WO2015180680A1 - 一种环肽类化合物的结晶粉末及其制备方法和用途 - Google Patents
一种环肽类化合物的结晶粉末及其制备方法和用途 Download PDFInfo
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- WO2015180680A1 WO2015180680A1 PCT/CN2015/080224 CN2015080224W WO2015180680A1 WO 2015180680 A1 WO2015180680 A1 WO 2015180680A1 CN 2015080224 W CN2015080224 W CN 2015080224W WO 2015180680 A1 WO2015180680 A1 WO 2015180680A1
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- 0 CCCCCOc(cc1)ccc1-c1cc(-c(cc2)ccc2C(N[C@](C2)(*[C@]2[C@](NC([C@]([C@]([C@@](C)C2)O)N2C([C@]([C@@](CC(N)=O)O)NC([C@]([C@@]([C@](c(cc2)cc(O*)c2O)O)O)NC([C@](C[C@](C2)O)N2C([C@]([C@@](C)O)N2)=O)=O)=O)=O)=O)O)C2=O)=O)n[o]1 Chemical compound CCCCCOc(cc1)ccc1-c1cc(-c(cc2)ccc2C(N[C@](C2)(*[C@]2[C@](NC([C@]([C@]([C@@](C)C2)O)N2C([C@]([C@@](CC(N)=O)O)NC([C@]([C@@]([C@](c(cc2)cc(O*)c2O)O)O)NC([C@](C[C@](C2)O)N2C([C@]([C@@](C)O)N2)=O)=O)=O)=O)=O)O)C2=O)=O)n[o]1 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/50—Cyclic peptides containing at least one abnormal peptide link
- C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
- C07K7/56—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation not occurring through 2,4-diamino-butanoic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/02—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length in solution
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- the present invention relates to a crystalline powder of a compound, and more particularly to a crystalline powder of a cyclic peptide compound, a process for the preparation thereof and use thereof.
- Micafungin is a new type of echinocandin antifungal drug that destroys the structure of fungal cells and dissolves them by inhibiting the ⁇ -1,3-D-glucan synthase, a component of the fungal cell wall. Micafungin is widely used to treat various infections, especially those caused by Aspergillus, Candida, Cryptococcus, Mucor, Actinomycetes, Histoplasma, Dermatophytes and Fusarium.
- Micafungin Sodium (also known as FK463) is the active pharmaceutical ingredient of the drug Mycamine.
- the chemical structure of micafungin sodium salt is shown in formula I:
- the compound of the formula I is a polypeptide compound with poor stability, and the degradation product formation may affect its quality and efficacy during transportation or long-term storage. Further, the compound of the formula I is difficult to be crystallized, and is usually in an amorphous state.
- the compound of formula I is degraded and the quality is degraded.
- WO 03/018615 of Fujisawa Pharmaceutical Co., Ltd. discloses a novel crystal form of the compound of the formula I and a preparation method thereof.
- WO03/018615 is prepared by dissolving an amorphous compound of the formula I in an aqueous alcoholic solution or an aqueous acetone solution, and adding a solvent such as ethyl acetate, dichloromethane, acetone and acetonitrile to obtain a needle-like crystal of the compound B82 of the formula I.
- the crystal was crystallized in an organic solvent, and the morphology under the microscope was needle-like crystals.
- X-ray powder diffraction had peaks at 2 ⁇ angles of 4.6°, 5.5°, 9.0°, 9.8°, and 16.9°.
- the inventors performed the B82 type needle crystal according to the method of Example 1 of the patent WO03/018615. Preparation, observation of the obtained crystal using an optical microscope, the size of about 1 um, using a Malven particle size analyzer to determine d50 in the range of 0.2-1.0 um, is a fine needle-like crystal.
- the inventors found in the process of subsequent filtration, drying and the like of the B82 type crystal that since the B82 type crystal is substantially in the form of a fine needle, the crystal of the compound of the formula I is difficult to filter and the operation time is long.
- the solvent content of the compound of formula I has a Dry/Wet (dry to wet weight ratio) of about 0.25 before the crystals are dried, and the crystals enclose a large amount of organic solvent.
- the drying process it is necessary to increase the drying temperature or prolong the drying time so that the solvent content meets the requirements of the drug substance.
- the use of the above drying process increases the degradation products of the compound of formula I, which seriously affects the quality and stability of the drug substance.
- the inventors found that the bulk density of B82 needle crystals is about 0.8g/mL, which is denser, which is not conducive to the evaporation of solvent in the drying process, which directly affects the crystal powder.
- the B82 type crystal is exposed to the environment, it is easy to absorb moisture and has poor stability.
- Another object of the present invention is to provide a process for the preparation of the crystalline powder.
- Yet another object of the invention is to provide the use of the crystalline powder.
- the present invention provides a crystalline powder of a compound of formula I.
- the crystalline powder has a bulk density of less than 0.6 g/mL.
- the crystalline powder has a bulk density of less than 0.5 g/mL.
- the crystalline powder has a d50 of from 10 to 100 um.
- the crystalline powder has a d50 of from 20 to 50 um.
- the crystalline powder has a d10 of from 1 to 9 um.
- the crystalline powder has a d10 of from 1 to 5 um.
- the crystalline powder has a d50 of 10-100 um before solid-liquid separation.
- the crystalline powder has a d50 of 20 to 50 um before solid-liquid separation.
- the crystalline powder has a d10 of from 1 to 9 um prior to solid-liquid separation.
- the crystalline powder has a d10 of 3-6 um before solid-liquid separation.
- the B82 type needle crystal disclosed in WO03/018615 has a fine needle-like morphology, is difficult to filter, is difficult to dry, and has poor stability.
- the inventors screened the crystallization solvent system using a different solvent combination in a three-phase system. After a long period of research, the inventors have unexpectedly discovered that a regular columnar crystal can be obtained in a specific three-phase solvent system. Subsequently, we conducted a large number of solvent screening tests to finally obtain a crystalline powder of a compound of formula I with better stability and better morphology, and determined the preparation process.
- the crystal of the present invention has a columnar shape, a large crystal particle, a small bulk density, easy filtration, and easy removal of a solvent in the crystal.
- the inventors have surprisingly found through research that the compound of the formula I is cooled or added poorly in an aqueous solution of methanol/isobutanol, methanol/isopropanol or methanol/n-propanol, ie a three-phase system solution or a four-phase solvent system.
- a solvent or the like which lowers the solubility of the compound of the formula I in a solution, a columnar crystal of a compound of the formula I, which is a crystalline powder of the compound of the formula I.
- the compound of the formula I obtained after filtration after crystallization has a high Dry/Wet (dry to wet weight ratio) before drying, a small organic solvent content, and a small bulk density after drying, and the organic solvent is easily removed.
- Powder bulk density by comparing the bulk and tightness of the powder, can be seen as a measure of the relative importance of the interaction of the particles.
- Methods for measuring the bulk density of a powder are known in the art, for example, using a cylinder measurement method, a volume measurement method, a container measurement method, or the like.
- the invention The crystalline powder of the compound of formula I is determined by a cylinder measurement having a bulk density of less than 0.7 g/mL, more preferably less than 0.6 g/mL; optimally less than 0.5 g/mL.
- Particle size distribution was determined using a Malvern particle sizer 2600C to analyze the size distribution (including d10 and d50) of the crystal before solid-liquid separation of the crystallizing liquid.
- d10 and d50 are known ways of indicating the particle size distribution
- d50 means a certain particle size value such that the size of 50 vol/% of the particles is smaller than the value.
- D10 means a certain particle size value such that the size of 10 vol/% of the particles is smaller than the stated value.
- a preferred method of determining d10 and d50 is laser diffraction.
- the crystalline powder of the compound of formula I of the present invention has a d50 of from 10 to 100 um and a d10 of from 1 to 9 um.
- d50 is at 20-50 um and d10 is at 1-5 um.
- the crystalline powder of the compound of formula I has a d50 of 10-100 um and a d10 of 1-9 um before solid-liquid separation. More preferably, its d50 is at 20-50 um and d10 is at 3-6 um.
- the crystalline powder of the compound of the formula I of the present invention is a columnar crystal under an optical microscope.
- the crystalline powder of the compound of formula I of the present invention has a shape substantially identical to that of Figure 1 prior to solid-liquid separation.
- HPLC High Performance Liquid Chromatography
- Diluent phosphate buffer of water
- Detection wavelength 210 nm
- Injection volume 10 ⁇ l.
- GC Gas chromatography separation and detection of trace impurities in compounds is an accurate, qualitative and quantitative analytical method.
- the content of the organic solvent in the crystalline powder of the compound of the formula I obtained by the preparation of the present invention is determined by gas chromatography (GC).
- X-ray powder diffraction also known as “X-ray polycrystalline diffraction (XRD or XRPD)
- XRD X-ray polycrystalline diffraction
- An X-ray powder diffractometer is used to generate a series of diffraction patterns when X-rays are transmitted through the crystal, in which different diffraction lines and their intensity are determined by a certain atomic group, thereby determining the crystal structure.
- Methods for determining X-ray powder diffraction of crystals are known in the art. For example, a copper radiation target is used to acquire a map using an X-ray powder diffractometer of the RIGAKU D/max 2550VB/PC model at a scanning speed of 2° per minute.
- the crystalline powder of the compound of the formula I of the present invention has a specific crystal form and has a specific characteristic peak in the X-ray powder diffraction pattern.
- the X-ray powder diffraction pattern of the crystalline powder of the compound of the present invention has characteristic peaks at the following 2 theta angles: 4.4 ⁇ 0.2 °, 5.2 ⁇ 0.2 °, 8.5 ⁇ 0.2 °, 9.6 ⁇ 0.2 °;
- the map also has characteristic peaks at the following 2 theta angles: 7.5 ⁇ 0.2°, 8.8 ⁇ 0.2°, 16.6 ⁇ 0.2°, 13.7 ⁇ 0.2°, 22.5 ⁇ 0.2°; in another preferred embodiment
- the map also has characteristic peaks at the following 2 theta angles: 12.6 ⁇ 0.2 °, 14.9 ⁇ 0.2 °, 15.6 ⁇ 0.2 °, 25.1 ⁇ 0.2 °.
- the crystalline powder of the compound of formula I of the present invention has characteristic peaks on the X-ray powder diffraction pattern at the following 2 theta angles: 4.4 ⁇ 0.1 °, 5.2 ⁇ 0.1 °, 8.5 ⁇ 0.1 °, 9.6 ⁇ 0.1 °;
- the map also has characteristic peaks at the following 2 theta angles: 7.5 ⁇ 0.1 °, 8.8 ⁇ 0.1 °, 16.6 ⁇ 0.1 °, 13.7 ⁇ 0.1 °, 22.5 ⁇ 0.1 °;
- the map also has characteristic peaks at the following 2 theta angles: 12.6 ⁇ 0.1 °, 14.9 ⁇ 0.1 °, 15.6 ⁇ 0.1 °, 25.1 ⁇ 0.1 °.
- the crystalline powder of the compound of formula I has an X-ray powder diffraction (XRPD) pattern substantially identical to that shown in FIG.
- the present invention provides a process for the preparation of a crystalline powder of a compound of formula I, the process comprising the steps of:
- step (c) The solid obtained in the step (b) is vacuum dried together with the aqueous system to obtain the crystalline powder.
- the alcohol mixed solution in the step (a) is selected from the group consisting of methanol/isobutanol, methanol/isopropanol, and methanol/n-propanol.
- the volume ratio of the two alcohols is 0.01-100. It is preferably 0.05-20, more preferably 0.1-10.
- the total volume ratio of the alcohol to water is from 0.1 to 100, preferably from 0.5 to 10, more preferably from 1 to 7.
- the temperature of dissolution in the step (a) is from 10 to 50 ° C, preferably from 20 to 40 ° C.
- step (a) comprises from 1 to 500 mg/ml, preferably from 5 to 100 mg/ml, more preferably from 10 to 50 mg/ml, based on the total volume of the solution.
- organic solvent (i) in the step (b) is selected from the group consisting of n-propanol, isopropanol, isobutanol, methyl acetate, ethyl acetate, n-propyl acetate, and isopropyl acetate.
- the temperature of the cooling described in the step (b) is -40 to 35 ° C, preferably -20 to 35 ° C, more preferably -10 to 30 ° C, and most preferably -5 to 15 ° C.
- volume ratio of the organic solvent (i) in the step (b) to the mixed alcohol solution in the step (a) is from 0.1 to 50, preferably from 0.1 to 10, more preferably from 1 to 5.
- the crystalline powder of the compound of formula I provided by the present invention can also be used directly for the preparation of a medicament for the treatment of fungal infections.
- a pharmaceutical composition comprising a crystalline powder of a compound of formula I, and a pharmaceutically acceptable carrier can be provided.
- crystal refers to a solid in which a molecule or atomic complex is in a particular arrangement.
- solid-liquid separation refers to the process of separating a solid and a liquid by filtration or the like after the compound of the formula I is crystallized in a solvent.
- “Dry/Wet” and “dry to wet weight ratio” are used interchangeably and refer to the ratio of the weight of the solvent free of the compound to the weight of the solvent.
- the wet weight of the crystal in the present invention is obtained by filtering the solid obtained by crystallization until no significant droplets flow out and weighing.
- the compound of formula I can be obtained using methods conventional in the art, such as, but not limited to, the preparation of the compound as reported in patent WO 96/11210; it is also commercially available, such as, but not limited to, such as Fujisawa Corporation of Japan.
- the term "pharmaceutically acceptable carrier” refers to a carrier for the administration of a therapeutic agent, including various excipients and diluents.
- the term refers to pharmaceutical carriers which are not themselves essential active ingredients and which are not excessively toxic after administration. Suitable carriers are well known to those of ordinary skill in the art. A thorough discussion of pharmaceutically acceptable excipients can be found in Remington's Pharmaceutical Sciences (Mack Pub. Co., N. J. 1991).
- Pharmaceutically acceptable carriers in the compositions can include liquids such as water, saline, glycerol and ethanol.
- auxiliary substances such as disintegrants, wetting agents, emulsifiers, pH buffering substances and the like may also be present in these carriers.
- a crystalline powder of a compound of formula I which is excellent in morphology and which is easy to filter and dry.
- a method for preparing a crystalline powder of the compound of the formula I is provided, and the method is easy to solid-liquid separation and easy to dry to remove residual solvent, which is very suitable for industrial production.
- Figure 1 is a photomicrograph of a crystal of a compound of formula I before solid-liquid separation.
- Figure 2 shows an X-ray powder diffraction (XRPD) pattern of a crystalline powder of a compound of formula I.
- the units in the weight percent by volume in the present invention are well known to those skilled in the art and, for example, refer to the weight of the solute in a 100 ml solution.
- a solid amorphous powder of the compound of formula I is prepared according to the method of U.S. Patent No. 7,199,248.
- Example 1 of the patent WO03/018615 a needle crystal was obtained, which was a B82 type crystal.
- the wet crystals were weighed after filtration, and the dry-wet weight ratio was calculated to be 0.25.
- the wet solid was weighed to calculate a dry-wet weight ratio of 0.45.
- the filtered solid is placed in a vacuum drying oven, and a tray of tap water is placed in the bottom of the drying box, and dried in a vacuum to obtain a crystalline powder.
- the filtered solid was placed in a vacuum drying oven, and a disk of ice water mixture was placed in the bottom of the drying oven, and dried in a vacuum to obtain a crystalline powder.
- the filtered solid was placed in a vacuum drying oven, and a tray of tap water was placed in the bottom of the drying oven to obtain a crystalline powder.
- the filtered solid was placed in a vacuum drying oven, and a tray of tap water was placed in the bottom of the drying cabinet, and dried in a vacuum to obtain a crystalline powder.
- the filtered solid was placed in a vacuum drying oven, and a disk of ice water mixture was placed in the bottom of the drying oven, and dried in a vacuum to obtain a crystalline powder.
- the filtered solid was placed in a vacuum drying oven, and a tray of tap water was placed in the bottom of the drying oven to obtain a crystalline powder.
- the filtered solid was placed in a vacuum drying oven, and a disk of pure water was placed in the bottom of the drying oven, and dried in a vacuum to obtain a crystalline powder.
- the filtered solid is placed in a vacuum drying oven, and a tray of tap water is placed in the bottom of the drying box, and dried in a vacuum to obtain a crystalline powder.
- Examples 2-10 A crystalline powder of a compound of formula I was prepared using 1-4 g of a compound of formula I, with a filtration time of up to only 27 min, while 0.5 g of a compound of formula I was used in Comparative Example 1 to prepare a B82 type crystal with a small scale. However, the filtration time is much longer than that of Examples 2-10. It can be seen that the crystalline powder of the compound of the formula I prepared by the present invention has obvious advantages in the filtration process.
- the comparative examples were compared with the drying process of the samples obtained in the examples.
- the precipitated 5 g solids were prepared according to the methods of Examples 2-10 and Comparative Examples 1-3, and placed at 25 ° C, and dried under vacuum with an aqueous system until detected by GC. The results showed that the organic solvent was not contained, and the drying time was compared. Analyze sample purity. The specific results are shown in the following table:
- Example 2 0.45 99.68% 99.68% 7h
- Example 3 0.43 99.63% 99.61% 6.5h
- Example 4 0.55 99.64% 99.64% 9h
- Example 5 0.6 99.52% 99.47% 10h
- Example 6 0.49 99.61% 99.6% 8.5h
- Example 7 0.6 99.65% 99.57% 9.5h
- Example 8 0.38 99.52% 99.46% 6h
- Example 9 0.54 99.42% 99.38% 8.5h
- Example 10 0.56 99.5% 99.43% 9h
- Comparative example 1 0.85 99.26% 97.96% 25h Comparative example 2 / 98.82% 96.21% 30h Comparative example 3 / 98.74% 96.17% 32h
- Crystal powder of formula I lactose Anhydrous citric Sodium hydroxide 2.5g 20g Moderate amount Moderate amount
- Example 2 0.2 g of the crystalline powder of the compound of the formula I obtained by the method of Example 2 was prepared, and an eye drop was prepared in accordance with Example 2 of US2007249546A1.
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Abstract
Description
样品 | 粒径分布 | 过滤时间 |
实施例2 | d10=3.3um,d50=32.6um | 10min |
实施例3 | d10=4.2um,d50=43.9um | 20min |
实施例4 | d10=5.7um,d50=54.3um | 17min |
实施例5 | d10=9um,d50=98.3um | 18min |
实施例6 | d10=5.8um,d50=50um | 9min |
实施例7 | d10=1um,d50=10um | 23min |
实施例8 | d10=3um,d50=20um | 20min |
实施例9 | d10=1.8um,d50=23.9um | 27min |
实施例10 | d10=8.7um,d50=100um | 16min |
比较例1 | d10=0.3um,d50=0.96um | 90min |
比较例2 | / | 150min |
比较例3 | / | 300min |
样品 | 堆积密度(g/mL) | 干燥前纯度 | 干燥后纯度 | 所需时间 |
实施例2 | 0.45 | 99.68% | 99.68% | 7h |
实施例3 | 0.43 | 99.63% | 99.61% | 6.5h |
实施例4 | 0.55 | 99.64% | 99.64% | 9h |
实施例5 | 0.6 | 99.52% | 99.47% | 10h |
实施例6 | 0.49 | 99.61% | 99.6% | 8.5h |
实施例7 | 0.6 | 99.65% | 99.57% | 9.5h |
实施例8 | 0.38 | 99.52% | 99.46% | 6h |
实施例9 | 0.54 | 99.42% | 99.38% | 8.5h |
实施例10 | 0.56 | 99.5% | 99.43% | 9h |
比较例1 | 0.85 | 99.26% | 97.96% | 25h |
比较例2 | / | 98.82% | 96.21% | 30h |
比较例3 | / | 98.74% | 96.17% | 32h |
式I化合物结晶粉末 | 乳糖 | 无水柠檬酸 | 氢氧化钠 |
2.5g | 20g | 适量 | 适量 |
Claims (17)
- 如权利要求1所述的环肽类化合物的结晶粉末,其特征在于,所述结晶粉末的堆积密度小于0.6g/mL,优选小于0.5g/mL。
- 如权利要求1所述的环肽类化合物的结晶粉末,其特征在于,所述结晶粉末的d50在10-100um,优选d50在20-50um。
- 如权利要求1所述的环肽类化合物的结晶粉末,其特征在于,所述结晶粉末的d10在1-9um,优选d10在1-5um。
- 如权利要求1所述的环肽类化合物的结晶粉末,其特征在于,所述结晶粉末在固液分离前,d50在10-100um,优选d50在20-50um。
- 如权利要求1所述的环肽类化合物的结晶粉末,其特征在于,所述结晶粉末在固液分离前,d10在1-9um,优选d10在3-6um。
- 一种制备如权利要求1-6任一所述的环肽类化合物的结晶粉末的方法,其特征在于,所述的方法包含以下步骤:(a)将如式I所示化合物溶解在含水的醇类混合溶液中;(b)通过降温和/或添加有机溶剂(i),得到固体;(c)步骤(b)中得到的固体与水体系一起进行真空干燥,得到如权利要 求1-6任一所述的结晶粉末。
- 如权利要求7所述的制备方法,其特征在于,步骤(a)中所述醇类混合溶液选自:甲醇/异丁醇、甲醇/异丙醇、甲醇/正丙醇。
- 如权利要求8所述的制备方法,其特征在于,步骤(a)中所述含水的醇类混合溶液中,两种醇体积比为0.01-100,优选0.05-20,更优选0.1-10。
- 如权利要求7所述的制备方法,其特征在于,步骤(a)中所述含水的醇类混合溶液中,醇总体积与水体积比为0.1-100,优选0.5-10,更优选1-7。
- 如权利要求7所述的制备方法,其特征在于,步骤(b)中所述有机溶剂(i)选自:正丙醇、异丙醇、异丁醇、乙酸甲酯、乙酸乙酯、乙酸正丙酯、乙酸异丙酯。
- 如权利要求7所述的制备方法,其特征在于,步骤(b)中所述的降温的温度为-40至35℃,优选-20至35℃,更优选-10至30℃,最优选-5至15℃。
- 如权利要求7所述的制备方法,其特征在于,步骤(b)中所述有机溶剂(i)与步骤(a)中含水的醇类混合溶液的体积比为0.1-50,优选0.1-10,更优选1-5。
- 如权利要求7所述的制备方法,其特征在于,步骤(c)中所述水体系选自:自来水、纯水、冰水混合物或其他能释放水蒸汽的物质。
- 一种如权利要求1-6任一所述的环肽类化合物结晶粉末的用途,其特征在于,用于制备治疗真菌感染的药物。
- 一种药物组合物,其特征在于,所述的药物组合物中含有如权利要求1-6任一所述的环肽类化合物结晶粉末和药学上可接受的载体。
- 一种如权利要求16所述的药物组合物的制备方法,其特征在于,所述的方法包含以下步骤:将如权利要求1-6任一所述的环肽类化合物结晶粉末和药学上可接受的载体混合,得到如权利要求16所述的药物组合物
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
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JP2016546139A JP6437004B2 (ja) | 2014-05-29 | 2015-05-29 | シクロペプチド系化合物の結晶粉末およびその製造方法と使用 |
US15/314,799 US10138275B2 (en) | 2014-05-29 | 2015-05-29 | Crystalline powder of cyclic peptide compound, preparation method for same, and uses thereof |
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US11634427B2 (en) | 2016-07-29 | 2023-04-25 | New Japan Chemical Co., Ltd. | Crystal nucleating agent for polyolefin resin, method for producing crystal nucleating agent for polyolefin resin, and method for improving fluidity of crystal nucleating agent for polyolefin resin |
US11746211B2 (en) | 2016-09-16 | 2023-09-05 | New Japan Chemical Co., Ltd. | Crystal nucleator for polyolefin resins, method for producing crystal nucleator for polyolefin resins, and method for improving fluidity of crystal nucleator for polyolefin resins |
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WO2003018615A1 (fr) * | 2001-08-31 | 2003-03-06 | Fujisawa Pharmaceutical Co., Ltd. | Nouveau cristal de compose lipopeptidique cyclique |
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CN102659930B (zh) * | 2012-03-30 | 2014-04-23 | 上海天伟生物制药有限公司 | 一种高纯度环肽类物质的晶体及其制备方法和用途 |
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US11634427B2 (en) | 2016-07-29 | 2023-04-25 | New Japan Chemical Co., Ltd. | Crystal nucleating agent for polyolefin resin, method for producing crystal nucleating agent for polyolefin resin, and method for improving fluidity of crystal nucleating agent for polyolefin resin |
US11746211B2 (en) | 2016-09-16 | 2023-09-05 | New Japan Chemical Co., Ltd. | Crystal nucleator for polyolefin resins, method for producing crystal nucleator for polyolefin resins, and method for improving fluidity of crystal nucleator for polyolefin resins |
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EP3150622B1 (en) | 2019-04-24 |
JP2016538330A (ja) | 2016-12-08 |
JP6437004B2 (ja) | 2018-12-12 |
CN104788545A (zh) | 2015-07-22 |
EP3150622A4 (en) | 2017-12-27 |
CN104788545B (zh) | 2019-03-01 |
EP3150622A1 (en) | 2017-04-05 |
US10138275B2 (en) | 2018-11-27 |
US20170101443A1 (en) | 2017-04-13 |
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