WO2018160004A1 - Blood serum or plasma separation composition, and container for blood test comprising same - Google Patents

Abstract

The present invention relates to a thixotropic blood serum or plasma separation composition that uses differences in specific gravities of blood components, and that separates blood serum or plasma from blood, and a container for a blood test comprising the same; and is characterised by containing a 1,4-cyclohexanedicarboxylic acid ester and a cyclopentadiene‐based oligomer. The present invention is a blood serum or plasma separation composition containing a cyclopentadiene‐based oligomer, that uses differences in specific gravities of blood components, so that lipid elements are not dispersed in the blood serum or plasma after centrifugation so not only is a blood sample not contaminated the effect of forming a stable partition wall for a long period is also exhibited.

Description

Serum or plasma separation composition, and a blood test container comprising the same

The present invention relates to a composition for use in separating serum or plasma from blood, and to a container for blood test, and more particularly, to a thixotropic serum or plasma that uses a specific gravity difference of blood components and separates serum or plasma from blood. A composition for separation, and a blood test container comprising the same.

In blood tests and the like, it is required to rapidly separate serum or plasma from blood. In general, a method using a specific gravity difference between a blood cell component (specific gravity of about 1.08) and serum or plasma (specific gravity of about 1.03) is widely used.

Since the gel-type serum or plasma separation composition has a specific gravity between the serum or plasma component and the blood clot or blood cell component, the serum or plasma is gradually raised from the collected blood base and forms an upper layer. Is to form a lower layer, it is possible to separate the blood serum or plasma components and blood or blood components.

In addition, when separating serum or plasma using specific gravity difference, in order to rapidly separate serum or plasma from blood cell components and the like, specific gravity is adjusted in the range of 1.03 to 1.08, more preferably in the range of 1.04 to 1.06. Compositions for separation of serum or plasma have been proposed but are not without problems.

For example, silicone, olefin-maleic acid diester copolymer, polyester polymer, acrylic polymer, chlorinated polybutene, cyclopentadiene resin, and the like are known as main components of the serum or plasma separation composition. In most cases, it is currently not used because of poor compatibility and hardening reactions caused by radiation sterilization, and also olefin-maleic acid diester copolymers, polyester polymers, acrylic polymers, modified products of cyclopentadiene resins, and the like. Likewise, having a polar group has a relatively small effect on the measurement of clinical test subjects in the blood, but often affects the measurement of blood drug concentrations (eg, antiepileptic drugs phenobarbital, carbamazepine, phenytoin, etc.). As polybutene is used, when incineration after use, Because generating a gas, damage the incineration furnace, or there is a problem in that the adverse effect on the environment.

In order to solve this problem, Sekisui Co., Ltd. has proposed a composition for separation of serum or plasma containing oligomers of cyclopentadiene and plasticizer components such as DIDP (diaisodecylphthalate) (Patent Documents 1: WO1997 / 08548; As a result, the entire contents of Patent Literature 1 are cited and incorporated herein as the prior art of the present specification).

However, in the composition, the compatibility of the components constituting the composition tends to be separated, so that the oily component tends to be separated, and the separated oily component may be suspended in serum or plasma after centrifugation. The oily component in which impurities are suspended may block the sampling nozzle of the analyzer or adhere to the surface of the electrolyte sensor, which may interfere with blood tests.

In addition, when such oil phase component separation occurs, when the blood vessel containing the composition is laid on its side or inverted, the oil phase component adheres to the tube wall or plug, or the homogeneity of the composition is impaired and the partition stability is lowered. It can also cause problems.

[Preceding technical literature]

(Patent Document 1) WO199708548 A (1997.12.01.)

SUMMARY OF THE INVENTION An object of the present invention is to solve the above-mentioned drawbacks of the prior art, and to separate serum or plasma using specific gravity of blood components containing cyclopentadiene-based oligomers, where an oily component is suspended in serum or plasma after centrifugation. It is providing the composition for serum or plasma separation, and the container for blood test using the composition.

The present invention has been made to solve the above problems of the prior art,

It provides a composition for serum or plasma separation comprising 1,4-cyclohexane dicarboxylic acid ester and cyclopentadiene-based oligomer.

In the present invention, the 1,4-cyclohexane dicarboxylic acid ester is contained in a ratio of 30 to 250 parts by weight based on 100 parts by weight of the cyclopentadiene-based oligomer provides a composition for serum or plasma separation do.

The present invention also provides a composition for separation of serum or plasma, characterized in that it further comprises at least one component selected from an organic gelling agent, an antifoaming agent, and an inorganic fine powder.

The present invention also provides a container for blood test comprising the container body and the composition for separation of serum or plasma according to any one of claims 1 to 3 contained in the container body.

The present invention is a composition for serum or plasma separation using the specific gravity difference of blood components containing a cyclopentadiene-based oligomer, the oil phase component is not suspended in the serum or plasma after centrifugation, there is no contamination of the blood sample as well as long-term It is effective to form a stable partition.

1 is a photograph showing a state in which blood is separated into a blood test container containing a composition for blood separation according to an embodiment of the present invention.

EMBODIMENT OF THE INVENTION Hereinafter, this invention is demonstrated in detail.

One aspect of the present invention is a composition for separation of serum or plasma, comprising 1,4-cyclohexane dicarboxylic acid ester and cyclopentadiene-based oligomer.

The composition for serum or plasma separation of the present invention contains 1,4-cyclohexane dicarboxylic acid ester.

In the conventional cyclopentadiene-based oligomer-based serum or plasma separation composition, phthalic acid ester is mainly used as a plasticizer, which is a substance having a polar interaction derived from an ester bond in a molecule and is a nonpolar hydrocarbon. Incompatibility with the cyclopentadiene-based oligomer is poor, there is a problem that separated oil phase components float in the centrifuged serum or plasma when blood samples are stored for a long time.

Accordingly, the present invention solved this problem by using 1,4-cyclohexane dicarboxylic acid ester as a plasticizer component that acts as a compatibilizer, and the composition of the present invention has a low viscous hyperactivity at room temperature. In addition to being suppressed, the oil phase component does not block the sampling nozzle of the separator or contaminate the reaction cell.

The 1,4-cyclohexane dicarboxylic acid ester used in the present invention is a compound prepared by esterifying a 1,4-cyclohexane dicarboxylic acid with an alcohol, and as a non-limiting example, 1,4-cyclo Hexane dicarboxylic acid n-octyl, 1,4-cyclohexane dicarboxylic acid isooctyl, 1,4-cyclohexane dicarboxylic acid isodecyl, 1,4-cyclohexane dicarboxylic acid 2-ethylhexyl, 1,4-cyclohexane dicarboxylic acid 2-octyl etc. are mentioned.

The alcohol which reacts with the said 1, 4- cyclohexane dicarboxylic acid can be suitably selected in consideration of elements, such as specific gravity and the range of viscosity which a person skilled in the art is preferable. Alcohols of 3 to 20 carbon atoms, i.e. propanol, butanol, pentaol, hexanol, heptanol, octanol, nonanol, decanol, undecanol, dodecanol, tridecanol, tetradecanol, pentadecanol, Heptadecanol, octadecanol, nonadecanol, ecosanol and the like can be used, but are not necessarily limited thereto.

It is preferable that the said 1, 4- cyclohexane dicarboxylic acid ester contains the said 1, 4- cyclohexane dicarboxylic acid ester in the ratio of 30-250 weight part with respect to 100 weight part of said cyclopentadiene system oligomers. If the 1,4-cyclohexane dicarboxylic acid ester is less than 30 parts by weight, the viscosity of the blend is too high, so strong centrifugal force may be required for separation of serum or plasma and blood cell components. On the contrary, when the 1,4-cyclohexane dicarboxylic acid ester exceeds 250 parts by weight, it is necessary to fill a large amount of inorganic fine powder in order to adjust the specific gravity of the blend to 1.04 or more, and the yield value increases over time to form partition walls. In addition to deterioration, the viscosity of the composition is too low, which is undesirable.

The cyclopentadiene-based oligomer of the present invention refers to a polymer in which the cyclopentadiene-based monomer is polymerized at a low molecular weight of 10,000 or less in molecular weight, and includes hydrogenated (including partial hydrogenation).

In addition, as said oligomer, a normal cyclopentadiene type oligomer and a hydrogenated cyclopentadiene type oligomer may be used each alone, or 2 or more types may be mixed and used, and other monomer components, such as an aromatic olefin, may be copolymerized, There may be. Moreover, the oligomer may be a mixture of such polymers or copolymers.

The cyclopentadiene-based monomer is not particularly limited, and examples thereof include alkyl substituents of cyclopentadiene, dicyclopentadiene and cyclopentadiene (for example, methyl cyclopentadiene).

Although it does not specifically limit as a cyclopentadiene type oligomer which can be used for this invention, For example, it selects from the polymer of a cyclopentadiene type monomer, for example, alkyl substituted derivatives of cyclopentadiene, dicyclopentadiene, cyclopentadiene, etc. And hydrogenated products of at least one monomer polymer.

Further, a hydrogenated product of a copolymer of at least one cyclopentadiene-based monomer and at least one aromatic monomer selected from styrene, methyl styrene, indene, methyl indene and the like can also be used.

The composition of the present invention may further comprise at least one component selected from an organic gelling agent, an antifoaming agent, and an inorganic fine powder.

That is, in the serum or plasma separation composition according to the present invention, various other components may be blended within the range not impairing the object of the present invention in addition to the essential components, and as such other components, an inorganic fine powder or an organic gel as a thixotropy-imparting agent Examples of the agent and specific gravity modifier include inorganic fine powders and polar organic solvents for gelling degree adjustment.

As the organic gelling agent, for example, a condensation product of sorbitol of dibenzylidene sorbitol, bis (p-ethylbenzylidene) sorbitol, sorbitol of bis (p-methylbenzylidene) sorbitol and aromatic aldehyde or N-lauroyl as sorbitol modified product And amino acid-based gelling agents of -L-glutamic acid-α and γ-di-n-butylamide, but are not limited thereto.

The more preferable concentration of the said organic gelling agent is 4 weight part or less with respect to 100 weight part of cyclopentadiene type oligomers, and further more preferable concentration is 2 weight part or less. When the content of the organic gelling agent exceeds the cyclopentadiene-based range above, viscous properties are increased during room temperature, and as a result, it is not a big problem when the centrifugal force is high and the centrifugal temperature is high, but on the contrary, the centrifugal force is small. In addition, when the temperature is low during centrifugation, there may be a problem in that it becomes difficult to form a partition wall.

As said inorganic fine powder, fine powders, such as a silica, kaolin, bentonite, an alumina, a synthetic silicate compound, and diatomaceous earth, etc. are mentioned, regardless of crystallinity and amorphousness.

As the inorganic fine powder, fine powder silica is preferable, and hydrophobic fine powder silica in which a part of hydroxyl groups on the surface of the primary particles of silica is substituted with an alkyl group is preferable. More preferably, the amorphous dry silica by gas phase method has a large specific surface area and the present composition. Since it is excellent in the dispersibility in the inside, it is preferable. This is because the dry silica has hydrophobicity, so that it is well dispersed in the composition, and it is not dissolved in blood and hemolyzed.

The specific surface area of the fine powder silica is preferably 10 m 2 / g, preferably 1000 m 2 / g, more preferably 30 m 2 / g, and more preferably 500 m 2 / g. By the specific surface area being in the said range, thixotropy of this composition can be adjusted suitably.

As for the primary particle diameter of the said fine powder silica, a preferable minimum is 1 nm, a preferable upper limit is 100 nm, a more preferable minimum is 5 nm, and a more preferable upper limit is 50 nm. By the primary particle size being in the above range, the thixotropy of the present composition can be suitably adjusted.

In terms of suitably adjusting the specific gravity and thixotropy of the composition, the amount of fine powder silica used is preferably 1 part by weight, preferably 20 parts by weight, or more preferably 100 parts by weight of the cyclopentadiene-based oligomer. 2 weight part and a more preferable upper limit is 10 weight part.

As said polar organic solvent, acetone, dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), ethylene glycol, propylene glycol, etc. are mentioned, for example.

Although the physical property of the said composition is not specifically limited, It is preferable that the softening point exists in the range of 70-140 degreeC, and specific gravity in 25 degreeC is in the range of 1.00-1.10, and specific gravity in 5 degreeC is 1.02-1.08 in the range. It is more preferable that is. If the specific gravity is too low or too high, it may be difficult to place it in the middle of the serum or plasma layer and the blood clot or blood cell layer.

Viscosity of the composition of the present invention, by the usual centrifugal separation operation, the composition is placed in the middle of the serum or plasma layer and the blood clot or blood cell layer, or filling operation into a blood test container such as a vacuum blood collection tube. In this easy point, the preferable lower limit of the viscosity at 50 ° C. when the shear rate of the Brookfield Co., Ltd. product (manufactured by Brookfield Co., Ltd.) is 1 (1 / sec) is 0.1 Pa · s, Preferable upper limit is 100 Pa.s. Moreover, the minimum with preferable viscosity in 25 degreeC is 10 Pa.s, and a preferable upper limit is 500 Pa.s. If the viscosity is too low or too high, handling may be difficult, and it may be difficult to place it in the middle of the serum or plasma layer and the blood clot or blood cell layer.

Another aspect of the present invention is a container for blood test, comprising a container body and the composition of the present invention contained in the container body.

The shape of the inspection container is not particularly limited, and a widely used bottomed tubular container may be employed.

Moreover, the material of a container is not specifically limited, either, The blood test container which consists of glass, synthetic resin, etc. can be used. However, since the serum or plasma separated from the outside can be easily confirmed by the naked eye, it would be desirable to configure the blood test container by the container having transparency.

The blood test container includes reagents such as blood coagulants or anticoagulants, glycolysis blockers and deproteinization agents, and stabilizers, inhibitors, and activators of the desired components, depending on the purpose of the test. A conventionally well-known adduct may be accommodated, such as a carrier of reagents and a member that assists in mixing these reagents with blood.

The blood test container can also be used as a so-called vacuum collection tube.

Hereinafter, an Example is given and this invention is demonstrated in detail. The following examples are merely examples for the detailed description of the invention, thereby making it clear that they are not intended to limit the scope of the rights.

Example

Examples 1 to 3

To prepare a composition and composition ratio blood separation composition as shown in Table 1.

The specific gravity of Examples 1-3 was 1.05, 1.05, and 1.04, respectively (electric density meter measurement).

Example 4

In terms of physical properties relating to plasma and blood cell separation, the composition of Example 1 showing more preferred physical properties was provided on the inner bottom to produce a vacuum blood vessel.

Comparative example

Comparative Example 1

Commercially available Sekisui SERUM SEPERATING GEL

Comparative Example 2

Commercially available Backton Dickinson SERUM SEPERATING GEL

Experimental Example

Example 4 prepared above, and the serum separation gel composition comprising a cyclopentadiene oligomer as a main component is a vacuum blood vessel (Comparative Example 1) provided at the bottom, and the gel composition for serum separation comprising an acrylate resin as a main component A comparative test was performed together with the vacuum blood vessel (Comparative Example 2) provided at the bottom. The total number of samples was 20 for each of the examples and the comparative examples.

After centrifugation at 25 rpm for 10 minutes at 25 ° C., the presence of bulkhead formation, hemolysis, oily component generation, and surface bubble generation were examined according to storage conditions.

The results were as shown in Table 2 below.

As can be seen in Table 2, Comparative Example 1 had an oil phase component, Comparative Example 2 had a problem that not only the oil phase component generation was very severe, but also surface bubbles occur.

On the contrary, in the vacuum blood vessel according to the embodiment of the present invention, oil-derived components did not occur at all and surface bubbles did not occur, and thus it was confirmed that the long-term storage stability was very excellent. In addition, even when the antifoaming agent was not used separately, there was no surface bubble generation, and the performance was very excellent.

Claims (4)

A composition for separation of serum or plasma, comprising 1,4-cyclohexane dicarboxylic acid ester and cyclopentadiene-based oligomer.

The composition for separation of serum or plasma according to claim 1, wherein the 1,4-cyclohexane dicarboxylic acid ester is contained in a proportion of 30 to 250 parts by weight based on 100 parts by weight of the cyclopentadiene-based oligomer.

The composition for separation of serum or plasma according to claim 1, further comprising at least one component selected from an organic gelling agent, an antifoaming agent, and an inorganic fine powder.

A container for blood test comprising the container body and the composition for separation of serum or plasma according to any one of claims 1 to 3 contained in the container body.

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