|HAO WANAT HA MARIAUS009731026B2 DEL MAR MAN UNIT MINIT (12 ) United States Patent ( 10 ) Patent No. : US 9 ,731 , 026 B2 Su et al. (45 ) Date of Patent: Aug. 15 , 2017 ( 54 ) NEAT LIQUID PHARMACEUTICAL (58 ) Field of Classification Search FORMULATIONS ??? . .. A61K 8 /02 See application file for complete search history . @( 71) Applicant : Massachusetts Institute of Technology , Cambridge, MA (US ) (56 ) References Cited U . S . PATENT DOCUMENTS @( 72 ) Inventors : Erzheng Su , Cambridge, MA (US ) ; Alexander M . Klibanov , Boston , MA 3 , 800 ,038 A 3 / 1974 Rudel ( US ) 5 ,405 ,617 A 4 / 1995 Gowan 7 , 763 ,653 B2 7 / 2010 Pacheco @( 73 ) Assignee : Massachusetts Institute of 2009/ 0004281 Al * 1 / 2009 Nghiem . .. .. .. .. A61K 9 / 0004 Technology , Cambridge , MA (US ) 424 /490 @( * ) Notice : Subject to any disclaimer , the term of this OTHER PUBLICATIONS patent is extended or adjusted under 35 U . S . C . 154 ( b ) by 0 days . Abbott , et al ., “ Novel solvent properties of choline chloride /urea mixtures " , Chem . Commun . , 1 : 70 - 71 ( 2003 ) . Abbott, et al. , “ Ionic liquid analogues formed from hydrated metal ( 21 ) Appl. No. : 14 / 951, 055 salts ” , Chem . , Eur. J . , 10 : 3769 -74 ( 2004 ) . Bica , et al ., “ Liquid forms of pharmaceutical co -crystals : Exploring (22 ) Filed : Nov . 24 , 2015 the boundaries of salt formation ” , Chem Comm ., 47 ( 8 ) : 2267- 9 ( 2011 ) . (65 ) Prior Publication Data Grodowska , et al. , “ Organic solvents in the pharmaceutical indus US 2016 / 0143848 A1 May 26 , 2016 try ” , Acta Polomine Pharma. , 67 ( 1 ) : 3 - 12 (2010 ) . International Search Report for Corresponding PCT/ US2015 / Related U . S . Application Data 062470 mailed Feb . 3 , 2016 . (60 ) Provisional application No .62 / 084 ,095 , filed on Nov. * cited by examiner 25 , 2014 . Primary Examiner — Rei - Tsang Shiao (51 ) Int. Ci. ( 74 ) Attorney , Agent, or Firm — Pabst Patent Group LLP A61K 8 / 02 ( 2006 .01 ) A61K 47 /48 ( 2006 . 01 ) (57 ) ABSTRACT A61K 31 /616 ( 2006 .01 ) Essentially non - aqueous liquid pharmaceutical formulations A61K 47 / 18 ( 2017 . 01) are formed by mixing at least one pharmaceutically active A61K 47 / 26 ( 2006 .01 ) ingredient and at least one other compound capable of A61K 31 /00 ( 2006 . 01) interacting with the active pharmaceutical ingredient A61K 9 / 00 ( 2006 .01 ) through non - covalent interactions to form a low - temperature (52 ) U . S . CI. transition mixture . The stable liquid formulations are readily CPC . .. A61K 47/ 48092 ( 2013 . 01 ) ; A61K 31/ 00 obtained , even with drugs that are poorly soluble and /or ( 2013 .01 ) ; A61K 31/ 616 (2013 .01 ) ; A61K unstable in water . 47186 ( 2013 .01 ) ; A61K 47 /26 ( 2013 .01 ) ; A61K 9 /0019 (2013 . 01) 20 Claims, 1 Drawing Sheet conU . S . Patent sAug . 15 , 2017 US 9 ,731 , 026 B2. * Acetic acid buffer (pH 2 .48 ) ChCI: ASP ( 1 : 2 ) ChCI: ASP :Xyl ( 2 : 1 : 1 ) w . y = 0 .0045x + 3 . 1302 youWill Ô www. ConcentrationofAspirin(mm) y = - 0 .0146x + 3 . 2482 22. twitter - 0 .0406x + 3 . 1003 ? In " o . .. .. oo 20 40 60 80 100 120 140 Time (min ) US 9 ,731 , 026 B2 NEAT LIQUID PHARMACEUTICAL It is a still further object of the invention to provide FORMULATIONS transparent and pharmaceutically elegant liquid formula tions of APIs that can be readily swallowed by a patient . CROSS -REFERENCE TO RELATED APPLICATIONS 5 SUMMARY OF THE INVENTION This application claims benefit of and priority to U . S . Ser. Low - temperature transition mixtures ( " LTTMs” ) (alter No . 62 /084 ,095 filed on Nov . 25, 2014 , which is incorpo - natively called " deep -eutectic solvents ” or “ DESs ” ) formed rated by reference in their entirety . from at least one solid API have been developed . The 10 LTTMs have a melting point that is lower than the melting STATEMENT REGARDING FEDERALLY point of the API by itself and are preferably liquid at room SPONSORED RESEARCH OR DEVELOPMENT temperature . In addition to the API, the LTTMs contain at least one other compound capable of interacting with the This invention was not made with government support. API through non - covalent interactions. Because the LTTMs 15 do not contain water or other diluents , the formulations can FIELD OF THE INVENTION be substantially more concentrated than conventional aque ous or nonaqueous solutions or suspensions. Since the The invention is generally directed to neat ( solvent- less ) LTTMs do not contain essentially any water, the API may liquid compositions of active pharmaceutical ingredients exhibit enhanced stability relative to when it is dissolved in including water sensitive drugs . 20 water. The formulations may be solids, liquids , or solids which are liquified by heating. BACKGROUND OF THE INVENTION BRIEF DESCRIPTION OF THE DRAWINGS Liquid formulations are commonly used to administer active pharmaceutical ingredients. Liquid formulations may 25 FIG . 1 depicts the thermal stability of two binary and be swallowed , injected , or directly applied to a variety of ternary , respectively , LTTMs ( choline chloride :aspirin ( 1 : 2 ) different tissues. Many nasal and ophthalmic products are [ square data points ] and choline chloride : aspirin :xylitol liquid formulations . Liquid formulations for oral adminis ( 2 : 1 : 1 ) ftriangle data points ] ) compared to a conventional tration are especially useful for patients who have difficulty aqueous formulation (aspirin dissolved in acetic acid aque swallowing solid dosage forms. Because liquids can be 30 ous buffer , pH 2 . 5 [ circle data points] ) . easily divided , it is much simpler to partition a liquid formulation into smaller doses than a solid formulation . DETAILED DESCRIPTION OF THE One of the simplest types of liquid formulation is an INVENTION aqueous solution . However , many active pharmaceutical ingredients (“ APIS " ) are not sufficiently soluble in water to 35 I. Definitions form practically useful solutions or those of desirable thera peutic strength . Additionally , many APIs are not stable in As used herein , the term “ active pharmaceutical ingredi aqueous solution , decomposing upon long - term storage ent” (or " API" ) refers to a chemical compound ( or mixture through a variety of pathways . For instance , many ester - of compounds) that causes a change in a biological substrate . group - containing pharmaceuticals , such as aspirin , undergo 40 Exemplary classes of APIs in the medical and biological arts hydrolysis upon prolonged storage in water. Heterocycle - include therapeutic , prophylactic , and diagnostic agents . The containing drugs , such as azacytidine and diazepam , APImay be a small -molecule or macromolecular drug . undergo hydration followed by ring opening . Electrophilic As used herein , the terms “ deep - eutectic solvent" drugs , such as cisplatin , can undergo nucleophilic exchange (“ DES ” ) and “ low - transition temperature mixture ” in the presence of water . Whether due to insufficient solu - 45 (“ LTTM ” ) are used interchangeably to describe liquid com bility , lack of stability , a combination of both , or another positions having at least two components which interact factor , many drugs cannot readily and conveniently , if at all, with each other via non - covalent bonds to form a low be formulated into aqueous solutions . transition -temperature mixture ( or deep - eutectic solvent) , Although organic solvents can be used to solubilize typically transparent and preferably liquid at room tempera certain drugs and minimize water- initiated decomposition , 50 ture , which exhibits a substantially lower melting point than the use of organic solvents is not a practical or desirable the isolated individual components . An eutectic system solution in most pharmaceutical settings . Organic solvents describes a homogeneous mix of chemical species, to form are disfavored on regulatory grounds , due to toxicity , flam - a joint super - lattice, by striking a unique atomic or molecu mability , volatility , or environmental concerns. Furthermore , lar percentage ratio between the components — as each pure many organic solvents have an unpleasant odor or taste . 55 component has its own distinct bulk lattice arrangement. It It is an object of this invention to provide liquid formu - is only in this atomic or molecular ratio that the eutectic lations of APIs , including poorly water- soluble or water system melts as a whole , at a specific temperature ( the sensitive ones, for which the preparation of solutions or eutectic temperature ) , the super -lattice releasing at once all suspensions in water or organic solvents is difficult, unde its components into a liquid mixture . The eutectic tempera sirable , or impossible . 60 ture is the lowest possible melting temperature over all of the It is an object of the present invention to provide liquid mixing ratios for the involved component species . Upon formulations having a high concentration of the API ( S ) , for heating any other mixture ratio and reaching the eutectic example , in order to reduce the dosing size or frequency temperature , one component' s lattice will melt first, while associated with the agent. the temperature of the mixture has to further increase for the It is a further object of the invention to provide liquid 65 other component ' s lattice to melt . Conversely , as a non formulations of APIs having enhanced stability relative to eutectic mixture cools down , each mixture ' s component will aqueous solutions of the active ingredient. solidify ( form its lattice ) at a distinct temperature , until