PEDIATRIC FORMULATION

Abstract

The present invention relates to pediatric drug formulation. Especially, this invention relates to the manufacturing of granules comprising a core comprising a drug having an unpleasant taste, which may be a primary bile acid, such as for example cholic acid, and a taste-masking coating. The purpose of the invention is to fully mask unpleasant taste of the drug, while ensuring its availability at the duodenum biological site.

Claims

1. Method of treating a pediatric patient suffering from a deficiency in primary bile acid synthesis comprising administering to said patient a pediatric formulation comprising at least one pediatric granule comprising a core, said core comprising unbuffered cholic acid and at least one binder; and a gastric-fluid-soluble-and-taste-masking coating surrounding the core, said coating consisting of Poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) (1:2:1); said at least one granule presenting a particle size distribution ranging from 90 μm to 500 μm wherein the granules larger than 355 μm is less than the 12% of the total particle size distribution; wherein said at least pediatric formulation comprises a therapeutically effective amount of cholic acid.

2. The method according to claim 1, wherein the pediatric patient has no bicarbonate secretion deficiency.

3. The method according to claim 1, wherein the pediatric patient has swallowing difficulty or swallowing disability.

4. The method according to claim 1, wherein the core of said at least one granule further comprises at least one excipient, referred to as Excipient A selected from the group consisting of sugars, polyols and polymers.

5. The method according to claim 1, wherein the at least one binder, is selected from the group consisting of natural polymers, synthetic polymers or sugars.

6. The method according to claim 1, wherein the amount of unbuffered cholic acid ranges from 10% w/w to 40% w/w in weight to the total weight of said at least one granule.

7. The method according to claim 1, wherein the amount of said a binder ranges from 1% w/w to 10% w/w, in weight to the total weight of said at least one granule.

8. The method according to claim 1, wherein the amount of Poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) (1:2:1) ranges from 10% w/w to 40% w/w, in weight to the total weight of said at least one granule.

9. The method according to claim 1, wherein the core of said granule further comprises at least one excipient, referred to as Excipient A selected from the group consisting of sugars, polyols and polymers; and wherein the amount of said excipient A ranges from more than 0% w/w to 40% w/w, in weight to the total weight of said granule.

10. The method according to claim 1, wherein the pediatric formulation comprises: from 30% to 50% in weight relative to the total weight of the at least one granule of unbuffered cholic acid; from 10% to 20% in weight relative to the total weight of the formulation of mannitol; from 10% to 20% in weight relative to the total weight of the formulation of microcrystalline cellulose; from 0.5% to 5% in weight relative to the total weight of the formulation of polyvinylpyrrolidone; and from 20% to 40% in weight relative to the total weight of the formulation of Poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) (1:2:1).

11. The method according to claim 1, wherein the said pediatric formulation further comprises at least one excipient B selected from at least one diluent, at least one disintegrant and at least one lubricant or a combination thereof.

12. The method according to claim 1, wherein the amount of unbuffered cholic acid ranges from 10% w/w to 40% w/w in weight to the total weight of the pediatric formulation.

13. The method according to claim 11, wherein the amount of said at least one excipient B ranges from 10% w/w to 60% w/w, in weight to the total weight of the formulation.

14. The method according to claim 11, wherein said at least one excipient B is selected from: at least one diluent further selected from microcrystalline cellulose, maltitol, and combinations thereof; at least one disintegrant further selected from crospovidone or sodium croscarmellose; at least one lubricant further selected from sodium stearyl fumarate or magnesium stearate; and a combination thereof.

15. The method according to claim 11, wherein: the formulation comprises from 10% to 20% in weight relative to the total weight of the formulation of unbuffered cholic acid; further comprises an excipient A being a mixture of Mannitol and Microcrystalline cellulose, each being in an amount from 1% to 12% in weight relative to the total weight of the formulation; and said binder is hydroxylpropylcellulose from 0.01% to 1.5% in weight relative to the total weight of the formulation wherein said coating surrounding the core consisting of Poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) (1:2:1) is in an amount from 8% to 18% in weight relative to the total weight of the formulation; and wherein said at least one Excipient B consists of: microcrystalline cellulose from 43% to 55% in weight relative to the total weight of the formulation; sodium croscarmellose from 0% to 10% in weight relative to the total weight of the formulation; and sodium stearyl fumarate from 0% to 10% in weight relative to the total weight of the formulation.

16. A process for the manufacturing a pediatric formulation comprising at least one granule comprising a core, said core comprising unbuffered cholic acid, at least one Excipient A selected from the group consisting of sugars, polyols and polymers and at least one binder; and a gastric-fluid-soluble-and-taste-masking coating surrounding the core, said coating consisting of Poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) (1:2:1); said granule presenting a particle size distribution ranging from 90 μm to 500 μm wherein the granules larger than 355 μm is less than the 12% of the total particle size distribution; wherein said formulation further comprises at least one excipient B selected from at least one diluent, at least one disintegrant and at least one lubricant or a combination thereof; wherein the process consists of: a) Mixing the unbuffered cholic acid, with at least one excipient A selected from sugars, polyols and polymers; b) Granulating the said granule containing the unbuffered cholic acid, and the at least one excipient A using a wet granulation in presence of at least one binder; c) Drying the said unbuffered cholic acid granules; d) Calibrating the said unbuffered cholic acid granules; e) Coating the said unbuffered cholic acid granules with Poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) (1:2:1); f) Drying the said coated unbuffered cholic acid granules; g) Calibrating the said coated unbuffered cholic acid granules to particle size distribution ranging from 90 μm to 500 μm wherein the granules larger than 355 μm is less than the 12% of the total particle size distribution; h) Mixing the said coated the unbuffered cholic acid granules with at least one excipient B; and i) Tableting the final blend to obtain dispersible or orodispersible tablets or filling the final blend in sprinkle capsules or sachets.

Description

DETAILED DESCRIPTION

[0073] In a first aspect, the present invention relates to a granule comprising: (1) a core comprising (i) at least one unbuffered primary bile acid, especially unbuffered cholic acid and (ii) at least one binder; and (2) a coating fully surrounding the core, said coating comprising at least one gastric-fluid-soluble-and-taste-masking compound. According to one embodiment, the core further comprises at least one excipient (Excipient A).

[0074] According to one embodiment, the granule of the invention comprises or consists of: (1) a core consisting of (i) at least one unbuffered primary bile acid, especially unbuffered cholic acid, (ii) one binder and optionally (iii) at least one excipient (Excipient A); and (2) a coating consisting of one gastric-fluid-soluble-and-taste-masking compound.

[0075] According to a first embodiment, the core of the granule comprises at least one unbuffered primary bile acid, especially unbuffered cholic acid and at least one binder, preferably selected from natural polymer, synthetic polymer or sugar.

[0076] According to a second embodiment, the core of said granule comprises at least one at least one unbuffered primary bile acid, especially at least one unbuffered cholic acid and at least one binder, preferably selected from natural polymer, synthetic polymer or sugar and at least one excipient (Excipient A) preferably selected from sugars, polyols, calcium salts and polymers.

[0077] According to third embodiment, the granule of the invention consists of: (1) a core consisting of (i) at least one unbuffered primary bile acid, especially unbuffered cholic acid, (ii) one binder and (iii) at least one excipient (Excipient A); and (2) a coating consisting of one gastric-fluid-soluble-and-taste-masking compound.

[0078] According to one embodiment, at least one unbuffered primary bile acid is selected from unbuffered cholic acid and unbuffered chenodeoxycholic acid. In a preferred embodiment, unbuffered primary bile acid is unbuffered cholic acid.

[0079] According to one embodiment the at least one binder may be selected from natural polymer, synthetic polymer or sugar. According to one embodiment, the at least one binder is selected from starch, pregelatinized starch, gelatin, acacia, alginic acid, sodium alginate, polyvinylpyrrolidone (PVP), methylcellulose, hydroxylpropylcellulose (HPC), hypromellose (HPMC), sodium carboxymethylcellulose (Na-CMC), ethylcellulose, glucose, sucrose, sorbitol and combinations thereof. According to one embodiment, the binder is selected from polyvinylpyrrolidone (PVP) or hydroxylpropylcellulose (HPC). According to one embodiment, the binder is polyvinylpyrrolidone (PVP). According to one embodiment, the binder is hydroxylpropylcellulose (HPC).

[0080] According to one embodiment, the at least one excipient A is selected from sugars, polyols, calcium salts and polymers. According to one embodiment, the at least one excipient A is selected from sugars, polyols and polymers. According to one embodiment, the at least one excipient A is selected from sugars, polyols and polymers. According to one embodiment, the at least one excipient A is selected from sugars. According to one embodiment, the at least one excipient A is selected from polyols. According to one embodiment, the at least one excipient A is selected from polymers. According to one embodiment, the excipient A or combinations of excipients A are selected from sucrose, lactose, maltose, lactulose, trehalose, cellobiose, melibiose, isomaltose, glycerol, erythriol, xylitol, arabitol, ribitol, sorbitol, dulcitol, mannitol, volemitol, maltitol, isomaltitol, lactitol, calcium carbonate, dicalcium phosphate, tricalcium phosphate, microcrystalline cellulose and combinations thereof. According to one embodiment, the excipient A or combinations of excipients A are selected from sucrose, lactose, maltose, lactulose, trehalose, cellobiose, melibiose, isomaltose, glycerol, erythriol, xylitol, arabitol, ribitol, sorbitol, dulcitol, mannitol, volemitol, maltitol, isomaltitol, lactitol, microcrystalline cellulose and combinations thereof. According to one embodiment, the excipient A or combinations of excipients A is selected from microcrystalline cellulose, mannitol, and dicalcium phosphate. According to one embodiment, the excipient A or combinations of excipients A is a combination of microcrystalline cellulose and mannitol. According to one embodiment, the excipient A is dicalcium phosphate. According to one embodiment, the excipient A is microcrystalline cellulose. According to one embodiment, the excipient A is mannitol.

[0081] According to one embodiment, the particle size distribution of said granule prior coating ranges from 30 μm to 710 μm or 30 μm to 500 μm. According to one embodiment, the particle size distribution of said granule prior coating ranges from 90 μm to 500 μm. According to one embodiment, the particle size distribution of said granule prior coating ranges from 90 μm to 355 μm, preferably 90 μm to 250 μm.

[0082] According to one embodiment, the particle size distribution of said granule prior coating ranges from 90 μm to 500 μm, preferably and the distribution of granules larger than 355 μm corresponds to less than the 2% of the granules.

[0083] According to one embodiment, the particle size distribution of said granule prior coating ranges from 90 μm to 355 μm, preferably and the distribution of granules larger than 250 μm corresponds to less than the 12% of the granules.

[0084] According to one embodiment gastric-fluid-soluble-and-taste-masking compound is selected from starches, polyvinylpyrrolidones, gelatin, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl methyl cellulose, microcrystalline cellulose and methacrylic acid copolymer and combinations thereof. According to one embodiment, the at least one gastric-fluid-soluble-and-taste-masking compound is selected from Eudragit®-type polymers (Evonik Industries AG, Darmstadt, Germany), sodium carboxymethylcellulose (Na-CMC) polyvinylpyrrolidone, hydroxylethylcellulose, hydroxypropylcellulose, hydroxypropyl methyl cellulose, microcrystalline cellulose polyvinyl acetate, polycarbophil, polyacrylic acid, cellulose ethers, cellulose ester, polyvinyl acetate, methyl acrylate, hydroxyl ethyl methacrylate, vinyl pyridine, and combinations thereof. According to one embodiment, the at least one gastric-fluid-soluble-and-taste-masking compound is preferably selected from Eudragit® E-type polymers, more preferably selected from Eudragit® E PO, Eudragit® E100 or Eudragit® E12.5, even more preferably selected from Eudragit® E PO. According to one embodiment, the at least one gastric-fluid-soluble-and-taste-masking compound is preferably selected from Basic Butylated Methacrylate Copolymer or Ammonio Methacrylate Copolymer, more preferably selected from Poly(butyl methacrylate-co-(2-demethylaminoeethyl) methacrylate-co-methyl methacrylate) 1:2:1, Poly(butyl methacylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) 1:2:1 or Poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) (1:2:1). According to a preferred embodiment, the at least one gastric-fluid-soluble-and-taste-masking compound is Eudragit® E PO (Poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) (1:2:1)).

[0085] According to one embodiment, the granule of the invention, comprises: [0086] cholic acid; [0087] polyvinylpyrrolidone; [0088] Poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) (1:2:1).

[0089] According to another embodiment, the granule of the invention, comprises: [0090] cholic acid; [0091] dicalcium phosphate; [0092] polyvinylpyrrolidone; [0093] Poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) (1:2:1).

[0094] According to another embodiment, the granule of the invention, comprises: [0095] cholic acid; [0096] mannitol; [0097] microcrystalline cellulose; [0098] hydroxylpropylcellulose; [0099] Poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) (1:2:1).

[0100] The Applicant found out that particles presenting a size distribution more than 500 μm aggregate and lead to non-homogeneous granules. According to one embodiment, the particle size distribution of said granule after coating ranges from 30 μm to 1 000 μm, preferably from 30 μm to 710 μm, more preferably from 90 μm to 500 μm, even more preferably from 125 μm to 500 μm.

[0101] According to one embodiment, the particle size distribution of said granule ranges from 90 μm to 500 μm and the distribution of granules larger than 355 μm corresponds to less than the 12% of the granules.

[0102] According to one embodiment, the particle size distribution of said granule ranges from 90 μm to 500 μm and the distribution of granules larger than 355 μm corresponds to less than the 8% of the granules.

[0103] According to one embodiment, the particle size distribution of said granule ranges from 90 μm to 500 μm and the distribution of granules larger than 355 μm corresponds to less than the 3% of the granules.

[0104] According to one embodiment, the particle size distribution of said granule ranges from 90 μm to 500 μm, with a mean distribution ranging from 125 μm to 180 μm and the distribution of granules larger than 355 μm corresponds to less than the 12% of the granules, less than the 8% of the granules or less than the 3% of the granules.

[0105] According to one embodiment, the particle size distribution of said granule ranges from 90 μm to 500 μm and the distribution of granules larger than 355 μm corresponds to less than the 12% of the granules, less than the 8% of the granules or less than the 3% of the granules.

[0106] According to one embodiment, the particle size distribution of said granule ranges from 90 μm to 500 μm, with a mean distribution ranging from 125 μm to 180 μm and the distribution of granules larger than 355 μm corresponds to less than the 12% of the granules, less than the 8% of the granules or less than the 3% of the granules.

[0107] According to one embodiment, the particle size distribution of said granule ranges from 90 μm to 500 μm, with a mean distribution ranging from 125 μm to 180 μm and the distribution of granules larger than 355 μm corresponds to less than the 8% of the granules.

[0108] According to one embodiment, the amount of unbuffered primary bile acid ranges from 1% w/w to 90% w/w, preferably from 5% to 80% w/w, more preferably from 5% w/w to 60% w/w, even more preferably from 10% w/w to 40% w/w in weight to the total weight of said granule.

[0109] According to a preferred embodiment, the amount of unbuffered primary bile acid ranges from 1% w/w to 90% w/w, preferably from 5% to 80% w/w, more preferably from 50% to 80% w/w in weight to the total weight of said granule when the granule consists of a core consisting of an unbuffered primary bile acid and a binder, and a coating.

[0110] According to another preferred embodiment, the amount of unbuffered primary bile acid ranges from 1% w/w to 90% w/w, more preferably from 5% w/w to 60% w/w, even more preferably from 10% w/w to 40% w/w in weight to the total weight of said granule when the granule consists of a core consisting of a unbuffered primary bile acid, an excipient and a binder, and a coating.

[0111] According to one embodiment, the amount of said a binder ranges from more than 0% w/w to 30% w/w, preferably from more than 0% w/w to 20% w/w, more preferably from 1% w/w to 10% w/w, in weight to the total weight of said granule.

[0112] According to one embodiment, the amount of said taste-masking compound ranges from 1% w/w to 90% w/w, preferably from 5% w/w to 50% w/w, more preferably from 10% w/w to 40% w/w, in weight to the total weight of said granule.

[0113] According to one embodiment, the amount of said excipient A ranges from 0% w/w to 70% w/w, preferably from 0% w/w to 60% w/w, more preferably from 0% w/w to 40% w/w, in weight to the total weight of said granule.

[0114] According to the invention, the gastric-fluid-soluble-and-taste-masking coating does not solubilize upon contact of the granules of the invention with the oral cavity (pH 6.5 to 7.4), and prevents the release of primary bile acid, especially cholic acid, therefore avoiding any perception of bitterness. At the time of arrival in the stomach, the pH between 1 and 5 solubilizes the coating thereby releasing the primary bile acid.

[0115] It is readily understandable that this invention, in a second aspect, also relates to a formulation comprising at least one unbuffered primary bile acid, especially cholic acid, for oral administration, wherein the unpleasant taste of primary bile acid, especially of cholic acid, is fully masked, i.e. not perceptible in the mouth. In one embodiment, the formulation encompasses at least one granule as described here above. According to one embodiment, the formulation comprises or consists of a composition comprising granules of the invention and at least one excipient B.

[0116] According to one embodiment, the at least one excipient B is selected from at least one diluent, at least one disintegrant and at least one lubricant or a combination thereof. According to one embodiment, the at least one excipient B is selected from sugars, polyols, calcium salts, natural polymer, synthetic polymer, hydrophobic or hydrophilic lubricants. According to one embodiment, the at least one excipient B is selected from sugars, polyols, natural polymer, synthetic polymer, hydrophobic or hydrophilic lubricants. According to one embodiment, the at least one excipient B is selected from natural polymer, synthetic polymer, hydrophobic or hydrophilic lubricants.

[0117] According to one embodiment, the at least one diluent is selected from sugars, polyols, calcium salts and polymers. According to one embodiment, the at least one diluent is selected from sugars, polyols and polymers. According to one embodiment, the at least one diluent is selected from sucrose, lactose, maltose, lactulose, trehalose, cellobiose, melibiose, isomaltose, glycerol, erythriol, xylitol, arabitol, ribitol, sorbitol, dulcitol, mannitol, volemitol, maltitol, isomaltitol, lactitol, calcium carbonate, dicalcium phosphate, tricalcium phosphate, microcrystalline cellulose and combinations thereof, preferably is selected from microcrystalline cellulose, maltitol, and combinations thereof. According to a first embodiment, the diluent is microcrystalline cellulose. According to a second embodiment, the diluent is maltitol.

[0118] According to one embodiment, the at least one disintegrant is selected from natural polymer or synthetic polymer. According to one embodiment, the at least one disintegrant is selected from povidone, crospovidone, microcrystalline cellulose, sodium croscarmellose, methylcellulose, starch, pregelatinized starch, carboxymethyl starch, alginic acid, sodium alginate. According to one embodiment, the disintegrant is preferably crospovidone or sodium croscarmellose. According to one embodiment, the disintegrant is preferably sodium croscarmellose.

[0119] According to one embodiment, the at least one lubricant is selected from hydrophobic or hydrophilic lubricants. According to one embodiment, the at least one lubricant is selected from stearic acid, magnesium stearate, sodium stearyl fumarate. According to one embodiment, the at least one lubricant is preferably sodium stearyl fumarate or magnesium stearate. According to one embodiment, the at least one lubricant is magnesium stearate. According to one embodiment, the at least one lubricant is sodium stearyl fumarate.

[0120] According to one embodiment, the at least one excipient B is a combination of microcrystalline cellulose, sodium croscarmellose and magnesium stearate.

[0121] According to one embodiment, the at least one excipient B is a combination of microcrystalline cellulose, sodium croscarmellose and sodium stearyl fumarate.

[0122] According to one embodiment, the formulation comprises: [0123] cholic acid; [0124] Mannitol; [0125] Microcrystalline cellulose; [0126] hydroxylpropylcellulose; [0127] Poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) (1:2:1); [0128] microcrystalline cellulose; [0129] sodium croscarmellose; [0130] magnesium stearate.

[0131] According to another embodiment, the formulation comprises: [0132] cholic acid; [0133] Mannitol; [0134] Microcrystalline cellulose; [0135] hydroxylpropylcellulose; [0136] Poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) (1:2:1); [0137] microcrystalline cellulose; [0138] sodium croscarmellose; [0139] sodium stearyl fumarate.

[0140] According to one embodiment, the amount of at least one unbuffered primary bile acid, especially unbuffered cholic acid, ranges from 1% w/w to 90% w/w, preferably from 5% w/w to 60% w/w, more preferably from 10% w/w to 40% w/w in weight to the total weight of the formulation.

[0141] According to one embodiment, the amount of said binder ranges from more than 0% w/w to 30% w/w, preferably from more than 0% w/w to 20% w/w, more preferably from more than 0.5% w/w to 10% w/w, in weight to the total weight of the formulation.

[0142] According to one embodiment, the amount of said taste-masking compound ranges from 1% w/w to 90% w/w, preferably from 2% w/w to 50% w/w, more preferably from 2% w/w to 25% w/w in weight to the total weight of the formulation.

[0143] According to one embodiment, the amount of said excipient A ranging from 0% w/w to 90% w/w, preferably from 5% w/w to 80% w/w, more preferably from 5% w/w to 70% w/w, even more preferably from 10% w/w to 60% w/w, in weight to the total weight of the formulation.

[0144] According to one embodiment, the amount of said excipient B ranging from more than 0% w/w to 90% w/w, preferably from 5% w/w to 70% w/w, more preferably from 10% w/w to 60% w/w, in weight to the total weight of the formulation.

[0145] According to one embodiment, the amount of said diluent ranging from 0% w/w to 90% w/w, preferably from 5% w/w to 70% w/w, more preferably from 10% w/w to 60% w/w, in weight to the total weight of the formulation.

[0146] According to one embodiment, the amount of said disintegrant ranging from 0% w/w to 15% w/w, preferably from 2% w/w to 12% w/w, more preferably from 2% w/w to 10% w/w, in weight to the total weight of the formulation.

[0147] According to one embodiment, the amount of said lubricant ranging from 0% w/w to 10% w/w, preferably from 0.1% w/w to 5% w/w, more preferably from 0.25% w/w to 2% w/w, in weight to the total weight of the formulation.

[0148] In a third aspect, the present invention relates to a process for manufacturing at least one granule of the invention comprising at least one binder wherein the steps are carried out in the following order: [0149] a1. Mixing at least one unbuffered primary bile acid; [0150] b1. Granulating the said at least one unbuffered primary bile acid with the at least one binder; [0151] c1. Coating the said granules with at least one gastric-fluid-soluble-and-taste-masking compound.

[0152] According to a first embodiment, steps of the said process for manufacturing at least one granule of the invention comprising at least one excipient A and at least one binder are carried out in the following order: [0153] a2. Mixing at least one unbuffered primary bile acid with at least one excipient A and at least one binder; [0154] b2. Granulating the said at least one unbuffered primary bile acid with the at least one excipient A and the at least one binder; [0155] c2. Coating the said granules with at least one gastric-fluid-soluble-and-taste-masking compound.

[0156] According to one embodiment, the granules obtained after the granulating step have a particle size distribution ranging from 10 μm to 710 μm, preferably from 10 μm to 500 μm, more preferably from 30 μm to 355 μm, even more preferably from 125 μm to 250 μm.

[0157] In a fourth aspect, the present invention relates a process for manufacturing a formulation of the invention comprising the following steps: [0158] Mixing at least one unbuffered primary bile acid with at least one binder and optionally at least one excipient A; [0159] Granulating the said at least one unbuffered primary bile acid the at least one binder and optionally with the at least one excipient A; [0160] Coating the said granules with at least one gastric-fluid-soluble-and-taste-masking compound; [0161] Mixing coated at least one unbuffered primary bile acid granules, with at least one excipient B.

[0162] According to a first embodiment, steps of the said process for manufacturing a formulation of the invention comprising at least one granule comprising at least one binder are carried out in the following order: [0163] a3. Mixing at least one unbuffered primary bile acid; [0164] b3. Granulating the said at least one unbuffered primary bile acid with the at least one binder; [0165] c3. Coating the said granules with at least one gastric-fluid-soluble-and-taste-masking compound; [0166] d3. Mixing coated at least one unbuffered primary bile acid granules, with at least one excipient B.

[0167] According to a second embodiment, steps of the said process for manufacturing a formulation of the invention comprising at least one granule further comprising at least one excipient A are carried out in the following order: [0168] a4. Mixing at least one unbuffered primary bile acid with at least one excipient A and at least one binder; [0169] b4. Granulating the said at least one unbuffered primary bile acid with the at least one excipient A and the at least one binder; [0170] c4. Coating the said granules with at least one gastric-fluid-soluble-and-taste-masking compound; [0171] d4. Mixing coated at least one unbuffered primary bile acid granules, with at least one excipient B.

[0172] According to one embodiment, the process of the invention can further comprise a step of calibration of the at least one unbuffered primary bile acid granules before coating.

[0173] According to one embodiment, the process of the invention can further comprise a step of drying of the coated at least one unbuffered primary bile acid granules after coating.

[0174] According to one embodiment, the process of the invention can further comprise a step of calibration of the at least one unbuffered primary bile acid granules after coating. According to one embodiment, the calibration of the at least one unbuffered primary bile acid granules after coating is performed after the step of drying.

[0175] According to one embodiment, the process of the invention can further comprise a final step of tableting the final blend to obtain dispersible or orodispersible tablets or filling the final blend in sprinkle capsules or sachets.

[0176] According to a preferred embodiment, the process for the manufacturing a formulation of the invention consists of: [0177] a5. Mixing at least one unbuffered primary bile acid, especially unbuffered cholic acid with at least one excipient A; [0178] b5. Granulating the said at least one unbuffered primary bile acid, especially unbuffered cholic acid with the at least one excipient A using a wet granulation in presence of at least one binder; [0179] c5. Drying the said granule containing at least one unbuffered primary bile acid granules, especially unbuffered cholic acid granules; [0180] d5. Calibrating the said at least one unbuffered primary bile acid granules, especially unbuffered cholic acid granules; [0181] e5. Coating the said at least one unbuffered primary bile acid granules, especially unbuffered cholic acid granules with at least one gastric-fluid-soluble-and-taste-masking compound; [0182] f5. Drying the said coated at least one unbuffered primary bile acid granules, especially coated unbuffered cholic acid granules; [0183] g5. Calibrating the said coated at least one unbuffered primary bile acid granules, especially coated unbuffered cholic acid granules; [0184] h5. Mixing the said coated at least one unbuffered primary bile acid granules, especially unbuffered cholic acid granules with at least one excipient B; and [0185] i5. Tableting the final blend to obtain dispersible or orodispersible tablets or filling the final blend in sprinkle capsules or sachets.

[0186] According to one embodiment, granulation can be a dry granulation performed with a swaying granulator (e.g. High Efficiency Swaying Granulator manufactured by Changzhou Kewei Mechanical Manufacturing Co., Ltd) or a high shear mixer-granulator (e.g. Aeromatic-Fielder™ manufactured by GEA Pharma Systems), or a wet granulation performed with air in a fluidized bed dryer granulator (e.g. GPCG1 Top Spray manufactured by Glatt) or an impeller in a high shear granulator (e.g. VG25 manufactured by Glatt), or screws in a twin screw granulator (e.g. Pharma 24 TSG Twin Screw Granulator manufactured by Thermo Scientific).

[0187] According to one embodiment, the granulation is a wet granulation. The liquid solution used for the wet granulation can be aqueous based or solvent based. Typical liquids include water, ethanol, isopropanol and combinations thereof.

[0188] According to one embodiment, the wet granulation is performed with a high shear impeller or a fluidized bed dryer granulator.

[0189] According to one embodiment, the wet granulation is performed with a high shear impeller using an aqueous liquid solution.

[0190] According to one embodiment, the wet granules are discharged and dried in a fluidized bed dryer. According to one embodiment, the wet granules are dried in a fluidized bed dryer at a temperature lower than 60° C., preferably lower than 46° C.

[0191] According to one embodiment, coating can be performed in a fluidized bed dryer granulator (e.g. GPCG1 Wurster manufactured by Glatt) using aqueous based or solvent based liquid solution; more preferably coating is performed in a fluidized bed dryer granulator using aqueous based liquid solution.

[0192] In a fifth aspect, the present invention relates to a pharmaceutical composition comprising at least one granule of the invention and at least one pharmaceutically acceptable carrier.

[0193] In a sixth aspect, the present invention relates to a medicament comprising at least one granule of the invention or the pharmaceutical composition of the invention as active ingredient.

[0194] In a seventh aspect, the present invention relates to a unit dosage form comprising a container containing at least one granule of the invention. In one embodiment, the unit dosage form comprises a container containing a formulation of the invention.

[0195] Generally, such unit dosages will contain between 10 and 1000 mg, and usually between 10 and 250 mg, preferably between 10 and 50 mg of cholic acid, e.g. about 10 mg, 25 mg, 50 mg per unit dosage.

[0196] In an eighth aspect, the present invention relates to a pharmaceutical composition comprising an effective amount of primary bile acid, especially cholic acid for use in the treatment of a patient suffering from a deficiency in primary bile acid synthesis.

[0197] The invention further provides the use of a granule according to the invention or a composition according to the invention for the manufacture of a medicament for the treatment of deficiency in primary bile acid synthesis.

[0198] The invention further relates to a method for treating a patient suffering from a deficiency in primary bile acid synthesis which comprises administering to a subject in need thereof a therapeutically effective amount of granules according to the invention or composition according to the invention. The present invention relates to a method for treating a patient suffering from a deficiency in primary bile acid synthesis comprising administering a formulation comprising an effective amount of at least one granule comprising at least one unbuffered primary bile acid, especially unbuffered cholic acid, and a coating comprising at least one gastric-fluid-soluble taste-making compound.

[0199] According to one embodiment, the patient suffers from a deficiency in primary bile acid synthesis.

[0200] According to one embodiment, the patient is a human.

[0201] According to one embodiment, the patient has no bicarbonate secretion deficiency.

[0202] According to a first embodiment, the patient is a pediatric patient aged 1 month to 6 years.

[0203] According to a second embodiment, the patient of any age has swallowing difficulty or swallowing disability.

EXAMPLES

[0204] The present invention is further illustrated by the following examples.

Example 1: Manufacturing of the Cholic Acid Pediatric Granules with Granulation, Coating then Mixing with an Excipient

[0205] Granule Composition 1

[0206] The following table presents the composition of the cholic acid pediatric pediatrics formulation.

TABLE-US-00001 Chemical name ingredient Dosage unit (mg) Quantity % (w/w) Cholic acid (CA) 25.00 16.67% PVP 2.50 1.66% Eudragit ® E PO 5.50 3.67% Maltitol Sweetpearl Roquette 117.00 78.0% Total 150.00 100.0%

[0207] Process of Manufacturing of the Pediatric Granules

[0208] 363.64 g of cholic acid were mixed with 36.36 g of polyvinylpyrrolidone K30 and then granulated by wet granulation using a high shear impeller. Water was used as granulation liquid. Cholic acid granules were then dried in a fluidized bed dryer (Glatt GPCG1). 400 g of cholic acid granules were then coated with an aqueous solution of Eudragit® EPO in a Wurster fluidized bed dryer granulator to achieve a mass of 5.5 mg for 25 mg of cholic acid (corresponding to 80 g of dry Eudragit® EP O). Spraying rate was of 6-7 g/min was applied and parameters were adjusted to ensure the product temperature was comprised between 25 and 30° C. Coated cholic acid granules were then dried and parameters were adjusted to ensure the temperature of the product to be not more than 40° C.

[0209] Finally, the powder was mixed with qs 100% of maltitol Sweetpearl Roquette.

Example 2: Manufacturing of the Cholic Acid Pediatric Granules with Granulation with an Excipient, then Coating

[0210] Granules Composition 2a

[0211] The following table presents the formulation of the cholic acid pediatric granules.

TABLE-US-00002 Chemical name ingredient Dosage unit (mg) Quantity % (w/w) Cholic acid (CA) 25.00 16.67% Dicalcium phosphate 87.50 58.33% PVP 11.25 7.50% Eudragit ® E PO 26.25 17.50% Total 150.00 100.0%

[0212] Process of Manufacturing of the Pediatric Granules

[0213] 80.7 g of cholic acid were mixed with 36.3 g of polyvinylpyrrolidone and 282 g of dicalcium phosphate and then granulated by wet granulation using a high shear impeller. Water was used as granulation liquid. Cholic acid granules were then dried in a fluidized bed dryer (Glatt GPCG1). 400 g of Cholic acid granules were then coated with an aqueous solution of Eudragit® EPO in a Wurster fluidized bed dryer granulator to achieve a mass of 26.25 mg for 25 mg of Cholic acid (corresponding to about 84 g of dry Eudragit® EP O). Spraying rate was of 6-7 g/min was applied and parameters were adjusted to ensure the product temperature was comprised between 25 and 30° C. Coated cholic acid granules were then dried and parameters were adjusted to ensure the temperature of the product to be not more than 40° C.

[0214] Granules Composition 2b

[0215] The following table presents another formulation of the cholic acid pediatric granules.

TABLE-US-00003 Chemical name ingredient Dosage unit (mg) Quantity % (w/w) Cholic acid (CA) 25.00 38.05% Mannitol 10.00 15.22% Microcristalline cellulose 10.00 15.22% HPC 1.40 2.13% Eudragit ® E PO 19.30 29.38% Total 65.70 100.0%

[0216] Process of Manufacturing of the Pediatric Granules

[0217] 25 g of cholic acid were mixed with 1.4 g of HPC, 10 g of mannitol and 10 g of microcrystalline cellulose and then granulated by wet granulation using a high shear impeller. Water was used as granulation liquid. Cholic acid granules were then dried in a fluidized bed dryer (Glatt GPCG1). 46.4 g of Cholic acid granules were then coated with an aqueous solution of Eudragit® EPO in a Wurster fluidized bed dryer granulator to achieve a mass of 19.30 mg for 25 mg of Cholic acid. Spraying rate was of 6-7 g/min was applied and parameters were adjusted to ensure the product temperature was comprised between 25 and 30° C. Coated cholic acid granules were then dried and parameters were adjusted to ensure the temperature of the product to be not more than 40° C.

Example 3: Manufacturing of the Cholic Acid Pediatric Formulation with Granulation with Excipients, then Coating and Tableting

[0218] Formulation 3a

TABLE-US-00004 Chemical name ingredient Dosage unit (mg) Quantity % (w/w) Cholic acid (CA) 25.00 16.67% Mannitol 10 6.67% Microcrystalline cellulose 10 6.67% HPC 1.40 0.93% Eudragit ® E PO 24.14 16.09% Microcrystalline cellulose 72.71 48.47% Sodium croscarmellose 6.00 4.00% Magnesium stearate 0.75 0.50% Total 150.00 100.00%

[0219] Formulation 3b

TABLE-US-00005 Chemical name ingredient Dosage unit (mg) Quantity % (w/w) Cholic acid (CA) 25.00 16.67% Mannitol 10 6.67% Microcrystalline cellulose 10 6.67% HPC 1.40 0.93% Eudragit ® E PO 19.30 12.87% Microcrystalline cellulose 77.55 51.70% Sodium croscarmellose 6.00 4.00% Sodium stearyl fumarate 0.75 0.50% Total 150.00 100.00%

[0220] Process of Manufacturing of the Pediatric Formulation

[0221] 377.16 g of cholic acid was mixed with 21.12 g of HPC, 150.86 g of microcrystalline cellulose and 150.86 g of mannitol and then granulated by wet granulation using a high shear impeller. Water was used as granulation liquid. Cholic acid granules were then dried in a fluidized bed dryer (Retsch).

[0222] 628.84 g of the prepared cholic acid granules were then coated with an aqueous solution of Eudragit® EPO in a Wurster fluidized bed dryer granulator to achieve a mass of 24.14 mg for 25 mg of cholic acid (corresponding to 327.16 g of dry Eudragit® EP O). Spraying rate was of 8-10 g/min was applied and parameters were adjusted to ensure the product temperature was comprised between 25 and 35° C. Coated cholic acid granules were then dried and parameters were adjusted to ensure the temperature of the product to be not more than 40° C.

[0223] 117.57 g of the coated cholic acid granules were mixed with 121.18 g of microcrystalline cellulose and 10.00 g of sodium croscarmellose and blended during 5 minutes at 2×22 rpm. 1.25 g of magnesium stearate or sodium stearyl fumarate was then added and the mixture was blended during 2 minutes at 2×22 rpm. The final blend was then tableted on a rotative press to obtain dispersible tablets. No cracking was observed during the tableting step.

Example 4: Bitterness Test

[0224] Formulation 4: EthylCellulose

TABLE-US-00006 Chemical name ingredient Dosage unit (mg) Quantity % (w/w) Cholic acid (CA) 25.00 81.7% PVP 2.17 7.1% Ethylcellulose + 3.43 11.2% Hypromellose 2910 Total 30.60 100.0%

[0225] Formulation 5: Eudragit® RL30D+Carboxymethylcellulose Sodique (Na-CMC)

TABLE-US-00007 Chemical name ingredient Dosage unit (mg) Quantity % (w/w) Cholic acid (CA) 25.00 81.94% PVP 2.17 7.13% Eudragit ® RL 30D + Na-CMC + 3.33 10.93% Polysorbate 80 + Talc Total 30.50 100.0%

[0226] Formulation 6: Eudragit® E PO

TABLE-US-00008 Chemical name ingredient Dosage unit (mg) Quantity % (w/w) Cholic acid (CA) 25.00 81.94% PVP 2.17 7.13% Eudragit ® E PO 3.33 10.93% Total 30.50 100.0%

[0227] Process of Manufacturing of the Pediatric Formulation

[0228] Cholic acid was mixed with polyvinylpyrrolidone K30 granulated by wet granulation using a Top Spray fluidized bed dryer granulator (Glatt GPCG1). Water was used as granulation liquid. Spraying rate was of 10-12 g/min was applied and parameters were adjusted to ensure the product temperature was comprised between 25 and 35° C. Coated cholic acid granules were then dried and parameters were adjusted to ensure the temperature of the product to be not more than 40° C.

[0229] Cholic acid granules were then coated with a taste-masking compound in a Wurster fluidized bed dryer granulator. Spraying rate of 6-7 g/min was applied and parameters were adjusted to ensure the product temperature was comprised between 25 and 45° C. Coated cholic acid granules were then dried and parameters were adjusted to ensure the temperature of the product to be not more than 45° C.

[0230] Results

[0231] The formulations 1-2-3-4-5-6 were then swallowed as it is, or/and in suspension in water to evaluate their bitterness. The rate of emergence of the bitterness and its intensity were then evaluated for each formulation by a panel of 5 persons. A score between 0 and ++ was assigned. ++ means that the formulation is highly bitter and 0 means there is no bitterness.

TABLE-US-00009 Rate of emergence of the bitterness Formulation Intensity Dry Suspension in water Formulation 1 0 — No bitter taste Formulation 2a 0 — No bitter taste Formulation 2b 0 — No bitter taste Formulation 3a 0 — No bitter taste Formulation 3b 0 — No bitter taste Formulation 4 ++ 0-10 seconds ~10 seconds Formulation 5 ++ 0-10 seconds ~10 seconds Formulation 6 + 0-10 seconds ~10 seconds

Example 5: Granule Size Distribution Before Coating

[0232] The size distribution of the granules was evaluated by a shear method in two batches of the formulation 3b.

[0233] Before Coating

TABLE-US-00010 % of particles retained per sieve Shear (μm) Batch 1 Batch 2 710 0.35 0.20 500 0.31 0.00 355 2.30 2.33 250 6.76 9.11 180 19.10 23.07 125 37.70 37.84 90 22.98 19.10 Bottom 11.09 8.35

[0234] The size distribution of the granules before coating was found to be practically between 90 μm and 500 μm. The mean distribution of the particle size was between 90 and 250 μm and less than 3% of the particles were larger than 250 μm.

[0235] After Coating

TABLE-US-00011 % of particles retained per sieve Shear (μm) Batch 1 Batch 2 710 0.04 0.20 500 0.98 1.52 355 5.04 10.28 250 16.45 26.08 180 26.17 27.48 125 28.55 23.36 90 15.66 8.12 Bottom 7.11 2.96

[0236] The size distribution of the granules after coating was found to be practically between 90 μm and 500 μm. The mean distribution of the particle size was from 90 to 355 μm, with less than 12% of the particles being larger than 355 μm.

Example 6: Uniformity of Dosage Units

[0237] Using the batch 2 of formulation 3b coated granules, two series of dispersible tablets were prepared as described in example 3.

[0238] Each series has been subjected to the uniformity test of the European Pharmacopeia 2.9.40.

TABLE-US-00012 (% of the indicated value) Batch 2 sample Series 1 Series 2 D1 104.53 108.73 D2 102.92 110.02 D3 105.09 106.45 M4 102.76 106.40 M5 103.70 103.94 M6 99.74 103.86 M7 103.13 104.30 F8 103.88 103.22 F9 104.30 104.57 F10 100.70 102.40 Mean Value 103.08 105.39 s 1.69 2.46 ETR 1.64 2.34 Acceptation value 5.62 9.80

[0239] Series 1 tablets showed and acceptation value of 5.62.

[0240] Series 2 tablets showed and acceptation value of 9.80.

[0241] Both series were found to conform with the European Pharmacopeia standards as they showed an inferior acceptation value (AV) to the maximum allowed acceptance value of 15.0.

[0242] Consequently, the primary bile acid formulations of the invention, present advantageous size and homogeneity, guarantying a stable dosing when administered to pediatric patients.