DISPERSIBLE COMPOSITIONS

Abstract

The present invention is concerned with dispersible compositions comprising bedaquiline fumarate as an active ingredient. Such compositions are useful in the treatment of tuberculosis and their inherent dispersibility properties lend themselves to be useful in particular amongst the pediatric or geriatric population.

Claims

1. A dispersible composition comprising bedaquiline fumarate as the active ingredient and wherein the composition comprises an intra-granular and extra-granular layer in which the intra-granular layer comprises a non-soluble excipient/diluent and is characterised in that the intra-granular layer is absent a soluble excipient/diluent that is starch.

2. A dispersible composition as claimed in claim 1, wherein the intra-granular layer is absent any soluble excipient/diluent.

3. A dispersible composition as claimed in claim 1, wherein the non-soluble excipient/diluent in the intra-granular layer is microcrystalline cellulose.

4. A dispersible composition comprising bedaquiline fumarate as the active ingredient and wherein the composition comprises an intra-granular and extra-granular layer in which the intra-granular layer comprises a non-soluble excipient/diluent that is microcrystalline cellulose.

5. A dispersible composition as claimed in claim 3, wherein the intra-granular layer is absent a soluble excipient/diluent.

6. A dispersible composition comprising by weight based on the total weight of the composition: 5 to 50% of bedaquiline fumarate; 35% to 90% of a non-soluble excipient/diluent; 2% to 10% of a disintegrant; 0.1 to 5% of a glidant; 0.01 to 5% of a wetting agent or surfactant; 0 to 10% of a binder or polymer; 0 to 5% of a lubricant; and solvent (qs).

7. A dispersible composition comprising by weight based on the total weight of the composition: 5 to 50% of active ingredient; 20% to 90% of a non-soluble excipient/diluent that is microcrystalline cellulose; 2% to 10% of a disintegrant; 0.1 to 5% of a glidant; 0.01 to 5% of a wetting agent or surfactant; 0 to 10% of a binder or polymer; 0 to 5% of a lubricant; solvent (qs).

8. A composition as claimed in claim 6, wherein they are further characterised in that they are absent a soluble excipient/diluent.

9. A composition, which composition consists of by weight, based on the total weight of the composition: 24.18% of active ingredient; 62.12% non-soluble excipient/diluent; 6% disintegrant; 2.5% glidant; 0.2% wetting agent or surfactant; 3% binder or polymer; 2% lubricant; Solvent (qs), if necessary.

10. A composition wherein the different parts of the composition, specifically the intra-granular and extra-granular fraction and binder portion, comprise the following ingredients by weight based on the total weight of the composition: Intra-granular fraction 5 to 50% of active ingredient; 10 to 50% of non-soluble excipient/diluent; 1 to 5% disintegrant; 0.1 to 5% glidant; Binder 1 to 10% 3% binder or polymer; 0.01 to 5% wetting agent or surfactant; Solvent (qs), if necessary Extra-granular fraction 10 to 50% of excipient/diluent; 1 to 5% disintegrant; 0 to 3% glidant; 0 to 5% lubricant.

11. A composition as claimed in claim 10, wherein the intra-granular layer is absent any soluble excipient/diluent; and/or, optionally, the extra-granular fraction is also absent any soluble excipient/diluent.

12. A composition as claimed in claim 10, which consists of the following compositions of intra-granular fraction, binder and extra-granular fraction, by weight based on the total weight of the composition: Intra-granular fraction 24.18% of active ingredient; 29.82% of non-soluble excipient/diluent; 3% disintegrant; 2% glidant; Binder 3% binder or polymer; 0.2% wetting agent or surfactant; Solvent—if necessary; Extra-granular fraction 32.3% of excipient/diluent; 3% disintegrant; 0.5% glidant; 2% lubricant.

13-18. (canceled)

Description

EXPERIMENTAL PART

[0218] The active ingredient, bedaquiline fumarate, may be prepared for example in accordance with the procedures described in international patent application WO 2008/068231. As seen from Table 1 below, TMC207 refers to Bedaquiline Fumarate.

Examples

[0219]

TABLE-US-00001 1) Effect of intra-granular filler Ingredient Intra-granular Part TMC207 24.18 24.18 24.18 Silicified Microcrystalline cellulose 14.91 . . . 29.82 Mannitol . . . 29.82 . . . Glucose monohydrate 14.91 . . . . . . Crospovidone 3.0 3.0 3.0 Colloidal Silicon Dioxide 2.0 2.0 2.0 Hypromellose 5 cps 3.0 3.0 3.0 Polysorbate 20 0.2 0.2 0.2 Extra-granular Part Silicified Microcrystalline cellulose 32.3 32.3 32.3 Crospovidone 3.0 3.0 3.0 Colloidal Silicon Dioxide 0.5 0.5 0.5 Sodium Stearyl Fumarate 2.0 2.0 2.0 Total (mg) 100 100 100 Dispersion time*(sec) 30-70 40-70 40-50 Hardness (N) 20-31 24-31 25-40

[0220] The soluble excipient in the intra-granular part did not show any additional improvement in the dispersion time. It was observed that the time required for dispersion of tablet was adversely affected by addition of soluble excipients intragranularly. Thus, it was decided to continue with the Silicified MCC.

TABLE-US-00002 2) Effect of extra-granular fillers Ingredients Intra-granular Part TMC207 24.18 24.18 Silicified Microcrystalline cellulose 29.82 29.82 Crospovidone 3.0 3.0 Colloidal Silicon Dioxide 2.0 2.0 Hypromellose 5 cps 3.0 3.0 Polysorbate 20 0.2 0.2 Extra-granular Part Mannitol 32.3 . . . Silicified Microcrystalline cellulose . . . 32.3 Crospovidone 3.0 3.0 Colloidal Silicon Dioxide 0.5 0.5 Sodium Stearyl Fumarate 2.0 2.0 Total 100 100 Dispersion time*(sec) 60 45 Hardness (N) 19-25 20-27

[0221] The soluble excipient in the extra-granular part did not show any additional improvement. It was observed that the time required for dispersion of tablet was adversely affected by addition of soluble excipients. Thus, it was decided to continue with the Silicified MCC.

TABLE-US-00003 3) Effect of grade of Crospovidone Ingredients Intra-granular Part TMC207 24.18 24.18 Silicified Microcrystalline cellulose 29.82 29.82 Crospovidone (Polyplasdone XL 10) 3.0 3.0 Colloidal Silicon Dioxide 2.0 2.0 Hypromellose 5 cps 3.0 3.0 Polysorbate 20 0.2 0.2 Extra-granular Part Silicified Microcrystalline cellulose 32.3 32.3 Crospovidone (Polyplasdone XL) . . . 3.0 Crospovidone (Polyplasdone XL 10) 3.0 . . . Colloidal Silicon Dioxide 0.5 0.5 Sodium Stearyl Fumarate 2.0 2.0 Total (mg) 100 100 Dispersion time*(sec) 90-100 55-75 Hardness (N) 25-34  25-34

[0222] Crospovidone (Polyplasdone XL) coarser grade showed better dispersion pattern and behavior as compared to the fine particle Crospovidone (Polyplasdone XL 10), thus it was decided to further continue with the Polyplasdone XL grade intra-granularly as well as extra-granularly.

Further Examples

[0223] The following composition of the invention was prepared in accordance with the techniques described herein:

TABLE-US-00004 TABLE 1 Current composition of TMC 207 dispersible tablet Tablet Tablet quantity quantity Ingredient Function (mg) (%) BEDAQUILINE FUMARATE API 24.18 24.18 (TMC 207) Silicified Microcrystalline Cellulose Filler 29.82 29.82 (Prosolv HD 90) Crospovidone (Polyplasdone XL) Disintegrant 3.0 3.0 Colloidal Silicon dioxide Glidant 2.0 2.0 (Aerosil 200) Hypromellose 5 cps Binder 3.0 3.0 (Methocel E 5 LV) Purified water .sup.(1) Solvent qs qs Polysorbate 20 (Tween 20) Surfactant 0.2 0.2 Silicified microcrystalline cellulose 32.3 32.3 (Prosolv HD 90) Crospovidone (Polyplasdone XL) Disintegrant 3.0 3.0 Colloidal Silicon dioxide Glidant 0.5 0.5 (Aerosil 200) Sodium Stearyl Fumarate (Pruv) Lubricant 2.0 2.0 Tablet weight 100 mg 100% .sup.(1) This material is a process aid and is removed during processing

Stability Data:

[0224]

TABLE-US-00005 Appearance, Assay and Chromatographic Purity Water content of % Assay in % Bedaquiline Parameter Appearance w/w fumarate Degradation compounds ≧0.05% (%) Test Visual KF-00131- HPLC- Method Examination V1 00129-V1 Total Storage Bedaquiline Any unspecified Degradation Storage Time fumarate degradation product (%) products Condition (Months) Result % w/w (%) U_RRT_0.74 U_RRT_1.04 (%) Initial Pass 4.4 98.1 <0.05 <0.05 <0.05 25° C./ 1 Pass 5.2 98.7 <0.05 0.05 0.05 60% RH 3 Pass 4.9 98.0 <0.05 <0.05 <0.05 6 Pass 4.6 99.1 <0.05 <0.05 <0.05 30° C./ 1 Pass 5.0 99.2 <0.05 <0.05 <0.05 75% RH 3 Pass 5.1 97.8 <0.05 <0.05 <0.05 6 Pass 5.3 99.0 <0.05 <0.05 <0.05 40° C./ 1 Pass 4.8 99.1 <0.05 <0.05 <0.05 75% RH 3 Pass 5.2 98.0 <0.05 0.05 0.05 6 Pass 5.4 99.1 <0.05 <0.05 <0.05 50° C. 1 Pass 4.2 98.5 <0.05 <0.05 <0.05 3 Pass 4.1 98.2 0.08 0.06 0.14 ICH Light 8 hours Pass 5.3 98.4 <0.05 <0.05 <0.05 Note: Light ICH: CIE85-ID65 700 W/m.sup.2 (Light study conducted on tablets packed in container) Where it is indicated “any specified degradation product”, this may be an impurity in the API (for instance one that arises from the process).

[0225] The composition of the invention was found to be stable under ICH conditions.

In Use Stability:

[0226] The stability for the dispersion of tablet in water was evaluated considering the lag time between the preparation and dosing of the dispersion.

Method:—

[0227] As the composition of the invention (i.e. dispersible tablet described above) was stable for up to 6 hrs, it can be administered up to 6 hrs after its preparation.

[0228] 5 tablet eq. to 100 mg dose were dispersed in 50 ml of water and further analyzed for assay and related substances after 0, 2, 4 and 6 hrs. in a clear glass flask at ambient conditions.

TABLE-US-00006 A known process Bedaquiline Sr. No. Time impurity in % Fumarate in % 1 0 hrs. 0.50 98.30 2 2 hrs. 0.50 97.99 3 4 hrs. 0.51 98.44 4 6 hrs. 0.50 98.09

[0229] Product was found to be stable in the form of water dispersion for 6 hrs. Further it was stable in a clear glass contained too, indicating that it was not light-sensitive.

[0230] Comparative Dissolution Profile of Adult Formulation Vs Pediatric Formulation Via Two Different Methods:

TABLE-US-00007 Formulation Adult Adult Pediatric Pediatric Batch No 136695 136695 HG-121019 HG-121019 Strength 100 mg 100 mg 5 × 20 mg 5 × 20 mg Result set ID 81938 82584 83398 83598 Disso Media 0.01N HCL 0.01N HCL 0.01N HCL 0.01N HCL No of units 6 6 6 6 Condition RT_6 M RT_6 M RT_1.5 Yrs RT_1.5 Yrs Volume 900 mL 900 mL 900 mL 900 mL Apparatus Basket Paddle Basket Paddle RPM 150 75 150 75  5 55.97 32.61 63.37 73.43 10 77.26 59.06 72.46 93.39 15 85.95 68.12 81.56 97.96 20 90.02 71.97 89.10 100.07 30 93.49 77.76 95.91 101.27 45 95.60 85.76 98.36 102.15 60 96.45 92.63 98.38 101.93 90 97.43 97.24 100.14 102.03 F2 66.6** 27.7* *wrt adult tablet; paddle 75 rpm **wrt adult tablet; basket 150 rpm RT = room temperature; 6 M = 6 months F2: The FDA and EMEA define similarity factor as a “logarithmic reciprocal square root transformation of one plus the mean squared (the average sum of squares) differences of drug percent dissolved between the test and the reference products”. If F2 > 50 the products are similar and if less than 50 then dissimilar.

[0231] Dissolution profile of pediatric formulation was faster as compared to adult formulation in both the dissolution methods.

Effect on Bioavailability:

[0232] 1) Food effect on bioavailability was reduced as compared to adult tablet

TABLE-US-00008 Regular breakfast Yoghurt Adult tablet 91% 32% Water dispersible tablet 82% 17% [0233] 2) Both adult and paediatric formulation tested with regular breakfast and yogurt showed that both formulations are bioequivalent despite dispersible tablets showing faster dissolution profile in vitro.

TABLE-US-00009 Panel 1 (standard breakfast) Water dispersible tablet Ratio (%) 90% CI Cmax 106.58 96.11-118.18 AUC.sub.72 h 98.43 91.85-105.47

TABLE-US-00010 Panel 2 (yoghurt) Water dispersible tablet Ratio (%) 90% CI Cmax 111.93 104.26-120.16 AUC.sub.72 h 112.95 105.94-120.42

[0234] Hence, the composition of the invention was found to be bioequivalent to adult conventional tablet formulation when tested in adult population in fasted, fed and with yogurt. The product (invention) decreased the food effect by 9% and by 15% when dosed with yogurt as compared to adult tablet formulation.

Additional Examples

[0235] Further development in the formulation was aimed at catering the clinical need of 10 mg dose increments. This was accomplished with developing a 20 mg formulation with a breakline to enable dosing in 10 mg dose increments if needed.

[0236] To achieve this, following changes were carried out in previous formulation that was tested in the bioequivalence study.

TABLE-US-00011 Bedquiline fumarate Bedquiline fumarate Dispersible tablet 20 mg Dispersible tablet 20 mg Parameter (Formulation described above) (Further formulation) Weight 100 mg 200 mg Tablet shape Circular Caplet Tablet surface Plain on both sides Break line on both sides Tablet Debossing None “2” & “0” separated by break line on one side and plain with break line on other side Hardness 20-40N 70-120N Dose(covered)  20 mg 10 mg and 20 mg Dispersion time About 30 sec (in 50 ml) About 60 sec (in 50 ml) - can be dispersed in 5 ml water Percentage of 62.12% 73.71% MCC (Avicel PH 102)- Insoluble excipient/diluent Percentage of API 24.18% 12.09%

Composition of Further Formulation:

[0237]

TABLE-US-00012 Bedaquiline fumarate Bedaquiline fumarate Dispersible tablet 20 mg Dispersible tablet 20 mg (Formulation of 100 mg weight (Further formulation of described above) 200 mg weight) Percent Percent Ingredients mg/unit w/w mg/unit w/w Intra Granular Portion Bedaquiline fumarate 24.18 24.18 24.18 12.09 Silicified Microcrystalline Cellulose 29.32 29.32 82.82 41.41 Crospovidone 3.00 3 6 3 Colloidal Silicon Dioxide 2.0 2 4 2 Hypromellose 5 cps 3.5 3.5 7 3.5 Polysorbate 20 0.2 0.2 0.4 0.2 Total (Intragranular Portion) 62.2 62.2 124.4 62.2 Extra granular Portion Sodium Stearyl Fumarate 2.0 2 4 2 Silicified Microcrystalline 32.3 32.3 64.6 32.3 Crospovidone 3.0 3 6 3 Colloidal Silicon Dioxide 0.5 0.5 1 0.5 Total (Extragranular Portion) 37.8 37.8 75.6 37.8 Tablet weight (mg) 100.0 100 200 100

Formulation Trials to Study Various Factors in Formulation

[0238]

TABLE-US-00013 1) Effect of Intragranular filler Vs. Extragranular filler Ingredients Example 1 Example 2 Intra-granular Portion Bedaquiline fumarate 24.18 24.18 Silicified Microcrystalline 82.82 115.12 Cellulose (Prosolv SMCC HD90) Crospovidone 6.00 6.00 (Polyplasdone XL) Colloidal Silicon Dioxide 4.00 4.00 (Aerosil 200Pharma) Hypromellose 5 cps 7.00 7.00 (Methocel E5 LV) Polysorbate 20 0.40 0.40 (Tween 20 HP) Purified Water* — — Weight of Intragranular 124.4 156.7 Extra-granular Portion Sodium Stearyl Fumarate 4.00 4.00 (Pruv) Silicified Microcrystalline 64.60 32.30 Cellulose (Prosolv SMCC HD90) Crospovidone 6.00 6.00 (Polyplasdone XL) Colloidal Silicon Dioxide 1.00 1.00 (Aerosil 200 Pharma) Dispersion time 75 sec (5 ml) 70-75 sec (5 ml) 50-55 sec (50 ml) Hardness 93-100N (95N) 92-107N (96N) Tablet weight (mg) 200.00 200.00 Conclusion: - Intragranular filler (silicified MCC) when varied between 41% to 58% did not show any impact on the critical quality attributes (CQAs) of the product. This change directly impacts the extragranular filler concentration which when varied between 32% and 16% does not impact the CQA's.

TABLE-US-00014 Effect of amount of Crospovidone Ingredients Example 1 Example 2 Intra-granular Portion Bedaquiline fumarate 24.18 24.18 Silicified Microcrystalline 82.82 85.82 Cellulose (Prosolv SMCC HD90) Crospovidone 6.00 3.00 (Polyplasdone XL) Colloidal Silicon Dioxide 4.00 4.00 (Aerosil 200Pharma) Hypromellose 5 cps 7.00 7.00 (Methocel E5 LV) Polysorbate 20 0.40 0.40 (Tween 20 HP) Purified Water* — — Weight of Intragranular 124.4 124.4 Extra-granular Portion Sodium Stearyl Fumarate 4.00 4.00 (Pruv) Silicified Microcrystalline 64.60 67.60 Cellulose (Prosolv SMCC HD90) Crospovidone 6.00 3.00 (Polyplasdone XL) Colloidal Silicon Dioxide 1.00 1.00 (Aerosil 200 Pharma) Dispersion time 75 sec (5 ml) 85-90 sec (5 ml) 50-55 sec (50 ml) Hardness 93-100N (95N) 87-105N (95N) Tablet weight (mg) 200.00 200.00 Conclusion: - Disintegrant (Crospovidone) concentrations were studied between 3% to 6% ranges in the formulation. This does not impact the CQA's but the dispersion time with 6% Crospovidone is slightly better than with 3%

TABLE-US-00015 2) Effect of amount of increased amount of binder Ingredients Example 1 Example 2 Intra-granular Portion Bedaquiline fumarate 24.18 24.18 Silicified Microcrystalline 82.82 79.32 Cellulose (Prosolv SMCC HD90) Crospovidone 6.00 6.00 (Polyplasdone XL) Colloidal Silicon Dioxide 4.00 4.00 (Aerosil 200Pharma) Hypromellose 5 cps 7.00 10.50 (Methocel E5 LV) Polysorbate 20 0.40 0.40 (Tween 20 HP) Purified Water* — — Weight of Intragranular 124.4 124.4 Extra-granular Portion Sodium Stearyl Fumarate 4.00 4.00 (Pruv) Silicified Microcrystalline 64.60 64.60 Cellulose (Prosolv SMCC HD90) Crospovidone 6.00 6.00 (Polyplasdone XL) Colloidal Silicon Dioxide 1.00 1.00 (Aerosil 200 Pharma) Dispersion time 75 sec (5 ml) 135-145 sec (5 ml) 50-55 sec (50 ml) Hardness 93-100N (95N) 89-104N (95N) Tablet weight (mg) 200.00 200.00 Conclusion:- Binder (HPMC) concentration was studied between 3.5% and 5.25%. Higher conc of binder showed higher dispersion time.

Initial & Stability Data of Further Dispersible Tablet Formulation:

[0239]

TABLE-US-00016 Further Formulation (of 200 mg tablet weight) Assay (%) RS (%) Water by KF (%) Initial sample 99.45 <RT 5.0 HDPE Bottle 99.74 <RT 4.1 1 M 40° C./75% RH HDPE Bottle 98.30 <RT 4.0 2 M 40° C./75% RH HDPE Bottle 99.30 0.05 3.1 3 M 40° C./75% RH HDPE Bottle 100.6 0.15 3.2 6 M 40° C./75% RH RT: Reporting threshold Formulation exhibited satisfactory stability till 6 months in HDPE Bottles.

TABLE-US-00017 Dissolution profile (0.01N HCl) - Comparison of 100 mg dispersible tablet formulation vs 200 mg dispersible tablet formulation 100 mg tablet 200 mg tablet formulation formulation Time in minutes % Release 5 80 78 10 98 93 15 101 95 20 101 96 30 102 97 45 103 97 100 mg & 200 mg tablet formulation dissolution profile is comparable.

Split Tablet Data:

[0240]

TABLE-US-00018 1 - Weight loss of split tablets Intact weight of tablet (mg) Fraction-1 Fraction-2 Weight loss (%) 202.9 100.8 102.2 −0.05 203.6 100.4 103 0.10 203 105.3 97.8 −0.05 201.5 103.4 97.3 0.40 201.5 102.6 99 −0.05 202.1 103.4 98.7 0.00 201.6 102.2 99.3 0.05 202.8 103.3 99.4 0.05 202.1 102.7 99.3 0.05 203.1 101.8 101.1 0.10 202.1 101.6 100.5 0.00 203.8 105 98.9 −0.05 201 101.2 99.5 0.15 202 101.5 100.3 0.10 202.6 103.1 99.4 0.05 202.9 100.8 102.2 −0.05 SD (for weight of split tablets, n = 30): 2.04 RSD (for weight of split tablets n = 30): 2.02% Friability of split tablets (100 revolutions): 0.06% Friability of split tablets (400 revolutions): 0.16%