Granular pharmaceutical composition of protein kinase mek inhibitor benzothiazole

Abstract

Provided in the present invention are a granular pharmaceutical composition comprising protein kinase Mek inhibitor benzothiazole, and the therapeutic use thereof.

Description

Granular pharmaceutical composition of a protein kinase Mek inhibitor benzothiazole TECHNICAL FIELD

[0001] The present application provides a granular pharmaceutical composition of a protein kinase Mek inhibitor benzothiazole and its therapeutic use. BACKGROUND

[0002] Over-activation of the Ras / Raf / Mek / Erk signaling pathway (hereinafter referred to as the Ras-RAF-MEK-ERK pathway) plays an important role in the proliferation and differentiation of cancer cells. This Ras / Raf / Mek / Erk pathway has been found to be continuously activated or over-activated in a variety of cancers such as pancreatic cancer, colon cancer, lung cancer, bladder cancer, kidney cancer, skin cancer, breast cancer, etc. Inhibition of the Ras / Raf / Mek / Erk pathway is helpful for the treatment of such over-proliferative diseases, in which Mek, a target downstream of Ras and Raf, plays a key role in the pathway, and the substrate of Mek phosphorylation is MAP kinase Erk. If Mek is inhibited, the Ras / Raf / Mek / Erk signaling pathway will be closed, and thus the proliferation of cancer cells will be inhibited. Therefore, Mek inhibitors can inhibit the growth of cancer cells, especially for cancers caused by over-activation of Ras or Raf. Meanwhile, Mek is also involved in diseases and symptoms of inflammation, including acute and chronic inflammation.

[0003] Chinese Patent Application No. 201210190520.4 discloses a number of benzothiazole compounds which exhibit protein kinase Mek inhibitory activity, including the compound 4-fluoro-5-(2-fluoro-4-iodophenylamino)-1H-benzo[d]thiazole-6-carboxylic acid (2-hydroxy-ethoxy)-amide (hereinafter referred to as Compound 1). However, Compound 1 belongs to the Biopharmaceutics Classification System (BCS) Class II drug, and its low solubility and low dissolution rate are the main reasons for low oral bioavailability.

[0004] Solid oral pharmaceutical dosage forms, such as tablets or capsules, are a common and useful pharmaceutical form for dispensing a pharmaceutically active compound. However, developing an acceptable solid oral pharmaceutical dosage form suitable for commercial scale is not simple. On one hand, each active pharmaceutical ingredient (API) exerts a specific therapeutic effect at a therapeutic concentration; on the other hand, many APIs, especially anti-tumor compounds, are often accompanied by undesirable side effects, such as toxicity (e.g., genotoxicity, teratogenicity) and undesirable physical or psychological manifestations. Formulation development needs to ensure the physical and chemical stability and uniform dispersion of the active ingredient during formulation processing and long-term storage, while meeting the specific dosage requirements to ensure that the effective concentration within the therapeutic window is reached while minimizing adverse reactions. These are particularly prominent for APIs with low solubility, such as Compound 1, which often leads to insufficient or inconsistent exposure after in vivo administration. More importantly, Compound 1 is photolabile and easily degrades to produce impurities (e.g., Impurity A) under light conditions, which seriously affects the safety and long-term storage stability of the drug itself.

[0005] Therefore, to overcome the problems of low solubility, low dissolution rate and photolability of Compound 1, it is necessary to develop a solid oral pharmaceutical dosage form of Compound 1 suitable for commercial scale production with ideal pharmacokinetic properties. SUMMARY

[0006] The present application provides a new pharmaceutical composition of Compound 1 and a preparation method thereof, aiming to overcome the problems of low oral bioavailability due to low solubility and low dissolution rate of Compound 1, and photolability in the prior art, which seriously affect the safety and storage stability of Compound 1.

[0007] To solve the above problems, the present application provides a granular pharmaceutical composition of Compound 1.

[0008] The composition significantly reduces the content of impurity (A) by adding specific surface stabilizers, binders and anti-adhesion agents, effectively improves the photostability of Compound 1 and improves the overall stability. Further, the use of specific proportions and types of surface stabilizers can significantly improve the efficiency during grinding and reduce the target grinding particle size, thereby accelerating the dissolution of Compound 1 and improving its oral bioavailability. In addition, the inventors have found that the nanoparticle morphology of the Compound 1 composition coated or coated by suspension can still maintain a D90 particle size of not more than 600 nm at the nanoscale after solidification.

[0009] These research results collectively contributed to the successful completion of the present application and helped to ensure safe and effective treatment.

[0010] The present application provides a granular pharmaceutical composition of Compound 1 and a method of preparing the pharmaceutical composition, aiming to overcome the problems of low oral bioavailability due to low solubility and low dissolution rate of Compound 1 and light instability in the prior art, which seriously affect the safety and storage stability of Compound 1.

[0011] To overcome the above technical problems, the first aspect of the present application provides a pharmaceutical composition of Compound 1.

[0012] The granular pharmaceutical composition of the present application significantly reduces the content of impurity (A), effectively improves the light stability of Compound 1, and improves the overall stability of Compound 1, which helps to ensure safe and effective treatment. Further, by adding a specific proportion of a surface stabilizer, the present application can significantly improve the efficiency of Compound 1 during grinding and reduce the target grinding particle size, thereby accelerating the dissolution of Compound 1 and improving its oral bioavailability, which helps to ensure safe and effective treatment. In addition, the inventors of the present application found that the Compound 1 composition coated or coated with a suspension maintains a particle size of the Compound 1 nanoparticle composition after reconstitution after solidification at the nanometer level, for example, the particle size is D90 no more than 600 nm, which helps to ensure safe and effective treatment.

[0013] Based on these findings, the inventors of the present application successfully completed the present application.

[0014] In the first aspect, the present application relates to a granular pharmaceutical composition comprising 4-fluoro-5-(2-fluoro-4-iodophenylamino)-1H-benzo[d]thiazole-6-carboxylic acid (2-hydroxy-ethoxy)-amide (Compound 1) or a pharmaceutically acceptable salt thereof, a surface stabilizer, a solid support, a binder, and an anti-adherent. In some embodiments, the solid support is coated or coated with a suspension containing Compound 1 or a pharmaceutically acceptable salt thereof and a surface stabilizer.

[0015] In some embodiments, the suspension is a suspension of Compound 1 and a surface stabilizer in water or ethanol.

[0016] In some embodiments, the suspension is a suspension of Compound 1 and a surface stabilizer in water.

[0017] In some embodiments, Compound 1 in the suspension has a D90 particle size of no more than 1000 nm. In some embodiments, Compound 1 in the Compound 1 suspension has a D90 particle size of no more than 800 nm, 600 nm, 450 nm, 300 nm, 200 nm, 100 nm, or 50 nm.

[0018] In some embodiments, the surface stabilizer is selected from one or more of cellulose, high molecular polymer, surfactant, and natural stabilizer; preferably, the cellulose is selected from one or more of methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, hypromellose, the high molecular polymer is selected from one or more of polyoxyethylene polyoxypropylene block copolymer, povidone, polyvinyl alcohol polyethylene glycol castor oil, and polyethylene glycol succinate, the surfactant is selected from one or more of sodium dodecyl benzene sulfonate, cibacron, sodium dodecyl sulfate, and the natural stabilizer is selected from one or more of sodium alginate, dextran, gum arabic, mannitol, lecithin, chitosan; more preferably one or more of hydroxypropyl cellulose, hypromellose, polyoxyethylene polyoxypropylene block copolymer, povidone, and mannitol; further preferably one or more of hydroxypropyl cellulose and hypromellose; more further preferably hypromellose.

[0019] In some embodiments, the weight percentage of the component part is calculated based on the total weight of the formulation of the pharmaceutical composition without solvent.

[0020] In some embodiments, the weight percentage of the surface stabilizer is 1-10%, preferably 1-5%, based on the total weight of the formulation.

[0021] In some embodiments, the weight percentage of Compound 1 is 0.1-60%, preferably 0.2-50%, more preferably 0.2-40%, further preferably 0.2-30%, based on the total weight of the formulation.

[0022] In some embodiments, the solid support is selected from one or more of lactose, starch, pregelatinized starch, dextrin, microcrystalline cellulose, mannitol, sucrose, sugar powder, erythrose, xylitol, sorbitol, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, calcium sulfate dihydrate, calcium sulfate, magnesium oxide, aluminum hydroxide, microcrystalline cellulose pellet core, sugar-starch microspheres, sucrose pellet core, starch pellets, tartaric acid pellet core, lactose pellet core.

[0023] In some embodiments, the weight percentage of the solid support is 1-99%, or 10-98%, or 20-98%, or 40-98%, or 60-98%, or 80-98%, based on the total weight of the formulation.

[0024] In some embodiments, the solid support is optionally dried after the suspension is coated or coated.

[0025] In some embodiments, the solid support coated with the suspension is further coated with a protective layer. In some embodiments, the protective layer comprises a binder and an anti-adherent.

[0026] In some embodiments, the binding agent comprises one or more of pregelatinized starch, dextrin, polyvinyl alcohol, carboxymethyl cellulose, hypromellose, hydroxypropyl cellulose, polyvinylpyrrolidone; preferably hypromellose. In some embodiments, the weight percentage of the binding agent is 1-30%, preferably 1-20%, more preferably 1-15%, further preferably 1-5%, based on the total weight of the formulation.

[0027] In some embodiments, the anti-adhesion agent comprises one or more of talc, microfine silica, hydrogenated vegetable oil, sodium stearyl fumarate, glyceryl behenate, sodium lauryl sulfate, polyethylene glycol, or magnesium stearate; preferably talc. In some embodiments, the weight percentage of the anti-adhesion agent is 0-5%, preferably 0-3%, more preferably 0.5-3%, based on the total weight of the formulation.

[0028] In some embodiments, the compound 1 pharmaceutical composition contains 0.01-50 mg, 0.1-40 mg, 0.25-30 mg, 0.5-20 mg, 0.5-15 mg, 0.5-12 mg, 0.5-6 mg of compound 1 per unit dose; preferably, the compound 1 nanoparticle oral solid formulation contains 0.5-15 mg of active ingredient, more preferably contains 0.5 mg, 2 mg, 3 mg, 6 mg, 12 mg, or 15 mg of compound 1 per unit dose.

[0029] In some embodiments, the granular pharmaceutical composition of the present application is in the form of a tablet, a capsule, or a granule. In some embodiments, the granular pharmaceutical composition of the present application is in the form of a capsule.

[0030] In a second aspect, the present application relates to a pharmaceutical composition comprising 4-fluoro-5-(2-fluoro-4-iodophenylamino)-1H-benzo[d]thiazole-6-carboxylic acid (2-hydroxy- ethoxy)-amide (Compound 1) or a pharmaceutically acceptable salt thereof, said compound having a surface stabilizer adsorbed on the surface thereof.

[0031] In some embodiments, the pharmaceutical composition is a suspension. In some embodiments, the suspension is a suspension of Compound 1 and a surface stabilizer in water.

[0032] In some embodiments, Compound 1 in the suspension has a D90 particle size of no more than 1000 nm. In some embodiments, Compound 1 in the Compound 1 suspension has a D90 particle size of no more than 800 nm, 600 nm, 450 nm, 300 nm, 200 nm, 100 nm, or 50 nm.

[0033] In some embodiments, the stabilizer is selected from one or more of cellulose, high molecular polymer, surfactant, and natural stabilizer; preferably, the cellulose is selected from one or more of methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, hypromellose, the high molecular polymer is selected from one or more of polyoxyethylene polyoxypropylene block copolymer, povidone, polyvinyl alcohol polyethylene glycol castor oil, and polyethylene glycol succinate, the surfactant is selected from one or more of sodium dodecyl benzene sulfonate, cibacron, sodium dodecyl sulfate, and the natural stabilizer is selected from one or more of sodium alginate, dextran, gum arabic, mannitol, lecithin, chitosan; more preferably one or more of hydroxypropyl cellulose, hypromellose, polyoxyethylene polyoxypropylene block copolymer, povidone, and mannitol; further preferably one or more of hydroxypropyl cellulose and hypromellose; and more further preferably hypromellose.

[0034] In some embodiments, the weight percentage of the component part is calculated based on the total weight of the formulation of the pharmaceutical composition without solvent.

[0035] In some embodiments, the weight percentage of the surface stabilizer is 1-10%, preferably 1-5%, based on the total weight of the formulation.

[0036] In some embodiments, the weight percentage of Compound 1 is 0.1-60%, preferably 0.2-50%, more preferably 0.2-40%, further preferably 0.2-30%, based on the total weight of the formulation.

[0037] In some embodiments, the pharmaceutical composition further comprises a solid support, wherein the solid support is coated or coated with the above-mentioned suspension containing Compound 1 or a pharmaceutically acceptable salt thereof and a surface stabilizer.

[0038] In some embodiments, the solid support is selected from one or more of lactose, starch, pregelatinized starch, dextrin, microcrystalline cellulose, mannitol, sucrose, sugar powder, erythrose, xylitol, sorbitol, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, calcium sulfate dihydrate, calcium sulfate, magnesium oxide, aluminum hydroxide, microcrystalline cellulose pellet core, sugar-starch microspheres, sucrose pellet core, starch micro-pellet, tartaric acid pellet core, lactose pellet core.

[0039] In some embodiments, the weight percentage of the solid support is 1-99%, or 10-98%, or 20-98%, or 40-98%, or 60-98%, or 80-98%, based on the total weight of the formulation.

[0040] In some embodiments, the solid support coated with the suspension is further coated with a protective layer. In some embodiments, the protective layer comprises a binder and an anti-adherent.

[0041] In some embodiments, the binding agent comprises one or more of pregelatinized starch, dextrin, polyvinyl alcohol, carboxymethyl cellulose, hypromellose, hydroxypropyl cellulose, polyvinylpyrrolidone; preferably hypromellose. In some embodiments, the weight percentage of the binding agent is 1-30%, preferably 1-20%, more preferably 1-15%, further preferably 1-5%, based on the total weight of the formulation.

[0042] In some embodiments, the anti-adhesion agent comprises one or more of talc, microfine silica, hydrogenated vegetable oil, sodium stearyl fumarate, glyceryl behenate, sodium lauryl sulfate, polyethylene glycol, or magnesium stearate; preferably talc. In some embodiments, the weight percentage of the anti-adhesion agent is 0-5%, preferably 0-3%, more preferably 0.5-3%, based on the total weight of the formulation.

[0043] In some embodiments, the compound 1 pharmaceutical composition contains 0.01-50 mg, 0.1-40 mg, 0.25-30 mg, 0.5-20 mg, 0.5-15 mg, 0.5-12 mg, 0.5-6 mg of compound 1 per unit dose; preferably, the compound 1 nanoparticle oral solid formulation contains 0.5-15 mg of active ingredient, more preferably contains 0.5 mg, 2 mg, 3 mg, 6 mg, 12 mg, or 15 mg of compound 1 per unit dose.

[0044] In a third aspect, the present application also provides a method for preparing a compound 1 pharmaceutical composition, the method comprising:

[0045] (1) preparing a drug-loaded suspension of compound 1 and a surface stabilizer in water or an alcoholic solvent;

[0046] (2) preparing a nanoparticle suspension from the drug-loaded suspension;

[0047] (3) solidifying the nanoparticle suspension to obtain a nanoparticle solidification product;

[0048] (4) adding a binding agent and an anti-adhesion agent to the nanoparticle solidification product to prepare a nanoparticle composition coated with a protective layer;

[0049] (5) optionally, preparing the nanoparticle composition into an oral solid formulation.

[0050] In some embodiments, the surface stabilizer is prepared into an aqueous solution or an alcoholic solution with a concentration of 0.1-15%, preferably a solution with a concentration of 1-10%, more preferably a solution with a concentration of 3-6%, and then mixed with compound 1 to prepare a nanoparticle suspension. In some embodiments, the alcoholic solvent is ethanol.

[0051] In some embodiments, the nanoparticle suspension can be prepared by one or more of a precipitation method, an emulsion method, a high pressure homogenization method, a media milling method, or a high pressure microfluidization method, preferably a media milling method. In some embodiments, the nanoparticle suspension of Compound 1 is prepared by a wet milling process, and the solvent is water.

[0052] In some embodiments, the surface stabilizer is first dissolved in water to form a surface stabilizer aqueous solution, Compound 1 is added, and mixed thoroughly; the resulting Compound 1 suspension is added to a mill, and wet milling is performed to obtain a nanoparticle suspension of Compound 1 having a desired particle size.

[0053] In some embodiments, the active pharmaceutical Compound 1 is added to the milling chamber for milling to prepare the nanoparticle suspension of Compound 1. Too high or too low a proportion of the active pharmaceutical can affect the milling efficiency and the particle size of the resulting nanoparticles. Therefore, in the preparation of the nanoparticle suspension of Compound 1, the proportion of Compound 1 is preferably 10-40% by weight.

[0054] In some embodiments, the nanoparticle suspension of Compound 1 is solidified, and the process can be selected from fluidized bed granulation, freeze-drying, spray-drying, or spray coating onto a solid support such as a sucrose pellet, a lactose pellet, a microcrystalline cellulose pellet, or other pharmaceutical excipients, preferably spray coating.

[0055] In some embodiments, the pharmaceutical composition can be prepared into various dosage forms, and the pharmaceutical preparation is a tablet, a granule, a capsule, a nasal administration preparation, or a transdermal preparation; according to the choice of medication compliance, oral solid preparations, including granules, capsules, and tablets, are preferred.

[0056] In a fourth aspect, the present application provides a method of treating a tumor, a chronic inflammatory disease, an inflammatory bowel disease, a skin disease, diabetes, an ocular disease, a disease associated with angiogenesis or vasculogenesis in a mammal, a disease associated with chronic pain, and other diseases modulated by the Mek cascade in a mammal, the method comprising administering to the mammal a granular pharmaceutical composition of the present application; a granular pharmaceutical composition of the present application for use in the treatment of a tumor, a chronic inflammatory disease, an inflammatory bowel disease, a skin disease, diabetes, an ocular disease, a disease associated with angiogenesis or vasculogenesis in a mammal, a disease associated with chronic pain, and other diseases modulated by the Mek cascade in a mammal; use of a granular pharmaceutical composition of the present application in the manufacture of a medicament for the treatment of a tumor, a chronic inflammatory disease, an inflammatory bowel disease, a skin disease, diabetes, an ocular disease, a disease associated with angiogenesis or vasculogenesis in a mammal, a disease associated with chronic pain, and other diseases modulated by the Mek cascade in a mammal. In some embodiments, the mammal is a human.

[0057] In some embodiments, the present application provides a method of treating a RAS or RAF mutant cancer in a mammal, comprising administering to the mammal a granular pharmaceutical composition of the present application. In some embodiments, the RAS or RAF mutant cancer is, for example, a KRAS mutant cancer, a NRAS mutant cancer, a HRAS mutant cancer, or a BRAF mutant cancer. In some embodiments, the RAS mutant cancer is, for example, pancreatic cancer, colorectal cancer, lung cancer, melanoma, acute myelogenous leukemia, bladder cancer, or head and neck cancer. In preferred embodiments, the cancer is a NRAS mutant cancer. In some embodiments, the NRAS mutant cancer is a NRAS mutant melanoma.

[0058] In some embodiments, KRAS comprises a mutation at one or more positions selected from codons 12, 13, 59, and 61. In some embodiments, the KRAS mutant form has a mutation at one or more amino acid positions selected from G12, G13, S17, P34, A59, and Q61. In some embodiments, the KRAS mutant form has one or more amino acid substitutions selected from G12C, G12S, G12R, G12F, G12L, G12N, G12A, G12D, G12V, G13C, G13S, G13D, G13V, G13P, S17G, P34S, A59E, A59G, A59T, Q61K, Q61L, Q61R, and Q61H. In some embodiments, the KRAS mutant form has a mutation at one or more amino acid positions selected from G12, G13, A59, Q61, K117, and A146. In some embodiments, the KRAS mutant form has one or more amino acid substitutions selected from G12C, G12R, G12S, G12A, G12D, G12V, G13C, G13R, G13S, G13A, G13D, G13V, A59E, A59G, A59T, Q61K, Q61L, Q61R, Q61H, K117N, K117R, K117E, A146P, A146T, and A146V. In some embodiments, the BRAF mutation is a BRAF V600E mutation.

[0059] In some embodiments, the NRAS comprises a mutation at one or more positions selected from codons 12, 13, 59, 61, and 146. In some embodiments, the mutant form of NRAS has a mutation at one or more amino acid positions selected from G12, G13, A59, Q61, K117, and A146. In some embodiments, the mutant form of NRAS has one or more amino acid substitutions selected from G12C, G12R, G12S, G12A, G12D, G12V, G13C, G13R, G13S, G13A, G13D, G13V, A59D, A59T, Q61K, Q61L, Q61R, Q61H, K117N, K117R, K117E, A146P, A146T, and A146V.

[0060] In some embodiments, the cancer is an early stage, intermediate stage, or late stage cancer. The cancer can be locally advanced or metastatic. In some embodiments, the cancer is pancreatic cancer, colorectal cancer, lung cancer, melanoma, acute myelogenous leukemia, bladder cancer, or head and neck cancer. In some embodiments, the mammal has previously received an immunotherapy. In some embodiments, the mammal has previously received an immunotherapy and has a NRAS-mutated, late stage melanoma. In some embodiments, the melanoma is selected from the group consisting of: advanced melanoma, unresectable melanoma, metastatic melanoma, melanoma with a BRAF mutation, melanoma with a NRAS mutation, cutaneous melanoma, or intraocular melanoma.

[0061] In some embodiments, the particulate pharmaceutical composition of the present application is used in combination with a chemotherapeutic agent, a KRAS inhibitor, a SHP2 inhibitor, a RAF inhibitor, or the chemotherapeutic agent and / or KRAS inhibitor and / or RAF inhibitor for the treatment of the above-mentioned cancers. In some embodiments, the chemotherapeutic agent is selected from the group consisting of cisplatin, carboplatin, paclitaxel, paclitaxel protein-bound, docetaxel, gemcitabine, vinorelbine, etoposide, and pemetrexed; the KRAS inhibitor is AMG-510, MRTX849, or BI 1701963; the RAF inhibitor is LY3009120, PLX4032, LGX818, GSK2118436, BI 882370, TAK580, or Vemurafenib; and the SHP2 inhibitor is JAB-3068, TNO155, BBP-398 (IACS-15509), JAB-3312, or SHP099.

[0062] The term "suspension" refers to a formulation in which the active ingredient nanoparticles remain in a suspended state, undissolved, in a liquid, such as water.

[0063] The measurement of particle size used herein is based on the measurement of the weight average particle size by conventional particle size measurement techniques well known to those skilled in the art. Such techniques include, for example, sedimentation field flow fractionation, photon correlation spectroscopy, light scattering and disc centrifugation. By "effective average particle size of no more than about 1000 nm" is meant that at least 50% of the particles of Compound 1 have an average particle size of no more than about 1000 nm when measured by the above techniques. Preferably, at least 70% of the particles have an average particle size of less than the effective average, i.e., about 1000 nm, more preferably, at least about 90% of the particles have an average particle size of less than the effective average. In preferred embodiments, the effective average particle size is no more than about 800 nm, no more than about 600 nm, no more than about 500 nm, no more than about 400 nm, no more than about 300 nm, no more than about 170 nm, no more than about 100 nm, no more than about 50 nm.

[0064] The phrase "pharmaceutically acceptable" is used in the present application to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0065] The term "pharmaceutically acceptable salt" as used herein refers to a derivative of a compound prepared by modifying the parent compound to form a salt thereof with an acid or base. Examples of pharmaceutically acceptable salts include, but are not limited to, salts of mineral acids or organic acids with basic residues such as amines; salts of an acid with an acidic residue such as a carboxylic acid; and the like. Pharmaceutically acceptable salts include conventional nontoxic salts or quaternary ammonium salts of a parent compound formed, for example, from non-toxic inorganic or organic acids. Such conventional nontoxic salts include, for example, those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts derived from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanesulfonic, oxalic, isethionic, and the like.

[0066] The pharmaceutically acceptable salts can be manufactured by conventional chemical methods from the parent compound, which contains a basic or acidic moiety by standard chemical methods. Generally, the salt will be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.

[0067] As to the pharmaceutical compositions of Compound 1 disclosed in the art, the pharmaceutical compositions of the present application exhibit unexpected properties, such as enhanced oral bioavailability or absorption and / or properties in terms of water solubility, stability, ease of manufacture and / or metabolism.

[0068] The pharmaceutical compositions of the present application can be used to prepare pharmaceutical formulations, such as in solid, semi-solid or liquid form, which contain one or more of the compounds of the present application as an active ingredient in admixture with a suitable organic or inorganic carrier or excipient for external, enteral or parenteral application. The active ingredient can be mixed with one or more conventional non-toxic, pharmaceutically-acceptable carriers, such as, for example, vehicles, diluents, and excipients. The pharmaceutical preparations can be subjected to conventional pharmaceutical operations such as, for example, tabletting, pilling, encapsulation, coating, and / or lyophilization. Such preparations can contain, apart from the active ingredient, one or more of the following: binders such as, for example, carboxymethylcellulose, cellulose acetate, dextrin, isinglass, pectin, sucrose, tragacanth, and / or xanthan gum; fillers such as, for example, calcium carbonate, calcium phosphate, corn starch, kaolin, lactose, magnesium stearate, mannitol, potato starch, sodium carbonate, starch, talc, and / or titanium dioxide; resins such as, for example, gelatin; humectants such as, for example, glycerol; lubricants such as, for example, magnesium stearate; flavoring agents such as, for example, peppermint; preservatives such as, for example, methyl paraben; and / or solubilizers such as, for example, propylene glycol. An effective amount of the active ingredient is included in the pharmaceutical composition to produce the desired effect.

[0069] The surface stabilizer can also be used in combination with one or more other surface stabilizers. Preferably, the other surface stabilizer is selected from known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products, and surfactants, and preferred other surface stabilizers include non-ionic and ionic surface stabilizers. Representative examples of excipients include gelatin, casein, lecithin (phosphatides), sodium alginate, dextrin, mannitol, lecithin, chitosan, acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl wax, sorbitan esters, polyoxyethylene-polyoxypropylene block polymers, povidone, polyvinyl alcohol polyoxyethylene castor oil, polyethylene glycol succinate, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycol, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, talc, carboxymethylcellulose calcium, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropyl methylcellulose phthalate, hydroxypropylcellulose, hypromellose, non-crystalline cellulose, magnesium aluminum silicate, sodium dodecylbenzenesulfonate, cibacron chloride, sodium dodecylsulfate, triethanolamine, polyvinyl alcohol, and polyvinylpyrrolidone (PVP). The surface stabilizer is commercially available and / or can be prepared by techniques known in the art.

[0070] Particularly preferred surface stabilizers which can be used in conjunction with the surface stabilizers described above include polyvinylpyrrolidone, block copolymer of ethylene oxide and propylene oxide, Tetronic 908, dextran, lecithin, sodium docusate, talc, oxyethylenated sorbitan fatty acid esters, polyethylene glycol.

[0071] Examples of fillers are lactose monohydrate, lactose anhydrous and various starches; examples of binders are various celluloses and cross-linked polyvinylpyrrolidone, microcrystalline cellulose such as Avicel PH 101 and PH 102, microcrystalline cellulose and silicified microcrystalline cellulose (SMCC).

[0072] Examples of solid supports for the nanoparticle composition base of the spray-dried or spray-coated nanoparticles include lactose, starch, pregelatinized starch, dextrin, microcrystalline cellulose, mannitol, sucrose, powdered sugar, erythrose, xylitol, sorbitol, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, calcium sulfate dihydrate, calcium sulfate, magnesium oxide, aluminum hydroxide, microcrystalline cellulose pellets, sugar-starch microspheres, sucrose pellets, starch pellets, tartaric acid pellets, lactose pellets or other pharmaceutical excipients well known in the art.

[0073] Suitable lubricants, including lubricants which act on the flowability of the powder to be compressed, are talc, colloidal silicon dioxide such as Aerosil 200, sodium dodecyl sulfate, stearic acid, magnesium stearate, calcium stearate and silica gel.

[0074] Examples of sweeteners are any natural or artificial sweetener, such as sucrose, xylitol, sodium saccharin, cyclamate, aspartame.

[0075] Examples of preservatives are potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, other p-hydroxybenzoic acid esters such as butylparaben, alcohols such as ethanol or benzyl alcohol, phenolic compounds such as phenol, or quaternary compounds such as benzalkonium chloride.

[0076] Suitable diluents include pharmaceutically acceptable inert fillers, for example microcrystalline cellulose, lactose, calcium hydrogen phosphate, mannitol, starch, sorbitol, sugars and / or mixtures of any of the foregoing fillers.

[0077] Suitable disintegrants include low-substituted hydroxypropylcellulose, corn starch, potato starch, corn starch and modified starches, crosscarmellose sodium, crospovidone, sodium starch glycolate and mixtures thereof. Examples of effervescent agents are paired effervescent agents such as organic acids and carbonates or bicarbonates. Suitable organic acids include, for example, citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid and alginic acid and anhydrides and acid salts. Suitable carbonates and bicarbonates include, for example, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, glycine sodium carbonate, L-lysine carbonate and arginine carbonate. Additionally, only the sodium bicarbonate component of the paired effervescent agent can be present.

[0078] The nanoparticulate drug particles of the present application can be prepared by first dispersing the compound 1 into a liquid dispersion medium and then reducing the particle size of the active ingredient by mechanical means in the presence of a milling medium to an effective average particle size of no more than about 1000 nm, preferably no more than about 600 nm, more preferably no more than about 300 nm. The drug particles can be reduced in size in the presence of the surface stabilizer or the drug particles can be contacted with the surface stabilizer after milling. In the present application, the particle size control criteria are that D10 is within the range of 70 - 170 nm, D50 is within the range of 200 - 300 nm and / or D90 is within the range of 400 - 600 nm and the Span value is < 2.5.

[0079] The process for milling the compound 1 to obtain a nanoparticulate dispersion includes dispersing the compound 1 particles in a liquid medium and then reducing the particle size of the compound by mechanical means in the presence of a milling medium to the desired effective average particle size. The particle size of the compound can be reduced in the presence of at least one surface stabilizer. Alternatively, the particles of the compound 1 can be contacted with one or more surface stabilizers after milling. Other compounds such as diluents can be added to the compound 1 / surface stabilizer composition during the particle size reduction process. The dispersions can be prepared continuously or in batch. The resulting nanoparticulate dispersions can be used as solid or liquid dosage forms such as controlled release dosage forms, solid fast dissolve dosage forms, aerosol dosage forms, tablets, capsules and the like.

[0080] Another method of preparing the desired nanoparticulate composition is by micro-precipitation, which is a method of preparing a stable dispersion of the compound 1 in the presence of one or more surface stabilizers. Such a method includes, for example: (1) dissolving the compound 1 in a suitable solvent; (2) adding the preparation of step (1) to a solution comprising at least one surface stabilizer to form a clear solution; and (3) precipitating the preparation of step (2) using a suitable non-solvent. Any salts that are produced, if present, are then removed by dialysis or diafiltration and the dispersion is concentrated by conventional means. The resulting nanoparticulate dispersion can be used in solid or liquid dosage forms.

[0081] A general method for preparing the pharmaceutical nanoparticles of the present application is as follows. The active ingredient can be obtained commercially or prepared in conventional coarse particulate form by techniques known in the art. The particle size of the selected drug, as determined by sieve analysis, is preferably, but not necessarily, no more than about 100 um.

[0082] If the particle size of the coarse drug particulate is greater than about 100 um, it is preferred that the drug particulate be reduced to no more than about 100 um in size by conventional milling techniques, such as air jet or attrition milling, prior to reducing the drug particulate to sub-micron size.

[0083] The coarse particulate of the drug can then be added to a liquid medium in which the drug is substantially insoluble to form a premix.

[0084] The concentration of the drug in the liquid medium can vary from about 0.1% to about 60% (w / w), but is preferably from about 0.2% to about 50% (w / w). It is preferred, but not necessary, that the surface stabilizer be present in the premix. The concentration of the surface stabilizer can vary from about 1% to about 98%, but is preferably from about 1% to about 95%, and more preferably from about 1% to about 90%, based on the total weight of the active ingredient and surface stabilizer. The apparent viscosity of the premix suspension is preferably no more than about 1000 centipoise. The average particle size of the dispersion is reduced by mechanically processing the premix to no more than about 1000 nm, preferably to no more than about 600 nm, more preferably to no more than about 300 nm, and most preferably to no more than about 100 nm, so that the premix can be used directly. It is preferred that the premix be used directly when milling is performed using a bead mill. Alternatively, the active ingredient and optionally the surface stabilizer can be dispersed in the liquid medium using a suitable agitation method, such as a tumbler mill or a Cowles-type mixer, until a homogenous dispersion is observed. In a homogenous dispersion, no large clumps are visible to the naked eye. When milling is performed using a circulation medium mill, the premix is preferably subjected to such a pre-milling dispersion step.

[0085] The mechanical process used to reduce the particle size of the active ingredient can be dispersion milling, suitable dispersion milling includes, but is not limited to, ball milling, attrition milling, vibratory milling, and media milling such as sand milling or bead milling. Media milling is preferred because the milling time required to provide the desired particle size reduction is relatively short. For media milling, the apparent viscosity of the premix is preferably from about 100 centipoise to about 1000 centipoise. For ball milling, the apparent viscosity of the premix is preferably from about 1 centipoise to about 100 centipoise. Such ranges tend to provide an optimal balance between effective particle comminution and media attrition.

[0086] The milling time can vary widely, depending primarily on the particular mechanical process and the processing conditions selected. For ball milling, processing times of up to 5 days or more can be required. Using high shear media milling, processing times of less than 1 day (residence times from 1 minute to up to several hours) can provide the desired results.

[0087] The pharmaceutical particles must be reduced in size at a temperature that does not significantly degrade the active ingredient. It is generally preferred that the processing temperature not exceed about 30-40°C. If desired, the processing equipment can be cooled using conventional cooling equipment.

[0088] If the surface stabilizer is not included in the premix, the surface stabilizer must be added to the premix after milling in the amounts described above. The dispersant can then be mixed by, for example, vigorous shaking. An ultrasonic treatment step, such as an ultrasonic generator, can optionally be used.

[0089] After milling is complete, the milling media is separated from the milled particle product using conventional separation techniques such as filtration, sieving through a screen, and the like. The surface stabilizer can be added to the milled particle product either before or after the milled product is separated from the milling media.

[0090] In a preferred milling process, the particles are produced continuously. In such a continuous process, a slurry of the active ingredient / surface stabilizer and optional additional surface stabilizers is continuously fed into a milling chamber, the active ingredient is continuously contacted with the milling media in the milling chamber to reduce the particle size of the active ingredient, and the active ingredient is continuously removed from the milling chamber. The surface stabilizer, alone or in combination with one or more additional surface stabilizers, can be continuously fed into the media chamber with the active ingredient or can be added to the active ingredient after milling and removal from the milling chamber.

[0091] The resulting dispersant of the present application is stable and comprises the liquid dispersion medium described above. The dispersant of the surface stabilizer and nanoparticulate active ingredient can be spray dried, spray coated onto a solid support such as a sucrose pellet or other pharmaceutical excipient using techniques well known in the art.

[0092] The grinding media used in the size reduction step can be selected from rigid media, preferably spherical or particulate in shape, and having an average particle size of no more than about 3 mm, more preferably no more than about 1 mm. Such media can provide the desired drug particles in a shorter processing time and with less attrition of the grinding equipment. The material of which the grinding media is made is not believed to be critical. Zirconium oxide, e.g., 95% ZrO stabilized with yttrium and 95% ZrO stabilized with magnesium oxide, zirconium silicate, and glass grinding media have been found to provide particles with an acceptable minimum level of contamination for use in the preparation of pharmaceutical compositions. Other media such as stainless steel, titanium oxide, and aluminum oxide can also be used. Preferably, the grinding media has a density greater than about 3 g / cm3.

[0093] The grinding media can comprise particles consisting essentially of a polymeric resin, preferably spherical in shape, e.g., beads. Alternatively, the grinding media can comprise particles having a core coated with a polymeric resin adhered thereto. The media can range in size from about 0.1 mm to about 3 mm. For fine grinding, the particle size is preferably from about 0.2 mm to about 2 mm, more preferably from about 0.25 mm to about 1 mm.

[0094] The polymeric resin has a density of from about 0.8 g / cm3to about 3.0 g / cm3. Higher density resins are preferred because such resins can more effectively reduce particle size.

[0095] One exemplary process for preparing a capsule of a nanoparticulate active ingredient includes slurry preparation, pre-grinding, media grinding, Wurster column coating, sieving, blending, and encapsulation.

[0096] After the active ingredient has been converted to nanoparticles during the grinding process, a "intermediate" nanoparticulate powder is obtained using a spray-drying process. In one exemplary spray-drying process, a solid active nanoparticulate suspension and the surface stabilizer are fed to a spray-drier using a peristaltic pump and sprayed to form a fine mist. The spray is exposed to hot air in a drying chamber, causing the water to evaporate from the mist. The resulting spray is passed through a cyclone, which separates and collects the powder. Alternative methods of spray-drying include fluid bed granulation, spray-drying granulation, rotary granulation, fluid bed / spray-drying granulation, extrusion, and spheronization.

[0097] After the spray-drying is complete, the collected spray-dried intermediate comprises the Compound 1 nanoparticles suspended in a solid polymeric matrix of the surface stabilizer. The moisture content of the intermediate is controlled by controlling the operating conditions of the spray-drying process. The properties of the nanoparticulate powder are critical to the development of a free-flowing powder that can be blended with other excipients suitable for direct encapsulation into hard gelatin capsules.

[0098] Generally, the pharmaceutical compositions of the present application comprise the compound 1 having a particle size of no more than about 1000 nm and a surface stabilizer, and the compositions are solid formulations. In a preferred embodiment, the pharmaceutical compositions comprise the compound 1 having a particle size of no more than about 1000 nm, a surface stabilizer, a solid support, a binder, and an antiadherent.

[0099] In one embodiment of the present application, the pharmaceutical compositions comprise the compound 1 having a particle size of no more than about 600 nm, a surface stabilizer, a solid support, a binder, and optionally an antiadherent.

[0100] In a preferred embodiment of the present application, the pharmaceutical compositions comprise the compound 1 having a particle size of less than 600 nm, a surface stabilizer, i.e., hypromellose, a solid support, i.e., sucrose pellet cores, a binder, i.e., hypromellose, and optionally an antiadherent, i.e., talc.

[0101] In a particular embodiment of the present application, the pharmaceutical compositions can comprise the compound 1 in dosage strengths of 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 6 mg, 12 mg, and 15 mg.

[0102] The concentration of the one or more surface stabilizers can vary from about 0.01% to about 98%, from about 1% to about 95%, from about 1% to about 90%, or from about 1.5% to about 90%, by total dry weight of the drug and the surface stabilizer. The concentration of the compound 1 can vary from about 0.1% to about 60%, from about 0.2% to about 50%, from about 0.2% to about 40%, or from about 0.2% to about 30%, by total dry weight of the compound, surface stabilizer, and other excipients.

[0103] Preferably, the surface stabilizer is used in an amount of about 0.1% to about 10 mg per square meter of surface area of the active ingredient, or about 1% to about 98%, more preferably about 1% to about 95%, by total weight of the dry granules, or the surface stabilizer is used in an amount of about 1-95% by weight, preferably about 1-90% by weight, more preferably about 1.5-90% by weight.

[0104] The solid support is used in an amount of about 1-99% by weight, preferably about 10-98% by weight, more preferably 40-98% by weight. Preferred solid supports include, but are not limited to, sugars, starches, and celluloses, such as sugar-starch microspheres, and in particular sucrose pellet cores.

[0105] The amount of the binder is about 1 to 30% by weight, preferably about 1 to 20% by weight, more preferably about 1 to 15% by weight, and further preferably about 1 to 5% by weight. Preferred binders include, but are not limited to, pregelatinized starch, dextrin, polyvinyl alcohol, carboxymethyl cellulose, hypromellose, hydroxypropyl cellulose, and polyvinylpyrrolidone, and particularly hypromellose.

[0106] The amount of the anti-adherent is about 0 to 5% by weight, preferably about 0 to 3% by weight, and more preferably about 0.5 to 3% by weight. Preferred anti-adherents include, but are not limited to, talc, finely powdered silica, hydrogenated vegetable oil, sodium stearyl fumarate, glyceryl behenate, sodium lauryl sulfate, polyethylene glycol, and magnesium stearate, and particularly talc.

[0107] In a preferred embodiment, the pharmaceutical composition comprises about 0.1 to 60% by weight of Compound 1 having a particle size of no more than about 1000 nm and about 1 to 98% by weight of a surface stabilizer.

[0108] In one embodiment of the present application, the pharmaceutical composition comprises Compound 1 having a particle size of no more than about 600 nm, a surface stabilizer, a solid support, a binder, and an anti-adherent.

[0109] One embodiment of the present application relates to a pharmaceutical composition comprising about 0.1 to 60% by weight of Compound 1 having a particle size of no more than about 1000 nm, about 1 to 98% by weight of a surface stabilizer, about 0 to 98% by weight of a solid support, about 0 to 50% by weight of a binder, and about 0 to 5% by weight of an anti-adherent, wherein the sum of all components is 100%.

[0110] One embodiment of the present application relates to a pharmaceutical composition comprising about 0.1 to 60% by weight of Compound 1 having a particle size of no more than about 1000 nm, about 1 to 90% by weight of a surface stabilizer, about 10 to 98% by weight of a solid support, about 0 to 50% by weight of a binder, and about 0 to 5% by weight of an anti-adherent, wherein the sum of all components is 100%.

[0111] One embodiment of the present application relates to a pharmaceutical composition comprising about 0.2 to 50% by weight of Compound 1 having a particle size of no more than about 1000 nm, about 1 to 80% by weight of hypromellose (surface stabilizer), about 20 to 98% by weight of sucrose pellet cores, about 1 to 30% by weight of hypromellose (binder), and about 0 to 3% by weight of talc, wherein the sum of all components is 100%.

[0112] One embodiment of the present application relates to a pharmaceutical composition comprising about 0.2-40% (w / w) of Compound 1 having a particle size of no more than about 1000 nm, about 1-20% (w / w) of Hypromellose (surface stabilizer), about 30-95% (w / w) of Sucrose pellet cores, about 1-20% (w / w) of Hypromellose (binder), and about 0.5-3% (w / w) of talc, wherein the sum of all components is 100%.

[0113] One embodiment of the present application relates to a pharmaceutical composition comprising about 10-30% (w / w) of Compound 1, about 70-90% (w / w) of Hypromellose, about 0-95% (w / w) of Sucrose pellet cores, about 20% (w / w) of Hypromellose (binder), and about 0-3% (w / w) of talc.

[0114] Another embodiment of the present application relates to a pharmaceutical composition comprising about 0.1-2% (w / w) of Compound 1, about 1-5% (w / w) of Hypromellose (surface stabilizer), about 85-95% (w / w) of Sucrose pellet cores, about 1-5% (w / w) of Hypromellose (binder), and about 1-5% (w / w) of talc.

[0115] Another embodiment of the present application relates to a pharmaceutical composition comprising about 0.5 mg of Compound 1, about 4 mg of Hypromellose (surface stabilizer), about 200 mg of Sucrose pellet cores, about 6.1 mg of Hypromellose (binder), and about 6.1 mg of talc.

[0116] Another embodiment of the present application relates to a pharmaceutical composition comprising about 2 mg of Compound 1, about 6 mg of Hypromellose (surface stabilizer), about 200 mg of Sucrose pellet cores, about 6.2 mg of Hypromellose (binder), and about 6.2 mg of talc.

[0117] Another embodiment of the present application relates to a pharmaceutical composition comprising about 3 mg of Compound 1, about 7.5 mg of Hypromellose (surface stabilizer), about 139.5 mg of Sucrose pellet cores, about 4.5 mg of Hypromellose (binder), and about 2.25 mg of talc.

[0118] Another embodiment of the present application relates to a pharmaceutical composition comprising about 6 mg of Compound 1, about 15 mg of Hypromellose (surface stabilizer), about 279 mg of Sucrose pellet cores, about 9 mg of Hypromellose (binder), and about 4.5 mg of talc.

[0119] One skilled in the art can prepare nanoparticle compositions of Compound 1 in different dosage strengths (e.g., 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 6 mg, 12 mg, and 15 mg, etc.) using the methods described herein. BRIEF DESCRIPTION OF DRAWINGS

[0120] The following drawings show embodiments of the present application, but the present application is not limited thereto.

[0121] Figure 1 shows the effect of different drug strengths on dissolution.

[0122] Figure 2 shows the effect of different drug strengths of capsules on PK. DETAILED DESCRIPTION

[0123] The present application is further described in detail by the following examples, but is not limited to the following examples. Any equivalent replacement or transformation made by one skilled in the art based on the present application, without departing from the essential content of the present application, is also within the scope of protection of the present application.

[0124] Unless otherwise indicated, the formulations of the present application are prepared according to the following general procedure:

[0125] (1) Preparation of drug-loaded suspension: a certain amount of surface stabilizer is weighed according to the formulation composition, and is completely dissolved (or uniformly dispersed) in a certain amount of solvent system such as water or alcohol solvent. Compound 1 is added under stirring, and stirring is continued until uniform dispersion. The dispersed suspension is subjected to homogeneous shearing, defoaming, and low-speed stirring to obtain a suspension for standby use.

[0126] (2) Medium grinding: the suspension prepared in step (1) is transferred to the cavity of the grinding machine, and appropriate parameters are set. Samples are taken at 2 h, 3 h, 5 h, 7 h, 9 h, 12 h, and 15 h, respectively, and the average particle size is measured by using a nanoparticle size analyzer to make the D90 not more than 600 nm, thereby obtaining a nanoparticle suspension of Compound 1 for standby use.

[0127] (3) Fluidized bed Wurster column coating: blank pellet cores are weighed according to the formulation composition, and are put into the coating pan. The inlet air volume is set, the inlet air temperature is 60°C, and the inlet air humidity is 40%-50% RH to preheat the bed temperature. When the material temperature exceeds 40°C, the suspension prepared in step (1) or the nanoparticle suspension prepared in step (2) is coated onto the blank pellet cores. After coating, the material is dried for 15 min, and the material is discharged to obtain coated pellets (also known as nanoparticle solidified material) for standby use.

[0128] (4) Preparation of protective layer solution: the binder and anti-adhesive are weighed according to the formulation composition, and are completely dissolved (or uniformly dispersed) in a certain amount of solvent system. Stirring is continued until uniform dispersion to obtain a suspension for standby use.

[0129] (5) Protective layer coating: The prepared protective layer solution was coated onto the drug-loaded pellets through a Wurster column to obtain a nanoparticle composition;

[0130] (6) Sieving: The pellets prepared in step (5) were sieved using a 24-60 mesh sieve for use;

[0131] (7) Capsule filling: The pellets prepared in step (6) were filled into hard gelatin capsules according to the actual loading amount to obtain a capsule.

[0132] Experimental equipment and experimental methods

[0133] A. Grinding

[0134] The grinding of the present application was carried out using a wet grinder (Quet (Shanghai) Machinery and Electrical Technology Co., Ltd., TC-2L) with the following parameters:

[0135] B. Particle size measurement

[0136] The particle size of the suspension was determined according to the particle size and particle size distribution determination method specified in Chinese Pharmacopoeia 2020 Edition Volume IV General Rule 0982 Third Method, and a Malvern laser particle size analyzer 3000 was used for measurement. The measurement conditions were as follows: the dispersing agent was water with a volume of 500 ml; the dispersing unit pump speed was 2500 rpm; the refractive index of the dispersing agent was 1.330; the obscuration lower / upper limit was 5% / 10%; the particle shape was irregular; the background measurement time was 12 seconds, the sample measurement time was 12 seconds; the sample refractive index was 1.50, the absorption rate was 0.01, and the test cycle was 3; the dispersing unit was flushed with the dispersing agent, and after cleaning, the dispersing agent was added to the dispersing unit, the background was deducted, the drug-loaded suspension was shaken on a vortex shaker for about 2 minutes, then the drug-loaded suspension was slowly added to the dispersing unit containing the dispersing agent with a dropper (avoiding the absorption of air bubbles) until the obscuration level reached between 5-10%, the sample was stopped, and the measurement was started after the obscuration value was stable. The average results and Span value of D (10) , D (50) , D (90) .

[0137] C. Fluidized bed coating

[0138] A multifunctional fluidized bed was used to coat the drug-loaded suspension onto the blank pellet cores to obtain drug-loaded pellets (i.e. drug-loaded layer coating), and to coat the protective layer onto the drug-loaded pellets (i.e. protective layer coating), wherein the fluidized bed parameters for the drug-loaded layer coating and the protective layer coating were as follows:

[0139] Summary of drug-loaded layer coating fluidized bed parameters

[0140] Fluidized bed parameters for protective layer coating

[0141] Note: N / A means not applicable.

[0142] D. Dissolution

[0143] Dissolution Method 1: The dissolution and release of the preparation of the present application were determined according to the dissolution and release determination method specified in Chinese Pharmacopoeia 2020 Edition Volume IV General Chapter 0931 First Method. The dissolution and release test was operated in the dark. The dissolution conditions were as follows: the basket method was used at 100 rpm / min, pH 1.0 hydrochloric acid solution was selected as the dissolution medium, the volume was 900 mL, and the temperature was maintained at 37 ± 0.5°C. 10 mL of solution was taken out at 5, 10, 15, 20, 30, 45, 60 minutes, and an equal amount of isothermal dissolution medium was supplemented at the same time. The dissolution solution was filtered through a 0.45 μm filter membrane, 8 mL of the initial filtrate was discarded, and the subsequent filtrate was collected, and the content of Compound 1 was determined by high performance liquid chromatography.

[0144] Dissolution Method 2: Paddle method, 100 rpm, 900 ml 0.1 mol / L hydrochloric acid solution.

[0145] Dissolution Method 3: Paddle method, 100 rpm, 900 ml pH 6.8 phosphate buffer.

[0146] Example 1: Preparation of the formulation

[0147] The formulations used in the present application were prepared according to the above general procedures, unless otherwise specified.

[0148] A. Light stability of the drug

[0149] During the development of the formulation of Compound 1, it was found that when directly exposed to ICH Q1B light conditions, the content of the degradation product observed at RRT = 1.2 (HPLC analysis) exceeded the ICH impurity limit.

[0150] Effect of excipients on light exposure

[0151] The compatibility of Compound 1 with various excipients was investigated. According to the relevant provisions of the NMPA Guidelines for Excipient Compatibility Tests, we mixed the conventional excipients with the API according to the normal formulation ratio to form a binary mixture system, which was placed under light conditions to compare the changes in impurities.

[0152] The test results show that compound 1 and the excipients used in the experimental design produce light degradation impurities with different contents in the sample under light conditions, and the compatibility of each excipient with the API under light conditions is different; combined with the compatibility results, compound 1 is more sensitive to light, in order to ensure the stability of the product, we choose hydroxypropyl methyl cellulose as the surface stabilizer of the drug-loaded suspension, hydroxypropyl methyl cellulose and talc as the coating material of the protective layer, and the capsule shell adopts opaque gelatin hollow capsules, and the inner packaging material selects a medicinal high-density polyethylene bottle and a cover.

[0153] Effect of capsule shell and packaging system on light exposure

[0154] 0.5, 2 and 6 mg of capsule contents were exposed to ICH light stability conditions and tested to provide baseline impurity information for comparison.

[0155] The test results of the above light condition show that the 0.5 mg, 2 mg, 3 mg and 6 mg specification preparation products can inhibit the increase of light degradation impurities under ICH light stability conditions, but still exceed the acceptable standard. The preparation product with packaging has no obvious increasing trend of light degradation impurities under ICH light stability conditions, and the related substances of the preparation product meet the quality standard requirements.

[0156] Structure of light degradation impurities

[0157] In view of the structure of the light degradation impurities, the pharmaceutical excipients, capsule shell and packaging system play an important role in protecting compound 1 from light degradation, which can block harmful wavelengths by physical means or prevent light-induced formation of impurities by providing chemical protection (eliminating oxidative free radicals).

[0158] B. Formulations 1-6

[0159] Table 1: Composition of Formulations 1-6 (The drug-loaded suspension prepared in Formulations 1-6 is directly coated on the fluidized bed without medium grinding)

[0160] C. Formulations 7-25

[0161] Unlike Formulations 1-6, in Formulations 7-25, the prepared drug-loaded suspension is ground with a medium to obtain a nanoparticle suspension of compound 1.

[0162] Table 2: Composition of Formulations 7-25

[0163] Formulation 26 (Comparative Example 1)

[0164] Preparation of formulation 26 (3 mg / mL suspension): Compound 1 was weighed into a mortar and ground for 2 minutes. Then 0.5% HPMC / 0.2% Tween 80 was added as a solvent and the mixture was ground for another 2 minutes until a fine, homogeneous suspension was formed. The solvent was then added to the total volume and the mixture was transferred to a glass container and stirred for 10 minutes using a magnetic stirrer to obtain formulation 26.

[0165] Example 2: Stability of drug-loaded suspensions

[0166] This example investigated the stability of the drug-loaded suspensions prepared in formulations 1-6. The stability of the drug-loaded suspensions of formulations 1-6 was investigated at the time of preparation and under accelerated test conditions (temperature 40°C, relative humidity 75%; temperature 50°C, relative humidity 75%; temperature 60°C, relative humidity 75%) and the results are summarized below:

[0167] The results of the tests showed that the drug-loaded suspension of formulation 2, which was prepared by coating the drug onto the suspension using purified water as the solvent, had not only less total impurities at 0 days, but also less total impurities under accelerated test conditions compared to the drug-loaded suspension of formulation 1, which was prepared by coating the drug onto the solution using ethanol as the solvent. Therefore, compound 1 was formulated into a drug-loaded suspension using purified water as the solvent. In addition, the total impurities of formulation 3, which contained Tween 80, increased significantly and the stability was poor, indicating that Tween 80 should not be added to the compound 1 drug-loaded pellet formulation. The impurities of formulation 6 were higher than those of formulation 2, indicating that hydroxypropyl methylcellulose provided better stability than hydroxypropyl cellulose as a protective agent in the drug-loaded suspension.

[0168] Example 3: Particle size of nanoparticle suspensions

[0169] A. This section investigated the particle size of nanoparticle suspensions of formulations 6-15 under different grinding times.

[0170] The above results showed that different mass ratios of surface stabilizers had an impact on the grinding efficiency of compound 1. The formulation combinations of formulations 8, 11, and 14 could improve the grinding efficiency to some extent and reduce the final grinding particle size.

[0171] B. This section investigated the effect of reconstitution on the particle size of nanoparticle suspensions

[0172] About 1 mL of nanoparticle suspension or about 2 g of nanoparticle composition was taken into a sample cell, and the particle size distribution was measured using a Malvern 3000 laser particle size analyzer, and D 50 and D 90 were selected as the measurement parameters. The particle size measurement results of each example are shown in the table below:

[0173] The above results show that the particle size Dv50 of the compound 1 nanoparticle suspension prepared by the compound 1 nanoparticles suspension of Example 20 and 23 is less than 600 nm, and the particle size distribution is uniform; and after the sample is redissolved, the particle size does not change significantly, which helps to ensure safe and effective treatment. 90 The particle size Dv50 of the compound 1 nanoparticle suspension prepared by the compound 1 nanoparticles suspension of Example 20 and 23 is less than 600 nm, and the particle size distribution is uniform; and after the sample is redissolved, the particle size does not change significantly, which helps to ensure safe and effective treatment.

[0174] Example 4: Dissolution test

[0175] The following dissolution test is carried out according to the dissolution operation in the "Experimental equipment and experimental method" section.

[0176] A. This part compares the dissolution test results of the coated micro-pellets of preparations 1-6 with the drug-loaded suspension of preparation 26 (comparative example 1).

[0177] The test results of preparations 2-6, 26 under "Dissolution method 2" show that the cumulative dissolution of preparation 2 without Tween 80 in 0.1 mol / L hydrochloric acid medium is only 54%, while the dissolution rate and extent of the drug-loaded micro-pellets of preparations 3-5 containing Tween 80 are significantly improved under the same conditions, and the dissolution rate is positively correlated with the amount of Tween 80. In addition, the same amount of Tween 80 is added to the drug-loaded layer or the protective layer, respectively, and there is no significant difference in the dissolution curve, but the dissolution rate and the cumulative dissolution are significantly lower than those of preparation 26 (comparative example 1).

[0178] Unexpectedly, although preparation 17 does not contain Tween 80, the dissolution rate and extent of the drug-loaded suspension of preparation 17 after grinding are significantly higher than those of preparations 3-5, similar to those of preparation 26 (comparative example 1); and the dissolution rate in pH 6.8 phosphate buffer medium (dissolution method 3) is faster than that of preparation 26 (comparative example 1), and the dissolution is more complete.

[0179] B. This part investigates the effect of the mass ratio of the surface stabilizer to compound 1 on dissolution (dissolution method 1)

[0180] The above table shows that the drug-loaded suspension is ground in the medium for the same time to obtain a nanoparticle suspension of compound 1, and the mass ratio of compound 1 to the surface stabilizer has an effect on dissolution, and the dissolution of preparations 8, 11, and 14 is higher.

[0181] C. This part investigates the effect of the binder and the anti-adhesive on dissolution (dissolution method 1)

[0182] The above table shows that the mass ratio of compound 1 to the binder and the anti-adhesive does not significantly affect the dissolution, and preparations 17, 20, and 23 are preferred to prevent the boundary effect of the preparation amount.

[0183] D. This part investigates the influence of different drug specifications on dissolution

[0184] This part investigates four drug specifications, i.e. preparation 17 (specification: 0.5 mg), preparation 20 (specification: 2 mg), preparation 23 (specification: 3 mg), and preparation 25 (specification: 6 mg). The dissolution test results are shown in Figure 1. The results show that the cumulative release rates of the four specifications of capsules are all more than 80% at 30 min under pH 1.0 dissolution conditions.

[0185] Example 5: Bioavailability

[0186] Healthy beagle dogs of 11-14 months of age were selected for a 2-period crossover test. Each was orally administered 2 mg once, with a one-week washout period. Blood was collected before administration (0) and at 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h and 24 h after administration. The upper plasma was taken and analyzed by LC-MS / MS to detect the bioavailability of preparation 20 and preparation 26 (Comparative Example 1). The test results are shown in the following table.

[0187] Table 9: Bioavailability test comparison table of preparation 20 and preparation 26 (Comparative Example 1)

[0188] As shown in the above table, in beagle dogs, the main pharmacokinetic parameters of preparation 20 and preparation 26 (Comparative Example 1) after single oral administration showed no significant statistical difference.

[0189] Example 6: Influence of capsules of different specifications on PK

[0190] The purpose of this test was to investigate the single oral administration of 6 mg / dog of preparation 20 (specification: 2 mg) and preparation 25 (specification: 6 mg) to beagle dogs, to quantitatively determine the concentration of compound 1 in the plasma of beagle dogs by liquid chromatography tandem mass spectrometry, and to compare the PK of the two specifications of capsule preparations. Figure 2 shows the average concentration-time curve of male beagle dogs after single oral administration of different specifications of compound 1 capsules (N = 4). Paired two-tailed T-test was performed on the pharmacokinetic parameters Cmax, AUClast, AUCINF, T1 / 2 and MRTINF, and the test results showed that the pharmacokinetic parameters of the two specifications of preparations had no significant difference (P > 0.05). In addition, preparation 23 (specification: 3 mg) and preparation 25 (specification: 6 mg) are equi-ratio preparations, and also have the same pharmacokinetic characteristics.

[0191] Obviously, the above embodiments are only examples for clearly illustrating the present application and are not intended to limit the present application. Based on the above description, other different forms of changes or variations can be made by those skilled in the art. Here, all the embodiments are not required to be enumerated. The obvious changes or variations derived from the above description are still within the protection scope of the present application.

Claims

1. A granular pharmaceutical composition comprising 4-fluoro-5-(2-fluoro-4- iodophenylamino)-lH-benzo[d]thiazole-6-carboxylic acid (2-hydroxy-ethoxy)-amide (Compound 1) or a pharmaceutically acceptable salt thereof, a surface stabilizer, a solid support, a binder and an anti-adherent.

2. The granular pharmaceutical composition of claim 1, wherein the solid support is coated or coated with a suspension comprising Compound 1 or a pharmaceutically acceptable salt thereof and a surface stabilizer.

3. The granular pharmaceutical composition of claim 2, wherein the suspension is a suspension of Compound 1 and a surface stabilizer in water.

4. The granular pharmaceutical composition of claim 3, wherein Compound 1 in the suspension has a D90 particle size of no more than 1000 nm.

5. The granular pharmaceutical composition of claim 4, wherein Compound 1 in the Compound 1 suspension has a D90 particle size of no more than 800 nm, 600 nm, 450 nm, 300 nm, 200 nm, 100 nm or 50 nm.

6. The granular pharmaceutical composition of claim 1, wherein the stabilizer is selected from one or more of a cellulose, a high molecular polymer, a surfactant and a natural stabilizer; preferably, the cellulose is selected from one or more of methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, hypromellose, the high molecular polymer is selected from one or more of polyoxyethylene polyoxypropylene block copolymer, povidone, polyvinyl alcohol polyoxyethylene castor oil and polyethylene glycol succinate, the surfactant is selected from one or more of sodium dodecylbenzenesulfonate, cibacron, sodium dodecyl sulfate, the natural stabilizer is selected from one or more of sodium alginate, dextran, acacia, mannitol, lecithin, chitosan; more preferably one or more of hydroxypropyl cellulose, hypromellose, polyoxyethylene polyoxypropylene block copolymer, povidone and mannitol; further preferably one or more of hydroxypropyl cellulose and hypromellose; more further preferably hypromellose.

7. The granular pharmaceutical composition of claim 1, wherein the weight percentage of the surface stabilizer is 1-10%, preferably 1-5%, based on the total weight of the formulation.

8. The granular pharmaceutical composition of claim 1, wherein the weight percentage of Compound 1 is 0.1-60%, preferably 0.2-50%, more preferably 0.2-40%, further preferably 0.2-30%, based on the total weight of the formulation.

9. The granular pharmaceutical composition of claim 1, wherein the solid support is selected from one or more of lactose, starch, pregelatinized starch, dextrin, microcrystalline cellulose, mannitol, sucrose, sugar powder, erythrose, xylitol, sorbitol, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, calcium sulfate dihydrate, calcium sulfate, magnesium oxide, aluminum hydroxide, microcrystalline cellulose pellet core, sugar-starch microspheres, sucrose pellet core, starch pellets, tartaric acid pellet core, lactose pellet core.

10. The granular pharmaceutical composition of claim 1, wherein the weight percent of the solid support is 1-99%, or 10-98%, or 20-98%, or 40-98%, or 60-98%, or 80-98% by weight of the total formulation.

11. The granular pharmaceutical composition of claim 1, wherein the solid support is optionally dried after the coating or the coating suspension.

12. The granular pharmaceutical composition of claim 1, wherein the solid support coated with the suspension is further coated with a protective layer.

13. The granular pharmaceutical composition of claim 12, wherein the protective layer comprises a binder and an anti-tacking agent.

14. The granular pharmaceutical composition of claim 13, wherein the binder comprises one or more of pregelatinized starch, dextrin, polyvinyl alcohol, carboxymethyl cellulose, hypromellose, hydroxypropyl cellulose, polyvinyl pyrrolidone; preferably hypromellose.

15. The granular pharmaceutical composition of claim 14, wherein the weight percent of the binder is 1-30%, preferably 1-20%, more preferably 1-15%, further preferably 1-5% by weight of the total formulation.

16. The granular pharmaceutical composition of claim 13, wherein the anti-tacking agent comprises one or more of talc, microfine silica, hydrogenated vegetable oil, sodium stearyl fumarate, glyceryl monostearate, sodium lauryl sulfate, polyethylene glycol, or magnesium stearate; preferably talc.

17. The granular pharmaceutical composition of claim 16, wherein the weight percent of the anti-tacking agent is 0-5%, preferably 0-3%, more preferably 0.5-3% by weight of the total formulation.

18. The granular pharmaceutical composition of claim 1, comprising 0.1-60% by weight of the compound 4-fluoro-5-(2-fluoro-4-iodophenylamino)-lH-benzo[d]thiazole-6- carboxylic acid (2-hydroxy-ethoxy)-amide having a particle size of less than 1000 nm, 1-98% by weight of a surface stabilizer, 0-98% by weight of a solid support, 0-50% by weight of a binder, and 0-5% by weight of an anti-tacking agent.

19. The granular pharmaceutical composition of claim 1, comprising 0.1-60% by weight of the compound 4-fluoro-5-(2-fluoro-4-iodophenylamino)-lH-benzo[d]thiazole-6- carboxylic acid (2-hydroxy-ethoxy)-amide having a particle size of less than 1000 nm, 1-90% by weight of a surface stabilizer, 10-98% by weight of a solid support, 0-50% by weight of a binder, and 0-5% by weight of an anti-tacking agent.

20. The granular pharmaceutical composition of claim 1, comprising 0.1-60% by weight of the compound 4-fluoro-5-(2-fluoro-4-iodophenylamino)-lH-benzo[d]thiazole-6- carboxylic acid (2-hydroxy-ethoxy)-amide having a particle size of less than 1000 nm, 1-90% by weight of hypromellose, 10-98% by weight of sucrose pellet cores, 0-50% by weight of hypromellose, and 0-5% by weight of talc.

21. The granular pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises 0.2-50% by weight of compound 4-fluoro-5-(2-fluoro-4-iodophenylamino)- 1 H-benzo [d] thiazole-6-carboxylic acid (2-hydroxy-ethoxy)-amide having a particle size of less than 1000 nm, 1-80% by weight of hydroxypropyl methylcellulose, 20-98% by weight of sucrose pellet cores, 1-30% by weight of hydroxypropyl methylcellulose, and 0-3% by weight of talc.

22. The granular pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises 0.2-40% by weight of compound 4-fluoro-5-(2-fluoro-4-iodophenylamino)- 1 H-benzo [d] thiazole-6-carboxylic acid (2-hydroxy-ethoxy)-amide, 1-20% by weight of hydroxypropyl methylcellulose, 30-95% by weight of sucrose pellet cores, 1-20% by weight of hydroxypropyl methylcellulose, and 0.5-3% by weight of talc.

23. The granular pharmaceutical composition of claim 1, wherein the granular pharmaceutical composition is in the form of a tablet, a capsule, or a granule.

24. A method of preparing the granular pharmaceutical composition of claim 1, the method comprising: (1) preparing a drug-loaded suspension of Compound 1 and a surface stabilizer in water or an alcoholic solvent; (2) preparing a nanoparticle suspension from the drug-loaded suspension; (3) solidifying the nanoparticle suspension to obtain a nanoparticle solidification; and (4) adding a binder and an anti-adherent to the nanoparticle solidification to prepare a granular pharmaceutical composition coated with a protective layer.

25. A method of treating a tumor, a chronic inflammatory disease, an inflammatory bowel disease, a skin disease, diabetes, an ocular disease, a disease associated with angiogenesis or vasculogenesis in a mammal, a disease associated with chronic pain, and other diseases modulated by the Mek cascade in a mammal, the method comprising administering to the mammal the granular pharmaceutical composition of claim 1.

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