OA16412A

OA16412A - 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.

Info

Publication number: OA16412A
Application number: OA1201300202
Authority: OA
Inventors: Roberto Bernardo Escudero; John Claude Savoir Vilbouef
Original assignee: Posi Visionary Solutions, Llp
Priority date: 2010-11-16
Filing date: 2011-11-15
Publication date: 2015-10-07

Abstract

The invention relates to a pharmaceutical formulation or composition intended to be administered orally in the form of a tablet, a coated tablet or a capsule, for the prevention or treatment of intestinal disorders, such as irritable bowel syndrome, comprising an intestinal motility modifier, an agent that prevents gas retention, digestive enzymes, a binding agent, a diluent, an adsorbent agent, a disintegrating agent, a lubricant and a glidant, effective for normalising colon transit, for providing an analgesic activity, for providing an antispasmodic activity and for reducing symptoms related to intestinal gas, such as distention, abdominal pain and flatulence.

Description

This invention involves a pharmaceutical composition and its préparation in the form of a tablet, coated tablet, or capsule to be used in the treatment of irritable bowel syndrome, also known as irritable colon syndrome, based on: an intestinal motility modifier, an agent that prevents gas 10 rétention, a digestive enzyme, a binding agent, a diluting agent, an adsorbent, a désintégrant, a lubricant, and a glidant.

BACKGROUND

Enzymes as médications hâve two important features that distinguish them from other types of drugs. First, enzymes normally bind and act upon their substrates with high affinity and specificity;

second, enzymes are catalytic molécules, meaning they decrease the activation energy of a determined reaction, through which they couvert multiple white molécules (substrates) into the desired products. The two aforementioned features inake pharmaceutical enzymes potent and spécifie so they can carry out a therapeutic biochemical activity in the body that small molécules cannot; as a resuit, scientists hâve worked on the development of various enzymes for use as therapeutic agents. This concept of therapeutic enzymology already existed as substitution therapy for use in cases of genetic deficiencîes in the 1960s. In 1987 the Food and DrugAdministration approved the first drug containing a recombinant enzyme, Activase® (alteplase, a recombînant human tissue plasminogen activator) for treatment of heart attacks caused by a clôt blocking a coronary artery. In 1990, Adagen®, a form of bovine adenosine deaminase (BAD) treated with polyethylene glycol was approved for use in patients with a type of severe combined immunodeficiency (SCID), which is caused by chronic BAD deficiency. In 1994 Ceredase® was approved, the first enzyme replacement therapy with a recombinant enzyme, for the treatment of Gaucher’s disease, reiated to lysosomal storage disease caused by glucoccrebrosidase deficiency. Sacarosidase, a fructohydrolase β-fructofüranoside obtained from Saccharomyces cerevisiae yeast, 5 is used in the treatment of congénital sucrase-isomaltase enzyme deficiency (CSID) in which patients are incapable of metabolizing sucrose. In the case of phenylketonuria, a genetic disease caused by reduced or non-existent activity of the phenylalanine hydroxylase enzyme, which couverts phenylalanine into tyrosine, an oral treatment is being used in oral treatment based on the phenylalanine ammonialyase enzyme that is derived from a yeast, which dégradés phenylalanine in 10 the gastrointestinal tract. Another enzyme, a pcptidase, is used in an oral formulation as a supplémentai therapy in cases of Celiac’s disease, a dîsorder of the small intestine caused by an autoimmune System reaction to the protein gliadin, which is found in products derived from wheat (Vellard, Michael. The enzyme as a drug: application of enzymes as pharmaceuticals. Current Opinion in Biotechnology.2003. Vol. 14: 444 - 450). The hydrolytic enzyme a-D-galactosidase, 15 used in the treatment of gastrointestinal disorders, transforms non-absorbable oligosaccharides in the intestinal tract to prevent them from being fermented by intestinal bacterial flora (a gas-producîng process); in reducing intestinal gas production, viscéral distention is decreased and therefore, symptoms like distention, abdominal pain and flatulence decrease as well (http://www.beanogas.com accessed on Aprîl 28, 2009). a-D-galactosidase hydrolyzes three 20 complex carbohydrates: raffinose, stachyose and verbascose lo transform them into monosaccharides: Glucose, galactose and fructose and into the disaccharide: sucrose (whose hydrolysis is instantaneous during normal digestion). The a-D-galactosidase enzyme is not normally produced by human beings, for which reason raffinose, stachyose and verbascose arrive intact at the colon, where they are fermented by bacterial flora in a chemical reaction that produces hydrogen and methane (gas). Administration of the enzyme with food breaks up these three oligosaccharides before they arrive at tbe colon, preventing fermentation and gas production. The a-D-galactosidase that is used as a médication cornes from the non-toxic food-grade fungus /Î5pergt7/i«’Hzger(hltp://www.bcanogas.com accessed on April 28, 2009), Varions other enzymes exist that are used medicinally for digestive disorders, among them amylase, β-D-galactosidase, cellulase, hemicellulase, lipase, papain, pcpsin, rutin, chymotrypsin and trypsin.

Irritable bowel syndrome (IBS), previously known as irritable colon syndrome, is a functîonal disorder of the intestine, characterized by symptoms of abdominal dîscomfort or pain that are associated with changes in bowel habits. IBS is currently understood to be a resuit of interactions 10 between many factors that contribute to the onset of symptoms, radier than as a singular disease. There is no single physiopathological mechanism that can explain it but there are at least 3 înterrelatcd factors that act in ways that vary from person to person.

The factors are:

i) Changed intestinal reactivity, ii) motility or sécrétion in response to provocative luminal stimuli (food, distention, inflammation, bacterial factors) or environmental stimuli (psycho-social stress) that result in symptoms of diarrhea or constipation and iii) bowel hypersensitivîty with increased viscéral perception and pain.

Changes in régulation of the “brain-intestine” axis.

Diagnosis of IBS is based on identifying positive symptoms, callcd the Rome III

Diagnostic Criteria (Longstreth, G.F. 2006. Functîonal bowel disorders. Gastroenterology. Vol. 130, No. 5:1480-91), and on rulîng out other intestinal tract diseases with similar manifestations. These criteria are:

Recurring abdominal discomfort or pain for at least three days per month for the last three months, associated with two or more of the following conditions: a) improvement with défécation, b) onset associated with a change in the frequency of bowel movements and c) onseï associated with a change in the appearance of stool.

In which discomfort refers to a disagreeable sensation not described as pain.

The criteria must hâve been fulfîlled in the last three months, with onset of symptoms at least six months before diagnosis.

IB S is one of the most common medical disorders in the world, occurring more frequently in women aged 30 to 50, with prevalence in Latin America between 9 and 18% (Schmulson, Max J. 2008. Limited diagnostic screening can decrease the direct économie impact of irritable bowel syndrome (IBS). Rev Med Chile. Vol. 136: 1398 - 1405).

The symptom pattern in Mexico is IBS with constipation; abdominal distention is a common symptom in this pattern of the disease. In the Mexican population, abdominal distention and gas are reported as symptoms with high frequency. Irritable bowel syndrome is a real pathological condition that has significant impact on those who suffer from il (symptom severity, functional impairment, diminished quality of life), in addition to constituting a significant économie burden for society and the state, in terms of the costs of medical care and absences from work (American Gastroenlerological Association; 2002; American Gastroenlerological Association position statement; “irritable bowel syndrome. Gastroenterology”. Vol. 123, No. 6:2105-7).

There is no idéal or standard treatment for this disease. Trimebutine maleate, commonly known as trimebutine, has been used since 1969 as treatment for functional bowel disorders, including irritable bowel syndrome. Its principal effects are regularïzation of intestinal motility and an elevated threshold for pain caused by viscéral distention (Roman F. J., et al. 1999.

Pharmacologtcal properties of trimebuline and N-monodesmethyllrimebutine. J Pharmacol Exp Ther. Vol. 289, No. 3:1391- 1397).

Abdominal pain, distention and flatulence represent very common symptoms in functîonal bowel disorders, including irritable bowel syndrome, but their physiopathology and treatment have not been completely explained. Patients frequently associate these symptoms with excessive gas production in the bowel and réduction of the iatter could represent an effective strategy for symptomatic improvement in irritable bowel syndrome, for which simethicone has been used. Simethicone is an inert silicon thaï acts directly on the surface tension of gastrointestinal mucous, thus affecting the formation of bubbles in the digestive tract, destroying them and encouragîng the confluence of small bubbles into bigger bubbles, which translates into the prévention of gas rétention and the associated discomforts. It is important to note that these symptoms may be produced or worsened in a patient with irritable bowel syndrome, not only by an increase in gas production, but also by the “normal” presence of gas in the digestive tube coupled with increased viscéral sensitivity. Strategies do currently exist for the treatment of this problem, such as the use ofactivatcd carbon,dietary restriction and probiotic consumption; however, none of these are idéal and the results obtained are contradictory in each case. In this context, the breakdown of non-absorbable oligosaccharides, found in legumes, fruits and vegetables, before they reach the colon (where they will be fermented by bacterial flora and will produce gas) may represent an attractive alternative. Administration of a-D-galactosidase may achieve this effect (Di Stefano M., et al. 2007; “The effect of oral alpha-galactosidase on intestinal gas production and gas-related symptoms”. Dig Dis Sci. January. Vol. 52, No. 1:78-83).

There are pharmaceutical products that modify intestinal motility for use with intestinal disorders, such as:

Trimebutine and its salts.

Fenoverine.

Mebeverine.

Dicycloverine.

Pinavcrium bromide.

Alosetron.

Tegaserod.

Loperamide.

Floroglucinol.

T ri met i I floroglucino l.

Butylscopolamine.

Pargeverine.

Ail of these can be used in combination with simcthicone to obtain a pharmaceutical formulation for oral administration to be used in intestinal disorders, as is the spécifie case with irritable bowel syndrome.

There are also various enzymes with physiological activity that are useful in the treatment of intestinal disorders, such as: a-D-galactosidasc, amylase, cellulase, hemicellulase, lipase, papain, rulin, chymotrypsin and trypsin.

AU of the aforementioned enzymes can be used in combination with simethicone and with intestinal motility modifiers to obtain a pharmaceutical formulation for oral administration to be used in intestinal disorders, as is the spécifie case with irritable bowel syndrome.

The combination of trimebutine and its salts, a regulating agent of intestinal motility with analgésie properties, simethicone, an agent that prevents gas rétention, and an enzyme or enzyme combination, results in an effective treatment for symptomatology réduction in patients with irritable bowel syndrome.

Considering that trimebutine acts upon Auerbach’s(muscular) and Meissner’s (submucosal) plexus specifically, it acts upon the enkephalinergic receptors responsible for regulating peristaltic movements. Trimebutine acts as much on hypermotility as on hypomotility, depressing or elevating peristalsis and leading to normalizalion of intestinal transit. Trimebutine also has analgesic(modulation of viscéral sensitivity), antispasmodic and antiemetic propeilies (Delvaux M. & Wingate D. 1997. Trimebutine: “Mechanism of action, effects on gaslrointestinal fonction and clinical results”. J Int Med Res. Vol. 25, No. 5:225-46).

Among the solutions that hâve been proposcd to treat IBS symptomatology, the paper W02001/047515 reports the use of trimebutine alone, to develop a useful médication to treat somatic pain and abdominal inflammation; however, it only focuses on symptom relief for this ailinent.

Similarly, numerous papers exist conceming the treatment of inflammation, abdominal pain and ailments associated with IBS; however, treatment of IBS at its source has not been resolved in any of said papers as shown by the following citations:

The paper MXPA02006376 refera to the use of trimebutine alone to prevent or treat somatic pain and inflammation associated with gastric ailments; however, when looking to alleviale symptoms, pain is not eradicated as a fonction of ils causal agent.

The paper US 2003/0119903 reports the use of trimebutine alone to préparé a médication to treat somatic inflammatory pain as well as chronic pain associated with gastric ailments.

The paper US 2004/0009234 reports a pharmaceutîcal composition and associated treatment to prevent gastrointestinal disorders, making use of trimebutine alone without achieving the desired end resuit of combatting the origin of these ailments.

The paper MX00PA05G10821A reports the use of trimebutine to treat constipation, without achievîng the desired end resuit of combating the origin of these ailments.

The paper WOl 995001803 reports the use of trimebutine to treat gastrointestinal pain and disorders such as indigestion caused by excessive food intake, gastro-esophageal reflux, 5 dyspepsia and constipation without achievîng the desired end resuit of combating the source of these ailments.

The paper W095001784 reports the use of a pharmaceutical composition for treating and alleviating indigestion, heartburn and other gastrointestinal disorders using famotidine, sucralfate, simethicone and a-D-galactosidase; however, the composition of the specîfied publication lacks an 10 agent that effectively promûtes rapid gastric emptying, which makes it inefficient in the treatment of

IBS, as the patient who is unable to defecate quickly wili not hâve a sensation of relief.

The paper US 2008/0038240 reports the use of enzymes to improve absorption of carbohydrates in humans, avoiding the formation of intestinal gases.

The paper US 4447412 reports an enzyinatic composition for the treatment of digestive dysfunction, composed of pancreatic and proteolytic enzymes.

The paper US 4079125 reports an extended-release enzymatic composition able to withstand several hours of exposure to gastric fluids, protecting the biological activity of the enzymes and releasing them after 5-30 minutes of exposure to intestinal fluids.

The papers US 5460812 and US 324514 report the use of enzymes in the treatment of 20 digestive disorders.

One objective of this invention is to provide a pharmaceutical composition for oral administration with application in intestinal disorders based on an intestinal motility modifier, an

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agent that prevents gas rétention, digestive enzymes, a binding agent, a diluting agent, an adsorbent, a disintegrant, a lubricant, and a glidant.

Another objective of this invention is to provide a pharmaceutical formulation for oral administration with application in intestinal disorders based on an intestinal motility modifier, an agent that prevents gas rétention, digestive enzymes, a binding agent, a diluting agent, an adsorbent, a disintegrant, a lubricant, and a glidant thaï is effective in normalizing intestinal transit.

Another objective of this invention is to provide a pharmaceutical formulation for oral administration with application in intestinal disorders based on an intestinal motility modifier, an agent that prevents gas rétention, digestive enzymes, a binding agent, a diluting agent, an adsorbent, a disintegrant, a lubricant, and a glidant that is effective in achieving analgésie activity in the treatment of gastrointestinal ailments.

Another objective of this invention is to provide a pharmaceutical formulation for oral administration with application in intestinal disorders based on an intestinal motility modifier, an agent that prevents gas rétention, digestive enzymes, a binding agent, a diluting agent, an adsorbent, a disintegrant, a lubricant, and a glidant that is effective in achieving antispasmodic activity.

A final objective of this invention is to provide a pharmaceutical composition or .formulation for oral administration with application in intestinal disorders based on an intestinal motility modifier, an agent that prevents gas rétention, digestive enzymes, a binding agent, a diluting agent, an adsorbent, a disintegrant, a lubricant, and a glidant that is effective in reducing symptoins related to intestinal gas such as distention, pain and flatulence.

DETAILED DESCRIPTION OF THE INVENTION %

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 rétention and digestive enzymes.

The intestinal motility modifier, the agent that prevents gas rétention, the digestive enzyme, the binding agent, the diluting agent, the disinlegrant, the lubrîcant, and the glidant, are mixed.

A binder solution is prepared.

The intestinal motility modifier, the enzyme a-D-galactosidase, the binding agent, the diluting agent, the disinlegrant, the lubricant, and the glidant are sîfted in order to break up any clumps.

Ail of the substances mentioned in the previous step are mixed and then moistened with the binder solution.

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

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

The tablets or capsules are packaged in packing material.

To carry out the specified manufacturing process, one will use the equipment that is conventionally used in the production of a pharmaceutical fomiulation with the indicated charactcristics. Ail of the raw materials used are of pharmaceutical grade. Below, some practical examples of how the formulations were prepared are detaiied for illustrative, but not restrictive, purposes.

Examples

An example of tablet formulation of Trimebutine Maleate/a-Dgalactosidase/Simethicone obtained by wet granulation.

Component	Amount
Trimebutine maleate	200.000 mg
Simethicone	75.000 mg
a-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
Dîbasic calcium phosphate	300.000 mg
Magnésium stéarate	10.000 mg

*90 mg is équivalent to 450 U/gal. U/Gal considering a raw material of a-D-galactosidase with 5 enzymatic activity of 5,,000 U/gal per gram.

Procedure for manufacturing tablets of Trimebutine Maleate/a-D-galactosidase/Simethicone by wet granulation.

1. Préparé a binder solution by dispersing 20% of the piegelatinized starch in a sufficient amount of water.

2. Pass the following raw materials through a sieve with mesh size of 420 to 2,000 microns:

- The rest of the piegelatinized starch (80%)

- The a-D-galactosidase

- Trimebutine maleate

- Lactose hydrous

- Croscarmellose sodium

- Dîbasic calcium phosphate

3. Add the dibasic calcium Phosphate and the pregelalinized starcli (80%) into the mixer/granulator and mix for 5 to 20 minutes at 50 to 200 rpm,

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.

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

6. Moisten with the binder solution from step 1.

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

8. Dry the product at a température of 30 to 60°C until it reaches a residual humidlty of

1.0 - 3.0%.

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.

10. Pass the microcrystalline Cellulose and the magnésium stcarate through a sieve with a mesh size from 420 to 2,000 microns.

11. Add the following products to the mixer;

The granules obtained in step 9;

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

12. Add the magnésium stéarate obtained in step 9 to the mixer and mix for 5 to 10 minutes at 15 to rpm.

13. Compress the product obtained in step 12.

An example of lhe formulation of Trimebutine Maleate/a-D-galactosîdase/Simethicone tablets obtained by direct compression.

Component	Amount
Trimebutine maleate	200,000 mg
Simethicone	75,000 mg
a-D-galactosidase	90,000 mg*
Croscarmellose sodium	30,000 mg
Microcrystalline cellulose	210,000 mg
Magnésium aluminometasilicate	310,000 mg
Magnésium stéarate	10,000 mg

*90 mg are équivalent to 450 U/gal. U/Gal considering a raw material of a-D-galactosidase with enzymatic activity of 5.000 U/gal per gram.

Example Procedure for the manufacture of Trimebutine Maleate/a-D-galactosidase/Simethicone tablets by direct compression.

1. Pass the following raw materials through a sieve with rnesh size of 420 to 2,000 microns:

- The a-D-galactosidase

- Trimebutine maleate

- Microcrystalline cellulose

- Croscarmellose sodium

- Dibasic calcium phosphate

2. Add the magnésium 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 tinte not to exceed 30 minutes (Mixture A).

3. Add the following products to a mixer:

Half of mixture A from step 2

Half of lhe microcrystalline Cellulose

Half of the Trimebutine maleate

The a-D-galactosidase

The Croscarmellose sodium

The rest of the Trimebutîne nialeate

The rest of the microcrystalline Cellulose

The rest of mixture A

And mix for 10 to 30 minutes at 15 to 30 rpm (mixture B)

4. Pass the magnésium stéarate through a sieve with mesh size of 420 to 2,000 microns.

5. Add the magnésium stéarate obtained in step 4 to mixture B and mix for 5 to 10 minutes at 15 to 30 rpm.

6. Compress the product obtained in step 5.

An example of manufacturîng Trimebutîne Maleale/a-D-galactosidase/Simethîcone tablets obtained through dry granulation.

Component	Amount
Trimebutîne maleate	200.000 mg
Simelhicone	75.000 mg
a-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
Magnésium stéarate	10.000 mg

*90 mg are équivalent to 450 U/gal. U/Gal eonsidering a raw material of a-D-galactosidase with enzymatic activity of 5000 U/gal per gram.

Example Procedure for the manufacture of Trimebutîne Maleate/a-D15 galactosidase/Simethicone tablets by dry granulation.

1. Pass the following raw matériels through a sieve with mesh size of 420 to 2,000 microns:

b

- The hydroxypropyl cellulose

- The a-D-galactosidase

- Trimebutine maleate

- Lactose hydrous

- 50% of the Crospovidone

Dibasic Calcium Phosphate.

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.

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

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

5. Compress the product obtained in step 4.

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

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

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

9. Pass the 50% of the Crospovidone, the microcrystalline cellulose, and the magnésium Stéarate through a sieve with a mesh size of 420 to 2,000 microns,

10. Add the following products to the mixer.

The granules obtained in step 8.

50% of the Croscarmellose Sodium from step 9.

The Microcrystalline cellulose obtained in step 9

And mix for 10 to 30 minutes at 15 to 30 rpm.

11. Add the magnésium stéarate obtained in step 9 to the mixer and mix for 5 to 10 minutes at 15 to 30 rpm.

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

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 magnésium silicate, colloïdal silicon dioxide, microcrystalline cellulose
Disintegrating Agent	Croscarmellose sodium, corn starch, crospovidone
Lubricating Agent	Magnésium stéarate, talc, stearic acid
Gliding Agent	Colloïdal Silicon Dioxide

-The diluting agent is selected from the excipients that hâve the function of increasing the apparent volume of the powder, and as such, increase the weight of the pill or capsule.

- The absorbing agent is selected from the excipients that are able to absorb certain amounts of liquid in an apparently dry condition.

-The disintegrating agent is selected from the excipients that are able to break (disintegrate) the pill and the granules when they corne into contact with a liquid.

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-The lubricating agent is selected from the excipients that are able lo reduce the friction between the granules and the wall of the matrix during the process of compression or filling of the capsules.

-The gliding agent is selected from the excipients that are able to 5 provide a flow to the granules of the hopper to the cavity of the matrix through the réduction of inter-paiticle friction.

-The binding agent is selected from the excipients that provide cohesiveness to the materials in powder form, forming granules.

Claims

1. Use of an intestinal motility modifier, an agent which prevents the rétention of gases, a digestive enzyme, a binding agent, a diluting agent, an absorbing agent, a disintegrating agent, a lubricating agent and a gliding agent in the manufacture of a pharmaceutical composition or

5 formulation for the prévention or treatment of intestinal disorders, said pharmaceutical composition or formulation being for oral administration in tablet, coated tablet or capsule form.

2. The use in accordance with claim 1, wherein the intestinal motility modifier is selected from a group which consists of trimebutine, fenoverine, mebeverine, dicycloverine, ethyl bromide, alosetron, tegaserod, loperamide, phloroglucinol, trimethylphloroglucinol, butylscopolamine, and

10 pargeverine.

3. The use in accordance with claim 1, wherein the absorbing agents are selected from the group that includes dibasic calcium phosphate, aluminum and magnésium silicate, colloïdal silicon dioxîde and microcrystalline cellulose.

15

4. The use in accordance with claim 1, wherein the disintegrating agents are selected from croscarmellose sodium, corn starch and crospovidone .

5. The use in accordance with claim 1, wherein the gliding agent is colloïdal silicon dioxide.

6. The use in accordance with claim 1, wherein the agent for the prévention of gases is simethicone.

7. The use in accordance with claim 1, wherein the enzyme is selected from a-D-

25 galactosidase, amylase, β-D-galactosidase, cellulase, hemicellulase, lipase, papain, pepsin, chymotrypsin, rutin, and trypsin.

8. The use in accordance with claim 7, wherein the digestive enzyme is a-D-galactosidase with an enzymic energy of 450 U gai.

S

9. A process to préparé a pharmaceutical composition for oral administration in tablet, coated tablet or capsule form for intestinal disorders, based on an intestinal motility modifier, an agent which prevents the rétention of gases and digestive enzymes, which includes mixing and sieving an intestinal motility modifier, an agent which prevents the rétention of gases and digestive

10 enzymes having been previously prepared, a binding solution to humidify the intestinal motility modifier and digestive enzyme; the mix is immediately grindcd, dried and sieved; obtaining a pharmaceutical formulation adapted for oral administration.