PHARMACEUTICAL COMPOSITION CONTAINING NITROXOLINE, NITROXOLINE TABLET, PREPARATION METHOD THEREFOR AND USE THEREOF

Abstract

Disclosed are a pharmaceutical composition containing nitroxoline, a nitroxoline tablet, a preparation method therefor, and a use thereof. The pharmaceutical composition comprises an active pharmaceutical ingredient and a pharmaceutically acceptable carrier, the active pharmaceutical ingredient being nitroxoline or a pharmaceutically acceptable salt thereof, and the active pharmaceutical ingredient having a particle size D.sub.90 of 10-100 μm. The pharmaceutical composition containing nitroxoline can be made into a nitroxoline tablet having an appropriate dissolution rate.

Claims

1. A pharmaceutical composition, wherein the pharmaceutical composition comprises an active pharmaceutical ingredient and a pharmaceutically acceptable carrier, the active pharmaceutical ingredient is nitroxoline or a pharmaceutically acceptable salt thereof, characterized in that the particle size D.sub.90 of the active pharmaceutical ingredient is 10 to 100μm.

2. The pharmaceutical composition according to claim 1, characterized in that the particle size D.sub.90 of the active pharmaceutical ingredient is 10 to 70 and preferably 40 to 70 and/or, the particle size D50 of the active pharmaceutical ingredient is 4 to 50 preferably 4 to 40 μm or 4 to 35 and more preferably 10 to 40.sub.Ilm; and/or, the particle size D.sub.90 of the active pharmaceutical ingredient is 0 to 10 and is not 0, preferably 0.1 to 6 μm or 2 to 10 and more preferably 2 to 6 μm; and/or, the active pharmaceutical ingredient is present in an amount of 20 to 65 parts by weight or 20 to 60 parts by weight, preferably 25 to 60 parts by weight, more preferably 40 to 61 parts by weight, and further more preferably 56 to 61 parts by weight per 100 parts by weight of the pharmaceutical composition.

3. The pharmaceutical composition according to claim 1, characterized in that the carrier comprises a filler; the filler is preferably one or more of starch, pregelatinized starch, partially pregelatinized starch, lactose, sucrose, mannitol, sorbitol, hydrous calcium phosphate, anhydrous calcium phosphate and microcrystalline cellulose, and more preferably one or more of starch, lactose and microcrystalline cellulose; the filler is preferably present in an amount of 30 to 300 parts by weight, more preferably 50 to 100 parts by weight, further more preferably 30 to 90 parts by weight, and still further more preferably 30 to 75 parts by weight per 100 parts by weight of the active pharmaceutical ingredient; and/or, the carrier comprises a binder; the binder is preferably one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone and starch, more preferably one or more of polyvinylpyrrolidone, hydroxypropyl methylcellulose and starch, and further more preferably polyvinylpyrrolidone and/or starch; the binder is preferably present in an amount of 0 to 100 parts by weight, and not 0, more preferably 2 to 50 parts by weight, and further more preferably 30 to 50 parts by weight per 100 parts by weight of the active pharmaceutical ingredient; and/or, the carrier comprises a disintegrant; the disintegrant is preferably one or more of low-substituted hydroxypropyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, croscarmellose sodium and crospovidone, more preferably low-substituted hydroxypropyl cellulose and/or crospovidone, and further more preferably low-substituted hydroxypropyl cellulose; the disintegrant is preferably present in an amount of 0 to 100 parts by weight, and not 0, more preferably 1 to 25 parts by weight or 5 to 25 parts by weight, further more preferably 1 to 10 parts by weight, 2 to 10 parts by weight or 5 to 10 parts by weight, and still further more preferably 5 to 6 parts by weight per 100 parts by weight of the active pharmaceutical ingredient; and/or, the carrier comprises a lubricant; the lubricant is preferably one or more of magnesium stearate, sodium stearyl fumarate and sodium dodecyl sulfate, and more preferably sodium stearyl fumarate and/or sodium dodecyl sulfate; the lubricant is preferably present in an amount of 0.25 to 20 parts by weight, more preferably 0.5 to 5 parts by weight, and further more preferably 2.5 to 4 parts by weight per 100 parts by weight of the active pharmaceutical ingredient; and/or, the carrier comprises a glidant; the glidant is preferably one or more of silica, talc and sodium dodecyl sulfate, more preferably silica and/or sodium dodecyl sulfate, and further more preferably sodium dodecyl sulfate; the glidant is preferably present in an amount of 0 to 20 parts by weight, and not 0, more preferably 0.5 to 10 parts by weight, and further more preferably 4 to 10 parts by weight per 100 parts by weight of the active pharmaceutical ingredient.

4. The pharmaceutical composition according to claim 1, characterized in that the carrier comprises a filler and a binder, the types of the filler and the binder are as defined in claim 3, and the filler and the binder are present in a total amount of 30 to 300 parts by weight, preferably 32 to 280 parts by weight, more preferably 32 to 140 parts by weight, and further more preferably 56.5 to 70 parts by weight per 100 parts by weight of the active pharmaceutical ingredient; and/or, the carrier comprises a lubricant and a glidant, the types of the lubricant and the glidant are as defined in claim 3, and the lubricant and the glidant are present in a total amount of 1 to 10 parts by weight, preferably 1 to 15 parts by weight, more preferably 2.5 to 10 parts by weight, and further more preferably 2.5 to 4 parts by weight per 100 parts by weight of the active pharmaceutical ingredient.

5. The pharmaceutical composition according to claim 1, characterized in that the pharmaceutical composition also comprises a coating agent; the coating agent is preferably hydroxypropyl methylcellulose and/or polyvinyl alcohol, and more preferably hydroxypropyl methylcellulose; the coating agent is preferably present in the pharmaceutical composition in an amount of 3% to 15% by mass, and more preferably 9% to 13% by mass relative to the mass of the uncoated pharmaceutical composition.

6. The pharmaceutical composition according to claim 1, characterized in that the pharmaceutical composition comprises an active pharmaceutical ingredient and a pharmaceutically acceptable carrier, the active pharmaceutical ingredient is nitroxoline or a pharmaceutically acceptable salt thereof; the particle size D.sub.90 of the active pharmaceutical ingredient is 10 to 100 the particle size D50 of the active pharmaceutical ingredient is 4 to 35 the particle size D.sub.90 of the active pharmaceutical ingredient is 0.1 to 6 μm; the active pharmaceutical ingredient is present in an amount of 56 to 61 parts by weight per 100 parts by weight of the pharmaceutical composition; the carrier comprises a filler and a binder, the filler is one or more of starch, lactose and microcrystalline cellulose, the binder is polyvinylpyrrolidone and/or starch; the filler and the binder are present in a total amount of 56.5 to 70 parts by weight per 100 parts by weight of the active pharmaceutical ingredient; the carrier comprises a disintegrant, the disintegrant is low-substituted hydroxypropyl cellulose; the disintegrant is present in an amount of 5 to 6 parts by weight per 100 parts by weight of the active pharmaceutical ingredient; the carrier comprises adjuvant I, the adjuvant I is sodium stearyl fumarate and/or sodium dodecyl sulfate; the adjuvant I is present in an amount of 2.5 to 4 parts by weight per 100 parts by weight of the active pharmaceutical ingredient; the pharmaceutical composition also comprises a coating agent, the coating agent is hydroxypropyl methylcellulose, the coating agent is present in the pharmaceutical composition in an amount of 9% to 13% by mass relative to the mass of the uncoated pharmaceutical composition.

7. A nitroxoline tablet, characterized in that the nitroxoline tablet is prepared from the pharmaceutical composition according to claim 1.

8. A method for preparing a nitroxoline tablet, characterized in that the pharmaceutical composition in the method is the pharmaceutical composition according to claim 1, the pharmaceutical composition comprises adjuvant II, the adjuvant II is a lubricant and/or a glidant; the method comprises the following steps of: subjecting the components in the pharmaceutical composition except adjuvant II to wet granulation, wet milling, drying and dry milling, adding adjuvant II, subjecting the resulting mixture to total mixing, and tableting to obtain the nitroxoline tablet; when the pharmaceutical composition comprises a coating agent, coating is performed after tableting.

9. Use of the pharmaceutical composition according to claim 1 in the preparation of a medicament for treating cancer; the cancer is preferably bladder cancer.

10. A method for treating cancer, wherein the method comprises the following step of: administering to a subject a therapeutically effective amount of the pharmaceutical composition according to claim 1.

11. A nitroxoline solid tablet composition, characterized in that it comprises an active pharmaceutical ingredient uniformly dispersed therein and a pharmaceutically acceptable carrier, the active pharmaceutical ingredient is nitroxoline or a pharmaceutically acceptable salt thereof, the particle size D.sub.90 of the active pharmaceutical ingredient is 10 to 100 μm, preferably 10 to 70 μm, and more preferably 40 to 70 μm.

12. The nitroxoline solid tablet composition according to claim 11, characterized in that the particle size D50 of the active pharmaceutical ingredient is 4 to 50 μm, preferably 4 to 40 μm, and more preferably 10 to 40 μm; and/or, the particle size D.sub.90 of the active pharmaceutical ingredient is 0 to 10 μm, and is not 0, preferably 2 to 10 μm, and more preferably 2 to 6 μm; and/or, the active pharmaceutical ingredient is present in an amount of 20 to 60 parts by weight, and preferably 25 to 60 parts by weight per 100 parts by weight of the pharmaceutical composition.

13. The nitroxoline solid tablet composition according to claim 11, characterized in that the pharmaceutically acceptable carrier is one or more of filler, disintegrant, binder, glidant, lubricant, colorant, pH adjuster, surfactant, stabilizer and fragrance; and preferably filler, disintegrant, binder, glidant and lubricant.

14. The nitroxoline solid tablet composition according to claim 13, characterized in that the filler is one or more of starch, pregelatinized starch, partially pregelatinized starch, lactose, sucrose, mannitol, sorbitol, hydrous calcium phosphate, anhydrous calcium phosphate and microcrystalline cellulose; preferably, the filler is present in an amount of 30 to 300 parts by weight, preferably 50 to 100 parts by weight, more preferably 30 to 90 parts by weight, and further more preferably 30 to 75 parts by weight per 100 parts by weight of the active pharmaceutical ingredient; or, the disintegrant is one or more of low-substituted hydroxypropyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, croscarmellose sodium and crospovidone; preferably, the disintegrant is present in an amount of 0 to 100 parts by weight, and not 0, preferably 5 to 25 parts by weight, and more preferably 5 to 10 parts by weight per 100 parts by weight of the active pharmaceutical ingredient; or, the binder is one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone and starch; preferably, the binder is present in an amount of 0 to 100 parts by weight, and not 0, preferably 2 to 50 parts by weight, and more preferably 30 to 50 parts by weight per 100 parts by weight of the active pharmaceutical ingredient; or, the lubricant is one or more of magnesium stearate, sodium stearyl fumarate and sodium dodecyl sulfate; preferably, the lubricant is present in an amount of 0.25 to 20 parts by weight, preferably 1 to 5 parts by weight, and more preferably 2.5 to 4 parts by weight per 100 parts by weight of the active pharmaceutical ingredient; or, the glidant is one or more of silica, talc and sodium dodecyl sulfate; preferably, the glidant is present in an amount of 0 to 20 parts by weight, and not 0, preferably 0.5 to 10 parts by weight, and more preferably 4 to 10 parts by weight per 100 parts by weight of the active pharmaceutical ingredient.

15. The nitroxoline solid tablet composition according to claim 11, characterized in that the nitroxoline solid tablet composition further comprising a film coating material; the film coating material is preferably hydroxypropyl methylcellulose and/or polyvinyl alcohol; the weight gain of the film coating material is preferably 3% to 15% per 100 parts by weight of the active pharmaceutical ingredient.

16. A nitroxoline tablet, characterized in that it comprises: TABLE-US-00015 nitroxoline 100 parts by weight, filler 30 to 300 parts by weight, preferably 50 to 100 parts by weight, disintegrant 0 to 100 parts by weight, preferably 5 to 25 or 5 to 10 parts by weight, binder 0 to 100 parts by weight, preferably 5 to 25 or 2 to 50 parts by weight, lubricant 0.25 to 20 parts by weight, preferably 2.5 to 4 or 0.5 to 5 parts by weight, glidant 0 to 20 parts by weight, preferably 4 to 10 or 0.5 to 10 parts by weight, and optional film coating powder 3% to 15% weight gain, and the particle size D.sub.90 of nitroxoline is 10 to 100 μm, preferably 10 to 70 μm, and more preferably 40 to 70 μm; preferably, the types of the filler, disintegrant, binder, lubricant and glidant are as defined in claim 14.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0078] The present invention is further described below by the examples, but the present invention is not limited to the scope of the examples. The experimental methods without specific conditions in the following examples were carried out according to conventional methods and conditions, or according to the product description. Known reagents, solvents and materials in the examples can be synthesized using or according to methods known in the art, or are commercially available.

[0079] I. Experimental reagents:

[0080] Nitroxoline: synthesized from the starting material 8-hydroxyquinoline through nitrosation and oxidation in two steps by reference to literatures “Chemistry of Heterocyclic Compounds (New York, N.Y., United States), 41(8), 1027-1030; 2005” and “International Journal of ChemTech Research, 2(1), 209-213; 2010”;

[0081] Nitroxoline lysine salt: prepared according to the method provided in the patent document (CN105228984A);

[0082] Starch: Liaoning Dongyuan Pharmaceutical Co., Ltd. or Roquette, France;

[0083] Pregelatinized starch: Shanghai Colorcon or Asahi Kasei, Japan;

[0084] Microcrystalline cellulose: Dupont, USA or Mingtai Chemical Co., Ltd., Taiwan, China;

[0085] Hydroxypropyl methylcellulose: Dow, USA or Shin-Etsu, Japan;

[0086] Polyvinylpyrrolidone: BASF, Germany or ISP, USA;

[0087] Lactose: Foremost Farms or Kerry, USA;

[0088] Hydroxypropyl cellulose: Huzhou Zhanwang Pharmaceutical Co., Ltd. or Shin-Etsu, Japan;

[0089] Sodium stearyl fumarate: Jiangxi Alpha Hi-tech Pharmaceutical CO., Ltd. or Rettenmaier, Germany;

[0090] Low-substituted hydroxypropyl cellulose: Huzhou Zhanwang Pharmaceutical Co., Ltd. or Shin-Etsu, Japan;

[0091] Sodium stearyl fumarate: Jiangxi Alpha Hi-tech Pharmaceutical CO., Ltd. or Rettenmaier, Germany;

[0092] Sodium dodecyl sulfate: Hunan Jiudian Pharmaceutical Co., Ltd. or BASF, Germany;

[0093] Silica: Huzhou Zhanwang Pharmaceutical Co., Ltd. or Evonik, Germany;

[0094] Magnesium stearate: Huzhou Zhanwang Pharmaceutical Co., Ltd. or Peter Greven, Germany;

[0095] Crospovidone: Chongqing Star-Tech & JRS Specialty Products Co., Ltd. or ISP, USA.

[0096] II. Experimental Instruments:

[0097] Mechanical mill: SF-130, Taizhou Tiantai Pharmacy Machinery Factory;

[0098] Jet mill: Mini-AJM, Shenzhen Xinyite Technology Co., Ltd.;

[0099] Malvern laser particle size analyzer: MS2000, Malvern;

[0100] Tableting machine: Shanghai Tianfan Machinery Factory, TDP-6;

[0101] Coating machine: BY-300B water chestnut type, Taizhou Jintai Pharmaceutical Machinery Factory;

[0102] High shear wet granulator: G10, Shenzhen Xinyite Technology Co., Ltd.;

[0103] Fluidized bed: WBF-3G, Chongqing Enger Granulating & Coating Technology Co., Ltd.;

[0104] Oven: DHG-9240A, Shanghai Bluepard Instruments Co., Ltd.

[0105] III. Processing Method of Raw Materials

[0106] The initial particle size D.sub.90 of the raw material nitroxoline or nitroxoline lysine salt was more than 100 μm. The raw material was pulverized with the mechanical mill to obtain the raw material having the particle size I, II, III or V in the following Table 1. The raw material was pulverized with the jet mill to obtain the raw material having the particle size IV in the following Table 1.

[0107] IV. Determination Method for Particle Size

[0108] Determination was carried out on the Malvern laser particle size analyzer MS2000 by wet method according to the operation requirements of the instrument, the dispersant was an aqueous Tween 80 solution, and the mass fraction of Tween 80 in the aqueous solution was 0.5%. The results are shown in Table 1 below.

TABLE-US-00002 TABLE 1 Particle size of each raw material batch Particle size Particle size parameter Raw material batch D.sub.10 (μm) D.sub.50 (μm) D.sub.90 (μm) I (Nitroxoline) 5.66 33.60 99.31 II (Nitroxoline) 3.99 14.95 70.58 III (Nitroxoline) 3.44 11.02 42.55 IV (Nitroxoline) 0.12 4.58 12.61 V (Nitroxoline lysine salt) 3.67 10.88 43.29

[0109] Example 1 Preparation Example I of Nitroxoline Tablets

[0110] The materials were weighed according to the following proportions:

TABLE-US-00003 Nitroxoline raw material (batch I) 100 parts by weight Starch 32 parts by weight Lactose 30 parts by weight Polyvinylpyrrolidone (for pulping) 8 parts by weight Low substituted hydroxypropyl cellulose 5 parts by weight Sodium stearyl fumarate 2.5 parts by weight

[0111] Specifically, nitroxoline raw material (batch I, 200 g), starch (64 g), lactose (60 g), polyvinylpyrrolidone (16 g, formulated into a solution by adding 64 g of water) and low substituted hydroxypropyl cellulose (10 g) were weighed respectively, and added into the high shear wet granulator for granulation. The resulting soft material was subjected to wet milling, and dried with the fluidized bed (the moisture was controlled to 2-5%).

[0112] The dried granules were subjected to dry milling, followed by the addition of sodium stearyl fumarate (5 g), and mixed for 10 min to obtain the total mixed granules. The total mixed granules were tableted by the tableting machine (φ6.5 mm). The resulting tablets were coated by the coating machine with hydroxypropyl methylcellulose as a film coating powder (64 g, formulated into a solution by adding 336 g of water), and the weight gain was 13%. The coated nitroxoline tablets were thus prepared.

[0113] Example 2 Preparation example II of nitroxoline tablets The materials were weighed according to the following proportions:

TABLE-US-00004 Nitroxoline raw material (batch II) 100 parts by weight Starch 30 parts by weight Lactose 25 parts by weight Starch (forpulping) 2.5 parts by weight Low substituted hydroxypropyl cellulose 5 parts by weight Sodium dodecyl sulfate 4 parts by weight

[0114] Specifically, nitroxoline raw material (batch II, 200 g), starch (60 g), lactose (50 g), starch (5 g, formulated into 5% starch pulp by adding 95 g of water) and low substituted hydroxypropyl cellulose (10 g) were weighed respectively, and added into the high shear wet granulator for granulation. The resulting soft material was subjected to wet milling, and dried with the oven (the moisture was controlled to 2-5%). The dried granules were subjected to dry milling, followed by the addition of s odium dodecyl sulfate (8 g), and mixed for 10 min to obtain the total mixed granules. The total mixed granules were tableted by the tableting machine (φ6.5 mm). The resulting tablets were coated by the coating machine with hydroxypropyl methylcellulose as a film coating powder (64 g, formulated into a solution by adding 336 g of water), and the weight gain was 11%. The coated nitroxoline tablets were thus prepared.

[0115] Example 3 Preparation Example III of Nitroxoline Tablets

[0116] The materials were weighed according to the following proportions:

TABLE-US-00005 Nitroxoline raw material (batch III) 100 parts by weight Starch 30 parts by weight Lactose 25 parts by weight Starch (for pulping) 2 parts by weight Low substituted hydroxypropyl cellulose 5 parts by weight Sodium dodecyl sulfate 4 parts by weight

[0117] Specifically, nitroxoline raw material (batch III, 200 g), starch (60 g), lactose (50 g), starch (4 g, formulated into 5% starch pulp by adding 76 g of water) and low substituted hydroxypropyl cellulose (10 g) were weighed respectively, and added into the high shear wet granulator for granulation. The resulting soft material was subjected to wet milling, and dried with the fluidized bed or oven (the moisture was controlled to 2-5%). The dried granules were subjected to dry milling, followed by the addition of s odium dodecyl sulfate (8 g), and mixed for 10 min to obtain the total mixed granules. The total mixed granules were tableted by the tableting machine (φ6.5 mm). The resulting tablets were coated by the coating machine with hydroxypropyl methylcellulose as a film coating powder (64 g, formulated into a solution by adding 336 g of water), and the weight gain was 9%. The coated nitroxoline tablets were thus prepared.

[0118] Example 4 Preparation Example IV of Nitroxoline Tablets

[0119] The materials were weighed according to the following proportions:

TABLE-US-00006 Nitroxoline raw material (batch IV) 100 parts by weight Microcrystalline cellulose 30 parts by weight Lactose 25 parts by weight Starch (for pulping) 1.5 parts by weight Low substituted hydroxypropyl cellulose 5 parts by weight Sodium dodecyl sulfate 4 parts by weight

[0120] Specifically, nitroxoline raw material (batch IV, 200 g), microcrystalline cellulose (60 g), lactose (50 g), starch (3 g, formulated into 5% starch pulp) and low substituted hydroxypropyl cellulose (10 g) were weighed respectively, and added into the high shear wet granulator for granulation. The resulting soft material was subjected to wet milling, and dried with the fluidized bed (the moisture was controlled to 2-5%). The dried granules were subjected to dry milling, followed by the addition of s odium dodecyl sulfate (8 g) was, and mixed for 10 min to obtain the total mixed granules. The total mixed granules were tableted by the tableting machine (φ6.5 mm). The resulting tablets were coated by the coating machine with hydroxypropyl methylcellulose as a film coating powder (64 g, formulated into a solution by adding 336 g of water), and the weight gain was 10%. The coated nitroxoline tablets were thus prepared.

[0121] Example 5 Preparation Example V of Nitroxoline Tablets

[0122] The materials were weighed according to the following proportions:

TABLE-US-00007 Nitroxoline lysine salt raw material (batch V) 100 parts by weight Microcrystalline cellulose 140 parts by weight Lactose 120 parts by weight Hydroxypropyl methylcellulose (for pulping) 5 parts by weight Low substituted hydroxypropyl cellulose 5 parts by weight Silica 5 parts by weight Magnesium stearate 4 parts by weight

[0123] Specifically, nitroxoline lysine salt (batch V, 200 g), microcrystalline cellulose (280 g), lactose (240 g), hydroxypropyl methylcellulose (10 g, formulated into a solution by adding 115 g of water) and low substituted hydroxypropyl cellulose (10 g) were weighed respectively, and added into the high shear wet granulator for granulation. The resulting soft material was subjected to wet milling, and dried with the fluidized bed (the moisture was controlled to 2-5%). The dried granules were subjected to dry milling, followed by the addition of s ilica (10 g) and magnesium stearate (8 g), and mixed for 10 min to obtain the total mixed granules. The total mixed granules were tableted by the tableting machine (φ10 mm). The resulting tablets were coated by the coating machine with hydroxypropyl methylcellulose as a film coating powder (96 g, formulated into a solution by adding 504 g of water), and the weight gain was 8%. The coated nitroxoline tablets were thus prepared.

[0124] Example 6 Preparation example VI of nitroxoline tablets

[0125] The materials were weighed according to the following proportions:

TABLE-US-00008 Nitroxoline raw material (batch I) 100 parts by weight Starch 150 parts by weight Lactose 130 parts by weight Sodium dodecyl sulfate 10 parts by weight

[0126] Specifically, nitroxoline (batch I, 100 g), starch (150 g) and lactose (130 g) were weighed respectively, and added together with an appropriate amount of water into the high shear wet granulator for granulation. The resulting soft material was subjected to wet milling, and dried with the fluidized bed (the moisture was controlled to 2-5%). The dried granules were subjected to dry milling, followed by the addition of s odium dodecyl sulfate (10 g), and mixed for 10 min to obtain the total mixed granules. The total mixed granules were tableted by the tableting machine (φ6.5 mm). The resulting tablets were coated by the coating machine with hydroxypropyl methylcellulose as a film coating powder (64 g, formulated into a solution by adding 336 g of water), and the weight gain was 11%. The coated nitroxoline tablets were thus prepared.

[0127] Example 7 Preparation Example VII of Nitroxoline Tablets

[0128] The materials were weighed according to the following proportions:

TABLE-US-00009 Nitroxoline raw material (batch I) 100 parts by weight Starch 30 parts by weight Lactose 20 parts by weight Starch (for pulping) 2 parts by weight Low substituted hydroxypropyl cellulose 6.7 parts by weight Sodium dodecyl sulfate 6.7 parts by weight

[0129] Specifically, nitroxoline (batch I, 150 g), starch (45 g), lactose (30 g), starch (3 g, formulated into 5% starch pulp by adding 57 g of water) and low substituted hydroxypropyl cellulose (10 g) were weighed respectively, and added into the high shear wet granulator for granulation. The resulting soft material e was subjected to wet milling, and dried with the fluidized bed (the moisture was controlled to 2-5%). The dried granules were subjected to dry milling, followed by the addition of s odium dodecyl sulfate (10 g), and mixed for 10 min to obtain the total mixed granules. The total mixed granules were tableted by the tableting machine (φ6.5 mm). The resulting tablets were coated by the coating machine with hydroxypropyl methylcellulose as a film coating powder (32 g, formulated into a solution by adding 168 g of water), and the weight gain was 3%. The coated nitroxoline tablets were thus prepared.

[0130] Example 8 Preparation Example VIII of Nitroxoline Tablets

[0131] The materials were weighed according to the following proportions:

TABLE-US-00010 Nitroxoline raw material (batch I) 100 parts by weight Starch 50 parts by weight Lactose 50 parts by weight Starch (for pulping) 2 parts by weight Low substituted hydroxypropyl cellulose 25 parts by weight Sodium dodecyl sulfate 5 parts by weight

[0132] Specifically, nitroxoline (batch I, 120 g), starch (60 g), lactose (60 g), starch (2.4 g, formulated into 5% starch pulp by adding 45.6 g of water) and low substituted hydroxypropyl cellulose (30 g) were weighed respectively, and added into the high shear wet granulator for granulation. The resulting soft material was subjected to wet milling, and dried with the fluidized bed (the moisture was controlled to 2-5%). The dried granules were subjected to dry milling, followed by the addition of s odium dodecyl sulfate (6 g), and mixed for 10 min to obtain the total mixed granules. The total mixed granules were tableted by the tableting machine (φ6.5 mm). The resulting tablets were coated by the coating machine with hydroxypropyl methylcellulose as a film coating powder (40 g, formulated into a solution by adding 210 g of water), and the weight gain was 5%. The coated nitroxoline tablets were thus prepared.

[0133] Example 9 Preparation Example IX of Nitroxoline Tablets

[0134] The materials were weighed according to the following proportions:

TABLE-US-00011 Nitroxoline raw material (batch I) 100 parts by weight Starch 50 parts by weight Lactose 50 parts by weight Starch (for pulping) 1.9 parts by weight Crospovidone 12 parts by weight Sodium dodecyl sulfate 4 parts by weight

[0135] Specifically, nitroxoline (batch I, 130 g), starch (65 g), lactose (65 g), starch (2.5 g, formulated into 5% starch pulp by adding 47.5 g of water) and crospovidone (15.6 g) were weighed respectively, and added into the high shear wet granulator for granulation.

[0136] The resulting soft material was subjected to wet milling, and dried with the fluidized bed (the moisture was controlled to 2-5%). The dried granules were subjected to dry milling, followed by the addition of s odium dodecyl sulfate (5.2 g), and mixed for 10 min to obtain the total mixed granules. The total mixed granules were tableted by the tableting machine (φ6.58.5 mm). The resulting tablets were coated by the coating machine with hydroxypropyl methylcellulose as a film coating powder (60 g, formulated into a solution by adding 315 g of water), and the weight gain was 15%. The coated nitroxoline tablets were thus prepared.

[0137] Experimental Example 1 Content and Weight Difference Assay of the Nitroxoline Tablets of the Present Invention

[0138] The active pharmaceutical ingredient (nitroxoline) content in the nitroxoline tablets was determined according to high performance liquid chromatography (general rule 0512 of volume IV of the Chinese Pharmacopoeia 2015 Edition).

[0139] Content % refers to the ratio of the average content to the theoretical amount of the active pharmaceutical ingredient in each tablet.

[0140] The tablet weight difference % was calculated as follows: 20 tablets were randomly selected and weighed, and the average value was calculated; each tablet was weighed separately, and the percentage ratio of the difference between the weight of each tablet and the average value to the average value was calculated.

[0141] The content and weight difference of the nitroxoline tablets of the present invention are shown in Table 2 below.

TABLE-US-00012 TABLE 2 Content and weight difference of the nitroxoline tablets of the present invention Sample information Content/% Tablet weight difference/% Example 1 98.8 −2.09~+1.42 Example 2 101.9 −1.03~+1.08 Example 3 100.3 −1.24~+1.67 Example 4 98.4 −7.28~+2.26

[0142] Conclusion: All results meet the requirements of Chinese Pharmacopoeia.

[0143] Experimental Example 2 Dissolution Rate Test of the Nitroxoline Tablets of the Present Invention

[0144] The nitroxoline tablets prepared in Example 1 to 4 were used. The operation was conducted in accordance with the test method of dissolution rate and release rate (general rule 0931 of volume IV of the Chinese Pharmacopoeia 2015 Edition), 1000 mL of 0.1 mol/L hydrochloric acid solution was used as the dissolution medium, the rotation speed was 60 revolutions per minute. At 60 minutes, the solution was taken and filtered through a membrane filter. 2 mL of the resulting filtrate was added into a 10 mL volumetric flask, and diluted with 0.1 mol/L hydrochloric acid solution until the liquid level reached the mark. The resulting solution was shaked well, and used as the test solution. An appropriate amount of nitroxoline reference substance was accurately weighed, dissolved in 0.1 mol/L hydrochloric acid solution, and quantitatively diluted to prepare a solution containing about 10 μg of nitroxoline per milliliter, as the reference substance solution. According to UV-visible spectrophotometry (general rule 0401 of volume IV of the Chinese Pharmacopoeia 2015 Edition) (UV-2700, Shimadzu), the absorbance was measured at a wavelength of 369 nm, and the dissolution rate of each tablet was calculated.

[0145] The dissolution profile of the nitroxoline tablets prepared in Examples 1 to 4 is shown in FIG. 1. The dissolution rates at 60 min were 103%, 97%, 98% and 76%, respectively. The above dissolution rates are moderate, and the specific explanations are as follows: The relatively rapid dissolution of an immediate-release formulation generally means that the dissolution rate at 15 min, 30 min or 45 min is more than 75%. The relatively slow dissolution of an immediate-release preparation generally means that the dissolution rate at 90 min or 120 min is more than 75%. The dissolution rate of the nitroxoline tablets obtained in the present invention at 60 min is more than 75%, that is, the nitroxoline tablets prepared from the phamaceutical composition of the present invention is an immediate-release preparation having a moderate dissolution rate.

[0146] Nitroxoline belongs to BCS class II drugs, which have low solubility and high permeability. Generally, in formulations containing this type of drugs, the smaller the particle size of the drug, the faster the dissolution of the formulation. However, the inventors unexpectedly found that the smaller the particle size of nitroxoline, the slower the dissolution of the formulation. As can be seen from FIG. 1, along with the reduction of the particle size of nitroxoline, the overall dissolution of the nitroxoline tablets of the present invention is slowed down. This is inconsistent with the dissolution profiles exhibited by conventional formulations containing such drugs. As for Examples 2 and 3, since the particle sizes of the two are relatively close, the two show relatively similar dissolution.

[0147] Experimental Example 3 Hardness test of the nitroxoline tablets of the present invention

[0148] The drug was placed into a hardness tester (SY-3, Yellow Sea) according to the operation requirements, and subjected to hardness test. 10 tablets were measured each time, that is, serial numbers 1 to 10. The hardness of the nitroxoline tablets prepared in Examples 1 to 4 is shown in Table 3 below.

TABLE-US-00013 TABLE 3 Hardness of the products (Examples 1 to 4) Hardness of the products/kg Sample No. Example 1 Example 2 Example 3 Example 4 1 10.95 10.18 9.15 8.78 2 12.37 10.53 8.77 7.3 3 11.73 9.35 9.29 12.89 4 11.9 9.02 8.82 9.01 5 12.17 9.86 8.51 8.15 6 12.89 9.66 9.56 8.36 7 11.95 10.67 8.35 8.48 8 11.27 9.76 8.11 8.64 9 11.26 8.99 8.75 7.91 10 10.86 9.17 9.07 8.74 Average value 11.74 9.72 8.84 8.83 Maximum value 12.89 10.67 9.56 12.89 Minimum value 10.86 8.99 8.11 7.3

[0149] It can be seen from the results of hardness test in the table above that the hardness of the products of Examples 1 to 4 is within the expected range, and the variation range of hardness is narrow.

[0150] Experimental Example 4 Fluidity test and compressibility test In this experiment, the fluidity of the particles was evaluated by measuring the Carr Index of the mixed particles, and the compressibility of the particles was evaluated by the Hsusner Ratio.

[0151] Carr Index refers to the percentage difference between the tap density and the bulk density of the particles. <10% indicates fairly excellent fluidity, 11 to 15% indicates excellent fluidity, 16 to 20% indicates good fluidity, 21 to 25% indicates passable fluidity, 26 to 31% indicates poor fluidity, and above 32% indicates very poor fluidity.

[0152] Hsusner Ratio refers to the ratio of the tap density to the bulk density of the particles. 1.00 to 1.11 indicates fairly excellent compressibility, 1.12 to 1.18 indicates excellent compressibility, 1.19 to 1.25 indicates good compressibility, 1.26 to 1.34 indicates passable fluidity, 1.35 to 1.45 indicates poor fluidity, and 1.46 to 1.59 indicates very poor fluidity.

[0153] Test method of the bulk density: About 20 g of the granules were weighed, and slowly added into a 100 mL measuring cylinder. The measuring cylinder was initially inclined, and slowly placed upright after the addition, vibration should be avoided during the process. The volume was read, and the bulk density was obtained by dividing the particle weight by the bulk volume.

[0154] Test method of the tap density: After the bulk density test, the measuring cylinder was placed on a tapping instrument, and tapped for 500 times. The volume value was read, and the tap density was obtained by dividing the particle weight by the tap volume.

[0155] Before tableting, the total mixed granules of Examples 1 to 4 were taken and tested as described above. The resulting Carr Index and Hsusner Ratio are shown in Table 4 below.

TABLE-US-00014 TABLE 4 Carr Index and Hsusner Ratio of the nitroxoline total mixed granules of Examples 1 to 4 Particle Bulk Bulk Tap Tap Carr Hsusner Sample mass/(g) volume/(cm.sup.3) density/(g/m.sup.3) volume/(cm.sup.3) density/(g/m.sup.3) Index/% Ratio Example 1 20.6101 43.0 0.4793 38.0 0.5424 13.2 1.13 Example 2 20.8697 40.0 0.5217 33.0 0.6324 21.2 1.21 Example 3 22.5043 44.0 0.5115 38.0 0.5922 15.7 1.16 Example 4 20.6105 36.0 0.5725 29.0 0.7107 24.1 1.24

[0156] It can be seen from Table 4 above that the Carr Indexes of the nitroxoline total mixed particles of the present invention are all less than 25%, indicating that the particles have good fluidity. Moreover, the Hsusner Ratios of the nitroxoline total mixed particles of the present invention are less than 1.25, indicating that the compressibility of the particles is good or better.

[0157] In summary, the pharmaceutical composition of nitroxoline or a salt thereof with specific particle size provided in the present invention allows the resulting nitroxoline tablets to have a moderate dissolution rate (the dissolution rate within 60 min is more than 75%), uniform content, narrow variation range in hardness, and good fluidity and compressibility. Moreover, the nitroxoline tablets are not only conducive to the absorption of active pharmaceutical ingredients in the body, but also have a simple preparation process that is suitable for industrial production.

[0158] Although the specific embodiments of the present invention are described above, those skilled in the art should understand that those are only for illustration, and the protection scope of the present invention is defined by the appended claims. Those skilled in the art can make various changes or modifications to these embodiments without departing from the principle and essence of the present invention, but these changes and modifications all fall within the protection scope of the present invention.