A neratinib maleate pharmaceutical composition and tablet for treating breast cancer and a preparation method thereof

Abstract

The present invention relates to a neratinib maleate pharmaceutical composition and tablets that can be used for treating breast cancer and a preparation method thereof, wherein the pharmaceutical composition comprises neratinib maleate, meglumine and sodium sulfate. The formulation solves the problems of granulation adhesion, dissolution and stability of neratinib maleate, and the obtained preparation can maintain good fluidity without granulation, has good dissolution and significantly improves the stability of neratinib maleate, and has a simple formulation process and good application value.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology and relates to a neratinib maleate pharmaceutical composition and tablets that can be used to treat breast cancer and a preparation method thereof. Background Art

[0002] Neratinib, also known in English as Neratinib and chemically known as (E)-N-{4-[3-chloro-4-(2-pyridylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide, is a highly selective HER2 and EGFR inhibitor. Neratinib and its salts can be used to treat cancers, including but not limited to pancreatic cancer, melanoma, lymphatic cancer, parotid gland tumors, Barrett's esophagus, esophageal cancer, head and neck cancer, ovarian cancer, epithelioid tumors, cancers of major organs such as the kidney, bladder, larynx, stomach, and lung, colon polyps, colorectal cancer, and prostate cancer. In recent years, neratinib has been found to have a good clinical therapeutic effect on triple-negative breast cancer, which is difficult to treat. Because neratinib has poor solubility and absorption, its maleate salt is often used in clinical preparations. The currently marketed neratinib maleate product is a tablet.

[0003] Neratinib maleate has poor stability and is prone to degradation. It is prone to sticking during the granulation process during the preparation of pharmaceutical formulations, which increases the difficulty of formulation. At the same time, there is room for further improvement in dissolution. To address the problems of the existing technology, the existing art has adopted many solutions. For example, Chinese application CN103893140B uses a large number of excipients and complex processes to address the problem of sticking during granulation; Chinese application CN106913529B uses a large number of excipients to address the problems of poor stability and dissolution, while also requiring strict control of granule moisture and other harsh process conditions; Chinese application CN116211859A also uses numerous excipients and complex processes to improve stability and dissolution. Although the above solutions can partially address the existing technical problems of neratinib maleate, they are costly and difficult to operate. At the same time, the use of a large number of excipients increases safety risks. In summary, in order to address the problems of difficulty in preparation of neratinib maleate formulations, poor dissolution and stability, the existing technologies all have limitations. The present inventors have obtained a pharmaceutical formulation of neratinib maleate and a preparation method thereof during a long and extensive study on neratinib maleate. The process is simple and the amount of excipients used is small. The prepared neratinib maleate preparation has extremely high quality and stability, thereby increasing the safety of medication. At the same time, the solubility is further improved compared with the prior art. Summary of the Invention

[0004] The object of the present invention is to provide a neratinib maleate preparation with low auxiliary material dosage, simple preparation process, stability and good solubility and a preparation method thereof.

[0005] The solution adopted by the present invention to solve the above technical problems is:

[0006] A pharmaceutical composition of neratinib maleate, comprising neratinib maleate, meglumine and sodium sulfate.

[0007] Furthermore, in parts by weight, the weight ratio of neratinib maleate, meglumine and sodium sulfate in the pharmaceutical composition is (30-50): (70-80): (30-36), more preferably 40: (70-80): (30-36), and even more preferably 40:75:35, wherein the mass of neratinib maleate is calculated by measuring the mass of neratinib free base therein.

[0008] The present invention also provides a method for preparing the above-mentioned composition, comprising the following steps:

[0009] (1) drying and sieving the raw materials of neratinib maleate, meglumine, and sodium sulfate to obtain raw material powders;

[0010] (2) Neratinib maleate, meglumine, and sodium sulfate powder are added in order and mixed thoroughly to obtain the neratinib maleate pharmaceutical composition.

[0011] Furthermore, the drying temperature used in step (1) is 50-70°C, for example, 55°C, 60°C, or 65°C.

[0012] Furthermore, the raw material after drying in step (1) is passed through a 70-90 mesh sieve, such as a 75 mesh sieve or an 80 mesh sieve, to obtain raw material powder.

[0013] Furthermore, in step (2), neratinib maleate and meglumine powder are first mixed evenly, and then sodium sulfate powder is added and mixed evenly.

[0014] The present invention also provides a neratinib maleate pharmaceutical tablet, which contains the above-mentioned pharmaceutical composition or the pharmaceutical composition obtained by the above-mentioned preparation method.

[0015] Furthermore, each tablet contains 30 to 50 mg of neratinib measured as neratinib free base, more preferably 40 mg.

[0016] Furthermore, the tablet comprises a film coating.

[0017] The present invention also provides a method for preparing the tablets, comprising the following steps: determining the tablet weight of the pharmaceutical composition comprising neratinib maleate, meglumine and sodium sulfate according to specifications, and tableting the tablets on a tabletting machine.

[0018] The present invention also provides use of the above-mentioned pharmaceutical composition or neratinib maleate pharmaceutical tablets in preparing drugs for treating breast cancer.

[0019] The preparation formula adopted by the present invention solves the problems of granulation adhesion, dissolution and stability of neratinib maleate. The obtained preparation can maintain good fluidity without granulation, has good dissolution and significantly improves the stability of neratinib maleate. The preparation process is simple and has good application value. DETAILED DESCRIPTION

[0020] For a better understanding of the present invention, the following examples are provided to further illustrate the present invention, but the present invention is not limited to the following examples.

[0021] The neratinib maleate raw material of the present invention can be prepared by using existing disclosed technologies, or can be purchased as a marketed product.

[0022] In the following examples, the mass of neratinib maleate is calculated based on the mass of neratinib, wherein the mass of neratinib is calculated based on the measured value of neratinib free base in neratinib maleate.

[0023] Example 1 Preparation of Neratinib Maleate Preparation Mixed Powder According to the Prescription Quantity of 1000 Preparation Units

[0024] Neratinib maleate, meglumine and sodium sulfate that had been dried at 65° C. in advance were sequentially passed through an 80-mesh sieve; 40 g of neratinib maleate (calculated as neratinib) and 70 g of meglumine were first thoroughly mixed, and then 30 g of sodium sulfate was added and mixed evenly.

[0025] Example 2 Preparation of Neratinib Maleate Preparation Mixed Powder According to the Prescription Quantity of 1000 Preparation Units

[0026] Neratinib maleate, meglumine and sodium sulfate that had been dried at 65° C. in advance were sequentially passed through an 80-mesh sieve; 40 g of neratinib maleate (calculated as neratinib) and 80 g of meglumine were first thoroughly mixed, and then 36 g of sodium sulfate was added and mixed evenly.

[0027] Example 3 Preparation of Neratinib Maleate Preparation Mixed Powder According to the Prescription Quantity of 1000 Preparation Units

[0028] Neratinib maleate, meglumine and sodium sulfate that had been dried at 65° C. in advance were sequentially passed through an 80-mesh sieve; 40 g of neratinib maleate (calculated as neratinib) and 80 g of meglumine were first thoroughly mixed, and then 30 g of sodium sulfate was added and mixed evenly.

[0029] Example 4 Preparation of Neratinib Maleate Preparation Mixed Powder According to the Prescription Quantity of 1000 Preparation Units

[0030] Neratinib maleate, meglumine and sodium sulfate that had been dried at 65° C. in advance were sequentially passed through an 80-mesh sieve; 40 g of neratinib maleate (calculated as neratinib) and 70 g of meglumine were first thoroughly mixed, and then 36 g of sodium sulfate was added and mixed evenly.

[0031] Example 5 Preparation of Neratinib Maleate Preparation Mixed Powder According to the Prescription Quantity of 1000 Preparation Units

[0032] Neratinib maleate, meglumine and sodium sulfate that had been dried at 65° C. in advance were sequentially passed through an 80-mesh sieve; 40 g of neratinib maleate (calculated as neratinib) and 75 g of meglumine were first thoroughly mixed, and then 35 g of sodium sulfate was added and mixed evenly.

[0033] Example 6 Preparation of Neratinib Maleate Preparation Mixed Powder According to the Prescription Quantity of 1000 Preparation Units

[0034] Neratinib maleate, meglumine and sodium sulfate that had been dried at 65° C. in advance were sequentially passed through an 80-mesh sieve; 40 g of neratinib maleate (calculated as neratinib) and 70 g of meglumine were first thoroughly mixed, and then 29 g of sodium sulfate was added and mixed evenly.

[0035] Example 7 Preparation of Neratinib Maleate Preparation Mixed Powder According to the Prescription Quantity of 1000 Preparation Units

[0036] Neratinib maleate, meglumine and sodium sulfate that had been dried at 65° C. in advance were sequentially passed through an 80-mesh sieve; 40 g of neratinib maleate (calculated as neratinib) and 80 g of meglumine were first thoroughly mixed, and then 38 g of sodium sulfate was added and mixed evenly.

[0037] Example 8 Preparation of Neratinib Maleate Preparation Mixed Powder According to the Prescription Quantity of 1000 Preparation Units

[0038] Neratinib maleate, meglumine and sodium sulfate that had been dried at 65° C. in advance were sequentially passed through an 80-mesh sieve; 40 g of neratinib maleate (calculated as neratinib) and 70 g of meglumine were first thoroughly mixed, and then 38 g of sodium sulfate was added and mixed evenly.

[0039] Example 9 Preparation of Neratinib Maleate Preparation Mixed Powder According to the Prescription Quantity of 1000 Preparation Units

[0040] Neratinib maleate, meglumine and sodium sulfate that had been dried at 65° C. in advance were sequentially passed through an 80-mesh sieve; 40 g of neratinib maleate (calculated as neratinib) and 80 g of meglumine were first thoroughly mixed, and then 29 g of sodium sulfate was added and mixed evenly.

[0041] The mixed powder of the neratinib maleate preparation obtained in Example 1-9 was tableted and its flowability was observed. The results are as follows:

[0042] The powders of Examples 1-5 have good fluidity and are easy to tablet.

[0043] Examples 6-9 have poor fluidity and are not convenient for tableting.

[0044] It can be seen that adding 70g-80g of meglumine and 30g-36g of sodium sulfate to every 40g of neratinib maleate (calculated as neratinib) can solve the problem of neratinib maleate sticking without granulation.

[0045] Example 10 Preparation of Neratinib Maleate Tablets (10,000 Preparation Units)

[0046] Pass neratinib maleate, meglumine and sodium sulfate, which have been dried at 65° C. in advance, through an 80-mesh sieve in sequence; add 400 g of neratinib maleate (calculated as neratinib) to 350 g of sodium sulfate and mix evenly; determine the content; determine the tablet weight according to the specification; press the tablets onto a tabletting machine, inspect, and package to obtain the product.

[0047] Example 11 Preparation of Neratinib Maleate Tablets (10,000 Preparation Units)

[0048] Neratinib maleate, meglumine and sodium sulfate that have been dried at 65° C. in advance are sequentially passed through an 80-mesh sieve; 400 g of neratinib maleate (calculated as neratinib) and 750 g of meglumine are thoroughly mixed and the content is determined; the tablet weight is determined according to the specification; the tablets are pressed onto a tabletting machine, inspected and packaged to obtain the product.

[0049] Example 12 Preparation of Neratinib Maleate Tablets (10,000 Preparation Units)

[0050] Neratinib maleate, meglumine and sodium sulfate that have been dried at 65° C. in advance are sequentially passed through an 80-mesh sieve; 400 g of neratinib maleate (calculated as neratinib) and 700 g of meglumine are thoroughly mixed, and then 300 g of sodium sulfate is added and mixed evenly. The content is determined, and the tablet weight is determined according to the specifications. The tablets are compressed on a tabletting machine, inspected, and packaged to obtain the product.

[0051] Example 13 Preparation of Neratinib Maleate Tablets (10,000 Preparation Units)

[0052] Sequentially sieve neratinib maleate, meglumine, and sodium sulfate, which have been dried at 65° C., through an 80-mesh sieve; thoroughly mix neratinib maleate 400 g (calculated as neratinib) and meglumine 800 g; then add 360 g of sodium sulfate and mix evenly; determine the content; determine the tablet weight according to the specification; press the tablets onto a tabletting machine, inspect, and package.

[0053] Example 14 Preparation of Neratinib Maleate Tablets (10,000 Preparation Units)

[0054] Sequentially sieve neratinib maleate, meglumine, and sodium sulfate, which have been dried at 65° C., through an 80-mesh sieve; thoroughly mix neratinib maleate 400 g (calculated as neratinib) and meglumine 750 g; then add 350 g of sodium sulfate and mix evenly; determine the content; determine the tablet weight according to the specification; press the tablets onto a tabletting machine, inspect, and package.

[0055] Example 15 Preparation of Neratinib Maleate Tablets (10,000 Preparation Units)

[0056] Neratinib maleate, meglumine and sodium sulfate that have been dried at 65° C. in advance are sequentially passed through an 80-mesh sieve; 400 g of neratinib maleate (calculated as neratinib) and 800 g of meglumine are thoroughly mixed, and then 300 g of sodium sulfate is added and mixed evenly. The content is determined, and the tablet weight is determined according to the specification. The tablets are pressed onto a tabletting machine, inspected, and packaged to obtain the product.

[0057] Example 16 Preparation of Neratinib Maleate Tablets (10,000 Preparation Units)

[0058] Sequentially sieve neratinib maleate, meglumine, and sodium sulfate, which have been dried at 65° C., through an 80-mesh sieve; thoroughly mix neratinib maleate 400 g (calculated as neratinib) and meglumine 700 g; then add 360 g of sodium sulfate and mix evenly; determine the content; determine the tablet weight according to the specification; press the tablets onto a tabletting machine, inspect, and package.

[0059] The neratinib maleate tablets obtained in Examples 10-16 were subjected to a dissolution test. At 37°C ± 0.5°C, 900 mL of a pH 1.0 hydrochloric acid solution and a pH 3.8 acetic acid solution were used as dissolution media, respectively. The dissolution rate of the tablets was measured using a paddle method at a speed of 50 rpm. Samples were taken after 15 min, 30 min, and 45 min, respectively. The results are shown in Tables 1 and 2.

[0060] Table 1 pH 1.0 dissolution test results

[0061]

[0062] Table 2 pH 3.8 dissolution test results

[0063]

[0064] It can be seen from the results in Table 1 and Table 2 that the addition of 70g-80g of meglumine and 30g-36g of sodium sulfate to every 40g of neratinib maleate (calculated as neratinib) can significantly improve the solubility of neratinib maleate, especially the addition of 75g of meglumine and 35g of sodium sulfate to every 40g of neratinib maleate (calculated as neratinib) has the best effect.

[0065] The neratinib maleate tablets obtained in Example 14 were subjected to an accelerated stability study (40°C ± 2°C, RH 75% ± 5%). The results are shown in Table 3.

[0066] Table 3 Accelerated test results of Neratinib Maleate Tablets

[0067]

[0068]

[0069] From the results in Table 3, it can be seen that the neratinib maleate drug prepared in Example 14 has good stability. The same test was also carried out on the neratinib maleate drug preparations prepared in Examples 12, 13, 15, and 16, and similar results were obtained.

[0070] The above description is only a preferred embodiment of the present invention, which certainly cannot be used to limit the scope of rights of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and changes can be made without departing from the principles of the present invention. These improvements and changes are also considered to be within the scope of protection of the present invention.

Claims

1. A pharmaceutical composition of neratinib maleate, characterized in that: The raw materials of the pharmaceutical composition are composed of neratinib maleate, meglumine and sodium sulfate; in parts by weight, the weight ratio of neratinib maleate, meglumine and sodium sulfate in the pharmaceutical composition is 40:(70-80):(30-36), wherein the mass of neratinib maleate is calculated by measuring the mass of neratinib free base therein.

2. A method for preparing the composition according to claim 1, characterized in that: The steps include: (1) drying and sieving the raw materials of neratinib maleate, meglumine and sodium sulfate respectively to obtain raw material powders; (2) Neratinib maleate, meglumine, and sodium sulfate powder are added in order and mixed thoroughly to obtain the neratinib maleate pharmaceutical composition.

3. The preparation method according to claim 2, characterized in that: The drying temperature used in step (1) is 50-70°C.

4. The preparation method according to claim 2, characterized in that: Step (2) firstly mix neratinib maleate and meglumine powder evenly, and then add sodium sulfate powder and mix evenly.

5. A pharmaceutical tablet of neratinib maleate, characterized in that: The pharmaceutical tablet comprises the pharmaceutical composition according to claim 1 or the pharmaceutical composition prepared by any one of claims 2 to 4.

6. The tablet according to claim 5, characterized in that Each tablet contains 30-50 mg of neratinib measured as neratinib free base.

7. The tablet according to claim 5, characterized in that The tablets comprise a film coating.

8. A method for preparing a tablet according to any one of claims 5 to 7, characterized in that: The method comprises the following steps: determining the tablet weight according to the specification of the pharmaceutical composition of claim 1 or the pharmaceutical composition obtained by any one of the preparation methods of claims 2 to 4, and tableting the tablets on a machine.

9. Use of a pharmaceutical composition in the preparation of a drug for treating breast cancer, characterized in that: The pharmaceutical composition is the pharmaceutical composition according to claim 1 or the pharmaceutical composition obtained by the preparation method according to any one of claims 2 to 4.

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