NO157368B - PROCEDURE FOR THE PREPARATION OF SOLID PHARMACEUTICAL PREPARATIONS CONTAINING NIFEDIPIN. - Google Patents
PROCEDURE FOR THE PREPARATION OF SOLID PHARMACEUTICAL PREPARATIONS CONTAINING NIFEDIPIN. Download PDFInfo
- Publication number
- NO157368B NO157368B NO812879A NO812879A NO157368B NO 157368 B NO157368 B NO 157368B NO 812879 A NO812879 A NO 812879A NO 812879 A NO812879 A NO 812879A NO 157368 B NO157368 B NO 157368B
- Authority
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- Norway
- Prior art keywords
- nifedipine
- preparation
- specific surface
- crystals
- preparations containing
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims description 27
- 238000000034 method Methods 0.000 title claims description 11
- 239000007787 solid Substances 0.000 title claims description 11
- 239000000825 pharmaceutical preparation Substances 0.000 title 1
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 claims description 30
- 229960001597 nifedipine Drugs 0.000 claims description 30
- 239000013078 crystal Substances 0.000 claims description 11
- 239000013543 active substance Substances 0.000 claims description 10
- 239000002775 capsule Substances 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- 239000000969 carrier Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 229920002472 Starch Polymers 0.000 claims description 3
- 239000008107 starch Substances 0.000 claims description 3
- 235000019698 starch Nutrition 0.000 claims description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- 235000019359 magnesium stearate Nutrition 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 claims description 2
- 239000007903 gelatin capsule Substances 0.000 claims 1
- 238000009472 formulation Methods 0.000 description 4
- 230000036470 plasma concentration Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 2
- 206010034972 Photosensitivity reaction Diseases 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000003973 paint Substances 0.000 description 2
- 230000036211 photosensitivity Effects 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000004438 BET method Methods 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 230000004531 blood pressure lowering effect Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229940126601 medicinal product Drugs 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
-
- 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
- A61P9/08—Vasodilators for multiple indications
-
- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Heart & Thoracic Surgery (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Cardiology (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Hydrogenated Pyridines (AREA)
Description
Oppfinnelsen vedrører fremgangsmåte til fremstilling av spesielle faste legemiddeltilberedninger inneholdende den kjente kretløpsvirksomme forbindelse nifedipin. The invention relates to a method for the production of special solid medicinal preparations containing the known circuit-active compound nifedipine.
Det er allerede kjent at forbindelsen nifedipin har meget sterke kretsløpspåvirkende virkninger (sammenlign britisk patent 1 173 862). Pga. nifedipins lysfølsomhet og tunge oppløselighet opptrer ved galenisk tilberedning av lege-middelspesialiter en rekke vanskeligheter, slik det fremgår av tallrike patent og patentsøknader for spesielle formuleringer av dette virksomme stoff. Således vedrører f.eks. US-patent 3 784 684 spesielle nifedipinholdige gelatin-bitekapsler, hvorved koronarvirkningen av nifedipin kan nyttes fordelaktig. I britisk patent 1 456 618 omtales videre faste legemiddeltilberedninger som likeledes sikrer en god biodisponerbarhet av nefedipin. Også i DT-OS 2 822 882 omtales faste legemiddelformer hvor det ved anvendelse av bestemte oppløsningsformidler og overflateaktive stoffer skal kompenseres for tungt oppløseligheten av nifedinpin. Også i europeisk Offenlegungsschrift 1 247 skal resorberbarheten av nifedipin forbedres ved anvendelse av polyetylenglykol og bestemte porøse bærestoffer. It is already known that the compound nifedipine has very strong circulatory effects (compare British patent 1 173 862). Because of. nifedipine's photosensitivity and heavy solubility present a number of difficulties in the galenic preparation of medical drug specialties, as is evident from numerous patents and patent applications for special formulations of this active substance. Thus, e.g. US Patent 3,784,684 special nifedipine-containing gelatin bite-sized capsules, whereby the coronary action of nifedipine can be advantageously used. In British patent 1 456 618 solid medicinal preparations are also mentioned which likewise ensure a good bioavailability of nefedipine. Also in DT-OS 2 822 882, solid pharmaceutical forms are mentioned where, by using specific solubilizers and surfactants, the poor solubility of nifedipine must be compensated for. Also in European Offenlegungsschrift 1 247, the resorbability of nifedipine is to be improved by the use of polyethylene glycol and certain porous carriers.
Alle tidligere forsøk på å kompensere den dårlige oppløse-lighet av nifedipin ved bestemte forholdsregler og samtidig å sikre en god biodisponerbarhet har en rekke ulemper. Anvendelsen av overflateaktive stoffer, oppløsningsfor-midlere og bestemte bærestoffer som har en spesiell overflate, f.eks. er porøse, fører hyppig til administrerings-former hvor preparatene er uønsket store. For å lette svelging overføres slike tabletter eller kapsler ofte i spesifikke former som f.eks. elypsolide eller langstrakte former, hvilket imidlertid ved preparat med en vekt over 400 mg heller ikke mer fører til tilfredsstillende resul-tater. Også den hyppige inntagning av mindre preparater er ingen tilfredsstillende løsning. All previous attempts to compensate for the poor solubility of nifedipine by certain precautions and at the same time to ensure good bioavailability have a number of disadvantages. The use of surface-active substances, solubilizers and specific carriers which have a special surface, e.g. are porous, often lead to forms of administration where the preparations are undesirably large. To facilitate swallowing, such tablets or capsules are often transferred in specific forms such as e.g. ellipsoidal or elongated forms, which, however, no longer leads to satisfactory results in the case of a preparation with a weight of more than 400 mg. The frequent intake of smaller preparations is also not a satisfactory solution.
For ]egemiddeltilberedningen gjelder at såvel tallet som også mengden av hjelpe- og bærestoffer skal holdes lavest mulig. Ved sammenligning av to legeir.iddelspesialiteter gir man all-tid det preparat fordelen som ved siden av det virksomme stoff inneholder minst mulig hjelpestoffer og tilsetnings-stoffer for mest mulig å unngå uønskede biologiske virkninger. For the preparation of the medicinal product, both the number and the quantity of excipients and carriers must be kept as low as possible. When comparing two medicinal specialties, the advantage is always given to the preparation which, in addition to the active substance, contains the least possible auxiliaries and additives in order to avoid undesirable biological effects as much as possible.
En ytterligere ulempe ved de hittil kjente nifedipinholdige preparater ligger i den omstendelige fremstillingsfremgangs-måten som spesielt gjelder for flytende tilberedninger og kapselpreparater. Nifedipins høye lysfølsomhet og tunge oppløselighet betinger omstendelige fremgangsmåteforholds-regler som spesielt ved flytende tilberedninger som lysbe-skyttelse krever utelukkelse av dagslys og anvendelse av natriumlys. A further disadvantage of the previously known nifedipine-containing preparations lies in the cumbersome manufacturing process, which particularly applies to liquid preparations and capsule preparations. Nifedipine's high photosensitivity and heavy solubility require elaborate process conditions which, especially in the case of liquid preparations as light protection, require the exclusion of daylight and the use of sodium light.
Oppfinnelsen vedrører altså en fremgangsmåte til fremstilling av faste legemiddeltilberedninger som inneholder nifedipinkrystaller, idet fremgangsmåten er karakterisert ved at nifedipinkrystaller dannet ved syntese males og/eller siktes ved vanlige metoder til en krystallblanding med spesifikk overflate 1-4 m 2/g, hvoretter disse nifedipinkrystallene etter vanlige metoder under anvendelse av hjelpe- og bærestoffer formuleres til faste legemiddeltilberedninger. The invention therefore relates to a method for the production of solid medicinal preparations containing nifedipine crystals, the method being characterized in that nifedipine crystals formed by synthesis are ground and/or sieved by conventional methods to a crystal mixture with a specific surface area of 1-4 m 2 /g, after which these nifedipine crystals after usual methods using excipients and carriers are formulated into solid medicinal preparations.
Som faste legemiddeltilberedninger skal det fortrinnsvis nevnes: tabletter, piller, drageer, kapsler, sakets og flerfasede preparater som f.eks. to-sjikt tabletter. The following should preferably be mentioned as solid medicinal preparations: tablets, pills, dragees, capsules, sachets and multi-phase preparations such as e.g. two-layer tablets.
Malingen kan f.eks. foregå med stiftmøller eller hammer-møller. Ved variasjon av møllens dreietall, den tilløp- The paint can e.g. take place with pin mills or hammer mills. By varying the mill's rotational speed, the accrual
ende produktmengde og/eller malingsvarighet kan nifedipin fremstilles med ønsket overflate. end product quantity and/or paint duration, nifedipine can be produced with the desired surface.
Den spesifikke overflate bestemmes etter gassadsorbsjons-metoden (BET-metode, sammenlign S. Brunauer: The Adsorption of Gases and Vapours, Princeton (1945)). The specific surface is determined according to the gas adsorption method (BET method, compare S. Brunauer: The Adsorption of Gases and Vapours, Princeton (1945)).
Overraskende viser de faste tilberedninger fremstilt ifølge oppfinnelsen en uventet høy biodisponerbarhet. I publika-sjonen av I.Sugomoto et al., Drug Development and Industrial Pharmacy, 6(2), 137-160/1980) betones uttrykkelig (s. 139) at nifedipin absorberes dårlig i krystallinsk form ved oral applikasjon og bare har en meget liten biodisponerbarhet. Det kunne derfor ikke ventes at etter oral applikasjon av tilberedningen fremstilt ifølge oppfinnelsen som inneholder krystallinsk nifedipin øker plasmakonsentrasjonen hurtig og holder seg over flere timer på en høy verdi. I tilfeller hvori nifedipin må inntas over lengere tidsrom er det på grunn av denne høye virkningsvarighet tilstrekkelig når det daglig appliseres en eller to tabletter. En ytterligere vesentlig fordel består i at meget små tabletter fremstilles med høyt virksomt stoffinnhold da det sterkt kan sees bort fra oppløsningsformidlere og overflateaktive stoffer og ekstra hjelpestoffer. Surprisingly, the solid preparations produced according to the invention show an unexpectedly high bioavailability. In the publication by I.Sugomoto et al., Drug Development and Industrial Pharmacy, 6(2), 137-160/1980) it is expressly emphasized (p. 139) that nifedipine is poorly absorbed in crystalline form upon oral application and only has a very low bioavailability. It could therefore not be expected that after oral application of the preparation prepared according to the invention which contains crystalline nifedipine, the plasma concentration increases rapidly and remains at a high value for several hours. In cases where nifedipine must be taken over a longer period of time, due to this high duration of action, it is sufficient when one or two tablets are applied daily. A further significant advantage consists in the fact that very small tablets are produced with a high active substance content, as solubilizers and surface-active substances and additional excipients can be largely disregarded.
Den uventede effekt med den lange virkningsvarighet er vesentlig for oppfinnelsen. I en deklarasjon av Eduard Porges er det påvist den overraskende "platåeffekt" av nifedipinkrystaller som anvendes ved fremgangsmåten ifølge oppfinnelsen til fremstilling av faste legemiddeltilberedninger. Med kjennskap til teknikkens stand ville man ha måttet vente at med økende spesifikk overflate, The unexpected effect with the long duration of action is essential for the invention. In a declaration by Eduard Porges, the surprising "plateau effect" of nifedipine crystals used in the method according to the invention for the production of solid medicinal preparations has been demonstrated. Knowing the state of the art, one would have had to expect that with increasing specific surface area,
dvs. med partikkelstørrelse som blir mindre, øker frigjør-ingsgraden. Videre var det for fagfolk å vente at virkningsvarigheten er lenger når det oppnås en høyere ut-gangskonsentrasjon av det virksomme stoff i plasma, da virkningsvarigheten utslagsgivende bestemmes ved metaboli-sering og eliminering. I en artikkel i tidsskriftet Clin. Pharmacol. Ther. volum 35, nr. 6, fra juni 1984, er dét av C.H. Kleinbloesem et al. vist at med de oralt i.e. with decreasing particle size, the degree of release increases. Furthermore, experts had to expect that the duration of action is longer when a higher initial concentration of the active substance is achieved in plasma, as the duration of action is decisively determined by metabolism and elimination. In an article in the journal Clin. Pharmacol. Ther. volume 35, no. 6, from June 1984, is that of C.H. Kleinbloesem et al. shown that with those orally
appliserte vanlige nifedipinkapsler oppnås riktignok et meget høyt plasmanivå som imidlertid etter 4-6 timer synker under det enda virksomme området. Ved applikasjon av tilberedningen fremstilt ifølge oppfinnelsen oppnås nå en mindre eller mykere økning av plasmakonsentrasjonen som imidlertid bibeholdes effektivt over mange timer. applied normal nifedipine capsules, it is true that a very high plasma level is achieved which, however, falls below the still effective range after 4-6 hours. When applying the preparation prepared according to the invention, a smaller or milder increase in the plasma concentration is now achieved, which is, however, effectively maintained over many hours.
Tablettenes små størrelser og den overraskende store virkningsvarighet av formuleringen fremstilt ifølge oppfinnelsen muliggjør at nifedipin kan anvendes til behandling av koronar sykdom over lengere tidsrom og også anvendes profil-aktisk og des"suten åpner disse formuleringer den mulighet å anvende en blodtrykksenkende virkning av nifedipin til behandling av hypertoni. Det ved formuleringen fremstilt ifølge oppfinnelsen oppnåelige langvarige blodspeil av det virksomme stoff er en utvidelse av de praktiske anvendelses-muligheter for nifedipin og betyr samtidig en lettelse for pasienten. The small sizes of the tablets and the surprisingly long duration of action of the formulation produced according to the invention make it possible for nifedipine to be used for the treatment of coronary disease over longer periods of time and also used prophylactically, and furthermore these formulations open up the possibility of using a blood pressure-lowering effect of nifedipine for treatment of hypertension.The long-term blood level of the active substance obtainable by the formulation produced according to the invention is an extension of the practical application possibilities for nifedipine and at the same time means relief for the patient.
Ved kjennskap til teknikkens stand hvorav det fremgår at fagverden i flere år har tilstrebet å finne brukbare til-beredningsformer for det vanskelig formulerbare virksomme stoff nifedipin er det å betegne som utpreget overraskende at ved valg av en spesifikk overflate av det virksomme stoff er det funnet et meget enkelt og virkningsfullt prinsipp til galenisk forarbeidelse. Knowing the state of the art, from which it appears that the professional world has for several years endeavored to find usable preparation forms for the difficult-to-formulate active substance nifedipine, it can be described as distinctly surprising that when choosing a specific surface of the active substance, a very simple and effective principle for galenic preparation.
De ifølge oppfinnelsen fremstilte faste tilberednings-former gir for pasienter en lettelse ved applikasjonen og øker samtidig sikringen for en behandling. The fixed preparation forms produced according to the invention provide patients with relief during application and at the same time increase the security for a treatment.
Til påvisning av den fordelaktige virkning av legemiddel-tilberedningen ifølge oppfinnelsen ble det ved hver gang 8.personer over flere timer etter applikasjon fastslått plasmakonsentrasjonen. Verdiene fremgår av følgende tabell: In order to demonstrate the beneficial effect of the medicinal preparation according to the invention, the plasma concentration was determined each time in 8th person over several hours after application. The values appear in the following table:
Oppfinnelsen skal forklares ved hjelp av følgende utførelses-eksempler. The invention will be explained with the help of the following design examples.
Eksemp_el_l Example_el_l
200 g nifedipinkrystaller med en spesifikk overflate på 200 g nifedipine crystals with a specific surface on
4 m 2/g blandes med 348 g mikrokrystallinsk cellulose, 4 m 2/g is mixed with 348 g of microcrystalline cellulose,
100 g laktose, 10 g "Tween 80", 70 g stivelse og 2 g magne-siumstearat. Av ytterligere 70 g stivelse fremstilles med vann på i og for seg kjent måte et klister som granuleres med ovennevnte blanding, vanligvis tørkes og deretter presses til tabletter med en enkeltvékt på 80 mg. Deretter markeres tablettene, de har en diameter på 6"mm. 100 g lactose, 10 g "Tween 80", 70 g starch and 2 g magnesium stearate. From a further 70 g of starch, a paste is prepared with water in a manner known per se, which is granulated with the above-mentioned mixture, usually dried and then pressed into tablets with an individual weight of 80 mg. The tablets are then marked, they have a diameter of 6" mm.
Til lakkering av 800 g tabletter benyttes f.eks. en suspen-sjon av For coating 800 g tablets, e.g. a suspension of
18 g hydroksypropylmetylcellulose 18 g of hydroxypropylmethylcellulose
6 g polyetylenglykol 6 g polyethylene glycol
5,4 g titandioksyd 5.4 g of titanium dioxide
0,6 : g jernoksyd 0.6 : g iron oxide
370 g vann eller etanol 370 g of water or ethanol
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19803033919 DE3033919A1 (en) | 1980-09-09 | 1980-09-09 | SOLID PHARMACEUTICAL PREPARATIONS CONTAINING NIFEDIPINE AND METHOD FOR THE PRODUCTION THEREOF |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NO812879L NO812879L (en) | 1982-03-10 |
| NO157368B true NO157368B (en) | 1987-11-30 |
Family
ID=6111496
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO812879A NO157368B (en) | 1980-09-09 | 1981-08-25 | PROCEDURE FOR THE PREPARATION OF SOLID PHARMACEUTICAL PREPARATIONS CONTAINING NIFEDIPIN. |
Country Status (20)
| Country | Link |
|---|---|
| EP (1) | EP0047899B2 (en) |
| JP (1) | JPS5914446B2 (en) |
| AR (1) | AR226377A1 (en) |
| AT (1) | ATE5761T1 (en) |
| AU (1) | AU558331B2 (en) |
| CA (1) | CA1180277A (en) |
| DD (1) | DD201974A5 (en) |
| DE (2) | DE3033919A1 (en) |
| DK (1) | DK154326C (en) |
| FI (1) | FI72648B (en) |
| GR (1) | GR78237B (en) |
| HU (1) | HU184879B (en) |
| IE (1) | IE51549B1 (en) |
| IL (1) | IL63749A (en) |
| NO (1) | NO157368B (en) |
| NZ (1) | NZ198285A (en) |
| PH (1) | PH24097A (en) |
| PL (1) | PL232951A1 (en) |
| PT (1) | PT73603B (en) |
| ZA (1) | ZA816213B (en) |
Families Citing this family (32)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5264446A (en) * | 1980-09-09 | 1993-11-23 | Bayer Aktiengesellschaft | Solid medicament formulations containing nifedipine, and processes for their preparation |
| JPS5846019A (en) * | 1981-09-14 | 1983-03-17 | Kanebo Ltd | Nifedipine preparation with prolonged action |
| DE3222367A1 (en) * | 1982-06-15 | 1983-12-15 | Bayer Ag, 5090 Leverkusen | Use of 1,4-dihydropyridines in antiarteriosclerotics and preparation thereof |
| JPS59101423A (en) * | 1982-12-02 | 1984-06-12 | Takada Seiyaku Kk | Novel solid pharmaceutical preparation of nifedipine |
| US4529733A (en) * | 1983-04-06 | 1985-07-16 | Merrell Dow Pharmaceuticals Inc. | Antihypertensive 3-furoyl-1,4-dihydropyridines |
| DE3318649A1 (en) * | 1983-05-21 | 1984-11-22 | Bayer Ag, 5090 Leverkusen | TWO-PHASE FORMULATION |
| HU198844B (en) * | 1984-06-14 | 1989-12-28 | Sandoz Ag | Process for producing new galenic pharmaceutical composition ensuring retarded release of active ingredient |
| IT1178511B (en) * | 1984-09-14 | 1987-09-09 | Pharmatec Spa | PROCEDURE FOR THE PREPARATION OF A SOLID FORM FOR ORAL USE BASED ON NIFEDIPINE WITH RELEASE |
| IT1187751B (en) * | 1985-10-15 | 1987-12-23 | Eurand Spa | PROCEDURE FOR THE PREPARATION OF SOLID FORMULATIONS OF NIFEDIPINE WITH HIGH BIO AVAILABILITY AND WITH PROLONGED EFFECT AND FORMULATIONS SO OBTAINED |
| US4940556A (en) * | 1986-01-30 | 1990-07-10 | Syntex (U.S.A.) Inc. | Method of preparing long acting formulation |
| US5198226A (en) * | 1986-01-30 | 1993-03-30 | Syntex (U.S.A.) Inc. | Long acting nicardipine hydrochloride formulation |
| CH673947A5 (en) * | 1986-09-23 | 1990-04-30 | Sandoz Ag | |
| JPS6464659A (en) * | 1987-09-03 | 1989-03-10 | Kenbi Kogaku Kenkyusho Kk | Preparation of safe and effective powder formulation |
| SE8703881D0 (en) * | 1987-10-08 | 1987-10-08 | Haessle Ab | NEW PHARMACEUTICAL PREPARATION |
| DE3814532A1 (en) * | 1988-04-29 | 1989-11-09 | Bayer Ag | DHP-RETARD-PREPARATION |
| JPH0298550U (en) * | 1989-01-25 | 1990-08-06 | ||
| GB8903328D0 (en) * | 1989-02-14 | 1989-04-05 | Ethical Pharma Ltd | Nifedipine-containing pharmaceutical compositions and process for the preparation thereof |
| US5271944A (en) * | 1991-04-05 | 1993-12-21 | Biofor, Ltd. | Pharmacologically enhanced formulations |
| DE4130173A1 (en) * | 1991-09-11 | 1993-03-18 | Bayer Ag | PHARMACEUTICAL PREPARATIONS WITH A SPECIAL CRYSTAL MODIFICATION OF 1,4-DIHYDRO-2,6-DIMETHYL-4- (3-NITROPHENYL) -3,5-PYRIDINDICARBONIC ACID ISOPROPYL- (2-METHOXYETHYL) ESTER |
| GB9200607D0 (en) * | 1992-01-13 | 1992-03-11 | Ethical Pharma Ltd | Pharmaceutical compositions containing nifedipine and process for the preparation thereof |
| US5455046A (en) * | 1993-09-09 | 1995-10-03 | Edward Mendell Co., Inc. | Sustained release heterodisperse hydrogel systems for insoluble drugs |
| US5773025A (en) * | 1993-09-09 | 1998-06-30 | Edward Mendell Co., Inc. | Sustained release heterodisperse hydrogel systems--amorphous drugs |
| US6726930B1 (en) | 1993-09-09 | 2004-04-27 | Penwest Pharmaceuticals Co. | Sustained release heterodisperse hydrogel systems for insoluble drugs |
| US5543099A (en) * | 1994-09-29 | 1996-08-06 | Hallmark Pharmaceutical, Inc. | Process to manufacture micronized nifedipine granules for sustained release medicaments |
| WO1996020707A1 (en) * | 1994-12-29 | 1996-07-11 | Dr. Rentschler Arzneimittel Gmbh & Co. | Pharmaceutical preparations containing nifedipine and process for producing it |
| JP3220373B2 (en) | 1995-11-28 | 2001-10-22 | バイエル薬品株式会社 | Long-acting nifedipine preparation |
| ATE417604T1 (en) | 1996-07-08 | 2009-01-15 | Penwest Pharmaceuticals Co | SUSTAINED RELEASE MATRIX FOR HIGH DOSE INSOLUBLE DRUGS |
| IT1284604B1 (en) * | 1996-09-27 | 1998-05-21 | Roberto Valducci | CONTROLLED RELEASE PHARMACEUTICAL COMPOSITIONS FOR ORAL ADMINISTRATION CONTAINING NIFEDIPINE AS THE ACTIVE SUBSTANCE |
| US6056977A (en) | 1997-10-15 | 2000-05-02 | Edward Mendell Co., Inc. | Once-a-day controlled release sulfonylurea formulation |
| CN1228043C (en) | 1999-09-30 | 2005-11-23 | 爱德华·孟岱尔股份有限公司 | Sustained release matrices for highly soluble drugs |
| DE602005007339D1 (en) | 2004-07-30 | 2008-07-17 | Torrent Pharmaceuticals Ltd | NEBIVOLOL AND ITS NON-PHARMACEUTICAL SALTS, METHOD OF MANUFACTURE AND PHARMACEUTICAL COMPOSITIONS OF NEBIVOLOL |
| DE102004062475A1 (en) * | 2004-12-24 | 2006-07-06 | Bayer Healthcare Ag | Solid, orally administrable, modified release pharmaceutical dosage forms |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3330727A (en) * | 1960-04-19 | 1967-07-11 | Glaxo Lab Ltd | Griseofulvin with high specific surface area |
| US3401221A (en) * | 1964-08-25 | 1968-09-10 | Norwich Pharma Co | Treatment of urinary tract infection |
| DE2348334C2 (en) * | 1973-09-26 | 1982-11-11 | Boehringer Mannheim Gmbh, 6800 Mannheim | New form of preparation of N-4- [2- (5-chloro-2-methoxybenzamido) ethyl] -phenyl-sulfonyl-N'-cyclohexylurea |
| DE2400819C2 (en) * | 1974-01-09 | 1982-04-22 | Bayer Ag, 5090 Leverkusen | Process for the production of solid preparations of poorly soluble active pharmaceutical ingredients in extremely fine distribution |
| GB1579818A (en) * | 1977-06-07 | 1980-11-26 | Yamanouchi Pharma Co Ltd | Nifedipine-containing solid preparation composition |
| JPS55129221A (en) * | 1979-03-29 | 1980-10-06 | Kaken Pharmaceut Co Ltd | Preparation of oral preparation containing hardly soluble medicine |
| 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 |
-
1980
- 1980-09-09 DE DE19803033919 patent/DE3033919A1/en not_active Ceased
- 1980-12-27 JP JP55185148A patent/JPS5914446B2/en not_active Expired
-
1981
- 1981-08-25 NO NO812879A patent/NO157368B/en unknown
- 1981-08-28 DE DE8181106729T patent/DE3161838D1/en not_active Expired
- 1981-08-28 AT AT81106729T patent/ATE5761T1/en not_active IP Right Cessation
- 1981-08-28 EP EP81106729A patent/EP0047899B2/en not_active Expired - Lifetime
- 1981-08-31 PH PH26121A patent/PH24097A/en unknown
- 1981-08-31 PT PT73603A patent/PT73603B/en unknown
- 1981-09-01 DD DD81232939A patent/DD201974A5/en not_active IP Right Cessation
- 1981-09-07 GR GR65968A patent/GR78237B/el unknown
- 1981-09-07 NZ NZ198285A patent/NZ198285A/en unknown
- 1981-09-07 IL IL63749A patent/IL63749A/en not_active IP Right Cessation
- 1981-09-07 FI FI812758A patent/FI72648B/en not_active Application Discontinuation
- 1981-09-08 AU AU75063/81A patent/AU558331B2/en not_active Expired
- 1981-09-08 PL PL23295181A patent/PL232951A1/xx unknown
- 1981-09-08 DK DK396381A patent/DK154326C/en not_active IP Right Cessation
- 1981-09-08 CA CA000385365A patent/CA1180277A/en not_active Expired
- 1981-09-08 ZA ZA816213A patent/ZA816213B/en unknown
- 1981-09-08 AR AR286686A patent/AR226377A1/en active
- 1981-09-08 IE IE2075/81A patent/IE51549B1/en not_active IP Right Cessation
- 1981-09-09 HU HU812594A patent/HU184879B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AU7506381A (en) | 1982-03-18 |
| IL63749A (en) | 1984-06-29 |
| PL232951A1 (en) | 1982-10-11 |
| ATE5761T1 (en) | 1984-01-15 |
| HU184879B (en) | 1984-10-29 |
| NO812879L (en) | 1982-03-10 |
| JPS5750913A (en) | 1982-03-25 |
| DK154326C (en) | 1995-03-13 |
| IL63749A0 (en) | 1981-12-31 |
| DE3161838D1 (en) | 1984-02-09 |
| EP0047899A1 (en) | 1982-03-24 |
| JPS5914446B2 (en) | 1984-04-04 |
| DK396381A (en) | 1982-03-10 |
| EP0047899B2 (en) | 1996-02-28 |
| FI812758L (en) | 1982-03-10 |
| PT73603A (en) | 1981-09-01 |
| IE51549B1 (en) | 1987-01-07 |
| DK154326B (en) | 1988-11-07 |
| IE812075L (en) | 1982-03-09 |
| PH24097A (en) | 1990-03-05 |
| CA1180277A (en) | 1985-01-02 |
| NZ198285A (en) | 1984-04-27 |
| AU558331B2 (en) | 1987-01-29 |
| DE3033919A1 (en) | 1982-04-22 |
| EP0047899B1 (en) | 1984-01-04 |
| AR226377A1 (en) | 1982-06-30 |
| ZA816213B (en) | 1982-09-29 |
| DD201974A5 (en) | 1983-08-24 |
| FI72648B (en) | 1987-03-31 |
| GR78237B (en) | 1984-09-26 |
| PT73603B (en) | 1982-11-10 |
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