Azotinib hydrochloride suspension and preparation method thereof

Abstract

The invention belongs to the technical field of anti-tumor medicine preparations, and particularly relates to an azotinib hydrochloride suspension and a preparation method thereof. The afatinib hydrochloride suspension disclosed by the invention is prepared from afatinib hydrochloride, eleostearic acid, glucan, sodium alginate, glycerol, a flavoring agent and water. By optimizing the prescription design, improving the preparation process and particularly adding the glucan and the eleostearic acid according to the ratio, not only is the problem that the afatinib hydrochloride is unstable when encountering high temperature solved, but also the whole suspension system is stable and shows good redispersibility.

Description

Technical Field

[0001] The present invention belongs to the technical field of anti-tumor drug preparations, and in particular relates to an alectinib hydrochloride suspension and a preparation method thereof. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance the understanding of the overall background of the invention, and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.

[0003] ALK-positive non-small cell lung cancer is a type of lung cancer with a specific molecular subtype, characterized by positive ALK gene rearrangement, which is not only a change at the gene sequence level, but also an important variation in this type of disease. Patients with ALK-positive non-small cell lung cancer may experience a series of symptoms, including chest pain, chest tightness, dyspnea, and hemoptysis. If left untreated, the disease is prone to metastasis, which may affect other parts of the body such as the lower back and buttocks. In addition, there may be symptoms of cancer cells spreading to the surrounding area or distant metastasis, such as hoarseness, chest pain, pleural effusion, ptosis, enophthalmos, painless masses, bone pain, joint effusion, pathological fractures, and nausea, vomiting, headache and other manifestations of increased intracranial pressure. Fortunately, ALK-positive non-small cell lung cancer is highly sensitive to the new targeted drug, ALK inhibitors. For example, the clinical effect of alectinib is very good, and the patient's survival can be significantly extended, and some can even reach 7-8 years or longer.

[0004] Alectinib hydrochloride was developed by Tokyo Pharmaceutical Company in Japan. It is a targeted therapy drug in the innovative drug stage. It is a tyrosine kinase inhibitor that can selectively inhibit the protein kinase activity produced by the ALK fusion gene, thereby blocking the signal transduction pathway, thereby blocking the growth and spread of tumor cells and achieving the effect of treating tumors. It is mainly used to treat ALK-positive advanced or metastatic non-small cell lung cancer, and has the advantages of good therapeutic effect and few toxic side effects.

[0005] A Chinese patent with publication number CN109381440A discloses an oral drug of alectinib, which contains 150g of alectinib with a D90 of 36 to 55 microns, 4 to 8g of Tween 80, 8 to 26g of fumed silica, 2 to 8g of calcium sulfate, 18 to 32g of hydroxypropyl cellulose, 20 to 46g of anhydrous lactose, 4N8g of disodium ethylenediaminetetraacetate, and 1.0N1.5g of magnesium stearate per thousand unit doses, which improves the dissolution of the main drug and improves the anti-hygroscopic performance during storage.

[0006] A Chinese patent with publication number CN1 11632066A discloses a pharmaceutical composition for treating and / or preventing ovarian cancer comprising alectinib. The active ingredients include cisplatin and alectinib in a weight ratio of 1:50 to 50:1. The different anti-cancer principles and interactions of the two drugs are utilized to produce a significant synergistic effect when used in the treatment of ovarian cancer, thereby greatly improving the therapeutic effect of ovarian cancer.

[0007] Chinese patent publication number CN114191435A discloses a pharmaceutical composition consisting of cabozantinib, alectinib and ceritinib. The pharmaceutical composition uses ceritinib, alectinib and / or cabozantinib as active ingredients, and excipients are acidic cellulose ester derivatives and polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymers. No crystal transformation occurs under accelerated conditions (40°C, 75% relative humidity) for at least 3 months.

[0008] Alectinib's low water solubility leads to poor absorption and low bioavailability. In addition, alectinib is a thermosensitive drug, and exposure to high temperatures will cause the drug to degrade, thereby reducing its efficacy and even producing harmful substances. Summary of the invention

[0009] In order to overcome the deficiencies of the prior art, the present invention provides an alectinib hydrochloride suspension. By rationally designing a prescription, a suspension with good system redispersibility and high physical stability is obtained, and the problem of poor thermal stability of alectinib hydrochloride is solved, thereby improving the stability of the alectinib hydrochloride suspension.

[0010] Specifically, the alectinib hydrochloride suspension of the present invention is composed of 100-200 parts by weight of alectinib hydrochloride, 2-8 parts by weight of eugenol (CAS No. 533-87-9), 4-16 parts by weight of dextran, 5-15 parts by weight of sodium alginate, 15-35 parts by weight of glycerol, a flavoring agent, and water.

[0011] Furthermore, the flavoring agents include but are not limited to sucrose, sucralose, aspartame, erythritol, xylitol, and mannitol, and are only used to adjust the taste.

[0012] In many embodiments, the weight ratio of the eleutherolic acid 2N8 to glucan is 1:2.

[0013] In one embodiment, the alectinib hydrochloride suspension is composed of 150 parts by weight of alectinib hydrochloride, 6 parts by weight of eleutheric acid, 12 parts by weight of dextran, 10 parts by weight of sodium alginate, 25 parts by weight of glycerol, flavoring agent, and water.

[0014] In one embodiment, the alectinib hydrochloride suspension is composed of 150 parts by weight of alectinib hydrochloride, 5 parts by weight of eugenol, 10 parts by weight of dextran, 12 parts by weight of sodium alginate, 20 parts by weight of glycerol, flavoring agent, and water.

[0015] Furthermore, the concentration of the alectinib hydrochloride suspension is 10 to 20 g / l.

[0016] The present invention also provides a method for preparing the above-mentioned alectinib hydrochloride suspension, comprising the following steps:

[0017] (1) Dissolve glucan and eleutheric acid in appropriate amount of water, heat in a water bath at 30°C to 40°C, stir until it becomes a paste, cool, and set aside;

[0018] (2) Dry-grinding alectinib hydrochloride, then adding 1 / 5 to 3 / 5 parts by weight of glycerol to perform liquid grinding, grinding until the particle size of alectinib hydrochloride is 0.5 to 10 μm, adding it to the paste of step (1), and stirring evenly;

[0019] (3) Add sodium alginate, the remaining glycerol, a buffer solution with a pH of 5.5 to 6.5, and a flavoring agent, stir, and gradually add water to the full amount.

[0020] In one embodiment, the water bath heating temperature in step (1) is 35°C.

[0021] In one embodiment, the amount of glycerol used in step (2) is 2 / 5 parts by weight of the formula.

[0022] Furthermore, the buffer solution is a citrate buffer solution, a carbonate buffer solution, a phosphate buffer solution, or a tartrate buffer solution, but is not limited thereto.

[0023] Compared with the prior art, the technical effects of the present invention are:

[0024] The invention optimizes the prescription design and improves the preparation process, especially the addition of glucan and eleutheric acid in a certain ratio, which not only solves the problem that alectinib hydrochloride is unstable when exposed to high temperature, but also stabilizes the entire suspension system and exhibits good redispersibility. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 It is the sedimentation volume ratio F of the alectinib hydrochloride suspensions of Examples 1 to 4 and Comparative Examples 1 to 5.

[0026] Figure 2 It is a graph showing the changes in impurity content of alectinib hydrochloride suspensions of Examples 1 to 4 and Comparative Examples 1 to 5.

[0027] Figure 3This is a graph showing changes in the alectinib hydrochloride content in the alectinib hydrochloride suspensions of Examples 1 to 4 and Comparative Examples 1 to 5.

[0028] Figure 4 This is the change curve of pH and alectinib hydrochloride content. DETAILED DESCRIPTION

[0029] In order to make the purpose and technical solution of the present invention clearer, the present invention is further described below in conjunction with embodiments, but the protection scope of the present invention is not limited to these embodiments, and the embodiments are only used to explain the present invention. It should be understood by those skilled in the art that any changes or equivalent substitutions that do not deviate from the concept of the present invention are included in the protection scope of the present invention.

[0030] Example 1 Alectinib hydrochloride suspension

[0031] Alectinib hydrochloride 150g, eleutheric acid 6g, dextran 12g, sodium alginate 10g, glycerol 25g, aspartame 0.002g, water.

[0032] Preparation method:

[0033] (1) Dissolve glucan and eleutheric acid in appropriate amount of water, heat in a water bath at 37°C, stir until it becomes a paste, cool, and set aside;

[0034] (2) Dry-grinding alectinib hydrochloride, then adding 2 / 5 weight parts of glycerol to perform liquid grinding, grinding until the particle size of alectinib hydrochloride is 0.5-10 μm, adding to the paste of step (1), and stirring evenly;

[0035] (3) Add sodium alginate, the remaining glycerol, a carbonate buffer solution with a pH of 6.2, and a flavoring agent, stir, and gradually add water to the full amount.

[0036] Example 2 Alectinib hydrochloride suspension

[0037] formula:

[0038] Alectinib hydrochloride 150g, eleutheric acid 5g, dextran 10g, sodium alginate 12g, glycerol 20g, aspartame 0.003g, water.

[0039] Preparation method:

[0040] (1) Dissolve glucan and eleutheric acid in appropriate amount of water, heat in a water bath at 37°C, stir until it becomes a paste, cool, and set aside;

[0041] (2) Dry-grinding alectinib hydrochloride, then adding 2 / 5 weight parts of glycerol to perform liquid grinding, grinding until the particle size of alectinib hydrochloride is 0.5-10 μm, adding to the paste of step (1), and stirring evenly;

[0042] (3) Add sodium alginate, the remaining glycerol, a carbonate buffer solution with a pH of 5.8, and a flavoring agent, stir, and gradually add water to the full amount.

[0043] Example 3 Alectinib hydrochloride suspension

[0044] formula:

[0045] Alectinib hydrochloride 100g, eleutheric acid 2g, dextran 4g, sodium alginate 5g, glycerol 15g, aspartame 0.004g, water.

[0046] Preparation method:

[0047] (1) Dissolve glucan and eleutheric acid in appropriate amount of water, heat in a water bath at 30°C, stir until it becomes a paste, cool, and set aside;

[0048] (2) Dry-grinding alectinib hydrochloride, then adding 1 / 5 weight portion of glycerol to perform liquid grinding, grinding until the particle size of alectinib hydrochloride is 0.5 to 10 μm, adding to the paste of step (1), and stirring evenly;

[0049] (3) Add sodium alginate, the remaining glycerol, a phosphate buffer solution with a pH of 5.5, and a flavoring agent, stir, and gradually add water to the full amount.

[0050] Example 4 Alectinib hydrochloride suspension

[0051] formula:

[0052] Alectinib hydrochloride 200g, eleutheric acid 8g, dextran 16g, sodium alginate 15g, glycerol 35g, aspartame 0.004g, water.

[0053] Preparation method:

[0054] (1) Dissolve glucan and eleutheric acid in appropriate amount of water, heat in a water bath at 40°C, stir until it becomes a paste, cool, and set aside;

[0055] (2) Dry-grinding alectinib hydrochloride, then adding 3 / 5 weight parts of glycerol to perform liquid grinding, grinding until the particle size of alectinib hydrochloride is 0.5-10 μm, adding to the paste of step (1), and stirring evenly;

[0056] (3) Add sodium alginate, the remaining glycerol, a tartrate buffer solution of pH=6.5, and a flavoring agent, stir, and gradually add water to the full amount.

[0057] Examples 5 to 9 Alectinib hydrochloride suspension

[0058] Embodiment 5 formula:

[0059] Alectinib hydrochloride 150g, eleutheric acid 5g, dextran 10g, sodium alginate 12g, glycerol 20g, sucrose 5g, water.

[0060] Embodiment 6 formula:

[0061] Alectinib hydrochloride 150g, eleugelic acid 5g, dextran 10g, sodium alginate 12g, glycerol 20g, sucralose 0.001g, water.

[0062] Embodiment 7 formula:

[0063] Alectinib hydrochloride 150g, eleutheric acid 5g, dextran 10g, sodium alginate 12g, glycerol 20g, erythritol 0.01g, water.

[0064] Embodiment 8 formula:

[0065] Alectinib hydrochloride 150g, eleutheric acid 5g, dextran 10g, sodium alginate 12g, glycerol 20g, xylitol 3g, water.

[0066] Embodiment 9 formula:

[0067] Alectinib hydrochloride 150g, eleutheric acid 5g, dextran 10g, sodium alginate 12g, glycerol 20g, mannitol 1g, water.

[0068] Embodiment 5~9 Alectinib hydrochloride suspension preparation method:

[0069] (1) Dissolve glucan and eleutheric acid in appropriate amount of water, heat in a water bath at 37°C, stir until it becomes a paste, cool, and set aside;

[0070] (2) Dry-grinding alectinib hydrochloride, then adding 2 / 5 weight parts of glycerol to perform liquid grinding, grinding until the particle size of alectinib hydrochloride is 0.5-10 μmm, adding to the paste of step (1), and stirring evenly;

[0071] (3) Add sodium alginate, the remaining glycerol, a carbonate buffer solution with a pH of 6.0, and a flavoring agent, stir, and gradually add water to the full amount.

[0072] Comparative Example 1 Alectinib hydrochloride suspension

[0073] formula:

[0074] Alectinib hydrochloride 150g, dextran 12g, sodium alginate 10g, glycerol 25g, aspartame 0.002g, water.

[0075] Preparation method:

[0076] (1) Dissolve glucan in an appropriate amount of water, heat in a water bath at 35°C, stir until it becomes a paste, cool, and set aside;

[0077] (2) Dry-grinding alectinib hydrochloride, then adding 2 / 5 weight parts of glycerol to perform liquid grinding, grinding until the particle size of alectinib hydrochloride is 0.5-10 μm, adding to the paste of step (1), and stirring evenly;

[0078] (3) Add sodium alginate, the remaining glycerol, a citrate buffer solution with a pH of 5.8, and a flavoring agent, stir, and gradually add water to the full amount.

[0079] Comparative Example 2 Alectinib hydrochloride suspension

[0080] formula:

[0081] Alectinib hydrochloride 150g, eleutheric acid 6g, sodium alginate 10g, glycerol 25g, aspartame 0.002g, water.

[0082] Preparation method:

[0083] (1) Dissolve eleutheric acid in an appropriate amount of water, heat in a water bath at 35°C, stir until it becomes a paste, cool, and set aside;

[0084] (2) Dry-grinding alectinib hydrochloride, then adding 2 / 5 weight parts of glycerol to perform liquid grinding, grinding until the particle size of alectinib hydrochloride is 0.5-10 μm, adding to the paste of step (1), and stirring evenly;

[0085] (3) Add sodium alginate, the remaining glycerol, a citrate buffer solution with a pH of 5.8, and a flavoring agent, stir, and gradually add water to the full amount.

[0086] Comparative Example 3 Alectinib hydrochloride suspension

[0087] formula:

[0088] Alectinib hydrochloride 150g, eleutheric acid 10g, dextran 2g, sodium alginate 10g, glycerol 25g, aspartame 0.002g, water.

[0089] Preparation method:

[0090] (1) Dissolve glucan and eleutheric acid in appropriate amount of water, heat in a water bath at 35°C, stir until it becomes a paste, cool, and set aside;

[0091] (2) Dry-grinding alectinib hydrochloride, then adding 2 / 5 weight parts of glycerol to perform liquid grinding, grinding until the particle size of alectinib hydrochloride is 0.5-10 μm, adding to the paste of step (1), and stirring evenly;

[0092] (3) Add sodium alginate, the remaining glycerol, a citrate buffer solution with a pH of 5.8, and a flavoring agent, stir, and gradually add water to the full amount.

[0093] Comparative Example 4 Alectinib Hydrochloride Suspension

[0094] formula:

[0095] Alectinib hydrochloride 150g, tragacanth gum 6g, dextran 12g, sodium alginate 10g, glycerol 25g, aspartame 0.002g, water.

[0096] Preparation method:

[0097] (1) Dissolve glucan and tragacanth gum in appropriate amount of water, heat in a water bath at 35°C, stir until it becomes a paste, cool, and set aside;

[0098] (2) Dry-grinding alectinib hydrochloride, then adding 2 / 5 weight parts of glycerol to perform liquid grinding, grinding until the particle size of alectinib hydrochloride is 0.5-10 μm, adding to the paste of step (1), and stirring evenly;

[0099] (3) Add sodium alginate, the remaining glycerol, a citrate buffer solution with a pH of 5.8, and a flavoring agent, stir, and gradually add water to the full amount.

[0100] Comparative Example 5 Alectinib hydrochloride suspension

[0101] formula:

[0102] Alectinib hydrochloride 150g, eleutheric acid 6g, dextran 12g, sodium alginate 10g, glycerol 25g, aspartame 0.002g, water.

[0103] Preparation method:

[0104] (1) Dissolve glucan and eleutheric acid in appropriate amount of water, stir into a paste, cool and set aside;

[0105] (2) Glycerol is first added to alectinib hydrochloride and ground until the particle size of alectinib hydrochloride is 0.5 to 10 μm, and then added to the paste of step (1) and stirred evenly;

[0106] (3) Add sodium alginate, pH=5.8 citrate buffer solution, and flavoring agent, stir, and gradually add water to the full amount.

[0107] Quality evaluation of alectinib hydrochloride suspension

[0108] Determination of sedimentation volume ratio

[0109] The sedimentation volume ratio of a suspension refers to the ratio of its volume to the volume of the suspension before sedimentation. The specific determination method is: use a stoppered measuring cylinder to measure 50 ml of the test sample, seal it tightly, shake it vigorously for 1 minute, record the initial height H0 of the suspension, let it stand for 3 hours, record the final height H of the suspension, and calculate it according to the following formula: sedimentation volume ratio F = H / H0, the F value is between 0 and 1, and the larger the F value, the more stable the suspension.

[0110] Figure 1 It is the sedimentation volume ratio F of the alectinib hydrochloride suspensions of Examples 1 to 4 and Comparative Examples 1 to 5. The height of the suspended matter of the alectinib hydrochloride suspensions of Examples 1 to 4 basically does not change before and after being shaken and left to stand for 3 hours, and the indoor stability is good. The height of the suspended matter of the alectinib hydrochloride suspensions of Comparative Examples 1 to 5 decreases significantly after being shaken and left to stand for 3 hours, and the stability is poor.

[0111] Table 1 Sedimentation volume ratio of alectinib hydrochloride suspension

[0112] F Example 5 0.97 Example 6 0.98 Example 7 0.96 Example 8 0.97 Example 9 0.99

[0113] Table 1 shows the sedimentation volume ratios F of the alectinib hydrochloride suspensions of Examples 5 to 9. The sedimentation volume ratios of the alectinib hydrochloride suspensions of Examples 5 to 9 are all higher than 0.9, which is in line with the provisions of the Chinese Pharmacopoeia, indicating that the selection of the flavoring agent does not affect the stability of the alectinib hydrochloride suspension.

[0114] Redispersion test

[0115] Examples 1 to 9 and Comparative Examples 1 to 5 were used as test samples. The alectinib hydrochloride suspension was placed at a temperature of 40 ± 2 ° C and a relative humidity of 75% ± 5% for 6 months. At the end of the 6th month, a redispersion test was performed. The suspension was placed in a 100 ml measuring cylinder and rotated at a speed of 20 r per min for a certain period of time. The sediment at the bottom of the measuring cylinder could be redispersed evenly, and the time required for each test sample to be evenly dispersed was recorded.

[0116] Table 2 Redispersion test of alectinib hydrochloride suspension

[0117] Time required for redispersion (s) Example 1 8～9 Example 2 7～8 Example 3 10～11 Example 4 12～13 Example 5 14～15 Example 6 11～12 Example 7 13～14 Example 8 9～10 Example 9 10～11 Comparative Example 1 31～32 Comparative Example 2 18～19 Comparative Example 3 24～25 Comparative Example 4 28～29 Comparative Example 5 19～20

[0118] Table 2 shows the time required for the redispersion test of each group of alectinib hydrochloride suspension. The test shows that it takes 7 to 15 seconds to redisperse the alectinib hydrochloride suspensions of Examples 1 to 9 of the present invention after storage for 6 months, and shaking can quickly achieve a uniformly dispersed state. The alectinib hydrochloride suspensions of Comparative Examples 1 to 5 are difficult to redisperse, and the redispersibility of the system is poor.

[0119] Stability of Alectinib Hydrochloride Suspension

[0120] To explore the stability of the alectinib hydrochloride suspension of the present invention, the alectinib hydrochloride suspensions of Examples 1 to 4 and Comparative Example 1N5 were used as test samples and placed at a temperature of 40±2°C and a relative humidity of 75%±5% for 6 months. Samples were taken at the end of the first month, the end of the second month, the end of the third month, and the end of the sixth month during the test to detect the impurity (CAS No. 1256584-83-4) content and the alectinib hydrochloride content.

[0121] Figure 2 It is a graph showing the changes in impurity content of alectinib hydrochloride suspensions of Examples 1 to 4 and Comparative Examples 1 to 5. Figure 3 The graph is a graph showing the change in the alectinib hydrochloride content in the alectinib hydrochloride suspensions of Examples 1 to 4 and Comparative Examples 1 to 5. The experiment shows that the alectinib hydrochloride suspension of the present invention has high stability, and the impurity content is low and the alectinib hydrochloride content remains substantially unchanged after being stored for 6 months under high temperature and high humidity conditions.

[0122] Effect of buffer solution pH on the stability of alectinib hydrochloride suspension

[0123] A single factor experiment was used to explore the issue. The variables were the pH values ​​of the buffer solutions at 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, and 7.5, respectively. The other preparation methods and prescriptions were the same as those in Example 1.

[0124] Figure 4 The curve of pH and alectinib hydrochloride content shows that the content of active ingredients in alectinib hydrochloride suspension is more stable within the pH range of 5.5 to 6.5.

Claims

1. An alectinib hydrochloride suspension, characterized in that: The alectinib hydrochloride suspension is composed of 100-200 parts by weight of alectinib hydrochloride, 2-8 parts by weight of eugenol, 4-16 parts by weight of dextran, 5-15 parts by weight of sodium alginate, 15-35 parts by weight of glycerol, a flavoring agent and water.

2. The alectinib hydrochloride suspension according to claim 1, characterized in that The flavoring agent is selected from sucrose, sucralose, aspartame, erythritol, xylitol, and mannitol.

3. The alectinib hydrochloride suspension according to claim 1, characterized in that The ratio of 2 to 8 parts by weight of eleutheric acid to glucan is 1:

2.

4. The alectinib hydrochloride suspension according to claim 1, characterized in that The alectinib hydrochloride suspension is composed of 150 parts by weight of alectinib hydrochloride, 6 parts by weight of eleutheric acid, 12 parts by weight of dextran, 10 parts by weight of sodium alginate, 25 parts by weight of glycerol, a flavoring agent, and water.

5. The alectinib hydrochloride suspension according to claim 1, characterized in that The alectinib hydrochloride suspension is composed of 150 parts by weight of alectinib hydrochloride, 5 parts by weight of eleutheric acid, 10 parts by weight of dextran, 12 parts by weight of sodium alginate, 20 parts by weight of glycerol, a flavoring agent, and water.

6. The alectinib hydrochloride suspension according to claim 1, characterized in that The alectinib hydrochloride suspension is 10-20 g / l.

7. A method for preparing the alectinib hydrochloride suspension according to claim 1, characterized in that: The method is: (1) Dissolve glucan and eleutheric acid in appropriate amount of water, heat in a water bath at 30°C to 40°C, stir until it becomes a paste, cool, and set aside; (2) Dry-grinding alectinib hydrochloride, then adding 1 / 5 to 3 / 5 parts by weight of glycerol to perform liquid grinding, grinding until the particle size of alectinib hydrochloride is 0.5 to 10 μm, adding it to the paste of step (1), and stirring evenly; (3) Add sodium alginate, the remaining glycerol, a buffer solution with a pH of 5.5 to 6.5, and a flavoring agent, stir, and gradually add water to the full amount.

8. The method according to claim 7, characterized in that The water bath heating temperature in step (1) is 35°C.

9. The method according to claim 7, characterized in that The amount of glycerol used in step (2) is 2 / 5 of the weight portion of the formula.

10. The method according to claim 7, characterized in that The buffer solution is a citrate buffer solution, a carbonate buffer solution, a phosphate buffer solution, or a tartrate buffer solution.

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