Film-coated tablet comprising a triazine derivative for use in the treatment of diabetes

Abstract

This invention pertains to a film-coated tablet comprising an inner core and an external coating, wherein the inner core comprises a high proportion of a specific triazine derivative, namely 2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine and pharmaceutically acceptable salts thereof, and a specific binder. It is also directed to the use of these tablets in the treatment of diabetes and/or complications thereof. This invention is further directed to a specific process for the manufacture of these film-coated tablets, which involves a granulation step in a high-shear mixer.

Claims

1. A film-coated tablet comprising: (a) an inner core comprising: at least 85 wt. % of a triazine derivative 2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine or pharmaceutically acceptable salts thereof, relative to the total weight of the tablet, hydroxypropylcellulose as a binder, at least one glidant, at least one disintegrant, and at least one lubricant; wherein the inner core is substantially free of povidone and crospovidone; and (b) an external coating comprising at least one water-soluble film-forming agent.

2. The film-coated tablet according to claim 1, characterized in that the triazine derivative is selected from the group consisting of (+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine and pharmaceutically acceptable salts thereof; (−)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine and pharmaceutically acceptable salts thereof; and their mixtures.

3. The film-coated tablet according to claim 2, characterized in that the triazine derivative is selected from the group consisting of (+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine and pharmaceutically acceptable salts, optionally mixed with (−)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine and pharmaceutically acceptable salts thereof in a (+):(−) weight ratio of at least 95:5.

4. The film-coated tablet according to claim 1, characterized in that the pharmaceutically acceptable salt is a hydrochloride salt.

5. The film-coated tablet according to claim 1, characterized in that the water-soluble film-forming agent is an acrylic polymer or a cellulosic polymer, and the coating optionally further includes at least one compound selected from an opacifying and/or coloring agent, plasticizing agents, fillers, sweeteners, lubricants, surfactants, and mixtures thereof.

6. The film-coated tablet according to claim 1, characterized in that the tablet comprises from 250 to 1000 mg of the triazine derivative.

7. The film-coated tablet according to claim 1, characterized in that the glidant is selected from the group consisting of: anhydrous colloidal silica, magnesium stearate, starch, talc, and mixtures thereof.

8. The film-coated tablet according to claim 1, characterized in that the disintegrant is selected from the group consisting of: sodium croscarmellose, sodium carboxymethyl starch, hydroxypropylcellulose, calcium carboxymethylcellulose, microcrystalline cellulose, calcium carbonate, magnesium aluminum silicate, sodium starch glycolate, pregelatinized starch, sodium alginate, alginic acid, guar gum, and their mixtures.

9. The film-coated tablet according to claim 1, characterized in that the lubricant is selected from the group consisting of: magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, sucrose fatty acid ester, talc, and mixtures thereof.

10. The film-coated tablet according to claim 1, characterized in that the binder consists of hydroxypropylcellulose.

11. The film-coated tablet according to claim 1, characterized in that it comprises: triazine derivative: at least 85 wt. %; hydroxypropylcellulose: 1.5-4.5 wt. %; disintegrant(s): 1.5-3 wt. %; glidant(s): 0.8-2.5 wt. %; lubricant(s): 0.5-1.5 wt. %; and coating: 2-3 wt. %, provided that the total content of the above ingredients amounts to 100 wt. %.

12. A process for the manufacture of the film-coated tablet according to claim 1, comprising the following successive steps: 1) Wet granulating the triazine derivative with hydroxypropylcellulose and optionally part of the glidant, in a high-shear mixer, using water as a granulation aid, 2) drying the granules, 3) mixing the granules with the remaining excipients, 4) compressing the resulting mixture on a tableting machine, and 5) coating the tablets thus obtained.

13. A method of treating diabetes or complications thereof in a subject, the method comprising administering to the subject the film coated tablet according to claim 1.

14. The film-coated tablet according to claim 5, wherein the water-soluble film-forming agent is hydroxypropylmethylcellulose.

15. The film-coated tablet according to claim 6, wherein the tablet comprises about 500 mg or about 750 mg of the triazine derivative.

16. The film-coated tablet according to claim 7, wherein the glidant is anhydrous colloidal silica.

17. The film-coated tablet according to claim 8, wherein the disintegrant is sodium croscarmellose.

18. The film-coated tablet according to claim 9, wherein the lubricant is magnesium stearate.

19. The film-coated tablet according to claim 1, wherein the triazine derivative is 2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine or hydrochloride salt thereof, the binder is hydroxypropyl cellulose, the disintegrant is sodium croscarmellose, the lubricant is magnesium stearate and the glidant is anhydrous colloidal silica.

20. The film-coated tablet of claim 1, which generates less than 2.0 wt. % of total degradation products, as measured by HPLC, after six-month storage at 40° C./75% HR in a packaging blister.

21. An oral film-coated tablet comprising an inner core which is substantially free of crospovidone and povidone and which comprises: at least 85 wt. % of 2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine or hydrochloride salt thereof, at least 1.5 wt. % of hydroxypropylcellulose, from 1.5 to 3 wt. % of sodium croscarmellose, from 0.8 to 2.5 wt. % of anhydrous colloidal silica, and from 0.5 to 1.5 wt. % of magnesium stearate, the percentage being relative to the total weight of the tablet; and an external coating accounting for 2 to 3 wt. % of the total weight of the tablet and comprising at least one water-soluble film-forming agent.

22. The film-coated tablet of claim 21, which generates less than 2.0 wt. % of total degradation products, as measured by HPLC, after six-month storage at 40° C./75% HR in a packaging blister.

23. The film-coated tablet of claim 1, wherein hydroxypropylcellulose accounts for at least 1.5% by weight relative to the total weight of the tablet.

Description

FIGURES

(1) FIG. 1 shows the dissolution rates of two tablets of this invention (optimized tablets) compared with that of conventional tablets, at pH 1.2.

(2) FIG. 2 shows the dissolution rates of two tablets of this invention (optimized tablets) compared with that of conventional tablets, at pH 6.8.

EXAMPLES

(3) This invention will be better understood in light of the following examples which are given for illustrative purposes only and do not intend to limit the scope of the invention, which is defined by the attached claims.

Example 1: Manufacture of Tablets According to this Invention

(4) Four tablets having the following compositions were prepared.

(5) TABLE-US-00001 Constituent Tablets 1 Tablets 2 Imeglimin 500 mg 750 mg 500 mg 750 mg Hydroxypropylcellulose 10.87 mg 16.30 mg 21.9 mg 33.0 mg Sodium croscarmellose 11.18 mg 16.77 mg 10.4 mg 16.0 mg Anhydrous colloidal 5.05 mg 7.58 mg 10.6 mg 15.8 mg silica (Aerosil ® 200) Magnesium stearate 5.33 mg 8.00 mg 5.5 mg 8.2 mg Opadry ® .sup.(1) 13.53 mg 20.30 mg 14.0 mg 21.0 mg Total 546.0 mg 819.00 mg 562.4 mg 844.0 mg .sup.(1) Hypromellose, polyethylene glycol, saccharin sodium, talc and titanium dioxide.

(6) Tablets 1 were manufactured according to a process comprising a first step of preparing a premix of imeglimin with anhydrous colloidal silica, then mixing this premix with hydroxypropylcellulose in a high-shear mixer. The granules thus obtained were dried with a fluid-bed dryer. The dried granules had a moisture content of about 0.8-1.0%, as measured by the Karl-Fischer Method, in accordance with Ph. EUR 2.5.12. They were then sieved and mixed with sodium croscarmellose and magnesium stearate within a container blender to obtain the final blend. This blend was compressed on a standard rotary press. The tablets cores thus obtained were then film-coated with an aqueous suspension of Opadry® in a standard coater. Tablets 2 were prepared similarly, except that anhydrous colloidal silica was added to the extragranular materials instead of being premixed with imeglimin.

Example 2: Comparative Tablets

(7) Tablets of two different strengths having the following compositions were prepared.

(8) TABLE-US-00002 Constituent Amount Amount Imeglimin 500 mg 750 mg Gelatin 27.8 mg 41.7 mg Microcrystalline cellulose 134.1 mg 201.2 mg Anhydrous colloidal silica 10.2 mg 15.4 mg (Aerosil ® 200) Sodium croscarmellose 21.0 mg 31.5 mg Magnesium stearate 7.0 mg 10.5 mg Opadry ® .sup.(1) 17.5 mg 24.7 mg Total 717.6 mg 1075.0 mg .sup.(1) Hypromellose, polyethylene glycol, saccharin sodium, talc and titanium dioxide

(9) These tablets were prepared as follows.

(10) Granules of imeglimin were prepared by using a premix of imeglimin with 50 wt. % of the silica, which was wet granulated using a standard process comprising fluid-bed granulation. Gelatin suspended in water was used as a granulation aid. The granules were dried within the fluid-bed granulator and then sieved and mixed with the remaining components within a contained blender to get the final blend. The ready-to-press mixture was compressed on a standard rotary press. The tablet cores thus obtained were then film-coated with an aqueous suspension of Opadry® in a standard coater.

(11) As can be seen from the above table, these conventional tablets are much heavier and thus larger than the tablets according to this invention, which makes them difficult to swallow.

Example 3: Dissolution Tests

(12) Dissolution rates indicative of bioavailability were performed according to US Pharmacopoeia <711> and European Pharmacopoeia 2.9.3 version using a paddle apparatus with a stirring speed of 75 rpm, a 900 mL sample and a buffer adjusted to pH 6.8. The dissolved concentration of imeglimin is determined minimal at a specified time point from each vessel by UV detection at 240 nm. The results of this experiment are provided in the following table for Tablets 1 and 2 of Example 1 when stored in PVC/PE/PVDC blisters under different conditions.

(13) TABLE-US-00003 Dissolution (%) within 30 min Tablets 1 (500 mg) Tablets 2 (500 mg) 40° C./ 30° C./ 40° C./ 30° C./ Time 75% HR 65% HR 75% HR 65% HR 0 month 101 101  99 99 3 months  98 — 101 99 6 months  99 100 100 99

(14) From this table it appears that imeglimin fully dissolves within 30 min and that this dissolution rate is stable with time. The tablets of this invention may thus allow immediate release of imeglimin within the stomach.

(15) Additional dissolution experiments were performed to compare the dissolution rates of the tablets according to this invention, as described in Example 1, with that of the conventional 500 mg tablets as described in Example 2. These experiments were conducted according to US Pharmacopoeia <711> and European Pharmacopoeia 2.9.3 version using a paddle apparatus with a stirring speed of 50 rpm, a 900 mL sample and a buffer adjusted either to pH 1.2 or to pH 6.8. The dissolved concentration of imeglimin is determined minimal at a specified time point from each vessel by UV detection at 240 nm. The results of these experiments are illustrated on FIGS. 1 and 2, wherein Batch 151907 refers to Tablet 1 and Batch 171055 refers to Tablet 2. As shown on these Figures, the dissolution rates of Tablets 1 and 2 is similar to, or even greater than, that of the conventional tablets, both at pH 1.2 and at pH 6.8.

Example 4: Stability Tests

(16) The variation in imeglimin content and total degradation products over time for Tablets 1 and 2 of Example 1 were assessed by HPLC suitable for gradient elution and UV detection at 215 nm. The calculation was done against an external standard. The results of these experiments are reported in the following table.

(17) TABLE-US-00004 Assay of imeglimin (%) Total degradation products (%) Tablets 1 (500 mg) Tablets 2 (500 mg) Tablets 1 (500 mg) Tablets 2 (500 mg) 40° C./ 30° C./ 40° C./ 30° C./ 40° C./ 30° C./ 40° C./ 30° C./ Time 75% HR 65% HR 75% HR 65% HR 75% HR 65% HR 75% HR 65% HR 0 month 97 97 97 97 0.08 0.08 <0.05 <0.05 3 months 100 — 98 97 <0.05 — <0.05 <0.05 6 months 99 98 98 98 0.06 0.15 <0.05 0.06

(18) These results demonstrate that imeglimin is chemically stable over time, with a content of active compound which remains within the 90-105% range and a content of total degradation products which remains well below 2.0%.