DK162475B - THERAPEUTIC PREPARATION CONTAINING HYDROGENERED ERGOTAL KALOIDS AND HEPARIN AND PROCEDURE FOR PREPARING THE PREPARATION - Google Patents
THERAPEUTIC PREPARATION CONTAINING HYDROGENERED ERGOTAL KALOIDS AND HEPARIN AND PROCEDURE FOR PREPARING THE PREPARATION Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Description
DK 162475 BDK 162475 B
Den foreliggende opfindelse angår et terapeutisk præparat, som indeholder et hydrogeneret ergotalkaloid med vasokonstriktorisk virkning eller et farmaceutisk tolerabelt syreadditionssalt deraf og et lavmolekylært heparin eller et farmaceutisk tolerabelt salt deraf, 5 samt en fremgangsmåde til fremstilling deraf.The present invention relates to a therapeutic composition which contains a hydrogenated ergot alkaloid with vasoconstrictor action or a pharmaceutically tolerable acid addition salt thereof and a low molecular weight heparin or a pharmaceutically tolerable salt thereof, and a process for its preparation.
Det terapeutiske præparat ifølge opfindelsen kan anvendes til profylakse af thromboser, især post-operative thromboser.The therapeutic composition of the invention can be used for the prophylaxis of thrombosis, especially post-operative thrombosis.
Det er kendt, at administration af naturligt heparin (gennemsnitlig molekylvægt 14.000-18.000) sammen med et hydrogeneret ergotalkaloid, 10 som har vasokonstriktoriske egenskaber, især dihydroergotamin, har særlige fordele ved profylakse af thromboser, især post-operative thromboser (jfr. fx DE-AS 2.554.533), og således er heparin/dihydro-ergotamin-terapi en værdifuld og almindeligt udbredt behandling af patienter med høj thromboserisiko, især som følge af operationer.It is known that administration of natural heparin (average molecular weight 14,000-18,000) together with a hydrogenated ergot alkaloid 10 having vasoconstrictory properties, especially dihydroergotamine, has particular advantages in the prophylaxis of thromboses, especially post-operative thromboses (cf. AS 2,554,533), and thus heparin / dihydro-ergotamine therapy is a valuable and widely used treatment for patients with high thrombosis risk, especially as a result of surgery.
15 Administrationen foretages generelt parenteralt, dvs. ved intravenøs injektion, og forskellige præparater, fx med forbedret stabilitet i sammenligning med sædvanlige opløsninger til anvendelse ved den ovenfor anførte indikation, er kendte fra litteraturen (jfr. US-PS 4.402.929) og kan fås i handelen.The administration is generally done parenterally, viz. by intravenous injection, and various compositions, for example, with improved stability compared to conventional solutions for use in the above indication, are known from the literature (cf. U.S. Pat. No. 4,402,929) and are commercially available.
20 Ifølge opfindelsen har det overraskende nok vist sig, at der fås særlig gode resultater ved profylakse af post-operative thromboser, såfremt heparinkomponenten i den fx fra DE-AS 2.554.533 kendte kombination har en i sammenligning med naturligt heparin lavere gennemsnitlig molekylvægt. Det har især vist sig, at der ved anven-25 delse af lavmolekylært heparin sammen med hydrogenerede ergotalka-loider, som har vasokonstriktoriske egenskaber, især dihydroergotamin, i stedet for kendte præparater, som indeholder naturligt heparin, fås en dramatisk forbedring af den terapeutiske anvendelighed, dvs. varigheden af den antithrombotiske virkning, hvorved den daglige 30 nødvendige dosis af heparin og den hydrogenerede ergotalka- loidkomponent til virksom thromboseprofylakse kan reduceres tilsvarende .Surprisingly, according to the invention, it has been found that particularly good results are obtained in the prophylaxis of post-operative thrombosis if the heparin component of the combination known, for example, from DE-AS 2,554,533 has a lower average molecular weight compared to natural heparin. In particular, it has been found that by using low molecular weight heparin together with hydrogenated ergot alkaloids which have vasoconstrictor properties, especially dihydroergotamine, instead of known preparations containing natural heparin, a dramatic improvement in therapeutic utility is obtained. , ie the duration of the antithrombotic effect, whereby the daily required dose of heparin and the hydrogenated ergot alkaloid component for active thrombosis prophylaxis may be similarly reduced.
Således bliver f.eks. plasmaspejlet af dihydroergotamin, som ved administration af dihydroergotamin alene efter 12 timer sædvanligvisThus, e.g. the plasma level of dihydroergotamine, as when administered with dihydroergotamine alone after 12 hours usually
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2 har nået en værdi nær ved O (Eur. J. Clinic. Pharm., 24, side 813-818, 1983) , ved tilsætning af lavmolekylært heparin påvirket således, at den venetoniserende effekt af dihydroergotamin varer længere end 24 timer.2 has reached a value close to 0 (Eur. J. Clinic. Pharm., 24, pp. 813-818, 1983), by the addition of low molecular weight heparin so that the venetizing effect of dihydroergotamine lasts longer than 24 hours.
5 Profylaktisk behandling med præparatet ifølge opfindelse én gang daglig giver derfor i det væsentlige samme resultat som profylaktisk behandling to til tre gange dagligt med præparatet ifølge DE-AS 2.554.533.Therefore, once daily prophylactic treatment with the composition of the invention gives substantially the same result as prophylactic treatment two to three times daily with the composition according to DE-AS 2,554,533.
Det er ydermere vist, at anvendelse af lavmolekylært heparin sammen 10 med dihydroergotamin undertrykker trombosedannelse i en forsøgsmodel med kaniner, og at denne virkning opnås både ved anvendelse af den lavmolekylære heparinkomponent i en dosis på 60 IE (internationale enheder) og i en dosis på 30 IE.Furthermore, it has been shown that the use of low molecular weight heparin in combination with dihydroergotamine suppresses thrombosis in a rabbit experimental model, and this effect is achieved both by using the low molecular weight heparin component at a dose of 60 IU (international units) and at a dose of 30 IU.
Den foreliggende opfindelse angår således et terapeutisk præparat, 15 ved hjælp af hvilket det er muligt væsentligt at sænke den til profylaktisk behandling af thromboser nødvendige dosis af kombinationen af et hydrogeneret ergotalkaloid med vasokontriktoriske egenskaber og heparin. Da kombinationen hensigtsmæssigt administreres ved injektion, er det ved hjælp af det terapeutiske præparat ifølge 20 opfindelsen også muligt at formindske patientens ubehag, da det kun er nødvendigt med én daglig administration. Dette er særlig vigtigt for patienter, der skal komme sig efter store operationer.Thus, the present invention relates to a therapeutic composition by which it is possible to substantially lower the dose necessary for the prophylactic treatment of thrombosis of the combination of a hydrogenated ergot alkaloid with vasoconstrictor properties and heparin. Since the combination is conveniently administered by injection, it is also possible, by means of the therapeutic composition of the invention, to reduce the patient's discomfort as only one daily administration is required. This is especially important for patients who need to recover after major surgery.
Den foreliggende opfindelse angår således et terapeutisk præparat, der indeholder 25 i) 0,2 - ca. 1,5 mg af et hydrogeneret ergotalkaloid medThus, the present invention relates to a therapeutic composition containing 25 1.5 mg of a hydrogenated ergot alkaloid with
vasokonstriktorisk virkning med den almene formel Ivasoconstrictor effect of general formula I
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3 O il ?“ |>r ϋ-ΝΗ-.ρ-γ^Ν^ X J ν^Λο i x.. I η I U<3 O il? “|> R ϋ-ΝΗ-.ρ-γ ^ Ν ^ X J ν ^ Λο i x .. I η I U <
HN -JHN -J
hvor R betegner hydrogen eller alkyl med 1-4 carbonatomer,wherein R represents hydrogen or alkyl of 1-4 carbon atoms,
Rj^ betegner methyl, ethyl eller isopropyl, R2 betegner isopropyl, sek.butyl, isobutyl eller benzyl, og 5 X betegner hydrogen eller methoxy, eller et farmaceutisk tolerabelt syreadditionssalt deraf og ii) et lavmolekylært heparin med en gennemsnitlig molekylevægt under 10.000 eller et farmaceutisk tolerabelt salt deraf med en aktivitet valgt således at komponent i) og det 10 lavmolekylære heparin forekommer i et forhold på 1 mg: 1000 - 10.000 IE.R 2 represents methyl, ethyl or isopropyl, R 2 represents isopropyl, sec-butyl, isobutyl or benzyl, and 5 X represents hydrogen or methoxy, or a pharmaceutically tolerable acid addition salt thereof, and ii) a low molecular weight heparin having an average molecular weight below 10,000 or a pharmaceutical one. tolerable salt thereof with an activity selected such that component i) and the low molecular weight heparin occur in a ratio of 1 mg: 1000 - 10,000 IU.
Ifølge i) foretrækkes især dihydroergotamin, 6-nor-6-isopropyl-9,10-dihydro-2'/3-methyl-5 'α-benzylergopeptin og dihydroergovalin eller farmaceutisk tolerable syreadditionssalte deraf.In particular, according to i), dihydroergotamine, 6-nor-6-isopropyl-9,10-dihydro-2 '/ 3-methyl-5' α-benzylergopeptin and dihydroergovaline or pharmaceutically tolerable acid addition salts thereof are preferred.
15 Som salte af hydrogenerede ergotalkaloider anvendes især methansul-fonatet, maleinatet og tartratet. Dihydroergotamin administreres især som methansulfonatet.Particularly used as the salts of hydrogenated ergot alkaloids are the methanesulfonate, maleinate and tartrate. Dihydroergotamine is especially administered as the methanesulfonate.
Som "lavmolekylært heparin" ifølge ii) anvendes ifølge opfindelsen et heparin, som fx fås ved isolering af de kortkædede dele eller ved 20 spaltning af kæderne i naturligt heparin. Således er det muligt at sænke heparinets gennemsnitlige molekylvægt væsentligt.As "low molecular weight heparin" according to ii), according to the invention, a heparin is used which is obtained, for example, by isolating the short chain parts or by cleavage of the chains in natural heparin. Thus, it is possible to significantly lower the average molecular weight of heparin.
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Det ifølge opfindelsen anvendte lavmolekylære heparin har en gennemsnitlig molekylvægt på ca. 10.000 eller derunder, især på ca.The low molecular weight heparin used according to the invention has an average molecular weight of approx. 10,000 or less, especially of approx.
8.000 eller derunder. Den gennemsnitlige molekylvægt er fortrinsvis ikke under ca. 4.000, især ikke under ca. 5.000, navnlig ikke under 5 ca. 6.000. Særlig foretrukne komponenter ifølge ii) har en gennemsnitlig molekylvægt på ca. 4.000 - ca. 10.000, især på ca. 5.000 -ca. 8.000, fx på ca. 7.000 ± 1.000 eller på ca. 6.000 ± 1.000. Det foretrækkes endvidere, at komponent ii) har relativt regelmæssig molelylvægtsfordeling, idet fx mindst 60%, især 80%, af 10 polymererihedeme har en molekylvægt, som ligger inden for de ovennævnte grænser, dvs. en molekylvægt på 10.000 eller derunder.8,000 or less. Preferably, the average molecular weight is not less than ca. 4,000, especially not less than approx. 5,000, in particular not less than 5 approx. 6000. Particularly preferred components according to ii) have an average molecular weight of approx. 4,000 - approx. 10,000, especially of approx. 5,000 -ca. 8,000, e.g. 7,000 ± 1,000 or approx. 6,000 ± 1,000. It is further preferred that component ii) has relatively regular mole weight distribution, for example, at least 60%, especially 80%, of the polymeric units have a molecular weight which is within the above limits, i. a molecular weight of 10,000 or less.
Egnede farmaceutisk tolerable salte af det lavmolekylære heparin som komponent ii) er calcium- og kaliumsaltene men især natriumsaltet.Suitable pharmaceutically tolerable salts of the low molecular weight heparin as component ii) are the calcium and potassium salts but especially the sodium salt.
Det lavmolekylære heparin eller de farmaceutisk tolerable salte 15 deraf, der anvendes som komponent ii), kan fremstilles på i og for sig kendt måde, fx ved isolering af fraktioner med en lav molekylvægt fra naturligt heparin, især ved fraktioneret udfældning og ultrafiltrering som beskrevet i DE-OS 29 45 591 eller ved depolymerisation af de højmolekylære fraktioner af naturligt heparin, 20 fx ved kemisk nedbrydning som fx beskrevet i belgisk patentskrift nr.The low molecular weight heparin or pharmaceutically tolerable salts thereof used as component ii) can be prepared in a manner known per se, for example, by isolating low molecular weight fractions from natural heparin, especially by fractional precipitation and ultrafiltration as described in DE-OS 29 45 591 or by depolymerization of the high molecular weight fractions of natural heparin, 20 for example by chemical degradation as described, for example, in Belgian patent no.
888.864 eller i europæisk patentansøgning nr. 27.089. Komponent ii) kan også fås ved kombination af disse fremgangsmåder, fx ved fraspaltning af de lavmolekylære dele fra naturligt heparin efterfulgt af depolymerisation af de tilbageværende højmolekylære 25 dele, hvorved der fås et lavmolekylært heparin, som eventuelt kan blandes med det ved fraspaltning vundne lavmolekylære heparin.888,864 or in European Patent Application No. 27,089. Component ii) can also be obtained by combining these processes, for example, by cleavage of the low molecular weight moieties from natural heparin followed by depolymerization of the remaining high molecular moiety, thereby obtaining a low molecular weight heparin which may be mixed with the low molecular weight obtained by cleavage. .
Ifølge opfindelsen foretrækkes et lavmolekylært heparin, som ikke er undergået nogen, eller nogen væsentlig, kemisk forandring.According to the invention, a low molecular weight heparin is preferred which has not undergone any, or any significant, chemical change.
I det terapeutiske præparat ifølge opfindelsen forekommer komponent 30 i) og ii) som nævnt i et forhold på 1 mg af komponent i) til 1.000- 10.000 IE af komponent ii). Såfremt komponent i) og/eller ii) forekommer i form af farmaceutisk tolerable salte, skal der anvendes en ækvivalent mængde af saltet, som svarer til det angivne forhold mellem komponenterne.In the therapeutic composition of the invention, components 30 i) and ii), as mentioned, are present in a ratio of 1 mg of component i) to 1,000-10,000 IU of component ii). If component (i) and / or (ii) occur in the form of pharmaceutically tolerable salts, an equivalent amount of the salt corresponding to the stated ratio of the components must be used.
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Præparatet ifølge opfindelsen administreres hensigtsmæssigt ved injektion. Således skal præparatet være i flydende form. Selv om det var muligt at fremstille en simpel vandig eller vandig-alkoholisk opløsning, er dette ikke aribefalelsesværdigt, da komponent i) og ii) 5 i fraværelse af en stabilisator ville reagere med hinanden under dannelse af et tungtopløseligt salt. Derfor er sådanne simple opløsninger uden praktisk værdi på grund af deres dårlige lagringsbestandighed.The composition of the invention is conveniently administered by injection. Thus, the composition must be in liquid form. Although it was possible to prepare a simple aqueous or aqueous-alcoholic solution, this is not desirable as components i) and ii) 5 in the absence of a stabilizer would react with each other to form a heavily soluble salt. Therefore, such simple solutions are of no practical value due to their poor storage resistance.
Foretrukne formuleringer er derfor sådanne, som fx er beskrevet i USA 10 patentskrift nr. 4.402.949 og som yderligere komponent iii) indeholder et farmaceutisk tolerabelt calcium- eller magnesiumsalt af ethylendiamintetraeddikesyre (EDTA) som stabiliseringsmiddel. Opløsningsmiddelmediet består af iv) vand og v) en farmaceutisk tolerabel mono- eller polyalkohol.Preferred formulations are therefore those described, for example, in U.S. Patent No. 4,402,949, and as additional component iii) contain a pharmaceutically tolerable calcium or magnesium salt of ethylenediaminetetraacetic acid (EDTA) as a stabilizing agent. The solvent medium consists of iv) water and v) a pharmaceutically tolerable mono- or polyalcohol.
15 Anbefalede calcium- og magnesiumsalte af EDTA som komponent iii) er monomagnesium- og monocalciumsalte og omfatter ligeledes farmaceutisk tolerable polyme talsal te, som foruden calcium- og magnesiumioner indeholder monovalente metalioner såsom natrium- eller kaliumioner.Recommended calcium and magnesium salts of EDTA as component iii) are monomagnesium and monocalcium salts and also comprise pharmaceutically tolerable polymeric salts which contain, in addition to calcium and magnesium ions, monovalent metal ions such as sodium or potassium ions.
Det ifølge opfindelsen foretrukne salt er monocalcium-bisnatrium-20 saltet (Ca Na2 EDTA), også kendt som calcium-titriplex. Monomagne-sium-biskaliumsaltet (Hg K2 EDTA) skal også omtales.The salt of the invention preferred is the monocalcium bis sodium salt (Ca Na 2 EDTA), also known as calcium titriplex. The monomagnesium bis-potassium salt (Hg K2 EDTA) is also mentioned.
Komponent iii) forekommer fortrinsvis i en mængde på 1-50 mg, især 1-25 mg, navnlig 1-10 mg, beregnet på en mængde på 5.000 IE af komponent ii). Komponenterne iv) og v) i opløsningsmiddelblandingen 25 er fortrinsvis til stede i en mængde på 45-72% og 28-55%, beregnet på præparatets totalvolumen. Som komponent v) foretrækkes ethanol, propylenglycol, polyethylenglycol (gennemsnitlig molekylvægt ca.Component iii) preferably occurs in an amount of 1-50 mg, especially 1-25 mg, in particular 1-10 mg, calculated on an amount of 5,000 IU of component ii). Components iv) and v) of the solvent mixture 25 are preferably present in an amount of 45-72% and 28-55%, based on the total volume of the composition. As component v), ethanol, propylene glycol, polyethylene glycol (average molecular weight ca.
400), diethylenglycol, triethylenglycol og glycerol og blandinger deraf. Komponent v) består især af a) ethanol og b) triethylenglycol 30 eller c) glycerol og d) propylenglycol. I sådanne blandinger er komponenterne a) og b) fortrinsvis til stede i et forhold på 1:6-10, især 1:8 (vægtforhold), og komponenterne c) og d) forekommer fortrinsvis i et forhold på 1:8-12, især 1:10 (vægtforhold). Ved en foretrukken udførelsesform indeholder opløsningerne af komponent i) 35 og ii) som yderligere komponent vi) et fysiologisk tolerabelt400), diethylene glycol, triethylene glycol and glycerol and mixtures thereof. Component v) consists mainly of a) ethanol and b) triethylene glycol 30 or c) glycerol and d) propylene glycol. In such mixtures, components a) and b) are preferably present in a ratio of 1: 6-10, especially 1: 8 (weight ratio), and components c) and d) are preferably present in a ratio of 1: 8-12. especially 1:10 (weight ratio). In a preferred embodiment, the solutions of component i) 35 and ii) as additional component vi) contain a physiologically tolerable
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6 anæstetikum. En anæs tetisk komponent vi) er fortrinsvis et anæstetikum med acetanilidstruktur. Der er her tale om aeetaniliner, især om 2-amino-N-phenyl-acetanilidderivater eller farmaceutisk tolerable salte deraf, som udvikler en anæstetisk virkning.6 anesthetics. An anesthetic component vi) is preferably an anesthetic with acetanilide structure. These are aeetanilines, in particular 2-amino-N-phenylacetanilide derivatives or pharmaceutically tolerable salts thereof, which develop an anesthetic effect.
5 Foretrukne acetanilider er 2-(diethylamino)-N-(2,6- dimethylphenyl)acetamid (også kendt som lidocain) , 2- (butylamino) -N-(2-chlor-6-methylphenyl)acetamid (også kendt som hostacain) og 2-(2-diethylaminoacetamido)-m-toluensyremethylester (også kendt som baycain).Preferred acetanilides are 2- (diethylamino) -N- (2,6-dimethylphenyl) acetamide (also known as lidocaine), 2- (butylamino) -N- (2-chloro-6-methylphenyl) acetamide (also known as hostacaine) ) and 2- (2-diethylaminoacetamido) -m-toluenic acid methyl ester (also known as baycain).
10 Sædvanligt anvendte salte af disse acetanilider er fx hydrochlorideme. Såfremt komponent vi) forekommer, skal dens andel andrage 1-2%, beregnet på præparatets totalvægt.Commonly used salts of these acetanilides are, for example, the hydrochlorides. If component (vi) occurs, its proportion shall be 1-2%, based on the total weight of the preparation.
Der skal endvidere henvises til, at det, selv om opløsninger som ovenfor anført er bedst egnede til anvendelse ifølge den 15 foreliggende opfindelse, også er muligt at anvende andre administrationsformer. Eksempler på sådanne andre former er lyofiliserede præparater, som før administration skal bringes i opløsning. Præparaterne ifølge opfindelsen kan også indeholde yderligere tilsætningsstoffer såsom bærestoffer, fortyndingsmidler, 20 stabilisatorer, konserveringsmidler, farvestoffer og overfladeaktive stoffer.It should also be noted that although solutions as indicated above are most suitable for use in accordance with the present invention, it is also possible to use other forms of administration. Examples of such other forms are lyophilized preparations which must be dissolved prior to administration. The compositions of the invention may also contain additional additives such as carriers, diluents, stabilizers, preservatives, dyes and surfactants.
Det terapeutiske præparat ifølge opfindelsen anvendes til profylakse af post-operative thromboser.The therapeutic composition of the invention is used for the prophylaxis of post-operative thrombosis.
Den gunstige anti-thrombotiske virkning af præparatet ifølge opfin- 125 25 delsen viser sig især ved I -fibrinogentesten.The beneficial anti-thrombotic effect of the composition of the invention is particularly evident in the I-fibrinogen test.
Princippet i denne test beror på den eksterne registrering af 125 strålingen af I -fibrinogen, som selektivt akkumuleres i thrombotisk materiale i benets vener [K.H. Frey et al., Med. Klin. 70 (1975), s. 1553-1558, især s. 1555].The principle of this test is based on the external detection of the 125 radiation of I-fibrinogen, which selectively accumulates in thrombotic material in the veins of the bone [K.H. Frey et al., Med. Klin. 70 (1975), pp. 1553-1558, especially pp. 1555].
30 Ved sammenligning af det fx fra DE-AS 25 54 533 kendte præparat med præparatet ifølge opfindelsen har det vist sig, at præparatet ifølge opfindelsen ved én daglig administration i doser på 0,5 mgBy comparing, for example, from DE-AS 25 54 533 with the composition according to the invention, it has been found that the composition according to the invention, at one daily administration in doses of 0.5 mg
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7 dihydroergotamin-methansulfonat og 2.500 IE lavmolekylært heparin (molekylvægt 7.000 ± 1.000), idet dosen af heparin endog kan sænkes til 1.500 IE, har samme profylaktiske virkning mod thromboser, især post-operative thromboser, som tre gange daglig administration af det 5 fra DE-AS 25 54 533 kendte præparat.7 dihydroergotamine methanesulfonate and 2,500 IU low molecular weight heparin (molecular weight 7,000 ± 1,000), the dose of heparin even being reduced to 1,500 IU, has the same prophylactic effect against thromboses, especially post-operative thromboses, as three times daily administration of the 5 from DE -AS 25 54 533 known composition.
En anbefalet daglig dosis af komponent i) skal ligge på 0,2 - ca. 1,5 mg, især 0,5 mg, og af komponent ii) på ca. 1.000 - 10.000 IE, især på ca. 1.500 - ca. 5.000 IE. Om ønsket kan det omhandlede præparat administreres i mindre doser 2-4 gange daglig. Administrationen 10 foretages fortrinsvis i enkelt dosis én gang daglig i enhedsdosisform. På den anden side er det dog også muligt at administrere komponent i) og ii) uafhængigt af hinanden.A recommended daily dose of component i) should be 0.2 - approx. 1.5 mg, in particular 0.5 mg, and of component ii) of approx. 1,000 - 10,000 IU, especially at approx. 1,500 - approx. 5,000 IU. If desired, the subject composition may be administered in smaller doses 2-4 times daily. The administration 10 is preferably done in a single dose once daily in unit dosage form. On the other hand, however, it is also possible to manage component i) and ii) independently of one another.
Egnede enhedsdoser indeholder for 0,5 mg af komponent i) ca. 1.500, ca. 2.500 eller ca. 5.000 IE af komponent ii).Suitable unit doses contain for 0.5 mg of component i) approx. 1,500, approx. 2,500 or approx. 5,000 IU of component ii).
15 Den foreliggende opfindelse angår endvidere en fremgangsmåde til fremstilling af det terapeutiske præparat ifølge opfindelsen. Til dette formål kan komponent i) blandes grundigt med komponent ii), eller komponent i) kan sammen med komponent ii) opløses i et farmaceutisk tolerabelt opløsningsmiddel. Såfremt der skal 20 fremstilles opløsninger, som også skal indeholde komponent iii), iv), v) og eventuelt også vi), kan fremgangsmåden udføres som beskrevet nedenfor: 1) Fremstilling af en opløsning af komponent i) og eventuelt komponent vi) i et opløsningsmiddelmiljø indeholdende 25 komponent v).The present invention further relates to a process for the preparation of the therapeutic composition of the invention. For this purpose, component i) can be thoroughly mixed with component ii) or component i) may be dissolved together with component ii) in a pharmaceutically tolerable solvent. If solutions are to be prepared which must also contain components iii), iv), v) and optionally also vi), the process can be carried out as described below: 1) Preparation of a solution of component i) and optionally component vi) solvent environment containing 25 component v).
2) Fremstilling af en opløsning af komponent ii) og komponent iii) i et opløsningsmiddelmiljø indeholdende komponent iv) .2) Preparation of a solution of component ii) and component iii) in a solvent environment containing component iv).
3) Sammenhældning af opløsningerne ifølge 1) og 2) og 30 4) eventuelt tilsætning af yderligere andele af komponent iv) og/eller v).3) Pouring the solutions according to 1) and 2) and 30 4) optionally adding additional proportions of component iv) and / or v).
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Fremgangsmåden foretages hensigtsmæssigt i en inert gasatmosfære, fx en CO2-atmosfære, og pH-værdien i den vundne opløsning indstilles fx ved tilsætning af en egnet farmaceutisk tolerabel syre, fx methansulfonsyre (ved anvendelse af methansulfonatet af komponent i)) 5 på 4-6. Såfremt der anvendes andre salte af komponent i), skal pH-værdiindstillingen foretages ved med de tilsvarende syrer. De således vundne præparater kan bringes i den ønskede administrationsform, fx kan de vundne, til injektion egnede opløsninger efter filtrering fyldes i injektionsampuller, hensigtsmæssigt under CO2-10 atmosfære.The process is conveniently carried out in an inert gas atmosphere, for example a CO2 atmosphere, and the pH of the solution obtained is adjusted, for example, by the addition of a suitable pharmaceutically tolerable acid, eg methanesulfonic acid (using the methanesulfonate of component i)) of 4-6. . If other salts of component i) are used, the pH value adjustment must be carried out with the corresponding acids. The compositions thus obtained can be brought into the desired administration form, for example, the obtained solutions suitable for injection after filtration can be filled into injection vials, conveniently under CO2-10 atmosphere.
Det terapeutiske præparat ifølge opfindelsen indholdende komponent i) og ii) anvendes fortrinsvis til profylaktisk behandling af thromboser, især post-operative thromboser. Til dette formål foretrækkes især et terapeutisk præparat, som foruden 0,5 mg 15 dihydroergotamin-methansulfonat indeholder 2.500, dog fortrinsvis 1.500, IE lavmolekylært heparing (gennemsnitlig molekylevægt 7.000 ± 1.000).The therapeutic composition of the invention containing components i) and ii) is preferably used for the prophylactic treatment of thrombosis, especially post-operative thrombosis. For this purpose, a therapeutic composition is preferred which contains, in addition to 0.5 mg of dihydroergotamine methanesulfonate, 2,500, though preferably 1,500, IU of low molecular weight pairing (average molecular weight 7,000 ± 1,000).
EKSEMPEL 1EXAMPLE 1
Fremstilling af heparin-na triumf rakt ioner i området fra 6.000 til ca.Preparation of heparin triumph reactions in the range of from 6,000 to approx.
20 9.000 molekylvægtsenheder 1000 g heparin-natrium med en gennemsnitlig molekylvægt på ca.20,000 molecular weight units 1000 g of heparin sodium with an average molecular weight of approx.
15.000 opløses i 6,66 liter destilleret vand, og denne opløsnings pH-værdi måles på et pH-meter. Opløsningen indstilles på pH-værdi 2,7 ved hjælp af ca. 145 ml 25%'s saltsyre og filtreres gennem et 25 foldefilter nr. 520 b 1/2 (diameter 320 mm) fra firmaet Schleicher &15,000 are dissolved in 6.66 liters of distilled water and the pH of this solution is measured on a pH meter. The solution is adjusted to pH 2.7 using approx. 145 ml of 25% hydrochloric acid and filtered through a 25 fold fold filter No. 520 b 1/2 (diameter 320 mm) from Schleicher & Co.
Schåll. Filtratet recirkuleres i 1 time gennem en ultraffiltrerings -membran med en nominel udelukkelsesgrænse på 10.000 molekylvægts-enheder ved nedenstående betingelser under udelukkelse af lys.Schåll. The filtrate is recirculated for 1 hour through an ultrafiltration membrane with a nominal exclusion limit of 10,000 molecular weight units under the following conditions, under light exclusion.
Temperatur: Stuetemperatur 30 Filter: Pellicon filterkassette (katalog nr. PTGC 00001 Fa. Millipore)Temperature: Room temperature 30 Filter: Pellicon filter cassette (catalog no. PTGC 00001 Fa. Millipore)
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Tryk på indgangssiden: 3,2 x 10·* PaPress on the input side: 3.2 x 10 · * Pa
Tryk på retentatsiden: 1,2 x 10-* PaPress the retentate side: 1.2 x 10- * Pa
Totalgennemstrømning: *200 ml/minutTotal flow: * 200 ml / minute
Gennemstrømning af retentat: *196 ml/minut 5 Gennemstrømning af filtrat: » 4 ml/minut.Flow of retentate: * 196 ml / minute 5 Flow of filtrate: »4 ml / minute.
Efter 1 times recirkulering ledes filtratstrømmen til en separat beholder og opsamles. Filtreringen afbrydes efter ca. 24 timer.After 1 hour of recycling, the filtrate stream is led to a separate container and collected. Filtration is stopped after approx. 24 hours.
Filtratet, ca. 1.000-1.200 ml, indstilles på et pH-meter på natrium -heparinopløsningens udgangsværdi, * pH 7, med ca. 3 ml 30%'s 10 natriumhydroxidopløsning. Denne opløsning er første fraktion.The filtrate, ca. 1,000-1,200 ml, adjusted to a pH meter of the sodium heparin solution starting value, * pH 7, with approx. 3 ml of 30% sodium hydroxide solution. This solution is the first fraction.
Retentatet indstilles på pH-værdi 3,5 med ca. 10 ml 30%'s natriumhydroxidopløsning og filtreres endnu engang i 24 timer under de ovenfor anførte betingelser. Det vundne filtrat, ca. 800 ml, indstilles på et pH-meter igen på udgangsværdien » pH 7. Denne opløsning er anden 15 fraktion.The retentate is adjusted to pH 3.5 with approx. 10 ml of 30% sodium hydroxide solution and filtered again for 24 hours under the above conditions. The filtrate obtained, ca. 800 ml, is adjusted to a pH meter again at the initial value »pH 7. This solution is another 15 fraction.
Retentatet fra denne filtrering indstilles på pH-værdi 4,2 med ca. 60 ml 30%'s natriumhydroxidopløsning og filtreres endnu engang under de ovenfor anførte betingelser i 24 timer. Det vundne filtrat, ca. 500 ml, indstilles på et pH-meter på udgangsværdien « pH 7. Denne 20 opløsning er tredje fraktion.The retentate from this filtration is adjusted to pH 4.2 with approx. 60 ml of 30% sodium hydroxide solution and again filtered under the above conditions for 24 hours. The filtrate obtained, ca. 500 ml is adjusted to a pH meter at the initial value «pH 7. This 20 solution is the third fraction.
De tre fraktioner oparbejdes hver for sig på følgende måde:The three fractions are worked up separately as follows:
Til det neutraliserede filtrat sættes et 1,1 gange så stort volumen acetone, og det i filtratet værende heparin-natrium udfældes. Det udfældede materiale (olieagtig, viskos væske) lades sætte sig natten 25 over, og det overstående opløsningsmiddel dekanteres. Remanensen overhældes med en ca. tre gange så stor mængde methanol og omrøres grundigt med en omrører ved ca. 1.000 omdrejninger/minut. Derved udfældes heparinet i form af et hvidligt bundfald, som derefter kan granuleres i en riveskål under methanol. Den derfra vundne suspension 30 frafiltreres. Remanensen tørres derpå ved 60eC og ca. 200 Pa i et vakuumtørreskab. Hvis indholdet af NaCl skulle være større end 0,5%, er en yderligere udfældning nødvendig.To the neutralized filtrate is added 1.1 times the volume of acetone and the heparin sodium contained in the filtrate is precipitated. The precipitated material (oily, viscous liquid) is allowed to settle overnight and the supernatant is decanted. The residue is poured with an approx. about three times the amount of methanol and stirred thoroughly with a stirrer at approx. 1,000 rpm. Thereby, the heparin is precipitated in the form of a whitish precipitate, which can then be granulated in a grating dish under methanol. The resulting suspension 30 is filtered off. The residue is then dried at 60 ° C and ca. 200 Pa in a vacuum drying cabinet. If the NaCl content should be greater than 0.5%, a further precipitation is necessary.
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De således vundne fraktioner har følgende specifikationer:The fractions thus obtained have the following specifications:
Elementaranalyse Fraktion 1 Fraktion 2 Fraktion 3 5 C 23,7% 24,9% 24,4% H 3,3% 3,1% 3,2% N 2,9% 2,4% 2,7% 0 47,1% 45,9% 46,8% S 11,7% 11,9% 11,6% 10 Na 12,3% 11,8% 11,3%Elemental Analysis Fraction 1 Fraction 2 Fraction 3 C 23.7% 24.9% 24.4% H 3.3% 3.1% 3.2% N 2.9% 2.4% 2.7% 0.47, 1% 45.9% 46.8% S 11.7% 11.9% 11.6% 10 After 12.3% 11.8% 11.3%
Heparinaktivitet »75±5 IE/mg »80±5 IE/mg »90±5 IE/mg (PTT-test, beregnet på WHO-standard III)Heparin activity »75 ± 5 IU / mg» 80 ± 5 IU / mg »90 ± 5 IU / mg (PTT test, calculated on WHO standard III)
Anti Xa-aktivitet »150±10 U/mg »155110 U/mg »160110 U/mg 15 Hyppigste molekylvægt »6.000+1.000 »8.000+1.000 »9.000±1.000Anti Xa activity »150 ± 10 U / mg» 155110 U / mg »160110 U / mg 15 Most common molecular weight» 6,000 + 1,000 »8,000 + 1,000» 9,000 ± 1,000
NaCl-Indhold <0,5% <0,5% <0,5% EKSEMPEL 2NaCl Content <0.5% <0.5% <0.5% Example 2
Fremstilling af en stabil injektionsopløsning indeholdende 1.500 IE lavmolekylært heparin (MW 6.000 ± 1.000 og 0,5 mg dihydroergotamin) 20 a) Fremstilling af dihydroergotaminopløsningen 1 et 50-liters røreapparatur hældes 18,4 kg propylenglycol og 1,84 kg vandfrit glycerol, og blandingen omrøres under (^-atmosfære i 10 minutter. Under yderligere omrøring og under CO2-atmosfære sættes der til blandingen i løbet af ca. 30 minutter 0,0286 kg dihydroergotamin- 25 mesylat og 0,426 kg lidocainhydrochlorid og opløses deri.Preparation of a stable injection solution containing 1,500 IU low molecular weight heparin (MW 6,000 ± 1,000 and 0.5 mg dihydroergotamine) 20 a) Preparation of the dihydroergotamine solution in a 50 liter stirrer is poured 18.4 kg propylene glycol and 1.84 kg anhydrous glycerol and the mixture The mixture is stirred under (2) atmosphere for 10 minutes. With further stirring and under CO2 atmosphere, 0.0286 kg of dihydroergotamine mesylate and 0.426 kg of lidocaine hydrochloride are added to the mixture and dissolved therein.
b) Fremstilling af opløsningen af lavmolekylært heparinb) Preparation of the solution of low molecular weight heparin
I et 30-liters røreapparatur hældes 18,4 kg vand (til injektionsformål) , og der omrøres i 10 minutter under CO2-atmosfære. Under yderligere omrøring og (^-atmosfære tilsættes der i løbet af 30 30 minutter 85,71 millioner I.E. lavmolekylært heparin (MWIn a 30-liter stirrer, 18.4 kg of water (for injection purposes) is poured and stirred for 10 minutes under a CO2 atmosphere. With further stirring and (2) atmosphere, 85.71 million I.E. low molecular weight heparin (MW) is added over 30 minutes.
6.000 + 1.000) i form af natriumsaltet (svarende til 1,7-2,5 kg6,000 + 1,000) in the form of the sodium salt (corresponding to 1.7-2.5 kg
DK 162475 BDK 162475 B
11 natriumsalt af lavmolekylært heparin ifølge dets aktivitet) og 0,114 kg calciumtitriplex (monocalcium-bisnatriumsalt af ethylendiamin-tetraeddikesyre) og opløses deri.11 sodium salt of low molecular weight heparin according to its activity) and 0.114 kg of calcium titriplex (monocalcium bis sodium salt of ethylenediamine tetraacetic acid) and dissolved therein.
c) Blanding af de under a) og b) fremstillede opløsninger.(c) Mixing the solutions prepared under (a) and (b).
5 Den ifølge b) fremstillede opløsning sættes under CO2-atmosfære til den ifølge a) fremstillede opløsning. Derefter spules den beholder, i hvilken opløsning b) blev fremstillet, med 1 kg vand (til injektions-formål), og dette sættes ligeledes til den ifølge a) fremstillede opløsning. De samlede opløsninger omrøres i 10 minutter under CO2-10 atmosfære (pH-værdien i de samlede opløsninger skal her være ca. 5,5) og bringes derefter ved tilsætning af vand (til injektions formal) op på en slutvægt på 42,810 kg (svarende til 40 liter væske).The solution prepared according to (b) is added under CO2 atmosphere to the solution prepared according to (a). Then, the container in which solution b) was prepared is flushed with 1 kg of water (for injection purposes) and this is also added to the solution prepared according to a). The total solutions are stirred for 10 minutes under CO2-10 atmosphere (the pH value of the total solutions should be about 5.5 here) and then brought to a final weight of 42,810 kg (equivalent to injection). to 40 liters of liquid).
d) Filtrering d^) Forfiltrering: Forfiltrering foretages gennem et membranfilter 15 (0,2 /im-Ultipor /<m Pali).d) Filtration d ^) Pre-Filtration: Pre-filtration is done through a membrane filter 15 (0.2 µm-Ultipor / <m Pali).
d2) Sterilfiltrering: Den ifølge c) fremstillede og forfiltrerede opløsning filtreres direkte på aftapningsmaskinen ved hjælp af CO2 over et steriliseret trykfiltreringsapparatur med membranfilter (0,2 /im-Ultipor /an Pali) under 1,7 bar's tryk.d2) Sterile filtration: The prepared and pre-filtered solution according to c) is filtered directly on the bottling machine by means of CO2 over a sterilized membrane filtration apparatus (0.2 µm Ultipor / an Pali) under 1.7 bar pressure.
20 Den sterilfiltrerede opløsning fyldes under aseptiske betingelser i 1 ml's ampuller (fyldevolumen 0,8 ml).The sterile-filtered solution is filled under aseptic conditions into 1 ml ampoules (volume 0.8 ml).
EKSEMPEL 3EXAMPLE 3
Fremstilling af en injektionsopløsning indeholdende 0,5 mg dihydro-ergotamin og 2.500 og 5.000 IE lavmolekylært heparin 25 Under anvendelse af den i eksempel 2 beskrevne fremgangsmåde og de der anførte bestanddele med den undtagelse, at andelen af natrium-heparinatet erstattes med en 1^/3 og en 3^/3 gange så stor mængde natriumheparinat (gennemsnitlig molekylvægt 6.000 ± 1.000), fås det i overskriften beskrevne præparat.Preparation of an injection solution containing 0.5 mg dihydro-ergotamine and 2,500 and 5,000 IU low molecular weight heparin 25 Using the procedure described in Example 2 and the ingredients listed, except that the proportion of the sodium heparinate is replaced by a 1 3 and a 3 ^ / 3 times the amount of sodium heparinate (average molecular weight 6,000 ± 1,000), the preparation described in the title is obtained.
Claims (10)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3245695 | 1982-12-10 | ||
| DE3245695 | 1982-12-10 |
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| Publication Number | Publication Date |
|---|---|
| DK565783D0 DK565783D0 (en) | 1983-12-08 |
| DK565783A DK565783A (en) | 1984-06-11 |
| DK162475B true DK162475B (en) | 1991-11-04 |
| DK162475C DK162475C (en) | 1992-05-11 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK565783A DK162475C (en) | 1982-12-10 | 1983-12-08 | THERAPEUTIC PREPARATION CONTAINING HYDROGENERED ERGOTAL KALOIDS AND HEPARIN AND PROCEDURE FOR PREPARING THE PREPARATION |
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| Country | Link |
|---|---|
| JP (1) | JPH0672101B2 (en) |
| AT (1) | AT382514B (en) |
| AU (1) | AU570658B2 (en) |
| BE (1) | BE898356A (en) |
| CA (1) | CA1224416A (en) |
| CH (1) | CH656533A5 (en) |
| CY (1) | CY1509A (en) |
| DD (1) | DD215469B3 (en) |
| DK (1) | DK162475C (en) |
| FR (1) | FR2537435B1 (en) |
| GB (1) | GB2131691B (en) |
| GR (1) | GR79745B (en) |
| HK (1) | HK23290A (en) |
| HU (1) | HU190513B (en) |
| IE (1) | IE56366B1 (en) |
| IL (1) | IL70406A (en) |
| IT (1) | IT1172368B (en) |
| LU (1) | LU85127A1 (en) |
| NL (1) | NL8304221A (en) |
| NZ (1) | NZ206523A (en) |
| PH (1) | PH23451A (en) |
| PT (1) | PT77803B (en) |
| SE (1) | SE468973B (en) |
| SG (1) | SG53989G (en) |
| ZA (1) | ZA839200B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3432661A1 (en) * | 1984-09-05 | 1986-03-06 | Albert Prof. Dr. 6907 Nußloch Landsberger | CARCINOM THERAPEUTIC |
| EP0337327A1 (en) * | 1988-04-09 | 1989-10-18 | Bioiberica, S.A. | Process for the preparation of new oligosaccharide fractions by controlled chemical depolimerization of heparin |
| IT1245761B (en) * | 1991-01-30 | 1994-10-14 | Alfa Wassermann Spa | PHARMACEUTICAL FORMULATIONS CONTAINING GLYCOSAMINOGLICANS ABSORBABLE ORALLY. |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE441142B (en) * | 1975-12-04 | 1985-09-16 | Sandoz Ag | PROCEDURE FOR PREPARING A THERAPEUTIC PREPARATION WITH ANTITHROMOBOTIC PROPERTIES |
| DE2809618A1 (en) * | 1978-03-06 | 1979-09-20 | Sandoz Ag | NEW THERAPEUTIC PREPARATION AND METHOD FOR THE PRODUCTION THEREOF |
| DE2554533C3 (en) * | 1975-12-04 | 1984-08-30 | Sandoz-Patent-Gmbh, 7850 Loerrach | Use of dihydroergotamine and heparin |
| DE3020895A1 (en) * | 1979-06-12 | 1980-12-18 | Sandoz Ag | ERGOPEPTIN DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THESE ERGOPEPTIN DERIVATIVES |
| DE2945636A1 (en) * | 1979-11-12 | 1981-05-21 | Sandoz-Patent-GmbH, 7850 Lörrach | STABLE SOLUTIONS OF HYDRATED ERGOTAL CALOIDS OR YOUR SALTS AND HEPARIN OR ITS SALTS AND METHOD FOR THE PRODUCTION THEREOF |
-
1983
- 1983-11-30 CH CH6407/83A patent/CH656533A5/en not_active IP Right Cessation
- 1983-12-02 FR FR8319446A patent/FR2537435B1/en not_active Expired
- 1983-12-02 BE BE1/10914A patent/BE898356A/en not_active IP Right Cessation
- 1983-12-06 PH PH29930A patent/PH23451A/en unknown
- 1983-12-07 AT AT0428483A patent/AT382514B/en not_active IP Right Cessation
- 1983-12-07 NL NL8304221A patent/NL8304221A/en not_active Application Discontinuation
- 1983-12-07 CY CY1509A patent/CY1509A/en unknown
- 1983-12-07 GB GB08332653A patent/GB2131691B/en not_active Expired
- 1983-12-07 IT IT49456/83A patent/IT1172368B/en active
- 1983-12-08 GR GR73193A patent/GR79745B/el unknown
- 1983-12-08 AU AU22221/83A patent/AU570658B2/en not_active Ceased
- 1983-12-08 CA CA000442829A patent/CA1224416A/en not_active Expired
- 1983-12-08 DK DK565783A patent/DK162475C/en active
- 1983-12-08 HU HU834202A patent/HU190513B/en not_active IP Right Cessation
- 1983-12-08 SE SE8306792A patent/SE468973B/en unknown
- 1983-12-08 NZ NZ206523A patent/NZ206523A/en unknown
- 1983-12-08 IL IL70406A patent/IL70406A/en not_active IP Right Cessation
- 1983-12-09 PT PT77803A patent/PT77803B/en not_active IP Right Cessation
- 1983-12-09 IE IE2896/83A patent/IE56366B1/en not_active IP Right Cessation
- 1983-12-09 LU LU85127A patent/LU85127A1/en unknown
- 1983-12-09 ZA ZA839200A patent/ZA839200B/en unknown
- 1983-12-09 JP JP58233457A patent/JPH0672101B2/en not_active Expired - Lifetime
- 1983-12-09 DD DD83257744A patent/DD215469B3/en not_active IP Right Cessation
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1989
- 1989-08-23 SG SG539/89A patent/SG53989G/en unknown
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1990
- 1990-03-29 HK HK232/90A patent/HK23290A/en unknown
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