A drug composition of danocizumab and a preparation method thereof

Abstract

This invention belongs to the field of pharmaceutical formulations, specifically relating to a dacomitinib pharmaceutical composition and its preparation method. The dacomitinib pharmaceutical composition, by weight, comprises 10-30 parts dacomitinib, 25-60 parts lactose, 25-60 parts microcrystalline cellulose, 1-15 parts sodium carboxymethyl starch, and 0.5-5 parts magnesium stearate. The average particle size D50 of the lactose is greater than or equal to 120 µm. The dacomitinib composition of this invention exhibits high dissolution, rapid disintegration, good flowability, avoids sticking and bubbling, and has good dissolution stability. The preparation process is simple.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, specifically relating to a dacomitinib pharmaceutical composition and its preparation method. Background Technology

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

[0003] In dacomitinib drug compositions, different particle sizes of the active pharmaceutical ingredient (API) can affect the stability of the finished product, such as dissolution. Currently, to ensure the stability of the finished dacomitinib drug composition, including dissolution, it is necessary to pre-screen and treat the API by particle size, which involves complex manufacturing processes.

[0004] For example, CN114099455A discloses a dacomitinib drug composition containing dacomitinib, a filler, a disintegrant, and a lubricant. This patent describes a process where dacomitinib, the filler, and the disintegrant are mixed uniformly, then dry-granulated using a sieve, tableted, and coated to obtain the dacomitinib drug composition. However, this production process requires pre-sieving the mixture of dacomitinib, the filler, and the disintegrant before dry granulation, making the preparation process complex. Furthermore, the stability of the resulting dacomitinib drug composition, such as its dissolution rate, varies. Summary of the Invention

[0005] This invention provides a dacomitinib pharmaceutical composition and its preparation method. The dacomitinib composition has high dissolution, rapid disintegration, good fluidity, good dissolution stability, and a simple preparation process.

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

[0007] In some embodiments, 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 carboxymethyl starch, and 0.5-2 parts of magnesium stearate.

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

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

[0010] In some embodiments, the dacomitinib pharmaceutical composition comprises 15 parts dacomitinib, 42.5 parts lactose, 39.2 parts microcrystalline cellulose, 2 parts sodium carboxymethyl starch, and 0.7 parts 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 implementations, the particle size D90 of dacomitinib is 5~100µm.

[0013] In some embodiments, the dacomitinib pharmaceutical composition is in the form of tablets.

[0014] In some embodiments, the tablet includes a tablet core and a film coating;

[0015] By weight, the tablet core components include 10-30 parts of dacomitinib, 25-60 parts of lactose, 25-60 parts of microcrystalline cellulose, 1-15 parts of sodium carboxymethyl starch, and 0.5-5 parts of magnesium stearate;

[0016] The film coating component includes 1 to 5 parts of film coating premix.

[0017] The present invention also provides a method for preparing a dacomitinib pharmaceutical composition, comprising the following steps:

[0018] a. Mix the raw materials and compress them into tablets to obtain tablet cores;

[0019] b. Coating the film core.

[0020] In some implementations, step a specifically includes:

[0021] Premix: Dacomitinib, lactose, microcrystalline cellulose, and sodium carboxymethyl starch are premixed to obtain a premixed powder;

[0022] Total Mixture: The premixed powder is mixed with magnesium stearate to obtain a total mixed powder;

[0023] Tableting: The total powder mixture is compressed into tablets to obtain tablet cores;

[0024] Step b specifically includes:

[0025] Coating: The tablet core is coated to obtain the dacomitinib drug composition.

[0026] In some embodiments, the premixing includes adding microcrystalline cellulose, dacomitinib, sodium carboxymethyl starch, and lactose into a mixing hopper, mixing at a speed of 5-15 rpm for 5-15 minutes to obtain a premixed powder.

[0027] In some embodiments, the premixing includes adding microcrystalline cellulose, dacomitinib, sodium carboxymethyl starch, and lactose into a mixing hopper, mixing at 10 rpm for 12 minutes to obtain a premixed powder.

[0028] In some embodiments, the total mixing includes: mixing magnesium stearate and premixed powder in a mixing hopper at a speed of 5-15 rpm for 5-15 min to obtain a total mixed powder.

[0029] In some embodiments, the total mixing includes: mixing magnesium stearate and premixed powder in a mixing hopper at a speed of 10 rpm for 8 minutes to obtain a total mixed powder.

[0030] In some embodiments, the tableting process includes: taking a circular die and installing it onto a tableting machine, pressing the total mixed powder into tablets, controlling the tablet weight difference limit to ±7.5%, and the hardness range to 30~80N, to obtain a tablet core.

[0031] In some embodiments, the coating process includes: adding a film coating premix to water under stirring, continuously stirring until the mixture is homogeneous to obtain a coating solution for later use; placing tablet cores in a coating pan for coating, controlling the coating weight gain to be between 2% and 4%.

[0032] In some embodiments, the film coating premix is ​​a gastrointestinal soluble coating premix.

[0033] The present invention also provides the use of lactose in the preparation of pharmaceutical compositions containing dacomitinib, wherein the average particle size D50 of the lactose is greater than or equal to 120 µm.

[0034] The dacomitinib composition of the present invention ensures high dissolution, rapid disintegration, and good flowability, thus avoiding sticking. Furthermore, the dacomitinib compositions prepared from dacomitinib raw materials of different particle sizes exhibit good dissolution stability.

[0035] Based on the optimized formulation, this invention allows for the direct mixing of dacomitinib raw material and excipients for tableting, eliminating the need for pre-screening of the raw material and dry granulation of the raw material and excipient powder before tableting. The preparation process is simple, the production cost is low, and it is suitable for large-scale production. Detailed Implementation

[0036] The present invention will be further described in detail below with reference to the embodiments, but this is not intended to limit the present invention. Any equivalent substitutions made in the art based on the disclosure of the present invention shall fall within the protection scope of the present invention.

[0037] In this application, the terms “comprising,” “including,” and “containing,” and their equivalents, shall be understood in an open, non-exclusive sense, meaning “including but not limited to,” implying that in addition to the listed elements, components, and steps, other unspecified elements, components, and steps may also be covered. In this document, unless the context clearly specifies otherwise, singular terms shall cover plural references, and vice versa.

[0038] The term "pharmaceutically acceptable" means that a carrier, delivery substance, diluent, excipient, and / or the salt formed therefrom is generally chemically or physically compatible with the other components constituting a drug dosage form and physiologically compatible with the receptor, without excessive toxicity, irritation, allergic reactions or other problems or complications, and is commensurate with a reasonable benefit / risk ratio.

[0039] The term "treatment" means administering the compound or preparation described in this application to improve or eliminate a disease or one or more symptoms associated with the disease, including inhibiting the progression of the disease or condition and alleviating the disease or condition.

[0040] In this application, D50 refers to the particle size value corresponding to 50% of the cumulative particle size distribution of the sample, indicating that particles with a size greater than and less than this value each account for 50%, also known as median diameter, median particle size, or average particle size. D90 refers to the particle size value corresponding to 90% of the cumulative particle size distribution of the sample, that is, 90% of the particles have a size less than or equal to this value.

[0041] 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).

[0042] In this application, portions may be expressed in milligrams.

[0043] In this application, the pharmaceutical excipients or reagents involved may be derived from commercial sources.

[0044] In this application, unless otherwise specified, "%" in the embodiments of this application refers to the mass percentage.

[0045] Example 1

[0046] The amounts of each raw material used in Example 1 are shown in Table 1. The preparation method of Example 1 is as follows.

[0047] Example 1: Preparation method of dacomitinib tablets

[0048] Batch size: 200,000 pieces / batch

[0049] Premix: Add microcrystalline cellulose, dacomitinib, sodium carboxymethyl starch and lactose into the mixing hopper, mix at 10 rpm for 12 min to obtain premixed powder.

[0050] Total mixing: Magnesium stearate and premixed powder are mixed in a mixing hopper at 10 rpm for 8 minutes to obtain total mixed powder.

[0051] Tableting: The total powder mixture is compressed into tablets to obtain tablet cores.

[0052] Take the circular die and install it on the tablet press to compress the total powder mixture into tablets. Control the tablet weight difference limit to ±7.5% and the hardness range to 30~80N to obtain the tablet core.

[0053] Coating: The tablet core is coated to obtain the dacomitinib drug composition.

[0054] Add the film coating premix to the water being stirred, and continue stirring until the mixture is homogeneous to obtain the coating solution, which is then set aside. Place the tablet cores in a coating pan for coating, controlling the coating weight gain to be between 2% and 4%. The film coating premix is ​​a stomach-soluble premix, comprising hydroxypropyl methylcellulose, polyethylene glycol, and titanium dioxide.

[0055] Table 1 Tablet Prescriptions

[0056]

[0057] 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 with an average particle size D50 of 133 µm.

[0058] Example 2-3

[0059] The only difference between Examples 2-3 and Example 1 is the average particle size of lactose. The average particle size of lactose in Examples 2-3 is shown in Table 2. The preparation method is the same as that in Example 1.

[0060] Table 2 Average particle size of lactose

[0061]

[0062] Examples 4-9

[0063] The only difference between Examples 4-9 and Example 1 is the amount of excipients (lactose, microcrystalline cellulose, sodium carboxymethyl starch, magnesium stearate). The amount of each excipient in each example is shown in Table 3. The preparation method is the same as that in Example 1.

[0064] Table 3 Tablet Prescriptions

[0065]

[0066] Examples 10-13

[0067] The only difference between Examples 10-13 and Example 1 is the amount of raw materials (lactose and sodium carboxymethyl starch). The amount of each raw material in each example is shown in Table 4. The preparation method is the same as that in Example 1.

[0068] Table 4 Tablet Prescriptions

[0069]

[0070] Examples 14-18

[0071] The only difference between Examples 14-18 and Example 1 is the particle size of dacomitinib. The particle size of dacomitinib in each example is shown in Table 5. The preparation method is the same as that in Example 1.

[0072] Table 5. Dacomitinib particle size

[0073]

[0074] Comparative Example 1

[0075] Reference formulation: Dacomitinib tablets (Duozerun).

[0076] Comparative Examples 2-3

[0077] Comparative example of average particle size of lactose

[0078] 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 is the same as that in Example 1.

[0079] Table 6 Average particle size of lactose

[0080]

[0081] Comparative Example 4-5

[0082] Comparative example of dacomitinib particle size

[0083] The only difference between Comparative Examples 4-5 and Comparative Example 3 is the particle size of dacomitinib. The particle size of dacomitinib in each comparative example is shown in Table 7. The preparation method is the same as that in Example 1.

[0084] Table 7 Dacomitinib Particle Size

[0085]

[0086] Example of effect

[0087] The overall powder flowability, core dissolution rate, and core disintegration time of the reference samples were examined.

[0088] 1. Sample:

[0089] Dacomitinib tablets prepared according to Examples 1-18 of this invention;

[0090] The reference formulation of Comparative Example 1, and the dacomitinib tablets prepared in Comparative Examples 2-5.

[0091] 2. Method:

[0092] 2.1. Methods for determining fluidity

[0093] Methods for determining flowability: Loose density and tapped density are determined using a powder density meter. The flowability is evaluated using the Hausner ratio, which is calculated as: Hausner ratio = loose density / tapped density.

[0094] 2.2. Dissolution test method

[0095] Dissolution test method: use hydrochloric acid buffer as dissolution medium, rotate at 50 revolutions per minute, and take samples after 15 minutes.

[0096] Determination method: High performance liquid chromatography (HPLC) was used for detection.

[0097] 2.3. Method for determining disintegration time

[0098] Disintegration time test method: Refer to the disintegration time limit test method in General Chapter 0921 of Part III of the Chinese Pharmacopoeia 2020. Take the test sample and place it in the glass tube of the disintegration time limit tester. The tablets should disintegrate completely within 15 minutes.

[0099] 2.4. Method for determining adhesion grade

[0100] Judging by the appearance of the chip core.

[0101] 3. The results of the investigation are shown in Table 8.

[0102] Table 8 Results of the study on the flowability of the mixed powder, the dissolution rate of the tablet core, the disintegration time of the tablet core, and the stickiness grade.

[0103]

[0104] As can be seen from Examples 1-18, the dacomitinib drug composition used in this invention has high dissolution, rapid disintegration, good fluidity, can avoid sticking, and has good dissolution stability.

[0105] As can be seen from Examples 1-18 and Comparative Example 1, the dissolution rate of the dacomitinib drug composition used in this invention is above 96.8%, and the disintegration time of the tablet core is within 5 minutes. In contrast, the dissolution rate of the reference formulation is 96.5%, and the disintegration time of the tablet core is 6 minutes. It is evident that the dacomitinib drug composition used in this invention has a higher dissolution rate and faster disintegration than the reference formulation.

[0106] As shown in Examples 1-3 and Comparative Examples 2-3, the dacomitinib drug composition (lactose D50 ≥ 120µm) used in this invention has a powder flowability below 1.36, a tablet core dissolution rate above 96.8%, and exhibits no or virtually no sticking. In contrast, the dacomitinib drug composition (lactose D50 < 120µm) used in Comparative Examples 2-3 has a powder flowability above 1.49, a tablet core dissolution rate below 81.5%, and exhibits sticking. Therefore, the use of larger particle size lactose (lactose D50 ≥ 120µm) in the dacomitinib drug composition used in this invention results in better powder flowability, higher dissolution, and improves and avoids sticking. In particular, the dacomitinib drug composition (lactose D50 ≥ 130µm) used in Examples 1 and 3 exhibited a powder mixing flowability below 1.17, a tablet core dissolution rate above 99.6%, and no sticking. This demonstrates that using larger particle size lactose (lactose D50 ≥ 130µm) in this invention can further improve the powder mixing flowability, dissolution, and prevent sticking. Clearly, in the dacomitinib drug composition, lactose particle size has a significant impact on powder mixing flowability, dissolution, and sticking. The dacomitinib drug composition (lactose D50 ≥ 120µm) used in this invention can improve dissolution, while simultaneously improving powder mixing flowability and preventing sticking.

[0107] As shown in Examples 1, 14-18, and Comparative Examples 3-5, the dissolution rates of the dacomitinib compositions (lactose D50 ≥ 120 µm) prepared using raw materials (dacomitinib) of different particle sizes in this invention are between 98.8% and 99.6%. This indicates that the dacomitinib compositions prepared using dacomitinib raw materials of different particle sizes in this invention have similar dissolution rates and high dissolution stability. However, the dacomitinib drug compositions (lactose D50 < 120 µm) used in Comparative Examples 3-5, when prepared using dacomitinib raw materials of different particle sizes, have dissolution rates of 81.5%, 90.8%, and 83.5%, respectively. This shows that the dissolution rates of the dacomitinib drug compositions (lactose D50 < 120 µm) prepared using dacomitinib raw materials of different particle sizes vary greatly. Therefore, the dacomitinib pharmaceutical composition used in this invention employs lactose with a larger particle size (lactose D50 ≥ 120µm), resulting in good dissolution when using dacomitinib raw materials of different particle sizes. This ensures that the dissolution of the dacomitinib composition is not affected by the particle size of the dacomitinib raw material. Thus, this invention eliminates the need for pre-screening and processing of the active pharmaceutical ingredient to obtain a dacomitinib pharmaceutical composition with stable dissolution, simplifying the production process.

[0108] As shown in Examples 1 and 4-9, lactose, microcrystalline cellulose, sodium carboxymethyl starch, and magnesium stearate in the dacomitinib pharmaceutical composition used in this invention all affect the flowability of the total powder, tablet core dissolution, tablet core disintegration time, and sticking / crushing. In particular, as shown in Examples 1 and 6-7, when the excipient amounts are 40-44 parts lactose, 38-42 parts microcrystalline cellulose, 1.5-2.5 parts sodium carboxymethyl starch, and 0.5-1 parts magnesium stearate, they have a significant positive impact on the flowability of the total powder, tablet core dissolution, tablet core disintegration time, and sticking / crushing. The dacomitinib pharmaceutical composition used in Example 1 (42.5 parts lactose, 39.2 parts microcrystalline cellulose, 2 parts sodium carboxymethyl starch, and 0.7 parts magnesium stearate) exhibits the best flowability of the total powder, tablet core dissolution, tablet core disintegration time, and sticking / crushing prevention effect.

[0109] As shown in Examples 1 and 10-13, the amount of sodium carboxymethyl starch in the dacomitinib pharmaceutical composition used in this invention has a significant impact on the dissolution rate of the tablet core. Especially in Example 13, when the amount of sodium carboxymethyl starch was greater than 2 parts, the dissolution rate of the tablet core decreased significantly. Therefore, when the amount of sodium carboxymethyl starch in the dacomitinib pharmaceutical composition used in this invention is no more than 2 parts, the tablet core disintegration time is better, and the tablet core dissolution rate is also excellent. The dacomitinib pharmaceutical composition used in Example 1 (42.5 parts lactose, 39.2 parts microcrystalline cellulose, 2 parts sodium carboxymethyl starch, and 0.7 parts magnesium stearate) showed good tablet core disintegration time and optimal tablet core dissolution rate.

[0110] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Various modifications and improvements made by those skilled in the art to the technical solutions of the present invention without departing from the spirit of the present invention should fall within the protection scope defined by the claims of the present invention.

Claims

1. A danoclintide pharmaceutical composition, characterized in that, The dasatinib pharmaceutical composition includes, in parts by weight, dasatinib 10-20 parts, lactose 30-50 parts, microcrystalline cellulose 30-50 parts, sodium carboxymethyl starch 1-5 parts, and magnesium stearate 0.5-2 parts, the average particle size D50 of the lactose is greater than or equal to 120 μm, the dasatinib pharmaceutical composition is a tablet, the tablet is obtained by directly compressing the mixture of dasatinib raw material and excipients, and the lactose is selected from 100、SuperTab 24AN or 90.

2. The danoclintib pharmaceutical composition of claim 1, wherein, The drug composition of the present application comprises 10-20 parts by weight of dasatinib, 30-50 parts by weight of lactose, 30-50 parts by weight of microcrystalline cellulose, 1-5 parts by weight of sodium carboxymethyl starch, and 0.5-2 parts by weight of magnesium stearate.

3. The danoclintib pharmaceutical composition of claim 2, wherein, The drug composition of the present application comprises 10-20 parts by weight of dasatinib, 30-50 parts by weight of lactose, 30-50 parts by weight of microcrystalline cellulose, 1-5 parts by weight of sodium carboxymethyl starch, and 0.5-2 parts by weight of magnesium stearate.

4. The danoclintib pharmaceutical composition of claim 1 or 2, wherein, The average particle size D50 of the lactose is greater than or equal to 130 μm.

5. The danociznib pharmaceutical composition of claim 1, wherein, The tablet comprises a tablet core and a film coating; The drug composition of the present application comprises 10-20 parts by weight of dasatinib, 30-50 parts by weight of lactose, 30-50 parts by weight of microcrystalline cellulose, 1-5 parts by weight of sodium carboxymethyl starch, and 0.5-2 parts by weight of magnesium stearate. The film coating component comprises 1-5 parts by weight of a film coating premix.

6. A method of preparing the danocizumab pharmaceutical composition according to any one of claims 1 to 5, characterized in that, The method comprises the following steps: a. mixing the raw materials and tabletting to obtain a tablet core; b. coating the tablet core.

7. The method of claim 6, wherein, The step a specifically comprises: Premixing: premixing dasatinib, lactose, microcrystalline cellulose, and sodium carboxymethyl starch to obtain a premixed powder; Total mixing: mixing the premixed powder with magnesium stearate to obtain a total mixed powder; Tabletting: tabletting the total mixed powder to obtain a tablet core; The step b specifically comprises: Coating: coating the tablet core to obtain the drug composition of dasatinib.

8. Use of lactose for the manufacture of a pharmaceutical composition containing dacomitinib, characterized in that, The average particle size D50 of the lactose is greater than or equal to 120 pm, the drug composition of dasatinib is a tablet, the tablet is obtained by directly compressing the mixture of dasatinib raw material and excipients, and the lactose is selected from 100. SuperTab 24AN or 90.

Images