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SI21638A - Pharmaceutical form with controlled release of ketopfofen - Google Patents

Pharmaceutical form with controlled release of ketopfofen Download PDF

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Publication number
SI21638A
SI21638A SI200300275A SI200300275A SI21638A SI 21638 A SI21638 A SI 21638A SI 200300275 A SI200300275 A SI 200300275A SI 200300275 A SI200300275 A SI 200300275A SI 21638 A SI21638 A SI 21638A
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SI
Slovenia
Prior art keywords
coating
acid
pellets
ketoprofen
polymer
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SI200300275A
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Slovenian (sl)
Inventor
Miha Tomaž Jaklič
Judita Širca
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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 SI200300275A priority Critical patent/SI21638A/en
Priority to EP04800455A priority patent/EP1703900A1/en
Priority to PCT/SI2004/000037 priority patent/WO2005046652A1/en
Publication of SI21638A publication Critical patent/SI21638A/en

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    • 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
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • 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
    • A61K9/48—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

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

The invention refers to a new pharmaceutical form with controlled release and comprises lined pellets containing an extruded core with ketoprofen and microcrystalline cellulose as well as a lining containing at least one acidoresistant polymer and least one insoluble polymer. The form is suitable for single daily dosing of ketoprofen.

Description

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

Farmacevtska oblika z nadzorovanim sproščanjem ketoprofenaKetoprofen controlled release pharmaceutical form

Področje izumaFIELD OF THE INVENTION

Izum spada v področje farmacevtske tehnologije in se nanaša na novo oralno farmacevtsko obliko ketoprofena z nadzorovanim sproščanjem, ki se uporablja za enkrat dnevno odmerjanje.The invention is within the field of pharmaceutical technology and relates to a novel oral controlled-release pharmaceutical formulation of ketoprofen used for once daily dosing.

Prikaz problemaView the problem

Ketoprofen, ki je kemijsko 2-(3-benzoilfenil) propionska kislina, je nesteroidni antirevmatik, ki deluje protivnetno, protibolečinsko in protivročinsko. Ketoprofen je šibko kisla učinkovina, ki je skoraj netopna v vodi, hitro se absorbira iz gornjega dela gastrointestinalnega trakta in hitro se izloči iz organizma.Ketoprofen, which is a chemical 2- (3-benzoylphenyl) propionic acid, is a non-steroidal anti-rheumatic agent that has anti-inflammatory, anti-pain and anti-rheumatic effects. Ketoprofen is a weakly acidic substance that is almost insoluble in water, rapidly absorbed from the upper gastrointestinal tract and rapidly excreted in the body.

Ker je terapija pogosto dolgotrajna, so za pacienta posebej ugodne oblike, ki jih je potrebno jemati samo enkrat na dan in hkrati preprečijo sproščanje kisle agresivne učinkovine v želodcu. Obstaja stalna potreba po varnih, pacientu prijaznih farmacevtskih oblikah z nadzorovanim sproščanjem ketoprofena, ki so primerne za enkrat dnevno jemanje.Because therapy is often time-consuming, it is especially advantageous for the patient to take only once a day while preventing the release of acidic aggressive substance in the stomach. There is an ongoing need for safe, patient-friendly, controlled release ketoprofen dosage forms suitable for once daily administration.

Stanje tehnikeThe state of the art

Iz patentne in druge literature so poznane številne farmacevtske oblike z nadzorovanim sproščanjem učinkovin. Med njimi so tudi večenotne oblike, npr.Many controlled-release pharmaceutical dosage forms are known from the patent and other literature. They also include multi-unit forms, e.g.

kapsule, ki vsebujejo granule, pelete ali tablete, ki so obložene z oblogo, ki nadzoruje sproščanje.capsules containing granules, pellets or tablets coated with a release-controlling coating.

EP 403 383 opisuje farmacevtske oblike ketoprofena, ki vsebujejo granule, v katerih je ekstrudirano jedro sestavljeno iz ketoprofena in mikrokristalne celuloze, obloga pa vsebuje v vodi topen celulozni derivat in 60 do 90% celuloznega derivata, ki je v vodi netopen. Prednostno obloga vsebuje etilcelulozo in hidroksipropilmetilcelulozo.EP 403 383 describes pharmaceutical forms of ketoprofen containing granules in which the extruded core is composed of ketoprofen and microcrystalline cellulose and the coating contains a water-soluble cellulose derivative and 60 to 90% water-insoluble cellulose derivative. Preferably the coating comprises ethylcellulose and hydroxypropylmethylcellulose.

V US 6197347 so opisane pelete, ki so sestavljene iz inertnega jedra, na katero je nanesen ketoprofen skupaj z vezalcem, v oblogi sta etilceluloza in shellac. Opisane so tudi kapsule, ki te pelete vsebujejo.US 6197347 describes pellets consisting of an inert kernel to which ketoprofen is applied together with a binder, containing ethylcellulose and shellac. Capsules containing these pellets are also described.

WO 00/64433 in WO 00/64432 se nanaša na pelete ketoprofena, ki vsebujejo ketoprofen nanešen na inertno jedro. Oblogo sestavljata Eudragit RL in Eudragit SR v razmerju približno 50:50 oziroma 90:10. Opisane so kapsule, ki vsebujejo 200 mg ketoprofena.WO 00/64433 and WO 00/64432 refer to ketoprofen pellets containing ketoprofen applied to an inert core. The lining consists of Eudragit RL and Eudragit SR in a ratio of approximately 50:50 and 90:10 respectively. Capsules containing 200 mg ketoprofen are described.

EP 653935 opisuje večenotne farmacevtske oblike, ki vsebujejo pelete. Učinkovina je nanesena na inertno jedro. Obloga vsebuje netopen polimer, acidorezistenten polimer in plastificirno sredstvo. Delež acidorezistentnega polimera v oblogi je najmanj 30%. Oblike so primerne za slabo topne nesteroidne protivnetne učinkovine, posebej za diklofenac, ketorolak in indometacin.EP 653935 describes multi-unit pharmaceutical formulations containing pellets. The active substance is applied to the inert core. The coating contains an insoluble polymer, an acid-resistant polymer and a plasticizing agent. The proportion of acid-resistant polymer in the coating is at least 30%. The formulations are suitable for poorly soluble non-steroidal anti-inflammatory drugs, especially diclofenac, ketorolac and indomethacin.

EP 288138 opisuje večenotne farmacevtske oblike s kontroliranim sproščanjem nesteroidnih protivnetnih učinkovin, v katerih sferoidna jedra vsebujejo najmanj 70% mikrokristalne celuloze ter najmanj en vodotopen in/ali nabrekajoč derivat celuloze, npr. hidroksipropil celulozo ali hidroksipropilmetilcelulozo.EP 288138 describes multifunctional controlled release non-steroidal anti-inflammatory drug formulations in which spheroid nuclei contain at least 70% microcrystalline cellulose and at least one water-soluble and / or swelling cellulose derivative, e.g. hydroxypropyl cellulose or hydroxypropylmethylcellulose.

Naloga tega izuma je varna farmacevtska oblika, ki vzdržuje ustrezne terapevtske nivoje ketoprofena skozi 24 ur in je primerna za enkrat dnevno jemanje.It is an object of the present invention to provide a safe pharmaceutical formulation that maintains adequate therapeutic levels of ketoprofen for 24 hours and is suitable for once daily administration.

Opis nove rešitveDescription of the new solution

Predmet izuma je večenotna farmacevtska oblika ketoprofena z nadzorovanim sproščanjem, ki se uporablja za enkrat dnevno odmerjanje. Prednostno je predmet izuma kapsula, ki vsebuje pelete ketoprofena, ki so sestavljene iz ekstrudiranega jedra in obloge. Obložene pelete so zasnovane tako, da v želodcu ne sproščajo učinkovine in na ta način zaščitijo sluznico želodca pred kislo učinkovino. Po prehodu pelet v nevtralno okolje dvanajstnika in tankega črevesa pa postopoma sproščajo učinkovino in tako zagotavljajo ustrezne plazemske koncentracije učinkovine v plazmi skozi daljši čas.The subject of the invention is a multifunctional controlled release pharmaceutical formulation of ketoprofen used for once daily dosing. Preferably, the invention provides a capsule containing ketoprofen pellets consisting of an extruded core and a coating. Coated pellets are designed so that they do not release the active substance in the stomach and thus protect the mucous membrane of the stomach from the acidic substance. However, upon passage of the pellets into the neutral environment of the duodenum and small intestine, they gradually release the active ingredient, thereby ensuring adequate plasma concentrations of the active substance in the plasma over time.

Predmet izuma so tudi pelete, ki vsebujejo ketoprofen. Sestava peletnih jeder je zelo enostavna in omogoča vgradnjo visokega deleža učinkovine v jedro. Peletna jedra lahko vsebujejo samo ketoprofen in mikrokristalno celulozo. Delež ketoprofena v peletnem jedru je od 50 do 97 ut./ut. %.The invention also provides pellets containing ketoprofen. The composition of the pellet cores is very simple and allows a high proportion of the substance to be incorporated into the core. Pellet cores may contain only ketoprofen and microcrystalline cellulose. The ketoprofen content in the pellet core is from 50 to 97 w / w. %.

Mikrokristalna celuloza je lahko katerakoli komercialno dostopna oblika mikrokristalne celuloze, npr. različne vrste Avicel®-a, Emocel®-a, Vivacel®-a ipd. Posebej primerna celuloza je Avicel® PH 101. Primerna je tudi silicificirana mikrokristalna celuloza, npr. Prosolv®. Delež mikrokristalne celuloze v peletnem jedru je od 3 do 50 ut./ut. %.Microcrystalline cellulose can be any commercially available form of microcrystalline cellulose, e.g. different types of Avicel®, Emocel®, Vivacel®, etc. Particularly suitable cellulose is Avicel® PH 101. Silicified microcrystalline cellulose, e.g. Prosolv®. The proportion of microcrystalline cellulose in the pellet core is from 3 to 50 w / w. %.

Peletna jedra lahko opcijsko vsebujejo tudi druge pomožne snovi kot so npr. vezalci, (npr.: različni tipi polivinilpirolidona, želatina, različne vrste škroba, različne karboksimetilceluloze, mono in disaharidi, ipd.), različne površinsko aktivne snovi (polisorbat 80, natrijev lavril sulfat ipd.), polnila (npr. laktoza in drugi mono in disaharidi, kalcijev fosfat, kalcijev hidrogen fosfat), razgrajevale! (razni škrobi, natrijev karboksimetil škrob, prečno premreženo natrijevo karboksimetil celulozo, prečno premrežen polivinilpirolidon, ipd).Pellet cores may optionally contain other excipients such as e.g. binders (eg: different types of polyvinylpyrrolidone, gelatin, different types of starch, different carboxymethylcelluloses, mono and disaccharides, etc.), various surfactants (polysorbate 80, sodium lauryl sulfate, etc.), fillers (eg lactose and other mono and disaccharides, calcium phosphate, calcium hydrogen phosphate), decomposed! (various starches, sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, etc.).

Obloga, ki je nanesena na jedro, vsebuje vsaj en acidorezistentni polimer in vsaj en netopni polimer. Uporabljena je ena sama obloga, ki omogoča zakasnjeno sproščanje ketoprofena v odvisnosti od pH in podaljšano sproščanje skozi daljšo dobo.The core-coated coating comprises at least one acid-resistant polymer and at least one insoluble polymer. A single coating is used to allow delayed release of ketoprofen as a function of pH and prolonged release over a longer period.

Obloga poleg polimerov prednostno vsebuje samo smukec in po potrebi barvilo. Ena obloga pomeni tehnološko prednost, saj oblogo pripravimo enkrat in enkrat nanesemo. Postopek izdelave je ekološko prijazen saj ne zahteva uporabe organskih topil. Voda je edino uporabljeno topilo.The coating, in addition to the polymers, preferably contains only talc and, if necessary, dye. One coating is a technological advantage, since the coating is prepared once and once applied. The manufacturing process is eco-friendly as it does not require the use of organic solvents. Water is the only solvent used.

Acidorezistentni polimer je lahko katerikoli polimer, ki je dosegljiv v obliki vodne disperzije, npr. akrilni polimeri (Eudragit®-i), celulozni acetatftalat (Aquateric®), hidroksipropilmetilcelulozni acetatsukcinat (Aqoat®), karboksimetiletilcelulozni eter (Duodcell®), polivinilacetatftalat (Sureteric®).An acid-resistant polymer may be any polymer that is available in the form of an aqueous dispersion, e.g. acrylic polymers (Eudragit®s), cellulose acetate phthalate (Aquateric®), hydroxypropylmethylcellulose acetate succinate (Aqoat®), carboxymethylethylcellulose ether (Duodcell®), polyvinyl acetate phthalate (Sureteric®).

Posebej primeren acidorezistentni polimer je Eudragit® L 30 D-55, ki je anionski kopolimer metakrilne kisline in metilmetakrilata v razmerju 1:1, ki je dosegljiv v obliki 30 % vodne disperzije.A particularly suitable acid-resistant polymer is Eudragit® L 30 D-55, which is a 1: 1 anionic copolymer of methacrylic acid and methyl methacrylate, which is available as a 30% aqueous dispersion.

Netopni polimer je lahko katerikoli polimer, ki je dosegljiv v obliki vodne disperzije, npr. etilceluloza (Surelease®, Aquacoat®) in akrilni polimeri za nadzorovano sproščanje, kot sta Eudragit® NE 30 D ali Eudragit® RS 30 D.The insoluble polymer can be any polymer that is available in the form of an aqueous dispersion, e.g. ethylcellulose (Surelease®, Aquacoat®) and controlled release acrylic polymers such as Eudragit® NE 30 D or Eudragit® RS 30 D.

Posebej primeren netopni polimer je v vodi netopni Eudragit® NE 30 D, ki je kopolimer etilakrilata in metilmetakrilata v razmerju 2:1, ki je dosegljiv v obliki 30 % vodne disperzije.A particularly suitable insoluble polymer is the water-insoluble Eudragit® NE 30 D, which is a 2: 1 copolymer of ethyl acrylate and methyl methacrylate, which is available as a 30% aqueous dispersion.

Razmerje netopnega polimera in acidorezistentnega polimera je lahko med 7:3 in 19:1, prednostno 3:1.The ratio of the insoluble polymer to the acid-resistant polymer may be between 7: 3 and 19: 1, preferably 3: 1.

Nanos obloge je lahko od 5 do 20 ut./ut. % obloge (glede na obloženo peleto) odvisno od želenega učinka. Prednostni nanos obloge obsega 8 do 12 ut./ut. % glede na obloženo peleto.Coating can be from 5 to 20 w / w. % coating (relative to coated pellet) depending on desired effect. The preferred coating application is 8 to 12 w / w. % relative to the coated pellet.

Obloga lahko nadalje vsebuje tudi druge pomožne snovi kot so npr. plastifikatorji (trietil citrat, tributil citrat, triacetin, dibutil ftalat, poiletilenglikoli (200, 400, 600, 6000), glicerol), antiadhezivi (smukec, magnezijev stearat, glicerolmonostearat), pigmente, barvila, sredstva za dispergiranje.The coating may further comprise other excipients such as e.g. plasticizers (triethyl citrate, tributyl citrate, triacetin, dibutyl phthalate, polyethylene glycols (200, 400, 600, 6000), glycerol), antiadhesives (talc, magnesium stearate, glycerol monostearate), pigments, colorants, dispersants.

Velikost obloženih pelet je lahko od 0,2 do 2,0 mm, prednostno pa so velikosti od 0,7 do 1,3 mm.The size of the coated pellets may be from 0.2 to 2.0 mm, preferably 0.7 to 1.3 mm.

Pelete, ki so predmet izuma, pripravimo po postopkih, ki so običajni v farmacevtski tehnologiji. Zmes prahov ketoprofena in mikrokristalne celuloze homogeno premešamo in granuliramo z demineralizirano vodo, v kateri po potrebi raztopimo vezalec. Granulat ekstrudiramo ter nato ekstrudat sferoniziramo. Tako pripravljena peletna jedra sušimo v vrtinčnoslojni napravi.The pellets which are the subject of the invention are prepared according to the methods customary in pharmaceutical technology. The mixture of ketoprofen powders and microcrystalline cellulose is homogeneously mixed and granulated with demineralized water, in which the binder is dissolved, if necessary. The granulate is extruded and then the extrudate is spheronized. The pellet cores thus prepared are dried in a vortex device.

Filmsko oblogo nanesemo prednostno z razprševanjem disperzije v vrtinčnoslojnih napravah kot so npr.: VVursterjeva komora, Huettlin Kugelcoater ipd. Parametri oblaganja so različni od naprave do naprave, pomembno pa je, da je temperatura produkta pod 30 °C. Tako pripravljenim peletam formiramo film od 2 do 24 ur pri temperaturah od 40 do 60 °C.The film coating is preferably applied by dispersion dispersion in eddy-layer devices such as, for example, the Wurster chamber, Huettlin Kugelcoater and the like. The coating parameters are different from device to device, but it is important that the product temperature is below 30 ° C. The pellets thus prepared form a film of 2 to 24 hours at temperatures of 40 to 60 ° C.

Tako pridobljene pelete polnimo v kapsule ali vrečke, lahko pa jih stisnemo v tablete.The pellets thus obtained are filled into capsules or bags, but can be compressed into tablets.

Farmacevtska oblika, ki je predmet izuma, je lahko tudi tableta. Pelete, ki vsebujejo ekstrudirano jedro s ketoprofenom, ki je obloženo z zgoraj opisano oblogo, so lahko stisnjene v tablete. Pelete zmešamo s pomožnimi snovmi ter zmes tabletiramo. Primerne pomožne snovi so lahko polnila (mikrokristalna celuloza, kalcijev hidrogen fosfat), razgrajevala (razni škrobi, natrijev karboksimetil škrob, prečno premrežena natrijeva karboksimetil celuloza, prečno premrežen polivinilpirolidon), drsita (smukec, magnezijev stearat ipd.).The pharmaceutical formulation of the invention may also be a tablet. Pellets containing an extruded ketoprofen core coated with the coating described above may be compressed into tablets. The pellets are mixed with excipients and the mixture is tableted. Suitable excipients may be fillers (microcrystalline cellulose, calcium hydrogen phosphate), decomposers (various starches, sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone), drsita (talc, magnesium).

Predmet izuma so lahko tudi vrečke, ki vsebujejo pelete.The invention may also be bags containing pellets.

Farmacevtska oblika ketoprofena, ki je predmet izuma, lahko vsebuje od 100 mg do 300 mg ketoprofena, prednostno 200 mg ketoprofena.The pharmaceutical form of the ketoprofen of the invention may contain from 100 mg to 300 mg of ketoprofen, preferably 200 mg of ketoprofen.

Iz farmacevtske oblike, ki je predmet izuma se pri testu raztapljanja po 2 urah v simuliranem želodčnem soku (pH=1,2) sprosti manj kot 10 % ketoprofena, nato pa zamenjamo medij v umetni črevesni sok (pH = 6,8) in po 2 h se sprosti 20 - 50 %, po 4 h 40 - 70 % po 6 h 55 - 90 %, po 18 h več kot 85 % ketoprofena. Testiranje izvedemo v aparatu št. 1 po USP (rotirajoča košarica).Less than 10% of ketoprofen is released in the simulated gastric juice (pH = 1.2) from the pharmaceutical composition of the invention in a dissolution test after 2 hours, after which the medium is changed to artificial gut juice (pH = 6.8) and after 2 - 20 - 50% release, 4 - 40 - 70% after 6 - 55 - 90%, more than 85% ketoprofen after 18 hours. Testing is performed in apparatus no. 1 per USP (rotating basket).

Farmacevtska oblika, ki je predmet izuma lahko namesto ketoprofena vsebuje druge učinkovine, ki so šibke kisline skoraj netopne v vodi. Taki učinkovini sta npr.: naproksen in indometacin.The pharmaceutical formulation of the invention may contain, instead of ketoprofen, other active ingredients which are weak acids almost insoluble in water. Such ingredients are, for example, naproxen and indomethacin.

Izvedbeni primeriImplementation examples

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

Primer 1Example 1

sestava / kapsulo composition / capsule JEDRO SAIL ketoprofen ketoprofen 200,0 mg 200.0 mg Avicel PH 101 Avicel PH 101 38,0 mg 38,0 mg demineralizirana voda demineralized water 132,0 mg 132.0 mg OBLOGA Lining Eudragit L 30 D-55 Eudragit L 30 D-55 14,5 mg 14,5 mg Eudragit NE 30 D Eudragit NO 30 D 43,6 mg 43,6 mg smukec talc 8,7 mg 8.7 mg rdeči železov oksid red iron oxide 0,2 mg 0.2 mg demineralizirana voda demineralized water 62,4 mg 62,4 mg

Postopek dela:Work process:

Zmes prahov ketoprofena in mikrokristalne celuloze smo homogeno premešali in granulirali, 1 minuto pri 100 obr./min, z demineralizirano vodo v hitrovrtečem mešalniku. Granulat smo ekstrudirali v polžastem ekstruderju skozi mrežo z odprtinami 1 mm pri 95 obr./min. Ekstrudat smo sferonizirali 60 s v sferonizatorju na nagubani plošči (obodna hitrost 12 m/s). Tako pripravljena peletna jedra smo sušili v vrtinčnoslojni napravi, ob zmerni fluidizaciji pri temperaturi vstopnega zraka 30 °C, do izgube pri sušenju pod 2 %.A mixture of ketoprofen powders and microcrystalline cellulose was stirred and granulated homogeneously, for 1 minute at 100 rpm, with demineralized water in a high-speed mixer. The granulate was extruded in a screw extruder through a mesh with 1 mm openings at 95 rpm. The extrudate was spheronized for 60 s in a spheronizer on a pleated plate (circumferential velocity 12 m / s). The pellet cores thus prepared were dried in a vortex apparatus, with moderate fluidization at an inlet air temperature of 30 ° C, to a drying loss below 2%.

Pelete smo presejali na sita velikosti 0,7 in 1,2 mm. Za filmsko oblaganje smo uporabili vmesno frakcijo pelet velikosti med 0,7 in 1,2 mm.The pellets were screened on sieves 0.7 and 1.2 mm in size. An intermediate pellet fraction between 0.7 and 1.2 mm in size was used for film coating.

Disperzijo za oblaganje smo pripravili tako, da smo posamezne sestavine združili in mešali. Med oblaganjem smo disperzijo vseskozi mešali.The coating dispersion was prepared by combining and mixing the individual components. During the coating, the dispersion was constantly stirred.

Peletna jedra smo obložili v vrtinčnoslojni napravi. Na peletna jedra smo ob zmerni fluidizaciji pelet pršili disperzijo za oblaganje in parametre oblaganja prilagodili tako, da smo ohranjali temperaturo produkta med 20 in 25 °C.The pellet cores were coated in a vortex device. With moderate fluidization, the pellet cores were sprayed with a coating dispersion and the coating parameters were adjusted to maintain the product temperature between 20 and 25 ° C.

Obloženim peletam smo formirali film 12 ur pri 40 °C. Pelete smo napolnili v kapsule št. 1.The coated pellets formed a film for 12 hours at 40 ° C. The pellets were filled into capsules no. 1.

Primer 2Example 2

sestava /kapsulo composition / capsule JEDRO SAIL ketoprofen ketoprofen 150,0 mg 150.0 mg Avicel PH 101 Avicel PH 101 45,0 mg 45,0 mg polivinilpirolidon K 25 polyvinylpyrrolidone K 25 5,0 mg 5.0 mg demineralizirana voda demineralized water 100,0 mg 100,0 mg OBLOGA Lining Eudragit L 30 D-55 Eudragit L 30 D-55 2,1 mg 2.1 mg Eudragit NE 30 D Eudragit NO 30 D 21,1 mg 21.1 mg smukec talc 5,3 mg 5,3 mg demineralizirana voda demineralized water 25,9 mg 25.9 mg

Postopek dela:Work process:

Zmes prahov ketoprofena in mikrokristalne celuloze smo homogeno premešali in granulirali, 1 minuto pri 100 obr./min, z demineralizirano vodo v hitrovrtečem mešalniku. Granulat smo ekstrudirali v polžastem ekstruderju skozi mrežo z odprtinami 1 mm pri 95 obr./min. Ekstrudat smo sferonizirali 60 s v sferonizatorju na nagubani plošči (obodna hitrost 12 m/s). Tako pripravljena peletna jedra smo sušili v vrtinčnoslojni napravi, ob zmerni fluidizaciji pri temperaturi vstopnega zraka 30 °C, do izgube pri sušenju pod 2 %.A mixture of ketoprofen powders and microcrystalline cellulose was stirred and granulated homogeneously, for 1 minute at 100 rpm, with demineralized water in a high-speed mixer. The granulate was extruded in a screw extruder through a mesh with 1 mm openings at 95 rpm. The extrudate was spheronized for 60 s in a spheronizer on a pleated plate (circumferential velocity 12 m / s). The pellet cores thus prepared were dried in a vortex apparatus, with moderate fluidization at an inlet air temperature of 30 ° C, to a drying loss below 2%.

Pelete smo presejali na sita velikosti 0,7 in 1,2 mm. Za filmsko oblaganje smo uporabili vmesno frakcijo pelet velikosti med 0,7 in 1,2 mm.The pellets were screened on sieves 0.7 and 1.2 mm in size. An intermediate pellet fraction between 0.7 and 1.2 mm in size was used for film coating.

Disperzijo za oblaganje smo pripravili tako, da smo posamezne sestavine združili in mešali. Med oblaganjem smo disperzijo vseskozi mešali.The coating dispersion was prepared by combining and mixing the individual components. During the coating, the dispersion was constantly stirred.

Peletna jedra smo obložili v vrtinčnoslojni napravi. Na peletna jedra smo ob zmerni fluidizaciji pelet pršili disperzijo za oblaganje in parametre oblaganja prilagodili tako, da smo ohranjali temperaturo produkta med 20 in 25 °C.The pellet cores were coated in a vortex device. With moderate fluidization, the pellet cores were sprayed with a coating dispersion and the coating parameters were adjusted to maintain the product temperature between 20 and 25 ° C.

Obloženim peletam smo formirali film 12 ur pri 40 °C. Pelete smo napolnili v kapsule št. 1.The coated pellets formed a film for 12 hours at 40 ° C. The pellets were filled into capsules no. 1.

Primer 3Example 3

Sproščanje učinkovine iz kapsule, ki je opisana v Primeru 1:Release of the active substance from the capsule described in Example 1:

čas (h) time (h) pH medija pH of the medium % sproščenega ketoprofena % ketoprofen released 2 2 1,2 1,2 1,1 1.1 4 4 4,5 4.5 2,4 2.4 6 6 6,8 6,8 36,9 36,9 8 8 6,8 6,8 57,7 57.7 10 10 6,8 6,8 72,1 72,1 12 12 6,8 6,8 82,4 82,4 14 14 6,8 6,8 88,9 88,9 16 16 6,8 6,8 93,5 93,5 18 18 6,8 6,8 96,0 96.0 20 20 6,8 6,8 97,2 97,2 22 22 6,8 6,8 97,8 97.8 24 24 6,8 6,8 97,8 97.8

Testiranje je bilo izvedeno z USP aparatom št. 1 pri 37 °C.Testing was performed with USP apparatus no. 1 at 37 ° C.

Claims (19)

Patentni zahtevkiPatent claims 1. Večenotna farmacevtska oblika z nadzorovanim sproščanjem, ki obsega obložene pelete, ki vsebujejo :1. A controlled release multifunctional pharmaceutical formulation comprising coated pellets containing: - ekstrudirano jedro, ki vsebuje ketoprofen in mikrokristalno celulozo- an extruded core containing ketoprofen and microcrystalline cellulose - oblogo, ki vsebuje vsaj en acidorezistentni polimer in vsaj en netopni polimer- a coating comprising at least one acid-resistant polymer and at least one insoluble polymer 2. Večenotna farmacevtska oblika po zahtevku 1, označena s tem, da vsebuje od 100 do 300 mg ketoprofena.2. A multi-dose pharmaceutical formulation according to claim 1, comprising from 100 to 300 mg of ketoprofen. 3. Večenotna farmacevtska oblika po zahtevkih 1 in 2 označena s tem, da vsebuje 200 mg ketoprofena.3. The multi-unit dosage form according to claims 1 and 2, characterized in that it contains 200 mg of ketoprofen. 4. Večenotna farmacevtska oblika po zahtevku 1, označena s tem, da je delež ketoprofena v jedru 50 do 97 ut./ut. %.Multiple dosage form according to claim 1, characterized in that the ketoprofen content in the core is 50 to 97 w / w. %. 5. Večenotna farmacevtska oblika po zahtevkih 1, označena s tem, da se kot acidorezistentni polimer uporabljajo vodne disperzije polimerov iz skupine ki obsega akrilne polimere, celulozni acetatftalat, hidroksipropilmetilcelulozni acetatsukcinat, karboksimetilcelulozni eter, polivinilacetatftalat.5. The multifunctional pharmaceutical form according to claim 1, characterized in that aqueous dispersions of polymers from the group comprising acrylic polymers, cellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylcellulose ether, polyvinyl acetate acetate are used as the acid-resistant polymer. 6. Večenotna farmacevtska oblika po zahtevku 1 in 5, označena s tem, da se kot acidorezistentni polimer uporablja kopolimer metakrilne kisline in metilmetakrilata.Multicellular pharmaceutical formulation according to claims 1 and 5, characterized in that a copolymer of methacrylic acid and methyl methacrylate is used as the acid-resistant polymer. 7. Večenotna farmacevtska oblika po zahtevku 1, označena s tem, da se kot netopni polimer uporablja polimer iz skupine, ki obsega etilcelulozo in akrilne polimere za nadzorovano sproščanje.Multicellular pharmaceutical formulation according to claim 1, characterized in that the polymer from the group consisting of ethylcellulose and acrylic polymers for controlled release is used as an insoluble polymer. 8. Večenotna farmacevtska oblika po zahtevku 1 in 7, označena s tem, da se kot netopni polimer uporablja kopolimer etilakrilata in metilmetakrilata v razmerju 2:1.Multicellular pharmaceutical formulation according to claims 1 and 7, characterized in that a copolymer of ethyl acrylate and methyl methacrylate in a ratio of 2: 1 is used as the insoluble polymer. 9. Večenotna farmacevtska oblika po zahtevku 1, označena s tem, da je razmerje acidorezistentnega polimera in netopnega polimera v oblogi med 3:7 in 1:19.9. A multi-unit pharmaceutical form according to claim 1, characterized in that the ratio of the acid-resistant polymer to the insoluble polymer is in the coating between 3: 7 and 1:19. 10. Večenotna farmacevtska oblika po zahtevkih 1 in 9, označena s tem, da je razmerje acidorezistentnega polimera in netopnega polimera v oblogi 1:3.Multiple dosage form according to claims 1 and 9, characterized in that the ratio of the acid-resistant polymer to the insoluble polymer is in the coating 1: 3. 11. Večenotna farmacevtska oblika po zahtevku 1, označena s tem, da obloga obsega 5 do 20 ut./ut. % glede na obložene pelete.A multi-unit pharmaceutical form according to claim 1, characterized in that the coating comprises 5 to 20 wt./ut. % relative to coated pellets. 12. Večenotna farmacevtska oblika po zahtevku 1 in 11, označena s tem, da obloga obsega 8 do 12 ut./ut. % glede na obložene pelete.Multiple dosage form according to claims 1 and 11, characterized in that the coating comprises 8 to 12 w / w. % relative to coated pellets. 13. Pelete, ki obsegajo ekstrudirano jedro, ki vsebujejo ketoprofen in mikrokristalno celulozo, ter oblogo, ki vsebuje vsaj en acidorezistentni polimer in vsaj en netopni polimer.13. Pellets comprising an extruded core containing ketoprofen and microcrystalline cellulose and a coating containing at least one acid-resistant polymer and at least one insoluble polymer. 14. Pelete po zahtevku 13, označene s tem, da je acidorezistentni polimer kopolimer metakrilne kisline in metilmetakrilata v razmerju 1:1 .Pellets according to claim 13, characterized in that the acid-resistant polymer is a copolymer of methacrylic acid and methyl methacrylate in a 1: 1 ratio. 15. Pelete po zahtevku 13, označene s tem, da je netopni polimer kopolimer etilakrilata in metilmetakrilata v razmerju 2:1.Pellets according to claim 13, characterized in that the insoluble polymer is a copolymer of ethyl acrylate and methyl methacrylate in a ratio of 2: 1. 16. Pelete po zahtevku 13, označene s tem, da je, da je razmerje acidorezistentnega polimera in netopnega polimera 1:3.Pellets according to claim 13, characterized in that the ratio of the acid-resistant polymer to the insoluble polymer is 1: 3. 17. Pelete po zahtevku 13, označene s tem, da je nanos obloge 8 do 12 ut./ut.% glede na obloženo peleto.17. Pellets according to claim 13, characterized in that the coating of the coating is 8 to 12 w / w% relative to the coated pellet. 18. Postopek za pripravo večenotne farmacevtske oblike po zahtevku 1, označen s tem, da obsega naslednje faze :18. A process for the preparation of a multi-unit pharmaceutical form according to claim 1, characterized in that it comprises the following stages: - pripravo homogene zmesi ketoprofena in mikrokristalne celuloze- preparation of a homogeneous mixture of ketoprofen and microcrystalline cellulose - vlažno granuliranje z demineralizirano vodo- wet granulation with demineralised water - iztiskanje vlažne zmesi skozi mrežo- extruding the wet mixture through the net - krogličenje- ball rolling - sušenje- drying - nanos obloge- coating - polnjenje pelet v kapsule ali vrečke ali tabletiranje- Filling pellets into capsules or bags or tabletting 19. Večenotna farmacevtska oblika z nadzorovanim sproščanjem, ki obsega obložene pelete, ki vsebujejo :19. A multifunctional controlled release pharmaceutical formulation comprising coated pellets containing: - ekstrudirano jedro, ki vsebuje učinkovine, ki so šibke kisline skoraj netopne v vodi in mikrokristalno celulozo- Extruded core containing active substances which are weak acids almost insoluble in water and microcrystalline cellulose - oblogo, ki vsebuje vsaj en acidorezistentni polimer in vsaj en netopni polimer- a coating comprising at least one acid-resistant polymer and at least one insoluble polymer
SI200300275A 2003-11-12 2003-11-12 Pharmaceutical form with controlled release of ketopfofen SI21638A (en)

Priority Applications (3)

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SI200300275A SI21638A (en) 2003-11-12 2003-11-12 Pharmaceutical form with controlled release of ketopfofen
EP04800455A EP1703900A1 (en) 2003-11-12 2004-11-11 Controlled release ketoprofen formulation
PCT/SI2004/000037 WO2005046652A1 (en) 2003-11-12 2004-11-11 Controlled release ketoprofen formulation

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US6197347B1 (en) * 1998-06-29 2001-03-06 Andrx Pharmaceuticals, Inc. Oral dosage for the controlled release of analgesic
FR2792527B1 (en) * 1999-04-22 2004-08-13 Ethypharm Lab Prod Ethiques KETOPROFENE MICROGRANULES, PREPARATION METHOD AND PHARMACEUTICAL COMPOSITIONS

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