NO320380B1 - Fremgangsmate for fremstilling av vedvarende frigivelsespartikler - Google Patents
Fremgangsmate for fremstilling av vedvarende frigivelsespartikler Download PDFInfo
- Publication number
- NO320380B1 NO320380B1 NO19971965A NO971965A NO320380B1 NO 320380 B1 NO320380 B1 NO 320380B1 NO 19971965 A NO19971965 A NO 19971965A NO 971965 A NO971965 A NO 971965A NO 320380 B1 NO320380 B1 NO 320380B1
- Authority
- NO
- Norway
- Prior art keywords
- diluent
- carrier
- fusible
- optionally
- soluble
- Prior art date
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- VMXUWOKSQNHOCA-LCYFTJDESA-N ranitidine Chemical compound [O-][N+](=O)/C=C(/NC)NCCSCC1=CC=C(CN(C)C)O1 VMXUWOKSQNHOCA-LCYFTJDESA-N 0.000 description 1
- 229960003320 roxatidine Drugs 0.000 description 1
- 229960002052 salbutamol Drugs 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229960002370 sotalol Drugs 0.000 description 1
- ZBMZVLHSJCTVON-UHFFFAOYSA-N sotalol Chemical compound CC(C)NCC(O)C1=CC=C(NS(C)(=O)=O)C=C1 ZBMZVLHSJCTVON-UHFFFAOYSA-N 0.000 description 1
- 239000012798 spherical particle Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- GGCSSNBKKAUURC-UHFFFAOYSA-N sufentanil Chemical compound C1CN(CCC=2SC=CC=2)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 GGCSSNBKKAUURC-UHFFFAOYSA-N 0.000 description 1
- 229960004739 sufentanil Drugs 0.000 description 1
- 229960000468 sulfalene Drugs 0.000 description 1
- KXRZBTAEDBELFD-UHFFFAOYSA-N sulfamethopyrazine Chemical compound COC1=NC=CN=C1NS(=O)(=O)C1=CC=C(N)C=C1 KXRZBTAEDBELFD-UHFFFAOYSA-N 0.000 description 1
- 229960004940 sulpiride Drugs 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229960002871 tenoxicam Drugs 0.000 description 1
- LZNWYQJJBLGYLT-UHFFFAOYSA-N tenoxicam Chemical compound OC=1C=2SC=CC=2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 LZNWYQJJBLGYLT-UHFFFAOYSA-N 0.000 description 1
- VCKUSRYTPJJLNI-UHFFFAOYSA-N terazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1CCCO1 VCKUSRYTPJJLNI-UHFFFAOYSA-N 0.000 description 1
- 229960001693 terazosin Drugs 0.000 description 1
- 229960000195 terbutaline Drugs 0.000 description 1
- 229960000351 terfenadine Drugs 0.000 description 1
- IWVCMVBTMGNXQD-UHFFFAOYSA-N terramycin dehydrate Natural products C1=CC=C2C(O)(C)C3C(O)C4C(N(C)C)C(O)=C(C(N)=O)C(=O)C4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-UHFFFAOYSA-N 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- MNRILEROXIRVNJ-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=NC=N[C]21 MNRILEROXIRVNJ-UHFFFAOYSA-N 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
- 229960005013 tiotixene Drugs 0.000 description 1
- 229960002872 tocainide Drugs 0.000 description 1
- 229960002277 tolazamide Drugs 0.000 description 1
- OUDSBRTVNLOZBN-UHFFFAOYSA-N tolazamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1CCCCCC1 OUDSBRTVNLOZBN-UHFFFAOYSA-N 0.000 description 1
- LLPOLZWFYMWNKH-UHFFFAOYSA-N trans-dihydrocodeinone Natural products C1C(N(CCC234)C)C2CCC(=O)C3OC2=C4C1=CC=C2OC LLPOLZWFYMWNKH-UHFFFAOYSA-N 0.000 description 1
- PHLBKPHSAVXXEF-UHFFFAOYSA-N trazodone Chemical compound ClC1=CC=CC(N2CCN(CCCN3C(N4C=CC=CC4=N3)=O)CC2)=C1 PHLBKPHSAVXXEF-UHFFFAOYSA-N 0.000 description 1
- 229960003991 trazodone Drugs 0.000 description 1
- ZEWQUBUPAILYHI-UHFFFAOYSA-N trifluoperazine Chemical compound C1CN(C)CCN1CCCN1C2=CC(C(F)(F)F)=CC=C2SC2=CC=CC=C21 ZEWQUBUPAILYHI-UHFFFAOYSA-N 0.000 description 1
- 229960002324 trifluoperazine Drugs 0.000 description 1
- XSCGXQMFQXDFCW-UHFFFAOYSA-N triflupromazine Chemical compound C1=C(C(F)(F)F)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 XSCGXQMFQXDFCW-UHFFFAOYSA-N 0.000 description 1
- 229960003904 triflupromazine Drugs 0.000 description 1
- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 description 1
- 229960001082 trimethoprim Drugs 0.000 description 1
- 229960001128 triprolidine Drugs 0.000 description 1
- CBEQULMOCCWAQT-WOJGMQOQSA-N triprolidine Chemical compound C1=CC(C)=CC=C1C(\C=1N=CC=CC=1)=C/CN1CCCC1 CBEQULMOCCWAQT-WOJGMQOQSA-N 0.000 description 1
- IRGJVQIJENCTQF-UHFFFAOYSA-N tritoqualine Chemical compound CN1CCC2=CC=3OCOC=3C(OC)=C2C1C1C2=C(OCC)C(OCC)=C(OCC)C(N)=C2C(=O)O1 IRGJVQIJENCTQF-UHFFFAOYSA-N 0.000 description 1
- UMKFEPPTGMDVMI-UHFFFAOYSA-N trofosfamide Chemical compound ClCCN(CCCl)P1(=O)OCCCN1CCCl UMKFEPPTGMDVMI-UHFFFAOYSA-N 0.000 description 1
- 229960000875 trofosfamide Drugs 0.000 description 1
- 229960001130 urapidil Drugs 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- 229960001255 viloxazine Drugs 0.000 description 1
- DKRSEIPLAZTSFD-LSDHHAIUSA-N viquidil Chemical compound C12=CC(OC)=CC=C2N=CC=C1C(=O)CC[C@@H]1CCNC[C@@H]1C=C DKRSEIPLAZTSFD-LSDHHAIUSA-N 0.000 description 1
- 229960003353 viquidil Drugs 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-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
-
- 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
-
- 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
- A61K9/1682—Processes
- A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
Landscapes
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Glanulating (AREA)
Description
Foreliggende oppfinnelse vedrører generelt en fremgangsmåte for fremstilling av farmasøytiske doseringsformer for human eller veterinær bruk, fortrinnsvis partikler med langvarig frigivningsvirkning, hvor slike partikler har diametre varierende fra 0,1 til 3,0 mm. Slike partikler kan inneholde analgetika, slik som morfin, eller andre aktive bestanddeler.
I søkerens samtidige GB-patentsøknad 9404928.5 beskrives en fremgangsmåte for fremstilling av partikler, fortrinnsvis partikler med langvarig frigivningsvirkning, som omfatter: (a) mekanisk bearbeidelse i en høyskjærblander av en blanding av et spesielt legemiddel og en partikkelformig, hydrofob og/eller hydrofil smeltbar bærer eller fortynningsmiddel som har et smeltepunkt fra 35 til 150°C og eventuelt en frigivningsregulerende komponent omfattende et vannoppløselig smeltbart materiale eller et partikkelformig, oppløselig eller uoppløselig organisk eller uorganisk materiale, ved en hastighet og et energiinntak som gjør at bæreren eller fortynningsmidlet smelter eller mykner hvorved det danner agglomerater; (b) nedbrytning av agglomeratene for oppnåelse av partikler med regulert
frigivningsvirkning; og eventuelt
(c) fortsettelse av mekanisk bearbeiding eventuelt med tilsetning av en lav
prosentandel av bæreren eller fortynningsmidlet; og eventuelt
(d) gjentagelse av trinn (c) og eventuelt (b) en eller flere ganger.
Det har nå blitt funnet at tilfredsstillende resultater også kan oppnås dersom, istedenfor klassifisering av det agglomererte materiale i trinn b), materialet fra trinn a) dannes til ekstrudater av forutbestemt størrelse, og i foretrukne utførelser kan høyere utbytter og/eller høyere legemiddelladninger, og større størrelsesensartethet, enn i den tidligere prosess som først er nevnt ovenfor, og fremdeles med oppnåelse av tilfredsstillende regulerte frigivningsegenskaper.
Foreliggende oppfinnelse innbefatter således ifølge et aspekt en fremgangsmåte for fremstilling av partikler, fortrinnsvis partikler med langvarig frigivningsvirkning, som innbefatter: (a) mekanisk bearbeidelse i en høyskjærblander, av en blanding av et partikulært legemiddel og en partikulær, hydrofob og/eller hydrofil smeltbar bærer eller fortynningsmiddel som har et smeltepunkt fra 35 til 150°C og eventuelt en frigivelseskontrollkomponent som innbefatter et vannløselig, smeltbart materiale eller et partikulært, løselig eller uløselig organisk eller uorganisk materiale, ved en hastighet og energitilførsel som gjør at bæreren eller fortynningsmidlet
smelter eller mykgjøres, hvorved det danner agglomerater; og
(b) ekstrudere materialet gjennom en pluralitet av åpninger, som danner ekstrudatet
til materialbiter,
(c) kontinuerlig mekanisk bearbeidelse av ekstrudatbitene eventuelt med tilsetning
av en lav prosentandel av bæreren eller fortynningsmidlet; og eventuelt
(d) gjenta trinn (c) og mulig (b) en eller flere ganger.
Ekstrudering og omdannelse til korte lengder ved oppskjæring kan utføres ved anvendelse av f. eks. en Alexanderwerk-, Caleva- eller Nica-maskin.
Ekstruderingsoperasjoner er velkjent innen formuleringsområdet og er beskrevet for eksempel i Pharmaceutical Dosage Forms, volum 2, utgiver Lieberman og Lachman, Marcel Dehker Inc., New York og Basel.
Denne fremgangsmåten er i stand til å gi et høyt utbytte, generelt over 85%, og fortrinnsvis over 90%, av partikler i et ønsket størrelsesområde, med en ønsket in vitro frigivningshastighet og jevnhet med hensyn til frigivningshastighet.
De resulterende partiklene kan siktes for å eliminere eventuelt materiale i overstørrelse eller understørrelse og derved foreta forming til de ønskede doseringsenhetene ved for eksempel innkapsling i harde gelatinkapsler inneholdende den nødvendige dosen av den aktive substansen eller ved tablettering, fylling i små poser eller støping til suppositorier, pessarer eller dannelse til andre egnede doseringsformer.
Legemidlet kan være vannoppløselig eller vannuoppløselig. Vannoppløselige legemidler vil vanligvis bli benyttet i mengder som gir for eksempel en ladning på opptil ca. 90% vekt/vekt i de resulterende partiklene; vannuoppløselige legemidler kan anvendes i større mengder f. eks. opptil 99% vekt/vekt av de resulterende partiklene. Eksempler på vannoppløselige legemidler som kan anvendes i foreliggende fremgangsmåte er morfin, hydromorfon, diltiazem, diamorfin og tramadol og farmasøytisk akseptable salter derav; eksempler på vannuoppløselige legemidler som kan anvendes i foreliggende fremgangsmåte er naproksen, ibuprofen, indometacin og nifedipin.
Blant de aktive bestanddelene som kan anvendes i foreliggende fremgangsmåte er følgende: Dihydrokodein, hydromorfon, morfin, diamorfin, fentanyl, alflentanil, sufentanyl, pentazocin, buprenorfln, nefopam, dekstropropoksyfen, flupirtin, tramadol, oksykodon, metamizol, propyfenazon, fenazon, nifenazon, paracetamol, fenylbutazon, oksyfenbutazon, mofebutazon, acetylsalicylsyre, diflunisal, flurbiprofen, ibuprofen, diklofenac, ketoprofen, indometacin, naproksen, meptazinol, metadon, petidin, hydrokodon, meloksikam, fenbufen, mefenaminsyre, piroksikam, tenoksikam, azapropazon, kodein.
Feniramin, dimetinden, terfenadin, astemizol, tritoqualin, loratadin, doksylamin, mequitazin, deksklorfeniramin, triprolidin, oksatomid.
Klonidin, moksonidin, metyldopa, doksazosin, prazosin, urapidil, terazosin, minoksidil, dihydralazin, deserpidin, acebutalol, alprenolol, atenolol, metoprolol, bupranolol, penbutolol, propranolol, esmolol, bisoprolol, ciliprolol, sotalol, metipranolol, nadolol, oksprenolol, nifedipin, nicadipin, verapamil, diltiazem, felodipin, nimodipin, flunarizin, quinapril, lisinopril, kaptopril, ramipril, fosinopril, cilazapril, enalapril.
Democlocyklin, doksycyklin, lymecyklin, minocyklin, oksytetracyklin, tetracyklin, sulfametopyrazin, ofloksacin, ciproflaksacin, aerosoksacin, amoksycillin, ampicillin, becampicillin, piperacillin, pivampicillin, cloksacillin, penicillin V, flucloksacillin, erythromycin, metronidazol, clindamycin, trimetoprim, neomycin, cefaklor, cefadroksil, cefiksim, cefpodoksim, cefuroksin, cefaleksin, cefradin.
Pirbuterol, orciprenalin, terbutalin, fenoterol, clenbuterol, salbutamol, procaterol, teofyllin, cholinteofyllinat, teofyllin-etylendiamin, ketofen.
Viquidil, procainamid, meksiletin, tocainid, propafenon, ipratropium.
Amantadin, levodopa, biperiden, benzotropin, bromocriptin, procyklidin, moclobemid, tranylcypromid, clomipramin, maprotilin, doksepin, opipramol, amitriptylin, desipramin, imipramin, fluroksamin, fluoksetin, paroksetin, trazodon, viloksazin, fiufenazin, perfenazin, prometazin, tioridazin, triflupromazin, protipendyl, tiotiksen, klorprotiksen, haloperidol, pipamperon, pimozid, sulpirid, fenetyllin, metylfenildat, trifluoperazin, tioridazin, oksazepam, lorazepam, bromoazepam, alprazolam, diazepam, clobazam, buspiron, piracetam.
Melfalan, cyklofosfamid, trofosfamid, klorambucil, lomustin, busulfan, prednimustin, fluorouracil, metotreksat, merkaptopurin, tioguanin, hydroksykarbamid, altretamin, prokarbazin.
Lisurid, metysergid, dihydroergotamin, ergotamin, pizotifen.
Cimetidin, famotidin, ranitidin, roksatidin, pirenzipin, omeprazol, misoprostol, proglumid, cisaprid, bromoprid, metoclopramid.
Tobutamid, glibenclamid, glipizid, gliquidon, gliborurid, tolazamid, acarbos og farmasøytisk aktive salter eller estere av de ovennevnte og kombinasjoner av to eller flere av de ovennevnte eller salter eller estere derav.
Hydrolysen av legemidler utgjør den mest hyppige, og kanskje derfor den viktigste, veien når det gjelder legemiddeldekomponering. Analyse av en samling av stabilitetsdata i Connors KA, Amidon GL, Stella VJ, Chemical stability of pharmaceuticals, A handbook for pharmacists, 2. utgave, New York; John Wiley & Sons, 1986, en standardtekst, viser at over 70% de studerte legemidlene gjennomgår hydrolytiske nedbrytningsreaksjoner. Av disse kan 61,4% klassifiseres som reaksjoner til karboksylsyrederivater (estere, amider, tiolestere, laktamer, imider), 20% ril karbonylderivater (iminer, oksimer), 14,3% til nukleofile forskyvninger, og 4,3% til fosforsyrederivater. Cefalosporiner, penicilliner og barbiturater er spesielt følsomme legemiddelklasser.
Foreliggende fremgangsmåte kan med fordel anvendes for fremstilling av doseringsformer som inneholder aktive substanser som nevnt ovenfor som er ustabile i nærvær av vann, f. eks. diamorfm. Stabile formuleringer av slike legemidler som har normale eller regulerte frigivningsegenskaper kan således oppnås ifølge foreliggende oppfinnelse.
I en foretrukket fremgangsmåte ifølge oppfinnelsen anvendes morfinsulfat, eller et annet vannoppløselig legemiddel, f. eks. tramadol, i en mengde som resulterer i partikler inneholdende f. eks. mellom <1% og 90%, spesielt mellom ca. 45% og ca. 85% f. eks. 75 vekt/vekt aktiv bestanddel for et høydoseprodukt og f. eks. <1 og 45% for et lavdoseprodukt.
I foreliggende fremgangsmåte blir fortrinnsvis alt av legemidlet tilsatt i trinn (a) sammen med en større mengde av den benyttede hydrofobe eller hydrofile smeltbare bæreren eller fortynningsmidlet. Mengden av smeltbar bærer eller fortynningsmiddel som tilsettes i trinn (a) er fortrinnsvis mellom f. eks. 10% og <99% vekt/vekt av totalmengden av bestanddeler som tilsettes i hele produksjonsoperasjonen.
I trinn (c) er mengden av eventuell ytterligere tilsatt smeltbar bærer eller fortynningsmiddel fortrinnsvis mellom 5% og 75% vekt/vekt av totalmengden av tilsatte bestanddeler. Det ytterligere materialet kan tilsettes trinnvis.
Trinn (a) i fremgangsmåten kan utføres i konvensjonelle høyskjærblandere med et standard indre av rustfritt stål, f. eks. en Collette Vactron 75 eller ekvivalent blander. Blandingen prosesseres inntil en lagtemperatur over 40"C er oppnådd og den resulterende blandingen får en kohesiv granulær tekstur, med partikkelstørrelser varierende fra ca. 1-3 mm til fint pulver i tilfelle for ikke-aggregert opprinnelig materiale. I forbindelse med de nedenfor beskrevne utførelser har slikt materiale utseende av agglomerater som ved avkjøling under 40°C har strukturell integritet og resistens overfor knusing mellom fingrene. Ved dette trinnet har agglomeratene en uregelmessig størrelse, form og utseende. Den resulterende massen blir deretter ekstrudert som beskrevet ovenfor.
I en foretrukket form av foreliggende fremgangsmåte fortsettes prosessering av de ekstruderte materialene inntil de hydrofobe og/eller hydrofile, smeltbare bærer- eller fortynningsmiddelmaterialene som benyttes begynner å mykne eller smelte og ytterligere hydrofobt og/eller hydrofilt, smeltbart bærer- eller fortynningsmiddel-materiale blir deretter tilsatt. Blanding fortsettes inntil blandingen har blitt omdannet til partikler i det ønskede, forutbestemte størrelsesområdet.
For å sikre jevnt energiinntak til bestanddelene i hurtigblanderen er det foretrukket å tilføre i det minste en del av energien ved hjelp av mikrobølgeenergi.
Energi kan også leveres gjennom andre midler slik som en varmekappe eller via blandeskovlene og kuttebladene.
Etter at partiklene har blitt dannet blir de siktet for å fjerne eventuelt materiale av overstørrelse eller understørrelse og deretter blir de avkjølt eller får avkjøles.
De resulterende partiklene kan benyttes for fremstilling av doseringsenheter, f. eks.
tabletter eller kapsler, på i og for seg kjent måte.
Det har blitt funnet at ved egnet utvalg av materialene som anvendes for dannelse av partiklene og ved tabletteringen og de mengdeforhold i hvilke de anvendes, så oppnås en betydelig grad av kontroll med hensyn til de endelige oppløsnings- og frigivningsmengdene av de aktive bestanddelene fra de komprimerte tablettene.
Egnede stoffer for bruk som hydrofobe bærer- eller fortynningsmiddelmaterialer er naturlige eller syntetiske vokser eller oljer, for eksempel hydrogenert vegetabilsk olje, hydrogenert ricinusolje, bivoks, karnaubavoks, mikrokrystallinsk voks og glycerolmonostearat, og de har hensiktsmessig smeltepunkter fra 35 til 150°C, fortrinnsvis fra 45 til 90°C.
Egnede stoffer for bruk som hydrofil bærer eller fortynningsmiddel er polyetylenglykoler (PEG'er) av varierende molekylvekter, f. eks. 1000 til 20.000, fortrinnsvis 4000 til 10.000.
Den eventuelt tilsatte frigivningsregulerende komponenten kan, når den er et vannoppløselig, smeltbart materiale, være et PEG-materiale av passende molekylvekt; egnede partikkelformige uorganiske og organiske materialer er dikalsiumfosfat, kolloidalt vannfritt silisiumdioksid, kalsiumsulfat, talk, laktose, poloksamerer, mikrokrystallinsk cellulose, stivelse, hydroksypropylcellulose, hydroksypropylmetyl-cellulose.
I foreliggende fremgangsmåte velges temperaturen i blandebeholderen gjennom hele den mekaniske bearbeidelsen slik at for sterk adhesjon unngås, hensiktsmessig for å minimalisere adhesjon av materialet til beholderens vegger. For å minimalisere adhesjon har det generelt blitt funnet at temperaturen verken bør være for høy eller for lav med hensyn til materialets smeltetemperatur og den kan lett optimaliseres for å unngå de ovennevnte problemene. I fremgangsmåtene som er beskrevet nedenfor i eksemplene har det for eksempel blitt funnet at en beholdertemperatur på ca. 50-60°C er tilfredsstillende og unngår adhesjon til beholderen. Det er ikke mulig å generalisere med hensyn til den passende temperaturen eller tidsperioden for den mekaniske bearbeidelsen for noen spesiell blanding som skal prosesseres. I praksis er det imidlertid her tale om enkel eksperimentering og observasjoner for å fastsette en egnet temperatur og prosesseringstid for en spesiell aktuell blanding.
For å fremstille tabletter ifølge oppfinnelsen kan partikler fremstilt som beskrevet i det ovenstående blandes med de ønskede eksipiensen(e), dersom slike benyttes, ved bruk av konvensjonelle prosedyrer, for eksempel ved anvendelse av en "Y-Cone" eller "bin"-blander og den resulterende blanding komprimeres ifølge konvensjonell tabletterings-prosedyre ved bruk av et tabletteringsverktøy av egnet størrelse. Det kan fremstilles tabletter ved bruk av konvensjonell tabletteringsapparatur, og bli fremstilt i de nedenfor beskrevne utførelsene i en standard F3 Manesty enkeltstansemaskin eller Kilian RLE 15 roterende tablettmaskin.
Generelt finner man at selv med sterkt vannoppløselige, aktive midler slik som salter av morfin elleer tramadol, så gir tabletter dannet ved komprimering i overensstemmelse med standard metoder meget lave in vitro frigivningsmengder av den aktive bestanddelen, f. eks. tilsvarende frigivning over en periode på over 24 timer, f. eks. over 36 timer. Det har blitt funnet at in vitro frigivriingsprofilen kan justeres på en rekke forskjellige måter. For eksempel i tilfelle for vannoppløselige legemidler vil en høyere ladning av legemidlet forbindes med forøkede frigivningsmengder; anvendelse av større mengdeforhold av det vannoppløselige, smeltbare materialet i partiklene eller overflate-aktivt middel i tabletteringsformuleringen vil også assosieres med en høyere frigivnings-mengde av den aktive bestanddelen. Således, ved regulering av de relative mengder av disse bestanddelene er det mulig å justere frigivningsprofilen til den aktive bestanddelen, enten denne er vannoppløselig eller vannuoppløselig.
For at oppfinnelsen skal fullt ut forstås, gis følgende eksempler som illustrasjon.
EKSEMPEL
700 g findelt, pulverisert morfinsulfat og 220 g findelt, pulverisert hydrogenert vegetabilsk olje ble plassert i beholderen til en 10 liters Collette Vactron blander (eller ekvivalent) utstyrt med blande- og granuleringsblader hvis hastighet kunne varieres. Bestanddelene ble blandet ved ca. 425 omdr./min idet kappetemperaturen var i området 55-65°C, inntil beholderens innhold var agglomerert. Massen ble ekstrudert gjennom 1
mm hull i en Alexanderwerk-ekstruder utstyrt med kutteblad plassert slik at ekstrudatet ble oppskåret til biter av en lengde på ca. 1,0 mm.
De korte lengdene av ekstrudatet ble oppsamlet og returnert til den varme beholderen i blanderen og blandeoperasjonen ble påbegynt på nytt. Etter at ekstrudatene ble generelt avrundet ble det tilsatt ytterligere 80 g findelt hydrogenert vegetabilsk olje til
beholderen, og blanding ble fortsatt i 3 minutter da ekstrudatene var generelt sfæriske.
De sfæriske partiklene ble fjernet fra beholderen, fikk avkjøles og ble deretter siktet for å isolere siktfraksjonen 0,5-2,0 mm.
Frigivningsmengdene for de siktede partiklene ble deretter bestemt ved hjelp av modifisert Ph. Eur. Basket metode ved 100 omdr./min i 900 ml vandig buffer (pH 6,5) inneholdende 0,05% vekt/vekt polysorbat 80 ved 37°C og resultatene er angitt i det nedenstående:
Claims (7)
1.
Fremgangsmåte for fremstilling av en vedvarende frigivelsespartikkel, karakterisert ved at den innbefatter: (a) mekanisk bearbeidelse i en høyskjærblander, av en blanding av et partikulært legemiddel og en partikulær, hydrofob og/eller hydrofil smeltbar bærer eller fortynningsmiddel som har et smeltepunkt fra 35 til 150°C og eventuelt en frigivelseskontrollkomponent som innbefatter et vannløselig, smeltbart materiale eller et partikulært, løselig eller uløselig organisk eller uorganisk materiale, ved en hastighet og energitilførsel som gjør at bæreren eller fortynningsmidlet smelter eller mykgjøres, hvorved det danner agglomerater; og (b) ekstrudere materialet gjennom en pluralitet av åpninger, som danner ekstrudatet til materialbiter, (c) kontinuerlig mekanisk bearbeidelse av ekstrudatbitene eventuelt med tilsetning av en lav prosentandel av bæreren eller fortynningsmidlet; og eventuelt (d) gjenta trinn (c) og mulig (b) en eller flere ganger.
2.
Fremgangsmåte ifølge krav 1, karakterisert ved at i løpet av den mekaniske bearbeidingen blir varme levert dertil ved mikrobølgestråling.
3.
Fremgangsmåte ifølge krav 2, karakterisert ved at kun en del av oppvarmingen leveres av mikrobølgestråling.
4.
Fremgangsmåte ifølge et hvilket som helst av kravene 1 til 2, karakterisert ved at legemidlet er morfintramadol, hydromorfon, oksykodon, diamorfin eller et farmasøytisk akseptabelt salt av en hvilken som helst av disse.
5.
Fremgangsmåte ifølge et hvilket som helst av kravene 1 til 4, karakterisert ved at den hydrofobe smeltbare bæreren eller fortynningsmidlet er en voks, for eksempel valgt fra hydrogenert vegetabilsk olje, hydrogenert kastorolje, bivoks, kamaubavoks, mikrokrystallinsk voks og glycerolmonostearat.
6.
Fremgangsmåte ifølge et hvilket som helst av kravene 1 til 5, karakterisert ved at det hydrofile smeltbare materialet eventuelt inkludert i blandingen i trinn (a) er PEG som har en molekylvekt på fra 1.000 til 20.000 eller en poloksamer.
7.
Fremgangsmåte ifølge et hvilket som helst av kravene 1 til 6, karakterisert ved at den smeltbare bæreren eller fortynningsmidlet tilsettes trinnvis i løpet av den mekaniske bearbeidingen i løpet av trinn (c).
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-
1994
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-
1995
- 1995-11-03 KR KR1019970702810A patent/KR100413581B1/ko not_active IP Right Cessation
- 1995-11-03 DK DK95936019T patent/DK0789559T4/da active
- 1995-11-03 US US08/817,956 patent/US6068855A/en not_active Expired - Lifetime
- 1995-11-03 TW TW084111629A patent/TW348062B/zh not_active IP Right Cessation
- 1995-11-03 JP JP51513496A patent/JP3504953B2/ja not_active Expired - Lifetime
- 1995-11-03 ZA ZA959308A patent/ZA959308B/xx unknown
- 1995-11-03 AU AU38110/95A patent/AU3811095A/en not_active Abandoned
- 1995-11-03 NZ NZ294897A patent/NZ294897A/xx not_active IP Right Cessation
- 1995-11-03 EP EP95936019A patent/EP0789559B2/en not_active Expired - Lifetime
- 1995-11-03 DE DE69509671T patent/DE69509671T3/de not_active Expired - Lifetime
- 1995-11-03 ES ES95936019T patent/ES2134501T5/es not_active Expired - Lifetime
- 1995-11-03 WO PCT/GB1995/002579 patent/WO1996014059A1/en active IP Right Grant
- 1995-11-03 AT AT95936019T patent/ATE179886T1/de active
-
1997
- 1997-04-28 NO NO19971965A patent/NO320380B1/no not_active IP Right Cessation
- 1997-05-02 FI FI971880A patent/FI114780B/fi not_active IP Right Cessation
-
1999
- 1999-08-10 GR GR990402019T patent/GR3030938T3/el unknown
-
2003
- 2003-08-12 JP JP2003292426A patent/JP2004043485A/ja active Pending
Also Published As
Publication number | Publication date |
---|---|
JPH10508597A (ja) | 1998-08-25 |
EP0789559B2 (en) | 2002-10-16 |
ES2134501T3 (es) | 1999-10-01 |
DE69509671T2 (de) | 2000-01-27 |
JP3504953B2 (ja) | 2004-03-08 |
DK0789559T4 (da) | 2002-11-25 |
FI971880A0 (fi) | 1997-05-02 |
KR970706801A (ko) | 1997-12-01 |
ZA959308B (en) | 1996-05-29 |
TW348062B (en) | 1998-12-21 |
NO971965L (no) | 1997-04-28 |
ES2134501T5 (es) | 2003-05-01 |
GR3030938T3 (en) | 1999-11-30 |
EP0789559A1 (en) | 1997-08-20 |
ATE179886T1 (de) | 1999-05-15 |
DE69509671D1 (de) | 1999-06-17 |
FI971880A (fi) | 1997-06-18 |
NZ294897A (en) | 1998-10-28 |
GB9422154D0 (en) | 1994-12-21 |
FI114780B (fi) | 2004-12-31 |
WO1996014059A1 (en) | 1996-05-17 |
KR100413581B1 (ko) | 2004-03-31 |
DK0789559T3 (da) | 1999-11-15 |
AU3811095A (en) | 1996-05-31 |
NO971965D0 (no) | 1997-04-28 |
JP2004043485A (ja) | 2004-02-12 |
EP0789559B1 (en) | 1999-05-12 |
US6068855A (en) | 2000-05-30 |
DE69509671T3 (de) | 2003-07-31 |
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