NO126102B - - Google Patents
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- NO126102B NO126102B NO16813767A NO16813767A NO126102B NO 126102 B NO126102 B NO 126102B NO 16813767 A NO16813767 A NO 16813767A NO 16813767 A NO16813767 A NO 16813767A NO 126102 B NO126102 B NO 126102B
- Authority
- NO
- Norway
- Prior art keywords
- coli
- aerogenes
- resistant
- preparations
- strains
- Prior art date
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- 238000000034 method Methods 0.000 claims description 16
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Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/0006—Controlling or regulating processes
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Physical Or Chemical Processes And Apparatus (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Description
Fremgangsmåte til fremstilling av et terapeutisk virksomt bakteriepreparat. Method for producing a therapeutically effective bacterial preparation.
Oppfinnelsen angår preparater til behandling av tarmsykdommer og til forebyg-gelse av tarmbeværligheter resp. -sykdom-mer, og spesielt en fremgangsmåte til fremstilling av terapeutisk virksomme bakteriepreparater. The invention relates to preparations for the treatment of intestinal diseases and for the prevention of intestinal disorders resp. -disease-more, and in particular a method for the production of therapeutically effective bacterial preparations.
Antibiotika, spesielt bredbånd-antibiotika har ved sin virkning også innflytelse Antibiotics, especially broad-spectrum antibiotics, also have an influence by their effect
på de symbiotisk levende tarmfysiologiske on the symbiotically living intestinal physiological
kim, som Escherichia coli og Aerobacter germs, such as Escherichia coli and Aerobacter
aerogenes. Etter anvendelse av antibiotika, aerogenes. After the use of antibiotics,
fremfor alt ved lengere tids bruk av bredbånd-antiobiotika, kan det inntre en vidt-gående eliminering av den tarmfysiologiske Above all, with long-term use of broad-spectrum antibiotics, a far-reaching elimination of the intestinal physiological
flora. Med dette er forbundet et tap av de flora. This is associated with a loss of them
symbiotiske funksjoner av disse kim, som symbiotic functions of these germs, which
vitaminsyntese, stoffvekselytelser, melke-syregj æring med antiseptisk virkning, som vitamin synthesis, metabolic benefits, lactic acid fermentation with an antiseptic effect, such as
bakeriell antagonisme. Til bortfalningen bakerial antagonism. To the demise
av disse funksjoner kan også føres tilbake of these functions can also be returned
de etter langvarig behandling med bred-båndantibiotika opptredende symptomer, the symptoms appearing after long-term treatment with broad-spectrum antibiotics,
som diaré, den hyppige overhåndtagen av as diarrhoea, the frequent upper handle of
forholdsvis antibiotikaresistente kim, f. eks. relatively antibiotic-resistant germs, e.g.
stafylokokker, som kan trekke med seg en staphylococci, which can carry a
betendelse i tarmen (stafylokokkogen ente-ritis etter bruk av bredbånd-antibiotika). inflammation of the intestine (staphylococcal enteritis after the use of broad-spectrum antibiotics).
Den foreliggende oppfinneles har det The present invention has it
mål å unngå de ulemper som kunne opp-tre ved en beskadigelse av den tarmfysiologiske flora. Videre har den til formål å aim to avoid the disadvantages that could arise from damage to the intestinal physiological flora. Furthermore, it aims to
skaffe et profylaktisk virkende middel som provide a prophylactic agent which
hindrer tarmforstyrrelser ved inngivning prevents intestinal disorders when administered
av antibiotika. Et videre mål er å fjerne of antibiotics. A further goal is to remove
slike følger som har innstillet seg ved terapeutisk anvendelse av antibiotika. Endelig such consequences as have occurred with the therapeutic use of antibiotics. Finally
har oppfinnelsen til mål å muliggjøre vi-dereføring av antibiotikabehandlinger når the invention aims to enable the continuation of antibiotic treatments when
det allerede har opptrådt tarmbesværligheter. bowel problems have already occurred.
Oppfinnerne har funnet, at det fås terapeutisk virksomme bakteriepreparater, som kan hindre eller bekjempe tarmforstyrrelser, hvis en funksjonsdyktig, natur-lig resistent, apatogen stamme av Escherichia coli og Aerobacter aerogenes, som ved tetracyclenkonsentrasjoner på over 50 mikrogram/ml, fortrinsvis på over 100 mikrogram/ml, fremdeles viser vekst og som er fullstendig ømfintlig like overfor kloramfenicol, særlig E. coli 14230 (NRRL nr. B 1958) eller A.aerogenes 16092 (NRRL B 1959) dyrkes i resp. på næringsmedier som inneholder en kvelstoffkilde og en kullstoff-kilde, og de erholdte kulturer forarbeides til tørrpreparater. The inventors have found that therapeutically effective bacterial preparations are available, which can prevent or combat intestinal disorders, if a functional, naturally resistant, apathogenic strain of Escherichia coli and Aerobacter aerogenes, as with tetracycline concentrations of over 50 micrograms/ml, preferably over 100 micrograms/ml, still showing growth and which are completely sensitive to chloramphenicol, especially E. coli 14230 (NRRL No. B 1958) or A.aerogenes 16092 (NRRL B 1959) are grown in resp. on nutrient media containing a nitrogen source and a carbon source, and the cultures obtained are processed into dry preparations.
Som kvelstoffkilder for de ved fremgangsmåten ifølge oppfinnelsen anvendte næringsmedier kommer eksempelvis på tale: et anorganisk salt som f. eks. na-triumnitrat eller ammoniumsulfat, et or-ganisk som f. eks. maisuttrekk, gjær, gjær-autolysat, peptoner, sojabønnemel o. 1. Næ-ringsmediet kan også inneholde mine-ralsalter, puffere o. 1. Examples of nitrogen sources for the nutrient media used in the method according to the invention include: an inorganic salt such as sodium nitrate or ammonium sulphate, an organic such as e.g. corn extract, yeast, yeast autolysate, peptones, soybean meal etc. 1. The nutrient medium may also contain mineral salts, buffers etc. 1.
Som kullstoffkilder for fremgangsmåten i henhold til oppfinnelsen kan det f. eks. anvendes dekstrin, stivelse, glyserin, galaktose, arabinose, rhamnose, xylose, glukose, lævulose, cellobiose, isonitt, inulin, mannitt, dulcitt, sorbitt, laktose, maltose, sakkarose o. 1. As carbon sources for the method according to the invention, it can e.g. dextrin, starch, glycerin, galactose, arabinose, rhamnose, xylose, glucose, levulose, cellobiose, isonite, inulin, mannitol, dulcitol, sorbitol, lactose, maltose, sucrose etc. 1 are used.
Utvinningen av mot antibiotika av tetracyklinrekken resistente funksjonsdyk-tige apatogene bakteriestammer skjer ved utvalg etter foretatte rekkeundersøkelser av avføring fra friske individer. For det formål kan undersøkelsesmaterialet inokuleres over på en endoplate og dyrkes (f. eks. i 20 timer ved 37° C). Typiske kolonier, f. eks. av Escherichia coli resp. Aerobacter aerogenes, som utvikler seg på endoplaten, kan så inokuleres pånytt for å isoleres, og etter at de er blitt rendyrket prøves de på i og for seg kjent måte angående deres bio-kjemisk forhold, f. eks. med hensyn til en forgjæring av laktose, dekstrose, sakkarose, mannitt, samt dannelse av H2S, indol, spalt-ning av urinstoff, vekst på citratnærings-bunner. «Vogess-Proskauerreaksjon» (på-visning av acetylmetylkarbinol) o. 1. Ved denne biokjemiske undersøkelse av som typiske stammer påviste kolonier, spesielt av E. coli og A. aerogenes, ble også deres resistens likeoverfor forskjellige antibiotika undersøkt. The extraction of functionally apathogenic bacterial strains resistant to antibiotics from the tetracycline series is carried out by selection after serial examinations of faeces from healthy individuals. For that purpose, the test material can be inoculated onto an endoplate and cultured (eg for 20 hours at 37° C). Typical colonies, e.g. of Escherichia coli resp. Aerobacter aerogenes, which develop on the endoplate, can then be inoculated again to be isolated, and after they have been purified, they are tested in a manner known per se as to their bio-chemical relationship, e.g. with regard to a fermentation of lactose, dextrose, sucrose, mannitol, as well as formation of H2S, indole, cleavage of urea, growth on citrate nutrient substrates. "Vogess-Proskauer reaction" (detection of acetylmethylcarbinol) etc. 1. In this biochemical examination of colonies identified as typical strains, especially of E. coli and A. aerogenes, their resistance to various antibiotics was also examined.
Den kvantitative resistensbestemmelse kan foregå i prøverør. Ved hjelp av en rekke fortynninger av vedkommende antibiotikum med faktoren y2, altså i geometrisk progresjon, hvorunder utgangsoppløsnin-gen fortynnes med en vanlig næringsbuljong, testes den bakteriostatiske virkning likeoverfor et konstant mokulat av stammen, som undersøkes, i en passende tid (f. eks. 20 timer). De derved erholdte anti-biogrammer karakteriserer de isolerte stammer, og man kan av dem erkjenne graden og arten av antibiotikaresistensen. The quantitative resistance determination can take place in a test tube. By means of a series of dilutions of the relevant antibiotic with the factor y2, i.e. in geometric progression, during which the starting solution is diluted with a normal nutrient broth, the bacteriostatic effect is tested directly opposite a constant moculate of the strain, which is examined, for a suitable time (e.g. . 20 hours). The anti-biograms thus obtained characterize the isolated strains, and the degree and nature of the antibiotic resistance can be recognized from them.
Blant de mot antibiotika av tetracyklinrekken særlig resistente stammer av coli- resp. aerogenes-rekken skal spesielt fremheves Escherichia coli 14230 (NRRL Nr. 1958) og Aearobacter aerogenes 16092 (NRRL Nr. 1959). Among the particularly resistant strains of coli resp. aerogenes series, Escherichia coli 14230 (NRRL No. 1958) and Aearobacter aerogenes 16092 (NRRL No. 1959) should be highlighted in particular.
Etter at det ved den orienterende for-undersøkelse ved hjelp av småbladprøven kvalitativt var fastslått en resistens overfor antibiotika av tetracyklinrekken, ble E. coli 14230 underkastet den kvantitative under-søkelse på sensibilitet resp. resistens ved hjelp av en rørprøve. Ved anvendelse av den nedenfor beskrevne metode og anvendelse av kjemisk rene prøvestoffer (standard) ble følgende verdier funnet: After a resistance to antibiotics of the tetracycline series had been qualitatively established in the orientation preliminary examination using the small leaf sample, E. coli 14230 was subjected to the quantitative examination of sensitivity resp. resistance using a pipe test. When applying the method described below and using chemically pure test substances (standard), the following values were found:
1. E. coli 14230 er ennå resistent: 1. E. coli 14230 is still resistant:
Ved en konsentrasjon på 110,0 mcg/ml klortetracyklin HC1, standard 329,0 mcg/ml oksytetracyklin HC1, standard 329,0 mcg/ml tetracyklin HC1, standard; At a concentration of 110.0 mcg/ml chlortetracycline HC1, standard 329.0 mcg/ml oxytetracycline HC1, standard 329.0 mcg/ml tetracycline HC1, standard;
2. E. coli 14230 er ennå ømfintlig: 2. E. coli 14230 is still sensitive:
Ved en konsentrasjon på 5,7 mcg/ml kloramfenikolstandard 3,8 mcg/ml dihydrostreptomycinsul-fat-standard 3,8 mcg/ml streptomycinsulfatstan-dard 13,05 mcg/ml erytromycin-standard 3. E. coli 14230 er videre resistent: Ved en konsentrasjon på 43,2 mcg/ml viomycin-standard 2222,2 mcg/ml bacitracin-standard 3333,9 mcg/ml neomycin-standard Pluss- og minussvingninger inntil y3 av de angitte verdier ligger innenfor feilgrense-området av den nedenfor anførte metode. At a concentration of 5.7 mcg/ml chloramphenicol standard 3.8 mcg/ml dihydrostreptomycin sulfate standard 3.8 mcg/ml streptomycin sulfate standard 13.05 mcg/ml erythromycin standard 3. E. coli 14230 is further resistant: At a concentration of 43.2 mcg/ml viomycin standard 2222.2 mcg/ml bacitracin standard 3333.9 mcg/ml neomycin standard Plus and minus fluctuations up to y3 of the specified values are within the error limit range of the method stated below.
Det viser seg videre at denne isolerte stamme såvel lyofilisert som også ved opp-bevaring ved værelsestemperatur i skrå-agarkultur i det det vesentlige bibeholdt sin sensibilitetsverdi overfor antibiotika. It also turns out that this isolated strain, both lyophilized and when stored at room temperature in slanted agar culture, essentially retained its sensitivity value to antibiotics.
Metode: Method:
Rørprøve: Pipe test:
Ved hjelp av en % fortynningsrekke av det tilsvarende antibiotikum undersøkes konsentrasjonen, hvor en bakteriostatisk virkning er tilstede på et bestemt og i hvert rør konstant inokulat av stammen E. coli 14230. Using a % dilution series of the corresponding antibiotic, the concentration is examined, where a bacteriostatic effect is present on a specific and in each tube constant inoculum of the strain E. coli 14230.
Skjematisk gjengivelse av metoden: Schematic representation of the method:
Behandling ved 37° C. Treatment at 37°C.
Avlesning efter 20 timer m. h. t. kimvekst (uklar) resp. bakteriostase (klar). Reading after 20 hours in terms of germination (unclear) or bacteriostasis (clear).
Konsentrasjonene av antibiotika-stam-oppløsningene, hvormed fortynningsrekken ble gjennomført, utgjorde ved: The concentrations of the antibiotic stock solutions, with which the dilution series was carried out, amounted to:
Antibiotika av tetracyklinrekken ble oppløst i aqua dest. som var innstilt med en orto-fosforsyre på pH 6,1. På samme måte ble den buljong som ble anvendt til prøve av antibiotika av tetracyklinrekken innstilt på pH 6,1 med n-orto-fosforsyre. Antibiotics of the tetracycline series were dissolved in aqua dest. which was adjusted with an ortho-phosphoric acid at pH 6.1. In the same way, the broth used for testing antibiotics of the tetracycline series was adjusted to pH 6.1 with n-ortho-phosphoric acid.
De øvrige antibiotika ble oppløst i aqua dest. The other antibiotics were dissolved in aqua dest.
A. aerogenes 16092 ble underkastet den samme kvalitative og kvantitative under-søkelse på sensibilitet resp. resistens ved hjelp av rørprøven. Ved anvendelse av den nedenfor beskrevne metode og anvendelse av kjemisk rene prøvestoffer (standard) ble følgende verdier fastslått: 1. A. aerogenes 16092 er ennå resistent: Ved en konsentrasjon av 164,8 mcg/ml klortetracyklin HC1, standard 493,8 mcg/ml oksytetracyklin HC1, standard 740,7 mcg/ml tetracyklin HC1, standard; 2. A. aerogenes 16092 er ennå ømfintlig: Ved en konsentrasjon på 5,7 mcg/ml kloramfenikol-standard 12,8 mcg/ml neomycin-standard; 3. A. aerogenes 16092 er videre resistent: Ved en konsentrasjon av 333,3 mcg/ml streptomycinsulfat-standard 222,2 mcg/ml erytromycin-standard 75,25 mcg/ml viomycin-standard; A. aerogenes 16092 was subjected to the same qualitative and quantitative examination of sensitivity resp. resistance using the pipe test. By applying the method described below and using chemically pure test substances (standard), the following values were determined: 1. A. aerogenes 16092 is still resistant: At a concentration of 164.8 mcg/ml chlortetracycline HC1, standard 493.8 mcg/ml oxytetracycline HC1, standard 740.7 mcg/ml tetracycline HC1, standard; 2. A. aerogenes 16092 is still sensitive: At a concentration of 5.7 mcg/ml chloramphenicol standard 12.8 mcg/ml neomycin standard; 3. A. aerogenes 16092 is further resistant: At a concentration of 333.3 mcg/ml streptomycin sulfate standard 222.2 mcg/ml erythromycin standard 75.25 mcg/ml viomycin standard;
Pluss- og minussvingninger inntil y3 av de angitte verdier ligger innen feilgrense-området av den nedenfor anførte metode. Det viste seg vidert at denne isolerte stamme lyofilisert i det vesentlig bibeholdt sine sensibilitetsverdier overfor antibiotika. Plus and minus fluctuations up to y3 of the specified values are within the error limit range of the method listed below. It was also found that this isolated strain lyophilized essentially retained its sensitivity values towards antibiotics.
Metode: Method:
Rørprøve: Pipe test:
Ved hjelp av en % fortynningsrekke av det tilsvarende antibiotikum undersøkes konsentrasjonen hvor en bakteriostatisk virkning er tilstede på et bestemt og i hvert rør konstant inokulat av stammen A. aerogenes 16092. Skjematisk gjengivelse av metoden : With the help of a % dilution series of the corresponding antibiotic, the concentration at which a bacteriostatic effect is present on a specific and in each tube a constant inoculum of the strain A. aerogenes 16092 is investigated. Schematic representation of the method:
Behandling ved 37° C. Treatment at 37°C.
Avlesning etter 20 timer med hensyn til kimvekst (uklar) resp. bakteriostase (klar). Reading after 20 hours with regard to germination (unclear) or bacteriostasis (clear).
Konsentrasjonene av antibiotika-stam-oppløsningene, hvormed fortynningsrekken ble gjennomført, utgjorde ved: The concentrations of the antibiotic stock solutions, with which the dilution series was carried out, amounted to:
Klortetracyklin HC1, Chlortetracycline HC1,
Tetracyklinrekkens antibiotika ble opp-løst i aqua dest., som med n-orto-fosforsyre The antibiotics of the tetracycline series were dissolved in aqua dest., as with n-ortho-phosphoric acid
var innstilt på pH 6,1. På samme måte ble was set to pH 6.1. In the same way was
den buljong som ble anvendt til prøving av antibiotika-tetracyklinrekken innstilt med n-orto-fosforsyre på pH 6,1. De øvrige antibiotika ble oppløst i aqua dest. the broth used for testing the antibiotic tetracycline series adjusted with n-ortho-phosphoric acid to pH 6.1. The other antibiotics were dissolved in aqua dest.
For å utelukke patogene former fra de mot antibiotika resistente stammer, blir de stammer som kommer på tale for terapeutisk anvendelse undersøkt — foruten på resistens — også på apatogenitet. For å utelukke eventuelle dyspepsistammer ble det rutinemessig foretatt serologiske agglutina-sjonsforsøk (objektbæremetoden) under anvendelse av dyspepsiseraene: 0 111 B4, 0 55 B3, 0 26 BG og 0 86. In order to exclude pathogenic forms from the antibiotic-resistant strains, the strains that come into question for therapeutic use are examined — in addition to resistance — also for apathogenicity. In order to rule out any dyspepsia strains, serological agglutination tests (the object carrier method) were routinely carried out using the dyspepsia sera: 0 111 B4, 0 55 B3, 0 26 BG and 0 86.
Stammene av Aerobacter aerogenes ble testet på apatogeniset ved forsøk med mus, hvor 50 g tunge mus hver gang ble inokulert med 0,1 ml av en i 20 timer dyrket buljong. The strains of Aerobacter aerogenes were tested for apathogenicity in experiments with mice, where 50 g of heavy mice were each time inoculated with 0.1 ml of a broth cultured for 20 hours.
Til fremstilling av de terapeutiske preparater blir det bare anvendt stammer som ved den ovennevnte prøve har vist seg å være apatogene. For the production of the therapeutic preparations, only strains are used which have been shown to be apathogenic in the above-mentioned test.
Ved fremstillingen av preparater i henhold til oppfinnelsen anvendes det fortrinsvis en bakteriestamme som er resistent likeoverfor minst et antibiotikum av tetracyklinrekken; det er av betydning at de resistente stammer er følsomme likeoverfor enkelte antibiotika, f. eks. likeoverfor kloramfenicol erytromycin, neomycin, viomycin, hvorved det er mulig, om nødvendig å trenge tilbake i legemet innførte bakteriestammer som bare er resistente likeoverfor bestemte antibiotika, ved anvendelse av en bestemt antibiotikaterapi. In the preparation of preparations according to the invention, preferably a bacterial strain is used which is resistant to at least one antibiotic of the tetracycline series; it is important that the resistant strains are equally sensitive to certain antibiotics, e.g. opposite to chloramphenicol erythromycin, neomycin, viomycin, whereby it is possible, if necessary, to penetrate back into the body introduced bacterial strains which are only resistant opposite to specific antibiotics, using a specific antibiotic therapy.
Hvis patienten gis flere stammer av bakterier inntrer en gjensidig komplette-ring av den bakterielt antigonistiske virkning. Ennvidere bevirker anvendelsen av flere stammer en forbedring av den poten-sielle tilpasning til det ofte meget forskjellige miljø i tarmens område. If the patient is given several strains of bacteria, a mutual complementation of the bacterial antagonistic effect occurs. Furthermore, the use of several strains improves the potential adaptation to the often very different environment in the area of the intestine.
Dyrkingen av de enkelte mot tetracyc-linresistente coli- resp. aerogenesstam-mene, skjer ved fremgangsmåten i henhold til oppfinnelsen prinsipielt adskilt, dvs. at hver resistent stamme dyrkes for seg, mens man ved tørkingen kan anvende såvel enkelte stammer for seg alene som også blan-dinger av forskjellige stammer. Skal man lagre et forråd av tørkede stammer, er det å anbefale å tørke hver enkelt stamme for seg. The cultivation of the individual tetracycline-resistant coli resp. the aerogenes strains, in the method according to the invention, are principally separated, i.e. that each resistant strain is cultivated separately, while during the drying process individual strains can be used individually as well as mixtures of different strains. If you are to store a supply of dried stems, it is recommended to dry each individual stem separately.
Ved fremstilling av tørrpreparatene av resistente stammer kan man eksempelvis går ut fra en buljong som er blitt behand-let i 20 timer ved ca. 37° C med vedkommende stamme, og som inokuleres over på agarplater. Etter en videre dyrking på disse agarplater (20 timer ved ca. 37° C) blir overflatekoloniene avspylet, eventuelt flere ganger, ved hjelp av fysiologiske koksalt-oppløsninger, som eventuelt kan være til-blandet i og for seg kjente vekstsubtrater, som laktose, fortrinsvis a-laktose, og vekst-stoff som biotin, p-aminobenzoesyre, niko-tinsyreamid (P. P.-faktor), aneurin (Bj), laktoflavin (B2), cyano-cobalamin (B12), fol-syre, pantotensyre eller liknende. Coli-resp. aerogenesstammer kan også fremstilles i stor målestokk ved overflate- resp. submer-metoden. Fra de således erholdte bakterieanrikninger kan deretter bakteriemassen utskilles ved hjelp av passende sen-trifuge, f. eks. Sharples-sentrifugen. Eventuelt kan man også ved gjentatte oppslem-inger i vann og fornyet utsentrifugering fjerne restene av næringsoppløsningen fra bakteriemassen. When producing the dry preparations of resistant strains, one can for example start from a broth that has been treated for 20 hours at approx. 37° C with the relevant strain, and which is inoculated onto agar plates. After further cultivation on these agar plates (20 hours at approx. 37° C), the surface colonies are rinsed off, possibly several times, using physiological saline solutions, which may optionally be mixed with known growth substrates, such as lactose, preferably α-lactose, and growth substances such as biotin, p-aminobenzoic acid, nicotinic acid amide (PP factor), aneurin (Bj), lactoflavin (B2), cyano-cobalamin (B12), folic acid, pantothenic acid or the like. Coli or aerogeneous strains can also be produced on a large scale by surface or the submer method. From the bacterial enrichments thus obtained, the bacterial mass can then be separated using a suitable centrifuge, e.g. The Sharples centrifuge. Optionally, the remains of the nutrient solution can also be removed from the bacterial mass by repeated slurries in water and renewed centrifugation.
De således erholdte bakteriesuspensjo-ner kan for utvinning av tørrpreparatene underkastes f. eks. en lyofilisering, hvorunder det for stabilisering av preparatet kan tilsettes beskyttelsesstoffer, som f. eks. pektinstoffer, eggehvitestoffer, tragant og liknende, før frysetørkingen. I preparater som er fremstilt av flere stammer av Escherichia coli og Aerobacter aerogenes blir vekstforholdet fortrinsvis avpasset slik at det på to deler av Escherichia coli i pro-duktet forefinnes 1 del A. aerogenes. For terapeutisk anvendelse fremstilles det hen-siktsmessig preparater med 20—50 mg bak-teriesubstans, til hvilket det kan blandes vekstsubtrater og vekststoffer i fast form. En mengde på ca. 50 mg er tilstrekkelig til i ca. 150 ml vann å gi en tett, uklar kim-suspensjon. Hvis preparatene skal fremstilles for dannelse av drikkeferdige suspen-sjoner, kan man ved tilsetning av puffer-stoffer skaffe en pH-verdi som er egnet for optimal utvikling av kimene. The bacterial suspensions obtained in this way can be subjected to extraction of the dry preparations, e.g. a lyophilization, during which protective substances can be added to stabilize the preparation, such as e.g. pectin substances, egg white substances, tragacanth and the like, before freeze-drying. In preparations made from several strains of Escherichia coli and Aerobacter aerogenes, the growth ratio is preferably adjusted so that for every two parts of Escherichia coli in the product, there is one part of A. aerogenes. For therapeutic use, appropriate preparations are prepared with 20-50 mg of bacterial substance, to which growth substrates and growth substances in solid form can be mixed. A quantity of approx. 50 mg is sufficient for approx. 150 ml of water to give a dense, cloudy germ suspension. If the preparations are to be prepared to form ready-to-drink suspensions, a pH value suitable for optimal development of the germs can be obtained by adding buffer substances.
Det kan også være fordelaktig å frem-stille preparatene i fast form, f. eks. som kapsler. Ved å anvende preparatene i så-dan form blir det betydelig mindre fare for bortsomling av coli- resp. aerogenes-bakterier ved bruken. It can also be advantageous to prepare the preparations in solid form, e.g. as capsules. By using the preparations in this form, there is significantly less risk of contamination of coli or aerogenes bacteria during use.
Eksempel 1. Example 1.
På i prøverør skrått stillet næringsagar fra firmaet Difco Laboratories, Detroit, Michigan, U.S.A., anbringes det underkul-turer av stammekulturen av den isolerte Escherichia coli 14230. De i en underkultur erholdte kim slemmes opp i 2 ml fysiologisk koksaltoppløsning, og innføres i en 100 mil-liliters erlenmeyerkolbe, i hvilken det er an-bragt 25 ml næringsoppløsning som har føl-gende sammensetning: 0,81 pst. «Nutrient-broth» fra Difco, Subcultures of the strain culture of the isolated Escherichia coli 14230 are placed on nutrient agar slanted in test tubes from the company Difco Laboratories, Detroit, Michigan, U.S.A. The germs obtained in a subculture are slurried in 2 ml of physiological saline solution, and introduced into a 100 milliliter Erlenmeyer flask, in which is placed 25 ml of nutrient solution which has the following composition: 0.81 percent "Nutrient broth" from Difco,
Laboratories, Detroit, U. S. A. Laboratories, Detroit, U.S.A.
0,3 pst. Na2HP04. 12H20, 0.3% Na2HPO4. 12H20,
0,3 pst. glukose, 0.3 percent glucose,
pH 7,2 (regulert med NaOH). pH 7.2 (adjusted with NaOH).
For å oppnå en jevn resistenshøyde hos kimene like overfor tetracyklin setter man til denne første submerforkulturs nærings- disse næringsbunner tilsatte tetracyklin-medium samt til den etterfølgende annen HCl-mengde utgjør 200 mg/ml. Av den submerforkulturs næringsmedium 200 mi- annen submer-forkultur blir 5 ml overført krogram tetracyklinhydroklorid/ml. Den i 500 ml næringsoppløsning av følgende podede næringsoppløsning rystes 24 timer sammensetning In order to achieve a uniform level of resistance in the germs just opposite to tetracycline, tetracycline medium is added to this first submersed pre-culture's nutrient, these nutrient bases and to the subsequent second amount of HCl amounts to 200 mg/ml. From the nutrient medium of the submer pre-culture 200 ml of another submer pre-culture, 5 ml is transferred krogram tetracycline hydrochloride/ml. The in 500 ml nutrient solution of the following inoculated nutrient solution is shaken for 24 hours composition
i et rundsvingningsrysteapparat ved 37° C, in an orbital shaker at 37° C,
og deretter blir 2 ml av denne kultur inn- and then 2 ml of this culture is introduced
podet i 25 ml næringsoppløsning av den 0,175 % kvelstoff i form av frasentrifugert samme sammensetning som angitt ovenfor. ølgjærautolysat Man ryster igjen 24 timer ved 37° C i et 0,15 % Na2HP04.12 H20 rundsvingnings-rysteapparat. 5 ml av denne 0,3 % NaCl inoculated in 25 ml nutrient solution of the 0.175% nitrogen in the form of centrifuged same composition as stated above. brewer's yeast autolysate Shake again for 24 hours at 37° C in a 0.15% Na2HP04.12 H20 rotary shaker. 5 ml of this 0.3% NaCl
annen submerkultur overføres i 500 ml næ- 0,02 % MgS04. 7 H20 another submer culture is transferred into 500 ml of 0.02% MgSO4. 7 H 2 O
ringsoppløsning som har følgende sammen- 0,3 % Glukose ring solution which has the following composition - 0.3% Glucose
setning: pH 7,2 (regulert med NaOH). statement: pH 7.2 (adjusted with NaOH).
0,2 pst. kvelstoff i form av frasentri- 0.2 percent nitrogen in the form of phrasentri-
fugert ølgjærautolysat jointed brewer's yeast autolysate
0,15 pst. Na2HP04 .12 H20 Næringsoppløsningen fylles i en 0,02 pst. M<g>S04.7 H20 2 liters erlenmeyerkolbe. Det rystes i 24 0,3 pst. glukose timer ved 37° C i et rundsvingnings-ryste-pH 7,2 (regulert med NaOH). apparat med 270 omdreininger pr. min. Næringsoppløsningen anbringes i en 2 Etter denne tids forlØP ut^r utbyttet av liters erlenmyerkolbe. Det rystes i 24 timer celletørrstoff 4 g/l næringsoppløsning. Den ved 37° C i et rundsvingnings-rysteapparat ovenfor beskrevne dyrking av organismen med 270 omdr./min. Etter denne tids for- må skje under stren^ aseptiske betingel-løp utgjør utbyttet av celletørrstoff 3 g pr. ser- Utvinningen av tørrsubstansen av liter næringsoppløsning. Den ovenfor be- Aerobacter aerogenes skjer på samme måte skrevne dyrking av organismen må foregå som utvinningen av tørrsubstansen av under strengt aseptiske betingelser. Der- Es<che>nchm bh i eksempel 1. 0.15 percent Na2HP04 .12 H20 The nutrient solution is filled into a 0.02 percent M<g>S04.7 H20 2 liter Erlenmeyer flask. The 0.3% glucose is shaken for 24 hours at 37° C in a circular oscillation-shaking pH 7.2 (regulated with NaOH). device with 270 revolutions per my. The nutrient solution is placed in a 2 After the course of this time, the yield of liter Erlenmeyer flask. Cell dry matter 4 g/l nutrient solution is shaken for 24 hours. The cultivation of the organism described above at 37° C in a rotary shaker at 270 rpm. After this period, which must be carried out under strict aseptic conditions, the yield of cell dry matter amounts to 3 g per ser- The recovery of the dry matter from liters of nutrient solution. The above be- Aerobacter aerogenes occurs in the same way written cultivation of the organism must take place as the extraction of the dry substance of under strictly aseptic conditions. There- Es<che>nchm bra in example 1.
etter blir bakteriecellen skilt fra nærings- after, the bacterial cell is separated from the nutrient
oppløsningen ved sentrifugering og ved to gangers vasking med hver gang 500 ml fy- Eksempel 3. the solution by centrifugation and by washing twice with each time 500 ml of phy- Example 3.
siologisk koksaltoppløsning samt hver gang ved etterfølgende sentrifugering befridd for Av de 1 henhold til eksempel 1 erholdte siological saline solution as well as each time by subsequent centrifugation freed from Of the 1 obtained according to example 1
rester av næringsoppløsningen. Det ren- lyofiliserte bakterietørrprodukter fremstil-sede bakterieslam suspenderes i til fryse- les det et farmasøytisk preparat hvorunder tørking egnede beskyttelsesoppløsninger, tas hensyn til optimal holdbarhet av coli-som f. eks. skummet melk, 1:4 fortynnet kulturen, beskyttelse mot innvirkning av næringsbuljong, 1 pst.s peptonvann, gelatin mavesyren og sikring av optimal utspred-eller 5 pst.s glukoseoppløsning, i sterile ninSs" °g vekstbetingelse i tarmtrakten. glasskåler over hvilke det spennes filtrer- For dette formål går man frem på følgende papir; i disse anbringes suspensjonen i tynt mate. remains of the nutrient solution. The pure lyophilized bacterial sludge produced from dry bacterial products is suspended in a pharmaceutical preparation during drying suitable protective solutions, taking into account the optimal shelf life of coli - such as e.g. skimmed milk, 1:4 diluted culture, protection against the influence of nutrient broth, 1 percent peptone water, gelatin, the stomach acid and ensuring optimal dispersion or 5 percent glucose solution, in sterile ninSs" °g growth conditions in the intestinal tract. glass dishes over which the strain filters- For this purpose, the following paper is used; in these, the suspension is placed in thin mat.
lag (ca. 1 mm høyt) og fryses ved —78° C. Av coli-materialet fremstilles et gra-Det frosne materiale tørkes så i frysetør- nulat som er bestemt for fylling av kaps-keanlegg til en restfuktighet på 1,0—0,5 pst. ler. Hver kapsel skal inneholde 20 mg Det tørkede cellemateriale lagres — inntil coli-tørrsubstans. Til 100 kapsler lager man det forarbeides videre — i en vakuumeksik- følgende sats: layer (approx. 1 mm high) and frozen at -78° C. A granule is produced from the coli material. 0.5 percent clay. Each capsule must contain 20 mg The dried cell material is stored — until coli dry substance. For 100 capsules, it is processed further — in a vacuum ex- following rate:
kator ved kjøleromtemperatur (-|- 2° C). cator at cold room temperature (-|- 2° C).
2 g coli-tørrsubstans 2 g coli dry substance
Eksempel 2. 12 g suppositoriemasse (Imhausen) Example 2. 12 g suppository mass (Imhausen)
3 g melkepulver 3 g milk powder
Av stammekulturen av den isolerte 1 g mannitt. From the stock culture of the isolated 1 g of mannitol.
Aerobacter aerogenes 16092 blir det an- Aerobacter aerogenes 16092 becomes an
brakt underkultur på skråttstillet nærings- brought subculture on inclined nutrient
agar fra Difco Laboratories i skråttstillede De faste stoffer innarbeides i suppo-prøverør. Den videre dyrking av organis- sitoriemassen og denne blir deretter gra-men skjer som i eksempel 1. Også næ- nulert. Granulatet blir under anvendelse ringsoppløsningen for den første og an- av 6 g eudragit L (Fa. Rohm & Haas G.m. nen submer-forkultur har den samme sam- b.H., Darmstadt) forsynt med et i mave-mensetning som i eksempel 1. Den til saft uoppløselig overtrekk ved oversprøy- agar from Difco Laboratories in slanted The solids are incorporated in suppo test tubes. The further cultivation of the organizational mass and this then becomes the gram happens as in example 1. Also nullified. The granulate is, using the ring solution for the first and on- of 6 g of eudragit L (Fa. Rohm & Haas G.m. nen submer pre-culture has the same sam- b.b.H., Darmstadt) provided with an in stomach composition as in example 1. The to juice insoluble coating by overspray
ting i en drageringskjel. Av det ferdige 1 things in a drag ring kettle. Of the finished 1
granulat fylles 200 mg i hver gelatinstikk- granules are filled 200 mg in each gelatin stick
kapsel. Kapslene legges i små flasker som inneholder silikagel og evakueres og lag- \capsule. The capsules are placed in small bottles containing silica gel and evacuated and layer- \
res koldt inntil de skal brukes. refrigerate until ready to use.
< <
1 1
Eksempel 4. Example 4.
< <
Av den i henhold til eksempel 2 er- Of the according to example 2 is-
holdte bakterietørrsubstans fremstilles det i kept bacterial dry matter is produced in
tabletter på følgende måte: tablets as follows:
En tablett skal inneholde 20 mg bak-terietørrsubstans. Til 100 tabletter lager man derfor følgende sats: < One tablet must contain 20 mg of dry bacterial substance. For 100 tablets, the following batch is therefore made: <
2 g tørrsubstans av Aerobacter aerogenes 2 g dry substance of Aerobacter aerogenes
2 g «Carbowax» 2 g "Carbowax"
3 g hvetestivelse 41,5 g melkesukker 3 g wheat starch 41.5 g milk sugar
1 g gelatin 1 g of gelatin
0,5 mg-stearat. 0.5 mg stearate.
Gelatinen løses i 5 ml vann og blir The gelatin is dissolved in 5 ml of water and becomes
sammen med stivelsen og melkesukkeret forarbeidet til et granulat, som tørkes 24 together with the starch and milk sugar processed into a granule, which is dried on 24
timer ved 40° C i tørreskap. Deretter blir bakteritørrsubstansen fordelt i det til 30° C oppvarmede «Carbowax» og innarbeidet i granulatet. Deretter tilsettes 0,5 g Mg- hours at 40° C in a drying cabinet. The bacterial dry substance is then distributed in the "Carbowax" heated to 30° C and incorporated into the granulate. Then 0.5 g of Mg-
stearat, og massen presses til tabletter som hver veier 500 mg. Disse tabletter blir ved inndypping i 8 g silikonharpikslakk forsynt med et i mavesaft uoppløselig overtrekk. stearate, and the mass is pressed into tablets each weighing 500 mg. When dipped in 8 g of silicone resin varnish, these tablets are provided with a coating insoluble in gastric juice.
De ferdige tabletter anbringes i flasker som The finished tablets are placed in bottles which
inneholder silikagel og som evakueres og som lagres koldt til de skal brukes. contain silica gel and which are evacuated and stored cold until they are to be used.
Eksempel 5. Example 5.
Lyofiliserte cellematerialer av Esche- Lyophilized cell materials of Esche-
richia coli erholdt i henhold til eksempel 1 og 2 blandes med hinannen i forholdet 2:1. Av denne blanding fremstilles det kapsler. I hver kapsel skal det finnes 20 richia coli obtained according to example 1 and 2 are mixed with each other in a ratio of 2:1. Capsules are made from this mixture. There should be 20 in each capsule
mg bakterietørrsubstans. Til 100 kapsler forarbeides følgende sats: mg bacterial dry substance. For 100 capsules, the following rate is processed:
2 g bakterietørrsubstans 2 g dry bacterial substance
2 g melkesukker 2 g of milk sugar
1 g kamilletørrekstrakt 1 g chamomile dry extract
10 g «Cremophor» (BASF). 10 g "Cremophor" (BASF).
De faste stoffer innarbeides i den til The solids are incorporated into it
30—35° C oppvarmede «Cremophor». I hver enkelt av de herdede gelatinstikkapsler fyl- 30-35° C heated "Cremophor". In each of the hardened gelatin suppositories fill
les det 150 g av massen. De ferdige kapsler anbringes i flasker som inneholder sili- read it 150 g of the mass. The finished capsules are placed in bottles containing silicon
kagel og evakueres og lagres koldt til de skal brukes. kagel and are evacuated and stored cold until they are to be used.
De kim som inneholdes i preparater The germs contained in preparations
fremstilt i henhold til oppfinnelsen behøver ikke å kultiveres før deres anvendelse, da det i hvert preparat er til stede et til tera- produced according to the invention do not need to be cultivated before their use, as each preparation contains an additional
peutisk behandling tilstrekkelig antall funksjon dyktige kim. Preparatene frem- peutic treatment sufficient number of function capable germs. The preparations
stilles fortrinsvis i en form som gjør dem godt oppløselige i vanlig drikkevann eller melk. Preparatene kan i denne form an- are preferably placed in a form that makes them well soluble in normal drinking water or milk. In this form, the preparations can
vendes oralt resp. rektalt. turned orally resp. rectally.
De oppløste preparater holder seg ved romtemperatur i minst 24 timer, slik at man er sikker på å få virkelige funksjons- The dissolved preparations stay at room temperature for at least 24 hours, so that you are sure to get real functional
dyktige kim. skilled germs.
De i henhold til oppfinnelsen frem- According to the invention, the
stilte preparater kan anvendes profylaktisk ved enhver lengre varende anvendelse av antibiotika, spesielt av tetracyklin sam- listed preparations can be used prophylactically for any long-term use of antibiotics, especially of tetracycline combined
men med antibiotikumet, spesielt fra den annen resp. tredje behandlingsdag. I til- but with the antibiotic, especially from the other resp. third treatment day. In to-
feller hvor det allerede har inntrådt følger etter terapeutisk anvendelse av tetracyklin har preparatene i henhold til oppfinnelsen som inneholder likeoverfor antibiotika re- cases where sequelae have already occurred following the therapeutic use of tetracycline, the preparations according to the invention, which contain opposite antibiotics re-
sistente stammer av ikke resistente gram- resistant strains of non-resistant gram-
negative bakteristammer, spesielt coli- og resp. eller aerogenstammer, vist seg meget gode. Ved opptreden av tarmbesværligheter etter behandling med tetracyklin kan an-tibiotikabehandlingen eventuelt føres vi- negative bacterial strains, especially coli and resp. or aerogenous strains, proved to be very good. If intestinal problems occur after treatment with tetracycline, the antibiotic treatment can possibly be
dere ved å anvende tetracyklinene i kom- by using the tetracyclines in com-
binasjon med preparater i henhold til opp- bination with preparations according to up-
finnelsen, spesielt slike som er blitt tilsatt kamilleekstrakt. Ennvidere kan de nye preparater gis ved begynnende forandring av tarmfloraen. Endelig kan de anvendes, the invention, especially those to which chamomile extract has been added. Furthermore, the new preparations can be given at the beginning of a change in the intestinal flora. Finally, they can be used,
eventuelt kombinert med tetracykliner, ved dysbakterier, dyspepsier og dysfermentier. possibly combined with tetracyclines, for dysbacteriosis, dyspepsia and dysfermentation.
Claims (3)
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NO16813767A NO126102B (en) | 1967-05-12 | 1967-05-12 | |
GB1230796D GB1230796A (en) | 1967-05-12 | 1968-04-25 | |
SE600568A SE344283B (en) | 1967-05-12 | 1968-05-03 | |
FR1568472D FR1568472A (en) | 1967-05-12 | 1968-05-10 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NO16813767A NO126102B (en) | 1967-05-12 | 1967-05-12 |
Publications (1)
Publication Number | Publication Date |
---|---|
NO126102B true NO126102B (en) | 1972-12-18 |
Family
ID=19910061
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO16813767A NO126102B (en) | 1967-05-12 | 1967-05-12 |
Country Status (4)
Country | Link |
---|---|
FR (1) | FR1568472A (en) |
GB (1) | GB1230796A (en) |
NO (1) | NO126102B (en) |
SE (1) | SE344283B (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4488239A (en) * | 1982-04-22 | 1984-12-11 | The Babcock & Wilcox Company | Temperature control system for olefin oxidation reactor |
NO311286B1 (en) * | 1998-06-17 | 2001-11-12 | Nyfotek As | Process for optimizing entropy production in one or more chemical reactors |
-
1967
- 1967-05-12 NO NO16813767A patent/NO126102B/no unknown
-
1968
- 1968-04-25 GB GB1230796D patent/GB1230796A/en not_active Expired
- 1968-05-03 SE SE600568A patent/SE344283B/xx unknown
- 1968-05-10 FR FR1568472D patent/FR1568472A/fr not_active Expired
Also Published As
Publication number | Publication date |
---|---|
GB1230796A (en) | 1971-05-05 |
FR1568472A (en) | 1969-05-23 |
SE344283B (en) | 1972-04-10 |
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