BLOOD SAMPLER CONTAINING ANTIPLATELET AGENT AND WATER-SOLUBLE MATRIX MATERIAL - Patent application

Abstract

A blood sampler is disclosed, which contains a solid mixture containing a compound selected from iloprost, beraprost, treprostinil, cicaprost, carbacyclin, EP157 ((Z)-7-[(1R,2R,3R,4S)-3-[(Z)-benzhydryloxyiminomethyl]-2-bicyclo[2.2.2]oct-5-enyl]hept-5-enoic acid), FK-788 (2-[[(6R)-6-(diphenylcarbamoyloxymethyl)-6-hydroxy-7,8-dihydro-5H-naphthalen-1-yl]oxy]acetic acid) and taprosten and any stereoisomers and salts thereof, wherein said compound is dispersed in a matrix of water-soluble polymeric material and / or sugar.

Description

[Technical Field]

[0001] The present invention relates to a blood sampler containing a prostacyclin analog dispersed in a water-soluble polymer that keeps the compound stable and allows for sufficient dissolution and dissolution rate of the prostacyclin analog upon contact with a blood sample. [Background technology]

[0002] Rapid access to blood tests is a mainstay in the diagnosis and treatment of acute illnesses. Oxygenation status and acid-base balance are determined by arterial blood gas (BG) analysis and constitute a central part of modern evidence-based treatment algorithms in critical care. Furthermore, devices intended for critical care testing allow for the assessment of, for example, electrolytes, renal function (creatinine), inflammation (C-reactive protein), and cardiac biomarkers.

[0003] A basic metabolic panel (BMP) is used to check the status of a person's kidneys, as well as their electrolyte and acid / base balance, and their blood glucose levels, all of which are related to a person's metabolism. It can also be used to monitor hospitalized patients and people with certain known illnesses, such as high blood pressure and hypokalemia.

[0004] Additionally, the white blood cell count (WBC) is an important biomarker for several diseases, and a differential WBC count can distinguish five different types of blood cells ("5-diff" or "5-part diff"): neutrophils, lymphocytes, monocytes, eosinophils, and even basophils. Alternatively, WBCs can be differentiated into granulocytes (neutrophils, basophils, and eosinophils reported as a group), lymphocytes, and monocytes ("3-diff" or "3-part diff"), each reported as a percentage. Changes in percentages may indicate a pathological condition.

[0005] Additionally, platelets (also called thrombocytes) can be counted as another parameter. Platelets are small fragments of cells that are essential for normal blood clotting. Platelet counts can be used to screen for or diagnose various diseases and illnesses that can cause problems with clot formation. It can be used as part of the workup for bleeding disorders, bone marrow disorders, or hypercoagulopathy, to name a few.

[0006] The test can be used as a monitoring tool for people with underlying diseases or who are being treated with drugs known to affect platelets. It can also be used to monitor people being treated for platelet disorders to determine whether therapy is effective.

[0007] However, blood samples must usually be prepared differently for diagnostic measurements of the above parameters. For example, for the analysis of BG and BMP parameters, the standard anticoagulant is heparin. While heparin prevents blood clotting, it does not prevent platelet (thrombocyte) activation and aggregation, which leads to the formation of platelet aggregates. Therefore, heparin is not currently used for complete blood count (CBC) analysis, including WBC, platelet count, 3-differential (3-diff) or 5-differential (5-diff), red blood cell (RBC) concentration, hematocrit, hemoglobin concentration, and RBC descriptive parameters. The measured platelet count in heparinized blood will likely be underestimated, especially when using state-of-the-art automated hematology analyzers that cannot distinguish between single platelets and clumps of aggregated platelets. Instead, platelet aggregates may be incorrectly classified as white blood cells by the hematology analyzer, resulting in an erroneously high WBC count, which can result in a faulty diagnosis or flag and error messages, rendering the results unusable.

[0008] Ethylenediaminetetraacetic acid (EDTA) is another standard anticoagulant commonly used in hematology in either the disodium, dipotassium, or tripotassium salts. The use of EDTA is generally recognized as safe and reliable for obtaining complete blood counts. Additionally, EDTA salts are compatible with, i.e., do not interfere with, standard staining protocols for blood smears. When problems with EDTA-dependent pseudothrombocytopenia arise, citrate is used as an alternative anticoagulant.

[0009] However, EDTA or citrate cannot be used for the analysis of BG and BMP parameters because these anticoagulants strongly interfere with electrolyte measurements. For example, EDTA and citrate form complexes with Ca2+, thus interfering with Ca2+ measurements, and these anticoagulants may even destroy the calcium sensor in automated analyzers.

[0010] Previously, hematology analyses, and CBC in particular, were performed on blood samples anticoagulated with EDTA or citrate, but not on heparinized blood samples. As a result, comprehensive analyses of CBC, BG, and BMP parameters had to be performed on separate instruments using blood samples anticoagulated in separate, different ways.

[0011] WO 2019 / 096598 discloses a method for preparing a blood sample that combines an anticoagulant, such as heparin, with an antiplatelet agent, such as iloprost, allowing for a "3-in-1" analysis of BG, BMP, and platelet count, as well as WBC (or CBC) count.

[0012] WO 2020 / 229580 further discloses that such methods can be performed even when the blood sample is exposed to stresses such as low temperatures. Japanese Patent No. H01 280466 discloses the preparation of a formulation of the antiplatelet agent prostacyclin by polymerizing polyacrylamide together with prostacyclin in an organic solvent, drying the resulting particles, and then dispersing the dried particles in a polymer solution in an organic solvent and allowing to dry until a polymer film is obtained. The polymer is not water-soluble. [Prior art documents] [Patent documents]

[0013] [Patent Document 1] International Publication No. 2019 / 096598 [Patent Document 2] International Publication No. 2020 / 229580 [Patent Document 3] Japanese Patent No. H01 280466 Summary of the Invention

[0014] Therefore, there is a need for new approaches to preparing blood samples for diagnostic assays. It would be advantageous if an antiplatelet agent such as iloprost and / or an anticoagulant such as heparin could be included in a blood sampler ready for use in a method such as that discussed above.

[0015] Some prostacyclin analogs (sometimes called prostaglandin analogs) have antiplatelet activity; however, they are typically not very stable. As an example, iloprost is sold as an inhalation solution under the trade name Ventavis®, which is approved for the treatment of pulmonary hypertension. The European Medicines Agency characterizes iloprost as being sensitive to temperature, light, and acidic conditions. The degradation products are primarily dimeric esters formed by the addition of two iloprost molecules.

[0016] Therefore, a need exists to include a prostacyclin analog, such as iloprost, in a blood sampler in a manner that prevents or retards known degradation while also allowing for sufficiently rapid dissolution of the prostacyclin analog upon exposure to a blood sample.

[0017] This need is met by the present invention, which in one aspect relates to a blood sampler containing a solid mixture comprising a compound selected from iloprost, beraprost, treprostinil, cicaprost, carbacyclin, EP157 ((Z)-7-[(1R,2R,3R,4S)-3-[(Z)-benzhydryloxyiminomethyl]-2-bicyclo[2.2.2]oct-5-enyl]hept-5-enoic acid), FK-788 (2-[[(6R)-6-(diphenylcarbamoyloxymethyl)-6-hydroxy-7,8-dihydro-5H-naphthalen-1-yl]oxy]acetic acid), and taprosten, and all stereoisomers and salts thereof, wherein the compound is dispersed in a matrix of a water-soluble polymer and / or sugar.

[0018] In a further aspect, the present invention relates to the use of a blood sampler according to the present invention for measuring albumin, alkaline phosphatase, lactate dehydrogenase, alanine transaminase, aspartate transaminase, amylase, lipase, total cholesterol, high density lipoprotein, low density lipoprotein, triglycerides, thyroid stimulating hormone, troponin, creatine kinase, myoglobin, D-dimer, N-terminal prohormone of brain natriuretic peptide (NT-proBNP), procalcitonin (PCT), C-reactive protein (CRP), beta-human chorionic gonadotropin, CBC, BG and BMP parameters in a blood sample. [Brief explanation of the drawings]

[0019] [Figure 1]Figure 1 shows the relative iloprost concentration results for test tubes containing a mixture of iloprost, PVP, and Tris stored as open or closed tubes at -18°C, 5°C, room temperature, or 32°C, compared to the concentration at the time of tube manufacture (time 0, t0). [Figure 2] Figure 2 shows the relative iloprost concentration compared to the iloprost concentration at the time of tube manufacture (time 0) for iloprost / PVP / Tris-sprayed blood collection tubes compared to iloprost / Tris and iloprost (uncompounded) stored either open or closed at a temperature of 32°C for approximately 1 week, 1 month, and 2 months. [Figure 3] FIG. 3 shows the effect of iloprost formulation on achieving rapid dissolution of iloprost. [Figure 4] FIG. 4 shows the effect of different water-soluble polymers on the dissolution rate of iloprost. [Figure 5] FIG. 5 shows the effect of sugars used in iloprost formulations on the dissolution rate of dry-formulated iloprost. [Figure 6] FIG. 6 shows the effect of the polymer and sugar mixture used in the iloprost formulation on the dissolution rate of dry-formulated iloprost. [Figure 7] FIG. 7 shows the dissolution rates of dry-formulated beraprost sodium, iloprost, and treprostinil. [Figure 8] FIG. 8 shows the blood analysis results of whole blood samples for blood drawn into tubes with the antiplatelet agents iloprost, beraprost sodium, and treprostinil. DETAILED DESCRIPTION OF THE INVENTION

[0020] definition In the context of the present invention, the term "blood sampler" is intended to mean a device for collecting blood, such as a syringe, capillary tube, or test tube, such as a suction sampler or a self-aspiration sampler, such as a PICO™ syringe (Radiometer Medical ApS), a vacuum test tube, or similar device designated for blood sampling. In one embodiment, the blood sampler is a device for collecting blood. In a further embodiment, the blood sampler is selected from a syringe, a capillary tube, a test tube, and a cuvette. In yet a further embodiment, the blood sampler is selected from a syringe, a capillary tube, and a test tube.

[0021] As used herein, the term "anticoagulant" refers to a substance that prevents or reduces the clotting of blood, i.e., the clotting cascade that leads to fibrin polymerization and thus the formation of a fibrin clot. Anticoagulants thereby prolong clotting time by inhibiting the clotting factor cascade following initial platelet aggregation.

[0022] As used herein, the term "antiplatelet agent" refers to a substance that reduces platelet aggregation and / or inhibits thrombus formation, i.e., inhibits platelet aggregation, the initial stage of blood clotting. Thus, antiplatelet agents interfere with the platelet activation cascade, which results in activated platelets that can adhere to fibrin fibers and other extracellular matrix components or aggregate into platelet aggregates. It is emphasized that the coagulation cascade and the platelet aggregation cascade are two separate cascades, even though some proteins, such as thrombin, may play a role in both cascades. Antiplatelet agents can reversibly or irreversibly inhibit the processes involved in platelet activation, resulting in a reduced tendency for platelets to adhere to each other, to damaged vascular endothelium, or to foreign surfaces, such as blood sampler materials. An example of an antiplatelet agent is iloprost. Iloprost has six asymmetric carbon atoms, five of which are shared with natural prostacyclin. Therefore, the molecular configurations are 8S, 9S, 11R, 12S, and 15S. The methyl group at C16 gives rise to two isomers: 16R and 16S. Thus, iloprost consists of two optically active diastereoisomers. Iloprost also contains two defined configurations of the carbon-carbon double bond: 5E and 13E—this stereospecific formation is common in prostacyclin chemistry. Another example is prostacyclin itself, also known as epoprostenol.

[0023] As used herein, the term "blood sample" or "blood analysis sample" refers to a sample of blood suitable for diagnostic or analytical purposes. Thus, a blood sample includes a relatively small amount of blood (20 pL to 10 mL of blood), i.e., does not include, for example, the amount required for a blood donation (up to about 450 mL of blood). A "blood sample suitable for BG and BMP parameter analysis and platelet counting" means that the blood sample is suitable for use in determining BG, BMP parameters, and performing platelet counting, where anticoagulants and / or antiplatelet agents do not interfere, or at least do not substantially interfere, with the determination of one of the parameters.

[0024] In the context of the present invention, the term "sugar" refers to a mono-, di-, or trisaccharide. Examples of sugars in the context of the present invention include glucose, raffinose, galactose, fructose, xylose, sucrose, lactose, maltose, isomaltulose, and trehalose.

[0025] In the context of the present invention, the term "matrix material" refers to the material used to form the matrix in which the antiplatelet agent is dispersed. The matrix material can be a water-soluble polymer, a sugar, or both.

[0026] When referring to the molecular weight of a polymer herein, unless otherwise specified, it refers to the weight average molecular weight. Water-soluble polymers The solubility of the solid mixture in water is advantageous in view of its intended use with blood samples. Many water-soluble polymers are known for pharmaceutical applications, e.g., as excipients for tablets, etc. These are chemically inert and do not interfere with active compounds such as prostacyclin or its analogs. Known water-soluble polymers suitable for use in the present invention include polyethylene oxide (PEO), PEO derivatives, poloxamer, poloxamine, polyvinylpyrrolidone (PVP), hydroxypropyl cellulose, hypromellose, hypromellose phthalate, hypromellose acetate succinate, polyacrylates, polymethacrylates, poly(isopropylacrylamide), polyacrylamide, polyethylene glycol (PEG), PEO / polypropylene glycol copolymers, PEG-modified starch, vinyl acetate-vinylpyrrolidone copolymers, polyacrylic acid copolymers, polymethacrylic acid copolymers, vegetable proteins, protein hydrolysates, polyelectrolytes, polyvinyl alcohol, poly(2-oxazoline), polyethyleneimine, cucurbit[n]uril hydrate, maleic anhydride copolymers, polyphosphates, polyphosphazenes, xanthan gum, pectin, chitosan derivatives, dextran, carrageenan, guar gum, cellulose ethers, hyaluronic acid, albumin, and starch and starch derivatives.Thus, in one embodiment, the water soluble polymer is selected from PEO, PEO derivatives, poloxamer, poloxamine, PVP, hydroxypropyl cellulose, hypromellose, hypromellose phthalate, hypromellose acetate succinate, polyacrylates, polymethacrylates, poly(isopropylacrylamide), polyacrylamide, PEG, PEO / polypropylene glycol copolymers, PEG-modified starch, vinyl acetate-vinylpyrrolidone copolymers, polyacrylic acid copolymers, polymethacrylic acid copolymers, plant proteins, protein hydrolysates, polyelectrolytes, polyvinyl alcohol, poly(2-oxazoline), polyethyleneimine, cucurbit[n]uril hydrate, maleic anhydride copolymers, polyphosphates, polyphosphazenes, xanthan gum, pectin, chitosan derivatives, dextran, carrageenan, guar gum, cellulose ethers, hyaluronic acid, albumin, starch and starch derivatives, and mixtures thereof. In further embodiments, the water soluble polymer is selected from PEO, poloxamer, poloxamine, PVP, hydroxypropyl cellulose, hypromellose, hypromellose phthalate, hypromellose acetate succinate, polyacrylates, polymethacrylates, poly(isopropylacrylamide), polyacrylamide, PEG, PEO / polypropylene glycol copolymer, vinyl acetate-vinylpyrrolidone copolymer, polyvinyl alcohol, poly(2-oxazoline), polyphosphate, polyphosphazene, xanthan gum, pectin, dextran, carrageenan, guar gum, cellulose ethers, hyaluronic acid, starch and starch derivatives, and mixtures thereof. In still further embodiments, the water soluble polymer is selected from PEO, PVP, hydroxypropyl cellulose, hypromellose, polyacrylates, polymethacrylates, polyacrylamides, PEG, PEO / polypropylene glycol copolymers, polyvinyl alcohol, polyphosphates, xanthan gum, pectin, dextran, carrageenan, guar gum, starch and starch derivatives and mixtures thereof.In yet a further embodiment, the water-soluble polymer is selected from PEO, PVP, hydroxypropyl cellulose, hypromellose, PEG, polyvinyl alcohol, xanthan gum, guar gum, starch and starch derivatives, and mixtures thereof. In another embodiment, the water-soluble polymer is selected from PEO, PVP, hydroxypropyl cellulose, hypromellose, PEG, polyvinyl alcohol, and mixtures thereof. In a further embodiment, the water-soluble polymer is selected from PVP, hydroxypropyl cellulose, hypromellose, and mixtures thereof. In yet another embodiment, the water-soluble polymer is selected from PVP, hypromellose, and mixtures thereof. In yet another embodiment, the water-soluble polymer is PVP.

[0027] Water-soluble polymers are typically available in many different molecular weights, with lower molecular weights typically having higher water solubility and faster dissolution. In one embodiment, the water-soluble polymer has a molecular weight in the range of 1,000 to 450,000 Da. In a further embodiment, the water-soluble polymer has a molecular weight in the range of 2,000 to 100,000 Da. In a further embodiment, the water-soluble polymer has a molecular weight in the range of 3,000 to 60,000 Da.

[0028] Prostacyclin analogues Prostacyclin and its analogs prevent the formation of platelet thrombi, which are involved in primary hemostasis (part of clot formation). They do this by inhibiting platelet activation. They are also effective vasodilators. In the context of the present invention, prostacyclin analogs include iloprost, beraprost, treprostinil, cicaprost, carbacyclin, EP 157 ((Z)-7-[(1R,2R,3R,4S)-3-[(Z)-benzhydryloxyiminomethyl]-2-bicyclo[2.2.2]oct-5-enyl]hept-5-enoic acid), FK-788 (2-[(6R)-6-(diphenylcarbamoyloxymethyl)-6-hydroxy-7,8-dihydro-5H-naphthalen-1-yl]oxy]acetic acid), and taprosten. These compounds can be in the form of the free acid or a salt thereof. Furthermore, they exist in various stereoisomeric forms. Thus, the compounds contained in the solid mixture contained in the blood sampler according to the present invention are selected from iloprost, beraprost, treprostinil, cicaprost, carbacyclin, EP 157 ((Z)-7-[(1R,2R,3R,4S)-3-[(Z)-benzhydryloxyiminomethyl]-2-bicyclo[2.2.2]oct-5-enyl]hept-5-enoic acid), FK-788 (2-[(6R)-6-(diphenylcarbamoyloxymethyl)-6-hydroxy-7,8-dihydro-5H-naphthalen-1-yl]oxy]acetic acid, and taprosten, as well as any stereoisomers and salts thereof.

[0029] In one embodiment, the compound contained in the solid mixture contained in the blood sampler according to the present invention is selected from iloprost, beraprost, treprostinil, cicaprost, carbacyclin, and EP 157 ((Z)-7-[(1R,2R,3R,4S)-3-[(Z)-benzhydryloxyiminomethyl]-2-bicyclo[2.2.2]oct-5-enyl]hept-5-enoic acid), and any stereoisomers and salts thereof. In a further embodiment, the compound contained in the solid mixture contained in the blood sampler according to the present invention is selected from iloprost, beraprost, treprostinil, cicaprost, and carbacyclin, and any stereoisomers and salts thereof. In yet a further embodiment, the compound contained in the solid mixture contained in the blood sampler according to the present invention is selected from iloprost, beraprost, and treprostinil, and any stereoisomers and salts thereof.

[0030] In another embodiment, the compound contained in the solid mixture contained in the blood sampler according to the present invention is iloprost or a salt of iloprost. In yet another embodiment, the compound contained in the solid mixture contained in the blood sampler according to the present invention is a salt of iloprost, such as the trometamol salt. In yet another embodiment, iloprost is the 8S, 9S, 11R, 12S, 16S-isomer of iloprost.

[0031] Those skilled in the art will understand that the amount of prostacyclin analog should be sufficient to exert its antiplatelet effect on the blood sample to be loaded into the blood sampler. Those skilled in the art will also understand that in practical applications, the amount of prostacyclin analog will be limited due to economic considerations. Furthermore, without being bound by any particular theory, an amount that avoids excessively high concentrations will help avoid degradation products, such as dimeric esters, known for iloprost. In one embodiment, the amount of a compound, such as iloprost or a salt thereof, contained in a solid mixture is in the range of 0.01 to 20.0% (w / w) of the solid mixture. In a further embodiment, the amount of a compound, such as iloprost or a salt thereof, contained in a solid mixture is in the range of 0.05 to 5.0% (w / w) of the solid mixture, for example, in the range of 0.1 to 2.5% of the solid mixture, for example, in the range of 0.2 to 1.5% of the solid mixture. In another embodiment, the amount of the compound, such as iloprost or a salt thereof, contained in the solid mixture is in the range of 0.5 to 10.0% (w / w) of the solid mixture, for example, in the range of 0.7 to 4.0% of the solid mixture.

[0032] Anticoagulants As discussed above, the "3-in-1" method involves the use of an anticoagulant in addition to an antiplatelet agent. The anticoagulant can be included in the blood sampler, or it can be added separately. Thus, in one embodiment, the blood sampler further includes an anticoagulant. In a further embodiment, the anticoagulant included in the blood sampler is separate from the water-soluble polymeric material matrix.

[0033] Many anticoagulants are known to those skilled in the art. These include heparinates and heparinoids. Heparinates include heparins, such as unfractionated heparin, high molecular weight heparin (HMWH), low molecular weight heparins (LMWH) including bemiparin, certoparin, dalteparin, enoxaparin, nadroparin, pamaparin, reviparin, tinzaparin; and oligosaccharides, such as fondaparinux and idraparinux. Heparinoids include danaparoid, dermatan sulfate, and sulodexide. In one embodiment, the anticoagulant is a heparinate selected from unfractionated heparin, high molecular weight heparin (HMWH), low molecular weight heparin (LMWH) including bemiparin, certoparin, dalteparin, enoxaparin, nadroparin, pamaparin, reviparin, tinzaparin; and oligosaccharides such as fondaparinux and idraparinux and salts thereof. In another embodiment, the anticoagulant comprises heparin.

[0034] Heparin is a naturally occurring polysaccharide that inhibits coagulation, the process that leads to thrombosis. Natural heparin consists of molecular chains of various lengths or molecular weights. It is also used as an anticoagulant (blood thinner). It binds to the enzyme inhibitor antithrombin III (AT), causing a conformational change that leads to its activation through increased flexibility of its reactive site loop. Activated AT then inactivates thrombin, factor Xa, and other proteases.

[0035] In one embodiment, the anticoagulant is electrolyte-balanced heparin (also referred to as "balanced heparin"). Heparin is known to bind positively charged electrolytes, which can interfere with electrolyte measurements. Formulations of electrolyte-balanced heparin can include lithium, zinc, sodium, potassium, calcium, magnesium, and / or ammonium salts of heparin. In further embodiments, the electrolyte-balanced heparin includes sodium, potassium, calcium, and / or magnesium salts of heparin.

[0036] In another embodiment, the heparin is human heparin, porcine heparin, or synthetic heparin. In yet another embodiment, the heparin is porcine heparin. In a further embodiment, the anticoagulant is unfractionated heparin.

[0037] In one embodiment, the anticoagulant can be in liquid form, also referred to as "liquid heparin," or in dry form, such as, for example, dry balanced heparin. An example of a dry form of an anticoagulant is a lyophilized anticoagulant, such as, for example, lyophilized heparin or lyophilized balanced heparin. In a further embodiment, the anticoagulant is in lyophilized form.

[0038] Buffers and sugars Some of the prostacyclin analogs according to the present invention are sensitive to certain pH conditions. For example, iloprost is sensitive to acidic pH. Therefore, in some cases, it may be beneficial to add a buffer to the solid mixture. Therefore, in one embodiment, the solid mixture further comprises a buffer material. In another embodiment, the buffer material is a Tris buffer.

[0039] Many different buffering agents are available, and most pH values ​​within the normal range of 0 to 14 can be achieved using buffering agents. In some cases, such as with iloprost, buffering agents that provide an alkaline pH are beneficial. Thus, in one embodiment, the buffering agent provides a pH in the range of 7.5 to 12.0. In a further embodiment, the buffering agent provides a pH in the range of 7.6 to 11.0. In yet a further embodiment, the buffering agent provides a pH in the range of 7.7 to 10.0. In yet a further embodiment, the buffering agent provides a pH in the range of 7.8 to 9.5. In another embodiment, the buffering agent provides a pH in the range of 7.9 to 9.0.

[0040] Without being bound by any theory, it is further contemplated that some prostacyclin analogs may benefit from increased stability by including a sugar in the solid mixture. Thus, in one embodiment, the solid mixture further comprises a sugar dispersed in a matrix of a water-soluble polymer. In another embodiment, the sugar is selected from the group consisting of glucose, raffinose, galactose, fructose, xylose, sucrose, lactose, maltose, isomaltulose, trehalose, and mixtures thereof. In yet another embodiment, the sugar is selected from the group consisting of glucose, raffinose, sucrose, and mixtures thereof.

[0041] It has also been found that sugars may themselves provide a water-soluble matrix and may provide increased solubility at a level similar to that of the water-soluble polymers defined herein. Thus, in one aspect, the present invention provides a method for treating iloprost, beraprost, treprostinil, cicaprost, carbacyclin, EP The present invention relates to a blood sampler containing a solid mixture comprising a compound selected from 157 ((Z)-7-[(1R,2R,3R,4S)-3-[(Z)-benzhydryloxyiminomethyl]-2-bicyclo[2.2.2]oct-5-enyl]hept-5-enoic acid), FK-788 (2-[(6R)-6-(diphenylcarbamoyloxymethyl)-6-hydroxy-7,8-dihydro-5H-naphthalen-1-yl]oxy]acetic acid, and taprosten, and all stereoisomers and salts thereof, wherein the compound is dispersed in a matrix of sugar. In one embodiment, the sugar is selected from the group consisting of glucose, raffinose, galactose, fructose, xylose, sucrose, lactose, maltose, isomaltulose, trehalose, and mixtures thereof. In another embodiment, the sugar is selected from the group consisting of glucose, raffinose, sucrose, and mixtures thereof.

[0042] In one embodiment, the matrix material comprises sugar and less than 5% by weight of the total matrix material of water soluble polymer, such as less than 2% by weight of the total matrix material, for example less than 1% by weight of the total matrix material. In another embodiment, the matrix material comprises only sugar and no water soluble polymer.

[0043] In further embodiments, the matrix material comprises a water-soluble polymer and less than 5% by weight of the total matrix material, e.g., less than 2% by weight of the total matrix material, e.g., less than 1% by weight of the total matrix material, of sugar. In still further embodiments, the matrix material comprises only a water-soluble polymer and no sugar.

[0044] In yet another embodiment, the matrix material comprises both a water-soluble polymer and a sugar. In a further embodiment, the matrix material comprises a water-soluble polymer and a sugar in a weight ratio of 70:30 to 30:70, e.g., a weight ratio of 60:40 to 40:60, e.g., a weight ratio of 50:50.

[0045] Further Aspects Specific embodiments are disclosed for each of the features of the present invention discussed above. It is further contemplated that the present invention may be directed to a combination of these embodiments. Thus, in one embodiment, the water-soluble polymer is selected from PEO, PVP, hydroxypropyl cellulose, hypromellose, PEG, polyvinyl alcohol, and mixtures thereof, and the compound contained in the solid mixture contained in the blood sampler according to the present invention is selected from iloprost, beraprost, treprostinil, cicaprost, carbacyclin, and EP 157 ((Z)-7-[(1R,2R,3R,4S)-3-[(Z)-benzhydryloxyiminomethyl]-2-bicyclo[2.2.2]oct-5-enyl]hept-5-enoic acid), and any stereoisomers and salts thereof. In a further embodiment, the water-soluble polymer is selected from PEO, PVP, hydroxypropyl cellulose, hypromellose, PEG, polyvinyl alcohol, and mixtures thereof, and the compound contained in the solid mixture contained in the blood sampler according to the present invention is selected from iloprost, beraprost, and treprostinil, and any stereoisomers and salts thereof. In yet a further embodiment, the water-soluble polymer is selected from PEO, PVP, hydroxypropyl cellulose, hypromellose, PEG, polyvinyl alcohol, and mixtures thereof, and the compound contained in the solid mixture contained in the blood sampler according to the present invention is iloprost or a salt of iloprost.

[0046] In another embodiment, the water-soluble polymer is selected from PVP, hypromellose, and mixtures thereof, and the compound contained in the solid mixture contained in the blood sampler according to the present invention is selected from iloprost, beraprost, treprostinil, cicaprost, carbacyclin, and EP 157 ((Z)-7-[(1R,2R,3R,4S)-3-[(Z)-benzhydryloxyiminomethyl]-2-bicyclo[2.2.2]oct-5-enyl]hept-5-enoic acid) and any stereoisomers and salts thereof. In yet another embodiment, the water-soluble polymer is selected from PVP, hypromellose, and mixtures thereof, and the compound contained in the solid mixture contained in the blood sampler according to the present invention is selected from iloprost, beraprost, and treprostinil and any stereoisomers and salts thereof. In yet another embodiment, the water-soluble polymer is selected from PVP, hypromellose and mixtures thereof, and the compound contained in the solid mixture contained in the blood sampler according to the present invention is iloprost or a salt of iloprost.

[0047] In a further embodiment, the water-soluble polymer is PVP, and the compound contained in the solid mixture contained in the blood sampler according to the present invention is selected from iloprost, beraprost, treprostinil, cicaprost, carbacyclin, and EP 157 ((Z)-7-[(1R,2R,3R,4S)-3-[(Z)-benzhydryloxyiminomethyl]-2-bicyclo[2.2.2]oct-5-enyl]hept-5-enoic acid), and any stereoisomers and salts thereof. In a still further embodiment, the water-soluble polymer is PVP, and the compound contained in the solid mixture contained in the blood sampler according to the present invention is selected from iloprost, beraprost, and treprostinil, and any stereoisomers and salts thereof. In a still further embodiment, the water-soluble polymer is PVP, and the compound contained in the solid mixture contained in the blood sampler according to the present invention is iloprost or a salt of iloprost.

[0048] In another embodiment, the water-soluble polymer is selected from PEO, PVP, hydroxypropyl cellulose, hypromellose, PEG, polyvinyl alcohol, and mixtures thereof, and the compound contained in the solid mixture contained in the blood sampler according to the present invention is selected from iloprost, beraprost, treprostinil, cicaprost, carbacyclin, and EP 157 ((Z)-7-[(1R,2R,3R,4S)-3-[(Z)-benzhydryloxyiminomethyl]-2-bicyclo[2.2.2]oct-5-enyl]hept-5-enoic acid) and any stereoisomers and salts thereof in an amount ranging from 0.05 to 5.0% by weight of the solid mixture. In yet another embodiment, the water-soluble polymer is selected from PEO, PVP, hydroxypropyl cellulose, hypromellose, PEG, polyvinyl alcohol, and a mixture thereof, and the compound contained in the solid mixture contained in the blood sampler according to the present invention is selected from iloprost, beraprost, and treprostinil, and any stereoisomers and salts thereof, in an amount ranging from 0.05 to 5.0% by weight of the solid mixture. In yet another embodiment, the water-soluble polymer is selected from PEO, PVP, hydroxypropyl cellulose, hypromellose, PEG, polyvinyl alcohol, and a mixture thereof, and the compound contained in the solid mixture contained in the blood sampler according to the present invention is iloprost or a salt of iloprost, in an amount ranging from 0.05 to 5.0% by weight of the solid mixture.

[0049] In a further embodiment, the water-soluble polymer is selected from PVP, hypromellose, and mixtures thereof, and the compounds contained in the solid mixture contained in the blood sampler according to the present invention are selected from iloprost, beraprost, treprostinil, cicaprost, carbacyclin, and EP 157 ((Z)-7-[(1R,2R,3R,4S)-3-[(Z)-benzhydryloxyiminomethyl]-2-bicyclo[2.2.2]oct-5-enyl]hept-5-enoic acid) and any stereoisomers and salts thereof, in an amount ranging from 0.05 to 5.0% by weight of the solid mixture. In yet a further embodiment, the water-soluble polymer is selected from PVP, hypromellose, and mixtures thereof, and the compounds contained in the solid mixture contained in the blood sampler according to the present invention are selected from iloprost, beraprost, and treprostinil and any stereoisomers and salts thereof, in an amount ranging from 0.05 to 5.0% by weight of the solid mixture. In yet a further embodiment, the water-soluble polymer is selected from PVP, hypromellose and mixtures thereof, and the compound contained in the solid mixture contained in the blood sampler according to the present invention is iloprost or a salt of iloprost in an amount ranging from 0.05 to 5.0% by weight of the solid mixture.

[0050] In another embodiment, the water-soluble polymer is PVP, and the compound contained in the solid mixture contained in the blood sampler according to the present invention is selected from iloprost, beraprost, treprostinil, cicaprost, carbacyclin, and EP 157 ((Z)-7-[(1R,2R,3R,4S)-3-[(Z)-benzhydryloxyiminomethyl]-2-bicyclo[2.2.2]oct-5-enyl]hept-5-enoic acid) and any stereoisomers and salts thereof, in an amount ranging from 0.05 to 5.0% by weight of the solid mixture. In yet another embodiment, the water-soluble polymer is PVP, and the compound contained in the solid mixture contained in the blood sampler according to the present invention is selected from iloprost, beraprost, and treprostinil, and any stereoisomers and salts thereof, in an amount ranging from 0.05 to 5.0% by weight of the solid mixture. In yet another embodiment, the water-soluble polymer is PVP, and the compound contained in the solid mixture contained in the blood sampler according to the present invention is iloprost or a salt of iloprost in an amount ranging from 0.05 to 5.0% by weight of the solid mixture.

[0051] In a further embodiment, the water-soluble polymer is selected from PEO, PVP, hydroxypropyl cellulose, hypromellose, PEG, polyvinyl alcohol, and mixtures thereof, and the compound contained in the solid mixture contained in the blood sampler according to the present invention is selected from iloprost, beraprost, treprostinil, cicaprost, carbacyclin, and EP 157 ((Z)-7-[(1R,2R,3R,4S)-3-[(Z)-benzhydryloxyiminomethyl]-2-bicyclo[2.2.2]oct-5-enyl]hept-5-enoic acid) and all stereoisomers and salts thereof, in an amount ranging from 0.1 to 2.5% by weight of the solid mixture. In yet a further embodiment, the water-soluble polymer is selected from PEO, PVP, hydroxypropyl cellulose, hypromellose, PEG, polyvinyl alcohol, and a mixture thereof, and the compound contained in the solid mixture contained in the blood sampler according to the present invention is selected from iloprost, beraprost, and treprostinil, and any stereoisomers and salts thereof, in an amount ranging from 0.1 to 2.5% by weight of the solid mixture. In yet a further embodiment, the water-soluble polymer is selected from PEO, PVP, hydroxypropyl cellulose, hypromellose, PEG, polyvinyl alcohol, and a mixture thereof, and the compound contained in the solid mixture contained in the blood sampler according to the present invention is iloprost or a salt of iloprost, in an amount ranging from 0.1 to 2.5% by weight of the solid mixture.

[0052] In a further embodiment, the water-soluble polymer is selected from PVP, hypromellose, and mixtures thereof, and the compounds contained in the solid mixture contained in the blood sampler according to the present invention are selected from iloprost, beraprost, treprostinil, cicaprost, carbacyclin, and EP 157 ((Z)-7-[(1R,2R,3R,4S)-3-[(Z)-benzhydryloxyiminomethyl]-2-bicyclo[2.2.2]oct-5-enyl]hept-5-enoic acid) and any stereoisomers and salts thereof, in an amount ranging from 0.1 to 2.5% by weight of the solid mixture. In yet a further embodiment, the water-soluble polymer is selected from PVP, hypromellose, and mixtures thereof, and the compounds contained in the solid mixture contained in the blood sampler according to the present invention are selected from iloprost, beraprost, and treprostinil and any stereoisomers and salts thereof, in an amount ranging from 0.1 to 2.5% by weight of the solid mixture. In yet a further embodiment, the water-soluble polymer is selected from PVP, hypromellose and mixtures thereof, and the compound contained in the solid mixture contained in the blood sampler according to the present invention is iloprost or a salt of iloprost in an amount ranging from 0.1 to 2.5% by weight of the solid mixture.

[0053] In another embodiment, the water-soluble polymer is PVP, and the compound contained in the solid mixture contained in the blood sampler according to the present invention is selected from iloprost, beraprost, treprostinil, cicaprost, carbacyclin, and EP 157 ((Z)-7-[(1R,2R,3R,4S)-3-[(Z)-benzhydryloxyiminomethyl]-2-bicyclo[2.2.2]oct-5-enyl]hept-5-enoic acid) and any stereoisomers and salts thereof, in an amount ranging from 0.1 to 2.5% by weight of the solid mixture. In yet another embodiment, the water-soluble polymer is PVP, and the compound contained in the solid mixture contained in the blood sampler according to the present invention is selected from iloprost, beraprost, and treprostinil and any stereoisomers and salts thereof, in an amount ranging from 0.1 to 2.5% by weight of the solid mixture. In yet another embodiment, the water-soluble polymer is PVP, and the compound contained in the solid mixture contained in the blood sampler according to the present invention is iloprost or a salt of iloprost in an amount ranging from 0.1 to 2.5% by weight of the solid mixture.

[0054] In another embodiment, the water-soluble polymer is selected from PEO, PVP, hydroxypropyl cellulose, hypromellose, PEG, polyvinyl alcohol, and mixtures thereof, and the compound contained in the solid mixture contained in the blood sampler according to the present invention is selected from iloprost, beraprost, treprostinil, cicaprost, carbacyclin, and EP 157 ((Z)-7-[(1R,2R,3R,4S)-3-[(Z)-benzhydryloxyiminomethyl]-2-bicyclo[2.2.2]oct-5-enyl]hept-5-enoic acid) and any stereoisomers and salts thereof, in an amount ranging from 0.2 to 1.5% by weight of the solid mixture. In yet another embodiment, the water-soluble polymer is selected from PEO, PVP, hydroxypropyl cellulose, hypromellose, PEG, polyvinyl alcohol, and a mixture thereof, and the compound contained in the solid mixture contained in the blood sampler according to the present invention is selected from iloprost, beraprost, and treprostinil, and any stereoisomers and salts thereof, in an amount ranging from 0.2 to 1.5% by weight of the solid mixture. In yet another embodiment, the water-soluble polymer is selected from PEO, PVP, hydroxypropyl cellulose, hypromellose, PEG, polyvinyl alcohol, and a mixture thereof, and the compound contained in the solid mixture contained in the blood sampler according to the present invention is iloprost or a salt of iloprost, in an amount ranging from 0.2 to 1.5% by weight of the solid mixture.

[0055] In a further embodiment, the water-soluble polymer is selected from PVP, hypromellose, and mixtures thereof, and the compounds contained in the solid mixture contained in the blood sampler according to the present invention are selected from iloprost, beraprost, treprostinil, cicaprost, carbacyclin, and EP 157 ((Z)-7-[(1R,2R,3R,4S)-3-[(Z)-benzhydryloxyiminomethyl]-2-bicyclo[2.2.2]oct-5-enyl]hept-5-enoic acid) and any stereoisomers and salts thereof, in an amount ranging from 0.2 to 1.5% by weight of the solid mixture. In yet a further embodiment, the water-soluble polymer is selected from PVP, hypromellose, and mixtures thereof, and the compounds contained in the solid mixture contained in the blood sampler according to the present invention are selected from iloprost, beraprost, and treprostinil and any stereoisomers and salts thereof, in an amount ranging from 0.2 to 1.5% by weight of the solid mixture. In yet a further embodiment, the water-soluble polymer is selected from PVP, hypromellose, and mixtures thereof, and the compound contained in the solid mixture contained in the blood sampler according to the present invention is iloprost or a salt of iloprost in an amount ranging from 0.2 to 1.5% by weight of the solid mixture.

[0056] In another embodiment, the water-soluble polymer is PVP, and the compound contained in the solid mixture contained in the blood sampler according to the present invention is selected from iloprost, beraprost, treprostinil, cicaprost, carbacyclin, and EP 157 ((Z)-7-[(1R,2R,3R,4S)-3-[(Z)-benzhydryloxyiminomethyl]-2-bicyclo[2.2.2]oct-5-enyl]hept-5-enoic acid) and any stereoisomers and salts thereof, in an amount ranging from 0.2 to 1.5% by weight of the solid mixture. In yet another embodiment, the water-soluble polymer is PVP, and the compound contained in the solid mixture contained in the blood sampler according to the present invention is selected from iloprost, beraprost, and treprostinil and any stereoisomers and salts thereof, in an amount ranging from 0.2 to 1.5% by weight of the solid mixture. In yet another embodiment, the water-soluble polymer is PVP, and the compound contained in the solid mixture contained in the blood sampler according to the present invention is iloprost or a salt of iloprost in an amount ranging from 0.2 to 1.5% by weight of the solid mixture.

[0057] Preparation of solid mixtures The solid mixture contained in the blood sampler of the present invention can be prepared by dissolving the compound and the water-soluble polymer in a suitable solvent, such as water or ethanol, stirring, and drying the solution. The solid mixture can also be prepared by spray-drying a solution containing the compound and the water-soluble polymer. A particularly useful spray-drying technique is ultrasonic spray coating. Ultrasonic spray coating uses ultrasound to create atomization of the liquid. A small airflow is used to direct the spray mist away from the nozzle and toward the desired surface. Very small amounts of liquid can be applied in a reproducible manner. This technique is useful for spray-coating the interior surfaces of blood samplers, such as tubes and syringes. The spray nozzle enters the blood sampler and sprays as the nozzle is withdrawn from the sampler. The atomized spray has a narrower droplet size distribution than conventional pressure-driven atomization, which increases the reproducibility of the spray. Ultrasonic spray coating equipment is available, among others, from Sono-Tek (e.g., the ExactaCoat® Coating System). [Example]

[0058] Preparation of solutions A. Dilute 1 mL of a 5 mg / mL solution of iloprost in methyl acetate (e.g., Cayman Chemical) with ethanol in a 25 mL volumetric flask to obtain a solution concentration of 0.2 mg / mL.

[0059] B. A 25 mM Tris solution is made by dissolving 0.07571 g of tris(hydroxymethyl)aminomethane (Merck No. 1.08382.0500) in Milli-Q water in a 25 mL volumetric flask.

[0060] C. PVP-Tris solution is made by dissolving 1.166 g of PVP-10 (e.g., Merck (Mw 10,000)) in approximately 35 mL of Milli-Q water in a 50 mL volumetric flask, adding 7.292 mL of 25 mM Tris solution (B), and filling to the 50 mL mark with Milli-Q water.

[0061] D. The final solution is made by mixing 1442 μL of iloprost solution (A) with 1224 μL of PVP-Tris solution (C). When other matrix polymers and sugars are tested, PVP is substituted by mass in the PVP-Tris solution (C). For mixtures of polymers and sugars, equal volumes of polymer-Tris and sugar-Tris solutions (612 μL each) are used in place of the PVP-Tris solution. For water-soluble polymers, the following products were used: HPMC (Merck, product number H8384), PVP (MW 10,000), Kolliphor P407 (Merck, product number 62035), PEG 10,000 (Merck, product number 92897), PEG 35,000 (Merck, product number 81310), and PVP 40,000 (Merck, product number PVP 40). Regarding sugars, the following products were used: D-(-)-fructose (Merck, product number F3510), D-(+)-galactose (Merck, product number G5388), glucose (Merck), raffinose (Merck, product number R0514) and sucrose (Merck, product number S7903).

[0062] When other antithrombotic agents are tested, substitutions are made for solution A to achieve the same molar concentration. Beraprost sodium (e.g., Merck) is first diluted to a 10 mM solution in saline, then further diluted with 30% ethanol in water to obtain a solution of the same molar concentration as iloprost in A. Treprostinil (e.g., Merck) is dissolved directly in ethanol.

[0063] Adding 10 μL of the final solution (D) to a blood collection tube, drying it, and adding 3 mL of Milli-Q water gives a theoretical iloprost concentration of 1000 nM.

[0064] Preparation of tubes 3 mL blood collection tubes (additive-free tubes, Greiner Bio-one, reference number 454001) were used for the test.

[0065] For storage stability and whole blood stabilization testing, 10 μL of mixture (D) was sprayed into each tube using an ExactaCoat ultrasonic sprayer manufactured by Sono-Tek. After spraying, the tube was evacuated to allow for loading with 3 mL of whole blood during venipuncture blood withdrawal.

[0066] For dissolution testing, 10 μL of solution mixture (D) was pipetted into a collection tube and left to dry at least overnight.

[0067] Dissolution test A 2mm x 7mm rounded PTFE-coated magnet was added to each blood collection tube, which was then placed vertically in a holder on a magnetic stirrer at 920 rpm. At time 0, 3mL of Milli-Q water was added, and 100µL was removed from the blood collection tube at times 10, 60, and 300 seconds. The iloprost concentration was determined by comparison with a standard curve by HPLC-MS. Beraprost and treprostinil were compared to the iloprost standard curve, so the concentrations of beraprost and treprostinil are only estimates.

[0068] Example 1 - Storage Stability Before exposing them to the test environment, the closed tubes were closed, and the open tubes were stored with their lids in an exicator with a saturated solution of NaCl in Milli-Q water to obtain a 75% RH atmosphere (excluding -18°C) and stored at the indicated temperatures. At the indicated storage times, 3 mL of Milli-Q water was added to each tube. The tubes were rotated or shaken at least three times to ensure proper dissolution for at least 10 minutes. The iloprost concentration was determined by HPLC-MS compared to a curve generated from standard solutions of 1 nM to 1500 nM iloprost.

[0069] Test tubes prepared as described above for the mixture of iloprost, PVP, and Tris were stored as open or closed tubes at −18° C., 5° C., room temperature, or 32° C. Relative iloprost concentrations compared to the concentration at the time of tube manufacture (time 0, t0) were measured after approximately 1 week, 1 month, 2 months, and 3 months.

[0070] The results are shown in Figure 1. They show that stability is highest at -18°C, but is also quite high at 32°C, especially in closed tubes. Relative iloprost concentrations compared to the iloprost concentration at the time of tube manufacture (time 0) were also determined for iloprost / PVP / Tris-sprayed blood collection tubes compared to iloprost / Tris and iloprost (unformulated) stored either open or closed at a temperature of 32° C. for approximately 1 week, 1 month, and 2 months. The results are shown in Figure 2. They indicate that the PVP matrix provides enhanced stability, and that the Tris also contributes to stability.

[0071] Example 2 - Dissolution Rate with and without Matrix The effect of iloprost formulations on achieving rapid dissolution of iloprost was examined. The iloprost concentrations extracted from dry-formulated iloprost / PVP(10,000) / Tris versus iloprost in blood collection tubes were determined. Iloprost concentrations were determined at extraction times of 10 seconds, 1 minute, and 5 minutes in four replicate tubes. The results are shown in Figure 3. They demonstrate a significant increase in dissolution rate in the PVP matrix.

[0072] Example 3 - Dissolution Rates for Different Polymers The effect of different water-soluble polymers on the dissolution rate of iloprost was tested. The iloprost concentration extracted from tubes containing dry-blended iloprost / polymer / Tris was determined for the polymers HPMC, PVP (MW 10,000; labeled IloPVPTris), Kolliphor P407, PEG 10,000, PEG 35,000, and PVP 40,000. Iloprost concentrations were determined for extraction times of 10 seconds, 1 minute, and 5 minutes for n=4 replicate tubes.

[0073] The results are shown in Figure 4. They demonstrate that PVP polymers of different molecular weights perform equally well. They further demonstrate that cellulose derivatives such as HPMC provide similar levels of dissolution.

[0074] Example 4 - Dissolution Rate in Different Sugars The effect of sugars used in iloprost formulations on the dissolution rate of dry-formulated iloprost was examined. The iloprost concentration extracted from tubes containing dry-formulated iloprost / sugar / Tris was determined for the sugars fructose (IloFruTris), galactose (IloGalTris), glucose (IloGluTris), raffinose (IloRafTris), and sucrose (IloSucTris). Iloprost concentrations were determined for extraction times of 10 seconds, 1 minute, and 5 minutes for n=3 or 4 replicate tubes.

[0075] The results are shown in Figure 5. They demonstrate that sugars by themselves can achieve dissolution similar to that obtained with water-soluble polymers. The effect of polymer and sugar mixture used in iloprost formulation on the dissolution rate of dry-formulated iloprost was also tested.The iloprost concentration extracted from tubes using dry-formulated iloprost / polymer+sugar mixture / Tris was determined for PVP(10'000) and glucose mixture (IloPVPGluTris) and PVP(10'000) and raffinose mixture (IloPVPRafTris).The iloprost concentration was determined for extraction times of 10 seconds, 1 minute and 5 minutes for n=3 replicate tubes.

[0076] The results are shown in Figure 6. They demonstrate that replacing half of the PVP with either glucose or raffinose provides similar dissolution.

[0077] Example 5 - Dissolution Rates of Other Antiplatelet Agents The dissolution rates of dry-formulated beraprost sodium, iloprost, and treprostinil were tested. The antiplatelet concentrations (estimated from an iloprost concentration standard curve) extracted from tubes containing the dry-formulated antiplatelet agents beraprost (BerPVPTris), iloprost (IloPVPTris), and treprostinil (TrePVPTris) were determined. Concentrations were determined for extraction times of 10 seconds, 1 minute, and 5 minutes for n=4 or 5 replicate tubes.

[0078] The results are shown in Figure 7. They demonstrate that dissolution of matrix formulations of beraprost and treprostinil is achieved at levels similar to that of iloprost.

[0079] Example 6 - Stability of Whole Blood Tubes containing the sprayed antiplatelet agents iloprost, beraprost sodium, and treprostinil, each formulated with PVP (molecular weight 10,000) / Tris matrix, were prepared by ultrasonic spraying as described above. Spraying was performed either 1) in tubes without additives, after which a heparinized filter paper brick (Hep brick) was added to the tube, or 2) in commercially available lithium heparin tubes (LiHep). The formulations were prepared to achieve a final antiplatelet agent concentration of 1 μM in whole blood. After preparation, the tubes were evacuated and capped to allow for accurate whole blood volume withdrawal during venipuncture. Blood from three different healthy volunteers was drawn into the prepared blood collection tubes and reference standard EDTA and lithium heparin (LiHep) tubes. Whole blood samples were analyzed on a Sysmex XN-9000 hematology analyzer within 6 hours of blood sample draw.

[0080] The results are shown in Figure 8. The Y-axis is the normalized PLT concentration relative to the EDTA sample. The results demonstrate that, unlike heparin alone, the antiplatelet activity of iloprost, treprostinil, and beraprost is as high as that of EDTA. Thus, in addition to increasing the stability and dissolution rate of the antiplatelet agent, the matrix formulation of the present invention does not interfere with antiplatelet activity. This specification includes the disclosure of the following inventions. [Item 1] A blood sampler containing a solid mixture comprising a compound selected from iloprost, beraprost, treprostinil, cicaprost, carbacyclin, EP157 ((Z)-7-[(1R,2R,3R,4S)-3-[(Z)-benzhydryloxyiminomethyl]-2-bicyclo[2.2.2]oct-5-enyl]hept-5-enoic acid), FK-788 (2-[[(6R)-6-(diphenylcarbamoyloxymethyl)-6-hydroxy-7,8-dihydro-5H-naphthalen-1-yl]oxy]acetic acid), and taprosten, and any stereoisomers and salts thereof, wherein the compound is dispersed in a matrix of a water-soluble polymer and / or sugar. [Item 2] The blood sampler according to item 1, wherein the blood sampler is selected from a syringe, a capillary tube, a test tube, and a cuvette, for example, a syringe, a capillary tube, and a test tube. [Item 3] The blood sampler according to Item 1 or 2, wherein the water-soluble polymer is selected from the group consisting of polyethylene oxide (PEO), PEO derivatives, poloxamer, poloxamine, polyvinylpyrrolidone (PVP), hydroxypropyl cellulose, hypromellose, hypromellose phthalate, hypromellose acetate succinate, polyacrylate, polymethacrylate, poly(isopropylacrylamide), polyacrylamide, polyethylene glycol (PEG), PEO / polypropylene glycol copolymer, PEG-modified starch, vinyl acetate-vinylpiperidin, and the like. A blood sampler selected from lolidone copolymer, polyacrylic acid copolymer, polymethacrylic acid copolymer, plant protein, protein hydrolysate, polyelectrolyte, polyvinyl alcohol, poly(2-oxazoline), polyethyleneimine, cucurbit[n]uril hydrate, maleic anhydride copolymer, polyphosphate, polyphosphazene, xanthan gum, pectin, chitosan derivatives, dextran, carrageenan, guar gum, cellulose ether, hyaluronic acid, albumin, starch and starch derivatives, and mixtures thereof. [Item 4] The blood sampler according to any one of Items 1 to 3, wherein the water-soluble polymer is selected from PVP, hydroxypropyl cellulose, and hypromellose. [Item 5] The blood sampler according to Item 3, wherein the water-soluble polymer is selected from PVP, hypromellose, and mixtures thereof. [Item 6] The blood sampler according to Item 3, wherein the water-soluble polymer is PVP. [Item 7] A blood sampler according to any one of Items 1 to 6, wherein the water-soluble polymer has a molecular weight in the range of 1,000 to 450,000 Da, for example, in the range of 2,000 to 100,000 Da, for example, in the range of 3,000 to 60,000 Da. [Item 8] The blood sampler according to any one of Items 1 to 7, comprising a compound selected from iloprost, beraprost, and treprostinil, and any stereoisomers and salts thereof. [Item 9] The blood sampler according to any one of Items 1 to 8, which contains iloprost or a salt of iloprost, preferably a salt of iloprost, such as trometamol salt. [Item 10] The blood sampler according to any one of Items 1 to 9, wherein the iloprost is the 8S, 9S, 11R, 12S, 16S-isomer of iloprost. [Item 11] A blood sampler according to any one of Items 1 to 10, wherein the amount of the compound contained in the solid mixture is in the range of 0.01 to 20.0% (w / w) of the solid mixture. [Item 12] A blood sampler according to Item 8, wherein the amount of the compound contained in the solid mixture is in the range of 0.05 to 5.0% (w / w) of the solid mixture, for example, in the range of 0.1 to 2.5% of the solid mixture. [Item 13] The blood sampler according to any one of Items 1 to 12, wherein the solid mixture further contains a buffer material. [Item 14] The blood sampler according to Item 13, wherein the buffer material is a Tris buffer. [Item 15] The blood sampler according to any one of Items 1 to 14, further comprising heparin or a salt thereof. [Item 16] The blood sampler according to Item 15, wherein the heparin or salt thereof is an electrolyte-balanced heparin. [Item 17] The blood sampler according to any one of Items 15 and 16, wherein the heparin or salt thereof is separate from the matrix of the water-soluble polymer material. [Item 18] A blood sampler according to any one of Items 1 to 17, wherein the solid mixture further contains a sugar dispersed in the matrix of the water-soluble polymer, and preferably the sugar is selected from the group consisting of glucose, raffinose, galactose, fructose, xylose, sucrose, lactose, maltose, isomaltulose, trehalose, and mixtures thereof. [Item 19] The blood sampler according to any one of Items 1 to 18, wherein the matrix material comprises a water-soluble polymer and less than 5% by weight of sugars based on the total weight of the matrix material. [Item 20] The blood sampler according to any one of Items 1 to 18, wherein the matrix material contains sugars and water-soluble polymers in an amount of less than 5% by weight of the total matrix material.

Claims

1. a blood sampler selected from a syringe, a capillary tube, a test tube, and a cuvette containing a solid mixture comprising a compound selected from iloprost, beraprost, treprostinil, cicaprost, carbacyclin, EP157 ((Z)-7-[(1R,2R,3R,4S)-3-[(Z)-benzhydryloxyiminomethyl]-2-bicyclo[2.2.2]oct-5-enyl]hept-5-enoic acid), FK-788 (2-[[(6R)-6-(diphenylcarbamoyloxymethyl)-6-hydroxy-7,8-dihydro-5H-naphthalen-1-yl]oxy]acetic acid), and taprosten, and all stereoisomers and salts thereof, wherein the compound is dispersed in a matrix of a water-soluble polymer and / or a sugar; the solid mixture further comprises a buffer material; the blood sampler contains heparin or a salt thereof, and The blood sampler does not contain EDTA, Blood sampler.

2. 10. The blood sampler of claim 1, wherein the blood sampler is selected from a syringe, a capillary tube, and a test tube.

3. 3. The blood sampler according to claim 1, wherein the water-soluble polymer is selected from the group consisting of polyethylene oxide (PEO), PEO derivatives, poloxamer, poloxamine, polyvinylpyrrolidone (PVP), hydroxypropyl cellulose, hypromellose, hypromellose phthalate, hypromellose acetate succinate, polyacrylate, polymethacrylate, poly(isopropylacrylamide), polyacrylamide, polyethylene glycol (PEG), PEO / polypropylene glycol copolymer, PEG-modified starch, and vinyl acetate-vinyl A blood sampler selected from pyrrolidone copolymers, polyacrylic acid copolymers, polymethacrylic acid copolymers, plant proteins, protein hydrolysates, polyelectrolytes, polyvinyl alcohol, poly(2-oxazoline), polyethyleneimine, cucurbit[n]uril hydrate, maleic anhydride copolymers, polyphosphates, polyphosphazenes, xanthan gum, pectin, chitosan derivatives, dextran, carrageenan, guar gum, cellulose ethers, hyaluronic acid, albumin, starch and starch derivatives, and mixtures thereof.

4. 4. The blood sampler according to claim 1, wherein the water-soluble polymer is selected from the group consisting of PVP, hydroxypropyl cellulose, and hypromellose.

5. 4. The blood sampler of claim 3, wherein the water-soluble polymer is selected from PVP, hypromellose, and mixtures thereof.

6. 4. The blood sampler of claim 3, wherein the water-soluble polymer is PVP.

7. 7. The blood sampler according to claim 1, wherein the water-soluble polymer has a molecular weight in the range of 2,000 to 100,000 Da.

8. 8. The blood sampler according to any one of claims 1 to 7, wherein the compound is selected from iloprost, beraprost and treprostinil, and any stereoisomers and salts thereof.

9. 9. The blood sampler according to claim 1, wherein the compound is iloprost or a salt of iloprost.

10. 10. The blood sampler according to any one of claims 1 to 9, wherein the iloprost is the 8S, 9S, 11R, 12S, 16S-isomer of iloprost.

11. 11. The blood sampler according to claim 1, wherein the amount of the compound contained in the solid mixture is in the range of 0.01 to 20.0% (w / w) of the solid mixture.

12. 9. The blood sampler of claim 8, wherein the amount of the compound contained in the solid mixture is in the range of 0.05 to 5.0% (w / w) of the solid mixture.

13. 13. The blood sampler according to any one of claims 1 to 12, wherein the buffer material is a Tris buffer.

14. 14. The blood sampler of any one of claims 1 to 13, wherein the heparin or salt thereof is an electrolyte-balanced heparin.

15. 15. The blood sampler according to any one of claims 1 to 14, wherein the heparin or a salt thereof is not contained in a matrix of a water-soluble polymer and / or a sugar.

16. 16. The blood sampler according to any one of claims 1 to 15, wherein the sugar is selected from the group consisting of glucose, raffinose, galactose, fructose, xylose, sucrose, lactose, maltose, isomaltulose, trehalose, and mixtures thereof.

17. 17. The blood sampler according to any one of claims 1 to 16, wherein the matrix comprises a water-soluble polymer and a sugar, the sugar being present in an amount of less than 5% by weight of the total matrix.

18. 17. The blood sampler according to any one of claims 1 to 16, wherein the matrix comprises a water-soluble polymer and a sugar, and the water-soluble polymer is present in an amount of less than 5% by weight of the total matrix.

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