WO2018109693A1

WO2018109693A1 - Improved composition of lansoprazole and simeticone and method for preparing same

Info

Publication number: WO2018109693A1
Application number: PCT/IB2017/057904
Authority: WO
Inventors: Esteban Alejandro Fiore
Original assignee: Siegfried Rhein, S.A. De C.V.
Priority date: 2016-12-14
Filing date: 2017-12-13
Publication date: 2018-06-21
Also published as: AR110183A1; CO2019006693A2; DOP2019000145A; CL2019001462A1; BR112019011966A2; MX2016016587A; PE20191654A1; CR20190290A

Abstract

The present invention relates to an orally administered pharmaceutical composition comprising a fixed-dose combination of simeticone in high-concentration microgranules and lansoprazole or the enantiomer thereof (dexlansoprazole) in enteric-release microgranules. The invention also relates to a method for obtaining the high-concentration simeticone microgranules.

Description

IMPROVED COMPOSITION OF LANSOPRAZOL AND SIMETICONE AND PROCESS

TO PREPARE IT.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a pharmaceutical composition for oral administration, comprising the fixed-dose combination of Simethicone in high concentration microgranules and Lansoprazole or its enantiomer (Dexlansoprazole) in enteric release microgranules and the process for obtaining high concentration microgranules. of Simethicone.

BACKGROUND OF THE INVENTION

The compound Lansoprazole was revealed as a product in European patent EP 174726 Bl and its equivalents, its owner was TAKEDA CHEMICAL INDUSTRIES and the priority date was 16-08-1984 (JP). The IUPAC nomenclature is 2- (((3-Methyl-4- (2, 2, 2-trifluoroethoxy) pyridin-2-i 1) methyl) sulfinyl) -1H-benzimidazole, and is represented by Formula (I),

Formula (I) This compound, belonging to the family of substituted benzimidazoles, is a proton pump inhibitor, since it suppresses gastric acid secretion by specific inhibition of the enzymatic system H ⁺ , K ⁺ - ATPase (proton pump) on the secretory surface of gastric parietal cells. The H ⁺ , K ⁺ - ATPase of the apical membrane of the parietal cell is the final mediator of acid secretion, that is to say that Lansoprazole blocks the last step in acid production. At neutral pH, Lansoprazole is a weak, chemically stable, fat-soluble base, devoid of inhibitory activity, and is destroyed in gastric acid. So, if administered in an oral solid pharmaceutical form, it must be protected from contact with acid gastric juices, and must be transferred without structural modification to the fraction of the gastrointestinal tract where the pH is close to neutral, which is where the rapid absorption of said compound. This compound is especially useful in patients with hypergastrinemia and is valuable in patients with peptic ulcer disease.

Lansoprazole is a racemic mixture of the Dexlansoprazole and Levolansoprazole isomers (also called R-Lansoprazole and S-Lansoprazole, respectively). The enantiomer that has demonstrated better clinical results is Dexlansoprazole, whose IUPAC formula is represented by formula (II):

Formula (II) The compound Simethicone is a mixture of Dimethicone with Silicon Dioxide. Its IUPAC nomenclature is α - (trimethylsilyl) - ω - methylpoli [oxy (dimethylsilylene)], mixed with silicon dioxide, and is represented by Formula (III):

20 <n <400

Formula (III)

The method of preparing methyl siloxane polymers was described in US Patent 2,441,098, whose priority date was 09-09-1946 (US), and its holder was CORNING GLASS WORKS.

In the Journal of Clinical Pharmacology, published on November 12, 1974, an article on the clinical evaluation of the use of Simethicone in the upper gastrointestinal tract, by the authors Joel E. Bernstein and Anthony M. Kasich, was included.

Simethicone is a chemically inert compound that is not absorbed in the gastrointestinal tract. It is excreted as ingested, in the feces and without evidence of entire hepatic circulation. Simethicone alters the surface tension of gas bubbles that form in the gastrointestinal tract, either in the digestive process itself or by lactose intolerance. Its action allows gas bubbles to break and form much smaller ones that are easily eliminated both orally and rectally. The clinical use of Simethicone is based on its antifoam property demonstrated in vitro. This compound is indicated in the treatment of functional gastrointestinal conditions in which gas retention can be a problem.

European patent EP 1,108,425 Bl, whose owner is Laboratorio Medinfar-Productos Farmaicos S.A. and the priority date is 16-12-1999 (PT), it claims stable pellets containing benzimidazole derivatives, on an inert core, with a polymeric coating and finally an enteric coating. Does not include Simethicone as active ingredient.

US patent application US 2004/0092511, whose owner is Billstein SA and with priority dates of 10-12-1999 and 27-11-2000 (US), claims combinations of 5-HT ₄ receptor agonists, or antagonists of 5- HT ₃ , with a co-agent, to treat gastrointestinal and viscera-abdominal disorders.

International patent application WO 2008/056200, whose owner is Ranbaxy Laboratories Limited, and priority date 10-11-2006 (IN), claims an oral pharmaceutical composition containing Simethicone adsorbed in an inert material, silicate salt and excipients in form of chewable tablet. It includes combinations with one or more antacids, antidiarrheals, antispasmodics, laxatives, antiemetics and anticholinergics. DETAILED DESCRIPTION OF THE INVENTION The object of the present invention relates to a pharmaceutical composition in a unit dose containing a combination of Simethicone in the form of high concentration microgranules and Lansoprazole or its enantiomer (Dexlansoprazole) in the form of enteric release microgranules. , in therapeutically effective amounts, contained in capsules or sachets. The composition is designed for the treatment of functional gastrointestinal disorders, especially dyspepsia with a pharmaceutical form that is easy to ingest.

In order to obtain the combination of the two active ingredients mentioned above, under a unit dose, it was necessary to combine two compounds of dissimilar physical and chemical characteristics. Simethicone, an inert molecule, which is not metabolized and not absorbed, acts on the surface tension of gas bubbles formed in the gastrointestinal tract. This compound in pure form is a very viscous liquid, almost a paste, this physical characteristic being an important technical impediment since it hinders its manipulation, its incorporation into a solid pharmaceutical form, and its combination with another active ingredient.

To incorporate this compound in a pharmaceutical form, the possibility of adsorbing it in inert solid materials such as colloidal silicon dioxide, microcrystalline cellulose and calcium phosphate, among others, was evaluated. This The methodology was discarded because two or three parts of inert material are needed in proportion to adsorb a part of Simethicone, generating a high final volume of adsorbed Simethicone, and as a consequence, a large and difficult to ingest dosage unit. With the known procedures it is not possible to obtain concentrations of Simethicone greater than 500 mg of Simethicone per gram of granulate, that is, it is not possible to obtain concentrations greater than 50%. In addition, the granulate obtained is very fragile and this is detrimental to its dosage in the chosen pharmaceutical form, since it does not have good fluidity generating variations in the dosage and caking of the granulate at the time of dosing the product either in capsules or in sachets.

In order to concentrate the desired dose of Simethicone in microgranules, we developed a novel procedure that consists of placing it in a solid wall coating pan or in a tangential rotor fluid bed type Sugar Spheres and while they are in the bearing, wet them at regular intervals with Simethicone and use a defined mixture of Colloidal Silicon Dioxide and Magnesium Carbonate to dry each wetting stage. Repeat the wetting and drying cycles until microgranules are obtained with the desired concentration of Simethicone.

In the case of Lansoprazole and its enantiomer, these compounds degrade in gastric medium (acid) and are stable in neutral to alkaline medium. The parietal cells, where they are, are absorbed through the bloodstream into the site of action. hydrolyzed into active metabolites that combine with H +, KH-ATPase (proton pump), inhibiting it in that way. So Lansoprazole and its enantiomer must be formulated gastro-resistant (enteric release). It was decided that the most suitable formulation for Lansoprazole or its enantiomer is to use enteric microgranules.

In accordance with the above, the technical solution found was to obtain high concentration microgranules of the desired dose of Simethicone and encapsulate or envelop them together with enteric microgranules of Lansoprazole or its enantiomer.

The fact of using Simethicone in the form of microgranules of high concentration allows its administration together with Lansoprazole or its enantiomer, in a single pharmaceutical form, of small volume and easy to ingest, and on the other hand it allows them to be dosed in capsules or in sachets with ease and using conventional equipment.

For example, the encapsulation of the microgranules of both active ingredients can be obtained using a conventional encapsulator equipped with two microgranule dispensers, working in the operating conditions characteristic of the solids encapsulation.

Finally, the in vitro release assays of the pharmaceutical form obtained that contain the combination of the two active ingredients, met the required specifications, releasing Simethicone immediately and the Lansoprazole or its enantiomer in the intestinal tract, the latter fulfilling gastro-resistance.

The previously mentioned aspects make this composition different from other compositions that contain the same active ingredients and that incorporate the adsorbed Simethicone and is, therefore, the main object of the present invention. Therefore, in one aspect the invention relates to a pharmaceutical composition for oral administration, comprising the fixed dose combination of Simethicone and Lansoprazole or its enantiomer, in therapeutically effective doses and pharmaceutical excipients. Simethicone is in the form of high concentration microgranules And Lansoprazole or its enantiomer is in the form of enteric release microgranules, both of which are contained in hard capsules or sachets. The therapeutically effective doses of Simethicone are in the range of 20 to 1000 mg, according to Martindale: The complete drug reference, Simethicone, Volume A, Edition 38, 2014, 1886: 1887. The therapeutically effective doses of Lansoprazole or its enantiomer are in the range of 10 mg to 180 mg per day, according to the well-known book Goodman & Gilman, H ⁺ Inhibitors, K ⁺ ATPase, The Pharmacological Bases of Therapeutics, 1996, 971-973. In another aspect the invention relates to the process for obtaining high concentration microgranules of Simethicone. Said microgranules are obtained by applying Simethicone on rolling sugar spheres in a solid-walled bed or in tangential rotor fluid bed equipment at regular intervals. Cycles of humidification of the microgranules are alternated with Simethicone and drying cycles consisting of sprinkling a defined amount of a mixture of colloidal silicon dioxide and magnesium carbonate, this drying stage being very important in order to fix the Simethicone in the microgranules. a high concentration of Simethicone.

The obtained microgranules are allowed to roll until they are completely dry and optionally coated with a protective membrane. The protective membrane is formed by a soluble polymer, preferably Polyvinylpyrrolidone.

In the following, in the following embodiments, the processes of the present invention are described in detail.

EXAMPLES OF REALIZATION

EXAMPLE 1. Simethicone capsules 120 mg + Lansoprazole 15 mg

The process for preparing a pharmaceutical formulation for oral administration, comprising the fixed dose combination of high-concentration microgranules of 120 mg of Simethicone and enteric-release microgranules of 15 mg of Lansoprazole, both being contained in a hard capsule.

Unit and batch formula:

Theoretical content of Simethicone in the microgranules:

600 mg / g of microgranules.

Enteric microgranules of mg per capsule Kg per batch

Lansoprazole oral 100,000 capsules

Lansoprazole 15.00 1.50

Sugar Spheres 31.80 3.18

Mannitol 9.75 0.975

Calcium ilylcellulose carboxymet 8.25 0.825

Magnesium carbonate 9.00 0.90

Hydrogenated disodium phosphate 9.00 0.90 Sugar 36.00 3.60

Hydroxypropyl methylcellulose E5 18.00 1.80

Hydroxypropyl methylcellulose 28.50 2.85 phthalate

Titanium Dioxide 1.50 0.15

Solvents that evaporate

during the process of

elaboration:

Purified water 12.60

Methylene Chloride 18.80

Ethyl Alcohol 18.80

Theoretical content of Lansoprazole in the microgranules mg / g of microgranules.

ELABORATION METHOD

High concentration microgranules of Simethicone (600 mg / g made in solid wall pail)

1) Mix Colloidal Silicon Dioxide and Magnesium Carbonate. Divide the mixture of Colloidal Silicon Dioxide and Magnesium Carbonate into 6 fractions of equal weight.

2) Fraction Simethicone into 6 fractions of equal weight.

3) Place the sugar spheres in a conventional solid-walled (non-perforated) wall coating pan and set the rotation speed of the drum between 10 and 15 rpm and the inlet air at 35 ² C with air flow of 25 cubic feet per minute.

4) Spray the first fraction of Simethicone on the sugar spheres using the following operating conditions: LongerPump Brand BT100 or similar peristaltic pump with an application flow of between 25 - 50 ml / min, using a 3-way spray gun Spraying System brand or similar with 2050 spout and nozzle 67228- 45 ² -SS of the Spraying System brand or similar. Atomization pressure: 1.5 - 2.0 bar and cylinder air: 0.5 bar.

5) Dry the wetted spheres using a fraction of the mixture of Colloidal Silicon Dioxide and Magnesium Carbonate io.

6) Repeat steps 4 and 5 until all of the Simethicone fractions and the mixture of

Colloidal Silicon Dioxide and Magnesium Carbonate.

7) Let the product roll in the pan for 5 minutes.

8) Sift through meshes of 2.0 mm pore. The microgranules obtained will be between 0.7 and 1.5 mm in diameter.

Enteric release Lansoprazole microgranules 1) Prepare a syrup by dissolving the sugar in 3.6 kg of purified water, heating at 40 ° - 45 ° C with stirring until homogenized.

2) Sift through 100 mesh: Lansoprazole, Magnesium carbonate, Mannitol, calcium carboxymethyl ilcellulose and hydrogenated disodium phosphate and mix in a medium speed dump mixer for 15 minutes. 3) Sprinkle the mixture obtained in step 2) on the sugar spheres in a stainless steel pail at 36 rpm, using the sugar syrup obtained in step 1) as an adhesive, until reaching microgranules of size between 0.4 and 0.9 mm diameter.

4) Dry the microgranules obtained in step c) at 45 ° C for 8 hours or until no more than 1% moisture is obtained.

5) Sift the dried microgranules by 1.0 mm mesh pore size.

6) Dissolve hydroxypropyl methylcellulose E5 in 9 kg of purified water, stirring until a colloidal solution is achieved.

7) Place the microgranules in the fluid bed and spray them with the colloidal solution obtained in point 6, under hot air flow to dry the cover. Continue placing the coating until the entire colloidal solution is used.

8) In a suitable container add hydroxypropylmethylcellulose phthalate and titanium dioxide in the mixture of methylene chloride and ethyl alcohol. Stir until homogenize the preparation. Pass the preparation through a colloid mill for 10 minutes through the finest step.

9) Place the microgranules obtained in point 7, in the fluid bed and spray them with the solution obtained in point 8, under hot air flow to dry the cover. Place the entire coating solution.

11) Sieve the enteric coated microgranules by 1.4 mm pore. The microgranules obtained will be between 0.5 and 1.2 mm in diameter. Encapsulated:

Encapsulate in number 1 capsules both microgranules obtained using a double station encapsulator placing:

Doser 1, Lansoprazole Microgranules: 166.80 mg ± 5% (158.46 mg - 175.14 mg).

Doser 2, Simethicone Microgranules: 200.00 mg ± 5% (190.00 mg - 210.00 mg).

Net content per capsule: 366.80 mg ± 10% (330 mg -

403 mg)

EXAMPLE 2. Simethicone 120 mg + Lansoprazole 30 mg capsules

Using the microgranules made in Example 1, capsules containing 120 mg of Simethicone and 30 mg of Lansoprazole are prepared.

Both microgranules are filled in gelatin capsules number 0 elongated using a double station encapsulator placing:

Doser 1, Lansoprazole Microgranules: 333.60 mg ± 5% (316.92 mg - 350.28 mg)

Doser 2, Simethicone Microgranules: 200.00 mg ± 5% (190.00 mg - 210.00 mg)

Net content per capsule: 533.60 mg ± 10% (480 mg - 587 mg) EXAMPLE 3. Envelopes for oral suspension of Simethicone 120 mg + Lansoprazole 15 mg

Using the microgranules made in Example 1, sachets containing 120 mg of Simethicone and 15 mg of Lansoprazole are prepared.

Ingredient mg per

on

Simethicone 200.0 microgranules (containing 120 mg of Simethicone)

Lansoprazole microgranules 166.8 (containing 15 mg of Lansoprazole)

100.0 corn starch

Sucralose powder 10.0

Ionized RD Xantana Gum 200.0

Anhydrous citric acid 20.0

Red Iron Oxide 5.0

Essence of Banana Powder 30.0

Essence of strawberry powder 40.0

Sugar 190.0

Granular Mannitol 3038.2 ELABORATION METHOD

The method of making Simethicone microgranules and Lansoprazole microgranules is the method described in Example 1.

The excipients for the suspension are prepared as follows: a) Mix Corn starch, Red iron oxide, Sucralose powder, Citric acid anhydrous, Essence of banana powder, Essence of strawberry powder and Sugar and Mannitol, for 10 minutes to 12 rpm

b) Grind the mixture obtained in point a) by Fitzpatrick mill, at 4800 rpm. with 40 mesh, hammers forward. c) Mix the grinding obtained in step b) with the Granular Mannitol and Ionized RD Xantana Gum and previously ground by Fitzpatrick mill with 1.7 mm mesh at 400 rpm, hammers forward for 20 minutes at 12 rpm.

Enveloped

Assemble the microgranules and the mixture of excipients using an envelope equipped with three dispensers with the following quantities: Doser 1, Lansoprazole Microgranules: 166.80 mg ±

5% (158.46 mg - 175.14 mg)

Doser 2, Simethicone Microgranules: 200.00 mg ± 5% (190.00 mg - 210.00 mg)

Doser 3, Excipient mixture: 3633.2 mg ± 5% (3451.54 mg - 3814.86) Net content above: 4000.0 mg ± 5% (3800.0 mg - 4200.0 mg)

EXAMPLE 4. Capsules of Simethicone 200 mg + Dexlansoprazole 60 mg

The process for preparing a pharmaceutical formulation for oral administration is described, comprising the fixed dose combination of 200 mg high concentration microgranules of Simethicone and 60 mg enteric release microgranules of Dexlansoprazole, both of which are contained in a hard capsule.

Simethicone microgranules of mg per capsule Kg per batch immediate oral release of 100,000 capsules

Simethicone 200.00 20.00

Sugar Spheres (diameter 70.00 7.00 300-500 microns)

Colloidal Silicon Dioxide 70.00 7.00

Magnesium carbonate 60.00 6.00

Theoretical content of Simethicone in the microgranules: 500 mg / g of microgranules.

Enteric microgranules of mg per capsule Kg per batch Oral dexlansoprazole of 100,000 capsules

Dexlansoprazole sesquihydrate 64.60 6.46 microni zado

(Equivalent to 60 mg of

Dexlansoprazole)

Sugar Spheres 96.00 9.60

Hydroxypropyl methylcellulose E5 20.00 2.00

Magnesium carbonate 28.00 2.80

Hydroxypropylcellulose LF 16.00 1.60

Sodium Lauryl Sulfate 2.00 0.20

Eudragit L100 16.00 1.60

Eudragit S100 48.00 4.80

Triethylcitrate 6.40 0.64

Talc 3.00 0.30

120.00 purified water

Ethyl Alcohol 80.00

Theoretical content of Dexlansoprazole in the microgranules: 200.0 mg / g of microgranules.

ELABORATION METHOD

Simethicone high concentration microgranules (500 mg / g made in a fluid bed with a tangential rotor)

1) Mix Colloidal Silicon Dioxide and Magnesium Carbonate. Divide the mixture of Colloidal Silicon Dioxide and Magnesium Carbonate into 8 fractions of equal weight. 2) Fraction Simethicone into 8 fractions of equal weight.

3) Place the sugar spheres in a fluid bed equipped with a Vector or similar brand tangential rotor and set the inlet air at 35 ² C with a flow rate between 80 and 120 cubic feet per minute and the rotor rotation speed at 50-100 rpm

4) Spray spray the first fraction of Simethicone on the sugar spheres using the following operating conditions: Peristaltic pump with application flow between 30 - 60 ml / min. Atomization pressure: 2.0 - 3.0 bar and cylinder air: 1.0 bar. 1.2 mm peak

5) Using a powder dispenser, apply the mixture of Colloidal Silicon Dioxide and Magnesium Carbonate on wetted spheres using a dosage rate of between 40 and 50 grams per minute.

6) Repeat steps 4 and 5 until all the Simethicone fractions and the mixture of Colloidal Silicon Dioxide and Magnesium Carbonate have been applied.

7) Let the product roll in rotor for 5 minutes at

20 rpm

Enteric-release Dexlansoprazole microgranules

1) Preparation of the active substance application suspension: Dissolve E5 Hydroxypropylmethylcellulose in 70 kg of purified water. Add the sodium lauryl sulfate and magnesium carbonate to the solution. Add the previously sieved mesh Dexlansoprazole to the suspension 100 to break any lumps. Keep the suspension in agitation.

2) Application of active ingredient: Place the sugar spheres in a fluid bed equipment and spray the suspension from the previous step.

3) Application of the insulating layer: Dissolve the hydroxypropylcellulose LF in 50 kg of purified water and apply this solution on the microgranules obtained in the previous step.

4) Intermediate drying: dry the microgranules in a fluid bed. Verify residual water content is less than 4%.

5) Gastro-resistant coating: Dissolve Eudragit L100-55, Eudragit S100 and triethylcitrate in ethyl alcohol. Scatter the talc in the solution. Apply the coating solution on the dried microgranules obtained in step d).

6) Screening: Pass the dried microgranules through a mesh of 1.4 mm in pore size.

Encapsulated:

Encapsulate in capsules number 00 both microgranules obtained using a double station encapsulator placing:

Doser 1, Dexlansoprazole Microgranules: 300.00 mg ± 5% (285.00 mg - 315.00 mg)

Doser 2, Simethicone Microgranules: 400.00 mg ± 5% (380.00 mg - 420.00 mg) Net content per capsule: 700.0 mg ± 10% (630.00 mg - 770.00 mg)

Example 5. Encapsulation tests

Using the microgranules of Example 4, the capsule entry of different doses was manually verified.

EXAMPLE 6. PHARMACOTECHNICAL DETERMINATIONS AND TESTS IN

Pharmaco-technical determinations and in vitro tests were performed to evaluate the physical characteristics of the microgranules of examples 1 and 4, and the dissolution of the formulations of examples 1, 2, 3 and 4. Pharmaco-technical determinations: methodology and equipment.

Density: VANDERKAMP equipment or equivalent is used to obtain density. In a 50 ml graduated cylinder with a cap, approximately 30 g of sample are weighed exactly, it is adjusted on the base of the equipment and 15 seconds of movement are applied. The surface is matched and the final volume is read.

The compacted density obtained should be between: 0.6 - 1.0 g / ml.

Average diameter of the microgranules: it is measured by means of a particle size analyzer Malvern model Mastersizer 2000, Equipped with a Laser transmitter and a detector.

Lansoprazole microgranules or Simethicone enantiomer

Example 1 0.980 mm 1,100 mm

Example 4 1,040 mm 1,145 mm Evaluation of Lansoprazole and enantiomer: by HPLC (High Performance Liquid Chromatography) according to the Lansoprazole Monographs of the United States Pharmacopoeia 32 Capsules (USP).

Simethicone Assessment: by Spectrophotometry

Infrared

Gastroristance test: according to USP 32 (United States Pharmacopoeia 32), General Tests and Tests <711>.

Antifoam activity: according to USP 32 (United States Pharmacopoeia 32). Test performed on bulk microgranules.

Dissolution test Lansoprazole or enantiomer: according to USP 32 (United States Pharmacopoeia 32) General Tests and Tests <711>. The SOTAX Type AT7 device or its equivalent was used.

Parameter EXAMPLE 1 EXAMPLE 2 EXAMPLE 3 EXAMPLE 4

Rating

Lansoprazole or 14.9 mg / capsule 29.5 14.3 mg / over 57.3 enantiomer (99.3%) mg / capsule (95.3%) mg / capsule

(expressed as mg (98.3%) (95.5%) per unit and as

% of theory)

Assessment

Simethicone 112 mg / capsule 111 mg / capsule 115 mg / over 197 mg / capsule

(93.3%) (92.5%) (95.8%) (98.5%)

Simethicone,

Activity

Antifoam: Complies Complies Complies Complies required time

for the collapse of

the foam should not be greater than 45

seconds .

Rehearsal of

gastro-resistance Average: Average: Average: Average:

(percentage of 98.3% 99.7% 95.2% 100.5% active substance

not dissolved with

With respect to

theoretical content

per dose)

Dissolution

Average Average: Average: Average: Average:

90.5% 93.0% 88.1% 81.3%

Claims

1. An oral pharmaceutical composition comprising between 120 mg and 200 mg of Simethicone and between 15 mg and 60 mg of Lansoprazole or Dexlansoprazole, characterized in that Simethicone is in the form of high concentration microgranules, said concentration being greater or equal to 500 mg / g, wherein the microgranules are formed by sugar spheres, colloidal silicon dioxide, magnesium carbonate and optionally other pharmaceutical excipients.

2. A composition according to claim 1, characterized in that the concentration of Simethicone in the microgranules is 600 mg / g.

3. A pharmaceutical composition according to claim 2, characterized in that it is formed by a hard capsule containing 120 mg of Simethicone in the form of high concentration microgranules and between 15 mg and 30 mg of Lansoprazole in enteric release microgranules.

4. A pharmaceutical composition according to claim 1, characterized in that it is formed by a hard capsule containing 200 mg of Simethicone in high concentration microgranules and between 30 mg and 60 mg of Dexlansoprazole in enteric release microgranules.

5. A pharmaceutical composition according to claim 2, characterized in that it is formed by an envelope containing 120 mg of Simethicone in microgranules of high concentration and between 15 mg and 30 mg of Lansoprazole in enteric release microgranules.

6. A process for preparing microgranules with a concentration greater than or equal to 500 mg / g of Simethicone, characterized in that it consists in placing a tangential rotor type fluid bed, sugar spheres, and a solid-wall coating bed. while they are in the bearing, wet them at regular intervals with Simethicone and dry them with a defined mixture of Colloidal Silicon Dioxide and Magnesium Carbonate.

7. A process according to claim 6, wherein the flow rate of application of Simethicone is 25 to 50 ml / minute using a peristaltic pump.

8. A process according to claim 6, wherein the average diameter of the microgranules of high concentration of Simethicone is within the range of 0.7 mm to 1.5 mm.

9. A process according to claim 6, wherein the flow rate of application of Simethicone is 25 to 50 ml / minute using a peristaltic pump.

10. A pharmaceutical composition according to claims 1 to 9, wherein said composition is used to treat functional gastrointestinal disorders, in particular dyspepsia.