Long-acting formulations

Abstract

The present invention relates to pharmaceutical compositions for administration by intramuscular or subcutaneous injection, comprising microparticles of the anti-TB compound bedaquiline suspended in an aqueous pharmaceutically acceptable carrier, and to the use of such pharmaceutical compositions in the treatment and prevention of pathogenic mycobacterial infections.

Description

[Technical Field]

[0001] The present invention relates to pharmaceutical compositions for administration by intramuscular or subcutaneous injection, comprising micro- or nanoparticles of the ATP synthase inhibitor compound bedaquiline (commercially available as Sirturo®, wherein bedaquiline is in the form of its fumarate salt) suspended in an aqueous pharmaceutically acceptable carrier, and the use of such pharmaceutical compositions in the treatment of bacterial infections (such as, for example, tuberculosis). [Background technology]

[0002] Bedaquiline is a known antituberculosis drug used in various combinations. It may be formulated in the form of a pharmaceutically acceptable salt, such as bedaquiline fumarate, which is commercially available as Sirturo®. It is believed to act as an ATP synthase inhibitor with a selectivity index of over 20,000 for mycobacterial ATP synthase compared to eukaryotic mitochondrial ATP synthase.

[0003] Bedaquiline is not only useful in treating mycobacterial infections, but has also been reported to be useful in killing dormant, latent, and persistent mycobacteria, particularly Mycobacterium tuberculosis, and can therefore be used to treat latent TB. Such uses of bedaquiline have been described in several publications, including the international patent publications WO 2004 / 011436 and WO 2006 / 067048. Bedaquiline is also known to be bactericidal against Mycobacterium leprae, as described, for example, in "Bacterial Activities of R207910 and other Antimicrobial Agents against Mycobacterium leprae in Mice," Antimicrobial Agents and Chemotherapy, April 2006, p. 1558, and "The Diarylquinolone R207910 is Bactericidal against Mycobacterium leprae in Mice and at Low Dose Administered Intermittently," Antimicrobial Agents and Chemotherapy, September 2009, p. 3989.

[0004] A goal of long-acting formulations may be to reduce drug burden, which is particularly useful for treatment regimens that may last several months.

[0005] The number and / or amount of dosage forms that need to be administered is commonly referred to as the "pill burden." A high pill burden is undesirable for many reasons, including the frequency of dosing combined with the inconvenience of having to swallow an often-large dosage form, and the need to store and transport many or large quantities of pills. A high pill burden increases the risk that patients will not take their full dose and thereby not comply with the prescribed dosing regimen. In addition to reducing the effectiveness of treatment, this can also lead to the emergence of resistance (e.g., bacterial resistance in the case of bedaquiline).

[0006] It would be attractive to provide a therapy that involves administration of dosage forms at long time intervals (eg, one week or more, or even one month or more).

[0007] Various formulations, including long-acting ones, are known in the art. For example, microsuspension and nanosuspension techniques are known to achieve long-acting formulations in the field of anti-HIV drugs, as described, for example, in International Patent Applications Nos. 2007 / 147882 and 2012 / 140220. Furthermore, nanoparticles known in the prior art are described, for example, in European Patent Application No. A-0499299. Such particles have an average particle size in the submicron range and consist of particles of crystalline drug substance with a surface modifier adsorbed to their surface. Nanoparticles have also been used to formulate poorly water-soluble active ingredients.

[0008] Long-acting formulations of the anti-tuberculosis drug bedaquiline are also described, for example, in WO 2019 / 012100, WO 2022 / 008643, and WO 2022 / 008645.

[0009] The importance of long-acting formulations relates to the intermittent administration of these micro- or nanoparticle formulations at time intervals of one week or more, resulting in plasma levels that may be sufficient to suppress the development of mycobacterial infection. This allows for a reduction in the frequency of administration, thereby benefiting patients in terms of pill burden and drug compliance. Therefore, micro- or nanoparticle formulations of bedaquiline may be useful for the long-term treatment of mycobacterial infections (e.g., tuberculosis, including latent tuberculosis, and leprosy).

[0010] Furthermore, intermittent administration of micro- or nanoparticulate formulations of bedaquiline at time intervals of one week or more results in plasma levels that may be sufficient to provide protection against transmission of mycobacterial infections, reducing the number of doses required, which is also advantageous in terms of pill burden and drug compliance for individuals at risk of infection.

[0011] Challenges with the manufacture and suitability of such long-acting formulations relate to the fact that they must be sterilized (e.g., important for injectables when intended for intravenous or subcutaneous administration). Several different methods exist for sterilizing such long-acting formulations, including heat sterilization, aseptic manufacturing processes, autoclaving, and gamma irradiation (γ-irradiation). Examples of some methods are described, for example, in U.S. Patents / Patent Applications Nos. 5,298,262, 5,346,702, and 2010 / 255102. For heat sterilization and autoclaving, it is important to be able to select excipients (e.g., surface modifiers or surfactants) that are autoclavable, e.g., do not decompose. Further challenges arise after such sterilization, and these are related to the desired stability of the long-acting formulation, undesired aggregation of particles of the active pharmaceutical ingredient (API) within the formulation, and the desired resuspension ability of the formulation (after sterilization, e.g., autoclaving).

[0012] The challenge is therefore not only to produce long-acting formulations, but also to find formulations that are suitable for maintaining a certain level of stability over a sufficient period of time.

[0013] Further alternative and / or improved long-acting formulations are now described, and the present invention relates to such formulations. Summary of the Invention [Means for solving the problem]

[0014] The present invention provides a pharmaceutical composition for administration by intramuscular or subcutaneous injection, comprising a therapeutically effective amount of bedaquiline or a pharmaceutically acceptable salt thereof in the form of a microparticle suspension prepared by a sterile manufacturing process; (a) bedaquiline or a pharmaceutically acceptable salt thereof in microparticulate form, present in an amount of 10% to 30% by weight (w / v) based on the total volume of the composition; (b) a surface modifier present at 5% to 15% (w / v) and comprising at least 30% PEG 4000 (or the like) and at least 30% poloxamer (e.g., poloxamer 338); and (c) a pharmaceutically acceptable aqueous carrier, Such compositions may be referred to herein as "compositions of the present invention."

[0015] The compositions of the present invention are suspensions, which means that the bedaquiline active ingredient is suspended in a pharmaceutically acceptable aqueous carrier.

[0016] The compositions (ie, suspensions) of the present invention contain a surface modifier which may be adsorbed onto the surface of the active ingredient bedaquiline.

[0017] In an embodiment, the invention therefore provides a pharmaceutical composition for administration by intramuscular or subcutaneous injection, comprising a therapeutically effective amount of bedaquiline or a pharmaceutically acceptable salt thereof in the form of a microparticle suspension prepared by a sterile manufacturing process, (a) bedaquiline or a pharmaceutically acceptable salt thereof in particulate form, having a surface modifier adsorbed to the surface thereof; and (b) a pharmaceutically acceptable aqueous carrier in which the bedaquiline active ingredient is suspended; Bedaquiline (or a pharmaceutically acceptable salt thereof) is present in an amount of 10% to 30% (w / v) by weight based on the total volume of the composition, and the surface modifier is present in an amount of 5% to 15% (w / v) and comprises at least 30% PEG 4000 (or the like) and at least 30% poloxamer (e.g., poloxamer 338).

[0018] The compositions of the present invention are suspensions of microparticles prepared by a sterile manufacturing process, in which bedaquiline (or a pharmaceutically acceptable salt thereof) and surface modifiers (PEG4000 and poloxamer) are present in certain amounts, as indicated, and in certain further embodiments, as follows: bedaquiline (or a pharmaceutically acceptable salt thereof) is present in an amount of about 15% to 25% (w / v), for example about 20% (w / v); and / or The surface modifier is present at about 8% to 12% (w / v) and comprises a PEG4000 to poloxamer ratio as described herein.

[0019] The compositions of the present invention are optimized based on several parameters, and the optimized amounts of surface modifiers are as described above. In certain further embodiments, they may be present in the following amounts: The surface modifier comprises 30% to 70% PEG 4000 (or similar), with the remainder consisting of 30% to 70% poloxamer. The surface modifier comprises 40% to 60% PEG 4000 and 40% to 60% poloxamer. The surface modifier comprises 45% to 55% PEG 4000 (e.g., about 50%) and 45% to 50% poloxamer (e.g., about 50%). The surface modifier comprises about 2-15% (e.g., 4-6%) PEG 4000 (w / v) and about 2-15% (e.g., 4-6%) poloxamer (w / v). The surface modifier comprises about 5% PEG 4000 (w / v) and about 5% poloxamer (w / v).

[0020] The compositions of the present invention may also contain a pharmaceutically acceptable carrier, which is described in more detail below.

[0021] The present invention further relates to methods of treating a subject infected with pathogenic mycobacteria, such as Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium leprae, Mycobacterium avium, and Mycobacterium marinum. In embodiments, the mycobacterium is Mycobacterium tuberculosis (including latent or dormant forms) or Mycobacterium leprae. The compositions of the present invention may be particularly suitable for treating Mycobacterium leprae and latent or dormant forms of Mycobacterium tuberculosis. This is because lower concentrations of bedaquiline in plasma may be effective against these particular infections, as described, for example, in Antimicrobial Agents and Chemotherapy, September 2009, pp. 3989-3991, by Robert Gelber, Koen Andries et al. (The contents of which are incorporated herein by reference. Essentially, low-frequency, intermittent dosing with bedaquiline has been reported to be promising for leprosy patients, whereas the minimum dose that kills 99% of the bacillus subunits of Mycobacterium tuberculosis is 30 mg / kg / week and <5.0 mg / kg / week for Mycobacterium leprae; therefore, monthly dosing may be as effective as 5 days / week. Other publications on the effect of bedaquiline against Mycobacterium leprae in mice include Antimicrobial Agents and Chemotherapy, April 2009, by Baohong Ji, Koen Andries et al. 2006, pp. 1558-1560, the contents of which are also incorporated herein by reference. Accordingly, the compositions of the present invention may be particularly suitable in methods for treating a subject infected with Mycobacterium leprae or latent / dormant Mycobacterium tuberculosis. Such methods for treating a subject infected with pathogenic mycobacteria comprise administering, by intramuscular or subcutaneous injection, a therapeutically effective amount of a pharmaceutical composition as specified above or below. Alternatively, the present invention relates to the use of a pharmaceutical composition as specified above or below for the manufacture of a medicament for treating a pathogenic mycobacterial infection (or for the use of such a medicament in a specific treatment regimen as described herein). In one embodiment, the composition is for long-term treatment of a pathogenic mycobacterial infection.In embodiments, the pathogenic mycobacterial infection may be as described above or below, e.g., an infection requiring long-term treatment (in further embodiments, an infection that may be further treated with relatively low plasma concentration levels of bedaquiline or its active metabolite, e.g., latent / dormant Mycobacterium tuberculosis or, in certain embodiments, Mycobacterium leprae).

[0022] In another aspect, there is provided a method for the long-term treatment of a subject infected with pathogenic mycobacteria, such as Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium leprae, Mycobacterium avium, and Mycobacterium marinum, comprising the administration of an effective amount of a pharmaceutical composition as specified above or below for administration by intramuscular or subcutaneous injection, wherein the composition is or will be administered intermittently at time intervals ranging from one week to one year, or from one week to two years.Alternatively, the present invention relates to the use of a pharmaceutical composition as specified above or below for the manufacture of a medicament for the long-term treatment of a subject infected with pathogenic mycobacteria, such as Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium leprae, Mycobacterium avium, and Mycobacterium marinum, for administration by intramuscular or subcutaneous injection, wherein the composition is or will be administered intermittently at time intervals ranging from one week to one year, or from one week to two years. Thus, the term "long-term treatment" will be understood to refer to treatment in which a single dose or administration (e.g., by intramuscular or subcutaneous injection) has a sustained therapeutic effect over a period of time, as described herein, e.g., over hours, weeks, or months (e.g., in embodiments, over a period of at least or up to 1 month, 3 months, or 6 months). See the Examples. In other words, long-term treatment can refer to a long period of time (as described herein) between doses / administrations when there is more than one dose / administration, i.e., the interval is a long period of time as described herein.

[0023] In another aspect, methods are provided for the long-term treatment of a subject infected with a pathogenic mycobacterium (e.g., any of the types described herein) as described herein (e.g., above), wherein a single dose or administration (e.g., an amount described herein, e.g., below) is provided / required (and, e.g., has a sustained effect over a period of time described herein). In another aspect, such long-term treatment regimens are provided wherein two such doses or administrations are provided / required, with the doses / administrations given spaced apart, the interval being as described herein, e.g., for a period of at least or up to one month, three months, or six months—e.g., a period during which a sustained therapeutic effect persists). In a further embodiment, such long-term treatment regimens are provided wherein three such doses or administrations are provided / required, with intervals as described herein. In yet a further embodiment, such long-term treatment regimens are provided wherein the long-term treatment regimens are as described herein, but preceded by an induction treatment phase (not a long-term treatment regimen, e.g., a once-daily administration course lasting for one week, two weeks, three weeks, or one month).

[0024] The present invention further relates to a method for preventing a pathogenic mycobacterial infection in a subject at risk of contracting a pathogenic mycobacterial infection, the method comprising administering to the subject an amount of a pharmaceutical composition as specified above or further specified below effective to prevent the pathogenic mycobacterial infection. Alternatively, the present invention relates to the use of a pharmaceutical composition as specified above or further specified below for the manufacture of a medicament for the prevention of a pathogenic mycobacterial infection in a subject at risk of contracting a pathogenic mycobacterial infection.

[0025] In another aspect, the present invention relates to a method for the long-term prevention of pathogenic mycobacterial infection in a subject at risk of contracting a pathogenic mycobacterial infection, the method comprising administering to the subject an effective amount of a pharmaceutical composition as specified above or further specified below, wherein the composition is or will be administered intermittently at time intervals ranging from 1 week to 1 year, or from 1 week to 2 years.

[0026] The present invention further relates to the use of a pharmaceutical composition as specified above or further specified below for the manufacture of a medicament for the long-term prevention of pathogenic mycobacterial infection in a subject at risk of contracting a pathogenic mycobacterial infection, wherein the composition is or will be administered intermittently at time intervals ranging from 1 week to 1 year, or from 1 week to 2 years.

[0027] In one embodiment, the invention relates to a use or method as specified herein, wherein the pharmaceutical composition is administered or will be administered at a time interval ranging from 1 week to 1 month, or from 1 month to 3 months, or from 3 months to 6 months, or from 6 months to 12 months, or from 12 months to 24 months.

[0028] In another embodiment, the invention relates to the uses or methods specified herein, wherein the pharmaceutical composition is or will be administered once every two weeks, or once a month, or once every three months.

[0029] Further pharmaceutical compositions, methods of treatment or prevention, as well as uses for the manufacture of medicaments based on these compositions are described below and are intended to be part of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0030] The compound used in the present invention is the compound TMC207, also known as bedaquiline.

[0031] Bedaquiline may be used in its non-salt form or in a suitable pharmaceutically acceptable salt form (e.g., an acid addition salt form or a base addition salt form). In an embodiment, bedaquiline is in its non-salt form in the compositions of the present invention.

[0032] Pharmaceutically acceptable acid addition salts are defined to include therapeutically active, non-toxic acid addition salt forms that bedaquiline can form. Such acid addition salts can be obtained by treating bedaquiline in free form with a suitable acid, such as inorganic acids, such as hydrohalic acids, especially hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid; organic acids, such as acetic acid, hydroxyacetic acid, propanoic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid, and pamoic acid. In particular, the fumarate salt is considered, given that this is the form used in the already commercially available product Sirturo®.

[0033] Possible therapeutically active non-toxic base addition salt forms can be prepared by treatment with appropriate organic and inorganic bases, including, for example, ammonium salts, alkali metal salts and alkaline earth metal salts (especially lithium salts, sodium salts, potassium salts, magnesium salts, calcium salts), salts with organic bases (e.g., benzathine, N-methyl-D-glucamine, hydrabamine salts), and salts with amino acids (e.g., arginine and lysine).

[0034] Conversely, said acid or base addition salt forms can be converted into the free forms by treatment with an appropriate base or acid.

[0035] The term addition salts as used within the framework of this application also includes solvates which bedaquiline and its salts are able to form. Such solvates are, for example, hydrates and alcoholates.

[0036] Whenever reference is made herein to bedaquiline (or TMC207), we are referring to the single stereoisomeric form used in the commercial product Sirturo® and disclosed in WO 2004 / 011436 as an antimycobacterial agent.

[0037] The physicochemical properties of bedaquiline allow for the production of a microparticle suspension with unique pharmacokinetic properties in that it can be used for the long-term treatment of pathogenic mycobacterial infections as well as for the long-term prevention of pathogenic mycobacterial infections, and for this purpose it has been found that only limited drug administrations are required, which is beneficial in terms of pill burden and patient compliance with the prescribed dosing regimen.

[0038] As used herein, the term "treatment of a pathogenic mycobacterial infection" relates to the treatment of a subject infected with a pathogenic mycobacterial infection.

[0039] The term "prevention of pathogenic mycobacterial infection" relates to preventing or avoiding a subject from contracting a pathogenic mycobacterial infection. The source of the infection can be various and can be, for example, a substance that contains a pathogenic mycobacterial infection.

[0040] The terms "therapeutically effective amount," "amount effective to prevent pathogenic mycobacterial infection," and similar terms refer to an amount or concentration of a composition of the invention (or an amount / concentration of the active ingredient bedaquiline within such a composition) that results in an effective plasma level. "Effective plasma level" refers to a plasma level of bedaquiline that provides effective treatment or effective prevention of pathogenic mycobacterial infection, as a given amount / dose / administration may relate to a desired exposure level or desired plasma level for effective treatment / prevention, e.g., as described herein (see, e.g., Examples).

[0041] The term "subject" particularly relates to humans.

[0042] The term "micro- or nanoparticle" refers to particles in the micrometer or nanometer range. The size of the particles should be below a maximum size above which administration by subcutaneous or intramuscular injection becomes impaired or no longer possible. The maximum size depends on the limitations imposed, for example, by the diameter of the needle or by the body's adverse reactions to large particles, or both. In one embodiment, the pharmaceutical composition of the invention comprises bedaquiline in microparticle form.

[0043] The average effective particle size of the microparticles of the present invention may be less than about 50 μm, or less than about 20 μm, or less than about 10 μm, or less than about 1000 nm, or less than about 500 nm, or less than about 400 nm, or less than about 300 nm, or less than about 200 nm. For example, both after preparation and after periods of up to 3 months (e.g., when stored at temperatures of about 5° C., 25° C., and 40° C.), generally A microsuspension (or composition of the invention) may, in embodiments, have a D90 of about 3-10 μm (e.g., about 4-7 μm, e.g., about 5 or 6 μm), a D50 of about 2-4 μm (e.g., about 2-3 μm, e.g., about 2.5 μm), and a D10 of about 0.3-1.5 μm (e.g., about 0.5-1 μm, e.g., about 0.7 or 0.8 μm), and all of these D10 / D50 / D90 values ​​may refer to values ​​after preparation (i.e., T0, or time 0), or may also refer to such values ​​after a certain period of time (e.g., 1 month / 1 month, 3 months, 6 months) when stored at a certain temperature (e.g., 30°C, 40°C, 50°C, or 5°C).

[0044] In embodiments, fine particles are used having an average effective particle size of less than about 50 μm, or less than about 20 μm, and greater than about 0.1 μm (100 nm), as measured by D10, D50 and / or D90 (in embodiments, as measured by D50). In embodiments, such microparticles used in the compositions of the present invention range from about 20 μm to about 0.1 μm (in further embodiments, from about 15 μm to greater than about 0.2 μm, and in further embodiments, from about 10 μm to greater than 0.2 μm, such as from about 10 μm to greater than 0.2 μm (see also the values ​​above and below where specific values ​​of D10 / D50 / D90 are measured). The above values ​​refer to measurements after preparation. However, they may also refer to measurements, in embodiments, after a period of up to 3 months (e.g., after 5 days, 1 week, 2 weeks, 1 month, 2 months, or 3 months) and after storage at various temperatures (e.g., at temperatures of about 5° C., 25° C., 30° C., 40° C., and 50° C.). An advantage of the microsuspensions of the present invention is the particle size distribution, as measured herein by the D10 / D50 / D90 values. The key is that the average effective particle size, also called particle size distribution (PSD), does not change significantly, but rather the D10 / D50 / D90 values ​​remain relatively stable, meaning that the deviation in the values ​​is less than 25%, e.g., less than 15%.

[0045] As used herein, the term average effective particle size has the conventional meaning known to those skilled in the art and can be measured by particle size measurement techniques known in the art, such as sedimentation field flow fractionation, photon correlation spectroscopy, laser diffraction, or disc centrifugal sedimentation. The average effective particle size referred to herein can be related to the volume distribution of particles. In this case, "effective average particle size less than about 50 μm" means that at least 50% of the volume of particles have a particle size less than the effective average of 50 μm, and the same applies to other referred effective particle sizes. Similarly, the average effective particle size can be related to the weight distribution of particles, which usually results in the same or approximately the same value for the average effective particle size.

[0046] The pharmaceutical compositions of the present invention provide release of the active ingredient bedaquiline over an extended period of time; therefore, they may also be referred to as sustained-release or delayed-release compositions. After administration, the compositions of the present invention remain in the body, steadily releasing bedaquiline and maintaining such levels of this active ingredient in the patient's system for an extended period of time, thereby providing adequate treatment or prevention of pathogenic mycobacterial infections during that period. Due to the fact that the pharmaceutical compositions of the present invention remain in the body and steadily release bedaquiline (and its active metabolite, referred to herein as M2, see below, the methyl-substituted metabolite), they may be referred to as pharmaceutical compositions suitable as long-acting (or depot) formulations.

[0047] As used herein with the term "long term" means a term (or time period) which may be in the range of 1 week to 1 year or up to 2 years, or a period in the range of 1 to 2 weeks, or 2 to 3 weeks, or 3 to 4 weeks, or 1 to 2 months, or 2 to 3 months, or 3 to 4 months, or 3 to 6 months, or 6 months to 12 months, or 12 months to 24 months, or a period of several days, for example 7, 10 or 12 days, or a period of several weeks, for example 2, 3 or 4 weeks, or a month, or several months, for example 2, 3, 4, 5 or 6 months, or an even longer period, for example 7, 8, 9 or 12 months.

[0048] The pharmaceutical compositions of the present invention can be applied for the long-term treatment or prophylaxis of pathogenic mycobacterial infections, or in other words, can be used for the long-term treatment or prophylaxis of pathogenic mycobacterial infections. The compositions of the present invention are effective in treating or preventing pathogenic mycobacterial infections for a long period of time, for example, for at least about one week or more, or for about one month or more. The expression "effective for at least about one week or more" means that the plasma level of the active ingredient bedaquiline (and / or its active metabolite M2) should exceed a threshold value. In the case of therapeutic applications, the threshold value is the minimum plasma level at which bedaquiline (and / or its active metabolite M2) provides effective treatment of pathogenic mycobacterial infections. In the case of applications in the prophylaxis of pathogenic mycobacterial infections, the threshold value is the minimum plasma level at which bedaquiline (and / or its active metabolite M2) is effective in preventing the spread of pathogenic mycobacterial infections.

[0049] For example, "long-term" when used in reference to "long-term prevention of pathogenic mycobacterial infection" or "long-term treatment of pathogenic mycobacterial infection" or similar terms means a period that may range from one week to up to one or up to two years, or longer, such as five or ten years. In particular, in the case of treatment of pathogenic mycobacterial infection, such periods will be longer, on the order of one to several months, one or more years. Such periods may also be relatively short, particularly in the case of prevention. Shorter periods are a few days, for example, 7, 10, or 12 days, or a few weeks, for example, 2, 3, or 4 weeks, or one month, or several months, for example, 2, 3, 4, 5, or 6 months, or even longer periods, such as 7, 8, 9, or 12 months. In one embodiment, the methods and uses according to the invention are for the prevention of pathogenic mycobacterial infection for one month, or for several months, for example, 2, 3, 4, 5, or 6 months, or even longer, such as 7, 8, 9, or 12 months.

[0050] The pharmaceutical composition of the present invention can be administered at various time intervals. When used in the prevention of pathogenic mycobacterial infection, the pharmaceutical composition of the present invention can be administered only once or a limited number of times (e.g., 2, 3, 4, 5, or 6 or more times). This may be recommended when prevention is needed for a limited period, such as during a period of risk of infection.

[0051] The pharmaceutical compositions of the present invention may be administered at the above-mentioned time intervals, for example, at intervals ranging from 1 week to 1 month, or from 1 month to 3 months, or from 3 months to 6 months, or from 6 months to 12 months. In one embodiment, the pharmaceutical compositions may be administered once every two weeks, or once a month, or once every three months. In another embodiment, the time intervals are between 1 and 2 weeks, or 2 and 3 weeks, or 3 and 4 weeks, or between 1 and 2 months, or 2 and 3 months, or 3 and 4 months, or 3 and 6 months, or 6 and 12 months, or 12 and 24 months. The time intervals may be at least 1 week, but may also be several weeks, e.g., 2, 3, 4, 5, or 6 weeks, or one or several months, e.g., 2, 3, 4, 5, or 6 months, or even longer, e.g., 7, 8, 9, or 12 months. In one embodiment, the pharmaceutical compositions of the present invention are administered at intervals of 1 month, 2 months, or 3 months. These longer periods between administrations of the pharmaceutical compositions of the present invention provide further improvements in pill burden and compliance. To further improve compliance, patients can be instructed to take the medication on certain days of the week when the composition is administered on a weekly schedule, or on certain days of the month when the composition is administered on a monthly schedule.

[0052] The length of the time interval between each administration of the composition of the present invention may vary. For example, the time interval may be selected as a function of the plasma level. The interval may be shorter if the plasma level of bedaquiline (and / or its active metabolite M2) is considered too low, for example, if they approach the minimum plasma level specified below. The interval may be longer if the plasma level of bedaquiline (and / or its active metabolite M2) is considered too high. In one embodiment, the composition of the present invention is administered at equal time intervals. The composition may be administered without any intervening additional administration; in other words, the composition may be administered at specific time points separated from each other by periods of varying or equal length, for example, a period of at least one week, or any other period specified herein, without further administration of bedaquiline. Having equal time intervals has the advantage of a simple administration schedule, for example, administration on the same day of the week or the same day of the month. Such dosing schedules therefore entail a limited "pill burden," thereby beneficially contributing to patient compliance with the prescribed dosing regimen.

[0053] The concentration (or "C") of bedaquiline (and / or its active metabolite M2) in the plasma of a subject being treated therewith is generally expressed as mass per unit volume, typically nanograms per milliliter (ng / ml). For convenience, this concentration may be referred to herein as the "plasma drug concentration" or "plasma concentration."

[0054] The dose (or amount) of bedaquiline administered depends on the amount of bedaquiline in the pharmaceutical composition of the present invention or the amount of a given composition administered. If higher plasma levels are desired, either a composition with a higher bedaquiline concentration or more of a given composition, or both, can be administered. Conversely, this applies if lower plasma levels are desired. Also, various time intervals and various dosing combinations can be selected to achieve a particular desired plasma level.

[0055] The dose (or amount) of bedaquiline administered also depends on the frequency of administration (i.e., the time interval between each administration). Typically, the dose is higher when the administration frequency is low. All of these parameters can be used to direct the plasma level to the desired value.

[0056] The dosing regimen also depends on whether prophylaxis or treatment of pathogenic mycobacterial infections is envisaged. In the case of therapy, the dose or dosing frequency of bedaquiline administered, or both, is selected to maintain the plasma concentration of bedaquiline above a minimum plasma level. In this context, "minimum plasma level" (or C 最小The term "bedaquiline" refers to a plasma level of bedaquiline (and / or its active metabolite M2) that provides effective treatment of pathogenic mycobacterial infections. In particular, the plasma level of bedaquiline (and / or its active metabolite M2) is maintained above a minimum plasma level of about 10 ng / ml, or above about 15 ng / ml, or above about 20 ng / ml, or above about 40 ng / ml. The plasma level of bedaquiline (and / or its active metabolite M2) may be maintained above a higher minimum plasma level, for example, above about 50 ng / ml, or above about 90 ng / ml, or above about 270 ng / ml, or above about 540 ng / ml. In one embodiment, the plasma level of bedaquiline (and / or its active metabolite M2) is maintained above a level of about 13.5 ng / ml or above a level of about 20 ng / ml. Alternatively, the plasma level of bedaquiline (and / or its active metabolite M2) may be maintained within a certain range, in particular starting from a minimum plasma level selected from those mentioned above and ending at a higher plasma level selected from those mentioned above and selected from 500 ng / ml and 1000 ng / ml (e.g., from a value approximately expressed in ng / ml to a value approximately expressed in ng / ml, such as 10-15, 10-20, 10-40, etc., or 15-20, or 15-40, or 15-90, etc., or 20-40, 20-90, or 20-270, etc., or 40-90, 40-270, or 40-540, etc.). In one embodiment, the range is from about 10 to about 20, from about 20 to about 90, from 90 to 270, from 270 to 540, or from 540 to 1000, in each case from about a value expressed in ng / ml to about a value expressed in ng / ml.

[0057] Plasma levels of bedaquiline (and / or its active metabolite M2) should be maintained above the minimum plasma levels mentioned above, because at lower levels the bacteria are no longer sufficiently suppressed and can proliferate with further risk of the emergence of mutations.

[0058] In the case of prevention, a "minimum plasma level" (or C 最小The term ) refers to the minimum plasma level of bedaquiline (and / or its active metabolite M2) that provides effective treatment / prevention of infection.

[0059] In particular, in the case of prophylaxis, the plasma level of bedaquiline (and / or its active metabolite M2) may be maintained at a level above the minimum plasma level mentioned above in connection with therapy. However, in prophylaxis, the plasma level of bedaquiline (and / or its active metabolite M2) may be maintained at a lower level, for example, above about 4 ng / ml, or about 5 ng / ml, or about 8 ng / ml. The plasma level of bedaquiline (and / or its active metabolite M2) should preferably be maintained above these minimum plasma levels because at lower levels, the drug is no longer effective, thereby increasing the risk of infection transmission. The plasma level of bedaquiline (and / or its active metabolite M2) may be maintained at a somewhat higher level to provide a safety margin. Such higher levels start from about 50 ng / ml or above. Plasma levels of bedaquiline (and / or its active metabolite M2) may be maintained at levels within the ranges described above in connection with the therapy, with lower limits including plasma levels of about 4 ng / ml, or about 5 ng / ml, or about 8 ng / ml.

[0060] An advantage of bedaquiline (and / or its active metabolite M2) is that it can be used up to relatively high plasma levels without significant side effects. Plasma concentrations of bedaquiline (and / or its active metabolite M2) can reach relatively high levels, but as with any drug, there is a maximum plasma level (or C), which is the plasma level at which bedaquiline (and / or its active metabolite M2) causes significant side effects. 最大 ) should not exceed the maximum plasma level (C) specified above. Additionally, compound release from tissues should also be considered, which is not accounted for in plasma levels. As used herein, the term "significant side effects" means that the side effects are present in the relevant patient population to the extent that they affect the normal functioning of the patient. In embodiments, the dose and frequency of administration of bedaquiline (and / or its active metabolite M2) to be administered should be such that the plasma concentration remains above the maximum plasma level (or C) specified above for an extended period of time. 最大) and the minimum plasma level (or C specified above) 最小 ) is selected to be maintained at a level included between

[0061] In certain instances, it may be desirable to maintain the plasma level of bedaquiline (and / or its active metabolite M2) at a relatively low level, for example, as close as possible to the minimum plasma level specified herein. This allows for a reduction in the frequency of administration and / or the amount of bedaquiline (and / or its active metabolite M2) administered with each administration. It also allows for the avoidance of undesirable side effects and contributes to the acceptance of the dosage form among a large proportion of the target population, who are healthy people at risk of infection and therefore less prone to tolerate side effects. In the case of prophylaxis, the plasma level of bedaquiline (and / or its active metabolite M2) can be maintained at a relatively low level. One embodiment relates to a use or method for the prophylaxis of an infection specified above or below, wherein the minimum plasma level of bedaquiline (and / or its active metabolite M2) is as specified herein and the maximum plasma level is approximately equal to the minimum plasma level that causes the active ingredient to be therapeutically active, also as specified herein.

[0062] In other embodiments, the plasma level of bedaquiline (and / or its active metabolite M2) is maintained at a level below a lower maximum plasma level of about 10 ng / ml, more particularly about 15 ng / ml, even more particularly about 20 ng / ml, and even more particularly about 40 ng / ml. In particular embodiments, the plasma level of bedaquiline (and / or its active metabolite M2) is maintained below a level of about 13.5 ng / ml. In one embodiment, the plasma level of bedaquiline (and / or its active metabolite M2) is maintained in the interval between the lower maximum blood level identified above and the minimum plasma level mentioned in connection with prophylaxis. For example, the plasma level of bedaquiline (and / or its active metabolite M2) is maintained below about 10 ng / ml and above a minimum level of about 4 ng / ml.

[0063] In other instances, it may be desirable to maintain plasma levels of bedaquiline (and / or its active metabolite M2) at relatively high levels, e.g., when the risk of infection is high and more frequent and / or higher doses are not an issue. In these cases, the minimum plasma level may be equal to the lowest plasma level of bedaquiline (and / or its active metabolite M2) that provides effective treatment of pathogenic mycobacterial infection, e.g., a particular level referred to herein.

[0064] For prophylaxis, the dose to be administered should be calculated based on about 0.2 mg / day to about 50 mg / day, or 0.5 mg / day to about 50 mg / day, or about 1 mg / day to about 10 mg / day, or about 2 mg / day to about 5 mg / day, for example, about 3 mg / day. This corresponds to a weekly dose of about 1.5 mg to about 350 mg, particularly about 3.5 mg to about 350 mg, particularly about 7 mg to about 70 mg, or about 14 mg to about 35 mg, for example, about 35 mg, or a monthly dose of 6 mg to about 3,000 mg, particularly about 15 mg to about 1,500 mg, more specifically about 30 mg to about 300 mg, or about 60 mg to about 150 mg, for example, about 150 mg. Doses for other dosing regimens can be easily calculated by multiplying the daily dose by the number of days between each administration.

[0065] For therapy, the dose to be administered should be somewhat higher, calculated based on about 1 mg / day to about 150 mg / day, or about 2 mg / day to about 100 mg / day, or about 5 mg / day to about 50 mg / day, or about 10 mg / day to about 25 mg / day, for example, about 15 mg / day. The corresponding weekly or monthly dose can be calculated as described above. For prophylactic applications, the dose may be lower, but the same dosing as for therapeutic applications may be used. In embodiments, doses / administrations are given at monthly intervals or at 3- or 6-monthly intervals, with the total treatment period being 3, 6, or 12 months. When doses / administrations are monthly, 3 times a month, or 6 times a month, in embodiments, the given dose (e.g., in a human subject) is calculated based on a daily dose of 400 mg given for 2 weeks. Thus, the total amount of bedaquiline administered per dose may be about 5600 mg (e.g., in the range of 3000 to 8000 mg), but may be up to one-fifth of such an amount (e.g., in the range of 500 to 2000 mg, e.g., about 1000 to 1500 mg).

[0066] In another embodiment, for prophylaxis or, particularly, therapy, the dose may be expressed in mg / kg. For example, in the examples, a particular dose may be administered based on body weight (e.g., in mammals, and as shown in the examples herein, in mice), and thus a dose of 1 mg / kg to 1000 mg / kg may be used (e.g., 40 mg / kg, 80 mg / kg, 160 mg / kg, 320 mg / kg, or 480 mg / kg may be used), and such a dose may remain effective over a 4-week, 8-week, or 12-week period (e.g., as shown in the examples). For example, one dose may be taken every 4 weeks (effectively seen as a 12-week treatment regimen, i.e., a total of 3 doses), or a single dose may be taken that effectively provides sufficient treatment (e.g., as defined by a reduction in CFUs, see the examples), as can be evidenced by monitoring over 12 weeks. Thus, in embodiments, to treat a bacterial infection, one dose (e.g., 1 mg / kg to 1000 mg / kg, e.g., 2 mg / kg to 500 mg / kg) may be taken, or one such dose may be taken every four weeks (e.g., two or three such doses may be taken). Such doses will depend on the bacterial infection to be treated. For example, in treating latent tuberculosis or leprosy, a lower dose may be required (compared to, e.g., multidrug-resistant tuberculosis) given that a lower amount of bedaquiline is needed to control the bacteria.

[0067] Once administered, the plasma levels of bedaquiline (and / or its active metabolite M2) have been found to be more or less stable, i.e., they fluctuate within a limited range. Plasma levels have been found to approach a near-steady-state mode or a near-zero-order release rate over an extended period of time. "Steady-state" refers to a state in which the amount of drug present in a subject's plasma remains at approximately the same level over an extended period of time. Plasma levels of bedaquiline (and / or its active metabolite M2) generally do not decline below the minimum plasma level at which the drug is effective. The term "remain at approximately the same level" does not exclude the possibility of small fluctuations in plasma concentration within acceptable limits, for example, fluctuations within a range of about ±30%, or about ±20%, or about ±10%, or about ±10%.

[0068] In some instances, there may be an initial plasma concentration peak after administration, after which the plasma level reaches a "steady state," as referred to below.

[0069] The composition of the present invention shows good local tolerance and ease of administration.Good local tolerance is related to minimal irritation and inflammation at the injection site, and ease of administration refers to the needle size and length of time required to administer a certain dose of a specific drug formulation.In addition, the composition of the present invention shows good stability and has an acceptable shelf life.

[0070] The microparticles of the present invention have a surface modifier adsorbed to their surface, the function of which is to act as a wetting agent and stabilizer for the colloidal suspension.

[0071] In one embodiment, the microparticles in the compositions of the present invention primarily comprise crystalline bedaquiline or a salt thereof and a surface modifier, the combined amount of which may constitute at least about 50%, or at least about 80%, or at least about 90%, or at least about 95%, or at least about 99% of the microparticles. As noted herein, in embodiments, bedaquiline is in its non-salt form (or its "free form"), and in further embodiments, in crystalline non-salt (or free) form. In this regard, as noted herein, bedaquiline can be prepared per se using the procedures described in WO 2004 / 011436 (or WO 2006 / 125769, which describes optical resolution with chiral reagents). Following such procedures, bedaquiline is obtained by precipitation from toluene / ethanol, indicating that the product crystallizes. Such forms of bedaquiline can be used to prepare the compositions of the present invention; further, such forms may be single crystalline polymorphs having the following characteristic features: (i) A DSC curve showing a melting endotherm at 181.5°C (endotherm onset) and melting of the product at approximately 182.5°C (immediately followed by decomposition, measured by differential scanning calorimetry (DSC) by transferring approximately 3 mg of compound into a standard aluminum TA-Instruments sample pan, the sample pan was closed at the appropriate temperature, and the DSC curve was recorded on a TA-Instruments Q2000 MTDSC equipped with an RCS cooling unit using the following parameters - initial temperature 25°C, heating range 10°C / min, final temperature 300°C, nitrogen flow 50 ml / min); (ii) In particular, about 1600 cm -1 , about 1450cm -1 , about 1400cm -1 , about 1340cm -1 , and approximately 1250 cm -1 Suitable micro-ATR accessory for developing infrared (IR) spectral peaks (32 scans) at 1 cm -1Analyze the sample using a Thermo Nexus 670 FTIR spectrometer, a DTGS with a KBr window detector, a Ge on KBr beam splitter, and a micro ATR accessory (Harrick Split Pea with a Si crystal); and / or (iii) X-ray powder diffraction (XRPD) showing diffraction peaks without the presence of halos indicative of the crystallinity of the product, with characteristic peaks at about 11.25° 2-theta, about 18° 2-theta, about 18.5° 2-theta, about 19° 2-theta, about 20.25° 2-theta, about 21.25° 2-theta, about 22.25° 2-theta, about 24.5° 2-theta, and about 27° 2-theta (wherein the analysis was performed on a PANalytical (Philips) X'PertPRO MPD diffractometer, the instrument being Cu LFF The X-ray tube was equipped and the compound was spread on a zero-background sample holder. The instrument parameters were generator voltage 45 kV, generator current 40 mA, geometry Bragg-Brentano, stage spinner stage, scanning mode continuous scan, scan range 3-50° 2θ, step size 0.02° / step, count time 30 s / step, spinner rotation time 1 s, and irradiation type CuKα.

[0072] Thus, in an embodiment, the bedaquiline used in the process for preparing the compositions of the invention (i.e., before conversion to microparticles) is in a crystalline form (e.g., of the particular form characterized above). In a further embodiment of the invention, the bedaquiline used in the compositions of the invention (i.e., after conversion to microparticles, for example, by milling) is also in a crystalline form (e.g., of the particular form characterized above). It is an advantage that the crystalline form that is part of the suspension / formulation of the invention does not substantially change when stored at a certain temperature for a certain period of time (e.g., as described below).

[0073] The compositions of the invention are as described herein, where bedaquiline is specified to be present in a certain amount (w / v), and the surface modifier is specified to contain PEG 4000 (or the like) and a poloxamer (such as poloxamer 338), where the total amount of surface modifier is specified, and the ratio (or amount by w / v) of PEG 4000 to poloxamer is also specified. While small or trace amounts of other surface modifiers (as defined herein) may be present so as not to significantly alter the properties (e.g., chemical and / or physical properties) of the composition with respect to the surface modifier, in aspects of the invention the surface modifier consists essentially of (e.g., consists of) PEG 4000 (or the like) and poloxamer in any of the amounts or ratios specified herein.

[0074] PEG 4000, or polyethylene glycol 4000, is a known high molecular weight polymer, where 4000 refers to the approximate average molecular weight in daltons. PEG 4000 is commercially available from suppliers such as Sigma-Aldrich and is therefore used as such. However, encompassed within the scope of the present invention (e.g., when the term "PEG 4000" or "PEG 4000 or similar" is used) are other high molecular weight polyethylene glycols, e.g., those greater than 1000 up to 8000 (e.g., PEG 1000 to PEG 8000, e.g., PEG 2000 to PEG 6000), although in certain embodiments, the PEG group, as referred to herein in the context of the present invention, is PEG 3000 to PEG 5000 (e.g., PEG 3500 to PEG 4500). As indicated herein, it is understood that most PEGs include molecules having a molecular weight distribution, i.e., they are polydisperse, and therefore the number next to PEG represents the average molecular weight in daltons.

[0075] Poloxamers used in the compositions of the invention may include poloxamers such as Pluronic™ F68, F108, and F127, which are block copolymers of ethylene oxide and propylene oxide; in embodiments, the poloxamer used in the compositions of the invention is Poloxamer 338 (equivalent to Pluronic™ F108). Pluronic™ F108 corresponds to Poloxamer 338 and has the general formula HO-[CHCHO] x -[CH(CH3)CH2O] y -[CH2CH2O] z -H, where the average values ​​of x, y, and z are 128, 54, and 128, respectively. Other trade names for poloxamer 338 are Hodag Nonionic™ 1108-F and Synperonic™ PE / F108.

[0076] Suitable surface modifiers, which may be present in small or trace amounts (in addition to the requisite PEG 4000 or similar and poloxamer), can be selected from known organic and inorganic pharmaceutical excipients, including various polymers, low molecular weight oligomers, natural products, and surfactants. Specific surface modifiers include nonionic and anionic surfactants. Representative examples of surface modifiers include gelatin, casein, lecithin, salts of negatively charged phospholipids or their acid forms (phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, phosphoric acid, and salts thereof, such as alkali metal salts, e.g., their sodium salts, e.g., egg phosphatidylglycerol sodium, such as products available under the trade name Lipoid™ EPG), gum acacia, stearic acid, benzalkonium chloride, polyoxyethylene alkyl ethers, e.g., macrogol ethers, such as cetomacrogol 1000, polyoxyethylene castor oil derivatives, polyoxyethylene stearate, colloidal silicon dioxide, sodium dodecyl sulfate, sodium carboxymethylcellulose, sodium taurocholate, Bile salts such as sodium desoxytaurocholate, sodium desoxycholate, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, magnesium aluminate silicate, polyvinyl alcohol (PVA), tyloxapol, vitamin E-TPGS (α-tocopheryl polyethylene glycol succinate, in particular α-tocopheryl polyethylene glycol 1000 succinate), poloxamines such as Tetronic™ 908 (T908), which is a tetrafunctional block copolymer derived from the sequential addition of ethylene oxide and propylene oxide to ethylenediamine, dextran, lecithin, dioctyl esters of sodium sulfosuccinate, e.g., those sold under the trade name AerosolExamples of suitable sucrose stearate and distearate mixtures include those commercially available under the tradenames Crodesta™ F110 and Crodesta™ SL-40, sodium lauryl sulfate (Duponol™ P), alkylaryl polyether sulfonate available under the tradename Triton™ X-200, polyoxyethylene sorbitan fatty acid esters (Tweens™ 20, 40, 60, and 80), sorbitan esters of fatty acids (Span™ 20, 40, 60, and 80 or Arlacel™ 20, 40, 60, and 80), polyethylene glycol (such as those commercially available under the tradenames Carbowax™ 3550 and 934), mixtures of sucrose stearate and sucrose distearate (e.g., products available under the tradenames Crodesta™ F110 or Crodesta™ SL-40), hexyldecyl trimethyl ammonium chloride (CTAC), polyvinylpyrrolidone (PVP), and the like. If desired, two or more surface modifiers can be used in combination.

[0077] Specific surface-modifying agents that may be present in small or trace amounts are selected from α-tocopheryl polyethylene glycol succinate, polyoxyethylene sorbitan fatty acid esters, and salts of negatively charged phospholipids or their acid forms. More specifically, the surface-modifying agent is selected from vitamin E TPGS, Tween™ 80, and Lipoid™ EPG (in a specific embodiment, vitamin E TPGS). Others include polyoxyethylene sorbitan fatty acid esters and phosphatidylglycerol salts (especially egg sodium phosphatidylglycerol).

[0078] The optimal relative amount of bedaquiline to the surface modifier depends on the surface modifier selected, the specific surface area of ​​the bedaquiline suspension, which is determined by the average effective particle size and bedaquiline concentration, the critical micelle concentration of the surface modifier when micelles are formed, etc. The relative amount (w / w) of bedaquiline to the surface modifier is preferably in the range of about 1:1 to about 10:1, particularly in the range of 1.5:1 to about 5:1, e.g., about 2:1.

[0079] The compositions of the present invention may need to be sterile so that they can be administered to a patient. Achieving a sterile composition can be done in several ways, including, for example, producing such compositions in a sterile process or environment following a sterile manufacturing process. Alternative methods include heat sterilization, autoclaving, and gamma irradiation, which serve as sterilization steps that can achieve the desired results. As specified, the compositions of the present invention are prepared according to a sterile manufacturing process (e.g., ensuring a sterile process, equipment, and environment). In a further embodiment, the compositions of the present invention are prepared according to a sterile manufacturing process, and the active pharmaceutical ingredient (API), i.e., bedaquiline (or a salt thereof), is separately gamma-irradiated. Due to the nature of the composition (including its manufacturing method), the compositions of the present invention may consequently have different chemical and / or physical properties. These are outlined in the presented data and can therefore be seen as advantageous properties. The resuspension ability of the compositions of the present invention is also an important aspect; indeed, such compositions were rapidly resuspendable (e.g., by gentle rotation).

[0080] The particles of the present invention can be prepared by micronization / particle size reduction, by mechanical means and controlled precipitation from supersaturated solutions, or by using supercritical fluids as in GAS techniques ("gas antisolvent"), or by any combination of such techniques. In one embodiment, a method is used that includes dispersing bedaquiline in a liquid dispersion medium and applying mechanical means in the presence of grinding media to reduce the particle size of bedaquiline to an average effective particle size of less than about 50 μm, in particular less than about 1,000 nm. The particles can be size-reduced in the presence of a surface modifier.

[0081] Thus, in general, the process for preparing the compositions of the present invention will include a milling step, such as roller milling, as described in more detail herein, but may also include other techniques, such as GMP methods, e.g., high shear bead milling (e.g., Netzsch milling), that allow for scale-up (including GMP scale-up) upon optimization of process parameters. Generally, all of these milling processes may be encompassed within the term "grinding media" as used herein.

[0082] A general procedure for preparing the particles of the present invention is: (a) obtaining bedaquiline in micronized form; (b) adding micronized bedaquiline to a liquid medium to form a premix / predispersion; (c) subjecting the premix to mechanical means in the presence of grinding media to reduce the average effective particle size.

[0083] Micronized forms of bedaquiline are prepared using techniques known in the art. Preferably, the average effective particle size of the bedaquiline active agent in the pre-dispersion is less than about 100 μm, as determined by sieve analysis. If the average effective particle size of the micronized bedaquiline is greater than about 100 μm, it is preferred to reduce the size of the particles of the bedaquiline compound to less than 100 μm (e.g., a size or size range as described herein).

[0084] The micronized bedaquiline can then be added to a liquid medium in which it is essentially insoluble to form a pre-dispersion. The concentration (weight / weight percentage) of bedaquiline in the liquid medium can vary widely and depends on the surface modifier selected and other factors. Suitable concentrations of bedaquiline in the composition vary between about 10% and about 30%, e.g., about 10%, 20%, or 30% (each percentage in this paragraph is w / v).

[0085] The premix can be used directly by subjecting it to mechanical means to reduce the effective average effective particle size in the dispersion to less than 2,000 nm. When a ball mill is used for attrition, it is preferable to use the premix directly. Alternatively, bedaquiline and, optionally, the surface modifier can be dispersed in a liquid medium using suitable agitation, such as, for example, a roller mill, until a homogeneous dispersion is achieved.

[0086] The mechanical means applied to reduce the effective average effective particle size of bedaquiline can conveniently take the form of a dispersion mill. Suitable dispersion mills include media mills such as ball mills, attritor / grinding mills, vibratory mills, planetary mills, sand mills, and bead mills. Media mills are preferred because they require a relatively short milling time to provide the desired particle size reduction. The beads are preferably ZrO2 beads. For example, for fine particles, the ideal bead size is about 2 mm.

[0087] Grinding media for the particle size reduction step can be selected from spherical or particulate rigid media (beads on the order of 200 μm) in form, preferably having an average size of less than 3 mm, more preferably less than 1 mm. Such media can desirably shorten processing time for the particles of the present invention and reduce wear on the milling equipment. Examples of grinding media are ZrO, such as magnesia-stabilized or yttrium-stabilized 95% ZrO, zirconium silicate, glass grinding media, polymer beads, stainless steel, titania, alumina, and the like. Preferred grinding media are 2.5 g / cm 3 It has a higher density and contains 95% ZrO2 stabilized with magnesia and polymer beads.

[0088] Attrition times can vary widely and depend primarily on the particular mechanical means and processing conditions selected. For rolling mills, processing times of up to two days or more may be required.

[0089] The particles should be reduced in size at a temperature that does not significantly degrade the bedaquiline compound. Processing temperatures below 30°C to 40°C are generally preferred. If necessary, the processing equipment can be cooled with conventional cooling equipment. The process is conveniently carried out under ambient temperature conditions and at processing pressures that are safe and effective for milling.

[0090] The pharmaceutical composition according to the present invention preferably contains a pharmaceutically acceptable aqueous carrier. The aqueous carrier comprises sterile water, optionally mixed with other pharmaceutically acceptable ingredients. The latter may include any component for use in an injectable formulation. Such components are optional. These components may be selected from one or more of suspending agents, buffers, pH adjusters, preservatives, tonicity adjusters, etc. In one embodiment, the component is selected from one or more of suspending agents, buffers, pH adjusters, and optionally, preservatives and tonicity adjusters. A particular component may function as two or more of these agents simultaneously, for example, acting as both a preservative and a buffer, or as both a buffer and a tonicity adjuster.

[0091] Suitable optional buffers and pH adjusters should be used in amounts sufficient to maintain the dispersion near neutral, preferably in the pH range of 5.5 to 7.5, e.g., near 5.5 to 6.6 (and in embodiments, the pH is preferably about pH 6). Particular buffers are salts of weak acids. Buffers and pH adjusters that can be added may be selected from tartaric acid, maleic acid, glycine, sodium lactate / lactic acid, ascorbic acid, sodium citrate / citric acid, sodium acetate / acetic acid, sodium bicarbonate / carbonic acid, sodium succinate / succinic acid, sodium benzoate / benzoic acid, sodium phosphate, tris(hydroxymethyl)aminomethane, sodium bicarbonate / sodium carbonate, ammonium hydroxide, benzenesulfonic acid, sodium benzoate / acid, diethanolamine, glucono-delta-lactone, hydrochloric acid, hydrogen bromide, lysine, methanesulfonic acid, monoethanolamine, sodium hydroxide, tromethamine, gluconic acid, glyceric acid, glutaric acid, glutamic acid, ethylenediaminetetraacetic acid (EDTA), triethanolamine, and mixtures thereof. In an embodiment, the composition of the present invention does not contain a buffer. In another embodiment, the compositions of the invention contain a buffering agent, such as citric acid (anhydrous) and disodium hydrogen phosphate (anhydrous parenteral), thus forming a citrate-phosphate buffer, which in embodiments is present at about 0.5% to 1.5% w / v, e.g., about 0.9% w / v (of which the citric acid is present at about 0.2% to 0.4% w / v, e.g., 0.3%, and the phosphate moiety is present at about 0.5% to 0.7% w / v, e.g., 0.6%). In embodiments, sodium hydroxide and / or hydrochloric acid may be initially used in the compositions of the invention to set the pH to about pH 5.5 to 6.5 (e.g., about pH 6).

[0092] Suitable optional preservatives include antimicrobials and antioxidants, which may be selected from the group consisting of benzoic acid, benzyl alcohol, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), chlorobutol, gallates, hydroxybenzoates, EDTA, phenol, chlorocresol, metacresol, benzethonium chloride, myristyl-γ-picolinium chloride, phenylacetate nitrate, and thimerosal. Radical scavengers include BHA, BHT, vitamin E, and ascorbyl palmitate, and mixtures thereof. Oxygen scavengers include sodium ascorbate, sodium sulfite, L-cysteine, acetylcysteine, methionine, thioglycerol, acetone sodium bisulfite, isoascorbic acid, and hydroxypropyl cyclodextrin. Chelating agents include sodium citrate, sodium EDTA, and malic acid. In an embodiment of the present invention, the compositions of the present invention are non-sticky.

[0093] An isotonizing agent or isotonifier may be present to ensure isotonicity of the pharmaceutical composition of the present invention, and includes sugars such as glucose, dextrose, sucrose, fructose, trehalose, and lactose; polyhydric sugar alcohols, preferably trihydric or higher sugar alcohols, such as glycerin, erythritol, arabitol, xylitol, sorbitol, and mannitol. Alternatively, sodium chloride, sodium sulfate, or other suitable inorganic salts can be used to make the solution isotonic. These isotonizing agents can be used alone or in combination. The suspension advantageously contains 0-10% (w / v), particularly 0-6%, of the isotonizing agent. Because electrolytes can affect colloidal stability, non-ionic isotonizing agents, such as glucose, are of interest. In an embodiment of the present invention, the composition of the present invention contains an isotonizing agent or isotonifier, which in a further embodiment is a non-ionic isotonizing agent, such as a suitable sugar, such as mannitol. In another embodiment, the compositions of the present invention do not contain a tonicity agent (also called an osmotic agent).

[0094] A desirable feature of the pharmaceutical compositions of the present invention relates to ease of administration. The viscosity of the pharmaceutical compositions of the present invention should be sufficiently low to allow administration by injection. In particular, they should be designed so that they can be easily taken up into a syringe (e.g., from a vial) and injected through a fine needle (e.g., a 20 G 1 1 / 2, 21 G 1 1 / 2, 22 G 2, or 22 G 1 1 / 4 needle) at reasonable time intervals. In one embodiment, the viscosity of the compositions of the present invention is less than about 75 mPa·s, or less than 60 mPa·s. Aqueous suspensions of such viscosity or less usually meet the above criteria.

[0095] As set out herein, in an embodiment, the invention therefore provides a pharmaceutical composition for administration by intramuscular or subcutaneous injection, comprising a therapeutically effective amount of bedaquiline or a pharmaceutically acceptable salt thereof in the form of a suspension of microparticles prepared by a sterile manufacturing process; and (a) bedaquiline or a pharmaceutically acceptable salt thereof in particulate form, having a surface modifier adsorbed to the surface thereof; and (b) a pharmaceutically acceptable aqueous carrier in which the bedaquiline active ingredient is suspended; Bedaquiline (or a pharmaceutically acceptable salt thereof) is present in an amount of 10% to 30% (w / v) by weight based on the total volume of the composition, and the surface modifier is present in an amount of 5% to 15% (w / v) and comprises at least 30% PEG 4000 (or the like) and at least 30% poloxamer (e.g., poloxamer 338).

[0096] The compositions of the present invention are suspensions of microparticles prepared by a sterile manufacturing process, in which bedaquiline (or a pharmaceutically acceptable salt thereof) and surface modifiers (PEG4000 and poloxamer) are present in certain amounts, as indicated, and in certain further embodiments, as follows: bedaquiline (or a pharmaceutically acceptable salt thereof) is present in an amount of about 15% to 25% (w / v), for example about 20% (w / v); and / or The surface modifier is present at about 8% to 12% (w / v) and comprises a PEG4000 to poloxamer ratio as described herein.

[0097] The compositions of the present invention are optimized based on several parameters, and the optimized amounts of surface modifiers are as described above. In certain further embodiments, they may be present in the following amounts: The surface modifier comprises 30% to 70% PEG 4000 (or similar), with the remainder consisting of 30% to 70% poloxamer. The surface modifier comprises 40% to 60% PEG 4000 and 40% to 60% poloxamer. The surface modifier comprises 45% to 55% PEG 4000 (e.g., about 50%) and 45% to 50% poloxamer (e.g., about 50%). The surface modifier comprises about 2-15% (e.g., 4-6%) PEG 4000 (w / v) and about 2-15% (e.g., 4-6%) poloxamer (w / v). The surface modifier comprises about 5% PEG 4000 (w / v) and about 5% poloxamer (w / v).

[0098] The compositions of the present invention are also described as containing pharmaceutically acceptable carriers, which will be described in more detail herein.For example, the compositions of the present invention may contain one or more buffering agents, one or more tonicity adjusting agents (also known as osmotic agents), and one or more preservatives (although in some embodiments, no preservatives are present); further, the compositions of the present invention may contain water for injection (amount appropriate) and a base (e.g., sodium hydroxide, amount appropriate) and / or an acid (amount appropriate), the latter two being present to initially set the pH (e.g., to about pH 6).

[0099] For example, a composition of the invention prepared by a sterile manufacturing process may include: (a) bedaquiline or a pharmaceutically acceptable salt thereof, present in an amount of about 180 mg / ml to about 220 mg / ml (e.g., about 200 mg / ml) (weights are based on the active moiety, not the salt component, if present); (b) a surface modifier comprising PEG 4000 or the like and a poloxamer (e.g., poloxamer 338), wherein the PEG 4000 or the like is present in an amount of about 40 mg / ml to 60 mg / ml (e.g., about 50 mg / ml) and the poloxamer is present in an amount of about 40 mg / ml to 60 mg / ml (e.g., about 50 mg / ml); (c) a buffer present at about 8 mg / ml to about 10 mg / ml (e.g., about 9 mg / ml), e.g., consisting of citric acid (present at about 2-4 mg / ml, e.g., about 3 mg / ml) and disodium hydrogen phosphate (present at about 5-7 mg / ml, e.g., about 6 mg / ml); (d) a tonicity agent (e.g., mannitol) present at about 5 mg / ml to about 20 mg / ml, e.g., between 10 and 15 mg / ml, e.g., about 13.5 mg / ml; however, in embodiments, no tonicity agent (e.g., mannitol) is present, which may be an advantage. (e) Preservatives, which may be present at 0 to about 20 mg / ml, but are not present in embodiments, it may be an advantage that no preservatives are required. (f) water for injection (qs), sodium hydroxide and / or hydrochloric acid (each qs to adjust the pH as described herein)

[0100] An acid or base may optionally be added to the suspension in an amount to bring the pH to a value of about pH 7. Suitable acids or bases are any physiologically acceptable, such as HCl, HBr, sulfuric acid, alkali metal hydroxides, such as NaOH. In embodiments, no such acids or bases need be added to the compositions of the present invention.

[0101] Administration of bedaquiline (or a pharmaceutically acceptable salt thereof) as in the present invention may be sufficient to treat pathogenic mycobacterial infections, although in many cases co-administration of other anti-TB drugs may be advisable.

[0102] In certain instances, treatment of pathogenic mycobacterial infections may be limited to the administration of bedaquiline (and / or its metabolites) compositions according to the invention, i.e., as monotherapy without the co-administration of additional anti-TB drugs. This option may be advisable, for example, for certain mycobacterial infections (e.g., for latent / dormant TB or Mycobacterium leprae) where lower concentrations of the active ingredient are able to treat the bacteria.

[0103] In a further aspect, the present invention relates to the use of a pharmaceutical composition comprising an effective amount of bedaquiline or a pharmaceutically acceptable salt thereof according to the present invention for the manufacture of a medicament for the maintenance treatment of a subject infected with a pathogenic mycobacterial infection, wherein the composition is or will be administered intermittently at time intervals ranging from 1 week to 1 year, or from 1 week to 2 years.

[0104] Thus, in a further aspect, the present invention provides a method for the long-term treatment of a patient infected with a pathogenic mycobacterial infection, the method comprising: (i) treatment of the patient with a combination of anti-TB drugs, followed by (ii) Intermittent administration of a pharmaceutical composition according to the present invention comprising an effective amount of bedaquiline or a pharmaceutically acceptable salt thereof, wherein the composition is administered at time intervals of at least one week.

[0105] When treatment is directed against Mycobacterium leprae, again, the treatment regimen can be given as monotherapy or in combination with existing drugs useful in treating Mycobacterium leprae (e.g., rifapentine). The compositions of the present invention may be administered by injection once or up to three times, e.g., monthly, at intervals. Advantages relate to compliance, lack of resistance by avoiding dapsone, and lack of stigma by avoiding clofazimine.

[0106] The present invention also relates to a pharmaceutical composition as described hereinabove for use as a medicament in the treatment or prevention of pathogenic mycobacterial infections.

[0107] Additionally, the present invention relates to the use of the pharmaceutical compositions described herein for the preparation of a medicament for the prevention or treatment of pathogenic mycobacterial infections.

[0108] The present invention further relates to a method of treating a subject infected with a pathogenic mycobacterial infection, the method comprising administering a therapeutically effective amount of a pharmaceutical composition described herein.

[0109] As used herein, the term "substantially" does not exclude "completely", for example, a composition that is "substantially free" of Y may be completely free of Y. Where necessary, the word "substantially" may be omitted from the definition of the invention. The term "about" in relation to a numerical value is meant to have its ordinary meaning in relation to the numerical value. Where necessary, the word "about" may be replaced by the numerical value ±10%, or ±5%, or ±2%, or ±1%.

[0110] All documents cited herein are incorporated by reference in their entirety.

[0111] The following examples are intended to illustrate the present invention and should not be construed as limiting the invention thereto. [Example]

[0112] Process Example: Preparation of Microsuspension The active ingredient bedaquiline may be used as is or may be converted into its pharmaceutically acceptable salt, such as the fumarate salt (e.g., the form used in the marketed product Sirturo®). As referred to herein, bedaquiline is used in its non-salt form unless otherwise specified.

[0113] The preparation process of the composition of the present invention is by a sterile manufacturing process, in which bedaquiline is γ-irradiated. The bedaquiline composition may be prepared as follows: Preparation of 200 mg / mL and 100 mg / mL microsuspensions.

[0114] Materials used: Zirconium beads 0.5mm (to aid in processing) Sterile water for injection (Viaflo) Bedaquiline (unmilled / unpolished) - This API is gamma-irradiated Surface modifiers (including, for example, PEG 4000 (or similar) (50 mg / ml) and poloxamer (50 mg / ml)) - excipients 2mm zirconium beads (to aid in processing) Mannitol (parenteral) - excipient

[0115] Glass bottles and ZrO2 beads (either 0.5 mm or 2 mm, depending on the desired microsuspension) used as milling media were sterilized in an autoclave. The drug substance (in an amount depending on the formulation to be prepared, see, for example, the formulations / suspensions below) was placed in a glass bottle along with an injectable aqueous solution of surface modifiers (PEG4000 (or similar) (50 mg / ml) and poloxamer (50 mg / ml)) (in an amount depending on the required / desired concentration, see, for example, the formulations / suspensions below). ZrO2-beads with an average particle size of 500 μm or 2 mm (depending on whether a microsuspension or nanosuspension is required / desired) were added. The bottle was placed on a roller mill. The suspension was micronized at 100 rpm for a period of up to 72 hours. For example, micronization may be performed at 100 rpm for 3 hours (or up to 3 hours). At the end of the milling process, the concentrated microsuspension was removed with a syringe and filled into vials. The resulting formulation (based on microsuspension) is described herein. The concentration was determined by HPLC / UV. If necessary, dilutions were made to a final concentration of 200 mg / ml of the active ingredient bedaquiline. The resulting suspension was protected from light.

[0116] Thus, in general, the process for preparing the compositions of the invention will include a step of milling, such as roller milling, as described in more detail herein, but may also include other techniques, such as GMP methods, e.g., high shear bead milling (such as Netzsch milling), that allow for scale-up (including GMP scale-up), e.g., upon optimization of process parameters.

[0117] Such formulations have been (and are) administered intramuscularly and subcutaneously to animals for PK studies to investigate possible long-acting effects (e.g., in the treatment of tuberculosis, e.g., latent tuberculosis, or even for the treatment of leprosy).

[0118] The physical stability of the suspension is followed by measuring the particle size after different storage conditions.

[0119] Certain embodiments of the formulation have the following features: -Microsuspension by using 2mm Zr beads -Mill at 200mg / mL (otherwise the concentration may be too high, e.g. 300mg / ml). -Longer milling results in nanosuspension Suitable surface modifiers, e.g., selected based on physical stability, such as the surface modifiers or wetting agents described herein.

[0120] Reference example of bedaquiline microsuspension The 200 mg / ml microsuspensions are referred to herein as Reference A (without buffer) and References B and C (with buffer). Reference example A

[0121] [Table 1]

[0122] [Table 2]

[0123] PSD measurements after one month indicate that the formulation remains relatively stable.

[0124] Stability testing using HPLC: An HPLC test method was used to determine how stable the long-acting injectable formulation of Reference Example A was. The objective was to measure the amount of bedaquiline relative to two known degradants after a specific period of time at room temperature.

[0125] HPLC procedure: Column - ProntoSIL 120-3-C18 SH, 100 mm length x 3.0 mm internal diameter, 3 μm particle size, or equivalent; column temperature 35°C; autosampler temperature 5°C; flow rate 0.5 mL / min; detection UV, wavelength 230 nm; data collection time 50 min; analytical run time 60 min; injection volume 10 μl; mobile phase A is 0.03 M hydrochloric acid in water; mobile phase B is methanol / acetonitrile / 2-propanol-45 / 45 / 10 (v / v / v).

[0126] [Table 3]

[0127] HPLC purity testing indicates that the formulation of Reference Example A is relatively stable over time (given that the relative amounts of degradants and bedaquiline remained stable).

[0128] Reference Examples B and C

[0129] [Table 4]

[0130] [Table 5]

[0131] The PSD of these formulations under a variety of conditions (including after autoclaving) indicates that the formulations remain relatively stable.

[0132] Reference example D PEG 4000 (or polyethylene glycol 4000), which can be supplied by Clariant GmbH, is used. PEG 4000 is a hydrophilic agent that can be used to increase the viscosity of the suspension vehicle and can act as a suspending agent.

[0133] [Table 6]

[0134] In this case, a buffer was added to avoid a drop in pH.

[0135] [Table 7]

[0136] The PSD of the microsuspension of Reference Example D shows that the formulation remains relatively stable even after autoclaving.

[0137] The approximate cloud point of the formulation of Reference Example D was calculated to be about 105 to 110°C.

[0138] The autoclaving of the microsuspension of Reference Example D was carried out in a Systec autoclave (VX / VE series), the parameters being: Sterilization temperature: 121°C (above the calculated cloud point). Sterilization time: 15 minutes Removal temperature: 80℃

[0139] In a typical autoclave cycle, a steam generator builds up the necessary steam pressure, which flows into the sterilization chamber and remains constant for the duration of the sterilization period after reaching the sterilization temperature, after which the cycle, with optional built-in cooling, cools down to the removal temperature.

[0140] Reference Examples E1 and E2

[0141] [Table 8]

[0142] A buffer was added to prevent a drop in pH.

[0143] [Table 9]

[0144] Objective Stability Testing Criteria -Various formulations / suspensions / concepts were tested, each of which was subjected to a specific sterilization technique. Autoclaving (see methods above for examples) gamma irradiation of the suspension (e.g., by methods such as those described above in the Background section) 〇 Aseptic manufacturing (using gamma-irradiated API) - Each type of sterilization technique may have certain advantages, and certain formulations may have advantages in that they may be suitable for or resistant to particular sterilization techniques, but formulations (or suspensions / concepts) may also be tested for their stability as follows:

[0145] chemical stability - Assay / Purity by UHPLC -Aldehyde content by UHPLC - VitE TPGS content determination by UHPL (for corresponding formulations containing it) -Peroxide content of gamma-irradiated suspensions by UPLC / MS -pH

[0146] physical stability -Appearance / Injectability / Resuspensionability -PSD -XRD

[0147] This can be done for all stability studies. - After 1 month, 3 months and 6 months for samples stored at a certain temperature and a certain relative humidity, e.g., 30°C / 75% RH and 40°C / 75% RH - and after 28 days for samples stored at 60°C (assay / purity) and 50°C (PSD and XRD)

[0148] Example Depending on the sterilization technique, formulations / suspensions may have different properties, for example different chemical and physical stability properties, and the following examples have been prepared and tested.

[0149] Example 1 - Microsuspension of the present invention Example 1A Formulation:

[0150] [Table 10]

[0151] In this case, a buffer is added to avoid a drop in pH, which in this case is a mixture of citric acid and phosphate (sodium phosphate, 50 mM phosphate-citrate buffer), and sodium hydroxide and / or hydrochloric acid may also be used to initially adjust the pH, with the target pH being pH 6.

[0152] It does not contain a tonicity agent (also called an osmotic agent) such as mannitol.

[0153] This Formulation Example 1A was prepared (with a gamma-irradiated API) using aseptic manufacturing. Thus, specifically, the API product (bedaquiline) is gamma-irradiated and then the suspension is made using aseptic manufacturing techniques, e.g., using sterilized equipment or other techniques to ensure that the final formulation / suspension produced is substantially free of bacteria.

[0154] As noted above, the formulation / suspension may also be autoclaved or the entire final formulation / suspension may be gamma-irradiated. However, Formulation Example 1A has advantages in chemical and / or physical stability compared to, for example, known bedaquiline long-acting formulations / suspensions or compared to formulations / suspensions prepared by other methods, such as autoclaving or gamma-irradiation of the entire formulation / suspension.

[0155] Stability test results Regarding the formulation of the present invention Chemical stability - this was tested at 30°C / 75% RH and 40°C / 75% RH - Assay / Purity by UHPLC

[0156] [Table 11] Here, for example, T=1M 30°C means a period of one month at a temperature of 30°C, 28D=28 days, etc. -Aldehyde (formaldehyde, acetaldehyde, propionaldehyde) content by UHPLC

[0157] [Table 12] -VitE TPGS content determination by UHPL is not applicable to this formulation / suspension. -pH

[0158] [Table 13]

[0159] Physical stability at 30°C / 75% RH and 40°C / 75% RH -Appearance / Injectability / Resuspensionability

[0160] [Table 14] -PSD

[0161] [Table 15] -XRD

[0162] [Table 16]

[0163] Conclusion - Chemical stability - The purity assay of Formulation Example 1A remained stable for up to 6 months. No impurities above the reporting threshold of 0.05% were detected. After 28 days at 60°C, impurity X was formed (approximately 0.10%) and had an RRT of 1.36. - The aldehyde content was measured. - For formulation example 1A, minimal or no change was observed in formaldehyde, acetaldehyde, and propionaldehyde content. -Minimal or no change in pH value was observed

[0164] Conclusion - Physical stability For Formulation Example 1A, some soft aggregates were observed after 1 month of storage at 30°C, 40°C, and 50°C (however, these were not seen at either the 3-month or 6-month time points measured at certain temperatures). - Change in particle size (PSD - particle size distribution) / No significant change was observed - XRD - x-ray diffraction - the preferred crystalline form was observed at all times (crystalline forms of bedaquiline described herein)

[0165] In summary, the formulations of the present invention / Example 1A may have chemical and / or physical stability advantages based on any of the criteria measured herein (e.g., purity analysis, aldehyde content, pH, appearance / resuspension / injectability, PSD and / or XRD).

[0166] Other concepts Other concepts:

[0167] [Table 17]

[0168] In this case, a buffer may be added to avoid a drop in pH, which in this case is a mixture of citric acid and phosphate (sodium phosphate), and sodium hydroxide and / or hydrochloric acid may also be used to initially adjust the pH, and the amount of buffer can be determined, for example, a 50 mM phosphate-citrate buffer is used with a target pH of 6.

[0169] The amount of mannitol (which may also be called a tonicity agent or osmotic agent) may also be determined, for example, based on the amount used in Examples 1A / 1B above.

[0170] This formulation concept A was prepared by autoclaving (see herein for method).

[0171] [Table 18]

[0172] In this case, a buffer may be added to avoid a drop in pH, which in this case is a mixture of citric acid and phosphate (sodium phosphate), and sodium hydroxide and / or hydrochloric acid may also be used to initially adjust the pH, and the amount of buffer can be determined, for example, a 50 mM phosphate-citrate buffer is used with a target pH of 6.

[0173] The amount of mannitol (which may also be called a tonicity agent or osmotic agent) may also be determined, for example, based on the amount used in Examples 1A / 1B above.

[0174] This formulation concept B was prepared by gamma irradiation of the final formulation / suspension.

[0175] [Table 19]

[0176] In this case, a buffer may be added to avoid a drop in pH, which in this case is a mixture of citric acid and phosphate (sodium phosphate), and sodium hydroxide and / or hydrochloric acid may also be used to initially adjust the pH, and the amount of buffer can be determined, for example, a 50 mM phosphate-citrate buffer is used with a target pH of 6.

[0177] The amount of mannitol (which may also be called a tonicity agent or osmotic agent) may also be determined, for example, based on the amount used in Examples 1A / 1B above.

[0178] This formulation concept C was prepared by gamma-irradiation of the final formulation / suspension.

[0179] [Table 20]

[0180] In this case, a buffer may be added to avoid a drop in pH, which in this case is a mixture of citric acid and phosphate (sodium phosphate), and sodium hydroxide and / or hydrochloric acid may also be used to initially adjust the pH, and the amount of buffer can be determined, for example, a 50 mM phosphate-citrate buffer is used with a target pH of 6.

[0181] The amount of mannitol (which may also be called a tonicity agent or osmotic agent) may also be determined, for example, based on the amount used in Examples 1A / 1B above.

[0182] This formulation concept D was prepared by gamma-irradiation of the final formulation / suspension.

[0183] The chemical and physical stability test criteria indicated the following: - Concept A failed physical stability testing for appearance / syringability / resuspensionability. - Random challenge at 40°C for 1 month and 3 months (and after 3 months, caking was detected at the bottom of the vial) 〇3 months at 25℃ due to needle clogging when removing Concepts B and C failed because the amount of Vit E TPGS decreased by approximately 20% immediately after γ-irradiation of the formulation / suspension, leaving only 75-80% of the Vit E TPGS (however, no further decrease was measured after this initial drop). - Concept D failed the physical stability test, at least visually, even at TO, caking of the formulation was already visible at the bottom of the flask.

[0184] Biological Example: Pharmacokinetic Study Example 1A was tested in rats with the following results:

[0185] [Table 21] * Median (min-max)

[0186] Example 1A was tested in dogs with the following results:

[0187] [Table 22] * Median (min-max)

Claims

1. A pharmaceutical composition for administration by intramuscular or subcutaneous injection, comprising a therapeutically effective amount of bedaquiline or a pharmaceutically acceptable salt thereof in the form of a microparticle suspension prepared by a sterile manufacturing process; (a) bedaquiline or a pharmaceutically acceptable salt thereof in microparticulate form, present in an amount of 10% to 30% by weight (w / v) based on the total volume of the composition; (b) a surface modifier present at 5% to 15% (w / v) and comprising at least 30% PEG 4000 (or the like) and at least 30% poloxamer (e.g., poloxamer 338), and (c) a pharmaceutically acceptable aqueous carrier.

2. A pharmaceutical composition for administration by intramuscular or subcutaneous injection, comprising a therapeutically effective amount of bedaquiline or a pharmaceutically acceptable salt thereof in the form of a microparticle suspension prepared by a sterile manufacturing process; (a) bedaquiline or a pharmaceutically acceptable salt thereof in particulate form, having a surface modifier adsorbed to the surface thereof; and (b) a pharmaceutically acceptable aqueous carrier in which the bedaquiline active ingredient is suspended; Including, 1. A pharmaceutical composition, wherein the bedaquiline (or a pharmaceutically acceptable salt thereof) is present in an amount of 10% to 30% by weight (w / v) based on the total volume of the composition, and the surface modifier is present in an amount of 5% to 15% (w / v), comprising at least 30% PEG 4000 (or the like) and at least 30% poloxamer (such as, for example, poloxamer 338).

3. 3. The composition according to claim 1 or 2, wherein bedaquiline is in its non-salt or free form, or in the form of a fumarate salt.

4. 4. The composition of any one of claims 1 to 3, wherein the bedaquiline (or a pharmaceutically acceptable salt thereof) is present at about 15% to 25% (w / v), such as about 20% (w / v).

5. 5. The composition of claim 1, wherein the surface modifier is present at about 8% to 12% (w / v) and comprises about 5% PEG 4000 (w / v) and about 5% poloxamer (w / v).

6. 5. The composition of any one of claims 1 to 4, wherein the microparticles of bedaquiline or a pharmaceutically acceptable salt thereof have an average effective particle size of less than about 50 μm.

7. Prepared by a sterile manufacturing process, and (a) bedaquiline or a pharmaceutically acceptable salt thereof, present in an amount of about 180 mg / ml to about 220 mg; (b) a surface modifier comprising PEG 4000 or the like and a poloxamer (e.g., poloxamer 338), wherein the PEG 4000 or the like is present in an amount of about 40 mg / ml to 60 mg / ml and the poloxamer is present in an amount of about 40 mg / ml to 60 mg / ml; (c) a buffering agent present at about 8 mg / ml to about 10 mg / ml, e.g., consisting of citric acid (present at about 2-4 mg / ml) and disodium hydrogen phosphate (present at about 5-7 mg / ml); 7. The composition of any one of claims 1 to 6, comprising (d) water for injection (qs), sodium hydroxide and / or hydrochloric acid (each in an amount sufficient to adjust the pH as described herein).

8. Use of a pharmaceutical composition according to any one of claims 1 to 7 for the manufacture of a medicament for the treatment of a pathogenic mycobacterial infection.

9. 9. The use according to claim 8, wherein the medicament is for the long-term treatment of Mycobacterium tuberculosis (such as latent / dormant forms) or Mycobacterium leprae.

10. 9. The use according to claim 8, wherein the medicament is for administration by intramuscular or subcutaneous injection, and the composition is administered intermittently at time intervals of from 1 week to 2 years.

11. The use according to claim 8, wherein the pharmaceutical composition is administered at intervals of at least one month to one year.

12. 9. The use according to claim 8, wherein the pharmaceutical composition is administered at time intervals ranging from 1 week to 1 month, or from 1 month to 3 months, or from 3 months to 6 months, or from 6 months to 12 months, or from 12 months to 24 months.

13. 9. The use according to claim 8, wherein the pharmaceutical composition is administered once every two weeks, once a month, or once every three months.

14. A process for preparing the pharmaceutical composition according to any one of claims 1 to 7, comprising: (a) obtaining bedaquiline or a pharmaceutically acceptable salt thereof in micronized form; (b) adding the micronized bedaquiline or pharmaceutically acceptable salt thereof to a liquid medium to form a premix / predispersion; (c) subjecting said premix to mechanical means in the presence of grinding media to reduce the average effective particle size.

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