Cordycepin-oxalate, and preparation method therefor and application thereof

Abstract

Cordycepin oxalate of formula (I) (C10H13N5O3.H2C2O4) is provided. A method of preparing cordycepin oxalate is also provided comprising the steps: (i) physical mixing: mixing oxalic acid and cordycepi

Description

The present invention belongs to the technical field of drug crystals, and relates to a cordycepin-oxalate, and a preparation method therefor and an application thereof. BACKGROUND Eutectic is a multi-component substance formed by interaction and linkage between a host molecule (API) and a guest molecule (and a second component ligand substance) in the form of neutral molecules via a non-covalent bond such as a hydrogen bond or a coordination bond according to a certain stoichiometric ratio. There are mainly three categories of preparation methods for the eutectic: a solution-mediated method, a non-solution-mediated method and other methods. The solution-mediated method comprises not only traditional cooling crystallization, reaction crystallization and evaporation crystallization, but also solution-mediated crystal slurry conversion co-crystallization, high-pressure homogenization (HPH), high-shear granulation (HSG), ultrasonic-assisted co-crystallization, liquid-assisted grinding (LAG), and the like, and has the advantage of quickly and efficiently screening an eutectic ligand. The non-solution-mediated method mainly refers to dry grinding, hot melting, spray cooling (SC), polymer-assisted grinding and other methods without assistance of any solvent, can prevent formation of a solvate, and is environmentally friendly, but it takes a long time. Other methods comprise microwave-assisted co-crystallization, freeze-drying crystallization, electrospray crystallization, lasering and resonant acoustic mixing crystallization. Cordycepin, also known as Cordyceps militaris and Cordyceps sinensis, has a chemical component of 3'-Deoxyadenosine (3'-dA for short), a molecular formula of C10H13N5O3 and a molecular weight of 251.25. The cordycepin belongs to a purine alkaloid, a conjugated structure on a purine ring enables the cordycepin to achieve strong ultraviolet absorption, and a maximum absorption wavelength is 259.0 nm. The cordycepin is soluble in water, hot ethanol and methanol, but insoluble in ether, chloroform and benzene. Ava HO—f ? Cordycepin Drug formation of the cordycepin serving as a hot substance in the medical field is a general trend. On one hand, it is necessary to systematically study a crystal form property and a transformation relationship before drug formation, and in order to avoid a recurrence of an incident of “Ritonavir Form”, basic crystal form data are provided and a stable crystal form is prepared, which are conductive to better exerting pharmacological effects of the cordycepin; and on the other hand, the cordycepin serving as a typical drug with a half-life <1 hour is obviously not suitable for sustained-release through a direct preparation, a structural modification process is complicated, and there are many miscellaneous and uncontrollable byproducts. A study on the sustained-release of the cordycepin through cocrystallization is expected to become a means to assist the sustained-release of the cordycepin, which provides a possibility for sustained-release of a drug or preparation of the cordycepin in a later stage. SUMMARY The technical problem to be solved by the present invention is that, aiming at the problems such as a short half-life of a drug of a cordycepin crystal and difficult control of preparation of a crystal form in the prior art, the present invention provides a preparation method for a stable eutectic salt of cordycepin, and a eutectic salt with a medicinal potential is obtained. In order to solve the above technical problem, the following technical solutions are used in the present invention. The present invention discloses a cordycepin-oxalate, wherein a molecular formula of the cordycepin-oxalate is CioHi3N503*H2C204; and a molecular structural formula of the cordycepin-oxalate is as follows: OH Further, the present invention discloses a preparation method for the cordycepin-oxalate above, which comprises the following steps: (1) physical mixing: fully and evenly mixing an oxalic acid and a cordycepin monohydrate form II crystal; (2) liquid-assisted grinding: adding an auxiliary agent, and continuously grinding to obtain a solid mixture; and (3) drying the solid mixture to obtain the cordycepin-oxalate. In some embodiments, in the step (1), a molar ratio of the oxalic acid to the cordycepin monohydrate form II crystal is 1: 1. In some embodiments, in the step (2), the auxiliary agent is water, ethanol-water solution below 10 vt.% or isopropanol-water solution below 10 vt.%; and / or, a mass of the auxiliary agent is 20%~70% of a total mass of the oxalic acid and the cordycepin monohydrate form II crystal; and / or, the grinding lasts for 1.0-8.0 hours. In some embodiments, preferably, in the step (2), the mass of the auxiliary agent is 20%~50% of the total mass of the oxalic acid and the cordycepin monohydrate form II crystal, further preferably 20%~40%, and more further preferably 25%~35%. In the step (2), an agate mortar is used for the grinding, and there is no specific requirement on a grain size of crystal powder, which may be a normal size of the crystal powder. In some embodiments, in the step (3), the drying is carried out under an atmospheric pressure; and / or, the drying is carried out at 40~60°C; and / or, the drying lasts for 8-12 hours. In some embodiments, in the step (1), the cordycepin monohydrate form II crystal is prepared by the following method, which comprises: mixing crude cordycepin with a solvent to obtain a crude cordycepin solution; and cooling the crude cordycepin solution, stably crystallizing an obtained crystal slurry mother liquor, then carrying out suction fdtration, washing a solid, and drying to obtain the cordycepin monohydrate form II crystal. In some embodiments, the solvent is water, an isopropanol-water solution below 80 vt.% or an ethanol-water solution below 10 vt.%; and / or, the crude cordycepin is mixed with the solvent at 40°C~60°C; and / or, a concentration of the crude cordycepin in the crude cordycepin solution is 30 g / L~70 g / L; and / or, the crude cordycepin solution is cooled, which specifically refers to cooling to 4~10°C at a cooling rate of 3~8°C / h; and / or, the crystal slurry mother liquor is stabilized at 4~10°C for 1-4 hours for crystallization; and / or, the washing specifically refers to washing with an ethanol-water solution below 70 vt.%; and / or, the drying is carried out at a drying temperature of 50°C~60°C; and / or, the drying lasts for 10-12 hours. In some embodiments, preferably, the solvent is the water. In some embodiments, preferably, the concentration of the crude cordycepin in the crude cordycepin solution is 40 g / L~70 g / L, and further preferably 40 g / L~60 g / L. In some embodiments, preferably, the crude cordycepin solution is cooled, which specifically refers to cooling to 4~8°C at a cooling rate of 3~5°C / h. In some embodiments, further preferably, the crude cordycepin solution is cooled, which specifically refers to cooling to 4~6°C at the cooling rate of 3~5°C / h. In some embodiments, more further preferably, the crude cordycepin solution is cooled, which specifically refers to cooling to 4°C at a cooling rate of 5°C / h. In some embodiments, preferably, the crystal slurry mother liquor is stabilized at 4~8°C for 1-4 hours for crystallization. In some embodiments, further preferably, the crystal slurry mother liquor is stabilized at 4~6°C for 1-4 hours for crystallization. In some embodiments, more further preferably, the crystal slurry mother liquor is stabilized at 4°C for 2 hours for crystallization. In a PXRD diffraction pattern of the prepared cordycepin monohydrate form II crystal measured with a Cu Ka-ray, 20 expressed in degrees has characteristic diffraction peaks at 5.6°±0.2°, 7.7°±0.2°, 12.2°±0.2°, 14.1°±0.2°, 19.7°±0.2° and 23.0°±0.2°. Preferably, in the PXRD diffraction pattern of the prepared cordycepin monohydrate form II crystal measured with the Cu Ka-ray, the 20 expressed in degrees has characteristic diffraction peaks at 5.6°, 7.7°, 12.2°, 14.1°, 19.7° and 23.0°. Further, the present invention discloses a sustained-release tablet, which comprises: (i) the cordycepin-oxalate above, and (ii) a pharmaceutically acceptable pharmaceutical excipient. In some embodiments, the pharmaceutically acceptable pharmaceutical excipient comprises a fdling agent and a wetting agent. In some embodiments, the filling agent is any one or a combination of two of microcrystalline cellulose and mannitol; or, the wetting agent is ethanol; or, a mass content of the filling agent in the sustained-release tablet is 50%~70%; or, a mass content of the cordycepin-oxalate in the sustained-release tablet is 30%~50%. In some embodiments, preferably, the filling agent is a composition of the microcrystalline cellulose and the mannitol. In some embodiments, preferably, when the filling agent is the composition of the microcrystalline cellulose and the mannitol, a mass ratio of the microcrystalline cellulose to the mannitol is 1.0: (1.2-2.8), further preferably 1.0: (1.5-2.5), and more further preferably 1.0: 2.0. In some embodiments, preferably, the mass content of the filling agent in the sustained-release tablet is 55%~65%. In some embodiments, preferably, the mass content of the cordycepin-oxalate in the sustained-release tablet is 35%~45%. In some embodiments, the pharmaceutically acceptable pharmaceutical excipient further comprises a lubricating agent. In some embodiments, when the pharmaceutically acceptable pharmaceutical excipient further comprises the lubricating agent, the lubricating agent is magnesium stearate. In some embodiments, when the pharmaceutically acceptable pharmaceutical excipient further comprises the lubricating agent, a mass content of the lubricating agent in the sustained-release tablet is 0.05%~3.00%. There is no special requirement on a dosage of the wetting agent, and a principle of the dosage lies in “agglomerating while holding and dispersing while touching”. Further, the present invention discloses a preparation method for the sustained-release tablet above, which comprises: mixing the cordycepin-oxalate above with the fdling agent, adding the wetting agent to prepare a wet mass, sieving the wet mass to obtain wet granules, and drying and tabletting the wet granules to obtain the sustained-release tablet. In some embodiments, the sieving is carried out with a sieve of 10-40 meshes; or, the drying is carried out at 40~60°C under an atmospheric pressure for 1-4 hours; or, a diameter of the sustained-release tablet is 5-15 mm; or, a tablet weight of the sustained-release tablet is 0.2-0.6 g. In some embodiments, preferably, the sieving is carried out with a sieve of 10-30 meshes, preferably a sieve of 20-30 meshes, and further preferably a sieve of 24 meshes. In some embodiments, preferably, the drying is carried out at 40~60°C under the atmospheric pressure for 1-2 hours. In some embodiments, preferably, the diameter of the sustained-release tablet is 8-12 mm, and preferably 10 mm. In some embodiments, preferably, the tablet weight of the sustained-release tablet is 0.2-0.5 g, and preferably 0.3-0.5 g. Beneficial effects: (1) The cordycepin of the present invention adopts a water system or a small amount of crystal obtained by organic dissolution, thereby avoiding the use of a large amount of organic solvent. (2) The cordycepin eutectic salt prepared in the present invention has a higher storage stability and a slower dissolution rate, which is conductive to a sustained-release action of the drug. (3) According to the method of the present invention, the cordycepin-oxalic acid eutectic salt is prepared for the first time, a dissolution rate of the cordycepin-oxalic acid eutectic salt is obviously lower than that of cordycepin reported in the prior art, and the cordycepin-oxalic acid eutectic salt has an extremely high potential medicinal application value. The cordycepin-oxalic acid eutectic salt has important technical innovation and market application potential due to a sustained-release effect. BRIEF DESCRIPTION OF THE DRAWINGS The present invention is further described in detail hereinafter with reference to the drawings and specific embodiments, and the advantages of the above and / or other aspects of the present invention will be clearer. FIG. 1 shows morphologic images of different cordycepin crystals. FIG. 2 shows PXRD diffraction patterns of different cordycepin crystals. FIG. 3 shows infrared spectrograms of different cordycepin crystals. FIG. 4 shows graphs of humidity stability data of different cordycepin crystals. FIG. 5 shows solubility data of different cordycepin crystals. FIG. 6 shows DSC curve graphs of a cordycepin monohydrate form II crystal, a ligand, a material obtained by physical mixing and a solid mixture obtained by liquid-assisted grinding. FIG. 7 shows powder X-ray diffraction patterns of the cordycepin monohydrate form II crystal, the ligand, the material obtained by physical mixing and the solid mixture obtained by liquid-assisted grinding. FIG. 8 shows infrared spectrograms of the cordycepin monohydrate form II crystal, the ligand, the material obtained by physical mixing and the solid mixture obtained by liquid-assisted grinding. FIG. 9 shows NMR spectra of different cordycepin eutectics and a cordycepin-oxalate, and their raw materials. FIG. 10 shows a representative liquid phase peak profile of standard cordycepin. FIG. 11 shows tabletting conditions of tablets of different cordycepin crystal forms. FIG. 12 shows disintegration images of tablets prepared from the different cordycepin eutectics and the cordycepin-oxalate. DETAILED DESCRIPTION The present invention can be better understood according to the following embodiments. However, those skilled in the art easily understand that the contents described in the embodiments are only used to illustrate the present invention, and shall not and will not limit the present invention described in detail in the claims. The experimental methods described in the following embodiments are all conventional methods unless otherwise specified. The reagents and materials can all be obtained from commercial sources unless otherwise specified. Embodiment 1: Preparation and characterization of cordycepin crystal Crude cordycepin was purchased from Nanjing Shengmingyuan Health Technology Co., Ltd., with a purity >85%. 1. Preparation of cordycepin anhydrate form I crystal About 20 g / L crude cordycepin was dissolved with 90% isopropanol-water solution at 40°C, and then slowly cooled to 5°C at a cooling rate of 3°C~5°C / h. An obtained crystal slurry mother liquor was stabilized at 5°C for 2 hours, and then filtered. A solid was washed with 90% isopropanol-water solution, and dried at 50°C~60°C overnight to obtain the cordycepin anhydrate form I crystal, with a purity above 99%, for later use. JADE 6 software was used to compare characteristic peaks of cordycepin crystal forms, and it was measured by thermogravimetric analysis (TG) that a water content of a cordycepin anhydrate form I crystal sample was 0.11%, which was close to a theoretical water content characteristic of an anhydrous crystal (0%) material. Crystallization data of the cordycepin anhydrate form I crystal were as follows: chemical formula: C10H13N5O3; molar mass: 251.25; crystal system: monoclinic; space group: P21; unit cell parameters a, b and c(A): 4.589 (4), 7.497 (5) and 16.073 (10); unit cell parameters a, P and y (°): 90, 85.06 (10) and 90; unit cell volume V(A3): 550.9(7); Z: 2; and unit cell density (g / cm3): 1.515. 2. Preparation of cordycepin anhydrate form II crystal About 50 g / L crude cordycepin was dissolved with 60% ethanol-water solution at 3 5 °C, and then slowly cooled to 5 °C at a cooling rate of 3°C~5°C / h. An obtained crystal slurry mother liquor was stabilized at 5°C for 2 hours, and then fdtered. A solid was washed with 60% ethanol-water solution, and dried at 50°C~60°C overnight to obtain the cordycepin anhydrate form II crystal, with a purity above 99%, for later use. JADE 6 software was used to compare characteristic peaks of cordycepin crystal forms, and it was measured by thermogravimetric analysis (TG) that a water content of a cordycepin anhydrate form II crystal sample was 0.05%, which was close to a theoretical water content characteristic of an anhydrous crystal (0%) material. Crystallization data of the cordycepin anhydrate form II crystal were as follows: chemical formula: C10H13N5O3; molar mass: 251.25; crystal system: orthorhombic; space group: P21212; unit cell parameters a, b and c(A): 10.231(4), 22.752(7) and 4.817(2); unit cell parameters a, P and y (°): 90, 90 and 90; unit cell volume V(A3): 1121.3(7); Z: 4; and unit cell density (g / cm3): 1.488. 3. Preparation of cordycepin monohydrate form II crystal: Under a condition of pure water, a crude cordycepin solution in which a concentration of crude cordycepin was 60 g / L was prepared at 40°C~60°C, and slowly cooled to 4°C at a cooling rate of 5°C / h. An obtained crystal slurry mother liquor was stabilized at 4°C for 2 hours, and then sucked and filtered. A solid was washed with 70% ethanol-water solution, and dried at 60°C for 12 hours to obtain the cordycepin monohydrate form II crystal, with a purity above 99%, for later use. JADE 6 software was used to compare characteristic peaks of cordycepin crystal forms, and it was measured by thermogravimetric analysis (TG) that a water content of a cordycepin monohydrate form II crystal sample was 6.71%, which was close to atheoretical water content characteristic of a monohydrate crystal (6.68%) material. According to the experimental verification, a pure water solvent could be replaced by an isopropanol-water solution below 80 vt.% or an ethanol-water solution below 10 vt.%, through which the cordycepin monohydrate form II crystal could be successfully obtained. 4. Characterization of cordycepin crystal: (1) TM-3000 observation of morphology of sample: a powder sample with the same particle size was evenly dispersed on a conductive tape of a sample stage, and because the cordycepin had no conductivity, the sample stage was placed in a sputter coater for sputter coating with gold to enhance the conductivity of the sample, and then the sample stage was fixed in an electron microscope main unit and a vacuum environment was ensured. After ending the preparation work, a sample crystal habit could be observed in a computer workstation, and photographed and saved. Morphologies of the cordycepin crystals were shown in FIG. 1, wherein FIG. a showed a morphology of the cordycepin anhydrate form I crystal; FIG. b showed a morphology of the cordycepin anhydrate form II crystal; and FIG. c showed a morphology of the cordycepin monohydrate form II crystal. (2) PXRD verification of crystal form of sample: an agate mortar was used to grind the sample to control a particle size of the sample at 0.1-10 pm. Bruker D8 was used to scan 20 in a range of 5°~45° at a rate of 10° / min under a voltage of 40 KV and a current of 40 mA with a Cu Ka-ray according to a scanning step size of 0.02°. A proper amount of ground sample was laid flat in a sample holder, and the sample holder was fixed in a center of a diffractometer main unit and scanned to obtain a diffraction pattern of the sample. PXRD diffraction patterns of the cordycepin crystals were as shown in FIG. 2. It could be seen from the figure that, the cordycepin anhydrate form I crystal had very obvious high-intensity sharp diffraction peaks at 5.5°, 11.0°, 13.0°, 16.2°, 19.7° and 21.5°. The cordycepin anhydrate form II crystal had very obvious high-intensity sharp diffraction peaks at 7.8°, 9.5°, 11.6°, 14.5°, 15.6° and 23.5°. The characteristic peaks of the two cordycepin anhydrate form crystals were consistent with those reported in the literatures (Radwan M. M., Wilson H. R. The structure of cordycepin [J], Acta Crystallographica Section B, 1980, 36(9): 2185-2187; Karthe P., GauthamN., Kumar A., etal. [beta]-d-3'-Deoxyadenosine (Cordycepin) [J], Acta Crystallographica Section C, 1997, 53(11): 1694-1696; and Mingsheng Wu, Liang Tang. Study on Infrared Spectrum and Powder X-ray Diffraction Pattern of Cordycepin Crystal [J]. World Science and Technology (Modernization of Traditional Chinese Medicine, 2011, 13(03): 579-584.). The cordycepin monohydrate form II crystal had very obvious high-intensity sharp diffraction peaks at 5.6°, 7.7°, 12.2°, 14.1°, 19.7° and 23.0°. (3) Infrared functional group analysis: results were as shown in FIG. 3 (wherein, Anhydrate-I referred to the cordycepin anhydrate form I crystal, Anhydrate-II referred to the cordycepin anhydrate form II crystal, and Monohydrate-II referred to the cordycepin monohydrate form II crystal), the cordycepin monohydrate form II crystal showed a characteristic peak of water of crystallization at about 3420.04 cm'1, which was significant different from those of the two anhydrate forms, showed a stretching vibration vn-h peak of primary amine at about 3300 cm'1, showed a stretching vibration peak of cordycepin-OH at 3140-3122 cm'1, which was lower than a normal vo-h peak because of extremely easy formation of an intramolecular hydrogen bond, resulting a shift to a low frequency, wherein an intensity was increased and a band was broadened at the same time, showed stretching vibration peaks of -CH and -CH2 at about 2920 cm'1, showed a stretching vibration peak of C=N on a heterocyclic ring at 1684-1668 cm'1, showed a deformation vibration 5n-h peak at 1614-1607 cm'1, and showed a stretching vibration vo-h peak of primary alcohol at about 1100 cm'1. Although each cordycepin crystal form had the same chemical composition, an arrangement difference of a crystal structure led to changes of unit cell parameters and corresponding changes of acting intensities of a hydrogen bond, a covalent bond and the like between molecules inside unit cells, and an infrared spectrum was an absorption spectrum caused by vibration-rotation energy level transition of the molecules, so that these changes could inevitably lead to a position offset of a functional group on the infrared spectrum. Infrared characterization of each cordycepin crystal form product prepared by the present invention was consistent with results reported in the literature (Zeya Li, Tianyu Du, Lei Bi, et al. Analysis and Detection of Cordycepin in Culture Medium Residue by High Performance Liquid Chromatography and Infrared Spectroscopy [J]. Journal of Beijing Union University, 2020, 34(02): 84-87.). (4) Evaluation of humidity stability: 1 g of cordycepin crystal was laid flat in a weighing bottle, placed in a constant temperature and humidity chamber at 25°C and different relative humidities (RH), and weighed regularly to calculate a percentage weight gain for hygroscopicity evaluation. Results were as shown in FIG. 4 (wherein, Anhydrate-I referred to the cordycepin anhydrate form I crystal, Anhydrate-II referred to the cordycepin anhydrate form II crystal, and Monohydrate-II referred to the cordycepin monohydrate form II crystal, and FIG. a showed a relative humidity of 43%RH, FIG. b showed a relative humidity of 63%RH, and FIG. c showed a relative humidity of 75%RH), and according to the Guidelines for the Hygroscopicity Testing of Drugs, in Pharmacopoeia 2020 (Chinese Pharmacopoeia Commission. Chinese Pharmacopoeia [M], Beijing: China Medical Science and Technology Press, 2020.), it could be known that: the cordycepin anhydrate form I crystal had a weight gain of 0.80% at 43%RH, with almost no hygroscopicity, a weight gain of 3.61% at 63%RH, with the hygroscopicity, and a weight gain of 20.92% at 75%RH, with high hygroscopicity, was significantly affected by environmental humidity, and was saturated in adsorption after 400 hours; the cordycepin anhydrate form II crystal had a weight gain of 0.24% at 43%RH, with almost no hygroscopicity, a weight gain of 1.27% at 63%RH, with slight hygroscopicity, and a weight gain of 9.00% at 75%RH, with the hygroscopicity, was less affected by environmental humidity than the cordycepin anhydrate form I crystal, and was saturated in adsorption after 200 hours; and the cordycepin monohydrate form II crystal had a weight gain of 4.07% at 43%RH, with the hygroscopicity, a weight gain of 4.18% at 63%RH, with the hygroscopicity, and a weight gain of 5.80% at 75%RH, with the hygroscopicity, but was slightly affected by environmental humidity, and was basically saturated in adsorption after 200 hours. Because of stabilizing the percentage weight gain at about 4% and being least affected by environmental humidity, the cordycepin monohydrate form II crystal had the highest humidity stability and was easy to store. (5) Solubility determination: a solubility of the cordycepin was determined by a static method, which was specifically operated as follows. (1) Three parts of aqueous solutions were prepared in 25 mL triangular flasks respectively, a temperature was changed at a solubility ranging from 298.5 K to 325 K, and the triangular flasks were sealed for storage. (2) The above triangular flasks were added with excessive cordycepin crystals respectively, and the triangular flasks were placed in a constant temperature water bath with a magnetic stirring function. (3) In order to ensure a solid-liquid balance of the cordycepin crystals, it was guaranteed that full dissolution was achieved at the temperature and a rotating speed was controlled at 150 rpm to stir for at least 6 hours; and meanwhile, in order to ensure full separation of solid and liquid phases, after turning off the magnetic stirring function, the solutions were allowed to stand at the temperature constantly for at least 3 hours. (4) A proper amount of supernatant was taken by a high-precision syringe, filtered by an organic membrane with a pore size of 0.22 pm, diluted by a certain multiple, and then subjected to concentration determination by an ultraviolet spectrophotometer, and triplicate experiments were conducted for each group to take a mean value. Specific experimental results were as shown in FIG. 5. It could be seen from the figure (wherein, Anhydrate-I referred to the cordycepin anhydrate form I crystal, Anhydrate-II referred to the cordycepin anhydrate form II crystal, and Monohydrate-II referred to the cordycepin monohydrate form II crystal) that a solubility of each cordycepin crystal form was improved with an increase of temperature, which indicated that the dissolution of the cordycepin was a typical endothermic process. The cordycepin monohydrate form II crystal was in a crystal form with the lowest solubility among the three crystal forms. To sum up, the cordycepin monohydrate form II crystal had characteristics such as a minimum solubility and a good humidity stability, so that the cordycepin monohydrate form II crystal was used as a raw material for eutectic preparation. Embodiment 2: Preparation and characterization of cordycepin eutectic 1. Preparation of cordycepin eutectic or cordycepin-ligand salt (1) Physical mixing: 10 mmol ligand and 10 mmol cordycepin monohydrate form II crystal (prepared in Embodiment 1) were fully and evenly mixed. (2) Liquid-assisted grinding: 1 mL of pure water was added as an auxiliary agent, and continuously ground in an agate mortar for 1.5 hours to obtain a solid mixture. (3) After grinding, the solid mixture was dried at an atmospheric pressure and 40°C for 8—12 hours to obtain the cordycepin eutectic or the cordycepin-ligand salt. The ligand was an oxalic acid, a gallic acid or a vanillic acid respectively, which was finally prepared into a cordycepin-oxalate (a molar ratio of the two ingredients was 1: 1), a cordycepin-gallic acid eutectic (a molar ratio of the two ingredients was 1: 1) and a cordycepin-vanillic acid eutectic (a molar ratio of the two ingredients was 1:1) respectively. The molar ratio of the cordycepin to the ligand in each cordycepin eutectic or cordycepin-ligand salt was calculated by a liquid phase mass balance. 1 g of cordycepin eutectic compound was taken, in which a content of cordycepin was determined by liquid chromatography, and according to 1: 1 molar ratio of the cordycepin to the ligand, a calculated mass was 1 g. The pure water in the step (2) was replaced by an ethanol-water solution below 10 vt.% or an isopropanol-water solution below 10 vt.%, through which the cordycepin eutectic or the cordycepin-ligand salt could also be successfully obtained. 2. Characterization of cordycepin eutectic or cordycepin-ligand salt (1) Thermal analysis: by differential scanning calorimetry, the cordycepin monohydrate form II crystal (dA-original sample), the oxalic acid, the gallic acid, the vanillic acid, a material (PM) obtained by physical mixing of cordycepin-oxalate, cordycepin-gallic acid eutectic and cordycepin-vanillic acid eutectic, and a solid mixture (LGA-Water) obtained by liquid-assisted grinding were dried at 100°C for 1~2 hours respectively to remove surface-adsorbed water, and then the samples were characterized by a thermal analyzer. Determination results were as shown in FIG. 6 (wherein, FIG. a showed related ingredients of the cordycepin-oxalate prepared from the oxalic acid serving as a raw material; FIG. b showed related ingredients of the cordycepin-gallic acid eutectic prepared from the gallic acid serving as a raw material; FIG. c showed related ingredients of the cordycepin-vanillic acid eutectic prepared from the vanillic acid serving as a raw material). It could be seen from the DSC curves that there were 3 endothermic peaks after physical mixing of the cordycepin and the oxalic acid, wherein the first one at 62.04°C was an endothermic peak of monohydrate dehydration of the cordycepin, the third one at 172.25°C was an endothermic peak of a melting point of the cordycepin, which was 27°C lower than that of a pure product, and the second one at 111.46°C was a melting point of the oxalic acid itself, which was 10°C higher than that of the pure product of the oxalic acid. It was inferred that a blend had a slight influence on melting of various substances, and a new single melting point appeared at 159.01 °C after liquid-assisted grinding, which was between melting points of two monomers comprising the cordycepin and the oxalic acid, and was also different from a melting point of a physical mixture of the two ingredients, so that the two ingredients after grinding were a new salt, which was the cordycepin-oxalate (FIG. a). A physical mixture of the cordycepin and the gallic acid still had two melting points at 101,34°C and 155.71°C. It was inferred that an influence of the mixture led to an increased melting point of the gallic acid at 81.83°C, and a decreased melting point of the cordycepin at 155.71°C (FIG. b). A mixture of the cordycepin and the vanillic acid had two melting points at 103.52°C and 206.7°C, while a new substance eutectic obtained by liquid-assisted grinding had only a fixed melting point at 197.43°C (FIG. c). (2) Powder X-ray diffraction pattern (PXRD pattern): the cordycepin monohydrate form II crystal (dA-original sample), the oxalic acid, the gallic acid, the vanillic acid, a material (PM) obtained by physical mixing of cordycepin-oxalate, cordycepin-gallic acid eutectic and cordycepin-vanillic acid eutectic, and a solid mixture (LGA-Water) obtained by liquid-assisted grinding were subjected to X-ray diffraction determination respectively. Determination results were shown in FIG. 7 (wherein FIG. a showed related ingredients of the cordycepin-oxalate prepared from the oxalic acid serving as a raw material; FIG. b showed related ingredients of the cordycepin-gallic acid eutectic prepared from the gallic acid serving as a raw material; and FIG. c showed related ingredients of the cordycepin-vanillic acid eutectic prepared from the vanillic acid serving as a raw material). It could be seen from the figure that the cordycepin formed a new phase with the oxalic acid, the gallic acid and the vanillic acid at a molar ratio of 1: 1, and the crystals subjected to LGA-assisted grinding showed obvious diffraction peaks in the case that an angle of 20 was 25 degrees, which indicated that the cordycepin eutectic or the cordycepin-oxalate was successfully obtained. (3) Infrared spectroscopy: a Fourier Transform infrared spectroscopy (FTIR) method was used to determine an infrared spectrum of the cordycepin eutectic. The cordycepin monohydrate form II crystal (dA-original sample), the oxalic acid, the gallic acid, the vanillic acid, the material (PM) obtained by physical mixing of cordycepin-oxalate, cordycepin-gallic acid eutectic and cordycepin-vanillic acid eutectic, and the solid mixture (LGA-Water) obtained by liquid-assisted grinding were subjected to infrared determination respectively. Results were as shown in FIG. 8. According to an infrared spectrum of the cordycepin monohydrate form II crystal, under a wave number of 4000-500, peak wave number and intensity of the LGA-Water after full physical grinding were significantly different from those of the pure product and the material obtained by simple physical mixing, which could prove that a copolymerization reaction occurred, and vibrational stretching of a chemical bond was changed, which proved that a copolymer of the cordycepin and the ligand could be produced under assisted grinding. (4) Nuclear magnetic resonance analysis: monomer nuclear magnetic resonances and eutectics of cordycepin and ligand substances were determined by nuclear magnetic resonance. Comparative analysis results were as shown in FIG. 9 (wherein, dA referred to the cordycepin monohydrate form II crystal, OA referred to the oxalic acid, dA-OA referred to the cordycepin-oxalate, GA referred to the gallic acid, dA-GA referred to the cordycepin-gallic acid eutectic, VA referred to the vanillic acid, and dA-VA referred to the cordycepin-vanillic acid eutectic; FIG. a showed a hydrogen nuclear magnetic resonance spectrum of the cordycepin-oxalate and the raw material, and FIG. d showed a carbon nuclear magnetic resonance spectrum of the cordycepin-oxalate and the raw material; FIG. b showed a hydrogen nuclear magnetic resonance spectrum of the cordycepin-gallic acid eutectic and the raw material, and FIG. e showed a carbon nuclear magnetic resonance spectrum of the cordycepin-gallic acid eutectic and the raw material; and FIG. c showed a hydrogen nuclear magnetic resonance spectrum of the cordycepin-vanillic acid eutectic and the raw material, and FIG. f showed a carbon nuclear magnetic resonance spectrum of the cordycepin-vanillic acid eutectic and the raw material), and a shift of a characteristic peak was represented by “*” 1H nuclear magnetic resonance spectrometry was as shown in FIG. a, FIG. b and FIG. c, wherein FIG. a showed that an H nuclear magnetic resonance spectrum of a dA-OA quasieutectic had no peak at about 11 ppm-12 ppm, while the OA itself had a carboxyl H peak at 11.31 ppm, which indicated a loss of H on the carboxyl, for example, proton transfer occurred, and the cordycepin and the oxalic acid formed salts; FIG. b and FIG. c showed that a dA-GA quasi-eutectic and a dA-VA quasi-eutectic had carboxyl H peaks at 12.24 ppm and 12.43 ppm respectively, and H nuclear magnetic resonance spectra of the quasi-eutectics showed superposition of two monomers, so that both of the quasi-eutectics formed cordycepin-ligand binary eutectics, and it could be obtained by integral quantification that stoichiometric ratios of the two quasi-eutectics were 1: 1. C nuclear magnetic resonance spectra of the dA-OA, the dA-GA and the dA-VA were as shown in FIG. d, FIG. e and FIG. f. It could be seen that carbonyl carbon of the dA-OA at 161.88 ppm had a low-field shift of 0.57 ppm relative to carbonyl carbon of the OA at 161.31 ppm; carbonyl carbon of the dA-GA at 167.92 ppm had almost no shift relative to carbonyl carbon of the GA at 167.91 ppm; and carbonyl carbon of the dA-VA at 167.68 ppm had almost no shift relative to carbonyl carbon of the VA at 167.66 ppm. Embodiment 3: In-vitro dissolution experiment of cordycepin polymorph and eutectic 1. Formulation of tablet and preparation method for tablet In a dissolution experiment of cordycepin polymorph and eutectic, the most commonly used oral tablet dosage forms were selected for determination, wherein microcrystalline cellulose (20%), mannitol (40%) and magnesium stearate (1%) were selected, and ethanol was used as an auxiliary solvent for tabletting and then removed by drying at 50°C. An active pharmaceutical ingredient (which was the cordycepin anhydrate form I crystal prepared in Embodiment 1, the cordycepin anhydrate form II crystal prepared in Embodiment 1, the cordycepin monohydrate form II crystal prepared in Embodiment 1, the cordycepin-oxalate prepared in Embodiment 2, the cordycepin-gallic acid eutectic prepared in Embodiment 2 or the cordycepin-vanillic acid eutectic prepared in Embodiment 2 respectively, accounting for 39%) and an excipient were ground, sieved and mixed, and added with ethanol as a binding agent to prepare a wet mass, then the wet mass was sieved with a 24-mesh sieve to prepare wet granules with a size of 0.8 mm, and the wet granules were dried at 40°C and an atmospheric pressure for 1 hour to remove residual ethanol, and then tabletted by a multistation tablet press to obtain tablets with a diameter of 10 mm and a tablet weight of 0.45 g. 2. Configuration of dissolution medium and design of sampling point According to the Method II of Dissolution Testing in General Requirements in Volume IV of 2020 Edition of the “Chinese Pharmacopoeia”, 900 mL of ultrasonically degassed dissolution medium was taken. In the experiment, 2 dissolution media, comprising a hydrochloric acid solution at pH=1.2 and a phosphate buffer at pH=6.8, were selected to simulate artificial gastric juice and artificial intestinal juice for a dissolution test, and when temperatures of the dissolution media were constant at 37±0.5°C and a rotating speed was 75 r / min, 6 cordycepin tablets were put into a dissolution vessel and timed immediately, samples were taken according to 2 mL dissolution medium volume after 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes and 60 minutes respectively, and isothermal and isovolumetric dissolution media were replenished after sampling. The sampled dissolution media were treated with a 0.22 pm microporous filter membrane, and then a content of cordycepin was determined by sample injection according to HPLC chromatographic conditions. The HPLC chromatographic conditions were as follows: quantification: external standard method (standard cordycepin, Nanjing Shengmingyuan Health Technology Co., Ltd., batch number GXD20220601, amorphous powder, and purity above 98%); separation column: 880975-914 SB-Aq, 4.6 mm><250 mm, 5 pm; detection instrument: Agilentl260; detection wavelength: 254 nm; sample injection volume: 20 pL; flow rate: 1.0 pL / min; column temperature: 30°C; isocratic elution; and mobile phase: potassium dihydrogen phosphate (0.01 mol / L): methanol = 75: 25, and degassing by 0.22 pm filter membrane before use. 3. Hardness detection of tablet Before dissolution determination, relative hardness of the cordycepin tablets prepared by the tablet press should be determined, and the tablets should have enough hardness to avoid being broken or worn in processes such as packaging and transportation, so as to ensure accurate dosage. There were several methods for determining and expressing the hardness of the tablets, wherein a YD-35 tablet hardness tester was an experimental instrument commonly used for measuring the hardness of the tablets, which was used for hardness and diameter measurement of the tablets. A method of characterizing the hardness of the tablets by a grinding strength was used in the study, wherein the cordycepin tablet was erected between two pressing plates of the YD-35 tablet hardness tester, and pressed along a diameter direction of the tablet, and a pressure required to grind the tablet was determined, which was the grinding strength. 4. Experimental results (1) Detection results of concentration of liquid phase Under this detection condition, a retention time of the standard cordycepin was 16.4 minutes, so that a standard curve y=0.0162x-0.106, R2=l obtained according to the determination was used to calculate actual release concentrations of cordycepin corresponding to different cordycepin crystal forms and different cordycepin eutectics under this retention time. A representative liquid phase peak profde of the standard cordycepin was as shown in FIG. 10. (2) Dissolution data and disintegration of tablet prepared from cordycepin polymorph Tablets with a diameter of 10 mm, atablet weight of 0.45 g / tablet and a hardness of about 50 N were obtained by tabletting through the multi-station tablet press. In the process of dissolution determination, tablets of different cordycepin crystal forms were as shown in FIG. 11 (wherein, FIG. a showed tablets prepared from the cordycepin anhydrate form I crystal; FIG. b showed tablets prepared from the cordycepin anhydrate form II crystal; and FIG. c showed tablets prepared from the cordycepin monohydrate form II crystal). It could be seen from the figure that the tablets prepared from the cordycepin anhydrate form I crystal had an obvious “oil exudation” phenomenon. It was inferred that the “oil exudation” phenomenon was caused by a phase change under a high pressure due to an instability of the cordycepin anhydrate form I crystal. Moreover, during hardness testing, there was a fluctuation of 50±4 N. The tablets prepared from the cordycepin anhydrate form II crystal and the tablets prepared from the cordycepin monohydrate form II crystal) had no difference, and hardnesses of the tablets were stable at 50 N, which indicated that the cordycepin anhydrate form II crystal and the cordycepin monohydrate form II crystal had better compressibility. Table 1 and Table 2 showed dissolution data of three cordycepin polymorphic crystals in the artificial gastric juice (pH=1.2) and the artificial intestinal juice (pH=6.8). It could be seen from Table 1 and Table 2 that the cordycepin anhydrate form I crystal was in the most sustained-release crystal form, and was completely released after 60 minutes, but both of a fluctuation of hardness and an “oil exudation” phenomenon of this crystal might affect its disintegration and release, so that this crystal form was not suitable for a sustained-release drug; the cordycepin anhydrate form II crystal was completely released after 10 minutes, thereby being released rapidly, which was inconsistent with an original sustained-release purpose of the present invention; and the release of the cordycepin monohydrate form II crystal could be delayed to complete cordycepin disintegration and release after 30 minutes, and this crystal was in the best crystal form for sustained-release, which further proved the above idea of preparing the eutectic from the cordycepin monohydrate form II crystal to achieve sustained-release. The three crystal forms also had a co-dissolution characteristic, which meant that the release in the gastric juice was faster than that in the intestinal juice, and it was mainly because the cordycepin belonged to a purine alkaloid and had better solubility at low pH. Table 1 Dissolution data of tablets prepared from three cordycepin polymorphic crystals in artificial gastric juice (pH=1.2) Time / minute Cumulative dissolution rate (%) Cordycepin anhydrate form I crystal Cordycepin anhydrate form II crystal Cordycepin monohydrate form II crystal 0 0 0 0 5 12.18 62.71 13.12 10 31.31 91.82 16.98 15 52.93 91.89 26.16 20 56.98 91.57 50.57 25 68.05 92.20 80.69 30 73.15 91.99 90.21 45 87.00 91.77 91.17 50 90.20 91.95 90.33 60 90.86 91.16 90.75 Table 2 Dissolution data of tablets prepared from three cordycepin polymorphic crystals in artificial intestinal juice (pH=6.8) Cumulative dissolution rate (%) Cordycepin Cordycepin Cordycepin Time / minute anhydrate form anhydrate form monohydrate I crystal II crystal form II crystal 0 0 0 0 5 8.06 43.59 7.16 10 14.44 92.39 13.13 15 32.15 93.97 20.70 20 54.77 93.81 29.83 25 69.84 93.67 61.36 30 71.80 91.95 89.28 45 88.51 92.52 90.88 50 92.28 92.12 90.44 60 90.80 91.13 90.83 (3) Dissolution data and disintegration of tablet prepared from cordycepin eutectic (3-1) Different disintegration situations: specific disintegration situations were as shown in FIG. 12, wherein FIG. a showed disintegration situations of the tablets prepared from the cordycepin-oxalate in the simulated gastric juice (pH 1.2), FIG. b showed disintegration situations of the tablets prepared from the cordycepin-oxalate in the simulated intestinal juice (pH 6.8), FIG. c showed the tablets prepared from the cordycepin-gallic acid eutectic in the simulated gastric juice (pH 1.2), FIG. d showed disintegration situations of the tablets prepared from the cordycepin-gallic acid eutectic in the simulated intestinal juice (pH 6.8), FIG. e showed disintegration situations of the tablets prepared from the cordycepin-vanillic acid eutectic in the simulated gastric juice (pH 1.2), and FIG. f showed disintegration situations of the tablets prepared from the cordycepin-vanillic acid eutectic in the simulated intestinal juice (pH 6.8). It could be seen from the figure that the disintegration situations of the tablets in various groups were consistent, wherein their disintegration and release rates in the gastric juice (pH 1.2) were greater than those in the intestinal juice (pH 6.8), which were consistent with the release situations of the tablets prepared from the cordycepin polymorphic crystals, and it was mainly due to alkaloid properties of the cordycepin itself. By comparison, it was found that: (a) the tablets prepared from the cordycepin-oxalate were completely released in the artificial gastric juice after 30 minutes, but could be sustainedly released in the artificial intestinal juice for 50 minutes, and in this case, there was still a "small amount of cumulative" drug residue in disintegration, so that the tablets were the slowest group of tablets in disintegration and release, and the release of the tablets for 30 minutes was longer than the release of the tablets prepared from the cordycepin monohydrate form II crystal, which indicated that the tablets were expected to achieve a sustained-release effect; (b) the tablets prepared from the cordycepin-gallic acid eutectic were completely released after 20 minutes in both of the artificial intestinal juice and the artificial gastric juice, and achieved a delayed-release effect compared with the tablets prepared from the cordycepin anhydrate form II crystal, but the effect of the tablets was poorer than that of the tablets prepared from the cordycepin monohydrate form II crystal, so that the cordycepin-gallic acid eutectic failed to achieve the sustained-release purpose; and (c) a complete-release time of the tablets prepared from the cordycepin-vanillic acid eutectic was the same as that of the tablets prepared from the cordycepin monohydrate form II crystal, both of which were 30 minutes, which meant to fail to play a role in reducing a cordycepin release rate. In contrast, the cordycepin-oxalate was a selected salt that was expected to achieve a significant sustained-release effect in the artificial intestinal juice. (3-2) Comparison of dissolution data: the dissolution data were as shown in Table 3 and Table 4. It could be seen from the data in the tablets only prepared from the cordycepin-oxalate had a relatively obvious sustained-release effect, and were completely released in the artificial gastric juice after 30 minutes, but the release could be delayed to 50 minutes in the artificial intestinal juice, which showed a significant sustained-release effect, and meanwhile, a dissolution rate of the tablets followed a rule of being slow first and then being rapid; compared with the cordycepin monohydrate form II crystal (30 minutes), the cordycepin-gallic acid eutectic showed a quick-release effect (20 minutes); and the same was true of the cordycepin-vanillic acid eutectic, but the sustained-release effect was slightly better than that of the cordycepin-gallic acid eutectic, and complete disintegration and release was prolonged for 5 minutes. Table 3 Dissolution data of tablets prepared from three cordycepin eutectics in artificial gastric juice (pH=1.2) Time / minute Cumulative dissolution rate (%) Cordycepin-oxalate Cordycepin-gallic acid eutectic Cordycepin- vanillic acid eutectic 0 0 0 0 3 7.29 6.75 14.28 5 11.02 13.40 19.53 10 15.01 27.38 34.01 15 20.06 87.31 54.01 20 27.07 90.88 73.43 25 41.26 92.20 88.18 30 86.95 90.40 87.64 45 89.49 91.17 90.05 50 89.37 90.15 88.53 60 89.37 91.00 90.45 Table 4 Dissolution data of tablets prepared from three cordycepin eutectics in artificial intestinal juice (pH=6.8) Cumulative dissolution rate (%) Time / minute Cordycepin-oxalate Cordycepin-gallic acid eutectic Cordycepin- vanillic acid eutectic 0 0 0 0 3 5.65 8.22 14.64 5 8.41 14.38 18.87 10 11.17 38.55 30.29 15 14.35 89.74 37.86 20 17.67 90.37 55.26 25 20.81 90.17 78.94 30 24.79 89.40 79.76 45 58.50 89.77 85.50 50 88.55 86.89 89.62 60 90.42 91.01 90.83 To sum up, the oxalic acid could effectively achieve the sustained-release of the cordycepin, and the best sustained-release effect was achieved in the intestinal juice. The present invention provides an idea and a method for a cordycepin-oxalate, and a preparation method therefor and an application thereof, with many methods and ways to realize the technical solution specifically. Those described above are merely the preferred embodiments of the present invention, and it should be pointed out that those of ordinary skills in the art may further make improvements and decorations without departing from the principle of the present invention, and these improvements and decorations should also be regarded as falling within the scope of protection of the present invention. All the unspecified components in the embodiments can be realized by the prior art.

Claims

1. A cordycepin-oxalate, wherein a molecular formula of the cordycepin-oxalate is CioHi3N503*H2C204; and a molecular structural formula of the cordycepin-oxalate is as follows:

2. A preparation method for the cordycepin-oxalate according to claim 1, comprising the following steps:(1) physical mixing: fully and evenly mixing an oxalic acid and a cordycepin monohydrate form II crystal;(2) liquid-assisted grinding: adding an auxiliary agent, and continuously grinding to obtain a solid mixture; and(3) drying the solid mixture to obtain the cordycepin-oxalate.

3. The preparation method according to claim 2, wherein, in the step (1), a molar ratio of the oxalic acid to the cordycepin monohydrate form II crystal is 1: 1; or,in the step (2), the auxiliary agent is water, ethanol-water solution below 10 vt.% or isopropanol-water solution below 10 vt.%; and / or, a mass of the auxiliary agent is 20%~70% of a total mass of the oxalic acid and the cordycepin monohydrate form II crystal; and / or, the grinding lasts for 1.0-8.0 hours; or,in the step (3), the drying is carried out under an atmospheric pressure; and / or, the drying is carried out at 40-60°C; and / or, the drying lasts for 8-12 hours.

4. The preparation method according to claim 2, wherein, in the step (1), the cordycepin monohydrate form II crystal is prepared by the following method, which comprises:mixing crude cordycepin with a solvent to obtain a crude cordycepin solution; andcooling the crude cordycepin solution, stably crystallizing an obtained crystal slurry mother liquor, then carrying out suction filtration, washing a solid, and drying to obtain the cordycepin monohydrate form II crystal.

5. The preparation method according to claim 4, wherein the solvent is water, an isopropanol-water solution below 80 vt.% or an ethanol-water solution below 10 vt.%; and / or, the crude cordycepin is mixed with the solvent at 40°C~60°C; and / or, a concentration of the crude cordycepin in the crude cordycepin solution is 30 g / L~70 g / L; and / or, the crude cordycepin solution is cooled, which specifically refers to cooling to 4~10°C at a cooling rate of 3~8°C / h; and / or, the crystal slurry mother liquor is stabilized at 4~10°C for 1-4 hours for crystallization; and / or, the washing specifically refers to washing with an ethanol-water solution below 70 vt.%; and / or, the drying is carried out at a drying temperature of 50°C~60°C; and / or, the drying lasts for 10-12 hours.

6. A sustained-release tablet, comprising:(i) the cordycepin-oxalate according to claim 1, and(ii) a pharmaceutically acceptable pharmaceutical excipient.

7. The sustained-release tablet according to claim 6, wherein the pharmaceutically acceptable pharmaceutical excipient comprises a filling agent and a wetting agent.

8. The sustained-release tablet according to claim 7, wherein the filling agent is any one or a combination of two of microcrystalline cellulose and mannitol; or, the wetting agent is ethanol; or, a mass content of the filling agent in the sustained-release tablet is 50%~70%; or, a mass content of the cordycepin-oxalate in the sustained-release tablet is 30%~50%.

9. A preparation method for the sustained-release tablet according to claim 7, comprising: mixing the cordycepin-oxalate according to claim 1 with the filling agent, adding the wetting agent to prepare a wet mass, sieving the wet mass to obtain wet granules, and drying and tabletting the wet granules to obtain the sustained-release tablet.

10. The preparation method according to claim 9, wherein the sieving is carried out with a sieve of 10-40 meshes; or, the drying is carried out at 40~60°C under an atmospheric pressure for 1-4 hours; or, a diameter of the sustained-release tablet is 5-15 mm; or, a tablet weight of the sustained-release tablet is 0.2-0.6 g.T +44(0)30 0300 2000Search report under Section 17 of the Patents Act 1977Application No.: GB2603131.0Claims searched: 1-10Date search completed: 2 April 2026International classificationSubclass and subgroup Valid from A61K31 / 7076 01 / 01 / 2006 A61K47 / 26 01 / 01 / 2006 A61K47 / 38 01 / 01 / 2006 A61K9 / 20 01 / 01 / 2006 C07C51 / 41 01 / 01 / 2006 C07C55 / 07 01 / 01 / 2006 C07H1 / 00 01 / 01 / 2006 C07H19 / 16 01 / 01 / 2006Field of searchWorldwide search of patent documents classified in the following areas of the IPC: C07H, C07CDatabases used in the preparation of this search report:CAS ONLINE; SEARCH-NPL; SEARCH-PATENTDocuments considered to be relevantPatent literatureCategory Relevant to claims Document of relevance X 1 CN 101985457 A (BEIJING RUNDEKANG MEDICAL TECH) - See whole document especially summary of invention which lists oxalic acid and examples X 1 CN 101984975 A (BEIJING RUNDEKANG MEDICAL TECH) - See whole document especially summary of invention and claim 2 whichT +44(0)30 0300 2000lists oxalic acid X 1 KR1020120054871 A (UNIV INJE IND ACAD COOPERATION) - See English translation which lists oxalic acid as a possible acid addition salt of cordycepin X 1 KR 1020150095012 A (COSMAX INC) - See whole document especially paragraph [0022] which lists oxalic acid A - CN 120535562 A (NANJING UNIVERSITY OF TECHNOLOGY) - See whole document especially examplesNon-patent literatureCategory Relevant to claims Document of relevance A - Industrial &Engineering Chemistry Research, 64, 08 / 07 / 2025, Pengpeng Yang et al., Theoretical and experimental exploration of multicomponent forms of cordycepin for sustained release, 14733-14743, See whole document especially abstract and sections 2.2, 2.3 and 2.4CategoriesLetter or symbol Description X Document indicating lack of novelty or inventive step. Y Document indicating lack of inventive step, if combined with another document of the same category. & Member of the same patent family. A Document indicating technological background. P Document published on or after the priority date but before the filing date of the present application. E Earlier application published on or after the filing date of the present application.

Images