EP0154622A1 - Compositions antimicrobiennes contenant de l'acide carboxylique de 1-ethyl-6-fluoro-1,4-dihydro-oxo-7-(1-piperazinyl)-3-quinoline ou ses sels metalliques et de la sulfadiazine d'argent - Google Patents

Compositions antimicrobiennes contenant de l'acide carboxylique de 1-ethyl-6-fluoro-1,4-dihydro-oxo-7-(1-piperazinyl)-3-quinoline ou ses sels metalliques et de la sulfadiazine d'argent

Info

Publication number
EP0154622A1
EP0154622A1 EP83903134A EP83903134A EP0154622A1 EP 0154622 A1 EP0154622 A1 EP 0154622A1 EP 83903134 A EP83903134 A EP 83903134A EP 83903134 A EP83903134 A EP 83903134A EP 0154622 A1 EP0154622 A1 EP 0154622A1
Authority
EP
European Patent Office
Prior art keywords
composition
accordance
carboxylic acid
metal salt
present
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.)
Withdrawn
Application number
EP83903134A
Other languages
German (de)
English (en)
Other versions
EP0154622A4 (fr
Inventor
Charles L. Fox, Jr.
Shanta M. Modak
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Research Corp
Original Assignee
Research Corp
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.)
Filing date
Publication date
Application filed by Research Corp filed Critical Research Corp
Publication of EP0154622A1 publication Critical patent/EP0154622A1/fr
Publication of EP0154622A4 publication Critical patent/EP0154622A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine

Definitions

  • Pseudomonas aeruginosa remain problems in seriously burned patients. Emergence and development of drug resistant species of bacteria have defied the control obtained through the regimen of potent antibiotics. In recent years, numerous reports of gentamicin resistant gram negative organisms (Shulman, J.A., Terry, P.M., Hough, C.E.: Colonization with a gentamicin resistant Pseudomonas aeruginosa pyocine type 5 in a burn unit. J. of Inf. Diseases 124;S18, 1971), especially Pseudomonas, have appeared in the literature.
  • (1-pi ⁇ erazinyl)-3-quinoline carboxylic acid and metal salts thereof (referred to hereinafter as QC and its metal salts as MeQC) possess high anti-Pseudomonas activity in vitro (Ito, A., Hira, K., Inoue, M., et al.: In vitro antibacterial activity of AM-715, a new nalidixic acid analog.
  • QC and MeQC e.g., AgQC
  • topical antimicrobials useful in burn therapy.
  • compositions comprising the silver salt of 1-ethyl-6-fluoro-1,4-dihydro4-oxo-7-(1-piperazinyl)-3-quinoline carboxylic acid and silver sufadiazine, in which the compounds are present in amounts which would be ineffective if only one of the compounds were present, are useful in the treatment of burns in animal and man.
  • These compositions may be applied to the affected surface or burned surface of a burn victim, either directly, or preferably in the form of a composition which includes a physiologically acceptable carrier, such as a water-dispersible hydrophilic carrier, e.g., an oil-in-water dispersion.
  • the metal salts of QC i.e., MeQC, viz.MgQC, CoQC, ZnQC, CeQC, and AgQC are also of interest and appear to be suitable topical antimicrobial agents.
  • MeQC viz.MgQC, CoQC, ZnQC, CeQC, and AgQC are also of interest and appear to be suitable topical antimicrobial agents.
  • AgQC which would appear to have the structure wherein the moiety of QC is changed t Ag+, is a potent antimicrobial.
  • the metal salts of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7(1-piperazinyl)-3-quinoline carboxylic acid i.e., MeQC
  • AgQC may be prepared as follows. QC is obtained directly or synthesized by known techniques.
  • the sodium salt of 1-ethyl-6-fluoro-1,4-dihydro-4oxo-7-(1-piperazinyl)-3-quinoline carboxylic acid, i.e., NaQC may then be prepared by adding an equimolar amount of sodium hydroxide to the QC.
  • the silver salt, i.e., AgQC may be prepared by reacting the NaQC in an aqueous solution with a stoichiometric quantity of a suitable silver salt such as silver nitrate, silver chloride, or the like.
  • Silver sulfadiazine is well known as an effective agent in burn therapy. However, the silver sulfadiazine must be employed in compositions in amounts or concentrations greater than about 1.0 percent by weight. At lesser amounts, silver sulfadiazine (AgSD) is ineffective.
  • compositions useful in burn therapy have been discovered in which the amounts of AgSD and of AgQC are below the amounts required for antibacterial activity or effectiveness if only one of the compounds is present or included.
  • compositions useful in burn therapy may be prepared in which the amount or concentration of AgQC is less than about 10mM, such as an amount from about 1mM up to about 10mM, e.g., about 3mM; and the amount or concentration of AgSD is less than about 1.0 percent by weight, such as an amount from about 10mM up to about 1.0 percent, e.g., about 30mM.
  • compositions of this invention may be applied directly to the surface of burn wounds or infections, or, preferably, may be employed in combination with a physiologically acceptable carrier.
  • the carrier is desirably a conventional water-dispersible, hydrophilic or oil-in-water carrier, particularly a conventional semi-soft or cream-like, water-dispersible or water-soluble, oil-in-water emulsion, which may be applied to an affected burn surface or infected surface with a minimum of discomfort.
  • suitable compositions may be prepared by merely incorporating or homogeneously admixing finely divided compounds with the hydrophilic carrier or base or ointment.
  • One technique in accordance with this invention for incorporating the metal salts, e.g., the silver salt, in a hydrophilic ointment, such as an oil-in-water emulsion involves reacting equimolar aqueous solutions of silver nitrate and NaQC to yield a white precipitate which is AgQC.
  • the resulting precipitate after washing and drying, is then mixed or blended with the candidate hydrophilic ointment, such as the oil-in-water emulsion, to yield a composition which includes the silver salt dispersed in the ointment.
  • the AgSD may be incorporated into the composition either together with the AgQC or independently.
  • compositions in accordance with this invention containing AgSD and MeQC dispersed in a water-dispersible, hydrophilic carrier or ointment are usually characterized by the following components and amounts by weight set forth in Table I:
  • Emulsifying Agents preferably non-ionic 4-16 Humectant 7-40 AgSD 10mM-1.0
  • Amounts are in percent by weight unless otherwise indicated.
  • the fatty alcohols, stearyl alcohol, cetyl alcohol, lauryl alcohol and myristyl alcohol are useful in the preparation of compositions in accordance with this invention. These preferential oil-soluble fatty alcohols act as stiffeners in the resulting compositions.
  • emulsifying agent sorbitan monooleate such as an amount in the range 0.5-4 percent by weight, and polyoxyl 40 stearate in an amount in the range 7-12 percent by weight
  • both non-ionic emulsifying agents are satisfactory.
  • a suitable humectant would be propylene glycol, sorbitol, or glycerin, or mixtures thereof, all being water-soluble compounds.
  • a suitable preservative would be any of the useful conventional watersoluble preservatives which exhibit anti-microbial activity, such as sorbic acid, benzoic methylparaben, propylparaben, and mixtures thereof.
  • the solid content i.e., the water-immiscible or water-insoluble components, e.g., fatty alcohol, such as stearyl alcohol, and/or petrolatum
  • the preservative e.g., methylparaben
  • Methylparaben as indicated, however, may also be used in combination with propylparaben.
  • compositions useful in the practices of this invention would include compositions comprising 0-25 percent by weight petrolatum, 7-45 percent by weight stearyl alcohol, 0-15 percent by weight isopropyl myristate, 5-20 percent by weight of an emulsifying agent, 7-40 percent by weight propylene glycol, 10mM-1.0 percent by weight AgSD and 1mM-10mM of AgQC, the remainder being water, as required, to bring the total percentage to 100 percent.
  • Other useful compositions would include compositions consisting essentially of 3mM AgQC, 30mM AgSD, 7-8 percent by weight propylene glycol, 38-44 percent by weight water,
  • composition useful in the practice of this invention would include the composition consisting essentially of 0-25 percent by weight petrolatum, 7-45 percent by weight of an aliphatic fatty alcohol having a carbon atom content in the range C 16 -C 22' 0-15 percent by weight of an emollient, 7-16 percent by weight of an emulsifying agent, 7-14 percent by weight of a humectant, 3mM AgQC, and 30mM AgSD.
  • Ps. Boston was the strain used in our previous investigations (Fox, Jr., C.L., Sampath, A.C, Stanford, J.W.: Virulence of pseudomonas infection in burned rats and mice. Arc. Surg. 101:508, 1970); Ps. Mangalore was isolated from a burn patient in Kasturba Medical College, Mangalore, India; Ps. 181 was obtained from Hospital de los Ninos, Lima, Peru; and AgSD resistant Ps. Boston was produced in our laboratory by repeatedly growing this organism in medium containing increasing amounts of AgSD.
  • In vitro assay of microbial inhibition Inhibition indices are obtained by tube dilution tests using nutrient broth. Growth in the presence and absence of drugs was observed by turbidity measurement after incubation at 37°C for 24-48 hours (Fox, Jr., C.L., Modak, S.M., Stanford, J.W.: Cerium sulfadiazine as a topical agent for burn wound infections: A comparison with silver sulfadiazine and zinc sulfadiazine. Burns 4:233, 1978).
  • the wounds were contaminated one hour post burn with freshly prepared 18-20 hour broth culture of pseudomonas diluted to optical density 0.30. Infection was induced by immersing the tail in the culture. The first treatment was administered 4 hours post infection by rubbing the medicated creams over all burned surfaces. All drugs used were mixed in a cream base such as described hereinabove. Thereafter, all animals were observed and treated once daily. The primary criteron was survival. Animals that succumbed were autoposied and the cardiac blood cultured to verify the presence of pseudomonas.
  • Control 10 40 100 100 100 100 100 100 100 100
  • mice anesthetized with ether were given a 30 percent scald by dipping the lower third of their body into a water bath at 68°C for 7 seconds.
  • mice were given 1 ml of Normosol by I.P. injection and then infected by dipping the tail in an overnight culture of pseudomonas diluted to 0.30 O.D. at 600nm.
  • the animals were divided at random into groups of 5, and topical therapy was initiated 4 hours post infection. Thereafter they were treated once daily. The primary criterion was survival. Animals that succumbed were autopsied and their cardiac blood was cultured to verify the presence of pseudomonas sepsis.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Compositions comprenant de l'acide carboxylique de 1-éthyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-pipérazinyl)-3-quinoline ou ses sels métalliques, par exemple des sels d'argent, de zinc, de cobalt ou de cérium, et de la sulfadiazine d'argent, efficaces dans le traitement de brûlures. Particulièrement intéressantes sont des compositions contenant de la sulfadiazine d'argent et le sel d'argent de l'acide carboxylique de la quinoline identifiée ci-dessus, où les compositions résultantes sont efficaces, même si chaque composé est présent en une concentration qui serait inefficace si le composé était utilisé séparément. Les compositions de la présente invention peuvent être appliquées sur la surface intéressée d'une victime de brûlures soit directement, soit en combinaison avec un support physiologiquement acceptable, tel qu'un support hydrophile pouvant se disperser dans l'eau.
EP19830903134 1983-09-12 1983-09-12 Compositions antimicrobiennes contenant de l'acide carboxylique de 1-ethyl-6-fluoro-1,4-dihydro-oxo-7-(1-piperazinyl)-3-quinoline ou ses sels metalliques et de la sulfadiazine d'argent. Withdrawn EP0154622A4 (fr)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US1983/001376 WO1985001208A1 (fr) 1983-09-12 1983-09-12 Compositions antimicrobiennes contenant de l'acide carboxylique de 1-ethyl-6-fluoro-1,4-dihydro-oxo-7-(1-piperazinyl)-3-quinoline ou ses sels metalliques et de la sulfadiazine d'argent

Publications (2)

Publication Number Publication Date
EP0154622A1 true EP0154622A1 (fr) 1985-09-18
EP0154622A4 EP0154622A4 (fr) 1987-03-16

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP19830903134 Withdrawn EP0154622A4 (fr) 1983-09-12 1983-09-12 Compositions antimicrobiennes contenant de l'acide carboxylique de 1-ethyl-6-fluoro-1,4-dihydro-oxo-7-(1-piperazinyl)-3-quinoline ou ses sels metalliques et de la sulfadiazine d'argent.

Country Status (3)

Country Link
EP (1) EP0154622A4 (fr)
JP (1) JPS61500067A (fr)
WO (1) WO1985001208A1 (fr)

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5753269A (en) * 1995-12-27 1998-05-19 Bayer Corporation Otic microbial combinations
ITMI20040943A1 (it) * 2004-05-11 2004-08-11 Icim Internat S R L Composizione farmaceutica cicatrizzante
US9511040B2 (en) 2007-06-20 2016-12-06 The Trustees Of Columbia University In The City Of New York Skin and surface disinfectant compositions containing botanicals
WO2008157092A1 (fr) 2007-06-20 2008-12-24 The Trustees Of Columbia University In The City Of New York Surfaces résistantes à la formation de biofilm
US9687429B2 (en) 2007-06-20 2017-06-27 The Trustees Of Columbia University In The City Of New York Antimicrobial compositions containing low concentrations of botanicals
US9981069B2 (en) 2007-06-20 2018-05-29 The Trustees Of Columbia University In The City Of New York Bio-film resistant surfaces
DK2773334T3 (da) 2011-11-03 2019-12-09 Univ Columbia Sammensætning med forlænget antimikrobiel aktivitet
US9968101B2 (en) 2011-11-03 2018-05-15 The Trustees Of Columbia University In The City Of New York Botanical antimicrobial compositions
TW201330856A (zh) 2011-12-06 2013-08-01 Univ Columbia 廣效性的天然防腐組成物
JP7326671B2 (ja) * 2018-10-23 2023-08-16 大阪ガスケミカル株式会社 抗菌剤組成物

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3761590A (en) * 1970-05-18 1973-09-25 Research Corp Silver sulfadiazine used in the treatment of burns
JPS53141286A (en) * 1977-05-16 1978-12-08 Kyorin Seiyaku Kk Novel substituted quinolinecarboxylic acid

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
No relevant documents have been disclosed. *
See also references of WO8501208A1 *

Also Published As

Publication number Publication date
WO1985001208A1 (fr) 1985-03-28
EP0154622A4 (fr) 1987-03-16
JPS61500067A (ja) 1986-01-16

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Inventor name: MODAK, SHANTA, M.