Oral pharmaceutical composition comprising CDK4 / 6 and DYRK2 dual-target inhibitor active ingredients and preparation method for oral pharmaceutical composition
Patent Information
- Authority / Receiving Office
- WO · WO
- Patent Type
- Applications
- Current Assignee / Owner
- JIANGSU TASLY DIYI PHARMACEUTICAL CO LTD
- Filing Date
- 2025-12-09
- Publication Date
- 2026-06-25
Smart Images
Figure CN2025141210_25062026_PF_FP_ABST
Abstract
Description
Oral pharmaceutical composition containing dual-target inhibitory active ingredients of CDK4 / 6 and DYRK2 and its preparation method Technical Field
[0001] This invention relates to the field of medicinal chemistry, and in particular to an oral pharmaceutical composition containing dual-target inhibitory active ingredients of CDK4 / 6 and DYRK2, and a method for its preparation. Background Technology
[0002] Cyclin-dependent kinase 4 / 6 (CDK4 / 6) and bispecific tyrosine phosphorylation-regulated kinase 2 (DYRK2) are two important targets that have attracted much attention in the field of cancer therapy 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 cell's progression from the G1 phase to the S phase, and some CDK4 / 6 inhibitors have already been approved for the treatment of advanced breast cancer. However, single-target inhibition strategies are prone to decreased efficacy due to drug resistance during treatment, which limits their clinical application.
[0003] DYRK2 is a protein kinase widely involved in biological processes such as cell proliferation, apoptosis, and DNA damage repair. Recent studies have shown that aberrant expression of DYRK2 promotes tumor cell growth and metastasis in various tumors. Therefore, DYRK2 inhibitors are considered potential targets for anti-tumor therapy, and their synergistic effect with CDK4 / 6 targets may enhance anti-tumor efficacy and overcome resistance to single-target drugs.
[0004] To improve the treatment efficacy of various cancers, researchers have increasingly focused on the development of dual-target inhibitors. CDK4 / 6 and DYRK2 dual-target inhibitors possess the ability to both inhibit cell cycle progression and interfere with tumor cell signaling pathways, showing promise for significant advantages in cancer treatment. The combined effect of dual-target inhibitors may not only enhance anti-tumor activity but also delay the development of drug resistance. However, currently, no oral drug compositions targeting both CDK4 / 6 and DYRK2 have been approved for marketing, and their development and preparation remain challenging. Summary of the Invention
[0005] Purpose of the invention:
[0006] To address 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 thereof. 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 flowability and easy crystallization.
[0007] Technical solution:
[0008] In a first aspect, the present invention provides an oral pharmaceutical composition containing dual-target inhibitory active ingredients of CDK4 / 6 and DYRK2, said oral pharmaceutical composition including, but not limited to, fillers, disintegrants, lubricants, and compound I having the following structural formula:
[0009] Further, the filler is one or more of microcrystalline cellulose, phosphates, mannitol, lactose, and starch; preferably, the filler is microcrystalline cellulose.
[0010] Further, the mass of the filler is 5%-80% of the mass of the oral pharmaceutical composition. Preferably, the mass of the filler is 20%-70% of the mass of the oral pharmaceutical composition; more preferably, the mass of the filler is 35%-52% of the mass of the oral pharmaceutical composition; more preferably, the mass of the filler is 42%-48% of the mass of the oral pharmaceutical composition. More preferably, the mass of the filler is 35%, 42%, 48%, or 52% of the mass of the oral pharmaceutical composition.
[0011] Further, the disintegrant is one or more of the following: croscarmellose sodium, sodium carboxymethyl starch, corn starch, CMC-Ca, CMC-Na, microcrystalline cellulose, croscarmellose PVP, low-substituted cellulose, alginate, sodium seagrassate, pregelatinized starch, or guar gum; preferably, the disintegrant is croscarmellose sodium.
[0012] Further, the mass of the disintegrant is 1%-15% of the mass of the oral pharmaceutical composition, preferably 3.8%-6.9% of the mass of the oral pharmaceutical composition, more preferably 4.7%-5.6% of the mass of the oral pharmaceutical composition, and even more preferably 3.8%, 4.7%, 5.6% or 6.9% of the mass of the oral pharmaceutical composition.
[0013] Further, the lubricant is one or more of the following: magnesium stearate, aluminum stearate, calcium stearate, zinc stearate, stearic acid, sodium stearate fumarate, talc, silica, sodium benzoate, glyceryl monostearate, glyceryl monostearate, glyceryl behenate, glyceryl hexadecene stearate, polyethylene glycol, liquid paraffin, hydrogenated cottonseed oil, castor oil, or sucrose ester; preferably, the lubricant is magnesium stearate.
[0014] Further, the mass of the lubricant is 0.1%-5% of the mass of the oral pharmaceutical composition; preferably, the mass of the lubricant is 0.95%-1.89% of the mass of the oral pharmaceutical composition, and more preferably, the mass of the lubricant is 1.19%-1.42% of the mass of the oral pharmaceutical composition. More preferably, the mass of the lubricant is 0.95%, 1.19%, 1.42%, or 1.89% of the mass of the oral pharmaceutical composition.
[0015] Furthermore, the oral pharmaceutical composition is in the form of a solid dosage form, including but not limited to tablets, capsules, granules, or dry suspensions.
[0016] Secondly, the present invention provides a method for preparing an oral pharmaceutical composition as described in any of the above claims, characterized in that the specific steps are as follows:
[0017] S1. According to the formulation of the oral pharmaceutical composition, first mix compound I with microcrystalline cellulose and croscarmellose sodium evenly, then add magnesium stearate for the first time, mix, and dry granulate;
[0018] S2. Add magnesium stearate to the obtained granules for the second time, mix, and obtain an oral pharmaceutical composition.
[0019] Furthermore, 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.
[0020] In S2, the prepared oral pharmaceutical composition can be compressed into tablets or encapsulated.
[0021] In the development of pharmaceutical formulations, the physicochemical properties of drugs have a significant impact on the design of dosage forms and preparation processes. The CDK4 / 6 and DYRK2 dual-target inhibitor active ingredients provided by this invention have high solubility, which is a significant advantage in improving drug bioavailability. However, this compound also suffers from poor flowability, easy crystallization, and low bulk density, directly affecting its filling density and uniformity in capsules, making it difficult to meet the requirements of industrial production.
[0022] To address this issue, this invention employs a dry granulation process to prepare oral pharmaceutical compositions containing dual-target inhibitors of CDK4 / 6 and DYRK2. Dry granulation, by compressing powder into granules, effectively increases the bulk density of the material while improving its flowability and uniformity, making it more suitable for capsule filling. Compared to wet granulation, dry granulation eliminates the need for solvents or binders, avoiding damage to compound properties (such as stability), while simplifying the production process, reducing energy consumption and costs, and is suitable for active ingredients sensitive to moisture or heat.
[0023] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention. Beneficial effects:
[0024] Compared with the prior art, the specific beneficial effects of the present invention are as follows:
[0025] This invention provides an oral pharmaceutical composition containing dual-target inhibitors of CDK4 / 6 and DYRK2, prepared using a dry granulation process. The composition does not come into contact with water or other reagents during preparation, and there is no heating step, thus solving the problems of poor flowability and easy crystallization of the active ingredients. This invention not only effectively solves the problem of low bulk density but also ensures the stability, uniformity, and production feasibility of the dosage form. This technological breakthrough will provide cancer patients with a more efficient and stable treatment option, while also providing technical support for the industrial production of dual-target drug compositions. Attached Figure Description
[0026] Figure 1: Dissolution curves for filler dosage study;
[0027] Figure 2: Dissolution curves for the study of disintegrant dosage;
[0028] Figure 3: Dissolution curve of lubricant dosage study. Detailed Implementation
[0029] The present invention will now be described in detail with reference to the embodiments.
[0030] Method for determining the angle of repose: 1. Place the angle of repose apparatus: Place the shock absorber in the positioning hole in the center of the instrument, then place the receiving tray and the angle of repose test platform, ensuring the upper surface of the test platform is horizontal. 2. Add material: Close the front door of the instrument, prepare the sample, open the vibrating screen cover, turn on the instrument's power switch and the vibrating screen switch, and slowly add material through the feeding port using a small spoon. The material will fall onto the sample platform through the screen and discharge port, forming a cone. 3. Determine the angle of repose: Stop adding material after the cone has formed, turn off the power to the vibrating screen, and measure the reading.
[0031] Method for determining dissolution profile: Add 500-1000 ml of prepared dissolution medium to the dissolution apparatus. After the temperature rises to 37.0 ± 0.5℃, add the sample and operate according to the method for determination of dissolution and release (General Chapter 0931, Part IV of the Chinese Pharmacopoeia). The rotation speed is 50-100 rpm, and the sampling time points are 5, 10, 15, 20, 30, and 45 minutes. Prepare the test solution and reference solution according to the method in the quality standard. Take the above two solutions separately and measure the absorbance at the specified wavelength by ultraviolet-visible spectrophotometry to calculate the dissolution amount.
[0032] Method for determining bulk density: Add a known weight of material to a graduated cylinder, read the volume, and calculate the volume as weight (g) / volume (ml). A low bulk density is detrimental to filling. Lower bulk density requires a deeper tablet press track or larger capsule volume.
[0033] Tests showed that the active ingredient of the CDK4 / 6 and DYRK2 dual-target inhibitor had a repose angle greater than 60° and a compressibility of 35%, indicating very poor flowability.
[0034] Comparison of excipient types in Example 1
[0035] Below are several examples of prescription components (prescription amount per capsule) for oral pharmaceutical compositions containing dual-target inhibitory active ingredients of CDK4 / 6 and DYRK2. It should be noted that the prescriptions listed in the table are merely examples and do not represent all possible solutions of this invention.
[0036] Table 1. Study on the types of auxiliary materials Note: The active ingredient mentioned in the table is compound I, a dual-target inhibitor of CDK4 / 6 and DYRK2.
[0037] Comparative Example 2: Preparation of Tablets by Direct Powder Compression
[0038] In this comparative example 2, all tablets were directly compressed from powder, and the specific formulation was selected as follows:
[0039] Composition 1: 100mg of active ingredient compound I (CDK4 / 6 and DYRK2 dual-target inhibitor), appropriate amount of mannitol, appropriate amount of microcrystalline cellulose, appropriate amount of croscarmellose sodium, appropriate amount of silica, appropriate amount of magnesium stearate, totaling 390mg; the angle of repose of the mixed powder is 50°.
[0040] Composition 2: 100mg of active ingredient compound I (CDK4 / 6 and DYRK2 dual-target inhibitor), appropriate amount of lactose, appropriate amount of microcrystalline cellulose, appropriate amount of sodium croscarmellose, appropriate amount of silicon dioxide, appropriate amount of magnesium stearate, totaling 440mg; the angle of repose of the mixed powder is 48°.
[0041] Composition 3: 100mg of active ingredient compound I (CDK4 / 6 and DYRK2 dual-target inhibitor), appropriate amount of mannitol, appropriate amount of microcrystalline cellulose, appropriate amount of croscarmellose sodium, appropriate amount of magnesium stearate, totaling 420mg; the angle of repose of the mixed powder is 47°.
[0042] Composition 4: 100mg of active ingredient compound I (CDK4 / 6 and DYRK2 dual-target inhibitor), appropriate amount of lactose, appropriate amount of microcrystalline cellulose, appropriate amount of sodium croscarmellose, appropriate amount of magnesium stearate, totaling 480mg; the angle of repose of the mixed powder is 45°.
[0043] Conclusion: The effect of excipients 1-4 in improving the flowability of powder mixtures is limited, resulting in a large angle of repose and low bulk density, which is not conducive to direct tableting.
[0044] Comparative Example 3: Capsules
[0045] All comparative examples used powder filling, and the specific formulations were selected as follows:
[0046] Composition 1: 100mg of active ingredient compound I (CDK4 / 6 and DYRK2 dual-target inhibitor), appropriate amount of mannitol, appropriate amount of croscarmellose sodium, appropriate amount of silica, appropriate amount of magnesium stearate, totaling 140mg; the angle of repose of the mixed powder is 55°.
[0047] Composition 2: 100mg of active ingredient compound I (CDK4 / 6 and DYRK2 dual-target inhibitor), appropriate amount of lactose, appropriate amount of sodium croscarmellose, appropriate amount of silicon dioxide, appropriate amount of magnesium stearate, totaling 140mg; the angle of repose of the mixed powder is 55°.
[0048] Composition 3: 100mg of active ingredient compound I (a dual-target inhibitor of CDK4 / 6 and DYRK2), appropriate amount of microcrystalline cellulose, appropriate amount of sodium croscarmellose, appropriate amount of silica, appropriate amount of magnesium stearate, totaling 140mg; the angle of repose of the mixed powder is 58°.
[0049] Composition 4: 100mg of active ingredient compound I (a dual-target inhibitor of CDK4 / 6 and DYRK2), appropriate amount of mannitol, appropriate amount of sodium croscarmellose, appropriate amount of silica, appropriate amount of magnesium stearate, totaling 172mg; the angle of repose of the mixed powder is 53°.
[0050] Composition 5: 100mg of active ingredient compound I (CDK4 / 6 and DYRK2 dual-target inhibitor), appropriate amount of lactose, appropriate amount of sodium croscarmellose, appropriate amount of silicon dioxide, appropriate amount of magnesium stearate, totaling 172mg; the angle of repose of the mixed powder is 53°.
[0051] Composition 6: 100mg of active ingredient compound I (a dual-target inhibitor of CDK4 / 6 and DYRK2), appropriate amount of microcrystalline cellulose, appropriate amount of sodium croscarmellose, appropriate amount of silica, appropriate amount of magnesium stearate, totaling 172mg; the angle of repose of the mixed powder is 56°.
[0052] Conclusion: The powders of components 1-6 have poor flowability, which can easily lead to large variations in fill volume, making it unfavorable for capsule filling. Larger capsule volumes are also required, which may result in poor patient compliance.
[0053] Therefore, the dry granulation process of this invention effectively improves flowability while maintaining the crystal form. It avoids the disadvantages of direct powder tableting and powder-to-capsule filling, allowing the use of a wider variety and greater quantity of excipients.
[0054] Implementation Method 1: Screening of filler type and dosage and dissolution profile
[0055] Table 2. Study on the types of fillers
[0056] Conclusion: All of the above-mentioned fillers can effectively improve API flowability. Mannitol and lactose exhibit adhesion to metal surfaces during dry granulation, which is detrimental to continuous mass production. Microcrystalline cellulose dry granulation demonstrates good compressibility and does not stick to equipment; the flowability of the pulverized particles meets production requirements. The following implementation methods all use microcrystalline cellulose as the filler and a pH 4.5 acetate buffer solution with different dissolution capabilities as the dissolution medium. Different amounts of microcrystalline cellulose were used in the implementation.
[0057] Table 3. Study on filler dosage
[0058] Conclusion: This product, with a microcrystalline cellulose content of 35%-52%, can effectively improve API flowability.
[0059] Table 4 Comparison of dissolution curves in the study of filler dosage
[0060] Conclusion: Referring to Figure 1, increasing the amount of microcrystalline cellulose accelerates particle disintegration, but excessive use can affect dissolution due to deposition. Increasing the amount of microcrystalline cellulose significantly accelerates particle disintegration, as evidenced by the dissolution curves at 5 and 10 minutes. Formulations containing 35%-52% microcrystalline cellulose in this product dissolve relatively quickly.
[0061] Implementation Method 2: Screening of Disintegrant Dosage and Dissolution Curve
[0062] Table 5. Study on the dosage of disintegrants
[0063] Conclusion: The disintegrant croscarmellose sodium has good flowability. The proportion of croscarmellose sodium in this product, ranging from 3.8% to 6.9%, does not affect particle flowability, and the angle of repose meets production requirements. Without the use of croscarmellose sodium, the original angle of repose of the particles is basically maintained; excessive use of croscarmellose sodium leads to an increase in the angle of repose.
[0064] Table 6 Comparison of dissolution curves in studies of disintegrant dosage.
[0065] Conclusion: As shown in Figure 2, increasing the amount of disintegrant accelerates particle disintegration, especially noticeable in the first 15 minutes of dissolution. Formulations with a disintegrant concentration of 3.8%-6.9% dissolve relatively quickly. Formulation 11, without added disintegrant, exhibits slower particle disintegration and significantly slower dissolution. Formulation 12, with an excessively high amount of disintegrant, results in rapid particle disintegration, reaching a dissolution plateau within 10 minutes.
[0066] Implementation Method 3: Study on Lubricant Dosage and Dissolution Curve
[0067] Table 7. Study on Lubricant Dosage
[0068] Conclusion: Lubricants can reduce friction between particles, between particles and capsules, and between particles and equipment. A lubricant concentration of 0.95%-1.89% in this product does not affect particle flowability, and the angle of repose meets production requirements. Neglecting or overusing lubricant both lead to an increased angle of repose.
[0069] Table 8 Comparison of dissolution curves in studies of lubricant dosage
[0070] Conclusion: Referring to Figure 3, excessive use of hydrophobic lubricants slows down formulation disintegration and affects dissolution. In Implementation Method 3, the amounts of magnesium stearate in Formulations 3-15 differ only slightly and are all standard amounts, thus not affecting formulation dissolution. A disintegrant concentration of 3.8%-6.9% in this product does not affect the dissolution rate. Formulation 16, lacking magnesium stearate, exhibits adhesion during dry granulation, making continuous production unsuitable. Formulation 17, with its excessively high amount of magnesium stearate, slows particle disintegration and dissolution significantly; this formulation is unsuitable for this product.
[0071] Implementation Method 4:
[0072] This embodiment provides a method for preparing an oral pharmaceutical composition containing dual-target inhibitory active ingredients of CDK4 / 6 and DYRK2, as detailed below:
[0073] Prescription 3: 100mg of active ingredient, 100mg of microcrystalline cellulose, 8mg of sodium croscarmellose, and 2mg of magnesium stearate; total 210mg.
[0074] The active ingredient (compound I, a dual-target inhibitor of CDK4 / 6 and DYRK2) was mixed with microcrystalline cellulose and croscarmellose sodium in a mixer until homogeneous. Then, 2 / 3 of the total magnesium stearate was added to the mixer, and the mixture was further mixed until homogeneous, yielding a powder. The powder was then dry-granulated using a dry granulator to obtain granules. The granules were then placed in a mixer, and the remaining 1 / 3 of the total magnesium stearate was added and mixed until homogeneous, yielding a final granule mixture. The final granule mixture was then filled into capsules using a capsule filling machine. This yielded an oral pharmaceutical composition containing dual-target inhibitors of CDK4 / 6 and DYRK2.
[0075] Formulation evaluation and results
[0076] The oral pharmaceutical composition containing dual-target inhibitory active ingredients of CDK4 / 6 and DYRK2 prepared in this embodiment was evaluated:
[0077] 1. Using 900 ml of 0.2% sodium dodecyl sulfate hydrochloric acid solution with pH=1.2, the operation was carried out according to the first basket method of General Chapter 0931 of the 2020 edition of the Chinese Pharmacopoeia, Part IV, at 37°C and 100 rpm. The drug composition prepared in this example can be rapidly dissolved.
[0078] 2. The active ingredient of the CDK4 / 6 and DYRK2 dual-target inhibitor has a repose angle greater than 60° and a compressibility of 35%, resulting in very poor flowability; the drug composition prepared in this example has a repose angle of 39° and a compressibility of 23%, resulting in better flowability.
[0079] The above embodiments are only for illustrating the technical concept and features of the present invention, and are intended to enable those skilled in the art to understand the content of the present invention and implement it accordingly. They should not be construed as limiting the scope of protection of the present invention. All equivalent transformations or modifications made in accordance with the spirit and essence of the present invention should be covered within the scope of protection 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, fillers, disintegrants, lubricants, and compound I having the following structural formula:
2. The oral pharmaceutical composition containing dual-target inhibitory active ingredients of CDK4 / 6 and DYRK2 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 a CDK4 / 6 and DYRK2 dual-target inhibitor active ingredient 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 a CDK4 / 6 and DYRK2 dual-target inhibitor active ingredient according to claim 1, characterized in that: The disintegrant is one or more of the following: croscarmellose sodium, carboxymethyl starch sodium, corn starch, CMC-Ca, CMC-Na, microcrystalline cellulose, croscarmellose PVP, low-substituted cellulose, alginate, sodium seaweedate, pregelatinized starch, or guar gum.
5. The oral pharmaceutical composition containing a CDK4 / 6 and DYRK2 dual-target inhibitor active ingredient according to claim 4, characterized by the fact that: The mass of the disintegrant is 1%-15% of the mass of the oral pharmaceutical composition.
6. The oral pharmaceutical composition containing a CDK4 / 6 and DYRK2 dual-target inhibitor active ingredient according to claim 1, characterized in that: The lubricant is one or more of the following: magnesium stearate, aluminum stearate, calcium stearate, zinc stearate, stearic acid, sodium stearate fumarate, talc, silica, sodium benzoate, glyceryl monostearate, glyceryl monostearate, glyceryl behenate, glyceryl hexadecene stearate, polyethylene glycol, liquid paraffin, hydrogenated cottonseed oil, castor oil, or sucrose ester.
7. The oral pharmaceutical composition containing a CDK4 / 6 and DYRK2 dual-target inhibitor active ingredient according to claim 6, characterized by the fact that: The mass of the lubricant is 0.1%-5% of the mass of the oral pharmaceutical composition.
8. The oral pharmaceutical composition containing a CDK4 / 6 and DYRK2 dual-target inhibitor active ingredient according to claim 1, characterized in that: The oral pharmaceutical composition is in the form of a solid dosage form, including but not limited to tablets, capsules, granules or dry suspensions.
9. A process for the preparation of an oral pharmaceutical composition as claimed in any one of claims 1 to 8, characterized in that: The specific steps are as follows: S1. According to the formulation of the oral pharmaceutical composition, first mix compound I with microcrystalline cellulose and croscarmellose sodium evenly, then add magnesium stearate for the first time, mix, and dry granulate; S2. Add magnesium stearate to the obtained granules for the second time, mix, and obtain an oral pharmaceutical composition.
10. The process for the preparation of an 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 encapsulated.