ORAL PHARMACEUTICAL COMPOSITION COMPRISING OTILONIUM BROMIDE AND SIMETHICONE WITH CERTAIN BULK DENSITY AND IMPROVED DISSOLUTION CHARACTERISTICS

Abstract

The present invention relates to a pharmaceutical composition for oral use comprising therapeutically effective amount of otilonium bromide in combination with therapeutically effective amount of simethicone, wherein the composition possesses certain bulk density and improved dissolution characteristics. Wherein a final blend prior to compression has a bulk density of at least 0.35 g/mL, and at least 85% of the otilonium bromide is released in 15 minutes in each of 0.1 N HCl, pH 4.5 and pH 6.8 buffer solutions at 370.5 C. using USP type II (paddle) apparatus rotating at 50 rpm.

Claims

1. An oral pharmaceutical composition comprising otilonium bromide in combination with simethicone, wherein a final blend prior to compression has a bulk density of at least 0.35 g/mL; and at least 85% of the otilonium bromide is released in 15 minutes in each of 0.1 N HCl, pH 4.5 and pH 6.8 buffer solutions at 370.5 C. using USP type II (paddle) apparatus rotating at 50 rpm.

2. The oral pharmaceutical composition according to claim 1, wherein the final blend prior to compression has a bulk density of at least 0.40 g/mL.

3. The oral pharmaceutical composition according to claim 1, wherein the oral pharmaceutical composition further comprises mannitol and a weight ratio of the simethicone to the mannitol is from 1:5 to 1:20.

4. The oral pharmaceutical composition according to claim 3, wherein the weight ratio of the simethicone to the mannitol is from 1:5 to 1:10.

5. The oral pharmaceutical composition according to claim 1, wherein the oral pharmaceutical composition further comprises xylitol and a weight ratio of the simethicone to the xylitol is from 1:5 to 1:20.

6. The oral pharmaceutical composition according to claim 5, wherein the weight ratio of the simethicone to the xylitol is from 1:5 to 1:10.

7. The oral pharmaceutical composition according to claim 1, wherein the simethicone is in liquid form.

8. The oral pharmaceutical composition according to claim 1, wherein the oral pharmaceutical composition comprises the otilonium bromide and the simethicone in separate granules.

9. The oral pharmaceutical composition according to claim 1, wherein the oral pharmaceutical composition is a tablet, a film-coated tablet, a dispersible tablet, an orally disintegrating tablet, a powder, a granule or a combination thereof.

10. The oral pharmaceutical composition according to claim 9, wherein oral pharmaceutical composition is the tablet.

11. (canceled)

12. (canceled)

13. The oral pharmaceutical composition according to claim 1, wherein a weight ratio of the otilonium bromide to the simethicone is from 1:1 to 1:5.

14. The oral pharmaceutical composition according to claim 1, wherein the oral pharmaceutical composition comprises the otilonium bromide in an amount of 40 mg and the simethicone in an amount of 80 mg per oral dosage unit.

15. The oral pharmaceutical composition according to claim 1, wherein the oral pharmaceutical composition is used for a treatment or alleviating a symptoms of irritable bowel syndrome (IBS) and pain/spasm in a gastrointestinal tract.

16. The oral pharmaceutical composition according to claim 4, wherein the weight ratio of the simethicone to the mannitol is from 1:5 to 1:8.

17. The oral pharmaceutical composition according to claim 16, wherein the weight ratio of the simethicone to the mannitol is 1:7.

18. The oral pharmaceutical composition according to claim 6, wherein the weight ratio of the simethicone to the xylitol is from 1:5 to 1:8.

19. The oral pharmaceutical composition according to claim 18, wherein the weight ratio of the simethicone to the xylitol is 1:7.

20. The oral pharmaceutical composition according to claim 13, wherein a weight ratio of the otilonium bromide to the simethicone is from 1:1 to 1:4

21. The oral pharmaceutical composition according to claim 20, wherein the weight ratio of the otilonium bromide to the simethicone is more preferably from 1:1 to 1:3.

22. The oral pharmaceutical composition according to claim 21, wherein the weight ratio of the otilonium bromide to the simethicone is 1:2.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0059] In the scope of the present invention various formulations comprising otilonium bromide and simethicone have been prepared using pharmaceutically acceptable excipients.

[0060] Suitable pharmaceutically acceptable excipients used according to this present invention include disintegrants, binders, lubricants, glidants, diluents/fillers, wetting agents, sweetening agents, flavoring agents and film-coating agents.

[0061] In one embodiment of the invention, the pharmaceutical composition comprises at least one disintegrant, selected from the group consisting of carboxymethylcellulose sodium, croscarmellose sodium, crospovidone, low substituted hydroxypropyl cellulose, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose, sodium alginate, sodium starch glycolate, silicified microcrystalline cellulose, starch, pregelatinized starch, carboxymethylcellulose calcium and any combination thereof.

[0062] In one embodiment of the invention, the pharmaceutical composition comprises at least one binder, selected from the group consisting of carbomer, carboxymethylcellulose sodium, dextrin, dextrose, maltodextrin, gelatin, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, ethylcellulose, methyl cellulose, hypromellose, magnesium aluminium silicate, methylcellulose, povidone, sodium alginate, starch, pregelatinised starch, liquid glucose, sucrose, tragacanth (gum benjamin), zein, acacia (gum arabic), alginic acid, guar gum, copovidone and any combination thereof.

[0063] In one embodiment of the invention, the pharmaceutical composition comprises at least one lubricant, selected from the group consisting of calcium stearate, glycerine monostearate, magnesium stearate, stearic acid, glyceryl palmitostearate, glyceryl behenate, hydrogenated castor oil, hydrogenated vegetable oil, sodium lauryl sulphate, magnesium lauryl sulphate, sodium stearyl fumarate, poloxamer, polyethylene glycol, sucrose ester of fatty acids, talc and any combination thereof.

[0064] In one embodiment of the invention, the pharmaceutical composition comprises at least one glidant, selected from the group consisting of tribasic calcium phosphate, calcium silicate, cellulose, colloidal silicon dioxide, magnesium silicate, magnesium tri silicate, starch, talc and any combination thereof.

[0065] In one embodiment of the invention, the pharmaceutical composition comprises at least one diluent/filler, selected from the group consisting of calcium carbonate, dibasic calcium phosphate anhydrous, calcium phosphate dihydrate, tribasic calcium phosphate, calcium sulphate, cellulose powdered, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose acetate, colloidal silicon dioxide, dextrin, dextrose, lactose, magnesium carbonate, maltodextrin, mannitol, xylitol, polydextrose, starch, pregelatinized starch, calcium phosphate and any combination thereof. Preferred diluent/filler is mannitol.

[0066] In one embodiment of the invention, the pharmaceutical composition comprises at least one wetting agent, selected from the group consisting of gelatin, cetostearyl alcohol, polyoxyethylene castor oil derivatives, polyethylene glycols, sodium lauryl sulphate, poloxamer, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, methylcellulose, hydroxyethyl cellulose, hydroxylpropyl cellulose, hydroxypropylmethyl cellulose phthalate, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol and any combination thereof.

[0067] In one embodiment of the invention, the pharmaceutical composition comprises otilonium bromide in combination with simethicone which is suitable for oral administration, such as tablet, film-coated tablet, dispersible tablet, orally disintegrating tablet, powder, granules or a combination thereof. Preferred dosage form is tablet.

[0068] The tablets may also contain sweetening agents such as aspartame, acesulfame potassium, saccharin sodium, cyclamates, sucralose, corn syrup, sorbitol (solution), maltitol (syrup), oligosaccharide, isomaltooligosaccharide, fructose, lactose, glucose, lycasin, xylitol, lactitol, erythritol, mannitol, isomaltose, polydextrose, dextrin or mixtures thereof.

[0069] The tablets may further contain natural and/or semi-synthetic or synthetic flavoring agents such as citrus, lemon, lime, orange, tangerine, grape fruit, peppermint, spearmint, apple, pear, plum, peach, apricot, strawberry, raspberry, cherry, banana, vanilla, watermelon, honey, bubble gum flavor or mixtures thereof.

[0070] Said pharmaceutical composition is compressed into tablets after direct compression or dry granulation or wet granulation. Water, ethanol, isopropyl alcohol and mixtures thereof can be used as solvents during wet granulation.

[0071] The tablets may be film-coated in a conventional manner. Suitable coatings include but not limited to hydroxypropylmethyl cellulose, ethyl cellulose, cellulose acetate, polyvinyl alcohol, acrylic and/or methacrylic co-polymers, resins, one or more plastifying agents (e.g., polyethylene glycol, propylene glycol, glycerin, triethyl citrate, diethyl phthalate, and mixtures thereof).

[0072] In a preferred embodiment of the invention, the pharmaceutical composition comprises otilonium bromide and simethicone in weight ratio from about 1:1 to 1:5, preferably from about 1:1 to 1:4, more preferably from about 1:1 to 1:3, most preferably about 1:2.

[0073] In one embodiment of the invention, mannitol and/or xylitol is used as the diluent/filler. The weight ratio of simethicone to mannitol and/or xylitol is about from 1:5 to 1:20, preferably from 1:5 to 1:10, more preferably from 1:5 to 1:8, most preferably is about 1:7. Other diluents/fillers may also be used.

[0074] Having described the invention with reference to certain embodiments, other embodiments will become apparent to the person skilled in the art from consideration of the specification. Certain specific aspects and embodiments of the invention will be further described in the following examples, which are provided solely for purposes of illustration and are not intended to limit the scope of the invention in any manner.

Example 1

[0075]

TABLE-US-00001 Unit Formula Formula I (mg) % Wet Phase I Otilonium Bromide 40.0 4.4 Granulation Lactose Monohydrate 797.0 88.6 (Lactose 200 Mesh) Sodium Starch 18.0 2.0 Glycolate (Primojel) Phase II Corn Starch 27.0 3.0 Phase III Magnesium Stearate 18.0 2.0 Total Core Tablet Weight 900.0 100

Brief Manufacturing Process (Example 1):

[0076] Step-1: Ingredients in Phase I are mixed to form a homogeneous blend.

[0077] Step-2: The mixture in Step-1 is granulated with binder solution (Phase II). Obtained wet granules are dried and sifted.

[0078] Step-3: Lubricant (Phase III) is added to the granules from Step-2 and mixed.

[0079] Step-4: The granule blend from Step-3 is compressed into tablets.

Example 2

[0080]

TABLE-US-00002 Unit Formula Formula II (mg) % Wet Phase I Otilonium Bromide 40.0 4.4 Granulation Simethicone (powder) 80.0 8.9 Lactose Monohydrate 717.0 79.7 (Lactose 200 Mesh) Sodium Starch 18.0 2.0 Glycolate (Primojel) Phase II Corn Starch 27.0 3.0 Phase III Magnesium Stearate 18.0 2.0 Total Core Tablet Weight 900.0 100

Manufacturing Process is Similar to as Described in Example 1.

[0081] The dissolution characteristics of tablets obtained from Example 1 and Example 2 are studied in various dissolution media simulating the gastrointestinal (GI) tract conditions (i.e., 0.1N HCl, pH 4.5, pH 6.8 buffer solutions at 370.5 C.), using the method described in Table 1. The mean values of otilonium bromide released in 15 minutes from Formula I and Formula II are compared in Table 2.

TABLE-US-00003 TABLE 1 Dissolution Method Equipment: UV Spectrophotometer (wavelength: 260 nm) Apparatus: USP type II (paddle) Rotation speed: 50 rpm Buffers: Aqueous solutions of 0.1N hydrochloric acid/acetate buffer/phosphate buffer Buffer volume: 900 mL Temperature: 37 C. 0.5 C.

TABLE-US-00004 TABLE 2 Released otilonium bromide in 15 minutes Otilonium bromide 40 mg Otilonium bromide 40 mg + Tablets Simethicone 80 mg Tablets (Example 1) (Example 2) pH 1.2 91% 81% pH 4.5 90% 60% pH 6.8 86% 43%

[0082] It has been found that while more than 85% of said otilonium bromide is released in 15 minutes from the tablets comprising 40 mg of otilonium bromide as the mere active substance, tablets comprising 40 mg of otilonium bromide admixed with 80 mg of simethicone (powder) release significantly less amount of said otilonium bromide in 15 minutes under same pH conditions. The decrease of dissolution rate is more obvious at higher pH conditions.

Example 3

[0083]

TABLE-US-00005 Unit Formula Formula III (mg) % Wet Phase I Microcrystalline 445 49.4 Granulation Cellulose (Avicel PH102) Crospovidone 45 5.0 (Polyplasdone XL-10) Colloidal Silicon 20 2.2 Dioxide (Aerosil 300) Phase II Simethicone (liquid) 80 8.9 Copovidone 27 3.0 (Kollidon VA 64) Phase III Otilonium Bromide 40 4.4 Lactose, Spray Dried 213 23.7 Copovidone 18 2.0 (Kollidon VA 64) Colloidal Silicon 7 0.8 Dioxide (Aerosil 200) Magnesium Stearat 5 0.6 Total Core Tablet Weight 900.0 100.0

Brief Manufacturing Process (Example 3):

[0084] Step-1: Microcrystalline cellulose, crospovidone, and colloidal silicon dioxide are mixed to form a homogeneous blend.

[0085] Step-2: The mixture in Step-1 is granulated with simethicone (liquid)

[0086] Step-3: The mixture in Step-2 is further granulated with binder solution comprising copovidone. Obtained wet granules are dried and sifted.

[0087] Step-4: Otilonium bromide, lactose spray dried, copovidone, and colloidal silicon dioxide are added to the granules from Step-3 and mixed.

[0088] Step-5: Magnesium stearate is added to the granules from Step-4 and mixed.

[0089] However, the final blend as prepared in Example 3 is not compressible into tablets. The bulk density of the final blend prior to compression is measured to be 0.32 g/mL.

Example 4

[0090]

TABLE-US-00006 Unit Formula Formula IV (mg) % Wet Phase I Otilonium Bromide 40.0 4.4 Granulation Mannitol 50.0 5.6 Microcrystalline 625.0 69.5 Cellulose (Avicel PH101) Crospovidone 30.0 3.3 (Polyplasdone XL-10) Colloidal Silicon 20.0 2.2 Dioxide (Aerosil 200) Colloidal Silicon 20.0 2.2 Dioxide (Aerosil 300) Phase II Simethicone (liquid) 80.0 8.9 Povidone (PVP K30) 30.0 3.3 Phase III Magnesium Stearate 5.0 0.6 Total Core Tablet Weight 900.0 100.0

Brief Manufacturing Process (Example 4):

[0091] Step-1: Ingredients in Phase I are mixed to form a homogeneous blend.

[0092] Step-2: The mixture in Step-1 is granulated with binder solution comprising povidone and liquid simethicone (Phase II). Obtained wet granules are dried and sifted.

[0093] Step-3: Magnesium stearate (Phase III) is added to the granules from Step-2 and mixed.

[0094] However, the final blend as prepared in Formula IV (Example 4) is not compressible into tablets. The bulk density of the final blend prior to compression as prepared in Example 4 is measured to be 0.32 g/mL and the weight ratio of simethicone to mannitol is about 1:0.6. The effect of amount of mannitol as a diluent/filler is investigated in Examples 5 and 6.

Example 5

[0095]

TABLE-US-00007 Unit Formula Formula V (mg) % Wet Phase I Otilonium Bromide 40.0 4.0 Granulation Mannitol 200.0 20.0 Lactose Monohydrate 620.0 62.0 (Lactose 200 Mesh) Microcrystalline 30.0 3.0 Cellulose (Avicel PH101) Phase II Simethicone (liquid) 80.0 8.0 Povidone (PVP K30) 25.0 2.5 Phase III Magnesium Stearate 5.0 0.5 Total Core Tablet Weight 1000.0 100

[0096] Manufacturing process is similar to as described in Example 4.

[0097] The bulk density of the final blend prior to compression as prepared in Formula V (Example 5) is measured to be 0.55 g/mL and the weight ratio of simethicone to mannitol is 1:2.5. The dissolution characteristics of tablets obtained from Example 5 are studied in solutions of pH 1.2, 4.5 and 6.8 using the method described in Table 1. The mean values of otilonium bromide released in 15 minutes are given in Table 3.

TABLE-US-00008 TABLE 3 Released otilonium bromide in 15 minutes Otilonium bromide 40 mg + Simethicone 80 mg Tablets (Example 5) pH 1.2 88% pH 4.5 86% pH 6.8 61%

[0098] Surprisingly, the amount of otilonium bromide released in 15 minutes increased to the desired level (>85%) at pH 1.2 and 4.5, but not in pH 6.8. This suggests that the amount of mannitol used in the formula with respect to simethicone needs to be increased even more, hence, the dissolution characteristics of otilonium bromide will be further improved to become more than 85% in 15 minutes not only pH 1.2 and 4.5, but also at pH 6.8. This is demonstrated in Example 6.

Example 6

[0099]

TABLE-US-00009 Unit Formula Formula VI (mg) % Wet Phase I Otilonium Bromide 40.0 4.4 Granulation Mannitol 575.0 63.9 Lactose Monohydrate 145.0 16.1 (Lactose 200 Mesh) Microcrystalline 30.0 3.3 Cellulose (Avicel PH101) Phase II Simethicone (liquid) 80.0 8.9 Povidone (PVP K30) 25.0 2.8 Phase III Magnesium Stearate 5.0 0.6 Total Core Tablet Weight 900.0 100

[0100] Manufacturing process is similar to as described in Example 4.

[0101] The bulk density of the final blend prior to compression as prepared in Formula VI (Example 6) is measured to be 0.52 g/mL and the weight ratio of simethicone to mannitol is 1:7.2. The dissolution characteristics of tablets obtained from Example 6 are studied in solutions of pH 1.2, 4.5 and 6.8 using the method described in Table 1. The mean values of otilonium bromide released in 15 minutes are given in Table 4. The amount of otilonium bromide released in 15 minutes reached the desired level (>85%) at all three pH conditions.

TABLE-US-00010 TABLE 4 Released otilonium bromide in 15 minutes Otilonium bromide 40 mg + Simethicone 80 mg Tablets (Example 6) pH 1.2 92% pH 4.5 89% pH 6.8 87%

Example 7

[0102] Alternatively, xylitol can be used in the formulation instead of mannitol. This is demonstrated in Example 7.

TABLE-US-00011 Unit Formula Formula VII (mg) % Wet Phase I Otilonium Bromide 40.0 4.4 Granulation Xylitol 575.0 63.9 Lactose Monohydrate 145.0 16.1 (Lactose 200 Mesh) Microcrystalline 30.0 3.3 Cellulose (Avicel PH101) Phase II Simethicone (liquid) 80.0 8.9 Povidone (PVP K30) 25.0 2.8 Phase III Magnesium Stearate 5.0 0.6 Total Core Tablet Weight 900.0 100

[0103] Manufacturing process is similar to as described in Example 4.

[0104] The dissolution characteristics of tablets obtained from Example 7 are studied in solutions of pH 1.2, 4.5 and 6.8 using the method described in Table 1. The mean values of otilonium bromide released in 15 minutes are given in Table 5. The amount of otilonium bromide released in 15 minutes reached the desired level (>85%) at all three pH conditions.

TABLE-US-00012 TABLE 5 Released otilonium bromide in 15 minutes Otilonium bromide 40 mg + Simethicone 80 mg Tablets (Example 7) pH 1.2 90% pH 4.5 88% pH 6.8 86%

Example 8

[0105]

TABLE-US-00013 Unit Formula Formula VIII (mg) % Wet Phase I Microcrystalline 575 63.9 Granulation Cellulose I (Avicel PH101) Crospovidone 30 3.4 (Polyplasdone XL-10) Colloidal Silicon 20 2.2 Dioxide (Aerosil 300) Phase II Simethicone (liquid) 80 8.9 Copovidone 18 2.0 (Kollidon VA 64) Wet Phase III Otilonium Bromide 40 4.4 Granulation Lactose Monohydrate 100 11.1 II (Lactose 200 Mesh) Copovidone 12 1.3 (Kollidon VA 64) Phase IV Colloidal Silicon 20 2.2 Dioxide (Aerosil 200) Magnesium Stearate 5 0.6 Total Core Tablet Weight 900 100

Brief Manufacturing Process (Example 8):

[0106] Step-1: Ingredients in Phase I are mixed to form a homogeneous blend.

[0107] Step-2: The mixture in Step-1 is granulated with binder solution comprising copovidone and liquid simethicone (Phase II). Obtained wet granules are dried and sifted.

[0108] Step-3: Ingredients in Phase III are mixed and granulated with water. The wet granules obtained are dried and sieved.

[0109] Step-4: The mixture from Step-2 and Step-3 are mixed.

[0110] Step-5: Ingredients in Phase IV are added to the mixture in Step-4 and mixed further to form a homogeneous blend.

[0111] However, the final blend as prepared in Example 8 is not compressible into tablets. The bulk density of the final blend prior to compression is measured to be 0.30 g/mL.

Example 9

[0112]

TABLE-US-00014 Unit Formula Formula IX (mg) % Wet Phase I Microcrystalline 445.0 49.4 Granulation Cellulose I (Avicel PH102) Crospovidone 45.0 5.0 (Polyplasdone XL-10) Colloidal Silicon 20.0 2.2 Dioxide (Aerosil 300) Simethicone (powder) 80.0 8.9 Phase II Copovidone 27.0 3.0 (Kollidon VA 64) Wet Phase III Otilonium Bromide 40.0 4.4 Granulation Lactose Monohydrate 213.0 23.7 II (Lactose 200 Mesh) Copovidone 18.0 2.0 (Kollidon VA 64) Phase IV Colloidal Silicon 7.0 0.8 Dioxide (Aerosil 200) Magnesium Stearate 5.0 0.6 Total Core Tablet Weight 900.0 100

Brief Manufacturing Process (Example 9):

[0113] Step-1: Ingredients in Phase I are mixed to form a homogeneous blend.

[0114] Step-2: The mixture in Step-1 is granulated with binder solution comprising copovidone (Phase II). Obtained wet granules are dried and sifted.

[0115] Step-3: Ingredients in Phase III are mixed and granulated with water. The wet granules obtained are dried and sieved.

[0116] Step-4: The mixture from Step-2 and Step-3 are mixed.

[0117] Step-5: Ingredients in Phase IV are added to the mixture in Step-4 and mixed further to form a homogeneous blend.

[0118] Step-6: The granule blend from Step-5 is compressed into tablets.

[0119] The bulk density of the final blend prior to compression as prepared in Formula IX (Example 9) is measured to be 0.41 g/mL. The dissolution characteristics of tablets obtained from Example 9 are studied in solutions of pH 1.2, 4.5 and 6.8 using the method described in Table 1. The mean values of otilonium bromide released in 15 minutes are given in Table 6. The amount of otilonium bromide released in 15 minutes reached the desired level (>85%) at all three pH conditions.

TABLE-US-00015 TABLE 6 Released otilonium bromide in 15 minutes Otilonium bromide 40 mg + Simethicone 80 mg Tablets (Example 9) pH 1.2 95% pH 4.5 87% pH 6.8 86%

[0120] Alternatively, liquid simethicone can be used in the formulation instead of powder simethicone. Tl is demonstrated in Example 10.

Example 10

[0121]

TABLE-US-00016 Unit Formula Formula X (mg) % Wet Phase I Microcrystalline 445.0 49.4 Granulation Cellulose I (Avicel PH102) Crospovidone 45.0 5.0 (Polyplasdone XL-10) Colloidal Silicon 20.0 2.2 Dioxide (Aerosil 300) Phase II Simethicone (liquid) 80.0 8.9 Copovidone 27.0 3.0 (Kollidon VA 64) Wet Phase III Otilonium Bromide 40.0 4.4 Granulation Lactose Monohydrate 213.0 23.7 II (Lactose 200 Mesh) Copovidone 18.0 2.0 (Kollidon VA 64) Phase IV Colloidal Silicon 7.0 0.8 Dioxide (Aerosil 200) Magnesium Stearate 5.0 0.6 Total Core Tablet Weight 900.0 100

Brief Manufacturing Process (Example 10):

[0122] Step-1: Microcrystalline cellulose, crospovidone, and colloidal silicon dioxide are mixed to form a homogeneous blend.

[0123] Step-2: Simethicone (liquid) is added to the mixture from Step-1 and mixed.

[0124] Step-3: The mixture in Step-2 is granulated with binder solution comprising copovidone. Obtained wet granules are dried and sifted.

[0125] Step-4: Otilonium bromide, lactose monohydrate and copovidone are mixed and granulated with water. The wet granules obtained are dried and sieved.

[0126] Step-5: The mixture from Step-3 and Step-4 are mixed.

[0127] Step-6: Colloidal silicon dioxide and magnesium Stearate are added to the mixture in Step-5 and mixed further to form a homogeneous blend.

[0128] Step-7: The granule blend from Step-6 is compressed into tablets.

[0129] The bulk density of the final blend prior to compression as prepared in Formula X (Example 10) is measured to be 0.42 g/mL. The dissolution characteristics of tablets obtained from Example 10 are studied in solutions of pH 1.2, 4.5 and 6.8 using the method described in Table 1. The mean values of otilonium bromide released in 15 minutes are given in Table 7. The amount of otilonium bromide released in 15 minutes reached the desired level (>85%) at all three pH conditions.

TABLE-US-00017 TABLE 7 Released otilonium bromide in 15 minutes Otilonium bromide 40 mg + Simethicone 80 mg Tablets (Example 10) pH 1.2 100% pH 4.5 99% pH 6.8 94%

[0130] The inventors have concluded that that when the interaction between simethicone and otilonium bromide is minimized/prevented, the compressibility disadvantage is conquered and the dissolution characteristics of the tablets are improved.

[0131] According to the first method of the invention, when the ratio of otilonium bromide to simethicone is from about 1:1 to 1:5, and the ratio of simethicone to mannitol is about from 1:5 to 1:20, it enables more than 85% of said otilonium bromide to be released in 15 minutes in 0.1 N HCl, pH 4.5, pH 6.8 buffer solutions at 370.5 C. using USP type II (paddle) apparatus rotating at 50 rpm, and the final blend prior to compression has a bulk density of at least 0.35 g/mL.

[0132] According to the second method of the invention when otilonium bromide and simethicone are prepared as separate granules to prevent direct contact of simethicone with otilonium bromide, it enables more than 85% of otilonium bromide to be released in 15 minutes in 0.1 N HCl, pH 4.5, pH 6.8 buffer solutions at 370.5 C. using USP type II (paddle) apparatus rotating at 50 rpm, and the final blend prior to compression has a bulk density of at least 0.40 g/mL.

[0133] While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes may be made to the invention by those skilled in the art which also fall within the scope of the invention as defined by the appended claims.