Darcotinib pharmaceutical composition and preparation method thereof

Abstract

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a dalcotinib pharmaceutical composition and a preparation method thereof.The dalcotinib pharmaceutical composition is prepared from, by weight, 10-30 parts of dalcotinib, 25-60 parts of lactose, 25-60 parts of microcrystalline cellulose, 1-15 parts of carboxymethyl starch sodium and 0.5-5 parts of magnesium stearate, and the dalcotinib pharmaceutical composition is prepared from, by weight, 10-30 parts of dalcotinib, 25-60 parts of lactose, 25-60 parts of microcrystalline cellulose, 1-15 parts of carboxymethyl starch sodium and 0.5-5 parts of magnesium stearate. The average particle size D50 of the lactose is greater than or equal to 120m. The dalcotinib composition disclosed by the invention is high in dissolution rate, quick in disintegration, good in fluidity, capable of avoiding sticking, good in dissolution rate stability and simple in preparation process.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, and particularly relates to a dacomitinib pharmaceutical composition and a preparation method thereof. Background Art

[0002] Dacomitinib is a second-generation EGFR tyrosine kinase inhibitor (TKI) used to treat locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletion mutation or exon 21 L858R substitution mutation.

[0003] In dacomitinib pharmaceutical compositions, varying particle sizes of the API can affect dissolution and other aspects of the finished product stability. Currently, to ensure dissolution and other aspects of the finished product stability of the dacomitinib pharmaceutical composition, the API must be pre-screened and processed for particle size, leading to complex production processes.

[0004] For example, CN114099455A discloses a dacomitinib pharmaceutical composition containing dacomitinib, a filler, a disintegrant, and a lubricant. This patent obtains a dacomitinib pharmaceutical composition by uniformly mixing dacomitinib, a filler, and a disintegrant, dry granulating the mixture with a sieve, tableting, and coating. However, this production process requires pre-sieving the mixture of dacomitinib, a filler, and a disintegrant, and then dry granulating it. The preparation process is complicated, and the stability of the finished product, such as the dissolution rate of the prepared dacomitinib pharmaceutical composition, also varies. Summary of the Invention

[0005] The present invention provides a dacomitinib pharmaceutical composition and a preparation method thereof. The dacomitinib composition has high solubility, fast disintegration, good fluidity, good dissolution stability, and a simple preparation process.

[0006] The present invention provides a dacomitinib pharmaceutical composition. The dacomitinib pharmaceutical composition comprises, by weight, 10 to 30 parts of dacomitinib, 25 to 60 parts of lactose, 25 to 60 parts of microcrystalline cellulose, 1 to 15 parts of sodium starch glycolate, and 0.5 to 5 parts of magnesium stearate. The average particle size D50 of the lactose is greater than or equal to 120 μm.

[0007] In some embodiments, the dacomitinib pharmaceutical composition includes 10-20 parts of dacomitinib, 30-50 parts of lactose, 30-50 parts of microcrystalline cellulose, 1-5 parts of sodium starch glycolate, and 0.5-2 parts of magnesium stearate.

[0008] In some embodiments, the dacomitinib pharmaceutical composition includes 13-17 parts of dacomitinib, 40-44 parts of lactose, 38-42 parts of microcrystalline cellulose, 1.5-2.5 parts of sodium starch glycolate, and 0.5-1 part of magnesium stearate.

[0009] In some embodiments, the dacomitinib pharmaceutical composition includes 15 parts of dacomitinib, 40-44 parts of lactose, 38-42 parts of microcrystalline cellulose, 1.5-2.5 parts of sodium starch glycolate, and 0.5-1 part of magnesium stearate.

[0010] In some embodiments, the dacomitinib pharmaceutical composition includes 15 parts of dacomitinib, 42.5 parts of lactose, 39.2 parts of microcrystalline cellulose, 2 parts of sodium starch glycolate, and 0.7 parts of magnesium stearate.

[0011] In some embodiments, the average particle size D50 of the lactose is greater than or equal to 130 μm.

[0012] In some embodiments, the particle size D90 of dacomitinib is 5 to 100 μm.

[0013] In some embodiments, the dacomitinib pharmaceutical composition is a tablet.

[0014] In some embodiments, the tablet comprises a core and a film coating; In parts by weight, the core tablet components include 10-30 parts of dacomitinib, 25-60 parts of lactose, 25-60 parts of microcrystalline cellulose, 1-15 parts of sodium starch glycolate and 0.5-5 parts of magnesium stearate; The film coating component includes 1 to 5 parts of film coating premix.

[0015] The present invention also provides a method for preparing a dacomitinib pharmaceutical composition, comprising the following steps: a. Mix the raw materials and compress them into tablets to obtain tablet cores; b. Coating the core tablets.

[0016] In some embodiments, step a specifically includes: Premixing: premixing dacomitinib, lactose, microcrystalline cellulose, and sodium starch glycolate to obtain a premixed powder; Total mixing: mixing the premixed powder with magnesium stearate to obtain a total mixed powder; Tableting: compressing the total mixed powder into tablets to obtain tablet cores; The step b specifically includes: Coating: Coating the core tablets to obtain the dacomitinib pharmaceutical composition.

[0017] In some embodiments, the premixing comprises: adding microcrystalline cellulose, dacomitinib, sodium starch glycolate, and lactose into a mixing hopper, rotating at a speed of 5 to 15 rpm, and mixing for 5 to 15 minutes to obtain a premixed powder.

[0018] In some embodiments, the premixing comprises: adding microcrystalline cellulose, dacomitinib, sodium starch glycolate, and lactose into a mixing hopper, rotating at 10 rpm, and mixing for 12 minutes to obtain a premixed powder.

[0019] In some embodiments, the total mixing comprises: mixing magnesium stearate and premixed powder in a mixing hopper at a rotation speed of 5 to 15 rpm for 5 to 15 minutes to obtain a total mixed powder.

[0020] In some embodiments, the total mixing comprises: mixing magnesium stearate and premixed powder in a mixing hopper at a rotation speed of 10 rpm for 8 minutes to obtain a total mixed powder.

[0021] In some embodiments, the tableting includes: taking a circular punch and installing it on a tablet press, tableting the total mixed powder, controlling the tablet weight difference limit to ±7.5%, and the hardness range to 30~80N, to obtain a tablet core.

[0022] In some embodiments, the coating comprises: adding a film coating premix to stirring water, stirring continuously until the mixture is uniformly mixed, thereby obtaining a coating solution for use. The tablet cores are placed in a coating pan and coated, with the coating weight gain controlled to be between 2% and 4%.

[0023] In some embodiments, the film coating premix is ​​a gastric soluble coating premix.

[0024] The present invention also provides the use of lactose in preparing a pharmaceutical composition containing dacomitinib, wherein the average particle size D50 of the lactose is greater than or equal to 120 μm.

[0025] The dacomitinib composition of the present invention ensures high solubility, rapid disintegration, good fluidity, and can avoid sticking. In addition, the dacomitinib composition prepared from dacomitinib raw materials with different particle sizes has good dissolution stability.

[0026] Based on an optimized prescription, the present invention can directly mix dacomitinib raw materials with auxiliary materials and then compress the tablets, without the need to pre-screen the raw materials and dry-granulate the mixed powder of raw and auxiliary materials before tableting. The preparation process is simple, the production cost is low, and the preparation is suitable for large-scale production. DETAILED DESCRIPTION

[0027] The present invention is further described in detail below with reference to the embodiments, but is not intended to limit the present invention. Any equivalent substitutions in the art made according to the disclosure of the present invention shall fall within the scope of protection of the present invention.

[0028] In this application, the terms "include", "comprising" and "containing" and their equivalents should be understood as open, non-exclusive, meaning "including but not limited to", meaning that in addition to the listed elements, components and steps, other unspecified elements, components and steps may also be included. In this document, unless the context clearly dictates otherwise, singular terms encompass plural referents and vice versa.

[0029] The term "pharmaceutically acceptable" means that a carrier, vehicle, diluent, excipient, and / or formed salt is generally chemically or physically compatible with the other ingredients constituting a pharmaceutical dosage form and physiologically compatible with the receptor without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0030] The term "treating" means administering the compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes inhibiting the progression of a disease or condition and alleviating a disease or condition.

[0031] In this application, D50 refers to the particle size value corresponding to the 50th percentile of the sample's cumulative particle size distribution, indicating that 50% of the particles have a diameter greater than this value and 50% of the particles have a diameter less than this value. It is also called the median diameter, median particle size, or average particle size. D90 refers to the particle size value corresponding to the 90th percentile of the sample's cumulative particle size distribution, indicating that 90% of the particles have a diameter less than or equal to this value.

[0032] In this application, unless otherwise specified, dacomitinib in the pharmaceutical composition refers to the dacomitinib compound (CAS: 1110813-31-4), and the weight fraction or proportion of dacomitinib in the composition refers to the weight fraction or proportion of the dacomitinib compound (i.e., the anhydrous compound).

[0033] In this application, parts may be measured in milligrams.

[0034] In this application, all pharmaceutical excipients or reagents involved can be from commercial sources.

[0035] In this application, unless otherwise specified, "%" in the examples of this application refers to mass percentage.

[0036] Example 1

[0037] The amounts of the raw materials used in Example 1 are shown in Table 1. The preparation method of Example 1 is as follows.

[0038] Example 1 Preparation method of dacomitinib tablets Batch: 200,000 pieces / batch Premixing: Add microcrystalline cellulose, dacomitinib, sodium starch glycolate, and lactose into a mixing hopper at a speed of 10 rpm and mix for 12 minutes to obtain a premixed powder.

[0039] Total mixing: Mix magnesium stearate and premixed powder in a mixing hopper at a speed of 10 rpm for 8 minutes to obtain a total mixed powder.

[0040] Tablet pressing: The total mixed powder is pressed into tablets to obtain tablet cores.

[0041] Receive a circular punch and install it on the tablet press to compress the total mixed powder into tablets, controlling the tablet weight variation limit to ±7.5% and the hardness range to 30~80N to obtain the tablet core.

[0042] Coating: Coating the core tablets to obtain the dacomitinib pharmaceutical composition.

[0043] Add the film coating premix to the stirring water and continue stirring until the mixture is uniform. This will create a coating solution, which is ready for use. Place the tablet cores in a coating pan and coat them, controlling the coating weight gain to 2% to 4%. The film coating premix is ​​a gastric-soluble coating premix consisting of hypromellose, polyethylene glycol, and titanium dioxide.

[0044] Table 1 Tablet prescription

[0045] In Table 1, 15.6 parts by weight of dacomitinib monohydrate is equivalent to 15 parts by weight of dacomitinib, the particle size of dacomitinib is 97.5 µm, and the lactose is FlowLac® 100, which has an average particle size D50 of 133 µm.

[0046] Example 2-3 The only difference between Example 2-3 and Example 1 is the average particle size of lactose. The average particle size of lactose in Example 2-3 is shown in Table 2. The preparation method refers to the preparation method of Example 1.

[0047] Table 2 Average particle size of lactose

[0048] Examples 4-9 The only difference between Examples 4-9 and Example 1 is the different amounts of excipients (lactose, microcrystalline cellulose, sodium starch glycolate, magnesium stearate). The amounts of each excipient in each example are shown in Table 3. The preparation method refers to the preparation method of Example 1.

[0049] Table 3 Tablet prescription

[0050] Examples 10-13 The only difference between Examples 10-13 and Example 1 is the different amounts of raw materials (lactose and sodium starch glycolate). The amounts of each raw material in each example are shown in Table 4. The preparation method refers to the preparation method of Example 1.

[0051] Table 4 Tablet prescription

[0052] Examples 14-18 The only difference between Examples 14-18 and Example 1 is the different particle sizes of dacomitinib. The particle sizes of dacomitinib in each example are shown in Table 5. The preparation methods refer to the preparation method of Example 1.

[0053] Table 5 Dacomitinib particle size

[0054] Comparative Example 1 Reference preparation: dacomitinib tablets (Duozirun).

[0055] Comparative Examples 2-3 Comparative example of average particle size of lactose The only difference between Comparative Examples 2-3 and Example 1 is the average particle size of lactose. The average particle size of lactose in each example is shown in Table 6. The preparation method refers to the preparation method of Example 1.

[0056] Table 6 Average particle size of lactose

[0057] Comparative Examples 4-5 Comparative example of dacomitinib particle size The only difference between Comparative Examples 4-5 and Comparative Example 3 is the different particle sizes of dacomitinib. The particle sizes of dacomitinib in each comparative example are shown in Table 7. The preparation method refers to the preparation method of Example 1.

[0058] Table 7 Dacomitinib particle size

[0059] Effect Examples The total mixed powder flowability, tablet core dissolution and tablet core disintegration time of the reference sample were investigated.

[0060] 1. Sample: Dacomitinib tablets prepared with reference to Examples 1-18 of the present invention; The reference preparation of Comparative Example 1, and the dacomitinib tablets prepared in Comparative Examples 2 to 5.

[0061] 2. Methods: 2.1. Flowability determination method Fluidity determination method: Use a powder density tester to measure bulk density and tap density. Fluidity evaluation method is Hausner ratio, Hausner ratio = bulk density / tap density.

[0062] 2.2. Dissolution test method Dissolution test method: Use hydrochloric acid buffer as the dissolution medium, the rotation speed is 50 revolutions per minute, and sampling is performed every 15 minutes.

[0063] Determination method: High performance liquid chromatography was used for detection.

[0064] 2.3. Disintegration time determination method Disintegration time test method: Refer to the disintegration time test method in the 2020 edition of the Chinese Pharmacopoeia, Part III, General Chapter 0921. Place the test sample in the glass tube of the disintegration time tester. All plain tablets should disintegrate within 15 minutes.

[0065] 2.4. Determination of viscosity level Judge by the appearance of the tablet core.

[0066] 3. The results of the survey are shown in Table 8 Table 8 Results of investigation on the flowability of the total mixed powder, tablet core dissolution, tablet core disintegration time and sticking grade

[0067] As can be seen from Examples 1 to 18, the dacomitinib pharmaceutical composition used in the present invention has high solubility, fast disintegration, good fluidity, can avoid sticking, and has good dissolution stability.

[0068] It can be seen from Examples 1 to 18 and Comparative Example 1 that the tablet core dissolution of the dacomitinib pharmaceutical composition used in the present invention is above 96.8%, and the tablet core disintegration time is within 5 minutes, while the solubility of the reference preparation is 96.5% and the tablet core disintegration time is 6 minutes. It can be seen that the dacomitinib pharmaceutical composition used in the present invention has a higher solubility and faster disintegration than the reference preparation.

[0069] As shown in Examples 1-3 and Comparative Examples 2-3, the dacomitinib pharmaceutical composition (lactose D50 ≥ 120 µm) used in the present invention has a mixed powder flowability of less than 1.36, a core tablet dissolution rate of greater than 96.8%, and no or substantially no sticking. In contrast, the dacomitinib pharmaceutical composition (lactose D50 < 120 µm) used in Comparative Examples 2-3 has a mixed powder flowability of greater than 1.49, a core tablet dissolution rate of less than 81.5%, and no sticking. This indicates that the use of larger lactose particles (lactose D50 ≥ 120 µm) in the dacomitinib pharmaceutical composition used in the present invention improves the composition's mixed powder flowability and dissolution rate, thereby improving and preventing sticking. In particular, the dacomitinib pharmaceutical compositions (lactose D50 ≥ 130µm) used in Examples 1 and 3 exhibited a powder flowability below 1.17, a tablet dissolution rate of 99.6% or higher, and no sticking. This indicates that the use of larger lactose particles (lactose D50 ≥ 130µm) in the present invention can further improve the powder flowability, dissolution, and sticking prevention of the composition. Clearly, lactose particle size significantly impacts the powder flowability, dissolution, and sticking of dacomitinib pharmaceutical compositions. The dacomitinib pharmaceutical compositions (lactose D50 ≥ 120µm) used in the present invention can improve dissolution, while also improving powder flowability and preventing sticking.

[0070] As shown in Examples 1, 14-18, and Comparative Examples 3-5, the core dissolution rates of the dacomitinib compositions (lactose D50 ≥ 120 µm) prepared using raw materials (dacomitinib) of varying particle sizes ranged from 98.8% to 99.6%. This indicates that the dacomitinib compositions prepared using raw materials of varying particle sizes had similar dissolution rates and high dissolution stability. In contrast, the core dissolution rates of the dacomitinib pharmaceutical compositions (lactose D50 < 120 µm) used in Comparative Examples 3-5, when prepared using raw materials of varying particle sizes, were 81.5%, 90.8%, and 83.5%, respectively. This indicates that the dissolution rates of the dacomitinib pharmaceutical compositions (lactose D50 < 120 µm) prepared using raw materials of varying particle sizes varied significantly. Therefore, the dacomitinib pharmaceutical composition employed in the present invention utilizes lactose with a larger particle size (lactose D50 ≥ 120 µm), resulting in improved dissolution even when prepared using dacomitinib raw materials of varying particle sizes. This ensures that the dissolution rate of the dacomitinib composition is unaffected by the particle size of the dacomitinib raw material. Consequently, the present invention eliminates the need for prior particle size screening and treatment of the raw material to produce a dacomitinib pharmaceutical composition with stable dissolution, simplifying the production process.

[0071] As can be seen from Examples 1 and 4-9, the lactose, microcrystalline cellulose, sodium starch glycolate, and magnesium stearate in the dacomitinib pharmaceutical composition used in the present invention have an impact on the overall mixed powder flowability, tablet core dissolution, tablet core disintegration time, and sticking. In particular, as can be seen from Examples 1 and 6-7, when the excipient dosage is 40-44 parts lactose, 38-42 parts microcrystalline cellulose, 1.5-2.5 parts sodium starch glycolate, and 0.5-1 part magnesium stearate, there is a significant positive effect on the overall mixed powder flowability, tablet core dissolution, tablet core disintegration time, and sticking. The dacomitinib pharmaceutical composition used in Example 1 (42.5 parts lactose, 39.2 parts microcrystalline cellulose, 2 parts sodium starch glycolate, and 0.7 parts magnesium stearate) has the best overall mixed powder flowability, tablet core dissolution, tablet core disintegration time, and sticking prevention effect.

[0072] As can be seen from Examples 1 and 10-13, the amount of sodium starch glycolate in the dacomitinib pharmaceutical composition used in the present invention has a significant effect on the dissolution rate of the tablet core. In particular, when the amount of sodium starch glycolate used in Example 13 is greater than 2 parts, the dissolution rate of the tablet core decreases significantly. Therefore, when the amount of sodium starch glycolate used in the dacomitinib pharmaceutical composition used in the present invention is not greater than 2 parts, the tablet core disintegration time is good and the tablet core dissolution effect is good. The dacomitinib pharmaceutical composition used in Example 1 (42.5 parts lactose, 39.2 parts microcrystalline cellulose, 2 parts sodium starch glycolate and 0.7 parts magnesium stearate) has a good tablet core disintegration time and the best tablet core dissolution effect.

[0073] The embodiments described above are merely descriptions of preferred implementations of the present invention and are not intended to limit the scope of the present invention. Without departing from the spirit of the present invention, various modifications and improvements made to the technical solutions of the present invention by ordinary technicians in this field should fall within the scope of protection determined by the claims of the present invention.

Claims

1. A dacomitinib pharmaceutical composition, characterized in that In parts by weight, the dacomitinib pharmaceutical composition includes 10 to 30 parts of dacomitinib, 25 to 60 parts of lactose, 25 to 60 parts of microcrystalline cellulose, 1 to 15 parts of sodium starch glycolate and 0.5 to 5 parts of magnesium stearate, and the average particle size D50 of the lactose is greater than or equal to 120 μm.

2. The dacomitinib pharmaceutical composition according to claim 1, characterized in that The dacomitinib pharmaceutical composition comprises 10-20 parts of dacomitinib, 30-50 parts of lactose, 30-50 parts of microcrystalline cellulose, 1-5 parts of sodium starch glycolate and 0.5-2 parts of magnesium stearate.

3. The dacomitinib pharmaceutical composition according to claim 2, characterized in that The dacomitinib pharmaceutical composition comprises 13-17 parts of dacomitinib, 40-44 parts of lactose, 38-42 parts of microcrystalline cellulose, 1.5-2.5 parts of sodium starch glycolate and 0.5-1 part of magnesium stearate.

4. The dacomitinib pharmaceutical composition according to claim 3, characterized in that The dacomitinib pharmaceutical composition comprises 15 parts of dacomitinib, 42.5 parts of lactose, 39.2 parts of microcrystalline cellulose, 2 parts of sodium starch glycolate and 0.7 parts of magnesium stearate.

5. The dacomitinib pharmaceutical composition according to claim 1 or 3, characterized in that The average particle size D50 of the lactose is greater than or equal to 130 μm.

6. The dacomitinib pharmaceutical composition according to claim 1, characterized in that The dacomitinib pharmaceutical composition is a tablet.

7. The dacomitinib pharmaceutical composition according to claim 6, characterized in that The tablet comprises a tablet core and a film coating; In parts by weight, the core tablet components include 10-30 parts of dacomitinib, 25-60 parts of lactose, 25-60 parts of microcrystalline cellulose, 1-15 parts of sodium starch glycolate and 0.5-5 parts of magnesium stearate; The film coating component includes 1 to 5 parts of film coating premix.

8. A method for preparing the dacomitinib pharmaceutical composition according to any one of claims 1 to 7, characterized in that: The following steps are involved: a. Mix the raw materials and compress them into tablets to obtain tablet cores; b. Coating the core tablets.

9. The method according to claim 8, characterized in that The step a specifically includes: Premixing: premixing dacomitinib, lactose, microcrystalline cellulose, and sodium starch glycolate to obtain a premixed powder; Total mixing: mixing the premixed powder with magnesium stearate to obtain a total mixed powder; Tableting: compressing the total mixed powder into tablets to obtain tablet cores; The step b specifically includes: Coating: Coating the core tablets to obtain the dacomitinib pharmaceutical composition.

10. Use of lactose in preparing a pharmaceutical composition containing dacomitinib, characterized in that: The average particle size D50 of the lactose is greater than or equal to 120 μm.

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