Liquid pharmaceutical composition based on stiripentol

Abstract

The present invention relates to a pharmaceutical composition comprising an aqueous solvent suspension of stiripentol having a viscosity of at least 50 Pa.s.

Description

[0001] LIQUID PHARMACEUTICAL COMPOSITION BASED ON STIRIPENTOL

[0002] Technical field of the invention

[0003] The present invention relates to an oral formulation of stiripentol, wherein the stiripentol is in the form of a suspension. In particular, the present invention relates to a pharmaceutical composition comprising an aqueous solvent suspension of stiripentol having a viscosity of at least 50 Pa.s.

[0004] Technical background

[0005] The solid pharmaceutical form is particularly disadvantageous when it is intended for children or elderly people with swallowing difficulties, or when the dosage of the active ingredient needs to be adjusted according to the patient's weight. In these situations, it is particularly convenient to administer the active ingredient in a liquid pharmaceutical form, for example in the form of a syrup or drops.

[0006] However, the oral administration of many medicines in liquid form is difficult due to the low solubility of the active ingredients and / or their instability. In addition, many active ingredients have a particularly unpleasant taste, which can complicate their administration in liquid form.

[0007] Stiripentol, marketed underthe name Diacomit®, is available in powder sachets for the extemporaneous preparation of a drinkable suspension, typically by dilution in a glass of water. However this form is not suitable for very young children. In addition, stiripentol is extremely poorly soluble in water, which may impair its efficacy, and its pronounced bitter taste is an obstacle to prolonged use of this medicine.

[0008] In order to improve the extemporaneous suspension of stiripentol, research has turned towards emulsifications of stiripentol. Zhang ef al (2014) European Journal of Pharmaceutical Sciences 62:301-308 proposed including stiripentol in mixed micelles of monomethoxypolyfethylene glycol)-b-poly(e-caprolactone) and sodium oleate. Lu ef al (2015) International Journal of Nanomedicine 10:4937-4946 propose stiripentol nanoemulsions prepared from poly(ethylene glycol) monooleate / intermediate chain triglycerides.

[0009] It is therefore desirable to develop a homogeneous and stable formulation of stiripentol to facilitate its administration, particularly for infants and children. Summary of the invention

[0010] The present invention arises from the unexpected finding by the inventors that an aqueous solvent suspension of stiripentol with a viscosity of at least 50 Pa.s enables the formulation to be stabilized in drinkable form.

[0011] Thus, the present invention relates to an aqueous solvent suspension of stiripentol.

[0012] Thus, the present invention relates to a pharmaceutical composition comprising an aqueous solvent suspension of stiripentol which is stable, in particular during up to 6 months, 1 year, 2 years or 3 years storage at a temperature between 1 °C and 40°C.

[0013] The present invention relates to a pharmaceutical composition comprising an aqueous solvent suspension of stiripentol with a viscosity of at least 50 Pa.s.

[0014] The present invention also relates to a pharmaceutical composition comprising an aqueous solvent suspension of stiripentol with a viscosity of at least 1.15 Pa.s, in particular from 1.15 Pa.s to 3 Pa.s, in particular measured using a rotary viscometer (Brookfield-type) with an L3 mobile at a rotation speed of 30 rpm for 1 minute, at 20°C.

[0015] The present invention also relates to a pharmaceutical composition comprising an aqueous solvent suspension of stiripentol comprising: from 2 % to 15% by weight of stiripentol; from 0.4% to 3% by weight of at least one viscosifying agent; from 8% to 35% by weight of at least one sweetening agent; from 5% to 30% by weight of at least one texturing agent; from 0.2% to 0.8% by weight of at least one preservative; from 0.01 % to 0.5% by weight of at least one pH adjuster agent; optionally from 0.10% to 0.50% by weight of at least one flavoring agent; based on the total volume of the pharmaceutical composition.

[0016] The present invention also relates to a pharmaceutical composition comprising an aqueous solvent suspension of stiripentol comprising from 2 % to 15% by weight of stiripentol, and between 0.4% and 3% by weight of a viscosifying agent based on the total volume of the pharmaceutical composition.

[0017] The present invention also relates to a pharmaceutical composition as defined above, for use in the prevention or treatment of a disease selected from the group consisting of Dravet syndrome, epileptic diseases, convulsive disorders, obsessive- compulsive disorders, autism spectrum disorders, attention deficit disorder with or without hyperactivity, a hyperkinetic syndrome, peripheral neuropathy, a disease associated with a dysregulation of the mTOR pathway, hyperammonemia, oxaluria, primary hyperoxaluria, ethylene glycol intoxication, renal lesions induced by primary hyperoxaluria and ethylene glycol intoxication, oxalocalcic nephropathy, tumors associated with the Epstein-Barr virus and glioblastoma.

[0018] The present invention also relates to a process for preparing an aqueous solvent suspension of stiripentol having a viscosity of at least 50 Pa.s. comprising the steps of: Al ) adding stiripentol in an aqueous solution having a pH between 5 and 7;

[0019] Bl ) adding at least one viscosifying agent in the aqueous solution comprising stiripentol.

[0020] The present invention also relates to a method of treating a pathology selected from the group consisting of Dravet syndrome, epileptic diseases, convulsive disorders, obsessive-compulsive disorders, autism spectrum disorders, attention deficit disorder with or without hyperactivity, a hyperkinetic syndrome, peripheral neuropathy, a disease associated with a dysregulation of the mTOR pathway, hyperammonemia, oxaluria, primary hyperoxaluria, ethylene glycol intoxication, renal lesions induced by primary hyperoxaluria and ethylene glycol intoxication, oxalocalcic nephropathy, tumours associated with the Epstein-Barr virus and glioblastoma in an individual, comprising administering to said individual a prophylactically or therapeutically effective amount of a pharmaceutical composition comprising an aqueous solvent suspension of stiripentol having a viscosity of at least 50 Pa.s

[0021] The present invention also relates to the pharmaceutical composition as defined above in combination with at least one additional compound.

[0022] The present invention also relates to a product comprising: the pharmaceutical composition as defined above, and at least one additional compound, as a combined preparation for simultaneous, separate or sequential use in an individual.

[0023] The present invention also relates to a dosing device comprising the pharmaceutical composition as defined above.

[0024] Detailed description of the invention

[0025] Definition

[0026] In the specification and in the claims, the terms "including", "comprising" and "containing” can be used interchangeably. These terms are open-ended terms and should be interpreted to mean “including”, but not limited to. Thus, when an object “comprises” or “contains” one or several elements, other elements than those mentioned may also be included in the object. These terms encompass the more restrictive terms “consisting essentially of” and “consisting of.” When an object is said to "consist of" one or several elements, the object is limited to the listed elements and cannot include other elements than those mentioned.

[0027] As used herein, the terms “x% (w / v)" and “x% w / v" are equivalent to “x g per 100 ml”. Unless indicated otherwise, all % value shall be taken to indicate x% w / v.

[0028] Pharmaceutical composition

[0029] Stiripentol

[0030] Stiripentol (Diacomit, l-penten-3-ol,l-(l,3-benzodioxol)-4,4-dimethyl or 4- dimethyl-l -[3,4-methylenedioxy-3,4)-phenyl]-l -penten-3-ol) is a racemic allylic alcohol. Stiripentol is represented by the following formula (I):

[0031] As will be clear for the person skilled in the art, compound of formula (I) include a compound of formulaf la), a compound of formula (lb) or a mixture of a compound of formula (la) and a compound of formula (lb), in particular the racemic mixture thereof.

[0032] French patent FR2173691 , which is incorporated herein by reference, describes the synthesis of stiripentol, in particular starting from methylenedioxy-3,4-phenyl-l- dimethyl-4,4-penten- 1 -on-3.

[0033] Preferably, stiripentol has a granulometry wherein the diameter d90 is less than or equal to 300 pm, in particular less than 280 pm. Preferably, the diameter d90 is about 280 pm, about 250 pm, about 220 pm, about 200 pm, about 180 pm, about 150 pm, such as from 150 m to 300 pm, from 150 pm to 280 pm from 150 pm to 250 pm, from 150 pm to 220 pm from 150 to 200 pm. Preferably, stiripentol has a granulometry wherein the diameter d50 is comprised between 50 pm and 150 pm, such as between 50 pm and 120 pm, between 50 pm and 100 pm, between 50 pm and 90 pm, between 50 pm and 85 pm or between 50 pm and 80 pm. Granulometry can be measured using any method well known by the person skilled in the art.

[0034] Preferably, the pharmaceutical composition comprises between 2% and 15%, in particular between 2,5% and 10% by weight of stiripentol relative to the total volume of the pharmaceutical composition. More preferably, the pharmaceutical composition comprises between 2,5% and 7%, or between 5 and 7% by weight stiripentol, even more preferably 5% by weight stiripentol relative to the total volume of the pharmaceutical composition.

[0035] Preferably, the stiripentol content is comprised between 20 mg / ml and 150 mg / ml, in particular between 25 mg / ml and 100 mg / ml, between 50 mg / ml and 70 mg / mg of pharmaceutical composition. More preferably, the stiripentol content is about 50 mg / ml of pharmaceutical composition. agent

[0036] Preferably, the pharmaceutical composition further comprises at least one viscosifying agent. The viscosifying agent can be chosen among any viscosifying agent well known to the person skilled in the art. Example of suitable viscosifying agent include xanthan gum, hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose (CMC), polyvinylpyrrolidone (PVP), gum arabic, guar gum, agar-agar, sodium alginate, carrageenan, gellan gum, gelatin, and mixtures thereof. Particularly preferably, the viscosifying agent is xanthan gum.

[0037] Preferably, the viscosifying agent is a thixotropic viscosifying agent. As used herein, a “thixotropic viscosifying agent” is a substance added to a formulation to control and modify its viscosity, specifically giving it thixotropic behavior. Advantageously, the thixotropic viscosifying agent helps the pharmaceutical composition according to the invention to stay stable during storage and allows it to flow or spread easily when a force is applied. In particular, the thixotropic viscosifying agent prevents sedimentation of stiripentol during storage, it allows the suspension to maintain gel-like structure at rest, thereby stabilizing the distribution of suspended particles and minimizing phase separation over time. Furthermore, upon shaking or agitation, the pharmaceutical composition become sufficiently fluid for accurate and convenient dosing.

[0038] Preferably, the thixotropic viscosifying agent is selected from the group consisting of xanthan gum, hydroxyethylcellulose, Carbopol, bentonite and mixtures thereof. More preferably, the thixotropic viscosifying agent according to the invention is xanthan gum.

[0039] Preferably, the pharmaceutical composition comprises between 0.4% and 3%, such as between 0.5% and 3%, such as between 0.5% and 2.5%, between 0.5% and 2%, between 0.5% and 1 .5% or between 0.5% and 1 %, 0.5% and 0.9%, 0.5% and 0.8%, or 0.5% and 0.7% by weight of at least one viscosifying agent relative to the total volume of the composition. Preferably, the amount of viscosifying agent in the pharmaceutical composition according to the invention is less than 1 % by weight relative to the total volume of the composition. Preferably, the amount of viscosifying agent is about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, or about 1 % by weight relative to the total volume of the composition.

[0040] Adjuvant

[0041] Preferably, the pharmaceutical composition according to the invention further comprises at least one adjuvant. The adjuvant can be chosen among any suitable adjuvant well known to the person skilled in the art. Example of adjuvant include sweetening agents, binders, disintegrants, fillers, lubricants, preservatives, coloring agents, antioxidants, pH adjusters, flavoring agents, solvent, co-solvents, wetting agent, antimicrobial agent, binder agent, thinner agent, texturing agent, etc.

[0042] Sweetening agent

[0043] Preferably, the pharmaceutical composition according to the invention further comprises at least one sweetening agent.

[0044] The sweetening agent according to the invention can be chosen among any ingredient or additive used to provide sweetness including any sweetening agent well known to the person skilled in the art. The sweetening agent is preferably chosen from the group consisting of natural or synthetic sweetening agent authorized for pharmaceutical use.

[0045] Preferably, the sweetening agent is selected from the group consisting of sugar, fructose, glucose, maltose, sucrose, dextrose, aspartame, saccharine, stevia, acesulfame potassium (acesulfame-K), monk fruit extract, sucralose, neotame, advantame, rebaudioside A, a polyol such as maltitol, sorbitol, xylitol, erythritol, isomalt, lactitol, mannitol, and combinations thereof.

[0046] In an embodiment of the present description, the pharmaceutical composition comprises at least two sweetening agents as defined above.

[0047] In an embodiment, the pharmaceutical composition according to the present invention comprises

[0048] - at least one sweeting agent selected from aspartame, sucralose, stevia, saccharine, acesulfame potassium (acesulfame-K), monk fruit extract, neotame, advantame, and rebaudioside A, and

[0049] - at least one polyol, in particular selected from the group consisting of maltitol, sorbitol, xylitol, erythritol, isomalt, lactitol, mannitol.

[0050] In an embodiment, the pharmaceutical composition according to the present invention comprises sucralose and at least one polyol or a mixture of polyols.

[0051] Preferably, the pharmaceutical composition according to the present invention comprises at least two sweetening agents comprising or consisting of sucralose and maltitol.

[0052] Preferably, the at least one sweetening agent is present in the pharmaceutical composition according to the invention in an amount from 8% to 35% by weight relative to the total volume of the pharmaceutical composition, in particular from 10% to 32%, from 10% to 30%, from 10% to 29%, from 10% to 28%, from 10% to 27%, from 10% to 26%, from 10% to 25%, from 1 1 % to 25%, from 12% to 25%, from 13% to 25%, from 14% to 25%, from 15% to 25%, or from 15% to 35%, from 20% to 35%, from 25% to 35% by weight.

[0053] Preferably, in the embodiment of the present description where the pharmaceutical composition comprises at least two sweeting agent:

[0054] - the amount of the sweetening agent selected from the group consisting of aspartame, sucralose, stevia, saccharine, acesulfame potassium (acesulfame-K), monk fruit extract, neotame, advantame, and rebaudioside A is comprised between 0.1 % and 0.35%, such as from 0.12% to 0.34%, from 0.14% to 0.32%, from 0.16% to 0.30%, from 0.18% to 0.30%, from 0.20% to 0.30%, from 0.22% to 0.30%, from 0.24% to 0.30%, or from 0.26% to 0.30%, and

[0055] - the amount of the at least one polyol, in particular selected from the group consisting of maltitol, sorbitol, xylitol, erythritol, isomalt, lactitol, and mannitol is comprised between 10% and 35%, such as from 12% to 35%, from 15% to 35%, from 20% to 35%, from 25% to 35% by weight.

[0056] In one embodiment, the pharmaceutical composition comprises form 0.1 % to 0.35% preferably from 0.20% to 0.30% sucralose and from 10% to 35%, preferably from 25% to 35% maltitol.

[0057] Advantageously, the at least one sweetening agent may bring one or more of the following effects: it adds a sweet taste to the palate, it helps stabilize the flavor, it mask bitterness of stiripentol, it enhances the overall sweetness or flavor profile of the composition making it more enjoyable to consume, it makes the composition easier to administer to children.

[0058] Texturing agent

[0059] Preferably, the pharmaceutical composition according to the invention further comprises at least one texturing agent. The term “texturing agent" is widely understood and used in pharmaceutical industry practice to describe excipients that primarily affect the sensory properties of pharmaceutical compositions more particularly the texturing agent contribute to the smoothness and mouthfeel of the pharmaceutical composition according to the invention.

[0060] The texturing agent can be chosen among any texturing agent well known to the person skilled in the art. Preferably, the texturing agent is glycerol. Preferably, the amount of texturing agent, in particular of glycerol, in the pharmaceutical composition is comprised between 5% and 30% by weight relative to the total volume of the pharmaceutical composition, such as from 5% to 20%, 5% to 15%, or from 8% to 20%, from 10% to 20%, from 12% to 20%, from 14% to 20%, from 15% to 20%, or from 10% to 19%, from 10% to 17%, or from 10% to 15%.

[0061] Advantageously, the texturing agent, in particular the glycerol, can help to keep particles uniformly distributed in the suspension and / or prevent sedimentation and / or ensure consistent dosing.

[0062] Preservative

[0063] Preferably, the pharmaceutical composition according to the invention further comprises at least one preservative. The preservative according to the invention can be chosen among any preservative well known to the person skilled in the art. Preferably, the preservative is selected from the group consisting of sorbic acid, sodium sorbate, potassium sorbate, methyl-p-hydroxybenzoate (methylparaben), ethyl-p-hydroxybenzoate (ethylparaben), propyl-p-hydroxybenzoate

[0064] (propylparaben), ascorbic acid, sodium ascorbate, potassium ascorbate, gallic acid and sodium or potassium gallates, or mixtures thereof. Sorbate potassium is particularly preferred. Preferably, the pharmaceutical composition according to the invention does not comprises methyl-p-hydroxybenzoate (methylparaben), ethyl-p- hydroxybenzoate (ethylparaben), propyl-p-hydroxybenzoate (propylparaben).

[0065] The amount of preservative in the pharmaceutical composition according to the invention is preferably from 0.2% to 0.8% by weight relative to the total volume of the pharmaceutical composition, such as from 0.2% to 0.6%, from 0.25% to 0.55%, from 0.25% to 0.50%, or from 0.30% to 0.45% by weight.

[0066] Advantageously, the preservative prevents the proliferation of bacteria, yeasts and molds. pH adjusting agent

[0067] Preferably, the pharmaceutical composition according to the invention further comprises at least one pH adjusting agent. The pH adjusting agent can be chosen among any suitable pH adjusting agent known to the person skilled in the art. Examples of pH adjusting agent include hydrochloric acid, citric acid, acetic acid, sodium citrate. Preferably, the pH adjusting agent according to the present invention is citric acid.

[0068] Preferably, the pH of the pharmaceutical composition according to the invention is between 5 and 7, preferably between 5 and 6 more preferably between 5 and 5.6.

[0069] Preferably, the pH adjuster is provided in the pharmaceutical composition in an amount sufficient to provide the pH as defined above, i.e. a pH between 5 and 7.

[0070] In one embodiment, the pharmaceutical composition according to the invention comprises from 0.01 % to 0.5% by weight of pH adjuster relative to the total volume of the pharmaceutical composition, in particular from 0.01 % to 0.48%, from 0.01 % to 0.46%, from 0.01 % to 0.44%, from 0.01 % to 0.42%, from 0.01 % to 0.4%, from 0.02% to 0.38%, from 0.02% to 0.36%, from 0.02% to 0.34%, from 0.02% to 0.32%, from 0.02% to 0.3%, from 0.03% to 0.3%, from 0.05% to 0.3%, from 0.08% to 0.3%, from 0.09% to 0.3%, or from 0.1 % to 0.3%. The pH adjusting agent enables the target pH to be achieved. Advantageously, antimicrobial efficacy is optimal at the pH defined above. In addition, the pH adjusting agent guarantees the effectiveness of the preservative. Advantageously also, the pH according to the invention helps to give a flavor that is compatible with the sweetening agent and / or flavoring agent. Citric acid has the added benefit of masking the bitterness associated with stiripentol.

[0071] Flavoring agent

[0072] Preferably, the pharmaceutical composition further comprises at least one flavoring agent.

[0073] The flavoring agent according to the present embodiments can be chosen among any flavoring agent well known to the person skilled in the art. Examples of flavoring agents include natural or synthetic flavor for example fruit flavors such as lemon flavor, grape flavor, cherry flavor, apple flavor, strawberry flavor, mandarin flavor, peach flavor, apricot flavor, raspberry flavor, orange flavor, pear flavor, melon flavor, etc.., vanilla flavors, caramel flavors, almond flavors, bubble gum and chocolate flavor.

[0074] Preferably, the flavoring agent is present in the pharmaceutical composition in an amount between 0.10% and 0.50% by weight relative to the total volume of the composition, preferably between 0.20% and 0.50%, between 0.25% and 0.40%, between 0.25% and 0.38%, between 0.25% and 0.35%. Even more preferably, the amount of flavoring agent in the composition is about 0.28%, orabout 0.30% by weight.

[0075] The flavoring agent is used to change the taste of the composition. Advantageously, the flavoring agent contributes to prolonged use of the pharmaceutical composition in particular without apprehension or disgust.

[0076] Water

[0077] The pharmaceutical composition according to the present invention comprises water. Water is typically present in an amount balancing the amounts of other ingredients to 100% by weight. In an embodiment water is present in an amount between 50% and 90% by weight, for example, from 50% to 85%, from 53% to 80%, from 55% to 80%, from 60% to 78%, from 60% to 75%, form 60% to 72%, or form 60% to 70%. The water can be selected from any type of water well-known by the person skilled in the art such as demineralized water, desalinated water, water filtered by reverse osmosis, deionized water, low ions content water or purified water. More preferably, water according to the invention is purified water.

[0078] Preferably, the pharmaceutical composition according to the invention does not comprise surfactants.

[0079] Preferably also, the pharmaceutical composition according to the invention does not comprise a suspending agent, in particular selected from aluminium magnesium silicate, microcrystalline cellulose, povidone, maltodextrin, pectin, pregelatinized starch, polycarbophil, carbomers, colloidal anhydrous silica , aluminum and magnesium silicate or their mixture.

[0080] Preferably, the pharmaceutical composition according to the invention does not comprise dispersing agents and / or wetting agents, in particular selected from the group consisting of sodium alkylethersulfate, poloxamer, docusate sodium, sodium lauryl sulfate (SLS), ammonium lauryl sulfate (ALS), sodium pareth sulphate and their mixtures.

[0081] Preferably, the pharmaceutical composition according to the invention does not comprise antifoaming agents, such as simethicone emulsion, dimethicone, lutrol and their mixtures.

[0082] Viscosity

[0083] The pharmaceutical composition according to the invention has a thixotropic viscosity, i.e. a viscosity that decreases when a force is applied to the composition, such as agitation or mixing.

[0084] The viscosity of the pharmaceutical composition is preferably measured according to the European Pharmacopeia 2.2.10 method. Preferably, viscosity is measured using a rotary viscometer, preferably a Brookfield-type viscometer fitted with the L3 mobile. The viscosity is measured at room temperature, i.e. at a temperature between 18°C and 22°C. Typically, the viscosity values are recorded by varying the speed of rotation of the rotor and the viscosities are expressed in the form of a graph as a function of the speed applied.

[0085] The viscosity value used in the present description is preferably the extrapolated viscosity at t(0). The extrapolated viscosity is determined by recording viscosity values over time under constant shear or at various shear rates. These values are then plotted, and the resulting curve is extrapolated back to time zero (t(0) ) to estimate the viscosity before the composition has been influenced by mechanical stress. Advantageously, the extrapolated viscosity is particularly relevant for thixotropic compositions.

[0086] The extrapolated viscosity at t(0) according to the invention is preferably of at least 50 Pa.s. in particular at least 55 Pa.s, at least 60 Pa.s, at least 65 Pa.s, at least 70 Pa.s, at least 75 Pa.s, at least 80 Pa.s, at least 90 Pa.s, notably measured using a rotary viscometer (Brookfield-type) with an L3 mobile at a rotation speed of 30 rpm for at least 1 minute, at 20°C and then extrapolated at t(0). Preferably, the viscosity of the pharmaceutical composition is less than 400 Pa.s, less than 380 Pa.s, less than 360 Pa.s, less than 340 Pa.s, less than 320 Pa.s, less than 300 Pa.s, less than 280 Pa.s, notably measured using a rotary viscometer (Brookfield-type) with an L3 mobile at a rotation speed of 30 rpm for at least 1 minute, at 20°C and then extrapolated at t(0). In an embodiment of the present description, the viscosity of the pharmaceutical composition at t(0) is comprised between 50 Pa.s and 350 Pa.s such as between 50 Pa.s and 300 Pa.s, between 50 Pa.s and 280 Pa.s, between 50 Pa.s and 260 Pa.s, between 50 Pa.s and 240 Pa.s, between 50 Pa.s and 220 Pa.s, between 50 Pa.s and 200 Pa.s, between 50 Pa.s and 180 Pa.s, between 50 Pa.s and 160 Pa.s, between 50 Pa.s and 140 Pa.s, between 50 Pa.s and 120 Pa.s, between 50 Pa.s and 100 Pa.s, between 50 Pa.s and 98 Pa.s between 50 Pa.s and 96 Pa.s, between 50 and 94 Pa.s, between 50 Pa.s and 92 Pa.s, between 50 Pa.s and 90 Pa.s, notably measured using a rotary viscometer (Brookfield-type) with an L3 mobile at a rotation speed of 30 rpm for at least 1 minute, at 20°C and then extrapolated at t(0).

[0087] Alternatively, the viscosity value can be expressed as the value obtained when measuring viscosity using a rotary viscometer with an L3 mobile, more specifically a Brookfield RV-DVII+ viscometer equipped with spindle type RV03, at a rotation speed of 30 rpm for 5 minutes, more preferably after a shearing time of 1 minute, at ambient temperature, i.e. between 18°C and 22°C and is preferably of at least 1.15 Pa.s, at least 1 .20 Pa.s, at least 1 .25 Pa.s, at least 1 .30 Pa.s, at least 1 .35 Pa.s, at least 1 .40 Pa.s, at least 1.45 Pa.s, at least 1.50 Pa.s, at least 1.60 Pa.s, at least 1.70 Pa.s, at least 1.80 Pa.s, at leastl .90 Pa.s, at least 2 Pa.s, preferably between 1.15 Pa.s and 3 Pa.s, or between 1 .30 Pa.s and 3 Pa.s, or between 1 .4 Pa.s and 3 Pa.s, in particular between

[0088] 1.4 Pa.s and 2.9 Pa.s, between 1.4 Pa.s and 2.8 Pa.s, between 1.4 Pa.s and 2.7 Pa.s, between 1 .4 Pa.s and 2.6 Pa.s, between 1 .4 Pa.s and 2.5 Pa.s, between 1 .4 Pa.s and

[0089] 2.4 Pa.s, between 1.4 Pa.s and 2.3 Pa.s, between 1.4 Pa.s and 2.2. Pa.s, between 1.4 Pa.s and 2.1 Pa.s. Viscosity according to the invention is controlled and is a critical parameter for ensuring the physical stability of the pharmaceutical composition according to the invention. Advantageously, the specific values of the viscosity of the pharmaceutical composition, such as of at least 50 Pa.s at t(0), contribute to the suspension's great stability over time in particular during up to 6 months, 1 year, 2 years or 3 years storage at a temperature between 1°C and 40°C, contribute to maintain homogeneity, prevent segregation of the suspension as a function of time and allow consistent and good dosing control and swallowing of the pharmaceutical composition.

[0090] Preferably, the viscosity of the pharmaceutical composition is stable during shelf-life of the composition, for example during up to 6 months, 1 year, 2 years or 3 years storage at a temperature from 1°C to 40°C.

[0091] Preferably, the viscosity of the pharmaceutical composition does not change significantly over time. Preferably, the decrease in viscosity is less than 10%, preferably less than 9%, less than 8%, less than 7%, less than 6%, less than 5% for at least 6 months, at least 1 year, at least 2 years or at least 3 years storage at a temperature of 1°C to 40°C.

[0092] Particle size distribution

[0093] Preferably, the pharmaceutical composition according to the invention has a particle size distribution (PSD) d90 less than 500 pm, less than 450 pm, less than 400 pm, less than 350 pm, less than 300 pm, less than 250 pm.

[0094] Preferably, the pharmaceutical composition according to the invention has a particle size d50 comprised between 50 pm and 150 pm, such as between 50 pm and 120 m, between 50 pm and 100 pm, between 50 pm and 90 pm, between 50 pm and 85 pm or between 50 pm and 80 pm. ivlethds for measuring the particle size distribution are well known by the person skilled in the art. Preferably, the particle size distribution of the pharmaceutical composition according to the invention is determined using laser diffraction techniques, employing a ivlastersizer instrument (e.g., iVlalvern ivlastersizer 3000) .

[0095] Stability

[0096] Preferably, the pharmaceutical composition is stable over time, in particular, the pH, the visual aspect and the concentration of stiripentol does not change during shelf-life of the pharmaceutical composition according to the invention for example during up to 6 months, 1 year, 2 years or 3 years storage at a temperature between l°C and 40°C.

[0097] Preferably, the pharmaceutical composition does not sediment during shelf-life for example for at least 6 months, at least 1 , at least 2 years or at least 3 years from packaging at a temperature of 1 °C to 40°C.

[0098] Preferably, the pharmaceutical composition according to the invention can be stored, transported and / or dispensed at a temperature of 1°C to 40°C for at least 6 months, at least 1 , at least 2 years or at least 3 years from packaging and remains suitable for use.

[0099] Pharmaceutical use

[0100] Preferably, the pharmaceutical composition according to the invention is for use in the prevention or treatment of at least one disease selected from the group consisting of Dravet syndrome, epileptic diseases, convulsive disorders, obsessive- compulsive disorders, autism spectrum disorders, attention deficit disorder with or without hyperactivity, a hyperkinetic syndrome, peripheral neuropathy, a disease associated with a dysregulation of the mTOR pathway, hyperammonemia, oxaluria, primary hyperoxaluria, ethylene glycol intoxication, renal lesions induced by primary hyperoxaluria and / or ethylene glycol intoxication, oxalocalcic nephropathy, tumors associated with the Epstein-Barr virus, diseases associated with elevated LDH, brain tumors, and glioblastoma.

[0101] In one embodiment, the invention relates to a method of treating a disease selected from the group consisting of Dravet syndrome, epileptic diseases, convulsive disorders, obsessive-compulsive disorders, autism spectrum disorders, attention deficit disorder with or without hyperactivity, a hyperkinetic syndrome, peripheral neuropathy, a disease associated with a dysregulation of the mTOR pathway, hyperammonemia, oxaluria, primary hyperoxaluria, ethylene glycol intoxication, renal lesions induced by primary hyperoxaluria and ethylene glycol intoxication, oxalocalcic nephropathy, tumours associated with the Epstein-Barr virus, diseases associated with elevated LDH, brain tumors and glioblastoma, in an individual comprising:

[0102] - selecting an individual in need of such treatment, and

[0103] - administering to said individual a prophylactically or therapeutically effective amount of a pharmaceutical composition comprising an aqueous solvent suspension of stiripentol having a viscosity of at least 50 Pa.s. Individual

[0104] The individual according to the invention is preferably a mammal, more preferably a human. Preferably also, the individual according to the invention is a child or an infant.

[0105] Preferably, the individual according to the invention includes infant from full term birth and pre-term neonates who are able to swallow.

[0106] In an embodiment, the individual according to the invention is a child from birth to 10 years, in particular form birth to 6 years.

[0107] In an embodiment, the individual according to the invention is a patient suffering from severe myoclonic epilepsy in infants.

[0108] In an embodiment, the individual is a patient suffering from epilepsy, orsuff ering from epileptic seizures or a patient who has experienced prolonged seizures, or has experienced recurrent seizures.

[0109] In one embodiment of the invention, the individual has a disturbance of brain function. Preferably, the individual according to the invention has at least one disorder selected from the group consisting of convulsions, seizures, confusion, agitation, disturbances of consciousness, lethargy, ataxia, stroke-type lesions, coma, psychosis, loss of vision, acute encephalopathy, cerebral oedema and cerebral hernia. More preferably, the individual according to the invention has convulsions or seizures.

[0110] In one embodiment of the invention, the individual has obsessions, obsessive thoughts, impulses ideas or images, compulsive behaviors, or compulsive acts.

[0111] In one embodiment, the individual according to the invention has at least one of hyperactivity, impulsivity, and attention deficit.

[0112] In one embodiment, the individual according to the invention has a mutation in a gene selected from TSC1 , TSC2, PTEN and SKI 1 genes. In another embodiment, the individual according to the invention presents at least one symptom of tuberous sclerosis or is diagnosed with a definite tuberous sclerosis, or a probable tuberous sclerosis, or a possible tuberous sclerosis or presents at least one symptom of a PTEN- related hamartoma syndrome, or at least one symptoms selected from the group consisting of Cowden syndrome (CS) and / or at least one symptom of Bannayan-Riley- Ruvalcaba syndrome (BRRS) and / or at least one symptom of PTEN-related proteus syndrome (PS) and / or at least one symptom of proteus-like syndrome. In one embodiment, the individual according to the invention has a urea cycle disorder.

[0113] In one embodiment, the individual according to the invention has glyoxylate metabolism disorders in particular an excess oxalate.

[0114] Additional compound

[0115] In an embodiment, the pharmaceutical composition according to the invention further comprises at least one additional compound selected from the group consisting of an anti-convulsant agent, a compound for the prevention or treatment of epileptic seizures, a compound intended for the prevention or treatment of obsessions and / or compulsions, a compound intended for the prevention or treatment of autism spectrum disorders, a compound intended for the prevention or treatment of attention deficit hyperactivity disorder (ADHD) or hyperkinetic syndrome, a compound for the prevention or treatment of peripheral neuropathies, an inhibitor of the mTOR pathway, a compound for the prevention or treatment of hyperammonemia or for the prevention or treatment of one or more symptoms associated with hyperammonemia, a compound for the prevention or treatment of oxaluria or primary hyperoxaluria, a compound for the prevention or treatment of diseases associated with elevated LDH, a compound for the prevention or treatment brain tumors, and a compound for the prevention or treatment glioblastoma.

[0116] As intended herein, the expression “compound intended for the prevention or treatment” of a disease relates to any compound intended to alleviate one or more of the symptoms of the disease or to treat or prevent the disease.

[0117] Preferably, the anti-convulsant or the compound for the prevention or treatment of epileptic seizures include valproic acid, phenytoin and carbamazepine and sodium valproate.

[0118] Preferably, the compound intended for the prevention or treatment of obsessions and / or compulsions includes selective serotonin reuptake inhibitors (SSRI), such as escitalopram, fluvoxamine, fluoxetine, paroxetine, and sertraline, tricyclic antidepressants (TCA), such as clomipramine, and neuroleptics, such as haloperidol and risperidone.

[0119] Preferably, the additional compound intended for the prevention or treatment of autism spectrum disorders is selected from the group consisting of serotonine, buspirone, clomipramine, fenfluramine, fluoxetine, fluvoxamine, sertraline, dopamine, haloperidol, L-dopa, pimozide, epinephrine, norepinephrine, beta-blockers, clonidine, desipramine, opiate antagonists, ACTH, clozapine, risperidone, vitamins B6 and Bl 2 and melatonin.

[0120] Preferably, the additional compound intended for the prevention or treatment of attention deficit hyperactivity disorder (ADHD) or hyperkinetic syndrome is selected from the group constituted of a stimulant such as methylphenidate, dextroamphetamine (also called dexamphetamine or dexamfetamine), dextroamphetamine-amphetamine (i.e. a combined preparation of dextramphetamine and amphetamine (also called amfetamine)), or lisdexamfetamine, atomoxetine, and an antidepressant such as bupropion, desipramine, clonidine or guanfacine.

[0121] Preferably, the additional compound for the prevention or treatment of peripheral neuropathies is selected from the group consisting of neuroprotective and / or analgesic, NGF, BDNF, CNTF, IGF-I, NT-3 and L-carnitine.

[0122] Preferably, the inhibitor of the mTOR pathway is selected from the group consisting of wortmannin, rapamycin and the analogs of rapamycin, such as temsirolimus and everolimus.

[0123] Preferably, the additional compound for the prevention or treatment of hyperammonemia or for the prevention or treatment of one or more symptoms associated with hyperammonemia is selected from the group consisting of neuroprotective drugs such as N-acetylcysteine, indomethacin, propofol, minocycline and mannitol anti-inflammatory drugs, sodium benzoate, sodium phenylbutyrate, glycerol phenylbutyrate, N-carbamylglutamate, sodium benzoate / sodium phenylacetate, lactulose, arginine hydrochloride, L-arginine, carglumic acid, a mixture of L-ornithine and L-aspartate, citrulline, and mixtures thereof.

[0124] As intended herein “combined” or “in combination” the pharmaceutical composition comprising an aqueous solvent suspension of stiripentol according to the invention is administered at the same time than the additional compound, either together, i.e. at the same administration site, or separately, or at different times, provided that the time period during stiripentol exerts its pharmacological effects on the individual and the time period during which the additional compound exerts its pharmacological effects on the individual, at least partially intersect. Administration

[0125] The pharmaceutical composition according to the invention is administered orally. The suspension can be drunk pure or diluted in a small quantity of beverage (e.g. water, milk, fruit juice).

[0126] Preferably, the pharmaceutical composition according to the invention is administered with a dosage regimen from 5 mg / kg / day to 500 mg / kg / day, such as from 20 mg / kg / day stiripentol to 500 mg / kg / day, in particular from 25 mg / kg / day to 350 mg / kg / day, from 50 mg / kg / day to 250 mg / kg / day, from 50 mg / kg / day to 200 mg / kg / day, from 50 mg / kg / day to 100 mg / kg / day stiripentol. More preferably the pharmaceutical composition according to the invention is administered with a dosage regimen of 20 mg / kg / day to 50 mg / kg / day, more preferably about 50 mg / kg / day stiripentol.

[0127] Preferably, the pharmaceutical composition is stored in a device, in particular a bottle. Preferably, the device, in particular the bottle, can comprise between 60 and 400 ml of pharmaceutical composition, such as from 60 ml to 360 ml, from 60 ml to 320 ml, from 60 ml to 300 ml, from 60 ml to 180 ml. The device, in particular the bottle, can be colored, for example it can be an amber bottle. The device, in particular the bottle, is preferably equipped with a childproof closing system such as a childproof cap. Preferably, the device is equipped with at least one dosing device, preferably at least one multi-dosing device such as a graduated syringe. The syringe can be graduated from 0.1 ml to 15 ml such as from 0.1 ml to 10 ml, or from 0.3 ml to 10 ml or from 0.3 ml to 5 ml, the syringe may for example be graduated with an increment of 0.1 ml, 0.2 ml, 0.3 ml, 0.4 ml, 0.5 ml or 1 ml. The syringe may also be graduated from 10 mg to 1000 mg, such as from 10 mg to 500 mg or from 30 mg to 500 mg, the syringe may for example be graduated with an increment of 5 mg or 10 mg. Preferably, the dosing device allows to deliver the required dose of stiripentol preferably in 2 or 3 or 4 doses.

[0128] In certain embodiments, the volumetric increments of the dosing device, such as graduated syringe, may correspond to specific amounts of stiripentol.

[0129] Advantageously, the dosing device, such as a graduated syringe, allows an easy and specific dosage and is configured to allow for precise and adjustable administration of the pharmaceutical composition. Advantageously also, the dosing device, such as a graduated syringe, facilitates individualized treatment, progressive dose escalation, and weight-based dosing. Preferably also, the dosing device allows to cover between 1 week and 3 months of treatment according to the patient weight, in particular 1 week to 1 month of treatment.

[0130] By contrast, fixed-dose formulations such as capsules or sachets, delivering for example 50 to 500 mg / kg / day of active substance, do not allow for flexible dose escalation or fine-tuning of the administered dose.

[0131] In a particularly preferred embodiment, the pharmaceutical composition described herein is administered using a graduated pipette with a dose adjusted in increments of 0.1 mL, corresponding to 5 mg of stiripentol per 0.1 mL, thereby allowing for individualized titration based on patient response or tolerance.

[0132] Process

[0133] In one embodiment of the present description, the process for preparing an aqueous solvent suspension of stiripentol having a viscosity of at least 50 Pa.s according to the invention comprises the steps of:

[0134] Al ) adding stiripentol in an aqueous solution having a pH between 5 and 7, preferably between 5 and 6 more preferably between 5 and 5.6,

[0135] Bl ) adding at least one viscosifying agent in the aqueous solution comprising stiripentol.

[0136] Preferably, the process according to the invention further comprises a step Cl ) of stirring until a homogeneous suspension is obtained.

[0137] Preferably, the aqueous solution of step Al ) above comprises at least one adjuvant. Preferably, the at least one adjuvant is selected from the group consisting of at least one sweetening agent, at least one preservative, at least one pH- adjusting agent, at least one texturing agent, and at least one flavoring agent.

[0138] Preferably, the aqueous solution of step Al ) is prepared by mixing the adjuvants, in particular the at least one sweetening agent, at least one preservative, at least one pH-adjusting agent, at least one texturing agent, optionally at least one flavoring agent, and water. Preferably, the adjuvants are introduced in the mixture one by one. Preferably, the mixture is stirred and / or homogenized between the addition of each adjuvant.

[0139] Preferably, the pH is adjusted between 5 and 7, preferably between 5 and 6 more preferably between 5 and 5.6 before the addition of stiripentol. Preferably, the mixture is stirred and / or homogenized after the addition of stiripentol.

[0140] Preferably, stiripentol in introduced in the aqueous solution as such, in granulated or powder form. Preferably, when added to the aqueous solution, the stiripentol is not added in the form of a mixture with an adjuvant, preferably, the stiripentol is not introduced in the form of an aqueous solution, an aqueous suspension or a slurry.

[0141] Preferably, at least one texturing agent is added in the mixture after the addition stiripentol in the aqueous solution and before the addition of the at least one viscosifying agent.

[0142] In another particular embodiment of the present description, the process for preparing an aqueous solvent suspension of stiripentol having a viscosity of at least 50 Pa.s according to the invention comprises a step of mixing an aqueous suspension comprising stiripentol with a dispersion comprising at least one viscosifying agent. According to this particular embodiment, the process comprises the following steps: A2) adding stiripentol in an aqueous solution having a pH between 5 and 7, preferably between 5 and 6 more preferably between 5 and 5.6;

[0143] B2) separately preparing a dispersion comprising at least one viscosifying agent;

[0144] C2) mixing the aqueous solution comprising stiripentol with the dispersion comprising a viscosifying agent.

[0145] Preferably, the process further comprises a step D2) of stirring until a homogeneous suspension is obtained.

[0146] Preferably, the dispersion comprising at least one viscosifying agent further comprises at least one adjuvant. Preferably, the at least on adjuvant is a texturing agent. More preferably, the at least one adjuvant is glycerol. Preferably, the dispersion comprising a viscosifying is prepared by mixing at least one viscosifying agent with at least one adjuvant, preferably at least one texturing agent, more preferably glycerol.

[0147] Preferably, the aqueous solution of step A2) is prepared as defined above.

[0148] The processes according to the invention may further comprises a step of packaging, bottling, or filling the pharmaceutical composition in an appropriate container.

[0149] The nature of the adjuvant and their quantity, as well and the amount of stiripentol to be used in the process according to the invention are as described below in the present description. The viscosity of the aqueous suspension obtained by the processes according to the invention are the same as described below in relation with the viscosity of the pharmaceutical composition according to the invention.

[0150] Mixing can be carried by any method well known by the person skilled in the art. By way of example, the mixing may include one or more means of blending, mixing, combining, stirring, and / or agitating ingredients such as dispersers, dispersion apparatus equipped with anchor or propeller type stirring blades, tri-blender, shear mixer, high shear rate mixer, stirrer, etc.

[0151] Homogenization can be carried by any method well known by the person skilled in the art. By way of example, homogenization can be performed using a homogenizer, a paddle blender, a propeller blender, a high-speed blender, a twin screw extruder, etc.

[0152] The person skilled in the art will be able to adapt the equipment, stirring times and stirring speed according to the desired quantities of aqueous suspension. The stirring speed can range, for example, from 100 revolutions per minute to 30,000 revolutions per minute. The stirring time can range from a few minutes to a few hours, for example from 5 minutes to 5 hours, preferably from 5 minutes to 2 hours.

[0153] Preferably, the processes according to the invention are carried out at room temperature.

[0154] Preferably, the pharmaceutical composition as disclosed above according to the invention is obtained or is obtainable by the processes according to the present description.

[0155] The invention will be further described by the following non-limiting Example.

[0156] EXAMPLE

[0157] The inventors have prepared an aqueous suspension of stiripentol according to the invention and studied its stability over time.

[0158] An aqueous suspension has been prepared using the ingredients given in the table 1 below.

[0159] Table 1 :

[0160] Maltitol and purified water are mixed together, then potassium sorbate, sucralose, the flavoring agent and citric acid are added one by one under stirring. Then stiripentol is added under stirring. The stirring is maintained for about 5 minutes and then an homogenization is performed until obtention of an homogeneous suspension.

[0161] Separately, a dispersion of xanthan in glycerol is prepared by adding xanthan in glycerol under stirring. Then, the dispersion of xanthan gum is incorporated in the aqueous suspension comprising stiripentol under stirring. The stirring is maintained for about 5 minutes and then an homogenization is performed until obtention of an homogeneous suspension.

[0162] The aqueous suspension has been conditioned in a transparent glass bottle and was subjected to a stability study under accelerated conditions at 40°C / 75% relative humidity for 6 months in order to monitor its development and stability over time. The parameters studied are visual appearance, sedimentation, stiripentol concentration, pH and viscosity. Results are given in the Table 2 below.

[0163] The viscosity was measured using a rotary viscometer equipped with an L3 mobile at a speed of 30 revolutions per minute for 5 minutes at a temperature of between 18°C and 22°C.

[0164] Table 2 :

[0165] The study of the stability of the aqueous suspension of stiripentol after 6 months at 40°C and 75% RH shows that:

[0166] The pH remains stable.

[0167] The viscosity remained stable, with a fall in viscosity of 8%, which is acceptable.

[0168] No sedimentation was observed, the suspension remain homogeneous and physically stable.

[0169] The stiripentol concentration is stable.

[0170] Therefore, after 6 months at 40°C and 75% RH, the aqueous suspension of stiripentol is stable in appearance, viscosity, sedimentation, pH and chemically. Thus, the aqueous suspension of stiripentol according to the invention is chemically and physically stable.

Claims

Claims1. A pharmaceutical composition comprising an aqueous solvent suspension of stiripentol having a viscosity of at least 50 Pa.s.

2. The pharmaceutical composition according to claim 1 , wherein the stiripentol content is about 50 mg / ml of pharmaceutical composition.

3. The pharmaceutical composition according to claim 1 or 2, comprising between 0.4% and 3% by weight of a viscosifying agent relative to the total weight of the composition.

4. The pharmaceutical composition according to claim 3, wherein the viscosifying agent is selected from the group consisting of xanthan gum, hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose (CMC), polyvinylpyrrolidone (PVP), gum arabic, guar gum, agar-agar, sodium alginate, carrageenan, gellan gum, gelatin, and mixtures thereof.

5. The pharmaceutical composition according to any one of claims 1 to 4, further comprising between 10% and 30% by weight of a sweetening agent relative to the total weight of the composition.

6. The pharmaceutical composition according to any one of claims 1 to 5, further comprising between 5% and 30% by weight of a texturing agent relative to the total weight of the composition.

7. The pharmaceutical composition according to any one of claims 1 to 6, further comprising at least one sweetening agent, at least one preservative, at least one pH- adjusting agent and optionally at least one flavoring agent.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the pH is between 5 and 6.

9. The pharmaceutical composition according to any one of claims 1 to 8, for use in the prevention or treatment of at least one disease selected from the group consisting of Dravet syndrome, epileptic diseases, convulsive disorders, obsessive-compulsive disorders, autism spectrum disorders, attention deficit disorder with or without hyperactivity, a hyperkinetic syndrome, peripheral neuropathy, a disease associated with a dysregulation of the mTOR pathway, hyperammonemia, oxaluria, primary hyperoxaluria, ethylene glycol intoxication, renal lesions induced by primary hyperoxaluria and / or ethylene glycol intoxication, oxalocalcic nephropathy, tumors associated with the Epstein-Barr virus, diseases associated with elevated LDH, brain tumors, and glioblastoma.

10. The pharmaceutical composition according to any one of claims 1 to 9, for administration with a dosage regimen of 5 mg / kg / day to 500 mg / kg / day stiripentol.

11. The pharmaceutical composition according to any one of claims 1 to 10, comprising at least one additional compound selected from the group consisting of an anti-convulsant agent, a compound for the prevention or treatment of epileptic seizures, a compound intended for the prevention or treatment of obsessions and / or compulsions, a compound intended for the prevention or treatment of autism spectrum disorders, a compound intended for the prevention or treatment of attention deficit hyperactivity disorder (ADHD) or hyperkinetic syndrome, a compound for the prevention or treatment of peripheral neuropathies, an inhibitor of the mTOR pathway, a compound for the prevention or treatment of hyperammonemia or for the prevention or treatment of one or more symptoms associated with hyperammonemia, a compound for the prevention or treatment of oxaluria, primary hyperoxaluria, a compound for the prevention or treatment of diseases associated with elevated LDH, a compound for the prevention or treatment brain tumors, and a compound for the prevention or treatment glioblastoma.

12. A process for preparing an aqueous solvent suspension of stiripentol having a viscosity of at least 50 Pa.s. comprising the steps of:Al ) adding stiripentol in an aqueous solution having a pH between 5 and 7;Bl ) adding at least one viscosifying agent in the aqueous solution comprising stiripentol.

13. The process according to claim 12, wherein the aqueous solution further comprises at least one sweetening agent, at least one preservative, at least one pH-adjusting agent and optionally at least one flavoring agent.

14. The process according to claim 12 or 13, wherein further comprising a step Cl ) of stirring until a homogeneous suspension is obtained.

15. The process according to any one of claims 12 to 14, wherein the viscosifying agent is selected from the group consisting of xanthan gum, hydroxypropylmethylcellulose(HPMC), sodium carboxymethylcellulose (CMC), polyvinylpyrrolidone (PVP), gum arabic, guar gum, agar-agar, sodium aginate, carrageenan, gellan gum, gelatin, polyacrylates and mixtures thereof.

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