WO2022184113A1 - Pharmaceutical composition comprising pyridopyrimidine derivative, and preparation method therefor - Google Patents

Abstract

A pharmaceutical composition comprising a pyridopyrimidine derivative as represented by formula (I), and a preparation method therefor. The pharmaceutical composition contains a compound of formula (I) or a pharmaceutically acceptable salt thereof and pregelatinized starch, and the composition has good mixing uniformity, fluidity and compressibility, and is suitable for industrial production.

Description

A kind of pharmaceutical composition comprising pyridopyrimidine derivatives and preparation method thereof technical field

The present disclosure belongs to the field of pharmaceutical preparations, and in particular relates to a pharmaceutical composition comprising pyridopyrimidine derivatives and a preparation method thereof.

Background technique

Toll-like receptors (toll-like receptors; TLRs) are an important class of receptors involved in innate immunity. TLRs are monomeric, transmembrane, non-catalytic receptors that are typically expressed in sentinel cells such as macrophages and dendritic cells and can recognize structurally conserved molecules produced by microorganisms. Once these microbes breach physical barriers such as the skin or intestinal mucosa, they are recognized by TLRs, which in turn activate immune cell responses (Mahla, R S. et al., Front Immunol. 4:248 (2013)). The ability of the immune system to broadly recognize pathogenic microorganisms is partly due to the widespread presence of Toll-like immune receptors.

There are at least 10 different TLRs in mammals. Ligands and corresponding signaling cascades for some of these receptors have been identified. TLR8 is a member of a subgroup of TLRs (TLRs 3, 7, 8, and 9), restricted to the endosomal compartment of cells that specialize in recognizing non-hexogenic nucleic acids. TLR8 is mainly expressed in humans by monocytes, NK cells and myeloid dendritic cells (mDCs). TLR8 agonists can lead to the release of various pro-inflammatory cytokines, such as IL-6, IL-12, TNF-α and IFN-γ.

At present, the research on oral small-molecule TLR8 agonists is relatively limited. Among them, Gilead's selgantolimod, which has progressed faster, has launched clinical phase II for the treatment of hepatitis B virus infection.

WO2020007275A discloses a novel pyridopyrimidine derivative whose structure is shown in formula (I). The compound showed strong TLR8 agonism and improved in clinical efficacy and safety.

SUMMARY OF THE INVENTION

The purpose of the present disclosure is to provide a pharmaceutical composition with good mixing uniformity, particle fluidity and compressibility, and a simple preparation process, which is suitable for large-scale industrial production.

The present disclosure provides a pharmaceutical composition comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and pregelatinized starch.

In some embodiments, the pharmaceutical composition further contains a filler selected from one or more of lactose, microcrystalline cellulose, mannitol, calcium hydrogen phosphate and sucrose, preferably lactose, microcrystalline cellulose and mannitol, most preferably lactose.

In some embodiments, the weight ratio of filler and pregelatinized starch is 10:1-1:1, preferably 9:1-2:1, non-limiting examples include: 9:1, 8:1 , 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, or any value in between.

In some embodiments, the content of the pregelatinized starch is 5%-45% based on the total weight of the composition, preferably 5%-35%, more preferably 10%-30%, non-limiting examples include: 10 %, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, or anything in between.

In some embodiments, the content of the filler is 50%-90% based on the total weight of the composition, preferably 60%-88%, non-limiting examples include: 60%, 61%, 62%, 63% , 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80 %, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, or any value in between.

In some embodiments, the pharmaceutical composition further comprises a disintegrant.

In some embodiments, the disintegrant is selected from one or more of croscarmellose sodium, starch, sodium carboxymethyl starch and crospovidone, preferably croscarmellose Sodium.

In some embodiments, the disintegrant is present in an amount of 1% to 10% based on the total weight of the composition.

In some embodiments, the pharmaceutical composition further comprises a lubricant.

In some embodiments, the lubricant is selected from one or more of talc, micronized silica gel and magnesium stearate, preferably talc and/or magnesium stearate.

In some embodiments, the lubricant is present in an amount of 0.01% to 10% based on the total weight of the composition.

In some embodiments, the active drug is present in an amount of 0.01%-10.0%, preferably 0.05%-5.0%, based on the total weight of the composition.

The present disclosure also provides a pharmaceutical composition, comprising:

1) 0.05-5.0 wt% of a compound of formula (I) or a pharmaceutically acceptable salt thereof;

2) 10-30wt% of pregelatinized starch;

3) 60-88wt% lactose;

4) 1-10wt% disintegrant, which is selected from one or more of croscarmellose sodium, starch, sodium carboxymethyl starch and crospovidone;

5) 0.01-10wt% lubricant, the lubricant is selected from one or more of talc, micropowder silica gel and magnesium stearate;

Wherein, the weight ratio of the lactose and pregelatinized starch is 10:1-1:1, preferably 9:1-2:1.

Further, the pharmaceutical compositions described in the present disclosure are solid preparations, including tablets, pills or granules, preferably tablets.

The pharmaceutical composition in the present disclosure can be prepared by methods common in the art, including the steps of mixing the compound represented by formula (I) or a pharmaceutically acceptable salt thereof with a filler, and further including wet granulation and dry granulation of the mixture. , the step of direct pressing of the powder, preferably dry granulation.

In another aspect, the present disclosure also provides the use of the aforementioned pharmaceutical composition in the preparation of a medicament for treating infection caused by a virus, preferably hepatitis B virus, hepatitis C virus, influenza virus, herpes virus and HIV.

Further, the present disclosure also provides the use of the aforementioned pharmaceutical composition in the preparation of a medicament for regulating the immune system.

Further, the present disclosure also provides the use of the aforementioned pharmaceutical composition in the preparation of a medicament for the treatment or prevention of tumors, wherein the tumor is selected from cancer, preferably selected from melanoma, lung cancer, liver cancer, basal cell carcinoma, kidney cancer, Myeloma, biliary tract cancer, brain cancer, breast cancer, cervical cancer, choriocarcinoma, colon cancer, rectal cancer, head and neck cancer, peritoneal tumor, fallopian tube cancer, endometrial cancer, esophageal cancer, gastric cancer, leukemia, lymphoma, sarcoma , neuroblastoma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, testicular cancer, skin cancer and thyroid cancer.

The present disclosure prepares a pharmaceutical composition by using pregelatinized starch and lactose as fillers, which can help disperse active ingredients with low dosage and small particle size, and the prepared material particles have good mixing uniformity and fluidity, and can be compressible. meet the actual production needs.

Description of drawings

Figure 1 is a pressure-hardness curve.

Detailed ways

The present disclosure is further illustrated in detail by the following examples. These examples are for illustrative purposes only and are not intended to limit the scope of the present disclosure.

Example 1

The compound of formula (I) was premixed with lactose, pregelatinized starch, microcrystalline cellulose and mannitol respectively according to the proportions in Table 1, passed through a 60-mesh sieve, and then mixed in a mixer. After mixing, samples were taken from different positions of the hopper to check the mixing uniformity.

Table 1

component	prescription 1	prescription 2	prescription 3	prescription 4
Compounds of formula (I)	0.8%	0.8%	0.8%	0.8%
lactose	/	99.2%	/	/
pregelatinized starch	99.2%	/	/	/
microcrystalline cellulose	/	/	99.2%	/
Mannitol	/	/	/	99.2%
total	100.0%	100.0%	100.0%	100.0%

Mixing uniformity results:

Table 2

From the results of mixing uniformity, the pregelatinized starch group has the highest content, the best dispersibility of active ingredients, and the best mixing uniformity.

Example 2:

Compound of formula (I), pregelatinized starch, lactose, microcrystalline cellulose, mannitol, croscarmellose sodium are premixed according to the composition and ratio in Table 3, and the premix is placed in a mixer Mixing in the middle, adding part of magnesium stearate and continuing to mix, carrying out dry granulation of the mixed material, adding the remaining amount of magnesium stearate after adjusting the particle size for total mixing to obtain pharmaceutical compositions of different filler formulations, sampling and testing Mixing uniformity, bulk density and particle size distribution of the blended particles, and finally the blended material is pressed into tablets.

table 3

Components (wt%)	Composition 1	Composition 2	Composition 3
Compounds of formula (I)	0.3125	0.3125	0.3125
pregelatinized starch	20	20	20
lactose	77.2875	/	/
microcrystalline cellulose	/	77.2875	/
Mannitol	/	/	77.2875
Croscarmellose sodium	2	2	2
Magnesium stearate	0.40	0.40	0.40
total	100	100	100

Experimental results:

1) Mixing uniformity after blending

Table 4

2) Bulk density after blending

table 5

project	Composition 1	Composition 2	Composition 3
Initial volume (ml)	53.0	56.0	61.0
Tap volume (ml)	41.0	41.0	45.0
Weight (g)	34.6847	34.0604	24.6197
Bulk density (g/cm 3 )	0.6544	0.6082	0.4036
Tap density (g/cm 3 )	0.8460	0.8307	0.5471
Carr Index	22.6%	26.8%	26.2%
Hausenby	1.29	1.37	1.36

3) Particle size distribution after blending

Table 6

Screen aperture (μm)	800	560	315	112	63	<63
Composition 1 (%)	0.20	4.82	24.99	43.49	16.68	9.82
Composition 2 (%)	0.16	1.39	14.12	49.84	16.17	18.32
Composition 3 (%)	0.05	2.48	13.81	39.23	23.07	21.36

According to the results of mixing uniformity, it can be seen that the mixing uniformity of each recipe has little difference; according to the bulk density and particle size distribution results, the fine powder content of composition 2 and composition 3 is higher than that of composition 1, and the fluidity is worse than that of composition 1 , and during the tableting process, composition 3 caused sticking phenomenon due to too much fine powder.

Example 3

The components were prepared according to the proportions in Table 7, and the pharmaceutical composition was prepared by the same method as in Example 2, and the mixing uniformity of the granules after blending was tested.

Table 7

Components (wt%)	Composition 4 *	Composition 5	Composition 6
Compounds of formula (I)	0.3125	0.3125	0.3125
pregelatinized starch	20	/	/
lactose	77.2875	77.2875	/
microcrystalline cellulose	/	20	20
Mannitol	/	/	77.2875
Croscarmellose sodium	2	2	2
Magnesium stearate	0.40	0.40	0.40
total	100	100	100

*

Composition 4 and Composition 1 are different batches of the same formulation.

Mixing uniformity:

Table 8

From the results of mixing uniformity, it can be concluded that the mixing uniformity of composition 4 is better, while the mixing uniformity of composition 5 and composition 6 is obviously poor.

Example 4

The components were prepared according to the proportions in Table 9, and the pharmaceutical composition was prepared by the same method as in Example 2, and the mixing uniformity of the materials after the total mixing was investigated. In addition, the prepared pharmaceutical composition was compressed into tablets, and the hardness of the tablets was examined with a hardness tester, and a pressure-hardness curve was drawn according to the results (Fig. 1).

Table 9

Components (wt%)	Composition 7	Composition 1	Composition 8	Composition 9	Composition 10
Compounds of formula (I)	0.3125	0.3125	0.3125	0.3125	0.3125
pregelatinized starch	10	20	30	50	70
lactose	87.2875	77.2875	67.2875	47.2875	27.2875
Croscarmellose sodium	2	2	2	2	2
Magnesium stearate	0.4	0.4	0.4	0.4	0.4
total	100	100	100	100	100

Mixing uniformity:

Table 10

2	94.91	97.06	96.90	102.43	97.44
3	94.24	96.16	97.73	103.81	99.04
4	93.73	96.99	97.34	103.55	98.72
5	95.07	97.02	97.57	104.10	99.97
average value(%)	94.8	96.4	97.5	103.3	98.6
RSD(%)	1.0	1.1	0.4	0.8	1.1

It can be seen from the results of mixing uniformity that there is no significant difference in the mixing uniformity of each recipe; it can be seen from the pressure-hardness curve (Fig. 1) that the maximum hardness of compositions 1, 7 and 8 all exceeds 40N.

Claims (18)

1. A pharmaceutical composition comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and pregelatinized starch,

   
2. The pharmaceutical composition according to claim 1, further comprising a filler selected from one or more of lactose, microcrystalline cellulose, mannitol, calcium hydrogen phosphate and sucrose, preferably lactose, microcrystalline Crystalline cellulose and mannitol, most preferably lactose.
3. The pharmaceutical composition of claim 2, wherein the weight ratio of the filler to the pregelatinized starch is 10:1-1:1, preferably 9:1-2:1.
4. The pharmaceutical composition according to any one of claims 1-3, wherein the content of the pregelatinized starch is 5%-45%, preferably 5%-35%, more preferably 10%- 30%.
5. The pharmaceutical composition according to any one of claims 2-4, wherein the content of the filler is 50%-90%, preferably 60%-88%, based on the total weight of the composition.
6. The pharmaceutical composition of any one of claims 1-5, further comprising a disintegrant.
7. The pharmaceutical composition of claim 6, wherein the disintegrant is selected from one or more of croscarmellose sodium, starch, sodium carboxymethyl starch and crospovidone, preferably Croscarmellose sodium.
8. The pharmaceutical composition of claim 6, wherein the disintegrant is present in an amount of 1% to 10% based on the total weight of the composition.
9. The pharmaceutical composition of any one of claims 1-8, further comprising a lubricant.
10. The pharmaceutical composition of claim 9, wherein the lubricant is selected from one or more of talc, micropowder silica gel and magnesium stearate, preferably talc and/or magnesium stearate.
11. The pharmaceutical composition of claim 10, wherein the content of the lubricant is 0.01%-10% based on the total weight of the composition.
12. The pharmaceutical composition according to any one of claims 1-11, wherein the content of the active drug is 0.01%-10.0%, preferably 0.05%-5.0%, based on the total weight of the composition.
13. A pharmaceutical composition comprising:

    1) 0.05-5.0 wt% of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof;

    2) 10-30wt% of pregelatinized starch;

    3) 60-88wt% lactose;

    4) 1-10wt% disintegrant, which is selected from one or more of croscarmellose sodium, starch, sodium carboxymethyl starch and crospovidone;

    5) 0.01-10wt% lubricant, the lubricant is selected from one or more of talc, micropowder silica gel and magnesium stearate;

    Wherein, the weight ratio of the lactose and pregelatinized starch is 10:1-1:1, preferably 9:1-2:1.
14. The pharmaceutical composition of any one of claims 1-13 in the form of tablets, granules or pills, preferably tablets.
15. A method for preparing the pharmaceutical composition according to any one of claims 1-14, comprising the step of mixing a compound shown in formula (I) or a pharmaceutically acceptable salt thereof with a filler, further comprising mixing the mixture by wet method The steps of granulation, dry granulation, and direct powder compression are preferably dry granulation.
16. Use of the pharmaceutical composition according to any one of claims 1-14 in the preparation of a medicament for treating infection caused by a virus, preferably hepatitis B virus, hepatitis C virus, influenza virus, herpes virus and HIV.
17. Use of the pharmaceutical composition of any one of claims 1-14 in the manufacture of a medicament for regulating the immune system.
18. Use of the pharmaceutical composition according to any one of claims 1-14 in the preparation of a medicament for the treatment or prevention of tumors, wherein the tumor is selected from cancer, preferably selected from melanoma, lung cancer, liver cancer, basal cell carcinoma, Kidney cancer, myeloma, biliary tract cancer, brain cancer, breast cancer, cervical cancer, choriocarcinoma, colon cancer, rectal cancer, head and neck cancer, peritoneal tumor, fallopian tube cancer, endometrial cancer, esophagus cancer, stomach cancer, leukemia, lymphatic tumor, sarcoma, neuroblastoma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, testicular cancer, skin cancer and thyroid cancer.

Images