WO2022188732A1 - 一种辅酶qh与烟酰胺的共晶及其制备方法和用途 - Google Patents

一种辅酶qh与烟酰胺的共晶及其制备方法和用途 Download PDF

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WO2022188732A1
WO2022188732A1 PCT/CN2022/079488 CN2022079488W WO2022188732A1 WO 2022188732 A1 WO2022188732 A1 WO 2022188732A1 CN 2022079488 W CN2022079488 W CN 2022079488W WO 2022188732 A1 WO2022188732 A1 WO 2022188732A1
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coenzyme
nicotinamide
crystal
composition
differential scanning
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PCT/CN2022/079488
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English (en)
French (fr)
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梅雪锋
张奇
鲍俊杰
陆鹂烨
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中国科学院上海药物研究所
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Priority to JP2023555295A priority Critical patent/JP2024509929A/ja
Priority to EP22766256.6A priority patent/EP4306507A1/en
Priority to US18/281,091 priority patent/US20240140897A1/en
Publication of WO2022188732A1 publication Critical patent/WO2022188732A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C50/00—Quinones
    • C07C50/26—Quinones containing groups having oxygen atoms singly bound to carbon atoms
    • C07C50/28—Quinones containing groups having oxygen atoms singly bound to carbon atoms with monocyclic quinoid structure
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C46/00—Preparation of quinones
    • C07C46/10—Separation; Purification; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to the technical field of coenzyme Q10, in particular, to a co-crystal of coenzyme QH and nicotinamide and a preparation method thereof.
  • the co-crystal Compared with the existing coenzyme QH, the co-crystal has a higher melting point and better stability.
  • the preparation method of the coenzyme QH co-crystal is simple, easy to control and has good reproducibility.
  • the invention greatly improves the convenience of use of the coenzyme QH, saves the cost during storage, transportation and use, and broadens the application range of the coenzyme QH.
  • Coenzyme Q10 is the only coenzyme Q substance in the human body, and it is a fat-soluble compound that exists widely in living organisms. It is a coenzyme in the respiratory chain that is not tightly bound to proteins, and plays an important role in proton translocation and electron transfer in the human respiratory chain. Coenzyme Q10, as an activator of cell metabolism and cellular respiration, is also an important antioxidant and non-specific immune enhancer. It can inhibit mitochondrial peroxidation, promote oxidative phosphorylation, and protect the structural integrity of biofilms. In addition, coenzyme Q10 has an enhanced effect on immune non-specificity, which can enhance the ability of antibody production and improve T cell function.
  • Coenzyme Q10 is essentially a metabolic activator, which can activate cellular respiration, accelerate the production of adenosine triphosphate, and play a role in detoxification and first aid; it can also change the hypoxic state of cells and tissues, and can affect the liver, brain, heart and nervous system. It has better protection and improvement effects, and enhances the non-specific immune response in the body.
  • coenzyme Q10 has been widely used in food, health products, cosmetics and pharmaceutical industries, and is favored by scholars and consumers.
  • Coenzyme Q10 exists in two forms: oxidized and reduced. Generally, in the human body, 40 to 90% of coenzyme Q10 exists in a reduced form. Reduced coenzyme Q10 is commonly referred to as coenzyme QH. Compared with oxidized coenzyme Q10, coenzyme QH has better antioxidant properties and more efficient absorption. However, coenzyme QH is easily oxidized in air and has poor stability, which limits its further application and development. To improve the stability of coenzyme QH, scientists have used various methods, such as adding antioxidants, preparing new crystal forms, and co-crystallization.
  • CN102381948A and CN101318889A disclose methods of adding ascorbic acid and derivatives thereof to stabilize coenzyme QH.
  • the inventors ground coenzyme QH with 10% by mass of ascorbic acid or a derivative thereof, and placed it in the air at 25° C. for 4 days, and about 13% of coenzyme QH was oxidized.
  • CN103635452A prepared a stable crystal form of coenzyme QH, but it will still be oxidized when placed in the air for a long time.
  • the inventors placed the crystal form in the air at 25° C. for 28 days, and still about 6% of the coenzyme QH was oxidized.
  • WO2019162429A discloses seven co-crystals of coenzyme QH, wherein the co-crystals of coenzyme QH with 3,4-dihydroxybenzoic acid and 3,5-dihydroxybenzoic acid have good stability.
  • these two ligands should not be used in large quantities in food, and the preparation method of the co-crystal is complicated, requiring stirring in a solvent for more than 3 days.
  • the present invention attempts to form co-crystals with coenzyme QH with various compounds through a large number of experiments. It was found that by adding edible nicotinamide (one of the forms of vitamin B3) as a ligand, stable co-crystals can be formed, thereby changing the intermolecular interactions and spatial arrangement of coenzyme QH molecules from the molecular level, enhancing the The stability of the coenzyme QH molecule to oxygen increases its melting point, thereby improving its chemical stability and broadening its application fields, while other similar compounds such as: niacin (one of the forms of vitamin B3), riboflavin (vitamin B2) , calcium pantothenate (vitamin B5), folic acid (vitamin B9), and ascorbic acid (vitamin C), etc., cannot increase the melting point of coenzyme QH by forming co-crystals with coenzyme QH, thereby improving its stability. Therefore, the following edible nicotinamide (one of the forms of
  • Co-enzyme QH co-crystals with more excellent stability can further broaden the application range of coenzyme QH. Therefore, the co-crystal of coenzyme QH and nicotinamide described in the present invention has strong practical application value.
  • One of the objectives of the present invention is to provide a co-crystal of coenzyme QH and nicotinamide.
  • Another object of the present invention is to provide a method for preparing the co-crystal of the coenzyme QH and nicotinamide.
  • the third object of the present invention is to provide a product comprising the above-mentioned co-crystal of coenzyme QH and nicotinamide, and the product is selected from health care products, food, cosmetics, medicines, pharmaceutical excipients and feedstuffs.
  • the fourth object of the present invention is to provide a use of the above-mentioned co-crystal of coenzyme QH and nicotinamide in preparing a product selected from health care products, food, cosmetics, medicines, pharmaceutical excipients and feeds.
  • One aspect of the present invention provides a co-crystal of coenzyme QH and nicotinamide, wherein the stoichiometric ratio of coenzyme QH and nicotinamide in the co-crystal is 1:1.
  • the X-ray powder diffraction patterns of the co-crystal of coenzyme QH and nicotinamide at 2 ⁇ angles are 4.3° ⁇ 0.2°, 5.7° ⁇ 0.2°, 17.1° ⁇ 0.2°, 17.9° ⁇ 0.2°, 18.9° ⁇ 0.2° , 19.8° ⁇ 0.2°, 20.8° ⁇ 0.2°, 23.1° ⁇ 0.2° have characteristic peaks; especially at 2 ⁇ angles of about 8.4° ⁇ 0.2°, 9.9° ⁇ 0.2°, 18.6° ⁇ 0.2°, 19.1 There are characteristic peaks at ° ⁇ 0.2°, 27.8° ⁇ 0.2°, and 30.3° ⁇ 0.2°. More particularly, the co-crystal of coenzyme QH and nicotinamide has an X-ray powder diffraction pattern substantially as shown in FIG. 1 .
  • the co-crystal of the coenzyme QH and nicotinamide was measured by differential scanning calorimetry, and when the temperature was increased at a rate of 10°C/min, the differential scanning calorimetry analysis spectrum was about 57 ⁇ 2°C. Characteristic endothermic peak; preferably, having a differential scanning calorimetry pattern substantially as shown in FIG. 2 .
  • the infrared spectrum of the co-crystal of coenzyme QH and nicotinamide has characteristic peaks at about 3465 cm -1 , 3170 cm -1 , and 1697 cm -1 ; especially at about 2964 cm -1 , 2945 cm -1 , 2907 cm -1 1 , 2847cm -1 , 1664cm -1 , 1607cm -1 , 1445cm -1 , 1422cm -1 , 1384cm -1 , 1280cm -1 , 1261cm -1 , 1197cm -1 , 1164cm -1 , 1149cm -1 , 1109cm -1 , There are characteristic peaks at 1009cm -1 , 907cm -1 , 877cm -1 , 795cm -1 , 751cm -1 , 599cm -1 , and 475cm -1 ; preferably, it has an infrared spectrum substantially as
  • the present invention provides a method for preparing the coenzyme QH co-crystal, which is one of the following methods:
  • Method 1 recrystallize coenzyme QH and nicotinamide in a solvent, and precipitate and dry to obtain a co-crystal of coenzyme QH and nicotinamide;
  • Method 2 ball-milling coenzyme QH and nicotinamide in a solvent for more than 10 minutes, and then drying the obtained solid to obtain a co-crystal of coenzyme QH and nicotinamide.
  • the solvent is selected from a solvent that has a certain solubility for the raw material and does not cause deterioration of the raw material.
  • the solvent is one or more selected from water, alcohols, ketones, esters, alkanes, aromatic hydrocarbons and halogenated alkanes; One or more of propanol, ethyl acetate, isopropyl acetate, acetone, methyl tert-butyl ether, n-hexane, n-heptane.
  • the preparation method involved in the invention has simple operation, easy control of the crystallization process, high crystallinity and good reproducibility, and can stably obtain the co-crystal of coenzyme QH and nicotinamide.
  • the present invention provides a coenzyme QH composition comprising the co-crystal of the above-mentioned coenzyme QH and nicotinamide.
  • the coenzyme QH composition may also contain excess nicotinamide, excess coenzyme QH, and other adjuvants. That is to say, in the raw material of the coenzyme QH composition, the molar ratio of coenzyme QH and nicotinamide is not particularly limited, as long as the raw material of the coenzyme QH composition can prepare the co-crystal of coenzyme QH and nicotinamide.
  • the stoichiometric ratio of coenzyme QH to nicotinamide in the coenzyme QH composition may be 2:1 to 1:2, wherein a part of the components exists in the form of co-crystals of coenzyme QH and nicotinamide, while another part of the components exists in the form of co-crystals of coenzyme QH and nicotinamide. exists in free form. It is preferable to form all co-crystals of coenzyme QH to overcome the defects of low melting point and poor stability of coenzyme QH.
  • excipients are not particularly limited and can be changed according to the application purpose, for example, when applied to medicines, they can be pharmaceutically acceptable excipients; when applied to health products, they can be acceptable excipients in health products; When used in food, it can be a food acceptable auxiliary material; when used in cosmetics, it can be a cosmetically acceptable auxiliary material; when used in feed, it can be a feed acceptable auxiliary material.
  • the stoichiometric ratio of coenzyme QH to nicotinamide in the coenzyme QH composition is 2:1.
  • the X-ray powder diffraction pattern of the coenzyme QH composition with the coenzyme QH and nicotinamide stoichiometric ratio of 2:1 is about 4.3° ⁇ 0.2°, 5.7° ⁇ 0.2°, 8.4° ⁇ 0.2° at the 2 ⁇ angle, 9.9° ⁇ 0.2°, 17.1° ⁇ 0.2°, 17.9° ⁇ 0.2°, 18.6° ⁇ 0.2°, 18.9° ⁇ 0.2°, 19.1° ⁇ 0.2°, 19.8° ⁇ 0.2°, 20.8° ⁇ 0.2°, 27.8° There are characteristic peaks at ⁇ 0.2° and 30.3° ⁇ 0.2°.
  • the coenzyme QH composition having a 2:1 stoichiometric ratio of coenzyme QH to nicotinamide has an X-ray powder diffraction pattern substantially as shown in FIG. 4 .
  • the coenzyme QH composition with the coenzyme QH and nicotinamide stoichiometric ratio of 2:1 was determined by differential scanning calorimetry. There is a characteristic endothermic peak at 57 ⁇ 2°C; preferably, a differential scanning calorimetry pattern substantially as shown in FIG. 5 .
  • the infrared spectrum of the coenzyme QH composition with the coenzyme QH and nicotinamide stoichiometric ratio of 2:1 is at about 3465 cm -1 , 3195 cm -1 , 2964 cm -1 , 2945 cm -1 , 2909 cm -1 , 2848 cm -1 , 1696 cm - 1 , 1664cm -1 , 1607cm -1 , 1445cm -1 , 1427cm -1 , 1384cm -1 , 1280cm -1 , 1261cm -1 , 1197cm -1 , 1164cm -1 , 1149cm -1 , 1109cm -1 , 1009cm -1 , There are characteristic peaks at 907 cm -1 , 877 cm -1 , 795 cm -1 , 751 cm -1 , 599 cm -1 , and 475 cm -1 ; preferably, it has an infrared spectrum substantially as shown in FIG
  • the stoichiometric ratio of coenzyme QH to nicotinamide in the coenzyme QH composition is 1:1.5.
  • the X-ray powder diffraction pattern of the coenzyme QH composition with the coenzyme QH and nicotinamide stoichiometric ratio of 1:1.5 is about 4.3° ⁇ 0.2°, 5.7° ⁇ 0.2°, 8.4° ⁇ 0.2° at 2 ⁇ angles, 9.9° ⁇ 0.2°, 17.1° ⁇ 0.2°, 17.9° ⁇ 0.2°, 18.6° ⁇ 0.2°, 18.9° ⁇ 0.2°, 19.1° ⁇ 0.2°, 19.8° ⁇ 0.2°, 20.8° ⁇ 0.2°, 27.8° There are characteristic peaks at ⁇ 0.2° and 30.3° ⁇ 0.2°.
  • the coenzyme QH composition having a 1:1.5 stoichiometric ratio of coenzyme QH to nicotinamide has an X-ray powder diffraction pattern substantially as shown in FIG. 7 .
  • the coenzyme QH composition with the coenzyme QH to nicotinamide stoichiometric ratio of 1:1.5 was determined by differential scanning calorimetry, and when the temperature was increased at a rate of 10°C/min, its differential scanning calorimetry analysis spectrum was about There is a characteristic endothermic peak at 57 ⁇ 2°C; preferably, a differential scanning calorimetry pattern substantially as shown in FIG. 8 .
  • the infrared spectrum of the coenzyme QH composition with the coenzyme QH and nicotinamide stoichiometric ratio of 1:1.5 is at about 3465cm -1 , 3367cm -1 , 3167cm -1 , 2944cm -1 , 2909cm -1 , 2845cm -1 , 1697cm - 1 , 1681cm -1 , 1619cm -1 , 1445cm -1 , 1422cm -1 , 1384cm -1 , 1280cm -1 , 1261cm -1 , 1197cm -1 , 1164cm -1 , 1149cm -1 , 1109cm -1 , 1009cm -1 , There are characteristic peaks at 907 cm -1 , 877 cm -1 , 795 cm -1 , 751 cm -1 , 599 cm -1 , and 475 cm -1 ; preferably, it has an in
  • the stoichiometric ratio of coenzyme QH to nicotinamide in the coenzyme QH composition is 1:2.
  • the X-ray powder diffraction pattern of the coenzyme QH composition whose stoichiometric ratio of coenzyme QH and nicotinamide is 1:2 is about 4.3° ⁇ 0.2°, 5.7° ⁇ 0.2°, 8.4° ⁇ 0.2° at 2 ⁇ angles, 9.9° ⁇ 0.2°, 14.8° ⁇ 0.2°, 17.1° ⁇ 0.2°, 17.9° ⁇ 0.2°, 18.6° ⁇ 0.2°, 18.9° ⁇ 0.2°, 19.1° ⁇ 0.2°, 19.8° ⁇ 0.2°, 20.8°
  • the coenzyme QH composition having a 1:2 stoichiometric ratio of coenzyme QH to nicotinamide had an X-ray powder diffraction pattern substantially as shown in FIG. 10 .
  • the coenzyme QH composition with the coenzyme QH and nicotinamide stoichiometric ratio of 1:2 was determined by differential scanning calorimetry. There is a characteristic endothermic peak at 57 ⁇ 2°C; preferably, a differential scanning calorimetry analysis pattern substantially as shown in FIG. 11 .
  • the infrared spectrum of the coenzyme QH composition with the coenzyme QH and nicotinamide stoichiometric ratio of 1:2 is at about 3465cm -1 , 3367cm -1 , 3167cm -1 , 2944cm -1 , 2909cm -1 , 2845cm -1 , 1697cm - 1 , 1681cm -1 , 1619cm -1 , 1445cm -1 , 1422cm -1 , 1384cm -1 , 1280cm -1 , 1261cm -1 , 1197cm -1 , 1164cm -1 , 1149cm -1 , 1109cm -1 , 1009cm -1 , There are characteristic peaks at 907 cm -1 , 877 cm -1 , 795 cm -1 , 751 cm -1 , 599 cm -1 , and 475 cm -1 ; preferably, it has an infrare
  • the present invention provides a coenzyme QH product, comprising a co-crystal of the coenzyme QH and nicotinamide or the above-mentioned coenzyme QH composition, and the product is selected from health care products, food, cosmetics, medicines, and pharmaceutical excipients and feed.
  • the present invention provides the use of the co-crystal of coenzyme QH and nicotinamide or the above-mentioned coenzyme QH composition in preparing a coenzyme QH product selected from health care products, food, cosmetics, medicines, and pharmaceutical excipients and feed.
  • the product may also contain other suitable raw materials required for the product, for example, the food may contain food main ingredients and edible food additives acceptable on food, such as sweeteners, flavoring agents, preservatives, flavoring agents, Colorants, etc.; cosmetics may contain cosmetically acceptable cosmetic ingredients and additives, such as solvents, fragrances, preservatives, essences, colorants, etc.; pharmaceuticals may contain pharmaceutically active ingredients and pharmaceutically acceptable excipients, For example, carriers, diluents, adjuvants, colorants, etc.; the feed may contain feed main materials, such as soybean meal, hay, etc., and feed additives acceptable in the feed, such as sweeteners, flavors, preservatives, flavors, Colorants and the like, but the present invention is not limited thereto.
  • the food may contain food main ingredients and edible food additives acceptable on food, such as sweeteners, flavoring agents, preservatives, flavoring agents, Colorants, etc.
  • cosmetics may contain cosmetically acceptable cosmetic ingredients and additives, such as solvents,
  • the above product is prepared by adding a co-crystal of coenzyme QH according to the present invention with nicotinamide or a coenzyme QH composition according to the present invention.
  • the preparation method of the product can be prepared according to its conventional method except for adding the co-crystal of coenzyme QH and nicotinamide of the present invention or the coenzyme QH composition according to the present invention.
  • the X-ray powder diffraction pattern is obtained by using a Bruker D8 Advanced X-ray eutectic diffractometer, which is irradiated with Cu-K ⁇ .
  • the scanning range was from 3° to 40° in the 2 ⁇ interval, and the scanning speed was 5°/min.
  • Differential scanning calorimetry was performed using TA DSC Q2000 equipment with a heating rate of 10K/min.
  • Thermo Scientific Nicolet 6700 was used as a Fourier transform infrared spectrometer.
  • the ball mill adopts Jingxin JX-2G planetary ball mill.
  • Liquid chromatography was performed using an Agilent 1260 Infinity HPLC.
  • “About” means that the stated value allows for some imprecision (some approximation in the value; approximately or reasonably close to the value; approximately). If “about” provides inaccuracy that is not understood in the art in its ordinary meaning, “about” as used herein means at least variations that can be produced by ordinary methods of measuring and using these parameters. For example, “about” can include a variation of less than or equal to 10%, less than or equal to 5%, less than or equal to 4%, less than or equal to 3%, less than or equal to 2%, less than or equal to 1%, or less than or equal to 0.5% , and in some aspects, less than or equal to 0.1% variation.
  • the invention provides a stable co-crystal of coenzyme QH and nicotinamide. Compared with coenzyme QH itself, the co-crystal has a significant improvement in chemical stability.
  • the method for preparing the cocrystal disclosed by the invention is simple, has good reproducibility, and has the advantages of low cost, environmental friendliness and easy control.
  • the co-crystal disclosed in the present invention has more excellent chemical stability, which can further broaden the application range of coenzyme QH. Therefore, the co-crystal of coenzyme QH and nicotinamide has strong practical application value.
  • Fig. 1 is the X-ray powder diffraction (XRPD) pattern of the co-crystal comprising coenzyme QH and nicotinamide (the stoichiometric ratio of the two is 1:1) provided by the present invention
  • DSC differential scanning calorimetry
  • Fig. 3 is the infrared spectrum (IR) figure of the co-crystal comprising coenzyme QH and nicotinamide (both stoichiometric ratio is 1:1) provided by the present invention
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • IR infrared spectrum
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • IR infrared spectrum
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • IR infrared spectrum
  • FIG. 13 is a differential scanning calorimetry (DSC) diagram of Coenzyme QH itself prepared in Example 1 of the present invention
  • DSC differential scanning calorimetry
  • DSC 16 is a differential scanning calorimetry (DSC) diagram of Comparative Example 3 provided by the present invention.
  • the content of coenzyme QH and nicotinamide in the obtained co-crystal of coenzyme QH and nicotinamide was determined by high performance liquid chromatography, and it was found that the content of coenzyme QH was about 86.1%, and the content of nicotinamide was about 12.6%. In this co-crystal, the stoichiometric ratio of coenzyme QH to nicotinamide is about 1:1.
  • This co-crystal was characterized by solid-state methods such as X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and infrared (IR) spectroscopy. The results are shown in Figures 1-3, respectively.
  • the X-ray powder diffraction pattern of the co-crystal of coenzyme QH and nicotinamide is about 4.3°, 5.7°, 8.4°, 9.9°, 17.1°, 17.9°, 18.6, 18.9° at 2 ⁇ angles , 19.1°, 19.8°, 20.8°, 23.1°, 27.8°, 30.3°, etc. have characteristic peaks.
  • the differential scanning calorimetry analysis spectrum of the co-crystal of coenzyme QH and nicotinamide has a characteristic endothermic peak at about 57°C.
  • the infrared spectrum of the co-crystal of coenzyme QH and nicotinamide is about 3465cm -1 , 3170cm -1 , 2964cm -1 , 2945cm -1 , 2907cm -1 , 2847cm -1 , 1697cm -1 , 1664cm -1 , 1607cm -1 , 1445cm -1 , 1422cm -1 , 1384cm -1 , 1280cm -1 , 1261cm -1 , 1197cm -1 , 1164cm -1 , 1149cm -1 , 1109cm -1 , 1009cm -1 , 907cm - 1 , 877 cm -1 , 795 cm -1 , 751 cm -1 , 599 cm -1 , and characteristic peaks at 475 cm -1 .
  • Example 2 0.122 g of nicotinamide and 0.87 g of coenzyme QH obtained in Example 1 were added to 2 ml of ethanol, stirred at 60° C. to dissolve, recrystallized to obtain a white solid, and the solid was dried in a vacuum drying oven at room temperature for 12 hours, A co-crystal of coenzyme QH and nicotinamide was obtained.
  • the content of coenzyme QH and nicotinamide in the obtained co-crystal of coenzyme QH and nicotinamide were determined by high performance liquid chromatography, and it was found that the content of coenzyme QH was about 84.0%, and the content of nicotinamide was about 11.8%. In this co-crystal, the stoichiometric ratio of coenzyme QH to nicotinamide is about 1:1.
  • This co-crystal was characterized by solid-state methods such as X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and infrared (IR) spectroscopy. The results are basically consistent with the co-crystal detection results of coenzyme QH and nicotinamide in Example 2, respectively.
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • IR infrared
  • This co-crystal was characterized by solid-state methods such as X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and infrared (IR) spectroscopy. The results are consistent with the co-crystal detection results of coenzyme QH and nicotinamide in Example 2, respectively.
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • IR infrared
  • the coenzyme QH composition was characterized by solid state methods such as X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and infrared (IR) spectroscopy. The results are shown in Figures 4-6, respectively.
  • the XRPD spectrum of the coenzyme QH composition is about 4.3°, 5.7°, 17.1°, 17.9°, 18.9° at 2 ⁇ angles, At 19.8°, 20.8°, and 23.1°, there are characteristic peaks of the co-crystal of the above-mentioned coenzyme QH and nicotinamide, indicating that the co-enzyme QH composition contains the above-mentioned co-crystal of coenzyme QH and nicotinamide.
  • the differential scanning calorimetry (DSC) diagram of FIG. 5 It can be seen from the differential scanning calorimetry (DSC) diagram of FIG. 5 that the differential scanning calorimetry analysis spectrum of the coenzyme QH composition has a characteristic endothermic peak at about 50°C-60°C, wherein the former One peak is basically consistent with the melting peak of coenzyme QH, and the latter peak is roughly consistent with the above co-crystal of coenzyme QH and nicotinamide. It is indicated that the composition is composed of co-crystal of coenzyme QH, coenzyme QH and nicotinamide.
  • the infrared spectrum of the coenzyme QH composition has the characteristic peaks of the co-crystal of the above-mentioned coenzyme QH and nicotinamide at about 3465 cm -1 , 3170 cm -1 , and 1697 cm -1 , indicating that The coenzyme QH composition contains the co-crystal of the above-mentioned coenzyme QH and nicotinamide.
  • the coenzyme QH composition was characterized by solid state methods such as X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and infrared (IR) spectroscopy. The results are shown in Figures 7-9, respectively.
  • the XRPD spectrum of the coenzyme QH composition is about 4.3°, 5.7°, 17.1°, 17.9°, 18.9° at 2 ⁇ angles, At 19.8°, 20.8°, and 23.1°, there are characteristic peaks of the co-crystal of the above-mentioned coenzyme QH and nicotinamide, indicating that the co-enzyme QH composition contains the above-mentioned co-crystal of coenzyme QH and nicotinamide.
  • the infrared spectrum of the coenzyme QH composition has the characteristic peaks of the co-crystal of the above-mentioned coenzyme QH and nicotinamide at about 3465 cm -1 , 3170 cm -1 , and 1697 cm -1 , indicating that The coenzyme QH composition contains the co-crystal of the above-mentioned coenzyme QH and nicotinamide.
  • there is a characteristic peak of nicotinamide at 3368 cm -1 indicating that the composition is composed of co-crystals of nicotinamide, coenzyme QH and nicotinamide.
  • the coenzyme QH composition was characterized by solid state methods such as X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and infrared (IR) spectroscopy. The results are shown in Figures 10-12, respectively.
  • the XRPD spectrum of the coenzyme QH composition is about 4.3°, 5.7°, 17.1°, 17.9°, 18.9° at 2 ⁇ angles, At 19.8°, 20.8°, and 23.1°, there are characteristic peaks of the co-crystal of the above-mentioned coenzyme QH and nicotinamide, indicating that the co-enzyme QH composition contains the above-mentioned co-crystal of coenzyme QH and nicotinamide.
  • the infrared spectrum of the coenzyme QH composition has the characteristic peaks of the co-crystal of the above-mentioned coenzyme QH and nicotinamide at about 3465 cm -1 , 3170 cm -1 , and 1697 cm -1 , indicating that The coenzyme QH composition contains the co-crystal of the above-mentioned coenzyme QH and nicotinamide.
  • there is a characteristic peak of nicotinamide at 3368 cm -1 indicating that the composition is composed of co-crystals of nicotinamide, coenzyme QH and nicotinamide.
  • the co-crystal or co-enzyme QH composition of the coenzyme QH obtained in Example 1 and the coenzyme QH obtained in Examples 4-6 and nicotinamide is used.
  • the difference in stability was compared between the co-crystals comprising coenzyme QH and nicotinamide obtained in Example 1 and Examples 4-6.
  • the co-crystals of coenzyme QH obtained in Example 1 and coenzyme QH obtained in Examples 4-6 were kept open and protected from light under the conditions of 25° C./60% relative humidity.
  • the weight ratio of coenzyme QH and oxidized coenzyme Q10 was analyzed by HPLC. The results are shown in Table 1.
  • the coenzyme QH composition or co-crystal disclosed in the present invention has more excellent stability, and can still be able to protect against oxygen without taking special protective measures. It remains stable for a long period of time, which indicates that the co-crystal of coenzyme QH of the present invention has significantly improved stability compared with coenzyme QH itself.
  • Example 2 0.244 g of nicotinic acid and 1.72 g of coenzyme QH obtained in Example 1 were added to a ball-milling jar, 1 ml of ethanol was added, ball-milled for 2 hours, and the solid was dried in a vacuum drying box at room temperature for 12 hours to obtain a yellow powder.
  • Example 2 Add 0.752 g of riboflavin and 1.72 g of coenzyme QH obtained in Example 1 into a ball milling jar, add 1 ml of ethanol, ball mill for 2 hours, and dry the solid in a vacuum drying box at room temperature for 12 hours to obtain a yellow powder.
  • Example 2 0.477 g of calcium pantothenate and 1.72 g of coenzyme QH obtained in Example 1 were added to a ball-milling tank, 1 ml of ethanol was added, ball-milled for 2 hours, and the solid was dried in a vacuum drying oven at room temperature for 12 hours to obtain an off-white powder.
  • Example 2 0.882 g of folic acid and 1.72 g of coenzyme QH obtained in Example 1 were added to a ball-milling jar, 1 ml of ethanol was added, ball-milled for 2 hours, and the solid was dried in a vacuum drying box at room temperature for 12 hours to obtain a yellow powder.
  • Example 2 0.352 g of ascorbic acid and 1.72 g of coenzyme QH obtained in Example 1 were added to a ball milling tank, 1 ml of ethanol was added, ball milled for 2 hours, and the solid was dried in a vacuum drying oven at room temperature for 12 hours to obtain an off-white powder.

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Abstract

本发明涉及一种辅酶QH与烟酰胺的共晶及其制备方法和用途。相比现有的辅酶QH，所述共晶的熔点更高，具有更加优良的稳定性。该辅酶QH共晶的制备方法简单，容易控制，重现性好。本发明极大提升了辅酶QH的运用便利性，节约储存，运输及使用过程中的成本并拓宽了辅酶QH的应用范围。

Description

一种辅酶QH与烟酰胺的共晶及其制备方法和用途 技术领域
本发明涉及辅酶Q10技术领域，具体而言，涉及一种辅酶QH与烟酰胺的共晶及其制备方法。相比现有的辅酶QH，所述共晶的熔点更高，具有更加优良的稳定性。该辅酶QH共晶的制备方法简单，容易控制，重现性好。本发明极大提升了辅酶QH的运用便利性，节约储存，运输及使用过程中的成本并拓宽了辅酶QH的应用范围。
背景技术
辅酶Q10是人体中唯一的辅酶Q类物质，是生物体内广泛存在的脂溶性化合物。它是呼吸链中一种与蛋白质结合不紧密的辅酶，其在人体呼吸链中质子移位及电子传递中起重要作用。辅酶Q10作为细胞代谢和细胞呼吸激活剂，也是重要的抗氧化剂和非特异性免疫增强剂，能抑制线粒体的过氧化，具有促进氧化磷酸化反应，保护生物膜结构完整性的作用。此外，辅酶Q10对免疫非特异性具有增强的作用，可以增强抗体产生的能力，改善T细胞功能。辅酶Q10实质上是一种代谢激活剂，能激活细胞呼吸，加速产生三磷酸腺苷，并起到解毒急救的作用；它还可改变细胞和组织的缺氧状态，对肝、脑、心脏及神经系统均有较好的保护和改善作用，增强体内的非特异性免疫应答。目前辅酶Q10已广泛地应用于食品、保健品、化妆品及医药行业，备受广大学者和消费者的青睐。
辅酶Q10分为氧化型和还原型2种存在形态。通常，在人体内，40～90％的辅酶Q10以还原型的形态存在。还原型辅酶Q10通常称为辅酶QH。与氧化型辅酶Q10相比，辅酶QH具有更好的抗氧化性和更高效的吸收。但是，辅酶QH在空气中容易被氧化，稳定性差，限制了其进一步的应用和开发。为了改善辅酶QH的稳定性，科学家们使用了各种方法，比如添加抗氧化剂、制备新晶型和共结晶等。
CN102381948A和CN101318889A公开了添加抗坏血酸及其衍生物的方法来稳定辅酶QH。发明人将辅酶QH与10％质量的抗坏血酸或其衍生物一起研磨后，于25℃在空气中放置4天，有13％左右的辅酶QH被氧化。
CN103635452A制备了一种辅酶QH的稳定晶型，但是其长期放置于空气中仍然会 被氧化。发明人将该晶型于25℃，在空气中放置28天，仍然有6％左右的辅酶QH被氧化。
WO2019162429A公开了辅酶QH的7种共结晶，其中辅酶QH与3,4-二羟基苯甲酸以及3,5-二羟基苯甲酸的共结晶具有良好的稳定性。但是，这2种配体不宜在食品中大量使用，且该共结晶的制备方法复杂，需要在溶剂中搅拌3天以上。
因此，需要进一步开发稳定的辅酶QH产品。
发明内容
为了提高辅酶QH产品的稳定性，本发明通过大量实验尝试多种化合物与辅酶QH形成共晶。结果发现，通过加入可食用的烟酰胺(维生素B3的形式之一)作为配体的方法，可以形成稳定的共晶，从而从分子水平改变辅酶QH分子的分子间相互作用和空间排列方式，增强辅酶QH分子对氧气的稳定性，提高它的熔点，进而改善其化学稳定性，拓宽其应用领域，而其他相似化合物如：烟酸(维生素B3的形式之一)、核黄素(维生素B2)、泛酸钙(维生素B5)、叶酸(维生素B9)和抗坏血酸(维生素C)等，均无法通过与辅酶QH形成共晶来提高辅酶QH的熔点，进而改善其稳定性。由此确定了采用烟酰胺与辅酶QH制备共晶的方案来解决上述技术问题，从而完成本发明。
具有更优异稳定性的辅酶QH共晶可以进一步拓宽辅酶QH应用范围。因此，本发明所述的辅酶QH与烟酰胺的共晶具有很强的现实应用价值。
本发明的目的之一在于提供一种辅酶QH与烟酰胺的共晶。
本发明的目的之二在于提供所述辅酶QH与烟酰胺的共晶的制备方法。
本发明的目的之三在于提供一种产品，其包含上述的辅酶QH与烟酰胺的共晶，所述产品选自保健品、食品、化妆品、药品、药用辅料和饲料。
本发明的目的之四在于提供一种上述的辅酶QH与烟酰胺的共晶在制备产品中的用途，所述产品选自保健品、食品、化妆品、药品、药用辅料和饲料。
本发明一方面，提供了一种辅酶QH与烟酰胺的共晶，所述共晶中辅酶QH与烟酰胺的化学计量比为1:1。
所述的辅酶QH与烟酰胺共晶的X-射线粉末衍射图谱在2θ角度为4.3°±0.2°，5.7°±0.2°，17.1°±0.2°，17.9°±0.2°，18.9°±0.2°，19.8°±0.2°，20.8°±0.2°，23.1°±0.2°处具有特征峰；特别是还在2θ角度约为8.4°±0.2°，9.9°±0.2°，18.6°±0.2°，19.1°±0.2°，27.8°±0.2°，30.3°±0.2°处具有特征峰。更特别地，所述辅酶QH与烟酰胺的共晶具有基 本上如图1所示的X-射线粉末衍射图谱。
特别地，所述辅酶QH与烟酰胺的共晶通过差示扫描量热法测定，在以10℃/min的速度升温时，其差示扫描量热分析谱图约在57±2℃处有特征吸热峰；优选地，具有基本如图2所示的差示扫描量热分析图谱。
特别地，所述辅酶QH与烟酰胺的共晶的红外图谱在约3465cm -1，3170cm -1，和1697cm -1处具有特征峰；特别是还在约2964cm -1，2945cm -1，2907cm -1，2847cm -1，1664cm -1，1607cm -1，1445cm -1，1422cm -1，1384cm -1，1280cm -1，1261cm -1，1197cm -1，1164cm -1，1149cm -1，1109cm -1，1009cm -1，907cm -1，877cm -1，795cm -1，751cm -1，599cm -1，475cm -1处具有特征峰；优选地，具有基本如图3所示的红外图谱。
第二方面，本发明提供了所述辅酶QH共晶的制备方法，所述方法为以下方法之一：
方法一：将辅酶QH与烟酰胺在溶剂中重结晶，沉淀干燥得到辅酶QH与烟酰胺的共晶；
方法二：将辅酶QH与烟酰胺在溶剂中球磨10分钟以上，再将所得固体干燥获得辅酶QH与烟酰胺的共晶。
其中，所述溶剂选自对原料有一定溶解度且不对原料造成变质的溶剂。优选地，所述溶剂为选自水、醇类、酮类、酯类、烷烃、芳香烃和卤代烷烃中的一种或多种；更优选地，所述溶剂为选自甲醇、乙醇、异丙醇、乙酸乙酯、乙酸异丙酯、丙酮、甲基叔丁基醚、正己烷、正庚烷中的一种或多种。
本发明涉及的制备方法操作简单，结晶过程容易控制，结晶度高，且重现性好，可稳定获得辅酶QH与烟酰胺的共晶。
第三方面，本发明提供一种辅酶QH组合物，其包含上述辅酶QH与烟酰胺的共晶。
在一些实施方式中，辅酶QH组合物中除本发明的辅酶QH与烟酰胺的共晶外，还可以含有过量的烟酰胺，也可以含有过量的辅酶QH，以及其他辅料。也即是说，在辅酶QH组合物的原料中，辅酶QH与烟酰胺的摩尔比没有特别限定，只要辅酶QH组合物的原料可以制备得到上述辅酶QH与烟酰胺的共晶即可。例如，在辅酶QH组合物中辅酶QH与烟酰胺的化学计量比可以为2：1～1：2，其中一部分组分以辅酶QH与烟酰胺的共晶的形式存在，而另一部分组分以游离形式存在。并优选将辅酶QH全部形成共晶，以克服辅酶QH熔点低、稳定差的缺陷。所述其他辅料没有特别限制，可以根据应用目的而变化，例如当应用于药物时，可以为药学上可接受的辅料；当应用于保健品 时，可以为保健品上可接受的辅料；当应用于食品时，可以为食品上可接受的辅料；当应用于化妆品时，可以为化妆品上可接受的辅料；当应用于饲料时，可以为饲料上可接受的辅料。
在一些实施方式中，所述辅酶QH组合物中辅酶QH与烟酰胺的化学计量比为2:1。
所述的辅酶QH与烟酰胺化学计量比为2:1的辅酶QH组合物的X-射线粉末衍射图谱在2θ角度约为4.3°±0.2°，5.7°±0.2°，8.4°±0.2°，9.9°±0.2°，17.1°±0.2°，17.9°±0.2°，18.6°±0.2°，18.9°±0.2°，19.1°±0.2°，19.8°±0.2°，20.8°±0.2°，27.8°±0.2°，30.3°±0.2°处具有特征峰。
所述辅酶QH与烟酰胺化学计量比为2:1的辅酶QH组合物具有基本上如图4所示的X-射线粉末衍射图谱。
所述辅酶QH与烟酰胺化学计量比为2:1的辅酶QH组合物通过差示扫描量热法测定，在以10℃/min的速度升温时，其差示扫描量热分析谱图约在57±2℃处有特征吸热峰；优选地，具有基本如图5所示的差示扫描量热分析图谱。
所述辅酶QH与烟酰胺化学计量比为2:1的辅酶QH组合物的红外图谱在约3465cm -1，3195cm -1，2964cm -1，2945cm -1，2909cm -1，2848cm -1，1696cm -1，1664cm -1，1607cm -1，1445cm -1，1427cm -1，1384cm -1，1280cm -1，1261cm -1，1197cm -1，1164cm -1，1149cm -1，1109cm -1，1009cm -1，907cm -1，877cm -1，795cm -1，751cm -1，599cm -1，475cm -1处具有特征峰；优选地，具有基本如图6所示的红外图谱。
在又一些实施方式中，所述辅酶QH组合物中辅酶QH与烟酰胺的化学计量比为1:1.5。
所述的辅酶QH与烟酰胺化学计量比为1:1.5的辅酶QH组合物的X-射线粉末衍射图谱在2θ角度约为4.3°±0.2°，5.7°±0.2°，8.4°±0.2°，9.9°±0.2°，17.1°±0.2°，17.9°±0.2°，18.6°±0.2°，18.9°±0.2°，19.1°±0.2°，19.8°±0.2°，20.8°±0.2°，27.8°±0.2°，30.3°±0.2°处具有特征峰。
所述辅酶QH与烟酰胺化学计量比为1:1.5的辅酶QH组合物具有基本上如图7所示的X-射线粉末衍射图谱。
所述辅酶QH与烟酰胺化学计量比为1:1.5的辅酶QH组合物通过差示扫描量热法测定，在以10℃/min的速度升温时，其差示扫描量热分析谱图约在57±2℃处有特征吸热峰；优选地，具有基本如图8所示的差示扫描量热分析图谱。
所述辅酶QH与烟酰胺化学计量比为1:1.5的辅酶QH组合物的红外图谱在约3465cm -1，3367cm -1，3167cm -1，2944cm -1，2909cm -1，2845cm -1，1697cm -1，1681cm -1，1619cm -1，1445cm -1，1422cm -1，1384cm -1，1280cm -1，1261cm -1，1197cm -1，1164cm -1，1149cm -1，1109cm -1，1009cm -1，907cm -1，877cm -1，795cm -1，751cm -1，599cm -1，475cm -1处具有特征峰；优选地，具有基本如图9所示的红外图谱。
在又一些实施方式中，所述辅酶QH组合物中辅酶QH与烟酰胺的化学计量比为1:2。
所述的辅酶QH与烟酰胺化学计量比为1:2的辅酶QH组合物的X-射线粉末衍射图谱在2θ角度约为4.3°±0.2°，5.7°±0.2°，8.4°±0.2°，9.9°±0.2°，14.8°±0.2°，17.1°±0.2°，17.9°±0.2°，18.6°±0.2°，18.9°±0.2°，19.1°±0.2°，19.8°±0.2°，20.8°±0.2°，25.3°±0.2°，25.8°±0.2°，27.3°±0.2°，27.8°±0.2°，30.3°±0.2°处具有特征峰。
所述辅酶QH与烟酰胺化学计量比为1:2的辅酶QH组合物具有基本上如图10所示的X-射线粉末衍射图谱。
所述辅酶QH与烟酰胺化学计量比为1:2的辅酶QH组合物通过差示扫描量热法测定，在以10℃/min的速度升温时，其差示扫描量热分析谱图约在57±2℃处有特征吸热峰；优选地，具有基本如图11所示的差示扫描量热分析图谱。
所述辅酶QH与烟酰胺化学计量比为1:2的辅酶QH组合物的红外图谱在约3465cm -1，3367cm -1，3167cm -1，2944cm -1，2909cm -1，2845cm -1，1697cm -1，1681cm -1，1619cm -1，1445cm -1，1422cm -1，1384cm -1，1280cm -1，1261cm -1，1197cm -1，1164cm -1，1149cm -1，1109cm -1，1009cm -1，907cm -1，877cm -1，795cm -1，751cm -1，599cm -1，475cm -1处具有特征峰；优选地，具有基本如图12所示的红外图谱。
再一方面，本发明提供了一种辅酶QH产品，其包含所述辅酶QH与烟酰胺的共晶或者上述辅酶QH组合物，所述产品选自保健品、食品、化妆品、药品、药用辅料和饲料。
又一方面，本发明提供了所述辅酶QH与烟酰胺的共晶或者上述辅酶QH组合物在制备辅酶QH产品中的用途，所述产品选自保健品、食品、化妆品、药品、药用辅料和饲料。
所述产品中还可以包含该产品所需的其他适合原料，例如食品中可以包含食品主料以及食品上可接受的可食用的食品添加剂，例如甜味剂、风味剂、防腐剂、香味剂、着 色剂等；化妆品中可以包含化妆品上可接受的化妆品主料和添加剂，例如溶剂、香味剂、防腐剂、香精、着色剂等；药品中可以包含药用活性成分以及药学上可接受的辅料，例如载体、稀释剂、佐剂、着色剂等；饲料中可以包含饲料主料，例如豆粕、干草等，以及饲料中可以接受的饲料辅料，例如甜味剂、风味剂、防腐剂、香味剂、着色剂等，但是本发明不限于此。
上述产品是通过添加根据本发明的辅酶QH与烟酰胺的共晶或者根据本发明的辅酶QH组合物而制备的。除了添加本发明的辅酶QH与烟酰胺的共晶或者根据本发明的辅酶QH组合物之外，所述产品的制备方法可以按照其常规方法制备。
本发明中X-射线粉末衍射图谱是采用Bruker D8 Advanced型号的X射线共晶衍射仪得到，该仪器采用Cu-Kα照射
Figure PCTCN2022079488-appb-000001
扫描范围在2θ区间自3°至40°，扫描速度为5°/分钟。
差示扫描量热法采用TA DSC Q2000设备，加热速度为10K/min。
傅里叶变换红外光谱仪采用Thermo Scientific Nicolet 6700。
球磨采用净信JX-2G行星式球磨仪。
液相色谱采用Agilent 1260 Infinity HPLC。
在上文中已经详细地描述了本发明，但是上述实施方式本质上仅是例示性，且并不欲限制本发明。此外，本文并不受前述现有技术或发明内容或以下实施例中所描述的任何理论的限制。
除非另有明确说明，在整个申请文件中的数值范围包括其中的任何子范围和以其中给定值的最小子单位递增的任何数值。除非另有明确说明，在整个申请文件中的数值表示对包括与给定值的微小偏差以及具有大约所提及的值以及具有所提及的精确值的实施方案的范围的近似度量或限制。除了在详细描述最后提供的工作实施例之外，本申请文件(包括所附权利要求)中的参数(例如，数量或条件)的所有数值在所有情况下都应被理解为被术语“约”修饰，不管“约”是否实际出现在该数值之前。“约”表示所述的数值允许稍微不精确(在该值上有一些接近精确；大约或合理地接近该值；近似)。如果“大约”提供的不精确性在本领域中没有以这个普通含义来理解，则本文所用的“大约”至少表示可以通过测量和使用这些参数的普通方法产生的变化。例如，“约”可以包括小于或等于10％，小于或等于5％，小于或等于4％，小于或等于3％，小于或等于2％，小于或等于1％或者小于或等于0.5％的变化，并且在某些方面，小于或等于0.1％的变化。
除非另有明确说明，在整个申请文件中的用语“包含”、“包括”、“具有”、“含有”或其他任何类似用语均属于开放性用语，其表示一共晶或制品除了包括本文所列出的这些要素以外，还可包括未明确列出但却是共晶或制品通常固有的其他要素。此外，在本文中，用语“包含”、“包括”、“具有”、“含有”的解读应视为已具体公开并同时涵盖“由…所组成”及“基本上由…所组成”等封闭式或半封闭式连接词。“基本上由…所组成”表示本文所列出的这些要素占该共晶或制品的95％以上，97％以上，或者在某些方面，99％以上。
有益效果
本发明提供一种稳定的辅酶QH与烟酰胺的共晶。相比于辅酶QH本身，该共晶在化学稳定性上具有显著的提升。本发明公开的共晶制备方法简单，重现性好，具有成本低，环境友好和容易控制的优势。并且，本发明公开的共晶具有更优异的化学稳定性，可以进一步拓宽辅酶QH的应用范围。因此，辅酶QH与烟酰胺的共晶具有很强的现实应用价值。
附图说明
图1是本发明提供的包含辅酶QH和烟酰胺(两者化学计量比为1:1)的共晶的X-射线粉末衍射(XRPD)图；
图2是本发明提供的包含辅酶QH和烟酰胺(两者化学计量比为1:1)的共晶的差示扫描量热分析(DSC)图；
图3是本发明提供的包含辅酶QH和烟酰胺(两者化学计量比为1:1)的共晶的红外光谱(IR)图；
图4是本发明提供的包含辅酶QH和烟酰胺(两者化学计量比为2:1)的辅酶QH组合物的X-射线粉末衍射(XRPD)图；
图5是本发明提供的包含辅酶QH和烟酰胺(两者化学计量比为2:1)的辅酶QH组合物的差示扫描量热分析(DSC)图；
图6是本发明提供的包含辅酶QH和烟酰胺(两者化学计量比为2:1)的辅酶QH组合物的红外光谱(IR)图；
图7是本发明提供的包含辅酶QH和烟酰胺(两者化学计量比为1:1.5)的辅酶QH组合物的X-射线粉末衍射(XRPD)图；
图8是本发明提供的包含辅酶QH和烟酰胺(两者化学计量比为1:1.5)的辅酶QH 组合物的差示扫描量热分析(DSC)图；
图9是本发明提供的包含辅酶QH和烟酰胺(两者化学计量比为1:1.5)的辅酶QH组合物的红外光谱(IR)图。
图10是本发明提供的包含辅酶QH和烟酰胺(两者化学计量比为1:2)的辅酶QH组合物的X-射线粉末衍射(XRPD)图；
图11是本发明提供的包含辅酶QH和烟酰胺(两者化学计量比为1:2)的辅酶QH组合物的差示扫描量热分析(DSC)图；
图12是本发明提供的包含辅酶QH和烟酰胺(两者化学计量比为1:2)的辅酶QH组合物的红外光谱(IR)图；
图13是本发明中实施例1制备的辅酶QH本身的差示扫描量热分析(DSC)图；
图14是本发明提供的对比例1的差示扫描量热分析(DSC)图；
图15是本发明提供的对比例2的差示扫描量热分析(DSC)图；
图16是本发明提供的对比例3的差示扫描量热分析(DSC)图；
图17是本发明提供的对比例4的差示扫描量热分析(DSC)图；
图18是本发明提供的对比例5的差示扫描量热分析(DSC)图。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白，以下结合附图及实施例，对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅仅用以解释本发明，并不用于限定本发明。
实施例1
往100克95％乙醇中加入10克氧化型辅酶Q10，6克L-抗坏血酸，在78℃搅拌进行还原反应，20小时后冷却至0℃，并保持在该温度继续搅拌1小时，减压过滤。滤饼用95％乙醇淋洗3次，减压干燥得到白色共晶。除减压干燥外，所有操作均在氮气保护下进行。所得样品中辅酶QH/氧化型辅酶Q10重量比为99.2/0.8。
此粉末通过差示扫描量热分析(DSC)检测，结果图13所示。由图13可以看出，QH在约49℃处有特征吸热峰。
实施例2
将0.4克烟酰胺与1克实施例1中所得的辅酶QH加入到10毫升异丙醇/乙酸异丙酯＝1/1的溶剂中，于40℃下搅拌溶清，重结晶得到白色沉淀物，通过布氏漏斗过滤沉 淀物，并将固体于真空干燥箱中常温干燥12小时，获得辅酶QH与烟酰胺的共晶。
通过高效液相色谱方法对所得辅酶QH与烟酰胺的共晶中辅酶QH和烟酰胺的含量分别进行了测定，发现辅酶QH含量约为86.1％，烟酰胺的含量约为12.6％，由此可知该共晶中，辅酶QH与烟酰胺的化学计量比约为1:1。
此共晶通过X-射线粉末衍射(XRPD)、差示扫描量热分析(DSC)和红外(IR)光谱等固态方法表征。结果分别如图1-图3所示。
如图1所示，所述的辅酶QH与烟酰胺共晶的X-射线粉末衍射图谱在2θ角度约为4.3°，5.7°，8.4°，9.9°，17.1°，17.9°，18.6，18.9°，19.1°，19.8°，20.8°，23.1°，27.8°，30.3°等处具有特征峰。
如图2所示，所述辅酶QH与烟酰胺的共晶的差示扫描量热分析谱图在约57℃处有特征吸热峰。
如图3所示，所述辅酶QH与烟酰胺的共晶的红外谱图在约3465cm -1，3170cm -1，2964cm -1，2945cm -1，2907cm -1，2847cm -1，1697cm -1，1664cm -1，1607cm -1，1445cm -1，1422cm -1，1384cm -1，1280cm -1，1261cm -1，1197cm -1，1164cm -1，1149cm -1，1109cm -1，1009cm -1，907cm -1，877cm -1，795cm -1，751cm -1，599cm -1，475cm -1处具有特征峰。
实施例3
将0.122克烟酰胺与0.87克实施例1中所得的辅酶QH加入到2毫升乙醇中，于60℃下搅拌溶清，重结晶得到白色固体，并将固体于真空干燥箱中常温干燥12小时，获得辅酶QH与烟酰胺的共晶。
通过高效液相色谱方法对所得辅酶QH与烟酰胺的共晶中辅酶QH和烟酰胺的含量分别进行了测定，发现辅酶QH含量约为84.0％，烟酰胺的含量约为11.8％，由此可知该共晶中，辅酶QH与烟酰胺的化学计量比约为1:1。
此通过X-射线粉末衍射(XRPD)、差示扫描量热分析(DSC)和红外(IR)光谱等固态方法表征。结果与实施例2的辅酶QH与烟酰胺的共晶检测结果分别基本一致。
实施例4
将0.244克烟酰胺与1.72克实施例1中所得的辅酶QH加入到球磨罐中，加入1毫升乙醇，球磨2小时，并将固体于真空干燥箱中常温干燥12小时，获得辅酶QH与烟酰胺的共晶。
此共晶通过X-射线粉末衍射(XRPD)、差示扫描量热分析(DSC)和红外(IR)光谱等固态方法表征。结果与实施例2的辅酶QH与烟酰胺的共晶检测结果分别基本一致。
实施例5
将0.244克烟酰胺与1.72克实施例1中所得的辅酶QH加入到球磨罐中，加入1毫升乙醇/乙酸乙酯＝1/1的溶剂，球磨2小时，并将固体于真空干燥箱中常温干燥12小时，获得辅酶QH与烟酰胺的共晶。
此共晶通过X-射线粉末衍射(XRPD)、差示扫描量热分析(DSC)和红外(IR)光谱等固态方法表征。结果与实施例2的辅酶QH与烟酰胺的共晶检测结果分别一致。
实施例6
将0.122克烟酰胺与1.72克实施例1中所得的辅酶QH加入到球磨罐中，加入1毫升乙醇，球磨2小时，并将固体于真空干燥箱中常温干燥12小时，获得一种辅酶QH组合物，其中辅酶QH与烟酰胺的化学计量比为2:1。
此辅酶QH组合物通过X-射线粉末衍射(XRPD)、差示扫描量热分析(DSC)和红外(IR)光谱等固态方法表征。结果分别如图4-图6所示。
通过图4的X-射线粉末衍射(XRPD)谱图可以看出，所述辅酶QH组合物的XRPD谱图中在在2θ角度约为4.3°，5.7°，17.1°，17.9°，18.9°，19.8°，20.8°，23.1°处具有上述辅酶QH与烟酰胺的共晶的特征峰，表明所述辅酶QH组合物中含有上述辅酶QH与烟酰胺的共晶。
通过图5的差示扫描量热分析(DSC)图可以看出，所述辅酶QH组合物的差示扫描量热分析谱图在约50℃-60℃处有特征吸热峰，其中，前一个峰与辅酶QH的熔融峰基本一致，后一个峰与上述辅酶QH与烟酰胺的共晶大体一致。说明该组合物由辅酶QH与辅酶QH和烟酰胺的共晶共同组成。
通过图6的红外谱图可以看出，所述辅酶QH组合物的红外谱图在约3465cm -1，3170cm -1，1697cm -1处具有上述辅酶QH与烟酰胺的共晶的特征峰，表明所述辅酶QH组合物中含有上述辅酶QH与烟酰胺的共晶。
实施例7
将0.366克烟酰胺与1.72克实施例1中所得的辅酶QH加入到球磨罐中，加入1毫升乙醇的溶剂，球磨2小时，并将固体于真空干燥箱中常温干燥12小时，获得一种辅酶QH组合物，其中辅酶QH与烟酰胺的化学计量比为1:1.5。
此辅酶QH组合物通过X-射线粉末衍射(XRPD)、差示扫描量热分析(DSC)和红外(IR)光谱等固态方法表征。结果分别如图7-图9所示。
通过图7的X-射线粉末衍射(XRPD)谱图可以看出，所述辅酶QH组合物的XRPD谱图中在在2θ角度约为4.3°，5.7°，17.1°，17.9°，18.9°，19.8°，20.8°，23.1°处具有上述辅酶QH与烟酰胺的共晶的特征峰，表明所述辅酶QH组合物中含有上述辅酶QH与烟酰胺的共晶。
通过图8的差示扫描量热分析(DSC)图可以看出，所述辅酶QH组合物的差示扫描量热分析谱图在约56℃处有特征吸热峰，与上述辅酶QH与烟酰胺的共晶大体一致。
通过图9的红外谱图可以看出，所述辅酶QH组合物的红外谱图在约3465cm -1，3170cm -1，1697cm -1处具有上述辅酶QH与烟酰胺的共晶的特征峰，表明所述辅酶QH组合物中含有上述辅酶QH与烟酰胺的共晶。同时，在3368cm -1处具有烟酰胺的特征峰，说明该组合物由烟酰胺与辅酶QH和烟酰胺的共晶共同组成。
实施例8
将0.488克烟酰胺与1.72克实施例1中所得的辅酶QH加入到球磨罐中，加入1毫升乙醇的溶剂，球磨2小时，并将固体于真空干燥箱中常温干燥12小时，获得一种辅酶QH组合物，其中辅酶QH与烟酰胺的化学计量比为1:2。
此辅酶QH组合物通过X-射线粉末衍射(XRPD)、差示扫描量热分析(DSC)和红外(IR)光谱等固态方法表征。结果分别如图10-图12所示。
通过图10的X-射线粉末衍射(XRPD)谱图可以看出，所述辅酶QH组合物的XRPD谱图中在在2θ角度约为4.3°，5.7°，17.1°，17.9°，18.9°，19.8°，20.8°，23.1°处具有上述辅酶QH与烟酰胺的共晶的特征峰，表明所述辅酶QH组合物中含有上述辅酶QH与烟酰胺的共晶。
通过图11的差示扫描量热分析(DSC)图可以看出，所述辅酶QH组合物的差示扫描量热分析谱图在约56℃处有特征吸热峰，与上述辅酶QH与烟酰胺的共晶大体一致。
通过图12的红外谱图可以看出，所述辅酶QH组合物的红外谱图在约3465cm -1，3170cm -1，1697cm -1处具有上述辅酶QH与烟酰胺的共晶的特征峰，表明所述辅酶QH组合物中含有上述辅酶QH与烟酰胺的共晶。同时，在3368cm -1处具有烟酰胺的特征峰，说明该组合物由烟酰胺与辅酶QH和烟酰胺的共晶共同组成。
实施例9(辅酶QH本身与本发明所述的辅酶QH共晶的稳定性比较)
采用实施例1得到的辅酶QH和实施例4-6得到的辅酶QH与烟酰胺的共晶或者辅酶QH组合物进行。
对实施例1得到的辅酶QH和实施例4-6得到的包含辅酶QH与烟酰胺的共晶进行稳定性差异的比较。将实施例1得到的辅酶QH和实施例4-6得到的辅酶QH共晶在25℃/60％相对湿度的条件下，敞口、避光保存。通过HPLC分析辅酶QH和氧化型辅酶Q10的重量比。结果如表1所示。
表1
Figure PCTCN2022079488-appb-000002
如上述结果所示，与实施例1制备的辅酶QH相比，本发明所公开的辅酶QH组合物或者共晶具有更优异的稳定性，且在不特意对氧气采取保护措施的条件下仍然能够在较长时间内保持稳定，由此表明本发明所述的辅酶QH共晶与辅酶QH本身相比，稳定性有显著的提高。
对比例1
将0.244克烟酸与1.72克实施例1中所得的辅酶QH加入到球磨罐中，加入1毫升乙醇，球磨2小时，并将固体于真空干燥箱中常温干燥12小时，获得黄色粉末。
此粉末通过差示扫描量热分析(DSC)检测，结果图14所示，与QH本身相比，熔点没有明显差异。
对比例2
将0.752克核黄素与1.72克实施例1中所得的辅酶QH加入到球磨罐中，加入1毫升乙醇，球磨2小时，并将固体于真空干燥箱中常温干燥12小时，获得黄色粉末。
此粉末通过差示扫描量热分析(DSC)检测，结果图15所示，与QH本身相比，熔点 没有明显差异。
对比例3
将0.477克泛酸钙与1.72克实施例1中所得的辅酶QH加入到球磨罐中，加入1毫升乙醇，球磨2小时，并将固体于真空干燥箱中常温干燥12小时，获得类白色粉末。
此粉末通过差示扫描量热分析(DSC)检测，结果图16所示，与QH本身相比，熔点没有明显差异。
对比例4
将0.882克叶酸与1.72克实施例1中所得的辅酶QH加入到球磨罐中，加入1毫升乙醇，球磨2小时，并将固体于真空干燥箱中常温干燥12小时，获得黄色粉末。
此粉末通过差示扫描量热分析(DSC)检测，结果图17所示，与QH本身相比，熔点没有明显差异。
对比例5
将0.352克抗坏血酸与1.72克实施例1中所得的辅酶QH加入到球磨罐中，加入1毫升乙醇，球磨2小时，并将固体于真空干燥箱中常温干燥12小时，获得类白色粉末。
此粉末通过差示扫描量热分析(DSC)检测，结果图18所示，与QH本身相比，熔点没有明显差异。
上述结果表明，烟酸、核黄素、泛酸钙、叶酸和抗坏血酸都不能与辅酶QH形成共晶来改善其稳定性。

Claims (10)

  1. 一种辅酶QH与烟酰胺的共晶，其特征在于，所述共晶中辅酶QH与烟酰胺的化学计量比为1:1。
  2. 根据权利要求1所述的辅酶QH与烟酰胺的共晶，其特征在于，所述共晶的X-射线粉末衍射图谱在2θ角度为4.3°±0.2°，5.7°±0.2°，17.1°±0.2°，17.9°±0.2°，18.9°±0.2°，19.8°±0.2°，20.8°±0.2°，23.1°±0.2°处具有特征峰；特别地，还在2θ角度为8.4°±0.2°，9.9°±0.2°，18.6°±0.2°，19.1°±0.2°，27.8°±0.2°，30.3°±0.2°处具有特征峰；特别地，所述共晶具有基本上如图1所示的X-射线粉末衍射图谱。
  3. 根据权利要求1所述的辅酶QH与烟酰胺的共晶，其特征在于，通过差示扫描量热法测定，在以10℃/min的速度升温时，所述共晶的差示扫描量热分析谱图在57±2℃处有特征吸热峰；优选地，所述共晶具有基本如图2所示的差示扫描量热分析图谱。
  4. 根据权利要求1所述的辅酶QH与烟酰胺的共晶，其特征在于，所述共晶的红外图谱在3465cm -1，3170cm -1，和1697cm -1处具有特征峰；特别地，还在2964cm -1，2945cm -1，2907cm -1，2847cm -1，1664cm -1，1607cm -1，1445cm -1，1422cm -1，1384cm -1，1280cm -1，1261cm -1，1197cm -1，1164cm -1，1149cm -1，1109cm -1，1009cm -1，907cm -1，877cm -1，795cm -1，751cm -1，599cm -1，475cm -1处具有特征峰；优选地，所述共晶具有基本如图3所示的红外图谱。
  5. 根据权利要求1-4中任一项所述的辅酶QH与烟酰胺的共晶的制备方法，所述方法为以下方法之一：
    方法一：将辅酶QH与烟酰胺在溶剂中重结晶，沉淀干燥得到辅酶QH与烟酰胺的共晶；
    方法二：将辅酶QH与烟酰胺在溶剂中球磨10分钟以上，再将所得固体干燥获得辅酶QH与烟酰胺的共晶。
  6. 根据权利要求5所述的制备方法，其特征在于，所述溶剂为选自水、醇类、酮类、酯类、烷烃、芳香烃和卤代烷烃中的一种或多种；更优选地，所述溶剂为选自甲醇、乙醇、异丙醇、乙酸乙酯、乙酸异丙酯、丙酮、甲基叔丁基醚、正己烷、正庚烷中的一 种或多种。
  7. 一种辅酶QH组合物，其含有如权利要求1-4任一项所述的辅酶QH与烟酰胺的共晶。
  8. 根据权利要求7所述的辅酶QH组合物，其特征在于，所述组合物中，辅酶QH与烟酰胺的化学计量比为2:1～1:2
  9. 一种辅酶QH产品，其包含根据权利要求1-4中任一项所述的辅酶QH与烟酰胺的共晶或者根据权利要求7或8所述的辅酶QH组合物，所述产品选自保健品、食品、化妆品、药品、药用辅料和饲料。
  10. 根据权利要求1-4中任一项所述的辅酶QH与烟酰胺的共晶或者根据权利要求7或8所述的辅酶QH组合物在制备辅酶QH产品中的用途，所述产品选自保健品、食品、化妆品、药品、药用辅料和饲料。
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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040197418A1 (en) * 2001-07-16 2004-10-07 Takahiro Ueda Method of stabilizing reduced coenzyme q10 and method of acidic crystallization
CN101318889A (zh) 2001-10-10 2008-12-10 株式会社钟化 还原型辅酶q10的稳定方法
EP2025662A1 (en) * 2006-04-28 2009-02-18 Kaneka Corporation Method for purification of reduced coenzyme q10
JPWO2008007415A1 (ja) * 2006-07-10 2009-12-10 金秀バイオ株式会社 包接化コエンザイムｑ１０、及び包接化コエンザイムｑ１０の製造方法
CN103635452A (zh) 2011-06-24 2014-03-12 株式会社钟化 稳定性优良的还原型辅酶q10晶体
CN107721902A (zh) * 2017-11-08 2018-02-23 中国科学院上海药物研究所 阿普斯特与烟酰胺的共结晶及其制备方法和应用
WO2019162429A1 (en) 2018-02-23 2019-08-29 Center For Intelligent Research In Crystal Engineering, S.L. Cocrystals of ubiquinol and compositions comprising them
CN113024362A (zh) * 2021-03-10 2021-06-25 中国科学院上海药物研究所 一种辅酶qh与烟酰胺的共晶及其制备方法和用途

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100982130B1 (ko) * 2007-11-09 2010-09-14 씨제이제일제당 (주) 코엔자임 ｑ10을 함유하는 안정화된 제제 및 이의 제조방법
WO2011014850A2 (en) * 2009-07-31 2011-02-03 Nuvo Research Inc. Topical eutectic-based formulations
CN104119209B (zh) * 2013-04-25 2018-03-02 浙江医药股份有限公司新昌制药厂 一种还原型辅酶q10干粉及其组合物以及制备方法
CN106222223B (zh) * 2016-09-05 2019-07-05 雄九（上海）医药技术股份有限公司 人血白蛋白的生产方法

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040197418A1 (en) * 2001-07-16 2004-10-07 Takahiro Ueda Method of stabilizing reduced coenzyme q10 and method of acidic crystallization
CN101318889A (zh) 2001-10-10 2008-12-10 株式会社钟化 还原型辅酶q10的稳定方法
CN102381948A (zh) 2001-10-10 2012-03-21 株式会社钟化 还原型辅酶q10的稳定方法
EP2025662A1 (en) * 2006-04-28 2009-02-18 Kaneka Corporation Method for purification of reduced coenzyme q10
JPWO2008007415A1 (ja) * 2006-07-10 2009-12-10 金秀バイオ株式会社 包接化コエンザイムｑ１０、及び包接化コエンザイムｑ１０の製造方法
CN103635452A (zh) 2011-06-24 2014-03-12 株式会社钟化 稳定性优良的还原型辅酶q10晶体
CN107721902A (zh) * 2017-11-08 2018-02-23 中国科学院上海药物研究所 阿普斯特与烟酰胺的共结晶及其制备方法和应用
WO2019162429A1 (en) 2018-02-23 2019-08-29 Center For Intelligent Research In Crystal Engineering, S.L. Cocrystals of ubiquinol and compositions comprising them
CN113024362A (zh) * 2021-03-10 2021-06-25 中国科学院上海药物研究所 一种辅酶qh与烟酰胺的共晶及其制备方法和用途

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