Novel tuberculosis sterilization formulations

Abstract

The present invention relates to a solid composition comprising microparticles of a diarylquinoline, such as TBAJ-876, dispersed within a matrix comprising one or more excipients, the one or more excipients selected from: docusate sodium (AOT), hydroxypropylmethyl cellulose (HPMC), lactose, mannitol, polyethylene glycol (PEG), poloxomers, polyoxyethylene (80) sorbitan monooleate, polyvinyl alcohol (PVA), polyvinyl alcohol-polyethylene glycol (PVA-PEG) graft copolymers, polyvinylpyrrolidones (PVP), sodium deoxycholate (NDC), sucrose, and combinations thereof.

Description

[0001] Novel Tuberculosis Sterilization Formulations

[0002] This invention was made with U.S. Government support under grant number Al 161809, awarded by the U.S. National Institutes of Health. The U.S. Government has certain rights in the invention.

[0003] The present invention relates to chemical compositions. The invention relates, more particularly, but not exclusively, to chemical compositions for the treatment and prophylaxis of infections, and has particular (but not exclusive) application in the treatment and prophylaxis of bacterial infections, such as tuberculosis.

[0004] BACKGROUND

[0005] Tuberculosis is an infectious disease primarily affecting the lungs and is usually caused by the bacterium Mycobacterium tuberculosis. The majority of cases are of latent tuberculosis and those with such an infection are non-symptomatic and non-infectious. A minority of cases, especially prevalent in those who are immunosuppressed, go on to develop symptoms indicative of active tuberculosis. Accordingly, even though the latent infection provides little risk in itself, the fact that it may progress to active disease warrants treatment of affected individuals. M. tuberculosis is resistant to degradation by macrophages due to a thick capsule that helps protect them from reactive oxygen species within the phagolysosome. In addition, granulomas form which isolate the bacteria, causing them to become dormant, resulting in a latent infection.

[0006] Public health initiatives prioritise the use of vaccines to limit the risk and spread of tuberculosis. However, these vaccines are not fully effective across the population and their effectiveness wanes over time. Therefore, a number of treatment protocols have been developed to address active and latent tuberculosis, generally comprising the administration of antibiotics over an extended period of time. For example, treatment of latent tuberculosis (generally referred to as “tuberculosis prevention”) takes at least one month, and typically takes three to nine months. Treatment of active tuberculosis typically takes four to nine months, but can take as long as two years for highly drugresistant forms. Due to the lengths of these treatment protocols, it is relatively common for patient adherence to treatment to be adversely affected, leading to incomplete and less effective or ineffective treatment, an issue that may be more common in latent tuberculosis as the patient is not suffering ill effects from the infection itself at the time of treatment. Poor adherence to treatment for active tuberculosis can be compounded by development of antibiotic resistance. Accordingly, many protocols use combinations of antibiotics in addition to requiring continued dosing for extended periods.

[0007] Diarylquinolines are a relatively new class of antibiotic, with the most well-known member bedaquiline being found to be effective against multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis (Conradie F, Diacon AH, Ngubane N, Howell P, Everitt D, Crook AM, Mendel CM, Egizi E, Moreira J, Timm J, McHugh TD, Wills GH, Bateson A, Hunt R, Van Niekerk C, Li M, Olugbosi M, Spigelman M, Nix-TB Trial Team. Treatment of highly drug-resistant pulmonary tuberculosis. A / Engl J Med. 2020;382(10):893-902). Next-generation diarylquinolines, such as TBAJ-876 and TBAJ-587, show superior in vivo efficacy. Despite these improvements over current standards of treatment, it is expected that patient adherence over relatively long courses of treatment will still be required for complete treatment using diarylquinolines.

[0008] To increase patient adherence, and hence successful treatment of the infection, it would be desirable to provide formulations of these antibiotics that are more efficacious and / or less onerous for the patient. For example, alternative dosage forms and / or reduced dosage frequency.

[0009] SUMMARY OF THE INVENTION

[0010] A first aspect of the present invention relates to solid composition comprising microparticles of a diarylquinoline, such as TBAJ-876, dispersed within a matrix comprising one or more excipients, the one or more excipients selected from: docusate sodium (AOT), hydroxypropylmethyl cellulose (HPMC), lactose, mannitol, polyethylene glycol (PEG), poloxomers, polyoxyethylene (80) sorbitan monooleate, polyvinyl alcohol (PVA), polyvinyl alcohol-polyethylene glycol (PVA-PEG) graft copolymers, polyvinylpyrrolidones (PVP), sodium deoxycholate (NDC), sucrose, and combinations thereof.

[0011] The one or more excipient may comprise a first excipient and a second excipient selected from the following combinations:

[0012] - HPMC and AOT

[0013] HPMC and poloxomer

[0014] PVA-PEG copolymer and PVP

[0015] PVA-PEG copolymer and PEG

[0016] PVA-PEG copolymer and poloxomer

[0017] - PVP and HPMC

[0018] - PVP and PVP

[0019] PVP and PVA-PEG copolymer

[0020] - PVP and PEG

[0021] PVP and poloxomer

[0022] - PVP and PVA

[0023] PVP and mannitol

[0024] PVP and polyoxyethylene (80) sorbitan monooleate lactose and PVP mannitol and HPMC mannitol and NDC mannitol and PEG mannitol and poloxomer mannitol and PVP

[0025] - NDC and HPMC

[0026] NDC and poloxomer

[0027] - PEG and HPMC PEG and lactose

[0028] - PEG and PVP

[0029] PEG and poloxomer

[0030] PEG and PVA-PEG copolymer

[0031] - PEG and PEG

[0032] - PEG and PVA poloxomer and PVA-PEG copolymer poloxmer and NDC poloxomer and PEG poloxomer and PVP poloxomer and poloxomer poloxomer and PVA poloxomer and sucrose

[0033] - PVA and NDC

[0034] PVA and poloxomer sucrose and poloxomer.

[0035] Preferably, the first excipient and the second excipient are selected from the following combinations:

[0036] PVA-PEG copolymer and PVP PVP and PVA-PEG copolymer

[0037] - PVP and PVP

[0038] PVP and mannitol

[0039] PVP and poloxomer

[0040] - PVP and PEG

[0041] - PEG and HPMC

[0042] - PEG and PVP

[0043] PEG and poloxomer poloxomer and PVP

[0044] More preferably, the first excipient and the second excipient are selected from the following combinations:

[0045] PVP and PVA-PEG copolymer

[0046] - PVP and PVP

[0047] - PEG and PVP

[0048] The mass ratio of first to second excipient is from 1:1 to 4:1 , preferably from 2:1 to 3:1.

[0049] The one or more excipient may comprise from 20 to 60 wt% of the solid composition, preferably from 30 to 50 wt% of the solid composition. Alternatively or additionally, the diarylquinoline comprises from 40 to 80 wt% of the solid composition, preferably from 50 to 70 wt% of the solid composition.

[0050] The one or more excipient may be PVP. The PVP may comprise from 10 to 60 wt% of the solid composition, preferably from 20 to 50 wt% of the solid composition. Alternatively or additionally, the diarylquinoline comprises from 40 to 90 wt% of the solid composition, preferably from 50 to 80 wt% of the solid composition.

[0051] The microparticles of diarylquinoline may have a particle size of from 0.1 to 3 pm, preferably from 0.5 to 2.9 pm, further preferably from 1 to 2.8 pm; and / or a polydispersity of less than 0.5. preferably less than 0.4, more preferably less than 0.3.

[0052] A second aspect of the present invention relates to process for preparing a solid composition of the first aspect of the present invention, the process comprising:

[0053] (a) providing an active solution comprising the diarylquinoline in a water- miscible solvent;

[0054] (b) providing an excipient solution comprising one or more excipients as defined in the first aspect of the present invention;

[0055] (c) mixing the solutions prepared in steps (a) and (b); and

[0056] (d) removing the mixed solvent to produce the solid composition.

[0057] Removing the mixed solvent may comprise spray-drying or freeze-drying.

[0058] A third aspect of the present invention relates to an aqueous dispersion comprising a plurality of microparticles of a diarylquinoline, such as TBAJ-876, dispersed in an aqueous medium and stabilised by one or more excipients, , the one or more excipients selected from: docusate sodium (AOT), hydroxypropylmethyl cellulose (HPMC), lactose, mannitol, (NDC), polyethylene glycol (PEG), (poloxomers), polyoxyethylene (80) sorbitan monooleate, polyvinyl alcohol (PVA), polyvinyl alcoholpolyethylene glycol (PVA-PEG) graft copolymers, polyvinylpyrrolidones (PVP), sodium deoxycholate (NDC), sucrose, and combinations thereof.

[0059] The one or more excipients may be as defined in the first aspect of the present invention. The diarylquinoline may be present in a concentration of from 10 to 500 mg / mL, preferably from 25 to 400 mg / mL, more preferably from 50 to 200 mg / mL.

[0060] A fourth aspect of the present invention relates to a process for preparing an aqueous dispersion according to the third aspect of the present invention, the process comprising dispersing a solid composition according to the first aspect of the present invention in an aqueous medium.

[0061] A fifth aspect of the present invention relates to a pharmaceutical composition comprising the solid composition of the first aspect of the present invention, or the aqueous dispersion of the third aspect of the present invention and, optionally, one or more further pharmaceutically acceptable excipients.

[0062] A sixth aspect of the present invention relates to an injectable formulation comprising the solid composition of the first aspect of the present invention, the aqueous dispersion of the third aspect of the present invention, or the pharmaceutical composition of the fifth aspect of the present invention, optionally wherein the injectable formulation is a subcutaneously or intramuscularly injectable formulation, further optionally wherein the injectable formulation is suitable for provision in depot form.

[0063] A seventh aspect of the present invention relates to a solid composition of the first aspect of the present invention, an aqueous dispersion of the third aspect of the present invention, a pharmaceutical composition of the fifth aspect of the present invention, or an injectable formulation of the sixth aspect of the present invention, for use as a medicament.

[0064] An eighth aspect of the present invention relates to a solid composition of the first aspect of the present invention, an aqueous dispersion of the third aspect of the present invention, a pharmaceutical composition of the fifth aspect of the present invention, or an injectable formulation of the sixth aspect of the present invention, for use in the treatment and / or prevention of tuberculosis, such as latent tuberculosis or active tuberculosis.

[0065] A ninth aspect of the present invention relates to a method of treating tuberculosis, such as latent tuberculosis or active tuberculosis, the method comprising a therapeutically effective amount of a solid composition of the first aspect of the present invention, an aqueous dispersion of the third aspect of the present invention, a pharmaceutical composition of the fifth aspect of the present invention, or an injectable formulation of the sixth aspect of the present invention to a patient suffering from tuberculosis.

[0066] A tenth aspect of the present invention relates to the use of a solid composition of the first aspect of the present invention, an aqueous dispersion of the third aspect of the present invention, a pharmaceutical composition of the fifth aspect of the present invention, or an injectable formulation of the sixth aspect of the present invention for the manufacture of a medicament for the treatment of tuberculosis, such as latent tuberculosis or active tuberculosis.

[0067] BRIEF DESCRIPTION OF THE DRAWINGS

[0068] Fig. 1 summarises the combinations of excipients found to be ‘hits’ for 50 wt% loadings of TBAJ-876 in Example 1.

[0069] Fig. 2 summarises the combinations of excipients found to be hits for 70 wt% loadings of TBAJ-876 in Example 2.

[0070] Fig. 3 shows representative DLS traces for formulations of (a) TBAJ-87670 / Kollidon™ K12PF20 / Kollidon™ K17PF and (b) TBAJ-8767o / Kollidon™ K12PF2o / Kollidon™ K17PF produced by freeze drying in Example 2.

[0071] Fig. 4 shows representative DLS traces for formulations of (a) TBAJ-876so / Plasdone™ C1537.5 / PVPK30I2.5, (b) TBAJ-87650 / Plasdone™ C1537.5 / Kollicoat™ IRI25, (c) TBAJ- 8765o / PEG400037.5 / Plasdone™ C15I25, and (d) TBAJ-8765o / Kollidon™ K12PF375 / Kollidon™ K17PFI2.S produced by spray drying at a 500 mg batch size in Example 3. Fig. 5 shows representative DLS traces for formulations of (a) TBAJ-87650 / Plasdone™ C1537.5 / PVPK30i2.5, (b) TBAJ-87650 / Plasdone™ C1537.5 / Kollicoat™ IR12.5, (c) TBAJ- 8765o / PEG400037.5 / Plasdone™ C15I2.5, and (d) TBAJ-8765o / Kollidon™ K12PF375 / Kollidon™ KI7PF12.5 produced by spray drying at a 1000 mg batch size in Example 3.

[0072] Fig. 6 shows representative DLS traces for formulations of (a) TBAJ-87650 / Kollidon™ K12PF5O, (b) TBAJ-87650 / Plasdone™ C1550, and (c) TBAJ-8765o / Kollidon™ K17PF50in Example 4.

[0073] Fig. 7 shows representative DLS traces for formulations of (a) TBAJ-87670 / Kollidon™ K12PF30, (b) TBAJ-87670 / Plasdone™ C1530, and (c) TBAJ-8767o / Kollidon™ K17PF30in Example 4.

[0074] Fig. 8 shows representative DLS traces for formulations of (a) TBAJ-8768o / Kollidon™ KI2PF20, (b) TBAJ-87680 / Plasdone™ C1520, and (c) TBAJ-8768o / Kollidon™ K17PF20in Example 4.

[0075] Fig. 9 shows the median plasma concentration of TBAJ-876 in mice following intramuscular injection of aqueous dispersions of (a) TBAJ-8768o / Kollidon™ KI2PF20, (b) TBAJ-87680 / Plasdone™ C1520, and (c) TBAJ-87680 / Kollidon™ K17PF20formulations with TBAJ-876 concentrations of 100, 200, or 400 mg / mL in Example 5. The horizontal dashed line represents the target Cmin of 35 ng / mL.

[0076] Fig. 10A shows the median plasma concentration of TBAJ-876 in mice following intramuscular injection of aqueous dispersions of (a) TBAJ-8768o / Kollidon™ KI2PF20, (b) TBAJ-87680 / Plasdone™ C1520, and (c) TBAJ-87680 / Kollidon™ K17PF20formulations with a TBAJ-876 concentrations of 50 mg / mL in Example 6. The horizontal dashed line represents the target Cmin of 35 ng / mL.

[0077] Fig. 10B shows the median plasma concentration of TBAJ-876 in mice following intramuscular injection of aqueous dispersions of TBAJ-8768o / Plasdone™ C1520, formulations with TBAJ-876 concentrations of 25, 50, or 100 mg / mL in Example 6. The horizontal dashed line represents the target Cmin of 35 ng / mL.

[0078] Fig. 11 shows M. tuberculosis colony-forming unit (CFU) counts in the lungs of mice up to 8 weeks after the start of treatment in Example 6. Data points represent the mean and error bars represent the standard deviation. Solid lines represent TBAJ-876 formulations injected intramuscularly (Groups 1 to 5), dashed lines represent orally- dosed comparator regimens (Groups 6 to 9), and the black dotted line with square data points represents the untreated negative control group (Group 10).

[0079] Panel A of Fig. 11 shows a comparison between the injections of the three TBAJ-876 formulations dosed at 50 mg / mL (Groups 1 , 2, and 3) against the orally dosed TBAJ- 876 with the same overall dosage (Group 6), the orally dosed bedaquiline (Group 8), the orally dosed isoniazid and rifapentine (Group 9), and the negative control (Group 10).

[0080] Panel B of Fig. 11 shows comparison between the injections of the second TBAJ-876 formulation at varying doses (Groups 2, 4, and 5) against the orally dosed TBAJ-876 with the same overall dosage as Group 2 (Group 6), the orally dosed TBAJ-876 with the same overall dosage as Group 5 (Group 7) the orally dosed bedaquiline (Group 8), the orally dosed isoniazid and rifapentine (Group 9), and the negative control (Group 10).

[0081] DEFINITIONS

[0082] Unless otherwise stated, the term “particle size” is used herein to refer to the Z-average hydrodynamic diameter. Particle size and polydispersity may be assessed by any suitable technique known in the art (e.g. laser diffraction, laser scattering, electron microscopy). In an embodiment of the invention, particle diameter and polydispersity (i.e. Z-average hydrodynamic diameter) are assessed by dispersing the solid composition in an aqueous medium at a concentration of 1 mg / mL and determining the particle diameter using dynamic light scattering, e.g. using a Malvern Panalytical Ltd Zetasizer Advance Ultra.

[0083] In the context of the present invention, the term microparticle may be interpreted broadly to include particles with a particle size that is less than 5 pm, preferably less than 3 pm.

[0084] The term “diarylquinoline” refers to antibiotic drugs in the diarylquinoline family as well as pharmaceutically acceptable salts, solvates and derivatives thereof, prodrugs thereof, as well as any polymorphic or amorphous forms thereof. Diarylquinolines are described in detail in WO 2004 / 011436 A1 , incorporated herein by reference in its entirety, and have the general formulae:

[0085] Or: or the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the tautomeric forms thereof and the N-oxide forms thereof, wherein:

[0086] R1is hydrogen, halo, haloalkyl, cyano, hydroxy, Ar, Het, alkyl, alkyloxy, alkylthio, alkyloxyalkyl, alkylthioalkyl, Ar-alkyl or di(Ar)alkyl; p is an integer equal to zero, 1 , 2,3 or 4;

[0087] R2is hydrogen, hydroxy, thio, alkyloxy, alkyloxyalkyloxy, alkylthio, mono or di(alkyl)amino or a radical of formula wherein Y is CH2, O, S, NH or N- alkyl;

[0088] R3is alkyl, Ar, Ar-alkyl, Het or Het-alkyl; q is an integer equal to zero, 1 , 2,3 or 4;

[0089] R4and R5each independently are hydrogen, alkyl or benzyl; or

[0090] R4and R5together and including the N to which they are attached may form a radical selected from the group of pyrrolidinyl, 2H-pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolyl, imidazolidinyl, pyrazolidinyl, 2-imidazolinyl, 2-pyrazolinyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, piperazinyl, imidazolidinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, morpholinyl and thiomorpholinyl, optionally substituted with alkyl, halo, haloalkyl, hydroxy, alkyloxy, amino, mono-or dialkylamino, alkylthio, alkyloxyalkyl, alkylthioalkyl and pyrimidinyl;

[0091] R6is hydrogen, halo, haloalkyl, hydroxy, Ar, alkyl, alkyloxy, alkylthio, alkyloxyalkyl, alkylthioalkyl, Ar-alkyl or di (Ar)alkyl; or two vicinal R6radicals may be taken together to form a bivalent radical of formula =C- C=C=C- ; r is an integer equal to 0, 1, 2,3, 4 or 5; and

[0092] R7is hydrogen, alkyl, Ar or Het;

[0093] R8is hydrogen or alkyl ;

[0094] R9is oxo; or

[0095] R8and R9together form the radical =N-CH=CH-. alkyl is a straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms; or is a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms; or is a a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms attached to a straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms; wherein each carbon atom can be optionally substituted with halo, hydroxy, alkyloxy or oxo;

[0096] Ar is a homocycle selected from the group of phenyl, naphthyl, acenaphthyl, tetrahydronaphthyl, each optionally substituted with 1 , 2 or 3 substituents, each substituent independently selected from the group of hydroxy, halo, cyano, nitro, amino, mono-or dialkylamino, alkyl, haloalkyl, alkyloxy, haloalkyloxy, carboxyl, alkyloxycarbonyl, aminocarbonyl, morpholinyl and mono-or dialkylaminocarbonyl ;

[0097] Het is a monocyclic heterocycle selected from the group of N-phenoxypiperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl; or a bicyclic heterocycle selected from the group of quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2,3- dihydrobenzo[1,4]dioxinyl or benzo[1,3]dioxolyl; each monocyclic and bicyclic heterocycle may optionally be substituted on a carbon atom with 1 , 2 or 3 substituents selected from the group of halo, hydroxy, alkyl or alkyloxy ; halo is a substituent selected from the group of fluoro, chloro, bromo and iodo and haloalkyl is a straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms or a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms, wherein one or more carbon atoms are substituted with one or more haloatoms.

[0098] Particular diarylquinolines are bedaquiline, TBAJ-587, and TBAJ-876. These drugs are typically poorly soluble in water.

[0099] Bedaquiline ((1 R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2- (naphthalen-1-yl)-1-phenylbutan-2-ol) has the following chemical structure:

[0100] TBAJ-587 ((1S,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)- 4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)butan-2-ol) has the following chemical structure:

[0101] TBAJ-876 ((1 R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)- 4-(dimethylamino)-1-(2,3,6-trimethoxypyridin-4-yl)butan-2-ol) has the following chemical structure:

[0102] Unless otherwise stated, the term “patient” includes both human patients and animal patients.

[0103] The term “other drugs” is used herein to refer to the following (non-exhaustive) list of other drugs that may be used in combination with the diarylquinoline indicated herein and formulated in accordance with the invention in a combination prophylactic and / or treatment therapy: ethambutol, isoniazid, pyrazinamide, streptomycin, aminoglycosides (e.g. amikacin, kanamycin), polypeptides (e.g. capreomycin, viomycin, enviomycin), fluoroquinolones (e.g. ciprofloxacin, levofloxacin, moxifloxacin), thioamides (e.g. ethionamide, prothionamide), cycloserine, terizidone, macrolides (e.g. clarithromycin, azithromycin), oxazolidinones (e.g. linezolid), clofazimine, thioacetazone, thioridazine, arginine, vitamin D, other diarylquinolines (e.g. bedaquiline, TBAJ-587, and TBAJ-876), rifamycins (e.g. rifamycin SV, rifampicin, rifabutin, rifapentine, rifalazil, and rifaximin), pretomanid, delamanid, as well as pharmaceutically acceptable salts, solvates and derivatives thereof, prodrugs thereof, and any polymorphic or amorphous forms thereof.

[0104] It is to be appreciated that references to “preventing” or “prevention” relate to prophylactic treatment and includes preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a patient that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition. It will be further appreciated that references to “treatment” or “treating” of a state, disorder or condition includes: (1) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof; or (2) relieving or attenuating the disease, i.e. causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

[0105] In the context of the invention, the terms “preventing” or “prevention” should not be considered to refer only to medicaments which are completely effective in treating a specific state, disorder or condition, but also to cover medicaments which are partially effective as well.

[0106] Moreover, when considered from the perspective of a population of patients for treatment, the terms “preventing” and “prevention” should be considered to cover medicaments which are useful at reducing the rate of incidence of a target disorder or condition (e.g. tuberculosis) in that target population, as well as medicaments which are useful at completely eradicating a target state, disorder or condition from that target population.

[0107] A “therapeutically effective amount” means the amount of a compound that, when administered to a patient for treating and / or preventing a disease, is sufficient to effect such treatment / prevention for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, etc., of the patient to be treated.

[0108] The term “consisting essentially of” is used herein to denote that a given product or method consists of only designated materials or steps and optionally other materials or steps that do not materially affect the characteristic(s) of the claimed invention. Suitably, a product which consists essentially of a designated material (or materials) comprises greater than or equal to 85% of the designated material, more suitably greater than or equal to 90%, more suitably greater than or equal to 95%, most suitably greater than or equal to 98% of the designated material(s).

[0109] Unless otherwise stated, the weight percentages (“wt%”) discussed herein relate to the % by weight of a particular constituent as a proportion of the total weight of the composition.

[0110] Unless otherwise stated, the term w / v% discussed herein relate to grams of solute in 100 mL of solvent (e.g. 10 w / v% is 10 g of solute in 100 mL of solvent).

[0111] Syringeability is a measure of whether a solution, dispersion, or suspension is suitable for administration via injection. A composition is considered to be syringeable if it can be manually passed through a 25G needle. It will be understood that the combination of the composition and 25G needle is purely to establish that a given composition is syringeable and that the compositions may be used in combination with needles of a lower gauge in practice. As is known in the art, 25G refers to a 25 gauge needle (i.e. a needle with an internal diameter of 0.26 mm and an external diameter of 0.514 mm).

[0112] DETAILED DESCRIPTION

[0113] Solid Compositions

[0114] The first aspect of the present invention relates to a solid composition comprising microparticles of a diarylquinoline, such as TBAJ-876, dispersed within a matrix comprising one or more excipients, the one or more excipients selected from: docusate sodium (AOT), hydroxypropylmethyl cellulose (HPMC), lactose, mannitol, polyethylene glycol (PEG), poloxomers, polyoxyethylene (80) sorbitan monooleate, polyvinyl alcohol (PVA), polyvinyl alcohol-polyethylene glycol (PVA-PEG) graft copolymers, polyvinylpyrrolidones (PVP), sodium deoxycholate (NDC), sucrose, and combinations thereof.

[0115] The diarylquinoline that comprises the microparticles may be amorphous (i.e. substantially non-crystalline in nature).

[0116] The solid excipient mixture is in the form of a matrix. In embodiments, the matrix is highly porous in nature and rapidly dissolves on contact with aqueous solutions. In alternative embodiments, the matrix is relatively dense, but still susceptible to dissolution on contact with aqueous solutions.

[0117] The solid composition of the present invention may be administered as it is to a patient, or further formulated to provide a pharmaceutical composition in the form of, for example, a tablet, capsule, lozenge, or a dispersible powder or granule formulation.

[0118] The microparticles of the diarylquinoline may have an average particle size of less than 5 pm, preferably less than 3 pm. In a particular embodiment, the microparticles have a particle size of from 0.1 to 3 pm, preferably from 0.5 to 2.9 pm, further preferably from 1 to 2.8 pm.

[0119] The microparticles of the diarylquinoline may have a polydispersity of less than 0.5. preferably of less than 0.4, more preferably of less than 0.3.

[0120] The particle diameter and polydispersity of the microparticles may be assessed by any suitable technique known in the art (e.g. laser diffraction, laser scattering, electron microscopy). In an embodiment of the invention, particle diameter and polydispersity (i.e. Z-average hydrodynamic diameter) are assessed by dispersing the solid composition in an aqueous medium at a concentration of 1 mg / mL and determining the particle diameter using dynamic light scattering, e.g. using a Malvern Panalytical Ltd Zetasizer Advance Ultra.

[0121] The solid composition may comprise particles or granules of larger size, for example, 5 to 30 microns (pm) in size, but each particle or granule may contain a plurality of microparticles of the diarylquinoline dispersed within a mixture of the first and second excipient. Alternatively, the solid composition may comprise a larger monolith, of any suitable shape or dimension. Furthermore, these monoliths, larger particles or granules disperse when the solid composition is mixed with an aqueous medium to form discrete microparticles of the diarylquinoline.

[0122] In an embodiment, the solid composition consists essentially of the diarylquinoline and the one or more excipients as described herein. In a further embodiment, the solid composition consists of the diarylquinoline and the one or more excipients as described herein.

[0123] Diarylquinoline

[0124] Diarylquinolines refer to a class of antibiotic drugs and are described in WO 2004011436 A1, incorporated herein by reference, and defined herein. Any suitable diarylquinoline or combination of diarylquinolines may be used in the present invention. Preferred diarylquinolines have the formula:

[0125] Wherein each of Ar1and Ar2are selected from Ar and Het, wherein:

[0126] Ar is a homocycle selected from the group of phenyl, such as phenyl or 2-fluoro-3- methoxybenzene, naphthyl, such as 2-naphthyl, acenaphthyl, tetrahydronaphthyl, each optionally substituted with 1, 2, or 3 substituents, each substituent independently selected from the group of hydroxy, halo, cyano, nitro, amino, mono-or dialkylamino, alkyl, haloalkyl, alkyloxy, haloalkyloxy, carboxyl, alkyloxycarbonyl, aminocarbonyl, morpholinyl and mono-or dialkylaminocarbonyl ;

[0127] Het is a monocyclic heterocycle selected from the group of N-phenoxypiperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, such as 4-(2,6-dimethoxypyridinyl) or 4-(2,3,6-trimethoxypyridyl), pyrimidinyl, pyrazinyl and pyridazinyl; or a bicyclic heterocycle selected from the group of quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2,3- dihydrobenzo[1,4]dioxinyl or benzo[1 ,3]dioxolyl; each monocyclic and bicyclic heterocycle may optionally be substituted on a carbon atom with 1, 2 or 3 substituents selected from the group of halo, hydroxy, alkyl or alkyloxy ; halo is a substituent selected from the group of fluoro, chloro, bromo and iodo and haloalkyl is a straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms or a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms, wherein one or more carbon atoms are substituted with one or more halo-atoms More preferably the diarylquinoline is selected from bedaquiline, TBAJ-587, TBAJ-876, and combinations thereof. Most preferably, the diarylquinoline is TBAJ-876.

[0128] Excipients

[0129] The one or more excipients may be selected from docusate sodium (AOT); hydroxypropylmethyl cellulose (HPMC); lactose, mannitol, polyethylene glycol (PEG), poloxamers, polyoxyethylene (80) sorbitan monooleate, polyvinyl alcohol (PVA), polyvinyl alcohol-polyethylene glycol (PVA-PEG) graft copolymers, polyvinylpyrrolidones (PVP), sodium deoxycholate (NDC), sucrose, and combinations thereof. The skilled person will understand that further excipients may be suitable for the purposes of the present invention. For example, the skilled person will understand that, in principle, any hydrophilic polymer, hydrophilic surfactant, or sugar suitable for use in pharmaceutical formulations may be employed in the present invention

[0130] HPMC is a water-soluble semi-synthetic polymer widely used in pharmaceutical formulations. The HPMC may have a number average molecular weight from 1000 to 20000 g / mol, preferably from 5000 to 15000 g / mol, such as about 10000 g / mol.

[0131] PEG is a polyether containing repeat units of ethylene oxide. PEG may occur in linear, branched, comb, or star forms. Preferably, the PEG is a linear PEG. The PEG may have a number average molecular weight of 100 to 20000 g / mol, preferably 500 to 10000 g / mol, more preferably 800 to 8000 g / mol, most preferably from 1000 about 4000 g / mol, such as about 1000 g / mol or about 4000 g / mol. In embodiments, the PEG may have a number average molecular weight of from 500 to 3500 g / mol, preferably from 700 to 2000 g / mol, such as about 1000 g / mol. Alternatively, the PEG may have a number average molecular weight of from 2000 g / mol to 10000 g / mol, such as from 3000 to 8000 g / mol, such as about 4000 g / mol.

[0132] Poloxomers are non-ionic triblock copolymers composed of a central hydrophobic chain of polyoxypropylene (polypropylene oxide)) flanked by two hydrophilic chains of polyoxyethylene (poly(ethylene oxide)), which are also known as poloxamers (such as those available in the Synperionics™, Pluronic™ and Kolliphor™ ranges, including Pluronic™ F68 and Pluronic™ F127). A “poloxamer” is typically named with the letter “P” followed by three numerical digits (e.g. P407), where the first two digits multiplied by 100 gives the approximate molecular mass of the polyoxypropylene chain, and the third digit multiplied by 10 provides the percentage polyoxyethylene content of the poloxamer. For example, P407 is a poloxamer having a polyoxypropylene molecular mass of about 4,000 g / mol and a polyoxyethylene content of about 70%, while P188 is a poloxamer having a polyoxypropylene molecular mass of about 1,800 g / mol and a polyoxyethylene content of about 80%. Poloxamers are also known as Pluronics®, as well as by several other commercial names. The poloxamer is suitably a pharmaceutically acceptable poloxamer. In a particular embodiment, the poloxamer is P407 or P188. PVA is a water-soluble polymer typically produced by the hydrolysis of polyvinyl acetate. In embodiments, the PVA has a weight average molecular weight of from 1 ,000 to 20,000 g / mol, preferably from 5,000 to 15,000 g / mol, more preferably from 8,000 to 12,000 g / mol, such as from 9,000 to 10,000 g / mol. The PVA may have a degree of hydrolysis from 50 to 100 %, preferably from 60 to 90%, such as about 80 %.

[0133] PVA-PEG graft copolymers are widely used in food and pharmaceutical applications due to their high water-solubility and low viscosity in aqueous solution. They have a PEG backbone with pendant PVA chains, typically in a ratio of about 1 :1 to 1 :5, such as about 1 :3. The viscosity of a 20% solution may be from 100 to 130 mPas, such as about 115 mPas, when determined according to EN ISO 2555:2018 at 23°C and a shear rate of 100 rpm.

[0134] PVP is a water soluble-polymer available from a range of sources (including PVP k30, such as is available as Kollidon™ 30, PVP k17, such as is available as Kollidon™ 17PF, PVP k15, such as is available as Plasdone™ C-15, and PVP k12, such as is available as Kollidon™ 12PF). In embodiments, the polyvinylpyrrolidone has a weight average molecular weight of 1000 to 1 ,000,000 g / mol. In a particular embodiment, the polyvinylpyrrolidone has a weight average molecular weight of 1000 to 40000 g / mol, preferably 2000 to 20000 g / mol. In embodiments, the polyvinylpyrrolidone has a K value between 5 and 40, preferably between 7 and 30, more preferably from 10 to 20, most preferably between 12 and 17. Alternatively, the K value may be from about 5 to about 14, such as about 12. Further alternatively, the K value may be from about 13 to about 16, such as about 15. Yet further alternatively, the K value may be from about 16 to about 20, such as about 17. As is known in the art, K value is derived from relative viscosity measurements and calculated according to Fikentscher’s equation.

[0135] In embodiments, the excipient is a combination of two excipients selected from docusate sodium (AOT), hydroxypropylmethyl cellulose (HPMC), lactose, mannitol, polyethylene glycol (PEG), poloxamers, polyoxyethylene (80) sorbitan monooleate, polyvinyl alcohol (PVA), polyvinyl alcohol-polyethylene glycol (PVA-PEG) graft copolymers, polyvinylpyrrolidones (PVP), sodium deoxycholate (NDC), and sucrose.

[0136] In embodiments, the one or more excipient comprises a combination of a first excipient and a second excipient selected from:

[0137] - HPMC and AOT;

[0138] HPMC and poloxomer. Preferably the poloxomer is P407;

[0139] PVA-PEG copolymer and PVP. Preferably, the PVP has a K value of from about 5 to about 14, such as about 12;

[0140] PVA-PEG copolymer and PEG. Preferably, the PEG has a number average molecular weight from 500 to 3500 g / mol, more preferably from 700 to 2000 g / mol, such as about 1000 g / mol;

[0141] PVA-PEG copolymer and poloxomer. Preferably the poloxomer is P188 or P407; PVP and HPMC. Preferably the PVP having a K value between 5 and 40, preferably between 7 and 30, more preferably from 10 to 20;

[0142] PVP and PVP, wherein each of the PVPs may be the same or different. Preferably, the first excipient is a PVP with a K value of from 5 to 14, such as about 12, and the second excipient is a PVP with a K value of from 16 to 20, such as about 17, or the first excipient is a PVP with a K value of from 13 to 20, such as about 15 or about 17, and the second excipient is a PVP with a K value of from 20 to 40, such as about 30;

[0143] PVP and PVA-PEG copolymer. Preferably the PVP having a K value of from 13 to 16, such as about 15;

[0144] PVP and PEG. Preferably the PVP has a K value of from 13 to 16 and the PEG has a molecular weight of from 100 to 20000 g / mol, preferably 400 to 10000 g / mol, or the PVP has a K value between 5 and 40, preferably between 7 and 30, more preferably from 10 to 20, and the PEG has a molecular weight of from 500 to 3500 g / mol, preferably from 700 to 2000 g / mol, such as about 1000 g / mol, or the PVP has a K value of from 20 to 40, such as about 30, or a K value of from 5 to 16, such as about 12 or about 15, and the PEG has a number average molecular weight of from 2000 g / mol to 10000 g / mol, more preferably from 3000 to 8000 g / mol, such as about 4000 g / mol;

[0145] PVP and poloxomer. Preferably the poloxomer is P407 and the PVP has a K value between 5 and 40, preferably between 7 and 30, more preferably from 10 to 20, or the poloxomer is P188 and the PVP has a K value of from 5 to 16, such as about 12 or about 15;

[0146] PVP and PVA. Preferably the PVP having a K value between 5 and 40, preferably between 7 and 30, more preferably from 10 to 20;

[0147] PVP and mannitol. Preferably, the PVP has a K value of from about 5 to about 14, such as about 12;

[0148] PVP and polyoxyethylene (80) sorbitan monooleate. Preferably the PVP has a K value of from 13 to 16, such as about 15; lactose and PVP. Preferably, the PVP has a K value of from 20 to 40, such as about 30; mannitol and HPMC; mannitol and NDC; mannitol and PEG. Preferably, the PEG has a number average molecular weight from 500 to 3500 g / mol, more preferably from 700 to 2000 g / mol, such as about 1000 g / mol; mannitol and poloxomer. Preferably the poloxomer is P188 or P407; mannitol and PVP. Preferably, the PVP has a K value of from 20 to 40, such as about 30;

[0149] - NDC and HPMC;

[0150] NDC and poloxomer. Preferably the poloxomer is P407;

[0151] PEG and HPMC. Preferably the PEG has a number average molecular weight from 500 to 10000 g / mol, more preferably 800 to 8000 g / mol, most preferably from 1000 about 4000 g / mol, such as about 1000 g / mol or about 4000 g / mol; PEG and lactose. Preferably, the PEG has a number average molecular weight from 500 to 3500 g / mol, more preferably from 700 to 2000 g / mol, such as about 1000 g / mol;

[0152] PEG and PVP. Preferably the PEG has a number average molecular weight of from 2000 g / mol to 10000 g / mol, more preferably from 3000 to 8000 g / mol, such as about 4000 g / mol, and the PVP has a K value of from 20 to 40, such as about 30, or the PEG has a number average molecular weight from 500 to 10000 g / mol, more preferably 800 to 8000 g / mol, most preferably from 1000 about 4000 g / mol, such as about 1000 g / mol or about 4000 g / mol, and the PVP has a K value of from 13 to 16, such as about 15;

[0153] PEG and poloxomer. Preferably the poloxomer is P188 or P407 and the PEG has a number average molecular weight from 500 to 10000 g / mol, more preferably 800 to 8000 g / mol, most preferably from 1000 about 4000 g / mol, such as about 1000 g / mol or about 4000 g / mol;

[0154] PEG and PVA-PEG copolymer. Preferably the PEG has a number average molecular weight of from 2000 g / mol to 10000 g / mol, such as from 3000 to 8000 g / mol, such as about 4000 g / mol;

[0155] PEG and PEG, wherein each of the PEGs may be the same PEG, or different PEGs with a number average molecular weight from 500 to 10000 g / mol, more preferably 800 to 8000 g / mol, most preferably from 1000 about 4000 g / mol, such as about 1000 g / mol or about 4000 g / mol. Preferably, the first excipient is a PEG with a number average molecular weight of from 2000 g / mol to 10000 g / mol, more preferably from 3000 to 8000 g / mol, such as about 4000 g / mol, and the second excipient is a PEG with a number average molecular weight of from 500 to 3500 g / mol, preferably from 700 to 2000 g / mol, such as about 1000 g / mol;

[0156] PEG and PVA. Preferably the PEG has a number average molecular weight of from 2000 g / mol to 10000 g / mol, such as from 3000 to 8000 g / mol, such as about 4000 g / mol; poloxomer and PVA-PEG copolymer. Preferably the poloxomer is P188; poloxmer and NDC. Preferably the poloxomer is P188; poloxomer and PEG. Preferably the poloxomer is P188 and the PEG has a number average molecular weight of from 500 to 3500 g / mol, preferably from 700 to 2000 g / mol, such as about 1000 g / mol; poloxomer and PVP. Preferably the poloxomer is P188 and the PVP has a K value of from 20 to 40, such as about 30, or a K value of from 13 to 16, such as about 15; poloxomer and poloxomer, wherein each of the poloxomers may be the same poloxomer, or a different poloxomer. For example, each of the first excipient and second excipient is P407, each of the first excipient and second excipient is P188, the first excipient is P407 and the second excipient is P188, or the first excipient is P188 and the second excipient is P407. Preferably, the first excipient is P407 and the second excipient is P188, or the first excipient is P188 and the second excipient is P407; poloxomer and PVA. Preferably the poloxomer is P188 or P407; poloxomer and sucrose. Preferably the poloxomer is P188;

[0157] - PVA and NDC

[0158] PVA and poloxomer. Preferably the poloxomer is P188; sucrose and poloxomer. Preferably the poloxomer is P188.

[0159] In preferred embodiments, the one or more excipient comprises a combination of a first excipient and a second excipient selected from:

[0160] PVA-PEG copolymer and PVP. Preferably, the PVP has a K value of from about 5 to about 14, such as about 12;

[0161] PVP and PVA-PEG copolymer. Preferably the PVP having a K value of from 13 to 16, such as about 15;

[0162] PVP and PVP. Preferably, the first excipient is a PVP with a K value of from 5 to 14, such as about 12, and the second excipient is a PVP with a K value of from 16 to 20, such as about 17, or the first excipient is a PVP with a K value of from 13 to 16, such as about 15, and the second excipient is a PVP with a K value of from 20 to 40, such as about 30;

[0163] PVP and mannitol. Preferably, the PVP has a K value of from about 5 to about 14, such as about 12;

[0164] PVP and poloxomer. Preferably the poloxomer is P407 and the PVP has a K value of from 7 to 30, more preferably from 10 to 20 most preferably between 12 and 17, for example, the K value may be about 12, about

[0165] 15, or about 17;

[0166] PVP and PEG. Preferably the PVP has a K value of from 20 to 40, such as about 30, or a K value of from 5 to 16, such as about 12 or about 15, and the PEG has a number average molecular weight of from 2000 g / mol to 10000 g / mol, more preferably from 3000 to 8000 g / mol, such as about 4000 g / mol;

[0167] PEG and HPMC. Preferably, the PEG has a number average molecular weight from 500 to 3500 g / mol, more preferably from 700 to 2000 g / mol, such as about 1000 g / mol;

[0168] PEG and PVP. Preferably the PEG has a number average molecular weight of from 2000 g / mol to 10000 g / mol, more preferably from 3000 to 8000 g / mol, such as about 4000 g / mol, and the PVP has a K value of from 20 to 40, such as about 30, or the PEG has a number average molecular weight from 500 to 10000 g / mol, more preferably 800 to 8000 g / mol, most preferably from 1000 about 4000 g / mol, such as about 1000 g / mol or about 4000 g / mol, and the PVP has a K value of from 13 to 16, such as about 15;

[0169] PEG and poloxomer. Preferably the poloxomer is P188 or P407 and the PEG has a number average molecular weight from 500 to 10000 g / mol, more preferably 800 to 8000 g / mol, most preferably from 1000 about 4000 g / mol, such as about 1000 g / mol or about 4000 g / mol; poloxomer and PVP. Preferably the poloxomer is P188 and the PVP has a K value of from 20 to 40, such as about 30, or a K value of from 13 to

[0170] 16, such as about 15. In further preferred embodiments, the one or more excipient comprises a combination of a first excipient and a second excipient selected from:

[0171] PVP and PVA-PEG copolymer. Preferably the PVP having a K value of from 13 to 16, such as about 15;

[0172] PVP and PVP. Preferably, the first excipient is a PVP with a K value of from 5 to 14, such as about 12, and the second excipient is a PVP with a K value of from 16 to 20, such as about 17, or the first excipient is a PVP with a K value of from 13 to 16, such as about 15, and the second excipient is a PVP with a K value of from 20 to 40, such as about 30;

[0173] PEG and PVP. Preferably the PEG has a number average molecular weight of from 2000 g / mol to 10000 g / mol, more preferably from 3000 to 8000 g / mol, such as about 4000 g / mol, and the PVP has a K value of from 13 to 16, such as about 15.

[0174] In the foregoing embodiments comprising the first excipient and second excipient combinations, the mass ratio of first to second excipient may be from 1:1 to 4:1, preferably from 2:1 to 3: 1 , such as about 3: 1.

[0175] In the foregoing embodiments comprising the first excipient and second excipient combinations, the first excipient and second excipient combined may comprise from 10 to 70 wt% of the solid composition, preferably from 20 to 60 wt% of the solid composition, more preferably from 30 to 50 wt% of the solid composition, such as about 30 wt% or about 50 wt%. The first excipient may comprise from 5 to 50 wt% of the solid composition, preferably from 10 to 40 wt% of the solid composition, more preferably from 20 to 37.5 wt% of the solid composition, such as about 20 wt% or about 37.5 wt%. The second excipient may comprise from 1 to 30 wt% of the solid composition, preferably from 5 to 20 wt% of the solid composition, more preferably from 10 to 12.5 wt% of the solid composition, such as about 10 or about 12.5 wt%.

[0176] In the foregoing embodiments comprising the first excipient and second excipient combinations, the diarylquinoline may comprise from 30 to 90 wt% of the solid composition, preferably from 40 to 80 wt% of the solid composition, most preferably from 50 to 70 wt% of the solid composition, such as about 50 wt% or about 70 wt%.

[0177] In the foregoing embodiments comprising the first excipient and second excipient combinations, the solid composition may comprise from 30 to 90 wt% of the diarylquinoline, from 5 to 50 wt% of the first excipient, and from 1 to 30 wt% of the second excipient, preferably the solid composition comprises from 40 to 80 wt% of the diarylquinoline, from 10 to 40 wt% of the first excipient, and from 5 to 20 wt% of the second excipient, more preferably the solid composition comprises from 50 to 70 wt% of the diarylquinoline, from 20 to 37.5 wt% of the first excipient and from 10 to 12.5 wt% of the second excipient. Particularly preferred solid compositions comprise 50 wt% of the diarylquinoline, 37.5 wt% of the first excipient, and 12.5 wt% of the second excipient, or 70 wt% of the diarylquinoline, 20 wt% of the first excipient, and 10 wt% of the second excipient. In a particular embodiment, the one or more excipient is PVP. The PVP may have a K value from 5 to 40, preferably from 7 to 30, more preferably from 10 to 20 most preferably between 12 and 17, for example, the K value may be about 12, about 15, or about 17.

[0178] In the foregoing embodiments wherein the one or more excipient is PVP, the diarylquinoline may comprise from 40 to 90 wt% of the solid composition, preferably from 50 to 80 wt% of the solid composition.

[0179] In the foregoing embodiments wherein the one or more excipient is PVP, the PVP may comprise from 10 to 60 wt% of the solid composition, preferably from 20 to 50 wt% of the solid composition.

[0180] In the foregoing embodiments wherein the one or more excipient is PVP, the solid composition may comprise from 40 to 90 wt% diarylquinoline and 10 to 60 wt% PVP, preferably the solid composition comprises from 50 to 80 wt% diarylquinoline and from 20 to 50 wt% PVP, such as 50 wt% diarylquinoline and 50 wt% PVP, 70 wt% diarylquinoline and 30 wt% PVP, or 80 wt% diarylquinoline and 20 wt% PVP.

[0181] Processes for Preparing Solid Compositions

[0182] Solid compositions of the present invention may be prepared by a number of methods well known in the art, including ‘top-down’ physical methods such as nano (or bead) milling and high-pressure homogenisation. Other suitable techniques for forming such compositions are described in general terms in Horn and Reiger, Angew. Chem. Int. Ed., 2001, 40, 4330-4361. For example, emulsion-templated freeze-drying, emulsion- templated spray-drying, and nanoprecipitation can each be effective techniques for forming such compositions, as is described in Zhang et al, Nature Nano., 2008, 3, 506- 511 ; Giardiello et al, Nature Communications 2016, 7, 13184; Bakshi et al, Nature Communications, 2018, 9, 315; Savage et al European Journal of Pharmaceutics and Biopharmaceutics, 2018, S0939-6411(18)30165-6; Hobson et al, Nature

[0183] Communications 2019, 10, 1413; and Hobson et al, Nanoscale, 2021, 13, 6410 - 6416.

[0184] In general terms, the process for preparing the solid compositions described herein comprises the steps of:

[0185] (a) providing an active solution comprising the diarylquinoline in a water- miscible solvent;

[0186] (b) providing an excipient solution comprising one or more excipients as defined herein;

[0187] (c) mixing the solutions prepared in steps (a) and (b); and

[0188] (d) removing the mixed solvent to produce the solid composition.

[0189] Substantially any water-miscible solvent, or combination or solvents, may be used. Suitable solvents may be selected from those described as Class 2 (such as acetonitrile, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1 ,4-dioxane, 2-ethoxyethanol, ethyleneglycol, formamide, methanol, 2-methoxyethanol, N-methylpyrrolidone, pyridine, sulfolane, t-butyl alcohol, tetra hydrofuran) or Class 3 (such as acetic acid, acetone, 1 -butanol, 2-butanol, dimethyl sulfoxide, ethanol, formic acid, 3-methyl-1 -butanol, 2-methyl-1 -propanol, 1 -pentanol, 1 -propanol, 2-propanol, and trimethylamine) in the ICH Q3C Guidelines, preferably being drawn from those described as Class 3. Suitable solvents may be selected from alcohols (such as methanol, ethanol, 1 -propanol, 2-propanol, 1 -butanol, 2-butanol, and isobutanol), ketones (such as acetone, butanone, 2-pentanone, 3-pentanone, and 3-Methyl-2- butanone), and mixtures thereof. Preferred solvents include methanol, acetone, and combinations thereof. A particularly preferred solvent is a mixture of methanol and acetone, in volume ratios of from 4:1 to 1 :4, preferably from 3:1 to 1 :3, more preferably from 2:1 to 1 :2, such as about 1 :1.

[0190] On mixing the solutions prepared in steps (a) and (b), the mixture may remain a singlephase solution. Alternatively, at least a portion of the diarylquinoline and / or the one or more excipients precipitates.

[0191] Removing the mixed solvent may be achieved by freeze-drying or spray-drying. It is preferred that the solid compositions of the foregoing embodiments comprising the first excipient and second excipient combinations are formed by freeze-drying. It is also preferred that the solid compositions of the foregoing embodiments wherein the one or more excipients is PVP are formed by spray-drying.

[0192] The mixed solvent may be from 5 to 40% organic solvent by volume, preferably from 10 to 30% organic solvent by volume, such as about 20% organic solvent by volume.

[0193] The mixed solvent may have a solids content of from 1 to 10 w / v%, preferably from 2 to 8 w / v%. For spray drying applications, it is particularly preferred that the mixed solvent has a solids content of from 3 to 5 w / v%, such as about 4 w / v%. For freeze-drying applications, it is particularly preferred that the mixed solvent has a solids content of from 1 to 5 w / v%, such as from 2 to 4 w / v%, such as about 2 w / v%.

[0194] Aqueous Dispersions

[0195] The present invention also provides an aqueous dispersion, obtainable by, obtained by, or directly obtained by dispersing the solid composition as defined herein in an aqueous medium.

[0196] When the solid composition is dispersed in the aqueous medium, the one or more excipients are dissolved within the aqueous medium to release the microparticles of the diarylquinoline in a dispersed form. The microparticles of the diarylquinoline, which were formerly dispersed within a solid mixture of the one or more excipients, then becomes dispersed within the aqueous medium and are stabilized by the one or more excipients, thereby preventing premature coagulation and aggregation.

[0197] In a particular embodiment, the aqueous medium comprises 20 to 99.5 wt% of the total aqueous dispersion. In a particular embodiment, the aqueous medium comprises 50 to 98 wt% of the total aqueous dispersion. In a particular embodiment, the aqueous medium comprises 70 to 95 wt% of the total aqueous dispersion. Suitably, the remaining proportion of the aqueous dispersion consists essentially of the diarylquinoline and one or more excipient, whose proportions within the aqueous dispersion as a whole are accordingly calculated (and scaled) by reference to the proportions recited in relation to the solid composition.

[0198] For aqueous dispersions of microparticles of the diarylquinoline, the concentration of the diarylquinoline may be at least 100 mg / mL, preferably at least 200 mg / mL, more preferably at least 300 mg / mL, and most preferably at least 400 mg / mL. Alternatively, the concentration of the diarylquinoline may be 100 to 1000 mg / mL, preferably 150 to 800 mg / mL, more preferably 200 to 600 mg / mL, yet more preferably 250 to 500 mg / mL and most preferably 300 to 400 mg / mL, such as about 400 mg / mL.

[0199] In a particular embodiment, the aqueous medium is water. In an alternative embodiment, the aqueous medium comprises water and one or more additional pharmaceutically acceptable diluents or excipients. In particular embodiments, the aqueous medium comprises saline or a phosphate buffered saline (PBS).

[0200] The microparticles of the diarylquinoline may have an average particle size of less than 5 pm, preferably less than 3 pm. In a particular embodiment, the microparticles have a particle size of from 0.1 to 3 pm, preferably from 0.5 to 2.9 pm, further preferably from 1 to 2.8 pm.

[0201] The microparticles of the diarylquinoline may have a polydispersity of less than 0.5. preferably less than 0.4, more preferably less than 0.3.

[0202] Process for preparing an aqueous dispersion

[0203] The present invention provides a process for preparing an aqueous dispersion, the process comprising dispersing a solid composition as defined herein in an aqueous medium.

[0204] In a particular embodiment, the aqueous medium is water. In an alternative embodiment, the aqueous medium comprises water and one or more additional excipients. In particular embodiments, the aqueous medium comprises saline or a phosphate buffered saline (PBS).

[0205] Dispersing the solid composition in the aqueous medium may comprise adding the solid composition to an aqueous medium (or visa versa) and suitably agitating the resulting mixture (e.g. by shaking, homogenisation, sonication, stirring, etc.).

[0206] Pharmaceutical compositions

[0207] The present invention provides a pharmaceutical composition comprising a solid composition or an aqueous dispersion as defined herein. The pharmaceutical compositions of the present invention may further comprise one or more additional pharmaceutically acceptable excipients. The solid compositions of the invention may be formulated into a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, or dispersible powders or granules) by techniques known in the art. As such, the solid compositions of the invention may be mixed with one or more additional pharmaceutical excipients during this process, such as antiadherants, binders, coatings, enterics, disintegrants, fillers, diluents, flavours, colours, lubricants, glidants, preservatives, sorbents, and sweeteners.

[0208] In a particular embodiment, the pharmaceutical composition is a tablet or capsule comprising the solid composition.

[0209] The aqueous dispersion of the present invention may be administered as it is or further formulated with one or more additional excipients to provide a dispersion, elixir or syrup that is suitable for oral use, or a dispersion that is suitable for parenteral administration (for example, a sterile aqueous dispersion for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing).

[0210] In a particular embodiment, the pharmaceutical composition is an aqueous dispersion as described herein. Such dispersed formulations can be used to accurately measure smaller dosages, such as those suitable for administration to children.

[0211] In a particular embodiment, the pharmaceutical composition is in a form suitable for parenteral delivery, whether via subcutaneous or intramuscular delivery.

[0212] It will be appreciated that different pharmaceutical compositions of the invention may be obtained by conventional procedures, using conventional pharmaceutical excipients, well known in the art.

[0213] The pharmaceutical compositions of the invention contain a therapeutically effective amount of the diarylquinoline. A person skilled in the art will know how to determine and select an appropriate therapeutically effective amount of the diarylquinoline to include in the pharmaceutical compositions of the invention.

[0214] Injectable formulations

[0215] The present invention provides an injectable formulation comprising the solid composition as described herein, the aqueous dispersion as described herein, or the pharmaceutical composition as described herein. In embodiments, the injectable formulation is intramuscularly injectable. In other embodiments, the injectable formulation is subcutaneously injectable.

[0216] Said formulations may be in solid form (or substantially solid form, e.g. a paste) or liquid form or semi-solid form, in which the diarylquinoline is present in the form of microparticles. The microparticles of the diarylquinoline may be dispersed within one or more carrier materials. When in liquid form, each microparticle of the diarylquinoline is stabilised by the one or more excipients. Long-Acting Injectable Formulations

[0217] The present invention provides a long-acting injectable formulation comprising the aqueous dispersion as described herein, or the pharmaceutical composition as described herein. The long-acting injectable formulation may be intramuscularly injectable or it may be subcutaneously injectable. The long-acting injectable formulation may, in addition to the microparticles of the diarylquinoline and the aqueous medium, further comprise one or more additional pharmaceutically acceptable excipients, such as thickeners, preservatives, and stabilizers.

[0218] The injectable formulations of microparticles of the diarylquinoline may be long-acting injectable formulations. Such formulations are advantageously designed for administration as an intramuscular or a subcutaneous injection that forms a depot at the site of the injection. Long-acting injectable formulations improve adherence to prophylaxis and / or treatment, especially in respect of bacterial illnesses which require extended treatment durations, such as tuberculosis, and the consequences that ensue. Furthermore, a depot injection is beneficial in that it may be easier to administer than conventional preparations and allows for simpler follow-up / on-going care.

[0219] The long-acting injectable formulations of the present invention permit the formation of a depot of microparticles of the diarylquinoline as these drugs are poorly soluble in aqueous media, preventing them from rapidly exiting the depot and entering the blood circulatory system of the patient. Generally, long-acting injectable formulations are administered intramuscularly or subcutaneously to certain sites, such as the deltoid, dorsogluteal, ventrogluteal, vastus lateralis, and rectus femoris muscles. Each site has a limit on the maximum volume that may be injected without prompting excessive discomfort in the patient or losing effectiveness. The maximum volume, even for the larger sites, is generally only as high as 3 mL. The administration also takes longer than a standard injection, typically taking 10 seconds to administer 1 mL.

[0220] This limitation on the number of suitable sites and volumes permitted in each means that it is important for the long-acting injectable formulations to contain high concentrations of the diarylquinoline so as to minimise the volume (and hence number and duration of injections) required to provide a depot capable of releasing a therapeutically effective amount of the diarylquinoline.

[0221] In addition, without wishing to be bound by theory, the diarylquinoline is thought to be released from the depot at a rate defined by its physicochemical properties (e.g. solubility controlling the rate at which each the diarylquinoline dissolves from the surface of the microparticles) and the local physiological environment. There is, therefore, a minimum concentration of the diarylquinoline that must be present in the depot in order to ensure that, as the diarylquinoline is released at the rate defined by its physicochemical properties and local physiological environments (which may themselves be further influenced by the introduction of the depot, e.g. through formulation of a granuloma around the depot), the amount that is released is a therapeutically effective amount (i.e. the concentration of the diarylquinoline in the formulation must be sufficient to produce a therapeutically effective concentration of the diarylquinoline in vivo). Furthermore, the therapeutically effective amount of the diarylquinoline must be maintained for the duration of the treatment, meaning that the depot must contain all of the diarylquinoline required for the duration of the treatment.

[0222] For long-acting injectable formulations of microparticles of diarylquinoline the concentration of the diarylquinoline may be at least 150 mg / mL, preferably at least 200 mg / mL, more preferably at least 300 mg / mL, and most preferably at least 400 mg / mL. Alternatively, the concentration of the diarylquinoline may be 100 to 1000 mg / mL, preferably 200 to 800 mg / mL, more preferably 300 to 500 mg / mL, such as about 400 mg / mL.

[0223] Preferably, the diarylquinoline is released into the blood circulatory system of the patient from the depot of microparticles of the diarylquinoline at a controlled rate such that a therapeutically effective amount of the diarylquinoline is achieved over a period of at least about two weeks from the date of administration. Further preferably the therapeutically effective amount of the diarylquinoline is achieved for at least about three weeks, more preferably at least about one month, most preferably at least about two months from the date of administration of the injection.

[0224] Therapeutic definitions

[0225] As used herein, “treatment” includes curative and prophylactic treatment. As used herein, a “patient” means an animal, preferably a mammal, preferably a human, in need of treatment.

[0226] The amount of the diarylquinoline administered should be a therapeutically effective amount where the diarylquinoline is used for the treatment of a disease or condition and a prophylactically effective amount where the diarylquinoline is used for the prevention of a disease or condition.

[0227] The term “therapeutically effective amount” used herein refers to the amount of the diarylquinoline needed to treat or ameliorate tuberculosis. The term “prophylactically effective amount” used herein refers to the amount of the diarylquinoline needed to prevent tuberculosis. The exact dosage will generally be dependent on the patient’s status at the time of administration. Factors that may be taken into consideration when determining dosage include the severity of the disease state in the patient, the general health of the patient, the age, weight, gender, diet, time, frequency and route of administration, drug combinations, reaction sensitivities and the patient’s tolerance or response to therapy. The precise amount can be determined by routine experimentation, but may ultimately lie with the judgement of the clinician. An effective dose may in instances be from 0.01 mg / kg / day (mass of drug compared to mass of patient) to 1000 mg / kg / day, e.g. 1 mg / kg / day to 100 mg / kg / day. Compositions may be administered individually to a patient or may be administered in combination with other agents, drugs or hormones. For a long-acting injectable, the composition may be administered in an amount sufficient to release the diarylquinoline at the above rates. Alternatively, the long-acting injectable may be administered in an amount of 0.1 mL to 10 mL, at an amount of 0.2 mL to 6 mL, at an amount of 0.5 mL to 5 mL, or at an amount of 1 mL to 3 mL.

[0228] Routes of administration

[0229] The solid compositions, aqueous dispersions, pharmaceutical compositions, or injectable formulations of the invention, may be administered to a patient by any convenient route of administration. More than one route of administration may be used in combination within a defined treatment and / or prophylactic regime, especially for a combination therapy, in which one component of the combination may be administered via one route, whilst another component of the combination may be administered via a different route. All such combinations are hereby contemplated.

[0230] Routes of administration include, but are not limited to, oral (e.g. by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eyedrops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; or by implantation of a depot, for example, subcutaneously or intramuscularly.

[0231] Most preferably, the route of administration is by injection (e.g. intramuscular or subcutaneous injection) of a depot.

[0232] Preferably, the injectable formulation of the present invention is a depot formulation administered so as to provide a controlled release in the patient over at least a period of about two weeks from the date of administration. Further preferably the period of release is at least about one month, more preferably at least about two months, more preferably at least about three months, and most preferably at least about four months from the date of administration of the injection.

[0233] Kit of Parts

[0234] The present invention provides a kit of parts comprising a solid composition as defined herein or pharmaceutical composition comprising the solid composition as defined herein, and a pharmaceutically acceptable aqueous diluent.

[0235] The solid composition or pharmaceutical composition comprising the solid composition as defined herein can be dispersed into the diluent to provide an aqueous dispersion as defined herein. Either the entire dispersion can then be administered, or a proportion of it can be measured and then administered (thereby providing a means of administering different dosages to individual patients).

[0236] EXAMPLES 1 : Formation of 50 wt% TBAJ-876 formulations by Single Phase Freeze

[0237] TBAJ-876 was dissolved in a 1:1 mixture of acetone and methanol at a concentration of 50 mg / mL and each of the first and second excipients were dissolved in water at concentrations of 12.5 mg / mL to form three stock solutions. 100 L of the TBAJ-876, 300 pL of the first excipient solution, and 100 pL of the second excipient solution were combined in a 4 mL glass vial, to give a mixture with a 1 :4 organic solvent to water volume ratio. The mixture was homogenously mixed using a Covaris S220x for 15 seconds with a duty cycle of 20, peak power of 385, and 500 cycles / burst in frequency sweeping mode to achieve an average power output of ~77 watts. The homogeneous single-phase mixtures were immediately frozen by immersion in liquid nitrogen, followed by freeze-drying for 48 hours using a VirTis Benchtop Pro with a condenser setting of -100°C and at a pressure of <40 pBar.

[0238] The resulting solid product was in the form of a monolith containing 50 wt% TBAJ-876, 37.5 wt% of the first excipient and 12.5 wt% of the second excipient. 529 binary combinations from the following list of excipients were created:

[0239] AOT is docusate sodium

[0240] BKC is benzalkonium chloride

[0241] HPMC is hydroxypropyl methylcellulose with a number average molecular weight of about 10,000

[0242] Kollicoat™ IR is a PVA-PEG graft copolymer

[0243] Kollidon™ 12PF (K12PF) is a polyvinylpyrrolidone with a K value of around 12 Kollidon™ 17PF (K17PF) is a polyvinylpyrrolidone with a K value of around 17 Kolliphor™ EL is a polyethoxylated castor oil formed by the reaction of castor oil with ethylene oxide in a 1:35 molar ratio Lactose

[0244] Mannitol

[0245] NDC is sodium deoxycholate

[0246] PEG400 is polyethylene glycol with a number average molecular weight of 400 PEG 1000 is polyethylene glycol with a number average molecular weight of 1000

[0247] PEG4000 is polyethylene glycol with a number average molecular weight of 4000

[0248] Plasdone™ C15 is polyvinylpyrrolidone with a K value of around 15

[0249] Pluronic™ F68 is poloxamer P188 (poloxamer with a polyoxypropylene molecular mass of 1800 g / mol and a 80% polyoxyethylene content)

[0250] Pluronic™ F127 is poloxamer P407 (poloxamer with a polyoxypropylene molecular mass of 4000 g / mol and a 70% polyoxyethylene content) PVA is polyvinyl alcohol

[0251] PVPK30 is polyvinylpyrrolidone with a mean molecular weight of 30,000

[0252] Solutol HS is polyoxyethylated 12-hydroxystearic acid Sucrose

[0253] TPGS is D-a-Tocopherol polyethylene glycol succinate

[0254] Tween™ 20 is Polysorbate 20 (Polyoxyethylene (20) sorbitan monolaurate) Tween™ 80 is Polysorbate 80 (Polyoxyethylene (80) sorbitan monooleate) Each solid composition was dispersed in water to give a particle dispersion with a TBAJ-876 concentration of 1 mg / mL. For each dispersion, the hydrodynamic diameter (Dz) of the resultant particles was measured by dynamic light scattering (DLS - also referred to as Photon Correlation Spectroscopy (PCS)) using a Zetasizer Advance Ultra (Malvern Panalytical Limited, UK). The measurements were performed in triplicate, at a temperature of 25°C and a measurement angle of 173° (backscatter). Data analysis was conducted using the general-purpose model within the ZS Xplorer software. The combinations of first and second excipients were considered “hits” (and thus warranting further development) if the dispersions had a Dz of less than 3000 nm and a PDI value of less than 0.5.

[0255] Those combinations that were deemed to be “hits” were further assessed for reproducibility and increased loading. In the first instance, repeat batches were made for intra and inter batch reproducibility, with those formulations that had low variability being selected as candidates to advance. Fig. 1 shows the combinations of excipients deemed as “hits” following the 50 wt% screening process.

[0256] Example 2 - Formation of 70 wt% TBAJ-876 formulations by Single Phase Freeze Drying

[0257] TBAJ-876 was dissolved in a 1:1 mixture of acetone and methanol at a concentration of 70 mg / mL and each of the first and second excipients were dissolved in water at concentrations of 7.5 mg / mL to form three stock solutions. 100 pL of the TBAJ-876, 300 pL of the first excipient solution, and 100 pL of the second excipient solution were combined in a 4 mL glass vial, to give a mixture with a 1:4 organic solvent to water mix. The mixture was homogenously mixed using a Covaris S220x for 15 seconds with a duty cycle of 20, peak power of 385, and 500 cycles / burst in freguency sweeping mode to achieve an average power output of ~77 watts. The homogeneous single-phase mixtures were immediately frozen by immersion in liguid nitrogen, followed by freeze- drying for 48 hours using a VirTis Benchtop Pro with a condenser setting of -100°C and at a pressure of <40 pBar.

[0258] The resulting solid product was in the form of a monolith containing 70 wt% TBAJ-876, 20 wt% of the first excipient and 10 wt% of the second excipient. The solid products were dispersed in water and analysed by DLS as in Example 1. Fig. 2 shows the combinations of excipients deemed as “hits” following the 70 wt% screening process. A representative DLS trace of a candidate is shown in Fig. 3. Details of the formulations found to be hits at both the 50 wt% and 70 wt% loadings of TBAJ-876 are shown in Table 1.

[0259] Table 1 - DLS data for formulations found to produce acceptable dispersions

[0260] Example 3 - Formation of 50 wt% TBAJ-876 formulations by Single Phase Spray Drying at 500 mg and 1000 mg Batch Sizes

[0261] TBAJ-876 was dissolved in a 1:1 mixture of acetone and methanol at a concentration of 100 mg / mL and each of the first and second excipients successful in Example 2 were dissolved in water at concentrations of 25 mg / mL to form three stock solutions. For the 500 mg batch size, 2.5 mL of the TBAJ-876 (250 mg), 7.5 mL of the first excipient solution (187.5 mg), and 2.5 mL of the second excipient solution (62.5 mg) were combined in a 40 mL glass vial containing a magnetic stirrer bar. For the 1000 mg batch size, twice the volume of each stock solution was used. Addition was conducted under stirring, using a hotplate stirrer set to 700 rpm and the heating function turned off. The resulting feedstock suspension has 4 w / v% solids and a solvent concentration of 20% by volume organic phase.

[0262] Precipitation occurred approximately 30-90 seconds after mixing, at which point the stirrer bar was removed and the suspension further mixed using 30 seconds of sonication. A Hielscher UP400S sonicator (Hielscher, Germany) fitted with a H7 probe was used for this, at 100% amplitude and a cycle of 1. The sonicated suspension was immediately spray dried using a Buchi B-290 spray dryer (Buchi, Switzerland) fitted with a two fluid nozzle and high-performance cyclone. The outlet temperature was set to 65°C and a flow of nitrogen gas used for atomisation, with a gas flow rate of 45 Ln / min measured using the Q-flow meter. The feedstock was pumped into the spray dryer at a rate of 5 mL / min using a Masterflex L / S peristaltic pump with two Easy Load II pump heads attached, and L / S 14 sized peroxide cured silicone tubing.

[0263] Sample was collected from the sample jar connected to the high-performance cyclone, with dry powder recovery greater than 50% of starting material. The solid products were dispersed in water and analysed by DLS as in Example 1. Representative DLS traces candidates are shown in Figs. 4 and 5 for the 500 mg and 1000 mg batch sizes respectively. Details of the formulations found to be hits at 50 wt% loadings of TBAJ- 876 are shown in Table 2.

[0264] Table 2 - DLS data for formulations found to produce acceptable dispersions

[0265] Example 4 - Formation of 50 wt% TBAJ-876 formulations by Single Phase Spray Drying using a Single Excipient

[0266] TBAJ-876 was dissolved in a 1:1 mixture of acetone and methanol at a concentration of 100 mg / mL and each of Kollidon™ K12PF, Plasdone™ C15, or Kollidon™ K17PF were dissolved in water at concentrations of 25 mg / mL. 5 mL of the TBAJ-876 (500 mg) and 20 mL of the PVP excipient solution (500 mg), were combined in a 40 mL glass vial containing a magnetic stirrer bar. Addition was conducted under stirring, using a hotplate stirrer set to 700 rpm and the heating function turned off. The resulting feedstock suspension has 4 w / v% solids and a solvent concentration of 20% by volume organic phase.

[0267] Precipitation occurred approximately 30-90 seconds after mixing, at which point the stirrer bar was removed and the suspension further mixed using 30 seconds of sonication. A Hielscher UP400S sonicator (Hielscher, Germany) fitted with a H7 probe was used for this, at 100% amplitude and a cycle of 1. The sonicated suspension was immediately spray dried using a Buchi B-290 spray dryer (Buchi, Switzerland) fitted with a two fluid nozzle and high-performance cyclone. The outlet temperature was set to 65°C and a flow of nitrogen gas used for atomisation, with a gas flow rate of 45 Ln / min measured using the Q-flow meter. The feedstock was pumped into the spray dryer at a rate of 5 mL / min using a Masterflex L / S peristaltic pump with 2 Easy Load II pump heads attached, and L / S 14 sized peroxide cured silicone tubing.

[0268] Sample was collected from the sample jar connected to the high-performance cyclone, with dry powder recovery greater than 70% of starting material.

[0269] This procedure was modified to produce formulations with 70 wt% TBAJ-876 at 714.3 mg batch size and 80 wt% TBAJ-876 at 625 mg batch size. Each achieved dry powder recovery of 70% of the starting material The solid products were dispersed in water and analysed by DLS as in Example 1. Representative DLS traces candidates are shown in Figs. 6, 7, and 8 for the 50 wt%, 70 wt% and 80 wt% formulations respectively. Details of the formulations are shown in Table 3.

[0270] Table 3 - DLS data for single-excipient formulations found to produce acceptable dispersions

[0271] The syringeability of each composition was tested at increasing concentrations of TBAJ-876. The dispersions were produced by vortex mixing the solid composition in water at the required concentrations for a period of 30 seconds. The dispersions were then passed through a 25G needle by hand. Those that passed through easily and without blockages, with a repeat one hour later, were considered to have passed. Each of the formulations was found to be syringeable at concentrations of up to 400 mg of TBAJ-876 in 1 mL of water (corresponding to total solids of 800 mg, 571 mg, and 500 mg for the 50 wt%, 70 wt%, and 80 wt% formulations respectively.

[0272] Example 5 - In Vivo Duration of TBAJ-876 following Intramuscular Injection

[0273] Nine aqueous dispersions in saline were prepared using the single excipient formulations with TBAJ-876 concentrations of 100, 200, and 400 mg / mL, as detailed below:

[0274] Group 1 - TBAJ-87680 / Kollidon™ K12PF20at 100 mg / mL of TBAJ-876, Group 2 - TBAJ-87680 / Kollidon™ K12PF20at 200 mg / mL of TBAJ-876, Group 3 - TBAJ-87680 / Kollidon™ K12PF20at 400 mg / mL of TBAJ-876, Group 4 - TBAJ-8768o / Plasdone™ C152o at 100 mg / mL of TBAJ-876, Group 5 - TBAJ-8768o / Plasdone™ C152o at 200 mg / mL of TBAJ-876, Group 6 - TBAJ-8768o / Plasdone™ C152o at 400 mg / mL of TBAJ-876, Group 7 - TBAJ-87680 / Kollidon™ K17PF20at 100 mg / mL of TBAJ-876, Group 8 - TBAJ-87680 / Kollidon™ K17PF20at 200 mg / mL of TBAJ-876, and Group 9 - TBAJ-87680 / Kollidon™ K17PF20at 400 mg / mL of TBAJ-876.

[0275] Female BALB / c mice (approx. 20g - Charles River) were injected intramuscularly into the left hind thigh with 50 pl of one of the formulations. Each group contained nine animals. Blood plasma was collected from the mandibular venous plexus periodically (3 mice sampled per group per time point) over the course of 1344 hours and the TBAJ- 876 concentrations therein quantified using LC / MS-MS. These data are graphed in Fig. 9 and show a gradual decline in the concentration of TBAJ-876 over the 56-day period of sampling. Each formulation was shown to maintain a median plasma concentration of TBAJ-876 over the target Cmin of 35 ng / mL (plotted as a dashed line) for the duration of the experiment.

[0276] Example 6 - In vivo Duration and Anti-Tubercular Activity of TBAJ-876 following Intramuscular Injection

[0277] Three aqueous dispersions in saline were prepared using the single excipient formulations with TBAJ-876 concentrations of 50 mg / mL, with a further two aqueous dispersions with TBAJ-876 concentrations of 25 and 100 mg / mL, as detailed below:

[0278] Group 1 - TBAJ-87680 / Kollidon™ K12PF20at 50 mg / mL of TBAJ-876,

[0279] Group 2 - TBAJ-876so / Plasdone™ C152o at 50 mg / mL of TBAJ-876,

[0280] Group 3 - TBAJ-87680 / Kollidon™ K17PF20at 50 mg / mL of TBAJ-876,

[0281] Group 4 - TBAJ-8768o / Plasdone™ C152o at 25 mg / mL of TBAJ-876, and

[0282] Group 5 - TBAJ-8768o / Plasdone™ C152o at 100 mg / mL of TBAJ-876,

[0283] Female BALB / c mice (approx. 20g - Charles River) were immunized via aerosol infection with M. bovis rBCG30 eight weeks prior to the start of dosing, and then infected via aerosol with Mycobacterium tuberculosis H37Rv four weeks prior to the start of dosing in order to establish the paucibacillary (latent) tuberculosis infection model. On the day of dosing (Day 0), the mice were injected intramuscularly into the left hind thigh with 50 pl of one of the formulations.

[0284] Control groups received comparator treatments administered orally (gavage) in 200 pl once daily, 5 days per week (Monday-Friday) for four weeks for a total of 20 doses, as follows:

[0285] Group 6 - TBAJ-876 tartrate (0.625 mg / mL) formulated in 20% hydroxypropyl-p- cyclodextrin solution with 1.5% 1 N HCI (receiving the same total dose of 125 mg / kg as Groups 1-3),

[0286] Group 7 - TBAJ-876 tartrate (1.25 mg / mL) formulated in 20% hydroxypropyl-p- cyclodextrin solution with 1.5% 1 N HCI (receiving the same total dose of 250 mg / kg as Group 5),

[0287] Group 8 - Bedaquiline (2.5 mg / mL) formulated in 20% hydroxypropyl-p-cyclodextrin solution with 1.5% 1 N HCI, and

[0288] Group 9 - Isoniazid (1 mg / mL) and rifapentine (1 mg / mL), each formulated separately in distilled water

[0289] Group 10 mice served as negative controls and did not receive any treatment.

[0290] Each group contained fifteen animals. For Groups 1-5, beginning 3 hours post-dose, blood plasma was collected from the mandibular venous plexus periodically over the course of 1008 hours and the TBAJ-876 concentrations therein quantified using LC / MS-MS. These data are graphed in Fig. 10A-B and show a gradual decline in the concentration of TBAJ-876 over the 42-day period of sampling. In addition, five mice were sacrificed before dosing on Day 0 and five mice per group in Groups 1-10 were sacrificed 4, 8 and 12 weeks after Day 0. At each time point, the lungs were removed, homogenized and cultured to quantify the number of CFU to measure the M. tuberculosis bacterial burden in order to determine the effects of each treatment on the bacterial burden. The results are shown in Table 4.

[0291] As can be seen in Fig. 11, it was found that the intramuscularly dosed TBAJ-876 reduced the bacterial burden to levels as low or lower than orally dosed TBAJ-876 at the same total TBAJ-876 dose level (i.e., Groups 1-3 vs. Group 6; Group 5 vs. Group 7) and resulted in lower bacterial burdens than did oral treatment with bedaquiline

[0292] (Group 8) and the shortest regimen recommended for tuberculosis preventive therapy by the World Health Organization, one month of daily isoniazid and rifapentine (Group 9). Table 4 - M. tuberculosis bacterial burden for each Group over the course of the experiment

Claims

CLAIMS:

1. A solid composition comprising microparticles of a diarylquinoline, such as TBAJ-876, dispersed within a matrix comprising one or more excipients, the one or more excipients selected from: docusate sodium (AOT), hydroxypropylmethyl cellulose (HPMC), lactose, mannitol, polyethylene glycol (PEG), poloxomers, polyoxyethylene (80) sorbitan monooleate, polyvinyl alcohol (PVA), polyvinyl alcohol-polyethylene glycol (PVA-PEG) graft copolymers, polyvinylpyrrolidones (PVP), sodium deoxycholate (NDC), sucrose, and combinations thereof.

2. The solid composition of claim 1, wherein the one or more excipient comprises a first excipient and a second excipient selected from the following combinations:- HPMC and AOTHPMC and poloxomerPVA-PEG copolymer and PVPPVA-PEG copolymer and PEGPVA-PEG copolymer and poloxomer- PVP and HPMC- PVP and PVPPVP and PVA-PEG copolymer- PVP and PEGPVP and poloxomer- PVP and PVAPVP and mannitolPVP and polyoxyethylene (80) sorbitan monooleate lactose and PVP mannitol and HPMC mannitol and NDC mannitol and PEG mannitol and poloxomer mannitol and PVP- NDC and HPMCNDC and poloxomer- PEG and HPMC PEG and lactose- PEG and PVPPEG and poloxomerPEG and PVA-PEG copolymer- PEG and PEG- PEG and PVA poloxomer and PVA-PEG copolymer poloxmer and NDCpoloxomer and PEG poloxomer and PVP poloxomer and poloxomer poloxomer and PVA poloxomer and sucrose- PVA and N DCPVA and poloxomer sucrose and poloxomer.

3. The solid composition of claim 2, wherein the first excipient and the second excipient are selected from the following combinations:PVA-PEG copolymer and PVPPVP and PVA-PEG copolymer- PVP and PVPPVP and mannitolPVP and poloxomer- PVP and PEG- PEG and HPMC- PEG and PVPPEG and poloxomer poloxomer and PVP4. The solid composition of claim 3, wherein the first excipient and the second excipient are selected from the following combinations:PVP and PVA-PEG copolymer- PVP and PVP- PEG and PVP5. The solid composition of any of claims 2 to 4, wherein the mass ratio of first to second excipient is from 1:1 to 4: 1 , preferably from 2:1 to 3: 1.

6. The solid composition of any of claims 1 to 5, wherein:(i) the one or more excipient comprises from 20 to 60 wt% of the solid composition, preferably from 30 to 50 wt% of the solid composition; and / or(ii) the diarylquinoline comprises from 40 to 80 wt% of the solid composition, preferably from 50 to 70 wt% of the solid composition.

7. The solid composition of claim 1, wherein the one or more excipient is PVP.

8. The solid composition of claim 7, wherein:(i) the PVP comprises from 10 to 60 wt% of the solid composition, preferably from 20 to 50 wt% of the solid composition; and / or(ii) the diarylquinoline comprises from 40 to 90 wt% of the solid composition, preferably from 50 to 80 wt% of the solid composition.

9. The solid composition of any of claims 1 to 8, wherein the microparticles of diarylquinoline have:(i) a particle size of from 0.1 to 3 pm, preferably from 0.5 to 2.9 pm, further preferably from 1 to 2.8 pm; and / or(ii) a polydispersity of less than 0.

5. preferably less than 0.4, more preferably less than 0.3.

10. A process for preparing a solid composition according to any one of claims 1 to 9, the process comprising:(e) providing an active solution comprising the diarylquinoline in a water- miscible solvent;(f) providing an excipient solution comprising one or more excipients as defined in any of claims 1 to 9;(g) mixing the solutions prepared in steps (a) and (b); and(h) removing the mixed solvent to produce the solid composition.

11. The process of claim 10, wherein removing the mixed solvent comprises spraydrying or freeze-drying.

12. An aqueous dispersion comprising a plurality of microparticles of a diarylquinoline, such as TBAJ-876, dispersed in an aqueous medium and stabilised by one or more excipients, , the one or more excipients selected from: docusate sodium (AOT), hydroxypropylmethyl cellulose (HPMC), lactose, mannitol, (NDC), polyethylene glycol (PEG), (poloxomers), polyoxyethylene (80) sorbitan monooleate, polyvinyl alcohol (PVA), polyvinyl alcohol-polyethylene glycol (PVA-PEG) graft copolymers, polyvinylpyrrolidones (PVP), sodium deoxycholate (NDC), sucrose, and combinations thereof.

13. The aqueous dispersion of claim 12, wherein the one or more excipients are as defined in any of claims 2 to 9.

14. The aqueous dispersion of claim 12 or claim 13, wherein the diarylquinoline is present in a concentration of from 10 to 500 mg / mL, preferably from 25 to 400 mg / mL, more preferably from 50 to 200 mg / mL.

15. A process for preparing an aqueous dispersion according to any one of claims 12 to 14, the process comprising dispersing a solid composition according to any of claims 1 to 9 in an aqueous medium.

16. A pharmaceutical composition comprising the solid composition of any of claims 1 to 9, or the aqueous dispersion of any of claims 12 to 14 and, optionally, one or more further pharmaceutically acceptable excipients.

17. An injectable formulation comprising the solid composition of any of claims 1 to 9, the aqueous dispersion of any of claims 12 to 14, or the pharmaceutical composition of claim 16, optionally wherein the injectable formulation is a subcutaneously or intramuscularly injectable formulation, further optionally wherein the injectable formulation is suitable for provision in depot form.

18. A solid composition according to any of claims 1 to 9, an aqueous dispersion according to any of claims 12 to 14, a pharmaceutical composition according to claim 16, or an injectable formulation according to claim 17, for use as a medicament.

19. A solid composition according to any of claims 1 to 9, an aqueous dispersion according to any of claims 12 to 14, a pharmaceutical composition according to claim 16, or an injectable formulation according to claim 17, for use in the treatment and / or prevention of tuberculosis, such as latent tuberculosis or active tuberculosis.

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