WO1999032124A1 - Compositions pharmaceutiques a base de (s)-cefuroxime axetil, et utilisation dans le traitement des infections bacteriennes - Google Patents

Compositions pharmaceutiques a base de (s)-cefuroxime axetil, et utilisation dans le traitement des infections bacteriennes Download PDF

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Publication number
WO1999032124A1
WO1999032124A1 PCT/EP1998/008208 EP9808208W WO9932124A1 WO 1999032124 A1 WO1999032124 A1 WO 1999032124A1 EP 9808208 W EP9808208 W EP 9808208W WO 9932124 A1 WO9932124 A1 WO 9932124A1
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WO
WIPO (PCT)
Prior art keywords
isomer
cefuroxime axetil
pharmaceutical composition
amorphous
cefuroxime
Prior art date
Application number
PCT/EP1998/008208
Other languages
English (en)
Inventor
David Samuel Deutsch
Original Assignee
Glaxo Group Limited
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 Glaxo Group Limited filed Critical Glaxo Group Limited
Priority to AU19683/99A priority Critical patent/AU1968399A/en
Publication of WO1999032124A1 publication Critical patent/WO1999032124A1/fr

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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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin

Definitions

  • This invention relates to a novel composition in the field of cephalosporin antibiotics. More particularly, the invention is concerned with a novel composition related to an ester derivative of (6R,7R)-3-carbamoyloxymethyl-7- [(Z)-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylic acid, which has the approved name 'cefuroxime'.
  • Cefuroxime is the subject of British Patent Specification No. 1453049 and is a valuable antibiotic characterised by broad spectrum activity against gram-positive and gram-negative micro- organisms, this property being enhanced by the very high stability of the compound to beta-lactamases produced by a range of gram-negative microorganisms.
  • Cefuroxime is poorly absorbed in the gastrointestinal tract and it is known that esterification of the carboxyl group at the 4-position of cefuroxime may improve the effectiveness of the antibiotic upon oral administration.
  • (S)-isomer' refers to the (S) configuration at the 1 -position of the 1 -acetoxyethyl group.
  • Cefuroxime axetil is known in both the crystalline and amorphous forms.
  • a pharmaceutical composition comprising a 1 :1 mixture of the amorphous (R)- and (S)- isomers of cefuroxime axetil has been marketed as Zinnat®. Isolation of the (R)- and (S)-isomers of cefuroxime axetil was described in GB Patent no. 1 ,571 ,683, (corresponding to Examples 9 and 8 respectively), and pharmaceutical compositions of essentially pure (R)-isomer were described and claimed in US Patent No. 5,063,224. US Patent No. 5,063,224 ('224) claims (R)-cefuroxime axetil and its use in treating bacterial infections.
  • cefuroxime axetil A problematic characteristic of the marketed formulation of cefuroxime axetil is its very unpleasant taste. Although taste-masking compositions have been marketed successfully, these are often undesirable for paediatric use where the child is may be unable to swallow a tablet without biting into it.
  • compositions comprising amorphous (S)-cefuroxime axetil, substantially free from the (R)-isomer are new. It has now been surprisingly found that, despite the teaching to the contrary, a pharmaceutical composition comprising amorphous (S)-cefuroxime axetil, substantially free from the (R)- isomer, has a clinically useful bioavailability. In addition, it has been found that pharmaceutical compositions comprising amorphous (S)-cefuroxime axetil, substantially free from the (R)-isomer, are more pleasant tasting than the amorphous 1:1 mixture of cefuroxime axetil isomers.
  • a pharmaceutical composition comprising amorphous (S)-cefuroxime axetil substantially free from the (R)-isomer, together with one or more pharmaceutically acceptable carriers.
  • the present invention provides amorphous (S)- cefuroxime axetil substantially free from the (R)-isomer for use in human therapy. According to a yet further aspect, the present invention provides amorphous (S)- cefuroxime axetil substantially free from the (R)-isomer for use in the manufacture of a medicament for combating bacterial infections of the human or animal body.
  • compositions comprising amorphous (S)-cefuroxime axetil substantially free from the (R)-isomer are defined as containing less than 10% by weight of (R)-isomer relative to the (S)-isomer. Preferably, less than 5% of the (R)-isomer relative to the (S)-isomer is present in the composition, most preferably, less than 1%.
  • compositions of (S)-cefuroxime axetil according to the invention may be used for oral administration and may be presented as a suspension, as a dry product for constitution with water or other suitable vehicle before use for administration as a suspension, or for direct administration and then washed down, if required, with water or other suitable liquid.
  • Such preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending and/or binding agents e.g. alkylcelluloses such as methyl cellulose hydroxyalkylcelluloses, hydroxypropylcellulose, and hydroxypropylmethylcellulose, sodium carboxymethylcellulose or mixtures thereof, pregelatinised maize starch or polyvinylpyrrolidone; fillers e.g.
  • sucrose, starch, lactose and microcrystalline cellulose adsorbents and flow aids such as talc, aluminium oxide and silicon dioxide; emulsifying or thickening agents e.g. lecithin or aluminium stearates; surface active agents e.g. sodium lauryl sulphate or non-ionic polyoxyethylenepolyoxypropylene copolymers; preservatives e.g. methyl or propyl hydroxybenzoates or sorbic acid; colouring agents, e.g. titanium dioxide pigments, lake colours and iron oxide pigments; flavouring agents e.g. "mint" flavours such as peppermint flavouring agents; and bulk sweeteners e.g.sorbitol and sucrose or artificial sweeteners e.g. saccharin sodium and sodium cyclamate.
  • adsorbents and flow aids such as talc, aluminium oxide and silicon dioxide
  • emulsifying or thickening agents e.g. lecit
  • (S)-cefuroxime axetil of the invention may be blended with the additives in the form of a dry mix or the additives may themselves be formulated into an excipient granule for blending with the active particles of the invention, or the particles of the invention may be granulated together with the additives using conventional techniques.
  • Such granulation techniques include the use of conventional granulators e.g. spray granulators, rotary granulators, centrifugal fluidised bed granulators, high speed mixer granulators and extrusion and comminution techniques. Drying may be carried out by conventional techniques, for example in the granulator or in a drying oven or hot air drier. It is, of course, desirable that the granules should be prepared by a method which is convenient to provide granules of the desired size; this may generally be achieved by conventional adjustment of the conditions of granulation and, if necessary, by screening of the granules thus produced.
  • conventional granulators e.g. spray granulators, rotary granulators, centrifugal fluidised bed granulators, high speed mixer granulators and extrusion and comminution techniques. Drying may be carried out by conventional techniques, for example in the granulator or in a drying oven or hot air drier. It is, of course,
  • the pharmaceutical composition of the invention formulated for oral administration as a suspension may be constituted with a suitable quantity of water, for use in oral administration of (S)-cefuroxime axetil.
  • the particles will typically be presented so as to give a multidose suspension containing the equivalent of 500 mg to 10 g cefuroxime or a single dose suspension containing the equivalent of 100-1000 mg cefuroxime.
  • compositions comprising (S)-cefuroxime axetil substantially free of (R)-isomer in a taste-masked or delayed release formulation.
  • Such formulations may be prepared according to US Patent No. 4,865,851 , which describes compositions of a 1:1 mixture of amorphous cefuroxime axetil isomers provided with integral iipid coatings.
  • Doses employed for human treatment will typically be in the range 100-3000 mg cefuroxime per day, e.g. 250 to 2000 mg cefuroxime per day for adults and 125 to 1000 mg cefuroxime per day for children, although the precise dose will depend on inter alia the frequency of administration.
  • the first taste trial (N1) compared the taste of amorphous (S)-cefuroxime axetil and amorphous racemic cefuroxime axetil, each suspended in 5 ml water with Hydroxypropylmethyl cellulose 0.5% w/v.
  • the second taste trial (N2) compared the taste of amorphous (S)-cefuroxime axetil and amorphous racemic cefuroxime axetil, each mixed with a sweetening agent (1.7 g sucrose) and suspended in 5 ml water. Each sample contained 300 mg of cefuroxime axetil, which is equivalent to 250 mg of cefuroxime.
  • the amorphous (S)-cefuroxime axetil scored better in terms of acceptability, sweetness, reduced bitterness and aftertaste compared with the amorphous racemic cefuroxime axetil mixture.
  • solubility curve was obtained by putting each powder in contact with water (thermostated at 25°C), and maintaining the stirring into the suspension during overall the trial. At the established time-points a sample of the suspension was withdrawn, filtered, and injected into an HPLC system, for the determination of drug substance dissolved.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une composition pharmaceutique comprenant un (S)-céfuroxime axetil amorphe sensiblement dépourvu de (R)-isomère, et comprenant par ailleurs un ou plusieurs vecteurs pharmaceutiquement acceptables. Ce type de composition pharmaceutique renfermant un (S)-céfuroxime axetil amorphe sensiblement dépourvu de (R)-isomère a un goût plus agréable que le mélange amorphe 1:1 d'isomères de céfuroxime axetil, et se prête donc mieux à un traitement des infections bactériennes par voie orale.
PCT/EP1998/008208 1997-12-19 1998-12-17 Compositions pharmaceutiques a base de (s)-cefuroxime axetil, et utilisation dans le traitement des infections bacteriennes WO1999032124A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU19683/99A AU1968399A (en) 1997-12-19 1998-12-17 Pharmaceutical compositios containing (s)-cefuroxime axetil and their use for the treatment of bacterial infections

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9726781.9A GB9726781D0 (en) 1997-12-19 1997-12-19 Pharmaceutical composition
GB9726781.9 1997-12-19

Publications (1)

Publication Number Publication Date
WO1999032124A1 true WO1999032124A1 (fr) 1999-07-01

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1998/008208 WO1999032124A1 (fr) 1997-12-19 1998-12-17 Compositions pharmaceutiques a base de (s)-cefuroxime axetil, et utilisation dans le traitement des infections bacteriennes

Country Status (3)

Country Link
AU (1) AU1968399A (fr)
GB (1) GB9726781D0 (fr)
WO (1) WO1999032124A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002057227A2 (fr) * 2001-01-19 2002-07-25 Rhodia/Chirex, Inc. Procede pour l'elaboration de composants aromatiques et parfumes a enrichissement enantiomere
WO2003043638A1 (fr) * 2001-11-23 2003-05-30 Glaxo Group Limited Compositions de cefuroxime axetil particulaire enrobe

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1571683A (en) * 1976-02-16 1980-07-16 Glaxo Operations Ltd Ester derivatives of cefuroxime
GB2127401A (en) * 1982-07-30 1984-04-11 Glaxo Group Ltd Amorphous cefuroxime axetil
US5063224A (en) * 1990-07-09 1991-11-05 Eli Lilly And Company R-cefuroxime axetil

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1571683A (en) * 1976-02-16 1980-07-16 Glaxo Operations Ltd Ester derivatives of cefuroxime
GB2127401A (en) * 1982-07-30 1984-04-11 Glaxo Group Ltd Amorphous cefuroxime axetil
US5063224A (en) * 1990-07-09 1991-11-05 Eli Lilly And Company R-cefuroxime axetil

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BARRETT MA ET AL: "Stereoselective absorption and hydrolysis of cefuroxime axetil diastereomers using the Caco-2 cell monolayer model.", EUROPEAN JOURNAL OF DRUG METABOLISM AND PHARMACOKINETICS, OCT-DEC 1997, 22 (4) P409-13, SWITZERLAND, XP002102126 *
MOSHER GL ET AL: "Esterase activity toward the diastereomers of cefuroxime axetil in the rat and dog.", PHARM RES, MAY 1992, 9 (5) P687-9, UNITED STATES, XP002102127 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002057227A2 (fr) * 2001-01-19 2002-07-25 Rhodia/Chirex, Inc. Procede pour l'elaboration de composants aromatiques et parfumes a enrichissement enantiomere
WO2002057227A3 (fr) * 2001-01-19 2002-11-07 Rhodia Chirex Inc Procede pour l'elaboration de composants aromatiques et parfumes a enrichissement enantiomere
WO2003043638A1 (fr) * 2001-11-23 2003-05-30 Glaxo Group Limited Compositions de cefuroxime axetil particulaire enrobe
FR2832635A1 (fr) * 2001-11-23 2003-05-30 Glaxo Group Ltd Composition a base de cefuroxime axetil et son utilisation
ES2201932A1 (es) * 2001-11-23 2004-03-16 Glaxo Group Limited Composicion farmaceutica.
BE1015217A5 (fr) * 2001-11-23 2004-11-09 Glaxo Group Ltd

Also Published As

Publication number Publication date
AU1968399A (en) 1999-07-12
GB9726781D0 (en) 1998-02-18

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