Solid unit with high fexofenadine content and process for the preparation thereof

Abstract

The present invention relates to pharmaceutical compositions intended to be used in the form of a solid unit such as a tablet, for oral administration, comprising a high content of fexofenadine and/or of at least one pharmaceutically acceptable salt thereof, and also to hot-melt processes for manufacturing solid units.

Claims

1. A solid unfractionated unit comprising a dose of 5 to 500 mg of fexofenadine, or a pharmaceutically acceptable salt thereof, the composition of which is the following: 45% to 92% by weight of fexofenadine, or a pharmaceutically acceptable salt thereof, optionally in combination with at least one other active ingredient; 4% to 20% by weight of a hot-melt excipient or mixture of hot-melt excipients, said hot-melt excipient(s) selected from the group consisting of polyethylene glycol and stearic acid; and 4% to 50% by weight of an additional excipient or of a plurality of additional excipients, the percentages by weight being expressed relative to the total weight of the composition.

2. The solid unfractionated unit according to claim 1, wherein the weight ratio of fexofenadine, or a pharmaceutically acceptable salt thereof, to the hot-melt excipient(s) is between 3.5 and 15.

3. The solid unfractionated unit according to claim 1, wherein the percentage by weight of fexofenadine, or a pharmaceutically acceptable salt thereof, is between 55% and 92%.

4. The solid unfractionated unit according to claim 1, wherein the percentage by weight of the hot-melt excipient(s) is in the range of from 4% to 17%.

5. The solid unfractionated unit according to claim 1, wherein the percentage by weight of the additional excipient(s) is in the range of from 4% to 35%.

6. The solid unfractionated unit according to claim 1, wherein the additional excipient(s) is (are) chosen from the group consisting of disintegrants, flow agents, lubricants and diluents.

7. The solid unfractionated unit according to claim 1, wherein the total weight of the solid unfractionated unit, excluding any coating or film-coating, is less than 400 mg, for a fexofenadine content of 180 mg.

8. A pharmaceutical composition comprising the solid unfractionated unit of claim 1.

9. A process for manufacturing a solid unfractionated unit comprising 5 to 500 mg of fexofenadine, or a pharmaceutically acceptable salt thereof, the process comprising at least the following steps: (i) the mixing of: 45% to 92% by weight of fexofenadine, or a pharmaceutically acceptable salt thereof, optionally in combination with at least one other active ingredient, with 4% to 20% by weight of a hot-melt excipient or of a mixture of hot-melt excipients, said hot-melt excipient(s) selected from the group consisting of polyethylene glycol and stearic acid; (ii) the granulation of the mixture obtained in step (i) at a temperature which allows the hot-melt excipient(s) to melt or to soften; (iii) the cooling of the grains resulting from step (ii); (iv) the calibration of the grains; (v) the homogenization of the calibrated grains in order to obtain a homogeneous mixture; and (vi) the forming of a solid unit from the homogeneous mixture, the percentages by weight being expressed relative to the total weight of the composition.

10. The process as claimed in claim 9, wherein the solid unfractionated unit further comprises an additional excipient or a plurality of additional excipients, in a content of from 4% to 50% by weight relative to the total weight of the solid unfractionated unit.

11. The process as claimed in claim 10, wherein the additional excipient(s) is (are) chosen from the group consisting of disintegrants, flow agents, lubricants and diluents, and which can be added during the calibration step (iv) and/or during the homogenization step (v).

12. The process according to claim 10, wherein the additional excipient(s) comprise(s) at least one disintegrant, wherein at least a part of the at least one disintegrant is introduced into the mixture during step (i).

13. The process according to claim 9, further comprising, after step (v), a step of coating or film-coating the solid unfractionated unit.

14. A method of treating allergies and/or urticaria in a patient in need thereof comprising administering the solid unfractionated unit of claim 1 to the patient in need thereof.

15. The solid unfractionated unit according to claim 1, comprising 78.88% fexofenadine hydrochloride, 9.32% PEG 6000, 10.00% sodium croscarmellose, 0.90% magnesium stearate, and 0.90% colloidal silica.

16. The solid unfractionated unit according to claim 1, comprising 63.50% fexofenadine hydrochloride, 8.82% PEG 6000, 10.58% pregelatinized starch, 5.29% microcrystalline cellulose, 10.00% sodium carboxymethyl starch, 0.90% magnesium stearate, and 0.90% colloidal silica.

17. The solid unfractionated unit according to claim 1, comprising 70.63% fexofenadine hydrochloride, 8.72% PEG 6000, 7.85% pregelatinized starch, 1.00% sodium croscarmellose, 0.90% magnesium stearate, 0.90% colloidal silica, and 10.00% microcrystalline cellulose.

18. The solid unfractionated unit according to claim 1, the composition of which is the following: 70% to 92% by weight of fexofenadine, or a pharmaceutically acceptable salt thereof, optionally in combination with at least one other active ingredient; 4% to 15% by weight of a hot-melt excipient or mixture of hot-melt excipients, said hot-melt excipient(s) selected from the group consisting of polyethylene glycol and stearic acid; and 4% to 15% by weight of an additional excipient or of a plurality of additional excipients, the percentages by weight being expressed relative to the total weight of the composition.

19. The solid unfractionated unit according to claim 1, the composition of which is the following: 60% to 92% by weight of fexofenadine, or a pharmaceutically acceptable salt thereof, optionally in combination with at least one other active ingredient; 4% to 10% by weight of a hot-melt excipient or mixture of hot-melt excipients, said hot-melt excipient(s) selected from the group consisting of polyethylene glycol and stearic acid; and 4% to 30% by weight of an additional excipient or of a plurality of additional excipients, the percentages by weight being expressed relative to the total weight of the composition.

Description

EXAMPLES

(1) The following example describes the preparation of solid units in accordance with the invention. This example is not limiting and merely illustrates the present invention.

(2) The percentages of the compounds below are expressed, unless otherwise indicated, by weight relative to the total weight of the composition or of the solid unit which contains them, as appropriate.

1. Compositions of Tablets According to the Invention

(3) By way of example, four pharmaceutical compositions 1A to 1D according to the invention, using PEG 6000 as hot-melt excipient and comprising only fexofenadine hydrochloride as active ingredient, are indicated by way of illustration in table 1 below.

(4) The nature of the ingredients of these compositions is indicated in said table, as is the content of said ingredients, expressed as % by weight of ingredient relative to the total weight of the composition/of the solid unit.

(5) TABLE-US-00001 TABLE 1 Composition 1A 1B 1C 1D Internal Fexofenadine 83.79% 45.31% 78.88% 79.38% phase hydrochloride PEG 6000 9.31% 5.03 9.32% 8.82% Sodium / / 5.00% / croscarmellose External Crospovidone 5.00% 10.00% / / phase Sodium / / 5.00% 10.00% croscarmellose Magnesium 0.95% 0.95% 0.90% 0.90% stearate Colloidal silica 0.95% 0.95% 0.90% 0.90% Micro- / 11.33% / / crystalline cellulose Lactose / 26.43% / /

(6) The composition comprises an “external” phase and an “internal” phase. The ingredients of the internal phase are used to manufacture the grain comprising the fexofenadine hydrochloride. The ingredients of the external phase are additional excipients, which make it possible, for example, to improve the processability of the formulation.

(7) The ratio of fexofenadine hydrochloride to hot-melt excipient in compositions 1A to 1D is respectively equal to 9, 9, 8.5 and 9.

2. Compositions of Internal Phase According to the Invention Comprising Various Hot-Melt Excipients

(8) Other grains (internal phase) were obtained using fexofenadine hydrochloride as active ingredient and hot-melt excipients other than PEG 6000. These examples of grain formulations 1E to 1H are given in table 2 below:

(9) TABLE-US-00002 TABLE 2 Composition 1E 1F 1G 1H Fexofenadine 90.00 90.00 90.00 90.00 hydrochloride Stearic acid 10.00 / / / Precirol ® / 10.00 / / (glyceryl palmitostearate) Poloxamer 407 / / 10.00 / Polyox ® / / / 10.00 (polyethylene oxide)

(10) The weight ratio of fexofenadine hydrochloride to hot-melt excipients in compositions 1E to 1H is 9.

3. Alternative Compositions According to the Invention

(11) In a manner similar to example 1, two other pharmaceutical compositions 2A and 2B were prepared according to the invention and are indicated by way of illustration in table 3 below.

(12) The nature of the ingredients of these compositions is indicated in said table, as is the content of said ingredients, expressed as % by weight of ingredient relative to the total weight of the composition/of the solid unit.

(13) TABLE-US-00003 TABLE 3 Composition 2A 2B Internal Fexofenadine hydrochloride 63.50%  70.63%  phase PEG 6000 8.82% 8.72% Pregelatinized starch 10.58%  7.85% Microcrystalline cellulose 5.29% / External Sodium carboxymethyl starch (type A) 10.00%  / phase Sodium croscarmellose / 1.00% Magnesium stearate 0.90% 0.90% Colloidal silica 0.90% 0.90% Microcrystalline cellulose / 10.00% 

(14) The ratio of fexofenadine hydrochloride to hot-melt excipient in compositions 2A and 2B is respectively equal to 7.2 and 8.1.

4. Manufacturing Process

(15) Tablets were manufactured using compositions 1A to 1H, 2A and 2B mentioned above and according to the process described below.

(16) The composition of the tablets 1E to 1H is indicated in table 4 below:

(17) TABLE-US-00004 TABLE 4 Composition 1E-1H Internal Fexofenadine hydrochloride 79.38%  phase Hot-melt excipient 8.82% External Crospovidone 10.00%  phase Magnesium stearate 0.90% Colloidal silica 0.90%

(18) A mixing step (i) of said process consists in mixing the ingredients of the internal phase of one of compositions 1A to 1H, 2A and 2B mentioned above, using a Turbula® or Servolift® tumbler mixer for approximately 210 revolutions.

(19) A granulation step (ii), which may be in continuous or batchwise mode, is then carried out. The continuous mode is carried out, for example, using a Consigma® 25 granulator with co-rotating screws rotating in a jacketed barrel. The batchwise mode is carried out, for example, using a fluidized air bed.

(20) For the granulator of Consigma® type, the parameters are: a powder mixture flow rate of 5 to 6 kg/h, a screw speed of 200 to 400 revolutions per minute, and a jacket temperature of 80 to 120° C.

(21) For the fluidized air bed, the parameters are: an air flow rate of 20 to 400 m.sup.3/hour depending on the type of fluidized air bed used, and a set heating temperature between 35° C. and 130° C. depending on the hot-melt excipient used.

(22) A cooling step (iii) then consists in cooling to approximately 20-25° C. by spreading on a plate or by pneumatic transport of said grains.

(23) Then, a calibration step (iv) is carried out on a Frewitt® TC-150 calibrator using a screen with a 1.5 mm mesh size.

(24) Magnesium stearate, colloidal silica, crospovidone and/or any other additional excipient are optionally added to the grains during step (iv). As appropriate, the mixing of the grains and the additional excipients is carried out for approximately 210 revolutions in a Turbula® ou Servolift® tumbler mixer for homogenization (v).

(25) Finally, the homogenized mixture undergoes a forming step (vi) by compression using a Korsh® XL 100 rotary press, a Kilian S100 rotary press or a Ronchi rotary press, with a compressive force of between 3 and 20 kN.

(26) Table 5 below groups together the characteristics of the tablets obtained at the end of a continuous or batchwise process, using the compositions respectively described above, and also the characteristics of the reference tablet obtained by wet granulation. More particularly, table 5 indicates, for each tablet, its total weight, its weight of fexofenadine hydrochloride and the percentage reduction in weight of the tablet relative to the reference tablet.

(27) TABLE-US-00005 TABLE 5 1D to Tablet 1A 1B 1C 1H 2A 2B Reference Weight of the 214.82 397.24 228.19 226.76 283.45 254.84 600.00 tablet (mg) Weight of 180.00 180.00 180.00 180.00 180.00 180.00 180.00 fexofenadine hydrochloride (mg) % reduction in 64.2 33.8 62.0 62.2 52.8 57.5 / weight Reference: Allegra ®

(28) Thus, for the same amount of active ingredient, the compositions according to the invention have a reduced weight and a reduced size compared with the reference tablet.

5. Hardness of the Tablets Obtained According to the Invention

(29) The hardness of the tablets is measured using a durometer. Each tablet is positioned between the two jaws of the durometer. The value of the force in Newtons, exerted on the tablet, obtained during the crushing of the tablet is noted. The average value of the hardnesses recorded on the durometer is indicated in table 6 below.

(30) TABLE-US-00006 TABLE 6 2A and Tablet 1A to 1D 1E 1F 1G 1H 2B Hardness (N) ≈100 ≈100 ≈65 ≈80 ≈50 ≈100

6. Dissolution of the Active Ingredient Contained in the Tablets According to the Invention

(31) 6.1. Procedure for Measuring the Dissolution of the Active Ingredient:

(32) A tablet is placed in a container containing 900 ml of non-degassed solution at pH 3.0 (0.001 N HCl) and at a temperature of 37° C. The stirring speed in the container is fixed at 50 rpm by means of a paddle. More particularly, the dissolution test is carried out using an Apparatus 2 in accordance with the European pharmacopeia 2.9.3 and with the United States pharmacopeia (USP)<711>.

(33) The amount of active ingredient dissolved as a function of time is measured by HPLC (high-performance liquid chromatography) assay, for example according to a methodology in accordance with the European pharmacopeia 2.2.29, “Liquid chromatogrphy” or in accordance with the United States pharmacopeia (USP) 621 “Chromatography”. Such a measurement is well known to those skilled in the art.

(34) 6.2. Results

(35) The weight percentage of fexofenadine hydrochloride dissolved for examples 1A, 1B and 1D and the reference are given in table 7 below.

(36) TABLE-US-00007 TABLE 7 Tablet 1A 1B 1D 1E 1F 1H 2A 2B Reference % 92.8 92.9 98.6 85.3 69.3 63.1 90.8 66.5 82.6 dissolved at t = 10 min % 96.0 95.5 101.8 92.3 80.0 80.0 96.5 85.0 93.1 dissolved at t = 30 min % 97.1 96.2 102.1 93.8 82.0 85.2 97.8 88.3 94.7 dissolved at t = 45 min Reference: Allegra ® 180 mg.
The dissolution profiles between the various examples and the reference are comparable and all the examples are in accordance with the European specification of the product.