NO841437L - PROCEDURE FOR THE PREPARATION OF ORAL DOSAGE FORMS OF MEDICINALLY ACTIVE 1,4-DIHYDROPYRIDINE DERIVATIVES - Google Patents
PROCEDURE FOR THE PREPARATION OF ORAL DOSAGE FORMS OF MEDICINALLY ACTIVE 1,4-DIHYDROPYRIDINE DERIVATIVESInfo
- Publication number
- NO841437L NO841437L NO841437A NO841437A NO841437L NO 841437 L NO841437 L NO 841437L NO 841437 A NO841437 A NO 841437A NO 841437 A NO841437 A NO 841437A NO 841437 L NO841437 L NO 841437L
- Authority
- NO
- Norway
- Prior art keywords
- nifedipine
- mixture
- medicinal substance
- preparation
- procedure
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 11
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical class C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 title claims description 6
- 238000002360 preparation method Methods 0.000 title description 6
- 239000006186 oral dosage form 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 18
- 229960001597 nifedipine Drugs 0.000 claims description 18
- 239000012907 medicinal substance Substances 0.000 claims description 16
- 150000005846 sugar alcohols Chemical class 0.000 claims description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- 239000000843 powder Substances 0.000 claims description 10
- 239000002775 capsule Substances 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 6
- 229930195725 Mannitol Natural products 0.000 claims description 6
- 239000000594 mannitol Substances 0.000 claims description 6
- 235000010355 mannitol Nutrition 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 5
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-GUCUJZIJSA-N galactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-GUCUJZIJSA-N 0.000 claims description 2
- 239000008240 homogeneous mixture Substances 0.000 claims description 2
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 239000000811 xylitol Substances 0.000 claims description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 2
- 235000010447 xylitol Nutrition 0.000 claims description 2
- 229960002675 xylitol Drugs 0.000 claims description 2
- NNJPGOLRFBJNIW-HNNXBMFYSA-N (-)-demecolcine Chemical compound C1=C(OC)C(=O)C=C2[C@@H](NC)CCC3=CC(OC)=C(OC)C(OC)=C3C2=C1 NNJPGOLRFBJNIW-HNNXBMFYSA-N 0.000 claims 1
- 239000002552 dosage form Substances 0.000 claims 1
- 239000000243 solution Substances 0.000 description 15
- 239000008187 granular material Substances 0.000 description 14
- 239000007903 gelatin capsule Substances 0.000 description 13
- 238000010521 absorption reaction Methods 0.000 description 7
- 238000004090 dissolution Methods 0.000 description 6
- 238000005469 granulation Methods 0.000 description 6
- 230000003179 granulation Effects 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 239000008186 active pharmaceutical agent Substances 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- 239000011230 binding agent Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 229940088679 drug related substance Drugs 0.000 description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000002270 dispersing agent Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 150000002148 esters Chemical group 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- ZQBAKBUEJOMQEX-UHFFFAOYSA-N phenyl salicylate Chemical compound OC1=CC=CC=C1C(=O)OC1=CC=CC=C1 ZQBAKBUEJOMQEX-UHFFFAOYSA-N 0.000 description 2
- 239000000049 pigment Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000009736 wetting Methods 0.000 description 2
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 238000003915 air pollution Methods 0.000 description 1
- 239000003945 anionic surfactant Substances 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 235000021552 granulated sugar Nutrition 0.000 description 1
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229960000969 phenyl salicylate Drugs 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- -1 polyoxyethylene stearate Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- RUOJZAUFBMNUDX-UHFFFAOYSA-N propylene carbonate Chemical compound CC1COC(=O)O1 RUOJZAUFBMNUDX-UHFFFAOYSA-N 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000007962 solid dispersion Substances 0.000 description 1
- WSWCOQWTEOXDQX-MQQKCMAXSA-N sorbic acid group Chemical group C(\C=C\C=C\C)(=O)O WSWCOQWTEOXDQX-MQQKCMAXSA-N 0.000 description 1
- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 1
- 229960002256 spironolactone Drugs 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- ZIBGPFATKBEMQZ-UHFFFAOYSA-N triethylene glycol Chemical compound OCCOCCOCCO ZIBGPFATKBEMQZ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
-
- 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
- A61K31/33—Heterocyclic compounds
- 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
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
Description
Denne oppfinnelse angår en fremgangsmåte som gjør det muligThis invention relates to a method which makes it possible
å fremstille fra 1,4-dihydropyridin-derivater stabile legemiddel-preparater somabsorberes godt fra fordøyelseskanalen. Det best kjente middel av de forbindelser som faller inn under de her om-talte forbindelser, er nifedipin, som er en kalsium-antagonist og virker som et koronar-terapeutisk middel og et anti-hyperten-sivt middel. På grunn av lysfølsomheten og den dårlige oppløse-lighet av nifedipin, er det vanskelig å tilberede gode farmasøy-tiske preparater fra denne. Denne vanskelighet vil klart fremgå av de tallrike patenter og patentansøkninger som angår dette stoff. Blant andre understreker publikasjonen I. Sugimoto et al. Drig Development and Industrial Pharmacy, 6 (62), 137-160 (1980) at nifedipin administrert oralt i fast form absorberes dårlig og at i slike tilfeller kan organismen utnytte den bare i mindre grad. to produce stable pharmaceutical preparations from 1,4-dihydropyridine derivatives which are well absorbed from the digestive tract. The best-known agent of the compounds that fall under the compounds mentioned here is nifedipine, which is a calcium antagonist and acts as a coronary therapeutic agent and an anti-hypertensive agent. Because of the sensitivity to light and the poor solubility of nifedipine, it is difficult to prepare good pharmaceutical preparations from it. This difficulty will be clear from the numerous patents and patent applications relating to this substance. Among others, the publication emphasizes I. Sugimoto et al. Drig Development and Industrial Pharmacy, 6 (62), 137-160 (1980) that nifedipine administered orally in solid form is poorly absorbed and that in such cases the organism can utilize it only to a lesser extent.
Det er gjort forsøk på å løse problemet med tilberedningAttempts have been made to solve the problem with preparation
av nifedipin-inneholdende legemidler på mange måter. Den løsning som er mest anvendt er sannsynligvis den hvor den aktive bestanddel i en flytende blanding innesluttes i en myk gelatinkapsel. Denne løsning er for eksempel beskrevet i fransk patent 2.150.848 og i japanske patentansøkninger 78-1117, 78-95388, 78-96355 og 80-126107. Dette produkt kalles en tyggbar gelatinkapsel. of nifedipine-containing medicines in many ways. The solution that is most used is probably the one where the active ingredient in a liquid mixture is enclosed in a soft gelatin capsule. This solution is described, for example, in French patent 2,150,848 and in Japanese patent applications 78-1117, 78-95388, 78-96355 and 80-126107. This product is called a chewable gelatin capsule.
Sammen med legemiddelstoffet er innkapslet en polyalkylenglykol (molekylvekt 200-4000), så vel som glycerol, propylenglykol Together with the medicinal substance, a polyalkylene glycol (molecular weight 200-4000), as well as glycerol, propylene glycol, is encapsulated
eller butylenglykol. Fremstillingsprosessen krever spesielt utstyr som få farmasøytiske fabrikanter har, på grunn av dets kompliserte konstruksjon og selvsagt dets pris. or butylene glycol. The manufacturing process requires special equipment that few pharmaceutical manufacturers have, due to its complicated construction and of course its price.
Forsøk er også gjort på å oppnå god oppløselighet og videre absorbsjon av legemiddelstoffet ved å fremstille et såkalt ko-precipitat fra nifedipin og polyvinylpyrrolidon, slik som det er beskrevet i publikasjonen Sugimoto et al., Drug Dev. Ind. Pharm. 1980 6 (2), 137-160. Denne metode har imidlertid heller ikke vært god, eftersom varmen og fuktigheten under lagring med-fører at oppløsningen av legemiddelstoffet blir langsommere. Attempts have also been made to achieve good solubility and further absorption of the medicinal substance by producing a so-called co-precipitate from nifedipine and polyvinylpyrrolidone, as described in the publication Sugimoto et al., Drug Dev. Ind. Pharm. 1980 6 (2), 137-160. However, this method has not been good either, since the heat and humidity during storage means that the dissolution of the medicinal substance becomes slower.
Forsøk har vært gjort på å forbedre absorbsjonen av nifedipin, for eksempel i japansk patentansøkning 80-160952, europeisk patentansøkning 1247, og i tysk patentpublikasjon 2.822.882,, også ved å oppløse legemiddelstoffet og et egnet fast stoff så som en polymer for å danne for eksempel en cellulose- eller polyvinylpyrrolidon-oppløsning, og derefter tørke oppløsningen. Denne metode kan innen farmasien ansees som en konvensjonell metode for fremstilling av en fast dispersjon, og anvendes nå bare for det aktive stoff nifedipin. Attempts have been made to improve the absorption of nifedipine, for example in Japanese Patent Application 80-160952, European Patent Application 1247, and in German Patent Publication 2,822,882, also by dissolving the drug substance and a suitable solid such as a polymer to form for example a cellulose or polyvinylpyrrolidone solution, and then drying the solution. In pharmacy, this method can be regarded as a conventional method for producing a solid dispersion, and is now only used for the active substance nifedipine.
I japanske patentansøkninger 80-133061, 80-19191 og 80-14413 blandes nifedipin, for å forbedre dens absorbsjon, med enten flytende polyetylenglykoler eller høymolekylær, fast polyetylenglykol som smeltes under fremstillingsprosessen. In Japanese Patent Applications 80-133061, 80-19191 and 80-14413, nifedipine is mixed, to improve its absorption, with either liquid polyethylene glycols or high molecular weight, solid polyethylene glycol which is melted during the manufacturing process.
I japanske patentansøkninger 77-143138 og 77-57490 er det gjort forsøk på å oppnå en fordelaktig tilberedning av nifedipin ved å anvende et anionisk Overflateaktivt middel i en mengde på det dobbelte av mengden av legemiddelstoffet. I dette tilfelle må man imidlertid vente en irritasjon i fordøyelseskanalen og giftvirkning i leveren ved lang tids anvendelse av disse stoffer. Disse preparater har også inneholdt fenylsalicylat som stabiliseringsmiddel. In Japanese patent applications 77-143138 and 77-57490, attempts have been made to achieve an advantageous preparation of nifedipine by using an anionic surfactant in an amount twice the amount of the drug substance. In this case, however, one must expect an irritation in the digestive tract and a toxic effect on the liver with long-term use of these substances. These preparations have also contained phenyl salicylate as a stabilizer.
I japanske patentansøkninger 77-120871 og 77-120872 er det også gjort forsøk på å anvende trietylenglykol og propylenkarbo-nat for å fremme oppløseligheten og absorbsjonen av nifedipin. Oppløsningen kunne i dette tilfelle pakkes i myk-gelatin-kapsler, med de fremstillingsproblemer som er omtalt ovenfor. In Japanese patent applications 77-120871 and 77-120872, attempts have also been made to use triethylene glycol and propylene carbonate to promote the solubility and absorption of nifedipine. In this case, the solution could be packaged in soft-gelatin capsules, with the manufacturing problems mentioned above.
Ifølge japanske patentansøkninger 78-120271 og 80-14413, fremstilles et stabilt pulver av nifedipin og kiselsyre, og faste legemiddeltormer fremstilles av dette pulver ved å anvende ytterligere polyetylenglykol eller polyvinylpyrrolidon som hjelpe-stoff . According to Japanese patent applications 78-120271 and 80-14413, a stable powder is prepared from nifedipine and silicic acid, and solid drug forms are prepared from this powder by using additional polyethylene glycol or polyvinylpyrrolidone as an auxiliary substance.
Videre er det med hensyn til formulering av nifedipin fore-slått i finsk patentansøkning 812758 å anvende et vanlig mikronisert legemiddelstoff i preparatet, selv om det i virkeligheten er et farmasøytisk grunnprinsipp at oppløsning av et dårlig opp-løselig legemiddelstoff alltid forbedres ved å øke pulverets oppløsende overflateareal og således ved mikronisering til en grense som ansees som normal. Pulveret som har et spesifikt overflateareal på o 0,5-6 m 2/g, angitt i kravene i nevnte ansøkning, må ansees som et helt konvensjonelt mikronisert pulver. Denne klassiske metode for forbedring av oppløseligheten ved tilberedning av et dårlig oppløselig legemiddelstoff, er velkjent, for eksempel i forbindelse med anvendelse av spironolakton. Furthermore, with regard to the formulation of nifedipine, it is proposed in Finnish patent application 812758 to use a common micronized medicinal substance in the preparation, although in reality it is a basic pharmaceutical principle that dissolution of a poorly soluble medicinal substance is always improved by increasing the powder's dissolving power surface area and thus by micronization to a limit that is considered normal. The powder which has a specific surface area of o 0.5-6 m 2 /g, stated in the requirements in the aforementioned application, must be considered a completely conventional micronized powder. This classic method for improving the solubility when preparing a poorly soluble medicinal substance is well known, for example in connection with the use of spironolactone.
Det er nå overraskende funnet at når derivater av 1,4-dihydropyridin granuleres sammen med sukkeralkoholer, fordelaktig amnnitol, oppnår man fra legemiddelstoffet en tablett eller en hard-gelatin-kapsel fra hvilken legemiddelstoffet opp-løses og absorberes godt, og enda betydelig bedre enn hva til-fellet er fra det tilsvarende produkt som tidligere har vært på markedet. It has now surprisingly been found that when derivatives of 1,4-dihydropyridine are granulated together with sugar alcohols, advantageously amniitol, one obtains from the medicinal substance a tablet or a hard gelatin capsule from which the medicinal substance dissolves and is absorbed well, and even significantly better than the case is from the corresponding product that has previously been on the market.
Sukkeralkoholer som er vesentlige for fremgangsmåten for fremstilling av granulene ifølge foreliggende oppfinnelse, er høyverdige alkoholer oppnådd ved reduksjon av sukkeret. Av disse kan nevnes 6-verdige alkoholer såsom mannitol, sorbitol og dulcitol. Deres kjemiske formel er CH-OH(CHOH)„CH„OH. De Sugar alcohols which are essential for the method for producing the granules according to the present invention are high-quality alcohols obtained by reducing the sugar. Of these, 6-valent alcohols such as mannitol, sorbitol and dulcitol can be mentioned. Their chemical formula is CH-OH(CHOH)„CH„OH. The
2 4 2 2 4 2
adskiller seg fra hverandre stereokjemisk. Xylitol er en tem-melig velkjent 5-verdig sukkeralkohol. Dens formel er CH2OH(CHOH)^Cr^OH, og også denne medfører de samme fordelaktige egenskaper som de 6-verdige alkoholer gjør. differ from each other stereochemically. Xylitol is a fairly well-known 5-valent sugar alcohol. Its formula is CH2OH(CHOH)^Cr^OH, and this too carries with it the same beneficial properties as the 6-valent alcohols do.
Grunnen til den raskere oppløsning og betydelig bedre absorbsjon av legemiddelstoffet når det inneholdes i tabletter og kapsler fremstilt ifølge oppfinnelsen, sammenlignet med de tidligere kjente produkter, er sannsynligvis at de funksjonelle grupper som er til stede i sukkeralkoholer, ikke danner bindin-ger som hindrer at de aktive 1,4-dihydropyridin-derivater så The reason for the faster dissolution and significantly better absorption of the medicinal substance when it is contained in tablets and capsules produced according to the invention, compared to the previously known products, is probably that the functional groups present in sugar alcohols do not form bonds that prevent the active 1,4-dihydropyridine derivatives so
som nifedipin, blir frigjort eller absorbert.such as nifedipine, is released or absorbed.
Granulene fremstilt ifølge oppfinnelsen som kan anvendes i The granules produced according to the invention which can be used in
tabletter eller hard-gelatin-kapsler, kan fremstilles ved å oppløse legemiddelstoffet^i et egnet oppløsningsmiddel, fortrinnsvis aceton, og ved å granulere en sukkeralkohol eller en blanding av slike alkoholer med denne oppløsning. Dannelse av en jevn og optimal sammenhengende granul med gode flyteegenskaper kan fortsettes efter oppløsningen av legemiddelstoffet ved å anvende et annet oppløsningsmiddel eller en bindemiddeloppløsning. tablets or hard-gelatin capsules, can be prepared by dissolving the drug substance in a suitable solvent, preferably acetone, and by granulating a sugar alcohol or a mixture of such alcohols with this solution. Formation of a uniform and optimally cohesive granule with good flow properties can be continued after the dissolution of the medicinal substance by using another solvent or a binder solution.
I henhold til den annen hovedutførelsesform kan granulene også fremstilles ved at et normalt mikronisert legemiddelstoff, eller fortrinnsvis et legemiddelstoff med et spesifikt overflateareal på o 6-10 m 2/g, blandes med sukkeralkoholer iinntil blandingen er homogen, og det oppnådde pulver granuleres ved anvendelse av enten et egnet oppløsningsmiddel eller en bindemiddeloppløs-ning. Hovedprinsippet er imidlertid alltid at derivatet av 1,4-dihydropyridin innføres i granulen på en slik måte at det danner en dispergert, homogen blanding med sukkeralkoholen. According to the second main embodiment, the granules can also be prepared by mixing a normally micronized medicinal substance, or preferably a medicinal substance with a specific surface area of o 6-10 m 2 /g, with sugar alcohols until the mixture is homogeneous, and the resulting powder is granulated by use of either a suitable solvent or a binder solution. However, the main principle is always that the derivative of 1,4-dihydropyridine is introduced into the granule in such a way that it forms a dispersed, homogeneous mixture with the sugar alcohol.
Egnede hjelpestoffer som i og for seg er kjent, kan selvsagt blandes med granulene fremstilt ifølge oppfinnelsen for å forme dem til tabletter eller kapsler. Nevnt efter sine virk-ninger kan slike stoffer for eksempel være fyllstoffer, binde-midler, smøremidler, dispergeringsmidler og overflateaktive midler som letter rask fuktning av tabletten eller kapselen. Suitable excipients, which are known in and of themselves, can of course be mixed with the granules produced according to the invention to form them into tablets or capsules. Mentioned according to their effects, such substances can for example be fillers, binders, lubricants, dispersants and surface-active agents that facilitate rapid wetting of the tablet or capsule.
Av de sistnevnte er forbindelser med ester-struktur, så som sorbimakrogololeat eller polyoksyetylenstearat, funnet å være særlig egnet i en sukkeralkoholmasse. Of the latter, compounds with an ester structure, such as sorbic macrogol oleate or polyoxyethylene stearate, have been found to be particularly suitable in a sugar alcohol mass.
Det er fordelaktig å belegge tablettene i komprimert form med en raskt oppløsende pigmentholdig film som er i og for seg kj ent. It is advantageous to coat the tablets in compressed form with a quickly dissolving pigment-containing film which is known per se.
En fordelaktig virkning ved absorbsjonen av nifedipin kan også oppnåes hvis legemiddelstoffet er i en sukkeralkohol-opp-løsning i en myk-gelatin-kapsel. A beneficial effect on the absorption of nifedipine can also be achieved if the medicinal substance is in a sugar alcohol solution in a soft gelatin capsule.
Vanlige granulatorer kan anvendes ved industriell fremstilling av de her beskrevne granuler. Både en granulator av hurtig-blander-typen og en granulator av luftsuspensjons-typen er meget egnet. Når organiske oppløsningsmidler anvendes, er en Topo granulator egnet. Ved dnene fremgangsmåte kan granula-sjonsoppløsningsmidlet gjenvinnes slik at det ikke oppstår noen luftforurensningsproblemer. Ordinary granulators can be used in the industrial production of the granules described here. Both a rapid mixer type granulator and an air suspension type granulator are very suitable. When organic solvents are used, a Topo granulator is suitable. With this method, the granulation solvent can be recovered so that no air pollution problems arise.
De følgende eksempeler illustrerer oppfinnelsen ytterligere. The following examples further illustrate the invention.
Den aktive bestanddel ble oppløst i aceton mens den ble holdt beskyttet mot lys. Granuleringen av mannitol ble igang-satt under anvendelse av den oppnådde oppløsning, og granuleringen ble fortsatt ytterligere under anvendelse av vann. The active ingredient was dissolved in acetone while it was kept protected from light. The granulation of mannitol was started using the solution obtained, and the granulation was further continued using water.
Granulene ble tørket og siktet. Ferdiggjøringsstoffene i tabletten ble blandet med granulene, og massen ble komprimert til The granules were dried and sieved. The finishing substances in the tablet were mixed with the granules, and the mass was compressed to
tabletter. Tablettene ble belagt med en i og for seg kjent pigmentfilm. pills. The tablets were coated with a pigment film known per se.
Fremstilling ifølge eksempel 1, bortsett fra at estrene som fremmer hurtig fuktning av tabletten, ble blandet med vann før granuleringen ble fortsatt. Preparation according to example 1, except that the esters which promote rapid wetting of the tablet were mixed with water before the granulation was continued.
Nifedipin og sukkeralkoholer ble blandet for å danne et homogent pulver. Dette pulver ble granulert under anvendelse av en vandig oppløsning av PVP-bindemidlet. Granulene ble tørket og siktet. Dispergeringsmidlet og smøremidlet ble blandet med granulene. Massen ble presset til tabletter. Eksempel 4: Hard- gelatin- kapsel Nifedipine and sugar alcohols were mixed to form a homogeneous powder. This powder was granulated using an aqueous solution of the PVP binder. The granules were dried and sieved. The dispersant and lubricant were mixed with the granules. The pulp was pressed into tablets. Example 4: Hard gelatin capsule
Den aktive bestanddel ble oppløst i aceton mens den ble beskyttet mot lys. Granuleringen av mannitol ble startet under anvendelse av den oppnådde oppløsning, og granuleringen ble fortsatt ytterligere under anvendelse av en vandig oppløsning av overflateaktive midler. Granulene ble tørket og siktet. Dispergeringsmidlet og smøremidlet ble blandet med granulene. Massen ble innkapslet i harde gelatin-kapsler. The active ingredient was dissolved in acetone while protected from light. The granulation of mannitol was started using the solution obtained, and the granulation was further continued using an aqueous solution of surfactants. The granules were dried and sieved. The dispersant and lubricant were mixed with the granules. The mass was encapsulated in hard gelatin capsules.
Eksempel 5; Hard- gelatin- kapsel Example 5; Hard gelatin capsule
Legemiddelstoffet ble oppløst i aceton mens det ble beskyttet mot lys, og mannitol ble granulert med oppløsningen. Granulene ble tørket og siktet og ble pakket i harde gelatin-kapsler. The drug substance was dissolved in acetone while protected from light, and mannitol was granulated with the solution. The granules were dried and sieved and packed in hard gelatin capsules.
Eksempel 6; Hard- gelatin- kapsel for sammenligningsformål Example 6; Hard gelatin capsule for comparison purposes
En referansekapsel ble fremstilt som beskrevet i eksempel 5, men sukkeralkoholen ble erstattet med granulert sukker, det vil si sakkarose. A reference capsule was prepared as described in Example 5, but the sugar alcohol was replaced with granulated sugar, i.e. sucrose.
Eksempel 7: Myk- gelacin- kapsel Example 7: Soft gelatin capsule
Sammensetning:Composition:
En oppløsning ble fremstilt ved å oppløse den angitte mengde nifedipin i en 70% mannitol-oppløsning som er tilgjengelig kom-mersielt. Oppløsningen er egnet for fremstilling av for eksempel en myk-gelatin-kapsel. A solution was prepared by dissolving the indicated amount of nifedipine in a commercially available 70% mannitol solution. The solution is suitable for producing, for example, a soft gelatin capsule.
SammenligningsforsøkComparison experiment
Tablettene og kapslene fremstilt ved fremgangsmåten ifølge oppfinnelsen ble sammenlignet, med hensyn til oppløsning og absorbsjon, med et kjent produkt tilgjengelig på markedet og også med kapselen fremtilt ifølge eksempel 6. The tablets and capsules produced by the method according to the invention were compared, with regard to dissolution and absorption, with a known product available on the market and also with the capsule produced according to example 6.
Resultatene oppnådd ved sammenligningsforsøkene er vist på de ledsagende figurer 1-4, som viser en grafisk illustrasjon av blodserum-nifedipin-konsentrasjonene hos forsøkspersoner som en funksjon av tid (figurene 2 og 3) og prosent oppløsning som en funksjon av tid (figurene 1 og 4). Som det vil sees klart av figurene 1 - 4, er de resultater som ble oppnådd under anvendelse av tablettene og kapslene fremstilt ifølge oppfinnelsen, betydelig bedre enn de som ble oppnådd under anvendelse av referanse-tablettene og -kapslene. The results obtained in the comparative experiments are shown in the accompanying Figures 1-4, which show a graphical illustration of the blood serum nifedipine concentrations in subjects as a function of time (Figures 2 and 3) and percent dissolution as a function of time (Figures 1 and 4). As will be clearly seen from Figures 1 - 4, the results obtained using the tablets and capsules produced according to the invention are significantly better than those obtained using the reference tablets and capsules.
Claims (4)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FI831232A FI72874B (en) | 1983-04-12 | 1983-04-12 | FOERFARANDE FOER FRAMSTAELLNING AV LAETT ABSORBERBAR ORAL DOSERINGSFORM AV LAEKEMEDEL AV NIFEDIPIN. |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO841437L true NO841437L (en) | 1984-10-15 |
Family
ID=8517039
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO841437A NO841437L (en) | 1983-04-12 | 1984-04-11 | PROCEDURE FOR THE PREPARATION OF ORAL DOSAGE FORMS OF MEDICINALLY ACTIVE 1,4-DIHYDROPYRIDINE DERIVATIVES |
Country Status (5)
| Country | Link |
|---|---|
| DE (1) | DE3413643A1 (en) |
| DK (1) | DK184484A (en) |
| FI (1) | FI72874B (en) |
| NO (1) | NO841437L (en) |
| SE (1) | SE8401968L (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3419129A1 (en) * | 1984-05-23 | 1985-11-28 | Bayer Ag, 5090 Leverkusen | NIFEDIPINE PREPARATIONS AND METHOD FOR THE PRODUCTION THEREOF |
| DE3419128A1 (en) * | 1984-05-23 | 1985-11-28 | Bayer Ag, 5090 Leverkusen | DIHYDROPYRIDINE PREPARATIONS AND METHOD FOR THE PRODUCTION THEREOF |
-
1983
- 1983-04-12 FI FI831232A patent/FI72874B/en not_active Application Discontinuation
-
1984
- 1984-04-09 SE SE8401968A patent/SE8401968L/en not_active Application Discontinuation
- 1984-04-10 DK DK184484A patent/DK184484A/en not_active Application Discontinuation
- 1984-04-11 DE DE19843413643 patent/DE3413643A1/en not_active Withdrawn
- 1984-04-11 NO NO841437A patent/NO841437L/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| FI831232L (en) | 1984-10-13 |
| FI72874B (en) | 1987-04-30 |
| FI831232A0 (en) | 1983-04-12 |
| DK184484A (en) | 1984-10-13 |
| SE8401968L (en) | 1984-10-13 |
| DE3413643A1 (en) | 1984-10-18 |
| DK184484D0 (en) | 1984-04-10 |
| SE8401968D0 (en) | 1984-04-09 |
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