EA042247B1 - DISPERSIBLE COMPOSITIONS - Google Patents

Description

The present invention relates to a pharmaceutical composition containing a certain antibacterial product, bedaquiline fumarate, as an active ingredient. More specifically, this invention relates to a dispersible or disintegrating tablet, a process for its preparation, as well as its use in the treatment of bacterial diseases such as tuberculosis. Such novel compositions are particularly suitable for the pediatric population. They may also be suitable for the elderly population.

The active ingredient in this case is bedaquiline in the form of a fumaric acid salt: (alpha-S, beta-R)-6-bromo-alpha-[2-(dimethylamino)ethyl]-2-methoxy-alpha-1-naphthalenyl-betaphenyl -3-quinolineethanol, in particular (alpha-S, beta-R)-6-bromo-alpha-[2-(dimethylamino)ethyl]-2methoxy-alpha-1-naphthalenyl-beta-phenyl-3-quinolineethanol-(2E )-2-butenedioate (1:1), and can be represented by the following formula:

This salt of fumaric acid according to the present invention can be obtained by reacting the corresponding free base with fumaric acid in the presence of a suitable solvent such as, for example, isopropanol.

This active ingredient product from Sirturo™ has already been approved for sale in certain territories, including the US, Russia, the EU, South Africa and the Republic of Korea.

The applicability of this invention is due to the active ingredient and its salt known to exhibit activity against Mycobacteria, including drug-resistant strains, in particular Mycobacterium tuberculosis, M. bovis, M. avium, M. leprae and M. marinum, especially against Mycobacterium tuberculosis, including drug-resistant strains of M. tuberculosis. This active ingredient, including its salt, is active against active, sensitive, susceptible strains of Mycobacteria and latent, dormant, persistent strains of Mycobacteria.

International patent application WO 2004/011436 discloses for the first time the activity of bedaquiline free base against Mycobacteria. More recent documents such as international patent applications WO 2005/117875 and WO 2006/067048 disclose further applications in the treatment of inter alia drug resistant and latent tuberculosis. International patent application WO 2008/068231 first describes the suitability of a fumaric acid salt as a drug product, indicating its acceptable bioavailability. This salt of fumaric acid and bedaquiline is described as non-hygroscopic and stable. This document also discloses the preparation of certain formulations and tablets containing bedaquiline fumarate.

In particular, WO 2008/068231 discloses the preparation of a drug formulation containing a bedaquiline fumarate salt, where the powder mixture is obtained and compressed into tablets. Such a formulation does not have the proper dispersibility/disintegration properties.

Mycobacterium tuberculosis causes more than 2 million deaths per year and is the leading cause of death in people infected with HIV. Despite several decades of tuberculosis (TB) control programs, about 2 billion people are infected with M. tuberculosis, even if they are asymptomatic. About 10% of these individuals are at risk of developing active TB during their lifetime. Thus, there is a high demand for drugs for the treatment of active TB.

The worldwide TB epidemic is fueled by the infection of TB patients with HIV and the emergence of multidrug-resistant TB strains (MDR-TB). Reactivation of latent TB is a high risk factor for the development of the disease and leads to 32% of deaths in HIV-infected individuals. To combat the TB epidemic, the development of new drugs that can also destroy dormant or latent bacilli is needed. Dormant TB can be reactivated to cause disease by several factors, such as suppression of host immunity with immunosuppressive agents such as antibodies against tumor necrosis factor-α or interferon-γ. In the case of HIV-positive patients, the only preventive treatment suitable for latent TB is rifampicin and pyrazinamide regimens for two to three months. The effectiveness of the treatment regimen has not yet been established and, in addition, the duration of treatment is an important limitation in resource-limited settings. Therefore, there is an urgent need to discover new drugs that can act as chemoprophylactic agents for individuals who are carriers of latent bacilli that cause TB.

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Tuberculosis bacilli enter the body of healthy individuals by inhalation; they are phagocytosed by alveolar macrophages of the lungs. This leads to a strong immune response and the formation of granulomas, which consist of M. tuberculosis-infected macrophages surrounded by T cells. After a 6-8 week period, the host's immune response causes the death of infected cells by necrosis and the accumulation of caseous material with isolated extracellular bacilli surrounded by macrophages, epithelioid cells, and layers of lymphoid tissue in the periphery. In the case of healthy individuals, most mycobacteria are killed under such conditions, but a small proportion of the bacilli still survive and are thought to exist in a state of reduced metabolism without reproduction and are resistant to killing by anti-TB drugs such as isoniazid. These bacilli can persist under altered physiological conditions even throughout the life of an individual without any clinical symptoms of the disease. However, in 10% of these cases, these latent bacilli can reactivate, causing disease. One hypothesis for the development of these persistent bacteria is the hypothesis of pathophysiological conditions in human lesions, namely reduced oxygen partial pressure, nutrient restriction, and acidic pH. It has been hypothesized that these factors cause these bacteria to become phenotypically resistant to major antimycobacterial drugs.

Although pharmaceutical formulations based on bedaquiline fumarate have been developed for the adult population, no formulation for children has been developed and made available to date. There are many approaches to drug formulation development, including direct compression, dry granulation, and wet granulation. Individual requirements remain for each approach, and this also depends on the drug, which must also be formulated. In addition, for a pediatric population, it may be necessary to obtain a dispersible tablet, and this may also involve additional requirements. This is particularly important from the perspective of developing such tablets, which are characterized by a correspondingly short dispersion time.

Among the techniques used to obtain tablets, the simplest is direct compression, which includes only mixing and compression. This technique has an advantage in terms of production speed, since fewer operations are required, less equipment is needed and, as a result, it is more efficient.

Direct pressing is followed by other manufacturing processes such as dry or wet granulation.

A dispersible composition (eg, tablet) is contemplated containing bedaquiline fumarate as the active ingredient. This may be referred to herein as a (dispersible) tablet according to the present invention.

By dispersible, the present inventors mean a composition (e.g. tablet) which disintegrates in an appropriate medium, e.g. an aqueous medium (water) or other suitable vehicle or vehicle for administration (e.g. milk, juice or even a semi-solid carrier such as yogurt, applesauce). More specifically, the authors of the present invention mean that the tablet disintegrates in a small volume of water in such a way that it is dispersed (for example, uniformly and/or quickly) with gentle agitation of the solution by rotating the vessel. For example, 100 mg of a tablet composition can be uniformly dispersed over 90 seconds in about 50 ml of water. Therefore, the equivalent of 1 mg of tablet formulation weight in 0.5 ml of water can be uniformly dispersed over 90 seconds. More preferably, the equivalent of 1 mg by weight of the tablet composition in 0.5 ml of water can be uniformly dispersed within 60 seconds, more preferably within 45 seconds. In particular, it can be dispersed in about (eg within) 30 seconds. Such dispersion times/dispersion rates are suitable, in particular, for composition weights of 20 to 400 mg (in particular, from about 50 to about 200 mg), as shown by the examples later in this document. Therefore, in particular, a 100 mg tablet formulation can be uniformly dispersed in 50 ml of water in about (or within) 30 seconds. This dispersion can pass through a sieve mesh with a nominal mesh size of 710 µm.

However, even though the equivalent of 1 mg by weight of the composition (eg, tablet composition) in 0.5 ml of water is mentioned in the context of a dispersion, it is the properties inherent in the tablet formulation that are key. For example, dispersion can take place in a much smaller volume of liquid, for example 100 mg of the composition can also be dispersed in a much smaller amount of water, for example only 1-5 ml ml of water). In this case, the resulting mixture can be described as a dispersion as well as a soft mass. In the case of such a soft mass, it cannot pass through the above sieve mesh (given the small volume of water with which it is mixed), but it may still be suitable for administration, i.e. this soft mass can suitably be administered with a spoon. Likewise, the composition can be administered by mixing with another suitable vehicle or vehicle for administration (as described above), which may be a dispersion, a soft mass (if, for example,

- 2 042247 the composition is only mixed with a relatively small volume of water) or another mixture (for example, a semi-solid composition).

In comparison, the composition disclosed in the examples in WO 2008/068231 does not have comparable dispersibility/disintegration properties. In particular, such prior art formulations may not have comparable dispersibility properties, and more specifically, they (e.g., 100 mg of the composition in 50 ml of water, or the weight-volume equivalent of the composition) can be dispersed in times greater than 90 seconds, such as greater than 120 seconds ( and can be dispersed in more than 180 seconds, for example about 240 seconds or even longer). Such relatively long dispersion times may be disadvantageous and may be undesirable.

By uniformly dispersible, the present inventors mean that the composition (eg, tablet composition) rapidly disintegrates in water into physically smaller particles which are distributed (or dispersed) throughout the water. This results in any equal parts of water containing approximately equal amounts of particles (by weight) of the composition (e.g. tablet composition), by which the present inventors mean within ±25%, preferably ±15% and especially ±10% (or less, for example, within ±5%). Therefore, if 100 mg of the tablet composition is dispersed in 50 ml of water, then each 25 ml portion of water (if separated) should contain approximately 50 mg by weight of the tablet composition, but with a possible deviation of ±25% (t i.e. ±12.5 mg), preferably ±15% (i.e. ±7.5 mg), and in particular ±10% (i.e. ±5 mg), most preferably the deviation will be ±5% (i.e. ±2.5 mg). Therefore, the composition in the form of a tablet is physically uniform or homogeneous throughout the volume of the aqueous environment in which it is placed (after the time required for dispersion; see above). It will be understood that the greater the volume of water per mg of tablet composition, the smaller the variation in dispersion may be.

If it is indicated that a water-dispersible composition (for example, a composition in the form of a tablet) can pass through a 710 μm sieve, it is that the dispersible composition (for example, a tablet) satisfies certain parameters / requirements regarding quality, for example, those in current (or future) editions of the British Pharmacopoeia and the European Pharmacopoeia. Therefore, the quality of the dispersion (passed through the sieve) is important as well as the dispersion time (dispersion within 30 seconds is most preferred). While these properties are important for a given dispersion in an aqueous medium, it will be understood that a dispersion (eg in water) need not be prepared and the dispersible tablet may be administered by alternative routes. For example, the dispersible tablet can be mixed with certain food products (as such or by forming a soft mass when the tablet composition is mixed with a small amount/volume of water, as described above). This is explained below.

The dispersible composition (eg tablet) according to the present invention will be described in more detail. Obviously, it is characterized by inherent properties, which provide properties of dispersibility (or disintegration).

Therefore, in an aspect of the present invention, there is provided a dispersible composition (e.g., tablet) containing bedaquiline fumarate as an active ingredient, wherein the tablet comprises an intragranular layer and an extragranular layer, wherein the intragranular layer contains an insoluble filler/diluent and is characterized in that in the intragranular layer there is no soluble filler/diluent that is starch (and in the most preferred embodiment, no soluble filler/diluent is present in the intragranular layer). For example, the intragranular layer may contain mannitol as a filler/diluent (which is classified as a soluble filler/diluent), but may not contain starch. In a preferred embodiment, the intragranular layer is free of mannitol and starch (and also free of any other soluble filler/diluent).

In an alternative aspect of this invention, the intragranular layer contains an insoluble filler/diluent that is microcrystalline cellulose, but such a layer is not necessarily free of a soluble filler/diluent.

In one embodiment, if a soluble filler/diluent is used, it is preferably not a starch. The reason is that starch can swell in water (eg, about 5-10%) at 37°C (it can become soluble in hot water at temperatures above the gelation temperature).

Preferably, the intragranular layer contains an insoluble filler/diluent which is microcrystalline cellulose, and this layer is also free of any soluble filler/diluent.

Where microcrystalline cellulose is mentioned, it is assumed that silicified microcrystalline cellulose is included. This insoluble filler/diluent in the intragranular portion of the tablet according to this invention is key to

- 3 042247 its inherent dispersibility/disintegration properties.

By absent, in the context of a soluble excipient/diluent, the present inventors mean that the composition (e.g., a tablet composition) contains a negligible amount of such ingredient (e.g., in this case, a soluble excipient/diluent), by which the present inventors mean less than 5 wt.% based on the total weight of the composition, more preferably less than 2.5 wt.%, for example less than 1 wt.%. Most preferably, this means that the ingredient is completely absent, ie. that 0 or about 0% by weight of this ingredient is present, which is a negligible amount.

Often, dispersible tablets are made using soluble excipients/diluents, such as sugar-based excipients such as xylitol, fructose, lactose, and the like. However, in this case, it was found that soluble fillers were disadvantageous in terms of dispersibility/disintegration properties (as indicated in the comparative example later in this document), for example, due to the fact that they can absorb water and form a saturated layer that prevents further diffusion. solution from a saturated fixed bed (according to the Noye-Whitney diffusion layer theory), this phenomenon can cause a negative effect on the desired dispersion time. It may also be that soluble fillers are more prone to absorb moisture from the environment. This can also occur if soluble excipients are used in combination with a partially soluble or insoluble excipient. In any case, it was clear that the use of an insoluble filler, in particular microcrystalline cellulose, especially within the intragranular part of the tablet formulation, was key in obtaining a dispersible tablet with the desired properties.

Therefore, in an aspect of the present invention, there is provided a dispersible composition (e.g., a tablet composition) comprising (e.g., consisting of) by weight, based on the total weight of the composition:

5-50% (eg 10-30%) active ingredient;

35%-90% (eg 50-70%) insoluble filler/diluent;

2%-10% (eg 4-8%) baking powder;

0.1-5% (eg 1.5-3.5%) of a glidant;

0.01-5% (eg 0.1-1%) wetting agent or surfactant;

0-10% (eg 2-5%) binder or polymer;

0-5% (eg 1-3%) lubricant;

solvent (qs), for example water, which may also be referred to as a composition according to this invention.

In the case of the above composition, where the insoluble filler is microcrystalline cellulose (such as silicified microcrystalline cellulose), then the amount by weight can be from 20 to 90%, with the remaining amounts of the composition as defined herein.

Compositions according to this invention, referred to in this document, may differ in that they do not contain a soluble filler/diluent.

For example, most preferably the composition (e.g., tablet composition) consists of, by weight, based on the total weight of the composition:

24.18% (or about 25%) active ingredient;

62.12% (or about 60%) insoluble filler/diluent (eg, microcrystalline cellulose, such as silicified microcrystalline cellulose);

6% (or about 6%) disintegrant (eg crospovidone such as Polyplasdone XL);

2.5% (or about 2.5%) of a glidant (eg, colloidal silicon dioxide, Aerosil 200);

0.2% (or about 0.2%) wetting agent or surfactant (eg, polysorbate 20, i.e. Tween 20);

3% (or about 3%) binder or polymer (eg, hypromellose, 5 cps, i.e. Methocel E 5 LV);

2% (or about 2%) lubricant (eg sodium stearyl fumarate (Pruv));

solvent (qs), such as water, if necessary (ie, only the required amount, if at all).

In another aspect, a composition (e.g., a tablet composition) is provided, wherein the various parts of the composition, in particular the intragranular and extragranular fraction and the binder portion, contain (e.g., consist of) the following ingredients by weight based on the total weight of the composition:

intragranular fraction:

5-50% (eg 10-30%) active ingredient;

10-50% (eg 20-40%) insoluble filler/diluent (eg microcrystalline cellulose such as silicified microcrystalline cellulose);

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1-5% (eg 2-4%) disintegrant (eg crospovidone such as Polyplasdone XL);

0.1-5% (eg 0.5-4%, such as 1-3%) of a glidant (eg colloidal silicon dioxide, Aerosil 200);

binder:

1-10% (eg 2-5%) 3% binder or polymer (eg hypromellose, 5 cps, ie Methocel E 5 LV);

0.01-5% (eg 0.1-1%) wetting agent or surfactant (eg polysorbate 20, i.e. Tween 20);

solvent (qs), such as water, if necessary (ie only the required amount, if at all).

extragranular fraction:

10-50% (eg 20-40%) of a filler/diluent (preferably an insoluble filler/diluent, eg microcrystalline cellulose such as silicified microcrystalline cellulose);

1-5% (eg 2-4%) disintegrant (eg crospovidone such as Polyplasdone XL);

0-3% (eg, 0.1-1%) of a glidant (eg, colloidal silicon dioxide, Aerosil 200);

0-5% (eg 1-3%) lubricant (eg sodium stearyl fumarate (Pruv)).

The compositions (eg, tablet compositions) according to the invention referred to herein may in particular be characterized in that no soluble filler/diluent is present in the intragranular layer. Therefore, the extragranular fraction is not required to be free of any soluble filler/diluent, although this is preferably the case where the extragranular fraction is also free of any soluble filler/diluent.

For example, most preferably the composition consists of the following compositions of the intragranular fraction, the binder and the extragranular fraction by weight based on the total weight of the composition:

intragranular fraction:

24.18% (or about 25%) active ingredient;

29.82% (or about 30%) insoluble filler/diluent (eg, microcrystalline cellulose, such as silicified microcrystalline cellulose);

3% (or about 3%) disintegrant (eg crospovidone such as Polyplasdone XL);

2% (or about 2%) glidant (eg, colloidal silicon dioxide, Aerosil 200);

binder:

3% (or about 3%) binder or polymer (eg, hypromellose, 5 cps, i.e. Methocel E 5 LV);

0.2% (or about 0.2%) wetting agent or surfactant (eg, polysorbate 20, i.e. Tween 20);

solvent (qs), such as water, if necessary (ie only the required amount, if at all).

extragranular fraction:

32.3% (or about 30%) filler/diluent (preferably an insoluble filler/diluent, eg microcrystalline cellulose such as silicified microcrystalline cellulose);

3% (or about 3%) disintegrant (eg crospovidone such as Polyplasdone XL);

0.5% (or approximately 0.5%) of a glidant (eg, colloidal silicon dioxide, Aerosil 200);

2% (or approximately 2%) lubricant (eg sodium stearyl fumarate (Pruv)).

The intragranular fraction (or portion) may contain up to 75% by weight of the total weight of the composition (eg tablets) and preferably contains 40 to 70% by weight (eg 50 to 65% by weight) of the composition (or tablet). Most preferably, the intragranular fraction (or portion) of the composition (eg, tablet composition) contains approximately 60% of the total weight of the composition. A fraction (or part or element) of the binder may contain up to 20 wt.% of the total weight of the composition (e.g. tablet composition), for example from 0.5 to 10 wt.% and preferably from 1 to 8 wt.% ( for example, about 3 wt.%. The extragranular layer may contain up to 60% by weight of the total weight of the composition (eg tablets) and preferably contains 20 to 50% by weight (eg 30 to 45%) of the composition (or tablet).

Most preferably, the extragranular fraction (or portion) of the composition (eg, tablet composition) contains approximately 37.5% of the total weight of the composition.

In the context of the compositions (eg, tablet compositions) described herein, aspects of the composition can be described as containing an intragranular and extragranular fraction and

- 5 042247 part of the binder (or fraction). Such fractions or parts of the composition are eventually mixed with one another. However, it will be understood (for example, with reference to the method of obtaining such a composition) that the peculiarity of these fractions (or parts) results in special properties of the resulting compositions.

Compositions according to the invention described herein may be a mixture or dry mixture of intragranular and extragranular fractions (or parts) and part of the binder, and may also, after they are subjected to an appropriate compression technique, take the form of a (single) dosage form such as a tablet.

In the aspects of the invention described herein, in particular the dispersible compositions described above, the total tablet weight can be about 100 mg (and therefore the active ingredient present can be from 5 to 50 mg, such as from about 10 to 30 mg, for example about 20 mg). Thus, a formulation for children (or the elderly) in which approximately 20 mg of the active ingredient is present can be provided. In other aspects, such as those described below, the total tablet weight may be higher (but may still deliver the same amount of active ingredient), for example, 200 mg of a dispersible formulation may also be provided to deliver approximately 20 mg of active ingredient, in aspects and percentages which may be described below.

In another aspect of this invention, dispersible compositions with the following features can also be provided, which apply in particular to compositions according to this invention where the total tablet weight is relatively higher (e.g., more than 100 mg, e.g., total tablet weight of 200 mg) :

provides a dispersible composition (for example, a tablet composition) containing (for example, consisting of) by weight, based on the total weight of the composition:

5-50% (eg 5-20% or 10-15%) active ingredient;

35%-90% (eg 60-80% or 70-75%) insoluble filler/diluent;

2%-10% (eg 4-8%) baking powder;

0.1-5% (eg 1.5-3.5%) of a glidant;

0.01-5% (eg 0.1-1%) wetting agent or surfactant;

0-10% (eg 2-5%) binder or polymer;

0-5% (eg 1-3%) lubricant;

solvent (qs), e.g. water, a dispersible composition (e.g., tablet composition) is provided, containing (e.g., consisting of) by weight, based on the total weight of the composition:

12.09% (or about 12%) active ingredient;

73.71% (or about 70%) insoluble filler/diluent (eg, microcrystalline cellulose, such as silicified microcrystalline cellulose);

6% (or about 6%) disintegrant (eg crospovidone such as Polyplasdone XL);

2.5% (or about 2.5%) of a glidant (eg, colloidal silicon dioxide, Aerosil 200);

0.2% (or about 0.2%) wetting agent or surfactant (eg, polysorbate 20, i.e. Tween 20);

3% (or about 3%) binder or polymer (eg, hypromellose, 5 cps, i.e. Methocel E 5 LV);

2% (or about 2%) lubricant (eg sodium stearyl fumarate (Pruv));

solvent (qs), such as water, if necessary (ie only the required amount, if at all).

In another aspect, in particular for such compositions according to this invention, where the total weight of the tablet is relatively high (for example, 200 mg), a composition (for example, a composition in the form of a tablet) is provided, where the various parts of the composition, in particular the intragranular and extragranular fraction and the part The binder contains (for example, consists of) the following ingredients by weight, based on the total weight of the composition:

intragranular fraction:

5-50% (eg 5-20% or 10-15%) active ingredient;

10-50% (eg 30-50% or 35-45%) insoluble filler/diluent (eg microcrystalline cellulose such as silicified microcrystalline cellulose);

1-5% (eg 2-4%) disintegrant (eg crospovidone such as Polyplasdone XL);

0.1-5% (eg 0.5-4%, such as 1-3%) of a glidant (eg colloidal silicon dioxide, Aerosil 200);

binder:

1-10% (eg 2-5%) 3% binder or polymer (eg hypromellose, 5 cps, ie Methocel E 5 LV);

0.01-5% (eg 0.1-1%) wetting agent or surfactant (eg polysorbate 20, ie Tween 20);

solvent (qs), such as water, if necessary (ie only the required amount, if at all).

extragranular fraction:

10-50% (eg 20-40%) filler/diluent (preferably an insoluble filler/diluent, eg microcrystalline cellulose such as silicified microcrystalline cellulose);

1-5% (eg 2-4%) disintegrant (eg crospovidone such as Polyplasdone XL);

0-3% (eg, 0.1-1%) of a glidant (eg, colloidal silicon dioxide, Aerosil 200);

0-5% (eg 1-3%) lubricant (eg sodium stearyl fumarate (Pruv));

provides a composition (for example, a composition in the form of a tablet), where the various parts of the composition, in particular the intragranular and extragranular fraction and part of the binder contain (for example, consist of) the following ingredients by weight, calculated on the total weight of the composition:

intragranular fraction:

12.09% (or about 12%) active ingredient;

41.41% (or about 40%) insoluble filler/diluent (eg, microcrystalline cellulose, such as silicified microcrystalline cellulose);

3% (or about 3%) disintegrant (eg crospovidone such as Polyplasdone XL);

2% (or about 2%) glidant (eg, colloidal silicon dioxide, Aerosil 200);

binder:

3% (or about 3%) binder or polymer (eg, hypromellose, 5 cps, i.e. Methocel E 5 LV);

0.2% (or about 0.2%) wetting agent or surfactant (eg, polysorbate 20, i.e. Tween 20);

solvent (qs), such as water, if necessary (ie only the required amount, if at all).

extragranular fraction:

32.3% (or about 30%) filler/diluent (preferably an insoluble filler/diluent, eg microcrystalline cellulose such as silicified microcrystalline cellulose);

3% (or about 3%) disintegrant (eg crospovidone such as Polyplasdone XL);

0.5% (or approximately 0.5%) of a glidant (eg, colloidal silicon dioxide, Aerosil 200);

2% (or approximately 2%) lubricant (eg sodium stearyl fumarate (Pruv)).

Compositions according to this invention are described as containing certain components or ingredients, which are explained below.

By active ingredient we mean bedaquiline fumarate, i.e. form of a salt of fumaric acid and bedaquiline. This is a form that is part of a composition for an adult, for which permission has been obtained from the regulatory authorities in some territories.

This document indicates that the compositions (eg, compositions in the form of tablets) according to this invention contain an insoluble filler/diluent. Where an excipient is already specified, such excipient/diluent may be starch, powdered cellulose, microcrystalline cellulose (such as silicified microcrystalline cellulose), calcium phosphates (e.g. dibasic calcium phosphate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate), calcium carbonate , calcium sulfate or the like. (or combinations thereof, i.e. co-treated insoluble fillers; others that may be contemplated include waxy hydrogenated oils and the like). It is clear that the most preferred insoluble filler/diluent is microcrystalline cellulose (eg, silicified microcrystalline cellulose), as it results in a composition with inherent properties that are advantageous. If it is mentioned that the filler/diluent should not be insoluble, sugars and polyols may also be included, for example, the following fillers/diluents may also be included: dextrates, dextrin, dextrose filler, fructose, kaolin, lactitol, anhydrous lactose, lactose monohydrate, mannitol, sorbitol, sodium chloride, sucrose, compressed sugar, confectioner's sugar, spray-dried mixture of lactose monohydrate and microcrystalline cellulose (75:25), commercially available as Microcelac®, co-processed spray-dried mixture of microcrystalline cellulose and colloidal silicon dioxide (98:2 ), commercially available as Prosolv® (variants of which include sugars and other soluble excipients/diluents).

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This document indicates that the compositions (for example, compositions in the form of tablets) according to this invention contain a disintegrant. Possible disintegrants include pharmaceutically acceptable disintegrants containing starch, ion exchange resins such as Amberlite, cross-linked polyvinylpyrrolidone, modified cellulose gum such as croscarmellose sodium (such as Ac-di-Sol®), sodium starch glycolate, sodium carboxymethylcellulose, sodium dodecyl sulfate, modified corn starch, microcrystalline cellulose, magnesium aluminum silicate, alginic acid, alginate, powdered cellulose, crospovidone (such as Polyplasdone XL). Other disintegrants that may be contemplated include L-HPC, xanthan gum, gellan gum, soy polysaccharides, and the like. The most preferred disintegrant is crospovidone, preferably coarse crospovidone (such as Polyplasdone XL).

This document indicates that the compositions (for example, compositions in the form of tablets) according to this invention contain a substance that promotes sliding. Possible glidants include pharmaceutically acceptable glidants containing talc, colloidal silicon dioxide, starch, magnesium stearate.

Preferred is colloidal silicon dioxide (Aerosil 200).

This document indicates that the compositions (eg, compositions in the form of tablets) according to this invention contain a wetting agent or surfactant. Such wetting agent (or surfactant) may be any of the physiologically tolerable wetting agents suitable for use in a pharmaceutical composition.

It is widely known in the art that a wetting agent is an amphiphilic compound; it contains polar, hydrophilic moieties as well as non-polar, hydrophobic moieties.

The terms hydrophilic or hydrophobic are relative terms.

The relative hydrophilicity or hydrophobicity of a wetting agent can be expressed in terms of its hydrophilic-lipophilic balance index (HLB index). Wetting agents with a lower HLB score are categorized as hydrophobic wetting agents, while wetting agents with a higher HLB score are categorized as hydrophilic wetting agents. As a general rule, wetting agents having an HLB index greater than about 10 are generally considered to be hydrophilic wetting agents; wetting agents having an HLB value of less than about 10 are generally considered to be hydrophobic wetting agents.

Compositions according to the present invention preferably contain a hydrophilic wetting agent.

It should be understood that the HLB value of a wetting agent is only a rough measure for indicating the hydrophilicity/hydrophobicity of a wetting agent. The HLB value of a particular wetting agent may vary depending on the method used to determine the HLB value; may vary depending on its commercial source; however, it is characterized by variability between batches. A person skilled in the art can readily identify hydrophilic wetting agents suitable for use in the pharmaceutical compositions of the present invention.

The wetting agent of the present invention may be an anionic, cationic, zwitterionic or non-ionic wetting agent, the latter being preferred. The wetting agent according to the present invention may also be a mixture of two or more wetting agents.

Suitable wetting agents for use in the compositions of the present invention are listed below. It should be emphasized that this list of wetting agents is only illustrative, indicative and not exhaustive. Thus, the present invention is not limited to the wetting agents listed below. Mixtures of wetting agents can also be used in the compositions of the present invention.

Suitable wetting agents that can be used in the present invention include:

a) fatty acid monoesters of polyethylene glycol, including esters of lauric acid, oleic acid, stearic acid, ricinoleic acid, and the like. with PEG 6, 7, 8, 9, 10, 12, 15, 20, 25, 30, 32, 40, 45, 50, 55, 100, 200, 300, 400, 600 etc., e.g. laurate or PEG-6 stearate, PEG-7 oleate or laurate, PEG-8 laurate or oleate or stearate, PEG-9 oleate or stearate, PEG-10 laurate or oleate or stearate, laurate or oleate or stearate, or PEG-12 ricinoleate, PEG15 stearate or oleate, PEG-20 laurate or oleate or stearate, PEG-25 stearate, PEG-32 laurate or oleate or stearate, PEG-30 stearate, laurate or oleate or PEG stearate -40, PEG-45 stearate, PEG-50 stearate, PEG-55 stearate, PEG-100 oleate or stearate, PEG-200 oleate, PEG-400 oleate, PEG-600 oleate (wetting agents belonging to this group are known, for example, as Cithrol, Algon, Kessco, Lauridac, Mapeg, Cremophor, Emulgante, Nikkol, Myrj, Crodet, Albunol, Lactomul);

b) diesters of fatty acids and polyethylene glycol containing diesters of lauri-

- 8 042247 new acid, stearic acid, palmitic acid, oleic acid and the like. with PEG-8, 10, 12,

20, 32, 400, etc. e.g. PEG-8 dilaurate or distearate, PEG-10 dipalmitate, PEG-12 dilaurate or distearate or PEG-12 dioleate, dilaurate or distearate or PEG-20 dioleate, dilaurate or distearate , or PEG-32 dioleate, PEG-400 dioleate or distearate (wetting agents belonging to this group are known, for example, as Mapeg, Polyalso, Kessco, Cithrol);

c) mixtures of mono- and diesters of fatty acids and polyethylene glycol, such as, for example, PEG 4-150 mono- and dilaurate, PEG 4-150 mono- and dioleate, PEG 4-150 mono- and distearate, and the like. (wetting agents belonging to this group are known, for example, as Kessco);

d) mixed esters of polyethylene glycol with glycerol and fatty acids, such as, for example, glyceryl laurate or glyceryl stearate or PEG-20 glyceryl oleate, PEG-30 glyceryl laurate or glyceryl oleate, PEG-15 glyceryl laurate, PEG-40 glyceryl laurate, and the like. (wetting agents belonging to this group are known, for example, as Tagat, Glycerox L, Capmul);

e) alcohol-oil transesterification products containing esters of alcohols or polyhydric alcohols such as glycerol, propylene glycol, ethylene glycol, polyethylene glycol, sorbitol, pentaerythritol, etc., with natural and/or hydrogenated oils or oil-soluble vitamins, such as castor oil , hydrogenated castor oil, vitamin A, vitamin D, vitamin E, vitamin K, edible vegetable oil such as corn oil, olive oil, peanut oil, palm kernel oil, apricot kernel oil, almond oil, etc., such as PEG -20 and castor oil, or hydrogenated castor oil, or corn glycerides, or almond glycerides, PEG-23 and castor oil, PEG-25 and hydrogenated castor oil or PEG-25 trioleate, PEG-35 and castor oil, PEG-30 and castor oil or hydrogenated castor oil, PEG38 and castor oil, PEG-40 and castor oil or hydrogenated castor oil or palm kernel oil, PEG-45 and hydrogenation castor oil, PEG-50 and castor oil or hydrogenated castor oil, PEG-56 and castor oil, PEG-60 and castor oil, or hydrogenated castor oil, or corn glycerides, or almond glycerides, PEG-80 and hydrogenated castor oil, PEG-100 and castor oil or hydrogenated castor oil, PEG200 and castor oil, PEG-8 and caprylic/capric glycerides, PEG-6 and caprylic/capric glycerides, lauroyl macrogol-32-glyceride, stearoyl macrogol glyceride, tocopheryl PEG-1000 -succinate (TPGS) (wetting agents belonging to this group are known, for example, as Emalex, Cremophor, Emulgante, Eumulgin, Nikkol, Thornley, Simulsol, Cerex, Crovol, Labrasol, Softigen, Gelucire, vitamin E TPGS);

f) polyglycerized fatty acids containing polyglycerol fatty acid esters such as, for example, polyglyceryl-10-laurate or oleate or stearate, polyglyceryl-10-mono- and dioleate, polyglyceryl polyricinoleate and the like. (wetting agents belonging to this group are known, for example, as Nikkol Decaglyn, Caprol or Polymuls);

g) sterol derivatives containing polyethylene glycol and sterol derivatives such as PEG24-cholesterol ether, PEG-30-cholestanol, PEG-25-phytosterol, PEG-30-soy sterol and the like. (wetting agents belonging to this group are known, for example, as Solulan™ or Nikkol BPSH);

h) mixed esters of polyethylene glycol and sorbitol with fatty acids, such as, for example, PEG-10 sorbitan laurate, PEG-20-sorbitan monolaurate, or sorbitan tristearate, or sorbitan monooleate, or sorbitan trioleate, or sorbitan monoisostearate, or sorbitan monopalmitate, or sorbitan monostearate, PEG4-sorbitan monolaurate, PEG-5-sorbitan monooleate PEG-6-sorbitan monooleate or sorbitan monolaurate or sorbitan monostearate PEG-sorbitol hexaoleate (Atlas G-1086) and the like. (wetting agents belonging to this group are known, for example, as Liposorb, Tween, Dacol MSS, Nikkol, Emalex, Atlas);

i) polyethylene glycol alkyl ethers such as, for example, PEG-10-oleyl ether or cetyl ether or stearyl ether, PEG-20-oleyl ether or cetyl ether or stearyl ether, PEG-9-lauryl ether, PEG- 23-lauryl ether (Laureth-23), PEG-100-stearyl ether, etc. (wetting agents belonging to this group are known, for example, as Volpo, Brij);

j) sugar esters such as, for example, sucrose distearate/monostearate, monostearate or monopalmitate or sucrose monolaurate and the like. (wetting agents belonging to this group are known, for example, as Sucro ester, Crodesta, Saccharose monolaurate);

k) polyethylene glycol alkyl phenols such as, for example, PEG-10-100-nonylphenol (Triton X series), PEG-15-100-octylphenol ether (Triton N series) and the like;

l) block copolymers of polyoxyethylene and polyoxypropylene (poloxamers), such as, for example, poloxamer 108, poloxamer 188, poloxamer 237, poloxamer 288 and the like. (wetting agents belonging to this group are known, for example, as Synperonic PE, Pluronic, Emkalyx, Lutrol™, Supronic, Monolan, Pluracare, Plurodac);

m) ionic wetting agents, including cationic, anionic and zwitterionic surfactants such as fatty acid salts, e.g. sodium oleate, sodium lauryl sulfate, sodium lauryl sarcosinate, sodium dioctylsulfosuccinate, sodium myristate, sodium palmitate property

- 9 042247 sodium, sodium ricinoleate and the like; such as bile salts, eg sodium cholate, sodium taurocholate, sodium glycocholate and the like; such as phospholipids, eg egg/soy lecithin, hydroxylated lecithin, lysophosphatidylcholine, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, and the like; such as esters of phosphoric acid, for example diethanolammonium polyoxyethylene-10-oleyl ester of phosphoric acid, esterification products of fatty alcohols or fatty alcohol ethoxylates with phosphoric acid or phosphoric anhydride; such as carboxylates, e.g. succinylated monoglycerides, sodium stearyl fumarate, stearoyl propylene glycol hydrogen succinate, mono/diacetylated tartaric acid esters which are mono- and diglycerides, citric acid esters which are mono- and diglycerides, mixed esters of glycerol, lactic acid and fatty acids, mixed esters of lactic acid and fatty acids, calcium/sodium stearoyl-2-lactylate, calcium/sodium stearoyl lactylate, alginate salts, propylene glycol alginate, ether carboxylates, and the like; such as sulfates and sulfonates, for example ethoxylated alkyl sulfates, alkyl benzene sulfates, alpha-olefin sulfonates, acyl isethionates, acyl taurates, alkyl glyceryl ether sulfonates, disodium octyl sulfosuccinate, disodium undecylenamido-MEA-sulfosuccinate, and the like; such as cationic wetting agents, for example hexadecyltriammonium bromide, decyltrimethylammonium bromide, cetyltrimethylammonium bromide, dodecylammonium chloride, alkylbenzyldimethylammonium salts, diisobutylphenoxyethoxydimethylbenzylammonium salts, alkylpyridinium salts, betaines (lauryl betaine), ethoxylated amines (polyoxyethylene-15-coco amine) and the like.

If the above list of suitable wetting agents lists various options such as, for example, PEG-20-oleyl ether, or cetyl ether, or stearyl ether, then this means that PEG-20-oleyl ether is meant, and PEG-20 -cetyl ether; and PEG-20 stearyl ether. Thus, for example, PEG-20 and castor oil or hydrogenated castor oil or corn glycerides or almond glycerides should be read as PEG-20 and castor oil and PEG-20 and hydrogenated castor oil and PEG-20 and corn glycerides , and PEG-20 and almond glycerides.

Preferred wetting agents in the compositions of the present invention are those belonging to the group of mixed fatty acid esters of polyethylene glycol and sorbitol, such as the wetting agents known as Tween, for example Tween 20, 60, 80. Most preferably the wetting agent is Tween 20 (polysorbate 20).

The preferred amount of wetting agent (or surfactant) is described herein, but, however, it is understood that when used in the compositions of the present invention, it may depend on the amount of active ingredient present in the composition, or on the particle size of the active ingredient. . Higher numbers or smaller particle sizes may require more wetting agent.

This document indicates that the compositions (eg tablet compositions) according to this invention contain a binder or polymer (eg for the binder fraction of the compositions according to this invention). Such a binder or polymer may be an organic polymer.

The organic polymer used in the compositions (eg tablets) according to this invention may be any of the physiologically tolerable water-soluble synthetic, semi-synthetic or non-synthetic organic polymers.

Thus, for example, the polymer may be a natural polymer such as a polysaccharide or polypeptide or derivative thereof, or a synthetic polymer such as polyalkylene oxide (eg PEG), polyacrylate, polyvinylpyrrolidone, etc. Mixed polymers, such as block copolymers and glycopeptides, of course, can also be used.

The polymer is conventionally characterized by a molecular weight in the range of 500D-2 MD and is conventionally characterized by an apparent viscosity of 1-15000 mPa.s, being in a 2% aqueous solution at 20°C. For example, the water-soluble polymer may be selected from the group consisting of alkylcelluloses such as methylcellulose, hydroxyalkylcelluloses such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxybutylcellulose, hydroxyalkylalkylcelluloses such as hydroxyethylmethylcellulose and hydroxypropylmethylcellulose, carboxyalkylcelluloses such as carboxymethylcellulose, alkali metal salts and carboxyalkylcelluloses such as such as sodium carboxymethylcellulose, carboxyalkylalkylcelluloses such as carboxymethylethylcellulose, carboxyalkylcellulose esters, starches, pectins such as sodium carboxymethylamylopectin, chitin derivatives such as chitosan,

- 10 042247 heparin and heparinoids, polysaccharides such as alginic acid, its alkali metal salts and its ammonium salts, carrageenans, galactomannans, tragacanth, agar-agar, gum arabic, guar gum, xanthan gum, polyacrylic acids and their salts, polymethacrylic acids and their salts, methacrylate copolymers, polyvinyl alcohol, polyvinylpyrrolidone, polyvinylpyrrolidone-vinyl acetate copolymers, polyalkylene oxides such as polyethylene oxide and polypropylene oxide, and ethylene oxide-propylene oxide copolymers, for example poloxamers and poloxamines.

Non-listed polymers that are pharmaceutically acceptable and have the appropriate physicochemical properties as defined herein above are equally suitable for preparing the compositions of the present invention.

Preferably the organic polymer is starch, polyvinylpyrrolidone or cellulose ether, for example PVP K29-32, PVP K90, methylcellulose, hydroxypropylcellulose, hydroxyethylpropylcellulose or hydroxypropylmethylcellulose (HPMC).

Said HPMC contains a sufficient amount of hydroxypropyl groups and methoxy groups to ensure its solubility in water. HPMC having a methoxy degree of substitution from about 0.8 to about 2.5 and a hydroxypropyl molar substitution from about 0.05 to about 3.0 are generally water soluble. Methoxy substitution refers to the average number of methyl ester groups present on the anhydroglucose moiety of the cellulose molecule. Hydroxypropyl molar substitution refers to the average number of propylene oxide moles that have reacted with each anhydroglucose moiety of the cellulose molecule. Preferred HPMC is hypromellose 2910 15 mPa.s or hypromellose 2910 5 mPa.s, in particular hypromellose 2910 15 mPa.s. Hydroxypropyl methylcellulose is the US name for hypromellose (see Martindale, The Extra Pharmacopoeia, 29th edition, page 1435). In the four-digit number 2910, the first two digits are the approximate percentage of methoxy groups, and the third and fourth digits are the approximate percentage of hydroxypropyl groups; 15 or 5 mPa-s is a value representative of the apparent viscosity of a 2% aqueous solution at 20°C.

Most preferably, the binder or polymer of the composition according to this invention is hypromellose 5 cps (ie Methocel E 5 LV).

This document indicates that the compositions (for example, compositions in the form of tablets) according to this invention contain a lubricant. Such a lubricant may be pharmaceutically acceptable lubricants such as magnesium stearate, calcium stearate, stearic acid, talc, polyethylene glycol, sodium lauryl sulfate, magnesium lauryl sulfate. Most preferably, the lubricant is sodium stearyl fumarate (Pruv).

Compositions according to the invention may use an active ingredient having a particle size of d ¹⁰ less than 50 µm (preferably less than 25 µm, eg less than 15 µm, eg about 9 µm (or even less);

d ⁵⁰ less than 100 microns (preferably less than 50 microns, such as less than 25 microns, such as about 22 microns (or even less);

d ⁹⁰ less than 200 microns (preferably less than 100 microns, such as less than 50 microns, such as approximately 48 microns (or even less).

As used herein, the term d ⁵⁰ is characterized by its generally accepted meaning, known to the person skilled in the art, and can be measured using particle size measurement techniques known in the art, such as, for example, sedimentation force flow fractionation, photon correlation spectroscopy, laser diffraction or disc centrifugation. d ⁵⁰ specified in this document may be associated with volume distributions of particles. In this case, d ⁵⁰ of 22 µm means that at least 50% of the particle volume has a particle size of less than 22 µm. The same applies to the other specified particle sizes, and d ¹⁰ and d ⁹⁰ are characterized by similar values. Typically, the volume and weight distributions give the same or about the same value for the average particle size.

Particle size can be an important factor in determining the rate of manufacture of tablets, in particular the fluidity and thus large scale processability of a particular dosage form or formulation, and the quality of the final product. For example, for capsules, the particle size may preferably range from about 5 to about 300 microns (d ⁵⁰ ); for tablets, the particle size is preferably less than 250 µm, more preferably less than 100 µm

- 11 042247 (eg less than 50 µm) (d ⁵⁰ ). Also, small particles can cause sticking of punches and process impurities to the tablet. The particle size affects the properties inherent in the compositions according to this invention.

The compositions described herein may additionally contain one or more pharmaceutically acceptable excipients such as, for example, plasticizers, flavors, sweeteners, colors, preservatives, and the like. (provided that such additional excipients do not contain soluble fillers/diluents, in case it is already indicated that the composition or fraction of this composition, if necessary, does not contain such soluble components). In an aspect of this invention, the compositions of this invention do not contain a plasticizer or other such optional excipient as specified herein. In particular, in the case of production by hot melt extrusion, said fillers should not be heat sensitive, in other words, they should not show any significant degradation or decomposition at the operating temperature of the melt extruder.

The advantage of the present combinations according to this invention, namely the dispersibility/disintegration properties, may be due to the presence of an insoluble filler (for example, microcrystalline cellulose, such as silicified microcrystalline cellulose), which may be characterized by the ability to quickly absorb water in the dispersion medium, i.e. it can be characterized by absorbent activity, which advantageously results in improved dispersing/disintegrating properties. In view of this, advantageously the compositions according to the present invention achieve acceptable dispersibility or disintegration, for example, in comparison with compositions known in the past, or in comparison with other compositions that may be described herein. As stated, the absorbent activity can lead to faster dispersion and the solubilization process can be avoided (e.g. liquid can be taken up or absorbed in such ways due to capillary activity and breaking bonds between particles, which leads to disintegration of the tablet/composition), which may be preferred. . Also, insoluble excipients/diluents can easily be resuspended even after a long period of time (eg 6 hours), this may have the advantage that the compositions of the present invention do not require a suspending agent to re-disperse the granules/particles.

The invention also relates to a process for preparing compositions of the invention (eg, tablet compositions), and therefore provides a process (eg, described hereinafter) for preparing a composition (eg, tablet) of the invention;

a product (eg, a composition according to this invention, eg, a dispersible tablet described herein) obtainable using a method according to this invention (eg, described below in this document).

As indicated above, the compositions according to this invention preferably contain various fractions/parts, an intragranular fraction, a binder part and an extragranular fraction.

Therefore, a process for preparing the process of the present invention is provided, which includes:

(a) obtaining an intragranular fraction using the components of the intragranular fraction specified in this document;

(b) obtaining a fraction of the binder using the components of the fraction of the binder specified in this document;

(c) obtaining an extragranular fraction using the components of the extragranular fraction specified in this document, and the use of these fractions to obtain a composition according to this invention.

More specifically, the intragranular fraction (as defined herein) can be obtained by blending or dry blending the respective components.

Direct compression may be used, but this may have the disadvantage that the mixture has poor flow properties and/or may adhere to the surface of the punches. Consequently, direct compression was followed by granulation. Dry granulation may be deficient in terms of flow properties (or compressibility properties) and the above sticking/aggregation phenomenon may also be retained. Therefore, for compositions according to this invention, it is preferred that a wet granulation process be used.

More specifically, therefore, a fraction/part of the binder can be obtained by bringing into contact or mixing the appropriate ingredients (i.e. binder or polymer and a wetting agent and, if necessary, a carrier, which may be aqueous or non-aqueous or combinations; the carrier is preferably water (qs), preferably purified water (qs)), and this fraction/part of the binder can be wet granulated using the intragranular fraction. Such a wet granulation process is preferably a low shear granulation (or top spray fluidized bed granulation) process and a low viscosity soluble polymer (preferably 5 cps or lower) is used in the binder fraction. The resulting granulate can then be dried and sized (or sieved) after which it is mixed or dry-blended with the components of the extra-granular fraction (as defined herein). Such mixing also, in fact, includes lubrication, in case the extragranular layer also includes a lubricant.

If the composition according to the present invention has been obtained, for example, in the manner provided above, including mixing intragranular, extragranular fractions and fractions of a binder, such a composition may optionally and preferably be converted into the form of tablets. In a preferred aspect of the process according to the invention, the compositions thus obtained are preferably compressed into tablet form, thus providing a dispersible tablet according to the invention. Such a tablet may be any suitable dose, but each unit dose may contain from 5 to 200 mg of the active ingredient (in which case the active ingredient of bedaquiline does not imply a component in the form of a fumaric acid salt). The unit dose may contain 100 mg bedaquiline (plus the appropriate weight of part of the fumaric acid salt) or, if the unit form is intended for the pediatric population, it is preferably 20 mg bedaquiline (corresponding to 24.18 mg bedaquiline fumarate).

The tablet manufacturing process itself is otherwise standardized and is readily operable to form a tablet from the desired dry blend or mixture of ingredients into an appropriate shape using a conventional tablet press.

The tablets of the present invention may be optionally coated to improve taste, ease of swallowing and appearance. In the prior art, a large number of suitable polymeric materials for shells are known. The preferred shell material is HPMC hydroxypropyl methylcellulose, in particular HPMC 2910 5 mPa-s. Other suitable shell polymers may also be used herein, including hydroxypropyl cellulose and copolymers of acrylic and methacrylic acids. In addition, the shell polymer, film shell may further contain a plasticizer (eg propylene glycol) and optionally a pigment (eg titanium dioxide). The shell slurry may also contain talc as an anti-adherent agent. In the immediate release tablets of the present invention, the film coat is small and, in terms of weight, accounts for less than about 3% (w/w) of the total weight of the tablet. In one embodiment according to this invention (for example, in a preferred embodiment), the tablets according to this invention are not coated.

As indicated above, the applicability according to this invention is due to the active ingredient and its salt, known to exhibit activity against Mycobacteria, including drug-resistant strains, in particular Mycobacterium tuberculosis, M. bovis, M. avium, M. leprae and M. marinum, especially against Mycobacterium tuberculosis, including drug-resistant M. tuberculosis strains. This active ingredient, including its salt, is active against active, sensitive, susceptible strains of Mycobacteria and latent, dormant, persistent strains of Mycobacteria.

Therefore, in an aspect of the present invention, compositions (e.g. tablets) according to the present invention are provided which are suitable for the treatment of bacterial infection, including mycobacterial infection, in particular diseases caused by pathogenic mycobacteria such as Mycobacterium tuberculosis (including their latent and drug-resistant forms), M. bovis, M. leprae, M. avium, M. leprae and M. marinum.

In addition, the present invention also relates to the use of a composition (e.g. tablet) according to this invention, pharmaceutically acceptable salts of its constituents, their solvates or their N-oxide forms, as well as any of the pharmaceutical compositions containing them described hereinafter, for obtaining a medicinal product for the treatment of a bacterial infection, including mycobacterial infection.

Accordingly, in another aspect, this invention provides a method of treating a patient suffering from a bacterial infection, including mycobacterial infection, or at risk of such, which comprises administering to the patient a therapeutically effective amount of a pharmaceutical composition (e.g., tablet) according to this invention.

Compositions of this invention may be combined with other therapeutic agents known to be useful in the treatment of bacterial infection as defined herein (and in particular for the treatment of mycobacterial infection, tuberculosis as defined herein). Such other antibacterial agents include β-lactam antibiotics such as natural penicillins, semi-synthetic penicillins, natural cephalosporins, semi

- 13 042247 synthetic cephalosporins, cephamycins, 1-oxacephems, clavulanic acids, penems, carbapenems, nocardicins, monobactams; tetracyclines, anhydrotetracyclines, anthracyclines; aminoglycosides; nucleosides such as N-nucleosides, C-nucleosides, carbocyclic nucleosides, blasticidin S; macrolides such as 12-membered ring macrolides, 14-membered ring macrolides, 16-membered ring macrolides; ansamycins; peptides such as bleomycins, gramicidins, polymyxins, bacitracins, large ring peptide antibiotics containing lactone bonds, actinomycins, amphomycin capreomycin, distamycin, enduracins, mikamycin, neocarcistatin, stendomycin, biomycin, virginiamycin; cycloheximide; cycloserine; variotin; sarcomycin A; novobiocin; griseofulvin; chloramphenicol; mitomycins; fumagillin; monensins; pyrrolnitrin; fosfomycin; fusidic acid; D-(p-hydroxyphenyl)glycine; D-phenylglycine; enediins.

Specific antibiotics that can be combined with the compositions of the present invention are, for example, benzylpenicillin (potassium salt, procaine, benzathine), phenoxymethylpenicillin (potassium salt), pheneticillin potassium salt, propicillin, carbenicillin (disodium salt, phenyl sodium salt, indanyl sodium salt), sulbenicillin, ticarcillin disodium, methicillin sodium, oxacillin sodium, cloxacillin sodium, dicloxacillin, flucloxacillin, ampicillin, mezlocillin, piperacillin sodium, amoxicillin, cyclacillin, hectacillin, sulbactam sodium, thalampicillin hydrochloride, cephalampicillin hydrochloride, baccacillinam hydrochloride cefaclor, cephaloglycine, cefadroxil, cephradine, cefroxadine, cefapirin sodium, cefalotin sodium, cefacetril sodium, cefsulodin sodium, cephaloridine, cefatrizine, cefoperazone sodium, cefamandol, cefotiam hydrochloride, cefazolin sodium, sodium Ceftizoxime Sodium, Cefotaxime Sodium, Cefmenoxime Hydrochloride, Cefuroxime, Ceftriaxone Sodium, Ceftazidime, Cefoxitin, Cefmetazole, Cefotetan, Latamoxef, Clavulanic Acid, Imipenem, Aztreonam, Tetracycline, Chlortetracycline Hydrochloride, Demethylchlortetracycline, Cycloxytetracycline, Mintetracycline , daunorubicin hydrochloride, doxorubicin, aclarubicin, kanamycin sulfate, becanamycin, tobramycin, gentamicin sulfate, dibekacin, amikacin, micronomycin, ribostamycin, neomycin sulfate, paromomycin sulfate, streptomycin sulfate, dihydrostreptomycin, destomycin A, hygromycin, nemycin B sulfate, spectinomycin hydrochloride, astromycin sulfate, validamycin, kasugamycin, polyoxin, blasticidin S, erythromycin, erythromycin estolate, oleandomycin phosphate, triacetyl oleandomycin, kitasamycin, josamycin, spiramycin, tylosin, ivermectin, midecamycin, bleomycin sulfate, peplomycin S sulfate, polygramycin S B, bacitracin, colistin sulfate, colistin methanesulfonate sodium, enramycin, mikamycin, virginiamycin, capreomycin sulfate, viomycin, enviomycin, vancomycin, actinomycin D, neocarzinostatin, bestatin, pepstatin, monensin, lazalocid, salinomycin, amphotericin B, nystatin, natamycin, trichomycin , lincomycin, clindamycin, clindamycin palmitate hydrochloride, flavophospholipol, cycloserine, pecilocin, griseofulvin, chloramphenicol, chloramphenicol palmitate, mitomycin C, pyrrolnitrin, fosfomycin, fusidic acid, bicosamycin, tiamulin, sikkanin.

Other antimycobacterial agents that can be combined with the compositions of the present invention are, for example, rifampicin (=rifampin); isoniazid; pyrazinamide; amikacin; ethionamide; ethambutol; streptomycin; para-aminosalicylic acid; cycloserine; capreomycin; kanamycin; thioacetazone; RA-824; quinolones/fluoroquinolones such as, for example, moxifloxacin, gatifloxacin, ofloxacin, ciprofloxacin, sparfloxacin; macrolides such as, for example, clarithromycin, clofazimine, amoxicillin with clavulanic acid; rifamycins; rifabutin; rifapentine.

It is understood that the term approximately in connection with a numerical value has its usual meaning in the context of a numerical value. If necessary, the word approximately can be replaced by a numerical value of ±10%, or ±5%, or ±2%, or ±1%.

All documents referenced in this document are incorporated by reference in their entirety.

The following examples are intended to illustrate the present invention.

experimental part

This bedaquiline fumarate active ingredient can be prepared, for example, according to the procedures described in international patent application WO 2008/068231. As can be seen from Table. 1 below, TMC207 refers to bedaquiline fumarate.

- 14 042247

Examples

1) The effect of intragranular filler.

Ingredient Intragranular part TMS207 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 Extragranular 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 fumarate 2.0 2.0 2.0 Total (mg) 100 100 100 Dispersion time*(s) 30-70 40-70 40-50 Strength (N) 20-31 24-31 25-40

The soluble filler in the intragranular portion did not show any further improvement in dispersion time. It has been observed that the time required to disperse the tablet was adversely affected by the addition of soluble excipients intragranularly. Thus, it was decided to proceed with silicified MCC.

2) The effect of extra-granular aggregates.

Ingredients Intragranular part TMS207 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 Extragranular part Mannitol 32.3 ...... Silicified microcrystalline cellulose ...... 32.3 Crospovidone 3.0 3.0 colloidal silicon dioxide 0.5 0.5 Sodium fumarate 2.0 2.0 General content 100 100 Dispersion time*(s) 60 45 Strength (N) 19-25 20-27

The soluble filler in the extragranular portion did not show any further improvement. It has been observed that the time required to disperse the tablet was adversely affected by the addition of soluble excipients. Thus, it was decided to proceed with silicified MCC.

- 15 042247

3) The effect of the quality of crospovidone.

Ingredients Intragranular part TMS207 24.1θ 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 Extragranular 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 fumarate 2.0 2.0 Total (mg) 100 100 Dispersion time*(s) 90-100 55-75 Strength (N) 25-34 25-34

Crospovidone (Polyplasdone XL) with coarse particles exhibited a better dispersion pattern and performance compared to crospovidone (Polyplasdone XL 10) with fine particles, so it was decided to proceed further with Polyplasdone XL brand in the intragranular layer as well as in the extragranular layer .

Additional examples.

The following composition according to this invention was obtained in accordance with the methods described in this document.

Table 1

The current composition of the dispersible tablet containing TMS 207

Ingredient Function Amount per tablet (mg) amount per tablet (%) Bedaquiline fumarate (TMS 207) API 24.18 24.18 Silicified microcrystalline cellulose (Prosolv HD 90) Aggregate 29.82 29.82 Crospovidone (Polyplasdone XL) Baking powder 3.0 3.0 Colloidal silicon dioxide (Aerosil 200) Gliding agent 2.0 2.0 Hypromellose 5 cps (Methocel E 5 LV) Binder 3.0 3.0 Purified water ⁽¹⁾ Solvent qs qs Polysorbate 20 (Tween 20) Surface- active substance 0.2 0.2 Silicified microcrystalline cellulose (Prosolv HD 90) 32.3 32.3 Crospovidone (Polyplasdone XL) Baking powder 3.0 3.0 Colloidal silicon dioxide (Aerosil 200) Gliding agent 0.5 0.5 Sodium Stearyl Fumarate (Pruv) Lubricating substance 2.0 2.0 Tablet weight 100 mg 100%

(1) This material is a processing aid and is removed during processing.

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Stability Data

Appearance, quantitation and chromatographic purity Parameter Appearance Contained water in % w/w % content of bedaquiline fumarate Degradable compounds >0.05% (%) Test method visual study KF- 00131-V1 HPLC-00129-V1 Conditions storage Storage time (months) Result weight/weight Bedaquiline a fumarate (%) Any unspecified degradable product (%) Total content of degradable products ^U_RR T_0.74 ^U_RR T_1.04 Start accepted 4.4 98.1 <0.05 <0.05 <0.05 25°C/60%RH 1 accepted 5.2 98.7 <0.05 0.05 0.05 3 accepted 4.9 98.0 <0.05 <0.05 <0.05 6 accepted 4.6 99.1 <0.05 <0.05 <0.05 30°C/75%RH 1 accepted 5.0 99.2 <0.05 <0.05 <0.05 3 accepted 5.1 97.8 <0.05 <0.05 <0.05 6 accepted 5.3 99.0 <0.05 <0.05 <0.05 40°C/75%RH 1 accepted 4.8 99.1 <0.05 <0.05 <0.05 3 accepted 5.2 98.0 <0.05 0.05 0.05 6 accepted 5.4 99.1 <0.05 <0.05 <0.05 50°C. 1 accepted 4.2 98.5 <0.05 <0.05 <0.05 3 accepted 4.1 98.2 0.08 0.06 0.14 ICH Light 8 ocloc'k accepted 5.3 98.4 <0.05 <0.05 <0.05 Note: Light ICH: CIE85-ID65 700 W/ ^m2 (Light exposure study conducted on tablets packed in a container) Where any specific degradable product is specified, it may represent an impurity in the API (eg, an impurity that is generated during the process). It was found that the composition according to this invention is stable under ICH conditions.

Shelf life after opening the package.

The stability of the tablet dispersion in water was evaluated taking into account the difference in time between preparation and dosing of the dispersion.

Way.

Since the composition according to this invention (ie, the dispersible tablet described above) was stable for up to 6 hours, it could be administered up to 6 hours after its preparation.

tablets with an equivalent dose of 100 mg were dispersed in 50 ml of water and additionally analyzed for the content of the main component and related substances after 0, 2, 4 and 6 hours in a transparent glass flask under ambient conditions.

No. p / p Time Known industrial impurity in % Bedaquiline fumarate in % 1 0 h 0.50 98.30 2 2 hours 0.50 97.99 3 4 hours 0.51 98.44 4 6 o'clock 0.50 98.09

The product was found to be stable in the form of an aqueous dispersion for 6 hours. In addition, it was also stable when kept in a clear beaker, indicating that it was not photosensitive.

Comparative solubility profile of an adult formulation versus a pediatric formulation obtained by two different methods.

Compound For an adult For an adult For children For children batch number 136695 136695 HG-121019 HG-121019 Dosage 100 mg 100 mg 5x20 mg 5x20 mg Result Set ID 81938 82584 83398 83598 Solv. Wednesday 0.01 n. HCL 0.01 n. HCL 0.01 n. HCL 0.01 n. HCL Number of units 6 6 6 6 Condition ^R T_6M ^R T_6M ^R T_1.5Yrs ^R T_1.5Yrs Volume 900 ml 900 ml 900 ml 900 ml Apparatus Rotating Stirrer with rotating Stirrer with

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I am a basket blade basket blade 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 thirty 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*

* Concerning a tablet for the adult; paddle mixer 75 rpm;

** relative to a tablet for an adult;

rotating basket 150 rpm.

RT=room temperature;

6M=6 months.

F2: The FDA and EMEA define the similarity factor as the logarithmic transformation of the inverse square root of unity plus the mean differences of squares (mean sum of squares) of the percentage of dissolved drug between investigational and comparator drugs. If F2 >50, the products are similar, and if less than 50, then they are different.

The dissolution profile of the pediatric formulation was faster than the adult formulation for both dissolution methods.

Effect on bioavailability.

1) The impact of nutrition on bioavailability was reduced compared to the adult tablet.

regular breakfast Yogurt Tablet for adult 91% 32% Water-dispersible tablet 82% 17%

2) Both the adult formulation and the pediatric formulation tested for both regular breakfast and yogurt cases demonstrated that both formulations are bioequivalent, although the dispersible tablets exhibited a faster in vitro dissolution profile.

Panel 1 (standard breakfast).

Water-dispersible tablet Ratio (%) 90%CI Stakh 106.58 96.11-118.18 AUC _72h 98.43 91.85-105.47

Panel 2 (yogurt).

Water-dispersible tablet Ratio (%) 90%CI Stakh 111.93 104.26-120.16 AUC _72h 112.95 105.94-120.42

Therefore, the composition of the present invention has been found to be bioequivalent to the conventional adult tablet formulation when tested in an adult population on an empty stomach, after a meal, and in the case of yogurt. The product (invention) reduced the effect of nutrition by 9% and by 15% when taken with yogurt compared to an adult formulation in the form of a tablet.

Additional examples.

Further development of the formulation was directed to meet the clinical need for dose escalation in 10 mg increments. This was done by developing a 20 mg formulation with a score line to allow dosing in increments of 10 mg as needed.

To achieve this, the following changes were made to the previous formulation tested in the bioequivalence study.

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Parameter Dispersible tablet containing 20 mg bedaquiline fumarate Dispersible tablet containing 20 mg bedaquiline fumarate (optional formulation) (composition described above) Weight 100 mg 200 mg Tablet form Round Caplet Tablet surface Smooth on both sides Separating cross line on both sides Embossing on tablet No 2 and 0, separated by a dividing transverse line on one side, and smooth with a dividing transverse line on the other side Strength 20-40 N 70-120 N Dose(coated) 2 0 mg 10 mg and 20 mg Time dispersed AND I Approximately 30 s (in 50 ml) Approximately 60 s (in 50 ml) can be dispersed in 5 ml of water Percentage MCC (Avicel RN 102)- insoluble filler/thinner 62.12% 73.71% API percentage 24.18% 12.09%

Composition of additional composition

Ingredients Dispersible tablet containing 20 mg bedaquiline fumarate (formulation relative to 100 mg weight described above) Dispersible tablet containing 20 mg of bedaquiline fumarate (additional formulation relative to 200 mg weight) mg/unit Percentage weight/weight mg/unit a Percentage weight/weight Intragranular part 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 dioxide silicon 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 General content (intragranular part) 62.2 62.2 124.4 62.2 Extragranular part Sodium fumarate 2.0 2 4 2 silicified microcrystalline 32.3 32.3 64.6 32.3 Crospovidone 3.0 3 6 3 colloidal dioxide silicon 0.5 0.5 1 0.5 General content (extragranular part) 37.8 37.8 75.6 37.8 Tablet weight (mg) 100.0 100 200 100

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Composition studies to examine various factors in relation to composition.

1) The effect of an intragranular filler compared to an extragranular filler.

Ingredients Example 1 Example 2 Intragranular part Bedaquiline fumarate 24.18 24.18 silicified microcrystalline cellulose (Prosolv SMCC HD90) 82.82 115.12 Crospovidone (Polyplasdone XL) 6.00 6.00 Colloidal silicon dioxide (Aerosil 200Pharma) 4.00 4.00 Hypromellose 5 cps (Methocel E5 LV) 7.00 7.00 Polysorbate 20 (Tween 20 HP) 0.40 0.40 Purified water* - - Weight of intragranular part 124.4 156.7 Extragranular part Sodium Stearyl Fumarate (Pruv) 4.00 4.00 silicified 64, 60 32.30 microcrystalline cellulose (Prosolv SMCC HD90) Crospovidone (Polyplasdone XL) 6.00 6.00 Colloidal silicon dioxide (Aerosil 200 Pharma) 100 1.00 Dispersion time 75 s (5 ml) 50-55 s (50 ml) 70-75 s (5 ml) Strength 93-100 I (95 I) 92-107 I (96 N) Tablet weight (mg) 200.00 200.00

Conclusion.

The intragranular filler (silicified MCC), when varied from 41 to 58%, does not have any effect on the critical quality characteristics (CQA) of the product. This change has a direct effect on the extragranular aggregate concentration, which, when varied from 32 to 16%, has no effect on CQA.

The effect of the amount of crospovidone

Ingredients I Example 1 I Example 2 Intragranular part Bedaquiline fumarate 24.18 24.18 silicified microcrystalline cellulose (Prosolv SMCC HD90) 82.82 85, 82 Crospovidone (Polyplasdone XL) 6.00 3.00 Colloidal silicon dioxide (Aerosil 200Pharma) 4.00 4.00 Hypromellose 5 cps (Methocel E5 LV) 7.00 7.00 Polysorbate 20 (Tween 20 HP) 0.40 0.40 Purified water* - - Weight of intragranular part 124.4 124.4 Extragranular part Sodium Stearyl Fumarate (Pruv) 4.00 4.00 silicified microcrystalline cellulose 64, 60 67, 60 (Prosolv SMCC HD90) Crospovidone (Polyplasdone XL) 6.00 3.00 Colloidal silicon dioxide (Aerosil 200 Pharma) 1.00 1.00 Dispersion time 75 s (5 ml) 50-55 s (50 ml) 85-90 s (5 ml) Strength 93-100 N (95 N) 87-105 N (95 N) Tablet weight (mg) 200.00 200.00

Conclusion.

Investigated the concentration values of baking powder (crospovidone) in the composition in the range from 3 to 6%. This does not affect CQA, but the dispersion time value at 6% crospovidone is slightly longer than at 3%.

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2) The effect of the amount of increased amount of binder.

Ingredients Example 1 Example 2 Intragranular part Bedaquiline fumarate 24.18 24.18 silicified microcrystalline cellulose (Prosolv SMCC HD90) 82.82 79, 32 Crospovidone (Polyplasdone XL) 6.00 6.00 Colloidal silicon dioxide (Aerosil 200Pharma) 4.00 4.00 Hypromellose 5 cps (Methocel E5 LV) 7.00 10.50 Polysorbate 20 (Tween 20 HP) 0.40 0.40 Purified water* - - Weight of intragranular part 124.4 124.4 Extragranular part Sodium Stearyl Fumarate (Pruv) 4.00 4.00 silicified microcrystalline cellulose (Prosolv SMCC HD90) 64, 60 64, 60 Crospovidone (Polyplasdone XL) 6.00 6.00 Colloidal silicon dioxide (Aerosil 200 Pharma) 1.00 100 Dispersion time 75 s (5 ml) 50-55 s (50 ml) 135-145 s (5 ml) Strength 93-100 N (95 N) 89-104 N (95 H) Tablet weight (mg) 200.00 200.00

Conclusion.

Investigated the concentration of the binder (HPMC) from 3.5 to 5.25%. At a higher binder concentration, a higher dispersion time was observed.

Initial data and stability data of the additional composition in the form of a dispersible tablet

Additional composition (relative to the weight of the tablet 200 mg) Quantitative data obtained from the analysis (%) RS (%) Water content by KF (%) original sample 99.45 <RT 5.0 HDPE bottle IM 40°C/75% RH 99.74 <RT HDPE bottle 2M 40°C/75% RH 98.30 <RT 4.0 HDPE bottle ZM 40°C/75% RH 99.30 0.05 3.1 HDPE bottle 6M 40°C/75% RH 100.6 0.15 3.2

RT: impurity registration threshold.

The formulation showed satisfactory stability up to 6 months in HDPE vials.

Dissolution profile (0.01N HCl) - comparison of a 100 mg dispersible tablet formulation with a 200 mg dispersible tablet formulation.

Time in minutes 100 mg tablet formulation 200 mg tablet formulation % release 5 80 78 10 98 93 15 101 95 20 101 96 thirty 102 97 45 103 97

The dissolution profile for the 100 and 200 mg tablet formulations is comparable.

Data on divided tablet.

- weight loss of divided tablets.

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Intact tablet weight (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 divided tablet weight, n=30): 2.04 RSD (for divided tablet weight n=30): 2.02%

Attrition of divided tablets (100 vol.): 0.06%.

Attrition of divided tablets (400 vol.): 0.16%.

Claims (22)

CLAIM 1. A tablet containing bedaquiline fumarate as an active ingredient, wherein the tablet contains an intragranular and extragranular layer, where the intragranular layer contains an insoluble filler/diluent, characterized in that there is no soluble filler/diluent in the intragranular layer, which is starch; and the extragranular layer contains an insoluble filler/diluent. 2. Tablet according to claim 1, wherein the intragranular layer is free of any soluble excipient/diluent. 3. Tablet according to claim 1 or 2, wherein the insoluble filler/diluent in the intragranular layer is microcrystalline cellulose. 4. A tablet containing bedaquiline fumarate as an active ingredient, wherein the tablet contains an intragranular layer and an extragranular layer, where the intragranular layer contains an insoluble filler/diluent which is microcrystalline cellulose and the extragranular layer contains an insoluble filler/diluent which is microcrystalline cellulose . 5. Tablet according to claim 4, wherein there is no soluble excipient/diluent in the intragranular layer. 6. Composition in the form of a tablet, containing by weight in terms of the total weight of the composition: 5-50% active ingredient bedaquiline fumarate; 35-90% insoluble filler/diluent; 2-10% baking powder; 0.1-5% glidant; 0.01-5% wetting agent or surfactant; 0-10% binder or polymer; 0-5% lubricant; solvent (qs). 7. Composition in the form of a tablet, containing by weight in terms of the total weight of the composition: 5-50% active ingredient; 20-90% insoluble filler/diluent, which is microcrystalline cellulose; 2-10% baking powder; 0.1-5% glidant; 0.01-5% wetting agent or surfactant; 0-10% binder or polymer; 0-5% lubricant; solvent (qs). 8. A tablet composition according to claim 6 or 7, further characterized in that it does not contain a soluble excipient/diluent. 9. A tablet composition according to any one of the preceding claims, wherein the composition consists of, by weight, based on the total weight of the composition: 24.18 or about 25% active ingredient; 62.12 or approximately 60% insoluble filler/diluent; 6 or approximately 6% baking powder; 2.5% or about 2.5% glidant; 0.2 or about 0.2% wetting agent or surfactant; - 22 042247 3 or about 3% binder or polymer; 2 or approximately 2% lubricant; solvent (qs), e.g. water, if necessary, i.e. only the amount needed, if at all. 10. A tablet composition according to any one of claims 1 to 8, wherein the composition consists of, by weight, based on the total weight of the composition: 12.09% active ingredient; 73.71% insoluble filler/diluent, for example microcrystalline cellulose, such as silicified microcrystalline cellulose; 6% disintegrant, such as crospovidone such as Polyplasdone XL; 2.5% glidant, eg colloidal silicon dioxide, Aerosil 200; 0.2% wetting agent or surfactant, eg polysorbate 20, i.e. Tween 20; 3.5% binder or polymer, such as hypromellose, 5 cps, i.e. Methocel E 5LV; 2% lubricant, eg sodium stearyl fumarate (Pruv); solvent (qs), e.g. water, if necessary, i.e. only the amount needed, if at all. 11. A composition in the form of a tablet, wherein the various parts of the composition, in particular the intragranular and extragranular fractions and part of the binder, contain the following ingredients by weight based on the total weight of the composition: intragranular fraction: 5-50% active ingredient; 10-50% insoluble filler/diluent; 1-5% baking powder; 0.1-5% glidant; binder: 1-10% binder or polymer; 0.01-5% wetting agent or surfactant; solvent (qs); extragranular fraction: 10-50% insoluble filler/diluent; 1-5% baking powder; 0-3% glidant; 0-5% lubricant. 12. Composition in the form of a tablet according to claim 10 or 11, where in the intragranular layer there is no soluble filler/diluent; and the extragranular fraction also lacks any soluble filler/diluent. 13. The tablet composition according to claim 10, 11 or 12, which consists of the following compositions of the intragranular fraction, the binder and the extragranular fraction by weight based on the total weight of the composition: intragranular fraction: 24.18 or about 25% active ingredient; 29.82 or approximately 30% insoluble filler/diluent; 3 or approximately 3% baking powder; 2 or about 2% glidant; binder: 3 or about 3% binder or polymer; 0.2 or about 0.2% wetting agent or surfactant; solvent (qs), e.g. water, if necessary, i.e. only the required amount, if at all; extragranular fraction: 32.3 or approximately 30% filler/diluent; 3 or approximately 3% baking powder; 0.5% or about 0.5% glidant; 2 or approximately 2% lubricant. 14. The tablet composition according to claim 11 or 12, which consists of the following compositions of the intragranular fraction, the binder and the extragranular fraction by weight, calculated on the total weight of the composition: intragranular fraction: 12.09% active ingredient; 41.41% insoluble filler/diluent, such as microcrystalline cellulose, such - 23 042247 silicified microcrystalline cellulose; 3% disintegrant, such as crospovidone such as Polyplasdone XL; 2% glidant, such as colloidal silicon dioxide, Aerosil 200; binder: 3.5% binder or polymer, such as hypromellose, 5 cps, i.e. Methocel E 5LV; 0.2% wetting agent or surfactant, eg polysorbate 20, i.e. Tween 20; solvent (qs), e.g. water, if necessary, i.e. only the required amount, if at all; extragranular fraction: 32.3% filler/diluent, preferably an insoluble filler/diluent, for example microcrystalline cellulose such as silicified microcrystalline cellulose; 3% disintegrant, such as crospovidone such as Polyplasdone XL; 0.5% glidant, eg colloidal silicon dioxide, Aerosil 200; 2% lubricant such as sodium stearyl fumarate (Pruv). 15. The tablet composition according to claim 13, which consists of the following: intragranular fraction: 24.18 mg bedaquiline fumarate; 29.82 mg silicified microcrystalline cellulose; 3 mg crospovidone; 2 mg colloidal silicon dioxide; 3 mg hypromellose, 5 cps; 0.2 mg polysorbate 20; purified water (qs); extragranular fraction: 32.3 mg silicified microcrystalline cellulose; 3 mg crospovidone; 0.5 mg colloidal silicon dioxide; 2 mg sodium stearyl fumarate. 16. The tablet composition according to claim 14, which consists of the following: intragranular fraction: 24.18 mg bedaquiline fumarate; 82.82 mg silicified microcrystalline cellulose; 6 mg crospovidone; 4 mg colloidal silicon dioxide; 7 mg hypromellose, 5 cps; 0.4 mg polysorbate 20; extragranular fraction: 64.6 mg silicified microcrystalline cellulose; 6 mg crospovidone; 1 mg colloidal silicon dioxide; 4 mg sodium stearyl fumarate. 17 . A composition in the form of a tablet, wherein the various parts of the composition, in particular the intragranular and extragranular fractions and part of the binder, contain the following ingredients by weight based on the total weight of the composition: intragranular fraction: 10-30% active ingredient bedaquiline fumarate; 20-40% insoluble microcrystalline cellulose filler/diluent; 2-4% crospovidone baking powder; 0.5-4% of a substance that promotes the sliding of colloidal silicon dioxide; binder: 2-5% binder or hypromellose polymer, 5 centipoise; 0.1-1% wetting agent or surfactant polysorbate 20; solvent (qs); extragranular fraction: 20-40% filler/diluent microcrystalline cellulose; 2-4% crospovidone baking powder; 0.1-1% colloidal silica glidant; 1-3% lubricant sodium stearyl fumarate. - 24 042247 18. The use of a tablet according to any one of claims 1 to 17 in the treatment of tuberculosis. 19. Use according to claim 18 in the pediatric and/or elderly population. 20. The use of a tablet according to any one of claims 1 to 17 in combination with one or more other therapeutic agents useful in the treatment of tuberculosis. 21. A combination containing a tablet according to any one of claims 1 to 17 and one or more other therapeutic agents applicable in the treatment of tuberculosis. 22. A method for preparing a tablet composition according to any one of claims 1 to 17, which includes: (a) obtaining an intragranular fraction using the components of the intragranular fraction specified in any of paragraphs.11-17; (b) obtaining a fraction of the binder using the components of the fraction of the binder specified in any one of paragraphs. 11-17; (c) obtaining an extragranular fraction using the components of the extragranular fraction specified in any one of paragraphs 11-17, and using these fractions to obtain a composition.