SI21301A - Pharmaceutical form with controlled release - Google Patents

Pharmaceutical form with controlled release Download PDF

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Publication number
SI21301A
SI21301A SI200200220A SI200200220A SI21301A SI 21301 A SI21301 A SI 21301A SI 200200220 A SI200200220 A SI 200200220A SI 200200220 A SI200200220 A SI 200200220A SI 21301 A SI21301 A SI 21301A
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Slovenia
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ketoprofen
pellet cores
pharmaceutical formulation
hours
pharmaceutical
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SI200200220A
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Slovenian (sl)
Inventor
Judita Širca
Milojka Mohar
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LEK farmacevtska družba d.d.
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Application filed by LEK farmacevtska družba d.d. filed Critical LEK farmacevtska družba d.d.
Priority to SI200200220A priority Critical patent/SI21301A/en
Priority to PCT/SI2003/000033 priority patent/WO2004024128A2/en
Priority to AU2003261067A priority patent/AU2003261067A1/en
Priority to EP03795550A priority patent/EP1539113A2/en
Publication of SI21301A publication Critical patent/SI21301A/en

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    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • 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
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

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  • 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)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

The invention relates to a pharmaceutical form of ketoprophen with controlled release, containing pellet cores which enable a quick release of ketoprophen and to coated pellets with sustained release, where the release is controlled for a longer period of time. The form is suitable for the two times a day dosage.

Description

Lek farmacevtska družba d. d.Lek pharmaceutical company d. d.

Farmacevtska oblika z nadzorovanim sproščanjemControlled release pharmaceutical form

Področje tehnike:Field of technology:

izum spada v področje farmacevtske tehnologije in se nanaša na farmacevtsko obliko z nadzorovanim sproščanjem, ki vsebuje ketoprofen.The invention relates to the field of pharmaceutical technology and relates to a controlled release pharmaceutical formulation containing ketoprofen.

Prikaz problema:View problem:

Pri skupini učinkovin, ki jo imenujemo nesteroidni antirevmatiki, obstaja stalna potreba po farmacevtskih oblikah, ki bi imele hiter analgetični učinek in antirevmatični učinek, ki bi trajal daljši čas. To težko dosežemo z običajnimi farmacevtskimi oblikami, ki hitro sprostijo vso učinkovino, imajo hiter analgetični učinek, antirevmatični učinek pa se izgubi. Nasprotno pri farmacevtskih oblikah s kontroliranim sproščanjem zaradi daljšega časa sproščanja učinkovine iz farmacevtske oblike dosežemo antirevmatični učinek, medtem ko je koncentracija učinkovine, ki se sprosti na začetku, premajhna za analgetični učinek.There is an ongoing need for pharmaceutical formulations in the group of substances called non-steroidal anti-rheumatics, which would have a rapid analgesic effect and a long-term anti-rheumatic effect. This is difficult to achieve with conventional dosage forms that rapidly release all the active substance, have a rapid analgesic effect, and the antirheumatic effect is lost. In contrast, controlled release pharmaceutical dosage forms have an antirheumatic effect due to the longer release time of the active substance, whereas the concentration of the active substance released initially is too low for analgesic effect.

Stanje tehnike:State of the art:

V US 4980170 so opisane farmacevtske oblike z učinkovinami iz skupine nesteroidnih antirevmatikov, ki vsebuje dve vrsti pelet. Prve so obložene z dvoslojno gastrorezistentno oblogo. Druga vrsta pelet je obložena s polprepustno oblogo za zadrževanje sproščanja.US 4980170 describes pharmaceutical formulations with active ingredients from the group of non-steroidal antirheumatics containing two types of pellets. The former are coated with a two-layer gastro-resistant coating. The second type of pellet is coated with a semi-permeable lining to hold the release.

US 5043167 se nanaša na farmacevtske oblike s programiranim sproščanjem nesteroidnih antirevmatikov, ki vsebuje dve vrsti granulata, granulat s hitrim sproščanjem in granulat s kontroliranim sproščanjem učinkovine. Sproščanje je uravnavano s sestavo granulata.US 5043167 relates to pharmaceutical formulations for the programmed release of non-steroidal anti-rheumatics, comprising two types of granulate, rapid-release granules and controlled-release granules. The release is controlled by the composition of the granulate.

V WO 99/12542 so opisane farmacevtske oblike z modificiranim sproščanjem nesteroidnih antirevmatikov, ki vsebujejo dve frakciji delcev z različnim profilom sproščanja. Prva frakcija, ki je lahko v obliki granul ali obloženih pelet, zagotavlja izredno hiter začeten terapevtski učinek. Že v 20 minutah se iz hitre frakcije sprosti najmanj 50 ut. % učinkovine. Druga frakcija so obložene pelete s troslojno oblogo, ki uravnava sproščanje učinkovine skozi daljši čas. Oblika je primerna tudi za enkrat dnevno doziranje.WO 99/12542 discloses modified release non-steroidal antirheumatic formulations containing two fractions of particles with different release profiles. The first fraction, which may be in the form of granules or coated pellets, provides an extremely rapid initial therapeutic effect. Within 20 minutes, at least 50 wt. % of the active substance. Another fraction is coated pellets with a three-layer coating that regulates the release of the active substance over time. The formulation is also suitable for once daily dosing.

Opis izuma:Description of the invention:

Izum se nanaša na farmacevtsko obliko ketoprofena z nadzorovanim sproščanjem, ki vsebuje peletna jedra, ki omogočajo hitro sproščanje ketoprofena in obložene pelete z zadržanim sproščanjem, pri katerih je sproščanje nadzorovano skozi daljši čas. Oblika vzdržuje ustrezne terapevtske nivoje ketoprofena v krvi skozi 12 ur in je primerna za dvakrat dnevno doziranje.The invention relates to a controlled release pharmaceutical form of ketoprofen containing pellet cores for the rapid release of ketoprofen and coated sustained release pellets in which release is controlled for a long time. The formulation maintains adequate therapeutic levels of ketoprofen in the blood for 12 hours and is suitable for twice daily dosing.

Farmacevtska oblika, ki je predmet izuma, je pacientu prijazna oblika. V želodcu zelo hitro razpade in pelete se porazdelijo po želodcu. S tem je lokalno draženje želodčne sluznice zelo zmanjšano v primerjavi s klasično farmacevtsko obliko, npr. tableto, ki celoten odmerek učinkovine združuje v eni enoti in povzroča močno lokalno draženje, kar lahko povzroči tudi poškodbe sluznice. Del pelet je obložen z oblogo, kar še dodatno ščiti sluznico.The pharmaceutical form of the invention is a patient-friendly form. It dissolves very quickly in the stomach and the pellets are distributed throughout the stomach. Thus, local irritation of the gastric mucosa is greatly reduced compared to the conventional pharmaceutical form, e.g. a pill that combines the entire dose of the active substance in one unit, causing severe local irritation, which can also cause mucosal damage. Part of the pellet is lined with liner, which further protects the mucous membrane.

Po dveh urah se iz oblike, ki je predmet tega izuma, sprosti 15 do 35 ut % ketoprofena, po šestih urah 50 do 80 ut. % ketoprofena in po osmih urah najmanj 85 ut. %. ketoprofena, merjeno 2 uri v 1000 ml simuliranega želodčnega soka s pH 1.2 , ure v 1000 ml fosfatnega pufra s pH 4.5 in 2 uri v 1000 ml fosfatnega pufra s pH 6.8, v rotirajoči košarici (USP 25) s 50 obrati na minuto.After two hours, 15 to 35% by weight of ketoprofen is released from the formulation of the present invention, 50 to 80% by weight after six hours. % ketoprofen and after eight hours at least 85 wt. %. ketoprofen, measured for 2 hours in 1000 ml of simulated gastric juice at pH 1.2, hours in 1000 ml of phosphate buffer at pH 4.5 and 2 hours in 1000 ml of phosphate buffer at pH 6.8, in a rotating basket (USP 25) at 50 rpm.

Sproščanje ketoprofena iz farmacevtske oblike, je nadzorovano s sestavo peletnih jeder, razmerjem neobloženih peletnih jeder in obloženih pelet ter s sestavo in debelino obloge.The release of ketoprofen from the pharmaceutical form is controlled by the composition of the pellet cores, the ratio of the uncoated pellet cores and the coated pellets, and by the composition and thickness of the coating.

Peletna jedra vsebujejo ketoprofen in pomožne snovi, ki se običajno uporabljajo pri izdelavi pelet. Peletna jedra lahko vsebujejo eno ali več polnil kot so laktoza, saharoza, glukoza, škrob, mikrokristalna celuloza, manitol, sorbitol, kalcijev hidrogen fosfat in druge, enega ali več vezalcev, kot so škrob, želatina, polivinilpirolidon, natrijev alginat, mikrokristalna celuloza, karboksimetilceluloza, nizko substituirana hidroksipropil celuloza in druge, enega ali več razgrajevalcev kot so, škrob, natrijeva kroskarmeloza, premreženi polivinilpirolidon, natrijev škrob glikolat in druge. Jedra lahko vsebujejo eno ali več površinsko aktivnih snovi kot so npr. ionske površinsko aktivne snovi, npr. natrijev lavril sulfat, neionske površinsko aktivne snovi, kot so naravni ali sintezni lecitini ter estri sorbitana in maščobnih kislin ( kot Špan®), estri polioksietiiensorbitana in maščobnih kislin (kot Polisorbati ali Tween®), polioksietilirana hidrogenirana ricinusova olja (kot Cremophor®) ali katerokoli kombinacije navedenih površinsko aktivnih spojin.Pellet cores contain ketoprofen and excipients commonly used in pellet making. Pellet cores may contain one or more fillers such as lactose, sucrose, glucose, starch, microcrystalline cellulose, mannitol, sorbitol, calcium hydrogen phosphate, and others, one or more binders such as starch, gelatin, polyvinylpyrrolidone, sodium alginate, microcrystalline cellulose, carboxymethylcellulose, low substituted hydroxypropyl cellulose and other, one or more degraders such as, starch, croscarmellose sodium, cross-linked polyvinylpyrrolidone, sodium starch glycolate and others. The nuclei may contain one or more surfactants such as e.g. ionic surfactants, e.g. sodium lauryl sulfate, non-ionic surfactants such as natural or synthetic lecithins, and sorbitan and fatty acid esters (such as Span®), esters of polyoxyethiensorbitan and fatty acids (such as Polysorbates or Tween®), polyoxyethylated hydrogenated castor oils any combination of said surfactants.

Farmacevtska oblika, ki je predmet izuma, vsebuje od 50 do 250 mg ketoprofena, prednostno 150 mg. Delež ketoprofena v peletnih jedrih je od 5 do 95 ut %, prednostno 60 do 90 ut.%.The dosage form of the invention comprises from 50 to 250 mg of ketoprofen, preferably 150 mg. The ketoprofen content in the pellet cores is from 5 to 95% by weight, preferably from 60 to 90% by weight.

Peletna jedra so lahko sestavljena tudi iz inertnega jedra, na katerega je nanesen ketoprofen skupaj z nekim vezalcem, ki je lahko škrob, želatina, polivinilpirolidon, natrijev alginat, mikrokristalna celuloza, karboksimetilceluloza, nizko substituirana hidroksipropil celuloza in drugi.Pellet cores may also be composed of an inert core to which ketoprofen is applied together with a binder, which may be starch, gelatin, polyvinylpyrrolidone, sodium alginate, microcrystalline cellulose, carboxymethylcellulose, low substituted hydroxypropyl cellulose and others.

Pelete za zadržano sproščanje so peletna jedra, na katere je nanešena pH neodvisna polimerna polprepustna obloga, ki uravnava sproščanje skozi daljši čas. Obloga prednostno vsebuje kopolimere amonijevega metakrilata, ki so opisani v USP 25 NF 20 kot popolnoma polimerizirani kopolimeri estrov akrilne in metakrilne kisline z nizko vsebnostjo kvarternih amonijevih skupin. Prednostna je obloga, ki vsebuje kombinacijo kopolimera amonijevega metakrilata tip A in kopolimera amonijevega metakrilata tip B (imenovanje po USP 25-NF 20) v razmerju od 7:3 do 3:7, prednostno 1:1. Komercialno sta polimera dostopna v obliki 30% vodne disperzije kot Eudragit RS 30 D in Eudragit RL 30 D (Rohm Pharma).Delayed release pellets are pellet cores that have a pH-independent polymeric semi-permeable coating that regulates release over time. The coating preferably contains copolymers of ammonium methacrylate, which are described in USP 25 NF 20 as fully polymerized copolymers of acrylic and methacrylic acid esters with low content of quaternary ammonium groups. A coating containing a combination of ammonium methacrylate type A copolymer and ammonium methacrylate type B copolymer (USP 25-NF 20 designation) in a ratio of 7: 3 to 3: 7, preferably 1: 1, is preferred. Commercially, the polymers are available in the form of 30% aqueous dispersion as Eudragit RS 30 D and Eudragit RL 30 D (Rohm Pharma).

Poleg naštetih polimerov obloga lahko vsebuje še enega ali več mehčalcev kot so polietilenglikoli različnih molskih mas, trietilcitrat, dibutilsebacat, tributilcitrat, cetilni alkohol, olivno ali ricinovo olje, monogliceride in druge običajne farmacevtsko sprejemljive pomožne snovi, ki se uporabljajo pri izdelavi oblog, kot so smukec, Polisorbat 80, pigmenti in magnezijev stearat.In addition to the above polymers, the coating may also contain one or more plasticizers such as polyethylene glycols of different molar masses, triethyl citrate, dibutylsebacate, tributyl citrate, cetyl alcohol, olive or castor oil, monoglycerides and other conventional pharmaceutically acceptable excipients used in the manufacture of the coating talc, Polysorbate 80, pigments and magnesium stearate.

Pelete z nadzorovanim sproščanjem ketoprofena vsebujejo od 3 do 50 ut. % obloge, prednostno od 5 do 15 ut. %.Controlled-release ketoprofen pellets contain from 3 to 50 wt. % lining, preferably from 5 to 15 wt. %.

Peletna jedra so izdelana na način, ki je običajen v farmacevtski industriji. Mokro zmes ketoprofena in pomožnih snovi ekstrudiramo na polžnem ekstrudorju in dobljen ekstrudat oblikujemo v pelete na sferonizatorju. Te potem sušimo v vrtinčasti plasti. Na peletna jedra lahko nanesemo polimerno oblogo s postopki, ki so običajni v farmacevtski tehnologiji.The pellet cores are manufactured in a manner customary in the pharmaceutical industry. The wet mixture of ketoprofen and excipients is extruded on a screw extruder and the resulting extrudate is molded into pellets on a spheronizer. These are then dried in a swirling layer. A polymer coating can be applied to the pellet cores using procedures customary in pharmaceutical technology.

Peletna jedra in obložene pelete v določenem razmerju polnimo v žeiatinske kapsule. Lahko pa jih skupaj s pomožnimi snovmi kot so npr laktoza, saharoza, glukoza, škrob, mikrokristalna celuloza, manitol, sorbitol, kalcijev hidrogen fosfat, nevtralna peletna jedra in druge, stisnemo tudi v tableto.The pellet cores and coated pellets are to a certain extent filled into zheatin capsules. However, they can also be compressed into a tablet together with excipients such as lactose, sucrose, glucose, starch, microcrystalline cellulose, mannitol, sorbitol, calcium hydrogen phosphate, neutral pellet cores and others.

Razmerje peletnih jeder in obloženih pelet v obliki, ki je predmet izuma, je od 80 : 20 do 20 : 80, prednostno približno 60 : 40 glede na odmerek ketoprofena v farmacevtski obliki. To pomeni, da je 60 ut % odmerka ketoprofena v obliki peletnih jeder in 40 ut. % odmerka ketoprofena v obliki obloženih pelet.The ratio of pellet cores and coated pellets of the present invention is from 80: 20 to 20: 80, preferably about 60: 40, relative to the dose of ketoprofen in the pharmaceutical form. This means that 60 wt% of the ketoprofen dose is in the form of pellet cores and 40 wt. % of the ketoprofen dose in the form of coated pellets.

Izum pojasnjujejo, vendar nikakor ne omejujejo naslednji izvedbeni primeri:The invention is explained, but in no way limited by the following embodiments:

Primer 1Example 1

JEDRA SAILS ketoprofen ketoprofen mg mg 150,00 150,00 Učinkovina The active ingredient Avicel PH101 Avicel PH101 mg mg 34,00 34.00 Polnilo Filler Laktoza 200 Lactose 200 mg mg 20,00 20,00 Polnilo Filler PVP K 25 PVP K 25 mg mg 10,00 10,00 Vezivo Binder Ac-Di-Sol Ac-Di-Sol mg mg 5,00 5,00 Razgrajevaiec Degrader Polisorbat 80 Polysorbate 80 mg mg 1,00 1.00 Površinsko aktivna snov Surfactant

OBLOGA Lining Eudragit RS 30 D Eudragit RS 30 D mg mg 34,84 34.84 Tvorec filma Creator of the movie Eudragit RL 30 D Eudragit RL 30 D mg mg 34,84 34.84 Tvorec filma Creator of the movie Trietilcitrat Triethylcitrate Mg Mg 5,00 5,00 Mehčalec Softener Polisorbat 80 Polysorbate 80 Mg Mg 0,04 0.04 Površinsko aktivna snov Surfactant Smukec Talc Mg Mg 6,00 6,00 Sredstvo proti lepljenju Anti-adhesive agent

Ketoprofen, mikrokristalno celulozo, laktozo, poiivinilpirolidon smo zmešali in dodali 140 g demineralizirane vode. Mokro zmes smo ekstrudirali na polžnem ekstrudorju in dobljen ekstrudat oblikovali v peiete na sferonizatorju. Tako dobljene mokre pelete smo posušili v vrtinčasti plasti. 60 ut % suhih pelet (peletna jedra) je počakalo na kapsuliranje, medtem ko smo preostalih 40 ut % peletnih jeder v nadaljevanju procesa obložili.Ketoprofen, microcrystalline cellulose, lactose, poivinylpyrrolidone were mixed and 140 g of demineralized water were added. The wet mixture was extruded on a screw extruder and the resulting extruder was molded into spheronizer pellets. The wet pellets thus obtained were dried in a swirling layer. 60 wt% of dry pellets (pellet cores) waited for encapsulation, while the remaining 40 wt% of pellet cores were coated during the process.

V napravo z vrtinčastim zrakom smo dali peletna jedra in nanje razprševali vodno disperzijo Eudragit RS 30 D in Eudragit RL 30 D, v katero smo dodali še trietilcitrat, Polisorbat in smukec.Pellet cores were added to the device with vortex air and sprayed with water dispersion Eudragit RS 30 D and Eudragit RL 30 D, to which were added triethyl citrate, polysorbate and talc.

Peletna jedra in obložene pelete smo na kapsulirki polnili v kapsule. V vsaki kapsuli je bilo 60 ut % peletnih jeder in 40 ut. % obloženih pelet.Pellet cores and coated pellets were filled into capsules on the capsule. Each capsule contained 60 wt% pellet cores and 40 wt. % coated pellets.

Test raztapljanjaDissolution test

Medij:Media:

Kisla faza Acid phase 1000 mL simuliranega želodčnega soka pH 1.2 1000 mL of simulated gastric juice pH 1.2 2 uri 2 hours Pufema faza The buffer phase 1000 mL fosfatnega pufra pH 4.5 1000 mL of phosphate buffer pH 4.5 4 ure 4 hours 1000 mL fosfatnega pufra pH 6.8 1000 mL of phosphate buffer pH 6.8 2 uri 2 hours

Aparat: Rotirajoča košarica (USP 25)Apparatus: Rotating basket (USP 25)

Obrati na minuto: 50RPM: 50

kapsula capsule % raztapljanja v urah % dissolution in hours 2 2 4 4 6 6 8 8 1 1 24,8 24,8 56,0 56,0 72,2 72,2 95,7 95,7 2 2 22,7 22.7 54,9 54,9 71,8 71,8 98,3 98.3 3 3 25,0 25,0 54,7 54.7 69,9 69,9 96,6 96.6 4 4 21,8 21.8 53,6 53,6 70,8 70,8 99,1 99.1 5 5 22,4 22,4 55,8 55,8 70,6 70.6 98,7 98.7 6 6 21,9 21.9 46,8 46,8 61,9 61.9 99,6 99.6 povprečje average 23,1 23.1 53,6 53,6 69,5 69.5 98,0 98.0 SD SD 1,4 1.4 3,5 3.5 3,8 3.8 1,5 1.5 RSD (%) RSD (%) 6,2 6.2 6,4 6.4 5,5 5.5 1,6 1.6 minimum minimum 21,8 21.8 46,8 46,8 61,9 61.9 95,7 95,7 maksimum maximum 25,0 25,0 56,0 56,0 72,2 72,2 99,6 99.6

Primer 2Example 2

JEDRA SAILS ketoprofen ketoprofen mg mg 150,00 150,00 Učinkovina The active ingredient Avicel PH101 Avicel PH101 mg mg 24,00 24,00 Polnilo Filler Laktoza 200 Lactose 200 mg mg 30,00 30,00 Polnilo Filler PVP K 25 PVP K 25 mg mg 7,00 7,00 Vezivo Binder Ac-Di-Sol Ac-Di-Sol mg mg 8,00 8,00 Razgrajevalec Degrader Polisorbat 80 Polysorbate 80 mg mg 1,00 1.00 Površinsko aktivna snov Surfactant

OBLOGA Lining Eudragit RS 30 D Eudragit RS 30 D mg mg 27,84 27.84 Tvorec filma Creator of the movie Eudragit RL 30 D Eudragit RL 30 D mg mg 27,84 27.84 Tvorec filma Creator of the movie T rietilcitrat T riethylcitrate Mg Mg 2,00 2.00 Mehčalec Softener Polisorbat 80 Polysorbate 80 Mg Mg 0,04 0.04 Površinsko aktivna snov Surfactant Smukec Talc Mg Mg 6,00 6,00 Sredstvo proti lepljenju Anti-adhesive agent

Ketoprofen, mikrokristalno celulozo, laktozo, polivinil pirolidon smo zmešali in nato dodali 140 g demineralizirane vode. Mokro zmes smo ekstrudirali na polžnem ekstrudorju in dobljen ekstrudat oblikovali v pelete na sferonizatorju. Tako dobljene mokre pelete smo sušili v vrtinčasti plasti. 60 ut % suhih pelet (peletna jedra) je počakalo na kapsuliranje, medtem ko smo preostalih 40 ut % suhih pelet v nadaljevanju procesa obložili.Ketoprofen, microcrystalline cellulose, lactose, polyvinyl pyrrolidone were mixed and then 140 g of demineralized water were added. The wet mixture was extruded on a screw extruder and the resulting extruder was molded into pellets on a spheronizer. The wet pellets thus obtained were dried in a vortex layer. 60 wt% of dry pellets (pellet cores) waited for encapsulation, while the remaining 40 wt% of dry pellets were coated in the process.

V napravo z vrtinčastim zrakom smo dali peletna jedra in nanje razprševali vodno disperzijo Eudragit RS 30 D in Eudragit RL 30 D, v katero smo dodali še trietilcitrat, Polisorbat in smukec,Pellet cores were added to the device with vortex air and sprayed with water dispersion Eudragit RS 30 D and Eudragit RL 30 D, to which were added triethyl citrate, polysorbate and talc,

Peletna jedra in obložene pelete smo na kapsulirki polnili v kapsule. V vsaki kapsuli je bilo 60 ut. % peletnih jeder in 40 ut. % obloženih pelet.Pellet cores and coated pellets were filled into capsules on the capsule. In each capsule, 60 wt. % pellet cores and 40 wt. % coated pellets.

Test raztapljanjaDissolution test

Medij:Media:

Kisla faza Acid phase 1000 mL simuliranega želodčnega soka pH 1.2 1000 mL of simulated gastric juice pH 1.2 2 uri 2 hours Puferna faza Buffer phase 1000 mL fosfatnega pufra pH 4.5 1000 mL of phosphate buffer pH 4.5 4 ure 4 hours 1000 mL fosfatnega pufra pH 6.8 1000 mL of phosphate buffer pH 6.8 2 uri 2 hours

Aparat: Rotirajoča košarica (USP 25)Apparatus: Rotating basket (USP 25)

Obrati na minuto: 50RPM: 50

kapsula capsule % raztapljanja v urah % dissolution in hours 2 2 4 4 6 6 8 8 1 1 21.4 21.4 50.0 50.0 66.2 66.2 98.4 98.4 2 2 23.9 23.9 51.5 51.5 65.5 65.5 92.7 92.7 3 3 25.0 25.0 53.7 53.7 69.7 69.7 97.1 97.1 4 4 26.4 26.4 55.6 55.6 70.6 70.6 96.6 96.6 5 5 27.4 27.4 56.8 56.8 70.0 70.0 96.6 96.6 6 6 25.9 25.9 55.5 55.5 69.2 69.2 96.9 96.9 7 7 26.1 26.1 59.3 59.3 72.2 72.2 97.0 97.0 8 8 24.2 24.2 54.7 54.7 70.1 70.1 95.7 95.7 9 9 25.4 25.4 55.5 55.5 70.6 70.6 98.8 98.8 10 10 25.4 25.4 56.8 56.8 71.4 71.4 96.5 96.5 11 11 24.5 24.5 56.1 56.1 72.1 72.1 97.7 97.7 12 12 24.5 24.5 56.0 56.0 70.8 70.8 95.5 95.5 Mean Mean 25.0 25.0 55.1 55.1 69.9 69.9 96.6 96.6 SD SD 1.5 1.5 2.5 2.5 2.1 2.1 1.6 1.6 RSD (%) RSD (%) 6.1 6.1 4.6 4.6 3.0 3.0 1.6 1.6 minimum minimum 21.4 21.4 50.0 50.0 65.5 65.5 92.7 92.7 maximum maximum 27.4 27.4 59.3 59.3 72.2 72.2 98.8 98.8

Claims (14)

PATENTNI ZAHTEVKIPATENT APPLICATIONS 1. Farmacevtska oblika ketoprofena z nadzorovanim sproščanjem, ki obsega peletna jedra s hitrim sproščanjem in obložene pelete z nadzorovanim sproščanjem ketoprofena, označena s tem, da se iz oblike po dveh urah sprosti 15 do 35 ut. % ketoprofena, po šestih urah 50 do 80 ut% ketoprofena in po osmih urah najmanj 85 ut % ketoprofena, merjeno po metodi rotirajoče košarice s 50 obrati na minuto, 2 uri v 1000 ml simuliranega želodčnega soka s pH 1.2; 4 ure v 1000 ml fosfatnega pufra s pH 4.5 in 2 uri v 1000 ml fosfatnega pufra s pH 6.8.1. A controlled release ketoprofen pharmaceutical formulation comprising rapid release pellet cores and ketoprofen coated release pellets, characterized in that 15 to 35 wt. ketoprofen%, after six hours 50 to 80 wt% ketoprofen and after eight hours at least 85 wt% ketoprofen, measured by the rotating basket method at 50 rpm, for 2 hours in 1000 ml of simulated gastric juice at pH 1.2; 4 hours in 1000 ml of phosphate buffer pH 4.5 and 2 hours in 1000 ml phosphate buffer pH 6.8. 2. Farmacevtska oblika po zahtevku 1, označena s tem, da vsebuje od 50 do 250 mg ketoprofena.Pharmaceutical form according to claim 1, characterized in that it contains from 50 to 250 mg of ketoprofen. 3. Farmacevtska oblika po zahtevku 1 in 2, označena s tem, da vsebuje 150 mg ketoprofena.Pharmaceutical formulation according to claims 1 and 2, characterized in that it contains 150 mg of ketoprofen. 4. Farmacevtska oblika po zahtevku 1, označena s tem, da je delež ketoprofena v peletnih jedrih od 5 do 90 ut. %.Pharmaceutical formulation according to claim 1, characterized in that the proportion of ketoprofen in the pellet cores is from 5 to 90% by weight. %. 5. Farmacevtska oblika po zahtevkih 1 in 4, označena s tem, da je delež ketoprofena v peletnih jedrih 60 do 90 ut. %.Pharmaceutical form according to claims 1 and 4, characterized in that the proportion of ketoprofen in the pellet cores is 60 to 90 wt. %. 6. Farmacevtska oblika po zahtevku 1, označena s tem, da so obložene petete sestavljene iz peletnih jeder in pH neodvisne polpropustne polimerne obloge.Pharmaceutical form according to claim 1, characterized in that the coated heels are composed of pellet cores and a pH-independent semi-permeable polymer coating. 7. Farmacevtska oblika po zahtevku 6, označena s tem, da obloga vsebuje kopolimere amonijevega metakrilata.Pharmaceutical form according to claim 6, characterized in that the coating contains copolymers of ammonium methacrylate. -1010-1010 8. Farmacevtska oblika po zahtevku 7, označena s tem, da obloga vsebuje kombinacijo kopolimera amonijevega metakrilata tip A in kopolimera amonijevega metakrilata tip B v razmerju od 7 : 3 do 3 : 7.Pharmaceutical form according to claim 7, characterized in that the coating contains a combination of ammonium methacrylate type A copolymer and ammonium methacrylate type B copolymer in a ratio of 7: 3 to 3: 7. 9. Farmacevtska oblika po zahtevku 7 in 8, označena s tem, da je razmerje kopolimera amonijevega metakrilata tip A in kopolimera amonijevega metakrilata tip B v oblogi 1:1.Pharmaceutical formulation according to claims 7 and 8, characterized in that the ratio of ammonium methacrylate copolymer is type A and ammonium methacrylate type B copolymer in a 1: 1 coating. 10. Farmacevtska oblika po zahtevku 1 in 6 označena s tem, da obložene pelete vsebujejo 3 do 50 ut.% obloge.Pharmaceutical formulation according to claims 1 and 6, characterized in that the coated pellets contain 3 to 50% by weight of the coating. 11. Farmacevtska oblika po zahtevkih 1 in 10, označena s tem, da obložene pelete vsebujejo 5 do 15 ut. % obloge.Pharmaceutical formulation according to claims 1 and 10, characterized in that the coated pellets contain 5 to 15 wt. % lining. 12. Farmacevtska oblika po zahtevku 1, označena s tem, da so peletna jedra in obložene pelete polnjene v želatinasto kapsulo.Pharmaceutical formulation according to claim 1, characterized in that the pellet cores and coated pellets are filled into a gelatin capsule. 13. Farmacevtska oblika po zahtevku 1, označena s tem, da je razmerje peletnih jeder in obloženih pelet od 80 : 20 do 20 : 80.Pharmaceutical formulation according to claim 1, characterized in that the ratio of pellet cores and coated pellets is from 80: 20 to 20: 80. 14. Farmacevtska oblika po zahtevku 1 in 13, označena s tem, da je razmerje peletnih jeder in obloženih pelet 60 : 40.Pharmaceutical formulation according to claims 1 and 13, characterized in that the ratio of pellet cores and coated pellets is 60: 40.
SI200200220A 2002-09-11 2002-09-11 Pharmaceutical form with controlled release SI21301A (en)

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PCT/SI2003/000033 WO2004024128A2 (en) 2002-09-11 2003-09-10 Modified release ketoprofen dosage form
AU2003261067A AU2003261067A1 (en) 2002-09-11 2003-09-10 Modified release ketoprofen dosage form
EP03795550A EP1539113A2 (en) 2002-09-11 2003-09-10 Modified release ketoprofen dosage form

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US20090208584A1 (en) * 2005-06-09 2009-08-20 Tomohiro Yoshinari Solid preparation
US10064828B1 (en) 2005-12-23 2018-09-04 Intellipharmaceutics Corp. Pulsed extended-pulsed and extended-pulsed pulsed drug delivery systems
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US9561188B2 (en) 2006-04-03 2017-02-07 Intellipharmaceutics Corporation Controlled release delivery device comprising an organosol coat
US20190083399A9 (en) * 2006-04-03 2019-03-21 Isa Odidi Drug delivery composition
US10960077B2 (en) 2006-05-12 2021-03-30 Intellipharmaceutics Corp. Abuse and alcohol resistant drug composition
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