THETWO TONDITIONWINKTURTINUS 20170232103A1 ( 19) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2017/ 0232103 A1 Soane et al. (43 ) Pub. Date : Aug . 17, 2017 ( 54 ) EXCIPIENT COMPOUNDS FOR plication No . 62/ 245 , 513 , filed on Oct . 23, 2015 , BIOPOLYMER FORMULATIONS provisional application No . 62/ 245 ,513 , filed on Oct . (71 ) Applicant : ReForm Biologics , LLC , Cambridge , 23 , 2015 . MA (US ) Publication Classification (51 ) Int. Cl. (72 ) Inventors : David S . Soane , Palm Beach , FL (US ) ; A61K 39 /395 ( 2006 . 01 ) Philip Wuthrich , Belmont, MA (US ) ; A61K 47 / 12 (2006 . 01 ) Rosa Casado Portilla , Peabody , MA CO7K 16 /22 ( 2006 .01 ) (US ) ; Robert P . Mahoney , Newbury , A61K 47 /22 (2006 . 01 ) MA (US ) ; Mark Moody , Concord , MA CO7K 16 / 24 ( 2006 .01 ) (US ) ; Daniel G . Greene , Belmont , MA COZK 16 / 32 ( 2006 .01 ) (US ) (52 ) U . S . CI. CPC . .. A61K 39 / 39591 (2013 . 01 ) ; CO7K 16 / 241 ( 21) Appl . No. : 15 /331 , 197 ( 2013 . 01 ) ; CO7K 16 / 32 (2013 .01 ) ; CO7K 16 / 22 ( 2013 . 01 ) ; A61K 47/ 48215 ( 2013 .01 ) ; A61K (22 ) Filed : Oct . 21 , 2016 47 / 22 ( 2013 . 01 ) ; A61K 47 / 12 ( 2013 . 01) ; COZK 2317 /21 ( 2013 .01 ) ; CO7K 2317 /24 (2013 .01 ) Related U . S . Application Data ( 57 ) ABSTRACT (63 ) Continuation - in -part of application No . 14 / 966 ,549 , The invention encompasses formulations and methods for filed on Dec. 11 , 2015 , now Pat . No . 9 ,605 , 051 , which the production thereof that permit the delivery of concen is a continuation of application No . 14 /744 , 847 , filed trated protein solutions. The inventive methods can yield a on Jun . 19 , 2015 . lower viscosity liquid protein formulation or a higher con (60 ) Provisional application No. 62 /014 ,784 , filed on Jun . centration of therapeutic or nontherapeutic proteins in the 20 , 2014 , provisional application No. 62 /083 ,623 , liquid formulation , as compared to traditional protein solu filed on Nov . 24 , 2014 , provisional application No. tions . The inventive methods can also yield a higher stability 62 / 136 , 763 , filed on Mar. 23 , 2015 , provisional ap of a liquid protein formulation . Patent Application Publication Aug. 17, 2017 Sheet10f 3 US2017 / 0232103A1 $ ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? . ? 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A.U minim i zimin os .. .. .. .. .. .. .. .. .. .. .. .. .. .. 6 8 10 121 Time (min ) FIG . 3 US 2017 /0232103 A1 Aug . 17 , 2017 EXCIPIENT COMPOUNDS FOR [ 0007 ] As an example , one approach to producing protein BIOPOLYMER FORMULATIONS formulations for injection is to transform the therapeutic protein solution into a powder that can be reconstituted to RELATED APPLICATIONS form a suspension suitable for SC or IM delivery . [0001 ] This application is a continuation - in - part of U . S . Lyophilization is a standard technique to produce protein application Ser . No. 14 / 966 , 549 filed Dec . 11 , 2015 which is powders . Freeze - drying , spray drying and even precipitation a continuation of U . S . application Ser. No . 14 /744 ,847 filed followed by super - critical - fluid extraction have been used to Jun . 19 , 2015 which claims the benefit of U . S . Provisional generate protein powders for subsequent reconstitution . Application No . 62 /014 ,784 filed Jun . 20 , 2014 , U . S . Pro Powdered suspensions are low in viscosity before re -disso visional Application No. 62 /083 ,623 , filed Nov . 24 , 2014 , lution ( compared to solutions at the same overall dose ) and and U . S . Provisional Application Ser . No . 62 / 136 , 763 filed thus may be suitable for SC or IM injection , provided the Mar . 23 , 2015 ; U . S . application Ser . No. 14 / 966 ,549 also particles are sufficiently small to fit through the needle . claims the benefit of U . S . Provisional Application No. However, protein crystals that are present in the powder 62/ 245 ,513 , filed Oct . 23 , 2015 ; this application also claims have the inherent risk of triggering immune response. The the benefit of U . S . Provisional Application No . 62 / 245 , 513 , uncertain protein stability / activity following re - dissolution filed Oct . 23 , 2015 . The entire contents of the each of the poses further concerns . There remains a need in the art for above applications are incorporated by reference herein . techniques to produce low viscosity protein formulations for therapeutic purposes while avoiding the limitations intro FIELD OF APPLICATION duced by protein powder suspensions. [ 0002 ] This application relates generally to formulations 10008 ] In addition to the therapeutic applications of pro for delivering biopolymers. teins described above , biopolymers such as enzymes , pep tides , and structural proteins can be used in non - therapeutic applications . These non - therapeutic biopolymers can be BACKGROUND produced from a number of different pathways, for example , [ 0003] Biopolymers may be used for therapeutic or non derived from plant sources , animal sources , or produced therapeutic purposes . Biopolymer -based therapeutics, such from cell cultures . as antibody or enzyme formulations , are widely used in [ 0009 ] The non - therapeutic proteins can be produced , treating disease . Non - therapeutic biopolymers , such as transported , stored , and handled as a granular or powdered enzymes , peptides, and structural proteins , have utility in material or as a solution or dispersion , usually in water . The non - therapeutic applications such as household , nutrition , biopolymers for non - therapeutic applications can be globu commercial , and industrial uses. lar or fibrous proteins , and certain forms of these materials [ 0004 ] Biopolymers used in therapeutic applications must can have limited solubility in water or exhibit high viscosity be formulated to permit their introduction into the body for upon dissolution . These solution properties can present treatment of disease . For example , it is advantageous to challenges to the formulation , handling , storage, pumping , deliver antibody and protein /peptide biopolymer formula and performance of the non - therapeutic materials , so there is tions by subcutaneous (SC ) or intramuscular ( IM ) routes a need for methods to reduce viscosity and improve solu under certain circumstances , instead of administering these bility and stability of non - therapeutic protein solutions . formulations by intravenous ( IV ) injections. In order to achieve better patient compliance and comfort with SC or [0010 ] Proteins are complex biopolymers, each with a IM injection though , the liquid volume in the syringe is uniquely folded 3 - D structure and surface energy map typically limited to 2 to 3 ccs and the viscosity of the (hydrophobic / hydrophilic regions and charges ). In concen formulation is typically lower than about 20 centipoise ( CP ) trated protein solutions , these macromolecules may strongly so that the formulation can be delivered using conventional interact and even inter - lock in complicated ways , depending medical devices and small -bore needles.