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WO 2016/005995 A2 14 January 2016 (14.01.2016) P O P C T

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WO 2016/005995 A2 14 January 2016 (14.01.2016) P O P C T (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 2016/005995 A2 14 January 2016 (14.01.2016) P O P C T (51) International Patent Classification: Not classified BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (21) International Application Number: HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, PCT/IN20 15/000279 KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, (22) International Filing Date: MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, July 2015 (09.07.2015) PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, (25) Filing Language: English TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (26) Publication Language: English (84) Designated States (unless otherwise indicated, for every (30) Priority Data: kind of regional protection available): ARIPO (BW, GH, 3414/CHE/2014 10 July 2014 (10.07.2014) IN GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, (71) Applicant: LEIUTIS PHARMACEUTICALS PVT. TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, LTD. [IN/IN]; Plot No. 23, V S R Complex, TIE 1st DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, Phase, Balanagar, Hyderabad 500 037, Andra Pradesh LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, (IN). SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). (72) Inventors: CHANDRASHEKHAR, Kocherlakota; Plot- 13, Sonali Cooperative Housing Society, Bhavana Enclave, Declarations under Rule 4.17 : Bowenpally, Tadbund, Secunderabad 500 009, Andhra — as to applicant's entitlement to apply for and be granted a Pradesh (IN). NAGARAJU, Banda; Flat 301, Kamalakar patent (Rule 4.1 7(H)) Rao Classic, Sapthagiri Colony, Kukatpally, Hyderabad 500 072, Andhra Pradesh (IN). — as to the applicant's entitlement to claim the priority of the earlier application (Rule 4.1 7(in)) (74) Agent: VADEHRA, Sharad; KAN AND KRISHME, A t torneys at Law, KNK House, A-l l , Shubham Enclave, — of inventorship (Rule 4.17(iv)) Paschim Vihar, 110 063 New Delhi (IN). Published: (81) Designated States (unless otherwise indicated, for every — without international search report and to be republished kind of national protection available): AE, AG, AL, AM, upon receipt of that report (Rule 48.2(g)) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, < © © v o (54) Title: GLYCOL FREE STABLE LIQUID COMPOSITIONS OF BENDAMUSTINE (57) Abstract: The present invention relates to ready to use stable liquid pharmaceutical formulations of Bendamustine or a pharma ceutically acceptable salt thereof; wherein the formulation is devoid of glycols. Further the present invention relates to pharmaceutic - al composition of Bendamustine hydrochloride comprising of saccharide, suitable solvent or mixture of solvents and suitable ad juvants thereof. [Complete specification Field of Invention The present invention relates to glycol free ready to use liquid pharmaceutical formulations of Bendamustine or its pharmaceutically acceptable salts, solvates and hydrates thereof. Further the present invention relates to pharmaceutical formulations of Bendamustine hydrochloride comprising one or more saccharides. Background of the invention Bendamustine was first synthesized in 1963 by Ozegowski and Krebs in East Germany. It was found useful in treating chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma and lung cancer. Bendamustine hydrochloride has the following structure: In the US, Bendamustine is available as powder for IV infusion and as Solution for IV infusion under the tradename Treanda ®. Treanda ® powder for IV infusion is supplied as a sterile non-pyrogenic white to off-white lyophilized powder in a single-use vial in lOOmg and 25mg strengths. Each vial contains lOOmg of Bendamustine HC1 and 170mg of mannitol, USP. The pH of the reconstituted solution is 2.5-3.5. Treanda ® injection is supplied in single-use vials containing either 45 mg/0.5 L or 180 mg/2 mL of Bendamustine HC1. Each 0.5 mL vial contains 45 g of Bendamustine hydrochloride, 162 mg of Propylene Glycol, USP and 293 n g of N,N-Dimethylacetamide, EP. Each 2 niL vial contains 180 mg of Bendamustine hydrochloride, 648 mg of Propylene Glycol, USP and 1172 mg of Ν,Ν-Dimethylacetamide, EP. An over fill of 0.2 mL is included in each vial. The injection is intended for intravenous infusion only after dilution with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP.lt is supplied as a sterile clear colorless to yellow solution in single-use vials at the concentration of 90 mg/mL of Bendamustine HC1. The reconstitution of the Bendamustine lyophilized powder is time consuming and cumbersome. Moreover, lyophilization of solids on a commercial scale requires specialized equipment and incurs significant expense. Because of the patient-specific dosing, repeated administration, and a dosage regimen of six 28-day cycles, there is a strong need for ready- to-use formulations with enhanced stability. Unfortunately, while various attempts have been made to stabilize Bendamustine, all or almost all of them suffer from several disadvantages. US 201 1/0184036A1 points out that stability of Bendamustine in aqueous solutions is very minimal and is limited to few hours; and is therefore, not suitable for long-term storage in liquid form. Certain non-aqueous propylene glycol formulations have been disclosed in US 8,344,006, US 2013/041004, US 2014/080881, US 2012/0157505 to increase long-term stability. Bendamustine solution formulated with non-aqueous polyethylene glycol (PEG) and/or propylene glycol (PG) are discussed in US Pat No. 8,609,707, U.S. patent applications 2013/253026, US 2014/024691, 2013/253025, 2013/210879 and 2014/094496. In still further known attempts, Bendamustine is combined with first charged cyclopolysaccharide and a stabilizing agent (which is a second charged cyclopolysaccharide) with a charge opposite to that of the first cyclopolysaccharide as discussed in WO 2012/127277, WO 2010/097700, and US 2010/0216858. Similarly, US 201 1/0015245 teaches use of various amphiphilic cationic compositions to stabilize Bendamustine, while WO 201 1/005714 teaches liposomal formulations encapsulating Bendamustine. In another approach, stability of Bendamustine HC1 (0.25mg/ml in 0.9% sodium chloride) in water was studied. Here, Bendamustine was stable at 4°C for 4 days and at 23°C for 9 hours. While the temperature had adverse effects on stability, it was found that moderate concentrations of chloride ions increased the stability to at least some degree (Pharmazie 1994; 49, 10: 775-777). However, such compositions were yet again not stable over extended periods, and thus provide at best limited use as a ready-to-use aqueous composition, even under refrigerated conditions. Alternatively, Bendamustine is immobilized in a polymeric carrier to increase stability (J Pharm Biomed Anal. 2008 Dec 1;48(4): 1143-50). However, such specialized formulations are often complex to manufacture and/or significantly increase the cost of production. US Patent No. 8,344,006 describes liquid formulations comprising Bendamustine or pharmaceutically acceptable salts thereof, and polar aprotic solvents like dimethylacetamide and propylene glycol. Propylene glycol has been identified by the American Academy of Pediatrics as a potentially dangerous additive. Even though propylene glycol is considered to be harmless, in high concentrations it causes lactic acidosis and hyperosmolarity, hemolysis, renal toxicity including tubular dysfunction and acute tubular necrosis. When propylene glycol is present in high doses in intravenous formulations, it increases the formulation osmolality. Hence its use in patients of diminished renal function, should be monitored by determining plasmatic osmolality daily. Further, solutions of Bendamustine in propylene glycol degrade to form impurities identified as propylene glycol esters of Bendamustine. Upon exposure to an alkylene glycol, for example, propylene glycol, esters of Bendamustine can form, e.g., PG-1 and PG- 2 depicted below. The 90 mg/mL non-aqueous formulation of liquid Bendamustine HC1 described in US Patent No 8,344,006 exhibits bendamustine-propylene glycol ester degradation products following 12 months of storage at 5°C that are not formed after 24 months of storage of the lyophilized product. These esters are present at a level greater than 1% which may not be advisable for the patient. The lyophilized product of Bendamustine possesses good chemical stability. However, reconstitution of the lyophilized product is clinically inconvenient, with implications of chemical instability. On the other hand, Bendamustine solutions formulated with non aqueous polyethylene glycol (PEG) and/or propylene glycol may be stable but the use of propylene glycol presents acceptability limitations. Hence there is a need for ready to use (RTU) Bendamustine formulations having enhanced stability. The present invention addresses this need. Summary of the invention The present invention relates to ready to use liquid formulations of Bendamustine including its pharmaceutically acceptable salts, solvates, hydrates thereof, and method of preparation of such compositions. Another aspect of the present invention provides glycol free formulations of Bendamustine or its pharmaceutically acceptable salts, solvates, hydrates thereof. Another aspect of the present invention is to provide ready to use pharmaceutical formulation comprising Bendamustine or its pharmaceutically acceptable salts, solvates, hydrates thereof; saccharides; suitable solvent or mixture of solvents; and other pharmaceutically acceptable adjuvants. Yet another aspect of the present invention is to provide ready to use pharmaceutical formulation comprising of Bendamustine or its pharmaceutically acceptable salts, solvates, hydrates thereof, saccharide syrup; suitable solvent or mixture of solvents; anti-oxidant; buffer and other pharmaceutically acceptable adjuvants thereof.
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