PHARMACEUTICALS CONTAINING SIMETICON AND ALVERINE CITRATE, PHARMACEUTICALS CONTAINING SIMETICON, PHARMACEUTICALS CONTAINING ALVERINE CITRATE, AND METHODS OF PREPARING THESE PHARMACEUTICALS

Abstract

The invention relates to an orally dissolvable powder containing simethicone and alverin citrate, and to a method of preparing it; to a dry powder containing simethicone and to a method of preparing it; and to an alverin citrate granular powder and to a method of preparing it. The medicinal composition of a mixture of alverin citrate and simethicone as described in the invention consists of granules composed of simethicone adsorbed onto a powder matrix, granules containing alverin citrate granules, the outer surface of which is covered with a film made of a masking agent, and a pharmaceutical excipient containing at least one flavoring agent, and / or at least one acidifier, and / or at least one sweetener, and / or at least one lubricant / anti-caking agent, and / or at least one filler. This invention is intended for use in pharmaceuticals.

Description

Pharmaceutical composition comprising simethicone and alverine citrate, pharmaceutical composition containing simethicone, pharmaceutical composition comprising alverine citrate, and methods of manufacturing them.

[0001] The invention relates to a pharmaceutical composition, in the form of an orodispersible powder, comprising simethicone and alverine citrate and its manufacturing process.

[0002] It also relates to a pharmaceutical composition, in dry form, containing simethicone and its manufacturing process.

[0003] It also relates to a pharmaceutical composition, in the form of grains, comprising alverine citrate and its manufacturing process.

[0004] Alverine citrate is a powdery compound that has an antispasmodic and musculotropic effect.

[0005] Alverine citrate also has a very bitter taste that is not acceptable to a patient and a powerful anesthetic effect.

[0006] In combination with anemone and turmeric, alverine citrate is used in herbal medicine to treat dyspepsia.

[0007] A pharmaceutical composition containing a combination of alverine citrate, anemone and turmeric is known. It comes in the form of an oral solution.

[0008] In combination with simethicone, alverine citrate allows the treatment of functional intestinal disorders such as digestive pain accompanied by bloating and has an antispasmodic and antiflatulent effect.

[0009] In this association, simethicone acts by modifying the surface tension of the gas bubbles, thus causing them to coalesce.

[0010] Simethicone comes in oil form at room temperature.

[0011] Used alone, simethicone can treat meteorism.

[0012] In combination with activated charcoal or a combination of activated charcoal and magnesium, or a combination of aluminum and magnesium, simethicone acts on meteorism and oesophago-gastroduodenal disorders.

[0013] Pharmaceutical compositions containing a combination of alverine citrate and simethicone are known.

[0014] A composition containing a combination of alverine citrate and simethicone, marketed under the brand name METEOSPASMYL ® is manufactured as a soft capsule, to be taken orally, containing a thick suspension comprising 300mg of simethicone and 60mg of alverine citrate.

[0015] In the form of soft capsules, when taken orally, Alverine citrate does not come into contact with the oral mucosa, so the patient does not feel the very bitter taste and the powerful anesthetic effect of Alverine citrate.

[0016] The soft capsule is taken orally with water, to facilitate its administration and dissolution in the stomach.

[0017] Patients suffering from digestive pain accompanied by bloating do not always have water available to them at the time of attacks.

[0018] To overcome this problem, the inventors conducted intensive research to find a pharmaceutical composition containing a combination of alverine citrate and simethicone which:can be taken without requiring the concomitant intake of water,has the same dissolution profile as METEOSPASMYL® or a dissolution profile sufficiently close to the dissolution profile of METEOSPASMYL ®to be considered equivalent from this point of view to METEOSPASMYL®, is accepted by the patient, that is to say whose bitter taste and the anesthetic effect of alverine citrate are masked,

[0019] Thus, the invention provides a pharmaceutical composition in the form of immediate-release orodispersible granules, comprising alverine citrate and / or simethicone, accepted by patients and having a dissolution profile equivalent to the dissolution profile of METEOSPAMYL®.

[0020] Therefore, a first subject of the invention is a pharmaceutical composition comprising a mixture of alverine citrate and simethicone comprising: grains composed of simethicone adsorbed on a powdery solid support, granules containing grains containing alverine citrate, these grains being coated on their external surface with a film of a masking agent, and pharmaceutically acceptable excipients (4) comprising at least one flavoring, and / or at least one acidifier, and / or at least one sweetener, and / or at least one lubricating / anti-aggregating agent and / or at least one bulking agent.

[0021] In this pharmaceutical composition, preferably, each alverine citrate-containing grain of the granules (b) consists of a core which is coated on its outer surface with a film of a mixture of alverine citrate and a binder.

[0022] Preferably, the binder used in this mixture of alverine citrate and binder is hydroxypropyl methyl cellulose.

[0023] Always preferably, the aforementioned core is made of mannitol.

[0024] As for the masking agent for the granules (b) covering the grain containing alverine citrate, it is preferably made up of a mixture of polysorbate 65 and glyceryl palmitate.

[0025] Still in this pharmaceutical composition, preferably, the powdery solid support on which the simethicone is adsorbed is hydrated colloidal silica.

[0026] Also preferably, in the pharmaceutical composition of the first embodiment of the invention, the pharmaceutically acceptable excipients (c) comprise menthol and spearmint flavors, citric acid and monosodium citrate as acidifier, xylitol and sucralose as sweeteners, xylitol as bulking agent and talc as lubricating / anti-aggregating agent.

[0027] In a preferred embodiment, the pharmaceutical composition of the orodispersible unit dose of the first subject of the invention comprises 300 mg of simethicone and 60 mg of alverine citrate.

[0028] Another subject of the invention is a pharmaceutical composition comprising alverine citrate. This pharmaceutical composition comprises granules coated on their external surface with a film of a masking agent, and containing grains coated with alverine citrate,

[0029] Preferably, in the pharmaceutical composition comprising alverine citrate of the invention, the masking agent constituting the film in a masking agent is a mixture of polysorbate 65 and glyceryl palmitate.

[0030] In the pharmaceutical composition comprising alverine citrate of the invention, preferably, each grain containing alverine citrate consists of a core coated on its external surface with a film of a mixture of alverine citrate and a binder.

[0031] Preferably, the core is mannitol.

[0032] Also preferably, the binder in the film-forming mixture of alverine citrate and a binder is hydroxypropyl methyl cellulose.

[0033] Still preferably, the pharmaceutical composition comprising alverine citrate according to the invention further comprises pharmaceutically acceptable excipients comprising at least one flavoring, and / or at least one acidifier, and / or at least one sweetener, and / or at least one bulking agent, and / or at least one lubricating / anti-aggregating agent.

[0034] In this case preferred pharmaceutically acceptable excipients include menthol and spearmint flavors, citric acid and monosodium citrate as acidifier, xylitol and sucralose as sweeteners, xylitol as bulking agent and talc as lubricating / anti-caking agent.

[0035] Yet another subject of the invention is a method for manufacturing a pharmaceutical composition containing alverine citrate according to the second subject of the invention, comprising the following steps:suspending, and mixing, in water, alverine citrate and a binder,coating grains of a solid support with the suspension obtained in step a) and removing the water, so that grains consisting of a core, coated on its outer surface with a film of a mixture of alverine citrate and a binder are obtained,preparation of a solution of a masking agent, and coating the grains obtained in step b) with this solution of a masking agent, so that granules coated on their outer surface with a film of a masking agent, and containing the grains containing alverine citrate are obtained.

[0036] Preferably, in the process for manufacturing a pharmaceutical composition containing alverine citrate according to the invention, the binder used in step a) is hydroxypropyl methyl cellulose and the mass ratio of alverine citrate / mass of hydroxypropyl methyl cellulose is between 10 and 20, preferably is equal to 15.

[0037] Also preferably, in the process for manufacturing a pharmaceutical composition containing alverine citrate of the invention, the solid support grains used in step b) are made of mannitol and the ratio mass of solid support grains / (mass of alverine citrate + mass of binder) is between 1 and 3, preferably is equal to 2.1.

[0038] Still preferably, in the process for manufacturing a pharmaceutical composition containing alverine citrate of the invention: the masking agent used in step c) is a mixture of glyceryl tripalmitate and polysorbate 65 at a glyceryl palmitate / polysorbate 65 mass ratio of between 5 and 7, preferably equal to 6.1, and the total mass of masking agent / mass of alverine citrate ratio is between 0.3 and 0.4, and preferably is equal to 0.33.

[0039] More preferably, the method for manufacturing a pharmaceutical composition containing alverine citrate of the invention further comprises a step d) of adding pharmaceutically acceptable excipients, these pharmaceutically acceptable excipients comprising at least one flavoring, and / or at least one acidifier, and / or at least one sweetener, and / or at least one bulking agent and / or at least one lubricating / anti-aggregating agent.

[0040] In this case, the preferred pharmaceutically acceptable excipients are menthol and spearmint flavors, anhydrous citric acid and monosodium citrate as acidifier, xylitol, and sucralose as sweeteners, and Xylitol as bulking agent and Talc as lubricating / anti-caking agent.

[0041] Still another object of the invention is a method for manufacturing a pharmaceutical composition comprising granules containing alverine citrate and simethicone according to the first object of the invention comprising the following steps:Manufacturing granules containing alverine citrate by the method for manufacturing granules containing alverine citrate of the invention,Adsorption of simethicone on a powdery solid support,Preparation of a premix I by mixing a portion of the simethicone adsorbed on a powdery solid support obtained in step B) with a sweetener,Preparation of a premix II by mixing the premix I with a lubricating / anti-aggregating agent with at least one flavoring and at least one acidifier,Mixing the remainder of the simethicone adsorbed on a powdery support obtained in step B), with the granules (3) obtained in step A), premix II obtained in step D) and at least one acidifier and at least one bulking agent.

[0042] Preferably, in this process:in step B), the powdered solid support is hydrated colloidal silica and the simethicone / hydrated colloidal silica mass ratio is between 2:1 and 1.3:1 and preferably is 1.6:1,in step C), the sweetener is sucralose and the grain 5 / sucralose mass ratio is between 6 and 8, preferably 6.87,in step D), the bulking and / or lubricating / anti-aggregating agent is talc, the acidifier is anhydrous citric acid, and the flavors are a spearmint flavor and a menthol flavor,in step E), the acidifier is monosodium citrate and the bulking agent is xylitol.

[0043] A method of manufacturing a pharmaceutical composition containing simethicone is also an object of the invention.

[0044] This process involves the adsorption of simethicone onto a powdered solid support, whereby grains containing simethicone are obtained.

[0045] Preferably, the powdered solid support is hydrated colloidal silica and the simethicone is adsorbed by mixing onto the hydrated colloidal silica grains.

[0046] A final object of the invention is a pharmaceutical composition containing simethicone in which the simethicone is adsorbed on hydrated colloidal silica.

[0047] The invention will be better understood and other characteristics thereof will appear more clearly in light of the explanatory description which follows and which is made with reference to the appended figures in which:the schematically represents a mixture, to be taken by the patient, of the composition according to the invention comprising a combination of alverine citrate and simethicone,the schematically represents a granule comprising alverine citrate, present in the mixture to be taken by the patient represented in,the schematically represents a grain comprising alverine citrate, present in the granule comprising alverine citrate represented in,the shows the dissolution curves of METEOSPASMYL® and of the pharmaceutical composition of the invention containing a combination of 300 mg of simethicone and 60 mg of alverine citrate at a pH of 1.2,shows the dissolution curves of METEOSPASMYL® and the pharmaceutical composition of the invention containing a combination of 300 mg of simethicone and 60 mg of alverine citrate at a pH of 4.5, shows the dissolution curves of METEOSPASMYL® and the pharmaceutical composition of the invention containing a combination of 300 mg of simethicone and 60 mg of alverine citrate at a pH of 6.8.,

[0048] The pharmaceutical composition comprising a combination of alverine citrate and simethicone, which is the first subject of the invention, consists of a mixture, noted 1 en.

[0049] This mixture constitutes an orodispersible powdered pharmaceutical composition which can be used as a replacement for METEOSPASMYL®.

[0050] As seen in, mixture 1 consists of grains, noted 5 in, comprising simethicone, and granules, noted 3 in, comprising alverine citrate.

[0051] A particularly preferred pharmaceutical composition comprising a combination of alverine citrate and simethicone is a unit dose comprising 300 mg of simethicone and 60 mg of alverine citrate for a unit dose mass of 1.4 g of the pharmaceutical composition.

[0052] As seen in, the grains (5) containing simethicone and the granules 3 comprising alverine citrate are included in a powdery solid phase consisting of pharmaceutically acceptable excipients, noted 4 in.

[0053] The pharmaceutically acceptable excipients 4 may comprise any pharmaceutically acceptable excipient capable of providing a taste and mouthfeel acceptable to the patient. More preferably, the pharmaceutical excipients will be chosen not only to provide an acceptable taste but also to allow rapid dissolution, rapid dispersion in the mouth, preferably in less than 10s and good flow of the powdered pharmaceutical composition, when packaged in sticks.

[0054] In particular, they may include at least one flavoring to give the mixture a taste acceptable to the patient.

[0055] Any flavoring can be used, such as red fruit, citrus, or mint.

[0056] A preferred flavor in the invention is a mixture of a spearmint flavor and a menthol flavor.

[0057] The pharmaceutically acceptable excipients 4 may also comprise at least one acidifier to promote salivation of the patient. Any acidifier known to promote salivation may be used. A preferred acidifier in the invention is a mixture of anhydrous citric acid and monosodium citrate.

[0058] The pharmaceutically acceptable excipients 4 may also comprise at least one sweetener to improve the acceptability of the granule 1 of the invention by the patient. Any known sweetener may be used. A preferred sweetener present in the pharmaceutically acceptable excipients 4 is a mixture of xylitol and sucralose.

[0059] The pharmaceutically acceptable excipients 4 may also comprise at least one lubricating and anti-aggregating agent. Any known lubricating and anti-aggregating agent may be used. A preferred lubricating and anti-aggregating agent for use as the pharmaceutically acceptable excipient 4 is talc.

[0060] Pharmaceutically acceptable excipients 4 may comprise all or only some of these types of excipients. They may comprise other pharmaceutically acceptable excipients other than those mentioned above.

[0061] The grains (5) containing simethicone are formed from simethicone adsorbed on a powdery solid support.

[0062] Indeed, simethicone is an oil at room temperature and to form a solid grain 5, it must be adsorbed on a powdery solid support. Any powdery solid support can be used such as for example sorbitol, activated charcoal, aluminum salts, etc.

[0063] The grains 5 are formed by mixing with at least one pharmaceutically acceptable excipient.

[0064] However, in the invention, the preferred powdered solid support is hydrated colloidal silica.

[0065] An example of a more suitable hydrated colloidal silica is hydrated colloidal silica manufactured by Grace under the reference Syloid XDP 3150, which has a particle size between 50 and 150 µm, a bulk density of 0.24 g / ml and a tapped density of 0.28 g / ml according to the manufacturer's specifications.

[0066] The average grain diameter 5 is generally between 50 µm and 200 µm.

[0067] This mean diameter is a volume mean diameter measured using a CAMSIZER X2 particle size analyzer, using the X-Jet method of dry measurement in an air stream passing through a Venturi nozzle. The applied dispersion pressure is 80.0 kPa.

[0068] The pharmaceutical composition containing simethicone adsorbed on hydrated colloidal silica alone or with pharmaceutically acceptable excipients is a second subject of the invention. Indeed, it can be used as such in applications other than in association with alverine citrate.

[0069] This pharmaceutical composition of the invention containing simethicone is manufactured by a process which is a third object of the invention.

[0070] This process includes an adsorption step by mixing the simethicone on a powdery solid support.

[0071] Any solid powdered carrier can be used, such as sorbitol, activated charcoal, aluminum salts, etc.

[0072] Preferably, the powdered solid support is hydrated colloidal silica.

[0073] Preferably, the mass ratio of simethicone to powdered solid carrier is between 2:1 and 1.3:1 and is preferably 1.6:1.

[0074] Preferably, the adsorption of the simethicone onto the powdered solid support is carried out by mixing the simethicone and the powdered solid support.

[0075] A fourth subject of the invention is a pharmaceutical composition containing alverine citrate, which can be used alone or in combination with other compounds and in particular in combination with the composition comprising simethicone according to the second subject of the invention to form the composition according to the first subject of the invention comprising simethicone and alverine citrate.

[0076] This pharmaceutical composition is composed of granules 3 comprising alverine citrate, the bitter taste and anesthetic effect of which are effectively masked.

[0077] Granules 3 consist of grains, denoted 7 in, comprising alverine citrate and a binder, deposited on a core, and coated with a masking agent, denoted 8 in.

[0078] The masking agent which has proven to be most effective in the invention is a mixture of polysorbate 65 and glyceryl palmitate. Preferably, the polysorbate 65 / glyceryl palmitate mass ratio is between 0.11 and 0.25, preferably 0.16, which makes it possible to obtain at the 3 pHs (pH = 1.2, pH = 4.5 and pH = 6.8) a dissolution profile for the pharmaceutical composition, according to the first subject of the invention, comprising simethicone and alverine citrate, which is equivalent to the dissolution profile of METEOSPASMYL®.

[0079] Grains 7 consist of a core, noted 10 enet, composed of a solid powdery support.

[0080] Any solid powdered support can be used.

[0081] However, in the invention, the preferred powdery solid carrier consists of mannitol.

[0082] On this core 10, a film consisting of a mixture of alverine citrate and a binder is deposited.

[0083] The preferred binder in the invention is hydroxypropyl methyl cellulose.

[0084] Preferably, the alverine citrate / hydroxypropyl methyl cellulose mass ratio is between 10 and 20, preferably 15.

[0085] The ratio of total mass of masking agent / mass of grain (7) of alverine citrate is preferably between 0.2 and 0.4, and preferably is 0.33.

[0086] A fifth subject of the invention is a method of manufacturing the pharmaceutical composition containing alverine citrate according to the fourth subject of the invention.

[0087] This method comprises the following steps: suspending and mixing, in water, alverine citrate and a binder, coating grains of a powdery solid support forming cores 10 with the suspension obtained in step a) and removing the water, so that grains 7 consisting of a core of the powdery solid support coated on its external surface with a film of a mixture of alverine citrate and a binder are obtained, preparing a solution of a masking agent, and coating the grains 7 obtained in step b) with this solution of a masking agent, so that granules 3 coated on their external surface with a film 8 of a masking agent, and containing grains 7 containing alverine citrate are obtained.

[0088] A fifth subject of the invention is a process for manufacturing a pharmaceutical composition containing alverine citrate according to the fourth subject of the invention, in which the binder used in step a) is hydroxypropyl methyl cellulose and the mass ratio of alverine citrate / mass of hydroxypropyl methyl cellulose is between 10 and 20, preferably is equal to 15.

[0089] Preferably, the powdery solid support used in step b) is mannitol and the ratio mass of powdery solid support / (mass of alverine citrate + mass of binder) is between 1 and 3, preferably is equal to 2.1.

[0090] A masking agent which has proven to be particularly effective, not only in masking the bitter taste and the anesthetic effect of alverine citrate, but also in enabling the pharmaceutical composition containing alverine citrate and simethicone according to the first subject of the invention to have a dissolution profile equivalent to the Météospasmyl® reference formula at pH 1.2 and at pH 4.5 and at pH 6.8, this masking agent used in step c) is a mixture of glyceryl tripalmitate and polysorbate 65.

[0091] Preferably, the glyceryl palmitate / polysorbate 65 mass ratio is between 5 and 7, preferably equal to 6.1.

[0092] Also preferably, the total mass ratio of masking agent / mass of the grain (7) of alverine citrate is between 0.2 and 0.4. Preferably, it is equal to 0.33.

[0093] The process for manufacturing a pharmaceutical composition containing alverine citrate according to the fifth subject of the invention optionally comprises a step d) of adding pharmaceutically acceptable excipients (4) comprising at least one flavoring, and / or at least one acidifier, and / or at least one sweetener, and / or at least one bulking agent and at least one lubricating / anti-aggregating agent.

[0094] These pharmaceutically acceptable excipients (4) are preferably those used in the pharmaceutical composition containing alverine citrate and simethicone according to the first subject of the invention and comprise menthol and spearmint flavors, anhydrous citric acid and monosodium citrate as acidifier, xylitol and sucralose as sweetener, Xylitol as bulking agent, and talc as lubricating / anti-aggregating agent.

[0095] A sixth subject of the invention is a method of manufacturing a pharmaceutical composition comprising a combination (1) of alverine citrate and simethicone according to the first subject of the invention.

[0096] This method comprises the following steps: Manufacture of granules (3) containing alverine citrate according to the manufacturing method which is the fifth subject of the invention, Adsorption of simethicone on a powdery solid support, Preparation of a premix I by mixing a part of the simethicone adsorbed on a powdery solid support obtained in step B) with at least one sweetener, Preparation of a premix II, by mixing a lubricating / anti-aggregating agent with at least one flavoring and at least one acidifier, and the premix I obtained in step C). Mixing the granules (3) obtained in step A) and the premix II obtained in step D) and the remainder of the simethicone adsorbed on a powdery solid support obtained in step B) and at least one acidifier and at least one filler.

[0097] Preferably: in step B), the powdered solid support is hydrated colloidal silica and the simethicone / hydrated colloidal silica mass ratio is between 2:1 and 1.3:1 and preferably 1.6:1 (1.6 of simethicone to 1 of hydrated colloidal silica), in step C), the sweetener is sucralose and the grain 5 / sucralose mass ratio is between 6 and 8, preferably 6.86, in step D), the lubricating / anti-aggregating agent is talc, the acidifier is anhydrous citric acid, and the flavors are a spearmint flavor and a menthol flavor, in step E), the acidifier is monosodium citrate and the bulking agent is xylitol.

[0098] It is particularly preferred that 1.4 g of mixture contains 300 mg of simethicone and 60 mg of alverine citrate contained in granules 3.

[0099] In order to better understand the invention, examples of its manufacture will be given, purely for illustrative and non-limiting purposes.

[0100] Example 1: Manufacture of grains (5) containing simethicone – pharmaceutical composition containing simethicone according to the second subject of the invention

[0101] Materials: simethicone reference Q7-2243 from Dupont colloidal silica reference Syloid XDP 3150 from Grace

[0102] 96.72 kg of hydrated colloidal silica are introduced into a granulator.

[0103] 154.50 kg of simethicone are added and granulated with hydrated colloidal silica.

[0104] The two components are mixed for 60 minutes at 5 rpm.

[0105] We got 5 grains.

[0106] Example 2: Manufacture of granules 3 containing alverine citrate – pharmaceutical composition comprising alverine citrate according to the fourth embodiment of the invention Preparation of an alverine citrate phase – preparation of grains 7

[0107] Materials:

[0108] Alverine citrate: reference 0368 from Centipharm

[0109] Hydroxypropyl methyl cellulose: reference KLUCEL EXF ULTRA PHARM® from Ashland

[0110] Mannitol: reference Mannitol Pearlitol 300DC® from Roquette Frères

[0111] Simethicone: reference Q7-2243 from Dupont

[0112] Purified water

[0113] It should be noted that simethicone is added at this stage in a very small quantity and is only used as an antifoaming agent, during the preparation of the alverine citrate suspension and should not be taken into account for the calculation of the quantity of simethicone contained in the alverine citrate – simethicone combination according to the first subject of the invention.

[0114] It is also noted that purified water is used as a solvent and is removed during the pellet manufacturing process 3.

[0115] 30.9 kg of alverine citrate and 2.06 kg of hydroxypropyl methyl cellulose are suspended by stirring in approximately 43.3 kg of purified water in a mixing vessel.

[0116] During stirring 0.001 kg of simethicone is added to break any foam forming.

[0117] 70.04 kg of mannitol is passed through a sieve having a mesh size of 0.8 mm and then transferred to a fluidized bed apparatus for particle coating in which the mannitol is coated with the aqueous suspension of alverine citrate and hydroxypropyl methyl cellulose.

[0118] For coating mannitol particles with the aqueous suspension of alverine citrate and hydroxypropyl methyl cellulose, Romaco's Ventilus® technology in a fluidized air bed is preferably used.Preparation of alverine citrate granules 3

[0119] Materials: Alverine citrate phase: obtained in step 1 above Glyceryl tripalmitate grade Dynasan 116 from IOI Oleo GmbH: Polysorbate 65, reference TWEEN 65-SO-(MV), from Croda

[0120] 103 kg of alverine citrate phase (grains 7) passed through a sieve with a mesh size of 1.0 mm are transferred to a fluidized air bed apparatus for particle coating.

[0121] 29.53 kg of glyceryl palmitate and 4.81 kg of polysorbate 65 are melted and mixed, then the grains 7 comprising alverine citrate are hot coated in the fluidized air bed apparatus with the molten solution of glyceryl palmitate and polysorbate 65 as prepared.

[0122] For coating grains 7 with the masking agent mixture of glyceryl palmitate + polysorbate 65, Ventilus® technology in a Romaco fluidized air bed is preferably used.

[0123] The grains 7 coated with the masking agent are then cooled and passed through a sieve having a mesh size of 1.0 mm.

[0124] 3 granules are obtained.

[0125] Example 3: Preparation of a composition comprising a combination of alverine citrate and simethicone according to the first subject of the invention

[0126] Materials: simethicone adsorbed on silica obtained in Example 1Sucralose (sweetener): EMPROVE® Ph. Eur. grade from MerckTalc: LUZENAC PHARMA from ImerysMenthol flavor: code SN791345 from IFFFresh mint flavor: code SC097260 from IFF.Anhydrous citric acid: Grade F3500 from JungbunzlauerXylitol: Xylisorb® 300 from Roquette FrèresMonosodium citrate: Grade F3500 from Jungbunzlauer

[0127] 21.2 kg grain 5 of simethicone adsorbed on silica obtained in Example 1 and 3.09 kg of sucralose are mixed in a mixer. A premix I is obtained.

[0128] 12.88 kg of talc, 14.42 kg of menthol flavor, 7.21 kg of fresh mint flavor and 5.15 kg of anhydrous citric acid and premix I, are passed through a sieve having a mesh size of 0.8 mm are mixed together.

[0129] This mixture is a mixture of part of the pharmaceutical excipients 4 and constitutes premix II.

[0130] 63.97 kg of this premix II, 276.83 kg of xylitol and 12.88 kg of monosodium citrate passed through a sieve having a mesh size of 1.0 mm are introduced into a mixer with 137.33 kg of granules 3 containing alverine citrate prepared in Example 2 and passed through a sieve having a mesh size of 1.3 mm and 230 kg of grain 5 simethicone adsorbed on silica, then mixed for 15 minutes at 6 revolutions per minute.

[0131] The pharmaceutical composition according to the first subject of the invention in the form of an orodispersible powder comprising, in each 1.4 g dosage unit, 300 mg of simethicone per 60 mg of alverine citrate is obtained.

[0132] Example 4: Comparison of the dissolution profiles of the pharmaceutical composition according to the invention comprising 300 mg of simethicone for 60 mg of alverine citrate with the dissolution profiles of METEOSPASMYL®

[0133] Meteospasmyl®, consisting of a soft gelatin capsule filled with a thick suspension containing 300 mg of simethicone and 60 mg of alverine citrate, was taken as a reference.

[0134] The dissolution profiles at pH 1.2, adjusted with HCl, at pH 4.5 adjusted with acetate buffer and at pH 6.8, adjusted with phosphate buffer, of Météospasmyl® and the orodispersible pharmaceutical composition, manufactured in Example 3 were determined by the dissolution test of the active substance alverine citrate using USP apparatus 3 (reciprocating cylinders) for the dissolution method (European Pharmacopoeia Method 2.9.3) and by HPLC / UV for the analytical method (European Pharmacopoeia Method 2.2.29).

[0135] The dissolution profiles obtained at pH 1.2 for Météospasmyl® and the composition of the invention are shown in which the dissolution profile of Météospasmyl® is noted 1 and the dissolution profile of the composition of the invention is noted 2.

[0136] The dissolution profiles obtained at pH 4.5 for Météospasmyl® and the composition of the invention are shown in which the dissolution profile of Météospasmyl® is noted 1 and the dissolution profile of the composition of the invention is noted 2.

[0137] The dissolution profiles obtained at pH 6.8 for Météospasmyl® and the composition of the invention are shown in which the dissolution profile of Météospasmyl® is noted 1 and the dissolution profile of the composition of the invention is noted 2.

[0138] Both compositions present an average dissolution percentage greater than 85% in 15 minutes at all pHs studied.

[0139] Therefore, the dissolution profiles of the two compositions studied can be considered equivalent according to the EMEA Guidelines on the investigation of bioequivalence (CPMC / EWP / QWP / 1404 / 95 Rev.1 / Corr**).

[0140] Thus, the dissolution profiles of Météospasmyl® and the composition of the invention are considered equivalent in the physiological pH range, i.e. at pH 1.2 and pH 4.5 and pH 6.8.

Claims

Pharmaceutical composition comprising a mixture (1) of alverine citrate and simethicone comprising: grains (5) composed of simethicone adsorbed on a powdered solid support, granules (3) containing grains (7) containing alverine citrate, the grains (7) being coated on their external surface with a film of a masking agent (8), pharmaceutically acceptable excipients (4) comprising at least one flavoring, and / or at least one acidifier, and / or at least one sweetener, and / or at least one lubricating / anti-aggregating agent and / or at least one bulking agent. Pharmaceutical composition according to claim 1, wherein each grain (7) consists of a core (10) which is coated on its external surface with a film (11) of a mixture of alverine citrate and a binder. Pharmaceutical composition according to claim 2, wherein the core (10) is mannitol. Pharmaceutical composition according to any one of the preceding claims, wherein the film (8) is a film of a mixture of polysorbate 65 and glyceryl palmitate. A pharmaceutical composition according to any one of claims 2 to 4, wherein the binder in the mixture constituting the film (11) is hydroxypropyl methyl cellulose. Pharmaceutical composition according to any one of the preceding claims, wherein the powdered solid support on which the simethicone is adsorbed is hydrated colloidal silica. Pharmaceutical composition according to any one of the preceding claims, comprising 300 mg of simethicone and 60 mg of alverine citrate for a total mass of the pharmaceutical composition of 1.4 g. A pharmaceutical composition according to any preceding claim, wherein the pharmaceutically acceptable excipients (4) comprise menthol and spearmint flavors, citric acid and monosodium citrate as acidifier, xylitol and sucralose as sweeteners, and talc as lubricating / anti-aggregating agent and xylitol as bulking agent. A pharmaceutical composition comprising alverine citrate, the pharmaceutical composition comprising granules (3), the granules (3):being coated on their outer surface with a film (8) of a masking agent, andcontaining grains (7) containing alverine citrate, Pharmaceutical composition according to claim 9, wherein the masking agent constituting the film (8) is a mixture of polysorbate 65 and glyceryl palmitate. Pharmaceutical composition according to claim 9 or 10, in which each grain (7) consists of a core (10) coated on its external surface with a film (11) of a mixture of alverine citrate and a binder. Pharmaceutical composition according to claim 11, wherein the core (10) is mannitol. A pharmaceutical composition according to claim 11 or 12, wherein the binder in the film-forming mixture (11) is hydroxypropyl methyl cellulose. Pharmaceutical composition according to any one of claims 9 to 13, further comprising pharmaceutically acceptable excipients (4), these pharmaceutical excipients (4) comprising at least one flavoring, and / or at least one acidifier, and / or at least one sweetener, and / or at least one lubricating / anti-aggregating agent and / or at least one bulking agent. A pharmaceutical composition according to claim 14, wherein the pharmaceutically acceptable excipients (4) comprise menthol and spearmint flavors, citric acid and monosodium citrate as acidifier, xylitol and sucralose as sweetener, and talc as binder and Xylitol as bulking agent. A method of manufacturing a pharmaceutical composition containing alverine citrate according to any one of claims 9 to 15, comprising the following steps:suspending, and mixing, in water, alverine citrate and a binder,coating grains of a solid support with the suspension obtained in step a) and removing the water, so that grains (7) consisting of a core (10) coated on its outer surface with a film (11) of a mixture of alverine citrate and a binder are obtained,preparing a solution of a masking agent, and coating the grains (7) obtained in step b) with this solution of a masking agent, so that granules (3) coated on their outer surface with a film (8) of a masking agent, and containing grains (7) containing alverine citrate are obtained. A method of manufacturing a pharmaceutical composition containing alverine citrate according to claim 16, wherein the binder used in step a) is hydroxypropyl methyl cellulose and the mass ratio of alverine citrate / mass of hydroxypropyl methyl cellulose is between 10 and 20, preferably is equal to 15. A method of manufacturing a pharmaceutical composition containing alverine citrate according to claim 16 or 17, wherein the solid support used in step b) is mannitol and the ratio mass of solid support / (mass of alverine citrate + mass of binder) is between 1 and 3, preferably is equal to 2.

1. A method of manufacturing a pharmaceutical composition containing alverine citrate according to any one of claims 16 to 18, wherein:the masking agent used in step c) is a mixture of glyceryl tripalmitate and polysorbate 65 at a glyceryl palmitate / polysorbate 65 mass ratio of between 5 and 7, preferably equal to 6.1, andthe total mass of masking agent / mass of alverine citrate grains (7) ratio is between 0.3 and 0.4, and preferably is equal to 0.

33. A method of manufacturing a pharmaceutical composition containing alverine citrate according to any one of claims 16 to 19, further comprising a step d) of adding pharmaceutically acceptable excipients (4) comprising at least one flavoring, and / or at least one acidifier, and / or at least one sweetener, and / or at least one filler and at least one lubricating / anti-aggregating agent. A method of manufacturing a pharmaceutical composition containing alverine citrate according to any one of claims 16 to 20 wherein the pharmaceutically acceptable excipients (4) comprise menthol and spearmint flavors, anhydrous citric acid and monosodium citrate as acidifier, xylitol and sucralose as sweeteners, and talc as lubricating / anti-aggregating agent and Xylitol as bulking agent. A method of manufacturing a pharmaceutical composition comprising a combination (1) of alverine citrate and simethicone according to any one of claims 1 to 9, the method comprising the following steps:Manufacturing granules (3) containing alverine citrate by the method according to any one of claims 16 to 20,Adsorption of simethicone on a powdery solid support, to obtain grains (5) containing simethicone,Preparation of a premix I by mixing a portion of the grains (5) of simethicone adsorbed on a powdery solid support obtained in step B) with a sweetener,Preparation of a premix II by mixing the premix I obtained in step (C) and a lubricating / anti-aggregating agent with at least one flavoring and at least one acidifier,Mixing the remainder of the grains (5) obtained in step B), with the granules (3) obtained in step A), and premix II obtained in step D and at least one acidifier and at least one bulking agent. A method according to claim 22 wherein:in step B), the powdered solid support is hydrated colloidal silica and the simethicone / hydrated colloidal silica mass ratio is between 2:1 and 1.3:1 and preferably 1.6:1, and the simethicone is adsorbed onto the hydrated colloidal silica by mixing,in step C), the sweetener is sucralose and the grains (5) / sucralose mass ratio is between 5 and 8, and preferably is equal to 6.87,in step D), the lubricating / anti-aggregating agent is talc, the acidifier is anhydrous citric acid, and the flavors are a spearmint flavor and a menthol flavor,in step E), the acidifier is monosodium citrate and the bulking agent is xylitol. A method of manufacturing a pharmaceutical composition containing simethicone comprising the following steps: adsorption of simethicone onto a powdery solid support, whereby grains (5) containing simethicone are obtained. wherein the powdery solid support is hydrated colloidal silica. A method of manufacturing a pharmaceutical composition containing simethicone according to claim 24 wherein the simethicone is adsorbed onto the hydrated colloidal silica by mixing. Pharmaceutical composition containing simethicone in which the simethicone is adsorbed on hydrated colloidal silica.