Drug – bio-affecting and body treating compositions – Plural fermentates of different origin
Patent
1997-03-14
1999-06-15
Goldberg, Jerome D.
Drug, bio-affecting and body treating compositions
Plural fermentates of different origin
514193, A61K 3500, A61K 3143
Patent
active
059119853
DESCRIPTION:
BRIEF SUMMARY
This invention relates to novel antibacterial formulations, in particular to formulations including 6-(substituted-methylene) penems and derivatives thereof having .beta.-lactamase inhibitory and antibacterial properties. The invention also relates to methods for the preparation of such formulations and to uses thereof.
The compound ceftazidime, 2-en-3-yl!methyl!pyridinium hydroxide inner salt, is a known and much used cephalosporin antibiotic compound. Ceftazidime is normally administered by injection as its pentahydrate. The term "ceftazidime" as used herein includes all forms of ceftazidime including the free acid, hydrates, salts and ester thereof. Ceftazidime is susceptible to hydrolysis by .beta.-lactamase enzymes, for example those of B. fragilis, S. aureus and enterobacteriaceae producing extended spectrum .beta.-lactamases or elevated levels of Class 1 enzymes.
The compound cefotaxime, carboxylic acid, is a known and much used cephalosporin antibiotic compound. Cefotaxime is normally administered by injection as its sodium salt. The term "cefotaxime" as used herein includes all forms of cefotaxime including the free acid, salts and ester thereof. Cefotaxime is susceptible to hydrolysis by .beta.-lactamase enzymes, for example those of B. fragilis, Group 1 enzymes (typically encountered in Enterobacter Citrobacter and Pseudomonas), or showing mutational changes around the active site of the Group 2 enzymes TEM-1 and SHV-1 (typically encountered in E. coli and Klebsiella.
The compound amoxycillin, known and much used antibiotic compound. Amoxycillin is normally administered orally in the form of amoxycillin trihydrate, or parenterally as sodium amoxycillin. The term "amoxycillin" as used herein includes all forms of amoxycillin including the free acid, salts and ester thereof. Amoxycillin is hydrolysed by a broad range of .beta.-lactamase enzymes, and is generally ineffective against organisms producing Group I and Group II .beta.-lactamases. Therefore amoxycillin is often administered together with a .beta.-lactamase inhibitor, for example clavulanic acid. carbonyl!amino!phenylacetyl!amino!-3,3-dimethyl-7-oxo4-thia-azabicyclo compound. Piperacillin is normally administered parenterally as its sodium salt. The term "piperacillin" as used herein includes all forms of piperacillin including the free acid, salts and ester thereof. Piperacillin is hydrolysed by .beta.-lactamase enzymes.
It is an object of this invention to provide novel combinations of .beta.-lactam antibiotics with a .beta.-lactamase inhibitor, having improved characteristics compared with known combinations.
According to the present invention, a pharmaceutical formulation comprises, in combination with a penem of formula (I): ##STR1## in which: R.sup.1 is hydrogen or an organic substituent group; ##STR2## wherein R.sup.4 and R.sup.5 are independently hydrogen or one or more substituents replacing hydrogen atoms in the ring system shown; m is 2 or 3; p is zero, 1 or 2; and R.sup.3 is hydrogen, a salt-forming cation or an ester-forming group; and the symbol .dbd./.dbd. indicates that the double bond may be in either the E or Z configuration; and a pharmaceutically acceptable carrier; a .beta.-lactam antibiotic selected from the group consisting of cefotaxime, amoxycillin, piperacillin and ceftazidime, and their pharmaceutically acceptable derivatives including salts and in vivo hydrolysable esters.
Compounds of formula (I) are disclosed in WO94/10178 the contents of which are incorporated herein by way of reference.
The compound of formula (I), its salts and esters, may exist in a number of isomeric forms, all of which, including racemic and diastereoisomeric forms are encompassed within the scope of the formulations of the present invention.
Moreover, the compounds of formula (I) may exist in two isomeric forms at the methylene group at the 8-position, ie the E- and Z-isomeric forms. The Z-isomer is generally preferred as generally being the more active form.
Consequently preferred forms of the compounds of the present invention have t
REFERENCES:
patent: 4258041 (1981-03-01), O'Callaghan et al.
patent: 5602250 (1997-02-01), Broom et al.
Journal of Antibiotics; Coleman et al. vol. 44 No. 3, Mar. 1991, pp. 338-343.
CA 115:2163, 1991.
CA 108:112059, 1987.
Coleman Kenneth
Neale Jane Elizabeth
Gimmi Edward R.
Goldberg Jerome D.
King William T.
SmithKline Beecham p.l.c.
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