There exists a need for improved formulations and methods for reducing the rate of blood sedimentation for a time sufficient for storage, transport, and shipping for research, diagnostic and therapeutic purposes.
The present invention relates generally to the reduction of sedimentation rate of one or more erythrocytes in a blood sample. In particular, the invention relates to formulations, compositions, articles of manufacture, kits and methods for the reduction of erythrocyte sedimentation rate in a blood sample.
Described herein, in some embodiments, are in vitro methods for reducing the erythrocyte sedimentation rate in a blood sample, comprising: combining a sample of blood with an amount of a formulation comprising sucralose, wherein the amount is sufficient to produce a treated blood sample having a sucralose concentration of at least about 5 mM sucralose, thereby reducing the erythrocyte sedimentation rate as compared to erythrocyte sedimentation rate in an untreated blood sample. In some embodiments, the treated blood sample has a sucralose concentration of about 5 mM sucralose to about 100 mM sucralose. In some embodiments, the treated blood sample has a sucralose concentration of about 10 mM sucralose to about 100 mM sucralose. In some embodiments, the treated blood sample has a sucralose concentration of about 20 mM sucralose to about 100 mM sucralose. In some embodiments, the treated blood sample has a sucralose concentration of about 24 mM sucralose to about 100 mM sucralose. In some embodiments, the treated blood sample has a sucralose concentration of about 15 mM sucralose to about 50 mM sucralose. In some embodiments, the treated blood sample has a sucralose concentration of about 5 mM sucralose to about 50 mM sucralose. In some embodiments, the treated blood sample has a sucralose concentration of about 5 mM sucralose to about 40 mM sucralose. In some embodiments, the treated blood sample has a sucralose concentration of about 10 mM sucralose to about 35 mM sucralose. In some embodiments, the treated blood sample has a sucralose concentration of about 10 mM sucralose to about 30 mM sucralose. In some embodiments, the treated blood sample has a sucralose concentration of about 5 mM sucralose to about 25 mM sucralose. In some embodiments, the treated blood sample has a sucralose concentration of about 5 mM sucralose up to but not including 25 mM sucralose. In some embodiments, the treated blood sample has a sucralose concentration of about 5 mM sucralose to about 20 mM sucralose. In some embodiments, the treated blood sample has a sucralose concentration of about 5 mM sucralose to about 15 mM sucralose. In some embodiments, the treated blood sample has a sucralose concentration of about 5 mM sucralose to about 10 mM sucralose. In some embodiments, the treated blood sample has a sucralose concentration of about 24 mM. In some embodiments, the treated blood sample has a sucralose concentration of about 25 mM. In some embodiments, erythrocyte sedimentation rate is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% of the erythrocyte sedimentation rate of the untreated blood sample. In some embodiments, the formulation is in the form of a powder, a solid, a lyophilized form, a solution, or an aqueous solution. In some embodiments, the formulation is a powder. In some embodiments, the formulation is a solid. In some embodiments, the formulation is lyophilized. In some embodiments, the formulation is a solution. In some embodiments, the solution is an aqueous solution. In some embodiments, the formulation consists of sucralose. In some embodiments, the formulation further comprises an anticoagulant. In some embodiments, the anticoagulant is selected from the group consisting of acid citrate dextrose solution (ACD), sodium heparin, sodium fluoride, lithium heparin, tri-potassium ethylenediaminetetraacetic acid (K3EDTA), di-potassium ethylenediaminetetraacetic acid (K2EDTA), hirudin, and sodium polyanethol sulfonate (SPS). In some embodiments, the anticoagulant is acid citrate dextrose solution (ACD). In some embodiments, the anticoagulant is sodium heparin. In some embodiments, the anticoagulant is sodium fluoride. In some embodiments, the anticoagulant is lithium heparin. In some embodiments, the anticoagulant is tri-potassium ethylenediaminetetraacetic acid (K3EDTA). In some embodiments, the anticoagulant is di-potassium ethylenediaminetetraacetic acid (K2EDTA). In some embodiments, the anticoagulant is hirudin. In some embodiments, the anticoagulant is sodium polyanethol sulfonate (SPS). In some embodiments, the formulation is contained within a blood collection tube, and the combining step occurs within the blood collection tube. In some embodiments, the blood collection tube is an evacuated blood collection tube. In some embodiments, the blood is collected from a subject. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.
Described herein, in some embodiments, are in vitro methods for maintaining one or more erythrocytes in suspension in a blood sample, comprising: combining a sample of blood with an amount of a formulation comprising sucralose, wherein the amount is sufficient to produce a treated blood sample having a sucralose concentration of at least about 5 mM sucralose, thereby maintaining the one or more erythrocytes in suspension for a period of at least 30 minutes as compared to an untreated blood sample. In some embodiments, the one or more erythrocytes remain in suspension for a period of at least 10 minutes, at least 20 minutes, at least 30 minutes, at least 40 minutes, at least 50 minutes, at least 60 minutes, at least 90 minutes, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 10 hours, at least 12 hours, at least 24 hours or at least 48 hours. In some embodiments, the treated blood sample has a sucralose concentration of about 5 mM sucralose to about 100 mM sucralose. In some embodiments, the treated blood sample has a sucralose concentration of about 10 mM sucralose to about 100 mM sucralose. In some embodiments, the treated blood sample has a sucralose concentration of about 20 mM sucralose to about 100 mM sucralose. In some embodiments, the treated blood sample has a sucralose concentration of about 24 mM sucralose to about 100 mM sucralose. In some embodiments, the treated blood sample has a sucralose concentration of about 15 mM sucralose to about 50 mM sucralose. In some embodiments, the treated blood sample has a sucralose concentration of about 5 mM sucralose to about 50 mM sucralose. In some embodiments, the treated blood sample has a sucralose concentration of about 5 mM sucralose to about 40 mM sucralose. In some embodiments, the treated blood sample has a sucralose concentration of about 10 mM sucralose to about 35 mM sucralose. In some embodiments, the treated blood sample has a sucralose concentration of about 10 mM sucralose to about 30 mM sucralose. In some embodiments, the treated blood sample has a sucralose concentration of about 5 mM sucralose to about 25 mM sucralose. In some embodiments, the treated blood sample has a sucralose concentration of about 5 mM sucralose up to but not including 25 mM sucralose. In some embodiments, the treated blood sample has a sucralose concentration of about 5 mM sucralose to about 20 mM sucralose. In some embodiments, the treated blood sample has a sucralose concentration of about 5 mM sucralose to about 15 mM sucralose. In some embodiments, the treated blood sample has a sucralose concentration of about 5 mM sucralose to about 10 mM sucralose. In some embodiments, the treated blood sample has a sucralose concentration of about 24 mM. In some embodiments, the treated blood sample has a sucralose concentration of about 25 mM. In some embodiments, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% of the one or more erythrocytes remain in suspension in the treated blood sample as compared to the untreated blood sample. In some embodiments, the formulation is a powder. In some embodiments, the formulation is a solid. In some embodiments, the formulation is lyophilized. In some embodiments, the formulation is a solution. In some embodiments, the solution is an aqueous solution. In some embodiments, the formulation consists of sucralose. In some embodiments, the formulation further comprises an anticoagulant. In some embodiments, the anticoagulant is selected from the group consisting of acid citrate dextrose solution (ACD), sodium heparin, sodium fluoride, lithium heparin, tri-potassium ethylenediaminetetraacetic acid (K3EDTA), di-potassium ethylenediaminetetraacetic acid (K2EDTA), hirudin, and sodium polyanethol sulfonate (SPS). In some embodiments, the anticoagulant is acid citrate dextrose solution (ACD). In some embodiments, the anticoagulant is sodium heparin. In some embodiments, the anticoagulant is sodium fluoride. In some embodiments, the anticoagulant is lithium heparin. In some embodiments, the anticoagulant is tri-potassium ethylenediaminetetraacetic acid (K3EDTA). In some embodiments, the anticoagulant is di-potassium ethylenediaminetetraacetic acid (K2EDTA). In some embodiments, the anticoagulant is hirudin. In some embodiments, the anticoagulant is sodium polyanethol sulfonate (SPS). In some embodiments, the formulation is contained within a blood collection tube, and the combining step occurs within the blood collection tube. In some embodiments, the blood collection tube is an evacuated blood collection tube. In some embodiments, the blood sample is collected from a subject. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.
Described herein, in some embodiments, are compositions comprising a blood sample and sucralose, wherein the sucralose is at a concentration of about 5 mM sucralose up to about 100 mM sucralose. In some embodiments, the sucralose is at a concentration of about 10 mM sucralose to about 100 mM sucralose. In some embodiments, the sucralose is at a concentration of about 20 mM sucralose to about 100 mM sucralose. In some embodiments, the sucralose is at a concentration of about 24 mM sucralose to about 100 mM sucralose. In some embodiments, the sucralose is at a concentration of about 15 mM sucralose to about 50 mM sucralose. In some embodiments, the sucralose is at a concentration of about 5 mM sucralose to about 50 mM sucralose. In some embodiments, the sucralose is at a concentration of about 5 mM sucralose to about 40 mM sucralose. In some embodiments, the treated blood sample has a sucralose concentration of about 10 mM sucralose to about 35 mM sucralose. In some embodiments, the treated blood sample has a sucralose concentration of about 10 mM sucralose to about 30 mM sucralose. In some embodiments, the sucralose is at a concentration of about 5 mM sucralose up to but not including 25 mM sucralose. In some embodiments, the sucralose is at a concentration of about 5 mM sucralose to about 20 mM sucralose. In some embodiments, the sucralose is at a concentration of about 5 mM sucralose to about 15 mM sucralose. In some embodiments, the sucralose is at a concentration of about 5 mM sucralose to about 10 mM sucralose. In some embodiments, the treated blood sample has a sucralose concentration of about 24 mM. In some embodiments, the treated blood sample has a sucralose concentration of about 25 mM. In some embodiments, the compositions further comprise an anticoagulant. In some embodiments, the anticoagulant is selected from the group consisting of acid citrate dextrose solution (ACD), sodium heparin, sodium fluoride, lithium heparin, tri-potassium ethylenediaminetetraacetic acid (K3EDTA), di-potassium ethylenediaminetetraacetic acid (K2EDTA), hirudin, and sodium polyanethol sulfonate (SPS). In some embodiments, the anticoagulant is acid citrate dextrose solution (ACD). In some embodiments, the anticoagulant is sodium heparin. In some embodiments, the anticoagulant is sodium fluoride. In some embodiments, the anticoagulant is lithium heparin. In some embodiments, the anticoagulant is tri-potassium ethylenediaminetetraacetic acid (K3EDTA). In some embodiments, the anticoagulant is di-potassium ethylenediaminetetraacetic acid (K2EDTA). In some embodiments, the anticoagulant is hirudin. In some embodiments, the anticoagulant is sodium polyanethol sulfonate (SPS). In some embodiments, the composition is contained within a blood collection tube. In some embodiments, the blood collection tube is an evacuated blood collection tube. In some embodiments, the blood is collected from a subject. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.
Described herein, in some embodiments, are articles of manufacture, comprising sucralose contained within a blood collection tube, wherein the sucralose is in a quantity sufficient to produce a final concentration of about 5 mM sucralose to about 100 mM sucralose in the blood sample. In some embodiments, the sucralose is in a quantity sufficient to produce a final concentration of about 10 mM sucralose to about 100 mM sucralose. In some embodiments, the sucralose is in a quantity sufficient to produce a final concentration of about 20 mM sucralose to about 100 mM sucralose. In some embodiments, the sucralose is in a quantity sufficient to produce a final concentration of about 24 mM sucralose to about 100 mM sucralose. In some embodiments, the sucralose is in a quantity sufficient to produce a final concentration of about 15 mM sucralose to about 50 mM sucralose. In some embodiments, the sucralose is in a quantity sufficient to produce a final concentration of about 5 mM sucralose to about 50 mM sucralose in the blood sample. In some embodiments, the sucralose is in a quantity sufficient to produce a final concentration of about 5 mM sucralose to about 40 mM sucralose in the blood sample. In some embodiments, the treated blood sample has a sucralose concentration of about 10 mM sucralose to about 35 mM sucralose. In some embodiments, the treated blood sample has a sucralose concentration of about 10 mM sucralose to about 30 mM sucralose. In some embodiments, the sucralose is in a quantity sufficient to produce a final concentration of about 5 mM sucralose to up to but not including 25 mM sucralose in the blood sample. In some embodiments, the sucralose is in a quantity sufficient to produce a final concentration of about 5 mM sucralose to about 20 mM sucralose in the blood sample. In some embodiments, the sucralose is in a quantity sufficient to produce a final concentration of about 5 mM sucralose to about 15 mM sucralose in the blood sample. In some embodiments, the sucralose is in a quantity sufficient to produce a final concentration of about 5 mM sucralose to about 10 mM sucralose in the blood sample. In some embodiments, the treated blood sample has a sucralose concentration of about 24 mM. In some embodiments, the treated blood sample has a sucralose concentration of about 25 mM. In some embodiments, the sucralose is a powder. In some embodiments, the sucralose is a solid. In some embodiments, the sucralose is lyophilized. In some embodiments, the sucralose is in solution. In some embodiments, the sucralose solution is an aqueous solution. In some embodiments, the blood collection tube is an evacuated blood collection tube. In some embodiments, the articles of manufacture further comprise an anticoagulant. In some embodiments, the anticoagulant is selected from the group consisting of acid citrate dextrose solution (ACD), sodium heparin, sodium fluoride, lithium heparin, tri-potassium ethylenediaminetetraacetic acid (K3EDTA), di-potassium ethylenediaminetetraacetic acid (K2EDTA), hirudin, and sodium polyanethol sulfonate (SPS). In some embodiments, the anticoagulant is acid citrate dextrose solution (ACD). In some embodiments, the anticoagulant is sodium heparin. In some embodiments, the anticoagulant is sodium fluoride. In some embodiments, the anticoagulant is lithium heparin. In some embodiments, the anticoagulant is tri-potassium ethylenediaminetetraacetic acid (K3EDTA). In some embodiments, the anticoagulant is di-potassium ethylenediaminetetraacetic acid (K2EDTA). In some embodiments, the anticoagulant is hirudin. In some embodiments, the anticoagulant is sodium polyanethol sulfonate (SPS).
Described herein, in some embodiments, are kits, comprising an article of manufacture provided herein, and a package insert.
All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.
The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:
The present invention relates to formulations, compositions, articles of manufacture, kits, and methods for reduction of sedimentation rate of one or more erythrocytes in a blood sample.
In some embodiments, the formulations, methods, and compositions provided herein provide for reduced sedimentation rate and thus storage of the one or more erythrocytes in a blood sample at the injection site of a microfluidic device. Reduction of sedimentation rate of one or more erythrocytes in a blood sample allows for the slow injection of one or more erythrocytes into the microinjection device without the need for prior sample mixing.
Erythrocyte sedimentation rate is used as a parameter for prognosis of diseases such as multiple myeloma, temporal arteritis, polymyalgia rheumatica, systemic lupus erythematosus, and rheumatoid arthritis. Thus, in some embodiments, the formulations, methods, and compositions for reduction of erythrocyte sedimentation rate in a blood sample provided herein may benefit patients with diseases that correlate with an increased rate of erythrocyte sedimentation.
As used in this specification and the appended claims, the singular forms “a”, “an”, and “the” include plural references unless the context clearly dictates otherwise. Thus, for example, references to “the method” includes one or more methods, and/or steps of the type described herein which will become apparent to those persons skilled in the art upon reading this disclosure and so forth.
“About” as used herein when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ±20%, or ±10%, or ±5%, or even ±1% from the specified value, as such variations are appropriate for the disclosed compositions or to perform the disclosed methods.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs.
The term “ambient temperature” as used herein refers to common indoor room temperatures. In some embodiments, ambient temperature is 15 to 32° C. In some embodiments, ambient temperature is 20 to 27° C.
As used herein, the terms “reduced sedimentation rate,” “reducing sedimentation rate,” and “reduction of sedimentation rate,” refer to the ability of a material to decrease the sedimentation rate of erythrocytes in a blood sample. In some embodiments, erythrocyte sedimentation rate is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% of the erythrocyte sedimentation rate of the untreated blood sample. In some embodiments, reduction of sedimentation rate refers to the ability of a material to prevent one or more erythrocytes in a blood sample from settling out of suspension due to the force of gravity. In some embodiments, one or more erythrocytes are maintained in suspension for at least 30 minutes. In some embodiments, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% of one or more erythrocytes remain in suspension in the treated blood sample as compared to the untreated blood sample. In some embodiments, one or more erythrocytes remain in suspension for at least 10 minutes, at least 20 minutes, at least 30 minutes, at least 40 minutes, at least 50 minutes, at least 60 minutes, at least 90 minutes, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 10 hours, at least 12 hours, at least 24 hours or at least 48 hours.
Formulation Reagents
pH Buffers
According to certain embodiments, the herein described formulations and compositions for the reduction of sedimentation rate of one or more erythrocytes in a blood sample include one or more pH buffers. In some embodiments, the pH buffer is any of a large number of compounds known in the art for their ability to resist changes in the pH of a solution, such as in an aqueous solution in which the pH buffer is present. Selection of one or more particular pH buffers for inclusion in a stable storage composition may be done based on the present disclosure and according to routine practices in the art, and may be influenced by a variety of factors including the pH that is desired to be maintained, the nature of the biological sample, the solvent conditions to be employed, the other components of the formulation to be used, and other criteria. For example, typically a pH buffer is employed at a pH that is within about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 or 1.0 pH unit of a proton dissociation constant (pKa) that is a characteristic of the buffer.
Non-limiting examples of pH buffers include citric acid, tartaric acid, malic acid, sulfosalicylic acid, sulfoisophthalic acid, oxalic acid, borate, CAPS (3-(cyclohexylamino)-1-propanesulfonic acid), CAPSO (3-(cyclohexylamino)-2-hydroxy-1-propanesulfonic acid), EPPS (4-(2-hydroxyethyl)-1-piperazinepropanesulfonic acid), HEPES (4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid), MES (2-(N-morpholino)ethanesulfonic acid), MOPS (3-(N-morpholino)propanesulfonic acid), MOPSO (3-morpholino-2-hydroxypropanesulfonic acid), PIPES (1,4-piperazinediethanesulfonic acid), TAPS (N-[tris(hydroxymethyl)methyl]-3-aminopropanesulfonic acid), TAPSO (2-hydroxy-3-[tris(hydroxymethyl)methylamino]-1-propanesulfonic acid), TES (N-[tris(hydroxymethyl)methyl]-2-aminoethanesulfonic acid), bicine (N,N-bis(2-hydroxyethyl)glycine), tricine (N-[tris(hydroxymethyl)methyl]glycine), tris (tris(hydroxymethyl)aminomethane) and bis-tris (2-[bis(2-hydroxyethy)amino]-2-(hydroxymethyl)-1,3-propanediol). In some embodiments, the formulations have a pH of about 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, or 9.0.
Disaccharide Derivatives
In certain embodiments, the formulations or compositions for reduction of sedimentation rate of erythrocytes in a blood sample include at least one halogenated disaccharide derivative. In some embodiments, the halogenated disaccharide derivative is a di- or tri-chlorinated disaccharide. In some embodiments, such di- or tri-chlorinated disaccharides unexpectedly are capable of reducing sedimentation rate of erythrocytes in a blood sample either alone or in the presence of only a buffer. Halogenated disaccharide derivatives are known, e.g., see US Patent Publication No. 2014/0065062, and include sucralose (1,6-dichloro-1,6-dideoxy-β-D-fructofuranosyl-4-chloro-4-deoxy-α-D-galactopyranoside), trichloronated maltose, 1,6-dichloro-1,6-dideoxy-β-D-fructofuranosyl-4-chloro-4-deoxy-6-O-monododecanoate-α-D-galactopyranoside, and 1,6-dichloro-1,6-dideoxy-β-D-fructofuranosyl-4-chloro-4-deoxy-6-O-monotetradecanoate-α-D-galactopyranoside. Selection of one or more particular halogenated disaccharide derivative for inclusion in a formulation or composition for reduction of sedimentation rate of erythrocytes in a blood sample may be done based on the present disclosure and according to routine practices in the art, and may be influenced by a variety of factors including other formulation components.
In some embodiments, the halogenated disaccharide derivative is sucralose. In some embodiments, the sucralose is provided in solution as a formulation for mixing with a blood sample. In some embodiments, the solution is an aqueous solution. In some embodiments, the sucralose is present in the formulation at about 5-500 mM. In some embodiments, the sucralose is present in the formulation at about 10-500 mM. In some embodiments, the sucralose is present in the formulation at about 50-500 mM. In some embodiments, the sucralose is present in the formulation at about 100-500 mM. In some embodiments, the sucralose is present in the formulation at about 250-500 mM. In some embodiments, the sucralose is present in the formulation at about 5-630 mM. In some embodiments, the sucralose is present in the formulation at about 5-750 mM. In some embodiments, the sucralose is present in the formulation at about 10-750 mM. In some embodiments, the sucralose is present in the formulation at about 50-750 mM. In some embodiments, the sucralose is present in the formulation at about 100-750 mM. In some embodiments, the sucralose is present in the formulation at about 250-750 mM. In some embodiments, the formulation is a mixture of water and sucralose.
In some embodiments, the formulation is provided in an amount sufficient to produce a final concentration of sucralose of about 5 to about 25 mM, when mixed with a blood sample. In some embodiments, the sucralose is present in the formulation at about 500 mM and is mixed with a blood sample at a ratio of 1:20 (v/v) (formulation to blood). In some embodiments, the sucralose is present in the formulation at greater than 25 mM up to 100 mM. In some embodiments, the sucralose is present in the formulation at about 13-24 mM. In some embodiments, the sucralose is provided in powder form as a formulation for mixing with a blood sample. In some embodiments, the sucralose powder is provided in an amount sufficient to produce a final concentration of sucralose of about 5 to about 25 mM, when mixed with a blood sample.
In some embodiments, the sucralose is present at a final concentration of about 5-100 mM, when mixed with a blood sample. In some embodiments, the sucralose is present at a final concentration of about 5-50 mM, when mixed with a blood sample. In some embodiments, the sucralose is present at a final concentration of about 5-25 mM, when mixed with a blood sample. In some embodiments, the sucralose is present at a final concentration of about 5 up to but not including 25 mM, when mixed with a blood sample. In some embodiments, the sucralose is present at a final concentration of about 5-20 mM, when mixed with a blood sample. In some embodiments, the sucralose is present at a final concentration of about 5-15 mM, when mixed with a blood sample. In some embodiments, the sucralose is present at a final concentration of about 10-20 mM, when mixed with a blood sample. In some embodiments, the sucralose is present at a final concentration of about 10-15 mM, when mixed with a blood sample. In some embodiments, the sucralose is present at a final concentration of about 5-10 mM, when mixed with a blood sample. In some embodiments, the sucralose and is present at a final concentration of about 25 mM, when mixed with a blood sample.
Anticoagulants
In some embodiments, an anticoagulant is included in the presently described formulations and compositions. Such anticoagulants are known in the art. Exemplary anticoagulants include acid citrate dextrose solution (ACD), ethylenediaminetetraacetic acid (EDTA), tri-potassium ethylenediaminetetraacetic acid (K3EDTA), di-potassium ethylenediaminetetraacetic acid (K2EDTA), heparin, sodium heparin, sodium fluoride, lithium heparin, sodium citrate, hirudin, and sodium polyanethol sulfonate (SPS). In some embodiments, the anticoagulant is contained within a blood collection tube.
Described herein, in some embodiments, are formulations comprising sucralose. In some embodiments, the sucralose is present at a final concentration of about 5 mM sucralose to about 50 mM sucralose, when mixed with a blood sample. In some embodiments, the sucralose is present at a final concentration of about 5 mM sucralose to about 25 mM sucralose, when mixed with a blood sample. In some embodiments, the sucralose is present at a final concentration of about 5 mM sucralose up to, but not including, 25 mM sucralose. In some embodiments, the sucralose is present at a final concentration of about 5 mM sucralose to about 20 mM sucralose. In some embodiments, the sucralose is present at a final concentration of about 5 mM sucralose to about 15 mM sucralose. In some embodiments, the sucralose is present at a final concentration of about 5 mM sucralose to about 10 mM sucralose. In some embodiments, the sucralose is present as a solution. In some embodiments, the solution is an aqueous solution. In some embodiments, the sucralose is present as a powder. In some embodiments, the formulations further comprise an anticoagulant. In some embodiments, the anticoagulant is selected from the group consisting of acid citrate dextrose solution (ACD), sodium heparin, sodium fluoride, lithium heparin, tri-potassium ethylenediaminetetraacetic acid (K3EDTA), di-potassium ethylenediaminetetraacetic acid (K2EDTA), hirudin, and sodium polyanethol sulfonate (SPS). In some embodiments, the anticoagulant is acid citrate dextrose solution (ACD). In some embodiments, the anticoagulant is sodium heparin. In some embodiments, the anticoagulant is sodium fluoride. In some embodiments, the anticoagulant is lithium heparin. In some embodiments, the anticoagulant is tri-potassium ethylenediaminetetraacetic acid (K3EDTA). In some embodiments, the anticoagulant is di-potassium ethylenediaminetetraacetic acid (K2EDTA). In some embodiments, the anticoagulant is hirudin. In some embodiments, the anticoagulant is sodium polyanethol sulfonate (SPS). In some embodiments, the formulation is contained within a blood collection tube.
Methods for preparing the formulations described herein for reduction of erythrocyte sedimentation rate in a blood sample employ techniques that are well-known to those skilled in the art and generally use commercially available reagents. In some embodiments, the formulations are prepared as concentrated stock solutions of the formulation reagents, e.g., 2×, 5×, 10×, 20× or the like, so as to be admixed with the blood sample at the appropriate ratios to produce the desired final concentrations of sucralose in the blood sample.
Described herein, in some embodiments, are compositions comprising a blood sample and sucralose, wherein the sucralose is at a concentration of about 5 mM sucralose up to, but not including, about 25 mM sucralose. In some embodiments, the compositions further comprise an anticoagulant. In some embodiments, the anticoagulant is selected from the group consisting of acid citrate dextrose solution (ACD), sodium heparin, sodium fluoride, lithium heparin, tri-potassium ethylenediaminetetraacetic acid (K3EDTA), di-potassium ethylenediaminetetraacetic acid (K2EDTA), hirudin, and sodium polyanethol sulfonate (SPS). In some embodiments, the anticoagulant is acid citrate dextrose solution (ACD). In some embodiments, the anticoagulant is acid citrate dextrose solution A (ACD-A). In some embodiments, the anticoagulant is acid citrate dextrose solution B (ACD-B). In some embodiments, the anticoagulant is sodium heparin. In some embodiments, the anticoagulant is sodium fluoride. In some embodiments, the anticoagulant is lithium heparin. In some embodiments, the anticoagulant is tri-potassium ethylenediaminetetraacetic acid (K3EDTA). In some embodiments, the anticoagulant is di-potassium ethylenediaminetetraacetic acid (K2EDTA). In some embodiments, the anticoagulant is hirudin. In some embodiments, the anticoagulant is sodium polyanethol sulfonate (SPS). In some embodiments, the composition is contained within a blood collection tube. In some embodiments, the blood collection tube is an evacuated blood collection tube. In some embodiments, the blood is collected from a subject. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the compositions of one or more erythrocytes in a blood sample with reduced sedimentation rate are stored in the formulations described herein for extended periods of time before analysis in, for example, a microfluidic device.
In certain embodiments, articles of manufacture are provided, which comprise a formulation provided herein, contained within a suitable blood collection tube, container or vessel for collection of a biological sample. In some embodiments, these articles of manufacture are used for reducing sedimentation rate of one or more erythrocytes in a blood sample at the time of biological sample collection. In certain embodiments, the blood collection tube is an evacuated blood tube having less than atmospheric pressure to withdraw a predetermined volume of whole blood. In some embodiments, the blood collection tube contains about 28.6 mg of sucralose powder and the blood collection tube is of a size to contain a blood draw volume of 3.0 mL blood to produce a final sucralose concentration of about 24 mM after the addition of 3.0 mL blood. In some embodiments, the blood collection tube contains about 33.4 mg of sucralose powder and the blood collection tube is of a size to contain a blood draw volume of 3.5 mL blood. In some embodiments, the blood collection tube contains about 42.9 mg of sucralose powder and the blood collection tube is of a size to contain a blood draw volume of 4.5 mL blood. In some embodiments, the blood collection tube contains about 52.4 mg of sucralose powder and the blood collection tube is of a size to contain a blood draw volume of 5.5 mL blood. In some embodiments, the blood collection tube contains about 95.4 mg of sucralose powder and the blood collection tube is of a size to contain a blood draw volume of 10 mL blood. In some embodiments, these articles of manufacture are used in the kits and methods described herein.
In certain embodiments, there are provided kits comprising any one of the articles of manufacture described herein and a package insert. In some embodiments, the components of the kit are supplied in a container. In some embodiments, the container is a compartmentalized plastic enclosure. In some embodiments, the container includes a hermetically sealable cover so that the contents of the kit can be sterilized and sealed for storage.
Described herein, in some embodiments, are in vitro methods for reducing the erythrocyte sedimentation rate in a blood sample, comprising: combining a sample of blood with an amount of a formulation comprising sucralose, wherein the amount is sufficient to produce a treated blood sample having a sucralose concentration of at least about 5 mM sucralose, thereby reducing the erythrocyte sedimentation rate as compared to erythrocyte sedimentation rate in an untreated blood sample. In some embodiments, the treated blood sample has a sucralose concentration of about 5 mM sucralose to about 50 mM sucralose. In some embodiments, the treated blood sample has a sucralose concentration of about 5 mM sucralose to about 25 mM sucralose. In some embodiments, the treated blood sample has a sucralose concentration of about 5 mM sucralose up to but not including 25 mM sucralose. In some embodiments, erythrocyte sedimentation rate is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% of the erythrocyte sedimentation rate of the untreated blood sample. In some embodiments, the formulation is a powder. In some embodiments, the formulation is a solution. In some embodiments, the solution is an aqueous solution. In some embodiments, the formulation consists of sucralose. In some embodiments, the formulation further comprises an anticoagulant. In some embodiments, the anticoagulant is selected from the group consisting of acid citrate dextrose solution (ACD), sodium heparin, sodium fluoride, lithium heparin, tri-potassium ethylenediaminetetraacetic acid (K3EDTA), di-potassium ethylenediaminetetraacetic acid (K2EDTA), hirudin, and sodium polyanethol sulfonate (SPS). In some embodiments, the anticoagulant is acid citrate dextrose solution (ACD). In some embodiments, the anticoagulant is sodium heparin. In some embodiments, the anticoagulant is sodium fluoride. In some embodiments, the anticoagulant is lithium heparin. In some embodiments, the anticoagulant is tri-potassium ethylenediaminetetraacetic acid (K3EDTA). In some embodiments, the anticoagulant is di-potassium ethylenediaminetetraacetic acid (K2EDTA). In some embodiments, the anticoagulant is hirudin. In some embodiments, the anticoagulant is sodium polyanethol sulfonate (SPS). In some embodiments, the formulation is contained within a blood collection tube, and the combining step occurs within the blood collection tube. In some embodiments, the blood collection tube is an evacuated blood collection tube. In some embodiments, the blood is collected from a subject. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.
Described herein, in some embodiments, are methods for maintaining one or more erythrocytes in suspension in a blood sample, comprising: combining a sample of blood with an amount of a formulation comprising sucralose, wherein the amount is sufficient to produce a treated blood sample having a sucralose concentration of at least about 5 mM sucralose, thereby maintaining the one or more erythrocytes in suspension for a period of at least 30 minutes as compared to an untreated blood sample. In some embodiments, the one or more erythrocytes remain in suspension for a period of at least 10 minutes, at least 20 minutes, at least 30 minutes, at least 40 minutes, at least 50 minutes, at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 10 hours, at least 12 hours, at least 24 hours or at least 48 hours. In some embodiments, the treated blood sample has a sucralose concentration of about 5 mM sucralose to about 25 mM sucralose. In some embodiments, the treated blood sample has a sucralose concentration of about 5 mM sucralose up to but not including 25 mM sucralose. In some embodiments, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% of the one or more erythrocytes remain in suspension in the treated blood sample as compared to the untreated blood sample. In some embodiments, the formulation is a powder. In some embodiments, the formulation is a solution. In some embodiments, the solution is an aqueous solution. In some embodiments, the formulation consists of sucralose. In some embodiments, the formulation further comprises an anticoagulant. In some embodiments, the anticoagulant is selected from the group consisting of acid citrate dextrose solution (ACD), sodium heparin, sodium fluoride, lithium heparin, tri-potassium ethylenediaminetetraacetic acid (K3EDTA), di-potassium ethylenediaminetetraacetic acid (K2EDTA), hirudin, and sodium polyanethol sulfonate (SPS). In some embodiments, the anticoagulant is acid citrate dextrose solution (ACD). In some embodiments, the anticoagulant is sodium heparin. In some embodiments, the anticoagulant is sodium fluoride. In some embodiments, the anticoagulant is lithium heparin. In some embodiments, the anticoagulant is tri-potassium ethylenediaminetetraacetic acid (K3EDTA). In some embodiments, the anticoagulant is di-potassium ethylenediaminetetraacetic acid (K2EDTA). In some embodiments, the anticoagulant is hirudin. In some embodiments, the anticoagulant is sodium polyanethol sulfonate (SPS). In some embodiments, the formulation is contained within a blood collection tube, and the combining step occurs within the blood collection tube. In some embodiments, the blood collection tube is an evacuated blood collection tube. In some embodiments, the blood sample is collected from a subject. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.
Blood collection tubes, bags, containers and vessels are well-known in the art and have been employed by medical practitioners for decades. Blood collected for reduction of erythrocyte sedimentation rate may be obtained using any method or apparatus commonly employed by those skilled in the art such as venipuncture or finger prick. In some embodiments, when the blood is collected by venipuncture, the formulation is located inside the blood collection tube, e.g., an evacuated tube (VACUTAINER® blood collection tube, Becton Dickinson or VACUETTE® blood collection tube, Greiner Bio-One) at the time that the blood sample is obtained from the subject. In some embodiments, when the blood is collected by venipuncture, the formulations are added to an already obtained whole blood sample, either immediately or shortly after it is withdrawn.
In some embodiments, the methods as described herein use the articles of manufacture and kits disclosed.
The following Examples are presented by way of illustration and not limitation.
This Example describes reduction of erythrocyte sedimentation in whole blood by addition of sucralose.
Fresh blood was collected into BD K2EDTA VACUTAINER® tubes and pooled. Blood and a solution of 0.5 M sucralose were mixed at a ratio of 20:1 by aliquotting 952 μL of fresh blood into 2 mL centrifuge tubes containing 48 μL of formulation, resulting in a concentration of about 24 mM sucralose. 48 μL of PBS and 0.9% saline served as controls. Blood with no formulation (NF) added served as an additional control. The filled centrifuge tubes were gently inverted five times to mix and stored upright on the benchtop at approximately 25° C. Tubes were photographed at 0 hours (
As shown in
This Example illustrates the effect on sucralose concentration and other saccharides on reduction of erythrocyte sedimentation rate in whole blood.
Fresh blood was collected into BD K2EDTA VACUTAINER® tubes and pooled. 952 μL of fresh blood was aliquot into 2 mL centrifuge tubes, each containing 48 μL of sucralose at the indicated concentration in
The filled centrifuge tubes were gently inverted five times to mix and stored upright on the benchtop at approximately 25° C. Tubes were photographed at 1 hour (
Homogeneity of whole blood in the presence of a high concentration of sucralose was not due to excessive hemolysis of erythrocytes, as shown by centrifugation of the sample after 7 hours of storage (
This Example describes the effect of addition of sucralose in powder form on reduction of erythrocyte sedimentation rate in whole blood.
Fresh blood was collected into BD K2EDTA VACUTAINER® tubes and pooled. 1 mL of fresh blood was aliquotted into 2 mL centrifuge tubes containing sucralose powder. Final concentrations of sucralose ranged from 7.5 mM to 100 mM, corresponding to 3.0 mg to 39.8 mg per mL of blood. The no formulation (NF) control sample received no addition of sucralose. Tubes were inverted at least five times until no visible undissolved material remained at the bottom of the tubes. Tubes were stored upright on the benchtop at approximately 25° C. Tubes were photographed at 1 hour (
Data in
This Example describes the effect of different anticoagulants present at the time of blood collection on reduction of erythrocyte sedimentation rate in whole blood.
To screen for collection conditions, fresh blood was collected into a series of BD VACUTAINER® or Greiner Bio-One VACUETTE® low-volume blood collection tubes containing different anticoagulants, including acid citrate dextrose solution B (ACD-B), tri-potassium ethylenediaminetetraacetic acid (K3EDTA), sodium heparin (NaHep), lithium heparin (LiHep), sodium fluoride (NaF), and sodium polyanethol sulfonate (SPS). Collection into tubes containing di-potassium ethylenediaminetetraacetic acid (K2EDTA) served as a control. 9524 of fresh blood was aliquot into 2 mL centrifuge tubes containing 48 μL of 0.5 M sucralose or PBS. No formulation (NF) added served as an additional control. The filled centrifuge tubes were gently inverted five times to mix and stored upright on the benchtop at approximately 25° C. Tubes were photographed at 2 hours (
This Example describes the effect of sucralose compared to the effect of polyols and halogenated polyols on reduction of erythrocyte sedimentation rate in whole blood.
Fresh blood was collected into BD K2EDTA VACUTAINER® tubes and pooled. 9524 of fresh blood was aliquot into 2 mL centrifuge tubes containing 484 of a solution of 0.5 M sucralose, the indicated polyol, or the indicated halogenated polyol. Additives at 0.25 M were adjusted to 300 mOsmol with NaCl. PBS and no formulation (NF) added served as controls. The filled centrifuge tubes were gently inverted five times to mix and stored upright on the benchtop at approximately 25° C. Tubes were photographed at 2 hours against a white background for visual analysis of sedimentation rate.
Data in
Unless the context requires otherwise, throughout the present specification and claims, the word “comprise” and variations thereof, such as, “comprises” and “comprising,” which is used interchangeably with “including,” “containing,” or “characterized by,” is inclusive or open-ended language and does not exclude additional, unrecited elements or method steps. The phrase “consisting of” excludes any element, step, or ingredient not specified in the claim. The phrase “consisting essentially of” limits the scope of a claim to the specified materials or steps and those that do not materially affect the basic and novel characteristics of the claimed invention. The present disclosure contemplates embodiments of the invention compositions and methods corresponding to the scope of each of these phrases. Thus, a composition or method comprising recited elements or steps contemplates particular embodiments in which the composition or method consists essentially of or consists of those elements or steps.
Reference throughout this specification to “one embodiment” or “an embodiment” or “an aspect” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
The various embodiments described above can be combined to provide further embodiments. These and other changes can be made to the embodiments in light of the above-detailed description. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims, but should be construed to include all possible embodiments along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure.
While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.
This application is a continuation of U.S. patent application Ser. No. 15/750,590, filed May 31, 2018, now allowed, which is a § 371 U.S. National Entry of PCT/US2016/065198, filed Dec. 6, 2016, which claims the benefit of U.S. Provisional Application No. 62/264,786, filed Dec. 8, 2015, each of which is incorporated by reference herein in its entirety.
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Number | Date | Country | |
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20210368779 A1 | Dec 2021 | US |
Number | Date | Country | |
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62264786 | Dec 2015 | US |
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Parent | 16798522 | Feb 2020 | US |
Child | 17400931 | US | |
Parent | 15780590 | US | |
Child | 16798522 | US |