FILM-COATED TABLET

Abstract

A gas layer is formed in a tablet core of the film-coated tablet after being immersed in acid. A mixture containing a permeation enhancer, a gas generating agent, and drug ingredients is compressed into a tablet. Then, the tablet is coated with a semipermeable film. After the film-coated tablet is immersed in acid for several seconds or longer, gas is generated from the tablet core to form a gas layer in the tablet core. Therefore, the tablet core becomes a two-layered structure, and the tablet floats. One of the layers is the gas layer. During a research process, the tablet core generates gas and expands, causing the film to rupture. After the film is ruptured, the tablet core can continue to float, and the drug release rate is related to the composition of the tablet core and is not affected by the film.

Claims

1. A film-coated tablet, wherein the film-coated tablet comprises a tablet core and a semipermeable film, wherein the tablet core comprises the following ingredients in percentage by weight: 2% to 15% of a drug, 3% to 50% of a penetration enhancer, 10% to 50% of a gas producing agent, 10% to 45% of a water-soluble swellable polymer and an excipient, and a sum of the ingredients is 100%; the semipermeable film comprises 20% to 80% of a water-insoluble polymer, 10% to 85% of micronized water-soluble particles, and 0% to 40% of other additives, and a sum of the ingredients is 100%; and a coating weight gain of the semipermeable film is not more than 5%.

2. The film-coated tablet according to claim 1, wherein the coating weight gain of the semipermeable film is greater than or equal to 2% but less then or equal to 5%.

3. The film-coated tablet according to claim 1, wherein the excipient is selected from one or more of a binder, a solubilizer, a filler, a glidant, or a lubricant.

4. The film-coated tablet according to claim 1, wherein the tablet core comprises the following ingredients in percentage by weight: 2% to 15% of the drug, 3% to 25% of the penetration enhancer, 10% to 25% of the gas generating agent, 10% to 45% of the water-soluble swellable polymer, 4% to 6% of the binder, 0.2% to 5% of the solubilizer, 1% to 50% of the filler, 0.5% to 1.5% of the glidant, 0.5% to 1.5% of the lubricant and 0% to 5% of a disintegrant, and a sum of the ingredients is 100%.

5. The film-coated tablet according to claim 1, wherein the drug is a drug with low solubility in acid; and the penetration enhancer is selected from one or more of potassium chloride, potassium sulfate, potassium hydrogen phosphate, sodium hydrogen phosphate, sodium chloride, citric acid or tartaric acid.

6. The film-coated tablet according to claim 1, wherein the gas generating agent is sodium bicarbonate, and the water-soluble swellable polymer is selected from hydroxypropyl methylcellulose, carbomer or polyethylene oxide.

7. The film-coated tablet according to claim 4, wherein the binder is selected from potato starch, wheat starch, corn starch, Arabic gum, alginic acid, guar gum; liquid glucose, povidone, polyethylene oxide, polyvinylpyrrolidone, poly-N-vinylamide, polyethylene glycol, gelatin, polypropylene glycol or tragacanth; the solubilizer is selected from polysorbate 80, β-cyclodextrin, poloxamer 188 or methanol; the filler is selected from mannitol, fructose, sucrose, lactose, xylitol, sorbitol, microcrystalline cellulose, calcium carbonate, calcium hydrogen phosphate or ternary calcium or calcium sulfate; the glidant is selected from silicon dioxide, magnesium trisilicate, tribasic calcium phosphate, calcium silicate or magnesium silicate; the lubricant is selected from sodium stearyl fumarate, magnesium stearate, aluminum stearate, calcium stearate, zinc stearate, polyethylene glycol, glyceryl monostearate, glyceryl monostearate, glyceryl behenate, mineral oil, sodium stearyl fumarate, stearic acid, hydrogenated vegetable oil or talc.

8. The film-coated tablet according to claim 1, wherein the semipermeable film comprises 20%-80% of the water-insoluble polymer, 10%-85% of the micronized water-soluble particles and 0%-40% of other additives, and a sum of the ingredients is 100%.

9. The film-coated tablet according to claim 8, wherein the water-insoluble polymer is one or more of polyvinyl alcohol, polyurethane, ethyl cellulose, methyl cellulose, cellulose acetate, cellulose acetate butyrate, polyvinyl chloride, polycarbonate, ethylene-vinyl acetate, polymethyl methacrylate or polypropylene; the micronized water-soluble particles are selected from one or more of sodium chloride, sodium bicarbonate or mannitol; and the other additives comprise dibutyl phthalate, triethyl citrate, polyethylene glycol (PEG), talc, stearic acid, magnesium stearate or colloidal silica.

10. A method for preparing the film-coated tablet according to claim 1, wherein tablet core materials are mixed, tableted, and then coated to form a semipermeable film.

11. The film-coated tablet according to claim 4, wherein the drug is a drug with low solubility in acid; and the penetration enhancer is selected from one or more of potassium chloride, potassium sulfate, potassium hydrogen phosphate, sodium hydrogen phosphate, sodium chloride, citric acid or tartaric acid.

12. The film-coated tablet according to claim 4, wherein the gas generating agent is sodium bicarbonate, and the water-soluble swellable polymer is selected from hydroxypropyl methylcellulose, carbomer or polyethylene oxide.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0043] FIG. 1 shows that a coated tablet is immersed in 0.1N HCl and begins to float within 3 minutes, and gas generated by the tablet core finally forms a gas layer.

[0044] FIG. 2 shows that a coated tablet expends to rupture a film; A is a side view with at least 10% of a surface of the tablet being exposed from the film crack; and B is a top view with at least 10% of the surface of the tablet being exposed from the film crack.

[0045] FIG. 3 shows that the tablet core further expands, and most of the tablet core “leaks” out of a film.

DETAILED DESCRIPTION

[0046] The foregoing examples are illustrative examples of the present disclosure and are exemplary only. Variations and modifications may be made by those skilled in the art without departing from the spirit and scope of the present disclosure. All such modifications and variations are intended to be included within the scope of the present disclosure.

[0047] The experimental methods in the following examples are all conventional methods unless otherwise specified. The test materials used in the following examples are purchased from conventional biochemical reagent stores unless otherwise specified.

Example 1

[0048] Two batches were prepared. The prescription is as follows:

TABLE-US-00001 210112-FC1 210112-FC2 Tablet core 5 6 Cabozantinib malate 10 10 Povidone K30 4.67 4.67 Tween-80 0.5 0.5 Hydroxypropyl methylcellulose 30 45 K100M Lactose 16.83 1.83 Sodium chloride 13 13 Sodium bicarbonate 20 20 Citric acid 3 3 Silicon dioxide 1 1 Sodium stearyl fumarate 1 1 % 100 100 Tablet weight mg 600 600 Coating EUDRAGIT RL PO 65.6% 65.6% Triethyl citrate 9.8% 9.8% Mannitol 16.4% 16.4% Talc 8.2% 8.2% Solid content 9.93% 9.93% Coating weight gain 2.50% 2.50%

[0049] The preparation process is as follows:

[0050] Mannitol jet milling: mannitol was taken for jet milling, and the particle size was D(90)=15.3 μm.

[0051] Tablet core: other tablet core materials except sodium stearyl fumarate were weighted according to a prescription amount, sieved with a 40-mesh sieve, and uniformly mixed in a post-placed mixer, sodium stearyl fumarate with a prescription amount was added, and the materials were uniformly mixed. The evenly mixed tablet was compressed by a rotary tablet press, stamped using a 11.5 mm round front concave punch with a main pressure of 7-10 KN, and tabletted.

[0052] Coating: a prescription amount of isopropanol and water were taken, and mixed evenly, ¾ of the solvent was taken and added with a prescription amount of Eudragit RL PO, and stirred for dissolving (NLT60 min) to form a clear solution; the other ¼ of the solvent was taken and added with a prescription amount of TEC, a prescription amount of mannitol and a prescription amount of talc, dispersed evenly and then added into the Eudragit solution, and the materials were stirred and mixed evenly. The prepared tablet core was coated by a high-efficiency coating pan, and the coating weight gain was 2.5%.

[0053] Result:

[0054] The tablets were placed in 0.1N HCl at 37° C. 210112-FC1 started to float within 5 seconds and the coating started to rupture within 30 seconds. While 210112-FC2 started to float within 1 minute and the coating started to rupture within 1 minute.

Example 2

[0055] Six batches were prepared. The preparation process was the same as that in Example 1, the coating prescription was the same, and the coating weight gain was 3.8% to 4.6%.

TABLE-US-00002 210115- 210115- 210115- 210105- 210105- 210105- FC1 FC2 FC3 FC1 FC2 FC3 Cabozantinib malate 10 10 10 10 10 10 Povidone K30 4.67 4.67 4.67 4.67 4.67 4.67 Tween-80 0.5 0.5 0.5 0.5 0.5 0.5 Hydroxypropyl 45 45 45 15 20 10 methylcellulose K100M Lactose 11.83 6.83 14.83 31.83 14.83 46.83 Sodium chloride 13 13 0 13 20 7 Sodium bicarbonate 10 15 20 20 25 16 Citric acid 3 3 3 3 3 3 Silicon dioxide 1 1 1 1 1 1 Sodium stearyl 1 1 1 1 1 1 fumarate % 100 100 100 100 100 100 Tablet weight mg 600 600 600 600 600 600 Coating (%) EUDRAGIT RL PO 66 66 66 66 66 66 Triethyl citrate 10 10 10 10 10 10 Mannitol 16 16 16 16 16 16 Talc 8 8 8 8 8 8 Solid content 11.88 11.88 11.88 11.88 11.88 11.88 Coating weight gain 3.86% 3.86% 3.86% 4.53% 4.53% 4.53%

[0056] Result:

[0057] The tablets were placed in 0.1N HCl at 37° C. The observations are as follows:

TABLE-US-00003 210115- 210115- 210115- 210105- 210105- 210105- FC1 FC2 FC3 FC1 FC2 FC3 Floating 3.75 3.5 4 2.5 2.25 2.75 started within ( ) minutes Coating 10 8 30 30 30 30 started to rupture within ( ) minutes

[0058] Dissolving experiment (900 mL, 0.1 NHCl+1.0% Tween-80) paddle method (CJL-3 type sediment basket was added) 50 rpm

TABLE-US-00004 Time 210115- 210115- 210115- 210105- 210105- 210105- (h) FC1 FC2 FC3 FC1 FC2 FC3 0.5 0 1 0 33 4 34 1 0 1 0 70 8 68 1.5 1 1 0 78 10 74 2 2 2 1 83 12 79 3 3 3 2 88 15 86 4 4 4 3 92 18 89 6 6 7 5 97 24 95

Example 3

[0059] Two batches were prepared. The preparation process was the same as that in Example 1, the prescriptions of the tablet core and coating were slightly adjusted, and the coating weight gain was about 4%.

TABLE-US-00005 210128-FC1 210128-FC2 Cabozantinib malate 13.33 13.33 Povidone K30 4.67 4.67 Tween-80 1 1 Hydroxypropyl methylcellulose K100M 30 30 Lactose 13 8 Croscarmellose sodium 0 5 Sodium chloride 13 13 Sodium bicarbonate 20 20 Citric acid 3 3 Silicon dioxide 1 1 Sodium stearyl fumarate 1 1 % 100 100 Tablet weight mg 450 450 Coating (%) EUDRAGIT RL PO 31.7 66 Triethyl citrate 16.7 10 Mannitol 51.7 16 Solid content 13 13 Coating weight gain 4% 4%

[0060] Result:

[0061] The tablets were placed in 0.1N HCl at 37° C. The observations are as follows:

TABLE-US-00006 210128-FC1 210128-FC2 Floating started within ( ) minutes 0.9 0.9 Coating started to rupture within ( ) minutes 60 60

Example 4

[0062] Two batches were prepared. The preparation process and the coating prescription were the same as those in Example 1, and the coating weight gain was 3.8% to 4.6%.

TABLE-US-00007 2101118-FC1 2101118-FC2 lenvatinib mesylate 3.33 3.33 Povidone K30 4.67 4.67 Tween-80 0.5 0.5 Hydroxypropyl 35 45 methylcellulose K100M Lactose 18.5 8.5 Sodium chloride 13 13 Sodium bicarbonate 20 20 Citric acid 3 3 Silicon dioxide 1 1 Sodium stearyl fumarate 1 1 % 100 100 Tablet weight mg 300 300 EUDRAGIT RL PO 65.6% 65.6% Triethyl citrate 9.8% 9.8% Mannitol 16.4% 16.4% talc 8.2% 8.2% Solid content 11.88% 11.88%

[0063] Result:

[0064] The tablets were placed in 0.1N HCl at 37° C. The observations are as follows:

TABLE-US-00008 2101118-FC1 2101118-FC2 Floating started within ( ) minutes (min) 2.5 2.8 Coating started to rupture within ( ) 30 30 minutes (min)

[0065] A sample (Batch No. 2101118-FC2) prepared in Example 4 floated in 0.1N HCl at 37° C. within 3 minutes, as shown in FIG. 1, and the tablet core generated gas to form a gas layer. The tablet core continued to expand, causing the film to rupture, and at least 10% of the surface of the tablet was exposed from the film crack (as shown in FIG. 2). After the film was ruptured, the tablet core could continue to float without dose dumping, and the drug was released along with the viscosity of a tablet core skeleton and was not affected by the film. After a longer period of time, the tablet core further expanded and most of the tablet core “leaked” out of the film (as shown in FIG. 3), but could continue to float for 6 hours or longer.