EP0593573A1 - Formulation pharmaceutique comprenant une beta-lactamine et de l'acide clavulanique ou un sel de celui-ci soluble dans l'eau - Google Patents

Formulation pharmaceutique comprenant une beta-lactamine et de l'acide clavulanique ou un sel de celui-ci soluble dans l'eau

Info

Publication number
EP0593573A1
EP0593573A1 EP92914294A EP92914294A EP0593573A1 EP 0593573 A1 EP0593573 A1 EP 0593573A1 EP 92914294 A EP92914294 A EP 92914294A EP 92914294 A EP92914294 A EP 92914294A EP 0593573 A1 EP0593573 A1 EP 0593573A1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutical formulation
acid
salt
formulation according
dicarboxylic acid
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Withdrawn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
EP92914294A
Other languages
German (de)
English (en)
Inventor
David Clapham
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 Ltd
Original Assignee
SmithKline Beecham Ltd
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 Ltd filed Critical SmithKline Beecham Ltd
Publication of EP0593573A1 publication Critical patent/EP0593573A1/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Withdrawn legal-status Critical Current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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof

Definitions

  • This invention relates to pharmaceutical formulations, in particular to formulations containing ⁇ -lactam antibiotics and the ⁇ -lactamase inhibitor clavulanic acid or derivatives thereof, especially aqueous suspension formulations.
  • compositions containing a ⁇ -lactam antibiotic and clavulanic acid or derivatives such as its salts are known.
  • Clavulanic acid in aqueous suspension or solution is known to suffer to some extent from instability, and one significant determinant of stability is the pH of the aqueous medium of the suspension or solution, pH 5.8 - 6.2 being known to be the optimum.
  • This invention provides novel improved pharmaceutical formulations containing clavulanic acid or derivatives thereof in which these problems have to some extent been alleviated, and further unexpected advantages have been achieved.
  • the invention provides a pharmaceutical formulation comprising;
  • the formulation may be an aqueous suspension or solution formulation, eg for oral administration or may alternatively be a dry powder, granular or tablet formulation provided primarily for reconstitution into an aqueous suspension or solution formulation.
  • the one or more ⁇ -lactam antibiotics may be penicillins or cephalosporins, especially amox cillin and ampicillin, preferably amoxycillin in the form of its trihydrate.
  • the clavulanic acid is preferably in the form of one of its salts with a pharmaceutically acceptable cation, especially potassium clavulanate.
  • the weight ratio of antibiotic: clavulanic acid or clavulanate anion equivalent is in the range 12 : 1 to 1 : 1, suitably 8 : 1 to 1.5 : 1.
  • concentration of antibiotic and clavulanic acid or clavulanate equivalent will vary depending upon the size of the unit dose in which it is intended to be administered.
  • formulations for oral administration are administered in unit doses of around 5ml spoonfuls or as paediatric drops for small children.
  • the total combined concentration of antibiotic and clavulanic acid or equivalent in such suspensions or solutions may be in the range 25 - 250 mg/ml, for example 30-125 mg/ml.
  • the formulation is in the form of dry powder, granules or tablets for reconstitution the quantity of antibiotic and clavulanic acid or equivalent may be derived accordingly.
  • the dicarboxylic acid salt eg. a succinic acid salt may be of a divalent cation such as calcium or other pharmaceutically acceptable cation, eg of a Group II metal, in which case a single such cation may replace both of the acidic hydrogen atoms.
  • each acidic hydrogen atom may be replaced by a monovalent cation such as sodium, potassium or other pharmaceutically acceptable monovalent cation.
  • Disodium succinate is preferred on account of its low cost, used in combination with succinic acid.
  • the weight ratio of succinic acid : disodium succinate may be in the range 1 : 50 to 1 : 0.05 representing a molar ratio of succinic acid : succinic acid salt in the range 1 : 33 to 3 : 1.
  • Suitable weight ratios of succinic acid : disodium succinate are around 1 : 30 to 1 : 15, for example 1 : 19 ⁇ 1.
  • Typical weight ranges for other salts may be calculated from these ranges on the basis of the corresponding weight of succinate anion.
  • the total molarity of succinic acid and succinate salt may be in the range 0.001M to 0.01M, suitably 0.001M to 0.0052 M, for example 0.005 ⁇ 0.0001 M.
  • the formulation is in the form of dry powder, granules or tablets for reconstitution the quantity of succinic acid and succinate salt may be derived accordingly.
  • the formulation may also optionally contain excipients which may be essentially conventional in the art.
  • aqueous suspension or solution formulations may typically contain suspending agents such as Xantham gum, for example 0.25-5 mg/ml, suitably 0.5 - 2.5 mg/ml, thickening agents such as cellulose derivatives, for example 1 - 100 mg/ml if present, sweeteners such as aspartame or equivalent sugars, eg 0.5-5 mg/ml, and flavouring agents such as fruit flavourings and syrup flavourings, eg 10-20 mg/ml etc.
  • suspending agents such as Xantham gum, for example 0.25-5 mg/ml, suitably 0.5 - 2.5 mg/ml
  • thickening agents such as cellulose derivatives, for example 1 - 100 mg/ml if present
  • sweeteners such as aspartame or equivalent sugars, eg 0.5-5 mg/ml
  • flavouring agents such as fruit flavourings and syrup flavourings, eg 10-20 mg
  • Silicas such as "Aerosil” may be present as thickening agents and/or as a powder flow aid, and other silicas such as "Syloid” may be present as an internal dessicant and bulking agent. Typically silicas may be present at eg 1-100 mg/ml. Dry powder, granule or tablet formulations for reconstitution may contain corresponding weights of these and/or other conventional excipients.
  • Aqueous suspension and solution formulations of this invention may be provided in entirely conventional bottles etc, and dry powder or granule formulations for reconstitution may be provided in conventional jars, sachets etc which are advisedly airtight.
  • the formulations of the invention appear to offer a number of advantages over known formulations which contain a ⁇ -lactam antibiotic in combination with clavulanic acid or clavulanate equivalent. These include improvement of stability in solution for example by 2-4% of the initial concentration on storage for 7 days at 5°C. The stability in solution is more robust in terms of pH differences in the water used to make up the suspension or solution and the quality of raw materials such as amoxycillin trihydrate. The presence of succinate ion appears to inhibit the colour change from white to pale cream that sometimes follows reconstitution, and there appears to be some enhancement of the flavour of reconstituted suspensions and solutions.
  • the invention also provides a process for the preparation of such a pharmaceutical formulation, comprising admixing the ⁇ -lactam antibiotic, the clavulanic acid or salt thereof, the dicarboxylic acid and the salt thereof, and optionally any excipients, and optionally making the product up with water or an aqueous medium to form a suspension or solution formulation.
  • the invention also provides a process for the use of a pharmaceutical formulation as described above in the manufacture of a medicament for the treatment of bacterial infections.
  • the invention also provides a pharmaceutical formulation as described above for use in the treatment of bacterial infections.
  • the invention also provides a method of treatment of bacterial infections in humans or animals which comprises the administration of a therapeutically effective amount of a pharmaceutical formulation as described above.
  • a unit dose of 5ml of this suspension contains 156 mg of amoxycillin clavulanic acid combination.
  • This suspension contains 112.5 mg per ml of amoxycillin clavulanic acid combination.
  • a unit dose of 5 ml of this suspension contains 312 mg of amoxycillin/clavulanic acid combination.
  • a unit dose of 5ml of this suspension contains 187 mg of amoxycillin clavulanic acid combination.

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)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

Formulation pharmaceutique comprenant une ou plusieurs bêta-lactamines, de l'acide clavulanique ou un sel de celui-ci, soluble dans l'eau, un acide dicarboxylique pharmaceutiquement acceptable, et un sel de l'acide dicarboxylique, dans lequel les deux atomes d'hydrogène acides sont remplacés par un cation.
EP92914294A 1991-07-11 1992-07-03 Formulation pharmaceutique comprenant une beta-lactamine et de l'acide clavulanique ou un sel de celui-ci soluble dans l'eau Withdrawn EP0593573A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB919114950A GB9114950D0 (en) 1991-07-11 1991-07-11 Pharmaceutical formulation
GB9114950 1991-07-11
PCT/GB1992/001207 WO1993000898A1 (fr) 1991-07-11 1992-07-03 Formulation pharmaceutique comprenant une beta-lactamine et de l'acide clavulanique ou un sel de celui-ci soluble dans l'eau

Publications (1)

Publication Number Publication Date
EP0593573A1 true EP0593573A1 (fr) 1994-04-27

Family

ID=10698173

Family Applications (1)

Application Number Title Priority Date Filing Date
EP92914294A Withdrawn EP0593573A1 (fr) 1991-07-11 1992-07-03 Formulation pharmaceutique comprenant une beta-lactamine et de l'acide clavulanique ou un sel de celui-ci soluble dans l'eau

Country Status (5)

Country Link
EP (1) EP0593573A1 (fr)
JP (1) JPH06508844A (fr)
AU (1) AU2230692A (fr)
GB (1) GB9114950D0 (fr)
WO (1) WO1993000898A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011142731A2 (fr) 2010-05-14 2011-11-17 Mahmut Bilgic Formulations comprenant une céphalosporine et un acide clavulanique de troisième génération
WO2011142730A1 (fr) 2010-05-14 2011-11-17 Mahmut Bilgic Composition pharmaceutique comprenant la céfixime et un composé dérivé de l'acide clavulanique
WO2011152808A1 (fr) 2010-06-03 2011-12-08 Mahmut Bilgic Formulation comprenant du cefpodoxime proxétil et de l'acide clavulanique

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL123563A (en) 1995-09-07 2002-02-10 Smithkline Beecham Corp Pharmaceutical formulations comprising amoxycillin and clavulanate in a weight ratio between 14:1 and 16:1 inclusive
US5759579A (en) * 1996-12-05 1998-06-02 American Home Products Corporation Pharmaceutical suspension systems
DE19706978A1 (de) * 1997-02-21 1998-08-27 Ulrich Dr Posanski Kombinationspräparat für oral applizierbare Antibiotika
US20010016577A1 (en) * 1998-08-24 2001-08-23 Douglas Joseph Dobrozsi Oral mucoadhesive compositions containing gastrointestinal actives
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
US6294199B1 (en) 1999-04-13 2001-09-25 Beecham Pharmaceuticals (Pte) Limited Method of treating a bacterial infection comprising administering amoxycillin
US6756057B2 (en) 2000-10-12 2004-06-29 Beecham Pharmaceuticals (Pte) Limited Amoxicillin and potassium clavulanate dosage form
AU2001292185A1 (en) 2000-10-12 2002-04-22 Beecham Pharmaceuticals (Pte) Limited Formulation containing amoxicillin
WO2007034924A1 (fr) 2005-09-22 2007-03-29 Meiji Seika Kaisha, Ltd. Inhibiteur de la métallo-pénicillinase
TR201000688A2 (tr) * 2010-01-29 2011-08-22 B�Lg�� Mahmut Aktif madde olarak sefaklor ve klavulanik asit içeren efervesan formülasyonlar.

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3266580D1 (en) * 1981-12-02 1985-10-31 Beecham Group Plc Pharmaceutical formulation comprising beta-lactam antibiotics
GB9007945D0 (en) * 1990-04-07 1990-06-06 Beecham Group Plc Pharmaceutical formulation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9300898A1 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011142731A2 (fr) 2010-05-14 2011-11-17 Mahmut Bilgic Formulations comprenant une céphalosporine et un acide clavulanique de troisième génération
WO2011142730A1 (fr) 2010-05-14 2011-11-17 Mahmut Bilgic Composition pharmaceutique comprenant la céfixime et un composé dérivé de l'acide clavulanique
WO2011152808A1 (fr) 2010-06-03 2011-12-08 Mahmut Bilgic Formulation comprenant du cefpodoxime proxétil et de l'acide clavulanique

Also Published As

Publication number Publication date
WO1993000898A1 (fr) 1993-01-21
AU2230692A (en) 1993-02-11
GB9114950D0 (en) 1991-08-28
JPH06508844A (ja) 1994-10-06

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