JPH0236113B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Technical Field> The present invention relates to an improved anticoagulant blood processor. More specifically, the present invention relates to a blood purifier with improved anticoagulability, which is formed by applying a fat emulsion containing a prostaglandin compound to a blood flow path.

<Prior Art> In recent years, rapid progress has been made in blood purification methods for extracorporeal circulation, as seen in hemodialysis, direct blood perfusion, plasma exchange therapy, heart-lung machine, and the like. However, when performing these extracorporeal circulations, anticoagulants are essential, and the important issue is how to perform extracorporeal circulation without causing blood clots in the blood flow path and without adversely affecting the living body. It is becoming. As is well known, the mainstream anticoagulant currently used for extracorporeal circulation is heparin. Heparin exhibits an antithrombin effect by binding with antithrombin, and is safe and easy to handle in most uncomplicated cases, but should not be used in cases with bleeding tendencies or bleeding foci. is considered dangerous to use. In addition, side effects associated with long-term use are becoming a problem, such as abnormal lipid metabolism, abnormal gastric metabolism, and hypercoagulable state due to decrease in antithrombin due to the increase in the number of long-term dialysis patients. In order to overcome these drawbacks of heparin, there have been efforts such as micro-heparinization therapy and local heparinization therapy using protamine sulfate, but at present these are not necessarily sufficient.

On the other hand, various new anticoagulants have been developed with the aim of more ideal extracorporeal circulation therapy, and among them, prostaglandin compounds are attracting attention.
Prostaglandin compounds are local hormones that regulate physiological functions in living organisms, and their activity is extremely strong even in minute amounts. Among them, prostaglandin I ₂ , prostaglandin D ₂ and prostaglandin E ₁ have a strong platelet aggregation inhibiting effect. That is, it has the effect of inhibiting platelet aggregation as an initial process of blood coagulation. Furthermore,
These have the common characteristics that they have a rapid action with an extremely short half-life, can be administered intravenously, are in vivo substances and are physiologically metabolized in the body, and can be used as local anticoagulants in extracorporeal circulation. It has already been studied clinically. However, on the other hand, it also has a strong peripheral vasodilatory effect, and for this reason, side effects such as a drop in blood pressure and headaches are a problem when directly intravenously injected or continuously injected into an extracorporeal circuit.

In order to overcome these drawbacks, attempts have been made to improve the anticoagulability of blood purifiers by applying these prostaglandin compounds to blood purifiers instead of continuous infusion. For example, JP-A-57-141434 discloses improving anticoagulability by coating the surface of a polycarbonate membrane with an acrylate polymer in which prostaglandins are dispersed. Further, Japanese Patent Application Laid-Open No. 117195/1983 discloses that prostacyclin or prostaglandin E ₁ is applied to the blood flow path of a blood purifier to prevent anti-allergic effects. All of these methods are excellent in that they allow only the advantages of prostaglandin compounds to be exerted locally, but they are not necessarily satisfactory in terms of stability and sustainability of effects during extracorporeal circulation.

<Objective of the present invention> In order to overcome the conventional drawbacks in extracorporeal circulation therapy, the present invention focuses on the excellent anti-platelet aggregation inhibitory effect of prostaglandin compounds, and aims to effectively and sustainably exert only that effect. The aim is to improve the anticoagulant properties of blood processing equipment and at the same time prevent a decrease in blood platelets.

<Structure of the Invention> As a result of intensive studies to achieve the above object, the present inventors have found that it is very effective to apply a fat emulsion containing a prostaglandin compound to the blood flow path of a blood processing device. Heading This invention is arrived at.

That is, the present invention provides an improved blood processing device and a blood processing device characterized in that a fat emulsion containing a prostaglandin compound is applied to at least a part of the blood-contacting region of the blood processing device. at least some of the areas that come into contact with blood;
The present invention provides a method for producing a blood processing device, which comprises depositing a fat emulsion containing a prostaglandin compound and having an average particle size of 0.01 to 1.0 μm.

The present invention will be explained in more detail below.

In the present invention, fat emulsion refers to vegetable oil 5 to 50%
% (w/v), phospholipid 1 to 100 parts vegetable oil
It consists primarily of 50 parts, preferably 5 to 30 parts, and a suitable amount of water. Furthermore, additives are added as necessary.

The content of prostandin compounds can be increased or decreased as appropriate, but in general, the content of prostandin compounds in the emulsion is extremely small, e.g.
It is sufficient to contain 100 to 0.2 μg/ml.

Here, the vegetable oils include edible oils such as soybean oil, palm kernel oil, grape oil, fallen raw oil, sunflower oil, corn oil, palm oil, sesame oil, safrole oil, and olive oil, with soybean oil being particularly preferred.
Furthermore, highly purified refined soybean oil is preferred.

Phospholipids are purified phospholipids such as egg yolk lecithin and soybean lecithin.

Adhesives include fatty acids or salts having 6 to 22 carbon atoms, emulsifying aids such as stearic acid and oleic acid, stabilizers such as cholesterol or phosphatidic acid, albumin, dextran, vinyl polymers, and nonionic polymeric substances such as surfactants, gelatin, and hydroxyethyl starch;
and isotonizing agents such as glycerin and grapes, which can be used as long as they are medicinally usable.

Prostaglandin compounds include prostaglandin I ₂ and its derivatives, prostaglandin
Any one of D ₂ and its derivatives, and prostaglandin E ₁ and its derivatives, as long as it has an inhibitory effect on platelet aggregation, may be used. Examples of prostaglandin I ₂ derivatives include 15-
Cyclopentyl-ω-pentanor-5(E)-6,9-
metano PGI ₂ , 15−Cyclopentyl−ω−pentanor
-5(Z)-7-fluoro-PGI ₂ and the like.
In addition, prostaglandin E ₁ derivatives include 16,
18-ethano-ω-homo-trans-Δ ² -prostaglandin E ₁ and the like. Among these, prostaglandin E ₁ is preferred in terms of handling and availability.

The fat emulsion of the present invention is produced, for example, by the following method. That is, predetermined amounts of vegetable oil, phospholipids, prostaglandin compounds, and other additives mentioned above are mixed and heated to form a solution,
A water-in-oil dispersion is prepared by homogenizing using a normal homogenizer (for example, a left-side injection type homogenizer), then the required amount of water is added thereto, and homogenization is performed again using the homogenizer. The fat emulsion of the present invention can be produced by converting it into an oil-in-water emulsion. The particle size of the fat emulsion thus produced is extremely fine, with an average particle size of 0.01 to 1.0 μm, and its storage stability is good.

The blood processing device in the present invention is provided with a membrane and/or an adsorbent for blood processing. That is, for example, by the dialysis principle, the filtration principle, the adsorption principle, or a combination thereof, such as a hemodialyzer, a plasma separator, an adsorber for an artificial liver assist device, etc.
It is a device that removes toxic substances from the blood, or a device that exchanges gases in the blood, such as an artificial heart-lung machine.

In addition, the part of the blood processing device that comes into contact with blood is a blood flow path or another part that comes into direct contact with blood. For example, blood inlet/outlet tubes, dialysis membranes, plasma separation membranes, adsorbents (including polymer-coated adsorbents), oxygen exchange membranes, blood distribution plates, blood circuits, etc., between the blood processing device and the patient. Including all the circuits through which it passes.

A feature of the present invention is that a fat emulsion containing a prostaglandin compound is applied to the blood flow path of the blood processing device. In other words, a fat emulsion is applied to the surface of a membrane such as a hemodialysis membrane, the surface of an adsorbent, or the surface of a blood circulation part, to inhibit platelet aggregation at these blood contact parts during blood perfusion, and to reduce the number of platelets in the blood. The goal is to prevent it.

A preferred method for applying the prostaglandin-containing fat emulsion to the blood flow path is to fill the blood flow path with the fat emulsion and adhere the fat emulsion to the surface. In addition, in the case of dialyzers, plasma separators, etc., after filling the fat emulsion, pressurization or negative pressure is applied through the membrane to filter the water in the fat emulsion, and the fat emulsion is deposited on the membrane surface. can also be attached. In the case of adsorbents, the adsorbent may be immersed in fat emulsion and then filled into adsorption containers, or in the case of adsorbers pre-filled with adsorbent, the adsorbent may be filled with fat emulsion. can be given.

The blood processing device is sterilized before being used clinically, but normal sterilization may be performed after applying the fat emulsion to the blood processing device or the extracorporeal circulation circuit attached to it, or the fat emulsion may be sterilized after the sterilization. Of course, the emulsion may be applied under aseptic conditions. In either case, it is desirable to wash the blood processing device or the like to which the fat emulsion has been applied with physiological saline before performing extracorporeal circulation.

<Effects of the Invention> As explained above, according to the present invention, by converting a prostaglandin compound into a fat emulsion, the chemical stability of the prostaglandin compound is improved, and at the same time, the fat emulsion can be used in blood treatment. By applying it to the blood flow path of the blood vessel, prostaglandin compounds are gradually and continuously released from the fat emulsion during extracorporeal circulation, suppressing platelet aggregation over a long period of time and improving anticoagulability. At the same time, it has the effect of preventing a decrease in platelets. In addition, since the effect is effectively exerted on surfaces that are in direct contact with blood, extracorporeal circulation is possible with a small dose, and it has the advantage of avoiding undesirable phenomena such as side effects.

The present invention will be specifically described below with reference to Examples.

Example 1 20g of refined soybean oil, 2.6g of lecithin, 1000μg of prostaglandin E ₁ , 0.1g of sodium oleate
and 0.1 g of phosphatidic acid were dissolved, and then 200 ml of water and 4.6 g of glycerin were added and rough emulsified using a homomixer. This was further homogenized using a pressurized injection homogenizer, and 5μ of prostaglandin E ₁ was added.
A fat emulsion containing g/ml and an average particle size of 0.1 μm was obtained.

The fat emulsion obtained by the above method was filled into the blood flow path side of a dialyzer having a membrane area of 80 cm ² made of regenerated cellulose hollow fibers, and left for 2 hours. After washing with physiological saline, human blood collected with hebarin was collected at approximately 0.8
It was circulated at a rate of ml/min. The number of platelets in the blood was measured after one hour, and the survival rate was found to be 90% compared to the number of platelets before circulation.

However, residual rate (%) = (number of platelets in blood after 1 hour/number of platelets in blood before circulation) x 100 Example 2 Prostaglandin E ₁ obtained in Example 1 was added to 5μ
The fat emulsion containing g/ml was filled into the blood flow path side of a plasma separator with a membrane area of 0.7 cm ² made of microporous hollow fibers, and filtered by suction. After washing with physiological saline, blood circulation was performed in the same manner as in Example 1. The platelet survival rate after 1 hour was 92%.

Comparative Example 1 Without applying the fat emulsion in Example 1,
Similar blood circulation was performed, and the platelet survival rate after 1 hour was 53%.

Example 3 Prostaglandin E ₁ obtained in Example 1 was
A dialysis machine having a membrane area of 320 cm ² made of regenerated cellulose was filled with a fat emulsion containing 5 μg/ml,
It was left for 2 hours. After washing this with physiological saline, an extracorporeal circulation experiment was performed using domestic rabbits. Before circulation, the rabbits were intravenously injected with 100 U/Kg of heparin, and then circulated for 2 hours at a blood flow rate of 5 ml/min. 0.5 hours later, 1
After 2 hours, blood was collected and the platelet count was measured. The survival rate relative to the number of platelets before circulation is
The percentage was 89% after 0.5 hours, 93% after 1 hour, and 91% after 2 hours. Furthermore, no increase in circuit pressure or decrease in rabbit blood pressure was observed during extracorporeal circulation. After circulation, the blood was returned with physiological saline and residual blood was observed in the blood analyzer, and no residual blood was observed. Comparative Example 2 Prostaglandin E ₁ was added to physiological saline at a concentration of 5.0 μg/ml. Dissolved in water. This was filled into a dialyzer having a membrane area of 320 cm ² made of regenerated cellulose, left for 2 hours, and an extracorporeal circulation experiment using domestic rabbits was conducted in exactly the same manner as in Example 3. the result
After 1.3 hours, the circuit pressure increased and circulation was stopped. The residual rate of platelet counts was 85% after 0.5 hours and 60% after 1 hour.

Claims (1)

[Scope of Claims] 1. An improved blood processing device characterized in that a fat emulsion containing a prostaglandin compound is applied to at least a portion of the blood-contacting region of the blood processing device. 2 The prostaglandin compound is prostaglandin I ₂ and its derivatives, prostaglandin
The improved blood processing device according to claim 1, which is at least one selected from the group consisting of D ₂ and its derivatives, and prostaglandin E ₁ and its derivatives. 3. Claim 1, wherein the blood processing device is equipped with a membrane and/or an adsorbent for blood processing.
Improved blood processing device as described in Section. 4. A method for producing a blood treatment device, which comprises adhering a fat emulsion containing a prostaglandin compound and having an average particle size of 0.01 to 1.0 μm to at least a portion of the blood-contacting portion of the blood treatment device.