GB2103085A - Antimicrobial compositions containing primycin and doxycycline and/or sisomycin or a derivative thereof - Google Patents
Antimicrobial compositions containing primycin and doxycycline and/or sisomycin or a derivative thereof Download PDFInfo
- Publication number
- GB2103085A GB2103085A GB08101818A GB8101818A GB2103085A GB 2103085 A GB2103085 A GB 2103085A GB 08101818 A GB08101818 A GB 08101818A GB 8101818 A GB8101818 A GB 8101818A GB 2103085 A GB2103085 A GB 2103085A
- Authority
- GB
- United Kingdom
- Prior art keywords
- composition
- sisomicin
- primycin
- doxycycline
- derivative
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 60
- 229950010664 primycin Drugs 0.000 title claims abstract description 50
- NYWSLZMTZNODJM-MCGDBQAWSA-N 2-[5-[(4e,20e)-35-butyl-19-[(2s,3s,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-10,12,14,16,18,22,26,30,34-nonahydroxy-3,5,21,33-tetramethyl-36-oxo-1-oxacyclohexatriaconta-4,20-dien-2-yl]-4-hydroxyhexyl]guanidine Chemical compound OC1CC(O)CC(O)CC(O)CC(O)CCCC\C(C)=C\C(C)C(C(C)C(O)CCCN=C(N)N)OC(=O)C(CCCC)C(O)C(C)CCC(O)CCCC(O)CCCC(O)\C(C)=C\C1O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 NYWSLZMTZNODJM-MCGDBQAWSA-N 0.000 title claims abstract description 49
- NYWSLZMTZNODJM-SDUQVVOESA-N primycin Natural products CCCC[C@H]1[C@H](O)[C@H](C)CC[C@@H](O)CCC[C@@H](O)CCC[C@@H](O)C(=C[C@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)[C@@H](O)C[C@H](O)C[C@@H](O)C[C@H](O)C[C@H](O)CCCCC(=C[C@@H](C)[C@@H](OC1=O)[C@H](C)[C@H](O)CCCNC(=N)N)C)C NYWSLZMTZNODJM-SDUQVVOESA-N 0.000 title claims abstract description 49
- URWAJWIAIPFPJE-YFMIWBNJSA-N sisomycin Chemical compound O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H](CC=C(CN)O2)N)[C@@H](N)C[C@H]1N URWAJWIAIPFPJE-YFMIWBNJSA-N 0.000 title claims abstract description 47
- URWAJWIAIPFPJE-UHFFFAOYSA-N Rickamicin Natural products O1CC(O)(C)C(NC)C(O)C1OC1C(O)C(OC2C(CC=C(CN)O2)N)C(N)CC1N URWAJWIAIPFPJE-UHFFFAOYSA-N 0.000 title claims abstract description 41
- 229960003722 doxycycline Drugs 0.000 title claims abstract description 38
- 230000000845 anti-microbial effect Effects 0.000 title claims abstract description 8
- XQTWDDCIUJNLTR-CVHRZJFOSA-N doxycycline monohydrate Chemical compound O.O=C1C2=C(O)C=CC=C2[C@H](C)[C@@H]2C1=C(O)[C@]1(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]1[C@H]2O XQTWDDCIUJNLTR-CVHRZJFOSA-N 0.000 title abstract 2
- 229960005456 sisomicin Drugs 0.000 claims abstract description 42
- 229930192786 Sisomicin Natural products 0.000 claims abstract description 40
- 230000002195 synergetic effect Effects 0.000 claims abstract description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- 238000002560 therapeutic procedure Methods 0.000 claims abstract description 3
- SGKRLCUYIXIAHR-AKNGSSGZSA-N (4s,4ar,5s,5ar,6r,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1=CC=C2[C@H](C)[C@@H]([C@H](O)[C@@H]3[C@](C(O)=C(C(N)=O)C(=O)[C@H]3N(C)C)(O)C3=O)C3=C(O)C2=C1O SGKRLCUYIXIAHR-AKNGSSGZSA-N 0.000 claims description 39
- 239000003708 ampul Substances 0.000 claims description 18
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- 125000000217 alkyl group Chemical group 0.000 claims description 4
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- 125000004103 aminoalkyl group Chemical group 0.000 claims description 2
- 239000004599 antimicrobial Substances 0.000 claims description 2
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- 238000004090 dissolution Methods 0.000 claims description 2
- 229960001172 doxycycline hyclate Drugs 0.000 claims description 2
- HALQELOKLVRWRI-VDBOFHIQSA-N doxycycline hyclate Chemical compound O.[Cl-].[Cl-].CCO.O=C1C2=C(O)C=CC=C2[C@H](C)[C@@H]2C1=C(O)[C@]1(O)C(=O)C(C(N)=O)=C(O)[C@@H]([NH+](C)C)[C@@H]1[C@H]2O.O=C1C2=C(O)C=CC=C2[C@H](C)[C@@H]2C1=C(O)[C@]1(O)C(=O)C(C(N)=O)=C(O)[C@@H]([NH+](C)C)[C@@H]1[C@H]2O HALQELOKLVRWRI-VDBOFHIQSA-N 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
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- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 239000004094 surface-active agent Substances 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
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- 238000007911 parenteral administration Methods 0.000 claims 1
- 208000004396 mastitis Diseases 0.000 abstract description 12
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- 241000191967 Staphylococcus aureus Species 0.000 description 12
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 241001138501 Salmonella enterica Species 0.000 description 6
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- 241000588724 Escherichia coli Species 0.000 description 4
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- 241001465754 Metazoa Species 0.000 description 3
- 241000607272 Vibrio parahaemolyticus Species 0.000 description 3
- 230000001476 alcoholic effect Effects 0.000 description 3
- 235000015165 citric acid Nutrition 0.000 description 3
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 3
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- 235000012222 talc Nutrition 0.000 description 3
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 2
- 208000003322 Coinfection Diseases 0.000 description 2
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- 241000194032 Enterococcus faecalis Species 0.000 description 2
- 241000186779 Listeria monocytogenes Species 0.000 description 2
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
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- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- CIKNYWFPGZCHDL-ZHFUJENKSA-N (2r,3r,4r,5r)-2-[(1s,2s,3r,4s,6r)-4,6-diamino-3-[[(2s,3r)-3-amino-6-(aminomethyl)-3,4-dihydro-2h-pyran-2-yl]oxy]-2-hydroxycyclohexyl]oxy-5-methyl-4-(methylamino)oxane-3,5-diol;sulfuric acid Chemical compound OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H](CC=C(CN)O2)N)[C@@H](N)C[C@H]1N.O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H](CC=C(CN)O2)N)[C@@H](N)C[C@H]1N CIKNYWFPGZCHDL-ZHFUJENKSA-N 0.000 description 1
- SGKRLCUYIXIAHR-NLJUDYQYSA-N (4r,4ar,5s,5ar,6r,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1=CC=C2[C@H](C)[C@@H]([C@H](O)[C@@H]3[C@](C(O)=C(C(N)=O)C(=O)[C@@H]3N(C)C)(O)C3=O)C3=C(O)C2=C1O SGKRLCUYIXIAHR-NLJUDYQYSA-N 0.000 description 1
- PTNZGHXUZDHMIQ-UHFFFAOYSA-N 4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide;hydrochloride Chemical compound Cl.C1=CC=C2C(C)C(C(O)C3C(C(O)=C(C(N)=O)C(=O)C3N(C)C)(O)C3=O)C3=C(O)C2=C1O PTNZGHXUZDHMIQ-UHFFFAOYSA-N 0.000 description 1
- 206010008631 Cholera Diseases 0.000 description 1
- 108010065152 Coagulase Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 241000588747 Klebsiella pneumoniae Species 0.000 description 1
- 241000186781 Listeria Species 0.000 description 1
- BZARQXGRENRAGM-YQALYVIGSA-N OS(O)(=O)=O.CCCCC1C(O)C(C)CCC(O)CCCC(O)CCCC(O)\C(C)=C\C(OC2OC(CO)C(O)C2O)C(O)CC(O)CC(O)CC(O)CC(O)CCCC\C(C)=C\C(C)C(OC1=O)C(C)C(O)CCCN=C(N)N.CCCCC1C(O)C(C)CCC(O)CCCC(O)CCCC(O)\C(C)=C\C(OC2OC(CO)C(O)C2O)C(O)CC(O)CC(O)CC(O)CC(O)CCCC\C(C)=C\C(C)C(OC1=O)C(C)C(O)CCCN=C(N)N Chemical compound OS(O)(=O)=O.CCCCC1C(O)C(C)CCC(O)CCCC(O)CCCC(O)\C(C)=C\C(OC2OC(CO)C(O)C2O)C(O)CC(O)CC(O)CC(O)CC(O)CCCC\C(C)=C\C(C)C(OC1=O)C(C)C(O)CCCN=C(N)N.CCCCC1C(O)C(C)CCC(O)CCCC(O)CCCC(O)\C(C)=C\C(OC2OC(CO)C(O)C2O)C(O)CC(O)CC(O)CC(O)CC(O)CCCC\C(C)=C\C(C)C(OC1=O)C(C)C(O)CCCN=C(N)N BZARQXGRENRAGM-YQALYVIGSA-N 0.000 description 1
- 239000004264 Petrolatum Substances 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 241000588769 Proteus <enterobacteria> Species 0.000 description 1
- 241000588767 Proteus vulgaris Species 0.000 description 1
- 235000004443 Ricinus communis Nutrition 0.000 description 1
- 241000607142 Salmonella Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- 244000037640 animal pathogen Species 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
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- 230000000052 comparative effect Effects 0.000 description 1
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- 201000003146 cystitis Diseases 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229960004082 doxycycline hydrochloride Drugs 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
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- 230000007774 longterm Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
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- 239000000463 material Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
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- 244000000010 microbial pathogen Species 0.000 description 1
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
-
- 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
- A61K31/65—Tetracyclines
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A pharmaceutical composition comprises (a) primycin or a derivative thereof; and (b) doxycycline or a derivative thereof and/or sisomicin or a derivative thereof; the ratio of components (a) and (b) being such that the composition exhibits a synergistic antimicrobial effect. The combination shows enhanced antimicrobial activity and is of interest for the therapy of infections, for example mastitis, caused by drug- resistant organisms.
Description
SPECIFICATION
Synergistic antimicrobial compositions
The present invention relates to new synergistic antimicrobial compositions.
Resistance of pathogens to the commercially available antimicrobials has increased to a great extent and thus several such substances, after a long period of effective use, cannot be used anymore.
In addition to the chromosomal resistance, the recently discovered "plasmid resistance" is responsible for the "resistance" phenomenon. The latter is the capability of pathogens to directly transfer their plasm it resistance to individuals belonging to the same species or even to other species.
Thus polyresistant pathogens may be produced within a short period.
Due to the above facts, the use of active ingredient combinations is becoming more important.
The interaction of simultaneously administered active ingredients-antagonism, synergism-has been
known for a long time. Synergism means an enhanced effect of the combination relative to its components, and this effect is especially important in case of mixed infections.
The present invention concerns synergistic antimicrobial pharmaceutical compositions comprising (a) primycin or a derivative thereof; and (b) doxycyline or a derivative thereof and/or sisomicin or a derivative thereof; the ratio of components (a) and (b) being such that the composition exhibits a synergistic antimicrobial effect.
The composition may include a pharmaceutically acceptable carrier and optionally one or more adjuvants.
The synergistic pharmaceutical compositions according to the invention have the following advantages:
1. By attacking the metabolism of the pathogens simultaneously at several points a bactericidal effect may be better achieved and this effect is more advantageous than the bacteriostatic effect, which is a simple inhibition of the development of the micro-organisms.
2. By attacking several metabolic routes, the resistance against the active ingredient combination does not occur at all or occurs only after a long time.
3. As a consequence of the synergistic effect between the active components, the amount of the active ingredients may be greatly reduced, having the following advantages:
a) During a long-term administration the toxicity of the components is greatly reduced, by
reducing the effective amounts introduced in to the organism.
b) In some expensive compositions the reduced weight of active ingredients may have an
economic advantage as well.
As further advantage one may mention that in case of some active ingredient combinations, not only are significantly lower MIC's observed, but in most cases the spectrum of activity is also broader.
Thus we have found that primycin and its derivatives [prepared e.g. from Thermomonospora galeriensis strain by fermentation (HU-PS 1 53 593)] in an amount e.g. of 5 to 50% by weight gives a synergistic effect with 95 to 50% by weight of sisomicin and/or doxycycline.
Due to the strong synergistic effect, the combinations according to the invention are effective and
have a broad spectrum of activity and thus may be successfully employed against polyresistant strongly pathogenic microorganisms causing severe epidemics and diseases. Their use is particularly favourable in the case of mixed infections.
Compositions according to the invention may preferably contain primycin in the form of
heterocolloidal primycin (GB-PS 1 512 604).
Compositions according to the invention e.g. contain as doxycycline derivative a doxycycline salt
of a mineral acid, preferably doxycycline-hydrochloride or doxycycline-hyclate.
As a sisomicin derivative the compositions according to the invention may contain sisomicin
substituted on the nitrogen atom by lower alkyl, hydroxy-lower alkyl, lower aminoalkyl or lower
alkanoyl or a sisomicin salt of an acid. As sisomicin derivatives preferably N-methyl, N-hydroxyethyl, N
acetyl-sisomicin or sisomicin-hydrochloride may be employed.
Doxycycline and its derivative mentioned above (GB-PS 845 649) and sisomicin and derivatives
thereof mentioned above (US-PS 3907771 and HU-PS 170 513) are known compounds.
According to one preferred embodiment of the present invention, as active ingredients primycin
and sisomicin are used. According to another feature of the invention, as active ingredients primycin
and doxycycline are used. In the above combinations the derivatives of said antibiotics mentioned
above may be employed as well.
A preferred composition according to the invention contains 30 to 35% primycin, 30 to 35%
doxycycline or an equivalent amount of the hydrochloride thereof and 30 to 35% by weight of
sisomicin related to the total active ingredient content.
The synergistic pharmaceutical compositions according to the invention may be formulated as
solid compositions such as tablets, capsules, dragées, suppositories, semi-solid compositions such as
ointments, or liquid compositions such as injectable solutions, suspensions or emulsions. As the most
advantageous formulations gels, ointments, talcs, injectable solutions or suspensions, and powder
ampoule-solvent-ampoule combinations may be mentioned. The compositions may be administered
orally, parenterally rectally or topically e.g. ointments.
The pharmaceutical compositions may contain pharmaceutically acceptable carriers, such as magnesium carbonate, magnesium stearate, starch, talc, water etc. and optionally excipients, e.g.
fillers, disintegrating agents, lubricants, emulsifiers etc.
Orally administered compositions may be in form of tablets, capsules or dragées.
The synergistic compositions may be employed in veterinary therapy too, for example as a powder mixture added to the feed or as a solution mixed in the watering mixture of the animals.
The parenterally employed compositions may be e.g. aqueous solutions, emulsions or suspensions. For topical use one may employ ointments, aqueous or oily emulsions or suspensions or sprays. A parenterally employable composition may be prepared by filling sisomicin and doxycycline into powder ampoules, e.g. in the presence of buffer materials such as sodium acetate, and into solvent ampoules heterocolloidal primycin and surfactants, preferably quaternary ammonium salts such as cetyl trimethylammonium bromide are placed. The content of the solvent ampoule is injected into the powder ampoule directly prior to use. After dissolving, a well employable veterinary injectable composition is obtained.
A parenterally administrable composition may preferably be prepared by admixing an aqueous alcoholic solution of primycin with a suitable carrier (e.g. castor-oil) and by suspending sisomicin and/or doxycycline in the castor-oil mixture obtained after distilling off alcohol and after cooling.
The ointments may be prepared by distributing the active ingredient components homogeneously in a conventionally used ointment e.g. petrolatum.
The biological (in vitro) activity of the compositions according to the invention is demonstrated in the following Examples.
The following international resistant and/or polyresistant human pathogen and/or animal pathogen microorganisms were used in the course of the tests:
1. Vibrio parahaemolyticus CCM. 5938,
2. Pseudomonas acidovorans CCM. 283,
3. Proteus vulgaris CCM. 1 799, 4. Proteus mirabilis CCM. 1944,
5. Shigella sonnei CCM. 1373,
6. Salmonella typhimurium CCM. 5445,
7. Salmonella cholerae-suis CCM. 5435, (Inst. Pasteur Stamm),
8. Salmonella cholerae-suis CCM. 5874, 9. Salmonella cholerae-suis subsp. Kunzendoff. CCM. 5967,
10. Escherichia coli DSM. 30038,
11. Escherichia collATTC 11775, (cystitis, poultry pathogen), 1 2. Escherichia coli CCM 180, lysogenicus, colicinogenicus,
13.Escherichia coil, CCM. 5863, haemolyticus,
14. Klebsiella pneumoniae CCM. 1 848, 1 5. Serratia macerscens CCM. 303, 1 6. Staphylococcus aureus CCM. 885,
17. Staphylococcus aureus DSM. 20231,
18. Staphylococcus aureus CCM. 231 7, human mastitis,
19. Staphylococcus aureus CCM. 2326 human mastitis,
20. Staphylococcus aureus CCM. 251 5 beta haemylysis,
21. Staphylococcus aureus CCM. 2515 coagulase positive,
22. Streptococcus faecalis CCM. 885,
23. Streptococcus agalactiae CCM. 5153, from milk of cows having mastitis
24. Streptococcus agalactiae CCM. 5534, from milk of cows having mastitis,
25. Bacillus cereus CCM. 2010,
26. Listeria monocytogenis CCM. 5576.
ATCC=The American Type Culture Collection,
CCM=Czechoslovak Collection of Microorganisms,
DSM=Deutsche Sammlung fur Mikroorganismen.
Abbreviations:
P=primycin sulphate
S=sisomicin sulphate
D=doxycycline sulphate yg/ml=microgramm/milliliter MlC=minimal inhibitory concentration
O=no growth, complete inhibition of the microorganism ~=poor growth
++=moderate growth +++=strong growth, no inhibition.
The tests were carried out on DIFCO Bouillon medium, evaluation after incubation for 24 and 48 hours at 370C.
Table I to XIII show that the combinations of primycin [prepared from the ferment broth of
Thermomonospora glariensis]--with sisomicin or doxycycline have a synergistic effect and the potentiating effect may increase the original activity by 30 to 40 times.
The pharmaceutical compositions according to the invention may contain other active ingredients such as chemotherapeutic agents as well.
Table I
Primycin+Sisomicin
Staphylococcus aureus Staphylococcus aureus Staphylococcus aureus
CCM. 2317 CCM. 2326 CCM. 2514
P S Incubation P S Incubation P S Incubation g./ml. g./ml. 24h 48h g./ml. g./ml. 24h 48h g./ml. g./ml. 24h 48h 0.1 0.1 0 0 0.5 0.5 0 0 0.5 0.5 0 0 0:0.75 0.1 0 0 0.25 0.25 0 0 0.25 0.25 0 0 0.075 0.075 0 0 0.1 0.25 0 0 0.1 0.25 0 0 0.05 0.1 0 0 0.075 0.25 0 0 0.075 0.25 0 0 0.05 0.075 0 0 0.1 0.1 0 +++ 0.1 0.1 0 +++ 0.025 0.075 0 0 0.1 0.075 0 +++ 0.1 0.075 0 +++ 0.05 0.05 0 + 0.075 0.1 0 +++ 0.075 0.1 0 +++ 0.025 0.05 0 + 0.075 0.075 0 +++ 0.075 0.075 + +++ 0.025 0.025 +++ +++ 0.05 0.01 +++ +++ 0.05 0.01 +++ +++ 0.01 0.01 +++ +++ 0.05 0.075 0 +++ 0.05 0.075 +++ +++
Control +++ +++ Control +++ +++ Control +++ +++
MIC : P=0.25 S=0.25 MIC : P=0.5, S=0.5 MIC: P=0.5.S=0.5
Table II
Primycin+Sisomicin
Staphylococcus aureus Streptococcus faecalis Streptococcus agalactiae
DSM. 20231 CCM. 1875 CCM. 5534
P S Incubation P S Incubation P S Incubation g./ml. g./ml. 24h 48h g./ml. g./ml. 24h 48h g./ml. g./ml. 24h 48h 0.5 0.5 0 0 1 2.5 0 0 0.5 2.5 0 0 0.25 0.25 0 0 0.75 1 0 0 0.25 1 0 0 0.1 0.25 0 0 0.75 0.75 0 0 0.25 0.75 0 0 0.075 0.25 0 0 0.5 1 0 0 0.1 1 0 0 0.1 0.1 0 +++ 0.5 0.75 0 0 0.1 0.75 0 0 0.1 0.075 0 +++ 0.5 0.5 0 0 0.25 0.5 0 +++ 0.075 0.1 0 +++ 0.25 1 0 0 0.1 0.5 + +++ 0.075 0.075 0 +++ 0.25 0.75 0 +++ 0.1 0.25 +++ +++ 0.05 0.01 +++ +++ 0.25 0.5 +++ +++ 0.1 0.1 +++ +++ 0.05 0.075 +++ +++ 0.25 0.25 +++ +++ 0.075 0.5 + +++
Control +++ +++ Control +++ +++ Control +++ +++
MIC : P=0.5, S=0.5 MIC : P=1, S=2.5 MIC :P=0.5, S=2.5 Table III
Primycin+Sisomicin
Bacillus cereus Vibrio parahaemolyticus Proteus vulgarls
CCM. 2010 CCM. 5938 CCM. 1799
P S Incubation P S Incubation P S Incubation g./ml. g./ml. 24h 48h g./ml. g./ml. 24h 48h g./ml. g./ml. 24h 48h 0.25 1 0 0 25 150 0 0 200 2.5 0 0 0.1 0.75 0 0 10 100 0 0 150 2.5 0 0 0.1 0.5 0 0 5 100 0 0 150 1 0 0 0.075 0.75 0 0 5 75 0 0 100 1 0 0 0.075 0.5 0 0 5 50 0 0 50 1 0 0 0.1 0.25 ++ +++ 2.5 100 0 0 50 0.75 0 0 0.1 0.1 +++ +++ 2.5 75 0 0 50 0.5 0 + 0.075 0.25 +++ +++ 2.5 50 0 0 25 1 + ++ 0.075 0.1 +++ +++ 2.5 25 ++ ++ 25 0.75 + ++ 0.05 0.1 +++ +++ 2.5 10 ++ ++ 25 0.25 +++ +++
Control +++ +++ Control +++ +++ Control +++ +++
MIC : P=0.25, S=1 MIC : P=25, S=150 MIC : P# 200, S=2.5
Table IV
Primycin+Sisomicin
Salmonella Cholerae-suis
Salmonella Cholerae-suis subsp. Kunzendorf.Escherichia coll
CCM. 5874 CCM. 5967 DSM. 30038
P S Incubation P S Incubation P S Incubation g./ml. g./ml. 24h 48h g./ml. g./ml. 24h 48h g./ml. g./ml. 24h 48h 75 2.5 0 0 200 2.5 0 0 200 2.5 0 0 50 1 0 0 150 2.5 0 0 150 2.5 0 0 50 0.75 0 0 100 1 0 0 150 1 0 0 25 1 0 0 50 1 0 0 100 1 0 0 25 0.75 0 0 50 0.75 0 +++ 50 1 0 0 10 1 0 0 50 0.5 0 +++ 50 0.75 0 0 25 0.5 0 + 25 1 0 # 50 0.5 0 0 10 0.75 0 ++ 25 0.75 0 +++ 25 1 # # 10 0.5 0 ++ 25 0.25 +++ +++ 25 0.75 # # 25 0.25 +++ +++ 25 0.25 +++ +++
Control +++ +++ Control +++ +++ Control +++ +++
MIC: P=75, S=2.5 MIC: P=200, S=2.5 MIC :P=200, S=2.5 Table V
Primycin+Doxycycline
Staphylococcus aureus Staphylococcus aureus Staphylococcus aureus
CCM. 885 CCM. 2326 CCM. 2514
P D Incubation P D Incubation P D Incubation g./ml. g./ml. 24h 48h g./ml. g./ml. 24h 48h g./ml. g./ml. 24h 48h 0.5 0.25 0 0 0.5 0.5 0 0 0.05 1 0 0 0.25 0.1 0 0 0.225 0.25 0 0 0.25 0.75 0 0 0.25 0.075 0 0 0.25 0.25 0 0 0.25 0.5 0 0 0.1 0.1 0 0 0.25 0.25 0 0 0.25 0.25 0 0 0.075 0.1 0 0 0.1 0.1 0 0 0.1 0.5 0 0 0.1 0.075 0 0 0.1 0.075 0 0 0.1 0.25 0 0 0.075 0.075 0 ++ 0.1 0.1 0 0 0.1 0.1 0 0 0.075 0.05 0 +++ 0.075 0.075 0 0 0.075 0.5 0 0 0.05 0.075 # +++ 0.075 0.01 0 + 0.075 0.1 0 0 0.05 0.05 +++ +++ 0.05 0.075 +++ +++ 0.05 0.05 +++ +++
Control +++ +++ Control +++ +++ Control +++ +++
MIC : P=0.5, D=0.25 MIC :P=0.5, D=1 MIC:P=0.5, D=1
Table VI
Primycin+Doxycycline
Staphylococcus aureus Staphylococcus aureus Streptococcus agalactiae
DSM. 20231 CCM. 2515 CCM. 5153
P D Incubation P D Incubation P D Incubation g./ml. g./ml. 24h 48h g./ml. g./ml. 24h 48h g./ml. g./ml. 24h 48h 0.5 0.5 0 0 0.25 0.25 0 0 0.5 0.5 0 0 0.25 0.25 0 0 0.1 0.1 0 0 0.25 0.25 0 0 0.1 0.25 0 0 0.1 0.075 0 0 0.1 0.25 0 0 0.075 0.25 0 0 0.075 0.1 0 0 0.075 0.25 0 0 0.1 0.1 0 + 0.075 0.075 0 0 0.1 0.1 0 + 0.075 0.1 0 +++ 0.075 0.05 0 +++ 0.075 0.1 0 + 0.075 0.075 + +++ 0.05 0.1 0 + 0.075 0.075 0 +++ 0.05 0.1 0 +++ 0.05 0.075 0 +++ 0.05 0.075 + +++ 0.05 0.075 +++ +++ 0.05 0.05 # +++ 0.05 0.05 ++ +++
0.025 0.025 +++ +++ 0.01 0.01 +++ +++
Control +++ +++ Control +++ +++ Control +++ +++
MIC : P=0.5, D=0.5 MIC : P=0.25, D=0.25 MIC :P=0.5, D=0.5 Table VII
Primycin+Doxycycline
Bacillus cereus Listeria monocytogenes Salmonella cholerae-suis
subsp.Kunzendorf.
CCM. 2010 CCM. 5576 CCM. 5967
P D Incubation P D Incubation P D Incubation g./ml. g./ml. 24h 48h g./ml. g./ml. 24h 48h g./ml. g./ml. 24h 48h 0.25 1 0 0 0.25 0.25 0 0 200 2.5 0 0 0.1 0.75 0 0 0.1 0.1 0 0 150 1 0 0 0.1 0.5 0 0 0.1 0.075 0 0 100 1 0 0 0.1 0.25 0 0 0.075 0.1 0 0 100 0.75 0 0 0.075 0.75 0 0 0.075 0.075 0 0 50 1 0 + 0.075 0.5 0 0 0.075 0.05 0 0 50 0.75 0 + 0.05 0.5 0 0 0.05 0.1 0 0 50 0.5 + ++ 0.075 0.25 0 0 0.05 0.075 0 + 25 1 # ++ 0.075 0.1 0 ++ 0.05 0.05 0 + 25 0.5 +++ +++ 0.05 0.1 ++ +++ 0.025 0.025 +++ +++ 10 0.5 +++ +++
Control +++ +++ Control +++ +++ Control +++ +++
MIC : P=0.25, D=1 MIC : P=0.25, D=0.25 MIC :P=200, D=2.5
Table VIII
Primycin+Sisomicin+Doxycycline
Staphylococcus aureus Staphylococcus aueus Staphylococcus aureus
CCM. 2326 CCM. 5967 CCM. 2515
P S D Incubation P S D Incubation P S D Incubation g./ml. g./ml. g./ml. 24h 48h g./ml. g./ml. g./ml. 24h 48h g./ml. g./ml. g./ml. 24h 48h 0.1 0.1 0.25 0 0 0.25 0.25 0.25 0 0 0.1 0.1 0.1 0 0 0.1 0.1 0.1 0 0 0.25 0.1 0.25 0 0 0.1 0.075 0.1 0 0 0.1 0.075 0.1 0 0 0.25 0.1 0.1 0 0 0.1 0.075 0.075 0 0 0.11 0.075 0.075 0 0 0.1 0.1 0.1 0 0 0.075 0.075 0.075 0 0 0.075 0.075 0.075 0 0 0.1 0.075 0.1 0 0 0.075 0.05 0.075 0 0 0.05 0.075 0.075 0 0 0.1 0.075 0.075 0 0 0.05 0.05 0.05 0 0 0.05 0.05 0.075 0 0 0.075 0.075 0.075 0 +++ 0.05 0.05 0.05 0 0 0.05 0.05 0.05 0 0 0.05 0.05 0.05 # +++ 0.025 0.05 0.05 0 0 0.025 0.025 0.025 0 0 0.05 0.05 0.025 +++ +++ 0.025 0.025 0.05 +++ +++ 0.01 0.025 0.025 +++ +++ 0.05 0.025 0.025 +++ +++ 0.025 0.025 0.025 +++ +++
Control +++ +++ Control +++ +++ Contro +++ +++
MIC: P=0.5, S=0.5, D=1. MIC: P=0.5, S=0.25, D=0.25 MIC : P=0.25, S=0.25, D=0.25 Table XI
Primycin+Sisomicin+Doxycycline
Streptococcus agalactiae Bacillus cereus LIsteria monocytogenes
CCM. 5153 CCM. 2010 CCM. 5576
P S D Incubation P S D Incubation P S D Incubation g./ml. g./ml. g./ml. 24h 48h g./ml. g./ml. g./ml. 24h 48h g./ml. g./ml. g./ml. 24h 48h 0.1 5 0.1 0 0 0.1 0.5 0.5 0 0 0.1 0.1 0.1 0 0 0.1 2.5 0.1 0 0 0.1 0.25 0.5 0 0 0.075 0.1 0.1 0 0 0.1 2.5 0.075 0 0 0.1 0.25 0.25 0 0 0.075 0.1 0.075 0 0 0.1 2.5 0.05 0 0 0.075 0.25 0.25 0 0 0.075 0.075 0.075 0 0 0.1 1 0.05 0 0 0.075 0.1 0.25 0 0 0.05 0.075 0.075 0 0 0.075 1 0.075 0 0 0.05 0.25 0.25 0 0 0.05 0.075 0.05 0 0 0.075 1 0.05 0 0 0.075 0.25 0.1 0 +++ 0.05 0.05 0.05 0 0 0.05 1 0.075 0 0 0.075 0.1 0.1 0 +++ 0.025 0.05 0.025 0 0 0.05 0.75 0.05 0 0 0.05 0.1 0.1 0 +++ 0.025 0.025 0.025 0 +++ 0.05 0.05 0.05 ++ +++ 0.05 0.075 0.075 ++ +++ 0.01 0.025 0.01 + +++
Control +++ +++ Control +++ +++ Contro +++ +++
MIC: P=0.5, S=50, D=0.5 MIC: P=0.25, S=1, D=1 MIC :P=0.25, S=0.75, D=0.25
Table X
Primycin+Sisomicin+Doxycycline
Vibrio parahaemolyticus Pseudomonas acidovorans Proteus mirabilis
CCM. 5938 CCM. 283 CCM. 1944
P S D Incubation P S D Incubation P S D Incubation g./ml. g./ml. g./ml. 24h 48h g./ml. g./ml. g./ml. 24h 48h g./ml. g./ml. g./ml. 24h 48h 10 100 0.25 0 0 5 10 0.1 0 0 100 1 75 0 0 10 50 0.25 0 0 5 5 0.1 0 0 100 1 50 0 0 5 50 0.25 0 0 1 1 0.1 0 0 50 1 25 0 0 5 50 0.1 0 0 5 5 0.075 0 0 50 0.5 25 0 0 2.5 25 0.1 0 0 5 5 0.05 0 0 25 0.5 10 0 0 1 25 0.1 0 0 5 2.5 0.075 0 0 10 0.5 10 0 0 2.5 10 0.1 + ++ 2.5 2.5 0.075 0 0 10 0.5 5 0 +++ 2.5 10 0.075 -+ ++ 2.5 2.5 0.05 0 0 10 0.5 2.5 0 +++ 2.5 10 0.05 ++ ++ 2.5 2.5 0.025 0 0 5 0.25 2.5 +++ +++ 1 10 0.1 + ++ 1 1 0.01 ++ +++ 5 0.1 2.5 +++ +++
+++ +++ +++ +++ +++ +++
MIC: P=25, S=150, D=0.5 MIC: P=50, S=50, D=0.5 MIC :P= > 200, S=2.5, D=150 Table XI
Primycin+Sisomicin+Doxycycline
Shigella sonnei Salmonella typhimurium Salmonella cholerae-suis
CCM. 1373 CCM. 5445 CCM. 5438
P S D Incubation P S D Incubation P S D Incubation g./ml. g./ml. g./ml. 24h 48h g./ml. g./ml. g./ml. 24h 48h g./ml. g./ml. g./ml. 24h 48h 100 1 1 0 0 100 0.5 2.5 0 0 50 0.5 2.5 0 0 50 1 1 0 0 50 0.5 2.5 0 0 25 0.5 2.5 0 0 25 1 1 0 0 25 0.5 2.5 0 0 25 0.25 1 0 0 10 0.5 1 0 0 25 0.25 2.5 0 0 10 0.25 1 0 0 10 0.5 0.5 0 0 10 0.1 1 0 0 5 0.25 1 0 0 10 0.5 0.25 0 0 5 0.1 2.5 0 0 5 0.1 1 0 0 5 0.5 0.5 0 0 10 0.075 2.5 0 +++ 1 0.1 1 0 0 5 0.25 0.5 0 0 5 0.075 2.5 0 +++ 2.5 0.1 0.75 0 0 5 0.1 0.5 0 0 10 0.075 1 +++ +++ 2.5 0.075 0.5 ++ +++ 5 0.1 0.25 +++ +++ 10 0.1 1 +++ +++ 2.5 0.05 0.5 +++ +++
Control +++ +++ Control +++ +++ Contro +++ +++
MIC: P=150, S=2.5, D=2.5 MIC: P=150, S=0.75, D=5 MIC :P=75, S=0.75, D=5
Table XII
Primycin+Sisomicin+Doxycycline
Salmonella cholera-suis Salmonella cholerae-suis Escherichia coli
subsq. Kunzendorf
CCM. 5874 CCM. 5967 DSM. 2515
P S D Incubation P S D Incubation P S D Incubation g./ml. g./ml. g./ml. 24h 48h g./ml. g./ml. g./ml. 24h 48h g./ml. g./ml. g./ml. 24h 48h 50 1 2.5 0 0 100 1 1 0 0 25 0.5 1 0 0 25 1 2.5 0 0 50 1 1 0 0 10 0.5 1 0 0 10 1 2.5 0 0 25 1 1 0 0 10 0.25 1 0 0 5 0.5 1 0 00 25 0.5 0.5 0 0 10 0.5 0.75 0 0 5 0.5 0.75 0 0 10 0.5 0.5 0 0 10 0.25 0.75 0 0 5 0.5 0.5 0 0 10 0.25 0.5 0 0 10 0.5 0.5 0 0 2.5 0.5 0.75 0 +++ 10 0.5 0.25 0 0 5 0.5 0.5 0 0 2.5 0.5 0.5 0 +++ 5 0.5 0.5 0 0 5 0.25 0.25 + +++ 2.5 0.25 0.5 +++ +++ 5 0.25 0.25 0 +++ 2.5 0.25 0.25 + +++ 2.5 0.25 0.25 +++ +++ 5 0.1 0.1 +++ +++ 1 0.25 0.25 +++ +++
Control +++ +++ Control +++ +++ Contro +++ +++
MIC: P=75, S=2.5, D=5.MIC: P=200, S=2.5, D=2.5 MIC : P=200, S=2.5, D=5 Table XIII
Primycin+Sisomicin+Doxycyclne
Escherichia coli Eschrichia coli Serratia Macrescens
ATCC. 11775 CCM. 180 CCM. 303
P S D Incubation P S D Incubation P S D Incubation g./ml. g./ml. g./ml. 24h 48h g./ml. g./ml. g./ml. 24 48h g./ml. g./ml. g./ml. 24h 48h 25 0.5 2.5 0 0 10 0.25 1 0 0 100 5 10 0 0 10 0.5 2.5 0 0 5 0.25 1 0 0 50 5 10 0 0 10 0.5 1 0 0 5 0.1 1 0 0 25 5 10 0 0 10 0.25 1 0 0 5 0.1 0.75 0 0 25 2.5 10 0 0 5 0.5 1 0 0 2.5 0.1 1 0 0 10 2.5 10 0 0 5 0.25 1 0 0 2.5 0.1 0.75 0 0 10 2.5 5 0 0 5 0.25 0.75 0 0 2.5 0.1 0.5 0 0 5 2.5 5 0 + 1 0.25 0.5 0 + 1 0.1 0.75 0 0 5 1 5 0 ++ 1 0.1 0.5 0 +++ 1 0.075 0.75 0 0 5 1 2.5 + ++ 1 0.05 1 +++ +++ 1 0.05 0.5 +++ +++ 5 0.75 2.5 +++ +++
Control +++ +++ Control +++ +++ Control +++ +++
MIC:P= > 200, S=1, D=5 MIC : P =200, S=0.75, D=2.5 MIC :P=200, S=10, D=25 Further details of the invention are illustrated by the following Examples which serve merely for illustration and not for limitation.
Examples 1. I. Composition of a powder ampoule
Sisomicin 0.10 g.
Doxycycline. HCI 0.10 g.
Sodium acetate 0.533 g.
II. Composition of a solvent ampoule
Primycin heterocolloid 10.0 g.
(active ingredient content: 0.1 g.) cetyl trimethyl ammonium
bromide 0.5 mg.
The composition is prepared as follows:
Sisomicin, doxycycline and previously pulverized sodium acetate are homogenized, measured into a powder ampoule and sealed (I). Cetyl trimethyl ammonium bromide is dissolved in heterocolloidal primycin and filled into 10 ml. ampoules and sealed (II). Prior to use the content of the solvent ampoule is injected into a powder ampoule and after dissolution it is injected into udderquarters with a plastic needle.
The same composition may be formulated by conventional methods into a two-chamber syringe.
2. Sisomicin 0.10 g.
Doxycycline . HCI 0.10 g.
Primycin-heterocolloidal (active ingredient content: 0.1 g.) 10.00 g.
Sodium acetate 0.97 g.
cetyl-trimethyl-ammonium-bromide 0.5 mg.
The composition is prepared as follows:
Sodium acetate is dissolved in primycin-heterocolloid, filled into powder ampoules and
lyophilized conventionally, Sisomicin and doxycycline are added to the lyophilized product in dried state and the powder ampoule is sealed with a rubber stopper conventionally. The content of the
powder ampoule is dissolved prior to use in 10 ml. of distilled water and injected into udder-quarters with a plastic needle or by other methods.
3. Primycin-heteroclloid (alcoholic) (active ingredient content: 0.1 g.) 10.00 g.
Castor-oil 10.00 g.
Cholesterol 0.25 g.
Sisomicin 0.10g.
Doxycycline. HCI 0.10g.
The composition is prepared as follows:
Alcoholic solution of primycin-heterocolloid is mixed with castor-oil and the alcohol is distilled
off, preferably in vacuo. Cholesterol is dissolved, preferably hot in the castor oil-primycin mixture. The
dried sisomicin and doxycycline are suspended conventionally in the cooled mixture of castor oil and
primycin.
The suspension thus obtained is filled into suitable plastic ampoules or an aluminium tube and equipped with a plastic needle most suitable for use.
4. 1. Composition of a powder ampoule
Sisomicin 0.10g.
Doxycycline. HCI 0.10 g.
II. Composition of a solvent ampoule
Primycin (active ingredient content: 0.1 g.) 10.0 g.
cetyl-trimethyl-ammonium-bromide 0.5 g.
disodium hydrogen phosphate 0.1716 g.
citric acid, cryst. 0.7596 g.
The composition is prepared as follows:
Doxycycline and sisomicin are mixed together and sealed into an ampoule (I). Cetyl-trimethylammonium bromide, crystalline disodium hydrogen phosphate (Na2HPO4. 12 H20) and citric acid are dissolved in primycine-heterocolloid (C6H8O7 . H20), filled into ampoules and sealed (II).
5. Ointment
Sisomicin 0.109.
Doxycycline. HCI 0.10 g.
Primycin 0.10 g.
Polyethyleneglycol 400 4.85 g.
Polyethyleneglycol 4000 4.85 g.
The composition is prepared as follows:
Sisomicin, doxycycline and primycin pulverized under 50 u are used for the preparation of the ointment. Polyethyleneglycol 400 and polyethylene 4000 are homogenized and the active ingredients are mixed with a small part of the homogenized excipients and gradually mixed with the rest of the excipients. The mixture is then filled into tubes.
6. Aerosol filmformer Sisomicin 0.10 g.
Doxycycline. HCI 0.10 g.
Primycin 0.10g.
Polyvinylpyrrolidone 2.0 g.
Anhydrous ethanol 47.7 g.
Freon 11/12 5050 50.0 g.
The composition is prepared as follows:
The dried and pulverized (under 50 y) Sisomicin, Doxycycline . HCI and Primycin are introduced into aerosol bottles whereafter the anhydrous ethanolic polyvinylpyrrolidone solution is added. The bottles are filled and sealed by methods known per se.
7. Aerosol talc
Sisomicin 0.10 g.
Doxycycline. HCI 0.10 g.
Primycin 0.10g.
Isopropyl myristate 1.0 g.
Freon 11/12 5050 98.7 g.
The composition is prepared as follows:
The previously dried and pulverized (Size < 50,u) sisomicin, doxycycline . HCI and primycin are homogenized and triturated with isopropylmyristate. Each dose is filled into aerosol bottles. The bottles are filled and sealed by method known peruse.
8. Comparative tests carried out with primycin and primycin-combinations on animals suffering from
mastitis
Primycin and primycin combination are examined on cows suffering clinically manifested mastitis. The tests were carried out by a thermographic method (cholesteric film set). As reference substances, active ingredients commercially available in Hungary, such as Neomaticur or Mastalone were employed.
Distribution of diseases:
simple catarrhal mastitis
acute contagious catarrhal mastitis
chronic contagious catarrhal mastitis
purulent mastitis with abscesses
Treatment:
1. Primycin 100 mg/udder quarter
8 recovered out of 1 5 cases.
2. Primycin-combination
Composition:
I. powder ampoule
sisomicin (dried) 85 mg.
doxycycline (dried) 100 mg.
sodium acetate (anhydrous) 533 mg.
prednisolone 10 mg.
ll. solvent
ampoule
primycin heterocolloid (active ingredient content: 0.1 g.) 20 ml.
cetyl trimethyl-ammoniumbromide 1.0 mg.
The primycin combination proved to be effective in 14 cases out of 1 6 cases. In the remaining one case the animal had to be sacrificed due to abscess-formation while the other case was a chronic contagious catarrhal mastitis.
The above results are confirmed by in vitro test-results.
Claims (14)
1. A pharmaceutical composition comprising (a) primycin or a derivative thereof; and (b) doxycycline or a derivative thereof and/or sisomicin or a derivative thereof; the ratio of components (a) and (b) being such that the composition exhibits a synergistic antimicrobial effect.
2. A composition as claimed in claim 1 wherein the mixture of components (a) and (b) comprises 5 to 50% by weight of (a) and 95 to 50% by weight of (b).
3. A composition as claimed in claim 1 or 2 comrising a doxycycline salt of a mineral acid.
4. A composition as claimed in claim 3 comprising doxycycline hydrochioride or doxycycline hyclate.
5. A composition as claimed in any of the preceding claims comprising as sisomicin derivative a sisomicin substituted on the nitrogen atom with lower alkyl, hydroxy(lower alkyl), lower aminoalkyl, lower alkanoyl, or a sisomicin salt formed with an acid.
6. A composition as claimed in claim 5 comprising as sisomicin derivative N-methyl, Nhydroxyethyl, N-acetyl-sisomicin or sisomicin-hydrochloride.
7. A composition as claimed in any of claims 1 to 6 comprising as components (a) and (b) primycin and sisomicin respectively, or derivatives thereof.
8. A composition as claimed in any of claims 1 to 6 comprising as components (a) and (b) primycin and doxycycline respectively, as derivatives thereof.
9. A composition according to any of claims 1 to 6 comprising primycin, sisomicin and doxycycline, or derivatives thereof.
10. A composition as claimed in claim 9 wherein the mixture of components (a) and (b) comprises 30 to 35% by weight of primycin, 30 to 35% by weight of doxycycline or an equivalent amount of the hydrochjoride thereof and 30 to 35% by weight of sisomicin.
11. A composition as claimed in any of the preceding claims wherein the primycin component is in the form of heterocolloidal primycin.
12. A composition as claimed in claim 11 for parenteral administration comprising heterocolloidal primycin and a surfactant in a first ampoule and component (b) in a second ampoule in the dry state, for dissolution in the contents of said first ampoule prior to use.
13. A composition as claimed in any of claims 1 to 11 including a pharmaceutically acceptable carrier and optionally one or more adjuvants.
14. A composition as claimed in claim 1 3 in the form of an ointment, talc or aerosol film former.
1 5. A composition as claimed in claim 13 in injectable form.
1 6. A composition as claimed in claim 1 5 in the form of an injectable solution, or suspension or a combination of powder and solvent ampoules.
1 7. A composition as claimed in claim 1 , substantially as described herein.
1 8. A composition as claimed in claim 1, substantially as described herein with reference to any one of Examples 1 to 7.
1 9. Mixtures of components (a) and (b) as defined in claim 1, for use as an antimicrobial agent for human or veterinary therapy.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB08101818A GB2103085B (en) | 1981-01-21 | 1981-01-21 | Antimicrobial compositions containing primycin and doxycycline and/or sisomycin or a derivative thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB08101818A GB2103085B (en) | 1981-01-21 | 1981-01-21 | Antimicrobial compositions containing primycin and doxycycline and/or sisomycin or a derivative thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2103085A true GB2103085A (en) | 1983-02-16 |
| GB2103085B GB2103085B (en) | 1984-03-21 |
Family
ID=10519108
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08101818A Expired GB2103085B (en) | 1981-01-21 | 1981-01-21 | Antimicrobial compositions containing primycin and doxycycline and/or sisomycin or a derivative thereof |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB2103085B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2557453A1 (en) * | 1983-12-29 | 1985-07-05 | Virbac Ctre Rech Biolog | Antibacterial medicinal and veterinary compsn. |
| EP0351698A1 (en) * | 1988-07-19 | 1990-01-24 | CHINOIN Gyogyszer és Vegyészeti Termékek Gyára RT. | Synergistic pharmaceutical composition with an antimicrobial action and process for preparing same |
| EP0347225A3 (en) * | 1988-06-16 | 1991-03-13 | CHINOIN Gyogyszer és Vegyészeti Termékek Gyára RT. | Pharmaceutical compositions containing primycin |
| EA019956B1 (en) * | 2011-02-24 | 2014-07-30 | Закрытое Акционерное Общество "Нита-Фарм" | Pharmaceutical composition for treating diseases of bacterial and mycoplasmal aetiology |
-
1981
- 1981-01-21 GB GB08101818A patent/GB2103085B/en not_active Expired
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2557453A1 (en) * | 1983-12-29 | 1985-07-05 | Virbac Ctre Rech Biolog | Antibacterial medicinal and veterinary compsn. |
| EP0347225A3 (en) * | 1988-06-16 | 1991-03-13 | CHINOIN Gyogyszer és Vegyészeti Termékek Gyára RT. | Pharmaceutical compositions containing primycin |
| EP0351698A1 (en) * | 1988-07-19 | 1990-01-24 | CHINOIN Gyogyszer és Vegyészeti Termékek Gyára RT. | Synergistic pharmaceutical composition with an antimicrobial action and process for preparing same |
| EA019956B1 (en) * | 2011-02-24 | 2014-07-30 | Закрытое Акционерное Общество "Нита-Фарм" | Pharmaceutical composition for treating diseases of bacterial and mycoplasmal aetiology |
Also Published As
| Publication number | Publication date |
|---|---|
| GB2103085B (en) | 1984-03-21 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |