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Pharmaceutical Composition and Kit for Treating Bacterial Infections

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Pharmaceutical Composition and Kit for Treating Bacterial Infections (19) TZZ _T (11) EP 2 772 248 A1 (12) EUROPEAN PATENT APPLICATION published in accordance with Art. 153(4) EPC (43) Date of publication: (51) Int Cl.: 03.09.2014 Bulletin 2014/36 A61K 9/00 (2006.01) A61K 38/21 (2006.01) A61K 31/445 (2006.01) A61K 31/06 (2006.01) (2006.01) (21) Application number: 12843639.1 A61P 31/00 (22) Date of filing: 25.10.2012 (86) International application number: PCT/RU2012/000871 (87) International publication number: WO 2013/062445 (02.05.2013 Gazette 2013/18) (84) Designated Contracting States: (72) Inventors: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB • IVACHTCHENKO, Alexandre Vasilievich GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO Encinitas, CA 92024 (US) PL PT RO RS SE SI SK SM TR • BICHKO, Vadim Vasilievich San Diego, CA 92129 (US) (30) Priority: 26.10.2011 RU 2011143086 • TKACHENKO, Sergey Yevgenievich San Diego, CA 92122 (US) (71) Applicants: • Ivachtchenko, Alexandre Vasilievich (74) Representative: Patentanwälte Encinitas, CA 92024 (US) Zellentin & Partner • Ivashchenko, Andrey Alexandrovich Rubensstrasse 30 Moscow 127576 (RU) 67061 Ludwigshafen (DE) • Savchuk, Nikolay Filippovich California 92067 (US) (54) PHARMACEUTICAL COMPOSITION AND KIT FOR TREATING BACTERIAL INFECTIONS (57) The invention relates to pharmacology and med- ically effective doses, and also pharmaceutical kit for icine, more particularly to novel pharmaceutical compo- treating diseases caused by bacterial and healthcare ac- sitions and pharmaceutical kits for treating bacterial in- quiredinfections, comprising pharmacologically effective fections, and to novel method for treating diseases doses of Rifamycin in the form of tablets, capsules or caused by bacterial infections including tuberculosis. injections, interferon inducer in the form of tablets, cap- The pharmaceutical composition is disclosed com- sules or injections, and instruction for administration of prising Rifamycin and interferon inducer in pharmacolog- the components of this pharmaceutical kit. EP 2 772 248 A1 Printed by Jouve, 75001 PARIS (FR) EP 2 772 248 A1 Description Field of invention 5 [0001] The invention relates to pharmacology and medicine, more particularly to novel pharmaceutical compositions and pharmaceutical kits for treating bacterial infections, and to novel method for treating diseases caused by bacterial infections including tuberculosis. Background of the invention 10 [0002] Until very recently investigation in the field of tuberculosis therapy had the trend of either searching for novel active compounds and their combinations with conventional medicaments (WO 1995/13807, publ. 26.05.1995; EP 0650728A1, publ.03.05.1995; EP 0398165A1, publ. 22.11.1990; US 5399558, publ. 21.03.1995), or creation of novel pharmaceutical formulations for such well-known drug substances as Isoniaside, Rifampicin, Ethambutol (WO88/006038, 15 publ. 25.08.1988; US 5811088, publ. 22.091998; RU 2143900C1, publ. 10.01.2000; RU 2087146C1, publ. 20.081997; RU2125451C1, publ.27.01.1999). [0003] A group of effective antibiotics Rifamycins exhibiting antibacterial action of wide range [Rifapentine (US4002752), Rifaximin (US4341785), Rifabutin (GB1603127), Rifampicine and Rifalazil]-belonging to the class of Ansamycins which are formed in biosynthesis by one of Actinomycetes, as well as their semi-synthetic derivatives are 20 well known. Among them Rifampicin and Rifalazil - semi-synthetic derivatives of Rifamycin SV - exhibit the widest range of antimicrobial action and good drug absorbability. 25 30 35 [0004] Many gram-positive microorganisms (minimal inhibiting concentration 0.001-0.1 mg/ml) and a large number of 40 gram-negative bacteria (minimal inhibiting concentration 1-10 mg/ml) are sensitive to Rifampicin. At low concentrations Rifampicin is active towardsMycobacterium tuberculosis, Mycobacterium avium complex, Chlamydia pneumoniae, Chlamydia trachomatis, Helicobacter pylory, Clostridium difficile, Bructlla spp., Legionella pntumophila, Rickettsia typhi, Mycobacterium leprae, Staphylococcus aureus, including methicillin-resistant strains,Staphylococcus epidermidis; streptococci; at high concentrations-towards some gram-negative microorganisms (Escherichia coli, Klebsiella, Proteus, 45 Neisseria meningitides, Neisseria gonorrhoeae, among them beta-lactam forming). It is active towardsHaemophilus influenza (including those resistant to Ampicillin and Chloramphenicol), Haemophilus ducreyi, and other gram-positive anaerobes. The unique property of Rifampicin is its high activity against tuberculosis Mycobacterium (minimal inhibiting concentration 0.005-0.5 mg/ml), that accounts for the leading position of this antibiotic in the commonly used schemes of treating tuberculosis. Rifampicin is highly active against gram-positive cocci, among them multi resistant cocci and 50 so named methicillin-resistant cocci. Over 95% of Streptococcus pyogenes which are resistant to penicillin and other antibiotics, as well as pneumococci, are sensitive to Rifampicin. Bacillus antrhracis and pathogenic Clostridia are highly sensitive to Rifampicin. It is active against many strains of bacteroides, Proteus, Providencias, causative agents of Legionella diseases and brucellosis. Rifampicin is one of the most active agents in leprosy treatment. It exceeds activity of various tetracyclines towards Chlamydias-Chlamydia trachomatis, parrot fever and lymphogranuloma causative 55 agents. Rifampicin is highly effective against Prowazeki Rickettsia. [0005] Mechanism of Rifampicin antimicrobial action differs from the mechanism of action of all the other antibiotics. It inhibits RNA synthesis by means of forming a complex with RNA-polymerase which is DNA-dependent. This effect is sufficiently selective. Rifampicin is acting as bactericidal agent on proliferating bacteria, it penetrates into the cells and 2 EP 2 772 248 A1 inhibits pathogens located there. Resistance to Rifampicin is rapidly developing in the course of treatment. In order to overcome this effect Rifampicin is prescribed in combination with other antibiotics. [0006] Synergy was discovered for combined action of Rifampicin and some other antibiotics, such as Erythromycin (towards staphylococci), Tetracycline (towards Salmonella, Escherichia, Shigela), and Novobiocin (towards Salmonella). 5 Synergistic or additive effect of Rifampicin and Trimethoprim in relation to many microorganisms was also detected. Therefore, fixed doses of combination of Rifampicin and Trimethoprim (Rifaprim agent) are used. In the treatment of tuberculosis Rifampicin is only prescribed together with other antituberculosis agents (Stretomycin, Ethambutol, Isoni- azid). Rifampicin is highly effective when taken orally: in some tissues it was found in concentrations exceeding its concentration in blood serum. It penetrates through hematoencephalic barrier, placental barrier, cell membranes; it is 10 removed from organism mainly with the bile. [0007] Rifalazil is also known as KRM-1648 or benzoxazinorifamycin [US 4690019 publ.01.09.1987; US 4983602, publ. 08.01.1991; US 6316433, 13.11.2001; US 6566354, publ. 20.05.2003], exhibits antibacterial activity towards wide range of pathogens (including Mycobacterium tuberculosis, Mycobacterium avium complex, Chlamydia pneumoniae, Chlamydia trachomatis, Helicobacter pylory Clostridium difficile, Mycobacteria, methicillin-resistant strains Staphyloco- 15 ccus aureus and other gram-positive polyresistant bacteria and healthcare acquired infections), prolonged half-life of elimination (more then 100 h), as well as high penetration into the cells (>300:1). Everything above said reveals higher effectiveness of Rifalazil in comparison with the drugs used in conventional therapy used for a number of diseases, among them tuberculosis and nongonococcal urethritis. [0008] Rifalazil is also used in combination therapy of bacterial infections together with beta-lactam inhibitors, amino 20 glycosides, Tetracyclines, lipopeptides, macrolides, ketolides, lincosamides, streptogramines, sulfanilamides, oxazolid- inones, quinolones, ciprofloxacin and the like [US 20110117154, publ. 19.05.2011]. Rifabutin as well as the drugs described above exhibits a wide range of antibacterial action[http://www.rlsnet.ru/mnn index id 2345.htm]. It inhibits selectively DNA-dependent RNA polymeraze in sensitive strains. It is highly effective towards extra- and intracellular located Mycobacterium spp., including Mycobacterium tuberculosis, complex Mycobacterium avium-intracellulare, My- 25 cobacterium fortuitum, Mycobacterium xenopi. It is more active then Rifampicin towards intracellular Mycobacterium tuberculosis (at concentrations 2 times less). For treatment of active tuberculosis it is used in combination with other antituberculous remedies. It has immune stimulative effect. [0009] Rifaximin [http://www.rlsnet.ru/tn_index_id_36028.htm#opisanie-lekarstvennoj-formy] is an antibacterial drug with wide range of action. Irreversibly binds to the beta subunit of the bacterial enzyme, DNA-dependent RNA polymeraze 30 and, therefore, inhibits synthesis of RNA and bacterial proteins. The result of irreversible binding to enzyme is its bac- tericidal properties towards sensitive bacteria. The drug has a wide range of antimicrobial activity including most of gram- negative and gram-positive, aerobic and anaerobic bacteria causing gastrointestinal infections, among them traveler’s diarrhea. It is highly effective towards aerobic Staphylococcus spp., Enterococcus spp., and anaerobic Peptostrepto- coccus spp. and others. The drug is used for treating gastrointestinal
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