NO127042B - - Google Patents
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- NO127042B NO127042B NO01830/68A NO183068A NO127042B NO 127042 B NO127042 B NO 127042B NO 01830/68 A NO01830/68 A NO 01830/68A NO 183068 A NO183068 A NO 183068A NO 127042 B NO127042 B NO 127042B
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- 230000003115 biocidal effect Effects 0.000 claims description 32
- 239000000203 mixture Substances 0.000 claims description 30
- 102000003712 Complement factor B Human genes 0.000 claims description 25
- 108090000056 Complement factor B Proteins 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 25
- 230000002829 reductive effect Effects 0.000 claims description 9
- 239000000126 substance Substances 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 2
- 238000010828 elution Methods 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- 230000036961 partial effect Effects 0.000 claims description 2
- 238000001179 sorption measurement Methods 0.000 claims description 2
- 239000012535 impurity Substances 0.000 claims 1
- 238000002360 preparation method Methods 0.000 description 15
- 239000003242 anti bacterial agent Substances 0.000 description 9
- 229940088710 antibiotic agent Drugs 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 229920001817 Agar Polymers 0.000 description 6
- 239000008272 agar Substances 0.000 description 6
- 230000002195 synergetic effect Effects 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 241000191967 Staphylococcus aureus Species 0.000 description 3
- 239000000356 contaminant Substances 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 238000011835 investigation Methods 0.000 description 3
- OFQCQIGMURIECL-UHFFFAOYSA-N 2-[2-(diethylamino)ethyl]-2',6'-dimethylspiro[isoquinoline-4,4'-oxane]-1,3-dione;phosphoric acid Chemical compound OP(O)(O)=O.O=C1N(CCN(CC)CC)C(=O)C2=CC=CC=C2C21CC(C)OC(C)C2 OFQCQIGMURIECL-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 235000014469 Bacillus subtilis Nutrition 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 241000970910 Streptomyces ostreogriseus Species 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 241000191938 Micrococcus luteus Species 0.000 description 1
- 241000193996 Streptococcus pyogenes Species 0.000 description 1
- 108010034396 Streptogramins Proteins 0.000 description 1
- 241000187747 Streptomyces Species 0.000 description 1
- 241001122767 Theaceae Species 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000002906 microbiologic effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 235000008935 nutritious Nutrition 0.000 description 1
- YGXCETJZBDTKRY-DZCVGBHJSA-N pristinamycin IA Chemical compound N([C@@H]1C(=O)N[C@@H](C(N2CCC[C@H]2C(=O)N(C)[C@@H](CC=2C=CC(=CC=2)N(C)C)C(=O)N2CCC(=O)C[C@H]2C(=O)N[C@H](C(=O)O[C@@H]1C)C=1C=CC=CC=1)=O)CC)C(=O)C1=NC=CC=C1O YGXCETJZBDTKRY-DZCVGBHJSA-N 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000010421 standard material Substances 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
- B65D1/00—Containers having bodies formed in one piece, e.g. by casting metallic material, by moulding plastics, by blowing vitreous material, by throwing ceramic material, by moulding pulped fibrous material, by deep-drawing operations performed on sheet material
- B65D1/34—Trays or like shallow containers
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
- B65D65/00—Wrappers or flexible covers; Packaging materials of special type or form
- B65D65/38—Packaging materials of special type or form
- B65D65/40—Applications of laminates for particular packaging purposes
- B65D65/403—Applications of laminates for particular packaging purposes with at least one corrugated layer
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B31—MAKING ARTICLES OF PAPER, CARDBOARD OR MATERIAL WORKED IN A MANNER ANALOGOUS TO PAPER; WORKING PAPER, CARDBOARD OR MATERIAL WORKED IN A MANNER ANALOGOUS TO PAPER
- B31B—MAKING CONTAINERS OF PAPER, CARDBOARD OR MATERIAL WORKED IN A MANNER ANALOGOUS TO PAPER
- B31B50/00—Making rigid or semi-rigid containers, e.g. boxes or cartons
- B31B50/59—Shaping sheet material under pressure
- B31B50/592—Shaping sheet material under pressure using punches or dies
Landscapes
- Engineering & Computer Science (AREA)
- Mechanical Engineering (AREA)
- Ceramic Engineering (AREA)
- Containers Having Bodies Formed In One Piece (AREA)
- Laminated Bodies (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Packaging Frangible Articles (AREA)
- Cartons (AREA)
Description
Fremgangsmåte til fremstilling av et komplektst antibiotikum. Method for the preparation of a kit antibiotic.
I patent nr. 93 920 er beskrevet en; In patent no. 93 920 one is described;
fremgangsmåte til fremstilling av et nytt! antibiotisk middel, der betegnet E. 129, og denne fremgangsmåte består i sine hovedtrekk i at man i et nærende medium inneholdende en assimilerbar kilde for nitrogen! og kullstoff, en energikilde samt nærende salter, dyrker organismen Streptomyces i procedure for the manufacture of a new! antibiotic agent, designated E. 129, and this method consists in its main features in a nutrient medium containing an assimilable source of nitrogen! and carbon, a source of energy as well as nutritious salts, the organism Streptomyces i
129, også kalt Streptomyces ostreogriseus(j hvorpå man skiller det herved dannede I antibiotiske middel fra kulturvæsken. 129, also called Streptomyces ostreogriseus (j whereupon the antibiotic agent thus formed is separated from the culture liquid.
Som nevnt i patentets beskrivelse viste j As mentioned in the patent's description, j
dette antibiotiske middel seg å bestå av! en blanding av flere stoffer av hvilke to eller flere viste seg å ha antibiotisk virkning. E. 129 ble også angitt å ligne et antibiotisk middel som er kalt streptogramin. this antibiotic means to consist of! a mixture of several substances of which two or more have been shown to have antibiotic action. E. 129 was also reported to resemble an antibiotic called streptogramin.
I et senere patent nr. 94 895 er beskrevet resultatet av videre forsøksarbeide med! hensyn til sammensetning av E. 129 i form av råprodukt og der er i patentet angitt en j fremgangsmåte til fremstilling av en be-1 standdel av samme, der betegnet Faktor B som er et nytt antibiotisk middel. I patent! nr. 94 895 nevnes der også at E. 129 i form! av råprodukt inneholder to andre bestanddeler med antibiotisk virkning, .der beteg-; net Faktor A og Faktor Z, og at disse ,to bestanddeler av oppfinnerne ble identifi-sert som identiske med to antibiotiske midler betegnet PA114A henholdsvis PA114B: av Chas. Pfizer & Co. Inc. (artikkel av W. D. Celmer og B. A. -Sobin i «Antibiotics Annual», 1955—56, side 437). In a later patent no. 94 895, the result of further experimental work with! regard to the composition of E. 129 in the form of raw product and there is specified in the patent a j method for the production of a component of the same, there designated Factor B which is a new antibiotic agent. In patent! no. 94 895 it is also mentioned that E. 129 in form! of raw product contains two other components with antibiotic effect, .der beteg-; net Factor A and Factor Z, and that these two components were identified by the inventors as identical to two antibiotic agents designated PA114A and PA114B respectively: by Chas. Pfizer & Co. Inc. (article by W. D. Celmer and B. A. -Sobin in "Antibiotics Annual", 1955-56, page 437).
Det er angitt at de to antibiotiske midler PA114A og PA114B sammen viser en synergistisk virkning ved at disse to stoffer i blanding gir større antibiotisk aktivitet enn det kan forklares ved en addisjon av aktivitetene av de enkelte bestanddeler i blandingen. Disse observasjoner er bekref-tet av oppfinneren. It has been stated that the two antibiotic agents PA114A and PA114B together show a synergistic effect in that these two substances in a mixture give greater antibiotic activity than can be explained by an addition of the activities of the individual components in the mixture. These observations are confirmed by the inventor.
Det er nu funnet at det antibiotiske middel Faktor Z av E. 129 (identisk med PA114B) gir en synergistisk virkning også når det bringes sammen med Faktor B .av E. 129. Denne bestanddel er som ovenfor nevnt et nytt stoff. Videre er blandinger av Faktor B og Faktor Z funnet å gi bety-delig større antibiotisk virkning enn sam-menlignbare blandinger av de antibiotiske midler PA114A og PA114B. It has now been found that the antibiotic agent Factor Z of E. 129 (identical to PA114B) gives a synergistic effect also when brought together with Factor B of E. 129. As mentioned above, this component is a new substance. Furthermore, mixtures of Factor B and Factor Z have been found to give significantly greater antibiotic effect than comparable mixtures of the antibiotic agents PA114A and PA114B.
Således er der f. eks. ved forsøk med •beskyttelse av dyr mot infeksjon av Staphylococcus aureus funnet en ED50 verdi på 104 for mus ved anvendelse av en blanding i vektsforhold 1 : 1 av Faktor B og FaTitor Z, mens en blanding likeledes i vektsforhbldet 1 : 1 av PA114A og PAT14B ga en ED,(1 verdi på 650. Thus there is e.g. in experiments with •protection of animals against infection by Staphylococcus aureus found an ED50 value of 104 for mice using a mixture in a 1:1 weight ratio of Factor B and FaTitor Z, while a mixture likewise in a 1:1 weight ratio of PA114A and PAT14B gave an ED, (1 value of 650.
ED30 verdien er det antall mikrogram antibiotisk middel pr. mus som kreves for å beskytte 50 % av de til forsøket anvendte dyr fra vedkommende infeksjon, når det antibiotiske middel anvendes i tre på hver-andre følgende døgn. The ED30 value is the number of micrograms of antibiotic agent per mice required to protect 50% of the animals used for the experiment from the relevant infection, when the antibiotic agent is used three times every other following day.
Der er videre funnet at Faktor B og Z bør være tilstede i mengdeforhold innen bestemte grenser for å oppnå særlig fordelaktige synergistiske virkninger. Det er videre funnet at der sammen med de to Faktorer B og Z ikke bør være tilstede forurensninger som dannes ved dyrkningen av Streptomyces ostreogriseus i mengdeforhold over noenlunde bestemte grenser, uansett om slike forurensninger har antibiotisk virkning eller ikke. It has further been found that Factors B and Z should be present in quantities within certain limits in order to achieve particularly advantageous synergistic effects. It has further been found that, together with the two Factors B and Z, there should not be any contaminants that are formed during the cultivation of Streptomyces ostreogriseus in quantities above roughly determined limits, regardless of whether such contaminants have an antibiotic effect or not.
Det er således funnet at vektsforhol-dene mellom E. 129 Faktor B og E. 129 Faktor Z i preparater inneholdende disse bestanddeler bør ligge innen området fra 1:5 til 5:1, og at preparatene samtidig ikke bør inneholde mere enn 70 vektprosent forurensninger som skriver seg fra dyrkningen for fremstilling av E. 129, foråt preparatene skal vise en god synergistisk virkning. It has thus been found that the weight ratios between E. 129 Factor B and E. 129 Factor Z in preparations containing these components should lie within the range from 1:5 to 5:1, and that the preparations should not contain more than 70% by weight of contaminants. which arises from the cultivation for the production of E. 129, so that the preparations must show a good synergistic effect.
Det karakteristiske hovedtrekk ved fremgangsmåten ifølge oppfinnelsen er at urenset E. 129 for delvis eller fullstendig fjernelse av Faktor A og andre dermed føl-gende stoffer behandles med organiske oppløsningsmidler, såsom metylisobutylke-ton eller etylacetat, særlig i motstrøm, hvoretter en del av den erholdte antibiotiske blanding hvis innhold av Faktor A er redusert, anrikes på Faktor Z, f. eks. ved å underkastes en motstrømsekstraksjon og/ eller kromatografisk adsorpsjon og påføl-gende eluering, hvorpå den antibiotiske blanding som er anriket på Faktor Z, blan-des med den resterende del av blandingen med redusert innhold av Faktor A. The characteristic main feature of the method according to the invention is that impure E. 129 is treated with organic solvents, such as methyl isobutyl ketone or ethyl acetate, in particular in a counter current, for the partial or complete removal of Factor A and other subsequent substances, after which part of the obtained antibiotic mixture whose content of Factor A is reduced, enriched with Factor Z, e.g. by subjecting it to a countercurrent extraction and/or chromatographic adsorption and subsequent elution, after which the antibiotic mixture enriched with Factor Z is mixed with the remaining part of the mixture with a reduced content of Factor A.
Et trekk ved oppfinnelsen går ut på at den antibiotiske blanding med redusert innhold av Faktor A tilsettes så meget av den på Faktor Z anrikede antibiotiske blanding av vektsforholdet Faktor Z : Faktor B i det erholdte komplekse antibiotikum blir 1:5 til 5:1, fortrinnsvis 1:1. Et annet trekk ifølge oppfinnelsen går ut på at den antibiotiske blanding med redusert innhold av Faktor A tilsettes så meget av den på Faktor Z anrikede blandng at den del som Faktor B utgjør av det erholdte komplekse antibiotikum, minst blir 15 vektprosent. Et ytterligere trekk ved oppfinnelsen går ut på at man ved behandling av det urensede E. 129 med organiske oppløsningsmidler fra skiller i det minste 30 vektprosent, fortrinnsvis minst 50 vektprosent, av andre stoffer enn Faktor B og Z og som foreligger i det urensede E. 129. A feature of the invention is that the antibiotic mixture with a reduced content of Factor A is added so much of the Factor Z-enriched antibiotic mixture that the weight ratio Factor Z: Factor B in the obtained complex antibiotic is 1:5 to 5:1, preferably 1:1. Another feature according to the invention is that the antibiotic mixture with a reduced content of Factor A is added so much of the mixture enriched in Factor Z that the part that Factor B makes up of the obtained complex antibiotic is at least 15 percent by weight. A further feature of the invention is that when treating the impure E. 129 with organic solvents, at least 30 percent by weight, preferably at least 50 percent by weight, of substances other than Factor B and Z that are present in the impure E are separated. 129.
Det er å merke at Faktor B synes fortrinnsvis å synergiseres av Faktor Z (PA 114B) og at tilsetning av PA114A (som er identisk med E. 129 Faktor A) til blandinger av Faktor B og Z i alminnelighet ikke gir noe tegn på vesentlig ytterligere syner-gisme. Hvis der imidlertid er tilstede et fremtredende overskudd av Faktor Z, kan tilsetning av PA114A forårsake noen økning i den totale aktivitet. It is noted that Factor B appears to preferentially synergize with Factor Z (PA 114B) and that addition of PA114A (which is identical to E. 129 Factor A) to mixtures of Factor B and Z generally gives no sign of significant additional synergism. If, however, a marked excess of Factor Z is present, addition of PA114A may cause some increase in total activity.
Det foretrekkes å arbeide slik i fremgangsmåten ifølge oppfinnelsen at meng-deforholdene mellom Faktor B og Z i pro-duktet ligger innenfor området fra 1:5 til 5 : 1. De beste resultater synes å oppnåes med produkter i hvilke vektsforholdet Faktor B til Z er 1 : 1 eller deromkring. It is preferred to work in such a way in the method according to the invention that the quantity ratio between Factor B and Z in the product is within the range from 1:5 to 5:1. The best results seem to be achieved with products in which the weight ratio of Factor B to Z is 1:1 or thereabouts.
Faktor B og Z lar seg vanskelig frem-stille i ren tilstand av E. 129 i form av råprodukt fremstillet ved dyrkning, men som det vil fremgå av det foregående er det ikke nødvendig at Faktorene befries fra andre stoffer som er dannet under dyrkningen, da sådanne bestanddeler, in-klusive de andre antibiotisk virkende bestanddeler øyensynlig ikke er ufordelaktige når det ferdige preparat gis f. eks gjennom munnen. Som foran nevnt bør ikke de nevnte andre stoffer utgjøre mere enn 70 % av det hele antibiotiske middel og bør fortrinnsvis ikke utgjøre mere enn 50 %. Det mengdeforhold av Faktor B som er tilstede bør være minst 15 vektprosent og fordelaktig mere enn 25 vektprosent. Factors B and Z are difficult to produce in a pure state from E. 129 in the form of raw product produced by cultivation, but as will be clear from the foregoing, it is not necessary that the Factors be freed from other substances formed during cultivation, as such ingredients, including the other antibiotic-acting ingredients, are apparently not disadvantageous when the finished preparation is given, for example, by mouth. As mentioned above, the aforementioned other substances should not make up more than 70% of the entire antibiotic and should preferably not make up more than 50%. The amount of Factor B present should be at least 15% by weight and advantageously more than 25% by weight.
I E. 129 i form av råprodukt vil mengdeforholdet av Faktor B i alminnelighet være større enn mengdeforholdet av Faktor Z, mens som nevnt produkter inneholdende omkring like vektsdeler av de to Faktorer viser den største synergistiske virkning. In E. 129 in the form of raw product, the quantity ratio of Factor B will generally be greater than the quantity ratio of Factor Z, while as mentioned products containing approximately equal parts by weight of the two Factors show the greatest synergistic effect.
De nye antibiotiske midler fremstillet ved fremgangsmåten ifølge oppfinnelsen kan anvendes på en hvilkensomhelst øn-sket måte. Således kan de avpasses for både oral og parenteral anvendelse. Preparater for oral anvendelse kan foreligge i form av f. eks. tabletter, kapsler, suspen-sjoner, siruper og miksturer. The new antibiotic agents produced by the method according to the invention can be used in any desired way. Thus, they can be adapted for both oral and parenteral use. Preparations for oral use can be available in the form of e.g. tablets, capsules, suspensions, syrups and mixtures.
Da Faktor B og Z ligner andre antibiotisk aktive Faktorer i E. 129, må man ta i betraktning metoder til identifisering og undersøkelse av disse to bestanddeler. As Factors B and Z resemble other antibiotically active Factors in E. 129, methods for identification and investigation of these two components must be taken into account.
Faktor B er fullt ut karakterisert i patent nr. 94 895 og en fremgangsmåte til utvinning av denne Faktor er beskrevet i dette patent. Faktor Z er som foran nevnt identisk med det tidligere beskrevne antibiotiske middel PA114B, men for å utelukke tvil om denne bestanddels karakteristika angis her følgende angående disse: Factor B is fully characterized in patent no. 94 895 and a method for extracting this Factor is described in this patent. As mentioned above, factor Z is identical to the previously described antibiotic agent PA114B, but to rule out doubts about the characteristics of this component, the following is stated here regarding these:
Smeltepunkt: 270° C (spaltning) Absorpsjon i spektrets ultrafiolette om-råde: sesmetoder for bestemmelse av mengdefor-holdene av Faktor A, B og Z i E. 129-materiale. Disse metoder er viktige for overveiel-sen av om et bestemt råmateriale inneholder Faktor B og Z i ønskede forhold innenfor de foran angitte områder for vektsforholdet mellom disse Faktorer. Disse under-søkelsesmetoder er mikrobiologiske og er derfor underkastet .slike metoders begrens-ninger med hensyn til nøyaktighet. To me-, toder (I) og (II) er følgende: Metode I: Man :skiller først de tre f ak- i torer (A, B, Z) ved kromatografi på filtrer-1 papirark. Disse legges derpå på agarplater; som er podet med passende mikroorganis-mer, og størrelsen av hemnlngssonene er-j holdt etter inkubasjon sammenlignes med; hemningssoner som er forårsaket av kjente' mengder av de tre bestanddeler. , Melting point: 270° C (decomposition) Absorption in the ultraviolet region of the spectrum: visual methods for determining the quantity ratios of Factor A, B and Z in E. 129 material. These methods are important for the consideration of whether a particular raw material contains Factors B and Z in the desired proportions within the ranges specified above for the weight ratio between these Factors. These examination methods are microbiological and are therefore subject to the limitations of such methods with regard to accuracy. Two methods (I) and (II) are as follows: Method I: The three factors (A, B, Z) are first separated by chromatography on filter paper sheets. These are then placed on agar plates; which are inoculated with suitable micro-organisms, and the size of the hemnlngzones is kept after incubation is compared with; zones of inhibition which are caused by known quantities of the three constituents. ,
Metode II: Metode II kan bare brukes' til bestemmelse av Faktor Z. Den er i det, vesentlige en utvikling av den vanlige pla-; teteknikk. Der brukes en mikroorganismej som er mere følsom overfor Faktor Z enn! overfor Faktor A eller B. Enhver innvirk-j ning av de to sistnevnte faktorer minskes \ ytterligere ved å føre inn i agarmediet enj mengde av Faktor A som ligger under den! 'hemmende mengde.. Method II: Method II can only be used for the determination of Factor Z. It is essentially a development of the usual pla-; tea technique. There, a microorganism is used that is more sensitive to Factor Z than! against Factor A or B. Any influence of the two latter factors is further reduced by introducing into the agar medium an amount of Factor A which lies below it! 'inhibiting amount..
Metode I: Utviklingsoppløsningen for den kro-j matografiske adskillelse av de tre faktorer' er toppfasen av en blanding av benzen,! cykloheksan, metanol og vann (5:5:6:4); til hvilken der tilsettes 0,5 % iseddik. Pas-j sende fortynninger av standardmengderj av faktorene utføres samtidig med fortyn-, ningen av de ukjente blandinger. j Ved sammenligning av hemningsso-J nene for de ukjiente blandinger med hem-j ningssonene for standardmegdene får manj kurver fra hvilke den mengde materiale! som er tilstede i prøven som undersøkes kan beregnes på vanlig måte. For bestemmelse av Faktor Z utføres utviklingen i omkring 7 timer, og agarplatene inneholder 0,05 (xg Faktor A pr. m-l. Som organisme for undersøkelsen brukes Staphylococcus aureus N.C.T.C. 7447 eller B. subtilis A.T. CC. 6633. For bestemmelse av Faktor A 'Og B er utviklingstiden 16-^24 timer, agarplatene inneholder 0,1 ^g pr. ml av Faktor Z og organisme for undersøkelsen er Sarcina lutea N.CiT.C. 611. Method I: The developing solution for the chromatographic separation of the three factors' is the top phase of a mixture of benzene,! cyclohexane, methanol and water (5:5:6:4); to which 0.5% glacial acetic acid is added. Appropriate dilutions of standard amounts of the factors are carried out simultaneously with the dilution of the unknown mixtures. By comparing the inhibition zones for the unknown mixtures with the inhibition zones for the standard amounts, manj curves are obtained from which the amount of material! which is present in the sample under investigation can be calculated in the usual way. For the determination of Factor Z, the development is carried out for about 7 hours, and the agar plates contain 0.05 (xg Factor A per m-l. Staphylococcus aureus N.C.T.C. 7447 or B. subtilis A.T. CC. 6633 is used as the organism for the examination. For the determination of Factor A ' And B is the development time 16-^24 hours, the agar plates contain 0.1 ^g per ml of Factor Z and the organism for the examination is Sarcina lutea N.CiT.C. 611.
• Metode II: • Method II:
Den organisme som brukes til under-søkelsen i denne metode er B. subtilis A.T. CC. 6633 og mediet (bestående av fast agar inneholder 4 ^g pr. ml av Faktor A. En standardoppløsning av Faktor 'Z i etanol fortynnes med citrat-pufferoppløsning med pH-verdi 6,3 så at man får konsentrasjoner på 4,0, 2,0 og 1,0 [xg pr. ml. Oppløsningene i disse fortynninger .påføres agarplaten på vanlig måte sammen med de oppløsninger som skal undersøkes 1 fortynninger. Pla-tene inkuberes natten over ved 37° C og sonenes størrelser måles. Logaritmen for dosenes vekt avsettes på et diaggram mot hemningssonenes diameter, hvorved man får en rett linje fra hvilken de undersøkte prøvers potensial kan bestemmes. The organism used for the investigation in this method is B. subtilis A.T. CC. 6633 and the medium (consisting of solid agar) contains 4 g per ml of Factor A. A standard solution of Factor Z in ethanol is diluted with citrate buffer solution of pH 6.3 so that concentrations of 4.0, 2 .0 and 1.0 [xg per ml. The solutions in these dilutions are applied to the agar plate in the usual way together with the solutions to be examined in 1 dilutions. The plates are incubated overnight at 37° C and the sizes of the zones are measured. The logarithm of the doses weight is plotted on a diagram against the diameter of the inhibition zones, whereby a straight line is obtained from which the potential of the examined samples can be determined.
Til ytterligere forklaring av oppfinnelsen gis der i det følgende detaljer fra un-dersøkelser som er utført angående den antibiotiske aktivitet for Faktor B og Z. For further explanation of the invention, details from studies carried out regarding the antibiotic activity for Factors B and Z are given in the following.
Forsøk 1: Attempt 1:
Aktiviteten ln vitro av blandinger inneholdende Faktor B og Z i forskjellige mengdeforhold ble bestemt. Resultatene var følgende: The activity in vitro of mixtures containing Factor B and Z in different proportions was determined. The results were as follows:
Forsøk 2: Attempt 2:
Aktiviteten in vivo av blandinger inneholdende Faktor B og Z i forskjellige mengdeforhold ble bestemt ved beskyttel- sesprøver under anvendelse av eksperimen-telle infeksjoner av mus med Staphylococcus aureus. Blandingene ble injisert subfcu-tant. Resultatene av to sett forsøk var føl-gende : The in vivo activity of mixtures containing Factor B and Z in different proportions was determined by protective tests using experimental infections of mice with Staphylococcus aureus. The mixtures were injected subcutaneously. The results of two sets of trials were as follows:
Forsøk 3: Attempt 3:
Effektiviteten av forskjellige blandin ger av Faktor B og Faktor Z gitt oralt i sammenligning med subkutan anvendelse ble studert med følgende resultater: The effectiveness of different mixts gers of Factor B and Factor Z given orally i comparison with subcutaneous application was studied with the following results:
Forsøk 4: Attempt 4:
Innhold av antibiotikum i blodet. Antibiotic content in the blood.
Tre preparater ble sammenlignet ved anvendelse på mennesker. Hvert preparat ble gitt oralt i doser på 2 g. Innholdet av antibiotikum i blodet ble bestemt ved den hemmende virkning på Streptococcus py-ogenes (idet man brukte E. 129 i form av råprodukt, ref. i eksempel 1, som standard-materiale). Resultatene ble uttrykt som E. 129-råprodukt mikrogram-ml ekvivalenter. Preparat I inneholdt 10 % Faktor Z og 25 % Faktor B. Preparat II inneholdt 23 % Faktor Z og 21 % Faktor B. Preparat III inneholdt 50 % Faktor Z og 50 % Faktor B. Three preparations were compared when applied to humans. Each preparation was given orally in doses of 2 g. The content of antibiotic in the blood was determined by the inhibitory effect on Streptococcus pyogenes (using E. 129 in the form of raw product, ref. in example 1, as standard material) . The results were expressed as E. 129 crude product microgram-ml equivalents. Preparation I contained 10% Factor Z and 25% Factor B. Preparation II contained 23% Factor Z and 21% Factor B. Preparation III contained 50% Factor Z and 50% Factor B.
I nedenstående tabell angis de resultater som ble funnet hos mennesker ved de i tabellen angitte tidsrom etter at pre-paratet var gitt. The table below shows the results that were found in humans at the time periods indicated in the table after the preparation was given.
Det vil sees at preparat II tiltross for It will be seen that preparation II in spite of
et litt lavere innhold av Faktor B er preparat I overlegent, hva der skyldes at Faktor a slightly lower content of Factor B is preparation I superior, what is due to Factor
B og Faktor Z er tilstede omtrentlig i det B and Factor Z are present approximately in it
optimale mengdeforhold 1:1. Det sees videre at preparat III er begge de andre preparater overlegent. I preparat III er det optimal quantity ratio 1:1. It can also be seen that preparation III is superior to both of the other preparations. In preparation III it is
fordelaktige mengdeforhold 1 : 1 kombinert advantageous quantity ratio 1:1 combined
med det høyeste innhold av Faktor B som with the highest content of Factor B which
er forenlig med disse mengdeforhold. is compatible with these quantity ratios.
Disse resultater stemmer således med These results are thus in agreement
forsøkene angående beskyttelse av dyr ved the experiments regarding the protection of animals by
at de viser at forholdet 1 : 1 mellom Faktor that they show that the ratio 1 : 1 between Factor
B og Z er det fordelaktigste. B and Z are the most advantageous.
Claims (4)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR106371A FR1530505A (en) | 1967-05-12 | 1967-05-12 | New carton, especially suitable for deep drawing |
Publications (1)
Publication Number | Publication Date |
---|---|
NO127042B true NO127042B (en) | 1973-04-30 |
Family
ID=8630824
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO01830/68A NO127042B (en) | 1967-05-12 | 1968-05-10 |
Country Status (11)
Country | Link |
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AT (1) | AT291734B (en) |
BE (1) | BE714716A (en) |
CH (1) | CH494112A (en) |
DE (2) | DE1761002B1 (en) |
ES (1) | ES150389Y (en) |
FI (1) | FI52953C (en) |
FR (1) | FR1530505A (en) |
GB (1) | GB1218671A (en) |
NL (1) | NL145186B (en) |
NO (1) | NO127042B (en) |
SE (1) | SE340746B (en) |
Families Citing this family (7)
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FR2336246A2 (en) * | 1975-02-05 | 1977-07-22 | Roth Sa Freres | MANUFACTURING PROCESS OF SHAPED PANELS BASED ON CARDBOARD AND FOAM, AND PANELS THUS REALIZED |
GB1555882A (en) * | 1976-07-14 | 1979-11-14 | Nissan Motor | Method and apparatusfor production of a laminated and non planar trim panel ofcorrugated paperboard base |
US4242399A (en) * | 1977-06-09 | 1980-12-30 | Nissan Motor Company, Limited | Corrugated paperboard for trim board and method of producing the same |
ITVE20080011A1 (en) * | 2008-02-14 | 2009-08-15 | Giorgio Trani | MULTILAYER PAPER MATERIAL PROCEDURE FOR OBTAINING SUCH MATERIALS WRAPPED BY THIS MATERIAL AND PROCEDURE TO OBTAIN THESE INSERT |
SE536107C2 (en) * | 2010-08-26 | 2013-05-07 | Stora Enso Oyj | Method of forming a package, a package and a blank |
DE102014106427A1 (en) | 2014-05-08 | 2015-11-12 | Technische Universität Dresden | Method and device for producing molded parts from a fiber material web |
DE102016106142A1 (en) | 2016-04-04 | 2017-10-05 | Technische Universität Dresden | Packaging comprising fiber material and method for its production by compression drawing |
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US2139138A (en) * | 1931-10-16 | 1938-12-06 | Wood Conversion Co | Corrugated structure |
GB736410A (en) * | 1952-06-24 | 1955-09-07 | Thompson And Norris Mfg Compan | Improvements in or relating to the manufacture of corrugated wrapping or packing materials |
DE1176459B (en) * | 1962-07-18 | 1964-08-20 | Rob Heymann & Co | Embossing plate pair and process for its manufacture |
-
1967
- 1967-05-12 FR FR106371A patent/FR1530505A/en not_active Expired
-
1968
- 1968-03-20 DE DE19681761002 patent/DE1761002B1/en not_active Withdrawn
- 1968-03-20 DE DE6608422U patent/DE6608422U/en not_active Expired
- 1968-03-27 NL NL686804297A patent/NL145186B/en not_active IP Right Cessation
- 1968-05-06 BE BE714716D patent/BE714716A/xx unknown
- 1968-05-08 SE SE06236/68A patent/SE340746B/xx unknown
- 1968-05-08 CH CH685468A patent/CH494112A/en not_active IP Right Cessation
- 1968-05-10 NO NO01830/68A patent/NO127042B/no unknown
- 1968-05-10 GB GB22343/68A patent/GB1218671A/en not_active Expired
- 1968-05-10 AT AT451368A patent/AT291734B/en not_active IP Right Cessation
- 1968-05-10 FI FI1321/68A patent/FI52953C/fi active
- 1968-05-11 ES ES1968150389U patent/ES150389Y/en not_active Expired
Also Published As
Publication number | Publication date |
---|---|
AT291734B (en) | 1971-07-26 |
NL6804297A (en) | 1968-11-13 |
GB1218671A (en) | 1971-01-06 |
DE6608422U (en) | 1971-08-19 |
CH494112A (en) | 1970-07-31 |
BE714716A (en) | 1968-09-30 |
SE340746B (en) | 1971-11-29 |
NL145186B (en) | 1975-03-17 |
ES150389U (en) | 1969-11-16 |
FI52953C (en) | 1978-01-10 |
ES150389Y (en) | 1971-01-01 |
DE1761002B1 (en) | 1972-05-31 |
FI52953B (en) | 1977-09-30 |
FR1530505A (en) | 1968-06-28 |
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