JPS6018762A - Stabilized coagulation check test - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to stabilized control products useful in the clinical field, and more particularly to stabilized coagulation control reagents and plasma-renin (re%i'rL) control reagents. It is related to.

The present invention is filed concurrently by the inventor of the present invention [stabilized multi-indicator
) Control Product (ORD-50) J.

Hemostasis is achieved by blood vessels, plasma, platelets, blood vessel walls, nerves and surface elements (
It is a complex life-saving method that involves the activation of humorαl), all aimed at stopping bleeding.

Particularly in recent decades, the process of coagulation and the general
Although much research has been done on hemostasis in O-, the details of the interaction of the contributing mechanisms are not completely understood. For example, it is known that the compound involved in the production of hard blood coagulation is S5 or higher. Thus, on the surface, blood clotting is one of the complex chemical processes that occur within the body. In fact, there are so many separated components in the process of coagulation that Internationala, l I
International Communte organized by the lttmatology Congress
eon Nomenciature for Bloo
The tl Coagwlalion adopted a series of names that have now become commonplace. The most common of these names (commonly used interchangeably) and internal designations include: factor 1 fibrinodan, factor ■ prothrombin, factor 111 plus norasten 16, factor W calcium, Factor ■ (Currently not used), Factor ■ Serum Protonobin Conversion Accelerator (S7) (:
', 4), stable factor, factor ■ antihemophilic factor (AHF), factor X Christmas factor, plasma thrombozocystin component <prc>, factor -(prower) factor, factor A, plasma thromboplastin precursor, factor X
Hageman factor, factor XI [I fibrin stabilizing factor, glophiprinolysin plasminodan, fibrinolysin plasmin.

Diagnostic determination of the presence and quantification of the above-mentioned factors is important because many CIA-related diseases are associated with abnormal coagulation. For example, the absence of factor 1 is a major cause of genetic coagulation defects such as hemophilia type A, which is common and more than 2.0006 times known. Deficiencies in in-IBM concentrations of factor X are commonly associated with genetically determined deficiencies that cause hemophilia type B.

Bleeding results from a lack of factors x and
l occurs. Also, if you have liver disease or vitamin X deficiency,
, 1, ■, and X coagulation factors have different values, and this is because these factors are mainly produced in the liver. Other causes of abnormal 'g# rigidity are associated with a decrease in the number of platelets, l1jl small platelets, and are often accompanied by abnormal values of coagulation factors No. 2, 2, 2 and X, the reason for which This is because the hepatic acid is produced in the liver. Other causes of abnormal blood pressure are related to decreased platelet counts, -13- thrombocytopenia, often associated with increased peripheral destruction by sadistic anemia, certain drug treatments, phototherapy or antibodies.

The clinical value of clotting time tests is not limited to the detection of genetic or pathological conditions, but is also useful for anticoagulant therapy. Anti-diaphragm agents typically inhibit coagulation mechanisms, such as by heparin-mediated inhibition of factor X by antithrombin m. Deficiencies in the clotting mechanism due to congenital defects, pathological conditions or anticoagulant therapy are commonly Robert D.
, Langdell.

In C11nical Diagnosis, Dav
Coa idson and Henry, 1979
gulation and 11emost α8i8” in Chapter 7.

As commonly understood, coagulation occurs by two routes, the so-called internal route and the extrinsic route. The former is generally stimulated by the presence of phospholipids and calcium on the surface (termed activators) through a number of processes that substantially stimulate the formation of a stabilized fibrin clot. will be launched in collaboration with

The partial thromboplastin (PTTI test) typically measures the internal pathway by which most congenital deficiencies occur; therefore, this type of test serves as an excellent preliminary surgical coagulation screening test; the reagents used for this test are Because it is primarily a platelet substitute, the PTT assay does not measure platelet purity.

The extrinsic route is generally initiated by damage to the assemblage;
The resulting histotron is then exuded from glastin and acts on factors Ⅰ and X, after which fibrin coagulation occurs through a series of processes. This extrinsic pathway is commonly tested by the so-called one-stage prothrombin time test, which detects most of the factors inhibited by anticoagulant versus anticoagulant therapy controls. Thrombin time tests typically measure mlo and reactivity of fipurinogun.

This test is a rapid quantitative test and is the key of choice for vascular anticoagulation and line/cord analysis. Summarizing the above, the following Table 1 shows Ort ) Lo D
iagnostics, Inc., Raritan
, New Jersey Publishing (7) [Conctrnt
ric Concepts of Coagulation
n 1971.1975J.

- 17 - In giving such attention to the clotting capacity of a particular patient and the presence or absence of special factors, ensure the proper operation of manual and automatic methods designed to measure the amount of these factors and coagulation in general. It is self-evident that appropriate controls must be obtained for this purpose. Traditionally, such nestable controls typically have relatively short lifetimes in both liquid and dry states, depending in part on the labile nature of the ingredients, or drying processes such as freeze-drying. It was characterized by an inability to withstand

It is an object of the present invention to provide plasma renin and coagulation control samples that contain suitable amounts of certain factors that are present in a stable state and that can be lyophilized.

It is another object of the present invention to provide a method by which coagulation control and plasma renin control reagents can be stabilized.

It is another object of the present invention to provide a stabilized state reagent useful for manual and automated renal hypertension testing and coagulation testing.

According to the objects and principles of the present invention, a layered stabilizing medium (pl
exiform stabilizing means
A coagulation control reagent and a blood plasma control reagent are provided that are substantially stabilized by the addition of .). For the coagulation control reagent, anti-isthmus 161 medium is added to the defibrillated plasma, which keeps the coagulation components intact and suppresses h'+W fibrin formation. Well, sucrose,
The layered stabilizing medium is selected from the group consisting of dermatogenic JP'i9 sugars and reducing disaccharide sugars of about 3-1.

Packaging, add as present as the final product of the last time. Favorable capsule-like stabilized 1'1' forms are selected from B'c consisting of maltose, mannitol, cellobiose, glucose and hylactose, the last being most preferred.

In addition, according to the desired type of coagulation control reagent, the amount of (1 stone c111 zitang or 1 child (plural)?Ue is No.■ and /'-ita1, ↑Xia factor is removed can do.

Plasma renin control reagents of the present invention are prepared using a selected dish containing an anticoagulant medium in which the coagulation components are kept substantially intact, and a saline stabilizing medium similar to that described in the coagulation control reagents. Consists of a spring. Anticoagulants are ideally selected from the group consisting of citrate, oxalate, EDTA (enalediaminetetraacetic acid), heparin and any combination thereof.

Most suitable concrete? 1, all water is centrally removed by known methods such as condensation drying.

The reagent products of the present invention are useful for use in manual as well as automated methods in chemical analysis, and are particularly useful for tests involving coagulation and plasma membrane activity. These tests include, for example, official blood pressure tests, actual coagulation tests,
angiotensin I
Includes tests for and/or ox, and renin activity tests, which are typically tested only in fresh human plasma. As expected, especially for the last test, it is difficult to obtain suitable control reagents, especially in a suitably stabilized state.

Such stabilized conditions are particularly desirable in the end pressure field to minimize costs and increase the comparative integrity of data on a daily test basis.

Ideally, the control reagent material should resemble the patient sample as closely as possible, except that the control may be artificially altered to some extent to provide the factor-absent control as normally expected in a given disease state. It is true. For example, patients who have suffered a heart infarction may be expected to have increased amounts of renin. It is known that renin acts on plasma proteins to produce angiotensin, which causes an increase in blood pressure resulting in narrowed blood vessels. Centrifugal Golmer Ruler-21
- (Golmerv, Lar) Renin, a proteolytic enzyme thought to occur in arterioles, reacts with hyper-9-tensinoquine to produce angiotensin (2).

The substance after this @ is decabezotide ormone, which not only affects vascular stenosis but also alters aldosterone secretion by the adrenal cortex. Angiotensin is also known as hypertensin. Aldosterone mainly acts to regulate sodium and potassium metabolism, thereby affecting cardiac function. It is a slaroid hormone that does not have the necessary effect.

Therefore, in order to confirm the correct test method, a blood plasma control trial is practically necessary and especially desirable in the case of stable conditions. Depending on the purpose of the present invention, such a comparison is possible here.

This would ideally consist of plasma from humans, preferably selected for its high renin content. In addition, an anticoagulant is added to retain the coagulated components at the base of the site, and to generate fibrin. Acid salt, oxalic acid Q, El) 7'' A, if heparin is added, select from 111- from I-1 combination.

The stability of the chamber is increased by adding an IL-forming medium selected from the group consisting of monomeric monomers and 4-disaccharide sugars. Preferred embodiments use maltose, mannitol, cellobiose, lactose, or glucose. The final latching degree is preferably about 3
A hard stabilizing medium is added in a range of 10% to 10%. A historical review of the related application 0RD-50 mentioned above.
Corsi, who received i6 in
It is thought to provide a "cow" structure, thereby holding components of the white matter, analytes, and control cells in a stabilized proximal position. Furthermore, the inventors of the present patent document believe that the layered stabilizing medium serves to retain all of the individual components in a substantially rigid state, thereby eliminating any degradation that may be caused by or associated with the physical movement of the analyte. Although we believe that this reduces the number of symptoms of anxiety or anxiety, we hope that this idea does not limit the invention.

Additionally, the award stabilizing medium may be a water-removal method such as freeze-drying.
Sanshin has the effect of helping water sublimate. The actual conditions under which this is achieved are unknown, but it is particularly important that the regeneration of the reagents after lyophilization is carried out quickly and with increased bottle-to-bottle visibility (ORI). -Gift of 50 mark application 1
It was discovered regarding the pressure chemical irradiation reagent. These advantages are also expected in the freeze-dried droplets of the control sample of the next invention.

Similarly, a coagulation control reagent would ideally be produced from plasma which has been treated with anti-coagulants as described above, so that the coagulation component is retained at its original 11, and residual fibrin formation is reduced. is suppressed. In addition to the above-mentioned starch-like stabilizing bodies, the coagulation control reagent can be tailored to remove one or more of the monoclonal coagulation factors according to the type of coagulation control reagent desired. For example, reagents that are substantially devoid of factor 1 (fibrinodan) or factor 2 (anti-[rl]) are desirable, and these components are then removed, for example by ethanol extraction or cooling. or other factors may be removed by other methods known in the art.

Together with the plasma renin control reagent, the reward stabilization medium provides a three-dimensional structure that greatly increases stability, speed of regeneration following lyophilization, and excellent bottle-to-bottle reproducibility. Additionally, as more fully explained in the ORD-50 patent application, the rate at which lyophilization is accomplished may actually be increased despite the lowered freezing point. This is thought to be mainly due to the removal of the eutectic plateau. 1) Additionally, for reasons that are clear and compelling, recycled materials typically exhibit greater optical clarity.

This is probably due, at least in part, to reduced protein degradation, particularly during lyophilization.

Other advantages are also obtained with the present invention, including that defibrinated plasma is more fertile than less stimulated defibrinated plasma by the addition of a stabilizing medium. This includes appearing to be completely defibrinated. Thus, the history seen here suggests that the roll-shaped clots evolved naturally from this, and that it also reflects the overall stability of other solid-phase clotting factors present in the plasma. It is shown that it can be obtained.

The most preferred reagents of the invention are also those in which substantially all of the water has been extracted by methods known in the art. Such methods include, without limitation, lyophilization, and serve to increase shelf life.

Ideally, the resulting dry bv product is stored at about 2-8° C. and raised prior to use.

Stability, as used herein, means that the initially measured activity is at least 90 times less than the subsequent measured activity.

As will be readily appreciated by those skilled in the art, numerous non-substantial modifications or substitutions of the above-described components can be made without departing from the nature or scope of the present invention.

%Customer: Oats Diagnostic Systems, Inc., l? Rated 27-

Claims (1)

[Claims] 1. a) hearing; b) an anticoagulant medium that retains coagulation components intact and inhibits fibrin formation; C) a final volume tt% range of about 3% to 10%. and d) the shaped plasma is manually manipulated to adjust one or more of the specific clotting factors according to the type of coagulation control reagent desired. A stabilized coagulation control reagent with special purpose. The reagent according to claim 1, wherein the zg-shaped stabilizing medium is selected from sucrose, lactose, mannitol, cellobiose and maltose. 3. The reagent according to claim 2, wherein the plasma is human plasma. 4. The reagent according to claim 3, wherein the anticoagulant is selected from the group consisting of citrate, oxalate, EDTA, heparin and combinations thereof. 5. The reagent according to claim 4, wherein the coagulation factor to be removed is selected from the group consisting of factor 1, factor 8, and combinations thereof. 6. The reagent according to claim 4, wherein the pleated stabilizing medium is lactose. 7. Claim 4, wherein the pleated stabilizing medium is sucrose
Reagents listed in section. 8. The reagent according to claim 4, wherein the pleated stabilizing medium is cellobiose. 9. The reagent according to claim 4r, in which substantially all water has been removed. 10. The reagent according to claim 6, wherein virtually all water is removed. 11. The reagent according to claim 7j, wherein substantially all of the water has been removed. iz The reagent according to claim 8'J-a, m:, wherein substantially all of the water has been removed. 1 & α) Prepare the entire area; f)) Remove substantially all cells (-sil) from the entire area to obtain 1f11 plasma; C) Retain coagulated components intact and remove fibrin; d) adjust the amount of specific clotting factors according to the type of solid control reagent desired; and 8) adjust the final volume concentration from about 3% to IO%. adding a stabilizing medium selected from the group consisting of sucrose, monosaccharide sugars and reducing disaccharide sugars such that the amount is present in the range of A method for producing an amended coagulation control reagent, characterized by: 14. The method of claim 13, wherein the stabilizing medium is selected from sucrose, lactose, mannitol, cellobiose, and hemaltose. 15. Patent l1ii in which the feminizing medium is lactose
1. The method according to item 13. 16, J anticoagulant medium is citrate, oxalate, EDT
A, heparin, and m units thereof. 17. The anticoagulant medium is citrate, oxalate, EDT
16. The method of claim 15, wherein the method is selected from the group consisting of A, I' IJ, and combinations thereof. 18. Claim 16, wherein the factor removal step includes a step selected from the group consisting of removal of factor #1 by cooling, removal of factor #1 by ethanol extraction, and combinations thereof.
The method described in section. 19. The removal process involves the removal of factor ① by cooling, and the removal of factor ① by ethanol extraction! 18. The method of claim 17, comprising steps selected from the group consisting of removal of factors and combinations thereof. 20. The method of claim 13, further comprising the step of substantially removing all water. 21. The method according to claim 18, further comprising the step of removing practically all the water. 2L The method of claim 19 further comprising the step of physically removing all water. 23. The method according to claim 20, wherein the water removal step is performed by freeze drying. 24. Claim 1 in which the water removal step is performed by freeze drying
llp, disciple 21, 'rRFti method. 25. The method according to claim 22, wherein the step of removing water is performed by freeze drying. 26 a) Plasma with a known renin level; b) an anticoagulant medium that maintains clot components intact and substantially suppresses fibrin formation; and C) a final volume coefficient of about 3 to 10 parts. A stabilized plasma renin control reagent useful for angiotensin testing, comprising: a plexiform stabilized medium selected from the group consisting of reducing monosaccharide sugars and reducing disaccharide sugars present in the range of . 27. The reagent according to claim 26, wherein the embedded stabilizing medium is selected from the group consisting of maltose, mannitol, cellobiose, lactose and hyglucose. 28. The reagent according to claim 26, wherein the pleated stabilizing medium is lactose. 29. The reagent according to claim 27, wherein the plasma is human plasma. 6-30 The plasma is that of human 1111.Claim 29.2 s B+1 on JK+ d1. :,','+
k. 31. The reagent of claim 29, wherein the Tj anticoagulant medium is from the group consisting of citrate, oxalate, E, DTA, heparin, and combinations thereof. 3λ type Warono Q solid medium is citrate, oxalate, E
31. The reagent according to claim 30, which is selected from the group consisting of: 1) TA, H-I'lln, and combinations thereof. a3. In fact, the reagent described in the patent publication, Toxocara 26, 1-11, in which all water is removed in a practical manner. 34. The reagent according to claim 27, wherein all water has been removed. 35. Claim 28:'-11i Yuko's reagent, in which virtually all water is removed. 36. The reagent according to claim 11, paragraph 29, wherein substantially all of the water has been removed. 37. The reagent according to claim 30, wherein substantially all of the water has been removed. 38, Patent W Uchigu no Range σ Old No. 31 Nooi 1h Kikawa Father's Shizukorashi from which virtually all water has been removed. 39.α) select plasma with known renin activity; b) add an anticoagulant medium that maintains the clot intact and substantially inhibits fibrin production; and C) approximately From the group consisting of reducing monosaccharides sucrose and reducing dicyclic sugars, as present in the range of ~lO% final volume, ? The above-mentioned (α) to (
C) Process of manufacturing a stabilized plasma renin control reagent suitable for angiotensin testing, characterized by inclusion of -f. 40-7J plate-shaped stabilizer contains maltose, manni 1.
39. The method according to claim 39. 41, Patent 6, where the eaves plexus weakening medium is lactose, N, 311, +4i11. : How to put it. 42, jrl1 prefecture is human plasma, and the anticoagulant medium is citrate, oxalate5. q''+I+I selected from the group consisting of EDTA, heparin and combinations thereof. 43. The plasma is human 1b'l plasma and the anticoagulant medium chlorate, sulfur 44. The method of claim 41, wherein the method is selected from the group consisting of acids, EDTAs, henocrine, and combinations thereof. 44. Feature 1- further comprising the step of removing substantially all the water. 45. The method of claim 40, further comprising the step of removing substantially all of the water. 46. The method of claim 40, further comprising the step of removing substantially all of the water. 47. The method of claim 42, further comprising the step of removing substantially all of the water. 48. The method of claim 42, further comprising the step of removing substantially all of the water. 44. The method of claim 43, further comprising the step of removing all water.