CA1158980A - Antibiotic preparations with increased efficacy, production thereof, and method of intensifying the action of antibiotics - Google Patents
Antibiotic preparations with increased efficacy, production thereof, and method of intensifying the action of antibioticsInfo
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- CA1158980A CA1158980A CA000361259A CA361259A CA1158980A CA 1158980 A CA1158980 A CA 1158980A CA 000361259 A CA000361259 A CA 000361259A CA 361259 A CA361259 A CA 361259A CA 1158980 A CA1158980 A CA 1158980A
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- hydrogen
- lower alkyl
- phenyl
- antibiotics
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Classifications
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- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K20/00—Accessory food factors for animal feeding-stuffs
- A23K20/10—Organic substances
- A23K20/195—Antibiotics
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
-
- 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
Abstract
Case 4-12545/+
Antibiotic preparations with increased efficacy, production thereof, and method of intensifying the action of antibiotics Abstract of the Disclosure The present invention relates to a method of intensifying the action of antibiotics, to antibiotic preparations having increased efficacy, and to the production thereof.
The method comprises the administration of an antibiotic selected from the group consisting of the .beta.-lactam antibiotics, aminoglycosides, tetracyclines, macrolides, lincomycins, polyene antibiotics, polypeptide antibiotics, anthracyclines, chloro- or thiamphenicols, cycloserins, fusidic acids or rifamycins, together with a muramylpeptide of the formula (I)
Antibiotic preparations with increased efficacy, production thereof, and method of intensifying the action of antibiotics Abstract of the Disclosure The present invention relates to a method of intensifying the action of antibiotics, to antibiotic preparations having increased efficacy, and to the production thereof.
The method comprises the administration of an antibiotic selected from the group consisting of the .beta.-lactam antibiotics, aminoglycosides, tetracyclines, macrolides, lincomycins, polyene antibiotics, polypeptide antibiotics, anthracyclines, chloro- or thiamphenicols, cycloserins, fusidic acids or rifamycins, together with a muramylpeptide of the formula (I)
Description
1 ls~n Case 4-12545/+
Antibiotic preparations with increased efficacy, production thereo, and method o intensiying the action of antibiotics ... ...
The present invention relates to a method of inte~fying the action of antibiotics, to antibiotic preparations having increased ef~icacy, and to the production thereof.
The method of intensifying the action of antibiotics comprises the administration o an antibiotic selec-ted from the group.consisting of the ~-lactam antibiotics, aminoglycosides, tetracyclines, macrolides, lincomycins, polyene antibiotics~ polypeptide antibiotics, anthracyclines, chloro- or thiamphenicols, cycloserins, fusidic acids or rifamycins, together with a muramylpeptide of the formula ca2oR2 --o ' H~. I ~ C(OH) (I) C-R
R3C~ o 1 4 1 5 COR6 -~
C - N - CHCNH - CXCH;~CH2COR7 O O
wherein Rl is lower alkyl, phenylj lower alkoxy or phenyl-lower alkoxy, each of which is substituted o~
unsubstituted, R2 is hydrogen or acyl, R3 is hydrogen or lower aLkyl; R4 is hydrogen or lower alkyL, and R5 is hydrogen or lower alk~l or phenyl 7 each of which is substituted or unsubstituted, or ~4 and R5 together are lower alkylene, and each of , .
' ' .
.
..
1 1~8~8~ -R6 and R7 is free or etherifi~d hydroxyl or substituted or unsubstituted amino, and/or one or more salts of a compound of the formula I containing at least one salt-forming group.
In the method of the present invention, an ef~ective or less than effective dose of the antibiotic is adminstered - depending on the nature of this latter, for example from about 50 to about 500 mg per single dose.
The muramylpeptide of the formula I is administer-ed in a single dose of about 5 mg to about half the amount of the antibiotic. It can also be administered up to 24 hours bef~ or after~ but preferably more or less simultaneously with, the antibio~ic. The antibiot~cs are administered by the customary routes, e.~. subcutaneously, intravenou~ly or orall~, whereas the a~ministration of the muramylpeptide is usually made subcutaneously, especially lf this latter is administered separa~ely from the an~ibiotics. In this method, it is possible ~o use individual antibiotics or mixtures thereof.
Preferred ~-lactam antibiotic~ are the penicillins, cephalosporins, penems 3 norcardicins, thienamycin~ and clavulanic acids. Penicillin antibiotics are in particular amoxycillin, ampicillin, carbenicillin, cloxacillin~
cyclacillin, dicloxacillin, mecillinam, methicillin, penicillin G, penicillin V, pivampicillin7 sulbenicillin, azlocillin, ticarcîllin~ mezlocillin, pivmecillinam or 6-(4-endoazatricyclo[5,2,2,02'63undec-~-enyl)-methylene-aminopenicillanic acid.
Representative examples of the group of ~he cephalosporins are: cefaclor, cefazaflur, cefazolin, cefadroxil, cefoxitin, cefuroxime,cephacetril, cephalexin, cephaloglycin, cephaloridin, cephalotin, cefamandol~ cephanon~
cephapirin, cefatrizin, cephraain, cefroxadin (7~[D-2-amino-2-(1,4-cycLohexadienyl)-acetamido]-3-methoxy-3-cephem-4-carboxylLc acid = CGP 9000), cefsulodin, ce~otaxime, , . , ~ , :
, 3 1 ~
cefotiam, ceftezol or cefazedon.
A representative example of the nocardicins is nocardicin A. ExampLes of the thienamycins and clavulanic acids are thienamycin and clavulanic acid respectively.
Aminoglycosides which merit special mention are streptomycins, e.g. streptomycin and streptomycin A, neomycins, e,g. neomycin B, tobramycins, e.g. tobramycin or dibekacin, kanamycins (e g. mixtures of kanamycin A, B and C), and amicacins, gentamycins ~e.g. mixtures of gentamycin A, Cl, C2 or C~a), or sisomicins such as sisomicin or netilmicin, as well as lividomycin, ribocamycin and paramomycin.
Suitable tetracyclines are in particular tetracycline, doxycycline, chlorotetracycline, oxytetracycline or methacycline.
Examples o~ macrolids are maridomycin, spiramycins such as spLramycin I, II and III, erythromycins such as erythromycin, oleandomycins such as oleandomycin and tetraacetyl~eandomycin. Examples of lincomycins are lincomycin and clindamycin. Suitable polyene antibiotics are in particular amphothericin B and its methyl ester, or nystalin.
Examples of suitable polypeptide antibiotics are:
colistin, gramicidin S,polymyxin B, virginamycin, tyrothri-cin, viomycin or vancomyci~. Suitable rifamycins are in particular rifamycin S, rifamycin SV or rifamycin B or their semisynthetic derivatives, especially rifampicin.
In the muramylpeptides of the formula I, the general terms are defined in particular as follows:
Substituents of substituted lower alkyl and lower alkoxy radicals Rl are e.g. free or functionally modified~ especially free vr etherified or esterified hydroxy or mercapto, such as hydroxy, alkoxy, e.g. lower alkoxy, alkanoyloxy~ e.g. lower alkanoyloxy, or halogen, as well as mercpato or alkylthio such as lower or higher alkylthio, or substituted or unsubstituted amino such as acylamino, e.g. alkanoylamino, whereas substituted lower alkyl R5 can contain3 as substituents, e.g. free or ,, ~
.
1 158~8~) unctionally modified, especlally free or etherified or esterified hydroxy or mercapto, such as hydroxy, alkoxy, e.g. lower alkoxy, alkanoyloxy, e.g. lower alkanoyloxy, or halogen or mercapto or alkylthio, e.g. lower alkylthio, as well as higher alkylthio, and in addition substituted or unsubstituted amino, e g. ami~o or acylamino, such as lower alkanoylamino, substituted or unsubstituted phenyl, or azaheterocyclyl such as monocyclic 5- or 6-membered monoaza-or diazacyclyL.
Substituents of phenyl and phenyl-lower alkoxy, in which latter both the alkyl and the phenyl moety can be substituted, are, in a phenyl moiety, e.g. lower alkyl or free or functionally modified, especially ree or etherified or esteriied hydroxy, such as hydroxy, lower alkoxy or halogen, and, in a lower alkyl moiety, e.g. free or functionally modified, especially free or etherified or esteri~ied hydroxy, such as hydroxy, lower alkoxy, lower alkanoyloxy or halogen.
Acyl denotes in particular the acyl radical of an organic carboxylicacid and contains e.g. up to and including 90, preferably up to and including 30, carbon atoms, and is in particular the acyl radical of a correspond-ing aliphatic carboxylic acid, as of a substituted or unsubstituted alkanecarboxyli~ or alkenecarboxylic acid. In acyl radicals of aliphatic c rboxylic aclds, substituents are in particuLar free or unctionally modified, e.g. free or etherified or est2rified hydro~y, eO~. hydroxy, alkoxy such as lower alkoxy, alkanoyloxy such as lower alkanoyloxy, or halogen.
Etherified hydroxy R6 or R7 is e.g. hydroxy which is etherified by an aliphatic radical, and is e.g. substitut-ed or unsubstituted lower alkoxy.
Subs~ituted or unsubstituted amino R6 or R7 contains, as substituent, e.g. lower alkyl which can itself be substituted by free or functionally modified , 1 ~ 5B~8n hydroxy, mercapto or carboxy, e.g. free or etherified or esterified hydroxy or mercapto, e.g. hydroxy, lower alkoxy or lower alkylthio, or free or esterified or amidated carboxy such as carboxy, lower alkoxycarbonyl or carbamoyl.
Throughout this specification, radicals and compounds quali~ied by the tenn "lower'~ preferably contain up to and including 7, most pre~erably up to and including 4, carbon atoms, Substituted radicals can contain one or more identical or different substituents.
Within the 5cope of the foregoing general defin~ions, the radicals and substituents referred to can have the following specific meanings.
Alkyl comprises lower alkyl, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, and also n-pentyl, isopentyl, neopentyl, n-hexyl or n-heptyl, or also higher alkyl such as straight chain or branched octy] 7 nonyl, d~ecyl, undecyl, dodecylg tridecyl, tetradecyl, penta-decyl, hexadecyl, heptadecyl, nonadecyl, or heneicosyl, and also higher alkyl radicals of the triacontyl, ~etracontyl, pentacontyl, hexacontyl, heptacontyl, oc~acontyl or nonacontyl series~
Alkenyl comprises lower alkenyl 3 e,g. allyl or methallyl, or higher alkenyl, e.g. decenyl. Phenyl-lower alkyl is e.g. benzyl or 1- or 2-phenylethyL.
Alkoxy is in particular lower alkoxy, e.g. methoxy, ethoxy, n-propyloxy, isopropyloxy or n-butyloxy. Phenyl-lower alkoxy is e.g. benzyLoxy or 1- or 2-phenylethoxy.
Alkanoyloxy comprises lower alkanoyloxy, e.g. acetyl-oxy, propionyloxy or butyryloxy, and also higher alkanoyl-oxy, e.g. lauroyloxy, myristinoyloxy, palmitoyloxy, stearoyl~
oxy or behenoyloxy.
Halogen is e.g. ~luorine, chlorine or bromine.
Alkanoylamino comprises lower alkanoylamino, e.g. acetyl-amino or propionylamino, as well as higher alkanoylamino, . . .
, .
,~ ' ' ~ 1~8~8 e.g. palmitoylamino.
Lower alkyLthio is e.g. methylthio or ethylthio, whilst higher alkylthio is e.g. tetradecylthio, hexadecyl~hio or octadecylthio.
The acyl radical of an alkanecarboxylic acid comprises lower alkanoyl, e.g. acetyl, propionyl, butyryl or hexanoyl~ or higher alkanoyl, e.g. lauroyl, myristinoyl, palmitoyl, stearoyl or behenoyl, whilst higher alkanoyl substituted e.g. by hydroxy can be mycoloyl The acyl radical of an alkanecarboxylic acid compris-es lower alkenoyl, e.g. allylcarbonyl, or higher alkenoyl, e.g. undecenoyl.
Alkylene is straight-chain or branched and is in particular lower alkylene, e.g. methylene, ethylene, 1,2 propylene, 1,3-propylene, or 1,6-hexylene, and also higher alkylene such as l,ll-undecylene.
Cycloalkyl is e.g. cyclopentyl or cyclohexyl, whilst cycloalkenyl is e.g. l-cyclohexenyl7 and cycloalkyl-alkyl is e.g. 3-cholanylmethyl or the hydroxy-substituted hydrocarbon moiety of the acyl radical o cholic acid.
Lower alkyl-substituted amino~ which can be substi-tuted in the lower alkyl moiety, comprises ~wer alkylamino, e.g. methylamino or ethylamino, or carboxy-lower alkylamino, e.g. carboxymethylamino. Lower alkoxycarbonyl is e.g.
methoxycarbonyl or ethoxycarbonyl.
The compounds of the f~ mula I can exist in the form of mixtures of isomers or of pure isomers. When R3 is lower alkyl, the radical of the formula -CH(R3)-(C=O)-which ls attached to the oxygen atom is preferably in optically activ~ form and has in particular the D-form7 whereas the radical of th~ amino acid of the formula -N(R4)-CH(R5)-C(=O)-, if R5 is different from hydrogen, is also preferably in optically active form, especialLy in the L-~orm; and the terminal a-aminoglutaric acid radcial is preferably in optically active form, especially in the . .: ,:
.
. . ' ~
il15 -- 7 ~
D-form. Further, the unsubstituted or substituted l-hydroxyl group can have the ~ or ~-configuration. However, the novel compounds of the formula I can also exist in the form of a mixture of the 1~- and l~-isomers.
Salt-forming groups in the compounds of the formula I
are e.g. carboxyl groups which may be present. Compounds of the formula I containlng such groups can thereore be in the form of salts, in particular pharmaceutically acceptable salts such as metal salts, especially alkali metal or alkaline earth metal salts, e.g. sodium, potassium, calcium or magnesium salts, or ammonium salts, e.g. wlth ammonia or organic amines such as lower alkylamines, e.g.
triethylamLne. Compounds of the ormula I containing amino groups, or example in the radical R5, can be in the orm of acid addition salts. Suitable acids for obtaining acid addition salts are in particular weak and pharmaceutically acceptable acids.
Especially useful compounds within the scope of the present invention are those of the formula I wherein R2 i~ hydrogen and the other radicals are as defined above, and the salts thereof.
Preferred eompounds are those of the general foxmula t--O
? ~(0~) (II) H-CO-Rl 3 ~ IR5 : 1 6 O ~ CH - CONH - CH - (CH2 j 2 - R7 .~ .
,: ~
~, .
' . . .
: `
~ ' ~
'~ 15~g~(3 wherein Rl is lower alkyl or phenyl, R2 is hydrogen or long-chain alkanoyl, R3 is hydrogen or methyl, R5 is hydrogen, Lower alkyl or hydroxymethyl a R6 is carbamoyl and R7 is carboxyl, and the salts thereof.
~ he most preferred compounds are those of the formula II wherein Rl is lower alkyl or phenyl, Rz is hydrogen, R3 is hydrogen or methyl, R5 is hydrogen, methyL or hydroxymethyl, R6 is carbamoyl and R7 is carboxyl, and the salts thereof.
The muramylpeptides employed for the production of the combination preparations of the invention are known or they can be obtained by methods which are known per se (cf. German Offenlegungsschrit 2 655 500).
The invention relates most particularly to anti-biotic preparations which contain one or more of the anti-biotics specified hereinabove and a muramylpeptide of the formula I. These preparations contain the customary amounts of antibiotic, e.g. from 50 to 1000 m~, preferably from about 200 to 500 mg, and a muramylpeptide of the formula I
in an amount from 5 mg to half the amount of the antibiotic.
Especially if used for oral administration, these preparations can additionally contain the customary amounts of ~harmacological carri~rs, extenders andlor diluents The pronounced antibiotic eficacy of the novel method and of the novel preparations can be demonstrated ~`
by in vivo tests on different species o animals~ especially mammals such as mice. In these tests, the animals are infected with a lethal or sub-lethal dose of a pathogenic microorganism and then the novel preparation or the individual doses of the muramylpeptide and antibiotic are administered. The action is determined as ED50, i.e. the dose at which 50 % of the animals survive.
Surprisingly, it has now been found that infection with pathogenic bacteria, especially with the less easily .
, - ~
1 158g8~1 .
controLlable gram-negative bacteria, e.g. strains of the Aerobacter Brucella, Escherichia, Klebsiella, Malleomyces, Meisseria, Pasteurella~ Proteus, Pseudomonas, Shigella and Vibro, and also gram-posltive bacteria such as actinomy-cetes, clostridia, corynebac~eria, diplococcae, mycobacteria or staphylococcae, or fungi such as Candida albicans, Cryptococcus neoformans, Plastomyces.dermatitides or Hystoplasma capsulatum, are to an increased degree inhibited and controlled.
To be singled out for special mention are pharmaw ceutical or vetinary preparations, as well as animal feedstuffs or additives therefor, which contain an effective or less than effective dose of the specified antibiotics and, in addition, a muramylpeptide of the formula I.
The pharmaceutical preparations of the present invention are preferably tablets or g ~ atin capsules which contain the active ingredients together with diluents, for example lactose, dextrose~ saccharose, mannite, sorbite,c~uk~e and/or glycine, and/or lubricants, for example silica, talc, stearic acid or salts thereof, such as magnesium or calcium steara~e, and/or polyethylene glycol. Tablets can also contain binding agents, for example magnesium aluminium silicate, starches, such as corn, wheat, rice or arrow root starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose and/or polyvinylpyrrolidone, and, if des~xed, disintegra~ors, for example starches, agar, alginic acid or asalt thereof, such as sodium algina~e, and/or effervescent mixtures, or adsorption agen~s, colourants, flavouring matters and sweeten~s. Injec~able preparations are preferably isotonic aqueous solutions or suspensions. Suppositories, ointments or creams are in particular fatty emulsions or suspensions. The pharmaceutical prepara~ions, can be sterilised and/or contain adjuvants, for example preservatives, stabilisers, l 1~8~
wetting agents and/or emulsifiers, solubility pr~moters, salts for regulating the osmotic pressure and/or buffers.
The pharmaceutical preparations of the invention, which if desired, can contain further pharmacologically useful substances, are manufactured in known manner, for example using con~entional mixing, granulating or confectioning methods, and they contain rom about 0.1 % to 75 %, especially from about L % to about 50 %, of the active ingredient.
The preparationsof the present invention for oral administration can also be provided with a coating which is resistant to gastric juices.
The invention is illustrated ln more detail by the following Examples. ~.
' ~' . .
:. . . . .
.. ~ , . .. . .
, ~158~n ExampLe l: Production of 1000 cap~ules containing 260 mg of the active ingredients per capsule Composition rifampicin 250 g N-acetyl-muramyl-L-alanyL-D-isoglutamine 10 g talcum 36 g corn starch 24 g magnesium stearate 16 g lactose 4 g 340 g Pre~aration The pulverulent substances are forced th~ ugh a `
sieve with a mesh si~e of 0.6 mm and thoroug~y mixed. 340 g of this mi~ture are filled into gelatin capsules in a capsule filling machine.
Example 2:Production of 1000 capsules containing 105 mg of active ingredients per capsule Compos~tion rifampicin 100 g N-acetyl-desmethylmuramyl L-alanyl-D-isoglutamine 5 g ethyl cellulose 3 g stearic acid 3 g ' 111 g Preparation Th~ ethyl cellulose and the stearic acid are dissolved in 120 ml of methylene chloride. The antibiotic is added and the mixture is forced through a 9 ieve (0.66 mm) ,, ;
~ 15~g~lt at a temperature of about 40C, in the process of which the methylene chloride is evaporated of. 156 mg of the granules obtained are filled into gelatin capsules to a capacity of 0.5 ml in a capsule filling machine.
ExampLe 3 Production of an animal feedstuff containing 0.005 % of active ingredients Premix rifampicin or chlorotetracycline 30 g N-benzoyl-6-0-stearoyl-desmethylmuramyl-L-alanyl-D- 10 g isoglutamine sugar powder 50 g soybean feed (extracted with solvents) 275 g 365 g Add_tive corn meal 500.0 kg soybean flour, 40 % protein 300.0 kg alfalfa flour 13.5 kg dlcalcium phosphate 18.0 kg calclum carbonate (ground) 4.5 kg salt 2~3 kg fish meal, 60 % protein 18.9 kg stabilised fa~ 27.0 kg dry whey residue : 18.0 kg manganese sulfate Ø2 kg zinc oxide L.3 kg d,l-methionine 0.7 kg vitamin premix : 4.5 kg 908.0 kg - ~, ', ~ , The vitamin premix contains in 4.5 kg: 16000,000 I.U. of vit.
A, 1000,000 I.U. of vit. D3, 5000 I.U. of vit. E acetate, 6 g of vit. K3, 6 mg of vit. Bl2, 3 g of ribo1avin~ 30 g o~ niacin, 5 g o calcium pantothenate and 100 g of ethoxyquin (1,2-dihydro-6-ethoxy-2,2,4-trimethylquinoline) and corn meal to make up 4.5 kg.
Preparation The active ingredients and sugar are thoroughly mixed, the mixture is forced through a sieve and then mixed with the soybean flour. The premix is then added to the feed in the amount corresponding to the desired final concen-tration and the whole is then homogenised in a horizontal drum mixer.
Example 4: Laboratory w~ite mice are infected i.p. with the pathogenic microorganisms listed in the table below in a salt solutio~, such that 90-100 % o~ the untreated controls die within 48 hours. Immadiately, and 3 hours ater infection, groups of 10 mice are treated with cefroxadin both alone (without MDP or nMDP) and in combination with N-acetyl-muramyl-L-alanyl-D-isoglutamine (MDP) or N-acetyl desmethyl-muramyl-L-alanyl-D-isoglutamine (nMDP). Administration is made twice subcutaneously and the active ingredients are in the form of aqueous solutions or suspensions. A count of the surviving animals is made 4 and 10 days after infection.
Most of these assays were carried out tw~ce and the median values determined. The results are reported in the table.
-' " , 1 1~8 Infective agents . without MDP or with with cu (colony forming unitq) n~lDP lo m ~ g lo m ~kg i.p. (~ 104) . _ .
Klebsiella pneumoniae 14.2 4.5 C2.5 329 (2) Klebsiella pneumoniae 75 ~0 <5 327 (60) Pasteurella multocida (0.1) 109 37 70 Salmonella typhimurium 277 22.5 7.6 11 (a) (40) Sal nella typhimurium ~73 39 22.5 14 (a) (400) Staphylococcus aureus 2999 58 45 35 (20 000) ~trep~ococc~s pyc~enes 3~ ~ 0.21: O.lô 0.1/
(a) Res~lts after 10 days.
Example 5: Combination preparations whlch, together with excipients and carriers9 contain the following active ingredients in the indicated amounts are obtained by procedures similar to those described in ExampLes 1 and 2:
a) 500 mg of csphalexin and 5 mg of 6-0-stearoyl-N-acetyl-muramyl-L-alanyl-D-isoglutamine, b) 750 mg of ampicillin a~d 40 mg of n-benzoyl-normuramyl-~ methylalanyl)-D-isoglutamine, c) 100 mg of doxycyclinP and 15 mg of N-acetyl-muramyl~L~
alanyl-D~glutamic acid, d) 300 mg of methacycline and 15 mg of dimethyl N-ben~oyl-desmethylmuramyl-L-alanyl-D-glutamate, e) 250 mg of erythromycin estolate and 30 mg of N-propionyl-desmethyl-m~ramyl-L-a-aminobutyryl-glutamic acid diamide.
, , ;: :
.
.
1 ~58~n Example 6: Preparation of a sterile solid for injection (lyophilisation).
With stirring, 500 mg of cesulodin and lO mg of N-acetyl-muramyl-L--aminobutyryl-D-isoglutamine are digsolved ln 5 ml of water. After sterile fi~ration, the solution is filled into a sterile ampoule (vial) under aseptic conditions and lyophilised. The solid can be dissolved in water or physiological solutions for parenteral application.
Example 7: Preparation o a sterile solid for ~jec~ion (powder filling) 500 mg of sterile cefsu~din and 15 mg of sterile N-propionyl-desmethylmuramyl-L-alanyl-D-isoglutamine are homogeneously mixed under aseptic conditions and the mixture is filled into a glass ampoule. The solid can be dissolved in water, or physiological sdutions for parenteral application.
Example 8: Ster~le solid mixtures for injection containing the following amounts of active ingredients are obtained by procedures similar to those described in Examples 6 and 7:
a) 1000 mg of oxacillin (sodium sal~) and 20 mg of N-acetyl-mura~yl-L--aminobutyryl-glutamic acid, b) 500 mg of cefazolin and 20 mg of diethyl N-acetyl-desmethylmuramyl-L-prolyl-D-glutamate, c) 80 g of gentamycin and 10 mg of ~-benzoyl-desmethyLmuramyl-L-alanyl-D-glutamic acid, d) 200 mg of doxycycline and 10 mg of N-propionyl-desmethyl-muramyl-L-alanyl-D- isoglutamine, e) 50 mg of amphotericin B and 41 mg of sodium desoxycholate and 5 mg of 6-0-s~earoyl-N-acetyl muramyl-L-alanyl-D-isoglutamine for the preparation of the stock solut;on.
f) 500 mg of vancomycin and 6-0-stearoyl-N-benzoyl-normuramyl-L-alanyl-D-isoglutamine.
, .
Antibiotic preparations with increased efficacy, production thereo, and method o intensiying the action of antibiotics ... ...
The present invention relates to a method of inte~fying the action of antibiotics, to antibiotic preparations having increased ef~icacy, and to the production thereof.
The method of intensifying the action of antibiotics comprises the administration o an antibiotic selec-ted from the group.consisting of the ~-lactam antibiotics, aminoglycosides, tetracyclines, macrolides, lincomycins, polyene antibiotics~ polypeptide antibiotics, anthracyclines, chloro- or thiamphenicols, cycloserins, fusidic acids or rifamycins, together with a muramylpeptide of the formula ca2oR2 --o ' H~. I ~ C(OH) (I) C-R
R3C~ o 1 4 1 5 COR6 -~
C - N - CHCNH - CXCH;~CH2COR7 O O
wherein Rl is lower alkyl, phenylj lower alkoxy or phenyl-lower alkoxy, each of which is substituted o~
unsubstituted, R2 is hydrogen or acyl, R3 is hydrogen or lower aLkyl; R4 is hydrogen or lower alkyL, and R5 is hydrogen or lower alk~l or phenyl 7 each of which is substituted or unsubstituted, or ~4 and R5 together are lower alkylene, and each of , .
' ' .
.
..
1 1~8~8~ -R6 and R7 is free or etherifi~d hydroxyl or substituted or unsubstituted amino, and/or one or more salts of a compound of the formula I containing at least one salt-forming group.
In the method of the present invention, an ef~ective or less than effective dose of the antibiotic is adminstered - depending on the nature of this latter, for example from about 50 to about 500 mg per single dose.
The muramylpeptide of the formula I is administer-ed in a single dose of about 5 mg to about half the amount of the antibiotic. It can also be administered up to 24 hours bef~ or after~ but preferably more or less simultaneously with, the antibio~ic. The antibiot~cs are administered by the customary routes, e.~. subcutaneously, intravenou~ly or orall~, whereas the a~ministration of the muramylpeptide is usually made subcutaneously, especially lf this latter is administered separa~ely from the an~ibiotics. In this method, it is possible ~o use individual antibiotics or mixtures thereof.
Preferred ~-lactam antibiotic~ are the penicillins, cephalosporins, penems 3 norcardicins, thienamycin~ and clavulanic acids. Penicillin antibiotics are in particular amoxycillin, ampicillin, carbenicillin, cloxacillin~
cyclacillin, dicloxacillin, mecillinam, methicillin, penicillin G, penicillin V, pivampicillin7 sulbenicillin, azlocillin, ticarcîllin~ mezlocillin, pivmecillinam or 6-(4-endoazatricyclo[5,2,2,02'63undec-~-enyl)-methylene-aminopenicillanic acid.
Representative examples of the group of ~he cephalosporins are: cefaclor, cefazaflur, cefazolin, cefadroxil, cefoxitin, cefuroxime,cephacetril, cephalexin, cephaloglycin, cephaloridin, cephalotin, cefamandol~ cephanon~
cephapirin, cefatrizin, cephraain, cefroxadin (7~[D-2-amino-2-(1,4-cycLohexadienyl)-acetamido]-3-methoxy-3-cephem-4-carboxylLc acid = CGP 9000), cefsulodin, ce~otaxime, , . , ~ , :
, 3 1 ~
cefotiam, ceftezol or cefazedon.
A representative example of the nocardicins is nocardicin A. ExampLes of the thienamycins and clavulanic acids are thienamycin and clavulanic acid respectively.
Aminoglycosides which merit special mention are streptomycins, e.g. streptomycin and streptomycin A, neomycins, e,g. neomycin B, tobramycins, e.g. tobramycin or dibekacin, kanamycins (e g. mixtures of kanamycin A, B and C), and amicacins, gentamycins ~e.g. mixtures of gentamycin A, Cl, C2 or C~a), or sisomicins such as sisomicin or netilmicin, as well as lividomycin, ribocamycin and paramomycin.
Suitable tetracyclines are in particular tetracycline, doxycycline, chlorotetracycline, oxytetracycline or methacycline.
Examples o~ macrolids are maridomycin, spiramycins such as spLramycin I, II and III, erythromycins such as erythromycin, oleandomycins such as oleandomycin and tetraacetyl~eandomycin. Examples of lincomycins are lincomycin and clindamycin. Suitable polyene antibiotics are in particular amphothericin B and its methyl ester, or nystalin.
Examples of suitable polypeptide antibiotics are:
colistin, gramicidin S,polymyxin B, virginamycin, tyrothri-cin, viomycin or vancomyci~. Suitable rifamycins are in particular rifamycin S, rifamycin SV or rifamycin B or their semisynthetic derivatives, especially rifampicin.
In the muramylpeptides of the formula I, the general terms are defined in particular as follows:
Substituents of substituted lower alkyl and lower alkoxy radicals Rl are e.g. free or functionally modified~ especially free vr etherified or esterified hydroxy or mercapto, such as hydroxy, alkoxy, e.g. lower alkoxy, alkanoyloxy~ e.g. lower alkanoyloxy, or halogen, as well as mercpato or alkylthio such as lower or higher alkylthio, or substituted or unsubstituted amino such as acylamino, e.g. alkanoylamino, whereas substituted lower alkyl R5 can contain3 as substituents, e.g. free or ,, ~
.
1 158~8~) unctionally modified, especlally free or etherified or esterified hydroxy or mercapto, such as hydroxy, alkoxy, e.g. lower alkoxy, alkanoyloxy, e.g. lower alkanoyloxy, or halogen or mercapto or alkylthio, e.g. lower alkylthio, as well as higher alkylthio, and in addition substituted or unsubstituted amino, e g. ami~o or acylamino, such as lower alkanoylamino, substituted or unsubstituted phenyl, or azaheterocyclyl such as monocyclic 5- or 6-membered monoaza-or diazacyclyL.
Substituents of phenyl and phenyl-lower alkoxy, in which latter both the alkyl and the phenyl moety can be substituted, are, in a phenyl moiety, e.g. lower alkyl or free or functionally modified, especially ree or etherified or esteriied hydroxy, such as hydroxy, lower alkoxy or halogen, and, in a lower alkyl moiety, e.g. free or functionally modified, especially free or etherified or esteri~ied hydroxy, such as hydroxy, lower alkoxy, lower alkanoyloxy or halogen.
Acyl denotes in particular the acyl radical of an organic carboxylicacid and contains e.g. up to and including 90, preferably up to and including 30, carbon atoms, and is in particular the acyl radical of a correspond-ing aliphatic carboxylic acid, as of a substituted or unsubstituted alkanecarboxyli~ or alkenecarboxylic acid. In acyl radicals of aliphatic c rboxylic aclds, substituents are in particuLar free or unctionally modified, e.g. free or etherified or est2rified hydro~y, eO~. hydroxy, alkoxy such as lower alkoxy, alkanoyloxy such as lower alkanoyloxy, or halogen.
Etherified hydroxy R6 or R7 is e.g. hydroxy which is etherified by an aliphatic radical, and is e.g. substitut-ed or unsubstituted lower alkoxy.
Subs~ituted or unsubstituted amino R6 or R7 contains, as substituent, e.g. lower alkyl which can itself be substituted by free or functionally modified , 1 ~ 5B~8n hydroxy, mercapto or carboxy, e.g. free or etherified or esterified hydroxy or mercapto, e.g. hydroxy, lower alkoxy or lower alkylthio, or free or esterified or amidated carboxy such as carboxy, lower alkoxycarbonyl or carbamoyl.
Throughout this specification, radicals and compounds quali~ied by the tenn "lower'~ preferably contain up to and including 7, most pre~erably up to and including 4, carbon atoms, Substituted radicals can contain one or more identical or different substituents.
Within the 5cope of the foregoing general defin~ions, the radicals and substituents referred to can have the following specific meanings.
Alkyl comprises lower alkyl, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, and also n-pentyl, isopentyl, neopentyl, n-hexyl or n-heptyl, or also higher alkyl such as straight chain or branched octy] 7 nonyl, d~ecyl, undecyl, dodecylg tridecyl, tetradecyl, penta-decyl, hexadecyl, heptadecyl, nonadecyl, or heneicosyl, and also higher alkyl radicals of the triacontyl, ~etracontyl, pentacontyl, hexacontyl, heptacontyl, oc~acontyl or nonacontyl series~
Alkenyl comprises lower alkenyl 3 e,g. allyl or methallyl, or higher alkenyl, e.g. decenyl. Phenyl-lower alkyl is e.g. benzyl or 1- or 2-phenylethyL.
Alkoxy is in particular lower alkoxy, e.g. methoxy, ethoxy, n-propyloxy, isopropyloxy or n-butyloxy. Phenyl-lower alkoxy is e.g. benzyLoxy or 1- or 2-phenylethoxy.
Alkanoyloxy comprises lower alkanoyloxy, e.g. acetyl-oxy, propionyloxy or butyryloxy, and also higher alkanoyl-oxy, e.g. lauroyloxy, myristinoyloxy, palmitoyloxy, stearoyl~
oxy or behenoyloxy.
Halogen is e.g. ~luorine, chlorine or bromine.
Alkanoylamino comprises lower alkanoylamino, e.g. acetyl-amino or propionylamino, as well as higher alkanoylamino, . . .
, .
,~ ' ' ~ 1~8~8 e.g. palmitoylamino.
Lower alkyLthio is e.g. methylthio or ethylthio, whilst higher alkylthio is e.g. tetradecylthio, hexadecyl~hio or octadecylthio.
The acyl radical of an alkanecarboxylic acid comprises lower alkanoyl, e.g. acetyl, propionyl, butyryl or hexanoyl~ or higher alkanoyl, e.g. lauroyl, myristinoyl, palmitoyl, stearoyl or behenoyl, whilst higher alkanoyl substituted e.g. by hydroxy can be mycoloyl The acyl radical of an alkanecarboxylic acid compris-es lower alkenoyl, e.g. allylcarbonyl, or higher alkenoyl, e.g. undecenoyl.
Alkylene is straight-chain or branched and is in particular lower alkylene, e.g. methylene, ethylene, 1,2 propylene, 1,3-propylene, or 1,6-hexylene, and also higher alkylene such as l,ll-undecylene.
Cycloalkyl is e.g. cyclopentyl or cyclohexyl, whilst cycloalkenyl is e.g. l-cyclohexenyl7 and cycloalkyl-alkyl is e.g. 3-cholanylmethyl or the hydroxy-substituted hydrocarbon moiety of the acyl radical o cholic acid.
Lower alkyl-substituted amino~ which can be substi-tuted in the lower alkyl moiety, comprises ~wer alkylamino, e.g. methylamino or ethylamino, or carboxy-lower alkylamino, e.g. carboxymethylamino. Lower alkoxycarbonyl is e.g.
methoxycarbonyl or ethoxycarbonyl.
The compounds of the f~ mula I can exist in the form of mixtures of isomers or of pure isomers. When R3 is lower alkyl, the radical of the formula -CH(R3)-(C=O)-which ls attached to the oxygen atom is preferably in optically activ~ form and has in particular the D-form7 whereas the radical of th~ amino acid of the formula -N(R4)-CH(R5)-C(=O)-, if R5 is different from hydrogen, is also preferably in optically active form, especialLy in the L-~orm; and the terminal a-aminoglutaric acid radcial is preferably in optically active form, especially in the . .: ,:
.
. . ' ~
il15 -- 7 ~
D-form. Further, the unsubstituted or substituted l-hydroxyl group can have the ~ or ~-configuration. However, the novel compounds of the formula I can also exist in the form of a mixture of the 1~- and l~-isomers.
Salt-forming groups in the compounds of the formula I
are e.g. carboxyl groups which may be present. Compounds of the formula I containlng such groups can thereore be in the form of salts, in particular pharmaceutically acceptable salts such as metal salts, especially alkali metal or alkaline earth metal salts, e.g. sodium, potassium, calcium or magnesium salts, or ammonium salts, e.g. wlth ammonia or organic amines such as lower alkylamines, e.g.
triethylamLne. Compounds of the ormula I containing amino groups, or example in the radical R5, can be in the orm of acid addition salts. Suitable acids for obtaining acid addition salts are in particular weak and pharmaceutically acceptable acids.
Especially useful compounds within the scope of the present invention are those of the formula I wherein R2 i~ hydrogen and the other radicals are as defined above, and the salts thereof.
Preferred eompounds are those of the general foxmula t--O
? ~(0~) (II) H-CO-Rl 3 ~ IR5 : 1 6 O ~ CH - CONH - CH - (CH2 j 2 - R7 .~ .
,: ~
~, .
' . . .
: `
~ ' ~
'~ 15~g~(3 wherein Rl is lower alkyl or phenyl, R2 is hydrogen or long-chain alkanoyl, R3 is hydrogen or methyl, R5 is hydrogen, Lower alkyl or hydroxymethyl a R6 is carbamoyl and R7 is carboxyl, and the salts thereof.
~ he most preferred compounds are those of the formula II wherein Rl is lower alkyl or phenyl, Rz is hydrogen, R3 is hydrogen or methyl, R5 is hydrogen, methyL or hydroxymethyl, R6 is carbamoyl and R7 is carboxyl, and the salts thereof.
The muramylpeptides employed for the production of the combination preparations of the invention are known or they can be obtained by methods which are known per se (cf. German Offenlegungsschrit 2 655 500).
The invention relates most particularly to anti-biotic preparations which contain one or more of the anti-biotics specified hereinabove and a muramylpeptide of the formula I. These preparations contain the customary amounts of antibiotic, e.g. from 50 to 1000 m~, preferably from about 200 to 500 mg, and a muramylpeptide of the formula I
in an amount from 5 mg to half the amount of the antibiotic.
Especially if used for oral administration, these preparations can additionally contain the customary amounts of ~harmacological carri~rs, extenders andlor diluents The pronounced antibiotic eficacy of the novel method and of the novel preparations can be demonstrated ~`
by in vivo tests on different species o animals~ especially mammals such as mice. In these tests, the animals are infected with a lethal or sub-lethal dose of a pathogenic microorganism and then the novel preparation or the individual doses of the muramylpeptide and antibiotic are administered. The action is determined as ED50, i.e. the dose at which 50 % of the animals survive.
Surprisingly, it has now been found that infection with pathogenic bacteria, especially with the less easily .
, - ~
1 158g8~1 .
controLlable gram-negative bacteria, e.g. strains of the Aerobacter Brucella, Escherichia, Klebsiella, Malleomyces, Meisseria, Pasteurella~ Proteus, Pseudomonas, Shigella and Vibro, and also gram-posltive bacteria such as actinomy-cetes, clostridia, corynebac~eria, diplococcae, mycobacteria or staphylococcae, or fungi such as Candida albicans, Cryptococcus neoformans, Plastomyces.dermatitides or Hystoplasma capsulatum, are to an increased degree inhibited and controlled.
To be singled out for special mention are pharmaw ceutical or vetinary preparations, as well as animal feedstuffs or additives therefor, which contain an effective or less than effective dose of the specified antibiotics and, in addition, a muramylpeptide of the formula I.
The pharmaceutical preparations of the present invention are preferably tablets or g ~ atin capsules which contain the active ingredients together with diluents, for example lactose, dextrose~ saccharose, mannite, sorbite,c~uk~e and/or glycine, and/or lubricants, for example silica, talc, stearic acid or salts thereof, such as magnesium or calcium steara~e, and/or polyethylene glycol. Tablets can also contain binding agents, for example magnesium aluminium silicate, starches, such as corn, wheat, rice or arrow root starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose and/or polyvinylpyrrolidone, and, if des~xed, disintegra~ors, for example starches, agar, alginic acid or asalt thereof, such as sodium algina~e, and/or effervescent mixtures, or adsorption agen~s, colourants, flavouring matters and sweeten~s. Injec~able preparations are preferably isotonic aqueous solutions or suspensions. Suppositories, ointments or creams are in particular fatty emulsions or suspensions. The pharmaceutical prepara~ions, can be sterilised and/or contain adjuvants, for example preservatives, stabilisers, l 1~8~
wetting agents and/or emulsifiers, solubility pr~moters, salts for regulating the osmotic pressure and/or buffers.
The pharmaceutical preparations of the invention, which if desired, can contain further pharmacologically useful substances, are manufactured in known manner, for example using con~entional mixing, granulating or confectioning methods, and they contain rom about 0.1 % to 75 %, especially from about L % to about 50 %, of the active ingredient.
The preparationsof the present invention for oral administration can also be provided with a coating which is resistant to gastric juices.
The invention is illustrated ln more detail by the following Examples. ~.
' ~' . .
:. . . . .
.. ~ , . .. . .
, ~158~n ExampLe l: Production of 1000 cap~ules containing 260 mg of the active ingredients per capsule Composition rifampicin 250 g N-acetyl-muramyl-L-alanyL-D-isoglutamine 10 g talcum 36 g corn starch 24 g magnesium stearate 16 g lactose 4 g 340 g Pre~aration The pulverulent substances are forced th~ ugh a `
sieve with a mesh si~e of 0.6 mm and thoroug~y mixed. 340 g of this mi~ture are filled into gelatin capsules in a capsule filling machine.
Example 2:Production of 1000 capsules containing 105 mg of active ingredients per capsule Compos~tion rifampicin 100 g N-acetyl-desmethylmuramyl L-alanyl-D-isoglutamine 5 g ethyl cellulose 3 g stearic acid 3 g ' 111 g Preparation Th~ ethyl cellulose and the stearic acid are dissolved in 120 ml of methylene chloride. The antibiotic is added and the mixture is forced through a 9 ieve (0.66 mm) ,, ;
~ 15~g~lt at a temperature of about 40C, in the process of which the methylene chloride is evaporated of. 156 mg of the granules obtained are filled into gelatin capsules to a capacity of 0.5 ml in a capsule filling machine.
ExampLe 3 Production of an animal feedstuff containing 0.005 % of active ingredients Premix rifampicin or chlorotetracycline 30 g N-benzoyl-6-0-stearoyl-desmethylmuramyl-L-alanyl-D- 10 g isoglutamine sugar powder 50 g soybean feed (extracted with solvents) 275 g 365 g Add_tive corn meal 500.0 kg soybean flour, 40 % protein 300.0 kg alfalfa flour 13.5 kg dlcalcium phosphate 18.0 kg calclum carbonate (ground) 4.5 kg salt 2~3 kg fish meal, 60 % protein 18.9 kg stabilised fa~ 27.0 kg dry whey residue : 18.0 kg manganese sulfate Ø2 kg zinc oxide L.3 kg d,l-methionine 0.7 kg vitamin premix : 4.5 kg 908.0 kg - ~, ', ~ , The vitamin premix contains in 4.5 kg: 16000,000 I.U. of vit.
A, 1000,000 I.U. of vit. D3, 5000 I.U. of vit. E acetate, 6 g of vit. K3, 6 mg of vit. Bl2, 3 g of ribo1avin~ 30 g o~ niacin, 5 g o calcium pantothenate and 100 g of ethoxyquin (1,2-dihydro-6-ethoxy-2,2,4-trimethylquinoline) and corn meal to make up 4.5 kg.
Preparation The active ingredients and sugar are thoroughly mixed, the mixture is forced through a sieve and then mixed with the soybean flour. The premix is then added to the feed in the amount corresponding to the desired final concen-tration and the whole is then homogenised in a horizontal drum mixer.
Example 4: Laboratory w~ite mice are infected i.p. with the pathogenic microorganisms listed in the table below in a salt solutio~, such that 90-100 % o~ the untreated controls die within 48 hours. Immadiately, and 3 hours ater infection, groups of 10 mice are treated with cefroxadin both alone (without MDP or nMDP) and in combination with N-acetyl-muramyl-L-alanyl-D-isoglutamine (MDP) or N-acetyl desmethyl-muramyl-L-alanyl-D-isoglutamine (nMDP). Administration is made twice subcutaneously and the active ingredients are in the form of aqueous solutions or suspensions. A count of the surviving animals is made 4 and 10 days after infection.
Most of these assays were carried out tw~ce and the median values determined. The results are reported in the table.
-' " , 1 1~8 Infective agents . without MDP or with with cu (colony forming unitq) n~lDP lo m ~ g lo m ~kg i.p. (~ 104) . _ .
Klebsiella pneumoniae 14.2 4.5 C2.5 329 (2) Klebsiella pneumoniae 75 ~0 <5 327 (60) Pasteurella multocida (0.1) 109 37 70 Salmonella typhimurium 277 22.5 7.6 11 (a) (40) Sal nella typhimurium ~73 39 22.5 14 (a) (400) Staphylococcus aureus 2999 58 45 35 (20 000) ~trep~ococc~s pyc~enes 3~ ~ 0.21: O.lô 0.1/
(a) Res~lts after 10 days.
Example 5: Combination preparations whlch, together with excipients and carriers9 contain the following active ingredients in the indicated amounts are obtained by procedures similar to those described in ExampLes 1 and 2:
a) 500 mg of csphalexin and 5 mg of 6-0-stearoyl-N-acetyl-muramyl-L-alanyl-D-isoglutamine, b) 750 mg of ampicillin a~d 40 mg of n-benzoyl-normuramyl-~ methylalanyl)-D-isoglutamine, c) 100 mg of doxycyclinP and 15 mg of N-acetyl-muramyl~L~
alanyl-D~glutamic acid, d) 300 mg of methacycline and 15 mg of dimethyl N-ben~oyl-desmethylmuramyl-L-alanyl-D-glutamate, e) 250 mg of erythromycin estolate and 30 mg of N-propionyl-desmethyl-m~ramyl-L-a-aminobutyryl-glutamic acid diamide.
, , ;: :
.
.
1 ~58~n Example 6: Preparation of a sterile solid for injection (lyophilisation).
With stirring, 500 mg of cesulodin and lO mg of N-acetyl-muramyl-L--aminobutyryl-D-isoglutamine are digsolved ln 5 ml of water. After sterile fi~ration, the solution is filled into a sterile ampoule (vial) under aseptic conditions and lyophilised. The solid can be dissolved in water or physiological solutions for parenteral application.
Example 7: Preparation o a sterile solid for ~jec~ion (powder filling) 500 mg of sterile cefsu~din and 15 mg of sterile N-propionyl-desmethylmuramyl-L-alanyl-D-isoglutamine are homogeneously mixed under aseptic conditions and the mixture is filled into a glass ampoule. The solid can be dissolved in water, or physiological sdutions for parenteral application.
Example 8: Ster~le solid mixtures for injection containing the following amounts of active ingredients are obtained by procedures similar to those described in Examples 6 and 7:
a) 1000 mg of oxacillin (sodium sal~) and 20 mg of N-acetyl-mura~yl-L--aminobutyryl-glutamic acid, b) 500 mg of cefazolin and 20 mg of diethyl N-acetyl-desmethylmuramyl-L-prolyl-D-glutamate, c) 80 g of gentamycin and 10 mg of ~-benzoyl-desmethyLmuramyl-L-alanyl-D-glutamic acid, d) 200 mg of doxycycline and 10 mg of N-propionyl-desmethyl-muramyl-L-alanyl-D- isoglutamine, e) 50 mg of amphotericin B and 41 mg of sodium desoxycholate and 5 mg of 6-0-s~earoyl-N-acetyl muramyl-L-alanyl-D-isoglutamine for the preparation of the stock solut;on.
f) 500 mg of vancomycin and 6-0-stearoyl-N-benzoyl-normuramyl-L-alanyl-D-isoglutamine.
, .
Claims (12)
1. A method of intensifying the action of antibiotics which comprises the administration of an antibiotic selected from the group consisting of the .beta.-lactam antibiotics, aminoglycosides, tetracyclines, macrolides, lincomycins, polyene antibiotics, polypeptide antibiotics, anthracyclines, chloro- or thiamphenicols, cycloserins, fusidic acids or rifamycins, together with a muramylpeptide of the formula (I) wherein R1 is lower alkyl, phenyl, lower alkoxy or phenyl-lower alkoxy, each of which is substituted or unsubstituted, R2 is hydrogen or acyl, R3 is hydrogen or lower alkyl, R4 is hydrogen or lower alkyl, and R5 is hydrogen or lower alkyl or phenyl, each of which is substituted or unsubstituted, or R4 and R5 together are lower alkylene, and each of R6 and R7 is free or etherified hydroxyl or substituted or unsubstituted amino, and/or one or more salts of a compound of the formula I containing at least one salt-forming group.
2. A method according to claim 1, which comprises the use of a muramylpeptide of the general formula II
(II) wherein R1 is lower alkyl or phenyl, R2 is hydrogen or long-chain alkanoyl, R3 is hydrogen or methyl, R5 is hydrogen, lower alkyl or hydroxymethyl, R6 is carbamoyl and R7 is carboxyl, and/or a salt thereof.
(II) wherein R1 is lower alkyl or phenyl, R2 is hydrogen or long-chain alkanoyl, R3 is hydrogen or methyl, R5 is hydrogen, lower alkyl or hydroxymethyl, R6 is carbamoyl and R7 is carboxyl, and/or a salt thereof.
3. A method according to claim 2, which comprises the use of a muramylpeptide of the formula II, wherein R1 is lower alkyl or phenyl, R2 is hydrogen, R3 is hydrogen or methyl, R5 is hydrogen, methyl or hydroxymethyl, R6 is carbamoyl and R7 is carboxyl, or of a salt thereof.
4. A method according to claim 2, which comprises the use of a muramylpeptide of the formula II as indicated in claim 2, wherein R1 is methyl, R2 is hydrogen or stearoyl, R3 is hydrogen or methyl, R5 is methyl, R6 is carbamoyl and R7 is carboxyl.
5. A method according to any one of claims 2 to 4, wherein the antibiotic is 7.beta.-[D-2-amino-2-(1,4-cyclohexadienyl)-acetamido]-3-methoxy-3-cephem-4-carboxylic acid.
6. A pharmaceutical preparation containing one or more antibiotics selected from the group consisting of the .beta.-lactam antibiotics, aminoglycosides, tetracyclines, macrolides, lincomycins, polyene antibiotics, polypeptide antibiotics, anthracyclines, chloro- or thiamphenicols, cycloserins, fusidic acids or rifamycins, and a muramyl-peptide of the formula (I) wherein R1 is lower alkyl, phenyl, lower alkoxy or phenyl-lower alkoxy, each of which is substituted or unsubstituted, R2 is hydrogen or acyl, R3 is hydrogen or lower alkyl, R4 is hydrogen or lower alkyl, and R5 is hydrogen or lower alkyl or phenyl,each of which is substituted or unsubstituted, or R4 and R5 together are lower alkylene, and each of R6 and R7 is free or etherified hydroxyl or substituted or unsubstitut-ed amino, and/or a salt of a compound of the formula I
containing at least one salt-forming group, together with a pharmaceutically acceptable carrier.
containing at least one salt-forming group, together with a pharmaceutically acceptable carrier.
7. A pharmaceutical preparation according to claim 6 which contains a muramylpeptide of the formula (II) wherein R1 is lower alkyl or phenyl, R2 is hydrogen or long-chain alkanoyl, R3 is hydrogen or methyl, R5 is hydrogen, lower alkyl or hydroxymethyl, R6 is carbamoyl and R7 is carboxyl, and/or a salt thereof.
8. A pharmaceutical preparation according to claim 7 which contains a muramylpeptide of the formula II as indicated in claim 7, wherein R1 is lower alkyl or phenyl, R2 is hydrogen, R3 is hydrogen or methyl, R5 is hydrogen, methyl or hydroxymethyl, R6 is carbamoyl and R7 is carboxyl, and/or a salt thereof.
9. A pharmaceutical preparation according to claim 7 which contains a muramylpeptide of the formula II as indicated in claim 7, wherein R1 is methyl, R2 is hydrogen or stearoyl, R3 is hydrogen or methyl, R5 is methyl, R6 is carbamoyl and R7 is carboxyl.
10. A pharmaceutical preparation according to any one of claims 7 to 9, wherein theantibiotic is rifampicin, chlorotetracycline, cephalexin, ampicillin, doxcycline, methacycline, erythromycin, cefsulodin, oxacilin, cefazolin, gentamycin, amphotericin B or vancomycin.
11. A pharmaceutical preparation according to any one of claims 7 to 9, wherein the antibiotic is 7.beta.-[D-2-amino-2-(1,4-cyclohexadienyl)-acetamido]-3-methoxy-3-cephem-4-carboxylic acid.
12. An nimal feedstuff or additive therefor which contains one or more antibiotics selected from the group consisting of the .beta.-lactam antibiotics, aminoglycosides, tetracyclines, macrolides, lincomycins, polyene antibiotics, polypeptide antibiotics, anthracyclines, chloro- or thiamphenicols, cycloserins, fusidic acids or rifamycins, and a muramyl-peptide of the formula (I) wherein R1 is lower alkyl, phenyl, lower alkoxy or phenyl-lower alkoxy, each of which is substituted or unsubstituted, R2 is hydrogen or acyl, R3 is hydrogen or lower alkyl, R4 is hydrogen or lower alkyl, and R5 is hydrogen or lower alkyl or phenyl,each of which is substituted or unsubstituted, or R4 and R5 together are lower alkylene, and each of R6 and R7 is free or etherified hydroxyl or substituted or unsubstitut-ed amino, and/or one or more salt of a-compound of the formula I
containing at least one salt-forming group.
containing at least one salt-forming group.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH8883/79 | 1979-10-02 | ||
| CH888379 | 1979-10-02 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1158980A true CA1158980A (en) | 1983-12-20 |
Family
ID=4345820
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000361259A Expired CA1158980A (en) | 1979-10-02 | 1980-09-30 | Antibiotic preparations with increased efficacy, production thereof, and method of intensifying the action of antibiotics |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0026746B1 (en) |
| JP (1) | JPS5659715A (en) |
| AU (1) | AU539451B2 (en) |
| CA (1) | CA1158980A (en) |
| DE (1) | DE3070457D1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011050319A2 (en) * | 2009-10-23 | 2011-04-28 | Oregon Health & Science University | Inhibiting the deleterious effect of anthracyclines |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0056560A1 (en) * | 1981-01-19 | 1982-07-28 | Ciba-Geigy Ag | Active antibiotic compositions, process for their manufacture and process for the antibiotic activity of antibiotics |
| EP0585514B1 (en) * | 1992-01-09 | 1998-10-07 | LEK, tovarna farmacevtskih in kemicnih izdelkov, d.d., Ljubljana | Animal feed and an additive thereto or to drinking water containing an antibiotic mixture of gentamicin with lincomycin or clindamycin |
| WO1993013791A1 (en) * | 1992-01-20 | 1993-07-22 | Peptech (Uk) Limited | Use of muramyl peptides for enhancing animal production |
| ATE172077T1 (en) * | 1992-11-08 | 1998-10-15 | Lek Tovarna Farmacevtskih | ANTIBIOTIC MIXTURE OF GENTAMICIN WITH LINCOMYCIN, VETERINARY PREPARATION CONTAINING AS A SUPPLEMENT FOR DRINKING WATER OR ANIMAL FEED AND ITS USE IN THE BREEDING OF PIGS |
| FR2715305B1 (en) * | 1994-01-25 | 1996-03-15 | Vacsyn Sa | Diesters of muramyl peptides in an oral form. |
| GB9419011D0 (en) * | 1994-09-21 | 1994-11-09 | Peptech Uk Ltd | Use of muramyl peptide compounds |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL7308450A (en) * | 1972-06-20 | 1973-12-27 | ||
| CH613709A5 (en) * | 1975-12-10 | 1979-10-15 | Ciba Geigy Ag | Process for the preparation of glucosamine derivatives |
| DE2603122C3 (en) * | 1976-01-28 | 1980-04-17 | Hans H. Dr. 2000 Hamburg Nagel | Process for the production of glycoproteins and their use |
| JPS53127813A (en) * | 1977-04-13 | 1978-11-08 | Kureha Chem Ind Co Ltd | Agent for increasing drug sensitivity of antibiotic-resistant bacteria |
| FR2410476B1 (en) * | 1977-11-30 | 1980-08-22 | Inst Nat Sante Rech Med | APPLICATION OF PEPTIDOGLYCANS EXTRACTED FROM BACTERIA, PARTICULARLY BACILLUS AS MEDICAMENTS, ESPECIALLY STIMULATING ANTI-TUMOR IMMUNITY |
-
1980
- 1980-09-26 DE DE8080810302T patent/DE3070457D1/en not_active Expired
- 1980-09-26 EP EP80810302A patent/EP0026746B1/en not_active Expired
- 1980-09-30 CA CA000361259A patent/CA1158980A/en not_active Expired
- 1980-10-01 AU AU62865/80A patent/AU539451B2/en not_active Ceased
- 1980-10-02 JP JP13682280A patent/JPS5659715A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011050319A2 (en) * | 2009-10-23 | 2011-04-28 | Oregon Health & Science University | Inhibiting the deleterious effect of anthracyclines |
| WO2011050319A3 (en) * | 2009-10-23 | 2011-09-29 | Oregon Health & Science University | Inhibiting the deleterious effect of anthracyclines |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5659715A (en) | 1981-05-23 |
| DE3070457D1 (en) | 1985-05-15 |
| EP0026746B1 (en) | 1985-04-10 |
| AU539451B2 (en) | 1984-09-27 |
| EP0026746A1 (en) | 1981-04-08 |
| AU6286580A (en) | 1981-04-09 |
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