Pharmaceutical composition comprising citrate and bicarbonate salts, and use thereof for treating cystinuria

Abstract

A solid oral pharmaceutical composition in the form of tablets including:a first solid oral pharmaceutical formulation in the form of at least one micro-tablet, the micro-tablet consisting of a core including at least one Krebs cycle precursor salt as active ingredient, and of a coating including at least one coating agent, anda second oral pharmaceutical formulation in the form of at least one mini-tablet, the mini-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 use thereof as a medicament, in particular in the treatment and/or prevention of cystinuria.

Claims

1. A solid pharmaceutical composition for oral use in the form of tablets for treating cystinuria, comprising: a first solid pharmaceutical formulation for oral use in the form of at least one microtablet, said microtablet being constituted by: a core comprising as active ingredient at least one Krebs cycle precursor salt selected from the group consisting of fumarates, malates, citrates, alpha-ketoglutarate, succinyl-coenzyme A, succinates and oxaloacetate, and a coating comprising at least one pH independent coating agent selected from the group consisting of ethyl cellulose, paraffin waxes, beeswax, carnauba wax, copolymers of ammonium methacrylate of type A and B, and polyacrylates with dispersion of about 30%, wherein the first formulation comprises from 1 to 3% by weight of said at least one coating agent relative to the total weight of the first formulation and has an in vitro dissolution in a dissolution medium buffered at any pH in a range between 1.3 and 7, with a dissolution apparatus of type 2, at a rate from 30 to 50% in 1 hour; and a second solid pharmaceutical formulation for oral use in the form of at least one mini-tablet, said mini-tablet being constituted by: a core comprising as active ingredient at least one bicarbonate salt selected from the group consisting of potassium bicarbonate, sodium bicarbonate and magnesium bicarbonate, and at least one sustained-release hydrophilic matrix selected from the group consisting of sodium salts of carboxymethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, the at least one sustained-release hydrophilic matrix being 10% to 30% by weight of the second-formulation; and a coating comprising from 1% to 20% by weight, relative to the total weight of the second formulation, of at least one pH independent coating agent selected from the group consisting of ethyl cellulose, paraffin waxes, beeswax, carnauba wax, copolymers of ammonium methacrylate of type A and B, and polyacrylates with dispersion of about 30%, wherein the second formulation has an in vitro dissolution in a dissolution medium buffered at any pH in a range between 1.3 and 7, with a dissolution apparatus of type 2, at a rate of 5% to 15% in one hour.

2. The composition according to claim 1, wherein the composition comprises from 30 to 70% of the first formulation and from 70 to 30% of the second formulation, by weight relative to the total weight of the composition.

3. The composition according to claim 1, wherein the first formulation comprises from 40% to 80% by weight of Krebs cycle precursor salt based on the total weight of the first formulation and the second formulation comprises from 40% to 80% by weight of bicarbonate salt based on the total weight of the second formulation.

4. The composition according to claim 1, wherein the first formulation comprises from 0.01% to 5% of coating agent of the microtablet of the first formulation relative to the total weight of the first formulation.

5. The composition according to claim 1, wherein the first formulation comprises from 55% to 70% of potassium citrate, from 20 to 30% of microcrystalline cellulose, from 0.02% to 2% of magnesium stearate, from 0.01% to 1% of glyceryl behenate and from 1 to 3% of ethyl cellulose, relative to the total weight of the first formulation.

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

7. A method for treating cystinuria and/or reducing the occurrence of lithiasis and cystinuria, comprising administering to a subject in need thereof and effective amount of the composition according to claim 1.

8. The composition according to claim 2, wherein the first formulation comprises from 40% to 80% by weight Krebs cycle precursor salt based on the total weight of the first formulation and the second formulation comprises from 40% to 80% by weight bicarbonate salt based on the total weight of the second formulation.

9. The composition according to claim 2, wherein the first formulation comprises from 0.01% to 5% coating agent of the microtablet of the first formulation relative to the total weight of the first formulation.

10. The composition according to claim 3, wherein the first formulation comprises from 0.01% to 5% coating agent of the microtablet of the first formulation relative to the total weight of the first formulation.

11. The composition according to claim 1, wherein the Krebs cycle precursor salt is a citrate salt selected from the group consisting of potassium citrate, sodium citrate and magnesium citrate.

12. The composition according to claim 1, wherein the coating agent of the microtablet of the first formulation is a polymer of ethylcellulose.

13. The composition according to claim 1, wherein the at least one bicarbonate salt in the second formulation is potassium bicarbonate.

14. The composition according to claim 1, wherein the coating agent of the second-formulation mini-tablet is a polymer of ethylcellulose.

15. The composition according to claim 1, wherein said sustained-release matrix of the second formulation is a hydroxypropyl methylcellulose.

16. The composition according to claim 1, wherein the second formulation 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 at a rate of at most 50% in 4 hours.

Description

(1) The invention is illustrated in the attached FIGS. 1 to 4, where:

(2) FIG. 1 shows the dissolution profile as the dissolution rate T (percentage of active ingredientpotassium citrate) as a function of time D (h:min) for a first formulation identified by A;

(3) FIG. 2 shows the dissolution profile as the dissolution rate T (percentage of active ingredientpotassium bicarbonate) as a function of time D (h:min) for a composition identified by I;

(4) FIG. 3 shows the variations in urinary pH as a function of the hours (h-h) over one day for one subject; and

(5) FIG. 4 shows the variations in urinary pH as a function of the hours (h-h) over one day for three other subjects.

(6) FIGS. 1, 2, 3 and 4 commented upon in Examples 1, 2, 3 and 4 below, respectively.

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

EXAMPLE 1

(8) A batch of microtablets of 2 mm size (average diameter) is produced according to the method described above, namely a step of mixing the powders, followed by a compression step, then a coating step. This batch is batch A, and consists of 200 g of microtablets. These microtablets have the following composition:

(9) Potassium citrate (active ingredient, source Dr Paul Lohmann): 66.9%

(10) Microcrystalline cellulose (binder, Ceolus KG-802 from the company Asahi): 19.7%

(11) Microcrystalline cellulose (binder, Ceolus UF-711 from the company Asahi): 9.8%

(12) Magnesium stearate (flow agent): 2.0%

(13) Glyceryl behenate (lubricant, commercial reference Compritol ATO 888 from the company GATTEFOSSE): 0.01%;

(14) Ethyl cellulose polymer (coating agent, commercial reference Ethocel 20 standard premium from the company Dow): 1.66%.

(15) These microtablets are very well accepted and tolerated by patients. Moreover, they have no taste and are easy to swallow.

(16) FIG. 1 shows the in vitro dissolution profile of one gram of these microtablets in water, under the conditions described below, over a period of 2 hours. Microtablets A were put in a Pharmatest dissolution apparatus, model PTW S3C, in which the temperature conditions are 37 C.0.5 C., and the rotary speed is 100 rpm. The dissolution medium is purified water at pH 7. A curve A was obtained, which illustrates the release of potassium citrate, which takes place gradually and evenly. As shown in FIG. 1, the microtablets are able to release the citrate salt in vitro in a dissolution medium of purified water at pH 7 at a rate of 4.5% in 15 minutes, 20.6% in 30 minutes, and 48.6% in one hour.

EXAMPLE 2

(17) A batch I of microtablets with a size (average diameter) of 2 mm was produced according to the method described above, namely a step of mixing the powders, followed by a compression step and then a coating step, at a rate of 200 g of microtablets per batch. These tablets have the following composition:

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

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

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

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

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

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

(24) Curve I in FIG. 2 shows the in vitro dissolution profile of these microtablets in purified water at pH 7.

(25) 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 with a rotary speed of 100 rpm.

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

(27) The microtablets I are very well accepted and tolerated by patients. Moreover, they have no taste and are easy to swallow.

(28) Curve I in FIG. 2 illustrates the release of potassium bicarbonate, which 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.

(29) Moreover, curve I illustrates the release of potassium bicarbonate that leads to almost complete dissolution after 12 to 15 hours.

EXAMPLE 3

(30) A composition according to the invention was prepared, based on one third (in % by weight) of the first formulation from Example 1 and two thirds (in % by weight) of the second formulation from Example 2.

(31) A healthy subject shows a baseline of urinary pH represented in FIG. 3 by curve 1, over one day without treatment.

(32) The subject was following a diet without alcoholic drinks, without carbonated drinks, and reduced in food that contains citric acid (i.e. no drinks of the orange juice type or canned food containing citric acid). Moreover, red meats and cheeses were forbidden.

(33) Three different tests were carried out on this subject (curves 2, 3 and 4). The urinary pH is measured on fresh urine just seconds following micturition with an electrode-type pH meter.

(34) Curve 2 shows the measurements of urinary pH of the patient at regular intervals throughout the 24-hour period for a daily dose of 18 grams in nine administrations (each shown by an arrow P), of citrate in immediate-release officinal formula.

(35) Curve 3 shows the measurements of urinary pH of the patient at regular intervals throughout the 24-hour period for a daily dose of 18 grams in nine administrations (each shown by an arrow P), of potassium bicarbonate in immediate-release officinal formula.

(36) Curve 4 shows the measurements of urinary pH of the patient at regular intervals throughout the 24-hour period for a daily dose of 18 grams in only two administrations (each shown by an arrow Q), of the composition according to the invention.

(37) It can be seen from FIG. 3 that only the composition according to the invention allows the patient's urinary pH to be maintained at values between 7 and 7.6, throughout the day. This is all the more remarkable because just two administrations per day make it possible to achieve such a result.

EXAMPLE 4

(38) The composition of Example 3 was tested on three different healthy subjects (two men referenced 1 and 3, and one woman referenced 2).

(39) FIG. 4 shows the variations of the urinary pH as a function of the time over the course of a day.

(40) For each of these patients i (i=1, 2 or 3), a baseline curve Bi is obtained, for urinary pH over the course of a day without treatment.

(41) Then these healthy subjects were administered two doses per day of the composition according to the invention, one dose of 9 g for each of the two male subjects and of 6 g for the female subject. The urinary pH is measured on the fresh urine just seconds after micturition using an electrode-type pH meter. The subjects were all following the same diet as the subject described in Example 3.

(42) Curves T1 and T2 that are shown represent, for subjects 1 and 2, the mean value of two experiments conducted at an interval of a month under the same conditions.

(43) By measuring the urinary pH while taking the composition according to the invention (curves T1, T2, and T3), relative to a reference without taking medicine (curves B1, B2 and B3), it can be seen that the composition of the invention makes it possible to obtain satisfactory control of urinary pH, in that this pH is never below a value of 7.