OA18325A

OA18325A - Dispersible compositions

Info

Publication number: OA18325A
Application number: OA1201700283
Authority: OA
Inventors: Manish Kumar GUPTA; Shripad Wasudeo MARATHE; Kaustubh Ramesh TAMBWEKAR; Shreedevi Velayudhan NAIR
Original assignee: Janssen Pharmaceutica Nv
Priority date: 2015-01-27
Filing date: 2016-01-26
Publication date: 2018-10-03

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.

Description

The présent invention concems a pharmaceutical composition containing a certain antibacterial product, bedaquiline fùmarate, as active ingrédient. More specifically, the invention relates to a dispersible, or disîntegrating, tablet, a process for preparing it, as well as its use in the treatmcnt of antibacterial diseases such as tuberculosis. Such novel compositions are particularly suited to the paediatric population. It can also suit 10 the gériatrie population.

The active ingrédient in this case is bedaquiline in the form of a fùmarate sait: (alpha S, betaR)-6-bromo-alpha-[2-(dimethyIamino)ethyl]-2-methoxy-alpha-l-naphthalenytbeta -phenyl-3-quinolineethanol, in particular (alpha S, beta R)-6-bromo-a!pha15 [2-(dimethy lamino)ethyl]-2-methoxy-alpha-1 -naphthalenyl-beta-phenyl-3quinolineethanol (2E)-2-butenedioatc (1:1) and may be represented by the following formula:

The fùmarate sait of the présent invention can be prepared by reacting the corresponding free base with fumaric acid in the presence of a suitable solvent, such as for example isopropanol.

This product Sirturo™ containing the active ingrédient has already received marketing approval in some tenitories including the US, Russia, the EU, South Africa and the Republic of Korea.

The utility ofthe invention arises from the active ingrédient, and sait thereof, being 30 known to show activity against Mycobacteria including drug résistant strains, in

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-2particular Mycobacterium tuberculosis, M. bovis, M. avium, M. leprae and M. marinum, especially against Mycobacterium tuberculosis, including drug-resistant M. tuberculosis strains. The active ingrédient, including sait thereof, shows activity against active, sensitive, susceptible Mycobacteria strains and latent, dormant, persistent Mycobacteria strains.

International patent application WO 2004/011436 first disclosed the activity of the free base of bedaquiline against Mycobacteria. Later documents such as international patent applications WO 2005/117875 and WO 2006/067048 disclose the further uses in the treatment of inter alia drug résistant tuberculosis and latent tuberculosis. International patent application WO 2008/068231 first described the suitablility of the fumarate sait as a drug product indicating its acceptable bioavilaibility. The fumarate sait ofbedaquiline is described as non-hygro scopie and stable. This document also discloses the préparation of certain formulations and tablets containing bedaquiline fumarate.

In particular, WO 2008/068231 discloses the préparation of a drug formulation comprising bedaquiline fumarate sait, where a powdcr mixture is obtained and compressed into tablets. Such a formulation does not hâve adéquate dispersibility/dis intégrât ing properties.

Mycobacterium tuberculosis résulta in more than 2 million deaths per year and is the leading cause of mortality in people infected with HIV. In spitc of décades of tuberculosis (TB) control programs, about 2 billion people are infected by M. tuberculosis, though asymptomatically. About 10% of these individuals are at risk of developing active TB during their lifespan. There is thus a high need for drugs to treat active TB.

The global épidémie of TB is fuelled by infection of HIV patients with TB and rise of multi-drug résistant TB strains (MDR-TB). The réactivation of latent TB is a high risk factor for disease development and accounts for 32% deaths in HIV infected individuals. To control TB épidémie, the need is to discover new drugs that can also kill dormant or latent bacilli. The donnant TB can get reactivated to cause disease by scveral factors like suppression of host immunity by use of immunosuppressive agents like antibodies against tumor necrosîs factor a or interferon-γ. In case of HIV positive patients the only prophylactic treatment available for latent TB is two- three months

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-3regîmens of rifampicîn, pyrazinamide. The cfficacy ofthe treatment régime îs still not clear and furthermore the length ofthe treatments is an important constrain in resourcelimited environments. Hence there is a drastic need to identify ncw drugs, which can act as chemoprophylatic agents for individuals harboring latent TB bacilli.

The tubercle bacilli enter healthy individuals by inhalation; they are phagocytosed by the alveolar macrophages of the lungs. This leads to potent immune response and formation of granulomas, which consist of macrophages infected with M. tuberculosis surrounded by T cells. After a period of 6-8 weeks the host immune response cause death of infected cells by necrosis and accumulation of caseous material with certain extracellular bacilli, surrounded by macrophages, epitheloid cells and layers of lymphoid tissue at the periphery. In case ofhealthy individuals, most ofthe mycobacteria are killed in these environments but a small proportion of bacilli still survive and are thought to exist in a non-replicating, hypometabolic state and are tolérant to killing by anti-TB drugs like isoniazid. These bacilli can remain in the altered physiological environments even for individual’s lifetime without showing any cünical symptoms of disease. However, in 10% ofthe cases these latent bacilli may reactivate to cause disease. One ofthe hypothcsis about development of these persistent bacteria is patho-physiological environment in human lésions namely, reduced oxygen tension, nutrient limitation, and acidic pH. These factors hâve been postulated to render these bacteria phenotypically tolérant to major anti-mycobacterial drugs.

Although pharmaceutical formulations of bedaquiline fumarate hâve been developed for the adult population, to date there has been no paediatric formulation developed and pursued. There are many approaches to developing drug formulations including direct compression, dry granulation and wet granulation. There remains individual challenges to each approach and it is also dépendent on the drug that is to be formulated too. Further, for the paediatric population, it may be desired to hâve a dispersible tablet, and this may also provide addîtional challenges. This is particularly so from the perspective of devising such tablets that hâve a suitably fast dispersion time.

Among the techniques used to préparé tablets, direct compression is the simplest, învolving only blending and compression. This has the advantage of speed of production as it requires fewer unit operations, less machinery and is, as a conséquence, 35 more efficient.

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-4Direct compression is followed by other manufacturing processes, such as dry or wet granulation.

There is now provided a dispersible composition (e.g. tablet) comprising bedaquilîne fumarate as the active ingrédient. This may be referred to herein as “the (dispersible) tablet ofthe invention”.

By “dispersible”, we mean a composition (e.g. tablet) that disîntegrates in appropriate media, for example aqueous media (water) or other suitable media or vehicles for 10 administration (e.g. milk, juice or even semi-solid like vehicles such as yogurt, apple sauce). More particularly, we mean that the tablet disîntegrates in a low volume of water such that it disperses (for example evenly and/or rapidly) by mild swirling. For example a 100 mg tablet composition may be evenly dispersed within 90 seconds in about 50 mi of water. Hence, an équivalent of 1 mg of tablet composition weight in 0.5 15 ml water may be evenly dispersed within 90 seconds. More preferably, an équivalent of 1 mg of tablet composition weight în 0.5 ml water may be evenly dispersed within 60 secs, more preferably within 45 seconds. In particular it may be dispersed in around (e.g. within) 30 seconds. Such dispersion times/ratios are applicable in particular for composition weights between 20 mg and 400 mg (particularly between about 50 mg 20 and about 200 mg) as shown by the examples hereinafter. Hence, in particular a tablet composition of 100 mg may be evenly dispersed in 50 ml water around (or within) 30 seconds. Such a dispersion may pass through a sieve screen with a nominal mesh apertureof710 μτη.

However, even though an équivalent of 1 mg of composition (e.g. tablet composition) weight in 0.5 ml water is referred to in the context of dispersion, it is the intrinsîc properties of the tablet formulation that are key. For exampte, dispersion may occur in a much smaller volume of fluid, for example a 100 mg composition may also be dispersed in a much lower quantity of water, for example as low as 1 ml to 5 ml (i.e. an 30 équivalent of 1 mg of tablet composition per 0.01 ml to 0.005 ml water). In this instance, the résultant mixture may be described as a dispersion but also as a soft mass. For such a soft mass, this may not pass through the above-mentïoned sieve screen (given the low volume of water with which it is mixed) but may ncvertheless be suitable for administration, i.e. that soft mass may suitably be administered by spoon.

Equal ly, the composition may be administered by mixing with another suitable medium or vehicle for administration (as described above), which may be a dispersion, soft

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-5mass (if e.g. the composition is only mixed with a relatively small volume of water) or another mixture (e.g. the composition with a semi-solid). '

In contrast, the formulation disclosed in the Exemples in WO 2008/068231 does not hâve comparable dispersibility/disintegrating properties. In particular, such prior formulations may not hâve comparable dispersibîlity properties, and more particularly they (e.g. a 100 mg composition in 50 mL of water, or équivalent compositions by weight to volume) may disperse in a time of greater than 90 seconds, e.g. greater than 120 seconds (and may disperse in greater than 180 seconds, e.g. around 240 seconds or 10 even longer). Such relatively long dispersion times may be disadvantageous and may not be désirable.

By “evenly dispersed”, wc mean that the composition (e.g. tablet composition) rapidly disintegrates in water into physically smaller particles that are spread out (or dispersed) 15 throughout the water. This résulte in any equal portion of the water containing approxîmately equal amounts of composition (e.g. tablet composition) particles (by weight), by which we mean within a déviation of ±25%, preferably ±15%, and espccially ±10% (or less e.g. within ±5%). Hence, if a 100 mg tablet composition is dispersed in 50 ml of water, then each portion of 25 ml of water (when divided) should 20 contain about 50 mg of tablet composition weight, but with a possible déviation of ±25% (Le. ±12.5 mg), preferably, ±15% (i.e. ± 7.5 mg) and especially±10% (Le. ± 5 mg) - most preferably the déviation will be ±5% (i.e. ±2.5 mg). Hence, the tablet compositon is physically uniform or homogenous throughout the water medium in which it is placed (after the necessary time for dispersion; see above). It will be 25 understood that the larger the volume of water per mg of tablet composition, the less déviation there may be in terms of dispersion.

Where it is indicated that the water-dispersible composition (e.g. tablet composition) may pass through a 710 gm sieve, this is in order that the dispersible composition (e.g.

tablet) meets certain quality thresholds/requirements, for example those in the current (or future) éditions ofthe British Pharmacopoeia and Européen Pharmacopoeia. Hence why the dispersion quality (passing through the sieve) is important, as well as the dispersion time (most preferably dispersion within 30 seconds). Although these properties are important for an actual dispersion in aqucous media, it will be understood that a dispersion (e.g. in water) need not be prepared, but the dispersible tablet may be administered in alternative ways. For example, the dispersible tablet may

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-6bc mixed with certain foods (as such or by forming a soft mass by mixing the tablet composition with a small quanity/volume of water as described above). This is elaborated upon below.

The dispersible composition (e.g. tablet) ofthe invention will now be described in more details. Clearly, it has intrinsic properties that allow for the dispersibility (or disintegration) properties.

Hence in an aspect of the invention there is provided a dispersible composition (e.g.

tablet) comprising bedaquiline fumarate as the active ingrédient and wherein the tablet comprises an intra-granular and extra-granular layer in which the intra-granular layer comprises a non-soluble excipient/diluent and is charaterised in that the intra-granular layer is absent a soluble excipient/diluent that is starch (and in the most preferred embodiment the intra-granular layer is absent any soluble excipient/diluent). For example the intra-granular layer may comprise mannitol as an excipient/diluent (which is classed as a soluble excipient/diluent) but may not contain starch. In the preferred embodiment, the intra-granular layer is absent mannitol and starch (and also absent any other soluble excipient/diluent).

In an alternative aspect of the invention, the intra-granular layer comprises a nonsoluble excipient/diluent that is microcrystalline cellulose, but such layer in not necessarily absent a soluble excipient/diluent.

In an embodiment, when a soluble excipient/diluent is employed, then it is preferably not starch. This is because starch may swell in water (e.g. by about 5-10%) at 37°C (it may become soluble in hot water at températures above the gelatinîzation température.

It is preferred that the intra-granular layer comprises a non-soluble excipient/diluent that is microcrystalline cellulose and that layer is also absent any soluble excipient/diluent.

When microcrystalline cellulose is referred to, it is intended to include silicified microcrystalline cellulose. This non-soluble excipient/diluent in the intra-granular portion of the tablet of the invention is key to its intrinsic dispersibility/disintegrating 35 properties.

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-7By “absent”, in the context of soluble excipient/diluent, we mean that the composition (e.g. tablet composition) contains an insîgnificant amount of such ingrédient (e.g. in this case soluble excipient/diluent), by which we mean less than 5 % by weight based on the total weight of the composition, more preferably, less than 2.5% by weight, e.g.

less than 1%. Most preferably, this means that the ingrédient is completely absent, i.e. that there is 0% or near 0% of that ingrédient (by weight) - that is a negligible amount of it.

Often, dispersible tablets are manufactured with soluble excipients/diluents, for example sugar-based excipients such as xylitol, fructose, lactose, and the like. However, in this case it was found that soluble excipients were disadvantageous to the dispersibility/disintegrating properties (as indicated in a référencé example hereinafter), for example, due to the fact that they may take up water and form a saturated layer preventing further diffusion of soluté from the saturated stagnant layer (as per Noyés

Whitney’s diffusion layer theory) - this phenomenon may be the cause of the adverse impact on the desired dispersion time. It may also be that the soluble excipients are more prone to absorbing environmental moîsture. This may also occur if soluble excipients are used in combination with with partly soluble, or insoluble, excipient. In any event, it was clear that the use of a non-soluble excipient, În particular microcryatline cellulose, especially within the intra-granular part of the tablet formulation was key in obtaining a dispersible tablet with the desired properties.

Hence, in an aspect of the invention there is provided a dispersible composition (e.g. tablet composition) comprising (e.g. consisting of) by weight based on the total weight 25 of the composition:

to 50% (e.g. 10 to 30%) of active ingrédient

35% to 90% (e.g. 50 to 70%) of a non-soluble excipient/diluent

2% to 10% (e.g. 4 to 8%) of a dîsintegrant

0.1 to 5% (e.g. 1.5 to 3.5%) ofa glidant

0.01 to 5% (e.g. 0.1 to 1 %) of a wetting agent or surfactant to 10% (e.g. 2 to 5%) ofa binder or polymer to 5% (e.g. 1 to 3%) of a lubricant solvent (qs) e.g. water which may also be referred to as a composition of the invention.

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-8In the case of the above composition, where the non-soluble excipient is microcrystalline cellulose (such as silicified microcrystalline cellulose), then the quantity by weight may be between 20% to 90%, with the remaining amounts of the composition as defined herein.

The compositions of the invention mentioned herein may be charactersied in that thcy are absent a soluble excipient/diluent.

For instance, 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%) of active ingrédient

62.12% (or about 60%) non-soluble excipient/diluent (e.g. microcrystalline cellulose, such as silicified microcrystalline cellulose)

6% (or about 6%) disintegrant (e.g. crospovidone, such as Polyplasdone XL)

2.5 % (or about 2.5%) güdant (e.g. colloïdal silicon dioxide, Aerosil 200)

0.2% (or about 0.2%) wetting agent or surfactant (e.g. polysorbate 20, i.e. Tween 20) 3% (or about 3%) binder or polymer (e.g. hypromellose 5 cps, i.e. Methocel E 5 LV) 2% (or about 2%) fabricant (e.g. sodium stearyl fumarate (Pruv))

Solvent (qs), e.g. water - if necessary (i.e. only the amount needed, if any)

In another aspect, there is provided a composition (e.g. tablet composition) wherein the different parts of the composition, specifically the intra-granular and extra-granular fraction and binder portion, comprise (e.g. consist of) the following ingrédients by weight based on the total weight of the composition:

IntTa-granular fraction to 50% (e.g. 10 to 30%) of active ingrédient to 50% (e.g. 20 to 40%) of non-so fable excipient/diluent (e.g. microcrystalline cellulose, such as silicified microcrystalline cellulose) to 5% (e.g. 2 to 4%) disintegrant (e.g. crospovidone, such as Polyplasdone XL)

0.1 to 5% (e.g. 0.5 to 4%, such as 1 to 3%) glidant (e.g. colloïdal silicon dioxide,

Aerosil 200) BindCE to 10% (e.g. 2 to 5%) 3% binder or polymer (e.g. hypromellose 5 cps, i.e. Methocel E 5LV)

0.01 to 5% (e.g. 0.1 to 1%) wetting agent or surfactant (e.g. polysorbate 20, i.e. Tween

20)

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-9Sotvent (qs), e.g. water - if necessary (i.e. only the amount needed, if any) Extra-granular fraction to 50% (e.g. 20 to 40%) of excipient/diluent (preferably a non-soluble excipient/diluent e.g. microcrystalline cellulose, such as silicified microcrystalline cellulose) to 5% (e.g. 2 to 4%) disintegrant (e.g. crospovidone, such as Polyplasdone XL) 0 to 3% (e.g. 0.1 to 1%) glidant (e.g. colloïdal silicon dioxide, Aerosil 200) to 5% (e.g. 1 to 3%) lubricant (e.g. sodium stearyl fùmarate (Pruv))

The compositions (e.g. tablet compositions) of the invention mentioned herein may be charactersied in that specifically the intra-granular layer is absent any soluble excipient/diluent. Hence, the extra-granular fraction need not be absent any soluble excipient/diluent, although, preferably, it is the case that the extra-granular fraction is also absent any soluble excipient/diluent.

For instance, most preferably the composition consista 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% (or about 25%) o f active ingrédient ·

29.82% (or about 30%) of non-soluble excipient/diluent (e.g. microcrystalline cellulose, such as silicified microcrystalline cellulose)

3% (or about 3%) disintegrant (e.g. crospovidone, such as Polyplasdone XL) % (or about 2%) glidant (e.g. colloïdal silicon dioxide, Aerosil 200)

Binder

3% (or about 3%) binder or polymer (e.g. hypromellose 5 cps, Le. Methocel E 5 LV) 0.2% (or about 0.2%) wetting agent or surfactant (e.g. polysorbate 20, i.e. Tween 20) Solvent (qs), e.g. water - if necessary (i.e. only the amount needed, if any) Extra-granular fraction

32.3% (or about 30%) of excipient/diluent (preferably a non-soluble excipient/diluent

e.g. microcrystalline cellulose, such as silicified microcrystalline cellulose) 3% (or about 3%) disintegrant (e.g. crospovidone, such as Polyplasdone XL) 0.5 % (or about 0.5%) glidant (e.g. colloïdal silicon dioxide, Aerosil 200) 2% (or about 2%) lubricant (e.g. sodium stearyl fùmarate (Pruv))

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-10The intra-granular fraction (or portion) may comprise up to 75% by weight of the total weight ofthe composition (e.g. tablet), and preferably comprises between 40 and 70% (e.g. between 50 and 65%) by weight of the composition (or tablet). Most preferably, the intra-granular fraction (or portion) ofthe composition (e.g. tablet composition) 5 comprises about 60% of the total weight of the composition. The binder fraction (or portion, or element) may comprise up to 20% by weight of the total weight of the composition (e.g. tablet composition), for exemple from 0.5 to 10% by weight and preferably between 1 and 8% by weight (e.g. about 3% by weight). The extra-granular layer may comprise up to 60% by weight ofthe total weight of the composition (e.g.

tablet), and preferably comprises between 20 and 50% (e.g. between 30 and 45%) by weight ofthe composition (or tablet). Most preferably, the extra-granular fraction (or portion) ofthe composition (e.g. tablet composition) comprises about 37.5% ofthe total weight of the composition.

In the context of the compositions (e.g.tablet compositions) described herein, the aspects of the composition may be described as comprising an intra-granular and extragranular fraction and a binder portion (or fraction). Such fractions or portions of the composition are ultimately intermîngled with each other. However, it will be appreciated (for example with reference to the process for preparing such compositions) that the distinction of these fractions (or portions) résulte in distinct properties for the résultant compositions.

The compositions of the invention described herein may be a mixture of or blend of the intra-granular and extra-granular fractions (or portions) and binder portion and may also, after being subjected to a suitable compression technique, take on a (unit) dosage form such as a tablet.

In aspects of the invention described herein, particularly the dispersible compositions described above, the total tablet weight may be about 100 mg (and hence, the active ingrédient présent may be between 5 to 50 mg, such as between about 10 mg and 30 mg, e.g. about 20 mg). In this manner a pédiatrie (or gériatrie) formulation may be provided in which there is about 20 mg of active ingrédient. In other aspects, particularly those described below, the total tablet weight may be higher (but may still deliver the same quantity of active ingrédient), for instance, a dispersible formulation of200 mg may be provided to also deliver about 20 mg of active ingrédient, for instance in the aspects and percentages that may be described below.

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-IIIn another aspect of the invention, there may also be provided dispersible compositions with the following fcatures, which applies in particular to compositions of the invention where the total tablet weight is relatively high (for instance greater than 100 mg, e.g. a total tablet weight of200 mg):

- there is provided a dispersible composition (e.g. tablet composition) comprising (e.g. consisting of) by weight based on the total weight of the composition:

to 50% (e.g. 5 to 20% or 10 to 15%) of active ingrédient

35% to 90% (e.g. 60 to 80% or 70 to 75%) of a non-soluble excipient/diluent 2% to 10% (e.g. 4 to 8%) of a disintegrant

0.1 to 5% (e.g. 1.5 to 3.5%) of a glidant

0.01 to 5% (e.g. 0.1 to 1 %) of a wetting agent or surfactant to 10% (e.g. 2 to 5%) of a binder or polymer to 5% (e.g. 1 to 3%) of a lubricant solvent (qs) e.g. water

- there is provided a dispersible composition (e.g. tablet composition) comprising (e.g. consisting of) by weight based on the total weight of the composition: 12.09% (or about 12%) of active ingrédient

73.71% (or about 70%) non-sohible excipient/diluent (e.g. microcrystalline cellulose, such as silicifïed microcrystalline cellulose)

6% (or about 6%) disintegrant (e.g. crospovidone, such as Polyplasdone XL) 2.5 % (or about 2.5%) glidant (e.g. colloïdal silicon dioxide, Aerosil 200) 0.2% (or about 0.2%) wetting agent or surfactant (e.g. polysorbate 20, i.e. Tween 20)

3% (or about 3%) binder or polymer (e.g. hypromellose 5 eps, ie. Methocel E 5 LV)

2% (or about 2%) lubricant (e.g. sodium stearyl fumarate (Pruv))

Solvent (qs), e.g. water - if necessary (i.e. only the amount needed, if any)

In another aspect, in particular to those compositions ofthe invention where the total tablet weight is relatively high (e.g. 200 mg):

- there is provided a composition (e.g. tablet composition) wherein the different parts of the composition, specifically the intra-granular and extra-granular fraction and binder portion, comprise (e.g. consist of) the following ingrédients by weight based on the total weight of the composition:

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-12Intra-granular fraction to 50% (e.g. 5 to 20% or 10 to 15%) of active ingrédient to 50% (e.g. 30 to 50% or 35 to 45%) of non-soluble excipient/diluent (e.g. microcrystalline cellulose, such as silicîfîed microcrystalline cellulose) to 5% (e.g. 2 to 4%) désintégrant (e.g. crospovidone, such as Polyplasdone XL)

0.1 to 5% (e.g. 0.5 to 4%, such as 1 to 3%) glidant (e.g. colloïdal silicon dioxide, Aerosil 200)

Binder to 10% (e.g. 2 to 5%) 3% binder or polymer (e.g. hypromellose 5 cps, i.e. Methocel E 5 LV)

0.01 to 5% (e.g. 0.1 to 1%) wetting agent or surfactant (e.g. polysorbate 20, i.e. Tween 20)

Solvent (qs), e.g. water - if necessary (i.e. only the amount needcd, if any) Extra-granular fraction to 50% (e.g. 20 to 40%) of excipient/diluent (preferably a non-soluble excipient/diluent e.g. microcrystalline cellulose, such as silicîfîed microcrystalline cellulose) to 5% (e.g. 2 to 4%) désintégrant (e.g. crospovidone, such as Polyplasdone XL) to 3% (e.g. 0.1 to 1%) glidant (e.g. colloïdal silicon dioxide, Aerosil 200) to 5% (e.g. 1 to 3%) lubricant (e.g. sodium stearyl fumarate (Pruv)) there is provided provided a composition (e.g. tablet composition) wherein the different parts of the composition, specifically the intra-granular and extragranular fraction and binder portion, comprise (e.g. consist of) the following ingrédients by weight based on the total weight of the composition: Intra-granular fraction

12.09% (or about 12%) of active ingrédient

41.41% (or about 40%) of non-soluble excipient/diluent (e.g. microcrystalline cellulose, such as silicîfîed microcrystalline cellulose)

3% (or about 3%) désintégrant (e.g. crospovidone, such as Polyplasdone XL) % (or about 2%) glidant (e.g. colloïdal silicon dioxide, Aerosil 200) Binder

3% (or about 3%) binder or polymer (e.g. hypromellose 5 cps. Le. Methocel E 5 LV)

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-130.2% (or about 0.2%) wetting agent or surfactant (e.g. polysorbate 20, i.e. Tween 20)

Solvent (qs), e.g. water - if necessary (i.e. only the amount needed, if any) Extra-granular fraction

32.3% (or about 30%) of excipient/diluent (preferably a non-soluble excipient/diluent e.g. microciystalline cellulose, such as silicified microcrystalline cellulose)

3% (or about 3%) disintegrant (e.g. crospovidone, such as Polyplasdone XL) 0.5 % (or about 0.5%) glidant (e.g. colloïdal silïcon dioxide, Aerosil 200) 2% (or about 2%) lubricant (e.g. sodium stearyl fumarate (Pruv))

The compositions of the invention are described as having certain components or ingrédients, which is elaborated below.

By “active ingrédient” we mean bedaquiline fumarate, i.e. the fumarate sait form of bedaquiline. This is the form that is a part of the adult composition that has been received regulatory approval in some territories.

It is indicated herein that the compositions (e.g. tabïet compositions) of the invention contain a non-soluble excipient/diluent. Unless that 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-processed nonsoluble excipients; others that may be considered include wax-like hydrogenated oils and the like). It is understood that the most preferred non-soluble excipient/diluent is microcrystalline cellulose (e.g. silicified microcrystalline cellulose) because this results in compositions with intrinsic properties that are advantageous. Where it is mentioned that the excipient/diluent need not be non-soluble, then sugars and polyols may also be considered, for instance the following excipients/diluents may also be considered: dextrates, dextrin, dextrose excipient, fructose, kaolin, lactitol, lactose anhydrous, lactose monohydrate, mannitol, sorbitol, sodium chloride, sucrose, compressible sugar, confectioner’s sugar, a spray-dried mixture of lactose monohydrate and microcrystalline cellulose (75:25), commercially available as Microcelac®, a coprocessed spray-dried mixture of microcrystalline cellulose and colloïdal silicon

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-14dioxidc (98:2), commercîally available as Prosolv* (which possibilities include sugars and other soluble excipients/diluents).

It is indicated herein that the compositions (e.g. tablet compositions) of the invention contain a disintegrant Possible disintegrants include pharmaceutically acceptable disintegrants comprising starch, ion exchange resins, e.g. Amberlite, cross-linked polyvinylpyrrolidone, modifïed cellulose gum, e.g. croscarmellose sodium (e.g. Ac-diSol*), sodium starch glycollate, sodium carboxymethylccllulose, sodium dodecyl sulphate, modifïed com starch, microcrystalline cellulose, magnésium aluminium silicate, alginic acid, alginate, powdered cellulose, crospovidone (such as Polyplasdone XL). Other disintegrants that may be considered include L-HPC, Xanthan gum, Gellan gum, soy polysaccharides, and the like. The most preferred disintegrant is crospovidone, preferably a coarse grade crospovidone (such as Polyplasdone XL).

It is indicated herein that the compositions (e.g. tablet compositions) of the invention contain a glidant. Possible glidants include pharmaceutically acceptable glidants comprising talc, colloïdal silicon dioxide, starch, magnésium stéarate. Preferred is colloïdal silicon dioxide (Aerosil 200)

It is indicated herein that the compositions (e.g. tablet compositions) of the invention contain a wetting agent or surfactant. Such wetting agent (or surfactant) may be any of the physiologically tolcrable wetting agents suitable for use in a pharmaceutical composition.

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

The terms “hydrophilic” or “hydrophobie are relative terme.

The relative hydrophilicity or hydrophobicity of a wetting agent may be expressed by its hydrophilic-tipophilic balance value (“HLB value). Wetting agents with a lower HLB value are catagorized as being “hydrophobie” wetting agents whereas wetting agents with a higher HLB value arc catagorized as being “hydrophilic” wetting agents. As a rule of thumb, wetting agents having a HLB value greater than about 10 are

WO 2016/120258 PCT/EP2016/051545

-15generally considered as being hydrophilic wetting agents; wetting agents having a HLB value tower than about 10 are generally considered as being hydrophobie wetting agents.

The présent compositions preferably comprise a hydrophilic wetting agent.

It should be appreciated that the HLB value of a wetting agent is only a rough guide to indicate the hydrophilicity/hydrophobicity of a wetting agent. The HLB value of a particular wetting agent may vary depending upon the method used to détermine the HLB value; may vary depending on its commercial source; is subject to batch to batch 10 variability. A person skilled in the art can readily identify hydrophilic wetting agents suitable for use in the pharmaceutical compositions of the présent invention.

The wetting agent ofthe présent invention can be an anionic, a cationic, a zwitterionic or a non-ionic wetting agent, the latter being preferred. The wetting agent of the 15 présent invention can also be a mixture of two or more wetting agents.

Suitable wetting agents for use in the compositions of the présent invention are listed below. It should be emphasized that said list ofwetting agents is only illustrative, représentative and not exhaustive. Thus the invention is not limited to the wetting 20 agents listed below. In the présent compositions, also mixtures of wetting agents may beused.

Suitable wetting agents which may be used in the présent invention comprise :

a) Polyethylene glycol fatty acid monoesters comprising esters of lauric acid, oleic 25 acid, stearic acid, ricinoic 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 and the like, for instance PEG-6 laurate or stéarate, PEG-7 oleatc or lauratc, PEG-8 laurate or oleate or stéarate, PEG-9 oleate or stéarate, PEG-10 laurate or oleate or stéarate, PEG-12 laurate or oleate or stéarate or ricinoleate, PEG-15 stéarate or oleate, PEG-20 laurate or oleate 30 or stéarate, PEG-25 stéarate, PEG-32 laurate or oleate or stéarate, PEG-30 stéarate, PEG-40 laurate or oleate or stéarate, PEG-45 stéarate, PEG-50 stéarate, PEG-55 stéarate, PEG-100 oleate or stéarate, PEG-200 oleate, PEG-400 oleate, PEG-600 oleate; (the wetting agents bclonging to this group are for instance known as Cithrol, Algon, Kessco, Lauridac, Mapeg, Cremophor, Emulgante, Nikkol, Myrj, Crodet,

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-16Albunol, Lactomul)

b) Polyethylene glycol fatty acid diesters comprising diesters of lauric acid, stearic acid, palmic acid, oleic acid and the like with PEG-8, 10,12,20,32,400 and the like, for instance PEG-8 dîlaurate or distearate, PEG-10 dipalmitate, PEG-12 dilaurate or distearate or dioleate, PEG-20 dîlaurate or distearate or dioleatePEG-32 dîlaurate or distearate or dioleate, PEG-400 dioleate or distearate; (the wetting agents belonging to this group are for instance known as Mapeg, Polyalso, Kessco, Cithrol)

c) Polyethylene glycol fatty acid mono-and diester mixtures 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; (the wetting agents belonging to this group are for instance known as Kessco)

d) Polyethylene glycol glycerol fatty acid estera such as for instance PEG-20 glyceryl laurate or glyceryl stéarate or glyceryl oleate, PEG-30 glyceryl laurate or glyceryl oleate, PEG-15 glyceryl laurate, PEG-40 glyceryl laurate and the like; (the wetting agents belonging to this group are for instance known as Tagat, Glycerox L, Capmul),

e) Alcohol-oil transestérification products comprising estera of alcohols or polyalcohols such as glycerol, propylene glycol, ethylene glycol, polyethylene glycol, sorbitol, pentaerythritol and the like with naturel and/or hydrogenated oils or oil-soluble vitamins such as castor oil, hydrogenated castor oil, vitamin A, vitamin D, vitamin E, vitamin K, an edible vegetable oil e.g. corn oil, olive oil, peanut oil, palm kernel oil, apricot kemel oil, almond oil and the like, such as PEG-20 castor oil or hydrogenated castor oil or com glycerides or almond glycerides, PEG-23 castor 25 oil, PEG-25 hydrogenated castor oit or trioleate, PEG-35 castor oil, PEG-30 castor oit or hydrogenated castor oil, PEG-38 castor oil, PEG-40 castor oil or hydrogenated castor oil or palm kemel oil, PEG-45 hydrogenated castor oil, PEG-50 castor oil or hydrogenated castor oil, PEG-56 castor oil, PEG-60 castor oil or hydrogenated castor oil or com glycerides or almond glycerides, PEG-80 hydrogenated castor oil, 30 PEG-100 castor oil or hydrogenated castor oil, PEG-200 castor oil, PEG-8 caprylic/capric glycerides, PEG-6 caprylic/capric glycerides, lauroyl macrogol-32 glyceride, stearoyl macrogol gtyceride, tocopheryl PEG-1000 succinate (TPGS); (the wetting agents belonging to this group are for instance known as Emalex, Cremophor, Emulgante, Eumulgin, Nikkol, Thomley, Simulsol, Cerex, Crovol, 35 Labrasol, Softigen, Gelucire, Vitamin E TPGS),

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f) polyglycerized fatty acids comprising polyglyccrol esters of fatty acids such as for instance potyglyceryl-10 laurate or oleate or stéarate, polyglyceryl-10 mono and dioleate, polyglyceryl polyricinoleate and the 1 ike; (the wetting agents belonging to this group are for instance known as Nikkol Decaglyn, Caprol or Polymuls)

g) Sterol dérivatives comprising polyethylene glycol dérivatives of sterol such as PEG24 cholestérol ether, PEG-30 cholestanol, PEG-25 phyto sterol, PEG-30 soya sterol and the like; (the wetting agents belonging to this group are for instance known as Solulan™ or Nikkol BPSH)

h) Polyethylene glycol sorbitan fatty acid esters such as for example PEG-10 sorbitan laurate, PEG-20 sorbitan mono laurate or sorbitan tristearate or sorbitan monooleate or sorbitan trioleate or sorbitan monoisostearate or sorbitan monopalmiate or sorbitan monostearate, PEG-4 sorbitan monolaurate, PEG-5 sorbitan monooleate, PEG-6 sorbitan monooleate or sorbitan monolaurate or sorbitan monostearate, PEG8 sorbitan monostearate, PEG-30 sorbitan tetraoleate, PEG-40 sorbitan oleate or sorbitan tetraoleate, PEG-60 sorbitan tetrastearate, PEG-80 sorbitan monolaurate,

PEG sorbitol hexaoleate (Atlas G-1086) and the like; (the wetting agents belonging to this group are for instance known as Liposorb, Tween, Dacol MSS, Nikkol, Emalex, Atlas)

i) Polyethylene glycol alkyl ethers such as for instance 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 and the like; (the wetting agents belonging to this group are for instance known as Volpo, Brij)

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

k) Polyethylene glycol alkyl phénols such as for instance PEG-10-100 nonyl phénol (Triton X sériés), PEG-15-100 ocyl phénol ether (TritonN sériés) and the like;

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

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m) ionic wetting agents including cationic, anionic and zwitterionic surfactans such as the fatty acid salts e.g. sodium oleate, sodium lauryl sulfate, sodium lauryl sarcosinate, sodium dioctyl sulfosuccinate, sodium myristate, sodium palmitate, sodium state, sodium ricinoleate and the like; such as bile salts e.g. sodium cholate, 5 sodium taurocholate, sodium glycocholate and the like; such as phospholipids e.g. egg/soy lecithîn, hydroxylated lecithin, lysophosphatîdylcholine, phosphatidylcholine, phosphatidyl ethanolamine, phosphatidyl glycerol, phosphatidyl serine and the like; such as phosphoric acid esters e.g. diethanolammonium polyoxyethylene-10 oleyt ether phosphate, estérification products of fatty atcohols or fatty alcohol ethoxylates with phosphoric acid or anhydride; such as carboxylates e.g. succinylated monoglycerides, sodium steaiyl fumarate, stcaroyl propylene glycol hydrogen succinate, mono/diacetylated tartane acid esters of mono-and diglyccridcs, citric acid esters of mono-and diglycerides, glyceryl-lacto esters of fatty acids, lactylic estera of fatty acids, calcium/sodium stearoyl-2-lactylate, calcium/sodium stcaroyl lactylate, alginate salts, propylene glycol alginate, ether carboxylates and the like; such as sulfates and sulfonates e.g. ethoxylated alkyl sulfates, alkyl benzene sulfates, alpha-olefin sulfonates, acyl isethionates, acyl taurates, alkyl glyceryl ether sulfonates, octyl sulfosuccinate disodium, disodium undecyleneamido-MEA-sulfosuccinate and the like; such as cationic wetting agents e.g. hexadecyl triammonium bromide, decyl trimethyl ammonium bromide, cetyl trimethyl ammonium bromide, dodecyl ammonium chloride, alkyl benzyldimethylammonium salts, diisobutyl phenoxyethoxydimethyl benzylammonium salts, alkylpyridinium salts, betaines (lauryl betaine), ethoxylated amines (polyoxyethylene-15 coconut amine) and the like.

When in the above list of suitable wetting agents, different possibilities are listed such as for example PEG-20 oleyl ether or cetyl ether or stearyl ether, this means that PEG20 oleyl ether and PEG-20 cetyl ether and PEG-20 stearyl ether are intended. Thus for instance PEG-20 castor oil or hydrogenated castor oil or corn glycerides or almond 30 glycerides has to be read as PEG-20 castor oil and PEG-20 hydrogenated castor oil and

PEG-20 corn glycerides and PEG-20 almond glycerides.

Prcferred wetting agents in the présent compositions are those agents belonging to the group of the polyethylene glycol sorbitan fatty acid esters, such as wetting agents known as Tween, e.g. Tween 20,60,80. Most preferably, the wetting agent is Twcen (polysorbate 20).

WO 2016/120258

PCT/EP2016/051545

-19The preferred quantity of wetting agent (or surfactant) is described herein, but it is apprcciated however that when used in the présent compositions, it may dépend on the amount of active ingrédient présent in the composition or on the particle size of the 5 active ingrédient. A higher amount or a smaller particle size may require more wetting agent.

It is indicated herein that the compositions (e.g. tablet compositions) of the invention contain a binder or polymer (for instance for the binder fraction of the compositions of 10 the invention). Such a binder or polymer may be an organic polymer.

The organic polymer used in the compositions (e.g. tablets) of the invention may be any of the physiologically tolerable water soluble synthetic, semi-synthetic or nonsynthetic organic polymers.

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

The polymer conveniently has a molecular weight in the range 500D to 2 MD, and conveniently has an apparent viscosity of 1 to 15,000 mPa.s when in a 2% aqueous solution at 20°C. For example, the watcr-soluble polymer can be selected from the group comprising

- alkylcelluloses such as methylcellulose,

- hydroxyakylcelluloses such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxybutylcellulose,

- hydroxyalkyl alkylcelluloses such as hydroxyethyl methylcellulose and hydroxypropyl methylcellulose,

- carboxyalkylcelluloses such as carboxymethylcellulose,

- alkali métal salts of carboxyalkylcelluloses such as sodium carboxymethylcellulose,

- carboxyalkylalkylcelluloses such as carboxymethylethylcellulose,

- carboxyalkylcellulose esters,

- starches,

- pectins such as sodium carboxymcthylamylopcctin,

- chitîn dérivâtes such as chitosan,

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-20- heparin and heparinoids,

- polysaccharides such as alginic acid, alkali métal and ammonium salts thereof, carrageenans, galactomannans, tragacanth, agar-agar, gum arable, guargum and xanthan gum,

- polyacrylic acids and the salts thereof,

- polymethacrylic acids and the salts thereof, méthacrylate copolymers,

- polyvinylalcohol,

- polyvinylpyrrolidone, copolymers of potyvinylpyrnolidone with vinyl acetate,

- polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide, e.g. poloxamers and poloxamines.

Non-enumerated polymère which are pharmaceutically acceptable and hâve appropriate physico-chemical properties as defined hereinbefore are equally suited for preparing compositions according to the présent invention.

Preferably the organic polymer is starch, polyvinylpyrrolidone or a cellulose ether, e.g.

PVP K29-32, PVP K90, methyl cellulose, hydroxypropylcellulose, hydroxycthyl methylcellulose, or hydroxypropyl methylcellulose (HPMC).

Said HPMC contains sufïïcient hydroxypropyl and methoxy groups to render it watersoluble. 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 degree of substitution refers to the average number of methyl 25 ether groups présent per anhydroglucose unit of the cellulose molécule. Hydroxypropyl molar substitution refera to the average number of moles of propylene oxide which hâve reacted with each anhydroglucose unit of the cellulose molécule. A preferred HPMC is hypromellose 2910 15 mPa.s or hypromellose 2910 5mPa.s, especially hypromellose 2910 15 mPa.s. Hydroxypropyl methylcellulose is the United 30 Statcs Adopted Name for hypromellose (see Martindale, The Extra Pharmacopoeia,

29th édition, page 1435). In the four digit number **2910”, the first two digits represent the approxîmate percentage of methoxyl groups and the third and fourth digits the approximate percentage composition of hydroxypropoxyl groups; 15 mPa.s or 5 mPa.s is a value indicative of the apparent viscosity of a 2 % aqueous solution at 20°C.

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-21It is most preferrcd that the binder or polymer of the compositions of the invention is hypromeliose 5 cps (Le. Methocel E 5 LV).

It is indicated herein that the compositions (e.g. tablet compositions) of the invention contain a lubricant. Such a fabricant may be pharmaceutically acceptable fabricants such as magnésium stéarate, calcium stéarate, stearic acid, talc, polyethylene glycol, sodium lauryl sulfate, magnésium lauryl sulphate. It is most preferred that the fabricant is sodium stearyl fumarate (Pruv).

The compositions of the invention may make use of active ingrédient having a particle size of:

- d’° less than 50pm (preferably less than 25pm, for instance less than 15pm, e.g. around 9pm (or even less)

- d⁵⁰ less than 1 OOpm (preferably less than 50pm, for instance less than

25 pm, e.g. around 22pm (or even less)

- d’° less than 200pm (preferably less than lOOpm, for instance less than 50pm, e.g. around 48pm (or even less)

As used herein, the term d^!0 has its conventional meaning as known to the person skilled in the art and can be measured by art-known particle size measuring techniques such as, for example, sédimentation field flow fractionation, photon corrélation spectroscopy, laser diffraction or disk centrifugation. The d^!0 mentioned herein may be related to volume distributions of the particles. In that instance, by a d⁵⁰ of 22 pm it is meant that at least 50% of the volume of the particles has a particle size of less than 22 pm. The same applies to the other particle sizes mentioned and d¹⁰ and d⁹⁰ hâve analogous meanings. Usually volume and weight distribution resuit in the same or about the same value for the average particle size.

The particle size can be an important factor determining the tabletting speed, in particular the flowability and therefore the manufacturability on a large scale of a particular dosage form or formulation, and the quality of the final product. For instance, for capsules, the particle size may range preferably from about 5 to about 300 pm (d^î0); for tablets the particle size is preferably less than 250 pm, more preferably less than 100 pm (e.g. less than 50 pm) (d^so). Too small particles can cause sticking on the tablet punches and manufacturability issues. The particle size has an effect on the intrinsic properties of the compositions of the invention.

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-22The compositions as described herein may further comprise one or more pharmaceutically acceptable excipients such as, for example, plasticizers, flavours, sweeteners, coluorants, preservatives and the like (provided that such additional excipients do not comprise soluble excipients/diluents, where it is already specifïed that the composition or fraction of that composition, as appropriate, does not comprise such soluble components). In an aspect of the invention, the compositions of the invention do not contain a plasticizer or another such optional excipient mentioned here. Especially in case of préparation by hot mclt extrusion, said excipients should not be heat-sensitive, in other words, they should not show any appréciable dégradation or décomposition at the working température of the melt-extruder.

The advantage of the présent combinations of the invention, and specifically the dispersibility/disintegrating properties, may stem from the presence ofthe non-soluble excipient (e.g. microcrystalline cellulose, such as silicified microcrystalline cellulose) which may hâve the ability to rapidly intake water in the dispersion medium, i.e. it may hâve a wicking action that advantageously résulta in the improved dispersibility/disintegrating properties. In view of this, advantageously, the compositions of thé invention achieve a favourable dispersibiltiy or disintegrating action, for cxample as compared to compositions previously known or as compared to other compositions as may be described herein. As indicated, wicking action may lcad to faster dispersion and may by-pass the solubilization process (for instance, liquid may be drawn up or “wicked” into these pathways through capilliary action and rupture the interparticulate bonds, causing the tablet/composîtion to break apart), which could be advantageous. Further, the non-soluble excipients/diluents may easily be re-suspended even after a long period of time (e.g. 6 hours) - this may hâve the advantage that the compositions of the invention do not require a suspending agent to re-disperse the granules/particles.

The invention also relates to process for preparing the compositions of the invention (e.g. the tablet compositions) and there is therefore provided:

A process (e.g. as described hereinbelow) for the préparation of / composition (e.g. tablet) of the invention

- A product (e.g. composition to the invention, e.g. a dispcrsiblc tablet as described herein) obtainable by a process of the invention (e.g. as described hereinbelow)

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-23As indicated above, the compositions of the invention preferably comprise different fractions/portions, an intra-granular fraction, a binder portion and an extra-granular fraction.

Hence, there is provided a process for the préparation of a process of the invention, which comprises:

(a) obtaining an intra-granular fraction using the intra-granular fraction components mentioned herein;

(b) preparing a binder fraction, using the binder fraction components mentioned herein;

(c) obtaining an extra-granular fraction using the extra-granular fraction components mentioned herein, and using those fractions to préparé a composition of the invention.

More specifically, the intra-granular fraction (as defined herein) may be prepared by mîxing or blending the relevant components.

Direct compression may be employed but this may hâve the disadvantage that the blend has poor fiow properties and/or there may be sticking on the surface of punches. Hence, direct compression was followed by granulation. Dry granulation may hâve disadvantages in relation to fiow (or compression) properties and the aforementioned sticking/picking phenomenon may also remain. Hence, for compositions of the invention, it is preferred that a wet granulation process is employed.

More specifically therefore, the binder fraction/portion, may be prepared by contacting or mixing the relevant ingrédients (i.e. the binder or polymer and wetting agent and, if necessary, a vehicle which may be aqueous or non-aqueous, or a combination; the vehicle is preferably water (qs), preferably purified water (qs)), and that binder fraction/portion may undergo a wet-granulatîon with the intra-granular fraction. Such wet granulation process is preferably a low shear granulation process (or top spray fluid bed granulation) and, in the binder fraction, a low viscosity soluble polymer (preferably viscosity 5 eps or lower) is employed. The obtained granulate may then be dried and sized (or sieved) after which it is mixed or blended with the components of the extragranular fraction (as defined herein). Such blending also inherently in volves lubrication, if the extra-granular Iayer also includes a fabricant.

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-24Once a composition of the invention has been prepared, for example as set out above, including the mixing of the intra-granular, extra-granular and binder fractions, such composition may optionally, and preferably, be converted into tablet forms. In a 5 preferred aspect of the process of the invention, the composit ions so prepared are preferably compressed into tablet form, thereby allowing for the préparation of a dispersible tablet of the invention. Such a tablet may be ofany suitable dose, but each unit may contain between 5 and 200 mg of active ingrédient (in this instance, meaning the active substatnee bedaquiline not consîdering the fumarate sait component). The 10 unit may contain 100 mg of bedaquiline (plus the corresponding weight of the fumarate sait portion) or, if the unit form is for the pédiatrie population, then it is preferably 20 mg of bedaquiline (corresponding to 24.18 mg of bedaquiline fumarate).

The tabletting process itself is otherwise standard and readily practised by forming a 15 tablet from desired blend or mixture of ingrédients into the appropriate shape using a conventional tablet press.

Tablets of the présent invention may further be film-coated to improve taste, to provide ease of swallowing and an élégant appearance. Many suitable polymeric film-coating 20 matériels are known in the art. A preferred film-coating matériel is hydroxypropyl methylcellulose HPMC, especially HPMC 2910 5 mPa.s. Other suitable film-fbrming polymers also may be used herein, including, hydroxypropylcellulose, and acrylatemethacrylate copolymers. Besïdes a film-forming polymer, the film coat may further comprise a plasticizer (e.g. propytene glycot) and optionally a pigment (e.g. titanium 25 dioxide). The film-coating suspension also may contain talc as an antî-adhesive. In immédiate rclease tablets according to the invention, the film coat is smalt and in terms of weight accounts for less than about 3 % (w/w) of the total tablet weight. In an embodiment of the invention (e.g. in a preferred embodiment), the tablets of the invention are not film-coated.

As indicated above, the utility of the invention anses from the active ingrédient, and sait thereof, being known to show activity against Mycobacteria including drug résistant strains, in particular Mycobacterium tuberculosis, M. bovis, M. avium, M. leprae and M. marinum, especially against Mycobacterium tuberculosis, including 35 drug-resistant M. tuberculosis strains. The active ingrédient, including sait thereof,

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-25shows activity against active, sensitive, susceptible Mycobacteria strains and latent, donnant, persistent Mycobacteria strains.

Hence, in an aspect of the invention, there is provided compositions (e.g. tablets) according to the invention, which are suitable for the treatment of a bacterial infection including a mycobacterial infection, partïcularly those diseases caused by pathogenic mycobacteria such as Mycobacterium tuberculosis (including the latent and drug résistant form thereof), M. bovis, M. leprae, M. avium, M. leprae and M. marinum.

Further, the présent invention also relates to the use ofa composition (e.g. tablet) ofthe invention, the pharmaceutically acceptable salts thereof, the solvatés thereof or the Noxide forms thereof, as well as any of the pharmaceutical compositions thereof as described hercinafter for the manufacture of a médicament for the treatment of a bacterial infection including a mycobacterial infection.

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

The compositions of the invention may be combined with other therapeutic agents that are known to be useful in the treatment of a bacterial infection as defîned herein (and particularly for the treatment ofa mycobacterial infection, tuberculosis as defîned herein). Such other antibacterial agents comprise antibiotics ofthe β-lactam group such as naturel penicillins, semisynthetic penicillins, naturel cephalosporins, semisynthetic cephalosporins, ccphamycins, 1-oxacephems, clavulanic acids, penems, carbapencms, nocardicins, monobactams; tctracyclines, anhydrotetracyclines, anthracyclines; aminoglycosides; nucleosides such as ΛΓ-nucleosides, C-nucleosides, carbocyclic nucleosides, blasticidin S; macrolides such as 12-membered ring macro lid es, 14-membercd ring macrolides, 16-membered ring macrolides; ansamycins; peptides such as bleomycins, gramicidins, polymyxins, bacitracins, large ring peptide antibiotics containîng lactone linkages, actinomycins, amphomycin, capreomycin, distamycin, enduracidins, mikamycin, neocarzinostatin, stendomycin, viotnycin, virginiamycin; cycloheximidc; cycloserine; variotin; sarkomycin A; novobiocin;

WO 2016/120258 PCT/EP2016/051545

-26griseofulvin; chloramphenicol; mitomycins; fumagillin; monensins; pyrrolnitrin; fosfomycin; fusidic acid; D-(p-hydroxyphenyl)glycine; D-phenytglycine; enediynes.

Spécifie antibiotics which may be combined with the présent compositions of the invention are for example benzylpenicillin (potassium, procaine, benzathine), phenoxymethylpenicillin (potassium), phenethicillin potassium, propîcill in, carbenicillin (disodium, phenyl sodium, indanyl sodium), sulbenicillin, ticarcillin disodium, methicillin sodium, oxacillin sodium, cloxacillin sodium, dicloxacillin, flucloxacillin, ampicillin, mezlocillin, piperacillin sodium, amoxicillin, ciclacillin, hectacîllin, sulbactam sodium, talampicillin hydrochloride, bacampicillin hydrochloride, pivmecillinam, cephalexin, cefaclor, cephaloglycin, cefadroxil, cephradine, cefroxadine, cephapirin sodium, cephalothin sodium, cephacetrile sodium, cefsutodin sodium, cephaloridine, cefatrizine, cefoperazone sodium, cefamandole, vefotiam hydrochloride, cefazolin sodium, ceftizoxîme sodium, cefbtaxime sodium, cefmenoxime hydrochloride, cefuroxime, ccftriaxone sodium, ccftazidimc, cefoxitin, cefmetazole, cefotetan, latamoxef, clavulanic acid, imipenem, aztreonam, tétracycline, chlortetracycline hydrochloride, demethylchlortetracyclîne, oxytetracycline, methacycline, doxycycline, rolitetracycline, minocycline, daunorubicin hydrochloride, doxorubicin, aclarubicin, kanamycin sulfate, bekanamycin, tobramycin, gentamycin sulfate, dibekacin, amikacin, micronomicin, ribostamycin, neomycin sulfate, paromomycin sulfate, streptomycin sulfate, dihydrostreptomycin, destomycin A, hygromycin B, apramycin, sisomicin, netilmicin sulfate, spectinomycin hydrochloride, astromicîn sulfate, validamycin, kasugamycin, polyoxin, blasticidin S, erythromycin, erythromycin estolate, oleandomycin phosphate, tracetyloleandomycin, kitasamycin, josamycin, spiramycin, tylosin, ivermectin, midecamycin, bleomycin sulfate, peplomycin sulfate, gramicidin S, polymyxin B, bacitracin, colistin sulfate, colistinmethanesulfonate sodium, enramycin, mikamycin, virginiamycin, capreomycin sulfate, viomycin, enviomycin, vancomycin, actinomycin D, neocarzinostatin, bestatin, pepstatin, monensin, lasalocid, satinomycin, amphotericin B, nystatin, natamycin, trichomycin, mithramycin, lincomycin, clindamycin, clindamycin palmitatc hydrochloride, flavophospholipol, cycloserine, pecilocin, griseofiilvin, chloramphenicol, chloramphenicol palmitate, mitomycin C, pyrrolnitrin, fosfomycin, fusidic acid, bicozamycin, tiamulin, siccanin.

WO 2016/120258 PCT/EP2016/051545

-27Other Mycobacterial agents which may be combined with the compositions of the invention are for example rifampicin (=rifampin); isoniazid; pyrazinamide; amikacin; ethionamide; ethambutol; streptomycin; para-amînosalicylic acid; cycloserine; capreomycin; kanamycin; thioacetazone; PA-824; quinolones/fluoroquinolones such as for example moxifloxacin, gatifloxacin, ofloxacin, ciprofloxacin, sparfloxacin; macrolidcs such as for exemple clarithromycin, clofazimîne, amoxycillin with clavulanic acid; rifamycins; rifabutin; rifapentine.

The term “about” as used herein in connection with a numerical value is meant to hâve its usual meaning in the context of the numerical value. Where necessary the word “about” may be replaced by the numerical value ±10%, or ±5%, or ±2%, or ±1%. Ail documents cited herein are incorporated by reference in their entirety.

The following examples are intended to illustrate the présent invention.

Expérimenta! part

The active ingrédient, 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.

WO 2016/120258 PCT/EP2016/051545

-28Examples

1) EfTect of intra-granular (Hier

Ingrédient

TMC207	24.18	24.18	24.18
Silicified Microcrystalline cellulose	14.91		29.82
Mannitol		29.82
Glucose monohydratc	14.91
Crospovidone	3.0	3.0	3.0
Colloïdal 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
lïï^jExtra-granülarParf	lji . .i j
Silicified Microcrystalline cellulose	32.3	32.3	32.3
Crospovidone	3.0	3.0	3.0
Colloïdal 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

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.

WO 2016/120258

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-292) EfTect of extra-granular flllers

Ingrédients

TMC207	24.18	24.18
Silicified Microcrystalline cellulose	29.82	29.82
Crospovidone	3.0	3.0
Colloïdal Silicon Dioxide	2.0	2.0
Hypromellose 5 eps	3.0	3.0
Polysorbate 20	0.2	0.2

Mannitol	323
Silicified Microcrystalline cellulose		323
Crospovidone	3.0	3.0
Colloïdal Silicon Dioxide	0.5	0.5
Sodium Stearyl Fumarate	2.0	2.0
Total	100	100
Dispersion tlme*(sec)	60	45
Hardness (N)	19-25	20-27

The soluble excipient in the extra-granular part did not show any addîtional 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.

WO 2016/120258

PCT/EP2O16/051545

-303) Effect of grade of Crospovidone

Ingrédients

TMC207	24.18	24.18
Sîlicified Microcrystalline cellulose	29.82	29.82
Crospovidone (Polyplasdone XL 10 )	3.0	3.0
Cotloidat Silicon Dioxide	2.0	2.0
Hypromellose 5 eps	3.0 3.0
Polysorbate 20	0.2	0.2

Sîlicified Microcrystalline cellulose	32.3	32.3
Crospovidone (Polyplasdone XL)		3.0
Crospovidone (Polyplasdone XL 10 )	3.0
Colloïdal Silicon Dioxide	0.5	0.5
Sodium Stearyl Fumarate	2.0	2.0
Total (mg)	100	100
Dispersion tlme*(sec)	90-100	55-75
Hardness (N)	25-34	25-34

Crospovidone (Polyplasdone XL) coarser grade showed better dispersion pattern and 5 behavior as compared to the fine particle Crospovidone (Polyplasdone XL 10), thus it was dccided to further continue with the Polyplasdone XL grade intra-granularly as well as extra-granularly.

Further Exemples

The following composition of the invention was prepared in accordance with the teachnîques described herein:

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-31Table 1: Current composition of TMC 207 dispersible tablet__________________

TeWct Tablet

Ingrédient Function quantity quantity (mg)

BEDAQUILINE FUMARATE (TMC 207)	API	24.18	24.18
Silicified Microcrystalline Cellulose	Filler	29.82	29.82
(Prosolv HD 90)
Crospovidone (Polyplasdone XL)	Désintégrant	3.0	3.0
Colloïdal Sllicon dioxide (Aerosil 200)	Glidant	2.0	2.0
Hypromellose 5 eps	Binder	3.0	3.0
(Methocel E 5 LV)
Purified water	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)	Disinte grant	3.0	3.0
Colloïdal Silicon dioxide (Aerosil 200)	Glidant	0.5	0.5
Sodium Stcaryl Fumaratc (Piuv)	Lubricant	2.0	2.0
Tablet weight		100 mg	100%

(I) TM· luleriil to · proew· ild md to imovad during pranaring

WO 2016/120258 PCT/EP2016/051545

-32Stability data:

Appearance, Assay and Chromatographie Purity

Parameter Appearance Water % Assay Dégradation compounds £0.05% (%) content of in % Bedaquiline w/w fumarate

Test Method Visual KF- HPLC-00129-V1

Examination 00131VI

Storage Storage Resuit % w/w Bedaquiline Any unspecified Total

Condition Time fumarate dégradation product (%) Dégradation

(Months)		(%)	U_RRT_0.74U_RRT_l .04products (%)
Initial	Pass	4.4	98.1	<0.05	<0.05	<0.05
25°C/60%RH 1	Pass	5.2	98.7	<0.05	0.05	0.05
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/75%RH 1	Pass	5.0	99.2	<0.05	<0.05	<0.05
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/75%RH 1	Pass	4.8	99.1	<0.05	<0.05	<0.05
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 700W/m² (Light study conducted on tablets packed in container) Where it is indicated “any specifîed dégradation product”, this may be an impurity in the API (for instance one that anses from the process).

The composition ofthe invention was found to be stable under ICH conditions.

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PCT/EP2016/051545

-33In Use Stablllty ;

The stability for the dispersion of tablet in water was evaluated considering the lag time between the préparation and dosing of the dispersion.

Method:As the composition ofthe invention (i.e. dispersible tablet described above) was stable for up to 6 hrs, it can be administered up to 6 hrs after its préparation.

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.

Sr.	Time	A known process	Bedaquiline
No.	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

Product was found to be stable in the form of water dispersion for 6 hrs. Further it was 15 stable in a clear glass contained too, incdîcating that it was not light-sensitive.

WO 2016/120258

PCT/EP2016/051545

-34Comparative dissolution profile of adult formulation vs Pédiatrie formulation via two different methods:

Formulation	Adult	Adult	Pédiatrie	Pédiatrie
BatchNo	136695	136695	HG-121019	HG-121019
Strength	lOOmg	lOOmg	5 x20mg	5 x 20mg
Resuit set ID	81938	82584	83398	83598
Disso Media	0.01NHCL	0.0IN HCL	0.0 IN HCL	0.01NHCL
No of units	6	6	6	6
Condition	RT_6M	RT_6M	RT_1.5Yrs	RTJ.5Yrs
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 température; 6M = 6 months

F2: The FDA and EMEA define similarity factor as a logarithmîc reciprocal square root transformation of one plus the mean squared (the average sum of squares) différences 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.

Dissolution profile of pédiatrie formulation was faster as compared to adult formulation în both the dissolution methods.

WO 2016/120258 PCT/EP2016/051545

-35Effect on Bioavallablllty:

1) Food effect on bîoavailability was reduced as compared to adult tablet

	Regular breakfast	Yoghurt
Adult tablet	91%	32%
Water dispersible tablet	82%	17%

2) Both adult and pacdiatric formulation tested with regular breakfast and yogurt showed that both formulations are bioequivalent despite dispersible tablets showing faster dissolution profile in vitro.

Panel 1 (standard breakfast)

Water dispersible tablet	Ratio (%)	90% CI
Cmax	106.58	96.11-118.18
AUC₇₂h	98.43	91.85- 105.47

Panel 2 (yoghurt)

Water dispersible tablet	Ratio (%)	90% CI
Cmax	111.93	104.26-120.16
AUC₇₂h	112.95	105.94 - 120.42

Hencc, the composition ofthe 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.

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-36Addit ional Examples

Further development in the formulation was aimed at catering the clinical need of 10 mg dose incréments. This was accomplished with developing a 20 mg formulation with 5 a breakline to enabte dosing in 10 mg dose incréments if needed.

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

Parameter	Bedqulline fùmarate Dlsperslble tablet 20 mg (Formulation described above)	Bedqulline fùmarate Dlsperslble tablet 20 mg (Furth er formulation)
Weight	100 mg	200 mg
Tablet shape	Circular	Caplet
Tablet surface	Plain on both sldes	Break line on both sldes
Tablet Debosslng	None	2” & O separated by break line on one slde and plain with break line on other slde
Hardness	20-40 N	70-120N
Dose(covered)	20 mg	10 mg and 20 mg
Dispersion time	About 30 sec (in 50 ml)	About 60 sec (In 50ml) - can be dispersed In 5 ml water
Percentage of MCC (Avicel PH 102)- Insoluble excipient/diluent	62.12%	73.71%
Percentage of API	24.18%	12.09%

WO 2016/120258 PCT/EP2016/051545

-37Compositlon of further formulation:

Ingrédients	Bedaqulline fumarate Dispersible tablet 20 mg (Formulation oflOO mg weight described above}	Bedaqulline fumarate Dispersible tablet 20 mg (Further formulation of 200 mg weight}
	mg/unit	Percent w/w	mg/unit	Percent w/w
Intra Granular Portion
Bedaqulline fumarate	24.18	24.18	24.18	12.09
Silicified Microcrystalllne Cellulose	29.32	29.32	82.82	41.41
Crospovidone	3.00	3	6	3
Colloïdal Silicon Dioxide	2.0	2	4	2
Hypromellose 5 cps	3.S	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
Colloïdal Silicon Dioxide	0.5	0.5	1	0.5
Total (Extragranufar Portion)	37.8	37.8	75.6	37.8
Tablet weight (mg)	100.0	100	200	100

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PCT/EP2016/051545

-38Formulation trials to studv various factors In formulation

1) Effect of Intragranular fil 1er Vs. Extragranular filler

Ingrédients	Example 1	Example 2
Intra-granular Portion
Bedaquiline fumarate	24.18	24.18
Siliclfied Microcrystalline Cellulose (ProsoIvSMCC HD90)	82.82	115.12
Crospovidone (Polyplasdone XL)	6.00	6.00
Colloïdal Sillcon Dloxlde (Aerosll 200P ha rm a)	4.00	4.00
Hypromellose 5 eps (Methocel E5 LV)	7.00	7.00
Polysorbate 20 (Tween 20 HP)	0.40	0.40
Purlfled Water*	-	-
Weight of Intragranular	124.4	156.7
Extra-granular Portion
Sodium Stearyl Fumarate (Pruv)	4.00	4.00
Siliclfied Mlcrocrystalllne Cellulose (Prosoiv SMCC HD90)	64.60	32.30
Crospovidone (Polyplasdone XL)	6.00	6.00
Colloïdal Silicon Dioxlde (Aerosil 200 Pharma)	1.00	1.00
Dispersion time	75 sec (5 ml) 50-55 sec (50 ml)	70-75 sec (5 ml)
Hardness	93-100 N (95N)	92-107 N (96N)
Tablet weight (mg)	200.00	200.00
Conclusion: - Intragranular filler (silici	ied 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.

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-39Effect of amount of Crospovldone

Ingrédients	Example 1	Example 2
Intra-granular Portion
Bedaquiline fumarate	24.18	24.18
Slllclfied Mlcrocrystalline Cellulose (ProsoIvSMCC HD90)	82.82	85.82
Crospovidone (Polyplasdone XL)	6.00	3.00
Colloïdal Sllicon Dloxide (Aerosll 200Pharma)	4.00	4.00
Hypromellose 5 cps (Methocel E5 LV)	7.00	7.00
Polysorbate 20 (Tween 20 HP)	0.40	0.40
Purlfled Water*	-	-
Weight of Intragranular	124.4	124.4
Extra-granular Portion
Sodium Stearyl Fumarate (Pruv)	4.00	4.00
Slllclfied Mlcrocrystalline Cellulose (ProsoIvSMCC HD90)	64.60	67.60
Crospovidone (Polyplasdone XL)	6.00	3.00
Colloïdal Sillcon Dloxide (Aerosll 200 Pharma)	1.00	1.00
Dispersion time	75 sec (5 ml) 50-55 sec (50 ml)	85-90 sec (5 ml)
Hardness	93-100 N (95N)	87-105 N (95N)
Tablet weight (mg)	200.00	200.00

Conclusion: - Désintégrant (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%

WO 2016/120258 PCT/EP2016/051545

-402) Effect of amount of Increased amount of bînder

fngredîents	Example 1	Example 2
Intra-granular Portion
Bedaqulline fuma rate	24.18	24.18
Silicified Mlcrocrystalllne Cellulose (ProsolvSMCCHD90)	82.82	79.32
Crospovldone (Polyplasdone XL)	6.00	6.00
Colloïdal Silicon Dioxlde (Aerosll 200Pharma)	4.00	4.00
Hypromellose 5 eps (Methocel E5 LV)	7.00	10.50
Polysorbate 20 (Tween 20 HP)	0.40	0.40
Purified Water*	-	-
Weight of Intragranular	124.4	124.4
Extra-granular Portion
Sodium Stearyl Fumarate (Pruv)	4.00	4.00
Silicified Mlcrocrystalllne Cellulose (Proso!vSMCCHD90)	64.60	64.60
Crospovldone (Polyplasdone XL)	6.00	6.00
Colloïdal Sllîcon Dioxlde (Aerosll 200 Pharma)	1.00	1.00
Dispersion time	75 sec (5 ml) 50-55 sec (50 ml)	135-145 sec (5 ml)
Hardness	93-100 N (95N)	89-104 N (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.

WO 2016/120258 PCT/EP2016/051545

-41Initial & Stability data of further dlsperslble tablet formulation:

Further Formulation (of 200 mg tablet weight)	Assay (%)	RS (%)	WaterbyKF(%)
Initial sample	99.45	<RT	5.0
HDPE Bottle IM 40°C/75 % RH	99.74	<RT	4.1
HDPE Bottle 2M 40°C/75 % RH	98.30	<RT	4.0
HDPE Bottle 3M 40°C/75 % RH	99.30	0.05	3.1
HDPE Bottle 6M 40°C/75 % RH	100.6	0.15	3.2

RT: Reporting threshold

Formulation exhibited satisfactory stability till 6 months in HDPE Bottlcs.

Dissolution profile (0.01N HCl) - Comparfson of lOOmg dlsperslble tablet formulation vs 200mg dlsperslble tablet formulation

Time in minutes	lOOmg tablet formulation	200mg tablet formulation
% Release
5	80	78
10	98	93
15	101	95
20	101	96
30	102	97
45	103	97

lOOmg & 200mg tablet formulation dissolution profile is comparable.

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-42Snlit tablet data;

- Weight ioss of split tablets

Intact weight of tablet (mg)	Fraction-1	Fraction-2	Weight Ioss (%)
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 %

Friabiïity of split tablets (100 révolutions): 0.06 %

Friabiïity of split tablets (400 révolutions): 0.16 %

WO 2016/120258 PCT/EP2016/051545

Claims

Claims

1. A dispersible composition (e.g tablet) comprising bedaquiline fùmarate as the active ingrédient and wherein the composition (e.g tablet) comprises an intra-granular and

5 extra-granular layer in which the intra-granular layer comprises a non-soluble excipient/diluent and is charaterised 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-gTanular layer is

10 absent any soluble excipient/diluent.
3. A dispersible composition as claimed in Claim 1 or Claim 2, wherein the non-soluble excipient/diluent in the intra-granular layer is microcrystalline cellulose.

15
4. A dispersible composition (e.g tablet) comprising bedaquiline fùmarate as the active ingrédient and wherein the composition (e.g tablet) comprises an intra-granular and extra-granular layer in which the intra-granular layer comprises a non-soluble excipient/diluent that is microcrystalline cellulose.

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

6. A dispersible composition (e.g. tablet composition) comprising (e.g. consisting of) by weight based on the total weight of the composition:

25 5 to 50% (e.g. 10 to 30%) of active ingrédient (Le. bedaquiline fùmarate)

35% to 90% (e.g. 50 to 70%) of a non-soluble excipient/diluent

2% to 10% (e.g. 4 to 8%) of a disintegrant

0.1 to 5% (e.g. 1.5 to 3.5%) of a glidant

0.01 to 5% (e.g. 0.1 to 1%) of a wetting agent or surfactant

30 0 to 10% (e.g. 2 to 5%) of a binder or polymer

0 to 5% (e.g. 1 to 3%) of a lubricant solvent (qs) e.g. water.

7. A dispersible composition (e.g. tablet composition) comprising (e.g. consisting of)

35 by weight based on the total weight of the composition:
5 to 50% (e.g. 10 to 30%) of active ingrédient

WO 2016/120258 PCT/EP2016/051545

-4420% to 90% (e.g. 50 to 70%) of a non-soluble excipient/diluent that is microcrystalline cellulose (such as silicified microcrystalline cellulose)

2% to 10% (e.g. 4 to 8%) of a désintégrant

0.1 to 5% (e.g. 1.5 to 3.5%) of a glidant

5 0.01 to 5% (e.g. 0.1 to 1%) of a wetting agent or surfactant

0 to 10% (e.g. 2 to 5%) of a binder or polymer

0 to 5% (e.g. 1 to 3%) of a fabricant solvent (qs) e.g. water.

10 8. A composition as claimed in Claim 6 or Claim 7, wherein they are further characterised in that they are absent a soluble excipient/diluent.

9. A the composition (e.g. tablet composition) as claimed in any of the preceding claîms, which composition consists of by weight, based on the total weight of the

15 composition:

24.18% (or about 25%) of active ingrédient

62.12% (or about 60%) non-soluble excipient/diluent (e.g. microcrystalline cellulose, such as silicified microcrystalline cellulose)
6% (or about 6%) disintegrant (e.g. crospovidone, such as Polyplasdone XL)

20 2.5 % (or about 2.5%) glidant (e.g. colloïdal silicon dioxide, Aerosil 200)

0.2% (or about 0.2%) wetting agent or surfactant (e.g. polysorbate 20, i.e. Twcen 20) 3% (or about 3%) binder or polymer (e.g. hypromellose 5 cps, Le. Methocel E 5 LV) 2% (or about 2%) fabricant (e.g. sodium stearyl fumarate (Pruv))

Solvent (qs), e.g. water - if necessary (i.e. only the amount needed, if any)
10. A composition (e.g. tablet composition) wherein the different parts of the composition, specifically the intra-granular and extra-granular fraction and binder portion, comprise (e.g. consist of) the following ingrédients by weight based on the total weight of the composition:

30 Intra-granular fraction

5 to 50% (e.g. 10 to 30%) of active ingrédient

10 to 50% (e.g. 20 to 40%) of non-soluble excipient/diluent (e.g. microcrystalline cellulose, such as silicified microcrystalline cellulose)

1 to 5% (e.g. 2 to 4%) disintegrant (e.g. crospovidone, such as Polyplasdone XL)

35 0.1 to 5% (e.g. 0.5 to 4%, such as 1 to 3%) glidant (e.g. colloïdal silicon dioxide,

Aerosil 200)

WO 2016/120258 PCTÆP2016/051545

-45Bînder

1 to 10% (e.g. 2 to 5%) 3% binder or polymer (e.g. hypromellose 5 eps, i.e. Methocel E 5LV)

5 0.01 to 5% (e.g. 0.1 to 1%) wetting agent or surfactant (e.g. polysorbatc 20, i.e. Tween

20)

Solvent (qs), e.g. water - if necessary (i.e. only the amount needed, if any) Extra-granular fraction

10 to 50% (e.g. 20 to 40%) of excipient/diluent (preferably a non-soluble

10 excipient/diluent e.g. microcrystalline cellulose, such as silicified microcrystalline cellulose)

1 to 5% (e.g. 2 to 4%) disintegrant (e.g. crospovidone, such as Polyplasdone XL) 0 to 3% (e.g. 0.1 to 1%) glidant (e.g. colloïdal silicon dioxide, Aerosil 200)

0 to 5% (e.g. 1 to 3%) lubricant (e.g. sodium stcaryl fumarate (Pruv))
11. A composition as claimed in Claim 10, wherein the intra-granular tayer is absent any soluble excipient/diluent; and/or, optionally, the extra-granular fraction îs also absent any soluble excipient/diluent.

20
12. A composition as claimed in Claim 10 or Claim 11, which consiste 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% (or about 25%) of active ingrédient

25 29.82% (or about 30%) of non-soluble excipient/diluent (e.g. microcrystalline cellulose, such as silicified microcrystalline cellulose)

3% (or about 3%) disintegrant (e.g. crospovidone, such as Polyplasdone XL)

2 % (or about 2%) glidant (e.g. colloïdal silicon dioxide, Aerosil 200) Binder

30 3% (or about 3%) binder or polymer (e.g. hypromellose 5 eps, i.e. Methocel E 5 LV)

0.2% (or about 0.2%) wetting agent or surfactant (e.g. polysorbate 20, i.e. Tween 20) Solvent (qs), e.g. water - if necessary (i.e. only the amount needed, if any) Extra-granular fraction

32.3% (or about 30%) of excipient/diluent (preferably a non-soluble excipient/diluent

35 e.g. microcrystalline cellutose, such as silicified microcrystalline cellulose)

3% (or about 3%) disintegrant (e.g. crospovidone, such as Polyplasdone XL)

WO 2016/120258 PCT/EP2016/051545

-460.5 % (or about 0.5%) glidant (e.g. colloïdal silicon dioxide, Aerosil 200) 2% (or about 2%) fabricant (e.g. sodium stearyl fumarate (Pruv))
13. A composition as ctaimed in any one of the preceding daims for use in the

5 treatment of tuberculosis (e.g. MDR tuberculosis).
14. A composition as claimed în Claim 13, for use in the pédiatrie and/or gériatrie population.

10 15. A composition as claimed in any one ofthe preceding daims for use in combination with one or more other therapeutic agent(s) useful in the treatment of tuberculosis.

16. A combination comprising a composition as claimed in any one of Claims 1 to 14
15 andoneor more other therapeutic agents useful in the treatment of tuberculosis.
17. A process for preparing a composition (e.g. the tablet compositions) as claimed in any one of Claims 1 to 12 which comprises:

(a) obtaining an intra-granular fraction using the intra-granular fraction

20 components mentioned in any one of Claim 10 to 12;

(b) preparing a binder fraction, using the binder fraction components mentioned in any one of Claims 10 to 12;

(c) obtaining an extra-granular fraction using the extra-granular fraction components mentioned in any one of Claims 10 to 12,

25 and using those fractions to préparé a composition.
18. A composition obtainable by the process as defined in Claim 17.