-branching hydrocarbon having a carbon-carbon double bond at the terminal. Specifically, α-olefins obtained by low-polymerization of ethylene are preferably used, but α-olefins obtained by low-polymerization of propylene, isobutylene and the like can also be used. In the case of these low-polymerized products, they are separated by means such as distillation and used as having a predetermined carbon number. In the present invention, an α-olefin having 6 to 20 carbon atoms may be used alone or as a mixture thereof.

If the α-olefin has more than 20 carbon atoms, the resulting copolymer becomes a solid at room temperature, which is not preferable. If it is less than 6, complicated operations such as performing a reaction under pressure during the synthesis of the copolymer are required. Is not preferred.

As the maleic diester, those represented by the following general formula [I] are preferably used.

(In the formula, R ¹ and R ² may be the same or different and each represents an alkyl group having 1 to 14 carbon atoms or an alkyl group having 1 to 14 carbon atoms including a halogen atom.) The above R ¹ and R ² Specific examples of the alkyl group of methyl, ethyl, n-propyl, i-propyl, n-
Examples thereof include a linear or branched alkyl group having 1 to 14 carbon atoms such as a butyl group, an i-butyl group, a t-butyl group, an n-hexyl group, an n-octyl group, an n-decyl group, and an n-dodecyl group. Can be If the number of carbon atoms is larger than 14, the maleic diester may become solid, and the copolymer with the α-olefin may also become solid, which is not preferable.

The alkyl group having 1 to 14 carbon atoms including a halogen atom includes a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom in the linear or branched alkyl group having 1 to 14 carbon atoms as described above. Things. As the halogen atom, a chlorine atom is particularly preferable.

In the present invention, it is an essential requirement that at least a part of the maleic diester in the copolymer of the α-olefin and the maleic diester contains a halogen atom in at least one of its ester chains. Accordingly, as the maleic acid diester represented by the general formula (I),
At least a portion of at least one of the ester chains
Finally, it is necessary to use one containing a halogen atom.

The maleic diester represented by the general formula [I] is composed of maleic anhydride and an alcohol having 1 to 14 carbon atoms and / or
Or 1 to 14 carbon atoms having at least one halogen atom
An alcohol catalyst such as p-toluenesulfonic acid,
Alternatively, it is produced by a method such as dehydration-condensation in the presence of an alkali catalyst or transesterification of a maleic acid diester with an alcohol having a predetermined number of carbon atoms in the presence of a similar acid or alkali catalyst. The maleic acid diester used in the present invention contains at least a halogen atom in at least one of its ester chains.
It may be produced by using a combination of an alcohol having 1 to 14 carbon atoms and an alcohol having 1 to 14 carbon atoms.

The liquid separating agent of the present invention is a copolymer of an α-olefin having 6 to 20 carbon atoms and a maleic diester, wherein at least a part of the maleic diester contains a halogen atom in at least one of its ester chains. α-olefin-
It is required that a maleic acid diester copolymer be an essential component. Therefore, for example, it is sufficient that at least a part of the maleic diester represented by the above general formula [I] contains a halogen atom in at least one of the ester chains. For example, only one ester chain of the maleic diester has a halogen atom. It may contain atoms, both ester chains may contain halogen atoms, or one or both ester chains may contain multiple halogen atoms. Further, only a part of the maleic acid diester may contain a halogen atom in its ester chain, or all of the maleic acid diesters may contain a halogen atom in both ester chains.

From the viewpoint of the performance as a liquid separating agent, the content of halogen atoms is preferably 2.5 to 60% by weight on average in one molecule of the α-olefin-maleic acid diester copolymer.
More preferably, it is 10 to 30% by weight.

The α-olefin-maleic acid diester copolymer, which is an essential component of the liquid separating agent of the present invention, is, for example, maleic diester (provided that 1 mol of the α-olefin is used)
At least a part of which contains a halogen atom in at least one of the ester chains) in an amount of 1 mol or more, preferably 1.0 mol
The mixture is usually heated to 100 to 200 ° C., preferably 110 to 170 ° C., for example, t-butyl peroxyoctoate, di-t-butyl peroxide, t-butylperoxybenzoate, dicumyl peroxide Can be produced by polymerization in the presence of a peroxide catalyst according to a conventional method.

The α-olefin-maleic acid diester copolymer thus obtained can be used as it is as a liquid separating agent, but the specific gravity or viscosity is adjusted as necessary depending on the kind of the object to be separated. Various additives can be blended for the purpose or for maintaining the shape as a liquid separating agent.

Examples of the liquidity modifier for adjusting the specific gravity or viscosity include α-olefin oligomers, polybutene oil, epoxidized soybean oil, alkyldimethylpolysiloxane, long-chain alkyl diester of adipic acid, and liquid paraffin. Among them, the α-olefin oligomer is an α-olefin oligomer having 6 to 18 carbon atoms, and preferably has a molecular weight of about 500 to 15,000.
These liquid property modifiers are preferably blended in an amount of usually 0 to 60 parts by weight with respect to 100 parts by weight of the α-olefin-maleic acid diester copolymer.

Further, as a gelling agent for keeping the liquid separating agent of the present invention in a stable non-flowing state before and after centrifugation, for example, glutamic acid amide, hydrogenated castor oil, dibenzylidene sorbitol, silica, aliphatic amines of smectite clay Derivatives and the like. The mixing ratio of these gelling agents is preferably in the range of 0.1 to 20 parts by weight based on 100 parts by weight of the α-olefin-maleic acid diester copolymer.

The liquid separating agent of the present invention prepared as described above,
It is pale yellow, transparent, odorless and especially inert to blood. That is, there is no danger of causing phenomena such as blood adsorption and elution, and it is stable over time, and does not cause physical or chemical changes even by radiation sterilization using γ-rays or the like.
Therefore, the liquid separating agent of the present invention is particularly suitable as a blood separating agent.

When the liquid separating agent of the present invention is used for blood separation, one having a specific gravity (25 ° C.) in the range of about 1.03 to 1.08 has an intermediate specific gravity between serum and other components. It is preferable because it is effective, exhibits favorable fluidity during centrifugation, and can be kept in a stable state for a relatively long time before and after the separation.

〔Example〕

Next, specific embodiments of the present invention will be described in more detail with reference to examples. However, the present invention is not limited to the following examples unless it exceeds the gist thereof.

Production Example 1 Production of bis (2-chloroethyl) maleate 98 g (1 mol) of maleic anhydride and 180 g (2.2 mol) of 2-chloroethanol were dissolved in xylene 1 and 1 g of p-toluenesulfonic acid was added. Distilled water was extracted while stirring at 10 ° C. for 10 hours. After allowing to cool, neutralize with an aqueous solution of sodium hydrogen carbonate and wash with water,
Magnesium sulfate was added, shaken for a while, filtered off, and the filtrate was concentrated. The filtrate was heated under reduced pressure to obtain the desired product. The yield was 230 g (94% yield).

Production Example 2 Production of methyl-2-chloroethyl maleate After dissolving 576 g (4 mol) of dimethyl maleate and 80 g (1 mol) of 2-chloroethanol in xylene 1,
1 g of p-toluenesulfonic acid was added, and methanol distilled out was extracted while heating and stirring at about 100 ° C. for 5 hours. After neutralization and dehydration in the same manner as in Production Example 1, recrystallization from xylene gave the desired product. 170g (88% yield)
Met.

Example 1 Dodecene (trade name: Dialen 12: manufactured by Mitsubishi Kasei Corporation) 3
6.2 g (0.22 mol), dimethyl maleate 28.8 g (0.20 mol), bis (2-chloroethyl) maleate 48.5 g (0.2
0 mol) in a four-necked flask and charged under a nitrogen atmosphere to 110
4.3 g of t-butyl peroxy octoate (trade name Kayaester O: manufactured by Kayaku Nuuri Co.)
02 mol) was added over about 8 hours. Then, after stirring at about 110 ° C. for 1 hour, the mixture was heated under reduced pressure to remove light boiling components.

The yield of the obtained copolymer was 109 g (96% yield), and the specific gravity was
1.16, copolymerization molar ratio: dodecene: dimethyl maleate:
Bis (2-chloroethyl) maleate = 1: 1: 1. 15 g of epoxidized soybean oil was added to 85 g of this copolymer to adjust the specific gravity to 1.05. 100 g of the copolymer after specific gravity adjustment
Add 0.25 g of dibenzylidene sorbitol to
After heating and stirring for an hour, the mixture was allowed to cool to perform gelation. The specific gravity of the gel was 1.05.

Example 2 56.0 g (0.33 mol) of dodecene and bis (2-maleate)
97.0 g (0.40 mol) of chloroethyl) was charged into a four-necked flask, and 4.3 g (0.02 mol) of t-butylperoxyoctoate was added under the same conditions as in Example 1. After this, about 110
After stirring at 1 ° C. for 1 hour, the mixture was heated under reduced pressure to remove light boiling components.

The yield of the obtained copolymer was 100 g (yield 97%), and the specific gravity was
1.18, copolymerization molar ratio: dodecene: bis (2-maleate)
Chloroethyl) = 1: 1.2.

Further, the specific gravity of the copolymer was adjusted to 1.05 in the same manner as in Example 1.

Example 3 Dodecene 56.0 g (0.33 mol), dimethyl maleate 24.
0 g (0.17 mol) and 32.2 g (0.17 mol) of methyl-2-chloroethyl maleate were charged into a four-necked flask, and di-t-butyl peroxide (trade name Kayabutyl D: Kayaku Nury) was prepared under the same conditions as in Example 1. 7.1 g (0.05 mol) was added over about 6 hours. Then, after stirring at about 150 ° C. for 1 hour, the mixture was heated under reduced pressure to remove light boiling components.

The yield of the obtained copolymer was 109 g (yield 97%), and the specific gravity was
1.04, copolymerization molar ratio: dodecene: dimethyl maleate:
Methyl maleate (2-chloroethyl) = 1: 0.5: 0.5.

Test Examples The copolymers or gelled products obtained in Examples 1 to 3 were evaluated by the following methods.

Take about 1.5 g each of the copolymer or its gelled product,
A test tube having a fixed diameter was placed in the test tube, and 1 cc of bovine serum containing a certain concentration of the drug was added thereto, and the mixture was allowed to stand at 20 ° C. 72 hours later,
Only bovine serum was collected and the amount of drug contained therein was measured by the immunofluorescent immunoassay. The ratio of the drug concentration in the bovine serum after standing for 72 hours relative to the drug concentration in the original bovine serum was determined and defined as the drug residual ratio.

Evaluation: Drug residual rate 85% or more: ○, 75-85% △, 75%
The following was evaluated as x.

The results are shown in Table 1. For comparison, a separating agent A (a chlorinated polybutene as a main component, which is gelled with silica gel) and a separating agent B (a polyester as a main component, which is a silica The same evaluation was performed using a gelled product of fine particles).

[Effect of the Invention] A copolymer of an α-olefin and a maleic acid diester, wherein at least a part of the maleic acid diester contains an halogen atom in at least one of its ester chains. The liquid separating agent of the present invention containing a polymer as an essential component has a small change with time of the component to be measured during the liquid separating operation, and is extremely useful in practice.

Claims (6)

(57) [Claims] 1. A copolymer of an α-olefin having 6 to 20 carbon atoms and a maleic diester, wherein at least a part of the maleic diester contains a halogen atom in at least one of its ester chains. A liquid separating agent used for separating components having different specific gravities coexisting in a liquid containing an olefin-maleic acid diester copolymer as an essential component by utilizing the difference in specific gravity. 2. A maleic acid diester represented by the following general formula [I], wherein at least a part of the maleic acid diester contains a halogen atom in at least one of its ester chains. Item 4. The liquid separating agent according to Item 1. (In the formula, R ¹ and R ² may be the same or different and each represents an alkyl group having 1 to 14 carbon atoms or an alkyl group having 1 to 14 carbon atoms including a halogen atom.) 3. The liquid separating agent according to claim 1, wherein the halogen atom is chlorine. 4. The liquid separating agent according to claim 1, further comprising a liquid conditioner. 5. The liquid property modifier is at least one selected from the group consisting of oligomers of α-olefins, polybutene oil, epoxidized soybean oil, alkyldimethylpolysiloxane, long-chain alkyl diesters of adipic acid, and liquid paraffin. The liquid separating agent according to claim 4, characterized in that: 6. The liquid separating agent according to claim 1, wherein the liquid is blood.