USE OF A MIXTURE OF LAUROYL MACROGOLGLYCERIDE AND POLYETHYLENE GLYCOL AS AN EXCIPIENT

Abstract

The invention concerns the use, as a pharmaceutical or cosmetic excipient, of a composition which is solid at ambient temperature and in the form of individualized particles, said composition comprising: lauroyl macrogolglyceride, polyethylene glycol.

Claims

1. A pharmaceutical or cosmetic excipient composition, said composition comprising: lauroyl macrogolglyceride, and polyethylene glycol, wherein said composition is solid at ambient temperature, and is in the form of individualized particles, wherein said composition does not comprise a therapeutic active principle.

2. The composition according to claim 1, wherein the PEG has a molar mass in the range 1500 g/mol to 8000 g/mol.

3. The composition according to claim 1, wherein said composition contains at least two PEGs with different molar masses, said molar masses being in the range 1500 g/mol to 8000 g/mol.

4. The composition according to claim 1, wherein the weight ratio of lauroyl macrogolglyceride/polyethylene glycol is in the range 40/60 to 70/30.

5. The composition according to claim 1, wherein said composition contains only lauroyl macrogolglyceride and PEG.

6. The composition according to claim 1, wherein the individualized particles are in the form of pellets with a dimension which is greater than or equal to 1 mm.

7. A method of preparing the composition according to claim 1, said method comprising: heating lauroyl macrogolglyceride and polyethylene glycol to a temperature T1 in a manner so as to obtain a liquid mixture of lauroyl macrogolglyceride and polyethylene glycol, cooling the mixture of lauroyl macrogolglyceride and polyethylene glycol to a temperature T2 which is lower than the temperature T1, while keeping the mixture liquid, dividing the cooled mixture, and cooling the divided mixture to a temperature T3 which is lower than the temperature T2, thereby obtaining the individualized solid particles.

8. The method according to claim 7, wherein the lauroyl macrogolglyceride and the polyethylene glycol are mixed with each other before the heating step, then the mixture of lauroyl macrogolglyceride and polyethylene glycol is heated to the temperature T1.

9. The method according to claim 7, wherein the temperature T1 is greater than or equal to 80° C.

10. The method according to claim 7, wherein the temperature T2 is greater than or equal to 45° C., and less than or equal to 60° C.

11. The composition according to claim 1, wherein the PEG has a molar mass in the range 4000 g/mol to 6000 g/mol.

12. The composition according to claim 11, wherein the weight ratio of lauroyl macrogolglyceride/polyethylene glycol is in the range 40/60 to 70/30.

13. The composition according to claim 3, wherein said composition contains only lauroyl macrogolglyceride and PEG.

14. The composition according to claim 2, wherein the individualized particles are in the form of pellets with a dimension which is greater than or equal to 1 mm.

15. The composition according to claim 3, wherein the individualized particles are in the form of pellets with a dimension which is greater than or equal to 1 mm.

16. The composition according to claim 12, wherein the individualized particles are in the form of pellets with a dimension which is greater than or equal to 1 mm.

17. The composition according to claim 16, wherein said composition contains only lauroyl macrogolglyceride and PEG.

18. The method according to claim 7, wherein said dividing the cooled mixture comprises diving the cooled mixture into the form of drops and droplets.

19. The method according to claim 7, wherein the temperature T2 is greater than or equal to 55° C., and less than or equal to 60° C.

20. The method according to claim 8, wherein the temperature T1 is greater than or equal to 80° C., and the temperature T2 is greater than or equal to 45° C., and less than or equal to 60° C.

Description

[0055] The invention and the advantages thereof will become apparent from the following examples, made with the aid of the accompanying drawings, in which:

[0056] FIG. 1 (described above) is an HPLC-CAD (Charged Aerosol Detector) graph which illustrates the distributions of Gelucire® 44/14 alone, PEG 6000 alone, and a mixture (denoted M) of Gelucire® 44/14/PEG 6000 in a weight ratio of 65/35 in accordance with the invention;

[0057] FIG. 2 is a photograph of solid pellets in accordance with the invention:

[0058] FIG. 3a is a graph illustrating the liberation of piroxicam as a function of time, for a number of formulations:

[0059] FIG. 3b is a graph illustrating the liberation of piroxicam as a function of time, for a number of formulations in addition to FIG. 3a:

[0060] FIG. 4 is a graph illustrating the liberation of terfenadine as a function of time, for a number of formulations:

[0061] FIG. 5 is a graph illustrating the liberation of ibuprofen as a function of time, for a number of formulations.

EXAMPLE 1: PREPARATION OF THE EXCIPIENT IN ACCORDANCE WITH THE INVENTION

[0062] Different formulations for solid pellets obtained using the method described above are listed in Table I below.

TABLE-US-00001 TABLE I Ratio Temperature of Cooling Gelucire ® 44/14/PEG mixture (° C.) temperature (° C.) Gelucire ® 44/14/PEG 1500 = 10/90 48-51 5.0-5.5 Gelucire ® 44/14/PEG 4000 = 40/60 55-58 4.5-6.5 Gelucire ® 44/14/PEG 4000 = 55/45 54-55 4.8-6.0 Gelucire ® 44/14/PEG 4000 = 60/40 51-54 4.0-5.0 Gelucire ® 44/14/PEG 4000 = 65/35 54-57 5.0-6.0 Gelucire ® 44/14/PEG 4000 = 70/30 55 6.5 Gelucire ® 44/14/PEG 6000 = 60/40 57-60 5.5 to 8.5 Gelucire ® 44/14/PEG 6000 = 65/35 56-57 4.5 to 6.5 Gelucire ® 44/14/PEG 6000 = 70/30 60 5.5 to 7.5 Gelucire ® 44/14/PEG 8000 = 80/20 55 6.0 Gelucire ® 44/14/PEG 6000 + PEG 53-57 5.5-6.5 1500 = 50/20 + 30 Gelucire ® 44/14/PEG 6000 + PEG 53-55 5.5-7.5 1500 = 50/30 + 20 Gelucire ® 44/14/PEG 6000 + PEG 54-59 7.2-8.0 1500 = 65/30 + 5 Gelucire ® 44/14/PEG 6000 + PEG 55 4.0 4000 = 65/25 + 10 Gelucire ® 44/14/PEG 6000 + PEG 57-59 6.0 4000 = 65/30 + 5 Gelucire ® 44/14/PEG 6000 + PEG 51-58 4.0-6.2 8000 = 65/30 + 5

[0063] The solid pellets obtained with a mixture of Gelucire® 44/14/PEG 6000 in the following proportions by weight: 65/35, are illustrated in FIG. 2. They were opaque and the flat face was in the form of a disk.

[0064] The mixture of Gelucire® 44/14/PEG 6000 in the proportions by weight of 65/35 had a dropping point which was determined to be 58.3° C. The mixture of Gelucire® 44/14/PEG 6000 in the proportions by weight of 60/40 had a dropping point which was determined to be 58.6° C.

EXAMPLE 2: IMPACT OF PEG ON DISSOLUTION OF ACTIVE PRINCIPLES

Example 2.1: Piroxicam

[0065] An active principle, piroxicam, was formulated with Gelucire® 44/14. The mixture obtained was cast into a capsule.

[0066] The solubility of piroxicam in water at 25° C. is 23 mg/L.

[0067] Capsules containing the following formulation were obtained: 20 mg of piroxicam, and 660 mg of Gelucire® 44/14.

[0068] The dissolution performance of piroxicam was compared with different formulations of solid pellets obtained in the same manner as described above, the difference being that the Gelucire® 44/14 had previously been prepared in the presence of PEG, as explained above.

[0069] The graphs of FIGS. 3a and 3b were obtained, illustrating the liberation L (%) of the active principle as a function of time t in minutes, in which:

[0070] FIG. 3a [0071] the curve B1 (invention) corresponds to a mixture of piroxicam/Gelucire® 44/14/PEG 4000, in which the ratio by weight of Gelucire® 44/14/PEG 4000 is 55/45: [0072] the curve B2 (invention) corresponds to a mixture of piroxicam/Gelucire® 44/14/PEG 6000, in which the ratio by weight of Gelucire® 44/14/PEG 6000 is 65/35: [0073] the curve B3 (invention) corresponds to a mixture of piroxicam/Gelucire® 44/14/PEG 4000, in which the ratio by weight of Gelucire® 44/14/PEG 4000 is 60/40: [0074] the curve B4 (invention) corresponds to a mixture of piroxicam/Gelucire® 44/14/PEG 6000, in which the ratio by weight of Gelucire® 44/14/PEG 6000 is 60/40: [0075] the curve B5 (invention) corresponds to a mixture of piroxicam/Gelucire® 44/14/PEG 6000, in which the ratio by weight of Gelucire® 44/14/PEG 6000 is 70/30: [0076] the curve B6 (invention) corresponds to a mixture of piroxicam/Gelucire® 44/14/PEG 4000, in which the ratio by weight of Gelucire® 44/14/PEG 4000 is 40/60: [0077] the curve B7 (control 1) corresponds to a mixture of piroxicam/PEG 6000: [0078] the curve B8 (control 2) corresponds to piroxicam alone.

[0079] FIG. 3b [0080] the curve B9 (invention) corresponds to a mixture of piroxicam/Gelucire® 44/14/PEG 6000+PEG 1500, in which the ratio by weight of Gelucire® 44/14/PEG 1+PEG 2 is 50/20+30: [0081] the curve B10 (invention) corresponds to a mixture of piroxicam/Gelucire® 44/14/PEG 6000+PEG 4000, in which the ratio by weight of Gelucire® 44/14/PEG 1+PEG 2 is 65/30+5: [0082] the curve B11 (invention) corresponds to a mixture of piroxicam/Gelucire® 44/14/PEG 6000+PEG 8000, in which the ratio by weight of Gelucire® 44/14/PEG 1+PEG 2 is 65/30+5: [0083] the curve B12 (invention) corresponds to a mixture of piroxicam/Gelucire® 44/14/PEG 6000+PEG 4000, in which the ratio by weight of Gelucire® 44/14/PEG 1+PEG 2 is 65/25+10: [0084] the curve B13 (invention) corresponds to a mixture of piroxicam/Gelucire® 44/14/PEG 6000+PEG 1500, in which the ratio by weight of Gelucire® 44/14/PEG 1+PEG 2 is 65/30+5.

[0085] It can be seen that all of the mixtures of piroxicam/Gelucire® 44/14/PEG (curves B1 to B6 and B9 to B13) lead to a greater liberation of piroxicam than that of the active principle alone (control 2, curve B8).

[0086] The mixtures comprising PEG (curves B1 to B5) resulted in more than 95% liberation after 2 hours, which was highly satisfactory, apart from the mixture of piroxicam/Gelucire® 44/14/PEG 4000, for which the ratio by weight of Gelucire® 44/14/PEG 4000 was 40/60 (curve B6).

[0087] The mixtures comprising a combination of two PEGs (curves B9 to B12) resulted in more than 90% liberation after 2 hours, which was satisfactory, apart from the mixture of piroxicam/Gelucire® 44/14/PEG 6000+PEG 1500, for which the ratio by weight of Gelucire® 44/14/PEG 6000+PEG 1500 was 65/30+5 (curve B13).

[0088] Furthermore, the performance of the PEG (control 1, curve B7) alone was far poorer than in a mixture with the Gelucire® 44/14.

Example 2.2: Terfenadine

[0089] Another active principle, terfenadine, was formulated with Gelucire® 44/14. The mixture was cast into a capsule in a manner that was similar to that of Example 1 above which used piroxicam.

[0090] The solubility of terfenadine in water at 25° C. is 250 mg/L.

[0091] The dose was 60 mg, for a total of 680 mg of formulation.

[0092] The graph of FIG. 4 was therefore obtained, illustrating the liberation L (%) of the active principle as a function of time t in minutes, in which: [0093] the curve C1 (invention) corresponds to a mixture of terfenadine/Gelucire® 44/14/PEG 6000, in which the ratio by weight of Gelucire® 44/14/PEG 6000 is 65/35: [0094] the curve C2 (invention) corresponds to a mixture of terfenadine/Gelucire® 44/14/PEG 6000, in which the ratio by weight of Gelucire® 44/14/PEG 6000 is 60/40; [0095] the curve C3 (control 1) corresponds to a mixture of terfenadine/PEG 6000; [0096] the curve C4 (control 2) corresponds to terfenadine alone.

[0097] Here again, it can be seen that the terfenadine/Gelucire® 44/14/PEG mixtures (curves C1 and C2) resulted in approximately 90% liberation after 90 minutes, which was highly satisfactory. This liberation is well above that of the active principle alone, which remained below 10% after 120 minutes (control 2, curve C4).

[0098] Furthermore, the performance of PEG alone (control 1, curve C3) was poorer than when mixed with Gelucire® 44/14.

Example 2.3: Ibuprofen

[0099] Another active principle, ibuprofen, was formulated with the Gelucire® 44/14/PEG mixtures. The mixture with the active principle was cast into a capsule, in a similar manner to Examples 2.1 and 2.2 above which used piroxicam and terfenadine.

[0100] The solubility of ibuprofen in water at 25° C. is 21 mg/L.

[0101] The dose was 200 mg, for a total of 680 mg of formulation.

[0102] The graph of FIG. 5 was therefore obtained, illustrating the liberation L (%) of the active principle as a function of time t in minutes, in which: [0103] the curve D1 (invention) corresponds to a mixture of ibuprofen/Gelucire® 44/14/PEG 6000, in which the ratio by weight of Gelucire® 44/14/PEG 6000 is 65/35: [0104] the curve D2 (invention) corresponds to a mixture of ibuprofen/Gelucire® 44/14/PEG 6000, in which the ratio by weight of Gelucire® 44/14/PEG 6000 is 60/40; [0105] the curve D3 (control 1) corresponds to a mixture of ibuprofen/PEG 6000; [0106] the curve D4 (control 2) corresponds to the ibuprofen alone.

[0107] It can be seen that the mixtures of active principle (ibuprofen)/Gelucire® 44/14/PEG (curves D1 and D2) resulted in approximately 40% liberation after 120 minutes, which was satisfactory and corresponded to a quantity which was 5 times higher than that liberated by the ibuprofen/PEG (control 1, curve D3) mixture or by the ibuprofen alone (control 2, curve D4).

[0108] PEG alone (control 1, curve D3) has no impact on the dissolution of the ibuprofen alone (control 2, curve D4) in the dissolving medium.