CN114349809A - Beta-nicotinamide mononucleotide crystal form A and preparation method thereof - Google Patents
Beta-nicotinamide mononucleotide crystal form A and preparation method thereofDownload PDFInfo
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Abstract
Translated fromChineseDescription
Translated fromChinese技术领域technical field
本发明涉及医药领域，具体涉及β-烟酰胺单核苷酸的晶型A及其制备方法。The invention relates to the field of medicine, in particular to the crystal form A of beta-nicotinamide mononucleotide and a preparation method thereof.
背景技术Background technique
本发明提供了β-烟酰胺单核苷酸的化学新晶型，结构式如式I所示，β-烟酰胺单核苷酸是人体固有的物质之一，在人体细胞能量中生成中扮演重要的角色，它参与细胞内NAD+(烟酰胺腺嘌呤双核苷酸，又称辅酶I，细胞能量转化的重要辅酶)的合成，在细胞的能量代谢中起到关键的作用，同时被用于抗衰老研究。The present invention provides a new chemical crystal form of beta-nicotinamide mononucleotide, the structural formula is shown in formula I, beta-nicotinamide mononucleotide is one of the inherent substances in the human body, and plays an important role in the generation of human cell energy It participates in the synthesis of intracellular NAD+ (nicotinamide adenine dinucleotide, also known as coenzyme I, an important coenzyme for cellular energy conversion), plays a key role in cellular energy metabolism, and is used for anti-aging Research.
近来因其在年龄相关退行性病变(如年龄相关性肥胖症、年龄相关性血脂水平增加、年龄相关性胰岛素敏感性降低、年龄相关性记忆功能降低和年龄相关性眼功能改变(如黄斑变性)的治疗、改善、减轻、减缓、控制、预防和/或逆转中的用途而获得关注。It has recently been implicated in age-related degeneration (eg, age-related obesity, age-related increases in blood lipid levels, age-related decreased insulin sensitivity, age-related memory impairment, and age-related changes in ocular function (eg, macular degeneration). of interest for its use in the treatment, amelioration, mitigation, mitigation, control, prevention and/or reversal.
同一种药物，晶型不同，其生物利用度也可能会存在差别，另外其稳定性、流动性、可压缩性也可能会不同，这些理化性质对药物的应用产生一定的影响。The same drug has different crystal forms, and its bioavailability may also be different. In addition, its stability, fluidity, and compressibility may also be different. These physical and chemical properties have a certain impact on the application of the drug.
因此，本领域需要提供一种溶剂残留小、稳定性高、适合成药的β-烟酰胺单核苷酸的晶型。Therefore, there is a need in the art to provide a crystal form of β-nicotinamide mononucleotide with little solvent residue, high stability and suitable for medicine.
发明内容SUMMARY OF THE INVENTION
本发明的目的是提供一种溶剂残留小、稳定性高、适合成药的β-烟酰胺单核苷酸的晶型。The purpose of the present invention is to provide a crystal form of β-nicotinamide mononucleotide with little solvent residue, high stability and suitable for medicine.
本发明第一方面，提供了β-烟酰胺单核苷酸的晶型A，所述晶型A具有3个或3个以上选自下组的X-射线粉末衍射特征峰(2θ)：19.9±0.2°、20.9±0.2°、21.7±0.2°、23.0±0.2°和23.3±0.2°。The first aspect of the present invention provides a crystal form A of β-nicotinamide mononucleotide, the crystal form A has 3 or more X-ray powder diffraction characteristic peaks (2θ) selected from the following group: 19.9 ±0.2°, 20.9±0.2°, 21.7±0.2°, 23.0±0.2° and 23.3±0.2°.
在另一优选例中，所述晶型A具有下组的X-射线粉末衍射特征峰：19.9±0.2°、20.9±0.2°、21.7±0.2°、23±0.2°和23.3±0.2°。In another preferred embodiment, the crystal form A has the following X-ray powder diffraction characteristic peaks: 19.9±0.2°, 20.9±0.2°, 21.7±0.2°, 23±0.2° and 23.3±0.2°.
在另一优选例中，所述晶型A具有1个或1个以上选自下组的X-射线粉末衍射特征峰：12.6±0.2°、18.9±0.2°、25.5±0.2°、26.5±0.2°和29.7±0.2°。In another preferred embodiment, the crystal form A has one or more X-ray powder diffraction characteristic peaks selected from the following group: 12.6±0.2°, 18.9±0.2°, 25.5±0.2°, 26.5±0.2 ° and 29.7±0.2°.
在另一优选例中，所述晶型A具有下组的X-射线粉末衍射特征峰：12.6±0.2°、18.9±0.2°、19.9±0.2°、20.9±0.2°、21.7±0.2°、23.0±0.2°、23.3±0.2°、25.5±0.2°、26.5±0.2°和29.7±0.2°。In another preferred example, the crystal form A has the following X-ray powder diffraction characteristic peaks: 12.6±0.2°, 18.9±0.2°, 19.9±0.2°, 20.9±0.2°, 21.7±0.2°, 23.0 ±0.2°, 23.3±0.2°, 25.5±0.2°, 26.5±0.2° and 29.7±0.2°.
在另一优选例中，所述晶型A具有1个或1个以上选自下组的X-射线粉末衍射特征峰：7.6±0.2°、11.5±0.2°、18.1±0.2°、30.3±0.2°和31.0±0.2°。In another preferred embodiment, the crystal form A has one or more X-ray powder diffraction characteristic peaks selected from the following group: 7.6±0.2°, 11.5±0.2°, 18.1±0.2°, 30.3±0.2 ° and 31.0±0.2°.
在另一优选例中，所述晶型A具有下组的X-射线粉末衍射特征峰：7.6±0.2°、11.5±0.2°、12.6±0.2°、18.1±0.2°、18.9±0.2°、19.9±0.2°、20.9±0.2°、21.7±0.2°、23.0±0.2°、23.3±0.2°、25.5±0.2°、26.5±0.2°、29.7±0.2°、30.3±0.2°和31.0±0.2°。In another preferred example, the crystal form A has the following X-ray powder diffraction characteristic peaks: 7.6±0.2°, 11.5±0.2°, 12.6±0.2°, 18.1±0.2°, 18.9±0.2°, 19.9 ±0.2°, 20.9±0.2°, 21.7±0.2°, 23.0±0.2°, 23.3±0.2°, 25.5±0.2°, 26.5±0.2°, 29.7±0.2°, 30.3±0.2° and 31.0±0.2°.
在另一优选例中，所述晶型A具有表1所示的X-射线粉末衍射特征峰。In another preferred example, the crystal form A has the characteristic peaks of X-ray powder diffraction shown in Table 1.
在另一优选例中，所述晶型A具有一个或多个选自下组的特征：In another preferred embodiment, the crystal form A has one or more features selected from the following group:
(a)所述晶型A的X-射线粉末衍射图谱(XRPD)基本如图1所示；(a) The X-ray powder diffraction pattern (XRPD) of the crystal form A is basically as shown in Figure 1;
(b)所述晶型A的差示扫描量热法图谱(DSC)基本如图2所示；和/或(b) the differential scanning calorimetry (DSC) spectrum of the crystal form A is substantially as shown in FIG. 2; and/or
(c)所述晶型A的热重分析图谱(TGA)基本如图3所示。(c) The thermogravimetric analysis spectrum (TGA) of the crystal form A is basically as shown in FIG. 3 .
本发明第二方面，提供了如本发明第一方面所述的晶型A的制备方法，包括步骤：The second aspect of the present invention provides the preparation method of crystal form A as described in the first aspect of the present invention, comprising the steps of:
提供β-烟酰胺单核苷酸在惰性溶剂中的混合物(通常为溶液)，低温析晶，从而得到所述晶型A。The crystal form A is obtained by providing a mixture (usually a solution) of β-nicotinamide mononucleotide in an inert solvent, and crystallizing at low temperature.
在另一优选例中，所述惰性溶剂选自下组：C1-C6烷基醇、乙腈、丙酮、N-甲基吡咯烷酮、四氢呋喃、1,4-二氧六环、DMF、DMSO、水，或其组合。In another preferred embodiment, the inert solvent is selected from the following group: C1-C6 alkyl alcohol, acetonitrile, acetone, N-methylpyrrolidone, tetrahydrofuran, 1,4-dioxane, DMF, DMSO, water, or a combination thereof.
在另一优选例中，所述惰性溶剂为水与选自下组的溶剂的混合溶剂：C1-C6烷基醇、乙腈、丙酮、N-甲基吡咯烷酮、四氢呋喃、1,4-二氧六环、DMF、DMSO。In another preferred embodiment, the inert solvent is a mixed solvent of water and a solvent selected from the following group: C1-C6 alkyl alcohol, acetonitrile, acetone, N-methylpyrrolidone, tetrahydrofuran, 1,4-dioxane Ring, DMF, DMSO.
在另一优选例中，所述混合溶剂中，水占所述混合溶剂体积的10-50％，较佳地20-40％，更佳地1/3。In another preferred embodiment, in the mixed solvent, water accounts for 10-50% of the volume of the mixed solvent, preferably 20-40%, more preferably 1/3.
在另一优选例中，所述低温为-10～10℃，更佳地4±2℃。In another preferred embodiment, the low temperature is -10-10°C, more preferably 4±2°C.
在另一优选例中，低温析出后，还包括分离(如过滤)和/或干燥步骤。In another preferred embodiment, after the precipitation at low temperature, separation (such as filtration) and/or drying steps are also included.
在另一优选例中，所述β-烟酰胺单核苷酸在所述惰性溶剂中的浓度为30mg/ml-200mg/ml，较佳地，如50mg/ml、100mg/ml或150mg/ml。In another preferred embodiment, the concentration of the β-nicotinamide mononucleotide in the inert solvent is 30mg/ml-200mg/ml, preferably, such as 50mg/ml, 100mg/ml or 150mg/ml .
本发明第三方面，提供了如本发明第一方面所述的的晶型A的又一制备方法，包括步骤：The third aspect of the present invention provides another preparation method of the crystal form A as described in the first aspect of the present invention, comprising the steps:
提供β-烟酰胺单核苷酸在水中的溶液，静置(如常温)挥发，从而得到所述晶型A。A solution of β-nicotinamide mononucleotide in water is provided, and it is left to stand (eg, normal temperature) to volatilize, thereby obtaining the crystal form A.
在另一优选例中，所述β-烟酰胺单核苷酸在水中的浓度为50-300mg/ml，如100mg/ml、150mg/ml或200mg/ml。In another preferred embodiment, the concentration of the β-nicotinamide mononucleotide in water is 50-300 mg/ml, such as 100 mg/ml, 150 mg/ml or 200 mg/ml.
本发明第四方面，提供了一种药物组合物，所述药物组合物包括：β-烟酰胺单核苷酸所述晶型A和药学上可接受的载体。A fourth aspect of the present invention provides a pharmaceutical composition comprising: the crystal form A of β-nicotinamide mononucleotide and a pharmaceutically acceptable carrier.
本发明第五方面，提供了如本发明第一方面所述的晶型A或本发明第四方面所述的药物组合物的用途，用于制备一药物，所述药物用于治疗和/或预防年龄相关退行性病变。The fifth aspect of the present invention provides the use of the crystal form A described in the first aspect of the present invention or the pharmaceutical composition described in the fourth aspect of the present invention for preparing a medicament for treatment and/or Prevention of age-related degenerative diseases.
在另一优选例中，所述年龄相关退行性病变选自下组：年龄相关性肥胖症、年龄相关性血脂水平增加、年龄相关性胰岛素敏感性降低、年龄相关性记忆功能降低和年龄相关性眼功能改变(如黄斑变性)，或其组合。In another preferred embodiment, the age-related degenerative disease is selected from the group consisting of: age-related obesity, age-related increase in blood lipid levels, age-related decreased insulin sensitivity, age-related decreased memory function and age-related Changes in eye function (eg, macular degeneration), or a combination thereof.
本发明第六方面，提供了一种治疗和/或预防年龄相关退行性病变的方法，包括步骤：向有需要的对象施用治疗或预防有效量的如本发明第一方面所述的晶型A或本发明第四方面所述的药物组合物。A sixth aspect of the present invention provides a method for treating and/or preventing age-related degenerative diseases, comprising the steps of: administering a therapeutically or prophylactically effective amount of the crystal form A according to the first aspect of the present invention to an object in need or the pharmaceutical composition of the fourth aspect of the present invention.
在另一优选例中，所述对象为哺乳动物。In another preferred example, the subject is a mammal.
在另一优选例中，所述哺乳动物选自下组：人、大鼠、小鼠。In another preferred embodiment, the mammal is selected from the group consisting of human, rat, and mouse.
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (eg, the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, it is not repeated here.
附图说明Description of drawings
图1为β-烟酰胺单核苷酸晶型A的XRPD图谱；Fig. 1 is the XRPD pattern of β-nicotinamide mononucleotide crystal form A;
图2为晶型A的DSC图谱；Fig. 2 is the DSC spectrum of crystal form A;
图3为晶型A的TGA图谱；Fig. 3 is the TGA spectrum of crystal form A;
图4为无定型形式的β-烟酰胺单核苷酸的XRPD图谱；Figure 4 is an XRPD pattern of β-nicotinamide mononucleotide in amorphous form;
图5为无定型形式的β-烟酰胺单核苷酸的TGA图谱；Figure 5 is a TGA map of β-nicotinamide mononucleotide in amorphous form;
图6为晶型A的光照稳定性XRPD对比图；Fig. 6 is the light stability XRPD comparison chart of crystal form A;
图7为晶型A的高温稳定性XRPD对比图；Fig. 7 is the high temperature stability XRPD comparison chart of crystal form A;
图8为晶型A的高湿(40℃，75％RH)稳定性XRPD对比图；Figure 8 is a high-humidity (40°C, 75%RH) stability XRPD comparison chart of Form A;
图9为晶型A的高湿(25℃，92.5％RH)稳定性XRPD对比图。FIG. 9 is a high-humidity (25°C, 92.5%RH) stability XRPD comparison chart of Form A. FIG.
具体实施方式Detailed ways
本发明人经过广泛而深入的研究，通过大量筛选和测试，提供了一种β-烟酰胺单核苷酸晶型A。意外地，所述晶型A溶剂残留小(100℃失重＜0.2％)，稳定性高、非常适合成药。在此基础上完成了本发明。The inventors have provided a β-nicotinamide mononucleotide crystal form A through extensive and in-depth research, extensive screening and testing. Unexpectedly, the crystal form A has little solvent residue (weight loss at 100° C. <0.2%), high stability, and is very suitable for finished medicine. The present invention has been completed on this basis.
术语the term
除非另有定义，否则本文中所用的全部技术术语和科学术语均具有如本发明所属领域普通技术人员通常理解的相同含义。Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
如本文所用，在提到具体列举的数值中使用时，术语“约”意指该值可以从列举的值变动不多于1％。例如，如本文所用，表述“约100”包括99和101和之间的全部值(例如，99.1、99.2、99.3、99.4等)。As used herein, when used in reference to a specifically recited value, the term "about" means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes all values between 99 and 101 and (eg, 99.1, 99.2, 99.3, 99.4, etc.).
如本文所用，术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。换言之，所述术语也包括“基本上由…构成”、或“由…构成”。As used herein, the terms "containing" or "including (including)" can be open, semi-closed, and closed. In other words, the term also includes "consisting essentially of," or "consisting of."
如本文所用，术语“室温”、“常温”是指温度为4-30℃，较佳地，20±5℃。As used herein, the terms "room temperature" and "normal temperature" refer to a temperature of 4-30°C, preferably 20±5°C.
如本文所用，术语“晶型”或“多晶型物”可互换使用。As used herein, the terms "crystalline form" or "polymorph" are used interchangeably.
如本文所用，术语“n个或n个以上”指包括n以及大于n的任意正整数(例如n、n+1、…)，其中上限Nup为该组中所有值的个数。例如“1个或1个以上”不仅包括1、2、3、4、5、6、7、8、9、10…上限Nup各个正整数，还包括“2个或2个以上”、“3个或3个以上”、“4个或4个以上”、“5个或5个以上”、“6个或6个以上”、“7个或7个以上”、“8个或8个以上”、“9个或9个以上”、“10个或10个以上”等范围。As used herein, the term "n or more" refers to including n and any positive integer greater than n (eg, n, n+1, . . . ), where the upper limit Nup is the number of all values in the set. For example, "1 or more" includes not only 1, 2, 3, 4, 5, 6, 7, 8, 9, 10... upper limit Nup each positive integer, but also "2 or more", "3 "3 or more", "4 or more", "5 or more", "6 or more", "7 or more", "8 or more" ", "9 or more", "10 or more" and other ranges.
活性成分Active ingredient
如本文所用，术语“活性成分”或“活性化合物”指本发明的β-烟酰胺单核苷酸晶型A。As used herein, the term "active ingredient" or "active compound" refers to the β-nicotinamide mononucleotide form A of the present invention.
制备方法Preparation
本发明的晶型A可用本领域常用的结晶方法制备。The crystal form A of the present invention can be prepared by crystallization methods commonly used in the art.
通常，可以通过操作溶液，使得感兴趣化合物的溶解度极限被超过，从而完成生产规模的结晶。这可以通过多种方法来完成，例如，在相对高的温度下溶解化合物，然后冷却溶液至饱和极限以下。或者通过沸腾、常压蒸发、真空干燥或通过其它的一些方法来减小液体体积。可通过加入抗溶剂或化合物在其中具有低的溶解度的溶剂或这样的溶剂的混合物，来降低感兴趣化合物的溶解度。另一种可选方法是调节pH值以降低溶解度。有关结晶方面的详细描述请参见Crystallization,第三版,J W Mullens,Butterworth-HeinemanLtd.，1993,ISBN 0750611294。Generally, production scale crystallization can be accomplished by manipulating the solution such that the solubility limit of the compound of interest is exceeded. This can be accomplished by a variety of methods, for example, dissolving the compound at a relatively high temperature and then cooling the solution below the saturation limit. Or by boiling, atmospheric evaporation, vacuum drying or by some other method to reduce the liquid volume. The solubility of the compound of interest can be reduced by adding an antisolvent or a solvent in which the compound has low solubility, or a mixture of such solvents. Another alternative is to adjust the pH to reduce solubility. For a detailed description of crystallisation see Crystallization, Third Edition, J W Mullens, Butterworth-Heineman Ltd., 1993, ISBN 0750611294.
结晶的优化可包括用所需形式的晶体作为晶种接种于结晶介质中。另外，许多结晶方法使用上述策略的组合。一个实施例是在高温下将感兴趣的化合物溶解在溶剂中，随后通过受控方式加入适当体积的抗溶剂，以使体系正好在饱和水平之下。此时，可加入所需形式的晶种(并保持晶种的完整性)，将体系冷却以完成结晶。Optimization of crystallization may include seeding the crystallization medium with crystals of the desired form as seeds. Additionally, many crystallization methods use a combination of the above strategies. One example is to dissolve the compound of interest in a solvent at elevated temperature, followed by the controlled addition of an appropriate volume of antisolvent to bring the system just below saturation levels. At this point, the desired form of seed crystals can be added (and the integrity of the seed crystals maintained) and the system cooled to complete crystallization.
药物组合物和施用方法Pharmaceutical compositions and methods of administration
由于本发明的晶型A具有优异的治疗年龄相关退行性病变的活性，因此本发明的晶型A以及含有本发明的晶型A为主要活性成分的药物组合物可用于治疗、改善、减轻、减缓、控制、预防和/或逆转年龄相关退行性病变。Since the crystal form A of the present invention has excellent activity for treating age-related degenerative diseases, the crystal form A of the present invention and the pharmaceutical composition containing the crystal form A of the present invention as the main active ingredient can be used for treatment, improvement, alleviation, Slow, control, prevent and/or reverse age-related degeneration.
本发明所述的晶型A可用于治疗以下疾病(但并不限于)：年龄相关性肥胖症、年龄相关性血脂水平增加、年龄相关性胰岛素敏感性降低、年龄相关性记忆功能降低和年龄相关性眼功能改变(如黄斑变性)，或其组合。The crystal form A of the present invention can be used to treat (but not limited to) the following diseases: age-related obesity, age-related increased blood lipid levels, age-related decreased insulin sensitivity, age-related decreased memory function and age-related decreased Changes in sexual eye function (eg, macular degeneration), or a combination thereof.
本发明的药物组合物包含安全有效量范围内的本发明的多晶型物及药学上可以接受的赋形剂或载体。The pharmaceutical composition of the present invention comprises a safe and effective amount of the polymorph of the present invention and a pharmaceutically acceptable excipient or carrier.
其中，“安全有效量”指的是：化合物(或多晶型物)的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明的多晶型物/剂，更佳地，含有10-200mg本发明的多晶型物/剂。较佳地，所述的“一剂”为一个胶囊或药片。Wherein, "safe and effective amount" refers to: the amount of the compound (or polymorph) is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the polymorph of the present invention/dose, more preferably, 10-200 mg of the polymorph of the present invention/dose. Preferably, the "one dose" is a capsule or tablet.
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的活性成分以及它们之间相互掺和，而不明显降低活性成分的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如
本发明的多晶型物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。The mode of administration of the polymorph or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性成分与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，微晶纤维素、淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、碳酸钠、交联聚维酮、交联羧甲基纤维素钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or compatibilizers, for example, Microcrystalline cellulose, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; ( c) humectants, eg, glycerol; (d) disintegrants, eg, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, sodium carbonate, crospovidone, cross-linked Sodium carboxymethylcellulose; (e) solubilizers such as paraffin; (f) absorption accelerators such as quaternary amine compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostearate; (h) Sorbents, eg, kaolin; and (i) lubricants, eg, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性成分的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性成分也可与上述赋形剂中的一种或多种形成微胶囊形式。Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active ingredient in such compositions may be in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes. If desired, the active ingredient may also be in microencapsulated form with one or more of the above-mentioned excipients.
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性成分外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active ingredient, liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, and the like.
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。Besides these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
除了活性成分外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。In addition to the active ingredient, suspensions may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
用于局部给药的本发明的多晶型物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。Dosage forms of the polymorphs of the invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
本发明的多晶型物可以单独给药，或者与其他药学上可接受的化合物联合给药。The polymorphs of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
使用药物组合物时，是将安全有效量的本发明的多晶型物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选10～500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。When using the pharmaceutical composition, a safe and effective amount of the polymorphic form of the present invention is suitable for mammals (such as humans) in need of treatment, wherein the dose is a pharmaceutically considered effective dose when administered, and for a human with a body weight of 60kg For example, the daily dosage is usually 1 to 2000 mg, preferably 10 to 500 mg. Of course, the specific dosage should also take into account the route of administration, the patient's health and other factors, which are all within the skill of the skilled physician.
本发明的主要优点包括：The main advantages of the present invention include:
1.本发明的β-烟酰胺单核苷酸晶型A具有高热稳定性、高湿稳定性、无溶剂残留、纯度高、溶解度高(＞450mg/ml水)，非常适合用于成药。1. The β-nicotinamide mononucleotide crystal form A of the present invention has high thermal stability, high humidity stability, no solvent residue, high purity and high solubility (>450mg/ml water), and is very suitable for use in finished medicines.
2.本发明的晶型A在分装等药品制造过程中，不易扬起，易收集，不易造成浪费，且有助于保护操作人员的身体健康。2. The crystal form A of the present invention is not easy to lift, easy to collect, not easy to cause waste, and helps to protect the health of operators during the pharmaceutical manufacturing process such as sub-packaging.
3.本发明的晶型A制备方法简单，生成成本低，可大规模制备。3. The crystal form A of the present invention has a simple preparation method, low production cost, and can be prepared on a large scale.
下面结合具体实施，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。The present invention will be further described below in conjunction with specific implementation. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. In the following examples, the experimental methods without specific conditions are usually in accordance with conventional conditions, or in accordance with the conditions suggested by the manufacturer. Percentages and parts are by weight unless otherwise indicated.
通用方法general method
X射线粉末衍射(XRPD)X-ray powder diffraction (XRPD)
本发明中X射线粉末衍射，操作和分析步骤如下：X-ray powder diffraction in the present invention, operation and analysis steps are as follows:
采用Rigaku Ultima IV粉末衍射仪，该仪器采用Cu-K照射(40kV，40mA)，于室温下使用D/tex Ultra检测器进行。扫描范围在2区间自3°至45°，扫描速度20°/分钟。A Rigaku Ultima IV powder diffractometer was used with Cu-K irradiation (40 kV, 40 mA) at room temperature using a D/tex Ultra detector. The scanning range is from 3° to 45° in 2 intervals, and the scanning speed is 20°/min.
由包括以下的多种因素产生与这类X射线粉末衍射分析结果相关的测量差异：(a)样品制备物(例如样品高度)中的误差，(b)仪器误差，(c)校准差异，(d)操作人员误差(包括在测定峰位置时出现的误差)，和(e)物质的性质(例如优选的定向误差)。校准误差和样品高度误差经常导致所有峰在相同方向中的位移。当使用平的支架时，样品高度的小差异将导致XRPD峰位置的大位移。系统研究显示1mm的样品高度差异可以导致高至1°的2θ的峰位移。可以从X射线衍射图鉴定这些位移，并且可以通过针对所述位移进行补偿(将系统校准因子用于所有峰位置值)或再校准仪器消除所述位移。如上所述，通过应用系统校准因子使峰位置一致，可校正来自不同仪器的测量误差。Measurement differences associated with the results of such X-ray powder diffraction analyses arise from a number of factors including: (a) errors in sample preparation (eg, sample height), (b) instrumental errors, (c) calibration differences, ( d) operator errors (including errors in determining peak positions), and (e) properties of the material (eg preferred orientation errors). Calibration errors and sample height errors often cause all peaks to shift in the same direction. When a flat holder is used, small differences in sample height will result in large shifts in the position of the XRPD peaks. Systematic studies have shown that a sample height difference of 1 mm can result in peak shifts of up to 1° in 2Θ. These shifts can be identified from the X-ray diffractograms and can be eliminated by compensating for them (using a system calibration factor for all peak position values) or recalibrating the instrument. Measurement errors from different instruments can be corrected for by applying a system calibration factor to make the peak positions consistent, as described above.
差示扫描量热(DSC)分析Differential Scanning Calorimetry (DSC) Analysis
本发明中，差示扫描量热(DSC)分析，操作和分析步骤如下：In the present invention, differential scanning calorimetry (DSC) analysis, operation and analysis steps are as follows:
采用TA Q2000差示扫描量热仪，采用N2气氛，升温速度为10℃/min。A TA Q2000 differential scanning calorimeter was used, aN2 atmosphere was used, and the heating rate was 10 °C/min.
热重(TGA)分析Thermogravimetric (TGA) Analysis
本发明中，热重(TGA)分析，操作和分析步骤如下：In the present invention, thermogravimetric (TGA) analysis, operation and analysis steps are as follows:
采用TA Q500热重分析仪，采用N2气氛，升温速度为10℃/min。A TA Q500 thermogravimetric analyzer was used with a N atmosphere and a heating rate of10 °C/min.
实施例1Example 1
β-烟酰胺单核苷酸的晶型A的制备Preparation of crystal form A of β-nicotinamide mononucleotide
1.1称取100mg的β-烟酰胺单核苷酸原料于容器中，加入1ml的水溶清，静置挥发，固体真空干燥后得到β-烟酰胺单核苷酸晶型A。1.1
1.2称取100mg的β-烟酰胺单核苷酸原料于容器中，加入1ml的水溶清，加入5-10倍的甲醇，析出固体，过滤得到固体，真空干燥后得到β-烟酰胺单核苷酸晶型A。1.2 Weigh 100 mg of β-nicotinamide mononucleotide raw material in a container, add 1 ml of water-soluble clear, add 5-10 times of methanol, separate out solid, filter to obtain solid, and vacuum dry to obtain β-nicotinamide mononucleoside Acid crystal form A.
1.3称取100mg的β-烟酰胺单核苷酸原料于容器中，加入1ml的水溶清，加入5-10倍的乙醇，析出固体，过滤得到固体，真空干燥后得到β-烟酰胺单核苷酸晶型A。1.3 Weigh 100mg of β-nicotinamide mononucleotide raw material in a container, add 1ml of water-soluble clear, add 5-10 times of ethanol, precipitate a solid, filter to obtain a solid, and vacuum dry to obtain β-nicotinamide mononucleoside Acid crystal form A.
1.4称取100mg的β-烟酰胺单核苷酸原料于容器中，加入1ml的水溶清，加入5-10倍的正丙醇，析出固体，过滤得到固体，真空干燥后得到β-烟酰胺单核苷酸晶型A。1.4 Weigh 100 mg of β-nicotinamide mononucleotide raw material in a container, add 1 ml of water-soluble clear, add 5-10 times of n-propanol, precipitate a solid, filter to obtain a solid, and vacuum dry to obtain β-nicotinamide mononucleotide. Nucleotide crystal form A.
1.5称取100mg的β-烟酰胺单核苷酸原料于容器中，加入1ml的水溶清，加入5-10倍的异丙醇，析出固体，过滤得到固体，真空干燥后得到β-烟酰胺单核苷酸晶型A。1.5 Weigh 100 mg of β-nicotinamide mononucleotide raw material in a container, add 1 ml of water-soluble clear, add 5-10 times of isopropanol, separate out solids, filter to obtain solids, and vacuum dry to obtain β-nicotinamide mononucleotides. Nucleotide crystal form A.
1.6称取100mg的β-烟酰胺单核苷酸原料于容器中，加入1ml的水溶清，加入5-10倍的乙腈，析出固体，过滤得到固体，真空干燥后得到β-烟酰胺单核苷酸晶型A。1.6 Weigh 100 mg of β-nicotinamide mononucleotide raw material in a container, add 1 ml of water-soluble clear, add 5-10 times of acetonitrile, precipitate a solid, filter to obtain a solid, and vacuum dry to obtain β-nicotinamide mononucleoside Acid crystal form A.
1.7称取100mg的β-烟酰胺单核苷酸原料于容器中，加入1ml的水溶清，加入5-10倍的丙酮，析出固体，过滤得到固体，真空干燥后得到β-烟酰胺单核苷酸晶型A。1.7 Weigh 100 mg of β-nicotinamide mononucleotide raw material in a container, add 1 ml of water-soluble clear, add 5-10 times of acetone, precipitate a solid, filter to obtain a solid, and vacuum dry to obtain β-nicotinamide mononucleoside Acid crystal form A.
1.8称取100mg的β-烟酰胺单核苷酸原料于容器中，加入1ml的水溶清，加入5-10倍的N-甲基吡咯烷酮，析出固体，过滤得到固体，真空干燥后得到β-烟酰胺单核苷酸晶型A。1.8 Weigh 100 mg of β-nicotinamide mononucleotide raw material in a container, add 1 ml of water-soluble clear, add 5-10 times of N-methylpyrrolidone, separate out solid, filter to obtain solid, and vacuum dry to obtain β-nicotine Amide mononucleotide crystal form A.
1.9称取100mg的β-烟酰胺单核苷酸原料于容器中，加入1ml的水溶清，加入5-10倍的四氢呋喃，析出固体，过滤得到固体，真空干燥后得到β-烟酰胺单核苷酸晶型A。1.9
1.10称取100mg的β-烟酰胺单核苷酸原料于容器中，加入1ml的水溶清，加入5-10倍的1,4-二氧六环，析出固体，过滤得到固体，真空干燥后得到β-烟酰胺单核苷酸晶型A。1.10
1.11称取100mg的β-烟酰胺单核苷酸原料于容器中，加入1ml的水溶清，加入5-10倍的DMF，析出固体，过滤得到固体，真空干燥后得到β-烟酰胺单核苷酸晶型A。1.11
1.12称取100mg的β-烟酰胺单核苷酸原料于容器中，加入1ml的水溶清，加入5-10倍的DMSO，析出固体，过滤得到固体，真空干燥后得到β-烟酰胺单核苷酸晶型A。1.12
1.13称取100mg的β-烟酰胺单核苷酸原料于容器中，加入体积比为1∶2的水和甲醇50℃溶清，缓慢冷却至4℃，析出固体，过滤得到固体，真空干燥后得到β-烟酰胺单核苷酸晶型A。1.13
1.14称取100mg的β-烟酰胺单核苷酸原料于容器中，加入体积比为1∶2的水和乙醇50℃溶清，缓慢冷却至4℃，析出固体，过滤得到固体，真空干燥后得到β-烟酰胺单核苷酸晶型A。1.14 Weigh 100mg of β-nicotinamide mononucleotide raw material in a container, add water and ethanol with a volume ratio of 1:2 to dissolve at 50°C, slowly cool to 4°C, separate out a solid, filter to obtain a solid, and vacuum dry. β-nicotinamide mononucleotide crystal form A is obtained.
1.15称取100mg的β-烟酰胺单核苷酸原料于容器中，加入体积比为1∶2的水和丙酮50℃溶清，缓慢冷却至4℃，析出固体，过滤得到固体，真空干燥后得到β-烟酰胺单核苷酸晶型A。1.15 Weigh 100mg of β-nicotinamide mononucleotide raw material in a container, add water and acetone with a volume ratio of 1:2 to dissolve at 50°C, slowly cool to 4°C, separate out solids, filter to obtain solids, and vacuum dry them. β-nicotinamide mononucleotide crystal form A is obtained.
1.16称取100mg的β-烟酰胺单核苷酸原料于容器中，加入体积比为1∶2的水和N-甲基吡咯烷酮50℃溶清，缓慢冷却至4℃，析出固体，过滤得到固体，真空干燥后得到β-烟酰胺单核苷酸晶型A。1.16
1.17称取100mg的β-烟酰胺单核苷酸原料于容器中，加入体积比为1∶2的水和四氢呋喃50℃溶清，缓慢冷却至4℃，析出固体，过滤得到固体，真空干燥后得到β-烟酰胺单核苷酸晶型A。1.17
1.18称取100mg的β-烟酰胺单核苷酸原料于容器中，加入体积比为1∶2的水和DMF50℃溶清，缓慢冷却至4℃，析出固体，过滤得到固体，真空干燥后得到β-烟酰胺单核苷酸晶型A。1.18
1.18称取100mg的β-烟酰胺单核苷酸原料于容器中，加入体积比为1∶2的水和DMSO50℃溶清，缓慢冷却至4℃，析出固体，过滤得到固体，真空干燥后得到β-烟酰胺单核苷酸晶型A。1.18
本发明制备的β-烟酰胺单核苷酸的晶型A。衍射图如图1所示，晶型A的XRPD图的衍射峰列于下表1：The crystal form A of the β-nicotinamide mononucleotide prepared by the present invention. The diffraction pattern is shown in Figure 1, and the diffraction peaks of the XRPD pattern of Form A are listed in Table 1 below:
表1晶型A的XRPD图Table 1 XRPD pattern of Form A
对实施例1中的晶型A做DSC分析，晶型A的DSC图如图2所示，其中吸热峰对应熔融分解过程。The DSC analysis of the crystal form A in Example 1 is carried out, and the DSC chart of the crystal form A is shown in FIG. 2 , wherein the endothermic peak corresponds to the melting decomposition process.
对实施例1中的晶型A做热重(TGA)分析，TGA图如图3所示，由图可知在分解前基本无失重(100℃前失重＜0.2％)。Thermogravimetric (TGA) analysis was performed on Form A in Example 1. The TGA diagram is shown in Figure 3. It can be seen from the figure that there is basically no weight loss before decomposition (weight loss before 100°C <0.2%).
无定型的β-烟酰胺单核苷酸XRPD图谱如图4所示，TGA图谱如图5所示。The amorphous β-nicotinamide mononucleotide XRPD pattern is shown in Figure 4, and the TGA pattern is shown in Figure 5.
由图5可知，无定型的β-烟酰胺单核苷酸100℃之前失重为1.655％，这提示其存在明显的溶剂残留。It can be seen from Fig. 5 that the weight loss of amorphous β-nicotinamide mononucleotide before 100°C is 1.655%, which suggests that there is obvious solvent residue.
此外，无定型的β-烟酰胺单核苷酸不稳定，在空气中放置48h易转变为晶型A。In addition, the amorphous β-nicotinamide mononucleotide is unstable, and is easily transformed into crystal form A when placed in the air for 48 hours.
而本发明的晶型A几乎没有溶剂残留，纯度高，且稳定性高。However, the crystal form A of the present invention has almost no solvent residue, high purity and high stability.
实施例2光照稳定性Example 2 Light Stability
实验条件：温度：25℃，4500Lux光照条件。Experimental conditions: Temperature: 25°C, 4500Lux light conditions.
如图6所示，结果显示晶型A在25℃4500Lux光照条件下5天和10天晶型稳定，具有很好的光照稳定性。As shown in Figure 6, the results show that the crystal form A is stable for 5 days and 10 days under the light condition of 4500Lux at 25°C, and has good light stability.
实施例3高温稳定性Example 3 High temperature stability
如图7所示，结果显示晶型A在60℃条件下5天和10天晶型稳定，具有很好的高温稳定性。As shown in Figure 7, the results show that the crystal form A is stable for 5 days and 10 days at 60 °C, and has good high temperature stability.
实施例4高湿稳定性1Example 4 High Humidity Stability 1
如图8所示，结果显示晶型A在40℃，75％RH条件下5天和10天晶型稳定。As shown in Figure 8, the results showed that Form A was stable for 5 days and 10 days under the conditions of 40 °C and 75% RH.
实施例5高湿稳定性2Example 5
如图9所示，结果显示晶型A在25℃，92.5％RH条件下5天和10天晶型稳定。As shown in Fig. 9, the results show that Form A is stable for 5 days and 10 days under the conditions of 25°C and 92.5% RH.
实施例6药物组合物Example 6 Pharmaceutical composition
β-烟酰胺单核苷酸晶型A 20gβ-nicotinamide mononucleotide crystal form A 20g
淀粉 140gStarch 140g
微晶纤维素 60gMicrocrystalline Cellulose 60g
按常规方法，将上述物质混合均匀后，装入普通明胶胶囊，得到1000颗胶囊。According to the conventional method, after the above-mentioned substances are mixed uniformly, they are loaded into ordinary gelatin capsules to obtain 1000 capsules.
综上，本发明的晶型A具有高热稳定性、高湿稳定性、无溶剂残留、纯度高、溶解度高(＞450mg/ml水)，非常适合用于成药。且本发明的晶型A在分装等药品制造过程中，不易扬起，易收集，不易造成浪费，且有助于保护操作人员的身体健康。In conclusion, the crystal form A of the present invention has high thermal stability, high humidity stability, no solvent residue, high purity, and high solubility (>450 mg/ml water), and is very suitable for use in finished medicines. In addition, the crystal form A of the present invention is not easy to be raised, easy to collect, not easy to be wasted, and helps to protect the health of operators during the pharmaceutical manufacturing process such as sub-packaging.
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。All documents mentioned herein are incorporated by reference in this application as if each document were individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.
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