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|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

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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 all US 9 ,731 ,026 B2 material is solid . The coordinates defining a eutectic point mucic , nitric , tetrafluoroboric , pamoic , pantothenic , phos are the eutectic percentage ratio on the molecular ratio or phoric , succinic , sulfuric , tartaric , p - toluenesulfonic , and the horizontal axis ) and the eutectic temperature (on the tem like . Suitable pharmaceutically acceptable bases include perature or vertical axis ) . inorganic and organic bases , such as sodium hydroxide , As used herein , the term “ non - covalent interactions” 5 potassium hydroxide, lithium hydroxide , calcium hydrox refers to electrostatic bonds , including ionic bonds , dipole ide, magnesium hydroxide, ammonium hydroxide , and dipole interactions, of which hydrogen bonds are a subset , amines . Van der Waals interactions , and /or London forces . As used herein , “ dipole - dipole interactions” refer to II . Deep Eutectic Solvents / Low Temperature attractions between an electropositive and electronegative 10 atoms or groups of atoms. “ Electropositive ” and “ electro Transition Mixtures negative ” describe atoms having lower, or greater electron density , respectively , surrounding the nucleus relative to the A . Solvents and LTTM atom in the elemental state . LTTMs, or DESs, are formed from the combination of The term " essentially water- free ” describes a liquid com - 15 two or more compounds which , when separate , have melting position that contains less than 5 % , less than 4 % , less than points higher than when the components are combined . For 3 % , less than 2 % , less than 1 % , less than 0 .5 % , less than instance, a deep - eutectic solvent is produced by combining 0 . 1 % , and 0 % weight by weight water, as measured using urea (mp = 133° C .) with choline chloride (mp = 302° C . ) in a the Karl Fischer titration method . 2 : 1 molar ratio . The resulting liquid has a melting point of The term “ hydrogen bond ” refers to electrostatic interac - 20 12° C . Chem . Commun . ( 2003 ) 70 -71 ; Chem ., Eur. J . ( 2004 ) tions between an electropositive hydrogen atom and an 10 : 3769 - 3774 . As DESs can be made from environmentally electronegative atom . Electropositive hydrogen atoms occur benign constituents , they have been explored as alternatives when a hydrogen atom is covalently bonded to an electro - to traditional solvents for chemical transformations. negative atom , such as oxygen or nitrogen . Exemplary The LTTMs disclosed herein contain at least two com functional groups having electropositive hydrogen atoms 25 pounds capable of associating with each other through include hydroxyl, oxime, thiol, carboxylic acid , sulfonic non - covalent interactions . In preferred embodiments , the acid , phosphoric acid , primary and secondary amides , pri non - covalent interactions include hydrogen bonds between mary and secondary amines , and imines . the two compounds . In certain embodiments, the LTTM is a Exemplary electronegative atoms capable of interacting binary mixture , and in other embodiments it is a ternary with an electropositive hydrogen via hydrogen -bonding 30 mixture . Higher order mixtures may also be formed . One or include oxygen , nitrogen , and fluorine . more of the compounds in the mixture is a pharmaceutically As used herein , the term “ hydrogen bond acceptor ” refers active agent, so long as it is also a hydrogen bond acceptor to a compound having at least one electronegative atom ( such as oxygen , nitrogen , and fluorine ) capable of interact and /or hydrogen bond donor. Such LTTMsmay also include ing with an electropositive hydrogen atom through a hydro - 35 other agents , such as sweeteners and other taste -masking gen bond . compounds, flavors, fragrances , colorants , and others . As used herein , the term “ hydrogen bond donor ” refers to For LTTMs that contain compounds that interact via a compound having at least one electropositive hydrogen hydrogen bonds, one of the compoundsmust contain at least atom capable of interacting with an electronegative atom one hydrogen bond accepting functional group and the other through a hydrogen bond . 40 compound must contain at least one hydrogen bond donating As used herein , the term “ primary amine ” refers to the functional group . One or more of the compounds in the functional group RNH , , wherein R is a non -hydrogen group mixture may contain both hydrogen bond donating and of atoms, such as alkyl or aryl. As used herein , the term hydrogen bond accepting groups . In some embodiments , one “ secondary amine ” refers to the functional group RR 'NH or more of the compounds in the mixture is taken from the wherein R and R ' are both non -hydrogen groups of atoms, 45 list of compounds identified by the FDA as Generally such as alkyl or aryl. Secondary amines include heterocyclic Recognized as Safe (“ GRAS” ) or contained in the FDA structures such as pyrrolidine and imidazole . The term Inactive - ingredient Guide (“ IIG ” ) . “ tertiary amine” refers to the functional group RR ' R " N , One of the compounds in the LTTM may contain at least wherein R , R ', and R " non - hydrogen atom non -hydrogen one carboxylic group . Exemplary carboxylic group contain groups of atoms, such as alkyl or aryl. Tertiary amines 50 ing compounds include oxalic acid , malonic acid , lactic include heterocyclic structures such as pyridine . acid , maleic acid , fumaric acid , malic acid , tartaric acid , As used herein , the term " primary amide” refers to the citric acid , itaconic acid , benzoic acid , 4 -hydroxybenzoic functional group RC = O )NH2 , wherein R is a non -hydro acid , cinnamic acid , caffeic acid , gallic acid , phenylacetic gen group of atoms, such as alkyl or aryl . acid , succinic acid , coumaric acid , adipic acid , sebacic acid , As used herein , the term “ secondary amine” refers to the 55 decanoic acid , stearic acid , oleic acid , linoleic acid , propi functional group RCZO )NHR ', wherein R and R ' are onic acid , and acetic acid . non -hydrogen group of atoms, such as alkyl or aryl . Sec One of the compounds in the LTTM may contain at least ondary amides include heterocyclic structures such as thy one hydroxyl group . Exemplary compounds having at least mineAs andused guanine herein . the term “ pharmaceutically acceptable 60 one hydroxyl group include ethanol, isopropanol , t -butanol , salts ” refers to salts prepared from pharmaceutically accept butanol, isobutanol , a - isosorbide, glycerol, propylene gly able acids and bases , including inorganic and organic acids col, and resorcinol. and bases . Suitable pharmaceutically acceptable acids One of the compounds in the LTTM may be a sugar. include inorganic and organic acids, such as acetic , benze - Exemplary sugars include glucose , sorbose , ribose , man nesulfonic , benzoic , camphorsulfonic , citric , ethanesulfonic, 65 nose , sucrose , lactose , fructose, fucose , rhamnose, lyxose , fumaric , gluconic , glutamic , hydrobromic , hydrochloric , ribose , arabinose , allose, altrose , gulose, idose , talose , galac isethionic , lactic , maleic , malic , mandelic , methanesulfonic , tose, and xylose . US 9 ,731 , 026 B2 One of the compounds in the LTTM may be a sugar 25, 20 , 15, 10 , or 5 cps, when measured at 25° C . using a alcohol. Exemplary sugar alcohols include glucitol, sorbitol, device such as a calibrated dropper. ribotol, mannitol, fucitol, ribitol, rhamnitol, arabitol , idotol, B . Pharmaceutically Acceptable Agents galactitol, and xylitol. APIs include pharmaceutically acceptable therapeutic , One of the compounds in the LTTM may be an amino 5 prophylactic , and /or diagnostic agents . They can be both acid . Exemplary amino acids include L -enantiomers of prescription and over- the -counter medications . histidine , isoleucine, leucine, lysine, methionine , phenylala Water sensitive APIs may exhibit increased stability when nine , threonine , tryptophan , valine, alanine , arginine , formulated as LTTMs relative to when they are dissolved in asparagine, aspartic acid , cysteine, glutamic acid , glutamine , aqueous solution . For example , the half - life of the agent in glycine , ornithine , proline, selenocysteine , serine, and tyro - a LTTM is often twice , five times , ten times, twenty times or sine . even fifty times or more , greater than that of the API One of the compounds in the LTTM may contain at least dissolved in water . one amide , carbamate , or carbamide group . Exemplary Exemplary APIs for use in LTTMs include non -steroidal compounds include acetamide , urea , 1 , 1 - dimethylurea , 1 , 3 anti- inflammatory drugs , such as aspirin , acetaminophen , dimethylurea , nicotinamide , tetramethylurea , propylene diflunisal, ibuprofen , naproxen , dexibuprofen , fenoprofen , urea , 1 -methylurea , 2 - imidazolidinone , and benzamide . dexketoprofen , flurbiprofen , oxaprozin , loxoprofen , keto One of the compounds in the LTTM may contain at least profen , diclofenac , sulindac , tolmetin , indomethacin , etod one amino group . Exemplary compounds include imidazole , olac , ketorolac , aceclofenac , piroxicam , meloxicam , tenoxi tinicethylamine acid , ,histidine trimethylamine, ( 2 -hydroxyethyl , alanine , glycine) -diethylamine , proline ,, articnico - 20 cam , droxicam , lornoxicam , isoxicam , mefenamic acid , aine , tetracaine , proxymetacaine , metoclopramide , procaine, meclofenamic acid , flufenamic acid , tolfenamic acid , cele lidocaine, cyclomethylcaine , piperocaine , chloroprocaine , coxib , rofecoxib , valdecoxib , parecoxib , lumiracoxib , etori etidocaine , benzocaine , phenylephrine , bupivacaine , mepi coxib , firoxocib , nimesulide, clonixin , licofelone, and phar vacaine, cinchocaine , and pharmaceutically acceptable salts maceutically acceptable salts thereof. thereof. In embodiments in which the LTTMs contain lido 25 The API may be an HMG -CoA reductase inhibitor , such caine , the mixture preferably does not contain a carboxylic as atorvastatin , cerivastatin , fluvastatin , lovastatin , mevas group containing compound , and more preferably does not tatin , pitavastatin , pravastatin , rosuvastatin , simvastatatin , contain acrylic acid or methacrylic acid . and pharmaceutically acceptable salts thereof. In certain embodiments , the LTTMs contain a quaternary z The API may be an opioid -derived analgesic , such as ammonium salt . Exemplary quaternary ammonium com morphine, codeine, diacetylmorphine, buprenorphine, etor pounds include pharmaceutically acceptable salts of tet - phine , hydrocodone , hydromorphone , oxycodone , oxymor raalkyl ammonium compounds , such as tetramethylammo- phone , and pharmaceutically acceptable salts thereof. nium , tetraethylammonium , betaine, choline , The active API may be an antidepressant or antipsychotic , 2 -chlorocholine , 2 -fluorocholine , acetylcholine , and deriva - 36 such as citalopram , escitalopram , paroxetine , fluoxetine , tives thereof. Phosphonium salts can be used as hydrogen fluvoxamine , sertraline, zimelidine , indalpine, desvenlafax bond acceptors. ine , duloxetine , levomilnacipran , milnacipran , tofenacin , In certain embodiments , the low - temperature transition venlafaxine , vilazodone, vortioxetine , etoperidone, tra mixtures may be depicted by the formula : zodone , nefazodone, reboxetine, viloxazine, atomoxetine , 40 amitriptyline, amitriptylinoxide , clomipramine, desipra A : B : C , mine, dibenzepin , dosulepin , doxepin , imipramine , lofe wherein A represents the API, B and C (when C is present) pramine , melitracen , nitroxazepine, nortriptyline , noxipti represent compounds capable of interacting with one of the line , pipofezine, protriptyline , trimipramine , butriptyline , other compounds in the mixture through non - covalent demexiptiline , imipraminoxide , iprindole, metapramine , bonds , and x , y and z are independently selected from any 45 propizepine , quinupramine , opipramol, tianeptine , aminep nunumber from 0 .25 to 5 . tine , tiazesim , amoxapine , maprotiline, mianserin , mirtazap In certain embodiments , z is 0 , B is a quaternary ammo - ine , setiptiline, mianserin , mirtazapine , setiptiline , isocar nium salt , and x is 1 . In other preferred embodiments , B is boxazid , phenelzine , tranylcypromine, benmoxin , a quaternary ammonium salt , x is 1 , and C is an amino acid , iproclozideiproniazid , mebanazine , nialamide , octamoxin , sugar, reduced sugar , or carboxylic group - containing com - 50 pheniprazine , phenoxypropazine, pivhydrazine , safrazine , pound . selegiline, caroxazone , metralindole , moclobemide , pirlin In other preferred embodiments , z is 0 , A is aspirin or d ole , toloxatone, eprobemide, minaprine , agomelatine, acetaminophen , and B is a pharmaceutically acceptable salt amisulpride , buprenorphine , bupropion , ketamine , lurasi of choline, such as choline chloride . In other preferred done , tandospirone , teniloxazine , etryptamine, medifoxam embodiments , A is aspirin , B is a quaternary ammonium salt , 55 ine, metryptamine , nomifensine , oxaflozane, ademetionine , and C is a reduced sugar. oxitriptan , tryptophan , aripiprazole , lurasidone , olanzapine , In certain embodiments , A is not lidocaine . quetiapine , risperidone , ziprasidone , buspirone , lithium , thy The LTTMs are characterized by a melting point that is roxine, triiodothyronine , and pharmaceutically acceptable lower than that of the API. In some embodiments , the LTTM salts thereof. may have a melting point that is less than about 100°, 75°, 60 The API may be an antihistamine , such as acrivastine , 50°, 40°, 35° , 30° , 250, 200, 150, 10°, 50, 0° , - 5° , - 10°, - 15° azelastine , emadastine , epinastine, brompheniramine, car or - 20° C . In some embodiments , the LTTM looks trans - binoxamine, cetirizine, chlorpheniramine , clamastine , parent to a naked eye . cyproheptadine , desloratidine , diphenhydramine , naphazo The LTTMs form liquids having viscosities suitable for line , fexofenadine , hydroxyzine, ketotifen , levociterizine , use in pharmaceutical and other biomedical applications. 65 loratadine , olopatadine , and pharmaceutically acceptable The liquids may have a viscosity less than about 10 , 000 , salts thereof. Montelukast , ipratropium and pharmaceuti 7 ,500 , 5000 , 2 ,500 , 1 ,000 , 750 , 500 , 250, 150, 100 , 75, 50 , cally acceptable salts thereof may also be employed . US 9 ,731 ,026 B2 The API may be mast cell stabilizer, such as cromolyn , IV . Methods of Using Low - Temperature- Transition lodoxamine , nedocromil, pemirolast , and pharmaceutically Mixtures acceptable salts thereof. The API may be a corticosteroid such as cortisone , The LTTMsmay be administered orally , by injection , and dexamethasone , fluticasonse propionate , fluticasone furoate , 5 topically . For oral administration , the mixtures optionally beclomethasone diproprionate , budesonide , ciclesonide , may be encapsulated in a suitable shell, such as those made flunisolide , hydrocortisone , loteprednol, mometasone from gelatin . Because the LTTMs do not require a separate furoate , methylprednisolone, prednisolone , prednisone, tri solvent, the physical size of the dosage form is often much amcinolone acetate , and pharmaceutically acceptable salts smaller than of conventional liquid formulations . Other thereof. 10 The APImay be a proton pump inhibitor , such as omepra " excipients include sweeteners , other taste masking agents, zole , lansoprazole , dexlansoprazole , esomeprazole , panto flavorings, and diluents . prazole , rabeprazole , illaprazole , and pharmaceutically The LTTMs may be administered via injection using acceptable salts thereof. The API may also be a H2- receptor conventional techniques . Since additional solvent is not antagonist, such as cimetidine , ranitidine, and pharmaceuacen - 15 required69 to form the liquid , the volume of fluid administered tically acceptable salts thereof. is typically much less than used in conventional formula The formulation may be a solid , liquid or solid which can be converted to liquid by heating . Liquids may be injectable For topical administration , the low - temperature transition or suspendable or dissolvable to form a dispersion or solu mixtures may be directly applied to the skin , mucosa , eye , tion for oral ingestion , in liquid form or in a soft or hard gel 20 ear , or other relevant tissue , including such modes of admin capsule . Sweeteners, other taste masking agents , flavors , istration as nasal, ocular, buccal , sublingual, anal, vaginal, colorants . In general , pharmaceutical compositions are pro and transdermal . Since the viscosity of the mixture may be vided including effective amounts of the active agent( s) and adjusted by selection of the appropriate components and optionally include pharmaceutically acceptable diluents , compound ratios, the mixture may be designed to adhere preservatives , solubilizers , emulsifiers , adjuvants and / or car - 25 closely to the targeted tissue . By direct application of a riers . Such compositions can include anti -oxidants ( e . g . , highly viscous liquid containing the API , a more concen ascorbic acid , sodium metabisulfite ), and preservatives ( e . g ., trated dose of drug may be administered to the tissue than is Thimersol, benzyl alcohol) and bulking substances ( e . g ., possible with conventional solution and suspension formu lactose , mannitol) . Examples of non - aqueous solvents or lations . Such applications may find use for the local admin vehicles including propylene glycol, polyethylene glycol, 30 istration of APIs to tumors and other discreet tissue targets . vegetable oils , such as olive oil and corn oil , gelatin , and Conversely , application of a low viscosity liquid to tissue injectable organic esters such as ethyl oleate . The formula will result in rapid disbursement of the drug over the entire tions may be lyophilized and redissolved / resuspended surface of the tissue . Such applications may find use in the immediately before use . The formulation may be sterilized application of drugs to surfaces such as those found on the by, for example , filtration through a bacteria retaining filter , 35 eye . by incorporating sterilizing agents into the compositions, by The present invention will be further understood by irradiating the compositions , or by heating the compositions. reference to the following non - limiting examples . III. Methods of Making EXAMPLES Low - Temperature - Transition Mixtures 40 Example 1 The LTTMs may be prepared by combining the individual components , heating the mixture to a temperature sufficient Preparation of Low - Temperature Transition to melt and form the LTTM , and the allowing the mixture to Mixtures cool to room temperature . Temperatures from about 30° C . 45 to about 100° C . are generally sufficient to generate the The following aspirin - containing low temperature transi LTTM . Preferably the temperature is from about 60° C . to tion mixtures were prepared by combining the individual about 100° C . solids in the listed ratios, mixing thoroughly, heating to The LTTM may then be stored at temperatures from about 60 - 100° C . , and cooling to room temperature . The results are - 20° C . to about 37° C . shown in Table 1 . TABLE 1 Summary of studies to prepare aspirin - containing LTTMs Choline Aspirin None 1 : 1 Extremely viscous liquid chloride Choline Aspirin None 1 : 2 Viscous liquid chloride Choline Aspirin None 1 :3 Viscous liquid chloride Choline Aspirin None 2 : 1 Unable to form a liquid OoovauAWN chloride Choline Aspirin None 1 : 2 Unable to form a liquid bitartrate Betaine Aspirin None Viscous liquid L - histidine Aspirin None Unable to form a liquid Glycine Aspirin None ?? Unable to form a liquid L -proline Aspirin None Unable to form a liquid L - glutamic Aspirin None AAAAA Unable to form a liquid US 9 ,731 , 026 B2 9 TABLE 1 - continued Summary of studies to prepare aspirin - containing LTTMs acid D - glucose Aspirin None 1 : 1 Unable to form a liquid 12 Choline Aspirin L - proline 1 : 1 : 1 Viscous liquid chloride 13 Betaine Aspirin L -proline 1 : 1 : 1 Viscous liquid Choline Aspirin D - glucose 1 : 1 : 1 Unable to form a liquid chloride 15a Choline Aspirin Tartaric 1 : 1 : 1 Unable to form a liquid chloride acid 15b Choline Aspirin Tartaric 3 : 1 : 1 Viscous liquid chloride acid 16a Choline Aspirin L -malic 1 : 1 : 1 Unable to form a liquid chloride acid 16b Choline Aspirin L -malic 2 : 1 : 1 Viscous liquid chloride acid 17a Choline Aspirin Citric acid 1 : 1 : 1 Viscous liquid chloride 17b Choline Aspirin Citric acid 2 : 1 : 1 Unable to form a liquid chloride 18a Choline Aspirin Urea 1 : 1 : 1 Unable to form a liquid chloride 18b Choline Aspirin Urea 2 : 1 :1 Viscous liquid chloride 19a Choline Aspirin Glycine 1 : 1 : 1 Unable to form a liquid chloride 95 Choline Aspirin Glycine 2 : 1 : 1 Unable to form a liquid chloride 20 Choline Aspirin D -xylitol 1 : 1 : 1 Liquid chloride Choline Aspirin D -xylitol 2 : 1 : 0 . 5 Unable to form a liquid chloride 2 Choline Aspirin D - xylitol 2 : 1 : 0 .65 Initially a liquid , chloride solidified after 48 hours 23 Choline Aspirin D - xylitol 2 : 1 : 0 .75 Initially a liquid , chloride solidified after 5 days 24 Choline Aspirin D -xylitol 2 : 1 : 1 Liquid chloride 25 Choline Aspirin D - xylitol 2: 1 : 1. 5 Initially a liquid , chloride solidified after 5 days 26 Choline Aspirin D -xylitol 2: 1 : 1. 75 Initially a liquid , chloride solidified after 4 days Choline Aspirin D -xylitol 2 : 1 : 2 Initially a liquid , chloride solidified after 5 hours 28 Choline Aspirin D - xylitol 2 : 1 : 3 Initial liquid , solidified chloride after 24 hours 29 Choline Aspirin D -xylitol 2 : 1 : 4 Initially a liquid , chloride solidified after 24 hours 30 Choline Aspirin D -xylitol 2 : 1 : 5 Initially a liquid , chloride solidified after 24 hours Choline Aspirin D -xylitol Unable to form a liquid chloride 3 :1 : 1 Choline Aspirin D -mannitol 2 : 1: 0 . 25 Unable to form a liquid chloride 333 Choline Aspirin D -mannitol 2 : 1 : 0 .5 Unable to form a liquid chloride 3 4 Choline Aspirin D -mannitol 2 : 1: 0 . 75 Initially a liquid , chloride solidified after 5 days 35 Choline Aspirin D -mannitol 2 :1 : 1 Initially a liquid , chloride crystallized after 11 days 36 Choline Aspirin D -mannitol 2 : 1 : 1 . 25 Unable to form a liquid chloride 3 7 Choline Aspirin D -mannitol 2 :1 : 1. 5 Initially a liquid , chloride solidified after 5 days 38 Choline D -mannitol 2 : 1 : 1 . 75 Initially a liquid , chloride solidified after 5 days 39 Choline Aspirin D -mannitol 2 : 1 : 2 Initially a liquid , chloride solidified after 24 hours Choline Aspirin D -mannitol 2: 1 : 3 Unable to form a liquid chloride 41 Choline Aspirin D -sorbitol 2 : 1 :0 . 5 Unable to form a liquid chloride Choline Aspirin D - sorbitol 2 : 1 : 0 . 65 Initially a liquid , chloride solidified after 3 days Choline Aspirin D -sorbitol 2 : 1: 0 .75 Initially a liquid , chloride solidified after 5 days Choline D - sorbitol 2 : 1 : 1 Initially a liquid , chloride solidified after 12 days 45 Choline Aspirin D - sorbitol 2 :1 : 1 .25 Viscous liquid , began to US 9 ,731 , 026 B2 li TABLE 1 - continued Summary of studies to prepare aspirin - containing LTTMs chloride crystallize after 3 days Choline Aspirin D - sorbitol 2 :1 : 1 . 5 Initially a liquid , chloride solidified after 2 days Choline Aspirin D - sorbitol 2 : 1 : 2 Initially a liquid , chloride solidified after 10 days Choline Aspirin D -sorbitol 2 : 1 : 2 . 25 Initially a liquid , chloride solidified after 3 hours Choline Aspirin D - sorbitol 2 : 1 : 2 . 5 Initially a liquid , chloride solidified after 18 hours Choline Aspirin D -sorbitol 2 : 1 : 3 Initially a liquid , chloride solidified after 4 days

Similar results as in the table above were obtained with 15 .inhibitor , an analgesic , an antidepressant, an antipsychotic , acetaminophen instead of aspirin . an antihistamine , a mast cell stabilizer, a corticosteroid , a proton pump inhibitor , and combinations thereof, non - co Example 2 valently bound to at least one pharmaceutically acceptable 20 excipient, Aspirin Thermal Stability Measurements in LTTMs wherein the LTTM conforms to the stoichiometric for Owing to its relatively unstable ester bond , aspirin can mula : undergo degradation to form salicylic and acetic acids . Low temperature transition mixtures # 2 and 24 from Example 1 Az: B :C , were subjected to further investigation with respect to aspi- - wherein A represents the pharmaceutically active agent; B rin ' s stability . Toward this end , the following procedures and , optionally C , are pharmaceutically acceptable were carried out: excipients capable of interacting with one of the other 1 ) Pretreated 3 - Å molecular sieve beads were added to compounds in the LTTM , including A , through non each LTTM in a vial . Then the vials containing the covalent bonds; and x , y , and z are independently LTTMs were placed in a desiccator under vacuum at 30 selected from any number between about 0 .25 to about room temperature for 24 h . 5 , 2 ) Transfer 3 mL of the dehydrated LTTM to a clean vial wherein the active agent is a hydrogen - bond donor or a containing a stirr bar . hydrogen bond acceptor, 3 ) Glycerol bath was heated to 95° C . 35 wherein the LTTM comprises a hydrogen - bond donor and 4 ) The vial was immersed in the glycerol bath , and the a hydrogen bond acceptor, and LTTM was stirred at 300 rpm until the temperature of wherein the melting point of the LTTM is lower than the the LTTM reached 95° C . melting point of the pharmaceutically acceptable 5 ) The LTTM samples were diluted to an appropriate excipient( s ), and the active agent alone . volume, and their absorbance at 300 nm (the maximum 40 2 . The LTTM of claim 1 , wherein the melting point of the absorption wavelength of salicylic acid ) was measured mixture is less than about 50°, 40° , 35° , 30°, 250 , 200, 150, using a UVN is spectrophotometer. The concentration 10°, 50 , 09, - 5°, - 10° , - 15° or - 20° C . of salicylic acid in the LTTM was calculated using a 3 . The LTTM of claim 1 which is pharmaceutically previously obtained standard curve , and then the acceptable for enteral administration and looks transparent residual concentration of aspirin was calculated using8 45 to a naked eye . the mass balance . 4 . The LTTM of claim 1 , wherein B and C are indepen The results obtained are shown in Table 2 , and FIG . 1 dently selected from the group consisting of a quaternary depicts the disappearance of aspirin over time when the ammonium salt , a phosphonium salt , an amino -containing LTTM mixtures and aqueous solution were heated to 95° C . compound , an amide -containing compound , a carboxylic The decomposition half - lives of the formulations are pre 50 acid - containing compound , and a hydroxyl - containing com sented below . pound . 5 . The LTTM of claim 1 , wherein B is a quaternary TABLE 2 ammonium salt and x is about 1 . Stability of aspirin over time when the LTTM mixtures 6 . The LTTM of claim 1 , wherein B is a quaternary and aqueous solution were heated to 95° C . _ 55 ammonium salt , x is about 1 , and C is selected from the group consisting of an amino acid , a sugar, a sugar alcohol, Formulation Half - life (min ) and a carboxylic group - containing compound . Aspirin in acetic acid buffer (pH 2 .5 ) 41. 2 7 . The LTTM of claim 1 wherein the therapeutic agent is Choline chloride : aspirin ( 1 : 2 ) 418 selected from the group consisting of aspirin , famotidine , Choline chloride: aspirin : xylitol ( 2 : 1 : 1) 106 60 cetirizine , acetaminophen , and ibuprofen . 8 . The LTTM of claim 1 , wherein B is a pharmaceutically acceptable salt of choline . We claim : 9 . The LTTM of claim 8 , wherein the pharmaceutically 1 . An essentially water- free , low - transition - temperature acceptable salt of choline is choline chloride . mixture (LTTM ) comprising at least one pharmaceutically 65 10 . The LTTM of claim 1, wherein A is aspirin or active agent selected from the group consisting of a non - acetaminophen , B is a quaternary ammonium salt , and C is steroidal anti- inflammatory drug , a HMG - CoA reductase a sugar alcohol . US 9 ,731 ,026 B2 13 14 11 . The LTTM of claim 10 , wherein the sugar alcohol is selected from the group consisting of xylitol, glucitol, sor bitol, ribotol, mannitol, fucitol, ribitol, rhamnitol, arabitol, idotol, and galactitol. 12 . The LTTM of claim 1 in a dosage formulation for 5 administration to an individual in need thereof. 13 . The LTTM of claim 12 wherein the dosage formula tion is for administration topically or by inhalation to a mucosal surface . 14 . The LTTM of claim 12 wherein the dosage formula - 10 tion is in a liquid form at room temperature . 15 . The LTTM of claim 12 wherein the dosage formula tion further comprises one or more excipients selected from the group consisting of taste masking agents, stabilizers , antioxidants , colorants , preservatives, and flavorings . 15 16 . A method of making the LTTM of claim 1 , comprising the steps of: a ) combining A , B , and , optionally , C in their solid state ; b ) heating the mixture to a temperature sufficient to melt the solids; and c ) cooling the mixture to ambient temperature to retain a liquid . 17 . The method of claim 16 wherein ambient temperature is between about 18 and 24° C . 18 . A method of delivering at least one active pharma- 25 ceutical compound comprising the step of administering the LTTM of claim 1 to an individual in need thereof. 19 . Themethod of claim 18 wherein the LTTM is admin istered orally , nasally , ocularly, or transdermally . 20 . The method of claim 18 wherein the LTTM is admin - 30 istered by injection . * * * * *