Long-acting complexes

Abstract

To provide long-acting pharmaceutical compositions of bedaquiline useful in treatment of a mycobacterial infection.SOLUTION: A pharmaceutical composition for administration by intramuscular or subcutaneous injection comprises a therapeutically effective amount of bedaquiline or a pharmaceutically acceptable salt thereof in the form of a suspension of micro- or nanoparticles. The suspension of micro- or nanoparticles comprises: (a) the bedaquiline or pharmaceutically acceptable salt thereof in a micro- or nanoparticle form, and a surface modifier; and (b) a pharmaceutically acceptable aqueous carrier.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention provides an ATP synthase inhibitor compound suspended in a pharma- ceutically acceptable aqueous carrier. bedaquiline (Sirturo®), which is marketed as The drug is administered by intramuscular or subcutaneous injection, containing micro- or nanoparticles of 1,2-dihydropyridine (in the form of a malonate salt). and pharmaceutical compositions for administering the same to patients in the treatment of bacterial infections, such as tuberculosis. Use of the composition. [Background technology]

[0002] Bedaquiline is a known antituberculosis drug that is used in various combinations. Pharmaceutically acceptable forms of bedaquiline fumarate, such as the form sold as turo® This is because the mitochondrial ATP synthase of eukaryotic cells can be compared to the ATP synthase of eukaryotic cells. The result showed that the ATPase had a selectivity index of over 20,000 and was highly selective for AT It is believed to function as a P synthase inhibitor.

[0003] Bedaquiline is already useful in treating mycobacterial infections and is a latent, dormant strain of Mycobacteria that cause persistent infections, specifically Mycobacterium tuberculosis (My It is useful in killing Cobacterium tuberculosis, As a result, it has been reported that bedaquiline can be used to treat latent TB. Such uses are described in WO 2004 / 011436 and WO 2006 / 0 This has been described in several publications, including Brochure No. 67048. Bacterial Activities of R207910 and othe r Antimicrobial Agents against Mycobacterium rium leprae in Mice” (Antimicrobial agent s and Chemotherapy, April 2006, p1558), and The Diarylquinolone R207910 is Bacterici dal against Mycobacterium leprae in mice and at Low Dose Administered Intermitte ntly”(Antimicrobial agents and Chemother As explained in (Apy, Sept 2009, p. 3989), bedaquiline is a mycobacterial It is bactericidal against Mycobacterium leprae. It is also known that

[0004] The goal of long-acting formulations is to reduce drug burden. This is particularly useful for treatment regimens that may continue for months.

[0005] The number and / or amount of dosage forms that need to be administered is commonly referred to as the "pill burden." High pill burdens are associated with many reasons, including frequency of ingestion, and are often associated with large pill burdens. The inconvenience of having to swallow tablets, as well as the need to store and transport multiple or large tablets. Frequently combined with sex, this is undesirable. High pill burdens can lead to patients not taking their full dose. This increases the risk of non-compliance with prescribed medication regimens, which may reduce treatment efficacy. Not only can it cause a decrease in the efficacy of the drug, but it can also lead to the development of resistance (e.g., in the case of bedaquiline, bacterial resistance). resistance).

[0006] Therapies that involve administration of dosage forms at extended intervals, such as one week or more, or even one month or more, are provided. It becomes attractive to offer

[0007] Various formulations, including long acting formulations, are known in the art. International Publication No. 2007 / 147882 Brochure and International Publication No. 2012 / 140220 As explained by FRET, micro- and nanosuspension technology has long been used in the field of anti-HIV drugs. It is known to obtain time-acting formulations. No. 99299 describes nanoparticles known in the art. Such particles are A crystalline preparation having an average particle size in the submicron range and having a surface modifier adsorbed on its surface. Nanoparticles are also used to incorporate active ingredients that are poorly soluble in water. There are.

[0008] A long-acting formulation of the anti-tuberculosis drug bedaquiline is described below. can be formulated in micro- or nanoparticle form, and such formulations can be used to treat, for example, tuberculosis. As a long-acting (or depot) formulation that can be used to treat a variety of bacterial infections, including It has now been discovered that it is possible.

[0009] The challenge with these combinations is the pharmacokinetic (PK) properties of the TB drugs, including bedaquiline, and With these PK characteristics in mind, the need to maintain plasma concentrations above the minimum concentration and Bedaquiline and its N-monodesmethyl metabolite (M2 metabolite) are believed to be present. The mean terminal elimination half-life of The elimination half-life is approximately 5.5 months. This probably reflects the sustained release of Kirin and M2 from peripheral tissues. At the UNION conference in Liverpool, the University of Ne Susan Swindells of Braska Medical Center xperience from Long-Acting HIV Drug Deve OPMENT,” in which existing TB drugs were considered ideal candidates (long-acting). The lack of a reliable pharmacological model was outlined.

[0010] The present invention further provides a method for determining plasma concentrations of ribozymes that may be sufficient to inhibit the growth of a mycobacterial infection. Intermittent administration of these micro- or nanoparticle formulations at time intervals of one week or more results in This reduces the frequency of administration, which is beneficial in terms of pill burden and compliance for patients. Thus, the micro- or nanoparticulate formulations of bedaquiline of the present invention are advantageous in that they In the long-term treatment of bacterial infections (e.g., tuberculosis, including latent tuberculosis, and leprosy) Could be useful.

[0011] Intermittent administration of micro- or nanoparticulate formulations of bedaquiline at time intervals of 1 week or more is also to produce plasma concentrations that may be sufficient to prevent transmission of mycobacterial infections. Again, the frequency of dosing must be reduced, again with a corresponding reduction in the pill burden of at-risk individuals. and is advantageous in terms of medication compliance. Summary of the Invention [Means for solving the problem]

[0012] The present invention relates to a method for administering a therapeutically effective amount of bedaquiline, or a pharma- ceutical acceptable salt thereof, to a patient in need thereof, in a micro- or nano-administration. A pharmaceutical composition for administration by intramuscular or subcutaneous injection, comprising a suspension of nanoparticles. The suspension of micro- or nanoparticles comprises (a) bedaquiline in micro- or nanoparticulate form, or a pharma- ceutically acceptable salt thereof, and A surface modifier; (b) a pharma- ceutically acceptable aqueous carrier, Such compositions may be referred to herein as "compositions of the invention."

[0013] The compositions of the present invention are suspensions, which are suspensions in which the bedaquiline active ingredient is dissolved in a pharma- ceutical acceptable aqueous solution. This means that the polymer is suspended in a polymeric carrier.

[0014] The compositions (i.e., suspensions) of the present invention are prepared by adsorbing the active ingredient, bedaquiline, onto the surface. It contains a surface modifier that can be added.

[0015] Thus, in one embodiment, the present invention provides a therapeutically effective amount of bedaquiline, or a pharmacologic equivalent thereof. The acceptable salt is administered in the form of a suspension of micro- or nano-particles by intramuscular or subcutaneous injection. 2. A pharmaceutical composition for administration to a patient, comprising a suspension of micro- or nanoparticles comprising: (a) bedaquiline in micro- or nanoparticulate form having a surface modifier adsorbed on its surface; or a pharma- ceutically acceptable salt thereof; (b) a pharma- ceutically acceptable aqueous carrier, in which the bedaquiline active ingredient is suspended. It relates to pharmaceutical compositions.

[0016] The present invention further relates to a method for the treatment of Mycobacterium tuberculosis. M tuberculosis, M. bovis, M. leprae eprae, M. avium, and M. marinum The present invention relates to a method for treating a subject infected with a pathogenic mycobacterium, such as Mycobacterium difficile. Mycobacteria are Mycobacterium tuberculosis (Mycobacterium tuberculosis) erium tuberculosis (including latent or dormant forms) or mycobacteria The composition of the present invention is Mycobacterium leprae. Mycobacterium leprae, and Mycobacterium tuberculosis in latent or dormant form This may be particularly suitable for the treatment of these particular When treating infections, low plasma concentrations of bedaquiline are effective in treating these infections. This is because, for example, Robert Gelber, Koen Antimicrobial Agents and Chemo by Andries et al. therapy (Sept 2009, p.3989-3991) The dosage is incorporated herein by reference; essentially, the low and intermittent administration of bedaquiline A reasonable dose of leprosy medication can be expected in leprosy patients, and the minimum effective dose that kills 99% of the bacilli is , 30 mg / kg / w for M. tuberculosis k, <5.0 mg / kg / wk for M. leprae, and therefore Dosing once a month can be as effective as dosing five times a week; Veda against Mycobacterium leprae Other publications on the effects of kirin include Baohong Ji, Koen An Antimicrobial Agents and Chemotherapy by Dries et al. rapy (April 2006, p.1558-1560), the contents of which are (The present invention is incorporated herein by reference in its entirety.) Thus, the compositions of the present invention are Mycobacterium leprae, or latent / dormant forms of Mycobacterium Mycobacterium tuberculosis sis) in a subject infected with such pathogenic mycobacteria. The method of treating a subject infected with RIA includes administering to a subject a therapeutically effective amount of a pharmaceutical agent as set forth above or below. The composition may be administered by intramuscular or subcutaneous injection. For the manufacture of a medicament for treating a mycobacterial infection (or for the manufacture of such a medicament) For use in a particular treatment regime as described herein, In one embodiment, the composition is for use in the treatment of pathogenic mycobacteria. In one embodiment, the present invention is directed to the long-term treatment of pathogenic mycobacterial infections. Infections are those described above or below, such as infectious diseases that require long-term treatment. In a further embodiment, the relatively low plasma concentration levels of bedaquiline or its active metabolites are further Infections that can be treated with antibiotics, such as latent / dormant Mycobacterium tuberculosis (M ycobacterium tuberculosis), or in a particular embodiment, Mycobacterium leprae do.

[0017] In another embodiment, Mycobacterium tuberculosis tuberculosis, M. bovis, M. leprae prae, M. avium, and M. marinum Methods are provided for chronically treating subjects infected with pathogenic mycobacteria such as The method includes administering the compound by intramuscular or subcutaneous injection as specified above or below. The composition comprises administering an effective amount of the pharmaceutical composition as described above for a period of from one week to one year, or is or will be administered intermittently at time intervals ranging from 1 week to 2 years. Alternatively, the present invention provides a mycobacterial agent for administration by intramuscular or subcutaneous injection. Mycobacterium tuberculosis, M. bovis, M. leprae, M. avium avium, and pathogenic mycobacteria such as M. marinum. The method according to any one of claims 1 to 5, wherein the subject is infected with Regarding the use of the pharmaceutical composition, the composition is for a period ranging from 1 week to 1 year, or from 1 week to 2 years. It is to be administered or administered intermittently at certain time intervals. Hence the term "long-term "Prolonged treatment" refers to a single dose or administration (e.g., by intramuscular or subcutaneous injection) of As described herein, a sustained therapeutic effect over a period of time, e.g., several hours, several A sustained therapeutic effect over a period of weeks or weeks (e.g., in one embodiment, at least or It is understood that the term "treatment" refers to a treatment having a duration of up to 1 month, 3 months, or 6 months. See the Examples. In other words, chronic treatment involves more than one dose / administration. In some cases, the interval between doses / administrations may be long (as described herein), i.e. That is, the interval may be referred to as a long period of time as described herein.

[0018] In another aspect, a pathogenic mycobacterium as described herein (e.g., above). (e.g., any of the types described herein) for the long-term treatment of a subject infected with Methods for treating a patient with a single dose or administration (e.g., as described herein, e.g., is provided / required (and may be, for example, in the amounts described herein) In another aspect, such a long-term treatment regimen is provided. where two such doses or administrations are provided / required, the doses / administrations being taken in between. The intervals may be provided at intervals, the duration of the intervals being as described herein, e.g., at least or For up to 1 month, 3 months, or 6 months (i.e., the period during which a sustained therapeutic effect persists) In a further embodiment, such a long-term treatment regimen is provided, wherein three such treatments are administered. Dosages or administration are provided / required at intervals as described herein. In the form described herein, a lead-in treatment phase (e.g., 1 week Long-term treatment regimens include once-daily courses lasting for 1, 2, 3 weeks, or 1 month. A long-term treatment regimen preceded by chemotherapy (not chemotherapy) is provided.

[0019] The present invention further relates to a method for the detection of pathogenic mycobacterial infection in a subject at risk of infection with a pathogenic mycobacterial infection. For a method of preventing sexual mycobacterial infection, said method comprises the steps of: a pharmaceutical composition effective to prevent a pathogenic mycobacterial infection as further defined below. Alternatively, the present invention relates to a method for treating a pathogenic mycobacterial infection comprising administering a composition to said subject. Drugs for preventing pathogenic mycobacterial infections in subjects at risk for infection - Patents.com The use of a pharmaceutical composition as specified above or further specified below for the manufacture of a medicament for Regarding.

[0020] In another aspect, the present invention further provides a method for treating a patient at risk of infection with a pathogenic mycobacterial infection. The present invention relates to a method for the long-term prevention of a pathogenic mycobacterial infection in a subject, the method comprising the steps of: administering to said subject an effective amount of a pharmaceutical composition as specified above or further specified below. wherein the composition has a shelf life ranging from 1 week to 1 year, or from 1 week to 2 years. The dose may be or will be administered intermittently at intervals.

[0021] The present invention further relates to a method for the detection of pathogenic mycobacterial infection in a subject at risk of infection with a pathogenic mycobacterial infection. The above-mentioned method for producing a drug for the long-term prevention of sexual mycobacterial infections is described. For the use of the pharmaceutical composition as described above or further specified below, the composition is administered for a period of from 1 week to 1 year. or be administered intermittently at time intervals ranging from 1 week to 2 years. become.

[0022] In one embodiment, the present invention relates to a use or method as defined herein, The composition may be stored for a period ranging from 1 week to 1 month, or from 1 month to 3 months, or from 3 months to 6 months. or at time intervals ranging from 6 months to 12 months, or from 12 months to 24 months. The drug will be administered orally.

[0023] In another embodiment, the present invention relates to a use or method as defined herein, comprising administering to said patient a pharmaceutical composition comprising: is or may be administered once every two weeks, once a month, or once every three months. It becomes.

[0024] Further pharmaceutical compositions, methods of treatment or prevention, and medicaments based on these compositions are also provided. Uses for this purpose are described below and are intended to be part of the present invention.

[0025] The invention will be further described with reference to the following figures. [Brief description of the drawings]

[0026] [Figure 1] "Plasma kinetics of TMC207 (bedaquiline; BDQ) and M2 (a metabolite of bedaquiline (see specification)) following a single dose of 30 mg / kg in mice." [Diagram 2] "Plasma kinetics of TMC207 in mice when administered IM or SC at a dose of 160 mg / kg from 200 mg / mL formulations (specifically, formulations of Examples 1A and 1B, i.e., nano- and microsuspensions, respectively)" (TMC207 is referred to as "UD" in the figure) [Diagram 3] "Plasma kinetics of M2 in mice when administered IM or SC at a dose of 160 mg / kg from 200 mg / mL formulations (specifically, formulations of Examples 1A and 1B, i.e., nano and micro suspensions, respectively)" (M2 is referred to as "met" in the figure) [Figure 4] "Plasma kinetics of TMC207 in mice when administered IM or SC at a dose of 80 mg / kg from 100 mg / mL formulations (specifically formulations of Examples 1C and 1D, i.e., nano- and microsuspensions, respectively)" (TMC207 is referred to as "UD" in the figure) [Diagram 5] "Plasma kinetics of M2 in mice when administered IM or SC at a dose of 80 mg / kg from 100 mg / mL formulations (specifically, formulations of Examples 1C and 1D, i.e., nano- and microsuspensions, respectively)" (M2 is referred to as "met" in the figure) [Figure 6]"Plasma kinetics of TMC207 in male rats following administration of a 200 mg / mL microformulation (see, for example, Formulation 1B in Example 1, i.e., microsuspension) at a dose of 40 mg / kg, either IM or SC" and "Plasma kinetics of TMC207 in male rats following administration of a 200 mg / mL nanoformulation (see, for example, Formulation 1A in Example 1, i.e., nanosuspension) at a dose of 40 mg / kg, either IM or SC" [Figure 7] "Plasma kinetics of TMC207 in male beagle dogs following administration of a 200 mg / mL microformulation (see, e.g., Formulation 1B in Example 1) at a dose of 40 mg / kg, either IM or SC" and "Plasma kinetics of TMC207 in male beagle dogs following administration of a 200 mg / mL nanoformulation (see, e.g., Formulation 1A in Example 1) at a dose of 40 mg / kg, either IM or SC" DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0027] The compound used in the present invention is the compound TMC207, also known as bedaquiline. can be.

[0028] Bedaquiline may be administered in its non-salt form or in any suitable form, such as an acid or base addition salt form. In one embodiment, bedaquiline is used as a medicament of the present invention. In the composition it is in its non-salt form.

[0029] Pharmaceutically acceptable acid addition salts are those therapeutically active, non-toxic acids which bedaquiline is capable of forming. The above acid addition salts are defined to include the addition salt forms. The above acid addition salts are intended to be used to prepare bedaquiline in the free form in an appropriate form. Acids, such as inorganic acids, such as hydrohalic acids, in particular hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids, such as acetic acid, hydroxyacetic acid, propanoic acid, lactic acid, pyruvic acid, oxalic acid Acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methane Sulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cycla by treatment with salicylic acid, p-aminosalicylic acid, and pamoic acid. Specifically, this is adopted in the already commercially available product Sirturo (registered trademark). Given that this is the form in which it is commonly used, the fumarate salt is considered.

[0030] 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 salts, etc. Metal salts and alkaline earth metal salts, specifically lithium salts, sodium salts, potassium salts, Magnesium and calcium salts, salts with organic bases, e.g., benzathine salts, N-methyl L-D-glucamine salts, hybramine salts, and salts with amino acids; Examples include salts with arginine and lysine.

[0031] Conversely, the above acid addition salt forms or base addition salt forms can be converted to the corresponding salts by treatment with an appropriate base or acid. It can be converted to the free form by

[0032] The term "addition salt" as used within the framework of this application refers to a solution capable of forming bedaquiline and its salts. Further included are solvates. Such solvates are, for example, hydrates and alcoholates.

[0033] Any reference to bedaquiline (or TMC207) used herein refers to It is used in the product Sirturo® and is disclosed in WO 2004 / 011436. It refers to a single stereoisomer that has been disclosed as an antimycobacterial agent in FRET.

[0034] The physicochemical properties of bedaquiline make it suitable for the long-term treatment of pathogenic mycobacterial infections and It is unique in that it can be used for the long-term prevention of infections with mycobacteria and pathogenic mycobacteria. It is now possible to produce micro- or nanoparticle suspensions with pharmacokinetic properties, It has been found that only a limited number of drug administrations are required for this purpose. There are benefits regarding pill burden and patient compliance with a given dosing regimen.

[0035] As used herein, the term "treatment of a pathogenic mycobacterial infection" refers to the treatment of a pathogenic mycobacterial infection. The present invention refers to the treatment of subjects infected with an isobacterial infection.

[0036] The term "prophylaxis of a pathogenic mycobacterial infection" refers to a method for preventing a pathogenic mycobacterial infection in a subject. The source of infection is, for example, a pathogenic mycobacterium. The substance may be a variety of substances, including those containing infectious diseases.

[0037] The terms "therapeutically effective amount," "an amount effective to prevent a pathogenic mycobacterial infection," and and similar terms refer to the amount or concentration (or equivalent) of a composition of the invention that results in an effective plasma concentration. "Effective plasma concentration" refers to the amount / concentration of bedaquiline, the active ingredient, in a given composition. The present study provides a novel therapeutic approach for the treatment and prevention of pathogenic mycobacterial infections. It means the plasma concentration, which means that a given amount / dose / administration is, for example, as described herein. The desired exposure level or desired plasma concentration (e.g., (see, for example,

[0038] The term "subject" particularly relates to humans.

[0039] The term "micro- or nanoparticle" refers to particles in the micrometer or nanometer range. The particle size should be less than the maximum diameter. If it exceeds this size, it will be difficult to administer by subcutaneous or intramuscular injection. The above maximum diameters may be reduced or even no longer possible. or the body's rejection of larger particles, or both. In one embodiment, the pharmaceutical composition of the present invention contains bedaquiline in microparticle form. In another embodiment, the pharmaceutical composition of the invention comprises bedaquiline in nanoparticulate form.

[0040] The average effective particle size of the micro- or nanoparticles of the present invention is 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 40 The average effective particle size may be less than about 0 nm, or less than about 300 nm, or less than about 200 nm. The lower diameter limit may be, for example, about 100 nm, or as low as about 50 nm. The average effective particle size is about 50 nm to about 50 μm, or about 50 nm to about 20 μm, or about 50 nm to about 20 μm. m to about 10 μm, or about 50 nm to about 1000 nm, about 50 nm to about 500 nm, or about 50 nm to about 400 nm, or about 50 nm to about 300 nm, or about 50 nm to about 250 nm m, or about 100 nm to about 250 nm, or about 150 nm to about 220 nm, or 100 200 nm, or in the range of about 150 nm to about 200 nm, for example, about 130 nm, or about 15 For example, generally, both after preparation and after a period of up to 3 months (e.g., about When stored at temperatures of 5°C, 25°C, and 40°C): The microsuspension, in one embodiment, has a particle size of about 3 to 10 μm (e.g., 3.5, 4, or 5 μm). and a D50 of about 2 to 4 μm (eg, 3 μm). The nanosuspension, in one embodiment, has a particle size of about 0.5 to 1.5 μm (e.g., about 1 μm or less, or about D90 of about 0.1 to 0.5 μm (for example, about 0.3 μm or less, or and a D50 of less than about 300 nm.

[0041] In one embodiment, microparticles are employed, where D10, D50, and / or D90 The average effective particle size, as measured by D50 (in one embodiment, as measured by D50), is about 5 0 μm, or less than about 20 μm and greater than about 0.1 μm (100 nm). In one embodiment, the range of such microparticles employed in the compositions of the present invention is from about 20 μm to about 0 In further embodiments, the thickness is from about 15 μm to about 0.2 μm (200 nm) or more. In some embodiments, the diameter is from about 10 μm to more than about 0.5 μm (500 nm), for example from about 10 μm to about 1 μm or less than about 1000 nm, or less than about 500 nm, or less than about 400 nm The above values ​​are based on the post-preparation values. However, these refer to measurements taken at various temperatures (e.g., about 5° C. , 25°C, and 40°C) for a period of up to 3 months (e.g., 5 days, 1 week, may refer to measurements taken after 2 weeks, 1 month, 2 months, or 3 months.

[0042] As used herein, the term average effective particle size has its conventional meaning known to those of ordinary skill in the art. For example, the method may be a method for detecting the presence of a magnetic field, such as a magnetic field, ... The average particle size may be measured by particle size measuring techniques known in the art, such as particle size distribution. The average effective particle size may be related to the volume distribution of particles. In that case, "an effective average particle size of less than about 50 μm" is "Average particle size" means particles having a particle size of which at least 50% of the volume of the particles is less than the effective mean of 50 μm. The same applies to the other stated effective particle sizes. Similarly, the average effective particle size is determined by the weight of the particles. Although this may be related to the mass distribution, typically this will have the same or nearly the same value for the average effective particle size. bring about.

[0043] The pharmaceutical composition of the present invention is a sustained release pharmaceutical composition, since it releases the active ingredient bedaquiline over a long period of time. After administration, the compositions of the present invention remain in the body and provide a therapeutic effect to the patient. By continuously releasing bedaquiline while maintaining the concentration of this active ingredient in the system for a long period of time, and provide adequate treatment or prevention of pathogenic mycobacterial infections during the above-mentioned period. The pharmaceutical compositions of the invention remain in the body and release bedaquiline (and its derivatives, referred to herein as M2). These drugs release active metabolites (see methyl-substituted metabolites below) in a continuous manner. can be referred to as a pharmaceutical composition suitable as a long-acting (or depot) formulation.

[0044] As used herein, the term "long-term" refers to a period of time ranging from one week up to one year or up to two years. A time period (or duration) that can be in the range, or 1-2 weeks, or 2-3 weeks, or A period ranging from 3 to 4 weeks, or 1 to 2 months, or 2 to 3 months, or 3 to 4 months months, 3-6 months, 6-12 months, or 12-24 months or for a period of a few days, e.g., 7, 10, or 12 days, or for a few weeks, e.g., 2, 3 , or 4 weeks, or 1 month, or several months, for example, 2, 3, 4, 5, or Means a period of 6 months or more, for example 7, 8, 9, or 12 months do.

[0045] The pharmaceutical compositions of the present invention are useful for the long-term treatment or long-term prevention of pathogenic mycobacterial infections. or, in other words, they can be used to treat pathogenic mycobacterial infections. The present invention can be used for long-term treatment or prevention of pathogenic mycobacterial infections. The compositions are useful for treating or preventing pathogenic mycobacterial infections for extended periods of time, e.g., at least Also, it is effective for about one week or more, or about one month or more. The expression is the plasma concentration of the active ingredient, bedaquiline (and / or its active metabolite, M2). In the case of therapeutic use, the above thresholds are and / or its active metabolite M2) provide effective treatment for pathogenic mycobacterial infections. For applications in the prevention of pathogenic mycobacterial infections, The above thresholds are based on the efficacy and safety of bedaquiline (and / or its active metabolite M2) in preventing pathogenic mycobacteria. This is the minimum plasma concentration effective in preventing the transmission of virulent infections.

[0046] For example, "long-term prevention of pathogenic mycobacterial infections" or "prophylaxis of pathogenic mycobacteria" "Long-term" as used in connection with "long-term treatment of acute respiratory infections" or similar terms means from one week to The period may range up to one or two years, or longer, for example five or ten years. In particular, when treating pathogenic mycobacterial infections, this period lasts for approximately 1 This can range from months to several months to a year or more. These periods are relatively long, especially in the case of prevention. A shorter period may be a few days, e.g., 7, 10, or 12 days, or several A week, e.g., 2, 3, or 4 weeks, or a month, or several months, e.g., 2, 3, or 4 , 5, or 6 months, or even longer, such as 7, 8, 9, or 12 months. In one embodiment, the method and use according to the invention can be carried out for one month or for several months, e.g. , 3, 4, 5, or 6 months, or more, for example, 7, 8, 9, or 12 months. , for preventing pathogenic mycobacterial infections.

[0047] The pharmaceutical compositions of the present invention may be administered at various time intervals. When used for the prevention of rheumatoid arthritis, the pharmaceutical composition of the present invention is administered only once or for a limited period of time. The drug may be administered multiple times, for example, 2, 3, 4, 5, or 6 times, or more. This may be recommended when prophylaxis is needed for a limited period of time, such as during the period when a risk of infection exists.

[0048] The pharmaceutical composition of the present invention can be administered at the above-mentioned time intervals, for example, within a range of 1 week to 1 month, or 1 month. For a time interval ranging from ~3 months, or from 3 months to 6 months, or from 6 months to 12 months In one embodiment, the pharmaceutical composition can be administered once every two weeks or once a month. In another embodiment, the time interval is: The time interval may range from 1 to 2 weeks, or 2 to 3 weeks, or 3 to 4 weeks, or the time interval may range from 1 ~2 months, or 2-3 months, or 3-4 months, or 3-6 months, or 6-12 months, or The time interval can range from 12 to 24 months. The time interval can be at least a week, but can be as long as several weeks. , for example, 2, 3, 4, 5, or 6 weeks, or for one or several months, for example 2, 3, 4, 5, or 6 months, or even longer, e.g., 7, 8, 9, or 12 In one embodiment, the pharmaceutical composition of the present invention may be administered at a time interval of 1, 2, or 3 months. The time between each administration of the pharmaceutical composition of the present invention is Longer duration of the medication further improves pill burden and compliance. On specific days of the week if the composition is administered on a weekly schedule, or on a monthly schedule. In the case of a schedule, the patient may be instructed to take the medication on certain days of the month.

[0049] The length of the time interval between each administration of the compositions of the present invention can vary. For example, the above time intervals can be: The choice may be made as a function of the plasma concentration of bedaquiline (and / or its active metabolite M2). If the plasma concentrations of the drugs are considered too low, for example if they fall below the minimum plasma concentrations specified below, This interval may be shorter if the dose approaches 100 mg / kg / day. If plasma concentrations of the pharmacokinetic (M2) compound are considered to be too high, this interval may be longer. In one embodiment, the compositions of the present invention are administered at equal time intervals. may be administered without intermediate booster doses, or in other words, the composition may be administered in a different or For periods of equal length, for example, a period of at least one week, or any other period specified herein. may be administered at specific times spaced apart from one another for a period of time during which no further bedaquiline is administered. The time intervals being equal in length may be, for example, administration on the same day of the week or the same day of the month. The advantage of this is that the administration schedule is simple, i.e., the administration is performed in a single dose. The schedule limits the "pill burden," which improves patient compliance with the prescribed medication regimen. Beneficially contributes to medication adherence.

[0050] in plasma of subjects treated with bedaquiline (and / or its active metabolite, M2) Its concentration (or "C") is generally expressed as mass per unit volume, usually in nanograms. For convenience, this concentration is referred to herein as "plasma These are sometimes called "medium drug concentrations" or "plasma concentrations."

[0051] The dose (or amount) of bedaquiline administered will depend on the amount of bedaquiline in the pharmaceutical composition of the present invention, or depending on the amount of a given composition administered. either a composition with a higher bedaquiline concentration or a higher amount of a given composition, Or both may be administered. The opposite is true if lower plasma concentrations are desired. Various time intervals and various dosing combinations can be used to achieve specific desired plasma concentrations. A combination may also be selected.

[0052] The dose (or amount) of bedaquiline administered depends on the frequency of administration (i.e., the time between each administration). The frequency of administration also depends on the interval between doses. Usually, the less frequent the dose, the higher the dose. The parameters can be used to direct the plasma concentration towards a desired value.

[0053] The drug regimen is intended to prevent pathogenic mycobacterial infection or to prevent pathogenic mycobacterial infection. It also depends on whether treatment of an isobacterial infection is envisaged. In the case of treatment, the The dose of bedaquiline administered, or the frequency of administration, or both, should be determined based on the maximum plasma concentration of bedaquiline. In this context, the term "minimum plasma concentration" is used to refer to a plasma concentration that is maintained above the minimum plasma concentration. Concentration" (or C min ) is a vector that provides effective treatment for pathogenic mycobacterial infections. This refers to the plasma concentration of daquiline (and / or its active metabolite M2). The plasma concentration of daquiline (and / or its active metabolite M2) is approximately 10 ng / mL. a concentration greater than the minimum plasma concentration, or greater than about 15 ng / mL, or greater than about 20 ng / mL, or Maintained at >40 ng / mL. Bedaquiline (and / or its active metabolite M2) For example, the plasma concentration of is greater than about 50 ng / mL, or greater than about 90 ng / mL, or greater than about 270 The plasma concentration is maintained at a higher level than the minimum plasma concentration of more than 540 ng / mL or more than about 540 ng / mL. In one embodiment, bedaquiline (and / or its active metabolite M2) The plasma concentration of is maintained at greater than about 13.5 ng / mL, or at greater than about 20 ng / mL Alternatively, bedaquiline (and / or its active metabolite M2 The plasma concentration of the drug should be within a certain range, starting from a minimum plasma concentration selected from the values ​​above. The plasma concentration is selected from the above values ​​and is between 500 ng / mL and 1 000ng / mL (e.g., 10-15, 10-20, 10-4 0, etc., or 15-20, or 15-40, or 15-90, etc., or 20-40, 20~90, or 20~270, etc., or 40~90, 40~270, or 40~54 0, etc., from approximate reading (ng / mL) to approximate reading (ng / mL) each time. In one embodiment, the above range is about 10 to about 20, about 20 to about 90, about 90 ~270, ~540, ~1000. The approximate readings for each time are ( ng / mL) to approximate indicated value (ng / mL).

[0054] At lower concentrations, the bacteria are no longer sufficiently inhibited, resulting in proliferation and mutation of the bacteria. bedaquiline (and / or its active metabolite M2) is associated with an increased risk of Plasma concentrations should be maintained above the minimum plasma concentrations mentioned above.

[0055] In the case of prevention, the term "minimal plasma concentration" (or C min ) is an effective treatment for infections / The minimum plasma concentration of bedaquiline (and / or its active metabolite M2) that provides protection Point.

[0056] In particular, in the case of prophylaxis, plasma concentrations of bedaquiline (and / or its active metabolite M2) The concentration may be maintained at levels above the minimum plasma concentrations described above for treatment. However, in the prophylaxis, plasma levels of bedaquiline (and / or its active metabolite M2) The concentration may be lower, for example, about 4 ng / mL, or about 5 ng / mL, or about 8 ng / mL. At lower concentrations, the drug may no longer be effective. bedaquiline (and / or its active derivatives) should be avoided as a result of increased risk of infection transmission. It is preferable that the plasma concentration of the pharmacokinetic (M2) compound be maintained above these minimum plasma concentrations. Plasma concentrations of bedaquiline (and / or its active metabolite M2) should be within the safety margin. Such higher concentrations may be maintained at approximately 50 ng / mL. Start with ≥ 1 mL. Plasma concentrations of bedaquiline (and / or its active metabolite M2) The concentration may be maintained within the above ranges when therapeutically relevant, with the lower limit being about 4 ng / mL, or about 5 ng / mL, or about 8 ng / mL.

[0057] The benefits of bedaquiline (and / or its active metabolite M2) are not considered to be related to any significant side effects. The advantage of this drug is that it can be used to achieve relatively high plasma concentrations without the side effects of (and / or its active metabolite M2) reach relatively high plasma concentrations. However, as with any drug, bedaquiline (and / or its active metabolite, M2) is the maximum plasma concentration (or C max )of In addition, release of the compound from tissues that is not included in the plasma concentration should be taken into consideration. As used herein, the term "serious adverse events" refers to any adverse events that may occur to the patient. This means that there are side effects in the population that affect the normal functioning of patients. In one embodiment, bedaquiline (and / or its active metabolite M2) is administered. The dose and frequency of administration should be determined so that the plasma concentration is maintained at the maximum plasma concentration (or C max ) and the minimum plasma concentration (or C min ) for a long period of time It is selected to be.

[0058] In certain cases, relatively low concentrations, such as the minimum plasma concentrations specified herein, may be possible. To obtain plasma concentrations of bedaquiline (and / or its active metabolite M2) as close as possible to the It may be desirable to maintain the dosage at a constant rate, which may affect the frequency of administration and / or the dosage administered with each administration. It is possible to reduce the amount of bedaquiline (and / or its active metabolite M2) that is released into the blood. This also makes it possible to avoid undesirable side effects, which may be A large target population of healthy people at risk of infection and therefore prone to intolerance of side effects This contributes in part to the acceptability of this dosage form. Plasma concentrations of the metabolite M2) may be maintained at relatively low levels in prophylaxis. One embodiment relates to a use or method for the prevention of an infectious disease as specified above or below, The minimum plasma concentration of daquiline (and / or its active metabolite M2) is specified herein. and the maximum plasma concentration is as defined herein, also as specified herein, This is approximately equal to the minimum plasma concentration that produces a therapeutic effect.

[0059] In other embodiments, the plasma concentration of bedaquiline (and / or its active metabolite M2) The concentration is about 10 ng / mL, more specifically about 15 ng / mL, and even more specifically about 2 0 ng / mL, and even more specifically a lower maximum plasma concentration of about 40 ng / mL. In one particular embodiment, bedaquiline (and / or its active metabolites) is maintained at a concentration of The plasma concentration of M2) is maintained below a concentration of about 13.5 ng / mL. In these conditions, the plasma concentrations of bedaquiline (and / or its active metabolite M2) are as defined above. Between the lower maximum blood concentration noted and the minimum plasma concentration noted in relation to prophylaxis For example, plasma concentrations of bedaquiline (and / or its active metabolite M2) are maintained at The concentration is maintained below about 10 ng / mL and above a minimum concentration of about 4 ng / mL.

[0060] In other cases, e.g., where there is a high risk of infection, more frequent and / or higher doses may be required. If this is not an issue, relatively high concentrations of bedaquiline (and / or its active metabolites) may be used. In some cases, it may be desirable to maintain a certain plasma concentration of M2. Intermediate concentrations, such as the specific concentrations described herein, may be used to treat or prevent pathogenic mycobacterial infections. The minimum plasma concentration of bedaquiline (and / or its active metabolite M2) that provides effective treatment It may be equal to the degree.

[0061] For prophylaxis, the dose to be administered is from about 0.2 mg / day to about 50 mg / day, or about 0. 5 mg / day to about 50 mg / day, or about 1 mg / day to about 10 mg / day, or about 2 mg / day The dose should be calculated based on about 5 mg / day, e.g. about 3 mg / day. This is About 1.5 mg to about 350 mg, specifically about 3.5 mg to about 350 mg, specifically about 7 a dose of about 35 mg to about 70 mg, or about 14 mg to about 35 mg, for example about 35 mg; or About 6mg to about 3000mg per month, specifically about 15mg to about 1,500mg, Typically, the dose is about 30 mg to about 300 mg, or about 60 mg to about 150 mg, for example, about 15 The doses for other dosing regimens are also calculated by dividing the daily dose by the number of days between doses. This can be easily calculated by multiplying by

[0062] For therapeutic purposes, the dose to be administered should be somewhat higher, approximately 1 mg / day. ~ about 150 mg / day, or about 2 mg / day to about 100 mg / day, or about 5 mg / day to about 50 Calculated based on about 10 mg / day to about 25 mg / day, e.g., about 15 mg / day The equivalent weekly or monthly dose should be calculated as above. For prophylactic applications, the same dosages may be used as for therapeutic use. In one embodiment, the dosages / administrations are at monthly intervals, or They are given at 3-month or 6-month intervals, for a total treatment duration of 3, 6, or 12 months. In one embodiment, when the dosing / administration is once a month, once every three months, or once every six months, In this case, the prescribed dose (e.g., in a human subject) is calculated based on a daily dose of 400 mg for 2 weeks. Therefore, the total amount of bedaquiline given per dose is 5600 mg. may be used (for example, within the range of 3000 to 8000 mg), but at most 1 / 5 of such amount. may be used (e.g., within the range of 500 and 2000 mg, e.g., about 1000 to 1500 mg). .

[0063] In the case of prophylaxis, or in the specific treatment, in another embodiment, the dose is expressed in mg / kg. For example, in the Examples, a particular dose may be calculated by weight (e.g., for mammals, and As shown in the Examples, the dose can be based on the amount of the drug administered (in mice). Doses of 0 mg / kg can be used (e.g., 40 mg / kg, 80 mg / kg, 16 0 mg / kg, 320 mg / kg, and 480 mg / kg can be used), The amount can remain effective for 4 weeks, 8 weeks, or 12 weeks (see, e.g., Examples). For example, one dose may be taken every four weeks (effectively for 12 weeks). treatment regimen, i.e., a total of three doses), or a 12-week monitoring period. Substantial sufficient treatment (e.g., as defined by a reduction in CFU) that can be demonstrated by screening A single dose may be taken that provides the desired effect (see Examples). In one embodiment, a single dose may be taken to treat a bacterial infection (e.g., 1 mg / kg~1000mg / kg (e.g. 2mg / kg~500mg / kg)), or once One such dose may be taken every four weeks (e.g., two or three such doses may be taken). Such doses vary depending on the bacterial infection to be treated. In the treatment of sexually transmitted tuberculosis or leprosy, lower doses of bedaquiline are required to control the bacteria. Lower doses may be required given the potential for An example of this is described below (Example 3), where A single dose of 160 mg / kg reduced CFU in a mouse model of latent tuberculosis infection. It has been shown that the effect of administering 160 mg / kg twice or three times is sufficient to reduce the The doses (the second and third doses administered at 4 and 8 weeks, respectively) were also shown to be effective in this model. It was also seen to be effective.

[0064] Once administered, plasma concentrations of bedaquiline (and / or its active metabolite M2) It has been found that the plasma concentration is somewhat stable, i.e. it fluctuates within limits. Periods, more or less approaching a steady-state mode, or more or less approaching a zero-order release rate. "Steady state" refers to the amount of drug present in the plasma of a subject that remains constant over an extended period of time. This means maintaining more or less the same concentration over a period of time. The plasma concentration of the active metabolite, M2, is generally below the minimum plasma concentration at which the drug is effective. "Maintaining more or less the same concentration" is acceptable. Small variations in plasma concentrations within a reasonable range, e.g., about ±30%, or about ±20%, or about ±10%, or does not exclude that there may be a variation within the range of about ±10%.

[0065] In some cases, there may be an initial plasma concentration peak after administration, which is followed by a rapid increase in plasma concentrations as described below. As shown, plasma concentrations reach a "steady state."

[0066] The compositions of the present invention exhibit good local tolerance and ease of administration. The ease of administration associated with minimal irritation and inflammation at the site allows for a single administration of a particular drug formulation. The size of the needle and the length of time required to administer the drug are also related to the composition of the present invention. It exhibits good stability and has an acceptable shelf life.

[0067] The micro- or nanoparticles of the present invention have a surface modifier adsorbed on their surface. Surface Modification The function of the agent is to act as a wetting agent and stabilizer for colloidal suspensions. It is to fulfill our role.

[0068] In one embodiment, the micro- or nanoparticles in the composition of the present invention comprise crystalline bedaquiline or is primarily comprised of a salt thereof, and a surface modifier, the combined amount of which is at least about 50% or at least about 80%, or at least about 90%, or at least about 95%, or less The micro- or nanoparticles may comprise at least about 99% of the nanoparticles. In one embodiment, bedaquiline is in its non-salt form (or in its "free form") and further In one embodiment, it is in a crystalline non-salt (or free) form. As explained in the fine print, bedaquiline is (or WO 2006 / 125769, which describes optical resolution involving chiral reagents) This can be prepared using the procedures described in the publication (published in the same publication as above). Precipitation from toluene / ethanol gave bedaquiline, and the product was crystalline. These forms of bedaquiline have been shown to be effective in preparing compositions of the present invention. and further, such form may be a single crystalline polymorph having the following characteristics: Possible: (i) A melting endotherm at 181.5°C (endothermic onset) and the product melting at approximately 182.5°C. (decomposition occurs immediately afterwards; Differential Scanning Calorimetry (DSC) Approximately 3 mg of compound was transferred to a standard aluminum TA-Instrument sample pan. The sample dish was covered with a suitable coer and the RCS cooling unit was installed. DSC curves were recorded on a TA-Instruments Q2000 MTDSC equipped with The following parameters are used: initial temperature 25°C, heating range 10°C / min, final temperature 300°C. nitrogen flow 50 mL / min); (ii) In particular, about 1600 cm -1 , about 1450cm -1 , about 1400cm -1 ,about 1340cm -1 , and about 1250 cm -1 Infrared (IR) spectrum peaks in (The sample had 32 scans and a resolution of 1 cm -1 The perfect micro ATR accessory , Thermo Nexus670 FTIR spectrometer, DTGS detector with KBr window, Ge on KBr beam splitter, and micro ATR accessory (Har with Si crystal) rick Split Pea); and / or (iii) a diffraction peak of about 11.25 nm, showing no halo, indicative of the crystallinity of the product; °2-θ, approximately 18°2-θ, approximately 18.5°2-θ, approximately 19°2-θ, approximately 20.25°2- θ, about 21.25° 2-θ, about 22.25° 2-θ, about 24.5° 2-θ, and about 27° X-ray powder diffraction (analysis) with characteristic 2-θ peaks was performed using PANalytical (Phili ps) were performed on an X'PertPRO MPD diffractometer using a Cu LFF X-ray tube. Provided that the compound is spread on a zero background sample holder, the instrument parameters The generator voltage was 45 kV, generator amperage was 40 mA, and the configuration was: Bragg-Brentano, Stage: Spinner stage, Scanning mode: Continuous, Scanning Range: 3~50°2θ, Step size: 0.02° / step, Counting time: 30 seconds / step Step, spinner rotation time: 1 second, radiation type: CuKα).

[0069] Thus, in one embodiment, the process for preparing the composition of the present invention includes Bedaquiline (i.e., before conversion to micro / nanoparticles) is present in a crystalline form (e.g., In a further embodiment of the present invention, the composition of the present invention is bedaquiline used in the formulation (i.e., converted into micro / nano particles, e.g. by milling) After conversion, the crystalline form is also a crystalline form (eg, of the specific form characterized above).

[0070] In a further aspect, the present invention provides a therapeutically effective amount of bedaquiline, or a pharma- ceutically acceptable salt thereof. in the form of a suspension of particles, for administration by intramuscular or subcutaneous injection. The suspension of particles is (1) bedaquiline in micro- or nanoparticulate form having a surface modifier adsorbed on its surface; or a pharma- ceutically acceptable salt thereof; (2) consisting essentially of a pharma- ceutically acceptable aqueous carrier, in which the active ingredient is suspended; It relates to pharmaceutical compositions.

[0071] Suitable surface modifiers include a variety of polymers, low molecular weight oligomers, natural products, and surfactants. The surface modifier may be selected from known organic and inorganic pharmaceutical excipients, including surface modifiers. Nonionic and anionic surfactants are included. Representative examples of surface modifiers include: Gelatin, casein, lecithin, salts of negatively charged phospholipids or their acid forms (e.g., phosphatides, tidylglycerol, phosphatidylinositol, phosphatidylserine, phosphatidyl Phosphatic acids and their salts, such as alkali metal salts, e.g. For example, their sodium salts, such as sodium egg phosphatidylglycerol, e.g., Li poid(TM) (products available under the trade name EPG), gum arabic, stearic acid, salt benzalkonium chloride, polyoxyethylene alkyl ethers, e.g. macrogol ether , such as cetomacrogol 1000, polyoxyethylene castor oil derivatives; Stearic acid, colloidal silicon dioxide, sodium dodecyl sulfate, carboxymethyl sodium cellulose, bile salts, e.g. sodium taurocholate, desoxytaurocholate Sodium deoxycholate, sodium deoxycholate; methylcellulose, hydroxyethyl Cellulose, Hydroxypropylcellulose, Hydroxypropylmethylcellulose, Ma Magnesium aluminate silicate, polyvinyl alcohol (PVA), ethylene oxide Poloxamers, which are block copolymers of ethylene oxide and propylene oxide, e.g., Pluro nic™ F68, F108, and F127; Tyloxapol; Vitamin E-TGP S (α-tocopheryl polyethylene glycol succinate, especially α-tocopheryl poly ethylene glycol 1000 succinate; poloxamines, e.g. ethylenediamine Tetrafunctional blocks derived from the sequential addition of ethylene oxide and propylene oxide to copolymer Tetronic™ 908 (T908); dextran; dioctyl esters of sodium sulfosuccinate, e.g. Aerosol OT (trade name); Products marketed under the trade name (AOT); sodium lauryl sulfate (Duponol ( Triton(TM)X-200; Polyoxyethylene sorbitan fatty acid esters (Tweens (trademark) 20, 40, 60, and 80; sorbitan esters of fatty acids (Span (trademark) ) 20, 40, 60, and 80, or Arlacel™ 20, 40, 60, and 8 0); polyethylene glycol (e.g., Carbowax® 3550 and 934) Sucrose stearate and sucrose distearate Mixtures such as Crodesta® F110 or Crodesta® SL- 40 products available under trade names; Hexyldecyltrimethylammonium chloride (CT AC); polyvinylpyrrolidone (PVP). If desired, two or more Combinations of surface modifiers may also be used.

[0072] Specific surface modifiers include poloxamer, α-tocopheryl polyethylene glycol scaffold, cyanate, polyoxyethylene sorbitan fatty acid ester, and salt of negatively charged phospholipid or More specifically, the surface modifier is selected from Pluronic™ in its acid form. F108, Vitamin E TPGS, Tween™ 80, and Lipoid™ EPG (and in a particular embodiment, this is Vitamin E TGPS) One or more of these surface modifiers may be used. F108 corresponds to poloxamer 338, which is a polyoxyethylene, polyoxypropylene copolymer. propylene block copolymers, which generally have the formula HO-[CHCHO]-[CH( CH3)CH2O]y-[CH2CH2O] z -H, where the average of x, y, and z The values ​​are 128, 54, and 128, respectively. Other trade names for Poloxamer 338 are H odag Nonionic(TM) 1108-F and Synperonic(TM) P E / F108. In one embodiment, the surface modifier is polyoxyethylene sorbitan fat. Acid esters and phosphatidylglycerol salts (especially egg phosphatidylglycerol sodium) This includes combinations with .

[0073] The optimal relative amount of bedaquiline to the surface modifier will depend on the surface modifier selected, the average effective The specific surface area of ​​bedaquiline suspensions determined by particle size and bedaquiline concentration, the surface modifier When micelles are formed, it depends on the critical micelle concentration. The relative amount of phosphorus (w / w) is preferably within the range of 1:2 to about 20:1, specifically 1:1 in the range of about 10:1, for example about 4:1.

[0074] The particles of the present invention can be prepared by mechanical means and by controlled precipitation from supersaturated solutions. Or, as in the GAS method ("gas anti-solvent") Microparticleization by the use of supercritical fluids such as Micronization / Micronization / Nanonization In one embodiment, the formulation can be prepared by dispersing bedaquiline in a liquid dispersion medium. Then, mechanical means are applied in the presence of grinding media to reduce the particle size of bedaquiline to less than about 50 μm, e.g. Specifically, a method is used that includes reducing the average effective particle size to less than about 1,000 nm. The size of the particles can be reduced in the presence of a surface modifier.

[0075] A general method for preparing the particles of the present invention includes: (a) obtaining bedaquiline in micronized form; (b) Adding microparticulated bedaquiline to a liquid medium to form a premix / predispersion. Formation and; (c) subjecting the premix to mechanical means in the presence of grinding media to reduce the average effective particle size. and; Includes.

[0076] Microparticulated forms of bedaquiline are prepared using techniques known in the art. The average effective particle size of the bedaquiline active agent in the predispersion is approximately 100 μm as determined by sieve analysis. Preferably, the average effective particle size of the micronized bedaquiline is less than about 100. If the bedaquiline compound particles exceed 100 μm, it is preferred to reduce the size of the particles to less than 100 μm. Preferably (e.g., up to a size or size range described herein).

[0077] The micronized bedaquiline may then be added to the liquid medium, which Since it is essentially insoluble in the liquid medium, it forms a predispersion. (wt / wt percentage) can vary widely and is dependent on the surface modifier selected and other factors. A suitable concentration of bedaquiline in the composition is from about 0.1% to about 60%, or from about 1% to about 6 0%, or about 10% to about 50%, or about 10% to about 30%, for example about 10%, 20%, or may vary by 30% (each percentage in this paragraph is with respect to w / v).

[0078] The premix is ​​subjected to mechanical means to reduce the average effective particle size in the dispersion to about 2,000 nm. If a ball mill is used for grinding, the powder can be used directly by reducing the temperature to less than 100°C. It is preferred to use the premix directly. Alternatively, bedaquiline and, optionally, the surface modifier may be 1. Mix the liquid medium with suitable agitation, such as a roller mill, until a uniform dispersion is achieved. It may be dispersed in.

[0079] Effective average effective particle size of bedaquiline Mechanical measures applied to reduce the active particle size are Conveniently, the dispersion may take the form of a dispersion mill. Suitable dispersion mills include ball mills, grinders / mills, etc. These include attritor mills, vibratory mills, planetary mills, media mills, such as sand mills and bead mills. Media mills are preferred because they require a relatively short milling time to achieve the desired particle size reduction. The beads are preferably ZrO2 beads. For example, in the case of nanoparticles, The ideal bead size is about 0.5 mm, and for microparticles, the ideal bead size is about It is 2mm.

[0080] The grinding media for the particle size reduction step is preferably less than 3 mm, more preferably less than 1 mm. Rigid media in spherical or particulate form with an average size of less than 200 μm (beads as small as 200 μm) Such media may be selected from the group consisting of: Examples of grinding media are magnesia stabilized or Yttrium stabilized 95% ZrO2, Zirconium silicate, Glass milling The media are polymeric beads, stainless steel, titania, alumina, etc. Preferred grinding media is 2.5g / cm 3 It has a density of over 10 ... Polymer beads are included.

[0081] Grinding times can vary widely and depend primarily on the particular mechanical means and processing conditions selected. In the case of rolling mills, processing times of up to two days or more may be required. .

[0082] The particle size should be reduced at a temperature that does not significantly degrade the bedaquiline compound. Processing temperatures below 40° C. are usually preferred. If desired, the processing equipment may be equipped with conventional cooling equipment. This method is conveniently safe and effective for the milling process. The process is carried out under ambient temperature conditions and under processing pressure, which is effective.

[0083] The pharmaceutical composition of the present invention preferably contains a pharma- ceutically acceptable aqueous carrier. The pharmaceutical carrier comprises sterile water, optionally mixed with other pharma- ceutically acceptable ingredients. The present disclosure includes optional ingredients for use in injectable formulations. These ingredients include suspending agents, buffers, pH adjusters, preservatives, tonicity agents, and other ingredients. In one embodiment, the above ingredients may be selected from one or more of the following: suspending agents, Selected from one or more of a buffering agent, a pH adjusting agent, an optional preservative, and a tonicity adjusting agent. Certain ingredients can function as two or more of these agents simultaneously, e.g. For example, it may act as a preservative and a buffer, or as a buffer and a tonicity agent. can be done.

[0084] Suitable optional buffers and pH adjusters can be used to adjust the dispersion to a pH range from neutral to preferably Should be used in sufficient quantity to make the solution very slightly alkaline, between 7 and 7.5 (maximum pH 8.5). A particular buffer is a salt of a weak acid. Buffers and pH adjusters that can be added are tartaric acid, maleic acid, glycine, sodium lactate / lactic acid, ascorbic acid, and citric acid. Sodium / Citrate, Sodium Acetate / Acetic Acid, Sodium Bicarbonate / Carbonate, Sodium Succinate Sodium / succinate, sodium benzoate / benzoic acid, sodium phosphate, tris(hydrogen (oxymethyl)aminomethane, sodium bicarbonate / sodium carbonate, ammonium hydroxide, Benzenesulfonic acid, sodium benzoate / benzoic acid, diethanolamine, gluconode Lactolactone, Hydrochloric Acid, Hydrogen Bromide, Lysine, Methanesulfonic Acid, Monoethanolamine, Water Sodium oxide, tromethamine, gluconic acid, glyceric acid, glutaric acid, glutamic acid , ethylenediaminetetraacetic acid (EDTA), triethanolamine, and mixtures thereof. In one embodiment, the composition of the present invention does not include a buffer.

[0085] Suitable optional preservatives are benzoic acid, benzyl alcohol, butylated hydroxyaniline. Sole (BHA), Butylated Hydroxytoluene (BHT), Chlorbutol, Gallic Acid Salt, Hydroxybenzoate, EDTA, Phenol, Chlorocresol, Metacresol Benzethonium chloride, myristyl-γ-picolinium chloride, phenylmercuric acetate, and thimerosal. Sequestrants include BHA, BHT, Vitamin E, and Ascorbyl Palmitate, and Oxygen scavengers include sodium ascorbate, sodium sulfite, and mixtures thereof. Sodium, L-cysteine, acetylcysteine, methionine, thioglycerol, acetonitrile Sodium bisulfite, isoacorbic acid, hydrochloric acid Chelating agents include sodium citrate, In one embodiment of the present invention, the present invention The composition does not contain a perseverative.

[0086] To ensure the isotonicity of the pharmaceutical composition of the present invention, an isotonicity agent may be present, such as Glucose, dextrose, sucrose, fructose, trehalose, lactose, etc. sugars; polyhydric sugar alcohols, preferably trihydric or tetrahydric or higher sugar alcohols, such as glyceryl; erythritol, arabitol, xylitol, sorbitol, and mannitol. Alternatively, sodium chloride, sodium sulfate, etc. may be used to give the solution isotonicity. or other suitable inorganic salts may be used. These tonicity adjusting agents may be used alone or in combination. The suspension may be used in any suitable form, conveniently containing 0 to 10% (w / v) of an isotonicity agent, particularly Contains 0-6%. Non-ionic tonicity agents, as electrolytes may affect colloidal stability. For example, glucose is of interest. In one embodiment of the invention, the compositions of the invention are isotonic. In a further embodiment, the composition further comprises a non-ionic surfactant, such as a suitable sugar, such as mannitol. It is a hydrophobic isotonic agent.

[0087] A preferred feature of the pharmaceutical composition of the present invention relates to ease of administration. The viscosity should be low enough to allow administration by injection. The pharmaceutical compositions of the present invention can be easily drawn up into a syringe (e.g., from a vial) and delivered in a thin, Needles (e.g., 20G1 1 / 2, 21G1 1 / 2, 22G2, or 22G1 1 / 4 needles) ) in a reasonably short period of time. In one embodiment, the viscosity of the composition of the present invention is less than about 75 mPa·s, or less than 60 mPa·s. Aqueous suspensions of such a viscosity or less will generally meet the above criteria. .

[0088] Ideally, the aqueous suspensions of the present invention are tolerable so as to keep injection volumes to a minimum. As much bedaquiline (or a pharma- ceutically acceptable salt thereof) as possible, specifically 3 to 70% (w / v), or 3-60% (w / v), or 3-40% (w / v), or 10-40% (w / v) bedaquiline (or a pharma- ceutically acceptable salt thereof). The aqueous suspension contains about 50% to 70% (w / v) bedaquiline (or a pharma- ceutically acceptable salt thereof). or about 40% to 60% (w / v) of bedaquiline (or a pharma- ceutically acceptable salt thereof) ), or about 30% to 50% (w / v) of bedaquiline (or a pharma- ceutically acceptable salt thereof). include.

[0089] In one embodiment, the aqueous suspension comprises, by weight based on the total volume of the composition: (a) 10-70% (w / v), or 20-60% (w / v), or 20-50 % (w / v), or 20-40% (w / v) of bedaquiline (or its pharma- ceutically acceptable salts) (able salt); (b) 0.5 to 20%, or 2 to 15% or 20% (w / v), or 5 to 15% (w / v) wetting agent; (c) One or more of the following: 0% to 10%, 0% to 5%, 0% to 2%, or 0% to 1% Buffers; (d) 0 to 20%, or 2 to 15% or 20% (w / v), or 5 to 15% (w / v ) isotonicity agent; (e) 0% to 2% (w / v) of a preservative; and (f) water for injection, qs.s. to total 100%;

[0090] In one embodiment, the aqueous suspension comprises, by weight relative to the total volume of the composition: (a) 3 to 50% (w / v), or 10 to 40% (w / v), or 10 to 30% (w / v ) bedaquiline (or a pharma- ceutically acceptable salt thereof); (b) 0.5% to 10%, or 0.5% to 2% (w / v) of a humectant; (c) One or more of the following: 0% to 10%, 0% to 5%, 0% to 2%, or 0% to 1% Buffers; (d) 0% to 10%, or 0% to 6% (w / v) of an isotonicity agent; (e) 0% to 2% (w / v) of a preservative; and (f) water for injection, qs.s. to total 100%;

[0091] An amount of acid or base may optionally be added to the suspension to bring its pH to about pH 7. Suitable acids or bases are any physiologically acceptable acid or base, such as HCl, HBr, sulfuric acid, and alkali metal hydroxides such as NaOH. No acid or base needs to be added to the compositions of the present invention.

[0092] Administration of bedaquiline (or a pharma- ceutically acceptable salt thereof) as in the present invention may be effective in preventing or alleviating the pathogenic mycobacteria. may be sufficient to treat TB infections, but in many cases other anti-TB drugs may be required. Coadministration may be recommended.

[0093] In certain cases, the treatment of pathogenic mycobacterial infections is with bedaquiline ( and / or its metabolites), i.e., without the simultaneous administration of an additional anti-TB drug. This option may be limited to administration only as a monotherapy with low active ingredients, for example. In the case of certain mycobacterial infections where the ingredients can treat the bacteria (e.g., latent / Dormant TB, or Mycobacterium lepr ae) can be recommended.

[0094] In a further aspect, the present invention provides a method for the maintenance of a subject infected with a pathogenic mycobacterial infection. An effective amount of bedaquiline or a pharma- ceutical acceptable salt thereof according to the present invention for the preparation of a medicament for therapy. Regarding the use of pharmaceutical compositions containing the possible salts, the compositions can be administered for a period of 1 week to 1 year, or for a period of 1 week to 2 years. It will be administered intermittently or at time intervals ranging from one year to the next.

[0095] Thus, in a further aspect, the present invention relates to a method for treating a mycobacterial infection comprising administering to a patient infected with the infection a pathogenic mycobacterial infection. 20. A method for the chronic treatment of a patient suffering from (i) treatment of the above patients with anti-TB drugs; and subsequently (ii) A pharmaceutical composition according to the present invention comprising a therapeutically effective amount of bedaquiline, or a pharma- ceutical acceptable salt thereof. Intermittent administration of a pharmaceutical composition, wherein the composition is administered at time intervals of at least one week. The method includes administering

[0096] Treatment for Mycobacterium leprae For this purpose, the regimen is again used as monotherapy or in combination with Mycobacterium replenishment. Existing drugs useful for the treatment of Mycobacterium leprae (e.g., The compositions of the present invention may be administered once or in combination with fluoxetine. It may be administered by up to three injections, for example, one month apart. The advantage is improved compliance. Absence of resistance by avoiding dapsone, spotting by avoiding clofazimine The absence of stigma.

[0097] The present invention further relates to the use of the compound as a pharmaceutical agent in the treatment or prevention of pathogenic mycobacterial infections. The present invention also relates to a pharmaceutical composition as described above for administering

[0098] The present invention further provides a method for preparing a medicament for preventing or treating a pathogenic mycobacterial infection. The present invention relates to the use of the pharmaceutical compositions described herein for the treatment of

[0099] The present invention further relates to a method for treating a subject infected with a pathogenic mycobacterial infection, comprising administering to said subject a therapeutically effective amount of The methods include administering a therapeutically effective amount of a pharmaceutical composition as described herein.

[0100] As used herein, the term "substantially" does not exclude "completely", e.g., Y may be "substantially A composition that is "substantially free" may be completely free of Y. may be omitted from the definition of the present invention. The term "about" in connection with a numerical value means Where necessary, the word "about" shall mean a numerical value plus or minus 10%. , ±5%, ±2%, or ±1%.

[0101] All documents cited herein are incorporated by reference in their entirety.

[0102] The following examples are intended to illustrate the present invention and are not to be construed as limiting the invention thereto. It should not be interpreted. EXAMPLES

[0103] Example 1: Preparation of micro- and nanosuspensions The active ingredient bedaquiline may be used as such or in its pharmaceutical form such as the fumarate. To convert it into a commercially available salt (e.g., the form used in the commercial product Sirturo®), When referred to herein, unless otherwise specified, bedaquiline is intended to be used interchangeably with its non- It is used in salt form.

[0104] The prototype bedaquiline formulation is as follows: Preparation of nano- and microsuspensions at 200 mg / mL and 100 mg / mL. Materials used: 0.5mm zirconium beads (to aid in processing) Sterile water for injection (Viaflo) Bedaquiline (unmilled / uncrushed) Tocopheryl PEG 1000 succinate - excipient 2mm zirconium beads (to aid in processing) Mannitol (parenteral) - excipient

[0105] A glass bottle and ZrO2 beads (nano or macro as desired) used as milling media. (either 0.5 mm or 2 mm depending on the micro suspension) were sterilized in an autoclave. For injection, the drug substance (amounts will vary depending on the formulation being prepared; see below for examples of formulations / suspensions): (see Suspended Solution) in water (amount required / Varies depending on desired concentration; see formulations / suspensions below for examples The average particle size was 500 μm or 2 mm (whether micro or nano suspension is required) Add 10 ... The suspension was micronized / nanoparticled at 100 rpm for a period of up to 72 hours. For example, micronization may be carried out at 100 rpm for 3 hours (or up to 3 hours); Nanoparticle formation may be carried out at 100 rpm for up to 46 hours (e.g., about 40 hours). Once the mixing process is complete, the concentrated micro or nano suspension is withdrawn with a syringe and then The resulting formulations (based on nano- and micro-suspensions) were then filled into glass bottles. The concentrations are listed in the table below. Concentrations were determined by HPLC / UV. Dilutions were made if necessary. The final concentration of the active ingredient, bedaquiline, was adjusted to 200 mg / mL. The solution was protected from light. Nano and micro formulations at 300 mg / mL and 100 mg / mL were included. Other concentrations were also made and tested.

[0106] Such combinations are investigated for their possible long-acting effects (e.g., in the treatment of leprosy). Animals have been (and will be) dosed intramuscularly and subcutaneously for PK studies to determine whether The physical stability of the suspension is followed by measuring particle size after various storage conditions.

[0107] Particular embodiments of the formulation have the following features: Microsuspension using 2mm Zr beads Milling at 200mg / mL (otherwise, e.g. 300mg / mL would be too high) (It may be too much.) Longer milling time to obtain nanosuspension Suitable surface modifiers, selected for example on the basis of physical stability, include, for example, T PGS, in another embodiment Tween.

[0108] Examples of bedaquiline micro- and nanosuspensions 200 mg / mL, referred to herein as Example 1A (nano) and Example 1B (micro), mL Nano and Micro Suspensions

[0109] [Table 1]

[0110] 100 mg / mL Nano and Micro Suspensions

[0111] [Table 2]

[0112] Particle size distribution (PSD) of the above blend Where applicable, ND = not determined

[0113] [Table 3]

[0114] [Table 4]

[0115] [Table 5]

[0116] [Table 6]

[0117] Example 2: Pharmacokinetic studies Study A - Pharmacokinetic profile in mice A single dose of bedaquiline was orally administered to mice, and bedaquiline itself (also known as TMC207) (also called "M2") and its major metabolite, N-monodesmethyl (also called "M3"), in plasma. Metabolic kinetics were measured over a 168-hour period. M2 appears to be the active metabolite, Its formation upon administration of Kirin (TMC207) has been observed in at least the following species: mice; rats / dogs, and humans (its formation is greatest in mice and least in humans) be).

[0118] The results are shown in Figure 1, “TMC207 and M2 after a single dose of 30 mg / kg in mice.” The plasma kinetics of morphine are as described in "Plasma kinetics of morphine".

[0119] We can see that: The plasma kinetics of TMC207 and M2 are slow, and M2 formation is also slow. Plasma exposure (AUC) of M2 is higher than that of TMC207 The lung concentrations of M2 are much higher than those of TMC207 After a period of 168 hours, the plasma TMC207 concentration was approximately 0.01 μg / mL, and M2 was approximately 0.01 μg / mL. Approximately 0.1 μg / mL

[0120] As described in Example 1, 200 mg / mL and 100 mg / mL microcapsules were The nanosuspensions (Examples 1A, 1B, 1C, and 1D) were tested in mice, where received one of the following: 80 mg / kg (in this case, a 100 mg / mL suspension was used (i.e., Example 1 C and 1D)) or 160 mg / kg (in this case, a 200 mg / mL suspension was used). (i.e., Examples 1A and 1B) was administered intramuscularly (IM) or subcutaneously (SM).

[0121] Each of the formulations 1A, 1B, 1C, and 1D was diluted with the suspension AP before administration to the mice. The API is 75- 142% (an unusually wide range). In these combinations, plasma concentrations of bedaquiline and its metabolites remain It was possible to measure and evaluate the results.

[0122] Results stage 1-672 hours FIG. 2: 200 mg / mL formulation (specifically, the formulations of Examples 1A and 1B, i.e. , nano- and microsuspensions, respectively) were administered IM or SC at a dose of 160 mg / kg. Plasma kinetics of TMC207 in mice when Referred to)

[0123] FIG. 3: 200 mg / mL formulation (specifically, the formulations of Examples 1A and 1B, i.e. , nano- and microsuspensions, respectively) were administered IM or SC at a dose of 160 mg / kg. Plasma kinetics of M2 in mice when administered 100 mg / kg of ...

[0124] In general, we can see the following: Regarding TMC207 concentration, C max The range is approximately 3000ng / mL (microsuspension dose The range is from about 100 ng / mL (maximum value for IM administration) to about 100 ng / mL (minimum value for microsuspension administration SC). R At 672 hours, the concentration was approximately 200 ng / mL (maximum value for microsuspension administration IM) to approximately 50 ng / mL / mL (minimum value for microsuspension SC administration) range, still measurable TMC20 There were 7 concentrations Regarding M2 concentration, C max The range is approximately 3000ng / mL (microsuspension administered IM Maximum value) to approximately 300 ng / mL (minimum value for microsuspension administration SC) At 672 hours, the concentration ranged from about 1000 ng / mL (maximum value for microsuspension administration IM) to about 200 Still measurable M2 concentrations in the range of ng / mL (minimum for microsuspension-administered SC) There was a degree

[0125] FIG. 4: 100 mg / mL formulations (specifically, formulations of Examples 1C and 1D, i.e. When the 100 mg / kg IV suspension (nano- and microsuspensions, respectively) was administered IM or SC at a dose of 80 mg / kg, Plasma kinetics of TMC207 in mice (TMC207 is shown as "UD" in the figure). (illuminated)

[0126] FIG. 5: 100 mg / mL formulations (specifically, formulations of Examples 1C and 1D, i.e. When the 100 mg / kg IV suspension (nano- and microsuspensions, respectively) was administered IM or SC at a dose of 80 mg / kg, Plasma kinetics of M2 in mice with and without rituximab (M2 is referred to as "met" in the figure)

[0127] In general, we can see the following: Regarding TMC207 concentration, C max The range is approximately 2000 ng / mL (nanosuspension administration I M) to about 400ng / mL (minimum value for nano- and microsuspension administration SC) is At 672 hours, the concentration was approximately 100 ng / mL (maximum value for microsuspension administration IM) to approximately 30 ng / mL / mL (minimum value for microsuspension SC administration) range, still measurable TMC20 Regarding the M2 concentration where 7 concentrations existed, C max The range is approximately 2000ng / mL (nanosuspended Range: 300ng / mL (maximum value for liquid administration IM) to approximately 300ng / mL (minimum value for microsuspension administration SC) is At 672 hours, the concentration was approximately 500 ng / mL (maximum value of microsuspension administration IM) to approximately 100 ng / mL Still measurable M2 concentrations in the range of 100 µg / mL (minimum for microsuspension-dosed SC) There was

[0128] Results stage 2-2 up to 184 hours Mice in these studies were further monitored for up to 2184 hours with the following results: Formulation 1A, i.e., nanosuspension with a concentration of 200 mg / mL, was administered SC( StDev = standard deviation), and when administered IM at 160 mg / kg

[0129] [Table 7]

[0130] Formulation 1C, i.e., nanosuspension with a concentration of 100 mg / mL, was administered SC at 80 mg / kg; and 80 mg / kg IM.

[0131] [Table 8]

[0132] Formulation 1B, i.e., a microsuspension with a concentration of 200 mg / mL, was administered at 160 mg / kg. SC (StDev = standard deviation) and IM at 160 mg / kg

[0133] [Table 9]

[0134] Formulation 1D, i.e., a microsuspension with a concentration of 100 mg / mL, was administered at 80 mg / kg in S C (StDev = standard deviation), and when administered IM at 80 mg / kg

[0135] [Table 10]

[0136] Study B - Pharmacokinetic profile in rats and beagle dogs In this study, nanosuspension (Formulation 1A) and microsuspension (Formulation 1B), both shown in Figure 1 above, were used. A formulation with a concentration of 200 mg / mL was used (i.e. , micro- and nanoparticles (of active bedaquiline) at a concentration of 200 mg / mL, plus TPG S (4:1 bedaquiline:TPGS) and 50 mg / mL mannitol in WFI ( Used in water).

[0137] These studies were carried out using the formulations described in Example 1 (specifically nano- and macro-formulas 1A and 1B). Microformulation) was administered subcutaneously (SC) and intramuscularly (IM) to male rats and male bees. It is demonstrated that it produces stable plasma concentrations over an extended period of time in Guru dogs.

[0138] Male rat The first experiment was carried out on male rats, in which 200 mg of each of the relevant compounds referenced above was administered. / mL nanosuspension and microsuspension at a concentration of 40 mg / kg (0.2 mL / kg) The drug was administered subcutaneously (SC) and intramuscularly (IM). An interim analysis was performed at 3 months. The study was conducted at 6 months. Twelve rats were used in the study. Six rats were administered intramuscular IM) and three of these rats were administered the 200 mg / mL nanosuspension (see above). See Example 1, Formulation 1A) and the other three mice received 200 mg / mL microsuspension ( Six rats were administered subcutaneous (SC) doses of Three of these rats received 200 mg / mL nanosuspension (formulation 1A above). (see Formulation 1B above) to the other three mice, and 200 mg / mL microsuspension (see Formulation 1B above) to the other three mice. was administered.

[0139] Results stage 1-2 up to 200 hours FIG. 6: 200 mg / mL microformulation (e.g., formulation 1B of Example 1, i.e., micro In male rats, the effect of 40 mg / kg of 5-chloro-1,5-dichloro-2,5-diphenyl-2-propanediol (see Suspension of 5-chloro-1,5-diphenyl-2-propanediol) administered IM or SC was "Plasma kinetics of TMC207 in 200 mg / mL nanoformulation (e.g., Example 1)" and " Formulation 1A (see nanosuspension) was administered IM or SC at a dose of 40 mg / kg. Plasma kinetics of TMC207 in male rats after administration of

[0140] The following parameters were calculated for TMC207 (see Figure 6):

[0141] [Table 11]

[0142] In general, we can see the following: After administration of the microsuspension, the AUC was higher (2.6-fold) after IM than after SC. After administration of Bioavailability (compared to 5 mg / kg IV) was minimal (microsuspension SC )=56%, other three>100% M2, which is not shown in the graph of Figure 6, is t max is later, and the AUC of M2 is smaller than that of TMC It has the same profile as TMC207, except that it is 1.5 to 2 times lower than TMC207. In general, this ratio is comparable to the PO pathway.

[0143] A comparison was also made with oral (PO) dosing in rats, which was also considered a 13-week toxicity study. can be made, where the following results have been observed: Exposure (C) after a single IM or SC dose of both formulations at 3 months max and AUC) are 1 Much less than the total exposure following PO administration at the maximum dose in the 3-week study; During the first 12 months, the IM / SC ranged from 34,500 to 91,500 ng.h / mL, whereas the PO Total exposure = 2,385,383ng.h / mL For M2, see above.

[0144] Male beagle dog A second experiment was conducted on male beagle dogs, in which each of the two corresponding 00mg / mL nanosuspension and microsuspension are 40mg / kg (0.2mL / kg) The drug was administered subcutaneously (SC) and intramuscularly (IM) at a concentration of 0.01 mg / kg / day. An interim analysis was performed at 3 months. The results were followed up at 6 months. Twelve dogs, whose weights ranged from 8 to 16 kg at the start of the study, were Healthy male beagle dogs were used. Each dog was identified by a number tattooed on its ear. Dogs were administered the drug intramuscularly (IM) into the left and right biceps femoris. Three of these dogs administered 200 mg / mL nanosuspension (see Example 1, Formulation 1A above) to the other three mice. were administered 200 mg / mL microsuspension (see Example 1, Formulation 1B). The dogs were given subcutaneous (SC) injections into the left and right biceps femoris muscles, and three of these dogs received 20 0 mg / mL nanosuspension (see Formulation 1A above), and the other three animals received 200 mg / m A microsuspension of L (see Formulation 1B above) was administered.

[0145] From the left jugular vein of all dogs, on day 0, at 0 hours (before administration), 20 minutes, and 1 hour after administration , 3rd hour, 8th hour, and 24th hour, and further at 2, 3, 6, 8, 10, 13, 1 6, 20, 23, 27, 29, 36, 43, 50, 57, 64, 71, 78, 85, and On day 92, at approximately 8 am, a 3 mL blood sample was drawn.

[0146] The blood samples were diluted with EDTA (EDTA Vacuette Greiner, Cat. No. 454086 (Greiner Labortechnik NV) During the 2-hour blood sampling, samples were centrifuged at approximately 1900 x g for 10 minutes at room temperature. The plasma was immediately transferred to a second tube and separated within 2 hours of the start of centrifugation. Plasma samples were analyzed by a validated LC-MS / MS method. TMC207 and its metabolite M2 were analyzed separately.

[0147] FIG. 7 "A 200 mg / mL microformulation (see, for example, Formulation 1B in Example 1) was added to 40 TMC207 in male beagle dogs when administered IM or SC at a dose of 100 mg / kg Plasma kinetics of "200 mg / mL nanoformulation (see, for example, Formulation 1A in Example 1) TMC in male beagle dogs when administered IM or SC at a dose of 40 mg / kg. Plasma kinetics of 207

[0148] The following parameters were calculated for TMC207 (see Figure 7):

[0149] [Table 12]

[0150] In general, we can see the following: After administration of the microsuspension, the AUC was higher (2-fold) after IM than after SC Similar AUC after administration of the nanosuspension, SC or IM C max was higher after IM than after SC for both formulations. Bioavailability (compared to 1 mg / kg IV) is >100% M2 is t max except that it is later and the AUC is 3-4 times lower than TMC207. The ratios for the PO pathway are generally comparable to those for the TMC207 pathway.

[0151] A comparison was also made with oral (PO) administration in rats, which was considered a 13-week toxicity study. where the following results were observed: C after IM nanosuspension and PO at 18 mg / kg max The largest C similar to max ; Exposure is much higher after PO than after IM / SC. Total exposure: 2 68000-549000ng.h / mL, whereas the total exposure of PO = 13,9 88,520ng.h / mL For M2, see above.

[0152] Based on the three-month interim results, the following conclusions were drawn: After IM / SC of nano / micro suspensions: AUC in rats: IM micro > SC nano ~ = IM nano (more rapid decline) > SC Micro AUC in dogs: IM micro>SC nano~=IM nano>SC micro (four processes) (Similar degradation in files)

[0153] Between PO and IM at 40 mg / kg after IM / SC nanosuspension / microsuspension C of TMC207 in dogs after nanosuspension IM is similar to that of max Except for both C of TMC207 / M2 in oral toxicity studies in max and AUC are covered.

[0154] Results stage 2-up to 4400 hours In all cases, plasma concentrations of BDQ or M2 were significantly higher in three animals (rat The concentration is calculated as the average of the concentrations of the control animals (dogs or cats).

[0155] Rat studies: Formulation 1B, a microsuspension with a concentration of 200 mg / mL, was administered in 40 mg / kg SC (StDev = standard deviation) and 40 mg / kg IM

[0156] [Table 13]

[0157] Rat studies: Formulation 1A, a nanosuspension with a concentration of 200 mg / mL, was administered in 40 mg / kg SC (StDev = standard deviation) and 40 mg / kg IM (this In cases where small sample sizes are applied to the calculation of summary variables)

[0158] [Table 14]

[0159] [Table 15]

[0160] Dog study: Formulation 1B, a microsuspension with a concentration of 200 mg / mL, was administered at 40 ml g / kg SC (StDev = standard deviation) and 40 mg / kg IM.

[0161] [Table 16]

[0162] [Table 17]

[0163] Dog study: Formulation 1A, a nanosuspension with a concentration of 200 mg / mL, was administered in a 40 mg / mL 40 mg / kg SC (StDev = standard deviation) and 40 mg / kg IM (this case (In this case, small sample sizes are applied to the calculation of summary variables.)

[0164] [Table 18]

[0165] Example 3 A paucibacillary mouse model of latent tuberculosis infection Evaluation of an injectable long-acting bedaquiline formulation in the 2010 model The purpose of this study was to investigate the effect of 4-HT2B12 on the expression of paucibacillary latent tuberculosis infection (LTBI) in mice. Long-acting bedaquiline (B LA ) formulation The bactericidal activity of B. niger at the standard dose of 25 mg / kg or B. LA For total medication administered as The activity of B given orally daily (5 days per week) at a lower dose consistent with the The initial research scheme is shown in Table 1. LA is the above As described in Example 1B, a microsuspension with a concentration of 200 mg / mL. The primary outcome was the survival of Mycobacterium tuberculosis (Mycobacter The primary outcome was a decrease in C. tuberculosis lung CFU counts.

[0166] [Table 19]

[0167] Regimen Justification Untreated mice were used to determine the level and stability of paucibacillary infection. R 10 (5 / 7) are alternative regimens for the treatment of LTBI in the United States and Canada. and administered for 4 months. This is used herein as a control to qualify the model. It was used. P 15 H 50 (1 / 7) is an alternative regimen for the treatment of LTBI in the United States, It is administered once a week for three months (12 doses). This is consistent with at least a nine-month isoform. It has been shown to be as effective as niazid, the most commonly used currently recommended regimen. It is absent and serves as a second control. B 25 (5 / 7) is a once-daily dose of B at a human-equivalent dose previously studied in paucibacillary models. This provides a total dose of 500 mg / kg every 28 days. B8(5 / 7) was administered in 3 doses every 28 days. LA The compound dose (i.e. 160 The dose was reduced to provide the same total dose (480 mg / kg) as the previous dose (1. B is once a day. B 5.33 (5 / 7) received 2 doses every 28 days, B LA The formulation dose (i.e. The dose was reduced to provide the same total dose (320 mg / kg) as the previous 160 mg / kg dose. The dose is B once a day. B 2.67 (5 / 7) was administered once, B LA Combination dose (i.e. 160 mg / kg g) once daily at a reduced dose to provide the same total dose (160 mg / kg) It's B. B LA-160 (1 / 28) × 3: 160 mg / kg administered every 28 days for a total of 3 doses B LA Therefore, the total B dose is B8(5 / 7) at each 28-day interval. ) group. B LA-160 (1 / 28) × 2: starting from day 0, 160 mg / kg for 28 B, given twice daily for a total of two doses LA Therefore, 12 (320 mg / kg per week) g) The total B dose administered up to 5.33 It will be the same as that of the (5 / 7) group. B LA-160 (1 / 28) × 1 was administered once on day 0 at 160 mg / kg. RuB LA Therefore, the total dose administered by week 12 (160 mg / kg) was B dose is B 2.67 It will be the same as that of the (5 / 7) group.

[0168] final result All CFU enumeration data were finalized and are shown in Table 2 below. Laboratory consensus finalized. B LA Treatment was limited to M. tuberculosis (M. tuberculosis) due to delays in obtaining supplies of berculosis challenge infection until approximately 13 weeks after the start of infection, and the timeline in Table 2 corresponds to For comparisons between different treatment groups, Bonferroni multiple ratios were used. Statistical analysis was performed using one-way ANOVA adjusted for correlation tests. The results were assessed for statistical significance.

[0169] [Table 20]

[0170] BCG immunization. 150 female BALB / c mice were immunized by aerosol with M. bovis (M The OD 600 10x culture suspension of 1.03 The bacterial suspension was diluted to 6.88 log and used for aerosol infection. 10 CFU / mL, which is 3.05 (SD0.10) log 10 CFU / Lung Average Implantation Six weeks later, the animals were challenged with M. tuberculosis. Upon infection, the mean BCG burden in mouse lungs was 4.95 (SD 0.11) log 10 At CFU By day 0, the BCG load had decreased by 3.27 (SD 0.45) log 10 CF U / lung stabilized, with similar lung burdens observed in untreated mice at 4, 8, and 12 weeks. Thus, as expected, low and stable levels of BCG infection were present in the lungs of these mice. Dyeing was established.

[0171] M. tuberculosis challenge, 6 weeks after BCG immunization After 1 h, mice were inoculated with M. tuberculosis by aerosol. s) Infected with H37Rv. OD 600 Dilute the culture suspension at 0.850 by 100 times The bacterial suspension was used for aerosol infection at a concentration of 4.73 log 10 CFU / mL, which is 2.11 (SD 0.09) log 10CFU / lung average implantation Implantation occurred about 1 log slower than expected. 10 CFU was high. By day 0, M. The M. tuberculosis load is approximately 4.8 log 10 CFU / The lung burden stabilized at weeks 4, 8, and 12, with similar lung burdens observed in untreated mice. Thus, despite the higher implantation rate, no stable M. tuberculosis was observed in the lungs of these mice. M. tuberculosis infection is established and, accordingly, stabilized. The lung CFU burden was approximately 1 log lower than that observed in previous studies (1–3). 10 Only the CFU increased.

[0172] Evaluation of bactericidal activity (Table 2). M. tuberculosis (M. tuberculosis CFU count, R 10 (5 / 7) The control regimen was The mean CFU counts were approximately 1, 2, and 3 log1 after 4, 8, and 12 weeks of treatment, respectively. 0 CFU / lung. 15 H 50 (1 / 7) The control regimen was 4 and 8, respectively. , and approximately 2, 3, and 4.5 logs after 12 weeks of treatment. 10 This resulted in a decrease in CFU. The relative magnitude of reduction in lung CFU counts for both control regimens was based on previous studies (1, 2). This is as expected. 25 (5 / 7) showed approximately 1% improvement after 4, 8, and 12 weeks of treatment. .7, 4.0, and 4.9log 10 This resulted in a reduction in CFU / lung, a result previously unreported. This is as expected based on previous studies (1-2). The CFU counts in the eyes were used to assess the relative efficacy of the drug against this stabilized bacterial population in the lungs of mice. It did not affect the activity.

[0173] For all B regimens, increasing doses resulted in increased activity at weeks 4, 8, and 12. It was observed. B LA-160 For mice receiving one or two doses of (1 / 28), The reduction in lung CFU counts compared to untreated mice was observed after 4 or 8 weeks of once daily administration, respectively. Decreased in mice receiving the same total dose of B8(5 / 7) administered as an oral regimen (p>0.05 at both time points). B delivered 160 mg / kg on day 0 L A-160 A single dose of is approximately 1.3 log 10 CFU / lung reduction at 4 weeks B8(5 / 7) is 1.5log 10 This resulted in a decrease in CFU / lung. LA-160 ( 1 / 28) for 2 doses, or 8 weeks of B8 (5 / 7) followed by any of these regimens In mice receiving either 10 It dropped by 12 After 1 week of treatment, CFU counts in the lungs were LA-160 Mice that received a single dose of B 2.67 (5 / 7) (p=0.0002) of patients had the same total dose of 100 mg once daily. lower than in mice that received daquiline (160 mg / kg) and in untreated control mice Compared to lung counts, the former regimen was approximately 3 log 10 CFU / lung, resulting in a decrease in The number of people is about 1.7 log 10 Two doses of B resulted in a decrease in CFU / lung. LA-160 ,also is B 5.33(5 / 7) A total of 320 mg / kg of vena cava in one dose In mice receiving the Kirin dose, the reduction in lung CFU counts was approximately 3 log 10 CFU / The results were similar in the lungs (p>0.05). LA-160 (1 / 28) by 4 For mice receiving a total bedaquiline dose of 80 mg / kg, lung CFU counts were significantly higher than those of B8( 5 / 7) once daily, was higher than mice receiving an equivalent total dose, but The difference was not statistically significant.

[0174] After 12 weeks of treatment, nearly all study regimens showed 10 (5 / 7) Equivalent to control regimen It has strong bactericidal activity and B 2.67 (5 / 7) Only regimen was significantly lower than the control The test regimen B8 (5 / 7) was bactericidal (p<0.0001). 15 H 50 ( 1 / 7) and B 25 (5 / 7) showed equal bactericidal activity against both control regimens. All other study regimens were more effective than either of these control regimens at week 12. However, CFU data recorded at 12 weeks were significantly less bactericidal. May not reflect the overall efficacy of the long-acting bedaquiline regimen. Day 0 A single dose of B LA-160 In mice receiving the drug, the bactericidal effect continued even 12 weeks after administration. Therefore, the use of 2 or 3 doses of B LA-160 In the lungs of mice receiving Bacterial load appears to decline even further at least 12 weeks after administration of the final dose. In addition, a single dose of B LA-160 was significantly higher in the 1st to 4th week and 5th to 8th week after administration than in the 1st to 4th week and The longer-acting β-lactams appeared to exert higher bactericidal activity at weeks 9-12 and 14-16. It is also of interest that this suggests a possible biphasic release kinetics of B from the medium.

[0175] conclusion Despite the expected higher bacterial implantation, stable M in BALB / c mice M. tuberculosis infection is established, which is called LTBI. It was suitable for evaluating treatment regimens. After 12 weeks of treatment, B LA-160 The monthly dose of each drug is 160 mg once a day. or 320 or 480 mg / kg total bedaquiline dose or showed equivalent bactericidal activity. A single dose of B LA-160 The bactericidal activity observed from It is clear, and likely, that CFU counts continue to decline in the lungs of mice receiving two and three doses. Together with the higher than expected baseline bacterial load in this study, Taken together, these findings suggest that healing may be possible after two or three injections. Therefore, over a longer period, these B LA Evaluate the bactericidal activity of the regimen This will be crucial to truly understand its potential for use in LTBI treatment. .

[0176] References 1) Zhang, T., Li, S., Williams, K., Andries, K., Nuermberger,E.2011.Short-course chemothe rapy with TMC207 and rifapentine in a mu rine model of latent tuberculosis infection ion.Am.J Respir.Crit.Care Med.184:732-73 7. 2) Lanoix, JP, Betoudji, F., Nuermberger, E. 2014.Novel regimens identified in mice f or treatment of latent tuberculosis infe ction in contacts of multidrug-resistant tuberculosis cases.Antimicrob.Agents Ch emother.58:2316-2321. 3) Zhang, T., M. Zhang, IMRosenthal, JHGro sset,and ELNuermberger.2009.Short-cour se therapy with daily rifapentine in am urine model of latent tuberculosis infec tion.Am.J Respir.Crit Care Med.180:1151- 1157. The present invention includes the following embodiments. [Claim 1] A therapeutically effective amount of bedaquiline, or a pharma- ceutically acceptable salt thereof, is suspended in a micro- or nanoparticle suspension. 2. A pharmaceutical composition for administration by intramuscular or subcutaneous injection, comprising the above compound in suspension form, The suspension of micro- or nanoparticles, (a) bedaquiline in micro- or nanoparticulate form, or a pharma- ceutically acceptable salt thereof, and A surface modifier; (b) a pharma- ceutically acceptable aqueous carrier. [Claim 2] The surface modifier may be poloxamer, α-tocopheryl polyethylene glycol succinate, from the group of salts of sorbitan esters, polyoxyethylene sorbitan fatty acid esters, and salts of negatively charged phospholipids The composition of claim 1, wherein [Claim 3] Bedaquiline is in its non-salt or free form or in the fumarate form. 3. The composition according to claim 1 or 2. [Claim 4] The surface modifiers include Pluronic F108, Vitamin E TGPS, Tw een(trademark) 80, and Lipoid(trademark) EPG. The composition described in any one of claims 1 to 4. [Claim 5] Average Effective Particle Size of Bedaquiline or Its Pharmaceutically Acceptable Salt That is Micro- or Nanoparticle is less than about 50 μm, specifically less than about 200 nm, according to any one of claims 1 to 4. The composition described in [Claim 6] Average Effective Particle Size of Bedaquiline or Its Pharmaceutically Acceptable Salt That is Micro- or Nanoparticle The composition according to any one of claims 1 to 4, wherein the average particle diameter is about 130 nm. [Claim 7] By weight relative to the total volume of said composition: (a) 10-70% (w / v), or 20-60% (w / v), or 20-50 % (w / v), or 20-40% (w / v) of bedaquiline (or its pharma- ceutically acceptable salts) (a) any salt thereof, but the w / v is calculated based on its non-salt form); (b) 0.5 to 20%, or 2 to 15% or 20% (w / v), or 5 to 15% (w / v) wetting agent; (c) One or more of the following: 0% to 10%, 0% to 5%, 0% to 2%, or 0% to 1% Buffers; (d) 0 to 20%, or 2 to 15% or 20% (w / v), or 5 to 15% (w / v ) isotonicity agent; (e) 0% to 2% (w / v) of a preservative; and (f) Water for injections, qs to 100%; 3. The composition of claim 1 or 2, comprising: [Claim 8] The method according to claims 1 to 7 for producing a medicament for treating a pathogenic mycobacterial infection. 2. Use of a pharmaceutical composition as defined in any one of claims 1 to 11. [Claim 9] The agent is an anti-Mycobacterium tuberculosis tuberculosis) (such as latent / dormant forms) or Mycobacterium leprae The method according to claim 8 is for the long-term treatment of Mycobacterium leprae. Use as described. [Claim 10] The medicament is for administration by intramuscular or subcutaneous injection, and the composition is administered for one week. The use according to claim 8, wherein the administration is intermittently at time intervals of from 10 to 2 years. [Claim 11] The pharmaceutical composition according to claim 8 is administered at intervals of at least one month to one year. use. [Claim 12] The pharmaceutical composition can be administered for a period ranging from 1 week to 1 month, or for a period ranging from 1 month to 3 months, or for a period ranging from 3 months to 4 months. A time interval ranging from 6 months, or from 6 to 12 months, or from 12 to 24 months The use according to claim 8, wherein the administration is [Claim 13] The pharmaceutical composition is administered once every two weeks, once a month, or once every three months. 9. The use according to claim 8. [Claim 14] (a) obtaining bedaquiline, or a pharma- ceutically acceptable salt thereof, in micronized form; ; (b) dissolving said microparticulated bedaquiline or a pharma- ceutically acceptable salt thereof in a liquid medium; adding to form a premix / predispersion; (c) subjecting the premix to mechanical means in the presence of grinding media to reduce the average effective particle size. and; A method for preparing a pharmaceutical composition as defined in any one of claims 1 to 7, comprising:

Claims

1. A pharmaceutical composition for administration by intramuscular or subcutaneous injection comprising bedaquiline or a pharma- ceutical acceptable salt thereof, said composition being used in combination therapy with other drugs, (a) bedaquiline or a pharma- ceutically acceptable salt thereof in micro- or nanoparticulate form, and a surface modifier; (b) a pharma- ceutically acceptable aqueous carrier; and in the form of a micro- or nanoparticle suspension comprising The pharmaceutical composition, wherein said other agent is an anti-TB agent or an agent useful in the treatment of Mycobacterium leprae.

2. 2. The composition of claim 1, wherein the surface modifier is selected from the group of poloxamers, α-tocopheryl polyethylene glycol succinates, polyoxyethylene sorbitan fatty acid esters, and salts of negatively charged phospholipids.

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

4. The composition of any one of claims 1 to 3, wherein the surface modifier is selected from Pluronic™ F108, alpha-tocopheryl polyethylene glycol succinate (vitamin E TPGS), Tween™ 80, and Lipoid™ EPG.

5. The composition of any one of claims 1 to 4, wherein the average effective particle size of the micro- or nanoparticulate bedaquiline or pharma- ceutically acceptable salt thereof is less than about 50 μm, or less than about 200 nm.

6. The composition of any one of claims 1 to 4, wherein the average effective particle size of the micro- or nanoparticulate bedaquiline or pharma- ceutically acceptable salt thereof is about 130 nm.

7. The surface modifier is a wetting agent, and the pharma- ceutically acceptable aqueous carrier comprises water for injection; By weight relative to the total volume of the composition: (a) 10-70% (w / v), or 20-60% (w / v), or 20-50% (w / v), or 20-40% (w / v) of bedaquiline (or a pharma- ceutically acceptable salt thereof, said w / v being calculated on the basis of the non-salt form thereof); (b) 0.5-20%, or 2-15% or 20% (w / v), or 5-15% (w / v) of a humectant; (c) one or more buffering agents from 0% to 10%, or from 0% to 5%, or from 0% to 2%, or from 0% to 1%; (d) 0-20%, or 2-15% or 20% (w / v), or 5-15% (w / v) of a tonicity agent; (e) 0% to 2% (w / v) of a preservative; and (f) Water for injection, qs to total 100%; The composition of claim 1 or 2, comprising:

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 a pathogenic mycobacterial infection.

9. A pharmaceutical composition as defined in any one of claims 1 to 7 for use in treating a pathogenic mycobacterial infection.

10. The pharmaceutical composition of claim 9 for use in the long-term treatment of a pathogenic mycobacterial infection, wherein the other drug is an anti-TB drug, and the treatment comprises: (i) treatment with an anti-TB drug; and (ii) intermittent administration of the pharmaceutical composition comprising bedaquiline or a pharma- ceutically acceptable salt thereof, wherein the intermittent administration is at a time interval of at least one week; 13. A pharmaceutical composition comprising:

11. 10. The pharmaceutical composition according to claim 9, for the long-term treatment of Mycobacterium tuberculosis (such as latent / dormant forms) or Mycobacterium leprae.

12. The pharmaceutical composition according to any one of claims 9 to 11, for administration by intramuscular or subcutaneous injection, said pharmaceutical composition being administered intermittently at time intervals ranging from 1 week to 2 years.

13. The pharmaceutical composition according to any one of claims 9 to 11, wherein the pharmaceutical composition is administered at intervals of at least one month to one year.

14. 12. The pharmaceutical composition according to any one of claims 9 to 11, wherein the pharmaceutical composition is administered at time intervals ranging from 1 week to 1 month, or ranging from 1 month to 3 months, or ranging from 3 months to 6 months, or ranging from 6 months to 12 months, or ranging from 12 months to 24 months.

15. The pharmaceutical composition according to any one of claims 9 to 11, wherein the pharmaceutical composition is administered once every two weeks, once a month, or once every three months.

16. The pharmaceutical composition of claim 9 for use in treating Mycobacterium leprae, wherein the other drug is a drug useful in treating Mycobacterium leprae, and the composition is administered by a single injection or up to three injections at monthly intervals.

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