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

Abstract

A pharmaceutical composition containing nitroxoline for the treatment of bladder cancer, a nitroxoline oral solid tablet, a preparation method therefor and use thereof. The pharmaceutical composition comprises nitroxoline, a filler, a disintegrating agent, a binder, and a lubricant. The lubricant is selected from one or two of sodium dodecyl sulfate and sodium stearyl fumarate. The pharmaceutical composition has a moderate dissolution rate, can avoid the burst release phenomenon, is moisture-proof and impermeable, has good stability, is secure and effective, is convenient to take, has strong patient compliance, and meets the requirements of being an oral solid tablet. The preparation method has stable production process, good reproducibility, easy mass production, and good clinical use value and social benefits.

Claims

1. A pharmaceutical composition comprising nitroxoline, characterized in that the pharmaceutical composition comprises nitroxoline, a filler, a disintegrating agent, a binder, and a lubricant; wherein the lubricant is selected from one or two of sodium dodecyl sulfate and sodium stearyl fumarate.

2. The pharmaceutical composition comprising nitroxoline according to claim 1, characterized in that the mass percentage of the nitroxoline in the pharmaceutical composition is 30%-65%, preferably 40%-60%; and/or, the filler is one or more of lactose, starch, pregelatinized starch, microcrystalline cellulose, dextrin, mannitol, calcium hydrophosphate, mannitol and sorbitol; preferably one or more of lactose, starch and microcrystalline cellulose; more preferably lactose and/or starch; further more preferably lactose and starch, and the mass percentage of lactose in the pharmaceutical composition is 10%-25%, the mass percentage of starch in the pharmaceutical composition is 23%-30%; wherein, the lactose is preferably lactose monohydrate, and the starch is preferably corn starch; and/or, the mass percentage of the filler in the pharmaceutical composition is 25%-65%, preferably 33%-55%; and/or, the disintegrating agent is one or more of hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch and sodium croscarmellose, preferably hydroxypropyl cellulose, more preferably low-substituted hydroxypropyl cellulose; and/or, the mass percentage of the disintegrating agent in the pharmaceutical composition is 1%-5%, preferably 2%-4%, more preferably 2%-3%; and/or, the binder is one or more of starch, povidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose and sodium carboxymethyl cellulose, preferably starch and/or hydroxypropyl methylcellulose, more preferably starch; wherein, the starch is preferably corn starch, and the hydroxypropyl methylcellulose is preferably E3 hydroxypropyl methylcellulose; and/or, the mass percentage of the binder in the pharmaceutical composition is 1%-4%, preferably 1%-3%; and/or, the lubricant is sodium dodecyl sulfate; and/or, the mass percentage of the lubricant in the pharmaceutical composition is 0.5%-4%, preferably 1%-2%.

3. The pharmaceutical composition comprising nitroxoline according to claim 1, characterized in that the pharmaceutical composition comprises a coating agent which is selected from one or more of Opadry, polyvinyl alcohol, Eudragit and gastric-soluble film coating premix, preferably gastric-soluble film coating premix; wherein, the gastric-soluble film coating premix preferably comprises titanium dioxide, talc, polyethylene glycol, hydroxypropyl methylcellulose and lake, more preferably a mixture consisting of titanium dioxide, talc, polyethylene glycol 6000, hydroxypropyl methylcellulose and tartrazine aluminum lake; wherein, the weight gain of the coating agent is preferably 7%-15%, more preferably 10%-12%.

4. The pharmaceutical composition comprising nitroxoline according to claim 1, characterized in that the pharmaceutical composition comprises the following components in the following mass percentage: 30%-65% nitroxoline, 25%-65% filler, 1%-5% disintegrating agent, 1%-4% binder and 0.5%-4% lubricant; preferably, the pharmaceutical composition comprises the following components in the following mass percentage: 40%-60% nitroxoline, 33%-55% filler, 2%-3% preferably 2%-2.5% disintegrating agent, 1%-3% binder and 1%-2% lubricant; more preferably, in the pharmaceutical composition, the filler is lactose and starch, and the mass percentage of lactose in the pharmaceutical composition is 10%-25%, the mass percentage of starch in the pharmaceutical composition is 23%-30%; the disintegrating agent is hydroxypropyl cellulose, the binder is starch, and the lubricant is sodium dodecyl sulfate.

5. A nitroxoline oral solid tablet, characterized in that the tablet comprises nitroxoline as an active ingredient, a filler, a disintegrating agent, a binder and a lubricant; wherein the lubricant is selected from one or two of sodium dodecyl sulfate and sodium stearyl fumarate.

6. The nitroxoline oral solid tablet according to claim 5, characterized in that the tablet comprises 30-65% preferably 45-55% nitroxoline, 25-65% preferably 30-55% filler, 1-5% preferably 2-4% disintegrating agent, 1-4% preferably 1.5-3% binder and 0.5-4% preferably 1-3% lubricant by mass based on the total weight of the tablet.

7. A nitroxoline oral solid tablet, characterized in that the tablet comprises nitroxoline as an active ingredient, a filler, a disintegrating agent, a binder and a lubricant; the tablet is further coated with one or more layers of coating agent; wherein the lubricant is selected from one or two of sodium dodecyl sulfate and sodium stearyl fumarate.

8. The nitroxoline oral solid tablet according to claim 7, characterized in that the tablet comprises 30-65% preferably 45-55% nitroxoline, 25-65% preferably 30-55% filler, 1-5% preferably 2-4% disintegrating agent, 1-4% preferably 1.5-3% binder and 0.5-4% preferably 1-3% lubricant by mass based on the total weight of the tablet; and the percentage of weight gain of the coating agent is 7-15%, preferably 9-12% by weight.

9. The nitroxoline oral solid tablet according to claim 5, characterized in that the filler is selected from one or more of lactose, starch, pregelatinized starch, microcrystalline cellulose, dextrin, mannitol, calcium hydrophosphate, mannitol and sorbitol, preferably lactose and/or starch; wherein, the lactose is preferably lactose monohydrate, and the starch is preferably corn starch.

10. The nitroxoline oral solid tablet according to claim 9, characterized in that the filler is lactose and starch, wherein the mass percentage of lactose is 10%-30%, preferably 15-25%, the mass percentage of starch is 15-35%, preferably 20-30% by mass based on the total weight of the tablet.

11. The nitroxoline oral solid tablet according to claim 5, characterized in that the disintegrating agent is selected from one or more of hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch and sodium croscarmellose, preferably hydroxypropyl cellulose, more preferably low-substituted hydroxypropyl cellulose.

12. The nitroxoline oral solid tablet according to claim 5, characterized in that the binder is selected from one or more of starch, povidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose and sodium carboxymethyl cellulose, preferably starch and/or hydroxypropyl methylcellulose; wherein, the starch is preferably corn starch, and the hydroxypropyl methylcellulose is preferably E3 hydroxypropyl methylcellulose.

13. The nitroxoline oral solid tablet according to claim 7, characterized in that the coating agent is selected from one or more of Opadry, polyvinyl alcohol, Eudragit and gastric-soluble film coating premix; preferably, the coating agent is gastric-soluble film coating premix; more preferably, the coating agent is gastric-soluble film coating premix, and the weight gain of the coating agent is 7%-15%, preferably 10%-12%.

14. The nitroxoline oral solid tablet according to claim 13, characterized in that the gastric-soluble film coating premix comprises titanium dioxide, talc, polyethylene glycol, hydroxypropyl methylcellulose and lake.

15. The nitroxoline oral solid tablet according to claim 7, characterized in that the tablet comprises 30-65% preferably 45-55% nitroxoline as active ingredient, 10-30% preferably 15-25% lactose and/or 15-35% preferably 20-30% starch as filler, 1-5% preferably 2-4% hydroxypropyl cellulose as disintegrating agent, 1-4% preferably 1.5-3% starch or hydroxypropyl methylcellulose as binder, and 0.5-4% preferably 1-3% sodium dodecyl sulfate or sodium stearyl fumarate as lubricant by mass based on the total weight of the tablet; and the tablet is further coated with gastric-soluble film coating premix, the percentage of weight gain of which is 7-15%, preferably 9-12% by weight.

16. A preparation method of the pharmaceutical composition comprising nitroxoline according to claim 1, characterized in that the preparation method comprises the following steps: S1: the nitroxoline, filler and disintegrating agent are mixed, which is then mixed with a solution comprising the binder to obtain a mixture; and the mixture is subject to wet granulation, drying and granulation to give the granules; S2: the granulated granules are mixed with the lubricant and then subjected to tableting to give the tablets; when the pharmaceutical composition comprises a coating agent, coating is performed after the tableting of step S2.

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

18. A method of treating bladder cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the nitroxoline oral solid tablet according to claim 5.

19. A method of treating bladder cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the nitroxoline oral solid tablet according to claim 7.

Description

DESCRIPTION OF THE DRAWINGS

[0064] FIG. 1 is the dissolution profile of the nitroxoline oral solid tablet core prepared in Comparative Example 1 in 0.1 mol/L hydrochloric acid.

[0065] FIG. 2 is the dissolution profile of the nitroxoline oral solid tablet core prepared in Example 1 in 0.1 mol/L hydrochloric acid.

[0066] FIG. 3 is the dissolution profile of the nitroxoline oral solid tablet of the present invention prepared in Example 6 in 0.1 mol/L hydrochloric acid.

DETAILED DESCRIPTION OF THE INVENTION

[0067] The embodiments of the present invention will be described in detail below by the examples. However those skilled in the art should understand that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention. If no specific conditions are indicated in the examples, it is carried out in accordance with the conventional conditions or the conditions recommended by the manufacturer. Similar commercially available products with the same functions can also be used as the raw materials or instruments besides those with specified manufacturer.

[0068] Experimental Materials:

TABLE-US-00001 Name Type/grade Source Water Purified water Shengjieda, Taizhou Hydrochloric acid AR Sinopharm Chemical Reagent Co., Ltd. Nitroxoline Bulk drug Self-manufactured by Asieris Pharmaceuticals Lactose Monohydrate, 312 FOREMOST FARMS USA Starch Com starch Liaoning Dongyuan Pharmaceuticals Hydroxypropyl cellulose Low-substituted Huzhou Zhanwang Pharmaceuticals Sodium dodecyl sulfate Pharmaceutical excipient Hunan Jiudian Pharmaceutical Microcrystalline cellulose PH101 Huzhou Zhanwang Pharmaceuticals Cross-linked PVP K30 BASF, Germany Pregelatinized starch Pharmaceutical excipient Huzhou Zhanwang Pharmaceuticals Sodium carboxymethyl Pharmaceutical excipient Huzhou Zhanwang Pharmaceuticals starch Cross-linked sodium Pharmaceutical excipient Anhui Sunhere carboxymethyl starch Magnesium stearate Pharmaceutical excipient Huzhou Zhanwang Pharmaceuticals Stearic acid Pharmaceutical excipient Huzhou Zhanwang Pharmaceuticals Sodium stearyl fumarate S96 Taiwan Standard Hydroxypropyl E3 Dow, USA methylcellulose Gastric-soluble film Yingyimei Beijing Yingmao Pharmaceuticals coating premix Opadry Opadry Colorcon Eudragit L100 Evonik Specialty Chemicals

[0069] The gastric-soluble film coating premix is a mixture consisting of titanium dioxide, talc, polyethylene glycol 6000, hydroxypropyl methylcellulose and tartrazine aluminum lake.

[0070] Experimental Instruments:

TABLE-US-00002 Name Model Source Wet granulation pan G10 Shenzhen Xinyite Technology Co., Ltd. Oscillating granulator YK-6 Jiangyin Dry Equipment Manufacture Co., Ltd. Blast drying oven DHG-9240A Shanghai Yiheng Scientific Instrument Co., Ltd. Rotary tablet press ZP-9 Taizhou Tiantai Pharmacy Machines UV spectrophotometer UV-2700 Shimadzu, Japan Coating pan BY-300 Taizhou Jintai Pharmaceutical Machinery Co., Ltd. Liquid chromatograph LC-20A Shimadzu, Japan Centrifuge LC-04C Zenith Lab (Jiangsu) Co., Ltd.

Comparative Example 1 Preparation of Nitroxoline Oral Solid Tablet Cores

[0071] In order to obtain a formula for tablet core that has a moderate dissolution rate and avoids burst release, the types and proportions of excipients are selected. Based on the total weight of the tablet core, the weight percentages of various components are shown in Table 1 below.

TABLE-US-00003 TABLE 1 Weight percentage of various components in each formula Component/Formula 1 2 3 4 5 6 7 Nitroxoline (%) 50 50 50 50 50 50 50 Lactose (%) 17.5 17.5 16 16 16 16 17.5 Starch (%) — — 30 28.5 28.5 28.5 28 Microcrystalline cellulose 15 — — — — — — (%) Pregelatinized starch (%) 15 15 — — — — — Starch (binder) (%) 1.5 1.5 3 3 3 3 1.5 Hydroxypropyl cellulose — 15 — — — — 2 (%) Cross-linked PVP (%) — — — 1.5 — — — Sodium carboxymethyl — — — — 1.5 — — starch (%) Cross-linked sodium — — — — — 1.5 — carboxymethyl starch (%) Magnesium stearate (%) 1 1 1 1 1 1 1

[0072] Preparation method of the nitroxoline oral solid tablet core:

[0073] (1) The nitroxoline, filler, disintegrating agent, binder and lubricant were respectively weighed according to the amount in the table above;

[0074] (2) The nitroxoline was sieved through a 10 mesh sieve and the other components were sieved through a 60 mesh sieve;

[0075] (3) Each amount of the binder was prepared into an aqueous solution at 5% mass concentration with purified water;

[0076] (4) Each amount of nitroxoline, filler and disintegrating agent were put into a wet granulation pan and mixed well, and then the aqueous solution of the binder prepared in step (3) was added. The mixture was stirred at high speed and discharged, which was then subjected to wet granulation by an oscillating granulator equipped with 20 mesh sieve. The granules were dried in a 60° C. blast drying oven and then subjected to dry granulation by an oscillating granulator equipped with 20 mesh sieve to give an uniform granule;

[0077] (5) Each amount of the lubricant was added to the granules prepared in step (4) and mixed. The mixture was tableted by a rotary tablet press (equipped with 6 mm round punch) to give the nitroxoline oral solid tablet core.

Comparative Example 2 Dissolution Test of the Nitroxoline Oral Solid Tablet Cores Prepared in Comparative Example 1

[0078] According to the Chinese Pharmacopoeia 2015 edition, Volume IV, General Requirements 0931, 1000 mL of 0.1 mol/L HCl was used as the dissolution medium, and the rotating speed of the automatic dissolution tester (model RC8MD, TDTF Company) was 50 revolutions per minute. The samples were collected at 5, 10, 20, 30, 45 and 60 minutes respectively, and the absorbance was measured at a wavelength of 369 nm by an UV spectrophotometer. The dissolution was calculated according to the external standard method.

[0079] Conclusion: The dissolution profile of the nitroxoline oral solid tablet cores prepared from various formulas in Comparative Example 1 is as shown in FIG. 1.

[0080] The results show that formula 1 and formula 2, which were firstly designed to investigate the dissolution of the bulk drug under natural release conditions, result in very fast dissolution rates. Formula 3, which was then designed to control the dissolution of the drug by delaying disintegration, result in very slow dissolution rate which is less than 80% in 60 minutes. Formula 4 to formula 7 were designed on the basis of formula 3. The results show that the tablet cores prepared with formula 7 has relatively moderate release rate.

Example 1 Preparation of Nitroxoline Oral Solid Tablet Cores

[0081] The above formula 7 with moderate release rate was taken as a sample. After a preliminary influencing factor test at 60° C. for 10 days (the tablet cores were placed in a blast drying oven at 60° C. for 10 days), it was found that the tablet could hardly disintegrate. Upon analysis and research, it is found that the reason may be that the nitroxoline as an ionic complexing agent deprives of the magnesium of magnesium stearate and frees the hydrophobic stearic acid with low melting point, which melts at the accelerated test temperature and thus blocks the water-permeable channels in the tablet, causing the reduction of the disintegration rate. In order to solve the problem of aging of the formula containing magnesium stearate, lubricants were screened and verified by using stearic acid as a positive control formula (formula 8) to obtain formula 8 to formula 10. At the same time, the amount of the disintegrating agent was also screened to obtain formula 11 to formula 13. Based on the total weight of the tablet core, the weight percentages of various components are shown in Table 2 below.

TABLE-US-00004 TABLE 2 Weight percentage of various components in each formula Functions Materials/Formula 8 9 10 11 12 13 Active Nitroxoline (%) 50 50 50 50 50 50 pharmaceutical ingredient Filler Lactose (%) 17.5 17.5 17.5 17.5 17.5 17.5 Filler Starch (%) 28 27 27 26.5 26 25 Disintegrating Hydroxypropyl cellulose (%) 2 2 2 2.5 3 4 agent Binder Starch (%) 1.5 1.5 1.5 1.5 1.5 1.5 Lubricant Stearic acid 1 — — — — — Lubricant Sodium dodecyl sulfate (%) — — 2 2 2 2 Lubricant Sodium stearyl fumarate (%) — 2 — — — —

[0082] Preparation method for the nitroxoline oral solid tablet core:

[0083] (1) The nitroxoline, filler, disintegrating agent, binder and lubricant were respectively weighed according to the amount in the table above;

[0084] (2) The nitroxoline was sieved through a 10 mesh sieve and the other components were sieved through a 60 mesh sieve;

[0085] (3) Each amount of the binder was prepared into an aqueous solution at 5% mass concentration with purified water;

[0086] (4) Each amount of nitroxoline, filler and disintegrating agent were put into a wet granulation pan and mixed well, and then the aqueous solution of the binder obtained in step (3) was added. The mixture was stirred at high speed and discharged, which was then subjected to wet granulation by an oscillating granulator equipped with 20 mesh sieve. The granules were dried in a 60° C. blast drying oven and then subjected to dry granulation by an oscillating granulator equipped with 20 mesh sieve to give an uniform granule;

[0087] (5) Each amount of the lubricant was added to the granules prepared in step (4) and mixed. The mixture was tableted by a rotary tablet press (equipped with 6 mm round punch) to give the nitroxoline oral solid tablet core.

Example 2 Dissolution Test of the Nitroxoline Oral Solid Tablet Cores Prepared in Example 1

[0088] According to Pharmacopoeia of the People's Republic of China, 2015 edition, Volume IV, General Requirements 0931, 1000 mL of 0.1 mol/L HCl was used as the dissolution medium, and the rotating speed of the automatic dissolution tester (model RC8MD, TDTF Company) was 50 revolutions per minute. The samples were collected at 5, 10, 20, 30, 45 and 60 minutes respectively, and the absorbance was measured at a wavelength of 369 nm by an UV spectrophotometer. The dissolution was calculated according to the external standard method.

[0089] Conclusion: The dissolution profile of the nitroxoline oral solid tablet cores prepared from various formulas in Example 1 is as shown in FIG. 2.

[0090] The results show that the dissolution rates of the tablet cores prepared with different lubricant of formula 8 to formula 10 are basically the same. However, after a preliminary influencing factor test at 60° C. for 10 days, it is found that the positive control tablet core of formula 8 can hardly disintegrate within 20 minutes, which supports the hypothesis that the nitroxoline causes the aging of the formula containing magnesium stearate. The release rates of Prescription 9 and Prescription 10 are almost unaffected. For formula 11 to formula 13, the dissolution rate is positively correlated with the amount of the disintegrating agent, and formula 11 is preferred.

Example 3 Nitroxoline Oral Solid Tablet Cores and Preparation Thereof

[0091] Based on the total weight of the tablet core, the weight percentages of various components are shown in Table 3 below. The weight percentage of the binder is the weight percentage of the solid binder, and the binder used in the preparation is an aqueous solution of starch at 5 wt %.

TABLE-US-00005 TABLE 3 Weight percentage of various components in each formula Formula (weight %) Use Component A B C D E F G H I J K L Active ingredient Nitroxoline 30 30 35 40 45 50 55 40 50 60 65 65 Filler Lactose 30 25 22 — 30 — 15 25 17.5 10 10 10 Starch 35 35 30 — 15 — 25 30 26.5 23 20 15 Microcrystalline cellulose — — 50 — 40 — — — — — — Disintegrating agent Hydroxypropyl cellulose 2 5 5 3 3 4 2 2 2.5 3 1 5 Binder Starch — 2 4 4 4 — — 1 1.5 3 — 4 Hydroxypropyl 2 — — — 4 1 — — — 3.5 methylcellulose Lubricant Sodium stealyl fumarate — 3 4 3 — 2 2 — — — — 1 Sodium dodecyl sulfate 1 — — — 3 — — 2 2 1 0.5

[0092] Preparation Method:

[0093] (1) The nitroxoline, filler, disintegrating agent, binder and lubricant were respectively weighed according to the amount in the table above;

[0094] (2) The nitroxoline was sieved through a 10 mesh sieve and the other components were sieved through a 60 mesh sieve;

[0095] (3) Each amount of the binder was prepared into an aqueous solution at 5% mass concentration with purified water;

[0096] (4) Each amount of nitroxoline, filler and disintegrating agent were put into a wet granulation pan and mixed well, and then the aqueous solution of the binder prepared in step (3) was added. The mixture was stirred at high speed and discharged, which was then subjected to wet granulation by an oscillating granulator equipped with 20 mesh sieve. The granules were dried in a 60° C. blast drying oven and then subjected to dry granulation by an oscillating granulator equipped with 20 mesh sieve to give an uniform granule;

[0097] (5) Each amount of the lubricant was added to the granules prepared in step (4) and mixed. The mixture was tableted by a rotary tablet press (equipped with 6 mm round punch) to give the nitroxoline oral solid tablet core.

Example 4 Preparation of Nitroxoline Oral Solid Coated Tablets

[0098] Nitroxoline has strong mobility and permeability. In order to investigate the isolating and masking performance of the film coating powder on the tablet core, the tablet core of formula I in Example 3 was selected for coating to screen the coating powder and the amount. The model of each coating powder and its weight gain percentage based on the total weight of the tablet core are shown in Table 4 below, wherein the gastric-soluble film coating premix is consisting of titanium dioxide, talc, polyethylene glycol 6000, hydroxypropyl methylcellulose and tartrazine aluminum lake.

TABLE-US-00006 TABLE 4 Weight percentage of various components in formula I Functions Materials/Formula I Active Nitroxoline (%) 50 50 50 50 50 50 pharmaceutical ingredient Filler Lactose (%) 17.5 17.5 17.5 17.5 17.5 17.5 Filler Starch (%) 26.5 26.5 26.5 26.5 26.5 26.5 Disintegrating Hydroxypropyl cellulose (%) 2.5 2.5 2.5 2.5 2.5 2.5 agent Binder Starch (%) 1.5 1.5 1.5 1.5 1.5 1.5 Lubricant Sodium dodecyl sulfate (%) 2 2 2 2 2 2 Coating agent Gastric-soluble film coating premix 5 7 9 11 13 15 (weight gain %) Weight percentage of various components in Formula I Functions Materials/Formula I Active Nitroxoline (%) 50 50 50 50 50 50 pharmaceutical ingredient Filler Lactose (%) 17.5 17.5 17.5 17.5 17.5 17.5 Filler Starch (%) 26.5 26.5 26.5 26.5 26.5 26.5 Disintegrating Hydroxypropyl cellulose (%) 2.5 2.5 2.5 2.5 2.5 2.5 agent Binder Starch (%) 1.5 1.5 1.5 1.5 1.5 1.5 Lubricant Sodium dodecyl sulfate (%) 2 2 2 2 2 2 Coating agent Polyvinyl alcohol (weight gain %) 5 7 9 11 13 15 Active Nitroxoline (%) 50 50 50 50 50 50 pharmaceutical ingredient Filler Lactose (%) 17.5 17.5 17.5 17.5 17.5 17.5 Filler Starch (%) 26.5 26.5 26.5 26.5 26.5 26.5 Disintegrating Hydroxypropyl cellulose (%) 2.5 2.5 2.5 2.5 2.5 2.5 agent Binder Starch (%) 1.5 1.5 1.5 1.5 1.5 1.5 Lubricant Sodium dodecyl sulfate (%) 2 2 2 2 2 2 Coating agent Opachy (weight gain %) 5 7 9 11 13 15

[0099] Preparation Method of the Nitroxoline Oral Solid Coated Tablets:

[0100] (1) The nitroxoline, filler, disintegrating agent, binder, lubricant and coating agent were respectively weighed according to the amount of the table above;

[0101] (2) The nitroxoline was sieved through a 10 mesh sieve and the other components were sieved through a 60 mesh sieve;

[0102] (3) Each amount of the binder was prepared into an aqueous solution at 5% mass concentration with purified water;

[0103] (4) Each amount of nitroxoline, filler and disintegrating agent were put into a wet granulation pan and mixed well, and then the aqueous solution of the binder prepared in step (3) was added. The mixture was stirred at high speed and discharged, which was then subjected to wet granulation by an oscillating granulator equipped with 20 mesh sieve. The granules were dried in a 60° C. blast drying oven and then subjected to dry granulation by an oscillating granulator equipped with 20 mesh sieve to give an uniform granule;

[0104] (5) Each amount of the lubricant was added to the granules prepared in step (4) and mixed. The mixture was tableted by a rotary tablet press (equipped with 6 mm round punch) to give the nitroxoline oral solid tablet core.

[0105] (6) The coating agent is formulated into a solid content of 12-16% with purified water. Coating of one layer is carried out in a coating pan at a speed of 3-15 rpm, an air inlet temperature of 55-75° C., a bed temperature at 30-50° C. and a atomization pressure at 0.2-0.3 MPa, and the weight gain percentage by mass is as shown in Table 4-1, Table 4-2 and Table 4-3. The nitroxoline oral solid coated tablets were obtained.

Example 5 Penetration Test of Nitroxoline Oral Solid Coated Tablets

[0106] Nitroxoline has strong mobility and permeability, and it easily dyes other materials in contact because it is yellow. In the present invention, the coated tablets with different weight gains prepared in Example 4 were respectively placed in white plastic bottle which was then placed in an oven at 60° C. for 10 days for investigation. It was observed whether the nitroxoline would penetrate the coating film and dye the white plastic bottle yellow. The penetrability results are as shown in Table 5 below.

TABLE-US-00007 TABLE 5 Penetration of nitroxoline to various coating agents Model/weight gain 5% 7% 9% 11% 13% 15% Gastric-soluble Penetration No No No No No film coating in 10 days penetration penetration penetration penetration penetration premix in 10 days in 10 days in 10 days in 10 days in 10 days Polyvinyl Penetration Penetration Penetration Penetration Penetration Penetration alcohol in 1 day in 3 days in 3 days in 5 days in 5 days in 10 days Opadly Penetration Penetration Penetration Penetration Penetration Penetration in 1 day in 3 days in 3 days in 5 days in 5 days in 10 days

[0107] It can be seen from Table 5 that the weight gain of polyvinyl alcohol and Opadry coating powder is 15%, and the coating can be penetrated at the high temperature of 60° C. for 10 days. Meanwhile, the gastric-soluble film coating premix has a weight gain of more than 7%, and the coating is not penetrated at the high temperature of 60° C. for 10 days, showing that it has strong isolating and masking properties and can meet the needs.

Example 6 Dissolution Test of the Nitroxoline Oral Solid Tablets of the Present Invention

[0108] The tablets were prepared according to Formula H, I, and J in Example 3, and were coated with the gastric-soluble film coating premix according to the method of Example 4. The coating weight gain was 11%, and the batch was 10,000 tablets/batch.

[0109] According to Pharmacopoeia of the People's Republic of China, 2015 edition, Volume IV, General Requirements 0931, 1000 mL of 0.1 mol/L HCl was used as the dissolution medium, and the rotating speed of the automatic dissolution tester (model RC8MD, TDTF Company) was 50 revolutions per minute. The samples were collected at 5, 10, 20, 30, 45 and 60 minutes respectively, and the absorbance was measured with an UV spectrophotometer. The dissolutions of coated tablets of formulas H, I and J were calculated according to the external standard method, and the dissolution profiles are as shown in FIG. 3. The results show that the nitroxoline coated tablets of the three formulas H, I, and J have similar dissolution profiles, and the dissolution is almost completed at 60 minutes.

Example 7 Quality Inspection of the Nitroxoline Oral Solid Coated Tablets of the Present Invention

[0110] The tablets were prepared according to formulas H, I, and J in Example 3, and were coated with the gastric-soluble film coating premix according to the method of Example 4. The coating weight gain was 11%, and the batch was 10,000 tablets/batch, wherein formula H of Example 3 was corresponding to the first batch, formula I of Example 3 was corresponding to the second batch, and formula J of Example 3 was corresponding to the third batch. The 3 batches were sampled for quality inspection.

[0111] Weight difference: 20 nitroxoline oral solid tablets were randomly taken and accurately weighed for the total weight to calculate the average tablet weight. Then each tablet was accurately weighed. The difference between the weight of each tablet and the average tablet weight should not exceed 7.5%.

[0112] Determination of the content: 10 nitroxoline oral solid tablets were randomly taken, accurately weighed and ground. An appropriate amount of the fine powder was accurately weighed and placed in a 100 mL measuring flask. Methanol was added to dissolve the powder and dilute to the mark. The solution was shaken well and filtered to prepare a solution containing 0.1 mg per 1 mL as the test solution. An appropriate amount of nitroxoline raw material was taken as control. Methanol was added to dissolve and dilute the nitroxoline to prepare a solution containing 0.1 mg per 1 mL, which was shaken well and used as the control solution. 10 μL of the test solution and the control solution were respectively injected into a liquid chromatograph and measured by using high-performance liquid chromatography (Pharmacopoeia of the People's Republic of China, 2015 edition, Volume IV, General Requirements 0512). The content was calculated with the peak area according to the external standard method. The content of nitroxoline should be 90.0-110.0%. The result is the average of samples in duplicate.

[0113] Determination of relative substance: 10 nitroxoline oral solid tablets were randomly taken and weighed for the average tablet weight. The tablets were ground into fine powder. The powder equivalent to 100 mg of the main drug (nitroxoline) was accurately weighed and put in a 100 mL measuring flask. Methanol was added to close to the mark. The mixture was ultrasonically extracted for 10 minutes and cooled to room temperature. The mixture was diluted to the mark with methanol, shaken well and centrifuged (3000 r/min). The supernatant was taken as the test solution. An appropriate amount of the test solution was diluted 100 folds with methanol as the control solution. 20 μL of the control solution and the test solution were respectively injected into the liquid chromatograph and measured by using high-performance liquid chromatography (Pharmacopoeia of the People's Republic of China, 2015 edition, Volume IV, General Requirements 0512). The sum of each impurity peak area should not exceed the main peak area of the control solution (1.0%). The result is the average of samples in duplicate. The weight difference, content and test results of the relative substance are shown in Table 6 below.

TABLE-US-00008 TABLE 6 Results of quality inspection of the nitroxoline oral solid tablets of the present invention Item/batch number 1 2 3 Appearance Orange tablet Orange tablet Orange tablet Weight difference (%) ≤7.5 ≤7.5 ≤7.5 Content (%) 101.0 99.6 102.0 Relative substances (%) 0.03 0.03 0.03

[0114] Conclusion: It can be seen from Table 6 above that the appearance, weight difference, content and quality indicators of relative substances of the 3 batches of samples are basically consistent, and all meet the quality standard requirements.

Example 8 Accelerated Stability Test of Nitroxoline Oral Solid Tablets of the Present Invention

[0115] The tablets were prepared according to formula H, I, and J in Example 3, and were coated with the gastric-soluble film coating premix according to the method of Example 4. The coating weight gain was 11%, and the batch was 10,000 tablets/batch, wherein formula H of Example 3 was corresponding to the first batch, formula I of Example 3 was corresponding to the second batch, and formula J of Example 3 was corresponding to the third batch. The 3 batches of samples were put into oral solid high-density polyethylene bottles sealed with bottle caps with inductive aluminum cap lining, and investigated at a temperature of 40° C.±2° C. and a relative humidity of 75%±5% for 6 months.

[0116] Determination of content: the method was the same as the determination method in Example 7.

[0117] Determination of relative substance: the method was the same as the determination method in Example 7.

[0118] Determination of dissolution: 6 nitroxoline oral solid tablets were randomly taken. According to the dissolution and release test method (Pharmacopoeia of the People's Republic of China, 2015 edition, Volume IV, General Requirements 0931), 1000 mL of 0.1 mol/L hydrochloric acid was used as the dissolution medium, the rotation speed was 50 revolutions per minute, the operation was in accordance with the method, and samples were taken after 60 minutes. According to UV-visible spectrophotometry (Pharmacopoeia of the People's Republic of China, 2015 edition, Volume IV, General Requirements 0401), the absorbance was measured at a wavelength of 369 nm, the dissolution rate of each tablet was calculated, and the average value of the dissolution rates of 6 tablets was used as the result. The criterion is not less than 80% of the labeled amount in 60 minutes.

[0119] The test results of content, relative substances and dissolution are shown in Table 7 below.

TABLE-US-00009 TABLE 7 Results of accelerated stability test of the nitroxoline oral solid tablets of the present invention Batch number of Relative Dissolution sample Time/Indicator Appearance Content (%) substances (%) (%) 1 0 month Orange tablet 100.0 0.03 95.6 1 month Orange tablet 98.7 0.03 96.1 2 months Orange tablet 100.6 0.04 95.0 3 months Orange tablet 98.9 0.04 95.7 6 months Orange tablet 99.0 0.03 96.2 2 0 month Orange tablet 99.6 0.03 96.7 1 month Orange tablet 100.7 0.03 97.4 2 months Orange tablet 100.6 0.03 96.6 3 months Orange tablet 98.5 0.03 95.6 6 months Orange tablet 98.6 0.04 96.6 3 0 month Orange tablet 101.0 0.03 96.6 1 month Orange tablet 99.6 0.03 95.3 2 months Orange tablet 99.0 0.03 95.5 3 months Orange tablet 99.4 0.03 95.8 6 months Orange tablet 99.7 0.03 95.1

[0120] The results show that after the accelerated stability investigation for 6 months, the indicators of the 3 batches of samples have no significant changes compared with those at 0 month.

Example 9 Long-Term Stability Test of the Nitroxoline Oral Solid Tablets of the Present Invention

[0121] The tablets were prepared according to formula H, I, and J in Example 3, and were coated with the gastric-soluble film coating premix according to the method of Example 4. The coating weight gain was 11%, and the batch was 10,000 tablets/batch, wherein formula H of Example 3 was corresponding to the first batch, formula I of Example 3 was corresponding to the second batch, and formula J of Example 3 was corresponding to the third batch. The 3 batches of samples were put into oral solid high-density polyethylene bottles sealed with bottle caps with inductive aluminum cap lining, and investigated at a temperature of 25° C.±2° C. and a relative humidity of 60%±5% for 24 months.

[0122] Determination of content: the determination method was the same as that in Example 7.

[0123] Determination of relative substances: the determination method was the same as that in Example 7.

[0124] Determination of dissolution: the determination method was the same as that in Example 8.

[0125] The test results of content, relative substances and dissolution are shown in Table 8 below.

TABLE-US-00010 TABLE 8 Results of long-term stability test of the nitroxoline oral solid tablets of the present invention Batch number of Relative sample substances Dissolution (Formula) Time/Indicator Appearance Content (%) (%) (%) 1 0 month Orange tablet 100.0 0.03 95.6 (H) 3 months Orange tablet 99.3 0.03 94.3 6 months Orange tablet 99.4 0.04 95.0 9 months Orange tablet 99.6 0.03 94.3 12 months Orange tablet 99.3 0.04 94.8 18 months Orange tablet 99.5 0.04 94.2 24 months Orange tablet 99.7 0.04 95.1 2 0 month Orange tablet 99.6 0.03 96.7 (I) 3 months Orange tablet 100.7 0.03 95.2 6 months Orange tablet 99.1 0.04 96.3 9 months Orange tablet 99.4 0.03 96.4 12 months Orange tablet 99.2 0.03 96.1 18 months Orange tablet 99.6 0.04 95.8 24 months Orange tablet 99.4 0.03 95.2 3 0 month Orange tablet 101.0 0.03 96.6 (J) 3 months Orange tablet 99.5 0.03 95.0 6 months Orange tablet 99.8 0.05 95.4 9 months Orange tablet 99.8 0.03 95.6 12 months Orange tablet 99.7 0.04 95.8 18 months Orange tablet 99.4 0.04 94.8 24 months Orange tablet 99.9 0.05 95.4

[0126] The results show that after the long-term stability investigation for 24 months, the indicators of the 3 batches of samples have no significant changes compared with those at 0 month.