Oral pharmaceutical composition containing CDK4 / 6 and DYRK2 double-target inhibitor active ingredients and preparation method thereof

Abstract

The invention relates to the technical field of medicinal chemistry, discloses an oral pharmaceutical composition containing active ingredients of a CDK4 / 6 and DYRK2 double-target inhibitor and a preparation method, and adopts a dry granulation process to prepare the oral pharmaceutical composition containing the active ingredients of the CDK4 / 6 and DYRK2 double-target inhibitor. In the preparation process, the composition is not in contact with water and other reagents, no heating step exists, and the problems that active ingredients are poor in mobility and prone to crystal transformation are solved. The invention not only can effectively solve the problem of low bulk density, but also can ensure the stability, uniformity and production feasibility of the dosage form.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemistry, and in particular to an oral pharmaceutical composition containing active ingredients of a CDK4 / 6 and DYRK2 dual-target inhibitor and a preparation method thereof. Background Art

[0002] Cyclin-dependent kinase 4 / 6 (CDK4 / 6) and dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2) are two important targets that have attracted much attention in the field of tumor treatment in recent years. CDK4 / 6 plays a key role in cell cycle regulation, and its abnormal activation is closely related to the occurrence and development of various tumors (such as breast cancer, lung cancer, and colorectal cancer). CDK4 / 6 inhibitors inhibit tumor cell proliferation by blocking the progression of cells from the G1 phase to the S phase. Currently, some CDK4 / 6 inhibitors have been approved for the treatment of advanced breast cancer. However, the single-target inhibition strategy is prone to reduced efficacy due to drug resistance during treatment, which limits its clinical application.

[0003] DYRK2 is a protein kinase that is widely involved in biological processes such as cell proliferation, apoptosis, and DNA damage repair. Studies in recent years have shown that abnormal expression of DYRK2 promotes tumor cell growth and metastasis in a variety of tumors. Therefore, DYRK2 inhibitors are considered to be potential anti-tumor therapeutic targets, and their synergistic effects with CDK4 / 6 targets may enhance anti-tumor efficacy and overcome the drug resistance of single-target drugs.

[0004] In order to improve the treatment effect of various tumors, researchers have gradually focused on the development of dual-target inhibitors. CDK4 / 6 and DYRK2 dual-target inhibitors have the functions of inhibiting cell cycle progression and interfering with tumor cell signaling pathways, and are expected to show significant advantages in tumor treatment. The combined action of dual-target inhibitors may not only enhance anti-tumor activity, but also delay the occurrence of drug resistance. However, no oral drug composition targeting CDK4 / 6 and DYRK2 dual targets has been approved for marketing on the market, and its research and development and preparation still face challenges. Summary of the invention

[0005] Purpose of the invention: In view of the problems existing in the prior art, the present invention provides an oral pharmaceutical composition containing CDK4 / 6 and DYRK2 dual-target inhibitor active ingredients and a preparation method. The oral pharmaceutical composition includes CDK4 / 6 and DYRK2 dual-target inhibitor active ingredients, fillers, disintegrants, lubricants and other substances, and is prepared by dry granulation, which solves the problems of poor fluidity and easy crystal transformation.

[0006] Technical solution: In the first aspect, the present invention provides an oral pharmaceutical composition containing a CDK4 / 6 and DYRK2 dual-target inhibitor active ingredient, wherein the oral pharmaceutical composition includes but is not limited to a filler, a disintegrant, a lubricant, and a compound I having the following structural formula: .

[0007] Furthermore, the filler is one or more of microcrystalline cellulose, phosphates, mannitol, lactose, and starch.

[0008] Furthermore, the mass of the filler is 5%-80% of the mass of the oral pharmaceutical composition.

[0009] Furthermore, the disintegrant is one or more of cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, corn starch, CMC-Ca, CMC-Na, microcrystalline cellulose, cross-linked PVP, alginic acid, sodium kelp, pregelatinized starch or guar gum.

[0010] Furthermore, the mass of the disintegrant is 1%-15% of the mass of the oral pharmaceutical composition.

[0011] Furthermore, the lubricant is one or more of magnesium stearate, aluminum stearate, calcium stearate, stearic acid, sodium stearyl fumarate, talc, sodium benzoate, glyceryl monofatty acid, glyceryl monostearate, glyceryl dibehenate, glyceryl hexadecenoate, polyethylene glycol, hydrogenated cotton oil, castor oil or sucrose ester.

[0012] Furthermore, the mass of the lubricant is 0.1%-5% of the mass of the oral pharmaceutical composition.

[0013] Furthermore, the oral pharmaceutical composition is in the form of a solid preparation, including but not limited to tablets, capsules, granules or dry suspensions.

[0014] In a second aspect, the present invention provides a method for preparing an oral pharmaceutical composition as described in any one of the above, characterized in that the specific steps are as follows: S1. According to the ratio of the oral pharmaceutical composition, compound I is first mixed with microcrystalline cellulose and cross-linked sodium carboxymethyl cellulose, and magnesium stearate is added for the first time, mixed, and dry granulated; S2. Add magnesium stearate to the prepared granules for a second time and mix them to obtain an oral pharmaceutical composition.

[0015] Further, in S1, the mass of magnesium stearate added for the first time is 2 / 3 of the total mass of magnesium stearate added; in S2, the mass of magnesium stearate added for the second time is 1 / 3 of the total mass of magnesium stearate added; In S2, the prepared oral pharmaceutical composition can be compressed into tablets or filled into capsules.

[0016] In the development process of pharmaceutical preparations, the physicochemical properties of drugs have an important influence on the design and preparation process of their dosage forms. The active ingredients of the CDK4 / 6 and DYRK2 dual-target inhibitors provided by the present invention have high solubility, which has significant advantages in improving the bioavailability of drugs. However, the compound also has the problems of poor fluidity, easy crystal transformation, and low bulk density, which directly affects its filling density and uniformity in the filled capsule, making it difficult to meet the requirements of industrial production.

[0017] To address this problem, the present invention adopts a dry granulation process to prepare an oral pharmaceutical composition containing active ingredients of CDK4 / 6 and DYRK2 dual-target inhibitors. Dry granulation forms granules by compressing powder, which can effectively increase the bulk density of the material, while improving the fluidity and uniformity of the powder, making it more suitable for capsule filling. Compared with wet granulation, dry granulation does not require the use of solvents or adhesives, avoids damage to the properties of the compound (such as stability), simplifies the production process, reduces energy consumption and costs, and is suitable for active ingredients that are sensitive to moisture or heat.

[0018] Beneficial effects: Compared with the prior art, the specific beneficial effects of the present invention are as follows: The present invention provides an oral pharmaceutical composition containing CDK4 / 6 and DYRK2 dual-target inhibitor active ingredients, prepared by a dry granulation process. During the preparation process, the composition does not contact water and other reagents, and there is no heating step, which solves the problems of poor fluidity and easy crystal transformation of the active ingredients. The present invention can not only effectively solve the problem of low bulk density, but also ensure the stability, uniformity and production feasibility of the dosage form. This technological breakthrough will provide more efficient and stable treatment options for cancer patients, and at the same time provide technical support for the industrial production of dual-target pharmaceutical compositions. DETAILED DESCRIPTION

[0019] The present invention is described in detail below in conjunction with the embodiments.

[0020] Implementation 1: This embodiment provides an oral pharmaceutical composition containing active ingredients of a CDK4 / 6 and DYRK2 dual-target inhibitor, the oral pharmaceutical composition comprising a filler, a disintegrant, a lubricant, and a compound I having the following structural formula:

[0021] Molecular formula: C 28 H 33 FN8OS•C4H6O4 molecular weight: 666.77.

[0022] Among them, the filler is one or more of microcrystalline cellulose, phosphates, mannitol, lactose, and starch, and its mass is 5%-80% of the mass of the oral pharmaceutical composition; the disintegrant is one or more of cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, corn starch, CMC-Ca, CMC-Na, microcrystalline cellulose, cross-linked PVP, alginic acid, sodium seaweed, pregelatinized starch or guar gum, and its mass is 1%-15% of the mass of the oral pharmaceutical composition; the lubricant is one or more of magnesium stearate, aluminum stearate, calcium stearate, stearic acid, sodium stearyl fumarate, talc, sodium benzoate, glyceryl monofatty acid, glyceryl monostearate, glyceryl dibehenate, glyceryl hexadecene stearate, polyethylene glycol, hydrogenated cotton oil, castor oil or sucrose ester, and its mass is 0.1%-5% of the mass of the oral pharmaceutical composition.

[0023] Several examples of prescription ingredients of oral pharmaceutical compositions containing CDK4 / 6 and DYRK2 dual-target inhibitor active ingredients (prescription amount per capsule) are provided below, as shown in Table 1. It should be noted that the prescriptions listed in the table are only examples and are not all solutions of the present invention.

[0024]

[0025] Note: The main drug mentioned in the table is the active ingredient compound I of the CDK4 / 6 and DYRK2 dual-target inhibitor.

[0026] Implementation 2: This embodiment provides a method for preparing an oral pharmaceutical composition containing active ingredients of a CDK4 / 6 and DYRK2 dual-target inhibitor, as follows: The main drug (CDK4 / 6 and DYRK2 dual-target inhibitor active ingredient compound I) is added to a mixer with microcrystalline cellulose and cross-linked sodium carboxymethyl cellulose and mixed evenly, and then part of the magnesium stearate (2 / 3 of the total amount of magnesium stearate added) is added to the mixer, and the mixture is continued to be mixed evenly to obtain a mixed powder. The obtained mixed powder is dry granulated using a dry granulator to obtain granules. The obtained granules are placed in a mixer, and the remaining magnesium stearate (2 / 3 of the total amount of magnesium stearate added) is added and mixed evenly to obtain a total mixed granule. The total mixed granule is filled into capsules using a capsule filling machine. An oral pharmaceutical composition containing the active ingredients of the CDK4 / 6 and DYRK2 dual-target inhibitor is obtained.

[0027] Formulation Evaluation and Results The oral pharmaceutical composition containing the active ingredients of the CDK4 / 6 and DYRK2 dual-target inhibitor prepared in Embodiment 2 was evaluated: 1. Using 900 ml of 0.2% sodium dodecyl sulfate hydrochloric acid solution with a pH of 1.2, the operation was performed according to the first basket method of 0931 of the fourth general rule of the Chinese Pharmacopoeia 2020 edition, and the test was performed at 37 ° C and 100 rpm. The pharmaceutical composition prepared in implementation mode 2 can be quickly dissolved.

[0028] 2. The angle of repose of the active ingredient of the CDK4 / 6 and DYRK2 dual-target inhibitor is greater than 60°, the compression is 35%, and the fluidity is very poor; the pharmaceutical composition prepared by implementation mode 2 has an angle of repose of 39°, a compression of 23%, and good fluidity.

[0029] The above embodiments are only for illustrating the technical concept and features of the present invention, and their purpose is to enable people familiar with the technology to understand the content of the present invention and implement it accordingly, and they cannot be used to limit the protection scope of the present invention. Any equivalent transformation or modification made according to the spirit of the present invention should be included in the protection scope of the present invention.

Claims

1. An oral pharmaceutical composition containing a CDK4 / 6 and DYRK2 dual-target inhibitor active ingredient, characterized in that: The oral pharmaceutical composition includes but is not limited to a filler, a disintegrant, a lubricant and a compound I having the following structural formula: 。 2. The oral pharmaceutical composition containing the active ingredients of CDK4 / 6 and DYRK2 dual-target inhibitor according to claim 1, characterized in that: The filler is one or more of microcrystalline cellulose, phosphates, mannitol, lactose and starch.

3. The oral pharmaceutical composition containing the active ingredients of CDK4 / 6 and DYRK2 dual-target inhibitor according to claim 2, characterized in that: The mass of the filler is 5%-80% of the mass of the oral pharmaceutical composition.

4. The oral pharmaceutical composition containing the active ingredients of CDK4 / 6 and DYRK2 dual-target inhibitor according to claim 1, characterized in that: The disintegrant is one or more of cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, corn starch, CMC-Ca, CMC-Na, microcrystalline cellulose, cross-linked PVP, alginic acid, sodium kelp, pregelatinized starch or guar gum.

5. The oral pharmaceutical composition containing the active ingredients of CDK4 / 6 and DYRK2 dual-target inhibitor according to claim 4, characterized in that: The mass of the disintegrant is 1%-15% of the mass of the oral pharmaceutical composition.

6. The oral pharmaceutical composition containing the active ingredients of CDK4 / 6 and DYRK2 dual-target inhibitor according to claim 1, characterized in that: The lubricant is one or more of magnesium stearate, aluminum stearate, calcium stearate, stearic acid, sodium stearyl fumarate, talc, sodium benzoate, glyceryl monofatty acid, glyceryl monostearate, glyceryl dibehenate, glyceryl hexadecenoate, polyethylene glycol, hydrogenated cotton oil, castor oil or sucrose ester.

7. The oral pharmaceutical composition containing the active ingredients of CDK4 / 6 and DYRK2 dual-target inhibitor according to claim 6, characterized in that: The mass of the lubricant is 0.1%-5% of the mass of the oral pharmaceutical composition.

8. The oral pharmaceutical composition containing the active ingredients of CDK4 / 6 and DYRK2 dual-target inhibitor according to claim 1, characterized in that: The oral pharmaceutical composition is in the form of a solid preparation, including but not limited to tablets, capsules, granules or dry suspensions.

9. A method for preparing an oral pharmaceutical composition according to any one of claims 1 to 8, characterized in that: The specific steps are as follows: S1. According to the ratio of the oral pharmaceutical composition, compound I is first mixed with microcrystalline cellulose and cross-linked sodium carboxymethyl cellulose, and magnesium stearate is added for the first time, mixed, and dry granulated; S2. Add magnesium stearate to the prepared granules for a second time and mix them to obtain an oral pharmaceutical composition.

10. The method for preparing the oral pharmaceutical composition according to claim 9, characterized in that: In S1, the mass of magnesium stearate added for the first time is 2 / 3 of the total mass of magnesium stearate added; In S2, the mass of magnesium stearate added for the second time is 1 / 3 of the total mass of magnesium stearate added; In S2, the prepared oral pharmaceutical composition can be compressed into tablets or filled into capsules.

Images