CA1306698C - Hemolysis depressant, and medical resin composition, medical implement and blood preserving liquid using the hemolysis depressant - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
A hemolysis depressant comprising a triglyceride compound, and resin compositions for medical appliances, medical implements and blood preserving liquid using the triglyceride compound as a hemolysis depressant are capable of preventing the blood held in contact therewith from the phenomenon of hemolysis by the activity of the compound in protecting erythrocytes.

Description

SPECIFICATION
HEMOLYSIS DEPRESSANT, AND MEDICAL RESIN COMPOSITION, MEDICAL IMPLEMENT AND BLOOD PRESERVING
LIQUID USING THE HEMOLYSIS DEPRESSANT
5BACKGROUND OF THE I~VENTION
Field of the Invention:
This invention relates to a hemolysis depressant exhibiting extremely high safety and permitting highly effective control of the phenomenon of hemolysis which 10 possibly occurs in blood while in storage and to a resin composition for medical appliances, medical implements and blood preserving liquids which make use of the hemolysis depressant.
Background of the Invention:
15when blood flows out of the blood vessel, it begins to show a visible sign of coagulation within 10 to 20 minutes' e~posure to the ambience. The clot which is formed by the coagulation is the final product of a series of chemical reactions which proceed during the conversion of 20 fibrinogen into fibrin. The fibrin are interconnected and, during the course of the interconnection, erythrocytes are entrapped in the clot. In order for the blood for transfusion to retain its original liquid state, therefore, ; a measure to preclude the normal reactions responsible for 25 the hemal coagulation must be taken during the extraction of the blood from a donor. Heretofore, the practice of adding a liquid anticoayulant as a blood preserving liquid to the freshly extracted blood has been in vogue. The liquid anticoagulant which is in popular use nowadays is intended 30 to effect the preclusion of the hemal coagulation by chelating the calcium ion which constitutes an important factor during the course of coagulation.
; Incidentally, the blood for transfusion secured as described above is treated, when necessary, for separation 35 of some o~ the components thereof and then is placed as in a blood bag, for example, to be preserved until use. When whole blood or a blood component such ~s concentrated red j9~3 cells (CRC) is preserved for a long time, there ensues the so-called hemolysis, i.e. a phenomenon which involves external liberation of hemoglobin from the erythrocyte. As main causes for the hemolysis, there can be cited the change 5 in the pressure of osmosis due to a difference in the ion composition in the blood, the difference in the pressure of colloidal osmosis due to such proteinaceous components as hemoglobin, the change in membrane proteins and lipids of erythrocytes, the hindrance to the active transport of Na+
10 and K , and the actions of medicines and poisons. The most important factor consists in the liquid anticoagulant to be used. Thus, numerous efforts have been devoted to improve the liquid anticoagulants. All the liquid anticoagulants currently in use are claimed to produce an anticoagulant 15 action and an action for protection of erythrocytes as well.
In the liquid anticoagulants of this type, however, the function as a protector for erythrocytes has not yet reached a point where it deserves to be called sufficient.
It is likewise important that the container such 20 as the blood bag for preserving the collected blood should be inactive to blood components. In the blood containers and othex similar medical implements which are currently in use, those made of flexible vinyl chloride resin are predominant. The di-2-ethylhexyl phthalate (DOP) which is 25 contained as a plasti~izer in the flexible vinyl chloride resin for such medical implements possesses a large capacity for migration. It is known that when the flexible vinyl chloride resin is exposed to blood, the di-2-ethylhexyl phthalate exudes from the container wall and dissolves into 30 the blood (The Japanese Journal of Medical Instrumentation, 54, 221 (198~)). It has been reported that this di-2-e~hylhexyl phthalate hinders the aggregating ability of platelets (Jouranl of Japan Society of Blood Transfusion, 28(3) 282 (1981)). When the preserving container made of 35 such flexible vinyl chloride resin as described above is used to preserve blood, for example, there is the possibility that the di-2-ethylhexyl phthalate will enter ' the donee's blood vessel as entrained by the preserved blood during the course of transfusion. This possibility poses a problem from the standpoint of the adverse effect exerted by this compound upon the function of platelets.
For the solution of this problem, the feasibility of the use of a material not containing this di-2-ethylhexyl phthalate has been studied. It has been learnt that when blood is preserved in containers made of materials not containing di-2-ethylhexyl phthalate, the erythrocytes in 10 the preserved blood are hemolyzed during the course of preservati~n. A search of the cause for this hemolysis has revealed ~hat di-2-ethylhexyl phthalate is effective in hindering hemolysis (Blood, 646 1270~(1984)). In other words, when blood is preserved in a blood container made of 15 the conventional flexible vinyl chloride resin which incorporates therein di-ethylhexyl phthalate as a plasticizer, the di-2-ethylhexyl phthalate dissolving into the preserved blood serves to hinder the hemolysis of erythrocytes.
As a measure against such an adverse phenomenon as described above, a contradictory method which comprises preserving blood in a container made of a material incapable of exuding an incorporated plasticizer tor a material not containing any plasticier~ and , prior to actual use of the 25 preserved blood, adding di-2-ethylhexyl phthalate to the blood thereby preventing the blood from hemolysis has been proposed (U.S. Patent No. 6,326,025). The idea of using di-2-ethylhe~yl phthalate as a hemolysis depressant, however, is nothing desirable from the standpoint of 30 physiological safety.
Further, the blood bag containing the blood e~tracted from a donor is generally forwarded to a hospital, as accompanied by a blood collection tube containing the same blood as ~hat in the blood bag so that the blood in ~he 35 tube may be used as a sample for testing the blood for adaptability to the patient's bloo~ in advance of the transfusion. As the time of storage of this blood bag ,. . .

increases to approach the 21st day of extraction ~ixed officially (in Japan) for the availability of concentrated red cells, the blood contained in the blood collection tube yields to hemolysis in much the same way as described above.
5 The hemoglobin liberated in consequence of the hemolysis brings about adverse effects on the results of various measurements performed for clinical test and inter~eres with the test. This fact has been posed as a problem.
As clearly gathered from the observations 10 illustrated above, the desirability of developing a material capable of producing a notable protective action for erythrocytes has found enthusiastic recognition in various fields including the medical field.
An object of this invention, therefore, is to 15 provide novel hemol~sis depressant and plasticizer. Another object of this invention ls to provide a resin composition for medical appliances, medical implements, and blood preserving liquids which make use of the novel hemolysis depressant.
This invention also aims to provide a hemolysis depressant capable of providing highly effective control of the phenomenon of hemolysis which occurs in blood during the course of preservation. Further, this invention aims to provide a hemolysis depressant which excels also in 25 physiological safety. This invention also aims to provide a hemolysis depressant which can be incorpora~ed in a resin composition or directly added to a liquid containing erythrocytes.
Further, this invention aims to provide a medical 30 resin composition capable of very effectively controlling the phenomenon of hemolysis in a erythrocyte-containing liquid held in contact with the resin composition. This invention also aims to provide a flexible type medical resin composition which contains no plasticizer or contains 35 substantially nonextractable plasticizer, excels in physiological sa~ety and produces a highly desirable effects in the inhibition o~ hemolysis, and suits best as a material for medical implements such as the blood bag. This ; - 4 -~3~ 8 invention further aims to provide a rigid type medical resin composition which produces a highly desirable effect in the inhibition of hemolysis and suits most as a material for such medical implements as the blood collection tube.
In addition, this invention aims to provide a medical implement capable of preserving blood components represented by the erythrocyte in a erythrocyte-containing liquid intact for a long time. This invention further aims to provide a medical implement abounding with physiological lO safety.
This invention further aims to provide a blood preserving liquid which possesses a highly desirable ability to preserve erythrocytes and abounds with safety. This invention also aims to provide a blood preserving liquid 15 which permits protracted preservation of blood. Further, this invention aims to provide a blood preserving liquid which can be used as a liquid preserver in the anticoagulant and the additive system.
[Disclosure of the Invention]
The various objects described above are accomplished by hemolysis depressant comprising a triglyceride compound represented by the general formula (I):
o CH - O - C - R

¦ O (I) C~2 ~ - C - R
o 30 (wherein Rl, R2, and R3 independently stand for an aliphatic hydrscarbon group of l to 20 carbon atoms and the total number of the carbon atoms of Rl, R2, and R3 is in the range of lO to 36).

~3C~6~8 This invention also discloses a hemolysis depressant wherein R , R , and R3 in the general formula (I) independently stand for an aliphatic hydrocarbon group of 1 to 10 carbon atoms and the total number of the carbon atoms 5 of Rl, R , and R3 is in the range of 10 to 30. This invention further discloses a hemolysis depressant, wherein at least one of the substituents, Rl, R2, and ~3, in the general formula (I) possesses a branched structure. This invention also discloses a hemolysis depressant wherein the 10 triglyceride compound represented by the general formula (I) is glyceryl tri-2~ethylhexanoate. This invention further discloses a hemolysis depressant which is incorporated in a synthetic resin composition. Further, this invention discloses a hemolysis depressant which is directly added to 15 an erythrocyte-containing solution. This invention also discloses a hemolysis depressant agent which is added in the form of emulsion to the erythrocyte-containing solution.
The various objects described above are further accomplished by a flexible vinyl chloride type resin 20 composition for use in medical appliances, which is characterized by comprising a vinyl chloride type resin, a ~ plasticizer, and a hemolysis depressant comprising a `~ triglyceride compound represented by the general formula O
Il 1 :
CH - o - C - R
CH - O - C - R
¦ O (I) It ~
.~

3~6~8 (wherein Rl, R2, and R3 independently stand for an aliphatic hydrocarbon group of 1 to 20 carbon atoms and the total number of the carbon atoms of ~1, R2, and R3 is in the range of 10 to 36).
This invention further discloses a flexible vinyl chloride type resin composition for medical appliances, which incorporates therein 10 to 45% by weight of a plasticizer and 1 to 20% by weight of triglyceride compound represented by the general formula (I). This invention also 10 discloses a flexible vinyl chloride type resin composition for medical appliances, which incorporates therein 3 to 10%
by weight of a triglyceride compound represented by the general formula (I). Further, this invention discloses a flexible vinyl chloride type resin composition for medical 15 appliances, wherein the plasticizer incorporated therein possesses a low exuding property. This invention also discloses a flexible vinyl chloride kype resin composition for medical appliances, wherein the plasticizer incorporated threrein is selected from the group consisting of trialkyl 20 trimellitates, di-normal alkyl phthalates, and tetraalkyl pyromellitates. This invention further discloses a flexible vinyl chloride type resin composition for medical appliances, wherein the plasticizer incorporated therein is di-normal decyl phthalate. This invention also discloses a 25 flexible vinyl chloride resin type composition for medical appliances, wherein the plasticizer incorporated therein is trioctyl trimellitate~
The various objects described above are furth2r accomplished by a flexible resin composition for medical 30 appIiances, which is characterized by incorporating in a flexible resin composition containing no plasticizer a hemolysis depressant comprislng a tri~lyceride compound represented by the general formula (I~:
::

.~ ~

~3~ 8 Il 1 IH2 ~ - C - R
CH - O - C - R

O (I) Il (Wherein Rl, R2, and R3 independently stand for an aliphatic hydrocarbon group of l to 20 carbon atmos and the total number of the carbon atoms of Rl, R2, and R3 is in the range lO of lO_to 36).
This invention further discloses a flexible resin composition for medical appliances, wherein the triglyceride compound represented by the general formula (I) is incorporated in a proportion falling in the range of 5 to 15 35~ by weight. This invention also discloses a flexible resin composition for medical appliances, wherein the flexible resin is an internally plasticized vinyl chloride type resin, a polyester, a polyurethane, an ethylene-vinyl acetate copolymer, or a polymer blend of polyvinyl chloride 20 with an ethylene-vinyl acetate copolymer or polyvinyl chloride with a polyurethane- or ethylene-type polymer.
This invention further discloses a flexible resin composition for medical appliances, wherein the internally plasticized vinyl chloride type resin incorporated therein 25 is an urethane-vinyl chloride copolymer, a vinyl acetate-vinyl chloride copolymer.
The various objects described above are further accomplished by a rigid resin composition for medical appliances, which is characterized by having incorporated in 30 a rigid resin composition a hemolysis depressant comprising a triglyceride compound represented by the general formula - (I):
.

.. . . . .

~ ~\
~3~ 38 CH - O - C - R
I O (I) (wherein Rl, R2, and R3 independently stand for an aliphatic hydrocarbon group of 1 to 20 carbon atoms and the total number of the carbon atoms of Rl, R~, and R3 is in the range 10 of 10 to 36).
This invention further discloses a rigid resin composition for medical appliances, wherein the triglyceride compound represented by the general formula (I) is incorporated therein in a proportion falling in the range of 15 0.5 to 5% by weight. This invention also discloses a rigid resin composition for medical appliances, wherein the rigid resin incorporated therein is selected from the group consisting of acryl type resins, styrene type resins, olefin type resins, thermoplastic polyester type resins, and 20 polycarbonates. Further, this invention discloses a rigid resin composition for medical appliances, wherein the acrylic type resin is a homopolymer or copolymer of methyl methacrylate, methyl acrylate, ethyl methacrylate, ethyl acrylate, acrylonitrile, or methacrylonitrile. This 25 invention also discloses a rigid resin composition for medical appliances, wherein the styrene type resin is polystyrene, an acrylonitrilre-syrene copolymer, or an acrylonitrile-butadiene styrene copolymer. This invention further discloses a rigid resin~ composition for medical ; 30 appliances, wherein the olefin~type resin is polyethylene, polypropylene, or an ethylene-propylene copolymer. This invention also discloses a rlqid resin composition for : :

~ - g _ medical appliances, wherein the thermoplastic polyester resin is polyethylene terephthalate or polybutylene terephthalate.
The various objects described above are also 5 accomplihsed by a medical implement, which is characterized by being substantially formed with a flexible vinyl chloride type resin composition comprising a vinyl chloride type resin, a plasticizerr and a hemolysis depressant comprising a triglyceride compound represented by the general formula 10 (I):
o Il 1 ~ C~2 ~ - C - R
CH - O - C - R

I O (I) 15 C~2 ~ - C - R

(wherein Rl, R2, and R3 independently stand for an aliphatic hydrocarbon group of l to 20 carbon atoms and the total number of the carbon atoms of Rl, R2, and R3 is in the range 20 of 10 to 36).
This invention further discloses a medical implement which is container for storing blood. This invention also discloses a medical implement which is capable of withstanding sterilization in an autoclave.
The various objects described above are further accomplished by a medical implement, which is characterized by being substantially formed with a flexible resin composition having incorporated in a flexible resin ; composition containing no plasticizer a hemolysis depressant ~: 30 comprising a triglyceride compound represented by the general formula (I):

06~g~

CH2 ~ O - C - R
CH O - C - R

I O (I) (wherein Rl, R2, and R3 independently stand for an aliphatic hydrocarbon group of 1 to 20 carbon atoms and the total number of the carbon atoms of Rl, R2, and R3 is in the range 10 of lO to 36).
This invention further discloses a medical implement which is a blood collection tube. This invention also discloses a medical implement which is capable of withstanding sterilization in an autoclave.
15The various objects described above are accomplished also by a medical implement, which is characterized by being substantially formed with a rigid resin composition incorporating in a riyid resin composition ~ a hemolysis depressant comprising a triglyceride compound ; 20 represented by the general formula (I):

O ...
Il 1 fH2 - o - c - R
CH - O - C - R

O ~I) ~ ~5 ~ ~H2 - o - C - R ~ ~
O
.-,:
:

"' ~

' .

3~

(wherein Rl~ R2~ and R3 independently stand for an aliphatic hydrocarbon group of l to 20 carbon a~oms and the total number of the carbon atoms of Rl, R2, and R3 is in the range of lO to 36).
This invention further discloses a medical implement which is a blood collection tube.
The various objects described above are also accompllshed by a blood preserving liquid composition, which is characterized by incorporating therein a hemolysis lO depressant comprising a triglyceride compound represented by the general formula (I):

CH - O - C - R

CH - O - C - R
15 1 3 (I) o (wherein Rl, R2, and R3 independently stand for an aliphatic ; hydrocarbon group of l to 20 carbon atoms and the total 20 number of the carbon atoms of Rl, R2, and R3 is in the range of lO to 36) and other blood preservative component.
This invention further discloses a blood preserving liquid composition, wherein the blood preserving liquid is an anticoagulant preserving liquid. This invention 25 also discloses a blood preserbing liquid composition, wherein the other blood preservative component is at least one compound selected from the group consisting of sodium citrate, citric acid, grape sugar, monosodium phosphate, adenine, sodium chloride, mannitol, maltosP, multitol, 30 sorbitol, sucrose, and lactose. This invention further discloses a blood preserving liquid composition, wherein the triglyceride compound represented by the general formula (I) is incorporated in a substratal liquid selected from the ~L3~6~8 group consisting of ACD solution, CPD, solution, CPDA-l solution, CPDA 2 solution, SAG solution, and an SAG solution incorporating therein mannitol, maltose, multitol, sorbitol, sucrose or lactose. This invention also discloses a blood 5 preserving liquid composition, wherein the triglycerid~
compound represented by the general formula (I) is incorporated therein in a final concentration falling in the range of lO ~M to lO mM. Further, this invention discloses a blood preserving liquid composition, wherein the lO triglyceride compound represented by the general formula (I) is incorporated therein in a final concentration falling in the range of 30~M to 5mM.
[Brief Descritpion of the Drawing]
Fig. l is a front view illustrating a blood bag as 15 a typical medical implement formed substantially of a flexible resin composition for medical appliances incorporating therein a hemolysis depressant as one embodiment of the present invention. Fig. 2 is a cross section illustrating a blood collection tube as a typical 20 implement formed substantially of a rigid resin composition for medical appliances incorporating therein a hemolysis depressant as another embodiment of the present invention.
Flgs. 3 and 4 are cross sections illustrating the conditions in which the embodiments mentioned above are put to use.
25 CDescription of Preferred Embodiments of the Invention]
The hemolysis depressant of the present invention comprises a triglyceride compound which is represented by the general formula (I):

Il 1 0 (I) ~H - 0 - C - R

2 ll O

~.3~

(wherein Rl, ~2, and R3 independently stand for an aliphatic hydrocarbon group of 1 to 20 carbon atoms and the total number of the carbon atoms of Rl, R2, and P3 is in the range of 10 to 36).
Glycerine esters of medium chain-length fatty acids like triglyceride compounds represented by the general formula (I) are compounds of such great safety as have been heretofore used as oily agents for cosmetic articles and medicines. As concerns the toxicity of these glycerine 10 esters of medium chain-length fatty acids as used in an independent from, the LD50 (lethal dose 50) of glycerine tricaprylate, for example administered in~ravenously to mice is 3,700 mg/kg [Acta Physiol. Scand., 40, 338 (1987)], whereas the LD50 of di-2~ethylhexyl phthalate similarly 15 administered is 1,600 mg/kg ~National Technical Information Service PB 250,102]. In the reproduction test using rats, the TDLo (toxic dose) of glyceryl tricaprylate administered orally is 250 g/kg [Studies in Medical Products, 4, 180 (1973)]r whereas the TDLo of di-2-ethylhexyl phthalate is 20 repGrted to be 7,140 mg/kg ~Toxicol. Appl. Pham.,36,253 (1973)]. From these data, it is clear that the triglyceride compounds represented by the general formula (I) are safe substances because of low toxicity. It is surprising to note that the triglyceride compounds represented by the 25 general formula (I) are capab]e of exhibiting an antihemolytic activity on erythrocytes similarly to di-2-ethylhe~yl phthalate and, unlike di-2-ethy]hexyl phthalate, are not recognized to manifest any activity in curbing the phenomenon of aggregation of blood platelets.
Furhter, the triglyceride compounds represented by the general formula (I) are invariably capable of being dispersed in erythrocyte-containing liquids and are capable of being uniformly dispersed therein particularly when they are in the form of emulsions. Thus, they can be added 35 directly to such erythrocyte-containing liquids. Since these compounds possess thorough compatibility with various synthetic resins represented by vinyl chloride type resins, they are enabled to function as a hemolysis depressant ~7hen they are incorporated in synthetic resin compositions. For example, when a synthetic resin composition incorporating therein a trlglyceride compounds represented by general 5 formula (I) is exposed to contact with an erythrocyte-containing liquid, the compounds exude from the xesin composition and pass into the erythrocyte-containing liquid and, therefore, bring about the same effect as when they are directly added to the erythrocyte-containing 10 liquid.
Further, in the embodiment which resides in incorporating the triglyceride compounds represented by general formula (I) in a flexible vinyl chloride type resin composition, the effect to be brought about by this 15 embodiment can be further enhanced by additionally incorporating therein a plasticizer other than di-2-ethylhexyl phthalate, particularly a plasticizer of the foregoing description which possesses high safety and a low exuding property. To be more specific, when the 20 aforementioned flexible vinyl chloride type resin composition is exposed to contact with blood, the hemolysis of erythrocytes is prevented by the action of triglyceride compounds represented by general formula (I) exuding from the resin composition and passing into the blood and, in the 25 meantime, the resin composition does not liberate through exudation any substance which inhibits platelets aggregation similarly to di-2-ethylhexyl phthalate. This resin composition, therefore, excels in physiological safety and in the ability to protect erythrocytes. The same thing 30 applies to the embodiment which resides in incorporating the triqlyceride compound represented by general formula (I) in a flexible resin composition containing no plasticizer.
(This is because the problem essentially due to the exudation of a plasticizer cannot arise in the present 35 embodiment.) For this reason, the flexible vinyl chloride type resin composition for medical use and the flexible resin composition for medical use contemplated by the ~ 3~ 38 present invention are suitable as materials for medical implements. Further, the shaped articles ~ormed by using these materials, owing to the excellence thereof in safety, fabricability, flexibility, transparency, and thermal 5 resistance, are enabled to manifest the effect thereof to the fullest extent when the shaped articles are used as medical implements. The effect is prominent particularly when the shaped articles are medical implements such as the blood bag destined to contact body fluids such as blood.
Similarly, in the embodiment which resides in incorporating the triglyceride compound represented by the general formula tI) in a rigid resin composition, triglyceride compound represented by the general formula (I) functions to prevent the hemolysis of erythrocytes and 15 offers highly satisfactory protection ~or erythrocytes. The resin composition, therefore, is suitable as a material for medical implements. The shaped articles formed by using this material, owing to their excellence in safety, fabricability, transparancy, and thermal resistance, are 20 enabled to manifest the effect to the fullest extent when the shaped articles are used as medical implements. The effect is prominent particularly when the shaped articles are medical implements such as the blood collection tubes which are destined to contact body fluids such as blood.
The aforementioned triglyceride compound represented by the general formula (I) is capable of being dispersed in the form of emulsion or clathrate compound in an aqueous solution. Further, it exhibits the aforementioned ability to prevent the hemolysis of 30 erythrocytes even when it is in the form mentioned above.
When it is incorporated in a blood preserving liquid with the aid of a suitable surf actant which is incapable of exerting any adverse effect upon blood components or an ~ -cyclodextrin, the produced blood preserving liquid 35 excels in the ability to protect erythrocytes as well as in physiological safety. When the blood preserving liquid of this invention is added to an erythrocyte-containing liquid 9~

such as whole blood or concentrated red cells, for example, most of the erythrocytes can be retained for a long time in the same state as immediately after blood extraction. Thus, the problem arising in the transfusion of preserved blood 5 can be eliminated.
Now, the present invention will be described more specifically below with reference to working examples. To facilitate comprehension of this invention, the paragraphs titled "Hemolysis Depressant," "Resin Composition for Medical 10 Appliances Incorporating the Hemolysis Depressant," "Medical Implement Incorporating the Hemolysis Depressnat," "Blood Preserving Liquid Incorporating the Hemolysis Depressant,"
and "Example, " will be covered in the following part of the text.
Hemol~s. ~
The Hemolysis Depressant of the present invention comprises a triglyceride compound represented by the general formula (I):

O (I) CH2 - O ~ C - R

25 (wherein Rl, R2, and R3 independently stand for an aliphatic hydrocarbon group of 1 to 20, more desirably 1 ro 14, and most desirably 6 to 10, carbon atoms and the total number of the carbon atoms of Rl, R2, and R3 is in the range of 10 to 36, more desirably 10 to 30, and most desirably 10 to 24).
In the general formula (I) representing the triglyceride compounds of this invention, the total number of the carbon atoms in Rl, R2, and R3 is limited to the range of 1 to 20 for the following reason. If the total number of the carbon atoms exceeds 20, the triglyceride compound assumes a solid state in the range of temperatures at which whole blood or an erythrocyte-containing solution such as a red cell concentrate is stored, and, therefore, is not smoothly 5 dispersed easily in the erythrocyte-containing solution and cannot be expected to manifest an antihemolytic action su~ficiently. When the triglyceride compound is used in the form incorporated in a varying synthetic resin composition, it has a possibility of losing compatibility with the resin 10 composition. This adverse effect is also produced when the total number of the carbon atoms in Rl, R2, and R3 exceeds 36. If the total number of the carbon atoms in R1, R2, and R is less than 10, the triglyceride compound has a possibility of inducing hemolysis. Then, in the general 15 formula (I) representing the triglyceride compounds of this invention, at least one of the substituents, Rl, R ,and R , is desired to possess a branched structure even from the standpoint o~ enhancing the antihemolytic effect of the triglyceride compound. For the triglyceride compound 20 represented by the general formula ~I), all the aliphatic hydrocarbon groups, Rl , R2, and R3, are not required to be indentical with one another. They may be a combination of aliphatic hydrocarbn groups differin~ in chain length from one another. Further, the aliphatic hydrocarbon groups, Rl, 25 R2, and R3, may be saturated aliphatic hydrocarbon groups or unsaturated aliphatic hydrocarbon groups, To concrete, the triglyceride compound represented by the general formula (I0 are glyceryl "~ trivalerate (trivalerin), glyceryl triisovalerate, glyceryl tricaproate, glyceryl tricaprylate, 30 glyceryl tri-2-ethylhexanoate, glyceryl trilaurate (trilaurin), butyryl divaleryl glycerin, butyryl diisovaleryl glycerin, valeryl dihexanoyl glycerin, hexanoyl dioctanoyl glycerin, hexanoyl bis-(2-ethylhexanoyl)glycerin ! octanoyl bis (2-ethylhexanoyl)glycerin, dioctanoyl 2-ethylhexanoyl 35 glycerin, 2-ethylhexanoyl didecanoyl glycerin, bis(2-ethylhexanoyl) decanoyl glycerin, decanoyl dilauroyl glycerinr and dilauroyl millistoyl glycerin Among other triglyceride compounds enumerated above, glyceryl tri-2-ethylhexanoate and octanoyl bis-(2-ethylhexanoyl)glycerin prove to be particularly desirable. The best all the triglyceride compounds is 5 glyceryl tri-2-ethylhexanoate.
The hemolysis depressant of the present invention comprising triglyceride compound represented by the general formula (I) can be used as directly added to the erythrocyte-containing liquid such as whole blood or 10 concentrated red cells (inclusive of the case wherein the addition is made to an erythrocyte-containing liquid contained in advance in a blood container such as the blood bag in combination with an anticoagulant preservative liquid such as ACD (acid-citrate dextrose) or CPD (citrate 15 phosphate dextrose) or it can be used as incorporated in a synthetic resin composition for medical use to form blood containers such as the blood bag and the blood collection tube and medical implements such as the catheter, transfusion set, and blood circuits which are destined to 20 contact an erythrocyte-containing liquid.
In the direct addition of the hemolysis depressant of this invention comprising the triglyceride compound represented by the general formula (I) to the erythrocyte-containing liquid, while the compounds to be ~5 described in detail later on may be added in their unmodified form, they are added more desirably in the form of emulsion or clathrate compound so as to be uniformly dispersed and mixed in the erythrocyte-containing liquid.
The preparation of the emulsion of the triglyceride compound 30 represented by the general formula (I) can be attained by dispersing the triglyceride compound in a suitable aqueous medium such as a saline water or buffer or in an anticoagulant preservative such as ACD liquld or CPD liquid with the aid of a surfactant~or curing castor oil which has 35 no adverse effect upon blood components as illustrated below. The preparation of the clathrate compound of the trig1yceride compound represented by the general ~ormula (I) 6~8 is attained by the use of ~ -cyclodextrin, for example.
The amount of the homolysis depressant to be added directly to the erythrocyte-containing liquid, though variable with the kind of the erythrocyte-containing liquid and the kind 5 of the triglyceride compound repr~sented by the general formula (I), falls in the range of 10 ~M to 10 mM, preferably 30 ~M to 5 mM, as final concentration based on the amount of whole blood.
In the incorporation of the hemolysis depressant 10 of the present invention comprising the triglyceride compound represented by the general formula (I) in a synthetic resin composition for medical use, since the triglycerlde compound represented by the general formula (I) can be uniformly dispersed and mixed in various resin 15 compositions such as, for example, vinyl chloride type resins, olefin type resins, styrene type resinsr (meth)acryl type resins, and carbonate type resins, it suffices to add the triglyceride compound to the synthetic resin composition while the resin composition is being blended. The synthetic 20 resin composition which has incorporated the triglyceride compound as descrihed above can be formed in a given shape by any of the conventional molding methods such as, for example, calender molding, extrusion molding, injection molding, and plastisol molding. The adhesion of the resin 25 composition to a surface can be attained by any of the conventional methods such as, for example, high-frequency welding, thermal welding and supersonic welding. When the triglyceride compound represented by the general formula tI) is incorporated in one of such various resin composition, 30 the triglyceride compound which exudes from the synthetic resin composition and comes into contact with the erythrocyte-containing liquid to manifest the action to protect erythrocytes. The amount of the hemolysis depressant comprising the triglyceride compound represented 35 by the general formula (I) to be incorporated in the synthetic resin composition, though variable with the kind of the synthetic resin composition used to incorporate the - 20 ~

i6~

hemolysis depressant and the kind of the triglyceride compound, is generally in the range of 1 to 20% by weight, preferably 3 to 10% by weight based on the amount of the resin composition. So long as the amount of the 5 triglyceride compound so incorporated falls in the aforementioned rangP, it brings about the action to protect erythrocytes effectively when the erythrocyte-containing liquid is brought into contact with the medical implement to be formed with the aforementioned synthetic resin 10 composition. The hemolysis depressant so incorporated does not substantially impair the physical properties of the synthetic re6in composition.
Resin Composition for Medical Appliances Incorporating the ... . _ Hemolysis depressant The resin composition contemplated for medical use by the present invention is obtained by incorporating in a varying synthetic resin composition the hemolysis depressant comprising the triglyceride compound represented by the general formula (I) discribed above.
As described above, the triglyceride compound represented by the general formula (I) possess compatibility with various synthetic resins and can be uniformly dispersed in various flexible and rigid synthetic resin compositions.
~ triglyceride compound represented by the general formula 25 (I) incorporated in a resin composition for medical use is in such quality that, when the synthetic resin composition comes into contact with an erythrocyte-containing liquid, the compound exudes from the resin composition and passes into the liquid and acts to protect the erythrocytes. The 30 resin composition for medical use according to this in~ention, therefore, is most suitable as a material for medical implements such as the blood bag and the blood collection tube which are destined to contact blood. The resin composition for medical use may be prepared as 35 flexible products or rigid products, depending on purposes for which the products are adopted. In various resin composition, flexible vinyl chloride type resin compositions ~ 21 -may be cited as most desirable. When the triglyceride compound represented by general ~ormula (I) is incorporatd in a flexible vinyl chloride type resin composition, the inhibition of hemolysis in a erythrocyte-containing liquid 5 is effected by the compound which exudes ~rom the resin composition and passes into the liquid. Thus, the resin composition is allowed to use a plasticizer other than di-2-ethylhexyl phthalate, particularly a plasticizer of the description which exhibits high physiological safety and a lO low exuding property.
Flexible _vinyl chloride type resin composition for medical use The flexible vinyl chloride type resin composition for medical use according to this invention is characterized 15 by a composition which comprises a vinyl chloride type resin, a plasticizer, and a hemolysis depressant comprising the triglyceride compound represented by the general formula (I).
As the vinyl chloride resin to be used in the 20 flexible vinyl chloride type resin composition contemplated by this inveniton for medical use, there can be used vinyl chloride homopolymer, polyvinylidene chloride, or a varying copolymer containin~ not less than ~0% by weight, more desirably not less than 65~ by wight, and most desirably not 25 less than 75% by weight, of vinyl chloride in addition to the balance of other copolymerizable monomer. The average polymerization degree of the vinyl chloride resin is in the range o 400 to 3,000, more desirably 600 to 2,700, and most desirably 800 to 1,700. Examples of the comonomer for vinyl 30 chloride in the copolymer include vinylidene chloride, ethylene, propylene, vinyl acetate, vinyl bromide, vinyl fluoride, styrene, vinyl toluene, vinyl pyridine, acrylic acid, alkyl acrylate (such as methyl acrylate, ethyl acrylate, isopropyl acrylate, n-butyl acrylate, and 35 2-ethylhexyl acrylate), methacrylic acid, alkyl methacrylates (such as methyl methacrylate, ethyl methacrylate, and 2-ethylhexyl methacrylate), acrylonitrile, ~3(~ 8 and methacrylonitrile. Optionally the vinyl chloride may incorporate therein styrene-acrylonitrile copolymer or styrene-methacrylonitrile copolymer.
The plasticizer to be used in the flexible vinyl 5 chloride type resin composition contemplated for medical use by the present invention is desired to possess high physiological safety and preferably exhibit a low exuding property. As examples of the plasticizer meeting this description, there can be cited dinormal alkyl phthalates 10 such as dinormal octyl phthalate, dinormal nonyl phthalate, dinormal decyl phthalate, dinormal undecyl phthalate, and dilauryl phthalate, trialkyl trimellitates such as tri 2-ethylhexyl trimellitate~ and tri-normal octyl trimetllitate, and tetraalkyl pyromellitates such as 15 tetra-2-ethylhexyl pyromellitate. Among other plasticizers enumerated above, di~normal decyl phthalate and trioctyl trimellitate prove to be particularly desirable. In the flexible vinyl chloride type resin composition for medical use according to the present invention, the plasticizer of 20 the foregoing description is incorpora-ted in an amount generally in the range of 10 to 45% by weight though variable with the kind of the plasticizer to be used. This range is important because the produced resin composition lacks flexibility if the amount of the plasticizer 25 incorporated is less than 10% by weight or because the composition is apt to induce the phenomenon of bleeding if the amount of the plasticizer exceed 45% by weight.
Then, in the flexible vinyl chloride type resin composition for medical appliances according with the 30 present invention, a hemolysis depressant comprising a triglycexide compound represented by the general formula (I) is incorporated. The triglyceride compound represented by the general formula (I) is thus incorporated for the purpose of pxeventing hemolysis. Since this triglyceride compound 35 exhibits a plasticizing property for vinyl chloride type resins as described fully later on, it fulfils an additional funct.ion function in enhancing the plasticization of a vinyl chloride type resin with a plasticizer.
In the flexible vinyl chloride type resin 5 composition for medical appliances according with the present invention, the triglyceride compound represented by the general formula (I) is i.ncorporated in a proportion falling in the range of 1 to 20~ by weight, preferably 3 to 10~ by weight. The proportion is limited to the range 10 mentioned above for the following reason. If the amount of the triglyceride compound represented by the general formula ~I) so incorporated in less than 1~ by weight, the activity manifested by the added triglyceride compound in curbing the hemolysis of erythrocytes is not sufficient. Conversely, if 15 this amount exceeds 20% by weight, the added triglyceride compound has a possibility of degrading the physical properties of the flexible vinyl chloride type resin composition.
Further, the fl.exible vinyl chloride type resin 20 composition for medical use according to the present i~vention, when necessary, may incorporate therein an epoxidized vegetabl.e oil such as epoxidized soy bean oil or epox.idized linseed oil intended as a combination stabilizer and auxiliary plasticizer; a metallic soap of calcium or 25 zinc salt of stearic acid, lauric acid, ricinoleic acid, or naphthenic acid intended as a stabilizer; a lubricant; an antioxidant; etc. The amount of the epoxidized vegetable oil to be additionally incorporated as a combination stabilizer and auxiliary plasticizer is in the range of 3 to 30 10% by weight, preferably 6 to 3% by weight and the amount of the metallic soap to be incorporated as a stabilizer is in the range of 0.05 to 3% by weight, preferably 0.1 to 1.5 by weight.
When the vinyl chloride typ~ resin composition for 35 medical use according to the present invention is to be formed in a desired shape, this formation can be accomplished by any of the conventional methods such as~ for -~ ~3~

example, calender molding, extrusion molding, and plastisol molding methods. When the resin composition is to be joined to a surface, the adhension can be effected by high frequency welding, thermal welding, or supersonic welding, 5 etc.
Flexible resin composition ~or medical use The homolysis depressant of the present invention can be incorporated as effectively in any flexible resin composition than the flexible vinyl chloride resin 10 composition as in the vinyl chloride resin composition, to give rise to a highly desirably flexible resin composition for medical use.
The flexible resin composition contemplated for medical use by the present invention, therefore, is 15 characterized by incorporating the hemolysis depressant comprising the triglyceride compound represented by general formula (I) described above into said flexible resin composition containing no plasticizer.
The flexible resin to be used in the manufactur~
20 of the 1exible resin composition for medical use is a flexible resin which exhibits sufficient plasticity, particularly flexibility, without being externally plasticized with a plasticizer (providing that the term "plasticizer" as used in the present specificaiton refers, ~5 unless otherwise defined particularly, to an external plasticizer in the narrow sense of the word). The flexible resin composition for medical use, therefore, contains no plasticizer. This means that this flexible resin composition for medical use is inherently incapable of 30 entailing as a problem the disadvantage that a plasticizer exudes from the resin composition and e~erts an adverse effect on blood components or on the vital system.
As examples of the flexible resin of the foregoing description, there can be cited internally plasticized vinyl 35 chloride type resins, polyethylene, thermoplastic polyester, polyurethane, ethylene-vinyl acetate copolymer, and polymer blends of polyvinyl chloride with polyurethane, ethylene ' 6~3 type polymers (such as, for example, a product marketed under trademar~ designation of "ELVALOY"), or caprolactone type polymers. Of course, these are not exclusive examples.
Examples of the internally plasticized vinyl chloride resin 5 lnclude urethane-vinyl chloride copolymer, vinyl acetate-vinyl chloride copolymer, and ethylene-vinyl acetate-vinyl chloride copolymer. In the internally plasticized vinyl chloride type resin of this nature, the gravimetric ratio of the vinyl chloride monomer component to 10 the monomer component bestowed with a plasticizing capacity and used for copolymerization falls in the range of about 7 : 3 to 3 : 7, preferably 6 : 4 to 4 : 6. The polyethylene for use in the copolymerization is desired to be a low-density polyethylene preferably possessing a melt index 15 in the range of about 0.1 to 5. The thermoplastic polyester for the copolymerization is typified by a polyethylene terephthalate film. Typical examples of the polyurethane include polyester type polyurethane and polyether type polyurethane elastomers. Preferably, the polyurethane is a 20 polyether type segmented polyurethane. In the ethylene-vinyl acetate copolymer, the gravimetric ratio of the ethylene monomer component to the vinyl acetate component is approximately in the range of 95 : 5 to 70 :
30, preferably 90 : 10 to 80 : 20. /-This invention does not discriminate the flexible resin composition for medical use particularly on account of the kind of flexible resin component. Among other various available flexible resin components, polyurethane and ethylene-vinyl acetate copolymer can be cited as 30 particularly desirable flexible resins components.
In the flexible resin composition of this invention for medical use, the aforementioned hemolysis depressant comprising the triglyceride compound represented by the general formula (I) is incorporated. The homolysis 35 depressant is incorporated in the flexible resin composition contemplated for medical use by this invention in a concentration in the ragne of 5 to 35% by weight, preferably ~3~66~38 10 to 25% by weight. This range is important because the produced composition manifests no sufficient action to inhibit hemolysis of erythrocytes if the concentration is less than 5% by weight or because the incorporated hemolysis S depressant possibly impair the physical properties of the flexible resin composition if the concentration exceeds 35%
by weight.
Optionally, the flexible resin composition of this invention for medical use may incorpoate therein such 10 additives as stabilizer, lubricant, and antioxidant.
When the flexible resin composition of this invention for medical use is to be formed in a given shape, this formation can be effected by any of the various conventional methods available for any flexible resin 15 composition, such as calender molding, extrusion molding, blow molding, and plastisol molidng. When the flexible resin composition is to be joined to a surface, the adhesion can be effected by high frequency welding, thermal welding, or supersonic welding, etc., depending on the kind of the 20 flexible resin.
Rigid resin composition for medical use The rigid resin composition of the present invention for medical use is characterized by incorporating the aforementioned hemolysis depressant comprising the 25 triglyceride compound represented by the general formula (I) into said rigid resin compositio~.
No particular limits are imposed on the rigid resin to be used in the rigid resin composition contemplated for medical use by this invention, except for the sole 30 requirement that this rigid resin should be physiologically safe and properly compatible with the triglyceride compound represented by the general formula (I). As examples of the rigid resin answering the description, there can be cited acrylic type resins, styrene type resins, olefinic type ; 35 resins, thermoplastic polyester type resins, and polycarbonate. The rigid resin described above is desired, without reference to the kind thereof, to possess a melt '' ' ~3~6~

flow index falling in the range of 0.5 to 30g/10 min., preferably falling in the range of 5 to 12 g/10 min.
Examples of the acrylic type resin include homopolymers and copolymers of alkyl (meth)acrylates such as methyl 5 methacrylate, methyl acrylate, ethyl methacrylate, and ethyl acrylate, acrylonitrile, and methacrylonitrile. Examples of the polystyrene type resin include polystyrene, acrylonitrile-styrene copolymer, and acrylonitrile-butadiene-styrene copolymer (ABS resin).
10 Examples of the ole~inic type resin include medium- to high-density polyethylenes, polypropylene, and copolymers by the combination of ethylene, propylene, and other ~ -olefins such as ethylene-propylene copolymer. Examples of the thermoplastic polyester type resin are polyethylene 15 terephthalate and polybutylene terephthalate. Examples of the polycarbonate include bisphenol-A type polycarbonate and polycarbonates possessing various carbonate ester type structures. Qf course, the rigid resin to be used in the rigid resin composition contemplated for medical use by this 20 invention is not limited to those enumerated above as examples. Polymer blends of various resins are also examples of the rigid resin usable herein.
In the rigid resin composition of the present invention for medical use, the aforementioned hemolysis 25 depressant comprising the triglyceride compound represented by the general formula (I) is i~ncorporated. In the rigid resin composition of this invention for medical use, the hemolysis depressant is incorporated in a concentration in the range of 0.5 to 5% by weight, preferably 2 to 3% by 30 weight. This range is important because the produced composition fails to manifest a sufficient action to inhibit hemolysis if the~concentration of the hemolysis depressant is less than 0.5~ by weight or because the incorporate~
hemolysis depressant possible impairs the physical 35~properties of the rigid resin composition if the concentration exceeds 5~ by weight.

.. . .

Optionall.y, the rigid resin composition of the present invention for medical use may incorporate therein additives such as stabilizer, lubricant, and antioxidant.
When the rigid resin composition of this invention 5 for medical use is to be formed in a given shape, this formation can be effected by any of the conventional methods availabl.e for any rigid resin composition such as, for example, injection molding and extrusion molding.
Medical Implement Incorporating the Hemolysis Depressant The medical implement of the present invention is formed substantially of the flexible vinyl chloride type resin composition for medical use, the flexible resin composition for medical use, or the rigid resin composition for medical use described above.
To be specific, the medical implement of the present invention is characterized by being made substantially of a flexible vinyl chloride tvpe resin composition comprising a vinyl chloride type resin, a plasticizer, and a hemolysis depressant, the triglyceride 20 compound represented by the general formula (I), mention above.
The medical implement is excellent in various properties such as safety, processibility, flexibility, and thermal resi.stance and particularly in the ability to 25 inhibit hem~lysis of erythrocytes.
The medical implement .which constitutes another aspect of this invention is characterized by being made substantially of a flexible resin composition incorporating a hemolysis depressant, triglyceride compound represented by 30 the general formula (I), mentioned above into said flexible resin composition containing no plasticizer. This medical : implement is excellent in ~arious properties such as safety, processibility, flexibility, and thermal resistance and particularly in the ability to inhibit hemolysis of 35 erythrocytes.

Concrete examples of the medical implement which is made of the flexible vinyl chloride type resin composition for medical use or the flexible resin composition for medical use according to the present 5 invention include blood containers such as blood bag, catheter, transfusion sets, and blood circuits which are destined to contact blood or other body fluids. Containers for packaging such medical implements as mentioned above and containers for prepared agents such as taklets are other 10 examples.
Now, the medical implement of the present invention as embodied in the form of a blood bag will be described below with reference to the accompanying drawing.
Fig. 1 illustrates the blood bag~ A blood collection bag 3 15 which is made of the aforementioned flexible vinyl chloride type resin composition or the aforementioned flexible resin composition and provided with a plurality of outlets fitted with peel tab and a connecting outlet 2 has the periphery 4 thereof heat sealed by high frequency heating or 20 some other suitable heating means. This blood collection bag 3 has connected thereto a blood collection tube 6 made of the aforementioned flexible vinyl chloride type resin composition or the aforementioned flexible resin composition and adapted to communicate with an inner space 5 of the 25 blood collection bag 3. A piercing needle 8 is fixed in a needle base 7 formed at the leading end of the blood collection tube 6. This piercing needle 8 is sheathed in a cap 9. To the connecting outlet 2 of the aforementioned blood collection bag 3 is joined a connection tube 17 30 through the medium of a connection needle 16 formed at the leading end thereof. A connection tube 13 provided with an outlet lO fitted with a peel tab, made of the aforementioned flexible vinyl chloride type resin composition or the aforementioned flexible resin composition, and adapted to 35 communicate with an inner space 12 of a first satellite bag 14 made of the aforementioned flexible ~inyl chloride type resin composition or the aforementioned flexible resin 3L3~698 composition and having the periphery thereof similarly heat sealed is caused to communicate with the connection tube 17 via a branched tube 15. Further, a connection tube 22 made of the aforementioned flexible vinyl chloride type resin 5 composition or the aforementioned flexible resin composition and adapted to communica,e with an inner space 20 of a second satellite bag 23 provided with an outlet 18 fitted with a peel tab, made of the aforementioned flexible vinyl chloride type resin composition or the aforementioned 10 flexible resin composition, and having the periphery ~hereof similarly heat sealed is caused to communicate with the connection tubes 17 and 13 via the branched tube 15.
This three component blood bag is capable of separating collected blood into components in a closed 15 system. From the piercing needle 8 plunged into the vein of a donor, a prescribed amount of blood is drawn into the blood collection bag 3 via the blood collection tube 6.
After the extraction of blood is completed, the blood collection bag 3 is subjected to centrifugal force to have 20 the blood separated into an upper layer of platelet rich plasma and a lower layer of hemocytes. Then, the platelet rich plasma of the upper layer is forced out of the blood collection bag 3 and tranferred via the connection tubes 17 and 13 to the first satellite bag 14. The first satellite 25 bag 14 now containing the platelet rich plasma is further subjected to centrifugal force so as to have the platelet rich plasma separated into an upper layer of platelet concentrate and a lower layer of pLatelet poor plasma. The platelet concentrate of the upper layer is forced out of the 30 first satellite bag _ and transferred via the connection tubes 13 and 22 into the second satellite bag 23. Even when the collected blood is exposed to contact with the blood bags and the tubes for a long time as by being centrifugally separated into components, distributed into pertinent blood 35 bags and then stored, the aforementioned flexible vinyl chloride type resin composition or the aforementioned flelxible resin composition of which the blood bags and the , .

tubes are made is excellent in the effect of protecting erythrocytes and incapable of interfering with the aggregating ability of platelets and, therefore, permits safe and efficient transfusion of components of blood.
This invention has been so far described as embodied in a blood bag. Other medical implements such as containers for body fluids, catheters, transfusion sets, and blood circuits, containers for packaging the aforementioned medical implements, and containers for prepared agents such 10 as tablets can be similarly advantageously made with the aforementioned flexible vinyl chloride type resin composition or the aforementioned flexible resin composition.
These medical implements by nature are subjected 15 to sterilization prior to use. This sterilization is effected with ethylene oxide or in an autoclave. The sterilization by use of an autoclave is adopted preferably.
In the autoclave, the medical implements is sterilized generally at 121C for abou~ 60 minutes. The medical 20 implements of the present invention, as described above, possesses ample thermal stability to endure the sterilizing conditions used in the autoclave.
; The medical implements which constitutes yet another aspect of this invention is characterized by being 25 made substantially of a rigid resin composition incorporating a hemolysis depressant, triglyceride compound represented by the general formula (I), mentioned above in said rigid resin composition. This medical implement is e~cellent in various physical properties such as 30 processibility and thermal resistance and particularly in the ability to inhibit hemolysis of erythrocyltes.
Particularly desirable examples of the medical implement of this invention which is made of the aorementioned rigid resin composition for medical use 35 defined above are blood collection tubes which are exposed, ; particularly for a long timel to contact with body fluids or solutions of body fluid components such as blood or ~ ~3~1~6~3 concentrated red cells. Other than these blood collection tubes, desirable examples of the medical implement include blood collection vials, test tubes, petri dishes, and housings for various artificial organs such as artificial 5 lungs and artificial kidneys and heat exchangers. Of course, these are not exclusive examples.
Now, the medical implements of the present invention as embodied in the form of a blood collection tube will be described below with reference to the accompanying 10 drawing. Fig. 2 illustrates a vacuum blood collection tube 31 which comprises a tubular member 32 closed at one end and opened at the other end thereof and made of the rigid resin composition for medical use according to the present invention and a pierceable stopper member 34 made of butyl 15 rubber and adapted to close airtighly an open end 33 of the aforementioned tubular member 32 so as to keep an inner space 35 in a vacuumized state. The vacuum blood collection tube 31 which is constructed as described above is put to use as follows. As illustrated in Fig. 3, the vacuum blood 20 collection tube 31 is inserted, with the aforementioned open end 33 in the lead, into a blood collection tube holder 38 opened at one end and closed at the other end thereof, made of the rigid resin composition for medical use according to the present invention, and provided with a blood collection 25 needle 37 helically fitted into a threaded hole 36 formed in a closed end 40. The blood collection needle 37 is enclosed with a luer elastic sheath member 39 made of rubber and formed of a blood vessel piercing part 37a and a stopper piercing part 37b. When the blood ~essel piercing part 37a 30 of the blood collection needle 37 is forcibly inserted into the closed end 40 of the blood collection tube holder 38, the stopper piercing part 37b of the blood collection needle 37 pierces the elastic sheath member 39 and the stopper member 34 and reaches the inner space 35 of the blood 35 colloection tube 31 to establish communication between the blood vessel and the aforementioned inner space 35, with the result that the blood inside the blood vessel, owing to the ~ .

negative pressure in the inner space 35, is caused to flow into the inner space of the blood collection tube 31 in a total amount corresponding to the prevailing degree o~
vacuum. The extraction of the blood is terminated by 5 removing the blood vessel piercing part 37b o~ the blood collection needle 37. Tne blood thus collected is preserved inside the blood collection tube 31 until it is subjected to test. Since the blood collection tube 31 is made of the rigid resin composition for medical use according to this 10 invention as described above, the hemolysis depressant which exudes from the composition and passes into the blood acts to inhibit hemolysis of erythrocytes. Even when the preservation of the blood protracted much in duration, therefore, various measurements made for clinical test are 15 not adversely affected by free homoglobin. Thus, the measurements are allowed to produce accurate results.
This invention has been so far described as embodied in the form of a blood collection tube. Other medical implements such as blood collection vials, test 20 tuebes, petri dishes, and housings for various artificial organs such as artificial lungs and kidneys and heat exchangers can be made similarly advantageously with the aforementioned rigid resin composition.
Blood Preserving Liquid The blood preserving liquid of the present invention is characterized by having incorporated therein a hemolysis depressant comprising the triglyceride compound represented by the general formula (I).
The triglyceride compound represented by he 30 general formula (I) is invariably capable of being dispersed in an aqueous solution by the use of a suitable surfactant or ~ -cyclodestrin which exerts no adverse effect on blood ~omponents. Even when it is so dispersed, it still retains the aforementioned ability to inhibit hemolysis of ; 35 erythrocytes. When a blood preserving liquid incorporates such a compound therein, it is enabled to acquire a notable -ability to protect erythrocytes while retaining ~highly

- 3~ -~6~

desirable physiological safety. By the addition of the blood preserving liquid to an erythrocyte-containing liquid such as whole blood or concen~rated red cells 9 the greater part of the erythrocytes are allowed to retain for a long 5 time the same state as immediately after extraction of b].ood. thus, the problem heretofor encountered in the trasfusion of preserved blood can be eliminated.
Uniform dispersion oE the triglyceride compound represented by the general formula (I) in the blood lO preserving liquid of the present invention can be advantageously accomplished by preparatorily preparing the compound in the form of an emulsion by the use of a surfactant incapable of exert.ing any ad~erse effect on blood components or a curing castor oil or in the form of a 15 clathrate compound by the use of ~ -cyclodextrin, for example. As concrete examples of the surfactant~ there can be cited polyoxyethylene sorbitan monoesters (represented by Tween*series) such as polyoxyethylene sorbitan monolaurate (Tween 20), polyoxyethylene sorbitan monopalmitate (Tween 20 40), polyoxyethylene sorbitan monostearate (Tween 60), and polyoxyethylene sorbitan monooleate (Tween* 80), polyoxyethylene polyoxypropylene block copolymers (represented by products of BASF marketed under trademark designation of "Pluradot HA-430"), and sorbitan monoacyl 25 esters ~represented by Span* series) such as sorbitan monoacyl laurate (Span* 20), sorbitan monoacyl palmitate (Span*~O),sorbitan monoacyl stearate (Span*60), and soxbitan monoacyl oleate (Span*80). Of course, the amount of the surfactant or ~ -cyclodextrin to be added for this purpose 30 is desired to be on the minimum level tolerable from the standpoint of physiological safety~ The triglyceride compound, even when it is added in the form of an emulsion or a clathrate compound~ possesses the ability to protect erythrocytes.
The hemolysis depressant comprising the triglyceride compound represented by the general formula tI) behaves in such a manner, though depending on the kind of : * trade-mark ~' ", , 9~
the hemolysis depressant used, in the blood preserving liquid of the present invention that is produces the ability to protect erythrocytes conspicuously when it is incorporated in the preserved blood in a final concentration 5 in the range of lOO~M to lOmM, preferably 30~M to 5mM.
The other components to be contained in the blood presexving liquid of the present invention include the same components as those contained in the conventional blood preserving liquid such as the anticoagulant preservative 10 which is added to whole blood collected or the conventional blood cell preserving liquid intended for addition to concentrated red cells in the additive system. Concrete examples of these components are sodium citrate, citric acid, glucose, monosodium phosphate, adenine, sodium 15 chloride, mannitol, maltose, sorbitol, multitol, sucrose, and lactose. To be specific, the blood preserving liquid o~
the present inveniton is desried to be prepared by using as a basic liquid an anticoagulant preservative liquid such as, ~or example, ACD solution (acid citrate dextrose 20 anticoagulant solution), CPD solution (citrate phosphate dextrose anticoagulant solution), CPDA-l solution (citrate phosphate dextrose (1.25 x CPD) plus 0.25 mM adenine), or CPDA-2 solution (citrate phosphate dextrose (1.75 x CPD) plus 0.50 mM adenine), ox a ~lood cell preserving liquid 25 such as, for example, SAG solution (saline-adenine-glucose solu~ion), or a modified SAG solution additionally incorporating therein mannitol, maltose, multitol, sorbitol, sucrose, or lactose (Japanese Patent Provisional Publication No. 139,419/81) and incorporating the triglyceride compound 30 represented by the general formula (I) in the basic liquid.
Of course, the blood preserving liquid of the present invention i5 not limited in any sense to the composition mentioned above. It is only required to incorporated the triglyceride compound represented by the general formula (I) 35 and to have a composltion safe physiologically.

~3C~6~i~8 Actual use of the blood preserving liquid of this invention may be effected by directly adding this liquid to the blood or by placing this liquid in advance in the medical implement such as blood bag and allowing it to be 5 mixed with the blood when the blood is introduced into the implement.
Example Now, for the purpose of ~acilitating the comprehension of this invention, a number of working examples lO will be cited below. These examples are intended pure'y as illustrations of the invention and are not meant to limit the scope of this invention in any respect.
Example 1 In 2,000 ~g/ml of a mixed polyoxyethylene 15 monooleate (guaranteed reagent, produced by Wako Junyaku K.K., and marketed under trademark designation of "Tween 80")/physiological saline glyceryl tri-2-ethylhexanoate (produced by Kao Co., Ltd.) was dispersed in a concentration of 4 mM. In a polypropylene tube fitted with a stopper, 0.2 20 ml of the resultant emulsion added in a final concentration indicated in Table l to a CPD-added human red cell concentrate adjusted in advance to a hematocrit value of about 70% (herei.nafter referred to as "CRC") was left standing at rest at 4C for 4 weeks. After the standing, the 25 contents of the tube were tested for plasma hemoglobin concentration by the TMB method CClin. Chem., 23, 749-(1977)]~ The results were as shown in Table l.
Controls l and 2 Emulsions were prepared by following the procedure 30 of Example l, excepting di-2-ethylhexyl phthalate (Control l) and glyceryl di-2-ethylhexanoate (Control 2) were used in the place of glyceryl tri-2-ethylhexanoate. They were severally added to CRC and left standing in the tube. After the standing, the contents of the tubes were tested for plasma 35 hemoglobin concen~ration. The results were as shown in Table 1.
Control 3 , ' '~ , P~

The CRC having 2,000 ~g/ml of a mixed polyoxyethylene monooleate (guaranteed reagent, produced by Wako Junyaku K.K., and marketed under trademark designation of "Tween 80")/physiological saline solution alone added 5 thereto was left standing in the tube similarly to Example 1.
The contents of the tube, after the standing, was tested for plasma hemoglobin concentration. The results were as shown in Table 1.

Table 1 Final Plasma concent- hemoglobin ration concent- -of sample ration Sample _ (~M) (mg/dl) 15 Example 1 G]yceryl tri-2- 400 27 ethylhexanoate40 47 Control 1 Di-2-ethylhexyl 400 36 phthalate 40 55 Control 2 Glycexyl di-2- 400 71 ethylhexanoate40 72 Control 3 - - 70 Example 2 The CRC adjusted to a hematocrit value of about 70% ~
and glyceryl tri-2-ethylhexanoate (produced by Kao Co., Ltd.) 25 added directly thereto in a final concentration indicated in Table 2 were gently stirred. In a tube of polypropylene fitted with a stopper, the resultant mixture was left standing at 4G for 4 weeks. At the end of the standing, the contents of the tube were tested for plasma hemoglobin 30 concentration similarly to Example 1. The results were as shown in Table 2.
Controls 4 and 5 Emulsions were prepared by following the procedure of Example 2, excepting di-2-ethylhexyl phthalate (Control 4) 35 and glyceryl di-2-ethylhexanoate (Control 5) were added to the CRC in the place of glyceryl tri-2-ethylhexanoate. The .

6~i9~

emulsions were left .standing at rest and, after the standing, tested for plasma hemoglobin concentration. The results were as shown in Table 2.
Control 6:
~he CRC was placed in the tube of polypropylene fitted with a stopper and left standing at rest in the same manner as in Example 2. After the standing, the contents of the tube were tested for plasma hemoglobin concentration.
The results were as shown in Table 2.

Table 2 Final Plasma ~ concent- hemoglobin ration concent-of sample ration Sample ~M) ~mg/d1) ; Example 2 Glyceryl tri-2- 400 35 ethylhexanoate 40 48 Control 4 Di-2-ethylhexyl 400 40 phthalate 40 61 20 Control 5 Glyceryl di-2- 400 72 ethylhexanoate 40 85 Control 6 - - 80 It is clearly noted from the results ~hat the CRC's having the hemolysis depressant of the present invention, 25 i.e. glyceryl tri-2-ethylhexanoate, added in some form or other were found to possess plasma hemoglobin concentrations (~xamples 1 and 2) substantially equal to those of the CRC
having di-2-ethylhexyl phthalate added in some form or other (Controls 1 and 4), indicating that they exhibited a highly 30 desirable protective action for erythrocytes.
Example 3 A flexible vinyl chloride resin composition using components as shown in Table 3 was roll kneaded at 160C for 10 minutes and then molded in the form of a sheet 0.4 mm in 35 thickness with an extruding machine. A miniature blood bag having an inner volume of 20 ml was produced by superposing two such sheets and sealing the superposed sheets by fusing prescribed portions thereof by high-frequency heating. ~bout 20 ml of the CRC adjusted in advance to a hematocrit value of about 70~ was placed in the bag and left standing at rest at 5 4C for 4 ~7eeks. After the standing, the CRC was tested for plasma hemoglobin concentration in the same manner as in Example 1. The resul.ts were as shown in Table 4.
Controls 7 and 8 Miniature blood bags were produced by following the 10 procedure of Example 3, excepting flexible vinyl chloride resin compositions using the same components in different proportions indicated in Table 3 were used instead. The CRC's were left standing at rest in the blood bags and, at the end of the standing, tested for plasma hemoglobin 15 concentration. The results were as shown in Table 4.

Table 3 Composition (parts_by weight) ~ ~ontrol 7 Control 8 Polyvinyl chloride 20 (average polymeriza- 100 100 100 tion degree, Pal,300) Di-2-ethylhe~yl - 50 - .-phthalate -Di-normal decyl 37 . - 50 25 phthalate Glyceryl tri-2- 15 ethylhe~anoate Epoxidized soybean oiI 8 8 8 Ca/Zn type stabilizer 0.1 ~ 0.1 0.1 :`
: :

' Table 4 Plasma hemoglobin concentration (mg/dl) Example 3 47 Control 7 46 Control 8 133 It is clearly noted from the results given above that the CRC preserved in the blood bag formed of the flexible vinyl chloride resin composition incorporating 10 therein the hemolysis depressant of this invention, i.e.
glyce~yl tri-2-ethylhexanoate (Example 3) was found to possess a plasma hemoglobin concentration substantially equal to the plasma hemoglobin concentration of the CRC preserved in the blood bag formed of the flexible vinyl chloride resin 15 composition incorporating di-2-ethylhexyl phthalate (Control 7), indicating that it exhibited a highly desirable protective action for erythrocytes.
In the CRC of Control 7, the amount of di-2-ethylhexyl phthalate exuded from the blood bag was 250 20 ppm, whereas the amount of glyceryl tri-2-ethylhexanoate exuded into the CRC of Example 3 was 46 ppm and that of di-normal decyl phthalate was 1 ppm.
Example 4 Pellets of a mixture of 100 parts by weight of an 25 ethylene-vinyl acetate copolymer (produced by Mitsubishi Pe~ro-Chemical Co., Ltd. and marketed under trademark designation of "Yukalcn EVA") and 20 parts ~y weight of glyceryl tri-2-ethylhexanoate were produced with a biaxial extruding machine provided with a vent. Sheets were produced 30 by extrusion molding these pellets. A miniature blood bag having an inner volume of 20 ml was produced by superposing two such sheets and sealing the superposed sheets by fusing prescribed portions thereo~ by high~frequency heating. About 20 ml of a CPD-added human red cell concentrate adjusted in 35 advance to a hematocrit value of about 70~ ~hereinafter ~ 41 -"

Table 5 Plasma hemoglobin Flexible concentraion resin Additiv~ _ (mg!dl) Example 4 Ethylene-vinyl Glyceryl tri-2- 28 acetate copolymer ethylhexanoate Control 9 Ethylene-vinyl - 92 acetate copolymer ;10 Example 5 Polyurethane Glyceryl tri-2- 30 ethylhexanoate Control 10 Polyurethane ~5 It is clearly noted from the results given in Table 5 that when the flexible resin c,omposition accordingwith this 15 invention was used (Examples 4 and 5), the hemolysis was crubed to a greater extent than when nothing was added to the flexible resin composition (Controls 9 and 10~.
Example 6 Pellets of a mixture of 100 parts by weight of 20 polyethylene terephthalate ~produced by Japan Unipet K.K. and marketed under trademarX designation of "Unipet RT560") and 3 parts by weight oE grecelyl tri-2-ethylhexanoate were produced by using a biaxial extruding machine provided with a vent. A blood collection tube having an inner volume of 5 , ~ 25 ml was produced by in;7ection molding the pellets. In the blood collection tube, about 3 ml ,of an EDTA-added human blood was left standing at 4C for 3 weeks. After the standing, the contents of the blood collectlon tube were tested for plasma hemoglobin concentration by the TMB method 30 [C1in. Chem~, 23 749- (1977)]. The results were as shown in Table 6.
~: :
Control 11 A blood collection tube was produced by following the procudure of Example 6, excepting pellets formed soley `
~ 35 with polyethylene terephthalate ~produced by Japan Unipet -' K.K. ~and marketed under trademark designation of 7'Unipet RT
~ 560")~ were used instead. This blood collection tube was ;~ similarly treated. The results were as shown in 17able 6, ;

-` ~3~

Table 5 Plasma hemoglobin Flexible concentraion resin Additive (mg/dl) Example 4 Ethylene-vinyl Glyceryl tri-2- 28 acetate copolymer ethylhexanoate Control 9 Ethylene-vinyl - 92 acetate copolymer lO Example 5 Polyurethane Glyceryl tri-2- 30 ethylhexanoate Control lO Polyurethane - 95 It is clearly noted from the results given in Table 5 that when the flexible resin composition accordingwith this 15 invention was used (Examples 4 and 5), the hemolysis was : crubed to a greateE extent than when nothing was added to the flexible resin composition (Controls 9 and lO).
Example 6 Pellets of a mixture of 100 parts by weight of 20 polyethylene terephthalate (produced by Japan Unipet K.K. and marketed under trademark designation of "Unipet RT560") and 3 parts by weight of grecelyl tri-2-ethylhexanoate were produced by using a biaxial extruding machine provided with a vent. A blood collection tube having an inner volume of 5 25 ml was produced by injection molding the pellets. In the blood collection tube, about 3 ml of an EDTA-added human blood was left standing at 4~C for 3 weeks. After the standing, the contents of the blood collection tube were : tested for plasma hemoglobin concentration by the TMB method 30 CClln. Chem., 23 749- (1977)]. The results were as shown in Table 6.
; Control ll : :~
; A blood collection tube was produced by following : the procudure of Example 6, excepting pellets formed soley 35 with polyethylene terephthalate (produced by Japan Unipet ~: ~ K.X. and marketed under trademark designation of "Unipet RT
~: 560") were used instead:. This blood collection tube was similarl.y treated. The results were as shown in Table 6.

Example 7 A blood collection tube was produced by following the procedure of Example 6, excepting polystyrene (produced by Nippon Steel Chemical Co., Ltd. and marketed under 5 trademark designation of "Estyrene G-12F") was used in the place of the polyethylene terephthalate. This blood collection tube was similarly treated. The results were as shown in Table 6.
Control 12 A blood collection tube was produced by following the procedure of Example ~, excepting polystyrene (produced by Nippon Steel Chemical Co., Ltd. and marketed under trademark designation of "Estyrene G-12F") alone was us~d instead. The blood collection tube was similarly treated.
15 The results were as shown in Table 6.
Example 8 A blood co]lection tube was produced by following the procedure of Example 6, excepting polymethyl methacrylate (produced by Kyowa Gas Chemical Industry Co., Ltd. and 20 marketed under trademark designation of "Parapet G") was used in the place of the polyethylene terephthalate. This blood collection tube was similarly treated. The results were as shown in Table 6.
Control 13 A blood collection tube was produced by following the procedure of Example 6, excepting pellets formed solely with polyethyl methacrylate (produced by Kyowa Gas Chemical Industry Co., Ltd. and marketed under trademark designation of "Parapet G") were used instead. This blood collection 30 tube was similarly treated. The results were as shown in Table 6.
Example 9 A blood collection tube was produced by following the procedure of Example 6, excepting polyacrylonitrile 3~ (produced by Vestron CoO and marketed under trademark ~3~ 8 designation of "sAREX 210") was used in the place of the polyethylene terephthalate. This blood collection tube -,Jas similarly treated. The results were as shown in Table 6.
Con-trol 14 A blood collection tube was produced by following the procedure of Example 6, excepting pellets formed solely with polyacrylonitrile (produced by Vestron Co. and marketed under trademark designation of "BAREX 210") were used instead. This blood collection tube was similarly treated.
10 The results were as shown in Table 6.
Table 6 _ _ Plasma hemoglobin concentration*
Rigid resin Additive (mg/dl) 15 Example Polyethylene Glyceryl tri-2- 61 6 terephthalate ethylhexanoate Control Polyethylene - 105 11 terephthalate Example Polystyrene Glyceryl tri-2- 65 7 ethylhexanoate Control Polystyrene - 110 Example Polymethyl Glyceryl tri-2- 60 8 methacrylate ethylhexanoate 25 Control Polymethyl - 97 13 methacrylate Example Poly- Glyceryl tri-2- 66 9 acrylonitrile ethylhexanoate Control Poly- - 120 - 30 14 acrylonitrile * The value of plasma hemoglobin concentration indicated represents an average of values obtained of three smaples.

It is clearly noted from the results given in Table 35 6 that wher~ the rigid resin composition according with the presen-t invention was used (Examples 6 through 9), the "` ~3~

hemolysis was curbed to a greater extent than when the rigid resin composition not containing the triglyceride compound of this invention and entailing virtually no exudation was used (Controls 11 through 14).
5 Example 10 An emulsion was produced by dissolving polyoxyethylene monooleate (guaranteed reagent, produced by Wako Junyaku K.X. and marketed under trademark designation of Tween 80 ) in a final concentration of 600 ~g/ml in the SAG
10 solution (composed of 140 mM of NaCl, 1.25 mM of glucose) and uniformly dispersing 1.2 mM of glyceryl tri-2-hexanoate in the resultant solution. In a tube of polypropylene fitted with a stopper, 1.0 ml of the emulsion prepared as described above and 2~0 ml of a human red cell concentrate adjusted in 15 advance to a hematocrit value of about 70% were left standing at rest at 4C for 5 weeks. After the standlng, the contents of the tube were tested for free hemoglobin concentration in plasma by the TMB method ~Clin~ Chem., 23 749-(1977)]o The results were as shown in Table 7.
20 Example 11 A blood preserving liquid was produced by following the procedure of Example 10, excepting the amount of glyceryl tri-2-ethylhexancate was changed to 0.12 mM. The contents of the tube were tested for free hemoglobin concentration in 25 plasma in the same manner as in Example 10. The results were as shown in Table 7.
Control 15 ~ blood preserving liquid was prepared by following the procedure of Exampie 10, excepting glyceryl 30 di-2-ethylhexanoate was used as a diglyceride compound in the place of glyceryl tri-2-ethylhexanoate. The change of free hemoglobin concentration in plasma was studied. The results were as shown in Table 7.
Control 16 , 6~

A blood preserving liquid was prepared by following the procedure of Control 15, excepting the amount glyceryl di-2-ethylhexanoate added was changed to 0.12 mM. The change of free hemoglobin concentration in plasma was studied. The 5 results were as shown in Table 7.
Control 17 A blood preserving liquid was prepared by following the procedure of Example 10, excepting di-2-ethylhexyl phthalate, a compound well known as possessing a hemolytic 10 activity, was used in the place of glyceryl tri-2-e~hylhexanoate. The change of free hemoglobin concentration in plasma was studied by following the procedure of Example 10. The results were as shown in Table 7.
15 Control 18 A blood preserving liquid was prepared by following the procedure of Control 17, excepting the amount of di-2-ethylhexyl phthalte added was changed to 0.12 m~. The change of free hemoglobin concentration in plasma was studied 20 by following the procedure of Control 17. The results were as shown in Table 7.

;98 Table 7 Final. concentration Free hemoglobin of additive in red concentration in Additive cell concentrate (mM) plasma (mg/dl) 5 Example Glyceryl tri-2-400 95 10 ethylhexanoate - Example Glyceryl tri-2-40 122 11 ethylhexanoate Control Glyceryl di 2-400 218 15 ethylhexanoate Control Glyceryl di-2- 40 210 16 ethylhexanoate Control Di-2-ethylhexyl 400 117 17 phthalate 15 Control Di-2-ethylhexyl40 132 18 phthalate Blank - - 213 It is clearly noted from Table 7 that the blood preserving liquid compositions (Examples 10 and 11) 20 incorporating therein triglyceride compounds represented by the general formula (I) according with the present invention manifested as high an antihemolytic activity as those incorporating therein di-2-ethylhexyl phthalate (Controls 17 and 18), ~ whereas those incorparating therein 25 di-2-ethyl-hexanoate, a diglyceride compound not falling within the range of the present invention, tControls 15 and 16) were found to manifest substantially no antihemolytic actlvity.
Example 12 A test for platelet function recovery was carried : out by the following procedure.
A methanolic solution containing glyceryl tri-2-ethylhexanoate in a concentration of 2,000 ~g/ml was ; : added to a human platelet poor plasma (hereinafter referred 35 to as "PPP") in a proportion of 1/100 by volume. A mixture of 2 ml of the PPP thus prepared and 1 ml of human platelet rich plasma (PRP) was: incubated at 37C for 90 minutes.
Thenj the platelets were washed ~Legrand et aI., Eur. J.
:::

- 4~ -~:
.

- ~3~ 8 Biochem. 1~2,465 (1984)], resuspended in Tyrode/BSA solu.ion (Tyrode solution of pH 7.35 containing 2 mM of CaC12, 1 mM of MgC12, 5 mM HEPES, and 3.5 mg/ml of BSA solution) having apyrase added thereto in a proportion of 2 ~g/ml of protein,

5 and was -tested for maximum aggregation capacity with respect to 50 ~M of ADP (adenosine diphosphate) and 10 mg/ml of collagen wi-th an instrument (produced by Kyoto Daiichi Kagaku K. K. and marketed under trademark designation of "Aggrecoder"). The results are shown in Table 8.
10 Controls 19 and 20 Two runs of the test for platelet function recovery were carried out by following the procedure of Example 12, excepting di-2-e~hylhexyl phthalate (Control 19) and di-normal decyl phthalate (Control 20) were respectively used 15 in a concentration of 2,000 ~g/ml in the place of the methanol solution of glyceryl tri-2-ethylhexanoate. The results were as shown in Table 8.
Control 21 A test for platelet function recovery was carried 20 out by following the procedure of Example 12, excepting methanol wa9 used in the place of the methanol solution of glyceryl tri-2-ethylhexyl phthalate. The results were as shown in Table ~.
Table 8 Maximum aggregation ratio (%) ADP 50 ~M Collagen 10 ~g/ml Example Glyceryl tri-2-10~4 77.9 12 ethylhexanoate Control Di-2-ethylhexyl6.5 46.9 3019 phthalate Control Di-normal decyl17.3 84.5 20 phthalate Control - 12~1 85.3 ! .. . ~ ~.3 ~

As shown in Table 8, di-2-ethylhexyl phthalate was found to manifest a discernible activity to repress the 5 recovery of the platelet aggregation ability. This fact implies that di-2-ethylhexyl phthalate, on entering the human body, possibly impairs the function of platelets. In contrast, glyceryl tri-2-ethylhexanoate used as a hemolysis depressant and di-normal decyl phthalate used as a 10 plasticizer in the present invention were not found to manifest any such repressive activity. The results indicate that they are highly safe substances.
[Industrial Appicability]
As described above, the hemolysis depressant 15 according with this invention possesses a highly desirable protective activity for erythrocytes and, at the same time, excels in safety. Furthermore, the hemolysis depressant is capable of being to various forms, for example, the form incorporated in a varying synthetic resin composition, and 20 the emulsion form into a varying aqueous medium. The hemolysis depressant is enabled -to prevent erythrocytes from hemolysis evenwhen it will be in these forms. Therefore, when the hemolysis depressant fo this invention is added to an erythrocyte-containin~3 liquid such as whole blood or 25 concentrated red cells, most of the erythrocytes can be retained for a long time in the same state as immediately after blood extraction. Thus, it should be said that the present invention offers distinguished contribusion to various technical fields, including transfusionics clinical 30 analytic as welI as medicine.

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Claims (74)

WHAT IS CLAIMED IS:

1. A hemolysis depressant comprising a triglyceride compound represented by the general formula (I):
(I) (wherein R1, R2, and R3 independently stand for an aliphatic hydrocarbon group of 1 to 20 carbon atoms and the total number of the carbon atoms of R1, R2, and R3 is in the range of 10 to 36).

2. A hemolysis depressant according to Claim 1, wherein R1, R2, and R3 in said general formula (I) independently stand for an aliphatic hydrocarbon group of 1 to 10 carbon atoms and the total number of the carbon atoms of R1, R2, and R3 is in the range of 10 to 30.

3. A hemolysis depressant according to Claim 2, wherein at least one of the substituents, R1, R2, and R3, in said general formula (I) possesses a branched structure.

4. A hemolysis depressant according to Claim 3, wherein said triglyceride compound represented by said general formula (I) is glyceryl tri-2-ethylhexanoate .

5. A hemolysis depressant according to one of Claims 1 through 4, which is to be incorporated in a synthetic resin composition.

6. A hemolysis depressant according to Claim 1, which is to be directly added to an erythrocyte-containing solution.

7. A hemolysis depressant according to Claim 6, which is added in the form of an emulsion to said erythrocyte-containing solution.

8. A flexible vinyl chloride type resin composition for medical appliances, which is characterized by consisting essentially of a vinyl chloride type resin, a plasticizer, and a hemolysis depressant comprising a triglyceride compound represented by the genral formula (I):
(I) (wherein R1, R2, and R3, independently stand for an aliphatic hydrocarbon group of 1 to 20 carbon atoms and the total number of the carbon atoms of R1, R2, and R3, is in the range of 10 to 36).

9. A flexible vinyl chloride type resin composition according to Claim 8, wherein the content of said plasticizer is in the range of 10 to 45% by weight and the content of said triglyceride compound in the range of 1 to 20% by weight.

10. A flexible vinyl chloride type resin composition according to Claim 9, wherein the content of said tri-glyceride compound represented by said general formula (I) is in the range of 3 to 10% by weight.

11. A flexible vinyl chloride type resin composition according to one of Claims 8 through 10, wherein R1, R2, and R3 in said general formula (I) independently stand for an aliphatic hydrocarbon group of 1 to 20 carbon atoms and the total number of the carbon atoms of R1, R2, and R3 is in the range of 10 to 30.

12. A flexible vinyl chloride type resin composition according to one of Claims 8 -through 10, wherein at least one of the substituents, R1, R2, and R3, in said general formula (I) possesses a branched structure.

13. A flexible vinyl chloride type resin composition according to one of Claims 8 through 10, wherein said triglyceride compound represented by said general formula (I) is glyceryl tri-2-ethylhexanoate.

14. A flexible vinyl chloride type resin composition according to one of Claims 8 through 10, wherein said plasticizer possesses a low exuding property.

15. A flexible vinyl chloride type resin composition according to Claim 8, wherein said plasticizer is selected from the group consisting of trialkyl trimellitates, di-normal alkyl phthalates, and tetraalkyl pyromellitates.

16. A flexible vinyl chloride type resin composition according to Claim 15, wherein said plasticizer is dinormal decyl phthalate.

17. A flexible vinyl chloride type resin composition according to Claim 15, wherein said plasticizer is trioctyl trimellitate.

18. A medical implement, characterized by being substantially formed with a flexible vinyl chloride type resin composition consisting essentially of a vinyl chloride type resin, a plasticizer, and a hemolysis depressant comprising a triglyceride compound represented by the general formula (I):
(I) (wherein R1, R2, and R3 independently stand for an aliphatic hydrocarbon group of 1 to 20 carbon atoms and the total number of the carbon atoms of R1, R2, and R3 is in the range of 10 to 36).

19. A medical implement according to Claim 18, wherein said flexible vinyl chloride type resin composition has the content of said plasticizer in the range of 10 to 45% by weight and the content of said triglyceridie compound represented by said general formula (I) in the range of 0 to 20% by weight.

20. A medical implement according to Claim 19, wherein the content of said triglyceride compound represented by said general formula (I) is in the range of 3 to 10% by weight.

21. A medical implement according to one of Claims 18 through 20, wherein R1, R2, and R3 in said general formula (I) independently stand for an aliphatic hydrocarbon group of 1 to 10 carbon atoms and the total number of the carbon atoms of R1, R2, and R3 is in the range of 10 to 30.

22. A medical implement according to one of Claims 18 through 20, wherein at least one of the substituents, R1, R2, and R3, in said general formula (I) possesses a branched structure.

23. A medical implement according to one of Claims 18 through 20, wherein said triglyceride compound represented by said general formula (I) is glyceryl tri-2-ethylhexanoate.

24. A medical implement according to one of Claims 18 through 20, wherein said plasticizer possesses a low exuding property.

25. A medical implement according to Claim 18, wherein said plasticizer is selected from the group consisting of trialkyl trimellitates, di-normal alkyl phthalates, and tetraalkyl pyromellitates.

26. A medical implement according to Claim 25, wherein said plasticizer is di-normal decyl phthalate.

27. A medical implement according to Claim 25, wherein said plasticizer is trioctyl trimellitate.

28. A medical implement according to one of Claims 18 through 20, or 25 through 27, which is a container for blood.

29. A medical implement according to one of Claims 18 through 20, or 25 through 27, which is capable of withstand-ing the conditions of sterilization in an autoclave.

30. A flexibe resin composition for medical appliances, which is characterized by having incorporated in a flexible resin composition containing no plasticizer, a hemolysis depressant comprising a triglyceride compound represented-by the general formula (I):
(I) (wherein R1, R2, and R3 independently stand for an aliphatic hydrocarbon group of 1 to 20 carbon atoms and the total number of the carbon atoms of R1, R2, and R3 is in the range of 10 to 36).

31. A flexible resin composition according to Claim 30, wherein the content of triglyceride compound represented by said general formula (I) is in the range of 5 to 35% by weight.

32. A flexible resin composition according to Claim 30 or Claim 31, wherein R1, R2, and R3 in said general formula (I) independently stand for an aliphatic hydrocarbon group of 1 to 10 carbon atoms and the total number of the carbon atoms of R1, R2, and R3 is in the range of 10 to 30.

33. A flexible resin composition according to Claim 30 or 31, wherein at least one of the substituents, R1, R2, and R3, in said general formula (I) possesses a branched structure.

34. A flexible resin composition according to Claim 30 or 31, wherein said triglyceride compound represented by said general formula (I) is glyceryl tri-2-ethylhexanoate.

35. A flexible resin comsposition according to Claim 30, wherein said flexible resin is an internally plasticized vinyl chloride type resin, a polyester, a polyurethane, an ethylene-vinyl acetate copolymer or a polymer blend of polyvinyl chloride with polyurethane, an ethylene polymer or a caprolactam type polymer.

36. A flexible resin composition according to Claim 35, wherein said internally plasticized vinyl chloride type resin is a urethane-vinyl chloride copolymer, a vinyl acetate-vinyl chloride copolymer, or an ethylene-vinyl acetate-vinyl chloride copolymer.

37. A medical implement r characterized by being substantially formed with a flexible resin composition having incorporated in a flexible resin composition containing no plasticizer a hemolysis depressant comprising a triglyceride compound represented by the general formula (I) (I) (wherein R1, R2, and R3 independently stand for an aliphatic hydrocarbon group of 1 to 20 carbon atoms and the total number of the carbon atoms of R1, R2, and R3 is in the range of 10 to 36).

38. A medical implement according to Claim 37, wherein the content of said triglyceride compound repesented by said general formula (I) is in the range of 5 to 35% by weight.

39. A medical implement, according to Claim 37 or Claim 38, wherein R1, R2, and R3 in said general formula (I) independently stand for an aliphatic hydrocarbon group of 1 to 10 carbon atoms and the total number of the carbon atoms of R1, R2, and R3 is in the range of 10 to 30.

40. A medical implement according to Claim 37 or 38, wherein at least one of the substituents, R1, R2, and R3, in said general formula (I) possesses as branched structure.

41. A medical implements according to Claim 37 or 38, wherein said triglyceride compound represented by said general formula (I) is glyceryl tri-2-ethylhexanoate.

42. A medical implement according to Claim 37, wherein said flexible resin is an internally plasticized vinyl chloride type resin composition, a polyethylene, a thermoplastic polyester, a polyurethane, an ethylene-vinyl chloride copolymer, or a polymer blend of polyvinyl chloride with a polyurethane, an ethylene polymer, or a caprolactone type polymer.

43. a medical implement according to Claim 42, wherein said internally plasticized vinyl chloride type resin is a urethane-vinyl chloride copolymer, a vinyl acetate-vinyl chloride copolymer, or an ethylene-vinyl acetate-vinyl chloride copolymer.

44. A medical implement according to Claim 37 38, 42 or 43, which is a container for blood.

45. A medical implement according to Claim 37 33, 42 or 43. which is capable of withstanding the conditions of sterilization in an autoclave.

46. A rigid resin composition, characterized by having incorporated in a rigid resin composition a hemolysis depressant comprising a triglyceride compound represented by the general formula (I):

(I) (wherein R1, R2, and R3 independently stand for an aliphatic hydrocarbon group of 1 to 20 carbon atoms and the total number of the carbon atoms of R1, R2, and R3 is in the range of 10 to 36).

47. A rigid resin composition according to Claim 46, wherein the content of said triglyceride compound represented by said general formula (I) is in the range of 0.5 to 5% by weight,

48. A rigid resin composition according to Claim 46 or Claim 47, wherein R1, R2, and R3 in said general formula (I) independently stand for an aliphatic hydrocarbon group of 1 to 10 carbon atoms and the total number of the carbon atoms of R1, R2, and R3 is in the range of 10 to 30.

49. A rigid resin compsosition according to Claim 46 or 47 , wherein at least one of the substituents, R1, R2, and R3, in said general formula (I) possesses a branched structure.

50. A rigid resin comsposition according to Claim 46 or 47, , wherein said triglyceride compound represented by said general formula (I) is glyceryl tri-2-ethylhexanoate.

51. A rigid resin composition according to Claim 46, wherein said rigid resin is selected from the group consisting of acrylic type resins, styrene type resins, olefin type resins, thermoplastic polyester type resins, and polycarbonates.

52. A rigid resin composition according to Claim 51, wherein said acrylic type resin is a homopolymer or copolymer of methyl methacrylate, methyl acrylate, ethyl methacrylate, ethyl acrylate, acrylonitrile, or methacrylonitrile.

53. A rigid resin composition according to Claim 51, wherein said styrene type resin is polystyrene, an acrylonitrile styrene copolymer, or an acrylonitrile-butadiene-styrene copolymer.

54. A rigid resin composition according to Claim 51, wherein said olefin type resin is polyethylene, polypropylene, or an ethylene-propylene copolymer.

55. A rigid resin composition according to Claim 51, wherein said thermoplastic polyester reisn is polyethylene terephthalate or polybutylene terephthalate.

560 A medical implement, characterized by being substantially formed with a rigid resin composition having incorporated in a rigid resin composition a hemolysis depressant comprising a triglyceride compound represented by the general formula (I):
(I) (wherein R1, R2, and R3 independently stand for an aliphatic hydrocarbon group of 1 to 20 carobn atoms and the total number of the carbon atoms of R1, R2, and R3 is in the range of 10 to 36).

57. A medical implement according to Claim 56, wherein said rigid resin composition has the content of said triglycerid compound represented by said general formula (I) in the range of 0.5 to 5% by weight.

58. A medical implement according to Claim 56 or Claim 57, wherein R1, R2, and R3 in said general formula (I) independently stand for an aliphatic hydrocarbon group of 1 to 10 carbon atoms and the total number of the carbon atoms of R1, R2, and R3 is in the range of 10 to 30.

59. A medical implement according to Claim 56 or 57 , wherein at least one of the substituents, R1, R2, and R3, in said general formula (I) possesses a branched structure.

60. A medical implement according to Claim 56 or 57 , wherein said triglyceride compound represented by said general formula (I) is glyceryl tri-2-ethylhexanoate.

61. A medical implement according to Claim 56, wherein said rigid resin is selected from the group consisting of acrylic type resins, styrene type resins, olefin type resins, thermoplastic polyester type resins, and polycarbonates.

62. A medical implement according to Claim 61, wherein said acrylic type resin is a homopolymer or copolymer of methyl methacrylate, methyl acrylate, ethyl metahcrylate, ethyl acrylate, acrylonitrile, or methacrylonitrile.

63. A medical implement according to Claim 61, wherein said styrene type resin is polystyrene, an acrylonitrile-styrene copolymer, or an acrylonitrile-butadiene-styrene copolymer.

64. A medical implement according to Claim 61, wherein said thermoplastic polyester resin is polyethylene, polypropylene, or an ethylene-propylene copolymer.

65. A medical implement according to Claim 61, wherein said thermoplastic polyester resin is polyethylene terephthalate or polybuthylene terephthalate.

66. A medical implement according to one of Claims 56, 57 or 61 through 65, which is a blood collection tube.

67. A blood preserving liquid composition, characterized by consisting essentially of a hemolysis depressant comprising a triglyceride compound represented by the general formula (I):

(I) (wherein R1, R2, and R3 independently stand for an aliphatic hydrocarbon group of 1 to 20 carbon atoms and the total number of the carbon atoms of R1, R2, and R3 is in the range of 10 to 36, and other blood preserving liquid component.

68. A blood preserving liquid composition according to Claim 67, wherein said blood preserving liquid is an anticoagulation preservative.

69. A blood preserving liquid composition according to Claim 67 or Claim 68, wherein said other blood preserving liquid component contains at least one compound selected from the group comprising sodium citrate, citric acid, glucose monosodium phosphate, adenine, sodium chloride mannitol, maltose, multitol, sorbitol, sucrose and lactose.

70. A blood preserving liquid composition according to Claim 67, wherein triglyceride compound represented by said general formula (I) is incorporated in a substratal solution selected from the group consisting of ACD solution, CPD
solution, CPDA-1 solution, CPDA-2 solution, SAG solution, and SAG solution having mannitol, maltose, multitol, sorbitol, sucrose, or lactose added thereto.

71. A blood preserving liquid composition according to Claim 67, 68 or 70, wherein R1, R2, and R3 in said general formula (I) independently stand for an aliphatic hydrocarbon group of 1 to 10 carbon atoms and the total number of the carbon atoms of R1, R2, and R3 is in the range of 10 to 30.

72. A blood preserving liquid composition according to Claim 67, 68 or 70 , wherein at least one of the substituents, R1, R2, and R3, in said general formula (I) possesses a branched strucutre.

73. A blood preserving liquid composition according to Claim. 67, 68 or 70, , wherein said triglyceride compound represented by said general formula (I) is glyceryl tri-2-ethylhexanoate.
74. A blood preserving liquid composition according to Claim 67, wherein said triglyceride compound represented by said general formula (I) is incorporated in a final concentration in the range of 10 µM
to 10 mM.
75. A blood preserving liquid composition according to

Claim 74, wherein said triglyceride compound represented by said general formula (I) is incorporated in a final concentration in the range of 30µM to 5mM.