OA16415A - Orally administred pharmaceutical composition and preparation method thereof, for the prevention and treatment of irritable bowel syndrome, comprising an intestinal motility modifier and a-D-galactosidase. - Google Patents

Abstract

The invention relates to a pharmaceutical formulation or composition in the form of a tablet, coated tablet, capsule or powder for reconstitution, for use in irritable bowel syndrome, comprising an intestinal motility modifier and enzyme a-D-galactosidase.

Description

PHARMACEUTICAL COMPOSITION ADAPTED FOR ORAL ADMINISTRATION AND THE PROCESS FOR ITS PREPARATION, FOR THE PREVENTION AND TREATMENT OF IRRITABLE BOWEL SYNDROME, BASED ON AN INTESTINAL MOTILITY MODIFIER

AND a-D-GALACTOSIDASE

TECHNICAL FIELD

This invention refers to a pharmaceutical composition or formulation in the form of a tablet, coated tablet, capsule or reconstîtutable powder for its use in irritable bowel syndrome, also known as irritable colon syndrome, based on an intestinal motility modifier and the enzyme a-Dgalactosidase.

BACKGROUND

Irritable bowel syndrome (IBS), previously known as irritable colon syndrome, is a functional disorder of the intestine, characterized by symptoms of intestinal discomfort or pain which are associated with alterations of intestinal habits. Currently IBS is understood as being the resuit of the interaction of many factors that contribute to the appearance of common symptoms, more than an illness with a spécifie etiology. It is important to note that there is no single physiopathological mechanism that explains the etiology of IBS; however, in patients who suffer from it, nonetheless, there are at least three interrelated factors that présent themselves, in ways that vary from individual to individual.

The three factors are:

• Altered intestinal reactivity, its motility or sécrétion, in response to luminal provocative stimuli (food, distention, inflammation, bacterial factors) or environmental stimuli (psychosocial stress), which resuit in symptoms of diarrhea or constipation.

• Hypersensitive intestine with încreased viscéral perception and pain.

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

Λ

The diagnosis of IBS is based on the identification of positive symptôme, also known as Roma III Criteria (Longstreth, G.F. 2006. Functional bowel disorders. Gastroenterology. Vol. 130, No. 5:1480-91) and in the ruling out of other illnesses of the intestinal tract with similar symptoms.

These criteria are:

Recurring abdominal discomfort or pain of at least three days a 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, c) onset associated with a 10 change in the appearance of stool.

In which discomfort means an unpleasant sensation not described as pain.

IBS can be considered when presented cases comply with the criteria in the previous three months, with the onset of symptoms at least six months before the diagnosis.

IBS is one of the world’s most common health disorders, occurring more frequently in women 15 between 30 and 50 years of âge, with a prevalence in Latin America of between 9 and 18% (Schmulson, Max J. 2008. Limited diagnostic close examination can reduce the direct économie impact of irritable bowel syndrome (IBS). Rev Med Chile. Vol. 136: 1398-1405),

The symptomatic pattern in Mexico is of IBS with constipation; abdominal distention is a common symptom in this pattern of the illness. In the Mexican population, abdominal distention 20 and gas are reported as symptoms with very high frequency. Irritable bowel syndrome is a real pathological entity that has a significant impact on the lives of those who suffer from it (severity of symptoms, functional impairment, diminished quality of life), in addition to being a serious économie burden for society and the state, in terms of the costs of medical attention and absenteeism in the workforce (American Gastroenterological Association. 2002. American

Gastroenterological Association position statement: irritable bowel syndrome. Gastroenterology.; Vol. 123, No.6:2105-7).

There is no idéal or standard treatment for this iîlness; however, trimebutîne maleate has been used, known commonly as trimebutine, since 1969 for the treatment of functional intestinal 5 disorders, including irritable bowel syndrome. Its principal effects are the regularization of intestinal motility and the élévation of the pain threshold provoked by viscéral distension (Roman F.J., et al. 1999. Pharmacological properties of trimebutine and Nmonodesmethyltrimebutine. J Pharmacol Exp. Ther.; Vol. 289, No. 3:1391-1397).

Abdominal pain, distention, and flatulence represent very frequent symptoms in functional intestinal disorders, including irritable bowel syndrome, but their physiopathology and treatment hâve not been folly explained. Patients frequently associate these symptoms with an excessive production of gas in the intestine and the réduction of the latter could represent an effective strategy in the symptomatic improvement of irritable bowel syndrome. It is important to note that 15 these symptoms can emerge or worsen in a patient with irritable bowel syndrome not only because of the increase in the production of gas, but also because of the “normal” presence of gas in the digestive tract combined with an increased viscéral sensîtivity. There are currently strategies for the treatment of this problem, such as activated carbon, dietary restrictions and probiotics; however, none of them is idéal and the results obtained from these strategies are 20 contradictory. In this context, the fragmentation of nonabsorbable oligosaccharides that are found in legumes, fruits, and vegetables, before they reach the colon (where they will be fermented by bacterial flora and gas will be produced), can represent an attractive alternative. The administration of a-D-galactosidase can 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 25 Sci. January, Vol. 52, No. 1:78-83).

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

t >

Trimebutine and its salts, Fenoverine, Mebeverine, Dicycloverine, Pinaverium Bromide, Alosetron, Tegaserod, Loperamide, Phloroglucinol, Trimethylphloroglucinol, Butylscopolamine, Pargeverine.

Ail the products cited above can be used in combination with a-D-galactosidase to préparé a pharmacological formulation for oral administration to treat, alleviate, and mitigate intestinal disorders, such as irritable bowel syndrome.

In another aspect of the same subject, a-D-galactosidase is produced by several microorganisms; the one which is used as a médication is derived from the nontoxic food grade fungus Aspergillus niger (http://www.beanogas.com consulted on April 28,2009).

The combination of trimebutine and its salts, a regulating agent of intestinal motility with analgésie properties and the a-D-galactosidase enzyme that ferments carbohydrates in the colon, reducing the production of gas (and thus, viscéral distention), is proposed as an effective treatment in the réduction of the symptoms in patients with irritable bowel syndrome.

The trimebutine acts on the Auerbach’s (myenteric) plexus and Meissner’s (submucosal) plexus, on the enkephalinergic receptors responsible for the régulation of peristaltic movements. The trimebutine acts on hypermotility as well as hypomotility, depresses or stimulâtes peristalsis and leads to a normalization of the intestinal tract. Trimebutine also possesses analgésie (modulâtes viscéral sensitivity), antispasmodic and antiemetic properties (Delvaux M. & Wingate D. 1997. Trimebutine: mechanism of action, effects on gastrointestinal function and clinical results. J. Int. Med. Res. Vol. 25, No. 5:225^16).

The a-D-galactosidase enzyme hydrolyzes nonabsorbable oligosaccharides in the intestinal tract avoiding their fermentation by intestinal bacterial flora (process that produces gas); in reducing the production of intestinal gas, it reduces the viscéral distension and, as such, symptoms such as distension,

>

* abdominal pain and flatulence (http://www.beanogas.com consulted on April 28, 2009). The aD-galactosidasc hydrolyzes three complex carbohydrates: raffinose, stachyose, and verbacose and changes them into monosaccharides: Glucose, galactose, and fructose, and into disaccharide sucrose (the hydrolysis is instant in normal digestion). The a-D-galactosidase enzyme is not normally produced by humans, for which reason the raffinose, stachyose, or verbacose reach the colon intact, where they are fermented by bacterial flora, a chemical reaction which produces hydrogen and methane (gas). The administration of the enzyme with food breaks up these three oligosaccharides prior to their arrivai at the colon, preventing the fermentation and production of gas.

The following are food items with a high content of raffinose, stachyose, and verbacose, several of which are very common in the diet of Mexicans (Di Stefano, M., et al. 2007. The effect of oral alpha-galactosidase on intestinal gas production and gas-related symptoms. Dig Dis Sci. J an, Vol. 52, No. 1:78-83): Cereals: Ricc, wheat, corn, oats, barley, muesli (a mix of cereal with dried fruit).

Legumes: Beans, chickpeas, lcntils, peas, soy, broad beans.

Fruits: oranges, bananas, kiwis, grapefiuit.

Nuts: peanuts, almonds, hazelnuts, walnuts, pine nuts, pistachios.

Vegetables: asparagus, broccoli, carrots, cabbage, cucumbers, onions, mushrooms, potatoes, peppers, leeks.

Several state-of-the-art solutions have been found for somatic pain and abdominal inflammation, for example, the paper W02001/047515 reports the use of trimebutine alone to préparé a médication; however, it only focuses on the relief of symptoms of this ailment and not on the ailment itself.

The application MXPA02006376 reports the use of trimebutine alone to prevent or treat somatic pain and inflammation associated with

gastric ailments; however, it is limited to the treatment of the symptoms, not to the ailment or the causes that provoke it.

The paper US 2003/0119903 reports the use of trimebutine alone to préparé a médication to prevent or treat inflammatory somatic pain as well as chronic pain, associated with gastric ailments, and once again it does not treat the source of the pain nor the source of inflammation associated with gastric ailments.

The paper US 2004/0009234 reports on a pharmaceutical composition and the associated 10 treatment for preventing gastrointestinal disorders making use of only trimebutine without achieving the prévention of gastrointestinal disorders, since it does not combat the source of said ailments.

The paper MX00PA05010821A reports the use of trimebutine for the treatment of constipation, 15 without achieving the desired final resuit, as it does not combat the source of these ailments.

The paper W0001995001803 reports the use of trimebutine for the prévention or the treatment of gastrointestinal pain and disorders such as indigestion, excessive ingestion of food, esophageal reflux, dyspepsia and constipation; however, it does not prevent gastrointestinal pain since it 20 does not résolve its causes.

One object of this invention is to provide a pharmaceutical formulation for oral administration, with application in intestinal disorders, based on an intestinal motility modifier and a-Dgalactosidase.

Another object of this invention is to provide a pharmaceutical foimulation for oral administration, with application in intestinal disorders, based on an intestinal motility modifier and a-D-galactosidase to normalize intestinal passage.

Yet another object of this invention is to provide a pharmaceutical formulation for oral administration, with application in intestinal disorders, based on an intestinal motility modifier and a-D-galactosidase, which is effective in achievîng analgésie activity in the treatment of gastrointestinal ailments.

Another object of this invention is to provide a pharmaceutical formulation for oral 5 administration, with application in intestinal disorders, based on an intestinal motility modifier and a-D-galactosidase, which is effective in achievîng antispasmodic activity.

An additional object of this invention is to provide a pharmaceutical formulation for oral administration, with application in intestinal disorders, based on an intestinal motility modifier 10 and a-D-galactosidase, which is effective in reducing symptoms related to intestinal gas, such as distension, pain, and flatulence.

DETAILED DESCRIPTION OF THE INVENTION

The pharmaceutical formulation in the form of a tablet, coated tablet, capsule, or reconstitutable powder to treat irritable bowel syndrome, also known as irritable colon syndrome, based on an intestinal motility modifier and the enzyme a-D-galactosidase, is prepared according to the foilowing procedure:

1. The intestinal motility modifier (100-200 mg) is mixed with the a-D-galactosidase enzyme, a binding agent (2-10%), a diluting agent (20-50%), a disintegrant (1-10%), a lubricant (0.25-5%), and a glidant (0.2-5%).

2. A binder solution is prepared.

3. The intestinal motility modifier, the a-D-galactosidase enzyme, a binding agent, a diluting agent, a disintegrant, a lubricant, and a glidant are sieved through a sieve with a

450 to 2,000 micron mesh in order to break up clumps.

4. Ail éléments mentioned in the prior step are mixed and then moistened with the binder solution.

5. The product resulting from the prior step is ground and dried, and then sieved.

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

7. The tablets/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 formulation with the indicated characteristics. Ail raw materials used are pharmaceutical grade. Some practical examples of how the formulations were prepared are described below:

EXAMPLES

Example l:

Component	Amount
Trimebutine Maleate	200,000 mg
a-D-galactosidase	450,000 GalU*
Hydroxypropyl cellulose	29,000 mg
Lactose hydrous	18,000 mg
Sodium starch glycolate	19,500 mg
Microcrystalline cellulose	100,000 mg
Lactose-cellulose 75:25	121,300 mg
Talc	12,000 mg
Colloïdal silicon dioxide	2,400 mg
Magnésium stcarate	7,800 mg

*450 mg of a-D-galactosidase is équivalent to 450 GalU. GalU refers to the enzymatic activity of the a-D-galactosidase, starting from a raw material with 10,000 GalU per gram.

»

Procedure for Example l: Production of trimebutine maleate, in combination with a-Dgalactosidase, by wet granulation. Intragranular addition of the enzyme,

1. Préparé a binder solution by dispersing 50% of the hydroxypropyl cellulose in a sufficient amount of water.

2. Pass the following raw materials through a sieve with a mesh size of420 to 2,000 microns:

- The rest of the hydroxypropyl cellulose (50%)

- The a-D-galactosidase

- Trimebutine maleate

- Lactose hydrous

Sodium starch glycolate

- Microcrystalline cellulose

3. Add the products from the previous step into the mixer/granulator equipment and mix for between 5 and 30 minutes at 50 to 200 rpm.

4. Begin moistening with the binder solution from step l.

5. Put the product obtained in step 4 through the grinder via sieve with a mesh size of 3,000 to 5,000 microns.

6. Dry the product at a température of 30 to 60°C until it reaches a residual humidity of l .03.0%.

7. Grind the product obtained in step 6 using a grinder with a 0.033 to 0.094 inch sieve at a speed of 500 to 1,500 rpm.

8. Mix an amount of Lactose-Cellulose 75:25 approximately equal to that of the colloïdal silicon dioxide and mix until a homogeneous distribution is obtained.

9. Pass the colloïdal silicon dîoxide-lactose-cellulose 75:25 mixture obtained in step 8, the talc, the rest of the lactose-cellulose 75:25, and the magnésium stéarate through a sieve with a mesh size of420 to 2,000 microns.

10. Add the following products to a mixer:

The granules obtained in step 7.

The lactose-cellulose 75:25 obtained in step 9.

The colloïdal silicon dioxide-lactose-cellulose 75:25 mixture obtained in step 9.

The talc obtained in step 9.

Μΐχ ali of this for 10 to 30 minutes at 15 to 30 rpm.

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

12. Compress the product.

Example 2:

Component	Amount
Trimebutine Maleate	200,000 mg
a -D-galactosidase	450,000 GalU*
Hydroxypropyl cellulose	29,000 mg
Lactose hydrous	108,000 mg
Sodium starch glycolate	19,500 mg
Microcrystalline cellulose	100,000 mg
Lactose-cellulose 75:25	121,300 mg
Talc	12,000 mg
Colloïdal silicon dioxide	2,400 mg
Magnésium stéarate	7,800 mg

*450 mg of a-D-galactosîdase is équivalent to 450 GalU. GalU refers to the enzymatic activity 10 of the a-D-galactosidase, starting from a raw material with 1,000 GalU per gram.

Procedure for Example 2: Production of trimebutine maleate, in combination with a-Dgalactosidase, by wet granulation. Extragranular addition of the enzyme,

1. Préparé a binder solution by dispersing 50% of the hydroxypropyl cellulose in a sufficient amount of water.

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

- The rest of the hydroxypropyl cellulose (50%)

- Trimebutine maleate

- Lactose hydrous

- Sodium starch glycolate

- Microcrystalline cellulose

3. Add the products from the previous step into the granulator equipment and mix for between 5 and 20 minutes at 50 to 200 rpm.

4. Begin moistening with the binder solution from step 1.

5. Put the product obtained in step 4 through the grinder with a sieve with a mesh size of 3,000 10 to 5,000 microns.

6. Dry the product at a température of 30 to 60°C until it rcaches a residual humidity of 1.03.0%.

7. Grind the product obtained in step 6 using a grinder with a 0.033 to 0.094 inch sieve and at a speed of 500 to 1,500 rpm.

8. Mix an amount of Lactose-Cellulose 75:25 approximately equal to that of the colloïdal silicon dioxide and mix until a homogeneous distribution is obtained.

9. Pass the colloïdal silicon dioxide-lactose-cellulose 75:25 mixture obtained in step 8, the talc, the rest of the lactose-cellulose 75:25, and the magnésium stéarate through a sieve with a mesh size of420 to 2,000 microns.

10. Add the following products to a mixer:

The granules obtained in step 7.

The lactose-cellulose 75:25 obtained in step 9.

The a-D-galactosidase.

The colloïdal silicon dioxide-lactose-cellulose 75:25 mixture obtained in step 9.

The talc obtained in step 9.

AU of this is mixed for 10 to 30 minutes at 15 to 30 rpm.

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

12. Compress the product.

Example 3:

Component	Amount
Trimebutine Maleate	200,000 mg
a-D-galactosidase	450,000 GalU*
Microcrystalline cellulose	277,000 mg
Croscarmellose sodium	18,000 mg
Talc	5,400 mg
Colloïdal silicon dioxide	1,800 mg
Magnésium stéarate	7,800 mg

*90 mg is équivalent to 450 GalU. GalU refers to the enzymatic activity of the a-Dgalactosidase, starting from a raw material with 5,000 GalU per gram.

Procedure for Example 3: Production of trimebutine maleate, in combination with a-D5 galactosidase, by direct compression.

1. Mix an amount of microcrystalline cellulose approximately equal to that of the colloïdal silicon dioxide and mix until a homogeneous distribution is obtained.

2. Sieve the mixture of colloïdal silicon dioxide-microcrystalline cellulose obtained in step 1 through a sieve with a mesh size of 420 to 2,000 microns.

3. Pass the following raw materials through a sieve with a mesh size of420 to 2,000 microns:

- Trimebutine maleate

- a-D-galactosidase

- Microcrystalline cellulose

- Croscarmellose sodium

- Talc

- Magnésium stéarate

4. Add into a mixer in the following order to ensure a good mix and thus a good homogeneity of the product:

- 1/3 of the microcrystalline cellulose

- Half of the a-D-galactosidase

- Half of the trimebutine maleate

- Half of the a-D-galactosidase

- Half of the trimebutine maleate

- 1/3 of the microcrystalline cellulose

- The talc

- The croscarmellose sodium

- The colloïdal silicon dioxide-microcrystalline cellulose mixture

- The rest ofthe microcrystalline cellulose

Mix for 10 to 30 minutes at 15 to 30 rpm.

5. Add the magnésium stéarate obtained in step 3 to the mixer and mix with the product for 5 to minutes at 15 to 30 rpm.

6. Compress the product.

Example 4

Component	Amount
Trimebutine Maleate	200,000 mg
a-D-galactosidase	450,000 GalU*
Microcrystalline cellulose and Sodium carboxymethyl cellulose	6,78 mg [sic]
Sucrose	400,000 mg
Colloïdal silicon dioxide	1,800 mg
Magnésium stéarate	7,800 mg

*90 mg is équivalent to 450 GalU. GalU refers to the enzymatic activity of the a-Dgalactosidase, starting from a raw material with 10,000 GalU per gram.

Procedure for Example 4: Production of trimebutine maleate, in combination with a-Dgalactosidase, by powder mixing. Reconstitutable powder.

1. Mix an amount of microcrystalline cellulose approximately equal to that of the colloïdal silicon dioxide and mix until a homogeneous distribution is obtained.

2. Sieve the mixture of colloïdal silicon dioxide-microcrystalline cellulose obtained in step 1 through a sieve with a mesh size of420 to 2,000 microns.

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

- Trimebutine maleate

- a-D-galactosidase

- Microcrystalline cellulose and Sodium carboxymethyl cellulose

- Sucrose

- Magnésium stéarate

4. Mix until a homogeneous distribution is obtained.

5. Fill the product.

The excipients that can properly fulfîll the indicated fonctions are iisted below:

Function	Excipient
Binding agent	Hydroxypropyl cellulose, corn starch, propyl cellulose, methyl cellulose
Diluting agent	Lactose, microcrystalline cellulose, dibasic calcium phosphate, mannitol, sucrose
Disintegrant	Croscarmellose sodium, corn starch, crospovidone
Lubricant	Magnésium stéarate, talc, stearic acid
Glidant	Colloïdal silicon dioxide
Suspending agent	Microcrystalline cellulose Sodium carboxymethylcellulose

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

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

- The disintegrant is selected from those excipients that are able to break up (disintegrate) the tablet and the granules when they corne in contact with liquid.

- The lubricant is selected from those excipients that are able to reduce the friction between the granules and the die wall during the process of compression or filling of capsules.

- The glidant is selected from those excipients that are able to create a flow of the granules from the hopper to the die chamber by reducing the interparticle friction.

- The suspending agent is selected from the excipients that increase viscosîty and slow sédimentation.

«

Claims (11)

1. A pharmaceutical composition adapted to be administered orally in the form of a tablet, coated tablet, capsule or reconstitutable powder, with application in intestinal disorders based on an intestinal motility modifier and the enzyme a-D-galactosidasc, the composition consisting primarily of the intestinal motility modifier, the a-D-galactosidase enzyme, a binding agent, a diluting agent, a lubricant, a glidant, and a disintegrant or a suspending agent.

2. The pharmaceutical composition in accordance with claim 1, wherein the intestinal motility modifier is selected from trimebutîne, fenoverine, mebeverine, dicycloverine, pinaverium bromide, alosetron, tegaserod, loperamide, phloroglucinol, trimethylphloroglucinol, butylscopolamine, pargeverine, and acceptable pharmaceutical salts thereof.

3. A process for preparing a pharmaceutical composition adapted for oral administration in the form of a reconstitutable powder wherein an intestinal motility modifier, an a-D-galactosidase enzyme, a diluting agent, a lubricant, a glidant, and a suspending agent are sieved.

4. A process for preparing a pharmaceutical composition adapted for oral administration in the form of a tablet, coated tablet, reconstitutable powder or capsule wherein an intestinal motility modifier, an a-D-galactosidase enzyme, a binding agent, a diluting agent, a disintegrant, a lubricant, and a glidant are mixed and then sieved.

5. A process for preparing a pharmaceutical composition adapted for oral administration in the form of a tablet, coated tablet or capsule wherein an intestinal motility modifier, an a-D-galactosidase enzyme, a binding agent, a diluting agent, a disintegrant, a lubricant, and a glidant are mixed and then sieved, the intestinal motility modifier and the a-Dgalactosidase are moistened with a previously prepared binder solution and the mixture is then ground, dried, and sieved.

« i

6. A process for preparing a pharmaceutîcal composition in accordance with claim 5, wherein the intestinal motility modifier is selected from trimebutine and its acceptable pharmaceutical salts.

7. Use of an intestinal motility modifier, the a-D-galactosidase enzyme, a binding agent, a diluting agent, a fabricant, a glidant, and a dîsintegrant or a suspending agent in the manufacture of a pharmaceutîcal composition for the prévention or treatment of intestinal disorders said composition being for oral administration.

8. Use of an intestinal motility modifier, the a-D-galactosidase enzyme, a binding agent, a diluting agent, a fabricant, a glidant, and a dîsintegrant or a suspending agent în the manufacture of a pharmaceutical composition for the prévention or treatment of irritable bowel syndrome said composition being for oral administration.

9. Use of an intestinal motility modifier, the a-D-galactosidase enzyme, a binding agent, a diluting agent, a fabricant, a glidant, and a dîsintegrant or a suspending agent in the manufacture of a pharmaceutical composition for the prévention or treatment of intestinal disorders to achieve antispasmodic and antiemetic activity said composition being for oral administration.

10. Use as claimed in any one of claims 7 to 9 inclusive, in which the intestinal motility modifier is selected from trimebutine, fenoverine, mebeverine, dicycloverine, pinaverium bromide, alosetron, tegaserod, loperamide, phloroglucinol, trimethylphloroglucinol, butylscopolamine, pargeverine, and acceptable pharmaceutical salts thereof.

11. Use as claimed in claim 10, in which the intestinal motility modifier is selected from trimebutine and its acceptable pharmaceutical salts.