RS52219B - POSTOLOGY OF CLADRIBIN FOR MULTIPLE SCLEROSIS TREATMENT - Google Patents

POSTOLOGY OF CLADRIBIN FOR MULTIPLE SCLEROSIS TREATMENT

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RS52219B
RS52219B RS20120161A RSP20120161A RS52219B RS 52219 B RS52219 B RS 52219B RS 20120161 A RS20120161 A RS 20120161A RS P20120161 A RSP20120161 A RS P20120161A RS 52219 B RS52219 B RS 52219B
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cladribine
months
period
pharmaceutical formulation
administered
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Giampiero De Luca
Arnaud Ythier
Alain Munafo
Maria Lopez-Bresnahan
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Merck Serono Sa.
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Priority claimed from PCT/EP2005/056954 external-priority patent/WO2006067141A1/en
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    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
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    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
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    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A61K38/215—IFN-beta

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Abstract

Farmaceutska formulacija kladribina za primenu u tretiranju multiple skleroze, gde se formulacija daje oralno, prateći sledeći niz koraka:(i) Indukcioni period koji traje od 2 meseca do 4 meseca, u kome se daje navedena farmaceutska formulacija kladribina i u kome je ukupna doza kladribina koja se dostiže na kraju indukcionog perioda od oko 1,7 mg/kg do oko 3,5 mg/kg;(ii) Period bez kladribina, koji traje od 8 meseci do 10 meseci, u kome se ne daje kladribin.(iii) Period održavanja koji traje 2 meseca do 4 meseca, u kome se daje navedena farmaceutska formulacija kladribina i u kome je ukupna doza kladribina koja se dostiže na kraju perioda održavanja manja od ukupne doze kladribina koja se dostiže na kraju indukcionog perioda (i);(iv) Period bez kladribina, u kome se ne daje kladribin.Prijava sadrži još 17 patentnih zahteva.A pharmaceutical formulation of cladribine for use in the treatment of multiple sclerosis, wherein the formulation is administered orally, following the following steps: (i) An induction period of 2 months to 4 months, wherein said pharmaceutical formulation of cladribine is administered and the total dose of cladribine is is reached at the end of the induction period from about 1.7 mg / kg to about 3.5 mg / kg, (ii) The cladribine-free period, which lasts from 8 months to 10 months, in which no cladribine is given. maintenance for 2 months to 4 months, in which said pharmaceutical formulation of cladribine is administered and in which the total dose of cladribine reached at the end of the maintenance period is less than the total dose of cladribine reached at the end of the induction period (i); without cladribine, in which no cladribine is given. The application contains 17 more patent claims.

Description

Oblast pronalaskaField of invention

[0001]Ovaj pronalazak se odnosi na višestruke doze „kladribina" za tretiranje multiple skleroze, naročito na relapsno remitentni oblik multiple skleroze ili rane sekundarne progresivne multiple skleroze. [0001] This invention relates to multiple doses of "cladribine" for the treatment of multiple sclerosis, in particular the relapsing-remitting form of multiple sclerosis or early secondary progressive multiple sclerosis.

Stanje tehnikeState of the art

[0002]Multipla skleroza (MS) je najpoznatije hronično zapaljenjsko oboljenje demijelinizacije centralnog nervnog sistema kod ljudi. Tipično, oboljenje nastaje u dobu 20 do 40 godina. Žene oboljevaju približno dva puta češće od muškaraca. [0002] Multiple sclerosis (MS) is the most well-known chronic inflammatory demyelinating disease of the central nervous system in humans. Typically, the disease occurs between the ages of 20 and 40. Women are affected approximately twice as often as men.

[0003]Tokom vremena, MS može da dovede do akumulacije različitih neuroloških invaliditeta. Pretpostavlja se da do kliničkog invaliditeta dolazi usled ponovljenih inflamatornih povreda, posle čega dolazi do gublenja mijelina i aksona, što dovodi do atrofije tkiva. [0003] Over time, MS can lead to the accumulation of various neurological disabilities. Clinical disability is thought to result from repeated inflammatory injury, followed by loss of myelin and axons, leading to tissue atrophy.

[0004]MS se manifestje fizičkim simptomima (recidivima i povećanjem invaliditeta), inflamacijom centralnog nervnog sistema (CNS), atrofijom mozga i oštećenjem kognitivnih sposobnosti. Ispoljeni simptomi uključuju fokalne senzorske deficite, fokalnu slabost, probleme sa vidom, ravnotežom i umor. može da dođe do oštećenja seksualnih funkcija i disfunkcije sfinktera. Oko polovine pacijenata sa MS ima smanjene kognitivne sposobnosti ili depresiju. [0004] MS is manifested by physical symptoms (relapses and increasing disability), inflammation of the central nervous system (CNS), brain atrophy and impairment of cognitive abilities. Presenting symptoms include focal sensory deficits, focal weakness, problems with vision, balance, and fatigue. impairment of sexual functions and sphincter dysfunction may occur. About half of MS patients have reduced cognitive abilities or depression.

[0005]Sada se smatra da je MS višefazno oboljenje i da se periodi kliničkog smirivanja (remisije) dešavaju između faza pogoršanja. Dužine remisija variraju i mogu da traju i po nekoliko godina, ali su retko permanentne. Izdvojena su četiri toka bolesti: relapsno-remitentna (RR), sekundarno progresivna (SP), primarno progresivna (PP) i progresivno-remitentna (PR) multipla skleroza. [0005] It is now believed that MS is a multiphasic disease and that periods of clinical remission occur between phases of exacerbation. The length of remissions varies and can last for several years, but they are rarely permanent. Four courses of the disease are distinguished: relapsing-remitting (RR), secondary progressive (SP), primary progressive (PP) and progressive-remitting (PR) multiple sclerosis.

[0006]Više od 80% pacijenata sa MS prvo će imati RR tok bolesti, sa kliničkim pogoršanjem neuroloških simptoma, posle čega dolazi do oporavka koji može ili ne mora biti potpun (Lublin i Reingold, Neurology, 1996, 46:907-911). [0006] More than 80% of MS patients will initially have a RR course of the disease, with clinical worsening of neurological symptoms, followed by recovery that may or may not be complete (Lublin and Reingold, Neurology, 1996, 46:907-911).

[0007]Tokom RRMS, nastaje povećanje invaliditeta usled nepotpunog oporavka posle recidiva. Oko polovine pacijenata sa RRMS prelaze na progresivan tok, nazvan SPMS, 10 godina posle otpočinjanja oboljenja. Za vreme SP faze, porast invaliditeta nastaje usled akumuliranja rezidualnih simptoma nakon pogoršanja, ali i zbog skrivene progresije između pogoršanja{ Lublin i Reingold above).10% MS pacijenata imaju PPMS, koja se odlikuje skrivenom progresijom simptoma počev od nastanka bolesti. Manje od 5 % pacijenata ima PRMS i često se smatra da imaju istu prognozu kao PPMS. Sugerisano je da u različitim podgrupama pacijenata učestvuju različiti patogeni mehanizmi i da za klasifikaciju oboljenja imaju širok spektar implikacija (Lassmann et al., 2001, Trends Mol. Med., 7, 115-121; Lucchinetti et al., Curr. Opin. Neurol.,2001, 14, 259-269). [0007] During RRMS, there is an increase in disability due to incomplete recovery after relapse. About half of patients with RRMS progress to a progressive course, called SPMS, 10 years after the onset of the disease. During the SP phase, the increase in disability occurs due to the accumulation of residual symptoms after exacerbations, but also due to hidden progression between exacerbations {Lublin and Reingold above).10% of MS patients have PPMS, which is characterized by a hidden progression of symptoms from the onset of the disease. Less than 5% of patients have PRMS and are often considered to have the same prognosis as PPMS. It has been suggested that different pathogenic mechanisms are involved in different subgroups of patients and that they have a wide range of implications for the classification of diseases (Lassmann et al., 2001, Trends Mol. Med., 7, 115-121; Lucchinetti et al., Curr. Opin. Neurol., 2001, 14, 259-269).

[0008]Kao početak MS definiše se događanje prvih neuroloških simptoma disfunkcije CNS. Progres u analizi cerebrospinalne tečnosti (CSF) i magnetnoj rezonantnoj tomografiji (MRI, od magnetic resonance imaging) uprostili su dijagnostički postupak i olakšali rano dijagnostikovanje (Noseworthy et al., The New England Journal of Medicine, 2000, 343, 13, 938-952/ Međunarodni skup (The International Panel) o dijagnostikovanju MS izdao je revidirane kriterijume koji olakšavaju dijagnostikovanje MS, uključujući MRI, uz kliničke i parakliničke dijagnostičke metode (Mc Donald et al., 2001, Ann. Neurol., 50:121-127). [0008] The onset of MS is defined as the occurrence of the first neurological symptoms of CNS dysfunction. Advances in the analysis of cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI) have simplified the diagnostic process and facilitated early diagnosis (Noseworthy et al., The New England Journal of Medicine, 2000, 343, 13, 938-952/ The International Panel on the diagnosis of MS issued revised criteria that facilitate the diagnosis of MS, including MRI, along with clinical and paraclinical diagnostic methods (Mc Donald et al., 2001, Ann. Neurol., 50:121-127).

[0009]Sadašnje lečenje MS, koje predstavlja tretman kojim se bolest modifikuje, tj., modifikuje tok MS, moduliše ili suprimuje imunski sistem. Postoje četiri imunomodulatorska agensa za RRMS koje je odobrila FDA: tri beta interferona (Betaseron®, Berlex; Avonex®, Biogen; Rebif®, Serono) i Glatimarer acetat (Copaxone®, Amgen). Postoji ijedan imunosupresorski lek koji je odobrila FDA, Mitoksantron, za pogoršanje MS (Novantrone®, Amgen). Koristi se i nekoliko drugih imunosupresorskih agenasa, mada ih nije odobrila FDA. [0009] The current treatment of MS, which is a disease-modifying treatment, i.e., modifies the course of MS, modulates or suppresses the immune system. There are four FDA-approved immunomodulatory agents for RRMS: three beta interferons (Betaseron®, Berlex; Avonex®, Biogen; Rebif®, Serono) and glatimarer acetate (Copaxone®, Amgen). There is one FDA-approved immunosuppressant drug, Mitoxantrone, for worsening MS (Novantrone®, Amgen). Several other immunosuppressive agents are also used, although they are not FDA approved.

[0010]Među njima, sugerisano je da je kladribin, hlorisani analogon purina, 2-hloro-2'dezoksiadenozin analog (2-CdA), koristan u lečenju MS (EP 626853B1 i US 5,506,214). [0010] Among them, cladribine, a chlorinated purine analogue, 2-chloro-2'deoxyadenosine analogue (2-CdA), has been suggested to be useful in the treatment of MS (EP 626853B1 and US 5,506,214).

[0011]U nekoliko kliničkih studija sa kladribinom kod pacijenata sa multiplom sklerozom ispitivana je upotreba i.v. i s.c. kladribina u MS. [0011] In several clinical studies with cladribine in patients with multiple sclerosis, the use of i.v. and s.c. cladribine in MS.

[0012]Obavljene su studije sa dve slepe probe, uz placebo kontrolu faze II, tretiranja hronične progresivne MS (Selby et al., 1998, Can. J. Neurol. Sci., 25:295-299), odnosno relapsno remitentnog oblika MS (Romine et al., 1999, Proceedings of the Association of American Phvsicians, 111, 1, 35-44). U prvom ispitivanju, primenjena doza kladribina bila je 0,1 mg/kg/dan tokom 7 dana kontinuiranom i.v. infuzijom. Tretman je ponavljan tokom 4 uzastopna meseca. U drugom kliničkom ispitivanju, primenjena doza kladribina bila je 0,07mg/kg/dan tokom 5 dana, davana subkutanim injeciranjnem. Tretman je ponavljan 6 uzastopnih meseci. Osim toga, izvedena je i studija sa placebo controlisanom fazom III kod pacijenata sa primarnom progresivnom (PP) ili sekundarnom progresivnom (SP) muitiplom sklerozom (Rice at al., 2000, Neurology, 54, 5, 1145-1155/ U ovoj studiji obe grupe pacijenata su dobijale kladribin subkutanom injekcijom, u dozi od 0,07 mg/kg/dan. Tretman je ponavljan ili tokom dva meseca, ili tokom 6 meseci. Klinička ispitivanja faze II pružile su dokaz o pozitivnim efektima kladribina kod pacijenata sa MS, izraženim pomoću rezultata Standardizovane Kurtzkeove proširene skale invaliditeta u MS (EDSS, od Kurtzke Extended Disability Status Scale), Skripsove skale neuroloških invaliditeta (SNRS od Scripps Neurologic rating Scale) i nalaza Magnetne rezonantne tomografije (MRI) [0012] Two-blind, placebo-controlled, phase II studies were conducted in the treatment of chronic progressive MS (Selby et al., 1998, Can. J. Neurol. Sci., 25:295-299), that is, relapsing-remitting form of MS (Romine et al., 1999, Proceedings of the Association of American Physicians, 111, 1, 35-44). In the first trial, the dose of cladribine administered was 0.1 mg/kg/day for 7 days by continuous i.v. infusion. The treatment was repeated for 4 consecutive months. In another clinical trial, the administered dose of cladribine was 0.07 mg/kg/day for 5 days, administered by subcutaneous injection. The treatment was repeated for 6 consecutive months. In addition, a placebo-controlled phase III study was performed in patients with primary progressive (PP) or secondary progressive (SP) multiple sclerosis (Rice et al., 2000, Neurology, 54, 5, 1145-1155/ In this study, both groups of patients received cladribine by subcutaneous injection, at a dose of 0.07 mg/kg/day. The treatment was repeated either for two months, or Phase II clinical trials provided evidence of positive effects of cladribine in patients with MS, as measured by Kurtzke Extended Disability Status Scale (EDSS), Scripps Neurologic Rating Scale (SNRS), and Magnetic Resonance Imaging (MRI) findings.

(Beutler et al., 1996, Proc. Nat. Acad. Sci. USA, 93, 1716-1720;Romine et al, 1999, citirano ).Rezultati ispitivanja faze III bili su pozitivni, pokazujući značajna smanjenja oštećenja mozga, merena pomoću MRI{ Rice at al, 2000, citirano).(Beutler et al., 1996, Proc. Nat. Acad. Sci. USA, 93, 1716-1720; Romine et al, 1999, cited). Phase III trial results were positive, showing significant reductions in brain damage, as measured by MRI {Rice et al, 2000, cited).

[0013]Sa najvećim dozama nađeni su i neki negativni efekti (AE, od adverse effects), kao što su povećana učestalost infekcija vezanih za ugroženu imunsku funkciju ili mijelosupresiju{ Selby et al, 1998, , citirano;Beutler et al., 1994, Acta hematol., 91:10-15). Zbog male margine bezbednosti između efikasne doze i doze na kojoj dolazi do AE, do danas su sva klinička ispitivanja kladribina u multiploj sklerozi izvođena i.v. ili s.c. davanjem. Zbog toga suBeutler et al.(Beutler et al., 1996, Seminars in Hematology, 33, I(S1), 45-52; isključili oralnu primenu kladribina u tretiranju multiple skleroze. [0013] Some negative effects (AE, from adverse effects) were also found with the highest doses, such as an increased frequency of infections related to compromised immune function or myelosuppression {Selby et al, 1998, cited; Beutler et al., 1994, Acta hematol., 91:10-15). Because of the small margin of safety between the effective dose and the dose at which AEs occur, to date all clinical trials of cladribine in multiple sclerosis have been performed i.v. or s.c. giving. Because of this, Beutler et al. (Beutler et al., 1996, Seminars in Hematology, 33, I(S1), 45-52; excluded the oral use of cladribine in the treatment of multiple sclerosis.

[0014]Grieb i dr. objavili su malu studiju na 11 pacijenata sa relapsno remitentnim oblikom multiple skleroze (Grieb et al., 1995, Archivum Immunologiae et Therapiae Experimentalis, 43 (5-6), 323-327), gde je kladribin davan oralno tokom 6 meseci, po 5 dana, sa ukupnom dozom od oko 4-5,7 mg/kg (pacijenti od oko 52, odnosno oko 75 kilograma) tj. ukupnom efektivnom dozom od 2-2,85 mg/kg. Kod nekih pacijenata, posle perioda od 3 ili 6 meseci bez kladribina, obavljanje ponovni jednokratan tretman od 5 dana, sa kumulativnom dozom od 0,4-0,66 mg/kg. Za bočne efekte primećene kod gornjeg režima rečeno je da su manje ozbiljni od efekata nađenih kod pacijenata sa hroničnom progresivnom multiplom sklerozom tretiranih i.v. infuzijom kladribina (Sipe et al., 1994, Lancet, 344, 9-13), ali da ih i dalje ima. Osim toga, stavljena je pod sumnju terapeutska efikasnost oralnog režima u odnosu na terapiju i.v. infuzijom{ Grieb et al, 1995, navedeno),a identifikovanaje i grupa koja ne reaguje (Stelmasiak et al., 1998, Laboratorv Investigations, 4(1), 4-8; Stelmasiak etal., 1998, Medical Science Monitor, 4(1), 4-8J. [0014] Grieb et al. published a small study on 11 patients with a relapsing-remitting form of multiple sclerosis (Grieb et al., 1995, Archivum Immunologiae et Therapiae Experimentalis, 43 (5-6), 323-327), where cladribine was administered orally for 6 months, 5 days at a time, with a total dose of about 4-5.7 mg/kg (patients of about 52, i.e. about 75 kilograms) i.e. with a total effective dose of 2-2.85 mg/kg. In some patients, after a period of 3 or 6 months without cladribine, performing a repeated single treatment of 5 days, with a cumulative dose of 0.4-0.66 mg/kg. The side effects observed with the above regimen were said to be less severe than those seen in patients with chronic progressive multiple sclerosis treated with i.v. infusion of cladribine (Sipe et al., 1994, Lancet, 344, 9-13), but that there are still some. In addition, the therapeutic efficacy of the oral regimen in relation to i.v. therapy has been questioned. infusion {Grieb et al, 1995, cited), and a non-responder group was identified (Stelmasiak et al., 1998, Laboratory Investigations, 4(1), 4-8; Stelmasiak et al., 1998, Medical Science Monitor, 4(1), 4-8J.

[0015]Prema tome, bilo bi poželjno imati terapiju multiple skleoze koja uključuje oralnu primenu kladribina, koja bi dala isti ili poboljšane efekte na MS lezije, a u isto vreme i smanjila učestalost i/ili težinu negativnih događaja. Osim toga, pošto je MS hronično oboljenje, bilo bi poželjno smanjiti učestalost i/ili težinu negativnih događaja, što omogućuje ponovne tretmane. Takođe je poželjno trajanje koristi od tretmana kladribinom između perioda tretiranja. [0015] Therefore, it would be desirable to have a multiple sclerosis therapy that includes oral administration of cladribine, which would provide the same or improved effects on MS lesions, while at the same time reducing the frequency and/or severity of adverse events. In addition, since MS is a chronic disease, it would be desirable to reduce the frequency and/or severity of adverse events, which allows for repeated treatments. Duration of benefit from cladribine treatment between treatment periods is also desirable.

Opis pronalaskaDescription of the invention

[0016]Ovaj pronalazak je usmeren na upotrebu kladribina za dobijanje farmaceutske formulacije za tretiranje multiple skleroze, gde ovaj preparat treba da se primenjuje oralno, kao što je definisano u zahtevima. Ovaj pronalazak je specifično usmeren na upotrebu kladribina za dobijanje leka za lečenje relapsno remitentnog oblika multiple skleroze ili rane sekundarne progresivne multiple skleroze u kome su mogući ponovljeni tretmani. [0016] This invention is directed to the use of cladribine for obtaining a pharmaceutical formulation for the treatment of multiple sclerosis, where this preparation is to be administered orally, as defined in the claims. The present invention is specifically directed to the use of cladribine for the preparation of a medicament for the treatment of a relapsing-remitting form of multiple sclerosis or early secondary progressive multiple sclerosis in which repeated treatments are possible.

[0017]Oblik koji se ovde opisuje pruža poboljšan režim doziranja kladribina u tretiraju multiple skleroze, kao što je definisano u zahtevima. [0017] The embodiment described herein provides an improved dosing regimen of cladribine in the treatment of multiple sclerosis, as defined in the claims.

[0018]Drugi oblik ovog pronalaska omogućuje upotrebu kladribina za dobijanje farmaceutske formulacije za lečenje multiple skleroze, gde su negativni efekti smanjeni, što dozvoljava dalje korišćenje kladribina, kao što je definisano u zahtevima. [0018] Another form of the present invention enables the use of cladribine to obtain a pharmaceutical formulation for the treatment of multiple sclerosis, where the negative effects are reduced, which allows further use of cladribine, as defined in the claims.

[0019]U jednom obliku ovaj pronalazak daje korišćenje kladribina za dobijanje farmaceutske formulacije za lečenje multiple skleroze kada formulaciju treba dati oralno, prateći niz sledećih koraka: [0019] In one embodiment, the present invention provides the use of cladribine for the preparation of a pharmaceutical formulation for the treatment of multiple sclerosis when the formulation is to be administered orally, following a series of the following steps:

1. (i) Period indukcije u trajanju od 2 meseca do 4 meseca, tokom koga se daje data farmaceutska formulacija kladribina i u kome je ukupna doza kladribina koja se postiže na kraju indukcionog perioda od oko 1,7 mg/kg do oko3,5 mg/kg; 2. (ii) Period bez kladribina u trajanju od 8 meseci do 10 meseci, u kome se ne daje kladribin. 3. (iii) Period održavanja, u trajanju od 2 meseca do 4 meseca, u kome se daje data farmaceutska formulacija i u kome je ukupna doza kladribina na kraju perioda održavanja niža od ukupne doze kladribina postignute do kraja indukcionog perioda (i). 1. (i) An induction period lasting from 2 months to 4 months, during which a given pharmaceutical formulation of cladribine is administered and in which the total dose of cladribine achieved at the end of the induction period is from about 1.7 mg/kg to about 3.5 mg/kg; 2. (ii) Cladribine-free period of 8 months to 10 months, during which no cladribine is given. 3. (iii) A maintenance period, lasting 2 months to 4 months, in which a given pharmaceutical formulation is given and in which the total dose of cladribine at the end of the maintenance period is lower than the total dose of cladribine achieved by the end of the induction period (i).

4. (iv) Period bez kladribina u kome se ne daje kladribin. 4. (iv) Cladribine-free period in which no cladribine is given.

U drugom obliku ovaj pronalazak daje farmaceutsku formulaciju kladribina za lečenje multiple skleroze koje podrazumeva oralnu primenu kladribina ili njegove formulacije kod pacijenta kome je to potrebno, prateći niz sledećih koraka: (i) Period indukcije u trajanju od 2 meseca do 4 meseca, u kome je ukupna doza kladribina koja se postiže na kraju indukcionog perioda od oko 1,7 mg/kg do oko3,5 mg/kg; (ii) Period bez kladribina u trajanju od 8 meseci do 10 meseci, u kome se ne daje kladribin. (iii) Period održavanja, u trajanju od 2 meseca do 4 meseca, u kome je ukupna doza kladribina na kraju perioda održavanja niža od ukupne doze postignute do kraja indukcionog perioda (i). In another embodiment, the present invention provides a pharmaceutical formulation of cladribine for the treatment of multiple sclerosis comprising oral administration of cladribine or a formulation thereof to a patient in need thereof, following the following steps: (i) An induction period of 2 months to 4 months, wherein the total dose of cladribine achieved at the end of the induction period is from about 1.7 mg/kg to about 3.5 mg/kg; (ii) Cladribine-free period of 8 months to 10 months, in which cladribine is not given. (iii) A maintenance period, lasting 2 months to 4 months, in which the total dose of cladribine at the end of the maintenance period is lower than the total dose achieved by the end of the induction period (i).

(iv) Period bez kladribina u kome se ne daje kladribin. (iv) Cladribine-free period in which no cladribine is administered.

Detaljan opis pronalaskaDetailed description of the invention

DefinicijeDefinitions

[0020]„Ukupna doza" ili „kumulativna doza" odnosi se na ukupnu dozu kladribina datog tokom lečenja, tj. doza koja se postiže na kraju tretmana i koja se izračunava sabiranjem dnevnih doza. Na primer, ukupna doza kladribina koja odgovara tretmanu od 0,7 mg/kg kladribina po danu, tokom 5 dana je 3,5 mg/kg, ili ukupna doza kladribina koja odgovara tretmanu od 0,35 mg/kg kladribina po danu, tokom 5 dana je 1,7 mg/kg. [0020] "Total dose" or "cumulative dose" refers to the total dose of cladribine given during treatment, i.e. the dose that is reached at the end of the treatment and is calculated by adding the daily doses. For example, the total dose of cladribine corresponding to a treatment of 0.7 mg/kg cladribine per day for 5 days is 3.5 mg/kg, or the total dose of cladribine corresponding to a treatment of 0.35 mg/kg cladribine per day for 5 days is 1.7 mg/kg.

[0021]„Ukupna efektivna doza" ili „kumulativna efektivna doza" odnosi se na bioraspoloživu dozu kladribina dostignutu na kraju tretmana, a koja se izračunava sabiranjem dnevnih doza umanjenih koeficijentom bioraspoloživosti. Na primer, ukupna efektivna doza kladribina koja odgovara tretmanu od 0,7 mg/kg kladribina po danu, tokom 5 dana, gde je bioraspoloživost kladribina oko 40% iznosi 1,4 mg/kg, ili ukupna efektivna doza kladribina koja odgovara tretmanu od 0,35 mg/kg kladribina po danu, tokom 5 dana, gde je bioraspoloživost kladribina oko 40%, iznosi 0,7 mg/kg. [0021] "Total effective dose" or "cumulative effective dose" refers to the bioavailable dose of cladribine reached at the end of the treatment, which is calculated by summing the daily doses reduced by the bioavailability coefficient. For example, the total effective dose of cladribine corresponding to a treatment of 0.7 mg/kg cladribine per day, for 5 days, where the bioavailability of cladribine is about 40% is 1.4 mg/kg, or the total effective dose of cladribine corresponding to a treatment of 0.35 mg/kg cladribine per day, for 5 days, where the bioavailability of cladribine is about 40%, is 0.7 mg/kg.

[0022]Tipično, bioraspoloživost kladribina ili formulacije kladribina primenjene u ovde opisanom kontekstu je od oko 30% do oko 90%, pretežno od oko 40% do oko 60%, kao što je oko 50%. [0022] Typically, the bioavailability of cladribine or a formulation of cladribine used in the context described herein is from about 30% to about 90%, predominantly from about 40% to about 60%, such as about 50%.

[0023]"Mesec" se odnosi na period vremena od 28, 29, 30 ili 31 dan. [0023] "Month" refers to a period of time of 28, 29, 30 or 31 days.

[0024]"Tretman" podrazumeva niz od „indukcionog tretmana" i, bar, „tretmana održavanja". Tipično, tretman prema ovom pronalasku obuhvata "indukcioni tretman" i oko jedan ili dva ili tri tretmana održavanja. Tipično, tretman prema ovom pronalasku iznosi 2 godine (24 meseca) ili 3 godine (36 meseci) ili 4 godine (48 meseci). [0024] "Treatment" means a series of "induction treatment" and, at least, "maintenance treatment". Typically, a treatment according to the present invention comprises an "induction treatment" and about one or two or three maintenance treatments. Typically, treatment according to the present invention is 2 years (24 months) or 3 years (36 months) or 4 years (48 months).

[0025]"Indukcioni tretman" sastoji se od niza (i) indukcionog perioda, u kome se kladribin ili farmaceutski preparat kladribina ovog pronalaska daje oralno i (ii) perioda bez kladribina. Indukcioni period traje do 4 meseca ili do 3 meseca ili do 2 meseca. Na primer, indukcioni period traje 2 do 4 meseca. Indukcioni period sastoji se u oralnom davanju kladribina ili njegovog farmaceutskog preparata tokom 1 do 7 dana svakog meseca. "Period bez kladribina" je period u kome se pacijentu ne daje kladribin. Tokom perioda bez kladribina pacijent može biti bez ikakvog primanja, ili mu se može davati placebo ili neki drugi lek. Period bez kladribina traje do 10 meseci ili do 9 meseci ili do 8 meseci. Na primer, period bez kladribina traje od 8 do 10 meseci, tipično najmanje 8 meseci. [0025] "Induction treatment" consists of a series of (i) an induction period, in which cladribine or a cladribine pharmaceutical preparation of the present invention is administered orally and (ii) a cladribine-free period. The induction period lasts up to 4 months or up to 3 months or up to 2 months. For example, the induction period lasts 2 to 4 months. The induction period consists of oral administration of cladribine or its pharmaceutical preparation for 1 to 7 days each month. A "cladribine-free period" is a period in which the patient is not given cladribine. During the cladribine-free period, the patient may be without any treatment, or may be given a placebo or another drug. The cladribine-free period lasts up to 10 months or up to 9 months or up to 8 months. For example, a cladribine-free period lasts 8 to 10 months, typically at least 8 months.

[0026]„Tretman održavanja" čini niz od (i) perioda održavanja u kome se kladribin ili farmaceutski preparat kladribina ovog pronalaska daje oralno u nižoj dozi nego tokom indukcionog tretmana i (ii) perioda bez kladribina. Period održavanja traje do 4 meseca, ili do 3 meseca, ili do 2 meseca, pretežno do 2 meseca. Na primer, period održavanja traje 2 do 4 meseca, pretežno 2 meseca. Period održavanja sastoji se u oralnom davanju kladribina ili njegovog farmaceutskog preparata tokom 1 do 7 dana svakog meseca. [0026] "Maintenance treatment" consists of (i) a maintenance period in which cladribine or a cladribine pharmaceutical preparation of the present invention is given orally at a lower dose than during the induction treatment and (ii) a cladribine-free period. The maintenance period lasts up to 4 months, or up to 3 months, or up to 2 months, mostly up to 2 months. For example, the maintenance period lasts 2 to 4 months, mostly 2 months. The maintenance period consists of oral administration of cladribine or its pharmaceutical preparation for 1 to 7 days each month.

[0027]U okviru ovde opisanog konteksta, blagotvoran efekt, uključujući slabljenje, smanjenje ublažavanje ili opadanje patološkog razvoja od nastanka bolesti, može se videti posle jednog ili više „tretmana", posle "indukcionog tretmana", posle "tretmana održavanja" ili za vreme perioda bez kladribina. [0027] Within the context described herein, a beneficial effect, including an attenuation, reduction, mitigation, or decline in pathological development since the onset of the disease, may be seen after one or more "treatments", after an "induction treatment", after a "maintenance treatment" or during a cladribine-free period.

[0028]"Dnevne doze" odnose se na ukupnu dozu oralno datog kladribina pacijentu svakog dana tretmana. Dnevna doza se može postići jednokratnim ili višekratnim davanjem na dan, kao što je, na primer, jednom dnevno, dva puta dnevno ili tri puta dnevno. [0028] "Daily doses" refer to the total dose of orally administered cladribine to the patient on each day of treatment. The daily dose can be achieved by single or multiple administrations per day, such as, for example, once a day, twice a day, or three times a day.

[0029]Doza primenjena na neku osobu, bilo kao jednokratna, bilo kao višekratna, zavisi od niza faktora, uključujući farmakokinetičke osobine, stanje pacijenta i njegove karakteristike (pol, starost, telesna težina, zdravstveno stanje, veličina), intenzitet simptoma, paralelne tretmane, učestalost tretmana i željene efekte. Prema Šumaherovim ili Pozerovim kriterijumima, pacijenti sa multiplom sklerozom mogu se definisati kao oni koji imaju klinički određenu ili laboratorijski određenu MS (Schumacher et al., 1965. Ann. NYAcad. Sci. 1965; 112:552-568, Poser etal., 1983, Ann. Neurol. 13(3): 227-31/ [0029] The dose applied to a person, either as a single or as a multiple, depends on a number of factors, including pharmacokinetic properties, the condition of the patient and his characteristics (gender, age, body weight, state of health, size), intensity of symptoms, parallel treatments, frequency of treatment and desired effects. According to the Schumacher or Poser criteria, multiple sclerosis patients can be defined as having clinically definite or laboratory definite MS (Schumacher et al., 1965. Ann. NYAcad. Sci. 1965; 112:552-568, Poser et al., 1983, Ann. Neurol. 13(3): 227-31/

[0030]"Relapsi" uključuju neurološke probleme koji se pojavljuju u kratkom vremenskom periodu, tipično tokom dana, ali ponekad i tako kratkom, kao što su sati, pa čak i minuti. Ovi napadi najčešće uključuju motorne, senzorske probleme, probleme sa vidom i sa koordinacijom u ranim fazama bolesti. Kasnije se mogu pojaviti i problemi sa bešikom, crevima, seksualni i kognitivni. Ponekad se početak napada dešava u toku nekoliko nedelja. Tipičan relaps MS obuhvata period pogoršanja, uz razvoj neuroloških deficita, zatim plato, u kome pacijentu nije ništa bolje, ali ni ništa gore, posle čega dolazi period oporavka. Oporavak obično nastaje u roku od nekoliko nedelja. [0030] "Relapses" include neurological problems that occur over a short period of time, typically within days, but sometimes as short as hours or even minutes. These attacks most often include motor, sensory, vision and coordination problems in the early stages of the disease. Bladder, bowel, sexual and cognitive problems may also occur later. Sometimes the onset of attacks occurs within a few weeks. A typical MS relapse includes a period of worsening, with the development of neurological deficits, then a plateau, in which the patient is no better, but no worse, followed by a period of recovery. Recovery usually occurs within a few weeks.

[0031]"Efikasnost" tretmana, kako je ovde opisano, može se meriti na osnovu toka bolesti prilikom odgovora na primenu prema ovom pronalasku. Na primer, efikasnost tretmana MS može se meriti učestalošću recidiva u RRMS i prisustvom ili odsustvom novih lezija u CNS, korišćenjem metoda kao što je tehnika MRI (Miller et al., 1996, Neurologv, 47(Suppl/ 4): S217; Evans et al., 1997, Ann. Neurologa 41:125-132). Nalaz smanjenja i/ili supresije TI lezija, dobijen pomoću MRI sa gadolinijumom (za koje se smatra da predstavljaju površine aktivne infiamacije) daje primarnu varijablu efikasnosti. Sekundarna varijabla efikasnosti uključuje povećanu zapreminu lezije mozga detektovanu preko MRI T| i povećani broj MRI Ti lezija, zapreminu MRI T2lezija (za koju se smatra da predstavlja ukupno opterećenje bolesti, tj., demijelinizaciju, gliozu, zapaljenje i gubitak aksona), povećanu MRI Tthipointenzivnu leziju (smatra se da ona predstavlja primarnu demijelinizaciju i gubitak aksona), tok MS, frekvenciju i ozbiljnost pogoršanja i vremena između pogoršanja, stanje na Proširenoj skali stanja invaliditeta i Scripps-ovoj neurološkoj skali stanja (SNRS od Scripps Neurologic Rating Scale) (Sipe et al., 1984, Neurologv, 34, 1368-1372). Načini ranog i tačnog dijagnostikovanja multiple skleroze i praćenje toka bolesti opisani su kod Mattsona, 2002, Expert Rev. Neurotherapeutics, 319-328. [0031] The "efficacy" of a treatment as described herein can be measured based on the course of the disease in response to the administration of the present invention. For example, the effectiveness of MS treatment can be measured by the frequency of relapses in RRMS and the presence or absence of new lesions in the CNS, using methods such as MRI techniques (Miller et al., 1996, Neurologv, 47(Suppl/ 4): S217; Evans et al., 1997, Ann. Neurologa 41:125-132). The finding of reduction and/or suppression of TI lesions obtained by gadolinium-enhanced MRI (considered to represent areas of active inflammation) provided the primary efficacy variable. A secondary efficacy variable included increased brain lesion volume detected via MRI T| and increased number of MRI Ti lesions, volume of MRI T2 lesions (considered to represent total disease burden, ie, demyelination, gliosis, inflammation, and axonal loss), increased MRI Tthypointense lesion (considered to represent primary demyelination and axonal loss), course of MS, frequency and severity of exacerbations and time between exacerbations, Extended Disability Status Scale and Scripps Neurological Status Scale (SNRS of Scripps Neurologic Rating Scale) (Sipe et al., 1984, Neurologv, 34, 1368-1372). Methods of early and accurate diagnosis of multiple sclerosis and monitoring the course of the disease are described in Mattson, 2002, Expert Rev. Neurotherapeutics, 319-328.

[0032]Stepen invaliditeta MS pacijenata može se, na primer, meriti Kurtzke-ovom proširenom skalom stanja invaliditeta (EDSS od Expanded Disabilitv Status Scale) (Kurtzke, 1983, Neurologv, 33, 1444-1452). Tipično, smanjenje EDSS rezultata odgovara poboljšanju bolesti i, obrnuto, povećanje EDSS rezultata odgovara pogoršanju bolesti. [0032] The degree of disability of MS patients can be measured, for example, by Kurtzke's Expanded Disability Status Scale (EDSS) (Kurtzke, 1983, Neurologv, 33, 1444-1452). Typically, a decrease in the EDSS score corresponds to an improvement in the disease and, conversely, an increase in the EDSS score corresponds to a worsening of the disease.

Kladribin ( 2- CM)Cladribine (2-CM)

[0033]2-CdA i njegove farmakološki prihvatljive soli mogu se koristiti u praksi ovog pronalaska. [0033] 2-CdA and its pharmacologically acceptable salts can be used in the practice of the present invention.

[0034]Kladribin se može formulisati bilo u koji farmaceutski preparat pogodan za oralnu primenu. Reprezentativne oralne formulacije 2-CdA opisane su u WO 96/19230;WO 96119229;US 6,194,395; US 5,506,214; WO 2004/087100; WO 2004/087101. Primeri sastojaka za oralne formulacije dati su niže. [0034] Cladribine can be formulated into any pharmaceutical preparation suitable for oral administration. Representative oral formulations of 2-CdA are described in WO 96/19230; WO 96119229; US 6,194,395; US 5,506,214; WO 2004/087100; WO 2004/087101. Examples of ingredients for oral formulations are given below.

[0035]Procesi za dobijanje 2-CdA dobro su poznati u struci. Na primer, preparat 2-CdA opisan je u EP 173,059; WO 04/028462; WO 04/028462; US 5,208,327; WO 00/64918 i Robins et al, J. Am. Chem. Soc, 1984, 106: 6379. Alternativno, farmaceutski preparati 2-CdA mogu se kupiti od Bedford Laboratories, Bedford, Ohio. [0035] Processes for obtaining 2-CdA are well known in the art. For example, the preparation 2-CdA is described in EP 173,059; WO 04/028462; WO 04/028462; US 5,208,327; WO 00/64918 and Robins et al, J. Am. Chem. Soc, 1984, 106: 6379. Alternatively, pharmaceutical preparations of 2-CdA may be purchased from Bedford Laboratories, Bedford, Ohio.

[0036]Oralna primena kladribina može biti u vidu kapsula, tableta, oralne suspenzije ili sirupa. [0036] Oral administration of cladribine can be in the form of capsules, tablets, oral suspension or syrup.

Tablete ili kapsule mogu sadržavati od oko 3 do 500 mg kladribina. Poželjno je da sadrže oko 3 do okolO mg kladribina, poželjnije oko 3, oko 5 ili oko 10 mg kladribina. Kapsule mogu biti od želatina i mogu da sadrže, pored kladribina u navedenim količinama, malu količinu, na primer manje od 5% težine, magnezijum stearat ili neki drugi punjač. Tablete mogu da sadrže navedene količine datih jedinjenja i vezivno sredstvo, koji može da bude rastvor želatina, pasta od škroba sa vodom, polivinil polivinil alkohol u vodi, itd, sa tipičnom oblogom od šećera. Tablets or capsules may contain from about 3 to 500 mg of cladribine. They preferably contain about 3 to about 0 mg of cladribine, more preferably about 3, about 5 or about 10 mg of cladribine. The capsules may be gelatin and may contain, in addition to the cladribine in the stated amounts, a small amount, for example less than 5% by weight, of magnesium stearate or some other filler. The tablets may contain the indicated amounts of the given compounds and a binding agent, which may be a solution of gelatin, starch paste with water, polyvinyl polyvinyl alcohol in water, etc., with a typical sugar coating.

KompozicijeCompositions

[0037]Ovde opisane kompozicije mogu da sadrže jedan ili više farmaceutski prihvatljivih dodatnih sastojaka, kao što su stipsa, stabilizatori, antimikrobijski agensi, puferi, boje, agensi za davanje određenog ukusa i dodaci. [0037] The compositions described herein may contain one or more pharmaceutically acceptable additional ingredients, such as alum, stabilizers, antimicrobial agents, buffers, colors, flavoring agents, and additives.

[0038]Ovde opisane kompozicije mogu biti u obliku tableta ili pastila formulisanih na uobičajen način. Na primer, tablete i kapsule za oralnu primenu mogu da sadrže uobičajene punjače, uključujući vezivna sredstva, punjače, maziva, dezintegratore i ovlaživače. Vezivna sredstva uključuju sirup, akaciju, želatin, sorbitol, tragakant, škrob i polivinilpirolidon. Punjači uključuju laktozu, šećer, mikrokristalnu celulozu, kukuruzni škrob, kalcijum fosfat i sorbitol. Maziva uključuju magnezijum stearat, stearinsku kiselinu, talk, polietilen glikol i siliku. Dezintegratori uključuju škrob krompira i natrijum škrob glikolat. Ovlaživači uključuju natrijum lauril sulfat. Tablete se mogu obložiti pomoću metoda dobro poznatih u struci. Ovde opisane kompozicije mogu takođe biti tečne formulacije, uključujući vodene ili uljne suspenzije, rastvore, emulzije, sirupe i eliksire. Kompozicije se takođe mogu formulisati kao suvi proizvodi koji se spajaju sa vodom ili drugim pogodnim nosačem pred upotrebu. Takvi tečni preparati mogu da sadrže i aditive, uključujući agense za suspendovanje, emulzifikatore, nevodene nosače i konzervanse. Agensi za suspendovanje uključuju sirup sorbitola, metil celulozu, sirup od glukoze i šećera, želatin, hidroksietil celulozu, karboksimetil celulozu, gel alumijum stearata i hidrogenisane jestive masti. Emulgatori uključuju lecitin, sorbitan monoleat i akaciju. Nevodeni nosači uključuju jestiva ulja, bademovo ulje, frakcionisano kokosovo ulje, uljne estre, propilen glikol i etil alkohol. Konzervansi uključuju metil ili propil p-hidroksibenzoat i sorbinsku kiselinu. [0038] The compositions described herein may be in the form of tablets or pastilles formulated in a conventional manner. For example, tablets and capsules for oral administration may contain conventional excipients, including binders, fillers, lubricants, disintegrants, and humectants. Binding agents include syrup, acacia, gelatin, sorbitol, tragacanth, starch and polyvinylpyrrolidone. Bulking agents include lactose, sugar, microcrystalline cellulose, corn starch, calcium phosphate and sorbitol. Lubricants include magnesium stearate, stearic acid, talc, polyethylene glycol and silica. Disintegrants include potato starch and sodium starch glycolate. Humectants include sodium lauryl sulfate. Tablets can be coated using methods well known in the art. The compositions described herein may also be liquid formulations, including aqueous or oily suspensions, solutions, emulsions, syrups and elixirs. The compositions may also be formulated as dry products which are combined with water or other suitable vehicle prior to use. Such liquid preparations may also contain additives, including suspending agents, emulsifiers, nonaqueous carriers and preservatives. Suspending agents include sorbitol syrup, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, and hydrogenated edible fats. Emulsifiers include lecithin, sorbitan monoleate and acacia. Non-aqueous carriers include edible oils, almond oil, fractionated coconut oil, oil esters, propylene glycol, and ethyl alcohol. Preservatives include methyl or propyl p-hydroxybenzoate and sorbic acid.

KombinacijeCombinations

[0039]Kladribin se može dati nekoj osobi pre, istovremeno ili u nizu sa drugim terapeutskim režimima ili agensima (npr., režimi sa više lekova), sam, ili u kombinaciji sa IFN-beta, profilaktički ili terapeutski, u terapeutski efikasnim količinama, naročito sa terapeutskim agensima za tretman multiple skleroze. Aktivni agensi koji se daju istovremeno sa drugim terapeutskim agensima mogu se dati u istom ili drugom sastavu, i na isti, ili različit način. [0039] Cladribine may be administered to an individual prior to, concurrently, or in sequence with other therapeutic regimens or agents (eg, multi-drug regimens), alone, or in combination with IFN-beta, prophylactically or therapeutically, in therapeutically effective amounts, particularly with therapeutic agents for the treatment of multiple sclerosis. Active agents administered simultaneously with other therapeutic agents may be administered in the same or different composition, and in the same or different manner.

[0040]U jednom obliku, kada kladribin treba dati u kombinaciji sa IFN-beta, IFN-beta se daje u periodu kada se ne daje kladribin. [0040] In one embodiment, when cladribine is to be administered in combination with IFN-beta, IFN-beta is administered during a period when cladribine is not administered.

[0041]U drugom obliku, kada kladribin treba dati u kombinaciji sa IFN-beta, IFN-beta se daje posle „tretmana" prema ovom pronalasku. [0041] In another embodiment, when cladribine is to be administered in combination with IFN-beta, the IFN-beta is administered after "treatment" according to the present invention.

[0042]Termin "interferon-beta (IFN-P)", kako se ovde koristi, uključuje fibroblastni interferon uglavnom humanog porekla, dobijen izolovanjem iz bioloških tečnosti ili dobijen tehnikama rekombinantne DNK iz prokariotskih ili eukariotskih ćelija-domaćina, kao i njegove soli, funkcionalne derivate, varijante, analogone i aktivne fragmente. Pogodan IFN-p prema ovom pronalasku je komercijalno dostupan, npr., kao Rebif® (Serono), Avonex® (Biogen) ili Betaferon® (Schering). U saglasnosti sa ovim pronalaskom, poželjna je upotreba interferona humanog porekla. Termin interferon, kako se ovde koristi, obuhvata i njihove soli, funkcionalne derivate, varijante, analogone i aktivne fragmente. Rebif® (rekombinantni human interferon-P) je najnoviji razvoj u terapiji multiple skleroze (MS) interferonom i predstavlja značajan napredak u lečenju. Rebif® je interferon (IFN)-beta la, koji prave ćelijske linije sisara. Utvrđeno je daje kada se interferon beta-la daje subkutano tri puta nedeljno efikasan u tretiranju relapsno remitentnog oblika multiple skleroze (RRMS). Interferon beta-la može da ima pozitivan efekt na dugotrajan tok MS smanjivanjem broja i ozbiljnosti relapsa i smanjivanjem opterećenja bolesti i aktivnosti bolesti, mereno pomoću MRI. [0042] The term "interferon-beta (IFN-P)", as used herein, includes fibroblastic interferon mainly of human origin, obtained by isolation from biological fluids or obtained by recombinant DNA techniques from prokaryotic or eukaryotic host cells, as well as its salts, functional derivatives, variants, analogs and active fragments. Suitable IFN-β according to the present invention is commercially available, eg, as Rebif® (Serono), Avonex® (Biogen) or Betaferon® (Schering). In accordance with the present invention, it is preferred to use interferon of human origin. The term interferon, as used herein, includes salts, functional derivatives, variants, analogs, and active fragments thereof. Rebif® (recombinant human interferon-P) is the latest development in multiple sclerosis (MS) interferon therapy and represents a significant advance in treatment. Rebif® is an interferon (IFN)-beta la, produced by mammalian cell lines. Interferon beta-la given subcutaneously three times a week has been found to be effective in treating relapsing-remitting multiple sclerosis (RRMS). Interferon beta-la may have a positive effect on the long-term course of MS by reducing the number and severity of relapses and by reducing disease burden and disease activity, as measured by MRI.

[0043]Doziranje IFN-P u tretiranju relapsno remitentnog oblika MS, prema ovom pronalasku zavisi od tipa IFN-P koji se koristi. [0043] The dosage of IFN-P in the treatment of the relapsing-remitting form of MS according to the present invention depends on the type of IFN-P used.

[0044] Prema ovom pronalasku, kada je IFN rekombinantan IFN-P lb koji proizvodiE. coli,komercijalno dostupan pod imenom Betaseron®, najbolje je davati ga subkutano svakog drugog dana u dozi od oko 250 do 300 |xg ili 8 MU do 9,6 MU po osobi. [0044] According to the present invention, when the IFN is recombinant IFN-β 1b produced by E. coli, commercially available under the name Betaseron®, is best given subcutaneously every other day at a dose of about 250 to 300 µg or 8 MU to 9.6 MU per person.

[0045] Prema ovom pronalasku, kada je IFN rekombinantan IFN-P la, koji proizvode ćelije ovarijuma kineskog hrčka (CHO, od Chinese Hamster Ovary), komercijalno dostupan pod imenom Avonex®, najbolje je davati ga intramuskularno jednom nedeljno, u dozi od oko 30ug do 33 (ig ili 6 MU do 6,6 MU po osobi. Prema ovom pronalasku, kada je IFN rekombinantan IFN-P la, koji proizvode ćelije ovarijuma kineskog hrčka (CHO ćelije), komercijalno dostupan pod imenom Rebif®, najbolje je davati ga subkutano tri puta nedeljno (TIW) u dozi od 22 do 44 ug ili 6 MU do 12 MU p. [0045] According to the present invention, when the IFN is recombinant IFN-P la, produced by Chinese Hamster Ovary (CHO) cells, commercially available under the name Avonex®, it is best administered intramuscularly once a week, at a dose of about 30 µg to 33 (ig or 6 MU to 6.6 MU per person. According to the present invention, when the IFN is recombinant IFN-P la, produced by Chinese Hamster Ovary cells (CHO cells), commercially available under the name Rebif®, it is best given subcutaneously three times a week (TIW) at a dose of 22 to 44 ug or 6 MU to 12 MU p.

PacijentiPatients

[0046] Ovde opisani pacijenti su pacijenti koji pate od multiple skleroze, pretežno od RRMS ili rane SPMS. [0046] The patients described here are patients suffering from multiple sclerosis, predominantly RRMS or early SPMS.

[0047] U jednom ovde opisanom obliku, selektovani pacijenti su muškarci ili žene između 18 i 55 godina. [0047] In one embodiment described herein, the selected patients are male or female between 18 and 55 years of age.

[0048] U drugom ovde opisanom obliki, pacijenti su imali najmanje jedan relaps u okviru prvih [0048] In another embodiment described herein, patients have had at least one relapse within the first

12 meseci tretiranja. 12 months of treatment.

Upotreba prema ovom pronalaskuUse according to the present invention

[0049] U jednom obliku, opisana je upotreba kladribina za dobijanje farmaceutske formulacije za tretiranje multiple skleroze, gde se formulacija daje oralno u nizu koraka koji slede: 1. (i) Indukcioni period koji traje od 2 meseca do 4 meseca, kada treba dati farmaceutsku formulaciju kladribina i gde je ukupna doza kladribina na kraju indukcionog perioda od oko 1,7 mg/kg do oko3,5 mg/kg; 2. (ii) Period bez kladribina koji traje od 8 meseci do 10 meseci, kada se ne daje kladribin. 3. (iii) Period održavanja, koji traje od 2 meseca do 4 meseca kada treba davati farmaceutsku formulaciju sa kladribinom i kada je ukupna doza kladribina koja se postiže na kraju perioda održavanja niža od ukupne doze kladribina nakupljene do kraja indukcionog perioda (i); [0049] In one form, the use of cladribine is described for obtaining a pharmaceutical formulation for the treatment of multiple sclerosis, where the formulation is administered orally in a series of steps as follows: 1. (i) An induction period lasting from 2 months to 4 months, when the pharmaceutical formulation of cladribine should be administered and where the total dose of cladribine at the end of the induction period is from about 1.7 mg/kg to about 3.5 mg/kg; 2. (ii) Cladribine-free period lasting from 8 months to 10 months, when no cladribine is given. 3. (iii) Maintenance period, which lasts from 2 months to 4 months when the pharmaceutical formulation with cladribine should be administered and when the total dose of cladribine achieved at the end of the maintenance period is lower than the total dose of cladribine accumulated by the end of the induction period (i);

4. (iv) Period bez kladribina kada ne treba davati kladribin. 4. (iv) Cladribine-free period when cladribine should not be given.

[0050]U jednom drugom obliku, ovde je opisana upotreba kada indukcioni period traje od 2 meseca do 4 meseca ili do 3 meseca ili 2 meseca. [0050] In another embodiment, the use described herein is when the induction period lasts from 2 months to 4 months or up to 3 months or 2 months.

In a further embodiment, a use is described herein vvherein the induction period lasts from 2 meseca up do 4 meseca ili up do 3 meseca ili 2 meseca. In a further embodiment, a use is described here and where the induction period lasts from 2 months up to 4 months or up to 3 months or 2 months.

[0051]U jednom drugom obliku, ovde je opisana upotreba kada indukcioni period traje 2 meseca [0051] In another embodiment, the use described herein is when the induction period lasts for 2 months

[0052]U jednom drugom obliku, ovde je opisana upotreba kada indukcioni period traje od 2 meseca do 4 meseca. [0052] In another embodiment, the use described herein is when the induction period lasts from 2 months to 4 months.

[0053]U jednom drugom obliku, ovde je opisana upotreba kada ukupna doza kladribina dostignuta na kraju indukcionog perioda iznosi oko 1,7 mg/kg. [0053] In another embodiment, the use described herein is when the total dose of cladribine reached at the end of the induction period is about 1.7 mg/kg.

[0054]U jednom drugom obliku, ovde je opisana upotreba kada ukupna doza kladribina dostignuta na kraju indukcionog perioda iznosi oko 3,5 mg/kg. [0054] In another embodiment, the use described herein is when the total dose of cladribine reached at the end of the induction period is about 3.5 mg/kg.

[0055]U jednom drugom navedenom obliku ovde je opisana primena kada period bez kladribina traje od 8 meseci do 10 meseci, ili do 9 meseci ili 8 meseci. [0055] In another stated form, the application is described here when the cladribine-free period lasts from 8 months to 10 months, or up to 9 months or 8 months.

[0056]U jednom drugom navedenom obliku ovde je opisana primena kada period bez kladribina traje 8 meseci. [0056] In another stated form, the application is described here when the cladribine-free period lasts for 8 months.

[0057]U jednom drugom navedenom obliku ovde je opisana primena kada period bez kladribina (ii) traje najmanje 8 meseci, sve do 10 meseci. [0057] In another stated form, the application is described here when the period without cladribine (ii) lasts at least 8 months, up to 10 months.

[0058]U jednom drugom navedenom obliku ovde je opisana primena kada period bez kladribina (iii) traje od 8 meseci, do 10 meseci. [0058] In another stated form, the application is described here when the period without cladribine (iii) lasts from 8 months to 10 months.

[0059]U jednom drugom navedenom obliku ovde je opisana primena kada period bez kladribina (iv) traje sve do 10 meseci. [0059] In another stated form, the application is described here when the period without cladribine (iv) lasts up to 10 months.

[0060]U jednom drugom navedenom obliku ovde je opisana primena kada period bez kladribina (iv) traje najmanje 8 meseci. [0060] In another stated form, the application is described here when the period without cladribine (iv) lasts at least 8 months.

[0061]U jednom drugom navedenom obliku ovde je opisana primena kada periodi bez kladribina (ii) i/ili (iv) traju između 8 i 10 meseci. [0061] In another stated form, the application is described here when periods without cladribine (ii) and/or (iv) last between 8 and 10 months.

[0062]U jednom drugom navedenom obliku, ovde je opisana primena kada se u toku perioda bez kladribina daje placebo pilula. [0062] In another embodiment, described herein is administration where a placebo pill is administered during the cladribine-free period.

[0063]U jednom drugom navedenom obliku, ovde je opisana primena kada se u periodu bez kladribina ne daje ništa. [0063] In another embodiment, described herein is an application when nothing is given in the cladribine-free period.

[0064]U jednom drugom navedenom obliku, ovde je opisana primena kada period održavanja traje od 2 meseca pa do 4 meseca, ili do 3 meseca, ili 2 meseca, najbolje 2 meseca. [0064] In another stated form, the application is described here when the maintenance period lasts from 2 months to 4 months, or up to 3 months, or 2 months, preferably 2 months.

[0065]U jednom drugom navedenom obliku, ovde je opisana primena kada je ukupna doza kladribina, dostignuta na kraju indukcionog perioda (iii) oko 1,7 mg/kg. [0065] In another embodiment, described herein is administration when the total dose of cladribine reached at the end of the induction period (iii) is about 1.7 mg/kg.

[0066]U jednom drugom navedenom obliku, ovde je opisana primena kada the korake (iii) do (iv) treba ponoviti bar jednom ili dva puta. [0066] In another stated form, the application is described here when the steps (iii) to (iv) should be repeated at least once or twice.

[0067]U najčešćem obliku, ovde je opisana primena kladribina za dobijanje farmaceutske formulacije za tretiranje multiple skleroze, kada formulaciju treba dati oralno, prateći niz navedenih koraka: 1. (i) Indukcioni period kada treba dati farmaceutsku formulaciju kladribina i gde je ukupna doza kladribina koja se postiže na kraju indukcionog perioda od oko 1,7 mg/kg do oko3,5 mg/kg; [0067] In the most common form, here is described the application of cladribine to obtain a pharmaceutical formulation for the treatment of multiple sclerosis, when the formulation should be given orally, following a series of steps: 1. (i) Induction period when the pharmaceutical formulation of cladribine should be given and where the total dose of cladribine achieved at the end of the induction period is from about 1.7 mg/kg to about 3.5 mg/kg;

2. (ii) Period bez kladribina kada se ne daje kladribin. 2. (ii) Cladribine-free period when no cladribine is administered.

3. (iii) Period održavanja, kada treba davati farmaceutsku formulaciju sa kladribinom i kada je ukupna doza kladribina koja se postiže na kraju perioda održavanja oko 1,7 mg/kg, 3. (iii) Maintenance period, when the pharmaceutical formulation with cladribine should be administered and when the total dose of cladribine achieved at the end of the maintenance period is about 1.7 mg/kg,

4. (iv) Period bez kladribina kada ne treba davati kladribin. 4. (iv) Cladribine-free period when cladribine should not be given.

kada indukcioni period traje od 2 meseca do 4 meseca, ili do 3 meseca, ili 2 meseca; period bez kladribina (ii) traje od 8 meseci do 10 meseci, ili do 9 meseci, ili 8 meseci; period održavanja (iii) traje 2 meseca; period bez kladribina (iv) traje 10 meseci i korake (iii) do (iv) treba ponavljati jedan, dva ili tri puta. when the induction period lasts from 2 months to 4 months, or up to 3 months, or 2 months; the cladribine-free period (ii) lasts from 8 months to 10 months, or up to 9 months, or 8 months; maintenance period (iii) lasts 2 months; the cladribine-free period (iv) lasts 10 months and steps (iii) to (iv) should be repeated one, two or three times.

[0068]Ovde je opisana upotreba kladribina za dobijanje farmaceutske formulacije za tretiranje multiple skleroze kada se formulacija daje oralno, prateći niz navedenih koraka: 1. (i) Indukcioni period kada treba dati farmaceutsku formulaciju kladribina i gde je ukupna efektivna doza kladribina postignuta do kraja indukcionog perioda od oko 0,7 mg/kg do oko 1,4 mg/kg; [0068] Described herein is the use of cladribine for obtaining a pharmaceutical formulation for the treatment of multiple sclerosis when the formulation is administered orally, following the following steps: 1. (i) Induction period when the pharmaceutical formulation of cladribine is to be administered and where the total effective dose of cladribine achieved by the end of the induction period is from about 0.7 mg/kg to about 1.4 mg/kg;

2. (ii) Period bez kladribina kada se ne daje kladribin. 2. (ii) Cladribine-free period when no cladribine is given.

3. (iii) Period održavanja, kada treba davati farmaceutsku formulaciju sa kladribinom i kada je ukupna efektivna doza kladribina koja se postiže na kraju perioda održavanja (iii) niža od ukupne efektivne doze kladribina postignute na kraju indukcionog perioda (i); 3. (iii) Maintenance period, when the pharmaceutical formulation with cladribine should be administered and when the total effective dose of cladribine achieved at the end of the maintenance period (iii) is lower than the total effective dose of cladribine achieved at the end of the induction period (i);

4. (iv) Period bez kladribina kada se ne daje kladribin. 4. (iv) Cladribine-free period when no cladribine is given.

[0069]Ovde je opisana upotreba kladribina za dobijanje farmaceutske formulacije za tretiranje multiple skleroze kada se formulacija daje oralno, prateći niz navedenih koraka: 1. (i) Indukcioni period kada treba dati farmaceutsku formulaciju kladribina i gde je ukupna efektivna doza kladribina na kraju indukcionog perioda od oko 0,7 mg/kg do oko 1,4 mg/kg; [0069] Described herein is the use of cladribine for obtaining a pharmaceutical formulation for the treatment of multiple sclerosis when the formulation is administered orally, following the following steps: 1. (i) Induction period when the pharmaceutical formulation of cladribine is to be administered and wherein the total effective dose of cladribine at the end of the induction period is from about 0.7 mg/kg to about 1.4 mg/kg;

2 (ii) Period bez kladribina kada se ne daje kladribin. 2 (ii) Cladribine-free period when no cladribine is given.

3. (iii) Period održavanja, kada treba davati farmaceutsku formulaciju sa kladribinom i kada 3. (iii) Maintenance period, when the pharmaceutical formulation with cladribine should be administered and when

je ukupna efektivna doza kladribina koja se postiže na kraju perioda održavanja niža od ukupne efektivne doze kladribina na kraju indukcionog perioda (i) is the total effective dose of cladribine achieved at the end of the maintenance period is lower than the total effective dose of cladribine at the end of the induction period (i)

4. (iv) Period bez kladribina kada se ne daje kladribin. 4. (iv) Cladribine-free period when no cladribine is given.

gde indukcioni period traje do 4 meseca, ili do 3 meseca, ili do 2 meseca; period bez kladribina (ii) traje do 10 meseci, ili do 9 meseci, ili do 8 meseci; period održavanja (iii) traje do 2 meseca; period bez kladribina (ii) traje do 10 meseci; ukupna efektivna doza kladribina postignuta do kraja perioda održavanja je oko 0,7 mg/kg i korake (iii) do (iv) treba ponavljati jedan, dva ili tri puta. where the induction period lasts up to 4 months, or up to 3 months, or up to 2 months; the cladribine-free period (ii) lasts up to 10 months, or up to 9 months, or up to 8 months; maintenance period (iii) lasts up to 2 months; the cladribine-free period (ii) lasts up to 10 months; the total effective dose of cladribine achieved by the end of the maintenance period is about 0.7 mg/kg and steps (iii) to (iv) should be repeated one, two or three times.

[0070]U najčešćem obliku, ovde je opisana upotreba kladribina kao leka za tretiranje multiple skleroze, kada se lek daje oralno, prateći niz navedenih koraka: 1 (i) Indukcioni period kada se daje farmaceutska formulacija kladribina i kada je ukupna doza kladribina na kraju indukcionog perioda od oko 1,7 mg/kg do oko 3,5 mg/kg; [0070] In the most common form, the use of cladribine as a drug for the treatment of multiple sclerosis is described here, when the drug is administered orally, following a series of steps: 1 (i) Induction period when the pharmaceutical formulation of cladribine is administered and when the total dose of cladribine at the end of the induction period is from about 1.7 mg/kg to about 3.5 mg/kg;

2 (ii) Period bez kladribina kada se ne daje kladribin. 2 (ii) Cladribine-free period when no cladribine is given.

3 (iii) Period održavanja, kada se daje farmaceutska formulacija sa kladribinom i kada je ukupna doza kladribina koja se postiže na kraju perioda održavanja oko 1,7 mg/kg; 3 (iii) Maintenance period, when the pharmaceutical formulation with cladribine is administered and when the total dose of cladribine achieved at the end of the maintenance period is about 1.7 mg/kg;

4 (iv) Period bez kladribina kada ne treba davati kladribin. 4 (iv) Cladribine-free period when cladribine should not be administered.

gde indukcioni period traje od 2 meseca do 4 meseca, ili do 3 meseca, ili 2 meseca; period bez kladribina (ii) traje od 8 meseci do 10 meseci, ili do 9 meseci, ili 8 meseci; period održavanja (iii) traje 2 meseca; period bez kladribina (iv) traje 10 meseci; i korake (iii) do (iv) treba ponavljati jedan, dva ili tri puta. where the induction period lasts from 2 months to 4 months, or up to 3 months, or 2 months; the cladribine-free period (ii) lasts from 8 months to 10 months, or up to 9 months, or 8 months; maintenance period (iii) lasts 2 months; the cladribine-free period (iv) lasts 10 months; and steps (iii) to (iv) should be repeated one, two or three times.

[0071]U jednom drugom obliku, ovde je opisana upotreba kladribina kada farmaceutsku formulaciju treba davati oralno, u dnevnoj dozi kladribina od oko 3 do 30 mg kladribina, bolje 5 do 20 mg kladribina, najbolje 10 mg kladribina [0071] In another embodiment, described herein is the use of cladribine when the pharmaceutical formulation is to be administered orally, at a daily dose of cladribine of about 3 to 30 mg of cladribine, preferably 5 to 20 mg of cladribine, most preferably 10 mg of cladribine.

[0072]U jednom drugom navedenom obliku, ovde je opisana primena kada je ukupna doza kladribina koja se postiže na kraju indukcionog perioda oko 3,5 mg/kg, a ukupna doza kladribina koja se postiže na kraju perioda održavanja oko 1,7 mg/kg. [0072] In another embodiment, described herein is administration when the total dose of cladribine achieved at the end of the induction period is about 3.5 mg/kg, and the total dose of cladribine achieved at the end of the maintenance period is about 1.7 mg/kg.

[0073]Ovde je opisana primena kada je ukupna efektivna doza kladribina koja se postiže na kraju indukcionog perioda oko 1,4 mg/kg, a ukupna efektivna doza kladribina koja se postiže na kraju perioda održavanja oko 0,7 mg/kg. [0073] Here is described the application when the total effective dose of cladribine achieved at the end of the induction period is about 1.4 mg/kg, and the total effective dose of cladribine achieved at the end of the maintenance period is about 0.7 mg/kg.

[0074]U jednom drugom obliku, ovde je opisana primena kada farmaceutsku formulaciju treba davati oralno jednom dnevno tokom indukcionog perioda. [0074] In another embodiment, described herein is an application where the pharmaceutical formulation is to be administered orally once daily during an induction period.

[0075]U jednom drugom obliku, ovde je opisana primena kada farmaceutsku formulaciju treba davati oralno nekoliko puta na dan tokom indukcionog perioda, poželjno dva ili tri puta na dan, najbolje dva puta dnevno. [0075] In another form, the application described herein is when the pharmaceutical formulation is to be administered orally several times a day during the induction period, preferably two or three times a day, preferably twice a day.

[0076]U jednom drugom obliku, ovde je opisana primena kada farmaceutsku formulaciju treba davati oralno 1 do 7 dana mesečno, poželjno od 5 do 7 dana mesečno, tokom indukcionog perioda. [0076] In another embodiment, described herein is an application where the pharmaceutical formulation is to be administered orally 1 to 7 days per month, preferably 5 to 7 days per month, during an induction period.

[0077]U jednom drugom obliku, opisana je primena kada farmaceutsku formulaciju treba davati oralno oko 0,02 dana/kg do oko 0,08 dana/kg mesečno tokom indukcionog perioda. [0077] In another embodiment, administration is described where the pharmaceutical formulation is to be administered orally for about 0.02 days/kg to about 0.08 days/kg per month during an induction period.

[0078]U jednom drugom obliku, ovde je opisana primena kada farmaceutsku formulaciju treba davati oralno oko 0,02 dana/kg do oko 0,08 dana/kg mesečno tokom perioda održavanja [0078] In another embodiment, described herein is an administration where the pharmaceutical formulation is to be administered orally at about 0.02 days/kg to about 0.08 days/kg per month during a maintenance period.

[0079]U jednom drugom obliku, ovde je opisana primena kada farmaceutsku formulaciju treba davati oralno u dnevnoj dozi od oko 10 mg kladribina od dana 1 do dana 2 svakog meseca tokom indukcionog perioda. [0079] In another embodiment, described herein is an application where the pharmaceutical formulation is to be administered orally at a daily dose of about 10 mg of cladribine from day 1 to day 2 of each month during an induction period.

[0080]U jednom drugom obliku, ovde je opisana primena kada farmaceutsku formulaciju treba davati oralno u dnevnoj dozi od oko 10 mg kladribina od dana 1 do dana 3 svakog meseca tokom indukcionog perioda. [0080] In another embodiment, described herein is an application where the pharmaceutical formulation is to be administered orally at a daily dose of about 10 mg of cladribine from day 1 to day 3 of each month during an induction period.

[0081]U jednom drugom obliku, ovde je opisana primena kada farmaceutsku formulaciju treba davati oralno u dnevnoj dozi od oko 10 mg kladribina od dana 1 do dana 4 svakog meseca tokom indukcionog perioda. [0081] In another embodiment, described herein is an application where the pharmaceutical formulation is to be administered orally at a daily dose of about 10 mg of cladribine from day 1 to day 4 of each month during an induction period.

[0082]U jednom drugom obliku, ovde je opisana primena kada farmaceutsku formulaciju treba davati oralno u dnevnoj dozi od oko 10 mg kladribina od dana 1 do dana 5 svakog meseca tokom indukcionog perioda. [0082] In another embodiment, described herein is an application where the pharmaceutical formulation is to be administered orally at a daily dose of about 10 mg of cladribine from day 1 to day 5 of each month during an induction period.

[0083]U jednom drugom obliku, ovde je opisana primena kada farmaceutsku formulaciju treba davati oralno u dnevnoj dozi od oko 10 mg kladribina od dana 1 do dana 6 svakog meseca tokom indukcionog perioda. [0083] In another embodiment, described herein is an application where the pharmaceutical formulation is to be administered orally at a daily dose of about 10 mg of cladribine from day 1 to day 6 of each month during an induction period.

[0084]U jednom drugom obliku, ovde je opisana primena kada farmaceutsku formulaciju treba davati oralno u dnevnoj dozi od oko 10 mg kladribina od dana 1 do dana 4 svakog meseca tokom indukcionog perioda i gde je farmaceutska formulacija ona koja je opisana u WO 2004/087101 ili u WO 2004/087100. [0084] In another embodiment, the use described herein is when the pharmaceutical formulation is to be administered orally at a daily dose of about 10 mg of cladribine from day 1 to day 4 of each month during the induction period and wherein the pharmaceutical formulation is that described in WO 2004/087101 or in WO 2004/087100.

[0085]U jednom drugom obliku, opisana je upotreba gde se farmaceutska formulacija daje u kombinaciji sa beta-interferonom. [0085] In another embodiment, a use is described wherein the pharmaceutical formulation is administered in combination with beta-interferon.

[0086]Ovde je opisana farmaceutska formulacija sa kladribinom za korišćenje u tretiranju multiple skleroze kada se formulacija daje oralno, prateći niz navedenih koraka: 1. (i) Indukcioni period kada treba dati farmaceutsku formulaciju sa kladribinom i gde je ukupna doza kladribina postignuta do kraja indukcionog perioda od oko 1,5 mg/kg do oko 3,5 mg/kg; [0086] Described herein is a pharmaceutical formulation with cladribine for use in the treatment of multiple sclerosis when the formulation is administered orally, following the following steps: 1. (i) An induction period when the pharmaceutical formulation with cladribine is to be administered and where the total dose of cladribine achieved by the end of the induction period is from about 1.5 mg/kg to about 3.5 mg/kg;

2. (ii) Period bez kladribina kada se ne daje kladribin. 2. (ii) Cladribine-free period when no cladribine is given.

3. (iii) Period održavanja, kada treba davati farmaceutsku formulaciju sa kladribinom i kada je ukupna doza kladribina koja se postiže na kraju perioda održavanja niža od ukupne doze kladribina postignute na kraju indukcionog perioda (i); 3. (iii) Maintenance period, when the pharmaceutical formulation with cladribine should be administered and when the total dose of cladribine achieved at the end of the maintenance period is lower than the total dose of cladribine achieved at the end of the induction period (i);

4. (iv) Period bez kladribina kada se ne daje kladribin. 4. (iv) Cladribine-free period when no cladribine is given.

[0087]Ovde je opisana farmaceutska formulacija sa kladribinom za korišćenje u tretiranju multiple skleroze kada se formulacija daje oralno, prateći niz navedenih koraka: [0087] Described herein is a pharmaceutical formulation with cladribine for use in the treatment of multiple sclerosis when the formulation is administered orally, following a series of steps:

1. (i) Indukcioni period kada treba dati farmaceutsku formulaciju kladribina i gde je ukupna efektivna doza kladribina postignuta do kraja indukcionog perioda od oko 0,7 mg/kg do oko 1,4 mg/kg; 2. (ii) Period bez kladribina kada se ne daje kladribin; 3. (iii) Period održavanja, kada treba davati farmaceutsku formulaciju sa kladribinom i kada je ukupna efektivna doza kladribina koja se postiže na kraju perioda održavanja niža od ukupne efektivne doze kladribina postignute na kraju indukcionog perioda (i); 1. (i) An induction period when the pharmaceutical formulation of cladribine is to be administered and wherein the total effective dose of cladribine achieved by the end of the induction period is from about 0.7 mg/kg to about 1.4 mg/kg; 2. (ii) Cladribine-free period when no cladribine is given; 3. (iii) Maintenance period, when the pharmaceutical formulation with cladribine should be administered and when the total effective dose of cladribine achieved at the end of the maintenance period is lower than the total effective dose of cladribine achieved at the end of the induction period (i);

4. (iv) Period bez kladribina kada se ne daje kladribin. 4. (iv) Cladribine-free period when no cladribine is given.

[0088]Ovde je opisana upotreba farmaceutske formulacije sa kladribinom kada korake (iii) do (iv) treba ponoviti najmanje jedan ili dva puta. Ovde je opisana farmaceutska formulacija sa kladribinom za korišćenje u tretiranju multiple skleroze kada se formulacija daje oralno, prateći niz navedenih koraka: 1. (i) Indukcioni period kada treba dati farmaceutsku formulaciju sa kladribinom i gde je ukupna doza kladribina postignuta do kraja indukcionog perioda od oko 1,5 mg/kg do oko 3,5 mg/kg; 2. (ii) Period bez kladribina kada se ne daje kladribin; 3. (iii) Period održavanja, kada treba davati farmaceutsku formulaciju sa kladribinom i kada je ukupna doza kladribina koja se postiže na kraju perioda održavanja niža od ukupne doze kladribina postignute na kraju indukcionog perioda (i); [0088] Described herein is the use of a pharmaceutical formulation with cladribine when steps (iii) to (iv) should be repeated at least once or twice. Described herein is a pharmaceutical formulation with cladribine for use in the treatment of multiple sclerosis when the formulation is administered orally, following a series of steps: 1. (i) An induction period when the pharmaceutical formulation with cladribine is to be administered and where the total dose of cladribine achieved by the end of the induction period is from about 1.5 mg/kg to about 3.5 mg/kg; 2. (ii) Cladribine-free period when no cladribine is given; 3. (iii) Maintenance period, when the pharmaceutical formulation with cladribine should be administered and when the total dose of cladribine achieved at the end of the maintenance period is lower than the total dose of cladribine achieved at the end of the induction period (i);

4. (iv) Period bez kladribina kada se ne daje kladribin. 4. (iv) Cladribine-free period when no cladribine is given.

[0089]Ovde je opisana upotreba farmaceutske formulacije sa kladribinom kada indukcioni period traje do 4 meseca, ili do 3 meseca, ili do 2 meseca. [0089] Described herein is the use of a pharmaceutical formulation with cladribine when the induction period lasts up to 4 months, or up to 3 months, or up to 2 months.

[0090]Ovde je opisana upotreba farmaceutske formulacije sa kladribinom kada je ukupna doza kladribina koja se dostigne na kraju indukcionog perioda oko 1,7 mg/kg. [0090] Described herein is the use of a pharmaceutical formulation with cladribine when the total dose of cladribine reached at the end of the induction period is about 1.7 mg/kg.

[0091]Ovde je opisana upotreba farmaceutske formulacije sa kladribinom kada je ukupna doza kladribina koja se dostigne na kraju indukcionog perioda oko 3,5 mg/kg. [0091] Described herein is the use of a pharmaceutical formulation with cladribine when the total dose of cladribine reached at the end of the induction period is about 3.5 mg/kg.

[0092]Ovde je opisana upotreba farmaceutske formulacije sa kladribinom kada je ukupna efektivna doza kladribina koja se dostigne na kraju indukcionog perioda oko 1,4 mg/kg. [0092] Described herein is the use of a pharmaceutical formulation with cladribine when the total effective dose of cladribine reached at the end of the induction period is about 1.4 mg/kg.

[0093]Ovde je opisana upotreba farmaceutske formulacije sa kladribinom kada period bez kladribina traje do 10 meseci, ili do 9 meseci, ili do 8 meseci. [0093] Described herein is the use of a pharmaceutical formulation with cladribine when the cladribine-free period lasts up to 10 months, or up to 9 months, or up to 8 months.

[0094]Ovde je opisana upotreba farmaceutske formulacije sa kladribinom kada period održavanja traje do 4 meseca, ili do 3 meseca, ili do 2 meseca. [0094] Described herein is the use of a pharmaceutical formulation with cladribine when the maintenance period is up to 4 months, or up to 3 months, or up to 2 months.

[0095]U drugom poželjnom obliku, opisana je upotreba farmaceutske formulacije sa kladribinom kada je ukupna doza kladribina koja se dostigne na kraju perioda održavanja oko 1,7 mg/kg. [0095] In another preferred embodiment, the use of a pharmaceutical formulation with cladribine is described when the total dose of cladribine reached at the end of the maintenance period is about 1.7 mg/kg.

[0096]U drugom poželjnom obliku, opisana je upotreba farmaceutske formulacije sa kladribinom kada je ukupna efektivna doza kladribina koja se dostigne na kraju perioda održavanja oko 0,7 mg/kg. [0096] In another preferred embodiment, the use of a pharmaceutical formulation with cladribine is described when the total effective dose of cladribine reached at the end of the maintenance period is about 0.7 mg/kg.

[0097]U drugom poželjnom obliku, opisana je upotreba farmaceutske formulacije sa kladribinom gde posle perioda održavanja dolazi period bez kladribina. [0097] In another preferred form, the use of a pharmaceutical formulation with cladribine is described where a maintenance period is followed by a period without cladribine.

[0098]U drugom poželjnom obliku, opisana je upotreba farmaceutske formulacije sa kladribinom kada je ukupna doza kladribina koja se dostigne na kraju indukcionog perioda oko 3,5 mg/kg, a ukupna doza kladribina, koja se postigne na kraju perioda održavanja, oko 1,7 mg/kg. [0098] In another preferred form, the use of a pharmaceutical formulation with cladribine is described when the total dose of cladribine reached at the end of the induction period is about 3.5 mg/kg, and the total dose of cladribine reached at the end of the maintenance period is about 1.7 mg/kg.

[0099]U drugom poželjnom obliku, opisana je upotreba farmaceutske formulacije sa kladribinom gde je ukupna efektivna doza kladribina koja se dostigne na kraju indukcionog perioda oko 1,4 mg/kg, a ukupna efektivna doza kladribina, koja se postigne na kraju perioda održavanja, oko 0,7 mg/kg. [0099] In another preferred form, the use of a pharmaceutical formulation with cladribine is described where the total effective dose of cladribine reached at the end of the induction period is about 1.4 mg/kg, and the total effective dose of cladribine reached at the end of the maintenance period is about 0.7 mg/kg.

[0100]U jednom drugom navedenom obliku , opisana je upotreba farmaceutske formulacije sa kladribinom gde se kladribin daje oralno u dnevnoj dozi od oko 3 do oko30 mg. [0100] In another embodiment, the use of a pharmaceutical formulation with cladribine is described wherein the cladribine is administered orally in a daily dose of about 3 to about 30 mg.

[0101]U jednom drugom navedenom obliku , opisana je upotreba farmaceutske formulacije sa kladribinom gde se kladribin daje oralno u dnevnoj dozi od oko 10 mg. [0101] In another embodiment, the use of a pharmaceutical formulation with cladribine is described, where the cladribine is administered orally in a daily dose of about 10 mg.

[0102]U jednom drugom navedenom obliku, opisana je upotreba farmaceutske formulacije sa kladribinom gde se kladribin daje oralno 1 do 7 dana mesečno tokom indukcionog perioda. [0102] In another embodiment, the use of a pharmaceutical formulation with cladribine is described wherein the cladribine is administered orally for 1 to 7 days per month during an induction period.

[0103]U jednom drugom navedenom obliku, opisana je upotreba farmaceutske formulacije sa kladribinom gde se koraci (iii) ponavljaju najmanje jednom ili dva puta. [0103] In another embodiment, the use of a pharmaceutical formulation with cladribine is described wherein steps (iii) are repeated at least once or twice.

[0104]U jednom drugom navedenom obliku, opisana je upotreba farmaceutske formulacije sa kladribinom gde se kladribin daje u kombinaciji sa beta- interferonom. [0104] In another embodiment, the use of a pharmaceutical formulation with cladribine is described wherein cladribine is administered in combination with beta-interferon.

PrimeriExamples

[0105]Sledeće skraćenice odnose se na donje deefinicije: kg (kilogram), ug (mikrogram), mg (miligram). AEs (dobijanje Adverse effects, negativni efekti), CNS (Centralni nervni sistem), CSF (Cerebrospinalna tečnost), EDSS (od Expanded Disabilitv Status Scale, Proširena skala stanja invaliditeta),SNRS(od Scripps Neurologic Rating Scale, Skripsova skala neuroloških invaliditeta),IFN(interferon), Iv. (intravenozni),MIU(od Million international units, Milion Internacionalnih jedinica),MS(multipla skleroza),MRI(od Magnetic resonance imaging, Magnetno reonantna tomografija),p.o.(per os),PPMS(Primarna progresivna multipla skleroza),PRMS(Progresivno-relapsna multipla skleroza),RRMS(Relapsno-remitentna multipla skleroza),SPMS(Sekundarna progresivna multipla skleroza), s.c. [0105] The following abbreviations refer to the definitions below: kg (kilogram), ug (microgram), mg (milligram). AEs (obtaining Adverse effects), CNS (Central Nervous System), CSF (Cerebrospinal fluid), EDSS (from Expanded Disabilitv Status Scale), SNRS (from Scripps Neurologic Rating Scale, Scripps scale of neurological disabilities), IFN (interferon), Iv. (intravenous), MIU (from Million international units), MS (multiple sclerosis), MRI (from Magnetic resonance imaging, Magnetic resonance tomography), p.o. (per os), PPMS (Primary progressive multiple sclerosis), PRMS (Progressive-relapsing multiple sclerosis), RRMS (Relapsing-remitting multiple sclerosis), SPMS (Secondary progressive multiple sclerosis), s.c.

(subkutano),TIW(Tri puta nedeljno), 2-CdA (2-hloro-2'dezoksiadenozin ili kladribin), UI (Internacionalna jedinica). (subcutaneous), TIW (Three times a week), 2-CdA (2-chloro-2'deoxyadenosine or cladribine), UI (International Unit).

[0106]Efikasnost i bezbednost oralnog davanja kladribina, eventualno davanje više doza, prema ovom pronalasku mogu se postići, na primer, poštovanjem sledećeg protokola: [0106] The efficacy and safety of oral administration of cladribine, possibly multiple doses, according to the present invention can be achieved, for example, by following the following protocol:

Primer 1: Oralni kladribin u tretiranju relapsnih oblika MSExample 1: Oral cladribine in the treatment of relapsing forms of MS

[0107]Urađena je studija na šesdeset pacijenata sa relapsnim oblicima klinički definisane multiple skleroze. Svakom pacijentu je prvo ispitano funkcionisanje jetre, bubrega i kostne srži da bi se ustanovile osnovne vrednosti. [0107] A study was conducted on sixty patients with relapsing forms of clinically defined multiple sclerosis. Each patient was first tested for liver, kidney and bone marrow function to establish baseline values.

[0108]Odabrani pacijenti bili su muškarci ili žene između 18 i 55 godina koji su u toku prethodnih 12 meseci imali jedan ili više relapsa. Među ženskim pacijentima nije bilo trudnica. [0108] Selected patients were men or women between 18 and 55 years of age who had one or more relapses during the previous 12 months. There were no pregnant women among the female patients.

[0109]Pacijenti su nasumično raspoređeni u jednu od grupa za tretman naveden u Tabeli 1: [0109] Patients were randomly assigned to one of the treatment groups listed in Table 1:

[0110]Svaki od pacijenata grupe 2 i 3 dobio je 3 mg ili 10 mg 2-CdA (u 1, 2 ili 3 navrata dnevno, zavisno od svoje telesne težine), kombinovano u formulaciji ciklodekstrina, kao što je opisano u WO 2004/087101, Primer 3. Sastavi formulacija kladribina sa tabletama od 3 mg ili 10 mg 2-CdA, koje sadrže hidroksipropil-betaciklodekstrin, navedeni su u Tabeli 2: [0110] Group 2 and 3 patients each received 3 mg or 10 mg of 2-CdA (1, 2 or 3 times a day, depending on their body weight), combined in a cyclodextrin formulation, as described in WO 2004/087101, Example 3. Cladribine formulation compositions with 3 mg or 10 mg 2-CdA tablets containing hydroxypropyl-betacyclodextrin, are listed in Table 2:

[0111]Primeri šema davanja u indukcionom periodu, zavisno od telesne težine pacijenta, dati su Tabelama 3 i 4 za ciljane doze od 1,75 mg/kg, odnosno 3,5 mg/kg. Primer šeme davanja iz Tabele 3 primenljiv je i za period održavanja. [0111] Examples of administration schemes in the induction period, depending on the patient's body weight, are given in Tables 3 and 4 for target doses of 1.75 mg/kg and 3.5 mg/kg, respectively. The example of the benefit scheme from Table 3 is also applicable for the maintenance period.

[0112]U Grupi 1 pacijenti dobijaju placebo (rastvor soli) tokom 4 meseca, posle čega dolazi period bez ikakvog tretmana. [0112] In Group 1, patients receive a placebo (saline solution) for 4 months, after which there is a period without any treatment.

[0113]U Grupi 2 pacijenti dobijaju dnevno oralno kladribin oko 5 dana mesečno, tokom 2 meseca (indukcioni period) u formulaciji ciklodekstrina 2-CdA, tako daje ukupna efektivna doza koja se da do kraja prva 2 meseca približno oko 0,7 mg/kg (ukupna doza od oko 1,75 mg/kg pri bioraspoloživosti od oko 40%); posle čega se daje placebo tokom 2 meseca; a sledećih 8 meseci su bez tretmana. [0113] In Group 2, patients receive daily oral cladribine for about 5 days per month, for 2 months (induction period) in the formulation of cyclodextrin 2-CdA, thus giving a total effective dose given by the end of the first 2 months of approximately 0.7 mg/kg (total dose of about 1.75 mg/kg with a bioavailability of about 40%); after which a placebo is given for 2 months; and the next 8 months are without treatment.

[0114]U Grupi 3 pacijenti dnevno dobijaju oralno kladribin oko 5 dana mesečno, tokom 4 meseca (indukcioni period) u 2-CdA ciklodekstrin formulaciji, tako daje ukupna efektivna doza koja se da do kraja prva 4 meseca približno oko 1,4 mg/kg (ukupna doza od oko 3,5 mg/kg pri bioraspoloživosti od oko 40%); a sledećih 8 meseci su bez tretmana. [0114] In Group 3, patients receive orally cladribine daily for about 5 days a month, for 4 months (induction period) in a 2-CdA cyclodextrin formulation, so that the total effective dose given by the end of the first 4 months is approximately 1.4 mg/kg (total dose of about 3.5 mg/kg with a bioavailability of about 40%); and the next 8 months are without treatment.

[0115]Počev od 13. meseca, sve 3 grupe pacijenata ponovo se tretiraju kladribinom u ciklodekstrinskoj formulaciji oko 5 dana mesečno, tokom 2 meseca (period održavanja) manjom dozom (tako daje ukupna efektivna doza koja se da do kraja prva 2 meseca približno oko 0,7 mg/kg), posle čega sledi 10 meseci bez tretmana. [0115] Starting at month 13, all 3 groups of patients are again treated with cladribine in a cyclodextrin formulation about 5 days per month, during 2 months (maintenance period) at a lower dose (so the total effective dose given until the end of the first 2 months is approximately 0.7 mg/kg), followed by 10 months without treatment.

[0116]1 na kraju, počev od 25. meseca, sve grupe pacijenata dobijaju ponovljeni tretman kladribinom u ciklodekstrin formulaciji oko 5 dana mesečno tokom 2 meseca (period održavanja) manjom dozom (tako daje ukupna efektivna doza koja se da do kraja prva 2 meseca približno oko 0,7 mg/kg) posle čega sledi još 10 meseci bez tretmana. [0116] 1 finally, starting from the 25th month, all groups of patients receive repeated treatment with cladribine in a cyclodextrin formulation about 5 days per month for 2 months (maintenance period) at a lower dose (so the total effective dose given until the end of the first 2 months is approximately 0.7 mg/kg) followed by another 10 months without treatment.

[0117]Pacijenti su praćeni pomoću MRI skeniranja i neuroloških ispitivanja kako su opisali [0117] Patients were followed up with MRI scans and neurological tests as described

Miller et al., 1996, citirano; Evans et al., 1997, citirano; Sipe et al., 1984 citirano;iMattson,Miller et al., 1996, cited; Evans et al., 1997, cited; Sipe et al., 1984 cited; and Mattson,

2002, citirano,da bi se odredilo da li dolazi do napredovanja ili poboljšanja oštećenja u mozgu vezanih za napredovanje MS. U 12. mesecu, svim pacijentima je određena osnovna vrednost i urađen MRI (mozga ili kičmene moždine, zavisno od lokacije oštećenja). 2002, cited, to determine whether there is progression or amelioration of brain damage associated with MS progression. At month 12, all patients had a baseline and an MRI (brain or spinal cord, depending on the location of the damage).

U 24 meseca, praćeni su napredovanje invaliditeta pacijenata i vreme do prvog relapsa, kao i udeo pacijenata bez relapsa tokom 24 meseca. At 24 months, patients' disability progression and time to first relapse were monitored, as was the proportion of patients without relapse over 24 months.

[0118]Kod pacijenata su praćeni limfocitni markeri i broj monocita. [0118] Lymphocyte markers and the number of monocytes were monitored in the patients.

[0119]Pacijenti u Grupama 2 i 3 imali su smanjenje oštećenja mozga. [0119] Patients in Groups 2 and 3 had a reduction in brain damage.

[0120]Podaci pokazuju daje 2-CdA režim, koji se sastoji u sukcesiji indukcionog tretmana i tretmana održavanja, efikasan u smanjivanju oštećenja mozga i da nisu nađeni ozbiljni negativni efekti. [0120] The data show that the 2-CdA regimen, which consists of a succession of induction treatment and maintenance treatment, is effective in reducing brain damage and that no serious adverse effects were found.

Claims (18)

1. Farmaceutska formulacija kladribina za primenu u tretiranju multiple skleroze, gde se formulacija daje oralno, prateći sledeći niz koraka: (i) Indukcioni period koji traje od 2 meseca do 4 meseca, u kome se daje navedena farmaceutska formulacija kladribina i u kome je ukupna doza kladribina koja se dostiže na kraju indukcionog perioda od oko 1,7 mg/kg do oko 3,5 mg/kg; (ii) Period bez kladribina, koji traje od 8 meseci do 10 meseci, u kome se ne daje kladribin. (iii) Period održavanja koji traje 2 meseca do 4 meseca, u kome se daje navedena farmaceutska formulacija kladribina i u kome je ukupna doza kladribina koja se dostiže na kraju perioda održavanja manja od ukupne doze kladribina koja se dostiže na kraju indukcionog perioda (i); (iv) Period bez kladribina, u kome se ne daje kladribin..1. A pharmaceutical formulation of cladribine for use in the treatment of multiple sclerosis, wherein the formulation is administered orally, following the following series of steps: (i) An induction period lasting from 2 months to 4 months, in which said pharmaceutical formulation of cladribine is administered and wherein the total dose of cladribine reached at the end of the induction period is from about 1.7 mg/kg to about 3.5 mg/kg; (ii) Cladribine-free period, lasting from 8 months to 10 months, during which no cladribine is given. (iii) A maintenance period lasting 2 months to 4 months, in which said pharmaceutical formulation of cladribine is administered and in which the total dose of cladribine achieved at the end of the maintenance period is less than the total dose of cladribine achieved at the end of the induction period (i); (iv) Cladribine-free period, in which cladribine is not given. 2. Upotreba kladribina za dobijanje farmaceutske formulacije za tretiranje multiple skleroze, gde se formulacija daje oralno, prateći sledeći niz koraka: (i) Indukcioni period koji traje od 2 meseca do 4 meseca, u kome se daje navedena farmaceutska formulacija kladribina i u kome je ukupna doza kladribina koja se dostiže na kraju indukcionog perioda od oko 1,7 mg/kg do oko 3,5 mg/kg; (ii) Period bez kladribina, koji traje od 8 meseci do 10 meseci, u kome se ne daje kladribin. (iii) Period održavanja koji traje od 2 meseca do 4 meseca, u kome se daje navedena farmaceutska formulacija kladribina i u kome je ukupna doza kladribina koja se dostiže na kraju perioda održavanja manja od ukupne doze kladribina koja se dostiže na kraju indukcionog perioda (i); (iv) Period bez kladribina, u kome se ne daje kladribin..2. Use of cladribine to obtain a pharmaceutical formulation for the treatment of multiple sclerosis, wherein the formulation is administered orally, following the following series of steps: (i) An induction period lasting from 2 months to 4 months, in which said pharmaceutical formulation of cladribine is administered and wherein the total dose of cladribine reached at the end of the induction period is from about 1.7 mg/kg to about 3.5 mg/kg; (ii) Cladribine-free period, lasting from 8 months to 10 months, during which no cladribine is given. (iii) A maintenance period lasting from 2 months to 4 months, in which said pharmaceutical formulation of cladribine is administered and in which the total dose of cladribine achieved at the end of the maintenance period is less than the total dose of cladribine achieved at the end of the induction period (i); (iv) Cladribine-free period, in which cladribine is not given. 3. Farmaceutska formulacija kladribina za primenu u tretiranju multiple skleroze, gde se formulacija daje oralno, prateći sledeći niz koraka: (i) Indukcioni period koji traje od 2 meseca do 4 meseca, u kome se daje navedena farmaceutska formulacija kladribina i u kome je ukupna doza kladribina koja se dostiže na kraju indukcionog perioda od oko 1,7 mg/kg do oko 3,5 mg/kg; (ii) Period bez kladribina, koji traje od 8 meseci do 10 meseci, u kome se ne daje kladribin. (iii) Period održavanja koji traje 2 meseca do 4 meseca, u kome se daje navedena farmaceutska formulacija kladribina i u kome je ukupna doza kladribina koja se dostiže na kraju perioda održavanja oko 1,7 mg/kg. (iv) Period bez kladribina, u kome se ne daje kladribin.3. A pharmaceutical formulation of cladribine for use in the treatment of multiple sclerosis, wherein the formulation is administered orally, following the following series of steps: (i) An induction period lasting from 2 months to 4 months, in which said pharmaceutical formulation of cladribine is administered and wherein the total dose of cladribine reached at the end of the induction period is from about 1.7 mg/kg to about 3.5 mg/kg; (ii) Cladribine-free period, lasting from 8 months to 10 months, during which no cladribine is given. (iii) A maintenance period lasting 2 months to 4 months, in which said pharmaceutical formulation of cladribine is administered and in which the total dose of cladribine reached at the end of the maintenance period is about 1.7 mg/kg. (iv) Cladribine-free period, in which cladribine is not administered. 4. Upotreba kladribina za dobijanje farmaceutske formulacije za tretiranje multiple skleroze, gde se formulacija daje oralno, prateći sledeći niz koraka: (i) Indukcioni period koji traje od 2 meseca do 4 meseca, u kome se daje navedena farmaceutska formulacija kladribina i u kome je ukupna doza kladribina koja se dostiže na kraju indukcionog perioda od oko 1,7 mg/kg do oko3,5 mg/kg; (ii) Period bez kladribina, koji traje od 8 meseci do 10 meseci, u kome se ne daje kladribin. (iii) Period održavanja koji traje 2 meseca do 4 meseca, u kome se daje navedena farmaceutska formulacija kladribina i u kome je ukupna doza kladribina koja se dostiže na kraju perioda održavanja oko 1,7 mg/kg; (iv) Period bez kladribina, u kome se ne daje kladribin.4. The use of cladribine for obtaining a pharmaceutical formulation for the treatment of multiple sclerosis, wherein the formulation is administered orally, following the following series of steps: (i) An induction period lasting from 2 months to 4 months, in which said pharmaceutical formulation of cladribine is administered and wherein the total dose of cladribine reached at the end of the induction period is from about 1.7 mg/kg to about 3.5 mg/kg; (ii) Cladribine-free period, lasting from 8 months to 10 months, during which no cladribine is given. (iii) A maintenance period lasting 2 months to 4 months, in which said pharmaceutical formulation of cladribine is administered and in which the total dose of cladribine reached at the end of the maintenance period is about 1.7 mg/kg; (iv) Cladribine-free period, in which cladribine is not given. 5. Farmaceutska formulacija sa kladribinom za primenu prema zahtevima 1 ili 3, ili primena prema zahtevima 2 ili 4, kada indukcioni period traje 4 meseca.5. A pharmaceutical formulation with cladribine for use according to claim 1 or 3, or use according to claim 2 or 4, when the induction period lasts 4 months. 6. Farmaceutska formulacija sa kladribinom za primenu prema zahtevima 1 ili 3, ili primena prema zahtevima 2 ili 4, kada indukcioni period traje 2 meseca.6. A pharmaceutical formulation with cladribine for use according to claim 1 or 3, or use according to claim 2 or 4, when the induction period lasts 2 months. 7. Upotreba farmaceutske formulacije sa kladribinom ili primena bilo prema kom prethodnom zahtevu, kada je ukupna doza kladribina koja se dostiže na kraju indukcionog perioda oko 1,7 mg/kg.7. Use of a pharmaceutical formulation with cladribine or administration according to any preceding claim, when the total dose of cladribine reached at the end of the induction period is about 1.7 mg/kg. 8. Upotreba farmaceutske formulacije sa kladribinom ili primena bilo prema kom prethodnom zahtevu, kada je ukupna doza kladribina koja se dostiže na kraju indukcionog perioda oko 3,5 mg/kg.8. Use of a pharmaceutical formulation with cladribine or administration according to any preceding claim, when the total dose of cladribine reached at the end of the induction period is about 3.5 mg/kg. 9. Upotreba farmaceutske formulacije sa kladribinom ili primena bilo prema kom prethodnom zahtevu, gde period bez kladribina (ii) traje 10 meseci.9. Use of a pharmaceutical formulation with cladribine or administration according to any preceding claim, where the cladribine-free period (ii) lasts for 10 months. 10. Upotreba farmaceutske formulacije sa kladribinom ili primena bilo prema kom prethodnom zahtevu, gde period bez kladribina (iv) traje 10 meseci.10. Use of a pharmaceutical formulation with cladribine or administration according to any preceding claim, where the period without cladribine (iv) lasts for 10 months. 11. Upotreba farmaceutske formulacije sa kladribinom ili primena bilo prema kom prethodnom zahtevu, gde period održavanja traje 2 meseca.11. Use of a pharmaceutical formulation with cladribine or application according to any previous claim, where the maintenance period lasts for 2 months. 12. Upotreba farmaceutske formulacije sa kladribinom prema zahtevu 3 ili primena prema zahtevu 4, gde se formulacija daje oralno, prateći sledeći niz koraka: (i) Indukcioni period u kome se daje navedena farmaceutska formulacija kladribina i u kome ukupna doza kladribina koja se dostiže na kraju indukcionog perioda iznosi od oko 1,7 mg/kg do oko 3,5 mg/kg; (ii) Period bez kladribina, u kome se ne daje kladribin; (iii) Period održavanja u kome se daje farmaceutska formulacija kladribina; (iv) Period bez kladribina, u kome se ne daje kladribin; gde period održavanja (iii) traje 2 meseca; period bez kladribina (iv) traje 10 meseci; ukupna doza kladribina koja se dostiže na kraju perioda održavanja iznosi oko 1,7 mg/kg i gde korake (iii) do (iv) treba ponavljati jednom, dva puta ili tri puta.12. Use of a pharmaceutical formulation with cladribine according to claim 3 or administration according to claim 4, wherein the formulation is administered orally, following the following series of steps: (i) An induction period in which said pharmaceutical formulation of cladribine is administered and in which the total dose of cladribine reached at the end of the induction period is from about 1.7 mg/kg to about 3.5 mg/kg; (ii) Cladribine-free period, in which no cladribine is administered; (iii) The maintenance period during which the pharmaceutical formulation of cladribine is administered; (iv) Cladribine-free period, in which no cladribine is given; where the maintenance period (iii) lasts 2 months; the cladribine-free period (iv) lasts 10 months; the total dose of cladribine reached at the end of the maintenance period is about 1.7 mg/kg and where steps (iii) to (iv) should be repeated once, twice or three times. 13. Upotreba farmaceutske formulacije sa kladribinom ili primena bilo prema kom prethodnom zahtevu, kada je ukupna doza kladribina koja se dostiže na kraju indukcionog perioda oko 3,5 mg/kg, a ukupna doza kladribina koja se dostiže na kraju perioda održavanja oko 1,7 mg/kg.13. Use of a pharmaceutical formulation with cladribine or administration according to any preceding claim, wherein the total dose of cladribine achieved at the end of the induction period is about 3.5 mg/kg, and the total dose of cladribine achieved at the end of the maintenance period is about 1.7 mg/kg. 14.Upotreba farmaceutske formulacije sa kladribinom ili primena bilo prema kom prethodnom zahtevu, kada se farmaceutska formulacija daje oralno, u dnevnoj dozi od 3 do 30 mg kladribina.14. Use of a pharmaceutical formulation with cladribine or application according to any previous requirement, when the pharmaceutical formulation is administered orally, in a daily dose of 3 to 30 mg of cladribine. 15.Upotreba farmaceutske formulacije sa kladribinom ili primena bilo prema kom prethodnom zahtevu, kada se farmaceutska formulacija daje oralno, u dnevnoj dozi od 10 mg kladribina.15. Use of a pharmaceutical formulation with cladribine or application according to any previous requirement, when the pharmaceutical formulation is administered orally, in a daily dose of 10 mg of cladribine. 16.Upotreba farmaceutske formulacije sa kladribinom ili primena bilo prema kom prethodnom zahtevu, kada se farmaceutska formulacija daje oralno, 1 do 7 dana mesečno tokom indukcionog perioda.16. Use of a pharmaceutical formulation with cladribine or administration according to any previous requirement, when the pharmaceutical formulation is administered orally, 1 to 7 days per month during the induction period. 17. Upotreba farmaceutske formulacije sa kladribinom ili primena bilo prema kom prethodnom zahtevu, kada korake (iii) do (iv) treba ponoviti najmanje jednom ili dva puta.17. Use of a pharmaceutical formulation with cladribine or administration according to any preceding claim, wherein steps (iii) to (iv) are to be repeated at least once or twice. 18.Upotreba farmaceutske formulacije sa kladribinom ili primena bilo prema kom prethodnom zahtevu, kada se farmaceutska formulacija daje u kombinaciji sa beta-interferonom18. Use of a pharmaceutical formulation with cladribine or administration according to any preceding claim, when the pharmaceutical formulation is administered in combination with beta-interferon
RS20120161A 2004-12-22 2005-12-20 POSTOLOGY OF CLADRIBIN FOR MULTIPLE SCLEROSIS TREATMENT RS52219B (en)

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