Pharmaceutical composition comprising simethicone and alverine citrate, pharmaceutical composition containing simethicone, pharmaceutical composition comprising alverine citrate, and their manufacturing processes.
The development of orodispersible granules with alverine citrate and simethicone, coated with a masking agent and flavored excipients, addresses the inconvenience of METEOSPASMYL® by providing a water-free, taste-masked, and therapeutically equivalent solution for digestive issues.
Patent Information
- Authority / Receiving Office
- FR · FR
- Patent Type
- Patents
- Current Assignee / Owner
- LABES MAYOLY SPINDLER R L
- Filing Date
- 2023-10-20
- Publication Date
- 2026-05-15
AI Technical Summary
Existing pharmaceutical compositions containing alverine citrate, such as METEOSPASMYL®, require water for administration and do not effectively mask the bitter taste and anesthetic effect of alverine citrate, making them inconvenient for patients experiencing digestive pain accompanied by bloating without access to water.
A pharmaceutical composition in the form of immediate-release orodispersible granules comprising alverine citrate and simethicone, coated with a masking agent and flavored excipients, adsorbed onto a powdery solid support, providing a dissolution profile equivalent to METEOSPASMYL® without the need for water and masking the bitter taste.
The composition allows for rapid dissolution and dispersion in the mouth, effectively masking the taste and anesthetic effect of alverine citrate, offering a convenient and equivalent therapeutic effect to METEOSPASMYL® without requiring water, with dissolution profiles matching at various pH levels.
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Abstract
Description
Title of the invention: Pharmaceutical composition comprising simethicone and alverine citrate, pharmaceutical composition containing simethicone, pharmaceutical composition comprising alverine citrate, and their manufacturing processes.
[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 granules, comprising alverine citrate and its manufacturing process.
[0004] Alverine citrate is a powdered compound which has an antispasmodic and musculotropic effect.
[0005] Alverine citrate also has a very bitter taste that is not very acceptable to a patient and a powerful anesthetic effect.
[0006] In association 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 is presented in the form of an oral solution.
[0008] In association 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 their coalescence.
[0010] Simethicone is in the form of an oil at room temperature.
[0011] Used alone, simethicone can be used to treat flatulence.
[0012] In combination with activated charcoal or a combination of activated charcoal and magnesium, or an association of aluminium and magnesium, simethicone acts on bloating and esophagogastroduodenal 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 in the form of soft capsule, to be taken orally, containing a thick suspension comprising 300mg of simethicone and 60mg of alverine citrate.
[0015] In soft capsule form, when taken orally, Alverine citrate does not come into contact with the buccal 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, in order to facilitate its administration and dissolution in the stomach.
[0017] Patients suffering from digestive pain accompanied by bloating do not always have water available 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 simultaneous 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 to METEOSPASMYL® from this point of view, - is accepted by the patient, meaning that the bitter taste and anesthetic effect of alverine citrate are masked,
[0019] Thus, the invention proposes 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 object of the invention is a pharmaceutical composition comprising a mixture of alverine citrate and simethicone comprising: a. grains composed of simethicone adsorbed onto a powdery solid support, b. granules containing grains containing alverine citrate, these grains being coated on their external surface with a film of a masking agent, and c. pharmaceutically acceptable excipients (4) comprising at least one flavouring, 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 grain containing alverine citrate of the granules (b) consists of a core which is coated on its external 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] 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] 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) include menthol and spearmint flavors, citric acid and monosodium citrate as acidifiers, xylitol and sucralose as sweeteners, xylitol as a bulking agent and talc as a lubricating / anti-aggregating agent.
[0027] In a preferred embodiment, the pharmaceutical composition of the orodispersible unit dose of the first object of the invention comprises 300 mg of simethicone and 60 mg of alverine citrate.
[0028] Another object of the invention is a pharmaceutical composition comprising alverine citrate. This pharmaceutical composition comprises granules - coated on their external surface with a film containing 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 into 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 made of a mixture of alverine citrate and a binder.
[0031] Preferably, the core is made of mannitol.
[0032] Also preferably, the binder in the mixture forming the film in a mixture of alverine citrate and a binder is hydroxypropyl methyl cellulose.
[0033] Preferably, the pharmaceutical composition comprising alverine citrate according to the invention further comprises pharmaceutically acceptable excipients including 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 flavorings, citric acid and monosodium citrate as acidifiers, xylitol and sucralose as sweeteners, xylitol as a bulking agent, and talc as a lubricating / anti-aggregating agent.
[0035] Yet another object of the invention is a method for manufacturing a pharmaceutical composition containing alverine citrate according to the second object of the invention, comprising the following steps: a. suspension and mixing, in water, of alverine citrate and a binder, b. coating grains of a solid support with the suspension obtained in step a) and removal of water, so that grains consisting of a core, coated on its external surface with a film of a mixture of alverine citrate and a binder are obtained, c. preparation of a masking agent solution, and coating of the grains obtained in step b) with this masking agent solution, so that granules coated on their external surface with a film of masking agent, and containing the grains containing alverine citrate are obtained.
[0036] Preferably, in the process of 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 equal to 15.
[0037] Also preferably, in the process of 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 equal to 2.1.
[0038] Preferably, in the manufacturing process of 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 with a glyceryl palmitate / polysorbate 65 mass ratio between 5 and 7, preferably 6.1, and - the ratio of total mass of masking agent / mass of alverine citrate is between 0.3 and 0.4, and preferably is equal to 0.33.
[0039] Preferably, the process 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 flavorings, anhydrous citric acid and monosodium citrate as an acidifier, xylitol, and sucralose as sweeteners, and Xylitol as a bulking agent and Talc as a lubricating / anti-aggregating agent.
[0041] 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: A. Manufacturing granules containing alverine citrate by the method for manufacturing granules containing alverine citrate of the invention, B. Adsorbing simethicone onto a powdered solid support, C. Preparing a premix I by mixing a portion of the simethicone adsorbed onto a powdered solid support obtained in step B) with a sweetener, D. Preparation of a premix II by mixing the premix I with a lubricating / anti-aggregating agent containing at least one flavouring and at least one acidifier, E. Mixture of the remainder of the simethicone adsorbed on a powder support obtained in step B), with the granules (3) obtained in step A), the premix II obtained in step D) and at least one acidifier and at least one filler.
[0042] Preferably, in this process: - in step B), the powdery 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 mass ratio 5 / sucralose 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 flavorings are spearmint flavoring and menthol flavoring, - in step E), the acidifier is monosodium citrate and the bulking agent is xylitol.
[0043] A method for manufacturing a pharmaceutical composition containing simethicone is also an object of the invention.
[0044] This process includes the adsorption of simethicone onto a powdery solid support, thereby obtaining grains containing simethicone.
[0045] Preferably, the powdery 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 onto hydrated colloidal silica.
[0047] The invention will be better understood and other features thereof will become more apparent in the light of the following explanatory description, which is made with reference to the accompanying figures in which: - Figure 1 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, - [Fig.2] schematically represents a granule containing alverine citrate, present in the mixture to be taken by the patient shown in [Fig.1], - [Fig.3] schematically represents a grain containing alverine citrate, present in the granule containing alverine citrate shown in [Fig.2], - Figure 4 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 1.2, - Figure 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 4.5, - Fig. 6 shows the dissolution curves of METEOSPASMYL® and the pharmaceutical composition of the invention containing an association of 300 mg of simethicone and 60 mg of alverine citrate at a pH of 6.8.
[0048] The pharmaceutical composition comprising an association of alverine citrate and simethicone, which is the first object of the invention, consists of a mixture, denoted 1 in [Fig. 1],
[0049] This mixture constitutes an orodispersible powder pharmaceutical composition which can be used as a replacement for METEOSPASMYL®.
[0050] As can be seen in [Fig.1], mixture 1 consists of grains, noted 5 in [Fig.1], comprising simethicone, and granules, noted 3 in [Fig.1], comprising alverine citrate.
[0051] A particularly preferred pharmaceutical composition comprising an association 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 [Fig.1], the grains (5) containing simethicone and the granules 3 comprising alverine citrate are included in a powdery solid phase made up of pharmaceutically acceptable excipients, noted 4 in [Fig.1].
[0053] Pharmaceutically acceptable excipients 4 may include any pharmaceutically acceptable excipient capable of providing a taste and mouthfeel acceptable to the patient. More preferably, the pharmaceutical excipients will chosen not only to obtain an acceptable taste but also to allow rapid dissolution, rapid dispersion in the mouth, preferably in less than 10 seconds 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 flavoring.
[0056] A preferred flavoring in the invention is a mixture of a spearmint flavoring and with a menthol aroma.
[0057] The pharmaceutically acceptable excipients 4 may also include at least one acidifier to promote patient salivation. 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 include 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] Pharmaceutically acceptable excipients 4 may also include 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 a pharmaceutically acceptable excipient 4 is talc.
[0060] Pharmaceutically acceptable excipients 4 may include all or only some of these types of excipients. They may include other pharmaceutically acceptable excipients besides those mentioned above.
[0061] The grains (5) containing simethicone are formed of simethicone adsorbed on a powdery solid support.
[0062] Indeed, simethicone is an oil at room temperature and, in order to form a solid grain 5, it must be adsorbed onto a powdered solid support. Any powdered solid support can be used, such as, for example, sorbitol, activated carbon, 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 powdery solid support is hydrated colloidal silica.
[0065] An example of a particularly suitable hydrated colloidal silica is the hydrated colloidal silica manufactured by the company Grâce under the reference Syloid XDP 3150, which has a particle size between 50 and 150 pm, an apparent density of 0.24 g / ml and a packed density of 0.28 g / ml according to the manufacturer's specifications.
[0066] The average diameter of the grains 5 is generally between 50 pm and 200 pm.
[0067] This average diameter is a volumetric average diameter measured using a CAMSIZER X2 particle size analyzer, using the X-Jet dry particle size measurement method in an airflow passing through a Venturi nozzle. The applied dispersion pressure is 80.0 kPa.
[0068] A second object of the invention is the pharmaceutical composition containing simethicone adsorbed onto hydrated colloidal silica, alone or with pharmaceutically acceptable excipients. Indeed, it can be used as such in applications other than in combination 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 simethicone on a powdery solid support.
[0071] Any powdery solid support can be used such as, for example, sorbitol, activated charcoal, aluminum salts, etc.
[0072] Preferably, the powdery solid support is hydrated colloidal silica.
[0073] Preferably, the simethicone / powdery solid support mass ratio is between 2:1 and 1.3:1 and is preferably 1.6:1.
[0074] Preferably, the adsorption of simethicone onto the powdered solid support is carried out by mixing the simethicone and the powdered solid support.
[0075] A fourth object of the invention is a pharmaceutical composition containing alverine citrate, which can be used alone or in association with other compounds and in particular in association with the composition comprising simethicone according to the second object of the invention to form the composition according to the first object of the invention comprising simethicone and alverine citrate.
[0076] This pharmaceutical composition consists of granules 3 comprising alverine citrate, the bitter taste and anesthetic effect of which are effectively masked.
[0077] The granules 3 consist of grains, noted 7 in [Fig.2], comprising alverine citrate and a binder, deposited on a core, and coated by a masking agent, noted 8 in [Fig.3].
[0078] The masking agent that has proven 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 pH levels (pH = 1.2, pH = 4.5 and pH = 6.8), a dissolution profile for the pharmaceutical composition, according to the first object of the invention, comprising simethicone and alverine citrate, which is equivalent to the dissolution profile of METEOSPASMYL®.
[0079] The grains 7 consist of a core, noted as 10 in [Fig.2] and [Fig.3], composed of a powdery solid support.
[0080] Any solid powdery support can be used.
[0081] However, in the invention, the preferred powdery solid support is made 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 object of the invention is a method for manufacturing the pharmaceutical composition containing alverine citrate according to the fourth object of the invention.
[0087] This process comprises the following steps: a. suspension and mixing, in water, of alverine citrate and a binder, b. coating of grains of a powdery solid support forming nuclei 10 with the suspension obtained in step a) and removal of water, so that grains 7 consisting of a nucleus in the powdery solid support coated on its external surface with a film in a mixture of alverine citrate and a binder are obtained, c. preparation of a masking agent solution, and coating the grains 7 obtained in step b) with this masking agent solution, so that granules 3 coated on their external surface with a film 8 in a masking agent, and containing grains 7 containing alverine citrate are obtained.
[0088] A fifth object of the invention is a method for manufacturing a pharmaceutical composition containing alverine citrate according to the fourth object of the invention, 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 equal to 15.
[0089] Preferably, the powdery solid support used in step b) is mannitol and the ratio of powdery solid support mass / (mass of alverine citrate + mass of binder) is between 1 and 3, preferably equal to 2.1.
[0090] A masking agent which has proven particularly effective, not only in masking the bitter taste and anesthetic effect of alverine citrate, but also in enabling the pharmaceutical composition containing alverine citrate and simethicone according to the first object of the invention to have a dissolution profile equivalent to the reference formula Météospasmyl® 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 ratio of total mass 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 object of the invention optionally includes 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 object of the invention and include menthol and spearmint flavors, anhydrous citric acid and monosodium citrate as an acidifier, xylitol and sucralose as a sweetener, xylitol as a bulking agent, and talc as a lubricating / anti-aggregating agent.
[0095] A sixth object of the invention is a method for manufacturing a pharmaceutical composition comprising an association (1) of alverine citrate and simethicone according to the first object of the invention.
[0096] This process comprises the following steps: A. Manufacture of granules (3) containing alverine citrate according to the manufacturing process which is the fifth object of the invention, B. Adsorption of simethicone onto a powdery solid support, C. Preparation of a premix I by mixing a portion of the simethicone adsorbed on a powdered solid support obtained in step B) with at least one sweetener, D. 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). E. Mixture of the granules (3) obtained in step A) and the premix II obtained in step D) and the remainder of the simethicone adsorbed on a solid support powder obtained in step B) and at least one acidifier and at least one filler.
[0097] Preferably: - in step B), the powdery 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 for 1 of hydrated colloidal silica), - in step C), the sweetener is sucralose and the grain mass / sucralose 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 flavorings are spearmint and menthol. - in step E), the acidifier is monosodium citrate and the bulking agent is xylitol.
[0098] It is particularly preferred that 1.4 g of the mixture contains 300 mg of simethicone and 60 mg of alverine citrate contained in granules 3.
[0099] In order to better understand the invention, we will give examples of its manufacture, purely illustrative and not limiting.
[0100] Example 1: Manufacture of grains (5) containing simethicone - pharmaceutical composition containing simethicone according to the second object of the invention
[0101] Materials: - Dupont's simethicone reference Q7-2243 - colloidal silica reference Syloid XDP 3150 from Grâce
[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 revolutions / minute.
[0105] Grains 5 were obtained.
[0106] Example 2: Manufacture of granules 3 containing alverine citrate - pharmaceutical composition comprising alverine citrate according to the fourth embodiment of the invention 1. Preparation of an alverine citrate phase - preparation of grains 7#
[0107] Materials:
[0108] Alverine citrate: Centipharm reference 0368
[0109] Hydroxypropyl methyl cellulose: Ashland reference KLUCEL EXF ULTRA PHARM®
[0110] Mannitol: reference Mannitol Pearlitol 300DC® from Roquette Frères
[0111] Simethicone: DuPont reference Q7-2243
[0112] Purified water
[0113] It should be noted that simethicone is added at this stage in very small quantity and is used only 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 association according to the first object of the invention.
[0114] It should also be noted that purified water is used as a solvent and is removed during the manufacturing process of granules 3.
[0115] 30.9 kg of alverine citrate and 2.06 kg of hydroxypropyl methyl cellulose are put suspended by stirring in about 43.3 kg of purified water in a mixing container.
[0116] During agitation, 0.001 kg of simethicone are added to break up any foam forming.
[0117] 70.04 kg of mannitol are passed through a sieve having a mesh size of 0.8 mm and are then transferred into 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 aqueous suspension of alverine citrate and hydroxypropyl methyl cellulose, Romaco's Ventilus® technology in a fluidized air bed is preferably used. 1. Preparation of 3 alverine citrate granules #
[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 (7 grains) passed through a sieve having a 1.0 mm mesh size particles are transferred into a fluidized air bed device 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 the grains 7 with the masking agent mixture of glyceryl palmitate + polysorbate 65, the 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] The granules 3 are obtained.
[0125] Example 3: Preparation of a composition comprising a combination of alverine citrate and simethicone according to the first object of the invention
[0126] Materials: simethicone adsorbed on silica obtained in example 1 Sucralose (sweetener): EMPROVE® Ph. Eur. grade. from Merck Talc: LUZENAC PHARMA by Imerys Menthol flavor: IFF code SN791345 Fresh mint flavor: IFF code SC097260. Anhydrous citric acid: Grade F3500 from Jungbunzlauer Xylitol: Xylisorb® 300 from Roquette Frères Monosodium 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 flavouring, 7.21 kg of fresh mint flavouring and 5.15 kg of anhydrous citric acid and premix I, are passed through a sieve having a mesh size of 0.8 mm and are mixed together.
[0129] This mixture is a mixture of a portion of 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 simethicone grain 5 adsorbed on silica, then mixed for 15 minutes at 6 revolutions per minute.
[0131] The pharmaceutical composition according to the first object of the invention in the form of an orodispersible powder comprising, in each dose unit of 1.4 g, 300 mg of simethicone for 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 per 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 Meteospasmyl® and the orodispersible pharmaceutical composition, prepared in Example 3, were determined by the dissolution test of the active substance alverine citrate using apparatus 3 of the USP (alternating cylinders) for the method dissolution (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 [Fig.4] 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 [Fig.5] 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 [Fig.6] 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 exhibit an average percentage of dissolution greater than 85% in 15 minutes at all pH levels studied.
[0139] Consequently, 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 to be equivalent in the range of physiological pH, i.e. at pH 1.2 and pH 4.5 and pH 6.8.
Claims
Demands
1. Pharmaceutical composition comprising a mixture (1) of alverine citrate and simethicone comprising: a. granules (5) composed of simethicone adsorbed on a powdered solid support, b. granules (3) containing granules (7) containing alverine citrate, the granules (7) being coated on their external surface with a film of a masking agent (8), c. 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.
2. 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) in a mixture of alverine citrate and a binder.
3. Pharmaceutical composition according to claim 2, wherein the core (10) is mannitol.
4. Pharmaceutical composition according to any one of the preceding claims, wherein the film (8) is a film in a mixture of polysorbate 65 and glyceryl palmitate.
5. 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.
6. Pharmaceutical composition according to any one of the preceding claims, wherein the powdery solid support on which simethicone is adsorbed is hydrated colloidal silica.
7. Pharmaceutical composition according to any one of the preceding claims, comprising 300mg of simethicone and 60mg of alverine citrate for a total mass of the pharmaceutical composition of 1.4g.
8. A pharmaceutical composition according to any one of the preceding claims, wherein the pharmaceutically acceptable excipients (4) include menthol and spearmint flavorings, citric acid, and monosodium citrate as an acidifier, xylitol and sucralose as sweeteners, and talc as a lubricating / anti-aggregating agent and xylitol as a bulking agent.
9. Pharmaceutical composition comprising alverine citrate, the pharmaceutical composition comprising granules (3), the granules (3): - being coated on their external surface with a film (8) of a masking agent, and - containing granules (7) containing alverine citrate,
10. Pharmaceutical composition according to claim 9, wherein the masking agent constituting the film (8) is a mixture of polysorbate 65 and glyceryl palmitate.
11. Pharmaceutical composition according to claim 9 or 10, wherein each grain (7) consists of a core (10) coated on its external surface with a film (11) in a mixture of alverine citrate and a binder.
12. Pharmaceutical composition according to claim 11, wherein the core (10) is mannitol.
13. Pharmaceutical composition according to claim 11 or 12, wherein the binder in the film-forming mixture (11) is hydroxypropyl methyl cellulose.
14. 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.
15. Pharmaceutical composition according to claim 14, wherein the pharmaceutically acceptable excipients (4) include menthol and spearmint flavorings, citric acid and monosodium citrate as acidifiers, xylitol and sucralose as sweeteners, and talc as a binder and xylitol as a filler.
16. A method for manufacturing a pharmaceutical composition containing alverine citrate according to any one of claims 9 to 15, comprising the following steps: a. suspension, and mixing, in water, of alverine citrate and a binder, b. coating of grains of a solid support with the suspension obtained in step a) and removal of the water, so that grains (7) consisting of a core (10) coated on its external surface with a film (11) of a mixture of alverine citrate and a binder are obtained, c. preparation of a solution of a masking agent, and coating of 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.
17. A method for 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 equal to 15.
18. A method for 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 equal to 2.
1.
19. A method for 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 with a glyceryl palmitate / polysorbate 65 mass ratio of between 5 and 7, preferably 6.1, and - the total mass ratio of masking agent / mass of alverine citrate granules (7) is between 0.3 and 0.4, and preferably 0.
33.
20. A method for 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 flavor,
21.
22. 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 for manufacturing a pharmaceutical composition containing alverine citrate according to any one of claims 16 to 20 wherein the pharmaceutically acceptable excipients (4) include menthol and spearmint flavorings, anhydrous citric acid and monosodium citrate as acidifiers, xylitol and sucralose as sweeteners, and talc as a lubricating / anti-aggregating agent and xylitol as a filler. A method for manufacturing a pharmaceutical composition comprising a combination (1) of alverine citrate and simethicone according to any one of claims 1 to 8, the method comprising the following steps: A. Manufacture of granules (3) containing alverine citrate by the process according to any one of claims 16 to 20, B. Adsorption of simethicone onto a powdery solid support, to obtain grains (5) containing simethicone, C. Preparation of a premix I by mixing a portion of the simethicone grains (5) adsorbed on a powdered solid support obtained in step B) with a sweetener, D. Preparation of a premix II by mixing the premix I obtained in step (C) and a lubricating / anti-aggregating agent with at least one flavouring and at least one acidifier, E. Mixture of the remaining grains (5) obtained in step B), with the granules (3) obtained in step A), and the premix II obtained in step D and at least one acidifier and at least one filler.
23. The method according to claim 22, wherein: - in step B), the powdery 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 mass ratio of grains (5) / sucralose is between 5 and 8, and preferably equal to 6.87, in step D), the lubricating / anti-aggregating agent is talc, the acidifier is anhydrous citric acid, and the flavors are spearmint flavor and menthol flavor, in step E), the acidifier is monosodium citrate and the bulking agent is xylitol.