WO1993000898A1 - Pharmaceutical formulation of a beta-lactam antibiotic and clavulanic acid or a water-soluble salt thereof - Google Patents

Pharmaceutical formulation of a beta-lactam antibiotic and clavulanic acid or a water-soluble salt thereof Download PDF

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Publication number
WO1993000898A1
WO1993000898A1 PCT/GB1992/001207 GB9201207W WO9300898A1 WO 1993000898 A1 WO1993000898 A1 WO 1993000898A1 GB 9201207 W GB9201207 W GB 9201207W WO 9300898 A1 WO9300898 A1 WO 9300898A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical formulation
acid
salt
formulation according
dicarboxylic acid
Prior art date
Application number
PCT/GB1992/001207
Other languages
French (fr)
Inventor
David Clapham
Original Assignee
Smithkline Beecham Plc
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 Plc filed Critical Smithkline Beecham Plc
Priority to JP5502080A priority Critical patent/JPH06508844A/en
Priority to EP92914294A priority patent/EP0593573A1/en
Publication of WO1993000898A1 publication Critical patent/WO1993000898A1/en

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    • 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.

Abstract

A pharmaceutical formulation comprising one or more β-lactam antibiotics, clavulanic acid or a water-soluble salt thereof, a pharmaceutically acceptable dicarboxylic acid, and a salt of the dicarboxylic acid in which both acidic hydrogen atoms are replaced by a cation.

Description

PHARMACEUTICAL FORMULATION OF A BETA-LACTAM ANTIBIOTIC AND CLAVULANIC ACID OR A WATER SOLUABLE SALT THEREOF
This invention relates to pharmaceutical formulations, in particular to formulations containing β-lactam antibiotics and the β-lactamase inhibitor clavulanic acid or derivatives thereof, especially aqueous suspension formulations.
Pharmaceutical formulations containing a β-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.
At present the pH of pharmaceutical formulations containing clavulanic acid in suspension or solution is modified by including succinic acid in the formulation. Attempts have been made to further control the pH by the use of buffer salts, but it is found that many commonly used pharmaceutically acceptable buffer salts such as phosphate, citrate, carbonate etc have a catalytic effect deleterious to the stability of the clavulanic acid, and moreover the increased ionic strength of the suspension is also believed to be deleterious to clavulanic acid stability.
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.
Accordingly the invention provides a pharmaceutical formulation comprising;
one or more β-lactam antibiotics;
clavulanic acid or a water-soluble salt thereof;
a pharmaceutically acceptable dicarboxylic acid, and;
a salt of the dicarboxylic acid in which both acidic hydrogen atoms are replaced by a cation.
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 β-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.
Typically 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. In an aqueous suspension or solution formulation the 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. Typically formulations for oral administration are administered in unit doses of around 5ml spoonfuls or as paediatric drops for small children. Typically 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. When 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.
Typical pharmaceutically acceptable dicarboxylic acids are those having a general formula HOOC.(CH2)nCOOH wherein n is 1-6 and in which two adjacent (CH2) groups may be replaced by CH=CH, for example succinic acid, malonic acid, maleic acid and fumaric acid. Of these succinic acid is preferred.
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. Alternatively 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.
Typically 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. Typically in an aqueous suspension or solution formulation 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. When 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. For example 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. 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 β-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 β-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.
The invention will now be described by way of example only. In these examples the abbreviation (fa) as used in connection with amoxycillin trihydrate and potassium clavulanate indicates that the weight is expressed as the equivalent of free acid, ie respectively amoxycillin and clavulanic acid.
Figure imgf000007_0001
A unit dose of 5ml of this suspension contains 156 mg of amoxycillin clavulanic acid combination.
Figure imgf000008_0001
This suspension contains 112.5 mg per ml of amoxycillin clavulanic acid combination.
Figure imgf000009_0001
A unit dose of 5 ml of this suspension contains 312 mg of amoxycillin/clavulanic acid combination.
The above three suspensions were made up in an entirely conventional manner by adding the ingredients to cold water and stirring. Shaking of the reconstituted suspension immediately prior to administration was found to be desirable to ensure resuspension.
Figure imgf000010_0001
A unit dose of 5ml of this suspension contains 187 mg of amoxycillin clavulanic acid combination.

Claims

Claims
1. A pharmaceutical formulation comprising; one or more β-lactam antibiotics; clavulanic acid or a water-soluble salt thereof; a pharmaceutically acceptable dicarboxylic acid, and; a salt of the dicarboxylic acid in which both acidic hydrogen atoms are replaced by a cation.
2. A pharmaceutical formulation according to claim 1 wherein the β- lactam antibiotic is amoxycillin or ampicillin.
3. A pharmaceutical formulation according to claim 1 or 2 wherein the clavulanic acid is in the form of potassium clavulanate.
4. A pharmaceutical formulation according to any one of the preceding claims wherein the ratio of antibiotic : clavulanic acid is in the range 12 :
1 to 1 : 1.
5. A pharmaceutical formulation according to any one of the preceding claims wherein the dicarboxylic acid has a general formula HOOC.(CH2)n-COOH wherein n is 1-6 and in which two adjacent (CH2) groups may be replaced by CH = CH.
6. A pharmaceutical formulation according to claim 5 wherein the dicarboxylic acid is selected from succinic acid, maleic acid, malonic acid and fumaric acid.
7. A pharmaceutical formulation according to any one of the preceding claims wherein the dicarboxylic acid salt is of a divalent cation which replaces both acidic hydrogen atoms.
8. A pharmaceutical formulation according to any one of claims 1-6 in which in the salt of the dicarboxylic acid each acidic hydrogen atom is replaced by a single monovalent cation.
9. A pharmaceutical formulation according to claim 8 wherein the salt of the dicarboxylic acid is disodium succinate.
10. A pharmaceutical formulation according to claim 9 wherein the molar ratio succinic acid : disodium succinate is in the range 1 : 33 to 3 : 1.
11. A pharmaceutical formulation according to claim 9 or 10 being an aqueous solution or suspension and having a total molarity of succinic acid and succinate salt in the range 0.001M to 0.01M.
12. A pharmaceutical formulation according to any one of the preceding claims substantially as hereinbefore described with reference to examples l to 4.
13. A process for the preparation of a pharmaceutical formulation as claimed in any one of claims 1 to 12, comprising admixing the β-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.
14. A process for the use of a pharmaceutical formulation as claimed in any one of claims 1 to 12 in the manufacture of a medicament for the treatment of bacterial infections.
15. A pharmaceutical formulation as claimed in any one of claims 1 to 12 for use in the treatment of bacterial infections.
16. 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 claimed in any one of claims 1 to 12.
PCT/GB1992/001207 1991-07-11 1992-07-03 Pharmaceutical formulation of a beta-lactam antibiotic and clavulanic acid or a water-soluble salt thereof WO1993000898A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP5502080A JPH06508844A (en) 1991-07-11 1992-07-03 Pharmaceutical formulations of beta-lactam antibiotics and clavulanic acid or its water-soluble salts
EP92914294A EP0593573A1 (en) 1991-07-11 1992-07-03 Pharmaceutical formulation of a beta-lactam antibiotic and clavulanic acid or a water-soluble salt thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB919114950A GB9114950D0 (en) 1991-07-11 1991-07-11 Pharmaceutical formulation
GB9114950.0 1991-07-11

Publications (1)

Publication Number Publication Date
WO1993000898A1 true WO1993000898A1 (en) 1993-01-21

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EP (1) EP0593573A1 (en)
JP (1) JPH06508844A (en)
AU (1) AU2230692A (en)
GB (1) GB9114950D0 (en)
WO (1) WO1993000898A1 (en)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998024414A1 (en) * 1996-12-05 1998-06-11 American Home Products Corporation Pharmaceutical suspension systems
WO1998036732A2 (en) * 1997-02-21 1998-08-27 Lindopharm Gmbh Combination preparation for orally administered antibiotics
WO2000010527A1 (en) * 1998-08-24 2000-03-02 The Procter & Gamble Company Oral mucoadhesive compositions containing gastrointestinal actives
US6660299B2 (en) 1999-04-13 2003-12-09 Beecham Pharmaceuticals Limited Modified release pharmaceutical formulation comprising amoxycillin
US6726908B2 (en) 1995-09-07 2004-04-27 Smithkline Beecham P.L.C. Pharmaceutical formulation
US6746692B2 (en) 1999-04-13 2004-06-08 Beecham Pharmaceuticals (Pte) Limited Modified release pharmaceutical formulation comprising amoxycillin
US6756057B2 (en) 2000-10-12 2004-06-29 Beecham Pharmaceuticals (Pte) Limited Amoxicillin and potassium clavulanate dosage form
US6783773B1 (en) 1999-04-13 2004-08-31 Beecham Pharmaceuticals (Pte) Limited Composition comprising amoxicillin and potassium clavulanate
US7011849B2 (en) 2000-10-12 2006-03-14 Beecham Pharmaceuticals (Pte) Limited Second release phase formulation
US20130028844A1 (en) * 2010-01-29 2013-01-31 Mahmut Bilgic Preparations for effervescent formulations comprising cephalosporin and uses thereof
US9260375B2 (en) 2005-09-22 2016-02-16 Meiji Seika Kaisha, Ltd. Metallo-β-lactamase inhibitors

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011142730A1 (en) 2010-05-14 2011-11-17 Mahmut Bilgic Pharmaceutical composition comprising cefixime and clavulanic acid derivative compound
EP2568959A2 (en) 2010-05-14 2013-03-20 Mahmut Bilgic Formulations comprising a third generation cephalosporin and clavulanic acid
EP2575777A1 (en) 2010-06-03 2013-04-10 Mahmut Bilgic Formulation comprising cefpodoxime proxetil and clavulanic acid

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0080862A1 (en) * 1981-12-02 1983-06-08 Beecham Group Plc Pharmaceutical formulation comprising beta-lactam antibiotics
WO1991015197A1 (en) * 1990-04-07 1991-10-17 Beecham Group Plc Pharmaceutical formulation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0080862A1 (en) * 1981-12-02 1983-06-08 Beecham Group Plc Pharmaceutical formulation comprising beta-lactam antibiotics
WO1991015197A1 (en) * 1990-04-07 1991-10-17 Beecham Group Plc Pharmaceutical formulation

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6726908B2 (en) 1995-09-07 2004-04-27 Smithkline Beecham P.L.C. Pharmaceutical formulation
WO1998024414A1 (en) * 1996-12-05 1998-06-11 American Home Products Corporation Pharmaceutical suspension systems
WO1998036732A2 (en) * 1997-02-21 1998-08-27 Lindopharm Gmbh Combination preparation for orally administered antibiotics
WO1998036732A3 (en) * 1997-02-21 1998-10-22 Glf Galenik Labor Gmbh Combination preparation for orally administered antibiotics
WO2000010527A1 (en) * 1998-08-24 2000-03-02 The Procter & Gamble Company Oral mucoadhesive compositions containing gastrointestinal actives
US6783773B1 (en) 1999-04-13 2004-08-31 Beecham Pharmaceuticals (Pte) Limited Composition comprising amoxicillin and potassium clavulanate
US6746692B2 (en) 1999-04-13 2004-06-08 Beecham Pharmaceuticals (Pte) Limited Modified release pharmaceutical formulation comprising amoxycillin
US6660299B2 (en) 1999-04-13 2003-12-09 Beecham Pharmaceuticals Limited Modified release pharmaceutical formulation comprising amoxycillin
US6878386B1 (en) 1999-04-13 2005-04-12 Beecham Pharmaceuticals (Pte) Limited Method of treating a bacterial infection comprising amoxycillin and potassium clavulanate
US7217430B2 (en) 1999-04-13 2007-05-15 Beecham Pharmaceuticals (Pte) Limited Compositions and methods of treatment comprising amoxicillin and potassium clavulanate with xanthan
US7250176B1 (en) 1999-04-13 2007-07-31 Beecham Pharmaceuticals (Pte) Limited Method of treating a bacterial infection
US6756057B2 (en) 2000-10-12 2004-06-29 Beecham Pharmaceuticals (Pte) Limited Amoxicillin and potassium clavulanate dosage form
US7011849B2 (en) 2000-10-12 2006-03-14 Beecham Pharmaceuticals (Pte) Limited Second release phase formulation
US9260375B2 (en) 2005-09-22 2016-02-16 Meiji Seika Kaisha, Ltd. Metallo-β-lactamase inhibitors
US20130028844A1 (en) * 2010-01-29 2013-01-31 Mahmut Bilgic Preparations for effervescent formulations comprising cephalosporin and uses thereof
US8956653B2 (en) * 2010-01-29 2015-02-17 Mahmut Bilgic Preparations for effervescent formulations comprising cephalosporin and uses thereof
US9603794B2 (en) 2010-01-29 2017-03-28 Mahmut Bilgic Preparations of effervescent formulations comprising cephalosporin and uses thereof

Also Published As

Publication number Publication date
EP0593573A1 (en) 1994-04-27
AU2230692A (en) 1993-02-11
GB9114950D0 (en) 1991-08-28
JPH06508844A (en) 1994-10-06

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