NO155602B - PROCEDURE FOR PREPARING A PHARMACEUTICAL PREPARATION FOR ORAL AND TOPICAL ADMINISTRATION. - Google Patents
PROCEDURE FOR PREPARING A PHARMACEUTICAL PREPARATION FOR ORAL AND TOPICAL ADMINISTRATION. Download PDFInfo
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- NO155602B NO155602B NO80800913A NO800913A NO155602B NO 155602 B NO155602 B NO 155602B NO 80800913 A NO80800913 A NO 80800913A NO 800913 A NO800913 A NO 800913A NO 155602 B NO155602 B NO 155602B
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- Prior art keywords
- amount
- lactoperoxidase
- preparation
- thiocyanate
- oral
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 10
- 239000000825 pharmaceutical preparation Substances 0.000 title claims description 8
- 238000011200 topical administration Methods 0.000 title claims description 5
- 108010023244 Lactoperoxidase Proteins 0.000 claims description 18
- 102000045576 Lactoperoxidases Human genes 0.000 claims description 18
- 229940057428 lactoperoxidase Drugs 0.000 claims description 18
- 238000002360 preparation method Methods 0.000 claims description 18
- VTIIJXUACCWYHX-UHFFFAOYSA-L disodium;carboxylatooxy carbonate Chemical compound [Na+].[Na+].[O-]C(=O)OOC([O-])=O VTIIJXUACCWYHX-UHFFFAOYSA-L 0.000 claims description 11
- 229940045872 sodium percarbonate Drugs 0.000 claims description 11
- 150000002978 peroxides Chemical class 0.000 claims description 10
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 claims description 9
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 claims description 9
- VGTPCRGMBIAPIM-UHFFFAOYSA-M sodium thiocyanate Chemical compound [Na+].[S-]C#N VGTPCRGMBIAPIM-UHFFFAOYSA-M 0.000 claims description 9
- 239000007787 solid Substances 0.000 claims description 9
- 230000000844 anti-bacterial effect Effects 0.000 claims description 8
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- 239000011241 protective layer Substances 0.000 claims description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims 1
- 239000000203 mixture Substances 0.000 description 13
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- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
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- WQGWDDDVZFFDIG-UHFFFAOYSA-N pyrogallol Chemical compound OC1=CC=CC(O)=C1O WQGWDDDVZFFDIG-UHFFFAOYSA-N 0.000 description 2
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- WZRJTRPJURQBRM-UHFFFAOYSA-N 4-amino-n-(5-methyl-1,2-oxazol-3-yl)benzenesulfonamide;5-[(3,4,5-trimethoxyphenyl)methyl]pyrimidine-2,4-diamine Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1.COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 WZRJTRPJURQBRM-UHFFFAOYSA-N 0.000 description 1
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
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- OLSYHLURTGEIBH-UHFFFAOYSA-N Pyrogallin Chemical compound C1=CC(=O)C(O)=C2C(O)=C(O)C=CC2=C1 OLSYHLURTGEIBH-UHFFFAOYSA-N 0.000 description 1
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- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
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- Medicinal Preparation (AREA)
Description
Foreliggende oppfinnelse vedrører en fremgangsmåte fo-r fremstilling av et farmasøytisk preparat for oral og topisk administrasjon. The present invention relates to a method for producing a pharmaceutical preparation for oral and topical administration.
Det er tidligere kjent at husdyr, spesielt unge dyr, ut- It is previously known that livestock, especially young animals,
settes for kraftige mage- og tarminfeksjoner som hoved-sakelig beror på infeksjoner av E. coli og forskjellige arter av Salmonella. Hittil kjente metoder for å eliminere disse infeksjoner omfatter enten administrasjon av en terapeutisk mengde antibiotika med risiko for dannelse av antibiotikaresistente bakteriearter, eller å foreta en vaksinasjon av bestanden, hvilket leder til store omkost-ninger siden vaksiner og vaksinasjoner er relativt kostbare. is used for severe stomach and intestinal infections which are mainly due to infections by E. coli and various species of Salmonella. Hitherto known methods for eliminating these infections include either administering a therapeutic amount of antibiotics with the risk of the formation of antibiotic-resistant bacterial species, or carrying out a vaccination of the population, which leads to large costs since vaccines and vaccinations are relatively expensive.
Et annet kjemoterapeutisk aktivt middel som benyttes, er Another chemotherapeutically active agent that is used is
blant annet trimetoprimsulfa. including trimethoprim sulfa.
Ifølge foreliggende oppfinnelse er det tilveiebragt en fremgangsmåte for fremstilling av et farmasøytisk preparat for oral og topisk administrasjon, og ved bruk av dette preparatet har man overraskende funnet det mulig å unngå According to the present invention, a method for the production of a pharmaceutical preparation for oral and topical administration is provided, and by using this preparation it has surprisingly been found possible to avoid
de ovennevnte ulemper og å hindre og/eller eliminere de omtalte bakterieinfeksjoner. Preparatet fremstilles ifølge foreliggende oppfinnelse ved at man til i og for seg kjente bestanddeler i farmasøytiske preparater (en farmasøytisk bærer) tilsetter et antibakterielt system inneholdende laktoperoksydase i en mengde på minst 1 mg/kg (50-5000 U/kg) preparat, et tiocyanat i en mengde på minst 16 ppm beregnet som natriumtiocyanat, og en fast vannoppløselig peroksyddonor. fra gruppen alkaliperkarbonater, jordalkaliperoksyder og karbamidperoksyd i en mengde på minst 21 ppm beregnet the above disadvantages and to prevent and/or eliminate the mentioned bacterial infections. The preparation is produced according to the present invention by adding an antibacterial system containing lactoperoxidase in an amount of at least 1 mg/kg (50-5000 U/kg) of the preparation, a thiocyanate, to ingredients known per se in pharmaceutical preparations (a pharmaceutical carrier) in an amount of at least 16 ppm calculated as sodium thiocyanate, and a solid water-soluble peroxide donor. from the group of alkali percarbonates, alkaline earth peroxides and carbamide peroxide in an amount of at least 21 ppm calculated
som natriumperkarbonat. such as sodium percarbonate.
Den vannoppløselige peroksyddonoren består fortrinnsvis av natriumperkarbonat som er belagt med et beskyttende lag The water-soluble peroxide donor preferably consists of sodium percarbonate which is coated with a protective layer
som er oppløselig i tarmkanalen og hvilket lag fortrinnvis består av celluloseacetatftalat. Tiocyanatet kan fordel- which is soluble in the intestinal tract and which layer preferably consists of cellulose acetate phthalate. The thiocyanate can benefit
aktig anvendes i en mengde på 160-3500, fortrinnsvis 160-1750 ppm/kg preparat beregnet som NaSCN, peroksyddonor i en mengde is used in an amount of 160-3500, preferably 160-1750 ppm/kg preparation calculated as NaSCN, peroxide donor in an amount
på 210-4000, fortrinnsvis 210-2000 ppm preparat beregnet som Na-perkarbonat, og laktoperoksydase i en mengde på 10-200, fortrinnsvis 10-100 mg/kg preparat. of 210-4000, preferably 210-2000 ppm preparation calculated as Na-percarbonate, and lactoperoxidase in an amount of 10-200, preferably 10-100 mg/kg preparation.
Det fremstilte preparat kan anvendes til behandling av mage-og tarminfeksjoner hos pattedyr inkludert mennesker som har mage- og tarminfeksjoner forårsaket av bakterier. The prepared preparation can be used to treat stomach and intestinal infections in mammals including humans who have stomach and intestinal infections caused by bacteria.
Dyr som behandles, er vanligvis griser, kalver og fjærkre, samt pelsproduserende dyr slik som mink og rev. Kjæledyr slik som katter og hunder kan også behandles. Animals treated are usually pigs, calves and poultry, as well as fur-producing animals such as mink and fox. Pets such as cats and dogs can also be treated.
Mengden av tiocyanat velges slik at man oppnår en konsentrasjon derav på minst 0,1, fortrinnsvis 0,2-0,4 mM, hvorved konsentrasjoner på 0,5-1,0 mM kan være nyttige i visse tilfeller, i fordøyelseskanalen, idet konsentrasjonen ikke bør overskride toksiske konsentrasjoner, (10 mM). Mengden av peroksyddonor velges slik at en ekvimolar mengde I^O^ oppnås, dvs. at konsentrasjonen av I^C^ som dannes, overskrider minst 0,1, fortrinnsvis 0,2-0,4 mM. Konsentrasjonen av ^ 2°2 skal i hvert tilfelle være mindre enn 4 ganger konsentrasjonen av tiocyanatet. Mengden av laktoperoksydase er avhengig av aktiviteten av enzymet, men basert på den antagelse at 1 mg inneholder 50 enheter (U), bør minst 1 mg enzym være til-stede pr. liter fordøyelsessaft. The amount of thiocyanate is chosen so as to achieve a concentration thereof of at least 0.1, preferably 0.2-0.4 mM, whereby concentrations of 0.5-1.0 mM may be useful in certain cases, in the digestive tract, as the concentration should not exceed toxic concentrations, (10 mM). The amount of peroxide donor is chosen so that an equimolar amount of I^O^ is obtained, i.e. that the concentration of I^C^ which is formed exceeds at least 0.1, preferably 0.2-0.4 mM. The concentration of ^ 2°2 must in each case be less than 4 times the concentration of the thiocyanate. The amount of lactoperoxidase depends on the activity of the enzyme, but based on the assumption that 1 mg contains 50 units (U), at least 1 mg of enzyme should be present per liters of digestive juices.
I en oppløsning anvendes en konsentrasjon av tiocyanat minst 0,1 mM, fortrinnsvis 0,2-0,4 mM, konsentrasjonen av peroksyddonor slik at konsentrasjonen av H202 er 0,1 mM, fortrinnsvis 0,2-0,4 mM, og konsentrasjonen av laktoperoksydase er 1 mg/l (50 U/l). In a solution, a concentration of thiocyanate of at least 0.1 mM, preferably 0.2-0.4 mM, the concentration of peroxide donor such that the concentration of H202 is 0.1 mM, preferably 0.2-0.4 mM, and the concentration of lactoperoxidase is 1 mg/l (50 U/l).
Konsentrasjonen av sistnevnte materiale kan også varieres, The concentration of the latter material can also be varied,
men bør være 1-2 mg/l (50-100 U/l) . but should be 1-2 mg/l (50-100 U/l) .
1 enhet laktoperoksydase er den mengde laktoperoksydase som danner 1 mg pyrogallin fra pyrogallol i løpet av 2 0 sek. 1 unit of lactoperoxidase is the amount of lactoperoxidase that forms 1 mg of pyrogallin from pyrogallol within 20 seconds.
ved pH 6,0 og 20°C. at pH 6.0 and 20°C.
Mengden av laktoperoksydase i storfemyse (upasteurisert) eller i ultrafiltrert myse kan naturligvis variere. Melk fra storfe inneholder, ifølge litteraturen, laktoperoksydase i en mengde på ca. 30 ml/l, hvorved mengden av laktoperoksydase i menneskemelk ifølge litteraturen er ca. 1/30 av den i melk fra storfe. Laktoperoksydase finnes også i andre storfemelkeprodukter som pulver av skummet melk som også kan benyttes. The amount of lactoperoxidase in bovine whey (unpasteurized) or in ultrafiltered whey can naturally vary. Milk from cattle contains, according to the literature, lactoperoxidase in an amount of approx. 30 ml/l, whereby the amount of lactoperoxidase in human milk according to the literature is approx. 1/30 of that in milk from cattle. Lactoperoxidase is also found in other bovine milk products such as skimmed milk powder, which can also be used.
Salter av tiocyanat som anvendes, er natrium-, kalium- og ammonium-salter. Salts of thiocyanate used are sodium, potassium and ammonium salts.
LD^q for tiocyanat er 484 mg/kg legemsvekt injisert intra-venøst til mus og 764 mg/kg legemsvekt administrert oralt til rotte. The LD^q for thiocyanate is 484 mg/kg body weight injected intravenously to mice and 764 mg/kg body weight administered orally to rats.
Bæreren som benyttes, kan være et fast, halvfast eller væskeformig fortynningsmiddel eller en kapsel. Vanligvis er mengden av aktive bestanddeler mellom 0,1 og 99 vekt-% av preparatet, hensiktsmessig mellom 52 vekt-% i preparater for oral administrasjon. The carrier used can be a solid, semi-solid or liquid diluent or a capsule. Generally, the amount of active ingredients is between 0.1 and 99% by weight of the preparation, suitably between 52% by weight in preparations for oral administration.
Ved fremstilling av det farmasøytiske preparat inneholdende det antibakterielle systemet i form av doseringsenheter for oral administrasjon, kan bestanddeler blandes med en fast, pulverformig bærer slik som f.eks. laktose, sakkarose, sorbitol, mannitol, stivelse slik som potetstivelse, maisstivelse, amylopektin, cellulosederivater eller gelatin, samt med et antifriksjonsmiddel slik som magnesiumstearat, kalsiumstearat, polyetylenglykolvokser og lignende, og presses til tabletter. Dersom det er ønskelig med belagte tabletter, kan den ovenfor fremstilte kjerne belegges med en oppløsning av en polymer som oppløses eller er permeabel i tarmkanalen. Til dette belegg kan ethvert fargestoff tilsettes for at man lett skal kunne skille mellom tabletter med forskjellige aktive forbindelser eller med forskjellig mengde av aktiv forbindelse. When preparing the pharmaceutical preparation containing the antibacterial system in the form of dosage units for oral administration, the ingredients can be mixed with a solid, powdery carrier such as e.g. lactose, sucrose, sorbitol, mannitol, starch such as potato starch, corn starch, amylopectin, cellulose derivatives or gelatin, as well as with an antifriction agent such as magnesium stearate, calcium stearate, polyethylene glycol wax and the like, and pressed into tablets. If coated tablets are desired, the core produced above can be coated with a solution of a polymer which dissolves or is permeable in the intestinal tract. Any dye can be added to this coating in order to easily distinguish between tablets with different active compounds or with different amounts of active compound.
Ved fremstilling av nye gelatinkapsler (perleformede, When manufacturing new gelatin capsules (pearl-shaped,
lukkede kapsler) som består av gelatin og f.eks. glycerin, eller ved fremstilling av lignende, lukkede kapsler, closed capsules) which consist of gelatin and e.g. glycerin, or in the manufacture of similar, closed capsules,
blandes den aktive forbindelse med en vegetabilsk olje. the active compound is mixed with a vegetable oil.
Harde gelatinkapsler kan inneholde granulater av den Hard gelatin capsules may contain granules of it
aktive forbindelse i kombinasjon med en fast, pulverformig bærer slik som laktose, sakkarose, sorbitol, mannitol, stivelse (f.eks. potetstivelse, maisstivelse og amylopektin), cellulosederivater eller gelatin. active compound in combination with a solid, powdered carrier such as lactose, sucrose, sorbitol, mannitol, starch (e.g. potato starch, corn starch and amylopectin), cellulose derivatives or gelatin.
Doseringsenheter for rektal administrasjon kan fremstilles Dosage units for rectal administration can be prepared
i form av suppositorier som inneholder det aktive stoff i en blanding med en nøytral fettbase, eller de kan fremstilles i form av gelatin-rektalkapsler som inneholder det aktive stoff i en blanding med en vegetabilsk olje eller paraffin-ol je. in the form of suppositories containing the active substance in a mixture with a neutral fatty base, or they can be produced in the form of gelatin rectal capsules containing the active substance in a mixture with a vegetable oil or paraffin oil.
Flytende preparater for oral administrasjon kan foreligge Liquid preparations for oral administration may be available
i form av siruper eller suspensjoner, f.eks. oppløsninger inneholdende 0,2-20 vekt-% av de beskrevne aktive stoffer, hvorved resten består av sukker og en blanding av etanol, in the form of syrups or suspensions, e.g. solutions containing 0.2-20% by weight of the described active substances, whereby the remainder consists of sugar and a mixture of ethanol,
vann, glycerol og propylenglykol. Om ønsket, kan slike flytende preparater inneholde fargestoffer, smaksstoffer, sakkarin og karboksymetylcellulose som fortykningsmiddel. Peroksyddonoren er her til stede i form av mikroinnkapslede partikler. water, glycerol and propylene glycol. If desired, such liquid preparations can contain dyes, flavourings, saccharin and carboxymethyl cellulose as a thickening agent. The peroxide donor is present here in the form of microencapsulated particles.
Fremstillingen av farmasøytiske tabletter for peroral anvendelse foretas på følgende måte. The production of pharmaceutical tablets for oral use is carried out in the following manner.
De aktuelle faste stoffer males eller siktes til en bestemt partikkelstørrelse. Bindemiddelet homogeniseres og suspende-res i en bestemt mengde oppløsningsmiddel. Den terapeutiske forbindelse og nødvendige hjelpestoffer blandes under en kon-tinuerlig og konstant blanding med bindemiddeloppløsningen som kan bestå av en polymer som oppløses eller er permeabel i tarmsaftene, og som fuktes slik at oppløsningen oppdeles ensartet i massen uten overfukting av noen celler. Mengden av oppløsningsmiddel tilpasses vanligvis slik at massen oppnår en konsistens som minner om fuktig snø. Fuktingen av den pulverformige blanding med bindemiddeloppløsningen forårsaker at partiklene samler seg til aggregatet, og den virkelige granuleringsprosess utføres på en slik måte at massen presses gjennom en sikt i form av et trådnett av rust-fritt stål med en maskestørrelse på ca. 1 mm. Massen anbringes deretter i tynne lag på et brett for tørking i et tørkeskap. Denne tørking forløper i 10 timer og må nøye stan-dardiseres ettersom fuktighetsgraden i granulatet er meget viktig for den påfølgende prosess og for tablettenes egenskaper. Tørking i et fluidsjikt kan muligens anvendes. I dette tilfellet anbringes massen ikke på et brett, men helles i en beholder som har en nettingbunn. The relevant solids are ground or sieved to a specific particle size. The binder is homogenized and suspended in a specific amount of solvent. The therapeutic compound and necessary auxiliary substances are mixed under a continuous and constant mixture with the binder solution, which can consist of a polymer that dissolves or is permeable in the intestinal juices, and which is moistened so that the solution is distributed uniformly in the mass without overwetting any cells. The amount of solvent is usually adjusted so that the mass achieves a consistency reminiscent of wet snow. The wetting of the powdery mixture with the binder solution causes the particles to aggregate into the aggregate, and the actual granulation process is carried out in such a way that the mass is pressed through a sieve in the form of a stainless steel wire mesh with a mesh size of approx. 1 mm. The mass is then placed in thin layers on a tray for drying in a drying cabinet. This drying takes place for 10 hours and must be carefully standardized as the degree of moisture in the granulate is very important for the subsequent process and for the properties of the tablets. Drying in a fluid bed can possibly be used. In this case, the mass is not placed on a tray, but poured into a container that has a mesh bottom.
Etter tørketrinnet siktes granulatene slik at den ønskede partikkelstørrelse oppnås. Under visse forhold må pulver fjernes. After the drying step, the granules are sieved so that the desired particle size is achieved. Under certain conditions, powder must be removed.
Til den såkalte sluttblanding tilsettes desintegrerings-, antifriksjons- og antiklebemidler. Etter denne sammenblanding skal massen ha sin rette sammensetning for tabletterings-trinnet. Disintegrating, anti-friction and anti-adhesive agents are added to the so-called final mixture. After this mixing, the mass must have the right composition for the tableting step.
Den rengjorte tablettmaskin forsynes med bestemte stanser hvoretter man utprøver passende justering for vekten av tablettene og graden av sammenpresning. Tablettvekten er av-gjørende for størrelsen på dosen i hver tablett og beregnes på grunnlag av mengden av terapeutisk middel i granulatene. Sammenpresningsgraden påvirker tablettstørrelsen, dens styrke og evne til å desintegreres i vann. Med spesielt henblikk på de to sistnevnte egenskaper må man foreta en avbalanse-ring av sammenpressingstrykket (0,5-5 tonn). Når den rette innstilling er fastsatt, begynner fremstillingen av tabletter og utføres slik at man fremstiller 20.000-200.000 tabletter pr. time. Tablettpressingen krever forskjellig tid og avhenger av størrelsen på den porsjon som skal fremstilles. Tablettene pakkes vanligvis av maskiner som har en elektronisk telleinnretning. Forskjellige typer forpakninger utgjøres av små glass eller■plastkrukker, men også bokser, rør og spesielt tilpassede doseringsforpakninger. The cleaned tablet machine is supplied with specific punches, after which the appropriate adjustment is tested for the weight of the tablets and the degree of compression. The tablet weight is decisive for the size of the dose in each tablet and is calculated on the basis of the amount of therapeutic agent in the granules. The degree of compression affects the tablet size, its strength and ability to disintegrate in water. With particular regard to the two latter properties, the compression pressure must be balanced (0.5-5 tonnes). Once the correct setting has been determined, the production of tablets begins and is carried out in such a way that 20,000-200,000 tablets are produced per hour. hour. The tablet pressing requires different time and depends on the size of the portion to be produced. The tablets are usually packaged by machines that have an electronic counting device. Different types of packaging consist of small glasses or plastic jars, but also cans, tubes and specially adapted dosage packaging.
Den daglige dose av det aktive stoff varierer og er avhengig av administrasjonstypen og bakteriell infeksjon, men som en generell regel er dosen 8-400 mg/dag av Na-tiocyanat og 10-500 mg/dag av Na-perkarbonat ved peroral administrasjon. The daily dose of the active substance varies and depends on the type of administration and bacterial infection, but as a general rule the dose is 8-400 mg/day of sodium thiocyanate and 10-500 mg/day of sodium percarbonate for oral administration.
Farmasøytiske preparater fremstilt ifølge oppfinnelsen har anvendelse ved behandling av bakterielle infeksjoner i mage- og tarmkanalen forårsaket f.eks. av Chigella, Salmonella, Vibero colera, Pseudomonas (Ps. pyocyanea), Staphylococcus (Staph. albus, aureus), Streptococcus (Strep. viri-dans, Strep. faecalis, (3-Streptococcus) , Proteus. Pharmaceutical preparations produced according to the invention are used in the treatment of bacterial infections in the gastrointestinal tract caused by e.g. of Chigella, Salmonella, Vibero cholera, Pseudomonas (Ps. pyocyanea), Staphylococcus (Staph. albus, aureus), Streptococcus (Strep. viri-dans, Strep. faecalis, (3-Streptococcus) , Proteus.
Oppfinnelsen skal beskrives mer detaljert i det nedenstående under henvisning til de angitte eksempler. The invention shall be described in more detail below with reference to the examples given.
Eksempel 1 Example 1
Laktoseperoksydasen ble blandet med laktose og ble granu-lert under anvendelse av en oppløsning av polyvinylpyrrolidon. The lactose peroxidase was mixed with lactose and was granulated using a solution of polyvinylpyrrolidone.
Natriumperkarbonat ble blandet med natriumtiocyanat og laktoperoksydasegranulatene. Magnesiumstearat ble tilsatt, hvoretter den granulære blanding ble tablettert. Sodium percarbonate was mixed with sodium thiocyanate and the lactoperoxidase granules. Magnesium stearate was added, after which the granular mixture was tableted.
De oppnådde tabletter hadde en gjennomsnittlig vekt på 212 mg og ble belagt med et lag bestående av "Eudragit ®" som er motstandsdyktig mot magesaft. The obtained tablets had an average weight of 212 mg and were coated with a layer consisting of "Eudragit ® " which is resistant to gastric juice.
Eksempel 2 Example 2
De tre aktive komponenter granuleres per se under anvendelse av polyvinylpyrrolidon som granuleringsmiddel. Laktose og The three active components are granulated per se using polyvinylpyrrolidone as granulating agent. Lactose and
magnesiumstearat tilsettes, hvoretter blandingen tabletteres. De oppnådde tabletter (100 stk.) med en gjennomsnittlig vekt på ca. 155 mg belegges med en oppløsning av celluloseacetatftalat som er bestandig overfor magesaft, i en oppløsnings-middelblanding av aceton og isopropanol (like deler). magnesium stearate is added, after which the mixture is tableted. The obtained tablets (100 pcs.) with an average weight of approx. 155 mg is coated with a solution of cellulose acetate phthalate, which is resistant to gastric juice, in a solvent mixture of acetone and isopropanol (equal parts).
Eksempel 3 Example 3
Karbamidperoksydet granuleres under anvendelse av en oppløs-ning av "Eudragit ®S». Laktoseperoksyden blandes med laktose og tiocyanat, og blandingen granuleres under anvendelse av "Eudragit^S. De to porsjonene med granulater kombineres og blandes med stearinsyrepulver, og slutt-blandingen tabletteres. Tablettene har en gjennomsnittlig vekt på ca. 175 mg. The carbamide peroxide is granulated using a solution of "Eudragit®S". The lactose peroxide is mixed with lactose and thiocyanate, and the mixture is granulated using "Eudragit®S. The two portions of granules are combined and mixed with stearic acid powder, and the final mixture is tableted. The tablets have an average weight of approx. 175 mg.
E ksempel 4 Example 4
Granulater ble fremstilt fra hver av I, II og III under anvendelse av en oppløsning av "Eudragit ^L". De kombinerte granulater ble blandet med et egnet smaksstoff slik som sukker, kakao, mikroinnkapslet sitronaroma, eller blandinger derav. Granules were prepared from each of I, II and III using a solution of "Eudragit ^L". The combined granules were mixed with a suitable flavoring agent such as sugar, cocoa, microencapsulated lemon flavor, or mixtures thereof.
Et doseringsredskap, f.eks. en skje, som rommer en dose på ca. 200 mg, legges ved forpakningen av den granulære blanding. Forpakningen lages av et fuktighetstett materiale som f.eks. laminert aluminiumfolie. A dosing tool, e.g. a spoon, which holds a dose of approx. 200 mg, is added to the packaging of the granular mixture. The packaging is made of a moisture-proof material such as laminated aluminum foil.
Biologisk effekt Biological effect
4 reagensrør inneholdende 10 ml myse med et innhold av 21 ppm (0,25 mM/ NaSCN, ble inkubert ved 30°C, idet mysen var in-okulert med Ps-fluoressens EF 1998. Et rør utgjorde kontroll-prøven. Natriumperkarbonat tilsvarende 0,1 mM, 0,2 mM 4 test tubes containing 10 ml of whey with a content of 21 ppm (0.25 mM/NaSCN, were incubated at 30°C, the whey having been inoculated with Ps fluorescence EF 1998. One tube constituted the control sample. Sodium percarbonate corresponding to 0 .1 mM, 0.2 mM
og 0,3 mM, respektivt H202, ble tilsatt til de tre andre reagensrørene. Mengden av bakterier ble bestemt ved in-okulering, og etter 2 timers inkubasjon. Laktoseperoksydase er til stede i 5^,ug/ml. and 0.3 mM, respectively H 2 O 2 , were added to the other three test tubes. The amount of bacteria was determined by inoculation, and after 2 hours of incubation. Lactose peroxidase is present at 5 µg/ml.
Resultatet er angitt i nedenstående tabell 1. The result is shown in table 1 below.
Som det fremgår fra tabellen, oppnås en meget stor for-bedring i antibakteriell effekt når 0,2 mM ^ 2^ 2 eller mer er til stede. Allerede tilsetningen av 0,1 mM f^C^ gir imidlertid en betydelig baktericid effekt. As can be seen from the table, a very large improvement in antibacterial effect is achieved when 0.2 mM ^ 2 ^ 2 or more is present. Already the addition of 0.1 mM f^C^, however, gives a significant bactericidal effect.
Ps-fluoressens EF 1998 ble inkubert ved 30°C i to reagens-rør 1) og 2), hvor rør 1) inneholdt 1 g kommersielt melkeerstatningsmiddel omfattende 15% ultrafiltrert mysepulver, 57% mysepulver, 8% fett, 16% animalsk protein og 4% vitaminer og mineraler i 10 ml vann, og inneholdt dermed 50^ug laktoperoksydase, idet 2 7,5 ppm natriumperkarbonat ble tilsatt, og hvor rør 2) inneholdende den samme mengde melkeerstatningsmiddel (50^ug laktoperoksydase) og hvorved 21 ppm natriumtiocyanat og 27,5 ppm natriumperkarbonat ble tilsatt. Ps-fluorescence EF 1998 was incubated at 30°C in two test tubes 1) and 2), where tube 1) contained 1 g of commercial milk replacer comprising 15% ultrafiltered whey powder, 57% whey powder, 8% fat, 16% animal protein and 4% vitamins and minerals in 10 ml of water, and thus contained 50 µg of lactoperoxidase, with 2 7.5 ppm of sodium percarbonate being added, and where tube 2) containing the same amount of milk replacer (50 µg of lactoperoxidase) and whereby 21 ppm of sodium thiocyanate and 27.5 ppm sodium percarbonate was added.
Mengden av bakterier i de forskjellige reagensrør er angitt i nedenstående tabell 2 hvor resultatene etter 0, 2, 4 og 6 timer er angitt. The amount of bacteria in the different test tubes is indicated in table 2 below, where the results after 0, 2, 4 and 6 hours are indicated.
Som det fremgår av tabellen er mengden av bakterier i rør 2) etter 6 timer bare 1/1000 av mengden i rør 1) på samme tid, hvorved ingen eller bare liten vekst har funnet sted i rør 1), As can be seen from the table, the amount of bacteria in tube 2) after 6 hours is only 1/1000 of the amount in tube 1) at the same time, whereby no or only little growth has taken place in tube 1).
men i rør 2) er mikroorganismene drept. but in tube 2) the microorganisms are killed.
Effekten av det antibakterielle system ble bestemt in vitro. Deretter ble forskjellig E. coli-stammer inkubert ved 37°C i en vandig oppløsning av 5 g mysepulver/100 ml, 21 ppm NaSCN og natriumperkarbonat tilsvarende 0,25 mM f^C^. Resultatet fra E. coli-drepingen etter 2 timer er angitt The effectiveness of the antibacterial system was determined in vitro. Then different E. coli strains were incubated at 37°C in an aqueous solution of 5 g whey powder/100 ml, 21 ppm NaSCN and sodium percarbonate corresponding to 0.25 mM f^C^. The result from the E. coli killing after 2 hours is indicated
i nedenstående tabell 3. in table 3 below.
Flere av de undersøkte E. coli-stammer er bestandige overfor antibiotika. Resultatene indikerer således en høy grad av anvendelsesgyldighet for systemet. Dette fremgår også fra det faktum at systemet har virkning på gram-positive bakterier. Several of the investigated E. coli strains are resistant to antibiotics. The results thus indicate a high degree of application validity for the system. This is also evident from the fact that the system has an effect on gram-positive bacteria.
For å illustrere den effekt som oppnås ved topisk administrasjon av det ifølge oppfinnelsen fremstilte preparat ble det i en dermal bærer av kremtypen med pH 5,0 innblandet laktoperoksydase, 5000 U/kg, natriumtiocyanat, 1 mM, og natriumperkarbonat tilsvarende 1 mM ^ 2°2' Denne krem (A) ble testet mot en Staphylococcus pyogenes A. Som kontroll ble benyttet den dermale bæreren med pH 5,0X samt samme bærer med pH 6,7 . Den inhibering og dreping av den angitte mikroorganisme som ble oppnådd, angitt i CFU, er angitt i tabell 4 nedenfor, To illustrate the effect achieved by topical administration of the preparation according to the invention, lactoperoxidase, 5000 U/kg, sodium thiocyanate, 1 mM, and sodium percarbonate corresponding to 1 mM ^ 2° were mixed into a dermal carrier of the cream type with pH 5.0 2' This cream (A) was tested against Staphylococcus pyogenes A. As a control, the dermal carrier with pH 5.0X and the same carrier with pH 6.7 were used. The inhibition and killing of the specified microorganism achieved, expressed in CFU, is set out in Table 4 below,
x (B),xx(C) x (B),xx(C)
Samme dermale bærer som i eksempelet ovenfor (A) ble benyttet som sammenligning med beredningen (C) ovenfor, hvorved pH var 6,7 i begge beredningene. Samme mikroorganisme ble benyttet som test. The same dermal carrier as in the above example (A) was used as a comparison with the preparation (C) above, whereby the pH was 6.7 in both preparations. The same microorganism was used as a test.
Samme beredninger som ovenfor (A) og (C) med pH 6,7 ble testet mot en penicillinaseproduserende mikroorganisme, Staph. aureus 3/71. The same preparations as above (A) and (C) with pH 6.7 were tested against a penicillinase-producing microorganism, Staph. aureus 3/71.
Det fremstilte preparat kan benyttes i både fast og flytende form, idet det antibakterielle system generelt tilsettes til farmasøytiske bærere av forskjellig art avhengig av type og mengde preparat som anvendes. The prepared preparation can be used in both solid and liquid form, as the antibacterial system is generally added to pharmaceutical carriers of different types depending on the type and amount of preparation used.
Claims (5)
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NO800913A NO155602C (en) | 1976-03-08 | 1980-03-28 | PROCEDURE FOR PREPARING A PHARMACEUTICAL PREPARATION FOR ORAL AND TOPICAL ADMINISTRATION. |
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SE7603075A SE420793B (en) | 1976-03-08 | 1976-03-08 | FEEDING AGENT CONTAINING AN ANTI-BACTERIAL SYSTEM |
NO770785A NO143297C (en) | 1976-03-08 | 1977-03-07 | Animal feed. |
NO800913A NO155602C (en) | 1976-03-08 | 1980-03-28 | PROCEDURE FOR PREPARING A PHARMACEUTICAL PREPARATION FOR ORAL AND TOPICAL ADMINISTRATION. |
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NO155602B true NO155602B (en) | 1987-01-19 |
NO155602C NO155602C (en) | 1987-04-29 |
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