Pharmaceutical composition of supramolecular complex of nintedanib

Abstract

Provided is a pharmaceutical composition of a supramolecular complex with low administration dose. The pharmaceutical composition comprises nintedanib or a pharmaceutically acceptable salt thereof, a supramolecular complex, and a targeting directing agent. The composition addresses the poor solubility of nintedanib, reduces the hepatotoxicity and gastrointestinal toxicity caused by first-pass metabolism of existing nintedanib products after oral administration, greatly improves the effective utilization rate of the drug and the enrichment concentration of the drug after oral administration at the target organs treated, improves the safety, and also improves the treatment effect.

Description

A pharmaceutical composition of nintedanib supramolecular complex Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a stable, low-dose, highly targeted pharmaceutical composition of a nintedanib supramolecular complex and uses thereof. Background Art

[0002] Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic interstitial lung disease that occurs most frequently in people over 65 years of age. Because IPF is relatively insidious in its early stages, the median survival after diagnosis is only 2.8 years, with a mortality rate higher than that of most cancers. Consequently, IPF is often referred to as a "carcinoid disease." Currently, clinically available treatment options are very limited, with only nintedanib ethanesulfonate soft capsules and pirfenidone capsules. To delay and control disease progression, patients must adhere to long-term medication. Nintedanib ethanesulfonate soft capsules account for over 60% of the market share for this disease. Given the limited availability of medications for this disease and the challenges of developing new drugs, improving the safety and efficacy of existing marketed drugs and enhancing patient compliance are crucial.

[0003] The chemical name of Nintedanib is 1H-indole-6-carboxylic acid, 2,3-dihydro-3-[[[4-[methyl[(4-methyl-1-piperazinyl)acetyl]amino]phenyl]amino]phenylmethylene]-2-oxygen-, methyl ester, (3Z)-, and its chemical structure is:

[0004] Nintedanib ethanesulfonate soft capsules (trade name: Vigate) was developed by Boehringer Ingelheim and is marketed in more than 60 countries around the world. Its specifications are 0.1g and 0.15g. The clinical dosage is oral, twice a day, 150mg each time, taken after meals. According to the soft capsule instructions, the oral absolute bioavailability of 100mg nintedanib soft capsule is 4.7%, which is equivalent to 6mg intravenous injection. The actual clinical dosage is much higher than the effective dose of the drug, which is a typical clinical high-dose medication. The most critical factor for the serious clinical toxic and side effects of soft capsules. According to its instructions, in an effectiveness study involving 723 IPF patients, about 14% of patients taking nintedanib soft capsules experienced elevated liver enzymes such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALKP), and γ-glutamyl transpeptidase (GGT), as well as elevated bilirubin, and abnormal liver function tests; severe liver damage or fatal events caused by severe liver damage occurred during clinical trials and after the drug was marketed. In addition to hepatotoxicity, 75.7% of patients who took nintedanib soft capsules experienced liver damage. Patients treated with soft capsules experienced severe diarrhea (31.6% in the placebo group) and even gastrointestinal perforation. According to data from a Phase 2 clinical trial in the US FDA CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW(S), gastrointestinal toxicity and hepatotoxicity were clearly dose-dependent. The incidence of gastrointestinal toxicity and hepatotoxicity increased from 36.0% and 4.7% at the low dose to 74.1% and 19.0% at the high dose, respectively, when nintedanib 50 mg or 150 mg was taken twice daily. According to the US FDA Pharmacology Review, the systemic distribution of intravenously administered nintedanib indicates that its high distribution volume is the primary cause of non-target tissue and organ toxicity. Therefore, to fundamentally improve the safety, efficacy, and patient compliance of currently marketed nintedanib products, it is imperative to explore new delivery technologies that, without sacrificing the convenience of oral administration, reduce the drug's first-pass metabolism after oral administration. This would significantly lower the clinical dosage, reduce hepatotoxicity caused by first-pass hepatic metabolism, and mitigate non-target tissue / organ toxicity. This would improve drug efficacy and safety while also enhancing patient compliance.

[0005] In order to address the above-mentioned clinical pain points of the existing first-generation nintedanib products, CN110623927A, CN107184549B, and CN115154406A respectively adopted lipid nanotechnology, self-microemulsification technology, or nanocrystal technology for improvement. Although certain effects have been achieved, the clinical translation of these technological achievements is limited by the large oral dosage of nintedanib, the drug loading capacity (2.9% and 5 mg / mL), and the physical / chemical stability of the existing technology.

[0006] In summary, existing technologies can partially solve the clinical medication problems of the first-generation nintedanib product, but the effect is very limited, and it also causes a significant increase in costs. More importantly, it cannot change the hepatotoxicity caused by the first-pass metabolism of nintedanib after oral administration. As a result, there is still no new generation nintedanib product on the market that is highly safe, effective, well-tolerated and cost-effective.

[0007] Currently, there are no reports that oral administration can reduce hepatic first-pass metabolism and achieve active lung targeting.

[0008] Summary of the Invention

[0009] Through extensive research, the inventors unexpectedly discovered that the use of supramolecular self-assembly nanotechnology, on the one hand, solves the poor solubility of nintedanib, reduces the first-pass metabolism of nintedanib after oral administration, significantly improves the effective utilization rate of the drug, and reduces the liver toxicity caused by first-pass metabolism in the liver. On the other hand, it also reduces the gastrointestinal toxic side effects caused by high-dose administration of current products. More importantly, it achieves lung targeting, reduces the toxicity of toxic drugs to non-target organs / tissues, and is cost-controllable, with good process reproducibility and easy industrialization.

[0010] To solve the above problems, the present invention provides the following technical solutions:

[0011] In one aspect, the present invention provides a nintedanib supramolecular complex comprising the following components:

[0012] (1) the active ingredient nintedanib; and

[0013] (2) a carrier I selected from the group consisting of one or more of the free form, sodium salt, potassium salt, ammonium salt or hydrate thereof of rebaudioside B (RBDS-B), steviolbioside (STVB), rubusoside (RSBD-Acid), steviolbioside arginine amide derivative (STVB-Arga), glycyrrhizic acid (GA), steviolbioside histidine amide (STVB-His); and

[0014] (3) carrier II, which is one or more selected from the group consisting of rebaudioside A (RBDS-A), rebaudioside D (RBDS-D), rebaudioside E (RBDS-E), rebaudioside M (RBDS-M), rubusoside (RSBD), stevioside (STVS), rebaudioside O (RBDS-O), rebaudioside N (RBDS-N), rebaudioside F (RBDS-F), rebaudioside C (RBDS-C), dulcoside, and mogroside (MGSDT),

[0015] The nintedanib supramolecular complex is preferably in a form suitable for oral, sublingual, buccal, colonic, rectal, vaginal, mucosal, subcutaneous, intramuscular, intravenous, arterial, skin, lung, or intranasal administration, preferably in a form suitable for mucosal, pulmonary inhalation, or oral administration.

[0016] In some embodiments, the active ingredient nintedanib is selected from one or more of the group consisting of nintedanib free base, nintedanib salts (e.g., ethanesulfonate, methanesulfonate, sulfate, hydrochloride, hydrobromide, tartrate, fumarate, maleate, succinate, citrate), or hydrates or solvates of their salts, preferably nintedanib free base, nintedanib ethanesulfonate, or a combination of the two.

[0017] In some embodiments, the ratio of the active ingredient nintedanib to the carrier (I + II) is 1:0.5-1:10 (w / w), and the carrier I accounts for 5%-75% of the weight of the carrier (I + II); preferably, the ratio of the active ingredient nintedanib to the carrier (I + II) is 1:0.7-1:3 (w / w), and the carrier I accounts for 5%-50% of the weight of the carrier (I + II).

[0018] In some embodiments, the nintedanib supramolecular complex may further contain a high molecular weight polymer, and the high molecular weight polymer is selected from one or more of the group consisting of hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose (HPMC), sodium carboxymethylcellulose (CMC-Na), hydroxypropyl cellulose (HPC), povidone (PVP), copovidone (vinyl pyrrolidone / vinyl acetate copolymer, such as PVP-VA64), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (such as Soluplus), and sodium hyaluronate (HA-Na).

[0019] In another aspect, a composition or kit is provided, comprising the nintedanib supramolecular complex as described above.

[0020] In some embodiments, the composition further comprises a targeting agent, wherein the targeting agent is selected from one or more of the group consisting of tanshinone IIA, cryptotanshinone, sodium tanshinone IIA sulfonate, curcumin, maslinic acid, and tanshinone component extracts.

[0021] In some embodiments, the kit further comprises a product instruction sheet. When the targeting agent and the nintedanib supramolecular complex are in the kit, the targeting agent and the nintedanib supramolecular complex are separately packaged. Preferably, the targeting agent and the nintedanib supramolecular complex are in a form suitable for oral, sublingual, buccal, colonic, rectal, vaginal, mucosal, subcutaneous, intramuscular, intravenous, arterial, skin, pulmonary, or intranasal administration, preferably in a form suitable for mucosal, pulmonary inhalation, or oral administration.

[0022] In some embodiments, the tanshinone component extract is composed of one or more of dihydrotanshinone, tanshinone IIA, cryptotanshinone, tanshinone I, tanshinone IIB, hydroxytanshinone IIA and tanshinone IIA anhydride; the curcumin may also contain demethoxycurcumin and bisdemethoxycurcumin.

[0023] In some embodiments, the weight ratio of the targeting agent to the active ingredient nintedanib in the composition is 100:1 to 1:5; preferably 20:1 to 1:2; more preferably 10:1 to 1:2.

[0024] In some embodiments, the targeting agent in the composition exists as a supramolecular complex. The targeting agent supramolecular complex can be prepared together with the active ingredient nintedanib or separately, preferably separately.

[0025] In some embodiments, the targeting agent supramolecular complex in the composition comprises a carrier, and the carrier is carrier I, and / or carrier II, and / or a high molecular polymer.

[0026] In some embodiments, the weight ratio of the targeting agent to carrier II in the targeting agent supramolecular complex is 1:1000 to 1:3.3; preferably 1:100 to 1:5; more preferably 1:20 to 1:10, and carrier I accounts for 5%-75% of the weight of carrier (I+II), preferably 5%-50%.

[0027] In some embodiments, the targeting agent is administered simultaneously with nintedanib, or the targeting agent is administered within 2 hours of nintedanib. Preferably, the targeting agent is released before nintedanib. In general, if the targeting agent is administered in advance, it will be released / dissolved from the preparation before nintedanib. There are two situations in which simultaneous administration occurs: one is that both are released from the preparation at the same time, and the other is that the targeting agent is released first (for example, if the tablet is made into a packaged core, the targeting agent is in the coating and nintedanib is in the core. After administration, the targeting agent in the coating dissolves first, and the nintedanib in the core is released only after the coating ruptures or dissolves). Here, "released before nintedanib" includes both the situation of early administration and simultaneous administration.

[0028] In some embodiments, in addition to the high molecular weight polymer in the nintedanib supramolecular complex and / or the targeting agent supramolecular complex, a high molecular weight polymer is further added, and the high molecular weight polymer is selected from one or more of the group consisting of hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose (HPMC), sodium carboxymethylcellulose (CMC-Na), hydroxypropyl cellulose (HPC), povidone (PVP), copovidone (vinyl pyrrolidone / vinyl acetate copolymer, such as PVP-VA64), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (such as Soluplus), and sodium hyaluronate (HA-Na).

[0029] In some embodiments, the composition or kit further contains a solubilizer, which is selected from one or more of the group consisting of vitamin E polyethylene glycol succinate (TPGS), sodium lauryl sulfate (SLS), docusate sodium, lecithin, Tween 80, Tween 20, polyoxyethylene castor oil, and polyoxyethylene hydrogenated castor oil, preferably vitamin E polyethylene glycol succinate (TPGS). Preferably, the solubilizer is added directly, or is added after being adsorbed to form a solid powder using one or more of silicon dioxide, calcium silicate, magnesium aluminum silicate, microcrystalline cellulose, and silicified microcrystalline cellulose.

[0030] In some embodiments, the composition or kit further contains a pharmaceutically acceptable excipient, wherein the excipient is selected from one or more of the group consisting of a filler, a disintegrant, a glidant, and a lubricant. Preferably, the filler is selected from one or more of the group consisting of mannitol, microcrystalline cellulose (MCC), silicified microcrystalline cellulose (SMCC), lactose, pregelatinized starch, sucrose, glucose, and sorbitol; the disintegrant is selected from one or more of the group consisting of cross-linked polyvinylpyrrolidone (PVPP), cross-linked sodium carboxymethyl cellulose (CCNa), sodium carboxymethyl starch (CMS-Na), and low-substituted hydroxypropyl cellulose (L-HPC); the glidant is silicon dioxide; and the lubricant is selected from one or more of the group consisting of magnesium stearate, sodium stearyl fumarate, and talc.

[0031] In some embodiments, the composition or kit, wherein the product instructions describe the daily dosage as nintedanib ethanesulfonate soft capsules 5% to 50% of the administered dose, preferably 10% to 40%.

[0032] In some embodiments, the composition or kit comprises 30 mg to 120 mg of the active ingredient nintedanib, or the product instructions describe a daily dosage of the active ingredient nintedanib of 30 mg to 120 mg, which is equivalent to the nintedanib ethanesulfonate soft capsule of Vigate 300mg.

[0033] In some embodiments, the composition or kit comprises 15 mg, 20 mg, 22.5 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg or 120 mg of the active ingredient nintedanib.

[0034] The nintedanib supramolecular complex or composition can be administered orally, sublingually, buccally, intracolonically, rectally, vaginally, mucosally, subcutaneously, intramuscularly, intravenously, intraarterially, skin, pulmonaryly, or intranasally, preferably by mucosal or pulmonary inhalation or oral administration.

[0035] The composition is preferably in the form of a solid oral preparation, more preferably in the form of a tablet, capsule, or granule.

[0036] The present invention also provides a use of a specific carboxylesterase (CES1) inhibitor, wherein the specific carboxylesterase (CES1) inhibitor is BI1015550 ([1-[[(5R)-2-[4-(5-chloropyrimidin-2-yl)piperidin-1-yl]-5-oxo-6,7-dihydrothiophene[3,2-d]pyrimidin-4-yl]amino]cyclobutyl]methanol). Since nintedanib is primarily degraded by CES1, a composition containing BI1015550 can inhibit the degradation of nintedanib by CES1, thereby improving the bioavailability of nintedanib.

[0037] Therefore, the nintedanib supramolecular complex or composition of the present invention may further contain a second therapeutic agent, a selective phosphodiesterase 4B inhibitor. The selective phosphodiesterase 4B inhibitor is preferably nerandomilast (developed by Boehringer Ingelheim, code number BI1015550, chemical name [1-[[(5R)-2-[4-(5-chloropyrimidin-2-yl)piperidin-1-yl]-5-oxo-6,7-dihydrothiophene[3,2-d]pyrimidin-4-yl]amino]cyclobutyl]methanol). The daily dosage of the second therapeutic agent BI1015550 is 1 mg to 72 mg, preferably 2 mg to 36 mg, and the unit dosage strength is 1 mg to 36 mg, preferably 1.5 mg to 18 mg.

[0038] In another aspect, the present invention provides a use of the nintedanib supramolecular complex or composition in the preparation of a medicament for treating and / or preventing pulmonary fibrosis, chronic fibrosing interstitial lung disease, systemic sclerosis-related interstitial lung disease, lung cancer, and chronic obstructive pulmonary disease (COPD).

[0039] Specifically, the present invention provides the following technical solutions:

[0040] 1. A nintedanib supramolecular complex comprising the following components:

[0041] (1) the active ingredient nintedanib; and

[0042] (2) a carrier I selected from the group consisting of one or more of the free form, sodium salt, potassium salt, ammonium salt or hydrate thereof of rebaudioside B (RBDS-B), steviolbioside (STVB), rubusoside (RSBD-Acid), steviolbioside arginine amide derivative (STVB-Arga), glycyrrhizic acid (GA), steviolbioside histidine amide (STVB-His); and

[0043] (3) carrier II, which is one or more selected from the group consisting of rebaudioside A (RBDS-A), rebaudioside D (RBDS-D), rebaudioside E (RBDS-E), rebaudioside M (RBDS-M), rubusoside (RSBD), stevioside (STVS), rebaudioside O (RBDS-O), rebaudioside N (RBDS-N), rebaudioside F (RBDS-F), rebaudioside C (RBDS-C), dulcoside, and mogroside (MGSDT),

[0044] The nintedanib supramolecular complex is preferably in a form suitable for oral, sublingual, buccal, colonic, rectal, vaginal, mucosal, subcutaneous, intramuscular, intravenous, arterial, skin, lung, or intranasal administration, preferably in a form suitable for mucosal, pulmonary inhalation, or oral administration.

[0045] 2. The nintedanib supramolecular complex according to claim 1, wherein the active ingredient nintedanib is selected from one or more of the group consisting of nintedanib free base, nintedanib salts (e.g., ethanesulfonate, methanesulfonate, sulfate, hydrochloride, hydrobromide, tartrate, fumarate, maleate, succinate, citrate), or hydrates or solvates of their salts, preferably nintedanib free base, nintedanib ethanesulfonate, or a combination of the two.

[0046] 3. The nintedanib supramolecular complex according to item 1 or 2, wherein the ratio of the active ingredient nintedanib to the carrier (I + II) is 1:0.5-1:10 (w / w), and the carrier I accounts for 5%-75% of the weight of the carrier (I + II); preferably, the ratio of the active ingredient nintedanib to the carrier (I + II) is 1:0.7-1:3 (w / w), and the carrier I accounts for 5%-50% of the weight of the carrier (I + II).

[0047] 4. The nintedanib supramolecular complex according to any one of items 1 to 3 further comprises a high molecular weight polymer, wherein the high molecular weight polymer is selected from one or more of the group consisting of hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose (HPMC), sodium carboxymethylcellulose (CMC-Na), hydroxypropyl cellulose (HPC), povidone (PVP), copovidone (vinyl pyrrolidone / vinyl acetate copolymer, such as PVP-VA64), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (such as Soluplus), and sodium hyaluronate (HA-Na).

[0048] 5. A composition or kit comprising the nintedanib supramolecular complex according to any one of items 1 to 4.

[0049] 6. The composition or kit according to item 5, further comprising a targeting agent, wherein the targeting agent is selected from one or more of the group consisting of tanshinone IIA, cryptotanshinone, sodium tanshinone IIA sulfonate, curcumin, maslinic acid, and tanshinone component extracts. The kit further comprises a product instruction sheet. When the targeting agent and the nintedanib supramolecular complex are in the kit, the targeting agent and the nintedanib supramolecular complex are separately packaged. Preferably, the targeting agent and the nintedanib supramolecular complex are in a form suitable for oral, sublingual, buccal, colonic, rectal, vaginal, mucosal, subcutaneous, intramuscular, intravenous, arterial, skin, pulmonary, or intranasal administration, preferably a form suitable for mucosal, pulmonary inhalation, or oral administration.

[0050] 7. The composition or kit according to item 6, wherein the tanshinone component extract is composed of one or more of dihydrotanshinone, tanshinone IIA, cryptotanshinone, tanshinone I, tanshinone IIB, hydroxytanshinone IIA and tanshinone IIA anhydride.

[0051] 8. The composition or kit according to item 6, wherein the curcumin further comprises demethoxycurcumin or bisdemethoxycurcumin.

[0052] 9. The composition or kit according to any one of items 6 to 8, wherein the weight ratio of the targeting agent to the active ingredient nintedanib is 100:1 to 1:5; preferably 20:1 to 1:2; more preferably 10:1 to 1:2.

[0053] 10. The composition or kit according to any one of items 6 to 9, wherein the targeting agent is present in the form of a targeting agent supramolecular complex, which is prepared by adding the targeting agent to the nintedanib supramolecular complex according to any one of items 1 to 4, or by mixing the targeting agent with carrier I and carrier II according to any one of items 1 to 4.

[0054] 11. The composition or kit according to item 10, wherein the targeting agent supramolecular complex further comprises a high molecular polymer.

[0055] 12. The composition or kit according to item 11, wherein the weight ratio of the targeting agent to carrier II is 1:1000 to 1:3.3; preferably 1:100 to 1:5; more preferably 1:20 to 1:10, and carrier I accounts for 5%-75% of the weight of carrier (I+II), preferably 5%-50%.

[0056] 13. The composition or kit according to any one of items 6 to 12, wherein the kit comprises a product instruction sheet, wherein the product instruction sheet describes that the targeting agent is administered simultaneously with the active ingredient nintedanib, or the targeting agent is administered within 2 hours before the active ingredient nintedanib, and preferably the targeting agent is released before the active ingredient nintedanib.

[0057] 14. The composition or kit according to item 11, wherein in addition to the high molecular weight polymer in the nintedanib supramolecular complex and / or the targeting agent supramolecular complex, a high molecular weight polymer is further added, wherein the high molecular weight polymer is selected from one or more of the group consisting of hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose (HPMC), sodium carboxymethylcellulose (CMC-Na), hydroxypropyl cellulose (HPC), povidone (PVP), copovidone (vinyl pyrrolidone / vinyl acetate copolymer, such as PVP-VA64), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (such as Soluplus), and sodium hyaluronate (HA-Na).

[0058] 15. The composition or kit according to any one of items 5 to 14 further comprises a solubilizer, wherein the solubilizer is selected from one or more of the group consisting of vitamin E polyethylene glycol succinate (TPGS), sodium lauryl sulfate (SLS), docusate sodium, lecithin, Tween 80, Tween 20, polyoxyethylene castor oil (EL35), and polyoxyethylene hydrogenated castor oil, preferably vitamin E polyethylene glycol succinate (TPGS). Preferably, the solubilizer is added directly, or is added after being adsorbed to form a solid powder using one or more of silicon dioxide, calcium silicate, magnesium aluminum silicate, microcrystalline cellulose, and silicified microcrystalline cellulose.

[0059] 16. The composition or kit according to any one of items 5 to 15, further comprising a pharmaceutically acceptable excipient, wherein the excipient is one or more selected from the group consisting of a filler, a disintegrant, a glidant, and a lubricant.

[0060] 17. A composition or kit according to claim 16, wherein the filler is selected from one or more of the group consisting of mannitol, microcrystalline cellulose (MCC), silicified microcrystalline cellulose (SMCC), lactose, pregelatinized starch, sucrose, glucose, and sorbitol; the disintegrant is selected from one or more of the group consisting of cross-linked polyvinylpyrrolidone (PVPP), cross-linked sodium carboxymethyl cellulose (CCNa), sodium carboxymethyl starch (CMS-Na), and low-substituted hydroxypropyl cellulose (L-HPC); the glidant is silicon dioxide; and the lubricant is selected from one or more of the group consisting of magnesium stearate, sodium stearyl fumarate, and talc.

[0061] 18. The composition or kit according to any one of items 5 to 17, wherein the product instructions describe the daily dosage as nintedanib ethanesulfonate soft capsules based on the active ingredient nintedanib. 5%-50% of the administered dose, preferably 10%-40%.

[0062] 19. The composition or kit according to any one of items 5 to 18, wherein the composition comprises 30 mg to 120 mg of the active ingredient nintedanib, or the product instructions describe a daily dosage of the active ingredient nintedanib of 30 mg to 120 mg.

[0063] 20. A composition or kit according to any one of items 5 to 19, comprising 15 mg, 20 mg, 22.5 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg or 120 mg of the active ingredient nintedanib.

[0064] 21. The composition or kit according to any one of items 5 to 20, wherein the composition is a solid oral preparation, preferably one of a tablet, a capsule, and a granule, or the nintedanib supramolecular complex and / or the targeting agent supramolecular complex in the kit is a solid oral preparation, preferably one of a tablet, a capsule, and a granule.

[0065] 22. The composition or kit according to any one of items 5 to 20, further comprising BI1015550, represented by ([1-[[(5R)-2-[4-(5-chloropyrimidin-2-yl)piperidin-1-yl]-5-oxo-6,7-dihydrothiophene[3,2-d]pyrimidin-4-yl]amino]cyclobutyl]methanol).

[0066] 23. The composition or kit according to item 22, wherein the content of BI1015550 is 1 mg-72 mg, preferably 2 mg-36 mg, 1 mg-36 mg, or 1.5 mg-18 mg.

[0067] 24. Use of the nintedanib supramolecular complex described in any one of items 1 to 4 or the composition described in any one of items 5 to 23 in the preparation of a medicament for treating and / or preventing pulmonary fibrosis, chronic fibrosing interstitial lung disease, systemic sclerosis-related interstitial lung disease, lung cancer or chronic obstructive pulmonary disease (COPD).

[0068] 25. Use of BI1015550 as a specific carboxylesterase inhibitor, wherein BI1015550 is represented by ([1-[[(5R)-2-[4-(5-chloropyrimidin-2-yl)piperidin-1-yl]-5-oxo-6,7-dihydrothienyl[3,2-d]pyrimidin-4-yl]amino]cyclobutyl]methanol).

[0069] definition:

[0070] Supramolecular complex: an ordered assembly formed by non-covalent interactions between different molecules, the performance of which is far superior to the sum of the properties of each single molecule.

[0071] Targeting guide agent: A substance that can guide therapeutic drugs or target components to selectively concentrate at the lesion site. The lesion site is often figuratively called the target site, which can be the target tissue, target organ, target cell or target point within the cell.

[0072] Highly soluble drugs: Determined based on the high / low solubility criteria in the BCS classification of drugs, that is, a 150mg dose that can dissolve in 250ml of physiological medium (0.6mg / ml) is a highly soluble drug, and a drug that cannot dissolve is a low solubility drug. Beneficial effects

[0073] The use of supramolecular composite technology addresses the poor solubility of nintedanib, reduces its first-pass metabolism, significantly improves its effective utilization rate, and reduces liver toxicity caused by first-pass metabolism and gastrointestinal side effects caused by high-dose medication. More importantly, it achieves lung targeting, reducing the toxicity of toxic drugs to non-target organs / tissues. Furthermore, the technology is cost-effective, has good process reproducibility, and is easy to commercialize. Furthermore, the use of a targeting agent helps achieve even better lung targeting. BRIEF DESCRIPTION OF THE DRAWINGS

[0074] Figure 1 Comparison of DSC spectra of nintedanib free base and D1-D5.

[0075] Figure 2 Infrared spectra of nintedanib free base and a typical supramolecular complex.

[0076] Figure 3 X-ray diffraction patterns of nintedanib free base and typical supramolecular complexes.

[0077] Figure 4 Comparison of relative bioavailability of different supramolecular complexes / compositions.

[0078] Figure 5A Average drug concentrations in plasma, lung, and liver tissues measured 3 hours after administration of different prescriptions.

[0079] Figure 5B shows the ratio of tissue / plasma drug concentrations after 3 hours of drug administration with different prescriptions.

[0080] Figure 6 Human liver microsomal esterase inhibition study.

[0081] Figure 7 Metabolic pathway of nintedanib after oral administration.

[0082] Figure 8 3D structure of human CES1.

[0083] Figure 9. Mechanism of the hydrolysis of nintedanib to BIBF1202 catalyzed by amino acid residue Ser221 in the CES1 catalytic triad.

[0084] Fig. 10 The possible mechanism by which BI 1015550 affects the metabolic effects of nintedanib on hepatic CES1. DETAILED DESCRIPTION

[0085] In order to make the objectives, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with specific embodiments and with reference to the accompanying drawings.

[0086] Instruments and methods used to collect data:

[0087] X-ray powder diffraction (XRPD) data were collected using a D / max-rB instrument with the following test conditions: CuKα light source, 40 kV voltage, 40 mA current, slits DS1°, SS1°, RS0.3 mm, sampling step width: 0.02°, scanning speed: 10° / min, and acquisition software: MDI Jade 5.0.

[0088] Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) data were collected using a Mettler-TGA / DSC1 / 1100LF instrument. Analytical parameters included a temperature range of 30°C to 350°C, a scan rate of 10°C / min, and nitrogen at 50 mL / min. The acquisition software was STARe.

[0089] Infrared spectroscopy (IR) data were collected using a Spectrum 65 instrument with a KBr pellet method and a scanning range of 400–4000 cm -1 .

[0090] The content, solubility, dissolution and quantitative detection of related substances are all determined by high performance liquid chromatography (HPLC), as follows:

[0091] (1) The chromatographic conditions for the solubility, content, and dissolution assays of nintedanib are as follows:

[0092] (2) The chromatographic conditions for the detection of nintedanib-related substances are as follows:

[0093] (3) The chromatographic conditions for the determination of the targeting agent content are as follows:

[0094] The content of nintedanib in biological samples (plasma, tissue homogenate) is determined by liquid chromatography-mass spectrometry, such as Waters Xevo TQ-S tandem liquid chromatography-mass spectrometry (LC / MS / MS).

[0095] The detection conditions of liquid chromatography and mass spectrometry are as follows:

[0096] The minimum quantification limit of the method is: LLOQ is 4 ng / mL (injection volume is 10 μL).

[0097] The media used in the solubility and dissolution experiments of the present invention were prepared with reference to the 2020 edition of the Chinese Pharmacopoeia and the current edition of the United States Pharmacopoeia, as follows:

[0098] (1) Pre-meal simulated gastric fluid (FaSSGF): Weigh 2 g of sodium chloride, 0.043 g of sodium taurocholate, and 0.015 g of lecithin, add to 800 mL of degassed deionized water, and sonicate at 40°C-50°C to dissolve. Adjust the pH to 1.60 with 1 M HCl, add 0.1 g of pepsin, add degassed deionized water to 1 L, and adjust the pH to 1.60.

[0099] (2) Pre-meal simulated intestinal fluid (FaSSIF-V2): 187 mL of FaSSGF was added to 63 mL of conditioning solution (8.806 g of maleic acid, 8.806 g of sodium hydroxide, 9.976 g of sodium chloride, 6.618 g of sodium taurocholate, and 0.551 g of lecithin were weighed, added to 1000 mL of degassed deionized water, and dissolved by ultrasonication at 40°C-50°C, and set aside). The pH was adjusted to 6.50.

[0100] (3) Postprandial simulated gastric fluid (FeSSGF): Weigh 13.85 g of sodium chloride, 2.44 g of anhydrous sodium acetate, and 1.028 g of glacial acetic acid, add 1000 mL of degassed deionized water and stir to dissolve, then add 1000 mL of whole milk and mix well, and adjust the pH to 5.00 with concentrated hydrochloric acid.

[0101] (4) Postprandial simulated intestinal fluid (FeSSIF): 150 mL of FeSSGF was added to 100 mL of conditioning solution (weighing 15.965 g of maleic acid, 8.165 g of NaOH, 7.9481 g of NaCl, 13.75 g of sodium taurocholate, 0.6089 g of sodium oleate, and 3.79 g of lecithin, adding 1000 mL of degassed deionized water, sonicating, and stirring to dissolve), and the pH was adjusted to 5.80.

[0102] The inventors determined the technical solution of the present invention through a large number of experiments and repeated verifications during the research process. In order to illustrate the characteristics and advantages of the present invention, the examples provide some experiments as illustrative examples, but the content of the present invention is not limited to the examples. The nintedanib free base (NDNB) and nintedanib ethanesulfonate used in the examples were purchased from Pinghu Aibo; the carriers, targeting agents, polymers, solubilizers, excipients, reagents, and solvents used in the present invention are not particularly limited and can be purchased commercially. The glycoside derivatives used in the present invention are prepared and characterized by the company according to the preparation method in patent PCT / CN2023 / 114977. Their chemical names, structural formulas and codes are shown in the table below.

[0103] Table 1 Material name and code

[0104] Unless otherwise specified, the RBDS-A, RBDS-C, RBDS-B, STVS and other vectors mentioned in the present invention indicate that the purity of the main peak is ≥90%.

[0105] The specific implementation plan is as follows:

[0106] Comparative Example 1 Nintedanib solid dispersion

[0107] (1) Preparation of Nintedanib solid dispersion

[0108] The prescription is shown in Table 2.

[0109] Table 2 Preparation formula of Nintedanib solid dispersion

[0110] Preparation method:

[0111] Nintedanib free base was passed through a 100-mesh sieve, and the prescribed amount was weighed and dissolved in a methanol-dichloromethane mixture (5:1, v / v). The corresponding amount of polymer from the prescription was then added and dissolved. The dispersion was spray-dried using a Yamato spray dryer with an inlet temperature of 100°C, a liquid inlet rate of 5, an air volume of 7, and an atomization pressure of 0.1 MPa. The solid dispersion was collected and dried under reduced pressure in a 40°C vacuum drying oven for 4 hours, with the loss on drying (LOD) controlled to not exceed 2%. The apparent solubility of the prepared solid dispersion was measured by DSC and in FaSSIF-V2 medium, and the results were compared with those of the nintedanib free base drug substance.

[0112] (2) Test results

[0113] 1)DSC test results

[0114] The DSC results of the nintedanib API indicate that the nintedanib free base exhibits a distinct endothermic peak near 256°C. However, the endothermic peak near 256°C disappeared from the DSC spectra of solid dispersions D2-D5, except for D1, indicating that solid dispersions have formed. However, the DSC spectrum of formulation D1 exhibits a distinct endothermic peak near 245°C, indicating that a solid dispersion cannot or cannot be fully formed at a 1:1 NDNB:PVP VA64 ratio. The DSC spectrum is shown in Figure 1.

[0115] 2) Chemical stability of solid dispersion

[0116] The test results of related substances of nintedanib API and solid dispersion on day 0 are shown in Table 3 below.

[0117] Table 3 Test results of related substances of Nintedanib API and solid dispersion on day 0

[0118] Note: \ means not detected.

[0119] According to the test results of relevant substances, compared with the nintedanib raw material, new impurities were generated in the preparation process of nintedanib solid dispersions prepared with different formulations. Among them, the polymer PVP K30 had the largest number of new impurities and the largest increase in total impurities, followed by HPMCAS and HPMC.

[0120] 3) Apparent solubility in FaSSIF-V2 medium (37°C)

[0121] A certain amount of solid dispersion, nintedanib free base API, or nintedanib esylate was weighed and added in small batches to a certain volume of medium (n=3). The mixture was shaken at 150 rpm on a 37°C air shaker. Samples were taken 0.5, 2, and 5 hours after shaking and filtered through a polyethersulfone (PES) syringe filter (25 mm diameter, 0.45 μm pore size). Approximately 2 mL of the filtrate was immediately diluted 2-fold with 50% acetonitrile. The nintedanib content was determined by HPLC using an external standard method. The apparent solubility results, measured at 37°C for 5 hours, are shown in Table 4 below.

[0122] Table 4 Apparent solubility in FaSSIF-V2 medium after shaking for 5 hours (37°C)

[0123] The apparent solubility test results show that after nintedanib and high molecular weight polymer were prepared into solid dispersions at a mass ratio of 1:2 to 1:3, the apparent solubility in FaSSIF-V2 medium after 5 hours did not significantly increase compared with nintedanib free base, and was far below the target solubility of 0.6 mg / mL (the solubility of highly soluble drugs). Further increasing the amount of high molecular weight polymer in the solid dispersion may improve the solubility, but according to The current clinical dosage of nintedanib ethanesulfonate soft capsules would make the developed product too large to swallow. Therefore, for a poorly soluble drug like nintedanib, which requires high clinical dosages, solid dispersion technology cannot address the rate-limiting effect of nintedanib's solubility at high pH on drug absorption.

[0124] Comparative Example 2 Supramolecular complex constructed with a single carrier

[0125] (1) Preparation of supramolecular complexes

[0126] The single carrier supramolecular complex of nintedanib was prepared according to the formulation in Table 5

[0127] Table 5 Single carrier supramolecular complex

[0128] Preparation process: Weigh nintedanib and carrier in the prescription, add organic solvent, stir in a 40°C water bath to completely dissolve the materials, add purified water dropwise while stirring until clear, remove the solvent on a rotary evaporator at 45°C, collect the sample, place it in a 45°C / -100kPa vacuum drying oven for 2 hours, and pass it through a 60-mesh sieve to obtain a single carrier nintedanib supramolecular complex.

[0129] (2) Apparent solubility determination in FaSSIF-V2 medium

[0130] The test was carried out according to the method of Comparative Example 1, with 3 parallel samples set for each formulation. The results are shown in Table 6.

[0131] Table 6 Apparent solubility in FaSSIF-V2 medium for 5 hours (37°C)

[0132] In summary, after nintedanib and a single carrier were prepared into a supramolecular complex at a mass ratio of 1:5 (w / w),

[0133] The apparent solubility in FaSSIF-V2 at 5 hours was 2 to 3 times higher than that of nintedanib free base in Table 3, among which

[0134] The supramolecular complex constructed by nintedanib-RBDS-A, 1:5 (w / w) was slightly better than other carriers, but still not satisfactory.

[0135] The minimum solubility requirement of 0.6 mg / mL was met. By reducing the ratio of nintedanib to carrier to 1:2, the apparent solubility also decreased.

[0136] decline.

[0137] (3) Chemical stability

[0138] Supramolecular complexes with different carriers were selected to investigate the factors affecting high-temperature packaging (sealed in aluminum foil bags) at 50°C. The stability was also compared with the API under the same conditions. The results are shown in the table below.

[0139] Table 7 Chemical stability of single carrier supramolecular complexes

[0140] Note: * The NDNB is from a different batch than that of Comparative Example 1.

[0141] These results indicate that after 30 days of unpacking at 50°C, NDNB and its supramolecular complexes showed slight increases in degradation impurities and total impurities compared to the day 0 results. However, the increase in any individual impurity did not exceed 0.2%, indicating good chemical stability for all formulations. Formulation D6 exhibited the best chemical stability, while formulation D7 exhibited slightly poorer stability. The chemical stability of supramolecular complexes constructed with a single carrier was superior to that of solid dispersions.

[0142] Example 1 Supramolecular complex constructed by composite carrier

[0143] (1) The composition of the prescription is shown in Table 8 below.

[0144] Table 8 Supramolecular complex formulation composition of composite carrier

[0145] (2) Preparation of supramolecular complexes

[0146] Weigh each component in the prescription, add an organic solvent, stir in a 40°C water bath to dissolve it, add purified water dropwise while stirring until it is clear, and spin dry the solution using a rotary evaporator in a 45°C water bath. Collect the sample, dry it under reduced pressure at 45°C / -100kPa for 2 hours, pass it through a 60-mesh sieve, and set aside.

[0147] (3) Detection of supramolecular complexes

[0148] 1) Apparent solubility of the supramolecular complex FaSSIF-V2 in medium

[0149] The apparent solubility of C1-C28 was determined according to the method of Comparative Example 1, with two replicates for each formulation. The results are shown in Table 9.

[0150] Table 9 Apparent solubility of supramolecular complexes in FaSSIF-V2 for 5 hours (37°C)

[0151] The apparent solubility of the supramolecular complex constructed with the composite carrier in FaSSIF-V2 medium for 5 hours was significantly higher than that of D6 in Comparative Example 2 (0.54 mg / mL, 37°C). When the mass ratio of active ingredient to carrier was 1:0.5, the apparent solubility of the supramolecular complex was 0.61 mg / mL in 5 hours, which met the solubility requirement of 150 mg of nintedanib per dose (0.6 mg / mL). When the amount of carrier was further increased, the apparent solubility also increased. Adding a certain amount of high molecular weight polymer to the supramolecular complex slightly increased the apparent solubility in 5 hours.

[0152] 2) Cumulative dissolution of the supramolecular complex in biological media before meals

[0153] Dissolution method: small cup method (250 mL), rotation speed 100 rpm, temperature 37 ° C;

[0154] Dissolution medium: 187 mL FaSSGF was tested for 0.5 h. After sampling, 63 mL FaSSIF-V2 adjustment solution was added to make 250 mL FaSSIF-V2 and the test was continued for 210 minutes. The supramolecular complex sample was subjected to dissolution test at 150 mg (calculated as NDNB free base) for comparison.

[0155] Sampling: At 5 min, 15 min, 30 min, 45 min, 60 min, 90 min, 120 min, 150 min, and 210 min, take 2 mL of the dissolution solution into a centrifuge tube and centrifuge at 37°C, 13000 rpm for 5 min. Take 0.2 mL of the supernatant and add 1 mL of 50% acetonitrile to dilute immediately. Detect the nintedanib content by HPLC and calculate the dissolution rate.

[0156] Table 10 Cumulative dissolution rate in 187 mL FaSSGF → 250 mL FaSSIF-V2 medium (150 mg)

[0157] Based on the cumulative dissolution rate in pre-meal biological media, the cumulative dissolution rates of supramolecular complexes C3, C5, C7, C11, C18, C20, C23, C24, C26, C27, and C28 in pre-meal biological media were significantly higher than those of nintedanib free base, nintedanib ethanesulfonate, the RLD, and comparative example D2. This indicates that supramolecular complexes can achieve higher dissolution rates than the free base raw material, salt, solid dispersion, and original formulation (RLD). For the poorly soluble drug nintedanib, higher dissolution rates are expected to provide higher and more sustained absorption in the human gastrointestinal tract (absorption site).

[0158] The cumulative dissolution rate of supramolecular complex D6 (NDNB / carrier, 1:5, w / w) constructed with a single carrier after ingestion into pre-meal intestinal fluid was essentially the same as that of C3. The cumulative dissolution rates of supramolecular complexes C11, C23, C24, C27, and C28 constructed with multiple carriers remained above 90% after ingestion into pre-meal intestinal fluid, slightly higher than those of the other formulations. The supramolecular complexes of formulations C3, C5, C7, C11, C18, C20, and C28 contained no polymers in their NDNB:carrier (w / w) ratios of 1:1, 1:1, 1:2, 1:1.1, 1:3, 1:1, and 1:1, respectively. The supramolecular complexes of formulations C23, C24, C26, and C27 contained polymers in the supramolecular complexes, with the weight ratios of NDNB to polymer being 1:1, 1:0.3, 1:0.3, and 1:0.75, respectively. It can be seen from this that the supramolecular complex constructed by the composite carrier can achieve higher or consistent dissolution rate than a single carrier at a lower carrier and / or high molecular polymer dosage, and the lower carrier dosage provides convenience for formulation molding, allowing for more dosage forms to be selected and making it more convenient for patients to take.

[0159] 3) Cumulative dissolution of the supramolecular complex in biological media after a meal

[0160] Dissolution medium: 150 mL FeSSGF → 250 mL FeSSIF-V2

[0161] Dissolution method: small cup method (250 mL), rotation speed 100 rpm, temperature 37°C; postprandial gastric fluid was tested for 2 hours, and then adjusted to postprandial intestinal fluid and continued to be tested for 210 minutes.

[0162] Dissolution sample: The homemade supramolecular complex composition and the comparative solid dispersion were both subjected to dissolution experiments at 150 mg (calculated as NDNB free base); the reference preparation 150mg soft capsule;

[0163] Sampling: Take 5 mL of the sample at 15 min, 30 min, 60 min, 90 min, 120 min, 150 min, 180 min, and 210 min and add 5 mL of blank medium into the dissolution cup. Filter the sample with a polytetrafluoroethylene (PTFE) filter membrane (diameter 25 mm, pore size 0.45 μm), discard 3 mL of the initial filtrate, take 0.5 mL of the subsequent filtrate, add 2 mL of acetonitrile, mix well, filter again, discard 1 mL of the initial filtrate, take 0.5 mL of the subsequent filtrate, add 1 mL of methanol for dilution, detect the content by HPLC, and calculate the cumulative dissolution rate.

[0164] Table 11 Cumulative dissolution rate in 150 mL FeSSGF → 250 mL FeSSIF-V2 medium (150 mg)

[0165] Based on the cumulative dissolution rate in the postprandial biological medium, the cumulative dissolution rates of nintedanib free base, nintedanib ethanesulfonate API, reference preparation, solid dispersion D2 and supramolecular complexes with different formulations in the postprandial intestinal fluid were basically the same, with no significant difference (±3%). This indicates that the postprandial biological medium has no discriminatory power on the dissolution behavior of nintedanib products with different formulations and preparation processes.

[0166] 4) Infrared spectroscopy and X-ray powder diffraction detection of supramolecular complexes

[0167] Infrared spectroscopy and X-ray powder diffraction were performed on the above-mentioned nintedanib free base and the typical supramolecular complexes (C3, C28, and C26) listed in Table 10. Comparison of the infrared spectra and X-ray powder diffraction patterns is shown in Figures 2 and 3, respectively. The infrared spectra and X-ray powder diffraction patterns indicate that the self-prepared supramolecular complex samples formed a supramolecular complex.

[0168] 5) Supramolecular complex stability test

[0169] The supramolecular complex was packaged in aluminum-plastic composite film bags and placed in accelerated test conditions at high temperature of 50°C and 40°C / RH75%. The sampling time for the influencing factors was 7 days, 14 days and 30 days; the sampling time for the accelerated test condition was 1 month and 3 months. The relevant substances were tested respectively and compared with the test results at 0 days. The test results are as follows:

[0170] Table 12 Results of stability study of supramolecular complex constructed by composite carrier

[0171] Note: The API used in D2 is different from batches C1-C28.

[0172] The chemical stability of the supramolecular complexes C3, C5, C7, C11, C18, C20, C23, C24, C26, C27, and C28 was superior to that of the comparative example D2 and the reference formulation, according to the results of related substance testing in samples stored at 50°C for 30 days. The stability of the supramolecular complexes containing polymers was slightly worse than that of the complexes without polymers. After 30 days at 50°C, the maximum concentration of any degradation impurity did not exceed 0.2% (except for D2 and the reference formulation), and the maximum concentration of any unknown single impurity did not exceed 0.1%. After 3 months of storage at 40°C / RH75% in packaging, the concentration of any degradation impurity in the supramolecular complexes increased slightly compared to day 0, but the increase was less than that of the comparative example D2 and the reference formulation. In summary, the supramolecular complexes exhibited excellent chemical stability.

[0173] Example 2 Compositions containing supramolecular complexes

[0174] (1) Formulation of a composition containing a supramolecular complex - Tablet (T)

[0175] Nintedanib is formulated according to the 50 mg dosage.

[0176] Table 13 Tablet formulation of composition containing supramolecular complex

[0177] (2) Preparation process of tablets containing supramolecular complexes

[0178] 1) Melt EL35 or TPGS in a water bath at 60°C, add adsorbent (SiO2 and / or MCC105) according to the prescribed ratio, stir evenly, cool, and pass through a 60-mesh sieve three times.

[0179] 2) Weigh the prescribed amount of raw and auxiliary materials, pass them through a 40-mesh sieve, and mix for 5 minutes;

[0180] 3) Use a 12# shallow round punch to compress the tablets according to a theoretical tablet weight of 300 mg and a hardness of 30-40 N. Crush the tablets and pass them through a 30-mesh sieve for granulation.

[0181] 4) Weigh the additional excipients, pass through a 40-mesh sieve, and mix with the granules for 5 minutes;

[0182] 5) Use 12mm*7.5mm capsule-shaped punching sheets.

[0183] Example 3 Composition capsule containing supramolecular complex

[0184] (1) Capsule formulation containing a supramolecular complex

[0185] Table 14 Composition of supramolecular complex capsule prescription

[0186] (2) Preparation process

[0187] 1) Melt TPGS in a water bath at 60°C. Add MCC 105 and SiO2 in a ratio of TPGS: MCC 105: SiO2 = 1:1:0.5 (w / w / w). Stir well, cool, and pass through a 60-mesh sieve three times.

[0188] 2) Weigh the prescribed amount of raw and auxiliary materials, pass them through a 40-mesh sieve, and mix for 5 minutes;

[0189] 3) Use a 12# shallow round punch to compress the tablets according to a theoretical tablet weight of 400 mg and a hardness of 30-40 N. Crush the tablets and pass them through a 24-mesh sieve for granulation.

[0190] 4) Weigh the additional excipients, pass through a 40-mesh sieve, add to the granules, and mix for 5 minutes;

[0191] 5) Fill into No. 1 gelatin or hypromellose capsule shell according to the theoretical content weight.

[0192] Experimental Example 1: Dissolution Investigation of Tablets or Capsules Containing a Supramolecular Complex

[0193] (1) Dissolution method:

[0194] Small cup method (250 mL), rotation speed 100 rpm, temperature 37 °C;

[0195] Dissolution medium: 187 mL FaSSGF medium for 30 minutes, then add 63 mL of adjustment solution to make 250 mL FaSSIF-V2, and continue monitoring for up to 210 minutes.

[0196] Samples to be tested: 150mg of reference preparation, one pill; homemade tablets or capsules, 3 tablets or 3 pills per dissolution cup, and each prescription was tested in parallel 3 times.

[0197] At 5 min, 15 min, 30 min, 45 min, 60 min, 90 min, 120 min, 150 min, and 210 min, take 2 mL of the dissolution solution into a centrifuge tube, centrifuge at 37°C, 13000 rpm for 5 min, take 0.2 mL of the supernatant and dilute it with 1 mL of 50% acetonitrile, and calculate the cumulative dissolution rate by HPLC.

[0198] Table 15 Cumulative dissolution in 187 mL FaSSGF → 250 mL FaSSIF-V2 medium

[0199] Compared with the reference preparation, the cumulative dissolution rate of the composition tablets or capsules containing the nintedanib supramolecular complex in the intestinal fluid before meals was significantly higher than that of the commercially available nintedanib ethanesulfonate soft capsules. The cumulative dissolution rate of the supramolecular complex prepared with the composite carrier after tableting was higher than that of the tablet T1 prepared with the same formulation in comparative example D6. The composition containing the supramolecular complex prepared into tablets or capsules had little effect on the dissolution rate in the intestinal fluid before meals.

[0200] Example 4 Targeting Agent Supramolecular Complex

[0201] (1) Prepare the targeting agent supramolecular complex according to the following formula

[0202] Table 16 Prescription of targeting guide agent supramolecular complex

[0203] (2) Preparation of supramolecular complexes of targeting agents

[0204] 1) Targeting agent tanshinone IIA (TSN-IIA), curcumin (CCM) and maslinic acid (MSA) were passed through a 100-mesh sieve and set aside.

[0205] 2) Weigh the prescribed amount of targeting agent, add organic solvent, and stir in a 40°C water bath to dissolve it.

[0206] 3) The corresponding high molecular weight polymer, carrier, SLS or TPGS in the prescription were dissolved in the aqueous phase, and the organic phase was slowly added dropwise to the aqueous phase while stirring. After the addition was completed, stirring was continued for 0.5 h. The sample was evaporated in a rotary evaporator at 45°C in a water bath. The dried sample was dried under reduced pressure at 45°C / -100 kPa for 2 hours and passed through a 60-mesh sieve for later use.

[0207] (3) Solubility determination of the supramolecular complex of the targeting agent

[0208] The test method was the same as that of Comparative Example 1, except that the medium was FaSSIF-V2 and the test temperature was 37° C. Two replicates were prepared for each sample, and the average value was taken.

[0209] The apparent solubility of each targeting agent after 5 hours was detected by HPLC.

[0210] Table 17 Apparent solubility of targeting agent compounds and targeting agent supramolecular complexes in FaSSIF-V2 for 5 hours (37°C)

[0211] Compared with the targeting agent compounds, the apparent solubility of the targeting agents was significantly improved after preparation into supramolecular complexes, with TSN-IIA, CCM and MSA increasing by 486-2418 times, 1219 times and 287 times, respectively.

[0212] (4) Pharmacokinetic study in rats

[0213] According to factors such as solubilization effect and drug loading capacity, C34, C31 and C33 supramolecular complexes were selected and loaded into 9# gelatin capsules for animal experiments.

[0214] The dosage of the targeting agent was 25 mg / kg body weight, the dosage of nintedanib was 50 mg / kg body weight, and the weight ratio of the targeting agent to nintedanib was 1:2.

[0215] Experimental animals: Clean-grade male Sprague-Dawley rats, purchased from the China Food and Drug Administration (license number: SCXK(Beijing)2022-0002), weighing 230-240 g, were randomly divided into four groups, with 5 animals in each group. All rats were fasted for at least 10 hours overnight and deprived of water for 1 hour before dosing.

[0216] Experimental sample: Nintedanib The contents of nintedanib ethylsulfonate soft capsules (RLD) were directly filled into 9# gelatin capsules and prepared before administration.

[0217] Dosing: One hour before nintedanib administration, experimental group G1-G3 rats were orally gavaged with targeting agent capsules. Control group rats were given empty 9# capsules and 1 mL of water. One hour later, RLD capsules were gavaged and then 1 mL of water was given. Two hours later, food and water were allowed ad libitum.

[0218] Table 18 In vivo pharmacokinetic dosing regimens of nintedanib containing supramolecular complexes with different targeting agents

[0219] Blood collection and plasma separation: After administration of nintedanib RLD, 0.5 ml of blood was collected from the inner canthus at 0.5 h, 1 h, 1.5 h, 2 h, 3 h, 4 h, 5 h, 7 h, 9 h, 12 h and 24 h. 3% sodium heparin was used as an anticoagulant. The blood was centrifuged at 4°C / 3000 rpm for 10 minutes, and the plasma was separated and stored in a -20°C refrigerator.

[0220] Sample Pretreatment: After removing plasma samples from the refrigerator and returning them to room temperature, accurately measure 150 μL of each plasma sample and add 10 μL of a 300 ng / mL YBTN internal standard solution. Vortex for 30 seconds, add 440 μL of methanol, vortex for 30 seconds, let stand for 10 minutes, vortex for 30 seconds, centrifuge at 4°C / 13,000 rpm for 10 minutes, and analyze the supernatant directly. Nintedanib content in plasma was determined by LC / MS / MS, using ibrutinib as the internal standard.

[0221] Based on the blood drug concentration data measured at different time points, Phoenix WinNonlin7.0 was used to calculate the pharmacokinetic parameters and provide AUC 0-t , AUC 0-∞ , Cmax, Tmax and T 1 / 2 Parameters and their means and standard deviations.

[0222] Relative bioavailability (%) = (AUC G ×Dose C ) / (AUC C ×Dose G )×100%

[0223] AUC G : Systemic exposure of experimental drugs (drugs in Examples) (ng·hr / ml);

[0224] Dose G : experimental drug dosage (mg / kg body weight);

[0225] AUC C: Systemic exposure of the reference drug (drug in the comparative example) (ng·hr / ml);

[0226] Dose C : Reference drug dosage (mg / kg body weight).

[0227] The results of the rat in vivo experiments are shown in the table below.

[0228] Table 19 In vivo experimental results in rats

[0229] When the dose ratio of targeting agent to nintedanib was 1:2 (w / w), the pharmacokinetic parameters of targeting agent TSN-IIA and CCM were basically consistent, and both could double the relative bioavailability of nintedanib.

[0230] Example 5 Composition of supramolecular complex containing targeting agent

[0231] (1) Prescription composition

[0232] The nintedanib supramolecular complex was re-prepared according to the C26 formulation.

[0233] Table 20 Composition formula of supramolecular complex containing targeting guide agent

[0234] (2) Preparation process

[0235] T27: Weigh the prescribed amount of raw and excipient ingredients and pass them through a 40-mesh sieve. Mix for 5 minutes. Use a #12 shallow round punch to compress the tablets to a theoretical tablet weight of 400 mg and a hardness of 30-40 N. Pulverize the tablets and pass through a 24-mesh sieve to size the granules.

[0236] Weigh the additional excipients, pass them through a 40-mesh sieve, add them to the granules, mix for 5 minutes, and use 16*10mm capsule-shaped punched tablets.

[0237] T28: Weigh the prescribed amount of tablet raw materials and excipients, pass through a 40-mesh sieve, mix for 5 minutes, and set aside;

[0238] Weigh the prescribed amount of outer coating raw materials and pass them through a 40-mesh sieve, mix for 5 minutes, and set aside;

[0239] The tablets are pressed using a chip-wrapped tablet press, with 8mm round punches for cores and 12mm round punches for chip-wrapped tablets.

[0240] T29: Weigh the prescribed amount of raw materials and auxiliary materials of layers I and II respectively, pass through a 40-mesh sieve, mix for 5 minutes, and set aside; use an 18*12mm capsule punch and a double-layer tablet press to compress the tablets.

[0241] Ca5: Weigh the raw materials and excipients for Granules 1 and 2, pass through a 40-mesh sieve, and mix for 5 minutes. Use a #12 shallow round punch to compress the tablets to a theoretical tablet weight of 400 mg and a hardness of 30-40 N. Pulp the tablets through a 24-mesh sieve to size the granules. Mix the granules with the excipients for 5 minutes and fill them into #0 gelatin or hydroxypropyl methylcellulose capsules according to the prescribed weight.

[0242] After the above prescription is prepared, it is directly packed into granules.

[0243] (3) Cumulative dissolution determination

[0244] In order to compare with the reference preparation, the dissolution test was carried out on 150 mg of the self-made preparation (calculated as nintedanib free base).

[0245] Dissolution method: small cup method, 37°C, rotation speed: 100 rpm;

[0246] Dissolution medium: 187 mL of FaSSGF was dissolved in the pre-meal biological medium for 30 minutes, and 63 mL of the conditioning solution was added to make 250 mL of FaSSIF-V2. The dissolution was continued for 210 minutes.

[0247] Sampling time: 5, 15, 30, 45, 60, 90, 120, 150 and 210 minutes;

[0248] Sampling method: Take 2 mL of sample and add 2 mL of blank medium at the same temperature

[0249] Sample Preparation: Dissolution samples were centrifuged at 37°C / 13,000 rpm for 5 min. 0.2 mL of the supernatant was diluted with 1 mL of 50% acetonitrile. The contents of nintedanib and targeting agent were determined by HPLC, and the cumulative dissolution rate was calculated.

[0250] Table 21 Cumulative dissolution in 187 mL FaSSGF → 250 mL FaSSIF-V2

[0251] After the supramolecular complex of nintedanib and the targeting agent was formulated into tablets or capsules, the cumulative dissolution rate of each tablet in the intestinal fluid before meals did not change significantly compared with the composition without the targeting agent (Table 15). The Ca 5 content decreased slightly, but was still significantly higher than that of the reference preparation. The cumulative dissolution rate of the targeting agent TSN-IIA in each formulation ranged from 87% to 92%.

[0252] (4) Relative bioavailability study in rats

[0253] 1) Investigation of relative bioavailability of supramolecular complexes / compositions in rats

[0254] Due to the limitations of 9# capsules, experiments were conducted using supramolecular complexes or a mixture of supramolecular complexes and high molecular weight polymers or surfactants and then encapsulated. The dosing regimen was as follows:

[0255] Table 22 Dosage regimen for relative bioavailability studies

[0256] According to the above-mentioned dosing regimen, the dosage of nintedanib was 20 mg / kg body weight except for D6, which was 25 mg / kg body weight, and all the others were administered in capsules.

[0257] Experimental Animals: Clean-grade male Sprague-Dawley rats, purchased from the China Food and Drug Administration (license number: SCXK(Beijing)2022-0002), weighing 218-253 g, were randomly divided into 11 groups, with 5 animals per group. All rats were fasted for at least 10 hours overnight before dosing and deprived of water for 1 hour before dosing. Water was freely available for 2 hours after dosing, and food was given 4 hours later.

[0258] All rats were gavage-administered one capsule of the corresponding prescription and 1 mL of water.

[0259] Blood collection and plasma separation:

[0260] Blood samples (0.5 mL) were collected from the inner canthus at 0.5, 1, 1.5, 2, 3, 4, 5, 7, 9, 12, and 24 hours after administration, using 3% sodium heparin as an anticoagulant. All samples were centrifuged at 4°C / 3000 rpm for 10 minutes to separate plasma, which was then stored at -20°C.

[0261] Plasma sample pretreatment: After the plasma samples returned to room temperature, accurately measured 150 μL of each plasma sample, accurately added 10 μL of 300 ng / mL YBTN internal standard solution, vortexed for 30 s, added 440 μL of methanol, vortexed for 30 s, let stand for 10 min, vortexed for 30 s, centrifuged at 4°C / 13000 rpm for 10 min, and the supernatant was taken for direct analysis.

[0262] Based on the blood drug concentration data measured at different time points, Phoenix WinNonlin7.0 was used to calculate the pharmacokinetic parameters and provide AUC 0-t , AUC 0-∞ , Cmax, Tmax and T 1 / 2 Parameters and their means and standard deviations.

[0263] Relative bioavailability (%) = (AUC G ×Dose C ) / (AUC C ×Dose G )×100%

[0264] AUCG : Systemic exposure of experimental drugs (drugs in Examples) (ng·hr / ml);

[0265] Dose G : experimental drug dosage (mg / kg body weight);

[0266] AUC C : Systemic exposure of the reference drug (drug in the comparative example) (ng·hr / ml);

[0267] Dose C : Reference drug dosage (mg / kg body weight).

[0268] The results of the rat in vivo experiments are shown in the table below.

[0269] Table 23 In vivo experimental results in rats

[0270] Note*: One rat each died from excessive anesthesia during blood draws in G6 and G10. Control group data are from Table 18.

[0271] In summary, according to the oral relative bioavailability study results in rats, the G4 group, which was administered with the supramolecular complex D6 prepared with a single carrier, had the lowest relative bioavailability of 206% compared to the control group. G6, administered with the supramolecular complex C15, in which carrier I was GA, accounting for 50% of the mass of carriers (I+II) and a 1:1 mass ratio of nintedanib to carriers (I+II), had a relative bioavailability of 447%. G10, administered with the targeting agent Ca5, had the highest relative bioavailability, at 1467% (14.7 times) of the control group, significantly improving the relative bioavailability compared to G9 (administered with Ca3), which did not contain a targeting agent. G13 (administered with T 20) was the next best, with a relative bioavailability of 1345%. Compared to the control group, the nintedanib supramolecular complex or combination of supramolecular complexes exhibited a relative bioavailability of 447% to 1467% (4.5-fold to 14.7-fold), significantly improving the oral relative bioavailability of nintedanib and significantly outperforming the supramolecular complex prepared using a single carrier, D6, as described in the comparative example. See Figure 4 for details.

[0272] (5) Stability investigation

[0273] The supramolecular complex composition tablets or capsules T2, T3, T4, T20, Ca3 and Ca5 prepared in Examples 2, 3 and 5 were sealed with aluminum-plastic composite film or aluminum-plastic blisters, and then covered with double aluminum bags. They were placed under high temperature (50°C ± 2°C) for 7 days, 14 days and 30 days, and under accelerated conditions (45°C ± 2°C / 75% RH ± 5% RH) for 1 month and 3 months, respectively. Samples were taken and tested for related substances. The results are as follows:

[0274] Table 24: Stability of Supramolecular Complex Composition Tablets or Capsules - Related Substance Test Results

[0275] After being placed at high temperature of 50°C for 30 days and at 40°C / RH75% for 3 months, the degradation impurities and the total amount of impurities increased slightly, but did not exceed 0.2%. The supramolecular complex composition has good chemical stability.

[0276] (6) Tissue distribution research

[0277] Tissue distribution studies were conducted using clean-grade SD male rats weighing 240g-253g. The rats were randomly divided into three groups, with six rats in each group and three rats at each sampling site.

[0278] Dosage: For ease of comparison, the control and experimental groups were both dosed at 20 mg / kg body weight (calculated as nintedanib free base), with each rat receiving 5 mg. Ca 3 and Ca 5 were prepared using the same method as for the relative bioavailability study, and the supramolecular composition was converted and packaged in 9# capsules.

[0279] Preparation of control group samples: Referring to the formulation C in Example 7 of patent CN105193720B, the control group dosage prescription was prepared. Medium-chain triglycerides, stearin, and lecithin were accurately weighed, stearin was mixed with part of the medium-chain triglycerides, lecithin, the remaining medium-chain triglycerides, and nintedanib free base that had been micronized and passed through a 100-mesh sieve were added, and ultrasonication at 45°C was performed to uniformly disperse the mixture to prepare a suspension containing approximately 200 mg of NDNB per mL. Each rat in the control group was orally administered with a 9# capsule containing 25 μL of the suspension.

[0280] Table 25 Tissue Distribution Study Dosage Regimen Dosage Regimen (n=6)

[0281] Rats were fasted for at least 10 hours overnight before administration, and water deprivation was stopped 1 hour before administration. Water was freely available 2 hours after administration. Three hours after oral administration, five rats from each group were anesthetized by injection of 1% sodium pentobarbital. Blood was collected from the posterior abdominal aorta, and the rats were sacrificed. The lungs and livers of the rats were quickly isolated and rinsed with 4°C saline. The tissue surface was blotted dry with absorbent paper and weighed. The tissue was minced and mixed at a ratio of tissue (g): saline (4°C, g) = 1:4 (w / w). The mixture was homogenized using a homogenizer, repeatedly frozen three times in liquid nitrogen, and centrifuged at 4°C / 13,000 rpm for 10 minutes. Carefully pipette 150 μL of tissue homogenate, add 20 μL of internal standard solution, and add 880 μL of methanol as a protein precipitant. Vortex for 30 seconds, let stand for 10 minutes, and centrifuge at 4°C / 13,000 rpm for 10 minutes. Remove 10 μL of the supernatant for analysis. If necessary, lung tissue samples from rats G15 and G16 may need to be further diluted with 50% acetonitrile. Liver tissue samples from rats in the control group may need to be further diluted before analysis.

[0282] The treatment of plasma samples was the same as the treatment steps under Example 5(4).

[0283] The nintedanib content in the above-mentioned biological samples was measured using LC / MS / MS and an internal standard method. The concentrations of nintedanib in the plasma, liver, and lung tissues of rats in different dosing groups 3 hours after administration are shown in Figure 5-1 , and the tissue / plasma concentration ratios measured in rats in different dosing groups are shown in Figure 5-2 . The lung is the target organ for this drug, and the liver is the first-pass organ of metabolism for oral drugs. A higher lung / plasma concentration ratio indicates better drug targeting, while a higher liver / plasma ratio indicates higher drug exposure in the liver and greater liver damage. As shown in Figure 5-2 , at the same dose, the liver / plasma concentration ratio of the control group was 74.4, while the liver / plasma drug concentration ratios of the G15 and G16 groups were 13.0 and 6.0, respectively, 3 hours after administration, significantly lower than those in the control group. The 3-hour lung / plasma drug concentration ratio of the control rats was 28.2, while the 3-hour lung / plasma drug concentration ratios of the G15 and G16 groups were 76.4 and 109.4, respectively, which were significantly higher than those of the control group, indicating that the G15 and G16 prescriptions had higher lung targeting efficiency.

[0284] Example 6 Supramolecular complex / composition containing a second therapeutic agent

[0285] The supramolecular complex or composition of the present invention may contain a second therapeutic agent, which is a phosphodiesterase 4B (PDE4B) inhibitor, such as Nerandomilast (developed by Boehringer Ingelheim, code BI 1015550, hereinafter abbreviated as NDML).

[0286] According to Clin Pharmacokinet. 2019 Sep. 58(9): 1131-1147, the metabolic pathway of nintedanib after oral administration is shown in Figure 7.

[0287] Among them, esterase metabolism is the most important of all metabolic pathways of nintedanib, accounting for about 59%. The largest contributor to nintedanib esterase metabolism is the specific carboxylesterase (CES1) in the liver. The catalytic triad contained in the catalytic domain of human CES1 (such as Ser 221 ,Glu 354 and His 468 Located at the interface of the three domains of CES1, it is crucial for the catalytic reaction mediated by carboxylesterase. 221 The residues divide the ligand binding pocket of CES1 into two pockets, one of which is a rigid pocket that makes CES1 selective for substrates with small alkyl alcohols and large carboxylates, and the other is a flexible pocket that makes CES1 selective for substrates with a variety of acyl groups. These properties enable CES1 to interact with a variety of chemically different ligands. The 3D structure of human CES1 is shown in Figure 8. 221 The mechanism by which amino acid residues catalyze the hydrolysis of nintedanib to BIBF1202 is shown in FIG9 .

[0288] According to Front Pharmacol. 2022;13:838449, BI 1015550 is a novel phosphodiesterase (PDE)4 inhibitor developed by Boehringer Ingelheim, with preferential enzymatic inhibition of PDE4B. In vitro, BI 1015550 inhibited lipopolysaccharide (LPS)-induced tumor necrosis factor-α (TNF-α) and lectin-induced interleukin-2 production in human peripheral blood mononuclear cells, as well as LPS-induced TNF-α production in human and rat whole blood. In vivo, oral administration of BI 1015550 to mice demonstrated potent anti-inflammatory activity. In vitro and in a mouse model of pulmonary fibrosis further confirmed the anti-fibrotic activity of BI 1015550 and the synergistic effect of BI 1015550 in inhibiting fibroblast proliferation when combined with nintedanib. According to the European Respiratory Journal 2022 60:4606, a post-hoc analysis of a Phase 2 clinical study evaluating the efficacy and safety of BI 1015550 in the treatment of idiopathic pulmonary fibrosis (IPF) showed that the mean change in adjusted forced vital capacity (FVC) at week 12 was +6.1 mL in the BI 1015550 group (not taking antifibrotic drugs), +23.4 mL in the BI 1015550 plus nintedanib group, and -18.8 mL in the BI 1015550 plus pirfenidone group. In the placebo group without prior antifibrotic drugs (nintedanib or pirfenidone), the mean change was -95.6 mL, while in the nintedanib group and the pirfenidone group, the mean change was -82.0 mL and -80.1 mL, respectively. Therefore, Boehringer Ingelheim is conducting a global multicenter Phase III clinical trial of BI1015550 for idiopathic pulmonary fibrosis.

[0289] After numerous in vitro and in vivo experiments, the inventors discovered that BI 1015550 can inactivate liver CES1, thereby protecting nintedanib from being metabolized by CES1 into inactive BIBF1202 as little as possible after oral administration into the liver, thereby improving the therapeutic effect of nintedanib.

[0290] The possible mechanism by which BI 1015550 affects the metabolic effects of nintedanib on hepatic CES1 is shown in FIG10 .

[0291] The groups on the structure of BI 1015550 are similar to Ser in the catalytic triad domain of CES1. 221 Glu 354and His 468 The residues inactivate CES1 through hydrogen bonding interactions, thereby reducing the first-pass metabolism of NDNB, as shown in Figure C.

[0292] BI1015550's chemical name is [1-[[(5R)-2-[4-(5-chloropyrimidin-2-yl)piperidin-1-yl]-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl]amino]cyclobutyl]methanol. Its Chinese chemical name is [1-[[(5R)-2-[4-(5-chloropyrimidin-2-yl)piperidin-1-yl]-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl]amino]cyclobutyl]methanol. Molecular formula / molecular weight: C20H25ClN6O2S, 448.97.

[0293] The chemical structure of BI1015550 is shown in formula (2):

[0294] (1) Human liver microsomal esterase metabolic inhibition experiment

[0295] Human liver microsomal protein was purchased from IPHAS, lot number K23J014, at a protein concentration of 20 mg / mL. It was diluted to 1 mg / mL using pH 7.4 phosphate buffer before use. The positive substrates p-nitrophenyl acetate (pNPA) and p-nitrophenol (pNP) and the positive inhibitor bis(4-nitrophenyl) phosphate (BNPP) were purchased from J&K Technology.

[0296] 1) Solution preparation

[0297] Nintedanib (NDNB) stock solution: Accurately weigh an appropriate amount of nintedanib free base, dissolve it in 80% methanol, and quantitatively dilute it to a concentration of approximately 5.0 mM as the NDNB stock solution. Accurately measure 0.5 mL and add 0.5 mL of 80% methanol to dilute it to a concentration of approximately 2.5 mM as the NDNB working solution.

[0298] p-Nitrophenyl acetate (pNPA) stock solution: Weigh approximately 25 mg of PNPA accurately, dissolve it in methanol, and quantitatively dilute it to a PNPA concentration of approximately 27.6 mM as the pNPA working solution.

[0299] p-Nitrophenol (pNP) stock solution: Take an appropriate amount of p-nitrophenol, accurately weigh it, dissolve it in methanol and quantitatively dilute it to make a solution with a concentration of 1.0 mM as the stock solution. Accurately measure 0.02 mL, 0.05 mL, 0.1 mL, 0.25 mL and 0.5 mL of the stock solution, place them in 10 mL volumetric flasks respectively, add 80% methanol to dilute to the scale, and make a series of solutions with concentrations of 2 μM, 5 μM, 10 μM, 25 μM and 50 μM as the linear solution.

[0300] Bis(4-nitrophenyl)phosphate (BNPP) stock solution: Accurately weigh approximately 5.0 mg of BNPP, dissolve it in dimethyl sulfoxide (DMSO), and quantitatively dilute it to a concentration of approximately 5.5 mM as the stock solution. Accurately measure an appropriate amount and dilute it with DMSO to a concentration of approximately 1.25 mM as the BNPP working solution.

[0301] BI 1015550 stock solution: Take an appropriate amount of BI 1015550, accurately weigh it, dissolve it in 80% methanol, and quantitatively dilute it to make a solution with a BI 1015550 concentration of approximately 3.13 mM. This is the BI 1015550 stock solution.

[0302] 2) Confirmation of CES esterase activity in human liver microsomal proteins

[0303] The positive substrate, p-nitrophenyl acetate (pNPA), is rapidly enzymatically hydrolyzed in the presence of CES esterase to form p-nitrophenol (pNP). The esterase activity in human liver microsomal protein is calculated based on the amount of p-nitrophenol produced using the following formula. p-Nitrophenol is detected using the external standard method using high-performance liquid chromatography.

[0304] ①The enzyme activity calculation formula is as follows:

[0305] Where:

[0306] X is esterase activity, U·mL -1 ;

[0307] c is the concentration of p-nitrophenol, μmol.mL -1 ;

[0308] V is the volume of p-nitrophenol solution, mL;

[0309] V' is the amount of liver microsomal protein solution, mL;

[0310] t is the action time, min.

[0311] ②pNP standard curve:

[0312] The concentration of the enzymatic hydrolysis product of the positive substrate was detected by high performance liquid chromatography. The high performance liquid chromatography conditions are shown in Table 26 below:

[0313] Table 26 Chromatographic conditions for pNP content determination

[0314] Table 27 Experimental study on the effect of BI 1015550 on the metabolism of nintedanib in human liver microsomal proteins

[0315] The reaction steps were carried out according to the enzyme activity assay experimental procedures. The residual concentration of nintedanib in the reaction system was determined by high performance liquid chromatography. The chromatographic conditions for nintedanib detection are shown in Table 28:

[0316] Table 28 Chromatographic conditions for determination of Nintedanib content

[0317] The experimental results are shown in Table 29 below:

[0318] Table 29 Elimination equation, elimination rate constant and half-life of Nintedanib in different reaction systems

[0319] According to the above results, nintedanib showed virtually no degradation in the negative control group after incubation at 37°C for 60 minutes. In the positive control group, nintedanib was degraded by approximately 48% over 60 minutes, with an elimination rate constant of 0.6355 and an elimination half-life of 1.09 hours. The elimination rate constant in the positive inhibitor group was significantly slower than the positive control, at 0.1245, and the elimination half-life was significantly longer at 5.57 hours. The elimination rate constant in the experimental group containing BI1015550 was 0.2516, with an elimination half-life of 2.75 hours. While faster than the positive inhibitor group, it was significantly slower than the positive control group, indicating that BI1015550 has a significant esterase inhibitory effect. See Figure 6 for details.

[0320] (2) Supramolecular complexes

[0321] prescription:

[0322] Table 30 NDNB / NDML supramolecular complex formulation

[0323] Preparation process:

[0324] Weigh each component in the prescription, add an organic solvent, stir in a 40°C water bath to dissolve it, add purified water dropwise while stirring until it is clear, and spin dry the solution using a rotary evaporator in a 45°C water bath. Collect the sample, dry it under reduced pressure at 45°C / -100kPa for 2 hours, pass it through a 60-mesh sieve, and set aside.

[0325] (3) Composition

[0326] Table 31 Tablet / capsule formulation of the composition comprising the supramolecular complex

[0327] (4) Preparation process of tablets / capsules containing supramolecular complexes

[0328] T30, T31, T33:

[0329] 1) Melt EL35 or TPGS in a 60°C water bath, add adsorbent (SiO2 and / or MCC105) according to the prescribed ratio, stir evenly, cool, and pass through a 60-mesh sieve three times. (This step is required for the preparation of T30)

[0330] 2) Weigh the prescribed amount of raw and auxiliary materials, pass them through a 40-mesh sieve, and mix for 5 minutes;

[0331] 3) Use a 12# shallow round punch to compress the tablets according to a theoretical tablet weight of 300 mg and a hardness of 30-40 N. Crush the tablets and pass them through a 30-mesh sieve for granulation.

[0332] 4) Weigh the additional excipients, pass through a 40-mesh sieve, and mix with the granules for 5 minutes;

[0333] 5) Tablets T30, T31, and T33 were prepared using an 8 mm round punch, a 10 mm round punch, and a 16 mm*10 mm capsule punch, respectively.

[0334] Ca6:

[0335] 1) Melt EL35 or TPGS in a water bath at 60°C, add adsorbent (SiO2 and / or MCC105) according to the prescribed ratio, stir evenly, cool, and pass through a 60-mesh sieve three times.

[0336] 2) Weigh the prescribed amount of raw materials and auxiliary materials of Inner Additive Granules 1 and Granules 2 respectively, pass through a 40-mesh sieve, and mix them for 5 minutes;

[0337] 3) Using a 12# shallow round punch, compress the tablets to a theoretical tablet weight of 300 mg and a hardness of 30-40 N. Crush the tablets and granulate them through a 30-mesh sieve to obtain Inner Added Granules 1 and Inner Added Granules 2.

[0338] 4) Weigh the external excipients, pass through a 40-mesh sieve, and mix with internal granules 1 and 2 for 5 minutes;

[0339] 5) Fill the contents into 0# gelatin or hypromellose capsule shells according to the theoretical weight of the contents to prepare capsules.

[0340] T32:

[0341] 1) Melt EL35 or TPGS in a water bath at 60°C, add adsorbent (SiO2 and / or MCC105) according to the prescribed ratio, stir evenly, cool, and pass through a 60-mesh sieve three times.

[0342] 2) Weigh the prescribed amount of the raw materials and auxiliary materials for Layer I and Layer II respectively, pass them through a 40-mesh sieve, and mix them separately for 5 minutes;

[0343] 3) Using a double-layer tablet press, 16 mm*10 mm capsule-shaped punched tablets were prepared into tablets.

[0344] (5) Apparent solubility of the supramolecular complex FaSSIF-V2 in the medium

[0345] The apparent solubility of C35 and C36 was determined according to the method of Comparative Example 1, with two replicates for each formulation. The results are shown in Table 32.

[0346] Table 32 Apparent solubility of supramolecular complex in FaSSIF-V2 for 5 hours (37°C)

[0347] According to the above results, the preparation of supramolecular complexes can also improve the solubility of NDML compared with the raw materials.

[0348] (6) Cumulative dissolution of the supramolecular complex composition in biological media before meals

[0349] Dissolution method: small cup method (250 mL), rotation speed 100 rpm, temperature 37 ° C;

[0350] Dissolution medium: 187 mL FaSSGF was tested for 0.5 h. After sampling, 63 mL FaSSIF-V2 adjustment solution was added to make 250 mL FaSSIF-V2 and the test was continued for 210 minutes. For comparison, the supramolecular complex composition samples were all 150 mg (calculated as NDNB free base, some samples were not whole tablets, and were divided and administered by weight) for dissolution experiments.

[0351] Sampling: At 5 min, 15 min, 30 min, 45 min, 60 min, 90 min, 120 min, 150 min, and 210 min, take 2 mL of the dissolution solution into a centrifuge tube and centrifuge at 37°C, 13000 rpm for 5 min. Take 0.2 mL of the supernatant and add 1 mL of 50% acetonitrile to dilute immediately. Detect the nintedanib content by HPLC and calculate the dissolution rate.

[0352] Table 33 Cumulative dissolution in 187 mL FaSSGF → 250 mL FaSSIF-V2 medium (NDNB 150 mg)

[0353] These results demonstrate that the second therapeutic agent, NDML, dissolves rapidly and completely in pre-meal biological media. When the second therapeutic agent, NDML, and nintedanib supramolecular complex are formulated into tablets or capsules, compared to compositions without NDML (Tables 15 and 21), the cumulative dissolution rates of NDNB and the targeting agent in pre-meal media for each tablet or capsule do not significantly change.

[0354] Example 7 Preparation of Pulmonary Inhalation

[0355] The supramolecular complex or composition of the present invention can be prepared into a pulmonary inhalant.

[0356] prescription:

[0357] Table 34 NDNB / NDML supramolecular complex formulation

[0358] Preparation process:

[0359] Weigh each component in the prescription, add an organic solvent, stir in a 40°C water bath to dissolve, add purified water dropwise while stirring until clarified, spray dry the solution, collect the sample, dry it under reduced pressure at 45°C / -100kPa for 2 hours, pass it through a 200-mesh sieve, and set aside.

[0360] Add appropriate amount of inhalation lactose to the above fine powder and mix evenly. Put it into inhalation capsules, vesicles or measuring cups. When using, use corresponding inhalation devices such as Xihao, Dubao, and Zhunna devices for inhalation administration.

[0361] Example 8 Relative bioavailability study in rats

[0362] The dosage formulation was prepared as follows:

[0363] Sus1: 150 mg of the contents of a known Vigate nintedanib ethanesulfonate soft capsule was added to approximately 9 mg of BI 1015550. The mixture was diluted with medium-chain triglycerides to create a suspension containing approximately 50 mg of nintedanib and approximately 3.0 mg of BI 1015550 per 1 mL. This suspension was administered orally to rats at a dose of 50 mg of nintedanib / kg body weight, with each rat receiving approximately 12.5 mg of nintedanib and 0.75 mg of BI 1015550.

[0364] Ca8: The C39 supramolecular complex is encapsulated in capsules. The dosage is calculated based on 20 mg / kg body weight of NDNB. Each capsule contains 10.75 mg of the supramolecular complex, approximately 5 mg of nintedanib, and approximately 0.75 mg of BI 1015550.

[0365] Table 35 Dosage regimen for relative bioavailability study

[0366] Experimental Animals: Clean-grade male Sprague-Dawley rats, purchased from the China Food and Drug Administration (license number: SCXK(Beijing)2022-0002), weighing 201-209 g, were randomly divided into two groups, with five animals in each group. All rats were fasted for at least 10 hours overnight before dosing and deprived of water for 1 hour before dosing. Water was freely available for 2 hours after dosing, and food was given 4 hours later.

[0367] The rats in group G17 were orally administered with 0.25 mL of the suspension, and the rats in group G18 were orally administered with 1 Ca8 capsule. All rats were given 1 mL of water after the orally administered drugs.

[0368] Blood collection and plasma separation:

[0369] Before administration and at 0.5, 1, 1.5, 2, 3, 4, 5, 7, 9, 12, and 24 hours after administration, 0.5 mL of blood was collected from the inner canthus with 3% sodium heparin as the anticoagulant. All samples were centrifuged at 4°C / 3000 rpm for 10 minutes to separate the plasma, which was then stored at -20°C.

[0370] Plasma sample pretreatment: After the plasma samples have returned to room temperature, accurately measure 150 μL of each plasma sample, accurately add 10 μL of 300 ng / mL YBTN internal standard solution, vortex for 30 seconds, add 440 μL of methanol, vortex for 30 seconds, let stand for 10 minutes, vortex for 30 seconds, centrifuge at 4°C / 13,000 rpm for 10 minutes, and take the supernatant to directly analyze the content of nintedanib.

[0371] Based on the blood drug concentration data measured at different time points, Phoenix WinNonlin7.0 was used to calculate the pharmacokinetic parameters and provide AUC 0-t , AUC 0-∞ , Cmax, Tmax and T 1 / 2 Parameters and their means and standard deviations.

[0372] Relative bioavailability (%) = (AUC G ×Dose C ) / (AUC C ×Dose G )×100%

[0373] AUC G : Systemic exposure of experimental drugs (drugs in Examples) (ng·hr / ml);

[0374] Dose G : experimental drug dosage (mg / kg body weight);

[0375] AUC C : Systemic exposure of the reference drug (drug in the comparative example) (ng·hr / ml);

[0376] Dose C : Reference drug dosage (mg / kg body weight).

[0377] The results of the rat in vivo experiments are shown in the table below.

[0378] Table 36 In vivo experimental results in rats

[0379] Note*: The data of the control group are from Table 18.

[0380] In summary, based on the results of the oral relative bioavailability study in rats, the G17 dosage formulation consisted of the contents of nintedanib ethylsulfonate capsules plus BI1015550. At the same dosage as the control group, the relative bioavailability was 508% of that of the control group, indicating that BI 1015550 had a certain inhibitory effect on CES esterase, which was consistent with the results of the in vitro liver microsome test. In the G18 group, nintedanib and BI1015550 were prepared into a supramolecular complex, and the amount of BI1015550 administered to each rat was kept consistent. The nintedanib dosage was reduced to 20 mg / kg body weight. Compared with the control group, the relative bioavailability was 1447%, which was basically consistent with the results of the group adding a targeting agent (G10, 1467%).

Claims

1. A nintedanib supramolecular complex, comprising the following components: (1) The active ingredient nintedanib; and (2) Carrier I, which is selected from one or more of the group consisting of the free state, sodium salt, potassium salt, ammonium salt or hydrate thereof of rebaudioside B (RBDS-B), steviolbioside (STVB), rubusoside (RSBD-Acid), steviolbioside arginine amide derivative (STVB-Arga), glycyrrhizic acid (GA), steviolbioside histamine amide (STVB-His); and (3) Carrier II, which is selected from one or more of the group consisting of rebaudioside A (RBDS-A), rebaudioside D (RBDS-D), rebaudioside E (RBDS-E), rebaudioside M (RBDS-M), rubusoside (RSBD), stevioside (STVS), rebaudioside O (RBDS-O), rebaudioside N (RBDS-N), rebaudioside F (RBDS-F), rebaudioside C (RBDS-C), dulcoside, mogroside (MGSDT), Preferably, the nintedanib supramolecular complex is in a form suitable for oral, sublingual, buccal, intracolonic, rectal, vaginal, mucosal, subcutaneous, intramuscular, intravenous, arterial, dermal, pulmonary, intranasal administration, preferably in a form suitable for mucosal, pulmonary inhalation, oral administration.

2. The nintedanib supramolecular complex according to claim 1, wherein, The active ingredient nintedanib is selected from one or more of the group consisting of nintedanib free base, nintedanib salts (such as ethanesulfonate, methanesulfonate, sulfate, hydrochloride, hydrobromide, tartrate, fumarate, maleate, succinate, citrate), or hydrates or solvates of its salts, preferably nintedanib free base, nintedanib ethanesulfonate or a combination of the two.

3. The nintedanib supramolecular complex according to claim 1 or 2, characterized in that, The ratio of the active ingredient nintedanib to carrier (I + II) is 1:0.5 - 1:10 (w / w), and carrier I accounts for 5% - 75% of the weight of carrier (I + II); preferably, the ratio of the active ingredient nintedanib to carrier (I + II) is 1:0.7 - 1:3 (w / w), and carrier I accounts for 5% - 50% of the weight of carrier (I + II).

4. The nintedanib supramolecular complex according to any one of claims 1-3 further comprises a high molecular polymer, characterized in that, The high molecular polymer is selected from one or more of the group consisting of hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose (HPMC), sodium carboxymethylcellulose (CMC-Na), hydroxypropyl cellulose (HPC), polyvinylpyrrolidone (PVP), copolyvinylpyrrolidone (vinylpyrrolidone / vinyl acetate copolymer, such as PVP-VA64), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (such as Soluplus), sodium hyaluronate (HA-Na).

5. A composition or kit, comprising the nintedanib supramolecular complex according to any one of claims 1 - 4.

6. The composition or kit according to claim 5 further comprises a targeting agent selected from one or more of the group consisting of tanshinone IIA, cryptotanshinone, sodium tanshinone IIA sulfonate, curcumin, maslinic acid, and tanshinone component extract. The kit further comprises a product instruction manual. When the targeting agent and the nintedanib supramolecular complex are in the kit, the targeting agent and the nintedanib supramolecular complex are separately packaged. Preferably, the targeting agent and the nintedanib supramolecular complex are in forms suitable for oral, sublingual, buccal, intracolonic, rectal, vaginal, mucosal, subcutaneous, intramuscular, intravenous, arterial, dermal, pulmonary, and intranasal administration, preferably in forms suitable for mucosal, pulmonary inhalation, and oral administration.

7. The composition or kit according to claim 6, wherein The tanshinone component extract consists of one or more of dihydrotanshinone, tanshinone IIA, cryptotanshinone, tanshinone I, tanshinone IIB, hydroxytanshinone IIA, and tanshinone IIA anhydride.

8. The composition or kit according to claim 6, characterized in that, The curcumin may further contain demethoxycurcumin and bisdemethoxycurcumin.

9. The composition or kit according to any one of claims 6-8, characterized in that, The weight ratio of the targeting agent to the active ingredient nintedanib is 100:1 to 1:5; preferably 20:1 to 1:2; more preferably 10:1 to 1:

2.

10. The composition or kit according to any one of claims 6-9, characterized in that, The targeting agent exists as a targeting agent supramolecular complex, which is prepared by adding the targeting agent to the nintedanib supramolecular complex according to any one of claims 1-4, or by mixing the targeting agent with carrier I and carrier II according to any one of claims 1-4.

11. The composition or kit according to claim 10, wherein The targeting agent supramolecular complex further comprises a polymer.

12. The composition or kit according to claim 11, characterized in that, The weight ratio of the targeting agent to carrier II is 1:1000 to 1:3.3; preferably 1:100 to 1:5; more preferably 1:20 to 1:

10. Carrier I accounts for 5%-75%, preferably 5%-50% of the weight of carrier (I+II).

13. The composition or kit according to any one of claims 6-12, characterized in that, The kit contains a product instruction manual, which describes that the targeting agent is administered simultaneously with the active ingredient nintedanib, or the targeting agent is administered within 2 hours before the active ingredient nintedanib. Preferably, the targeting agent is released before the active ingredient nintedanib.

14. The composition or kit according to claim 11 further comprises a polymer added in addition to the polymer in the nintedanib supramolecular complex and / or the targeting agent supramolecular complex. The polymer is selected from one or more of the group consisting of hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose (HPMC), sodium carboxymethylcellulose (CMC-Na), hydroxypropyl cellulose (HPC), polyvinylpyrrolidone (PVP), copovidone (vinylpyrrolidone / vinyl acetate copolymer, such as PVP-VA64), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (such as Soluplus), and sodium hyaluronate (HA-Na).

15. The composition or kit according to any one of claims 5 - 14 further comprises a solubilizer selected from one or more of the group consisting of d-alpha-tocopheryl polyethylene glycol succinate (TPGS), sodium lauryl sulfate (SLS), sodium docusate, lecithin, Tween 80, Tween 20, polyoxyl 35 castor oil (EL35), and polyoxyl hydrogenated castor oil, preferably d-alpha-tocopheryl polyethylene glycol succinate (TPGS). Preferably, the solubilizer is added directly or added after being adsorbed by one or more of silica, calcium silicate, magnesium aluminum silicate, microcrystalline cellulose, and siliconized microcrystalline cellulose to form a solid powder.

16. The composition or kit according to any one of claims 5 - 15 further contains a pharmaceutically acceptable excipient selected from one or more of the group consisting of a filler, a disintegrant, a glidant, and a lubricant.

17. The composition or kit according to claim 16, characterized in that, The filler is selected from one or more of the group consisting of mannitol, microcrystalline cellulose (MCC), siliconized microcrystalline cellulose (SMCC), lactose, pregelatinized starch, sucrose, glucose, and sorbitol; the disintegrant is selected from one or more of the group consisting of crospovidone (PVPP), croscarmellose sodium (CCNa), sodium carboxymethyl starch (CMS-Na), and low-substituted hydroxypropyl cellulose (L-HPC); the glidant is silica; and the lubricant is selected from one or more of the group consisting of magnesium stearate, sodium stearyl fumarate, and talc.

18. The composition or kit according to any one of claims 5-17, wherein the product specification describes that the daily dosage is nintedanib ethanesulfonate soft capsules in terms of the active ingredient nintedanib 5%-50%, preferably 10%-40% of the dosage.

19. The composition or kit according to any one of claims 5 - 18, wherein the composition comprises 30 mg - 120 mg of the active ingredient nintedanib, or the product specification describes the daily dosage of the active ingredient nintedanib as 30 mg - 120 mg.

20. The composition or kit according to any one of claims 5 - 19 comprises 15 mg, 20 mg, 22.5 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, or 120 mg of the active ingredient nintedanib.

21. The composition or kit according to any one of claims 5 - 20, wherein the composition is a solid oral preparation, preferably one of tablets, capsules, and granules, or the nintedanib supramolecular complex and / or the targeting agent supramolecular complex in the kit is a solid oral preparation, preferably one of tablets, capsules, and granules.

22. The composition or kit according to any one of claims 5 - 20 further contains BI1015550, represented by ([1-[[(5R)-2-[4-(5-chloropyrimidin-2-yl)piperidin-1-yl]-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl]amino]cyclobutyl]methanol).

23. The composition or kit according to claim 22, wherein the content of BI1015550 is 1 mg - 72 mg, preferably 2 mg - 36 mg, 1 mg - 36 mg, or 1.5 mg - 18 mg.

24. Use of the nintedanib supramolecular complex according to any one of claims 1 - 4 or the composition according to any one of claims 5 - 23 in the preparation of a medicament for the treatment and / or prevention of pulmonary fibrosis, chronic fibrotic interstitial lung disease, systemic sclerosis - associated interstitial lung disease, lung cancer, or chronic obstructive pulmonary disease (COPD).

25. Use of BI1015550 as a specific carboxylesterase inhibitor, wherein the BI1015550 is represented by ([1 - [[(5R)-2 - [4-(5 - chloropyrimidin - 2 - yl)piperidin - 1 - yl]-5 - oxo - 6,7 - dihydrothieno[3,2 - d]pyrimidin - 4 - yl]amino]cyclobutyl]methanol).

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