DK161728B - PARTICULAR FEED ADMINISTRATOR FOR DRUGS AND PROCEDURES FOR ITS MANUFACTURING - Google Patents
PARTICULAR FEED ADMINISTRATOR FOR DRUGS AND PROCEDURES FOR ITS MANUFACTURING Download PDFInfo
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- DK161728B DK161728B DK369283A DK369283A DK161728B DK 161728 B DK161728 B DK 161728B DK 369283 A DK369283 A DK 369283A DK 369283 A DK369283 A DK 369283A DK 161728 B DK161728 B DK 161728B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K20/00—Accessory food factors for animal feeding-stuffs
- A23K20/10—Organic substances
- A23K20/142—Amino acids; Derivatives thereof
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K20/00—Accessory food factors for animal feeding-stuffs
- A23K20/20—Inorganic substances, e.g. oligoelements
- A23K20/30—Oligoelements
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K40/00—Shaping or working-up of animal feeding-stuffs
- A23K40/30—Shaping or working-up of animal feeding-stuffs by encapsulating; by coating
- A23K40/35—Making capsules specially adapted for ruminants
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K50/00—Feeding-stuffs specially adapted for particular animals
- A23K50/10—Feeding-stuffs specially adapted for particular animals for ruminants
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Abstract
Description
DK 161728 BDK 161728 B
oisland
Den foreliggende opfindelse angår et partikelformet fodertilsætningsmiddel til drøvtyggere, hvilket tilsætningsmiddel tjener til at forbedre drøvtyggeres tilførsel af essentielle aminosyrer.The present invention relates to a particulate feed additive for ruminants, which additive serves to improve the delivery of essential amino acids by ruminants.
5 Tidligere er der udfoldet store anstrengelser for at forbedre drøvtyggeres tilførsel af næringsstoffer som f.eks. proteiner eller frie essentielle aminosyrer. Problemet består ved den orale fodring hovedsagelig deri, at disse stoffer, for virkelig at være til rådighed for dyret, skal passere vommen prak-10 tisk taget ubeskadigede. Med dette formål for øje beskyttes eksempelvis aminosyrer ved kemisk behandling eller ved omhyl-ning med et lag, der ikke angribes i vommen. Herved opstår igen det problem , at netop i vommen skal der foregå en beskyttelse af aminosyren, men at denne beskyttelse dog ikke i 15 den efterfølgende fordøjelseskanal må hindre resorptionen af aminosvrerne. Det mål, der derfor bør tilstræbes, at opnå en 100%'s beskyttelse i vommen og i den efterfølgende fordøjelseskanal en 100%‘s resorption, kunne tidligere ikke tilnærmelsesvis opnås. Det er tværtimod blevet konstateret, at ved de 20 på kendt måde beskyttede aminosyrer var beskyttelsen i vommen utilstrækkelig, eller at resorptionen i den efterfølgende fordøjelseskanal ikke svarede til forventningerne. Dette viste sig især ved in vivo-forsøg, ved hvilke blodserummets indhold af væsentlige aminosyrer i relation til tilførslen af beskvt-25 tede aminosyrer er blevet undersøgt. I denne sammenhæng henvises til en artikel af dr. K. Kuther i "Rinderwelt" nr. 1, 1982, side 3-8, og til Degussa-Informationsdienst fur die Mischfutter-industrie 1/1979, side 1-5, hvor-det nyeste udviklingsstadium ses, især med hensyn til den aminosyre, der inden for fagvidenska-30 ben anses for særlig betydningsfuld for drøvtyggere - frem for alt for højtydende køer - nemlig methionin. Af de mange forslag, der angår metoder til beskyttelse af biologisk aktive stoffer i vommen på drøvtyggere, henvises eksempelvis til tyske patentskrifter nr. 2.212.568 og 3.013.000, til USA patentskrift 35 nr. 3.655.864, engelsk patentskrift nr. 1.137.214 og norsk patentskrift nr. 120.058 samt til de i disse trykskrifter nævnte publikationer.5 In the past, great efforts have been made to improve the supply of nutrients by ruminants, e.g. proteins or free essential amino acids. The problem with oral feeding consists mainly in the fact that these substances, in order to really be available to the animal, have to pass through the rumen practically undamaged. For this purpose, for example, amino acids are protected by chemical treatment or by wrapping with a layer which is not attacked in the rumen. This again raises the problem that precisely in the rumen there must be protection of the amino acid, but that such protection must not, however, prevent the resorption of the amino acids in the subsequent digestive tract. The goal, which should therefore be sought to achieve a 100% protection in the rumen and in the subsequent digestive tract a 100% resorption, could previously not be achieved approximately. On the contrary, it has been found that in the 20 known amino acids protected, the protection in the rumen was inadequate or that the resorption in the subsequent digestive tract did not meet expectations. This was particularly evident in in vivo experiments in which the blood serum content of essential amino acids in relation to the supply of damaged amino acids has been investigated. In this context, reference is made to an article by dr. K. Kuther in "Rinderwelt" No. 1, 1982, pages 3-8, and to the Degussa-Information Information Service for the Die Mischfutter industry 1/1979, pages 1-5, where the latest stage of development is seen, especially with regard to the amino acid which, in the field of scientific knowledge, is considered particularly important for ruminants - especially for high-yielding cows - namely methionine. Of the many proposals relating to methods of protecting biologically active substances in rumen ruminants, for example, reference is made to German Patent Nos. 2,212,568 and 3,013,000 to United States Patent 35,365,864, English Patent No. 1,137. 214 and Norwegian Patent Publication No. 120,058 and to the publications mentioned in these publications.
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På grund af den her skildrede^, utilstrækkelige^kendte teknik er det således opfindelsens formål at angive et fodertilskudsmiddel til drøvtyggere, der ikke blot kan fremstilles så simpelt som muligt, men også som foder til drøvtyggere giver 5 en bedre kombination af vompassage og resorption i den efterfølgende fordøjelseskanal for essentielle aminosyrer end de kendte fodertilskudsmidler og derved forbedrer den faktiske tilgængelighed af de essentielle aminosyrer.Thus, because of the prior art described herein, the object of the invention is to provide a feed supplement for ruminants which can not only be produced as simply as possible, but also as a feed for ruminants provides a better combination of rumen passage and resorption in the subsequent digestive tract for essential amino acids than the known feed additives, thereby improving the actual availability of the essential amino acids.
Til opfyldelse af dette formål foreslås et partikel-10 formet fodertilskudsmiddel til drøvtyggere af den i patentkravene kendetegnede art samt en fremgangsmåde til fremstilling heraf.In order to fulfill this purpose, a particulate feed additive for ruminants of the kind claimed in the patent is proposed, and a method of making them.
Som allerede nævnt ovenfor, regnes methionin ifølge den seneste erkendelse som den for drøvtyggere vigtigste væsent-15 lige aminosyre, dvs. den anses for at være første begrænsende aminosyre. Følgelig vil opfindelsen i det følgende blive beskrevet ved hjælp af et fodertilskudsmiddel ifølge opfindelsen, der forbedrer drøvtyggeres forsyning med methionin.As already mentioned above, methionine is considered to be the most important amino acid for ruminants, i.e. it is considered to be the first limiting amino acid. Accordingly, the invention will be described hereinafter by means of a feed supplement according to the invention that improves ruminants' supply of methionine.
Zink-OÉ-aminosyre-komplekssalte og især zink-methionin-20 -komplekssalte med et molforhold mellem zink og aminosyre på 1:1 (jfr. tysk fremlæggelsesskrift 2.436.946 og USA patentskrifter nr. 3.463.858, 3.941.818 og 4.021.569) er kendte. De nævnte salte er vandopløselige komplekssalte, hvis enkelt positivt ladede kation består af et zink-a-aminosyrekompleks, medens anionen kan 25 vælges efter behag (se f.eks. de i tysk fremlæggelsesskrift nr. 2.436.946, USA patentskrift nr. 3.941.818 og 4.021.569 viste strukturformler). I de anførte trykskrifter sker afhjælpningen hovedsagelig derved, at disse zinkforbindelser egner sig godt for menneske- og dyrekroppen som særligt nemt tilgængelige zink-30 kilder. Mere i forbigående nævnes desuden, at disse forbindelser også er egnede stoffer, der er egnet til at forsyne dyr med essentielle aminosyrer. Derimod kommer man ikke ind på de særlige problemer, der optræder hos drøvtyggere, i disse trykskrifter.Zinc-OÉ amino acid complex salts and, in particular, zinc-methionine-20 complex salts having a zinc to amino acid molar ratio of 1: 1 (cf. German Patent Specification 2,436,946 and U.S. Patent Nos. 3,463,858, 3,941,818 and 4,021. 569) are known. Said salts are water-soluble complex salts whose single positively charged cation consists of a zinc-α-amino acid complex, while the anion can be selected at will (see, for example, those in German Patent Specification No. 2,436,946, U.S. Patent No. 3,941. 818 and 4,021,569 shown structural formulas). In the aforementioned printed matter, the remedy is mainly because these zinc compounds are well suited for the human and animal bodies as particularly easily available zinc sources. Further in passing, it is further mentioned that these compounds are also suitable substances suitable for supplying animals with essential amino acids. On the other hand, the special problems of ruminants are not addressed in these printed matter.
Det er heller ikke så mærkeligt, da de beskrevne komplekssal-35 te er vandopløselige forbindelser, som ved fodring af drøvtyggere opløses i vommen og derfor ikke når de efterfølgende 3It is also not strange, since the complex salts described are water-soluble compounds which, when feeding ruminants, dissolve in the rumen and therefore do not reach the subsequent 3
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afsnit af fordøjelseskanalen, og således heller ikke kan sørge for ekstra tilskud til drøvtyggere af essentielle aminosyrer.section of the digestive tract, and thus cannot provide additional supplements to ruminants of essential amino acids.
Endvidere beskrives i tysk fremlæggelsesskrift nr.Furthermore, German publication no.
5 2.704.746 anvendelsen af det også ifølge opfindelsen egnede zinkmethionat 1:2 som bestanddel af fodertilskudsmidler.No. 2,704,746 uses the zinc methionate 1: 2 also suitable for use in the invention as a component of feed additives.
Som det fremgår af indledningen til krav 1 og angivelserne i beskrivelsen, angår dette skrift et middel til vækstfrem-ning og foderbesparelse ved intensiv opfodring af kalve 10 (hos disse er drøvtyggernes komplicerede fordøjelsessystem endnu ikke fuldt udviklet, således at vombestandigheden af foderkomponenter ikke spiller nogen som helst rolle), kreaturer og får. Intetsteds i tysk fremlæggelsesskrift nr.As can be seen from the preamble of claim 1 and the disclosures in the specification, this specification relates to a means of growth promotion and feed saving by intensive feeding of calves 10 (of these, the complicated digestive system of ruminants is not yet fully developed, so that the rumen resistance of feed components does not play any any role), creatures and sheep. Nowhere in German submission no.
2.704.746 findes den ringeste henvisning til, at vanduopløse-15 lige zinkkomplekser af essentielle aminosyrer, som anvendes ifølge den foreliggende opfindelse, udviser en vis vombe-standighed.2,704,746 is the slightest reference to the fact that water-insoluble zinc complexes of essential amino acids used in the present invention exhibit some womens resistance.
Ifølge opfindelsen har det nu overraskende vist sig, at de vanduopløselige zinkkomplekser, der dannes ved omsæt-20 ning af essentielle aminosyrer med vandopløselige zinksalte ved egnet pH-værdi er forholdsvis vomstabile. Med dalende pH-værdi, senest efter saltsur hydrolyse i kallunet ved pH 2-4 opløses disse forbindelser igen i deres komponenter og står i de efterfølgende afsnit af fordøjelseskanalen til 25 rådighed for resorptionen. Derved forøges tilgængeligheden i de efter vommen følgende afsnit af fordøjelseskanalen og dermed den resorption, der kan følges ved hjælp af blodserum-værdierne, betydeligt ved, at man forøger vomstabiliteten, idet de partikelformede vanduopløselige zink/aminosyrekom-30 plekser blandes eller omhylles med en fra teknikkens stade kendt vomstabil matriks.According to the invention, it has now surprisingly been found that the water-insoluble zinc complexes formed by the reaction of essential amino acids with water-soluble zinc salts at suitable pH are relatively water stable. With decreasing pH value, most recently after hydrochloric acid hydrolysis in the colony at pH 2-4, these compounds are redissolved in their components and are available for resorption in subsequent sections of the digestive tract. Thereby, the availability in the subsequent sections of the digestive tract and, consequently, the resorption which can be followed by the blood serum values, is significantly increased by increasing vomiting stability as the particulate water-insoluble zinc / amino acid complexes are mixed or enclosed with a state of the art known womens stable matrix.
Fremstillingen af fodertilskudsmidlet ifølge opfindelsen sker ved, at methionin ved stuetemperatur opløses i vand ved tilsætning af syre, f.eks. saltsyre. Herefter tilsættes un-35 der omrøring et zinksalt, f.eks. zinksulfat (vandfrit eller hydra-tiseret), til opløsningen, hvorved saltet hurtigt opløses. Me- 4The preparation of the feed additive according to the invention takes place by dissolving methionine at room temperature in water by the addition of acid, e.g. hydrochloric acid. Then, with stirring, a zinc salt, e.g. zinc sulphate (anhydrous or hydrated), to the solution, thereby rapidly dissolving the salt. Me- 4
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thionin og zinksalt anvendes derved i et molforhold på 2:1. Den opnåede klare opløsning indstilles derefter under kraftig omrøring til en pH-værdi på 7,5, hvilket fortrinsvis sker ved til-drypning af en alkalihydroxid. Efter at pH-værdien er indstil-5 let til 7,5, omrøres endnu et stykke tid, før det udfældede bundfald fraskilles, vaskes med vand og tørres. Fremstillingen af vanduopløselige zinkkomplekser af histidin, phenylalanin og valin sker på analog måde. Endvidere skal det i denne sammenhæng nævnes, at det opnåede bundfald ofte ikke blot består af 10 de vanduopløselige zinkkomplekser af aminosyrerne, men også kan indeholde til dels betydelige mængder af samtidig fældet zink" hydroxid.Thionine and zinc salt are thereby used in a 2: 1 molar ratio. The clear solution obtained is then adjusted with vigorous stirring to a pH of 7.5, which is preferably done by adding an alkali hydroxide. After adjusting the pH to 7.5, stir for a while before the precipitated precipitate is separated, washed with water and dried. The preparation of water-insoluble zinc complexes of histidine, phenylalanine and valine takes place in an analogous manner. Furthermore, it should be mentioned in this connection that the precipitate obtained often consists not only of the water-insoluble zinc complexes of the amino acids, but may also contain, in part, significant amounts of simultaneously precipitated zinc hydroxide.
Det på den oven for beskrevne måde fremstillede partikelformede vanduopløselige zink/methioninkompleks blandes 15 eller omhylles med en vomstabil matriks. Dette sker på kendt måde som f.eks. ved sprøjtekrystallisation (jfr. tysk patentskrift nr. 2.451.510). Andre egnede fremgangsmåder er beskrevet i de ovenfor i forbindelse med vomfast lagpåføring nævnte trykskrifter. Især henvises til tysk offentliggørel-20 sesskrift nr. 3.013.000 og til Chemie, Ingenieur und Technik 51 (1979), nr. 11, side 996-998 og 45 (1973), nr. 23 side 1339. Naturligvis kan også blandinger af zinkkomplekser med to eller flere essentielle aminosyrer blandes eller omhylles med en vomstabil matriks.The particulate water-insoluble zinc / methionine complex prepared in the manner described above is mixed or enclosed with a water-stable matrix. This is done in a known manner, e.g. by spray crystallization (cf. German Patent No. 2,451,510). Other suitable methods are described in the prints mentioned above in connection with womens layer coatings. In particular, reference is made to German Publication 20,013,000 and to Chemie, Ingenieur und Technik 51 (1979), 11, pages 996-998 and 45 (1973), 23 to 1339. Of course, mixtures of zinc complexes with two or more essential amino acids are mixed or enveloped with a rumen stable matrix.
25 Som vomstabil matriks til blanding med til omhylning af zinkkomplekserne anvendt ved opfindelsen egner sig fra teknikkens stade kendte materialer. Hertil hører eksempelvis triglycerider, mættede fedtsyrer og salte heraf, blandinger af mono-, di- og triglycerider og blandinger af glyceroltri-30 stearat med flydende umættede højere fedtsyrer samt kombinationer af de nævnte beskyttelsesmaterialer. Der henvises detaljeret til de allerede nævnte trykskrifter og de i disse omtalte referencer, idet der desuden henvises til de tyske offentliggørelsesskrifter nr. 2.838.278, 2.838.298 og 35 2.838.309. Beregnet på den samlede vægt af fodertilskudsmid let ifølge opfindelsen udgør mængden af vomstabil matriks 525 As a womens stable matrix for mixing with the envelope of the zinc complexes used in the invention, suitable materials are known from the state of the art. These include, for example, triglycerides, saturated fatty acids and salts thereof, mixtures of mono-, di- and triglycerides and mixtures of glycerol tri-stearate with liquid unsaturated higher fatty acids and combinations of said protective materials. Reference is made in detail to the prints already mentioned and to the references cited therein, and reference is also made to German publication publications Nos. 2,838,278, 2,838,298 and 35 2,838,309. Calculated based on the total weight of feed additive blacks according to the invention, the amount of rumble matrix is 5
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op til 90% og fortrinsvis 45-65%. Som regel bør det tilstræbes, at andelen af vomstabil matriks holdes så lav som muligt. Partikelstørrelsen af fodertilskudsmidlet ifølge opfindelsen af zinkkompleks og vomstabil matriks ligger i inter-5 vallet fra 0f3 til 1,0 mm, idet et interval på ca. 0,3-0,6 mm foretrækkes. Denne forholdvis lille partikelstørrelse udgør i forhold til de i praksis kendte vompasserende.fodertilskudsmidler med en vomstabil matriks, der fremstilles med en partikelstørrelse på ca. 1,0 mm og mere, en ikke 10 uvæsentlig fordel, da på den ene side overfladen forøges, men samtidig passagetiden i formaven forkortes. Hertil kommer blandingstekniske fordel, da disse finere partikler har ca. den samme størrelse som bestanddelene i melformige (ikke pelletterede) foderblandinger og derfor ikke har tilbøjelig-15 hed til at skille sig ud.up to 90% and preferably 45-65%. As a rule, the aim should be to keep the proportion of ruminant matrix as low as possible. The particle size of the feed additive according to the invention of zinc complex and womens stable matrix ranges from 0f3 to 1.0mm, with an interval of approx. 0.3-0.6 mm is preferred. This relatively small particle size, in comparison with the practice-known rumen feed additives, has a rum stable matrix produced with a particle size of approx. 1.0 mm and more, not an insignificant advantage, since on the one hand the surface is increased, but at the same time the passage time in the preform is shortened. In addition, mixing technology is advantageous as these finer particles have approx. the same size as the constituents of flour-shaped (non-pelleted) compound feed and therefore do not tend to stand out.
En betydelig ulempe ved de fra teknikkens stade kendte vompasserende fodertilskudsmidler består endvidere deri, at disse ikke kan pelletteres, da den kemiske eller fysiske beskyttelse på grund af de termiske og mekaniske indflydelser ved 20 pelletteringen kan blive skadeligt påvirket. Denne egenskab begrænser anvendelsen af de kendte vorapasserende fodertilskudsmidler, da fodere (blandingsfodere) fortrinsvis nu til dags fremstilles i pelletteret form. I modsætning hertil kan fodertilskudsmidlet ifølge opfindelsen pelletteres, uden at der 25 herved forekommer en væsentlig beskadigelse af beskyttelsesvirk-ningen i vommen. Dette beror på den store termiske stabilitet hos zinkkomplekserne anvendt ved opfindelsen samt på deres upåvirkelighed af vand ved den umiddelbart før pelletteringen foretagne kon-ditioneringsproces med hed vanddamp, så at den ringe nedsæt-30 telse af matriksens beskyttelsesvirkning på grund af pelletteringen ikke har nogen betydning.Furthermore, a considerable disadvantage of the prior art feed additives known in the art consists in the fact that these cannot be pelleted since the chemical or physical protection due to the thermal and mechanical influences of the pelleting can be adversely affected. This feature restricts the use of the prior art feed additives, since feeders (blend feeders) are nowadays preferably prepared in pelleted form. In contrast, the feed additive according to the invention can be pelleted without causing any significant damage to the protective effect in the rumen. This is due to the high thermal stability of the zinc complexes used in the invention as well as to their insensitivity to water in the hot water vapor conditioning process immediately prior to pelleting, so that the slight reduction of the protective effect of the matrix due to the pelleting is of no significance. .
Doseringen af fodertilskudsmidlet ifølge opfindelsen retter sig naturligvis efter behovet hos det pågældende dyr for de forskellige essentielle aminosyrer. Således har f.eks. ef-35 fektivitetsforsøg med køer en sådan mængde fodertilskudsmiddel vist sig egnet, som svarer til en ekstra tilførsel af 1-30 gThe dosage of the feed supplement according to the invention, of course, is directed to the needs of the animal concerned for the various essential amino acids. Thus, e.g. Efficacy tests with cows such an amount of feed supplement proved to be suitable which corresponds to an additional feed of 1-30 g
OISLAND
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6 methionin/dag og fortrinsvis ca. 15 g methionin/dag. På grund af den højere andel af det methionin, der effektivt når blod-serummet, må det forventes, at den daglige tilførsel af fodertilskudsmidlet ifølge opfindelsen i sammenligning med kendte 5 midler endog kan ligge lavere. Særlig betydning har den ekstra orale indgivelse af methionin for får, eftersom svovlholdige aminosyrer har en væsentlig indflydelse på ulddannelsen. Til et får med en kropsvægt på ca. 50 kg svarer en dosering af fodertilskudsmidlet ifølge opfindelsen omtrent til en mængde, der 10 betyder en ekstra indgivelse af ca. 5 g methionin.6 methionine / day and preferably about 15 g of methionine / day. Due to the higher proportion of the methionine that efficiently reaches the blood serum, it is expected that the daily supply of the feed supplement of the invention in comparison with known agents may even be lower. Of particular importance is the extra oral administration of methionine to sheep, since sulfur-containing amino acids have a significant influence on wool formation. For a sheep with a body weight of approx. 50 kg, a dosage of the feed supplement according to the invention corresponds approximately to an amount which means an extra administration of approx. 5 g of methionine.
Doseringen af fodertilskudsmidler ifølge opfindelsen, som indeholder andre aminosyrer end methionin, kan bestemmes ved hjælp af dyreforsøg, således som det eksempelvis beskrives i de følgende eksempler.The dosage of feed additives of the invention containing amino acids other than methionine can be determined by animal testing, as described, for example, in the following examples.
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Eksempel 1 89,4 g (0,6 mol) methionin opløses ved stuetemperatur i 1500 ml vand ved tilsætning af 200 ml 1 N saltsyre. Derefter tilsættes under omrøring 86,2 g (0,3 mol) zinksulfat 20 (ZnSO^ x 7 H2O) til opløsningen, hvorved saltet hurtigt opløses . Den opnåede klare opløsning bringes ved tildrypning af 45¾1s kaliumhydroxid på pH 7,5, idet der omrøres kraftigt.Example 1 89.4 g (0.6 mol) of methionine is dissolved at room temperature in 1500 ml of water by the addition of 200 ml of 1 N hydrochloric acid. Then, with stirring, 86.2 g (0.3 mole) of zinc sulfate 20 (ZnSOO x 7 H₂O) is added to the solution, whereby the salt is rapidly dissolved. The clear solution obtained is brought to pH 7.5 with 45 µl of potassium hydroxide by stirring vigorously.
Efter endt tilsætning omrøres endnu i 10 minutter, det udfældede bundfald skilles fra, vaskes med vand (2 x 300 ml) og tør-25 res ved 110°C.After the addition is complete, stir for another 10 minutes, the precipitate is separated, washed with water (2 x 300 ml) and dried at 110 ° C.
Udbyttet af zink/methioninkompleks i forholdet 1:2 (bruttoformel: cioN20N2°4S2Zn^ er 104,1 g (= 95,9% af det teoretiske) . Produktet undersøges ved analytisk rutineprocedure for indhold af zink og methionin. Der fås følgende værdier: 30 18,5% zink (teoretisk: 18,15%) og 78,5% methionin (teoretisk: 81,85%).The yield of zinc / methionine complex in a ratio of 1: 2 (gross formula: cioN20N2 ° 4S2Zn ^ is 104.1 g (= 95.9% of theory). The product is examined by analytical routine procedure for zinc and methionine content. The following values are obtained: 18.5% zinc (theoretical: 18.15%) and 78.5% methionine (theoretical: 81.85%).
Eksempel 2 29,8 g (0,2 mol) methionin opløses i 500 ml vand ved 35 tilsætning af 40 ml 2 N saltsyre ved stuetemperatur. Derefter tilsættes 8,14 g (0,1 mol) zinkoxid til opløsningen, der brin-Example 2 29.8 g (0.2 mole) of methionine are dissolved in 500 ml of water by the addition of 40 ml of 2N hydrochloric acid at room temperature. Then 8.14 g (0.1 mole) of zinc oxide are added to the solution which
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7 ges i fuld opløsning ligeledes ved tilsætning af fortyndet saltsyre. Ved tildrypning af en 45%'s kaliumhydroxid indstilles blandingen derefter på en pH-værdi på 7,5. Det udfældede kompleks skilles fra, vaskes med 600 ml vand og tørres ved 110°C.7 is given in full solution also by the addition of dilute hydrochloric acid. Then, by adding a 45% potassium hydroxide, the mixture is adjusted to a pH of 7.5. The precipitated complex is separated, washed with 600 ml of water and dried at 110 ° C.
5 Udbyttet er 33,0 g (= 91,2% af det teoretiske), og analysen viser 18,4% zink og 77,6% methionin.The yield is 33.0 g (= 91.2% of theory) and the analysis shows 18.4% zinc and 77.6% methionine.
Ved yderligere gængse rensningsoperationer kan det i eksempel 1 og 2 fremstillede zink-methioninkompleks renses y-derligere, om ene dette ikke er nødvendigt til formåle-10 ne ifølge opfindelsen. På grund af de i eksemplerne 1 og 2 valgte volumen- og mængdeforhold begynder udfældningen af bundfald allerede, før pH-værdien har nået 7,5.In further conventional purification operations, the zinc-methionine complex prepared in Examples 1 and 2 may be further purified, if this is not necessary for the purposes of the invention. Due to the volume and volume ratios selected in Examples 1 and 2, the precipitation of sediment begins even before the pH reaches 7.5.
Eksempel 3 15 Det ifølge eksempel 1 fremstillede zink-methioninkom pleks afprøves ved et fodringsforsøg med køer.EXAMPLE 3 The zinc-methionine complex instead of Example 1 is tested in a feeding test with cows.
En prøvet metode ved bestemmelsen af aminosyrebehovet hos dyr er en stigende tilførsel af den pågældende aminosyre med parallelt udtagne blodprøver. Så længe behovet for denne 20 aminosyre ikke er dækket, forbliver niveauet i serummet konstant. Så snart behovet er dækket (og eventuelt en anden aminosyre virker limiterende) stiger indholdet i blodserummet tydeligt. Der henvises her til Degussa-Informationsdienst fur die Mischfutter- industrie 1/1979, side 1-5, hvor den skitserede metode er de-25 taljeret beskrevet, og de beskrevne kendsgerninger fremstillet grafisk på side 2.A tried and tested method for determining amino acid requirements in animals is an increasing supply of the amino acid in question with blood samples taken in parallel. As long as the need for this 20 amino acid is not met, the serum level remains constant. As soon as the need is met (and possibly another amino acid is limiting), the blood serum content increases clearly. Reference is made here to the Degussa-Information Service Fur die Mischfutter-industrie 1/1979, pages 1-5, where the outlined method is described in detail and the facts described are graphically prepared on page 2.
Med henblik på en sammenlignende afprøvning af de beskyttede aminosyrers beskyttelse og deres tilgængelighed hos drøvtyggere er det indlysende at indgive en mængde, der ligger 30 over dyrets behov, saledes at det foreventede serumindhold til stadighed skulle ligge på den stigende kurve (se dén grafiske fremstilling i det ovennævnte litteratursted). På denne måde kan forskellige vompasserende fodertilskudsmidler med defineret methioninindhold afprøves og sammenlignes eksempelvis med de 35 ved kalluninfusion opnåede serumværdier. Denne metode har den fordel, at sammen med den methioninmængde, der når blodserum- 8For a comparative test of the protection of the protected amino acids and their availability to ruminants, it is obvious to administer an amount in excess of the animal's needs, so that the expected serum content should remain on the rising curve (see the graph in the above-mentioned literature site). In this way, various ruminant feed additives with defined methionine content can be tested and compared, for example, with the serum values obtained by calf infusion. This method has the advantage that along with the amount of methionine that reaches the blood serum 8
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met omfattes beskyttelsen i vommen og tilgængeligheden i de efterfølgende afsnit af fordøjelseskanalen.This includes the protection of the rumen and accessibility in the subsequent sections of the digestive tract.
Da passagetiden gennem formaverne og også resorptionshastigheden ved anvendelse af forskellige methioninformer kan 5 differere, vælges der ved de gennemførte forsøg hyppige små tilførsler ved oral indgivelse, medens infusionerne sker kontinuerligt.Since the passage time through the preforms and also the rate of resorption using different methionine informants can differ, frequent small infusions are selected during oral administration, while the infusions are continuous.
De ved de gennemførte forsøg anvendte methioninformer og -mængder samt de pågældende målte blodserumværdier er anført 10 i nedenstående tabeller. Behandlingsperioden for den enkelte ko er 1 uge. De orale indgivelser sker i 6 ens store portioner/dag regelmæssigt fordelt mellem kl. 6.00 og 18.30.The methionine information and amounts used in the experiments and the measured blood serum values in question are listed in the tables below. The treatment period for each cow is 1 week. The oral administration is done in 6 equal portions / day, regularly distributed between 10 am and 3 pm. 6.00 and 18.30.
15 Tabel ITable I
&&
Methioninindh. i serum ^ug/mlMethioninindh. in serum µg / ml
Methioninform_ Ko nr. 1_Ko nr. 2_ uden methionintilførsel 2,7 3,1 60 g (i 6 doser) oralt indgivet me-20 thioninkompleks (1:2)/dag svar. til ca. 47 g DL-methionin 3,7 3,7 10 g infunderet DL-methionin i kallun/dag 7,6 11,7 25 * Hver værdi er middelværdien af tre analyser fra tre prøvetag- ningstidspunkter. Forsøgsdyrene er malkekøer.Methioninform_Co # 1_Co # 2_ without methionine supply 2.7 3.1 60g (in 6 doses) orally administered methionine complex (1: 2) / day response. to approx. 47 g DL-methionine 3.7 3.7 10 g infused DL-methionine in turkey / day 7.6 11.7 25 * Each value is the average of three assays from three sampling times. The experimental animals are dairy cows.
I ovennævnte tabel viser de anførte resultater, at den orale‘indgivelse af zink-methioninkomplekset anvendt ved opfin-30 delsen tydeligt forøger indholdet af methionin i blodserummet, hvilket ikke er tilfældet med vandopløselig methionin. Efter infusion med methionin opnås dog blodserumindholdene langt fra.In the above table, the results indicated show that the oral administration of the zinc-methionine complex used in the invention clearly increases the content of methionine in the blood serum, which is not the case with water-soluble methionine. However, after infusion with methionine, blood serum levels are far from achieved.
35 935 9
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Eksempel 4Example 4
De i eksempel 3 beskrevne forsøg gentages, idet zinkkomplekset blandes med en matriks af mættede triglycerider. Fremstillingen af denne blanding sker efter den ovenfor 5 beskrevne sprøjtekrystallisationsmetode, ved hvilken den af zinkkomplekset og triglyceriderne fremstillede varme smelte under tryk sprøjtes mod en kold luftstrøm. Indholdet af zinkkompleks, beregnet som methionin, er 30%. Til sammenligning blandes normalt methionin på samme måde med den nævnte 10 matriks. Også her er indholdet af methionin 30%.The experiments described in Example 3 are repeated, mixing the zinc complex with a matrix of saturated triglycerides. This mixture is prepared according to the above-described syringe crystallization method, in which the heat produced by the zinc complex and the triglycerides is melted under pressure against a cold air stream. The content of zinc complex, calculated as methionine, is 30%. In comparison, methionine is usually mixed in the same manner with the said matrix. Here, too, the content of methionine is 30%.
De opnåede forsøgsresultater er anført i nedenstående tabel. Serumprøverne udtages den sidste dag i hver behandlingsperiode kl. 14.00. altså en behandlingsvarighed på knap en uge.The obtained test results are listed in the table below. The serum samples are taken on the last day of each treatment period at. 14.00. thus a treatment duration of just under a week.
1515
Tabel IITable II
Methioninindh♦ i serum ,ug/mlMethionine content in serum, µg / ml
Methioninform-(tilførsel pr. dag)_Ko nr. 1_Ko nr. 2 150 g normal beskyttet methionin, 20 (30%'s) = 45 g methionin 2,6 2,7 7,5 g infunderet DL-methionin i kallun 4,0 9,0 uden methionintilførsel 1/8 2,0 150 g methionin beskyttet ifølge op-25 findelsen (30%'s) = 45 g methionin 6,0 10,0 15 g infunderet DL-methionin i kallun 8,0 12,0 * Hver værdi fremkommer som middelværdien af to analyser. For-30 søgsdyrene er malkekøer.Methionine (daily feed) _Ko # 1_Ko # 2 150 g of normal protected methionine, 20 (30%) = 45 g of methionine 2.6 2.7 7.5 g of infused DL-methionine in turkey 4, 0 9.0 without methionine supply 1/8 2.0 150 g of methionine protected according to the invention (30%) = 45 g of methionine 6.0 10.0 15 g of infused DL-methionine in turkey 8.0 12, 0 * Each value appears as the mean of two analyzes. The test animals are dairy cows.
Ovennævnte resultater viser, at zink-methioninkomplek-set, der alene kun begrænset forøger blodserumværdierne, sammen med matriksen af mættede triglycerider giver en over-35 ordentlig stor forøgelse af den effektivt resorberede methio-ninmængde. Desuden fremgår det klart af ovennævnte resul-The above results show that the zinc-methionine complex set, which alone only increases blood serum values, together with the matrix of saturated triglycerides, provides an extremely large increase in the effective amount of resorbed methionine. In addition, it is clear from the above-mentioned results.
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10 tater, at anvendelsen af beskyttelsesmatriksen af mættede triglycerider alene har en forholdsvis ringe virkning.10 states that the use of the protective matrix of saturated triglycerides alone has a relatively minor effect.
Den anvendte beskyttelsesmatriks har følgende fedtsyres ammensætning (mættede fedtsyrer): 5 C16 : 20,5% C^g : 53,8% C2Q : 13,8% C22 : 7'8%The protective matrix used has the following fatty acid (saturated) fatty acids composition: 5 C16: 20.5% C 2 g: 53.8% C 2Q: 13.8% C22: 7'8%
Andre: 4,0% 10 100 %Other: 4.0% 10 100%
Eksempel 5Example 5
Det ifølge eksempel 2 fremstillede 2ink-methioninkom-pleks blandes som beskrevet i eksempel 4 med en matriks af di-15 og triglycerider og oparbejdes efter sprøjtekrystallisationsmetoden. Det således fremstillede produkt afprøves på den i eksempel 3 beskrevne måde i et fodringsforsøg med køer, hvor der som sammenligning afprøves yderligere 5 produkter, der enten er i handelen værende produkter eller produkter fremstil-20 let ifølge teknikkens stade, hvorom det er dokumenteret eller beskrevet, at de er vomstabile. Alle produkter indgives i en dosering, så at køerne omregnet får 45 g methionin/dag (opdelt i 6 daglige doser på hver 7,5 g).The 2ink-methionine complex prepared according to Example 2 is mixed as described in Example 4 with a matrix of di-15 and triglycerides and worked up by the spray crystallization method. The product thus prepared is tested in the manner described in Example 3 in a feeding test with cows comparing another 5 products which are either commercially available or manufactured according to the state of the art, as documented or described. that they are rumble stable. All products are administered in a dosage so that the cows receive 45 g of methionine / day (divided into 6 daily doses of 7.5 g each).
Forsøgsdyrene er 2 køer med en middel-lav mælkeydel-25 se (gennemsnitlig 18 1 og 33 1 pr. dag). Køerne behandles hele tiden ens. De to køer reagerer med forskellig tydelighed på methionintilførslen (ko nr. 2 viser den kraftigste reaktion). Disse individuelle forskelle er kendt. Mellem produkttyperne varder med hensyn til rangfølgen for de til serummet "fremkom-30 ne" mængder methionin god sammenlignelighed.The test animals are 2 cows with a medium-low milk yield-25 se (average 18 1 and 33 1 per day). The cows are treated the same all the time. The two cows respond with distinct clarity to the methionine supply (cow # 2 shows the strongest reaction). These individual differences are known. Between the product types, in terms of the order of the amounts of methionine obtained for the serum, good comparability is maintained.
Enkeltværdierne for de gennemførte analyser (udtaget kl. 11 og kl. 14)viser ret store analytiske udsving. Derfor foretages mindst 4 enkeltanalyser pr. produkt og ko. Ligesom i eksempel 3 er behandlingsperioderne for den enkelte ko en 35 uge.The single values for the analyzes performed (sampled at 11 am and 2 pm) show quite large analytical fluctuations. Therefore, at least 4 individual analyzes per product and cow. As in Example 3, the treatment periods for each cow are 35 weeks.
1111
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DK 161728BDK 161728B
Foruden det med D betegnede produkt ifølge opfindelsen undersøges følgende yderligere produkter med sammenligning for øje:In addition to the product designated by D according to the invention, the following additional products are examined for comparison:
Produkt A: Hydroxymethyl-methionin-calciumsalt (Degussa-5 Mepron).Product A: Hydroxymethyl-methionine calcium salt (Degussa-5 Mepron).
Produkt B: Methionin-hydroxy-analog-calciumsalt.Product B: Methionine hydroxy analog calcium salt.
Produkt C: Methionin, der er omhyllet med en matriks af di- og triglycerider samt en emulgator.Product C: Methionine encapsulated with a matrix of di- and triglycerides as well as an emulsifier.
Produkt D: Methionin beskyttet ifølge opfindelsen, som 10 ligeledes er omhyllet med en matriks af di- og triglycerider samt en emulgator (som produkt C).Product D: Methionine protected according to the invention, which is also enveloped with a matrix of di- and triglycerides as well as an emulsifier (as product C).
Produkt E: Methionin, som er omhyllet af en matriks af overvejende mættede fedtsyrer.Product E: Methionine, which is enveloped by a matrix of predominantly saturated fatty acids.
Produkt F: Methionin, som er omhyllet med en matriks lige-15 ledes af overvejende mættede fedtsyrer.Product F: Methionine, which is enveloped with a matrix equal to 15, is led by predominantly saturated fatty acids.
Produkterne A og B findes på markedet. I stedet for methionin indeholder produkt A methionin, der har en hydroxyme-thylgruppe ved aminogruppen. Produkt B er en forbindelse svarende til methionin, hvor aminogruppen er erstattet med en hy-20 droxygruppe. I begge tilfælde omdannes de anvendte forbindelser af dyret dog in vivo til methionin. Produkterne E og F er to typer, der ligner hinanden, og som kun adskiller sig lidt fra hinanden ved matriksens fedtsyresammensætning.Products A and B are on the market. Instead of methionine, product A contains methionine which has a hydroxymethyl group at the amino group. Product B is a compound similar to methionine, wherein the amino group is replaced by a hydroxy group. In both cases, however, the compounds used by the animal are converted in vivo to methionine. The products E and F are two similar types and differ only slightly in the fatty acid composition of the matrix.
De opnåede forsøgsresultater er anført i nedenstående 25 tabel III.The obtained test results are listed in Table III below.
30 3530 35
Tabel IIITable III
DK 161728BDK 161728B
1212
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Methioninindh. i serumMethioninindh. in serum
Per i- ^,ug/ml ode Anvendt mthioninpræparat_Ko nr. 1 Ko nr. 2 c 1 uden methionintilførsel 1,7 2,4 2 Produkt A 2,1 2,9 3 uden methionintilførsel 2,3 2,2 4 Produkt B 2,4 4,5 5 Produkt C 3,3 5,2 10 6 uden methionintilførsel 2,5 2,7 7 Produkt D iflg. opfindelsen 5,2 10,0 8 uden methionintilførsel 2,4 3,6 9 Produkt E 2,8 4,9 10 uden methionintilførsel 2,0 2,6 15 11 Produkt F 2,9 4,8 12 uden methionintilførsel 2,3 3,3Per µg / ml ode Used mthionine preparation_Ko # 1 Co # 2 c 1 without methionine supply 1.7 2.4 2 Product A 2.1 2.9 3 without methionine supply 2.3 2.2 4 Product B 2 4 4.5 5 Product C 3.3 5.2 10 6 without methionine supply 2.5 2.7 7 Product D according. invention 5.2 10.0 8 without methionine supply 2.4 3.6 9 Product E 2.8 4.9 10 without methionine supply 2.0 2.6 15 11 Product F 2.9 4.8 12 without methionine supply 2.3 3.3
Det gennemsnitlige methioninniveau i serummet under perioderne uden methionintilførsel lå for ko nr. 1 tydeligt un- 20 der ko nr. 2's niveau. Den højere værdi i periode 8 uden methionintilførsel hos ko nr. 2 kan bero på en eftervirkning af det anvendte ifølge opfindelsen beskyttede methionin, eftersom den første enkeltværdi fra denne periode var klart højere og var 5,6yug/ml.The average methionine level in the serum during the periods without methionine supply was clearly below cow # 2 below that of cow # 2. The higher value in period 8 without methionine supply in cow # 2 may be due to an after effect of the methionine protected according to the invention, since the first single value from this period was clearly higher and was 5.6 yug / ml.
2525
De i ovenstående tabel anførte resultater viser tydeligt, at af de 6 former for undersøgt beskyttet methionin giver formen ifølge opfindelsen langt de bedste resultater og er dermed de øvrige produkter langt overlegen. Som i eksempel 4 viser også de foreliggende resultater, at anvendelse af en beskyttel-30 sesmatriks alene har en forholdsvis ringe virkning.The results given in the above table clearly show that of the six forms of protected methionine tested, the form of the invention gives by far the best results and thus the other products are far superior. As in Example 4, the present results also show that using a protective matrix alone has a relatively minor effect.
3535
Claims (6)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3230292A DE3230292C2 (en) | 1982-08-14 | 1982-08-14 | Particulate feed additive for ruminants and process for their manufacture |
| DE3230292 | 1982-08-14 |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| DK369283D0 DK369283D0 (en) | 1983-08-12 |
| DK369283A DK369283A (en) | 1984-02-15 |
| DK161728B true DK161728B (en) | 1991-08-12 |
| DK161728C DK161728C (en) | 1992-04-06 |
Family
ID=6170884
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK369283A DK161728C (en) | 1982-08-14 | 1983-08-12 | PARTICULAR FEED ADMINISTRATOR FOR DRUGS AND PROCEDURES FOR ITS MANUFACTURING |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0100974B1 (en) |
| AT (1) | ATE19342T1 (en) |
| AU (1) | AU553414B2 (en) |
| CA (1) | CA1220663A (en) |
| DE (1) | DE3230292C2 (en) |
| DK (1) | DK161728C (en) |
| NZ (1) | NZ205249A (en) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4664917A (en) * | 1984-11-13 | 1987-05-12 | Central Soya Company, Inc. | Method of providing cattle with proteinaceous feed materials |
| US4737365A (en) * | 1986-01-13 | 1988-04-12 | Central Soya Company, Inc. | Method of feeding cattle to improve protein utilization |
| FR2656772B1 (en) * | 1989-12-28 | 1992-09-18 | Rhone Poulenc Nutrition Animal | PROCESS FOR INCORPORATION INTO PELLETS OF ACTIVE INGREDIENTS PROTECTED AGAINST DEGRADATION IN THE BODY OF RUMINANTS. |
| FR2678145B1 (en) * | 1991-06-28 | 1993-09-03 | Rhone Poulenc Nutrition Animal | COMPOSITIONS IN THE FORM OF PELLETS CONTAINING ACTIVE INGREDIENTS PROTECTED WITH RESPECT TO THE RUMINANTS 'BODY ASSOCIATED WITH ACTIVE INGREDIENTS PROTECTED AGAINST DEGRADATION IN THE RUMINANTS' BODY. |
| US6306427B1 (en) | 1989-12-28 | 2001-10-23 | Rhone-Poulenc Nutrition Animale | Pellets containing active ingredients protected against degradation in the rumen of ruminants |
| TW233264B (en) | 1992-02-03 | 1994-11-01 | Otsuka Pharma Co Ltd | |
| US5278329A (en) * | 1992-02-21 | 1994-01-11 | Zinpro Corporation | L-form 1:1 metal methionine complexes |
| DE4308498C2 (en) * | 1993-03-17 | 1997-01-09 | Degussa | Animal feed additive based on fermentation broth, process for its preparation and its use |
| DE19735126C1 (en) * | 1997-08-13 | 1999-01-21 | Infectopharm Arzneimittel Und | Process for the preparation of an oral composition containing a zinc compound and its use for the treatment of colds |
| CA2255130A1 (en) | 1997-12-16 | 1999-06-16 | Archer Daniels Midland Company | Process for making granular l-lysine feed supplement |
| FR2988091B1 (en) * | 2012-03-16 | 2014-08-15 | Innov Ia 3I | PULVERULENT COMPOSITIONS OF A COMPLEX BETWEEN ACID AND METAL AND PROCESS FOR PREPARING THE SAME |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3463858A (en) * | 1965-05-06 | 1969-08-26 | Dean R Anderson | Organic zinc feed additive and method of making same |
| ES342680A1 (en) * | 1966-07-16 | 1968-08-01 | Fischer | A universally jointed shaft coupling for incorporation in a constructional toy |
| US3655864A (en) * | 1970-09-21 | 1972-04-11 | Smith Kline French Lab | Glyceryl tristerate and higher fatty acid mixture for improving digestive absorption |
| US4021569A (en) * | 1973-08-20 | 1977-05-03 | Zinpro Corporation | Method of nutritional supplementation for zinc and methionine by ingesting 1:1 zinc methionine complexes |
| US3941818A (en) * | 1973-08-20 | 1976-03-02 | Zinpro Corporation | 1:1 Zinc methionine complexes |
| CH621686A5 (en) * | 1976-04-08 | 1981-02-27 | Interchemie Ag | Method for feeding cattle and sheep |
| US4177255A (en) * | 1977-09-02 | 1979-12-04 | Eastman Kodak Company | Rumen-stable pellets |
| DE3013000C2 (en) * | 1980-04-03 | 1982-12-09 | Degussa Ag, 6000 Frankfurt | Rumen penetrating feed additive for ruminants and its use for feeding ruminants |
-
1982
- 1982-08-14 DE DE3230292A patent/DE3230292C2/en not_active Expired
-
1983
- 1983-07-11 AU AU16717/83A patent/AU553414B2/en not_active Ceased
- 1983-07-14 CA CA000432448A patent/CA1220663A/en not_active Expired
- 1983-07-29 EP EP83107481A patent/EP0100974B1/en not_active Expired
- 1983-07-29 AT AT83107481T patent/ATE19342T1/en not_active IP Right Cessation
- 1983-08-12 DK DK369283A patent/DK161728C/en not_active IP Right Cessation
- 1983-08-12 NZ NZ205249A patent/NZ205249A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CA1220663A (en) | 1987-04-21 |
| AU1671783A (en) | 1984-02-23 |
| ATE19342T1 (en) | 1986-05-15 |
| EP0100974A1 (en) | 1984-02-22 |
| DK161728C (en) | 1992-04-06 |
| DE3230292A1 (en) | 1984-02-16 |
| DE3230292C2 (en) | 1986-12-18 |
| DK369283A (en) | 1984-02-15 |
| NZ205249A (en) | 1986-04-11 |
| AU553414B2 (en) | 1986-07-17 |
| DK369283D0 (en) | 1983-08-12 |
| EP0100974B1 (en) | 1986-04-23 |
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