NO176995B - Process for the preparation of a tablet tablet interferon composition - Google Patents
Process for the preparation of a tablet tablet interferon composition Download PDFInfo
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- NO176995B NO176995B NO882983A NO882983A NO176995B NO 176995 B NO176995 B NO 176995B NO 882983 A NO882983 A NO 882983A NO 882983 A NO882983 A NO 882983A NO 176995 B NO176995 B NO 176995B
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Description
Oppfinnelsen angår en framgangsmåte for framstilling av en interferon-blanding i The invention relates to a method for producing an interferon mixture i
tablettform, som angitt i den innledende del av patentkrav 1. tablet form, as stated in the introductory part of patent claim 1.
Bakgrunn Background
"Interferon" er et uttrykk som generisk omfatter en gruppe glycoproteiner og proteiner fra virveldyr som er kjent å ha forskjellige biologiske aktiviteter, så som antiviral, antiproliferative og immunitetskontrollerende aktivitet i det minste i arten av dyr fra hvilke slike stoffer er framstilt. Følgende definisjon for interferon er akseptert av en internasjonal komite sammensatt for å etablere et system for systematisk nomenklatur for interferoner: "for å kvalifisere til å være et interferon må en faktor være et protein som utøver antiviral aktivitet uavhengig av arten virus i det minste i homologe celler gjennom cellemetaboliske prosesser som omfatter synteser av både RNA og proteiner". Journal of Interferon Research, 11 pp. vi "Interferon" is a term that generically encompasses a group of glycoproteins and vertebrate proteins known to have various biological activities, such as antiviral, antiproliferative and immune-controlling activity at least in the species of animal from which such substances are derived. The following definition for interferon has been accepted by an international committee composed to establish a system of systematic nomenclature for interferons: "to qualify as an interferon a factor must be a protein that exerts antiviral activity regardless of the species of virus at least in homologous cells through cellular metabolic processes that include syntheses of both RNA and proteins". Journal of Interferon Research, 11 pp. vi
(1980). "Interferon" slik som brukt heri å beskrive den foreliggende oppfinnelsen skal forstås ifølge denne definisjonen. (1980). "Interferon" as used herein to describe the present invention shall be understood according to this definition.
Siden den første beskrivelsen av interferon av Isaacs og Lindeman [See, Proe. Roy. Soc. London (Ser. B), Vol. 147, side 258 et seg. (1957) og US patentskrift 3.699.222], har interferon vært tema for intensiv forskning over hele verden. Literaturen er proppfull av publikasjoner angående fremstilling av interferon, dets foreslåtte molekylære karakterisering, dets kliniske anvendelser og foreslåtte mekanismer for dets antitumor, antiviral og immunsystem-aktiviteter. Since the first description of interferon by Isaacs and Lindeman [See, Proe. Roy. Soc. London (Ser. B), Vol. 147, page 258 et seq. (1957) and US Patent 3,699,222], interferon has been the subject of intensive research worldwide. The literature is replete with publications regarding the preparation of interferon, its proposed molecular characterization, its clinical applications, and proposed mechanisms for its antitumor, antiviral, and immune system activities.
Pga. intensiteten og den spredte forskning angående interferon og dets karakteristika og bruk, eksisterer det en betydelig mangel på ensartethet i slik anliggender som klassifisering av interferontyper. Det er også mange, av og til motstridende, teorier angående virkemåten for interferon ved frembringelse av kliniske effekter. Because of. the intensity and spread of research concerning interferon and its characteristics and uses, there exists a considerable lack of uniformity in such matters as the classification of interferon types. There are also many, sometimes conflicting, theories regarding the mode of action of interferon in producing clinical effects.
Selv om interferon opprinnelig ble isolert fra celler fra fugler (allantoiske celler fra kyllinger), er det observert produksjon i celler fra alle klasser av virveldyr, innbefattet pattedyr, amfibier, fugler og krypdyr. Produksjon av interferon av virveldyrceller er sjelden spontan, men kan ofte lett "fremkalles" ved behandling av celler (in vivo eller in vi tro) med en rekke substanser omfattende vimser, nukleinsyrer (omfattende de av viral opprinnelse såvel som syntetiske polynukleotider), lipopolysakkarider, og forskjellige antigener og mitogener. Although interferon was originally isolated from avian cells (chicken allantoic cells), production has been observed in cells from all classes of vertebrates, including mammals, amphibians, birds and reptiles. Production of interferon by vertebrate cells is rarely spontaneous, but can often be easily "induced" by treatment of cells (in vivo or in vitro) with a variety of substances including viruses, nucleic acids (including those of viral origin as well as synthetic polynucleotides), lipopolysaccharides, and various antigens and mitogens.
I dets første anvendelser ble interferon brukt bare som antiviralt middel og de mest vellykkede kliniske terapeutiske anvendelsene frem til idag har vært i behandling av virale eller virusrelaterte sykdomsstadier. Det ble imidlertid innlysende at eksogen interferon noen ganger var i stand til å slå tilbake eller midlertidig bedre forskjellige metastatiske sykdommer. En oversikt over kliniske forsøk hittil med interferon som et antiviralt og antiproliferalt terapeutisk middel er beskrevet i Interferon: In Vivo and Clinical Studies, Volume 4, Eds: N. B. Finer and R. K. Oldham, Academic Press, New York, 1985. In its first applications, interferon was used only as an antiviral agent and the most successful clinical therapeutic applications to date have been in the treatment of viral or virus-related disease stages. However, it became apparent that exogenous interferon was sometimes able to reverse or temporarily improve various metastatic diseases. An overview of clinical trials to date with interferon as an antiviral and antiproliferative therapeutic agent is described in Interferon: In Vivo and Clinical Studies, Volume 4, Eds: N. B. Finer and R. K. Oldham, Academic Press, New York, 1985.
Det kliniske midlet som velges pr. dato er menneskelik leukocyt-interferon, "masse-produsert" ifølge framgangsmåter omfattende innsamling og rensing av store mengder av menneskelige leukocytter med brungult overtrekk, indusering med virus og isolasjon fra kulturer. The clinical agent chosen per dato is human leukocyte interferon, "mass-produced" according to procedures involving the collection and purification of large quantities of human leukocytes with a brown-yellow coating, induction with virus and isolation from cultures.
I arbeidet beskrevet ovenfor, ble interferon gitt parenteralt, dvs. intramuskulært og intradermisk, med noen tilfeller av topisk og invortes bruk rapportert. Det har sjelden blitt gitt intravenøst pga. betydelige uønskete effekter som kan tilskrives "forurensninger" i rå- og til og med svært rensete isolater. In the work described above, interferon was given parenterally, i.e. intramuscularly and intradermally, with some cases of topical and intravenous use reported. It has rarely been given intravenously because significant adverse effects attributable to "contaminants" in crude and even highly purified isolates.
Som beskrevet ovenfor, har det vært betydelige forskningsanstrengelser rettet mot evalueringen av terapeutiske effekter av interferon for en lang rekke sykdommer med en auto- immuno-patologisk basis. Før beskrivelsen av vellykket oral dosering av interferon i US patentskrift 4.462.985, var det ingen anerkjennelse blant fagfolk av potensialet tilbudt ved oral dosering av interferon. Den generelle tro var at interferon ikke kunne overleve fordøyelsesbetingelsene i den øvre ernæringskanalen. As described above, there has been considerable research effort directed at the evaluation of the therapeutic effects of interferon for a wide variety of diseases with an auto-immuno-pathological basis. Prior to the description of successful oral dosing of interferon in US Patent 4,462,985, there was no recognition among those skilled in the art of the potential offered by oral dosing of interferon. The general belief was that interferon could not survive the digestive conditions of the upper alimentary canal.
Interferon med opprinnelse fra mennesker og mus er i teknikken kvantifisert i form av internasjonale enheter ("IU"). Slik som brukt heri skal en "enhet" av interferon (til forskjell fra "IU") bety den tilsvarende mengde av en fortynning av interferon-inneholdende materiale som bestemt ved forsøk, inhiberer halvparten av antall av flater av et utfordrervirus, hvor utfordrerviruset er vesiculer stomatitis virus ("VSV"). En "enhet" av interferon bestemt på denne måte er rutinemessig funnet å være omtrent 1/10 av mengden av interferon representert ved en "IU". Med andre ord, for formål under den foreliggende oppfinnelsen, er: en "enhet" « 0.1 IU. Interferon of human and murine origin is quantified in the technique in terms of international units ("IU"). As used herein, a "unit" of interferon (as distinguished from "IU") shall mean the equivalent amount of a dilution of interferon-containing material that, as determined experimentally, inhibits half the number of surfaces of a challenger virus, where the challenger virus is vesicles stomatitis virus ("VSV"). A "unit" of interferon determined in this manner is routinely found to be about 1/10 of the amount of interferon represented by an "IU". In other words, for the purposes of the present invention: a "unit" is « 0.1 IU.
Formål Purpose
Formålet med oppfinnelsen er å anvise en framgangsmåte for framstilling av en interferpnblanding i tablettform for oppløsing i konakt med en pasients slimhinne i munnhulen og frigjøring av interferonet ved kontakt generelt med slimhinnene i munnhule og svelg. The purpose of the invention is to provide a method for producing an interferon mixture in tablet form for dissolution in contact with a patient's mucous membrane in the oral cavity and releasing the interferon upon contact in general with the mucous membranes in the oral cavity and pharynx.
Oppfinnelsen The invention
Dette formål oppnås med en framgangsmåte ifølge den karakteriserende del av patentkrav 1. Ytterligere fordelaktige trekk framgår av de tilhørende uselvstendige kravene 2-5. This purpose is achieved with a method according to the characterizing part of patent claim 1. Further advantageous features appear from the associated independent claims 2-5.
Den foreliggende oppfinnelsen er basert på oppdagelsen at interferon kan brukes som et konsekvent effektivt terapeutisk middel for behandling av sykdommer med en immuno-patologisk basis - karakterisert ved utilstrekkelig immunreaksjon og sykdommens standhaftighet eller ved en innlysende hyperaktiv immunreaksjon som fører til nedbrytende betennelsestilstander i vev og relaterte fysikalske utslag. Interferon som bringes i kontakt med slimhinnen i munnhule og svelg i mengder på 0.02 til 11 IU/kg kroppsvekt pr. dag, er konsekvent effektivt for behandling av sykdommer overfor hvilke immunsystemet til mange varmblodige virveldyr ikke reagerer effektivt. The present invention is based on the discovery that interferon can be used as a consistently effective therapeutic agent for the treatment of diseases with an immuno-pathological basis - characterized by an insufficient immune reaction and the persistence of the disease or by an obvious hyperactive immune reaction leading to degrading inflammatory conditions in tissues and related physical effects. Interferon that is brought into contact with the mucous membrane in the oral cavity and pharynx in amounts of 0.02 to 11 IU/kg body weight per today, is consistently effective for treating diseases to which the immune system of many warm-blooded vertebrates does not respond effectively.
Det er kritisk at interferonet gis i en doseringsform tilpasset til å forsikre maksimal kontakt av interferonet i nevnte doseringsform med slimhinnene i munnhule og svelg til mennesket eller dyret under behandling. Kontakt av interferon med sUmhinnen kan forbedres ved å maksimalisere oppholdstiden til behandlingsoppløsningen i munnhulen eller svelget. Således synes det at de beste resultatene blir oppnådd med menneskelige pasienter når pasienten bes om å holde nevnte løsning med interferon i munnen i en tid. Kontakt av interferon med sUmhinnen i munnhule og svelg og deretter med lymfesystemet til det behandlete mennesket eller dyret er uomtvistelig den mest effektive framgangsmåte for å dosere immunoterapeutiske mengder av interferon. It is critical that the interferon is given in a dosage form adapted to ensure maximum contact of the interferon in said dosage form with the mucous membranes in the oral cavity and pharynx of the person or animal undergoing treatment. Contact of interferon with the mucosa can be improved by maximizing the residence time of the treatment solution in the oral cavity or pharynx. Thus, it appears that the best results are obtained with human patients when the patient is asked to keep said solution with interferon in the mouth for a period of time. Contact of interferon with the mucosa in the oral cavity and pharynx and then with the lymphatic system of the treated human or animal is indisputably the most effective method of dosing immunotherapeutic amounts of interferon.
Eksempler på menneskelige virusinfeksjoner som viser bemerkelsesverdige reaksjoner på behandling ifølge den foreliggende oppfinnelsen er infeksjoner forårsaket av menneskelig rhinovirus (vanlig forkjølelse), herpes simplex I virus Examples of human viral infections that show remarkable responses to treatment according to the present invention are infections caused by human rhinovirus (common cold), herpes simplex I virus
(forkjølelsessår) og menneskelig papovavirus (vorter). Basert på behandlingsresultater til dato er det ventet at kontakt av interferon i små doser med sUmhinnen i munnhule og svelg vil gi en effektiv behandling for "Acquired Immune Deficiency Syndrome" (cold sores) and human papovavirus (warts). Based on treatment results to date, it is expected that contact of interferon in small doses with the mucosa in the oral cavity and pharynx will provide an effective treatment for "Acquired Immune Deficiency Syndrome"
(AIDS) og sykdomstilstander med herpes simplex n viruset det forårsakende midlet. En pasient med en tilstand av viral nyocarditis har reagert fordelaktig på en slik behandling. Vorter forsvinner ofte innen 6-8 uker etter påbegynnelse av behandling. (AIDS) and disease states with the herpes simplex n virus as the causative agent. A patient with a condition of viral neocarditis has responded favorably to such treatment. Warts often disappear within 6-8 weeks of starting treatment.
Videre, ved å stimulere immunsystemet ved oral kontakt med små doser interferon antas å hjelpe kroppen å motstå bakterieinfeksjoner. Behandling alene eller i kombinasjon med terapeutiske mengder av antibiotika kan være særUg effektivt i å slå ned infeksjoner fra mikroorganismer resistente mot antibiotika. Furthermore, by stimulating the immune system by oral contact with small doses of interferon is believed to help the body resist bacterial infections. Treatment alone or in combination with therapeutic amounts of antibiotics can be particularly effective in suppressing infections from microorganisms resistant to antibiotics.
DagUge doser av interferon kan gis som en enkeltdose eUer, fortrinnsvis, deles og gis i flere doser pr. dag. En oppstykket behandling, f.eks. en til tre dager behandling pr. uke eller måned, kan brukes som et alterantiv til kontinuerUg dagUg behandling. Daily doses of interferon can be given as a single dose or, preferably, divided and given in several doses per day. A divided treatment, e.g. one to three days of treatment per week or month, can be used as an alternative to continuous daily treatment.
Interferon framstilt ifølge den foreUggende oppfinnelsen administreres i Interferon produced according to the present invention is administered i
tablettform, tilpasset for å oppløses ved kontakt med spytt i munnen med eller uten hjelp av tygging. Denne doseringsformen er utformet for å frigi 1 til 1500 IU interferon ved oppløsning i munnen for kontakt med sUmhinnen i munnen og svelget. Således kan enhetlige doser av interferon fremstilles ifølge kjente teknikker for å danne komprimerte tabletter slik som tyggeUge vitaminer. På liknende måte kan interferon innbefattes i stivelsesbaserte gel-typer for å danne en tablett som vil løse seg opp og frigi interferon for kontakt med sUmhinnen i munnhulen når den holdes i munnen. Faste enhetsdoser av interferon framstilt ifølge den foreUggende oppfinnelsen kan fremstilles ved bruk av kjent teknikk for slike. pH for slike utforminger kan variere fra 4 til 8.5. Ved framstilling av en interferonblnading må en etter tilsats av interferon unngå at blandingen utsettes for temperaturer over 50°C. tablet form, adapted to dissolve on contact with saliva in the mouth with or without the aid of chewing. This dosage form is designed to release 1 to 1,500 IU of interferon upon dissolution in the mouth for contact with the mucosa of the mouth and pharynx. Thus, uniform doses of interferon can be prepared according to known techniques to form compressed tablets such as chewable vitamins. Similarly, interferon can be incorporated into starch-based gel types to form a tablet that will dissolve and release the interferon for contact with the mucosa of the oral cavity when held in the mouth. Fixed unit doses of interferon produced according to the present invention can be produced using known techniques for such. The pH for such designs can vary from 4 to 8.5. When preparing an interferon mixture, one must avoid exposing the mixture to temperatures above 50°C after adding interferon.
Framstilling av humant alfa- interferon Production of human alpha interferon
Menneskelig alfa-interferon kan framstilles med følgende framgangsmåte, vanligvis henvist til som kantell-metoden. Framgangsmåten begynner med pakninger av menneskelige leukocytter. De gulbrune beleggene i disse pakningene slås sammen i sentrifugeflasker, for så å fortynnes med 0.83% ammoniumklorid. Blandingen inkuberes i 15 minutter, rystes periodisk og sentrifugeres så i 20 minutter ved 2000 opm. Sentrifugatet slås bort, og celleklumpene løses på nytt i et minimalt volum av steril fosfatbufret saltløsning (PBS). Blandingen fortynnes så med ammoniumklorid og sentrifugeres. Sentrifugatet slås bort på nytt, og de gjenværende celleklumpene løses på nytt med et minimalt volum av en vevskultur slik som "Minimal Essential Medium (MEM), tilgjengelig fra KC Biological. Cellekonsentrasjonen bestemmes med en Coluter teller. Human alpha-interferon can be prepared by the following procedure, commonly referred to as the Kantell method. The procedure begins with packs of human leukocytes. The yellow-brown coatings in these packages are combined in centrifuge bottles, and then diluted with 0.83% ammonium chloride. The mixture is incubated for 15 minutes, shaken periodically and then centrifuged for 20 minutes at 2000 rpm. The centrifuge is discarded, and the cell clumps are redissolved in a minimal volume of sterile phosphate-buffered saline (PBS). The mixture is then diluted with ammonium chloride and centrifuged. The centrifuge is discarded again, and the remaining cell clumps are resuspended with a minimal volume of a tissue culture medium such as "Minimal Essential Medium (MEM), available from KC Biological. The cell concentration is determined with a Coluter counter.
Indusering med interferon finner sted i glass eller plastflasker. Induksjonsmediet inneholder MEM, 75 mM Hepes (tilgjengelig fra Calbiochem), 75mM Tricine (tilgjengelig fra Sigma Chemical Co.), menneskelig agammaserum (18mg/ml), og gentamycin sulfat (M.A. Bioproducts; 50mcg/ml). Cellene tilsettes induksjonskaret i en sluttkonsentrasjon på 5 til 10 millioner celler pr. milliliter. Induksjonskaret inkuberes i et vannbad ved 37°C, og alfa-interferon tilsettes som en starter. Induction with interferon takes place in glass or plastic bottles. The induction medium contains MEM, 75 mM Hepes (available from Calbiochem), 75 mM Tricine (available from Sigma Chemical Co.), human agammaserum (18mg/ml), and gentamycin sulfate (M.A. Bioproducts; 50mcg/ml). The cells are added to the induction vessel in a final concentration of 5 to 10 million cells per milliliters. The induction vessel is incubated in a water bath at 37°C, and alpha-interferon is added as a starter.
Etter to timer tilsettes Sendai-virus til induksj onsblandingen. Dette forårsaker produksjon av alfa-interferon i det øvre væskelaget av leukocyttene. Etter en inkubasjonstid på 12-18 timer sentrifugeres induksjonsblandingen. Cellene kastes og sentrifugatet renses. After two hours, Sendai virus is added to the induction mixture. This causes the production of alpha-interferon in the upper fluid layer of the leukocytes. After an incubation time of 12-18 hours, the induction mixture is centrifuged. The cells are discarded and the centrifuge is cleaned.
Råinterferonet avkjøles til 10°C eller lavere i et isbad. Fem molar natriumthiocyanat tilsettes for å oppnå en ferdig konsentrasjon på 0,5 M. Denne oppløsningen omrøres i 15 minutter og pH senkes til 3.3 ved tilsats av saltsyre. Blandingen sentrifugeres så ved 2800 omdreininger pr. minutt i 30 minutter, og sentrifugatet kastes. Klumpene resuspenderes så i 95% etanol og omrøres i 15 minutter. Denne suspensjonen sentrifugeres ved 2800 opm i 20 minutter, og klumpene kastes. pH til sentrifugatet justeres så til 5.8 med natriumhydroksid. Blandingen omrøres i 10 minutter og sentrifuges så ved 2800 opm i 20 minutter. Klumpene kastes. pH til sentifugatet justeres så til 8 med natriumhydroksid. Løsningen omrøres i 10 minutter, etterfulgt av sentrifugering ved 2800 opm i 20 minutter. Sentrifugatet kastes, og klumpene suspenderes pånytt i 0.5M natriumthiocyanat i en 0.1M natriumfosfat-buffer. Denne suspensjonen omrøres ved 4°C. The crude interferon is cooled to 10°C or lower in an ice bath. Five molar sodium thiocyanate is added to achieve a final concentration of 0.5 M. This solution is stirred for 15 minutes and the pH is lowered to 3.3 by adding hydrochloric acid. The mixture is then centrifuged at 2800 rpm. minute for 30 minutes, and the centrifuge is discarded. The clumps are then resuspended in 95% ethanol and stirred for 15 minutes. This suspension is centrifuged at 2800 rpm for 20 minutes, and the clumps are discarded. The pH of the centrifuge is then adjusted to 5.8 with sodium hydroxide. The mixture is stirred for 10 minutes and then centrifuged at 2800 rpm for 20 minutes. The lumps are thrown away. The pH of the centrifuge is then adjusted to 8 with sodium hydroxide. The solution is stirred for 10 minutes, followed by centrifugation at 2800 rpm for 20 minutes. The centrifuge is discarded, and the clumps are resuspended in 0.5 M sodium thiocyanate in a 0.1 M sodium phosphate buffer. This suspension is stirred at 4°C.
Deretter sentrifugeres suspensjonen ved 2000 opm i 20 minutter, og klumpene kastes. pH til sentrifugatet justeres til 5.3 med saltsyre. Etter omrøring i 10 minutter og sentrifugering, justeres pH til sentrifugatet til 2.8 med saltsyre, etterfulgt av ytterligere omrøring i 20 minutter. Denne blandingen sentrifugeres ved 2800 opm, og den resulterende klumpen er renset menneskelig alfa-interferon. The suspension is then centrifuged at 2000 rpm for 20 minutes, and the clumps are discarded. The pH of the centrifuge is adjusted to 5.3 with hydrochloric acid. After stirring for 10 minutes and centrifugation, the pH of the centrifugate is adjusted to 2.8 with hydrochloric acid, followed by further stirring for 20 minutes. This mixture is centrifuged at 2800 rpm and the resulting pellet is purified human alpha interferon.
Klumpen suspenderes på nytt i 0.5M natriumthiocyanat i 0.1M natriumfosfat-buffer, med en pH på 8.0. Det dialyseres så mot PBS ved 4°C, med to utskiftninger PBS. Denne blandingen sentrifugeres så og bunnfallet kastes. Det gjenværende rensete alfa-interferon steriliseres ved filtrering gjennom et 0.2 fim filter. Et menneskelig alfa-interferon produseres ifølge denne framgangsmåte av Immuno Modulators Laboratories, Inc., Stafford, Texas og selges under varemerket Agriferon<*> for bruk i kveg og Equiferon<*> for bruk i hester. The pellet is resuspended in 0.5M sodium thiocyanate in 0.1M sodium phosphate buffer, with a pH of 8.0. It is then dialysed against PBS at 4°C, with two changes of PBS. This mixture is then centrifuged and the precipitate discarded. The remaining purified alpha-interferon is sterilized by filtration through a 0.2 µm filter. A human alpha interferon is produced according to this procedure by Immuno Modulators Laboratories, Inc., Stafford, Texas and sold under the trade names Agriferon<*> for use in cattle and Equiferon<*> for use in horses.
Andre framgangsmåter kjent for fagmenn er tilgjengelige for framstilling av interferoner, slik som menneskelig alfa-interferon og menneskelig gamma-interferon. F.eks. US patentskrifter 4.376.821 og 4.460.685 beskriver framgangsmåter for framstilling av menneskelig gamma-interferon. En framgangsmåte for å framstille bovin fibroblast (beta) interferon er beskrevet i US patentskrift 4.462.985. Other methods known to those skilled in the art are available for the production of interferons, such as human alpha interferon and human gamma interferon. E.g. US Patents 4,376,821 and 4,460,685 describe methods for the production of human gamma interferon. A procedure for producing bovine fibroblast (beta) interferon is described in US patent document 4,462,985.
Interferon- dosis- utforminger Interferon Dose Designs
1) tabletter 1) tablets
Tabletter basert på en stivelsesdel inneholdende interferon fremstilles ved sammenblanding av 150 gram sucrose, 550 ml. fosfatbuffer-saltløsning og 250 gram av en stivelse løselig i kaldt vann slik som den beskrevet i US patentskrift 4.465.702, oppvarming av denne blandingen under omrøring til en temperatur på omtrent 75°C, avkjøling av blandingen til omtrent 30°C og deretter innblanding i den pastaliknende massen 50 ml av fosfatbufferet saltløsning PBS inneholdende menneskelig alfainterferon i en konsentrasjon på 250 IU/ml. Blandingen er så formet til mange porsjoner på 5 til 10 gram hver som settes på stativ under tørkende betingelser til en stivelses-sukkertøyliknende konsistens. Tablettene således framstilt kan gis til pasienter enkeltvis eller i kombinasjon. Pasienten gis instruks om å holde tabletten i munnen inntil den er fullstendig oppløst for å frigi interferon-komponenten for kontakt med sUmhinnen i munnen. Tablets based on a starch component containing interferon are prepared by mixing 150 grams of sucrose, 550 ml. phosphate buffer saline and 250 grams of a starch soluble in cold water such as that described in US Patent 4,465,702, heating this mixture with stirring to a temperature of about 75°C, cooling the mixture to about 30°C and then mixing in the paste-like mass 50 ml of phosphate-buffered saline solution PBS containing human alpha interferon in a concentration of 250 IU/ml. The mixture is then formed into many portions of 5 to 10 grams each which are placed on racks under drying conditions to a starch candy-like consistency. The tablets thus produced can be given to patients individually or in combination. The patient is instructed to hold the tablet in the mouth until it is completely dissolved to release the interferon component for contact with the oral mucosa.
(2) Tyggelige vitaminer (2) Chewable vitamins
En tyggelig vitaminutforming fremstilles, f.eks. ifølge beskrivelsen i US patentskrift 3.8S7.939 ved å belegge en eller flere komponenter derav før det lages tabeletter med en interferon-oppløsning i en mengde tilstrekkelig til å frembringe 1 til 1500 enheter av interferon i hver tyggelig vitamintablett. A chewable vitamin formulation is prepared, e.g. according to the description in US patent document 3.8S7.939 by coating one or more components thereof before making tablets with an interferon solution in an amount sufficient to produce 1 to 1500 units of interferon in each chewable vitamin tablet.
(3) Brusende tablett (3) Effervescent tablet
En tablettblanding omfattende et farmasøytisk akseptabelt alkalimetall-karbonat eller -bikarbonat, en organisk syre slik som sitronsyre, menneskelig interferon (fortrinnsvis fordelt på en passende organisk eller uorganisk bærer derav) i en mengde tilstrekkelig til å frembringe en dose pr. tablett på 1-1500 enheter av interferon, og videre innbefatte egnete tilsetninger for fremstilling av tabletter slik som smøremidler og bindemidler, komprimeres til en enhetlig dosisform av interferon. Den komprimerte tabletten bruser opp ved kontakt med vann for å frigi interferon til den resulterende bufferoppløsningen. Dosen av interferon er umiddelbart tilgjengelig i løsning for kontakt med slimhinnene i munnhule og svelg til pasienten. A tablet composition comprising a pharmaceutically acceptable alkali metal carbonate or bicarbonate, an organic acid such as citric acid, human interferon (preferably distributed in a suitable organic or inorganic carrier thereof) in an amount sufficient to produce a dose per tablet of 1-1500 units of interferon, and further including suitable additives for the production of tablets such as lubricants and binders, compressed into a uniform dosage form of interferon. The compressed tablet effervesces on contact with water to release interferon into the resulting buffer solution. The dose of interferon is immediately available in solution for contact with the mucous membranes in the oral cavity and pharynx of the patient.
Claims (5)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US92783486A | 1986-11-06 | 1986-11-06 | |
| PCT/US1987/002998 WO1988003411A1 (en) | 1986-11-06 | 1987-11-06 | Improved interferon therapy |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| NO882983D0 NO882983D0 (en) | 1988-07-05 |
| NO882983L NO882983L (en) | 1988-09-06 |
| NO176995B true NO176995B (en) | 1995-03-27 |
| NO176995C NO176995C (en) | 1995-07-05 |
Family
ID=26776406
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO882983A NO176995C (en) | 1986-11-06 | 1988-07-05 | Process for the preparation of a tablet tablet interferon composition |
Country Status (2)
| Country | Link |
|---|---|
| DK (1) | DK172974B1 (en) |
| NO (1) | NO176995C (en) |
-
1988
- 1988-07-05 NO NO882983A patent/NO176995C/en not_active IP Right Cessation
- 1988-07-05 DK DK198803743A patent/DK172974B1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| DK172974B1 (en) | 1999-10-25 |
| DK374388D0 (en) | 1988-07-05 |
| DK374388A (en) | 1988-09-05 |
| NO882983D0 (en) | 1988-07-05 |
| NO176995C (en) | 1995-07-05 |
| NO882983L (en) | 1988-09-06 |
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