Probenecid formulations

Abstract

The present invention relates to a core-shell formulation presenting a core, said core comprising probenecid in an amount ranging from 10% to 70% in weight relative to the total weight of the core, in association with at least one pharmaceutically acceptable excipient; wherein the core is coated with a shell coating comprising triethyl citrate, a mineral charge, polyvinyl acetate, polyvinylpyrrolidone and sodium lauryl sulfate, wherein the weight ratio of polyvinyl acetate on polyvinylpyrrolidone ranges from 1.5 to 4.

Description

PROBENECID FORMULATIONSFIELD OF INVENTION

[0001] The present invention relates to modified release pharmaceutical formulations of probenecid and in particular pediatric probenecid formulations. The invention further relates to such formulations for their use in the treatment of epilepsy.BACKGROUND OF INVENTION

[0002] Probenecid is a benzoic acid derivative with an excellent safety profile that was developed in the 1950's to decrease the renal tubular excretion of penicillin; and has been used to increase the serum concentration of several antibiotics and antivirals. During the initial studies using probenecid (referred to as Benemid), probenecid was observed to have a strong uricosuric effect and quickly became the standard of treatment of gout. It was found to decrease uric acid levels in the serum and increase serum concentration of several organic acid compound by acting as a competitive inhibitor of the organic anion transporters (OATs) and especially the URAT 1 (member of the OAT family) and thus preventing URAT 1 -mediated reuptake of uric acid from the urine to the serum. Even though probenecid has a minimal adverse effect profile, it was formulated as large tablets, and its pharmacokinetic prolife required taking 4 doses per day to maintain a pharmacological effect. Therefore, its clinical use has declined significantly as other therapies for gout were developed with dosage forms enabling a better compliance.

[0003] As disclosed in the international application W02019 / 012109, probenecid is also suitable for treating epilepsy, among other neurological diseases, in a subject in need thereof, such as for example in pediatric subjects.

[0004] Considering that the half-life of probenecid is limited and dose-dependent, based on the currently available probenecid formulations, treating epilepsy would necessitatethe administration of 4 intakes per day. Furthermore, probenecid is a highly lipophile molecule. Thus, there is a need to supply a high-charge probenecid formulation that is suitable for the probenecid’s physicochemical properties and that shall ensure the patients’ compliance by limiting the number of intakes per day to up to one or two intakes per day.

[0005] Furthermore, given the specificities of the pediatric subjects, and in particular the limited volume of excipients to be administered, the high charge probenecid formulation needs to enable the minimal possible amount of excipients. In addition, pediatric formulations need to be easy to ingest, and advantageously compatible with food or drink compositions, in order to ensure the pediatric patients’ compliance.

[0006] In addition, probenecid formulations need to be compliant with good manufacturing processes, present sufficient stability during shelf-life and present a good reproducibility among the produced batches.

[0007] The present invention addresses the above needs by supplying a modified release formulation of probenecid as disclosed herein. In particular the present formulation can present up to 50% w / w probenecid charge, despite the highly lipophile profile of probenecid, as well as a prolonged liberation of probenecid, thereby limiting the number of medication intakes to up to one or twice a day. Advantageously, this can be achieved by enabling a quantitatively and qualitatively limited amount of excipients. More advantageously, the formulation is compatible with food ingredients and can be dispersed into food or drink compositions in order to ensure the subject’s, in particular the pediatric subject’s, compliance. Furthermore, the liberation of probenecid is compliant to the therapeutic purposes of epilepsy treatment and the manufacturing process of the present formulations allows a reproducible quality profile among the produced batches that present a sufficient shelf-life stability.SUMMARY

[0008] The present invention relates to a core-shell formulation comprising: a core, said core comprising probenecid in an amount ranging from 10% to 70% in weight relative to the total weight of the core, in association with at least one pharmaceutically acceptable excipient; and a shell coating comprising triethyl citrate, a mineral charge, polyvinyl acetate, polyvinylpyrrolidone and sodium lauryl sulfate, wherein the weight ratio of polyvinyl acetate on polyvinylpyrrolidone ranges from 1.5 to 4.

[0009] In some embodiments, the core- shell formulation comprises in weight relative to the total weight of the core- shell formulation: from 0.4% to 1.0%, preferably from 0.5% to 0.8%, of triethyl citrate, from 8.0% to 16%, preferably from 10% to 12%, of polyvinyl acetate, from 2.0% to 6.0%, preferably from 3.0% to 4.5%, polyvinylpyrrolidone, from 0.05% to 0.2% of sodium lauryl sulfate, and from 1.0% to 6.0%, preferably from 3.0% to 5.0%, of a mineral charge, wherein the mineral charge is preferably talc.

[0010] The shell coating may represent from 2% to 30%, preferably from 10% to 30%, more preferably from 15% to 25%, typically about 20% in weight relative to the total weight of the core-shell formulation.

[0011] The core may be a mixed core, wherein said mixed core is a mixture of probenecid with the least one pharmaceutically acceptable excipient. Alternatively, the core may be a coated inert core, wherein said coated inert core comprises a particle of an inert core consisting of at least one pharmaceutically acceptable excipient, that is coated with a first coating comprising probenecid.

[0012] 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 silica; preferably the at least one pharmaceutically acceptable excipient is microcrystalline cellulose.

[0013] According to some embodiments, where the core is a coated inert core, the first coating may comprise, in weight relative to the total weight of the coated inert core: from 10% to 70% w / w of probenecid; from 20% to 40% w / w of hydroxypropylcellulose; from 1% to 3% w / w of a surfactant; and optionally an anti-foaming agent.

[0014] According to some indicative embodiments, the surfactant is a non-ionic surfactant, preferably the surfactant is polyoxyethylene (20) sorbitan monooleate.

[0015] According to some embodiments, the first coating may represent from 50% to 80% in weight relative to the total weight of the coated inert core.

[0016] Furthermore, such inert core may consist of microspheres consisting of at least one pharmaceutically acceptable excipient as described above that may present an average diameter ranging from 100 pm to 5 mm. According to some embodiments, the inert core consists of microcrystalline cellulose microspheres presenting an average diameter ranging from 100 pm to 800 pm, more preferably from 300 pm to 400 pm, the average diameter being determined with the sieving method.

[0017] Optionally, the core may further comprise a seal-coating in an amount ranging from 2% to 20% in weight relative to the total weight of the core , said seal-coating comprising: polyvinyl alcohol in association with talc, titanium dioxide, glyceryl mono and dicaprylocaprate, and sodium lauryl sulfate; polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol, and silicone dioxide; hydroxypropylmethylcellulose (hypromellose) and talc; or a mixture thereof.

[0018] The formulation may optionally further comprise a final coating in an amount ranging from 2% to 20% in weight relative to the total weight of the core-shell formulation. For instance, such final coating may comprise: polyvinyl alcohol in association with talc, titanium dioxide, glyceryl mono and dicaprylocaprate, and sodium lauryl sulfate; polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol, and silicone dioxide; hydroxypropylmethylcellulose (hypromellose) and talc; or a mixture thereof.

[0019] The formulation may also optionally further comprise an outer layer of lubricant; preferably the lubricant is talc.

[0020] According to a further aspect, the invention relates to the formulation according to the invention for use as a drug. According to a specific embodiment, the formulation may be for use in the treatment of epilepsy.

[0021] Lastly, the invention relates to a process for preparing the core-shell formulation to the invention, comprising the steps of: a) supplying cores, said cores comprising probenecid in an amount ranging from 10% to 70% in weight relative to the total weight of the cores, in association with at least one pharmaceutically acceptable excipient; b) coating the cores of step a), preferably by spray drying, with a shell coating composition, thereby leading to shell-coated cores; said shell coating composition comprising triethyl citrate, a mineral charge, polyvinyl acetate, polyvinylpyrrolidone and sodium lauryl sulfate, wherein the weight ratio of polyvinyl acetate on polyvinylpyrrolidone ranges from 1.5 to 4,; c) optionally further coating the shell-coated cores of step b), preferably by spray drying, with a final coating composition, thereby leading to final-coated cores; said final coating composition comprising polyvinyl alcohol in association with talc, titanium dioxide, glyceryl mono and dicaprylocaprate, and sodium lauryl sulfate;polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol, and silicone dioxide; hypromellose and talc; or a mixture thereof; d) optionally, subjecting the coated cores of step b) or step c) to a curing step, comprising heating the coated cores at a temperature ranging from 35°C to 45°C, preferably about 40°C, for a period of time ranging from 30 minutes to 2 hours, preferably about 1 hour; e) recovering the core-shell formulation obtained in any one of steps b), c) or d); and f) optionally contacting the formulation of step e) with a lubricant, thereby leading to the formation of an outer layer of lubricant on the core-shell formulation.

[0022] According to the variant where the cores are coated inert cores, step a) may comprise: al) supplying inert cores, said inert cores consisting of at least one pharmaceutically acceptable excipient; preferably the inert cores are microcrystalline cellulose microspheres; a2) coating the inert cores, preferably by spray drying, with a first coating composition, thereby leading to coated inert cores, said first coating composition comprising, in weight relative to the total weight of the coated inert cores:- from 10% to 70% w / w of probenecid;- from 20% to 40% w / w of hydroxypropylcellulose;- from 1% to 3% w / w of a surfactant; and- optionally an anti-foaming agent; a3) optionally, further coating the coated inert cores of step a2), preferably by spray drying, with a seal coating composition , thereby leading to seal-coated inert cores; said seal-coating composition comprising polyvinyl alcohol in association with talc, titanium dioxide, glyceryl mono and dicaprylocaprate, and sodium lauryl sulfate; polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol, and silicone dioxide; hypromellose and talc; or a mixture thereof; and a4) recovering the cores obtained in step a2) or in step a3).DETAILED DESCRIPTION

[0023] This invention relates to modified release (MR) formulations of probenecid that present a high charge of such active pharmaceutical ingredient, that present a sufficient stability during shelf-life, and that are particularly suitable for pediatric subjects.

[0024] Especially, the invention relates to modified release (MR) formulations of probenecid based on immediate release (IR) formulations of probenecid that are coated with a shell coating composition enabling to modify the release of probenecid.Modified release (MR) formulation

[0025] The invention thus relates to a core-shell formulation of probenecid comprising: a core, said core comprising probenecid and at least one pharmaceutically acceptable excipient; and a shell coating, said shell coating being able to prolong and / or delay the release of probenecid compared to an immediate release formulation.

[0026] The core-shell formulation according to the invention is preferably a core-shell particulate formulation. In some embodiments, the formulation of the invention is under the form of granules, especially microgranules. In other embodiments, the formulation of the invention is under the form of tablets, especially microtablets. The forms microgranules or microtablets depend on the core used to manufacture the formulation according to the invention, as detailed hereafter.

[0027] The invention thus relates to a core-shell probenecid formulation, wherein the core is a formulation that comprises probenecid in an amount ranging from 10% to 70% in weight relative to the total weight of the core, in association with at least one pharmaceutically acceptable excipient; said core being coated with a coating composition (herein referred to as “shell coating composition” or “second coating composition”) as described herein below, leading to a shell coating. The coating of the core with the shell coating composition can be carried out by for example by spray drying.

[0028] The second or shell coating composition comprises triethyl citrate, a mineral charge, polyvinyl acetate, polyvinylpyrrolidone and sodium lauryl sulfate, wherein the weight ratio of polyvinyl acetate on polyvinylpyrrolidone ranges from1.5 to 4, preferably from 2.5 to 3.5. In some embodiments, the weight ratio of polyvinyl acetate on polyvinylpyrrolidone ranges from 3.0 to 3.5, typically about 3.3. In some other embodiments, the weight ratio of polyvinyl acetate on polyvinylpyrrolidone ranges from2.5 to less than 3.0, or preferably is about 2.6. In the context of the present invention, “about” preceding a figure means plus or less 10%, typically plus or less 5% of the value of said figure.

[0029] 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 from 70% to 90%, preferably about 80%, of vehicle (e.g. water), in weight relative to the total weight of the shell coating composition.

[0030] Once coated on the core, the shell coating composition forms a “shell coating”. The shell coating is advantageously in an amount sufficient to modulate the liberation of probenecid. As for the shell coating composition, the shell coating comprises triethyl citrate, a mineral charge, polyvinyl acetate, polyvinylpyrrolidone and sodium lauryl sulfate, wherein the weight ratio of polyvinyl acetate (PVAc) on polyvinylpyrrolidone (PVP) ranges from 1.5 to 4. Above embodiments relative to the weight ratio of PVAc on PVP in the shell coating composition also apply similarly to the shell coating.

[0031] Probenecid refers to the active pharmaceutical ingredient compound having the CAS number 57-66-9 and presenting the structure of formula (I):

[0032] Probenecid encompasses free -base probenecid (sometimes also referred to as 4-(dipropylsulfamoyl)benzoic acid, 4- [(dipropylamino) sulfonyl] -benzoic acid or PBN), as well as pharmaceutically acceptable salts thereof (4-(dipropylsulfamoyl)benzoate saltsor 4-[(dipropylamino)sulfonyl]-benzoate salts). Also encompassed are prodrugs, isomers, and polymorphs of probenecid. Probenecid can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Probenecid may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

[0033] 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 determined by the sieve method. Alternatively, the probenecid is in the form of particles, typically crystals, wherein according to the laser diffraction method, the d(0,9) is about 150 pm.

[0034] According to some other embodiments, the probenecid particles may present a d(0,9) of less than 40 pm according to the laser diffraction method, that can be herein characterized as micronized probenecid. For instance, the probenecid particles may present a d(0,9) of 21 pm, a d(0,5) of 8 pm and a d(0,l) of 2,2 pm according to the laser diffraction method.

[0035] The invention thus relates to a core-shell formulation comprising: a core, said core comprising probenecid in an amount ranging from 10% to 70% in weight relative to the total weight of the core, in association with at least one pharmaceutically acceptable excipient; and a shell coating, said shell coating comprising triethyl citrate, a mineral charge, polyvinyl acetate, polyvinylpyrrolidone and sodium lauryl sulfate, wherein the weight ratio of polyvinyl acetate on polyvinylpyrrolidone ranges from 1.5 to 4.

[0036] In some embodiments, the shell coating represents from 2% to 30%, preferably from 10% to 30%, more preferably from 15% to 25%, typically about 20% in weight relative to the total weight of the core-shell formulation.

[0037] In some embodiments, the core- shell formulation of the invention comprises in weight relative to the total weight of the core- shell formulation: from 0.4% to 1.0%, preferably from 0.5% to 0.8%, of triethyl citrate, from 8.0% to 16%, preferably from 10% to 12%, of polyvinyl acetate, from 2.0% to 6.0%, preferably from 3.0% to 5.0%, of polyvinylpyrrolidone, from 0.05% to 0.2% of sodium lauryl sulfate, and from 1.0% to 6.0%, preferably from 3.0% to 5.0%, of a mineral charge.

[0038] In some embodiments, the shell coating comprises in weight relative to the total weight of the shell coating: from 2.0% to 5.0%, preferably from 2.5% to 4.0% of triethyl citrate as a plasticizer, from 40.0% to 82.0%, preferably from 50.0% to 60.0% of polyvinyl acetate as a coating polymer, from 10% to 30.0%, preferably from 15% to 25.0% of polyvinylpyrrolidone as a pore-forming agent, from 0.25% to 1.0 %, of sodium lauryl sulfate, and from 5.0% to 30.0%, more preferably from 15.0% to 25.0% of a mineral charge.

[0039] Accordingly, in some embodiments, the shell coating composition comprises in weight relative to the total dry weight of the shell coating composition: from 2.0% to 5.0%, preferably from 2.5% to 4.0% of triethyl citrate as a plasticizer, from 40.0% to 82.0%, preferably from 50.0% to 60.0% of polyvinyl acetate as a coating polymer, from 10% to 30.0%, preferably from 15% to 25.0% of polyvinylpyrrolidone as a pore-forming agent, from 0.25% to 1.0 %, of sodium lauryl sulfate, and from 5.0% to 30.0%, more preferably from 15.0% to 25.0% of a mineral charge.

[0040] The mineral charge can act as a filler and / or as an opacifying agent. Any mineral charge known in the art that is can be pharmaceutically acceptable can be formulated in the present formulation such as for example talc, calcium carbonate, calcium chloride etc. In some embodiments, the mineral charge is talc.

[0041] The binder, or “coating polymer” of the shell coating is polyvinyl acetate (PVAc), exerting the coating function of the shell coating. Polyvinylpyrrolidone (PVP, also known as povidone), acting as a pore-forming agent in the PVAc coating layer is also added in order to ensure an efficient probenecid dissolution and absorption by the subject that ingests the present formulation. Without willing to be bound by a theory, the presence of PVAc and PVP in the presently claimed ratios ensures not only the protection of the probenecid that is present in the core, but also ensures its timely release in the upper gastrointestinal tract where the active absorption of probenecid takes place thereby enhancing the treatment efficacy.

[0042] In some embodiments, compositions comprising PVAc, PVP and sodium lauryl sulfate are readily available in the market, such as for example Kollicoat ® SR 30 D, wherein the PVAc / PVP ratio is about 10. However, in that case, in order to ensure the PVAc / PVP weight ratio of the invention, an additional source of PVP needs to be used, such as for example PVP K30®. Alternatively, it is in the purview of the skilled artisan to prepare the shell coating composition of the invention by mixing separate sources of PVAc, PVP and sodium lauryl sulfate by enabling any commercial source of such excipients.

[0043] The coating of the immediate release (IR) cores with the shell coating composition may be carried out by any means known in the art such as for example by a spray-drying process as described herein below.

[0044] It is of note that the present modified release core- shell formulations present a sufficient stability during shelf-life. Optionally, the core-shell formulations as herein described may present an additional coating, herein designated as “final coating”, that coats the shell coating. Advantageously, the final coating may improve the stability of the formulation overtime, especially by ensuring a protection to moisture. In some embodiments, the final coating may be present in an amount ranging from 2% to 20%, preferably from 10% to 20% in weight relative to the core-shell formulation. The final coating can be obtained by coating (for example by spray drying) the core-shellformulation of the invention comprising a shell coating, using a “final coating composition”.

[0045] The final coating composition may comprise: a composition comprising polyvinyl alcohol in association with talc, titanium dioxide, glyceryl mono and dicaprylocaprate and sodium lauryl sulfate, such as for example the commercially available Opadry® AMB composition; a composition comprising polyvinyl alcohol-polyethylene glycol graft copolymer, typically in an amount ranging from 55% to 65%, polyvinyl alcohol, typically in an amount ranging from 35% to 45%, and silicon dioxide, typically in an amount ranging from 0.1% to 0.3%, the percentages being in weight relative to the total weight of the final coating composition. An exemplary embodiment of such final coating composition is the commercially available Kollicoat® Protect composition; a composition comprising hypromellose and talc, such as for example the commercially available Opadry® 03A69 composition; or a mixture thereof.

[0046] Accordingly, the final coating may comprise: polyvinyl alcohol in association with talc, titanium dioxide, glyceryl mono and dicaprylocaprate, and sodium lauryl sulfate; or polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol, and silicon dioxide; or hypromellose and talc; or a mixture thereof.

[0047] In some embodiments, the core-shell formulation of the invention may further comprise an outer layer of lubricant. The presence of an outer lubricant is advantageous for the handling of the formulation, especially with regards to flowing and electro staticity. The outer layer of lubricant can comprise one or more lubricants. The lubricant can be for example talc. In one embodiment, the outer lubricant is present in an amount ranging from 0.1% to 2% in with of the total weight of the core-shell formulation; preferably from 0.2% to 1%, more preferably about 0.5%. In one embodiment, the outer lubricant consistsof talc and is present in an amount ranging from 0.1% to 2% in with of the total weight of the core-shell formulation; preferably from 0.2% to 1%, more preferably about 0.5%.The Core

[0048] The core-shell formulation of the invention is based on a core that comprises probenecid. Especially, the core comprises probenecid in association with at least one pharmaceutically acceptable excipient.

[0049] The core is thus a formulation, according to any formulation in the purview of the skilled artisan, also referred to as an immediate release formulation, that comprises probenecid in an amount ranging from 10% to 70%, from 10% to 60%, from 20% to 60%, or from 25% to 50%, in weight relative to the total weight of the core. Such core formulation may also be characterized herein as an immediate release formulation of probenecid.

[0050] In some embodiments, the at least one pharmaceutically acceptable excipient is selected from cellulose, microcrystalline cellulose, cellulose derivatives such as hydroxycellulose, hydroxypropylcellulose or hydroxypropylmethylcellulose, starch, modified starch such as hydrolyzed starch, dextran, maltodextrin, sucrose, lactose, mannitol, sorbitol, maltitol, trehalose, calcium carbonate, magnesium carbonate, and silica. In some embodiments, the at least one pharmaceutically acceptable excipient is selected from cellulose, microcrystalline cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, preferably microcrystalline cellulose.

[0051] In some embodiments, two variants can be considered for the core:(i) a mixed core, wherein said mixed core is a mixture of probenecid with at least one pharmaceutically acceptable excipient; and(ii) a coated inert core, wherein said coated inert core comprises a particle of an inert core consisting of at least one pharmaceutically acceptable excipient, that is coated with a first coating comprising probenecid.

[0052] According a first variant (“mixed core”), the core is a mixture of probenecid with at least one pharmaceutically acceptable excipient. For instance, probenecid may bemixed with at least one pharmaceutically acceptable excipient, such as for example those as described herein above, and then be compressed into a core.

[0053] In some embodiments, the mixed core as described above present an average diameter ranging from 1.5 mm to 12 mm, preferably from 5 mm to 10 mm. In this case, the resulting core- shell formulation according to the invention is under the form of microtablets. The mixed core as described above can present an average diameter ranging from 1.5 mm to 7 mm, preferably of about 5 mm, which is particularly adapted for children from 2 to 6 years old. Alternatively, the mixed core as described above can present an average diameter ranging from 7 to 12 mm, preferably of about 10 mm, which is particularly adapted for children from 6 to 12 years old. The average diameter can be determined by the sieving method.

[0054] According to a second variant (“coated inert core”), the core is a particle of an inert core consisting of at least one pharmaceutically acceptable excipient, such as for example those as described herein above, that is coated with a first coating comprising probenecid. This first coating can be for example a direct coating with probenecid, i.e. the probenecid compound being adsorbed or absorbed on the surface of the inert core. Alternatively, probenecid can be mixed with at least one pharmaceutically acceptable excipient to form a coating composition (herein referred to as a first coating composition) that coats the inert cores. In such case, the first coating comprises probenecid and at least one pharmaceutically acceptable excipient.

[0055] In some embodiments, the inert core may consist of microspheres consisting of at least one pharmaceutically acceptable excipient, as described above, presenting an average diameter ranging from 100 pm to 5 mm, from 100 pm to 2 mm, from 100 pm to 1000 pm, preferably from 100 pm to 800 pm, more preferably from 180 pm to 800 pm, even more preferably from 200 pm to 600 pm, such as from 300 pm to 400pm. In this case, the resulting core- shell formulation according to the invention is under the form of microgranules.

[0056] In one embodiment, the inert core consists of microcrystalline cellulose microspheres. Microcrystalline cellulose (MCC) is a natural polymer composed ofglucose units joined by a 1-4 beta glycosidic bond. Preferably, the MCC microspheres present and average diameter ranging from, 100 pm to 800 pm, 300 pm to 400 pm, typically about 350 pm, as determined by the sieve method, such as for example Cellets® 350.

[0057] According to some exemplary embodiments, the core is a particle of an inert core consisting of microcrystalline cellulose (MCC) that is coated with a first coating composition comprising probenecid, thereby forming coated cores of MCC with the first coating composition.

[0058] In some embodiments, the first coating comprises in weight relative to the total weight of the coated inert core: probenecid in an amount ranging from 10% to 70%, preferably from 20% to 50%, more preferably from 30% to 50%, typically about 40%; a binder, in particular hydroxypropylcellulose, in an amount ranging from 20% to 40%, preferably from 25% to 35%, typically about 30%; a surfactant, such as polyoxyethylene (20) sorbitan monooleate, in an amount ranging from 1% to 3%, preferably from 1.5% to 2.5%, typically about 2.0%, and optionally an anti-foaming agent, such as simethicone; preferably, when present, the anti-foaming agent is in an amount ranging from 0.02% to 0.2%, typically about 0.1%.

[0059] According to an alternative description of the first coating, it can be described by expressing the amounts of the excipients as relative to the amount of the active pharmaceutical ingredient, probenecid. Accordingly, the first coating may comprise, in weight relative to the total weight of the comprised probenecid: a binder, in particular hydroxypropylcellulose, in an amount ranging from 55% to 85%, preferably from 60% to 80%, more preferably from 70% to 80% typically about 75%; a surfactant, such as polyoxyethylene (20) sorbitan monooleate, in an amount ranging from 2% to 8%, preferably from 3% to 6%, typically about 5%, andoptionally an anti-foaming agent, such as simethicone, preferably, when present, the anti-foaming agent is in an amount ranging from 0.05% to 0.5%, typically about 0.2%.

[0060] In some embodiments, in the first coating of the core, the binder is hydroxypropylcellulose (HPC). The selection of HPC as binder according to the exemplary embodiments, enables not only the high charge of the formulation particles with probenecid, but also allowed a repeatable production of particles with a reliable dosage of the formulation in probenecid, i.e. wherein the amount of the probenecid in the first coating composition is quantitively charged on the MCC microspheres, with no substantial losses of probenecid during coating.

[0061] Hydroxypropylcellulose (HPC) is non-ionic cellulose ether, that is typically used in pharmaceutical compositions as a binder. Typically, the molar substitution degree of the glucose monomers by hydroxypropyl moieties ranges from 2.0 to 4.0. In some embodiments, the HPC presents a hydroxypropyl substitution ranging from more than 14%, more than 15% or more than 20% in weight relative to total weight of the HPC composition. For instance, the HPC used in the first composition coating may be Pharmacoat® 606.

[0062] The first coating, according to some exemplary embodiments, also comprises a surfactant, that may typically act as a wetting agent that, without willing to be bound by a theory, facilitates the homogenous dispersion of probenecid within the first coating composition and as a consequence on the coated inert cores, typically on the MCC microspheres. According to some embodiments, the surfactant is a non-ionic surfactant in an amount ranging from 0.5% to 8%, preferably from 1% to 5%, more preferably from 1% to 3%, even more preferably from 1.5% to 2.5%, typically about 2% in 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 polysorbate 80.

[0063] The coating of the inert core, e.g. the MCC microsphere cores, may be carried out by any means known in the art such as for example by a spray-drying process as described herein below. In order to facilitate the coating procedure, the first coatingcomposition may further comprise an anti-foaming agent in an amount ranging from 0.02% to 0.2% relative to the total weight of the coated cores or from 0.05% to 0.5% in weight relative to the total weight of the comprised probenecid. According to some embodiments, the anti-foaming agent is simethicone (CAS n° 8050-81-5).

[0064] 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 from 70% to 90%, preferably about 80%, of vehicle (e.g. water), in weight relative to the total weight of the first coating composition.

[0065] The amount of coating or coating percentage may define the amount of the probenecid that is charged onto the formulation. The amount or the percentage of coating can be determined by any means known in the art such as for example by comparing the weight of the obtained coated inert cores to the weight of the used inert cores. In some embodiments, the first coating composition represents from 50% to 90%, preferably from 50% to 80%, more preferably from 65% to 75%, typically about 75% in weight relative to the total weight of the coated core.

[0066] Optionally, the cores, or “immediate release particles” as herein described may present an additional coating, herein designated as seal-coating.

[0067] The seal-coating, when present, may be in an amount sufficient to impermeabilize the core (i.e. the immediate release formulation) of the invention. Advantageously, the seal-coating may limit, if any, the migration of probenecid in the formulation. In some embodiments, the seal-coating is in an amount ranging from 2% to 20%, preferably from 10% to 20% in weight relative to the total weight of the core, i.e. the formulation of the cores according to the first variant (mixed core) or the coated inert cores of the second variant. The seal-coating can be obtained by coating the core, for example by spray drying, using a “seal-coating composition”. In the case of a coated inert core, the seal-coating is applied on the first coating present on the inert core.

[0068] Indicatively, the seal-coating composition may comprise: a composition comprising polyvinyl alcohol in association with talc, titanium dioxide, glyceryl mono and dicaprylocaprate and sodium lauryl sulfate, such as for example the commercially available Opadry® AMB composition; a composition comprising polyvinyl alcohol-polyethylene glycol graft copolymer, typically in an amount ranging from 55% to 65%, polyvinyl alcohol, typically in an amount ranging from 35% to 45%, and silicone dioxide, typically in an amount ranging from 0.1% to 0.3%, the percentages being in weight relative to the total weight of the final-coating composition. An exemplary embodiment of such final coating composition is the commercially available Kollicoat® Protect composition; a composition comprising hydroxypropylmethylcellulose and talc, such as for example the commercially available Opadry® 03A69 composition; or a mixture thereof.

[0069] Accordingly, the seal-coating may comprise: polyvinyl alcohol in association with talc, titanium dioxide, glyceryl mono and dicaprylocaprate, and sodium lauryl sulfate; or polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol, and silicon dioxide; or hypromellose and talc; or a mixture thereof.

[0070] Hydroxypropylmethylcellulose (HPMC), also known as hypromellose is nonionic cellulose ether, typically made from natural cotton fiber under series of chemical processing by etherification of the cellulose moieties of the cellulose backbone structure having the CAS n° 9004-65-3. It is an odorless, tasteless and non-toxic white powder that can be dissolved in cold water to form a transparent viscous solution with the gelling and / or thickening properties. HPMC can typically present a methoxy substitution of the hydroxyl moieties of the cellulose backbone in an amount ranging from 15.0% to 30.0%, typically from 19.0% to 30.0%, preferably from 27.0% to 30.0% or from 19.0% to 27.0%, in weight relative to total weight of the HPMC composition.

[0071] In some embodiment, and as schematized in Figure 3, the core- shell formulation of the invention can be summarized as a formulation comprising: a core (1) comprising probenecid in an amount ranging from 10% to 70% in weight relative to the total weight of the core, in association with at least one pharmaceutically acceptable excipient; wherein the core may be, according to a first variant of the invention, a mixed core (la), or according to the second variant of the invention, a coated inert core (lb), wherein an inert core (lb 1 ) is coated with a first coating (lb2), such as for example according to the exemplary embodiments described above; optionally, the core may further comprise a seal-coating (2), which is coating the core, or which is coating the first coating of the inert core according to the second variant; a shell coating (3) as described above (also referred to as second coating when the core comprises a first coating), optionally, a final coating (4) as described above, and optionally, an outer layer of lubricant (5), as described above.Pharmaceutical composition and uses

[0072] The invention further relates to a pharmaceutical composition comprising the immediate or the modified release formulation of the invention as such or in association with at least one pharmaceutically acceptable excipient that is in the purview of the skilled artisan such as for example at least one excipient selected from bulking agents, taste or smell enhancing agents, and flow-improving agents.

[0073] According to another aspect, the invention relates to the formulation or the pharmaceutical composition of the invention for its use as a drug. The invention also relates to the use of the formulation or the pharmaceutical composition of the invention for the manufacture of a drug.

[0074] In some indicative embodiments, the drug is for use in the treatment of a disease selected from gout, hyperuricemia and epilepsy. According to some preferred embodiments, the drug is for use in the treatment of epilepsy.

[0075] The invention also relates to the formulation or the pharmaceutical composition of the invention for use in the treatment of a disease selected from gout, hyperuricemia and epilepsy, in a subject in need thereof.

[0076] The invention also relates to the use of the formulation or the pharmaceutical composition of the invention, for the manufacturing of a medicament for the treatment of a disease selected from gout, hyperuricemia and epilepsy.

[0077] The invention also relates to a method for treating a disease selected from gout, hyperuricemia and epilepsy, comprising administering to a subject in need thereof a therapeutically effective amount of the formulation or the pharmaceutical composition of the invention.

[0078] As used herein, the term “subject” refers to an animal, preferably a warmblooded animal, more preferably a mammal, even more preferably a human. In one embodiment, a subject may be a mammal. Mammals include, but are not limited to, all primates (human and non-human), cattle (including 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., is awaiting the receipt of, or is receiving medical care or was / is / will be the object of a medical procedure, or is monitored for the development of an epileptic disease, disorder or condition. In one embodiment, the subject is an adult (for example a subject above the age of 18). In another embodiment, the subject is a child (for example a subject below the age of 18). In one embodiment, the subject is a male. In another embodiment, the subject is a female.

[0079] According to some embodiments, the subject may be a substantially healthy subject. In the case 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 condition. In one embodiment, a substantially healthy subject shows no onsetof an epileptic disease, disorder or condition, i.e., the subject has not yet acquired, developed, or first experienced epileptic seizures.

[0080] As used herein, the terms “treating” or “treatment” or “alleviation” refers to both therapeutic treatment and prophylactic or preventative measures; wherein the object is to prevent or slow down (lessen) the targeted pathologic condition or disorder, such as for example an epileptic 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 successfully “treated” for a specific disease, disorder or condition, such as for example an epileptic disease, disorder or condition if, after receiving a therapeutic amount of probenecid according to the present invention, the subject shows observable and / or measurable reduction in one or more of the followings: epileptic seizures, in particular clinical epileptic seizures (that may be completely absent); reduced morbidity and mortality; improvement in quality-of-life issues. The above parameters for assessing successful treatment and improvement in the disease, disorder or condition are readily measurable by routine procedures familiar to a physician.

[0081] As used herein, the terms “therapeutically effective amount” mean level or amount of agent that is aimed at, without causing significant negative or adverse side effects to the target, (1) delaying or preventing the onset of a target disease, disorder, or condition; (2) slowing down or stopping the progression, aggravation, or deterioration of one or more symptoms of the target disease, disorder, or condition; (3) bringing about ameliorations of the symptoms of the target disease, disorder, or condition; (4) reducing the severity or incidence of the target disease, disorder, or condition; or (5) curing the target disease, disorder, or condition. A therapeutically effective amount may be administered prior to the onset of the target disease, disorder, or condition, for a prophylactic or preventive action. Alternatively or additionally, the therapeutically effective amount may be administered after initiation of the target disease, disorder, or condition, for a therapeutic action. The determination of the therapeutically effective amount can be determined by the physician. For instance, the therapeutically effectiveamount of probenecid for the treatment of epilepsy in pediatric subjects can range from 10 to 50 mg of probenecid per kg of the subject per day.Process

[0082] The invention also relates to a process for preparing the core-shell formulation of the invention.

[0083] According to some embodiments the process comprises the steps of: a) Supplying a composition of cores comprising probenecid in an amount ranging from 10% to 70% in weight relative to the total weight of the core, in association with at least one pharmaceutically acceptable excipient, as described above. It is of note that the cores may be in any one of the two variants of the core as described above. According the first variant (mixed core), the core is a mixture of probenecid with at least one pharmaceutically acceptable excipient. For instance, probenecid may be mixed with at least one pharmaceutically acceptable excipient, such as for example as described herein above, and then be compressed into a core. According to the second variant (coated inert core), the core is a particle of an inert core consisting of at least one pharmaceutically acceptable excipient, as described herein above, that is coated with a first coating composition comprising or consisting of probenecid; b) Coating the cores with a shell coating composition comprising triethyl citrate, a mineral charge, polyvinyl acetate, polyvinylpyrrolidone and sodium lauryl sulfate, wherein the weight ratio of polyvinyl acetate on polyvinylpyrrolidone ranges from 1.5 to 4, leading to a core-shell formulation (i.e. shell-coated cores).

[0084] The coating step b) can be carried out by any means in the purview of the skilled artisan. For example, the cores can be coated by spray drying, e.g. by spray drying on a fluid-bed machine.

[0085] The core-shell formulation can be recovered after the coating step b).

[0086] Alternatively, the process may further comprise step c): c) Optionally coating the formulation of step b) with a final coating, as described above, thereby leading to final-coated cores.

[0087] Optionally, the process may further comprise a step d), wherein the coated cores obtained in steps b) or c) can be subjected to a curing step, comprising heating the coated cores at a temperature ranging from 35°C to 45°C, preferably about 40°C, for a period of time ranging from 30 minutes to 2 hours, preferably about 1 hour.

[0088] The curing step d) advantageously allows to set the coatings by drying their constituents, thereby increasing the stability of the formulation. The curing step also allows to limit the amount of water in the formulation overtime.

[0089] Thus, according to some optional embodiments, the core-shell formulation of the invention can be obtained in any one of steps b), c) or d).

[0090] The process can also comprise a further optional terminal step, to form the outer layer of lubricant, as described above, comprising contacting the core-shell formulation obtained in any one of steps b), c) or d) with a lubricant, thereby leading to the formation of an outer layer of lubricant on the core-shell formulation.

[0091] As set above, the core is a formulation, according to any formulation in the purview of the skilled artisan, that comprises probenecid in an amount ranging from 10% to 70% in weight relative to the total weight of the core, as detailed above. When referring to the second variant of the invention (coated inert core), step a) can be indicatively further described as comprising: al) Supplying a composition of inert core consisting of at least one pharmaceutically acceptable excipient, such as for example MCC inert cores, preferably MCC microspheres; a2) Coating the inert cores, preferably by spray drying, with a first coating composition, thereby leading to coated inert cores, wherein the first coating composition comprises, in weight relative to the total weight of the coated inert cores:- from 10% to 70% w / w of probenecid;- from 20% to 40% w / w of hydroxypropylcellulose;- from 1% to 3% w / w of a surfactant; and- optionally an anti-foaming agent; a3) optionally, further coating the coated inert cores of step a2), preferably by spray drying, with a seal-coating composition as described above, thereby leading to seal- coated inert cores; a4) recovering the cores obtained in step a2) or in step a3).BRIEF DESCRIPTION OF THE DRAWINGS

[0092] Figure 1 is a graph showing the dissolution profiles of probenecid in a pH 6.8 buffer from the core-shell formulation “MR2”, “MR2 with curing”, “MR2 with curing and lubricant” and “MR2 with seal coating and curing”, compared to an immediate release formulation IR.

[0093] Figure 2 is a graph showing the in vivo exposure level to probenecid (plasmatic concentration in ng / mL) over time (h) after the administration of the MR2 formulation according to the invention.

[0094] Figure 3 provides schematic representations of the core-shell formulation according to the invention with the relative position of the coatings, including optional coatings (Figure 3A), and two variants of the core (Figure 3B).EXAMPLES

[0095] The present invention is further illustrated by the following examples.Example 1: Preparation of exemplary immediate -release cores (“coated inert core”)Materials and Methods

[0096] Immediate -release (IR) cores, or “coated inert cores”, were prepared according to Table 1. Quantities are provided in weight relative to the total weight of the resulting coated cores:Table 1: Indicative IR core of probenecid

[0097] Ingredients B-E were suspended in water by mixing with Ultraturrax®, thereby supplying a first coating composition which is an aqueous composition. Preferably, ingredients B-E represent about 17% in weight relative to the total weight of this aqueous first coating composition.

[0098] The microcrystalline cellulose inert cores were then coated by fluid-bed spraydrying with the fluid bed coater Glatt GPCG1 at a bottom spray configuration, using the above aqueous first coating composition comprising ingredients B-E, thereby leading to coated inert cores “IR”.

[0099] A sample of the obtained coated inert cores “IR” was further coated with a seal coating, leading to seal-coated inert cores “seal coated-IR”. The seal coating composition was the commercially available Kollicoat® Protect composition, comprising polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol, and silicon dioxide. The seal-coating was added to represent 10% in weight relative to the total weight of the resulting core.

[0100] The obtained immediate release formulations were then assessed on the probenecid (API) in vitro dissolution assay in pH 6.8 buffer, with paddles rotating at 50 rotations per minute according to Ph. Eur 2.9.3. (01 / 2023:20903).Results

[0101] The immediate release formulations presented insignificant amount of agglomerates and with a satisfying yield of 89.1%.

[0102] The immediate-release formulation “IR” presented a liberation of probenecid in the dissolution medium of at least 80% in about 2.5 hours, more specifically a liberation of more than 95% in 30 min as reported in Figure 1.Example 2: Preparation of modified-release core-shell formulation of the inventionMaterials and Methods

[0103] The immediate -release coated cores of Example 1 (“IR” and“seal coated-IR”) were used as cores for the manufacturing of core-shell formulations according to the invention.

[0104] Two modified-release core-shell formulations (“MR1” and “MR2”) were prepared according to the composition of Table 2 hereinbelow, using the coated inert cores “IR” of Example 1.

[0105] The immediate-release coated cores “IR” of Example 1 were coated by fluid-bed spray-drying with the fluid bed coater Glatt GPCG1 at a bottom spray configuration using the shell coating composition presented in Table 2, leading to “MR1” and “MR2” respectively. Quantities are provided in weight relative to the total weight of the resulting core- shell formulation.Table 2: Modified release formulations MR1 and MR2 according to the invention.*Kollicoat® SR30D is a commercially available coating mix of an aqueous dispersion of polyvinyl acetate (PVAc:27%), sodium lauryl sulfate (0.3%) and inherently comprising PVP (hereinabove indexed as PVPk 2.7%). The dry extract of Kollicoat SR30D, e.g. after spray drying, thus comprises about 90% PVAc, about 9% PVPk and about 10% sodium lauryl sulfate. The total PVP in the MR formulation consists in the sum of the exogenously added PVP and the PVPk comprised in the Kollicat® mixture.

[0106] A sample of the obtained “MR2” formulation was further subjected to a curing step, i.e. by heating the sample at a temperature of about 40°C for 1 to 2 hours, leading to the cured formulation “MR2 with curing”.

[0107] A sample of the obtained “MR2 with curing” formulation was further subjected to the formation of an outer layer of talc as lubricant, leading to the formulation“MR2 with curing and lubricant”. For this formulation, the cured formulation “MR2 with curing” was mixed with talc. The resulting formulation comprises about 0.5% of talc in weight relative to the total weight of the formulation.

[0108] Another core-shell formulation, “MR2 with seal coating and curing”, was prepared as for “MR2 with curing”, but starting from the seal-coated inert cores “seal coated-IR” of Example 1.

[0109] The obtained modified release formulations were then assessed on the probenecid (API) in vitro dissolution assay in pH 6.8 buffer with paddles rotating at 50 rotations per minute according to Ph. Eur 2.9.3. (01 / 2023:20903).Results

[0110] The modified release core-shell formulations presented a homogenous shell coating and their dissolution was as follows:MR1: 80% dissolution of probenecid was achieved by 20h of the dissolution assay;MR2: 80% dissolution of probenecid was achieved by 7 hours, and a dissolution of more than 90% was achieved by 9 hours.

[0111] The dissolution profiles of “MR2”, “MR2 with curing”, “MR2 with curing and lubricant” and “MR2 with seal coating and curing” are reported in Figure 1, together with the dissolution profile of the immediate release (IR) cores “IR” of Example 1. The release of probenecid is clearly delayed with the core- shell formulation of the invention, compared with the immediate release formulation.Example 3: In vivo liberation of probenecid with a formulation according to the invention

[0112] Formulations IR (of example 1) and MR2 (of example 2) were orally administered to minipigs (2g probenecid / minipig) during a single administration and cross over study into two groups of subjects (IR and MR2).

[0113] With a focus on the dosage of the plasmatic unbound probenecid, that is responsible for the biological effects, the pharmacokinetic properties are presented intable 3 for the IR formulation and table 4 for the core- shell formulation according to the invention, MR2.Table 3. The Pharmacokinetic parameters of unbound Probenecid in mini pig plasma samples -Group IRTable 4. The Pharmacokinetic parameters of unbound Probenecid in mini pig plasma samples - Group MR2

[0114] Interestingly, the formulation MR2 according to the invention increased the halflife (ti / 2) by a factor of 2.3 for the unbound probenecid. It is of note that, the unbound form of probenecid is the form that shall bind to the pharmacological targets exert its pharmacological effects.

[0115] Still more interestingly, the formulation allows to enhance the mean residency time (MRT) by a factor of 1.7, so that when the minipig pharmacokinetic evidence is transposed to humans, a twice-a-day administration of the formulation shall supply therapeutically effective amounts of probenecid in the plasma. Indeed, as illustrated in Figure 2, the administration of MR2 formulation according to the invention lead to an exposure level sufficient for a subject to be treated with an intake of up to two intakes of the formulation according to the invention per day.

Claims

CLAIMS1. A core-shell formulation comprising:- a core, said core comprising probenecid in an amount ranging from 10% to 70% in weight relative to the total weight of the core, in association with at least one pharmaceutically acceptable excipient; and- a shell coating, said shell coating comprising triethyl citrate, a mineral charge, polyvinyl acetate, polyvinylpyrrolidone and sodium lauryl sulfate, wherein the weight ratio of polyvinyl acetate on polyvinylpyrrolidone ranges from 1.5 to 4.

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

3. The formulation according to claim 1 or claim 2, wherein the shell coating represents from 2% to 30% in weight relative to 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 said mixed core is a mixture of probenecid with the at least one pharmaceutically acceptable excipient; or(ii) a coated inert core, wherein said coated inert core comprises a particle of an inert core consisting of the at least one pharmaceutically acceptable excipient, that is 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 maltodextrinsucrose, lactose, mannitol, sorbitol, maltitol, trehalose, calcium carbonate, magnesium carbonate, and silica; 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 the first coating comprises, in weight relative to the total weight of the coated inert core: from 10% to 70% w / w of probenecid; from 20% to 40% w / w of hydroxypropylcellulose; from 1% to 3% w / w of a surfactant; and optionally an anti-foaming agent.

7. The formulation according to claim 6, wherein the surfactant is a non-ionic 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 represents from 50% to 80% in weight relative to the total weight of the coated inert core.

9. The formulation according to any one of claims 4 to 8, wherein the inert core consists of microspheres consisting of the at least one pharmaceutically acceptable excipient presenting an average diameter ranging from 100 pm to 5 mm; preferably the inert core consists of microcrystalline cellulose microspheres presenting an average diameter ranging from 100 pm to 800 pm; more preferably from 300 pm to 400 pm, the average diameter being determined with the sieving method.

10. The formulation according to any one of claims 1 to 9, wherein the core further comprises a seal-coating in an amount ranging from 2% to 20% in weight relative to the total weight of the core, said seal-coating comprising: polyvinyl alcohol in association with talc, titanium dioxide, glyceryl mono and dicaprylocaprate, and sodium lauryl sulfate; polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol, and silicone dioxide;hypromellose and talc; or a mixture thereof.

11. The formulation according to any one of claims 1 to 10, further comprising a final coating in an amount ranging from 2% to 20% in weight relative to the total weight of the core-shell formulation, said final coating comprising: polyvinyl alcohol in association with talc, titanium dioxide, glyceryl mono and dicaprylocaprate, and sodium lauryl sulfate; polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol, and silicone dioxide; hypromellose and talc; or a mixture thereof.

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. The formulation according to any one of claims 1 to 12, for use as a drug.

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

15. A process for preparing the core-shell formulation according to any one of claims 1 to 12, comprising the steps of: a) supplying cores, said cores comprising probenecid in an amount ranging from 10% to 70% in weight relative to the total weight of the cores in association with at least one pharmaceutically acceptable excipient; b) coating the cores of step a), preferably by spray drying, with a shell coating composition, thereby leading to shell-coated cores; said shell coating composition comprising triethyl citrate, a mineral charge, polyvinyl acetate, polyvinylpyrrolidone and sodium lauryl sulfate, wherein the weight ratio of polyvinyl acetate on polyvinylpyrrolidone ranges from 1.5 to 4;c) optionally further coating the shell-coated cores of step b), preferably by spray drying, with a final coating composition, thereby leading to final-coated cores; said final coating composition comprising polyvinyl alcohol in association with talc, titanium dioxide, glyceryl mono and dicaprylocaprate, and sodium lauryl sulfate; polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol, and silicone dioxide; hypromellose and talc; or a mixture thereof; d) optionally, subjecting the coated cores of step b) or step c) to a curing step, comprising heating the coated cores at a temperature ranging from 35°C to 45°C, preferably about 40°C, for a period of time ranging from 30 minutes to 2 hours, preferably about 1 hour; e) recovering the core-shell formulation obtained in any one of steps b), c) or d); and f) optionally contacting the formulation of step e) with a lubricant, thereby leading to the formation of an outer layer of lubricant on the core- shell formulation.

16. The process according to claim 15, wherein step a) comprises: al) supplying inert cores, said inert cores consisting of the at least one pharmaceutically acceptable excipient; preferably the inert cores are microcrystalline cellulose microspheres; a2) coating the inert cores, preferably by spray drying, with a first coating composition, thereby leading to coated inert cores, said first coating composition comprising, in weight relative to the total weight of the coated inert cores:- from 10% to 70% w / w of probenecid;- from 20% to 40% w / w of hydroxypropylcellulose;- from 1% to 3% w / w of a surfactant; and- optionally an anti-foaming agent;a3) optionally, further coating the coated inert cores of step a2), preferably by spray drying, with a seal-coating composition, thereby leading to seal-coated inert cores; said seal-coating composition comprising polyvinyl alcohol in association with talc, titanium dioxide, glyceryl mono and dicaprylocaprate, and sodium lauryl sulfate; polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol, and silicone dioxide; hypromellose and talc; or a mixture thereof; and a4) recovering the cores obtained in step a2) or in step a3).

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