FR2989279A1 - USE OF CINNAMIC ACID FOR PREVENTING OR TREATING INFECTIONS CAUSED BY A RESISTANT ANTIGEN OR A COMBINATION OF ANTIGENS - Google Patents
USE OF CINNAMIC ACID FOR PREVENTING OR TREATING INFECTIONS CAUSED BY A RESISTANT ANTIGEN OR A COMBINATION OF ANTIGENS Download PDFInfo
- Publication number
- FR2989279A1 FR2989279A1 FR1354070A FR1354070A FR2989279A1 FR 2989279 A1 FR2989279 A1 FR 2989279A1 FR 1354070 A FR1354070 A FR 1354070A FR 1354070 A FR1354070 A FR 1354070A FR 2989279 A1 FR2989279 A1 FR 2989279A1
- Authority
- FR
- France
- Prior art keywords
- cinnamic acid
- medicament
- use according
- combined
- treating
- Prior art date
- Legal status (The legal status 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 status listed.)
- Granted
Links
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/11—Aldehydes
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- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- 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
- A61P31/04—Antibacterial agents
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Engineering & Computer Science (AREA)
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
La présente invention concerne l'utilisation de l'acide cinnamique, de ses métabolites, ses sels, ses composés d'inclusions et ses solvates pour l'obtention d'un médicament destiné à prévenir ou traiter les infections provoquées par un antigène résistant ou par une combinaison d'antigènes dont au moins l'un peut être résistant.The present invention relates to the use of cinnamic acid, its metabolites, its salts, its inclusion compounds and its solvates for obtaining a medicament for preventing or treating infections caused by a resistant antigen or by a combination of antigens at least one of which may be resistant.
Description
UTILISATION DE L'ACIDE CINNAMIQUE POUR PREVENIR OU TRAITER DES INFECTIONS PROVOQUEES PAR UN ANTIGENE RESISTANT OU UNE COMBINAISON D' ANTIGENES La présente invention concerne l'utilisation de l'acide cinnamique pour prévenir ou traiter des infections provoquées par un antigène résistant ou une combinaison d'antigènes. The present invention relates to the use of cinnamic acid for the prevention or treatment of infections caused by a resistant antigen or a combination of the use of cinnamic acid to prevent or treat infections caused by a resistant antigen or a combination thereof. antigens.
De nos jours, l'acide cinnamique est une molécule qui est largement utilisée dans divers domaines. En effet, on peut trouver l'acide cinnamique dans l'industrie du parfum ; il sert également pour la composition d'exhausteurs de goût. Nowadays, cinnamic acid is a molecule that is widely used in various fields. Indeed, cinnamic acid can be found in the perfume industry; it is also used for the composition of flavor enhancers.
Par ailleurs, il est connu depuis fort longtemps que l'acide cinnamique possède des propriétés antiseptique et antifongique. De ce fait, on le trouve également dans certains produits pharmaceutiques. Actuellement, de nombreux antigènes sont traités par l'utilisation d'antibiotiques. Cependant, l'utilisation massive de ces derniers par l'homme a entraîné la résistance de certains d'entre eux vis-à-vis des antibiotiques. En effet, les antibiotiques exercent une pression sélective très forte et éliminent les antigènes sensibles mais les antigènes présentant une mutation leur permettant d'y survivre continuent quant à eux à se reproduire, en transmettant à leur descendance leurs gènes de résistance, produisant rapidement une génération d'antigènes pleinement ou majoritairement résistants. Il est à noter que ce phénomène de résistance n'est pas propre aux antibiotiques mais existe également pour d'autres familles de molécules telles que les antifongiques, les corticoïdes ou les antiviraux. Furthermore, it has long been known that cinnamic acid has antiseptic and antifungal properties. As a result, it is also found in certain pharmaceutical products. Currently, many antigens are treated by the use of antibiotics. However, the massive use of these by humans has led to the resistance of some of them to antibiotics. In fact, antibiotics exert a very strong selective pressure and eliminate the sensitive antigens, but the antigens with a mutation allowing them to survive continue to reproduce themselves, by transmitting to their offspring their resistance genes, producing rapidly a generation. antigens fully or predominantly resistant. It should be noted that this phenomenon of resistance is not specific to antibiotics but also exists for other families of molecules such as antifungals, corticosteroids or antivirals.
De plus, lorsque les antigènes se trouvent sous forme combinée, ces derniers perdent leur individualité. Par conséquent, dans ce cas, les antibiotiques soit ne s'avèrent pas être efficaces ou bien lorsqu'ils sont efficaces, la co-prescription d'une autre famille d'antibiotique doit être administrée au patient. Il en est de même pour les antifongiques, les corticoïdes et les antiviraux. La résistance des germes conduit donc soit à une 10 augmentation de la durée du traitement ou à la nécessité d'associer plusieurs familles de molécules simultanément, et d'en augmenter le dosage. Il serait donc très avantageux de trouver un palliatif aux antibiotiques, antifongiques, corticoïdes et antiviraux 15 classiquement utilisés. Or, la Demanderesse a trouvé de façon surprenante que l'utilisation d'acide cinnamique permettait de répondre à cette problématique en étant efficace, à des doses raisonnables, sur des antigènes combinés ou des antigènes 20 résistants. De plus, l'utilisation d'acide cinnamique peut être associée à une autre substance active pour compléter son action sans augmenter sa durée de traitement. Par ailleurs, la petite taille de la molécule d'acide 25 cinnamique présente un avantage non négligeable vis-à-vis des antibiotiques ou des antifongiques lui permettant de passer plus facilement à travers les cellules. De ce fait, l'acide cinnamique s'avère être plus efficace que les antibiotiques ou antifongiques classiquement utilisés sur 30 certains antigènes résistants. L'objet de la présente invention est donc l'utilisation d'acide cinnamique, de ses métabolites, ses sels, ses composés d'inclusions et ses solvates pour l'obtention d'un médicament destiné à prévenir ou traiter des infections provoquées par un antigène résistant ou par une combinaison d'antigènes dont l'un au moins peut être résistant. Moreover, when the antigens are in combined form, the latter lose their individuality. Therefore, in this case, the antibiotics either do not prove to be effective or when they are effective, the co-prescription of another family of antibiotics must be administered to the patient. The same is true for antifungals, corticosteroids and antivirals. The resistance of the germs therefore leads either to an increase in the duration of the treatment or the need to associate several families of molecules simultaneously, and to increase the dosage. It would therefore be very advantageous to find a palliative antibiotic, antifungal, steroids and antiviral 15 classically used. Now, the Applicant has surprisingly found that the use of cinnamic acid makes it possible to respond to this problem by being effective, at reasonable doses, on combined antigens or resistant antigens. In addition, the use of cinnamic acid may be associated with another active substance to complete its action without increasing its duration of treatment. Furthermore, the small size of the cinnamic acid molecule has a significant advantage over antibiotics or antifungals allowing it to pass more easily through the cells. As a result, cinnamic acid is found to be more effective than the antibiotics or antifungals conventionally used on certain resistant antigens. The object of the present invention is therefore the use of cinnamic acid, its metabolites, its salts, its inclusion compounds and its solvates in order to obtain a medicament intended to prevent or treat infections caused by a resistant antigen or by a combination of antigens at least one of which may be resistant.
Dans la présente demande, on entend par "antigène" la désignation soit d'une bactérie, d'une levure, d'un champignon, d'un germe ou d'un virus. En l'absence d'indication spécifique, dans la présente invention, le terme "acide cinnamique" couvre l'acide cinnamique lui-même, ses différentes formes isomériques, ses métabolites, ses sels, ses composés d'inclusions et ses solvates. On utilisera indifféremment le terme d'"acide cinnamique" ou de "cinnamaldéhyde". Par "antigène résistant", on entend un antigène 15 présentant des résistances au traitement qui lui est spécifique (antibiotiques, antifongiques, corticoïdes et antiviraux). Par combinaison d'antigènes, on entend l'association d'au moins deux antigènes de même nature ou de nature 20 différente. Les antigènes résistants qui peuvent être traités conformément à l'invention sont choisis dans le groupe comprenant des bactéries telles que Escherichia coli antibiorésistant, Staphylococcus aureus résistant à l'acide 25 fusidique, l'érythromycine et aux pyridones, Staphylococcus Aureus Resistant Methyl (SARM), Streptococcus pyogenes résistant aux antibiotiques et particulièrement à l'érythromycine et ciprofloxacine et aux pyridones, S. pyogenes antibiorésistant, Gardnerella vaginalis résistante 30 aux antibiotiques et particulièrement au métronidazole et à l'acide fusidique, propionibacterium acnes résistant aux antibiotiques et antiseptique, tout particulièrement à l'érythromycine, l'acide fusidique, le peroxyde de benzoyle et la chloréxidine et aux pyridones, pneumocoques résistants aux antibiotiques et particulièrement aux pénicillines, à l'ampicilline, l'amoxicilline et l'érythromycine; des levures ou champignons tels que Candida albicans résistant aux quinolones, imidazolés, pyridones, aminopénicillines, nitrofuranes et sulfamides; et des virus tels que l'haemophillus influenza type A, paramixoviridae, le virus ourlien, le VZV ou herpès simplex type 1, 2 et 3, ces virus ayant subi des mutations. In the present application, the term "antigen" means the designation of a bacterium, a yeast, a fungus, a germ or a virus. In the absence of specific indication, in the present invention, the term "cinnamic acid" covers cinnamic acid itself, its various isomeric forms, its metabolites, its salts, its inclusion compounds and its solvates. The term "cinnamic acid" or "cinnamaldehyde" is used interchangeably. By "resistant antigen" is meant an antigen with resistance to the specific treatment (antibiotics, antifungals, corticosteroids and antivirals). By combination of antigens is meant the combination of at least two antigens of the same or different nature. Resistant antigens that can be treated according to the invention are selected from the group consisting of bacteria such as antibiotic-resistant Escherichia coli, fusidic acid resistant Staphylococcus aureus, erythromycin and pyridones, Staphylococcus Aureus Resistant Methyl (MRSA). Antibiotic-resistant Streptococcus pyogenes, particularly erythromycin and ciprofloxacin and pyridones, antibiotic-resistant S. pyogenes, Gardnerella vaginalis resistant to antibiotics and particularly to metronidazole and fusidic acid, antibiotic-resistant propionibacterium acnes and antiseptic, especially erythromycin, fusidic acid, benzoyl peroxide and chlorhexidine and pyridones, pneumococci resistant to antibiotics and especially penicillins, ampicillin, amoxicillin and erythromycin; yeasts or fungi such as quinolone-resistant Candida albicans, imidazoles, pyridones, aminopenicillins, nitrofurans and sulfonamides; and viruses such as haemophillus influenza type A, paramixoviridae, mumps virus, VZV or herpes simplex type 1, 2 and 3, which have undergone mutations.
Parmi les combinaisons d'antigènes connues, on peut citer E.coli & Proteus spp, E.coli et Klebsiella spp, E.coli et Pseudomonas spp, E.coli et Pasteurella spp, E.coli et Staphylococcus spp, E.coli et Candida spp, E.coli et Trichophyton spp, E.coli et Microsporum spp, E.coli et Epidemophyton spp, E.coli et Gardnerella spp, E.coli et Propionibacterium spp, E.coli et Pneumococcus spp, C.albicans et Staphylococcus spp, C.albicans et Pseudomonas spp, C.albicans et Streptococcus spp, C.albicans et Propionibacterium spp, C.albicans et Trichophyton spp, C.albicans et Microsporum spp, C.albicans et Epidemophyton spp, C.albicans et Malassezia spp, C.albicans et Gardnerella spp, C.albicans et Pneumococcus spp, S.aureus et Streptococcus spp, S.aureus et Trichophyton, S.aureus et Microsporum spp, S.aureus et Epidemophyton spp, S.aureus et Gardnerella spp, S.aureus et Propionibacterium spp, S.aureus et Malassezia spp, S.aureus et Pneumococcus spp. Selon un mode préféré de l'invention, l'acide cinnamique permet de traiter les pathologies provoquées par la combinaison d'au moins deux des antigènes choisis dans 30 le groupe comprenant Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, Pseudomonas aeruginosa et Pasteurella multocida. Among the known combinations of antigens, mention may be made of E. coli & Proteus spp., E. coli and Klebsiella spp., E. coli and Pseudomonas spp., E. coli and Pasteurella spp., E. coli and Staphylococcus spp. Candida spp., E. coli and Trichophyton spp., E. coli and Microsporum spp., E. coli and Epidemophyton spp., E.coli and Gardnerella spp., E. coli and Propionibacterium spp., E. coli and Pneumococcus spp., C.albicans and Staphylococcus spp. spp, C.albicans and Pseudomonas spp., C.albicans and Streptococcus spp., C.albicans and Propionibacterium spp., C.albicans and Trichophyton spp., C.albicans and Microsporum spp., C.albicans and Epidemophyton spp., C.albicans and Malassezia spp. , C.albicans and Gardnerella spp, C.albicans and Pneumococcus spp, S.aureus and Streptococcus spp, S.aureus and Trichophyton, S.aureus and Microsporum spp, S.aureus and Epidemophyton spp, S.aureus and Gardnerella spp, S .aureus and Propionibacterium spp, S.aureus and Malassezia spp, S.aureus and Pneumococcus spp. According to a preferred embodiment of the invention, cinnamic acid makes it possible to treat the pathologies caused by the combination of at least two of the antigens chosen from the group comprising Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, Pseudomonas aeruginosa and Pasteurella multocida.
Selon l'invention, l'acide cinnamique utilisé peut se trouver sous forme de mélange racémique, c'est-à-dire présentant une quantité égale d'acide trans-cinnamique et d'acide cis-cinnamique, ou bien il peut se présenter sous la forme d'un mélange non racémique. Selon un mode de réalisation préféré de l'invention, l'acide cinnamique utilisé se trouve sous sa forme d'acide trans-cinnamique à plus de 90%, de préférence à plus de 95% et plus préférentiellement encore à plus de 98%. According to the invention, the cinnamic acid used can be in the form of a racemic mixture, that is to say having an equal amount of trans-cinnamic acid and cis-cinnamic acid, or it can occur in the form of a non-racemic mixture. According to a preferred embodiment of the invention, the cinnamic acid used is in its trans-cinnamic acid form to more than 90%, preferably more than 95% and more preferably more than 98%.
Selon un autre mode de réalisation, l'acide cinnamique peut se trouver sous forme de sels, de solvates ou bien former des composés d'inclusion avec par exemple des cyclodextrines. A titre d'exemples de sels possibles, on peut citer 15 l'acétate, adipate, aspartate, benzoate, bésylate, bicarbonate, carbonate, bisulfate, sulfate, borate, camsylate, citrate, cyclamate, édisylate, ésylate, formiate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate,hibenzate, chlorure, chlorhydrate, 20 bromure, bromhydrate, iodure, iodhydrate, isothionate, lactate, malate, maléate, malonate, mésylate, méthylsulfate, naphtylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate,bphosphate/hydrogeno-phosphate/dihydrogeno- 25 phosphate, pyroglutamate, saccharate, stéarate, succinate, tannate, tartrate, tosylate, trifluoroacétate et xinofoate, de préférence le sel est le succinate. Le terme solvate est utilisé ici pour décrire un complexe moléculaire comprenant l'acide cinnamique et au 30 moins une molécule solvant pharmaceutiquement acceptable, par exemple l'eau ou l'éthanol. Selon l'invention, le médicament peut être administré par voie orale, trans-cutanée, trans-cutanéomuqueuse ou topique, la voie orale incluant la voie aérienne par masque ou brumisation est incluse dans la voie orale. Selon un mode de réalisation préféré de l'invention, la voie d'administration privilégiée est la voie orale. According to another embodiment, the cinnamic acid may be in the form of salts, solvates or may form inclusion compounds with for example cyclodextrins. By way of examples of possible salts, mention may be made of acetate, adipate, aspartate, benzoate, besylate, bicarbonate, carbonate, bisulphate, sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate and gluceptate. , gluconate, glucuronate, hexafluorophosphate, hibenzate, chloride, hydrochloride, bromide, hydrobromide, iodide, iodohydrate, isothionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, bphosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate, preferably the salt is succinate. The term solvate is used herein to describe a molecular complex comprising cinnamic acid and at least one pharmaceutically acceptable solvent molecule, for example water or ethanol. According to the invention, the medicament can be administered orally, transcutaneously, transcutaneousomucous or topical, the oral route including the airway mask or mist is included in the oral route. According to a preferred embodiment of the invention, the preferred route of administration is the oral route.
La voie topique a une action par la molécule mère uniquement. En revanche, les voies orales et trans cutanéomuqueuses ont une métabolisation de la molécule mère en 2 métabolites essentiels (acide hippurique et benzoïque) retrouvés essentiellement dans les urines à 93% créant 10 ainsi un milieu non favorable à la prolifération de germes. Ces métabolites sont donc actifs tous les deux vis-à-vis des infections de l'arbre urinaire. Par arbre urinaire, on entend l'ensemble constitué par les reins, l'uretère (droite et gauche), la vessie et l'urètre. 15 De façon surprenante, les inventeurs ont trouvé que les métabolites acides hippurique et benzoïque ont une activité également par voie topique sur les germes résistants. Les formes galéniques seront choisies selon les 20 pathologies à traiter, et les voies d'administration choisies. A titre d'exemple on peut citer notamment des formes solides, semi-solides, souples, liquides, vaporisées ou pressurisées, vaporisations et diffusions ultrasoniques. Parmi les formes galéniques solides, on peut citer les 25 présentations sous forme de bâton, cachet, comprimé, enrobé ou non, effervescent, soluble, orodispersible, pelliculé, gastrorésistant ou à libération modifiée, capsule à enveloppe molle, dragée, gélule (capsules à enveloppe dure: HPMC, algues, cartilage, os) pelliculée ou non, 30 gastrorésistante ou non, gomme ou pâte à mâcher, granule, granulé, pilule, pastille, poudre orale ou pour application topique, poudre lyophilisée soluble dans un liquide chaud ou froid, tablette, suppositoire ou ovule. Parmi les formes galéniques souples, on peut citer les dispositifs transdermiques, de vernis souples, de tissus imprégnés. Parmi les formes galéniques semi-solides, on peut citer le cataplasme, crème, emplâtres médicamenteux, gel, émulsion, pâte, huile ou pommade. Parmi les formes galéniques liquides, on peut citer les formulations sous forme d'émulsion buvable, de suspension buvable, d'huiles de macération, de teinture officinale, de teinture mère, d'huile végétale en topique, liniment, liquide oral, lotion, mousse, sirop. Parmi les formes galéniques pressurisées ou pneumatiques, on peut citer les formulations sous forme de nébuliseur, inhalateur (par exemple pressurisé à valve doseuse ou à poudre) et diffuseur sonique. The topical route has an action by the parent molecule only. On the other hand, the oral and trans-cutaneous-mucous routes metabolize the parent molecule into two essential metabolites (hippuric and benzoic acid) found mainly in the urine at 93%, thus creating a medium that is not favorable to the proliferation of germs. These metabolites are therefore both active against infections of the urinary shaft. Urinary tree is the group consisting of the kidneys, the ureter (right and left), the bladder and the urethra. Surprisingly, the inventors have found that the hippuric and benzoic acid metabolites have activity also topically on resistant germs. The galenic forms will be chosen according to the pathologies to be treated and the routes of administration chosen. By way of example, mention may be made especially of solid, semi-solid, flexible, liquid, vaporized or pressurized forms, vaporizations and ultrasonic diffusions. Among the solid dosage forms, mention may be made of stick, cachet, tablet, coated or uncoated, effervescent, soluble, orodispersible, film-coated, gastroresistant or modified-release formulations, soft-shell capsules, capsules, capsules hard shell: HPMC, algae, cartilage, bone) film-coated or not, gastroresistant or not, gum or chewing paste, granule, granule, pill, lozenge, oral powder or for topical application, freeze-dried powder soluble in a hot or cold liquid , tablet, suppository or ovum. Among the flexible dosage forms include transdermal devices, soft varnishes, impregnated fabrics. Among the semi-solid dosage forms, mention may be made of poultice, cream, medicated plasters, gel, emulsion, paste, oil or ointment. Among the liquid dosage forms, mention may be made of formulations in the form of an oral emulsion, oral suspension, maceration oils, officinal dye, mother tincture, topical vegetable oil, liniment, oral liquid, lotion, mousse, syrup. Among the pressurized or pneumatic dosage forms, there may be mentioned formulations in the form of a nebulizer, an inhaler (for example pressurized with a metering or powder valve) and a sonic diffuser.
Selon la forme galénique utilisée, différents excipients ou véhicules acceptables sur le plan physiologique, essentiellement inertes, peuvent être présents, comme des solutions isotoniques, tamponnées, salines, des sels, gommes, sucres, agents stabilisants, épaississants, édulcorants, gélifiants, tensio-actifs, etc. Dans le cas de gélules ou capsules, on utilise typiquement du stéarate de magnésium et/ou de la silice colloïdale et/ou de la maltodextrine ou de la silice organique ou diverses huiles de macération ou d'expression obtenues par pressage à froid ou à chaud. Par ailleurs, l'enveloppe de ces capsules ou gélules peut être constituée de gélatine d'origine animale, végétale ou de poisson, d'algues, d'hydroxypropyl méthylcellulose (HPMC) et de cellulose. Elles peuvent être revêtues d'une couche gastrorésistante ou non et être modifiées pour effectuer une libération prolongée dans le tractus digestif. Depending on the dosage form used, different excipients or physiologically acceptable carriers, essentially inert, may be present, such as isotonic, buffered, saline solutions, salts, gums, sugars, stabilizing agents, thickeners, sweeteners, gelling agents, surfactants, and the like. assets, etc. In the case of capsules or capsules, there is typically used magnesium stearate and / or colloidal silica and / or maltodextrin or organic silica or various maceration or expression oils obtained by cold pressing or hot pressing . Furthermore, the envelope of these capsules or capsules may consist of gelatin of animal, vegetable or fish, algae, hydroxypropyl methylcellulose (HPMC) and cellulose. They may be coated with a gastroresistant layer or not and be modified to perform a sustained release in the digestive tract.
Selon l'invention, la concentration en acide cinnamique dans le médicament diffère en fonction du mode d'administration. En effet, dans le cas d'une administration par voie orale 5 ou transcutanéo-muqueuse, la concentration de l'acide cinnamique à titre de principe actif dans le médicament est comprise entre 0,03g et 40g/jour, de préférence entre O,lg et 18g/jour et plus préférentiellement encore entre 0,4g et 7,2g/jour. 10 Dans le cas d'une administration par voie topique, la concentration de l'acide cinnamique à titre de principe actif dans le médicament est comprise entre 0,01g et 25g/jour, de préférence entre O,lg et 16g/jour et plus préférentiellement encore 0,3g et 10g/jour. 15 Selon l'invention, les infections à prévenir ou à traiter sont des infections en urologie, gynécologie, dermatologie, ORL, pneumologie, gastroentérologie et allergologie. Parmi les pathologies cibles essentielles, on peut 20 citer les infections cutanéo-muqueuses bactériennes telles que l'impétigo, l'impétigo bulleux, la folliculite, le furoncle et la furonculose, l'anthrax, l'érysipèle, les plaies simples, infectées et surinfectées, cystite aiguë, chronique ou interstitielle, les urétrites, les néphrites 25 et pyélonéphrites, les prostatites, les vaginites et les vaginoses ; les infections cutanéo-muqueuses bactériennes et mycosique telles que la perlèche, la glossite, la stomatite, le muguet, la candidose anorectale, les candidoses génitales. 30 On peut également citer les infections cutanéo-muqueuses pulmonaires telles que la grippe, la bronchite, la pneumonie ; les infections cutanéo-muqueuses d'origine virale tels que l'herpès digital, buccal, anorectal et vaginal ; les infections cutanée d'origine virale tels que la rougeole, les oreillons, la varicelle, le zona. Selon un mode de réalisation particulier et pour une administration par voie orale ou injectable, l'invention porte sur l'utilisation d'acide cinnamique pour traiter des infections de l'appareil urinaire, des voies basses ou hautes, et notamment de la cystite, en particulier de la cystite aigue, chronique ou interstitielle. Dans ce mode de réalisation et dans le cas d'une 10 administration par voie orale, la concentration de l'acide cinnamique à titre de principe actif dans le médicament est comprise entre 0,03g et 40g/jour, de préférence entre 0,1g et 18g/jour et plus préférentiellement encore entre 0,4g et 7,2g/jour et dans le cas d'une administration par voie 15 injectable la concentration de l'acide cinnamique à titre de principe actif dans le médicament est comprise entre 0,001g et 5g/jour, de préférence entre O,Olg et 3,5g/jour et plus préférentiellement encore entre O,Olg et 2g/jour De façon préférée, ce médicament destiné au traitement 20 de la cystite aigue, chronique ou interstitielle comprend du transcinnamaldéhyde en tant que principe actif. Selon un autre mode de réalisation, et pour une administration par voie trans-cutanéomuqueuse, l'invention porte sur l'utilisation d'acide cinnamique pour prévenir ou 25 traiter des infections génitales telles que la vaginite ou la vaginose. Selon un autre mode de réalisation particulier et pour une administration par voie topique, l'invention porte sur l'utilisation d'acide cinnamique pour prévenir ou traiter 30 des infections dermatologiques telles que le psoriasis ou l'eczéma. L'utilisation selon l'invention peut être faite seule, en traitement de première intention, ou en combinaison ou alternance avec d'autres traitements, notamment avec les antibiotiques, antifongiques, corticoïdes ou antispasmodiques. Elle permet de réduire la sévérité de l'infection, de bloquer son développement ou de la supprimer totalement. Elle permet de faciliter la défense de l'organisme contre l'infection. Elle est utilisable chez l'humain, mais également chez tout mammifère. Ainsi, selon un autre mode de réalisation, l'invention porte sur l'utilisation d'acide cinnamique en combinaison avec au moins un autre agent thérapeutiquement efficace pour prévenir ou traiter les infections urinaires telles que les cystites aigue, chronique ou interstitielle ou pour traiter les infections dermatologiques telles que le psoriasis ou l'eczéma. According to the invention, the cinnamic acid concentration in the drug differs depending on the mode of administration. Indeed, in the case of oral or transcutaneous-mucous administration, the concentration of cinnamic acid as active principle in the drug is between 0.03 g and 40 g / day, preferably between 0, 1 g and 18 g / day and more preferably still between 0.4 g and 7.2 g / day. In the case of topical administration, the concentration of cinnamic acid as an active ingredient in the medicament is between 0.01 g and 25 g / day, preferably between 0.1 g and 16 g / day and more. preferentially still 0.3g and 10g / day. According to the invention, the infections to be prevented or treated are infections in urology, gynecology, dermatology, ENT, pneumology, gastroenterology and allergology. Among the essential target pathologies are bacterial cutaneous and mucosal infections such as impetigo, bullous impetigo, folliculitis, furuncle and furunculosis, anthrax, erysipelas, simple, infected wounds and the like. superinfected, acute, chronic or interstitial cystitis, urethritis, nephritis and pyelonephritis, prostatitis, vaginitis and vaginosis; bacterial and mycotic skin and mucocutaneous infections such as perleche, glossitis, stomatitis, thrush, anorectal candidiasis, genital candidiasis. Mention may also be made of pulmonary mucocutaneous infections such as influenza, bronchitis, pneumonia; mucocutaneous infections of viral origin such as digital, oral, anorectal and vaginal herpes; skin infections of viral origin such as measles, mumps, chickenpox, shingles. According to a particular embodiment and for oral or injectable administration, the invention relates to the use of cinnamic acid to treat infections of the urinary tract, low or high pathways, and in particular cystitis, especially acute, chronic or interstitial cystitis. In this embodiment and in the case of oral administration, the concentration of cinnamic acid as an active ingredient in the medicament is between 0.03 g and 40 g / day, preferably between 0.1 g and 18 g / day and even more preferably between 0.4 g and 7.2 g / day and in the case of administration by injection the concentration of cinnamic acid as active ingredient in the drug is between 0.001 g and 5 g / day, preferably between 0.5 g / day and 3.5 g / day, and still more preferably between 0.5 g / day and 2 g / day. Preferably, this medicament for the treatment of acute, chronic or interstitial cystitis comprises transcinnamaldehyde. as an active ingredient. According to another embodiment, and for trans-cutaneous-mucous administration, the invention relates to the use of cinnamic acid to prevent or treat genital infections such as vaginitis or vaginosis. According to another particular embodiment and for topical administration, the invention relates to the use of cinnamic acid for preventing or treating dermatological infections such as psoriasis or eczema. The use according to the invention may be made alone, as a first-line treatment, or in combination or alternation with other treatments, in particular with antibiotics, antifungals, corticosteroids or antispasmodics. It can reduce the severity of the infection, block its development or remove it completely. It helps to facilitate the defense of the body against infection. It can be used in humans, but also in any mammal. Thus, according to another embodiment, the invention relates to the use of cinnamic acid in combination with at least one other therapeutically effective agent for preventing or treating urinary infections such as acute, chronic or interstitial cystitis or for treating dermatological infections such as psoriasis or eczema.
Un tel agent thérapeutiquement efficace pouvant être utilisé en association avec l'acide cinnamique est choisi dans le groupe comprenant les antibiotiques, les antifongiques, les antiviraux, les antispasmodiques, les anti-inflammatoires, et leurs mélanges. Such a therapeutically effective agent that can be used in combination with cinnamic acid is selected from the group consisting of antibiotics, antifungals, antivirals, antispasmodics, anti-inflammatories, and mixtures thereof.
Parmi les combinaisons possibles, on peut trouver le cinnamaldéhyde et amoxicilline +/- phloroglucinol, cinnamaldéhyde et ciprofloxacine pour le traitement de l'arbre urinaire, ou le cinnamaldéhyde et amoxicilline pour le traitement de la colite bactérienne, ou le cinnamaldéhyde et diprosone, cinnamaldehyde et protopic pour le traitement de l'eczéma, ou le cinnamaldéhyde en solution H/E ou E/H et hydrothérapie riche en sélénium, cinnamaldéhyde et daivobet, le cinnamaldéhyde et acide salicylique + corps gras pour le traitement du psoriasis, ou le cinnamaldéhyde et kétoconazole / éconazole pour le traitement des états pelliculaires ; ou le cinnamaldehyde et ibuprofène pour le traitement des sinusites, ou le cinnamaldéhyde et phloroglucinol pour le traitement des colites spasmodiques ; ou le cinnamaldéhyde et pyostacine pour le traitement des plaies infectées ; ou le cinnamaldéhyde et monazole , cinnamaldéhyde et éconazole pour le traitement des vaginoses, ou cinnamaldehyde et polyginax, cinnamaldehyde et monazole / éconazole pour le traitement des vaginites infectieuses. De façon particulière, on peut utiliser les combinaisons suivantes: - Voie orale : o Traitement de l'arbre urinaire, en gélule ^ cinnamaldéhyde et amoxicilline +/phloroglucinol ^ cinnamaldéhyde et ciprofloxacine o traitement de la colite bactérienne, en gélule gastrorésistante ^ cinnamaldéhyde et amoxicilline/ - voie topique : o traitement de l'eczéma, en crème hydratante ^ cinnamaldéhyde et diprosone ^ cinnamaldehyde et protopic o traitement du psoriasis, en crème ^ cinnamaldéhyde en solution H/E ou E/H et hydrothérapie riche en sélénium ^ cinnamaldéhyde et daivobet ^ cinnamaldéhyde et acide salicylique + corps gras o traitement des états pelliculaires, en shampoing ^ cinnamaldéhyde et kétoconazole / éconazole o traitement des sinusites ^ cinnamaldehyde et ibuprofène o traitement des colites spasmodiques ^ cinnamaldéhyde et phloroglucinol o traitement des brûlures du 1° et 2° degré infectées, en onction : ^ cinnamaldéhyde et o traitement des plaies infectées, en pommade ^ cinnamaldéhyde et pyostacine - voie vaginale o traitement des vaginoses, en ovule ^ cinnamaldéhyde et monazole ^ cinnamaldéhyde et éconazole o traitement des vaginites infectieuses, en ovule ^ cinnamaldehyde et polyginax ^ cinnamaldehyde et monazole / éconazole D'autres aspects et avantages de la présente invention apparaîtront à la lecture des exemples qui suivent, qui doivent être considérés comme illustratifs et non limitatifs. La présente invention sera illustrée par les exemples suivants, qui sont donnés à titre d'illustration uniquement. EXEMPLES Etude de la comparaison de l'activité entre l'acide cinnamique et des antifongiques, antiviraux et antibiotiques contre des antigènes résistants Objectif et principe de l'étude Déterminer la CMI (Concentration Minimale Inhibitrice) d'acide cinnamique; versus antibiotiques, antifongiques et antiviraux vis-à-vis d'antigènes résistants et/ou de combinaison d'antigènes. Among the possible combinations are cinnamaldehyde and amoxicillin +/- phloroglucinol, cinnamaldehyde and ciprofloxacin for the treatment of the urinary shaft, or cinnamaldehyde and amoxicillin for the treatment of bacterial colitis, or cinnamaldehyde and diprosone, cinnamaldehyde and protopic for the treatment of eczema, or cinnamaldehyde in O / W or W / H solution and selenium-rich hydrotherapy, cinnamaldehyde and daivobet, cinnamaldehyde and salicylic acid + fat for the treatment of psoriasis, or cinnamaldehyde and ketoconazole / econazole for the treatment of dandruff conditions; or cinnamaldehyde and ibuprofen for the treatment of sinusitis, or cinnamaldehyde and phloroglucinol for the treatment of spasmodic colitis; or cinnamaldehyde and pyostacine for the treatment of infected wounds; or cinnamaldehyde and monazole, cinnamaldehyde and econazole for the treatment of vaginosis, or cinnamaldehyde and polyginax, cinnamaldehyde and monazole / econazole for the treatment of infectious vaginitis. In particular, the following combinations can be used: - Oral route: o Treatment of the urinary tree, in capsule ^ cinnamaldehyde and amoxicillin + / phloroglucinol ^ cinnamaldehyde and ciprofloxacin o treatment of bacterial colitis, in gastroresistant capsule ^ cinnamaldehyde and amoxicillin / - topical route: o treatment of eczema, moisturizing cream, cinnamaldehyde and diprosone, cinnamaldehyde and protopic treatment of psoriasis, cinnamaldehyde cream in O / W or W / H solution and selenium-rich cinnamaldehyde and daivobet hydrotherapy ^ cinnamaldehyde and salicylic acid + oily fats o treatment of dandruff conditions, cinnamaldehyde shampoo and ketoconazole / econazole o treatment of sinusitis ^ cinnamaldehyde and ibuprofen o treatment of spasmodic colitis ^ cinnamaldehyde and phloroglucinol o Treatment of 1st and 2nd degree burns infected, anointed: ^ cinnamaldehyde and o treatment of wounds infec cinnamaldehyde and pyostacine ointment - vaginal treatment o treatment of vaginosis, in ova ^ cinnamaldehyde and monazole ^ cinnamaldehyde and econazole o treatment of infectious vaginitis, in ovule ^ cinnamaldehyde and polyginax ^ cinnamaldehyde and monazole / econazole Other aspects and advantages of the present invention will appear on reading the examples which follow, which should be considered as illustrative and not limiting. The present invention will be illustrated by the following examples, which are given by way of illustration only. EXAMPLES Study of the Comparison of the Activity Between Cinnamic Acid and Antifungals, Anti-Virals and Antibiotics Against Resistant Antigens Objective and Principle of the Study Determine the MIC (Minimum Inhibitory Concentration) of Cinnamic Acid; versus antibiotics, antifungals and antivirals against resistant antigens and / or combination of antigens.
Méthodologie et protocole standardisé La méthode est basée sur la détermination de la capacité de micro-organismes à produire une croissance visible dans un bouillon contenant des dilutions en série 5 de l'agent antimicrobien. Des contrôles qualité sont réalisés sur au minimum deux souches bactériennes de référence parmi les 6 souches proposées dans la norme, et ces deux souches sont testées dans les mêmes conditions que les solutions bactériennes testées. L'acide trans- 10 cinnamique est obtenu par synthèse chimique. La détermination de la CMI de l'acide transcinnamique est réalisée par microdilution en bouillon, conformément à la norme internationale NF EN ISO 20776-1 (Avril 2007) : Systèmes d'essais en laboratoire et de diagnostic in vitro 15 - Sensibilité in vitro des agents infectieux et évaluation des performances des dispositifs pour antibiogrammes - Partie 1 : Méthode de référence pour la détermination de la sensibilité in vitro aux agents antimicrobiens des bactéries aérobies à croissance rapide impliquées dans les 20 maladies infectieuses. L'ensemble des manipulations et préparations, est réalisé sous le poste de sécurité microbiologique, dans des conditions stériles. La préparation de l'acide transcinnamique est réalisée dans de l'eau physiologique additionnée de Tween 20 0.5%(v/v) afin 25 de faciliter la solubilisation. La préparation des solutions antibiotiques est réalisée avec les mêmes solutions que celles utilisées pour l'acide transcinnamique. Les plaques de microdilution préparées pour les 30 essais, les témoins des essais, les témoins de croissance positifs et les témoins de croissance négatifs, doivent être inoculées dans les 30 minutes suivant la normalisation (10 <6> CFU/ml) de la suspension bactérienne afin de maintenir la concentration du nombre de cellules viables. 50pL de suspension bactérienne à 10 CFU/mL sont ainsi déposés dans chacune des cupules contenant 50pL d'essai de chaque solution antibactérienne, préparation à base d'acide 5 transcinnamique ou d'antibiotique ou bien contenant 50pL de bouillon (témoins de croissance positifs). Dénombrement des solutions bactériennes d'essai immédiatement après l'inoculation. Les plaques de microdilution et les géloses de dénombrement sont incubées à 37°C pendant 18 + 2 heures. 10 Résultats Contrôle de la viabilité du test Les témoins de croissance, la pureté et le nombre de cellules dans l'inoculum sont vérifiés : - témoins de croissance positifs : une turbidité 15 est observée - témoins de croissance négatifs : aucune turbidité n'est observée - pureté : un seul type de colonies est observé sur les géloses de dénombrement 20 - nombre de cellules : le nombre de colonies sur les géloses est compris entre 20 et 80 (valeur minimale). Le test n'est validé que si ces 4 points sont tous vérifiés, si le degré de croissance dans chaque cupule du 25 contrôle qualité est comparable à celui des témoins de croissance positifs et si la CMI de l'antibiotique pour les bactéries témoins se trouve dans les plages de référence. L'ensemble des résultats est reporté dans les tableaux 1 et 2. 30 Le tableau 1 représente les résultats issus de la comparaison de la concentration minimale d'inhibition CMI nécessaire entre différents produits contre une souche de champignons. Methodology and Standardized Protocol The method is based on determining the ability of microorganisms to produce visible growth in broth containing serial dilutions of the antimicrobial agent. Quality controls are carried out on at least two reference bacterial strains among the 6 strains proposed in the standard, and these two strains are tested under the same conditions as the bacterial solutions tested. Transcinnamic acid is obtained by chemical synthesis. The determination of the MIC of trans-cinnamic acid is carried out by microdilution in broth, in accordance with the international standard NF EN ISO 20776-1 (April 2007): Laboratory and in vitro diagnostic test systems 15 - In vitro sensitivity of infectious agents and performance evaluation of antibiogram devices - Part 1: Reference method for the determination of in vitro susceptibility to antimicrobial agents of fast-growing aerobic bacteria involved in infectious diseases. All manipulations and preparations are performed under the microbiological safety station, under sterile conditions. The transcinnamic acid preparation is carried out in physiological saline supplemented with 0.5% Tween (v / v) in order to facilitate solubilization. The preparation of the antibiotic solutions is carried out with the same solutions as those used for transcinnamic acid. Microdilution plates prepared for the assays, test controls, positive growth controls, and negative growth controls should be inoculated within 30 minutes of normalization (10 <6> CFU / ml) of the bacterial suspension. in order to maintain the concentration of the number of viable cells. 50 μL of bacterial suspension at 10 CFU / mL are thus deposited in each of the wells containing 50 μL of each antibacterial solution, preparation based on transcinnamic acid or antibiotic or containing 50 μL of broth (positive growth controls). . Enumeration of bacterial test solutions immediately after inoculation. Microdilution plates and count plates are incubated at 37 ° C for 18 + 2 hours. Results Control of test viability The growth controls, the purity and the number of cells in the inoculum are checked: - positive growth controls: turbidity is observed - negative growth controls: no turbidity is observed purity: only one type of colony is observed on count plates - number of cells: the number of colonies on the agar plates is between 20 and 80 (minimum value). The test is validated only if these 4 points are all verified, if the degree of growth in each well of the quality control is comparable to that of the positive growth controls and if the MIC of the antibiotic for the control bacteria is in the reference ranges. The overall results are reported in Tables 1 and 2. Table 1 represents the results from the comparison of the minimum concentration of MIC inhibition required between different products against a fungal strain.
Le tableau 2 représente les résultats issus de la comparaison de la CMI nécessaire entre différents produits contre des souches de bactéries. Le tableau 1 montre les résultats pour trois souches 5 de C.albicans. Les souches 1 et 2 sont dites classiques et la souche 3 est dite résistante. Ces résultats mettent clairement en évidence que l'acide transcinnamique est bien plus efficace que des antifongiques sur une telle souche résistante. En effet la CMI pour combattre la souche 10 résistante est de 250 pour le Kétoconazole ou de 52 pour l'éconazole alors qu'elle n'est que de 0,013 pour le Kétoconazole et de 2 pour l'éconazole lorsqu'il s'agit d'une souche classique. En revanche, la CMI nécessaire reste la même pour 15 l'acide transcinnamique lorsqu'il s'agit de la souche classique ou bien de la souche résistante, cette dernière étant égale à 98. Le tableau 2 montre les résultats pour des souches bactériennes, notamment E.coli et S.pyogenes. Il en résulte 20 les mêmes conclusions que celles évoquées précédemment. En effet, la CMI nécessaire pour combattre une souche résistante de E.coli est multipliée par un facteur 16 pour l'amoxiciline et d'un facteur 8 pour la nitrofurantoine par rapport à celle nécessaire pour combattre une souche 25 classique de E.coli alors que ce facteur n'est que de 2 pour l'acide transcinnamique. Il en est de même pour la souche S.pyogenes puisque la CMI nécessaire pour combattre une souche résistante est multipliée par un facteur 2 pour l'amoxiciline et d'un 30 facteur 4 pour la nitrofurantoine par rapport à celle nécessaire pour combattre une souche classique, alors que la CMI reste inchangée pour l'acide transcinnamique. Table 2 shows the results from the comparison of the MIC required between different products against strains of bacteria. Table 1 shows the results for three strains of C. albicans. The strains 1 and 2 are said to be conventional and the strain 3 is said to be resistant. These results clearly demonstrate that transcinnamic acid is much more effective than antifungals on such a resistant strain. Indeed the MIC to fight the resistant strain is 250 for ketoconazole or 52 for econazole while it is only 0.013 for ketoconazole and 2 for econazole when it comes to a classic strain. On the other hand, the necessary MIC remains the same for transcinnamic acid in the case of the classical strain or the resistant strain, the latter being equal to 98. Table 2 shows the results for bacterial strains, especially E.coli and S.pyogenes. This results in the same conclusions as those mentioned above. Indeed, the MIC needed to fight a resistant strain of E. coli is multiplied by a factor of 16 for amoxicillin and by a factor of 8 for nitrofurantoin compared with that required to combat a classical strain of E. coli then this factor is only 2 for transcinnamic acid. It is the same for the S.pyogenes strain since the MIC needed to fight a resistant strain is multiplied by a factor 2 for amoxicillin and a factor 4 for nitrofurantoin compared to that required to fight a classical strain. , while the MIC remains unchanged for transcinnamic acid.
L'ensemble de ces résultats mettent clairement en évidence que l'utilisation d'acide transcinnamique permet de combattre certaines souches résistantes contre lesquelles les antibiotiques, antifongiques, antiviraux ou corticoïdes sont peu ou pas efficaces. Souches C.albicans souche 1 C.albicans souche 2 C.albicans souche 3 Produits tests CMI (mg/L) Trans- 49 49 49 Cinnamaldéhyde Kétoconazole 0,015 0,013 250 Econazole 2 2 52 Tableau 1 : Comparaison entre différents produits de la CMI nécessaire contre une souche de champignons Souches E.coli souche 1 E.coli souche 2 S.pyogenes souche 1 S.pyogenes souche 2 Produits tests CMI (mg/L) Trans- 98 196 98 98 Cinnamaldéhyde Amoxiciline 32 512 512 1024 Nitrofurantoine 16 128 512 2048 Tableau 2 : Comparaison entre différents produits de la CMI 10 nécessaire contre des souches de bactéries All of these results clearly demonstrate that the use of transcinnamic acid makes it possible to combat certain resistant strains against which antibiotics, antifungals, antivirals or corticosteroids are little or not effective. Strains C.albicans strain 1 C.albicans strain 2 C.albicans strain 3 Test products MIC (mg / L) Trans-49 49 49 Cinnamaldehyde Ketoconazole 0.015 0.013 250 Econazole 2 2 52 Table 1: Comparison between different products of the MIC required against a strain of fungi Strains E. coli strain 1 E. coli strain 2 S.pyogenes strain 1 S.pyogenes strain 2 Test products MIC (mg / L) Trans- 98 196 98 98 Cinnamaldehyde Amoxicillin 32 512 512 1024 Nitrofurantoin 16 128 512 2048 Table 2: Comparison Between Different Products of the Required MIC 10 Against Bacterial Strains
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