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(12) Patent Application Publication (10) Pub. No.: US 2015/0071925 A1 Larson Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2015/0071925 A1 Larson Et Al US 2015 0071925A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0071925 A1 Larson et al. (43) Pub. Date: Mar. 12, 2015 (54) LIQUID PROTEINFORMULATIONS Publication Classification CONTAININGVISCOSTY-LOWERING AGENTS (51) Int. Cl. A647/22 (2006.01) (71) Applicant: Arsia Therapeutics, Inc., Waltham, MA C07K 6/28 (2006.01) (US) A619/00 (2006.01) C07K 6/22 (2006.01) (72) Inventors: Alyssa M. Larson, Dana Point, CA C07K 6/24 (2006.01) (US); Kevin Love, Boston, MA (US); A 6LX39/395 (2006.01) Alisha K. Weight, Mill Creek, WA (US); A647/20 (2006.01) Alan Crane, Waban, MA (US); Robert (52) U.S. Cl. S. Langer, Newton, MA (US); CPC ............. A6IK 47/22 (2013.01); A61 K39/3955 Alexander M. Klibanov, Boston, MA (2013.01); C07K 16/2863 (2013.01); A61 K (US) 47/20 (2013.01); C07K 16/22 (2013.01); C07K I6/241 (2013.01); C07K 16/2839 (2013.01); (21) Appl. No.: 14/484,160 C07K 16/2887 (2013.01); A61 K9/0019 (2013.01) (22) Filed: Sep. 11, 2014 USPC ................... 424/134.1; 424/133.1; 424/142.1 (57) ABSTRACT Related U.S. Application Data Concentrated, low-viscosity, low-volume liquid pharmaceu (60) Provisional application No. 62/030,521, filed on Jul. tical formulations of proteins have been developed. Such 29, 2014, provisional application No. 62/026,497, formulations can be rapidly and conveniently administered filed on Jul. 18, 2014, provisional application No. by Subcutaneous or intramuscular injection, rather than by 62/008,050, filed on Jun. 5, 2014, provisional applica lengthy intravenous infusion. These formulations include tion No. 61/988,005, filed on May 2, 2014, provisional low-molecular-weight and/or high-molecular-weight pro application No. 61/946,436, filed on Feb. 28, 2014, teins, such as mAbs, and Viscosity-lowering agents that are provisional application No. 61/943,197, filed on Feb. typically bulky polar organic compounds, such as many of the 21, 2014, provisional application No. 61/940,227, GRAS (US Food and Drug Administration List of com filed on Feb. 14, 2014, provisional application No. pounds generally regarded as safe) and inactive injectable 61/876,621, filed on Sep. 11, 2013. ingredients and FDA approved therapeutics. Patent Application Publication Mar. 12, 2015 Sheet 1 of 7 US 2015/0071925 A1 Viscosities of biosimilar Erix with and with O. v. CSA 4 : 3. 8: r f s f exe or rxYx 3. & O f f ee CSA &WX f 20oo R g :{ , / A /s SY Y- *- ? 8. d&xosowska&s: so do so aco asso so so ado biosimilar Erbitux, mg/ml. fy. biosimilar Erbit ux), ng/m. f/ Patent Application Publication Mar. 12, 2015 Sheet 2 of 7 US 2015/0071925 A1 Wiscosities of Osiri. Ayos w is y O. v. CSA & {{ {{{ f s i soo | & : wr 8 & i & C { 8. 8. i > *wu& y f: -- f 8 •-- CSAsix &{} f : - wasawww.swax&W-8Aaaaaswgao- s Mwakes-Moses,sox s {R S8) : St. 3{X} biosimilar Avastin, mg/n a S. so{ |f 60 w8-- - s: R $:w s ox- CSA.& 20 ar x { $x. Q } {Y& 3) biosimilar Avostin, mg/ . Af, Patent Application Publication Mar. 12, 2015 Sheet 3 of 7 US 2015/0071925 A1 Wiscosity dependence of solutions of biosimilar Avast in on phi at 2CO38 mg/mL and O.25 M Soft k r sus--------------------------------------------------------e- Phosphate-citrate buffer 2 Occ -- CSAA occi Patent Application Publication Mar. 12, 2015 Sheet 4 of 7 US 2015/0071925 A1 fold improvement in viscosity of solutions of biosimilar Awastin as a function of phi & Viscosities of biosimilar Erbit ux as a function of p- and protein concentration with O.25 V CSAA 3i r www.www.ww.Yaa-XX-Y-axw------s-s-s-s-s-s-s-----www.law.www. - -- 2 O2 A-5 rig/ini T -- 229 7.5 m g/n Patent Application Publication Mar. 12, 2015 Sheet 5 of 7 US 2015/0071925 A1 SEC races of Renicode for ridets with a without hydrophobic soit 3oo Y Remicade drug product - Day O following reconstitution 1. : : as& C. Day 3O --- Day 6O o Cy QC - - - - - th 200 3. 1so too s s: & s y 8 3 12 is rhin Af. Patent Application Publication Mar. 12, 2015 Sheet 6 of 7 US 2015/0071925 A1 Aggregates of drug Odici (ccost for KO. As of its protein is sapie. s -e- O.25 M Phosphate | 3 Oo Buffer xe O, vi ay, 2- C y so -- O.25 M APM 21C | f W y f f 3 ( | / g S. / i / A {} / { so do so. 2do 25o 3oo (Biosimilar Avostin), mg/m. fe. Patent Application Publication Mar. 12, 2015 Sheet 7 of 7 US 2015/0071925 A1 use O25 M Phosphate 38 Suffes ; X-O. M TPP | Sy ii & s ^ // so --> s as: X o so too so 20o 25o 3oo Biosimilar Awastin , ng/ml. x: { -- O.5 M Phosphate Buffer '99 -- O. 15 M Thiamine HC p { so do so 28c. 25o 3do (Simponi, ng/mi Af. US 2015/007 1925 A1 Mar. 12, 2015 LIQUID PROTEINFORMULATIONS cause pain at the site of injection, are often imprecise, and/or CONTAININGVISCOSTY-LOWERING may have decreased chemical and/or physical stability. AGENTS 0005. These characteristics result in manufacturing, stor age, and usage requirements that can be challenging to CROSS-REFERENCE TO RELATED achieve, in particular for formulations having high concen APPLICATIONS trations of high-molecular-weight proteins, such as mAbs. 0001. This application claims priority to and the benefit of All protein therapeutics to some extent are subject to physical U.S. Provisional Application No. 62/030,521, filed Jul. 29, and chemical instability, Such as aggregation, denaturation, 2014, entitled “Low-Viscosity Protein Formulations Con crosslinking, deamidation, isomerization, oxidation, and taining Hydrophobic Salts: U.S. Provisional Application clipping (Wang et al., J. Pharm. Sci. 96:1-26, 2007). Thus, No. 62/026,497, filed Jul. 18, 2014, entitled “Low-Viscosity optimal formulation development is paramount in the devel Protein Formulations Containing GRAS Viscosity-Reducing opment of commercially viable protein pharmaceuticals. Agents:” U.S. Provisional Application No. 62/008,050, filed 0006 High protein concentrations pose challenges relat Jun. 5, 2014, entitled “Low-Viscosity Protein Formulations ing to the physical and chemical stability of the protein, as Containing Ionic Liquids; U.S. Provisional Application No. well as difficulty with manufacture, storage, and delivery of 61/988,005, filed May 2, 2014, entitled “Low-Viscosity Pro the protein formulation. One problem is the tendency of pro tein Formulations Containing Organophosphates: U.S. Pro teins to aggregate and form particulates during processing visional Application No. 61/946,436, filed Feb. 28, 2014, and/or storage, which makes manipulations during further entitled “Concentrated, Low-Viscosity Infliximab Formula processing and/or delivery difficult. Concentration-depen tions.” U.S. Provisional Application No. 61/943,197, filed dent degradation and/or aggregation are major challenges in Feb. 21, 2014, entitled “Concentrated, Low-Viscosity, High developing protein formulations at higher concentrations. In Molecular-Weight-Protein Formulations: U.S. Provisional addition to the potential for non-native protein aggregation Application No. 61/940,227, filed Feb. 14, 2014, entitled and particulate formation, reversible self-association in aque “Concentrated, Low-Viscosity High-Molecular-Weight Pro ous solutions may occur, which contributes to, among other tein Formulations; and U.S. Provisional Application No. things, increased viscosity that complicates delivery by injec 61,876,621, filed Sep. 11, 2013, entitled “Concentrated, Low tion. (See, for example, Steven J. Shire et al., J. Pharm. Sci. Viscosity, High-Molecular-Weight Protein Formulations.” 93: 1390-1402, 2004.) Increased viscosity is one of the key the disclosures of which are expressly incorporated hereby by challenges encountered in concentrated protein compositions reference. affecting both production processes and the ability to readily deliver Such compositions by conventional means. (See, for FIELD OF THE INVENTION example, J. Jezek et al., Advanced Drug Delivery Reviews 63:1107-1117, 2011.) 0002 The invention is generally in the field of injectable 0007 Highly viscous liquid formulations are difficult to low-viscosity pharmaceutical formulations of highly concen manufacture, draw into a syringe, and inject Subcutaneously trated proteins and methods of making and using thereof. or intramuscularly. The use of force in manipulating the vis cous formulations can lead to excessive frothing, which may BACKGROUND OF THE INVENTION further denature and inactivate the therapeutically active pro 0003 Monoclonal antibodies (mAbs) are important pro tein. High viscosity Solutions also require larger diameter tein-based therapeutics for treating various human diseases needles for injection and produce more pain at the injection Such as cancer, infectious diseases, inflammation, and site. autoimmune diseases. More than 20 mAb products have been 0008 Currently available commercial mAb products approved by the U.S. Food and Drug Administration (FDA), administered by SC or IM injection are usually formulated in and approximately 20% of all biopharmaceuticals currently aqueous buffers, such as a phosphate or L-histidine buffer, being evaluated in clinical trials are mabs (Daugherty et al., with excipients or Surfactants, such as mannitol. Sucrose, Adv. Drug Deliv Rev. 58:686–706, 2006; and Buss et al., Curr: lactose, trehalose, POLOXAMER(R) (nonionic triblock Opinion in Pharmacol. 12:615-622, 2012). copolymers composed of a central hydrophobic chain of 0004 mAb-based therapies are usually administered polyoxypropylene (poly(propylene oxide)) flanked by two repeatedly over an extended period of time and require sev hydrophilic chains of polyoxyethylene (poly(ethylene eral mg/kg dosing. Antibody solutions or Suspensions can be oxide))) or POLYSORBATER 80 (PEG(80)sorbitan mono administered via parenteral routes, such as by intravenous laurate), to prevent aggregation and improve stability.
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