Probenecid preparation

Abstract

The present invention relates to a core-shell formulation having a core comprising probenecid in an amount of 10% to 70% by weight relative to the total weight of the core, said probenecid in combination with at least one pharmaceutically acceptable excipient; wherein the core is coated with a shell coating, the shell coating comprises triethyl citrate, inorganic filler, polyvinyl acetate, polyvinylpyrrolidone and lauryl sodium sulfate, and the weight ratio of polyvinyl acetate to polyvinylpyrrolidone is 1.5 to 4.

Description

TECHNICAL FIELD

[0001] The present invention relates to a modified release pharmaceutical formulation of probenecid, in particular a pediatric probenecid formulation. The present invention also relates to the use of such a formulation for the treatment of epilepsy. BACKGROUND

[0002] Probenecid is a benzoic acid derivative with excellent safety profile, developed in the 1950s for the reduction of tubular excretion of penicillins; and has been used to increase serum concentrations of several antibiotics and antiviral drugs. In the initial studies with probenecid, known as Benemid, it was observed that probenecid has a strong uricosuric effect and rapidly became the standard of treatment for gout. It was found that it reduces serum uric acid levels by acting as a competitive inhibitor of organic anion transporters (OATs), in particular URAT1, a member of the OAT family, and thus prevents the URAT1 -mediated reuptake of uric acid from the urine to the serum, and increases the serum concentrations of several organic acid compounds. Despite the small side effects of probenecid, it is formulated in large tablets, and its pharmacokinetic profile requires 4 daily administrations to maintain the pharmacological effect. Therefore, its clinical use has significantly decreased with the development of other formulations for the treatment of gout that can have better compliance.

[0003] As disclosed in international application WO2019 / 012109, probenecid is also useful for the treatment of epilepsy in subjects in need thereof, for example in pediatric subjects, and other neurological diseases.

[0004] Considering the limited and dose-dependent half-life of probenecid, based on the currently available probenecid formulations, the treatment of epilepsy requires 4 daily administrations. In addition, probenecid is a highly lipophilic molecule. Therefore, there is a need to provide a high loading probenecid formulation that is suitable for the physicochemical properties of probenecid, and which should ensure patient compliance by limiting the number of daily intakes to a maximum of once or twice a day.

[0005] In addition, given the particularities of pediatric subjects, in particular the limited volume of excipients that can be administered, a high loading probenecid formulation needs to be able to use the minimum amount of excipients. In addition, in order to ensure the compliance of pediatric patients, a pediatric formulation needs to be easy to ingest and, advantageously, compatible with food or beverage compositions.

[0006] In addition, a probenecid formulation needs to comply with good manufacturing practices, have sufficient stability over the shelf life, and have good reproducibility between batches produced.

[0007] The present invention meets the above-mentioned needs by providing a probenecid modified release formulation as disclosed herein. Despite the high lipophilicity of probenecid, the present formulation can present a probenecid loading up to 50% w / w, as well as a prolonged release of probenecid, limiting the number of intakes to a maximum of once or twice a day. Advantageously, this can be achieved by a quantitative and qualitative limitation of excipients. More advantageously, the formulation is compatible with food ingredients and can be dispersed into food or beverage compositions to ensure compliance of subjects, in particular pediatric subjects. Moreover, the release of probenecid is in line with the therapeutic purpose of epilepsy treatment and the manufacturing process of the present formulation allows reproducible quality characteristics between batches of production and exhibits sufficient shelf-life stability. SUMMARY

[0008] The present invention relates to a core-shell formulation comprising:

[0009] - a core comprising probenecid in an amount of 10 to 70% by weight relative to the total weight of the core, the probenecid being combined with at least one pharmaceutically acceptable excipient; and

[0010] - a shell coating comprising triethyl citrate, a mineral charge, polyvinyl acetate, polyvinylpyrrolidone and sodium lauryl sulfate, wherein the weight ratio of polyvinyl acetate to polyvinylpyrrolidone is 1.5 to 4.

[0011] In some embodiments, the core-shell formulation comprises, by weight relative to the total weight of the core-shell formulation:

[0012] - 0.4 to 1.0%, preferably 0.5 to 0.8% of triethyl citrate,

[0013] - 8.0 to 16%, preferably 10 to 12% of polyvinyl acetate,

[0014] - 2.0 to 6.0%, preferably 3.0 to 4.5% of polyvinylpyrrolidone,

[0015] - 0.05 to 0.2% of sodium lauryl sulfate, and

[0016] - 1.0 to 6.0%, preferably 3.0 to 5.0% of a mineral charge, wherein the mineral charge is preferably talc.

[0017] The shell coating can represent 2 to 30% by weight, preferably 10 to 30% by weight, more preferably 15 to 25% by weight, typically about 20% by weight relative to the total weight of the core-shell formulation.

[0018] The core can be a mixed core, wherein the mixed core is a mixture of propulsid® and at least one pharmaceutically acceptable excipient. Alternatively, the core can be a coated inert core, wherein the coated inert core comprises particles of an inert core consisting of at least one pharmaceutically acceptable excipient, coated with a first coating layer comprising propulsid®.

[0019] According to some embodiments, the at least one pharmaceutically acceptable excipient can be selected from cellulose, microcrystalline cellulose, cellulose derivatives, starch, modified starch, dextran, maltodextrin, sucrose, lactose, mannitol, sorbitol, maltitol, trehalose, calcium carbonate, magnesium carbonate, and silicon dioxide; preferably the at least one pharmaceutically acceptable excipient is microcrystalline cellulose.

[0020] According to some embodiments, wherein the core is a coated inert core, the first coating layer can comprise, by weight relative to the total weight of the coated inert core:

[0021] - 10% w / w to 70% w / w of propulsid®;

[0022] - 20% w / w to 40% w / w of hydroxypropyl cellulose;

[0023] - 1% w / w to 3% w / w of surfactant; and

[0024] - optionally an antifoaming agent.

[0025] According to some exemplary embodiments, the surfactant is a non-ionic surfactant, preferably the surfactant is polyoxyethylene (20) sorbitan monooleate.

[0026] According to some embodiments, the first coating layer can represent from 50% to 80% by weight relative to the total weight of the coated inert core.

[0027] Further, such inert core can consist of microspheres of at least one pharmaceutically acceptable excipient as described above, having an average diameter comprised between 100 pm and 5 mm. According to some embodiments, the inert core consists of microcrystalline cellulose microspheres having an average diameter comprised between 100 pm and 800 pm, more preferably between 300 pm and 400 pm, the average diameter being measured by sieving.

[0028] Optionally, the core can further comprise a seal coating layer in an amount comprised between 2% and 20% by weight relative to the total weight of the core, the seal coating layer comprising:

[0029] - polyvinyl alcohol in combination with talc, titanium dioxide, glyceryl mono and dicaprylocaprate, and sodium lauryl sulfate;

[0030] - polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol, and silica;

[0031] - hydroxypropyl methylcellulose (hypromellose) and talc; or

[0032] - a mixture thereof.

[0033] The formulation can also optionally further comprise an outer layer of lubricant; preferably the lubricant is talc.

[0034] - polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol, and silica;

[0035] - polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol, and silica;

[0036] - hydroxypropyl methylcellulose (hypromellose) and talc; or

[0037] - a mixture thereof.

[0038] The formulation can also optionally further comprise an outer layer of lubricant; preferably the lubricant is talc.

[0039] According to other aspects, the present application relates to the formulation according to the present application for use as a medicament. According to particular embodiments, the formulation can be used for the treatment of epilepsy.

[0040] Finally, the present application relates to a process for the preparation of the core-shell formulation of the present application, comprising the following steps:

[0041] a) providing a core comprising propene sulfourea in an amount of 10 to 70% by weight relative to the total weight of the core, the propene sulfourea being combined with at least one pharmaceutically acceptable excipient;

[0042] b) coating the core of step a) using a shell coating composition, preferably by spray-drying, thereby obtaining a shell-coated core; the shell coating composition comprising triethyl citrate, an inorganic filler, polyvinyl acetate, polyvinylpyrrolidone and sodium dodecyl sulfate, wherein the weight ratio of polyvinyl acetate to polyvinylpyrrolidone is 1.5 to 4;

[0043] c) optionally, further coating the shell-coated core of step b) using a final coating composition, preferably by spray-drying, thereby obtaining a final-coated core; the final coating composition comprising polyvinyl alcohol, the polyvinyl alcohol being combined with talc, titanium dioxide, glyceryl mono-dicaprylocaprate and sodium dodecyl sulfate; polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol, and silica; hydroxypropyl methylcellulose and talc; or a mixture thereof;

[0044] d) optionally, subjecting the coated core of step b) or step c) to a solidification step, comprising heating the coated core at a temperature of 35°C to 45°C, preferably about 40°C, for 30 minutes to 2 hours, preferably about 1 hour;

[0045] e) recovering the core-shell preparation obtained in any one of steps b), c) or d); and

[0046] f) optionally, contacting the preparation of step e) with a lubricant, thereby forming an outer layer of lubricant on the core-shell preparation.

[0047] According to a variant in which the core is a coated inert core, step a) can comprise:

[0048] a1) providing an inert core consisting of at least one pharmaceutically acceptable excipient; preferably the inert core is microcrystalline cellulose microspheres;

[0049] a2) coating the inert core with a first coating composition, preferably by spray-drying coating, thereby obtaining a coated inert core, the first coating composition comprising, by weight relative to the total weight of the coated inert core:

[0050] - 10% w / w to 70% w / w of propylsulfourea;

[0051] - 20% w / w to 40% w / w of hydroxypropyl cellulose;

[0052] - 1% w / w to 3% w / w of a surfactant; and

[0053] - optionally an antifoaming agent;

[0054] a3) optionally, further coating the coated inert core of step a2) with a sealing coating composition, preferably by spray-drying coating, thereby obtaining a sealed coated inert core; the sealing coating composition comprising polyvinyl alcohol in combination with talc, titanium dioxide, glyceryl mono-dicaprylate and laurate, and sodium lauryl sulfate; polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol, and silicon dioxide; hydroxypropyl methylcellulose and talc; or a mixture thereof; and

[0055] a4) recovering the core obtained in step a2) or in step a3). DETAILED DESCRIPTION

[0056] The present invention relates to a modified release (MR) formulation of propylsulfourea, having a high dose of this active pharmaceutical ingredient, sufficient stability over shelf life, and being particularly suitable for pediatric subjects.

[0057] In particular, the present application relates to a modified release (MR) formulation of propenecid based on an immediate release (IR) formulation of propenecid coated with a shell coating composition capable of modulating the release of propenecid.

[0058] Modified release (MR) formulation

[0059] Accordingly, the present application relates to a core-shell formulation of propenecid comprising:

[0060] - a core comprising propenecid in combination with at least one pharmaceutically acceptable excipient; and

[0061] - a shell coating capable of prolonging and / or delaying the release of propenecid compared to an immediate release formulation.

[0062] The core-shell formulation according to the present application is preferably a core-shell granule formulation. In some embodiments, the formulation of the present application is in the form of a granule, in particular a microgranule. In other embodiments, the formulation of the present application is in the form of a tablet, in particular a microtablet. The form of microgranule or microtablet depends on the core used to manufacture the formulation according to the present application, as detailed below.

[0063] Accordingly, the present application relates to a core-shell propenecid formulation, wherein the core is a formulation comprising propenecid in an amount of 10% to 70% by weight relative to the total weight of the core in combination with at least one pharmaceutically acceptable excipient; said core is coated with a coating composition as described below (herein referred to as "shell coating composition" or "second coating composition") forming a shell coating. Coating the core with the shell coating composition can be performed by, for example, spray-drying.

[0064] The second coating composition or shell coating composition comprises triethyl citrate, an inorganic filler, polyvinyl acetate, polyvinylpyrrolidone and sodium dodecyl sulfate, wherein the weight ratio of polyvinyl acetate to polyvinylpyrrolidone is 1.5 to 4, preferably 2.5 to 3.5. In some embodiments, the weight ratio of polyvinyl acetate to polyvinylpyrrolidone is 3.0 to 3.5, typically about 3.3. In some other embodiments, the weight ratio of polyvinyl acetate to polyvinylpyrrolidone is 2.5 to less than 3.0, or preferably about 2.6. In the context of the present application, "about" before a number means the value of the number ± 10%, typically ± 5%.

[0065] Preferably, the shell coating composition is an aqueous composition, more preferably an aqueous solution or an aqueous suspension. In some embodiments, the shell coating composition comprises 70% to 90% by weight, preferably about 80% by weight of a carrier (e.g. water) relative to the total weight of the shell coating composition.

[0066] Once coated on the core, the shell coating composition forms a "shell coating". The amount of shell coating is advantageously sufficient to modulate the release of probenecid. For the shell coating composition, the shell coating comprises triethyl citrate, inorganic filler, polyvinyl acetate, polyvinylpyrrolidone and sodium dodecyl sulfate, wherein the weight ratio of polyvinyl acetate (PVAc) to polyvinylpyrrolidone (PVP) is from 1.5 to 4. The above embodiments regarding the weight ratio of PVAc to PVP in the shell coating composition apply equally to the shell coating.

[0067] Probenecid refers to the active pharmaceutical ingredient compound of CAS number 57-66-9 and having the structure of formula (I):

[0068]

[0069] Probenecid includes probenecid in free base form (sometimes also referred to as 4-(dipropylamino sulfonyl)benzoic acid, 4-[(dipropylamino)sulfonyl]-benzoic acid or PBN), and pharmaceutically acceptable salts thereof (4-(dipropylamino sulfonyl)benzoate or 4-[(dipropylamino)sulfonyl]-benzoate). Also included are prodrugs, isomers and polymorphs of probenecid. Probenecid can exist in non-solvated as well as solvated forms, including hydrates. In general, solvated forms are equivalent to unsolvated forms and are included within the scope of the present application. Probenecid can exist in a variety of crystalline forms or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present application and are intended to be within the scope of the present application.

[0070] According to some embodiments, the probenecid is in the form of particles, typically crystals, wherein at least 70%, preferably at least 90% or 92% of the probenecid particles are smaller than 75 pm as measured by sieving. Alternatively, the probenecid is in the form of particles, typically crystals, wherein the d(0,9) is about 150 pm according to laser diffraction.

[0071] According to some other embodiments, the probenecid particles can exhibit a d(0,9) of less than 40 pm according to laser diffraction, which can be characterized herein as micronized probenecid. For example, the probenecid particles can exhibit a d(0,9) of 21 pm, a d(0,5) of 8 pm and a d(0,1) of 2.2 pm according to laser diffraction.

[0072] The present application thus relates to a core-shell formulation comprising:

[0073] - a core comprising probenecid in an amount of from 10% to 70% by weight relative to the total weight of the core, the probenecid being combined with at least one pharmaceutically acceptable excipient; and

[0074] - a shell coating comprising triethyl citrate, inorganic filler, polyvinyl acetate, polyvinylpyrrolidone and sodium dodecyl sulfate, wherein the weight ratio of polyvinyl acetate to polyvinylpyrrolidone is 1.5 to 4.

[0075] In some embodiments, the shell coating comprises 2 to 30 wt.%, preferably 10 to 30 wt.%, more preferably 15 to 25 wt.%, typically about 20 wt.% relative to the total weight of the core-shell formulation.

[0076] In some embodiments, the core-shell formulation of the present application comprises, by weight relative to the total weight of the core-shell formulation:

[0077] - 0.4 to 1.0%, preferably 0.5 to 0.8% of triethyl citrate,

[0078] - 8.0 to 16%, preferably 10 to 12% of polyvinyl acetate,

[0079] - 2.0 to 6.0%, preferably 3.0 to 5.0% of polyvinylpyrrolidone,

[0080] - 0.05 to 0.2% of sodium dodecyl sulfate, and

[0081] - 1.0 to 6.0%, preferably 3.0 to 5.0% of inorganic filler.

[0082] In some embodiments, the shell coating comprises, by weight relative to the total weight of the shell coating:

[0083] - 2.0 to 5.0%, preferably 2.5 to 4.0% of triethyl citrate as plasticizer,

[0084] - 40.0 to 82.0%, preferably 50.0 to 60.0% of polyvinyl acetate as coating polymer,

[0085] - 10 to 30.0%, preferably 15 to 25.0% of polyvinylpyrrolidone as pore former,

[0086] - 0.25 to 1.0% of sodium dodecyl sulfate, and

[0087] - 5.0 to 30.0%, more preferably 15.0 to 25.0% of inorganic filler.

[0088] Thus, in some embodiments, the shell coating composition comprises, by weight relative to the total dry weight of the shell coating composition:

[0089] - 2.0% to 5.0%, preferably 2.5% to 4.0% of triethyl citrate as a plasticizer,

[0090] - 40.0% to 82.0%, preferably 50.0% to 60.0% of polyvinyl acetate as a coating polymer,

[0091] - 10% to 30.0%, preferably 15% to 25.0% of polyvinylpyrrolidone as a pore former,

[0092] - 0.25% to 1.0% of sodium lauryl sulfate, and

[0093] - 5.0% to 30.0%, more preferably 15.0% to 25.0% of an inorganic filler.

[0094] The inorganic filler can act as a filler and / or as an opacifier. Any pharmaceutically acceptable inorganic filler known in the art can be formulated in the formulation of the present application, such as talc, calcium carbonate, calcium chloride, etc. In some embodiments, the inorganic filler is talc.

[0095] The binder of the shell coating or "coating polymer" is polyvinyl acetate ((PVAc), which exerts the coating properties of the shell coating. Polyvinylpyrrolidone ((PVP, also known as povidone) is also added as a pore former in the PVAc coating to ensure that the subject ingesting the present formulation effectively dissolves and absorbs probenecid. Without wishing to be bound by theory, the presence of PVAc and PVP in the ratios presently claimed not only ensures the protection of probenecid present in the core, but also ensures its timely release in the upper gastrointestinal tract where active absorption of probenecid occurs, thereby enhancing the therapeutic effect.

[0096] In some embodiments, the composition comprising PVAc, PVP and sodium lauryl sulfate is readily available on the market, such as Kollicoat® ® SR 30D, wherein the ratio of PVAc / PVP is approximately 10. However, in this case, in order to ensure the PVAc / PVP weight ratio of the present application, the use of an additional source of PVP, such as PVP K30 ® Alternatively, the shell coating composition of the present application is prepared by mixing different sources of PVAc, PVP and sodium lauryl sulfate, by utilizing any commercial source of these excipients, which is within the capabilities of a person skilled in the art.

[0097] Coating the immediate release (IR) core with the shell coating composition can be performed by any means known in the art, such as by the spray-drying method described below.

[0098] It is worth noting that the modified release core-shell formulation of the application exhibits sufficient stability over the shelf life. Optionally, the core-shell formulation as described herein can present an additional coating, herein referred to as "final coating", which coats the shell coating. Advantageously, the final coating can improve the stability of the formulation over time, in particular by ensuring moisture protection. In some embodiments, the final coating can represent from 2 to 20% by weight, preferably from 10 to 20% by weight, relative to the core-shell formulation. The final coating can be obtained by coating (e.g. by spray-drying) the core-shell formulation of the application comprising the shell coating with a "final coating composition".

[0099] The final coating composition can comprise:

[0100] - a composition comprising polyvinyl alcohol in combination with talc, titanium dioxide, capryol 820®, and sodium lauryl sulfate, such as the commercially available Opadry® ® AMB composition;

[0101] - a composition comprising a polyvinyl alcohol-polyethylene glycol graft copolymer in an amount typically from 55% to 65%, a polyvinyl alcohol in an amount typically from 35% to 45%, and a silicon dioxide in an amount typically from 0.1% to 0.3%, relative to the total weight of the final coating composition. An exemplary embodiment of such a final coating composition is the commercially available Kollicoat® ® Protect composition;

[0102] - a composition comprising hydroxypropyl methylcellulose and talc, such as the commercially available Opadry® ® 03A69 composition; or

[0103] - a mixture thereof.

[0104] Thus, the final coating can comprise:

[0105] - polyvinyl alcohol in combination with talc, titanium dioxide, capryol 820®, and sodium lauryl sulfate; or

[0106] - a polyvinyl alcohol-polyethylene glycol graft copolymer, a polyvinyl alcohol, and a silicon dioxide; or

[0107] - hydroxypropyl methylcellulose and talc; or

[0108] - a mixture thereof.

[0109] In some embodiments, the core-shell formulation of the present application can also comprise an outer layer of lubricant. The presence of an outer layer of lubricant facilitates handling of the formulation, in particular in terms of flowability and anti-static properties. The outer layer of lubricant can comprise one or more than one lubricant. The lubricant can be, for example, talc. In one embodiment, the outer layer of lubricant is present in an amount of 0.1% to 2% of the total weight of the core-shell formulation; preferably 0.2% to 1%, more preferably about 0.5%. In one embodiment, the outer layer of lubricant consists of talc and it is present in an amount of 0.1% to 2% of the total weight of the core-shell formulation; preferably 0.2% to 1%, more preferably about 0.5%.

[0110] Core

[0111] The core-shell formulation of the present application is based on a core comprising probenecid. In particular, the core comprises probenecid in combination with at least one pharmaceutically acceptable excipient.

[0112] Thus, the core is a formulation, according to any formulation within the range of understanding of the person skilled in the art, also referred to as a constant release formulation, comprising probenecid in an amount of 10% to 70%, 10% to 60%, 20% to 60% or 25% to 50% by weight relative to the total weight of the core. Such a core formulation can also be characterized herein as a constant release formulation of probenecid.

[0113] In some embodiments, the at least one pharmaceutically acceptable excipient is selected from cellulose, microcrystalline cellulose, cellulose derivatives, such as hydroxycellulose, hydroxypropyl cellulose or hydroxypropyl methyl cellulose, starch, modified starch, such as hydrolyzed starch, dextran, maltodextrin, sucrose, lactose, mannitol, sorbitol, maltitol, trehalose, calcium carbonate, magnesium carbonate, and silicon dioxide. In some embodiments, the at least one pharmaceutically acceptable excipient is selected from cellulose, microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, preferably microcrystalline cellulose.

[0114] In some embodiments, two variants can be considered for the core:

[0115] (i) a mixed core, wherein the mixed core is a mixture of probenecid and at least one pharmaceutically acceptable excipient; and

[0116] (ii) a coated inert core, wherein the coated inert core comprises particles of an inert core consisting of at least one pharmaceutically acceptable excipient, coated with a first coating layer comprising probenecid.

[0117] According to a first variant ("mixed core"), the core is a mixture of propulsid® and at least one pharmaceutically acceptable excipient. For example, propulsid® can be mixed with at least one pharmaceutically acceptable excipient, such as those excipients described herein, and then compressed into a core.

[0118] In some embodiments, the mixed core as described above has an average diameter of 1.5 mm to 12 mm, preferably 5 mm to 10 mm. In this case, the resulting core-shell formulation according to the application is in the form of a mini-tablet. The mixed core as described above has an average diameter of 1.5 mm to 7 mm, preferably about 5 mm, which is particularly suitable for children aged 2 to 6 years. Alternatively, the mixed core as described above has an average diameter of 7 mm to 12 mm, preferably about 10 mm, which is particularly suitable for children aged 6 to 12 years. The average diameter can be measured by sieving.

[0119] According to a second variant ("coated inert core"), the core is a particle of an inert core composed of at least one pharmaceutically acceptable excipient, such as those excipients described above, coated with a first coating comprising propulsid®. The first coating can be, for example, coated directly with propulsid®, i.e. the propulsid® compound is adsorbed or absorbed on the surface of the inert core. Alternatively, propulsid® can be mixed with at least one pharmaceutically acceptable excipient to form a coating composition (herein referred to as the first coating composition) to coat the inert core. In this case, the first coating comprises propulsid® and at least one pharmaceutically acceptable excipient.

[0120] In some embodiments, the inert core can consist of microspheres composed of at least one pharmaceutically acceptable excipient, as described above, having an average diameter of 100 pm to 5 mm, 100 pm to 2 mm, 100 pm to 1000 pm, preferably 100 pm to 800 pm, more preferably 180 pm to 800 pm, still more preferably 200 pm to 600 pm, for example 300 pm to 400 pm. In this case, the resulting core-shell formulation according to the application is in the form of a microgranule.

[0121] In one embodiment, the inert core consists of microcrystalline cellulose microspheres. Microcrystalline cellulose (MCC) is a natural polymer composed of glucose units linked by 1-4 beta glycosidic bonds. Preferably, the MCC microspheres have an average diameter of 100 pm to 800 pm, 300 pm to 400 pm, typically about 350 pm, for example Cellets® 200 M (Pharmacosmos) or Avicel® PH 101 (FMC Biopolymer). ® 350.

[0122] According to some exemplary embodiments, the core is a particle of an inert core composed of microcrystalline cellulose (MCC) coated with a first coating composition comprising propulsid®, thereby forming a coated core of MCC with the first coating composition.

[0123] In some embodiments, the first coating comprises, by weight relative to the total weight of the coated inert core:

[0124] - propulsulfone in an amount of 10% to 70%, preferably 20% to 50%, more preferably 30% to 50%, typically about 40%;

[0125] - a binder, in particular hydroxypropylcellulose, in an amount of 20% to 40%, preferably 25% to 35%, typically about 30%;

[0126] - a surfactant, for example polyoxyethylene (20) sorbitan monooleate, in an amount of 1% to 3%, preferably 1.5% to 2.5%, typically about 2.0%; and

[0127] - optionally an antifoaming agent, for example simethicone; preferably, when present, the antifoaming agent is in an amount of 0.02% to 0.2%, typically about 0.1%.

[0128] According to an alternative description of the first coating, the amounts of excipients can be expressed relative to the amount of the active pharmaceutical ingredient propulsulfone. Thus, the first coating can comprise, by weight relative to the total weight of the contained propulsulfone:

[0129] - a binder, in particular hydroxypropylcellulose, in an amount of 55% to 85%, preferably 60% to 80%, more preferably 70% to 80%, typically about 75%;

[0130] - a surfactant, for example polyoxyethylene (20) sorbitan monooleate, in an amount of 2% to 8%, preferably 3% to 6%, typically about 5%; and

[0131] - optionally an antifoaming agent, for example simethicone; preferably, when present, the antifoaming agent is in an amount of 0.05% to 0.5%, typically about 0.2%.

[0132] In some embodiments, in the first coating of the core, the binder is hydroxypropylcellulose (HPC). According to exemplary embodiments, HPC is chosen as the binder not only to achieve a high loading of the formulation particles with propulsulfone, but also to allow reproducible production of particles of the formulation with a reliable dose of propulsulfone, i.e. where the amount of propulsulfone in the first coating composition is quantitatively loaded on the MCC microspheres with no substantial loss of propulsulfone during the coating process.

[0133] Hydroxypropyl cellulose (HPC) is a non-ionic cellulose ether, typically used as a binder in pharmaceutical compositions. Typically, the glucose monomers are partially substituted with hydroxypropyl moieties at a molar substitution degree of 2.0 to 4.0. In some embodiments, the HPC exhibits a degree of hydroxypropyl substitution of more than 14%, more than 15%, or more than 20% relative to the total weight of the HPC composition. For example, the HPC used in the first composition coating can be Pharmacoat 606. ® 606.

[0134] According to some exemplary embodiments, the first coating further comprises a surfactant, which typically can act as a wetting agent, without wishing to be bound by theory, which facilitates the uniform dispersion of propyl sulfourea within the first coating composition and thereby achieving a uniform dispersion on the coated inert core, typically on the MCC microsphere. According to some embodiments, the surfactant is a non-ionic surfactant in an amount of 0.5% to 8% by weight, preferably 1% to 5% by weight, more preferably 1% to 3% by weight, still more preferably 1.5% to 2.5% by weight, typically about 2% by weight, relative to the total weight of the core. According to some specific embodiments, the surfactant is polyoxyethylene (20) sorbitan monooleate, also known as Tween 80 ® or sorbitan polyoleate 80.

[0135] The coating of the inert core, for example the MCC microsphere core, can be performed by any means known in the art, for example by the spray-drying method described below. In order to facilitate the coating step, the first coating composition can further comprise 0.02% to 0.2% by weight of an antifoaming agent, relative to the total weight of the coated core, or 0.05% to 0.5% by weight of an antifoaming agent, relative to the total weight of the propyl sulfourea comprised. According to some embodiments, the antifoaming agent is simethicone (CAS number 8050-81-5).

[0136] Preferably, the first coating composition is an aqueous composition, more preferably an aqueous solution or an aqueous suspension. In some embodiments, the first coating composition comprises 70% to 90% by weight, preferably about 80% by weight, of a carrier (for example water), relative to the total weight of the first coating composition.

[0137] The amount of coating or the percentage of coating can define the amount of propyl sulfourea added to the formulation. The amount or percentage of coating can be determined by any means known in the art, for example, by comparing the weight of the coated inert core obtained with the weight of the inert core used. In some embodiments, the first coating composition represents 50% to 90% by weight, preferably 50% to 80% by weight, more preferably 65% to 75% by weight, typically about 75% by weight, relative to the total weight of the coated core.

[0138] Optionally, the core or "constant release granule" described herein can present an additional coating, referred to herein as a sealing coating.

[0139] When it is present, the amount of sealing coating is sufficient to render the core of the application, i.e. the constant release formulation, impermeable. Advantageously, the sealing coating can limit the migration of propulsid in the formulation, if any. In some embodiments, the amount of sealing coating is comprised between 2% and 20% by weight, preferably between 10% and 20% by weight, relative to the total weight of the core, i.e. of the formulation of the core according to the first variant (mixed core) or of the coated inert core according to the second variant. The sealing coating can be obtained by coating the core with a "sealing coating composition", for example by spray-drying. In the case of a coated inert core, the sealing coating is applied on the first coating present on the inert core.

[0140] Illustratively, the sealing coating composition can comprise:

[0141] - a composition comprising polyvinyl alcohol in combination with talc, titanium dioxide, glyceryl mono-diglucocates and sodium lauryl sulfate, such as the commercially available Opadry® ® AMB composition;

[0142] - a composition comprising, in percentage by weight relative to the total weight of the final coating composition, a polyvinyl alcohol-polyethylene glycol graft copolymer in an amount generally comprised between 55% and 65%, a polyvinyl alcohol in an amount generally comprised between 35% and 45% and a silicon dioxide in an amount generally comprised between 0.1% and 0.3%. An illustrative embodiment of such a final coating composition is the commercially available Kollicoat® ® Protect composition;

[0143] - a composition comprising hydroxypropyl methylcellulose and talc, such as the commercially available Opadry® ® 03A69 composition; or

[0144] - a mixture thereof.

[0145] Thus, the sealing coating can comprise:

[0146] - polyvinyl alcohol in combination with talc, titanium dioxide, glyceryl mono-diglucocates and sodium lauryl sulfate; or

[0147] - a polyvinyl alcohol-polyethylene glycol graft copolymer, a polyvinyl alcohol and a silicon dioxide; or

[0148] - hydroxypropyl methylcellulose and talc; or

[0149] - a mixture thereof.

[0150] Hydroxypropyl methylcellulose (HPMC), also known as hypromellose, is a non-ionic cellulose ether, usually prepared by etherification of a cellulose fraction having the cellulose backbone structure of CAS number 9004-65-3, from natural cotton fibers, through a series of chemical treatments. It is a white powder, odorless, tasteless, non-toxic, which can be dissolved in cold water to form a transparent viscous solution with gelling and / or thickening properties. HPMC can generally introduce a methoxyl substituent at the hydroxyl portion of the cellulose backbone, in an amount of 15.0 wt% to 30.0 wt%, typically 19.0 wt% to 30.0 wt%, preferably 27.0 wt% to 30.0 wt% or 19.0 wt% to 27.0 wt%, relative to the total weight of the HPMC composition.

[0151] In some embodiments, as shown in Figure 3 The core-shell formulation of the application can be summarized, as shown in

[0152] - a core (1) comprising propenecid in an amount of 10 wt% to 70 wt% relative to the total weight of the core, in combination with at least one pharmaceutically acceptable excipient; wherein, according to a first variant of the application, the core can be a mixed core (1a), or according to a second variant of the application, the core can be an inert core (1b) coated with a first coating (1b2), for example according to the exemplary embodiments described above;

[0153] - optionally, the core can further comprise a seal coating (2) coating the core, or according to the second variant, the first coating of the inert core;

[0154] - a shell coating (3) as described above (also referred to as a second coating when the core comprises a first coating);

[0155] - optionally, a final coating (4) as described above; and

[0156] - optionally, an outer layer (5) of lubricant as described above.

[0157] Pharmaceutical compositions and uses

[0158] The present application also relates to a pharmaceutical composition comprising the immediate or modified release formulation of the application per se, or in combination with at least a pharmaceutically acceptable excipient, within the knowledge of the person skilled in the art, for example an excipient selected from at least one of a bulking agent, a taste or odor enhancer, and a flow-improving agent.

[0159] According to another aspect, the present application relates to the formulation or pharmaceutical composition of the present application for use as a medicament. The present application also relates to the use of the formulation or pharmaceutical composition of the present application for the manufacture of a medicament.

[0160] In some exemplary embodiments, the medicament is for the treatment of a disease selected from gout, hyperuricemia and epilepsy. According to some preferred embodiments, the medicament is for the treatment of epilepsy.

[0161] The present application also relates to the use of the formulation or pharmaceutical composition of the present application for the manufacture of a medicament for the treatment of a disease selected from gout, hyperuricemia and epilepsy.

[0162] The present application also relates to the use of the formulation or pharmaceutical composition of the present application for the manufacture of a medicament for the treatment of a disease selected from gout, hyperuricemia and epilepsy.

[0163] The present application also relates to a method for the treatment of a disease selected from gout, hyperuricemia and epilepsy, said method comprising administering to a subject in need thereof a therapeutically effective amount of the formulation or pharmaceutical composition of the present application.

[0164] As used herein, the term "subject" refers to an animal, preferably a warm-blooded animal, more preferably a mammal, and still more preferably a human. In one embodiment, the subject can be a mammal. Mammals include, but are not limited to, all primates (humans and other non-human primates), cows, horses, pigs, sheep, goats, dogs, and cats. In one embodiment, the subject is a human. In one embodiment, the subject is a patient, i.e., a subject awaiting, or undergoing, or having undergone, a medical procedure, or being monitored for the development of an epileptic disease, disorder or symptom. In one embodiment, the subject is an adult (e.g., a subject over 18 years of age). In another embodiment, the subject is a child (e.g., a subject under 18 years of age). In one embodiment, the subject is a male. In another embodiment, the subject is a female.

[0165] According to some embodiments, the subject can be a substantially healthy subject. In the context of epilepsy, a substantially healthy subject is a subject who has not been previously diagnosed or identified as having or suffering from an epileptic disease, disorder or symptom. In one embodiment, a substantially healthy subject does not exhibit an onset of an epileptic disease, disorder or symptom, i.e., the subject has not acquired, developed or first experienced a seizure.

[0166] As used herein, the term "treatment" or "therapy" or "relief" refers to therapeutic treatment and prophylactic or preventative measures; wherein the aim is to prevent or slow down (lessen) a target pathological condition or disorder, e.g., a seizure disease, disorder or condition. Those in need of treatment include those already with the disease, disorder or condition, as well as those prone to have the disease, disorder or condition, or those in whom the disease, disorder or condition is to be prevented. A subject is considered to have been successfully "treated" for a particular disease, disorder or condition, e.g., a seizure disease, disorder or condition, if, after receiving a therapeutic amount of probenecid according to the present application, the subject exhibits an observable and / or measurable reduction in one or more of the following: seizures, particularly clinical seizures (which can be completely absent); morbidity and mortality; improvements in quality of life issues. The above parameters for assessing successful treatment and improvement of a disease, disorder or condition can be readily measured by routine procedures familiar to a physician.

[0167] As used herein, the term "therapeutically effective amount" refers to an amount of an agent that, without causing significant negative or adverse side effects on the target, is effective for: (1) delaying or preventing the onset of a target disease, disorder or condition; (2) slowing down or stopping the progression, aggravation or worsening of one or more symptoms of a target disease, disorder or condition; (3) causing an improvement in a target disease, disorder or condition; (4) reducing the severity or incidence of a target disease, disorder or condition; or (5) curing a target disease, disorder or condition. A therapeutically effective amount can be administered prior to the onset of a target disease, disorder or condition for prophylactic effect. Alternatively or additionally, a therapeutically effective amount can be administered after the onset of a target disease, disorder or condition for therapeutic effect. Determination of a therapeutically effective amount can be made by a physician. For example, a therapeutically effective amount of probenecid for treating epilepsy in a pediatric subject can be 10 mg to 50 mg of probenecid per kilogram of the subject per day.

[0168] Methods

[0169] The present application also relates to a method for preparing the core-shell formulation of the present application.

[0170] According to some embodiments, the method comprises the following steps:

[0171] a) providing a core composition comprising propulsid in an amount of 10% to 70% by weight relative to the total weight of the core, in combination with at least one pharmaceutically acceptable excipient, as described above. Notably, the core can be either of the two variants of cores described above. According to a first variant (mixed core), the core is a mixture of propulsid and at least one pharmaceutically acceptable excipient. For example, propulsid can be mixed with at least one pharmaceutically acceptable excipient, such as those excipients described above, and then compressed into a core. According to a second variant (coated inert core), the core is a particle of an inert core composed of at least one pharmaceutically acceptable excipient, as described above, coated with a first coating composition comprising or consisting of propulsid;

[0172] b) coating the core with a shell coating composition comprising triethyl citrate, inorganic filler, polyvinyl acetate, polyvinylpyrrolidone and sodium lauryl sulfate, wherein the weight ratio of polyvinyl acetate to polyvinylpyrrolidone is 1.5 to 4, to obtain a core-shell formulation (i.e. a shell-coated core).

[0173] The coating step b) can be performed by any means within the understanding of the person skilled in the art. For example, the core can be coated by spray-drying, for example spray-drying performed on a fluidized bed machine.

[0174] The core-shell formulation can be recovered after the coating step b).

[0175] Alternatively, the method can further comprise a step c):

[0176] c) optionally, coating the formulation of step b) with a final coating, as described above, to obtain a finally coated core.

[0177] Optionally, the method can further comprise a step d) in which the coated core obtained in step b) or step c) can be subjected to a solidification step comprising heating the coated core at a temperature of 35°C to 45°C, preferably about 40°C, for 30 minutes to 2 hours, preferably about 1 hour.

[0178] The solidification step d) advantageously allows fixing the coating by drying its constituents, thereby increasing the stability of the formulation. The solidification step also allows limiting the amount of water in the formulation over time.

[0179] According to some optional embodiments, the core-shell formulation of the application can thus be obtained in any of the steps b), c) or d).

[0180] The process can also comprise an optional final step to form an outer layer of lubricant, as described above, comprising contacting the core-shell formulation obtained in any one of steps b), step c) or step d) with a lubricant, thereby forming an outer layer of lubricant on the core-shell formulation.

[0181] As described above, the core is a formulation, according to any formulation within the understanding of the person skilled in the art, comprising propulsid in an amount of 10% to 70% by weight relative to the total weight of the core, as described above. When referring to the second variant of the application (coated inert core), step a) can also be exemplarily described as comprising:

[0182] a1) providing a composition of an inert core consisting of at least one pharmaceutically acceptable excipient, such as a MCC inert core, preferably a MCC microsphere;

[0183] a2) coating the inert core with a first coating composition, preferably by spray-drying coating, thereby obtaining a coated inert core, wherein the first coating composition comprises, by weight relative to the total weight of the coated inert core:

[0184] - 10% w / w to 70% w / w of propulsid;

[0185] - 20% w / w to 40% w / w of hydroxypropyl cellulose;

[0186] - 1% w / w to 3% w / w of surfactant; and

[0187] - optionally an antifoam agent;

[0188] a3) optionally, further coating the coated inert core of step a2) with a sealing coating composition, as described above, preferably by spray-drying coating, thereby obtaining a sealing coated inert core;

[0189] a4) recovering the core obtained in step a2) or in step a3). BRIEF DESCRIPTION OF DRAWINGS

[0190] Figure 1 is a graph showing the dissolution profile of propulsid from the core-shell formulation "MR2", "cured MR2", "cured MR2 with lubricant" and "cured MR2 with sealing coating" in pH 6.8 buffer compared to the immediate release formulation IR.

[0191] Figure 2 is a graph showing the in vivo propulsid exposure level (plasma concentration in ng / mL) as a function of time (h) after administration of the MR2 formulation according to the application.

[0192] Figure 3A schematic representation of a core-shell formulation according to the present application is provided with the relative position of the coating Figure 3 A), as well as two variants of the core Figure 3 B) are provided.

[0193] Examples

[0194] The present application is also illustrated by the following examples.

[0195] Example 1 : Preparation of an exemplary immediate release core ("coated inert core")

[0196] Materials and methods

[0197] An immediate release (IR) core or “coated inert core” was prepared according to Table 1. The amounts are provided in weight relative to the total weight of the resulting coated core.

[0198] Table 1: Exemplary IR core of propulsulfone

[0199]

[0200] Ingredients B-E were suspended in water by mixing with Ultraturrax® to provide a first coating composition which is an aqueous composition. Preferably, ingredients B-E represent about 17% by weight relative to the total weight of the aqueous first coating composition.

[0201] Subsequently, the coated inert core of microcrystalline cellulose “IR” was obtained by fluid bed spray drying coating of the inert core using the above described aqueous first coating composition comprising ingredients B-E with a fluid bed coater Glatt GPCG1 in bottom spray configuration.

[0202] A sample of the obtained coated inert core “IR” was further coated with a seal coating to obtain a seal coated inert core “seal coated IR”. The seal coating composition was a commercially available Kollicoat® Protect composition comprising a polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol, and silicon dioxide. The seal coating represented 10% by weight relative to the total weight of the resulting core.

[0203] Then, the in vitro dissolution of propulsulfone (API) of the obtained immediate release formulation was determined according to European Pharmacopoeia 2.9.3 (01 / 2023:20903) in a pH 6.8 buffer with a paddle rotating at 50 rotations per minute.

[0204] Results

[0205] The amount of agglomerates of the immediate release formulation was not significant and had a satisfactory yield of 89.1%.

[0206] As Figure 1The immediate release formulation "IR" is shown to release at least 80% of probenecid in the dissolution medium within about 2.5 hours, more particularly, over 95% within 30 minutes.

[0207] Example 2: Preparation of a modified release core shell formulation according to the present application

[0208] Materials and methods

[0209] The immediate release coated cores of example 1 ("IR" and "sealed coated IR") were used as cores for the preparation of core-shell formulations according to the present application.

[0210] Two modified release core-shell formulations ("MR1" and "MR2") were prepared using the coated inert cores of example 1 "IR" according to the compositions of table 2 below.

[0211] The immediate release coated cores of example 1 ("IR" and "sealed coated IR") were used as cores for the preparation of core-shell formulations according to the present application.

[0212] Table 2: Modified release formulations MR1 and MR2 according to the present application.

[0213]

[0214] Kollicoat® SR30D is a commercially available coating mixture of an aqueous dispersion of polyvinyl acetate (PVAc: 27%), sodium dodecyl sulfate (0.3%), and inherently contains PVP (indicated as PVP in the table above k 2.7%). Thus, the dry extract of Kollicoat SR30D, e.g. after spray drying, comprises about 90% PVAc, about 9% PVP k and about 10% sodium dodecyl sulfate. The total PVP in the MR formulations is composed of the sum of the exogenously added PVP and the PVP contained in the Kollicoat® mixture. k

[0215] A sample of the obtained "MR2" formulation was further subjected to a solidification step, i.e. heating at a temperature of about 40°C for 1 to 2 hours, resulting in a solidified formulation "solidified MR2".

[0216] A sample of the obtained "solidified MR2" formulation was further formed into an outer layer of talc as lubricant, resulting in the formulation "solidified MR2 with lubricant". For this formulation, the solidified formulation "solidified MR2" was mixed with talc. The resulting formulation comprises about 0.5% talc by weight relative to the total weight of the formulation. ​

[0217] Another core-shell formulation "MR2 with a sealing coating and cured" was prepared according to the same method as "cured MR2", but starting from the sealing coated inert core of Example 1 "sealed IR".

[0218] The resulting modified release formulation was then subjected to in vitro dissolution of propulsid (API) according to European Pharmacopoeia 2.9.3 (01 / 2023:20903) in pH 6.8 buffer using a paddle at a speed of 50 rotations per minute.

[0219] Results

[0220] The modified release core-shell formulation presented a uniform shell coating and the dissolution profile was as follows:

[0221] - MR1 : propulsid reached 80% dissolution in 20 hours of dissolution test;

[0222] - MR2: propulsid reached 80% dissolution in 7 hours and more than 90% dissolution in 9 hours.

[0223] The dissolution profiles of "MR2", "cured MR2", "cured MR2 with a lubricant" and "MR2 with a sealing coating and cured" were plotted in Figure 1 Figure 2 together with the dissolution profile of the immediate release (IR) core of Example 1 "IR". The core-shell formulations of the application significantly delayed the release of propulsid compared to the immediate release formulation.

[0224] Example 3: In vivo release of probenecid using a formulation according to the present application

[0225] The formulations IR (of Example 1) and MR2 (of Example 2) were orally administered to minipigs (2 g of propulsid per minipig) during a single administration and divided into two groups of subjects (IR and MR2) in a cross-over study.

[0226] The pharmacokinetic properties of the IR formulation focused on the dose of unbound propulsid in plasma responsible for the biological effect are listed in Table 3 and the pharmacokinetic properties of the core-shell formulation MR2 according to the application are listed in Table 4.

[0227] Table 3. Pharmacokinetic parameters of unbound propulsid in plasma samples of minipigs - IR group

[0228]

[0229] Table 4. Pharmacokinetic parameters of unbound propulsid in plasma samples of minipigs - MR2 group

[0230]

[0231] Interestingly, the formulation MR2 according to the present application increased the half-life (t 1 / 2 ) of unbound probenecid by 2.3 fold. Notably, the unbound form of probenecid is the form that binds the pharmacological target and exerts its pharmacological effect.

[0232] More interestingly, the formulation increased the mean residence time (MRT) by 1.7 fold, thus, when translating the pharmacokinetic evidence in minipigs to humans, twice daily administration of the formulation would provide a therapeutically effective amount of probenecid in plasma. Indeed, as Figure 2 shown, the exposure level reached with the MR2 formulation according to the present application is sufficient for a subject to be treated with a maximum of twice daily intake of a formulation according to the present application.

Claims

1. A core-shell formulation comprising: - A core comprising 10% to 70% by weight of probenecid relative to the total weight of the core, the probenecid being combined with at least one pharmaceutically acceptable excipient; and - A shell coating comprising triethyl citrate, an inorganic filler, polyvinyl acetate, polyvinylpyrrolidone, and sodium dodecyl sulfate, wherein the weight ratio of polyvinyl acetate to polyvinylpyrrolidone is 1.5 to 4.

2. The formulation according to claim 1, comprising, by weight relative to the total weight of the core-shell formulation: - 0.4% to 1.0%, preferably 0.5% to 0.8% of triethyl citrate, - 8.0% to 16%, preferably 10% to 12% polyvinyl acetate, - 2.0% to 6.0%, preferably 3.0% to 4.5% of polyvinylpyrrolidone, - 0.05% to 0.2% sodium dodecyl sulfate, and - 1.0% to 6.0%, preferably 3.0% to 5.0% of inorganic filler, wherein the inorganic filler is preferably talc.

3. The formulation according to claim 1 or claim 2, wherein the shell coating accounts for 2% to 30% of the total weight of the core-shell formulation.

4. The formulation according to any one of claims 1 to 3, wherein the core is: (i) a mixed core, wherein the mixed core is a mixture of probenecid and at least one pharmaceutically acceptable excipient; or (ii) A coated inert core, wherein the coated inert core comprises particles of an inert core consisting of at least one pharmaceutically acceptable excipient, coated with a first coating comprising probenecid.

5. The formulation according to any one of claims 1 to 4, wherein the at least one pharmaceutically acceptable excipient is selected from cellulose, microcrystalline cellulose, cellulose derivatives, starch, modified starch, dextran, maltodextrin, sucrose, lactose, mannitol, sorbitol, maltitol, trehalose, calcium carbonate, magnesium carbonate, and silicon dioxide; preferably, the at least one pharmaceutically acceptable excipient is microcrystalline cellulose.

6. The formulation according to any one of claims 4 or 5, wherein the core is a coated inert core, and wherein, by weight relative to the total weight of the coated inert core, the first coating comprises: - Probenecid from 10% w / w to 70% w / w; - 20% w / w to 40% w / w hydroxypropyl cellulose; - Surfactants ranging from 1% w / w to 3% w / w; and - Optional defoamer.

7. The formulation according to claim 6, wherein the surfactant is a nonionic surfactant; preferably, the surfactant is polyoxyethylene (20) sorbitan monooleate.

8. The formulation according to any one of claims 4 to 7, wherein the first coating accounts for 50% to 80% by weight of the total weight of the coated inert core.

9. The formulation according to any one of claims 4 to 8, wherein the inert core is composed of microspheres consisting of at least one pharmaceutically acceptable excipient having an average diameter of 100 µm to 5 mm; preferably, the inert core is composed of microcrystalline cellulose microspheres having an average diameter of 100 µm to 800 µm; more preferably, 300 µm to 400 µm, wherein the average diameter is determined by sieving.

10. The formulation according to any one of claims 1 to 9, wherein the core further comprises a sealing coating in an amount of 2% to 20% by weight relative to the total weight of the core, the sealing coating comprising: - Polyvinyl alcohol, in combination with talc, titanium dioxide, glyceryl mono- and di-caprylate, and sodium lauryl sulfate; - Polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol, and silicon dioxide; - Hydroxypropyl methylcellulose and talc; or - Its mixture.

11. The formulation according to any one of claims 1 to 10, further comprising a final coating in an amount of 2% to 20% by weight relative to the total weight of the core-shell formulation, said final coating comprising: - Polyvinyl alcohol, in combination with talc, titanium dioxide, glyceryl mono- and di-caprylate, and sodium lauryl sulfate; - Polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol, and silicon dioxide; - Hydroxypropyl methylcellulose and talc; or - Its mixture.

12. The formulation according to any one of claims 1 to 11, further comprising an outer layer of lubricant; preferably, the lubricant is talc.

13. A formulation according to any one of claims 1 to 12, which is used as a medicine.

14. A formulation according to any one of claims 1 to 12, for the treatment of epilepsy.

15. A method for preparing a core-shell formulation according to any one of claims 1 to 12, comprising the following steps: a) Provide a core comprising a probenecid amounting to 10% to 70% by weight relative to the total weight of the core, the probenecid being combined with at least one pharmaceutically acceptable excipient; b) Coating the core of step a) with a shell coating composition, preferably by spray drying, to obtain a shell-coated core; the shell coating composition comprises triethyl citrate, inorganic filler, polyvinyl acetate, polyvinylpyrrolidone and sodium dodecyl sulfate, wherein the weight ratio of polyvinyl acetate to polyvinylpyrrolidone is 1.5 to 4. c) Optionally, the shell-coated core of step b) is further coated with a final coating composition, preferably by spray drying, to obtain a finally coated core; The final coating composition comprises polyvinyl alcohol, in combination with talc, titanium dioxide, glyceryl mono- and di-caprylate, and sodium dodecyl sulfate; polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol, and silica; hydroxypropyl methylcellulose and talc; or mixtures thereof; d) Optionally, the coated core of step b) or c) is subjected to a curing step, which includes heating the coated core at a temperature of 35°C to 45°C, preferably about 40°C, for 30 minutes to 2 hours, preferably about 1 hour. e) Recover the core-shell formulation obtained in any of steps b), c), or d); and f) Optionally, the formulation of step e) is brought into contact with a lubricant to form an outer layer of lubricant on the core-shell formulation.

16. The method of claim 15, wherein step a) comprises: a1) Provide an inert core, said inert core being composed of at least one pharmaceutically acceptable excipient; preferably said inert core is microcrystalline cellulose microspheres; a2) Coating the inert core with a first coating composition, preferably by spray drying, to obtain a coated inert core, wherein the first coating composition comprises, by weight relative to the total weight of the coated inert core: - Probenecid from 10% w / w to 70% w / w; - 20% w / w to 40% w / w hydroxypropyl cellulose; - Surfactants ranging from 1% w / w to 3% w / w; as well as - Optional defoamer; a3) Optionally, the coated inert core of step a2) is further coated with a sealing coating composition, preferably by spray drying, to obtain a sealed inert core; said sealing coating composition comprising polyvinyl alcohol, said polyvinyl alcohol combined with talc, titanium dioxide, glyceryl mono- and di-caprylate, and sodium dodecyl sulfate; polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol, and silica; hydroxypropyl methylcellulose and talc; or mixtures thereof; and a4) Recover the nuclei obtained in step a2) or step a3).

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