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WO2022042738A1 - Composition pharmaceutique contenant un inhibiteur de cdk4/6 - Google Patents

Composition pharmaceutique contenant un inhibiteur de cdk4/6 Download PDF

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Publication number
WO2022042738A1
WO2022042738A1 PCT/CN2021/115486 CN2021115486W WO2022042738A1 WO 2022042738 A1 WO2022042738 A1 WO 2022042738A1 CN 2021115486 W CN2021115486 W CN 2021115486W WO 2022042738 A1 WO2022042738 A1 WO 2022042738A1
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WIPO (PCT)
Prior art keywords
pharmaceutical composition
fluoro
microcrystalline cellulose
compound
lactose monohydrate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2021/115486
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English (en)
Chinese (zh)
Inventor
尹磊
姚郑林
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Gan and Lee Pharmaceuticals Co Ltd
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Gan and Lee Pharmaceuticals Co Ltd
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Priority to CN202180053613.XA priority Critical patent/CN116113628A/zh
Publication of WO2022042738A1 publication Critical patent/WO2022042738A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention belongs to the field of pharmaceutical preparations, in particular to a kind of 5-fluoro-4-(7'-fluoro-2'-methyl spiro[cyclopentane-1,3'-indol]-5'-yl)-N
  • the cell cycle is an important part of cell life activities. In the normal cell growth process, the realization of the cell cycle process depends on the precise and tight regulation of the cell cycle by various regulatory factors.
  • the core of these regulatory factors is cyclin-dependent protein kinase (Cyclin Dependent Kinase, CDK) and its positive and negative regulators - cyclin (Cyclin) and cyclin-dependent protein kinase inhibitor (CDI).
  • CDK-Cyclin complex formed by cyclin-dependent protein kinases and cyclins is involved in cell growth, proliferation, dormancy or entering apoptosis.
  • cyclins are periodically and continuously expressed and degraded, and respectively bind to their transiently activated CDKs. Through CDK activity, they catalyze the phosphorylation of different substrates to achieve the advancement of different phases of the cell cycle. and transformation.
  • CDK1-CDK13 13 members of the CDK family have been found, namely CDK1-CDK13; CDK1, CDK2, CDK3, CDK4 and CDK6 are involved in regulating cell proliferation, and CDK7, CDK8, CDK9, CDK11, CDK12 and CDK13 are involved in regulating transcription.
  • Cyclin is divided into A-L subtypes, and different CDKs are connected to different subtypes of Cyclin.
  • Cyclin D family (Cyclin D1, D2, D3) begins to express in G1 phase, binds and activates CDK4 and CDK6, and forms CDK4/6-Cyclin D complex, including retinoblastoma protein (Rb) phosphorylation of a series of substrates. After Rb is phosphorylated, it releases the proteins that bind to it and are inhibited by it, mainly transcription factors E2F, etc.
  • Rb retinoblastoma protein
  • E2F activates and transcribes some genes necessary for entering the S phase (Ma Ke, Research Progress in Anti-tumor Effects of CDK4/6 Inhibitors, "Foreign Studies” Medicine and Antibiotics Volume, 2013, 34(5): 197-202). If the balance is disturbed due to various factors, whether the signal that promotes cell proliferation is increased, or the signal that inhibits cell proliferation is weakened to a certain extent, cell proliferation will be out of control, and tumors will appear. Studies have found that about 80% of human tumors have abnormalities in the Cyclin D-CDK4/6-INK4-Rb pathway (1.Malumbres M, Barbacid M., To cycle or not to cycle: a critical decision in cancer[J]. Nature Reviews Cancer, 2001, 1(3): 222; 2.
  • CDK4/6 as an anti-tumor target are: (1) Most proliferating cells depend on CDK2 or CDK4/6 for proliferation, but CDK4/6 inhibitors do not show the cytotoxicity of "pan-CDK inhibitors", such as Myelosuppression and intestinal reaction; (2) Preclinical experiments have shown that if the level of Cyclin D in cells is increased or p16INK4a is inactivated, the sensitivity of cells to drugs can be increased. increased drug targeting.
  • a technical problem to be solved by the present invention is to provide a pharmaceutical composition based on compound 1 as an active ingredient that meets the needs of oral administration.
  • Another technical problem to be solved by the present invention is to provide a pharmaceutical composition based on Compound 1 as an active ingredient with improved solubility properties and lower risk of food effects.
  • Another technical problem to be solved by the present invention is to provide a pharmaceutical composition based on Compound 1 as an active ingredient with reduced hygroscopicity.
  • Another technical problem to be solved by the present invention is to provide a pharmaceutical composition based on Compound 1 as an active ingredient with improved fluidity.
  • Another technical problem to be solved by the present invention is to provide a pharmaceutical composition based on Compound 1 as an active ingredient with improved dissolution properties.
  • Another technical problem to be solved by the present invention is to provide a pharmaceutical composition based on Compound 1 as an active ingredient with improved stability.
  • Another technical problem to be solved by the present invention is to provide a pharmaceutical composition based on Compound 1 as an active ingredient having two or more of the above properties (preferably having all of the above properties).
  • Another technical problem to be solved by the present invention is to provide a solid oral pharmaceutical preparation made from the above-mentioned pharmaceutical composition.
  • the present invention provides a pharmaceutical composition using Compound 1 or a pharmaceutically acceptable salt thereof as an active ingredient, the pharmaceutical composition dissolves rapidly, has improved solubility, stability, fluidity and reduced moisture absorption Sexual and food effect risks, and the quality is stable and controllable.
  • the present invention provides a pharmaceutical composition containing, as an active ingredient, 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3] '-Indol]-5'-yl)-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine or a pharmaceutically acceptable salt thereof and dilution It is characterized in that the diluent is selected from one or more of microcrystalline cellulose, lactose or its hydrate, and sugar alcohol.
  • the pharmaceutically acceptable salt is selected from 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5' -yl)-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine fumarate, maleate, adipate and succinic acid one or more of the salts.
  • the pharmaceutically acceptable salt is 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5' -yl)-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine fumarate (hereinafter referred to as "Compound A").
  • the solubility of the pharmaceutical compositions of the present invention will be significantly improved relative to the use of the free base of Compound 1, while allowing the pharmaceutical compositions of the present invention to have a reduced risk of food effects , and compared to the use of other salts of compound 1 such as hydrochloride and mesylate, the obtained pharmaceutical composition can also have improved hygroscopicity.
  • the content of Compound 1 or a pharmaceutically acceptable salt thereof is 3.0% or more, preferably 4.0% or more, preferably 4%- 80%, preferably 5%-62%, preferably 6%-50%, more preferably 6%-25%, most preferably 8%-23%.
  • the pharmaceutical composition of the present invention contains different dosages of active pharmaceutical ingredients, which can meet the needs of different patients, and choose different dosages of medicines according to the severity of different diseases, which is helpful for individualized treatment and avoids adverse effects caused by improper medication.
  • the diluent is selected from one or more of microcrystalline cellulose, lactose monohydrate, mannitol and sorbitol.
  • the diluent is a mixture of microcrystalline cellulose and lactose monohydrate, or a mixture of microcrystalline cellulose and mannitol.
  • the microcrystalline cellulose is microcrystalline cellulose PH101 or microcrystalline cellulose PH102; preferably, the lactose monohydrate is lactose monohydrate FlowLac 100 or lactose monohydrate Tablettose 80; preferably, the mannitol It is mannitol 100SD.
  • the diluent is a mixture of mannitol 100SD and microcrystalline cellulose PH101, a mixture of lactose monohydrate Tablettose 80 and microcrystalline cellulose PH102, or a mixture of microcrystalline cellulose PH102 and lactose monohydrate FlowLac 100 mixture.
  • the weight ratio of lactose monohydrate and microcrystalline cellulose is 5:1-1:5, preferably 3:1-1:3, more preferably 1.5:1-1:1.5, most preferably Preferably it is 1:1; or the weight ratio of the mannitol and microcrystalline cellulose is 5:1-1:5, preferably 3:1-1:3, more preferably 1.5:1-1:1.5, most preferably 1:1.
  • the further selection of the diluent and the dosage ratio of the diluent in the present invention is beneficial to improve the dissolution rate of the pharmaceutical composition and has good dissolution consistency.
  • the content of the diluent is more than 20% of the total weight of the pharmaceutical composition, preferably more than 30%, preferably more than 40%, preferably 20-90%, preferably 50-90% , preferably 60-90%, more preferably 60%-85%, further preferably 65%-80%.
  • the pharmaceutical composition may further include a glidant, the glidant is selected from one or both of talc and colloidal silicon dioxide, more preferably, the glidant For colloidal silica.
  • the content of the glidant is 0.5%-15% of the total weight of the pharmaceutical composition, preferably 1%-10%, more preferably 1%-3%, most preferably 1% , 2% or 3%.
  • the addition of the glidant in the invention is beneficial to improve the fluidity of the pharmaceutical composition, improve the stability of the filling amount of the filling capsule, and the difference in the filling amount is small.
  • the pharmaceutical composition may further comprise a disintegrant, preferably, the disintegrant is selected from the group consisting of croscarmellose sodium, sodium carboxymethyl starch, crospovidone and low Substituting one or more of hydroxypropyl cellulose, more preferably, the disintegrant is croscarmellose sodium.
  • the disintegrant is selected from the group consisting of croscarmellose sodium, sodium carboxymethyl starch, crospovidone and low Substituting one or more of hydroxypropyl cellulose, more preferably, the disintegrant is croscarmellose sodium.
  • the content of the disintegrant is 0.5%-15% of the total weight of the pharmaceutical composition, preferably 1%-10%, more preferably 1%-5%, more preferably 1% -3%, most preferably 1%, 2%, 3%, 4%, or 5%.
  • the disintegrant and the selection of the dosage of the present invention help to improve the dissolution rate of the pharmaceutical composition and have good dissolution consistency.
  • the pharmaceutical composition may further include a lubricant, preferably, the lubricant is selected from one of magnesium stearate, stearic acid, sodium stearoyl fumarate and zinc stearate One or more, more preferably, the lubricant is magnesium stearate.
  • the content of the lubricant is 0.1%-5% of the total weight of the pharmaceutical composition, preferably 0.5%-3%, more preferably 1%-2%, most preferably 1%.
  • the selection of the lubricant and its dosage of the present invention further reduces the friction between the powders and between the powders and the mold wall, and is helpful for filling capsules or tableting.
  • the present invention provides a pharmaceutical composition containing the following components by weight:
  • the diluent is a mixture of microcrystalline cellulose and lactose monohydrate a mixture, or a mixture of microcrystalline cellulose and mannitol;
  • glidant is colloidal silica
  • disintegrant preferably, the disintegrant is selected from one of croscarmellose sodium, sodium carboxymethyl starch, crospovidone and low-substituted hydroxypropyl cellulose or various; and
  • the lubricant is selected from magnesium stearate, stearic acid , one or more of sodium stearoyl fumarate and zinc stearate.
  • the weight ratio of lactose monohydrate and microcrystalline cellulose is 5:1-1:5, preferably 3:1-1:3, more preferably 1.5 : 1-1: 1.5, most preferably 1: 1; or the weight ratio of the mannitol and microcrystalline cellulose is 5: 1-1: 5, preferably 3: 1-1: 3, more preferably 1.5: 1-1:1.5, most preferably 1:1.
  • the pharmaceutical composition in the pharmaceutical composition, 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5'- yl)-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine free base, the pharmaceutical composition comprises 0.1-1000 mg, preferably 1- 100 mg, more preferably 8 to 50 mg of active ingredient.
  • the present invention also provides a solid oral pharmaceutical preparation made from the pharmaceutical composition, preferably a powder, a capsule, a tablet or a granule, more preferably a capsule, wherein the capsule is made of the pharmaceutical composition as filler.
  • the solid oral pharmaceutical preparation comprises 0.1 ⁇ 1000mg, preferably 1 to 100 mg, more preferably 8 to 50 mg of active ingredient.
  • the capsules are prepared using a powder direct filling process.
  • the capsules of the present invention are loaded according to the free base content of compound 1, and a capsule filling machine is used to fill the medicinal powder, that is, the pharmaceutical composition of the present invention, into hard capsule shells of different specifications, and the differences in the loading of the capsules are investigated to avoid Affect product content and uniformity.
  • the present invention also provides the pharmaceutical composition of the present invention or the solid oral pharmaceutical preparation of the present invention, which is used for the treatment of CDK4/6-mediated disorders or diseases.
  • the present invention also provides the use of the pharmaceutical composition of the present invention or the solid oral pharmaceutical preparation of the present invention in preparing a medicament for treating CDK4/6-mediated disorders or diseases.
  • the present invention also provides a method for treating a CDK4/6-mediated disorder or disease, comprising administering the pharmaceutical composition of the present invention or the solid oral pharmaceutical formulation of the present invention to a subject in need thereof.
  • the CDK4/6 mediated disorder or disease is cancer, AIDS, atherosclerosis or restenosis after stent implantation, wherein the cancer is preferably a malignant solid tumor or a malignant non-solid tumor, more Breast cancer, lung cancer, prostate cancer, leukemia, brain cancer or gastric cancer are preferred, and glioma is even more preferred.
  • the present invention can significantly improve the fluidity of the obtained pharmaceutical composition powder, the obtained pharmaceutical composition has a larger bulk density, a smaller Carr index and an angle of repose, and the pharmaceutical composition powder has a uniform color and no color difference. .
  • the solubility of the pharmaceutical composition of the present invention will be further improved relative to the use of the free base of compound 1, and the pharmaceutical composition of the present invention will have a reduced risk of food effects, and is relatively
  • the pharmaceutical composition of the present invention has high stability under the experimental conditions of high temperature (60°C), high humidity (75%RH), strong light (5000lux) and acceleration (40°C/75%RH).
  • the pharmaceutical composition of the present invention can realize the preparation of capsules by directly filling the capsules with powder, the process is simple, the filling volume stability of the capsules prepared by filling is good, and the filling volume difference is small.
  • Figure 1 is a 1 H-NMR chart of the fumarate salt of compound 1 in CD 3 OD.
  • Figure 2 is a 1 H-NMR chart of the maleate salt of compound 1 in CD 3 Cl.
  • Figure 3 is a 1 H-NMR chart of the adipate salt of Compound 1 in CD 3 OD.
  • Figure 4 is a 1 H-NMR chart of the succinate salt of compound 1 in CDCl 3 .
  • Figure 5 is a 1 H-NMR chart of the mesylate salt of Compound 1 in CD 3 OD.
  • Figure 6 is the dissolution curve of the 10 mg specification pilot batch of Test Example 11 in pH 1.2 hydrochloric acid buffer.
  • Figure 7 is the dissolution curve of the 50 mg specification pilot batch of Test Example 11 in pH 1.2 hydrochloric acid buffer.
  • Mannitol 100SD Mannitol 100SD.
  • Microcrystalline Cellulose PH101 Microcrystalline Cellulose
  • Microcrystalline Cellulose PH102 Microcrystalline Cellulose
  • Lactose Monohydrate FlowLac 100 Lactose Monohydrate
  • Lactose Monohydrate Tablettose 80 Lactose Monohydrate
  • Colloidal Silica 200 Colloidal Silica
  • diluent refers to an excipient used to increase the weight and/or volume of a pharmaceutical composition to facilitate molding and sub-dosing.
  • the diluent described in the present invention is selected from one or more of microcrystalline cellulose, lactose or its hydrate, and sugar alcohol, preferably selected from one or more of microcrystalline cellulose, lactose monohydrate, mannitol and sorbitol one or more.
  • the diluent may be a single diluent or a mixture of two diluents.
  • the diluent is a mixture of two diluents, it is preferably microcrystalline cellulose (eg, microcrystalline cellulose PH101 or microcrystalline cellulose PH102) and lactose monohydrate (eg, lactose monohydrate FlowLac 100 or lactose monohydrate).
  • microcrystalline cellulose eg, microcrystalline cellulose PH101 or microcrystalline cellulose PH102
  • lactose monohydrate eg, lactose monohydrate FlowLac 100 or lactose monohydrate
  • Tablettose 80 or a mixture of microcrystalline cellulose (eg, microcrystalline cellulose PH101 or microcrystalline cellulose PH102) and mannitol (eg, mannitol 100SD), and the weight of the lactose monohydrate and microcrystalline cellulose
  • the ratio is 5:1-1:5, preferably 3:1-1:3, more preferably 1.5:1-1:1.5, most preferably 1:1; or the weight ratio of the mannitol and microcrystalline cellulose It is 5:1-1:5, preferably 3:1-1:3, more preferably 1.5:1-1:1.5, most preferably 1:1.
  • the "glidant" in the present invention refers to an excipient used to increase the fluidity of a material.
  • the glidant of the present invention is selected from one or both of talc and colloidal silicon dioxide, more preferably, the glidant is colloidal silicon dioxide.
  • the "disintegrant” in the present invention refers to an excipient used to promote the disintegration of the pharmaceutical composition in the gastrointestinal tract and increase the dissolution of the active ingredient.
  • the disintegrant of the present invention is selected from one or more of croscarmellose sodium, sodium carboxymethyl starch, crospovidone and low-substituted hydroxypropyl cellulose, more preferably, The disintegrating agent is croscarmellose sodium.
  • the "lubricant" used in the present invention refers to an excipient used to reduce the frictional force between particles of a pharmaceutical composition and improve the transmission and distribution of force.
  • the lubricant of the present invention is selected from one or more of magnesium stearate, stearic acid, sodium stearoyl fumarate and zinc stearate, more preferably, the lubricant is stearic acid magnesium.
  • compositions of the present invention may also contain other excipients other than diluents, glidants, disintegrants and lubricants.
  • excipients other than diluents, glidants, disintegrants and lubricants.
  • specific examples thereof include binders, flavoring agents, dispersing agents, coloring agents, fragrances, and the like.
  • solid oral pharmaceutical preparation in the present invention refers to a solid pharmaceutical preparation for oral administration.
  • the present invention relates to a solid oral pharmaceutical preparation made from the above-mentioned pharmaceutical composition, and its specific dosage form is preferably powder, capsule, tablet or granule, more preferably capsule, wherein the capsule is filled with the pharmaceutical composition .
  • the pharmaceutical composition of the present invention or its solid oral pharmaceutical preparation may contain 0.1-1000 mg, preferably 1-100 mg, more preferably 8-50 mg of active ingredients in the form of 5-fluoro-4-(7'-fluoro-2'-methylspiro) [Cyclopentane-1,3'-indol]-5'-yl)-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine free base content meter.
  • the content of the active ingredient in the pharmaceutical composition of the present invention or its solid oral pharmaceutical preparation can be 0.1 mg, 0.2 mg, 0.25 mg, 0.5 mg, 1 mg, 2 mg, 2.5 mg, 5 mg, 8 mg, 10 mg, 20 mg, 25 mg, 40mg, 50mg, 100mg, 150mg, 200mg, 250mg, 300mg, 500mg, 1000mg, etc.
  • the administration subject may be a human or a non-human mammal, more preferably a human.
  • the term “comprising” or similar terms “comprising” and “comprising” generally express an open meaning, but also includes a closed meaning defined by “consisting of” within its scope. condition.
  • a pharmaceutical composition comprising also includes the case of "a pharmaceutical composition consisting of”.
  • the above solution was filtered through a microporous filter, and transferred to the reactor, stirred, and dichloromethane and ethanol were distilled off at normal pressure, and then the temperature of the reactor was kept to 80 ⁇ 5 degrees Celsius, and the fumaric acid ( 1.0eq) of ethanol solution (12 volumes) was slowly dropped into the reaction kettle through a microporous filter, and kept stirring overnight. Cool to 20-30 degrees Celsius, continue stirring for at least 1 hour, centrifuge, and collect the filter cake.
  • the purpose of this test example is to compare the solubility of various salts (also called salt forms) and free bases obtained by the present invention.
  • the sample and the solvent were mixed in a centrifuge tube (the initial feeding amount was 10 mg/ml), and then the centrifuge tube was sealed and fixed on a rotating disk with a rotation speed of 25 rpm, and rotated and mixed at 37 °C. Samples were taken after 24 hours. The turbid samples were centrifuged, and the filtered supernatant was used to measure the HPLC concentration. If the sample dissolves, test the concentration of the resulting solution.
  • Test subjects free base, maleate, fumarate, adipate and succinate of compound 1.
  • Test results See Tables 1-3, solubility of different salt forms and free bases in water, simulated fasting intestinal fluid (FaSSIF) and simulated fed intestinal fluid (FeSSIF).
  • the solubility of maleate, fumarate, adipate and succinate of compound 1 in water was 12.9, 6.3, 6.5 and 7.5 mg/ml, respectively, which was significantly higher than that of the free base in water. Solubility in water (0.075 mg/ml). This suggests that when the above-mentioned salt of the present invention is used to formulate the pharmaceutical composition of the present invention, the solubility of the active ingredient Compound 1 can be significantly improved.
  • This test example compares the hygroscopicity of various salt forms and free bases of compound 1 provided by the present invention.
  • the dynamic moisture adsorption (DVS) test was used to test the moisture adsorption capacity of the salt and free base of compound 1 of the present invention when the humidity reached 80% RH, so as to compare the hygroscopicity.
  • Test subjects Compound 1 free base, maleate, fumarate, adipate, succinate, mesylate and hydrochloride.
  • the preparation method of the pharmaceutical composition powder of embodiment 2-3 is as follows:
  • step (2) the pretreatment powder obtained in step (2) is mixed with mannitol 100SD, microcrystalline cellulose PH101, and the winner is mixed powder for subsequent use;
  • step (4) adding magnesium stearate to the main mixed powder prepared in step (4) and mixing to obtain a total mixed powder of pharmaceutical composition powder.
  • Compound A is 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)-N-(5-( The fumarate salt of 1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine.
  • the bulk density of the pharmaceutical composition of Example 2-3 is significantly increased compared to the single active ingredient raw material Compound A, and the angle of repose and Carr's index are significantly reduced, indicating that the pharmaceutical composition of Example 2-3 is combined.
  • the fluidity of the powder is significantly improved, and it can realize the preparation of capsules by a simple powder direct filling process, reduce the risk of large differences in the filling volume of the capsules, and meet the requirements of capsule filling and industrialization. production requirements.
  • the pharmaceutical composition powders of Examples 4-6 were prepared by adopting the steps similar to those in Example 2-3.
  • the bulk density of the pharmaceutical composition powder of Example 4-6 is significantly increased compared to the single active ingredient raw material Compound A, and the angle of repose and Carr's index are significantly reduced, indicating that the medicine of Example 4-6 Compared with the single active ingredient compound A, the fluidity of the composition powder is significantly improved, and when it is subsequently used to prepare a preparation in the form of capsules, it will be able to reduce the risk of large differences in the filling volume of the capsules, and meet the requirements and requirements of capsule filling. requirements for industrial production.
  • the preparation method of the capsule of embodiment 7-9 is as follows:
  • step (2) (4) mixing the pretreated powder obtained in step (2) with microcrystalline cellulose PH102, lactose monohydrate FLOWLAC100 and croscarmellose sodium, and the winner is mixed powder for subsequent use;
  • step (4) adding magnesium stearate to the main mixed powder prepared in step (4) and mixing to obtain a total mixed powder of pharmaceutical composition powder.
  • 50mg capsules are based on 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5'-yl)-N-( The content of the free base of 5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine.
  • Compound A is 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)-N-(5-(1-methyl)
  • the dissolution rate of the prepared capsules of Examples 7-9 was determined. Using 900 ml of PH1.2 hydrochloric acid buffer as the medium, the water temperature was 37 ⁇ 0.5 °C, and the rotation speed was 50 rpm, and samples were taken at 6 time points such as 5 min, 15 min, 30 min, 45 min, 60 min, and 75 min, respectively. Each sampling volume was 10 ml and was filtered with a PFS filter (0.45 ⁇ m to 10 ⁇ m). For each dissolution test, repeat 3 capsules or 6 capsules. The dissolution results are shown in Table 10 below.
  • the pharmaceutical composition powders of Examples 10-13 were obtained by the steps similar to those of Examples 2-3.
  • the pharmaceutical compositions of Examples 11-13 with colloidal silicon dioxide added to the formula As can be seen from the data in Table 12, compared to the pharmaceutical composition of Example 10 without colloidal silicon dioxide, the pharmaceutical compositions of Examples 11-13 with colloidal silicon dioxide added to the formula, the angle of repose is further reduced. , the fluidity is further improved, and when the amount of colloidal silicon dioxide is in the range of about 1% to 3%, the fluidity of the pharmaceutical composition powder has no significant change.
  • the dissolution rate of the capsules obtained in Examples 14-15 was measured according to the method of Test Example 5, and the test results are shown in Table 14 below.
  • 10mg capsules are based on 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indole]-5'-yl)-N-( The content of the free base of 5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine.
  • Compound A is 5-fluoro-4-(7'-fluoro-2'-methylspiro[cyclopentane-1,3'-indol]-5'-yl)-N-(5-(1-methyl)
  • the dissolution rate of the capsules obtained in Example 16 was measured according to the method of Test Example 5, and the test results are shown in Table 16.
  • Example 7 50mg specification
  • Example 16 10 capsules were sampled respectively, and the weight of a single capsule was detected (the first, middle and last three stages respectively) Refers to 5 minutes after the start of capsule filling, about half of the filling is completed, and 5 minutes before the end of filling), according to the "Chinese Pharmacopoeia" 2015 edition four 0103 capsules under the difference inspection method detection, the test results are shown in Tables 17 and 18.
  • Example 7 50 mg strength
  • Example 16 10 mg strength
  • the two specifications of the samples were placed under the same conditions for 10 days and 30 days under accelerated conditions of 40°C/75%RH (opening), respectively.
  • the free base content of compound A in the capsules was determined by HPLC, and the method of Test Example 5 was used. Determination of dissolution; respectively at 60°C (open), 25°C/75%RH (open), light (intensity 5000lux) (open), 40°C/75%RH (open), 40°C/75%RH (closed)
  • the changes of related substances were determined by HPLC.
  • the test results of changes in capsule content, dissolution results and related substances are as follows:
  • Capsule content means "free base content of compound A in capsules”.
  • Capsules were prepared using the formulations of Example 7 (50 mg strength) and Example 16 (10 mg strength), and 10,000 capsules were prepared each, and were divided into three batches.
  • the packaging adopts oral solid medicinal high density polyethylene bottle and oral solid medicinal child safety cap.
  • the drug properties were observed by visual observation, the free base content of Compound A and the changes of related substances were determined by HPLC, the dissolution was determined by the first method (basket method) of "Chinese Pharmacopoeia” 2015 Edition Part Four 0931 Dissolution Determination Method, and the "Chinese Pharmacopoeia” 2015 Edition Chinese Pharmacopoeia 2015 edition four 0832 moisture determination method first method (Fischer's method) to measure moisture absorption weight gain, the result is shown in table 23-26.
  • test results show that the capsules of the present invention obtained through enlarged production are stable after long-term storage under the conditions of high temperature (60° C.), strong light (illumination 5000 lux), and high humidity (75% RH), and the results of each test item are not significant. changes to meet quality standard limits. It is further proved that under the conditions of scaled-up production, the obtained pharmaceutical composition of the present invention also has high stability, and the preparation production process adopted in the present invention is simple and stable, and can meet the needs of large-scale industrial production.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • Hematology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne une composition pharmaceutique contenant de la 5-fluoro-4-(7'-fluoro-2'-méthylspiro[cyclopentane-1,3'-indole]-5'-yl)-N-(5-[1-méthylpipéridine-4-yl] pyridine-2-yl)pyrimidine-2-amine comme ingrédient actif ou un sel pharmaceutiquement acceptable de celle-ci et un diluant. La composition pharmaceutique se dissout rapidement, présente une solubilité, une stabilité et une fluidité améliorées, présente une absorption d'humidité et des effets alimentaires réduits, ainsi qu'une qualité stable et contrôlable. En outre, la composition pharmaceutique présente une formule et un procédé de préparation simples et convient mieux à la production industrielle de masse.
PCT/CN2021/115486 2020-08-31 2021-08-31 Composition pharmaceutique contenant un inhibiteur de cdk4/6 Ceased WO2022042738A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102007124A (zh) * 2008-02-15 2011-04-06 里格尔制药公司 嘧啶-2-胺化合物及其作为jak激酶抑制剂的用途
CN102264725A (zh) * 2008-12-22 2011-11-30 伊莱利利公司 蛋白激酶抑制剂
CN106810536A (zh) * 2015-11-30 2017-06-09 甘李药业股份有限公司 一种蛋白激酶抑制剂及其制备方法和医药用途
WO2020253875A1 (fr) * 2019-06-21 2020-12-24 甘李药业股份有限公司 Sels de composés, leurs formes cristallines, procédé de préparation correspondant et utilisation associée

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HK1243351A1 (zh) * 2016-02-04 2018-07-13 江苏恒瑞医药股份有限公司 一种含有吡啶并嘧啶类衍生物或其可药用盐的药物组合物

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102007124A (zh) * 2008-02-15 2011-04-06 里格尔制药公司 嘧啶-2-胺化合物及其作为jak激酶抑制剂的用途
CN102264725A (zh) * 2008-12-22 2011-11-30 伊莱利利公司 蛋白激酶抑制剂
CN106810536A (zh) * 2015-11-30 2017-06-09 甘李药业股份有限公司 一种蛋白激酶抑制剂及其制备方法和医药用途
WO2020253875A1 (fr) * 2019-06-21 2020-12-24 甘李药业股份有限公司 Sels de composés, leurs formes cristallines, procédé de préparation correspondant et utilisation associée

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BRONNER, S. M. ET AL.: "Design of a brain-penetrant CDK4/6 inhibitor for glioblastoma", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 29, 26 June 2019 (2019-06-26), XP085759050, DOI: 10.1016/j.bmcl.2019.06.021 *
LEI YIN, HENG LI, WENJIAN LIU, ZHENGLIN YAO, ZHENZHEN CHENG, HUABEI ZHANG, HUI ZOU: "A highly potent CDK4/6 inhibitor was rationally designed to overcome blood brain barrier in gliobastoma therapy", EUROEPAN JOURNAL OF MEDICINAL CHEMISTRY, ELSEVIER, pages 1 - 28, XP055766971, [retrieved on 20210120] *

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