Long-acting formulations

Abstract

The present invention relates to pharmaceutical compositions for intramuscular or subcutaneous injection administration comprising microparticles of the anti-TB compound bedaquiline suspended in a pharmaceutically acceptable aqueous 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 a pharmaceutical composition for administration via intramuscular or subcutaneous injection, comprising the ATP synthase inhibitor compound bedaquiline (trade name The invention relates to micro- or nano-particles of bedaquiline (in the form of its fumarate salt) for sale; and also relates to the use of such pharmaceutical compositions in the treatment of bacterial infections such as tuberculosis. Background Art

[0002] Bedaquiline is a known anti-tuberculosis drug used in various combinations. Bedaquiline can be formulated in the form of a pharmaceutically acceptable salt, such as bedaquiline fumarate, available under the trade name Bedaquiline is believed to act as an ATP synthase inhibitor with a selectivity index of over 20,000 for mycobacterial ATP synthase versus eukaryotic mitochondrial ATP synthase.

[0003] Bedaquiline has been reported to be useful for treating mycobacterial infections and can also be used to kill dormant, latent, persistent mycobacteria, particularly Mycobacterium tuberculosis, and is therefore useful for treating latent TB. Such uses of bedaquiline have been described in several publications including international patent documents WO 2004 / 011436 and WO 2006 / 067048. Bedaquiline is also known to have a bactericidal effect against Mycobacterium leprae, for example, as described in "Bacterial Activities of R207910 and other Antimicrobial Agents against Mycobacterium leprae in Mice", Antimicrobial agents and Chemotherapy, April 2006, page 1558 and "The Diarylquinolone R207910 is Bactericidal against Mycobacterium leprae in mice and at Low Dose Administered Intermittently", Antimicrobial agents and Chemotherapy, September 2009, page 3989.

[0004] The purpose of a long-acting formulation may be to reduce the drug burden. This is particularly useful for treatment regimens that may last for several months.

[0005] The number and / or volume of dosage forms that need to be administered is often referred to as the "pill load". A high pill load is undesirable for many reasons, such as frequency of intake, which often has the inconvenience of having to swallow a large dosage form, along with the need to store or transport a large number or volume of pills. A high pill load increases the risk that patients do not take their full dose, thereby failing to adhere to the prescribed dosage regimen. Likewise, the effectiveness of treatment is reduced, which also leads to the development of resistance (e.g., bacterial resistance in the case of bedaquiline).

[0006] It would therefore be attractive to provide a treatment involving administration of a dosage form at long intervals, such as a week or more, or even a month or more.

[0007] A variety of formulations are known in the art, including long-acting formulations. For example, known micron and nano suspension technologies have achieved long-acting formulations in the field of anti-HIV drugs, such as those described in international patent applications WO 2007 / 147882 and WO 2012 / 140220. In addition, nanoparticles known in the prior art have been described, for example, in EP-A-0 499 299. Such particles have an average particle size in the submicron range and are composed of particles of a crystallized bulk drug, which have a surface modifier adsorbed on their surface. Nanoparticles have also been used to formulate active ingredients that are poorly soluble in water.

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

[0009] The importance of long-acting formulations relates to the intermittent use of these micron or nanoparticle formulations at one week or longer intervals, which produces a plasma level sufficient to inhibit the growth of mycobacterial infection. This allows to reduce the number of administrations, which is beneficial with respect to the patient's pill load and drug compliance. Therefore, the micron or nanoparticle formulations of bedaquiline can be used for long-term treatment of mycobacterial infection (e.g. tuberculosis (including latent tuberculosis) and leprosy).

[0010] Intermittent administration of micro- or nanoparticle formulations of bedaquiline at intervals of one week or longer also results in plasma levels that may be sufficient to provide prevention of the spread of mycobacterial infection. Also in this case, the number of administrations needs to be reduced, which is also advantageous in terms of pill load or medication compliance for individuals at risk of infection.

[0011] The challenge related to the manufacture and suitability of such long-acting formulations relates to the fact that they must be sterilized (which is important for injections, for example, if they are intended to be administered intravenously or subcutaneously). There are a variety of different ways to sterilize such long-acting formulations, including by heat sterilization, aseptic manufacturing process, autoclave and gamma radiation (γ-radiation). Examples of some methods are described in, for example, U.S. Patents / Applications US 5,298,262, US 5,346,702 and US2010 / 255102. For heat sterilization and autoclave, it is important to be able to select autoclave-sterilizable (for example, non-degradable) excipients (for example, surface modifiers or surfactants). Further challenges occur after such sterilization, which are associated with the desired stability of the long-acting formulation, the undesirable aggregation of the active pharmaceutical ingredient (API) particles in the formulation, and the desired re-suspendability (re-suspendability) of the formulation (after sterilization (for example, autoclave)).

[0012] Therefore, the challenge is not only to produce a long-acting formulation, but also to find one that is suitable for maintaining a certain level of stability for a sufficient period of time.

[0013] Additional alternative and / or improved long acting formulations are now described, and the present invention relates to such formulations. Summary of the invention

[0014] The present invention relates to 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 micronized particles, the pharmaceutical composition being prepared by an aseptic manufacturing process and comprising:

[0015] (a) bedaquiline or a pharmaceutically acceptable salt thereof in the form of micronized particles, 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;

[0016] (b) a surface modifier present at 5% to 15% (w / v) and comprising at least 30% PEG4000 (or an analog) and at least 30% poloxamer (such as poloxamer 338); and

[0017] (c) a pharmaceutically acceptable aqueous carrier,

[0018] And wherein such compositions may be referred to herein as "composition(s) of the invention".

[0019] The composition of the present invention is a suspension, by which we mean that the bedaquiline active ingredient is suspended in a pharmaceutically acceptable aqueous carrier.

[0020] The composition (ie, suspension) of the present invention contains a surface modifier that can be adsorbed onto the surface of the active ingredient bedaquiline.

[0021] Thus, in an embodiment, the present invention may be directed to 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 micronized particles, the pharmaceutical composition being prepared by an aseptic manufacturing process and comprising:

[0022] (a) bedaquiline or a pharmaceutically acceptable salt thereof in the form of micron particles, on the surface of which a surface modifier is adsorbed; and

[0023] (b) a pharmaceutically acceptable aqueous carrier; wherein the bedaquiline active ingredient is suspended, wherein the bedaquiline (or a pharmaceutically acceptable salt thereof) is present at 10% to 30% (w / v) by weight based on the total volume of the composition, and the surface modifier is present at 5% to 15% (w / v), and comprises at least 30% PEG4000 (or an analogue) and at least 30% poloxamer (such as poloxamer 338).

[0024] The composition of the present invention is a suspension of micronized particles prepared by a sterile manufacturing process, and as indicated, the bedaquiline (or a pharmaceutically acceptable salt thereof) and the surface modifier (PEG4000 and poloxamer) are present in an amount; in certain other embodiments, they are present in the following amounts:

[0025] - bedaquiline (or a pharmaceutically acceptable salt thereof) is present at about 15% to 25% (w / v), such as about 20% (w / v); and / or

[0026] - The surface modifier is present at about 8% to 12% (w / v), the surface modifier comprising the ratio of PEG4000 to poloxamer described herein.

[0027] The compositions of the present invention have been optimized based on a number of parameters, and the amounts of the optimized surface modifiers are as described above; in certain additional embodiments, they may also be present in the following amounts:

[0028] - the surface modifier comprises 30% to 70% PEG4000 (or the like), the remainder therefore consisting of 30% to 70% poloxamer;

[0029] - The surface modifier comprises 40% to 60% PEG4000 and 40% to 60% poloxamer

[0030] - the surface modifier comprises 45% to 55% (e.g. about 50%) of PEG4000 and 45% to 50% (e.g. about 50%) of poloxamer

[0031] - the surface modifier comprises about 2% to 15% (e.g., 4% to 6%) PEG4000 (w / v) and about 2% to 15% (e.g., 4% to 6%) poloxamer (w / v)

[0032] - The surface modifier comprises about 5% PEG4000 (w / v) and about 5% poloxamer (w / v).

[0033] The compositions of the present invention are also indicated to contain a pharmaceutically acceptable carrier, which is described in more detail below.

[0034] The present invention further relates to a method of treating a subject infected with pathogenic mycobacteria such as Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium leprae, Mycobacterium avium and Mycobacterium marinum. In an embodiment, the mycobacterium is Mycobacterium tuberculosis (including latent or dormant forms) or Mycobacterium leprae. The composition of the present invention may be particularly suitable for treating Mycobacterium leprae and latent or dormant forms of Mycobacterium tuberculosis. This is because for the treatment of these specific infections, lower concentrations of bedaquiline in the plasma may be effective against such infections, as described, for example, in Robert Gelber, Koen Andries et al., Antimicrobial Agents and Chemotherapy, September 2009, pp. 3989-3991 (the contents of which are incorporated herein by reference), and wherein, essentially, low doses and intermittent administration of bedaquiline were reported to show promise for leprosy patients; however, the lowest dose that killed 99% of the bacteria for Mycobacterium tuberculosis was 30 mg / kg / wk, and the lowest dose for Mycobacterium leprae was <5.0 mg / kg / wk, so once a month administration was as effective as 5 days a week; other publications on the effects of bedaquiline on Mycobacterium leprae in mice include Antimicrobial Agents and Chemotherapy, April 2006, pp. 1558-1560 by Baohong Ji, Koen Andries et al. - the contents of which are also incorporated herein by reference. Therefore, the composition of the present invention can be particularly suitable for treating the method for the experimenter of the mycobacterium tuberculosis infected with mycobacterium leprae or latent / dormant form.The method for the experimenter of the pathogenic mycobacterium infected with this type of treatment includes the pharmaceutical composition as described in detail above or below by intramuscular or subcutaneous injection for the treatment of effective dose.Or alternatively, the present invention relates to the purposes of the pharmaceutical composition as described in detail above or below, for the manufacture of the medicine for treating pathogenic mycobacterium infection (or for using such medicine in the special treatment scheme as described herein).In one embodiment, the composition is used for the long-term treatment of pathogenic mycobacterium infection.In embodiments, pathogenic mycobacterium infection can be as described above or below, such as needing the infection of long-term treatment (in other embodiments, can further use the relatively low plasma concentration level of bedaquiline or its active metabolite to treat such as latent / dormant mycobacterium tuberculosis infection, or in specific embodiments, treat mycobacterium leprae infection).

[0035] In another aspect, a method for long-term treatment of a subject infected with pathogenic mycobacteria (such as Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium leprae, Mycobacterium avium and Mycobacterium marinum) is provided, the method comprising administering an effective amount of a pharmaceutical composition as described in detail above or below by intramuscular or subcutaneous injection; wherein the composition is intermittently administered or to be administered at intervals ranging from one week to one year, or one week to two years. Alternatively, the present invention relates to the use of a pharmaceutical composition as described in detail above or below for the manufacture of a subject infected with pathogenic mycobacteria such as Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium leprae, Mycobacterium avium and Mycobacterium marinum, and a medicament for administration by intramuscular or subcutaneous injection, wherein the composition is intermittently administered or to be administered at intervals ranging from one week to one year, or one week to two years. Thus, it is understood that the term "long-term treatment" refers to treatment in which a single dose or application (e.g., by intramuscular or subcutaneous injection) will have a sustained therapeutic effect over a period of time as described herein, such as a few hours, weeks, or months (e.g., in embodiments, over a period of at least or up to one month, three months, or six months; see the Examples. In other words, long-term treatment may refer to a long period of time (i.e., intervals) between doses / applications (as described herein) in the case of more than one dose / application, as described herein.

[0036] In another aspect, as described herein (e.g., above), a method for treating a subject infected with pathogenic mycobacteria (e.g., any type of pathogenic mycobacteria as described herein) for a long term is provided herein, wherein a single administration / application (e.g., of an amount as described herein, as described below) is provided / required (and a single administration / application has a sustained effect, e.g., within a time period as described herein). In another aspect, a long-term treatment regimen is provided herein, wherein two such administrations or applications are provided / required, and these administrations / applications are administered at intervals, wherein the interval time period is as described herein, e.g., at least or up to a period of one month, three months, or six months-e.g., within the time period during which the sustained therapeutic effect lasts. In a further embodiment, a long-term treatment regimen is provided, wherein three such administrations or applications are provided / required at such intervals as described herein. In yet another embodiment, a long-term treatment regimen as described herein is provided, but it is performed before introducing a treatment period (which is not a long-term treatment regimen, e.g., a once-daily administration process, which lasts for one week, two weeks, three weeks, or one month).

[0037] The present invention further relates to a method for preventing pathogenic mycobacterial infection in a subject at risk of infection with pathogenic mycobacterial infection, the method comprising administering to the subject an amount of the pharmaceutical composition as described in detail above or in further detail below in an amount effective to prevent pathogenic mycobacterial infection. Alternatively, the present invention relates to the use of the pharmaceutical composition as described in detail above or in further detail below for the manufacture of a medicament for preventing pathogenic mycobacterial infection in a subject at risk of infection with pathogenic mycobacterial infection.

[0038] In another aspect, the present invention relates to a method for 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 described in detail above or further described below, wherein the composition is administered or is to be administered intermittently at time intervals ranging from one week to one year, or from one week to two years.

[0039] The present invention also relates to the use of a pharmaceutical composition as described in detail above or in detail 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 administered or is to be administered intermittently at time intervals ranging from one week to one year, or from one week to two years.

[0040] In one embodiment, the invention relates to the use or method as described in detail herein, wherein the pharmaceutical composition is administered or is to be administered intermittently at time intervals ranging from one week to one month, or ranging from one month to three months, or ranging from three months to six months, or ranging from six months to twelve months, or ranging from 12 months to 24 months.

[0041] In another embodiment, the invention relates to the use or method as specified herein, wherein the pharmaceutical composition is administered or is to be administered once every two weeks, or once every month, or once every three months.

[0042] Additional pharmaceutical compositions, methods of treatment or prevention, and uses for the production of medicaments based on these compositions are described below and are intended to be part of the present invention. DETAILED DESCRIPTION

[0043] The compound used in the present invention is the compound TMC207, also known as bedaquiline.

[0044] Bedaquiline may be used in its non-salt form or in the form of a suitable pharmaceutically acceptable salt, such as an acid addition salt form or a base addition salt form. In an embodiment, in the composition of the present invention, bedaquiline is in its non-salt form.

[0045] Pharmaceutically acceptable acid addition salts are defined as non-toxic acid addition salt forms with therapeutic activity that bedaquiline can form. The acid addition salt can be obtained by treating the free form of bedaquiline with an appropriate acid, and the acid is, for example, an inorganic acid, such as a hydrohalic acid, particularly hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid; an organic acid, such as acetic acid, glycolic acid, propionic 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, fumarate is contemplated because this is a product already sold on the market. The form used in.

[0046] Possible therapeutically active non-toxic base addition salt forms can be prepared by treatment with appropriate organic and inorganic bases. Suitable base salt forms include, for example, ammonium salts, alkali metal salts and alkaline earth metal salts (particularly lithium salts, sodium salts, potassium salts, magnesium salts and calcium salts); salts with organic bases (e.g., benzathine penicillin, N-methyl-D-glucamine, hydrabamine salts); and salts with amino acids such as arginine and lysine.

[0047] Conversely said acid or base addition salt forms can be converted into the free forms by treatment with an appropriate base or acid.

[0048] The term addition salt as used in the framework of the present application also includes the solvates that are able to form bedaquiline and its salts. Such solvates are, for example, hydrates and alcoholates.

[0049] Whenever we refer to the use of bedaquiline (or TMC207) in this article, we are referring to the commercially available product and disclosed in WO 2004 / 011436 as a single stereoisomeric form of an antimycobacterial agent.

[0050] It has been found that the physico-chemical properties of bedaquiline allow the manufacture of micron or nanoparticle suspensions with unique pharmacokinetic properties, which can be used for long-term treatment of pathogenic mycobacterial infections as well as for long-term prevention of pathogenic mycobacterial infections, and for this purpose, only a limited number of drug administrations are required. This is beneficial in terms of pill burden as well as patient compliance with a prescribed dosage regimen.

[0051] As used herein, the term "treating a pathogenic mycobacterial infection" relates to treating a subject infected with a pathogenic mycobacterial infection.

[0052] The term "preventing pathogenic mycobacterial infection" relates to preventing or avoiding a subject from contracting a pathogenic mycobacterial infection. The source of infection can be various, such as material containing a pathogenic mycobacterial infection.

[0053] The term "therapeutically effective amount", "amount effective to prevent pathogenic mycobacterium infection" and similar terms refer to the amount or concentration of the composition of the present invention (or the amount / concentration of the active ingredient bedaquiline in such composition) that produces an effective plasma level. "Effective plasma level" refers to those plasma levels of bedaquiline, which provide effective treatment or effective prevention of pathogenic mycobacterium infection. This is because the amount / dose / application given can be associated with the exposure level or required plasma level required for effective treatment / prevention, for example as described herein (see, for example, Examples).

[0054] The term "subject" particularly relates to a human being.

[0055] The term "micron or nanoparticle" refers to particles in the micron or nanometer range. The size of the particle should be lower than the maximum size, beyond which administration by subcutaneous or intramuscular injection becomes impaired or even no longer possible. The maximum size depends on, for example, the limits imposed by the needle diameter or the adverse reactions of the body to large particles, or both. In one embodiment, the pharmaceutical composition of the present invention comprises bedaquiline in the form of micron particles.

[0056] The average effective particle size of the microparticles of the present invention can 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, after preparation and after a period of up to 3 months (e.g., when stored at temperatures of about 5° C., 25° C., and 40° C.), typically:

[0057] - In an embodiment, the microsuspension (or composition of the invention) may have a D90 of about 3 μm to 10 μm (e.g., about 4 μm to 7 μm, such as about 5 μm or 6 μm); a D50 of about 2 μm to 4 μm (e.g., about 2 μm to 3 μm, such as about 2.5 μm) and a D10 of about 0.3 μm to 1.5 μm (e.g., about 0.5 μm to 1 μm, such as about 0.7 μm or 0.8 μm) - All these D10 / D50 / D90 values ​​may refer to those values ​​after preparation (i.e., at T0 or time zero), or may also refer to those values ​​after a specific period of time (e.g., 1 month / 1M, 3M, 6M), where they are stored at a specific temperature (e.g., 30°C, 40°C, 50°C or 5°C).

[0058] In embodiments, micronized particles are used, wherein the average effective particle size as measured by D10, D50 and / or D90 (as measured by D50 in embodiments) is less than about 50 μm, or less than about 20 μm, and greater than about 0.1 μm (100 nm). In embodiments, the range of such micronized particles used in the compositions of the present invention is between about 20 μm and about 0.1 μm, in further embodiments, between about 15 μm and greater than about 0.2 μm, and in further embodiments, between about 10 μm and greater than 0.2 μm, for example between about 10 μm and greater than 0.2 μm (see also above and below values, where specific values ​​of D10 / D50 / D90 are measured). The above values ​​refer to the measured values ​​after preparation. However, in embodiments, they may also refer to measurements after a period of up to 3 months (e.g., after 5 days, one week, two weeks, one month, two months, or three 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 that the average effective particle size (as measured herein by the D10 / D50 / D90 values, also referred to as particle size distribution (PSD)) does not change significantly, but rather the D10 / D50 / D90 values ​​remain relatively stable - meaning that there is less than 25%, e.g., less than 15%, deviation within these values.

[0059] As used herein, the term average effective particle size has its conventional meaning as known to those of ordinary skill in the art, and can be measured by particle size measurement techniques known in the art, such as, for example, sedimentation field flow fractionation, photon correlation spectroscopy, laser diffraction or disc centrifugation. The average effective particle size mentioned herein can relate to the volume distribution of particles. In that case, "effective particle size less than about 50 μm" means that at least 50% of the volume of particles has an effective average particle size less than 50 μm, and the same applies to the other effective particle sizes mentioned. In a similar manner, the average effective particle size can relate to the weight distribution of these particles, but generally this will result in the same or approximately the same value for the average effective particle size.

[0060] The pharmaceutical composition of the present invention provides the release of active ingredient bedaquiline with the time period of extension, and therefore can also be referred to as sustained or slow release composition.After administration, the composition of the present invention stays in the body and stably releases bedaquiline, keeps such level of the active ingredient in the patient's system for a time period of extension, thus providing the appropriate treatment or prevention of pathogenic mycobacterium infection in the time period.Because of the following fact: the pharmaceutical composition of the present invention stays in the body and slowly releases bedaquiline (and its active metabolite, referred to herein as M2; Via hereinafter, methyl-substituted metabolite), so they can be referred to as being suitable for being a pharmaceutical composition as a long-acting (or depot) formulation.

[0061] As used herein, the term "extended period of time" refers to a period (or time period) that can range from one week to up to one year or up to two years, or a period ranging from one to two weeks, or two to three weeks, or three to four weeks, or a period ranging from one to two months, or two to three months, or three to four months, or three to six months, or six months to 12 months, or 12 months to 24 months, or a period ranging from a few days (e.g., 7, 10 or 12 days), or a few weeks (e.g., 2, 3 or 4 weeks), or a month, or a few months (e.g., 2, 3, 4, 5 or six months or even longer, such as 7, 8, 9 or 12 months).

[0062] The pharmaceutical composition of the present invention can be applied to the long-term treatment or long-term prevention of pathogenic mycobacterium infection, or in other words, the pharmaceutical composition of the present invention can be used for treating pathogenic mycobacterium infection in an extended time period, or preventing pathogenic mycobacterium infection. In the treatment or prevention of pathogenic mycobacterium infection, the composition of the present invention is effective for an extended time period, for example, for at least about one week or longer, or for about 1 month or longer. The statement "effective for at least about one week or longer" refers to that the plasma level of active ingredient bedaquinoline (and / or its active metabolite M2) will be higher than the threshold value. In the case of therapeutic application, the threshold value is the minimum plasma level that bedaquinoline (and / or its active metabolite M2) provides the effective treatment of pathogenic mycobacterium infection. In the case of the prevention application of pathogenic mycobacterium infection, the threshold value is the minimum plasma level that bedaquinoline (and / or its active metabolite M2) can effectively prevent pathogenic mycobacterium infection from spreading.

[0063] Wherein "long-term", for example, in relation to "long-term prevention of pathogenic mycobacterial infection" or "long-term treatment of pathogenic mycobacterial infection", or similar terms, refers to multiple periods, ranging from one week to up to one year or up to two years, or longer, such as five years or 10 years. In particular, in the case of treatment of pathogenic mycobacterial infection, such a period will be very long, about one to several months, one year or longer. Such a period can also be shorter, especially in the case of prevention. Shorter periods are those of a few days, such as 7, 10 or 12 days, or a few weeks, such as 2, 3 or 4 weeks, or a month, or a few months, such as 2, 3, 4, 5 or six months or even longer, such as 7, 8, 9 or 12 months. In one embodiment, the method and use according to the present invention are used to prevent pathogenic mycobacterial infection during a month, or a few months, such as 2 months, 3 months, 4 months, 5 months or six months or even longer, such as 7 months, 8 months, 9 months or 12 months.

[0064] The pharmaceutical composition of the present invention may be administered at various time intervals. When used to prevent pathogenic mycobacterial infection, the pharmaceutical composition of the present invention may be administered only once or a limited number of times, such as twice, three times, four times, five times or six times, or more. This may be recommendable in cases where prevention is required during a limited period of time (e.g., a period of time in which there is a risk of infection).

[0065] The pharmaceutical composition of the present invention can be applied at the above-mentioned time interval, such as one week to one month with a scope, or a scope of one month to three months, or a scope of three months to six months, or a scope of six months to twelve months. In one embodiment, the pharmaceutical composition can be applied once every two weeks, or once every month, or once every three months. In another embodiment, the time interval range is one week to two weeks, or two weeks to three weeks, or three weeks to four weeks, or the time interval range is one month to two months, or two months to three months, or three months to four months, or three months to six months, or six months to 12 months, or 12 months to 24 months. The time interval can be at least one week, but can also be a few weeks, for example 2,3,4,5 or 6 weeks, or the time interval is one month, or several months, for example 2,3,4,5 or 6 months or even longer, for example 7,8,9 or 12 months. In one embodiment, the pharmaceutical composition of the present invention is applied at a time interval of one month, two months or three months. These longer periods between each application of the pharmaceutical composition of the present invention provide further improvements with respect to pill load and compliance. To further improve compliance, patients may be instructed to take their medications with the composition administered on a day mid-week in the case of a weekly schedule, or on a day mid-month in the case of a monthly schedule.

[0066] The time interval length between each application of the composition of the present invention can vary. For example, the time interval can be selected according to the plasma level. In the case where the plasma level of bedaquiline (and / or its active metabolite M2) is thought to be too low, for example, when these levels are close to the minimum plasma level described in detail below, the interval can be shorter. In the case where the plasma level of bedaquiline (and / or its active metabolite M2) is thought to be too high, the interval can be longer. In one embodiment, the composition of the present invention is applied at equal time intervals. The composition can be applied without any intermediate additional application, or in other words, the composition can be applied at a specific time point spaced apart from each other by a time period (for example, a time period of at least one week, or any other time period described in detail here) of varying or equal length, during which bedaquiline is not applied in addition. Having the same length time interval has the advantage that the application plan is simple, for example, application occurs on the same day in the middle of the week, or on the same day in the month. Therefore, such an application plan involves a limited "pill load", thereby beneficially promoting the compliance of the patient to the prescribed dosage regimen.

[0067] The concentration (or "C") of bedaquiline (and / or its active metabolite M2) in the plasma of a subject treated with it is usually expressed as mass per unit volume, typically nanograms per milliliter (ng / ml). For convenience, the concentration may be referred to herein as "plasma drug concentration" or "plasma concentration."

[0068] The dosage (or amount) of the bedaquiline used depends on the amount of bedaquiline in the pharmaceutical composition of the present invention, or depends on the amount of the given composition used. In the case of wishing a higher plasma level, the composition of a higher bedaquiline concentration or any one or both of more given compositions can be used. If wishing a lower plasma level, this in turn also can be applied. And the combination of the administration of the time interval and the variation of the variation can be selected to reach the plasma level of a certain hope.

[0069] The dosage (or amount) of the bedaquiline used also depends on the frequency of application (i.e. the time interval between each application). Usually, when the frequency of application is lower, dosage will be higher. All these parameters can be used to guide blood plasma levels to the value of hope.

[0070] The dosage regimen also depends on whether it is the prevention or treatment of pathogenic mycobacterial infection that is envisioned. In the case of treatment, the dosage or dosing frequency or both of the bedaquiline used are selected so that the plasma concentration of bedaquiline is maintained above the minimum plasma level. In this context, the term "minimum plasma level" (or C min) refers to the plasma level that shellfish reaches quinoline (and / or its active metabolite M2) and provides the effective treatment of pathogenic mycobacteria infection.Especially, the plasma level of shellfish reaches quinoline (and / or its active metabolite M2) and is maintained at the level higher than about 10ng / ml or higher than about 15ng / ml or higher than about 20ng / ml or higher than about 40ng / ml minimum plasma level.The plasma level of shellfish reaches quinoline (and / or its active metabolite M2) can be maintained at higher than higher minimum plasma level, and the higher minimum plasma level is for example higher than about 50ng / ml or higher than about 90ng / ml or higher than about 270ng / ml or higher than about 540ng / ml.In one embodiment, the plasma level of shellfish reaches quinoline (and / or its active metabolite M2) and is maintained at the level higher than about 13.5ng / ml, or is maintained at the level higher than about 20ng / ml. Or the plasma level of bedaquiline (and / or its active metabolite M2) can be maintained within a certain range, in particular the following range: 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 500ng / ml and 1000ng / ml (e.g., from 10 to 15, 10 to 20, 10 to 40, etc., or from 15 to 20, or 15 to 40, or 15 to 90, etc., or 20 to 40, 20 to 90, or 20 to 270, etc., or 40 to 90, 40 to 270, or 40-540, etc., each time from about the indicated value in ng / ml to about the indicated value in ng / ml). 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, from 540 to 1000, each time from about the indicated value in ng / ml to about the indicated value in ng / ml.

[0071] Plasma levels of bedaquiline (and / or its active metabolite M2) should be maintained above the above minimum plasma levels, since at lower levels the bacteria are no longer sufficiently inhibited and it can proliferate, bringing with it an additional risk of mutations arising.

[0072] In the context of prevention, the term "minimum plasma level" (or C min ) refers to the lowest plasma level of bedaquiline (and / or its active metabolite M2) that provides effective treatment / prevention of infection.

[0073] In particular, in the case of prevention, the plasma level of bead reaches quinoline (and / or its active metabolite M2) can remain on the level higher than the above-mentioned minimum plasma level related to treatment. However, in prevention, the plasma level of bead reaches quinoline (and / or its active metabolite M2) can remain on lower levels, for example, at a level higher than about 4ng / ml or about 5ng / ml or about 8ng / ml. The plasma level of bead reaches quinoline (and / or its active metabolite M2) should preferably remain higher than these minimum plasma levels, because at a lower level medicine can no longer be effective, thus increasing the risk of infection transfer. The plasma level of bead reaches quinoline (and / or its active metabolite M2) can remain on slightly higher levels, to have a safety margin. Such higher levels start from about 50ng / ml or higher. The plasma level of bead reaches quinoline (and / or its active metabolite M2) can remain on the level in the above-mentioned scope related to treatment, but wherein the lower limit includes the plasma level of about 4ng / ml or about 5ng / ml or about 8ng / ml.

[0074] An advantage of bedaquiline (and / or its active metabolite M2) is that it can be used at relatively high plasma levels without any significant side effects. Plasma concentrations of bedaquiline (and / or its active metabolite M2) may reach relatively high levels, but as with any drug, the maximum plasma level (or C max ), i.e., the plasma level at which bedaquiline (and / or its active metabolite M2) causes significant side effects. In addition, the release of the compound from the tissue should also be considered, which is not considered within the plasma level. As used herein, the term "significant side effects" refers to side effects present in the relevant patient population to the extent that the side effects affect the patient's normal function. In an embodiment, the amount and frequency of administration of bedaquiline (and / or its active metabolite M2) to be administered are selected so that the plasma concentration is maintained at a level for a long time, which is included in the maximum plasma level (or C as described in detail above). max ) and minimum plasma level (or C as specified above) min )between.

[0075] In some cases, it may be desirable to maintain the plasma level of bedaquiline (and / or its active metabolite M2) at a relatively low level, such as close to the minimum plasma level described in detail herein as much as possible. This will allow the amount of the bedaquiline (and / or its active metabolite M2) used by reducing the frequency of application and / or each administration. It will also be allowed to avoid undesirable side effects, which will contribute to the acceptability of the dosage form in most target population groups, which are healthy people with risk of infection and therefore less inclined to tolerate side effects. In the case of prevention, the plasma level of bedaquiline (and / or its active metabolite M2) can be maintained at a relatively low level. As described above or in detail below, it is related to an embodiment of the purposes or method for preventing infection, wherein the minimum plasma level of bedaquiline (and / or its active metabolite M2) is as described in detail here, and the maximum plasma level is approximately equal to the minimum plasma level causing active ingredient to play a therapeutic effect, which is also described in detail as text.

[0076] In other embodiments, the plasma level of bedaquiline (and / or its active metabolite M2) is maintained at a level lower than the lower maximum plasma level, and the lower maximum plasma level is about 10ng / ml, more particularly about 15ng / ml, further particularly about 20ng / ml, still more particularly about 40ng / ml. In a specific embodiment, the plasma level of bedaquiline (and / or its active metabolite M2) is maintained at a level lower than about 13.5ng / ml. In one embodiment, the plasma level of bedaquiline (and / or its active metabolite M2) is maintained at the interval of the minimum plasma level mentioned when the lower maximum plasma level described in detail above and the prevention is related. For example, the plasma level of bedaquiline (and / or its active metabolite M2) remains lower than about 10ng / ml and higher than the minimum level of about 4ng / ml.

[0077] In other cases, it may be desirable to maintain the plasma level of bedaquiline (and / or its active metabolite M2) at a relatively high level, for example, when there is a high risk of infection and more frequent and / or higher dosage is not a problem. In these cases, minimum plasma level can be equal to the minimum plasma level at which bedaquiline (and / or its active metabolite M2) provides an effective treatment of pathogenic mycobacterium infection, such as the specific level mentioned herein.

[0078] In the case of prevention, the dosage to be applied 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 the following weekly dosage: 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 corresponds to the following monthly dosage: 6 mg to about 3000 mg, particularly about 15 mg to about 1,500 mg, more particularly about 30 mg to about 300 mg, or about 60 mg to about 150 mg, for example, about 150 mg. The dosage of other dosing regimens can be easily calculated by multiplying the daily dose with the number of days between each administration.

[0079] In the case of treatment, the dosage to be applied should be higher to some extent and should be calculated based on about 1mg / day to about 150mg / day, or about 2mg / day to about 100mg / day, or about 5mg / day to about 50mg / day, or about 10mg / day to about 25mg / day, for example, about 15mg / day. The corresponding weekly or monthly dosage can be calculated as described above. For use in prevention, the dosage can be lower, although the dosage identical with the therapeutic application can also be used. In embodiments, administration / application is given at monthly intervals or every three months or every six months, and the total treatment duration is three, six months or 12 months. In the case where administration / application is monthly, every three months or every six months, in embodiments, the dosage given (for example, in human subjects) is calculated based on the 400mg daily dosage given for 2 weeks. Thus, the total amount of bedaquiline administered per administration may be about 5600 mg (e.g., in the range of 3000 to 8000 mg), but may be up to one-fifth of this amount (e.g., in the range of 500 to 2000 mg, such as between about 1000 and 1500 mg).

[0080] In another embodiment, in the case of prevention or particularly treatment, dosage can also be represented by mg / kg.For example, in an embodiment, it is possible to apply certain dosages based on body weight (e.g., mammals, and as shown in the embodiments herein, in mice), therefore it is possible to use a dosage between 1mg / kg and 1000mg / kg (e.g., 40mg / kg, 80mg / kg, 160mg / kg, 320mg / kg or 480mg / kg), and such dosages can keep the period of 4 weeks, 8 weeks or 12 weeks (e.g., as shown in the embodiments) effective.For example, a dosage (effectively regarded as a 12-week treatment regimen, i.e., a total of three dosages) can be taken every 4 weeks, or a single dose (e.g., defined by the reduction of CFU, referring to the embodiments) effectively providing enough treatment can be taken, and the enough treatments can be monitored and proved by the period of 12 weeks. Therefore, on the one hand, in order to treat bacterial infection, a dosage (for example between 1mg / kg and 1000mg / kg, for example between 2mg / kg and 500mg / kg) or a such dosage (for example two or three such dosages) can be taken every 4 weeks. Such dosage depends on bacterial infection to be treated. For example, in the treatment of latent tuberculosis or leprosy, because the content of bedaquinoline required for controlling antibacterial is lower, it may be necessary to give lower dosage (compared with for example multidrug-resistant tuberculosis).

[0081] It has been found that once used, the plasma level of bedaquiline (and / or its active metabolite M2) is almost stable, i.e. fluctuates within limited limits. It has been found that during the extended time period, the plasma level approaches almost steady state mode, or finds approximate almost zero order of magnitude release rate." steady state " refers to the extended time period, wherein the amount of the medicine present in the subject's plasma remains on the situation of almost the same level. The plasma level of bedaquiline (and / or its active metabolite M2) does not show any situation that drops to the effective minimum plasma level below the drug usually. The term "remaining on almost the same level" does not exclude that there may be a small fluctuation of the plasma concentration within an acceptable range, such as about ± 30% or about ± 20% or about ± 10% or about ± 10% fluctuation in the scope.

[0082] In some cases, there may be an initial peak plasma concentration following administration, after which plasma levels reach a "steady state," as described below.

[0083] The compositions of the present invention show good local tolerance and are easy to apply. Good local tolerance refers to minimal irritation and inflammation at the injection site; ease of application refers to the size of the needle and the length of time required to apply a particular drug formulation. In addition, the compositions of the present invention also show good stability and have an acceptable shelf life.

[0084] The micronized particles of the present invention have a surface modifier adsorbed on their surface. The surface modifier functions as a wetting agent and a stabilizer for the colloidal suspension.

[0085] In one embodiment, the micron particles in the composition of the present invention mainly comprise crystalline bedaquiline or its salt; and a surface modifier, the combined amount of which can contain 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 micron particles. As indicated herein, in embodiments, bedaquiline is in its non-salt form (or in its "free form"), and in other embodiments, it is in a crystalline non-salt (or in free) form. In this regard, as mentioned herein, bedaquiline can be prepared as is using the procedure described in international patent application WO 2004 / 011436 (or WO 2006 / 125769, which describes an optical resolution performed with a chiral reagent). According to such procedures, bedaquiline is obtained by precipitation from toluene / ethanol, and it is shown that the product has crystallized. Such forms of bedaquiline can be used to prepare the composition of the present invention, and in addition, such forms can be single polymorphs with the following characteristics:

[0086] (i) melting endotherm at 181.5°C (endotherm onset) and DSC curve indicating melting of the product at about 182.5°C (followed by immediate decomposition; measured by differential scanning calorimetry (DSC) by transferring about 3 mg of the compound into a standard aluminum TA-Instrument sample pan, closing the sample pan with an appropriate coer, and recording the DSC curve on a TA-Instruments Q2000 MTDSC equipped with RCS cooling using the following parameters - initial temperature 25°C; heating range 10°C / min; final temperature 300°C, nitrogen flow 50 ml / min);

[0087] (ii) In particular, the infrared (IR) spectrum has a peak at about 1600 cm -1 、About 1450cm -1 , about 1400cm -1 、About 1340cm -1 and about 1250cm -1 (Use can be 1cm -1 Samples were analyzed using a suitable microATR accessory with a resolution of 32 scans, a ThermoNexus 670 FTIR spectrometer, DTGS with a KBr window detector, Ge on KBr beam splitter and a microATR accessory (Hairick Split-Pea with Si crystal); and / or

[0088] (iii) X-ray powder diffraction (XRPD) characteristic peaks at about 11.25° 2-θ, about 18° 2-θ, about 18.5° 2-θ, about 19° 2-θ, about 20.25° 2-θ, about 21.25° 2-θ, about 22.25° 2-θ, about 24.5° 2-θ and about 27° 2-θ, showing that there is no halo around the diffraction peaks, indicating the crystallinity of the product (wherein the analysis was performed on a PANalytical (Philips) X'PertPRO MPD diffractometer equipped with a Cu LFF X-ray tube, and the compound was spread on a zero background sample holder; instrument parameters were: generator voltage - 45 kV; generator current intensity - 40 mA; geometry - Bragg-Brentano; stage - rotating stage; scanning mode - continuous; scanning range 3° to 50° 2θ, step size 0.02° / step; counting time 30 sec / step; rotator rotation time - 1 sec; radiation type CuKα).

[0089] Therefore, in an embodiment, the bedaquiline used in the method for preparing the composition of the present invention (i.e., before being converted into micron particles) is in a crystalline form (e.g., a specific form characterized above). In another embodiment of the present invention, the bedaquiline used in the composition of the present invention (i.e., after being converted into micron particles, for example, by grinding) is also in a crystalline form (e.g., a specific form characterized above). Advantageously, the crystalline form as part of the suspension / preparation of the present invention does not substantially change when stored for a specific period of time at a specific temperature (e.g., as described below).

[0090] The composition of the present invention is as described herein, wherein bedaquiline is present in a certain amount (w / v) and the surface modifier contains PEG4000 (or an analogue) and poloxamer (such as poloxamer 338) in detail, wherein the total amount of the surface modifier is detailed, and the ratio of PEG4000 to poloxamer in a certain ratio (or the amount in w / v) is also detailed. With regard to the surface modifier, although there may be a small amount or trace amount of other surface modifiers (as defined herein) so that they do not significantly change the properties (e.g., chemical properties and / or physical properties) of the composition, in one aspect of the present invention, the surface modifier is essentially composed of (e.g., composed of) PEG4000 (or an analogue) and poloxamer in any of the amounts or ratios described in detail herein.

[0091] PEG4000 (or polyethylene glycol 4000) is a known high molecular weight polymer, wherein 4000 refers to the approximate average molecular weight in daltons. PEG4000 is commercially available from sources such as Sigma-Aldrich, so PEG4000 is used as such. However, included within the scope of the present invention (e.g., when the term "PEG4000" or "PEG4000, etc.") are other high molecular weight polyethylene glycols, such as those above 1000 and up to 8000 (e.g., PEG1000 to PEG8000, such as PEG2000 to PEG6000), even in a specific embodiment, when referred to herein in the context of the present invention, the PEG group is PEG3000 to PEG5000 (e.g., PEG3500 to PEG4500). As indicated herein, the number next to PEG represents the average molecular weight in daltons, and as should be understood, most PEGs include molecules with molecular weight distributions, i.e., they are polydisperse.

[0092] Poloxamers useful in the compositions of the present invention may include poloxamers such as Pluronic TM F68, F108 and F127, which are block copolymers of ethylene oxide and propylene oxide; in an embodiment, the poloxamer used in the composition of the present invention is poloxamer 338 (which corresponds to Pluronic TM F108). Pluronic TM F108 corresponds to poloxamer 338 and is a polyoxyethylene, polyoxypropylene block copolymer which generally conforms to the formula HO-[CH2CH2O] 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 of Poloxamer 338 are Hodag Nonionic TM 1108-F and Synperonic TM PE / F108.

[0093] Suitable Surface modifiers(Except for the necessary PEG4000 or the like and poloxamer) can be selected from known organic and inorganic pharmaceutical excipients, including a variety of 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 acidic forms (such as phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, phosphatidic acid and their salts, such as alkali metal salts, for example, their sodium salts, such as sodium phosphatidylglycerol of eggs, such as the product sold under the trade name Lipoid TM EPG available products), gum arabic, stearic acid, benzalkonium chloride, polyoxyethylene alkyl ethers (e.g., polyethylene glycol ethers, such as cetochrome 1000, polyoxyethylene castor oil derivatives); polyoxyethylene stearate, colloidal silicon dioxide, sodium lauryl sulfate, sodium carboxymethylcellulose, bile salts, such as sodium taurocholate, sodium deoxytaurocholate, sodium deoxycholate; methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, magnesium aluminum silicate, polyvinyl alcohol (PVA); tyloxapol; vitamin E-TPGS (α-tocopheryl polyethylene glycol succinate, especially α-tocopheryl polyethylene glycol 1000 succinate); poloxamines, such as Tetronic TM 908 (T908), which is a tetrafunctional block copolymer obtained by the sequential addition of ethylene oxide and propylene oxide to ethylenediamine; dextran; lecithin; sodium dioctyl sulfosuccinate, such as in the trade name Aerosol OT TM Products sold under (AOT); Sodium Lauryl Sulfate (Duponol TM P); trade name Triton TM X-200 obtained alkyl aryl polyether sulfonate; polyoxyethylene sorbitan fatty acid ester (Tweens TM 20, 40, 60 and 80); sorbitan esters of fatty acids (Span TM 20, 40, 60 and 80 or Arlacel TM 20, 40, 60 and 80); polyethylene glycol (such as in the trade name Carbowax TM 3550 and 934); sucrose stearate and sucrose distearate mixtures, such as those sold under the trade name Crodesta TM F110 or Crodesta TM SL-40 obtained product; hexyldecyltrimethylammonium chloride (CTAC); polyvinylpyrrolidone (PVP). If necessary, two or more surface modifiers can be used in combination.

[0094] Specific surface modifiers that may be present in small or trace amounts are selected from α-tocopherol polyethylene glycol succinate, polyoxyethylene sorbitan fatty acid esters, and salts or acid forms of negatively charged phospholipids. More particularly, the surface modifier is selected from vitamin E TPGS, Tween TM 80 and Lipoid TM EPG (and in a particular embodiment, the surface modifier is vitamin ETPGS). Others include polyoxyethylene sorbitan fatty acid esters and phosphatidylglycerol salts (particularly sodium egg phosphatidylglycerol).

[0095] The optimal relative amount of bedaquiline to the surface modifier depends on the selected surface modifier, the specific surface area of ​​the bedaquiline suspension (which is determined by the average effective particle size and the bedaquiline concentration), the critical micelle concentration of the surface modifier (if 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, specifically in the range of 1.5:1 to about 5:1, for example about 2:1.

[0096] The compositions of the present invention may need to be sterile so that they can be administered to patients. Sterile compositions can be achieved in a variety of ways, including making such compositions in an aseptic process or in an aseptic environment, for example, following an aseptic manufacturing process. Alternatives include heat sterilization, high pressure sterilization, and gamma irradiation as sterilization steps that can achieve the desired results. As noted, the compositions of the present invention herein are prepared according to an aseptic manufacturing process (e.g., ensuring aseptic processes, equipment, and environment); in another embodiment, the compositions of the present invention are prepared according to an aseptic manufacturing process, and wherein the active pharmaceutical ingredient (API), i.e., bedaquiline (or its salt), is γ-irradiated alone. Due to the nature of the compositions of the present invention (including their methods of manufacture), the compositions may have different chemical and / or physical properties - these properties are outlined in the data provided and can therefore be considered as advantageous properties. The resuspendability of the compositions of the present invention is also an important aspect, and indeed such compositions are rapidly resuspendable (e.g., by gentle vortexing). -

[0097] The particles of the present invention may be prepared by mechanical micronization / particle size reduction and by controlled precipitation from a supersaturated solution, or by using a supercritical fluid as in the GAS technique ("gas antisolvent"), or any combination of such techniques. In one embodiment, a method comprising the steps of dispersing bedaquiline in a liquid separation medium and applying mechanical means in the presence of a milling medium to reduce the particle size of bedaquiline to an average effective particle size of less than about 50 μm, particularly less than about 1,000 nm is used. The size of the particles may be reduced in the presence of a surface modifier.

[0098] Generally speaking, the method for preparing the composition of the present invention will therefore include a milling (e.g., roller milling) step, which is described in more detail herein, but may also include other techniques, such as GMP methods, e.g., high shear bead milling (Netzsch milling, etc.), which allow for scale-up (including GMP scale-up), e.g., when process parameters are optimized. In general, all of these milling methods may be encompassed within the term "milling media" as used herein.

[0099] The general procedure for preparing the particles of the present invention includes:

[0100] (a) obtaining bedaquiline in micronized form;

[0101] (b) adding micronized bedaquiline to a liquid medium to form a premix / predispersion; and

[0102] (c) mechanically treating the premix in the presence of milling media to reduce the average effective particle size;

[0103] Bedaquiline is prepared in micronized form using technology known in the art. The average effective particle size of the bedaquiline active agent in the pre-dispersion is preferably less than about 100 μm (as measured by sieve analysis). When the average effective particle size of micronized bedaquiline is greater than about 100 μm, the particle size of the bedaquiline compound is preferably reduced to less than 100 μm (for example, particle size or particle size range as described herein).

[0104] Micronized bead quinoline can then be added to the liquid medium, wherein micronized bead quinoline is substantially insoluble and forms a pre-dispersion. The concentration (weight to weight percentage) of bead quinoline in the liquid medium can vary greatly and depends on selected surface modifiers and other factors. The suitable concentration of bead quinoline in the composition changes between approximately 10% to approximately 30%, for example approximately 10%, 20% or 30% (each percentage value in this paragraph relates to w / v).

[0105] Can be directly used to reduce the effective average effective particle size in the dispersion to less than 2,000nm by mechanical means treatment of premix.When using ball mill to wear, preferably directly use premix.Alternately, using suitable stirring, such as rolling mill, bedaquinoline and optional surface modifier can be dispersed in liquid medium, until realize uniform dispersion.

[0106] The mechanical means for reducing the effective average effective particle size of bedaquinoline can conveniently adopt the form of dispersion mill.Suitable dispersion mill comprises ball mill grinding machine, attritor / milling machine, vibrating mill, planar mill, media mill, such as sand mill and bead mill.Media mill is preferred, because need relatively short milling time to provide required particle size reduction.Bead is preferably ZrO2 bead.For example, for micron particle, the ideal size is about 2mm.

[0107] The grinding media used in the particle size reduction step can be selected from rigid media, preferably spherical or microgranular, having an average particle size of less than 3 mm, more preferably less than 1 mm (down to 200 μm beads). Such media can provide the particles of the present invention with shorter processing times as desired and with less wear on the grinding equipment. Examples of grinding media are ZrO2, such as 95% ZrO2 stabilized with magnesium oxide or stabilized with yttrium, zirconium silicate, glass grinding media, polymer beads, stainless steel, titanium dioxide, aluminum oxide, etc. Preferred grinding media have a particle size greater than 2.5 g / cm 3 density and comprises 95% ZrO2 stabilized with MgO, and polymeric beads.

[0108] Wear times can vary widely and depend primarily on the specific mechanical means and processing conditions selected. For rolling mills, processing times of up to 2 days or more may be required.

[0109] The size of the particles should be reduced at a temperature that does not significantly degrade the bedaquiline compound. Usually preferably, the processing temperature is lower than 30°C to 40°C. If necessary, the processing equipment can be cooled with conventional cooling equipment. The method is conveniently carried out under ambient temperature and processing pressure conditions that are safe and effective for the milling process.

[0110] According to the present invention, the pharmaceutical composition contains a preferably pharmaceutically acceptable aqueous carrier. The aqueous carrier includes sterile water optionally mixed with other pharmaceutically acceptable ingredients. The latter is included in any ingredients used in injectable formulations. Such ingredients are optional. These ingredients can be selected from one or more of the following: suspending agents, buffers, pH regulators, preservatives, isotonic agents and other ingredients. In one embodiment, the ingredients are selected from one or more of the following: suspending agents, buffers, pH regulators, and optionally, preservatives and isotonic agents. Specific ingredients can play the role of two or more of these agents at the same time, for example, behave like preservatives and buffers, or behave like buffers and isotonic agents.

[0111] Suitable optional BufferThe amount of the pH adjusting agent should be sufficient to maintain the dispersion at approximately neutrality, preferably in the pH range of 5.5 to 7.5, for example about 5.5 to 6.6 (in an embodiment, preferably pH is about pH 6). Specific buffers are salts of weak acids. The buffers and pH adjusting agents that can be added can 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, including mixtures thereof. In an embodiment, the composition of the present invention does not contain a buffer. In another embodiment, the composition of the invention does contain a buffer, such as citric acid (anhydrous) and sodium phosphate dibasic (anhydrous parenteral) - thus forming a citrate-phosphate buffer - in embodiments, the buffer is present at about 0.5% w / v to 1.5% w / v, such as about 0.9% w / v (wherein the citric acid is present at about 0.2% w / v to 0.4% w / v, such as 0.3% w / v, and the phosphate portion is present at about 0.5% w / v to 0.7% w / v, such as 0.6% w / v). In embodiments, sodium hydroxide and / or salts may be used initially in the composition of the invention to set the pH to about pH 5.5 to 6.5 (e.g., about pH 6).

[0112] Suitable optional preservative The present invention also includes antimicrobial agents and antioxidants that can be selected from the group consisting of the following: benzoic acid, benzyl alcohol, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), chlorobutanol, gallate, hydroxybenzoate, EDTA, phenol, chlorocresol, metacresol, benzethonium chloride, myristyl-γ-picoline chloride, phenylmercuric acetate and thimerosal. Free radical scavengers include BHA, BHT, vitamin E and palmitic acid ascorbyl ester and their mixtures. Oxygen scavengers include sodium ascorbate, sodium sulfite, L-cysteine, acetylcysteine, methionine, thioglycerol, acetone sodium bisulfite, isoascorbic acid, hydroxypropyl cyclodextrin. Chelating agents include sodium citrate, sodium EDTA and malic acid. In an embodiment of the present invention, the composition of the present invention does not contain preservatives.

[0113] Can exist Isotonic agentOr isotonic agent (isotonifier) ​​to ensure the isotonicity of the pharmaceutical composition of the present invention, and include sugars, such as glucose, dextrose, sucrose, fructose, trehalose, lactose; Polyhydroxy sugar alcohol, preferably trihydroxy or higher sugar alcohol, such as glycerol, 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 isotonic substances can be used alone or in combination. The suspension conveniently includes isotonicity from 0 to 10% (w / v), especially 0 to 6%. Interested is non-ionic isotonic substances, such as glucose, because electrolytes can affect colloidal stability. In an embodiment of the present invention, the composition of the present invention contains an isotonic agent or isotonic agent, which is a non-ionic isotonic agent in another embodiment, such as a suitable sugar such as mannitol. In another embodiment, the composition of the present invention does not contain an isotonic agent (also called an osmotic agent).

[0114] Desirable features of the pharmaceutical compositions of the present invention relate to ease of administration. The viscosity of the pharmaceutical compositions of the present invention should be low enough to allow administration by injection. In particular, they should be designed so that they can be easily drawn into a syringe (e.g., from a vial), injected through a thin needle (e.g., 20G 1 1 / 2, 21G 1 1 / 2, 22G 2 or 22G1 1 / 4 needle). In one embodiment, the viscosity of the composition of the present invention is less than about 75mPa·s, or less than 60mPa·s. Aqueous suspensions of such viscosity or lower generally meet the above criteria.

[0115] As indicated herein, therefore, in embodiments, the present invention may be directed to 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 micronized particles, prepared by an aseptic manufacturing process, and comprising:

[0116] (a) bedaquiline or a pharmaceutically acceptable salt thereof in the form of micron particles, on the surface of which a surface modifier is adsorbed; and

[0117] (b) a pharmaceutically acceptable aqueous carrier; wherein the bedaquiline active ingredient is suspended, wherein the bedaquiline (or a pharmaceutically acceptable salt thereof) is present at 10% to 30% (w / v) by weight based on the total volume of the composition, and the surface modifier is present at 5% to 15% (w / v), and comprises at least 30% PEG4000 (or an analogue) and at least 30% poloxamer (such as poloxamer 338).

[0118] The composition of the present invention is a suspension of micronized particles prepared by a sterile manufacturing process, and as indicated, the bedaquiline (or a pharmaceutically acceptable salt thereof) and the surface modifier (PEG4000 and poloxamer) are present in an amount; in certain other embodiments, they are present in the following amounts:

[0119] - bedaquiline (or a pharmaceutically acceptable salt thereof) is present at about 15% to 25% (w / v), such as about 20% (w / v); and / or

[0120] - The surface modifier is present at about 8% to 12% (w / v), the surface modifier comprising the ratio of PEG4000 to poloxamer described herein.

[0121] The compositions of the present invention have been optimized based on a number of parameters, and the amounts of the optimized surface modifiers are as described above; in certain additional embodiments, they may also be present in the following amounts:

[0122] - the surface modifier comprises 30% to 70% PEG4000 (or the like), the remainder therefore consisting of 30% to 70% poloxamer;

[0123] - The surface modifier comprises 40% to 60% PEG4000 and 40% to 60% poloxamer

[0124] - the surface modifier comprises 45% to 55% (e.g. about 50%) of PEG4000 and 45% to 50% (e.g. about 50%) of poloxamer

[0125] - the surface modifier comprises about 2% to 15% (e.g., 4% to 6%) PEG4000 (w / v) and about 2% to 15% (e.g., 4% to 6%) poloxamer (w / v)

[0126] - The surface modifier comprises about 5% PEG4000 (w / v) and about 5% poloxamer (w / v).

[0127] The compositions of the present invention are also indicated as containing a pharmaceutically acceptable carrier, which is described in more detail herein. For example, the compositions of the present invention may include one or more buffers, one or more isotonic agents (also referred to as osmotic agents), and one or more preservatives (although in embodiments, no preservative is present); in addition, the compositions of the present invention may contain water for injection (amount) and a base (e.g., sodium hydroxide; amount) and / or an acid (amount), wherein the latter two are present to set the pH to (e.g., about pH 6) at the beginning.

[0128] For example, a composition of the invention prepared by an aseptic manufacturing process may comprise:

[0129] (a) bedaquiline or a pharmaceutically acceptable salt thereof, said bedaquiline or a pharmaceutically acceptable salt thereof being present in an amount of about 180 mg / ml to about 220 mg / ml (e.g., about 200 mg / ml) (and wherein said amount is based on the active moiety and not on the salt component, if any);

[0130] (b) a surface modifier comprising PEG4000 or an analog and a poloxamer (e.g., poloxamer 338), wherein the PEG4000 or an analog 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).

[0131] (c) a buffer, present, for example, at about 8 mg / ml to about 10 mg / ml (e.g., about 9 mg / ml), consisting of citric acid (present at about 2 mg / ml to 4 mg / ml, e.g., about 3 mg / ml) and sodium phosphate dibasic (present at about 5 mg / ml to 7 mg / ml, e.g., about 6 mg / ml)

[0132] (d) an isotonic agent (e.g., mannitol) present at about 5 mg / ml to about 20 mg / ml, e.g., 10 mg / ml to 15 mg / ml, e.g., about 13.5 mg / ml; however, in embodiments, the isotonic agent (e.g., mannitol) is not present, which may be advantageous

[0133] (e) a preservative, which may be present from 0 mg / ml to about 20 mg / ml, but is absent in embodiments; it may be advantageous not to require a preservative

[0134] (f) Water for injection (appropriate amount), sodium hydroxide and / or hydrochloric acid (both appropriate amounts to adjust pH as described herein)

[0135] An amount of acid or base may optionally be added to these suspensions to bring the pH to a value of about pH 7. Suitable acids or bases are any of those that are physiologically acceptable, such as HCl, HBr, sulfuric acid, alkali metal hydroxides (e.g., NaOH). In embodiments, such acids or bases need not be added to the compositions of the invention.

[0136] Administration of bedaquiline (or a pharmaceutically acceptable salt thereof) in the present invention may be sufficient to treat pathogenic mycobacterial infection, although in many cases, co-administration of other anti-TB drugs may be recommended.

[0137] In some cases, the treatment of pathogenic mycobacterial infections may be limited to the administration of a composition of bedaquiline (and / or its metabolites) according to the invention alone, i.e. as a monotherapy, without co-administration of additional anti-TB drugs. This option may be recommended, for example, for certain mycobacterial infections where low concentrations of the active ingredient can treat bacteria (e.g., latent / dormant TB or Mycobacterium leprae).

[0138] 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 maintenance therapy of a subject infected with a pathogenic mycobacterial infection, wherein the composition is administered or is to be administered intermittently at time intervals ranging from one week to one year, or from one week to two years.

[0139] Thus, in a further aspect, the present invention provides a method for long-term treatment of a patient infected with a pathogenic mycobacterium infection, the method comprising

[0140] (i) treating the patient with a combination of anti-TB drugs; and then

[0141] (ii) intermittently administering the pharmaceutical composition comprising an effective amount of bedaquiline or a pharmaceutically acceptable salt thereof according to the present invention, wherein the composition is administered at intervals of at least one week.

[0142] If the treatment is for M. leprae, then again a monotherapy or treatment regimen in combination with existing drugs available for the treatment of M. leprae (e.g. rifapentine) can be used. For example, the composition of the invention can be administered by injection once or up to three times as monthly intervals. The advantages are related to compliance, avoiding the development of drug resistance by avoiding the use of dapsone, and avoiding the development of stigma by avoiding the use of clofazimine.

[0143] The present invention also relates to a pharmaceutical composition as described above, for use as a medicament for treating or preventing pathogenic mycobacterial infection.

[0144] Furthermore, the present invention relates to the use of the pharmaceutical composition as described herein for preparing a medicament for preventing or treating pathogenic mycobacterial infection.

[0145] The present invention also 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 as described herein.

[0146] As used herein, the word "substantially" does not exclude "completely", for example, a composition "substantially free" of Y may be completely free of Y. If necessary, the word "substantially" may be omitted from the definition of the present invention. The term "about" in conjunction with a numerical value is intended to have its usual meaning in the context of the numerical value. If necessary, the word "about" may be replaced by a numerical value of ±10%, or ±5%, or ±2%, or ±1%.

[0147] All documents cited herein are incorporated by reference in their entirety.

[0148] The following examples are intended to illustrate the present invention and should not be construed as limiting the present invention thereto.

[0149] Example

[0150] Method Example: Preparation of Micron Suspension

[0151] The active ingredient bedaquiline can be used as such or can be converted into its pharmaceutically acceptable salt, such as the fumarate salt (e.g. the commercially available product Unless otherwise specified, bedaquiline referred to herein is used in its non-salt form.

[0152] The preparation method of the composition of the present invention is carried out by an aseptic manufacturing process, wherein bedaquiline is γ-irradiated. The bedaquiline composition can be prepared according to the following steps:

[0153] Preparation of 200 mg / mL and 100 mg / mL microsuspensions.

[0154] Materials used :

[0155] Zirconium beads 0.5mm (to assist processing)

[0156] Sterile Water for Injection (Viaflo)

[0157] Bedaquiline (unmilled / ground) - This API is gamma-irradiated

[0158] Surface modifier (e.g., containing PEG4000 (or the like) (50 mg / ml) and poloxamer (50 mg / ml)) - excipient

[0159] Zirconium beads 2mm (to assist processing)

[0160] Mannitol (parenteral) - excipient

[0161] A glass bottle and ZrO2 beads (0.5 mm or 2 mm, depending on the desired microsuspension) used as a milling medium are sterilized in an autoclave. A solution of the drug substance (the amount depends on the formulation to be prepared; see, e.g., the formulation / suspension below) and a surface modifier (PEG4000 (or analog) (50 mg / ml) and poloxamer (50 mg / ml)) dissolved in water for injection (the amount depends on the required / desired concentration; see, e.g., the formulation / suspension below) are placed in a glass bottle. ZrO2-beads with an average particle size of 500 μm or 2 mm (depending on whether a microsuspension or a nanosuspension is required / desired) are added. The bottle is placed on a rolling mill. The suspension is micronized at 100 rpm for a period of up to 72 hours. For example, the micronization can be performed at 100 rpm for a period of 3 hours (or up to 3 hours). At the end of the milling process, the concentrated microsuspension is taken out with a syringe and filled into a vial. The resulting formulation (based on the microsuspension) is described herein. The concentration was determined by HPLC / UV. If necessary, a dilution was made with a final concentration of 200 mg / ml of the active ingredient bedaquiline. The resulting suspension was kept in the dark.

[0162] Generally speaking, methods for preparing the compositions of the invention will therefore include a milling (e.g. roller milling) step, which is described in more detail herein, but may also include other techniques, such as GMP methods, for example high shear bead milling (Netzsch milling, etc.), which allow for scale-up (including GMP scale-up), for example when optimizing process parameters.

[0163] Such formulations have been (and will be) administered intramuscularly and subcutaneously in animals for pharmacokinetic studies, to investigate possible long-acting effects (eg in the treatment of tuberculosis (eg latent tuberculosis), or even for the treatment of leprosy).

[0164] The physical stability of the suspension will be followed by measuring the particle size under different storage conditions.

[0165] Certain embodiments of the formulations have the following features:

[0166] -Use a micron suspension of 2 mm Zr beads

[0167] - Mill at 200mg / mL (otherwise the concentration may be too high, e.g. 300mg / ml)

[0168] - Longer milling time will result in nanosuspension

[0169] - a suitable surface modifier, such as one selected based on physical stability, for example, a surface modifier or wetting agent as described herein

[0170] Reference Example of Bedaquiline Micron Suspension

[0171] The 200 mg / ml microsuspension is referred to herein as Reference Example A (without buffer) and Reference Example B. and C (with buffer)

[0172] Reference Example A

[0173] mg / ml Bedaquiline 200 TPGS 50 Mannitol 50 Sterile Water for Injection Moderate

[0174] Particle size distribution (PSD)

[0175] Storage time Storage temperature(℃) D10(μm) D50(μm) D90(μm) 0 0.820 1.99 4.96 1 month 25℃ 0.704 1.59 3.64

[0176] PSD measurements after 1 month indicated that the formulation remained relatively stable.

[0177] Stability testing using HPLC :

[0178] The HPLC test method was used to determine the stability of the long-acting injectable formulation of Reference Example A. The objective was to measure the amount of bedaquiline relative to two known degradants after a certain period of time at room temperature.

[0179] HPLC procedure: column - ProntoSIL 120-3-C18 SH, 100 mm length × 3.0 mm inner 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 minutes; analytical run time 60 minutes; 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).

[0180]

[0181] HPLC purity testing indicated that the formulation of Reference Example A remained relatively stable over an extended period of time (in terms of the relative amounts of degradants and bedaquiline remaining stable).

[0182] Reference Examples B and C

[0183]

[0184] Particle size distribution (PSD)

[0185]

[0186] The PSD of these formulations under various conditions, including after autoclaving, indicated that these formulations remained relatively stable.

[0187] Reference Example D

[0188] PEG4000 (or polyethylene glycol 4000) was used, which can be supplied by Clariant GmbH. PEG4000 is a hydrophilic agent that can be used to increase the viscosity of the suspension vehicle and can act as a suspending agent.

[0189] mg / ml Bedaquiline 200 PEG4000 50 TPGS 5 Buffer - Citrate-Phosphate 0.01N(pH 6) Mannitol 50 Sterile Water for Injection Moderate

[0190] In this case, a buffer is added to avoid a decrease in pH.

[0191] Particle size distribution (PSD)

[0192] condition D10(μm) D50(μm) D90(μm) Before autoclaving 1.27 3.29 10.4 After autoclaving 1.22 2.74 6.72

[0193] The PSD of the microsuspension of Reference Example D shows that the formulation remains relatively stable even after autoclaving.

[0194] The approximate cloud point of the formulation of Reference Example D was calculated to be about 105°C to 110°C.

[0195] The Reference Example D microsuspension was autoclaved in a Systec autoclave (VX / VE series) with the current parameters being:

[0196] Sterilization temperature: 121°C (higher than the calculated cloud point)

[0197] Sterilization time: 15 minutes

[0198] No-load temperature: 80℃

[0199] Typical autoclave cycle - steam generator builds up required steam pressure, steam flows into sterilization chamber, after reaching sterilization temperature, temperature is kept constant during sterilization time period and after this time period has elapsed, cycle with optional built-in cooling device is cooled down until no-load temperature is reached.

[0200] Reference Examples E1 and E2

[0201] Reference Example E1 Reference Example E2 API(mg / ml) Bedaquiline 200mg / ml Bedaquiline 200mg / ml Surface modifier (mg / ml) P338 (20 mg / ml) P188 (40 mg / ml) Buffer Citrate-Phosphate Citrate Isotonicity Agents Mannitol Mannitol Sterile Water for Injection Moderate Moderate

[0202] Buffer was added to avoid pH drop.

[0203] Particle size distribution (PSD)

[0204] Reference Example E1 Reference Example E2 D10(μm) 0.844 1.03 D50(μm) 3.08 3.44 D90(μm) 8.6 10.0

[0205] Objective stability testing standards

[0206] - Various formulations / suspensions / concepts were tested, each of which underwent a specific sterilization technique:

[0207] o Autoclaving (see e.g. methods above)

[0208] o gamma-irradiating the suspension (using such methods as described above, e.g., in the Background section)

[0209] ο Aseptic manufacturing (using gamma-irradiated API)

[0210] - While each type of sterilization technique may have specific advantages, and certain formulations may have advantages in that they may be amenable or resistant to a particular sterilization technique, the stability of a formulation (or suspension / concept) may also be tested as follows:

[0211] Chemical stability

[0212] -Assay / purification by UHPLC

[0213] - Determination of aldehyde content by UHPLC

[0214] - Measurement of VitE TPGS content by UHPL (for the corresponding formulations containing it)

[0215] - Determination of peroxide content by UPLC / MS for gamma-irradiated suspensions

[0216] -pH

[0217] Physical stability

[0218] - Appearance / injectability / resuspendability

[0219] -PSD

[0220] -XRD

[0221] For all stability tests, you can:

[0222] - For samples stored at a specific temperature and a specific relative humidity (e.g., 30°C / 75% RH and 40°C / 75% RH), the

[0223] - and after 28 days for samples stored at 60°C (assay / purification) and 50°C (PSD and XRD)

[0224] Example

[0225] Depending on the sterilization technique, the formulation / suspension may have different properties, such as different chemical and physical stability properties, and the following examples were prepared and tested.

[0226] Example 1 - Micronized suspension of the present invention

[0227] Example 1A Formulation :

[0228] mg / ml (where applicable) Bedaquiline 200 PEG4000 50 Poloxamer 338 50 Citric Acid, Anhydrous 3.068 Sodium hydrogen phosphate, anhydrous 6.076 Sterile Water for Injection Moderate Sodium hydroxide Appropriate amount, adjust to pH 6 Concentrated hydrochloric acid Appropriate amount, adjust to pH 6

[0229] In this case, a buffer is added to avoid a decrease in pH; and in this case, the buffer is a mixture of citric acid and phosphate (sodium phosphate; 50 mM phosphate-citrate buffer); in addition, sodium hydroxide and / or hydrochloric acid can be used to adjust the pH at the beginning. The target pH is pH 6.

[0230] It does not contain isotonic agents (also called osmotic agents), such as mannitol.

[0231] This Formulation Example 1A is prepared using aseptic manufacturing (using a γ-irradiated API) - thus specifically, the API product (bedaquiline) is γ-irradiated and then the suspension is formulated using aseptic manufacturing techniques, such as the use of sterile equipment or other techniques to ensure that the resulting final formulation / suspension is substantially free of bacteria.

[0232] As described 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 stability and / or physical stability, e.g., compared to known bedaquiline long-acting formulations / suspensions, or compared to formulations / suspensions prepared by other methods (e.g., autoclaving), or gamma-irradiation of the entire formulation / suspension.

[0233] Stability test results

[0234] For the formulations of the present invention

[0235] Chemical stability - tested at 30°C / 75%RH and 40°C / 75%RH

[0236] -Assay / purification by UHPLC

[0237]

[0238] For example, T = 1M 30°C means a period of 1 month at 30°C, 28D = 28 days, etc.

[0239] - Aldehyde (formaldehyde, acetaldehyde, propionaldehyde) content determined by UHPLC

[0240]

[0241] -VitE TPGS content measurement by UHPL is not applicable for this formulation / suspension

[0242] -pH

[0243]

[0244] Physical stability tested at 30℃ / 75% RH and 40℃ / 75% RH

[0245] - Appearance / injectability / resuspendability

[0246]

[0247] -PSD

[0248]

[0249] -XRD

[0250] Preparations condition XRD Example 1A T0, T=1M, T=3M Bedaquiline, preferably in crystalline form

[0251] Conclusion - Chemical Stability

[0252] - The purity assay of Formulation Example 1A remained stable for up to 6 months; no impurities were detected above the 0.05% reporting threshold; Impurity X (-0.10%) was formed after 28 days at 60°C - wherein Impurity X had an RRT of 1.36.

[0253] - aldehyde content was measured and; - for Formulation Example 1A, minimal or no change was observed in the formaldehyde, acetaldehyde, propionaldehyde content

[0254] - Minimal or no changes in pH observed

[0255] Conclusion - Physical Stability

[0256] - For Formulation Example 1A, some soft aggregates were observed after 1 M storage at 30°C, 40°C and 50°C (however, these soft aggregates were not observed for measurements taken at 3M and 6M time points at that particular temperature)

[0257] - No change / no significant change in particle size observed (according to PSD - particle size distribution)

[0258] - XRD - X-ray diffraction - the preferred crystalline form (the crystalline form of bedaquiline described herein) was observed at all times

[0259] In summary, the inventive Formulation / Example 1A may have advantages in chemical and / or physical stability based on any of the criteria measured herein (e.g., purity analysis, aldehyde content, pH, appearance / resuspendability / syringability, PSD, and / or XRD).

[0260] For other concepts

[0261] Other concepts :

[0262] Concept A Formulation - Preparation by Autoclaving :

[0263] mg / ml (where applicable) Bedaquiline 200 PEG4000 50 Poloxamer 338 50 Mannitol TBD Citric Acid, Anhydrous TBD Sodium hydrogen phosphate, anhydrous TBD Sterile Water for Injection Moderate Sodium hydroxide Appropriate amount, adjust to pH 6 Concentrated hydrochloric acid Appropriate amount, adjust to pH 6

[0264] In this case, a buffer can be added to avoid a drop in pH; and in this case, the buffer is a mixture of citric acid and phosphate (sodium phosphate); in addition, to adjust the pH at the beginning, sodium hydroxide and / or hydrochloric acid can be used; the amount of buffer can be determined - for example, using 50mM phosphate-citrate buffer, the target pH is 6.

[0265] The amount of mannitol (isotonic agent, or also referred to as osmotic agent) can also be determined, for example, based on the amount used in the above-mentioned Example 1A / 1B.

[0266] This formulation Concept A was prepared by autoclaving (see Methods herein).

[0267] Concept B Formulation - Preparation by gamma-irradiation of the final formulation / suspension :

[0268] mg / ml (where applicable) Bedaquiline 200 PEG4000 50 Vitamin E TPGS 10 Mannitol TBD Citric Acid, Anhydrous TBD Sodium hydrogen phosphate, anhydrous TBD Sterile Water for Injection Moderate Sodium hydroxide Appropriate amount, adjust to pH 6 Concentrated hydrochloric acid Appropriate amount, adjust to pH 6

[0269] In this case, a buffer can be added to avoid a drop in pH; and in this case, the buffer is a mixture of citric acid and phosphate (sodium phosphate); in addition, to adjust the pH at the beginning, sodium hydroxide and / or hydrochloric acid can be used; the amount of buffer can be determined - for example, using 50mM phosphate-citrate buffer, the target pH is 6.

[0270] The amount of mannitol (isotonic agent, or also referred to as osmotic agent) can also be determined, for example, based on the amount used in the above-mentioned Example 1A / 1B.

[0271] This formulation concept B is prepared by gamma-irradiation of the final formulation / suspension

[0272] Concept C Formulation - Preparation by gamma-irradiation of the final formulation / suspension :

[0273]

[0274]

[0275] In this case, a buffer can be added to avoid a drop in pH; and in this case, the buffer is a mixture of citric acid and phosphate (sodium phosphate); in addition, to adjust the pH at the beginning, sodium hydroxide and / or hydrochloric acid can be used; the amount of buffer can be determined - for example, using 50mM phosphate-citrate buffer, the target pH is 6.

[0276] The amount of mannitol (isotonic agent, or also referred to as osmotic agent) can also be determined, for example, based on the amount used in the above-mentioned Example 1A / 1B.

[0277] This formulation concept C was prepared by gamma-irradiation of the final formulation / suspension.

[0278] Concept D Formulation - Preparation by gamma-irradiation of the final formulation / suspension :

[0279] mg / ml (where applicable) Bedaquiline 200 PEG4000 50 Poloxamer 338 50 Mannitol TBD Citric Acid, Anhydrous TBD Sodium hydrogen phosphate, anhydrous TBD Sterile Water for Injection Moderate Sodium hydroxide Appropriate amount, adjust to pH 6 Concentrated hydrochloric acid Appropriate amount, adjust to pH 6

[0280] In this case, a buffer can be added to avoid a drop in pH; and in this case, the buffer is a mixture of citric acid and phosphate (sodium phosphate); in addition, to adjust the pH at the beginning, sodium hydroxide and / or hydrochloric acid can be used; the amount of buffer can be determined - for example, using 50mM phosphate-citrate buffer, the target pH is 6.

[0281] The amount of mannitol (isotonic agent, or also referred to as osmotic agent) can also be determined, for example, based on the amount used in the above-mentioned Example 1A / 1B.

[0282] This formulation concept D was prepared by gamma-irradiation of the final formulation / suspension.

[0283] In the chemical stability and physical stability test standards, the following is noted :

[0284] - Concept A failed the following physical stability tests for appearance / syringability / resuspension:

[0285] ο At 1M and 3M, 40°C, due to extraction challenges (and after 3M, agglomeration was detected at the bottom of the vial)

[0286] οAt 3M, 25°C, due to needle clogging during extraction

[0287] - Concepts B and C failed the test because the amount of Vitamin E TPGS dropped by -20% immediately after gamma-irradiation of the formulation / suspension - only 75% to 80% Vitamin E TPGS remained (although no further drop was measured after this initial drop)

[0288] - Concept D failed the physical stability test, at least visually, and even failed the test at T0, with lumps of the formulation observed at the bottom of the flask.

[0289] Biological Example: Pharmacokinetic Study

[0290] Example 1A was tested in rats with the following results.

[0291]

[0292] * Median (minimum - maximum)

[0293] Example 1A was tested in dogs with the following results.

[0294]

[0295] * Median (minimum - maximum)

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 suspension of micronized particles, the pharmaceutical composition being prepared by an aseptic manufacturing process and comprising: (a) bedaquiline or a pharmaceutically acceptable salt thereof in the form of micron particles, wherein the bedaquiline or a pharmaceutically acceptable salt thereof is present in an amount of 1:10% by weight based on the total volume of the composition. 10% to 30% (w / v) present; (b) a surface modifier present at 5% to 15% (w / v) and comprising at least 30% PEG4000 (or the like) and at least 30% poloxamer (such as 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 suspension of micronized particles, the pharmaceutical composition being prepared by an aseptic manufacturing process and comprising: (a) bedaquiline or a pharmaceutically acceptable salt thereof in the form of micron particles, on the surface of which a surface modifier is adsorbed; and (b) a pharmaceutically acceptable aqueous carrier; wherein the bedaquiline active ingredient is suspended, wherein the bedaquiline (or a pharmaceutically acceptable salt thereof) is present at 10% to 30% (w / v) by weight based on the total volume of the composition, and the surface modifier is present at 5% to 15% (w / v), and comprises at least 30% PEG4000 (or an analogue) and at least 30% poloxamer (such as poloxamer 338).

3. A 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. A composition according to 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. The composition according to any one of claims 1 to 4, wherein the surface modifier is present at about 8% to 12% (w / v), the surface modifier comprising about 5% PEG4000 (w / v) and about 5% poloxamer (w / v).

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

7. A composition according to any one of claims 1 to 6, prepared by an aseptic manufacturing process and comprising: (a) bedaquiline or a pharmaceutically acceptable salt thereof, wherein the bedaquiline or a pharmaceutically acceptable salt thereof is present in an amount of about 180 mg / ml to about 220 mg (b) a surface modifier comprising PEG4000 or an analog and a poloxamer (e.g., poloxamer 338), wherein the PEG4000 or an analog 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 buffer, present at, for example, about 8 mg / ml to about 10 mg / ml, the buffer consisting of citric acid (present at about 2 mg / ml to 4 mg / ml) and disodium hydrogen phosphate (present at about 5 mg / ml to 7 mg / ml) (d) Water for injection (as appropriate), sodium hydroxide and / or hydrochloric acid (both as appropriate to adjust pH as described herein).

8. Use of a pharmaceutical composition as defined in any one of claims 1 to 7 for the manufacture of a medicament for the treatment of pathogenic mycobacterial infections.

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

10. The use according to claim 8, wherein the medicament is for administration by intramuscular injection or subcutaneous injection; wherein the composition is administered intermittently at intervals of one week to two 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. The use according to claim 8, wherein the pharmaceutical composition is administered at intervals ranging from one week to one month, or ranging from one month to three months, or ranging from three months to six months, or ranging from six months to twelve months, or ranging from 12 months to 24 months.

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

14. A method for preparing a pharmaceutical composition as defined in any one of claims 1 to 7, the method comprising (a) obtaining bedaquiline or a pharmaceutically acceptable salt thereof in a micronized form; (b) adding micronized bedaquiline or a pharmaceutically acceptable salt thereof to a liquid medium to form a premix / predispersion; as well as (c) mechanically treating the premix in the presence of milling media to reduce the average effective particle size.

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