WO2021189343A1 - 一种含笑内酯二甲基胺富马酸盐的水合物、其制备方法和用途 - Google Patents

一种含笑内酯二甲基胺富马酸盐的水合物、其制备方法和用途 Download PDF

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WO2021189343A1
WO2021189343A1 PCT/CN2020/081349 CN2020081349W WO2021189343A1 WO 2021189343 A1 WO2021189343 A1 WO 2021189343A1 CN 2020081349 W CN2020081349 W CN 2020081349W WO 2021189343 A1 WO2021189343 A1 WO 2021189343A1
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solvent
hydrate
dimethylamine
cancer
fumarate
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PCT/CN2020/081349
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English (en)
French (fr)
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李中华
龚俊波
侯宝红
吴送姑
陈悦
邱传将
朱兴华
齐杰
王桂燕
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天津尚德药缘科技股份有限公司
南开大学
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Priority to IL295869A priority Critical patent/IL295869A/en
Priority to US17/905,127 priority patent/US20230089334A1/en
Priority to KR1020227028865A priority patent/KR20220130212A/ko
Priority to AU2020437428A priority patent/AU2020437428B2/en
Priority to PCT/CN2020/081349 priority patent/WO2021189343A1/zh
Priority to EP20926506.5A priority patent/EP4071143A4/en
Priority to JP2023500114A priority patent/JP2023522792A/ja
Priority to CA3164892A priority patent/CA3164892A1/en
Publication of WO2021189343A1 publication Critical patent/WO2021189343A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/15—Fumaric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
    • 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
    • C07B2200/07—Optical isomers
    • 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 invention belongs to the technical field of drug crystallization, and specifically relates to a hydrate of mircolactone dimethylamine fumarate, a preparation method and application thereof.
  • Parthenolide is a main active ingredient extracted from the Asteraceae herbs wild chamomile and tansy. It is a natural sesquiterpene lactone compound. Traditionally parthenolide is mainly used for fever , Rheumatoid arthritis, migraine, toothache and other diseases. In recent years, domestic and foreign studies have found that parthenolide also has anti-tumor effects, but this compound is unstable under acidic or alkaline conditions.
  • Micheliolide MCL
  • Esters have the effect of treating cancer diseases, but they have poor water solubility.
  • the sinolactone derivative namely sinolactone dimethylamine, is obtained by heating reaction in a methanol solvent with the molecular formula C 17 H 27 NO 3 and the structural formula is as follows ,
  • the English name is Dimethylaminomicheliolide (DMAMCL).
  • DMAMCL Compared with MCL, DMAMCL has a certain degree of improvement in water solubility, but it will degrade and become unstable when placed for a long time. In order to further improve its water solubility and stability, it is usually prepared in the form of a salt. The inventors have discovered that mircolactone dimethylamine fumarate prepared from parthenolide is derived. At the same time, patent WO2011/131103A1 discloses the preparation method of micolactone derivatives or their salts including micolactone dimethylamine fumarate, their pharmaceutical compositions, and their use in the preparation of cancer drugs.
  • Lactone dimethylamine fumarate has a molecular formula of C 21 H 31 NO 7 and a relative molecular weight of 409. It is a white crystalline powder, tasteless and odorless, soluble in water, methanol, ethanol, tetrahydrofuran, 1,4-di Oxane, acetone, acetonitrile, and isopropyl acetate are almost insoluble in cyclohexane, n-hexane, n-heptane, dichloromethane, isopropyl ether, and toluene.
  • the chemical structure is as follows:
  • Polymorphism refers to the existence of different molecular arrangements or conformations in the crystal lattice of the same substance, resulting in different crystal structures. According to statistics, polymorphism exists in 80% of the drugs on the market. Different crystal forms of the same drug have significant differences in physical and chemical properties such as color, solubility, melting point, density, hardness, crystal morphology, etc., which in turn causes quality differences in drug stability, dissolution, and bioavailability, which affect the subsequent processing and processing of the product. Treatment, and to a certain extent affect the efficacy and safety of the drug. In the process of drug quality control and the design of new drug forms, the research of drug polymorphs has become an indispensable and important part.
  • Chinese patent CN103724307B discloses the crystalline form A of mirinolactone dimethylamine fumarate and its preparation method.
  • the patent uses XRPD to characterize the crystalline form A, which is represented by 2 ⁇ at 7.10°, 7.58°, 11.72°, 12.26° , 13.30°, 14.24°, 15.70°, 16.38°, 17.04°, 19.02°, 19.86°, 20.14°, 20.66°, 21.20°, 21.78°, 22.64°, 23.58°, 23.8°, 24.48°, 25.08°, 26.24 °, 27.08°, 27.60°, 28.40°, 28.94°, 34.48°, 34.82°, 36.12°, 38.72°, 45°, there are characteristic peaks, crystal form A is prepared by recrystallization in ethyl acetate solvent, in this method The natural cooling method is used to prepare the product, and the crystallization process is controlled by both thermodynamics and kinetics
  • the natural cooling crystallization condition fluctuates greatly due to environmental influences, and the cooling rate is difficult to control.
  • the product particle size is small, the main particle size is 35.8 ⁇ m, and the bulk density is small , It only reaches 0.270g/mL, the angle of repose is 62°, the fluidity is poor, and the quality of crystal products varies greatly between different batches.
  • the stability of crystal form A is poor, and crystal form conversion is prone to occur, and the solid powder still has a strong electrostatic effect, which leads to the phenomenon of dust during the production process, which will bring many problems to the later processing and handling.
  • the present invention provides a hydrate of mircolactone dimethylamine fumarate, a preparation method and application thereof, and a method of reactive crystallization is used to prepare a hydrate with high crystallinity, high bulk density and good fluidity.
  • a method of reactive crystallization is used to prepare a hydrate with high crystallinity, high bulk density and good fluidity.
  • the present invention provides a hydrate of sinolactone dimethylamine fumarate, which is characterized in that the hydrate is crystal form D, and the molar ratio of sinolactone dimethylamine fumarate to water is It is 1:1 and the molecular formula is C 17 H 27 NO 3 ⁇ C 4 H 4 O 4 ⁇ H 2 O.
  • the hydrate of mircolactone dimethylamine fumarate is characterized in that the differential scanning calorimetry spectrum has a dehydration endothermic peak at 75 ⁇ 5°C, at 148 ⁇ There is a characteristic melting peak at 5°C.
  • the hydrate of mircolactone dimethylamine fumarate provided by the present invention is characterized in that the hydrate uses Cu-K ⁇ radiation, as shown in FIG. 2 by X-ray powder diffraction at 2 ⁇ angles. 7.8 ⁇ 0.2°, 11.1 ⁇ 0.2°, 11.4 ⁇ 0.2°, 12.6 ⁇ 0.2°, 12.9 ⁇ 0.2°, 14.4 ⁇ 0.2°, 15.3 ⁇ 0.2°, 17.0 ⁇ 0.2°, 18.7 ⁇ 0.2°, 19.7 ⁇ 0.2°, There are characteristic peaks at 20.6 ⁇ 0.2°, 21.0 ⁇ 0.2°, 22.5 ⁇ 0.2°, 23.7 ⁇ 0.2°, 24.3 ⁇ 0.2°, 25.5 ⁇ 0.2°, 26.2 ⁇ 0.2°, of which 7.8 ⁇ 0.2° is the initial peak, and 20.6
  • the relative intensity of the characteristic peak at ⁇ 0.2° is 100%
  • the crystal form D is an orthorhombic system
  • the space group is P212121
  • the unit cell volume is
  • the hydrate of mircolactone dimethylamine fumarate provided by the present invention is characterized in that the hydrate uses Cu-K ⁇ radiation, and the X-ray powder diffraction expressed at an angle of 2 ⁇ is still at 10.5 ⁇ 0.2°, 11.7 ⁇ 0.2°, 12.0 ⁇ 0.2°, 15.6 ⁇ 0.2°, 15.9 ⁇ 0.2°, 16.2 ⁇ 0.2°, 21.3 ⁇ 0.2°, 22.1 ⁇ 0.2°, 23.0 ⁇ 0.2°, 26.4 ⁇ 0.2°, 27.2 ⁇ 0.2°, There are characteristic peaks at 28.2 ⁇ 0.2°, 28.6 ⁇ 0.2°, 29.3 ⁇ 0.2°, 30.4 ⁇ 0.2°, and 31.1 ⁇ 0.2°.
  • the present invention also provides a method for preparing the hydrate of mircolactone dimethylamine fumarate, which can be achieved by a method of reaction crystallization: under stirring, dimethylamine mircolactone and fumaric acid are added to the temperature In the mixed solvent system of solvent S1 and solvent S2 at a constant temperature of 30°C-70°C, the mass ratio of solvent S2 to solvent S1 is (0-3):1, and the molar ratio of dimethylamine mirin and fumaric acid is ( 1-1.6):1, react for 5-10h, filter, and dry at 25-45°C under normal pressure for 6-10h to obtain crystal form D of mircolactone dimethylamine fumarate.
  • the solvent S1 is a mixed solvent of any one of acetone, tetrahydrofuran, 1,4-dioxane, acetonitrile, and methyl isobutyl ketone and water
  • the solvent S2 is a mixed solvent of ester and ether solvents.
  • the ester solvent is selected from any one or two of methyl acetate, ethyl acetate, hexyl acetate, and isopropyl acetate.
  • the ether solvent is selected from the group consisting of diethyl ether, methyl ethyl ether, methyl tert-butyl ether, dipropyl ether, dibutyl ether, ethylene glycol dimethyl ether, ethylene glycol monomethyl ether, 1,4-dioxide Any one or two of six rings, tetrahydrofuran, and 2-methyltetrahydrofuran.
  • the solvent S1 is a mixed solvent of any one of acetone, tetrahydrofuran, 1,4-dioxane, acetonitrile, and methyl isobutyl ketone and water.
  • the mass ratio of the ester solvent to the ether solvent in the solvent S2 is (1-3):1.
  • the mass ratio of the solid raw material of dimethylamine mircolactone to S1 is 1: (6-10).
  • the present invention studies the crystal habit of the hydrate of sarcolide dimethylamine fumarate.
  • the scanning electron micrograph is shown in Figure 3.
  • the crystals are regular block crystal habit, and the surface of the particles is smooth and free of coalescence.
  • the average particle size of the crystal is large, which can reach 300 ⁇ m, the bulk density is 0.65g/mL, the angle of repose is 32°, the product has high bulk density and good fluidity.
  • the main particle size of the product is 35.8um
  • the bulk density is only 0.270g/mL
  • the angle of repose is 62°.
  • the scanning electron micrograph is shown in attached Figure 4.
  • the mircolactone dimethylamine fumarate hydrate crystal form D product provided by the invention obviously increases the particle size and solves the problems of low bulk density and poor fluidity of the crystal form A product.
  • the stability of the hydrate of mircolide dimethylamine fumarate is investigated, and the crystal-free compound product is uniformly distributed in an open petri dish, and the temperature is controlled at 45°C and the humidity is 75%, the thickness of the sample is less than 5mm, sealed and placed in a desiccator for 30 days, and then XRD detection is performed on the samples that have been placed for 7, 14, and 30 days, and the results are compared with the detection results on day 0.
  • the specific map is shown in Figure 5. The result shows that the XRD pattern has no obvious change.
  • the mircolactone dimethylamine fumarate hydrate provided by the present invention can be used to prepare mircolactone dimethylamine fumarate solvent-free compound crystal form B.
  • the preparation method of the crystal form B is as follows: The hydrate of lactone dimethylamine fumarate was heated at a constant temperature of 80°C-120°C for 10min-30min to obtain the crystalline form B of the solvent-free compound of mircolactone dimethylamine fumarate, and its X-ray powder diffraction pattern See attached figure 6, expressed in 2 ⁇ angles at 8.1 ⁇ 0.2°, 10.7 ⁇ 0.2°, 11.5 ⁇ 0.2°, 11.9 ⁇ 0.2°, 13.0 ⁇ 0.2°, 13.3 ⁇ 0.2°, 14.7 ⁇ 0.2°, 15.9 ⁇ 0.2°, 16.1 ⁇ 0.2°, 16.7 ⁇ 0.2°, 17.1 ⁇ 0.2°, 19.0 ⁇ 0.2°, 19.9 ⁇ 0.2°, 20.3 ⁇ 0.2°, 21.2 ⁇ 0.2°, 21.5 ⁇ 0.2°, 22.1 ⁇ 0.2°, 23.0 ⁇ 0.2°, 23.5 ⁇ 0.2°, 24.4 ⁇ 0.2°
  • the mircolactone dimethylamine fumarate hydrate of the present invention also provides a pharmaceutical composition, which contains pharmaceutically acceptable excipients, and can also contain the hydration of mircolactone dimethylamine fumarate One, two or more pharmacologically active ingredients other than substances.
  • the pharmaceutical excipients include, but are not limited to, other non-pharmacologically active ingredients other than the active ingredient such as dimethylamine mircolactone fumarate in crystalline form, for example, non-pharmacologically active ingredients that can be used in the pharmaceutical composition of the present invention , which includes carriers or excipients, such as fillers, glidants, lubricants, binders, stabilizers and/or other auxiliary materials.
  • the filler includes but is not limited to at least one of corn starch, glucose, mannitol, sorbitol, silicon dioxide, microcrystalline cellulose, sodium carboxymethyl starch, composite starch, and pregelatinized starch.
  • the glidant includes but is not limited to at least one of silica, hydrated silica, light anhydrous silicic acid, dry aluminum hydroxide gel, aluminum silicate, and magnesium silicate.
  • the lubricant includes, but is not limited to, wheat starch, rice starch, corn starch, stearic acid, calcium stearate, magnesium stearate, hydrated silicon dioxide, light anhydrous silicic acid, synthetic aluminum silicate, dry hydrogen At least one of alumina gel, talc, magnesium aluminum metasilicate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, sucrose fatty acid ester, paraffins, hydrogenated vegetable oil, and polyethylene glycol.
  • a pharmaceutical preparation is prepared, which is characterized in that the pharmaceutical preparation comprises a tablet, capsule or granule dosage form of the pharmaceutical composition. It is more preferably a capsule.
  • the present invention also provides the use of the sinolactone dimethylamine fumarate hydrate or the pharmaceutical composition in the preparation of a medicine for the treatment or prevention of a disease or condition, and the disease or condition is preferably cancer.
  • Said cancer is selected from leukemia, breast cancer, prostate cancer, nasopharyngeal cancer, colorectal cancer, lung cancer, liver cancer, esophageal cancer, stomach cancer, intestinal cancer, kidney cancer, oral cancer, Hodgkin's lymphoma, pancreatic cancer, rectal cancer , Cervical cancer, non-Hodgkin’s lymphoma, glioma, melanoma, bladder cancer, ovarian cancer, thyroid cancer or Kaposi’s sarcoma.
  • the hydrate of the present invention has better fluidity and is more suitable for the preparation of medicines in the later stage.
  • the fluidity of the active ingredient itself is difficult to meet the filling conditions of capsules or microcapsules.
  • auxiliary materials such as pregelatinized starch, silicon dioxide and magnesium stearate, in order to meet the filling conditions for fluidity. Requirements to achieve the desired dosage form quality and production efficiency. Take the 100mg capsule specification as an example. If other forms such as crystal form A are used as the active ingredient, the weight of the capsule content will reach about 310mg after the addition of auxiliary materials. The largest 0# capsule shell must be used, and larger specifications cannot be prepared. A capsule containing 200 mg of active ingredient.
  • the crystalline form D of mircolactone dimethylamine fumarate hydrate can reduce the amount of excipients added, even without adding excipients.
  • the crystal form A needs to add a large amount of auxiliary materials to have the same fluidity as the hydrate crystal form D, and the stability is poor. Therefore, the hydrate crystal form D also improves the stability of the preparation.
  • the preparation method of mircolactone dimethylamine fumarate hydrate crystal form D has simple operation steps, high product yield, good reproducibility, high crystallinity, and the surface of the particles is smooth and does not coalesce. No static electricity, high bulk density, which is more conducive to mass production.
  • Fig. 1 The thermogravimetric analysis/differential scanning calorimetry diagram of mircolide dimethylamine fumarate hydrate of the present invention.
  • Fig. 2 X-ray diffraction pattern of mircolide dimethylamine fumarate hydrate of the present invention.
  • Fig. 3 Scanning electron micrograph of sinolactone dimethylamine fumarate hydrate of the present invention (magnification 40 times).
  • Fig. 4 is a scanning electron micrograph (200 times magnification) of a crystal form product prepared according to the method disclosed in the patent CN103724307B.
  • Fig. 5 Comparison of the stability test patterns of the milanolide dimethylamine fumarate hydrate of the present invention, wherein the XRD patterns of the samples stored for 0 days, 7 days, 14 days, and 30 days from bottom to top.
  • Fig. 6 The X-ray diffraction pattern of the crystalline form B of the solvent-free compound of miracrolactone dimethylamine fumarate of the present invention.
  • solvent S1 is composed of 1.598g acetone solvent and 0.16g water
  • solvent S2 is composed of 0.879g ethyl acetate and 0.879g ether. After reacting for 5 hours, it is filtered and dried at 25°C under normal pressure for 6 hours to obtain mircolactone dimethylamine Fumarate D crystal product.
  • the thermogravimetric analysis/differential scanning calorimetry analysis of the product is consistent with Figure 1.
  • thermogravimetric analysis shows a weight loss of 4.22% before decomposition
  • differential scanning calorimetry analysis shows a dehydration endothermic peak at 75°C, at 148 °C has a characteristic melting peak.
  • the X-ray powder diffraction pattern of the product is consistent with Figure 2, and the diffraction angle 2 ⁇ is expressed at 7.8°, 11.1°, 11.4°, 12.6°, 12.9°, 14.4°, 15.3°, 17.0°, 18.7°, 19.7°, 20.6
  • characteristic peaks at °, 21.0°, 22.5°, 23.7°, 24.3°, 25.5°, 26.2°, of which 7.8° is the initial peak, and the relative intensity of the characteristic peak at 20.6° is 100%.
  • the X-ray powder diffraction pattern of the product is expressed in 2 ⁇ angles at 10.5 ⁇ 0.2°, 11.7 ⁇ 0.2°, 12.0 ⁇ 0.2°, 15.6 ⁇ 0.2°, 15.9 ⁇ 0.2°, 16.2 ⁇ 0.2°, 21.3 ⁇ 0.2°, 22.1 ⁇
  • the SEM photo of the crystal morphology is consistent with Figure 4, it is a bulk crystal, the average particle size of the particles is large, which can reach 300 ⁇ m, the bulk density of the test is 0.646g/mL, and the angle of repose is 32.5°.
  • the quality of solvent S2 is 2 of that of solvent S1.
  • the solvent S1 is composed of 12.306g tetrahydrofuran solvent and 1.758g water
  • the solvent S2 is composed of 21.096g isopropyl acetate and 7.032g methyl tert-butyl ether. After 8 hours of reaction, it is filtered and dried under normal pressure at 30°C for 10 hours. The crystalline form D product of mircolactone dimethylamine fumarate was obtained.
  • thermogravimetric analysis/differential scanning calorimetry analysis of the product is consistent with Figure 1.
  • the thermogravimetric analysis shows that there will be a weight loss of 4.20% before decomposition, and the differential scanning calorimetry analysis shows that there is a dehydration endothermic peak at 78°C, at 150 °C has a characteristic melting peak.
  • the X-ray powder diffraction pattern of the product is consistent with Figure 2, and the diffraction angle 2 ⁇ is expressed at 8.0°, 11.2°, 11.5°, 12.7°, 12.9°, 14.5°, 15.4°, 17.1°, 18.8°, 19.8°, 20.6
  • the X-ray powder diffraction pattern of the product is expressed in 2 ⁇ angles at 10.6°, 11.8°, 12.2°, 15.1°, 15.7°, 16.0°, 21.4°, 22.0°, 22.3°, 23.1°, 27.3°, 28.2°, 28.7 There are characteristic peaks at °, 29.4°, 30.5°, 30.6°, and 31.3°.
  • the SEM photo of the crystal morphology is consistent with Figure 4, it is a massive crystal, the average particle size of the particles is large, which can reach 300 ⁇ m, the bulk density of the test is 0.655g/mL, and the angle of repose is 32°.
  • thermogravimetric analysis shows that there will be a 3.97% weight loss before decomposition
  • differential scanning calorimetry analysis shows that there is a dehydration endothermic peak at 75°C, at 145°C. °C has a characteristic melting peak.
  • the X-ray powder diffraction pattern of the product is consistent with Figure 2, and the diffraction angle 2 ⁇ is expressed at 7.8°, 11.0°, 11.4°, 12.5°, 12.8°, 14.4°, 15.3°, 17.0°, 18.7°, 19.7°, 20.6
  • the X-ray powder diffraction pattern of the product is expressed in 2 ⁇ angles at 10.5°, 11.7°, 12.0°, 15.6°, 15.9°, 16.2°, 21.3°, 22.2°, 22.9°, 26.4°, 27.3°, 28.2°, 28.6 There are characteristic peaks at °, 29.3°, 30.4°, and 31.1°.
  • the SEM photo of the crystal morphology is consistent with Figure 4, it is a massive crystal, the average particle size of the particles is large, which can reach 300 ⁇ m, the bulk density of the test is 0.65g/mL, and the angle of repose is 32°.
  • thermogravimetric analysis shows that there will be a weight loss of 4.10% before decomposition
  • differential scanning calorimetry analysis shows that there is a dehydration endothermic peak at 80°C, at 150 °C has a characteristic melting peak.
  • the X-ray powder diffraction pattern of the product is consistent with Figure 2, and the diffraction angle 2 ⁇ is expressed at 7.8°, 11.1°, 11.4°, 12.6°, 12.9°, 14.4°, 15.4°, 17.0°, 18.8°, 19.8°, 20.6
  • characteristic peaks at °, 21.0°, 22.5°, 23.7°, 24.4°, 25.5°, 26.2°, of which 7.8° is the initial peak, and the relative intensity of the characteristic peak at 20.6° is 100%.
  • the X-ray powder diffraction pattern of the product is expressed in 2 ⁇ angles at 10.6°, 11.8°, 12.1°, 15.9°, 16.3°, 21.4°, 22.2°, 23.0°, 26.5°, 27.3°, 28.7°, 29.3°, 30.4 There are characteristic peaks at ° and 31.1°.
  • the SEM photo of the crystal morphology is consistent with Figure 4, it is a bulk crystal, the average particle size of the particles is large, which can reach 300 ⁇ m, the bulk density of the test is 0.659g/mL, and the angle of repose is 32.2°.
  • solvent S1 is composed of 1.598 g of acetonitrile solvent and 0.16 g of water
  • solvent S2 is composed of 0.879 g of isopropyl acetate and 0.879 g of ethylene glycol monomethyl ether. After reacting for 5 hours, it is filtered and dried under normal pressure at 25°C for 6 hours to obtain a smile. Lactone dimethylamine fumarate D crystal product. The thermogravimetric analysis/differential scanning calorimetry analysis of the product is consistent with Figure 1.
  • thermogravimetric analysis shows a weight loss of 4.22% before decomposition
  • differential scanning calorimetry analysis shows a dehydration endothermic peak at 75°C, at 148 °C has a characteristic melting peak.
  • the X-ray powder diffraction pattern of the product is consistent with Figure 2, and the diffraction angle 2 ⁇ is expressed at 7.8°, 11.1°, 11.4°, 12.6°, 12.9°, 14.4°, 15.3°, 17.0°, 18.7°, 19.7°, 20.6
  • characteristic peaks at °, 21.0°, 22.5°, 23.7°, 24.3°, 25.5°, 26.2°, of which 7.8° is the initial peak, and the relative intensity of the characteristic peak at 20.6° is 100%.
  • the X-ray powder diffraction pattern of the product is expressed in 2 ⁇ angles at 10.5 ⁇ 0.2°, 11.7 ⁇ 0.2°, 12.0 ⁇ 0.2°, 15.6 ⁇ 0.2°, 15.9 ⁇ 0.2°, 16.2 ⁇ 0.2°, 21.3 ⁇ 0.2°, 22.1 ⁇
  • the SEM photo of the crystal morphology is consistent with Figure 4, it is a massive crystal, the average particle size of the particles is large, which can reach 300 ⁇ m, the bulk density of the test is 0.645g/mL, and the angle of repose is 32°.
  • the quality of solvent S2 is 3 of that of solvent S1.
  • the solvent S1 is composed of 39g methyl isobutyl ketone solvent and 7.88g water
  • the solvent S2 is composed of 46.88g methyl acetate, 46.88g isopropyl acetate, 23.44g tetrahydrofuran and 23.44g dibutyl ether.
  • thermogravimetric analysis/differential scanning calorimetry analysis of the product is consistent with Figure 1.
  • the thermogravimetric analysis shows that there will be a 3.97% weight loss before decomposition, and the differential scanning calorimetry analysis shows that there is a dehydration endothermic peak at 75°C, at 145°C. °C has a characteristic melting peak.
  • the X-ray powder diffraction pattern of the product is consistent with Figure 2, and the diffraction angle 2 ⁇ is expressed at 7.8°, 11.0°, 11.4°, 12.5°, 12.8°, 14.4°, 15.3°, 17.0°, 18.7°, 19.7°, 20.6
  • the X-ray powder diffraction pattern of the product is expressed in 2 ⁇ angles at 10.5°, 11.7°, 12.0°, 15.6°, 15.9°, 16.2°, 21.3°, 22.2°, 22.9°, 26.4°, 27.3°, 28.2°, 28.6 There are characteristic peaks at °, 29.3°, 30.4°, and 31.1°.
  • the SEM photo of the crystal morphology is consistent with Figure 4, it is a bulk crystal, the average particle size of the particles is large, which can reach 300 ⁇ m, the bulk density of the test is 0.65g/mL, and the angle of repose is 32.3°.
  • solvent S1 is composed of 12.306g methyl isobutyl ketone solvent and 1.758g water
  • solvent S2 is composed of 21.096g methyl acetate and 7.032g 2-methyltetrahydrofuran. After 9 hours of reaction, filter, and normal pressure at 30°C. After drying for 10 hours, the D crystal form of mircolactone dimethylamine fumarate was obtained.
  • the thermogravimetric analysis/differential scanning calorimetry analysis of the product is consistent with Figure 1.
  • thermogravimetric analysis shows that there will be a weight loss of 4.20% before decomposition
  • differential scanning calorimetry analysis shows that there is a dehydration endothermic peak at 78°C, at 150 °C has a characteristic melting peak.
  • the X-ray powder diffraction pattern of the product is consistent with Figure 2, and the diffraction angle 2 ⁇ is expressed at 8.0°, 11.2°, 11.5°, 12.7°, 12.9°, 14.5°, 15.4°, 17.1°, 18.8°, 19.8°, 20.6
  • the X-ray powder diffraction pattern of the product is expressed in 2 ⁇ angles at 10.6°, 11.8°, 12.2°, 15.1°, 15.7°, 16.0°, 21.4°, 22.0°, 22.3°, 23.1°, 27.3°, 28.2°, 28.7 There are characteristic peaks at °, 29.4°, 30.5°, 30.6°, and 31.3°.
  • the SEM photo of the crystal morphology is consistent with Figure 4. It is a massive crystal with a large average particle size, which can reach 300 ⁇ m.
  • the bulk density is 0.65g/mL and the angle of repose is 32°.
  • thermogravimetric analysis shows that there will be a weight loss of 4.10% before decomposition
  • differential scanning calorimetry analysis shows that there is a dehydration endothermic peak at 80°C, at 150 °C has a characteristic melting peak.
  • the X-ray powder diffraction pattern of the product is consistent with Figure 2, and the diffraction angle 2 ⁇ is expressed at 7.8°, 11.1°, 11.4°, 12.6°, 12.9°, 14.4°, 15.3°, 17.0°, 18.7°, 19.7°, 20.6
  • characteristic peaks at °, 21.0°, 22.5°, 23.7°, 24.3°, 25.5°, 26.2°, of which 7.8° is the initial peak, and the relative intensity of the characteristic peak at 20.6° is 100%.
  • the X-ray powder diffraction pattern of the product is expressed in 2 ⁇ angles at 10.5 ⁇ 0.2°, 11.7 ⁇ 0.2°, 12.0 ⁇ 0.2°, 15.6 ⁇ 0.2°, 15.9 ⁇ 0.2°, 16.2 ⁇ 0.2°, 21.3 ⁇ 0.2°, 22.1 ⁇
  • the SEM photo of the crystal morphology is consistent with Figure 4, it is a massive crystal, the average particle size of the particles is large, which can reach 300 ⁇ m, the bulk density of the test is 0.654g/mL, and the angle of repose is 32.1°.
  • solvent S1 is composed of 1.598 g of acetone solvent and 0.16 g of water
  • solvent S2 is composed of 0.879 g of isopropyl acetate and 0.879 g of dipropyl ether. After reacting for 7 hours, it is filtered and dried at 25°C under normal pressure for 6 hours to obtain mircolactone II. Methylamine fumarate D crystal product. The thermogravimetric analysis/differential scanning calorimetry analysis of the product is consistent with Figure 1.
  • thermogravimetric analysis shows a weight loss of 4.22% before decomposition
  • differential scanning calorimetry analysis shows a dehydration endothermic peak at 75°C, at 148 °C has a characteristic melting peak.
  • the X-ray powder diffraction pattern of the product is consistent with the attached figure 2, and the diffraction angle 2 ⁇ is expressed at 7.8°, 11.0°, 11.4°, 12.5°, 12.8°, 14.4°, 15.3°, 17.0°, 18.7°, 19.7°, 20.6
  • characteristic peaks at °, 21.0°, 22.4°, 23.7°, 24.3°, 25.4°, 26.2°, of which 7.8° is the initial peak, and the relative intensity of the characteristic peak at 20.6° is 100%.
  • the X-ray powder diffraction pattern of the product is expressed in 2 ⁇ angles at 10.5°, 11.7°, 12.0°, 15.6°, 15.9°, 16.2°, 21.3°, 22.2°, 22.9°, 26.4°, 27.3°, 28.2°, 28.6 There are characteristic peaks at °, 29.3°, 30.4°, and 31.1°.
  • the SEM photo of the crystal morphology is consistent with Figure 4, it is a bulk crystal, the average particle size of the particles is large, which can reach 300 ⁇ m, the bulk density of the test is 0.645g/mL, and the angle of repose is 32.3°.
  • Example 1 Weigh 0.1g of the product in Example 1 and place it in a variable temperature X-ray diffractometer, heat it at a constant temperature of 80°C for 30 minutes, and sample and analyze the XRD pattern to be consistent with Figure 6, which proves that the mircolactone dimethylamine fumarate is solvent-free
  • Figure 6 The morphology of the compound crystal form B is the same as that of Figure 5 with the scanning electron micrograph of the solid, and it still maintains the bulk crystal habit.
  • Example 3 Weigh 0.15g of the product in Example 3, place it in a variable temperature X-ray diffractometer, heat it at a constant temperature of 120°C for 10 minutes, and sample and analyze the XRD pattern to be consistent with Figure 6, which proves that the mircolactone dimethylamine fumarate is solvent-free
  • Figure 6 The morphology of the compound crystal form B is the same as that of Figure 5 with the scanning electron micrograph of the solid, and it still maintains the bulk crystal habit.
  • Example 4 Weigh 0.1g of the product in Example 4, place it in a variable temperature X-ray diffractometer, heat it at a constant temperature of 100°C for 20 minutes, and sample and analyze the XRD pattern to be consistent with Figure 6, which proves that the mircolactone dimethylamine fumarate is solvent-free
  • Figure 6 The morphology of the compound crystal form B is the same as that of Figure 5 with the scanning electron micrograph of the solid, and it still maintains the bulk crystal habit.
  • crystal form A capsule 1 The preparation prescription of crystal form A capsule 1 is as follows:
  • Example 13 The recipe in Example 13 was repeated and the following process was used: (1) Crystal form A and pre-crossed starch were passed through an 80-mesh sieve together, the sieving effect was improved, but it was still not ideal, and the static electricity was relatively high; (2) Silica After passing through an 80-mesh sieve, it is mixed with the above powder in a ziplock bag for 3 minutes; (3) Magnesium stearate is passed through an 80-mesh sieve and mixed with the above powder in a ziplock bag for 1 minute; (4) Hand-filled 0# gelatin capsule.
  • the preparation prescription of hydrate crystal form D capsule is as follows, without other auxiliary materials:

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Abstract

一种含笑内酯二甲基胺富马酸盐的水合物、其制备方法和用途。所述水合物为晶型D，结晶度高、颗粒表面光洁无聚结、堆密度高、流动性好，具有良好的稳定性和重现性；其制备方法为：在搅拌作用下，将二甲胺含笑内酯与富马酸加入到温度恒定在30℃-70℃的混合溶剂体系进行反应结晶，反应结束后进行过滤，过滤后的固体经过常压干燥即可获得含笑内酯二甲基胺富马酸盐晶型D，制备方法简单，产品收率较高，适合于后期制备成药，有利于大规模生产。

Description

一种含笑内酯二甲基胺富马酸盐的水合物、其制备方法和用途 技术领域
本发明属于药物结晶技术领域，具体涉及一种含笑内酯二甲基胺富马酸盐的水合物、其制备方法和用途。
背景技术
小白菊内酯(Parthenolide)是一种从菊科植物草药野甘菊和艾菊中提取的主要活性成分，是一种天然的倍半萜内酯类化合物，传统上的小白菊主要用于发热、类风湿关节炎和偏头痛及牙痛等疾病的治疗，近年来国内、国外研究发现小白菊内酯也具有抗肿瘤作用，但是这种化合物在酸性或碱性条件下性质不稳定。
为了提高其稳定性，对化合物小白菊内酯进行修饰得到含笑内酯，英文名称为Micheliolide(MCL)，属于愈创木烷型倍半萜内酯类化合物，已有相关文献及专利报道含笑内酯具有治疗癌症疾病的作用，但是水溶性较差。为了提高水溶性与生物活性，在三乙胺作为催化剂条件下甲醇溶剂中，通过加热反应得到含笑内酯衍生物，即含笑内酯二甲基胺，分子式为C 17H 27NO 3，结构式如下，英文名称为Dimethylaminomicheliolide(DMAMCL)，DMAMCL相比于MCL在水溶性方面有一定程度上的提高，但是长时间放置会发生降解，不稳定。为了进一步提高其水溶性与稳定性，通常将其制备成盐的形式，发明人已发现由小白菊内酯衍生制备得到的含笑内酯二甲基胺富马酸盐。同时，专利WO2011/131103A1公开了包括含笑内酯二甲基胺富马酸盐在内的含笑内酯衍生物或其盐、其药物组合物的制备方法及在用于制备治疗癌症药物的用途。
含笑内酯二甲基胺富马酸盐的分子式C 21H 31NO 7，相对分子质量409，为白色结晶性粉末，无味无臭，溶于水、甲醇、乙醇、四氢呋喃、1，4-二氧六环、丙酮、乙腈、乙酸异丙酯，几乎不溶于环己烷、正己烷、正庚烷、二氯甲烷、异丙醚、甲苯。化学结构式如下：
Figure PCTCN2020081349-appb-000001
多晶型是指同一物质在其晶格中存在不同的分子排列或者是构象，从而导致形成的晶体结构不同，据统计市售80％的药物中存在多晶型现象。同一药物不同的晶型在颜色、溶解度、熔点、密度、硬度、晶体形态等理化性质方面有显著差异，进而造成药物的稳定性、溶出度、生物利用度等的质量差异，影响产品后续加工和处理，并且在一定程度上影响药物的疗效和安全性。在药品质量控制及新药剂型的设计过程中，药物多晶型的研究已经成为不可缺少的重要组成部分。
中国专利CN103724307B公开了含笑内酯二甲基胺富马酸盐晶型A及其制备方法，该专利通过使用XRPD来表征晶型A，用2θ表示在7.10°、7.58°、11.72°、12.26°、13.30°、14.24°、15.70°、16.38°、17.04°、19.02°、19.86°、20.14°、20.66°、21.20°、21.78°、22.64°、23.58°、23.8°、24.48°、25.08°、26.24°、27.08°、27.60°、28.40°、28.94°、34.48°、34.82°、36.12°、38.72°、45°处有特征峰，通过在乙酸乙酯溶剂中重结晶制备晶型A，该方法中采用自然冷却的方式来制备产品，而结晶过程受到热力学和动力学同时控制，自然冷却结晶条件受环境影响波动大，降温速率难以控制，产品粒度较小，主粒度为35.8μm，堆密度较小，仅达到0.270g/mL，休止角为62°，流动性差，晶体产品质量在不同批次之间差异性较大。同时，晶型A稳定性较差，易发生晶型转化，并且固体粉末还存在很强的静电作用，导致生产过程中存在扬尘现象，会给后期的加工和处理带来很多问题。
发明内容
为解决上述问题，本发明提供了含笑内酯二甲基胺富马酸盐的水合物、其制备方法和用途，采用反应结晶的方法制备得到一种结晶度高、堆密度高、流动性好、颗粒粒度大、晶体表面光洁无聚结、稳定性好的含笑内酯二甲基胺富马酸盐水合物晶体产品，该制备方法简单，产品收率较高，重现性好，有利于大规模生产。
本发明提供的一种含笑内酯二甲基胺富马酸盐的水合物，其特征在于，所述水合物为晶型D，含笑内酯二甲基胺富马酸盐与水的摩尔比为1∶1，分子式为C 17H 27NO 3·C 4H 4O 4·H 2O，如热重分析/差式扫描量热分析图所示，热重分析中在分解前会有3.97％～4.22％的失重；所述的含笑内酯二甲基胺富马酸盐的水合物，其特征在于，差示扫描量热分析图谱在75±5℃有脱水吸热峰，在148±5℃有特征熔融峰。
本发明提供的含笑内酯二甲基胺富马酸盐的水合物，其特征在于，所述水合物使用Cu-Kα辐射，如附图2所示以2θ角度表示的X-射线粉末衍射在7.8±0.2°、11.1±0.2°、11.4±0.2°、12.6±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、17.0±0.2°、18.7±0.2°、19.7±0.2°、20.6±0.2°、21.0±0.2°、22.5±0.2°、23.7±0.2°、24.3±0.2°、25.5±0.2°、26.2±0.2°处有特征峰，其中7.8±0.2°为起始峰，20.6±0.2°处特征峰的相对强度为100％，所述晶型D为正交晶系，空间群为P212121，晶胞参数为
Figure PCTCN2020081349-appb-000002
α＝90°，β＝90°，γ＝90°，晶胞体积为
Figure PCTCN2020081349-appb-000003
本发明提供的含笑内酯二甲基胺富马酸盐的水合物，其特征在于，所述水合物使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射还在10.5±0.2°、11.7±0.2°、12.0±0.2°、15.6±0.2°、15.9±0.2°、16.2±0.2°、21.3±0.2°、22.1±0.2°、23.0±0.2°、26.4±0.2°、27.2±0.2°、28.2±0.2°、28.6±0.2°、29.3±0.2°、30.4±0.2°、31.1±0.2°处有特征峰。
本发明还提供了含笑内酯二甲基胺富马酸盐的水合物的制备方法，可以通过反应结晶的方法实现：在搅拌作用下，将二甲胺含笑内酯与富马酸加入到温度恒定在30℃-70℃的溶剂S1与溶剂S2的混合溶剂体系中，溶剂S2与溶剂S1的质量比为(0-3)∶1，二甲胺含笑内酯与富马酸摩尔比为(1-1.6)∶1，反应5-10h，过滤，25-45℃常压条件下干燥6-10h得到含笑内酯二甲基胺富马酸盐晶型D。
所述溶剂S1是丙酮、四氢呋喃、1，4-二氧六环、乙腈、甲基异丁基酮中的任意一种溶剂和水的混合溶剂
所述溶剂S2是酯类和醚类溶剂的混合溶剂。
所述酯类溶剂选自乙酸甲酯、乙酸乙酯、乙酸己酯、乙酸异丙酯中的任意一种或两种。
所述醚类溶剂选自乙醚、甲基乙基醚、甲基叔丁基醚、二丙醚、二丁醚、乙二醇二甲醚、乙二醇单甲醚、1，4-二氧六环、四氢呋喃、2-甲基四氢呋喃中任意的一种或两种。
所述溶剂S1是丙酮、四氢呋喃、1，4-二氧六环、乙腈、甲基异丁基酮中的任意一种溶剂和水的混合溶剂。
所述溶剂S2中酯类溶剂与醚类溶剂的质量比为(1-3)∶1。
所述二甲胺含笑内酯固体原料与S1质量比为1∶(6-10)。
本发明对含笑内酯二甲基胺富马酸盐的水合物的晶习进行了研究，其扫描电镜图见附图3，晶体为规整的块状晶习，颗粒表面光洁且无聚结，晶体平均粒度大，可以达到300μm，堆密度为0.65g/mL，休止角为32°，产品堆密度高，流动性好。相比于采用专利CN103724307B公开的自然冷却重结晶方法制备的晶型A，产品主粒度为35.8um，堆密度只达到0.270g/mL，休止角为62°，其扫描电镜图见附图4，本发明提供的含笑内酯二甲基胺富马酸盐水合物晶型D产品明显提高了颗粒粒度，解决了晶型A产品堆密度小、流动性差的问题。
本发明对含笑内酯二甲基胺富马酸盐的水合物的稳定性进行了考察，将所述无水晶型化合物产品均匀分摊在敞口的培养皿中，控制温度在45℃，湿度为75％，样品厚度小于5mm，密封置于干燥器内放置30天，然后对放置7天、14天、30天的样品分别进行XRD检测，并与第0天的检测结果进行对比。具体图谱见附图5，结果显示XRD图谱并没有明显变化，同时，对放置7天、14天、30天的样品分别进行纯度分析，和第0天的纯度检测结果对比，发现第7天的样品纯度只变化了0.015％，第14天的样品纯度只变化了0.027％，第30天的样品纯度只变化了0.046％，显示样品的纯度没有发生明显变化。综合XRD图谱和纯度分析结果，证明含笑内酯二甲基胺富马酸盐的水合物稳定性较好。
本发明提供的含笑内酯二甲基胺富马酸盐水合物，可以用于制备含笑内酯二甲基胺富马酸盐无溶剂化合物晶型B，晶型B的制备方法如下：将含笑内酯二甲基胺富马酸盐的水合物在80℃-120℃恒温加热10min-30min，得到含笑内酯二甲基胺富马酸盐无溶剂化合物晶型B，其X射线粉末衍射图谱见附图6，以2θ角度表示在8.1±0.2°、10.7±0.2°、11.5±0.2°、11.9±0.2°、13.0±0.2°、13.3±0.2°、14.7±0.2°、15.9±0.2°、16.1±0.2°、16.7±0.2°、17.1±0.2°、19.0±0.2°、19.9±0.2°、 20.3±0.2°、21.2±0.2°、21.5±0.2°、22.1±0.2°、23.0±0.2°、23.5±0.2°、24.4±0.2°、26.0±0.2°、26.6±0.2°、26.9±0.2°、27.4±0.2°、27.9±0.2°、28.6±0.2°、29.4±0.2°、30.2±0.2°、31.0±0.2°处有特征峰。其扫描电镜照片和附图5相似，说明晶习和水合物保持一致，为块状，并且颗粒粒度大。
本发明所述的含笑内酯二甲基胺富马酸盐水合物还提供一种药物组合物，包含药学上可接受的辅料，还可包含含笑内酯二甲基胺富马酸盐的水合物之外的其他一种、两种或更多种药理活性成分。
所述药用辅料包括但不限于除活性成分如结晶形式的二甲胺含笑内酯富马酸盐之外的其他非药理活性成分，例如可用于本发明所述药物组合物的非药理活性成分，其包括载体或赋形剂，例如填充剂、助流剂、润滑剂、粘合剂、稳定剂和/或其他辅料。
所述填充剂包括但不限于玉米淀粉、葡萄糖、甘露醇、山梨醇、二氧化硅、微晶纤维素、羧甲基淀粉钠、复合淀粉、预胶化淀粉中的至少一种。
所述助流剂包括但不限于二氧化硅、水合二氧化硅、轻质无水硅酸、干燥氢氧化铝凝胶、硅酸铝、硅酸镁中的至少一种。
所述润滑剂包括但不限于小麦淀粉、水稻淀粉、玉米淀粉、硬脂酸、硬脂酸钙、硬脂酸镁、水合二氧化硅、轻质无水硅酸、合成硅酸铝、干燥氢氧化铝凝胶、滑石、偏硅酸铝镁、磷酸氢钙、无水磷酸氢钙、蔗糖脂肪酸酯、石蜡类、氢化植物油、聚乙二醇中的至少一种。
根据本发明的所述的药物组合物制备药物制剂，其特征在于，该药物制剂包含药物组合物的片剂、胶囊或颗粒剂剂型。更优选为胶囊剂。
本发明还提供了所述含笑内酯二甲基胺富马酸盐水合物或所述药物组合物在制备用于治疗或预防疾病或病症药物中的用途，所述疾病或病症优选癌症，所述癌症选自白血病、乳腺癌、前列腺癌、鼻咽癌、大肠癌、肺癌、肝癌、食道癌、胃癌、肠道癌、肾癌、口腔癌、何杰金淋巴瘤、胰腺癌、直肠结肠癌、子宫颈癌、非何杰金淋巴癌、神经胶质瘤、黑瘤、膀胱癌、卵巢癌、甲状腺癌或卡波西肉瘤。
有益效果
本发明所述水合物具有较好的流动性，更适于后期制备成药。众所周知， 通常活性成分本身流动性难以满足胶囊剂或微囊剂的灌装条件，需要加入辅料，如预胶化淀粉、二氧化硅和硬质酸镁，才可满足灌装条件对流动性的要求，实现期望的剂型质量和生产效率。以100mg胶囊规格为例，如以其他形态如晶型A为活性成分，添加辅料后，将导致胶囊内容物的重量达到310mg左右，必须使用最大的0#胶囊壳，而且无法制备更大规格如含活性成分200mg的胶囊。为此，患者服药时将不得不通过增加胶囊服用量或给药次数来实现高剂量给药，这将显著降低患者的依从性。然而，发明人发现，含笑内酯二甲基胺富马酸盐水合物晶型D优异的流动性使得其在即使不加入辅料的情况下，也可达到32°休止角，为此可以在显著降低辅料用量，甚至不添加任何辅料的情况下，达到胶囊或微囊剂灌装条件需要的流动性。而且，辅料用量的降低使得生产高剂量规格的胶囊成为可能，显著改善患者的依从性。
更进一步地，由于含笑内酯二甲基胺富马酸盐水合物晶型D能够降低辅料的加入量，甚至不添加辅料。而晶型A需添加大量辅料才能和水合物晶型D具有相同的流动性，稳定性较差，因此水合物晶型D还改善了制剂的稳定性。
此外，含笑内酯二甲基胺富马酸盐水合物晶型D的制备方法操作步骤简单，产物收率较高，重现性好，结晶度高，颗粒表面光洁无聚结，颗粒之间无静电，堆密度高，更有利于大规模生产。
附图说明
图1本发明含笑内酯二甲基胺富马酸盐水合物的热重分析/差式扫描量热分析图。
图2本发明含笑内酯二甲基胺富马酸盐水合物的X-射线衍射图。
图3本发明含笑内酯二甲基胺富马酸盐水合物扫描电镜图(放大40倍)。
图4按照专利CN103724307B公开方法制备出的A晶型产品的扫描电镜图(放大200倍)。
图5本发明含笑内酯二甲基胺富马酸盐水合物的稳定性试验图谱比较，其中从下到上依次为放置0天、7天、14天、30天的样品的XRD谱图。
图6本发明含笑内酯二甲基胺富马酸盐无溶剂化合物B晶型的X-射线衍射图。
具体实施方式
以下将通过实施例形式的具体实施方式，对本发明的上述内容作进一步的详细说明，但不应该将此理解为本发明上述主题的范围仅限于以下实施例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
实施例1
含笑内酯二甲基胺富马酸盐的水合物的制备
在搅拌作用下，将0.293g二甲胺含笑内酯与0.116g富马酸加入到温度恒定在30℃的溶剂S1与溶剂S2的混合溶剂体系中，溶剂S1的质量与溶剂S2的质量相同，其中溶剂S1由1.598g丙酮溶剂与0.16g水组成，溶剂S2由0.879g乙酸乙酯和0.879g乙醚组成，反应5h后，过滤，25℃下常压干燥6h，得到含笑内酯二甲基胺富马酸盐D晶型产品。产品的热重分析/差式扫描量热分析和附图1一致，热重分析显示在分解前会有4.22％的失重，差示扫描量热分析显示在75℃有脱水吸热峰，在148℃有特征熔融峰。产品的X射线粉末衍射图谱和附图2一致，以衍射角2θ表示在7.8°、11.1°、11.4°、12.6°、12.9°、14.4°、15.3°、17.0°、18.7°、19.7°、20.6°、21.0°、22.5°、23.7°、24.3°、25.5°、26.2°处有特征峰，其中7.8°为起始峰，20.6°处特征峰的相对强度为100％。产品的X射线粉末衍射图谱以2θ角度表示还在10.5±0.2°、11.7±0.2°、12.0±0.2°、15.6±0.2°、15.9±0.2°、16.2±0.2°、21.3±0.2°、22.1±0.2°、23.0±0.2°、26.4±0.2°、27.2±0.2°、28.2±0.2°、28.6±0.2°、29.3±0.2°、30.4±0.2°、31.1±0.2°处有特征峰。晶体形貌SEM照片和附图4一致，为块状晶体，颗粒平均粒度大，可以达到300μm，测试其堆密度为0.646g/mL，休止角为32.5°。
实施例2
含笑内酯二甲基胺富马酸盐的水合物的制备
在搅拌作用下，将1.758g二甲胺含笑内酯与0.58g富马酸加入到温度恒定在50℃的溶剂S1与溶剂S2的混合溶剂体系中，溶剂S2的质量是溶剂S1的质量的2倍，其中溶剂S1由12.306g四氢呋喃溶剂与1.758g水组成，溶剂S2由21.096g乙酸异丙酯和7.032g甲基叔丁基醚组成，反应8h后，过滤，30℃下常压干燥10h，得到含笑内酯二甲基胺富马酸盐D晶型产品。产品的热重分析/差式扫描量热分析和附图1一致，热重分析显示在分解前会有4.20％的失重，差示扫描量热分析显示在78℃ 有脱水吸热峰，在150℃有特征熔融峰。产品的X射线粉末衍射图谱和附图2一致，以衍射角2θ表示在8.0°、11.2°、11.5°、12.7°、12.9°、14.5°、15.4°、17.1°、18.8°、19.8°、20.6°、21.1°、22.5°、23.7°、24.5°、25.6°、26.3°处有特征峰，其中7.8°为起始峰，20.6°处特征峰的相对强度为100％。产品的X射线粉末衍射图谱以2θ角度表示还在10.6°、11.8°、12.2°、15.1°、15.7°、16.0°、21.4°、22.0°、22.3°、23.1°、27.3°、28.2°、28.7°、29.4°、30.5°、30.6°、31.3°处有特征峰。晶体形貌SEM照片和附图4一致，为块状晶体，颗粒平均粒度大，可以达到300μm，测试其堆密度为0.655g/mL，休止角为32°。
实施例3
含笑内酯二甲基胺富马酸盐的水合物的制备
在搅拌作用下，将4.688g二甲胺含笑内酯与1.16g富马酸加入到温度恒定在70℃的溶剂S1与溶剂S2的混合溶剂体系中，溶剂S2的质量是溶剂S1的质量的3倍，其中溶剂S1由39g1，4-二氧六环溶剂与7.88g水组成，溶剂S2由93.76g乙酸甲酯和46.88g甲基乙基醚组成，反应10h后，过滤，45℃下常压干燥8h，得到含笑内酯二甲基胺富马酸盐D晶型产品。产品的热重分析/差式扫描量热分析和附图1一致，热重分析显示在分解前会有3.97％的失重，差示扫描量热分析显示在75℃有脱水吸热峰，在145℃有特征熔融峰。产品的X射线粉末衍射图谱和附图2一致，以衍射角2θ表示在7.8°、11.0°、11.4°、12.5°、12.8°、14.4°、15.3°、17.0°、18.7°、19.7°、20.6°、21.0°、22.4°、23.7°、24.3°、25.4°、26.2°处有特征峰，其中7.8°为起始峰，20.6°处特征峰的相对强度为100％。产品的X射线粉末衍射图谱以2θ角度表示还在10.5°、11.7°、12.0°、15.6°、15.9°、16.2°、21.3°、22.2°、22.9°、26.4°、27.3°、28.2°、28.6°、29.3°、30.4°、31.1°处有特征峰。晶体形貌SEM照片和附图4一致，为块状晶体，颗粒平均粒度大，可以达到300μm，测试其堆密度为0.65g/mL，休止角为32°。
实施例4
含笑内酯二甲基胺富马酸盐的水合物的制备
在搅拌作用下，将4.102g二甲胺含笑内酯与1.16g富马酸加入到温度恒定在60℃的溶剂S1与溶剂S2的混合溶剂体系中，溶剂S2的质量是溶剂S1的质量的3倍，其中溶剂S1由35.8925g乙腈溶剂与5.1275g水组成，溶剂S2由87.9 g乙酸己酯和35.16g乙二醇二甲醚组成，反应10h后，过滤，45℃下常压干燥9h，得到含笑内酯二甲基胺富马酸盐D晶型产品。产品的热重分析/差式扫描量热分析和附图1一致，热重分析显示在分解前会有4.10％的失重，差示扫描量热分析显示在80℃有脱水吸热峰，在150℃有特征熔融峰。产品的X射线粉末衍射图谱和附图2一致，以衍射角2θ表示在7.8°、11.1°、11.4°、12.6°、12.9°、14.4°、15.4°、17.0°、18.8°、19.8°、20.6°、21.0°、22.5°、23.7°、24.4°、25.5°、26.2°处有特征峰，其中7.8°为起始峰，20.6°处特征峰的相对强度为100％。产品的X射线粉末衍射图谱以2θ角度表示还在10.6°、11.8°、12.1°、15.9°、16.3°、21.4°、22.2°、23.0°、26.5°、27.3°、28.7°、29.3°、30.4°、31.1°处有特征峰。晶体形貌SEM照片和附图4一致，为块状晶体，颗粒平均粒度大，可以达到300μm，测试其堆密度为0.659g/mL，休止角为32.2°。
实施例5
含笑内酯二甲基胺富马酸盐的水合物的制备
在搅拌作用下，将0.293g二甲胺含笑内酯与0.116g富马酸加入到温度恒定在30℃的溶剂S1与溶剂S2的混合溶剂体系中，溶剂S1的质量与溶剂S2的质量相同，其中溶剂S1由1.598g乙腈溶剂与0.16g水组成，溶剂S2由0.879g乙酸异丙酯和0.879g乙二醇单甲醚组成，反应5h后，过滤，25℃下常压干燥6h，得到含笑内酯二甲基胺富马酸盐D晶型产品。产品的热重分析/差式扫描量热分析和附图1一致，热重分析显示在分解前会有4.22％的失重，差示扫描量热分析显示在75℃有脱水吸热峰，在148℃有特征熔融峰。产品的X射线粉末衍射图谱和附图2一致，以衍射角2θ表示在7.8°、11.1°、11.4°、12.6°、12.9°、14.4°、15.3°、17.0°、18.7°、19.7°、20.6°、21.0°、22.5°、23.7°、24.3°、25.5°、26.2°处有特征峰，其中7.8°为起始峰，20.6°处特征峰的相对强度为100％。产品的X射线粉末衍射图谱以2θ角度表示还在10.5±0.2°、11.7±0.2°、12.0±0.2°、15.6±0.2°、15.9±0.2°、16.2±0.2°、21.3±0.2°、22.1±0.2°、23.0±0.2°、26.4±0.2°、27.2±0.2°、28.2±0.2°、28.6±0.2°、29.3±0.2°、30.4±0.2°、31.1±0.2°处有特征峰。晶体形貌SEM照片和附图4一致，为块状晶体，颗粒平均粒度大，可以达到300μm，测试其堆密度为0.645g/mL，休止角为32°。
实施例6
含笑内酯二甲基胺富马酸盐的水合物的制备
在搅拌作用下，将4.688g二甲胺含笑内酯与1.16g富马酸加入到温度恒定在70℃的溶剂S1与溶剂S2的混合溶剂体系中，溶剂S2的质量是溶剂S1的质量的3倍，其中溶剂S1由39g甲基异丁基酮溶剂与7.88g水组成，溶剂S2由46.88g乙酸甲酯、46.88g乙酸异丙酯、23.44g四氢呋喃和23.44g二丁醚组成，反应10h后，过滤，45℃下常压干燥8h，得到含笑内酯二甲基胺富马酸盐D晶型产品。产品的热重分析/差式扫描量热分析和附图1一致，热重分析显示在分解前会有3.97％的失重，差示扫描量热分析显示在75℃有脱水吸热峰，在145℃有特征熔融峰。产品的X射线粉末衍射图谱和附图2一致，以衍射角2θ表示在7.8°、11.0°、11.4°、12.5°、12.8°、14.4°、15.3°、17.0°、18.7°、19.7°、20.6°、21.0°、22.4°、23.7°、24.3°、25.4°、26.2°处有特征峰，其中7.8°为起始峰，20.6°处特征峰的相对强度为100％。产品的X射线粉末衍射图谱以2θ角度表示还在10.5°、11.7°、12.0°、15.6°、15.9°、16.2°、21.3°、22.2°、22.9°、26.4°、27.3°、28.2°、28.6°、29.3°、30.4°、31.1°处有特征峰。晶体形貌SEM照片和附图4一致，为块状晶体，颗粒平均粒度大，可以达到300μm，测试其堆密度为0.65g/mL，休止角为32.3°。
实施例7
含笑内酯二甲基胺富马酸盐的水合物的制备
在搅拌作用下，将1.758g二甲胺含笑内酯与0.58g富马酸加入到温度恒定在50℃的溶剂S1与溶剂S2的混合溶剂体系中，溶剂S2的质量是溶剂S1的质量的2倍，其中溶剂S1由12.306g甲基异丁基酮溶剂与1.758g水组成，溶剂S2由21.096g乙酸甲酯和7.032g 2-甲基四氢呋喃组成，反应9h后，过滤，30℃下常压干燥10h，得到含笑内酯二甲基胺富马酸盐D晶型产品。产品的热重分析/差式扫描量热分析和附图1一致，热重分析显示在分解前会有4.20％的失重，差示扫描量热分析显示在78℃有脱水吸热峰，在150℃有特征熔融峰。产品的X射线粉末衍射图谱和附图2一致，以衍射角2θ表示在8.0°、11.2°、11.5°、12.7°、12.9°、14.5°、15.4°、17.1°、18.8°、19.8°、20.6°、21.1°、22.5°、23.7°、24.5°、25.6°、26.3°处有特征峰，其中7.8°为起始峰，20.6°处特征峰的相对强度为100％。产品的X射线粉末衍射图谱以2θ角度表示还在10.6°、11.8°、12.2°、15.1°、15.7°、16.0°、21.4°、22.0°、22.3°、23.1°、27.3°、28.2°、28.7°、29.4°、30.5°、30.6°、31.3°处有特征峰。晶体形貌 SEM照片和附图4一致，为块状晶体，颗粒平均粒度大，可以达到300μm，测试其堆密度为0.65g/mL，休止角为32°。
实施例8
含笑内酯二甲基胺富马酸盐的水合物的制备
在搅拌作用下，将4.102g二甲胺含笑内酯与1.16g富马酸加入到温度恒定在60℃的溶剂S1与溶剂S2的混合溶剂体系中，溶剂S2的质量是溶剂S1的质量的3倍，其中溶剂S1由35.8925g四氢呋喃溶剂与5.1275g水组成，溶剂S2由87.9g乙酸甲酯和35.16g1，4-二氧六环组成，反应10h后，过滤，45℃下常压干燥9h，得到含笑内酯二甲基胺富马酸盐D晶型产品。产品的热重分析/差式扫描量热分析和附图1一致，热重分析显示在分解前会有4.10％的失重，差示扫描量热分析显示在80℃有脱水吸热峰，在150℃有特征熔融峰。产品的X射线粉末衍射图谱和附图2一致，以衍射角2θ表示在7.8°、11.1°、11.4°、12.6°、12.9°、14.4°、15.3°、17.0°、18.7°、19.7°、20.6°、21.0°、22.5°、23.7°、24.3°、25.5°、26.2°处有特征峰，其中7.8°为起始峰，20.6°处特征峰的相对强度为100％。产品的X射线粉末衍射图谱以2θ角度表示还在10.5±0.2°、11.7±0.2°、12.0±0.2°、15.6±0.2°、15.9±0.2°、16.2±0.2°、21.3±0.2°、22.1±0.2°、23.0±0.2°、26.4±0.2°、27.2±0.2°、28.2±0.2°、28.6±0.2°、29.3±0.2°、30.4±0.2°、31.1±0.2°处有特征峰。晶体形貌SEM照片和附图4一致，为块状晶体，颗粒平均粒度大，可以达到300μm，测试其堆密度为0.654g/mL，休止角为32.1°。
实施例9
含笑内酯二甲基胺富马酸盐的水合物的制备
在搅拌作用下，将0.293g二甲胺含笑内酯与0.116g富马酸加入到温度恒定在30℃的溶剂S1与溶剂S2的混合溶剂体系中，溶剂S1的质量与溶剂S2的质量相同，其中溶剂S1由1.598g丙酮溶剂与0.16g水组成，溶剂S2由0.879g乙酸异丙酯和0.879g二丙醚组成，反应7h后，过滤，25℃下常压干燥6h，得到含笑内酯二甲基胺富马酸盐D晶型产品。产品的热重分析/差式扫描量热分析和附图1一致，热重分析显示在分解前会有4.22％的失重，差示扫描量热分析显示在75℃有脱水吸热峰，在148℃有特征熔融峰。产品的X射线粉末衍射图谱和附图2一致，以衍射角2θ表示在7.8°、11.0°、11.4°、12.5°、12.8°、14.4°、15.3°、17.0°、18.7°、19.7°、 20.6°、21.0°、22.4°、23.7°、24.3°、25.4°、26.2°处有特征峰，其中7.8°为起始峰，20.6°处特征峰的相对强度为100％。产品的X射线粉末衍射图谱以2θ角度表示还在10.5°、11.7°、12.0°、15.6°、15.9°、16.2°、21.3°、22.2°、22.9°、26.4°、27.3°、28.2°、28.6°、29.3°、30.4°、31.1°处有特征峰。晶体形貌SEM照片和附图4一致，为块状晶体，颗粒平均粒度大，可以达到300μm，测试其堆密度为0.645g/mL，休止角为32.3°。
实施例10
含笑内酯二甲基胺富马酸盐无溶剂化合物B晶型的制备
称取实施例1中产品0.1g放置在变温X射线衍射仪中，在80℃恒温加热30min，取样分析XRD图谱和附图6一致，证明得到含笑内酯二甲基胺富马酸盐无溶剂化合物晶型B，固体的扫描电镜照片和附图5形貌一致，仍然保持块状晶习。
实施例11
含笑内酯二甲基胺富马酸盐无溶剂化合物B晶型的制备
称取实施例3中产品0.15g放置在变温X射线衍射仪中，在120℃恒温加热10min，取样分析XRD图谱和附图6一致，证明得到含笑内酯二甲基胺富马酸盐无溶剂化合物晶型B，固体的扫描电镜照片和附图5形貌一致，仍然保持块状晶习。
实施例12
含笑内酯二甲基胺富马酸盐无溶剂化合物B晶型的制备
称取实施例4中产品0.1g放置在变温X射线衍射仪中，在100℃恒温加热20min，取样分析XRD图谱和附图6一致，证明得到含笑内酯二甲基胺富马酸盐无溶剂化合物晶型B，固体的扫描电镜照片和附图5形貌一致，仍然保持块状晶习。
实施例13
晶型A胶囊剂1的制备处方如下：
Figure PCTCN2020081349-appb-000004
Figure PCTCN2020081349-appb-000005
工艺：(1)晶型A过100目筛，发现过筛困难，残留多，过筛后静电大；(2)预交化淀粉和二氧化硅过80目筛后与晶型A自封袋混合5分钟；(3)硬脂酸镁过80目筛后与上述混粉自封袋混合1分钟；(4)手工灌装0#明胶胶囊。
检测结果表明，本实施例胶囊剂的休止角为32.91°，与实施例1测得的水合物晶型D流动性数据接近。
实施例14
晶型A胶囊剂2的制备
重复采用实施例13处方，使用如下工艺：(1)晶型A和预交化淀粉一起过80目筛，过筛效果有所改善，但仍不理想，静电较大；(2)二氧化硅过80目筛后与上述混粉在自封袋中混合3分钟；(3)硬脂酸镁过80目筛后与上述混粉在自封袋中混合1分钟；(4)手工灌装0#明胶胶囊。
检测结果表明，本实施例胶囊剂的休止角为32.88°，与实施例5水合物晶型D的流动性接近，进一步进行影响因素实验。
实施例15
水合物晶型D胶囊剂的制备处方如下，无其他辅料：
处方 mg/粒
晶型D(实施例1) 100
工艺：(1)取处方量的实施例1制备的水合物晶型D，过80目筛；(2)灌装3#明胶胶囊，轻轻将原料铺平，盖上胶囊盖，进行影响因素实验。
实施例16
影响因素实验
A.高温试验
取实施例14和15的胶囊剂产品100粒，置敞口培养皿中，在60℃的恒温箱中放置，于5天、10天分别取样。观察性状，检查有关物质，测定含量。
B.高湿试验
取实施例14和15的胶囊剂产品100粒，置敞口培养皿中，放置在相对湿度 90±5％(硝酸钾饱和溶液)的密闭容器中放置，于5天、10天分别取样。观察性状，检查有关物质，测定含量。
C.强光照射试验
取实施例14和15的胶囊剂产品100粒，置敞口培养皿中，于4500±500LX的日光灯下照射，于5天、10天分别取样。观察性状，检查有关物质，测定含量。
实验结果汇总如下：
实施例14的晶型A胶囊剂影响因素实验结果
Figure PCTCN2020081349-appb-000006
实施例15的水合物晶型D胶囊剂影响因素实验结果
Figure PCTCN2020081349-appb-000007
Figure PCTCN2020081349-appb-000008
上述结果表明，在相近的流动性下，水合物晶型D胶囊剂的各影响因素实验中，5天内的MCL(含笑内酯)含量无显变化，而在晶型A胶囊剂的实验中，5天以上的MCL含量均显著增加。因此，水合物晶型D优异的流动性使得其无需添加辅料即可制备为胶囊剂，并应用于临床。相反，即使通过增加辅料和优化工艺改善晶型A胶囊剂的流动性，其稳定性也明显劣于水合物晶型D。因此，水合物晶型D无论在制备工艺、稳定性和依从性方面，都优于晶型A的胶囊剂。

Claims (10)

  1. 一种含笑内酯二甲基胺富马酸盐的水合物，其特征在于，所述水合物为晶型D，含笑内酯二甲基胺富马酸盐与水的摩尔比为1∶1，分子式为C 17H 27NO 3·C 4H 4O 4·H 2O，热重分析中在分解前会有3.97％～4.22％的失重；差示扫描量热分析图谱在75±5℃有脱水吸热峰，在148±5℃有特征熔融峰。
  2. 根据权利要求1所述的含笑内酯二甲基胺富马酸盐的水合物，其特征在于，所述水合物使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在7.8±0.2°、11.1±0.2°、11.4±0.2°、12.6±0.2°、12.9±0.2°、14.4±0.2°、15.3±0.2°、17.0±0.2°、18.7±0.2°、19.7±0.2°、20.6±0.2°、21.0±0.2°、22.5±0.2°、23.7±0.2°、24.3±0.2°、25.5±0.2°、26.2±0.2°处有特征峰，其中7.8±0.2°为起始峰，20.6±0.2°处特征峰的相对强度为100％，所述晶型D为正交晶系，空间群为P2 12 12 1，晶胞参数为
    Figure PCTCN2020081349-appb-100001
    α＝90°，β＝90°，γ＝90°，晶胞体积为
    Figure PCTCN2020081349-appb-100002
  3. 根据权利要求1所述的含笑内酯二甲基胺富马酸盐的水合物，其特征在于，所述水合物使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射还在10.5±0.2°、11.7±0.2°、12.0±0.2°、15.6±0.2°、15.9±0.2°、16.2±0.2°、21.3±0.2°、22.1±0.2°、23.0±0.2°、26.4±0.2°、27.2±0.2°、28.2±0.2°、28.6±0.2°、29.3±0.2°、30.4±0.2°、31.1±0.2°处有特征峰。
  4. 根据权利要求1-3所述任意一项的含笑内酯二甲基胺富马酸盐的水合物的制备方法，其特征在于通过反应结晶制备：在搅拌作用下，将二甲胺含笑内酯与富马酸加入到温度恒定在30℃-70℃的溶剂S1与溶剂S2的混合溶剂体系中，溶剂S2与溶剂S1的质量比为(0-3)∶1，二甲胺含笑内酯与富马酸摩尔比为(1-1.6)∶1，反应5-10h，过滤，25-45℃常压条件下干燥6-10h得到含笑内酯二甲基胺富马酸盐晶型D；
    所述溶剂S1是丙酮、四氢呋喃、1，4-二氧六环、乙腈、甲基异丁基酮中的任意一种溶剂和水的混合溶剂；
    所述溶剂S2是酯类和醚类的混合溶剂；
    所述酯类溶剂可以选自乙酸甲酯、乙酸乙酯、乙酸己酯、乙酸异丙酯中的任意一种或两种；
    所述醚类溶剂可以选自乙醚、甲基乙基醚、甲基叔丁基醚、二丙醚、二丁醚、 乙二醇二甲醚、乙二醇单甲醚、1，4-二氧六环、四氢呋喃、2-甲基四氢呋喃中的任意一种或两种。
  5. 根据权利要求4所述溶剂S1中丙酮、四氢呋喃、1，4-二氧六环、乙腈、甲基异丁基酮中的任意一种溶剂与水的质量比为(5-10)∶1；
    所述溶剂S2中酯类溶剂与醚类溶剂的质量比为(1-3)∶1；
    所述二甲胺含笑内酯固体原料与S1质量比为1∶(6-10)。
  6. 根据权利要求1所述的含笑内酯二甲基胺富马酸盐水合物可以用于制备含笑内酯二甲基胺富马酸盐无溶剂化合物晶型B，制备含笑内酯二甲基胺富马酸盐无溶剂化合物晶型B的方法是：将含笑内酯二甲基胺富马酸盐的水合物在80℃-120℃恒温加热10min-30min，得到含笑内酯二甲基胺富马酸盐无溶剂化合物晶型B。
  7. 根据权利要求1所述的含笑内酯二甲基胺富马酸盐水合物还提供一种药物组合物，包含药学上可接受的辅料，还可包含含笑内酯二甲基胺富马酸盐的水合物之外的其他一种、两种或更多种药理活性成分。
  8. 根据权利要求7所述药用辅料包括但不限于除活性成分如结晶形式的含笑内酯二甲基胺富马酸盐之外的其他非药理活性成分，例如可用于本发明所述药物组合物的非药理活性成分，其包括载体或赋形剂，例如填充剂、助流剂、润滑剂、粘合剂、稳定剂和/或其他辅料；
    所述填充剂包括但不限于玉米淀粉、葡萄糖、甘露醇、山梨醇、二氧化硅、微晶纤维素、羧甲基淀粉钠、复合淀粉、预胶化淀粉中的至少一种；
    所述助流剂包括但不限于二氧化硅、水合二氧化硅、轻质无水硅酸、干燥氢氧化铝凝胶、硅酸铝、硅酸镁中的至少一种；
    所述润滑剂包括但不限于小麦淀粉、水稻淀粉、玉米淀粉、硬脂酸、硬脂酸钙、硬脂酸镁、水合二氧化硅、轻质无水硅酸、合成硅酸铝、干燥氢氧化铝凝胶、滑石、偏硅酸铝镁、磷酸氢钙、无水磷酸氢钙、蔗糖脂肪酸酯、石蜡类、氢化植物油、聚乙二醇中的至少一种。
  9. 权利要求7所述的药物组合物制备药物制剂，其特征在于，该药物制剂包含药物组合物的片剂、胶囊或颗粒剂剂型。
  10. 本发明还提供了权利要求1所述含笑内酯二甲基胺富马酸盐的水合物或 所述药物组合物在制备用于治疗或预防疾病或病症药物中的用途，所述疾病或病症优选癌症，所述癌症选自白血病、乳腺癌、前列腺癌、鼻咽癌、大肠癌、肺癌、肝癌、食道癌、胃癌、肠道癌、肾癌、口腔癌、何杰金淋巴瘤、胰腺癌、直肠结肠癌、子宫颈癌、非何杰金淋巴癌、神经胶质瘤、黑瘤、膀胱癌、卵巢癌、甲状腺癌或卡波西肉瘤。
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011131103A1 (zh) 2010-04-23 2011-10-27 天津尚德药缘科技有限公司 含笑内酯衍生物，其药物组合物及其制备方法和用途
CN103724307A (zh) 2012-10-12 2014-04-16 天津尚德药缘科技有限公司 含笑内酯二甲基胺富马酸盐的晶型及制备方法
WO2015006893A1 (zh) * 2013-07-15 2015-01-22 天津尚德药缘科技有限公司 倍半萜内酯类化合物及其衍生物在制备药物中的用途
CN104876899A (zh) * 2014-02-28 2015-09-02 天津尚德药缘科技股份有限公司 二甲胺含笑内酯富马酸盐及其用途
WO2017128163A1 (zh) * 2016-01-28 2017-08-03 天津国际生物医药联合研究院 含笑内酯二甲基胺的应用
CN111303100A (zh) * 2018-12-12 2020-06-19 天津尚德药缘科技股份有限公司 一种含笑内酯二甲基胺富马酸盐的水合物、其制备方法和用途

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111303098B (zh) * 2018-12-12 2022-10-04 天津尚德药缘科技股份有限公司 一种含笑内酯二甲基胺富马酸盐晶型e及其制备方法
CN111303097B (zh) * 2018-12-12 2022-09-30 天津尚德药缘科技股份有限公司 二甲胺含笑内酯富马酸盐晶型c及其制备方法
CN111303099B (zh) * 2018-12-12 2022-12-02 天津尚德药缘科技股份有限公司 含笑内酯二甲基胺富马酸盐晶型f及其制备方法

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011131103A1 (zh) 2010-04-23 2011-10-27 天津尚德药缘科技有限公司 含笑内酯衍生物，其药物组合物及其制备方法和用途
CN103724307A (zh) 2012-10-12 2014-04-16 天津尚德药缘科技有限公司 含笑内酯二甲基胺富马酸盐的晶型及制备方法
WO2014056410A1 (zh) * 2012-10-12 2014-04-17 天津尚德药缘科技有限公司 含笑内酯二甲基胺富马酸盐的晶型及制备方法
WO2015006893A1 (zh) * 2013-07-15 2015-01-22 天津尚德药缘科技有限公司 倍半萜内酯类化合物及其衍生物在制备药物中的用途
CN104876899A (zh) * 2014-02-28 2015-09-02 天津尚德药缘科技股份有限公司 二甲胺含笑内酯富马酸盐及其用途
WO2017128163A1 (zh) * 2016-01-28 2017-08-03 天津国际生物医药联合研究院 含笑内酯二甲基胺的应用
CN111303100A (zh) * 2018-12-12 2020-06-19 天津尚德药缘科技股份有限公司 一种含笑内酯二甲基胺富马酸盐的水合物、其制备方法和用途

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BOMMAGANI SHOBANBABU, PENTHALA NARSIMHA REDDY, JANGANATI VENUMADHAV, PARKIN SEAN, CROOKS PETER A.: "13-(N, N-Dimethylamino)micheliolide 0.08-hydrate.", ACTA CRYSTALLOGRAPHICA SECTION E, vol. 69, no. 12, 15 December 2013 (2013-12-15), GB, pages 01789 - 01790+8, XP055853364, ISSN: 1600-5368, DOI: 10.1107/S1600536813030304 *
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