DES-impregnated fiber aggregate as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of clinical detection, and particularly relates to a DES-impregnated fiber aggregate as well as a preparation method and application thereof. The DES-impregnated fiber agglomerate provided by the invention consists of a PPF (polypropylene fiber) fiber agglomerate and DES (deep eutectic solvent) impregnated in the PPF fiber agglomerate, so that efficient extraction and high-throughput detection of non-polar drug molecules and weak-polar drug molecules in body fluid can be realized by virtue of the characteristics of the PPF fiber agglomerate and the advantages of the DES; moreover, economy and environmental protection are both considered, the clinical detection requirements of portability, standardization and instant use can be met, and a green, economical, extensible and operation-simplified alternative scheme is provided for traditional sample pretreatment.

Description

Technical Field

[0001] This invention belongs to the field of clinical testing technology, specifically relating to a DES-impregnated fiber aggregate, its preparation method, and its application. Background Technology

[0002] The accurate detection of nonpolar and weakly polar drug molecules in body fluids is crucial in clinical pharmacology, therapeutic drug monitoring, and toxicological analysis, but it also faces numerous technical challenges. These drugs typically exist at extremely low concentrations in biological samples such as serum and urine, and the matrix composition is complex (containing proteins, lipids, inorganic salts, and a large number of endogenous metabolites), often resulting in severe interference during direct analysis and insufficient sensitivity and selectivity. Therefore, developing efficient and reliable biological sample pretreatment techniques is a key step in improving detection performance.

[0003] Currently, pretreatment methods for such biological samples mainly include classic techniques such as liquid-liquid extraction (LLE), solid-phase extraction (SPE), and dispersive liquid-liquid microextraction (DLLME). While these methods can meet some analytical needs to a certain extent and exhibit good enrichment and selectivity in specific scenarios, they still have several significant drawbacks that limit their widespread application in routine clinical testing. Liquid-liquid extraction relies on the partition differences of analytes between two immiscible solvents for separation. Although simple to operate, it usually requires a large volume of organic solvent and has limited extraction efficiency for weakly polar compounds. Solid-phase extraction selectively retains target analytes through adsorbents, effectively removing some matrix interference and is easily automated, but its column bed is prone to clogging and the method development cycle is long. Dispersive liquid-liquid microextraction, as a miniaturized extraction technique, is advantageous due to its rapid operation and small solvent usage, making it particularly suitable for trace analysis. However, in practical applications, it often faces problems such as difficult phase separation and reproducibility significantly affected by operational factors. Furthermore, the reproducibility of these methods is greatly affected by human factors, and their low standardization further reduces their applicability in standardized clinical testing systems. Therefore, developing new pretreatment technologies that are greener, more efficient, automated, and have higher throughput has become an important research direction for promoting the detection of drug molecules in body fluids towards routine clinical applications. Summary of the Invention

[0004] To address the above-mentioned technical problems, this invention provides a DES-impregnated fiber aggregate, its preparation method, and its applications. This DES-impregnated fiber aggregate leverages the characteristics of PPF (polypropylene fiber) fiber aggregates and the advantages of DES (eutectic solvent) to achieve efficient extraction and high-throughput detection of non-polar and weakly polar drug molecules in body fluids. It also balances economic efficiency and environmental friendliness, meeting the requirements for portable, standardized, and ready-to-use clinical testing.

[0005] To achieve the above-mentioned objectives, the present invention adopts the following technical solution: The first aspect of the present invention provides a DES-impregnated fiber aggregate, which is composed of PPF fiber aggregate and DES impregnated in the PPF fiber aggregate.

[0006] Demodified esters (DES) are eutectic mixtures formed by mixing hydrogen bond donors and acceptors in a specific ratio and then reacting them through hydrogen bonding. Compared with traditional organic solvents, DES has the following advantages: good biocompatibility (degradable and non-cytotoxic), avoiding health risks to operators and environmental pollution; strong designability, allowing precise control of solvent polarity to match the enrichment requirements of drugs with different polarities by adjusting the types and ratios of components; and its unique hydrogen bond network and hydrophobic regions can efficiently encapsulate lipophilic drug molecules, resulting in significantly higher extraction efficiency than conventional organic solvents. However, DES has a low melting point and is mostly liquid at room temperature, making it prone to loss with the sample and difficult to recover, which limits its large-scale application in high-throughput detection.

[0007] PPF possesses excellent hydrophobic and lipophilic properties, and is commonly used to manufacture products such as oil-absorbing sheets and pads for cleaning kitchen spills. This invention creatively uses PPF as a carrier to impregnate DES with PPF fiber aggregates to construct immobilized DES units, solving the problems of DES easily being lost with samples and difficult to recover. Furthermore, PPF, as a carrier for pharmaceutical analysis, has multiple advantages such as good detection compatibility, high chemical purity, low background interference, and strong chemical inertness, as well as practical properties such as high mechanical strength, resistance to organic solvent corrosion, and reusability. In addition, the PPF synthesis process is mature, with good batch-to-batch consistency, ensuring the stability of analyte extraction using this DES-impregnated fiber aggregate; it is also highly adaptable, as it can be processed into fiber balls or irregular fiber aggregates, facilitating DES immobilization and handling.

[0008] This DES-impregnated fiber aggregate, leveraging the aforementioned properties of PPF fiber aggregates and the advantages of DES, enables "input-output" phase separation without centrifugation. This facilitates efficient extraction and high-throughput detection of nonpolar and weakly polar drug molecules in body fluids, while also being both economical and environmentally friendly. Its structure makes it easy to manufacture individually packaged "ready-to-use" consumables, meeting the need for portable testing. By controlling the standardized production of this DES-impregnated fiber aggregate, the influence of human factors can be reduced, the standardization of testing can be improved, and its applicability in clinical testing can be enhanced.

[0009] Preferably, the DES is made from menthol and thymol, menthol and n-butanol, menthol and camphor, camphor and thymol, menthol and oleic acid, or thymol and decanoic acid in a molar ratio of (1~3):(1~2). This DES-impregnated cellulose aggregate is suitable for the extraction of nonpolar drugs, such as tyrosine kinase inhibitors (TKIs) crizotinib (CRI), gefitinib (GEF), afatinib (AFA), erlotinib (ERL), pazopanib (PAZ), nilotinib (NIL), sunitinib (SUN), alectinib (ALE), and lenvatinib (LEN).

[0010] More preferably, the DES is prepared from menthol and thymol in a molar ratio of 2:1, or camphor and thymol in a molar ratio of 1:1, or thymol and decanoic acid in a molar ratio of 1:1. Using this DES-impregnated fiber aggregate for TKI extraction can achieve high recovery rates for a wider range of TKIs.

[0011] More preferably, the DES is made of menthol and thymol in a molar ratio of 2:1. This DES can meet the extraction requirements of more TKIs and has a higher recovery rate.

[0012] Preferably, the DES is made from methyltrioctylammonium bromide and decanoic acid in a molar ratio of 1:3. This DES-impregnated fiber aggregate is suitable for the extraction of various nonsteroidal anti-inflammatory drugs (NSAIDs) and tricyclic antidepressants (TCAs), such as the NSAIDs sulindac (SLD), loxoprofen (LOX), naproxen (NPX), flurbiprofen (FBP), diclofenac (DCF), and ibuprofen (IBU), and the tricyclic antidepressants venlafaxine (VEN), citalopram (CIT), imipramine (IMP), amitriptyline (AMP), and fluoxetine (FLX).

[0013] Preferably, the mass of the PPF fiber aggregate is 3-10 mg, and the volume of the DES is 15-30 µL.

[0014] More preferably, the mass of the PPF fiber aggregate is 5 mg, and the volume of the DES is 20 µL.

[0015] Preferably, the PPF fiber aggregates are spherical.

[0016] More preferably, the average density of the spherical PPF fiber aggregates is 68~86 mg / cm³. 3 For example, the diameter of 5 mg of spherical PPF fiber agglomerates is approximately 5 ± 0.2 mm.

[0017] The second aspect of the present invention provides a method for preparing the above-mentioned DES-impregnated fiber agglomerates, comprising the following operations: preparing PPF fibers into PPF fiber agglomerates, slowly adding the DES dropwise to fully impregnate the voids of the PPF fiber agglomerates, thereby obtaining the product.

[0018] Optionally, the PPF can be obtained by removing the surface layer of the oil-absorbing cotton and drying it in an environment of 30±2℃ for 2 hours.

[0019] Preferably, the preparation method further includes individually packaging the DES-impregnated fiber aggregates.

[0020] More preferably, the individual packaging is sealed packaging.

[0021] Optionally, the individual packaging can be in the form of disposable PVC plastic blister packs or light-proof sealed bags.

[0022] A third aspect of the present invention provides the application of the above-mentioned DES-impregnated fiber aggregates in the detection of nonpolar or weakly polar drugs in body fluids.

[0023] Preferably, the bodily fluid is blood.

[0024] Preferably, the nonpolar or weakly polar drug includes tyrosine kinase inhibitors, nonsteroidal anti-inflammatory drugs, and tricyclic antidepressants.

[0025] More preferably, the DES in the DES-impregnated fiber aggregate is made of menthol and thymol, menthol and n-butanol, menthol and camphor, camphor and thymol, menthol and oleic acid, or thymol and decanoic acid in a molar ratio of (1~3):(1~2), and the application is for detecting tyrosine kinase inhibitors in blood.

[0026] More preferably, the tyrosine kinase inhibitor includes crizotinib, gefitinib, afatinib, erlotinib, pazopanib, nilotinib, sunitinib, alectinib, and lenvatinib.

[0027] More preferably, the DES is made of menthol and thymol in a molar ratio of 2:1, or camphor and thymol in a molar ratio of 1:1, or thymol and decanoic acid in a molar ratio of 1:1.

[0028] More preferably, the DES is made of menthol and thymol in a molar ratio of 2:1.

[0029] More preferably, the DES in the DES-impregnated fiber aggregate is made of methyltrioctylammonium bromide and decanoic acid in a molar ratio of 1:3, and the application is to detect nonsteroidal anti-inflammatory drugs and / or antidepressants in blood.

[0030] More preferably, the nonsteroidal anti-inflammatory drug includes sulindac, loxoprofen, naproxen, flurbiprofen, diclofenac, and ibuprofen.

[0031] More preferably, the tricyclic antidepressant includes venlafaxine, citalopram, imipramine, amitriptyline, and fluoxetine.

[0032] Preferably, the PPF fiber aggregates are spherical.

[0033] A fourth aspect of this invention provides a method for detecting nonpolar or weakly polar drugs in blood for non-diagnostic purposes, specifically comprising the following operations: The blood sample to be tested was diluted and adjusted with a diluent containing 0-20% wt sodium chloride at a pH of 5-9 to prepare the sample solution. Place one of the above-mentioned DES-impregnated fiber aggregates in 0.2~2 mL of the sample solution, vortex at 700~800 rpm for at least 10 min, then wash the DES-impregnated fiber aggregates with water, and then vortex in at least 50 μL of desorption solvent for at least 2 min to obtain the test solution. The nonpolar or weakly polar drug is determined in the test solution.

[0034] Preferably, the diluent is pure water. Using pure water as the diluent can achieve a higher recovery rate and is simpler to operate.

[0035] This method can employ isotope internal correction. During sample determination, the dilution factor of the linear spiked sample and the actual sample should be consistent, and can be conventionally selected based on actual testing conditions. Optionally, the dilution factor is 10-fold.

[0036] Preferably, the first vortexing time is 20-25 minutes. After 20 minutes of vortexing, the drug basically reaches distribution equilibrium between the DES and the aqueous phase, and the recovery rate does not significantly improve after the time is extended.

[0037] Preferably, the second vortex lasts for 2 to 3 minutes.

[0038] Preferably, the desorption solvent is acetone, acetonitrile, ethanol, isopropyl alcohol, or methanol.

[0039] More preferably, the desorption solvent is ethanol. Ethanol has high extraction and recovery rates for most drugs and also has advantages such as low toxicity, environmental friendliness, low cost, and wide applicability.

[0040] The beneficial effects of this invention are as follows: This invention provides a "ready-to-use" DES-impregnated fiber aggregate and establishes a green microextraction method for high-throughput determination of drugs in serum, offering a green, economical, scalable, and simplified alternative to traditional sample pretreatment. Compared with traditional sample pretreatment techniques, this method has the following significant advantages: (1) Economic and environmental protection: DES has the characteristics of good biocompatibility, degradability and non-cytotoxicity. In this invention, the amount used is small and the cost is extremely low. It replaces traditional toxic volatile organic solvents, taking into account both good environmental protection and economy.

[0041] (2) Simple and fast separation: By impregnating DES with PPF fiber aggregates to construct "immobilized DES units", relying on the porous structure and solid phase characteristics of PPF fiber aggregates, during extraction, only the DES-impregnated fiber aggregates need to be put into the body fluid sample and shaken. After extraction, the phase separation can be completed directly without the need for complex operations such as protein precipitation, centrifugation, nitrogen blowing or other special instruments, which significantly simplifies the pretreatment steps.

[0042] (3) Consumable standardization: Drawing on the concept of independent aluminum foil packaging for pharmaceuticals, the "immobilized DES unit" is made into a ready-to-use consumable, which does not require pre-preparation or activation of the extractant and is convenient to use. The sealed packaging can isolate air and moisture to ensure the stability of the DES loading (avoiding loss during storage), while ensuring that the DES loading and extraction performance of each DES-impregnated fiber aggregate are consistent, meeting the clinical testing requirements for standardized methods and rapid sample processing.

[0043] (4) High throughput and high adaptability: This method can be flexibly adapted to equipment such as multi-hole shakers and various models of vortex mixers. The number of samples processed can be flexibly adjusted according to the specifications of the shaker equipment, with no theoretical upper limit. This feature can significantly improve sample processing throughput and detection efficiency, and is suitable for large-scale clinical applications and pharmacokinetic studies.

[0044] (5) High efficiency and selective extraction: Due to its designability, DES can accurately match the enrichment requirements of drugs with different polarities such as TKIs, NSAIDs, and TCAs, and its extraction efficiency is significantly better than that of conventional organic solvents. Combined with conventional chemical detection, even in complex serum matrices, this method has high sensitivity (LOQ range of 0.02-1.0 ng / mL) and good selectivity. Attached Figure Description

[0045] Figure 1 This is a schematic diagram of the structure of the DES-impregnated fiber balls in Embodiment 1 of the present invention and a schematic diagram of their individual packaging. Figure 2 The extraction recovery rate of the six DES-impregnated fiber balls in Example 1 of this invention is used to test the extraction recovery rate. Figure 3The MRM chromatograms of the aqueous solution of water after vortex-assisted DES-impregnated fiber ball liquid phase microextraction in Example 1 of the present invention, the standard solution containing 9 TKIs, and the aqueous solution of the standard solution after vortex-assisted DES-impregnated fiber ball liquid phase microextraction are shown. Figure 4 To test the effectiveness of different DES-impregnated fiber pellets in extracting different TKIs from serum in Example 2 of this invention; Figure 5 To test the effectiveness of different DES-impregnated fiber pellets in extracting different TKIs from serum in Example 3 of this invention; Figure 6 To test the effectiveness of different DES-impregnated fiber pellets in extracting different TKIs from serum in Example 4 of this invention; Figure 7 To test the extraction effect of DES-impregnated fiber balls on TKIs in serum treated by different methods in Example 6 of this invention; Figure 8 To test the extraction effect of DES-impregnated fiber balls on TKIs in serum treated by different methods in Example 7 of this invention; Figure 9 To test the extraction effect of DES-impregnated fiber balls on TKIs after extraction for different times in Example 8 of this invention; Figure 10 This invention is used to test the recovery rate of TKIs after desorption at different times in Example 9. Figure 11 This invention provides the recovery rate of TKIs after desorption by different desorption solvents in Example 10. Figure 12 This is to demonstrate the recovery rate of TKIs after desorption by different volumes of desorption solvent in Example 11 of this invention. Figure 13 To test the effectiveness of DES-impregnated fiber balls in extracting NSAIDs from aqueous media in Example 14 of this invention; Figure 14 To test the effectiveness of DES-impregnated fiber balls in extracting TCAs from aqueous media in Example 14 of this invention; Figure 15 The chromatograms of water, NSAIDs standard solution, and aqueous solution of the standard solution after vortex-assisted DES-impregnated fiber ball liquid microextraction in Example 14 of the present invention are shown. Figure 16 The chromatograms are of water, TCA standard solution, and aqueous solution of the standard solution after vortex-assisted DES-impregnated fiber ball liquid phase microextraction in Example 14 of the present invention. Detailed Implementation

[0046] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to specific embodiments. It should be understood that the specific embodiments described herein are for illustrative purposes only and are not intended to limit the invention. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without inventive effort fall within the protection scope of this invention.

[0047] The detection of nonpolar and weakly polar drug molecules in bodily fluids (such as serum and urine) is often limited by low concentrations and complex matrices, requiring reliable pretreatment. Current mainstream biosample pretreatment techniques include liquid-liquid extraction, solid-phase extraction, and dispersion-liquid-microextraction, which have been developed for extracting analytes from complex biological fluids. However, they still have significant drawbacks, such as the use of highly toxic organic solvents, relatively complex and time-consuming procedures, and low throughput. These limitations make them unsuitable for the high-throughput, rapid reporting needs of clinical laboratories, thus restricting their applicability in routine clinical applications.

[0048] To address the above problems, embodiments of the present invention provide a DES-impregnated fiber agglomerate, which is composed of PPF fiber agglomerate and DES impregnated in the PPF fiber agglomerate.

[0049] The present invention also provides a method for preparing the above-mentioned DES-impregnated fiber aggregates and their application in detecting non-polar or weakly polar drugs in body fluids.

[0050] This invention also provides a method for detecting nonpolar or weakly polar drugs in blood for non-diagnostic purposes.

[0051] The present invention will be described below through specific embodiments.

[0052] Materials and reagents used in the following examples: Chromatographic grade acetonitrile and methanol were purchased from Thermo Fisher Scientific (Fair Lawn, NJ, USA), and LC / MS grade formic acid was supplied by Sigma-Aldrich (St. Louis, MO, USA). Analytical grade dimethyl sulfoxide was purchased from Adamas-beta® (Shanghai, China), and analytical grade ethanol, isopropanol and acetone, sodium hydroxide, hydrochloric acid, phosphoric acid, disodium hydrogen phosphate, and sodium dihydrogen phosphate were purchased from Sinopharm Chemical Reagent Co., Ltd. (Shanghai, China). Ultrapure water was used from the Milli-Q A10 purification system (Merck Millipore, Burlington, MA, USA). Thymol and DL-menthol used for the synthesis of natural DES were purchased from Shanghai Jizhi Biochemical Technology Co., Ltd. and Shanghai Titan Technology Co., Ltd., respectively.

[0053] Crizotinib (CRI) and gefitinib (GEF) were sourced from Shanghai Yien Chemical Technology Co., Ltd., and afatinib (AFA) from Beijing LuoYa Technology Co., Ltd. Other analytes, including erlotinib (ERL), pazopanib (PAZ), nilotinib (NIL), and sunitinib (SUN), were provided by Aladdin Biotechnology Co., Ltd. (Shanghai, China). Alectinib (ALE) and lenvatinib (LEN) were procured through Shanghai Jizhi Biotechnology Co., Ltd. The corresponding deuterated internal standards (LEN-d4 and ALE-d6) were provided by Shanghai Zhenzhun Biotechnology Co., Ltd. (Shanghai, China).

[0054] The oil-absorbing cotton was purchased from Nantong Zhongshui Environmental Protection Equipment Co., Ltd., and its product name is Industrial Oil Absorbent Sheet, with specifications of 400×500×3 mm; the degreased cotton balls were purchased from Shandong Renwei Medical Equipment Co., Ltd.

[0055] Unless otherwise specified, the experimental methods used in the following examples are conventional methods or methods described in the instrument / product manual. Other materials and reagents used in the following examples are commercially available unless otherwise specified.

[0056] Example 1 This embodiment provides a DES-impregnated fiber ball. The specific steps of its preparation method are as follows: S1, DES preparation: Weigh menthol and thymol (molar ratio 1:1) into a round-bottom flask, place them in a 70°C water bath and heat and stir until a clear liquid is formed, which is DES. S2. Fiber pretreatment: Remove the surface layer of the oil-absorbing cotton and dry it at 30℃ for 2 hours to obtain polypropylene fiber (PPF) for later use. S3, DES loading: Weigh 5 mg of pretreated polypropylene fiber, roll it into a ball (5 ± 0.2 mm in diameter), and slowly add 20 μL of DES to ensure that the DES fully wets the pores of the fiber ball to obtain DES-impregnated fiber ball. S4. Individual Packaging: Pack DES-impregnated fiber balls into disposable PVC plastic blister packs (external dimensions: 80×35×9mm), seal with pure silver aluminum foil, and store in a cool, dark place.

[0057] Example 2 This embodiment provides a DES-impregnated fiber ball. Its preparation method is basically the same as that in Example 1, except that thymol in S1 is replaced with n-butanol, that is, DES is made from menthol and n-butanol in a molar ratio of 1:1.

[0058] Example 3 This embodiment provides a DES-impregnated fiber ball. Its preparation method is basically the same as that in Example 1, except that thymol in S1 is replaced with camphor, that is, DES is made from menthol and camphor in a molar ratio of 1:1.

[0059] Example 4 This embodiment provides a DES-impregnated fiber ball. Its preparation method is basically the same as that in Example 1, except that menthol in S1 is replaced with camphor, that is, DES is made from camphor and thymol in a molar ratio of 1:1.

[0060] Example 5 This embodiment provides a DES-impregnated fiber ball. Its preparation method is basically the same as that in Example 1, except that thymol in S1 is replaced with oleic acid, that is, DES is made from menthol and oleic acid in a molar ratio of 1:1.

[0061] Example 6 This embodiment provides a DES-impregnated fiber ball. Its preparation method is basically the same as that in Example 1, except that menthol in S1 is replaced with decanoic acid, that is, DES is made from thymol and decanoic acid in a molar ratio of 1:1.

[0062] Examples 7-9 Examples 7-9 each provide a DES-impregnated fiber ball. The specific steps of its preparation method are basically the same as those in Example 1, except that the molar ratio of menthol and thymol in S1 is 3:1, 2:1, and 1:2, respectively.

[0063] Examples 10-12 Examples 10-12 each provide a DES-impregnated fiber ball. The specific steps of their preparation methods are basically the same as those in Example 1, the only difference being that the mass of polypropylene fiber in S3 is 3 mg, 8 mg, and 10 mg, respectively.

[0064] Examples 13-15 Examples 13-15 each provide a DES-impregnated fiber ball. The specific steps of their preparation methods are basically the same as those in Example 1, the only difference being that the volume of DES in S3 is 15 μL, 25 μL, and 30 μL, respectively.

[0065] Example 16 This embodiment provides a DES-impregnated fiber ball. The specific steps of its preparation method are basically the same as those in Embodiment 1, except that the oil-absorbing cotton in S2 is replaced with PP filter cotton.

[0066] Example 17 This embodiment provides a DES-impregnated fiber ball. The specific steps of its preparation method are basically the same as those in Embodiment 1, except that the oil-absorbing cotton in S2 is replaced with a sprayed fleece cloth.

[0067] Example 18 This embodiment provides a DES-impregnated fiber ball. Its preparation method is as follows: S1, DES preparation: Methyltrioctylammonium bromide and decanoic acid (molar ratio of 1:3) were weighed and placed in a round-bottom flask, heated and stirred in a 60°C water bath for 5 minutes to form a yellow transparent liquid, which is DES. S2. Fiber ball pretreatment: Same as in Example 1; S3, DES load: Same as in Example 1; S4. Individual packaging: Same as Example 1.

[0068] Comparative Example 1 This comparative example provides a DES-impregnated fiber ball. Its preparation method is basically the same as in Example 1, except that the molar ratio of menthol to thymol in S1 is 1:3. During the preparation process, insoluble particles of DES appeared, making further preparation impossible.

[0069] Comparative Example 2 This comparative example provides a DES-impregnated fiber ball. Its preparation method is basically the same as in Example 1, except that the mass of polypropylene fiber in S3 is 15 mg.

[0070] Comparative Examples 3 and 4 Comparative Examples 3 and 4 each provided a DES-impregnated fiber ball. Their preparation methods were basically the same as in Example 1, the only difference being that the volume of DES in S3 was 5 μL and 10 μL, respectively.

[0071] Comparative Example 5 This comparative example provides a DES-impregnated fiber ball. The specific steps of its preparation method are as follows: S1, DES preparation: Same as in Example 1; S2. Fiber pretreatment: Take degreased cotton balls and dry them at 30℃ for 2 hours to obtain degreased cotton ball fibers; S3, DES loading: Weigh 5 mg of pretreated degreased cotton ball fibers, roll them into balls (5 ± 0.2 mm in diameter), and slowly add 20 μL of DES to ensure that the DES fully saturates the degreased cotton ball.

[0072] Comparative Example 6 This comparative example provides a DES-impregnated fiber ball. The specific steps of its preparation method are as follows: S1, DES preparation: Same as in Example 1; S2. Fiber pretreatment: Dry kapok at 30℃ for 2 hours to obtain kapok fibers; S3, DES loading: Weigh 5 mg of pretreated kapok fiber, roll it into a ball, and slowly add 20 μL of DES to ensure that the DES fully wets the pores of the fiber ball, thus obtaining DES-impregnated fiber ball.

[0073] Example 19 This embodiment provides a method for detecting tyrosine kinase inhibitors (TKIs) in blood for non-diagnostic purposes.

[0074] 1. Serum dilution Dilute the serum to be tested 10 times with pure water to prepare the sample solution.

[0075] 2. Vortex-assisted DES-impregnated fiber sphere liquid-phase microextraction (1) Take one DES-impregnated fiber ball prepared in any of Examples 1 to 17 into 1 mL of sample solution and vortex at 700 rpm for 20 min; (2) After the vortexing is completed, transfer the DES-impregnated fiber balls to 500 μL H2O and vortex wash at 700 rpm for 5 min to remove adsorbed water-soluble compounds such as proteins. (3) Place the cleaned DES-impregnated fiber balls into 150 μL of desorption solvent (ethanol) and vortex at 700 rpm for 2 min to transfer the TKIs back into the solution for subsequent LC-MS / MS determination.

[0076] 3. LC-MS / MS determination method TKIs were quantified using a Waters ACQUITY UPLC and Xevo TQ-S triple quadrupole mass spectrometry platform (Waters Corp., USA). The chromatographic column was a BEH C18 (2.1 × 50 mm, 1.7 μm), and the mobile phase was (A) 0.1% formic acid in water and (B) acetonitrile at a flow rate of 0.3 mL / min. Gradient elution was performed for 6 min: 0–4 min, 15%–95% B; 4.0–4.5 min, 95% B; 4.5–4.7 min, 95%–15% B; 4.7–6 min, 15% B. The column temperature was set to 40 °C, and the injection volume was 3 μL. MS detection was performed in multiple reaction monitoring (MRM) mode with a +3.5 kV capillary voltage, a desolventizing temperature of 500 °C, and a nitrogen flow rate of 1000 L / h. Other mass spectrometry parameters for the nine specific TKIs and the internal standard are detailed in Table 1. Instrument control and data processing were performed using MassLynx 4.2 software (Waters Corporation, Milford, MA, USA).

[0077] Table 1. Mass spectrometry parameters for 9 specific TKIs and internal standards.

[0078] Examples 20-23 Examples 20-23 provide a method for detecting TKIs in blood for non-diagnostic purposes. The steps are basically the same as those in Example 19, except that the serum to be tested is diluted 10 times with disodium hydrogen phosphate-sodium dihydrogen phosphate buffer solutions with pH values ​​of 5, 6, 8, and 9 (the pH is adjusted to a predetermined value with HCl and NaOH) to prepare sample solutions.

[0079] Examples 24-27 Examples 24-27 provide a method for detecting TKIs in blood for non-diagnostic purposes. The steps are basically the same as those in Example 19, except that the serum to be tested is diluted 10 times with saline containing 5%, 10%, 15%, and 20% wt sodium chloride, respectively, to prepare the sample solution.

[0080] Examples 28-33 Examples 28-33 provide a method for detecting TKIs in blood for non-diagnostic purposes. The steps are basically the same as those in Example 19, except that the vortexing time after placing the DES-impregnated fiber balls into the sample solution is 10, 15, 25, 30, 35, and 40 min, respectively.

[0081] Examples 34-38 Examples 34-38 provide a method for detecting TKIs in blood for non-diagnostic purposes. The steps are basically the same as those in Example 19, except that the time for vortexing the cleaned DES-impregnated fiber balls in ethanol is 5, 8, 10, 15, and 20 minutes, respectively.

[0082] Examples 39-42 Examples 39-42 provide a method for detecting TKIs in blood for non-diagnostic purposes. The steps are basically the same as those in Example 19, except that the desorption solvent is acetone, acetonitrile, isopropanol or methanol, respectively.

[0083] Examples 43-47 Examples 43-47 provide a method for detecting TKIs in blood for non-diagnostic purposes. The steps are basically the same as those in Example 19, except that the amount of desorption solvent used is 50, 100, 200, 250, and 300 μL, respectively.

[0084] Example 48 This embodiment provides a method for detecting nonsteroidal anti-inflammatory drugs (NSAIDs) and tricyclic antidepressants (TCAs) in blood for non-diagnostic purposes.

[0085] 1. Serum dilution Dilute the serum to be tested 10 times with pure water to prepare the sample solution.

[0086] 2. Vortex-assisted DES-impregnated fiber sphere liquid-phase microextraction (1) Take one DES-impregnated fiber ball prepared in Example 18 into 1 mL of sample solution and vortex at 800 rpm for 25 min; (2) After the vortexing is completed, transfer the DES-impregnated fiber balls to 500 μL H2O and vortex wash at 800 rpm for 5 min to remove adsorbed water-soluble compounds such as proteins. (3) Place the cleaned DES-impregnated fiber balls into 500 μL of desorption solvent (acetonitrile) and vortex at 800 rpm for 2 min. Then centrifuge the desorption solution for 5 min and take 200 μL of the supernatant after centrifugation for subsequent LC-UV detection.

[0087] 3. LC-UV Measurement Method (1) Nonsteroidal anti-inflammatory drugs Chromatographic column: C18 column (4.6 mm × 250 mm, 5 μm); Mobile phase: 45% mobile phase A (0.1% formic acid water): 55% mobile phase B (acetonitrile), elution time 20 min; Column temperature: 30℃; Flow rate: 1.0 mL / min; Ultraviolet detection wavelength: 230 nm; Injection volume: 10 μL.

[0088] (2) Antidepressants Chromatographic column: C18 column (4.6 mm × 250 mm, 5 μm); Mobile phase: 60% mobile phase A (phosphate buffer (25 mM, pH 2.85)): 40% mobile phase B (acetonitrile), elution time 12 min; Column temperature: 35℃; Flow rate: 1.0 mL / min; Ultraviolet detection: wavelength 230 nm; Injection volume: 10 μL.

[0089] Comparative Examples 7 and 8 Comparative Examples 7 and 8 respectively provide methods for detecting TKIs in blood for non-diagnostic purposes. The steps are basically the same as those in Example 19, except that the serum to be tested is treated with pH 3 and 4, respectively.

[0090] Comparative Example 9 This comparative example provides a method for detecting TKIs in blood for non-diagnostic purposes. The steps are basically the same as in Example 19, except that the vortexing time after placing the DES-impregnated fiber balls into the sample solution is 5 min.

[0091] Test Example 1 This test case investigated the effect of DES-impregnated fiber pellets from Examples 1 to 6 on the extraction of different TKIs from serum using the method of Example 19.

[0092] 1. Material Preparation 1.1 A standard working solution of 1.0 mg / mL TKIs and internal standard was prepared by dissolving in dimethyl sulfoxide and stored at -20 °C. A mixed standard solution was prepared by stepwise dilution of individual stock solutions, followed by continuous dilution with methanol and water to achieve the target concentration, used to obtain a standard curve.

[0093] 1.2 Serum Sample Collection Following ethical approval by the Institutional Review Committee (No.: LKW-2025-0009), waste serum samples (blank serum) from five verified healthy blood donors and patients receiving the medication were obtained from Tianjin Cancer Hospital Airport Hospital (Tianjin, China). None of the blood donors or patients had taken crizotinib (CRI), gefitinib (GEF), afatinib (AFA), erlotinib (ERL), pazopanib (PAZ), nilotinib (NIL), sunitinib (SUN), alectinib (ALE), or lenvatinib (LEN). All biomatrixes were stored at -80°C and thawed at room temperature prior to experimental treatment. Working solutions were prepared by adding 10 µL of different concentrations of TKI solutions to 100 µL of blank serum to achieve the target concentrations.

[0094] The TKIs in the above standard solution and working solution were detected according to the method of Example 19.

[0095] 2. Experimental Results 2.1 Extraction and recovery rates of different TKIs by different DES-impregnated fiber balls Extraction recovery rates of six types of DES-impregnated fiber balls, such as Figure 2 As shown in Table 2, DES1-DES6 correspond to the DES-impregnated fiber balls of Examples 1 to 6, respectively.

[0096] The experimental results show that the DES-impregnated fiber balls of each embodiment have high recovery rates for a variety of TKIs. Among them, the DES-impregnated fiber balls made from DES of menthol:thymol (Example 1), camphor:thymol (Example 4), and thymol:decanoic acid (Example 6) exhibit higher extraction recovery rates for most TKIs than the other three embodiments. The DES-impregnated fiber balls of Example 1 have even higher extraction recovery rates for most TKIs.

[0097] Table 2 Recovery rates of different TKIs from different DES-impregnated fiber balls

[0098] 2.2 Interference Investigation like Figure 3 As shown, curve a is the MRM chromatogram of the aqueous solution after vortex-assisted DES-impregnated fiber microextraction, curve b is the MRM chromatogram of the standard solution containing 9 TKIs (20 ng / mL each), and curve c is the MRM chromatogram of the aqueous solution of the standard solution after vortex-assisted DES-impregnated fiber microextraction. As can be seen from curves a and c, no interference from DES or polypropylene fibers was detected in any of the 9 TKIs, confirming the accuracy and reliability of the results.

[0099] As can be seen from curves b and c, the signal intensity of all analytes was significantly enhanced after vortex-assisted DES-impregnated fiber ball liquid phase microextraction.

[0100] Test Example 2 Using the serum sample from Example 1, the effectiveness of DES-impregnated fiber pellet extraction of TKIs from serum in Examples 1, 7-9 was examined according to the method of Example 19.

[0101] The results are as follows Figure 4 As shown, good recovery rates were achieved for most TKIs using DES-impregnated fiber spheres. The highest TKI recovery rate was observed when the molar ratio of menthol to thymol was 2:1. This is likely because the polarity of DES matched the nonpolar TKIs best at this molar ratio, and the hydrogen bond network structure was stable, allowing for efficient encapsulation and enrichment of the target drug. When the ratio deviated from 2:1 (e.g., 3:1 or 1:2), the polarity of DES became too strong or too weak, leading to decreased solubility of TKIs and reduced recovery rate.

[0102] Test Example 3 Using the serum sample from Test Example 1, the effectiveness of DES-impregnated fiber pellet extraction of TKIs from serum in Examples 1, 10-12 and Comparative Example 2 was investigated according to the method of Example 19.

[0103] The results are as follows Figure 5As shown, when the PPF dosage increased from 3 mg to 5 mg, the recoveries of most TKIs increased; however, when the PPF dosage exceeded 10 mg, the recoveries of all TKIs decreased significantly. This is presumably because excessive PPF aggregation led to uneven DES distribution, and excessive PPF may have adsorbed impurities in the sample, competing for TKI binding sites, or desorbed incompletely. Considering both recovery rate and cost-effectiveness, 5 mg is the optimal PPF dosage.

[0104] Test Example 4 Using the serum sample from Test Example 1, the effectiveness of DES-impregnated fiber pellets in extracting TKIs from serum was examined according to the method of Example 19, in accordance with Examples 1, 13-15, and Comparative Examples 3 and 4.

[0105] The results are as follows Figure 6 As shown, when the DES volume is 5 μL or 10 μL, the recovery rates of TKIs are mostly low. As the DES volume increases, the recovery rates of most TKIs gradually increase. This may be because the DES more fully wets the pores of 5 mg PPF, improving the extraction capacity of the "supported DES unit". When the DES volume exceeds 20 μL, the recovery rate does not increase significantly. This may be because 20 μL of DES has reached saturation extraction, and excess DES is easily lost with the aqueous solution vortex, resulting in a decrease in recovery rate and increased difficulty in subsequent desorption.

[0106] Test Example 5 Using the serum sample from Example 1, the effectiveness of DES-impregnated fiber pellets in extracting TKIs from serum was investigated according to the method of Example 19, as described in Example 19. Specifically, when using DES-impregnated fiber pellets in Comparative Example 6, the desorbed solution was centrifuged (14000 rpm, 3 minutes) before LC-MS / MS analysis, and the supernatant was used for LC-MS / MS analysis.

[0107] The results are shown in Table 3. Polypropylene fibers exhibited the best overall extraction performance, with fiber balls using oil-absorbing cotton as a carrier showing the highest recovery rates for most TKIs and good stability. Although PP filter cotton and sprayed cotton cloth are both polypropylene materials, their extraction efficiencies fluctuated due to differences in fiber structure, porosity, and surface properties, which may be related to the influence of fiber morphology on the uniformity of DES loading and drug mass transfer efficiency. In contrast, the extraction recovery rates of cotton fibers (degreased cotton balls) and kapok fibers were generally low (most below 30%), which may be consistent with their inherent characteristics of strong hydrophilicity and weak affinity for lipophilic drugs, further confirming the key role of hydrophobic and lipophilic carriers in the enrichment of nonpolar drugs.

[0108] Table 3. Effects of DES-impregnated fiber pellets made from different fibers on the extraction of TKIs from serum.

[0109] Test Example 6 The serum sample from Test Example 1 and the DES-impregnated fiber balls from Example 1 were used to detect TKIs according to the methods of Examples 19-23 and Comparative Examples 7 and 8, respectively, to investigate the extraction effect of DES-impregnated fiber balls on TKIs after serum was treated by different methods.

[0110] The results are as follows Figure 7 As shown, when the pH of the diluent is in the range of 5 to 9, the recovery rate of most TKIs is higher than that when the pH of the diluent is 3 to 4; when the pH of the diluent is in the range of 6 to 7, the recovery rate of most TKIs is even higher. This may be because at this pH, TKIs mainly exist in a neutral molecular form and are more easily enriched by nonpolar DES. When pH < 5 or pH > 7, TKIs undergo protonation or deprotonation, their polarity increases, their affinity for DES decreases, and the recovery rate decreases.

[0111] Test Example 7 The serum sample from Test Example 1 and the DES-impregnated fiber balls from Example 1 were used to detect TKIs according to the methods of Examples 19 and 24-27, respectively, to investigate the extraction effect of DES-impregnated fiber balls on TKIs after serum was treated by different methods.

[0112] The results are as follows Figure 8 As shown, the extraction efficiency of TKIs by DES-impregnated fiber balls is affected to some extent by the salting-out effect, but a relatively high recovery rate can still be maintained. The TKIs recovery rate is the highest when no additional salt is added; as the salt concentration increases, the recovery rate shows a continuous downward trend. This may be because the high-salt environment increases the sample viscosity, reduces the mass transfer efficiency of TKIs to the DES phase, and NaCl may compete with TKIs for DES adsorption sites.

[0113] Test Example 8 The serum sample from Test Example 1 and the DES-impregnated fiber balls from Example 1 were used to detect TKIs according to the methods of Examples 19, 28-33 and Comparative Example 9, respectively, to investigate the extraction effect of DES-impregnated fiber balls on TKIs after extraction for different times.

[0114] The results are as follows Figure 9 As shown, the recovery rate of TKIs increased with time and reached a stable level at about 20 min, indicating that the TKIs had reached a distribution equilibrium between the DES and aqueous phases, and that extending the extraction time did not significantly improve the recovery rate.

[0115] Test Example 9 Using the serum sample from Test Example 1 and the DES-impregnated fiber balls from Example 1, TKIs were detected according to the methods of Examples 19 and 34-38, respectively, to investigate the recovery rate of TKIs after desorption at different times.

[0116] The results are as follows Figure 10 As shown, the recovery rate of TKIs reached its optimal level when the desorption time was 2 min, indicating that the desorption kinetics of ethanol on TKIs is relatively fast and efficient elution can be completed in 2 min; extending the desorption time to 20 min did not significantly improve the recovery rate.

[0117] Test Example 10 The serum sample from Test Example 1 and the DES-impregnated fiber balls from Example 1 were used to detect TKIs according to the methods of Examples 19 and 39-42, respectively, to investigate the recovery rate of TKIs after desorption by different desorption solvents.

[0118] The results are as follows Figure 11 As shown, ethanol exhibits high extraction recoveries for all TKIs. This superior performance can be attributed to the moderate compatibility of ethanol with DES, which effectively disrupts the interaction between DES and TKIs while also providing good solubility for TKIs, thus enabling efficient elution.

[0119] Test Example 11 The serum sample from Test Example 1 and the DES-impregnated fiber balls from Example 1 were used to detect TKIs according to the methods of Examples 19 and 43-47, respectively, to investigate the recovery rate of TKIs after desorption by different volumes of desorption solvent.

[0120] The results are as follows Figure 12 As shown, when the desorption solvent volume is 150 μL, the extraction recovery rate of most compounds reaches its peak and no longer increases with increasing volume.

[0121] Test Example 12 To address the issue of DES potentially being lost due to adhesion to the inner wall of the packaging during storage and transportation, this test case evaluated the reliability of the DES-impregnated fiber balls (with a molar ratio of menthol to thymol of 2:1) prepared in Example 8 as a "ready-to-use" microextraction consumable during actual storage, transportation, and long-term use. The test focused on two key indicators: "DES loss during storage and transportation" and "extraction performance after long-term storage".

[0122] (1) Using a single-groove tablet plate consistent with actual applications as the packaging carrier, DES-impregnated fiber balls were individually packaged and sealed to simulate the packaging form of industrial consumables; then the packaged sample was placed on an oscillator and vibrated for 2 hours to simulate the vibration and bumpy environment in logistics transportation.

[0123] Experimental results show that the DES load loss rate is less than 2% after 2 hours of oscillation, indicating that this packaging method can effectively avoid DES loss during storage and transportation and ensure the consistency of DES load in each unit.

[0124] (2) The DES loading loss rate and target drug (TKI) extraction efficiency of individually packaged DES-impregnated fiber balls under different storage times (0, 1, 2, and 3 months) were tested according to the method in Example 19. The results showed that after 3 months of sealed storage at room temperature and 4°C, the DES loading loss rate was less than 2%, and the extraction recovery rate of TKIs was less than 15% different from that of freshly prepared consumables, as shown in Table 4. This result confirms that the DES-impregnated fiber balls have good long-term storage stability and can meet the standardized testing requirements of "prepared in advance and used as needed".

[0125] Table 4. Changes in TKI extraction recovery rate after different storage times of DES-impregnated fiber balls

[0126] The results above show that DES-impregnated fiber balls exhibit extremely low DES adhesion loss during storage and transportation when sealed in tablet blister packs. Furthermore, their extraction performance did not show a significant decline within 3 months of sealed storage at room temperature and in a cool, dark place, fully meeting the storage and usage requirements for "ready-to-use" microextraction consumables.

[0127] Test Example 13 To assess matrix-related interference, this test example used DES-impregnated fiber balls prepared in Example 8 to compare serum samples and aqueous solutions (all at a concentration of 100 ng / mL) containing different TKIs, following the method described in Example 19. The response values ​​of the target drug in serum matrix and water were compared, and an isotope-labeled internal standard (IS) was used to correct for matrix effects. The results are shown in Table 5, with the matrix effect after internal standard normalization ranging from 92.11% to 110.61%.

[0128] Table 5. Matrix effect after internal standard normalization

[0129] This test case also evaluated the quantitative performance of the method in terms of linearity, sensitivity, and precision.

[0130] Calibration curves were generated by plotting the ratio of the peak area of ​​TKIs to that of the internal standard to the ratio of the concentration of the known analyte in the biological matrix. The results are shown in Table 6, with correlation coefficients (R²)... 2 The linear relationship was good between 0.990 and 0.999. The limit of quantitation (LOQ) was defined as 0.02–1.0 ng / mL with a signal-to-noise ratio of 10.

[0131] Precision was assessed through intra-day and inter-day repeatability and accuracy. Intra-day RSD was calculated by extracting low, medium, and high levels of blank serum five times within a single day. Inter-day precision was determined by analyzing independently prepared spiked samples over three consecutive days. As shown in Table 7, the recoveries ranged from 86.78% to 110.30%, and all RSDs were less than 14.10%, meeting the requirements of the "Guideline for Validation of Quantitative Analysis Methods for Biological Samples," demonstrating the stability and accuracy of the method.

[0132] Table 6 Linear Results

[0133] Table 7. Intra-day and inter-day precision results

[0134] Test Example 14 This test case investigated the effects of the DES-impregnated fiber ball extract from aqueous medium of Example 18 on steroidal anti-inflammatory drugs (NSAIDs) and tricyclic antidepressants (TCAs) using the method of Example 48.

[0135] To prepare the standard solutions, single standard solutions containing 1 mg / mL sulindac (SLD), loxoprofen (LOX), naproxen (NPX), flurbiprofen (FBP), diclofenac (DCF), and ibuprofen (IBU) were prepared using methanol. A specific volume was accurately pipetted and added to methanol to prepare a mixed standard solution of NSAIDs, which was then diluted with water to a concentration of 2 µg / mL.

[0136] Single standard solutions containing 1 mg / mL venlafaxine (VEN), citalopram (CIT), imipramine (IMP), amitriptyline (AMP), and fluoxetine (FLX) were prepared using methanol. A specific volume was accurately pipetted and added to methanol to prepare a mixed standard solution of TCAs, which was then diluted with water to a TCAs standard solution with a concentration of 5 µg / mL.

[0137] The NSAIDs or TCAs in the above standard solution were detected according to the method of Example 48.

[0138] 2. Experimental Results 2.1 Recovery rates of different NSAIDs or TCAs like Figure 13 As can be seen, the extraction recoveries of most NSAIDs range from 60% to 90%, with relative standard deviations (RSD, n=3) below 15%. Figure 14 It is evident that for NSAIDs, representative drugs such as amitriptyline have also achieved recovery rates of over 50%.

[0139] 2.2 Interference Investigation Figure 15 In the figure, curve c is the chromatogram of water, curve b is the chromatogram of NSAID standard solution, and curve a is the chromatogram of aqueous solution of NSAID standard solution after vortex-assisted DES-impregnated fiber ball liquid phase microextraction. Figure 16 In the figure, curve c is the chromatogram of water, curve b is the chromatogram of TCA standard solution, and curve a is the chromatogram of aqueous solution of TCA standard solution after vortex-assisted DES-impregnated fiber ball liquid phase microextraction.

[0140] like Figure 15 and Figure 16 As can be seen, after vortex-assisted DES-impregnated fiber microextraction, the standard solutions of NSAIDs and TCAs exhibited characteristic chromatographic peaks with retention times consistent with those of the standard solutions (b) in (a), and the peak area of ​​the target compounds was significantly increased after DES-impregnated fiber microextraction, while no obvious interfering peaks were observed in water (c). These results demonstrate that this method can effectively enrich target drugs from aqueous media, and that the DES-impregnated fiber microextraction and the operational process did not introduce significant background interference.

[0141] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A DES-impregnated fiber agglomerate, characterized in that, It consists of PPF fiber aggregates and DES impregnated in the PPF fiber aggregates.

2. The DES-impregnated fiber aggregate according to claim 1, characterized in that, The DES is made from menthol and thymol, menthol and n-butanol, menthol and camphor, camphor and thymol, menthol and oleic acid, or thymol and decanoic acid in a molar ratio of (1~3):(1~2); or The DES is made from methyltrioctylammonium bromide and decanoic acid in a molar ratio of 1:

3.

3. The DES-impregnated fiber aggregate according to claim 2, characterized in that, The PPF fiber aggregate has a mass of 3-10 mg, and the DES has a volume of 15-30 µL; and / or The PPF fiber aggregates are spherical.

4. The method for preparing DES-impregnated fiber aggregates according to any one of claims 1 to 3, characterized in that, The process includes the following steps: forming PPF fiber aggregates from PPF fibers, slowly adding DES dropwise to allow the DES to fully impregnate the voids in the PPF fiber aggregates, thus obtaining the final product.

5. The preparation method according to claim 4, characterized in that, The preparation method further includes individually packaging the DES-impregnated fiber aggregates.

6. The use of the DES-impregnated fiber aggregate according to any one of claims 1 to 3 in the detection of nonpolar or weakly polar drugs in body fluids.

7. The application according to claim 6, characterized in that, The bodily fluid is blood; and / or The nonpolar or weakly polar drugs include tyrosine kinase inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), and tricyclic antidepressants; and / or The PPF fiber aggregates are spherical.

8. The application according to claim 6 or 7, characterized in that, The DES in the DES-impregnated fiber aggregate is prepared from menthol and thymol, menthol and n-butanol, menthol and camphor, camphor and thymol, menthol and oleic acid, or thymol and decanoic acid in a molar ratio of (1~3):(1~2), and the application is for detecting tyrosine kinase inhibitors in blood; or, the DES in the DES-impregnated fiber aggregate is prepared from methyltrioctylammonium bromide and decanoic acid in a molar ratio of 1:3, and the application is for detecting nonsteroidal anti-inflammatory drugs and / or antidepressants in blood; or The tyrosine kinase inhibitors include crizotinib, gefitinib, afatinib, erlotinib, pazopanib, nilotinib, sunitinib, alectinib, and lenvatinib; or The nonsteroidal anti-inflammatory drugs include sulindac, loxoprofen, naproxen, flurbiprofen, diclofenac, and ibuprofen; or The tricyclic antidepressants include venlafaxine, citalopram, imipramine, amitriptyline, and fluoxetine.

9. A method for detecting nonpolar or weakly polar drugs in blood for non-diagnostic purposes, characterized in that, Specifically, the following steps are included: diluting the blood sample to be tested with a diluent containing 0-20% wt sodium chloride at a pH of 5-9, and adjusting it to prepare the sample solution; Place one DES-impregnated fiber agglomerate according to any one of claims 1 to 3 into 0.2 to 2 mL of the sample solution, vortex at 700 to 800 rpm for at least 10 min, then wash the DES-impregnated fiber agglomerate with water, and then vortex it in at least 50 μL of desorption solvent for at least 2 min to obtain the test solution. The nonpolar or weakly polar drug is determined in the test solution.

10. The method according to claim 9, characterized in that, The diluent is pure water; and / or The first vortex lasts for 20-25 minutes; and / or The second vortex lasts for 2 to 3 minutes; and / or The desorption solvent is acetone, acetonitrile, ethanol, isopropanol, or methanol.

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