RS51883B

RS51883B - KAPECITABIN PEDIATRIC TABLETS

Info

Publication number: RS51883B
Application number: RS20110124A
Authority: RS
Inventors: Martin Howard Infeld; Maria Oksana Bachynsky; Mohammad Rashed; Navnit Hargovindas Shah
Original assignee: F.Hoffmann - La Roche Ag.
Priority date: 2006-10-06
Filing date: 2007-09-26
Publication date: 2012-02-29

Abstract

PEDIJATRIJSKE TABLETE KAPECITABINA. Film-obložena farmaceutska kompozicija koja sadrži kapecitabin i bar jedan dezintegrant, naznačena time, što se raspada u vodi na 37°C u USP uređaju za isitivanje raspadljivosti tableta, za manje od 2 minute i ima čvrstoću od oko 56-91N (2-13 strong Cobb-Units).Prijava sadrži još 41 patentni zahtev.KAPECITABIN PEDIATRIC TABLETS. Film-coated pharmaceutical composition comprising capecitabine and at least one disintegrant, which decomposes in water at 37 ° C in a USP tablet breakdown device in less than 2 minutes and has a strength of about 56-91N (2-13 strong Cobb-Units). The application contains another 41 patent claims.

Description

[0001]Predmetni pronalazak se odnosi na novi brzo disintegrišući (raspadljivi) farmaceutski dozni oblik koji kao aktivni sastojak sadrži 5'-dezoksi-5-fluoro-N-[(pentiloksi)-karbonil]-citidin (kapecitabin). Novi dozni oblik je pogodan za svakog pacijenta i posebno za pacijente koji imaju problema sa gutanjem čvrstih doznih oblika, uključujući pedijatrijske i gerijatrijske populacije. [0001] The present invention relates to a new rapidly disintegrating pharmaceutical dosage form containing 5'-deoxy-5-fluoro-N-[(pentyloxy)-carbonyl]-cytidine (capecitabine) as an active ingredient. The new dosage form is suitable for any patient and especially for patients who have problems swallowing solid dosage forms, including pediatric and geriatric populations.

[0002]Kapecitabin je fluoropirimidin karbamat sa antineoplastičnom aktivnošću. To je [0002] Capecitabine is a fluoropyrimidine carbamate with antineoplastic activity. That's it

oralno administriran sistmeski prolek 5'-dezoksi-5-fluorouridina (5'-DFUR), antineoplastičnog agensa. Kapecitabin je plasiran na tržištu Sjedinjenih Američki država od strane Roche Laboratories pod zaštićenim nazivom Xeloda®. Hemijski naziv za kapecitabin je 5'-dezoksi-5-fluor-N-[(pentiloksi)-karbonil]-citidin i ima sledeću strukturnu formulu: orally administered systemic prodrug of 5'-deoxy-5-fluorouridine (5'-DFUR), an antineoplastic agent. Capecitabine is marketed in the United States by Roche Laboratories under the trade name Xeloda®. The chemical name for capecitabine is 5'-deoxy-5-fluoro-N-[(pentyloxy)-carbonyl]-cytidine and has the following structural formula:

[0003]Kapecitabine je obuhvaćen u US patentima, uključujući US Pat. No. 4,966,891 i 5,472,949 i USSN 60/667,509, podnet Aprila 1, 2005. Poboljšanje metode za proizvodnju kapecitabina su opisane u US Pat. No. 5,453,497 i 5,476,932, i prijavi USSN 60/532,266, podnetoj Decembra 22, 2003. U meri u kojoj je to potrebno, bilo koji i svi prethodno navedeni patenti i prijave su ovde dati kao reference.. [0003] Capecitabine is covered by US patents, including US Pat. No. 4,966,891 and 5,472,949 and USSN 60/667,509, filed Apr. 1, 2005. Improved methods for the production of capecitabine are described in US Pat. No. 5,453,497 and 5,476,932, and application USSN 60/532,266, filed Dec. 22, 2003. To the extent necessary, any and all of the foregoing patents and applications are incorporated herein by reference.

[0004]U Sjedinjenim Amreičkim Državama, Kapecitabin je trenutno odobren za lečenje kancera debelog creva i kancera dojke. Trenutno odobrena/preporučena doza JB 14/08/2007 kapecitabina u ovim indikacijama iznosi 1250 mg/m<2>administriran oralno dva puta na dan (ekvivalentno 2500 mg/m<2>ukupne dnevne doze) tokom 14 dana nakon čega sledi 7-dnevni odmor kao ciklus od 3-nedelje, dokle god je potrebno. Videti odobreno uputstvo u pakovanju. Obično srednja dužina trajanja tretmana je ciklus od 3 do 6 nedelja. Trenutno odobreni jedinični dozni oblici su tablete svetlo-kajsija boje koje sadrže 150 mg kapecitabina i tablete svetlo-kajsija boje koje sadrže 500 mg kapecitabina. [0004] In the United States, Capecitabine is currently approved for the treatment of colon and breast cancer. The currently approved/recommended dose of JB 14/08/2007 capecitabine in these indications is 1250 mg/m<2>administered orally twice daily (equivalent to 2500 mg/m<2>total daily dose) for 14 days followed by 7 days off as a 3-week cycle, for as long as needed. See the approved package insert. Usually, the average length of treatment is a cycle of 3 to 6 weeks. The currently approved unit dosage forms are light apricot colored tablets containing 150 mg capecitabine and light apricot colored tablets containing 500 mg capecitabine.

[0005]Kapecitabin tabletama koje su strenutno na tržištu (Xeloda® Roche) obično je potrebno oko 7-12 minuta za dezintegraciju u vodi (USP Disintegration Test),u zavisnosti od veličine tableta. Tradicionalni eksipijensi koji se trenutno koriste u ovim tabletama, kao što je laktoza iu natrijum kroskarmeloza, sami ne mogu da nadjačaju kohezivne osobine kapecitabina u tabletama. Krajni rezultat je taj da se tablete koje se nalaze na tržištu polako dezintegrišu površinskom erozijom i tako nisu podložne brzoj disperziji ili dezintegraciji u vodi pre oralne administracije pacijentu gutanjem. [0005] Capecitabine tablets currently on the market (Xeloda® Roche) usually require about 7-12 minutes to disintegrate in water (USP Disintegration Test), depending on the size of the tablet. Traditional excipients currently used in these tablets, such as lactose and croscarmellose sodium, alone cannot overcome the cohesive properties of capecitabine tablets. The end result is that tablets on the market slowly disintegrate by surface erosion and thus are not subject to rapid dispersion or disintegration in water prior to oral administration to the patient by ingestion.

[0006]Shodno tome, tablete kapecitabina koje se nalaze na tržištu mogu da budu teške za gutanje za pedijatrijske i gerijatrijske pacijente, kao i az pacijente sa blokadama prilikom gutanja. [0006] Accordingly, commercially available capecitabine tablets may be difficult to swallow for pediatric and geriatric patients, as well as for patients with swallowing blockages.

[0007]Prema tome, brzo dezintegrišuće tablete, kao one sa brzo dispergujućim matriksom, a bolje brzo dezintegrišuće aromatizirane tablete, su poželjne za otklanjanje navedenih teškoća vezanih za sporu eroziju tableta u vodi pre oralne administracije. [0007] Accordingly, rapidly disintegrating tablets, such as those with a rapidly dispersing matrix, and preferably rapidly disintegrating flavored tablets, are desirable to overcome the aforementioned difficulties related to the slow erosion of tablets in water prior to oral administration.

[0008]Predmetni pronalazak obezbeđuje brzo dezintegrišuće farmaceutske dozne oblike za oralnu administraciju 5'-dezoksi-5-fluoro-N-[(pentiloksi)-karbonil]-citidin (kapecitabin) koji je pogodan za administraciju pacijentima teško gutaju čvrste oralne dozne oblike. [0008] The present invention provides rapidly disintegrating pharmaceutical dosage forms for oral administration of 5'-deoxy-5-fluoro-N-[(pentyloxy)-carbonyl]-cytidine (capecitabine) which are suitable for administration to patients with difficulty in swallowing solid oral dosage forms.

[0009]Prdmetni pronalazak obezbeđuje brzo dezintegrišuće farmaceutske dozne oblike kapecitabina obložene filmom koji su pogodni za oralnu administraciju. Poželjno, tableta se dezintegriše u vodi na 37°C{ USP Disintegration Test)za manje od 2 minuta, a bolje za manje od oko 1 minuta, i ima čvrstoću od oko 8-13 jedinicaStrong Cobb- Units(scu). Ručnim mešanjem u vodi na sobnoj temperaturi, tableta se dezintegriše za manje od ili za oko 3 minute. U poželjnoj realizaciji, kompozicija obuhvata, bazirano na ukupnoj težini u konačnoj doznoj jedinici, od oko 10% do oko 50%, bolje od oko 25% do oko 35%, još bolje oko 30%, kapecitabina i od oko 10% do oko 50%, bolje od oko 20% do oko 40%, a najbolje od oko 30%, po doznoj jedinici bar jednoh dizintegranta. [0009] The present invention provides rapidly disintegrating film-coated pharmaceutical dosage forms of capecitabine suitable for oral administration. Preferably, the tablet disintegrates in water at 37°C (USP Disintegration Test) in less than 2 minutes, more preferably in less than about 1 minute, and has a strength of about 8-13 Strong Cobb-Units (scu). By mixing by hand in water at room temperature, the tablet disintegrates in less than or about 3 minutes. In a preferred embodiment, the composition comprises, based on the total weight in the final dosage unit, from about 10% to about 50%, preferably from about 25% to about 35%, even more preferably about 30%, of capecitabine and from about 10% to about 50%, preferably from about 20% to about 40%, and preferably from about 30%, per dosage unit of at least one disintegrant.

[0010]Sledeća poželjna realizacija predmetnog pronalaska odnosi se na sastav tableta bez laktoze koje su namenjene osobama sa netolerancijom na lakrozu pri čemu je doza zamenjena manitolom. [0010] The next preferred embodiment of the present invention relates to the composition of lactose-free tablets intended for people with lacrosse intolerance, in which the dose is replaced by mannitol.

[0011]Dodatno, direktno kompresibilan polihidroksilni alkohol, kao što je manitol, o mikrokristala celuloza su suštinski važni za održavanje čvrstoće tablete bez promene dezintegracije tablete. Sastav manitola iznosi od oko 2% do oko 25%, a bolje od oko 4% do oko 20% i još bolje 6% do oko 16% i sastav mikrokristaline celulozae iznosi od oko 4% do oko 30%, bolje od oko 8% do oko 25% i još bolje od oko 12% do oko 22% po jedničnom doznom obliku. [0011] Additionally, directly compressible polyhydroxyl alcohols, such as mannitol, and cellulose microcrystals are essential for maintaining tablet strength without altering tablet disintegration. The mannitol composition is from about 2% to about 25%, preferably from about 4% to about 20% and even better from 6% to about 16% and the microcrystalline cellulose composition is from about 4% to about 30%, preferably from about 8% to about 25% and even better from about 12% to about 22% per unit dosage form.

[0012]Poželjno, kompozicija sadži od oko 50mg do oko 1500mg, bolje 100 mg do oko 750 mg, i još bolje od oko 125 mg do oko 500 mg, kapecitabina. Najbolje, kompozicija sadrži po jediničnom doznom obliku, 125 mg, 150 mg, 175 mg, 250 mg ,350 mg ili 500mg kapecitabina. [0012] Preferably, the composition comprises from about 50 mg to about 1500 mg, more preferably from 100 mg to about 750 mg, and more preferably from about 125 mg to about 500 mg, of capecitabine. Preferably, the composition contains, per unit dosage form, 125 mg, 150 mg, 175 mg, 250 mg, 350 mg or 500 mg of capecitabine.

[0013]Korisni dezintegranti su, ali nisu ograničeni na, krospovidon sa veličinom čestica u opsegu od 90% ispod 15 mikrona do veličine čestica u opsegu od 90% ispod 400 mikrona, natrijum kroskarmeloza, škrobni natrijum glikolat, hidroksi propil celuloza( lovv- substituted hydroksipropilceluloza),ili bilo koji komercijalno dostupni dezintegrant, kao što je Pharmaburst C™ , manitol/sorbitol kombinacija koja je opisana i čija se zaštita traži u US Patentu No.7,118,765 koji je ovde dat kao referenca (dostupno od SPI Pharma, New Castle, Delaware) ili bilo koja njihova kombinacija. [0013] Useful disintegrants include, but are not limited to, crospovidone with a particle size in the range of 90% below 15 microns to a particle size in the range of 90% below 400 microns, croscarmellose sodium, starch sodium glycolate, hydroxy propyl cellulose (low-substituted hydroxypropyl cellulose), or any commercially available disintegrant, such as Pharmaburst C™, a mannitol/sorbitol combination. which is described and claimed in US Patent No. 7,118,765 incorporated herein by reference (available from SPI Pharma, New Castle, Delaware) or any combination thereof.

[0014]Farmaceutske kompozicije mogu da sadrže i dodatne terapeutski inertne neorganske ili organske nosače ili eksipijense. Na primer, ove kompozicije mogu da sadrže koragense ukusa kao što je vanilin, smeša za maskiranje gorkog ukusa smeše, aroma jagode ili druga aroma ili kombinacije aroma koje se obično dodatju u farmaceutske preparate čineći ih prijatnim za oralnu administraciju. [0014] Pharmaceutical compositions may also contain additional therapeutically inert inorganic or organic carriers or excipients. For example, these compositions may contain flavoring agents such as vanillin, bitter taste masking compound, strawberry flavoring, or other flavorings or combinations of flavorings commonly added to pharmaceutical preparations to make them palatable for oral administration.

[0015]Kompozicije takođe mogu da sadrže zaslađivače kao što su natrijum saharin, aspartam, sukraloza, acesulfame-K, i sukroza. [0015] The compositions may also contain sweeteners such as sodium saccharin, aspartame, sucralose, acesulfame-K, and sucrose.

[0016]Kompozicije takođe mogu da sadrže vezivna sredstva kao što je hidroksipropil metilceluloza, hidroksipropilceluloza, povidon, preželatiniziran škrob ili drugi kukuruzni škrob za bubrenje na hladno. [0016] The compositions may also contain binding agents such as hydroxypropyl methylcellulose, hydroxypropylcellulose, povidone, pregelatinized starch, or other cold swelling corn starch.

[0017]Kompozicije takođe mogu da sadrže vezivna sredstva kao što su anhidrovana laktoza ili mikrokristalna celuloza. [0017] The compositions may also contain binding agents such as anhydrous lactose or microcrystalline cellulose.

[0018]Kompozicije takođe mogu da sadrže agense za bojenje, agense za oblaganje, antioksidanse, stabilizatore, sredstva za klizenje (npr., magnezijum stearat), sredstva za granulaciju, pomoćna sredstva za klizenje, i druge agense i materijale su poznati prosečnom stručnjaku i oblasti dobijanja farmaceutskih doznih oblika za humanu oralnu konzumaciju. [0018] The compositions may also contain coloring agents, coating agents, antioxidants, stabilizers, glidants (eg, magnesium stearate), granulating agents, glidants, and other agents and materials known to one of ordinary skill in the art of preparing pharmaceutical dosage forms for human oral consumption.

[0019]U jednoj realizaciji, dozni jedinični oblik je tableta, poželjno film obložena tableta. Obloga može da sadrži ekspijense kao što je ekspijens za formiranje filma (polimer), plastifikator,supstanca a postizanje neprozračnosti, pigmente, boje i si.. Smatra se da su odabir ovih materijala i upotrebljene količine obuhvaćeni tehnikom. Sastav film obloge može da bude odabran od, na primer, Hipromeloze, Polivinil Alkohola, Titan Dioksida, Talka, boje gvožđe oksida bez ili sa plastifikatora, kao što je Polietilen Glikol, Polisorbat 80, ili Triacetin. Sledeći primeri ilustruju realizacije koje se odnose na jedinične dozne oblike u skladu sa pronalaskom. U svakom slučaju, jeidnični dozni oblik je film obložena tableta. [0019] In one embodiment, the dosage unit form is a tablet, preferably a film-coated tablet. The coating may contain excipients such as film-forming excipient (polymer), plasticizer, substance to achieve opacity, pigments, dyes, etc. It is considered that the selection of these materials and the amounts used are covered by the technique. The film coating composition can be selected from, for example, Hypromellose, Polyvinyl Alcohol, Titanium Dioxide, Talc, Iron Oxide paint without or with plasticizers, such as Polyethylene Glycol, Polysorbate 80, or Triacetin. The following examples illustrate embodiments relating to unit dosage forms in accordance with the invention. In any case, the unit dosage form is a film-coated tablet.

Primeri 1 - 6Examples 1 - 6

Formulacija kompozicijeComposition formulation

[0020] [0020]

[0021]Procedura: [0021]Procedure:

1. Pomešati Kapecitabin sa anhdirovanom laktozom i delom krospovidona 1. Mix capecitabine with lactose anhydrous and part of crospovidone

2. Rastvoriti Hipromelozu u čistoj vodi 2. Dissolve Hypromellose in clean water

3. Granulisati smešu iz Koraka 1 sa rastvorom za granulaciju iz Koraka 2 3. Granulate the mixture from Step 1 with the granulation solution from Step 2

4. Samleti vlažni granulat i Koraka 3 4. Grind the wet granulate from Step 3

5. Osuštiti i samleti granule iz Koraka 4 5. Dry and grind the granules from Step 4

6. Pomešati granule iz Koraka 5 sa Pharmaburst-om C, ostatkom krospovidona, 6. Mix the granules from Step 5 with Pharmaburst C, the rest of the crospovidone,

manitolom, mikrokristallinnom celulozzom, aspartamom, natrijum saharinom, vanilinom, agensom za maskiranje gorkog ukusa, i aromom jagode mannitol, microcrystalline cellulose, aspartame, sodium saccharin, vanillin, bitter taste masking agent, and strawberry flavor

7. Prosejati magnezijum stearat, i dodati u smešu iz Koraka 6 i pomešati 7. Sieve the magnesium stearate, and add to the mixture from Step 6 and mix

8. Komprimovati smešu za tabletiranje iz Koraka 7 u jezgra 8. Compress the tableting mixture from Step 7 into cores

9. Pripremiti film suspenziju za oblaganje dispergovanjem film smeše za oblaganje u prečišćenoj vodi 10. Obložiti filmom jezgra iz Koraka 8 pomoću film suspenzijom za oblaganje iz koraka 9. Prepare the coating film suspension by dispersing the coating film mixture in purified water 10. Coat the core film from Step 8 using the coating film suspension from step

Step 9 Step 9

Primeri 7- 12Examples 7- 12

[0022]Sledeće kompozicije predstavljaju poželjne formulacije bazirane na mg po tableti pri čemu je laktoza zamenjena manitolom [0022] The following compositions represent preferred formulations based on mg per tablet wherein lactose is replaced by mannitol.

Formulacija kompozicijeComposition formulation

[0023] [0023]

[0024]Procedura: Slična onoj opisanoj za primere 1-6, izuzev što je anhidrovana laktoza zamenjena Manitolom u Koraku 1. [0024] Procedure: Similar to that described for Examples 1-6, except that anhydrous lactose is replaced by Mannitol in Step 1.

Primeri 13- 18Examples 13- 18

[0025]Sledćee kompozicije predstavljaju poželjne formulacije bazirane na mg po težini [0025] The following compositions represent the preferred formulations based on mg by weight

tablete, pri čemu su zamenjeni Pharmaburst C i Laktoza. tablets, whereby Pharmaburst C and Lactose were replaced.

Formulacija kompozicijeComposition formulation

[0026] [0026]

[0027]Procedura: Slična onoj datoj za primere 1-6, izuzev što je anhidrovana laktoza zamenjena Manitolom u Koraku 1 i uklonjen Pharmaburst C u Koraku 6. [0027] Procedure: Similar to that given for Examples 1-6, except that anhydrous lactose was replaced with Mannitol in Step 1 and Pharmaburst C was removed in Step 6.

Aspekti dezintegracije ( raspadljivosti doznih oblikaAspects of disintegration (degradability of dosage forms

[0028]Sledi poređenje vremna dezintegracije za tablete predmetnog pronalaska koje se brzo raspadaju ( brzo dezintegrišuće) i tableta koje se nalaze na tržištu, manje i veće čvrstoće. [0028] The following is a comparison of the disintegration time for the rapidly disintegrating tablets of the subject invention (rapidly disintegrating) and tablets available on the market, of lower and higher strength.

[0029]Vremena raspadanja su dobijena pomoću uređaja za ispitivanje raspadljivosti tableta (USP Disintegration Apparatus) bez diskova i u vodi na 37°C. Praćena su vremena eksperimentalne test metode i dobijenih vremena raspadljivosti (dezintgracije) prema metodi:USP Disintegration Test Method(USP 29, General Chapters, Phvsical Tests, <709> koji je ovde dat referencom). [0029] Disintegration times were obtained using a tablet disintegration apparatus (USP Disintegration Apparatus) without discs and in water at 37°C. The times of the experimental test method and the obtained times of disintegration (disintegration) were monitored according to the method: USP Disintegration Test Method (USP 29, General Chapters, Physical Tests, <709> which is given here by reference).

[0030]Za potrebe ovog testa, dezintegracija ne podrazumeva potpuno rastvaranje jedinice ili čak njene aktivne komponente. Potpuna dezintegracija je definisana kao stanje u kojem bilo kakav ostatak jedinice, izuzev fragmenata nerastvome obloge ili omotač (čaura) kaspule, koji zaostaje na nosaču test aparata je meka masa bez opipljivog čvrstog jezgra. [0030] For the purposes of this test, disintegration does not mean complete dissolution of the unit or even its active component. Complete disintegration is defined as a condition in which any remnant of the unit, other than fragments of the insoluble lining or capsule shell, remaining on the test apparatus support is a soft mass without a palpable solid core.

USP uređaj za isitivanie raspadljivosti tableta ( USP Disintegration Apparatus)USP Disintegration Apparatus

[0031]Aparat se sastoji od sklopa žičane korpe, 1000-mL, suda, 138 do 160 mm visine i unutrašnjeg prečnika od 97 do 115 mm za tečnost u koju uranja uređaj, termostatički deo za zagrevanje tenčnosti između 35 i 39 , i uređaj za podizanje žičane korpe u tečnosti pri konstantnoj frekvenci između 29 i 32 ciklusa u minuti duž rastojanja ne manje od 53 mm i ne veće od 57 mm. Zapremina tečnosti u suduje takva da u najvišoj tačci pri pokretu na gore žičano sito ostaje bar 15 mm ispod površine tečnosti i spušta se na ne manje od 25 mm od dna suda pri pokretu na dole. Ni u jednom momenut vrh sklopa korpe ne treba da bude potopljen. Vreme potrebno za pokret na gore je jedna vremenu portrebnom za pokret na dole, i pramena smera kretanja je bez zapinjanja, znači bez naglog povratnog pokreta. Žičani sklop se pokreće vertikalno duž svoje ose. Nije poželjno horizontalno kretanje ili pokreti duž ose koja nije vertiklana. [0031] The apparatus consists of a wire basket assembly, a 1000-mL vessel, 138 to 160 mm high and an internal diameter of 97 to 115 mm for the liquid in which the device is immersed, a thermostatic part for heating the thinness between 35 and 39 , and a device for raising the wire basket in the liquid at a constant frequency between 29 and 32 cycles per minute along a distance of not less than 53 mm and not larger than 57 mm. The volume of liquid in the container is such that at the highest point when moving up, the wire sieve remains at least 15 mm below the surface of the liquid and descends to no less than 25 mm from the bottom of the container when moving down. At no point should the top of the basket assembly be submerged. The time required for the upward movement is the same as the time required for the downward movement, and the strand of the direction of movement is without sticking, that is, without a sudden return movement. The wire assembly is driven vertically along its axis. Horizontal movement or movements along an axis that is not vertical is not desirable.

[0032]Žičani sklop- Ovaj sklop se sastoji od šest providnih cilindara sa otvorenim krajem, dužine 77.5 ± 2.5 mm i unutrašnjeg prečnika od 20.7 do 23 mm i zid debljine od 1.0 do 2.8mm , cilinidre u vertiklanom položaju drže dve ploče, svaka prečnika 88 do 92 mm i debljine 5 do 8.5 mm, sa šest rupa, svaka prečnika 22 do 26 mm, podjednako udaljene od centra ploče i podjednako udaljene jedna od druge. Pričvršćena ispod površine donje ploče je tkanina od čeličnih niti , koja ima ravnu kvadratasto sitasto dno sa otvorima od 1.8- do 2.2-mm, a prečnik žice (žičane niti) iznosi 0.57 do 0.66 mm. Sastavni delovi parata su sklopljeni i kruto pričvršćeni pomoću tri šrafa koja prolaze kroz dve ploče. Postavljen je i dodatak koji zaustavlja žičanu korpu od spuštanja i podizanja aparata pomoću naznačenih tačaka na na osi. [0032] Wire assembly- This assembly consists of six transparent cylinders with an open end, length 77.5 ± 2.5 mm and inner diameter from 20.7 to 23 mm and wall thickness from 1.0 to 2.8 mm, cylinders in vertical position hold two plates, each diameter 88 to 92 mm and thickness 5 to 8.5 mm, with six holes, each diameter 22 to 26 mm, equidistant from the center of the plate and equidistant from each other. Attached below the surface of the bottom plate is a fabric made of steel threads, which has a flat square mesh bottom with 1.8- to 2.2-mm openings, and the diameter of the wire (wire strands) is 0.57 to 0.66 mm. The component parts of the parata are assembled and rigidly fixed by means of three screws passing through two plates. There is also an attachment that stops the wire basket from lowering and raising the apparatus using the indicated points on the axis.

[0033]Izgled sklopa može donekle da varira, pod uslovom da ostaje specifikacija staklenih cilindara i the screen mesh siže. [0033] The appearance of the assembly can vary somewhat, provided that the specification of the glass cylinders and the screen mesh remains.

[0034]Nije korišćen sistem sa diskovima( engl. Disks- Disks).[0034] No disk system was used.

PROCEDURAPROCEDURE

[0035]neobložene ili obložene tablete - Postaviti 1 doznu jedinicu u svaki od šest cilindara u korpi. Podesiti aparat tako da koristi vodu ili naznačeni medijum kao tečnost za uranjanje, odražavajući temperaturu na 37 ± 2. Pred kraj vremena naznačenog u monografu, podići korpu iz tečnosti i pogledati da li su sve tablete dezintegrisale u potpunosti. Ukoliko se 1 ili 2 tablete nisu potpuno dezintegrisale, ponoviti test na 12 dodatnih tableta. Uslov je ispunjen ako je dezintegrisano ne manje od 16 tableta od ukupno 18 testiranih tableta. [0035] uncoated or coated tablets - Place 1 dosage unit in each of the six cylinders in the basket. Adjust the apparatus to use water or the specified medium as the immersion liquid, reflecting the temperature at 37 ± 2. Towards the end of the time indicated in the monograph, lift the basket from the liquid and see if all the tablets have disintegrated completely. If 1 or 2 tablets have not completely disintegrated, repeat the test on 12 additional tablets. The condition is met if no less than 16 tablets out of a total of 18 tested tablets are disintegrated.

Vremena dezintegracije (raspadljivosti) u vodi na 37°C (USP uređaj za isitivanje raspadljivosti Disintegration times in water at 37°C (USP disintegration heater

tableta) tablet)

[0036]Kao što je dato u prethodnoj tabeli, tablete kapecitabina predmetnog pronalaska koje se brzo dezintegrišu imaju vremena dezintegracije (raspadljivosti) u vodi koja su približno osam- do trinaest puta kraća od vremena dezintegracije tableta koja se trenutno nalaze na tržištu, pri manjim i većim čvrstoćama. [0036] As given in the preceding table, the rapidly disintegrating capecitabine tablets of the present invention have disintegration times in water that are approximately eight to thirteen times shorter than the disintegration times of tablets currently on the market, at lower and higher strengths.

[0037]U isto vreme dok je pronalazak ilustrovan referencom na specifične i poželjne realizacije, prosečan stručnjak iz oblasti tehnike će da su moguće varijacije i modifikacije kroz rutinsko izvođenje eksperimenata pronalaska i praksu. Prema tome, pronalazak ni na koji način ne ograničava prethodno dat opis, već je definisan zahtevima i njihovim ekvivalentima. [0037] While the invention is illustrated by reference to specific and preferred embodiments, one of ordinary skill in the art will recognize that variations and modifications are possible through the routine performance of experiments of the invention and practice. Therefore, the invention is in no way limited by the foregoing description, but is defined by the claims and their equivalents.

REFERENCE CITIRANE U OPISUREFERENCES CITED IN THE DESCRIPTION

Ovaj spisak referenci koje citira Prijavilac je samo za čitaoca. On ne predstavlja deo ovog EvropskogThis list of references cited by the Applicant is for the reader only. It is not part of this European one

patenta. Iako su reference prikupljene s velikom pažnjom, nemoguće je isključiti greške ili propuste, tepatent. Although the references have been compiled with great care, it is impossible to exclude errors or omissions, and

se EPO ograđuje od svake odgovornosti u tom pogledu.the EPO disclaims any liability in this respect.

Patenta dokumentacija citiran u opisuPatent documentation cited in the description

•US4966891Ar00031• US5472949Ar00031• USSN60667509P[ 00031•US5453497A100031• US5476932Af00031•USSN60532266Pr00031•US7118765B [ 00131•US4966891Ar00031• US5472949Ar00031• USSN60667509P[ 00031•US5453497A100031• US5476932Af00031•USSN60532266Pr00031•US7118765B [ 00131

Claims

1. A film-coated pharmaceutical composition comprising capecitabine and at least one disintegrant, characterized in that it disintegrates in water at 37°C in a USP tablet disintegrator in less than 2 minutes and has a strength of about 56-91N (2-13 strong Cobb-Units).

2. The composition according to claim 1, characterized in that capecitabine, based on the total weight of the core of the composition, constitutes from about 10% to about 50%.

3. The composition according to claim 2, characterized in that it contains from about 50 mg to about 1500 mg of capecitabine.

4. The composition according to claim 3, characterized in that it contains from about 100 mg to about 750 mg of capecitabine.

5. Composition according to claim 3, characterized in that it contains 125 mg, 175 mg, 250 mg, 350 mg or 500 mg of capecitabine.

6. Pharmaceutical composition according to claim 1, characterized in that at least one disintegrant is selected from the group consisting of crospovidone with a particle size in the range of 90% below 15 microns to a particle size in the range of 90% below 400 microns, croscarmellose sodium, starch sodium glycolate, low-substituted hydroxypropyl cellulose, Pharmaburst C or any combination of these disintegrants.

7. The composition according to claim 5, characterized in that the disintegrant constitutes from about 10 to about 50% per unit dosage form.

8. The composition according to claim 6, characterized in that the disintegrant constitutes from about 20% to about 40% per unit dosage form.

9. Composition according to claim 7, characterized in that the disintegrant makes up about 30% per unit dosage form.

10. Pharmaceutical composition according to claim 1, characterized in that it additionally contains directly compressible polyhydroxyl alcohol.

11. The composition according to claim 9, characterized in that the alcohol is mannitol and is from about 2% to about 25% per unit dosage form

12. Composition according to claim 10, characterized in that the amount of mannitol is from 4% to about 20% per unit dosage form.

13. The composition according to claim 11, characterized in that the amount of mannitol is about 6% to about 16% per unit dosage form.

14. Pharmaceutical composition according to claim 1, characterized in that it contains from about 4% to about 30% of microcrystalline cellulose per unit dosage form.

15. The composition according to claim 13, characterized in that it contains from about 8% to about 25% of microcrystalline cellulose per unit dosage form.

16. The composition according to claim 14, characterized in that it contains about 12% to about 22% microcrystalline cellulose per unit dosage form.

17. Composition according to claim 1, characterized in that the disintegration time is less than 1 minute.

18. The composition according to claim 1, characterized in that it contains a binding agent selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropylcellulose, povidone, pre-gelatinized starch and cold swelling corn starch.

19. The composition according to claim 17, characterized in that the amount of capecitabine is from about 50 mg to about 1500 mg per unit dosage form.

20. The composition according to claim 19, characterized in that the amount of capecitabine is from about 100 mg to about 750 mg per unit dosage form.

21. Composition according to claim 18, characterized in that the amount of capecitabine is 125 mg, 150 mg, 175 mg, 250 mg, 350 mg or 500 mg per unit dosage form.

22. The pharmaceutical composition according to the claim, characterized in that it disintegrates in water at 37°C in a USP tablet disintegrator in less than 1 minute, and contains capecitabine, at least one disintegrant, binding agent, one filler, glidant, at least one sweetener and at least one flavoring agent.

23. Pharmaceutical composition according to claim 22, characterized in that it is coated with a film.

24. Pharmaceutical composition according to claim 1 or 22, characterized in that it does not contain lactose.

25. Pharmaceutical composition according to claim 23, characterized in that 125 mg of capecitabine, 35.72 mg of anhydrous lactose, 3.57 mg of hypromellose, 37.50 mg of crospovidone, 89.30 mg of Pharmaburst C, 23.21 mg of mannitol, 46.82 mg of microcrystalline cellulose, 8.22 mg of magnesium stearate, 15.54 mg aspartame, 3.22 mg sodium saccharin, 7.86 mg vanillin, 1.47 mg bitter taste masking agent and 2.97 mg strawberry flavor.

26. The pharmaceutical composition according to claim 23, The pharmaceutical composition according to the claim contains 150 mg of capecitabine, 42.90 mg of anhydrous lactose, 4.28 mg of hypromellose, 45.00 mg of crospovidone, 107.16 mg of Pharmaburst C, 27.85 mg of mannitol, 56.18 mg of microcrystalline cellulose, 9.86 mg of magnesium stearate, 18.64 mg aspartame, 3.86 mg sodium saccharin, 9.43 mg vanillin, 1.76 mg aftertaste masking agent and 3.56 mg strawberry flavor.

27. Pharmaceutical composition according to claim 23, indicated by the fact that it contains 175 mg of capecitabine, 50.06 mg of anhydrous lactose, 5.00 mg of hypromellose, 52.50 mg of crospovidone, 125.00 mg of Pharmaburst C, 32.50 mg of mannitol, 65.54 mg of microcrystalline cellulose, 11.50 mg of magnesium stearate, 21.75 mg aspartame, 4.50 mg sodium saccharin, 11.00 mg vanillin, 2.06 mg bitter taste masking agent and 4.15 mg strawberry flavor.

28. Pharmaceutical composition according to claim 23, indicated by the fact that it contains 250 mg of capecitabine, 71.49 mg of anhydrous lactose, 7.14 mg of hypromellose, 75.00 mg of crospovidone, 178.60 mg of Pharmaburst C, 46.43 mg of mannitol, 93.63 mg of microcrystalline cellulose, 16.43 mg of magnesium stearate, 31.07 mg aspartame, 6.43 mg sodium saccharin, 15.71 mg vanillin, 2.94 mg bitter taste masking agent and 5.93 mg strawberry flavor.

29. Pharmaceutical composition according to claim 23, characterized by the fact that it contains 350 mg of capecitabine, 100.12 mg of anhydrous lactose, 10.00 mg of hypromellose, 105.00 mg of crospovidone, 250.00 mg of Pharmaburst C, 65.00 mg of mannitol, 131.08 mg of microcrystalline cellulose, 23.00 mg of magnesium. stearate, 43.50 mg aspartame, 9.00 mg sodium saccharin, 22.00 mg vanillin, 4.12 mg bitter taste masking agent and 8.30 mg strawberry flavor.

30. Pharmaceutical composition according to claim 23, indicated by the fact that it contains 500 mg of capecitabine, 142.88 mg of anhydrous lactose, 14.28 mg of hypromellose, 150.00 mg of crospovidone, 357.20 mg of Pharmaburst C, 92.84 mg of mannitol, 187.28 mg of microcrystalline cellulose, 32.88 mg of magnesium. stearate, 62.16 mg aspartame, 12.88 mg sodium saccharin, 31.44 mg vanillin, 5.88 mg taste masking agent and 11.88 mg strawberry flavor.

31. Pharmaceutical composition according to claim 1, characterized by the fact that it contains 125.00 mg of capecitabine, 3.57 mg of hypromellose, 37.50 mg of crospovidone, 89.30 mg of Pharmaburst C, 58.93 mg of mannitol, 46.82 mg of microcrystalline cellulose, 8.22 mg of magnesium stearate, 15.54 mg of aspartame, 3.22 mg sodium saccharin, 7.86 mg vanillin, 1.47 mg off-taste masking agent and 2.97 mg strawberry flavor.

32. Pharmaceutical composition according to claim 1, indicated by the fact that it contains 150.00 mg of capecitabine, 4.28 mg of hypromellose, 45.00 mg of crospovidone, 107.16 mg of Pharmaburst C, 70.75 mg of mannitol, 56.18 mg of microcrystalline cellulose, 9.86 mg of magnesium stearate, 18.64 mg of aspartame, 3.86 mg sodium saccharin, 9.43 mg vanillin, 1.76 mg taste masking agent and 3.56 mg strawberry flavor.

33. Pharmaceutical composition according to claim 1, characterized by the fact that it contains 175.00 mg of capecitabine, 5.00 mg of hypromellose, 52.50 mg of crospovidone, 125.00 mg of Pharmaburst C, 82.56 mg of mannitol, 65.54 mg of microcrystalline cellulose, 11.50 mg of magnesium stearate, 21.75 mg of aspartame, 4.50 mg sodium saccharin, 11.00 mg vanillin, 2.06 mg bitter taste masking agent and 4.15 mg strawberry flavor.

34. Pharmaceutical composition according to claim 1, characterized by the fact that it contains 250.00 mg of capecitabine, 7.14 mg of hypromellose, 75.00 mg of crospovidone, 178.60 mg of Pharmaburst C, 117.92 mg of mannitol, 93.63 mg of microcrystalline cellulose, 16.43 mg of magnesium stearate, 31.07 mg of aspartame, 6.43 mg sodium saccharin, 15.71 mg vanillin, 2.94 mg taste masking agent and 5.93 mg strawberry flavor.

35. Pharmaceutical composition according to claim 1, characterized by the fact that it contains 350.00 mg of capecitabine, 10.00 mg of hypromellose, 105.00 mg of crospovidone, 250.00 mg of Pharmaburst C, 165.12 mg of mannitol, 131.08 mg of microcrystalline cellulose, 23.00 mg of magnesium stearate, 43.50 mg aspartame, 9.00 mg sodium saccharin, 22.00 mg vanillin, 4.12 mg taste masking agent and 8.30 mg strawberry flavor.

36. Pharmaceutical composition according to claim 1, characterized by the fact that it contains 500.00 mg of capecitabine, 14.28 mg of hypromellose, 150.00 mg of crospovidone, 357.20 mg of Pharmaburst C, 235.72 mg of mannitol, 187.28 mg of microcrystalline cellulose, 32.88 mg of magnesium stearate, 62.16 mg aspartame, 12.88 mg sodium saccharin, 31.44 mg vanillin, 5.88 mg taste masking agent and 11.88 mg strawberry flavor.

37. Pharmaceutical composition according to claim 1, characterized by the fact that it contains 125.00 mg capecitabine, 3.57 mg hypromellose, 62.50 mg crospovidone, 58.93 mg mannitol, 82.26 mg microcrystalline cellulose, 7.41 mg magnesium stearate, 15.54 mg aspartame, 3.22 mg sodium saccharin, 7.86 mg vanillin, 1.47 mg off-taste masking agent and 2.97 mg strawberry flavor.

38. Pharmaceutical composition according to claim 1, characterized by the fact that it contains 150.00 mg of capecitabine, 4.28 mg of hypromellose, 75.01 mg of crospovidone, 70.75 mg of mannitol, 98.71 mg of microcrystalline cellulose, 8.90 mg of magnesium stearate, 18.64 mg of aspartame, 3.86 mg of sodium saccharin, 9.43 mg vanillin, 1.76 mg off-taste masking agent and 3.56 mg strawberry flavor.

39. Pharmaceutical composition according to claim 1, characterized by the fact that it contains 175.00 mg of capecitabine, 5.00 mg of hypromellose, 87.50 mg of crospovidone, 82.50 mg of mannitol, 115.16 mg of microcrystalline cellulose, 10.37 mg of magnesium stearate, 21.76 mg of aspartame, 4.50 mg of sodium saccharin, 11.00 mg vanillin, 2.06 mg bitter taste masking agent and 4.15 mg strawberry flavor.

40. Pharmaceutical composition according to claim 1, characterized by the fact that it contains 250.00 mg of capecitabine, 7.14 mg of hypromellose, 125.00 mg of crospovidone, 117.86 mg of mannitol, 164.52 mg of microcrystalline cellulose, 14.82 mg of magnesium stearate, 31.08 mg of aspartame, 6.44 mg of sodium saccharin. 15.72 mg vanillin, 2.94 mg taste masking agent and 5.94 mg strawberry flavor.

41. Pharmaceutical composition according to claim 1, characterized by the fact that it contains 350.00 mg of capecitabine, 10.00 mg of hypromellose, 175.00 mg of crospovidone, 165.00 mg of mannitol, 230.32 mg of microcrystalline cellulose, 20.74 mg of magnesium stearate, 43.52 mg of aspartame, 9.00 mg of sodium saccharin. 22.00 mg vanillin, 4.12 mg off-taste masking agent and 8.30 mg strawberry flavor.

42. Pharmaceutical composition according to claim 1, characterized by the fact that it contains 500.00 mg of capecitabine, 14.28 mg of hypromellose, 250.00 mg of crospovidone, 235.72 mg of mannitol, 329.04 mg of microcrystalline cellulose, 29.64 mg of magnesium stearate, 62.16 mg of aspartame, 12.88 mg of sodium saccharin, 31.44 mg vanillin, 5.88 mg taste masking agent and 11.88 mg strawberry flavor.