WO2025132345A1 - Pharmaceutical composition comprising benzydamine hydrochloride and cetylpyridinium chloride - Google Patents

Abstract

The invention relates to a pharmaceutical composition comprising benzydamine hydrochloride and cetylpyridinium chloride. The composition comprises a soft core and an outer layer surrounding the soft core.

Description

PHARMACEUTICAL COMPOSITION COMPRISING

BENZYDAMINE HYDROCHLORIDE AND CETYLPYRIDINIUM CHLORIDE

FIELD OF THE INVENTION

[0001] Priority is claimed of Slovenian patent application no. SI 2023 00169 that was filed on December 22, 2023.

[0002] The invention relates to a pharmaceutical composition comprising benzydamine hydrochloride and cetylpyridinium chloride. The composition comprises a soft core and an outer layer surrounding the soft core.

BACKGROUND OF THE INVENTION

[0003] Benzydamine hydrochloride (I) is a nonsteroidal anti-inflammatory drug (NSAID) with local anaesthetic and analgesic properties for pain relief and anti-inflammatory treatment of inflammatory conditions of the mouth and throat. Cetylpyridinium chloride (II) is a quaternary ammonium compound with antiseptic properties.

[0004] A fixed dose combination of cetylpyridinium chloride and benzydamine hydrochloride is commercially available under the tradenames Septabene, Septolete, Andolex-C, Difflam, Benz-C and Sobenz.

[0005] Septabene and Septolete lozenges contain 3 mg of benzydamine hydrochloride, 1 mg of cetylpyridinium chloride, isomalt, citric acid, flavoring agents (eucalyptus, levomenthol, peppermint oil, lemon, honey), sucralose and colorant. The lozenges are used for anti-inflammatory, analgesic and antiseptic treatment of irritations in the throat, mouth and gums, in gingivitis and pharyngitis.

[0006] Difflam lozenge contains 3 mg of benzydamine hydrochloride, 1.33 of mg cetylpyridinium chloride, isomalt, menthol, citric acid monohydrate, sucralose, flavoring agent and colorant.

[0007] Sobenz lozenge contains 3 mg of benzydamine hydrochloride, 1.33 of mg cetylpyridinium chloride, povidone, sorbitol, citric acid, aspartame, levomenthol, colloidal silicon dioxide, magnesium stearate, flavoring agents (melon, orange) and colorants (green, yellow). The lozenge is used to relieve inflammation and pain in the throat and in the treatment of infections of the mouth and throat.

[0008] Benz-C lozenge contains 3 mg of benzydamine hydrochloride, 1.33 of mg cetylpyridinium chloride, isomalt, copovidone, microcrystalline cellulose, ammonium glycyrrhizinate, sucralose, colloidal silicon dioxide, sodium citrate dihydrate, silicon dioxide, magnesium stearate, flavoring agents and colorants. The lozenge is used to relieve inflammation and pain in the mouth, denture ulcers and sore gums.

[0009] WO 96 26724 discloses lozenges comprising 1.0 mg of cetylpyridinium chloride, 3.0 mg of benzydamine hydrochloride, sorbitol, mannitol, magnesium stearate, mint flavor and aspartame.

[0010] WO 2003 089007 discloses lozenges comprising benzydamine hydrochloride, cetylpyridinium chloride, phenylephrine hydrochloride, ascorbic acid, menthol, citric acid, acesulfame-K and isomalt.

[0011] WO 2016 126217 discloses pharmaceutical compositions comprising benzydamine hydrochloride, cetylpyridinium chloride and lidocaine.

[0012] WO 2023 046680 discloses pharmaceutical dosage form comprising cetylpyridinium chloride and benzydamine hydrochloride for use in the prevention and/or treatment of a coronavirus infection.

[0013] The solid dosage forms of the prior art comprise benzydamine hydrochloride and cetylpyridinium chloride in the form of monolithic dosage forms that have uniform taste and texture. There is still a need in the art for better tasting and stabile solid oral dosage forms by providing the consumer with a contrasting mouthfeel of a hard outer layer and a soft core.

DETAILED DESCRIPTION OF THE INVENTION

[0014] The invention relates to a pharmaceutical composition comprising a) benzydamine hydrochloride; b) cetylpyridinium chloride; c) a soft core; and d) an outer layer surrounding the soft core.

[0015] Benzydamine hydrochloride and cetylpyridinium chloride are active ingredients.

[0016] The amount of cetylpyridinium chloride in the pharmaceutical composition may be in the range of 0.2-1.8 mg, preferably 0.6-1.6 mg, and even more preferably 0.8-1.4 mg. Most preferably, the amount of cetylpyridinium chloride is 1.0 mg.

[0017] The amount of benzydamine hydrochloride in the pharmaceutical composition may be in the range of 1.0-5.0 mg, preferably 2.0-4.0 mg, and even more preferably 2.5-3.5 mg. Most preferably, the amount of benzydamine hydrochloride is 3.0 mg. [0018] The pharmaceutical composition according to invention is preferably a solid oral composition such as tablet or lozenge. Preferably, the pharmaceutical composition is a lozenge. Lozenges are medicated dosage forms intended to be sucked and held in the mouth or pharynx. Tablets and lozenges may be of any suitable shape, for example, they may be round, oval, oblong or square.

[0019] The total mass of the pharmaceutical composition according to invention is preferably in the range of 2000-4000 mg, preferably 2500-3500 mg, and most preferably 2800-3200 mg. The mass of the soft core is preferably in the range of 200-700 mg, preferably 300-600 mg, and most preferably in the range of 400- 600 mg. The mass ratio between the outer layer and the soft core is preferably in the range of 3 -20, preferably 4-12, and most preferably in the range of 4-8.

[0020] The active ingredients may be present in the soft core and/or in the outer layer. Preferably, the active ingredients are present in the outer layer. Most preferably, the active ingredients are present in the outer layer and not in the soft core.

[0021] As used herein, the term “core” refers to the innermost region of the pharmaceutical composition. The core is completely surrounded by the outer layer so that the liquid material in the core cannot leak out of the pharmaceutical composition.

[0022] The texture of the soft core is different from the texture of the outer layer, thereby providing the consumer with the contrasting mouthfeel of a hard outer layer and a soft core.

[0023] As used herein, the term “soft” in the context of a soft core refers to a liquid and/or semi-solid material. For example, the liquid material may be a solvent, solution, emulsion and/or suspension. The semisolid material may be gel, cream and/or paste.

[0024] The soft core according to invention comprises a liquid and/or semi-solid material. The soft core may comprise a solvent, solution, emulsion, suspension, gel, cream and/or paste. The solvent may be water or non-aqueous solvent such as ethanol, propylene glycol and/or glycerol. Preferably, the soft core comprises a solution, suspension and/or emulsion. The solution and suspension may be aqueous or non-aqueous. Most preferably, the soft core comprises an aqueous solution.

[0025] The outer layer is a hard solid material completely surrounding the soft core. Preferably, the outer layer comprises an amorphous material. Outer layer may be opaque, translucent or transparent.

[0026] The pharmaceutical composition according to invention may comprise conventional excipients that are known to the skilled person such as carriers, fillers, diluents, binders, matrix polymers, glidants, lubricants, disintegrants, surfactants, pH modifiers, osmolarity modifiers, moisture scavengers, humidifiers, antioxidants, preservatives, chelating agents, flavoring agents (flavors, flavorings), flavor enhancers, sweeteners, taste masking agents, colorants and the like. [0027] In preferred embodiments, the pharmaceutical composition comprises a sweetener. The sweetener may be natural or artificial. It may be selected from the group consisting of sugar alcohols including isomalt, maltitol, sorbitol, mannitol, lactitol, erythritol and xylitol; artificial sweeteners including sucralose, saccharin, sodium saccharin, aspartame, acesulfame, thaumatin, glycyrrhizin, cyclamate, dihydrochalcone, ali- tame, miraculin and monellin; sugars including glucose, fructose, sucrose, dextrose, maltose, galactose, maltodextrin, lactose; Stevia and combinations thereof.

[0028] Preferably, the sweetener is sugar alcohol, artificial sweetener, sugar or combination thereof. More preferably, the sweetener is sugar alcohol, artificial sweetener or combination thereof. Even more preferably, the sweetener is sugar alcohol. Most preferably, the sweetener is a combination of sugar alcohol and artificial sweetener.

[0029] Preferably, the sweetener is isomalt, maltitol, sucralose or combination thereof. Preferably, the sweetener is the combination of isomalt and maltitol. Most preferably, the sweetener is the combination of isomalt, maltitol and sucralose.

[0030] In preferred embodiments, the pharmaceutical composition comprises isomalt.

[0031] In preferred embodiments, the pharmaceutical composition comprises maltitol.

[0032] In preferred embodiments, the pharmaceutical composition comprises sucralose.

[0033] In preferred embodiments, the pharmaceutical composition comprises isomalt or maltitol.

[0034] In preferred embodiments, the pharmaceutical composition comprises isomalt and maltitol.

[0035] Most preferably, the pharmaceutical composition comprises isomalt, maltitol and sucralose. Isomalt (E953) is a mixture of two diastereomeric disaccharides 1-O-a-D-glucopyranosido-D-mannitol (1,1-GPM) and 6-O-a-D-glucopyranosido-D-sorbitol (1,6-GPS). Maltitol is 4-O-a-glucopyranosyl-D-sorbitol. Maltitol is preferably used in the form of a syrup (aqueous solution), more preferably a syrup according to European Pharmacopoeia monograph for liquid maltitol (07/2019: 1236), such as those sold by Roquette under the trade name Lycasin®, such as Lycasin® 80/55 and Lycasin® 85/55. Alternatively, other commercially available syrups may be used, such as those sold under the names Polysorb®, Hystar®, Maltidex®, Maltisorb®, Finmalt®, Maltisweet® and Malbit®. Sucralose (E955) is l,6-Dichloro-l,6-dideoxy-P-D-fructofuranosyl 4- chloro-4-deoxy-a-D-galactopyranoside.

[0036] The sweetener may be present in the soft core and/or in the outer layer. Preferably, the sweetener is present in the soft core and in the outer layer.

[0037] In preferred embodiments, the soft core comprises sugar, sugar alcohol and/or artificial sweetener. They may be selected from those described herein above. Preferably, the soft core comprises a sugar alcohol and/or artificial sweetener. More preferably, the soft core comprises a sugar alcohol and artificial sweetener. Most preferably, the soft core comprises maltitol and sucralose.

[0038] In preferred embodiments, the soft core comprises a sugar alcohol. Preferably, the soft core comprises maltitol. The amount of maltitol in the soft core may be in the range of 10-500 mg, preferably 50-400 mg, and most preferably in the range of 100-300 mg.

[0039] The amount of sucralose in the composition according to invention may be in the range of 0. 1-10 mg. Alternatively, the amount of sucralose in the composition according to invention may be in the range of 0.01-0.2 %, preferably 0.05-0. 15%, and most preferably in the range of 0.08-0.12%.

[0040] The amount of isomalt in the composition according to invention may be at least 40 % (w/w), preferably at least 50 % (w/w), and most preferably at least 60 % (w/w).

[0041] In preferred embodiments, the soft core comprises maltitol and artificial sweetener.

[0042] In preferred embodiments, the soft core comprises an aqueous solution comprising a sugar, sugar alcohol and/or artificial sweetener. They may be selected from those described herein above. Preferably, the soft core comprises an aqueous solution comprising a sugar alcohol and/or artificial sweetener. More preferably, the soft core comprises an aqueous solution comprising a sugar alcohol and artificial sweetener. Most preferably, the soft core comprises an aqueous solution comprising maltitol and sucralose.

[0043] In preferred embodiments, the soft core comprises an aqueous solution comprising maltitol. The aqueous solution may comprise at least 10 % (w/w), preferably at least 20 % (w/w) and most preferably at least 30 % (w/w) of maltitol.

[0044] It has been observed that when a pharmaceutical composition according to invention comprises maltitol, especially in the soft core, the composition shows improved physical stability during storage. The inventors have found that maltitol surprisingly reduces the crystallization rate of the amorphous outer layer by reducing the water migration from the soft core to the outer layer. Physical state of the sweetener can have a critical influence on the appearance, texture and shelf life of the composition. Therefore, it is desirable to reduce the phase transitions in the composition during storage.

[0045] In preferred embodiments, the outer layer comprises sugar, sugar alcohol and/or artificial sweetener. They may be selected from those described herein above. Preferably, the outer layer comprises a sugar alcohol and/or artificial sweetener. More preferably, the outer layer comprises a sugar alcohol and artificial sweetener. Even more preferably, the outer layer comprises isomalt and sucralose. Most preferably, the outer layer comprises isomalt, maltitol and sucralose. [0046] In preferred embodiments, the outer layer comprises a sugar alcohol. Preferably, the outer layer comprises isomalt. More preferably, the outer layer comprises isomalt and maltitol.

[0047] In preferred embodiments, the outer layer comprises isomalt and artificial sweetener. Preferably, the outer layer comprises isomalt, maltitol and artificial sweetener.

[0048] In preferred embodiments, the soft core comprises maltitol and the outer layer comprises isomalt. More preferably, the soft core comprises an aqueous solution comprising maltitol and the outer layer comprises isomalt. Even more preferably, the soft core comprises an aqueous solution comprising maltitol, and the outer layer comprises isomalt and maltitol. Still even more preferably, the soft core comprises an aqueous solution comprising maltitol and artificial sweetener, and the outer layer comprises isomalt, maltitol and artificial sweetener. Most preferably, the soft core comprises an aqueous solution comprising maltitol and sucralose and the outer layer comprises isomalt, maltitol and sucralose.

[0049] In preferred embodiments, the pharmaceutical composition comprises maltitol, wherein benzyda- mine hydrochloride and cetylpyridinium chloride are present in the outer layer.

[0050] In preferred embodiments, the soft core comprises maltitol and the outer layer comprises isomalt, wherein benzydamine hydrochloride and cetylpyridinium chloride are present in the outer layer.

[0051] In preferred embodiments, the soft core comprises maltitol and the outer layer comprises isomalt and maltitol, wherein benzydamine hydrochloride and cetylpyridinium chloride are present in the outer layer.

[0052] In preferred embodiments, the pharmaceutical composition comprises an acid. The acid may be organic or inorganic. Preferably, the acid is a carboxylic acid, ascorbic acid or combination thereof. The carboxylic acid is preferably an aliphatic carboxylic acid, more preferably selected from the group consisting of aliphatic carboxylic acids, aliphatic hydroxy carboxylic acids, aliphatic dicarboxylic acids, aliphatic hydroxy dicarboxylic acids, aliphatic tricarboxylic acids and aliphatic hydroxy tricarboxylic acids. Preferably, the carboxylic acid is selected from citric acid, malic acid, lactic acid, glycolic acid acetic acid, succinic acid, fumaric acid and combinations thereof. More preferably, the acid is citric acid, malic acid, ascorbic acid or combination thereof. Most preferably, the acid is citric acid.

[0053] The amount of citric acid in the composition according to invention may be in the range of 1-100 mg, preferably 10-70 mg, and most preferably in the range of 25-50 mg. Alternatively, the amount of citric acid in the composition according to invention may be in the range of 0.5-3 %, preferably 0.5-2 %, and most preferably in the range of 1.0-1.5 %.

[0054] The acid may be present in the soft core and/or in the outer layer. [0055] In preferred embodiments, the acid is present in the soft core and in the outer layer. More preferably, the acid in the soft core and in the outer layer is a carboxylic acid, ascorbic acid or combination thereof. Most preferably, the acid in the soft core and in the outer layer is citric acid.

[0056] In preferred embodiments, the soft core comprises an aqueous solution comprising an acid. More preferably, the soft core comprises an aqueous solution comprising a carboxylic acid, ascorbic acid or combination thereof. Most preferably, the soft core comprises an aqueous solution comprising citric acid.

[0057] In preferred embodiments, the soft core comprises an aqueous solution comprising citric acid and the outer layer comprises citric acid.

[0058] In preferred embodiments, the pharmaceutical composition comprises a flavoring agent. The flavoring agent may be natural, artificial or synthetic and may be chosen from flavor oils and extracts derived from plants, leaves, flowers, fruits and combinations thereof. Flavoring agent may be selected from the group consisting of peppermint oil, levomenthol, strawberry, wild strawberry, citrus, lemon, honey, pear, caramel, lime, orange, black current, blood orange, cranberry, cloudberry, goji berry, raspberry, sea buckthorn, cherry, melon, kiwi, papaya, pineapple, passion fruit, coconut, herbs, tea, anise, water grass, lemon grass, cooling agent ginger, coffee, mango, mangosten, peppermint, spearmint, wintergreen, cinnamon, ca- cao/cocoa, vanilla, liquorice, salt, pepper, chili, menthol, aniseeds, mint, menthol, levomethol, menthyl acetate, menthyl lactate, camphor, eucalyptus, eucalyptus oil, eucalyptol, anethole, eugenol, cassia, oxanone, x-irisone, propenyl guaiethol, thymol, linalool, benzaldehyde, cinnamaldehyde, N-ethyl-p-menthan-3-car- boxamine, N,2,3-trimethyl-2-isopropylbutanamide, 3- l-menthoxypropane-l,2-diol, cinnamaldehyde glycerol acetal (CGA), methone glycerol acetal (MGA) and combinations thereof.

[0059] In preferred embodiments, the flavoring agent is selected from peppermint oil, levomenthol, strawberry, wild strawberry, citrus, lemon, honey, pear, caramel and combinations thereof. Most preferably, the flavoring agent is peppermint oil, levomenthol, ginger, lemon, honey or combination thereof.

[0060] The amount of flavoring agent in the composition according to invention may be in the range of 0.1-25 mg.

[0061] The flavoring agent may be present in the soft core and/or in the outer layer.

[0062] In preferred embodiments, the flavoring agent is present in the soft core and in the outer layer. Most preferably, the flavoring agent in the soft core is ginger, lemon or combination thereof, and the flavoring agent in the outer layer is peppermint oil, levomenthol, lemon, honey or combination thereof.

[0063] The pharmaceutical composition according to invention may comprise a colorant. The colorant may be organic or inorganic, water soluble or water insoluble. The colorant may be selected from colorants used in the food industry such as titanium oxide, iron oxide, iron sesquioxide, yellow iron sesquioxide, carmine, curcumine, caramel, chlorophyllin copper complex, brilliant blue FCF and combinations thereof.

[0064] In preferred embodiments, the colorant is carmine, curcumine, caramel, chlorophyllin copper complex, brilliant blue FCF or combination thereof. Most preferably, the colorant is curcumine.

[0065] The amount of colorant in the composition according to invention may be in the range of 0. 1-10 mg.

[0066] The colorant may be present in the soft core and/or in the outer layer. Preferably, the colorant is present in the outer layer only. Most preferably, the colorant is curcumine and is present in the outer layer only.

[0067] Water content of the soft core after being incorporated into the lozenge may be less than 25 % (w/w), preferably less than 20 % (w/w), and more preferably in the range of 10-16 % (w/w). Water content of the outer layer may be less than 5 %, preferably less than 4 % and more preferably less than 3 %. Most preferably, water content of the soft core after being incorporated into the lozenge is in the range of 10-16 % (w/w) and water content of the outer layer is less than 3 %.

[0068] The viscosity at 37.0 °C of the soft core after being incorporated into a pharmaceutical composition may be less than 500 Pas, preferably less than 200 Pas and most preferably in the range of 130-170 Pas.«

[0069] In preferred embodiments, the pharmaceutical composition comprises a sweetener and an acid. They may be selected from those described herein above. Preferably, the pharmaceutical composition according to the invention comprises a sugar alcohol and an acid selected from carboxylic acid, ascorbic acid and combination thereof. More preferably, the pharmaceutical composition comprises maltitol and citric acid. Even more preferably, the pharmaceutical composition comprises maltitol, isomalt and citric acid. Most preferably, the pharmaceutical composition comprises maltitol, isomalt, sucralose and citric acid.

[0070] In preferred embodiments, the soft core comprises maltitol, and the pharmaceutical composition comprises citric acid.

[0071] In preferred embodiments, the soft core comprises maltitol, the outer layer comprises isomalt, and the pharmaceutical composition comprises citric acid.

[0072] In preferred embodiments, the soft core comprises an aqueous solution comprising maltitol, and the pharmaceutical composition comprises citric acid.

[0073] In preferred embodiments, the soft core comprises an aqueous solution comprising maltitol, the outer layer comprises isomalt, and the pharmaceutical composition comprises citric acid. [0074] In preferred embodiments, the soft core comprises an aqueous solution comprising maltitol, the outer layer comprises isomalt, and the pharmaceutical composition comprises citric acid, wherein benzy da- mine hydrochloride and cetylpyridinium chloride are present in the outer layer.

[0075] In preferred embodiments, the pharmaceutical composition comprises maltitol, an acid, a flavoring agent and a colorant.

[0076] In preferred embodiments, the pharmaceutical composition comprises maltitol, a flavoring agent, a colorant and an acid selected from carboxylic acid, ascorbic acid and combination thereof.

[0077] In preferred embodiments, the pharmaceutical composition comprises maltitol, citric acid, a flavoring agent and a colorant.

[0078] In preferred embodiments, the pharmaceutical composition comprises maltitol, isomalt, citric acid, a flavoring agent and a colorant.

[0079] In preferred embodiments, the pharmaceutical composition comprises isomalt, an acid, a flavoring agent and a colorant.

[0080] In preferred embodiments, the pharmaceutical composition comprises isomalt, a flavoring agent, a colorant and an acid selected from carboxylic acid, ascorbic acid and combination thereof.

[0081] In preferred embodiments, the pharmaceutical composition comprises isomalt, citric acid, a flavoring agent and a colorant.

[0082] In preferred embodiments, the pharmaceutical composition comprises maltitol, isomalt, a flavoring agent, a colorant and an acid selected from carboxylic acid, ascorbic acid and combination thereof.

[0083] In preferred embodiments, the pharmaceutical composition comprises maltitol, isomalt, citric acid, a flavoring agent and a colorant.

[0084] In preferred embodiments, the soft core comprises maltitol, the outer layer comprises isomalt and maltitol, and the pharmaceutical composition comprises citric acid.

[0085] In preferred embodiments, the soft core comprises maltitol, the outer layer comprises isomalt and maltitol, and the pharmaceutical composition comprises citric acid.

[0086] In preferred embodiments, the soft core comprises maltitol and sucralose, the outer layer comprises isomalt, maltitol and sucralose, and the pharmaceutical composition comprises citric acid.

[0087] In preferred embodiments, the soft core comprises maltitol and citric acid, and the outer layer comprises isomalt, maltitol and citric acid. [0088] In preferred embodiments, the soft core comprises maltitol, citric acid and sucralose, and the outer layer comprises isomalt, maltitol, citric acid and sucralose.

[0089] In preferred embodiments, the soft core comprises an aqueous solution comprising maltitol, the outer layer comprises isomalt, and the pharmaceutical composition comprises citric acid.

[0090] In preferred embodiments, the soft core comprises an aqueous solution comprising maltitol, the outer layer comprises isomalt and maltitol, and the pharmaceutical composition comprises citric acid.

[0091] In preferred embodiments, the soft core comprises an aqueous solution comprising maltitol and citric acid, and the outer layer comprises isomalt, maltitol and citric acid.

[0092] In preferred embodiments, the soft core comprises an aqueous solution comprising maltitol, citric acid and sucralose, and the outer layer comprises isomalt, maltitol, citric acid and sucralose.

[0093] In preferred embodiments, the soft core comprises an aqueous solution comprising maltitol, citric acid and sucralose, and the outer layer comprises isomalt, maltitol, citric acid and sucralose, wherein ben- zydamine hydrochloride and cetylpyridinium chloride are present in the outer layer.

[0094] In preferred embodiments, the soft core comprises an aqueous solution comprising maltitol, sucralose, citric acid and flavoring agent, the outer layer comprises isomalt, sucralose, citric acid and flavoring agent, wherein benzydamine hydrochloride and cetylpyridinium chloride are present in the outer layer.

[0095] In preferred embodiments, the soft core comprises an aqueous solution comprising maltitol, sucralose, citric acid and flavoring agent, the outer layer comprises isomalt, maltitol, sucralose, citric acid and flavoring agent, wherein benzydamine hydrochloride and cetylpyridinium chloride are present in the outer layer.

[0096] In preferred embodiments, the soft core comprises glycerol. Preferably, the soft core comprises glycerol and maltitol. More preferably, the soft core comprises glycerol, maltitol and citric acid. Even more preferably, the soft core comprises glycerol, maltitol, citric acid and sucralose.

[0097] In preferred embodiments, the soft core comprises an aqueous solution comprising glycerol. Preferably, the soft core comprises an aqueous solution comprising glycerol and maltitol. More preferably, the soft core comprises an aqueous solution comprising glycerol, maltitol and citric acid. Most preferably, the soft core comprises an aqueous solution comprising glycerol, maltitol, citric acid and sucralose.

[0098] In preferred embodiments, the soft core comprises glycerol, and the outer layer comprises isomalt. Preferably, the soft core comprises glycerol and maltitol, and the outer layer comprises isomalt. More preferably, the soft core comprises glycerol, maltitol and citric acid, and the outer layer comprises isomalt. Even more preferably, the soft core comprises glycerol, maltitol, citric acid and sucralose, and the outer layer comprises isomalt.

[0099] In preferred embodiments,, the soft core comprises an aqueous solution comprising glycerol, and the outer layer comprises isomalt. Preferably, the soft core comprises an aqueous solution comprising glycerol and maltitol, and the outer layer comprises isomalt and maltitol. More preferably, the soft core comprises an aqueous solution comprising glycerol, maltitol and citric acid and the outer layer comprises isomalt and maltitol. Even more preferably, the soft core comprises an aqueous solution comprising glycerol, maltitol, citric acid and sucralose, and the outer layer comprises isomalt and maltitol.

[0100] In preferred embodiments,, the soft core comprises an aqueous solution comprising glycerol, maltitol and citric acid, and the outer layer comprises isomalt, maltitol and ascorbic acid. Preferably, the soft core comprises an aqueous solution comprising glycerol, maltitol, citric acid and sucralose, and the outer layer comprises isomalt, maltitol, ascorbic acid and sucralose.

[0101] The following examples further illustrate the invention but are not to be construed as limiting its scope.

EXAMPLES

[0102] Examples 1-5: Lozenges

[0103] Lozenges are manufactured in a special process on dedicated equipment. Isomalt, sucralose and organic acid are dissolved in purified water and then cooked and vacuumed in a vacuum chamber to reduce moisture content below 3 % (w/w) to obtain melt. Sucralose, organic acid and flavoring agents are dissolved in maltitol syrup to obtain a soft core fill. The soft core fill is heated to approximately 60°C and added to melt by dosing pump. Flavoring agents and colorants are dissolved in purified water or anhydrous ethanol and separately added by dosing pumps to the melt. Melted mixture is formed into lozenges in a lozenge former and soft core lozenges are solidified in a cooling tunnel.

[0104] Examples 6-10: Lozenges

[0105] Lozenges are manufactured in a special process on dedicated equipment. Isomalt, sucralose and organic acid are dissolved in purified water and then cooked and vacuumed in a vacuum chamber to reduce moisture content below 3 % (w/w) to obtain melt. Sucralose, organic acid and flavoring agents are dissolved in maltitol syrup to obtain a soft core fill. The soft core fill is heated to approximately 60°C and added to melt by dosing pump. Flavoring agents and colorants are dissolved in purified water or anhydrous ethanol and separately added by dosing pumps to the melt. Melted mixture is formed into lozenges in a lozenge former and soft core lozenges are solidified in a cooling tunnel.

[0106] Examples 11-15: Lozenges

[0107] Lozenges are manufactured in a special process on dedicated equipment. Isomalt, maltitol syrup, sucralose and organic acid are dissolved in purified water and then cooked and vacuumed in a vacuum chamber to reduce moisture content to obtain melt. Sucralose, organic acid and flavoring agents are dissolved in liquid maltitol to obtain a soft core fill. Glycerol can be added to improve consistency of soft core fill. The soft core fill is heated to approximately 60°C and added to melt by dosing pump. Flavoring agents and colorants are dissolved in purified water or anhydrous ethanol and separately added by dosing pumps to the melt. Melted mixture is formed into lozenges in a lozenge former and soft core lozenges are solidified in a cooling tunnel.

[0108] Example 16: Lozenges

[0109] Lozenges are manufactured in a special process on dedicated equipment. Isomalt, sucralose and organic acid are dissolved in purified water and then cooked and vacuumed in a vacuum chamber to reduce moisture content to obtain melt. Sucrose and glucose syrup are dissolved in purified water and then cooked and vacuumed in a vacuum chamber to reduce moisture content and obtain center filling syrup. Sage oil is dissolved in center filling syrup to obtain a soft core fill. The soft core fill is heated to approximately 60°C and added to melt by dosing pump. Flavoring agents and colorants are dissolved in purified water or anhydrous ethanol and separately added by dosing pumps to the melt. Melted mixture is formed into lozenges in a lozenge former and soft core lozenges are solidified in a cooling tunnel.

[0110] Example 17: Stability during storage

[0111] Lozenges were stored at certain temperature and relative humidity. After storage the lozenges were cut in half and the cross-section was analyzed by a Raman microscope. From the magnified image of the cross-section the thickness of the crystallized layer formed in the outer layer next to the soft core was measured.

[0112] Example 18: Water content and viscosity

[0113] Water content of the soft core was determined by Karl Fischer titration method. The lozenges were cut in half and the soft core was separated from the outer layer before determination of water content.

[0114] The viscosity of the soft core separated from the outer layer was measured by rotational rheometer at 37.0 °C. The mean values of viscosity in the range of shear rate from 10 to 100 s ¹ are presented below.

Claims

1. A pharmaceutical composition comprising a) benzydamine hydrochloride; b) cetylpyridinium chloride; c) a soft core; and d) an outer layer surrounding the soft core.

2. The pharmaceutical composition according to claim 1, wherein the soft core comprises a liquid and/or a semi-solid material.

3. The pharmaceutical composition according to claim 1 or 2, wherein the soft core comprises solvent, solution, emulsion, suspension, gel, cream and/or paste.

4. The pharmaceutical composition according to any of the preceding claims, wherein the soft core comprises an aqueous solution.

5. The pharmaceutical composition according to any of the preceding claims, wherein the pharmaceutical composition comprises a sweetener.

6. The pharmaceutical composition according to claim 5, wherein the sweetener is a sugar alcohol, artificial sweetener, sugar or combination thereof.

7. The pharmaceutical composition according to claim 5 or 6, wherein the sweetener is a sugar alcohol, artificial sweetener or combination thereof.

8. The pharmaceutical composition according to any of claims 5 to 7, wherein the sweetener is a sugar alcohol.

9. The pharmaceutical composition according to any of claims 5 to 8, wherein the sweetener is the combination of sugar alcohol and artificial sweetener.

10. The pharmaceutical composition accordingto any of claims 5 to 9, wherein the sweetener is isomalt, maltitol, sucralose or combination thereof.

11. The pharmaceutical composition according to any of claims 5 to 10, wherein the sweetener is the combination of isomalt and maltitol.

12. The pharmaceutical composition according to any of claims 5 to 11, wherein the sweetener is the combination of isomalt, maltitol and sucralose.

13. The pharmaceutical composition according to any of the preceding claims, wherein the pharmaceutical composition comprises isomalt.

14. The pharmaceutical composition according to any of the preceding claims, wherein the pharmaceutical composition comprises maltitol.

15. The pharmaceutical composition according to any of the preceding claims, wherein the pharmaceutical composition comprises sucralose.

16. The pharmaceutical composition according to any of the preceding claims, wherein the pharmaceutical composition comprises isomalt, maltitol and sucralose.

17. The pharmaceutical composition according to any of the preceding claims, wherein the soft core comprises a sugar alcohol and/or artificial sweetener.

18. The pharmaceutical composition according to any of the preceding claims, wherein the soft core comprises a sugar alcohol.

19. The pharmaceutical composition according to any of the preceding claims, wherein the soft core comprises maltitol.

20. The pharmaceutical composition according to any of the preceding claims, wherein the soft core comprises a sugar alcohol and artificial sweetener.

21. The pharmaceutical composition according to any of the preceding claims, wherein the soft core comprises maltitol and sucralose. L. The pharmaceutical composition according to any of the preceding claims, wherein the soft core comprises an aqueous solution comprising maltitol.

23. The pharmaceutical composition according to any of the preceding claims, wherein the soft core comprises an aqueous solution comprising a sugar alcohol and/or artificial sweetener.

24. The pharmaceutical composition according to any of the preceding claims, wherein the soft core comprises an aqueous solution comprising a sugar alcohol and artificial sweetener.

25. The pharmaceutical composition according to any of the preceding claims, wherein the soft core comprises an aqueous solution comprising maltitol and sucralose.

26. The pharmaceutical composition according to any of the preceding claims, wherein the outer layer comprises a sugar alcohol and/or artificial sweetener. 1. The pharmaceutical composition according to any of the preceding claims, wherein the outer layer comprises isomalt and artificial sweetener.

28. The pharmaceutical composition according to any of the preceding claims, wherein the outer layer comprises isomalt and sucralose.

29. The pharmaceutical composition according to any of the preceding claims, wherein the outer layer comprises isomalt, maltitol and sucralose.

30. The pharmaceutical composition according to any of the preceding claims, wherein the soft core comprises maltitol, and the outer layer comprises isomalt.

31. The pharmaceutical composition according to any of the preceding claims, wherein the soft core comprises an aqueous solution comprising maltitol, and the outer layer comprises isomalt.

32. The pharmaceutical composition according to any of the preceding claims, wherein the soft core comprises an aqueous solution comprising maltitol, and the outer layer comprises isomalt and maltitol.

33. The pharmaceutical composition according to any of the preceding claims, wherein the soft core comprises an aqueous solution comprising maltitol and artificial sweetener, and the outer layer comprises isomalt, maltitol and artificial sweetener.

34. The pharmaceutical composition according to any of the preceding claims, wherein the soft core comprises an aqueous solution comprising maltitol and sucralose, and the outer layer comprises isomalt, maltitol and sucralose.

35. The pharmaceutical composition according to any of the preceding claims, wherein the pharmaceutical composition comprises an acid.

36. The pharmaceutical composition according to claim 35, wherein the acid is carboxylic acid, ascorbic acid or combination thereof.

37. The pharmaceutical composition according to claim 35 or 36, wherein the acid is citric acid, malic acid, ascorbic acid or combination thereof.

38. The pharmaceutical composition according to any of claims 35 to 37, wherein the acid is citric acid.

39. The pharmaceutical composition according to any of claims 35 to 38, wherein the acid is present in the soft core and in the outer layer.

40. The pharmaceutical composition according to any of claims 35 to 39, wherein the acid in the soft core and in the outer layer is a carboxylic acid, ascorbic acid or combination thereof.

41. The pharmaceutical composition according to claim 39 or 40, wherein the acid in the soft core and in the outer layer is citric acid.

42. The pharmaceutical composition according to any of the preceding claims, wherein the soft core comprises an aqueous solution comprising citric acid.

43. The pharmaceutical composition according to any of the preceding claims, wherein the pharmaceutical composition comprises isomalt, a flavoring agent, a colorant and an acid selected from carboxylic acid, ascorbic acid and combination thereof.

44. The pharmaceutical composition according to any of the preceding claims, wherein the soft core comprises an aqueous solution comprising maltitol, the outer layer comprises isomalt, and the pharmaceutical composition comprises citric acid.

45. The pharmaceutical composition according to any of the preceding claims, wherein the soft core comprises an aqueous solution comprising maltitol, citric acid and sucralose, and the outer layer comprises isomalt, maltitol, citric acid and sucralose.

46. The pharmaceutical composition according to any of the preceding claims, wherein benzydamine hydrochloride and cetylpyridinium chloride are present in the outer layer.

47. The pharmaceutical composition according to any of the preceding claims, wherein benzydamine hydrochloride and cetylpyridinium chloride are present in the outer layer and not in the soft core.

48. The pharmaceutical composition according to any of the preceding claims, wherein the soft core comprises an aqueous solution comprising maltitol, sucralose, citric acid and flavoring agent, the outer layer comprises isomalt, sucralose, citric acid and flavoring agent, wherein benzydamine hydrochloride and cetylpyridinium chloride are present in the outer layer.

49. The pharmaceutical composition according to any of the preceding claims, wherein the soft core comprises an aqueous solution comprising maltitol, sucralose, citric acid and flavoring agent, the outer layer comprises isomalt, maltitol, sucralose, citric acid and flavoring agent, wherein benzydamine hydrochloride and cetylpyridinium chloride are present in the outer layer.