Pharmaceutical composition and preparation method therefor and uses thereof

Abstract

The present disclosure belongs to the field of pharmaceutical preparations, and discloses a pharmaceutical composition and a preparation method therefor and uses thereof. The pharmaceutical composition comprising EGFR inhibitor (C-005) and the pharmaceutical tablets prepared therefrom of the present disclosure are suitable for the treatment of cancer, preferably lung cancer, particularly non-small cell lung cancer.

Claims

1. A pharmaceutical composition comprising: (a) from 3 to 70 parts of a pharmaceutical substance; (b) from 5 to 95 parts of one or more pharmaceutical diluents; (c) from 0.5 to 45 parts of one or more pharmaceutical disintegrants; (d) from 0 to 5 parts of one or more pharmaceutical solubilizers; and (e) from 0 to 5 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 100; and wherein the pharmaceutical substance is N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide citrate; the one or more pharmaceutical diluents is selected from any one or more of microcrystalline cellulose, calcium phosphate, calcium sulfate cellulose acetate (or 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; the one or more pharmaceutical disintegrants is selected from the group consisting of alginic acid, calcium alginate, sodium alginate, chitosan, calcium carboxymethylcellulose (CMC-Ca), sodium carboxymethylcellulose (CMC-Na), croscarmellose sodium (CCNa), povidone (PVP), crospovidone (crosslinked polyvinylpyrrolidone; PVPP), guar gum, low-substituted hydroxypropyl cellulose (L-HPC), sodium carboxymethyl starch (CMS-Na), colloidal silica (micronized silica gel; SiO.sub.2), and starch.

2. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises from 5 to 60 parts of the pharmaceutical substance.

3. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises from 10 to 85 parts of the one or more pharmaceutical diluents.

4. The pharmaceutical composition according to claim 1, wherein 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 microcrystalline cellulose constitutes from 10 wt % to 90 wt % of the pharmaceutical diluent.

5. The pharmaceutical composition according to claim 1, wherein a) 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 crospovidone constitutes from 10 wt % to 90 wt % of the pharmaceutical disintegrant; b) when the pharmaceutical disintegrant consists of one component, said one component is low-substituted hydroxypropyl cellulose; and 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 10 wt % to 90 wt % of the pharmaceutical disintegrant; c) 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 sodium carboxymethyl starch constitutes from 10 wt % to 50 wt % of the pharmaceutical disintegrant; or d) when the pharmaceutical disintegrant consists of one component, said one component is colloidal silica; and when the pharmaceutical disintegrant consists of multiple components, one of said multiple components is colloidal silica and colloidal silica constitutes from 10 wt % to 50 wt % of the pharmaceutical disintegrant.

6. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises from 0 to 3 parts of one or more pharmaceutical solubilizers (d).

7. The pharmaceutical composition according to claim 1, wherein the solubilizer is selected from 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.

8. The pharmaceutical composition according to claim 1, wherein 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 sodium lauryl sulfate constitutes from 10 wt % to 90 wt % of the pharmaceutical solubilizer.

9. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises from 0 to 4 parts of the one or more pharmaceutical lubricants.

10. The pharmaceutical composition according to claim 1, wherein the lubricant is selected from any one or more of stearic acid, magnesium stearate, sodium stearate, calcium stearate, zinc stearate, glyceryl behenate, glyceryl dibehenate, glyceryl tribehenate, glyceryl monostearate, glyceryl distearate, glyceryl tristearate, myristic acid, palmitic acid, sodium stearyl fumarate, and talc.

11. A pharmaceutical tablet comprising a tablet core, wherein the tablet core comprises the pharmaceutical composition according to claim 1, wherein the tablet core optionally has a coating.

12. A method for treating lung cancer, comprising a step of administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition according to claim 1.

13. A method for treating lung cancer, comprising a step of administering to a subject in need thereof a therapeutically effective amount of the tablet according to claim 11.

14. A pharmaceutical composition comprising (a) from 10 to 45 parts of a pharmaceutical substance which is N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide or a pharmaceutically acceptable salt thereof; (b) from 30 to 70 parts of one or more pharmaceutical diluents; (c) from 0.5 to 45 parts of one or more pharmaceutical disintegrants; (d) from 0 to 5 parts of one or more pharmaceutical solubilizers; and (e) from 0 to 5 parts of one or more pharmaceutical lubricants; wherein all parts are parts by weight and a sum of these parts in (a), (b), (c), (d) and (e) is 100 parts by weight.

15. The pharmaceutical composition of claim 14, wherein the pharmaceutical substance is present as the citrate salt; and the parts of the one or more pharmaceutical diluents is 40 to 70 parts, wherein a) when the pharmaceutical diluent consists of one component, said one component is microcrystalline cellulose; and b) when the pharmaceutical diluent consists of multiple components, one of said multiple components is microcrystalline cellulose, and microcrystalline cellulose constitutes from 10 wt % to 90 wt % of the pharmaceutical diluent.

16. The pharmaceutical composition of claim 15, wherein a) 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 crospovidone constitutes from 10 wt % to 90 wt % of the pharmaceutical disintegrant; b) when the pharmaceutical disintegrant consists of one component, said one component is low-substituted hydroxypropyl cellulose; and 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 10 wt % to 90 wt % of the pharmaceutical disintegrant; c) 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 sodium carboxymethyl starch constitutes from 10 wt % to 50 wt % of the pharmaceutical disintegrant; or d) when the pharmaceutical disintegrant consists of one component, said one component is colloidal silica; and when the pharmaceutical disintegrant consists of multiple components, one of said multiple components is colloidal silica, and colloidal silica constitutes from 10 wt % to 50 wt % of the pharmaceutical disintegrant.

17. A tablet comprising the pharmaceutical composition of claim 14, wherein the tablet comprises a compressed mixture of a) granules comprising the pharmaceutical substance, the one or more pharmaceutical diluents, the one or more pharmaceutical disintegrants, the one or more pharmaceutical lubricants; and b) a mixture of the one or more pharmaceutical diluents, the one or more pharmaceutical disintegrants, and the one or more pharmaceutical lubricants.

18. The pharmaceutical composition of claim 1, wherein the one or more pharmaceutical diluents is selected from the group consisting of microcrystalline cellulose, isomaltitol, lactitol, lactose, mannitol, sorbitol, and polydextrose; the one or more pharmaceutical disintegrants is selected from the group consisting of low-substituted hydroxypropyl cellulose (L-HPC), sodium carboxymethyl starch (CMS-Na), crospovidone (crosslinked polyvinylpyrrolidone; PVPP), croscarmellose sodium (CCNa), and colloidal silica (micronized silica gel; SiO.sub.2); the one or more pharmaceutical solubilizers is present and is selected from the group consisting of sodium lauryl sulfate (SLS), cetylpyridinium chloride (CPC), and sorbitan tristearate (ST); and the one or more pharmaceutical lubricants is present and is selected from the group consisting of magnesium stearate, calcium stearate, myristic acid, palmitic acid, and sodium stearyl fumarate.

19. A tablet comprising the pharmaceutical composition of claim 18, wherein the tablet comprises a compressed mixture of a) granules comprising the pharmaceutical substance, the one or more pharmaceutical diluents, the one or more pharmaceutical disintegrants, the one or more pharmaceutical lubricants; and b) a mixture of the one or more pharmaceutical diluents, the one or more pharmaceutical disintegrants, and the one or more pharmaceutical lubricants.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 shows the XRPD pattern of C-005 citrate in crystal form in the pharmaceutical composition or the pharmaceutical tablet of the present disclosure.

(2) FIG. 2 shows the dissolution profiles of Plain tablet 1A in four dissolution media.

(3) FIG. 3 shows the dissolution profiles of Plain tablet 1B in four dissolution media.

(4) FIG. 4 shows the dissolution profiles of Plain tablet 1C in four dissolution media.

(5) FIG. 5 shows the dissolution profiles of Plain tablet 2 in four dissolution media.

(6) FIG. 6 shows the dissolution profiles of Plain tablets 3A to 3C in a dissolution medium at pH 4.5.

(7) FIG. 7 shows the dissolution profiles of Plain tablets 3A to 3C in a dissolution medium at pH 6.8.

(8) FIG. 8 shows the dissolution profiles of Plain tablet 4 in four dissolution media.

(9) FIG. 9 shows the dissolution profiles of Plain tablets 5A to 5C in a dissolution medium at pH 4.5.

(10) FIG. 10 shows the dissolution profiles of Plain tablets 5A to 5C in a dissolution medium at pH 6.8.

(11) FIG. 11 shows the dissolution profiles of Plain tablets 6A to 6C and Plain tablet 5C in a dissolution medium at pH 4.5.

(12) FIG. 12 shows the dissolution profiles of Plain tablets 6A to 6C and Plain tablet 5C in a dissolution medium at pH 6.8.

(13) FIG. 13 shows the dissolution profiles of Plain tablet 7 in four dissolution media.

(14) FIG. 14 shows the dissolution profiles of Coated tablets 8A to 8C in a dissolution medium at pH 4.5.

(15) FIG. 15 shows the dissolution profiles of Coated tablets 8A to 8C in a dissolution medium at pH 6.8.

(16) FIG. 16 shows the dissolution profiles of a blend in capsule in a dissolution medium at pH 4.5 and a dissolution medium at pH 6.8.

DETAILED DESCRIPTION OF THE INVENTION

(17) In the first aspect, provided in the present disclosure is a pharmaceutical composition. This pharmaceutical composition comprises: (a) from 3 to 70 parts of a pharmaceutical substance; (b) from 5 to 95 parts of one or more pharmaceutical diluents; (c) from 0 to 50 parts of one or more pharmaceutical disintegrants; (d) from 0 to 5 parts of one or more pharmaceutical solubilizers; and (e) from 0 to 5 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 100; and wherein this pharmaceutical substance is N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide or a pharmaceutically acceptable salt thereof.

Pharmaceutical Substance

(18) In the context of the present disclosure, “pharmaceutical substance” refers to C-005 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.

Pharmaceutically Acceptable Salt

(19) In the context of the present disclosure, “pharmaceutically acceptable salt” refers to a non-toxic 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.

(20) 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-005.

(21) In one embodiment of the present disclosure, the pharmaceutical substance in the above-mentioned pharmaceutical composition is C-005 citrate. This citrate is capable of existing in amorphous or crystalline form.

(22) C-005 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 5.4°±0.2°, 12.0°±0.2°, and 21.2°±0.2°, preferably has at least one characteristic peak at 2θ values of 10.8°±0.2°, 17.5°±0.2°, 24.9°±0.2°, and 25.4°±0.2°, and more preferably has at least one characteristic peak at 2θ values of 9.0°±0.2°, 12.4°±0.2°, 13.3°±0.2°, 16.0°±0.2°, and 20.4°±0.2°.

(23) In one embodiment of the present disclosure, the above-mentioned pharmaceutical composition may comprise the pharmaceutical substance (a) in an amount limited to any one of the ranges listed below: from 3 to 70 parts by weight; from 4 to 70 parts by weight; from 4 to 65 parts by weight; from 5 to 60 parts by weight; from 6 to 60 parts by weight; from 7 to 50 parts by weight; from 8 to 45 parts by weight. from 9 to 45 parts by weight; and from 10 to 45 parts by weight.

Pharmaceutical Diluent

(24) 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.

(25) In one embodiment of the present disclosure, the pharmaceutical diluent in the above-mentioned pharmaceutical composition includes any one or more of microcrystalline cellulose, calcium phosphate, calcium sulfate, cellulose acetate, ethyl cellulose, erythritol, fructose, inulin, isomaltitol, lactitol, lactose, maltitol, maltodextrin, maltose, mannitol, sorbitol, polydextrose, polyethylene glycol, starch, sucrose, trehalose, and xylitol.

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

(27) 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 10 wt % to 90 wt % of the pharmaceutical diluent (b).

(28) In one embodiment of the present disclosure, the above-mentioned range is from 15 wt % to 90 wt %.

(29) In one embodiment of the present disclosure, the above-mentioned range is from 20 wt % to 90 wt %.

(30) In one embodiment of the present disclosure, the above-mentioned pharmaceutical composition may comprise the pharmaceutical diluent (b) in an amount limited to any one of the ranges listed below: from 5 to 95 parts by weight; from 10 to 90 parts by weight; from 10 to 85 parts by weight; from 15 to 80 parts by weight; from 15 to 70 parts by weight; from 20 to 70 parts by weight. from 30 to 70 parts by weight; and from 40 to 70 parts by weight.

Pharmaceutical Disintegrant

(31) 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.

(32) In one embodiment of the present disclosure, the pharmaceutical disintegrant in the above-mentioned pharmaceutical composition includes any one or more of alginic acid, calcium alginate, sodium alginate, chitosan, calcium carboxymethylcellulose, sodium carboxymethylcellulose, croscarmellose sodium, povidone, crospovidone, guar gum, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, colloidal silica, and starch.

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

(34) 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 10 wt % to 90 wt % of the pharmaceutical disintegrant (c).

(35) In one embodiment of the present disclosure, the above-mentioned range is from 15 wt % to 90 wt %.

(36) In one embodiment of the present disclosure, the above-mentioned range is from 20 wt % to 90 wt %.

(37) In one embodiment of the present disclosure, the pharmaceutical disintegrant in the above-mentioned pharmaceutical composition consists of one component, that is, low-substituted hydroxypropyl cellulose.

(38) 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, the remaining component(s) include(s) any one or more of crospovidone, sodium carboxymethyl starch, croscarmellose sodium and colloidal silica, and low-substituted hydroxypropyl cellulose constitutes from 10 wt % to 90 wt % of the pharmaceutical disintegrant (c).

(39) In one embodiment of the present disclosure, the above-mentioned range is from 15 wt % to 90 wt %.

(40) In one embodiment of the present disclosure, the above-mentioned range is from 20 wt % to 90 wt %.

(41) 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.

(42) 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 10 wt % to 50 wt % of the pharmaceutical disintegrant (c).

(43) In one embodiment of the present disclosure, the above-mentioned range is from 15 wt % to 50 wt %.

(44) In one embodiment of the present disclosure, the above-mentioned range is from 20 wt % to 50 wt %.

(45) In one embodiment of the present disclosure, the pharmaceutical disintegrant in the above-mentioned pharmaceutical composition consists of one component, that is, colloidal silica.

(46) 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, the remaining component(s) include(s) any one or more of crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium and sodium carboxymethyl starch, and sodium carboxymethyl starch constitutes from 10 wt % to 50 wt % of the pharmaceutical disintegrant (c).

(47) In one embodiment of the present disclosure, the above-mentioned range is from 15 wt % to 50 wt %.

(48) In one embodiment of the present disclosure, the above-mentioned range is from 20 wt % to 50 wt %.

(49) In one embodiment of the present disclosure, the above-mentioned pharmaceutical composition may comprise the pharmaceutical disintegrant (c) in an amount limited to any one of the ranges listed below: from 0 to 50 parts by weight; from 0.5 to 45 parts by weight; from 0.5 to 40 parts by weight; from 0.5 to 30 parts by weight; from 0.5 to 20 parts by weight; from 0.5 to 15 parts by weight; from 1 to 15 parts by weight; and from 2 to 15 parts by weight.

Pharmaceutical Solubilizer

(50) 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.

(51) In one embodiment of the present disclosure, 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.

(52) 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.

(53) 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 10 wt % to 90 wt % of the pharmaceutical solubilizer (d).

(54) In one embodiment of the present disclosure, the above-mentioned range is from 15 wt % to 90 wt %.

(55) In one embodiment of the present disclosure, the above-mentioned range is from 20 wt % to 90 wt %.

(56) In one embodiment of the present disclosure, the above-mentioned pharmaceutical composition may comprise the pharmaceutical solubilizer (d) in an amount limited to any one of the ranges listed below: from 0 to 5 parts by weight; from 0 to 3 parts by weight; from 0 to 2 parts by weight; from 0 to 1 parts by weight; and from 0 to 0.5 parts by weight.

Pharmaceutical Lubricant

(57) 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.

(58) 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.

(59) 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.

(60) 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 10 wt % to 90 wt % of the pharmaceutical lubricant (e).

(61) In one embodiment of the present disclosure, the above-mentioned range is from 15 wt % to 90 wt %.

(62) In one embodiment of the present disclosure, the above-mentioned range is from 20 wt % to 90 wt %.

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

(64) 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 10 wt % to 90 wt % of the pharmaceutical lubricant (e).

(65) In one embodiment of the present disclosure, the above-mentioned range is from 15 wt % to 90 wt %.

(66) In one embodiment of the present disclosure, the above-mentioned range is from 20 wt % to 90 wt %.

(67) In one embodiment of the present disclosure, the above-mentioned pharmaceutical composition may comprise the pharmaceutical lubricant (e) in an amount limited to any one of the ranges listed below: from 0 to 5 parts by weight; from 0 to 4 parts by weight; from 0.5 to 4 parts by weight; from 0.8 to 3 parts by weight; and from 1 to 2 parts by weight.

(68) 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 a pharmaceutical substance, a diluent, a disintegrant, a solubilizer, and a lubricant.

(69) In the third aspect, provided in the present disclosure is use of the above-mentioned pharmaceutical composition as a cancer therapeutic agent.

Cancer and Cancer Therapeutic Agent

(70) 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.

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

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

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

(74) In the fourth aspect, provided in the present disclosure is the above-mentioned pharmaceutical composition, which is used as a cancer therapeutic agent.

(75) In one embodiment of the present disclosure, the above-mentioned pharmaceutical composition is used as a therapeutic agent for lung cancer.

(76) In a preferred embodiment, the above-mentioned pharmaceutical composition is used as a therapeutic agent for non-small cell lung cancer.

(77) In a more preferred embodiment, the above-mentioned pharmaceutical composition is used as a therapeutic agent for advanced non-small cell lung cancer.

(78) In the fifth aspect, provided in the present disclosure is use of the above-mentioned pharmaceutical composition in the preparation of a pharmaceutical preparation for treating cancer.

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

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

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

(82) In the sixth aspect, provided in the present disclosure is a pharmaceutical tablet. The pharmaceutical tablet comprises a tablet core, the tablet core comprises the above-mentioned pharmaceutical composition, preferably, the tablet core has a coating.

Coating

(83) 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).

(84) 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®.

(85) In the seventh 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.

(86) In the eighth aspect, provided in the present disclosure is use of the above-mentioned pharmaceutical tablet as a cancer therapeutic agent.

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

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

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

(90) In the ninth aspect, provided in the present disclosure is the above-mentioned pharmaceutical tablet, which is used as a cancer therapeutic agent.

(91) In one embodiment of the present disclosure, the above-mentioned pharmaceutical tablet is used as a therapeutic agent for lung cancer.

(92) In a preferred embodiment, the above-mentioned pharmaceutical tablet is used as a therapeutic agent for non-small cell lung cancer.

(93) In a more preferred embodiment, the above-mentioned pharmaceutical tablet is used as a therapeutic agent for advanced non-small cell lung cancer.

(94) In the tenth aspect, provided in the present disclosure is a method for treating cancer. This method comprises a step of administering a therapeutically effective amount of the above-mentioned pharmaceutical composition or the above-mentioned pharmaceutical tablet to a cancer patient.

Therapeutically Effective Amount

(95) 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: (1) preventing or treating a specific disease, condition or disorder; (2) alleviating, improving or eliminating one or more symptoms of a specific disease, condition or disorder; or (3) preventing or delaying the onset of one or more symptoms of a specific disease, condition or disorder.

Administration

(96) 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.

(97) In one embodiment of the present disclosure, the administration in the above-mentioned method is oral administration.

(98) In one embodiment of the present disclosure, the cancer in the above-mentioned method is lung cancer.

(99) In a preferred embodiment, the cancer in the above-mentioned method is non-small cell lung cancer.

(100) In a more preferred embodiment, the cancer in the above-mentioned method is advanced non-small cell lung cancer.

Patient

(101) 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).

(102) In one embodiment of the present disclosure, the patient in the above-mentioned method is a mammalian patient.

(103) In a preferred embodiment, the patient in the above-mentioned method is a primate mammalian patient.

(104) In a more preferred embodiment, the patient in the above-mentioned method is a human patient.

(105) 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 1), materials, reagents and the like used in the following examples may be obtained by conventional commercial means.

(106) TABLE-US-00002 TABLE 1 Experimental equipments used in the examples of the present disclosure Equipment name Manufacturer Mode electronic balance METTLER-TOLEDU ME203E electronic balance METTLER-TOLEDU ME3002E electronic balance METTLER-TOLEDU PL203 electronic balance METTLER-TOLEDU PL4001 angle of repose tester China Research Institute of Daily Chemical AR-1 Industry tap density tester Tianjin Tianda Tianfa Technology Co., Ltd. ES-2E Comil ® milling and sorting Quadro Engineering Corp. U5 machine dry granulator Zhangjiagang Kaichuang Machinery GL25 Manufacturing Co., Ltd. tablet machine Beijing Gylongli Sci. & Tech. Co., Ltd. ZP10A friability tester Shanghai Huanghai Drug Testing Instrument Co., CJY-300B Ltd. hardness tester Tianjin Tianda Tianfa Technology Co., Ltd. YD-35 disintegration tester Shanghai Huanghai Drug Testing Instrument Co., LB-2D Ltd. sieve shaker Shanghai Chemlab Laboratory Instrument Co., EML300 Ltd. coating machine Zhejiang Xiaolun Pharmaceutical Machinery Co., BGB-5F Ltd.

Example 1: Ordinary Tablets (Specification: 50 Mg)

(107) Tabletting was conducted in accordance with Formulations 1A to 1C in Table 2, so as to obtain Plain tablets 1A to 1C.

(108) TABLE-US-00003 TABLE 2 Formulation lists of Plain tablets 1A to 1C Formulation No. 1A (Specification: 50 mg) Theoretical amount (g) Name of raw material 200 tablets/ and excipients Manufacturer Batch No. mg/tablet wt % batch Inner portion API.sup.b Self-produced SLB-F170829 69.2.sup.a 26.67% 13.84 (C-005 citrate) mannitol Merck & Co. M809594 132.8 51.17% 26.56 Inc. microcrystalline JRS Pharma 5610264526 37.5 14.45% 7.50 cellulose (MCC PH102) low-substituted Shin-Etsu 6121472 12.5 4.81% 2.50 hydroxypropyl Chemical Co., cellulose Ltd. (L-HPC) sodium stearyl Standard S96-0607 5.0 1.93% 1.00 fumarate Chem. & Pharm. CO., LTD. Total of inner portion 257.0 99.04 51.40 Outer portion sodium stearyl Standard S96-0607 2.5 0.96% 0.50 fumarate Chem. & Pharm. CO., LTD. Total of outer portion 2.5 0.96% 0.50 Total of inner and outer 259.5 100.00% 51.90 portions Formulation No. 1B (Specification: 50 mg) Theoretical amount (g) Name of raw material 200 tablets/ and excipients Manufacturer Batch No. mg/tablet wt % batch Inner portion API Self-produced SLB-F170829 69.2 26.93% 13.84 (C-005 citrate) lactose monohydrate DFE Pharma 100M3MM 134.0 52.14% 26.80 microcrystalline JRS Pharma 5610264526 37.5 14.59% 7.50 cellulose (MCC PH102) low-substituted Shin-Etsu 6121472 12.5 4.86% 2.50 hydroxypropyl Chemical Co., cellulose Ltd. (L-HPC) magnesium stearate Faci Chemicals MGS-R0317 1.3 0.51% 0.26 Co., Ltd. Total of inner portion 254.5 99.03% 50.90 Outer portion magnesium stearate Faci Chemicals MGS-R0317 2.5 0.97% 0.50 Co., Ltd. Total of outer portion 2.5 0.97% 0.50 Total of inner and outer 257.0 100.00% 51.40 portions Formulation No. 1C (Specification: 50 mg) Theoretical amount (g) Name of raw material 200 tablets/ and excipients Manufacturer Batch No. mg/tablet wt % batch Inner portion API Self-produced SLB-F170829 69.2 27.68% 13.84 (C-005 citrate) lactose monohydrate DFE Pharma 100M3MM 57.0 22.80% 11.40 microcrystalline JRS Pharma 5610264526 100.0 40.00% 20.00 cellulose (MCC PH102) sodium carboxymethyl Yung Zip SSG2015004 20.0 8.00% 4.00 starch Chemical Ind. (CMS-Na) Co., Ltd. magnesium stearate Faci Chemicals MGS-R0317 1.3 0.52% 0.26 Co., Ltd. Total of inner portion 247.5 99.00% 49.50 Outer portion magnesium stearate Faci Chemicals MGS-R0317 2.5 1.00% 0.50 Co., Ltd. Total of outer portion 2.5 1.00% 0.50 Total 250.0 100.00% 50.00 .sup.aEquivalent to 50 mg of C-005 in the form of free base; .sup.bi.e., active pharmaceutical ingredients or raw material, also referred to as pharmaceutical substance. The same applied to the following content.

Preparation Processes 1A to 1C

(109) (1) The raw material was sieved through an 80-mesh sieve and all excipients were sieved through a 60-mesh sieve for later use. (2) The formulated amount of the API (C-005 was prepared in accordance with the method described in Example 12 in the specification of PCT/CN2015/088643, and its citrate with crystal form E was prepared in accordance with the method described in Example 6 in the specification of PCT/CN2018/070011), the diluent, and the disintegrant were weighed, charged into the same ziplock bag and uniformly mixed. (3) The formulated amount of the lubricant was weighed, and the lubricant for use as the inner portion was charged into the above-mentioned ziplock bag and uniformly mixed with the mixture therein. (4) Dry granulating was carried out with a pressure of 3 MPa and a feed rate of 10 rpm. (5) Comil U5 was used for sorting, a B040G03122*(1016) sieve was used for sieving, and the rotating speed was 2191 rpm. (6) The granules and the lubricant for use as the outer portion were charged into the same ziplock bag and uniformly mixed with the mixture therein. (7) Tabletting was conducted by using a Ø9 mm shallow arc punch. In Preparation process 1A, the tablet had a weight of 260 mg and a hardness of 30 N, the main pressure was 8.8 KN, and the rotating speed was 10 rpm. In Preparation process 1B, the tablet had a tablet weight of 257 mg and a hardness of 30N, the main pressure was 9.7 KN, and the rotating speed was 10 rpm. In Preparation process 1C, the tablet had a tablet weight of 250 mg and a hardness of 30N, the main pressure was 9.5 KN, and the rotating speed was 10 rpm. The tablet thickness, friability and disintegration time were determined.

(110) TABLE-US-00004 TABLE 3 Test results of the tablet thickness, friability, and disintegration time of Plain tablets 1A to 1C Tablet Tablet Main Disintegration No. weight Hardness thickness pressure Friability time 1A 260 mg 30 N 4.67 mm 8.8 KN 0.19% 19 min 1B 257 mg 30 N 4.23 mm 9.7 KN 0.23% 18 min 1C 250 mg 30 N 4.21 mm 9.5 KN 0.12% 1 min 41 s

(111) Similar to AZD9291, C-005 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 1.2 (hereinafter simply referred to as pH 1.2), a solution at pH 4.5 (hereinafter simply referred to as pH 4.5) and a solution at pH 6.8 (hereinafter simply referred to as pH 6.8), were selected for the investigation. Among these, pH 6.8 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 15, 30 and 60 minutes under conditions of pH 4.5 and pH 6.8, 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 0931 of CP2015.

(112) The preparation method of the dissolution media was as described below. (1) The solution at pH 1.2:45.9 mL of hydrochloric acid was measured and added into 6 L of degassed water, the mixture was stirred and uniformly mixed, and the above solution was obtained; (2) The solution at pH 4.5:17.8 g of sodium acetate was weighed and added into 6 L of degassed water, 9.5 mL 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; (3) The solution at pH 6.8:40.83 g of potassium dihydrogen phosphate and 5.4 g of sodium hydroxide were weighed and added into 6 L of degassed water, the mixture was stirred and uniformly mixed, and the above solution was obtained; (4) Water: purified water.

(113) Dissolution method: The dissolution test was carried out at 37° C., 5.0 mL of sample was recovered from the dissolution medium at 0/5/10/15/20/30/45/60/90/120 minutes, filtered through the glass wool endremover filter (Acrodisc glass wool GxF (Component No. 4529) or its equivalent), and the first 2.5 ml of the filtrate was discarded. Quantification was carried out by UV analysis under a wavelength of 312 nm (ACE C18, 4.6*250 5 μm). 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 1.2, pH 4.5 and pH 6.8), and the results were as shown in Table 4 and FIGS. 2 to 4.

(114) TABLE-US-00005 TABLE 4 Test results of the dissolution of Plain tablets 1A to 1C Time (mm) Medium No. 0 5 10 15 20 30 45 60 90 120 H.sub.2O 1A 0  4 17 26 35 51 69 80 88 96 1B 0  6 22 30 35 50 65 76 89 95 1C 0 28 56 67 72 75 77 78 80 81 pH 1.2 1A 0 19 32 44 51 66 84 94 99 98 1B 0 16 31 42 53 69 88 95 98 98 1C 0 48 79 89 91 91 92 93 95 96 pH 4.5 1A 0 11 24 31 42 57 79 87 96 95 1B 0 10 23 32 41 54 70 84 94 96 1C 0 48 61 71 74 77 79 81 82 84 pH 6.8 1A 0  4 19 33 44 58 71 85 89 92 1B 0  6 21 31 40 53 69 80 88 90 1C 0 20 66 77 80 81 83 85 86 87

Example 2: Ordinary Tablets (Specification: 240 Mg)

(115) Tabletting was conducted in accordance with Formulation 2 in Table 5, so as to obtain Plain tablet 2.

(116) TABLE-US-00006 TABLE 5 Formulation list of Plain tablet 2 Formulation No. Name of raw material and 2 (Specification: 240 mg) excipients Manufacturer Batch No. mg/tablet wt % Inner portion API Self-produced SLB-F170929-1 332.12.sup.a 33.21% (C-005 citrate) colloidal silica EVONIK  156021114 90.00 9.00% (SiO.sub.2) Corporation low-substituted hydroxypropyl Shin-Etsu Chemical   6121472 230.00 23.00% cellulose Co., Ltd. (L-HPC) sodium lauryl sulfate BASF Corporation 0016990215 15.00 1.50% (SLS) Total of inner portion 667.12 66.71% Outer portion microcrystalline cellulose JRS Pharma 5610264526 272.88 27.29% (MCC PH102) low-substituted hydroxypropyl Shin-Etsu Chemical   6121472 50.00 5.00% cellulose Co., Ltd. (L-HPC) magnesium stearate Faci Chemicals Co., MGS-R0317 10.00 1.00% Ltd. Total of outer portion 332.88 33.29% Total of inner and outer portion 1000.00 100.00% .sup.aEquivalent to 240 mg of C-005 in the form of free base

Preparation Process 2 (100 Tablets/Batch)

(117) (1) The raw material was sieved through an 80-mesh sieve and all excipients were sieved through a 60-mesh sieve for later use. (2) The formulated amount of the API, the solubilizer, and the disintegrant for use as the inner portion were weighed, charged into the same ziplock bag and uniformly mixed. (3) Dry granulating was carried out with a pressure of 3 MPa, a feed rate of 10 rpm, and a rolling speed of 10 rpm. (4) A 24-mesh sieve was used for dry sorting. (5) The granules, the diluent, and the disintegrant for use as the outer portion were charged into the same ziplock bag and uniformly mixed with the mixture therein. (6) Afterwards, the lubricant was charged into the same ziplock bag and uniformly mixed with the mixture therein. (7) Tabletting was conducted by using a Ø20*10 mm capsule-shaped punch, the tablet weight was 999 mg, and the hardness was 130.1N. The tablet thickness, friability and disintegration time were determined.

(118) TABLE-US-00007 TABLE 6 Test results of the tablet thickness, friability, and disintegration time of Plain tablet No. Tablet weight Tablet thickness Hardness Friability Disintegration time 2 999 mg 6.61 mm 130.1 N 0.01% 9 min

(119) The dissolution of the above-mentioned Plain tablet 2 was tested in four dissolution media (water, pH 1.2, pH 4.5 and pH 6.8), and the results were as shown in Table 7 and FIG. 5.

(120) TABLE-US-00008 TABLE 7 Test results of the dissolution of Plain tablet 2 Time (minutes) Medium No. 0 5 10 15 20 30 45 60 90 120 H.sub.2O 2 0 15 31 55 78 89  90 90 90 90 pH 1.2 2 0 15 30 48 73 99 100 99 99 99 pH 4.5 2 0 15 27 46 71 93  93 93 93 93 pH 6.8 2 0 15 29 50 68 79  79 78 78 77

(121) As could be seen from the results in Table 7, the plateau level of dissolution was reached after 30 minutes in the medium at pH 6.8, and the dissolution percentage could reach 80% or so; the plateau level of dissolution was also reached after 30 minutes in the other three media, and the dissolution percentage could reach 85% or higher.

Example 3: Ordinary Tablets Comprising Different Disintegrants (Specification: 240 Mg)

(122) Tabletting was conducted in accordance with Formulations 3A to 3C in Table 8, so as to obtain Plain tablets 3A to 3C.

(123) TABLE-US-00009 TABLE 8 Formulation lists of Plain tablets 3A to 3C Formulation No. Name of raw material and 3A (Specification: 240 mg) excipients Manufacturer Batch No. mg/tablet wt % Inner portion API Self-produced SLB-F17002 332.12.sup.a 33.21% (C-005 citrate) colloidal silica EVONIK Corporation  156021114 30.00 3.00% (SiO.sub.2) microcrystalline cellulose JRS Pharma 5610274323 100.00 10.00% (MCC PH102) croscarmellose sodium FMC BioPolymer TN17831072 50.00 5.00% (CCNa) Corporation magnesium stearate Faci Chemicals Co., MGS-R0317 10.00 1.00% Ltd. Total of inner portion 522.12 52.21% Outer portion low-substituted hydroxypropyl Shin-Etsu Chemical   6121472 50.00 5.00% cellulose Co., Ltd. (L-HPC) microcrystalline cellulose JRS Pharma 5610274323 407.88 40.79% (MCC PH102) magnesium stearate Faci Chemicals Co., MGS-R0317 20.00 2.00% Ltd. Total of outer portion 477.88 47.79% Total of inner and outer portion 1000.00 100.00% Formulation No. Name of raw material and 3B (Specification: 240 mg) excipients Manufacturer Batch No. mg/tablet wt % Inner portion API Self-produced SLB-F17002 332.12 33.21% (C-005 citrate) colloidal silica EVONIK Corporation  156021114 30.00 3.00% (SiO.sub.2) microcrystalline cellulose JRS Pharma 5610274323 100.00 10.00% (MCC PH102) crospovidone Ashland Group OOO1926358 80.00 8.00% (PVPP) Corporation magnesium stearate Faci Chemicals Co., MGS-R0317 10.00 1.00% Ltd. Total of inner portion 552.12 55.21% Outer portion low-substituted hydroxypropyl Shin-Etsu Chemical   6121472 50.00 5.00% cellulose Co., Ltd. (L-HPC) microcrystalline cellulose JRS Pharma 5610274323 387.88 38.79% (MCC PH102) magnesium stearate Faci Chemicals Co., MGS-R0317 10.00 1.00% Ltd. Total of outer portion 478.88 47.89% Total of inner and outer portion 1000.00 100.00% Formulation No. Name of raw material and 3C (Specification: 240 mg) excipients Manufacturer Batch No. mg/tablet wt % Inner portion API Self-produced SLB-F17002 332.12 33.21% (C-005 citrate) colloidal silica EVONIK Corporation  156021114 10.00 1.00% (SiO.sub.2) microcrystalline cellulose JRS Pharma 5610274323 100.00 10.00% (MCC PH102) low-substituted hydroxypropyl Shin-Etsu Chemical   6121472 10.00 1.00% cellulose Co., Ltd. (L-HPC) mannitol Merck & Co., Inc. M809594 110.00 11.00% magnesium stearate Faci Chemicals Co., MGS-R0317 10.00 1.00% Ltd. Total of inner portion 572.12 57.21% Outer portion low-substituted hydroxypropyl Shin-Etsu Chemical   6121472 40.00 4.00% cellulose Co., Ltd. (L-HPC) microcrystalline cellulose JRS Pharma 5610274323 372.88 37.29% (MCC PH102) magnesium stearate Faci Chemicals Co., MGS-R0317 15.00 1.50% Ltd. Total of outer portion 427.88 42.79% Total of inner and outer portion 1000 100.00% .sup.aEquivalent to 240 mg of C-005 in the form of free base

Preparation Processes 3A to 3C

(124) (1) The raw material was sieved through an 80-mesh sieve and all excipients were sieved through a 60-mesh sieve for later use. (2) The formulated amount of the API, the disintegrant for use as the inner portion, and the diluent for use as the inner portion were weighed, charged into the same ziplock bag, uniformly mixed, and then sieved by using a 60-mesh sieve for 3 times. (3) The formulated amount of the lubricant for use as the inner portion was weighed and charged into the same ziplock bag together with the sieved materials in (2), and the resulting mixture was uniformly mixed. (4) Dry granulating was carried out with a pressure of 3 MPa, a feed rate of 17 rpm, and a rolling speed of 10 rpm. (5) The resulting mixture was sieved through a 24-mesh sieve. (6) The formulated amount of the disintegrant for use as the outer portion and the diluent for use as the outer portion were weighed, both of them were charged into the same ziplock bag together with the dry granules, and the resulting mixture was uniformly mixed. (7) The formulated amount of the lubricant for use as the outer portion was weighed, charged into the same ziplock bag and uniformly mixed with the mixture therein. (8) Tabletting was conducted by using a 20*10 mm capsule-shaped punch. In Preparation process 3A, the tablet had a tablet weight of 1000 mg and a hardness of 154.2 N. In Preparation process 3B, the tablet had a tablet weight of 1000 mg and a hardness of 155.3 N. In Preparation process 3C, the tablet had a tablet weight of 1000 mg and a hardness of 166.4 N. The tablet thickness, friability and disintegration time were determined.

(125) TABLE-US-00010 TABLE 9 Test results of the tablet thickness, friability, and disintegration time of Plain tablets 3A to 3C No. Tablet weight Thickness Hardness Friability Disintegration time 3A 1000 mg 6.53 mm 154.2 N 0.13%  3 min 15 s 3B 1000 mg 6.53 mm 155.3 N 0.16% 10 min 58 s 3C 1000 mg 6.39 mm 166.4 N 0.23% 28 min 13 s

(126) The dissolution of the above-mentioned Plain tablets 3A to 3C was tested in four dissolution media (water, pH 1.2, pH 4.5 and pH 6.8), and the results were as shown in Table 10 and FIGS. 6 to 7.

(127) TABLE-US-00011 TABLE 10 Test results of the dissolution of Plain tablets 3A to 3C Time (minutes) Medium No. 0 5 10 15 20 30 45 60 90 120 pH 4.5 3A 0 31 61 67 70 71 72 72 74 83 3B 0 19 45 91 95 96 96 96 97 97 3C 0  8 12 16 20 29 42 56 73 98 pH 6.8 3A 0 25 52 58 57 57 57 56 56 59 3B 0 17 46 80 85 85 84 83 82 82 3C 0  7 11 13 16 23 36 50 66 82 H.sub.2O 3B 0 16 40 80 94 95 95 95 95 95 pH 1.2 3B 0 20 40 79 98 98 98 98 98 98

(128) As could be seen from the results in Table 10, Plain tablets 3A to 3C were mostly capable of reaching the plateau levels of dissolution in four media after 20 minutes. Among these, the dissolution percentage of Plain tablet 3B could reach 91% within 15 minutes in the medium at pH 4.5, reach 85% within 20 minutes and then reach the plateau level of dissolution in the medium at pH 6.8, and respectively reach the plateau level of dissolution after 20 minutes in water and the medium at pH 1.2.

Example 4: Ordinary Tablets Comprising Different Diluents (Specification: 240 Mg)

(129) In Formulation 4 of this Example, MCC PH200 was used as a diluent instead of MCC PH102 in Formulation 3B. Tabletting was conducted in accordance with Formulation 4 in Table 11, so as to obtain Plain tablet 4.

(130) TABLE-US-00012 TABLE 11 Formulation list of Plain tablet 4 Formulation No. Name of raw material and 4 (Specification: 240 mg) excipients Manufacturer Batch No. mg/tablet wt % Inner portion API Self-produced SLB-F17002 332.12.sup.a 33.21% (C-005 citrate) colloidal silica EVONIK Corporation 156021114 30.00 3.00% (SiO.sub.2) microcrystalline cellulose FMC BioPolymer PN14827536 100.00 10.00% (MCC PH200) Corporation crospovidone Ashland Group OOO1926358 80.00 8.00% (PVPP) Corporation magnesium stearate Faci Chemicals Co., MGS-R0317 10.00 1.00% Ltd. Total of inner portion 552.12 55.21% Outer portion low-substituted hydroxypropyl Shin-Etsu Chemical  6121472 50.00 5.00% cellulose Co., Ltd. (L-HPC) microcrystalline cellulose FMC BioPolymer PN14827536 387.88 38.79% (MCC PH200) Corporation magnesium stearate Faci Chemicals Co., MGS-R0317 10.00 1.00% Ltd. Total of outer portion 478.88 47.89% Total of inner and outer portion 1000.00 100.00% .sup.aEquivalent to 240 mg of C-005 in the form of free base

Preparation Process 4

(131) (1) The raw material was sieved through an 80-mesh sieve and all excipients were sieved through a 60-mesh sieve for later use. (2) The formulated amount of the API, the diluent for use as the inner portion, and the disintegrant for use as the inner portion were weighed, charged into the same ziplock bag, uniformly mixed, and then sieved by using a 60-mesh sieve for 3 times. (3) The formulated amount of the lubricant for use as the inner portion was weighed and charged into the same ziplock bag together with the sieved materials in (2), and the resulting mixture was uniformly mixed. (4) Dry granulating was carried out with a pressure of 3 MPa, a feed rate of 19 rpm, and a rolling speed of 20 rpm. (5) The resulting mixture was sieved through a 24-mesh sieve. (6) The formulated amount of the disintegrant for use as the outer portion and the diluent for use as the outer portion were weighed, both of them were charged into the same ziplock bag together with the dry granules, and the resulting mixture was uniformly mixed. (7) The formulated amount of the lubricant for use as the outer portion was weighed, charged into the same ziplock bag and uniformly mixed with the mixture therein. (8) Tabletting was conducted by using a 20*10 mm capsule-shaped punch. The tablet thickness, friability and disintegration time were determined.

(132) TABLE-US-00013 TABLE 12 Test results of the tablet thickness, friability, and disintegration time of two batches of Plain tablet 4 Tablet Disintegration Phenomenon No. weight Thickness Hardness Friability time during tabletting 4 1004 mg 6.74 mm 177.7 N 0.10% 3 min 55 s No obvious sticking 1001 mg 6.74 mm 164.3 N Results obtained by rotating same 0.53% plain tablets in a friability tester for 3 times

(133) The dissolution of the above-mentioned Plain tablet 4 was tested in four dissolution media (water, pH 1.2, pH 4.5 and pH 6.8), and the results were as shown in Table 13 and FIG. 8.

(134) TABLE-US-00014 TABLE 13 Test results of the dissolution of Plain tablet 4 Time (minutes) Medium No. 0 5 10 15 20 30 45 60 90 120 H.sub.2O 4 0 57 92 93 94 95 95 95 96 96 pH 1.2 4 0 75 96 97 97 97 97 97 97 97 pH 4.5 4 0 50 97 98 98 99 99 99 99 99 pH 6.8 4 0 56 83 84 83 83 82 82 81 82

(135) As could be seen from the results in Tables 12 and 13, as compared with Plain tablet 3B, Plain tablet 4 in which the diluent was replaced with MCC PH200 had increased fluidity of granules and faster disintegration (the disintegration time was shortened from about 11 min to about 4 min); meanwhile, the dissolution was also significantly improved and Plain tablet 4 was capable of achieving rapid and complete dissolution in four media (the plateau level of dissolution was reached after 10 min).

Example 5: Ordinary Tablets (Specification: 240 Mg)

(136) Tabletting was conducted in accordance with Formulations 5A to 5C in Table 14, so as to obtain Plain tablets 5A to 5C.

(137) TABLE-US-00015 TABLE 14 Formulation lists of Plain tablets 5A to 5C Formulation No. 5A Theoretical amount (g) Name of raw material 100 tablets/ and excipients Manufacturer Batch No. mg/tablet wt % batch Inner portion API Self-produced SLB-F17002 332.12.sup.a 33.21% 33.212 (C-005 citrate) microcrystalline FMC PN14827536 130.00 13.00% 13.000 cellulose BioPolymer (MCC PH200) Corporation crospovidone Ashland Group OOO1926358 80.00 8.00% 8.000 (PVPP) Corporation magnesium stearate Faci Chemicals MGS-R0317 10.00 1.00% 1.000 Co., Ltd. Total of inner portion 552.12 55.21% 55.212 Outer portion low-substituted Shin-Etsu 6121472 50.00 5.00% 5.000 hydroxypropyl cellulose Chemical Co., (L-HPC) Ltd. microcrystalline FMC PN14827536 387.88 38.79% 38.788 cellulose BioPolymer (MCC PH200) Corporation magnesium stearate Faci Chemicals MGS-R0317 10.00 1.00% 1.000 Co., Ltd. Total of outer portion 447.88 44.79% 44.788 Total 1000.00 100.00% 100.000 Formulation No. 5B Theoretical amount (g) Name of raw material 100 tablets/ and excipients Manufacturer Batch No. mg/tablet wt % batch Inner portion API Self-produced SLB-F17002 332.12 33.21% 33.212 (C-005 citrate) colloidal silica EVONIK 156021114 30.00 3.00% 3.000 (SiO.sub.2) Corporation microcrystalline FMC PN14827536 100.00 10.00% 10.000 cellulose BioPolymer (MCC PH200) Corporation crospovidone Ashland Group OOO1926358 80.00 8.00% 8.000 (PVPP) Corporation magnesium stearate Faci Chemicals MGS-R0317 10.00 1.00% 1.000 Co., Ltd. Total of inner portion 552.12 55.21% 55.212 Outer portion microcrystalline FMC PN14827536 437.88 43.79% 43.788 cellulose BioPolymer (MCC PH200) Corporation magnesium stearate Faci Chemicals MGS-R0317 10.00 1.00% 1.000 Co., Ltd. Total of outer portion 447.88 44.79% 44.788 Total 1000.00 100.00% 100.000 Formulation No. 5C Theoretical amount (g) Name of raw material 100 tablets/ and excipients Manufacturer Batch No. mg/tablet wt % batch Inner portion API Self-produced SLB-F17002 332.12 33.21% 33.212 (C-005 citrate) microcrystalline FMC PN14827536 130.00 13.00% 13.000 cellulose BioPolymer (MCC PH200) Corporation crospovidone Ashland Group OOO1926358 80.00 8.00% 8.000 (PVPP) Corporation magnesium stearate Faci Chemicals MGS-R0317 10.00 1.00% 1.000 Co., Ltd. Total of inner portion 552.12 55.21% 55.212 Outer portion microcrystalline FMC PN14827536 437.88 43.79% 43.788 cellulose BioPolymer (MCC PH200) Corporation magnesium stearate Faci Chemicals MGS-R0317 10.00 1.00% 1.000 Co., Ltd. Total of outer portion 447.88 44.79% 44.788 Total 1000.00 100.00% 100.000 .sup.aEquivalent to 240 mg of C-005 in the form of free base

Preparation Processes 5A to 5C

(138) (1) The raw material was sieved through an 80-mesh sieve and all excipients were sieved through a 60-mesh sieve for later use. (2) The formulated amount of the API, the disintegrant for use as the inner portion, and the diluent for use as the inner portion were weighed, charged into the same ziplock bag, uniformly mixed, and then sieved by using a 60-mesh sieve for 3 times. (3) The formulated amount of the lubricant for use as the inner portion was weighed and charged into the same ziplock bag together with the sieved materials in (2), and the resulting mixture was uniformly mixed. (4) Dry granulating was carried out. In Preparation process 5A, the pressure was 3 MPa, the feed rate was 12 rpm, and the rolling speed was 18 rpm. In Preparation process 5B, the pressure was 3 MPa, the feed rate was 22 rpm, and the rolling speed was 18 rpm. In Preparation process 5C, the pressure was 3 MPa, the feed rate was 12 rpm, and the rolling speed was 18 rpm. (5) The resulting mixture was sieved through a 24-mesh sieve. (6) The formulated amount of the disintegrant for use as the outer portion and the diluent for use as the outer portion were weighed, both of them were charged into the same ziplock bag together with the dry granules, and the resulting mixture was uniformly mixed. (7) Tabletting was conducted by using a 20*10 mm capsule-shaped punch. The tablet thickness, friability and disintegration time were determined.

(139) TABLE-US-00016 TABLE 15 Test results of the tablet thickness, friability, and disintegration time of Plain tablets 5A to 5C Tablet Disintegration Phenomenon No. weight Thickness Hardness Friability time during tabletting 5A  997 mg 6.71 mm 151.1 N 0.19% 2 min 33 s No obvious sticking  996 mg 6.71 mm 152.3 N 5B 1000 mg 6.86 mm 163.2 N 0.24% 3 min 3 s  No obvious sticking 1004 mg 6.86 mm 170.2 N 5C 1014 mg 6.74 mm 173.5 N 0.20% 4 min 10 s No obvious sticking 1010 mg 6.74 mm 163.5 N

(140) The dissolution of the above-mentioned Plain tablets 5A to 5C was tested in two media (pH 4.5 and pH 6.8), and the results were as shown in Table 16 and FIGS. 9 to 10.

(141) TABLE-US-00017 TABLE 16 Test results of the dissolution of Plain tablets 5A to 5C Time (minutes) Medium No. 0 5 10 15 20 30 45 60 90 120 pH 4.5 5A 0 80 92 92 92 93 93 93 94 95 5B 0 85 91 91 92 93 93 94 95 97 5C 0 46 93 96 97 97 98 98 99 99 pH 6.8 5A 0 79 83 84 84 84 84 84 83 84 5B 0 67 83 84 84 85 85 84 84 85 5C 0 71 86 86 87 86 87 86 85 86

(142) 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 15 and Table 16, 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 10 minutes, and the dissolution of these three plain tablets had no significant difference.

Example 6: Study on the Formulation and Preparation Process of Ordinary Tablets Comprising Different Amount of Disintegrant

(143) Tabletting was conducted in accordance with Formulations 6A to 6C in Table 17, so as to obtain Plain tablets 6A to 6C.

(144) TABLE-US-00018 TABLE 17 Formulation lists of Plain tablets 6A to 6C Formulation No. Name of raw material and 6A (PVPP: 2%) excipients Manufacturer Batch No. mg/tablet wt % Inner portion API Self-produced SLB-F17002 332.12.sup.a 33.21% (C-005 citrate) microcrystalline cellulose FMC BioPolymer PN14827536 130.00 13.00% (MCC PH200) Corporation crospovidone Ashland Group OOO2139987 20.00 2.00% (PVPP) Corporation magnesium stearate Mallinckrodt 1611000023 10.00 1.00% Pharmaceuticals Total of inner portion 492.12 49.21% Outer portion microcrystalline cellulose FMC BioPolymer PN14827536 497.88 49.79% (MCC PH200) Corporation magnesium stearate Mallinckrodt 1611000023 10.00 1.00% Pharmaceuticals Total of outer portion 507.88 50.79% Total 1000.00 100.00% Formulation No. Name of raw material and 6B (PVPP: 5%) excipients Manufacturer Batch No. mg/tablet wt % Inner portion API Self-produced SLB-F17002 332.12 33.21% (C-005 citrate) microcrystalline cellulose FMC BioPolymer PN14827536 130.00 13.00% (MCC PH200) Corporation crospovidone Ashland Group OOO2139987 50.00 5.00% (PVPP) Corporation magnesium stearate Mallinckrodt 1611000023 10.00 1.00% Pharmaceuticals Total of inner portion 522.12 52.21% Outer portion microcrystalline cellulose FMC BioPolymer PN14827536 467.88 46.79% (MCC PH200) Corporation magnesium stearate Mallinckrodt 1611000023 10.00 1.00% Pharmaceuticals Total of outer portion 477.88 47.79% Total 1000.00 100.00% Formulation No. Name of raw material and 6C (PVPP: 10%) excipients Manufacturer Batch No. mg/tablet wt % Inner portion API Self-produced SLB-F17002 332.12 33.21% (C-005 citrate) microcrystalline cellulose FMC BioPolymer PN14827536 130.00 13.00% (MCC PH200) Corporation crospovidone Ashland Group OOO2139987 100.00 10.00% (PVPP) Corporation magnesium stearate Mallinckrodt 1611000023 10.00 1.00% Pharmaceuticals Total of inner portion 572.12 57.21% Outer portion microcrystalline cellulose FMC BioPolymer PN14827536 417.88 41.79% (MCC PH200) Corporation magnesium stearate Mallinckrodt 1611000023 10.00 1.00% Pharmaceuticals Total of outer portion 427.88 42.79% Total 1000.00 100.00% .sup.aEquivalent to 240 mg of C-005 in the form of free base

Preparation Processes 6A to 6C

(145) (1) The raw material was sieved through an 80-mesh sieve and all excipients were sieved through a 60-mesh sieve for later use. (2) The formulated amount of the API, the disintegrant, and the diluent for use as the inner portion were weighed, charged into the same ziplock bag, uniformly mixed, and then sieved by using a 60-mesh sieve for 3 times. (3) The formulated amount of the lubricant for use as the inner portion was weighed and charged into the same ziplock bag together with the sieved materials in (2), and the resulting mixture was uniformly mixed. (4) Dry granulating was carried out. In Preparation process 6A, the pressure was 3 MPa, the feed rate was 13 rpm, and the rolling speed was 18 rpm. In Preparation process 6B, the pressure was 3 MPa, the feed rate was 13 rpm, and the rolling speed was 18 rpm. In Preparation process 6C, the pressure was 3 MPa, the feed rate was 12 rpm, and the rolling speed was 18 rpm. (5) The resulting mixture was sieved through a 24-mesh sieve. (6) The formulated amount of the diluent for use as the outer portion was weighed and charged into the same ziplock bag together with the dry granules, and the resulting mixture was uniformly mixed. (7) The formulated amount of the lubricant for use as the outer portion was weighed, charged into the same ziplock bag and uniformly mixed with the mixture therein. (8) Tabletting was conducted by using Gylongli ZP-10A tablet machine and a 20*10 mm capsule-shaped punch. The tablet thickness, friability and disintegration time were determined.

(146) TABLE-US-00019 TABLE 18 Test results of the tablet thickness, friability, and disintegration time of Plain tablets 6A to 6C Batch Tablet Disintegration Phenomenon No. weight Thickness Hardness Friability time during tabletting 6A 1004 mg 6.92 mm 159.9 N 0.17% 3 min 53 s No obvious sticking 6B 1001 mg 6.75 mm 157.1 N 0.24% 2 min 55 s No obvious sticking 6C 1004 mg 6.74 mm 166.6 N 0.17% 2 min 40 s No obvious sticking

(147) As could be seen from the results in Table 18, 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 5% or more, the amplitude of variation of the disintegration time of the plain tablet would be gradually decreased.

(148) The dissolution of the above-mentioned Plain tablets 6A to 6C was tested in two media (pH 4.5 and pH 6.8), and the results were as shown in Table 19 and FIGS. 11 to 12.

(149) TABLE-US-00020 TABLE 19 Test results of the dissolution of Plain tablets 6A to 6C (Plain tablet SC was tested together) Time (minutes) Medium No. 0 5 10 15 20 30 45 60 90 120 pH 4.5 6A (PVPP: 2%) 0 51 74 91 97 98 98 99 99 100 6B (PVPP: 5%) 0 61 89 91 92 93 94 95 97  99 5C (PVPP: 8%) 0 46 93 96 97 97 98 98 99  99  6C (PVPP: 10%) 0 87 95 95 97 96 97 97 97  98 pH 6.8 6A (PVPP: 2%) 0 66 82 83 83 83 83 83 83  84 6B (PVPP: 5%) 0 74 82 83 83 83 83 82 82  83 5C (PVPP: 8%) 0 71 86 86 87 86 87 86 85  86  6C (PVPP: 10%) 0 78 86 87 87 87 86 86 86  86

(150) As could be seen from the results in Table 19, in the medium at pH 4.5, when the amount of disintegrant reached 8% or more, the plain tablet could reach the plateau level of dissolution after 10 minutes and achieve a dissolution percentage of approximately 95%; while in the medium at pH 6.8, when the amount of disintegrant reached 8% or more, the plain tablet could reach the plateau level of dissolution after 10 minutes and achieve a dissolution percentage of approximately 85%.

Example 7: Ordinary Tablets in which the Lubricant was Added in Different Manners

(151) Tabletting was conducted in accordance with Formulation 7 in Table 20, so as to obtain Plain tablet 7.

(152) TABLE-US-00021 TABLE 20 Formulation list of Plain tablet 7 Formulation No. Name of raw material and 7 (Inner lubricant: 2%, Outer lubricant: 0.5%) excipients Manufacturer Batch No. mg/tablet wt % Inner portion API Self-produced SLB-F17002 332.12.sup.a 33.21% (C-005 citrate) microcrystalline cellulose FMC BioPolymer PN16829974 130.00 13.00% (MCC PH200) Corporation crospovidone Ashland Group OOO2139987 80.00 8.00% (PVPP) Corporation magnesium stearate Mallinckrodt 1611000023 20.00 2.00% Pharmaceuticals Total of inner portion 562.12 56.21% Outer portion microcrystalline cellulose FMC BioPolymer PN16829974 432.88 43.29% (MCC PH200) Corporation magnesium stearate Mallinckrodt 1611000023 5.00 0.50% Pharmaceuticals Total of outer portion 437.88 43.79% Total of inner and outer 1000.00 100.00% portion .sup.aEquivalent to 240 mg of C-005 in the form of free base

Preparation Process 7

(153) (1) The raw material was sieved through an 80-mesh sieve and all excipients were sieved through a 60-mesh sieve for later use. (2) The formulated amount of the API, the disintegrant, and the diluent for use as the inner portion were weighed, charged into the same ziplock bag and uniformly mixed. (3) The formulated amount of the lubricant for use as the inner portion was weighed and charged into the same ziplock bag together with the sieved materials in (2), and the resulting mixture was uniformly mixed. (4) Dry granulating was carried out with a pressure of 3 MPa, a feed rate of 13 rpm, and a rolling speed of 18 rpm. (5) The resulting mixture was sieved through a 24-mesh sieve. (6) The formulated amount of the diluent for use as the outer portion was weighed and charged into the same ziplock bag together with the dry granules, and the resulting mixture was uniformly mixed. (7) The formulated amount of the lubricant for use as the outer portion was weighed, charged into the same ziplock bag and uniformly mixed with the mixture therein. (8) Tabletting was conducted by using Gylongli ZP-10A tablet machine and a 20*10 mm capsule-shaped punch. The tablet thickness, friability, and disintegration time were determined.

(154) TABLE-US-00022 TABLE 21 Test results of the tablet thickness, friability, and disintegration time of Plain tablet 7 Tablet Disintegration Phenomenon No. weight Thickness Hardness Friability time during tabletting 7 1002 mg 6.5 mm 169.6 N 0.09% 6 min 25 s No obvious 1002 mg 6.5 mm 169.9 N sticking

(155) As could be seen from the results in Table 21, 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 7 was increased by 2 minutes or so. It could be seen that a formulation in which the amount of lubricant for use as the inner portion was four times of that for use as the outer portion would prolong the disintegration process.

(156) The dissolution of the above-mentioned Plain tablet 7 was tested in four dissolution media (water, pH 1.2, pH 4.5 and pH 6.8), and the results were as shown in Table 22 and FIG. 13.

(157) TABLE-US-00023 TABLE 22 Test results of the dissolution of Plain tablet 7 Time (minutes) Medium No. 0 5 10 15 20 30 45 60 90 120 H.sub.2O 7 0 28 63 98 100 100 100 100 100 100 pH 1.2 7 0 23 58 92  95  96  96  97  96  96 pH 4.5 7 0 28 69 95  96  97  97  97  97  97 pH 6.8 7 0 27 73 89  86  85  86  85  85  85

(158) As could be seen from the results in Table 22, 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 7 could reach the plateau level of dissolution at about 15 minutes in the four media and achieve a dissolution percentage of 85% or more, and the dissolution effect was significantly superior to that of Plain tablet 5C.

Example 8: Coated Tablets

(159) Coated tablets 8A to 8C were prepared and obtained in accordance with Formulations 8A to 8C in Table 23.

(160) TABLE-US-00024 TABLE 23 Formulation lists of Coated tablets 8A to 8C Formulation No. Name of raw material and 8A (900 tablets in theory) excipients Manufacturer Batch No. mg/tablet wt % Inner portion API Self-produced SLB-F180102 332.12.sup.a 33.21% (C-005 citrate) microcrystalline cellulose FMC BioPolymer PN16829974 130.00 13.00% (MCC PH200) Corporation crospovidone Ashland Group OOO2139987 80.00 8.00% (PVPP) Corporation magnesium stearate Mallinckrodt 1611000023 20.00 2.00% Pharmaceuticals Total of inner portion 562.12 56.21% Outer portion microcrystalline cellulose FMC BioPolymer PN16829974 432.88 43.29% (MCC PH200) Corporation magnesium stearate Mallinckrodt 1611000023 5.00 0.50% Pharmaceuticals Total of outer portion 437.88 43.79% Total 1000.00 100.00% Formulation No. Name of raw material and 8B (900 tablets in theory) excipients Manufacturer Batch No. mg/tablet wt % Inner portion API Self-produced SLB-F180103 332.12 33.21% (C-005 citrate) microcrystalline cellulose FMC BioPolymer PN16829974 130.00 13.00% (MCC PH200) Corporation crospovidone Ashland Group OOO2139987 80.00 8.00% (PVPP) Corporation magnesium stearate Mallinckrodt 1611000023 20.00 2.00% Pharmaceuticals Total of inner portion 562.12 56.21% Outer portion microcrystalline cellulose FMC BioPolymer PN16829974 432.88 43.29% (MCC PH200) Corporation magnesium stearate Mallinckrodt 1611000023 5.00 0.50% Pharmaceuticals Total of outer portion 437.88 43.79% Total 1000.00 100.00% Formulation No. Name of raw material and 6C (1600 tablets in theory) excipients Manufacturer Batch No. mg/tablet wt % Inner portion API Self-produced SLB-F180102 83.03 33.21% (C-005 citrate) microcrystalline cellulose FMC BioPolymer PN16829974 32.50 13.00% (MCC PH200) Corporation crospovidone Ashland Group OOO2139987 20.00 8.00% (PVPP) Corporation magnesium stearate Mallinckrodt 1611000023 5.00 2.00% Pharmaceuticals Total of inner portion 140.53 56.21% Outer portion microcrystalline cellulose FMC BioPolymer PN16829974 108.22 43.29% (MCC PH200) Corporation magnesium stearate Mallinckrodt 1611000023 1.25 0.50% Pharmaceuticals Total of outer portion 109.47 43.79% Total 250.00 100.00% .sup.aEquivalent to 240 mg of C-005 in the form of free base

Preparation Processes 8A to 8C

(161) (1) The raw material was sieved through an 80-mesh sieve and all excipients were sieved through a 60-mesh sieve for later use. (2) 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 15 rpm, and the resulting mixture was mixed for 10 min. (3) The formulated amount of the lubricant for use as the inner portion was weighed and charged into a mixer with a rotating speed of 15 rpm, and the resulting mixture was mixed for 5 min. (4) Dry granulating was carried out with a pressure of 3 MPa, a feed rate of 9 rpm, and a rolling speed of 22 rpm. A 1.0 mm sieve was used for sorting, and the speed of sorting was 50 rpm. (5) 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 15 rpm, and the resulting mixture was mixed for 10 min. (6) The formulated amount of the lubricant for use as the outer portion was weighed and charged into a mixer with a rotating speed of 15 rpm, and the resulting mixture was mixed for 5 min. (7) Tabletting was conducted by using Gylongli ZP-10A tablet machine. A 20*10 mm capsule-shaped punch was used for tabletting in Preparation processes 8A and 8B and a 9 mm 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. (8) Plain tablets 8A to 8C were coated with Opadry 85G640044 series coating material (Colorcon Corporation, Batch No.: THL46201, solid content: 15%), the target coating weight gain was 3%, and Coated tablets 8A to 8C were obtained. The dissolution of Coated tablets 8A to 8C was determined.

(162) TABLE-US-00025 TABLE 24 Test results of the friability and the disintegration time of Plain tablets 8A to 8C No. Friability Disintegration time Phenomenon during tabletting 8A 0.21% 2 min 2 s No obvious sticking 8B 0.07% 3 min No obvious sticking 8C 0.00% 1 min 33 s No obvious sticking

(163) The dissolution of the above-mentioned Coated tablets 8A to 8C was tested in two media (pH 4.5 and pH 6.8), and the results were as shown in Table 25 and FIGS. 14 to 15.

(164) TABLE-US-00026 TABLE 25 Test results of the dissolution of Coated tablets 8A to 8C Time (minutes) Medium No. 0 5 10 15 20 30 45 60 90 120 pH 4.5 8A 0 51 94 96  97  98  98  98  99 100 8B 0 44 96 99  99 100 100 101 101 102 8C 0 68 98 99 100 101 101 102 103 104 pH 6.8 8A 0 63 86 86  87  87  87  86  86  88 8B 0 37 83 87  86  88  87  88  87  88 8C 0 41 81 86  87  84  85  87  87  93

(165) As could be seen from the results in Table 25, Coated tablets 8A to 8C could reach the plateau level of dissolution at about 10 to 15 minutes in both media, at least achieve a dissolution percentage of 85% and exhibit good dissolution behavior.

Comparative Example: A Blend in Capsule

(166) In the previous research process, C-005 citrate and microcrystalline cellulose were once blended at a weight ratio of 1:2 and filled into a non-transparent white HPMC capsule shell (size 0#) to prepare a blend in capsule. The filling amount was approximately 60 mg of C-005 in the form of free base in each capsule, and the formulation list was as shown in Table 26.

(167) TABLE-US-00027 TABLE 26 Formulation list of the blend in capsule Formulation No. 1A (Specification: 60 mg) Theoretical amount (g) Name of raw material 100 tablets/ and excipients Manufacturer Batch No. mg/capsule wt % batch API Self-produced SLB-F170829 83.03.sup.a 33.33% 8.30 (C-005 citrate) microcrystalline JRS Pharma 5610264526 166.06 66.67% 16.61 cellulose (MCC PH102) Total 249.09 100% 24.91 .sup.aEquivalent to 60 mg of C-005 in the form of free base

(168) The dissolution of the above-mentioned blend in capsule was tested in two media (pH 4.5 and pH 6.8), and the results were as shown in Table 27 and FIG. 16.

(169) TABLE-US-00028 TABLE 27 Test results of the dissolution of the blend in capsule Time (minutes) Medium No. 0 5 10 15 20 30 45 60 90 120 pH 4.5 10 0.0 8 14 20 26 42 75 93 93 94 pH 6.8 10 0   7 12 16 23 37 64 75 80 85

(170) As could be seen from the results in Table 27, in the medium at pH 6.8, only a release percentage of 37% was achieved after 30 minutes, 75% was achieved after 60 minutes, and 85% was basically achieved after 120 minutes. In the medium at pH 4.5, a release percentage of 75% was achieved after 45 minutes, and 93% was basically achieved after 60 minutes. As compared with the tablets in the aforementioned Examples, the dissolution of the blend in capsule was not satisfactory, and it was difficult to reduce or avoid risks caused by the inter-dose and/or inter-patient variability of absorption. By contrast, the pharmaceutical tablet of the present disclosure was exactly capable of solving the above-mentioned problems and was suitable for the follow-up drug development.