Vitamin D eutectic, its preparation method and application

Abstract

To provide a vitamin D eutectic crystal excellent in chemical stability, a method for preparing the same, and applications thereof.SOLUTION: Vitamin D and a eutectic ligand are comprised, wherein the Vitamin D is vitamin D2 or vitamin D3, and the eutectic ligand is idebenone or vitamin K3. The vitamin D cocrystal according to the present invention not only can significantly improve the chemical stability of vitamin D under light and heat conditions, but also can avoid the problems caused by physically mixing vitamin D with other APIs.SELECTED DRAWING: Figure 1

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This invention claims priority from a Chinese patent application bearing application number 202410829393.0 and entitled "Vitamin D Cocrystal and Its Preparation Method and Application" filed with the State Intellectual Property Office of the People's Republic of China on June 25, 2024, the entire contents of which are incorporated into and constitute part of the present invention and may be used for all purposes. [Technical Field]

[0002] The present invention belongs to the field of pharmaceutical technology and relates to vitamin D eutectic and its preparation method and application. [Background technology]

[0003] The information disclosed in this background section is intended only to enhance understanding of the overall background of the present invention, and does not necessarily constitute an admission or any indication that the information provided constitutes existing technology known to those skilled in the art.

[0004] Vitamin D is a fat-soluble vitamin and steroid derivative necessary for the maintenance of life in higher animals. Its anti-rickets properties have led to its widespread use as the anti-rickets vitamin. While vitamin D is typically obtained from food, the difficulty of obtaining sufficient vitamin D from food has led to widespread vitamin D deficiency worldwide. A large amount of international, in-depth research on vitamin D has shown that vitamin D is no longer considered a nutritional necessity for preventing rickets in children. The health benefits of vitamin D are becoming more widely recognized and have been demonstrated in numerous clinical trials. Vitamin D and its metabolites can regulate calcium and phosphorus balance in higher animals, favoring new bone formation and mineralization. Vitamin D is also a selective immunomodulator, demonstrating potential clinical application in the treatment of cancer, immunotherapy, cardiovascular disease, metabolic syndrome, and other diseases. In general, the treatment and prevention of vitamin D deficiency are crucial for the overall health and development of all people, especially women and children.

[0005] The most important members of the vitamin D family are vitamin D2 and vitamin D3. Vitamin D2, also known as ergocalciferol, has the chemical name 9,10-open-ring ergosta-5,7,10(19),22-tetraen-3-ol, the chemical structure of which is shown below: [ka]

[0006] Vitamin D3, also known as cholecalciferol, has the chemical name 9,10-open-ring cholesterol-5,7,10(19)-trien-3-ol, and its chemical structure is shown below: [ka]

[0007] Vitamin D2 and vitamin D3, after being metabolized by the liver and kidneys in the body, promote calcium absorption in the small intestine and can be used as supplementary medication for calcium deficiency patients. Vitamin D2 and vitamin D3 are unstable, sensitive to light and heat, and easily decomposed into many products and inactivated by oxidation or photolysis in the air.

[0008] At the same time, when two or more drugs are used in combination in clinical settings, compound formulations are generally developed and used to enhance the drug compatibility of the combined drug. However, because the two or more active ingredients in a compound drug are a physical mixture, many shortcomings exist. First, there is the issue of different compound drug quality control standards. Although the two or more active pharmaceutical ingredients (APIs) in a compound drug are mixed in a fixed ratio, the reproducibility of the content standards is relatively low. Due to physical mixing, the X-ray powder diffraction responses of different active ingredients vary, making it more difficult to establish a standard for crystalline form. Second, there is the issue of the dispersibility of different active ingredients during the formulation process. The active ingredients contained in a drug product per unit dose are only at the milligram or even microgram level, making it difficult to ensure uniform dispersion during the formulation process. Finally, there is the issue of storage stability of the drug substance. Physically mixed active ingredients are less stable than single components. Summary of the Invention [Problem to be solved by the invention]

[0009] The present invention unexpectedly obtains a vitamin D (including vitamin D2 and vitamin D3) eutectic using an API as a co-coordinating ligand, which not only significantly enhances the chemical stability of vitamin D (including vitamin D2 and vitamin D3) under photothermal and heating conditions, but also avoids the problems associated with physically mixing vitamin D with other APIs. Based on the above research results, the object of the present invention is to provide a vitamin D eutectic, its preparation method, and applications. [Means for solving the problem]

[0010] To achieve the above objectives, the present invention provides the following technical solutions:

[0011] According to a first aspect, there is provided a vitamin D eutectic comprising vitamin D and a eutectic ligand, wherein the vitamin D is vitamin D2 or vitamin D3, and the eutectic ligand is idebenone or vitamin K3.

[0012] Idebenone has the chemical formula C 19 H 30 It is O5, and its chemical structure is shown below. [ka]

[0013] Vitamin K3, also known as menaquinone, has the chemical formula C 11 HO, the chemical structure of which is shown below: [ka]

[0014] In some embodiments, the molar ratio of vitamin D to eutectic ligand is about 1:0.9-1.1, about 1:0.95-1.05, about 1:0.99-1.01, or about 1:1.

[0015] In some embodiments, the molar ratio of vitamin D2 to idebenone is about 1:0.9-1.1, about 1:0.95-1.05, about 1:0.99-1.01, or about 1:1.

[0016] In some embodiments, the molar ratio of vitamin D3 to idebenone is about 1:0.9-1.1, about 1:0.95-1.05, about 1:0.99-1.01, or about 1:1.

[0017] In some embodiments, the molar ratio of vitamin D2 to vitamin K3 is about 1:0.9-1.1, about 1:0.95-1.05, about 1:0.99-1.01, or about 1:1.

[0018] In some embodiments, the molar ratio of vitamin D3 to vitamin K3 is about 1:0.9-1.1, about 1:0.95-1.05, about 1:0.99-1.01, or about 1:1.

[0019] In some embodiments, the eutectic of vitamin D2 and idebenone has characteristic peaks at approximately 11.19±0.2°, 16.85±0.2°, 17.19±0.2°, 21.76±0.2°, 22.41±0.2°, 22.57±0.2°, 24.55±0.2°, 38.01±0.2°, and 44.22±0.2° in an X-ray powder diffraction (PXRD) spectrum expressed as diffraction angles 2θ measured using Cu-Kα radiation.

[0020] In some embodiments, the eutectic of vitamin D2 and idebenone further has characteristic peaks at approximately 7.45±0.2° and 12.09±0.2° in an X-ray powder diffraction spectrum expressed as a diffraction angle 2θ measured using Cu-Kα radiation.

[0021] In some embodiments, the eutectic of vitamin D2 and idebenone further has characteristic peaks at approximately 15.73±0.2° and 17.57±0.2° in an X-ray powder diffraction spectrum represented by a diffraction angle 2θ measured using Cu-Kα radiation.

[0022] In some embodiments, the eutectic of vitamin D2 and idebenone further has characteristic peaks at approximately 21.21±0.2° and 22.06±0.2° in an X-ray powder diffraction spectrum expressed as a diffraction angle 2θ measured using Cu-Kα radiation.

[0023] In some embodiments, the eutectic of vitamin D2 and idebenone further has characteristic peaks at approximately 28.64±0.2° and 38.01±0.2° in an X-ray powder diffraction spectrum expressed as a diffraction angle 2θ measured using Cu-Kα radiation.

[0024] In some embodiments, the eutectic of vitamin D2 and idebenone further has characteristic peaks at approximately 12.35±0.2°, 13.22±0.2°, 14.21±0.2°, 14.91±0.2°, 15.38±0.2°, and 15.54±0.2° in an X-ray powder diffraction spectrum represented by diffraction angles 2θ measured using Cu-Kα radiation.

[0025] In some embodiments, the eutectic of vitamin D2 and idebenone further has characteristic peaks at approximately 18.09±0.2° and 19.52±0.2° in an X-ray powder diffraction spectrum expressed as a diffraction angle 2θ measured using Cu-Kα radiation.

[0026] In some embodiments, the eutectic of vitamin D2 and idebenone exhibits an X-ray powder diffraction spectrum represented by diffraction angles 2θ measured using Cu-Kα radiation of approximately 7.45±0.2°, 11.19±0.2°, 12.09±0.2°, 12.35±0.2°, 13.22±0.2°, 14.21±0.2°, 14.91±0.2°, 15.38±0.2°, 15.54±0.2°, and 15. Characteristic peaks are observed at 73±0.2°, 16.85±0.2°, 17.19±0.2°, 17.57±0.2°, 18.09±0.2°, 19.52±0.2°, 21.21±0.2°, 21.76±0.2°, 22.06±0.2°, 22.41±0.2°, 22.57±0.2°, 24.55±0.2°, 28.64±0.2°, 38.01±0.2°, and 44.22±0.2°.

[0027] In some embodiments, using Cu-Kα radiation detection, the eutectic of vitamin D2 and idebenone has an X-ray powder diffraction pattern substantially identical to the eutectic shown in FIG.

[0028] In some embodiments, the eutectic of vitamin D3 and idebenone has characteristic peaks at approximately 11.18±0.2°, 15.76±0.2°, 18.00±0.2°, 21.80±0.2°, 22.46±0.2°, and 38.02±0.2° in an X-ray powder diffraction spectrum expressed as a diffraction angle 2θ measured using Cu-Kα radiation.

[0029] In some embodiments, the eutectic of vitamin D3 and idebenone further has characteristic peaks at approximately 5.06±0.2° and 12.99±0.2° in an X-ray powder diffraction spectrum expressed as a diffraction angle 2θ measured using Cu-Kα radiation.

[0030] In some embodiments, the eutectic of vitamin D3 and idebenone further has characteristic peaks at approximately 15.17±0.2° and 16.18±0.2° in an X-ray powder diffraction spectrum expressed as a diffraction angle 2θ measured using Cu-Kα radiation.

[0031] In some embodiments, the eutectic of vitamin D3 and idebenone further has characteristic peaks at approximately 21.21±0.2° and 22.73±0.2° in an X-ray powder diffraction spectrum expressed as a diffraction angle 2θ measured using Cu-Kα radiation.

[0032] In some embodiments, the eutectic of vitamin D3 and idebenone further has characteristic peaks at approximately 24.46±0.2° and 44.22±0.2° in an X-ray powder diffraction spectrum expressed as a diffraction angle 2θ measured using Cu-Kα radiation.

[0033] In some embodiments, the eutectic of vitamin D3 and idebenone further has characteristic peaks at approximately 13.21±0.2°, 13.64±0.2°, and 14.95±0.2° in an X-ray powder diffraction spectrum expressed as a diffraction angle 2θ measured using Cu-Kα radiation.

[0034] In some embodiments, the eutectic of vitamin D3 and idebenone has characteristic peaks at approximately 5.06±0.2°, 11.18±0.2°, 12.99±0.2°, 13.21±0.2°, 13.64±0.2°, 14.95±0.2°, 15.17±0.2°, 15.76±0.2°, 16.18±0.2°, 18.00±0.2°, 21.21±0.2°, 21.80±0.2°, 22.46±0.2°, 22.73±0.2°, 24.46±0.2°, 38.02±0.2°, and 44.22±0.2° in an X-ray powder diffraction spectrum expressed as diffraction angles 2θ measured using Cu-Kα radiation.

[0035] In some embodiments, using Cu-Kα radiation detection, the eutectic of vitamin D3 and idebenone has an X-ray powder diffraction pattern substantially identical to the eutectic shown in FIG.

[0036] In some embodiments, the eutectic of vitamin D2 and vitamin K3 has characteristic peaks at approximately 11.76±0.2°, 12.41±0.2°, 16.92±0.2°, 17.27±0.2°, 18.15±0.2°, 25.76±0.2°, 27.10±0.2°, and 38.00±0.2° in an X-ray powder diffraction spectrum expressed as diffraction angles 2θ measured using Cu-Kα radiation.

[0037] In some embodiments, the eutectic of vitamin D2 and vitamin K3 further has characteristic peaks at approximately 10.13±0.2° and 12.90±0.2° in an X-ray powder diffraction spectrum represented by a diffraction angle 2θ measured using Cu-Kα radiation.

[0038] In some embodiments, the eutectic of vitamin D2 and vitamin K3 further has characteristic peaks at approximately 15.76±0.2° and 16.92±0.2° in an X-ray powder diffraction spectrum represented by a diffraction angle 2θ measured using Cu-Kα radiation.

[0039] In some embodiments, the eutectic of vitamin D2 and vitamin K3 further has characteristic peaks at approximately 17.65±0.2° and 19.01±0.2° in an X-ray powder diffraction spectrum represented by a diffraction angle 2θ measured using Cu-Kα radiation.

[0040] In some embodiments, the eutectic of vitamin D2 and vitamin K3 further has characteristic peaks at approximately 24.04±0.2°, 27.45±0.2°, and 44.20±0.2° in an X-ray powder diffraction spectrum represented by a diffraction angle 2θ measured using Cu-Kα radiation.

[0041] In some embodiments, the eutectic of vitamin D2 and vitamin K3 further has characteristic peaks at approximately 5.08±0.2° and 9.12±0.2° in an X-ray powder diffraction spectrum represented by a diffraction angle 2θ measured using Cu-Kα radiation.

[0042] In some embodiments, the eutectic of vitamin D2 and vitamin K3 further has characteristic peaks at approximately 13.43±0.2°, 14.27±0.2°, and 15.47±0.2° in an X-ray powder diffraction spectrum represented by a diffraction angle 2θ measured using Cu-Kα radiation.

[0043] In some embodiments, the eutectic of vitamin D2 and vitamin K3 further has characteristic peaks at approximately 21.76±0.2° and 23.55±0.2° in an X-ray powder diffraction spectrum represented by a diffraction angle 2θ measured using Cu-Kα radiation.

[0044] In some embodiments, the eutectic of vitamin D2 and vitamin K3 has an X-ray powder diffraction spectrum represented by diffraction angles 2θ measured using Cu-Kα radiation of approximately 5.08±0.2°, 9.12±0.2°, 10.13±0.2°, 11.76±0.2°, 12.41±0.2°, 12.90±0.2°, 13.43±0.2°, 14.27±0.2°, 15.47±0.2°, and 16. Characteristic peaks are observed at 76±0.2°, 16.47±0.2°, 16.92±0.2°, 17.27±0.2°, 17.65±0.2°, 18.15±0.2°, 19.01±0.2°, 21.76±0.2°, 23.55±0.2°, 24.04±0.2°, 25.76±0.2°, 27.10±0.2°, 27.45±0.2°, 38.00±0.2°, and 44.20±0.2°.

[0045] In some embodiments, using Cu-Kα radiation detection, the co-crystal of vitamin D2 and vitamin K3 has an X-ray powder diffraction pattern substantially identical to the co-crystal shown in FIG.

[0046] In some embodiments, the eutectic of vitamin D3 and vitamin K3 has characteristic peaks at approximately 11.70±0.2°, 16.19±0.2°, 18.02±0.2°, 27.03±0.2°, and 38.01±0.2° in an X-ray powder diffraction spectrum expressed as a diffraction angle 2θ measured using Cu-Kα radiation.

[0047] In some embodiments, the eutectic of vitamin D3 and vitamin K3 further has characteristic peaks at approximately 5.08±0.2° and 13.02±0.2° in an X-ray powder diffraction spectrum represented by a diffraction angle 2θ measured using Cu-Kα radiation.

[0048] In some embodiments, the eutectic of vitamin D3 and vitamin K3 further has characteristic peaks at approximately 13.71±0.2° and 21.78±0.2° in an X-ray powder diffraction spectrum represented by a diffraction angle 2θ measured using Cu-Kα radiation.

[0049] In some embodiments, the eutectic of vitamin D3 and vitamin K3 further has characteristic peaks at approximately 27.03±0.2° and 44.19±0.2° in an X-ray powder diffraction spectrum represented by a diffraction angle 2θ measured using Cu-Kα radiation.

[0050] In some embodiments, the eutectic of vitamin D3 and vitamin K3 further has characteristic peaks at approximately 23.56±0.2°, 23.97±0.2°, and 25.70±0.2° in an X-ray powder diffraction spectrum represented by a diffraction angle 2θ measured using Cu-Kα radiation.

[0051] In some embodiments, the eutectic of vitamin D3 and vitamin K3 has characteristic peaks at approximately 5.08±0.2°, 11.70±0.2°, 13.02±0.2°, 13.71±0.2°, 15.18±0.2°, 15.48±0.2°, 16.19±0.2°, 18.02±0.2°, 27.03±0.2°, 21.78±0.2°, 23.56±0.2°, 23.97±0.2°, 25.70±0.2°, 27.03±0.2°, 38.01±0.2°, and 44.19±0.2° in an X-ray powder diffraction spectrum expressed as diffraction angles 2θ measured using Cu-Kα radiation.

[0052] In some embodiments, using Cu-Kα radiation detection, the co-crystal of vitamin D3 and vitamin K3 has an X-ray powder diffraction pattern substantially identical to the co-crystal shown in FIG.

[0053] In some embodiments, the eutectic of vitamin D2 and idebenone has a characteristic melting peak at about 89±2° C. (onset temperature) in its differential scanning calorimetry (DSC) diagram.

[0054] In some embodiments, the eutectic of vitamin D2 and idebenone has a differential scanning calorimetry chart substantially identical to the eutectic shown in FIG.

[0055] In some embodiments, the eutectic of vitamin D3 and idebenone has a characteristic melting peak at about 50±2° C. (onset temperature) in its differential scanning calorimetry (DSC) diagram.

[0056] In some embodiments, the eutectic of vitamin D3 and idebenone has a differential scanning calorimetry chart substantially similar to the eutectic shown in FIG.

[0057] In some embodiments, a eutectic of vitamin D2 and vitamin K3 has a characteristic melting peak at about 69±2° C. (onset temperature) in its differential scanning calorimetry (DSC) diagram.

[0058] In some embodiments, the eutectic of vitamin D2 and vitamin K3 has a differential scanning calorimetry chart substantially similar to the eutectic shown in FIG.

[0059] In some embodiments, a eutectic of vitamin D3 and vitamin K3 has a characteristic melting peak at about 52±2° C. (onset temperature) in its differential scanning calorimetry (DSC) diagram.

[0060] In some embodiments, the eutectic of vitamin D3 and vitamin K3 has a differential scanning calorimetry chart substantially similar to the eutectic shown in FIG.

[0061] In some embodiments, the thermogravimetric (TG) diagram of the eutectic of vitamin D2 and idebenone shows that weight loss begins at about 140°C and continues at about 450°C, resulting in a 96% weight loss.

[0062] In some embodiments, the eutectic of vitamin D2 and idebenone has approximately the same weight loss characteristics as the eutectic shown in FIG.

[0063] In some embodiments, the thermogravimetric analysis chart of the eutectic of vitamin D3 and idebenone shows that weight loss begins at about 190°C and continues at 99% weight loss by about 460°C.

[0064] In some embodiments, the eutectic of vitamin D3 and idebenone has approximately the same weight loss characteristics as the eutectic shown in FIG.

[0065] In some embodiments, a eutectic of vitamin D2 and vitamin K3 begins to lose weight at about 100°C on its thermogravimetric analysis chart, and loses 99% of its weight by about 450°C.

[0066] In some embodiments, the eutectic of vitamin D2 and vitamin K3 has approximately the same weight loss characteristics as the eutectic shown in FIG.

[0067] In some embodiments, the thermogravimetric analysis chart of a eutectic of vitamin D3 and vitamin K3 shows that weight loss begins at about 100°C and continues at 99% weight loss by about 440°C.

[0068] In some embodiments, the eutectic of vitamin D3 and vitamin K3 has approximately the same weight loss characteristics as the eutectic shown in FIG.

[0069] In some embodiments, the co-crystal of vitamin D2 and idebenone has a nuclear magnetic resonance hydrogen spectrum (H) nearly identical to the co-crystal shown in FIG. 1 H-NMR diagram.

[0070] In some embodiments, the co-crystal of vitamin D3 and idebenone has a nuclear magnetic resonance hydrogen spectrum (H) nearly identical to the co-crystal shown in FIG. 1 H-NMR diagram.

[0071] In some embodiments, the co-crystal of vitamin D2 and vitamin K3 has a nuclear magnetic resonance hydrogen spectrum (H) substantially identical to the co-crystal shown in FIG. 1 H-NMR diagram.

[0072] In some embodiments, the co-crystal of vitamin D3 and vitamin K3 has a nuclear magnetic resonance hydrogen spectrum (H) substantially identical to the co-crystal shown in FIG. 1 H-NMR diagram.

[0073] According to a second aspect, there is provided a pharmaceutical composition comprising a vitamin D co-crystal according to the first aspect of the invention and a medicinal auxiliary material.

[0074] The pharmaceutical compositions of the present invention can be prepared using well-known and readily available ingredients according to known methods. In preparing the pharmaceutical compositions of the present invention, the active ingredient is typically mixed with a carrier or adjuvant. The pharmaceutical compositions can be prepared in solid, semi-solid, or liquid form, including tablets, pills, powders, capsules, suspensions, and other formulations suitable for various modes of administration, including inhalation, oral, rectal, parenteral (including subcutaneous, intradermal, intramuscular, and intravenous), implantable, and transdermal administration. The optimal route of administration will depend on the duration of the subject's condition, the desired duration of treatment, the nature and severity of the condition being treated, and the specific formulation being used.

[0075] According to a third aspect, there is provided a method for preparing the vitamin D co-crystal according to the first aspect of the present invention, wherein a grinding method is employed to make the vitamin D and the co-crystal ligand into a eutectic.

[0076] In some embodiments, the steps of the milling method are as follows:

[0077] An organic solvent is added to vitamin D and the eutectic ligand, and then the mixture is ground, and upon completion of the grinding, a vitamin D eutectic is obtained.

[0078] Specifically, the organic solvent is one or more selected from ethanol, methanol, isopropanol, tetrahydrofuran, acetone, and acetonitrile.

[0079] In some embodiments, vitamin D and the eutectic ligand are placed in a grinding tank, followed by adding grinding balls (e.g., stainless steel grinding balls), and then dripping a small amount of organic solvent into the grinding tank, or the grinding tank is placed in a ball mill (e.g., in some embodiments of the present invention, a planetary ball mill BM6pro is used). After operation is complete, the grinding tank is removed and the sample is scraped with a cleaning scraper to obtain the vitamin eutectic described in the present invention.

[0080] In some embodiments, the molar ratio of vitamin D to eutectic ligand added before milling is about 1:0.9-1.1, about 1:0.95-1.05, about 1:0.99-1.01, or about 1:1.

[0081] In some embodiments, the molar ratio of vitamin D2 to idebenone added before milling is about 1:0.9-1.1, about 1:0.95-1.05, about 1:0.99-1.01, or about 1:1.

[0082] In some embodiments, the molar ratio of vitamin D3 to idebenone added before milling is about 1:0.9-1.1, about 1:0.95-1.05, about 1:0.99-1.01, or about 1:1.

[0083] In some embodiments, the molar ratio of vitamin D2 to vitamin K3 added before milling is about 1:0.9-1.1, about 1:0.95-1.05, about 1:0.99-1.01, or about 1:1.

[0084] In some embodiments, the molar ratio of vitamin D3 to vitamin K3 added before milling is about 1:0.9-1.1, about 1:0.95-1.05, about 1:0.99-1.01, or about 1:1.

[0085] In some embodiments, the mass of the grinding balls is about 2 to 10 times, or about 3 to 5 times, the total mass of the vitamin D and eutectic ligand.

[0086] In some embodiments, the rotation speed during the grinding process is about 100 to 1000 rpm, about 300 to 6000 rpm, or about 500 rpm, and the grinding method is a grinding time of about 1 to 5 minutes, an interval of about 1 to 5 minutes, and 1 to 5 cycles.

[0087] According to the research results of the present invention, in the above preparation method, the grinding method can greatly shorten the time and reduce the cost, and has better prospects for industrial application.

[0088] According to a fourth aspect, there is provided the use of a vitamin D cocrystal according to the first aspect of the invention or a pharmaceutical composition according to the second aspect of the invention in the preparation of a medicament or a complex calcium preparation for the prevention or treatment of vitamin D deficiency or calcium deficiency.

[0089] In some embodiments, the medicament is used to prevent or treat rickets or chondropathy.

[0090] According to a fifth aspect, there is provided the use of a vitamin D cocrystal according to the first aspect of the invention or a pharmaceutical composition according to the second aspect of the invention in food, cosmetics, medicinal supplements or animal feed.

[0091] In some embodiments, the food is a general food or a health food (abbreviated as health food).

[0092] According to a sixth aspect, there is provided a method for treating vitamin D deficiency or calcium deficiency, the method comprising administering to a subject a therapeutically effective amount of a vitamin D cocrystal according to the first aspect of the invention or a pharmaceutical composition according to the third aspect of the invention.

[0093] In some embodiments, the vitamin D deficiency or calcium deficiency is chondropathy or chondropathy.

[0094] Terminology The term "substantially the same" as used herein means that a person skilled in the art would consider the detected image and the reference image to be identical within a range of variation recognized by a person skilled in the art. While the variation may be due to the detection equipment, operating conditions, or human factors, in the present invention, two X-ray diffraction spectra are considered to be substantially the same if the change in the characteristic peak positions between the two X-ray diffraction patterns is within ±2%. Specifically, two X-ray diffraction spectra are considered to be substantially the same if the change in the 2θ angle of the characteristic peaks between the two X-ray diffraction patterns is within ±0.2°.

[0095] The term "medicinal auxiliary materials" as used herein refers to excipients and additives used in the manufacture of pharmaceuticals and the formulation of prescriptions. While these medicinal auxiliary materials typically lack pharmaceutical activity, they possess a variety of useful properties, such as improving the stability, sterility, and bioavailability of pharmaceutical compositions and reducing the difficulty of formulation. Examples of medicinal auxiliary materials that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids, binders, disintegrants, antioxidants, solubilizers, seasonings, flavorings, preservatives, etc. Here, the sterile liquid may be water, such as pure water, buffer solutions, saline, etc., or oils, including petroleum-derived hydrocarbons, animal- or plant-derived fats or higher fatty acids, artificially synthesized liquid organic substances, etc. Those skilled in the art can select from conventional ingredients in the art, such as lactose, glucose, sucrose, sorbitol, mannitol, starch, gum, gum arabic, calcium phosphate, alginate, tracant gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methyl and propyl hydroxybenzoates, talc, magnesium stearate, polyethylene glycol, polyethylene glycol and mineral oil. The pharmaceutical compositions of the present invention can be formulated to provide quick, sustained or extended release of the active ingredient after administration to a patient by methods well known in the art.

[0096] The term "prevention" as used in the present invention refers to the ability to delay, reduce, avoid, or stop the appearance of a disease or disease-related symptoms before the administration of the relevant drug, and on the condition that the disease or disease-related symptoms do not appear. "Prevention" does not necessarily mean completely preventing the appearance of a disease or disease-related symptoms; for example, if the risk of a subject developing a particular disease or disease-related symptoms after administration of the relevant drug can be reduced, or if the severity of related symptoms that subsequently appear can be attenuated, then both can be considered to "prevent" the appearance or progression of the disease.

[0097] The term "treatment" as used herein refers to the ability to alleviate, reduce, improve, or eliminate the disease or disease-related symptoms targeted by the relevant drug after administration of the relevant drug. For example, a subject can be "treated" if they receive a therapeutically effective amount of a vitamin D eutectic or a pharmaceutical composition containing a vitamin D eutectic according to the methods of the present invention and one or more pathological parameters (or medical parameters) or disease-related symptoms of the subject show an observable and / or detectable increase, decrease, or improvement. Furthermore, it should be understood that treatment of a disease or disease-related symptoms includes not only complete treatment, but also those in which some biologically or medically relevant results are achieved, such as a pathological parameter (or medical parameter) moving toward a normal range, even though complete treatment is not achieved.

[0098] The term "subject" as used herein refers to an animal that has been the object of, or respectively the object of, treatment, observation or experiment, such as a human or non-human mammal (e.g., mouse, rat, guinea pig, rabbit, dog, pig, sheep, cow, etc.).

[0099] The term "therapeutically effective amount" as used herein refers to an amount of the vitamin D eutectic of the present invention or a pharmaceutical composition containing the vitamin D eutectic of the present invention sufficient to elicit the biological or medical response in a tissue system or patient desired by a researcher or clinician. A therapeutically effective amount generally varies depending on factors such as the vitamin D eutectic and its biological activity, the pharmaceutical composition used for administration, the time of administration, the route of administration, the rate of compound excretion, the duration of treatment, the type and severity of the disease state or disorder being treated, medications used in combination with or concomitantly with the vitamin D eutectic of the present invention, and the patient's age, weight, overall health, sex, and diet. Such a therapeutically effective amount can be determined by one of ordinary skill in the art based on their own knowledge, the state of the art, and the present disclosure. Generally, the vitamin D eutectic described in the present invention may be administered in a daily therapeutic dose of about 1 to 1,000 milligrams. [Effects of the Invention]

[0100] The beneficial effects of the above one or more technical solutions of the present invention are as follows:

[0101] The co-crystal of vitamin D2 or vitamin D3 with idebenone or vitamin K3 can significantly improve the light and heat stability of vitamin D2 or vitamin D3, effectively reducing production, storage, and transportation costs. It can also be prepared by room temperature grinding, which is simple to operate, easy to implement, low cost, and convenient for large-scale use in industrial pharmaceuticals. [Brief explanation of the drawings]

[0102] The specification drawings forming a part of this invention are used to provide a further understanding of the invention, and the exemplary embodiments of the invention and the description thereof are for the purpose of illustrating the invention and do not constitute an undue limitation on the invention. [Figure 1] FIG. 1 is an X-ray powder diffraction (PXRD) diagram of the vitamin D2-idebenone eutectic of Example 1. [Figure 2]FIG. 1 is a differential scanning calorimetry (DSC) diagram of the vitamin D2-idebenone eutectic of Example 1. [Figure 3] FIG. 1 is a thermogravimetric analysis (TG) diagram of the vitamin D2-idebenone eutectic of Example 1. [Figure 4] FIG. 1 is a nuclear magnetic resonance hydrogen spectrum ( 1 H-NMR) of the vitamin D2-idebenone eutectic of Example 1. [Figure 5] FIG. 1 is an X-ray powder diffraction (PXRD) diagram of the vitamin D3-idebenone eutectic of Example 6. [Figure 6] FIG. 1 is a differential scanning calorimetry (DSC) diagram of the vitamin D3-idebenone eutectic of Example 6. [Figure 7] FIG. 1 is a thermogravimetric analysis (TG) diagram of the vitamin D3-idebenone eutectic of Example 6. [Figure 8] FIG. 1 is a nuclear magnetic resonance hydrogen spectrum ( 1 H-NMR) of the vitamin D3-idebenone eutectic of Example 6. [Figure 9] FIG. 1 is an X-ray powder diffraction (PXRD) diagram of the vitamin D2-vitamin K3 co-crystal of Example 11. [Figure 10] FIG. 1 is a differential scanning calorimetry (DSC) diagram of the vitamin D2-vitamin K3 eutectic of Example 11. [Figure 11] FIG. 11 is a thermogravimetric analysis (TG) diagram of the vitamin D2-vitamin K3 eutectic of Example 11. [Figure 12] FIG. 1 is a nuclear magnetic resonance hydrogen spectrum ( 1 H-NMR) of the vitamin D2-vitamin K3 eutectic of Example 11. [Figure 13] FIG. 1 is an X-ray powder diffraction (PXRD) diagram of the vitamin D3-vitamin K3 co-crystal of Example 16. [Figure 14] FIG. 1 is a differential scanning calorimetry (DSC) diagram of the vitamin D3-vitamin K3 eutectic of Example 16. [Figure 15] FIG. 16 is a thermogravimetric analysis (TG) diagram of the vitamin D3-vitamin K3 eutectic of Example 16. [Figure 16] FIG. 1 is a nuclear magnetic resonance hydrogen spectrum ( 1 H-NMR) of the vitamin D3-vitamin K3 eutectic of Example 16. DETAILED DESCRIPTION OF THE INVENTION

[0103] In order to make those skilled in the art understand the technical solution of the present invention more clearly, the technical solution of the present invention will be described in detail below with reference to specific examples and comparative examples.

[0104] Detection devices and methods in the following examples: The X-ray powder diffraction (PXRD) was performed using a Bruker D8 Advance diffractometer with Cu Kα radiation at a voltage of 40 kilovolts and a current of 40 milliamperes. The peak positions were calibrated using a standard sample provided with the instrument before use. The acquisition software was Diffrac Plus XRD Commander, and the analysis software was MDI Jade 6.0. Samples were tested at room temperature, and samples requiring detection were placed on organic glass slides. Detailed detection conditions were as follows: 2θ angle range: 3–40°, step size: 0.02°, and speed: 0.1 s / step. Unless otherwise specified, samples were not ground prior to detection.

[0105] Differential scanning calorimetry (DSC) data were collected using a Mettler Toledo DSC1 differential scanning calorimeter. The instrument control software and analysis software were all provided by the manufacturer. The sample was heated from 30 to 350 °C at a rate of 10 °C / min, while the software recorded the thermal changes of the sample during the temperature increase.

[0106] Thermogravimetric analysis (TGA) data were collected using a Mettler Toledo DSC1 / TGA. The instrument control software and analysis software were all provided by the manufacturer. The sample was heated from 60 to 400°C at a heating rate of 10°C / min under the protection of 20 mL / min of dry nitrogen. The software simultaneously recorded the weight change of the sample during the temperature increase.

[0107] The nuclear magnetic resonance spectrum was measured using an AVANCE III HD 600 superconducting pulse Fourier transform nuclear magnetic resonance spectrometer manufactured by Bruck, Germany, at room temperature, with TMS as the internal standard and CDCl3 as the solvent.

[0108] Example 1 Using an analytical balance, 1.98 g of vitamin D2 and 1.69 g of idebenone were accurately weighed into a 50 mL grinding tank, 0.5 mL of absolute ethanol was added using a micropipette, and 40 g of grinding balls were placed inside. The grinding tank was placed in a planetary ball mill (BM6pro). The rotation speed was set to 500 rpm, and the grinding time was 5 minutes, with 3-minute intervals for five cycles. After the operation was completed, the grinding tank was removed, and the sample was scraped with a cleaning scraper to obtain a eutectic of vitamin D2 and idebenone. The molar ratio of vitamin D2 to idebenone in the eutectic was 1:1. The X-ray powder diffraction (PXRD) pattern is shown in Figure 1, the differential scanning calorimetry (DSC) pattern is shown in Figure 2, the thermogravimetry (TG) pattern is shown in Figure 3, and the nuclear magnetic resonance (NMR) spectrum ( 1 The H-NMR diagram is shown in Figure 4.

[0109] Figure 1 shows the PXRD spectrum of the eutectic of vitamin D2 and idebenone prepared and obtained in Example 1, as well as the PXRD spectrum of vitamin D2 and idebenone. The PXRD spectrum of the eutectic of vitamin D2 and idebenone prepared and obtained shows the following: 7.45±0.2°, 11.19±0.2°, 12.09±0.2°, 12.35±0.2°, 13.22±0.2°, 14.21±0.2°, 14.91±0.2°, 15.38±0.2°, 15.54±0.2°, 15.73±0.2°, 16.85±0.2°, 17.19±0.2°, 17.57±0.2°. A series of characteristic peaks appeared at 2°, 18.09±0.2°, 19.52±0.2°, 21.21±0.2°, 21.76±0.2°, 22.06±0.2°, 22.41±0.2°, 22.57±0.2°, 24.55±0.2°, 28.64±0.2°, 38.01±0.2°, and 44.22±0.2°, whose peak positions differed from those of vitamin D2 and idebenone. The PXRD spectrum peaks of the three curves changed significantly, indicating the formation of a new phase.

[0110] Figure 2 shows the DSC spectrum of the eutectic of vitamin D2 and idebenone prepared in Example 1, as well as the DSC spectrum of vitamin D2 and idebenone. In the figure, the melting points of the eutectic of vitamin D2 and idebenone are 95±2°C, 121±2°C, and 60±2°C, respectively. The melting points of the eutectic are different from those of the drug substance and precursor, proving the formation of a new phase.

[0111] Figure 3 shows the TGA spectrum of the eutectic of vitamin D2 and idebenone prepared in Example 1, as well as the TGA spectrum of vitamin D2 and idebenone. Under nitrogen atmosphere testing conditions, the thermogravimetric curve of the eutectic of vitamin D2 and idebenone shows a weight loss beginning at 140°C, with a 96% weight loss by 450°C. The thermogravimetric curve of the vitamin D2 drug substance shows a weight loss beginning at 100°C, with a 92% weight loss by 460°C. The formation of a new phase is also evident.

[0112] As shown in FIG. 4, the nuclear magnetic resonance hydrogen spectrum ( 1 The H-NMR diagram and the nuclear magnetic resonance hydrogen spectrum can prove that the molar ratio of vitamin D2 to idebenone in the eutectic is approximately 1:1.

[0113] Example 2 Using an analytical balance, 1.98 g of vitamin D2 and 1.69 g of idebenone were accurately weighed into a 50 mL grinding tank, 0.4 mL of anhydrous methanol was added using a micropipette, and 40 g of grinding balls were added. The grinding tank was placed in a planetary ball mill BM6pro, and the rotation speed was set to 600 rpm. The grinding time was 4 minutes, with 2-minute intervals between each cycle. After the operation was completed, the grinding tank was removed and the sample was scraped with a cleaning scraper to obtain a eutectic of vitamin D2 and idebenone.

[0114] Example 3 Using an analytical balance, 1.98 g of vitamin D2 and 1.69 g of idebenone were accurately weighed into a 50 mL grinding tank. 0.3 mL of anhydrous acetone was added using a micropipette, and 45 g of grinding balls were added. The grinding tank was placed in a planetary ball mill BM6pro, and the rotation speed was set to 450 rpm. The grinding time was 5 minutes, with 2-minute intervals between each cycle. After the operation was completed, the grinding tank was removed, and the sample was scraped with a cleaning scraper to obtain a eutectic of vitamin D2 and idebenone.

[0115] Example 4 Using an analytical balance, 1.98 g of vitamin D2 and 1.69 g of idebenone were accurately weighed into a 50 mL grinding tank, 0.4 mL of ethyl acetate was added using a micropipette, and 40 g of grinding balls were added. The grinding tank was placed in a planetary ball mill BM6pro, and the rotation speed was set to 500 rpm. The grinding time was 4 minutes, with 2-minute intervals for 5 cycles. After the operation was completed, the grinding tank was removed and the sample was scraped with a cleaning scraper to obtain a eutectic of vitamin D2 and idebenone.

[0116] Example 5 Using an analytical balance, 1.98 g of vitamin D2 and 1.69 g of idebenone were accurately weighed into a 50 mL grinding tank, 0.2 mL of anhydrous acetonitrile was added using a micropipette, and 45 g of grinding balls were added. The grinding tank was placed in a planetary ball mill BM6pro, and the rotation speed was set to 550 rpm. The grinding time was 4 minutes, with 2-minute intervals for 5 cycles. After the operation was completed, the grinding tank was removed and the sample was scraped with a cleaning scraper to obtain a eutectic of vitamin D2 and idebenone.

[0117] Example 6 Using an analytical balance, 1.92 g of vitamin D3 and 1.69 g of idebenone were accurately weighed into a 50 mL grinding tank, 0.5 mL of absolute ethanol was added using a micropipette, and 38 g of grinding balls were added. The grinding tank was placed in a planetary ball mill BM6pro, and the rotation speed was set to 500 rpm. The grinding time was 5 minutes, with 3-minute intervals for five cycles. After the operation was completed, the grinding tank was removed and the sample was scraped with a cleaning scraper to obtain a eutectic of vitamin D3 and idebenone. The molar ratio of vitamin D3 to idebenone in the eutectic was 1:1. Its X-ray powder diffraction (PXRD) pattern is shown in Figure 5, its differential scanning calorimetry (DSC) pattern is shown in Figure 6, its thermogravimetry (TG) pattern is shown in Figure 7, and its nuclear magnetic resonance (NMR) spectrum ( 1 The H-NMR diagram is shown in Figure 8.

[0118] As shown in FIG. 5, the PXRD spectrum of the eutectic of vitamin D3 and idebenone prepared and obtained in Example 6 is shown, which is the PXRD spectrum of vitamin D3 and the PXRD spectrum of idebenone. As can be seen from the PXRD spectrum of the prepared eutectic of vitamin D3 and idebenone, a series of characteristic peaks appear at 5.06±0.2°, 11.18±0.2°, 12.99±0.2°, 13.21±0.2°, 13.64±0.2°, 14.95±0.2°, 15.17±0.2°, 15.76±0.2°, 16.18±0.2°, 18.00±0.2°, 21.21±0.2°, 21.80±0.2°, 22.46±0.2°, 22.73±0.2°, 24.46±0.2°, 38.02±0.2°, and 44.22±0.2°, and the peak positions of these characteristic peaks differ from those of vitamin D3 and idebenone. The PXRD spectrum peaks of the three curves changed significantly, demonstrating the formation of a new phase.

[0119] Figure 6 shows the DSC spectrum of the eutectic of vitamin D3 and idebenone prepared in Example 6, as well as the DSC spectrum of vitamin D3 and idebenone. In the figure, the melting points of the eutectic of vitamin D3 and idebenone are 57±2°C, 92±2°C, and 60±2°C, respectively. The melting points of the eutectic are different from those of the drug substance and precursor, proving the formation of a new phase.

[0120] Figure 7 shows the TGA spectrum of the eutectic of vitamin D3 and idebenone prepared in Example 6, as well as the TGA spectrum of vitamin D3 and idebenone. Under nitrogen atmosphere testing conditions, the thermogravimetric curve of the eutectic of vitamin D3 and idebenone shows a weight loss beginning at 190°C, with a 99% weight loss by 460°C. The thermogravimetric curve of the vitamin D3 drug substance shows a weight loss beginning at 210°C, with a 97% weight loss by 320°C. The formation of a new phase is also evident.

[0121] As shown in FIG. 8, the nuclear magnetic resonance hydrogen spectrum ( 1 The H-NMR diagram shows that the molar ratio of vitamin D3 to idebenone in the eutectic is approximately 1:1.

[0122] Example 7 Using an analytical balance, 1.92 g of vitamin D3 and 1.69 g of idebenone were accurately weighed into a 50 mL grinding tank. 0.4 mL of anhydrous methanol was added using a micropipette, and 35 g of grinding balls were added. The grinding tank was placed in a planetary ball mill BM6pro, and the rotation speed was set to 600 rpm. The grinding time was 4 minutes, with 2-minute intervals between each cycle. After the operation was completed, the grinding tank was removed, and the sample was scraped with a cleaning scraper to obtain a eutectic of vitamin D3 and idebenone.

[0123] Example 8 Using an analytical balance, 1.92 g of vitamin D3 and 1.69 g of idebenone were accurately weighed into a 50 mL grinding tank, 0.3 mL of anhydrous acetone was added using a micropipette, and 42 g of grinding balls were added. The grinding tank was placed in a planetary ball mill BM6pro, and the rotation speed was set to 450 rpm. The grinding time was 4 minutes, with 2-minute intervals between each cycle. After the operation was completed, the grinding tank was removed and the sample was scraped with a cleaning scraper to obtain a eutectic of vitamin D3 and idebenone.

[0124] Example 9 Using an analytical balance, 1.92 g of vitamin D3 and 1.69 g of idebenone were accurately weighed into a 50 mL grinding tank, 0.4 mL of ethyl acetate was added using a micropipette, and 38 g of grinding balls were added. The grinding tank was placed in a planetary ball mill BM6pro, and the rotation speed was set to 500 rpm. The grinding time was 4 minutes, with 2-minute intervals for 5 cycles. After the operation was completed, the grinding tank was removed and the sample was scraped with a cleaning scraper to obtain a eutectic of vitamin D3 and idebenone.

[0125] Example 10 Using an analytical balance, 1.92 g of vitamin D3 and 1.69 g of idebenone were accurately weighed into a 50 mL grinding tank, 0.2 mL of anhydrous acetonitrile was added using a micropipette, and 45 g of grinding balls were added. The grinding tank was placed in a planetary ball mill BM6pro, and the rotation speed was set to 550 rpm. The grinding time was 4 minutes, with 2-minute intervals for 5 cycles. After the operation was completed, the grinding tank was removed and the sample was scraped with a cleaning scraper to obtain a eutectic of vitamin D3 and idebenone.

[0126] Example 11 Using an analytical balance, 1.98 g of vitamin D2 and 0.86 g of vitamin K3 were accurately weighed into a 50 mL grinding tank, 0.5 mL of absolute ethanol was added using a micropipette, and 30 g of grinding balls were added. The grinding tank was placed in a planetary ball mill BM6pro, and the rotation speed was set to 500 rpm. The grinding time was 5 minutes, with 3-minute intervals for 5 cycles. After the operation was completed, the grinding tank was removed and the sample was scraped with a cleaning scraper to obtain a eutectic of vitamin D2 and vitamin K3. The molar ratio of vitamin D2 to vitamin K3 in the eutectic was 1:1. The X-ray powder diffraction (PXRD) pattern is shown in Figure 9, the differential scanning calorimetry (DSC) pattern is shown in Figure 10, the thermogravimetry (TG) pattern is shown in Figure 11, and the nuclear magnetic resonance (NMR) spectrum ( 1 The H-NMR diagram is shown in Figure 12.

[0127] 9 shows the PXRD spectrum of the eutectic of vitamin D2 and vitamin K3 prepared and obtained in Example 11, which is the PXRD spectrum of vitamin D2 and the PXRD spectrum of vitamin K3. As can be seen from the PXRD spectrum of the eutectic of vitamin D2 and vitamin K3 prepared and obtained, the peaks are 5.08±0.2°, 9.12±0.2°, 10.13±0.2°, 11.76±0.2°, 12.41±0.2°, 12.90±0.2°, 13.43±0.2°, 14.27±0.2°, 15.47±0.2°, 15.76±0.2°, 16.47±0.2°, 16.92±0.2°, 17.27±0.2°. A series of characteristic peaks appeared at 17.65±0.2°, 18.15±0.2°, 19.01±0.2°, 21.76±0.2°, 23.55±0.2°, 24.04±0.2°, 25.76±0.2°, 27.10±0.2°, 27.45±0.2°, 38.00±0.2°, and 44.20±0.2°, which differed in peak position from those of vitamin D2 and vitamin K3. The PXRD spectrum peaks of the three curves changed significantly, indicating the formation of a new phase.

[0128] Figure 10 shows the DSC spectrum of the eutectic of vitamin D2 and vitamin K3 prepared in Example 11, as well as the DSC spectrum of vitamin D2 and vitamin K3. In the figure, the melting points of the eutectic of vitamin D2 and vitamin K3 are 77±2°C, 121±2°C, and 113±2°C, respectively. The melting points of the eutectic are different from those of the drug substance and precursor, proving that a new phase is formed.

[0129] Figure 11 shows the TGA spectra of the eutectic of vitamin D2 and vitamin K3 prepared in Example 11, as well as the TGA spectrum of vitamin D2 and vitamin K3. Under nitrogen atmosphere testing conditions, the thermogravimetric curve of the eutectic of vitamin D2 and vitamin K3 shows a weight loss beginning at 100°C, with a 99% weight loss by 450°C. The thermogravimetric curve of the vitamin D2 drug substance shows a weight loss beginning at 100°C, with a 92% weight loss by 460°C. The formation of a new phase is also evident.

[0130] As shown in FIG. 12, the nuclear magnetic resonance hydrogen spectrum ( 1 The H-NMR diagram shows that the molar ratio of vitamin D2 to vitamin K3 in the eutectic is approximately 1:1.

[0131] Example 12 Using an analytical balance, 1.98 g of vitamin D2 and 0.86 g of vitamin K3 were accurately weighed into a 50 mL grinding tank. 0.4 mL of anhydrous methanol was added using a micropipette, and 30 g of grinding balls were added. The grinding tank was placed in a BM6pro planetary ball mill, and the rotation speed was set to 600 rpm. The grinding time was 4 minutes, with 2-minute intervals between each cycle. After the operation was completed, the grinding tank was removed, and the sample was scraped with a cleaning scraper to obtain a eutectic of vitamin D2 and vitamin K3.

[0132] Example 13 Using an analytical balance, 1.98 g of vitamin D2 and 0.86 g of vitamin K3 were accurately weighed into a 50 mL grinding tank. 0.3 mL of anhydrous acetone was added using a micropipette, and 35 g of grinding balls were added. The grinding tank was placed in a BM6pro planetary ball mill, and the rotation speed was set to 450 rpm. The grinding time was 5 minutes, with 2-minute intervals between each cycle. After the operation was completed, the grinding tank was removed, and the sample was scraped with a cleaning scraper to obtain a eutectic of vitamin D2 and vitamin K3.

[0133] Example 14 Using an analytical balance, 1.98 g of vitamin D2 and 0.86 g of vitamin K3 were accurately weighed into a 50 mL grinding tank. 0.4 mL of ethyl acetate was added using a micropipette, and 30 g of grinding balls were added. The grinding tank was placed in a BM6pro planetary ball mill, and the rotation speed was set to 500 rpm. The grinding time was 4 minutes, with 2-minute intervals between each cycle. After the operation was completed, the grinding tank was removed, and the sample was scraped with a cleaning scraper to obtain a eutectic of vitamin D2 and vitamin K3.

[0134] Example 15 Using an analytical balance, 1.98 g of vitamin D2 and 0.86 g of vitamin K3 were accurately weighed into a 50 mL grinding tank. 0.2 mL of anhydrous acetonitrile was added using a micropipette, and 35 g of grinding balls were added. The grinding tank was placed in a planetary ball mill BM6pro, and the rotation speed was set to 550 rpm. The grinding time was 4 minutes, with 2-minute intervals between each cycle. After the operation was completed, the grinding tank was removed, and the sample was scraped with a cleaning scraper to obtain a eutectic of vitamin D2 and vitamin K3.

[0135] Example 16 Using an analytical balance, 1.92 g of vitamin D3 and 0.86 g of vitamin K3 were accurately weighed into a 50 mL grinding tank, 0.5 mL of absolute ethanol was added using a micropipette, and 28 g of grinding balls were added. The grinding tank was placed in a planetary ball mill BM6pro, and the rotation speed was set to 500 rpm. The grinding time was 5 minutes, with 3-minute intervals for 5 cycles. After the operation was completed, the grinding tank was removed and the sample was scraped with a cleaning scraper to obtain a eutectic of vitamin D3 and vitamin K3. The molar ratio of vitamin D3 to vitamin K3 in the eutectic was 1:1. The X-ray powder diffraction (PXRD) pattern is shown in Figure 13, the differential scanning calorimetry (DSC) pattern is shown in Figure 14, the thermogravimetry (TG) pattern is shown in Figure 15, and the nuclear magnetic resonance (NMR) spectrum ( 1 The H-NMR diagram is shown in Figure 16.

[0136] FIG. 13 shows the PXRD spectrum of the eutectic of vitamin D3 and vitamin K3 prepared and obtained in Example 16, which is the PXRD spectrum of vitamin D3 and the PXRD spectrum of vitamin K3. As can be seen from the PXRD spectrum of the prepared vitamin D3 and vitamin K3 eutectic, a series of characteristic peaks appear at 5.08±0.2°, 11.70±0.2°, 13.02±0.2°, 13.71±0.2°, 15.18±0.2°, 15.48±0.2°, 16.19±0.2°, 18.02±0.2°, 27.03±0.2°, 21.78±0.2°, 23.56±0.2°, 23.97±0.2°, 25.70±0.2°, 27.03±0.2°, 38.01±0.2°, and 44.19±0.2°, and the peak positions of these characteristic peaks differ from those of vitamin D3 and vitamin K3. The PXRD spectrum peaks of the three curves changed significantly, demonstrating the formation of a new phase.

[0137] 14 shows the DSC spectrum of the eutectic of vitamin D3 and vitamin K3 prepared in Example 2, as well as the DSC spectrum of vitamin D3 and vitamin K3. In the figure, the melting points of the eutectic of vitamin D3 and vitamin K3 are 58±2°C, 92±2°C, and 113±2°C, respectively. The melting points of the eutectic are different from the melting points of the drug substance and precursor, proving that a new phase is formed.

[0138] Figure 15 shows the TGA spectrum of the eutectic of vitamin D3 and vitamin K3 prepared in Example 16, as well as the TGA spectrum of vitamin D3 and vitamin K3. Under nitrogen atmosphere testing conditions, the thermogravimetric curve of the eutectic of vitamin D3 and vitamin K3 shows a weight loss beginning at 100°C, with a 99% weight loss by 440°C. The thermogravimetric curve of the vitamin D3 drug substance shows a weight loss beginning at 210°C, with a 97% weight loss by 320°C. The formation of a new phase is also evident.

[0139] As shown in FIG. 16, the nuclear magnetic resonance hydrogen spectrum ( 1 The H-NMR diagram shows that the molar ratio of vitamin D3 to vitamin K3 in the eutectic is approximately 1:1.

[0140] Example 17 Using an analytical balance, 1.92 g of vitamin D3 and 0.86 g of vitamin K3 were accurately weighed into a 50 mL grinding tank. 0.4 mL of anhydrous methanol was added using a micropipette, and 25 g of grinding balls were added. The grinding tank was placed in a BM6pro planetary ball mill, and the rotation speed was set to 600 rpm. The grinding time was 4 minutes, with 2-minute intervals between each cycle. After the operation was completed, the grinding tank was removed, and the sample was scraped with a cleaning scraper to obtain a eutectic of vitamin D3 and vitamin K3.

[0141] Example 18 Using an analytical balance, 1.92 g of vitamin D3 and 0.86 g of vitamin K3 were accurately weighed into a 50 mL grinding tank. 0.3 mL of anhydrous acetone was added using a micropipette, and 32 g of grinding balls were added. The grinding tank was placed in a BM6pro planetary ball mill, and the rotation speed was set to 450 rpm. The grinding time was 4 minutes, with 2-minute intervals between each cycle. After the operation was completed, the grinding tank was removed, and the sample was scraped with a cleaning scraper to obtain a eutectic of vitamin D3 and vitamin K3.

[0142] Example 19 Using an analytical balance, 1.92 g of vitamin D3 and 0.86 g of vitamin K3 were accurately weighed into a 50 mL grinding tank. 0.4 mL of ethyl acetate was added using a micropipette, and 28 g of grinding balls were added. The grinding tank was placed in a BM6pro planetary ball mill, and the rotation speed was set to 500 rpm. The grinding time was 5 minutes, with 2-minute intervals between each cycle. After the operation was completed, the grinding tank was removed, and the sample was scraped with a cleaning scraper to obtain a eutectic of vitamin D3 and vitamin K3.

[0143] Example 20 Using an analytical balance, 1.92 g of vitamin D3 and 0.86 g of vitamin K3 were accurately weighed into a 50 mL grinding tank. 0.2 mL of anhydrous acetonitrile was added using a micropipette, and 35 g of grinding balls were added. The grinding tank was placed in a BM6pro planetary ball mill, and the rotation speed was set to 550 rpm. The grinding time was 5 minutes, with 2-minute intervals between each cycle. After the operation was completed, the grinding tank was removed, and the sample was scraped with a cleaning scraper to obtain a eutectic of vitamin D3 and vitamin K3.

[0144] The stability of the eutectics prepared in Examples 1, 6, 11, and 16 was examined, specifically as follows.

[0145] The vitamin D2 and idebenone eutectic and vitamin D2 drug substance prepared in Example 1 were left under light (4500LX±500LX) conditions for 5 days and 10 days, left under high temperature (60°C) conditions for 100 days, and left under accelerated conditions (40°C±2°C / RH75±5%) for 1 month, and their stability was examined. The results are shown in Table 1. [Table 1]

[0146] As can be seen from the test results, after vitamin D2 and idebenone were co-crystallized, the decomposition of vitamin D2 could be effectively alleviated, and the accelerated stability was obviously improved.

[0147] The vitamin D3 and idebenone eutectic and vitamin D3 bulk prepared in Example 6 were left under light (4500LX±500LX) conditions for 5 days and 10 days, and then left under high temperature (60°C) conditions for 100 days, and then left under accelerated conditions (40°C±2°C / RH75±5%) for 1 month to examine their stability. The results are shown in Table 2. [Table 2]

[0148] As can be seen from the test results, after vitamin D3 and idebenone were co-crystallized, the decomposition of vitamin D3 could be effectively alleviated, and the accelerated stability was obviously improved.

[0149] The vitamin D2 and vitamin K3 eutectic and vitamin D2 bulk prepared in Example 11 were left under light (4500LX±500LX) conditions for 5 days, 10 days, high temperature (60°C) conditions for 10 days, and accelerated conditions (40°C±2°C / RH75±5%) for 1 month to examine their stability. The results are shown in Table 3. [Table 3]

[0150] As can be seen from the test results, after vitamin D2 and vitamin K3 were co-crystallized, the decomposition of vitamin D2 could be effectively alleviated, and the accelerated stability was obviously improved.

[0151] The vitamin D3 and vitamin K3 eutectic and vitamin D3 bulk prepared in Example 16 were left under light (4500LX±500LX) conditions for 5 days, 10 days, and 10 days under high temperature (60°C) conditions, and then left under accelerated conditions (40°C±2°C / RH75±5%) for 1 month to examine their stability. The results are shown in Table 4. [Table 4]

[0152] As can be seen from the test results, after vitamin D3 and vitamin K3 co-crystallized, the decomposition of vitamin D3 can be effectively alleviated, and no obvious improvement in stability was observed under other conditions.

[0153] Comparative Example 1 Using an analytical balance, 1.98 g of vitamin D2 and 1.44 g of shikonin were accurately weighed into a 50 mL grinding tank. 0.2 mL of absolute ethanol was added using a micropipette, and 35 g of grinding balls were added. The grinding tank was placed in a planetary ball mill BM6pro, and the rotation speed was set to 500 rpm. The grinding time was 5 minutes, with 2-minute intervals between each cycle. After the operation was completed, the grinding tank was removed and the sample was scraped using a cleaning scraper. DSC characterization showed that no eutectic was formed between vitamin D2 and shikonin.

[0154] Comparative Example 2 Using an analytical balance, 1.92 g of vitamin D3 and 0.71 g of 2-chloro-p-benzoquinone were accurately weighed into a 50 mL grinding tank. 0.2 mL of absolute ethanol was added using a micropipette, and 35 g of grinding balls were added. The grinding tank was placed in a BM6pro planetary ball mill, and the rotation speed was set to 500 rpm. The grinding time was 3 minutes, with 2-minute intervals between each cycle. After the run, the grinding tank was removed and the sample was scraped using a cleaning scraper. DSC characterization showed no eutectic formation between vitamin D3 and 2-chloro-p-benzoquinone.

[0155] The above description is only a preferred embodiment of the present invention, and is not used to limit the present invention, and those skilled in the art can make various modifications and variations to the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention should be included within the protection scope of the present invention.

Claims

1. A vitamin D eutectic consisting of vitamin D and a eutectic ligand, The vitamin D is vitamin D ２ or vitamin D ３ and The eutectic ligand is idebenone or vitamin K ３ A vitamin D eutectic characterized by:

2. The vitamin D eutectic described in claim 1, characterized in that the molar ratio of the vitamin D to the eutectic ligand is 1:0.9 to 1.

1.

3. The vitamin D is vitamin D2, the eutectic ligand is idebenone, 2. The vitamin D eutectic according to claim 1, characterized in that the X-ray powder diffraction spectrum, measured using Cu-Kα radiation and expressed as a diffraction angle 2θ, has peaks at 11.19±0.2°, 16.85±0.2°, 17.19±0.2°, 21.76±0.2°, 22.41±0.2°, 22.57±0.2°, and 24.55±0.2°.

4. The vitamin D eutectic of claim 3, further characterized by having a melting peak at 89±2°C in a differential scanning calorimetry chart.

5. The vitamin D is vitamin D3, the eutectic ligand is idebenone, 2. The vitamin D eutectic according to claim 1, characterized in that the X-ray powder diffraction spectrum, measured using Cu-Kα radiation and expressed as a diffraction angle 2θ, has peaks at 11.18±0.2°, 15.76±0.2°, 18.00±0.2°, 21.80±0.2°, and 22.46±0.2°.

6. The vitamin D eutectic of claim 5, further characterized by having a melting peak at 50±2°C in a differential scanning calorimetry chart.

7. The vitamin D is vitamin D2, the eutectic ligand is vitamin K3; 2. The vitamin D eutectic according to claim 1, characterized in that the X-ray powder diffraction spectrum, measured using Cu-Kα radiation and expressed as a diffraction angle 2θ, has peaks at 11.76±0.2°, 12.41±0.2°, 16.92±0.2°, 17.27±0.2°, 18.15±0.2°, 25.76±0.2°, and 27.10±0.2°.

8. The vitamin D eutectic of claim 7, further characterized by having a melting peak at 69±2°C in a differential scanning calorimetry chart.

9. The vitamin D is vitamin D3, the eutectic ligand is vitamin K3; 2. The vitamin D eutectic according to claim 1, characterized in that the X-ray powder diffraction spectrum, expressed as a diffraction angle 2θ measured using Cu-Kα radiation, has peaks at 11.70±0.2°, 16.19±0.2°, 18.02±0.2°, and 27.03±0.2°.

10. The vitamin D eutectic of claim 9, further characterized by having a melting peak at 52±2°C in a differential scanning calorimetry chart.

11. A pharmaceutical composition comprising the vitamin D eutectic according to any one of claims 1 to 10 and a medicinal auxiliary material.

12. A method for preparing a vitamin D eutectic described in any one of claims 1 to 10, characterized in that it includes a step of forming a eutectic by adding an organic solvent to the vitamin D and the eutectic ligand and grinding them.

13. The method of claim 12, wherein the organic solvent is one or more selected from the group consisting of ethanol, methanol, isopropanol, tetrahydrofuran, acetone, and acetonitrile.

14. The preparation method described in Claim 12, characterized in that the mass of the grinding balls used for grinding is 2 to 10 times the total mass of vitamin D and the eutectic ligand.

15. The preparation method described in Claim 12, characterized in that the process comprises grinding for 1 to 5 minutes followed by a rest period of 1 to 5 minutes, and this process is carried out 1 to 5 times.

16. Use of the vitamin D cocrystal according to any one of claims 1 to 10 in the manufacture of a pharmaceutical composition for preventing or treating vitamin D deficiency or calcium deficiency.

17. 17. The use according to claim 16, wherein the pharmaceutical composition is used for preventing or treating rickets or chondropathy.

18. A food, cosmetic, or feed containing the vitamin D eutectic described in any one of claims 1 to 10.

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