Device

Abstract

The present invention relates to a fluid sample collection device comprising an end cap comprising a composition comprising a substance suitable for use as an internal standard substance, the composition being sealed within the end cap in an atmosphere that protects the substance suitable for use as an internal standard substance from degradation, and wherein the end cap is configured to be coupleable to a sample container and controllably release the composition into an interior of the sample container. The invention also relates to a sample container for fluid sample collection comprising a composition comprising a substance suitable for use as an internal standard, said composition being sealed in an atmosphere that protects said substance suitable for use as an internal standard from degradation, and wherein the sample container comprises means for removing the composition from the protective atmosphere and introducing the composition into the sample container while providing a sample, or wherein the sample container comprises means for removing the composition from the protective atmosphere and introducing the composition into the sample container prior to providing a sample. The invention also relates to a kit of parts comprising said fluid sample collection device and / or said sample container, as well as methods and uses thereof.

Description

Technical Field

[0001] The present invention relates to a fluid sample collection device comprising an end cap including a composition comprising a substance suitable for use as an internal standard, the composition being sealed within the end cap in an atmosphere protecting the substance suitable for use as an internal standard from degradation, and wherein the end cap is configured to be coupled to a sample container and to controllably release the composition into the interior of the sample container.

[0002] The present invention also relates to a sample container for fluid sample collection, comprising a composition including a substance suitable for use as an internal standard, the composition being sealed in an atmosphere protecting the substance suitable for use as an internal standard from degradation, and wherein the sample container includes parts for removing the composition from the protective atmosphere and introducing the composition into the sample container at the same time as or before the sample is provided.

[0003] The present invention also relates to a component kit comprising a fluid sample collection device and / or a sample container, as well as methods and uses thereof. Background Technology

[0004] Many clinical treatments require the analysis of compounds in bodily fluid samples, such as the serum concentration of a drug. For example, dose range studies are a component of Phase I and / or Phase II clinical trials. The primary goal of dose range studies is to analyze the half-life of a drug in both the plasma and urine of healthy volunteers, which requires acquiring multiple bodily fluid samples over a wide time span and measuring the drug concentration in these samples.

[0005] In addition, in some cases, some patients require continuous body fluid sampling to analyze the concentration of target compounds, such as drug addicts.

[0006] Personalized medicine, which tailors medical treatments to the individual characteristics of each patient, is gaining increasing importance because it allows for adjustments to drug dosages based on an individual's specific blood or plasma levels, resulting in more effective treatments and fewer side effects.

[0007] Typically, to analyze bodily fluids, subjects need to travel to a clinical setting where medical professionals obtain samples and send them to a laboratory for analysis. For blood samples, these are usually obtained through venipuncture and the extraction of large volumes of blood, which are then sent for analysis. The half-life of drugs in blood varies, and they often continue to degrade even after being removed from the body. Therefore, during the time between sample acquisition and analysis in the laboratory, drugs typically degrade at an unknown rate, meaning that no reliable quantification of drug content can be achieved at the time of sampling.

[0008] More specifically, after blood samples are collected, drugs can degrade due to factors such as transport time, temperature changes, exposure to oxygen, hydrolysis, and photodegradation. Furthermore, analyte yields can vary between samples from different individuals. Standard procedure in analytical laboratories is to add an internal standard only before analysis. However, any analyte loss during sample transport and yield loss during sample preparation cannot be compensated for, potentially leading to an underestimation of true blood concentrations.

[0009] Therefore, there is a need for devices and methods that allow for the quantification of drug content in fluid samples during sample acquisition.

[0010] WO 2020 / 156849 describes a method for blood sampling in which an internal standard is added directly to the extraction solution during kit production. However, chemicals such as internal standards are generally unstable in solutions, especially at low concentrations. This invention relates to protecting internal standards by separating them from solvents, light, and other potential degradation agents before use.

[0011] The advantage of these kits is that they require only a small blood sample. However, to provide accurate data on drug concentration in the blood at the time of sampling, the sample must be processed as quickly as possible after acquisition. This means that samples must be acquired in a clinical setting where analytical instruments can be used quickly for accurate analysis. Any delay in analysis will ultimately lead to inaccurate results.

[0012] Therefore, there is a need for improved equipment and methods to achieve high-level accurate analysis of drug concentrations in samples, which are not affected by delays in subsequent sample analysis and allow subjects to self-sample outside of the clinical setting. Summary of the Invention

[0013] According to the present invention, a fluid sample collection device is provided, comprising an end cap, wherein the end cap comprises a composition comprising a substance suitable for use as an internal standard, wherein the composition is sealed within the end cap in an atmosphere that protects the substance suitable for use as an internal standard from degradation, and wherein the end cap is configured to be coupled to a sample container and to controllably release the composition into the interior of the sample container, the device being referred to below as "the device of the present invention".

[0014] For the avoidance of doubt, substances suitable for use as internal standards are interchangeably referred to herein as "internal standards" or "IS". In the context of chemical analysis, the term internal standard refers to a compound used to detect sample loss of an analyte to be determined (e.g., an analyte in a sample). An internal standard is a known substance that has similar analytical behavior to the substance being evaluated (i.e., the target compound / part present in the sample), such as a stable or analogous isotope of the analyte. Internal standards can also be, for example, chemicals substituted with stable isotopes, or nearly identical to the chemicals measured in the sample. These substances are located in the sample and are "also processed"—and are therefore internal standards—compared to external standards. In chromatographic bioanalysis, for example, internal standards are added to all samples, including calibration standards, as well as quality control and samples prior to extraction. Thus, internal standards serve as a reference for analyzing and quantifying the presence of a target compound / part present in the sample.

[0015] The end cap can be coupled to the sample container in any way to achieve a seal, such as by coupling it to the top or bottom of the sample container. Preferably, the end cap can be coupled to the top of the sample container.

[0016] The term "sample vessel" refers to a container having a reservoir suitable for containing and retaining fluid samples. Such a container may have an opening to which an end cap, as defined herein, may be coupled.

[0017] Sample containers may include analytical / extraction solutions (e.g., protein precipitation solutions, anticoagulants, and / or other solvent mixtures for preserving analytes in biological fluids and / or facilitating analysis).

[0018] The analytical / extraction solution may include 2-propanol, methanol, acetonitrile, ZnSO4, acetone, water, formic acid, and mixtures thereof. Preferably, the analytical / extraction solution includes at least two of these components; for example, the analytical / extraction solution may consist primarily of two or three of these components.

[0019] The analytical / extraction solution may further include one or more pH adjusters. The term "pH adjuster" should be understood as any compound that adjusts the acidity or alkalinity of the solution to minimize acid / base-catalyzed degradation of the analyte and / or to obtain increased yield in the solvent protein precipitation step.

[0020] A list of suitable pH adjusters that can be included in the analysis / extraction solution is available, consisting of formic acid and acetic acid.

[0021] The analytical / extraction solution may comprise a mixture of 2-propanol and methanol or a mixture of 2-propanol and methanol in a ratio of about 1:10 to about 10:1, such as about 1:5 to 5:1, for example about 1:1. Optionally, formic acid is also present in an amount of about 0.01 vol.% to about 0.5 vol.%, such as about 0.05 to about 0.2 vol.%.

[0022] The analytical / extraction solution may alternatively comprise a mixture of acetonitrile and methanol or consist of a mixture of acetonitrile and methanol in a ratio of about 1:20 to about 20:1, such as about 1:10 to 10:1, for example about 90:10. Optionally, formic acid is also present in an amount of about 0.01 vol.% to about 0.5 vol.%, such as about 0.05 to about 0.2 vol.%.

[0023] The analytical / extraction solution may alternatively comprise or consist of a mixture of ZnSO4 and water, wherein the ratio of ZnSO4 to water is from about 1:20 to about 20:1, such as from about 1:10 to 10:1, for example, about 10:90, and optionally, wherein formic acid is also present in an amount from about 0.01 vol.% to about 0.5 vol.%, such as from about 0.05 to about 0.2 vol.%.

[0024] The analytical / extraction solution may alternatively comprise a mixture of acetonitrile and acetone or consist of a mixture of acetonitrile and acetone in a ratio of about 1:20 to about 20:1, such as about 1:10 to 10:1, for example about 8:2. Optionally, formic acid is also present in an amount of about 0.01 vol.% to about 0.5 vol.%, such as about 0.05 to about 0.2 vol.%.

[0025] The volume of the analytical / extraction solution in the sample container can be from about 100 μL to about 2000 μL, such as from about 200 μL to about 1000 μL, or for example from about 250 μL to about 750 μL.

[0026] Sample containers can be configured to be compatible with standard laboratory analytical equipment. For example, the size and shape of the sample containers can be configured to be compatible with centrifuge equipment and / or high-performance liquid chromatography (HPLC) equipment and / or liquid chromatography-mass spectrometry or tandem mass spectrometry equipment, such as (LC-MS / MS), mass spectrometry (MS / MS), or gas chromatography (GC-MS / MS). For example, the sample containers can be microtubes, such as microtubes configured to hold an internal liquid volume of about 0.5 mL to about 5 mL, such as about 0.5 mL to about 3 mL, for example about 1 mL to about 2 mL.

[0027] The sample container can be roughly cylindrical in shape.

[0028] The end cap can be reversibly or permanently coupled to the sample container. For example, when reversibly coupled in use, the user can couple the end cap to the sample container and remove it once the composition has been released into the interior of the sample container. The end cap can be reversibly coupled to the sample container in any manner known in the art. For example, the end cap can be a nut including a threaded portion, and the sample container can include a corresponding threaded portion, such that the end cap can be screwed onto the sample container in use and then removed by loosening. Alternatively, the end cap can be configured such that it is pushed into and fitted onto the sample container and can be removed.

[0029] When provided to a user, the end cap may already be coupled to a sample container, which includes an analytical / extraction solution as defined above. That is, the device of the present invention may include an end cap coupled (reversibly or permanently) to a sample container, which includes an analytical / extraction fluid.

[0030] When the end cap is permanently coupled to the sample container, the end cap and / or the sample container may include locking parts (e.g., a locking mechanism) such that when the end cap is coupled to the sample container, the locking parts are locked in place, and the end cap cannot be removed by a user without, for example, specialized equipment or without disassembling the equipment. That is, while it is stated that the end cap is permanently coupled to the sample container, the end cap can still be removed, or access to the interior of the sample container can still be made, allowing for sample analysis; however, doing so would require damaging the equipment and rendering it unusable.

[0031] Therefore, the device is intended for single use. Furthermore, the device can be sterilized and placed in a sealed package for single use.

[0032] By sealing the composition within an end cap in an atmosphere that protects the internal standard from degradation, the composition, including the internal standard, is stored within the end cap and protected from the atmosphere and sunlight outside the end cap. For example, the composition may be stored in an area within the end cap surrounded by a light-impermeable material. Furthermore, the atmosphere in which the internal standard is stored may be an inert atmosphere that prevents degradation. For example, the atmosphere may be an inert gas atmosphere (e.g., a nitrogen atmosphere or an argon atmosphere). The components within the composition and the environment in which the composition is stored within the end cap also protect the internal standard from degradation via photochemical, oxidative, or solvent decomposition.

[0033] The end cap may include an orifice for receiving a sampler or a rod member attached to the cap, within which a composition including an internal standard is positioned, and wherein the end cap is configured to release the composition into the interior of a sample container by introducing the sampler or the rod member of the cap through the orifice. The sampler may be configured to sample a defined volume of sample fluid. For example, the sampler may be a capillary configured to sample a defined volume of sample fluid. For the avoidance of doubt, the orifice may be configured to receive both the sampler and the rod member of the cap, wherein the composition is first released into the sample container using the rod member, and then the rod member is removed, allowing the sampler to pass through the orifice to introduce the sample into the sample container.

[0034] The sampler may include a handle portion, and the sampler may be removable from the handle portion, so that the sampler can be removed from the handle once the sample has been introduced into the sample container using the sampler.

[0035] The handle portion can also function as a cap for attaching / coupling to the top of the end cap after the sampler has been introduced through the orifice. For example, the handle portion may include a threaded portion, with the end cap including a corresponding threaded portion, such that once the sampler has been introduced through the orifice, the handle portion can be screwed onto the end cap to act as a cap. Other methods of coupling the handle portion to the end cap are envisioned, such as using a push-in fit.

[0036] As an alternative to using a capillary, the sampler can be a pipette or syringe configured to sample a defined volume of fluid and configured to pass through an orifice to release the composition into the interior of a sample container, or to introduce a sample into the sample container after the composition has been released using a rod member of a cap. In use, after the fluid sample has entered, the fluid sample can be released from the pipette or syringe into the interior of the sample container by squeezing the pipette bulb or advancing the plunger into the syringe. Afterward, the sampler can be removed from the sample container, and the end cap can be closed with a cap (e.g., a cap as defined above with respect to a capillary handle, or a cap including a rod member). Therefore, the device may also include a cap reversibly or permanently coupled to the end cap. For the avoidance of doubt, the cap does not necessarily need to be coupled to the sampler and form a handle for the sampler. Therefore, the cap can be separate from the sampler.

[0037] Such samplers can be configured to sample a limited volume of fluid that cannot be adjusted by the user, or alternatively, the sampler may include volume markings that allow the user to sample a certain volume of fluid and judge it visually, meaning that a range of volumes can be sampled as needed.

[0038] The sampler can be configured to sample any predetermined volume of fluid. For example, the sampler can be configured to sample 10 to 500 μL, such as 10 to 200 μL, for example 10 to 100 μL, and preferably 20 to 50 μL of fluid.

[0039] By configuring a sampler to sample a predetermined volume of fluid, the risk of sampling error is reduced and the accuracy of sampling and subsequent analysis is increased.

[0040] The fluid to be sampled can be, for example, bodily fluids such as blood, urine, or saliva.

[0041] The fluid to be sampled can come from any source, such as an animal subject (e.g., a mammal, such as a human or animal). The source can also be, for example, a water sample (e.g., a drinking water sample or a wastewater sample), or any other sample that may include or is suspected of including the target compound.

[0042] The cover may include a rod member, a rod protrusion element, and / or a pin, for example, a member that protrudes from and / or extends from the cover.

[0043] "Rack member" can be understood as a member extending from the lid, for example, where the rack member extends in a direction substantially perpendicular to the plane of the lid, the orifice, and / or the permeable membrane.

[0044] "Basically vertical" can be understood as an angle of approximately 60 to 120 degrees, such as approximately 70 to 110 degrees, such as approximately 80 to 100 degrees, such as approximately 85 to 95 degrees, such as approximately 88 to 92 degrees.

[0045] The rod member may extend above and / or below the cap (i.e., on the underside of the cap), for example, where the rod member extends from the top (e.g., the outside) or bottom (e.g., the inside) of the cap. That is, when the rod member is on the bottom side, the rod member may reside within the orifice of the end cap once the cap is coupled to the end cap.

[0046] The rod member may have a length of about 1 mm to about 10 cm, for example, 2 mm to about 5 cm, such as about 0.5 cm to about 4 cm, such as about 1 cm to about 3 cm.

[0047] The cap, including the rod member, can be configured to penetrate an orifice, such as piercing a permeable membrane, thereby releasing the composition into the interior of the sample container. The cap, including the rod member, can be used in a pre-activation step to release the composition into the interior of the sample container before introducing a fluid sample into it.

[0048] By using a cap that includes a rod component, the activation step that breaks the permeable membrane can be performed with minimal force, thereby reducing the risk of sample loss.

[0049] The rod can be conical in shape, for example, wider at the point adjacent to the lid than at its farthest point from the lid. When it is conical in shape and located under the lid, this helps to seal the opening and close the sample container with the lid after the sample has been added to the inside of the sample container.

[0050] A cap including a rod member may include other features as defined herein. For example, the cap may include a handle portion and / or be reversibly or permanently coupled to an end cap. Preferably, a cap including a rod member is reversibly or permanently coupled to an end cap.

[0051] The composition can be sealed on both sides of the orifice by an upper and lower permeable membrane, such that when the sampler or the rod member of the cap is introduced through the orifice, the permeable membrane breaks, thereby releasing the composition into the interior of the sample container. Any membrane that provides a seal but is permeable by the sampler or the rod member can be used. For example, the membrane can be an aluminum foil film, a plastic film, or a plastic-coated aluminum film.

[0052] The composition may have a mass of about 1 mg to about 20 mg, such as about 1 mg to about 10 mg, for example about 1 mg to about 5 mg.

[0053] The diameter of the composition at its longest dimension can be from about 5 mm to about 15 mm, such as from about 5 mm to about 10 mm.

[0054] Compositions containing substances suitable for use as internal standards can be matrix compositions. The purpose of a matrix is ​​to adsorb the internal standard and simultaneously release the biological sample and the internal standard into solution via a capture-and-release principle. The purpose of a matrix is ​​also to protect the analyte from unwanted reactions, such as solvent decomposition or reactions between solvents (water, ethanol, or other reactive solvents) in the tube or atmosphere.

[0055] Matrix compositions may include, for example, reversed-phase silica stationary phases or polymeric stationary phases that retain one or more internal standards through hydrophobic interactions transmitted from concomitant aliphatic groups (C1-C18 chains, phenyl, diphenyl, or other functional groups used in the field of liquid chromatography). These matrix compositions may also, or alternatively, include mixed-mode stationary phases, reversed-phase silica, or polymeric phases modified with polar groups, such as aromatic or aliphatic hydroxyl groups, aromatic or aliphatic amines, or other groups that retain the internal standard through both hydrophobic and polar interactions (having anionic and cationic interactions).

[0056] The matrix composition may also or alternatively include reversed-phase silica gel or polymers (e.g., polypropylene, polyethylene, polyamide, etc., including non-woven polypropylene, preferably polypropylene, polyethylene, polyamide, etc.) for adsorbing internal standards. The matrix composition may also include co-solvents (e.g., pure C8 MTC oil, mineral oil, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), methyl esters of natural oils and their constituent fatty acids (e.g., rapeseed oil methyl ester), preferably added in small amounts to increase the release reaction rate and increase the solubility of poorly soluble compounds. The matrix composition may also or alternatively include a solid phase soluble in any solution used in the tube, such as analytical / extraction solutions (e.g., protein precipitation solutions, anticoagulants, and / or other solvent mixtures used to preserve analytes in biological fluids and / or facilitate analysis). For example, the composition may include excipients, and its matrix may contain substances suitable for use as internal standards. The matrix composition may further comprise a solid (e.g., a solid made of tert-butanol, carboxymethyl cellulose, gum arabic, coconut wax, etc.) containing an internal standard but soluble in a solvent used for protein precipitation (i.e., a solvent in the analytical / extraction solution as defined below). To further increase the stability of the internal standard adsorbed onto the matrix, the composition may include scavengers, such as antioxidants (vitamin E, beta-carotene, 2,6-diisopropylphenol), to further protect the internal standard. Such antioxidants may be selected from the following list of compositions: vitamin E (tocopherol), beta-carotene, 2,6-diisopropylphenol, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), and ascorbic acid (vitamin C).

[0057] When antioxidants are incorporated into a composition, they can be sterically hindered. For example, they can be configured to be sterically hindered so as not to interact with components in the matrix that include oxidizing groups, but still be able to act as antioxidants against free oxygen and reactive oxygen species (ROS) generated / introduced during storage. Suitable sterically hindered oxidants include butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA).

[0058] Preferably, the matrix composition comprises a nonwoven polypropylene fabric having a thickness of about 0.05 mm to about 0.5 mm, such as about 0.1 mm to about 0.3 mm.

[0059] The matrix composition may include silica particles to which a substance suitable for use as an internal standard may be adsorbed, such that the substance may be released from the surface of the silica particles upon entering the interior of the sample container.

[0060] The composition may further include one or more beads, balls, gems, pellets, mixers, and / or wires, such as metal balls or other materials, such as stainless steel balls or any related materials. Preferably, the composition includes a plurality of stainless steel balls. For the avoidance of doubt, when referring to "composition," this means any composition suitable for storage within the orifice of an end cap and is not necessarily limited to matrix compositions, but any aspect of the composition as defined herein may be incorporated into the matrix composition defined above.

[0061] Alternatively, one or more beads, spheres, gems, pellets, mixers, and / or wires may be disposed inside the sample container, such as within the analytical / extraction solution.

[0062] By incorporating beads into a composition or sample container, the mixing of sample fluids, compositions, and / or analytical / extraction solutions is improved due to enhanced mixing during agitation (e.g., shaking) of the sample device after sample introduction. This reduces sample preparation time, enhances homogeneous protein precipitation, and provides quantitative release of internal standards from the composition during mixing, with negligible negative impact on analytical results. Stainless steel beads may be particularly advantageous for providing higher yields and reduced variation in measured results.

[0063] When the matrix composition includes a polymer, such as nonwoven polypropylene, the inventors have found that the additional weight provided by beads (especially stainless steel balls) proves to be very effective in achieving rapid preparation time and enhanced precipitation.

[0064] The mass of the beads included in or incorporated into the sample container within the composition may be from about 50 mg to about 500 mg, such as from about 100 mg to about 200 mg, for example from about 150 mg to about 250 mg.

[0065] The interior of the composition or sample container contains about 1 to about 20 beads, such as about 2 to about 10 beads, such as about 3 to about 7 beads.

[0066] The beads can have a diameter of about 1 mm to about 1 cm, such as about 2 mm to about 5 mm, such as about 2.5 to about 3.5 mm.

[0067] Preferably, the interior of the composition or sample container includes one or more beads and a solubilizer as defined above. The combination of beads and solvent has proven particularly advantageous in precipitating proteins from analytical / extraction solutions, resulting in a significant improvement in the accuracy of analytical results.

[0068] Furthermore, when the composition or sample container contains beads, manually shaking a device containing steel balls yields significantly better results (i.e., improved precipitation, higher yield, and reduced variation in measured results) compared to shaking a device without balls in a laboratory machine, thus encouraging users to use the device.

[0069] The composition may further include an indicator compound.

[0070] The term "indicator compound" should be understood as any chemical compound that causes a color change (i.e., a visual change) when added to the analytical / extraction solution, such as a chemical compound that causes a color change in the analytical / extraction solution after the composition is released into the interior of the sample container and the indicator (i.e., the composition) is mixed with the analytical / extraction solution. In this way, the indicator compound can act as a visual aid and allow the user to visually monitor the activation process as the color of the analytical / extraction solution changes after the composition is added. Furthermore, the indicator compound can provide visual identification, for example, in the event that the bottom seal is damaged before sampling (e.g., during storage or transport), resulting in the composition being released earlier, unintentionally, or accidentally into the analytical / extraction solution.

[0071] Indicator compounds can further act as antioxidants. "Antioxidant" can be understood to include means for minimizing the oxidation of the internal standard, thereby protecting the internal standard from excessive oxidation to extend the shelf life of the equipment, sample containers, and / or component kits. Adding antioxidants to the internal standard not only protects the internal standard but also protects the collected blood samples (including their components) from oxidation.

[0072] The indicator compound can be any suitable dye compound or colorant. Suitable indicator compounds may be selected from one or more of the following: triarylmethane basic dyes, flavin basic dyes, auramine basic dyes, safranine basic dyes, phloxine basic dyes, xanthracene basic dyes, and methylene blue base.

[0073] Other suitable indicator compounds may be selected from one or more of the following: methyl violet, crystal violet, magenta, basic cyanine 6G, basic cyanine EX, Victoria Pure Blue BO, Victoria Blue B concentrate, Brilliant Green GX, malachite green, basic yellow 1, basic red 2, basic red 12, basic blue GO, neomethylene blue NX, methyl violarin, methyl red, methylene blue, methyl orange, ruthenium(II) tri(bipyridine)chloride, rhodamine B, rose bengal, brilliant blue, indigo carmine, patent blue, direct yellow, ServaBlue, Prussian blue, triarylmethane, flavin, xanthracene, bikaverin, fluorescein, and eosin. Preferably, the indicator compound is selected from one or more of methylene blue and rhodamine B. More preferably, the indicator compound is methylene blue.

[0074] The indicator compound may be included in the composition in an amount from about 0.001 wt.% to about 0.1 wt.%, such as from about 0.001 wt.% to about 0.05 wt.%, for example, from about 0.001 wt.% to about 0.01 wt.%.

[0075] The internal standard may be included in the composition in an amount from about 0.001 wt.% to about 0.05 wt.%, for example, from about 0.001 wt.% to about 0.01 wt.%.

[0076] The internal standard may be included in the composition in an amount from about 0.001 wt.% to about 0.1 wt.%, such as from about 0.001 wt.% to about 0.05 wt.%, for example, from about 0.001 wt.% to about 0.01 wt.%.

[0077] The composition may further include one or more free radical inhibitors or one or more oxygen free radical inhibitors. The terms "oxygen free radical inhibitor" and "free radical inhibitor" should be understood to include any chemical compound that prevents the formation of free radicals from oxygen or other materials and / or terminates free radical chain reactions, thereby stabilizing the materials within the composition.

[0078] Suitable free radical inhibitors that may be included can be selected from the following list: hydroquinone, tert-butylhydroquinone (TBHQ), phenol, polyphenols, gallic acid, naringin, and quercetin.

[0079] The composition may further include one or more pH adjusters. The term "pH adjuster" should be understood as any chemical compound that adjusts the acidity or alkalinity of a solution to stabilize a sensitive chemical substance that is readily degradable in certain pH environments. In this context, the pH adjuster is used to adjust the solution in the sample container when the composition is introduced into the sample container.

[0080] Suitable pH adjusters that may be included are available from the following list: citric acid, formic acid, acetic acid, sodium hydroxide, hydrochloric acid, TRIS (tris(hydroxymethyl)aminomethane) and similar buffers.

[0081] The composition may further include one or more scavengers. The term "scavenger" should be understood as any chemical compound that reacts with and / or neutralizes reactive species within the composition, such as oxygen, peroxides, or metal ions that can catalyze degradation reactions.

[0082] Suitable scavengers that can be included can be selected from a list consisting of free ethylenediaminetetraacetic acid (EDTA), activated carbon, and sodium bisulfite.

[0083] The composition may further include one or more stabilizers. The term "stabilizer" should be understood to include any chemical compound that helps maintain the integrity and functionality of the chemicals and materials within the composition over time by preventing degradation through various mechanical means.

[0084] Suitable stabilizers that can be included are available from a list of polyvinylpyrrolidone (PVP) and glycerol.

[0085] The composition may further include one or more preservatives. The term "preservative" should be understood to include any compound that prevents the growth of microorganisms (e.g., bacterial growth, fungal growth, and other microbial growth) that may potentially lead to the degradation of materials within the composition. The term "preservative" also encompasses antimicrobial agents.

[0086] Suitable preservatives / antimicrobial agents that may be included are selected from the following list: sodium benzoate, parabens (e.g., methylparaben and propylparaben), sorbic acid, silver ions, triclosan, and chlorhexidine.

[0087] The composition may further include one or more humectants. The term "humectant" should be understood to include any chemical compound that retains moisture to prevent the product from drying out and degrading.

[0088] Suitable moisturizers that can be included are available from a list of those consisting of glycerol and 2,5-hexanediol.

[0089] The composition can be dry particles and can also be shaped such that the dry particles can penetrate the membrane when pressure is applied. For example, the lower end of the dry particles that is permeable to the membrane can be shaped into a tapered point, such that when the rod member of the sampler or cap passes through the orifice of the end cap, pressure is applied to the top of the dry particles, and because the bottom end of the particles is tapered, this pierces the lower membrane, thereby allowing the particles to enter the interior of the sample container.

[0090] According to another aspect of the invention, a component kit is provided, comprising a sample container as defined above, a sampler configured to sample a defined volume of sample fluid, and an end cap, wherein the sample container and the end cap are configured to be coupled together.

[0091] The component kit may include multiple sample containers, samplers, and end caps. By using the term "multiple," we envision that each component of the component kit has at least 10, such as at least 20, 30, 40, 50, or 100.

[0092] The component kit may further include a cover that includes a rod member, such as a cover that includes a rod member as defined above.

[0093] In the component kit, the sample container may include an analytical / extraction solution, which may be an analytical / extraction solution as defined above.

[0094] The component kit may further include a lancet. For the avoidance of doubt, the term "lancet" refers to a skin puncture device comprising a needle or narrow, sharp blade that punctures a small hole in the skin to obtain capillary blood. In the context of this invention, a lancet is used to extract blood from a subject through the skin for a sampler to draw.

[0095] The sampler included in the component kit can be the sampler defined above.

[0096] In an alternative aspect of the invention, a sample container for fluid sample collection is provided, coupled to an end cap as defined above, the sample container being referred to below as the "sample container of the present invention".

[0097] Sample containers used for fluid sample collection can be used for future analysis of the samples, and the sample containers include: Storage device; A composition comprising a substance suitable for use as an internal standard in the analysis; The composition is sealed in an atmosphere that protects the substance suitable for use as an internal standard from degradation; and The sample container includes parts for removing the composition from the protective atmosphere and introducing the composition into the reservoir while providing the sample to the reservoir.

[0098] In an alternative aspect of the sample container of the present invention, the sample container includes parts for removing the composition from a protective atmosphere and introducing the composition into the reservoir before the sample is provided to the reservoir.

[0099] The sample container of the present invention may include any of the features defined above with respect to the device of the present invention. Specifically, the sample may be provided to the reservoir by using a sampler, or by using a lid including a rod member as defined above. Furthermore, the sample container may be the sample container as defined above.

[0100] The term "concurrently" means that the sample and the composition are introduced into the sample container substantially simultaneously. For example, the composition may be introduced into the reservoir within one minute of the sample, such as within 30, 20, or 10 seconds of the sample, or for example, within 9, 8, 7, 6, 5, 4, 3, 2, or 1 second.

[0101] Alternatively, the composition may be introduced into the sample container before the sample is introduced into the sample container, as defined above. For example, the composition may be introduced into a reservoir, and the sampler containing the sample may be introduced within 120 seconds of introducing the composition into the reservoir, such as within 110, 100, 90, 80, 70, 60, 50, 40, 30, 20, 15, or 10 seconds before the sample.

[0102] The sample container of the present invention may be included in a component kit, which may contain any of the other features detailed above with respect to a component kit containing end caps.

[0103] The component kit may include multiple sample containers, such as at least 10, or at least 20, 30, 40, 50 or 100 sample containers.

[0104] Both the device and the sample container of the present invention can be used to sample fluids (e.g., bodily fluids such as blood, urine, or saliva).

[0105] This application can be to sample target compounds in fluids for future quantification and identification. Such compounds can be biomarkers, pharmaceutically active compounds, endogenous or exogenous toxins, illicit drugs, veterinary drugs, or other valuable chemical substances in body fluids, preferably in blood. In this document, chemical substances, compounds, and biomarkers that may be present in one or more body fluid samples may be referred to as “target chemical substances / compounds” or “analytes.”

[0106] It is envisioned that the equipment / sample container is supplied to the end user along with the compound intended for analysis, and therefore, the internal standard contained in the composition may have been pre-selected as a suitable internal standard for future analysis, quantification, and / or identification of the target compound.

[0107] When the composition including the internal standard is stored in an atmosphere that protects it from degradation, the amount of undegraded internal standard will be known when the device is supplied to the user. Simultaneously with the release of the composition including the internal standard into the sample container, the internal standard and the target compound will degrade at the same rate. This means that, for future analyses, the concentration of the target compound in the fluid at the time of sampling can be reliably determined based on the relative concentration of the internal standard, given that both the internal standard and the target compound degrade at the same rate.

[0108] One particular advantage of this invention is that the user (e.g., a patient) can obtain the sample themselves without the need for a medical professional. Therefore, patients can sample bodily fluids at home rather than in a hospital setting. Another advantage of this invention is that analysis to reliably calculate the concentration of the target compound in the fluid sample is not required immediately after sample acquisition, meaning that delays in laboratory analysis will not affect the reliability of the analysis. This implies that the technology is suitable for routine mail transport to laboratories without affecting the reliability of the analysis due to time differences from sampling to delivery and then to analysis.

[0109] Additionally, users can be supplied with component kits comprising multiple devices, allowing for the sampling of bodily fluids over a period of time. Thus, by sampling the serum levels of the active pharmaceutical ingredient over time after administration of a pharmaceutical composition, and by analyzing the levels of the target compound in the sample, a drug dosage can be tailored to the specific patient. Such devices can be useful, for example, in precision medicine settings. Accordingly, these kits can also be found for use in clinical trials where trial candidates can obtain their own samples and send them to a laboratory setting for further analysis, rather than leaving the candidates in a hospital setting for serum level analysis.

[0110] Therefore, the device can be used to sample the serum levels of pharmaceutically active compounds that have been administered to subjects.

[0111] Subjects can be mammals, such as humans or animals.

[0112] Suitable target compounds that can be sampled by this invention may be compounds with a narrow therapeutic index, such as those selected from the list of compounds with the following composition: abemaciclib, acalabrutinib, aceenocoumarol, alatrofloxacin, aldesleukin, alectinib, alemtuzumab, alpelisib, tretamine, amikacin, amineptine, aminoglutethimide, aminophylline, amiodarone, amitriptyline, amitriptylinoxide, amoxapine, and amphotericin B. B) Amsacrine, Anagrelide, Arbekacin, Argatroban, Arsenic trioxide, Asparaginase Erwinia chrysanthemi, Asparaginase Escherichia coli Coli, Astemizole, Atezolizumab, Avelumab, Axitinib, Azacitidine, Baricitinib, Bekanamycin, Belinostat, Bendamustine, Bevacizumab, Bicalutamide, Binimetinib, Bleomycin, Blinatumomab, Bortezomib, Bosutinib, BrentuximabVedotin, Brigatinib, Busulfan, Butriptyline, Cabazitaxel, Cabergoline, Cabozantinib, Capecitabine, Capreomycin, Carbamazepine, Carboplatin, Carfilzomib, Carmustine, Cemiplimab, Ceritinib, Cetuximab, Chlorambucil, Chloramphenicol succinate, cisplatin, cladribine, clofarabine, clomipramine, clonidine, cobimetinib, colistin, conivaptan, copanlisib, crizotinib, cyclophosphamide, cyclosporine, cytarabine, dabrafenib, dacarbazine, dacomitinib, actinomycin D, dalfampridine, daratumumab, dasatinib, daunorubicin, decitabine, denileukindiftitox, desipramine, dibekacin, dibenzepin, dicoumarol, digitoxin, digoxin, dihydroergotamine, dinutuximab, docetaxel, dofetilide, dosulepin, doxorubicin, dronedarone, durvalumab, elotuzumab, enasidipine Enib, Entrectinib, Epirubicin, Erdafitinib, Ergotamine, Eribulin, Erlotinib, Etoposide, Everolimus, Flecainide, Floxridine, Fludarabine, Fluindione, Fluorouracil, Fosphenytoin, Gallium Nitrate, Gemcitabine, Gemtuzumab ozogamicin, gentamicin, gentamicin C1a, heparin, hydroxyurea, idarubicin, edalalisib, ifosfamide, imipramine, imipramine oxide, izizumab / ozogamicin, interferon alpha-2balfa-2b, iobenguane, ipilimumab, iprindole, irinotecan, isatuximab, isepamicin, ivosidenib, ixabepilone, ixazomib, kanamycin, levacetylmethadol, levothyroxine, lithium carbonate, lithium citrate, lithium hydroxide, lomitapide, lomustine, mechlorethamine, melitracen, melphalan, melphalan fluoxetine Flufenamide, Mercaptopurine, Methotrexate, Micronomicin, Midostaurin, Mitomycin, Mitotane, Mitoxantrone, Mogamulizumab, Moxetumomab pasudotox, Mycophenolic acid, Necitumumab, Nedaplatin, Nelarabine, Neomycin, Neratinib, Netilmicin, Nilotinib, Niraparib, Nortriptyline, Olaparib, Omacetaxine mepesuccinate, opipraprol, osimertinib, oxaliplatin, paclitaxel, palbociclib, panobinostat, pazopanib, pegylated interferon alpha-2°alfa-2°, Pemetrexed, Pentostatin, Pexidartinib, Phenindione, Phenobarbital, Phenprocoumon, Phenytoin, Pimozide, Pixantrone, Plazomicin, Pomalidomide, Ponatinib, Pralatrexate, Procainamide, Methylbenzyl Hydrazine, Protriptyline, Quinidine, Raltitrexed, Ramucirumab, Regorafenib, Ribociclib, Ribostamycin, Rituximab, Romidepsin, Rucaparib, Ruxolitinib, Siponimod, Sirolimus, Sisomicin, Sodium Phosphate32. Sonidegib, Sorafenib, Sotalol, Streptomycin, Streptozocin, Sunitinib, Tacrolimus, Tagraxofusp, Talazoparib, Tamoxifen, Tegafur, Teicoplanin, Temoporfin, Temozolomide, Temsirolimus Teniposide, Theophylline, Thiopental, Thiotepa, Tianeptine, Tioguanine, Tipiracil, Tizanidine, Tobramycin, Tolvaptan, Topotecan, Trabectedin, Trametinib, Trastuzumab, Trastuzumab entazoline The following are listed: emtansine, trilostane, trimetrexate, trimipramine, uracil mustard, valproic acid, vancomycin, vandetanib, vemurafenib, venetoclax, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vorinostat, warfarin, zanubrutinib, ziconotide, and mixtures thereof.

[0113] Suitable substances for use as internal standards may be derivatives of the target compound intended for analysis, wherein the internal standard is isotopically substituted (e.g., labeled). Substitution (e.g., labeling) may be performed via non-radioactive isotopes (i.e., stable isotopes) or via radioactive isotopes. Preferably, the internal standard is substituted (e.g., labeled) with a stable isotope. Alternatively, suitable substances for use as internal standards may be compounds that are structurally different from the target compound but are known to degrade at the same rate as the target compound. Such internal standards may be isotopically substituted compounds as defined above.

[0114] The isotopes of a compound that have undergone isotopic substitution can be selected from the following list: deuterium ( 2 H, d ), carbon-13 ( 13 C), Nitrogen 15 ( 15 N), Oxygen 18 ( 18 O) and its mixtures. To avoid any doubt, the compound suitable as an internal standard may be substituted at a single or multiple positions.

[0115] Preferred substances used as internal standards are derivatives of the target compound being analyzed, consisting of isotopically substituted variants of the compound. Stable isotopes, such as deuterium (²H), carbon-13 (¹³C), or nitrogen-15 (¹³C), are preferred. 5 N) can replace hydrogen, carbon, or nitrogen atoms on the compound being analyzed, thereby forming structurally similar molecules that differ slightly in mass but exhibit the same chemical properties, making them optimal for precise quantification in mass spectrometry.

[0116] Alternatively, a suitable internal standard could be a compound with a similar structure to the analyte, but which is not naturally present in the sample. For example, using a stereoisomer (such as doxorubicin) as an internal standard for measuring epirubicin ensures the same chemical stability, despite different chromatographic properties. Ideally, the internal standard degrades at the same rate as the analyte.

[0117] In addition, the composition may include a variety of substances suitable for use as internal standards, enabling the device to sample a variety of target compounds for subsequent analysis, quantification and / or identification.

[0118] This invention can also be used to quantify the fluid content (e.g., blood content) of antifungal drugs. Such antifungal drugs can be selected from the list presented in Table 1 below, which shows suitable internal standards that can be incorporated into the composition for analysis of the drug.

[0119] Table 1. Examples of antifungal drugs and internal standards used.

[0120]

[0121] This invention can also be used to quantify the fluid content (e.g., blood content) of antiviral drugs. Such antiviral drugs can be selected from the list presented in Table 2 below, which shows suitable internal standards that can be incorporated into the composition for analysis of the drug.

[0122] Table 2. Examples of antiviral drugs and internal standards used.

[0123]

[0124]

[0125] This invention can also be used to quantify the fluid content (e.g., blood content) of anticonvulsants. Such anticonvulsants can be selected from the list presented in Table 3 below, which shows suitable internal standards that can be incorporated into the composition for the analysis of anticonvulsants.

[0126] Table 3. Examples of anticonvulsant drugs and internal standards used.

[0127]

[0128]

[0129] This invention can also be used to quantify the fluid content (e.g., blood content) of antidepressants. Such antidepressants can be selected from the list presented in Table 4 below, which shows suitable internal standards that can be incorporated into the composition for the analysis of the antidepressants.

[0130] Table 4. Examples of antidepressants and internal standards used.

[0131]

[0132]

[0133]

[0134] This invention can also be used to quantify the fluid content (e.g., blood content) of anticancer drugs. Such anticancer drugs can be selected from the list presented in Table 5 below, which shows suitable internal standards that can be incorporated into the composition for the analysis of anticancer drugs.

[0135] Table 5. Examples of anticancer drugs and internal standards used.

[0136]

[0137]

[0138]

[0139] Common pharmaceuticals and abused drugs that can be analyzed using the device / container of this invention may be selected from the following list: Alprazolam (Diazepam-D5), Amitriptyline (Mianserin-D3), Amphetamine (Amphetamine-D5), Benzoyllecgonine (Amphetamine-D5), Bromazepam (Diazepam-D5), Buprenorphine (Methadone-D3), and Chlordiazepoxide (Diazepam-D5). Chlorprothixene (Mianserin-D3), Citalopram (Mianserin-D3), Clonazepam (Diazepam-D5), 7-Aminochloronitrazepam (Diazepam-D5), Clozapine (Mianserin-D3), Cocaine (Methadone-D3), Codeine (Methadone-D3), Diazepam (Diazepam-D5), Flunitrazepam (Diazepam-D5), 7-Aminofluoronitrazepam (Diazepam-D5), Fluoxetine (Mianserin-D3), Ketamine (Amphetamine-D5), Ketobemidone (Amphetamine-D5), Lamotrigine (Mianserin-D3) Levomepromazine (Mianserin-D3), Lidocaine (Mianserin-D3), Lorazepam (Diazepam-D5), 6-MAM (Amphetamine-D5), MDA (Amphetamine-D5), MDEA (Amphetamine-D5), MDMA (Amphetamine-D5), Methamphetamine (Amphetamine-D5), Methadone (Methadone-D3), Metoclopramide (Dibenzepine), Metoprolol (Mianserin-D3) D3), ​​Mianserin (Mianserin-D3), Mirtazapine (Mianserin-D3), Morphine (Methadone-D3), Nitrazepam (Diazepam-D5), 7-Aminonitrazepam (Diazepam-D5), Norfluoxetine (Dibenzonatase), Nortriptyline (Mianserin-D3), Orphenadrine (Mianserin-D3), Oxazepam (Diazepam-D5), Oxycodone (Dibenzonatase), Paroxetine (Dibenzonatase), Promethazine (Mianserin-D3), Quetiapine (Mianserin-D3), Sertraline (Dibenzonatase)Tramadol (mianserin-D3), triazolam (diazepam-D5), venlafaxine (mianserin-D3), zaleplon (methadone-D3), and combinations thereof.

[0140] The device / container of the present invention can also be used to sample the fluid content of controlled substances (such as anesthetics and stimulants), such as controlled substances selected from the list consisting of: heroin, cannabis, LSD, codeine, fentanyl, hydrocodone, combinations of hydrocodone (e.g., with acetaminophen), hydromorphone, morphine, methadone, oxycodone, combinations of oxycodone (e.g., with acetaminophen), tapentadol, amphetamine, methamphetamine and methylphenidate, cocaine, pentobarbital, secobarbital, buprenorphine, dronabinol, ketamine, tramadol, alprazolam, diazepam, clonazepam, lorazepam, midazolam, and combinations thereof.

[0141] In addition to measuring the fluid content of active pharmaceutical ingredients, the device / container of the present invention can also be used to diagnose diseases or conditions by, for example, measuring certain target compounds in bodily fluid samples that indicate those diseases.

[0142] For example, the device / container of the present invention can be used to diagnose diseases or conditions selected from the group consisting of: addiction (e.g., drug addiction or alcoholism), cancer (e.g., breast cancer or prostate cancer), cardiovascular disease, hypertension, viral infection, fungal infection, bacterial infection, epilepsy, depression, pain, vitamin deficiency, immunodeficiency, and steroid deficiency.

[0143] The device may already include a sample container coupled to an end cap, rather than having an end cap separate from the sample container for end-user construction.

[0144] Sample containers may contain an analytical solution, also referred to as an extraction fluid or solution. This analytical / extraction solution may include chemicals that increase the stability of target molecules, enabling cold chain-free transport. Chemicals may also be added to pretreat samples by enriching target molecules or to further reduce processing time in the laboratory. Known methods for preserving analytes in samples include precipitation with a water-miscible solvent such as acetone, 1-butanol, 2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol, dimethylformamide, dimethyl sulfoxide, 1,4-dioxane, dimethylpropenylurea, and sulfonates. Preservation via the principle of "salting out" is, for example, through ammonium sulfate and magnesium sulfate, and obtained by salting out assisted liquid / liquid extraction with acetonitrile. Chemicals act as pH adjusters, such as acids like formic acid, trifluoroacetic acid, acetic acid, trichloroacetic acid (10 to 20%), acetone containing trichloroacetic acid, and methanol containing ammonium acetate. Bases, such as ammonia, tris(hydroxymethyl)aminomethane, triethylamine, and nonnucleophilic amines (e.g., N,N-diisopropylethylamine, 1,8-diazabicycloundecane-7-ene, 1,5-diazabicyclo(4.3.0)non-5-ene, 2,6-di-tert-butylpyridine); and buffers, such as amines protonated to 10 to 90% by hydrochloric acid as exemplified above, ammonium acetate, phosphate-buffered saline, triEDTA buffer, Britton-Robinson buffer, 2,2'-[(2-amino-2-oxoethyl)azonium-dimethyl]diacetic acid, N-(2-acetamido)-2-aminoethanesulfonic acid, HEPES, HEPBS, and HEPPPS.

[0145] The use of the device or sample container according to the present invention can follow a method including the following steps: a. Provide a sampler that includes a fluid sample; and b. Introduce the sampler into the interior of the sample container so that the sample and a composition including a substance suitable for use as an internal standard are introduced into the interior of the sample container simultaneously.

[0146] According to another aspect of the present invention, a method for using a device, sample container, or component kit according to the present invention is provided, wherein the method includes the following steps: a. Providing a sampler comprising a fluid sample, a sample container comprising a composition positioned within an orifice, and a lid optionally comprising a rod member; and b. Introduce the sampler into the sample container to bring the fluid sample into contact with the analytical / extraction solution and simultaneously release the composition into the sample container, or in the presence of a lid including a rod member. c. Introduce the rod member through the orifice to release the composition into the interior of the sample container; and d. Introduce the sampler into the sample container to bring the fluid sample into contact with the analytical / extraction solution.

[0147] Following step b or d above, the method may further include the step of coupling a cap to an end cap to seal the interior of the device.

[0148] To avoid any doubt, when using the rod member of the cap to introduce the composition into the interior of the sample container, remove the rod member from the orifice before introducing the sampler.

[0149] According to another aspect of the present invention, a method is provided for analyzing, quantifying, and / or identifying the presence and / or concentration of a target compound in a fluid sample from a subject, the method comprising the following steps: Provide a kit of components for sampling fluids as defined above; Distribute the component kits to the subjects' locations; A sample container that receives a fluid sample, wherein an end cap is coupled to the sample container; Processing and analyzing samples to determine the concentrations of target compounds and internal standards; and Calculate the concentration of the target compound in the fluid sample at the time of sampling.

[0150] Methods for using devices, sample containers, or component kits and / or methods for analyzing, quantifying, and / or identifying the presence and / or concentration of a target compound in a fluid sample from a subject may include a step of shaking the sample container for a period of time from about 1 second to about 10 minutes, such as from about 10 seconds to about 1 minute, such as greater than 30 seconds, such as from about 30 seconds to about 2 minutes, such as from about 30 seconds to about 60 seconds.

[0151] Shaking can be done manually or mechanically, such as by using a homogenizer.

[0152] The processing steps may include centrifuging the sample to remove proteins and / or polar chemicals from the sample.

[0153] In any aspect of this invention, a sample may be analyzed by any method known in the art that is suitable for calculating the concentration of the target compound in the sample. For example, a sample may be analyzed using liquid chromatography-mass spectrometry or tandem mass spectrometry, such as LC-MS / MS, mass spectrometry (MS / MS), or gas chromatography (GC-MS / MS).

[0154] The device may be manufactured in accordance with regulatory guidelines. It may be sold online or directly to customers in pharmacies, or provided to end customers at healthcare facilities with instructions on how to use it.

[0155] The customer / patient can pack the device in a box containing sampling procedure instructions, which includes the following items that can be included in a component kit as defined herein and used according to the following methods: 1: A small disinfectant towel used to disinfect the area to be pierced; 2. Used to pierce the skin, such as a lancet at the fingertip; 3. A capillary tube for collecting a specified exact amount, preferably 20 to 50 μL, of blood; 4. Plaster; 5. A device (fluid sample collector) that can be marked with a specific and unique barcode and numbers or analog solutions to mark the sampling date and time. 6. Envelopes with pre-filled addresses and prepaid postage, for mailing to the laboratory; 7. The results will be returned to the customer (patient or healthcare institution) who registered the unique barcode.

[0156] Regarding point 5, the device of the present invention can be identified by a unique identifier (e.g., a barcode) that identifies the sample for subsequent analysis. Attached Figure Description

[0157] Figure 1 A lateral cross-sectional view of the end cap according to the present invention is shown.

[0158] Figure 2 exhibit Figure 1 An aerial view of the end cap.

[0159] Figure 3 exhibit Figure 1 and Figure 2 A lateral non-cross-sectional view of the end cap.

[0160] Figures 4A to 4C illustrate a series of depictions of how to use an embodiment of the device according to the invention, wherein Figure 4A shows a sampler and a sample container separated from each other, Figure 4B shows a sampler extending through an orifice through an end cap, and Figure 4C shows a sample holder coupled to an end cap.

[0161] Figures 5A to 5E illustrate a series of depictions of how to use another embodiment of the device according to the invention, wherein Figures 5A to 5C show how the syringe and plunger sampler are used with a sample container coupled to an end cap according to the invention, and Figures 5D and 5E show how the end cap can be coupled to the cap after sample introduction.

[0162] Figures 6A to 6H illustrate a series of depictions of how to use the device according to another embodiment of the invention, wherein Figure 6A shows a sample container, Figure 6B shows a lid and sample container including rod members separated from each other, Figure 6C shows a lid including rod members extending through an orifice of an end cap, Figure 6D shows a lid and sample container including rod members separated from each other, and a composition inside the sample container, Figure 6E shows a sampler and sample container separated from each other, Figure 6F shows a sampler extending through an orifice of an end cap, Figure 6G shows a lid and sample container including rod members separated from each other, and a composition and fluid sample inside the sample container, and Figure 6H shows how the end cap can be coupled to the lid including rod members after sample introduction.

[0163] Figure 7 The dose-response curves (0 to 1000 nM epirubicin) obtained at different time points (over a period of 7 days) using the device according to the invention and conventional methods are shown.

[0164] Figure 8 This demonstrates the low effect of hematocrit concentration on the epirubicin signal when analyzed using the method of the apparatus according to the invention. Detailed Implementation

[0165] Specific embodiments of the invention will now be described with reference to the accompanying drawings.

[0166] Figure 1 A side profile cross-sectional view of the end cap (100) according to the invention is shown. The end cap (100) includes an orifice (102) in which dry particles (104) are positioned. The dry particles contain a substance suitable for use as an internal standard. The dry particles (104) are sealed to both sides of the orifice (102) by a permeable membrane (106). The end cap (100) has two sets of threads, one set located at the lower portion (108) for coupling to a sample container, and the other set located at the upper portion (110) for coupling to a cap or sampler handle.

[0167] Figure 2 exhibit Figure 1 The upper outline view of the end cap (100) shows the orifice (102) in the center. On this end cap (100), the outer section (112) has a series of ridges for user handling.

[0168] Figure 3 exhibit Figure 1 The side profile of the end cap is shown in a non-cross-sectional view. The upper threaded portion (110) can be seen more clearly here.

[0169] Figures 4A, 4B, and 4C illustrate embodiments of the present invention.

[0170] When in use, the user provides a fluid sample for analysis. The fluid sample can be provided in any manner, such as by drawing blood through a finger puncture using a lancet. When providing the fluid (e.g., blood), the user holds the sampler (200) via the handle portion (202) and immerses the exposed end (204) of the sampler (in this case, the capillary) into the blood sample. In doing so, the capillary absorbs a predetermined amount of the blood sample.

[0171] Following this, the user takes a sample container (300) coupled to an end cap (100) and pushes a capillary tube (204) through an orifice, thereby penetrating the upper membrane and pushing the dry particles (104) through the lower membrane, exposing the dry particles to the interior of the sample container (300). The sample container (300) contains an analytical / extraction solution (302), shown in Figure 4B, and upon penetrating the lower membrane (106), the dry particles (104) fall into the analytical / extraction solution (302), releasing a substance suitable for use as an internal standard into the solution. Simultaneously, the user pushes the capillary tube (204) fully into the sample container (300) and brings the end of the capillary tube into contact with the analytical / extraction solution (302). In doing so, the blood sample and the dry particles (104) are simultaneously in contact with the analytical / extraction solution.

[0172] As the capillary (204) is fully advanced into the sample container (300), the handle portion (202) of the sampler (200) then screws onto the top of the end cap for storage.

[0173] Figures 5A, 5B, 5C, 5D and 5E illustrate alternative embodiments of the present invention.

[0174] In this embodiment, when in use, the user provides a fluid sample for analysis. The fluid sample can be provided in any manner, such as by drawing blood through a finger puncture using a lancet. When providing the fluid (e.g., blood), the user holds a sampler (400), which in this embodiment is in the form of a syringe (402) with a plunger (404), and the blood sample is drawn into the syringe (402) by withdrawing the plunger (404). In this embodiment, the syringe may include volume markings so that the user can draw a defined amount of fluid (e.g., blood).

[0175] Following this, the user takes the sample container (300) coupled to the end cap (100) and pushes the end of the syringe (402) through the orifice (102), thereby penetrating the upper membrane and pushing the dry particles (104) through the lower membrane, exposing the dry particles to the interior of the sample container (300). The sample container (300) contains an analytical / extraction solution (302), shown in Figure 4B, and upon penetrating the lower membrane (106), the dry particles (104) fall into the analytical / extraction solution (302), releasing a substance suitable for use as an internal standard into the solution. Simultaneously, the user presses the plunger (404) on the syringe (402) to expel the fluid sample into the interior of the sample container (300).

[0176] When the fluid sample has been completely expelled from the syringe, the user can remove the syringe from the end cap orifice (102) and attach the cap (500) to the top of the end cap (100) to close the device.

[0177] Figures 6A, 6B, 6C, 6D, 6E, 6F, 6G, and 6H illustrate alternative embodiments of the present invention.

[0178] In use, the user holds the sample container (300) coupled to the end cap (100). The user holds the cap (600) including the rod member (602) and pushes the end of the rod member (602) through the orifice (102), thereby penetrating the upper membrane and pushing the dry particles (104) through the lower membrane and exposing the dry particles to the interior of the sample container (300). The sample container (300) contains an analytical / extraction solution (302), shown in Figure 6C, and upon penetrating the lower membrane (106), the dry particles (104) fall into the analytical / extraction solution (302), releasing a substance suitable for use as an internal standard into the solution. The user removes the cap (600) including the rod member (602).

[0179] The user provides a fluid sample for analysis. The fluid sample can be provided in any manner, such as by drawing blood through a finger prick using a lancet. When providing the fluid (e.g., blood), the user holds a sampler (400), which in this embodiment is in the form of a syringe (402) with a plunger (404), and the blood sample is drawn into the syringe (402) by withdrawing the plunger (404). In this embodiment, the syringe may include volume markings so that the user can draw a defined amount of fluid (e.g., blood).

[0180] After this, the user pushes the end of the syringe (402) through the orifice (102) and presses the plunger (404) on the syringe (402) to expel the fluid sample into the interior of the sample container (300).

[0181] When the fluid sample has been completely expelled from the syringe, the user can withdraw the syringe from the end cap orifice (102) and attach the cap (600) including the rod member to the top of the end cap (100) to close the device.

[0182] The device can then be shaken to mix the sample, suitable substances, and analytical / extraction solutions. This allows for homogeneous protein precipitation and quantitative release of internal standards from the composition.

[0183] exist Figure 7 The method demonstrated uses doxorubicin as an internal standard to determine the concentration of epirubicin. The device is used according to the method of using the device, sample container, or component kit as defined above. The sample container contains beads in the form of stainless steel spheres.

[0184] Once the sample and the substance suitable as an internal standard have been contacted with the analytical / extraction solution, the device is closed and further analysis of the target compound can be performed. For example, the analysis of the target compound can be performed by any method known in the art, such as liquid chromatography-mass spectrometry (LC-MS / MS). In cases where the fluid sample and the substance suitable as an internal standard are simultaneously contacted with the analytical / extraction solution, or where the substance suitable as an internal standard is contacted with the analytical / extraction solution before the fluid sample, and where the substance suitable as an internal standard has been previously protected from degradation in the device, the target compound and the internal standard will degrade at the same rate.

[0185] With the mass of the internal standard known before contact analysis / extraction of the solution, the concentration of the target compound in the fluid sample at the time of sample acquisition can be calculated.

[0186] Therefore, the device of the present invention provides several advantages, including: ● Easy to use and does not necessarily require trained medical professionals, meaning users can collect samples themselves; ● Accurately analyzes the content of target compounds in fluid samples, and the reliability is not affected by processing delays; and ● Costs are reduced because users can collect samples themselves and the process is not performed in a clinical setting.

[0187] Example Example 1: Application of the sample equipment in determining the concentration of epirubicin using doxorubicin as an internal standard. Overview The method for quantifying a drug, namely epirubicin, in a biological sample using the device according to the invention compares the performance of the method with that of typical "conventional" analytical methods. The device according to the invention facilitates convenient and timely sample collection, allowing samples to be mailed to a laboratory for accurate analysis using liquid chromatography-tandem mass spectrometry (LC-MS / MS).

[0188] Material chemical substances Epirubicin-HCl (catalog number 992, batch number 3559), doxorubicin-HCl (catalog number 990, batch number 3285), and daunorubicin-HCl (code D0125000, batch number 5.0) were obtained from the British Pharmacopoeia Reference Chemical Standards. Acetone (99.5%), acetonitrile (HPLC grade), methanol (>99.9%), formic acid (95%), methylene blue (M4159-25G), 2-propanol (99.9%), and zinc sulfate heptahydrate (Essential+ grade) were all obtained from Sigma-Aldrich. Lutrol micro 127 was from BASF.

[0189] equipment Waters Acquity Premier UPLC binary solvent manager. Waters Acquity Premier sample manager. Waters Acquity Premier column manager. Waters Xevo TQ-Sμ triple quadrupole mass spectrometer. Acquity HSS T3 column (2.1 × 100 mm, 1.7 μm). Eppendorf Multipette. Mettler Toledo analytical precision balance (XPR204S / A): using the following ion transitions: epirubicin (544.3>397), doxorubicin (544.3>397), and daunorubicin (528.3>321.2).

[0190] Material The non-woven polypropylene (PP) (Milisten, 172×150×0.2 cm; 800g, part number 75925CNDVBCYJ04IRK2PZQW) was obtained from Amazon Sweden (amazon.se). The cap was sealed by placing a heat-sealing foil between the bottom cap and a heat sealer (Vevor, WT-90DS230421320820010) at 170°C for 3 seconds. The stainless steel studs (24 / 6, Rapid) were obtained from 123ink.se.

[0191] method Sample preparation Venous blood samples (EDTA, 3 × 10 mL) were collected from the subjects. Stock solutions were prepared in methanol with epirubicin, doxorubicin, and daunorubicin at 2000 μM. The stock solutions were diluted to 100 μM for calibration series preparation.

[0192] Calibration samples were prepared by injecting different concentrations of epirubicin (0 to 1000 nM) into fresh blood.

[0193] Equipment preparation according to the present invention The apparatus / equipment used in this study is equivalent to Figures 6a to 6h The apparatus described herein. In this section, we will refer to this apparatus and the method of using this apparatus as "the apparatus according to the invention" or "the method of using the apparatus according to the invention," etc.

[0194] Insert the PP matrix (8.0 mm inner diameter) into the device cap and seal it with puncture-resistant alumina heat-sealing foil (170°C, 3 seconds). Insert the PP matrix into the bottom sealing hole and add an internal standard (10 μL) consisting of doxorubicin, daunorubicin (400 nM each), and a reagent that encapsulates the internal standard (IS) on the matrix, such as polyethylene glycol (PEG, Lutrol Micro127), which is non-reactive and soluble in the solvent used for protein precipitation. Add a dye and antioxidant (such as methylene blue (1.0 mM)) to the PP matrix inserted into the hole in the bottom sealing cap.

[0195] Add a stainless steel grinding ball (6 × 2 mm inner diameter) and precipitation solution (500 μL IPA:MeOH, 1:1, 0.1% formic acid (FA)) to a 1.5 mL vial. If not using the cap directly, seal it within 1 hour after adding the IS.

[0196] Traditional methods and apparatus preparation Add doxorubicin (10 μL, 400 nM) to the precipitation solution (500 μL LPA:MeOH, 1:1, 0.1% FA) in a 1.5 mL vial with a screw cap.

[0197] Sample additions and main differences Add blood or plasma (20 μL or 50 μL) using the following device (same procedure): 1. Laboratory pipettes 2. Blood sampling capillary tube (Sarstedt POCT 20 μL or 50 μL) According to the device of the invention: after adding a sample of 20 μL of blood (or plasma), the device is sealed and shaken for at least 30 seconds. The grinding balls in the tube enhance protein precipitation.

[0198] Traditional method: After adding blood / plasma (20 μL) to the precipitation solution, the sample is shaken to mix (maximum rpm for 30 seconds).

[0199] result Enhanced protein precipitation using mixing spheres versus conventional vibratory mixing: a comparative study.

[0200] Protein precipitation experiments were performed using six different solvent mixtures, as shown in Table 6. For each solvent, the precipitation volume was fixed at 500 μl. For each shaking technique of the corresponding protein precipitation solution, blood samples cultured with epirubicin (111 nM) and control samples without epirubicin were prepared.

[0201] The shaking techniques employed included manual shaking for 30 seconds, vortexing for 10 seconds (1 × 10 seconds), vortexing for 60 seconds (6 × 10 seconds), shaking with a Thermomix at 1200 rpm for 20 minutes, and manual shaking with three steel balls (2.8 mm diameter) for 30 seconds. The precipitate was visually inspected, and its quality was assessed based on the relative grade and homogeneity of the fine grinding. After precipitation, all samples were stored at room temperature for 3 days before analysis by LC-MS / MS.

[0202] Visually assess the quality of the precipitate, describing it as "not completely precipitated," "fluffy," "almost entirely precipitated," "poor precipitate," or "completely precipitated." Additionally, record the appearance after sonication and centrifugation, noting clarity and the presence of precipitate on the plastic walls. Evaluate the suitability of the samples for LC-MS analysis and label those deemed appropriate accordingly. LC-MS / MS results confirm that samples shaken manually with steel balls yield the highest yield and best accuracy, but the apparatus according to the invention can still provide usable precipitate without the need for steel balls.

[0203] The key findings of the experiment showed that the use of steel balls improved precipitation quality in all solvent systems. Manual shaking and short vortex mixing times typically produced fluffy and incompletely precipitated samples.

[0204] Extended vortex mixing (60 seconds) and Thermomix shaking showed different results, with some improvements observed in certain solvent mixtures. The sample precipitated with steel balls in IPA:MeOH (1:1) exhibited the best precipitation quality, with a clear supernatant after centrifugation.

[0205] Table 6

[0206]

[0207] Dose-response curves of epirubicin-cultured blood samples and at sampling (protein precipitation) and laboratory conditions. The impact of the time elapsed between reasoning and analysis.

[0208] A comparative validation study was conducted to compare the method using the device according to the invention with conventional analytical methods (conventional measurement methods – conventional methods) to validate the method and device of the invention. Blood samples cultured with epirubicin were measured using the method utilizing the device according to the invention and conventional methods over time spans from immediately after preparation to 18 hours, 3 days, 7 days, up to 14 days of delay, until sonication, centrifugation, and analysis.

[0209] Figure 7 Dose-response curves (0 to 1000 nM epirubicin) obtained at different time points (over a 7-day period) using the device and method according to the invention and conventional methods are shown. Figure 7 In the diagram, the Y-axis shows the signal intensity ratio of epirubicin (Epi) to doxorubicin (Dox). The X-axis shows the concentration (nM) of epirubicin in the cultured blood sample.

[0210] The method using the apparatus according to the invention also measures daunorubicin as a second internal standard. While conventional methods require immediate sample processing, the method and apparatus of the invention allow for processing of samples stored for several days to two weeks prior to analysis. As shown in Table 7, the highest AUC for epirubicin was observed after 7 days using both methods, demonstrating consistent performance over time.

[0211] Figure 7 The comparison consists of eight plots, each representing a linear regression analysis of epirubicin concentration versus the epirubicin / doxorubicin signal ratio at four different time points using both methods. The linear regression equation and R² value are indicated in each subplot. Comparisons were made at the highest epirubicin concentration (1000 nM). However, the same pattern of high variability was observed when analyzing samples immediately (directly) and at 18 hours at lower epirubicin concentrations.

[0212] Surprisingly, after storage at room temperature for 3 to 14 days, gentle shaking (300 rpm, 10 seconds; 0 rpm, 5 minutes) yielded (3% to 8% CV), while samples processed directly and those processed after 18 hours yielded very poor results, despite being sonicated (on ice for 15 minutes) prior to analysis.

[0213] Measured values: The data compare the performance of two methods (the traditional method and the inventive method) in measuring the concentrations of epirubicin and doxorubicin in blood samples at different time intervals (0 hours, 18 hours, 3 days, 7 days, and 14 days). The inventive method, using the apparatus according to the invention, also measures daunorubicin.

[0214] To investigate the effect of time on the concentration of stored samples, we compared the results of 1000 nM epirubicin blood samples treated at various time points prior to analysis (Table 7). The “Method Ratio (Trad / Inv)” column represents the ratio of the epirubicin / doxorubicin ratio using the conventional method to the epirubicin / doxorubicin ratio using the device according to the invention at each time point. This ratio indicates the degree of correlation between the two methods by comparing the AUC Epi / AUC Dox ratio.

[0215] Table 7. Comparison of AUC of rubella, doxorubicin and daunorubicin (Inv only) with the time elapsed between blood addition and analysis at room temperature.

[0216]

[0217]

[0218] Hematocrit and AUC of epirubicin In this study, blood samples with different hematocrit levels (7 to 18 g / dL) were artificially generated by separating plasma from whole blood and recombining it with different amounts of red blood cells, in order to investigate the effect of hematocrit concentration on epirubicin signaling. Figure 8 ). Figure 8 This demonstrates the low effect of hematocrit concentration on the epirubicin signal when analyzed using the method according to the apparatus of the present invention.

[0219] discuss The collected data show that the method using the apparatus according to the invention performs comparably to conventional methods.

[0220] The device according to the invention, designed for self-sampling and delayed analysis, was compared with conventional methods that require immediate sample processing. That is, in conventional methods, sample analysis is performed in a laboratory with minimal delay between the protein precipitation step (where IS is added) and sonication of the sample prior to centrifugation and separation of the clarified eluent for LC-MS / MS analysis. The results of both methods were evaluated at various time intervals (0 hours, 18 hours, 3 days, 7 days, and 14 days) to assess the effect of storage time on analytical measurements. Surprisingly, the method of the invention provided consistent results, with better performance observed after 3, 7, and even 14 days of storage at room temperature compared to samples processed directly and after 18 hours. Data showed that the highest yields of epirubicin were obtained on days 3 and 7 for both methods. This indicates that prolonged storage helps to delay the equilibration process, thereby releasing epirubicin from difficult-to-extract pockets and thus smoothing out changes in blood precipitation.

[0221] Specifically, for both methods, the highest AUC for epirubicin was observed after 7 days, demonstrating the stability and robustness of the device and method of the present invention over time. The introduction of stainless steel balls improves the method of the present invention by grinding the blood sample during protein precipitation, but complete precipitation is still possible in the absence of the steel balls. Furthermore, the inclusion of antioxidants to preserve the internal standard proved effective. The robust data from these studies allow for entry into the clinical validation phase, where early measurements are promising.

[0222] The device of this invention allows for sampling several days prior to laboratory processing and analysis. Data show that extended storage times (3 days, 7 days, and 14 days) improved dose-response relationships and reduced variability in all measured analytes compared to samples processed immediately using two different methods. This unexpected positive effect suggests that delayed analysis can facilitate a more uniform drug extraction process, thereby improving analytical results.

[0223] The variability observed in samples processed immediately and those processed after 18 hours can be attributed to incomplete extraction of the analyte. Notably, conventional methods typically require 30 minutes to several hours from adding blood to protein precipitates, while the ability of the method of this invention to maintain analytical integrity over extended storage periods demonstrates its potential for more flexible and patient-friendly sample collection. The three- to seven-day delay would be beneficial compared to the rapid processing of samples using conventional methods.

[0224] Almost all analytical methods for measuring drugs are performed on plasma / serum matrices because these matrices have lower levels of interference, such as ion suppression. However, if blood samples are processed with a long delay, the signal of epirubicin in blood at normal hematocrit levels is almost as strong as in plasma (see [link to relevant documentation]). Figure 8 ).

[0225] Key findings: Enhanced protein precipitation can be achieved by using a steel ball. The best precipitation is obtained by hand-shaking the ball for 30 seconds, which is better than vibration mixing (6 x 10 seconds).

[0226] Consistency over time The true-dose method demonstrated stable performance at different time points, with the epirubicin / doxorubicin ratio remaining constant. The method ratios (conventional / inventive) showed high consistency within the range of 84.6% to 102.3%, indicating minimal variability between methods.

[0227] Effect of hematocrit level: Hematocrit studies showed that different hematocrit levels (7 to 18 g / dL) did not significantly affect the epirubicin signal, confirming the reliability of the true dose method under different hematocrit conditions.

[0228] in conclusion The method using the device according to the invention demonstrates significant promise for reliable and consistent quantification of epirubicin in blood samples, even with processing delays from the time of sample acquisition. Its stability over time supports its use for home-based self-sampling, enhancing patient compliance and comfort, while maintaining the accuracy required for effective treatment monitoring. Future research should explore the application of the method and device of the invention in different pharmaceutical and clinical settings to further validate its utility in personalized medicine.

[0229] The method and apparatus of this invention provide a reliable alternative to conventional methods for measuring drug concentrations in blood samples. Their ability to maintain accuracy and precision over extended storage periods makes them highly suitable for home-based self-sampling, thereby improving patient compliance and convenience. The strong correlation between the method of this invention and conventional methods across various conditions and time points supports its potential for broad clinical application, particularly in therapeutic drug monitoring and personalized medicine.

Claims

1. A fluid sample collection device comprising an end cap, wherein the end cap comprises a composition including a substance suitable for use as an internal standard, wherein the composition is sealed within the end cap in an atmosphere that protects the substance suitable for use as an internal standard from degradation, and wherein the end cap is configured to couple to a sample container and controllably release the composition into the interior of the sample container.

2. The fluid sample collection device of claim 1, wherein the end cap includes an orifice, the composition is positioned within the orifice, optionally wherein the orifice is for receiving a sampler and / or a rod member attached to the cap, and wherein the end cap is configured to release the composition into the interior of the sample container by introducing the sampler or the rod member through the orifice.

3. The fluid sample collection device of claim 2, wherein the composition is sealed on both sides of the orifice by an upper permeable membrane and a lower permeable membrane, optionally wherein the permeable membrane breaks when the sampler or the rod member is introduced through the orifice, thereby causing the composition to be released into the interior of the sample container.

4. The fluid sample collection device according to any of the preceding claims, wherein the composition is a matrix composition.

5. The fluid sample collection device of claim 4, wherein the matrix composition comprises a polymeric stationary phase that retains the internal standard through hydrophobic interactions.

6. The fluid sample collection device according to any of the preceding claims, wherein the composition comprises one or more beads, spheres, gemstones, projectiles, mixers and / or wires.

7. The fluid sample collection device according to any of the preceding claims, wherein the composition comprises an antioxidant.

8. The fluid sample collection apparatus according to any of the preceding claims, wherein the substance suitable for use as an internal standard is a known substance having analytical behavior similar to that of a predetermined substance to be evaluated in the sample.

9. The fluid sample collection apparatus according to any of the preceding claims, wherein the substance suitable for use as an internal standard is a derivative of a target compound intended for analysis, and the internal standard is substituted with an isotope.

10. The fluid sample collection apparatus according to any one of claims 1 to 8, wherein the substance suitable for use as an internal standard is a compound that is structurally different from the target compound intended for analysis but degrades at the same rate as the intended substance to be evaluated in the sample.

11. The fluid sample collection device according to any of the preceding claims, wherein the internal standard is present in the composition in an amount of about 0.001 wt.% to about 0.1 wt.%, such as about 0.001 wt.% to about 0.05 wt.%, for example, about 0.001 wt.% to about 0.01 wt.%.

12. The fluid sample collection device according to any of the preceding claims, wherein the composition is dry particles.

13. The fluid sample collection device of claim 12, wherein the ends of the dry particles facing the lower permeable membrane are molded into cone-shaped points.

14. The fluid sample collection device according to any of the preceding claims, wherein the device includes a sample container reversibly coupled to the end cap.

15. The fluid sample collection device of claim 14, wherein the sample container comprises an analysis / extraction solution.

16. The fluid sample collection device according to any of the preceding claims, wherein the composition comprises an indicator compound.

17. The fluid sample collection device of claim 16, wherein the end cap includes an orifice, the composition is positioned within the orifice, wherein the composition is sealed on both sides of the orifice by an upper permeable membrane and a lower permeable membrane, and wherein the matrix composition includes a polymeric stationary phase that retains the internal standard through hydrophobic interactions.

18. The fluid sample collection device of claim 16 or claim 17, wherein the indicator compound causes a color change when added to the analytical / extraction fluid.

19. A component kit comprising a sample container according to any one of claims 1 to 13, a sampler configured to sample a defined volume of sample fluid, and an end cap, wherein the sample container and the end cap are configured to be coupled together.

20. The component kit of claim 19, wherein the sample container comprises an analysis / extraction solution.

21. The component kit according to claim 19 or 20, further comprising a lancet.

22. The component kit according to any one of claims 19 to 21, wherein the sampler includes a handle portion.

23. The component kit according to any one of claims 19 to 22, further comprising a cover including a rod member.

24. A sample container for collecting fluid samples for future analysis, the sample container comprising: Storage device; A composition comprising a substance suitable for use as an internal standard in the analysis; The composition is sealed in an atmosphere that protects the substance suitable for use as an internal standard from degradation; and The sample container includes components for removing the composition from the protective atmosphere and introducing the composition into the reservoir while providing the sample to the reservoir.

25. Use of a fluid sample collection device according to any one of claims 1 to 18, a component kit according to any one of claims 19 to 23, or a sample container according to claim 24, for analyzing fluid samples.

26. A method of using a component kit according to any one of claims 19 to 23, wherein the method comprises the following steps: a. Provide a capillary tube containing a fluid sample; as well as b. Introduce the capillary tube into the interior of the sample container to bring the fluid sample into contact with the analytical / extraction solution, while simultaneously releasing the composition into the interior of the sample container.

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