EP0782443A1 - Formulations pharmaceutiques comprenant de l'acide clavulanique ou des derives et un acide ou sel organique - Google Patents

Formulations pharmaceutiques comprenant de l'acide clavulanique ou des derives et un acide ou sel organique

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Publication number
EP0782443A1
EP0782443A1 EP95931176A EP95931176A EP0782443A1 EP 0782443 A1 EP0782443 A1 EP 0782443A1 EP 95931176 A EP95931176 A EP 95931176A EP 95931176 A EP95931176 A EP 95931176A EP 0782443 A1 EP0782443 A1 EP 0782443A1
Authority
EP
European Patent Office
Prior art keywords
acid
calcium
pharmaceutically acceptable
pharmaceutical formulation
clavulanate
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Withdrawn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
EP95931176A
Other languages
German (de)
English (en)
Inventor
Patrick John Crowley
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
Priority claimed from GB9417953A external-priority patent/GB9417953D0/en
Priority claimed from GBGB9503752.9A external-priority patent/GB9503752D0/en
Application filed by SmithKline Beecham Ltd filed Critical SmithKline Beecham Ltd
Publication of EP0782443A1 publication Critical patent/EP0782443A1/fr
Withdrawn legal-status Critical Current

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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
    • A61K31/424—Oxazoles condensed with heterocyclic ring systems, e.g. clavulanic acid
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • This invention relates to pharmaceutical formulations comprising derivatives of clavulanic acid, and to their use.
  • Clavulanic acid is a ⁇ -lactamase inhibitor, and its pharmaceutically acceptable salts (herein individually and collectively referred to as "clavulanate” unless specific salts are identified) may be formulated in antibacterial medicament formulations with antibiotics, particularly ⁇ -lactam antibiotics, to increase their resistance to the ⁇ -lactamase enzymes produced by certain microorganisms.
  • a widely used pharmaceutically acceptable salt of clavulanic acid is potassium clavulanate, which is commercially co-formulated with the ⁇ -lactam antibiotic amoxycillin, generally in the form of amoxycillin trihydrate, in formulations for oral administration, such as compacted tablets, granules etc..
  • WO 93/00898 discloses formulations of potassium clavulanate with succinic acid and disodium succinate, in which the latter two compounds are used to buffer the pH when the formulation is made up into aqueous solution, with the intention of improving solution stability.
  • An effervescent formulation which is a chewable tablet which includes clavulanate is disclosed in EP 0396335 A, which uses tartaric, citric or malic acid as the acid component of an effervescent couple together with an alkali metal carbonate or bicarbonate.
  • WO 92/19227 discloses compacted tablet formulations which incorporate sodium starch glycollate as a disintegrant at low ratios with the clavulanate.
  • Citrate salts are known for use in rehydrating formulations.
  • US 3873695 discloses a veterinary rehydrating formulation which comprises 8-hydroxyquinoline, an astringent based upon bismuth or aluminium salts, and a rehydrating agent selected from the magnesium, sodium, potassium or calcium salts of organic acids.
  • the present invention is based upon a novel effect observed with co-formulations or co-administrations of clavulanate with salts and salt-like derivatives of organic acids, and novel formulations based upon this effect.
  • a solid pharmaceutical formulation for oral administration comprising in combination clavulanate and a pharmaceutically acceptable organic acid or a pharmaceutically acceptable salt-like derivative thereof or components which can react together to form such a salt-like derivative, with the exclusion: of succinic acid; of tartaric acid, citric acid or malic acid when these acids form a component of an effervescent couple with an alkali metal carbonate or bicarbonate in a chewable tablet; of the combination of disodium succinate and succinic acid; and of sodium starch glycollate in a ratio sodium starch glycollate : clavulanate of ⁇ 1 : 1.4.
  • the invention also provides a method of use of clavulanate, and a pharmaceutically acceptable organic acid or a pharmaceutically acceptable salt-like derivative thereof or such components, subject to the abovementioned exclusion, together in the manufacture of a solid antibacterial medicament formulation.
  • the invention also provides a method for the preparation of a pharmaceutical formulation as defined above, which method comprises admixing the combination of clavulanate and the said pharmaceutically acceptable organic acid and/or a pharmaceutically acceptable salt-like derivative thereof or such components.
  • the invention also provides a pharmaceutical formulation as defined above for use as an active therapeutic substance, particularly in the treatment of bacterial infections in humans or animals.
  • the invention also provides a method of suppressing the gastro intestinal intolerance associated with oral dosing of clavulanate-containing products, the method comprising oral co-administration of clavulanate in combination with a pharmaceutically acceptable organic acid or a pharmaceutically acceptable salt-like derivative thereof or components which can react together to form such a salt-like derivative.
  • the invention also provides a pharmaceutical formulation including clavulanate, in which the gastro intestinal intolerance associated with oral dosing of clavulanate-containing products, is suppressed by a pharmaceutically acceptable organic acid or a pharmaceutically acceptable salt-like derivative thereof.
  • the invention also provides a method of treatment of bacterial infections in humans, which comprises the administration to a patient in need of treatment an effective amount of a pharmaceutical formulation as defined above.
  • the solid pharmaceutical formulations of this invention include tablets, pills, granules, powders etc., including such solid formulations which are intended to be reconstituted to form liquid suspensions for administration to patients, and powder or granulate formulations which are intermediate products for subsequent compaction into tablets.
  • a preferred solid formulation is a compacted tablet formulation, for example made by compaction of powdered and/or granulated ingredients.
  • salt-like derivative refers to salts themselves, and to derivatives of the acid in which acid groups in the acid are ionically associated with cations in any way..
  • the clavulanate is preferably the potassium salt of clavulanic acid, ie potassium clavulanate. Salts of clavulanic acid are very hygroscopic. Therefore potassium clavulanate should be handled under dry conditions, preferably under conditions of low relative humidity, e.g. 30% RH or less, in the manufacture of formulations of this invention.
  • a single pharmaceutically acceptable organic acid or a single pharmaceutically acceptable salt-like derivative thereof may be used, or two or more of such may be used in combination.
  • the organic acid is preferably a pharmaceutically acceptable mono-carboxylic acid, or a pharmaceutically acceptable solid poly-carboxylic acid.
  • the formulations of this invention are solid formulations, and therefore preferred pharmaceutically acceptable organic acids such as mono- and poly- carboxylic acids when used as the free acids in the formulation and method are solid acids.
  • Suitable generic classes and specific examples of pharmaceutically acceptable monocarboxylic acids include solid alkyl mono- and poly- carboxylic acids and aryl mono- and poly- carboxylic acids; pharmaceutically acceptable aminoacids such as glycine; and macromolecular carboxylic acids which include a macromolecular system such as a carbohydrate or polypeptide system, such as pectic acid.
  • the formulation of the invention comprises in combination clavulanate and one or more pharmaceutically acceptable salts of one or more carboxylic acids.
  • Suitable generic classes and specific examples of salts of the abovementioned pharmaceutically acceptable organic, e.g carboxylic, acids include salts with pharmaceutically acceptable cations, particularly cations of Group I or II metals, e.g. sodium, potassium, calcium or magnesium.
  • the organic acid includes two or more carboxylate groups one, some or all of these may form salts with the cation, for example forming acid salts in which some carboxylate groups remain associated with their acid proton, and also if there are more than one acid group these may all form salts with the same or different c?'ion.
  • the cation has two or more positive charges it may ionically associate in the salt-like derivative with two same or different anions of the organic acid.
  • Suitable generic classes of salts of pharmaceutically acceptable carboxylic acids include salts of the following generic classes and specific examples of carboxylic acids: lower, preferably with a Cj.io alkyl chain length or alkyl group size alkylcarboxylic acids, e.g. with a straight, branched or cyclic alkyl chain, e.g. acetic acid, propionic acid, butyric acid, pentanoic acid, hexanoic acid, heptanoic acid and octanoic acid; higher alkylcarboxylic acids such as those with a CI Q-25 carbon chain such as stearic, palmitic, oleic etc.
  • Suitable generic classes and specific example of salts of aromatic acids include salts of monocyclic, and polycyclic aryl, e.g. naphthyl carboxylic acids in which the aryl ring system(s) may be substituted, and in which the one or more carboxylate groups may be linked to the aryl ring(s) either directly or by means of linking groups such as alkyl chains, such as benzoic acid and 6-methoxy- ⁇ -methyl- 2-naphthalene acetic acid.
  • organic acids which comprise an organic moiety such as an alkyl or aryl system (e.g. as defined above) combined with an inorganic acid group such as a phosphoric or sulphonic acid group, such as phytic acid (1, 2, 3, 4, 5, 6-cyclohexanehexolphosphoric acid).
  • Preferred salts are therefore sodium, potassium, magnesium but particularly calcium, salts of lower alkyl mono- and poly- carboxylic acids, lower mono- or poly- hydroxy mono- and poly- carboxylic acids, and monocyclic carboxylic acids with an unsubstituted ring.
  • Suitable specific examples of such salts include: calcium acetate, calcium lactate, calcium propionate, calcium caseinate, calcium ascorbate, calcium gluconate, calcium tartrate, calcium malate, calcium citrate, calcium maleate, calcium benzoate, calcium pectate, calcium sorbate, calcium stearate, calcium levulinate, calcium succinate, sodium lactate, trisodium citrate (e.g in anhydrous form), disodium hydrogen citrate, sodium propionate, sodium stearate, tripotassium citrate, sodium starch glycollate, calcium phytate, disodium edetate, sodium acetate and magnesium lactate.
  • Such salts may be used in their anhydrous or hydrated forms.
  • calcium citrate USP is the tetrahydrate
  • calcium lactate is known as a pentahydrate
  • calcium propionate is known as a mono- and a tri- hydrate
  • calcium succinate is known as a trihydrate.
  • Preferred salts are calcium citrate, calcium lactate, calcium propionate, calcium benzoate, calcium succinate, sodium lactate, trisodium citrate, disodium hydrogen citrate, sodium benzoate, tripotassium citrate, and magnesium lactate, particularly calcium citrate and calcium lactate.
  • the pharmaceutically acceptable salt-like derivative of the organic acid may be used as such, or additionally or alternatively the salt-like derivative may be generated in situ by reaction of components such as an acid or base such as an alkali metal or alkaline earth metal hydroxide, carbonate or hydrogen carbonate which together, e.g. in contact with water, form the derivative.
  • the components may form an effervescent couple, e.g.
  • the organic acid and/or a pharmaceutically acceptable salt-like derivative thereof or components which can react together to form such a salt-like derivative may be used together with, e.g. coformulated with in a formulation, a pharmaceutically a. table acid neutralising material.
  • acid neutralising material used herein includes pharmaceutically acceptable alkalis and bases, i.e. compounds which can potentially combine with acids to produce a salt of the acid plus water. More specifically the term includes materials normally referred to as "antacids" i.e. having the ability to neutralise gastric acidity.
  • acid neutralising materials include the following generally water insoluble materials: Group II metal carbonates, hydrogen carbonates, oxides (other than calcium oxide), hydroxides (other than calcium hydroxide) and silicates, such as magnesium carbonate, calcium carbonate and calcium silicate; Group III metal carbonates, hydrogen carbonates, oxides, hydroxides and silicates, such as aluminium carbonate, aluminium hydrogen carbonate, aluminium oxide, aluminium hydroxide and aluminium silicate (e.g. Kaolin).
  • Such materials may be used singly or in mixtures with other acid neutralising materials, for example a magnesium carbonate/magnesium hydroxide mixture, for example that having the overall stoichiometry (MgCO3)4 Mg(OH)2 5H O.
  • Preferred acid neutralising materials are calcium carbonate and magnesium carbonate. It should be noted however that magnesium salts can themselves cause diarrhea, and the use of magnesium compounds in quantities known to cause diarrhea should be avoided.
  • the combinations calcium citrate 4- calcium carbonate, calcium lactate + calcium carbonate, calcium lactate + magnesium carbonate, and calcium lactate + calcium citrate + calcium carbonate are particularly preferred.
  • the organic acid and/or a pharmaceutically acceptable salt-like derivative thereof or components which can react together to form such a salt-like derivative may be used together with, e.g. coformulated with in a formulation, a pharmaceutically acceptable adsorbent material.
  • Group II metal carbonates, hydrogen carbonates, oxides, hydroxides and silicates, Group III metal carbonates, hydrogen carbonates, oxides, hydroxides and silicates mentioned above have adsorbent properties in addition to their acid neutralising properties and in the formulations and methods of this invention may additionally or alternatively function as adsorbent materials.
  • some forms of aluminium oxide, aluminium hydroxide and aluminium silicate e.g. Kaolin which may indeed have little or no acid neutralising property; molecular sieves, celluloses, Group n/m metal silicates such as calcium aluminosilicates and other clays, and charcoal may for example be used as adsorbent materials.
  • Such materials may be used singly or in mixtures with other acid neutralising materials and/or adsorbent materials.
  • the organic acid and/or a pharmaceutically acceptable salt-like derivative thereof or components which can react together to form such a salt-like derivative may be used together with, e.g coformulated with in a formulation, a pharmaceutically acceptable methacrylic copolymer.
  • Suitable generic classes and specific examples of pharmaceutically acceptable methacrylic acid copolymers are those described in the USP 22/NF 17, and such polymers of types A, B and C as described therein may be suitable.
  • Suitable generic classes and specific examples of pharmaceutically acceptable methacrylic acid copolymer are known polymers which are copolymers of acrylic and methacrylic esters with a low content of quaternary ammonium groups, for example having a molar ratio of such ammonium groups : remaining (meth)acrylic esters of 1 : _ ⁇ . 10, for example around 1 : 20 or 1 : 40, and with a mean molecular weight of around 150000.
  • Such polymers correspond to USP/NF 2 "Ammonio methacrylate copolymers, Type A and Type B".
  • methacrylic acid copolymer examples include polymers which are copolymers, anionic in character, based on methacrylic acid and methyl methacrylate, for example having a ratio of free carboxyl groups : methyl-esterified carboxyl groups of 1 : >3, e.g around 1 : 1 or 1 : 2, and with a mean molecular weight of 135000.
  • Such polymers are sold under the trade name Eudragit TM, such as the
  • Eudragit L series e.g. Eudragit L 12.5 TM, Eudragit L 12.5P TM, Eudragit L100 TM, Eudragit L 100-55 TM, Eudragit L-30 D TM, Eudragit L-30 D-55 TM, the Eudragit S TM series e.g. Eudragit S 12.5, Eudragit S 12.5P TM, Eudragit SI 00 TM, the Eudragit NETM series e.g Eudragit NE 30D *", the Eudragit RL TM series, e.g.
  • enteric polymers the term "enteric polymer” is a term of the art referring to a polymer which is preferentially soluble in the less acid environment of the intestine relative to the more acid environment of the stomach), for example having a solubility in aqueous media at pH 5.5 and above.
  • Suitable pharmaceutically acceptable polymers include for example methyl acrylate-methacrylic acid copolymer, methacrylate-methacrylic acid-octyl acrylate copolymer, etc. These may be used either alone or in combination, or together with other polymers than those mentioned above.
  • the clavulanate is preferably also co ⁇ formulated with an antibiotic compound.
  • the antibiotic compound is suitably a ⁇ - lactam antibiotic such as penicillins, which term as used herein includes antibiotic compounds having a nucleus derived from the penicillin ring system, such as penems and carbapenems; or cephalosporins, which term as used herein includes antibiotic compounds having a nucleus derived from the cephalosporin ring system, such as carbacephs.
  • a preferred ⁇ -lactam antibiotic is amoxycillin, e.g.
  • antibiotics include those suitable for oral admistration selected from: ampicillin, apalcillin, aspoxicillin, azidocillin, azlocillin, aztreonam, benzylpenicillin, bacampicillin, carbenicillin, cloxacillin, cyclacillin, dicloxicillin, epicillin, flucloxacillin, le ampicillin, mecillinam, methicillin, mezlocillin, phenoxymethylpenicillin, piperacillin, pivampicillin, propicillin, sulbenicillin, talampicillin, ticarcillin, cefaclor, cefadroxil, cefatrizine, cefclidine, cefamandole, cefazolin, cefbuperazone, cefcanel daloxate, cefdinir,
  • the weight ratio clavulanate : antibiotic compound in the formulations and methods of this invention may vary within a wide range, e.g. 1 :1 to 1:30, expressed in terms of the free acids.
  • the said ratio may for example be between 1:1 to 1:15, for example 1:1 to 1:12, for example between 1: 1 to 1:8, for example 1 : 4 to 1 :7 by weight.
  • a preferred formulation of the invention is therefore one which contains potassium clavulanate, amoxycillin in the form of its trihydrate or as sodium amoxycillin, within the weight ratio range clavulanate : amoxycillin 1 : 2 to 1 : 12, for example 1 : 4 to 1: 8.
  • the clavulanate, the optional antibiotic material, and the pharmaceutically acceptable organic acid or a pharmaceutically acceptable salt-like derivative thereof or components which can react together to form such a salt-like derivative are consequently preferably formulated together for oral administration, and are preferably administered together by this route.
  • the clavulanate and optional antibiotic material may be formulated and/or administered together and the pharmaceutically acceptable organic acid or a pharmaceutically acceptable salt-like derivative thereof or components which can react together to form such a salt-like derivative may be separately formulated for oral administration and separately orally administered.
  • the constituents comprising such an oral formulation, ie clavulanate, pharmaceutically acceptable organic acid(s) and/or a pharmaceutically acceptable salt-like derivative(s) thereof or components which can react together to form such a salt-like derivative may be formulated for oral administration in various ways.
  • the constituents may for example be formulated simply as a dry powder or granules comprising the constituents, and methods of preparing such a formulation will be apparent to those skilled in the art.
  • Such powders or granules may be presented for example in a dry form in a sachet or capsules.
  • the constituents may be formulated into a compacted tablet, for example including conventional excipients such as fillers, diluents, compaction aids, disintegrants, lubricants, wetting agents, flavours, colourants etc. as are known in the art.
  • Such tablets may also include an effervescent couple, and/or a chewable base.
  • Such tablets may be made by processes well known in the art, for example blending of powdered constituents, granulation eg by slugging or roller compaction, then compaction into a tablet form in a conventional tablet press.
  • Such sachets, capsules or tablets may suitably comprise a unit dosage form, each containing a unit dose of the active constituents.
  • the formulation may be provided as a dry product for reconstitution as a liquid formulation with water or an appropriate vehicle before use.
  • the amount of clavulanate and any antibiotic compound such as amoxycillin included in the formulation may be generally the same as that contained in known formulations containing these.
  • the formulation may contain from 12.5 to lOOOmg (expressed as the free acid), preferably from 12.5 to 250mg of clavulanate, e.g. 12.5, 25, 50, 75, 100, 125, 150, 200 or 250mg of potassium clavulanate.
  • the amount of the antibiotic, for example amoxycillin may be in the range from 125 to 3000 mg (expressed as the free acid), suitably from 125 to lOOOmg.
  • the antibiotic compound may be used in a weight proportion of the overall solid dosage form, such as a compacted tablet, similar to that in which it is conventionally used.
  • the antibiotic may comprise 5 to 80 wt%, e.g. 50 to 80 wt%, and the clavulanate may comprise 0.5 to 30 wt%, of the solid dosage form such as a compacted tablet.
  • Suitable quantities of the pharmaceutically acceptable organic acid and/or a pharmaceutically acceptable salt-like derivative thereof or components which can react together to form such a salt-like derivative for use in the formulations and methods of the present invention vary between wide limits and may be determined by experimentation, for example by clinical trials observing symptoms of gastrointestinal intolerance with various combinations of clavulanate, antibiotic and the pharmaceutically acceptable organic acid and/or a pharmaceutically acceptable salt-like derivative thereof or components which can react together to form such a salt-like derivative.
  • the weight of a pharmaceutical tablet intended for swallowing by a patient it is generally desirable to limit the weight of a pharmaceutical tablet intended for swallowing by a patient to a reasonable size to facilitate swallowing, e.g around 1-2 g maximum per tablet, 1.5 g generally being a comfortable maximum in practice. Consequently the total quantity of the pharmaceutically acceptable organic acid or a pharmaceutically acceptable salt-like derivative thereof or components which can react together to form such a salt-like derivative included in a single tablet may suitably be around 25 - 500 mg, for example around 100 - 300 mg, and for example these quantities may be combined with 100 - 300 mg of the above-described acid neutralising and/or adsorbent materials.
  • the quantity of the pharmaceutically acceptable organic acid and/or a pharmaceutically acceptable salt-like derivative thereof or components which can react together to form such a salt-like derivative may comprise 0.5 - 50 wt% of the solid dosage form such as a compacted tablet, for example 10 - 50 wt% .
  • gastrointestinal intolerance For example reduction of gastrointestinal intolerance may be observed on oral coadministration of clavulanate together with amoxycillin and the above ⁇ mentioned pharmaceutically acceptable organic acid and/or a pharmaceutically acceptable salt-like derivative thereof or components which can react together to form such a salt-like derivative, such as calcium propionate, calcium lactate, calcium citrate or sodium lactate, in ratios of clavulanate : pharmaceutically acceptable organic acid and/or a pharmaceutically acceptable salt-like derivative thereof in the range 10 : 1 to 1 : 10, relative to the gastrointestinal intolerance observed with the oral administration of these amounts of clavulanate and amoxycillin without the salt-like derivative.
  • a salt-like derivative such as calcium propionate, calcium lactate, calcium citrate or sodium lactate
  • the weight ratio potassium clavulanate pharmaceutically acceptable organic acid and/or a pharmaceutically acceptable salt-like derivative thereof or components which can react together to form such a salt-like derivative, such as calcium citrate or calcium lactate, may conveniently but not exclusively range between 1 : 3 and 3 : 1, suitably between 1 : 2 and 2 : 1 inclusive in the solid formulations of this invention.
  • the remaining bulk of the dosage form may be made up to 100 wt% by the above mentioned excipients, which may be used in conventional proportions as known in the art.
  • General methods of making a compacted tablet comprising potassium clavulanate and an antibiotic such as amoxycillin trihydrate, together with the abovementioned excipients are well known, for example as disclosed in GB 2005538A and WO92/ 19227 which disclose methods and formulations such as dry compaction of powders, granulation of the amoxycillin and clavulanate and compaction of the granules or inclusion of the powdered ingredients or granules in a sachet.
  • Example 1 Evaluation of Effects of Agents on intestinal and gastric fluid secretion in the gastro-intestinal system of the rat.
  • the abdomen was opened and the small intestine clamped at the pyloric sphincter and ileocaecal junction; the intestinal segment thus isolated was carefully removed from the abdominal cavity, the length measured .nd then weighed, emptied of its fluid conte ⁇ and reweighed. Enteropooling is expressed as mg. of fluid / cm. of intestine.
  • Gastric fluid secretion or gastric enteropooling was determined according to the following methods. Male Sprague-Dawley rats weighing 200- 300 g were housed in individual wire-bottomed cages to restrict coprophagia. Animals were food deprived for 24 hr prior to perimentation with water provided ad libitum est agents dissolved or suspended in water were administered to conscious rats by gavage at a dose volume of 1 ml. Animals were sacrificed at a standard time, usually 60 min, following dosing.
  • the abdomen was opened and the stomach clamped at the pyloric sphincter and lower esophagal sphincter; the stomach thus isolated was carefully removed from the abdominal cavity, weighed, emptied of its fluid contents and reweighed. Enteropooling is expressed as total grams of fluid.
  • Formulation 1 Component mg per tablet wt%
  • Formulation 2 Component mg per tablet wt%

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Epidemiology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention se rapporte à des formulations pharmaceutiques comprenant des dérivés d'acide clavulanique et à leur utilisation, notamment à des formulations pharmaceutiques solides pour administration orale comprenant en combinaison un cluvanate et un acide organique pharmaceutiquement acceptable ou un dérivé de celui-ci pharmaceutiquement acceptable tel qu'un sel.
EP95931176A 1994-09-03 1995-08-21 Formulations pharmaceutiques comprenant de l'acide clavulanique ou des derives et un acide ou sel organique Withdrawn EP0782443A1 (fr)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
GB9417953 1994-09-03
GB9417953A GB9417953D0 (en) 1994-09-03 1994-09-03 Pharmaceutical formulations
GB9503752 1995-02-24
GBGB9503752.9A GB9503752D0 (en) 1995-02-24 1995-02-24 Pharmaceutical formulations
US46044195A 1995-06-02 1995-06-02
US460441 1995-06-02
PCT/EP1995/003322 WO1996007408A1 (fr) 1994-09-03 1995-08-21 Formulations pharmaceutiques comprenant de l'acide clavulanique ou des derives et un acide ou sel organique

Publications (1)

Publication Number Publication Date
EP0782443A1 true EP0782443A1 (fr) 1997-07-09

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Family Applications (1)

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EP95931176A Withdrawn EP0782443A1 (fr) 1994-09-03 1995-08-21 Formulations pharmaceutiques comprenant de l'acide clavulanique ou des derives et un acide ou sel organique

Country Status (8)

Country Link
EP (1) EP0782443A1 (fr)
JP (1) JPH10505595A (fr)
AU (1) AU3471995A (fr)
DZ (1) DZ1926A1 (fr)
IL (1) IL115125A0 (fr)
MA (1) MA23663A1 (fr)
TR (1) TR199501082A2 (fr)
WO (1) WO1996007408A1 (fr)

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1093812A3 (fr) 1995-09-07 2001-06-06 SmithKline Beecham Corporation Composition pharmaceutique contenant de l'amoxicilline et du clavulanate
IL131201A (en) * 1997-02-14 2005-06-19 Smithkline Beecham Lab Pharmaceutical formulations comprising amoxycillin and clavulanate
US6706290B1 (en) 1998-07-06 2004-03-16 Olvai E. Kajander Methods for eradication of nanobacteria
KR100661413B1 (ko) * 1998-07-06 2006-12-27 나노박 오와이 나노박테리아 박멸 방법
US6878386B1 (en) 1999-04-13 2005-04-12 Beecham Pharmaceuticals (Pte) Limited Method of treating a bacterial infection comprising amoxycillin and potassium clavulanate
US6294199B1 (en) 1999-04-13 2001-09-25 Beecham Pharmaceuticals (Pte) Limited Method of treating a bacterial infection comprising administering amoxycillin
US7250176B1 (en) 1999-04-13 2007-07-31 Beecham Pharmaceuticals (Pte) Limited Method of treating a bacterial infection
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
US8614315B2 (en) * 2009-12-25 2013-12-24 Mahmut Bilgic Cefdinir and cefixime formulations and uses thereof
TR201000688A2 (tr) 2010-01-29 2011-08-22 B�Lg�� Mahmut Aktif madde olarak sefaklor ve klavulanik asit içeren efervesan formülasyonlar.
EP2575782A2 (fr) * 2010-06-03 2013-04-10 Mahmut Bilgic Formulations effervescentes comprenant de la céphalosporine et de l'acide clavulcanique

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2861607D1 (en) * 1977-11-26 1982-03-11 Beecham Group Plc Derivatives of clavulanic acid and pharmaceutical compositions containing them
NZ198241A (en) * 1980-09-27 1983-12-16 Beecham Group Ltd Tablet containing amoxycillin and potassium clavulanate
AU5863894A (en) * 1993-01-22 1994-08-15 Smithkline Beecham Plc Pharmaceutical formulations comprising clavulanic acid alone or in combination with other beta-lactam antibiotics

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Title
See references of WO9607408A1 *

Also Published As

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IL115125A0 (en) 1995-12-31
TR199501082A2 (tr) 1996-06-21
DZ1926A1 (fr) 2002-02-17
AU3471995A (en) 1996-03-27
MA23663A1 (fr) 1996-04-01
JPH10505595A (ja) 1998-06-02
WO1996007408A1 (fr) 1996-03-14

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