Pharmaceutical preparation containing TOLL-like receptor inhibition compound hydrochloride and preparation method and application thereof

Abstract

The invention belongs to the technical field of biological medicines, and particularly relates to a pharmaceutical preparation containing a TOLL-like receptor inhibition compound or hydrochloride thereof, and a preparation method and application thereof. The pharmaceutical preparation containing the TOLL-like receptor inhibiting compound or the hydrochloride thereof has the advantages that the in-vivo drug exposure amount or the bioavailability can be improved.

Description

Technical Field

[0001] This disclosure belongs to the field of biomedical technology, specifically relating to pharmaceutical preparations containing hydrochloride of TOLL-like receptor inhibitory compounds, their preparation methods, and uses. Background Technology

[0002] Toll-like receptors (TLRs) are pattern recognition receptors of the innate immune system. They are activated when conserved molecular signatures on microbial or host molecules [pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs)]. TLRs consist of an extracellular cellular domain, a single-channel transmembrane domain, and a cytoplasmic Toll / interleukin-1 receptor domain. TLRs play a crucial role in the first line of defense against infection. After recognizing specific ligands of pathogens or damaged cells, TLRs initiate multiple downstream signaling cascades, including nuclear factor kappa-B (NF-κB), type I interferon, and inflammasome signaling pathways, producing corresponding inflammatory factors, antiviral cytokines, and chemokines. TLRs also play a role in certain immune diseases; inhibiting TLR activity can have therapeutic effects on these diseases.

[0003] Currently, most drug formulations containing Toll-like receptors are immediate-release film-coated tablets, which often result in low in vivo drug exposure or low bioavailability.

[0004] Therefore, a pharmaceutical formulation containing a TOLL-like receptor inhibitory compound or its hydrochloride salt is to be developed. Summary of the Invention

[0005] The technical problem to be solved by this disclosure is that most drug formulations containing TOLL-like receptors are immediate-release film-coated tablets, which often result in low in vivo drug exposure or low bioavailability. The goal is to develop a drug formulation containing a TOLL-like receptor inhibitory compound or its hydrochloride salt to improve in vivo drug exposure or bioavailability.

[0006] To achieve the above-mentioned technical objectives, the technical solution adopted in this disclosure is as follows:

[0007] On one hand, this disclosure provides a pharmaceutical formulation comprising an active ingredient, a TOLL-like receptor inhibitory compound or its hydrochloride salt, and optional pharmaceutically suitable excipients, wherein the TOLL-like receptor inhibitory compound has the structure shown in formula (I); the TOLL-like receptor inhibitory compound is designated as compound (I); the TOLL-like receptor inhibitory compound hydrochloride salt is designated as compound (I) hydrochloride salt; and the compound (I) or its hydrochloride salt accounts for 1% to 20% of the total mass of the pharmaceutical formulation.

[0008] The TOLL-like receptor inhibitory compound has the structure shown in formula (I):

[0009]

[0010] The pharmaceutical formulation containing the hydrochloride of the TOLL-like receptor inhibitory compound disclosed herein can improve drug stability, increase in vivo drug exposure, or improve bioavailability.

[0011] In some preferred embodiments of this disclosure, the hydrochloride salt of compound (I) accounts for 1% to 15% of the total mass of the pharmaceutical preparation.

[0012] In some preferred embodiments of this disclosure, the hydrochloride salt of the compound of formula (I) accounts for 1% to 10% or 2% to 8% of the total mass of the pharmaceutical preparation.

[0013] In some preferred embodiments of this disclosure, the hydrochloride salt of the compound of formula (I) accounts for 3% to 7% of the total mass of the pharmaceutical preparation.

[0014] In some preferred embodiments of this disclosure, the hydrochloride salt of the compound of formula (I) accounts for 4% to 6.5% of the total mass of the pharmaceutical preparation.

[0015] In some preferred embodiments of this disclosure, the hydrochloride salt of the compound of formula (I) accounts for 4.5% to 6% of the total mass of the pharmaceutical preparation.

[0016] In some preferred embodiments of this disclosure, the compound of formula (I) accounts for 1% to 15% of the total mass of the pharmaceutical preparation, based on the compound of formula (I).

[0017] In some preferred embodiments of this disclosure, the compound of formula (I) accounts for 1% to 10% or 2% to 8% of the total mass of the pharmaceutical preparation, based on the compound of formula (I).

[0018] In some preferred embodiments of this disclosure, the compound of formula (I) accounts for 3% to 7% of the total mass of the pharmaceutical preparation, based on the compound of formula (I).

[0019] In some preferred embodiments of this disclosure, the compound of formula (I) accounts for 4% to 6.5% of the total mass of the pharmaceutical preparation, based on the compound of formula (I).

[0020] In some preferred embodiments of this disclosure, the compound of formula (I) accounts for 4.5% to 6% of the total mass of the pharmaceutical preparation, based on the compound of formula (I).

[0021] In some preferred embodiments of this disclosure, the excipients include one or more of ionic polymers, binders, fillers, disintegrants, flow aids, and lubricants.

[0022] In some preferred embodiments of this disclosure, the excipients include ionic polymers, adhesives, fillers, disintegrants, flow aids, and lubricants.

[0023] In some preferred embodiments of this disclosure, the pharmaceutical formulation comprises, by weight percentage, the following components: 1%–20% hydrochloride of compound (I), 5%–30% ionic polymer, 15%–50% binder, 15%–50% filler, 3%–15% disintegrant, 0.05%–1.0% flow aid, and 0.1%–5% lubricant.

[0024] In some preferred embodiments of this disclosure, the pharmaceutical formulation comprises, by weight percentage: 1% to 20% of the compound of formula (I), 5% to 30% of the ionic polymer, 15% to 50% of the binder, 15% to 50% of the filler, 3% to 15% of the disintegrant, 0.05% to 1.0% of the flow aid, and 0.1% to 5% of the lubricant.

[0025] In some preferred embodiments of this disclosure, the ionic polymer pharmaceutical formulation comprises 8% to 25% of its total mass.

[0026] In some preferred embodiments of this disclosure, the ionic polymer accounts for 10% to 25% of the total mass of the pharmaceutical preparation.

[0027] In some preferred embodiments of this disclosure, the ionic polymer accounts for 10% to 22% of the total mass of the pharmaceutical preparation.

[0028] In some preferred embodiments of this disclosure, the ionic polymer accounts for 12% to 22% of the total mass of the pharmaceutical preparation.

[0029] In some preferred embodiments of this disclosure, the adhesive accounts for 20% to 45% of the total mass of the pharmaceutical preparation.

[0030] In some preferred embodiments of this disclosure, the adhesive accounts for 25% to 40% of the total mass of the pharmaceutical preparation.

[0031] In some preferred embodiments of this disclosure, the adhesive accounts for 28% to 40% of the total mass of the pharmaceutical preparation.

[0032] In some preferred embodiments of this disclosure, the adhesive accounts for 30% to 35% of the total mass of the pharmaceutical preparation.

[0033] In some preferred embodiments of this disclosure, the filler accounts for 20% to 45% of the total mass of the pharmaceutical preparation.

[0034] In some preferred embodiments of this disclosure, the filler accounts for 25% to 40% of the total mass of the pharmaceutical preparation.

[0035] In some preferred embodiments of this disclosure, the filler accounts for 28% to 40% of the total mass of the pharmaceutical preparation.

[0036] In some preferred embodiments of this disclosure, the filler accounts for 30% to 35% of the total mass of the pharmaceutical preparation.

[0037] In some preferred embodiments of this disclosure, the disintegrant accounts for 5% to 12% of the total mass of the pharmaceutical preparation.

[0038] In some preferred embodiments of this disclosure, the disintegrant accounts for 5% to 11% of the total mass of the pharmaceutical preparation.

[0039] In some preferred embodiments of this disclosure, the disintegrant accounts for 6% to 10% of the total mass of the pharmaceutical preparation.

[0040] In some preferred embodiments of this disclosure, the disintegrant accounts for 7% to 9% of the total mass of the pharmaceutical preparation.

[0041] In some preferred embodiments of this disclosure, the gliding agent accounts for 0.1% to 0.8% of the total mass of the pharmaceutical preparation.

[0042] In some preferred embodiments of this disclosure, the gliding agent accounts for 0.1% to 0.5% of the total mass of the pharmaceutical preparation.

[0043] In some preferred embodiments of this disclosure, the gliding agent accounts for 0.1% to 0.3% of the total mass of the pharmaceutical preparation.

[0044] In some preferred embodiments of this disclosure, the gliding agent accounts for 0.15% to 0.25% of the total mass of the pharmaceutical preparation.

[0045] In some preferred embodiments of this disclosure, the lubricant accounts for 0.5% to 4% of the total mass of the pharmaceutical preparation.

[0046] In some preferred embodiments of this disclosure, the lubricant accounts for 0.5% to 2.5% of the total mass of the pharmaceutical preparation.

[0047] In some preferred embodiments of this disclosure, the lubricant accounts for 0.8% to 1.5% of the total mass of the pharmaceutical preparation.

[0048] In some preferred embodiments of this disclosure, the lubricant accounts for 0.9% to 1.2% of the total mass of the pharmaceutical preparation.

[0049] In some preferred embodiments of this disclosure, the pharmaceutical formulation comprises, by weight percentage, the following components: 1%–15% hydrochloride of compound (I), 8%–25% ionic polymer, 20%–45% binder, 20%–45% filler, 5%–12% disintegrant, 0.1%–0.8% flow aid, and 0.5%–4% lubricant.

[0050] In some preferred embodiments of this disclosure, the pharmaceutical formulation comprises, by weight percentage, the following components: 1%–10% hydrochloride of compound (I), 10%–25% ionic polymer, 25%–40% binder, 25%–40% filler, 5%–11% disintegrant, 0.1%–0.5% flow aid, and 0.5%–2.5% lubricant.

[0051] In some preferred embodiments of this disclosure, the pharmaceutical formulation comprises, by weight percentage: 2%–8% of the hydrochloride of compound (I), 10%–25% of the ionic polymer, 28%–40% of the binder, 28%–40% of the filler, 6%–10% of the disintegrant, 0.1%–0.3% of the flow aid, and 0.8%–1.5% of the lubricant.

[0052] In some preferred embodiments of this disclosure, the pharmaceutical formulation comprises, by weight percentage: 4%–6% hydrochloride of compound (I), 10%–22% ionic polymer, 30%–38% binder, 30%–38% filler, 7%–9% disintegrant, 0.15%–0.25% flow aid, and 0.9%–1.3% lubricant.

[0053] In some preferred embodiments of this disclosure, the pharmaceutical formulation comprises, by weight percentage, the following components: 4.5% to 6% of the hydrochloride of compound (I), 12% to 22% of the ionic polymer, 30% to 35% of the binder, 30% to 35% of the filler, 7% to 9% of the disintegrant, 0.15% to 0.25% of the flow aid, and 0.9% to 1.2% of the lubricant.

[0054] In some preferred embodiments of this disclosure, the pharmaceutical formulation comprises, by weight percentage, the following components: 1% to 15% of compound (I), 8% to 25% of ionic polymer, 20% to 45% of binder, 20% to 45% of filler, 5% to 12% of disintegrant, 0.1% to 0.8% of flow aid, and 0.5% to 4% of lubricant.

[0055] In some preferred embodiments of this disclosure, the pharmaceutical formulation comprises, by weight percentage: 1% to 10% of the compound of formula (I), 10% to 25% of the ionic polymer, 25% to 40% of the binder, 25% to 40% of the filler, 5% to 11% of the disintegrant, 0.1% to 0.5% of the flow aid, and 0.5% to 2.5% of the lubricant.

[0056] In some preferred embodiments of this disclosure, the pharmaceutical formulation comprises, by weight percentage: 2%–8% of the compound of formula (I), 10%–25% of the ionic polymer, 28%–40% of the binder, 28%–40% of the filler, 6%–10% of the disintegrant, 0.1%–0.3% of the flow aid, and 0.8%–1.5% of the lubricant.

[0057] In some preferred embodiments of this disclosure, the pharmaceutical formulation comprises, by weight percentage: 4%–6% of the compound of formula (I), 10%–22% of the ionic polymer, 30%–38% of the binder, 30%–38% of the filler, 7%–9% of the disintegrant, 0.15%–0.25% of the flow aid, and 0.9%–1.3% of the lubricant.

[0058] In some preferred embodiments of this disclosure, the pharmaceutical formulation comprises, by weight percentage: 4.5% to 6% of compound (I), 12% to 22% of ionic polymer, 30% to 35% of binder, 30% to 35% of filler, 7% to 9% of disintegrant, 0.15% to 0.25% of flow aid, and 0.9% to 1.2% of lubricant.

[0059] In some preferred embodiments of this disclosure, the pharmaceutical formulation comprises, by weight percentage: 1% to 10% of the compound of formula (I), 15% to 25% of the ionic polymer, 25% to 40% of the binder, 25% to 40% of the filler, 5% to 11% of the disintegrant, 0.1% to 0.5% of the flow aid, and 0.5% to 2.5% of the lubricant.

[0060] In some preferred embodiments of this disclosure, the pharmaceutical formulation comprises, by weight percentage: 2% to 8% of the compound of formula (I), 15% to 25% of the ionic polymer, 28% to 40% of the binder, 28% to 40% of the filler, 6% to 10% of the disintegrant, 0.1% to 0.3% of the flow aid, and 0.8% to 1.5% of the lubricant.

[0061] In some preferred embodiments of this disclosure, the pharmaceutical formulation comprises, by weight percentage: 4%–6% of the compound of formula (I), 15%–25% of the ionic polymer, 30%–38% of the binder, 30%–38% of the filler, 7%–9% of the disintegrant, 0.15%–0.25% of the flow aid, and 0.9%–1.3% of the lubricant.

[0062] In some preferred embodiments of this disclosure, the pharmaceutical formulation comprises, by weight percentage: 4%–6% of the compound of formula (I), 16%–24% of the ionic polymer, 30%–38% of the binder, 30%–38% of the filler, 7%–9% of the disintegrant, 0.15%–0.25% of the flow aid, and 0.9%–1.3% of the lubricant.

[0063] In some preferred embodiments of this disclosure, the pharmaceutical formulation comprises, by weight percentage: 4.5% to 6% of compound (I), 18% to 22% of ionic polymer, 30% to 35% of binder, 30% to 35% of filler, 7% to 9% of disintegrant, 0.15% to 0.25% of flow aid, and 0.9% to 1.2% of lubricant.

[0064] In some preferred embodiments of this disclosure, the ionic polymer is one or more selected from hydroxypropyl methylcellulose succinate, hydroxypropyl methylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), polyvinyl acetate phthalate (PVAP), and methacrylic acid copolymer.

[0065] In some preferred embodiments of this disclosure, the ionic polymer is selected from one or more of hydroxypropyl methylcellulose succinate, hydroxypropyl methylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), and cellulose acetate trimellitate (CAT).

[0066] In some preferred embodiments of this disclosure, the ionic polymer is hydroxypropyl methylcellulose succinate.

[0067] In some preferred embodiments of this disclosure, the adhesive is selected from one or more of microcrystalline cellulose, methylcellulose, carboxycellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and alginate.

[0068] In some preferred embodiments of this disclosure, the adhesive is selected from one or more of microcrystalline cellulose, methylcellulose, carboxycellulose, hydroxypropylcellulose, and hydroxypropyl methylcellulose.

[0069] In some preferred embodiments of this disclosure, the adhesive is microcrystalline cellulose.

[0070] In some preferred embodiments of this disclosure, the filler is selected from one or more of lactose monohydrate, sucrose, dextrin, starch, dicalcium phosphate, anhydrous dicalcium phosphate, and calcium phosphate.

[0071] In some preferred embodiments of this disclosure, the filler is selected from one or more of lactose monohydrate, sucrose, dextrin, and starch.

[0072] In some preferred embodiments of this disclosure, the filler is lactose monohydrate.

[0073] In some preferred embodiments of this disclosure, the disintegrant is selected from one or more of croscarmellose sodium, low-substituted hydroxypropyl cellulose, croscarmellose, sodium carboxymethyl starch, and calcium carboxymethyl cellulose.

[0074] In some preferred embodiments of this disclosure, the disintegrant is selected from one or more of croscarmellose sodium, low-substituted hydroxypropyl cellulose, and sodium carboxymethyl starch.

[0075] In some preferred embodiments of this disclosure, the disintegrant is croscarmellose sodium.

[0076] In some preferred embodiments of this disclosure, the flow aid is selected from one or more of colloidal silica, magnesium trisilicate, talc, powdered cellulose, and starch.

[0077] In some preferred embodiments of this disclosure, the flow aid is selected from one or more of colloidal silica, magnesium trisilicate, and talc.

[0078] In some preferred embodiments of this disclosure, the flow aid is colloidal silica.

[0079] In some preferred embodiments of this disclosure, the lubricant is selected from one or more of magnesium stearate, calcium stearate, micronized silica gel, and sodium dodecyl sulfate.

[0080] In some preferred embodiments of this disclosure, the lubricant is selected from one or more of magnesium stearate and calcium stearate.

[0081] In some preferred embodiments of this disclosure, the lubricant is magnesium stearate.

[0082] In some preferred embodiments of this disclosure, the ionic polymer is selected from one or more of hydroxypropyl methylcellulose succinate, hydroxypropyl methylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), polyvinyl acetate phthalate (PVAP), and methacrylic acid copolymers.

[0083] In some preferred embodiments of this disclosure, the adhesive is selected from one or more of microcrystalline cellulose, methylcellulose, carboxycellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and alginate.

[0084] In some preferred embodiments of this disclosure, the filler is selected from one or more of lactose monohydrate, sucrose, dextrin, starch, dicalcium phosphate, anhydrous dicalcium phosphate, and calcium phosphate.

[0085] In some preferred embodiments of this disclosure, the disintegrant is selected from one or more of croscarmellose sodium, low-substituted hydroxypropyl cellulose, croscarmellose, sodium carboxymethyl starch, and calcium carboxymethyl cellulose.

[0086] In some preferred embodiments of this disclosure, the flow aid is selected from one or more of colloidal silica, magnesium trisilicate, talc, powdered cellulose, and starch.

[0087] In some preferred embodiments of this disclosure, the lubricant is selected from one or more of magnesium stearate, calcium stearate, micronized silica gel, and sodium dodecyl sulfate.

[0088] In some preferred embodiments of this disclosure, the pharmaceutical preparation comprises, by mass percentage, the following components: 1%–20% of the hydrochloride of compound (I), 5%–30% of hydroxypropyl methylcellulose acetate succinate, 15%–50% of microcrystalline cellulose, 15%–50% of lactose monohydrate, 3%–15% of croscarmellose sodium, 0.05%–1.0% of colloidal silica, and 0.1%–5% of magnesium stearate.

[0089] In some preferred embodiments of this disclosure, the hydroxypropyl methylcellulose succinate accounts for 8% to 25% of the total mass of the pharmaceutical preparation.

[0090] In some preferred embodiments of this disclosure, hydroxypropyl methylcellulose succinate accounts for 10% to 25% of the total mass of the pharmaceutical preparation.

[0091] In some preferred embodiments of this disclosure, hydroxypropyl methylcellulose succinate accounts for 10% to 22% of the total mass of the pharmaceutical preparation.

[0092] In some preferred embodiments of this disclosure, hydroxypropyl methylcellulose succinate accounts for 12% to 22% of the total mass of the pharmaceutical preparation.

[0093] In some preferred embodiments of this disclosure, the hydroxypropyl methylcellulose succinate accounts for 15% to 25% of the total mass of the pharmaceutical preparation.

[0094] In some preferred embodiments of this disclosure, hydroxypropyl methylcellulose succinate accounts for 16% to 24% of the total mass of the pharmaceutical preparation.

[0095] In some preferred embodiments of this disclosure, hydroxypropyl methylcellulose succinate accounts for 18% to 22% of the total mass of the pharmaceutical preparation.

[0096] In some preferred embodiments of this disclosure, microcrystalline cellulose accounts for 20% to 45% of the total mass of the pharmaceutical preparation.

[0097] In some preferred embodiments of this disclosure, microcrystalline cellulose accounts for 25% to 40% of the total mass of the pharmaceutical preparation.

[0098] In some preferred embodiments of this disclosure, microcrystalline cellulose accounts for 28% to 40% of the total mass of the pharmaceutical preparation.

[0099] In some preferred embodiments of this disclosure, microcrystalline cellulose accounts for 30% to 35% of the total mass of the pharmaceutical preparation.

[0100] In some preferred embodiments of this disclosure, lactose monohydrate accounts for 20% to 45% of the total mass of the pharmaceutical preparation.

[0101] In some preferred embodiments of this disclosure, lactose monohydrate accounts for 25% to 40% of the total mass of the pharmaceutical preparation.

[0102] In some preferred embodiments of this disclosure, lactose monohydrate accounts for 28% to 40% of the total mass of the pharmaceutical preparation.

[0103] In some preferred embodiments of this disclosure, lactose monohydrate accounts for 30% to 35% of the total mass of the pharmaceutical preparation.

[0104] In some preferred embodiments of this disclosure, croscarmellose sodium accounts for 5% to 12% of the total mass of the pharmaceutical preparation.

[0105] In some preferred embodiments of this disclosure, croscarmellose sodium accounts for 5% to 11% of the total mass of the pharmaceutical preparation.

[0106] In some preferred embodiments of this disclosure, croscarmellose sodium accounts for 6% to 10% of the total mass of the pharmaceutical preparation.

[0107] In some preferred embodiments of this disclosure, croscarmellose sodium accounts for 7% to 9% of the total mass of the pharmaceutical preparation.

[0108] In some preferred embodiments of this disclosure, colloidal silica accounts for 0.1% to 0.8% of the total mass of the pharmaceutical preparation.

[0109] In some preferred embodiments of this disclosure, colloidal silica accounts for 0.1% to 0.5% of the total mass of the pharmaceutical preparation.

[0110] In some preferred embodiments of this disclosure, colloidal silica accounts for 0.1% to 0.3% of the total mass of the pharmaceutical preparation.

[0111] In some preferred embodiments of this disclosure, colloidal silica accounts for 0.15% to 0.25% of the total mass of the pharmaceutical preparation.

[0112] In some preferred embodiments of this disclosure, magnesium stearate accounts for 0.5% to 4% of the total mass of the pharmaceutical preparation.

[0113] In some preferred embodiments of this disclosure, magnesium stearate accounts for 0.5% to 2.5% of the total mass of the pharmaceutical preparation.

[0114] In some preferred embodiments of this disclosure, magnesium stearate accounts for 0.8% to 1.5% of the total mass of the pharmaceutical preparation.

[0115] In some preferred embodiments of this disclosure, magnesium stearate accounts for 0.9% to 1.2% of the total mass of the pharmaceutical preparation.

[0116] In some preferred embodiments of this disclosure, the pharmaceutical preparation comprises, by mass percentage, the following components: 1%–15% of the hydrochloride of compound (I), 8%–25% of hydroxypropyl methylcellulose acetate succinate, 20%–45% of microcrystalline cellulose, 20%–45% of lactose monohydrate, 5%–12% of croscarmellose sodium, 0.1%–0.8% of colloidal silica, and 0.5%–4% of magnesium stearate.

[0117] In some preferred embodiments of this disclosure, the pharmaceutical preparation comprises, by mass percentage, the following components: 1%–10% of the hydrochloride of compound (I), 10%–25% of hydroxypropyl methylcellulose acetate succinate, 25%–40% of microcrystalline cellulose, 25%–40% of lactose monohydrate, 5%–11% of croscarmellose sodium, 0.1%–0.5% of colloidal silica, and 0.5%–2.5% of magnesium stearate.

[0118] In some preferred embodiments of this disclosure, the pharmaceutical preparation comprises, by weight percentage, the following components: 2%–8% of the hydrochloride of compound (I), 10%–25% of hydroxypropyl methylcellulose acetate succinate, 28%–40% of microcrystalline cellulose, 28%–40% of lactose monohydrate, 6%–10% of croscarmellose sodium, 0.1%–0.3% of colloidal silica, and 0.8%–1.5% of magnesium stearate.

[0119] In some preferred embodiments of this disclosure, the pharmaceutical preparation comprises, by weight percentage, the following components: 4%–6% of compound (I) hydrochloride, 10%–22% of hydroxypropyl methylcellulose acetate succinate, 30%–38% of microcrystalline cellulose, 30%–38% of lactose monohydrate, 7%–9% of croscarmellose sodium, 0.15%–0.25% of colloidal silica, and 0.9%–1.3% of magnesium stearate.

[0120] In some preferred embodiments of this disclosure, the pharmaceutical preparation comprises, by weight percentage, the following components: 4.5%–6% of compound (I) hydrochloride, 12%–22% of hydroxypropyl methylcellulose acetate succinate, 30%–35% of microcrystalline cellulose, 30%–35% of lactose monohydrate, 7%–9% of croscarmellose sodium, 0.15%–0.25% of colloidal silica, and 0.9%–1.2% of magnesium stearate.

[0121] In some preferred embodiments of this disclosure, the pharmaceutical preparation comprises, by weight percentage, the following components: 1%–15% of compound (I), 8%–25% of hydroxypropyl methylcellulose acetate succinate, 20%–45% of microcrystalline cellulose, 20%–45% of lactose monohydrate, 5%–12% of croscarmellose sodium, 0.1%–0.8% of colloidal silica, and 0.5%–4% of magnesium stearate.

[0122] In some preferred embodiments of this disclosure, the pharmaceutical preparation comprises, by weight percentage, the following components: 1%–10% of compound (I), 10%–25% of hydroxypropyl methylcellulose acetate succinate, 25%–40% of microcrystalline cellulose, 25%–40% of lactose monohydrate, 5%–11% of croscarmellose sodium, 0.1%–0.5% of colloidal silica, and 0.5%–2.5% of magnesium stearate.

[0123] In some preferred embodiments of this disclosure, the pharmaceutical preparation comprises, by weight percentage, the following components: 2%–8% of compound (I), 10%–25% of hydroxypropyl methylcellulose acetate succinate, 28%–40% of microcrystalline cellulose, 28%–40% of lactose monohydrate, 6%–10% of croscarmellose sodium, 0.1%–0.3% of colloidal silica, and 0.8%–1.5% of magnesium stearate.

[0124] In some preferred embodiments of this disclosure, the pharmaceutical preparation comprises, by weight percentage, the following components: 4%–6% of compound (I), 10%–22% of hydroxypropyl methylcellulose acetate succinate, 30%–38% of microcrystalline cellulose, 30%–38% of lactose monohydrate, 7%–9% of croscarmellose sodium, 0.15%–0.25% of colloidal silica, and 0.9%–1.3% of magnesium stearate.

[0125] In some preferred embodiments of this disclosure, the pharmaceutical preparation comprises, by weight percentage, the following components: 4.5%–6% of compound (I), 12%–22% of hydroxypropyl methylcellulose acetate succinate, 30%–35% of microcrystalline cellulose, 30%–35% of lactose monohydrate, 7%–9% of croscarmellose sodium, 0.15%–0.25% of colloidal silica, and 0.9%–1.2% of magnesium stearate.

[0126] In some preferred embodiments of this disclosure, the pharmaceutical preparation comprises, by weight percentage, the following components: 1%–10% of compound (I), 15%–25% of hydroxypropyl methylcellulose acetate succinate, 25%–40% of microcrystalline cellulose, 25%–40% of lactose monohydrate, 5%–11% of croscarmellose sodium, 0.1%–0.5% of colloidal silica, and 0.5%–2.5% of magnesium stearate.

[0127] In some preferred embodiments of this disclosure, the pharmaceutical preparation comprises, by weight percentage, the following components: 2%–8% of compound (I), 15%–25% of hydroxypropyl methylcellulose acetate succinate, 28%–40% of microcrystalline cellulose, 28%–40% of lactose monohydrate, 6%–10% of croscarmellose sodium, 0.1%–0.3% of colloidal silica, and 0.8%–1.5% of magnesium stearate.

[0128] In some preferred embodiments of this disclosure, the pharmaceutical preparation comprises, by weight percentage, the following components: 4%–6% of compound (I), 15%–25% of hydroxypropyl methylcellulose acetate succinate, 30%–38% of microcrystalline cellulose, 30%–38% of lactose monohydrate, 7%–9% of croscarmellose sodium, 0.15%–0.25% of colloidal silica, and 0.9%–1.3% of magnesium stearate.

[0129] In some preferred embodiments of this disclosure, the pharmaceutical preparation comprises, by weight percentage, the following components: 4%–6% of compound (I), 16%–24% of hydroxypropyl methylcellulose acetate succinate, 30%–38% of microcrystalline cellulose, 30%–38% of lactose monohydrate, 7%–9% of croscarmellose sodium, 0.15%–0.25% of colloidal silica, and 0.9%–1.3% of magnesium stearate.

[0130] In some preferred embodiments of this disclosure, the pharmaceutical preparation comprises, by weight percentage, the following components: 4.5%–6% of compound (I), 18%–22% of hydroxypropyl methylcellulose acetate succinate, 30%–35% of microcrystalline cellulose, 30%–35% of lactose monohydrate, 7%–9% of croscarmellose sodium, 0.15%–0.25% of colloidal silica, and 0.9%–1.2% of magnesium stearate.

[0131] In some preferred embodiments of this disclosure, the pharmaceutical preparation is a tablet, pill, capsule, powder, granule, emulsion, solution, suspension, injection, or suppository.

[0132] In some preferred embodiments of this disclosure, the pharmaceutical preparation is a tablet, pill, capsule, powder, or granule.

[0133] In some preferred embodiments of this disclosure, the pharmaceutical preparation is a tablet, powder, or granule.

[0134] In some preferred embodiments of this disclosure, the pharmaceutical preparation is a tablet.

[0135] In some preferred embodiments of this disclosure, the pharmaceutical preparation is a solid dispersible tablet.

[0136] On the other hand, this disclosure provides a method for preparing a pharmaceutical formulation as described above, wherein the pharmaceutical formulation is a solid dispersible tablet; the method for preparing the solid dispersible tablet includes the following steps:

[0137] (1) The preparation steps of the solid dispersion of compound (I) hydrochloride include: dissolving compound (I) hydrochloride and ionic polymer in an organic solvent to obtain a sample solution; spray drying the sample solution to obtain the solid dispersion of compound (I) hydrochloride;

[0138] (2) The preparation steps of the solid dispersion tablet of compound (I) hydrochloride include: preparing solid dispersion tablet of compound (I) hydrochloride using the solid dispersion of compound (I).

[0139] In some preferred embodiments of this disclosure, the method for preparing the solid dispersion sheet includes the following steps:

[0140] (1) The preparation steps of the solid dispersion of compound (I) hydrochloride include: dissolving compound (I) hydrochloride and ionic polymer in an organic solvent to obtain a sample solution; spray drying the sample solution to obtain the solid dispersion of compound (I) hydrochloride;

[0141] (2) The preparation steps of the solid dispersion tablets of the hydrochloride of compound (I) include:

[0142] (2a) Premixing: Premixing a mixture of adhesive, hydrochloride solid dispersion of compound (I), filler, disintegrant and flow aid to obtain premix 1; adding 0.1 to 0.9 times the amount of lubricant to premix 1 to obtain premix 2;

[0143] (2b) Dry granulation: Premix 2 is subjected to dry granulation to obtain the granules;

[0144] (2c) Final blend: The prepared granules are mixed with the remaining amount of added lubricant to obtain the final blend;

[0145] (2d) Tableting: The final mixture is compressed to obtain solid dispersion tablets of the hydrochloride of compound (I).

[0146] In some preferred embodiments of this disclosure, the method for preparing the solid dispersion sheet includes the following steps:

[0147] (1) The preparation steps of the solid dispersion include: dissolving the hydrochloride of compound (I) and the ionic polymer in an organic solvent to obtain a sample solution; and spray drying the sample solution to obtain a solid dispersion.

[0148] (2) The preparation steps of the solid dispersion tablets of the hydrochloride of compound (I) include:

[0149] (2a) Premixing: Premixing a mixture of adhesive, solid dispersion, filler, disintegrant and flow aid to obtain premix 1; adding 0.3 to 0.7 times the amount of lubricant to premix 1 to obtain premix 2;

[0150] (2b) Dry granulation: Premix 2 is subjected to dry granulation to obtain the granules;

[0151] (2c) Final blend: The prepared granules are mixed with the remaining amount of added lubricant to obtain the final blend;

[0152] (2d) Tableting: The final mixture is compressed to obtain solid dispersion tablets of the hydrochloride of compound (I).

[0153] In some preferred embodiments of this disclosure, the method for preparing the solid dispersion sheet includes the following steps:

[0154] (1) The preparation steps of the solid dispersion include: dissolving the hydrochloride of compound (I) and the ionic polymer in an organic solvent to obtain a sample solution; and spray drying the sample solution to obtain a solid dispersion.

[0155] (2) The preparation steps of the solid dispersion tablets of the hydrochloride of compound (I) include:

[0156] (2a) Premixing: Premixing a mixture of adhesive, solid dispersion, filler, disintegrant and flow aid to obtain premix 1; adding 0.4 to 0.6 times the amount of lubricant to premix 1 to obtain premix 2;

[0157] (2b) Dry granulation: Premix 2 is subjected to dry granulation to obtain the granules;

[0158] (2c) Final blend: The prepared granules are mixed with the remaining amount of added lubricant to obtain the final blend;

[0159] (2d) Tableting: The final mixture is compressed to obtain solid dispersion tablets of the hydrochloride of compound (I).

[0160] In some preferred embodiments of this disclosure, the method for preparing the solid dispersion sheet includes the following steps:

[0161] (1) The preparation steps of the solid dispersion include: dissolving the hydrochloride of compound (I) and the ionic polymer in an organic solvent to obtain a sample solution; and spray drying the sample solution to obtain a solid dispersion.

[0162] (2) The preparation steps of the solid dispersion tablets of the hydrochloride of compound (I) include:

[0163] (2a) Premixing: Premixing the mixture of adhesive, solid dispersion, filler, disintegrant and glidant to obtain premix 1; adding 0.5 times the amount of lubricant to premix 1 to obtain premix 2;

[0164] (2b) Dry granulation: Premix 2 is subjected to dry granulation to obtain the granules;

[0165] (2c) Final blend: The prepared granules are mixed with the remaining amount of added lubricant to obtain the final blend;

[0166] (2d) Tableting: The final mixture is compressed to obtain solid dispersion tablets of the hydrochloride of compound (I).

[0167] In some preferred embodiments of this disclosure, the preparation steps of the solid dispersion tablet of compound (I) hydrochloride further include a pretreatment step: mixing the binder, the solid dispersion of compound (I) hydrochloride, the filler, the disintegrant, and the flow aid, and sieving to obtain a mixture.

[0168] In some preferred embodiments of this disclosure, the organic solvent in the pretreatment step is methanol and dichloromethane.

[0169] In some preferred embodiments of this disclosure, the mass percentage of methanol in the pretreatment step is 0.1% to 5%.

[0170] In some preferred embodiments of this disclosure, the mass percentage of methanol is 0.5% to 3%.

[0171] In some preferred embodiments of this disclosure, the mass percentage of methanol is 0.6% to 2%.

[0172] In some preferred embodiments of this disclosure, the mass percentage of dichloromethane in the pretreatment step is 0.2% to 10%.

[0173] In some preferred embodiments of this disclosure, the mass percentage of dichloromethane in the pretreatment step is 0.5% to 5%.

[0174] In some preferred embodiments of this disclosure, the mass percentage of dichloromethane in the pretreatment step is 1% to 3%.

[0175] In some preferred embodiments of this disclosure, the method for preparing the solid dispersion sheet includes the following steps:

[0176] (1) The preparation steps of the solid dispersion of compound (I) hydrochloride include: dissolving compound (I) hydrochloride and hydroxypropyl methylcellulose acetate succinate in an organic solvent to obtain a sample solution; spray drying the sample solution to obtain the solid dispersion of compound (I) hydrochloride;

[0177] (2) The preparation steps of the solid dispersion tablets of the hydrochloride of compound (I) include:

[0178] (2a) Premixing: A mixture of microcrystalline cellulose, solid dispersion of compound (I) hydrochloride, lactose monohydrate, croscarmellose sodium and colloidal silica is premixed to obtain premix 1; 0.1 to 0.9 times the amount of magnesium stearate in the formulation is added to premix 1 to obtain premix 2;

[0179] (2b) Dry granulation: Premix 2 is subjected to dry granulation to obtain the granules;

[0180] (2c) Final blend: The prepared granules are mixed with the remaining amount of added magnesium stearate to obtain the final blend;

[0181] (2d) Tableting: The final mixture is compressed to obtain solid dispersion tablets of the hydrochloride of compound (I).

[0182] In some preferred embodiments of this disclosure, the method for preparing the solid dispersion sheet includes the following steps:

[0183] (1) The preparation steps of the solid dispersion include: dissolving compound (I) hydrochloride and hydroxypropyl methylcellulose acetate succinate in an organic solvent to obtain a sample solution; spray drying the sample solution to obtain a solid dispersion;

[0184] (2) The preparation steps of the solid dispersion tablets of the hydrochloride of compound (I) include:

[0185] (2a) Premixing: A mixture of microcrystalline cellulose, solid dispersion, lactose monohydrate, croscarmellose sodium and colloidal silica is premixed to obtain premix 1; 0.3 to 0.7 times the amount of magnesium stearate in the formulation is added to premix 1 to obtain premix 2;

[0186] (2b) Dry granulation: Premix 2 is subjected to dry granulation to obtain the granules;

[0187] (2c) Final blend: The prepared granules are mixed with the remaining amount of added magnesium stearate to obtain the final blend;

[0188] (2d) Tableting: The final mixture is compressed to obtain solid dispersion tablets of the hydrochloride of compound (I).

[0189] In some preferred embodiments of this disclosure, the method for preparing the solid dispersion sheet includes the following steps:

[0190] (1) The preparation steps of the solid dispersion include: dissolving compound (I) hydrochloride and hydroxypropyl methylcellulose acetate succinate in an organic solvent to obtain a sample solution; spray drying the sample solution to obtain a solid dispersion;

[0191] (2) The preparation steps of the solid dispersion tablets of the hydrochloride of compound (I) include:

[0192] (2a) Premixing: A mixture of microcrystalline cellulose, solid dispersion, lactose monohydrate, croscarmellose sodium and colloidal silica is premixed to obtain premix 1; 0.4 to 0.6 times the amount of magnesium stearate in the formulation is added to premix 1 to obtain premix 2;

[0193] (2b) Dry granulation: Premix 2 is subjected to dry granulation to obtain the granules;

[0194] (2c) Final blend: The prepared granules are mixed with the remaining amount of added magnesium stearate to obtain the final blend;

[0195] (2d) Tableting: The final mixture is compressed to obtain solid dispersion tablets of the hydrochloride of compound (I).

[0196] In some preferred embodiments of this disclosure, the method for preparing the solid dispersion sheet includes the following steps:

[0197] (1) The preparation steps of the solid dispersion include: dissolving compound (I) hydrochloride and hydroxypropyl methylcellulose acetate succinate in an organic solvent to obtain a sample solution; spray drying the sample solution to obtain a solid dispersion;

[0198] (2) The preparation steps of the solid dispersion tablets of the hydrochloride of compound (I) include:

[0199] (2a) Premixing: The mixture of microcrystalline cellulose, solid dispersion, lactose monohydrate, croscarmellose sodium and colloidal silica is premixed to obtain premix 1; 0.5 times the amount of magnesium stearate in the formulation is added to premix 1 to obtain premix 2;

[0200] (2b) Dry granulation: Premix 2 is subjected to dry granulation to obtain the granules;

[0201] (2c) Final blend: The prepared granules are mixed with the remaining amount of added magnesium stearate to obtain the final blend;

[0202] (2d) Tableting: The final mixture is compressed to obtain solid dispersion tablets of the hydrochloride of compound (I).

[0203] In some preferred embodiments of this disclosure, the preparation steps of the solid dispersion tablets of compound (I) hydrochloride further include a pretreatment step: mixing microcrystalline cellulose, solid dispersion of compound (I) hydrochloride, lactose monohydrate, cross-linked sodium carboxymethyl cellulose and colloidal silica, and sieving to obtain a mixture.

[0204] On the other hand, this disclosure provides a method for preparing a pharmaceutical formulation as described above, wherein the pharmaceutical formulation is a solid dispersible tablet; the method for preparing the solid dispersible tablet includes the following steps:

[0205] (1) The preparation steps of the solid dispersion of compound (I) include: dissolving compound (I) and ionic polymer in an organic solvent to obtain a sample solution; spray drying the sample solution to obtain the solid dispersion of compound (I);

[0206] (2) The preparation steps of solid dispersion tablets of compound (I) include: preparing solid dispersion tablets of compound (I) using solid dispersion of compound (I).

[0207] In some preferred embodiments of this disclosure, the method for preparing the solid dispersion sheet includes the following steps:

[0208] (1) The preparation steps of the solid dispersion of compound (I) include: dissolving compound (I) and ionic polymer in an organic solvent to obtain a sample solution; spray drying the sample solution to obtain the solid dispersion of compound (I);

[0209] (2) The preparation steps of the solid dispersion tablet of compound (I) include:

[0210] (2a) Premixing: Premixing a mixture of adhesive, solid dispersion of compound (I), filler, disintegrant and flow aid to obtain premix 1; adding 0.1 to 0.9 times the amount of lubricant to premix 1 to obtain premix 2;

[0211] (2b) Dry granulation: Premix 2 is subjected to dry granulation to obtain the granules;

[0212] (2c) Final blend: The prepared granules are mixed with the remaining amount of added lubricant to obtain the final blend;

[0213] (2d) Tableting: The final mixture is compressed to obtain a solid dispersion tablet of compound (I).

[0214] In some preferred embodiments of this disclosure, the method for preparing the solid dispersion sheet includes the following steps:

[0215] (1) The preparation steps of the solid dispersion include: dissolving the (I) compound and the ionic polymer in an organic solvent to obtain a sample solution; and spray drying the sample solution to obtain a solid dispersion.

[0216] (2) The preparation steps of the solid dispersion tablet of compound (I) include:

[0217] (2a) Premixing: Premixing a mixture of adhesive, solid dispersion, filler, disintegrant and flow aid to obtain premix 1; adding 0.3 to 0.7 times the amount of lubricant to premix 1 to obtain premix 2;

[0218] (2b) Dry granulation: Premix 2 is subjected to dry granulation to obtain the granules;

[0219] (2c) Final blend: The prepared granules are mixed with the remaining amount of added lubricant to obtain the final blend;

[0220] (2d) Tableting: The final mixture is compressed to obtain a solid dispersion tablet of compound (I).

[0221] In some preferred embodiments of this disclosure, the method for preparing the solid dispersion sheet includes the following steps:

[0222] (1) The preparation steps of the solid dispersion include: dissolving the (I) compound and the ionic polymer in an organic solvent to obtain a sample solution; and spray drying the sample solution to obtain a solid dispersion.

[0223] (2) The preparation steps of the solid dispersion tablet of compound (I) include:

[0224] (2a) Premixing: Premixing a mixture of adhesive, solid dispersion, filler, disintegrant and flow aid to obtain premix 1; adding 0.4 to 0.6 times the amount of lubricant to premix 1 to obtain premix 2;

[0225] (2b) Dry granulation: Premix 2 is subjected to dry granulation to obtain the granules;

[0226] (2c) Final blend: The prepared granules are mixed with the remaining amount of added lubricant to obtain the final blend;

[0227] (2d) Tableting: The final mixture is compressed to obtain a solid dispersion tablet of compound (I).

[0228] In some preferred embodiments of this disclosure, the method for preparing the solid dispersion sheet includes the following steps:

[0229] (1) The preparation steps of the solid dispersion include: dissolving the (I) compound and the ionic polymer in an organic solvent to obtain a sample solution; and spray drying the sample solution to obtain a solid dispersion.

[0230] (2) The preparation steps of the solid dispersion tablet of compound (I) include:

[0231] (2a) Premixing: Premixing the mixture of adhesive, solid dispersion, filler, disintegrant and glidant to obtain premix 1; adding 0.5 times the amount of lubricant to premix 1 to obtain premix 2;

[0232] (2b) Dry granulation: Premix 2 is subjected to dry granulation to obtain the granules;

[0233] (2c) Final blend: The prepared granules are mixed with the remaining amount of added lubricant to obtain the final blend;

[0234] (2d) Tableting: The final mixture is compressed to obtain a solid dispersion tablet of compound (I).

[0235] In some preferred embodiments of this disclosure, the preparation steps of the solid dispersion tablet of formula (I) compound further include a pretreatment step: mixing the binder, the solid dispersion of formula (I) compound, the filler, the disintegrant, and the flow aid, and sieving to obtain a mixture.

[0236] In some preferred embodiments of this disclosure, the organic solvent in the pretreatment step is methanol and dichloromethane.

[0237] In some preferred embodiments of this disclosure, the mass percentage of methanol in the pretreatment step is 0.1% to 5%.

[0238] In some preferred embodiments of this disclosure, the mass percentage of methanol is 0.5% to 3%.

[0239] In some preferred embodiments of this disclosure, the mass percentage of methanol is 0.6% to 2%.

[0240] In some preferred embodiments of this disclosure, the mass percentage of dichloromethane in the pretreatment step is 0.2% to 10%.

[0241] In some preferred embodiments of this disclosure, the mass percentage of dichloromethane in the pretreatment step is 0.5% to 5%.

[0242] In some preferred embodiments of this disclosure, the mass percentage of dichloromethane in the pretreatment step is 1% to 3%.

[0243] In some preferred embodiments of this disclosure, the method for preparing the solid dispersion sheet includes the following steps:

[0244] (1) The preparation steps of the solid dispersion of compound (I) include: dissolving compound (I) and hydroxypropyl methylcellulose acetate succinate in an organic solvent to obtain a sample solution; spray drying the sample solution to obtain the solid dispersion of compound (I);

[0245] (2) The preparation steps of the solid dispersion tablet of compound (I) include:

[0246] (2a) Premixing: A mixture of microcrystalline cellulose, solid dispersion of compound (I), lactose monohydrate, croscarmellose sodium and colloidal silica is premixed to obtain premix 1; 0.1 to 0.9 times the amount of magnesium stearate in the formulation is added to premix 1 to obtain premix 2;

[0247] (2b) Dry granulation: Premix 2 is subjected to dry granulation to obtain the granules;

[0248] (2c) Final blend: The prepared granules are mixed with the remaining amount of added magnesium stearate to obtain the final blend;

[0249] (2d) Tableting: The final mixture is compressed to obtain a solid dispersion tablet of compound (I).

[0250] In some preferred embodiments of this disclosure, the method for preparing the solid dispersion sheet includes the following steps:

[0251] (1) The preparation steps of the solid dispersion include: dissolving compound (I) with hydroxypropyl methylcellulose acetate succinate in an organic solvent to obtain a sample solution; spray drying the sample solution to obtain a solid dispersion;

[0252] (2) The preparation steps of the solid dispersion tablet of compound (I) include:

[0253] (2a) Premixing: A mixture of microcrystalline cellulose, solid dispersion, lactose monohydrate, croscarmellose sodium and colloidal silica is premixed to obtain premix 1; 0.3 to 0.7 times the amount of magnesium stearate in the formulation is added to premix 1 to obtain premix 2;

[0254] (2b) Dry granulation: Premix 2 is subjected to dry granulation to obtain the granules;

[0255] (2c) Final blend: The prepared granules are mixed with the remaining amount of added magnesium stearate to obtain the final blend;

[0256] (2d) Tableting: The final mixture is compressed to obtain a solid dispersion tablet of compound (I).

[0257] In some preferred embodiments of this disclosure, the method for preparing the solid dispersion sheet includes the following steps:

[0258] (1) The preparation steps of the solid dispersion include: dissolving compound (I) with hydroxypropyl methylcellulose acetate succinate in an organic solvent to obtain a sample solution; spray drying the sample solution to obtain a solid dispersion;

[0259] (2) The preparation steps of the solid dispersion tablet of compound (I) include:

[0260] (2a) Premixing: A mixture of microcrystalline cellulose, solid dispersion, lactose monohydrate, croscarmellose sodium and colloidal silica is premixed to obtain premix 1; 0.4 to 0.6 times the amount of magnesium stearate in the formulation is added to premix 1 to obtain premix 2;

[0261] (2b) Dry granulation: Premix 2 is subjected to dry granulation to obtain the granules;

[0262] (2c) Final blend: The prepared granules are mixed with the remaining amount of added magnesium stearate to obtain the final blend;

[0263] (2d) Tableting: The final mixture is compressed to obtain a solid dispersion tablet of compound (I).

[0264] In some preferred embodiments of this disclosure, the method for preparing the solid dispersion sheet includes the following steps:

[0265] (1) The preparation steps of the solid dispersion include: dissolving compound (I) with hydroxypropyl methylcellulose acetate succinate in an organic solvent to obtain a sample solution; spray drying the sample solution to obtain a solid dispersion;

[0266] (2) The preparation steps of the solid dispersion tablet of compound (I) include:

[0267] (2a) Premixing: The mixture of microcrystalline cellulose, solid dispersion, lactose monohydrate, croscarmellose sodium and colloidal silica is premixed to obtain premix 1; 0.5 times the amount of magnesium stearate in the formulation is added to premix 1 to obtain premix 2;

[0268] (2b) Dry granulation: Premix 2 is subjected to dry granulation to obtain the granules;

[0269] (2c) Final blend: The prepared granules are mixed with the remaining amount of added magnesium stearate to obtain the final blend;

[0270] (2d) Tableting: The final mixture is compressed to obtain a solid dispersion tablet of compound (I).

[0271] In some preferred embodiments of this disclosure, the preparation steps of the solid dispersion tablets of formula (I) further include a pretreatment step: mixing microcrystalline cellulose, solid dispersion of formula (I), lactose monohydrate, cross-linked sodium carboxymethyl cellulose and colloidal silica, and sieving to obtain a mixture.

[0272] In some preferred embodiments of this disclosure, the organic solvent in the pretreatment step is methanol and dichloromethane.

[0273] On the other hand, this disclosure provides the use of the pharmaceutical formulation as described above or the preparation method as described above in the preparation of a medicament for TOLL-like receptor (TLR) related diseases.

[0274] This disclosure has the following advantages:

[0275] (1) This disclosure provides a pharmaceutical formulation containing a TOLL-like receptor inhibitory compound or its hydrochloride salt, which can increase the drug exposure in vivo.

[0276] (2) This disclosure provides a pharmaceutical formulation containing a TOLL-like receptor inhibitory compound or its hydrochloride salt, which can improve bioavailability. Attached Figure Description

[0277] To more clearly illustrate the technical solutions in the specific embodiments of this disclosure or the prior art, the accompanying drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of this disclosure. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort. The accompanying drawings are incorporated in and constitute a part of this specification, illustrating embodiments consistent with this specification, and are used together with the specification to explain the principles of this specification.

[0278] Figure 1 XRPD diagrams of the crystal forms of compound (I) under different conditions are shown.

[0279] Figure 2 XRPD diagrams of the crystal forms of the hydrochloride salt of formula (I) under different conditions are shown. Detailed Implementation

[0280] Definitions and Explanations

[0281] To facilitate understanding of this disclosure, certain technical and scientific terms are specifically defined below. In this disclosure, unless otherwise stated, the scientific and technical terms used herein have meanings commonly understood by those skilled in the art. Furthermore, the cell and tissue culture, microbiology-related terms, and laboratory procedures used herein are all widely used terms and routine procedures in their respective fields. Meanwhile, to better understand this disclosure, definitions and explanations of relevant terms are provided below. It should be understood that this disclosure is not limited to specific methods, reagents, compounds, compositions, or biological systems, and variations thereof are certainly possible. It should also be understood that the terminology used in this application is for describing specific embodiments only and is not intended to be limiting.

[0282] Unless otherwise expressly stated, the terms “a,” “an,” and “the” as used in this specification and the appended claims cover one or more types.

[0283] As used herein, the terms “comprising” and “having”, and any variations thereof, are intended to cover non-exclusive inclusion. For example, a process, method, apparatus, product, or device that includes a series of steps is not limited to the steps or modules listed, but may optionally include steps not listed, or may optionally include other steps inherent to such process, method, product, or device.

[0284] In the description herein, references to “some embodiments,” “some implementations,” or “some implementation schemes” describe a subset of all possible embodiments. However, it is understood that “some embodiments” may be the same subset or different subsets of all possible embodiments and may be combined with each other without conflict.

[0285] Example

[0286] To make the objectives, technical solutions, and advantages of the embodiments of this disclosure clearer, the technical solutions in the embodiments of this disclosure are described clearly and completely. Obviously, the described embodiments are only some embodiments of this disclosure, not all embodiments. The following is merely a further description of this disclosure, and the scope of protection of this disclosure is not limited thereto. In the embodiments, comparative examples, and experimental examples of this disclosure, the technical means or methods, etc., not specifically described are conventional technical means or methods in the art. Unless otherwise specified, the materials, reagents, etc., used in the embodiments, comparative examples, and experimental examples of this disclosure are all commercially available.

[0287] <Compound hydrochloride of formula (I)>

[0288] The hydrochloride salt of formula (I) was obtained by referring to the preparation method of the hydrochloride salt of formula (I) described in the patent document with patent application number CN202210357455.3 (publication number CN114478374A).

[0289] <Compound of Formula (I)>

[0290] The preparation steps of compound (I) are as follows:

[0291] (1) Preparation of potassium carbonate aqueous solution: Add potassium carbonate to purified water and stir until completely dissolved;

[0292] (2) Add the hydrochloride of compound (I) to the prepared potassium carbonate aqueous solution, control the temperature to 20-30℃, stir for 4h, filter and wash the filter cake with purified water.

[0293] (3) The filter cake is slurried with purified water 1-2 times to obtain the crude product of the free state of compound (I);

[0294] (4) The crude product of formula (I) in its free state is dissolved by heating with DMAC, and purified water is added dropwise until the product precipitates. After filtration, washing with water and drying, the free state of formula (I) is obtained, which is the compound of formula (I).

[0295] <Preparation of the crystal form of compound (I)>

[0296] The solid dispersion of compound (I) is produced by spray drying, and the specific process steps are as follows:

[0297] Dissolving the active pharmaceutical ingredient: Measure the amount of methanol and dichloromethane in the formula, mix them evenly, and add the amounts of A1, A2, A3, A4, A5, and A6 in the formula respectively. Stir until clear to obtain the sample solution.

[0298] A1, A2, A3, A4, A5, and A6 are as follows:

[0299] A1: Active pharmaceutical ingredient (I) compound, hydroxypropyl methylcellulose acetate succinate [HPMC AS (model: HMP)];

[0300] A2: Active pharmaceutical ingredient (I) compound, hydroxypropyl methylcellulose acetate succinate [HPMC AS (model: HMP)], sodium dodecyl sulfate;

[0301] A3: Active pharmaceutical ingredient (I) compound, hydroxypropyl methylcellulose acetate succinate [HPMC AS (model: HMP)], vitamin E polyethylene glycol succinate;

[0302] A4: Active pharmaceutical ingredient (I) compound, hydroxypropyl methylcellulose acetate succinate [HPMC AS (model: HMP)];

[0303] A5: Active pharmaceutical ingredient (I) compound, hydroxypropyl methylcellulose acetate succinate [HPMC AS (model: HMP)], sodium dodecyl sulfate;

[0304] A6: Active pharmaceutical ingredient (I) compound, hydroxypropyl methylcellulose acetate succinate [HPMC AS (model: HMP)], vitamin E polyethylene glycol succinate.

[0305] Spray drying: The sample solution is spray dried with the spray drying inlet air temperature set at 60°C and the atomization pressure at 0.05-0.20 MPa. After spray drying, a solid dispersion of the hydrochloride of compound (I) is obtained.

[0306] XRPD diagrams of the crystal forms of compound (I) under different conditions are shown in Figure 1. Figure 1 The specific conditions are as follows:

[0307]

[0308] <Preparation of the crystal form of compound (I) hydrochloride>

[0309] The production process of the hydrochloride solid dispersion of compound (I) is spray drying, and the specific process steps are as follows:

[0310] Dissolving the active pharmaceutical ingredient: Measure the amount of methanol and dichloromethane specified in the formula, mix them evenly, add the amounts of B1, B2, B3, B4, B5, and B6 specified in the formula, and stir until clear to obtain the sample solution.

[0311] Among them, B1, B2, B3, B4, B5, and B6 are as follows:

[0312] B1: Active pharmaceutical ingredient (I) compound hydrochloride, hydroxypropyl methylcellulose acetate succinate [HPMC AS (model: HMP)];

[0313] B2: Active pharmaceutical ingredient (I) compound hydrochloride, hydroxypropyl methylcellulose acetate succinate [HPMC AS (model: HMP)], sodium dodecyl sulfate;

[0314] B3: Active pharmaceutical ingredient (I) compound hydrochloride, hydroxypropyl methylcellulose acetate succinate [HPMC AS (model: HMP)], and vitamin E polyethylene glycol succinate;

[0315] B4: Active pharmaceutical ingredient (I) compound hydrochloride, hydroxypropyl methylcellulose acetate succinate [HPMC AS (model: HMP)];

[0316] B5: Active pharmaceutical ingredient (I) compound hydrochloride, hydroxypropyl methylcellulose acetate succinate [HPMC AS (model: HMP)], sodium dodecyl sulfate;

[0317] B6: Active pharmaceutical ingredient (I) compound hydrochloride, hydroxypropyl methylcellulose acetate succinate [HPMC AS (model: HMP)], and vitamin E polyethylene glycol succinate.

[0318] Spray drying: The sample solution is spray dried with the spray drying inlet air temperature set at 60°C and the atomization pressure at 0.05-0.20 MPa. After spray drying, a solid dispersion of the hydrochloride of compound (I) is obtained.

[0319] XRPD diagrams of the crystal forms of the hydrochloride salt of formula (I) under different conditions are shown below. Figure 2 The specific conditions are as follows:

[0320]

[0321]

[0322] Example 1

[0323] The formulation of the solid dispersion tablets of compound (I) hydrochloride is as follows:

[0324]

[0325] methanol [1] dichloromethane [2] It is removed during the process as a solvent in the preparation of solid dispersions.

[0326] 1.2 The preparation method of the solid dispersion tablet of the hydrochloride of compound (I) includes the following steps:

[0327] (1) The production process of the hydrochloride solid dispersion of compound (I) is spray drying, and the specific process steps are as follows:

[0328] Dissolving the active pharmaceutical ingredient: Measure the amount of methanol and dichloromethane in the formula, mix them evenly, add the amount of active pharmaceutical ingredient (I) compound hydrochloride and hydroxypropyl methylcellulose acetate succinate [HPMC AS (model: HMP)] in the formula, stir until clear, and obtain the sample solution.

[0329] Spray drying: The sample solution is spray dried with the spray drying inlet air temperature set at 60°C and the atomization pressure at 0.05-0.20 MPa. After spray drying, a solid dispersion of the hydrochloride of compound (I) is obtained.

[0330] (2) The production process of the hydrochloride solid dispersion tablets of formula (I) is a dry granulation process. The specific process steps for the 28.5mg tablet specification are as follows:

[0331] Pretreatment: Microcrystalline cellulose, solid dispersion of compound (I) hydrochloride, colloidal silica, cross-linked sodium carboxymethyl cellulose and lactose monohydrate were added sequentially into a hopper mixer and mixed for 15 minutes to obtain a preliminary mixture.

[0332] Premix: Add the initial mixture to the hopper mixer and mix for 10 minutes. Then add 0.5 times the amount of internally added magnesium stearate (passed through a 40-mesh sieve) and continue mixing for 10 minutes to obtain the premix.

[0333] Dry granulation: The premix is ​​fed into a dry granulator, the roller pressure is set to 3-8KN, and the roller speed is 3-10rpm to perform dry granulation and obtain the granules 1.

[0334] Dry granulation: The prepared granules 1 are passed through 10-mesh and 18-mesh sieves in sequence to obtain the prepared granules 2.

[0335] Final mixing: Add the prepared granules 2 and 0.5 times the amount of magnesium stearate (added) to the hopper mixer and mix for 20 minutes to obtain the final mixture.

[0336] Tableting: After the final mixture passes the test, it is compressed into tablets to obtain solid dispersion tablets of compound (I) hydrochloride; specification: 28.5mg; theoretical tablet weight: 570mg; hardness: 90-140N.

[0337] Example 2

[0338] 2.1 The formulation of the solid dispersion tablets of compound (I) hydrochloride is as follows:

[0339]

[0340] methanol [1] dichloromethane [2] It is removed during the process as a solvent in the preparation of solid dispersions.

[0341] 2.2 The preparation method of the solid dispersion tablet of the hydrochloride of compound (I) includes the following steps:

[0342] (1) The production process of the hydrochloride solid dispersion of compound (I) is spray drying, and the specific process steps are as follows:

[0343] Dissolving the active pharmaceutical ingredient: Measure the amount of methanol and dichloromethane according to the formula, mix them evenly, add the amount of active pharmaceutical ingredient and hydroxypropyl methylcellulose acetate succinate [HPMC AS (model: HMP)] according to the formula, stir until clear, and obtain the sample solution.

[0344] Spray drying: The sample solution is spray dried with the inlet air temperature set at 60℃ and the atomization pressure at 0.05~0.20Mpa. After spray drying, the hydrochloride solid dispersion of compound (I) is obtained.

[0345] (2) The production process of the hydrochloride solid dispersion tablets of formula (I) is a dry granulation process. The specific process steps for the 28.5mg tablet specification are as follows:

[0346] Pretreatment: Microcrystalline cellulose, compound (I) hydrochloride solid dispersion, colloidal silica, cross-linked sodium carboxymethyl cellulose and lactose monohydrate were added sequentially into a hopper mixer and mixed for 15 minutes to obtain a preliminary mixture.

[0347] Premix: Add the initial mixture to the hopper mixer and mix for 10 minutes. Then add 0.5 times the amount of magnesium stearate as per the formula and continue mixing for 10 minutes to obtain the premix.

[0348] Dry granulation: The premix is ​​fed into a dry granulator, the roller pressure is set to 3-8KN, and the roller speed is 3-10rpm to perform dry granulation and obtain the granules 1.

[0349] Dry granulation: The prepared granules 1 are passed through 10-mesh and 18-mesh sieves in sequence to obtain the prepared granules 2.

[0350] Final mixing: Add the prepared granules 2 and 0.5 times the amount of magnesium stearate (added) to the hopper mixer and mix for 20 minutes to obtain the final mixture.

[0351] Tableting: After the final mixture passes the test, it is compressed into tablets to obtain solid dispersion tablets of compound (I) hydrochloride; specification: 28.5mg; theoretical tablet weight: 570mg; hardness: 90-140N.

[0352] Example 3

[0353] 3.1 The formulation of the solid dispersion tablet of compound (I) is as follows:

[0354]

[0355] methanol [1] dichloromethane [2] It is removed during the process as a solvent in the preparation of solid dispersions.

[0356] 3.2 The preparation method of the solid dispersion tablet of compound (I) includes the following steps:

[0357] (1) The production process of the solid dispersion of compound (I) is spray drying, and the specific process steps are as follows:

[0358] Dissolving the active pharmaceutical ingredient: Measure the amount of methanol and dichloromethane according to the formula, mix them evenly, add the amount of active pharmaceutical ingredient (I) and hydroxypropyl methylcellulose acetate succinate [HPMC AS (model: HMP)] according to the formula, stir until clear, and obtain the sample solution.

[0359] Spray drying: The sample solution is spray dried with the spray drying inlet air temperature set at 60°C and the atomization pressure at 0.05-0.20 MPa. After spray drying, a solid dispersion of compound (I) is obtained.

[0360] (2) The production process of solid dispersion tablets of compound (I) is a dry granulation process. The specific process steps for 28.5mg tablets are as follows:

[0361] Pretreatment: Microcrystalline cellulose, solid dispersion of compound (I), colloidal silica, cross-linked sodium carboxymethyl cellulose and lactose monohydrate were added sequentially to a hopper mixer and mixed for 15 minutes to obtain a preliminary mixture.

[0362] Premix: Add the initial mixture to the hopper mixer and mix for 10 minutes. Then add 0.5 times the amount of internally added magnesium stearate (passed through a 40-mesh sieve) and continue mixing for 10 minutes to obtain the premix.

[0363] Dry granulation: The premix is ​​fed into a dry granulator, the roller pressure is set to 3-8KN, and the roller speed is 3-10rpm to perform dry granulation and obtain the granules 1.

[0364] Dry granulation: The prepared granules 1 are passed through 10-mesh and 18-mesh sieves in sequence to obtain the prepared granules 2.

[0365] Final mixing: Add the prepared granules 2 and 0.5 times the amount of magnesium stearate (added) to the hopper mixer and mix for 20 minutes to obtain the final mixture.

[0366] Tableting: After the final mixture passes the test, it is compressed into tablets to obtain solid dispersion tablets of compound (I); Specification: 28.5mg; theoretical tablet weight 570mg; hardness: 90-140N.

[0367] Comparative Example 1

[0368] The formulation of the hydrochloride drug preparation of compound (I) is as follows:

[0369]

[0370] Purified water [1] It is a wetting agent for internal adhesives, which is removed during the process.

[0371] Purified water [2] It is a dispersant for coating powder and is removed during the process.

[0372] The preparation method of the pharmaceutical formulation of the hydrochloride salt of compound (I) includes the following steps:

[0373] Pretreatment of active pharmaceutical ingredient (API): The hydrochloride salt of API (I) is air-jet pulverized to achieve a particle size D90≤10μm; lactose monohydrate, microcrystalline cellulose, hydroxypropyl cellulose, 0.5 times the amount of cross-linked sodium carboxymethyl cellulose (added internally), and colloidal silica are all sieved through a 40-mesh sieve.

[0374] Premixing: Add raw and auxiliary materials to a wet mixing granulator according to the principle of adding auxiliary materials first and then raw materials, and premix for 5 minutes (stirring speed 160 rpm, shearing speed 800 rpm) to obtain a premix.

[0375] Granulation: Add the amount of purified water specified in the formula to the granulator (stirring speed 150 rpm, shearing speed 500 rpm); after the water is added, granulation is performed (stirring speed 150 rpm, shearing speed 500 rpm, granulation time 15 s) to obtain the granules 1.

[0376] Wet granulation: The prepared granules are wet granulated using a high-speed granulator with a screen aperture of 5.0mm*5.0mm square holes and a granulation speed of 350rpm to obtain granules 2.

[0377] Drying: The prepared granules 2 are placed in a fluidized bed, and the inlet air temperature is set to 70℃, and dried until the moisture content is <2.0%.

[0378] Dry granulation: Dry granules 1 are granulated using a high-speed granulator with a screen aperture of 1.2mm and a granulation speed of 350rpm to obtain dry granules 2.

[0379] Final mixing: The obtained dry granules 2, 0.5 times the amount of added cross-linked sodium carboxymethyl cellulose (added) and magnesium stearate were added to the hopper mixer for mixing at a speed of 15 rpm for 10 min to obtain the final mixture.

[0380] Tableting: After the final mixture passes the test, it is compressed into tablets to obtain tablets containing the hydrochloride salt of compound (I); 50mg specification: theoretical tablet weight 125mg; hardness: 50-90N; 200mg specification: theoretical tablet weight 500mg; hardness: 100-150N.

[0381] Coating: Preparation of coating solution: Prepare coating solution according to the ratio of film coating premix (gastric-soluble type): purified water = 10:90 (W:W), inlet air temperature: 40-60℃; coating weight gain: 5%, and coat the tablet containing the hydrochloride of compound (I) to obtain the pharmaceutical preparation of the hydrochloride of compound (I).

[0382] Comparative Example 2

[0383] The formulation of the solid dispersion tablets of compound (I) is as follows:

[0384]

[0385] methanol [1] dichloromethane [2] It is removed during the process as a solvent in the preparation of solid dispersions.

[0386] The preparation method of the solid dispersion tablet of compound (I) includes the following steps:

[0387] (1) The production process of the solid dispersion of compound (I) is spray drying, and the specific process steps are as follows:

[0388] Dissolving the active pharmaceutical ingredient: Measure the amount of methanol and dichloromethane according to the formula, mix them evenly, add the amount of active pharmaceutical ingredient and hydroxypropyl methylcellulose acetate succinate [HPMC AS (model: HMP)] according to the formula, stir until clear, and obtain the sample solution.

[0389] Spray drying: The sample solution is spray dried with the inlet air temperature set at 60℃ and the atomization pressure at 0.05~0.20Mpa. After spray drying, a solid dispersion of compound (I) is obtained.

[0390] (2) The production process of solid dispersion tablets of compound (I) is a dry granulation process. The specific process steps for 28.5mg tablets are as follows:

[0391] Pretreatment: Microcrystalline cellulose, solid dispersion of compound (I), colloidal silica, cross-linked sodium carboxymethyl cellulose and lactose monohydrate were added sequentially to a hopper mixer and mixed for 15 minutes to obtain a preliminary mixture.

[0392] Premix: Add the initial mixture to the hopper mixer and mix for 10 minutes. Then add 0.5 times the amount of magnesium stearate as per the formula and continue mixing for 10 minutes to obtain the premix.

[0393] Dry granulation: The premix is ​​fed into a dry granulator, the roller pressure is set to 3-8KN, and the roller speed is 3-10rpm to perform dry granulation and obtain the granules 1.

[0394] Dry granulation: The prepared granules 1 are passed through 10-mesh and 18-mesh sieves in sequence to obtain the prepared granules 2.

[0395] Final mixing: Add the prepared granules 2 and 0.5 times the amount of magnesium stearate (added) to the hopper mixer and mix for 20 minutes to obtain the final mixture.

[0396] Tableting: After the final mixture passes the test, it is compressed into tablets to obtain solid dispersion tablets of compound (I); Specification: 28.5mg; theoretical tablet weight 570mg; hardness: 90-140N.

[0397] Experimental Example 1

[0398] The effects of simulated gastric juice on the solid dispersible tablets of compound (I) hydrochloride from Example 1, Compound (I) hydrochloride from Example 2, Compound (I) hydrochloride from Example 3, Compound (I) hydrochloride pharmaceutical preparation from Comparative Example 1, and Compound (I) hydrochloride solid dispersible tablets from Comparative Example 2 were studied.

[0399] (1) Preparation of dissolution medium

[0400] Fasting simulated gastric fluid: 88.40g of FaSSGF buffer was added to 2310ml of degassed purified water, 0.144g of Powde-3F was added, and the mixture was stirred evenly. The pH values ​​were measured as follows: pH 1: 1.69, pH 2: 1.68, with an average value of 1.7.

[0401] Fasting simulated intestinal fluid: 164.74g of FaSSIF buffer was added to 3800ml of degassed purified water, 8.86g of Powde-3F was added, and the mixture was stirred evenly. The pH values ​​were measured as follows: pH 1: 6.52, pH 2: 6.5, and the average value was 6.5.

[0402] FaSSGF Buffer, FaSSIF Buffer, and Powde-3F were all purchased from Beijing Zhongke Runtian Trading Co., Ltd., and the product brand is Biorelevant.

[0403] (2) Dissolution test

[0404] Six tablets each of the following compounds were prepared: Formula (I) hydrochloride solid dispersible tablets from Example 1, Example 2, Example 3, Comparative Example 1, and Comparative Example 2. Six tablets of each compound were used in a Fox dissolution apparatus (model FADT-801RC) on a fasting simulated gastric fluid medium. Dissolution and release assays (USP Method II - Paddle Method) were performed with a dissolution medium volume of 80 ml and a rotation speed of 75 rpm. Samples of 1.5 ml were taken at 10 and 30 minutes, and 1.5 ml of the solution was added. After 30 minutes, 160 ml of fasting simulated intestinal fluid was added, and samples of 1.5 ml were taken at 45, 60, 90, and 120 minutes, and 1.5 ml of the solution was added. The rotation speed was changed to 200 rpm, and samples were taken after 150 min. The concentration of compound (I) hydrochloride in the sample solution of solid dispersible tablets of formula (I) in Example 1, solid dispersible tablets of formula (I) hydrochloride in Example 2, and solid dispersible tablets of formula (I) hydrochloride in Comparative Example 1 was determined by liquid chromatography, and the cumulative dissolution rate was calculated. The concentration of compound (I) in the sample solution of solid dispersible tablets of formula (I) in Example 3 and solid dispersible tablets of formula (I) in Comparative Example 2 was determined by liquid chromatography, and the cumulative dissolution rate was calculated. The results are shown in Table 1.

[0405] Table 1. Effects of simulated gastric juice and simulated intestinal juice on drugs

[0406]

[0407]

[0408] As shown in Table 1, compared with the hydrochloride drug formulation of Formula (I) in Comparative Example 1, the TollB solid dispersion tablets of Example 1 showed a significantly higher drug concentration in simulated intestinal fluid; the hydrochloride solid dispersion tablets of Formula (I) in Example 2 also showed a significant increase in drug concentration in simulated intestinal fluid.

[0409] Compared to the solid dispersion tablet of compound (I) in Comparative Example 2, the solid dispersion tablet of compound (I) in Example 3 showed a significantly higher drug concentration in simulated intestinal fluid. The experimental results indicate that, compared to the hydrochloride drug formulation of compound (I) in Comparative Example 1, both the solid dispersion tablets of compound (I) in Example 1 and Compound (I) in Example 2 can significantly increase the drug exposure in the intestine, thereby improving drug absorption in the intestine. Compared to the solid dispersion tablet of compound (I) in Comparative Example 2, the solid dispersion tablet of compound (I) in Example 3 can significantly increase the drug exposure in the intestine, thereby improving drug absorption in the intestine.

[0410] Experimental Example 2

[0411] The solid dispersible tablets of the hydrochloride of compound (I) in Example 1, the solid dispersible tablets of the hydrochloride of compound (I) in Example 2, the solid dispersible tablets of the hydrochloride of compound (I) in Example 3, the pharmaceutical preparation of the hydrochloride of compound (I) in Comparative Example 1, and the solid dispersible tablets of the hydrochloride of compound (I) in Comparative Example 2 were subjected to in vivo PK (monkey) experiments.

[0412] Ten female monkeys were administered the drug orally after an overnight fast. Blood samples (1 mL) were collected from the jugular vein at 15 min, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, and 24 h post-administration. Blood samples were placed in tubes containing EDTA-K2 and stored on ice until centrifugation. Blood samples were centrifuged at 4000 rpm for 10 min (4 °C), and plasma was separated within 1 hour and stored at -80 °C. 20 μL of the prepared plasma sample was mixed with 180 μL of acetonitrile solution, vortexed for 3 min, centrifuged for 10 min (4000 rpm, 4 °C), and 130 μL of the supernatant was mixed with 130 μL of 50% acetonitrile-water solution, vortexed for 5 min, and then injected into 10 μL of the solution for LC-MS / MS analysis. In vivo pharmacokinetic (PK) data are shown in Table 2.

[0413] Liquid chromatography: LC: ExionLC AD, AB Sciex

[0414] Autosampler: RACK CHANGER II, Shimadzu

[0415] Chromatographic column: Waters ACQUITY UPLC HSS T3 1.8μm (2.1*50mm)

[0416] Mobile phase A: An aqueous solution containing 0.1% formic acid

[0417] Mobile phase B: Acetonitrile solution containing 0.1% formic acid

[0418] Elution gradient:

[0419]

[0420]

[0421] Column temperature: 40℃

[0422] Injector temperature: 4℃

[0423] Injection volume: 10 μL

[0424] Mass spectrometry: Triple Quad TM 5500+, AB Sciex

[0425] Ion pair: m / z: 266.0 / 223.2

[0426] Ion source: Electrospray ionization source (ESI);

[0427] Scanning mode: Positive ion mode

[0428] Scan mode: MRM

[0429] Electrospray voltage (IS): 5500V;

[0430] Ion source temperature (TEM): 600℃;

[0431] Curtain gas (CUR): 30 psi;

[0432] Nebulizer gas (GS1): 55 psi;

[0433] Auxiliary heating gas (GS2): 55 psi;

[0434] De-clustering voltage (DP): 120V;

[0435] Collision energy (CE): 42 eV.

[0436] Table 2. In vivo PK (monkey) data

[0437] Comparative Example 1 Example 1 Example 2 Example 3 Comparative Example 2 Cmax(ng / ml) 2828 18718 7182 20644 2496 AUC 0-24h 32807 95114 56175 108326 28109

[0438] As shown in Table 2, compared to the hydrochloride drug formulation of Formula (I) in Comparative Example 1, the maximum plasma concentration (Cmax) of the solid dispersible tablet of Formula (I) in Example 1 is about 6 times that of the comparative example; the maximum plasma concentration (Cmax) of the solid dispersible tablet of Formula (I) in Example 2 is about 2.5 times that of the comparative example. The maximum plasma concentration (Cmax) of the solid dispersible tablets of Formula (I) in Examples 1 and 2 is significantly increased.

[0439] Compared to the solid dispersion tablet of compound (I) in Comparative Example 2, the maximum plasma concentration (Cmax) of the drug in the solid dispersion tablet of compound (I) in Example 3 is approximately 8.3 times that of Comparative Example 2; the maximum plasma concentration (Cmax) of the drug in the solid dispersion tablet of compound (I) in Example 3 is significantly increased.

[0440] Compared to the hydrochloride drug formulation of Formula (I) in Comparative Example 1, the total amount of drug in vivo (AUC 0-24h) of the solid dispersible tablet of Formula (I) in Example 1 was approximately 3 times that of the comparative example; the total amount of drug in vivo (AUC 0-24h) of the solid dispersible tablet of Formula (I) in Example 2 was approximately 2 times that of the comparative example. The total amount of drug in vivo (AUC 0-24h) of the solid dispersible tablet of Formula (I) in Examples 1 and 2 was significantly increased.

[0441] Compared to the solid dispersion tablet of compound (I) of Comparative Example 2, the total amount of drug in vivo (AUC 0-24h) of the solid dispersion tablet of compound (I) of Example 3 was approximately 3.85 times that of Comparative Example 2; the total amount of drug in vivo (AUC 0-24h) of the solid dispersion tablet of compound (I) of Example 3 was significantly increased.

[0442] These findings demonstrate that, compared to the pharmaceutical formulation of the hydrochloride salt of compound (I) in Comparative Example 1, both the solid dispersion tablets of the hydrochloride salt of compound (I) in Example 1 and the solid dispersion tablets of the hydrochloride salt of compound (I) in Example 2 can increase in vivo drug exposure or improve bioavailability. Compared to the solid dispersion tablet of the compound (I) in Comparative Example 2, the solid dispersion tablet of the compound (I) in Example 3 can increase in vivo drug exposure or improve bioavailability.

[0443] The foregoing description of specific exemplary embodiments of this disclosure is for illustrative and explanatory purposes. These descriptions are not intended to limit this disclosure to the precise forms disclosed, and it will be apparent that many changes and variations can be made in accordance with the foregoing teachings. The exemplary embodiments were chosen and described in order to explain the specific principles of this disclosure and their practical application, thereby enabling those skilled in the art to implement and utilize various different exemplary embodiments of this disclosure, as well as various different choices and variations. The scope of this disclosure is intended to be defined by the claims and their equivalents.

Claims

1. A pharmaceutical preparation, characterized in that, The active ingredient comprises a TOLL-like receptor inhibitory compound or its hydrochloride salt, and optionally pharmaceutically suitable excipients, wherein the TOLL-like receptor inhibitory compound has the structure shown in formula (I); the TOLL-like receptor inhibitory compound is referred to as compound (I). The TOLL-like receptor inhibitory compound hydrochloride is denoted as compound (I) hydrochloride. The compound of formula (I) or its hydrochloride salt accounts for 1% to 20% of the total mass of the pharmaceutical preparation; The TOLL-like receptor inhibitory compound has the structure shown in formula (I):

2. The pharmaceutical preparation according to claim 1, characterized in that, The excipients include one or more of ionic polymers, adhesives, fillers, disintegrants, flow aids, and lubricants.

3. The pharmaceutical preparation according to claim 1 or 2, characterized in that, The pharmaceutical preparation comprises, by weight percentage, the following components: 1%–20% of the compound of formula (I) or its hydrochloride salt, 5%–30% of the ionic polymer, 15%–50% of the binder, 15%–50% of the filler, 3%–15% of the disintegrant, 0.05%–1.0% of the flow aid, and 0.1%–5% of the lubricant.

4. The pharmaceutical preparation according to claim 3, characterized in that, The ionic polymer is selected from one or more of hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, cellulose acetate benzotriester, polyacrylamide phthalate, and methacrylic acid copolymer. The adhesive is selected from one or more of microcrystalline cellulose, methylcellulose, carboxycellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and alginate; The filler is selected from one or more of the following: lactose monohydrate, sucrose, dextrin, starch, dicalcium phosphate, anhydrous dicalcium phosphate, and calcium phosphate. The disintegrant is selected from one or more of croscarmellose sodium, low-substituted hydroxypropyl cellulose, croscarmellose, sodium carboxymethyl starch, and calcium carboxymethyl cellulose; The flow aid is selected from one or more of colloidal silica, magnesium trisilicate, talc, powdered cellulose, and starch; The lubricant is selected from one or more of magnesium stearate, calcium stearate, micronized silica gel, and sodium dodecyl sulfate.

5. The pharmaceutical preparation according to claim 1, characterized in that, The pharmaceutical preparation comprises, by weight percentage, the following components: 1%–20% of the compound of formula (I) or its hydrochloride salt, 5%–30% of hydroxypropyl methylcellulose acetate succinate, 15%–50% of microcrystalline cellulose, 15%–50% of lactose monohydrate, 3%–15% of croscarmellose sodium, 0.05%–1.0% of colloidal silica, and 0.1%–5% of magnesium stearate.

6. The pharmaceutical preparation according to claim 1, characterized in that, The pharmaceutical preparation comprises, by weight percentage, the following components: 1%–10% of the compound of formula (I) or its hydrochloride salt, 10%–25% of hydroxypropyl methylcellulose acetate succinate, 25%–40% of microcrystalline cellulose, 25%–40% of lactose monohydrate, 5%–11% of croscarmellose sodium, 0.1%–0.5% of colloidal silica, and 0.5%–2.5% of magnesium stearate.

7. The pharmaceutical preparation according to claim 1, characterized in that, The pharmaceutical preparations are tablets, pills, capsules, powders, granules, emulsions, solutions, suspensions, injections, or suppositories.

8. The method for preparing a pharmaceutical preparation according to any one of claims 1 to 7, characterized in that, The method for preparing the solid dispersion tablets includes the following steps: Step (1): The solid dispersion of compound (I) hydrochloride is obtained by dissolving compound (I) hydrochloride and ionic polymer in an organic solvent to obtain a sample solution; the sample solution is then spray-dried to obtain the solid dispersion of compound (I) hydrochloride. Step (2): The preparation steps of the solid dispersion tablets of compound (I) hydrochloride include: (2a) Premixing: The mixture of adhesive, solid dispersion of compound (I) hydrochloride obtained in step (1), filler, disintegrant and flow aid is premixed to obtain premix 1; 0.1 to 0.9 times the amount of lubricant is added to premix 1 to obtain premix 2; (2b) Dry granulation: Premix 2 is subjected to dry granulation to obtain the granules; (2c) Final blend: The prepared granules are mixed with the remaining amount of added lubricant to obtain the final blend; (2d) Tableting: The final mixture is compressed into tablets to obtain solid dispersion tablets of the hydrochloride of compound (I); Preferably, the method for preparing the solid dispersion tablet includes the following steps: Step (1): The solid dispersion of compound (I) is obtained by dissolving compound (I) and ionic polymer in an organic solvent to obtain a sample solution; the sample solution is then spray-dried to obtain the solid dispersion of compound (I). Step (2): The preparation steps of the solid dispersion tablet of compound (I) include: (2a) Premixing: The mixture of adhesive, solid dispersion of compound (I) prepared in step (1), filler, disintegrant and flow aid is premixed to obtain premix 1; 0.1 to 0.9 times the amount of lubricant is added to premix 1 to obtain premix 2; (2b) Dry granulation: Premix 2 is subjected to dry granulation to obtain the granules; (2c) Final blend: The prepared granules are mixed with the remaining amount of added lubricant to obtain the final blend; (2d) Tableting: The final mixture is compressed to obtain a solid dispersion tablet of compound (I).

9. The preparation method according to claim 8, characterized in that, The method for preparing the solid dispersion tablets includes the following steps: Step (1): The solid dispersion of compound (I) hydrochloride was dissolved in an organic solvent to obtain a sample solution; the sample solution was dried to obtain the solid dispersion of compound (I) hydrochloride. Step (2): The preparation steps of the solid dispersion tablets of compound (I) hydrochloride include: (2a) Premixing: The mixture of microcrystalline cellulose, the solid dispersion of compound (I) prepared in step (1), lactose monohydrate, cross-linked sodium carboxymethyl cellulose and colloidal silica is premixed to obtain premix 1; 0.1 to 0.9 times the amount of magnesium stearate is added to premix 1 to obtain premix 2; (2b) Dry granulation: Premix 2 is subjected to dry granulation to obtain the granules; (2c) Final blend: The prepared granules are mixed with the remaining amount of added magnesium stearate to obtain the final blend; (2d) Tableting: The final mixture is compressed into tablets to obtain solid dispersion tablets of the hydrochloride of compound (I); Preferably, the method for preparing the solid dispersion tablet includes the following steps: Step (1): The solid dispersion of compound (I) is obtained by dissolving the hydrochloride of compound (I) and hydroxypropyl methylcellulose acetate succinate in an organic solvent to obtain a sample solution; the sample solution is then dried to obtain the solid dispersion of compound (I). Step (2): The preparation steps of the solid dispersion tablet of compound (I) include: (2a) Premixing: The mixture of microcrystalline cellulose, the solid dispersion of compound (I) prepared in step (1), lactose monohydrate, cross-linked sodium carboxymethyl cellulose and colloidal silica is premixed to obtain premix 1; 0.1 to 0.9 times the amount of magnesium stearate is added to premix 1 to obtain premix 2; (2b) Dry granulation: Premix 2 is subjected to dry granulation to obtain the granules; (2c) Final blend: The prepared granules are mixed with the remaining amount of added magnesium stearate to obtain the final blend; (2d) Tableting: The final mixture is compressed to obtain solid dispersion tablets of the hydrochloride of compound (I).

10. Use of the pharmaceutical preparation according to any one of claims 1 to 7 or the preparation method according to any one of claims 8 to 9 in the preparation of a medicament for TOLL-like receptor-related diseases.

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