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Batch Preparation and Component US 20110178470A1 (19) United States (12) Patent Application Publication (10) Pub. N0.2 US 2011/0178470 A1 Kocherlakota et al. (43) Pub. Date: Jul. 21, 2011 (54) PHARMACEUTICAL COMPOSITIONS (60) Provisional application No. 61/141,287, ?led on Dec. COMPRISING BORONIC ACID COMPOUNDS 30, 2008, provisional application No. 61/148,555, ?led on Jan. 30, 2009, provisional application No. (75) Inventors: Chandrasekhar Kocherlakota, 61/185,263, ?led on Jun. 9, 2009. Secunderabad (IN); Lavanya Nallamothu, Hyderabad (IN); (30) Foreign Application Priority Data Krishnam Raju Kovoru, East Godavari District (IN); Nagaraju Oct. 1, 2008 (IN) ......................... .. 2415/CHE/2008 Banda, Hyderabad (IN); Mittapally Dec. 16, 2008 (IN) . .. 3160/CHE/2008 Sridhar, Karimnagar (IN); Keni Feb. 18, 2009 (IN) ........................... .. 363/CHE/2009 Devendra Chandrkanth, Mumbai (IN); Soogareddy Channareddy Publication Classi?cation Shantreddy, Hyderabad (IN); Wagh Sanj ay Chhagan, (51) Int. Cl. Hyderabad (IN); Pillai Raviraj A61K 31/69 (2006.01) Sukumar, Hyderabad (IN); A61P 35/00 (2006.01) Bandari Sreedhar, Karimnager A61M 5/1 78 (2006.01) (IN); Hinge Kranthikumar, A61J 1/05 (2006.01) Warangal (IN) (52) us. c1. .......................... .. 604/187; 514/64; 604/403 (73) Assignees: DR. REDDY’S LABORATORIES LTD., Hyderabad (IN); DR. (57) ABSTRACT REDDY’S LABORATORIES, Pharmaceutical compositions comprising borteZomib for INC., BridgeWater, N] (U S) oral or parenteral administration. Speci?c aspects relate to (21) Appl. No.: 13/076,839 stable, sugar free pharmaceutical compositions of bort eZomib, including its pharmaceutically acceptable salts or (22) Filed: Mar. 31, 2011 solvates, in the form of ready-to-use solutions, lyophiliZed forms, or physical admixtures, and the preparation thereof. Related US. Application Data Other aspects include processes for preparing compositions (63) Continuation of application No. PCT/US2009/ and methods of using compositions for treating various types 058929, ?led on Sep. 30, 2009. of cancers in mammals. A B C D PRE-WASHED READY 30 mL vm. W1TH 20 mm ALUMWUM DISPENSE I-EUTVL TO STERILIZE 20mm 20 mm NECK FLIP-OFF SEALS W ALCOHOL E1 DRUG GREV BROMOBUTVL RUBBER STOPPERS PREPARATIONAREA COMPOUNDING/ WASHING. ANDCOMPONENT MIXING VESSEL STERILIZATION S1 BATCHPREPARATION DEPVRDGENATIDN FILTRATION DRYING OF 0.22 pm (PTFE sterile STOPPERS capsule filter) 1 FILLING VESSEL! HOLDING VESSEL FILLING 81 PARTIAL IN-LINE FILTRATION STDPPERING . pm (PTFE Membrane) ASEPTIC PROCESSING LYOPHILIZATION & - AREA COMPLETE STOFFERING SEALING SEALING AREA OPTICAL INSPECTION LABELING & PACKAGING FINISHED GOODS WAREHOUSE TRANSFER Patent Application Publication Jul. 21, 2011 US 2011/0178470 A1 FIG. 1 A B D .. PRE-WASHED READY 30 mL VIAL WITH 20 mm ALUMINUM DISPENSE t-BUTYL TO STERILIZE 20mm ZOmmNECK FLlP-OFFSEALS T §,_§§ ALCOHOL & DRUG GREY BROMOBUTYL : |-ZE( : RUBBER STOPPERS :5 §§<Z :5 a ?g a I E < E I I: E85 5 COMPOUNDINGI STEAM MIXING VESSEL STERILIZATION STERILIZATION&WASHING, E 52%LE<'I E DEPYROGENATION 5 m a E I I J : ............ .: FILTRATION DRYING OF 0.22 pm (PTFE sterile STOPPERS capsule filter) : o- = > aI Em—(D : : Lul-ucc : : <n8< 5 FILLING VESSEL/ E ‘in: : : D- E HOLDING VESSEL I FILLING & PARTIAL IN-LINE FILTRATION STOPPERING 0.22 pm (PTFE Membrane) 5 PROCESSINGASEPTIC 5 COMPLETE STOPPERING ELYOPHILIZATION & ‘ SEALINGAREAPACKAGING AREAAREA OPTICAL INSPECTION LABELING & PACKAGING FINISHED GOODS WAREHOUSE TRANSFER nu".. US 2011/0178470 A1 Jul. 21, 2011 PHARMACEUTICAL COMPOSITIONS monomeric boronic acid. The drug substance exists in its COMPRISING BORONIC ACID COMPOUNDS cyclic anhydride form as a trimeric boroxine. [0007] The chemical name for borteZomib, the monomeric INTRODUCTION boronic acid, is [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2 [0001] Aspects of the present invention relate to pharma [(pyraZinylcarbonyl)amino]propyl]amino]butyl]boronic ceutical compositions comprising boronic acid compounds acid. The solubility of borteZomib, as the monomeric boronic or modi?ed boronic acid compounds. Further aspects of the acid, in Water is 3.3 to 3.8 mg/mL over a pH range of2 to 6.5. present invention relate to pharmaceutical compositions for BorteZomib has the folloWing chemical structure. oral or parenteral administration comprising borteZomib, including its pharmaceutically acceptable salts or solvates. Also included are processes for preparing such compositions and methods of using such compositions for treating various types of cancers in mammals. [0002] A boronic acid is an alkyl or aryl substituted boric acid containing a carbon-to-boron chemical bond, belonging to the larger class of organo-boranes. Boronic acids act as LeWis acids. They have the unique feature of being capable of forming reversible covalent complexes With sugars, amino acids, hydroxamic acids, etc. (molecules With vicinal, (1,2-) or occasionally (1 ,3-) substituted LeWis base donors (alcohol, amine, carboxylate). The pKa of a boronic acid is about 9, but upon complexion in aqueous solutions they form tetrahedral [0008] BorteZomib is a reversible inhibitor of the chymot boronate complexes With pKa about 7. rypsin-like activity of the 26S proteasome in mammalian [0003] Boronic acid and ester compounds display a variety cells. The 26S proteasome is a large protein complex that of pharmaceutically useful biological activities. Shenvi et al., degrades ubiquitinated proteins. The ubiquitin-proteasome US. Pat. No. 4,499,082 (1 985), discloses that peptide boronic pathWay plays an essential role in regulating the intracellular acids are inhibitors of certain proteolytic enZymes. Kettner concentration of speci?c proteins, thereby maintaining and Shenvi, US. Pat. No. 5,187,157 (1993), US. Pat. No. homeostasis Within cells. Inhibition of the 26S proteasome 5,242,904 (1993), and US. Pat. No. 5,250,720 (1993), prevents this targeted proteolysis, Which can affect multiple describe a class of peptide boronic acids that inhibit trypsin signaling cascades Within the cell. This disruption of normal like proteases. Kleeman et al., US. Pat. No. 5,169,841 homeostatic mechanisms can lead to cell death. (1992), discloses N-terminally modi?ed peptide boronic [0009] Commercially, borteZomib is available in a product acids that inhibit the action of renin. Kinder et al., US. Pat. sold as VELCADE® sterile lyophiliZed poWder for intrave No. 5,106,948 (1992), discloses that certain tripeptide nous infusion and available in single-dose vials. Each single boronic acid compounds inhibit the groWth of cancer cells. dose vial contains 3.5 mg of borteZomib as a sterile lyo [0004] Unfortunately, alkylboronic acids are relatively dif philiZed poWder. The inactive ingredient is 35 mg mannitol, ?cult to obtain in analytically pure form. H. R. Snyder et al., USP, per vial. “Aryl Boronic Acids. ll. Aryl Boronic Anhydrides and their Amine Complexes,” Journal of ZheAmerican Chemical Soci [0010] US. Pat. Nos. 6,699,835, 6,713,446, 6,958,319, and 7,109,323 describe stable pharmaceutical compositions of ezy, Vol. 80, 3611-3615 (1958), teaches that alkylboronic acid compounds readily form boroxines (anhydrides) under dehy boronic acid compounds Which are prepared by lyophiliZing drating conditions. Also, alkylboronic acids and their borox an aqueous mixture comprising a boronic acid compound and a compound having at least tWo hydroxyl groups Which pro ines are often air-sensitive. S. Korcek et al., “Absolute Rate duces a stable composition that readily releases the boronic Constants for the Autoxidation of Organometallic Com pounds. Part II. BenZylboranes and l-Phenylethylboranes,” acid compound upon dissolution in aqueous media. Journal oflhe Chemical Society, Perkin Transactions 2, pp. [0011] International Application Publication No. WO 242-248 (1972), teaches that butylboronic acid is readily 2006/063154 describes pharmaceutical compositions com oxidiZed by air to generate 1-butanol and boric acid. These prising a practically insoluble proteasome inhibitor and a dif?culties limit the pharmaceutical utility of boronic acid cyclodextrin. The invention uses cyclodextrins to increase the compounds, complicating the characterization of pharmaceu solubility of the practically insoluble proteasome inhibitors. tical agents comprising boronic acid compounds and limiting But the invention is restricted to proteasome inhibitors such their shelf life. as peptide epoxy ketones Which are more highly proteasome [0005] There is a need to prepare improved and stable for speci?c inhibitors that could have feWer toxic side effects mulations of boronic acid compounds. ldeally, such formu When compared to other proteasome inhibitors such as bort lations Would be conveniently prepared, Would exhibit eZomib. More speci?cally the application excludes bort enhanced stability and longer shelf life as compared to the eZomib and restricts the invention to peptide epoxy ketones. other boronic acid compound, and Would readily liberate the [0012] HoWever, formulating borteZomib has not proven to bioactive boronic acid compound When administered to a be an easy task, typically due to stability and solubility issues. subject in need of boronic acid therapy. There remains a need for preparing borteZomib formulations [0006] BorteZomib is a modi?ed di-peptidyl boronic acid. With improved stability and increased solubility. It is the ?rst therapeutic proteasome inhibitor to be tested in [0013] There also exists an immediate need for making humans. The product is provided commercially as a mannitol stable borteZomib compositions for
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