WO2009092810A2 - Composition pharmaceutique unique contenant des antibiotiques et des probiotiques - Google Patents

Composition pharmaceutique unique contenant des antibiotiques et des probiotiques Download PDF

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Publication number
WO2009092810A2
WO2009092810A2 PCT/EP2009/050803 EP2009050803W WO2009092810A2 WO 2009092810 A2 WO2009092810 A2 WO 2009092810A2 EP 2009050803 W EP2009050803 W EP 2009050803W WO 2009092810 A2 WO2009092810 A2 WO 2009092810A2
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WO
WIPO (PCT)
Prior art keywords
antibiotic
probiotic
pharmaceutical composition
probiotics
time
Prior art date
Application number
PCT/EP2009/050803
Other languages
English (en)
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WO2009092810A3 (fr
Inventor
Vygantas Kirejevas
Original Assignee
Bacterfield Oü
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Bacterfield Oü filed Critical Bacterfield Oü
Publication of WO2009092810A2 publication Critical patent/WO2009092810A2/fr
Publication of WO2009092810A3 publication Critical patent/WO2009092810A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/745—Bifidobacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/747—Lactobacilli, e.g. L. acidophilus or L. brevis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/06—Fungi, e.g. yeasts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics

Definitions

  • the present invention provides novel method of use antibiotic and probiotic combination in single pharmaceutical composition, whereas the release of the probiotics is time-controlled.
  • the single pharmaceutical composition is useful for the effective treatment of infection and in addition minimizing of the side effect of the antibiotic treatment.
  • Probiotics are currently used in several indications together with antibiotic (not in a single pharmaceutical composition), either in an attempt to ameliorate the antibiotic effect of the treatment itself, or to mitigate mainly gastrointestinal side effects often associated with application of antibiotics.
  • time controlled ANTIPRO concept is developed (see Fig. 2.) by the authors of the present invention.
  • a fast-acting antibiotic e.g. clarithomycin
  • a probiotic e.g. lactobacillus
  • the objective of current invention is to merge the antibiotic and probiotic into a single pharmaceutical composition or product, separated by a time-controlled protective layer so that the antibiotic deploys its effect first against infection, then the probiotic exert its protective action between two separate intakes (double mechanism of action) of the pharmaceutical composition according to the present invention.
  • the probiotic bacteria initiate rapid multiplication between two antibiotic doses.
  • the probiotic warrants competitive exclusion conditions against pathogens through production of bacteriocins (for example lactic acid) helping to minimize pathogenic bacteria activity between two intakes, thus playing a protective role.
  • bacteriocins for example lactic acid
  • the effect is to be achieved through the utilization of multi layer tablets or capsules where the probiotic, or a mixture of probiotic and a carrier (e.g. fish oil, gum and etc), would constitute the core of the pharmaceutical form.
  • This core would be coated with an antibiotic-resistant layer allowing time-controlled release.
  • the antibiotic, alone or together with a carrier, is formulated around the core containing the probiotic (with or without carrier) and then coated with an additional protective layer, which may or may not provide time-controlled release, depending on target application.
  • the pharmaceutical composition according to the present invention can be in the form of tablet, capsule, suppositories or other known forms of the pharmaceutical dosage or application forms.
  • the fast acting antibiotic is released to exert its primary activity.
  • the layer between the antibiotic and probiotic dissolves at a point in time when the antibiotic activity has faded out allowing the probiotic bacteria to initiate rapid multiplication by colonizing the microflora and thus inhibiting the growth of remaining pathogens via a number of mechanisms: including competitive inhibition (occupation of specific environmental niches), production of inhibitory factors, modification of the local environment (production of organic acids, volatile fatty acids, hydrogen peroxide and other compounds), or effects on local inflammatory and immune responses.
  • Time of releasing the probiotic depends on the predetermined antibiotic/probiotic ratio, which enables rapid multiplication of the probiotics to suppress further pathogenic activity between two intakes of the pharmaceutical compositions according to present invention.
  • H. pylori is a gram-negative, microaerophilic bacterium that inhabits various areas of the stomach and duodenum. It causes a chronic low-level inflammation of the stomach lining and is strongly linked to the development of duodenal and gastric ulcers and stomach cancer. Acute infection with the bacterium are usually asymptomatic.
  • the standard first-line therapy is a one week triple therapy consisting of the antibiotics: amoxicillin and clarithromycin, and a proton pump inhibitor such as omeprazole (Mirbagheri et al., 2006). Variations of the triple therapy have been developed over the years, such as using a different proton pump inhibitor, as with pantoprazole or rabeprazole, or replacing amoxicillin with metronidazole for people who are allergic to penicillin (Malfertheiner et al., 2007). Typically treatment lasts for 7 days with twice daily oral applications.
  • the present invention time-controlled pharmaceutical composition of probiotic and antibiotic combination treatment described above can help to reduce such problems and in addition side effects which can appear during or after antibiotic treatment.
  • Antibiotic-associated gastrointestinal side effects such as diarrhoea, nausea, vomiting, bloating and abdominal pain may represent a serious drawback of anti-///?y/ ⁇ /7therapies, although they are mild in most cases, usually resulting in discontinue therapy (Bell et al., 1992). These manifestations have been related to quantitative and qualitative changes in the intestinal microflora because of unabsorbed or secreted antibiotics in the intestinal content, with a resulting reduction in normal saprophytic flora and overgrowth by persistence of potentially pathogenic antibiotic resistant indigenous strains (Kabir et al., 1997). Also unabsorbed antibiotics are leading to the prolonged contact with the Gl wall, which in it case can lead to irritations or allergies.
  • ANTIPRO concept pharmaceutical composition of fast acting antibiotic and probiotic can have a positive impact on H. /?y/ ⁇ /7treatment.
  • the time-controlled probiotic component of ANTIPRO concept promotes competitive exclusion conditions against pathogens through production of bacteriocins (for example lactic acid), helping to minimize pathogenic bacteria activity between two intakes, thus playing a protective role.
  • Probiotic microorganism within ANTIPRO concept has a therapeutic effect in humans to cure, to mitigate, to treat, to prevent a disease or minimize its side effects.
  • Fig. 1 illustrates the current treatment of the bacteriological infection where is used the antibiotic treatment
  • Fig.2 illustrates the ANTIPRO concept treatment where is used the pharmaceutical compositions containing time-controlled probiotics and fast acting antibiotics.
  • the present invention provides method of use of the combination of the antibiotics and probiotics with time-controlled release in single pharmaceutical composition.
  • the pharmaceutical composition contains two active substances (the antibiotic and the probiotic) in clearly defined ratio dependant on an infection type.
  • ANTIPRO concept brings high concentrations of viable probiotic cells to their destination at the gut mucosa (or other type of microflora) to foster quick restoration of microflora between pharmaco-cinetic cycles of antibiotics.
  • Employing a well-identified timing for release of the probiotic which ensures that antibiotic concentration/effectiveness is below a level that effects viability and multiplication of probiotic may increase beneficial effects compared to current use of probiotic preparations separately outside of single pharmaceutical composition described in the scope of the present invention.
  • the probiotics are released shortly before the end of the pharmaco-cinetic cycle of the antibiotic present in the same pharmaceutical composition according to the present invention.
  • ANTIPRO can be employed to any fast acting antibiotic and to all the indications these antibiotics are used for.
  • probiotics are in use as probiotics, either as monovalent or as multivalent preparation combining different organisms.
  • the most important classes of probiotic organisms include Lactobacilli, bifidobacteria, streptococcus and certain Saccharomyces strains.
  • the number of the probiotics is between 10 4 to 10 17 CFU per single dose of the pharmaceutical composition.
  • probiotics used in the pharmaceutical composition shall not be resistant to the antibiotic within in the same pharmaceutical composition.
  • Combining an effective probiotic with an antibiotic in a single pharmaceutical composition may reduce side effect burden on patients, increase compliance and to improve the effectiveness and/or efficacy of antibiotic therapy.
  • ANTIPRO concept has been described for a fixed combination product of clarithromycin and a probiotic for H. pylori eradication triple therapy as an example.
  • clarithromycin is used in many other types of infections.
  • Clarithromycin 500 mg Modified Release Tablets from Abbott Laboratories are indicated for treatment of infections caused by susceptible organisms, including lower respiratory tract infections for example, acute and chronic bronchitis, and pneumonia as well as upper respiratory tract infections for example, sinusitis and pharyngitis.
  • ANTIPRO concept can be applied in various disease treatments.
  • the probiotic component is formulated with excipients as the tablet core and then protected by a coating or lacquer with time-controlled release characteristics.
  • a mixture of the antibiotic ingredient and excipients is then press-coated as a layer "around" the probiotic tablet core and may be also lacquered with a time controlling lacquer or coat for controlled immediate dissolution.
  • ANTIPRO concept delivered in capsules with appropriate probiotic or mixture of the probiotic with a carrier (e.g. fish oil) in the core of the capsule.
  • a carrier e.g. fish oil
  • This mixture is coated with the reliable/time-controlled layer which is resistant to the antibiotics use in the capsule.
  • Another concept idea could be the development of a divided doseformulation (e.g. pellets or microcapsules) with different coating systems, where the antibiotic component is lacquered to have immediate release characteristics and the probiotic ingredient is coated or lacquered with a gastric resistant lacquer or coat.
  • the differently lacquered or coated probiotic and antibiotic divided dose formulations are then filled into hard gelatin capsules of the desired capsule size.
  • McFarland LV Epidemiology, risk factors and treatments for antibiotic associated diarrhea. Digestive Diseases 1998; 10: 292-307

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Mycology (AREA)
  • Microbiology (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Alternative & Traditional Medicine (AREA)
  • Biotechnology (AREA)
  • Botany (AREA)
  • Medical Informatics (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention porte sur un procédé d'utilisation d'une combinaison d'antibiotique et de probiotique de façon contrôlée dans le temps dans une composition pharmaceutique unique, procédé suivant lequel, lors de l'utilisation de la composition pharmaceutique à une première étape du cycle pharmaco-cinétique, l'antibiotique déploie son effet contre une infection, permettant d'obtenir le taux maximal suivi par une libération contrôlée dans le temps des probiotiques. Après obtention du taux maximal, peu de temps avant la fin du cycle pharmaco-cinétique de la dose unique, la population probiotique est libérée, le temps de libération du probiotique dépendant du rapport antibiotique/probiotique, qui permet une multiplication rapide des probiotiques pour diminuer encore l'activité pathogène entre deux cycles pharmaco-cinétiques.
PCT/EP2009/050803 2008-01-24 2009-01-23 Composition pharmaceutique unique contenant des antibiotiques et des probiotiques WO2009092810A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US2326308P 2008-01-24 2008-01-24
US61/023,263 2008-01-24

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WO2009092810A2 true WO2009092810A2 (fr) 2009-07-30
WO2009092810A3 WO2009092810A3 (fr) 2009-12-17

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120177650A1 (en) * 2009-09-23 2012-07-12 Borody Thomas J Therapy for enteric infections
US20160000839A1 (en) * 2009-12-31 2016-01-07 Ira Milton Trachtman Compositions and method for treatment and prophylaxis of inflammatory bowel disease
EP3946392A4 (fr) * 2019-03-28 2022-12-07 Mybiotics Pharma Ltd Compositions de biofilm probiotique et leurs procédés de préparation
US11680257B2 (en) 2015-05-11 2023-06-20 Mybiotics Pharma Ltd. Systems and methods for growing a biofilm of probiotic bacteria on solid particles for colonization of bacteria in the gut
US11679136B2 (en) 2016-05-25 2023-06-20 Mybiotics Pharma Ltd. Composition and methods for microbiota therapy

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000010582A2 (fr) * 1998-08-24 2000-03-02 Ganeden Biotech, Inc. Bacteries probiotiques produisant de l'acide lactique et leurs utilisations
US6306391B1 (en) * 1997-03-27 2001-10-23 Cadila Pharmaceuticals, Ltd. Preparation of an oral pharmaceutical formulation containing an anti-infective agent and a microorganism
US20020192201A1 (en) * 1998-09-24 2002-12-19 Ira Shafran Crohn's disease treatment methods
WO2004067013A1 (fr) * 2003-01-24 2004-08-12 Flora Technology Inc. Compositions et procedes pour restaurer la flore bacterienne
EP1566176A1 (fr) * 2004-02-16 2005-08-24 Sanjeev Prem Nivas Khandelwal Formulation antibacterielle synergique et méthode de péparation

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6306391B1 (en) * 1997-03-27 2001-10-23 Cadila Pharmaceuticals, Ltd. Preparation of an oral pharmaceutical formulation containing an anti-infective agent and a microorganism
WO2000010582A2 (fr) * 1998-08-24 2000-03-02 Ganeden Biotech, Inc. Bacteries probiotiques produisant de l'acide lactique et leurs utilisations
US20020192201A1 (en) * 1998-09-24 2002-12-19 Ira Shafran Crohn's disease treatment methods
WO2004067013A1 (fr) * 2003-01-24 2004-08-12 Flora Technology Inc. Compositions et procedes pour restaurer la flore bacterienne
EP1566176A1 (fr) * 2004-02-16 2005-08-24 Sanjeev Prem Nivas Khandelwal Formulation antibacterielle synergique et méthode de péparation

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120177650A1 (en) * 2009-09-23 2012-07-12 Borody Thomas J Therapy for enteric infections
US20160000839A1 (en) * 2009-12-31 2016-01-07 Ira Milton Trachtman Compositions and method for treatment and prophylaxis of inflammatory bowel disease
US9492488B2 (en) * 2009-12-31 2016-11-15 Ira Milton Trachtman Compositions and method for treatment and prophylaxis of inflammatory bowel disease
US20170056456A1 (en) * 2009-12-31 2017-03-02 Ira Milton Trachtman Compositions and method for treatment and prophylaxis of inflammatory bowel disease
US9649348B2 (en) 2009-12-31 2017-05-16 Ira Milton Trachtman Compositions and method for treatment and prophylaxis of inflammatory bowel disease
US11680257B2 (en) 2015-05-11 2023-06-20 Mybiotics Pharma Ltd. Systems and methods for growing a biofilm of probiotic bacteria on solid particles for colonization of bacteria in the gut
US11679136B2 (en) 2016-05-25 2023-06-20 Mybiotics Pharma Ltd. Composition and methods for microbiota therapy
EP3946392A4 (fr) * 2019-03-28 2022-12-07 Mybiotics Pharma Ltd Compositions de biofilm probiotique et leurs procédés de préparation

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Publication number Publication date
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