Pharmaceutical composition comprising bicarbonate salt, and use thereof as a medicament in the treatment and/or prevention of urinary lithiases and related diseases

Abstract

A solid oral pharmaceutical composition in the form of at least one tablet, the tablet consisting of a core including at least one bicarbonate salt as active ingredient and at least one prolonged-release matrix, and of a coating including at least one coating agent, the composition allowing continuous release in vivo over a period from after a quarter of an hour and up to twelve hours after taking a single dose, for use thereof as a medicament, in particular in the treatment and/or prevention of urinary lithiasis and related diseases, occurring at a physiological pH and/or during urinary acidosis and/or during hypobicarbonataemia and/or during hypocitraturia and/or during hypercalciuria and/or during hyperoxaluria.

Claims

1. Solid pharmaceutical composition for oral administration in the form of a tablet, said tablet consisting of: (i) a core comprising from 40% to 80% by weight of at least one bicarbonate salt as the sole active ingredient, the salt being selected from the group consisting of potassium bicarbonate, sodium bicarbonate and magnesium bicarbonate, and a sustained-release matrix comprising from 10% to 30% by weight of at least one selected from the group consisting of sodium salts of carboxymethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, and combinations thereof; and (ii) a coating comprising from 1% to 20% by weight of at least one pH independent coating agent selected from the group consisting of ethyl cellulose, waxes, ammonium methacrylate copolymers of type A and type B, polyacrylates of about 30% dispersion, and combinations thereof, each of said percentages by weight being relative to the total weight of the composition, said composition providing continuous release in vivo of said bicarbonate salt over a period of 15 minutes to twelve hours after the oral administration of a single dose of said composition to a subject, wherein the composition has a dissolution profile that has pH-independent kinetics, and wherein the composition is able to release the bicarbonate salt in vitro in a dissolution medium of purified water at pH 7 with a dissolution apparatus of type 2, according to the European Pharmacopoeia 2.9.3 Dissolution test for solid dosage forms, at a rate within a range of 5% to 15% in one hour, at a rate within a range of 35% to 55% in five hours, and at a rate within a range of 70% to 90% in ten hours, and the composition is able to release the bicarbonate salt in vitro in a dissolution medium of solution buffered at pH 1.3 with a dissolution apparatus of type 2, according to the European Pharmacopoeia 2.9.3 Dissolution test for solid dosage forms, at a rate within a range of 5% to 15% in one hour, at a rate within a range of 35% to 55% in five hours, and at a rate within a range of 70% to 90% in ten hours.

2. The composition according to claim 1, wherein the composition further comprises from 5% to 20% by weight, relative to the total weight of the composition, of a binder selected from the group consisting of microcrystalline celluloses, polyvidone, polyvinylpyrrolidone, copovidone, shellac, gelatin, polymethacrylates, synthetic resins, acrylates, maltodextrin, and starches.

3. The composition according to claim 1, wherein the composition further comprises from 0.01% to 5% by weight, relative to the total weight of the composition, of a flow agent selected from the group consisting of stearic acid, polyethylene glycol, magnesium stearate, calcium stearate, zinc stearate, talc, silica, hydrogenated castor oil, glyceryl behenate, and glyceryl palmitostearate.

4. The composition according to claim 1, wherein said tablet has a size within a range of 2 pm to 25 mm.

5. The composition according to claim 1, wherein the composition comprises from 60% to 70% potassium bicarbonate, from 15% to 25% hydroxypropyl methylcellulose, from 7% to 17% microcrystalline cellulose, from 1% to 3% glyceryl behenate, from 0.01% to 1% magnesium stearate, and from 1.5% to 3% ethyl cellulose, relative to the total weight of the composition.

6. The composition according to claim 1, wherein the at least one bicarbonate salt is potassium bicarbonate.

7. The composition according to claim 1, wherein the composition comprises from 50% to 80% by weight bicarbonate salt based on the total weight of the composition.

8. The composition according to claim 1, wherein the composition comprises from 15% to 25% by weight of the sustained-release matrix relative to the total weight of the composition.

9. The composition according to claim 2, wherein the composition further comprises from 5% to 10% by weight, relative to the total weight of the composition, of microcrystalline cellulose.

10. The composition according to claim 1, wherein the composition further comprises from 0.01% to 3% by weight, relative to the total weight of the composition, of magnesium stearate.

11. A solid pharmaceutical composition for oral administration in the form of a tablet, the tablet comprising: a core comprising from 50% to 80% by weight of at least one bicarbonate salt selected from the group consisting of potassium bicarbonate, sodium bicarbonate and magnesium bicarbonate, and a sustained-release matrix comprising from 15% to 25% by weight of hydroxypropyl methylcellulose; and a coating comprising from 1.5% to 3% by weight of ethyl cellulose, each of said percentages by weight being relative to the total weight of the composition said composition providing continuous release in vivo of said bicarbonate salt over a period of 15 minutes to twelve hours after the oral administration of a single dose of said composition to a subject, wherein the composition has a dissolution profile that has pH-independent kinetics, and wherein the composition is able to release the bicarbonate salt n vitro in a dissolution medium of purified water at pH 7 with a dissolution apparatus of type 2, according to the European Pharmacopoeia 2.9.3 Dissolution test for solid dosage forms, at a rate within a range of 5% to 15% in one hour, at a rate within a range of 35% to 55% in five hours, and at a rate within a range of 70% to 90% in ten hours, and the composition is able to release the bicarbonate salt in vitro in a dissolution medium of solution buffered at pH 1.3 with a dissolution apparatus of type 2, according to the European Pharmacopoeia 2.9.3 Dissolution test for solid dosage forms, at a rate within a range of 5% to 15% in one hour, at a rate within a range of 35% to 55% in five hours, and at a rate within a range of 70% to 90% in ten hours.

12. The composition according to claim 11, wherein the core comprises 60% to 70% by weight of potassium bicarbonate.

13. The composition according to claim 12, wherein the composition further comprises from 5% to 10% by weight of microcrystalline cellulose, and from 0.01% to 3% by weight of magnesium stearate, each of said percentages by weight being relative to the total weight of the composition.

14. A solid pharmaceutical composition for oral administration in the form of a tablet, the tablet comprising: a core comprising from 50% to 80% by weight of at least one bicarbonate salt as the sole active ingredient and which is selected from the group consisting of potassium bicarbonate, sodium bicarbonate and magnesium bicarbonate, and a sustained-release matrix comprising from 10% to 30% by weight of hydroxypropyl methylcellulose; and a coating comprising from 1 to 20% by weight of wax, each of said percentages by weight being relative to the total weight of the composition said composition providing continuous release in vivo of said bicarbonate salt over a period of 15 minutes to twelve hours after the oral administration of a single dose of said composition to a subject, wherein the composition has a dissolution profile that has pH-independent kinetics, and wherein the composition is able to release the bicarbonate salt in vitro in a dissolution medium of purified water at pH 7 with a dissolution apparatus of type 2, according to the European Pharmacopoeia 2.9.3 Dissolution test for solid dosage forms, at a rate within a range of 5% to 15% in one hour, at a rate within a range of 35% to 55% in five hours, and at a rate within a range of 70% to 90% in ten hours, and the composition is able to release the bicarbonate salt in vitro in a dissolution medium of solution buffered at pH 1.3 with a dissolution apparatus of type 2, according to the European Pharmacopoeia 2.9.3 Dissolution test for solid dosage forms, at a rate within a range of 5% to 15% in one hour, at a rate within a range of 35% to 55% in five hours, and at a rate within a range of 70% to 90% in ten hours.

15. The composition according to claim 14, wherein the bicarbonate salt is potassium bicarbonate.

16. The composition according to claim 14, wherein the coating comprises about 19% by weight of carnauba wax.

17. A method of treating alkalization of the urine and/or treating or reducing the incidence of urinary lithiasis and related diseases in a subject, comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition of claim 1.

18. Solid pharmaceutical composition for oral administration in the form of a tablet, said tablet consisting of: a core comprising from 40% to 80% by weight of at least one bicarbonate salt as an active ingredient, the salt being selected from the group consisting of potassium bicarbonate, sodium bicarbonate and magnesium bicarbonate; a sustained-release matrix comprising from 10% to 30% by weight of hydroxypropyl methylcellulose polymer; and a coating comprising from 1.5% to 3% by weight of ethyl cellulose polymer, each of said percentages by weight being relative to the total weight of the composition, said composition providing continuous release in vivo of said bicarbonate salt over a period of 15 minutes to twelve hours after the oral administration of a single dose of said composition to a subject, wherein the composition has a dissolution profile that has pH-independent kinetics, and wherein the composition is able to release the bicarbonate salt in vitro in a dissolution medium of purified water at pH 7 with a dissolution apparatus of type 2, according to the European Pharmacopoeia 2.9.3 Dissolution test for solid dosage forms, at a rate within a range of 5% to 15% in one hour, at a rate within a range of 35% to 55% in five hours, and at a rate within a range of 70% to 90% in ten hours, and the composition is able to release the bicarbonate salt in vitro in a dissolution medium of solution buffered at pH 1.3 with a dissolution apparatus of type 2, according to the European Pharmacopoeia 2.9.3 Dissolution test for solid dosage forms, at a rate within a range of 5% to 15% in one hour, at a rate within a range of 35% to 55% in five hours, and at a rate within a range of 70% to 90% in ten hours.

19. The composition according to claim 18, said tablet consisting of: a core comprising from 60% to 70% by weight of potassium bicarbonate; a sustained-release matrix comprising from 15% to 25% by weight of hydroxypropyl methylcellulose; and a coating comprising from 1.5% to 3% by weight of ethyl cellulose; the composition further comprising: a binder comprising from 7% to 17% microcrystalline cellulose; and a flow agent comprising from 1% to 3% glyceryl behenate and from 0.01% to 1% magnesium stearate, each of said percentages by weight being relative to the total weight of the composition.

20. The composition according to claim 14, wherein the coating comprises from 1 to 20% by weight of carnauba wax.

21. The solid pharmaceutical composition of claim 11, wherein said at least one bicarbonate salt is the sole active ingredient.

22. The solid pharmaceutical composition of claim 18, wherein said at least one bicarbonate salt is the sole active ingredient.

23. The solid pharmaceutical composition of claim 1, wherein said wax is paraffin wax.

24. The solid pharmaceutical composition of claim 1, wherein said wax is carnauba wax.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) The invention is illustrated in the attached FIGS. 1 and 2.

(2) FIG. 1 shows the dissolution profile as the dissolution rate T (percentage of active ingredient: potassium bicarbonate) as a function of time D (h:min) for three different compositions identified by I, II and III.

(3) FIG. 2 shows the dissolution profile as dissolution rate T (percentage of active ingredient: potassium bicarbonate) as a function of time D (h:min) for two different compositions identified by A and D.

(4) FIG. 1 is referred to in Example 1 below.

(5) FIG. 2 is referred to in Example 2 below.

(6) The following examples illustrate the invention without however limiting it.

Example 1

(7) Batch I: Curve I

(8) A batch I of microtablets of 2 mm size (average diameter) was produced according to the method described above, namely a step of mixing the powders, followed by a compression step, then a coating step, at a rate of 2000 g of microtablets per batch. These tablets have the following composition:

(9) Potassium bicarbonate (active ingredient, source Dr Paul Lohmann): 66.4%

(10) Hypromellose (matrix, HPMC 100 000 90SH0): 19.5%

(11) Hypromellose is a hydroxypropyl methylcellulose.

(12) Microcrystalline cellulose (binder, commercial reference Ceolus UF-711 from the company Asahi-Kasei): 9.8%

(13) Magnesium stearate (flow agent): 0.01%

(14) Glyceryl behenate (lubricant, commercial reference Compritol ATO 888 from the company GATTEFOSSE): 2%

(15) Ethyl cellulose (polymer) (coating material, commercial reference Ethocel 20 standard premium from the company Dow Chemical): 2.3%.

(16) Curve I in FIG. 1 shows the in vitro dissolution profile of these microtablets in purified water at pH 7.

(17) Such a profile was obtained by placing the mini-tablets in a Pharmatest dissolution apparatus, model PTW S3C, at a temperature of 37 C.0.5, with a volume of the dissolution vessel of 1 L and at a rotary speed of 100 rpm.

(18) The potassium bicarbonate is analysed by conductometry according to an analytical method validated according to the ICH recommendations CPMP/ICH/381/95-ICH Q2 (R1).

(19) Batch II: Curve II

(20) A batch II of microtablets of 2 mm size (average diameter) was produced according to the method described above, namely a step of mixing the powders, followed by a compression step, then a coating step, at a rate of 1000 g of microtablets per batch. These tablets have the following composition:

(21) Potassium bicarbonate (active ingredient, source Dr Paul Lohmann): 68.4%

(22) Hypromellose (matrix, HPMC 100 000 90SH): 19.6%

(23) Microcrystalline cellulose (binder, commercial reference Ceolus UF-711 from the company Asahi-Kasei): 9.8%

(24) Magnesium stearate (flow agent): 0.06%

(25) Ethyl cellulose (polymer) (coating material, commercial reference Ethocel 20 standard premium from the company Dow Chemical): 2.3%.

(26) Curve II in FIG. 1 shows the in vitro dissolution profile of these microtablets in purified water at pH 7. This profile and analysis of potassium bicarbonate were performed as for batch I.

(27) Batch III: Curve III

(28) A batch III of microtablets of 2 mm size (average diameter) was produced according to the method described above, namely a step of mixing the powders, followed by a compression step, then a coating step, at a rate of 2000 g of microtablets per batch. These tablets have the following composition:

(29) Potassium bicarbonate (active ingredient, source Dr Paul Lohmann): 66.4%

(30) Hypromellose (matrix, HPMC 100 000 90SH): 19.5%

(31) Microcrystalline cellulose (binder, commercial reference Ceolus UF-711 from the company Asahi-Kasei): 9.8%

(32) Magnesium stearate (flow agent): 0.01%

(33) Glyceryl behenate (lubricant, commercial reference Compritol ATO 888 from the company GATTEFOSSE): 2%

(34) Ethyl cellulose (polymer) (coating material, commercial reference Ethocel 20 standard premium from the company Dow Chemical): 2.3%.

(35) Curve III in FIG. 1 shows the in vitro dissolution profile of these microtablets in purified water at pH 7.

(36) Such a profile and analysis of potassium bicarbonate were achieved as for batch I.

(37) The microtablets I, II and Ill are very well accepted and tolerated by the subjects. Moreover, they have no taste and are easy to swallow.

(38) Curves I, II and III have substantially similar shapes, and each of the dissolution profiles corresponding to these curves I, II and III comply with the preferred conditions claimed for the composition of the present invention.

(39) Thus, each of the three curves I, II and III illustrates release of potassium bicarbonate that is gradual and even, meeting the criteria of a rate of at most 50% in 4 hours, at most 75% in 6 hours, and at most 90% in 8 hours.

(40) Moreover, each of the three curves I, II and III illustrates release of potassium bicarbonate that leads to almost complete dissolution after 12 to 15 hours.

Example 2

(41) Two batches A and D of tablets of 12 mm size (average diameter) were produced according to the method described above, namely a step of mixing the powders, followed by a compression step, then a coating step, at a rate of 200 g of tablets per batch. These tablets have the following composition:

(42) Curve A: Batch A

(43) Potassium bicarbonate (active ingredient, source Dr Paul Lohmann): 56%

(44) Hypromellose (sustained-release matrix, HPMC 100 000 90SH, source SEPPIC): 25%

(45) Carnauba wax (coating material): 19%

(46) Curve D: Batch D

(47) Potassium bicarbonate (active ingredient, source Dr Paul Lohmann): 71%

(48) Hypromellose (sustained-release matrix, HPMC 100 000 90SH, source SEPPIC): 10%

(49) Carnauba wax (coating material): 19%

(50) Curves A and D in FIG. 2 show the in vitro dissolution profiles of such 12-mm tablets in purified water at pH 7. The tablets are put in a Pharmatest dissolution apparatus, model PTW S3C, in which the temperature conditions are 37 C.0.5, the volume of the dissolution vessel is 1 L and the rotary speed is 100 rpm.

(51) The potassium bicarbonate is analysed by conductometry according to an analytical method validated according to the ICH recommendations CPMP/ICH/381/95-ICH Q2 (R1).

(52) Tablets A and D are very well accepted and tolerated by the subjects. Moreover, they have no taste and are easy to swallow.

(53) Curves A and D have substantially similar shapes, and each of these dissolution profiles A and D complies with the preferred conditions claimed for the composition of the present invention.

(54) Thus, each of the two curves A and D illustrates release of potassium bicarbonate that takes place gradually and evenly, meeting the criteria of a rate of at most 50% in 4 hours, at most 75% in 6 hours, and at most 90% in 8 hours.

(55) Moreover, each of the two curves D and A illustrates release of potassium bicarbonate that leads to almost complete dissolution after 12 to 15 hours.