BR112019011966A2 - improved lansoprazole and simethicone composition and process for preparation - Google Patents

Abstract

The present invention relates to an orally administered pharmaceutical composition comprising a fixed dose combination of simethicone in high concentration microgranules and lansoprasol or the enantiomer thereof (dexlansoprasol) in enteric release microgranules and the process for obtaining simethicone microgranules. high concentration.

Description

IMPROVED COMPOSITION OF LANSOPRAZOL AND SIMETICONE AND PROCESS FOR PREPARATION

TECHNICAL FIELD OF THE INVENTION [0001] The present invention relates to a pharmaceutical composition for oral administration, which comprises the combination with a fixed dose of Simethicone in high concentration microgranules and Lansoprazole or its enantiomer (Dexlansoprazole) in enteral release microgranules to the process to obtain the high concentration microgranules of Simethicone.

BACKGROUND OF THE INVENTION [0002] The compound Lansoprazole, was revealed as a product in the European patent EP 174726 BI and its equivalents, its holder was TAKEDA CHEMICAL INDUSTRIES and the priority date was August 16, 1984 (JP). The IUPAC nomenclature is 2 - [[[3-methyl-4- (2,2,2-trifluoroethoxy) pyridyl] methyl] sulfinyl] benzimidazole and is represented by Formula (I),

[0003] This compound, belonging to the substituted benzimidazole family, is a proton pump inhibitor, since it suppresses gastric acid secretion by specific inhibition of the enzyme system H <+>, K <+> - ATPasa (proton pump) on the secretory surface of the parietal cells

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2/22 gastric. The H <+>, K <+> - ATPasa of the apical membrane of the parietal cell is the final mediator of acid secretion, meaning that Lansoprazole blocks the last step in acid production. At neutral pH, Lansoprazole is a weak, chemically stable, fat-soluble base, with no inhibitory activity and is destroyed in gastric acid. So, if administered in a solid oral pharmaceutical form, it must be protected from contact with acidic gastric juices and must be transferred without industrial modification to the fraction of the gastrointestinal tract where the pH is close to neutral, which is where absorption occurs of said compound. This compound is especially useful in patients with hypergastrinemia and is valuable in patients with peptic ulcer disease.

[0004] Lansoprazole is a racemic mixture of the isomers Dexlansoprazole and Levolansoprazole (also called R-Lansoprazole and S-Lansoprazole respectively). The enantiomer that has shown the best clinical results is Dexlansoprazole, whose IUPAC formula is represented by formula (II):

[0005] The compound Simethicone, is a mixture of

Dimethicone with silicon dioxide. Its IUPAC nomenclature is (trimethylsilyl) -ω-methylpoli [oxy (dimethylsilylene)], mixed

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3/22 with silicon dioxide and is represented by Formula (III):

[0006] The method of preparing methyl siloxane polymers was described in US patent 2,441,098, whose priority date was September 9, 1946 (US) and its holder was CORNING GLASS WORKS.

[0007] The Journal of Clinical Pharmacology, published on November 12, 1974, included an article on the clinical evaluation of the use of Simethicone in the upper gastrointestinal tract, by authors Joel E. Bernstein and Anthony M. Kasich.

[0008] Simethicone is a chemically inert compound that is not absorbed in the gastrointestinal tract. It is excreted as it was ingested in the faeces and without evidence of enterohepatic circulation. Simethicone alters the surface tension of gas bubbles that form in the gastrointestinal tract, either in the digestive process itself or due to lactose intolerance. Its action allows gas bubbles to burst and form much smaller ones that are easily eliminated both orally and rectally. The clinical use of Simethicone is based on its anti-foam property demonstrated in vitro. This compound is indicated for the treatment of conditions

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4/22 functional gastrointestinals in which gas retention can be a problem.

[0009] European patent EP 1,108,425 Bi, whose holder is Laboratorio Medinfar-Productos Farmacêuticos SA and the priority date is December 16, 1999 (PT), claims stable pellets containing bencimidazole derivatives, in an inert core, with a polymeric coating and, finally, an enteric coating. It does not include Simethicone as an active ingredient.

The US patent application US 2004/0092511, whose holder is Billstein SA and with priority dates of December 10, 1999 and November 27, 2000 (US), claims combinations of 5-HT4 receptor agonists, or 5-HT3 antagonists, with a coagent, to treat gastrointestinal and visceral-abdominal disorders.

[0011] The international patent application WO 2008/056200, whose holder is Ranbaxy Laboratories Limited and the priority date of November 10, 2006 (IN), claims an oral pharmaceutical composition containing Simethicone adsorbed on an inert material, silicate salt and excipients in the form of a chewable tablet. It includes combinations with one or more antacids, antidiarrheals, antispasmodics, laxatives, antiemetics and anticholinergics.

DETAILED DESCRIPTION OF THE INVENTION [0012] The purpose of the present invention relates to a pharmaceutical composition in unit dose containing a combination of Simethicone in the form of high concentration microgranules and Lansoprazole or its enantiomer (Dexlansoprazole)

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5/22 in the form of enteric-release microgranules, in therapeutically effective amounts, contained in capsules or envelopes. The composition is designed for the treatment of functional gastrointestinal disorders, in particular, dyspepsia with a pharmaceutical form that is easy to ingest.

[0013] To obtain the combination of the two active ingredients mentioned, under a unit dose, it was necessary to make compatible two compounds with different physical and chemical characteristics. Simethicone is an inert molecule, which does not metabolize and is 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 makes it difficult to manipulate, its incorporation in a solid pharmaceutical form and its combination with another active ingredient.

[0014] To incorporate this compound in a pharmaceutical form, the possibility of adsorption in inert solid materials such as colloidal silicon dioxide, microcrystalline cellulose and calcium phosphate, among others, was evaluated. This methodology was discarded, since two or three parts of inert material are needed to adsorb one part of Simethicone, generating a high final volume of adsorbed Simethicone, and as a consequence, a large and difficult to ingest unit unit. With known procedures it is not possible to obtain Simethicone concentrations greater than 500 mg of Simethicone per gram of granules, in other words, it is not possible to obtain concentrations greater than 50%. In addition, the

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6/22 granules obtained are very fragile and this is harmful to your dosage in the chosen pharmaceutical form, since it does not have good fluidity, generating variations in the dosage and agglomeration of the granules when dispensing the product, either in capsules or in envelopes.

[0015] In order to concentrate the desired dose of Simethicone in microgranules, an innovative procedure is developed that consists of placing in a pan of solid wall covering or in a fluid bed equipment of the tangential rotor type of Sugar Spheres while they are in bearing, humidify them at regular intervals with and use a defined mixture of Colloidal Silicon Dioxide and Magnesium Carbonate to dry each humidification step. Repeat the humidification and drying cycles until microgranules are obtained with the desired concentration of Simethicone.

[0016] In the case of Lansoprazole and its enantiomer, these compounds degrade in the gastric (acidic) environment and are stable in neutral to alkaline environments. They are absorbed in the small intestine reaching the bloodstream at the site of action in the parietal cells, where they are hydrolyzed into active metabolites that combine with H +, KH — ATPasa (proton pump), thereby inhibiting it. So that Lansoprazole and its enantiomer must be formulated in a gastro-resistant manner (enteric release). It was decided that the most suitable formulation for Lansoprazole or its enantiomer is to use enteric microgranules.

[0017] According to the above, the technical solution found is to obtain microgranules of high concentration

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7/22 of the desired dose Simethicone and encapsulate or envelop together with enteric microgranules of Lansoprazole or its enantiomer.

[0018] The use of Simethicone in the form of high concentration microgranules allows its administration together with Lansoprazole or its enantiomer, in a unique pharmaceutical form, of small volume and easy to ingest, and, on the other hand, allows it to be dosed in capsules or envelopes with ease and using conventional equipment.

[0019] For example, the encapsulation of the microgranules of both active ingredients, can be obtained by using a conventional encapsulator equipped with two microgranule dispensers, operating in the operational conditions of the encapsulation of solids.

[0020] Finally, the in vitro release tests of the obtained pharmaceutical form that contain the combination of the two active ingredients met the required specifications, releasing Simethicone immediately and Lansoprazole or its enantiomer in the intestinal tract, the same taking into account gastro-resistance.

[0021] The aspects mentioned previously make this composition different from other compositions that contain the same active principles and that incorporate the adsorbed Simethicone and is, therefore, the main objective of the present invention.

[0022] Therefore, in one aspect, the invention relates to a pharmaceutical composition for oral administration, which comprises the combination of a fixed dose of Simethicone and Lansoprazole or its enantiomer, in therapeutically doses

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8/22 effective and pharmaceutical excipients. Simethicone is below the form of high-concentration microgranules and Lansoprazole or its enantiomer is below the form of enteric-release microgranules, both contained in hard capsules or envelopes.

[0023] Therapeutically effective doses of Simethicone are in the range of 20 to 1000 mg, according to Martindale: The complete drug reference, Simethicone, Volumen A, Edición 38, 2014, 1886: 1887.

[0024] Therapeutically effective doses of Lansoprazole or its enantiomer are in the range of 10 mg to 180 mg per day, according to the recognized book Goodman & Gilman, Inhibidores de la H <+>, K <+> ATPasa, Las Pharmacological bases of therapeutic therapy, 1996, 971 to 973.

[0025] In another aspect, the invention relates to the process for obtaining the high concentration microgranules of Simethicone.

[0026] Said microgranules are obtained by applying Simethicone at regular intervals on the rolling sugar spheres in a solid-walled pan or in a tangential rotor fluid bed equipment. Humidification cycles of the microgranules with Simethicone and drying cycles are alternated, which consist of sprinkling a defined amount of a mixture of colloidal silicon dioxide and magnesium carbonate, this drying step being very important to fix Simethicone to the microgranules maintaining a concentration discharge of Simethicone.

[0027] The microgranules are left rolling until

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9/22 that are completely dry and optionally coated with a protective membrane. The protective membrane is formed by a soluble polymer, preferably Polyvinylpyrrolidone.

[0028] In the following embodiment examples, the processes of the present invention are described in detail.

EXAMPLES OF ACHIEVEMENT

EXAMPLE 1. Simethicone 120 mg capsules + Lansoprazole 15 mg [0029] The process for preparing a pharmaceutical formulation for oral administration is described comprising the combination of a fixed dose of 120 mg high concentration microgranules of Simethicone and microgranules of enteric release of 15 mg Lansoprazole, both contained in a hard capsule.

Unit and batch formula:

Simethicone microgranules of immediate release mg per oral capsule Kg per batch of 100,000 capsules Simethicone 120.00 12.00 Sugar Spheres (diameter 300 to 500 microns) 30.00 3.00 Colloidal silicon dioxide 30.00 3.00 Magnesium carbonate 20.00 2.00

Theoretical content of Simethicone in the microgranules: 600 mg / g of microgranules.

Lansoprazole enteric microgranules mg per oral capsule Kg per batch of 100,000 capsules Lansoprazole 15.00 1.50 Sugar Spheres 31.80 3, 18 Mannitol 9.75 0.975 Calcium carboxymethyl cellulose 8.25 0.825

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Magnesium carbonate 9.00 0.90 Hydrogenated disodium phosphate 9.00 0.90 Sugar 36.00 3.60 Hydroxypropylmethylcellulose E5 18.00 1.80 Phthalate hydroxypropylmethylcellulose 28.50 2.85 Titanium dioxide 1.50 0.15 Solvents that evaporate during the elaboration process Purified water 12.60 Methylene chloride 18.80 Ethyl alcohol 18.80

Theoretical content of Lansoprazole in microgranules: 89.90 mg / g microgranules.

METHOD OF ELABORATION

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

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 the Simethicone into 6 fractions of equal weight.

3) Place the sugar spheres in a conventional solid wall pan (unperforated) and set the drum rotation speed between 10 and 15 rpm and the incoming air at 35 ° C with an air flow of 0.71 cubic meters per minute (25 cubic feet per minute).

4) Spray the first fraction of Simethicone over the sugar spheres using a sprinkler using the following operating conditions: LongistPump peristaltic pump, model BT100 or similar, with an application flow between 25 to 50 ml / min, using a spray gun. brand 3-way sprinkler

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Spraying System or similar with nozzle 2050 and nozzle 67228-45 ^{1 2 3 4} -SS from Spraying System or similar. Atomization pressure: 150 to 200 KPa (1.5 to 2.0 bar) and cylinder air: 50 KPa (0.5 bar).

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

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

7) Leave the product rolling in the pan for 5 minutes.

8) Sieve through 2.0 mm pore mesh. The microgranules obtained will be between 0.7 and 1.5 mm in diameter.

Entero-release Lansoprazole microgranules

1) Prepare a syrup by dissolving the sugar in 3.6 kg of purified water, heating to 40 ° to 45 ° C with stirring until smooth.

2) Sieve through 100 mesh: Lansoprazole, Magnesium carbonate, Mannitol, Calcium carboxymethylcellulose and hydrogenated disodium phosphate and mix in a rotary mixer at medium speed for 15 minutes.

3) Sprinkle the mixture obtained in step 2) over the sugar spheres in a stainless steel pan at 36 rpm, using the sugar syrup obtained in step 1) as an adhesive until microgranules of size between 0.4 and 0.9 are reached mm in diameter.

4) Dry the microgranules obtained in step 3) at 45 ° C

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12/22 for 8 hours or until no more than 1% moisture is obtained.

5) Sieve the dry microgranules through a 1.0 mm pore size mesh.

6) Dissolve hydroxypropylmethylcellulose E5 in 9 kg of purified water, stirring until a colloidal solution is obtained.

7) Place the microgranules in the fluid bed and spray the colloidal solution obtained in point 6, under a stream of hot air to dry the cover. Continue placing the coating until all the colloidal solution is used.

8) In a suitable container, add hydroxypropyl methylcellulose phthalate and titanium dioxide to the mixture of methylene chloride and ethyl alcohol. Stir until the preparation is homogeneous. Pass the preparation through a colloid mill for 10 minutes through the thinnest passage.

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

10) Sieve the microgranules with an enteric coating through 1.4 mm of pore. The microgranules obtained will be between 0.5 and 1.2 mm in diameter.

Package:

[0030] Encapsulate in capsules number 1 both microgranules obtained using a double station encapsulator placing:

[0031] Doser 1, Lansoprazole microgranules:

166.80 mg ± 5% (158.46 mg to 175.14 mg).

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13/22 [0032] Doser 2, Simethicone microgranules: 200.00 mg ± 5% (190.00 mg to 210.00 mg).

[0033] Content per capsule: 366.80 mg ± 10% (330 mg to 403 mg).

EXAMPLE 2. Simethicone 120 mg capsules + Lansoprazole 30 mg [0034] Using the microgranules made in Example 1, capsules containing 120 mg of Simethicone and 30 mg of Lansoprazole are prepared.

[0035] Both microgranules are filled in elongated number 0 gelatin capsules using a double station encapsulator placing:

[0036] Doser 1, Lansoprazole microgranules: 333.60 mg ± 5% (316.92 mg to 350.28 mg) [0037] Doser 2, Simethicone microgranules: 200.00 mg ± 5% (190.00 mg to 210.00 mg) [0038] Content per capsule: 533.60 mg ± 10% (480 mg to 587 mg)

EXAMPLE 3. Surplus for oral suspension of Simethicone 120 mg + Lansoprazole 15 mg [0039] When using microgranules made in

Example 1, envelopes are prepared containing 120 mg of

Simethicone and 15 mg Lansoprazole.

Ingredient mg per envelope Simethicone microgranules (containing 120 mg of Simethicone) 200.0 Lansoprazole microgranules (containing Lansoprazole 15 mg) 16 6.8

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Maize starch 100.0 Sucralose powder 10.0 Ionized RD Xanthan Gum 200.0 Anhydrous citric acid 20.0 Red iron oxide 5.0 Powdered banana essence 30.0 Powdered strawberry essence 40.0 Sugar 190.0 Granular Mannitol 3038.2

ELABORATION METHOD [0040] The method of making Simethicone microgranules and Lansoprazole microgranules is the method described in Example 1.

[0041] The excipients for the suspension are prepared as follows:

a) Mix corn starch, red iron oxide, powdered Sucralose, anhydrous citric acid, powdered banana essence, powdered strawberry essence, sugar and mannitol for 10 minutes at 12 rpm

b) Grind a mixture obtained in point a) by a Fitzpatrick mill, at 4800 rpm. 40 mesh, with hammers forward.

c) Mix the grind obtained in step b) with granular Mannitol and Xanthan Gum Ionized and previously ground by a Fitzpatrick mill with a mesh of 1.7 mm at 400 rpm, with hammers forward for 20 minutes at 12 rpm.

Enveloping [0042] Enveloping the microgranules and the mixture of excipients using an envelope equipped with three

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15/22 dispensers with the following quantities:

[0043] Doser 1, Lansoprazole microgranules:

166.80 mg ± 5% (158.46 mg to 175.14 mg) [0044] Doser 2, Simethicone microgranules:

200.00 mg ± 5% ( [0045] 190.00 mg to 210.00 mg) Doser 3, Mixing excipients: 3633.2 mg ± 5% (3451.54 mg to 3814.86) [0046] Content by envelope: 4000.0 mg ± 5% (3800.0 mg at 4200.0 mg) [0047] EXAMPLE 4. Capsules of 200 mg Simethicone +

mg of Dexlansoprazole [0048] The process for preparing a pharmaceutical formulation for oral administration is described comprising the combination of a fixed dose of 200 mg high concentration microgranules of Simethicone and 60 mg enteric-release microgranules of Dexlansoprazole, both contained in a hard capsule.

Simethicone microgranules of immediate release mg per oral capsule Kg per batch of 100,000 capsules Simethicone 200.00 20.00 Sugar Spheres (diameter 300 to 500 microns) 70.00 7.00 Colloidal silicon dioxide 70.00 7.00 Carbonate magnesium 60.00 6.00

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

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Enteric microgranules of Dexlansoprazole mg per oral capsule Kg per batch of 100.00 capsules Dexlansoprazole sesqui- hydrate Micronized (Equivalent to 60 mg of Dexlansoprazole) 64.60 6.46 Sugar Spheres 96.00 9.60 Hydroxypropylmethylcellulose E5 20.00 2.00 Magnesium carbonate 28.00 2.80 Hydroxypropylmethylcellulose 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 Baby powder 3.00 0.30 Purified water 120.00 Ethyl alcohol 80.00

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

METHOD OF ELABORATION

High concentration microgranules of Simethicone (500 mg / g made in fluid bed with 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 the Simethicone into 8 fractions of equal weight.

3) Place the sugar spheres in a fluid bed equipped with a tangential rotor of the Vector brand or similar and fix the inlet air at 35 ° C with a flow between 2.27 to 3.4 cubic meters per minute (80 and 120 cubic feet per minutes) and the rotor rotation speed at 50 to 100 rpm.

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4) Sprinkle the first fraction of Simethicone over the sugar spheres using a sprinkler using the following operating conditions: Peristaltic pump with application flow between 30 to 60 ml / min. Atomization pressure: 200 to 300 KPa (2.0 to 3.0 bar) and cylinder air: 100 KPa (1.0 bar). 1.2 mm nozzle

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

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

7) Leave the product in the rotor for 5 minutes at 20 rpm.

8) Sieve through 2.0 mm pore mesh. The microgranules obtained will be between 0.7 and 1.5 mm in diameter.

Enteric-release Dexlansoprazole microgranules

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

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

3) Application of the insulating layer: Dissolve the

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18/22 hydroxypropylcellulose LF in 50 kg of purified water and apply this solution to the microgranules obtained in the previous step.

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

5) Gastro-resistant coating: Dissolve Eudragit L100-55, Eudragit S100 and triethylcitrate in ethyl alcohol. Disperse the talc in the solution. Apply the coating solution to the dry microgranules obtained in step 4).

6) Sieving: Pass the dry microgranules through a 1.4 mm pore size mesh.

Package:

[0049] Encapsulate in number 00 capsules both microgranules obtained using a double station encapsulator placing:

[0050] Doser 1, Dexlansoprazole microgranules: 300.00 mg ± 5% (285.00 mg to 315.00 mg) [0051] Doser 2, Simethicone microgranules: 400.00 mg ± 5% (380.00 mg to 420.00 mg) [0052] Content per capsule: 700.0 mg ± 10% (630.00 mg to 770.00 mg) [0053] Example 5. Encapsulation tests [0054] When using the microgranules of Example 4 , capsule entry at different doses was checked manually.

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Weight microgranules Simethicone Dexlansoprazole microgranules weight Total content weight Capsule entry check Simethicone 120 mg + Dexlansoprazole 15 mg 240.00 mg 75.00 mg 315.00 mg n ° 1 Simethicone 120 mg + Dexlansoprazole 30 mg 240.00 mg 150.00 mg 390.00 mg n ° 0 Simethicone 120 mg + Dexlansoprazole 60 mg 240.00 mg 300.00 mg 540.00 mg Elongated n ° 0 Simethicone 200 mg + Dexlansoprazole 30 mg 400.00 mg 150.00 mg 550.00 mg Elongated n ° 0 Simethicone 200 mg + Dexlansoprazole 90 mg 400.00 mg 450.00 mg 820.00 mg Without capsule entry n ° 00

EXAMPLE 6. PHARMACOTECHNICAL DETERMINATIONS AND IN VITRO TESTS [0055] Pharmacotechnical determinations and tests were performed to evaluate physical characteristics of the microgranules of examples 1 and 4, and the dissolution of the formulations of examples 1, 2, 3 and 4.

[0056] Pharmacotechnical determinations: methodology and equipment.

[0057] Density: the VANDERKAMP equipment or

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Equivalent 20/22 is used to obtain the density. In a 50 graduated cylinder with a lid, approximately 30 g of sample was accurately weighed, adjusted on the base of the equipment and 15 were applied according to the movement. The surface is combined and the final volume is read.

[0058] The compacted density obtained must be between: 0.6 to 1.0 g / ml.

Lansoprazole microgranules or enantiomer Simethicone microgranules Example 1 0.81 g / ml 0.77 g / ml Example 4 0.79 g / ml 0.74 g / ml

[0059] Average diameter of the microgranules: it is measured by means of a Malvern particle size analyzer model

Mastersizer 2000, equipped with a Laser transmitter and a detector.

Microgranules of Lansoprazole or enantiomer Microgranules of Simethicone Example 1 0.980 mm 1,100 mm Example 4 1,040 mm 1,145 mm

[0060] Evaluation of Lansoprazole and enantiomer: by HPLC (High Performance Liquid Chromatography) according to the monograph of Lansoprazole Capsules from the United States Pharmacopeia 32 (USP, for its abbreviations in English).

[0061] Simethicone Evaluation: by Infrared Spectrophotometry.

[0062] Gastroresistance Test: according to USP 32 (United States Pharmacopeia 32), General Tests and Tests <711>.

[0063] Anti-foam activity: according to USP 32

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21/22 (United States Pharmacopoeia 32). Test performed in bulk microgranules.

[0064] Lansoprazole or enantiomer dissolution test: according to USP 32 (United States Pharmacopeia 32) General tests and Tests <711>. AT7 type SOTAX equipment or its equivalent was used.

Parameter EXAMPLE 1 EXAMPLE 2 EXAMPLE 3 EXAMPLE 4 Evaluation of Lansoprazole or enantiomer (expressed in mg per unit and in% of the theoretical value 14.9 mg / capsule (93.3%) 29.5 mg / capsule (98.3%) 14.3mg / aging (95.3%) 57.3 mg / capsule (95.5%) Simethicone Evaluation 112 mg / capsule (93.3%) 111 mg / capsule (92.5%) 115 mg / envelope (95.5%) 197 mg / capsule (98.5%) Symmetry, Anti-foam activity: The time required for the foam to collapse should not exceed 45 seconds Answer Answer Answer Answer

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Gastro-resistance test (percentage of undissolved active ingredient compared to theoretical content per dose) Average: 98.3% Average: 99.7% Average: 95.2% Average: 100.5% Medium Dissolution Average: 90.5% Average: 93.0% Average: 88.1% Average: 81.3%

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Claims (10)

1. Pharmaceutical composition for oral administration comprising between 120 mg and 200 mg of Simethicone and between 15 mg and 60 mg of Lansoprazole or Dexlansoprazole, characterized by the fact that Simethicone is below the form of high concentration microgranules, in which said concentration is greater than or equal to 500 mg / g, wherein the microgranules are formed by spheres of sugar, colloidal silicon dioxide, magnesium carbonate and optionally other pharmaceutical excipients. 2. Composition according to claim 1, characterized by the fact that the concentration of Simethicone in the microgranules is 600 mg / g. 3. Pharmaceutical composition according to claim 2, characterized by the fact that it is formed by a hard capsule containing 120 mg of Simethicone under the form of high concentration microgranules and between 15 mg and 30 mg of Lansoprazole in release microgranules enteric. 4. Pharmaceutical composition according to claim 1, characterized by the fact that it is formed by a hard capsule containing 200 mg of Simethicone in microgranules of high concentration and between 30 mg and 60 mg of Dexlansoprazole in microgranules of enteric release. 5. Pharmaceutical composition according to claim 2, characterized by the fact 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 microgranules of enteric release. 6. Process for preparing microgranules with a Petition 870190053999, of 12/06/2019, p. 4/10 2/2 concentration greater than or equal to 500 mg / g of Simethicone, characterized by the fact that it consists of placing, in a pan of solid wall covering or in a fluid bed equipment of the tangential rotor type, sugar spheres and, while they are on a roller to moisten them at regular intervals with Simethicone and dry them with a defined mixture of Colloidal Silicon Dioxide and Magnesium Carbonate. 7. Process according to claim 6, in which the application rate of Simethicone is 25 to 50 ml / minute using a peristaltic pump. Process according to claim 6, in which the average diameter of the high concentration microgranules of Simethicone is within the range from 0.7 mm to 1.5 mm. 9. Process according to claim 6, in which the application rate of Simethicone is 25 to 50 ml / minute using a peristaltic pump. Pharmaceutical composition according to claims 1 to 9, wherein said composition is used to treat functional gastrointestinal disorders, in particular dyspepsia.