NO175513B - Process for the preparation of pellet moldings - Google Patents
Process for the preparation of pellet moldingsInfo
- Publication number
- NO175513B NO175513B NO871350A NO871350A NO175513B NO 175513 B NO175513 B NO 175513B NO 871350 A NO871350 A NO 871350A NO 871350 A NO871350 A NO 871350A NO 175513 B NO175513 B NO 175513B
- Authority
- NO
- Norway
- Prior art keywords
- pellets
- binder
- molds
- filled
- mold
- Prior art date
Links
- 239000008188 pellet Substances 0.000 title claims abstract description 60
- 238000000034 method Methods 0.000 title claims description 25
- 238000000465 moulding Methods 0.000 title claims 2
- 238000002360 preparation method Methods 0.000 title 1
- 239000011230 binding agent Substances 0.000 claims abstract description 38
- 239000011159 matrix material Substances 0.000 claims abstract description 8
- 230000003111 delayed effect Effects 0.000 claims abstract description 3
- 238000004519 manufacturing process Methods 0.000 claims description 11
- 238000010438 heat treatment Methods 0.000 claims description 8
- 238000002844 melting Methods 0.000 claims description 8
- 230000008018 melting Effects 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 7
- 210000004051 gastric juice Anatomy 0.000 claims description 6
- 229920001223 polyethylene glycol Polymers 0.000 claims description 6
- 239000003380 propellant Substances 0.000 claims description 6
- 239000013543 active substance Substances 0.000 claims description 4
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 229930195729 fatty acid Natural products 0.000 claims description 3
- 239000000194 fatty acid Substances 0.000 claims description 3
- 150000004665 fatty acids Chemical class 0.000 claims description 3
- 235000007983 food acid Nutrition 0.000 claims description 3
- 238000007711 solidification Methods 0.000 claims description 3
- 230000008023 solidification Effects 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 150000005846 sugar alcohols Chemical class 0.000 claims description 3
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- 150000001720 carbohydrates Chemical class 0.000 claims description 2
- 238000005336 cracking Methods 0.000 claims 1
- 239000002966 varnish Substances 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 abstract description 2
- 239000011449 brick Substances 0.000 abstract 1
- 238000013270 controlled release Methods 0.000 abstract 1
- 238000000576 coating method Methods 0.000 description 12
- 239000011248 coating agent Substances 0.000 description 11
- 239000011888 foil Substances 0.000 description 7
- 239000002775 capsule Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 5
- 238000013461 design Methods 0.000 description 5
- 230000000979 retarding effect Effects 0.000 description 5
- 239000003814 drug Substances 0.000 description 4
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 3
- 229910052782 aluminium Inorganic materials 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000007903 gelatin capsule Substances 0.000 description 3
- 238000005245 sintering Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 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 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 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Chemical compound 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 description 2
- 239000000654 additive Substances 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- 238000003825 pressing Methods 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 238000009475 tablet pressing Methods 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 1
- 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 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000005056 compaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 239000000374 eutectic mixture Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 238000009499 grossing Methods 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000008385 outer phase Substances 0.000 description 1
- 238000013021 overheating Methods 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229940093430 polyethylene glycol 1500 Drugs 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000012254 powdered material Substances 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 229920002379 silicone rubber Polymers 0.000 description 1
- 239000004945 silicone rubber Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 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
- A61K9/20—Pills, tablets, discs, rods
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
- A61J3/06—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of pills, lozenges or dragees
-
- 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
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
-
- 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
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
- A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J2200/00—General characteristics or adaptations
- A61J2200/20—Extrusion means, e.g. for producing pharmaceutical forms
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Preparation (AREA)
- Medical Preparation Storing Or Oral Administration Devices (AREA)
- Processing And Handling Of Plastics And Other Materials For Molding In General (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Processes Of Treating Macromolecular Substances (AREA)
- Encapsulation Of And Coatings For Semiconductor Or Solid State Devices (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Perforating, Stamping-Out Or Severing By Means Other Than Cutting (AREA)
- Processing Of Solid Wastes (AREA)
- Preparation Of Clay, And Manufacture Of Mixtures Containing Clay Or Cement (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Compounds Of Unknown Constitution (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
Abstract
Description
Foreliggende oppfinnelse angår en fremgangsmåte for fremstilling av formlegemer av pellets. The present invention relates to a method for producing shaped bodies from pellets.
På området for perorale depotformer inntar retarderte virkestoffholdige pellets en betydelig stilling. Vanligvis fylles disse pellets på gelatinkapsler som pasienten inntar uåpnet. En stor ulempe ved denne applikasjonsform er at en fleksibel dosering av det retarderte legemiddel bare er mulig i et helt antall ganger av kapselens enhetsdose. Delmengder av legemidlet, dvs. en på forhånd bestemt og reproduserbar dose, kan ikke tas av pasienten under kontrollerte betingelser. Den sikre oppbevaring av resten av legemidlet kan ikke garanteres. In the area of oral depot forms, retarded active ingredient-containing pellets occupy a significant position. Usually these pellets are filled in gelatin capsules which the patient takes unopened. A major disadvantage of this form of application is that a flexible dosage of the retarded drug is only possible in a whole number of times the unit dose of the capsule. Portions of the drug, i.e. a predetermined and reproducible dose, cannot be taken by the patient under controlled conditions. The safe storage of the rest of the medicine cannot be guaranteed.
Av sikkerhetsgrunner er dessuten flere kapseltyper forsynt med en sikkerhetsforsegling som fører til at kapslene ødelegges ved åpning. For safety reasons, several capsule types are also provided with a safety seal which causes the capsules to be destroyed when opened.
Mange pasienter finner det utpreget ubehagelig å svelge ned et legemiddel i den kommersielle gelatinkapselform fordi kapselen føles som et fremmedlegeme. Denne følelse kan være så utpreget at svelgemekanismen fullstendig lammes. Many patients find it distinctly uncomfortable to swallow a drug in the commercial gelatin capsule form because the capsule feels like a foreign body. This feeling can be so pronounced that the swallowing mechanism is completely paralyzed.
I slike tilfeller ville det være fordelaktig å kunne løse kapselen i litt vann og så svelge de derved frigjorte pellets som "vandige suspensjoner". Som kjent løser kommersielle gelatinkapsler seg ikke opp i vann ved romtemperatur. In such cases, it would be advantageous to be able to dissolve the capsule in a little water and then swallow the pellets thus released as "aqueous suspensions". As is known, commercial gelatin capsules do not dissolve in water at room temperature.
Det er også kjent på fagområdet at pellets ikke kan presses til tabletter. Det nødvendig høye press som i så fall måtte benyttes, fører i det minste delvis til en ødeleggelse av pellet-legemet slik at forholdene ved virkestoff-fri-gjøringen endres i ugunstig retning. Bestrebelser på å utvikle en pellet som motstår de nødvendige høye trykk ved tablett-pressingen, er forbundet med drastiske begrensninger i utvalget av overtrekksmaterialer og pellet-størrelse (sml. DE-OS 23 36 218). It is also known in the field that pellets cannot be pressed into tablets. The necessary high pressure, which in that case had to be used, leads at least partially to a destruction of the pellet body so that the conditions for the release of the active substance change in an unfavorable direction. Efforts to develop a pellet that withstands the necessary high pressures during tablet pressing are associated with drastic limitations in the selection of coating materials and pellet size (cf. DE-OS 23 36 218).
Foreliggende oppfinnelse har hatt til oppgave å tilveie-bringe en fremgangsmåte for fremstilling av formlegemer av pellets, som ikke i løpet av fremstillingen fordrer anvendelse av de høye presstrykk som vanligvis trengs ved tablett-pressing. The present invention has had the task of providing a method for the production of shaped bodies from pellets, which does not during the production require the use of the high pressing pressures that are usually needed in tablet pressing.
Det har dessuten vært en oppgave å foreslå en fremgangsmåte for fremstilling av galenisk tablettform som tillater oppdeling én eller flere ganger under bibehold av de karakteristiske egenskaper, som f.eks. retard-virkning. It has also been a task to propose a method for the production of galenic tablet form which allows division one or more times while maintaining the characteristic properties, such as e.g. retard action.
En ytterligere oppgave-har bestått i å foreslå en fremgangsmåte for fremstilling av en galenisk pelletform som brytes ned i et vandig miljø og frigjør de enkelte pellets i løpet av et akseptabelt tidsrom. A further task has consisted in proposing a method for the production of a galenic pellet form which breaks down in an aqueous environment and releases the individual pellets during an acceptable period of time.
I henhold til foreliggende oppfinnelse løses oppgaven ved en fremgangsmåte hvor pellets innleires i en smeltbar (sinterbar) matriks, hvor formlegemet eventuelt kan ha inn-retninger, f.eks. innhakk, for bedre oppdeling. According to the present invention, the task is solved by a method where pellets are embedded in a fusible (sinterable) matrix, where the shaped body can possibly have devices, e.g. notch, for better division.
I henhold til oppfinnelsen tilveiebringes en fremgangsmåte for fremstilling av et formlegeme av pellets med retardert kontrollert virkestoff-frigjøring i en smeltbar matriks av et farmakologisk akseptabelt, vannløslig eller vann-emulgerbart bindemiddel med smeltepunkt under 100°C, som omfatter sukkeralkoholer eller deres estere med næringsmiddelsyrer, fettsyrer eller deres mono- eller diglycerider, sakkarider eller polyetylenglykoler eller blandinger av de nevnte stoffer. According to the invention, a method is provided for the production of a molded body of pellets with delayed controlled active substance release in a meltable matrix of a pharmacologically acceptable, water-soluble or water-emulsifiable binder with a melting point below 100°C, which comprises sugar alcohols or their esters with food acids , fatty acids or their mono- or diglycerides, saccharides or polyethylene glycols or mixtures of the aforementioned substances.
Fremgangsmåten karakteriseres ved at enten The procedure is characterized by either
a) pellets fylles i former og deretter støpes ut med det smeltede bindemiddel, a) pellets are filled into molds and then cast out with the molten binder,
eller or
b) pelletene omhyllet med bindemiddel, fylles i former og deretter gis en kortvarig oppvarming, b) the pellets are coated with binder, filled into molds and then briefly heated,
eller or
c) pelletene blandet med bindemiddel, fylles i former og deretter gis en kortvarig oppvarming, c) the pellets mixed with binder, filled into molds and then briefly heated,
eller or
d) peiletene fylles sammen med bindemidlet og et drivmiddel i former og gis en kortvarig oppvarming, d) the gauges are filled together with the binder and a propellant in molds and given a brief heating,
idet bindemidlet anvendes i en mengde på 5 - 50 vekt-% basert på mengden av pellets. the binder being used in an amount of 5 - 50% by weight based on the amount of pellets.
Begrepet smeltbar eller sinterbar matriks står for en matriks som fastner under fremstillingen enten ved stivning av en smelte eller ved sintring (kortvarig oppvarming) av et pulverformet materiale. The term fusible or sinterable matrix stands for a matrix that sticks during production either by solidification of a melt or by sintering (short-term heating) of a powdered material.
Ved begrepet formlegeme skal det i henhold til oppfinnelsen ikke bare forstås tablett- eller kapsel-lignende former, men alle utførelser som danner en form og egner seg for oral applikasjon. According to the invention, the term molded body shall not only mean tablet- or capsule-like forms, but all designs which form a form and are suitable for oral application.
For formlegemet fremstilt i henhold til oppfinnelsen stilles ingen begrensende krav til stabiliteten av pellet-innkapslingen eller til pellet-størrelsen. Som pellets er alle produkter fremstillet etter kjente drasjerings- resp. over-trekks-metoder egnet. Til disse regnes uretarderte (dvs. direkte oppløselige), pellets med mavesaft-resistent overtrekk og retardpellets. Matriksen består av bindemidler og eventuelt tilsetningsstoffer av de typer som vanligvis finner anvendelse innen den galeniske teknikk. Bindemidlet bør være vannløselig eller i det minste emulgerbart i vann, eventuelt i avhengighet av pH-verdien, og fortrinnsvis oppvise et smeltepunkt på under 100°C. For the shaped body produced according to the invention, no limiting requirements are placed on the stability of the pellet encapsulation or on the pellet size. As pellets, all products are manufactured according to known coating or overdraft methods suitable. These include unretarded (i.e. directly soluble), pellets with a gastric juice-resistant coating and retarded pellets. The matrix consists of binders and possibly additives of the types that usually find use within the galenic technique. The binder should be water-soluble or at least emulsifiable in water, possibly depending on the pH value, and preferably have a melting point below 100°C.
Foretrukne bindemidler er sukkeralkoholer, som f.eks. manitt, xylitt og sorbitt samt deres estere med næringsmiddelsyrer, så som vinsyre, sitronsyre, eplesyre, melkesyre; fettsyrer og deres mono- eller diglycerider, sukkerblandinger, f.eks. mono- eller disakkarider, eller glukosesirup, mono-eller diglycerider og deres derivater, eller blandinger av de nevnte stoffer. Preferred binders are sugar alcohols, such as e.g. mannitol, xylitol and sorbitol and their esters with food acids, such as tartaric acid, citric acid, malic acid, lactic acid; fatty acids and their mono- or diglycerides, sugar mixtures, e.g. mono- or disaccharides, or glucose syrup, mono- or diglycerides and their derivatives, or mixtures of the aforementioned substances.
Som hjelpestoffer med høyt smeltepunkt anvendes fortrinnsvis evtektiske blandinger med et smeltepunkt på mindre enn 100°C. Eutectic mixtures with a melting point of less than 100°C are preferably used as auxiliaries with a high melting point.
Et egnet bindemiddel for en smeltbar matriks er en blanding av sukker, melkesukker, sorbitt, stivelsessirup og vann som i litteraturen også omtales som "Basic Mix". Dette er en glassaktig masse med et mykningspunkt på 55-90°C og en residualvann-mengde på ca. 0,5-2%. A suitable binder for a fusible matrix is a mixture of sugar, milk sugar, sorbitol, starch syrup and water, which is also referred to in the literature as "Basic Mix". This is a glassy mass with a softening point of 55-90°C and a residual water quantity of approx. 0.5-2%.
Spesielt foretrukne bindemidler er polyetylenglykoler som for eksempel Polywachs 1500, Polywachs 6000 eller Polywachs 20.000, som har et stivnepunkt på mellom 25 og 60°C. Particularly preferred binders are polyethylene glycols such as Polywachs 1500, Polywachs 6000 or Polywachs 20,000, which have a solidification point of between 25 and 60°C.
Formlegemer fremstilt i henhold til oppfinnelsen som inneholder polyetylenglykoler som bindemiddel, utgjør en foretrukket utførelsesform, idet formlegemet raskt faller sammen i et vandig miljø og disse pellets kan lett svelges som en slags "vandig suspensjon". Shaped bodies produced according to the invention which contain polyethylene glycols as a binder are a preferred embodiment, as the shaped body quickly collapses in an aqueous environment and these pellets can be easily swallowed as a kind of "aqueous suspension".
Et ytterligere kriterium for valget av bindemiddel er at det er forlikelig med det retarderte polymer-overtrekk på pelleten. A further criterion for the choice of binder is that it is compatible with the retarded polymer coating on the pellet.
I mer detalj kan fremgangsmåten i henhold til oppfinnelsen gjennomføres som følger: a) Pellets som fremstilles etter metoder kjent fra litteraturen, og som er forsynt med et retarderende overtrekk, fylles i egnede former, hvoretter formen overhelles med en tilstrekkelig mengde av det smeltede bindemiddel. Mengden av anvendt bindemiddel, eventuelt tilsatt galeniske tilsetningsstoffer, utgjør mellom 5 og 50 vektprosent, fortrinnsvis 10-25 vektprosent, beregnet på basis av mengden av pellets. Etter avkjøling tas de ferdige formlegemer ut av formen og konfeksjoneres. For å forenkle uttaket kan formen på forhånd påføres et glattemiddel. Egnede former er slike som muliggjør enkelt uttak av det avkjølte formlegemet. In more detail, the method according to the invention can be carried out as follows: a) Pellets which are produced according to methods known from the literature, and which are provided with a retarding coating, are filled into suitable molds, after which the mold is poured over with a sufficient amount of the molten binder. The amount of binder used, optionally added galenic additives, is between 5 and 50 percent by weight, preferably 10-25 percent by weight, calculated on the basis of the amount of pellets. After cooling, the finished molded bodies are removed from the mold and assembled. To simplify removal, a smoothing agent can be applied to the mold in advance. Suitable molds are those which enable easy removal of the cooled molded body.
b) Etter en annen utførelsesform i henhold til oppfinnelsen, påføres bindemidlet i egnet tykkelse på de allerede retarderte b) According to another embodiment according to the invention, the binder is applied in a suitable thickness to the already retarded
pellets. Dette kan eksempelvis foregå etter en drasjerings-metode. Tykkelsen av bindemiddelskiktet avhenger i det vesentlige av pellet-størrelsen og kan fastslås gjennom enkle forsøk. Mengden anvendt bindemiddel ligger i alminnelighet mellom 5 og 50 vektprosent, fortrinnsvis mellom 10 og 25 vektprosent, beregnet på basis av pelletmengden. pellets. This can, for example, take place using a coating method. The thickness of the binder layer essentially depends on the pellet size and can be determined through simple experiments. The amount of binder used is generally between 5 and 50 percent by weight, preferably between 10 and 25 percent by weight, calculated on the basis of the amount of pellets.
Bindemiddelovertrukne pellets fylles i former og forbindes med hverandre ved kortvarig oppvarming, hvorved bindemidlet en kort stund smelter, i det minste på overflaten. Den nødvendige varme for smeltingen av bindemidlet kan til-føres via formen ved passende utformede former som dessuten eventuelt også er forsynt med avkjølingsanordninger. Om temperaturtilførsel ikke er mulig gjennom formen, kan den nødvendige energi for den kortvarige smelting tilføres "utenfra", eksempelvis ved mikrobølgebestråling eller i en varmeinnretning som f.eks. en enkel ovn. Det dreier seg i det vesentlige om å sikre at retardskiktet for de enkelte pellets ikke skades ved overopphetning. Binder-coated pellets are filled into molds and connected to each other by brief heating, whereby the binder briefly melts, at least on the surface. The necessary heat for the melting of the binder can be supplied via the mold by means of suitably designed molds which are also optionally equipped with cooling devices. If temperature supply is not possible through the mold, the necessary energy for the short-term melting can be supplied "from outside", for example by microwave irradiation or in a heating device such as a simple oven. It is essentially about ensuring that the retarder layer for the individual pellets is not damaged by overheating.
c) Etter en annen utførelsesform i henhold til oppfinnelsen blandes de retarderte pellets sammen med bindemidlet og fylles c) According to another embodiment according to the invention, the retarded pellets are mixed together with the binder and filled
over i en form. Den videre bearbeidning skjer som beskrevet under b). into a form. The further processing takes place as described under b).
d) Ved en ytterligere utførelsesform i henhold til oppfinnelsen blir de ellers retarderte pellets anbrakt sammen med d) In a further embodiment according to the invention, the otherwise retarded pellets are placed together with
bindemidlet i en form. Ved oppvarming blir bindemidlet jevnt fordelt mellom pelletene ved utvikling av et drivmiddel slik at det ønskede formlegeme oppstår etter avkjølingen. Som drivmiddel egner seg forbindelser som er farmakologisk akseptable og har et dekomponeringspunkt i området for binde-midlets smeltepunkt. Dessuten er lavtkokende oppløsnings-midler, som f.eks. hydrokarboner, halogenerte hydrokarboner, perhalogenerte hydrokarboner og alkoholer egnet som drivmiddel dersom disse er forlikelige med det retarderende overtrekk. Ved spesielt utformede former kan en inert gass, f.eks. press-luft, nitrogen, finne anvendelse som drivmiddel. the binder in a form. When heated, the binder is evenly distributed between the pellets by developing a propellant so that the desired shape is created after cooling. Suitable propellants are compounds that are pharmacologically acceptable and have a decomposition point in the range of the binder's melting point. In addition, low-boiling solvents, such as e.g. hydrocarbons, halogenated hydrocarbons, perhalogenated hydrocarbons and alcohols suitable as propellant if these are compatible with the retarding coating. With specially designed forms, an inert gas, e.g. compressed air, nitrogen, find use as a propellant.
Ved oppvarming (sintring) av formlegemet, spesielt ved de beskrevne fremgangsmåter b) og c), skjer det som følge av mykningen av pelletmassen en liten volumkontraksjon. For å forhindre sprekker og for å oppnå et enhetlig utseende, er det en fordel å utsette det fremdeles varme formlegemet for et lite trykk for å understøtte den ønskede forming. Herunder må de anvendte trykk selvsagt være så lave at pelletene, spesielt retarderingen av disse, ikke kan skades. Ved en egnet utforming av formene er det tilstrekkelig at formene skakes kortvarig for å oppnå en sammenpakning. When heating (sintering) the shaped body, especially in the described methods b) and c), a small volume contraction occurs as a result of the softening of the pellet mass. In order to prevent cracks and to achieve a uniform appearance, it is an advantage to subject the still warm mold body to a small pressure to support the desired shaping. Below this, the applied pressures must of course be so low that the pellets, especially their retardation, cannot be damaged. In the case of a suitable design of the forms, it is sufficient that the forms are shaken briefly to achieve compaction.
I en spesiell utførelsesform av fremgangsmåten i henhold til oppfinnelsen, benyttes dyptrukne folier av kunststoff med passende utforminger for formlegemet (med eventuell ytterligere utforminger for dannelse av delehakket). In a special embodiment of the method according to the invention, deep-drawn foils made of plastic are used with suitable designs for the mold body (with any additional designs for forming the dividing notch).
Fyllingen av foliene og fremstillingen av formlegemene foregår etter en av de fremgangsmåter som er beskrevet under a-d, idet folien samtidig benyttes som form. Etter avkjøling av formlegemene forsegles folien med aluminiumfolie. Ved bruk trykkes formlegemet ut gjennom aluminiumfolien. The filling of the foils and the production of the shaped bodies takes place according to one of the methods described under a-d, the foil being used as a mold at the same time. After the molds have cooled, the foil is sealed with aluminum foil. When in use, the molded body is pressed out through the aluminum foil.
Et formlegeme fremstillet etter fremgangsmåtene b, c eller d, kan alt etter mengden av det anvendte bindemiddel, oppvise en ujevn overflate. Dette har imidlertid ingen inn-flytelse på virkestoff-frigjøringsforholdene. Depending on the amount of binder used, a molded body produced according to methods b, c or d may have an uneven surface. However, this has no influence on the active substance release conditions.
Formlegemer fremstillet etter fremgangsmåte b oppviser en porøs indre struktur. Forbindelsen mellom de enkelte pellets består kun i de respektive berøringspunkter. Slike formlegemer har derfor gunstigere sønderdelingsegenskaper, ved at vann eller de tilsvarende fordøyelsesvæsker trenger hurtigere inn og kan oppløse bindemidlet. Shaped bodies produced according to method b have a porous internal structure. The connection between the individual pellets only consists of the respective contact points. Such shaped bodies therefore have more favorable disintegration properties, in that water or the corresponding digestive fluids penetrate faster and can dissolve the binder.
Når det ønskes, kan det oppnås en jevn overflate ved hjelp av et ytterligere overtrekk av bindemiddel eller en lakkering av formlegemet. When desired, a smooth surface can be achieved by means of a further coating of binder or a varnishing of the molded body.
I en spesiell utførelsesform for fremgangsmåter i henhold til oppfinnelsen kan formlegemene dessuten overtrekkes med en mavesaft-resistent eller retarderende lakkering. In a special embodiment of methods according to the invention, the shaped bodies can also be coated with a gastric juice-resistant or retarding coating.
I en spesiell utførelsesform kan det også benyttes mavesaft-resistente bindemidler slik at pellet-frigjøringen først skjer ved passasje gjennom tarmen. In a special embodiment, gastric juice-resistant binders can also be used so that the pellet is released only when it passes through the intestine.
Anordninger for oppdeling av formlegemet, f.eks. ved delehakk kan innføres ved tilsvarende utformede former eller foretas etterpå med et oppvarmet verktøy eller i det fremdeles myke, dvs. ikke avkjølte formlegeme, ved bearbeidning med et passende utformet verktøy. Devices for dividing the molded body, e.g. by partial notching can be introduced by correspondingly designed molds or carried out afterwards with a heated tool or in the still soft, i.e. not cooled, mold body by processing with a suitably designed tool.
En vesentlig fordel ved formlegemer av pellets fremstilt i henhold til oppfinnelsen, er at det ikke skjer noen mekanisk beskadigelse av de enkelte pellets. Herved bibeholdes de retarderende egenskaper av de enkelte pellets fullstendig, spesielt også etter en deling av formlegemt. Det er en selv-følge at formlegemene av pellets fremstilt i henhold til oppfinnelsen også kan fremstilles fra slike pellets som ikke er forsynt med en retarderende eller mavesaft-resistent omhylling. A significant advantage of shaped bodies made of pellets produced according to the invention is that no mechanical damage occurs to the individual pellets. In this way, the retarding properties of the individual pellets are completely retained, especially also after a division of the molded body. It is a matter of course that the shaped bodies of pellets produced according to the invention can also be produced from such pellets which are not provided with a retarding or gastric juice-resistant coating.
De etterfølgende eksempler skal illustere oppfinnelsen ytterligere uten å begrense oppfinnelsen til de illustrerte former. De former som er vist i Eksempel 1, ble fremstillet under bruk av vanlige fremgangsmåter for retarderte pellets. The following examples shall further illustrate the invention without limiting the invention to the illustrated forms. The shapes shown in Example 1 were produced using normal methods for retarded pellets.
Eksempel 1 Example 1
Ang. Fig. 1 Pellets av denne charge ble fylt over i fordyp ninger for kapsler i dyptrekksfolie og utstøpt med Ref. Fig. 1 Pellets of this charge were filled into depressions for capsules in deep-drawing foil and cast with
Polywachs 6000. Polywax 6000.
Ang. Fig. 2 Pellets av samme charge ble fylt over på Ref. Fig. 2 Pellets of the same charge were filled over
pulverformet Polywachs 6000 i mengdeforholdet 1:1 i en kapsellignende form, smeltet ved ca. 65°C og skjøvet inn i powdered Polywachs 6000 in a ratio of 1:1 in a capsule-like form, melted at approx. 65°C and pushed into
hverandre. Formen ble fjernet etter avkjølingen. each other. The mold was removed after cooling.
Ang. Fig.3 Fremstilling av et mulig delehakk. Fig.3 Production of a possible dividing notch.
Ang. Fig. 4 Pellets av samme charge ble oppvarmet med 20% Ref. Fig. 4 Pellets of the same charge were heated with 20%
Polywachs 20.000 i et begerglass og deretter omrørt med en glass-stav til fullstendig stivning. De således Polywachs-overtrukne pellets ble fylt over i en kapsel-lignende form med over- og under-del og oppvarmet til ca.65°C, hvorved formen langsomt ble skjøvet sammen. Etter Polywachs 20,000 in a beaker and then stirred with a glass rod until completely solidified. The Polywachs-coated pellets were filled into a capsule-like mold with an upper and lower part and heated to approximately 65°C, whereby the mold was slowly pushed together. After
avkjøling ble formen fjernet. cooling, the mold was removed.
Ang. Fig. 5 I en form-underdel ble det anbrakt 15-20% Ref. Fig. 5 In a mold lower part, 15-20% was placed
Polywachs 20.000 og litt ammoniumbikarbonat, hvorpå pelletene ble påfylt. Deretter ble en form-overdel med flere hull skjøvet over og blandingen sintret ved ca. Polywachs 20,000 and some ammonium bicarbonate, after which the pellets were filled. Then a mold top with several holes was pushed over and the mixture sintered at approx.
65°C. Overskuddet av gass og Polywachs kunne unnslippe.Ang. Fig. 6 Formlegemene ble fremstillet på samme måte som under 4. Det øvre formlegeme inneholdt 20% det nedre 30% Polywachs 20.000. Illustrasjonene viser forstørrede formlegemer. I tillegg til de tidligere beskrevne eksempler ble det fremstillet stangformer for å understreke utform-ningsmulighetene av de delbare formlegemer fremstilt i henhold til oppfinnelsen. 65°C. The surplus of gas and Polywachs could escape.Ang. Fig. 6 The molds were produced in the same way as under 4. The upper mold contained 20%, the lower 30% Polywachs 20,000. The illustrations show enlarged molded bodies. In addition to the previously described examples, rod forms were produced to emphasize the design possibilities of the divisible shaped bodies produced according to the invention.
Eksempel 2 Example 2
Placebo-pellets av siktfraksjon 0,6-0,71 mm ble forsynt med et overtrekk av 20 vektprosent polyetylenglykol 1500 i en drasjeringskjele. Placebo pellets of sieve fraction 0.6-0.71 mm were provided with a coating of 20% by weight polyethylene glycol 1500 in a coating pan.
Formene ble støpt av silikongummi ved å gjøre bruk av finmekanisk fremstillede stangmodeller av aluminium. Ved direkte sintring av ovennevnte pellets i en mikrobølgeovn og lett inntrykking av formen for hånd, oppsto stengene vist i The molds were cast from silicone rubber using finely machined aluminum rod models. By direct sintering of the above pellets in a microwave oven and lightly pressing the mold by hand, the rods shown in
Fig. 7. Fig. 7.
For å lukke mellomrommene ble det også fremstillet formlegemer som besto av pellets samt en ytterligere "ytre fase" av pulverformet polyetylenglykol (Fig. 8). In order to close the spaces, molded bodies were also produced which consisted of pellets as well as a further "outer phase" of powdered polyethylene glycol (Fig. 8).
De bekrevne plastisk-elastiske former muliggjør også fremstilling av innsnevrede formlegemer (Fig. 9). The required plastic-elastic forms also enable the production of narrowed shaped bodies (Fig. 9).
I Fig. 10 er det vist enkelte mulige utførelsesformer av formlegemene fremstilt i henhold til oppfinnelsen. In Fig. 10, some possible embodiments of the shaped bodies produced according to the invention are shown.
Claims (7)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19863610878 DE3610878A1 (en) | 1986-04-01 | 1986-04-01 | PELLET SHAPES |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| NO871350D0 NO871350D0 (en) | 1987-03-31 |
| NO871350L NO871350L (en) | 1987-10-02 |
| NO175513B true NO175513B (en) | 1994-07-18 |
| NO175513C NO175513C (en) | 1994-10-26 |
Family
ID=6297660
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO871350A NO175513C (en) | 1986-04-01 | 1987-03-31 | Process for the preparation of pellet moldings |
Country Status (17)
| Country | Link |
|---|---|
| EP (1) | EP0239983B1 (en) |
| JP (1) | JPS638327A (en) |
| KR (1) | KR950002881B1 (en) |
| AT (1) | ATE69547T1 (en) |
| AU (1) | AU600712B2 (en) |
| CA (1) | CA1314480C (en) |
| DE (2) | DE3610878A1 (en) |
| DK (1) | DK162887A (en) |
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| FI (1) | FI94313C (en) |
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| IL (1) | IL82065A0 (en) |
| MX (1) | MX5814A (en) |
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| NZ (1) | NZ219823A (en) |
| PT (1) | PT84604B (en) |
| ZA (1) | ZA872326B (en) |
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| KR100208052B1 (en) * | 1991-09-10 | 1999-07-15 | 모리따 가쓰라 | Divisible tablet |
| GB9422154D0 (en) | 1994-11-03 | 1994-12-21 | Euro Celtique Sa | Pharmaceutical compositions and method of producing the same |
| US5965161A (en) | 1994-11-04 | 1999-10-12 | Euro-Celtique, S.A. | Extruded multi-particulates |
| AUPP279698A0 (en) * | 1998-04-03 | 1998-04-30 | Sunscape Developments Limited | Sustained release formulation |
| DE19918325A1 (en) | 1999-04-22 | 2000-10-26 | Euro Celtique Sa | Extruded drug dosage form, e.g. granulate for tableting, comprising an active agent in a polysaccharide-containing matrix, giving a release profile which is controllable by extrusion conditions and/or the inclusion of additives |
| US7217381B2 (en) | 2001-09-28 | 2007-05-15 | Mcneil-Ppc, Inc. | Systems, methods and apparatuses for manufacturing dosage forms |
| CN1638740A (en) | 2001-09-28 | 2005-07-13 | 麦克内尔-Ppc股份有限公司 | Modified release dosage forms |
| US7122143B2 (en) | 2001-09-28 | 2006-10-17 | Mcneil-Ppc, Inc. | Methods for manufacturing dosage forms |
| US6837696B2 (en) | 2001-09-28 | 2005-01-04 | Mcneil-Ppc, Inc. | Apparatus for manufacturing dosage forms |
| US7838026B2 (en) | 2001-09-28 | 2010-11-23 | Mcneil-Ppc, Inc. | Burst-release polymer composition and dosage forms comprising the same |
| US6982094B2 (en) | 2001-09-28 | 2006-01-03 | Mcneil-Ppc, Inc. | Systems, methods and apparatuses for manufacturing dosage forms |
| US7807197B2 (en) | 2002-09-28 | 2010-10-05 | Mcneil-Ppc, Inc. | Composite dosage forms having an inlaid portion |
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|---|---|---|---|---|
| US2996431A (en) * | 1953-12-16 | 1961-08-15 | Barry Richard Henry | Friable tablet and process for manufacturing same |
| FR1540950A (en) * | 1967-04-27 | 1968-10-04 | Process for packaging oral absorbable medicinal substances | |
| DE1766546C3 (en) * | 1968-06-11 | 1974-11-28 | Karl Gunnar Lidingoe Eriksson | Process for the production of solid drug preparations in the form of tablets or tablets |
| NL6808619A (en) * | 1968-06-19 | 1969-12-23 | ||
| DK123806B (en) * | 1970-06-08 | 1972-08-07 | Pharmacia As | Process for the preparation of tablets or pills with slow release of an active substance. |
| GB1425550A (en) * | 1973-04-25 | 1976-02-18 | Alza Corp | Device for releasing active agent and process for producing the same |
| DE2336218C3 (en) * | 1973-07-17 | 1985-11-14 | Byk Gulden Lomberg Chemische Fabrik Gmbh, 7750 Konstanz | Oral dosage form |
| SE414386B (en) * | 1976-03-10 | 1980-07-28 | Aco Laekemedel Ab | VIEW TO PREPARE AND AT THE SAME PACKAGE PHARMACEUTICAL DOSAGE UNITS |
| DE2620456A1 (en) * | 1976-05-08 | 1977-11-10 | Enterofagos Gmbh | Tablets contg. discrete granules esp. of pectin - are bonded together by fillers contg. vitamins and trace elements and give exact dosage |
| US4258027A (en) * | 1979-03-26 | 1981-03-24 | Mead Johnson & Company | Multi-fractionable tablet structure |
| DE3532692A1 (en) * | 1985-09-13 | 1987-03-19 | Boehringer Mannheim Gmbh | METHOD FOR PRODUCING TABLETS FROM PELLETS |
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1986
- 1986-04-01 DE DE19863610878 patent/DE3610878A1/en not_active Ceased
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1987
- 1987-03-30 FI FI871378A patent/FI94313C/en not_active IP Right Cessation
- 1987-03-30 KR KR1019870002929A patent/KR950002881B1/en not_active IP Right Cessation
- 1987-03-31 NZ NZ219823A patent/NZ219823A/en unknown
- 1987-03-31 JP JP62079534A patent/JPS638327A/en active Pending
- 1987-03-31 ZA ZA872326A patent/ZA872326B/en unknown
- 1987-03-31 AT AT87104716T patent/ATE69547T1/en not_active IP Right Cessation
- 1987-03-31 IL IL82065A patent/IL82065A0/en not_active IP Right Cessation
- 1987-03-31 CA CA000533393A patent/CA1314480C/en not_active Expired - Fee Related
- 1987-03-31 ES ES198787104716T patent/ES2027246T3/en not_active Expired - Lifetime
- 1987-03-31 DK DK162887A patent/DK162887A/en not_active IP Right Cessation
- 1987-03-31 NO NO871350A patent/NO175513C/en unknown
- 1987-03-31 DE DE8787104716T patent/DE3774601D1/en not_active Expired - Lifetime
- 1987-03-31 MX MX581487A patent/MX5814A/en unknown
- 1987-03-31 EP EP87104716A patent/EP0239983B1/en not_active Expired - Lifetime
- 1987-04-01 AU AU70956/87A patent/AU600712B2/en not_active Ceased
- 1987-04-01 PT PT84604A patent/PT84604B/en not_active IP Right Cessation
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1992
- 1992-01-27 GR GR920400090T patent/GR3003661T3/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP0239983A2 (en) | 1987-10-07 |
| DK162887A (en) | 1987-10-02 |
| DE3774601D1 (en) | 1992-01-02 |
| KR870009719A (en) | 1987-11-30 |
| PT84604A (en) | 1987-05-01 |
| GR3003661T3 (en) | 1993-03-16 |
| FI871378A (en) | 1987-10-02 |
| AU7095687A (en) | 1987-10-08 |
| DE3610878A1 (en) | 1987-10-08 |
| NO871350D0 (en) | 1987-03-31 |
| PT84604B (en) | 1989-11-30 |
| KR950002881B1 (en) | 1995-03-28 |
| NO871350L (en) | 1987-10-02 |
| DK162887D0 (en) | 1987-03-31 |
| FI94313C (en) | 1995-08-25 |
| CA1314480C (en) | 1993-03-16 |
| FI871378A0 (en) | 1987-03-30 |
| IL82065A0 (en) | 1987-10-20 |
| NZ219823A (en) | 1990-05-28 |
| JPS638327A (en) | 1988-01-14 |
| ES2027246T3 (en) | 1992-06-01 |
| ZA872326B (en) | 1988-12-28 |
| FI94313B (en) | 1995-05-15 |
| EP0239983B1 (en) | 1991-11-21 |
| MX5814A (en) | 1993-10-01 |
| EP0239983A3 (en) | 1988-11-30 |
| ATE69547T1 (en) | 1991-12-15 |
| AU600712B2 (en) | 1990-08-23 |
| NO175513C (en) | 1994-10-26 |
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