Pharmaceutical composition of pyridazine derivative type inhibitor and preparation method therefor

Abstract

A pharmaceutical composition of a pyridazine derivative type inhibitor and a preparation method therefor. Specifically provided are a pharmaceutical composition, comprising a compound of formula (I) or an isomer, solvate, hydrate or pharmaceutically acceptable salt thereof or a combination thereof as an active ingredient, and at least one pharmaceutically acceptable excipient, and a preparation method for the pharmaceutical composition. The pharmaceutical composition is used for treating psoriasis and psoriatic arthritis.

Description

Pharmaceutical composition of pyridazine derivative inhibitor and preparation method thereof TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical composition, and particularly relates to a pharmaceutical composition of pyridazine derivative inhibitor and a preparation method thereof. BACKGROUND

[0002] Janus kinase (JAK) is an intracellular non-receptor tyrosine kinase that mediates the signal transduction and activation of various cytokines. The JAK kinase family is divided into four subtypes, JAK1, JAK2, JAK3 and TYK2, each of which mediates different types of cytokine signaling pathways. JAK-1, JAK-2 and TYK-2 are expressed in various tissues of the human body, and JAK-3 is mainly expressed in hematopoietic cells. The common feature of cytokine receptors is that the receptor itself does not have kinase activity, but the intracellular segment of the receptor has a binding site for tyrosine kinase JAK. When the cytokine receptor binds to its ligand, the receptor-coupled JAKs are activated, and then the receptor is phosphorylated. The phosphorylated tyrosine site can bind to STAT protein containing SH2 domain, thereby recruiting STAT to the receptor and phosphorylating it through JAKs. Subsequently, the phosphorylated tyrosine mediates STAT dimerization, and the activated STAT dimer moves to the nucleus and activates the transcription of its target genes, thereby regulating various functions of cells such as growth, activation, differentiation, etc.

[0003] TYK2 is the first subtype of the JAK family to be discovered, and it mediates the functions of cytokines such as IFN-alpha, IL-6, IL-10, IL-12 and IL-23. Studies have shown that TYK2 deletion mutations can effectively inhibit the occurrence of immune diseases such as allergy, autoimmunity and inflammation. IL-23 plays a crucial role in the development of psoriasis. Recent studies have shown that the pathogenesis of psoriasis is that endogenous unknown antigens activate antigen-presenting cells (APCs) to secrete IL-23, which activates Th17 cells to secrete cytokines such as IL-17, inducing keratinocyte differentiation and division and secreting IL-23, further stimulating inflammation and keratinocyte proliferation to produce psoriasis. TYK2 and JAK2 jointly mediate the downstream signaling pathway of IL-23, and inhibition of JAK2 can lead to anemia and other blood-related side effects, so targeting TYK2 is a good strategy for inhibiting the IL-23 signaling pathway to treat psoriasis.

[0004] The early TYK2 inhibitors such as Tofacitinib and the like belong to JAK non-selective inhibitors, and are the first oral JAK inhibitors, which have significant inhibitory activity on JAK1, 2 and 3 subtypes. The increased inhibitory activity on other subtypes such as JAK1, JAK2 and JAK3 increases the efficacy of Tofacitinib, but at the same time brings more serious side effects, including infection, tuberculosis, tumor, anemia, liver damage and increased cholesterol, etc. Since the JAK2 activity is related to the differentiation of erythroid cells and the process of lipid metabolism, the above-mentioned adverse reactions such as anemia are considered to be related to the insufficient selectivity of Tofacitinib on JAK-2, which is caused by the non-selective inhibition of the drug. At present, there is no TYK2 selective inhibitor on the market, and the early JAK inhibitors mainly compete with the binding of the kinase domain and ATP to play a role, so there is a general problem of low selectivity.

[0005] The compound of formula (I) is a TYK2 selective inhibitor with higher safety, which has great clinical application potential for the treatment of psoriasis and other inflammatory diseases. A series of pyridazine derivative inhibitors are disclosed in the patent PCT / CN2020 / 073152, but the compound has the characteristics of low solubility, so it is an urgent technical problem to be solved at present to find a pharmaceutical composition with high solubility, stable quality and suitable for clinical application and a preparation method suitable for scale-up production. SUMMARY

[0006] The purpose of the present application is to provide a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which has the characteristics of good stability, fast disintegration rate and high solubility.

[0007] The purpose of the present application is achieved by the following technical solutions:

[0008] A pharmaceutical composition of a compound of formula (I) or its isomers, solvates, hydrates or pharmaceutically acceptable salts thereof, or a combination thereof as an active ingredient, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable excipient.

[0009] In some embodiments of the present application, the active ingredient accounts for 0.1-20% (calculated by the weight of the free base) of the total weight of the pharmaceutical composition; preferably 1-10%; more preferably 1-8%; further preferably 4-8%, for example 5%, 6% or 7%.

[0010] In a preferred embodiment of the present application, the pharmaceutical composition comprises a filler, which is preferably selected from one or more of microcrystalline cellulose, mannitol, sorbitol, calcium hydrogen phosphate, calcium sulfate, dextran, starch, pregelatinized starch, cellulose, lactose, maltose or sucrose, preferably one or more of microcrystalline cellulose, mannitol or lactose;

[0011] Preferably, the filler accounts for 60-99% of the total weight of the pharmaceutical composition, preferably 78-95%, more preferably 84-94%, further preferably 85-90%, for example 86%, 87%, 88% or 89%.

[0012] In a preferred embodiment of the present application, the filler is selected from microcrystalline cellulose and lactose.

[0013] In the present application, the effects of different fillers on the disintegration rate, dissolution rate and process of the formulation prescription are investigated, and the results show that when microcrystalline cellulose and lactose are selected as the fillers, the prescription disintegrates faster, the dissolution result is better, and the granulation process is more controllable.

[0014] In a more preferred embodiment of the present application, the microcrystalline cellulose accounts for 20-60% of the total weight of the pharmaceutical composition, preferably 30-50%, more preferably 40-47%, for example 42%, 43%, 44%, 45% or 46%; and the lactose accounts for 20-50% of the total weight of the pharmaceutical composition, preferably 30-48%, more preferably 40-47%, for example 42%, 43%, 44%, 45% or 46%.

[0015] In a further preferred embodiment of the present application, the ratio of the amount of microcrystalline cellulose to lactose is 1-3:3-1, preferably 1-2:2-1, more preferably 1:1 or 2:1, further preferably 1:1.

[0016] In the present application, the effects of the ratio of the fillers on the disintegration rate, dissolution rate and process of the formulation prescription are investigated, and the results show that when microcrystalline cellulose and lactose are selected as the fillers with a ratio of 1:1 or 2:1, the disintegration is faster, the dissolution result is better, and the granulation and tabletting process is more controllable.

[0017] In a preferred embodiment of the present application, the composition comprises a disintegrant, wherein the disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch or cross-linked povidone, preferably one or more of cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose or cross-linked povidone, more preferably cross-linked sodium carboxymethyl cellulose.

[0018] Preferably, the disintegrant accounts for 0.1-20% of the total weight of the pharmaceutical composition, preferably 3-10%, more preferably 4-8%, further preferably 4-6%, for example 4%, 5% or 6%.

[0019] In the present application, the effects of different disintegrants on the disintegration rate, dissolution rate and process of the preparation formulation are investigated. The results show that when cross-linked sodium carboxymethyl cellulose is selected as the disintegrant, the formulation disintegrates faster, and the dissolution result is better, with a dissolution of more than 85% at 30 min and faster dissolution.

[0020] In a preferred embodiment of the present application, the pharmaceutical composition further comprises a lubricant.

[0021] Preferably, the lubricant is selected from one or more of talc, stearic acid, sodium stearyl fumarate, glyceryl monostearate or magnesium stearate, preferably sodium stearyl fumarate, magnesium stearate or stearic acid;

[0022] More preferably, the lubricant accounts for 0-5% of the total weight of the pharmaceutical composition; preferably 0.5-3%, more preferably 0.5%-1.5%, for example 0.5%, 1.0% or 1.5%.

[0023] In a preferred embodiment of the present application, a pharmaceutical composition of a compound or a pharmaceutically acceptable salt thereof, the weight percentage of each component is as follows:

[0024] Preferably, the weight percentage of each component is as follows:

[0025] More preferably, the weight percentage of each component is as follows:

[0026] Further preferably

[0027] More preferably

[0028] More preferably

[0029] More preferably

[0030] More preferably

[0031] More preferably

[0032] In a preferred embodiment of the present application, a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof, the unit dose of the active ingredient is 0.1-20 mg, preferably 1 mg, 3 mg, 5 mg, 6 mg, 10 mg, 12 mg.

[0033] The pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt of the present application comprises the administration routes suitable for oral and injection, preferably the oral administration route. The dosage forms include tablets, capsules, dispersions and suspensions, preferably tablets and capsules, more preferably tablets, and further preferably common tablets.

[0034] The present application also provides a preparation method of the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt, which adopts wet granulation, dry granulation or mixed direct compression, preferably dry granulation.

[0035] In the preferred embodiment of the present application, the preparation method comprises the following steps:

[0036] (1) mixing the active ingredient with the filler and the disintegrant;

[0037] (2) mixing uniformly and then performing dry granulation;

[0038] (3) optionally, mixing the granules after dry granulation with the lubricant and then performing tabletting or filling capsules.

[0039] The preparation process of the pharmaceutical composition of the present application is simple, convenient and feasible, has good repeatability, is easy to scale up production, and ensures the production requirements of the product.

[0040] Another object of the present application is to provide the use of the pharmaceutical composition in the treatment of inflammatory diseases and autoimmune diseases, preferably in the treatment of rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, dermatitis, Sjogren's syndrome, psoriasis, systemic lupus erythematosus, discoid lupus erythematosus, lichen planopilaris or inflammatory bowel disease.

[0041] The pharmaceutical composition of the present application has the following beneficial effects:

[0042] 1. Good stability, under the conditions of high temperature (40℃, 60℃), high humidity (25℃ / RH75%, 25℃ / RH90%), light (total ultraviolet irradiance not less than 200w·hr / m2, total irradiance not less than 1.2×10 6 lux·hr), accelerated test (40℃ / RH75%) and long-term test (30℃ / RH65%), compared with the results of 0 days, the quality indicators of the sample do not change obviously, and the stability is high.

[0043] 2. Excellent dissolution rate, the 30min cumulative dissolution rate of the pharmaceutical composition is >85%.

[0044] 3. Fast disintegration rate, which can be completely disintegrated within 30s.

[0045] 4. Robust process, strong production compliance, easy for industrial production and batch scaling up. Detailed Implementation

[0046] To further illustrate the present invention, specific embodiments will be described below, but the scope of protection of the present invention is not limited to the specific embodiments.

[0047] In vitro dissolution study: The dissolution method adopted was the second method (paddle method) in General Chapter 0931 of Part IV of the 2020 Chinese Pharmacopoeia for the determination of dissolution and release. The dissolution medium was pH 6.8 phosphate buffer (containing 0.05% SLS), 900 ml, and the rotation speed was 50 rpm. The sampling time points were 5, 10, 15, 20, 30, 45 and 60 min.

[0048] Drug disintegration time determination: The disintegration time determination method of General Chapter 0921 of Part IV of the 2020 edition of the Chinese Pharmacopoeia was adopted.

[0049] Example 1: Dry Granulation

[0050] Table 1

[0051] Dry granulation: Weigh out the formula I compound, lactose, microcrystalline cellulose, and croscarmellose sodium according to the prescription amount, mix them evenly, and perform dry granulation. After mixing the resulting dry granulated granules with magnesium stearate, capsule filling / tableting is performed. The unprocessed tablets have a faster disintegration rate.

[0052] Example 2: Filler Screening

[0053] Granulation preparation: Refer to the dry granulation preparation method in Example 1.

[0054] The results showed that the formulation in the example disintegrated quickly, had good dissolution results, and was relatively complete.

[0055] Example 3: Investigation of filler ratio

[0056] Table 2

[0057] Granulation preparation: Refer to the dry granulation preparation method in Example 1.

[0058] The results showed that the formulation in the example disintegrated quickly, had good dissolution results, and was relatively complete.

[0059] Example 4: Screening of disintegrants

[0060] Table 4

[0061] Granulation preparation: Refer to the dry granulation preparation method in Example 1.

[0062] The results show that the disintegration of the example prescription is faster, and the dissolution result is better, with a dissolution of more than 85% at 30 min, and faster dissolution.

[0063] Example 5: Disintegrant amount screening

[0064] Table 5

[0065] Granule preparation: dry granulation preparation method according to Example 1.

[0066] The results show that when the amount of disintegrant is in the range of 3%-7%, the dissolution is faster and more complete.

[0067] Example 6: Different specifications of active ingredient composition prescriptions are as follows

[0068] Table 6

[0069] Granule preparation: dry granulation preparation method according to Example 1.

[0070] The results show that the dissolution result of the example prescription is better, with a dissolution of more than 85% at 30 min, faster dissolution, and more complete dissolution.

[0071] Example 7: Stability study of prescriptions 1, 10, 11 and 12

[0072] The tablets prepared according to prescriptions 1, 10, 11 and 12 were placed in high temperature (40°C, 60°C), high humidity (25°C / RH 75%, 25°C / RH 90%), light (total ultraviolet irradiance not less than 200 w·hr / m2, total irradiance not less than 1.2×10 6 lux·hr), accelerated experiment (40°C / RH 75%) and long-term experiment (30°C / RH 65%) conditions for stability study, with content and related substance level as evaluation index. The results are shown in Tables 7A-7G.

[0073] Table 7A: Results of prescriptions 1, 10, 11 and 12 (40°C)

[0074] Table 7B: Results of prescriptions 1, 10, 11 and 12 (60°C)

[0075] Table 7C: Results of prescriptions 1, 10, 11 and 12 (25°C / RH 75%)

[0076] Table 7D: Results of prescriptions 1, 10, 11 and 12 (25°C / RH 90%)

[0077] Table 7E: Results of the study of Formulations 1, 10, 11 and 12 (light)

[0078] Table 7F: Results of the study of Formulations 1, 10, 11 and 12 (accelerated experiment)

[0079] Table 7G: Results of the study of Formulations 1 and 11 (long-term experiment)

[0080] The results show that the tablets prepared from Formulations 1, 10, 11 and 12 have small changes in related substances and content compared with 0 days under the conditions of high temperature, high humidity, light and accelerated experiment, and have good stability;

[0081] The tablets prepared from Formulations 1 and 11 have small changes in related substances and content compared with 0 days under the conditions of long-term experiment, and have good stability.

Claims

1. A pharmaceutical composition, characterized by, comprising a compound of Formula (I) or its isomers, solvates, hydrates, or pharmaceutically acceptable salts thereof, or combinations thereof, as an active ingredient, and at least one pharmaceutically acceptable adjuvant, 2. The pharmaceutical composition of claim 1, wherein, The active ingredient is 0.1-20% of the total weight of the pharmaceutical composition; preferably 1-10%; more preferably 1-8%; further preferably 4-8%.

3. The pharmaceutical composition of claim 1, wherein, The excipient comprises a filler, preferably one or more of microcrystalline cellulose, mannitol, sorbitol, calcium hydrogen phosphate, calcium sulfate, dextran, starch, pregelatinized starch, cellulose, lactose, maltose or sucrose, more preferably one or more of microcrystalline cellulose, mannitol or lactose; Further preferably, the filler is 60-99% of the total weight of the pharmaceutical composition, preferably 78-95%, more preferably 84-94%, further preferably 85-90%.

4. The pharmaceutical composition of claim 3, wherein, The filler is selected from microcrystalline cellulose and lactose; Preferably, the ratio of the amount of microcrystalline cellulose to lactose is 1-3:3-1, preferably 1-2:2-1; more preferably 1:

1.

5. The pharmaceutical composition of claim 4, wherein, The microcrystalline cellulose is 20-60% of the total weight of the pharmaceutical composition, preferably 30-50%, more preferably 40-47%; the lactose is 20-50% of the total weight of the pharmaceutical composition, preferably 30-48%, more preferably 40-47%.

6. The pharmaceutical composition of claim 1, wherein, The excipient comprises a disintegrant, preferably one or more of low-substituted hydroxypropyl cellulose, croscarmellose sodium, sodium carboxymethyl starch or crospovidone, more preferably one or more of croscarmellose sodium, low-substituted hydroxypropyl cellulose or crospovidone; Further preferably, the disintegrant is 0.1-20% of the total weight of the pharmaceutical composition, preferably 3-10%, more preferably 4-8%, further preferably 4-6%.

7. The pharmaceutical composition of claim 1, wherein, The pharmaceutical composition further comprises a lubricant.

8. The pharmaceutical composition of claim 7, wherein, The lubricant is selected from one or more of talc, stearic acid, sodium stearyl fumarate, glyceryl behenate or magnesium stearate, preferably sodium stearyl fumarate, magnesium stearate or stearic acid; Preferably, the lubricant is 0-5% of the total weight of the pharmaceutical composition; preferably 0.5-3%, more preferably 0.5-1.5%.

9. The pharmaceutical composition according to claims 1-8, characterized in that, The weight percentages of the components are as follows: Preferably, the weight percentages of the components are as follows: More preferably, the weight percentages of the components are as follows: It is further preferred that the weight percentages of the components are as follows:

10. A process for the preparation of a pharmaceutical composition as claimed in claim 1, characterized in that, The preparation method uses wet granulation, dry granulation or direct compression, preferably dry granulation.

11. The preparation method according to claim 10, characterized in that, The dry granulation process comprises the following steps: (1) mixing the active ingredient with the filler and the disintegrant; (2) mixing uniformly and then dry granulating; (3) optionally, mixing the dry granulated particles with the lubricant and then tabletting or filling into capsules.

12. Use of a pharmaceutical composition of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-9 in the manufacture of a medicament for the treatment of an inflammatory disease and an autoimmune disease; wherein the inflammatory disease and the autoimmune disease is selected from rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, dermatitis, Sjogren's syndrome, psoriasis, systemic lupus erythematosus, discoid lupus erythematosus, lichen planopilaris or inflammatory bowel disease.

Images