ORALLY ADMINISTERED PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF IRRITABLE BOWEL SYNDROME, COMPRISING AN INTESTINAL MOTILITY MODIFIER, AN AGENT THAT PREVENTS GAS RETENTION, AND DIGESTIVE ENZYMES, AND PREPARATION METHOD THEREOF

Abstract

A pharmaceutical composition or formulation adapted for oral administration in tablet, coated tablet, capsule or reconstitutable powder form for the prevention or treatment of intestinal disorders such irritable bowel syndrome, also known as irritable colon syndrome, based on an intestinal motility modifier, an agent that prevents gas retention, of digestive enzymes, a binding agent, a diluting agent, an absorbent agent, a lubricant, aglidant, and an disintegrating agent or suspending agent, effective in the normalization of intestinal disorders, to achieve an analgesic activity, to achieve an anti-spasmic activity and to reduce the symptoms associated with intestinal gas such as distention, abdominal pain and flatulence.

Claims

1. A method comprising (a) identifying a patient having recurring abdominal discomfort or pain for at least three days per month for the last three months, wherein the recurring abdominal discomfort or pain is associated with two or more of the following conditions in the patient: a) improvement with defecation, b) onset associated with a change in the frequency of bowel movements, and c) onset associated with a change in the appearance of stool, and wherein the discomfort is a disagreeable sensation not described as pain, and (b) administering to the patient a pharmaceutical composition in an amount effective for treating the recurring abdominal discomfort or pain in the patient, wherein the pharmaceutical composition consists of trimebutine or a pharmaceutically acceptable salt thereof, simethicone, -D-galactosidase, and pharmaceutically acceptable excipients.

2. The method of claim 1, wherein the pharmaceutically acceptable salt of trimebutine is trimebutine maleate.

3. The method of claim 2, wherein the composition has 200 mg of the trimebutine maleate.

4. The method of claim 1, wherein the composition has 75 mg of the simethicone.

5. The method of claim 1, wherein the composition has 90 mg of the -D-galactosidase.

6. The method of claim 1, wherein the enzymatic activity of the -D-galactosidase is 450 U/gal.

7. The method of claim 1, wherein the pharmaceutically acceptable excipients consist of a binding agent, a diluting agent, an absorbing agent, a disintegrating agent, a lubricating agent and a gliding agent.

8. The method of claim 7, wherein the binding agent is selected from the group consisting of hydroxypropyl cellulose, corn starch, propyl cellulose and methyl cellulose.

9. The method of claim 7, wherein the diluting agent is selected from the group consisting of lactose, Microcrystalline cellulose, mannitol and sucrose.

10. The method of claim 7, wherein the absorbing agent is selected from the group consisting of dibasic calcium phosphate, aluminum and magnesium silicate, colloidal silicon dioxide and microcrystalline cellulose.

11. The method of claim 7, wherein the disintegrating agent is selected from the group consisting of croscarmellose sodium, corn starch and crospovidone.

12. The method of claim 7, wherein the lubricating agent is selected from the group consisting of magnesium stearate, talc and stearic acid.

13. The method of claim 7, wherein the gliding agent is colloidal silicon dioxide.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0051] The pharmaceutical formulation is prepared in the form of a tablet, coated tablet, or capsule, for use in irritable bowel syndrome, also known as irritable colon syndrome, based on an intestinal motility modifier, an agent that prevents gas retention and digestive enzymes.

[0052] The intestinal motility modifier, the agent that prevents gas retention, the digestive enzyme, the binding agent, the diluting agent, the disintegrant, the lubricant, and the glidant, are mixed.

[0053] A binder solution is prepared.

[0054] The intestinal motility modifier, the enzyme -D-galactosidase, the binding agent, the diluting agent, the disintegrant, the lubricant, and the glidant are sifted in order to break up any clumps.

[0055] All of the substances mentioned in the previous step are mixed and then moistened with the binder solution.

[0056] The product resulting from the previous step is ground, dried and sifted.

[0057] If the final composition is solid, the mixture is compressed to form a tablet or a coated tablet; otherwise capsules are prepared.

[0058] The tablets or capsules are packaged in packing material.

[0059] To carry out the specified manufacturing process, one will use the equipment that is conventionally used in the production of a pharmaceutical formulation with the indicated characteristics. All of the raw materials used are of pharmaceutical grade. Below, some practical examples of how the formulations were prepared are detailed for illustrative, but not restrictive, purposes.

EXAMPLES

[0060] An example of tablet formulation of Trimebutine Maleate/-D-galactosidase/Simethicone obtained by wet granulation.

TABLE-US-00001 Component Amount Trimebutine maleate 200.000 mg Simethicone 75.000 mg -D-galactosidase 90.000 mg* Pregelatinized starch 75.000 mg Lactose hydrous 105.000 mg Croscarmellose sodium 30.000 mg Microcrystalline cellulose 115.000 mg Dibasic calcium phosphate 300.000 mg Magnesium stearate 10.000 mg *90 mg is equivalent to 450 U/gal. U/Gal considering a raw material of -D-galactosidase with enzymatic activity of 5,,000 U/gal per gram.

Procedure for Manufacturing Tablets of Trimebutine Maleate/-D-Galactosidase/Simethicone by Wet Granulation.

[0061] 1. Prepare a binder solution by dispersing 20% of the pregelatinized starch in a sufficient amount of water.

[0062] 2. Pass the following raw materials through a sieve with mesh size of 420 to 2,000 microns: [0063] The rest of the pregelatinized starch (80%) [0064] The -D-galactosidase [0065] Trimebutine maleate [0066] Lactose hydrous [0067] Croscarmellose sodium [0068] Dibasic calcium phosphate

[0069] 3. Add the dibasic calcium Phosphate and the pregelatinized starch (80%) into the mixer/granulator and mix for 5 to 20 minutes at 50 to 200 rpm.

[0070] 4. At the end of this mixing and without stopping the stirring, manually add the simethicone in string form over a time period not to exceed 15 minutes.

[0071] 5. Add the Trimebutine Maleate, -D-galactosidase, Lactose hydrous and Croscarmellose sodium to the mixer and mix for 5 to 20 minutes at 50 to 200 rpm.

[0072] 6. Moisten with the binder solution from step 1.

[0073] 7. Pass the product obtained from the grinder in step 6 through a sieve with openings from 3,000 to 5,000 microns.

[0074] 8. Dry the product at a temperature of 30 to 60 C. until it reaches a residual humidity of 1.0-3.0%.

[0075] 9. Grind the product obtained in step 8 through a grinder with a sieve from 0.033 to 0.094 inches and at a speed of 500 to 1,500 rpm.

[0076] 10. Pass the microcrystalline Cellulose and the magnesium stearate through a sieve with a mesh size from 420 to 2,000 microns.

[0077] 11. Add the following products to the mixer:

[0078] The granules obtained in step 9;

[0079] the microcrystalline Cellulose obtained in step 10 and mix for 10 to 30 minutes at 15 to 30 rpm.

[0080] 12. Add the magnesium stearate obtained in step 9 to the mixer and mix for 5 to 10 minutes at 15 to 30 rpm.

[0081] 13. Compress the product obtained in step 12.

[0082] An example of the formulation of Trimebutine Maleate/-D-galactosidase/Simethicone tablets obtained by direct compression.

TABLE-US-00002 Component Amount Trimebutine maleate 200,000 mg Simethicone 75,000 mg -D-galactosidase 90,000 mg* Croscarmellose sodium 30,000 mg Microcrystalline cellulose 210,000 mg Magnesium 310,000 mg Magnesium stearate 10,000 mg *90 mg are equivalent to 450 U/gal. U/Gal considering a raw material of -D-galactosidase with enzymatic activity of 5.000 U/gal per gram.

Example Procedure for the Manufacture of Trimebutine Maleate/-D-Galactosidase/Simethicone Tablets by Direct Compression.

[0083] 1. Pass the following raw materials through a sieve with mesh size of 420 to 2,000 microns: [0084] The -D-galactosidase [0085] Trimebutine maleate [0086] Microcrystalline cellulose [0087] Croscarmellose sodium [0088] Dibasic calcium phosphate

[0089] 2. Add the magnesium Aluminometasilicate to a mixer and begin stirring at a speed between 40 and 100 rpm. Without stopping the stirring, manually add the Simethicone in string form very gradually over a time not to exceed 30 minutes (Mixture A).

[0090] 3. Add the following products to a mixer: [0091] Half of mixture A from step 2 [0092] Half of the microcrystalline Cellulose [0093] Half of the Trimebutine maleate [0094] The -D-galactosidase [0095] The Croscarmellose sodium [0096] The rest of the Trimebutine maleate [0097] The rest of the microcrystalline Cellulose [0098] The rest of mixture A [0099] And mix for 10 to 30 minutes at 15 to 30 rpm (mixture B)

[0100] 4. Pass the magnesium stearate through a sieve with mesh size of 420 to 2,000 microns.

[0101] 5. Add the magnesium stearate obtained in step 4 to mixture B and mix for 5 to 10 minutes at 15 to 30 rpm.

[0102] 6. Compress the product obtained in step 5.

[0103] An example of manufacturing Trimebutine Maleate/-D-galactosidase/Simethicone tablets obtained through dry granulation.

TABLE-US-00003 Component Amount Trimebutine maleate 200.000 mg Simethicone 75.000 mg -D-galactosidase 90.000 mg* Hydroxypropyl cellulose 50.000 mg Lactose hydrous 110.000 mg Crospovidone 30.000 mg Microcrystalline cellulose 125.000 mg Dibasic calcium phosphate 310.000 mg Magnesium stearate 10.000 mg *90 mg are equivalent to 450 U/gal. U/Gal considering a raw material of -D-galactosidase with enzymatic activity of 5000 U/gal per gram.

[0104] Example Procedure for the Manufacture of Trimebutine Maleate/-D-Galactosidase/Simethicone Tablets by Dry Granulation.

[0105] 1. Pass the following raw materials through a sieve with mesh size of 420 to 2,000 microns: [0106] The hydroxypropyl cellulose [0107] The -D-galactosidase [0108] Trimebutine maleate [0109] Lactose hydrous [0110] 50% of the Crospovidone [0111] Dibasic Calcium Phosphate.

[0112] 2. Incorporate the Dibasic Calcium Phosphate and the hydroxpropyl cellulose to the granulating mixing equipment and mix for 5 and 20 minutes at 50 to 200 rpm.

[0113] 3. After mixing and without stopping stirring, manually add the simethicone in string form for no longer than 30 minutes.

[0114] 4. Add Trimbutine Maleate, -D-galactosidase, Microcrystalline Cellulose, 50% of the Crospovidone to the mixer and mix between 5 and 20 minutes at 50 to 200 rpm.

[0115] 5. Compress the product obtained in step 4.

[0116] 6. Grind the product obtained in step 5 with the granulating equipment with a mesh size of 1,180 to 2,000 microns.

[0117] 7. Compress the granules that were obtained in step 6 again.

[0118] 8. Grind the product obtained in step 7 with the granulating equipment with a mesh size of 1,400 to 1,700 microns.

[0119] 9. Pass the 50% of the Crospovidone, the microcrystalline cellulose, and the magnesium Stearate through a sieve with a mesh size of 420 to 2,000 microns,

[0120] 10. Add the following products to the mixer: [0121] The granules obtained in step 8. [0122] 50% of the Croscarmellose Sodium from step 9. [0123] The Microcrystalline cellulose obtained in step 9 [0124] And mix for 10 to 30 minutes at 15 to 30 rpm.

[0125] 11. Add the magnesium stearate obtained in step 9 to the mixer and mix for 5 to 10 minutes at 15 to 30 rpm.

[0126] 12. Compress the product obtained in step 11. Below are the excipients which can adequately perform the indicated functions:

TABLE-US-00004 Function Excipient Binding Agent Hydroxypropyl cellulose, corn starch, propyl cellulose, methyl cellulose. Diluting Agent Lactose, Microcrystalline cellulose, mannitol, sucrose Absorbing Agent Dibasic calcium phosphate, aluminum and magnesium silicate, colloidal silicon dioxide, microcrystalline cellulose Disintegrating Agent Croscarmellose sodium, corn starch, crospovidone Lubricating Agent Magnesium stearate, talc, stearic acid Gliding Agent Colloidal Silicon Dioxide [0127] The diluting agent is selected from the excipients that have the function of increasing the apparent volume of the powder, and as such, increase the weight of the pill or capsule. [0128] The absorbing agent is selected from the excipients that are able to absorb certain amounts of liquid in an apparently dry condition. [0129] The disintegrating agent is selected from the excipients that are able to break (disintegrate) the pill and the granules when they come into contact with a liquid. [0130] The lubricating agent is selected from the excipients that are able to reduce the friction between the granules and the wall of the matrix during the process of compression or filling of the capsules. [0131] The gliding agent is selected from the excipients that are able to provide a flow to the granules of the hopper to the cavity of the matrix through the reduction of inter-particle friction. [0132] The binding agent is selected from the excipients that provide cohesiveness to the materials in powder form, forming granules.