CN114028400B - Pharmaceutical composition containing cyclin kinase inhibitor and preparation method thereof - Google Patents
Pharmaceutical composition containing cyclin kinase inhibitor and preparation method thereof Download PDFInfo
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- CN114028400B CN114028400B CN202111451044.2A CN202111451044A CN114028400B CN 114028400 B CN114028400 B CN 114028400B CN 202111451044 A CN202111451044 A CN 202111451044A CN 114028400 B CN114028400 B CN 114028400B
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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
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- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/282—Organic compounds, e.g. fats
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
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Abstract
The invention relates to a pharmaceutical composition containing a cyclin inhibitor and a preparation method thereof, in particular to a pharmaceutical composition which takes N-cyclopentyl-5- (2- ((5- ((4-ethylpiperazine-1-yl) methyl) pyridine-2-yl) amino) -5-fluoropyrimidine-4-yl) -4-methylthiazol-2-amine or salt thereof as an active ingredient, and the prepared oral solid preparation has excellent dissolution behavior and good bioavailability, meets the clinical application requirements, has extremely low impurity content and better stability, and can ensure controllable quality of the medicine; meanwhile, the preparation process of wet/dry granulation is simple and easy to operate, and is beneficial to the industrialized production of medicines.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and in particular relates to a pharmaceutical composition containing a cyclin-dependent kinase inhibitor and a preparation method thereof.
Background
Cyclin-dependent kinases (CDKs) are a set of Ser/Thr kinase systems corresponding to cell cycle progression. They are associated with various cyclin subunits and play a critical role in a variety of important regulatory pathways in cells, including cell cycle control, apoptosis, neuronal physiology, differentiation and transcription. Currently there are more than 20 CDKs, which are functionally divided into two major classes, cell cycle modulator CDK and transcriptional modulator CDK. Cell cycle modulators CDK include CDK1, CDK2, CDK3, CDK4 and CDK6, which interact with cyclin ligands (e.g., cyclin A, B, D1, D2, D3, E and F) to modulate cell cycle progression. Transcriptional modulators CDK include CDK7, CDK8, CDK9 and CDK11, which interact with cyclin C, H, K, L1, L2, T1 and T2, primarily involved in transcriptional regulation. Based on this it can be concluded that CDKs are closely related to cell proliferative diseases and disorders, in particular cancer. Cell proliferation is the result of a direct or indirect uncontrolled cell division cycle, with CDKs playing a critical role in the regulation of various phases of the cycle. Inhibitors of CDKs and their associated cyclin are therefore considered effective targeted drugs for cancer treatment.
The CDK4/6 has the advantages as an anti-tumor target: (1) CDK4/6 inhibitors do not exhibit cytotoxicity of pan CDK inhibitors, such as myelosuppression and intestinal responses; (2) The increase of the level of the cyclin D or the inactivation of the P161NK4a can increase the sensitivity of the cells to the drugs, and compared with the normal cells, the tumor cells have the phenomenon, so that the targeting of the drugs is increased to a certain extent.
The compound of formula I is a targeted CDK4/6 kinase inhibitor, and can selectively inhibit cyclin dependent kinase 4/6, restore cell cycle control and block proliferation of tumor cells.
However, the solubility in water of the compound of formula I and its salts is about 40 μg/mL, insoluble or almost insoluble, which directly affects the absorption and bioavailability of the compound in vivo, thus requiring layer-by-layer screening and optimization of the prescription, dosage form and prescription process to obtain a pharmaceutical composition with excellent dissolution and bioavailability.
Disclosure of Invention
The invention aims to provide a pharmaceutical composition containing a CDK4/6 kinase inhibitor, which has the advantages of good stability, rapid dissolution and high bioavailability, and the preparation process of the pharmaceutical composition is simple and is more suitable for industrial production.
The technical scheme for solving the technical problems is as follows:
in a first aspect the present invention provides a pharmaceutical composition comprising an active ingredient of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, the active ingredient comprising from 25% to 75% by weight of the pharmaceutical composition,
further, the salt of the compound of formula I is succinate, and the excipient comprises one or more of a disintegrant, a diluent or a lubricant;
further, the diluent is selected from one or more of sugar, sugar alcohol, starch or cellulose, and the diluent accounts for 15-60% of the weight of the pharmaceutical composition;
further, the disintegrating agent is selected from one or more of povidone or cellulose derivatives, and the disintegrating agent accounts for 1-15% of the weight of the pharmaceutical composition;
further, the lubricant is selected from talcum powder, and the lubricant accounts for 0.1-5% of the weight of the pharmaceutical composition;
the second aspect of the invention provides a pharmaceutical composition, which comprises the following components in parts by weight:
wherein the diluent is selected from one or more of lactose, microcrystalline cellulose or starch; the disintegrating agent is one or more selected from crospovidone or croscarmellose sodium; the lubricant is selected from talcum powder;
in a preferred embodiment, the invention provides a pharmaceutical composition which comprises the following components in parts by weight:
optionally, the pharmaceutical composition may further comprise one or more of a flavoring agent, a coloring agent, or a coating agent;
meanwhile, in order to ensure that the pharmaceutical composition has good bioavailability, the pharmaceutical composition is preferably prepared into an oral solid preparation, more preferably into a tablet or a capsule;
the dissolution rate of the pharmaceutical composition is measured according to a second method (paddle method) for measuring the dissolution rate of the four-part rule 0931 of the Chinese pharmacopoeia 2020 edition, wherein the dissolution rate of the active ingredient is more than or equal to 90 percent in 30 minutes, preferably more than or equal to 95 percent;
the third aspect of the present invention provides two methods for preparing the above pharmaceutical compositions:
the first method is accomplished by wet granulation, comprising the steps of:
(1) Premixing a compound of formula I or a salt thereof and most excipients including disintegrants in a hopper mixer or wet granulator to obtain a premix;
(2) Adding a wetting agent, and granulating the premix in the step (1) in a wet granulator or a fluidized bed;
(3) Drying the granules of step (2) in a fluidized bed dryer or a drying oven;
(4) Optionally, crushing and screening the dry particles in the step (3) by a granulator;
(5) Mixing the dried granules of step (4) with the remaining excipients in a hopper mixer to obtain a final mixture;
(6) Optionally, preparing a capsule by filling the mixture of step (5) above by a suitable capsule filling machine;
(7) Optionally, compressing the mixture of step (5) by a suitable tabletting machine to form tablet cores;
(8) Optionally, film coating the tablet cores of step (7) with a film coating.
The second method is accomplished by dry granulation, comprising the steps of:
(1) Mixing a compound of formula I or a salt thereof and most excipients including disintegrants in a hopper mixer to obtain a premix;
(2) Compacting the mixture of step (1) in a suitable dry granulator to obtain a ribbon;
(3) Crushing the ribbons of step (2) into granules by a dry granulator through a suitable crushing or sieving step;
(4) Mixing step (3) and the remaining excipients in a mixer to obtain a final mixture;
(5) Optionally, preparing a capsule by filling the mixture of step (4) above by a suitable capsule filling machine;
(6) Optionally, compressing the mixture of step (4) by a suitable tabletting machine to form tablet cores;
(7) Optionally, film coating the tablet cores of step (6) with a film coating.
In a fourth aspect, the present invention provides the use of a pharmaceutical composition as described above in the manufacture of a medicament for the treatment and prophylaxis of a disease or condition caused by a proliferative disorder, preferably in the manufacture of an anti-cancer medicament.
The Chinese naming of the compound in the invention conflicts with the structural formula, and the structural formula is taken as the reference; except for obvious structural errors.
The invention has the beneficial effects that: the invention provides a pharmaceutical composition taking N-cyclopentyl-5- (2- ((5- ((4-ethylpiperazine-1-yl) methyl) pyridine-2-yl) amino) -5-fluoropyrimidine-4-yl) -4-methylthiazol-2-amine or a salt thereof as an active ingredient, wherein the pharmaceutical composition has excellent dissolution behavior and good bioavailability, meets the clinical application requirements, has extremely low impurity content and better stability, and can ensure the safety, effectiveness and quality controllability of a medicament; meanwhile, the preparation process is simple, and is beneficial to the large-scale production of medicines.
Detailed Description
The invention is illustrated but not limited by the following examples. Simple alternatives and modifications of the invention will be apparent to those skilled in the art and are within the scope of the invention as defined by the appended claims.
Definition of the definition
The term "cancer" includes, but is not limited to, the following cancers: leukemia, breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, esophageal cancer, gastric cancer, skin cancer, lung cancer, bone cancer, colon cancer, pancreatic cancer, thyroid cancer, biliary tract cancer, pharyngeal cancer, lip cancer, tongue cancer, oral cancer, throat cancer, small intestine cancer, colorectal cancer, rectal cancer, cancer of the brain and central nervous system, malignant glioma, bladder cancer, liver cancer, kidney cancer, lymphatic cancer, neuroendocrine tumor, and the like.
Example 1: screening of reference prescriptions
The insoluble medicine is developed into an oral solid preparation, and the improvement of the bioavailability of the medicine in animals is particularly critical because of the lower solubility of the medicine. In the in vivo animal test of screening the formulation prescription, a true solution group and a suspension group are designed and respectively compared with a reference prescription group of the formulation prescription. The composition and preparation method of each prescription are shown in the following table.
Each of the above-prepared formulations was orally administered to cynomolgus monkeys, and the bioavailability was measured, and the formulations were pre-evaluated, and the results are shown in the following table. The oral capsule preparation of cynomolgus monkey has higher exposure to plasma drugs, the average bioavailability is 50%, and the average bioavailability is 1 time higher than that of a true solution group and a suspension group, thus unexpected results are obtained. A baseline prescription for prescription optimization and process development comprising 40.0% succinate salt of the compound of formula I, 40.0% microcrystalline cellulose, 17.0% lactose and 3.0% crospovidone by weight of the pharmaceutical composition was screened by in vivo animal test comparison.
Example 2: screening optimization of prescriptions
(1) Unit prescription composition (Unit: mg)
Note that: "/" means not added
(2) Preparation
And (3) putting the succinate of the compound of the formula I with the prescription amount of 1000 tablets and other excipients into a hopper mixer for uniform mixing, controlling the content and uniformity, and filling capsules.
(3) Quality assessment
After mixing according to the proportion in the prescription table, the bulk density of the obtained preparation particles is 0.29-0.30 g/cm 3 The angle of repose is 46.67 deg. to 48.18 deg., and the prescription process still needs to be optimized.
The dissolution test result shows that for capsules with 100mg specification, the dissolution of each prescription for 30 minutes can meet the expected requirement.
Example 3: optimization of prescription process
(1) Composition of Unit prescription (Unit: mg)
(2) Preparation
And (3) putting the succinate of the compound shown in the formula I with the prescription amount of 1000 tablets and other excipients into a wet granulator, uniformly mixing, granulating by a wet method, finishing granules after drying by a fluidized bed, obtaining total mixed granules after total mixing, controlling the content and uniformity, and filling capsules.
(3) Quality assessment
And (3) observing the stability of the influence factors according to the rule of Chinese pharmacopoeia 2020, and respectively sampling and detecting at the 5 th day and the 10 th day under the conditions of high temperature, high humidity and illumination, wherein the detection results are shown in the following table:
the capsules obtained by the different prescription processes have good fluidity, the loose filling density meets the filling requirement, and the obtained capsule finished products are dissolved within 30 minutes and meet the requirement. And (3) carrying out influence factor test investigation under high temperature, high humidity and illumination conditions, wherein single impurities and total impurities are within an acceptable range, and the dissolution within 30 minutes meets the requirements.
Example 4: optimization of lubricants
(1) Composition of Unit prescription (Unit: mg)
(2) Preparation
And (3) putting the succinate of the compound shown in the formula I with the prescription amount of 1000 tablets and other excipients into a wet granulator, uniformly mixing, granulating by a wet method, finishing granules after drying by a fluidized bed, obtaining total mixed granules after total mixing, controlling the content and uniformity, and filling capsules.
(3) Dissolution data
(4) Stability investigation
The accelerated stability test of example 4 was performed according to the principle of guiding the stability test of the crude drug and the preparation (rule of four parts of Chinese pharmacopoeia 2020 edition), and the test results were shown in the following table, wherein the test results were obtained by placing the test results under the acceleration condition of 40.+ -. 2 ℃/75.+ -. 5% RH for 6 months and the sampling time points were 1, 2, 3 and 6 months.
The experimental results show that the composition obtained by the invention has the advantages of low impurity content, high dissolution rate, good stability and the like. Since the drug dissolution rate measurement is closely related to the in vivo bioavailability of the drug, the dissolution rate measurement can be used for evaluating the bioavailability of the drug and researching substitution. Therefore, the results also show that the pharmaceutical composition containing the cyclin-kinase inhibitor, which is obtained after the prescription and the process screening, also has good bioavailability and meets the clinical medication requirements.
The foregoing is merely a preferred embodiment of the present invention, and it should be noted that modifications and improvements could be made by those skilled in the art without departing from the inventive concept, which falls within the scope of the present invention.
Claims (4)
1. A pharmaceutical composition comprising a pharmaceutically acceptable salt of a compound of formula I as an active ingredient, and a pharmaceutically acceptable excipient, wherein the active ingredient accounts for 25 to 75 percent of the weight of the pharmaceutical composition, the salt of the compound of formula I is succinate, the excipient comprises a disintegrant, a diluent and a lubricant, the diluent is lactose and microcrystalline cellulose, the diluent accounts for 15 to 60 percent of the weight of the pharmaceutical composition, the disintegrant is crospovidone, the disintegrant accounts for 1 to 15 percent of the weight of the pharmaceutical composition, the lubricant is selected from talcum powder, the lubricant accounts for 0.1 to 5 percent of the weight of the pharmaceutical composition,
2. the pharmaceutical composition is characterized by comprising the following components in parts by weight:
wherein the diluent is lactose and microcrystalline cellulose; the disintegrant is selected from crospovidone; the lubricant is selected from talc.
3. The pharmaceutical composition according to any one of claims 1 to 2, wherein the dissolution rate of the pharmaceutical composition is determined according to the second method (paddle method) of dissolution rate determination by the fourth rule 0931 of the chinese pharmacopoeia 2020 edition, and the dissolution rate of the active ingredient is 90% or more in 30 minutes.
4. Use of a pharmaceutical composition according to any one of claims 1-2 in the manufacture of an anti-cancer medicament.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202111451044.2A CN114028400B (en) | 2021-12-01 | 2021-12-01 | Pharmaceutical composition containing cyclin kinase inhibitor and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202111451044.2A CN114028400B (en) | 2021-12-01 | 2021-12-01 | Pharmaceutical composition containing cyclin kinase inhibitor and preparation method thereof |
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| Publication Number | Publication Date |
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| CN114028400A CN114028400A (en) | 2022-02-11 |
| CN114028400B true CN114028400B (en) | 2023-10-31 |
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| CN115636826B (en) * | 2022-10-31 | 2024-06-25 | 常州英诺升康生物医药科技有限公司 | Preparation method of CDK inhibitor |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108349964A (en) * | 2015-08-04 | 2018-07-31 | 常州千红生化制药股份有限公司 | N-（Pyridine -2- bases）-4-（Thiazole -5- bases）Pyrimidine -2- aminated compounds is as therapeutic compound |
| CN112239466A (en) * | 2020-11-10 | 2021-01-19 | 常州千红生化制药股份有限公司 | Succinate salt of a selective CDK4/6 inhibitor and crystalline forms thereof |
| WO2021222967A1 (en) * | 2020-05-06 | 2021-11-11 | Aucentra Therapeutics Pty Ltd | Treatment of proliferative diseases of the cns |
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- 2021-12-01 CN CN202111451044.2A patent/CN114028400B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108349964A (en) * | 2015-08-04 | 2018-07-31 | 常州千红生化制药股份有限公司 | N-（Pyridine -2- bases）-4-（Thiazole -5- bases）Pyrimidine -2- aminated compounds is as therapeutic compound |
| WO2021222967A1 (en) * | 2020-05-06 | 2021-11-11 | Aucentra Therapeutics Pty Ltd | Treatment of proliferative diseases of the cns |
| CN112239466A (en) * | 2020-11-10 | 2021-01-19 | 常州千红生化制药股份有限公司 | Succinate salt of a selective CDK4/6 inhibitor and crystalline forms thereof |
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