WO1996004907A1 - Composition pharmaceutique - Google Patents

Composition pharmaceutique Download PDF

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Publication number
WO1996004907A1
WO1996004907A1 PCT/EP1995/003150 EP9503150W WO9604907A1 WO 1996004907 A1 WO1996004907 A1 WO 1996004907A1 EP 9503150 W EP9503150 W EP 9503150W WO 9604907 A1 WO9604907 A1 WO 9604907A1
Authority
WO
WIPO (PCT)
Prior art keywords
granules
core
antibiotic
granule
coating
Prior art date
Application number
PCT/EP1995/003150
Other languages
English (en)
Inventor
David Roy Merrifield
Steven White
Ernest Lionel Gilbert Rivett
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 JP8507001A priority Critical patent/JPH10504295A/ja
Priority to EP95929820A priority patent/EP0776205A1/fr
Publication of WO1996004907A1 publication Critical patent/WO1996004907A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • 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 for oral administration, comprising an antibiotic and a ⁇ -lactamase inhibitor.
  • Oral formulations of this type are known, but generally need to be administered three times daily. It is desirable to produce such a formulation in a delayed or sustained release form which may be suitable for less frequent administration.
  • a particularly effective ⁇ -lactamase inhibitor is the known compound clavulanic acid and its derivatives (hereinafter collectively termed "clavulanate” unless otherwise specifically identified), especially the potassium salt of clavulanic acid, but clavulanate is very sensitive to moisture. It is therefore desirable to provide clavulanate in an oral formulation in which the clavulanate has improved resistance to environmental moisture.
  • the invention therefore provides a pharmaceutical granule, comprising a core which comprises a ⁇ -lactam antibiotic and a ⁇ -lactamase inhibitor, and a surrounding layer around the core, the surrounding layer having a different composition to the core and comprising antibiotic.
  • Preferred ⁇ -lactam antibiotics are ⁇ -lactam antibiotics, for example penicillins and cephalosporins, in particular amoxycillin, for example in the form of amoxycillin trihydrate.
  • a preferred ⁇ -lactamase inhibitor is clavulanate, particularly potassium clavulanate.
  • the ratio antibiotic : ⁇ -lactamase inhibitor may vary between wide limits, in the case of clavulanate for example varying between 1 : 1 to 30 : 1, for example amoxycillin : clavulanate between 1 : 1 to 30 : 1, e.g 2 : 1, 3 : 1, 4 : 1, 5 : 1, 6 : 1, 7 : 1 or 8 : 1 inclusive expressed as the equivalent weight ratios of the parent free acids.
  • the core may suitably contain a ratio amoxycillin : clavulanate between 1 : 1 to 4 : 1.
  • the core may be made by a conventional granulating process as known in the art.
  • the core is made by a dry granulation procedure for example slugging then milling, or by roller compaction then milling.
  • the core may include conventional additives introduced as a result of the granulation process, e.g. lubricants such as magnesium stearate, in conventional quantities, e.g. ca. 1 wt% of magnesium stearate.
  • the core is a core granule of 10 - 40 mesh size, for example 12 - 30 mesh size.
  • the surrounding layer may suitably comprise the same antibiotic as is used in the core, for example a ⁇ -lactam antibiotic such as amoxycillin trihydrate.
  • the layer may suitably be applied to the core as a mixture of antibiotic with a granulating material, particularly of a type which assists spray granulation, such as cellulose derivatives, e.g. ethylcelluloses, hydroxypropylcelluloses, hydroxypropyl- methylcelluloses or polyvinylpyrrolidone etc or mixtures thereof.
  • a plasticiser material such as propylene glycol, acetyltriethylcitrate, triethyl citrate, dibutyl sebucate, diethylphthalate etc, and dissolved or suspended in a suitable solvent such as water or an organic solvent.
  • the layer may consequently include such materials as well as the antibiotic.
  • Examples of combinations of granulating material and plasticiser include hydroxypropyl celluloses, hydroxypropylmethyl celluloses and ethyl celluloses, mixed with propylene glycol or acetyltriethylcitrate.
  • the ratio of antibiotic : granulating material : plasticiser in the layer may be in the range 5-10 : 1 - 2 : 1-2 by weight.
  • the rate of dissolution of the surrounding layer and/or permeability of the layer to water may be varied.
  • the ratio antibiotic : ⁇ -lactamase inhibitor may also vary between wide limits, in the case of clavulanate for example varying between 30 : 1 to 1 : 1 , for example amoxycillin : clavulanate between 30 : 1 to 1 : 1, e.g 1 : 1, 2 : 1, 3 : 1, 4 : 1, 5 : 1, 6 : 1, 7 : 1 or 8 : 1 expressed as equivalent weight ratios of the parent free acids.
  • the overall ratio may be in the range around (e.g. ⁇ 10%) 2 : 1 to 4 : 1.
  • a ratio of around 4 : 1 may be achieved by using a core having a ratio around 3.2 : 1, with a surrounding layer which contains enough amoxycillin to bring the overall ratio up to around 4 : 1.
  • a ratio of around 2 : 1 may be achieved by using a core having a ratio around 1 : 1, with a surrounding layer which contains enough amoxycillin to bring the overall ratio up to around 2 : 1.
  • the granule is preferably coated with a coating layer of a dissolution- retarding coating.
  • This coating may be a polymeric material, for example an enteric polymer (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).
  • An enteric coating may be an essentially conventional coating material known for enteric coating of antibiotic granules, for example enteric polymers such as cellulose acetate phthalate, cellulose acetate succinate, methylcellulose phthalate, ethylhydroxycellulose phthalate, polyvinylacetate phthalate, polyvinylbutyrate acetate, vinyl acetate-maleic anhydride copolymer, styrene-maleic mono-ester copolymer, methyl acrylate-methacrylic acid copolymer, methacrylate-methacrylic acid-octyl aery late copolymer, etc. These may be used either alone or in combination, or together with other polymers than those mentioned above.
  • enteric polymers such as cellulose acetate phthalate, cellulose acetate succinate, methylcellulose phthalate, ethylhydroxycellulose phthalate, polyvinylacetate phthalate, polyvinylbutyrate acetate, vinyl acetate-male
  • the enteric coating may also include insoluble substances which are neither decomposed nor solubilized in living bodies, such as alkyl cellulose derivatives such as ethyl cellulose, crosslinked polymers such as styrene-divinylbenzene copolymer, polysaccharides having hydroxyl groups such as dextran, cellulose derivatives which are treated with bifiinctional crosslinking agents such as epichlorohydrin, dichlorohydrin, 1, 2-, 3, 4-diepoxy butane, etc.
  • the enteric coating may also include starch and/or dextrin.
  • enteric coating materials are the commercially available "Eudragit” (Trade Mark) enteric polymers, such as “Eudragit L” (Trade Mark), “Eudragit S” (Trade Mark), and “Eudragit NE” (Trade Mark) or mixtures thereof used either alone or with a plasticiser.
  • Such coatings are normally applied using a liquid medium, and the nature of the plasticiser, depends upon whether the medium is aqueous or non-aqueous.
  • Aqueous plasticisers include propylene glycol or "Citroflex” or Citroflex A2" (Trade Marks) (mainly triethyl citrate or acetyl triethyl citrate).
  • Non-aqueous plasticers include these, and also diethyl and dibutyl phthalate, and dibutyl sebacate.
  • the quantity of plasticiser included will be apparent to those skilled in the art.
  • the enteric coating may also include an anti-tack agent such as talc, silica or glyceryl monostearate.
  • the quantity of plasticiser and anti-tack agent may be generally conventional to the art.
  • the coating may include around 10 - 25 wt. % plasticiser and up to around 50 wt% of anti tack agent, e.g. 5 - 20 wt. % of anti-tack agent.
  • the enteric coating may be applied to the granules by dissolving or suspending the enteric coating materials in a suitable medium, such as water, methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, methylene dichloride, ethylene chloride, ethyl acetate, etc. or mixtures thereof, and the resultant solution or suspension may be sprayed on the granules to coat them, followed by drying sufficiently with an air flow and screening.
  • a suitable medium such as water, methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, methylene dichloride, ethylene chloride, ethyl acetate, etc. or mixtures thereof.
  • the enteric coating material may be dissolved or suspended in a solvent for example water and coated onto the granules using a fluidised bed system. If water is used, preferably an anti-foaming agent such as activated polymethylsiloxane is also included.
  • a suitable organic solvent is a propanol-methylene dichloride mixture.
  • the coating layer may be applied sequentially to the granules, in a batch or continuous process.
  • the granules may be removed from the equipment being used to apply the surrounding layer and coated later.
  • the nature of the coating solution or suspension may be changed after application of a suitable quantity of the surrounding layer.
  • the surrounding layer may be pre-treated to apply a hydrophobic material such as a wax, a stearate or a silicone, prior to application of the coating layer, to reduce the rate of water ingress into the granule.
  • a hydrophobic material such as a wax, a stearate or a silicone
  • the core may comprise some 30 - 65 wt. % . of the overall granule weight.
  • the surrounding layer may comprise some 15 - 40 wt. % of the overall granule weight.
  • the coating layer may comprise 15 - 40 wt. % of the overall granule weight.
  • the invention therefore also provides a method for the preparation of such a granule, which method comprises forming a core which comprises an antibiotic and a ⁇ -lactamase inhibitor, and forming thereon a surrounding layer around the core, the surrounding layer having a different composition to the core and comprising antibiotic, and optionally also coating the granule with a coating layer of a dissolution-retarding coating.
  • the granules of the invention may be made up into a formulation for oral administration, including appropriate additives and/or pharmaceutically aceptable carriers, in a number of forms.
  • One form is a compressed tablet formulation comprising granules of the invention dispersed in a matrix which include a ⁇ -lactam antibiotic, optionally but preferably together with a ⁇ -lactamase inhibitor, which may be the same antibiotic and/or ⁇ -lactamase inhibitor which are used in the granule of the invention.
  • a preferred marix antibiotic is amoxycillin, for example amoxycillin trihydrate, and a preferred matrix ⁇ -lactamase inhibitor is clavulanate, particularly potassium clavulanate.
  • the ratio antibiotic : ⁇ -lactamase inhibitor may vary between wide limits, for example between 1 : 1 to 30 :1, for example amoxycillin: clavulanate between 1:1 to 12:1, e.g. 2:1, 3:1, 4: 1, 5: 1, 6:1, 7:1 or 8:1 inclusive expressed as the equivalent weight ratios of the parent free acids.
  • the matrix amoxycillin : clavulanate ratio is between 2:1 and 4:1.
  • the overall amoxycillin : clavulanate ratio in the tablet may suitably be in the range 1: 1 to 30:1, for example amoxycillinxlavulanate between 1:1 to 12:1, 3:1, 4:1, 5:1, 6:1, 7:1, or 8:1 inclusive expressed as the equivalent weight ratios of the parent free acids.
  • the overall tablet amoxycillinxlavulanate ratio may be in the range 2:1 to 8:1.
  • matrix amoxycillin may be in the ratio 2:1 to 1:2, typically around 1.5:1 ⁇ 10%
  • matrix clavulanate may also be in the ratio 2:1 to 1:2, typically around 1.5:1 ⁇ 10%
  • the matrix in such a tablet may also include diluents such as calcium carbonate, magnesium carbonate, dicalcium phosphate or mixtures thereof, binders such as hydroxypropylmethylcellulose, hydroxy-propylcellulose, polyvinyl ⁇ pyrrolidone, pre-gelatinised starch or gum acacia or mixtures thereof, disintegrants such as cross-linked polyvinylpyrrolidone, sodium starch glycoUate, croscarmellose sodium or mixtures thereof, lubricants, such as magnesium stearate or stearic acid, glidants or flow aids, such as colloidal silica, talc or starch, stabilisers such as desiccating amorphous silica, suspending agents, and compression aids such as microcrystalline cellulose, in conventional amounts.
  • diluents such as calcium carbonate, magnesium carbonate, dicalcium phosphate or mixtures thereof
  • binders such as hydroxypropylmethylcellulose, hydroxy-propylcellulose
  • the invention further provides a method for making such a tablet, comprising admixing the granules of the invention and a ⁇ -lactam antibiotic, and compressing the mixture into a tablet.
  • a tablet may advantageously produce a sustained release effect, whereby antibiotic and inhibitor are released initially from the matrix, then subsequently or more slowly from the granules. If the granules are coated with an enteric polymer, release may be delayed until the granules pass into the intestine.
  • Another form is a rapidly-dispersing tablet for swallowing directly, which may comprise compacted granules of this invention. Methods of compacting granules to form a tablet are well known in the art.
  • Such tablets may be made by any substantially conventional tabletting process, eg compaction of the matrix materials, the granules and any other additives in a tabletting press. During compaction some loss of integrity on crushing of some of the granules may occur, but tablets including such crushed granules are included within the scope of this invention. Such loss of integrity may be reduced by the use of known compaction acids such as starch and microcrystalline celluloses in the matrix.
  • a chewable tablet Another form is a chewable tablet.
  • Appropriate additives comprise a chewable base such as mannitol, microcrystalline cellulose or sorbitol, or mixtures thereof, binders such as polyvinylpyrrolidone (eg Kollidon K12-K30, Trade Mark), an optional disintegrant such as sodium starch glycoUate, cross-linked polyvinyl- pyrrolidone, croscarmellose sodium or mixtures thereof, lubricants such as magnesium stearate or stearic acid, glidants or flow aids, such as colloidal silica, talc or starch, and stabilisers such as desiccating amorphous silica.
  • binders such as polyvinylpyrrolidone (eg Kollidon K12-K30, Trade Mark)
  • an optional disintegrant such as sodium starch glycoUate, cross-linked polyvinyl- pyrrolidone, croscarmellose sodium or mixtures
  • Such a chewable tablet may alternatively be made up as a fizzy chewable tablet by incorporating into it an effervescent couple, ie a mixture of an acid and a carbonate that evolves carbon dioxide on contact with water.
  • Typical acids include citric and tartaric acid
  • typical carbonates include sodium hydrogen carbonate, sodium glycine carbonate and sodium carbonate.
  • a disintegrant such as those mentioned above into such a fizzy chewable tablet, a fizzy chewable dispersible tablet may be produced.
  • Such chewable, fizzy chewable and fizzy chewable dispersible tablets may be made by essentially conventional processes apparent to those skilled in the art.
  • Another form is an oral suspension, i.e. containing the components in a liquid vehicle for swallowing.
  • Appropriate additives comprise diluents such as methylcellulose, sorbitol, mannitol or starch, or mixtures thereof, suspending agents, such as sodium carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropyl- methylcellulose, gum acacia or mixtures thereof, sweetening agents such as sodium saccharin, sodium cyclamate, acesulfane-K, aspartame or mixtures thereof, preservatives, such as sodium benzoate, sorbic acid, lower alkyl derivatives of p-hydroxybenzoate, flow modifiers such as colloidal silica or amorphous silica, stabilisers, such as desiccating amorphous silica, suspending agents, and colouring and flavouring agents to conventional amounts.
  • suspending agents such as sodium carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropyl- methylcellulose, gum acacia or mixtures thereof
  • sweetening agents such as sodium saccharin
  • Oral suspensions may be made up from such ingredients into a liquid vehicle in an entirely conventional manner.
  • Another form is a single dose sachet for make up into an aqueous suspension for swallowing immediately prior to dosing.
  • the chemical nature of the additives may be the same as for the oral suspension described immediately above, typically diluents, sweetening agents, flow modifiers, stabilisers, and colouring and flavouring agents to conventional amounts.
  • the sachet for such formulations may be entirely conventional but they are advisably substantially airtight to exclude atmospheric moisture.
  • Another form is swallowable granules, i.e. dry granules for swallowing directly, e.g. washed down with water. Alternatively the granules could be sprinkled onto a meal.
  • Appropriate additives for this form comprise, diluents, such as mannitol, microcrystalline cellulose or sorbitol, or mixtures thereof, binders such as polyvinylpyrrolidone (e.g.
  • Kollidon K12-K30 or VA64, Trade Marks disintegrants such as sodium starch glycoUate, cross-linked polyvinylpyrrolidone or croscarmellose sodium or mixtures thereof, lubricants such as magnesium stearate or stearic acid, glidants or flow aids such as colloidal silica, talc or starch, and stabilisers such as dessicating amporphous silica, sweeteners and flavours to suit local tastes.
  • disintegrants such as sodium starch glycoUate, cross-linked polyvinylpyrrolidone or croscarmellose sodium or mixtures thereof
  • lubricants such as magnesium stearate or stearic acid
  • glidants or flow aids such as colloidal silica, talc or starch
  • stabilisers such as dessicating amporphous silica, sweeteners and flavours to suit local tastes.
  • the components and additives may be made up into swallowable granules in an essentially conventional manner using for example water, an aqueous solution of a binder, pharmaceutically permitted organic solvents or a solution of a binder in such a solvent.
  • Another form comprises a capsule formulation in which the first, second, third and optionally fourth components are contained within a water-soluble capsule, e.g. of gelatin.
  • a chewable bar comprises a bar substrate, such as an oil or cellulose based or other carbohydrate based substance capable of being formed of low temperatures and low moisture content into a bar with suitable organoleptic properties, a sweetener to form the bulk of the bar such as mannitol, and an intense sweetener such as saccharin or aspartame.
  • the coating layer material is preferably selected so as to withstand compaction. Some loss of integrity of the coating material may take place during compaction.
  • the above-described formulations may comprise solely granules of the invention, in which case such granules may be all essentially identical, or else the granules may differ, for example in their relative antibiotic and/or ⁇ -lactamase inhibitor content, the distribution of antibiotic between the core and the surrounding layer, die ratios of antibiotic and ⁇ -lactamase inhibitor, the dimensions of the core, surrounding layer and/or the coating, size etc..
  • the formulations may include antibiotic or ⁇ - lactamase inhibitor present in particles, e.g. powder and/or granules, other than the above-described granules of this invention and for example having different dissolution characteristics to the granules of the invention.
  • antibiotic or ⁇ - lactamase inhibitor present in particles, e.g. powder and/or granules, other than the above-described granules of this invention and for example having different dissolution characteristics to the granules of the invention.
  • the above-mentioned formulations for oral administration may contain quantities of antibiotic and ⁇ -lactamase inhibitor up to the maximum amount allowed by regulatory authorities.
  • the total amount of amoxycillin may be 875 - ⁇ 100 mg (expressed as the parent free acids), and of clavulanate 250 mg for a daily dose, divided up between one or more unit dosage forms.
  • Clavulanic acid and its derivatives, e.g. salts such as potassium clavulanate are extremely moisture sensitive, and all operations carried out to prepare granules and formulations of this invention which contain clavulanate should be carried out under conditions of low relative humidity, e.g. less than 30% RH, ideally as low as possible.
  • the present invention also provides a pharmaceutical formulation as described herein for use as an active therapeutic substance.
  • the present invention also provides a pharmaceutical formulation as described herein for use in the treatment of bacterial infections.
  • the present invention also provides the use of a granule or formulation as described herein in the manufacture of a medicament for use in the treatment of bacterial infections.
  • the present invention also provides a mediod of treatment of bacterial infections in humans or animals which comprises the administration of an effective amount of a pharmaceutical formulation as described herein.
  • Fig 1 shows a cross section through a granule of the invention
  • Fig 2 shows a cross section through a tablet of the invention.
  • the granule of Fig 1 consists of a core 1 , a surrounding layer 2 and a coating 3.
  • the tablet of Fig 2 consists of the granules of Fig 1 , 4 dispersed within a matrix 5.
  • Figs 1 and 2 although the granules are shown as spherical, in practice they may have irregular shapes, and the size of the granules 4 is greatly exaggerated relative to the size of the overall tablet.
  • the ingredients for die core granules were dry blended, then dry granulated by slugging and milling. Granules between 12 and 30 mesh were retained for application of the surrounding layer.
  • the core granules were coated with the amoxycillin (dispersed in a solvent system with the binder and plasticiser) in a fluidised bed coater and retained for final enteric coating.
  • the granules were men coated with Eudragit L30D (trade mark), in an aqueous system with additional plasticiser and anti-tack agents, in a fluidised bed coater.
  • the components were dry blended ⁇ en slugged.
  • the slugs are reduced by milling.
  • Granules between 16-30 mesh size are retained as the final product.
  • the granules are stored double wrapped in polythene with dessicant between the layers in a dessicated fibreboard keg.
  • the granules from 2 were coated wid Eudragit by co-current spraying in a fluidised bed.
  • Microcrystalline cellulose (Avicel q.s.*
  • the components were screened and blended, and compressed to prepare oval tablets 19.0 x 9.0 mm, nominal weight 1000 mg having the structure shown in Fig 2.
  • This formulation provides a 100/150 mg split between quick and delayed release amoxycillin and a 25/37.5 mg split between quick and delayed release clavulanate.
  • the delayed release granules from 3 contain 4:1 amoxycillinxlavulanate.

Abstract

L'invention concerne des compositions pharmaceutiques destinées à être administrées par voies orales, comprenant un antibiotique et un inhibiteur de β-lactamase, se présentant sous la forme d'un noyau contenant une β-lactamine et un inhibiteur de β-lactamase, ce noyau étant enrobé d'une couche.
PCT/EP1995/003150 1994-08-17 1995-08-08 Composition pharmaceutique WO1996004907A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP8507001A JPH10504295A (ja) 1994-08-17 1995-08-08 医薬処方
EP95929820A EP0776205A1 (fr) 1994-08-17 1995-08-08 Composition pharmaceutique

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9416599.0 1994-08-17
GB9416599A GB9416599D0 (en) 1994-08-17 1994-08-17 Pharmaceutical formulation

Publications (1)

Publication Number Publication Date
WO1996004907A1 true WO1996004907A1 (fr) 1996-02-22

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Application Number Title Priority Date Filing Date
PCT/EP1995/003150 WO1996004907A1 (fr) 1994-08-17 1995-08-08 Composition pharmaceutique

Country Status (4)

Country Link
EP (1) EP0776205A1 (fr)
JP (1) JPH10504295A (fr)
GB (1) GB9416599D0 (fr)
WO (1) WO1996004907A1 (fr)

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996034605A1 (fr) * 1995-05-03 1996-11-07 Smithkline Beecham Plc Compositions a base d'amoxycilline et d'acide clavulanique
WO2001047499A1 (fr) * 1999-12-23 2001-07-05 Smithkline Beecham P.L.C. Preparations pharmaceutiques comprenant de l'amoxycilline de sodium et du clavulanate de potassium
US6299903B1 (en) * 1994-08-17 2001-10-09 Smithkline Beecham P.L.C. Delayed release pharmaceutical formulation containing a β-lactam antibiotic
GB2351661B (en) * 1999-04-13 2001-10-10 Beecham Pharma Novel method of treatment
WO2002019991A1 (fr) * 2000-09-07 2002-03-14 Röhm GmbH & Co. KG Forme pharmaceutique multiparticualire et son procede de preparation
US6358528B1 (en) 1994-04-14 2002-03-19 Smithkline Beecham P.L.C. Pharmaceutical formulation
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
WO2006072424A1 (fr) * 2005-01-03 2006-07-13 Nextpharma Gmbh Composition pharmaceutique pour une liberation controlee de ?-lactamines en association avec des inhibiteurs de ?-lactamase
EP1701705A2 (fr) * 2003-12-24 2006-09-20 Advancis Pharmaceutical Corporation Absorption amelioree de formes de dosage a liberation modifiee

Families Citing this family (1)

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Publication number Priority date Publication date Assignee Title
KR101931489B1 (ko) * 2012-10-12 2018-12-24 이에이 파마 가부시키가이샤 칼슘 길항약／안지오텐신 ｉｉ 수용체 길항약 함유 의약 제제의 제조 방법

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GB2005538A (en) * 1977-10-11 1979-04-25 Beecham Group Ltd Compositions containing amoxycillin trihydrate and potassium clavulanate
EP0080862A1 (fr) * 1981-12-02 1983-06-08 Beecham Group Plc Préparation pharmaceutique contenant des antibiotiques béta-lactame
WO1991015197A1 (fr) * 1990-04-07 1991-10-17 Beecham Group Plc Formulation pharmaceutique
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EP0080862A1 (fr) * 1981-12-02 1983-06-08 Beecham Group Plc Préparation pharmaceutique contenant des antibiotiques béta-lactame
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US6358528B1 (en) 1994-04-14 2002-03-19 Smithkline Beecham P.L.C. Pharmaceutical formulation
US6838094B2 (en) 1994-04-14 2005-01-04 Smithkline Beecham P.L.C. Tablet containing a coated core
US6299903B1 (en) * 1994-08-17 2001-10-09 Smithkline Beecham P.L.C. Delayed release pharmaceutical formulation containing a β-lactam antibiotic
WO1996034605A1 (fr) * 1995-05-03 1996-11-07 Smithkline Beecham Plc Compositions a base d'amoxycilline et d'acide clavulanique
EP1013274A2 (fr) 1995-05-03 2000-06-28 Smithkline Beecham Plc Composition comprenant amoxycillin et acide clavulanique
US6726908B2 (en) 1995-09-07 2004-04-27 Smithkline Beecham P.L.C. Pharmaceutical formulation
US7217430B2 (en) 1999-04-13 2007-05-15 Beecham Pharmaceuticals (Pte) Limited Compositions and methods of treatment comprising amoxicillin and potassium clavulanate with xanthan
GB2351661B (en) * 1999-04-13 2001-10-10 Beecham Pharma Novel method of treatment
US6660299B2 (en) 1999-04-13 2003-12-09 Beecham Pharmaceuticals Limited Modified release pharmaceutical formulation comprising amoxycillin
US6746692B2 (en) 1999-04-13 2004-06-08 Beecham Pharmaceuticals (Pte) Limited Modified release pharmaceutical formulation comprising amoxycillin
US6783773B1 (en) 1999-04-13 2004-08-31 Beecham Pharmaceuticals (Pte) Limited Composition comprising amoxicillin and potassium clavulanate
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
WO2001047499A1 (fr) * 1999-12-23 2001-07-05 Smithkline Beecham P.L.C. Preparations pharmaceutiques comprenant de l'amoxycilline de sodium et du clavulanate de potassium
WO2002019991A1 (fr) * 2000-09-07 2002-03-14 Röhm GmbH & Co. KG Forme pharmaceutique multiparticualire et son procede de preparation
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
EP1701705A2 (fr) * 2003-12-24 2006-09-20 Advancis Pharmaceutical Corporation Absorption amelioree de formes de dosage a liberation modifiee
EP1701705A4 (fr) * 2003-12-24 2007-08-08 Advancis Pharmaceutical Corp Absorption amelioree de formes de dosage a liberation modifiee
AU2004308419B2 (en) * 2003-12-24 2011-06-02 Victory Pharma, Inc. Enhanced absorption of modified release dosage forms
WO2006072424A1 (fr) * 2005-01-03 2006-07-13 Nextpharma Gmbh Composition pharmaceutique pour une liberation controlee de ?-lactamines en association avec des inhibiteurs de ?-lactamase

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JPH10504295A (ja) 1998-04-28
EP0776205A1 (fr) 1997-06-04
GB9416599D0 (en) 1994-10-12

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