EP0675716A1 - Preparations pharmaceutiques a base d'acide clavulanique et d'un agent antimycobacterien - Google Patents

Preparations pharmaceutiques a base d'acide clavulanique et d'un agent antimycobacterien

Info

Publication number
EP0675716A1
EP0675716A1 EP94918998A EP94918998A EP0675716A1 EP 0675716 A1 EP0675716 A1 EP 0675716A1 EP 94918998 A EP94918998 A EP 94918998A EP 94918998 A EP94918998 A EP 94918998A EP 0675716 A1 EP0675716 A1 EP 0675716A1
Authority
EP
European Patent Office
Prior art keywords
clavulanic acid
acceptable salt
formulation according
pharmaceutically acceptable
agent
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Withdrawn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
EP94918998A
Other languages
German (de)
English (en)
Inventor
James Arthur Smithkline Beecham Pharm. Poupard
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.)
SmithKline Beecham Corp
Original Assignee
SmithKline Beecham 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 SmithKline Beecham Corp filed Critical SmithKline Beecham Corp
Publication of EP0675716A1 publication Critical patent/EP0675716A1/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Withdrawn legal-status Critical Current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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems

Definitions

  • This invention relates to pharmaceutical formulations, in particular to novel uses of formulations in connection with the treatment of infection by mycobacteria.
  • Mycobacteria include M. tuberculosis and nontuberculosis mycobacterial species such as M.fortuitum, M.kansasii, M.marinum and M. avium complex.
  • the invention provides a pharmaceutical formulation which comprises a pharmaceutically acceptable salt of clavulanic acid, in combination with an antimycobacterial agent, and optionally one or more other antimicrobial agents.
  • the formulation of the invention is suitable for use in the treatment of infection by mycobacteria in humans or animals.
  • the present invention also provides a method of use of a pharmaceutically acceptable salt of clavulanic acid and an antimycobacterial agent, and optionally one or more other antimicrobial agents, together in combination in the manufacture of a medicament formulation, pa ⁇ icularly a formulation for the treatment of infection of humans or animals by mycobacteria.
  • the present invention further provides a method for the preparation of a pharmaceutical formulation as defined above, which method comprises admixing the combination of a pharmaceutically acceptable salt of clavulanic acid, and an antimycobacterial agent and optionally one or more other antimicrobial agents.
  • the present invention further provides a pharmaceutical formulation as defined above for use as an active therapeutic substance, particularly in the treatment of infection of humans or animals by mycobacteria.
  • the present invention also provides the use of a pharmaceutically acceptable salt of clavulanic acid to enhance the antimycobacterial effectiveness of an antimycobacterial agent.
  • the invention provides a method for the treatment of an infection by mycobacteria in humans or animals, which comprises administering thereto, simultaneously or successively in any order, a pharmaceutically acceptable salt of clavulanic acid and an antimycobacterial agent, and optionally one or more other antimicrobial agents.
  • a pharmaceutically acceptable salt of clavulanic acid and an antimycobacterial agent and optionally one or more other antimicrobial agents.
  • the clavulanic acid and antimycobacterial agent may be co-administered together, optionally also together with one or more other antimicrobial agents, e.g. as a pharmaceutical composition.
  • Typical mycobacteria are M. tuberculosis, M.fortuitum, M. kansasii, M. marinwn, and M. avium complex.
  • the most pharmaceutically stable salt of clavulanic acid is the potassium salt, ie potassium clavulanate.
  • a suitable antimycobacterial agent is ethambutol [that is, 2.2'-(l,2- ethanediyldiimino)di-l-butanol; d-N,N'-bis(l-hydroxymethylpropyl) ethylene diamine] or derivatives thereof such as the hydrochloride or dihydrochloride.
  • Suitable optional other antimicrobial agents which may be included in the formulations and methods of this invention as described herein include antibiotics, e.g ⁇ -lactam antibiotics such as penicillins and cephalosporins.
  • Suitable antibiotics include those for example listed in GB 1578739, e.g on page 3 line 25 to 36 thereof.
  • Suitable ⁇ -lactam antibiotics include the penicillins: amoxycillin, ampicillin, apalcillin, aspoxicillin, azidocillin, azlocillin, aztreonam, benzylpenicillin, bacampicillin, carbenicillin, cloxacillin, cyclacillin, dicloxicillin, epicillin, flucloxacillin, lenampicillin, mecillinam, methicillin, mezlocillin, phenoxy- methylpenicillin, piperacillin, pivampicillin, propicillin, sulbenicillin, talampicillin, and ticarcillin; and the cephalosporins: cefaclor, cefadroxil, cefatrizine, cefclidine, cefamandole, cefazolin, cefbuperazone, cefcanel daloxate, cefdinir, cefepime, cefetamet pivoxil, cefixime, cefminox,
  • cefmetazole cefonicid, cefoperazone, cefotaxime, cefotetan, cefotiam, cefotiam hexetil, cefoxitin, cefpimizole, cefpiramide, cefrirome, cefpodoxime proxetil ,cefprozil, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime axetil, cefuroxime, cephacetrile, cephalexin, cephaloridine, cephalothin, cephamanadole nafate, cephapirin, cephoperazone, cefsulodin, cefuzonam, cephradine, loracarbef, DQ 2556, ME1207, S-1006, SCE-2787 and moxalactam.
  • Amoxycillin is a preferred ⁇ -lactam antibiotic, for example used in the form of amoxycillin trihydrate or sodium amoxycillin, for example anhydrous crystalline sodium amoxycillin in the form described in EP 0131147.
  • the clavulanic acid and antimycobacterial agent and other optional antimicrobial agents, as used in this invention, whether in the form of the free acids, salts, esters or derivatives thereof are preferably each in a substantially pure form, e.g. at least 60% pure, more suitably at least 75% pure, preferably at least 85% especially at least 98% pure on a weight basis.
  • the formulations of the invention may be in a form adapted for oral or parenteral use and may be used for the treatment of infection in humans and animals especially mammals, including in particular domesticated animals (including farm animals).
  • the formulations of the invention may, for example, be made up in the form of tablets, suspensions, solutions, reconstitutable powders, and sterile forms suitable for injection or infusion.
  • Such formulations may contain conventional pharmaceutically acceptable materials, for example solid or liquid diluents, colours and preservatives, in accordance with conventional pharmaceutical practice in a manner well understood by those skilled in the art of formulating antibiotics. Normally all such ingredients are predried. Aqueous solutions are normally provided in the form of dry ingredients for reconstitution immediately prior to use.
  • the compounds are present in sterile form, including in sterile crystalline form.
  • a further preferred form of the formulation of the invention is one in which the formulation is in injectable or infusable form.
  • One injectable or infusable form of the formulation of the invention is an injectable or infusable solution, which suitably comprises an aqueous solution of a pharmaceutically acceptable salt of clavulanic acid and an antimycobacterial agent, and optionally one or more other antimicrobial agents, in a sterile pyrogen-free liquid, for example water or aqueous ethanol. Because of the water sensitivity of salts of clavulanic acid such a formulation should be provided as the dry constituents and be made up with water immediately prior to use.
  • a further injectable or infusable form of the formulation of the invention is an injectable or infusable suspension, in which case the salt of clavulanic acid, and antimycobacterial agent are advantageously present in finely paniculate form.
  • the suspension may be an aqueous suspension in, for example, sterile water or sterile saline, which may additionally include a suspending agent, for example poly- vinylpyrrolidone.
  • the suspension may be an oily suspension in a pharmaceutically acceptable oil suspending agent, for example arachis oil, which should be dry. Because of the water sensitivity of clavulanic acid salts such aqueous suspensions should be made up from dry constituents immediately prior to use.
  • a formulation according to the invention may be in unit dosage form, for example unit dosage form for parenteral administration, which will primarily include administration by injection or infusion, especially intramuscular and intravenous administration.
  • the antimycobacterial agent may be administered to the patient in an antibacterially effective amount, and the salt of clavulanic acid may be administered in an amount effective to inhibit ⁇ -lactamase enzymes.
  • the salt of clavulanic acid will generally be administered in an amount sufficient to inhibit the ⁇ -lactamase enzyme(s) associated with infecting bacterial and/or mycobacterial organism(s). To that end, it may suitably be administered to the patient at a daily dosage of from 0.3 to 15 mg kg, preferably from 0.7 to 10 g/kg, for example from 0.7 to 7 mg/kg, of body weight. For an adult human (of approximately 70 kg body weight), from 25 to 1000 mg, preferably from 50 to 500 mg, of the salt of clavulanic acid may be administered daily, suitably in from 1 to 6, preferably from 2 to 4, separate doses. Higher or lower dosages may, however, be used in accordance with clinical practice.
  • each unit dose may suitably comprise from 12.5 to 1000 mg, preferably from 12.5 to 250 mg, of the salt of clavulanic acid.
  • Each unit dose may, for example, be 12.5, 25, 50, 75, 100, 125, 150, 200, or 250 mg of the salt of clavulanic acid.
  • the ratio of the amount of the salt of clavulanic acid used according to the invention : amount of any other optional antimicrobial agent present may vary within a wide range, e.g 1:1 to 1:30 by weight.
  • the said ratio may, for example, be from 1:1 to 1:12; more particularly, it may, for example, be from 1:1 to 1:7, 1:1 to 1:4 or 1:1 to 1:2, by weight.
  • the amount of any optional other antimicrobial agent, e.g amoxycillin or salts or esters thereof in a formulation according to the invention will normally be approximately similar to the amount in which it is conventionally used per se.
  • amoxycillin for example from 125 to 3000 mg per day, and from 125 to 3000 mg per unit dose, advantageously from about 125 to 1000 mg per unit dose, from 2 to 4 times daily may be administered.
  • ticarcillin for example a maximum of 3.2 g six to eight hourly may be administered.
  • the amount of antimycobacterial agent in a formulation according to the invention will normally be approximately similar to the amount in which it is conventionally used per se. For example in the case of ethambutol up to 25 mg/kg per day may be administered.
  • An example of a suitable formulation for oral administration according to the invention is one comprising from 12.5 to 250 mg, preferably from 25 to 125 mg, of potassium clavulanate, in admixture or conjunction with 100 to 400 mg of ethambutol or a derivative thereof per unit dose, optionally also comprising 125 to 3000mg of amoxycillin trihydrate.
  • An example of a suitable formulation for parenteral administration according to this invention is one comprising from 12.5 to 250mg, preferably from 25 to 125 mg, of potassium clavulanate, in admixture or conjunction with 100 to 400 mg of ethambutol or a derivative thereof per unit dose, optionally also comprising 125 to 3000 mg of sodium amoxycillin.
  • the following example illustrates the synergistic antibacterial activity of a combination of a salt of clavulanic acid and the antimycobacterial agent ethambutol, together with the antimicrobial agent amoxycillin, and compares this combination with the activity of amoxycillin and a salt of clavulanic acid alone, and of ethambutol alone, against mycobacteria.
  • Example 1 illustrates the synergistic antibacterial activity of a combination of a salt of clavulanic acid and the antimycobacterial agent ethambutol, together with the antimicrobial agent amoxycillin, and compares this combination with the activity of amoxycillin and a salt of clavulanic acid alone, and of ethambutol alone, against mycobacteria.
  • Example 1 illustrates the synergistic antibacterial activity of a combination of a salt of clavulanic acid and the antimycobacterial agent ethambutol, together with the antimicrobial agent
  • the susceptibility of four mycobacterial species to amoxycillin plus clavulanate, and ethambutol was determined.
  • Microdilution MIC methodology was used to test 24 M.fortuitum, M. kansasii and M. m rinum strains and BACTEC methodology was used to test 20 M. avium complex (MAC) isolates.
  • kansasii and four M. marinum isolates was increased compared to either amoxyciUin/clavulanate or ethambutol alone.
  • the data obtained indicate that the concentrations of amoxyciUin/clavulanate alone and in combination with ethambutol required to inhibit mycobacterial growth in vitro are within the therapeutic range of amoxyciUin/clavulanate.
  • MICs ⁇ g/ml results for M. kansasii and M. marinum. MICs were determined in middlebrook broth with OADC (oleic acid, albumin, dextrose and catalase) enrichment inocculated with 5 x 10 ⁇ CFU/ml of the mycobacteria. After sufficient growth the MICs were determined as the lowest concentration of antibiotic(s) which inhibited growth.
  • OADC oleic acid, albumin, dextrose and catalase
  • clav. clavulanate alone
  • amx. amoxyciUin alone
  • etham. ethambutol alone
  • clav/amx clavulanate + amoxycillin
  • clav/amx/etham clavulanate + amoxycillin + ethambutol.

Landscapes

  • 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

Préparations pharmaceutiques comportant un sel pharmacocompatible d'acide clavulanique tel que le clavulanate de potassium en combinaison avec un agent antimycobactérien tel que l'éthambutol, et facultativement un ou plusieurs autres agents antimicrobiens tels que l'amoxycilline. Ces préparations sont utilisables dans des thérapies de lutte contre des infections mycobactériennes.
EP94918998A 1993-05-28 1994-05-16 Preparations pharmaceutiques a base d'acide clavulanique et d'un agent antimycobacterien Withdrawn EP0675716A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB939311030A GB9311030D0 (en) 1993-05-28 1993-05-28 Pharmaceutical formulations
GB9311030 1993-05-28
PCT/IB1994/000204 WO1994027600A1 (fr) 1993-05-28 1994-05-16 Preparations pharmaceutiques a base d'acide clavulanique et d'un agent antimycobacterien

Publications (1)

Publication Number Publication Date
EP0675716A1 true EP0675716A1 (fr) 1995-10-11

Family

ID=10736272

Family Applications (1)

Application Number Title Priority Date Filing Date
EP94918998A Withdrawn EP0675716A1 (fr) 1993-05-28 1994-05-16 Preparations pharmaceutiques a base d'acide clavulanique et d'un agent antimycobacterien

Country Status (3)

Country Link
EP (1) EP0675716A1 (fr)
GB (1) GB9311030D0 (fr)
WO (1) WO1994027600A1 (fr)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1289084C (zh) 1995-09-07 2006-12-13 史密丝克莱恩比彻姆有限公司 药物制剂
US6294199B1 (en) 1999-04-13 2001-09-25 Beecham Pharmaceuticals (Pte) Limited Method of treating a bacterial infection comprising administering amoxycillin
US6878386B1 (en) 1999-04-13 2005-04-12 Beecham Pharmaceuticals (Pte) Limited Method of treating a bacterial infection comprising amoxycillin and potassium clavulanate
US7250176B1 (en) 1999-04-13 2007-07-31 Beecham Pharmaceuticals (Pte) Limited Method of treating a bacterial infection
OA11926A (en) * 1999-04-13 2006-04-12 Beecham Pharmacueticals Pte Lt Novel method of treatment
WO2002030392A2 (fr) 2000-10-12 2002-04-18 Beecham Pharmaceuticals (Pte) Limited Nouvelle formulation
US6756057B2 (en) 2000-10-12 2004-06-29 Beecham Pharmaceuticals (Pte) Limited Amoxicillin and potassium clavulanate dosage form

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9427600A1 *

Also Published As

Publication number Publication date
GB9311030D0 (en) 1993-07-14
WO1994027600A1 (fr) 1994-12-08

Similar Documents

Publication Publication Date Title
AU2011373912B2 (en) Pharmaceutical compositions comprising beta-lactam antibiotic, sulbactam and beta-lactamase inhibitor
EP0680322B1 (fr) Utilisation de clavulanate et un antibiotique pour le traitement d'infections
KR950703346A (ko) 결정성 페니실린 유도체, 그의 제법 및 용도(Crystalline Penicillin Derivative, and Its Production and Use)
AU2013308128B2 (en) Antibacterial compositions
WO1994027600A1 (fr) Preparations pharmaceutiques a base d'acide clavulanique et d'un agent antimycobacterien
US20030109503A1 (en) Pharmaceutical formulations comprising clavulanic acid alone or in combination with other beta-lactam antibiotics
CN113194943A (zh) 一种质量稳定的β内酰胺酶抑制剂组合物及其用途和方法
US5658887A (en) Pharmaceutical formulations comprising a clavulanic acid salt and erithromycin derivatite
US5049384A (en) Antibacterial composition for medical use and a process for the preparation thereof
US7169792B2 (en) Method of treating bacterial infections using gemifloxacin or a salt thereof and a β-lactam antibiotic
EP0804220A1 (fr) Formulations pharmaceutiques comprenant un sel d'acide clavulanique, de la vancomycine et une ou plusieurs beta-lactamines
AU648792B2 (en) Veterinary treatment for pigs
WO2021116420A1 (fr) Utilisation d'agonistes tlr7 et/ou tlr8 pour le traitement de la leptospirose
JPH0243726B2 (fr)
CA2054440A1 (fr) Formulations pharmaceutiques
GB2157565A (en) Synergistic antibiotic composition

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19950504

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): BE CH DE FR GB IT LI NL

17Q First examination report despatched

Effective date: 19990413

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 19990824