Pharmaceutical composition comprising simeticone and alverine citrate, pharmaceutical composition containing simeticone, pharmaceutical composition comprising alverine citrate, and methods for manufacturing same

Abstract

The present invention relates to a pharmaceutical composition in the form of an oral dispersion powder comprising simethicone and alverine citrate and a method for preparing the same, to a pharmaceutical composition comprising a dry form of simethicone and a method for preparing the same, and to a pharmaceutical composition comprising a particulate form of alverine citrate and a method for preparing the same. The pharmaceutical composition comprising a mixture of alverine citrate and simethicone according to the present invention comprises microparticles comprising simethicone adsorbed on a powdery solid carrier, and particles comprising microparticles comprising alverine citrate, wherein the outer surface of the microparticles comprising alverine citrate is coated with a film made of a masking agent, and a pharmaceutically acceptable excipient comprising at least one flavoring agent, and / or at least one acidifying agent, and / or at least one sweetening agent, and / or at least one lubricant / anti-aggregating agent, and / or at least one filler. The invention is intended for the pharmaceutical industry.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202480067166.7 (22) Application Date 2024.10.18 (30) Priority Data FR2311373 2023.10.20 FR (85) PCT International Application Entering National Phase Date 2026.04.20 (86) PCT International Application Application Data PCT / EP2024 / 079562 2024.10.18 (87) PCT International Application Publication Data WO2025 / 083244 FR 2025.04.24 (71) Applicant: Maiolis Binder Laboratory Address: Rueil-Marmaison, France (72) Inventor: O. Guth (74) Patent Agency: Beijing Gecheng Intellectual Property Agency Co., Ltd. 11314 Patent Attorney Cheng Wei Li Yuan (51) Int.Cl. A61K 9 / 16 (2006.01) A61K 31 / 137 (2006.01) (54) Invention Title Pharmaceutical Composition Containing Simethicone and Alverne Citrate, Pharmaceutical Composition Containing Simethicone, Pharmaceutical Composition Containing Alverne Citrate, and Methods for Preparing the Same (57) Abstract This invention relates to a pharmaceutical composition in the form of an orally dispersed powder containing simethicone and Alverne Citrate and a method for preparing the same, a pharmaceutical composition in the form of a dried simethicone containing simethicone and a method for preparing the same, and a pharmaceutical composition in the form of microparticles containing Alverne Citrate and a method for preparing the same. The pharmaceutical composition comprising a mixture of arverine citrate and simethicone according to the present invention comprises microparticles of simethicone adsorbed on a powdered solid carrier, particles containing arverine citrate microparticles, wherein the outer surface of the arverine citrate microparticles is coated with a film made of a masking agent, and pharmaceutically acceptable excipients comprising at least one flavoring agent, and / or at least one acidifier, and / or at least one sweetener, and / or at least one lubricant / anti-aggregating agent and / or at least one filler. The present invention is intended for use in the pharmaceutical industry.Claims 3 pages, Description 10 pages, Drawings 3 pages, CN 122094666 A 2026.05.26 CN 1 22 09 46 66 A 1. A pharmaceutical composition comprising a mixture (1) of arverine citrate and simethicone, said pharmaceutical composition comprising: a. microparticles (5) consisting of simethicone adsorbed on a powdered solid carrier, b. particles (3) containing microparticles (7) of arverine citrate, said microparticles (7) having a film coated on their outer surface with a masking agent (8), c. pharmaceutically acceptable excipients (4) comprising at least one flavoring agent, and / or at least one acidifier, and / or at least one sweetener, and / or at least one lubricant / anti-aggregating agent and / or at least one filler. 2. The pharmaceutical composition according to claim 1, wherein each microparticle (7) comprises a core (10) having a film (11) coated on its outer surface with a mixture of arverine citrate and a binder. 3. The pharmaceutical composition according to claim 2, wherein the core (10) is made of mannitol. 4. The pharmaceutical composition according to any one of the preceding claims, wherein the film (8) is a film made of a mixture of polysorbate 65 and glyceryl palmitate. 5. The pharmaceutical composition according to any one of claims 2 to 4, wherein the binder in the mixture constituting the film (11) is hydroxypropyl methylcellulose. 6. The pharmaceutical composition according to any one of the preceding claims, wherein the powdered solid carrier adsorbed with simethicone is hydrated colloidal silica. 7. The pharmaceutical composition according to any one of the preceding claims, wherein for a total mass of 1.4 g, it comprises 300 mg of simethicone and 60 mg of arvilin citrate. 8. The pharmaceutical composition according to any one of the preceding claims, wherein the pharmaceutically acceptable excipient (4) comprises menthol and spearmint as flavoring agents, citric acid and sodium citrate as acidifying agents, xylitol and sucralose as sweeteners, talc as a lubricant / anti-aggregating agent, and xylitol as a filler. 9. A pharmaceutical composition comprising arverine citrate, the pharmaceutical composition comprising particles (3), said particles (3) being: - coated with a masking film (8) on their outer surface, and - containing particles (7) comprising arverine citrate. 10. The pharmaceutical composition of claim 9, wherein the masking agent constituting the film (8) is a mixture of polysorbate 65 and glyceryl palmitate. 11. The pharmaceutical composition of claim 9 or 10, wherein each particle (7) comprises a core (10) having a film (11) on its outer surface coated with a mixture of arverine citrate and an adhesive.12. The pharmaceutical composition of claim 11, wherein the core (10) is made of mannitol. 13. The pharmaceutical composition of claim 11 or 12, wherein the binder in the mixture forming the film (11) is hydroxypropyl methylcellulose. 14. The pharmaceutical composition of any one of claims 9 to 13, further comprising a pharmaceutically acceptable excipient (4), said excipient (4) comprising at least one flavoring agent, and / or at least one acidifier, and / or at least one sweetener, and / or at least one lubricant / anti-aggregating agent and / or at least one filler. 15. The pharmaceutical composition of claim 14, wherein said pharmaceutically acceptable excipient (4) comprises menthol and spearmint as flavoring agents, citric acid and sodium citrate as acidifiers, xylitol and sucralose as sweeteners, talc as a binder, and xylitol as a filler. 16. A method for preparing a pharmaceutical composition containing arverine citrate according to any one of claims 9 to 15, the method comprising the steps of: a. suspending and mixing arverine citrate and an adhesive in water; b. coating a solid carrier microparticle with the suspension obtained in step a) and removing water to obtain microparticles (7) consisting of a core (10) having a film (11) made of a mixture of arverine citrate and an adhesive coated on its outer surface; c. preparing a masking solution and coating the microparticles (7) obtained in step b) with the masking solution to obtain a masking film (8) coated on its outer surface and particles (3) containing microparticles (7) containing arverine citrate. 17. The method for preparing a pharmaceutical composition comprising arviline citrate according to claim 16, wherein the binder used in step (a) is hydroxypropyl methylcellulose, and the mass ratio of arviline citrate to hydroxypropyl methylcellulose is between 10 and 20, preferably 15. 18. The method for preparing a pharmaceutical composition comprising arviline citrate according to claim 16 or 17, wherein the solid carrier used in step (b) is mannitol, and the mass ratio of the solid carrier to (mass of arviline citrate + mass of binder) is between 1 and 3, preferably 2.1. 19. The method for preparing a pharmaceutical composition comprising arverine citrate according to any one of claims 16 to 18, wherein: - the masking agent used in step (c) is a mixture of tripalmitoyl glycerol and polysorbate 65, the mass ratio of tripalmitoyl glycerol / polysorbate 65 being between 5 and 7, preferably equal to 6.1, and - the ratio of the total mass of the masking agent to the mass of the arverine citrate microparticles (7) being between 0.3 and 0.4, preferably equal to 0.33.20. A method for preparing a pharmaceutical composition comprising arverine citrate according to any one of claims 16 to 19, the method further comprising step (d) of adding a pharmaceutically acceptable excipient (4), said excipient (4) comprising at least one flavoring agent, and / or at least one acidifying agent, and / or at least one sweetener, and / or at least one filler and at least one lubricant / anti-aggregating agent. 21. A method for preparing a pharmaceutical composition comprising arverine citrate according to any one of claims 16 to 20, wherein said pharmaceutically acceptable excipient (4) comprises menthol and spearmint as flavoring agents, anhydrous citric acid and sodium citrate as acidifying agents, xylitol and sucralose as sweeteners, talc as a lubricant / anti-aggregating agent, and xylitol as a filler. 22. A method for preparing a pharmaceutical composition comprising a combination (1) of arverine citrate and simethicone according to any one of claims 1 to 9, the method comprising the steps of: A. preparing granules (3) containing arverine citrate by the method according to any one of claims 16 to 20; B. adsorbing simethicone onto a powdered solid carrier to obtain granules (5) containing simethicone; C. preparing premix I by mixing a portion of the simethicone granules (5) adsorbed on the powdered solid carrier obtained in step B) with a sweetener; D. preparing premix II by mixing premix I obtained in step (C) with a lubricant / anti-aggregating agent with at least one flavoring agent and at least one acidifier; E. mixing the remaining granules (5) obtained in step B) with the granules (3) obtained in step A) and premix II obtained in step D, as well as at least one acidifier and at least one filler. 23. The method according to claim 22, wherein: (Claims 2 / 3, page 3, CN 122094666 A) - In step B), the powdered solid carrier is hydrated colloidal silica, the mass ratio of simethicone oil to hydrated colloidal silica is between 2:1 and 1.3:1, preferably 1.6:1, and the simethicone oil is adsorbed onto the hydrated colloidal silica by mixing; - In step C), the sweetener is sucralose, the mass ratio of microparticles (5) to sucralose is between 5 and 8, preferably 6.87; - In step D), the lubricant / anti-aggregating agent is talc, the acidifier is anhydrous citric acid, and the flavoring agent is spearmint flavoring agent and menthol flavoring agent; - In step E), the acidifier is sodium citrate, and the filler is xylitol. 24. A method for preparing a pharmaceutical composition containing simethicone, the method comprising the steps of: - adsorbing simethicone onto a powdered solid carrier to obtain simethicone-containing microparticles (5), wherein the powdered solid carrier is hydrated colloidal silica.25. The method for preparing a pharmaceutical composition containing simethicone according to claim 24, wherein the simethicone is adsorbed onto hydrated colloidal silica by mixing. 26. A pharmaceutical composition containing simethicone, wherein the simethicone is adsorbed onto hydrated colloidal silica. Claims 3 / 3 Page 4 CN 122094666 A Pharmaceutical composition containing simethicone and alverine citrate, a pharmaceutical composition containing simethicone, a pharmaceutical composition containing alverine citrate, and a method for preparing the same. Technical Field

[0001] This invention relates to a pharmaceutical composition in the form of an orally dispersed powder containing simethicone and alverine citrate, and a method for preparing the same.

[0002] This invention also relates to a pharmaceutical composition in the form of a dried simethicone and a method for preparing the same.

[0003] This invention also relates to a pharmaceutical composition in the form of a grain containing alverine citrate and a method for preparing the same. Background Art

[0004] Alverine citrate is a powdered compound with antispasmodic and musculotrope effects.

[0005] Alverine citrate also has a very bitter taste that is unacceptable to patients and has a strong anesthetic effect.

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

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

[0008] In combination with simethicone, alverine citrate is able to treat functional bowel disorders (e.g., digestive pain accompanied by bloating) and has antispasmodic and antiflatulent effects.

[0009] In this combination, simethicone works by altering the surface tension of bubbles, causing them to coalesce.

[0010] Simethicone is available as an oil at room temperature.

[0011] When used alone, simethicone can treat flatulence.

[0012] When combined with activated charcoal or a combination of activated charcoal and magnesium or a combination of aluminum and magnesium, simethicone can act on flatulence and esophageal-gastric-duodenal disorders.

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

[0014] Compositions containing a combination of silymarin citrate and simethicone are formulated as oral soft capsules and marketed under the trade name METEOSPASMYL®, said oral soft capsules containing a thick suspension comprising 300 mg of simethicone and 60 mg of silymarin citrate.

[0015] In soft capsule form, when administered orally, silymarin citrate does not come into contact with the oral mucosa, so the patient does not experience the very bitter taste and strong anesthetic effect of silymarin citrate.

[0016] The soft capsules are administered orally with water to facilitate their administration and dissolution in the stomach.

[0017] Patients suffering from digestive pain accompanied by bloating do not always have water available to them during an attack.

[0018] In order to overcome this problem, the inventors conducted in-depth research to discover a pharmaceutical composition containing a combination of arverine citrate and simethicone, which: - can be administered without the need for water, - has the same dissolution profile as METEOSPASMYL®, or has a dissolution profile that is sufficiently close to the dissolution profile of METEOSPASMYL®, and is considered equivalent to METEOSPASMYL® from this perspective, , Specification 1 / 10 page 5 CN 122094666 A - is accepted by patients, i.e., masks the bitterness and anesthetic effect of arverine citrate, Summary of the Invention

[0019] Therefore, the present invention provides a pharmaceutical composition in the form of an immediate-release oral dispersible granule containing arverine citrate and / or simethicone, which is accepted by patients and has a dissolution profile equivalent to that of METEOSPAMYL®.

[0020] Therefore, a first object of the present invention is a pharmaceutical composition comprising a mixture of arverine citrate and simethicone, comprising: a. microparticles consisting of simethicone adsorbed on a powdered solid carrier; b. particles containing microparticles of arverine citrate, said microparticles having a masking film coated on their outer surface; and c. pharmaceutically acceptable excipients (4) comprising at least one flavoring agent, and / or at least one acidifier, and / or at least one sweetener, and / or at least one lubricant / anti-aggregating agent and / or at least one filler.

[0021] In this pharmaceutical composition, preferably, each microparticle of arverine citrate (b) comprises a core having a film coated on its outer surface with a mixture of arverine citrate and an adhesive.

[0022] Preferably, the adhesive used in the mixture of arverine citrate and the adhesive is hydroxypropyl methylcellulose.

[0023] Preferably, the core is made of mannitol.

[0024] The masking agent covering the particles (b) containing alveryl citrate microparticles is preferably composed of a mixture of polysorbate 65 and glyceryl palmitate.

[0025] Also in this pharmaceutical composition, preferably, the powdered solid carrier adsorbed with simethicone is hydrated colloidal silica.

[0026] More preferably, in the pharmaceutical composition of the first embodiment of the invention, the pharmaceutically acceptable excipient (c) comprises menthol and spearmint as flavoring agents, citric acid and sodium citrate as acidifying agents, xylitol and sucralose as sweeteners, xylitol as a filler, and talc as a lubricant / anti-aggregating agent.

[0027] In a preferred embodiment, the oral dispersible unit dose pharmaceutical composition of the first object of the present invention comprises 300 mg of simethicone and 60 mg of arverine citrate.

[0028] Another object of the present invention is a pharmaceutical composition comprising arverine citrate. The pharmaceutical composition comprises particles: - coated with a masking film on their outer surface, and - containing microparticles coated with arverine citrate. Preferably, in the pharmaceutical composition comprising arverine citrate of the present invention, the masking agent constituting the masking film is a mixture of polysorbate 65 and glyceryl palmitate.

[0029] In the pharmaceutical composition comprising arverine citrate of the present invention, preferably, each microparticle comprising arverine citrate consists of a core of a film coated on its outer surface with a mixture of arverine citrate and an adhesive.

[0030] Preferably, the core is made of mannitol.

[0031] Also preferably, the adhesive in the mixture forming the film of the mixture of arverine citrate and the adhesive is hydroxypropyl methylcellulose.

[0032] Preferably, the pharmaceutical composition comprising arverine citrate according to the present invention further comprises pharmaceutically acceptable excipients, said excipients comprising at least one flavoring agent, and / or at least one acidifying agent, and / or at least one sweetener, and / or at least one filler, and / or at least one lubricant / anti-aggregating agent.

[0033] In this case, pharmaceutically acceptable preferred excipients comprise menthol and spearmint as flavoring agents, citric acid and sodium citrate as acidifying agents, xylitol and sucralose as sweeteners, xylitol as a filler, and talc as a lubricant / anti-aggregating agent.

[0034] Another object of the present invention is a method for preparing a pharmaceutical composition containing arverine citrate according to a second object of the present invention, the method comprising the steps of: a. suspending and mixing arverine citrate and a binder in water; b. coating a solid carrier microparticles with the suspension obtained in step a) and removing water, thereby obtaining microparticles consisting of a core, the core having a film made of a mixture of arverine citrate and the binder coated on its outer surface; c. preparing a masking agent solution and coating the microparticles obtained in step b) with the masking agent solution, thereby obtaining particles having a masking agent film coated on their outer surface and containing microparticles containing arverine citrate.

[0035] Preferably, in the method for preparing a pharmaceutical composition containing arverine citrate according to the present invention, the binder used in step a) is hydroxypropyl methylcellulose, and the mass ratio of arverine citrate to hydroxypropyl methylcellulose is between 10 and 20, preferably 15.

[0036] More preferably, in the method for preparing the pharmaceutical composition containing arvilin citrate of the present invention, the solid carrier particles used in step b) are mannitol, and the ratio of the mass of the solid carrier particles to (mass of arvilin citrate + mass of binder) is between 1 and 3, preferably 2.1.

[0037] Preferably, in the method for preparing the pharmaceutical composition containing arvilin citrate of the present invention: - The masking agent used in step c) is a mixture of tripalmitoyl glycerol and polysorbate 65, the mass ratio of tripalmitoyl glycerol / polysorbate 65 is between 5 and 7, preferably 6.1, and - The ratio of the total mass of the masking agent to the mass of arvilin citrate is between 0.3 and 0.4, preferably equal to 0.33.

[0038] Preferably, the method for preparing the pharmaceutical composition containing arviline citrate of the present invention further includes step d) of adding a pharmaceutically acceptable excipient, said pharmaceutically acceptable excipient comprising at least one flavoring agent, and / or at least one acidifying agent, and / or at least one sweetener, and / or at least one filler, and / or at least one lubricant / anti-aggregating agent.

[0039] In this case, preferred pharmaceutically acceptable excipients are menthol and spearmint as flavoring agents, anhydrous citric acid and sodium citrate as acidifying agents, xylitol and sucralose as sweeteners, xylitol as a filler, and talc as a lubricant / anti-aggregating agent.

[0040] Furthermore, another object of the present invention is a method for preparing a pharmaceutical composition comprising particles containing aceverine citrate and simethicone according to the first object of the present invention, the method comprising the following steps: A. preparing aceverine citrate particles by the method for preparing aceverine citrate particles of the present invention; B. adsorbing simethicone onto a powdered solid carrier; C. preparing premix I by mixing a portion of the simethicone adsorbed on the powdered solid carrier obtained in step B) with a sweetener; D. preparing premix II by mixing premix I and a lubricant / anti-aggregating agent with at least one flavoring agent and at least one acidifier; E. mixing the remaining simethicone adsorbed on the powdered carrier obtained in step B) with the particles (3) obtained in step A), the premix II obtained in step D), and at least one acidifier and at least one filler.

[0041] Preferably, in the method: - In step B), the powdered solid carrier is hydrated colloidal silica, and the mass ratio of simethicone to hydrated colloidal silica is between 2:1 and 1.3:1, preferably 1.6:1; - In step C), the sweetener is sucralose, and the mass ratio of microparticles 5 to sucralose is between 6 and 8, preferably 6.87; - In step D), the filler and / or lubricant / anti-aggregating agent is talc, the acidifier is anhydrous citric acid, and the flavoring agent is spearmint flavoring agent and menthol flavoring agent; - In step E), the acidifier is sodium citrate, and the filler is xylitol.

[0042] Another object of the present invention is a method for preparing a pharmaceutical composition containing simethicone.

[0043] The method comprises adsorbing simethicone onto a powdered solid carrier to generate microparticles containing simethicone.

[0044] Preferably, the powdered solid carrier is hydrated colloidal silica, and simethicone is adsorbed onto the hydrated colloidal silica particles by mixing.

[0045] The ultimate object of the present invention is a pharmaceutical composition containing simethicone, wherein the simethicone is adsorbed onto hydrated colloidal silica.

[0046] The invention will be better understood from the following illustrative description with reference to the accompanying drawings, in which: - [Figure 1] schematically represents a mixture of the composition according to the invention comprising a combination of arverine citrate and simethicone, administered to a patient; - [Figure 2] schematically represents a particle comprising arverine citrate present in the mixture shown in [Figure 1] for administration to a patient; - [Figure 3] schematically represents a microparticle comprising arverine citrate present in the arverine citrate-containing particle shown in [Figure 2]; - ​​[Figure 4] shows the dissolution profile of METEOSPASMYL® with the pharmaceutical composition of the invention comprising 300 mg simethicone and 60 mg arverine citrate at pH 1.2; - [Figure 5] shows the dissolution profile of METEOSPASMYL® with the pharmaceutical composition of the invention comprising 300 mg simethicone and 60 mg arverine citrate at pH 4.5. Dissolution profiles of the pharmaceutical composition containing 300 mg of simethicone and 60 mg of acetyl citrate, shown in Figure 6, are displayed at pH 6.8 for METEOSPASMYL® and the pharmaceutical composition of the present invention containing 300 mg of simethicone and 60 mg of acetyl citrate. Detailed Description

[0047] The pharmaceutical composition comprising the combination of acetyl citrate and simethicone, which is the first object of the present invention, consists of the mixture labeled 1 in Figure 1.

[0048] This mixture is an orally dispersible powder pharmaceutical composition that can be used as a substitute for METEOSPASMYL®.Instructions for Use, Page 4 / 10, CN 122094666 A

[0049] As shown in [Figure 1], mixture 1 consists of microparticles labeled 5 in [Figure 1] containing simethicone and particles labeled 3 in [Figure 1] containing arvilin citrate.

[0050] For an administration unit mass of 1.4 g of the pharmaceutical composition, a particularly preferred combination of arvilin citrate and simethicone is an administration unit dose containing 300 mg of simethicone and 60 mg of arvilin citrate.

[0051] As shown in [Figure 1], the microparticles (5) containing simethicone and the particles 3 containing arvilin citrate are contained in a powdered solid phase consisting of a pharmaceutically acceptable excipient labeled 4 in [Figure 1].

[0052] The pharmaceutically acceptable excipient 4 may include any pharmaceutically acceptable excipient that can provide a patient-acceptable taste and mouthfeel. More preferably, the pharmaceutical excipients should be selected not only to achieve an acceptable taste, but also to enable the powdered pharmaceutical composition to dissolve rapidly when packaged into sticks, disperse rapidly in the mouth (preferably within less than 10 seconds), and flow well.

[0053] In particular, they may contain at least one flavoring agent to give the mixture a patient-acceptable taste.

[0054] Any flavoring agent can be used, such as red fruit, citrus, or mint flavoring agents.

[0055] A preferred flavoring agent in this invention is a mixture of spearmint flavoring agent and menthol flavoring agent.

[0056] The pharmaceutically acceptable excipient 4 may also contain at least one acidifier to promote salivation in the patient. Any known acidifier that promotes salivation can be used. A preferred acidifier in this invention is a mixture of anhydrous citric acid and sodium citrate.

[0057] The pharmaceutically acceptable excipient 4 may also contain at least one sweetener to enhance the patient acceptability of the granules 1 of this invention. Any known sweetener can be used. The preferred sweetener found in pharmaceutically acceptable excipient 4 is a mixture of xylitol and sucralose.

[0058] Pharmaceutically acceptable excipient 4 may also contain one or more lubricants and anti-aggregating agents. Any known lubricant and anti-aggregating agent may be used. A preferred lubricant and anti-aggregating agent used as pharmaceutically acceptable excipient 4 is talc.

[0059] Pharmaceutically acceptable excipient 4 may contain all or only some of these types of excipients. They may contain other pharmaceutically acceptable excipients besides those listed above.

[0060] The simethicone-containing particles (5) are formed by adsorbing simethicone onto a powdered solid carrier.

[0061] In fact, simethicone is an oil at room temperature, and in order to form the solid particles 5, it must be adsorbed onto a powdered solid carrier. Any powdered solid carrier may be used, such as sorbitol, activated carbon, aluminum salts, etc.

[0062] The particles 5 are formed by mixing with at least one pharmaceutically acceptable excipient.

[0063] However, in this invention, the preferred powdered solid carrier is hydrated colloidal silica.

[0064] An example of a more particularly suitable hydrated colloidal silica is hydrated colloidal silica prepared by Grace with reference number Syloid XDP 3150, which, according to the manufacturer's instructions, has a particle size between 50 and 150 μm, an apparent density of 0.24 g / ml, and a bulk density of 0.28 g / ml.

[0065] The average diameter of the particles 5 is typically between 50 μm and 200 μm.

[0066] This average diameter is the volume average diameter measured using a CAMSIZER X2 particle size analyzer with an X-Jet dry measurement method over an airflow passing through a Venturi effect nozzle. The applied dispersion pressure is 80.0 kPa.

[0067] A second objective is a pharmaceutical composition containing simethicone oil, alone or together with a pharmaceutically acceptable excipient, adsorbed onto hydrated colloidal silica. In fact, it can be used as is in other applications besides in combination with arverine citrate.

[0068] The pharmaceutical composition containing simethicone oil of the present invention is prepared by a method according to a third objective of the invention. Specification 5 / 10 pages 9 CN 122094666 A

[0069] The method comprises an adsorption step by mixing simethicone oil onto a powdered solid carrier.

[0070] Any powdered solid carrier can be used, such as sorbitol, activated carbon, aluminum salts, etc.

[0071] Preferably, the powdered solid carrier is hydrated colloidal silica.

[0072] Preferably, the mass ratio of simethicone oil to powdered solid carrier is between 2:1 and 1.3:1, preferably 1.6:1.

[0073] Preferably, the adsorption of the powdered solid carrier by the simethicone is achieved by mixing the simethicone and the powdered solid carrier.

[0074] The fourth objective is a pharmaceutical composition containing arverine citrate, which can be used alone or in combination with other compounds, particularly in combination with a simethicone-containing composition according to the second objective of the invention, to form a composition containing simethicone and arverine citrate according to the first objective.

[0075] The pharmaceutical composition consists of particles 3 containing arverine citrate, the bitterness and anesthetic effect of which are effectively masked.

[0076] Particles 3 consist of microparticles labeled 7 in [Figure 2], which contain arverine citrate and a binder, deposited on a core and coated with a masking agent labeled 8 in [Figure 3].

[0077] The most effective masking agent in this invention has been shown to be a mixture of polysorbate 65 and glyceryl palmitate.Preferably, the mass ratio of polysorbate 65 / glyceryl palmitate is 0.11 to 0.25, preferably 0.16, which provides dissolution profiles of the pharmaceutical composition comprising simethicone and arverine citrate according to the first object of the present invention at three pH values ​​(pH=1.2, pH=4.5 and pH=6.8), which are equivalent to the dissolution profile of METEOSPASMYL®.

[0078] The microparticles 7 consist of a core labeled 10 in [Figures 2] and [Figures 3], which consists of a powdered solid carrier.

[0079] Any powdered solid carrier can be used.

[0080] However, in the present invention, the preferred powdered solid carrier is mannitol.

[0081] A film consisting of a mixture of arverine citrate and an adhesive is deposited on the core 10.

[0082] The preferred adhesive in the present invention is hydroxypropyl methylcellulose.

[0083] Preferably, the mass ratio of arverine citrate to hydroxypropyl methylcellulose is between 10 and 20, and more preferably 15.

[0084] The ratio of the total masking agent mass to the mass of the arverine citrate particles (7) is preferably between 0.2 and 0.4, and more preferably 0.33.

[0085] A fifth objective is a method for preparing a pharmaceutical composition containing arverine citrate according to a fourth objective of the present invention.

[0086] The method includes the following steps: a. suspending and mixing arviline citrate and a binder in water; b. coating the powdered solid carrier particles forming the core 10 with the suspension obtained in step a), and removing the water to obtain particles 7 consisting of the core in the powdered solid carrier, the core having a film of a mixture of arviline citrate and a binder coated on its outer surface; c. preparing a masking agent solution and coating the particles 7 obtained in step b) with the masking agent solution to obtain a film of masking agent 8 coated on its outer surface and particles 3 containing particles 7 containing arviline citrate.

[0087] A fifth object of the present invention is a method for preparing a pharmaceutical composition containing arviline citrate according to a fourth object of the present invention, wherein the binder used in step a) is hydroxypropyl methylcellulose, and the mass ratio of arviline citrate to hydroxypropyl methylcellulose is between 10 and 20, preferably 15.

[0088] Preferably, the powdered solid carrier used in step b) is mannitol, and the ratio of the mass of the powdered solid carrier (page 6 / 10, CN 122094666 A) to (mass of citric acid alverine + mass of binder) is between 1 and 3, preferably 2.1.

[0089] A masking agent, which has been shown to be particularly effective not only in masking the bitterness and anesthetic effects of arverine citrate, but also in giving pharmaceutical compositions containing arverine citrate and simethicone according to the first object of the invention dissolution profiles at pH 1.2 and pH 4.5 and pH 6.8 equivalent to the reference formulation Météospasmyl®, is used in step (c) as a mixture of tripalmitoyl glycerol and polysorbate 65.

[0090] Preferably, the mass ratio of tripalmitoyl glycerol / polysorbate 65 is between 5 and 7, preferably 6.1.

[0091] Also preferably, the ratio of the total mass of the masking agent to the mass of the arverine citrate microparticles (7) is between 0.2 and 0.4. Preferably, it is equal to 0.33.

[0092] The method for preparing a pharmaceutical composition containing arverine citrate according to the fifth object of the present invention optionally includes step d) of adding a pharmaceutically acceptable excipient (4), said excipient (4) comprising at least one flavoring agent, and / or at least one acidifying agent, and / or at least one sweetener, and / or at least one filler and at least one lubricant / anti-aggregating agent.

[0093] These pharmaceutically acceptable excipients (4) are preferably those used in the pharmaceutical compositions containing arverine citrate and simethicone according to the first object of the present invention, and comprise menthol and spearmint as flavoring agents, anhydrous citric acid and sodium citrate as acidifying agents, xylitol and sucralose as sweeteners, xylitol as a filler and talc as a lubricant / anti-aggregating agent.

[0094] The sixth object of the present invention is a method for preparing a pharmaceutical composition containing a combination (1) of arverine citrate and simethicone according to the first object of the present invention.

[0095] The method comprises the following steps: A. Preparing particles (3) containing citric acid alverine according to the preparation method of the fifth object of the present invention; B. Adsorbing simethicone onto a powdered solid carrier; C. Preparing premix I by mixing a portion of the simethicone adsorbed on the powdered solid carrier obtained in step (B) with at least one sweetener; D. Preparing premix II by mixing a lubricant / anti-aggregating agent with at least one flavoring agent and at least one acidifier and the premix I obtained in step (C).

[0096] E. Mixing the particles (3) obtained in step A), the premix II obtained in step D), and the remaining simethicone adsorbed on the powdered solid carrier obtained in step B) with at least one acidifier and at least one filler.

[0097] Preferably: - In step B), the powdered solid carrier is hydrated colloidal silica, and the mass ratio of simethicone oil to hydrated colloidal silica is between 2:1 and 1.3:1, preferably 1.6:1 (1.6 simethicone oil to 1 hydrated colloidal silica); - In step C), the sweetener is sucralose, and the mass ratio of particulate 5 to sucralose is between 6 and 8, preferably 6.86; - In step D), the lubricant / anti-aggregating agent is talc, the acidifier is anhydrous citric acid, and the flavoring agents are spearmint flavoring agent and menthol flavoring agent; - In step E), the acidifier is sodium citrate, and the filler is xylitol.

[0098] Particularly preferably, 1.4 g of the mixture contains 300 mg of simethicone oil and 60 mg of acetyl citrate contained in particulate 3.

[0099] To better understand the present invention, preparation examples are given for illustrative purposes only and not exhaustively. Specification 7 / 10 pages 11 CN 122094666 A

[0100] Example 1: Preparation of a pharmaceutical composition containing simethicone-containing microparticles (5) according to the second object of the present invention: Materials: - Simethicone, reference number Q7-2243, from DuPont - Colloidal silica, reference number Syloid XDP 3150, from Grace 96.72 kg of hydrated colloidal silica was introduced into a granulator.

[0101] 154.50 kg of simethicone was added and granulated together with the hydrated colloidal silica.

[0102] The two components were mixed at 5 rpm for 60 minutes.

[0103] We obtained microparticles 5.

[0104] Example 2: Preparation of a pharmaceutical composition containing Alverne Citrate 3 according to the fourth embodiment of the present invention 1. Preparation of Alverne Citrate Phase - Preparation of Particles 7# Materials: Alverne Citrate: Reference No. 0368, from Centipharm Hydroxypropyl Methylcellulose: Ashland KLUCEL EXF ULTRA PHARM® Mannitol: Mannitol with Reference No. Pearlitol 300DC®, from Roquette Frères Simethicone: Reference No. Q7-2243, from DuPont Purified Water It should be noted that, according to the first purpose of the present invention, simethicone is added in a very small amount in this step and is used only as an antifoaming agent in the preparation of the Alverne Citrate suspension, and is not taken into account when calculating the amount of simethicone contained in Combination 1 Alverne Citrate-Simethicone.

[0105] It should also be noted that purified water is used as a solvent and is removed during the process of preparing particles 3.

[0106] 30.9 kg of Alverne citrate and 2.06 kg of hydroxypropyl methylcellulose were suspended in approximately 43.3 kg of purified water in a mixing vessel by stirring.

[0107] During stirring, 0.001 kg of simethicone was added to break any foam that formed.

[0108] 70.04 kg of mannitol was passed through a sieve with a mesh size of 0.8 mm and then transferred to a fluidized air bed apparatus for particle coating, wherein the mannitol was coated with an aqueous suspension of Alverne citrate and hydroxypropyl methylcellulose.

[0109] For coating mannitol particles with an aqueous suspension of Alverne citrate and hydroxypropyl methylcellulose, Romaco's Ventilus® technology in a fluidized air bed is preferred.

[0110] 1. Preparation of Alverine Citrate Particles 3 # Materials: - Alverine Citrate Phase: obtained in step 1 above - Tripalmitoylglycerol, Dynasan 116 grade, from IOI Oleo GmbH - Polysorbate 65, reference number TWEEN 65-SO-(MV), from Croda 103 kg of the Alverine Citrate Phase (particles 7) passed through a sieve with a sieve size of 1.0 mm was transferred to a fluidized bed apparatus for particle coating.

[0111] 29.53 kg of glycerol palmitate and 4.81 kg of polysorbate 65 were melted and mixed, and then the prepared molten solution of glycerol palmitate and polysorbate 65 was used to hot coat the particles 7 containing Alverine Citrate in a fluidized air bed apparatus. (Instruction manual 8 / 10 pages 12 CN 122094666 A)

[0112] For the microparticles 7 coated with a mixture of masking agents glyceryl palmitate and polysorbate 65, the Ventilus® technology in a Romaco fluidized air bed is preferred.

[0113] The masking-coated microparticles 7 are then cooled and passed through a sieve with a mesh size of 1.0 mm.

[0114] Particles 3 are obtained.

[0115] Example 3: Preparation of a compositional material comprising a combination of citric acid alverine and simethicone according to the first objective of the present invention: - Simethicone adsorbed on silica, obtained in Example 1 - Sucralose (sweetener): EMPROVE® Ph. Eur, from Merck - Talc: LUZENAC PHARMA, from Imerys - Menthol flavoring agent: IFF No. SN791345 - Fresh peppermint flavoring agent: IFF No. SC097260 - Anhydrous citric acid: F3500 grade, from Jungbunzlauer - Xylitol: Xylisorb® 300, from Roquette Frères - Sodium citrate: F3500 grade, from Jungbunzlauer 21.2 kg of simethicone particles 5 adsorbed on silica obtained in Example 1 and 3.09 kg of sucralose were mixed in a mixer. Premix I was obtained.

[0116] 12.88 kg of talc, 14.42 kg of menthol flavoring agent, 7.21 kg of fresh peppermint flavoring agent, and 5.15 kg of anhydrous citric acid and premix I were passed through a sieve with a mesh size of 0.8 mm and mixed together.

[0117] This mixture is a mixture of pharmaceutical excipients 4 and is premix II.

[0118] 63.97 kg of this premix II, 276.83 kg of xylitol, and 12.88 kg of sodium citrate passing through a sieve with a mesh size of 1.0 mm were introduced into a mixer along with 137.33 kg of citric acid-containing arverine particles 3 prepared in Example 2 and passed through a sieve with a mesh size of 1.3 mm and 230 kg of simethicone oil particles 5 adsorbed on silica, and then mixed at 6 rpm for 15 minutes.

[0119] A pharmaceutical composition according to the first objective of the invention was obtained, which is in the form of an orally dispersible powder containing 300 mg of simethicone and 60 mg of arverine citrate in each 1.4 g administration unit.

[0120] Example 4: The dissolution profile of the pharmaceutical composition according to the invention containing 300 mg of simethicone and 60 mg of arverine citrate was compared with the dissolution profile of METEOSPASMYE®. METEOSPASMYE® consists of gelatin soft capsules filled with a thick suspension containing 300 mg of simethicone and 60 mg of arverine citrate, as a reference.

[0121] Dissolution tests were conducted on the active ingredient, Alverne citrate, using a USP apparatus 3 (reciprocating cylinder) as the dissolution method (European Pharmacopoeia Method 2.9.3) and HPLC / UV as the analytical method (European Pharmacopoeia Method 2.2.29). Dissolution profiles of Météospasmyl® and the oral dispersible pharmaceutical composition prepared in Example 3 were determined at pH 1.2 (adjusted with HCl), pH 4.5 (adjusted with acetate buffer), and pH 6.8 (adjusted with phosphate buffer).

[0122] The dissolution profiles of Météospasmyl® and the composition of the present invention obtained at pH 1.2 are shown in [Figure 4], where the dissolution profile of Météospasmyl® is labeled 1 and the dissolution profile of the composition of the present invention is labeled 2.

[0123] The dissolution profiles of Météospasmyl® and the composition of the present invention obtained at pH 4.5 are shown in [Figure 5], wherein the dissolution profile of Météospasmyl® is labeled 1 and the dissolution profile of the composition of the present invention is labeled 2. Specification 9 / 10 pages 13 CN 122094666 A

[0124] The dissolution profiles of Météospasmyl® and the composition of the present invention obtained at pH 6.8 are shown in [Figure 6], wherein the dissolution profile of Météospasmyl® is labeled 1 and the dissolution profile of the composition of the present invention is labeled 2.

[0125] At all pH values ​​studied, both compositions showed an average dissolution percentage greater than 85% within 15 minutes.

[0126] Therefore, according to the EMEA Directive on Bioequivalence Studies (CPMC / EWP / QWP / 1404 / 95 Rev.l / Corr**), the dissolution profiles of the two compositions under consideration can be considered equivalent.

[0127] Therefore, the dissolution profiles of Météospasmyl® and the compositions of the present invention are considered equivalent in the physiological pH range, i.e., pH 1.2 and pH 4.5 and pH 6.8. (See Figures 1-3, 14, CN 122094666 A, Figure 1, Figure 2, 1-3, 15, CN 122094666 A, Figure 3, Figure 4, 2-3, 16, CN 122094666 A, Figure 5, Figure 6, 3-3, 17, CN 122094666 A)

Claims

1. A pharmaceutical composition comprising a mixture (1) of alverine citrate and simethicone, comprising: a. microparticles (5) consisting of simethicone adsorbed on a powdery solid support, b. granules (3) containing microparticles (7) comprising alverine citrate, coated on their outer surface with a film of a masking agent (8), c. pharmaceutically acceptable excipients (4) comprising at least one flavouring agent, and / or at least one acidifying agent, and / or at least one sweetening agent, and / or at least one lubricant / anti-agglomerating agent and / or at least one filler.

2. The pharmaceutical composition according to claim 1, wherein each microparticle (7) consists of a core (10) coated on its outer surface with a film (11) of a mixture of alverine citrate and a binding agent.

3. The pharmaceutical composition according to claim 2, wherein the core (10) is made of mannitol.

4. The pharmaceutical composition according to any one of the preceding claims, wherein the film (8) is a film made of a mixture of polysorbate 65 and glyceryl palmitate.

5. The pharmaceutical composition according to any one of claims 2 to 4, wherein the binding agent in the mixture forming the film (11) is hydroxypropyl methylcellulose.

6. The pharmaceutical composition according to any one of the preceding claims, wherein the powdery solid support on which simethicone is adsorbed is hydrated colloidal silicon dioxide.

7. The 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 1.4 g of pharmaceutical composition.

8. The pharmaceutical composition according to any one of the preceding claims, wherein the pharmaceutically acceptable excipients (4) comprise as flavouring agents menthol and spearmint, as acidifying agents citric acid and monosodium citrate, as sweetening agents xylitol and sucralose, as lubricant / anti-agglomerating agent talc and as filler xylitol.

9. A pharmaceutical composition comprising alverine citrate, comprising granules (3) which: - are coated on their outer surface with a film (8) of a masking agent, and - contain granules (7) comprising alverine citrate.

10. The pharmaceutical composition according to claim 9, wherein the masking agent forming the film (8) is a mixture of polysorbate 65 and glyceryl palmitate.

11. The pharmaceutical composition according to claim 9 or 10, wherein each microparticle (7) consists of a core (10) coated on its outer surface with a film (11) of a mixture of alverine citrate and a binding agent.

12. The pharmaceutical composition according to claim 11, wherein the core (10) is made of mannitol.

13. The pharmaceutical composition according to claim 11 or 12, wherein the binding agent in the mixture forming the film (11) is hydroxypropyl methylcellulose.

14. The pharmaceutical composition according to any one of claims 9 to 13, further comprising pharmaceutically acceptable excipients (4) comprising at least one flavouring agent, and / or at least one acidifying agent, and / or at least one sweetening agent, and / or at least one lubricant / anti-aggregating agent and / or at least one filler.

15. The pharmaceutical composition according to claim 14, wherein the pharmaceutically acceptable excipients (4) comprise menthol and spearmint as flavouring agents, citric acid and monosodium citrate as acidifying agents, xylitol and sucralose as sweetening agents, talc as lubricant / anti-aggregating agent and xylitol as filler.

16. A method for preparing a pharmaceutical composition comprising alverine citrate according to any one of claims 9 to 15, comprising the following steps: a. suspending alverine citrate and a binding agent in water and mixing, b. coating the microparticles of the solid support with the suspension obtained in step a) and removing the water, thereby obtaining microparticles (7) consisting of a core (10) coated on its outer surface with a film (11) made of a mixture of alverine citrate and a binding agent, c. preparing a solution of a masking agent and coating the microparticles (7) obtained in step b) with the solution of the masking agent, thereby obtaining granules (3) containing microparticles (7) comprising alverine citrate coated on their outer surface with a film (8) of the masking agent.

17. The method for preparing a pharmaceutical composition comprising alverine citrate according to claim 16, wherein the binding agent used in step (a) is hydroxypropyl methylcellulose and the ratio between the mass of alverine citrate and the mass of hydroxypropyl methylcellulose is between 10 and 20, preferably equal to 15.

18. The method for preparing a pharmaceutical composition comprising alverine citrate according to claim 16 or 17, wherein the solid support used in step (b) is mannitol and the ratio between the mass of the solid support and the mass of (alverine citrate mass + binding agent mass) is between 1 and 3, preferably equal to 2.

1.

19. The method for preparing a pharmaceutical composition comprising 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, the ratio between the mass of glyceryl tripalmitate / polysorbate 65 is between 5 and 7, preferably equal to 6.1, and - the ratio between the total mass of the masking agent and the mass of the alverine citrate microparticles (7) is between 0.3 and 0.4, preferably equal to 0.

33.

20. The method for preparing a pharmaceutical composition comprising 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 flavouring agent, and / or at least one acidifying agent, and / or at least one sweetening agent, and / or at least one filler and at least one lubricant / anti-aggregating agent.

21. The method for preparing a pharmaceutical composition comprising arvilin citrate according to any one of claims 16 to 20, wherein the pharmaceutically acceptable excipient (4) comprises menthol and spearmint as flavoring agents, anhydrous citric acid and sodium citrate as acidifying agents, xylitol and sucralose as sweeteners, talc as a lubricant / anti-aggregating agent, and xylitol as a filler.

22. A method for preparing a pharmaceutical composition comprising a combination (1) of arvilin citrate and simethicone according to any one of claims 1 to 9, the method comprising the following steps: A. Prepare particles containing citric acid alverine by the method according to any one of claims 16 to 20 (3). B. Simethicone oil is adsorbed onto a powdered solid carrier to obtain microparticles containing simethicone oil (5). C. Premix I is prepared by mixing a portion of the simethicone microparticles (5) adsorbed on the powdered solid carrier obtained in step B) with a sweetener. D. Premix II is prepared by mixing the premix I obtained in step (C) and the lubricant / anti-aggregating agent with at least one flavoring agent and at least one acidifying agent. E. The remaining microparticles (5) obtained in step B) are mixed with the particles (3) obtained in step A) and the premix II obtained in step D, as well as at least one acidifier and at least one filler.

23. The method according to claim 22, wherein: - In step B), the powdered solid carrier is hydrated colloidal silica, and the mass ratio of simethicone oil to hydrated colloidal silica is between 2:1 and 1.3:1, preferably 1.6:

1. The simethicone oil is adsorbed onto the hydrated colloidal silica through mixing. - In step C), the sweetener is sucralose, and the mass ratio of microparticles (5) to sucralose is between 5 and 8, preferably 6.

87. - In step D), the lubricant / anti-agglomeration agent is talc, the acidifier is anhydrous citric acid, and the flavoring agents are spearmint flavoring agent and menthol flavoring agent. - In step E), the acidifying agent is sodium citrate and the filler is xylitol.

24. A method for preparing a pharmaceutical composition containing simethicone, the method comprising the following steps: - Simethicone is adsorbed onto a powdered solid carrier to obtain microparticles containing simethicone (5). The powdered solid carrier is hydrated colloidal silica.

25. The method for preparing a pharmaceutical composition containing simethicone according to claim 24, wherein the simethicone is adsorbed onto hydrated colloidal silica by mixing.

26. A pharmaceutical composition containing simethicone, wherein the simethicone is adsorbed onto hydrated colloidal silica.

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