WO 2016/ Al. S between 20N and 200N and friability value is less than 0.6%. 20 October 2016 ( ) P O P C T

Transcription

1 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2016/ Al 20 October 2016 ( ) P O P C T (51) International Patent Classification: (74) Agent: BULUT, Pinar; FarmaPatent Limited Sirketi, A61K 9/16 ( ) A61K 31/4196 ( ) GMK Bulvan No:42/5, Maltepe, Ankara (TR). A61K 9/20 ( ) (81) Designated States (unless otherwise indicated, for every (21) International Application Number: kind of national protection available): AE, AG, AL, AM, PCT/TR20 15/ AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (22) International Filing Date: DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, 16 April 2015 ( ) HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (25) Filing Language: English KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (26) Publication Language: English PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (72) Inventor; and SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, (71) Applicant : OGUN, Yusuf Toktamis [TR/TR]; Ardi TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. Farma Ilac Pazarlama Tic. Ltd. Sti., Kucukyah San. Sitesi, (84) Designated States (unless otherwise indicated, for every Girne Mah. Irmak Sok. A Blok No: 15, kind of regional protection available): ARIPO (BW, GH, Maltepe/istanbul (TR). GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, (72) Inventors: AGCAYAZI, Mehmet; Ardi Farma ilac Pazar TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, lama Tic. Ltd. Sti., Kvicukyali San. Sitesi, Girne Mah. Ir TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, mak Sok. A Blok No: 15, Maltepe/istanbul (TR). DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, CANBAGI, Hatice; Ardi Farma Ilac Pazarlama Tic. Ltd. LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, Sti., Kvicukyali San. Sitesi, Girne Mah. Irmak Sok. A Blok SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, No: 15, Maltepe/istanbul (TR). OZTURK, Fatma; GW, KM, ML, MR, NE, SN, TD, TG). Ardi Farma Ilac Pazarlama Tic. Ltd. Sti., Kvicukyali San. Published: Sitesi, Girne Mah. Irmak Sok. A Blok No: 15, Malte pe/istanbul (TR). with international search report (Art. 21(3)) (54) Title: DISPERSIBLE TABLETS COMPRISING DEFERASIROX (57) Abstract: This invention is related to a dispersible tablet formulation which comprises 42% to 50% deferasirox or pharmaceut i ically acceptable salt thereof in weight based on the total weight of the tablet and at least one disintegrant, whose tablet hardness is S between 20N and 200N and friability value is less than 0.6%.

2 DISPERSIBLE TABLETS COMPRISING DEFERASIROX Technical Field This invention is related to dispersible tablet formulation comprising deferasirox. Prior Art Deferasirox is an oral iron chelating agent used for the treatment of excessive iron accumulation. Chemical name is 4-[3,5-Bis (2-hydroxyphenyl)-lH-l,2,4-triazole-l-yl]benzoic acid (Formula I). Formula I Dispersible tablets of deferasirox are commercially available in America, Europe and many other countries under the brand name EXJADE. Its free acid form, salts and crystallized forms are described in PCT application W097/ The molecular formula of deferasirox is C21H15N3O4 and its molecular weight is g/mo. Deferasirox does not dissolve in water. It has a high lipophilicity, thus it has a good permeability. According to the Biopharmaceutical Classification System (BCS), deferasirox molecule is a Class 2 molecule. Namely it has a ow solubility and high permeability. Although deferasirox does not dissolve in water, its solubility is high in mediums with high ph. The deferasirox molecule which does not practically dissolve in water and aqueous mediums generally shows a low dissolution profile and low bioavailability. There is need for a preparation whose dissolution profile and physical features such as hardness and friability are improved and which comprises deferasirox drug substance with high absorption. PCT application WO2004/ (Novartis AG) is related to dispersible tablet dosage form comprising 5% to 40% deferasirox by weight. Equivalent EP B covers 5% to 40% deferasirox and 0% to 35% disintegrant by weight. PCT application WO2007/ (Novartis AG) is related to dispersible tablet dosage form comprising deferasirox 42% to 65% by weight and specific amounts of tablet excipients. Equivalent EP was deemed to be withdrawn. PCT application WO2005/ (Novartis AG) is related to dispersible tablet dosage form comprising 42% to 65% deferasirox by weight. Equivalent EP was deemed to be withdrawn.

3 PCT application WO2009/ (Teva Pharmaceutical Industries Ltd) is related to the pharmaceutical preparation prepared by grinding at least two excipients which are surfactant and another excipient with deferasirox. Description of the Invention The present invention is related to the pharmaceutical formulation of dispersible tablet of deferasirox. The present invention comprises 42% - 50% deferasirox or pharmaceutically acceptable salt thereof in weight based on the total weight of the tablet and at least one disintegrant. Dispersible tablet comprises preferably 44% to 46% and more preferably 45% deferasirox or pharmaceutically acceptable salt thereof. The invention is characterized in that the hardness of the tablet is 20N-200N, preferably N, and more preferably N and the friability test value is less than 0.6% in weight based on the total weight of the tablet, preferably less than 0.5% and more preferably less than 0.4% by weight. Tests are carried out in accordance with USP. The dispersible tablet formulation comprises excipients in ratios given below: At least one filler 10% to 20% by weight, At least one disintegrant 5% to 35% by weight. At least one surfactant 0.5% to 1.5% by weight, At least one binder % to 5% by weight, At least one glidant 0% to 1.5% by weight, At least one lubricant 1% to 10% by weight. By decreasing the amounts of excipients which will be used in the formulation according to the present invention, a tablet with lower weight, suitable hardness and friability values, which disperse faster and dissolves in water is obtained. Pharmaceutical formulations according to the present invention may comprise 125 g, 250 g or 500 mg deferasirox or its pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomers or combinations thereof. In terms of polymorphic structure, deferasirox may be in the form of crystal, amorphous or combinations thereof. Pharmaceutical formulations according to the invention comprise at least one excipient selected among filler, disintegrant, surfactant, binder, glidant and lubricant groups. According to the invention the filler may be selected among calcium carbonate, dibasic caicium phosphate, microcrystalline cellulose, dextrose, fructose, iactitol, lactose, magnesium carbonate, maltose, mannitol, sorbitol, sodium caseinate, potassium casemate, calcium caseinate. According to the invention, the disintegrant may be selected among carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, crosscarmellose sodium, crospovidone, hydroxypropyl cellulose, microcrystalline cellulose, methyl cellulose, starch, sodium starch glycolate.

4 According to the invention the surfactant may be selected among sodium lauryl sulphate, sodium tripolyphosphate, polysorbate, polyoxyethylene, polyoxypropylene glycol and similar agents. According to the invention the lubricant may be selected among talc, magnesium stearate, PEG 6000, sodium chloride, silicon dioxide, stearic acid, sodium stearyl fumarate and/or a combination thereof. According to the invention glidant may be selected among magnesium carbonate, calcium silicate, colloidal silicon dioxide, talc or mixtures thereof. According to the invention binder may be selected among polyvinylpyrrolidone, polyethyleneglycol, hydroxypropyl cellulose. According to the invention dispersible tablets are obtained by the implementation of the production process below: Preparation of granulation solution which comprises at least one binder and at least one surfactant (Step I) Granulation of at least one filler and deferasirox with the granulation solution of Step I (Step II) Mixing of granules obtained in Step II with at least one pharmaceutically available excipient in order to obtain a mixture (Step III) Compression of the mixture of Step III with a suitable punch (Step IV) Examples Dispersible tablet dosage forms are shown in Table.

5 Test formulations are produced with the process below. 1. 1/4 of PVP 30 and all of Sodium lauryl sulphate are mixed in distilled water until they are entirely dissolved. 2. The rest of the mannitol, microcrystalline cellulose, deferasirox and polyvinylpyrrolidone are mixed in the granulator. 3. The granulation process is carried out by adding the granulation solution prepared in the first step onto the powder mixture in the granulator. 4. Granules are dried in fluidized bed drier or drying oven. 5. The dried granules are sieved through a suitable mesh. 6. Crospovidone, sodium chloride present in the outer phase are mixed by adding aerosol Finally, it is lubricated by the addition of magnesium stearate. 8. Tablets are compressed with a suitable punch. Dissolution Reference products (Exjade 125 mg, 250 mg and 500 mg dispersible tablet) and all formulations are tested in the dissolution conditions (ph 6.8 phosphate buffer comprising 0.5% Tween 20, paddle method, 50 rpm, 900 ml sampling times, 5, 10, 15, 20, 30, 45 minute) provided by FDA. Test results are given in Table 2. Table 2: Dissolution test results As can be seen in the table, the test formulations and reference products have shown similar dissolution results and since more than 85% of them have dissolved in the dissolution medium (ph 6.8 phosphate buffer comprising 0.5% Tween 20), they are accepted as compatible without the requirement of f 2 calculation according to CPMP/QWP/EWP/ 140 1/98.

6 In accordance with the results obtained above, in line with the 500 mg tablet, also the 250 mg and 25 mg dispersible tablet formulations were studied and results similar to the ones obtained with high dosage products were obtained. Hardness and Friability Reference products (Exjade 125 mg, 250 mg and 500 mg dispersible tablet) and all formulations are tested for hardness and friability. Test results are given in Table 3. Table 3 Description of the Figures Figure 1. Dissolution profiles of 500 mg Formula 1 and Formula II with 500 mg original product (Dissolution medium: ph 6.8 phosphate buffer comprising 0.5% Tween 20)

7 CLAIMS 1) A dispersible tablet characterized in that it comprises 42% to 50% deferasirox or pharmaceutically acceptable salt thereof in weight based on the total weight of the tablet and at least one disintegrant, wherein its hardness value is between 20N and 200N and friability value is less than 0.6% in weight based on the total weight of the tablet. 2) A dispersible tablet according to Claim 1 wherein it comprises 44% to 46% deferasirox or pharmaceutically acceptable salt thereof by the total tablet weight. 3) A dispersible tablet according to Claim 2 wherein it comprises 45% deferasirox or pharmaceutically acceptable salt thereof by the total tablet weight. 4) A dispersible tablet according to Claim 1 wherein it comprises 5% to 35% disintegrant by the total tablet weight. 5) A dispersible tablet according to Claim 1 wherein its hardness is between 100N and 180N. 6) A dispersible tablet according to Claim 5 wherein its hardness is between 140N and 160N. 7) A dispersible tablet according to Claim 1 wherein its friability value is less than 0.5%. 8) A dispersible tablet according to Claim 7 wherein its friability value is less than 0.4%. 9) A dispersible tablet according to any of the previous claims wherein it comprises at least one lubricant selected among talc, magnesium stearate, sodium chloride, PEG silicon dioxide, stearic acid, sodium stearyl fumarate and/or a combination thereof. 10) A dispersible tablet according to any of the previous claims wherein it comprises 125 mg, 250 mg or 500 mg deferasirox or pharmaceutically acceptable salt thereof. 11) A dispersible tablet according to any of the previous claims; wherein it is obtained by the application of the production process below: Preparation of granulation solution which comprises at least one binder and at least one surfactant (Step I) Granulation of at least one filler and deferasirox with the granulation solution of Step I (Step II) Mixing of granules obtained in Step II with at least one pharmaceutically available exeipient in order to obtain a mixture (Step III) Compression of the mixture of Step III with a suitable punch (Step IV)

8

9 International application No PCT/TR2015/0OQ154 A. CLASSIFICATION OF SUBJECT MATTER INV. A61K9/16 A61K9/20 A61K31/4196 ADD. According to International Patent Classification (IPC) or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched A61K (classification system followed by classification symbols Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched Electronic data base consulted during the international search (name of data base and, where practicable, search terms used) EPO-Internal, BIOSIS, WPI Data C. DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with Indication, where appropriate, of the relevant passages Relevant to claim No. Y WO 2014/ Al (NOVAPJIS AG [CH] ; GHOSH 1-11 I NDRAJ I T [US] ; ZHANG JIA-AI [UA] ) 12 September 2014 ( ) page 17 Y W0 2012/ Al ( AT I 0 PHA GMBH [DE] ; 1-11 PAETZ JANA [DE] ; RIMKUS KATRIN [DE] ) 12 January 2012 ( ) page 19, l ines ; examples Y EP Al (TEVA PHARMA [ I L] ) May 2009 ( ) exampl e s Y W0 2009/ A2 (CI PLA LTD [IN] ; LULLA 1-11 AMAR [IN] ; MALH0TRA GEENA [IN] ; CURTIS PHI LI P AN) 3 September 2009 ( ) exampl e 2 Further documents are listed in the continuation of Box C. * Special categories of cited documents : "A" document defining the general state of the art which is not considered to be of particular relevance "E" earlier application or patent but published on or after the International filing date "L" document which may throw doubts on priority claim(s) orwhich is cited to establish the publication date of another citation or other special reason (as specified) "O" document referring to an oral disclosure, use, exhibition or other means "P" document published prior to the international filing date but later than the priority date claimed Date of the actual completion of the international search See patent family annex. "T" later document published after the international filing date or priority date and not in conflict with the application but cited to understand the principle or theory underlying the invention "X" document of particular relevance; the claimed invention cannot be considered novel or cannot be considered to involve an inventive step when the document is taken alone " document of particular relevance; the claimed invention cannot be considered to involve an inventive step when the document is combined with one or more other such documents, such combination being obvious to a person skilled in the art "&" document member of the same patent family Date of mailing of the international search report 25 June /07/2015 Name and mailing address of the ISA/ Authorized officer European Patent Office, P.B Patentlaan 2 NL HV Rijswijk Tel. (+31-70) , Fax: (+31-70) Gimenez Mi a l les, J

10 Information on patent family members International application No PCT/TR2015/0OQ154 Patent document Publication Patent family Publication cited in search report date member(s) date WO A l CA A l T A US A l UY A O A l W A l CA A l EA A l EP A l KR A US A l W A l EP A l EP A l US A l WO A l WO A NONE