WO 2015/ Al. 21 May 2015 ( ) 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 2015/ Al 21 May 2015 ( ) P O P C T (51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, A61K 9/16 ( ) A61K 9/48 ( ) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, A61K 9/20 ( ) A61K 31/4184 ( ) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (21) International Application Number: KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, PCT/EP2014/ MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (22) International Filing Date: PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, 14 November 2014 ( ) SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every (26) Publication Language: English kind of regional protection available): ARIPO (BW, GH, (30) Priority Data: GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, November 2013 ( ) EP TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (71) Applicant: SANDOZ AG [CH/CH]; Lichstrasse 35, CH- DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, 4056 Basel (CH). LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, (72) Inventors: RANEBURGER, Johannes; c/o Sandoz GW, KM, ML, MR, NE, SN, TD, TG). GmbH, Biochemiestrasse 10, A-6250 Kundl (AT). SCHWARZ, Franz Xaver; c/o Sandoz GmbH, Biochemi Published: estrasse 10, A-6250 Kundl (AT). with international search report (Art. 21(3)) (74) Agent: BLECHA, Andreas; c/o Sandoz International before the expiration of the time limit for amending the GmbH, Industriestrasse 25, Holzkirchen (DE). claims and to be republished in the event of receipt of (81) Designated States (unless otherwise indicated, for every amendments (Rule 48.2(h)) kind of national protection available): AE, AG, AL, AM, (54) Title: PHARMACEUTICAL COMPOSITIONS OF IBRUTINIB o (57) Abstract: Ibrutimb is novel BTK inhibitor currently tested in clinical phase III against different kinds of cancer. Pharmaceutical compositions comprising Ibrutinib, a water soluble carrier selected from the group consisting of sugars, sugar alcohols and mixtures thereof, and at least one hydrophilic polymeric pharmaceutically acceptable excipient show homogeneous distribution of the active ingredient, improved stability, fast disintegration and dissolution and high bioavailability.

2 PHARMACEUTICAL COMPOSITIONS OF IBRUTINIB FIELD OF INDUSTRIAL APPLICABILITY The present invention relates to pharmaceutical formulations of Ibrutinib, processes for their preparation and their medical use. BACKGROUND OF THE DISCLOSURE Ibrutinib is novel BTK inhibitor currently tested in clinical phase III against different kinds of cancer, in particular mantle-cell lymphoma and chronic lymphocytic leukemia. WO 2008/ A2 discloses the chemical synthesis of Ibrutinib and its analogues. It also discloses in general terms pharmaceutical compositions containing it and capsules containing 750 mg of starch and 100 mg of a compound of the invention. For this formulation a large amount of starch and consequently the biggest size (00) of capsules are needed. Considering that the typical dosage of Ibrutinib consists of three capsules, each containing 140 mg of active ingredient, taken three times a day for a total of 1260 mg per day, this translates into a tremendous pill burden for the patient, who has to take three difficult to swallow capsules three times a day. Ibrutinib is a weak base, is poorly soluble in water and shows an electrostatic behavior and a strong tendency to agglomerate. This results in a low bulk density and in difficulties to get a homogeneous distribution of the active ingredient within solid oral dosage forms, like immediate release capsules and tablets. Moreover formulations of Ibrutinib with sugars or sugar alcohols show less disintegration when filled in capsules or compressed into tablets when stored at higher temperature and/or humidity, which has a negative influence on dissolution and bioavailability. An object of the present invention is thus the provision of pharmaceutical compositions of Ibrutinib having a homogeneous distribution of the active ingredient.

3 A further object of the present invention is the provision of pharmaceutical compositions of Ibrutinib having a high drug load. A further object of the present invention is the provision of pharmaceutical compositions of Ibrutinib having fast disintegration after dispersion in water. A further object of the present invention is the provision of pharmaceutical compositions of Ibrutinib having fast dissolution and high bioavailability. A further object of the present invention is the provision of pharmaceutical compositions of Ibrutinib having less scattering of blood levels and optimal absorption into the blood. A further object of the present invention is the provision of pharmaceutical compositions of Ibrutinib for use in the treatment of cancer having reduced pill burden and improved patient compliance. A further object of the present invention is the provision of pharmaceutical compositions of Ibrutinib for use in the treatment of cancer having lower dosages of the active ingredient. SUMMARY OF THE DISCLOSURE The present disclosure provides pharmaceutical compositions comprising ibrutinib, a water soluble carrier selected from the group consisting of sugars, sugar alcohols and mixtures thereof, and at least one hydrophilic polymeric pharmaceutically acceptable excipient. DETAILED DESCRIPTION OF THE DISCLOSURE Surprisingly it was found that if ibrutinib is mixed with a water soluble carrier selected from the group consisting of sugars, sugar alcohols and mixtures thereof and with at least one hydrophilic polymeric pharmaceutically acceptable excipient, the before mentioned problems can be solved and an homogeneous distribution of the active ingredient in capsules or tablets can be achieved. In addition no negative effect of temperature and/or humidity is observed on disintegration and dissolution of the pharmaceutical compositions.

4 Suitable sugars include lactose, saccharose, fructose, glucose, mannose, maltose, galactose, rhamnose, dextrin, maltodextrin and trehalose. Preferred sugars include lactose, saccharose and glucose. The most preferred sugar is lactose. Suitable sugar alcohols include mannitol, sorbitol, xylitol, isomalt, lactitol, maltitol, erythritol and arabitol. Preferred sugar alcohols include mannitol and sorbitol. The most preferred sugar alcohol is mannitol. The hydrophilic polymeric pharmaceutically acceptable excipients are preferably selected from the group consisting of cellulose and cellulose derivatives, starch and starch derivatives, polyvinylpyrrolidones and their derivatives and mixtures thereof. Cellulose and cellulose derivatives include macrocrystalline cellulose, microfine cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and croscaramellose sodium. Preferred cellulose and cellulose derivatives include microcrystalline cellulose and sodium carboxymethylcellulose. Starch and starch derivatives include maize starch, rice starch, potato starch, wheat starch, pregelatinized starch, carboxymethyl starch, sodium carboxymethyl starch (sodium starch glycolate), hydroxyethyl starch. The preferred starch derivative is sodium carboxymethyl starch. Polyvinylpyrrolidones and their derivatives include polyvinylpyrrolidone K17, K25, K30 or K90, polyvinylpolypyrrolidone and vinyl acetate / vinyl alcohol copolymer (VA64). Preferred polyvinylpyrrolidones are polyvinylpyrrolidone K25 and K30, polyvinylpolypyrrolidone and vinyl acetate / vinyl alcohol copolymer (VA64). The water soluble carrier is preferably used in an amount between 15 and 60% of the total weight of the pharmaceutical composition, preferably in an amount between 20 and 50%.

5 The hydrophilic polymeric pharmaceutically acceptable excipient is preferably used in an amount between 1 and 40%, preferably in an amount between 2 and 30%. Preferred pharmaceutical compositions are tablets, capsules, granules, preferably tablets. The compositions of the invention can be manufactured by mixing the ingredients and filling them into capsules or by directly compressing them into tablets. Alternatively they may be made by wet or dry granulation. The pharmaceutical composition of the invention can be advantageously used in the treatment of cancer, in particular mantle-cell lymphoma and chronic lymphocytic leukemia. The compositions of the invention show a homogeneous distribution of Ibrutinib and the excipients, which allows filling into capsules or compression into tablets with high drug load. This results in small capsule and tablet size and consequently a reduced pill burden and improved patient compliance. In addition such compositions show improved stability, fast disintegration after dispersion in water, fast dissolution of Ibrutinib and consequently high bioavailability, less scattering of blood levels, optimal absorption into the blood and lower dosages of the active ingredient. EXAMPLES Example 1: Capsules: Ibrutinib 140 mg, lactose spray dried 53 mg, microcrystalline cellulose phl02 49 mg, crosspovidone 5 mg, fumed silica (Aerosil) 1.25 mg, magnesium stearate 1.5 mg - total 250 mg, filled in a hard gelatine capsule size 1. Manufacturing procedure is two step mixing (blender, high shear mixer) - first mixing Ibrutinib with all excipients except magnesium stearate - second mixing with magnesium stearate and afterwards filling the mixture into capsules. Example 2

6 Capsules: Ibrutinib 140 mg, mannitol DC 102 mg, microcrystalline cellulose phl02 47 mg, croscaramellose sodium (Acdisol) 8 mg, fumed silica (Aerosil) 1 mg, magnesium stearate 1.5 mg - total 300 mg filled in hard gelatine capsule size 0. For the manufacturing procedure see example 1. Example 3 Capsules: Ibrutinib 140 mg, lactose monohydrate 96 mg, sodium starch glycolate 8 mg, fumed silica (Aerosil) 3 mg, magnesium stearate 1.5 mg, sodium lauryl sulfate 1.2 mg - in total 250 mg; manufacturing procedure is wet granulation of all components except magnesium stearate, mixing granules with magnesium stearate and filling them into capsule size 1. Example 4 Capsules: ibrutinib 140 mg, mannitol 90 mg, povidone 10 mg, croscaramellose sodium (Acdisol) 7 mg, magnesium stearate 2 mg, sodium lauryl sulfate 1 mg - in total 250 mg, manufacturing process similar to example 3. Example 5 Capsules: ibrutinib 280 mg, lactose 270 mg, povidone 25 mg, croscaramellose sodium 15 mg, sodium lauryl sulfate 5 mg, magnesium stearate 5 mg - in total 500 mg filled into capsule size 0 - elongated; manufacturing procedure similar to example 3. Example 6 Tablets: ibrutinib 140 mg, microcrystalline cellulose phlol internal 8 1 mg, lactose monohydrate 116 mg, povidone K30 10 mg, sodium starch glycolate internal 7.5 mg, microcrystalline cellulose phi 02 external 37.5 mg, crosspovidone XL external 5 mg, fumed silica (Aerosil) 1.2 mg, magnesium stearate 1.5 mg - in total 400 mg tablet; manufacturing is wet granulation with inner phase, mixing the resulting granules with the external phase, compression. Example 7

7 Tablets: Ibnitinib 140 mg, mannitol 62 mg, microcrystalline cellulose phlol internal 38mg, hydroxypropyl methylcellulose 3 cp 6.4 mg, sodium lauryl sulfate 1 mg, croscaramellose sodium (Acdisol) internal 6.2 mg, microcrystalline cellulose phl02 external 32 mg, croscaramellose sodium (Acdisol) external 8 mg, fumed silica (Aerosil) 3 mg, magnesium stearate 4 mg - in total 300 mg tablet, manufacturing procedure similar to example 6.

8 CLAIMS What is claimed is: 1. A pharmaceutical composition comprising Ibrutinib, a water soluble carrier selected from the group consisting of sugars, sugar alcohols and mixtures thereof, and at least one hydrophilic polymeric pharmaceutically acceptable excipient. 2. The pharmaceutical composition of claim 1, wherein the sugar is selected from lactose, saccharose, fructose, glucose, mannose, maltose, galactose, rhamnose, dextrin, maltodextrin and trehalose, preferably from lactose, saccharose and glucose, most preferably the sugar is lactose. 3. The pharmaceutical composition of claim 1-2, wherein the sugar alcohol is selected from mannitol, sorbitol, xylitol, isomalt, lactitol, maltitol, erythritol and arabitol, preferably from mannitol and sorbitol, most preferably the sugar alcohol is mannitol. 4. The pharmaceutical composition of claim 1-3, wherein the hydrophilic polymeric pharmaceutically acceptable excipient is selected from the group consisting of cellulose and cellulose derivatives, starch and starch derivatives, polyvinylpyrrolidones and their derivatives and mixtures thereof. 5. The pharmaceutical composition of claim 4, wherein the cellulose and cellulose derivatives are selected from microcrystalline cellulose, microfine cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and croscaramellose sodium, preferably from microcrystalline cellulose and sodium carboxymethylcellulose. 6. The pharmaceutical composition of claim 4, wherein the starch and starch derivatives are selected from maize starch, rice starch, potato starch, wheat starch, pregelatinized starch, carboxymethyl starch, sodium carboxymethyl starch (sodium starch glycolate), hydroxyethyl starch, preferably the starch derivative is sodium carboxymethyl starch. 7. The pharmaceutical composition of claim 4, wherein polyvinylpyrrolidones and their derivatives are selected from polyvinylpyrrolidone K17, K25, K30 or K90, polyvinylpolypyrrolidone and vinyl acetate / vinyl alcohol copolymer (VA64). 8. The pharmaceutical composition of claims 1-7, wherein the water soluble carrier is used in an amount between 15 and 60% of the total weight of the pharmaceutical composition, preferably in an amount between 20 and 50%.

9 9. The pharmaceutical composition of claims 1-8, wherein the hydrophilic polymeric pharmaceutically acceptable excipient is used in an amount between 1 and 40%, preferably in an amount between 2 and 30%. 10. The pharmaceutical composition of claims 1-9, which is selected from tablets, capsules, granules. 11. The pharmaceutical composition of claims 1-10, which is a tablet. 12. A process for the preparation of the pharmaceutical composition of claims 1-11 comprising the steps of mixing the ingredients and filling them into capsules or compressing them into tablets. 13. The process according to claim 12 comprising the additional step of granulating the ingredients prior to filling them into capsules or compressing them into tablets. 14. The pharmaceutical composition of claims 1-11 for use in the treatment of cancer. 15. The pharmaceutical composition of claim 15, wherein the cancer is mantle-cell lymphoma and chronic lymphocytic leukemia.

10 A. CLASSIFICATION OF SUBJECT MATTER INV. A61K9/16 A61K9/20 A61K9/48 A61K31/4184 ADD. According to International Patent Classification (IPC) or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) A61K 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, WPI Data C. DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. UY A (PHARMACYCLICS INC [US] ) 1-5, October 2013 ( ) page 1, paragraph 2 3, 7, 8 page 42, paragraph 62 page 102, paragraph 173 page 151, paragraph pages pages ; exampl e 11 WO 2013/ A2 (PHARMACYCLICS INC [US] ) 1-4,6-8, 25 Apri l 2013 ( ) 10, 12, 14, 15 pages 57-58, paragraph 186 page 150, paragraph pages page 205 ; exampl e 24c -/- X Further documents are listed in the continuation of Box C. See patent family annex. * Special categories of cited documents : "A" document defining the general state of the art which is not considered to be of particular relevance "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 "E" earlier application or patent but published on or after the international "X" document of particular relevance; the claimed invention cannot be filing date considered novel or cannot be considered to involve an inventive "L" documentwhich may throw doubts on priority claim(s) orwhich is step when the document is taken alone cited to establish the publication date of another citation or other "Y" document of particular relevance; the claimed invention cannot be special reason (as specified) considered to involve an inventive step when the document is "O" document referring to an oral disclosure, use, exhibition or other combined with one or more other such documents, such combination means being obvious to a person skilled in the art "P" document published prior to the international filing date but later than the priority date claimed "&" document member of the same patent family Date of the actual completion of the international search Date of mailing of the international search report 12 February /03/2015 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) Raposo, Antoni o

11 C(Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. WO 2008/ A2 (PHARMACYCLICS INC [US] ; 3, 7, 8 HONIGBERG LEE [US] ; VERNER ERI K [US] ; PAN ZHEN) 3 Apri l 2008 ( ) c i ted i n the appl i cati on page 6, paragraph 34 pages 30-31, paragraph 204 page 40, paragraph pages "Gl ucose, Li qui d " I n : Anonymous : "Handbook of Pharmaceuti cal Exci pi ents", 2006, Pharmaceuti cal Press, XP , page 299, the whol e document "Sugar, Confecti oner ' s " I n : Anonymous : "Handbook of Pharmaceuti cal Exci pi ents", 2006, Pharmaceuti cal Press, XP , page 750, the whol e document

12 Patent document Publication Patent family Publication cited in search report date member(s) date UY A AU Al CA Al I L A T A US Al US Al UY A O Al W A AU Al CA Al CN A EP A P A KR A US Al WO A W A AT T AU Al AU Al B R PI A B R PI A CA Al CA Al CN A CN A CN A CN A DK T EA Al EA Al EA Al EP A EP Al EP Al EP Al EP A EP A EP Al EP Al EP Al EP Al EP Al ES T P B P B J P B J P A J P A J P A J P A KR A KR A KR A KR A NZ A NZ A page 1 of 2

13 Patent document Publication Patent family Publication cited in search report date member(s) date NZ A PT E S G Al SI Tl US Al US Al US Al US Al US Al US Al US Al us Al us Al us Al us Al us Al us Al us Al us Al us Al us Al us Al us Al us Al us Al us Al us Al us Al us Al us Al us Al us Al us Al us Al us Al us Al us Al us Al us Al us Al us Al us Al us Al us Al us Al us Al us Al o A page 2 of 2