DK170016B1 - Composition with controlled release of the active substance - Google Patents
Composition with controlled release of the active substance Download PDFInfo
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
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- A—HUMAN NECESSITIES
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- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
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Description
DK 170016 B1DK 170016 B1
Den foreliggende opfindelse angår farmaceutiske præparater med kontrolleret afgivelse af aktive stoffer, der har indflydelse på blodcirkulationen, herunder hjertet, og som indeholder en 4-(2,1,3-ben-zoxadiazol-4-yl)-1,4-dihydro-2,6-dimethyl-3,5-pyridin-dicarboxylate-5 ster, især darodipin og isradipin.The present invention relates to controlled-release pharmaceutical compositions affecting blood circulation, including the heart, and containing a 4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-4 2,6-dimethyl-3,5-pyridine dicarboxylate esters, especially darodipine and isradipine.
Dansk patentansøgning nr. 1426/81 beskriver en lang række præparater med stærkt varierende indhold med hensyn til lægemidlets art, mens der i øvrigt ikke gives nogen specifikke informationer om den nødvendige administrationsfrekvens for præparaterne. Det samme gælder for 10 dansk fremlæggelsesskrift nr. 162511.Danish Patent Application No. 1426/81 discloses a wide variety of preparations with widely varying contents with respect to the nature of the drug, while otherwise no specific information on the required administration frequency of the preparations is provided. The same applies to 10 Danish petition no. 162511.
Dansk patentansøgning nr. 867/85 vedrører retardpræparater med ét bestemt lægemiddel, nemlig Bromocriptin, som imidlertid er helt forskelligt i sin struktur og beskaffenhed fra de lægemidler, der indgår i præparaterne ifølge den foreliggende opfindelse.Danish Patent Application No. 867/85 relates to retarded preparations with one particular drug, namely Bromocriptine, which, however, is quite different in its structure and nature from the drugs included in the compositions of the present invention.
15 I modsætning til ovenstående kendte retardforbindelser har retardfor-bindelser med Israpidin og Daropidin som aktivt stof den fordel, at det kun er nødvendigt at indtage disse forbindelser én gang i døgnet.Contrary to the above known retard compounds, retard compounds with Israpidine and Daropidin as the active substance have the advantage that it is only necessary to take these compounds once a day.
Darodipin er det generiske navn for diethyl-4-(2,1,3-benzoxadiazol-4-yl)-l,4-dihydro-2,6-dimethyl-3,5-pyridindicarboxylat. Det er be-20 skrevet i britisk patentskrift nr. 2.037.766 B. Til farmaceutisk anvendelse anvendes darodipin som den frie base.Darodipine is the generic name for diethyl 4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylate. It is described in British Patent Specification No. 2,037,766 B. For pharmaceutical use, darodipine is used as the free base.
De farmakologiske og kliniske egenskaber er blevet omfattende undersøgt. Darodipin er en stærk calciumantagonist på isolerede coronarar-terier og andre perifere blodkar. Hæmodynamiske undersøgelser af 25 sunde individer viser en nedgang i den totale perifere modstand og arterieblodtrykket.The pharmacological and clinical properties have been extensively studied. Darodipine is a potent calcium antagonist on isolated coronary arteries and other peripheral blood vessels. Hemodynamic studies of 25 healthy individuals show a decrease in total peripheral resistance and arterial blood pressure.
Darodipin er indikeret til behandling af angina pectoris, hypertension, slagtilfælde og cerebrale vasospasmer.Darodipine is indicated for the treatment of angina pectoris, hypertension, stroke and cerebral vasospasm.
Sædvanlige orale daglige doser er fx til behandling af angina pec-30 toris 75-300 mg, som fortrinsvis indgives i 3 delte doser, og til 2 DK 170016 B1 behandling af hypertension 37,5-150 mg, som indgives i 2-3 delte doser.Usual oral daily doses are, for example, for the treatment of angina pectoris 75-300 mg, which is preferably administered in 3 divided doses, and for 2 treatment of hypertension 37.5-150 mg, administered in 2-3 divided doses. doses.
Isradipin er det generiske navn for isopropylmethyl-4-(2,l,3-benz-oxadiazol-4-yl) -1,4- dihydro -2,6- dimethyl -3,5 -pyridin- dicarboxylat.Isradipine is the generic name for isopropylmethyl-4- (2,1,3-benz-oxadiazol-4-yl) -1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylate.
5 Det administreres sædvanligvis som den frie base. Det er beskrevet i britisk patentskrift nr. 2.037.766 B. *It is usually administered as the free base. It is described in British Patent Specification No. 2,037,766 B. *
Isradipins farmakologiske og kliniske egenskaber er blevet grundigt undersøgt. Det er en kraftig calciumantagonist og indvirker navnlig på coronararterien og de perifere arterier. Lægemidlet indikeres især 10 til behandling af fx hypertension, angina pectoris og cerebral insufficiens. De sædvanlige orale daglige doser er 10-20 mg, der fortrinsvis er delt i mindre doser på 5-10 mg to gange daglig.The pharmacological and clinical properties of isradipine have been extensively studied. It is a potent calcium antagonist and affects the coronary and peripheral arteries in particular. In particular, the drug is indicated for the treatment of, for example, hypertension, angina pectoris and cerebral insufficiency. The usual oral daily doses are 10-20 mg, preferably divided into smaller doses of 5-10 mg twice daily.
Administrationen af de ovennævnte aktive stoffer kan af og til være forbundet med uønskede bivirkninger, fx hovedpine i tilfælde af 15 darodipin, og hovedpine, rødmen, palpitation og tachycardi, når isradipin administreres.The administration of the above-mentioned active substances may sometimes be associated with undesirable side effects, eg headache in the case of darodipine, and headache, redness, palpitation and tachycardia when isradipine is administered.
Det har nu vist sig at være foretrukket at holde koncentrationen af det aktive stof på et terapeutisk aktivt niveau inden for snævre grænser og undgå den sædvanlige kraftige afgivelse af lægemidlet lige 20 efter administration af præparater, som ikke har kontrolleret afgivelse, hvilket medfører midlertidige høje blodniveauer og deraf følgende stærke uønskede bivirkninger.It has now been found to be preferable to maintain the concentration of the active substance at a therapeutically active level within narrow limits and to avoid the usual vigorous delivery of the drug just after administration of non-controlled release preparations, resulting in temporary high blood levels. and resulting strong unwanted side effects.
Terapi kan forbedres ved to eller tre gange daglig at administrere mindre doser, der tilsammen er lige så store som den totale daglige 25 dosis. Dette er imidlertid besværligt og opfylder ikke det krav, at der kun fås blodniveauer af det aktive stof inden for snævre grænser.Therapy can be improved by administering two or three times daily smaller doses that are equal to the total daily dose. However, this is cumbersome and does not meet the requirement that blood levels of the active substance be obtained only within narrow limits.
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Den foreliggende opfindelse angår et præparat med kontrolleret afgivelse af de aktive stoffer og med forlænget virkning af de aktive stoffer, således at det antal gange, det aktive stof skal admini- * 30 streres hver dag, nedsættes, og visse negative reaktioner reduceres.The present invention relates to a composition with controlled release of the active substances and with prolonged action of the active substances, so that the number of times the active substance must be administered daily is reduced and certain negative reactions are reduced.
Endvidere giver præparaterne ifølge opfindelsen under testbetingel- 3 DK 170016 B1 serne fortræffelig biotilgængelighed i fødeinteraktionsundersøgelser, fx som beskrevet i eksempel 4 nedenfor.Further, under the test conditions, the compositions of the invention provide excellent bioavailability in food interaction studies, e.g., as described in Example 4 below.
Den foreliggende opfindelse angår således et præparat med kontrolleret afgivelse til oral administration, hvilket præparat som aktivt 5 stof indeholder en 4-(2,l,3-benzoxadiazol-4- yl)-l,4-dihydro-2,6-dimethyl-3,5-pyridin-dicarboxylatester, et farmaceutisk acceptabelt hydrofilt kvældbart cellulosehydro-kolloid og eventuelt 10 - et farmaceutisk acceptabelt inert fedtholdigt materiale.Thus, the present invention relates to a controlled-release preparation for oral administration which contains as an active substance a 4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-2,6-dimethyl-1 3,5-pyridine-dicarboxylate ester, a pharmaceutically acceptable hydrophilic swellable cellulose hydrocolloid and optionally a pharmaceutically acceptable inert fatty material.
I et yderligere aspekt angår den foreliggende opfindelse et præparat med kontrolleret afgivelse til oral administration, hvilket præparat indeholder isradipin og har en relativ biotilgængelighed på over 65% sammenlignet med et oralt isradipinpræparat, som ikke har kontrol-15 leret afgivelse, efter administration til en fastende forsøgsperson.In a further aspect, the present invention relates to a controlled release preparation for oral administration which contains isradipine and has a relative bioavailability of over 65% compared to a non-controlled oral isradipine preparation after administration to a fasting agent. subjects.
I et yderligere aspekt angår den foreliggende opfindelse et præparat med kontrolleret afgivelse til oral administration, hvilket præparat indeholder en 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-2,6-dimethyl- 3,5-pyridin-dicarboxylatester, hvilket præparat har biotilgængelig-20 hedsforskelle efter administration til en fastende forsøgsperson og en ikke-fastende forsøgsperson på højst 20%.In a further aspect, the present invention relates to a controlled-release preparation for oral administration containing a 4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-2,6-dimethyl-3 , 5-pyridine dicarboxylate ester, which has bioavailability differences after administration to a fasting subject and a non-fasting subject not exceeding 20%.
Foretrukne mængder af darodipin i enhedsdosisform er 10-200 mg, især 20-150, fx 100 mg.Preferred amounts of darodipine in unit dosage form are 10-200 mg, especially 20-150, eg 100 mg.
Foretrukne mængder af isradipin i enhedsdosisform er 5-40 mg, især 25 10-20 mg.Preferred amounts of isradipine in unit dose form are 5-40 mg, especially 10-20 mg.
Et foretrukket kvældbart stof er en celluloseforbindelse, der i vand omdannes til et kolloid.A preferred swellable substance is a cellulose compound which is converted into a colloid in water.
4 DK 170016 B14 DK 170016 B1
Foretrukne hydrofile kvældbare stoffer omfatter én eller flere naturlige, delvis eller helt syntetiske, anioniske eller, fortrinsvis, ikke-ioniske hydrofile gummier, modificerede cellulosestoffer eller proteinøse stoffer som fx acaciagummi, traganthgummi, johannesbrød- * 5 kernegummi, guargummi, karayagummi, agar, peptin, carrageen, opløselige og uopløselige alginater, methylcellulose, hydroxypropylmet-hylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, natrium- * carboxymethylcellulose, carboxypolymethylen og gelatine.Preferred hydrophilic swellable substances include one or more natural, partially or wholly synthetic, anionic or, preferably, nonionic hydrophilic rubbers, modified cellulose or proteinaceous substances such as, for example, acacia gum, tragacanth gum, locust bean gum, guar gum, karaya gum, , carrageenan, soluble and insoluble alginates, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, sodium * carboxymethylcellulose, carboxypolymethylene and gelatin.
Foretrukne stoffer er cellulosehydrokolloider, som omfatter methyl-10 cellulose, hydroxypropylcellulose og især hydroxypropylmethylcellulo-se og natriumcarboxymethylcellulose.Preferred substances are cellulose hydrocolloids which include methyl cellulose, hydroxypropyl cellulose and especially hydroxypropyl methyl cellulose and sodium carboxymethyl cellulose.
Fortrinsvis er vægtforholdet mellem darodipin og det kvældbare stof 1:0,2-1:2, især 1:0,5-1, og isradipin og det kvældbare stof 1:2-1:20, især 1:4-1:10.Preferably, the weight ratio of darodipine to the swellable substance is 1: 0.2-1: 2, especially 1: 0.5-1, and isradipine and the swellable substance is 1: 2-1: 20, especially 1: 4-1: 10. .
15 Egnede farmaceutisk acceptable inerte fedtholdige materialer omfatter bivoks; fedtsyrer; langkædede fedtalkoholer som fx cetylalkohol, myristylalkohol, stearylalkohol, estere, fx glycerider såsom glyce-rylestere af fedtsyrer eller hydrogenerede aliphatiske syrer såsom fx glycerylmonostearat, glyceryldistearat, glycerylestere af hydroge-20 neret ricinusolie og lignende; olier såsom mineralolier og lignende.Suitable pharmaceutically acceptable inert fatty materials include beeswax; fatty acids; long chain fatty alcohols such as, for example, cetyl alcohol, myristyl alcohol, stearyl alcohol, esters, e.g., glycerides such as glyceryl esters of fatty acids or hydrogenated aliphatic acids such as, for example, glyceryl monostearate, glyceryl distearate, glyceryl esters of hydrogenated castor oil and the like; oils such as mineral oils and the like.
Fedtholdige materialer er fortrinsvis sådanne med smeltepunkter mellem 30 og 90°C.Greasy materials are preferably those with melting points between 30 and 90 ° C.
De fleste foretrukne fedtholdige materialer har et smeltepunkt på 45-65°C og omfatter glycerider såsom glycerylpalmitater og -stearater 25 og fedtsyrer såsom hydrogeneret ricinusolie og fedtsyreestere såsom cetylpalmitat.Most preferred fatty materials have a melting point of 45-65 ° C and include glycerides such as glyceryl palmitate and stearate 25 and fatty acids such as hydrogenated castor oil and fatty acid esters such as cetyl palmitate.
Fortrinsvis er vægtforholdet mellem darodipin og det fedtholdige i materiale 10:0,2-10:5, især 10:0,5-10:1, og mellem isradipin og det fedtholdige materiale 1:0,3-1:2, især 1:0,5-1:1,5, fortrinsvis 1:0,5-30 1:1.Preferably, the weight ratio of darodipine to fat in material is 10: 0.2-10: 5, especially 10: 0.5-10: 1, and between isradipine and fatty material is 1: 0.3-1: 2, especially 1 : 0.5-1: 1.5, preferably 1: 0.5-30 1: 1.
Præparaterne indeholder fortrinsvis både hydroxypropylmethylcellulose 5 DK 170016 B1 som det kvældbare middel og cetylpalmitat som det fedtholdige materiale.The compositions preferably contain both hydroxypropyl methylcellulose as the swellable agent and cetyl palmitate as the fatty material.
Det er også hensigtsmæssigt i præparatet at inkorporere mindst én af andre opløselige eller uopløselige farmaceutiske excipienser såsom 5 calciumsulfat, calciumphosphat, lactose, mannitol, saccharose, sorbitol, kolloidt siliciumdioxid og magnesiumstearat. Fortrinsvis er en opløselig excipiens, især lactose, til stede. Hvis disse andre excipienser er til stede, er vægtforholdet mellem darodipin og de øvrige excipienser hensigtsmæssigt 10:1-10:2, især 5:1-1:1, og mellem isra-10 dipin og de øvrige excipienser 1:4-1:15, især 1:5-1:10.It is also convenient to incorporate in the composition at least one of other soluble or insoluble pharmaceutical excipients such as calcium sulfate, calcium phosphate, lactose, mannitol, sucrose, sorbitol, colloidal silica and magnesium stearate. Preferably, a soluble excipient, especially lactose, is present. If these other excipients are present, the weight ratio of darodipine to the other excipients is suitably 10: 1-10: 2, especially 5: 1-1: 1, and between isra-10 dipine and the other excipients 1: 4-1: 15, especially 1: 5-1: 10.
Formuleringen kan fremstilles på konventionel måde ved sammenblanding af bestanddelene, fortrinsvis ved smeltning af det fedtholdige materiale. Den resulterende blanding er i pulverform. Pulveret kan presses til en tablet, men fyldes fortrinsvis i en kapsel.The formulation can be prepared in a conventional manner by mixing the ingredients, preferably by melting the fatty material. The resulting mixture is in powder form. The powder can be pressed into a tablet, but preferably filled into a capsule.
15 Hvis det fedtholdige materiale er smeltet, kan lægemidlet og yderligere excipienser såsom lactose, siliciumdioxid, calciumsulfat eller calciumphosphat optages i det smeltede fedtholdige materiale. Blandingen lades derefter størkne og deles derefter i små partikler (granuler).If the fatty material is molten, the drug and additional excipients such as lactose, silica, calcium sulfate or calcium phosphate may be taken up in the molten fatty material. The mixture is then allowed to solidify and then divided into small particles (granules).
20 Det resulterende granulat kan blandes med et fortrinsvis porøst hydrofilt kvældbart stof og yderligere excipienser, fx magnesiumstea-rat, og blandingen kan presses til en tablet eller kan fortrinsvis fyldes i en kapsel.The resulting granule may be mixed with a preferably porous hydrophilic swellable substance and additional excipients, e.g., magnesium stearate, and the mixture may be compressed into a tablet or preferably filled into a capsule.
I et foretrukket aspekt angår den foreliggende opfindelse således et 25 præparat, der indeholder det aktive stof i et matrixgranulat af et fedtholdigt materiale, idet granulatpartiklerne er i kontakt med et hydrofilt kvældbart stof.Thus, in a preferred aspect, the present invention relates to a composition containing the active substance in a matrix granule of a fatty material, the granulate particles being in contact with a hydrophilic swellable substance.
Det kvældbare stof foreligger fortrinsvis i porøs form.The swellable substance is preferably in porous form.
Det har overraskende vist sig, at præparaterne har en fortræffelig 30 stabilitet på trods af, at de aktive stoffer er følsomme over for mange kemiske reagenser. Endvidere har præparaterne en tilfredsstil- DK 170016 B1 e lende farmakodynamisk og farmakokinetisk profil. De resulterende præparater har generelt en biotilgængelighed i kliniske standardforsøg, som er sammenlignelig med konventionelle præparater uden forlænget afgivelse, som indeholder de samme mængder aktivstoffer. Selv 5 hvis præparaterne administreres én gang daglig, kan de give en terapeutisk virkning i mindst 24 timer og endog i så meget som 35 timer.Surprisingly, it has been found that the compositions have excellent stability despite the fact that the active substances are sensitive to many chemical reagents. Furthermore, the compositions have a satisfactory pharmacodynamic and pharmacokinetic profile. The resulting compositions generally have bioavailability in standard clinical trials comparable to conventional prolonged-release preparations containing the same amounts of active substances. Even if the compositions are administered once daily, they can provide a therapeutic effect for at least 24 hours and even for as much as 35 hours.
Darodipin- og isradipinpræparaterne kan administreres kun én gang om * dagen ved de kendte indikationer for de aktive stoffer med omtrentlig samme daglige doser, som anvendes i de konventionelle former uden 10 forlænget afgivelse. "Steady-state"-undersøgelser viser et snævert område mellem de maksimale og minimale niveauer af aktivt stof i blodet.The darodipine and isradipine preparations can be administered only once a day by the known indications for the active substances at approximately the same daily doses used in the conventional forms without prolonged release. "Steady-state" studies show a narrow range between the maximum and minimum levels of active substance in the blood.
Præparaterne ifølge opfindelsen tåles godt.The compositions of the invention are well tolerated.
Endvidere udviser præparaterne ifølge opfindelsen lignende aktivi-15 tetsprofiler i fødeinteraktionsundersøgelser, fx før og efter indtagelse af morgenmad, med fastende forsøgspersoner.Furthermore, the compositions of the invention exhibit similar activity profiles in food interaction studies, e.g., before and after breakfast, with fasting subjects.
Præparaterne til administration én gang dagligt kan formuleres på konventionel måde, fx til en kapsel eller tablet, og kan indeholde 10-200 mg aktivt stof. De har fortrinsvis en afgivelsesprofil som 20 bestemt ved in vivo- eller in vitro-opløsningstest, fx en afgivelse af ca. 34% darodipin og 50-65% isradipin i løbet af 6 timer i 0,1 NHC1, fx under de i eksemplerne anførte forsøgsbetingelser.The once-daily administration formulations may be formulated in a conventional manner, e.g., into a capsule or tablet, and may contain 10-200 mg of active ingredient. They preferably have a release profile as determined by in vivo or in vitro dissolution tests, e.g. 34% darodipine and 50-65% isradipine over 6 hours in 0.1 NHC1, for example under the experimental conditions set forth in the Examples.
I nedenstående eksempler er alle temperaturer ukorrigerede.In the examples below, all temperatures are uncorrected.
Yderligere information om egenskaberne, etc. hos nedenstående farma-25 ceutiske excipienser kan fås fra fabrikanten, der er angivet nedenfor, salgsbrochurer eller andre kilder, især H.P. Fiedler Lexikon der Hilfstoffe fur Pharmazie, Kosmetik und angrenzende Gébiete, 2. ud-gave, 1981, Edito Cantor, Aulendorf, Vesttyskland.Further information on the properties, etc. of the pharmaceutical excipients below can be obtained from the manufacturer listed below, sales brochures or other sources, especially H.P. Fiedler Lexikon der Hilfstoffe fur Pharmazie, Cosmetics and adjoining Gébiete, 2nd edition, 1981, Edito Cantor, Aulendorf, West Germany.
Siliciumdioxid er fx mærket Aerosil 200, som fås fra Deutsche-Gold 30 und Silberscheideanstalt, Frankfurt, Vesttyskland.For example, silicon dioxide is the brand Aerosil 200, which is available from Deutsche-Gold 30 und Silberscheideanstalt, Frankfurt, West Germany.
7 DK 170016 B17 DK 170016 B1
Glycerolditripalmitostearat er fx mærket Precirol Ato 5, som fås fra ETS Gattefosse 929100 Boulogne-Brillancourt, Frankrig.For example, glycerol dithripalmito stearate is labeled Precirol Ato 5, available from ETS Gattefosse 929100 Boulogne-Brillancourt, France.
Hydroxypropylmethylcellulose 15000 cps og 4000 cps er fx mærkerne Methocel K15M og Methocel 4EM, som fås fra Dow Chemical Company, 5 Michigan 48640, USA.For example, hydroxypropyl methyl cellulose 15000 cps and 4000 cps are the Methocel K15M and Methocel 4EM labels available from the Dow Chemical Company, Michigan, 48640, USA.
Cetylpalmitat er fx mærket Cutina CPA, som fås fra Henkel 4000,Cetyl palmitate is, for example, the brand Cutina CPA, which is available from Henkel 4000,
Dusseldorf, Vesttyskland, fra Gattefosse, eller fra A/S Johan C.Dusseldorf, West Germany, from Gattefosse, or from A / S Johan C.
Martens & Company, Bergen, Norge.Martens & Company, Bergen, Norway.
EKSEMPEL 1 10 Bestanddel mg a) Darodipin 100 b) Lactose (200 mesh, 0,074 mm) 30 c) Cetylpalmitat 8 d) Hydroxypropylmethylcellulose 15 (100.000 cps) 60 e) Magnesiumstearat 2 200EXAMPLE 1 Component mg a) Darodipine 100 b) Lactose (200 mesh, 0.074 mm) c) Cetyl palmitate 8 d) Hydroxypropyl methylcellulose 15 (100,000 cps) 60 e) Magnesium stearate 2 200
Fremstilling 20 Bestanddelene a) og b) sigtes og blandes. Bestanddel c) smeltes ved opvarmning til 60°C og sættes til blandingen, som opvarmes til 55eC.Preparation 20 The ingredients a) and b) are sieved and mixed. Component c) is melted by heating to 60 ° C and added to the mixture which is heated to 55 ° C.
Massen omrøres i 2 minutter, eller indtil den er en homogen blanding, og afkøles natten over. Den størknede masse brydes i stykker og sigtes (gennem 250 /zm åbninger). Bestanddele d) og e) sigtes (gennem 25 360 μτα åbninger) og tilblandes i løbet af 10 minutter. Blandingen hældes derefter i kapsler.The mass is stirred for 2 minutes or until it is a homogeneous mixture and cooled overnight. The solidified mass is broken and sieved (through 250 µm apertures). Ingredients d) and e) are sieved (through 25 360 μτα apertures) and mixed over 10 minutes. The mixture is then poured into capsules.
8 DK 170016 B18 DK 170016 B1
In vitro-afgivelseIn vitro delivery
Tid (timer) Afgivelse af darodipin 1 7 2 14 5 4 25 6 34 24 97 EKSEMPEL 2 Kapsel 10 Bestanddele mg a) Isradipin 10 b) Lactose 97 c) Glycerol-ditripalmitostearat 10 d) Hydroxypropylmethyl- 15 cellulose (4000 cps) 60 e) Siliciumdioxid 1 f) Magnesiumstearat 2 180 20 Fremstilling (portion på 6000 kapsler)Time (hours) Delivery of Darodipine 1 7 2 14 5 4 25 6 34 24 97 EXAMPLE 2 Capsule 10 Ingredients mg a) Isradipine 10 b) Lactose 97 c) Glycerol-ditripalmitostearate 10 d) Hydroxypropylmethyl cellulose (4000 cps) 60 e ) Silicon dioxide 1 f) Magnesium stearate 2 180 20 Preparation (6000 capsule portion)
Bestanddelene a) og b) sigtes og blandes. Bestanddel c) smeltes ved opvarmning til 56°C (smeltepunkt 54°C) og sættes til blandingen, der opvarmes til 55°C. Massen omrøres i 2 minutter, eller indtil den er en homogen blanding, og afkøles natten over. Den størknede masse 25 brydes i stykker og sigtes (gennem 250 jum åbninger). Bestanddelene d), e) og f) sigtes (gennem 360 /im åbninger) og tilblandes i løbet af 10 minutter. Blandingen hældes derefter i kapsler.The ingredients a) and b) are sieved and mixed. Component c) is melted by heating to 56 ° C (melting point 54 ° C) and added to the mixture which is heated to 55 ° C. The mass is stirred for 2 minutes or until it is a homogeneous mixture and cooled overnight. The solidified mass 25 is broken and sieved (through 250 µm openings). Ingredients d), e) and f) are sieved (through 360 µm openings) and mixed in 10 minutes. The mixture is then poured into capsules.
9 DK 170016 B19 DK 170016 B1
In vitro-afgivelseIn vitro delivery
Tid (timer) Afgivelse, % 1 ii 2 19 5 4 43 6 64 24 102 EKSEMPEL 3 Kapsel 10 Bestanddele mg a) Isradipin 10 b) Mikrokrystallinsk cellulose 97 c) Cetylpalmitat 5 d) Hydroxypropylmethyl- 15 cellulose (4000 cps) 45 e) Siliciumdioxid 1 f) Magnesiumstearat 2 160 20 Fremstilling På analog måde med det i eksempel 6 beskrevne In vitro-afgivelseTime (hours) Release,% 1 ii 2 19 5 4 43 6 64 24 102 EXAMPLE 3 Capsule 10 Ingredients mg a) Isradipine 10 b) Microcrystalline cellulose 97 c) Cetyl palmitate 5 d) Hydroxypropylmethyl cellulose (4000 cps) 45 e) Silicon dioxide 1 f) Magnesium stearate 2 160 20 Preparation By analogy with the in vitro release described in Example 6
Tid (timer) Afgivelse, % 1 11 25 2 20 4 36 6 52 24 96 10 DK 170016 B1 EKSEMPEL 4 KapselTime (hours) Delivery,% 1 11 25 2 20 4 36 6 52 24 96 10 DK 170016 B1 EXAMPLE 4 Capsule
Bestanddele mg ' a) Isradipin 10 * 5 b) Mikrokrystallinsk cellulose 47 c) Cetylpalmitat 10 d) Hydroxypropylmethyl- cellulose (15000 cps) 90 e) Siliciumdioxid 1 10 f) Magnesiumstearat 2 160 I en klinisk test havde præparatet ifølge eksempel 8 en særdeles god retard-profil og relativ biotilgængelighed hos fastende og ikke-fas-15 tende forsøgspersoner sammenlignet med ikke-retardkapsler, som indeholdt den samme mængde isradipin.Ingredients mg a) Isradipine 10 * 5 b) Microcrystalline cellulose 47 c) Cetyl palmitate 10 d) Hydroxypropyl methyl cellulose (15000 cps) 90 e) Silicon dioxide 1 10 f) Magnesium stearate 2 160 In a clinical test, the preparation of Example 8 had a very good retard profile and relative bioavailability in fasting and non-fasting subjects compared to non-retard capsules containing the same amount of isradipine.
Fremstilling På analog måde med det i eksempel 6 beskrevne.Preparation By analogy with that described in Example 6.
In vivo-afgivelseIn vivo delivery
20 I en undersøgelse til bedømmelse af biotilgængeligheden af kapslen ifølge eksempel 8, blev denne kapsel og en sammenligningskapsel indeholdende isradipin i en form uden forlænget afgivelse administreret til fastende forsøgspersoner. Kapslen med forlænget afgivelse blev endvidere administreret til ikke-fastende forsøgspersoner. TIn a study to assess the bioavailability of the capsule of Example 8, this capsule and a comparison capsule containing isradipine in a prolonged-release form were administered to fasting subjects. The prolonged-release capsule was further administered to non-fasting subjects. T
25 Sammensætningen af den konventionelle sammenligningskapsel indehol- t dende isradipin i en form uden forlænget afgivelse var som følger: 11 DK 170016 B1The composition of the conventional comparator capsule containing isradipine in a form without prolonged delivery was as follows: 11 DK 170016 B1
Bestanddele mg a) Isradipin 10 b) Lactose 167 c) Majsstivelse 128 5 d) Natriumlaurylsulfat 5,5 e) Siliciumdioxid 1,5 f) Polyethylenglycol 6000 8,0 I undersøgelsen blev der anvendt en "open-label" trevejs randomiseret kryds-forsøgsudformning på ni sunde frivillige mandlige forsøgsper-10 soner. Forsøgspersonerne modtog en enkelt oral dosis af enten en sammenligningskapsel uden forlænget afgivelse (10 mg) i fastende tilstand eller en kapsel med forlænget afgivelse ifølge eksempel 18 (10 mg) i fastende og i ikke-fastende tilstand. Intervallerne mellem de tre forskellige administrationsperioder var mindst 7 dage.Ingredients mg a) Isradipine 10 b) Lactose 167 c) Corn starch 128 5 d) Sodium lauryl sulfate 5.5 e) Silicon dioxide 1.5 f) Polyethylene glycol 6000 8.0 The study used an "open-label" three-way randomized cross-trial design on nine healthy volunteer male probation-10 zones. Subjects received a single oral dose of either a prolonged-release comparator (10 mg) in the fasted state or a prolonged-release capsule according to Example 18 (10 mg) in the fasted and non-fasted state. The intervals between the three different administration periods were at least 7 days.
15 Blodprøver fra hver forsøgsperson blev indsamlet 0-48 timer efter hver dosis, og plasmaet blev analyseret for isradipin under anvendelse af en RIA-teknik (detektionsgrænse 0,1 nanogram/ml).15 Blood samples from each subject were collected 0-48 hours after each dose and the plasma was analyzed for isradipine using a RIA technique (detection limit 0.1 nanogram / ml).
De gennemsnitlige tidsbestemte plasmakoncentrationsdata er vist grafisk i fig. 1, hvor 20 · =10 mg kapsel med forlænget afgivelse i fastende tilstand, O = 10 mg kapsel med forlænget afgivelse i ikke-fastende til stand og Δ = 10 mg af en konventionel kapsel uden forlænget afgivelse.The mean timed plasma concentration data are shown graphically in FIG. 1, where 20 · = 10 mg prolonged-release capsule in the fasted state, O = 10 mg prolonged-release non-fasting capsule and Δ = 10 mg of a conventional non-prolonged-release capsule.
Plasmakoncentrationen er i nanogram/ml mod tiden i timer.Plasma concentration is in nanograms / ml against time in hours.
12 DK 170016 B112 DK 170016 B1
Ud fra kurverne beregnes følgende data:The following data is calculated from the curves:
Kapsler med for- Kapsler med for- Sammenligningslænget afgivelse længet afgivelse tabletter (10 mg), ikke- (10 mg), (10 mg), 5 fastende tilstand fastende tilstand fastende tilstand i AUC4q 34,73 34,67 49,65 i ng time/ml < 10 C 3,70 1,77 14,22 .max . i i ng/ml T 8,55 9 1,89 (iatimer) 15 _Capsules with for- Capsules with for- Comparative prolonged release prolonged release tablets (10 mg), non- (10 mg), (10 mg), 5 fasting state fasting state fasting state in AUC4q 34.73 34.67 49.65 in ng hour / ml <10 C 3.70 1.77 14.22 .max. T in 8.55 9 1.89 (in hours) 15
Geometrisk gennemsnit for n = 9 forsøgspersonerGeometric mean for n = 9 subjects
Λ OΛ Oh
AUC g = areal under kurven fra 0 til 48 timer.AUC g = area under the curve from 0 to 48 hours.
Sammenlignet med sammenligningsformen er den relative biotilgængelighed over 65%.Compared to the comparative form, the relative bioavailability is over 65%.
20 EKSEMPEL 5EXAMPLE 5
Kapsel (uden fedtholdigt stof)Capsule (without fatty substance)
Bestanddele mgIngredients mg
Isradipin 10Isradipine 10
Mikrokrystallinsk cellulose 57 25 Hydroxypropylmethyl- cellulose (4000 cps) 90Microcrystalline cellulose 57 Hydroxypropylmethyl cellulose (4000 cps) 90
Siliciumdioxid 1Silicon dioxide 1
Magnesiumstearat 2 " 5 30 160 i· 13 DK 170016 B1 EKSEMPEL 6Magnesium stearate 2 "5 30 160 i · 13 DK 170016 B1 EXAMPLE 6
Tablet (uden fedtholdigt stof)Tablet (without fatty substance)
Bestanddele mgIngredients mg
Isradipin 10 5 Lactose 287Isradipine 10 5 Lactose 287
Hydroxypropylmethyl-cellulose (15000 cps) 30Hydroxypropyl methyl cellulose (15000 cps) 30
Hydroxypropyl- methylcellulose (4000 cps) 45 10 Polyvinylpyrrolidon 20Hydroxypropylmethyl cellulose (4000 cps) 45 Polyvinylpyrrolidone 20
Siliciumdioxid 4Silica 4
Magnesiumstearat 4 400 15 EKSEMPEL 7Magnesium stearate 4,400 EXAMPLE 7
Kapselcapsule
Bestanddele mgIngredients mg
Isradipin 2,5Isradipine 2.5
Mikrokrystallinsk cellulose 54,5 20 Hydroxypropylmethyl- cellulose (4000 cps) 90,0Microcrystalline cellulose 54.5 Hydroxypropylmethyl cellulose (4000 cps) 90.0
Siliciumdioxid 1,0Silicon dioxide 1.0
Magnes iums tearat 2,0Magnes iums tearate 2.0
Cetylpalmitat 10,0 25 - 160,0Cetyl palmitate 10.0 - 160.0
Claims (8)
Applications Claiming Priority (10)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8524135 | 1985-10-01 | ||
| GB858524135A GB8524135D0 (en) | 1985-10-01 | 1985-10-01 | Darodipine compositions |
| GB858524653A GB8524653D0 (en) | 1985-10-07 | 1985-10-07 | Pharmaceutical formulations |
| GB8524653 | 1985-10-07 | ||
| GB858531419A GB8531419D0 (en) | 1985-12-20 | 1985-12-20 | Pindolol compositions |
| GB8531419 | 1985-12-20 | ||
| GB8603097 | 1986-02-07 | ||
| GB868603097A GB8603097D0 (en) | 1986-02-07 | 1986-02-07 | Pharmaceutical formulations |
| GB868605037A GB8605037D0 (en) | 1986-02-28 | 1986-02-28 | Oral pharmaceutical compositions |
| GB8605037 | 1986-02-28 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK464686D0 DK464686D0 (en) | 1986-09-29 |
| DK464686A DK464686A (en) | 1987-04-02 |
| DK170016B1 true DK170016B1 (en) | 1995-05-01 |
Family
ID=27516617
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK464686A DK170016B1 (en) | 1985-10-01 | 1986-09-29 | Composition with controlled release of the active substance |
Country Status (20)
| Country | Link |
|---|---|
| KR (1) | KR920008817B1 (en) |
| AT (1) | AT402257B (en) |
| BE (1) | BE905516A (en) |
| CA (1) | CA1298784C (en) |
| CH (1) | CH669524A5 (en) |
| DE (1) | DE3632201C2 (en) |
| DK (1) | DK170016B1 (en) |
| ES (1) | ES2002508A6 (en) |
| FR (1) | FR2589732B1 (en) |
| GR (1) | GR862457B (en) |
| HK (1) | HK392A (en) |
| HU (1) | HU197201B (en) |
| IE (1) | IE59589B1 (en) |
| IL (1) | IL80182A (en) |
| LU (1) | LU86615A1 (en) |
| NL (1) | NL194822C (en) |
| NZ (1) | NZ217732A (en) |
| PT (1) | PT83456B (en) |
| SE (1) | SE503222C2 (en) |
| SG (1) | SG103391G (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6440457B1 (en) | 1993-05-27 | 2002-08-27 | Alza Corporation | Method of administering antidepressant dosage form |
| EP1383496B1 (en) * | 2001-02-20 | 2008-10-01 | Dinan, Timothy Gerard | Treatment of fibromyalgia using pindolol |
| TW200616681A (en) * | 2004-10-05 | 2006-06-01 | Recordati Ireland Ltd | Lercanidipine capsules |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH630257A5 (en) * | 1975-03-17 | 1982-06-15 | Hoffmann La Roche | Sustained release formulation |
| CH639659A5 (en) * | 1978-12-18 | 1983-11-30 | Sandoz Ag | NEW 1,4-DIHYDROPYRIDINE DERIVATIVES, THEIR PRODUCTION AND USE. |
| DD145004A3 (en) * | 1978-09-25 | 1980-11-19 | Reinhard Huettenrauch | METHOD FOR PRODUCING SOLID A NOMENCLATES |
| CA1146866A (en) * | 1979-07-05 | 1983-05-24 | Yamanouchi Pharmaceutical Co. Ltd. | Process for the production of sustained release pharmaceutical composition of solid medical material |
| JPS6056122B2 (en) * | 1980-05-21 | 1985-12-09 | 塩野義製薬株式会社 | sustained release formulation |
| GB2084017B (en) * | 1980-09-18 | 1984-08-22 | Sandoz Ltd | Pharmaceutical compositions effective against coronary heat disease and hypertension |
| US4369172A (en) * | 1981-12-18 | 1983-01-18 | Forest Laboratories Inc. | Prolonged release therapeutic compositions based on hydroxypropylmethylcellulose |
| CA1208558A (en) * | 1982-10-07 | 1986-07-29 | Kazuo Kigasawa | Soft buccal |
| GB2154874B (en) * | 1984-02-29 | 1987-11-04 | Sandoz Ltd | Bromoscriptine compositions |
| KR850700212A (en) * | 1984-03-21 | 1985-12-26 | 죠지 드모트 | Sustained Release Pharmaceutical Wexel |
| JPS6124516A (en) * | 1984-07-12 | 1986-02-03 | Fujisawa Pharmaceut Co Ltd | Long active tablet |
-
1986
- 1986-09-19 HU HU864004A patent/HU197201B/en unknown
- 1986-09-19 NL NL8602370A patent/NL194822C/en not_active IP Right Cessation
- 1986-09-22 CH CH3780/86A patent/CH669524A5/de not_active IP Right Cessation
- 1986-09-23 DE DE3632201A patent/DE3632201C2/en not_active Expired - Lifetime
- 1986-09-29 NZ NZ217732A patent/NZ217732A/en unknown
- 1986-09-29 GR GR862457A patent/GR862457B/en unknown
- 1986-09-29 IL IL80182A patent/IL80182A/en not_active IP Right Cessation
- 1986-09-29 IE IE256586A patent/IE59589B1/en not_active IP Right Cessation
- 1986-09-29 PT PT83456A patent/PT83456B/en unknown
- 1986-09-29 SE SE8604112A patent/SE503222C2/en not_active IP Right Cessation
- 1986-09-29 DK DK464686A patent/DK170016B1/en not_active IP Right Cessation
- 1986-09-29 KR KR1019860008136A patent/KR920008817B1/en not_active IP Right Cessation
- 1986-09-29 CA CA000519302A patent/CA1298784C/en not_active Expired - Lifetime
- 1986-09-30 ES ES8602313A patent/ES2002508A6/en not_active Expired
- 1986-09-30 LU LU86615A patent/LU86615A1/en unknown
- 1986-09-30 BE BE1/011554A patent/BE905516A/en not_active IP Right Cessation
- 1986-09-30 AT AT0260486A patent/AT402257B/en not_active IP Right Cessation
- 1986-10-01 FR FR868613668A patent/FR2589732B1/en not_active Expired
-
1991
- 1991-12-04 SG SG1033/91A patent/SG103391G/en unknown
-
1992
- 1992-01-02 HK HK3/92A patent/HK392A/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| SE8604112L (en) | 1987-04-02 |
| HU197201B (en) | 1989-03-28 |
| ATA260486A (en) | 1996-08-15 |
| PT83456B (en) | 1989-05-12 |
| HUT44701A (en) | 1988-04-28 |
| IL80182A0 (en) | 1986-12-31 |
| DE3632201C2 (en) | 1997-05-07 |
| KR870003777A (en) | 1987-05-04 |
| GR862457B (en) | 1987-01-29 |
| BE905516A (en) | 1987-03-30 |
| PT83456A (en) | 1986-10-01 |
| NZ217732A (en) | 1990-07-26 |
| NL194822B (en) | 2002-12-02 |
| DK464686D0 (en) | 1986-09-29 |
| CH669524A5 (en) | 1989-03-31 |
| KR920008817B1 (en) | 1992-10-09 |
| CA1298784C (en) | 1992-04-14 |
| AT402257B (en) | 1997-03-25 |
| SE503222C2 (en) | 1996-04-22 |
| DE3632201A1 (en) | 1987-04-02 |
| IE59589B1 (en) | 1994-03-09 |
| IL80182A (en) | 1991-01-31 |
| DK464686A (en) | 1987-04-02 |
| NL194822C (en) | 2003-04-03 |
| FR2589732A1 (en) | 1987-05-15 |
| ES2002508A6 (en) | 1988-08-16 |
| SG103391G (en) | 1992-01-17 |
| SE8604112D0 (en) | 1986-09-29 |
| IE862565L (en) | 1987-04-01 |
| HK392A (en) | 1992-01-10 |
| FR2589732B1 (en) | 1989-07-13 |
| LU86615A1 (en) | 1987-04-02 |
| NL8602370A (en) | 1987-05-04 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| B1 | Patent granted (law 1993) | ||
| PUP | Patent expired |