Patent Description:
Non-small cell lung cancer (NSCLC) includes all cancers of lung epithelial cells except small cell lung cancer (SCLC) and accounts for about <NUM>% of lung cancers. According to the statistical data from American Cancer Society (ACS), there are approximately <NUM>,<NUM> new cases of NSCLC patients in the United States each year, of which <NUM>% or more of the cases are in stage III or stage IV at the time of diagnosis. Apart from the fact that some advanced NSCLCs may be surgically removed after induction therapy, most of them still need to be intervened by way of radiotherapy or chemotherapy. However, it needs to be particularly noted that, chemotherapeutic drugs have significant systemic toxicities and side effects, which may cause considerable pain to patients. Therefore, the search for targeting drugs with high efficiency and low toxicity will become an inevitable trend for the development of antitumor drugs.

Epidermal growth factor receptor (EGFR) is a member of the ErbB receptor family, which has become a popular target for the development of anticancer drugs. Clinical data indicates that certain mutant forms of EGFR will eventually lead to the resistance to therapies by using drugs such as gefitinib and erlotinib. In view of the importance of these mutations in resistance to EGFR-targeting therapies, it may be speculated that drugs capable of inhibiting mutant EGFR will be effective for cancer treatment. In addition, there is still an urgent need for compounds that exhibit relatively high inhibitory effect on mutant EGFR and have no obvious inhibitory effect on wild-type (WT) EGFR, and such compounds are more suitable for use as therapeutic agents for cancers (especially NSCLCs). AZD9291, developed and launched by AstraZeneca, is the first third-generation oral and irreversible EGFR mutation-selective inhibitor, which may be used to inhibit both activated form and resistant mutant form of EGFR. The competition for new drugs is rather fierce since the third-generation EGFR inhibitors have unique efficacy and there are extremely limited products launched in the market at present.

As disclosed in <CIT>, a series of derivatives of <NUM>-arylaminopyridine, pyrimidine or triazine also have relatively high EGFR inhibitory activity while exhibiting relatively low inhibitory activity against WT EGFR. The compound as represented by Formula I is described in this patent application and is referred to as "C-<NUM>" with a chemical name of "N-(<NUM>-((<NUM>-(dimethylamino)ethyl)(methyl)amino)-<NUM>-methoxy-<NUM>-((<NUM>- (<NUM>-methyl-<NUM>-pyrrolo[<NUM>,<NUM>-b]pyridin-<NUM>-yl)pyrimidin-<NUM>-yl)amino)phenyl)acrylamide". C-<NUM> is a member of the above-mentioned series of derivatives of <NUM>-arylaminopyridine, pyrimidine or triazine. C-<NUM> may be used to inhibit both activated form and resistant mutant form of EGFR while exhibiting relatively low inhibitory activity against WT EGFR. Furthermore, the preparation and characterization of a variety of salts and crystal forms of C-<NUM> is disclosed in <CIT>. The follow-up research and development of the pharmaceutical preparations of C-<NUM> based on the above-mentioned technical information will have important clinical significance and application prospects.

As is known to all, oral drugs may be absorbed at many different sites along the gastrointestinal tract (including stomach, duodenum, jejunum, ileum and colon) after administration. With the significant change of pH value between stomach (pH <NUM> to <NUM>) and small intestine (pH <NUM> to <NUM>), pH values may also be different at the above-mentioned absorption sites. As could be seen from the physical and chemical properties of C-<NUM>, C-<NUM> has significant pH-dependent solubility and permeability. For example, it has been found that, compared to the solubility in aqueous solution (pH <NUM>), C-<NUM> in its free form has approximately <NUM> times higher solubility and C-<NUM> mesylate even has more than <NUM> times higher solubility in a simulated gastric fluid (pH <NUM>). In such cases, the solubility of the drug varies with pH and is highest under acidic conditions while being lowest under alkaline conditions, thus possibly causing the drug to precipitate out of the solution as it passes through the gastrointestinal tract. Since a drug needs to be present in a solution to enable its absorption, such precipitation may cause variability in the degree and/or rate of drug absorption, which may also result in that the amount of drug reaching the patient's systemic circulation varies significantly between one dose and the next dose in a given patient, and may also result in that the amount of drug reaching the patient's systemic circulation varies significantly between one patient and another patient. In principle, it is possible to adjust these differences by in-vivo monitoring or controlling the administration, however, it will definitely reduce the drug efficacy or increase the safety risk, as well as bringing additional economic burden and unfavorable clinical experience for the patients.

As for C-<NUM> citrate, its solubility is significantly higher than that of C-<NUM> in the free-base form under the pH conditions in intestine. Once formed, the solution of C-<NUM> citrate appears to be stable and does not precipitate for a time period of at least <NUM> hours. Based on this, it is expected that a simple "blend in capsule" formed by C-<NUM> citrate and microcrystalline cellulose will have favorable characteristics, including the rapid and complete dissolution within the physiological pH range, so as to avoid all the problems mentioned above. Unfortunately, however, the "blend in capsule" has a relatively long time limitation in terms of the expected destruction of the capsule shell, such that only <NUM>% release is achieved after <NUM> minutes, <NUM>% release is achieved after <NUM> minutes and <NUM>% release is basically achieved after <NUM> minutes at pH <NUM>. Therefore, there still remain certain problems in providing an improved way to administer drugs to patients, and the improved way should reduce/avoid the risk and/or severity of the above-mentioned problems caused by the inter-patient variability of absorption and/or the inter-dose variability of absorption.

The present disclosure provides solutions to one or more of the above-mentioned problems and relates to a novel pharmaceutical composition comprising a pharmaceutical substance. The pharmaceutical composition of the present disclosure is in the form of a tablet, which exhibits improved dissolution characteristics under physiologically relevant conditions and/or a relatively high total release of the pharmaceutical substance under physiologically relevant conditions. It is expected that achieving a faster initial dissolution rate and/or a relatively high total release of the pharmaceutical substance will reduce the risk caused by the inter-dose and inter-patient variability of drug absorption. This drug has a pH-dependent solubility as demonstrated by C-<NUM>. Meanwhile, as could be seen from the screening of multiple formulations, among four dissolution media, i.e. a dissolution medium at pH <NUM>, a dissolution medium at pH <NUM>, water, and a dissolution medium at pH <NUM>, the dissolution effect is the worst under a condition of pH <NUM>. Therefore, a medium at the most rigorous pH (pH <NUM>) and a medium at a moderate pH (pH <NUM>) are generally selected as the media used for investigating the dissolution effect. In general, the dissolution effect becomes better as the dissolution time becomes shorter and the plateau level of dissolution is higher, and the dissolution effect needs to at least meet the requirement of being superior to that of the "blend in capsule".

The pharmaceutical composition of the present disclosure exhibits significantly increased level of drug dissolution in a solution at pH <NUM> after <NUM>, <NUM>, and <NUM> minutes. The general procedure of the second method (paddle method) in General Rule <NUM> of Chinese Pharmacopoeia (<NUM>) is adopted, the average value of three dissolution percentages at pH <NUM> is obtained, and the data is as shown in the table below.

It could be seen from the above table that, all examples except for Examples 1A, 1B, <NUM>, 3A and 3C (which are not according to the invention) meet the requirement that the dissolution approaches or reaches <NUM>% of the maximum dissolution within <NUM> minutes; Example <NUM> also meets the requirement that the dissolution approaches or reaches <NUM>% of the maximum dissolution within <NUM> minutes; and Examples 1A and 1B also meet the requirement that the dissolution approaches or reaches <NUM>% of the maximum dissolution within <NUM> minutes. In addition, most of the above-mentioned examples have achieved better dissolution effects than that of the "blend in capsule".

In the first aspect, provided in the present disclosure is a pharmaceutical tablet comprising a tablet core, wherein the tablet core contains a pharmaceutical composition comprising:.

In the present disclosure, "wt%" refers to "percentage by weight" and has its ordinary meaning in the art. Therefore, "wt%" refers to the proportion of Component X in Component Y comprising the same, and is calculated based on the weights of Component X and Component Y in each case (different from other physical parameters, such as the volume or the number of moles, if present). For example, if <NUM> of Component X is contained in <NUM> of Component Y, then Component X constitutes <NUM> wt% of Component Y.

In the present disclosure, by the wording "all parts are by weight" means that the amount of each component in the pharmaceutical composition is described by the unit "part(s)". It should be understood that such expression simply defines the relative proportions of these components, wherein said proportions are defined based on relative weights (different from other physical parameters, such as the volume or the number of moles, if present). For example, if a mixture contains <NUM> of Component X and <NUM> of Component Z, when the sum of the parts of Component X and Component Z is defined as <NUM>, then in this example, the mixture contains <NUM> parts of Component X and <NUM> parts of Component Z.

Further, in the above-mentioned pharmaceutical composition, the pharmaceutical substance is a pharmaceutically acceptable salt of N-(<NUM>-((<NUM>-(dimethylamino)ethyl)(methyl)amino)-<NUM>-methoxy-<NUM>-((<NUM>-(<NUM>-methyl-<NUM>-pyrrolo[<NUM>,<NUM>-b]pyridin-<NUM>-yl)pyrimidin-<NUM>-yl)amino)phenyl)acrylamide, the pharmaceutically acceptable salt is an acid addition salt, and the acid is any one or more selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, citric acid, maleic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, oxalic acid, formic acid, acetic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid, preferably any one or more selected from the group consisting of hydrochloric acid, phosphoric acid, citric acid, methanesulfonic acid, and p-toluenesulfonic acid.

Still further, in the above-mentioned pharmaceutical composition, the pharmaceutical substance is N-(<NUM>-((<NUM>-(dimethylamino)ethyl)(methyl)amino)-<NUM>-methoxy-<NUM>-((<NUM>-(<NUM>-methyl-<NUM>-pyrrolo[<NUM>,<NUM>-b]pyridin-<NUM>-yl)pyrimidin-<NUM>-yl)amino)phenyl)acrylamide citrate disclosed in <CIT>, which has crystal form E and the X-ray powder diffraction (XRPD) pattern thereof has at least one characteristic peak at 2θ values of <NUM>° ± <NUM>°, <NUM>° ± <NUM>°, and <NUM>° ± <NUM>°, preferably further has at least one characteristic peak at 2θ values of <NUM>° ± <NUM>°, <NUM>° ± <NUM>°, <NUM>° ± <NUM>°, and <NUM>° ± <NUM>°, and more preferably further has at least one characteristic peak at 2θ values of <NUM>° ± <NUM>°, <NUM>° ± <NUM>°, <NUM>° ± <NUM>°, <NUM>° ± <NUM>°, and <NUM>° ± <NUM>°.

Further, the pharmaceutical composition comprises the pharmaceutical substance (a) in an amount limited to any one of the ranges listed below:.

Further, in the above-mentioned pharmaceutical composition, the pharmaceutical diluent consisting of multiple components includes, other than microcrystalline cellulose, any one or more of calcium phosphate, calcium sulfate, cellulose acetate (referred to as acetyl cellulose), ethyl cellulose, erythritol, fructose, inulin, isomaltitol, lactitol, lactose, maltitol, maltodextrin, maltose, mannitol, sorbitol, polydextrose, polyethylene glycol, starch, sucrose, trehalose, and xylitol.

Further, the pharmaceutical composition comprises the pharmaceutical diluent (b) in an amount limited to any one of the ranges listed below:.

Still further, in the above-mentioned pharmaceutical composition, when the pharmaceutical diluent consists of one component, said one component is microcrystalline cellulose; and when the pharmaceutical diluent consists of multiple components, one of said multiple components is microcrystalline cellulose, and the the remaining component(s) include(s) any one or more of isomaltitol, lactitol, lactose, mannitol, sorbitol and polydextrose, and microcrystalline cellulose constitutes from <NUM> wt% to <NUM> wt%, preferably from <NUM> wt% to <NUM> wt%, and more preferably from <NUM> wt% to <NUM> wt%, of the pharmaceutical diluent (b).

Further, in the above-mentioned pharmaceutical composition, the disintegrant consisting of multiple components includes, other than crospovidone or sodium carboxymethyl starch, any one or more of alginic acid, calcium alginate, sodium alginate, chitosan, calcium carboxymethylcellulose (CMC-Ca), sodium carboxymethylcellulose (CMC-Na), croscarmellose sodium (CCNa), povidone (PVP), guar gum, low-substituted hydroxypropyl cellulose (L-HPC), colloidal silica, and starch.

Further, the pharmaceutical composition comprises the pharmaceutical disintegrant (c) in an amount limited to any one of the ranges listed below:.

Still further, in the above-mentioned pharmaceutical composition, when the pharmaceutical disintegrant consists of one component, said one component is crospovidone; and when the pharmaceutical disintegrant consists of multiple components, one of said multiple components is crospovidone, and the remaining component(s) include(s) any one or more of low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, croscarmellose sodium and colloidal silica, and crospovidone constitutes from <NUM> wt% to <NUM> wt%, preferably from <NUM> wt% to <NUM> wt%, and more preferably from <NUM> wt% to <NUM> wt%, of the pharmaceutical disintegrant (c).

Still further, in the above-mentioned pharmaceutical composition, when the pharmaceutical disintegrant consists of multiple components, one of said multiple components is low-substituted hydroxypropyl cellulose, and low-substituted hydroxypropyl cellulose constitutes from <NUM> wt% to <NUM> wt%, preferably from <NUM> wt% to <NUM> wt%, and more preferably from <NUM> wt% to <NUM> wt%, of the pharmaceutical disintegrant (c).

Still further, in the above-mentioned pharmaceutical composition, when the pharmaceutical disintegrant consists of one component, said one component is sodium carboxymethyl starch; and when the pharmaceutical disintegrant consists of multiple components, one of said multiple components is sodium carboxymethyl starch, and the remaining component(s) include(s) any one or more of crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium and colloidal silica, and the sodium carboxymethyl starch constitutes from <NUM> wt% to <NUM> wt%, preferably from <NUM> wt% to <NUM> wt%, and more preferably from <NUM> wt% to <NUM> wt%, of the pharmaceutical disintegrant (c).

Still further, in the above-mentioned pharmaceutical composition, when the pharmaceutical disintegrant consists of multiple components, one of said multiple components is colloidal silica, and colloidal silica constitutes from <NUM> wt% to <NUM> wt%, preferably from <NUM> wt% to <NUM> wt%, and more preferably from <NUM> wt% to <NUM> wt%, of the pharmaceutical disintegrant (c).

Further, in the above-mentioned pharmaceutical composition, the solubilizer includes any one or more of benzalkonium chloride, benzyl benzoate, cetylpyridinium chloride (CPC), cyclodextrin, diethylene glycol monoethyl ether, lecithin, oleyl alcohol, poloxamer, sodium lauryl sulfate (SLS), sorbitan tristearate (ST), and glyceryl trioleate, preferably includes any one or more of sodium lauryl sulfate, cetylpyridinium chloride, and sorbitan tristearate, and more preferably includes sodium lauryl sulfate.

Further, the pharmaceutical composition comprises the pharmaceutical solubilizer (d) in an amount limited to any one of the ranges listed below:.

Still further, in the above-mentioned pharmaceutical composition, when the pharmaceutical solubilizer consists of one component, said one component is sodium lauryl sulfate; and when the pharmaceutical solubilizer consists of multiple components, one of said multiple components is sodium lauryl sulfate, and the remaining component(s) include(s) any one or more of cetylpyridinium chloride and sorbitan tristearate, and sodium lauryl sulfate constitutes from <NUM> wt% to <NUM> wt%, preferably from <NUM> wt% to <NUM> wt%, and more preferably from <NUM> wt% to <NUM> wt%, of the pharmaceutical solubilizer (d).

Further, in the above-mentioned pharmaceutical composition, the lubricant includes any one or more of stearic acid, magnesium stearate, sodium stearate, calcium stearate, zinc stearate, glyceryl monobehenate, glyceryl dibehenate, glyceryl tribehenate, glyceryl monostearate, glyceryl distearate, glyceryl tristearate, myristic acid, palmitic acid, sodium stearyl fumarate, and talc, preferably includes any one or more of magnesium stearate, calcium stearate, myristic acid, palmitic acid, and sodium stearyl fumarate, and more preferably includes any one or more of magnesium stearate and sodium stearyl fumarate.

Further, the pharmaceutical composition comprises the pharmaceutical lubricant (e) in an amount limited to any one of the ranges listed below:.

Still further, in the above-mentioned pharmaceutical composition, when the pharmaceutical lubricant consists of one component, said one component is sodium stearyl fumarate; and when the pharmaceutical lubricant consists of multiple components, one of said multiple components is sodium stearyl fumarate, the remaining component(s) include(s) any one or more of magnesium stearate, calcium stearate, myristic acid and palmitic acid, and sodium stearyl fumarate constitutes from <NUM> wt% to <NUM> wt%, preferably from <NUM> wt% to <NUM> wt%, and more preferably from <NUM> wt% to <NUM> wt%, of the pharmaceutical lubricant (e).

Still further, in the above-mentioned pharmaceutical composition, when the pharmaceutical lubricant consists of one component, said one component is magnesium stearate; and when the pharmaceutical lubricant consists of multiple components, one of said multiple components is magnesium stearate, the remaining component(s) include(s) any one or more of sodium stearyl fumarate, calcium stearate, myristic acid and palmitic acid, and magnesium stearate constitutes from <NUM> wt% to <NUM> wt%, preferably from <NUM> wt% to <NUM> wt%, and more preferably from <NUM> wt% to <NUM> wt%, of the pharmaceutical lubricant (e).

In the second aspect, provided in the present disclosure is a preparation method of the above-mentioned pharmaceutical composition, which comprises a step of mixing the above-defined pharmaceutical substance, diluent, disintegrant, solubilizer, and lubricant. This aspect of the disclosure is not claimed.

In the third aspect, the tablet core of the invention, preferably, has a coating.

In the fourth aspect, provided in the present disclosure is a preparation method of the above-mentioned pharmaceutical tablet, which comprises the following steps: mixing each component comprised in the pharmaceutical composition; subjecting the mixture to dry granulating, sorting, tabletting and coating; and then obtaining the pharmaceutical tablet. This aspect of the disclosure is not claimed.

In the fifth aspect, provided in the present disclosure is the above-mentioned pharmaceutical tablet for use in the treatment of cancer.

Further, in the above-mentioned use, the cancer is lung cancer, preferably non-small cell lung cancer, and more preferably advanced non-small cell lung cancer.

Further, in the above-mentioned use, the administration is oral administration.

Further, in the above-mentioned use, the patient is a mammalian patient, preferably a primate mammalian patient, and more preferably a human patient.

The pharmaceutical composition and the pharmaceutical tablet prepared therefrom of the present disclosure are capable of inhibiting mutant EGFR with high efficacy while exhibiting relatively low inhibitory activity against wild-type EGFR, thereby showing relatively high selectivity and improving the safety of drug administration. The pharmaceutical tablets of the present disclosure have relatively ideal disintegration time (most of the tablets are capable of realizing disintegration within <NUM> minutes, and some tablets even disintegrate within <NUM> to <NUM> minutes) and dissolution (most of the dissolution percentages are capable of reaching <NUM>% or so and some of them even reach <NUM>%, while most of the plateau levels of dissolution appear after about <NUM> to <NUM> minutes and some of them even appear after about <NUM> minutes), thus being suitable for being developed into a drug for treating cancer (preferably lung cancer, especially non-small cell lung cancer) and having important social and economic values.

The tablets 1A, 1B, <NUM>, 3A and 3C, and the blend in capsule are not according to the invention.

In the context of the present disclosure, "pharmaceutical substance" refers to C-<NUM> as represented by Formula I above or a pharmaceutically acceptable salt thereof, which is capable of exerting inhibitory activity on epidermal growth factor receptor (EGFR) and belongs to EGFR inhibitors.

In the context of the present disclosure, "pharmaceutically acceptable salt" refers to a nontoxic acid addition salt formed by reacting an active pharmaceutical ingredient with an acid. The acids used to form this acid addition salt include not only inorganic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and the like, but also organic acids, for example, trifluoroacetic acid, citric acid, maleic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, oxalic acid, formic acid, acetic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like.

In one embodiment of the present disclosure, the pharmaceutical substance in the above-mentioned pharmaceutical composition is any one or more selected from the group consisting of the hydrochloride, phosphate, citrate, mesylate and p-toluenesulfonate of C-<NUM>.

In one embodiment of the present disclosure, the pharmaceutical substance in the above-mentioned pharmaceutical composition is C-<NUM> citrate. This citrate is capable of existing in amorphous or crystalline form.

C-<NUM> citrate existed in crystalline form has crystal form E. The XRPD pattern of the crystal form E has at least one characteristic peak at 2θ values of <NUM>° ± <NUM>°, <NUM>° ± <NUM>°, and <NUM>° ± <NUM>°, preferably has at least one characteristic peak at <NUM> values of <NUM>° ± <NUM>°, <NUM>° ± <NUM>°, <NUM>° ± <NUM>°, and <NUM>° ± <NUM>°, and more preferably has at least one characteristic peak at 2θ values of <NUM>° ± <NUM>°, <NUM>° ± <NUM>°, <NUM>° ± <NUM>°, <NUM>° ± <NUM>°, and <NUM>° ± <NUM>°.

The above-mentioned pharmaceutical composition comprises the pharmaceutical substance (a) in an amount limited to any one of the ranges listed below:.

In the context of the present disclosure, "pharmaceutical diluent" (or referred to as "pharmaceutical filler") refers to a class of pharmaceutical excipients that are used to increase the weight or volume of a tablet to facilitate tabletting. Commonly used pharmaceutical diluents include starches, saccharides and sugar alcohols, celluloses, inorganic salts, and the like.

In one embodiment of the present disclosure, the pharmaceutical diluent in the above-mentioned pharmaceutical composition consists of multiple components being, other than microcrystalline cellulose, any one or more of calcium phosphate, calcium sulfate, cellulose acetate (referred to as acetyl cellulose), ethyl cellulose, erythritol, fructose, inulin, isomaltitol, lactitol, lactose, maltitol, maltodextrin, maltose, mannitol, sorbitol, polydextrose, polyethylene glycol, starch, sucrose, trehalose, and xylitol.

In one embodiment of the present disclosure, the pharmaceutical diluent in the above-mentioned pharmaceutical composition consists of one component, that is, microcrystalline cellulose.

In one embodiment of the present disclosure, the pharmaceutical diluent in the above-mentioned pharmaceutical composition consists of multiple components, one of the multiple components is microcrystalline cellulose, the remaining component(s) include(s) any one or more of isomaltitol, lactitol, lactose, mannitol, sorbitol and polydextrose, and microcrystalline cellulose constitutes from <NUM> wt% to <NUM> wt% of the pharmaceutical diluent (b).

In one embodiment of the present disclosure, the above-mentioned range is from <NUM> wt% to <NUM> wt%.

The above-mentioned pharmaceutical composition comprises the pharmaceutical diluent (b) in an amount limited to any one of the ranges listed below:.

In the context of the present disclosure, "pharmaceutical disintegrant" refers to a class of pharmaceutical excipients that are used to enable a tablet to quickly break into fine particles in the digestive tract thereby enabling an active pharmaceutical ingredient to be quickly dissolved in the gastrointestinal fluid and absorbed by the subject. Commonly used pharmaceutical disintegrants include starch or the salts thereof, cellulose or the salts thereof, alginic acid or the salts thereof, povidones, and the like.

In one embodiment of the present disclosure, the pharmaceutical disintegrant in the above-mentioned pharmaceutical composition consists of multiple components being, other than crospovidone or sodium carboxymethyl starch, any one or more of alginic acid, calcium alginate, sodium alginate, chitosan, calcium carboxymethylcellulose (CMC-Ca), sodium carboxymethylcellulose (CMC-Na), croscarmellose sodium (CCNa), povidone (PVP), guar gum, low-substituted hydroxypropyl cellulose (L-HPC), colloidal silica, and starch.

In one embodiment of the present disclosure, the pharmaceutical disintegrant in the above-mentioned pharmaceutical composition consists of one component, that is, crospovidone.

In one embodiment of the present disclosure, the pharmaceutical disintegrant in the above-mentioned pharmaceutical composition consists of multiple components, one of the multiple components is crospovidone, the remaining component(s) include(s) any one or more of low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, croscarmellose sodium and colloidal silica, and crospovidone constitutes from <NUM> wt% to <NUM> wt% of the pharmaceutical disintegrant (c).

In one embodiment of the present disclosure, the pharmaceutical disintegrant in the above-mentioned pharmaceutical composition consists of multiple components, one of the multiple components is low-substituted hydroxypropyl cellulose, and low-substituted hydroxypropyl cellulose constitutes from <NUM> wt% to <NUM> wt% of the pharmaceutical disintegrant (c).

In one embodiment of the present disclosure, the pharmaceutical disintegrant in the above-mentioned pharmaceutical composition consists of one component, that is, sodium carboxymethyl starch.

In one embodiment of the present disclosure, the pharmaceutical disintegrant in the above-mentioned pharmaceutical composition consists of multiple components, one of the multiple components is sodium carboxymethyl starch, the remaining component(s) include(s) any one or more of crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium and colloidal silica, and sodium carboxymethyl starch constitutes from <NUM> wt% to <NUM> wt% of the pharmaceutical disintegrant (c).

In one embodiment of the present disclosure, the pharmaceutical disintegrant in the above-mentioned pharmaceutical composition consists of multiple components, one of the multiple components is colloidal silica, and colloidal silica constitutes from <NUM> wt% to <NUM> wt% of the pharmaceutical disintegrant (c).

The above-mentioned pharmaceutical composition comprises the pharmaceutical disintegrant (c) in an amount limited to any one of the ranges listed below:.

In the context of the present disclosure, the term "pharmaceutical solubilizer" refers to a class of pharmaceutical excipients that are used to increase the solubility of a poorly soluble active pharmaceutical ingredient in a solution (generally, the gastrointestinal fluid under physiological conditions) so as to form a solution as clear as possible. Commonly used pharmaceutical solubilizers include alkyl sulfuric acid or the salts thereof, tetraalkylammonium halides, alkylpyridinium halides, cyclodextrins, polyethylene glycol monoethers, higher fatty alcohols, sugar alcohols or the fatty acid esters thereof, glycerin or the fatty acid esters thereof, and the like.

The pharmaceutical solubilizer in the above-mentioned pharmaceutical composition includes any one or more of benzalkonium chloride, benzyl benzoate, cetylpyridinium chloride, cyclodextrin, diethylene glycol monoethyl ether, lecithin, oleyl alcohol, poloxamer, sodium lauryl sulfate, sorbitan tristearate, and glyceryl trioleate.

In one embodiment of the present disclosure, the pharmaceutical solubilizer in the above-mentioned pharmaceutical composition consists of one component, that is, sodium lauryl sulfate.

In one embodiment of the present disclosure, the pharmaceutical solubilizer in the above-mentioned pharmaceutical composition consists of multiple components, one of the multiple components is sodium lauryl sulfate, the remaining component(s) include(s) any one or more of cetylpyridinium chloride and sorbitan tristearate, and sodium lauryl sulfate constitutes from <NUM> wt% to <NUM> wt% of the pharmaceutical solubilizer (d).

The above-mentioned pharmaceutical composition comprises the pharmaceutical solubilizer (d) in an amount limited to any one of the ranges listed below:.

In the context of the present disclosure, "pharmaceutical lubricant" is a lubricant in a narrow sense, which refers to a class of pharmaceutical excipients that are used to reduce the friction between tablets (or granules) and the die wall and/or punch of tablet machine so as to prevent the difficulty of tabletting and enable the tablets to have uniform and consistent density as well as smooth and flat surface. Commonly used pharmaceutical lubricants include higher fatty acids, higher fatty acid salts, higher fatty acid glycerides, polyacid fatty alcohol monoesters or the salts thereof, talc, and the like.

In one embodiment of the present disclosure, the pharmaceutical lubricant in the above-mentioned pharmaceutical composition includes any one or more of stearic acid, magnesium stearate, sodium stearate, calcium stearate, zinc stearate, glyceryl monobehenate, glyceryl dibehenate, glyceryl tribehenate, glyceryl monostearate, glyceryl distearate, glyceryl tristearate, myristic acid, palmitic acid, sodium stearyl fumarate, and talc.

In one embodiment of the present disclosure, the pharmaceutical lubricant in the above-mentioned pharmaceutical composition consists of one component, that is, sodium stearyl fumarate.

In one embodiment of the present disclosure, the pharmaceutical lubricant in the above-mentioned pharmaceutical composition consists of multiple components, one of the multiple components is sodium stearyl fumarate, the remaining component(s) include(s) any one or more of magnesium stearate, calcium stearate, myristic acid and palmitic acid, and sodium stearyl fumarate constitutes from <NUM> wt% to <NUM> wt% of the pharmaceutical lubricant (e).

In one embodiment of the present disclosure, the pharmaceutical lubricant in the above-mentioned pharmaceutical composition consists of one component, that is, magnesium stearate.

In one embodiment of the present disclosure, the pharmaceutical lubricant in the above-mentioned pharmaceutical composition consists of multiple components, one of the multiple components is magnesium stearate, the remaining component(s) include(s) any one or more of sodium stearyl fumarate, calcium stearate, myristic acid and palmitic acid, and magnesium stearate constitutes from <NUM> wt% to <NUM> wt% of the pharmaceutical lubricant (e).

The above-mentioned pharmaceutical composition comprises the pharmaceutical lubricant (e) in an amount limited to any one of the ranges listed below:.

In the second aspect, provided in the present disclosure is a preparation method of the above-mentioned pharmaceutical composition. This preparation method comprises a step of mixing the above-defined pharmaceutical substance, diluent, disintegrant, solubilizer, and lubricant. This aspect of the disclosure is not claimed.

In the third aspect, provided in the present disclosure is the above-mentioned tablet for use in the treatment of cancer.

In the context of the present disclosure, "cancer" generally refers to all malignant tumors, including brain cancer, nasopharyngeal cancer, esophageal cancer, gastric cancer, colorectal cancer, liver cancer, pancreatic cancer, lung cancer, bladder cancer, prostate cancer, breast cancer, bone cancer, blood cancer (leukemia, lymphoma, and myeloma), and the like. "Cancer therapeutic agent" refers to a pharmaceutical composition or a pharmaceutical preparation for treating cancer.

In one embodiment of the present disclosure, the cancer in the above-mentioned use is lung cancer.

In a preferred embodiment, the cancer in the above-mentioned use is non-small cell lung cancer.

In a more preferred embodiment, the cancer in the above-mentioned use is advanced non-small cell lung cancer.

In the fourth aspect, the tablet is used for the treatment of lung cancer.

In a preferred embodiment, the above-mentioned tablet is used for the treatment of non-small cell lung cancer.

In a more preferred embodiment, the above-mentioned tablet is used for the treatment of advanced non-small cell lung cancer.

In the fifth the tablet core of the invention, preferably, has a coating.

In the context of the present disclosure, "coating" refers to a multifunctional protective layer formed on the outer surface of an intermediate particle or a tablet core (or referred to as a plain tablet).

In a preferred embodiment, the coating in the above-mentioned pharmaceutical tablet is prepared by using a series of coating materials under the brand name of Opadry®.

In the sixth aspect, provided in the present disclosure is a preparation method of the above-mentioned pharmaceutical tablet. This preparation method comprises the following steps: mixing each component comprised in the above-mentioned pharmaceutical composition; subjecting the mixture to dry granulating, sorting, tabletting and coating; and then obtaining the pharmaceutical tablet. This aspect of the disclosure is not claimed.

In the context of the present disclosure, "therapeutically effective amount" refers to the amount of a biologically active substance that is capable of achieving any one of the following effects: (<NUM>) preventing or treating a specific disesase, condition or disorder; (<NUM>) alleviating, improving or eliminating one or more symptoms of a specific disesase, condition or disorder; or (<NUM>) preventing or delaying the onset of one or more symptoms of a specific disesase, condition or disorder.

In the context of the present disclosure, "administration" (or referred to as drug administration) refers to a behavior of administering an active pharmaceutical ingredient, a prodrug, a pharmaceutical composition or a pharmaceutical preparation (for example, the pharmaceutical composition or the pharmaceutical preparation of the present disclosure) to a patient (including a subject, an in-vivo/in-vitro/ex-vivo cell, tissue or organ). Common administration modes (or referred to as administration routes) include oral administration, skin administration (including topical administration, transdermal administration, and the like), ocular administration, nasal administration, pulmonary administration, mucosal administration (including intra-oral administration, intra-aural administration, vaginal administration, rectal administration, and the like), injection administration (including administration via intravenous injection, administration via subcutaneous injection, administration via intramuscular injection, and the like), and the like.

In the present disclosure, the administration in the above-mentioned use is oral administration.

In the context of the present disclosure, "patient" refers to an object (including not only a whole/macroscopic object such as a subject, but also a partial/microscopic object such as an in-vivo/in-vitro/ex-vivo cell, tissue or organ) that has suffered from or will suffer from a specific disease. In the present disclosure, a patient may be not only a human patient, but also other animal patients (for example, fishes, amphibians, reptiles, birds, and mammals).

In one embodiment of the present disclosure, the patient in the above-mentioned use is a mammalian patient.

In a preferred embodiment, the patient in the above-mentioned use is a primate mammalian patient.

In a more preferred embodiment, the patient in the above-mentioned use is a human patient.

The technical solutions of the present disclosure will be further illustrated below in conjunction with specific examples. It should be understood that the following examples are merely provided for explaining and illustrating the present disclosure and are not intended to limit the protection scope of the present disclosure. Unless otherwise specified, all the instruments (as shown in Table <NUM>), materials, reagents and the like used in the following examples may be obtained by conventional commercial means.

Tabletting was conducted in accordance with Formulations 1A to 1C in Table <NUM>, so as to obtain Plain tablets 1A to 1C. Tablets 1A and 1B are not according to the invention.

Similar to AZD9291, C-<NUM> also exhibited significant pH-dependent solubility, and it was therefore necessary to investigate its dissolution in a variety of media. Four media, i.e., water, a solution at pH <NUM> (hereinafter simply referred to as pH <NUM>), a solution at pH <NUM> (hereinafter simply referred to as pH <NUM>) and a solution at pH <NUM> (hereinafter simply referred to as pH <NUM>), were selected for the investigation. Among these, pH <NUM> was relatively close to the dissolution environment of a pharmaceutical substance when the pharmaceutical substance was absorbed in vivo, and the pharmaceutical tablets were capable of exhibiting significantly increased level of drug dissolution at <NUM>, <NUM> and <NUM> minutes under conditions of pH <NUM> and pH <NUM>, therefore, the dissolution in these two media had more reference value. The dissolution data was obtained in accordance with the paddle method described in Chinese Pharmacopoeia (CP), specifically the second method in General Rule <NUM> of CP2015.

The preparation method of the dissolution media was as described below. (<NUM>) The solution at pH <NUM>: <NUM> of hydrochloric acid was measured and added into <NUM> of degassed water, the mixture was stirred and uniformly mixed, and the above solution was obtained; (<NUM>) The solution at pH <NUM>: <NUM> of sodium acetate was weighed and added into <NUM> of degassed water, <NUM> of acetic acid was then added after the dissolution of sodium acetate, the mixture was stirred and uniformly mixed, and the above solution was obtained; (<NUM>) The solution at pH <NUM>: <NUM> of potassium dihydrogen phosphate and <NUM> of sodium hydroxide were weighed and added into <NUM> of degassed water, the mixture was stirred and uniformly mixed, and the above solution was obtained; (<NUM>) Water: purified water.

Dissolution method: The dissolution test was carried out at <NUM>, <NUM> of sample was recovered from the dissolution medium at <NUM>/<NUM>/<NUM>/<NUM>/<NUM>/<NUM>/<NUM>/<NUM>/<NUM>/<NUM> minutes, filtered through the glass wool endremover filter (Acrodisc glass wool GxF (Component No. <NUM>) or its equivalent), and the first <NUM> of the filtrate was discarded. Quantification was carried out by UV analysis under a wavelength of <NUM> (ACE C18, <NUM>*<NUM><NUM>). Generally, the result of dissolution was the average value based on three repeated tests. The dissolution of the above-mentioned Plain tablets 1A to 1C was tested in four dissolution media (water, pH <NUM>, pH <NUM> and pH <NUM>), and the results were as shown in Table <NUM> and <FIG>.

Tabletting was conducted in accordance with Formulation <NUM> in Table <NUM>, so as to obtain Plain tablet <NUM> (not according to the invention).

The dissolution of the above-mentioned Plain tablet <NUM> was tested in four dissolution media (water, pH <NUM>, pH <NUM> and pH <NUM>), and the results were as shown in Table <NUM> and <FIG>.

As could be seen from the results in Table <NUM>, the plateau level of dissolution was reached after <NUM> minutes in the medium at pH <NUM>, and the dissolution percentage could reach <NUM>% or so; the plateau level of dissolution was also reached after <NUM> minutes in the other three media, and the dissolution percentage could reach <NUM>% or higher.

Tabletting was conducted in accordance with Formulations 3A to 3C in Table <NUM>, so as to obtain Plain tablets 3A to 3C. Tablets 3A and 3C are not according to the invention.

The dissolution of the above-mentioned Plain tablets 3A to 3C was tested in four dissolution media (water, pH <NUM>, pH <NUM> and pH <NUM>), and the results were as shown in Table <NUM> and <FIG>.

As could be seen from the results in Table <NUM>, Plain tablets 3A to 3C were mostly capable of reaching the plateau levels of dissolution in four media after <NUM> minutes. Among these, the dissolution percentage of Plain tablet 3B could reach <NUM>% within <NUM> minutes in the medium at pH <NUM>, reach <NUM>% within <NUM> minutes and then reach the plateau level of dissolution in the medium at pH <NUM>, and respectively reach the plateau level of dissolution after <NUM> minutes in water and the medium at pH <NUM>.

In Formulation <NUM> of this Example, MCC PH200 was used as a diluent instead of MCC PH102 in Formulation 3B. Tabletting was conducted in accordance with Formulation <NUM> in Table <NUM>, so as to obtain Plain tablet <NUM>.

As could be seen from the results in Tables <NUM> and <NUM>, as compared with Plain tablet 3B, Plain tablet <NUM> in which the diluent was replaced with MCC PH200 had increased fluidity of grannules and faster disintegration (the disintegration time was shortened from about <NUM> to about <NUM>); meanwhile, the dissolution was also significantly improved and Plain tablet <NUM> was capable of achieving rapid and complete dissolution in four media (the plateau level of dissolution was reached after <NUM>).

Tabletting was conducted in accordance with Formulations 5A to 5C in Table <NUM>, so as to obtain Plain tablets 5A to 5C.

The dissolution of the above-mentioned Plain tablets 5A to 5C was tested in two media (pH <NUM> and pH <NUM>), and the results were as shown in Table <NUM> and <FIG>.

As compared with Formulations 5A and 5B, Formulation 5C comprised neither L-HPC as the disintegrant for use as the outer portion nor colloidal silica as the glidant. As could be seen from the results in Table <NUM> and Table <NUM>, although the disintegration time of Plain tablet 5C was slightly longer than those of Plain tablets 5A and 5B, all three plain tablets could reach the plateau level of dissolution after <NUM> minutes, and the dissolution of these three plain tablets had no significant difference.

Tabletting was conducted in accordance with Formulations 6A to 6C in Table <NUM>, so as to obtain Plain tablets 6A to 6C.

As could be seen from the results in Table <NUM>, the disintegration time of the plain tablet would be gradually shortened with the increase of the amount of disintegrant in the formulation, however, when the amount of disintegrant reached <NUM>% or more, the amplitude of variation of the disintegration time of the plain tablet would be gradually decreased.

The dissolution of the above-mentioned Plain tablets 6A to 6C was tested in two media (pH <NUM> and pH <NUM>), and the results were as shown in Table <NUM> and <FIG>.

As could be seen from the results in Table <NUM>, in the medium at pH <NUM>, when the amount of disintegrant reached <NUM>% or more, the plain tablet could reach the plateau level of dissolution after <NUM> minutes and achieve a dissolution percentage of approximately <NUM>%; while in the medium at pH <NUM>, when the amount of disintegrant reached <NUM>% or more, the plain tablet could reach the plateau level of dissolution after <NUM> minutes and achieve a dissolution percentage of approximately <NUM>%.

Tabletting was conducted in accordance with Formulation <NUM> in Table <NUM>, so as to obtain Plain tablet <NUM>.

As could be seen from the results in Table <NUM>, as compared with Plain tablet 5C in which the amount of lubricant for use as the inner portion was equal to that for use as the outer portion, the disintegration time of Plain tablet <NUM> was increased by <NUM> minutes or so. It could be seen that a formulation in which the amount of lubricant for use as the inner portion was fout times of that for use as the outer portion would prolong the disintegration process.

As could be seen from the results in Table <NUM>, as compared with Plain tablet 5C in which the amount of lubricant for use as the inner portion was equal to that for use as the outer portion, Plain tablet <NUM> could reach the plateau level of dissolution at about <NUM> minutes in the four media and achieve a dissolution percentage of <NUM>% or more, and the dissolution effect was significantly superior to that of Plain tablet 5C.

Coated tablets 8A to 8C were prepared and obtained in accordance with Formulations 8A to 8C in Table <NUM>.

(<NUM>) The raw material was sieved through an <NUM>-mesh sieve and all excipients were sieved through a <NUM>-mesh sieve for later use. (<NUM>) The formulated amount of the API, the disintegrant, and the diluent for use as the inner portion were weighed and charged into a mixer with a rotating speed of <NUM> rpm, and the resulting mixture was mixed for <NUM>. (<NUM>) The formulated amount of the lubricant for use as the inner portion was weighed and charged into a mixer with a rotating speed of <NUM> rpm, and the resulting mixture was mixed for <NUM>. (<NUM>) Dry granulating was carried out with a pressure of <NUM> MPa, a feed rate of <NUM> rpm, and a rolling speed of <NUM> rpm. A <NUM> sieve was used for sorting, and the speed of sorting was <NUM> rpm. (<NUM>) The formulated amount of the diluent for use as the outer portion was weighed and charged into a mixer together with the dry granules, the rotating speed was <NUM> rpm, and the resulting mixture was mixed for <NUM>. (<NUM>) The formulated amount of the lubricant for use as the outer portion was weighed and charged into a mixer with a rotating speed of <NUM> rpm, and the resulting mixture was mixed for <NUM>. (<NUM>) Tabletting was conducted by using Gylongli ZP-10A tablet machine. A <NUM>*<NUM> capsule-shaped punch was used for tabletting in Preparation processes 8A and 8B and a <NUM> shallow arc punch was used for tabletting in Preparation process 8C, so as to obtain Plain tablets 8A to 8C. The friability and the disintegration time were determined. (<NUM>) Plain tablets 8A to 8C were coated with Opadry 85G640044 series coating material (Colorcon Corporation, Batch No.: THL46201, solid content: <NUM>%), the target coating weight gain was <NUM>%, and Coated tablets 8A to 8C were obtained. The dissolution of Coated tablets 8A to 8C was determined.

The dissolution of the above-mentioned Coated tablets 8A to 8C was tested in two media (pH <NUM> and pH <NUM>), and the results were as shown in Table <NUM> and <FIG>.

As could be seen from the results in Table <NUM>, Coated tablets 8A to 8C could reach the plateau level of dissolution at about <NUM> to <NUM> minutes in both media, at least achieve a dissolution percentage of <NUM>% and exhibit good dissolution behavior.

A blend in capsule In the previous research process, C-<NUM> citrate and microcrystalline cellulose were once blended at a weight ratio of <NUM> : <NUM> and filled into a non-transparent white HPMC capsule shell (size <NUM>#) to prepare a blend in capsule. The filling amount was approximately <NUM> of C-<NUM> in the form of free base in each capsule, and the formulation list was as shown in Table <NUM>.

The dissolution of the above-mentioned blend in capsule was tested in two media (pH <NUM> and pH <NUM>), and the results were as shown in Table <NUM> and <FIG>.

Claim 1:
A pharmaceutical tablet comprising a tablet core, wherein the tablet core contains a pharmaceutical composition comprising:
(a) from <NUM> to <NUM> parts, preferably from <NUM> to <NUM> parts, of a pharmaceutical substance;
(b) from <NUM> to <NUM> parts, preferably from <NUM> to <NUM> parts, of a pharmaceutical diluent;
(c) from <NUM> to <NUM> parts, preferably from <NUM> to <NUM> parts, of a pharmaceutical disintegrant;
(d) from <NUM> to <NUM> parts, preferably from <NUM> to <NUM> parts, of a pharmaceutical solubilizer; and
(e) from <NUM> to <NUM> parts, preferably from <NUM> to <NUM> parts, of one or more pharmaceutical lubricants;
wherein all parts are by weight and a sum of these parts in (a), (b), (c), (d) and (e) is <NUM>; and
wherein
the pharmaceutical substance is N-(<NUM>-((<NUM>-(dimethylamino)ethyl)(methyl)amino)-<NUM>-methoxy-<NUM>-((<NUM>-(<NUM>-methyl-<NUM>-pyrrolo[<NUM>,<NUM>-b]pyridin-<NUM>-yl)pyrimidin-<NUM>-yl)amino)phenyl)acrylamide or a pharmaceutically acceptable salt thereof; and
the pharmaceutical diluent (b) consists of
- one component, said one component being microcrystalline cellulose or
- multiple components, one of said multiple components being microcrystalline cellulose in a quantity ranging from <NUM> wt% to <NUM> wt% of the pharmaceutical diluent; and
the pharmaceutical disintegrant (c) consists of
- one component, said one component being crospovidone or sodium carboxymethyl starch or
- multiple components, one of said multiple components being crospovidone in a quantity ranging from <NUM> wt% to <NUM> wt% of the pharmaceutical disintegrant or
- multiple components, one of said multiple components being sodium carboxymethyl starch in a quantity ranging from <NUM> wt% to <NUM> wt% of the pharmaceutical disintegrant; and
the pharmaceutical solubilizer (d) includes any one or more of benzalkonium chloride, benzyl benzoate, cetylpyridinium chloride, cyclodextrin, diethylene glycol monoethyl ether, lecithin, oleyl alcohol, poloxamer, sodium lauryl sulfate, sorbitan tristearate, and glyceryl trioleate.