THOUTLULUKUUNTURUS009750810B2 (12 ) United States Patent ( 10 ) Patent No. : US 9 , 750 ,810 B2 Bannister et al. ( 45 ) Date of Patent: * Sep . 5 , 2017
(54 ) COMPOSITIONS AND METHODS FOR A61K 31/ 202 (2006 .01 ) TREATING CHRONIC INFLAMMATION A61K 31 /337 ( 2006 .01 ) AND INFLAMMATORY DISEASES A61K 31 / 704 (2006 .01 ) A61K 31 / 25 ( 2006 . 01) ( 71 ) Applicant: Infirst Healthcare Limited , London (52 ) U . S . Cl. (GB ) ??? . A61K 47 / 14 ( 2013 .01 ) ; A61K 9 / 08 ( 2013 .01 ) ; A61K 9 / 2013 (2013 .01 ) ; A61K ( 72 ) Inventors : Robin M . Bannister , Essex (GB ) ; John 31/ 192 ( 2013 .01 ) ; A61K 31/ 60 ( 2013 .01 ) ; Brew , Hertfordshire (GB ) ; Wilson A61K 47 / 10 ( 2013 .01 ) ; A61K 47 /44 ( 2013 . 01 ) ; Caparros - Wanderely , Buckinghamshire A61K 31 /202 ( 2013 .01 ) ; A6IK 31 / 25 (GB ) ; Suzanne J . Dilly , Oxfordshire ( 2013. 01 ); A61K 31/ 337 (2013 .01 ) ; A61K (GB ); Olga Pleguezeulos Mateo , 31/ 704 (2013 .01 ) (58 ) Field of Classification Search Bicester (GB ) ; Gregory A . Stoloff , CPC . .. A61K 31/ 201 ; A61K 31/ 25 ; A61K 31/ 337 ; London (GB ) A61K 31/ 704 ( 73 ) Assignee : Infirst Healthcare Limited , London USPC .. 514 /557 , 570 (GB ) See application file for complete search history. (56 ) References Cited ( * ) Notice : Subject to any disclaimer, the term of this patent is extended or adjusted under 35 U . S . PATENT DOCUMENTS U . S .C . 154 (b ) by 0 days . 3 ,228 ,831 A 1/ 1966 Nicholson et al. This patent is subject to a terminal dis 3 , 800 , 038 A 3 / 1974 Rudel 4 , 571 ,400 A 2 / 1986 Arnold claimer . 4 ,684 ,666 A 8 / 1987 Haas 4 , 918 , 103 A 4 / 1990 Park et al. (21 ) Appl. No. : 15 /043 , 327 5 ,011 , 852 A 4 / 1991 Park et al . 5 ,059 , 626 A 10 / 1991 Park et al. ( 22 ) Filed : Feb . 12 , 2016 5 ,552 , 160 A 9 / 1996 Liversidge et al . 5 ,645 , 856 A 7 / 1997 Lacy et al. 5 , 955 ,451 A 9 / 1999 Lichtenberger et al . (65 ) Prior Publication Data 6 , 214 , 386 B1 4 / 2001 Santus US 2016 /0158361 A1 Jun . 9 , 2016 6 , 264 , 981 B1 7 /2001 Zhang 6 , 267, 985 B1 7 / 2001 Chen et al. 6 , 294 , 192 B1 . 9 / 2001 Patel et al . Related U .S . Application Data (Continued ) (63 ) Continuation of application No . 14 / 155 ,042 , filed on Jan . 14 , 2014 , now Pat. No. 9 , 271, 950 , which is a FOREIGN PATENT DOCUMENTS continuation - in - part of application No . 13 /365 ,824 , filed on Feb . 3 , 2012 , now Pat. No . 8, 895 ,536 , which CN 1736369 2 /2006 is a continuation - in - part of application No . CN 101129335 A 2 / 2008 PCT/ GB2011 / 052115 , filed on Oct. 31 , 2011 , said ( Continued ) application No. 14 / 155 ,042 is a continuation - in -part of application No . 13 /365 ,828 , filed on Feb . 3 , 2012 , OTHER PUBLICATIONS now Pat . No . 8 , 895 ,537 . Csizmazia , E ., et al. , Penetration enhancer effect of sucrose laurate and Transcutol on ibuprofen , Journal of Drug Delivery Science and (60 ) Provisional application No . 61 /752 ,309 , filed on Feb . Technology, vol. 21 , No . 5 Sep . 2011 XP009168551 . 4 , 2013 , provisional application No . 61/ 752 ,356 , filed Hesson Chung, et al. , Oil Components Modulate Physical Charac on Jan . 14 , 2013 . teristics and Function of the Natural Oil Emulsions as Drug or Gene Delivery System , Journal of Controlled Release 71 : 339 - 350 ( 2001) . (30 ) Foreign Application Priority Data List et al ., Hydrogenation of Soybean Oil Triglycerides: Effect of Pressure on Selectivity . JAOCS (2000 ) , vol. 77, pp . 311 -314 . Oct. 29 , 2010 (GB ) ...... 1018289 .7 PCT International Preliminary Report on Patentability , PCT/ Feb . 4 , 2011 (GB ) ...... 1101937 . 9 GB2011 /050189 , pp . 11 ( Aug . 7 , 2012 ) . Aug . 10 , 2011 (GB ) ...... 1113728 .8 (Continued ) Aug . 10 , 2011 (GB ) ...... 1113729 .6 Aug . 10 , 2011 (GB ) ...... 1113730 .4 Primary Examiner - Kevin E Weddington (74 ) Attorney, Agent, or Firm — One3 IP Management, (51 ) Int. Cl. P . C . ; Dean G . Stathakis ; Peter D . Weinstein A61K 31 / 19 ( 2006 .01 ) (57 ) A61K 47/ 14 ( 2017 .01 ) ABSTRACT A61K 31 / 192 ( 2006 . 01 ) The present specification discloses pharmaceutical compo A61K 9 / 08 ( 2006 . 01 ) sitions, methods of preparing such pharmaceutical compo A61K 4744 ( 2017 . 01 ) sitions, and methods and uses of treating a chronic inflam A61K 9 / 20 ( 2006 .01 ) mation and /or an inflammatory disease in an individual A61K 31/ 60 ( 2006 .01 ) using such pharmaceutical compositions. A61K 47 / 10 ( 2017 .01 ) 20 Claims, 4 Drawing Sheets US 9 , 750 ,810 B2 Page 2
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FIG . 1 Effect of oil / ethanol formulated ibuprofen on H1N1 influenza induced murine survival
Ctrol ORAL
ibuprofen 335 ugo / e ORAL %survivalofmice (BC1054 ) + ibuprofen 335 ug ORAL
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FIG . 4
PBS 1 - Enbrel + Vehicle methylcellulose Pawthickness(mm) O - 40 mg/ kg parent drug - BC1054 vehicle - . - BC1054 20 mg /kg ~ BC1054 30 mg/ kg BGEEEEN
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COMPOSITIONS AND METHODS FOR ings ; and 5 ) increase migration of leukocytes , mainly granu TREATING CHRONIC INFLAMMATION locytes , from the blood vessels into the tissue . An acute AND INFLAMMATORY DISEASES inflammatory response requires constant stimulation to be sustained and must be actively terminated when no longer This continuation claims the benefit of priority and the 5 needed . Hence , acute inflammation ceases once the injurious filing date pursuant to 35 U . S . C . $ 120 to U .S . Non - Provi- stimulus has been removed . sional patent application Ser . No . 14 / 155 ,042 , filed Jan . 14 , 2014 , a continuation - in - part application that claims priority However , severe or prolonged noxious stimulation results to U . S . Non -Provisional patent application Ser . No . 13 /365 , in a chronic inflammatory response that leads to a progres 824 , filed Feb . 3 , 2012 , a continuation - in -part application 10 sive shift in the type of cells present at the site of tissue that claims priority to patent application PCT/ GB2011 / injury . Chronic inflammation may be characterized as the 052115 , filed Oct . 31 , 2011 , an international patent appli simultaneous destruction and healing of tissue from the cation that claims priority to GB patent application inflammatory process, with the net result of provoking 1018289. 7 , filed Oct . 29, 2010 , and claims priority to U . S . injury rather than mediating repair . As such , chronic inflam Non -Provisional patent application Ser . No . 13 / 365, 828, 15 matmation is a disease . As an inflammatory response can occur filed Feb . 3 , 2012 , and claims priority to GB patent appli anywhere in the body , chronic inflammation has been impli cation 1113730 . 4 , filed Aug . 10 , 2011, GB patent application cated in the pathophysiology of a wide range of seemingly 1113729 . 6 , filed Aug . 10 , 2011 , GB patent application unrelated disorders which underlay a large and varied group 1113728 . 8 , filed Aug . 10 , 2011 , and GB patent application of human diseases. For example, chronic inflammation is 1101937 . 9 , filed Feb . 4 , 2011 , and U . S . Non - Provisional 20 involved in diseases as diverse as cardiovascular diseases, patent application Ser . No . 14 / 155, 042 , filed Jan . 14 , 2014 , cancers , allergies , obesity, diabetes , digestive system dis claims priority pursuant to 35 U . S . C . $ 119 ( e ) to U . S . Pro eases , degenerative diseases, auto - immune disorders , and visional Patent Application 61 /752 ,309 , filed Jan . 14 , 2013 , Alzheimer 's disease . and U . S . Provisional Patent Application 61/ 752, 356 , filed Attempts to treat chronic inflammation have met with Jan . 14 , 2013 , each of which is hereby incorporated by 25 limited success. This is due , in part, to the fact that the reference in its entirety . etiology of chronic inflammation is a complex response Inflammation involves the activation of the immune sys based in part on the various inflammation inducing mol tem in response to harmful stimuli , such as , e . g . , a pathogen , ecules and the multitude of inflammation mediating and infection , irritant, or damage to cells . As a stereotyped sensitizing molecules that appear to elicit inflammation via response , inflammation is a mechanism of innate immunity , 30 redundant mechanism . In addition , besides blocking pro as compared to adaptive immunity , which is specific for each inflammatory molecules, many anti- inflammatory drugs , pathogen . Inflammation can be classified as either acute or also inhibit regulatory loops that release endogenous anti chronic. Generally speaking , acute inflammation is mediated inflammatory molecules . For example , NSAIDs reduce by granulocytes, while chronic inflammation is mediated by inflammation by blocking the enzymatic activity of mononuclear cells such as monocytes and lymphocytes. 35 cyclooxygenase , a key enzyme that catalyzes the conversion Acute inflammation is an initial protective response of the of arachidonic acid to prostaglandins and leukotrienes . Thus , body to remove an injurious stimulus by maintaining tissue NSAIDs reduce inflammation by preventing the synthesis of integrity and contributing to tissue repair . It a part of the all prostaglandins . However, NSAIDs not only prevents the body ' s natural defense system against injury and disease, synthesis of proinflammatory prostaglandins, these com and in the absence of acute inflammation , wounds and 40 pounds also prevent the synthesis of anti - inflammatory infections would never heal and progressive destruction of prostaglandins . Hence , NSAIDs have limited success as they the tissue would compromise the survival of the organism . block endogenous anti- inflammatory response, which in The process of acute inflammation is initiated by cells some instances may prolong chronic inflammation . There already present in all tissues, mainly resident macrophages , fore, compounds, compositions, uses, and methods prefer dendritic cells , histiocytes, Kupffer cells , mastocytes, vas - 45 entially inhibiting pro - inflammatory responses would be cular endothelial cells , and vascular smooth muscle cells . At highly desirable for the treatment of chronic inflammation . the onset of a harmful stimulus, these cells undergo activa - The present specification discloses pharmaceutical com tion and release inflammatory mediating and sensitizing positions and methods for treating an individual suffering molecules , such as , e . g ., pro -inflammatory cytokines , pro - from a chronic inflammation . The pharmaceutical compo inflammatory prostaglandins , leukotrienes , histamine , sero - 50 sitions disclosed herein are essentially a lipid delivery tonin , neutral proteases , bradykinin and nitric oxide. These system that enables a therapeutic compound having anti inflammatory molecules modulate a complex series of bio - inflammatory activity to be delivered in a manner that more logical events involving cellular and acellular components effectively inhibits a pro - inflammatory response . The end of the local vascular system , the immune system , and the result is an improved treatment for chronic inflammation . injured tissue site to propagate and mature the inflammatory 55 response . These events are responsible for eliciting an acute SUMMARY inflammatory response, typically characterized by 1 ) vaso dilatation which increases blood flow into the tissue thereby Aspects of the present specification disclose a pharma causing erythema (redness and warmth ) , which may extend ceutical composition comprising a therapeutic compound beyond this site ( the flare response ) ; 2 ) blood vessel perme- 60 and a pharmaceutically -acceptable adjuvant. A therapeutic ability which increases plasma leakage into the tissue compound may have an anti - inflammatory activity . Other thereby causing edema ( swelling ) ; 3 ) alter the excitability of aspects of the present specification disclose a pharmaceuti certain sensory neurons causing hypersensitivity and pain ; cal composition comprising a therapeutic compound dis 4 ) stimulate the release of inflammation inducing molecules closed herein , a pharmaceutically -acceptable solvent, and a such as , e . g ., neuropeptides like substance P ( SP ) and 65 pharmaceutically -acceptable adjuvant. In other aspects , the calcitonin gene -related peptide (CGRP ) , prostaglandins, and pharmaceutical compositions disclosed herein further com amino acids like glutamate , from the peripheral nerve end prise a pharmaceutically -acceptable stabilizing agent. US 9 ,750 ,810 B2 Other aspects of the present specification disclose a effects of a pharmaceutical composition disclosed herein on method of preparing a pharmaceutical composition , the in vivo levels of the Th2 cytokine IL - 4 in the lungs of method comprising the step of contacting a therapeutic surviving mice . BC1054 ORAL =Group A ; Vehicle compound with a pharmaceutically -acceptable adjuvant ORAL = Group B ; and BC1054 Lipid ORAL =Group C . under conditions which allow the formation of the pharma - 5 FIGS . 3A - C shows the effects of a pharmaceutical com ceutical composition . Other aspects of the present specifi- position disclosed herein on in vivo levels of Th2 cytokines cation disclose a method of preparing a pharmaceutical in the lungs of surviving mice . FIG . 3A shows a graph of the composition , the method comprising the steps : a ) contacting effects of a pharmaceutical composition disclosed herein on a pharmaceutically -acceptable solvent with a therapeutic in vivo levels of the Th2 cytokine IL - 10 in the lungs of compound under conditions which allow the therapeutic 10 surviving mice ; FIG . 3B shows a graph of the effects of a compound to dissolve in the pharmaceutically - acceptable pharmaceutical composition disclosed herein on in vivo solvent, thereby forming a solution , wherein the therapeutic levels of the Th2 cytokine TNF - a in the lungs of surviving compound has anti - inflammatory activity , and b ) contacting mice ; and FIG . 3C shows a graph of the effects of a the solution formed in step ( a ) with a pharmaceutically . pharmaceutical composition disclosed herein on in vivo acceptable adjuvant under conditions which allow the for- 15 levels of the Th2 cytokine IFN - y in the lungs of surviving mation of the pharmaceutical composition . In other aspects , mice . BC1054 ORAL = Group A ; Vehicle ORAL = Group B ; the method of preparing disclosed herein further comprises and BC1054 Lipid ORAL = Group C . c ) removing the pharmaceutically -acceptable solvent from FIG . 4 shows the effects of a pharmaceutical composition the pharmaceutical composition . disclosed herein on arthritis using an a - collagen antibody Other aspects of the present specification disclose a 20 induced arthritis ( ACAIA ) murine model . PBS = Group A ; pharmaceutical composition , the pharmaceutical composi - Enbrel =Group B ; Vehicle methylcellulose =Group C ; 40 tion made according to a method comprising the step of mg/ kg parent drug = Group D ; BC1054 vehicle =Group E ; contacting a therapeutic compound with a pharmaceutically - BC1054 20 mg/ kg = Group F ; and BC1054 30 mg/ kg = Group acceptable adjuvant under conditions which allow the for- G . mation of the pharmaceutical composition . Other aspects of 25 the present specification disclose a pharmaceutical compo DESCRIPTION sition , the pharmaceutical composition made according to a method comprising the steps: a ) contacting a pharmaceuti Aspects of the present specification disclose , in part , a cally - acceptable solvent with a therapeutic compound under composition . A composition disclosed herein is generally conditions which allow the therapeutic compound to dis - 30 administered as a pharmaceutical acceptable composition . solve in the pharmaceutically -acceptable solvent, thereby As used herein , the term " pharmaceutically acceptable " forming a solution , wherein the therapeutic compound has refers any molecular entity or composition that does not anti - inflammatory activity , and b ) contacting the solution produce an adverse , allergic or other untoward or unwanted formed in step ( a ) with a pharmaceutically -acceptable adju reaction when administered to an individual. As used herein , vant under conditions which allow the formation of the 35 the term “ pharmaceutically acceptable composition ” is syn pharmaceutical composition . In other aspects , the method of onymous with " pharmaceutical composition ” and means a making a pharmaceutical composition disclosed herein fur - therapeutically effective concentration of an active ingredi ther comprises c ) removing the pharmaceutically - acceptable ent, such as , e . g ., any of the therapeutic compounds dis solvent from the pharmaceutical composition . closed herein . A pharmaceutical composition disclosed Other aspects of the present specification disclose a 40 herein is useful for medical and veterinary applications . A method of treating an individual with a chronic inflamma - pharmaceutical composition may be administered to an tion , the method comprising the step of administering to the individual alone , or in combination with other supplemen individual in need thereof a pharmaceutical composition tary active ingredients , agents , drugs or hormones. disclosed herein , wherein administration results in a reduc - A pharmaceutical composition disclosed herein may tion in a symptom associated with the chronic inflammation , 45 optionally include a pharmaceutically -acceptable carrier that thereby treating the individual. facilitates processing of an active ingredient into pharma Other aspects of the present specification disclose a use of ceutically -acceptable compositions. As used herein , the term a pharmaceutical composition disclosed herein in the manu - " pharmacologically -acceptable carrier” is synonymous with facture of a medicament for the treatment of a chronic " pharmacological carrier” and means any carrier that has inflammation . 50 substantially no long term or permanent detrimental effect Other aspects of the present specification disclose a use of when administered and encompasses terms such as “ phar a pharmaceutical composition disclosed herein for the treat macologically acceptable vehicle , stabilizer , diluent, addi ment of a chronic inflammation . tive , auxiliary or excipient . " Such a carrier generally is mixed with an active compound or permitted to dilute or BRIEF DESCRIPTION OF THE DRAWINGS 55 enclose the active compound and can be a solid , semi- solid , or liquid agent. It is understood that the active ingredients FIG . 1 shows the effects of a pharmaceutical composition can be soluble or can be delivered as a suspension in the disclosed herein on survival against Influenza A / PR / 8 /34 desired carrier or diluent . Any of a variety of pharmaceuti lethal challenge . Ibuprofen 335 ug = Group A ; Ctrol cally acceptable carriers can be used including , without ORAL = Group B ; and ibuprofen 335 ug ole ORAL 60 limitation , aqueous media such as, e . g . , water , saline , gly (BC1054 ) = Group C . cine, hyaluronic acid and the like ; solid carriers such as, e . g ., FIGS . 2A - B shows the effects of a pharmaceutical com mannitol, lactose , starch , magnesium stearate , sodium sac position disclosed herein on in vivo levels of Th2 cytokines charin , talcum , cellulose , glucose , sucrose, magnesium car in the lungs of surviving mice . FIG . 2A shows a graph of the bonate , and the like; solvents ; dispersion media ; coatings ; effects of a pharmaceutical composition disclosed herein on 65 antibacterial and antifungal agents ; isotonic and absorption in vivo levels of the Th2 cytokine IL - 10 in the lungs of delaying agents ; or any other inactive ingredient. Selection surviving mice , whereas FIG . 2B shows a graph of the of a pharmacologically acceptable carrier can depend on the US 9 ,750 ,810 B2 mode of administration . Except insofar as any pharmaco Aspects of the present specification disclose , in part , a logically acceptable carrier is incompatible with the active therapeutic compound . A therapeutic compound is a com ingredient, its use in pharmaceutically acceptable composi- pound that provides pharmacological activity or other direct tions is contemplated . Non - limiting examples of specific effect in the diagnosis , cure , mitigation , treatment, or pre uses of such pharmaceutical carriers can be found in Phar - 5 vention of disease , or to affect the structure or any function maceutical Dosage Forms and Drug Delivery Systems of the body of man or animals . A therapeutic compound (Howard C . Ansel et al. , eds. , Lippincott Williams & Wilkins disclosed herein may be used in the form of a pharmaceu Publishers , 7th ed . 1999 ) ; REMINGTON : THE SCIENCE tically acceptable salt, solvate , or solvate of a salt , e .g . the AND PRACTICE OF PHARMACY (Alfonso R . Gennaro hydrochloride . Additionally , therapeutic compound dis ed . , Lippincott , Williams & Wilkins , 20th ed . 2000 ) ; Good - 10 closed herein may be provided as racemates , or as individual man & Gilman ' s The Pharmacological Basis of Therapeu - enantiomers , including the R - or S - enantiomer. Thus , the tics ( Joel G . Hardman et al. , eds. , McGraw -Hill Profes - therapeutic compound disclosed herein may comprise a sional, 10th ed . 2001) ; and Handbook of Pharmaceutical R -enantiomer only , a S -enantiomer only , or a combination of Excipients (Raymond C . Rowe et al ., APHA Publications, both a R - enantiomer and a S - enantiomer of a therapeutic 4th edition 2003 ). These protocols are routine procedures 15 compound . A therapeutic compound disclosed herein may and any modifications are well within the scope of one have anti - inflammatory activity . skilled in the art and from the teaching herein . In an embodiment, a therapeutic compound disclosed A pharmaceutical composition disclosed herein can herein has an anti - inflammatory activity capable of reducing optionally include , without limitation , other pharmaceuti - the levels of an inflammation inducing molecule . In an cally acceptable components ( or pharmaceutical compo - 20 aspect of this embodiment, a therapeutic compound dis nents ) , including , without limitation , buffers , preservatives , closed herein has an anti - inflammatory activity capable of tonicity adjusters , salts, antioxidants , osmolality adjusting reducing the levels of substance P (SP ) , calcitonin gene agents , physiological substances, pharmacological sub - related peptide ( CGRP ) , glutamate , or a combination stances, bulking agents, emulsifying agents , wetting agents , thereof. In other aspects of this embodiment, a therapeutic sweetening or flavoring agents , and the like . Various buffers 25 compound disclosed herein has an anti -inflammatory activ and means for adjusting pH can be used to prepare a ity capable of reducing the levels of SP , CGRP, glutamate , pharmaceutical composition disclosed herein , provided that or a combination thereof released from a sensory neuron by, the resulting preparation is pharmaceutically acceptable . e . g . , at least 10 % , at least 15 % , at least 20 % , at least 25 % , Such buffers include , without limitation , acetate buffers , at least 30 % , at least 35 % , at least 40 % , at least 45 % , at least citrate buffers , phosphate buffers , neutral buffered saline , 30 50 % , at least 55 % , at least 60 % , at least 65 % , at least 70 % , phosphate buffered saline and borate buffers . It is understood at least 75 % , at least 80 % , at least 85 % , at least 90 % or at that acids or bases can be used to adjust the pH of a least 95 % . In yet other aspects of this embodiment, a composition as needed . Pharmaceutically acceptable anti- therapeutic compound disclosed herein has an anti - inflam oxidants include , without limitation , sodium metabisulfite , matory activity capable of reducing the levels of SP , CGRP, sodium thiosulfate , acetylcysteine , butylated hydroxyani - 35 glutamate , or a combination thereof released from a sensory sole and butylated hydroxytoluene . Useful preservatives neuron in a range from , e . g ., about 10 % to about 100 % , include , without limitation , benzalkonium chloride , chlo - about 20 % to about 100 % , about 30 % to about 100 % , about robutanol, thimerosal , phenylmercuric acetate , phenylmer - 40 % to about 100 % , about 50 % to about 100 % , about 60 % curic nitrate , a stabilized oxy chloro composition and chel - to about 100 % , about 70 % to about 100 % , about 80 % to ants , such as, e . g ., DTPA or DTPA -bisamide , calcium 40 about 100 % , about 10 % to about 90 % , about 20 % to about DTPA , and CaNaDTPA -bisamide . Tonicity adjustors useful 90 % , about 30 % to about 90 % , about 40 % to about 90 % , in a pharmaceutical composition include, without limitation , about 50 % to about 90 % , about 60 % to about 90 % , about salts such as, e . g . , sodium chloride , potassium chloride, 70 % to about 90 % , about 10 % to about 80 % , about 20 % to mannitol or glycerin and other pharmaceutically acceptable about 80 % , about 30 % to about 80 % , about 40 % to about tonicity adjustor. The pharmaceutical composition may be 45 80 % , about 50 % to about 80 % , or about60 % to about 80 % , provided as a salt and can be formed with many acids, about 10 % to about 70 % , about 20 % to about 70 % , about including but not limited to , hydrochloric , sulfuric , acetic , 30 % to about 70 % , about 40 % to about 70 % , or about 50 % lactic , tartaric , malic , succinic , etc . Salts tend to be more to about 70 % . soluble in aqueous or other protonic solvents than are the Prostaglandinsmediate a local inflammatory response and corresponding free base forms. It is understood that these 50 are involved in all inflammatory functions through action on and other substances known in the art of pharmacology can prostaglandin receptors and mediate inflammatory signaling be included in a pharmaceutical composition . including chemotaxis (macrophages , neutrophils and In one embodiment, a pharmaceutical composition dis - eosinophils ) , vasodilation and algesia . However , the PG closed herein comprises a therapeutic compound having mediated inflammatory response is self - limiting ( resolving ) . anti - inflammatory activity and a pharmaceutically -accept - 55 The principle resolution factor is a prostaglandin called able adjuvant. In another embodiment, a pharmaceutical 150PGJ2 , which is an endogenous agonist of peroxisome composition disclosed herein comprises a therapeutic com - proliferator- activator receptor gamma (PPAR - y ) signaling . pound having anti- inflammatory activity , a pharmaceuti- PPARy signaling pathway 1 ) induces apoptosis of Macro cally - acceptable solvent, and a pharmaceutically - acceptable phage M1 cells , thereby reducing the levels of Th1 pro adjuvant. In aspects of this embodiment, a pharmaceutical 60 inflammatory cytokines and 2 ) promotes differentiation of composition disclosed herein may further comprise a phar- monocytes into Macrophage M2 cells .Macrophage M2 cells maceutically - acceptable stabilizing agent. In other aspects produce and release Th2 anti - inflammatory cytokines . of this embodiment, a pharmaceutical composition disclosed In an embodiment, a therapeutic compound disclosed herein may further comprise a pharmaceutically -acceptable herein has an anti- inflammatory activity capable of reducing carrier , a pharmaceutically -acceptable component, or both 65 the levels of an inflammation inducing prostaglandin . In pharmaceutically -acceptable carrier and pharmaceutically other aspects of this embodiment, a therapeutic compound acceptable component. disclosed herein has an anti - inflammatory activity capable of US 9 , 750 ,810 B2 reducing the levels of a inflammation inducing prostaglandin lating all PPAR signaling pathways. Such a therapeutic released from a sensory neuron by , e . g ., at least 10 % , at least compound includes a PPAR pan - agonist. In other embodi 15 % , at least 20 % , at least 25 % , at least 30 % , at least 35 % , ments , a therapeutic compound disclosed herein has an at least 40 % , at least 45 % , at least 50 % , at least 55 % , at least anti - inflammatory activity capable of stimulating one or two 60 % , at least 65 % , at least 70 % , at least 75 % , at least 80 % , 5 of the PPAR signaling pathways . Such a therapeutic com at least 85 % , at least 90 % or at least 95 % . In yet other pound includes a selective PPAR agonist. aspects of this embodiment, a therapeutic compound dis - In another embodiment, a therapeutic compound dis closed herein has an anti - inflammatory activity capable of closed herein has an anti - inflammatory activity capable of reducing the levels of a inflammation inducing prostaglandin stimulating a PPAR - a signaling pathway . In aspects of this released from a sensory neuron in a range from , e . g . , about 10 embodiment , a therapeutic compound disclosed herein 10 % to about 100 % , about 20 % to about 100 % , about 30 % stimulates a PPAR - a signaling pathway by , e . g . , at least 5 % , to about 100 % , about 40 % to about 100 % , about 50 % to at least 15 % , at least 25 % , at least 50 % , at least 60 % , at least about 100 % , about 60 % to about 100 % , about 70 % to about 70 % , at least 80 % , or at least 90 % . In other aspects of this 100 % , about 80 % to about 100 % , about 10 % to about 90 % , embodiment, a therapeutic compound disclosed herein about 20 % to about 90 % , about 30 % to about 90 % , about 15 stimulates a PPAR - a signaling pathway in a range from , 40 % to about 90 % , about 50 % to about 90 % , about 60 % to e . g . , about 5 % to about 100 % , about 50 % to about 100 % , about 90 % , about 70 % to about 90 % , about 10 % to about about 60 % to about 100 % , about 70 % to about 100 % , about 80 % , about 20 % to about 80 % , about 30 % to about 80 % , 80 % to about 100 % , about 25 % to about 90 % , about 50 % to about 40 % to about 80 % , about 50 % to about 80 % , or about about 90 % , about 60 % to about 90 % , about 70 % to about 60 % to about 80 % , about 10 % to about 70 % , about 20 % to 20 90 % , about 80 % to about 90 % , about 25 % to about 80 % , about 70 % , about 30 % to about 70 % , about 40 % to about about 50 % to about 80 % , about 60 % to about 80 % , about 70 % , or about 50 % to about 70 % . 70 % to about 80 % , about 25 % to about 70 % , about 50 % to In another embodiment , a therapeutic compound dis - about 70 % , about 25 % to about 60 % , about 50 % to about closed herein has an anti - inflammatory activity substantially 60 % , or about 25 % to about 50 % . similar to 150PGJ2 . In aspects of this embodiment, a thera - 25 In another embodiment, a therapeutic compound dis peutic compound disclosed herein an anti - inflammatory closed herein has an anti- inflammatory activity capable of activity that is , e . g ., at least 5 % , at least 15 % , at least 25 % , stimulating a PPAR - S signaling pathway . In aspects of this at least 50 % , at least 55 % , at least 60 % , at least 65 % , at least embodiment , a therapeutic compound disclosed herein 70 % , at least 75 % , at least 80 % , at least 85 % , at least 90 % stimulates a PPAR - S signaling pathway by , e . g ., at least 5 % , or at least 95 % of the activity observed for 150PGJ2 . In 30 at least 15 % , at least 25 % , at least 50 % , at least 60 % , at least other aspects of this embodiment, a therapeutic compound 70 % , at least 80 % , or at least 90 % . In other aspects of this disclosed herein an anti - inflammatory activity that is in a embodiment, a therapeutic compound disclosed herein range from , e . g . , about 5 % to about 100 % , about 50 % to stimulates a PPAR - d signaling pathway in a range from , e . g . , about 100 % , about 60 % to about 100 % , about 70 % to about about 5 % to about 100 % , about 50 % to about 100 % , about 100 % , about 80 % to about 100 % , about 25 % to about 90 % , 35 60 % to about 100 % , about 70 % to about 100 % , about 80 % about 50 % to about 90 % , about 60 % to about 90 % , about to about 100 % , about 25 % to about 90 % , about 50 % to about 70 % to about 90 % , about 80 % to about 90 % , about 25 % to 90 % , about 60 % to about 90 % , about 70 % to about 90 % , about 80 % , about 50 % to about 80 % , about 60 % to about about 80 % to about 90 % , about 25 % to about 80 % , about 80 % , about 70 % to about 80 % , about 25 % to about 70 % , 50 % to about 80 % , about 60 % to about 80 % , about 70 % to about 50 % to about 70 % , about 25 % to about 60 % , about 40 about 80 % , about 25 % to about 70 % , about 50 % to about 50 % to about 60 % , or about 25 % to about 50 % of the 70 % , about 25 % to about 60 % , about 50 % to about 60 % , or activity observed for 15dPGJ2 . about 25 % to about 50 % . The peroxisome proliferator- activated receptors (PPARs ) In another embodiment, a therapeutic compound dis are a group of nuclear receptor proteins that function as closed herein has an anti - inflammatory activity capable of transcription factors regulating the expression of genes . All 45 stimulating a PPARy signaling pathway . A therapeutic com PPARs are known to heterodimerize with the retinoid X pounds disclosed herein may be capable of binding to all receptor (RXR ) and bind to specific regions on the DNA of isoforms of PPAR - y , or may be capable of selectively target genes called peroxisome proliferator hormone binding to either PPAR - y1 , PPAR -y2 , PPAR - 3 , or any response elements ( PPREs ) . PPARs play essential roles in combination of two thereof. In aspects of this embodiment, the regulation of cellular differentiation , development , and 50 a therapeutic compound disclosed herein stimulates a metabolism ( carbohydrate , lipid , protein ), and tumorigen - PPARy signaling pathway by, e . g ., at least 5 % , at least 15 % , esis of higher organisms. The family comprises three mem - at least 25 % , at least 50 % , at least 60 % , at least 70 % , at least bers, PPAR - Q , PPAR -y , and PPAR -d (also known as PPAR 80 % , or at least 90 % . In other aspects of this embodiment, B ) . PPAR - a is expressed in liver , kidney , heart , muscle , a therapeutic compound disclosed herein stimulates a adipose tissue , as well as other tissues . PPAR - O is expressed 55 PPARy signaling pathway in a range from , e . g . , about 5 % to in many tissues but markedly in brain , adipose tissue , and about 100 % , about 50 % to about 100 % , about 60 % to about skin . PPAR - y comprises three alternatively - spliced forms, 100 % , about 70 % to about 100 % , about 80 % to about 100 % , each with a different expression pattern . PPAR -yl is about 25 % to about 90 % , about 50 % to about 90 % , about expressed in virtually all tissues , including heart , muscle , 60 % to about 90 % , about 70 % to about 90 % , about 80 % to colon , kidney, pancreas, and spleen . PPAR - y2 is expressed 60 about 90 % , about 25 % to about 80 % , about 50 % to about mainly in adipose tissue. PPAR - y3 is expressed in macro 80 % , about 60 % to about 80 % , about 70 % to about 80 % , phages , large intestine, and white adipose tissue . Endog about 25 % to about 70 % , about 50 % to about 70 % , about enous ligands for the PPARs include free fatty acids and 25 % to about 60 % , about 50 % to about 60 % , or about 25 % eicosanoids. PPAR - y is activated by PGJ2 ( a prostaglandin ), to about 50 % . whereas PPAR - a is activated by leukotriene B4 . 65 Macrophages are activated and polarized into distinct In an embodiment, a therapeutic compound disclosed phenotypes expressing unique cell surface molecules and herein has an anti - inflammatory activity capable of stimu - secreting discrete sets of cytokines and chemokines . The US 9 ,750 ,810 B2 10 classical M1 phenotype supports pro - inflammatory Th1 100 % , about 50 % to about 100 % , about 60 % to about 100 % , responses driven by cytokines such as, e. g . , Interleukin - 6 about 70 % to about 100 % , about 80 % to about 100 % , about ( IL - 6 ) , IL - 12 and IL - 23 , while the alternate M2 phenotype 10 % to about 90 % , about 20 % to about 90 % , about 30 % to is generally supportive of anti - inflammatory processes about 90 % , about 40 % to about 90 % , about 50 % to about driven by IL - 10 . M2 cells can be further classified into 5 90 % , about 60 % to about 90 % , about 70 % to about 90 % , subsets , M2a , M2b , and M2c , based on the type of stimu - about 10 % to about 80 % , about 20 % to about 80 % , about lation and the subsequent expression of surface molecules 30 % to about 80 % , about 40 % to about 80 % , about 50 % to and cytokines . about 80 % , or about 60 % to about 80 % , about 10 % to about In yet another embodiment, a therapeutic compound 70 % , about 20 % to about 70 % , about 30 % to about 70 % , disclosed herein has an anti - inflammatory activity capable of 10 about 40 % to about 70 % , or about 50 % to about 70 % . promoting the resolving phenotypic change ofM1 to M2. In In another aspect of this embodiment, a therapeutic com an aspect of this embodiment, a therapeutic compound pound disclosed herein has an anti - inflammatory activity disclosed herein has an anti- inflammatory activity capable of capable of reducing the levels of IFNY, TNF - a , IL - 12 , or a inducing apoptosis of Macrophage M1 cells. In another combination thereof released from a Thl cell and increasing aspect of this embodiment, a therapeutic compound dis - 15 the levels of IL - 10 released from a Th2 cell. In other aspects closed herein has an anti - inflammatory activity capable of of this embodiment , a therapeutic compound disclosed promoting differentiation of Macrophage M2 cells . In yet herein has an anti - inflammatory activity capable of reducing another aspect of this embodiment, a therapeutic compound the levels of IFNY, TNF - a , IL - 12 , or a combination thereof disclosed herein has an anti - inflammatory activity capable of released from a Thl cell by, e . g ., at least 10 % , at least 15 % , inducing apoptosis of Macrophage M1 cells and promoting 20 at least 20 % , at least 25 % , at least 30 % , at least 35 % , at least differentiation of Macrophage M2 cells . 40 % , at least 45 % , at least 50 % , at least 55 % , at least 60 % , In still another embodiment, a therapeutic compound at least 65 % , at least 70 % , at least 75 % , at least 80 % , at least disclosed herein has an anti - inflammatory activity capable of 85 % , at least 90 % or at least 95 % , and capable of increasing modulating Th1 and Th2 cytokines . In an aspect of this the levels of IL - 10 released from a Th2 cell by, e . g . , at least embodiment, a therapeutic compound disclosed herein has 25 10 % , at least 15 % , at least 20 % , at least 25 % , at least 30 % , an anti - inflammatory activity capable of reducing the levels at least 35 % , at least 40 % , at least 45 % , at least 50 % , at least of Interferon - gamma ( IFNY) , Tumor necrosis factor- alpha 55 % , at least 60 % , at least 65 % , at least 70 % , at least 75 % , ( TNF - a ) , Interleukin - 12 ( IL - 12 ) , or a combination thereof at least 80 % , at least 85 % , at least 90 % or at least 95 % . In released from a Th1 cell . In other aspects of this embodi- yet other aspects of this embodiment, a therapeutic com ment, a therapeutic compound disclosed herein has an 30 pound disclosed herein has an anti - inflammatory activity anti - inflammatory activity capable of reducing the levels of capable of reducing the levels of IFNY, TNF - a , IL - 12 , or a IFNY, TNF - a , IL - 12 , or a combination thereof released from combination thereof released from a Th1 cell in a range a Th1 cell by , e . g . , at least 10 % , at least 20 % , at least 30 % , from , e . g . , about 5 % to about 100 % , about 10 % to about at least 40 % , at least 50 % , at least 60 % , at least 70 % , at least 100 % , about 20 % to about 100 % , about 30 % to about 100 % , 80 % , or at least 90 % . In yet other aspects of this embodi- 35 about 40 % to about 100 % , about 50 % to about 100 % , about ment, a therapeutic compound disclosed herein has an 60 % to about 100 % , about 70 % to about 100 % , about 80 % anti- inflammatory activity capable of reducing the levels of to about 100 % , about 10 % to about 90 % , about 20 % to about IFNy, TNF - a , IL - 12 , or a combination thereof released from 90 % , about 30 % to about 90 % , about 40 % to about 90 % , a Thl cell in a range from , e . g . , about 5 % to about 100 % , about 50 % to about 90 % , about 60 % to about 90 % , about about 10 % to about 100 % , about 20 % to about 100 % , about 40 70 % to about 90 % , about 10 % to about 80 % , about 20 % to 30 % to about 100 % , about 40 % to about 100 % , about 50 % about 80 % , about 30 % to about 80 % , about 40 % to about to about 100 % , about 60 % to about 100 % , about 70 % to 80 % , about 50 % to about 80 % , or about 60 % to about 80 % , about 100 % , about 80 % to about 100 % , about 10 % to about about 10 % to about 70 % , about 20 % to about 70 % , about 90 % , about 20 % to about 90 % , about 30 % to about 90 % , 30 % to about 70 % , about 40 % to about 70 % , or about 50 % about 40 % to about 90 % , about 50 % to about 90 % , about 45 to about 70 % , and capable of increasing the levels of IL - 10 60 % to about 90 % , about 70 % to about 90 % , about 10 % to released from a Th2 cell in a range from , e . g ., about 10 % to about 80 % , about 20 % to about 80 % , about 30 % to about about 100 % , about 20 % to about 100 % , about 30 % to about 80 % , about 40 % to about 80 % , about 50 % to about 80 % , or 100 % , about 40 % to about 100 % , about 50 % to about 100 % , about 60 % to about 80 % , about 10 % to about 70 % , about about 60 % to about 100 % , about 70 % to about 100 % , about 20 % to about 70 % , about 30 % to about 70 % , about 40 % to 50 80 % to about 100 % , about 10 % to about 90 % , about 20 % to about 70 % , or about 50 % to about 70 % . about 90 % , about 30 % to about 90 % , about 40 % to about In another aspect of this embodiment, a therapeutic com 90 % , about 50 % to about 90 % , about 60 % to about 90 % , pound disclosed herein has an anti - inflammatory activity about 70 % to about 90 % , about 10 % to about 80 % , about capable of increasing the levels of IL - 10 released from a Th2 20 % to about 80 % , about 30 % to about 80 % , about 40 % to cell. In other aspects of this embodiment, a therapeutic 55 about 80 % , about 50 % to about 80 % , or about 60 % to about compound disclosed herein has an anti - inflammatory activ 80 % , about 10 % to about 70 % , about 20 % to about 70 % , ity capable of increasing the levels of IL - 10 released from a about 30 % to about 70 % , about 40 % to about 70 % , or about Th2 cell by, e. g ., at least 10 % , at least 15 % , at least 20 % , at 50 % to about 70 % . least 25 % , at least 30 % , at least 35 % , at least 40 % , at least A therapeutic compound disclosed herein may have a log 45 % , at least 50 % , at least 55 % , at least 60 % , at least 65 % , 60 P value indicating that the compound is soluble in an organic at least 70 % , at least 75 % , at least 80 % , at least 85 % , at least solvent. As used herein , the term “ log P value ” refers to the 90 % or at least 95 % . In yet other aspects of this embodi- logarithm (base 10 ) of the partition coefficient ( P ) for a ment, a therapeutic compound disclosed herein has an compound and is a measure of lipophilicity . Typically , P is anti - inflammatory activity capable of increasing the levels of defined as the ratio of concentrations of a unionized com IL - 10 released from a Th2 cell in a range from , e . g . , about 65 pound in the two phases of a mixture of two immiscible 5 % to about 100 % , about 10 % to about 100 % , about 20 % to solvents at equilibrium . Thus , log P = Log 10 ( P ) , where about 100 % , about 30 % to about 100 % , about 40 % to about P = [ solute in immiscible solvent 1 ] / [ solute in immiscible US 9 ,750 ,810 B2 12 solvent 2 ]. With regard to organic and aqueous phases , the nm ?, between 2 . 0 nm² and 6 .0 nm ? , between 2 .0 nm ? and 5 . 5 log P value of a compound is constant for any given pair of nm ?, between 2. 0 nm² and 5 .0 nm ? , between 2. 0 nm² and 4 . 5 aqueous and organic solvents , and its value can be deter - nm ? , between 2. 5 nm² and 6 .5 nm ?, between 2 .5 nm² and 6 . 0 mined empirically by one of several phase- partitioning nm ? , between 2. 5 nm² and 5 .5 nm ?, between 2 .5 nm² and 5. 0 methods known to one skilled in the art including , e . g . , a 5 nm " , or between 2 . 5 nm - and 4 . 5 nm - . shake flask assay, a HPLC assay , and an interface between A therapeutic compound disclosed herein may be a non two immiscible electrolyte solutions (ITIES ) assay. steroidal anti - inflammatory drug (NSAID ) . NSAIDs are a In aspects of this embodiment , a therapeutic compound large group of therapeutic compounds with analgesic , anti disclosed herein may have a log P value indicating that the inflammatory , and anti - pyretic properties . NSAIDs reduce compound is substantially soluble in an organic solvent. In 10 inflammation by blocking cyclooxygenase . NSAIDs aspects of this embodiment, a therapeutic compound dis - include , without limitation , Aceclofenac , Acemetacin , Act closed herein may have a log P value indicating that the arit , Alcofenac , Alminoprofen , Amfenac, Aloxipirin , compound is , e . g . , at least 50 % soluble in an organic solvent , Aminophenazone , Antraphenine , Aspirin , Azapropazone , at least 60 % soluble in an organic solvent, at least 70 % Benorilate , Benoxaprofen , Benzydamine , Butibufen , Cele soluble in an organic solvent, at least 80 % soluble in an 15 coxib , Chlorthenoxacin , Choline Salicylate , Clometacin , organic solvent, or at least 90 % soluble in an organic Dexketoprofen , Diclofenac , Diflunisal, Emorfazone, Epir solvent. In aspects of this embodiment, a therapeutic com - izole ; Etodolac , Etoricoxib , Feclobuzone , Felbinac , Fen pound disclosed herein may have a log P value indicating bufen , Fenclofenac , Flurbiprofen , Glafenine , Hydroxylethyl that the compound is between , e . g ., about 50 % to about salicylate , Ibuprofen , Indometacin , Indoprofen , Ketoprofen , 100 % soluble in an organic solvent, about 60 % to about 20 Ketorolac , Lactyl phenetidin , Loxoprofen , Lumiracoxib , 100 % soluble in an organic solvent, about 70 % to about Mefenamic acid , Meloxicam , Metamizole , Metiazinic acid , 100 % soluble in an organic solvent, about 80 % to about Mofebutazone ,Mofezolac , Nabumetone , Naproxen , Nifena 100 % soluble in an organic solvent, or about 90 % to about zone , Niflumic acid , Oxametacin , Phenacetin , Pipebuzone , 100 % soluble in an organic solvent. Pranoprofen , Propyphenazone , Proquazone , Protizinic acid , In aspects of this embodiment, a therapeutic compound 25 Rofecoxib , Salicylamide , Salsalate , Sulindac , Suprofen , disclosed herein may have a log P value of, e . g . , more than Tiaramide, Tinoridine, Tolfenamic acid , Valdecoxib , and 1. 1 , more than 1 . 2 , more than 1 . 4 , more than 1 . 6 , more than Zomepirac . 1. 8 , more than 2 . 0 , more than 2 .2 , more than 2 . 4 , more than NSAIDsmay be classified based on their chemical struc 2 . 6 , more than 2 . 8 , more than 3 . 0 , more than 3 . 2 , more than ture or mechanism of action . Non - limiting examples of 3 .4 , or more than 3 . 6 . In other aspects of this embodiment, 30 NSAIDs include a salicylate derivative NSAID , a p -amino a therapeutic compound disclosed herein may have a log P phenol derivative NSAID , a propionic acid derivative value in the range of, e .g . , between 1 . 8 and 4 . 0 , between 2 . 0 NSAID , an acetic acid derivative NSAID , an enolic acid and 4 . 0 , between 2 . 1 and 4 . 0 , between 2 . 2 and 4 . 0 , or derivative NSAID , a fenamic acid derivative NSAID , a between 2 . 3 and 4 . 0 , between 2 . 4 and 4 .0 , between 2 . 5 and non - selective cyclo - oxygenase (COX ) inhibitor, a selective 4 .0 , between 2 . 6 and 4 . 0 , or between 2 . 8 and 4 . 0 . In other 35 cyclooxygenase 1 (COX 1 ) inhibitor, and a selective aspects of this embodiment, a therapeutic compound dis - cyclooxygenase 2 (COX 2 ) inhibitor. A NSAID may be a closed herein may have a log P value in the range of, e . g ., profen . Examples of a suitable salicylate derivative NSAID between 3 . 0 and 4 . 0 , or between 3 . 1 and 4 . 0 , between 3 . 2 include, without limitation , Acetylsalicylic acid ( asprin ) , and 4 . 0 , between 3 . 3 and 4 .0 , between 3 . 4 and 4 . 0 , between Diflunisal, and Salsalate . Examples of a suitable p - amino 3 . 5 and 4 . 0 , or between 3 .6 and 4 . 0 . In still other aspects of 40 phenol derivative NSAID include , without limitation , Par this embodiment, a therapeutic compound disclosed herein acetamol and Phenacetin . Examples of a suitable propionic may have a log P value in the range of , e . g . , between 2 . 0 and acid derivative NSAID include , without limitation , Almino 2 . 5 , between 2 . 0 and 2 . 7 , between 2 . 0 and 3 . 0 , or between profen , Benoxaprofen , Dexketoprofen , Fenoprofen , Flurbi 2 .2 and 2 .5 . profen , Ibuprofen , Indoprofen , Ketoprofen , Loxoprofen , A therapeutic compound disclosed herein may have a 45 Naproxen , Oxaprozin , Pranoprofen , and Suprofen . polar surface area that is hydrophobic . As used herein , the Examples of a suitable acetic acid derivative NSAID term “ polar surface area ” refers to the surface sum over all include , without limitation , Aceclofenac, Acemetacin , Act of the polar atoms in the structure of a compound and is a arit , Alcofenac , Amfenac , Clometacin , Diclofenac , Etod measure of hydrophobicity. Typically , these polar atoms olac , Felbinac , Fenclofenac , Indometacin , Ketorolac , Meti include , e . g . , oxygen , nitrogen , and their attached hydro - 50 azinic acid , Mofezolac, Nabumetone , Naproxen , gens . In aspects of this embodiment, a therapeutic com - Oxametacin , Sulindac , and Zomepirac . Examples of a suit pound disclosed herein may have a polar surface area of, able enolic acid (Oxicam ) derivative NSAID include , with e . g. , less than 8 .0 nm ?, less than 7 .0 nm ?, less than 6 . 0 nm ?, out limitation , Droxicam , Isoxicam , Lornoxicam , Meloxi less than 5 . 0 nm , less than 4 . 0 nm², or less than 3 . 0 nm2. In cam , Piroxicam , and Tenoxicam . Examples of a suitable other aspects of this embodiment, a therapeutic compound 55 fenamic acid derivative NSAID include, without limitation , disclosed herein may have a polar surface area in the range Flufenamic acid , Mefenamic acid , Meclofenamic acid , and of, e . g . , between 3 .0 nm² and 6 . 5 nm ? , between 3 . 0 nm2 and Tolfenamic acid . Examples of a suitable selective COX - 2 6 . 0 nm ? , between 3 . 0 nm² and 5 . 5 nm², between 3 . 0 nm² and inhibitors include , without limitation , Celecoxib , Etoricoxib , 5 . 0 nm², between 3 . 0 nm - and 4 . 5 nm ? , between 3 . 5 nm and Firocoxib , Lumiracoxib , Meloxicam , Parecoxib , Rofecoxib , 6 . 5 nm ? , between 3 . 5 nm² and 6 . 0 nm ? , between 3 . 5 nm² and 60 and Valdecoxib . 5 . 5 nm ? , between 3 . 5 nm² and 5 . 0 nm ? , between 3 . 5 nm2 and A therapeutic compound disclosed herein may be a 4 . 5 nm², between 4 . 0 nm² and 6 . 5 nm , between 4 . 0 nm ? and PPARy agonist. Examples of a suitable PPARy agonist 6 .0 nm ? , between 4 . 0 nm2 and 5 . 5 nm ? , or between 4 . 0 nm include , without limitation , Benzbromarone , a cannabidiol, and 5 . 0 nm , between 4 . 0 nm2 and 4 . 5 nm , or between 4 . 5 Cilostazol, Curcumin , Delta ( 9 ) - tetrahydrocannabinol, gly nm² and 5 . 5 nm² . In yet other aspects of this embodiment, 65 cyrrhetinic acid , Indomethacin , Irbesartan , Monascin ,myco a therapeutic compound disclosed herein may have a polar phenolic acid , Resveratrol, 6 - shogaol, Telmisartan , a thiazo surface area in the range of, e. g. , between 2 .0 nm² and 6 . 5 lidinedione like Rosiglitazone, Pioglitazone , and US 9 ,750 ,810 B2 13 14 Troglitazone , a NSAID , and a fibrate. Other suitable PPARY HDL in blood . Examples of a suitable niacin include , agonists are described in Masson and Caumont- Bertrand , without limitation , acipimox , niacin , nicotinamide , and vita PPAR Agonist Compounds, Preparation and Uses , US 2011 / min B3 . 0195993, which is hereby incorporated by reference in its A therapeutic compound disclosed herein may be a bile entirety . 5 acid sequestrant. Bile acid sequestrants ( also known as A therapeutic compound disclosed herein may be a resins ) are a class of therapeutic compounds used to bind nuclear receptor binding agent. Examples of a suitable certain components of bile in the gastrointestinal tract. They nuclear receptor binding agent include , without limitation , a disrupt the enterohepatic circulation of bile acids by seques Retinoic Acid Receptor ( RAR ) binding agent, a Retinoid X tering them and preventing their reabsorption from the gut. Receptor (RXR ) binding agent, a Liver X Receptor (LXR ) 10 Bile acid sequestrants are particularly effective for lowering binding agent and a Vitamin D binding agent. LDL and cholesterol by sequestering the cholesterol- con A therapeutic compound disclosed herein may be an taining bile acids released into the intestine and preventing anti -hyperlipidemic agent. There are several classes of anti their reabsorption from the intestine . In addition , a bile acid hyperlipidemic agents (also known as hypolipidemic sequestrant may also raise HDL levels . Examples of a agents ) . They may differ in both their impact on the cho - 15 suitable bile acid sequestrant include , without limitation , lesterol profile and adverse effects. For example , somemay Cholestyramine, Colesevelam , and Colestipol. lower low density lipoprotein (LDL ) , while others may A therapeutic compound disclosed herein may be a cho preferentially increase high density lipoprotein (HDL ) . lesterol absorption inhibitor. Cholesterol absorption inhibi Clinically , the choice of an agent will depend on the cho tors are a class of therapeutic compounds that inhibits the lesterol profile of an individual, cardiovascular risk of an 20 absorption of cholesterol from the intestine . Decreased cho individual, and /or the liver and kidney functions of an lesterol absorption leads to an upregulation of LDL - recep individual. Examples of a suitable anti- hyperlipidemic agent tors on the surface of cells and an increased LDL -cholesterol include , without limitation , a fibrate , a statin , a tocotrienol, uptake into these cells , thus decreasing levels of LDL in the a niacin , a bile acid sequestrants ( resin ) , a cholesterol blood plasma. Examples of a suitable cholesterol absorption absorption inhibitor, a pancreatic lipase inhibitor, and a 25 inhibitor include , without limitation , Ezetimibe, a phytos sympathomimetic amine . terol, a sterol and a stanol. A therapeutic compound disclosed herein may be a therapeutic compound disclosed herein may be a fat fibrate . Fibrates are a class of amphipathic carboxylic acids absorption inhibitor . Fat absorption inhibitors are a class of with lipid level modifying properties . These therapeutic therapeutic compounds that inhibits the absorption of fat compounds are used for a range of metabolic disorders . One 30 from the intestine . Decreased fat absorption reduces caloric non - limiting use is as an anti -hyperlipidemic agent where it intake . In one aspect, a fat absorption inhibitor inhibits may lower levels of, e . g . , triglycerides and LDL as well as pancreatic lipase, an enzyme that breaks down triglycerides increase levels of HDL . Examples of a suitable fibrate in the intestine . Examples of a suitable fat absorption include , without limitation , Bezafibrate , Ciprofibrate , Clo - inhibitor include , without limitation , Orlistat. fibrate , Gemfibrozil, and Fenofibrate . 35 A therapeutic compound disclosed herein may be a sym A therapeutic compound disclosed herein may be a statin . pathomimetic amine. Sympathomimetic amines are a class Statins ( or HMG - CoA reductase inhibitors) are a class of of therapeutic compounds that mimic the effects of trans therapeutic compounds used to lower LDL and / or choles - mitter substances of the sympathetic nervous system such as terol levels by inhibiting the enzyme HMG - CoA reductase , catecholamines , epinephrine ( adrenaline ), norepinephrine which plays a central role in the production of cholesterol in 40 (noradrenaline ) , and/ or dopamine . A sympathomimetic the liver . To compensate for the decreased cholesterol avail amine may act as an a - adrenergic agonist, a ß -adrenergic ability , synthesis of hepatic LDL receptors is increased , agonist , a dopaminergic agonist, a monoamine oxidase resulting in an increased clearance of LDL particles from the (MAO ) inhibitor, and a COMT inhibitor . Such therapeutic blood . Examples of a suitable statin include , without limi- compounds, among other things, are used to treat cardiac tation , Atorvastatin , Fluvastatin , Lovastatin , Pitavastatin , 45 arrest, low blood pressure , or even delay premature labor. Pravastatin , Rosuvastatin , and Simvastatin . Examples of a suitable sympathomimetic amine include , A therapeutic compound disclosed herein may be a tocot- without limitation , Clenbuterol, Salbutamol, ephedrine , rienol. Tocotrienols are another class of HMG - CoA reduc - pseudoephedrine, methamphetamine , amphetamine, phe tase inhibitors and may be used to lower LDL and /or nylephrine , isoproterenol, dobutamine , methylphenidate , cholesterol levels by inducing hepatic LDL receptor up - 50 lisdexamfetamine , cathine , cathinone , methcathinone , regulation and /or decreasing plasma LDL levels . Examples cocaine , benzylpiperazine (BZP ) , methylenedioxypyrovale of a suitable tocotrienol include, without limitation , a y -to - rone (MDPV ) , 4 -methylaminorex , pemoline , phenmetra cotrienol and a d -tocotrienol . zine , and propylhexedrine . A therapeutic compound disclosed herein may be a niacin . A therapeutic compound disclosed herein may be an ester Niacins are a class of therapeutic compounds with lipid level 55 of a therapeutic compound . An ester of a therapeutic com modifying properties . For example , a niacin may lower LDL pound increases the log P value relative to the same thera by selectively inhibiting hepatic diacyglycerol acyltrans - peutic compound , but without the ester modification . An ferase 2 , reduce triglyceride synthesis , and VLDL secretion ester group may be attached to a therapeutic compound by, through a receptor HM74 and HM74A or GPR109A . These e. g. , a carboxylic acid or hydroxyl functional group present therapeutic compounds are used for a range of metabolic 60 of the therapeutic compound . An ester of a therapeutic disorders . One non - limiting use is as an anti- hyperlipidemic compound may have an increased hydrophobicity , and as agent where it may inhibit the breakdown of fats in adipose such , may be dissolved in a reduced volume of solvent tissue . Because a niacin blocks the breakdown of fats , it disclosed herein . In some instances , an ester of a therapeutic causes a decrease in free fatty acids in the blood and , as a compound may be combined directly with an adjuvant consequence , decreases the secretion of very - low - density 65 disclosed herein , thereby eliminating the need of a solvent. lipoproteins (VLDL ) and cholesterol by the liver. By low - An ester of a therapeutic compound may enable the making ering VLDL levels , a niacin may also increase the level of of a pharmaceutical composition disclosed herein , in situa US 9 ,750 ,810 B2 15 16 tions where a non - esterified form of the same therapeutic ( DMF ) , acetonitrile (MeCN ) , dimethyl sulfoxide (DMSO ) . compound is otherwise immiscible in a solvent disclosed pharmaceutically - acceptable polar protic solvent includes , herein . An ester of a therapeutic compound may still be without limitation , acetic acid , formic acid , ethanol, n -bu delivered in a manner that more effectively inhibits a pro tantanol , 1 -butanol , 2 -butanol , isobutanol, sec -butanol , tert inflammatory response as long as the compound is combined 5 butanol, n - propanol, isopropanol, 1 , 2 propan - diol, methanol, with an adjuvant disclosed herein . In one embodiment, a glycerol, and water. A pharmaceutically -acceptable non therapeutic compound may be reacted with ethyl ester in polar solvent includes, without limitation , pentane , cyclo order to form an ethyl ester of the therapeutic compound pentane, hexane , cyclohexane , benzene , toluene , 1 , 4 -Diox In another embodiment, a pharmaceutical composition ane , chloroform , n -methyl -pyrrilidone (NMP ) , and diethyl disclosed herein does not comprise a pharmaceutically - 10 ether. acceptable solvent disclosed herein . In an aspect of this Apharmaceutical composition disclosed herein may com embodiment, a pharmaceutical composition comprises a prise a solvent in an amount sufficient to dissolve a thera therapeutic compound and a pharmaceutically -acceptable peutic compound disclosed herein . In other aspects of this adjuvant, but does not comprise a pharmaceutically - accept- embodiment, a pharmaceutical composition disclosed herein able solvent disclosed herein . 15 may comprise a solvent in an amount of, e . g . , less than about Apharmaceutical composition disclosed herein may com - 90 % ( v / v ), less than about 80 % ( v / v ), less than about 70 % prise a therapeutic compound in an amount sufficient to (v / v ) , less than about 65 % ( v / v ), less than about 60 % ( v / v ) , allow customary administration to an individual. In aspects less than about 55 % ( v / v ), less than about 50 % ( v / v ) , less of this embodiment, a pharmaceutical composition disclosed than about 45 % ( v / v ) , less than about 40 % ( v / v ), less than herein may be, e . g ., at least 5 mg, at least 10 mg, at least 15 20 about 35 % ( v / v ), less than about 30 % ( v / v ) , less than about mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 25 % ( v / v ), less than about 20 % ( v / v ) , less than about 15 % mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 ( v / v ) , less than about 10 % ( v / v ) , less than about 5 % ( v / v ) , or mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 less than about 1 % ( v / v ). In other aspects of this embodi mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 ment, a pharmaceutical composition disclosed herein may mg , or at least 100 mg of a therapeutic compound . In other 25 comprise a solvent in an amount in a range of, e . g . , about 1 % aspects of this embodiment, a pharmaceutical composition ( v / v ) to 90 % ( v / v ) , about 1 % ( v / v ) to 70 % ( v / v ) , about 1 % disclosed herein may be , e. g ., at least 5 mg, at least 10 mg, ( v / v ) to 60 % ( v / v ) , about 1 % ( v / v ) to 50 % ( v / v ) , about 1 % at least 20 mg, at least 25 mg, at least 50 mg, at least 75 mg, (v /v ) to 40 % ( v /v ), about 1 % ( v /v ) to 30 % ( v /v ), about 1 % at least 100 mg, at least 200 mg, at least 300 mg, at least 400 ( v / v ) to 20 % ( v / v ) , about 1 % ( v / v ) to 10 % ( v / v ) , about 2 % mg, at least 500 mg, at least 600 mg, at least 700 mg, at least 30 (v /v ) to 50 % ( v / v ), about 2 % ( v /v ) to 40 % ( v /v ), about 2 % 800 mg, at least 900 mg, at least 1 , 000 mg, at least 1 , 100 mg, ( v / v ) to 30 % ( v / v ) , about 2 % ( v / v ) to 20 % ( v / v ) , about 2 % at least 1 , 200 mg, at least 1, 300 mg, at least 1 , 400 mg , or at ( v / v ) to 10 % ( v / v ) , about 4 % ( v / v ) to 50 % ( v / v ), about 4 % least 1 , 500 mg of a therapeutic compound . In yet other ( v / v ) to 40 % ( v / v ) , about 4 % ( v / v ) to 30 % ( v / v ) , about 4 % aspects of this embodiment, a pharmaceutical composition ( v / v ) to 20 % ( v / v ) , about 4 % ( v / v ) to 10 % ( v / v ) , about 6 % disclosed herein may be in the range of, e .g . , about 5 mg to 35 ( v / v ) to 50 % ( v / v ) , about 6 % ( v / v ) to 40 % ( v / v ) , about 6 % about 100 mg, about 10 mg to about 100 mg, about 50 mg ( v / v ) to 30 % ( v / v ) , about 6 % ( v / v ) to 20 % ( v / v ) , about 6 % to about 150 mg, about 100 mg to about 250 mg, about 150 ( v / v ) to 10 % ( v / v ) , about 8 % ( v / v ) to 50 % ( v / v ) , about 8 % mg to about 350 mg, about 250 mg to about 500 mg, about ( v / v ) to 40 % ( v / v ) , about 8 % ( v / v ) to 30 % ( v / v ) , about 8 % 350 mg to about 600 mg, about 500 mg to about 750 mg, ( v / v ) to 20 % ( v / v ) , about 8 % ( v / v ) to 15 % ( v / v ) , or about 8 % about 600 mg to about 900 mg, about 750 mg to about 1 ,000 40 ( v / v ) to 12 % ( v / v ) . mg, about 850 mg to about 1 ,200 mg, or about 1 , 000 mg to In one embodiment, a solvent may comprise a pharma about 1 , 500 mg. In still other aspects of this embodiment, a ceutically -acceptable alcohol. As used herein , the term pharmaceutical composition disclosed herein may be in the “ alcohol” refers to an organic molecule comprising a range of, e . g ., about 10 mg to about 250 mg, about 10 mg hydroxyl functional group ( OH ) bond to a carbon atom , to about 500 mg, about 10 mg to about 750 mg, about 10 mg 45 where the carbon atom is saturated . In aspects of this to about 1 , 000 mg, about 10 mg to about 1, 500 mg, about 50 embodiment, the alcohol may be , e .g ., a C2- 4 alcohol, a C , . 4 mg to about 250 mg, about 50 mg to about 500 mg, about alcohol, a C1- 5 alcohol, a C1- alcohol, a C1- 10 alcohol, a 50 mg to about 750 mg, about 50 mg to about 1 , 000 mg, C1- 15 alcohol, or a C1- 20 alcohol. In other aspects of this about 50 mg to about 1 ,500 mg, about 100 mg to about 250 embodiment , an alcohol may be , e . g . , a primary alcohol , a mg, about 100 mg to about 500 mg , about 100 mg to about 50 secondary alcohol, or a tertiary alcohol. In other aspects of 750 mg, about 100 mg to about 1 ,000 mg, about 100 mg to this embodiment, an alcohol may be , e . g . , an acyclic alcohol, about 1 ,500 mg, about 200 mg to about 500 mg, about 200 a monohydric alcohol, a polyhydric alcohol (also known as mg to about 750 mg, about 200 mg to about 1 ,000 mg, about a polyol or sugar alcohol) , an unsaturated aliphatic alcohol , 200 mg to about 1 , 500 mg, about 5 mg to about 1 , 500 mg, an alicyclic alcohol, or a combination thereof. Examples of about 5 mg to about 1, 000 mg, or about 5 mg to about 250 55 a monohydric alcohol include, without limitation , methanol, mg . ethanol, propanol, butanol , pentanol, and 1 -hexadecanol . Aspects of the present specification disclose , in part , a Examples of a polyhydric alcohol include, without limita pharmaceutically -acceptable solvent. A solvent is a liquid , tion , glycol, glycerol, arabitol, erythritol, xylitol, maltitol, solid , or gas that dissolves another solid , liquid , or gaseous sorbitol (gluctiol ) , mannitol, inositol, lactitol, galactitol ( idi the solute ), resulting in a solution . Solvents useful in the 60 tol) , and isomalt. Examples of an unsaturated aliphatic pharmaceutical compositions disclosed herein include, with alcohol include , without limitation , prop - 2 -ene - 1 -ol , 3 , 7 out limitation , a pharmaceutically - acceptable polar aprotic dimethylocta - 2 , 6 -dien - 1 - ol, and prop - 2 - in - 1 - ol. Examples solvent, a pharmaceutically - acceptable polar protic solvent of an alicyclic alcohol include, without limitation , cyclo and a pharmaceutically -acceptable non -polar solvent. A hexane -1 , 2, 3 ,4 ,5 , 6 -hexol and 2 -( 2 -propyl ) - 5 -methyl -cyclo pharmaceutically -acceptable polar aprotic solvent includes , 65 hexane - 1 -ol . without limitation , dichloromethane (DCM ) , tetrahydro - In another embodiment, a solvent may comprise an ester furan ( THF ), ethyl acetate , acetone , dimethylformamide of pharmaceutically -acceptable alcohol and an acid . Suitable US 9 , 750 ,810 B2 17 18 pharmaceutically - acceptable alcohols include the ones dis whereas PEG polymers of a higher molecular mass are closed herein . Suitable acids include , without limitation , solids. A PEG polymer include , without limitation , PEG acetic acid , butaric acid , and formic acid . An ester of an 100 , PEG 200 , PEG 300 , PEG 400 , PEG 500 , PEG 600 , alcohol and an acid include , without limitation , methyl PEG 700 , PEG 800 , PEG 900 , PEG 1000 , PEG 1100 , PEG acetate , methyl buterate, methyl formate , ethyl acetate , ethyl 5 1200 , PEG 1300 , PEG 1400 , PEG 1500 , PEG 1600 , PEG buterate , ethyl formate, propyl acetate , propyl buterate , 1700 , PEG 1800 , PEG 1900 , PEG 2000 , PEG 2100 , PEG propyl formate , butyl acetate , butyl buterate , butyl formate, 2200 , PEG 2300 , PEG 2400 , PEG 2500 , PEG 2600 , PEG isobutyl acetate , isobutyl buterate , isobutyl formate , pentyl 2700 , PEG 2800 , PEG 2900 , PEG 3000 , PEG 3250 , PEG acetate , pentyl buterate , pentyl formate , and 1 -hexadecyl 3350 , PEG 3500 , PEG 3750 , PEG 4000 , PEG 4250 , PEG acetate , 1 -hexadecyl buterate , and 1 - hexadecyl formate. 10 4500 , PEG 4750 , PEG 5000 , PEG 5500 , PEG 6000 , PEG In another embodiment, a solvent may comprise a phar - 6500 , PEG 7000 , PEG 7500 , PEG 8000 , PEG 8500 , PEG maceutically - acceptable glycol ether. Glycol ethers are a 9000 , PEG 9500 , PEG 10 ,000 , PEG 11 ,000 , PEG 12 , 000 , group of solvents based on alkyl ethers of ethylene glycol. PEG 13 ,000 , PEG 14 ,000 , PEG 15 ,000 , PEG 16 ,000 , PEG Non - limiting examples include diethylene glycol monom - 17, 000 , PEG 18 , 000 , PEG 19 ,000 , or PEG 20, 000 . ethyl ether (2 - (2 -methoxyethoxy )ethanol ) , diethylene glycol 15 In another embodiment, a solvent may comprise a phar monoethyl ether ( 2 - ( 2 - ethoxyethoxy Jethanol) , diethylene maceutically - acceptable glyceride . Glycerides comprise a glycol monopropyl ether ( 2 - ( 2 - propoxyethoxy ) ethanol) , substituted glycerol , where one , two , or all three hydroxyl diethylene glycol monoisopropyl ether (2 - ( 2 - isopropoxy - groups of the glycerol are each esterified using a fatty acid ethoxy ) ethanol) , and diethylene glycol mono - n -butyl ether to produce monoglycerides , diglycerides, and triglycerides , ( 2 -( 2 -butoxyethoxy ) ethanol) . Diethylene glycol monoethyl 20 respectively . In these compounds, each hydroxyl groups of ether ( 2 - ( 2 - ethoxyethoxy Jethanol) is commercially available glycerolmay be esterified by different fatty acids . Addition as TRANSCUTOL® . ally , glycerides may be acetylated to produce acetylated In another embodiment, a solvent may comprise a phar - monoglycerides , acetylated diglycerides , and acetylated tri maceutically - acceptable diol. A diol or double alcohol is a glycerides . chemical compound containing two hydroxyl groups (- OH 25 In one embodiment, a solvent may comprise a pharma groups ) . ceutically -acceptable solid solvent. Solid solvents may be In another embodiment , a solvent may comprise a phar - useful in the manufacture of a solid dose formulation of a maceutically - acceptable propylene glycol. Propylene gly pharmaceutical composition disclosed herein . Typically , a col , also called 1 , 2 - propanediol or propane - 1 , 2 - diol , is an solid solvent is melted in order to dissolve a therapeutic organic compound with formula C H20 , or HO - CH , - 30 compound . A pharmaceutically -acceptable solid solvent CHOH - CHZ. includes , without limitation , menthol and PEG polymers In another embodiment , a solvent may comprise a phar- above about 20 , 000 g /mol . maceutically - acceptable dipropylene glycol. Dipropylene Aspects of the present specification disclose , in part , a glycol is a mixture of three isomeric chemical compounds, pharmaceutically - acceptable adjuvant. An adjuvant is a 4 - oxa - 2 , 6 -heptandiol , 2 - ( 2 -Hydroxy - propoxy ) - propan - 1 - ol, 35 pharmacological agent that modifies the effect of other and 2 - ( 2 -Hydroxy - 1 -methyl - ethoxy ) - propan - 1 - ol. agents , such as , e .g ., a therapeutic compound disclosed In another embodiment, a solvent may comprise a phar - herein . In addition , an adjuvant disclosed herein may be maceutically - acceptable polypropylene glycol ( PPG ) poly - used as a solvent that dissolves a therapeutic compound mer . PPG polymers polymers , also known as polypropylene disclosed herein , forming a adjuvant solution . An adjuvant oxide (PPO ) polymers or polyoxypropylene (POP ) poly - 40 disclosed herein facilitates delivery of a therapeutic com mers , are prepared by polymerization of propylene oxide pound in a manner that more effectively inhibits a pro and are commercially available over a wide range of inflammatory response . In one embodiment, an adjuvant molecular weights from 100 g/ mol to 10 ,000 ,000 g /mol . disclosed herein facilitates the delivery of a therapeutic PPG polymers with a low molecular mass are liquids or compound disclosed herein into macrophages. low -melting solids, whereas PPG polymers of a higher 45 pharmaceutical composition disclosed herein may com molecular mass are solids. A PPG polymer include , without prise a pharmaceutically - acceptable adjuvant in an amount limitation , PPG 100 , PPG 200 , PPG 300 , PPG 400 , PPG sufficient to mix with a solution disclosed herein or an 500 , PPG 600 , PPG 700 , PPG 800 , PPG 900 , PPG 1000 , emulsion disclosed herein . In other aspects of this embodi PPG 1100 , PPG 1200 , PPG 1300 , PPG 1400 , PPG 1500 , ment, a pharmaceutical composition disclosed herein may PPG 1600 , PPG 1700 , PPG 1800 , PPG 1900 , PPG 2000 , 50 comprise an adjuvant in an amount of, e . g . , at least 10 % PPG 2100 , PPG 2200 , PPG 2300 , PPG 2400 , PPG 2500 , (v / v ) , at least 20 % ( v / v ) , at least 30 % ( v / v ), at least 35 % PPG 2600 , PPG 2700 , PPG 2800 , PPG 2900 , PPG 3000 , ( v / v ), at least 40 % ( v / v ), at least 45 % ( v / v ), at least 50 % PPG 3250 , PPG 3350 , PPG 3500 , PPG 3750 , PPG 4000 , (v / v ) , at least 55 % ( v /v ), at least 60 % (v / v ), at least 65 % PPG 4250 , PPG 4500 , PPG 4750 , PPG 5000 , PPG 5500 , ( v / v ) , at least 70 % ( v / v ) , at least 75 % ( v / v ) , at least 80 % PPG 6000 , PPG 6500 , PPG 7000 , PPG 7500 , PPG 8000 , 55 (v /v ), at least 85 % (v / v ), at least 90 % ( v / v ), at least 95 % PPG 8500 , PPG 9000 , PPG 9500 , PPG 10 , 000 , PPG 11, 000 , ( v / v ) , or at least 99 % ( v / v ) . In other aspects of this embodi PPG 12 ,000 , PPG 13 ,000 , PPG 14 ,000 , PPG 15 ,000 , PPG ment, a pharmaceutical composition disclosed herein may 16 ,000 , PPG 17, 000 , PPG 18 ,000 , PPG 19, 000 , or PPG comprise an adjuvant in an amount in a range of, e. g ., about 20 , 000 . 30 % ( v / v ) to about 99 % ( v /v ) , about 35 % ( v / v ) to about 99 % In another embodiment, a solvent may comprise a phar - 60 ( v / v ) , about 40 % ( v / v ) to about 99 % ( v / v ) , about 45 % ( v / v ) maceutically - acceptable polyethylene glycol (PEG ) poly - to about 99 % ( v / v ), about 50 % ( v / v ) to about 99 % ( v / v ) , mer. PEG polymers , also known as polyethylene oxide about 30 % (v / v ) to about 98 % ( v /v ), about 35 % ( v /v ) to ( PEO ) polymers or polyoxyethylene (POE ) polymers , are about 98 % ( v /v ), about 40 % ( v /v ) to about 98 % ( v /v ) , about prepared by polymerization of ethylene oxide and are com - 45 % ( v /v ) to about 98 % ( v / v ), about 50 % (v /v ) to about 98 % mercially available over a wide range of molecular weights 65 ( v / v ) , about 30 % ( v / v ) to about 95 % ( v / v ) , about 35 % ( v / v ) from 100 g /mol to 10 , 000 , 000 g /mol . PEG polymers with a to about 95 % ( v / v ) , about 40 % ( v / v ) to about 95 % ( v / v ) , low molecular mass are liquids or low -melting solids, about 45 % (v / v ) to about 95 % (v /v ) , or about 50 % ( v /v ) to US 9 ,750 ,810 B2 19 20 about 95 % ( v / v ). In yet other aspects of this embodiment, a ( 20 : 1 ) , Dihomo- y - linolenic acid ( 20 : 3 ) , Mead acid (20 : 3 ) , pharmaceutical composition disclosed herein may comprise Arachidonic acid (20 : 4 ) , Eicosapentaenoic acid ( 20 : 5 ) , an adjuvant in an amount in a range of, e . g . , about 70 % ( v / v ) Heneicosylic acid (21 :0 ) , Behenic acid (22 : 0 ) , Erucic acid to about 97 % ( v / v ) , about 75 % ( v / v ) to about 97 % ( v / v ) , (22 : 1) , Docosahexaenoic acid (22 : 6 ), Tricosylic acid ( 23 : 0 ) , about 80 % ( v / v ) to about 97 % ( v / v ), about 85 % ( v / v ) to 5 Lignoceric acid (24 : 0 ) , Nervonic acid ( 24 : 1 ) , Pentacosylic about 97 % ( v / v ) , about 88 % ( v / v ) to about 97 % ( v / v ) , about acid ( 25 : 0 ) , Cerotic acid ( 26 : 0 ) , Heptacosylic acid ( 27 : 0 ) , 89 % ( v / v ) to about 97 % ( v / v ) , about 90 % ( v / v ) to about 97 % Montanic acid ( 28 : 0 ) , Nonacosylic acid (29 : 0 ) , Melissic acid ( v / v ) , about 75 % ( v / v ) to about 96 % ( v / v ) , about 80 % ( v / v ) to about 96 % ( v / v ) , about 85 % ( v / v ) to about 96 % ( v / v ) , ( 30 :0 ) , Henatriacontylic acid (31 :0 ) , Lacceroic acid (32 : 0 ), about 88 % ( v / v ) to about 96 % ( v / v ), about 89 % ( v / v ) to 10 Psyllic acid ( 33 : 0 ) , Geddic acid (34 : 0 ) , Ceroplastic acid about 96 % ( v / v ) , about 90 % ( v / v ) to about 96 % ( v / v ), about (35 :0 ), and Hexatriacontylic acid (36 : 0 ). 75 % ( v /v ) to about 93 % ( v / v ) , about 80 % ( v / v ) to about 93 % A lipid useful in the pharmaceutical compositions dis ( v /v ), about 85 % ( v / v ) to about 93 % ( v /v ), about 88 % (v / v ) closed herein may be a pharmaceutically -acceptable par to about 93 % ( v / v ), about 89 % ( v / v ) to about 93 % ( v / v ) , or tially hydrogenated lipid . The process of hydrogenation adds about 90 % ( v / v ) to about 93 % ( v / v ) . 15 hydrogen atoms to unsaturated lipid , eliminating double In one embodiment, an adjuvant may be a pharmaceuti bonds and making them into partially or completely satu cally -acceptable lipid . A lipid may be broadly defined as a rated lipid . Partial hydrogenation is a chemical rather than hydrophobic or amphiphilic small molecule . The amphiphi- enzymatic , that converts a part of cis -isomers into trans lic nature of some lipids allows them to form structures such unsaturated lipids instead of hydrogenating them com as vesicles , liposomes, or membranes in an aqueous envi - 20 pletely . In the first reaction step , one hydrogen is added , with ronment. Non - limiting examples, of lipids include fatty the other, coordinatively unsaturated , carbon being attached acids , glycerolipids ( like monoglycerides, diglycerides, and to the catalyst . The second step is the addition of hydrogen triglycerides ), phospholipids, sphingolipids , sterol lipids, to the remaining carbon , producing a saturated fatty acid . prenol lipids, saccharolipids, and polyketides. A pharmaceu - The first step is reversible , such that the hydrogen is reab tical composition disclosed herein may comprise a lipid such 25 sorbed on the catalyst and the double bond is re -formed . The as, e . g . an oil, an oil -based liquid , a fat, a fatty acid , a wax , intermediate with only one hydrogen added contains no a fatty acid ester , a fatty acid salt, a fatty alcohol, a glyceride double bond and can freely rotate . Thus, the double bond can (mono -, di- or triglyceride ), a partially hydrolyzed glycero - re - form as either cis or trans, of which trans is favored , lipid , a phospholipids , a glycol ester, a sucrose ester , a regardless the starting material. glycerol oleate derivative , a medium chain triglyceride , or a 30 In an embodiment, an adjuvant may be a pharmaceuti mixture thereof. Other examples of pharmaceutically - ac - cally -acceptable saturated or unsaturated fatty acid . In ceptable lipids useful as adjuvants are described in , e . g ., aspects of this embodiment, a saturated or unsaturated fatty U . S . Pat. No. 6 , 923 ,988 , U . S . Pat. No . 6 ,451 , 339, U . S . Pat. acid comprises , e . g ., at least 8 , at least 10 , at least 12 , at least No . 6 ,383 ,471 , U . S . Pat. No . 6 ,294 , 192 , and U . S . Pat . No. 14 , at least 16 , at least 18 , at least 20 , at least 22 , at least 24 , 6 , 267, 985 , each of which is hereby incorporated by refer - 35 at least 26 , at least 28 , or at least 30 carbon atoms. In other ence in its entirety . aspects of this embodiment, a saturated or unsaturated fatty A lipid useful in the pharmaceutical compositions dis acid comprises , e . g . , between 4 and 24 carbon atoms, closed herein may be a pharmaceutically - acceptable fatty between 6 and 24 carbon atoms, between 8 and 24 carbon acid . A fatty acid comprises a carboxylic acid with a long atoms, between 10 and 24 carbon atoms, between 12 and 24 unbranched hydrocarbon chain which may be either satu - 40 carbon atoms, between 14 and 24 carbon atoms, or between rated or unsaturated . Thus arrangement confers a fatty acid 16 and 24 carbon atoms, between 4 and 22 carbon atoms, with a polar , hydrophilic end, and a nonpolar, hydrophobic between 6 and 22 carbon atoms, between 8 and 22 carbon end that is insoluble in water. Most naturally occurring fatty atoms, between 10 and 22 carbon atoms, between 12 and 22 acids have a hydrocarbon chain of an even number of carbon carbon atoms, between 14 and 22 carbon atoms, or between atoms, typically between 4 and 24 carbons, and may be 45 16 and 22 carbon atoms, between 4 and 20 carbon atoms, attached to functional groups containing oxygen , halogens, between 6 and 20 carbon atoms, between 8 and 20 carbon nitrogen , and sulfur. Synthetic or non -natural fatty acids may atoms, between 10 and 20 carbon atoms, between 12 and 20 have a hydrocarbon chain of any number of carbon atoms carbon atoms, between 14 and 20 carbon atoms, or between from between 3 and 40 carbons . Where a double bond exists , 16 and 20 carbon atoms. If unsaturated , the fatty acid may there is the possibility of either a cis or a trans geometric 50 have , e . g ., 1 or more , 2 or more , 3 or more , 4 or more , 5 or isomerism , which significantly affects the molecule 's more , or 6 or more double bonds . molecular configuration . Cis -double bonds cause the fatty I n aspects of this embodiment, a pharmaceutically - accept acid chain to bend , an effect that is more pronounced the able saturated or unsaturated fatty acid is liquid at room more double bonds there are in a chain . Most naturally temperature . The melting point of a fatty acid is largely occurring fatty acids are of the cis configuration , although 55 determined by the degree of saturation / unsaturation of the the trans form does exist in some natural and partially hydrocarbon chain . In aspects of this embodiment , a satu hydrogenated fats and oils . Examples of fatty acids include, rated or unsaturated fatty acid has a melting point tempera without limitation , Capryllic acid (8 :0 ) , pelargonic acid ture of, e. g ., 20° C . or below , 15° C . or below , 10° C . or ( 9 : 0 ) , Capric acid ( 10 : 0 ) , Undecylic acid ( 11 : 0 ) , Lauric acid below , 5º C . or below . 0° C . or below , - 5° C . or below , - 10° ( 12 : 0 ) , Tridecylic acid (13 : 0 ), Myristic acid ( 14 : 0 ), Myris - 60 C . or below , - 15° C . or below , or - 20° C . or below . In other toleic acid ( 14 : 1 ) , Pentadecyclic acid ( 15 : 0 ) , Palmitic acid aspects of this embodiment, a saturated or unsaturated fatty ( 16 : 0 ) , Palmitoleic acid ( 16 : 1 ) , Sapienic acid ( 16 : 1 ) , Mar- acid has a melting point temperature in the range of, e . g . , garic acid ( 17: 0 ), Stearic acid (18 :0 ), Oleic acid ( 18: 1 ), about - 20° C . to about 20° C ., about - 20° C . to about 18° Elaidic acid ( 18 : 1 ) , Vaccenic acid ( 18 : 1 ) , Linoleic acid C . , about - 20° C . to about 16° C ., about - 20° C . to about 12° ( 18 :2 ) , Linoelaidic acid ( 18 : 2 ) , a -Linolenic acid ( 18 : 3 ), 65 C . , about - 20° C . to about 8° C . , about - 20° C . to about 4° y - Linolenic acid ( 18 :3 ), Stearidonic acid (18 : 4 ) , Nonade - C ., about - 20° C . to about 0° C ., about - 15° C . to about 20° cylic acid ( 19 : 0 ) , Arachidic acid (20 : 0 ) , Eicosenoic acid C . , about - 15° C . to about 18° C ., about - 15° C . to about 16° US 9 , 750 ,810 B2 21 C ., about - 15° C . to about 12° C ., about - 15° C . to about 8° without limitation , Linoleic acid ( 18 : 2 ) , y -linolenic acid C ., about - 15° C . to about 4° C ., about - 15° C . to about 0° (18 :3 ) , Calendic acid ( 18 : 3 ), Eicosadienoic acid (20 : 2 ), C . Dihomo - y - linolenic acid ( 20 : 3 ) , Arachidonic acid ( 20 : 4 ) , In another embodiment, an adjuvant may comprise one Docosadienoic acid ( 22 : 2 ) , Adrenic acid ( 22 : 4 ) , Docosapen kind of pharmaceutically - acceptable fatty acid . In aspects of 5 taenoic acid (22 : 5 ) , Tetracosatetraenoic acid ( 24 : 4 ) , and this embodiment , an adjuvant may comprise only palmitic Tetracosapentaenoic acid ( 24 : 5 ) . acid , only stearic acid , only oleic acid , only linoleic acid , or Omega - 7 fatty acids ( also known as n -7 fatty acids or 0 - 7 only linolenic acid . fatty acids ) are a family of unsaturated fatty acids that have In another embodiment, an adjuvant may comprise a in common a final carbon - carbon double bond in the n - 7 plurality of different pharmaceutically - acceptable fatty 10 position , that is , the seventh bond , counting from the methyl acids . In aspects of this embodiment, an adjuvant may end of the fatty acid . An omega - 7 fatty acid includes , comprise , e . g . , two or more different fatty acids , three or without limitation , 5 -Dodecenoic acid ( 12 : 1 ) , 7 - Tetrade more different fatty acids, four or more different fatty acids, cenoic acid ( 14 : 1 ) , 9 -Hexadecenoic acid ( Palmitoleic acid ) five or more different fatty acids, or six or more different ( 16 : 1 ) , 11 - Decenoic acid ( Vaccenic acid ) ( 18 : 1 ) , 97 , 11E fatty acids . 15 conjugated Linoleic acid (Rumenic acid ) ( 18 : 2 ), 13 -Eicose In other aspects of this embodiment, an adjuvant may noic acid (Paullinic acid ) ( 20 : 1) , 15 -Docosenoic acid (22 : 1) , comprise two or more different pharmaceutically - acceptable and 17 - Tetracosenoic acid ( 24 : 1 ) . fatty acids including at least palmitic acid , stearic acid , oleic Omega - 9 fatty acids ( also known as n - 9 fatty acids or 0 - 9 acid , linoleic acid and /or linolenic acid , and any combina - fatty acids ) are a family of unsaturated fatty acids that have tion thereof. In other aspects of this embodiment, an adju - 20 in common a final carbon - carbon double bond in the n - 9 vant may comprise a ratio of palmitic acid and /or stearic acid position , that is , the ninth bond , counting from the methyl and / or oleic acid : linolenic acid and /or linoleic acid of, e . g ., end of the fatty acid . An omega - 9 fatty acid includes, at least 2 : 1, at least 3 :1 , at least 4 : 1 , at least 5 : 1 , at least 6 : 1, without limitation , Oleic acid (18 : 1 ), Elaidic acid (18 : 1 ), at least 7 : 1 , at least 8 : 1 , at least 9 : 1 , at least 10 : 1 , at least Eicosenoic acid ( 20 : 1 ) , Mead acid ( 20 : 3 ) , Erucic acid ( 22 : 1 ) , 15 : 1, or at least 20 : 1. In yet other aspects of this embodi- 25 Nervonic acid (24 : 1 ), and Ricinoleic acid . ment, an adjuvant may comprise a ratio of palmitic acid A lipid useful in the pharmaceutical compositions dis and / or stearic acid and /or oleic acid :linolenic acid and / or closed herein may be a pharmaceutically -acceptable fat. linoleic acid in a range of, e . g . , about 1 : 1 to about 20 : 1 , Also known as a hard fat or solid fat, a fat includes any fatty about 2 : 1 to about 15 : 1, about 4 : 1 to about 12 : 1, or about 6 : 1 acid that is solid at normal room temperature , such as , e . g . to about 10 : 1 . 30 about 20° C . Fats consist of a wide group of compounds that In other aspects of this embodiment, an adjuvant may are generally soluble in organic solvents and generally comprise four or more different pharmaceutically -accept - insoluble in water. A fat suitable as a lipid useful in the able fatty acids including at least palmitic acid , stearic acid , pharmaceutical compositions disclosed herein , may be a oleic acid , linoleic acid and / or linolenic acid , and any triglyceride , a triester of glycerol or any of several fatty combination thereof. In other aspects of this embodiment, an 35 acids . adjuvant may comprise a ratio of palmitic acid ; stearic lipid useful in the pharmaceutical compositions dis acid : linolenic acid : linoleic acid of, e . g . , 10 : 10 : 1 : 1 , 9 : 9 : 1 : 1 , closed herein may be a pharmaceutically -acceptable oil. An 8 :8 : 1 : 1, 7 :7 :1 : 1 , 6 :6 :1 : 1, 5 :5 : 1: 1, 4 :4 : 1: 1, 3: 3 : 1 : 1, 2 :2 :1 : 1, or oil, also known as a liquid fat , includes any fatty acid that is 1 : 1 : 1 : 1 . In other aspects of this embodiment, an adjuvant liquid at normal room temperature, such as , e . g . about 20° C . may comprise a ratio of palmitic acid ; stearic acid : linolenic 40 An oil suitable as a lipid useful in the pharmaceutical acid : linoleic acid in a range of, e . g . , about 10 : 10 : 1 : 1 to about compositions disclosed herein , may be a natural oil , a 6 :6 : 1 : 1 , about 8 : 8 : 1 : 1 to about 4 : 4 : 1 : 1 , or about 5 : 5 : 1 : 1 to vegetable oil or any substance that does not mix with water about 1 : 1 : 1 : 1 . and has a greasy feel. Examples of suitable natural oils A lipid useful in the pharmaceutical compositions dis - include , without limitation , mineral oil , triacetin , ethyl closed herein may be a pharmaceutically - acceptable omega 45 oleate , a hydrogenated natural oil , or a mixture thereof . fatty acid . Non -limiting examples of an omega fatty acid Examples of suitable vegetable oils include , without limi include omega - 3 , omega -6 , omega - 7 , and omega - 9 . tation , almond oil , arachis oil , avocado oil , canola oil , castor Omega - 3 fatty acids ( also known as n - 3 fatty acids or 0 - 3 oil , coconut oil, corn oil, cottonseed oil , grape seed oil , fatty acids ) are a family of essential unsaturated fatty acids hazelnut oil, hemp oil , linseed oil ( flax seed oil ), olive oil , that have in common a final carbon - carbon double bond in 50 palm oil, peanut oil , rapeseed oil , rice bran oil, safflower oil, the n - 3 position , that is , the third bond , counting from the sesame oil, soybean oil , soya oil , sunflower oil , theobroma methyl end of the fatty acid . The omega - 3 fatty acids are oil ( cocoa butter ), walnut oil , wheat germ oil, or a mixture " essential ” fatty acids because they are vital for normal thereof. Each of these oils is commercially available from a metabolism and cannot be synthesized by the human body . number of sources well recognized by those skilled in the An omega - 3 fatty acid includes , without limitation , Hexa - 55 art . decatrienoic acid ( 16 : 3 ) , a - Linolenic acid ( 18 : 3 ) , Steari An oil is typically a mixture of various fatty acids . For donic acid ( 18 : 4 ) , Eicosatrienoic acid ( 20 : 3 ) , Eicosatetra - example , Rapeseed oil , obtained from the seeds of Brassica enoic acid (20 : 4 ) , Eicosapentaenoic acid ( 20 : 5 ) , napus, includes both omega - 6 and omega - 3 fatty acids in a Heneicosapentaenoic acid (21 : 5 ) , Docosapentaenoic acid ratio of about 2 : 1 . As another example , linseed oil, obtained ( Clupanodonic acid ) (22 : 5 ) , Docosahexaenoic acid (22 : 6 ) , 60 from the seeds of Linum usitatissimum , includes abut 7 % Tetracosapentaenoic acid ( 24 : 5 ) , Tetracosahexaenoic acid palmitic acid , about 3 . 4 - 4 . 6 % stearic acid , about 18 . 5 - 22 . 6 % (Nisinic acid ) ( 24 : 6 ) . oleic acid , about 14 . 2 - 17 % linoleic acid , and about 51 . 9 Omega - 6 fatty acids (also known as n - 6 fatty acids or w - 6 55 . 2 % a - linolenic acid . As another example , theobroma oil , fatty acids ) are a family of unsaturated fatty acids that have obtained from the seeds of Theobroma cacao , includes in common a final carbon - carbon double bond in the n - 6 65 glycerides derived from palmitic acid , stearic acid , oleic position , that is , the sixth bond , counting from the methyl acid , linoleic acid , and arichidic acid , with melting point of end of the fatty acid . An omega - 6 fatty acid includes, 34 - 38° C . In aspects of this embodiment, a pharmaceutical US 9 , 750 ,810 B2 23 24 composition comprises an oil including at least two different glycol elaidate , propylene glycol vaccinate , propylene gly fatty acids , at least three different fatty acids , at least four col linoleate , propylene glycol linoelaidate , propylene gly different fatty acids, at least five different fatty acids, or at col a -linolenate , propylene glycol y - linolenate , propylene least six different fatty acids . glycol stearidonate , propylene glycol capprylocaprate , pro A lipid useful in the pharmaceutical compositions dis - 5 pylene glycol dicapprylocaprate , dipropylene glycol capry closed herein may be a pharmaceutically - acceptable glyc - late , dipropylene glycol pelargonate , dipropylene glycol erolipid . Glycerolipids are composed mainly ofmono -, di- , caprate , dipropylene glycol undecylate , dipropylene glycol and tri- substituted glycerols . One group of glycerolipids is laurate , dipropylene glycol tridecylate, dipropylene glycol the glycerides, where one, two , or all three hydroxyl groups myristate , dipropylene glycol myristolate , dipropylene gly of glycerol are each esterified using a fatty acid disclosed 10 col pentadecyclate , dipropylene glycol palmitate , dipropyl herein to produce monoglycerides , diglycerides , and triglyc ene glycol palmitoleate , dipropylene glycol sapienate , dipro erides , respectively . In these compounds, each hydroxyl pylene glycol margarate , dipropylene glycol stearate , groups of glycerol may be esterified by different fatty acids. dipropylene glycol palmitostearate , dipropylene glycol Additionally , glycerides may be acetylated to produce acety oleate , dipropylene glycol elaidate , dipropylene glycol vac lated monoglycerides, acetylated diglycerides, and acety - 15 cinate , dipropylene glycol linoleate , dipropylene glycol lino lated triglycerides. One group of glycerolipids is the glyc - elaidate , dipropylene glycol a - linolenate , dipropylene gly erides, where one, two, or all three hydroxyl groups of col y - linolenate , dipropylene glycol stearidonate , glycerol have sugar residues attached via a glycosidic link dipropylene glycol capprylocaprate , dipropylene glycol age . dicapprylocaprate , or any combination thereof. A lipid useful in the pharmaceutical compositions dis - 20 lipid useful in the pharmaceutical compositions dis closed herein may be a pharmaceutically -acceptable par - closed herein may be a pharmaceutically -acceptable tially hydrolyzed glycerolipid . In an aspect of this embodi - polyether fatty acid ester. A pharmaceutically - acceptable ment, a pharmaceutically - acceptable partially hydrolyzed polyether fatty acid ester can be a mono - fatty acid ester of glycerolipid is a triglyceride partially hydrolyzed into a polyether, a di- fatty acid ester of a polyether, or a tri- fatty mixture of mono - , di- , and triglycerides . 25 acid ester of a polyether . A polyether fatty acid ester A lipid useful in the pharmaceutical compositions dis - includes, without limitation , a PEG fatty acid ester, a PEG closed herein may be a pharmaceutically -acceptable glycol glyceryl fatty acid , a PEG fatty acid ester glyceride, a PPG fatty acid ester . A pharmaceutically -acceptable glycol fatty fatty acid ester , a PPG glyceryl fatty acid , and a PPG fatty acid ester can be a monoester of a glycol, a diester of a acid ester glyceride . APEG or PPG may be a molecular mass glycol , or a triester of a glycol. A glycol fatty acid ester 30 of, e . g . , 5 - 20 ,000 . Non - limiting examples of polyether fatty include , without limitation , a ethylene glycol fatty acid ester , acid esters include , e . g . , a PEG caprylate , a PEG pelargo a diethylene glycol fatty acid ester, a propylene glycol fatty nate , a PEG caprate , a PEG undecylate , a PEG laurate , a acid ester, and a dipropylene fatty acid ester . Non - limiting PEG tridecylate , a PEG myristate , a PEG myristolate , a PEG examples of glycol fatty acid esters include , e . g ., ethelene pentadecyclate , a PEG palmitate , a PEG palmitoleate , a PEG glycol caprylate , ethelene glycol pelargonate , ethelene gly - 35 sapienate , a PEG margarate , a PEG stearate , a PEG palmi col caprate , ethelene glycol undecylate, ethelene glycol tostearate , PEG oleate , PEG elaidate , PEG vaccinate , PEG laurate , ethelene glycol tridecylate , ethelene glycol linoleate , PEG linoelaidate , PEG a - linolenate , PEG y - lino myristate , ethelene glycol myristolate , ethelene glycol pen - lenate, PEG stearidonate , PEG capprylocaprate , PEG dicap tadecyclate , ethelene glycol palmitate , ethelene glycol prylocaprate , a PEG glyceryl caprylate , a PEG glyceryl palmitoleate , ethelene glycol sapienate , ethelene glycolmar - 40 pelargonate , a PEG glyceryl caprate , a PEG glyceryl garate , ethelene glycol stearate , ethelene glycol palmitoste - undecylate , a PEG glyceryl laurate , a PEG glyceryl tridecy arate , ethelene glycol oleate , ethelene glycol elaidate , ethe - late , a PEG glyceryl myristate , a PEG glyceryl myristolate , lene glycol vaccinate , ethelene glycol linoleate , ethelene a PEG glyceryl pentadecyclate , a PEG glyceryl palmitate , a glycol linoelaidate, ethelene glycol a - linolenate , ethelene PEG glyceryl palmitoleate, a PEG glyceryl sapienate, a PEG glycol y - linolenate , ethelene glycol stearidonate , ethelene 45 glycerylmargarate , a PEG glyceryl stearate , a PEG glyceryl glycol capprylocaprate , ethelene glycol dicapprylocaprate , palmitostearate , PEG glyceryl oleate , PEG glyceryl elaidate , diethelene glycol caprylate , diethelene glycol pelargonate , PEG glyceryl vaccinate , PEG glyceryl linoleate , PEG glyc diethelene glycol caprate, diethelene glycol undecylate , eryl linoelaidate , PEG glyceryl a - linolenate , PEG glyceryl diethelene glycol laurate , diethelene glycol tridecylate , y - linolenate , PEG glyceryl stearidonate , PEG glyceryl cap diethelene glycol myristate , diethelene glycol myristolate , 50 prylocaprate , PEG glyceryl dicapprylocaprate , a capryloyl diethelene glycol pentadecyclate , diethelene glycol palmi- PEG glyceride , a pelargonoyl PEG glyceride , a caproyl PEG tate , diethelene glycol palmitoleate , diethelene glycol sapi glyceride , an undecyloyl PEG glyceride, a lauroyl PEG enate , diethelene glycol margarate , diethelene glycol stear glyceride, a tridecyloyl PEG glyceride, a myristoyl PEG ate , diethelene glycol palmitostearate, diethelene glycol glyceride , a myristoloyl PEG glyceride, a pentadecycloyl oleate , diethelene glycol elaidate , diethelene glycol vacci - 55 PEG glyceride, a palmitoyl PEG glyceride , a palmitoleoyl nate , diethelene glycol linoleate , diethelene glycol linoelai PEG glyceride , a sapienoyl PEG glyceride, a margaroyl date , diethelene glycol a - linolenate , diethelene glycol y - li - PEG glyceride , a stearoyl PEG glyceride , a palmitostearoyl nolenate, diethelene glycol stearidonate , diethelene glycol PEG glyceride , an oleoyl PEG glyceride, an elaidoyl PEG capprylocaprate , diethelene glycol dicapprylocaprate , pro - glyceride, a vaccinoyl PEG glyceride , a linoleoyl PEG pylene glycol caprylate , propylene glycol pelargonate , pro - 60 glyceride , a linoelaidoyl PEG glyceride, an a - linolenoyl pylene glycol caprate , propylene glycol undecylate , propyl PEG glyceride, a y - linolenoyl PEG glyceride, a stearidonoyl ene glycol laurate , propylene glycol tridecylate , propylene PEG glyceride, a capprylocaproyl PEG glyceride , a dicap glycol myristate , propylene glycol myristolate , propylene prylocaproyl PEG glyceride , a PPG caprylate , a PPG pelar glycol pentadecyclate , propylene glycol palmitate , propyl - gonate , a PPG caprate , a PPG undecylate , a PPG laurate , a ene glycol palmitoleate , propylene glycol sapienate , propyl- 65 PPG tridecylate , a PPG myristate , a PPG myristolate , a PPG ene glycol margarate , propylene glycol stearate , propylene pentadecyclate , a PPG palmitate , a PPG palmitoleate , a PPG glycol palmitostearate , propylene glycol oleate , propylene sapienate , a PPG margarate , a PPG stearate , a PPG palmi US 9 , 750 , 810 B2 25 26 tostearate, a PPG oleate , a PPG elaidate , a PPG vaccinate , a C . In aspects of this embodiment, a mixture of pharmaceu PPG linoleate , a PPG linoelaidate , a PPG a - linolenate , a tically - acceptable lipids includes a mixture of mono -, di- , PPG y - linolenate , a PPG stearidonate , a PPG capprylo - and /or triglycerides having a melting point of, e. g ., about caprate , a PPG dicapprylocaprate , a PPG glyceryl caprylate , 30° C . to about 44° C . , about 30° C . to about 45° C ., about a PPG glyceryl pelargonate , a PPG glyceryl caprate , a PPG 5 30° C . to about 46° C . , about 30° C . to about 47° C ., about glyceryl undecylate , a PPG glyceryl laurate , a PPG glyceryl 30° C . to about 48° C ., about 30° C . to about 49° C ., about tridecylate , a PPG glyceryl myristate , a PPG glycerylmyris - 30° C . to about 50° C ., about 32° C . to about 44° C . , about tolate , a PPG glyceryl pentadecyclate , a PPG glyceryl palmi- 32° C . to about 45° C ., about 32° C . to about 46° C ., about tate, a PPG glyceryl palmitoleate , a PPG glyceryl sapienate , 32° C . to about 47° C ., about 32° C . to about 48° C ., about a PPG glyceryl margarate , a PPG glyceryl stearate , a PPG 10 32° C . to about 49° C . , about 32° C . to about 50° C ., about glyceryl palmitostearate , a PPG glyceryl Oleate , a PPG 34° C . to about 44° C ., about 34° C . to about 45° C ., about glyceryl elaidate , a PPG glyceryl vaccinate , a PPG glyceryl 34° C . to about 46° C ., about 34° C . to about 47° C ., about linoleate , a PPG glyceryl linoelaidate , a PPG glyceryl a - li 34° C . to about 48° C . , about 34° C . to about 49° C . , about nolenate , a PPG glyceryl y - linolenate , a PPG glyceryl steari - 34° C . to about 50° C ., about 36° C . to about 44° C ., about donate , a PPG glyceryl capprylocaprate , a PPG glyceryl 15 36° C . to about 45° C ., about 36° C . to about 46° C . , about dicapprylocaprate , a capryloyl PPG glyceride, a pelargonoyl 36° C . to about 47° C . , about 36° C . to about 48° C ., about PPG glyceride, a caproyl PPG glyceride , an undecyloyl PPG 36° C . to about 49° C ., about 36° C . to about 50° C . , about glyceride, a lauroyl PPG glyceride , a tridecyloyl PPG glyc 38° C . to about 44° C ., about 38° C . to about 45° C . , about eride , a myristoyl PPG glyceride , a myristoloyl PPG glyc - 38° C . to about 46° C . , about 38° C . to about 47° C . , about eride , a pentadecycloyl PPG glyceride, a palmitoyl PPG 20 38° C . to about 48° C ., about 38° C . to about 49° C ., about glyceride , a palmitoleoyl PPG glyceride , a sapienoyl PPG 38° C . to about 50° C ., about 40° C . to about 44° C . , about glyceride , a margaroyl PPG glyceride , a stearoyl PPG glyc - 40° C . to about 45° C ., about 40° C . to about 46° C . , about eride, a palmitostearoyl PPG glyceride , an oleoyl PPG 40° C . to about 47° C ., about 40° C . to about 48° C ., about glyceride , an elaidoyl PPG glyceride , a vaccinoyl PPG 40° C . to about 49° C . , about 40° C . to about 50° C . , about glyceride, a linoleoyl PPG glyceride , a linoelaidoyl PPG 25 42° C . to about 44° C . , about 42° C . to about 45° C . , about glyceride, an a - linolenoyl PPG glyceride, a y - linolenoyl 42° C . to about 46° C . , about 42° C . to about 47° C . , about PPG glyceride, a stearidonoyl PPG glyceride , a capprylo - 42° C . to about 48° C ., about 42° C . to about 49° C . , or about caproyl PPG glyceride , a dicapprylocaproyl PPG glyceride, 42° C . to about 50° C . or any combination thereof . In other aspects of this embodiment, a mixture of phar Commercially available pharmaceutically -acceptable 30 maceutically - acceptable lipids includes a mixture PEG fatty polyether fatty acid esters include, without limitation , capry - acid esters having a melting point of, e .g . , about 33° C . , locaproyl macrogol- 8 glycerides (LABRASOL® ), propyl - about 34° C . , about 35° C ., about 36° C ., about 37° C . , about ene glycol monopalmitostearate (MONOSTEOL® ) , glyc - 38° C ., about 39° C ., about 40° C ., about 41° C ., about 43° eryl dibehenate (COMPRITOL® 888 ) , glycerol behenate C ., about 43° C . , about 44° C ., about 45° C ., about 45° C . , ( COMPRITOL® E ATO ), behenoyl pollyoxyl- 8 glycerides 35 about 47° C ., about 48° C . , about 49° C . , about 50° C . In (COMPRITOL® HD5 ATO ), triglycerol diisostearate aspects of this embodiment, a mixture of pharmaceutically ( PLUROL® Diisostearique ) , PEG - 8 beeswax (APIFIL® ) , acceptable lipids includes a mixture PEG fatty acid esters lauroyl macrogol- 32 glycerides (GELUCIRE 44 / 14 ) , having a melting point of, e . g ., about 30° C . to about 44° C ., stearoyl macrogol- 32 glycerides (GELUCIRE 50 . 13 ) , pro - about 30° C . to about 45° C ., about 30° C . to about 46° C . , pylene glycol dicaprylocaprate (LABRAFAC® PG ) , 40 about 30° C . to about 47° C . , about 30° C . to about 48° C . , polyglycerol- 3 dioleate (PLUROL® Oleique CC 497 ) , pro about 30° C . to about 49° C ., about 30° C . to about 50° C ., pylene glycol monolaurate ( type I ) (LAUROGLYCOL® about 32° C . to about 44° C . , about 32° C . to about 45° C . , FCC ) , propylene glycol monolaurate ( type II) (LAURO - about 32° C . to about 46° C . , about 32° C . to about 47° C . , GLYCOL® 90 ), propylene glycol monocaprylate (type I ) about 32° C . to about 48° C ., about 32° C . to about 49° C . , (CAPRYOL® PGMC ), propylene glycol monocaprylate 45 about 32° C . to about 50° C ., about 34° C . to about 44° C . , ( type II ) (CAPRYOL® 90 ) , linoleoylmacrogol - 6 glycerides about 34° C . to about 45° C . , about 34° C . to about 46° C . , (LABRAFIL® M2125CS ) , oleoyl macrogol - 6 glycerides about 34° C . to about 47° C ., about 34° C . to about 48° C . , (LABRAFIL® M1944CS ) , lauroyl macrogol- 6 glycerides about 34° C . to about 49° C . , about 34° C . to about 50° C . , (LABRAFIL® M2130CS ) , glycerol dipalmitostearate about 36° C . to about 44° C . , about 36° C . to about 45° C . , (Biogapress Vegetal BM297ATO ) , glycerol distearate (type 50 about 36° C . to about 46° C ., about 36° C . to about 47° C . , I ) ( PRECIROL® ATO 5 ) , and glycerol monolinoleate about 36° C . to about 48° C . , about 36° C . to about 49° C . , (MAISINETM 35 - 1 ). about 36° C . to about 50° C . , about 38° C . to about 44° C ., A lipid useful in the pharmaceutical compositions dis about 38° C . to about 45° C ., about 38° C . to about 46° C ., closed herein may be a mixture of pharmaceutically -accept - about 38° C . to about 47° C ., about 38° C . to about 48° C . , able lipids. Examples of mixtures of pharmaceutically - 55 about 38° C . to about 49° C ., about 38° C . to about 50° C . , acceptable lipids include , without limitation , a mixture of about 40° C . to about 44° C ., about 40° C . to about 45° C . , one or more glycerolipids disclosed herein , a mixture of one about 40° C . to about 46° C . , about 40° C . to about 47° C . , or more glycol fatty acid esters disclosed herein , a mixture about 40° C . to about 48° C . , about 40° C . to about 49° C . , of more polyether fatty acid esters disclosed herein , a about 40° C . to about 50° C . , about 42° C . to about 44° C . , mixture of more glycerides disclosed herein . 60 about 42° C . to about 45° C ., about 42° C . to about 46° C . , In aspects of this embodiment , a mixture of pharmaceu - about 42° C . to about 47° C ., about 42° C . to about 48° C . , tically -acceptable lipids includes a mixture of mono -, di -, about 42° C . to about 49° C ., or about 42° C . to about 50° and / or triglycerides having a melting point of, e .g ., about C . 33° C . , about 34° C ., about 35° C . , about 36° C . , about 37° In other aspects of this embodiment, a mixture of phar C ., about 38° C ., about 39° C . , about 40° C ., about 41° C ., 65 maceutically -acceptable lipids includes a mixture ofmono -, about 43° C ., about 43° C ., about 44° C ., about 45° C ., about di- , and /or triglycerides and PEG fatty acid esters having a 45° C ., about 47° C . , about 48° C . , about 49° C . , about 50° melting point of, e . g . , about 33° C ., about 34° C . , about 35° US 9 ,750 ,810 B2 28 C . , about 36° C ., about 37° C ., about 38° C . , about 39° C ., tical composition disclosed herein are normally immiscible , about 40° C ., about 41° C ., about 43° C ., about 43° C ., about an emulsifying agent disclosed herein is used to create a 44° C ., about 45° C ., about 45° C ., about 47° C . , about 48° homogenous and stable emulsion . An emulsifying agent C . , about 49° C ., about 50° C . In aspects of this embodiment, includes , without limitation , a surfactant, a polysaccharide , a mixture of pharmaceutically - acceptable lipids includes a 5 a lectin , and a phospholipid . mixture of mono -, di- , and / or triglycerides and PEG fatty I n an aspect of this embodiment, an emulsifying agent acid esters having a melting point of, e . g . , about 30° C . to may comprise a surfactant. As used hereon , the term " sur about 44° C . , about 30° C . to about 45° C ., about 30° C . to factant” refers to a natural or synthetic amphiphilic com about 46° C . , about 30° C . to about 47° C ., about 30° C . to pound . A surfactant can be non - ionic , zwitterionic , or ionic . about 48° C . , about 30° C . to about 49° C ., about 30° C . to 10 Non - limiting examples of surfactants include polysorbates about 50° C ., about 32° C . to about 44° C ., about 32° C . to like polysorbate 20 ( TWEEN® 20 ) , polysorbate 40 about 45° C . , about 32° C . to about 46° C . , about 32° C . to ( TWEEN® 40 ) , polysorbate 60 ( TWEEN® 60 ) , polysorbate about 47° C . , about 32° C . to about 48° C ., about 32° C . to 61 (TWEEN® 61) , polysorbate 65 ( TWEEN® 65 ) , poly about 49° C . , about 32° C . to about 50° C . , about 34° C . to sorbate 80 ( TWEEN® 80 ) , and polysorbate 81 ( TWEEN® about 44° C . , about 34° C . to about 45° C . , about 34° C . to 15 81 ) ; poloxamers (polyethylene - polypropylene copolymers ) , about 46° C . , about 34° C . to about 47° C ., about 34° C . to like Poloxamer 124 (PLURONIC® L44 ) , Poloxamer 181 about 48° C . , about 34° C . to about 49° C . , about 34° C . to (PLURONIC® L61) , Poloxamer 182 (PLURONIC® L62 ) , about 50° C . , about 36° C . to about 44° C ., about 36° C . to Poloxamer 184 (PLURONIC® L64 ) , Poloxamer 188 about 45° C . , about 36° C . to about 46° C ., about 36° C . to (PLURONIC® F68 ) , Poloxamer 237 (PLURONIC® F87 ) , about 47° C . , about 36° C . to about 48° C ., about 36° C . to 20 Poloxamer 338 ( PLURONIC® L108 ) , Poloxamer 407 about 49° C ., about 36° C . to about 50° C . , about 38° C . to (PLURONIC® F127 ) , polyoxyethyleneglycol dodecyl about 44° C . , about 38° C . to about 45° C . , about 38° C . to ethers , like BRIJ® 30 , and BRIJ® 35 ; 2 -dodecoxyethanol about 46° C ., about 38° C . to about 47° C ., about 38° C . to (LUBROL® -PX ) ; polyoxyethylene octyl phenyl ether ( TRI about 48° C . , about 38° C . to about 49° C ., about 38° C . to TON® X - 100 ) ; sodium dodecyl sulfate (SDS ); 3 - [ ( 3 about 50° C . , about 40° C . to about 44° C . , about 40° C . to 25 Cholamidopropyl) dimethylammonio ] - 1 - propanesulfonate about 45° C ., about 40° C . to about 46° C . , about 40° C . to (CHAPS ); 3 -[ ( 3 -Cholamidopropyl ) dimethylammonio ) - 2 about 47° C . , about 40° C . to about 48° C ., about 40° C . to hydroxy - 1 -propanesulfonate (CHAPSO ) ; sucrose monolau about 49° C ., about 40° C . to about 50° C ., about 42° C . to rate ; and sodium cholate . Other non -limiting examples of about 44° C . , about 42° C . to about 45° C ., about 42° C . to surfactant excipients can be found in , e . g . , Ansel , supra , about 46° C ., about 42° C . to about 47° C ., about 42° C . to 30 ( 1999) ; Gennaro , supra , (2000 ); Hardman , supra , (2001 ) ; about 48° C ., about 42° C . to about 49° C . , or about 42° C . and Rowe, supra , ( 2003 ) , each of which is hereby incorpo to about 50° C . rated by reference in its entirety . Commercially available mixtures of pharmaceutically . In an aspect of this embodiment, an emulsifying agent acceptable lipids include, without limitation , mixtures of may comprise a polysaccharide . Non -limiting examples of PEG -6 stearate and ethylene glycol palmitostearate and 35 polysaccharides include guar gum , agar , alginate , calgene , a PEG -32 stearate ( TEFOSE® 1500 ; TEFOSE® 63 ) ,mixtures dextran (like dextran 1K , dextran 4K , dextran 40K , dextran of triceteareth - 4 phosphate and ethylene glycol palmitoste 60K , and dextran 70K ), dextrin , glycogen , inulin , starch , a arate and diethylene glycol palmitostearate ( SEDEFOS® starch derivative ( like hydroxymethyl starch , hydroxyethyl 75 ) , mixtures of glycerol monostearate and PEG -75 stearate starch , hydroxypropyl starch , hydroxybutyl starch , and (GELOT® ) , mixtures of cetyl alcohol and ethoxylated fatty 40 hydroxypentyl starch ) , hetastarch , cellulose , FICOLL , alcohols ( seteth - 2 - , steareth - 20 ) ( EMULCIRE® ) , mixtures methyl cellulose (MC ) , carboxymethyl cellulose (CMC ) , of saturated C10 - C18 triglycerides having a melting point hydroxyethyl cellulose (HEC ), hydroxypropyl cellulose around 33° C . (GELUCIRE® 33/ 01 ), mixtures of saturated (HPC ) , hydroxyethyl methyl cellulose (NEMC ), hydroxy C10 - C18 triglycerides having a melting point around 39° C . propyl methyl cellulose (HPMC ) ; polyvinyl acetates (PVA ) ; (GELUCIRE? 39 / 01) , mixtures of saturated C1 - C18 tri- 45 polyvinyl pyrrolidones (PVP ), also known as povidones , glycerides having a melting point around 43° C . (GELU having a K - value of less than or equal to 18 , a K -value CIRE® 43 /01 ) , mixtures of glycerol monostearate 40 - 55 greater than 18 or less than or equal to 95 , or a K - value ( type I ) and diglycerides (GELEOL® Mono and Diglycer - greater than 95 , like PVP 12 (KOLLIDON® 12 ) , PVP 17 ides) , and mixtures ofmedium - chain triglycerides (LABRA (KOLLIDON 17 ) , PVP 25 (KOLLIDON® 25 ) , PVP 30 FAC® Lipophile WL 1349) . 50 (KOLLIDON® 30 ) , PVP 90 (KOLLIDON® 90 ) ; and poly Aspects of the present specification disclose , in part , a ethylene imines ( PEI) . pharmaceutically -acceptable stabilizing agent. A stabilizing In an aspect of this embodiment, an emulsifying agent agent reduces or eliminates formation of esters of a thera - may comprise a lectin . Lectins are sugar - binding proteins peutic compound that may result as a unwanted reaction that are highly specific for their sugar moieties . Lectins may with the particular solvent used . A stabilizing agent include , 55 be classified according to the sugar moiety that they bind to , without limitation , water, a sacrificialacid comprising a fatty and include , without limitation , mannose -binding lectins , acid component and acetic acid , ethyl acetate , a sodium galactose / N -acetylgalactosamine -binding lectins, N - acetyl acetate / acetic acid ( E262 ) , a monoglyceride , an acetylated gluxosamine- binding lectins, N - acetylneuramine -binding monoglyceride , a diglyceride , an acetylated monoglyceride, lectins, N -acetylneuraminic acid - binding lectins , and an acetylated diglyceride , a fatty acid , and a fatty acid salt . 60 fucose - binding lectins . Non - limiting examples of surfac In one embodiment, a pharmaceutically -acceptable stabi - tants include concanavain A , lentil lectin , snowdrop lectin , lizing agent may comprise a pharmaceutically - acceptable Roin , peanut agglutinin , jacain , hairy vetch lectin , wheat emulsifying agent. An emulsifying agent (also known as an germ agglutinin , elderberry lectin , Maackia anurensis leu emulgent) is a substance that stabilizes an emulsion com - koagglutinin , Maackia anurensis hemoagglutinin , Ulex prising a liquid dispersed phase and a liquid continuous 65 europaeus agglutinin , and Aleuria aurantia lectin . phase by increasing its kinetic stability. Thus, in situations In an aspect of this embodiment, an emulsifying agent where the solvent and adjuvant used to make a pharmaceu - may comprise a phospholipid . The structure of the phos US 9 ,750 ,810 B2 29 30 pholipid generally comprises a hydrophobic tail and a Once triglyceride stores are distributed , the chylomicron hydrophilic head and is amphipathic in nature . Most phos - returns APOC2 to the HDL (but keeps APOE ), and , thus , pholipids contain a diglyceride , a phosphate group , and a becomes a chylomicron remnant, now only 30 - 50 nm . simple organic molecule such as choline; one exception to APOB48 and APOE are important to identify the chylomi this rule is sphingomyelin , which is derived from sphin - 5 cron remnant in the liver for endocytosis and breakdown gosine instead of glycerol. Phospholipids include , without into lipoproteins ( VLDL , LDL and HDL ) . These lipopro limitation , diacylglycerides and phosphosphingolipids . teins are processed and stored by competent cells , including , Non - limiting examples of diacylglycerides include a phos - e . g . , hepatocytes , adipocytes and macrophages. Thus , with phatidic acid (phosphatidate ) ( PA ) , a phosphatidyletha - out wishing to be limited by any theory , upon oral admin nolamine ( cephalin ) (PE ) , a phosphatidylcholine ( lecithin ) 10 istration , a pharmaceutical composition disclosed herein can ( PC ), a phosphatidylserine (PS ), and a phosphoinositide be processed into micelles while in the gastrointestinal tract , including phosphatidylinositol (PI ) , phosphatidylinositol absorbed by enterocytes and assembled into nascent chylo phosphate (PIP ), phosphatidylinositol bisphosphate (PIP2 ), microns, remain associated with chylomicron remnants and phosphatidylinositol triphosphate (PIP3 ) . Non - limiting taken up by the liver , and ultimately loaded into macro examples of phosphosphingolipids include a ceramide phos - 15 phages which are present in inflamed tissues . phorylcholine (sphingomyelin ) (SPH ) , ceramide phospho - As another example , a pharmaceutical composition dis rylethanolamine ( sphingomyelin ) (Cer -PE ), and ceramide closed herein may facilitate the delivery of a therapeutic phosphorylglycerol . compound disclosed herein into dentritic cells . One possible In one embodiment, a pharmaceutically - acceptable stabi- mechanism to achieve selective biodistribution of the phar lizing agent does not comprise a pharmaceutically -accept - 20 maceutical compositions disclosed herein may be to take able emulsifying agent . advantage of the endocytotic /phagocytotic activity of den In another embodiment , a pharmaceutical composition tritic cells . Dendritic cells are immune cells forming part of does not comprise a pharmaceutically - acceptable emulsify the mammalian immune system . The main function of ing agent. dendritic cells is to process antigen material and present it on The pharmaceutical compositions disclosed herein act as 25 the surface to other cells of the immune system . Thus, a delivery system that enable a therapeutic compound dis - dendritic cells function as antigen -presenting cells that act as closed herein to be more effectively delivered or targeted to messengers between innate and adaptive immunity. Den a cell type , tissue , organ , or region of the body in a manner dritic cells are present in tissues in contact with the external that more effectively inhibits a pro - inflammatory response . environment, such as, e . g ., the skin (where there is a This inhibition results in an improved treatment of a chronic 30 specialized dendritic cell type called Langerhans cells ) and inflammation . For example , a pharmaceutical composition the inner lining of the nose , lungs , stomach and intestines . disclosed herein may facilitate the delivery of a therapeutic These cells can also be found in an immature state in the compound disclosed herein into macrophages . One possible blood . Once activated , they migrate to the lymph nodes mechanism that achieves this selective biodistribution is that where they interact with T cells and B cells to initiate and the pharmaceutical compositions disclosed herein may be 35 shape the adaptive immune response . Dendritic cells are designed to take advantage of the activity of chylomicrons. known to endocytose and phagocytose lipid particles as part Chylomicrons are relatively large lipoprotein particles hav - of their environmental monitoring and antigen presentation ing a diameter of 75 nm to 1 , 200 nm . Comprising triglyc processes . Without wishing to be limited by any theory , upon erides (85 - 92 % ) , phospholipids ( 6 - 12 % ) , cholesterol ( 1 - 3 % ) topical or inhalatory administration , a pharmaceutical com and apolipoproteins ( 1 - 2 % ), chylomicrons transport dietary 40 position disclosed herein can penetrate into the skin or inner lipids from the intestines to other locations in the body. lining of the nose , lungs , stomach and intestines , be endo Chylomicrons are one of the five major groups of lipopro - cytosed /phagocytosed by dentritic cells, and ultimately teins, the others being VLDL , IDL , low -density lipoproteins loaded into T cells and /or B cells which are present in (LDL ) , high - density lipoproteins (HDL ), that enable fats and inflamed tissues . cholesterol to move within the water -based solution of the 45 Aspects of the present specification disclose , in part, a bloodstream . method of preparing a pharmaceutical composition dis During digestion , fatty acids and cholesterol undergo closed herein . A method disclosed herein comprises the step processing in the gastrointestinal tract by the action of of contacting a pharmaceutically - acceptable adjuvant dis pancreatic juices including lipases and emulsification with closed herein with a therapeutic compound disclosed herein bile salts to generate micelles. These micelles allow the 50 under conditions which allow the therapeutic compound to absorption of lipid as free fatty acids by the absorptive cells dissolve in the pharmaceutically -acceptable adjuvant, of the small intestine , known as enterocytes. Once in the thereby forming a pharmaceutical composition disclosed enterocytes, triglycerides and cholesterol are assembled into herein . nascent chylomicrons. Nascent chylomicrons are primarily Aspects of the present specification disclose , in part, a composed of triglycerides (85 % ) and contain some choles - 55 method of preparing a pharmaceutical composition dis terol and cholesteryl esters . The main apolipoprotein com - closed herein . A method disclosed herein comprises the ponent is apolipoprotein B - 48 ( APOB48 ) . These nascent steps of a ) contacting a pharmaceutically -acceptable solvent chylomicrons are released by exocytosis from enterocytes disclosed herein with a therapeutic compound disclosed into lacteals, lymphatic vessels originating in the villi of the herein under conditions which allow the therapeutic com small intestine , and are then secreted into the bloodstream at 60 pound to dissolve in the pharmaceutically -acceptable sol the thoracic duct ' s connection with the left subclavian vein . vent, thereby forming a solution ; and b ) contacting the While circulating in lymph and blood , chylomicrons solution formed in step ( a ) with a pharmaceutically - accept exchange components with HDL . The HDL donates apoli able adjuvant disclosed herein under conditions which allow poprotein C - II ( APOC2 ) and apolipoprotein E (APOE ) to the formation of a pharmaceutical composition . The meth the nascent chylomicron and thus converts it to a mature 65 ods of preparing disclosed herein may further comprise a chylomicron (often referred to simply as “ chylomicron " ) . step ( c ) of removing the pharmaceutically - acceptable sol APOC2 is the cofactor for lipoprotein lipase (LPL ) activity . vent from the pharmaceutical composition . US 9 ,750 ,810 B2 32 The amount of a therapeutic compound that is contacted solvent. However, in other embodiments of the method, step with the pharmaceutically - acceptable solvent in step ( a ) of ( a ) may be carried out at a temperature that is less than room the method may be in any amount desired . Factors used to temperature , e . g. , less than 10° C . , greater than 5° C ., greater determine the amount of a therapeutic compound used than 0° C . , greater than - 10° C . or greater than - 20° C . The include , without limitation , the final amount the therapeutic 5 contacting in Step ( a ) may comprise mixing the therapeutic compound desired in the pharmaceutical composition , the compound and the pharmaceutically - acceptable solvent, desired concentration of a therapeutic compound in the e . g . , by stirring , inversion , sonication , or vortexing . The solution , the hydrophobicity of the therapeutic compound , mixing may be carried out for, e . g . , at least 1 second , at least the lipophobicity of the therapeutic compound , the tempera - 5 seconds, at least 10 seconds, at least 20 seconds, at least ture under which the contacting step ( a ) is performed , and 10 30 seconds, at least 45 seconds, at least 60 seconds , or more , the time under which the contacting step ( a ) is performed until the therapeutic compound is fully dissolved in the The volume of a pharmaceutically - acceptable solvent solvent. used in step ( a ) of the method may be any volume desired . After contacting , the concentration of a therapeutic com Factors used to determine the volume of a pharmaceutically - pound disclosed herein in the solution may be in any acceptable solvent used include , without limitation , the final 15 concentration desired . In aspects of this embodiment, the amount of a pharmaceutical composition desired , the desired concentration of a therapeutic compound disclosed herein in concentration of a therapeutic compound in the solution , the the solution may be , e . g . , at least 0 . 00001 mg/mL , at least hydrophobicity of the therapeutic compound , and the lipo 0 .0001 mg/ mL , at least 0 .001 mg/mL , at least 0 . 01 mg/ mL , phobicity of the therapeutic compound . at least 0 . 1 mg/ mL , at least 1 mg/ mL , at least 10 mg/ mL , at In aspects of this embodiment , the amount of a therapeutic 20 least 25 mg/ mL , at least 50 mg/ mL , at least 100 mg/mL , at compound that is contacted with the solvent in step ( a ) may least 200 mg/mL , at least 500 mg/mL , at least 700 mg/ mL , be , e . g ., at least 10 mg, at least 20 mg, at least 30 mg, at least at least 1 , 000 mg/mL , or at least 1 , 200 mg/ mL . In other 40 mg , at least 50 mg, at least 60 mg, at least 70 mg, at least aspects of this embodiment, the concentration of a thera 80 mg, at least 90 mg , at least 100 mg, at least 200 mg , at peutic compound disclosed herein in the solution may be , least 300 mg, at least 400 mg, at least 500 mg, at least 600 25 e . g . , at most 1 , 000 mg/mL , at most 1 , 100 mg/ mL , at most mg, at least 700 mg, at least 800 mg, at least 900 mg, at least 1 , 200 mg/ mL , at most 1 , 300 mg/ mL , at most 1 , 400 mg/mL , 1 , 000 mg , at least 1 , 100 mg, at least 1 , 200 mg, at least 1 ,300 at most 1 ,500 mg/ mL , at most 2 , 000 mg/mL , at most 2 , 000 mg, at least 1 , 400 mg, or at least 1 ,500 mg. In other aspects mg/ mL , or at most 3 , 000 mg/ mL . In other aspects of this of this embodiment, the amount of a therapeutic compound embodiment, the concentration of a therapeutic compound that is contacted with the solvent in step ( a ) may be in the 30 disclosed herein in the solution may be in a range of, e . g . , range of , e . g . , about 10 mg to about 100 mg, about 50 mg about 0 . 00001 mg/ mL to about 3 , 000 mg/ mL , about 0 .0001 to about 150 mg, about 100 mg to about 250 mg, about 150 mg/mL to about 3 , 000 mg/ mL , about 0 .01 mg/ mL to about mg to about 350 mg, about 250 mg to about 500 mg, about 3 , 000 mg/mL , about 0 . 1 mg/mL to about 3 ,000 mg/ mL , 350 mg to about 600 mg, about 500 mg to about 750 mg, about 1 mg/ mL to about 3 ,000 mg/mL , about 250 mg/ mL to about 600 mg to about 900 mg, about 750 mg to about 1 ,000 35 about 3 ,000 mg/ mL , about 500 mg/ mL to about 3 , 000 mg, about 850 mg to about 1 , 200 mg, or about 1 , 000 mg to mg/ mL , about 750 mg/mL to about 3 ,000 mg/mL , about about 1 , 500 mg. In other aspects of this embodiment, the 1 , 000 mg/ mL to about 3 ,000 mg/mL , about 100 mg/ mL to amount of a therapeutic compound that is dissolved in the about 2, 000 mg/ mL , about 250 mg/mL to about 2, 000 solvent in step ( a ) may be in the range of, e . g . , about 10 mg mg/mL , about 500 mg/ mL to about 2 ,000 mg/ mL , about 750 to about 250 mg, about 10 mg to about 500 mg, about 10 mg 40 mg/ mL to about 2 , 000 mg/mL , about 1 , 000 mg/ mL to about to about 750 mg, about 10 mg to about 1 , 000 mg, about 10 2 , 000 mg/ mL , about 100 mg/ mL to about 1 ,500 mg/ mL , mg to about 1 , 500 mg , about 50 mg to about 250 mg, about about 250 mg/ mL to about 1, 500 mg/ mL , about 500 mg/ mL 50 mg to about 500 mg, about 50 mg to about 750 mg, about to about 1, 500 mg/mL , about 750 mg/ mL to about 1, 500 50 mg to about 1 , 000 mg, about 50 mg to about 1 ,500 mg, mg/ mL , about 1 , 000 mg/ mL to about 1 ,500 mg/mL , about about 100 mg to about 250 mg, about 100 mg to about 500 45 100 mg/mL to about 1 , 200 mg/mL , about 250 mg/ mL to mg, about 100 mg to about 750 mg, about 100 mg to about about 1, 200 mg/ mL , about 500 mg/ mL to about 1 ,200 1 ,000 mg, about 100 mg to about 1, 500 mg , about 200 mg mg/mL , about 750 mg/ mL to about 1 , 200 mg /mL , about to about 500 mg, about 200 mg to about 750 mg, about 2001 , 000 mg/mL to about 1 , 200 mg/mL , about 100 mg/ mL to mg to about 1 , 000 mg, or about 200 mg to about 1 ,500 mg. about 1 ,000 mg/ mL , about 250 mg/ mL to about 1 , 000 Step ( a ) may be carried out at room temperature, in order 50 mg/ mL , about 500 mg/ mL to about 1 ,000 mg/ mL , about 750 to allow a therapeutic compound to dissolve fully in the mg/ mL to about 1 , 000 mg/mL , about 100 mg/ mL to about pharmaceutically -acceptable solvent. However, in other 750 mg/ mL , about 250 mg /mL to about 750 mg/ mL , about embodiments of the method , Step ( a ) may be carried out at 500 mg/ mL to about 750 mg/mL , about 100 mg/ mL to about a temperature that is greater than room temperature . In 500 mg/ mL , about 250 mg/ mL to about 500 mg/mL , about aspects of this embodiment, Step ( a ) may be carried out at 55 0 .00001 mg/mL to about 0 . 0001 mg/ mL , about 0 .00001 a temperature that is , e . g . , greater than 21° C . , greater than mg/ mL to about 0 . 001 mg/ mL , about 0 .00001 mg/ mL to 25° C ., greater than 30° C ., greater than 35° C . or greater about 0 . 01 mg/ mL , about 0 . 00001 mg/mL to about 0 . 1 than 37° C . , greater than 40° C ., greater than 42° C . , greater mg/ mL , about 0 .00001 mg/ mL to about 1 mg/ mL , about than 45º C ., greater than 50° C . , greater than 55° C . , or 0 .001 mg/mL to about 0 .01 mg/mL , about 0 . 001 mg/mL to greater than 60° C . In aspects of this embodiment, Step ( a ) 60 about 0 . 1 mg/ mL , about 0 . 001 mg/ mL to about 1 mg/mL , may be carried out at a temperature that is between , e . g . , about 0 .001 mg/ mL to about 10 mg/mL , or about 0 .001 about 20° C . to about 30° C ., about 25° C . to about 35° C . , mg/ mL to about 100 mg/ mL . about 30° C . to about 40° C . , about 35° C . to about 45° C ., The volume of a pharmaceutically - acceptable adjuvant about 40° C . to about 50° C ., about 45° C . to about 55° C ., used in Step ( b ) of the method may be any volume desired . or about 50° C . to about 60° C . In certain cases, Step ( a ) may 65 Factors used to determine the volume of a pharmaceutically be carried out at temperatures below room temperature , in acceptable adjuvant used include , without limitation , the order to allow a therapeutic compound to dissolve fully in final amount of a pharmaceutical composition desired , the US 9 , 750 ,810 B2 33 34 desired concentration of a therapeutic compound in the greater than room temperature are used to allow a therapeu pharmaceutical composition , the ratio of solvent: adjuvant tic compound to dissolve fully in the pharmaceutically used , and the miscibility of solvent and adjuvant. acceptable solvent and /or to allow the solution comprising In aspects of this embodiment, the ratio of solution : the therapeutic compound to form the pharmaceutical com adjuvant may be , e . g . , at least 5 : 1 , at least 4 : 1 , at least 3 : 1 , 5 position . In aspects of this embodiment , a rapid cooling step at least 2 : 1, at least 0 : 1, at least 1 : 1 , at least 1 : 2 , at least 1 :3 , results in a temperature decrease of, e . g. , about 30° C . in 20 at least 1 : 4 , at least 1 : 5 , at least 1 : 6 , at least 1 : 7 , at least 1: 8 , minutes , about 25° C . in 20 minutes , about 20° C . in 20 at least 1 : 9 , at least 1 : 10 , at least 1 : 15 , at least 1 : 20 , or at minutes, about 15º C . in 20 minutes , about 30° C . in 15 least 1 : 25 . In other aspects of this embodiment, the ratio of minutes , about 25° C . in 15 minutes , about 20° C . in 15 solution : adjuvant may be in a range of, e . g . , about 5 : 1 to 10 minutes , about 15° C . in 15 minutes , about 30° C . in 10 about 1 : 25 , about 4 : 1 to about 1 :25 , about 3 : 1 to about 1 : 25 , minutes , about 25º C . in 10 minutes , about 20° C . in 10 about 2 : 1 to about 1: 25 , about 0 : 1 to about 1: 25 , about 1 :1 minutes, about 15º C . in 10 minutes, about 30° C . in 5 to about 1: 25 , about 1 : 2 to about 1 :25 , about 1 : 3 to about minutes , about 25° C . in 5 minutes, about 20° C . in 5 1 : 25, about 1 : 4 to about 1 :25 , about 1 : 5 to about 1 : 25 , about minutes, about 15° C . in 5 minutes . In other aspects of this 5 : 1 to about 1: 20 , about 4 : 1 to about 1: 20 , about 3 : 1 to about 15 embodiment, a rapid cooling step results in a temperature 1 : 20 , about 2 : 1 to about 1 : 20 , about 0 : 1 to about 1 : 20 , about decrease of, e . g . , about 20° C . to about 30° C . in 20 minutes , 1 : 1 to about 1 : 20 , about 1 : 2 to about 1 : 20 , about 1 : 3 to about about 20° C . to about 30° C . in 15 minutes , about 20° C . to 1 : 20 , about 1 : 4 to about 1 :20 , about 1 : 5 to about 1 : 20 , about about 30° C . in 10 minutes , about 20° C . to about 30° C . in 5 : 1 to about 1 : 15 , about 4 : 1 to about 1 : 15 , about 3 : 1 to about 5 minutes, about 15° C . to about 25° C . in 20 minutes, about 1 : 15 , about 0 : 1 to about 1 : 15 , about 2 : 1 to about 1 : 15 , about 20 15° C . to about 25° C . in 15 minutes , about 15° C . to about 1 : 1 to about 1 : 15 , about 1 : 2 to about 1 : 15 , about 1 : 3 to about 25° C . in 10 minutes , about 15° C . to about 25° C . in 5 1 : 15 , about 1 : 4 to about 1 : 15 , about 1 : 5 to about 1 : 15 , about minutes , about 10° C . to about 20° C . in 20 minutes, about 5 : 1 to about 1 : 12 , about 4 : 1 to about 1 : 12 , about 3 : 1 to about 10° C . to about 20° C . in 15 minutes , about 10° C . to about 1 : 12 , about 2 : 1 to about 1 : 12 , about 0 : 1 to about 1 : 12 , about 20° C . in 10 minutes , or about 10° C . to about 20° C . in 5 1 : 1 to about 1 : 12 , about 1 :2 to about 1: 12 , about 1 : 3 to about 25 minutes. 1 : 12 , about 1 : 4 to about 1 : 12 , about 1 : 5 to about 1 : 12 , about In yet aspects of this embodiment, a rapid cooling step 1 : 6 to about 1 : 12 , about 1 : 7 to about 1 : 12 , about 1 : 8 to about results in a temperature decrease of, e . g . , about 2 .0° C . /min 1 : 12 , about 5 : 1 to about 1 : 10 , about 4 : 1 to about 1 : 10 , about ute , about 1 .9° C . /minute , about 1 .8° C ./ minute , about 1 . 7° 3 : 1 to about 1 : 10 , about 2 : 1 to about 1 : 10 , about 0 : 1 to about C . /minute , about 1 .6° C . /minute , about 1 . 5° C . /minute , 1 : 10 , about 1 : 1 to about 1 : 10 , about 1 :2 to about 1 : 10 , about 30 about 1. 4° C ./ minute , about 1. 3° C ./ minute , about 1. 2° 1 : 3 to about 1 : 10 , about 1 : 4 to about 1 : 10 , about 1 : 5 to about C ./ minute , about 1 . 1° C . /minute , about 1 .0° C ./ minute , 1 : 10 , about 1 :6 to about 1 : 10 , about 1: 7 to about 1 : 10 , or about 0 . 9° C ./ minute , about 0 .8° C . /minute , about 0 . 7° about 1 : 8 to about 1 : 10 . C ./ minute , about 0 .6° C ./ minute , about 0 .5° C ./ minute , Step (b ) may be carried out at room temperature , in order about 0 .4° C ./ minute , about 0 .3° C . /minute , about 0 . 2° to allow the solution comprising the therapeutic compound 35 C . /minute , or about 0 . 1° C ./ minute . In still aspects of this to form the pharmaceutical composition . However , in other embodiment, a rapid cooling step results in a temperature embodiments of the method , Step ( b ) may be carried out at decrease of, e . g . , about 0 . 1° C . to about 0 . 4° C . /minute , a temperature that is greater than room temperature. In about 0 .2° C . to about 0 .6° C . /minute , about 0 . 4° C . to about aspects of this embodiment, Step ( b ) may be carried out at 0 .8° C ./ minute , about 0 .6° C . to about 1 . 0° C . /minute , about a temperature that is, e. g. , greater than 21° C ., greater than 40 0 .8° C . to about 1. 2° C ./ minute , about 1 .0° C . to about 1. 4° 25° C ., greater than 30° C ., greater than 35° C . or greater C ./ minute , about 1 . 2° C . to about 1 .6° C ./ minute , about 1 . 4° than 37° C . , greater than 40° C ., greater than 42° C ., greater C . to about 1 .8° C ./ minute , about 1 .6° C . to about 2 .0° than 45º C . , greater than 50° C ., greater than 55° C . , or C ./ minute , about 0 . 1°C . to about 0 . 5º C . /minute , about 0 . 5° greater than 60° C . In aspects of this embodiment, Step ( a ) C . to about 1 .0° C ./ minute , about 1. 0° C . to about 1. 5° may be carried out at a temperature that is between , e . g ., 45 C . /minute , about 1 . 5° C . to about 2 . 0° C . /minute , about 0 . 5° about 20° C . to about 30° C . , about 25° C . to about 35° C ., C . to about 1 . 5° C ./ minute , or about 1 .0° C . to about 2 .0° about 30° C . to about 40° C ., about 35° C . to about 45° C . , C . /minute . about 40° C . to about 50° C . , about 45° C . to about 55° C ., In some embodiments, temperatures greater than room or about 50° C . to about 60° C . In certain cases , Step (b )may temperature employed in either Step (a ) or Step ( b ) or both be carried out at temperatures below room temperature , in 50 may be used to remove the solvent from a pharmaceutical order to allow a therapeutic compound to dissolve fully in a composition . In other embodiment, removal of solvent from pharmaceutically -acceptable solvent. However , in other a pharmaceutical composition requires a separate Step ( c ). In embodiments of the method , step ( b ) may be carried out at Step ( c ) , the solvent removal from a pharmaceutical com a temperature that is less than room temperature , e. g. , less position may be accomplished using one of a variety of than 10° C . , greater than 5° C ., greater than 0° C . , greater 55 procedures known in the art , including , without limitation , than - 10° C . or greater than - 20° C . The contacting in Step evaporation , dialyzation , distillation , lypholization , and fil ( b ) may comprise mixing the solution and the pharmaceu - tration . These removal procedures may be done under con tically -acceptable adjuvant, e . g . , by stirring , inversion , soni- ditions of ambient atmosphere , under low pressure, or under cation , or vortexing. The mixing may be carried out for , e . g . , a vacuum and either at ambient temperature or at tempera at least 1 second , at least 5 seconds, at least 10 seconds, at 60 tures requiring heating . least 20 seconds, at least 30 seconds, at least 45 seconds, at In one embodiment, Step ( c ) may result in the complete least 60 seconds , or more , until the pharmaceutical compo - removal of a pharmaceutically -acceptable solvent from the sition is formed . pharmaceutical composition disclosed herein . In aspects of In certain embodiments , a rapid cooling step may be used this embodiment, Step ( c ) may result in , e . g ., at least 5 % , at to reduce the temperature of a pharmaceutical composition 65 least 10 % , at least 15 % , at least 20 % , at least 25 % , at least disclosed herein after its formation . For example , a rapid 30 % , at least 35 % , at least 40 % , at least 45 % , at least 50 % , cooling step may be used in procedures were temperatures at least 55 % , at least 60 % , at least 65 % , at least 70 % , at least US 9 ,750 ,810 B2 35 36 75 % , at least 80 % , at least 85 % , at least 90 % , at least 93 % , herein may be of any concentration desired . In an aspect of at least 95 % , at least 97 % , or at least 99 % removal of a this embodiment, the final concentration of a therapeutic pharmaceutically - acceptable solvent from the pharmaceuti compound in a pharmaceutical composition may be a thera cal composition disclosed herein . peutically effective amount. In other aspects of this embodi Step ( c ) is conducted at a temperature that allows for the 5 ment, the final concentration of a therapeutic compound in evaporation of a pharmaceutically - acceptable solvent dis - a pharmaceutical composition may be , e . g ., at least 0 .00001 closed herein , and as such , an evaporation temperature is mg/ mL , at least 0 . 0001 mg /mL , at least 0 . 001 mg/ ml , at solvent dependant. Factors which influence an evaporation least 0 . 01 mg/ mL , at least 0 . 1 mg/ mL , at least 1 mg/ mL , at temperature of a solvent disclosed herein include , without least 10 mg/ mL , at least 25 mg/ mL , at least 50 mg/ mL , at limitation , the particular solvent used , the amount of solvent 10 least 100 mg/ mL , at least 200 mg/ mL , at least 500 mg/mL , present, the particular therapeutic compound present, the at least 700 mg/ mL , at least 1 ,000 mg/mL , or at least 1 , 200 particular adjuvant present, the stability of the therapeutic mg/ mL . In other aspects of this embodiment, the concen compound present, the reactivity of the therapeutic com - tration of a therapeutic compound disclosed herein in the pound present , the particular atmospheric pressure used , the solution may be , e . g. , at most 1 ,000 mg/ mL , at most 1 , 100 time desired for complete evaporation . Generally , a phar- 15 mg /mL , at most 1 , 200 mg/mL , at most 1 , 300 mg/mL , at maceutical composition will require heating if the evapora - most 1 , 400 mg/mL , at most 1 , 500 mg/mL , at most 2 , 000 tion step is conducted at ambient pressure , e . g ., 1 atm . mg/ mL , at most 2 , 000 mg/mL , or at most 3 , 000 mg/ mL . In However, under high vacuum conditions, the evaporation other aspects of this embodiment, the final concentration of step may be conducted at temperatures below ambient a therapeutic compound in a pharmaceutical composition temperature , e . g ., less than 22° C . 20 may be in a range of , e . g . , about 0 .00001 mg/mL to about In one embodiment, removal of solvent from the phar - 3 , 000 mg/mL , about 0 . 0001 mg/ mL to about 3 ,000 mg/mL , maceutical composition disclosed herein may be carried out about 0 .01 mg/ mL to about 3 , 000 mg/ mL , about 0 . 1 mg/ mL at ambient atmospheric pressure and at a temperature above to about 3 ,000 mg/ mL , about 1 mg/mL to about 3 ,000 ambient temperature . In aspects of this embodiment, mg/ mL , about 250 mg/mL to about 3 , 000 mg/ mL , about 500 removal of solvent from the pharmaceutical composition 25 mg/ mL to about 3 , 000 mg/mL , about 750 mg/ mL to about disclosed herein may be carried out at ambient atmospheric 3 ,000 mg/ mL , about 1 ,000 mg/mL to about 3 , 000 mg/ mL , pressure and at a temperature of, e . g ., more than 25° C ., about 100 mg/ mL to about 2 ,000 mg/ mL , about 250 mg/ mL more than 30° C ., more than 35° C ., more than 40° C ., more to about 2 ,000 mg/ mL , about 500 mg/mL to about 2 ,000 than 45º C ., more than 50° C . , more than 55° C . , more than mg/ mL , about 750 mg/ mL to about 2 ,000 mg/ mL , about 60° C . , more than 65° C . , more than 70° C . , more than 80° 30 1 ,000 mg/mL to about 2 ,000 mg/mL , about 100 mg/mL to C . , or more than 25° C . In other aspects of this embodiment, about 1 ,500 mg/ mL , about 250 mg/ mL to about 1 ,500 removal of solvent from the pharmaceutical composition mg/ mL , about 500 mg/mL to about 1 , 500 mg/ mL , about 750 disclosed herein may be carried out at ambient atmospheric mg/ mL to about 1 , 500 mg/ mL , about 1 ,000 mg/mL to about pressure and at a temperature in a range of, e . g ., about 25º 1 , 500 mg/mL , about 100 mg/mL to about 1 , 200 mg/ mL , C . to about 100° C . , about 25° C . to about 95° C ., about 25° 35 about 250 mg/mL to about 1 , 200 mg/ mL , about 500 mg/mL C . to about 90° C . , about 25° C . to about 85° C . , about 25° to about 1 , 200 mg/mL , about 750 mg/mL to about 1 , 200 C . to about 80° C ., about 25° C . to about 75° C ., about 250 mg/ mL , about 1, 000 mg/mL to about 1, 200 mg/ mL , about C . to about 70° C ., about 25° C . to about 65° C ., or about 25° 100 mg/ mL to about 1, 000 mg/mL , about 250 mg/ mL to C . to about 60° C . about 1 , 000 mg/ mL , about 500 mg/ mL to about 1 , 000 In another embodiment, removal of solvent from the 40 mg/ mL , about 750 mg/mL to about 1 ,000 mg /mL , about 100 pharmaceutical composition disclosed herein may be carried mg/ mL to about 750 mg/mL , about 250 mg/mL to about 750 out under vacuum and at a temperature below ambient mg/mL , about 500 mg/ mL to about 750 mg/mL , about 100 temperature. In aspects of this embodiment, removal of mg/ mL to about 500 mg/ mL , about 250 mg/mL to about 500 solvent from the pharmaceutical composition disclosed mg/ mL , about 0 . 00001 mg/ mL to about 0 .0001 mg/ mL , herein may be carried out under vacuum and at a tempera - 45 about 0 .00001 mg/ mL to about 0. 001 mg/ mL , about 0 .00001 ture of, e . g . , less than 20° C . , less than 18° C ., less than 16° mg/ mL to about 0 .01 mg/ mL , about 0 .00001 mg/ mL to C . , less than 14° C . , less than 12° C . , less than 10° C . , less about 0 . 1 mg/mL , about 0 .00001 mg / mL to about 1 mg/ mL , than 8° C ., less than 6° C ., less than 4° C ., less than 2° C ., about 0 .001 mg/mL to about 0. 01 mg/mL , about 0 .001 or less than 0° C . In other aspects of this embodiment, mg/mL to about 0 . 1 mg/ mL , about 0 .001 mg/mL to about 1 removal of solvent from the pharmaceutical composition 50 mg/mL , about 0 .001 mg/ mL to about 10 mg/ mL , or about disclosed herein may be carried out under vacuum and at a 0 .001 mg/mL to about 100 mg/mL . temperature in a range of, e . g. , about - 20° C . to about 20° pharmaceutical composition produced using the meth C ., about - 20° C . to about 18° C ., about - 20° C . to about 16º o ds disclosed herein may be formulated for either local or C ., about - 20° C . to about 14° C ., about - 20° C . to about 12° systemic delivery using topical, enteral or parenteral routes C . , about - 20° C . to about 10° C ., about - 20° C . to about 8° 55 of administration . Additionally , a therapeutic compound C ., about - 20° C . to about 6° C ., about - 20° C . to about 4° disclosed herein may be formulated by itself in a pharma C . , about - 20° C . to about 2° C ., about - 20° C . to about 0° ceutical composition , or may be formulated together with C . , about - 15° C . to about 20° C ., about - 10° C . to about 20° one or more other therapeutic compounds disclosed herein C . , about - 5° C . to about 20° C . , about 0° C . to about 20° in a single pharmaceutical composition . C ., about - 10° C . to about 20° C ., about - 10° C . to about 18° 60 A pharmaceutical composition produced using the meth C ., about - 10° C . to about 16° C ., about - 10° C . to about 14° ods disclosed herein may be a liquid formulation , semi- solid C ., about - 10° C . to about 12° C . , about - 10° C . to about 10° formulation , or a solid formulation . A formulation disclosed C ., about - 10° C . to about 8° C ., about - 10° C . to about 6° herein can be produced in a manner to form one phase , such C ., about - 10° C . to about 4° C . , about - 10° C . to about 2° as, e . g . , an oil or a solid . Alternatively , a formulation C . , or about - 10° C . to about 0° C . 65 disclosed herein can be produced in a manner to form two The final concentration of a therapeutic compound dis - phase, such as, e . g ., an emulsion . A pharmaceutical compo closed herein in a pharmaceutical composition disclosed sition disclosed herein intended for such administration may US 9 ,750 ,810 B2 37 38 be prepared according to any method known to the art for the by weight, about 1 % to about 20 % by weight, about 1 % to manufacture of pharmaceutical compositions . Semi- solid about 15 % by weight, about 1 % to about 10 % by weight , formulations suitable for topical administration include , about 1 % to about 5 % by weight, about 5 % to about 45 % by without limitation , ointments , creams, salves, and gels. weight, about 5 % to about 40 % by weight, about 5 % to A liquid formulation may be formed by using various 5 about 35 % by weight , about 5 % to about 30 % by weight , lipids like oils of other fatty acids that remain as liquids in about 5 % to about 25 % by weight, about 5 % to about 20 % the temperature range desired . In an embodiment, a phar- by weight, about 5 % to about 15 % by weight, about 5 % to maceutical composition disclosed herein is liquid at room about 10 % by weight, about 10 % to about 45 % by weight, temperature . In aspects of this embodiment, a pharmaceu about 10 % to about 40 % by weight, about 10 % to about 35 % tical composition disclosed herein may be formulated to be 10 by weight, about 10 % to about 30 % by weight, about 10 % a liquid at a temperature of , e . g . , about 25° C . or higher , to about 25 % by weight, about 10 % to about 20 % by weight, about 23° C . or higher , about 21° C . or higher , about 19° C . about 10 % to about 15 % by weight, about 15 % to about 45 % or higher , about 17° C . or higher, about 15° C . or higher, by weight, about 15 % to about 40 % by weight, about 15 % about 12° C . or higher, about 10° C . or higher, about 8° C . to about 35 % by weight, about 15 % to about 30 % by weight, or higher , about 6° C . or higher, about 4° C . or higher, or 15 about 15 % to about 25 % by weight, about 15 % to about 20 % about 0° C . or higher. by weight, about 20 % to about 45 % by weight, about 20 % In liquid and semi- solid formulations , a concentration of to about 40 % by weight , about 20 % to about 35 % by weight, a therapeutic compound disclosed herein typically may be about 20 % to about 30 % by weight, about 20 % to about 25 % between about 50 mg/mL to about 1 , 000 mg/mL . In aspects by weight, about 25 % to about 45 % by weight, about 25 % of this embodiment, a therapeutically effective amount of a 20 to about 40 % by weight, about 25 % to about 35 % by weight, therapeutic compound disclosed herein may be from , e . g . , or about 25 % to about 30 % by weight. about 50 mg/ mL to about 100 mg/ mL , about 50 mg/ mL to In one embodiment, a liquid formulation comprises a about 200 mg/mL , about 50 mg/mL to about 300 mg/mL , therapeutic compound , a glycol ether , a partially -hydroge about 50 mg/mL to about 400 mg /mL , about 50 mg /mL to nated fat, an oil, and an alcohol. In an aspect of this about 500 mg/mL , about 50 mg/mL to about 600 mg/mL , 25 embodiment, a liquid formulation comprises about 15 % to about 50 mg/ mL to about 700 mg/mL , about 50 mg/ mL to about 35 % by weight of therapeutic compound , about 5 % to about 800 mg/mL , about 50 mg/mL to about 900 mg/mL , about 25 % by weight of glycol ether, about 15 % to about about 50 mg/mL to about 1 , 000 mg/ mL , about 100 mg /mL 40 % by weight of partially -hydrogenated fat , about 15 % to to about 200 mg/mL , about 100 mg/ mL to about 300 about 40 % of an oil , and about 1 % to about 15 % of an mg/ mL , about 100 mg/ mL to about 400 mg/mL , about 100 30 alcohol. In another aspect of this embodiment, a liquid mg /mL to about 500 mg/ mL , about 100 mg/mL to about 600 formulation comprises about 20 % to about 30 % by weight mg/ mL , about 100 mg/ mL to about 700 mg/mL , about 100 of therapeutic compound , about 10 % to about 20 % by mg/ mL to about 800 mg/mL , about 100 mg/ mL to about 900 weight of glycol ether, about 20 % to about 35 % by weight mg/ mL , about 100 mg/ mL to about 1 ,000 mg/mL , about 200 of partially -hydrogenated fat, about 20 % to about 35 % of an mg/ mL to about 300 mg/ mL , about 200 mg /mL to about 400 35 oil, and about 2 % to about 10 % of an alcohol. In yet another mg/mL , about 200 mg/ mL to about 500 mg/ mL , about 200 aspect of this embodiment , a liquid formulation comprises mg/ mL to about 600 mg/ mL , about 200 mg/ mL to about 700 about 23 % to about 27 % by weight of therapeutic com mg/mL , about 200 mg /mL to about 800 mg/ mL , about 200 pound , about 13 % to about 17 % by weight of glycol ether , mg/mL to about 900 mg/ mL , about 200 mg/ mL to about about 25 % to about 30 % by weight of partially -hydroge 1 , 000 mg/ mL , about 300 mg/ mL to about 400 mg /mL , about 40 nated fat, about 25 % to about 30 % of an oil , and about 4 % 300 mg /mL to about 500 mg/mL , about 300 mg/ mL to about to about 8 % of an alcohol. In still another aspect of this 600 mg/mL , about 300 mg/ mL to about 700 mg/mL , about embodiment, a liquid formulation comprises about 24 % to 300 mg/mL to about 800 mg /mL , about 300 mg/mL to about about 26 % by weight of therapeutic compound , about 14 % 900 mg/mL , about 300 mg/mL to about 1 ,000 mg/ mL , about to about 16 % by weight of glycol ether , about 26 % to about 400 mg/mL to about 500 mg/mL , about 400 mg/mL to about 45 28 % by weight of partially -hydrogenated fat, about 26 % to 600 mg/ mL , about 400 mg/ mL to about 700 mg/ mL , about about 28 % of an oil , and about 5 % to about 7 % of an 400 mg/mL to about 800 mg/mL , about 400 mg/mL to about alcohol. In other aspects of this embodiment , an oil is 900 mg/ mL , about 400 mg/ mL to about 1 , 000 mg/ mL , about rapeseed oil or theobroma oil . 500 mg /mL to about 600 mg/mL , about 500 mg/mL to about In another embodiment, a liquid formulation comprises a 700 mg/ mL , about 500 mg/mL to about 800 mg/ mL , about 50 therapeutic compound , a glycol ether, a glyceryl monoli 500 mg /mL to about 900 mg/mL , about 500 mg/mL to about noleate , an oil , and an alcohol. In an aspect of this embodi 1, 000 mg/ mL , about 600 mg/ mL to about 700 mg/ mL , about ment, a liquid formulation comprises about 15 % to about 600 mg/ mL to about 800 mg/mL , about 600 mg/ mL to about 35 % by weight of therapeutic compound , about 5 % to about 900 mg/ mL , or about 600 mg/mL to about 1 ,000 mg/mL . 25 % by weight of glycol ether , about 15 % to about 40 % by In semi- solid and solid formulations , an amount of a 55 weight of glyceryl monolinoleate , about 15 % to about 40 % therapeutic compound disclosed herein typically may be of an oil, and about 1 % to about 15 % of an alcohol. In between about 0 .01 % to about 45 % by weight. In aspects of another aspect of this embodiment, a liquid formulation this embodiment, an amount of a therapeutic compound comprises about 20 % to about 30 % by weight of therapeutic disclosed herein may be from , e . g ., about 0 . 1 % to about 45 % compound , about 10 % to about 20 % by weight of glycol by weight, about 0 . 1 % to about 40 % by weight, about 0 . 1 % 60 ether, about 20 % to about 35 % by weight of glyceryl to about 35 % by weight, about 0 . 1 % to about 30 % by monolinoleate , about 20 % to about 35 % of an oil , and about weight, about 0 . 1 % to about 25 % by weight, about 0 . 1 % to 2 % to about 10 % of an alcohol. In yet another aspect of this about 20 % by weight, about 0 . 1 % to about 15 % by weight, embodiment, a liquid formulation comprises about 23 % to about 0 . 1 % to about 10 % by weight, about 0 . 1 % to about 5 % about 27 % by weight of therapeutic compound, about 13 % by weight, about 1 % to about 45 % by weight, about 1 % to 65 to about 17 % by weight of glycol ether, about 25 % to about about 40 % by weight, about 1 % to about 35 % by weight, 30 % by weight of glyceryl monolinoleate , about 25 % to about 1 % to about 30 % by weight, about 1 % to about 25 % about 30 % of an oil, and about 4 % to about 8 % of an US 9 , 750 , 810 B2 39 40 alcohol. In still another aspect of this embodiment , a liquid by weight of therapeutic compound , about 2 % to about 6 % formulation comprises about 24 % to about 26 % by weight by weight of an ethyl acetate, and about 87 % to about 95 % of therapeutic compound , about 14 % to about 16 % by of an oil . In still another aspect of this embodiment, a liquid weight of glycol ether, about 26 % to about 28 % by weight formulation comprises about 4 % to about 6 % by weight of of glycerylmonolinoleate , about 26 % to about about 28 % of 5 therapeutic compound , about 3 % to about 5 % by weight of an oil , and about 5 % to about 7 % of an alcohol. In other an ethyl acetate , and about 90 % to about 92 % of an oil . In aspects of this embodiment, an oil is rapeseed oil or theo - other aspects of this embodiment, an oil is rapeseed oil or broma oil. theobroma oil . In another embodiment, a liquid formulation comprises an In another embodiment, a liquid formulation comprises an ibuprofen , a diethylene glycol monoethyl ether , a glyceryl 10 ibuprofen , an ethyl acetate , and an oil. In an aspect of this monolinoleate , an oil , and an alcohol. In an aspect of this embodiment, a liquid formulation comprises about 1 % to embodiment, a liquid formulation comprises about 15 % to about 10 % by weight of an ibuprofen , about 1 % to about about 35 % by weight of an ibuprofen , about 5 % to about 10 % by weight of an ethyl acetate , and about 80 % to about 25 % by weight of diethylene glycol monoethyl ether , about 98 % of an oil. In another aspect of this embodiment, a liquid 15 % to about 40 % by weight of glyceryl monolinoleate , 15 formulation comprises about 2 % to about 8 % by weight of about 15 % to about 40 % of an oil , and about 1 % to about an ibuprofen , about 1 % to about 7 % by weight of an ethyl 15 % of an alcohol. In another aspect of this embodiment, a acetate , and about 85 % to about 97 % of an oil . In yet another liquid formulation comprises about 20 % to about 30 % by aspect of this embodiment, a liquid formulation comprises weight of an ibuprofen , about 10 % to about 20 % by weight about 3 % to about 7 % by weight of an ibuprofen , about 2 % of diethylene glycol monoethyl ether, about 20 % to about 20 to about 6 % by weight of an ethyl acetate , and about 87 % 35 % by weight of glyceryl monolinoleate , about 20 % to to about 95 % of an oil . In still another aspect of this about 35 % of an oil , and about 2 % to about 10 % of an embodiment, a liquid formulation comprises about 4 % to alcohol . In yet another aspect of this embodiment, a liquid about 6 % by weight of an ibuprofen , about 3 % to about 5 % formulation comprises about 23 % to about 27 % by weight by weight of an ethyl acetate , and about 90 % to about 92 % of an ibuprofen , about 13 % to about 17 % by weight of 25 of an oil . In other aspects of this embodiment, an ibuprofen diethylene glycol monoethyl ether , about 25 % to about 30 % may be a free acid of a salt of ibuprofen . In other aspects of by weight of glyceryl monolinoleate , about 25 % to about this embodiment, an oil is rapeseed oil or theobroma oil . 30 % of an oil, and about 4 % to about 8 % of an alcohol. In In one embodiment, a solid or semi- solid formulation still another aspect of this embodiment, a liquid formulation disclosed herein is formulated without a hydrophilic solvent comprises about 24 % to about 26 % by weight of an ibu - 30 like water. Such formulations result in the formation of profen , about 14 % to about 16 % by weight of diethylene co - crystals of the lipids and therapeutic compound . Stated glycolmonoethyl ether, about 26 % to about 28 % by weight another way , such formulations do not form liposomal of glyceryl monolinoleate , about 26 % to about 28 % of an emulsions and / or micellular particles , which require hydro oil , and about 5 % to about 7 % of an alcohol. In other aspects philic solvent . of this embodiment, an ibuprofen may be a free acid of a salt 35 In one embodiment, a solid formulation comprises a of ibuprofen . In other aspects of this embodiment, an oil is therapeutic compound , a hard fat , a partially -hydrogenated rapeseed oil or theobroma oil. fat, and a polyethylene glycol. In an aspect of this embodi In one embodiment, a liquid formulation comprises a ment, a solid formulation comprises about 1 % to about 30 % therapeutic compound , an ester of an alcohol, and an oil . In by weight of therapeutic compound , about 8 % to about 70 % an aspect of this embodiment, a liquid formulation com - 40 by weight of hard fat, about 2 % to about 65 % by weight of prises about 1 % to about 10 % by weight of therapeutic partially - hydrogenated fat , and about 1 % to about 15 % of compound , about 1 % to about 10 % by weight of an ester of polyethylene glycol. In another aspect of this embodiment, an alcohol, and about 80 % to about 98 % of an oil. In another a solid formulation comprises about 10 % to about 30 % by aspect of this embodiment, a liquid formulation comprises weight of therapeutic compound , about 20 % to about 50 % about 2 % to about 8 % by weight of therapeutic compound , 45 by weight of hard fat, about 10 % to about 30 % by weight of about 1 % to about 7 % by weight of an ester of an alcohol, partially - hydrogenated fat, and about 5 % to about 15 % of and about 85 % to about 97 % of an oil. In yet another aspect polyethylene glycol. In yet another aspect of this embodi of this embodiment, a liquid formulation comprises about ment, a solid formulation comprises about 20 % to about 3 % to about 7 % by weight of therapeutic compound, about 30 % by weight of therapeutic compound , about 30 % to 2 % to about 6 % by weight of an ester of an alcohol, and 50 about 50 % by weight of hard fat, about 10 % to about 30 % about 87 % to about 95 % of an oil . In still another aspect of by weight of partially -hydrogenated fat, and about 7 % to this embodiment, a liquid formulation comprises about 4 % about 13 % of polyethylene glycol. In still another aspect of to about 6 % by weight of therapeutic compound , about 3 % this embodiment, a solid formulation comprises about 20 % to about 5 % by weight of an ester of an alcohol, and about to about 30 % by weight of therapeutic compound , about 90 % to about 92 % of an oil. In other aspects of this 55 35 % to about 50 % by weight of hard fat, about 15 % to about embodiment, an oil is rapeseed oil or theobroma oil . 25 % by weight of partially -hydrogenated fat, and about 7 % In another embodiment, a liquid formulation comprises a to about 13 % of polyethylene glycol. In a further aspect of therapeutic compound , an ethyl acetate , and an oil. In an this embodiment, a solid formulation comprises about 23 % aspect of this embodiment, a liquid formulation comprises to about 27 % by weight of therapeutic compound , about about 1 % to about 10 % by weight of therapeutic compound , 60 41 % to about 47 % by weight of hard fat, about 18 % to about about 1 % to about 10 % by weight of an ethyl acetate , and 22 % by weight of partially -hydrogenated fat, and about 9 % about 80 % to about 98 % of an oil . In another aspect of this to about 11 % of polyethylene glycol. In other aspects of this embodiment, a liquid formulation comprises about 2 % to embodiment, a polyethylene glycol is , e . g. , a PEG 100 , a about 8 % by weight of therapeutic compound , about 1 % to PEG 200 , a PEG 300 , a PEG 400 , a PEG 500 , a PEG 600 , about 7 % by weight of an ethyl acetate , and about 85 % to 65 or a PEG 700 . about 97 % of an oil . In yet another aspect of this embodi - In another embodiment , a solid formulation comprises a ment, a liquid formulation comprises about 3 % to about 7 % therapeutic compound , a mixture of mono -, di- , and triglyc US 9 , 750 ,810 B2 erides and PEG fatty acid esters , a glyceryl monolinoleate , noleate , and about 9 % to about 11 % of polyethylene glycol. and a polyethylene glycol. In an aspect of this embodiment, In other aspects of this embodiment, a polyethylene glycol a solid formulation comprises about 1 % to about 30 % by is , e . g . , a PEG 100 , a PEG 200 , a PEG 300 , a PEG 400 , a weight of therapeutic compound , about 8 % to about 70 % by PEG 500 , a PEG 600 , or a PEG 700 . weight of a mixture ofmono - , di- , and triglycerides and PEG 5 In another embodiment, a solid formulation comprises a fatty acid esters , about 2 % to about 65 % by weight of a therapeutic compound , a hard fat, a partially -hydrogenated glyceryl monolinoleate , and about 1 % to about 15 % of fat , a polyethylene glycol, and a propylene glycol. In an polyethylene glycol. In another aspect of this embodiment, aspect of this embodiment , a solid formulation comprises a solid formulation comprises about 10 % to about 30 % by about 1 % to about 30 % by weight of therapeutic compound , weight of therapeutic compound , about 20 % to about 50 % 10 about 8 % to about 70 % by weight of hard fat, about 2 % to by weight of a mixture of mono - , di - , and triglycerides and about 65 % by weight of partially -hydrogenated fat , about PEG fatty acid esters , about 10 % to about 30 % by weight of 1 % to about 15 % of polyethylene glycol, and about 1 % to a glyceryl monolinoleate , and about 5 % to about 15 % of about 15 % of propylene glycol. In another aspect of this polyethylene glycol . In yet another aspect of this embodi embodiment, a solid formulation comprises about 10 % to ment, a solid formulation comprises about 20 % to about 15 about 30 % by weight of therapeutic compound , about 20 % 30 % by weight of therapeutic compound , about 30 % to to about 50 % by weight of hard fat, about 10 % to about 30 % about 50 % by weight of a mixture of mono - , di- , and by weight of partially -hydrogenated fat , about 5 % to about triglycerides and PEG fatty acid esters , about 10 % to about 15 % of polyethylene glycol, and about 5 % to about 15 % of 30 % by weight of a glycerylmonolinoleate , and about 7 % propylene glycol. In yet another aspect of this embodiment, to about 13 % of polyethylene glycol . In still another aspect 20 a solid formulation comprises about 20 % to about 30 % by of this embodiment , a solid formulation comprises about weight of therapeutic compound , about 30 % to about 50 % 20 % to about 30 % by weight of therapeutic compound , by weight of hard fat, about 10 % to about 30 % by weight of about 35 % to about 50 % by weight of a mixture of mono -, partially -hydrogenated fat , about 7 % to about 13 % of poly di- , and triglycerides and PEG fatty acid esters , about 15 % ethylene glycol, and about 7 % to about 13 % of propylene to about 25 % by weight of a glyceryl monolinoleate , and 25 glycol. In still another aspect of this embodiment, a solid about 7 % to about 13 % of polyethylene glycol. In a further formulation comprises about 20 % to about 30 % by weight aspect of this embodiment, a solid formulation comprises of therapeutic compound , about 35 % to about 50 % by about 23 % to about 27 % by weight of therapeutic com - weight of hard fat, about 15 % to about 25 % by weight of pound , about 41 % to about 47 % by weight of a mixture of partially -hydrogenated fat , about 7 % to about 13 % of poly mono - , di- , and triglycerides and PEG fatty acid esters , 30 ethylene glycol, and about 7 % to about 13 % of propylene about 18 % to about 22 % by weight of a glyceryl monoli - glycol. In a further aspect of this embodiment , a solid noleate, and about 9 % to about 11 % of polyethylene glycol. formulation comprises about 23 % to about 27 % by weight In other aspects of this embodiment, a polyethylene glycol of therapeutic compound , about 41 % to about 47 % by is , e . g . , a PEG 100 , a PEG 200 , a PEG 300 , a PEG 400 , a weight of hard fat, about 18 % to about 22 % by weight of PEG 500 , a PEG 600 , or a PEG 700 . 35 partially -hydrogenated fat , about 9 % to about 11 % of poly In another embodiment, a solid formulation comprises an ethylene glycol, and about 9 % to about 11 % of propylene ibuprofen , a mixture of mono -, di- , and triglycerides and glycol. In other aspects of this embodiment, a polyethylene PEG fatty acid esters , a glyceryl monolinoleate , and a glycol is , e . g ., a PEG 100 , a PEG 200 , a PEG 300 , a PEG polyethylene glycol. In an aspect of this embodiment, a solid 400 , a PEG 500 , a PEG 600 , or a PEG 700 . formulation comprises about 1 % to about 30 % by weight of 40 In another embodiment , a solid formulation comprises a an ibuprofen , about 8 % to about 70 % by weight of a mixture therapeutic compound , a mixture of mono - , di- , and triglyc of mono - , di - , and triglycerides and PEG fatty acid esters , erides and PEG fatty acid esters , a glyceryl monolinoleate , about 2 % to about 65 % by weight of a glyceryl monoli- a polyethylene glycol, and a propylene glycol . In an aspect noleate , and about 1 % to about 15 % of polyethylene glycol. of this embodiment, a solid formulation comprises about 1 % In another aspect of this embodiment, a solid formulation 45 to about 30 % by weight of therapeutic compound , about 8 % comprises about 10 % to about 30 % by weight of an ibu - to about 70 % by weight of a mixture of mono - , di- , and profen , about 20 % to about 50 % by weight of a mixture of triglycerides and PEG fatty acid esters , about 2 % to about mono - , di- , and triglycerides and PEG fatty acid esters , 65 % by weight of a glyceryl monolinoleate , about 1 % to about 10 % to about 30 % by weight of a glyceryl monoli - about 15 % of polyethylene glycol, and about 1 % to about noleate , and about 5 % to about 15 % of polyethylene glycol. 50 15 % of propylene glycol. In another aspect of this embodi In yet another aspect of this embodiment, a solid formulation ment, a solid formulation comprises about 10 % to about comprises about 20 % to about 30 % by weight of an ibu - 30 % by weight of therapeutic compound , about 20 % to profen , about 30 % to about 50 % by weight of a mixture of about 50 % by weight of a mixture of mono - , di- , and mono -, di- , and triglycerides and PEG fatty acid esters , triglycerides and PEG fatty acid esters , about 10 % to about about 10 % to about 30 % by weight of a glyceryl monoli - 55 30 % by weight of a glyceryl monolinoleate , about 5 % to noleate , and about 7 % to about 13 % of polyethylene glycol. about 15 % of polyethylene glycol, and about 5 % to about In still another aspect of this embodiment, a solid formula 15 % of propylene glycol. In yet another aspect of this tion comprises about 20 % to about 30 % by weight of an embodiment, a solid formulation comprises about 20 % to ibuprofen , about 35 % to about 50 % by weight of a mixture about 30 % by weight of therapeutic compound , about 30 % of mono - , di - , and triglycerides and PEG fatty acid esters , 60 to about 50 % by weight of a mixture of mono - , di - , and about 15 % to about 25 % by weight of a glyceryl monoli - triglycerides and PEG fatty acid esters , about 10 % to about noleate, and about 7 % to about 13 % of polyethylene glycol. 30 % by weight of a glyceryl monolinoleate, and about 7 % In a further aspect of this embodiment, a solid formulation to about 13 % of polyethylene glycol, and about 7 % to about comprises about 23 % to about 27 % by weight of an ibu - 13 % of propylene glycol. In still another aspect of this profen , about 41 % to about 47 % by weight of a mixture of 65 embodiment, a solid formulation comprises about 20 % to mono - , di- , and triglycerides and PEG fatty acid esters , about 30 % by weight of therapeutic compound, about 35 % about 18 % to about 22 % by weight of a glyceryl monoli - to about 50 % by weight of a mixture of mono -, di- , and US 9 , 750 , 810 B2 43 44 triglycerides and PEG fatty acid esters , about 15 % to about about 25 % to about 45 % by weight of partially -hydroge 25 % by weight of a glyceryl monolinoleate , about 7 % to nated fat, about 8 % to about 18 % of polyethylene glycol , about 13 % of polyethylene glycol, and about 7 % to about and about 2 % to about 6 % of propylene glycol. In another 13 % of propylene glycol. In a further aspect of this embodi- aspect of this embodiment, a semi- solid formulation com ment, a solid formulation comprises about 23 % to about 5 prises about 20 % to about 50 % by weight of therapeutic 27 % by weight of therapeutic compound , about 41 % to compound , about 10 % to about 16 % by weight of hard fat , about 47 % by weight of a mixture of mono - , di- , and about 25 % to about 45 % by weight of partially - hydroge triglycerides and PEG fatty acid esters , about 18 % to about 22 % by weight of a glyceryl monolinoleate , about 9 % to nated fat, about 10 % to about 16 % of polyethylene glycol, about 11 % of polyethylene glycol, and about 9 % to about 10 and about 2 % to about 6 % of propylene glycol. In yet 11 % of propylene glycol. In other aspects of this embodi another aspect of this embodiment, a semi- solid formulation ment, a polyethylene glycol is , e . g . , a PEG 100 , a PEG 200 , comprises about 20 % to about 50 % by weight of therapeutic a PEG 300 , a PEG 400 , a PEG 500 , a PEG 600 , or a PEG compound , about 11 % to about 15 % by weight of hard fat, 700 . about 30 % to about 40 % by weight of partially -hydroge In another embodiment, a solid formulation compriseses an 1515 hatenated fat, about 11 % to about 15 % of polyethylene glycol, ibuprofen , a mixture of mono - , di- , and triglycerides and and about 3 % to about 5 % of propylene glycol. In still PEG fatty acid esters, a glyceryl monolinoleate, a polyeth - another aspect of this embodiment, a semi- solid formulation ylene glycol, and a propylene glycol. In an aspect of this comprises about 25 % to about 44 % by weight of therapeutic embodiment, a solid formulation comprises about 1 % to compound , about 12 % to about 14 % by weight of hard fat , about 30 % by weight of an ibuprofen , about 8 % to about 20 about 32 % to about 39 % by weight of partially -hydroge 70 % by weight of a mixture ofmono - , di- , and triglycerides nated fat, about 12 % to about 14 % of polyethylene glycol, and PEG fatty acid esters , about 2 % to about 65 % by weight and about 4 % of propylene glycol. In other aspects of this of a glyceryl monolinoleate , about 1 % to about 15 % of embodiment, a polyethylene glycol is , e . g . , a PEG 100 , a polyethylene glycol, and about 1 % to about 15 % of propyl- PEG 200 , a PEG 300 , a PEG 400 , a PEG 500 , a PEG 600 , ene glycol. In another aspect of this embodiment, a solid 25 or a PEG 700 . formulation comprises about 10 % to about 30 % by weight In another embodiment, a semi- solid formulation com of an ibuprofen , about 20 % to about 50 % by weight of a prises a therapeutic compound , a mixture of mono -, di -, and mixture of mono - , di- , and triglycerides and PEG fatty acid triglycerides and PEG fatty acid esters, a glyceryl monoli esters , about 10 % to about 30 % by weight of a glyceryl noleate , a polyethylene glycol, and a propylene glycol. In an monolinoleate , about 5 % to about 15 % of polyethylene 30 aspect of this embodiment , a semi- solid formulation com glycol , and about 5 % to about 15 % of propylene glycol. In prises about 15 % to about 55 % by weight of therapeutic yet another aspect of this embodiment, a solid formulation compound , about 7 % to about 20 % by weight of a mixture comprises about 20 % to about 30 % by weight of an ibu - of mono - , di - , and triglycerides and PEG fatty acid esters , profen , about 30 % to about 50 % by weight of a mixture of about 20 % to about 50 % by weight of a glyceryl monoli mono - , di -, and triglycerides and PEG fatty acid esters , 35 noleate , about 7 % to about 20 % of polyethylene glycol, and about 10 % to about 30 % by weight of a glyceryl monoli - about 1 % to about 8 % of propylene glycol. In another aspect noleate , and about 7 % to about 13 % of polyethylene glycol , of this embodiment , a semi- solid formulation comprises and about 7 % to about 13 % of propylene glycol. In still about 20 % to about 50 % by weight of therapeutic com another aspect of this embodiment, a solid formulation pound , about 8 % to about 18 % by weight of a mixture of comprises about 20 % to about 30 % by weight of an ibu - 40 mono - , di- , and triglycerides and PEG fatty acid esters , profen , about 35 % to about 50 % by weight of a mixture of about 25 % to about 45 % by weight of a glyceryl monoli mono - , di- , and triglycerides and PEG fatty acid esters , noleate , about 8 % to about 18 % of polyethylene glycol, and about 15 % to about 25 % by weight of a glyceryl monoli about 2 % to about 6 % of propylene glycol. In another aspect noleate, about 7 % to about 13 % of polyethylene glycol, and of this embodiment, a semi- solid formulation comprises about 7 % to about 13 % of propylene glycol. In a further 45 about 20 % to about 50 % by weight of therapeutic com aspect of this embodiment, a solid formulation comprises pound , about 10 % to about 16 % by weight of a mixture of about 23 % to about 27 % by weight of an ibuprofen , about mono - , di -, and triglycerides and PEG fatty acid esters , 41 % to about 47 % by weight of a mixture ofmono - , di - , and about 25 % to about 45 % by weight of a glyceryl monoli triglycerides and PEG fatty acid esters , about 18 % to about noleate , about 10 % to about 16 % of polyethylene glycol, 22 % by weight of a glyceryl monolinoleate , about 9 % to 50 and about 2 % to about 6 % of propylene glycol. In yet about 11 % of polyethylene glycol, and about 9 % to about another aspect of this embodiment, a semi- solid formulation 11 % of propylene glycol. In other aspects of this embodi comprises about 20 % to about 50 % by weight of therapeutic ment, a polyethylene glycol is , e . g. , a PEG 100 , a PEG 200 , compound , about 11 % to about 15 % by weight of a mixture a PEG 300 , a PEG 400 , a PEG 500 , a PEG 600 , or a PEG of mono - , di- , and triglycerides and PEG fatty acid esters , 700 . 55 about 30 % to about 40 % by weight of a glyceryl monoli In another embodiment, a semi- solid formulation com - noleate , and about 11 % to about 15 % of polyethylene glycol, prises a therapeutic compound , a hard fat, a partially - and about 3 % to about 5 % of propylene glycol. In still hydrogenated fat, a polyethylene glycol, and a propylene another aspect of this embodiment, a semi- solid formulation glycol. In an aspect of this embodiment, a semi- solid for comprises about 25 % to about 44 % by weight of therapeutic mulation comprises about 15 % to about 55 % by weight of 60 compound , about 12 % to about 14 % by weight of a mixture therapeutic compound , about 7 % to about 20 % by weight of ofmono - , di- , and triglycerides and PEG fatty acid esters , hard fat, about 20 % to about 50 % by weight of partially about 32 % to about 39 % by weight of a glyceryl monoli hydrogenated fat, about 7 % to about 20 % of polyethylene noleate , about 12 % to about 14 % of polyethylene glycol, glycol, and about 1 % to about 8 % of propylene glycol. In and about 4 % of propylene glycol. In other aspects of this another aspect of this embodiment, a semi- solid formulation 65 embodiment, a polyethylene glycol is , e. g ., a PEG 100 , a comprises about 20 % to about 50 % by weight of therapeutic PEG 200 , a PEG 300 , a PEG 400 , a PEG 500 , a PEG 600 , compound , about 8 % to about 18 % by weight of hard fat , or a PEG 700 . US 9 ,750 ,810 B2 45 46 In another embodiment, a semi- solid formulation com a semi- solid formulation comprises about 20 % to about 24 % prises an ibuprofen , a mixture ofmono - , di- , and triglycer - by weight of a free acid of a therapeutic compound , about ides and PEG fatty acid esters , a glyceryl monolinoleate , a 5 % to about 20 % by weight of a salt of a therapeutic polyethylene glycol, and a propylene glycol. In an aspect of compound , about 12 % to about 14 % by weight of hard fat , this embodiment, a semi- solid formulation comprises about 5 about 32 % to about 39 % by weight of partially -hydroge 15 % to about 55 % by weight of an ibuprofen , about 7 % to nated fat , about 12 % to about 14 % of polyethylene glycol, about 20 % by weight of a mixture of mono -, di- , and and about 4 % of propylene glycol. In other aspects of this triglycerides and PEG fatty acid esters, about 20 % to about embodiment, a polyethylene glycol is , e . g ., a PEG 100 , a 50 % by weight of a glyceryl monolinoleate , about 7 % to PEG 200 , a PEG 300 , a PEG 400 , a PEG 500 , a PEG 600 , about 20 % of polyethylene glycol, and about 1 % to about 10 or a PEG 700 . 8 % of propylene glycol. In another aspect of this embodi- In another embodiment, a semi- solid formulation com ment, a semi- solid formulation comprises about 20 % to prises a therapeutic compound , a mixture of mono -, di - , and about 50 % by weight of an ibuprofen , about 8 % to about triglycerides and PEG fatty acid esters, a glyceryl monoli 18 % by weight of a mixture of mono -, di- , and triglycerides noleate , a polyethylene glycol, and a propylene glycol. In an and PEG fatty acid esters , about 25 % to about 45 % by 15 aspect of this embodiment, a semi- solid formulation com weight of a glyceryl monolinoleate , about 8 % to about 18 % prises about 10 % to about 35 % by weight of a free acid of of polyethylene glycol, and about 2 % to about 6 % of a therapeutic compound , about 1 % to about 30 % by weight propylene glycol. In another aspect of this embodiment, a of a salt of a therapeutic compound , about 7 % to about 20 % semi- solid formulation comprises about 20 % to about 50 % by weight of a mixture of mono - , di- , and triglycerides and by weight of an ibuprofen , about 10 % to about 16 % by 20 PEG fatty acid esters, about 20 % to about 50 % by weight of weight of a mixture ofmono - , di- , and triglycerides and PEG a glyceryl monolinoleate , about 7 % to about 20 % of poly fatty acid esters , about 25 % to about 45 % by weight of a ethylene glycol, and about 1 % to about 8 % of propylene glyceryl monolinoleate, about 10 % to about 16 % of poly - glycol . In another aspect of this embodiment, a semi- solid ethylene glycol, and about 2 % to about 6 % of propylene formulation comprises about 15 % to about 30 % by weight glycol. In yet another aspect of this embodiment, a semi- 25 of a free acid of a therapeutic compound , about 1 % to about solid formulation comprises about 20 % to about 50 % by 25 % by weight of a salt of a therapeutic compound , about weight of an ibuprofen , about 11 % to about 15 % by weight 10 % to about 16 % by weight of a mixture of mono -, di- , and of a mixture of mono - , di - , and triglycerides and PEG fatty triglycerides and PEG fatty acid esters , about 25 % to about acid esters , about 30 % to about 40 % by weight of a glyceryl 45 % by weight of a glyceryl monolinoleate , about 10 % to monolinoleate , and about 11 % to about 15 % of polyethylene 30 about 16 % of polyethylene glycol, and about 2 % to about glycol, and about 3 % to about 5 % of propylene glycol. In 6 % of propylene glycol. In yet another aspect of this still another aspect of this embodiment , a semi- solid formu - embodiment, a semi-solid formulation comprises about 15 % lation comprises about 25 % to about 44 % by weight of an to about 30 % by weight of a free acid of a therapeutic ibuprofen , about 12 % to about 14 % by weight of a mixture compound , about 1 % to about 25 % by weight of a salt of a of mono - , di - , and triglycerides and PEG fatty acid esters , 35 therapeutic compound , about 11 % to about 15 % by weight about 32 % to about 39 % by weight of a glyceryl monoli - of a mixture of mono - , di - , and triglycerides and PEG fatty noleate , about 12 % to about 14 % of polyethylene glycol, acid esters, about 30 % to about 40 % by weight of a glyceryl and about 4 % of propylene glycol. In other aspects of this monolinoleate , and about 11 % to about 15 % of polyethylene embodiment, a polyethylene glycol is , e . g ., a PEG 100 , a glycol, and about 3 % to about 5 % of propylene glycol. In PEG 200 , a PEG 300 , a PEG 400 , a PEG 500 , a PEG 600 , 40 still another aspect of this embodiment, a semi- solid formu or a PEG 700 . lation comprises about 20 % to about 24 % by weight of a free In another embodiment, a semi- solid formulation com - acid of a therapeutic compound, about 5 % to about 20 % by prises a therapeutic compound , a hard fat, a partially weight of a salt of a therapeutic compound , about 12 % to hydrogenated fat, a polyethylene glycol, and a propylene about 14 % by weight of a mixture of mono -, di- , and glycol. In an aspect of this embodiment, a semi- solid for - 45 triglycerides and PEG fatty acid esters , about 32 % to about mulation comprises about 10 % to about 35 % by weight of 39 % by weight of a glyceryl monolinoleate , about 12 % to a free acid of a therapeutic compound , about 1 % to about about 14 % of polyethylene glycol, and about 4 % of propyl 30 % by weight of a salt of a therapeutic compound , about ene glycol. In other aspects of this embodiment, a polyeth 7 % to about 20 % by weight of hard fat , about 20 % to about ylene glycol is , e . g . , a PEG 100 , a PEG 200 , a PEG 300 , a 50 % by weight of partially -hydrogenated fat , about 7 % to 50 PEG 400 , a PEG 500 , a PEG 600 , or a PEG 700 . about 20 % of polyethylene glycol, and about 1 % to about In another embodiment, a semi- solid formulation com 8 % of propylene glycol. In another aspect of this embodi- prises an ibuprofen , a mixture of mono -, di- , and triglycer ment, a semi- solid formulation comprises about 15 % to ides and PEG fatty acid esters , a glyceryl monolinoleate , a about 30 % by weight of a free acid of a therapeutic com - polyethylene glycol, and a propylene glycol. In an aspect of pound , about 1 % to about 25 % by weight of a salt of a 55 this embodiment, a semi- solid formulation comprises about therapeutic compound , about 10 % to about 16 % by weight 10 % to about 35 % by weight of a free acid of an ibuprofen , of hard fat, about 25 % to about 45 % by weight of partially about 1 % to about 30 % by weight of a salt of an ibuprofen , hydrogenated fat , about 10 % to about 16 % of polyethylene about 7 % to about 20 % by weight of a mixture of mono -, di- , glycol, and about 2 % to about 6 % of propylene glycol. In yet and triglycerides and PEG fatty acid esters , about 20 % to another aspect of this embodiment, a semi- solid formulation 60 about 50 % by weight of a glyceryl monolinoleate , about 7 % comprises about 15 % to about 30 % by weight of a free acid to about 20 % of polyethylene glycol, and about 1 % to about of a therapeutic compound , about 1 % to about 25 % by 8 % of propylene glycol. In another aspect of this embodi weight of a salt of a therapeutic compound , about 11 % to ment, a semi- solid formulation comprises about 15 % to about 15 % by weight of hard fat , about 30 % to about 40 % about 30 % by weight of a free acid of an ibuprofen , about by weight of partially -hydrogenated fat, about 11 % to about 65 1 % to about 25 % by weight of a salt of an ibuprofen , about 15 % of polyethylene glycol, and about 3 % to about 5 % of 10 % to about 16 % by weight of a mixture ofmono -, di - , and propylene glycol. In still another aspect of this embodiment, triglycerides and PEG fatty acid esters , about 25 % to about US 9 ,750 ,810 B2 47 48 45 % by weight of a glyceryl monolinoleate , about 10 % to C . to about 25° C ., about 24° C . to about 26° C ., about 25° about 16 % of polyethylene glycol, and about 2 % to about C . to about 27° C ., about 26° C . to about 28° C ., about 27° 6 % of propylene glycol. In yet another aspect of this C . to about 29° C ., about 28° C . to about 30° C ., about 29° embodiment, a semi- solid formulation comprises about 15 % C . to about 31° C ., about 30° C . to about 32° C ., about 31° to about 30 % by weight of a free acid of an ibuprofen , about 5 C . to about 33° C . , about 32° C . to about 34° C . , or about 33° 1 % to about 25 % by weight of a salt of an ibuprofen , about C . to about 35° C . In other aspects of this embodiment, a 11 % to about 15 % by weight of a mixture of mono -, di- , and pharmaceutical composition disclosed has a melting point triglycerides and PEG fatty acid esters , about 30 % to about temperature in the range of, e. g ., about 22° C . to about 26° 40 % by weight of a glyceryl monolinoleate , and about 11 % C ., about 24° C . to about 28° C . , about 26° C . to about 30° to about 15 % of polyethylene glycol, and about 3 % to about 10 C ., about 28° C . to about 32° C . , or about 30° C . to about 34° 5 % of propylene glycol. In still another aspect of this C . embodiment, a semi- solid formulation comprises about 20 % Aspects of the present specification disclose , in part , a to about 24 % by weight of a free acid of an ibuprofen , about method of treating an individual with a chronic inflamma 5 % to about 20 % by weight of a salt of an ibuprofen , about tion . In one embodiment, the method comprises the step of 12 % to about 14 % by weight of a mixture of mono - , di- , and 15 administering to an individual in need thereof a pharmaceu triglycerides and PEG fatty acid esters , about 32 % to about tical composition disclosed herein , wherein administration 39 % by weight of a glyceryl monolinoleate , about 12 % to reduces a symptom associated with the chronic inflamma about 14 % of polyethylene glycol, and about 4 % of propyl tion , thereby treating the individual. ene glycol. In other aspects of this embodiment, a polyeth - Aspects of the present specification disclose , in part , ylene glycol is , e . g . , a PEG 100 , a PEG 200 , a PEG 300 , a 20 treating an individual suffering from a chronic inflammation . PEG 400 , a PEG 500 , a PEG 600 , or a PEG 700 . As used herein , the term “ treating , ” refers to reducing or A solid or semi- solid formulation disclosed herein takes eliminating in an individual a clinical symptom of a chronic advantage of the different melting point temperatures of the inflammation ; or delaying or preventing in an individual the various adjuvants like fatty acids . Formation of a solid or onset of a clinical symptom of a chronic inflammation . For semi- solid dosage form can be by modifying the respective 25 example , the term " treating " can mean reducing a symptom concentrations of the fatty acids comprising a pharmaceu - of a condition characterized by a chronic inflammation by , tical composition disclosed herein . For example , linolenic e. g ., at least 20 % , at least 25 % , at least 30 % , at least 35 % , acid has a melting point temperature ( T ) of about - 11° C ., at least 40 % , at least 45 % , at least 50 % , at least 55 % , at least linoleic acid has a Tm of about – 5° C . , oleic acid has a Tm 60 % , at least 65 % , at least 70 % , at least 75 % , at least 80 % , of about 16° C ., palmitic acid has a T , of about 61- 62° C ., 30 at least 85 % , at least 90 % at least 95 % , or at least 100 % . The and Stearic acid has a Tm of about 67- 72° C . Increasing the actual symptoms associated with chronic inflammation are proportion ( s ) of palmitic , stearic or oleic acid would well known and can be determined by a person of ordinary increase the overall melting temperature of a composition , skill in the art by taking into account factors , including , while, conversely , increasing the proportion ( s ) of linoleic without limitation , the location of the chronic inflammation , and linolenic acid would decrease the melting temperature 35 the cause of the chronic inflammation , the severity of the of a composition . Thus, by controlling the types and chronic inflammation , and /or the tissue or organ affected by amounts of the adjuvant components added , a pharmaceu - the chronic inflammation . Those of skill in the art will know tical composition disclosed herein can be made that is the appropriate symptoms or indicators associated with a substantially solid or semi- solid at room temperature , but specific type of chronic inflammation and will know how to melts when it is ingested , and reaches body temperature . The 40 determine if an individual is a candidate for treatment as resulting melted composition readily forms micelles which disclosed herein . are absorbed by the intestine, assembled into chylomicrons, Chronic inflammation symptoms include, without limita and ultimately absorbed by macrophages . The solid dosage tion , edema, hyperemia , erythema , bruising , tenderness , form may be a powder , granule , tablet , capsule or supposi stiffness , swollenness, fever, chills , stuffy nose , stuffy head , tory . 45 breathing problems, fluid retention , blood clots , loss of In an embodiment, a pharmaceutical composition dis - appetite , increased heart rate , formation of granulomas , closed herein is solid at room temperature . In aspects of this fibrinous , pus , non - viscous serous fluid , or ulcer and pain . embodiment, a pharmaceutical composition disclosed herein The actual symptoms associated with a chronic inflamma may be formulated to be a solid at a temperature of, e . g . , tion are well known and can be determined by a person of about 35º C . or lower, about 33° C . or lower, about 31° C . 50 ordinary skill in the art by taking into account factors , or lower, about 29° C . or lower , about 27° C . or lower , about including, without limitation , the location of the inflamma 25° C . or lower, about 23° C . or lower, about 21°C . or lower, tion , the cause of the inflammation , the severity of the about 19° C . or lower , about 17° C . or lower , about 15° C . inflammation , the tissue or organ affected , and the associated or lower, about 12° C . or lower , about 10° C . or lower, about disorder . 8° C . or lower, about 6° C . or lower, about 4° C . or lower, 55 Specific patterns of chronic inflammation are seen during or about 0° C . or lower. particular situations that arise in the body , such as when In other aspects of this embodiment, a pharmaceutical inflammation occurs on an epithelial surface , or pyogenic composition disclosed has a melting point temperature of , bacteria are involved . For example , granulomatous inflam e . g . , 5° C . or higher , 10° C . or higher , 15° C . or higher, 22° mation is an inflammation resulting from the formation of C . or higher , 23° C . or higher, 24° C . or higher , 25° C . or 60 granulomas arising from a limited but diverse number of higher , 26° C . or higher, 27° C . or higher, 28° C . or higher, diseases, include, without limitation , tuberculosis , leprosy, 29° C . or higher , 30° C . or higher , 31° C . or higher, 32° C . sarcoidosis , and syphilis . Purulent inflammation is an or higher, 33° C . or higher , 34° C . or higher, or 35° C . or inflammation resulting in large amount of pus, which con higher . In other aspects of this embodiment, a pharmaceu - sists of neutrophils , dead cells , and fluid . Infection by tical composition disclosed has a melting point temperature 65 pyogenic bacteria such as staphylococci is characteristic of in the range of, e . g . , about 5° C . to about 24° C . , about 10° this kind of inflammation . Serous inflammation is an inflam C . to about 24° C . about 22° C . to about 24° C ., about 23° mation resulting from copious effusion of non - viscous US 9 , 750 ,810 B2 49 50 serous fluid , commonly produced by mesothelial cells of inflammation , a cartilage inflammation , a lung inflamma serous membranes, butmay be derived from blood plasma. tion , a heart inflammation , a liver inflammation , a pancreatic Skin blisters exemplify this pattern of inflammation . Ulcer - inflammation , a kidney inflammation , a bladder inflamma ative inflammation is an inflammation resulting from the tion , a stomach inflammation , an intestinal inflammation , a necrotic loss of tissue from the epithelial surface , exposing 5 neuron inflammation , and a brain inflammation . lower layers and forming an ulcer . In another embodiment, a chronic inflammation com A chronic inflammation symptom can be associated with prises a systemic inflammation . Although the processes a large , unrelated group of disorders which underlay a involved are identical to tissue inflammation , systemic variety of diseases and disorders . The immune system is inflammation is not confined to a particular tissue but in fact often involved with chronic inflammatory disorders , dem - 10 overwhelms the body , involving the endothelium and other onstrated in both allergic reactions and some myopathies , organ systems. When it is due to infection , the term sepsis with many immune system disorders resulting in abnormal is applied , with the terms bacteremia being applied specifi inflammation . Non - immune diseases with etiological origins cally for bacterial sepsis and viremia specifically to viral in chronic inflammatory processes include cancer , athero - sepsis . Vasodilation and organ dysfunction are serious prob sclerosis , and ischaemic heart disease . Non - limiting 15 lems associated with widespread infection that may lead to examples of disorders exhibiting chronic inflammation as a septic shock and death . symptom include , without limitation , acne , acid reflux In another embodiment, a chronic inflammation com heartburn , age related macular degeneration ( AMD ) , allergy , prises an arthritis . Arthritis includes a group of conditions allergic rhinitis , Alzheimer ' s disease , amyotrophic lateral involving damage to the joints of the body due to the sclerosis , anemia , appendicitis , arteritis , arthritis, asthma, 20 inflammation of the synovium including, without limitation atherosclerosis , autoimmune disorders, balanitis , blephari- osteoarthritis, rheumatoid arthritis, juvenile idiopathic tis , bronchiolitis , bronchitis, a bullous pemphigoid , burn , arthritis , spondyloarthropathies like ankylosing spondylitis , bursitis , cancer , cardiac arrest , carditis , celiac disease , cel reactive arthritis ( Reiter ' s syndrome) , psoriatic arthritis , lulitis , cervicitis , cholangitis , cholecystitis , chorioamnioni- enteropathic arthritis associated with inflammatory bowel tis , chronic obstructive pulmonary disease ( COPD ), cirrho - 25 disease , Whipple disease and Behcet disease , septic arthritis , sis , colitis, congestive heart failure, conjunctivitis , gout (also known as gouty arthritis , crystal synovitis , meta cyclophosphamide- induced cystitis , cystic fibrosis , cystitis , bolic arthritis ) , pseudogout ( calcium pyrophosphate deposi common cold , dacryoadenitis , dementia , dermatitis , der - tion disease ), and Still ' s disease. Arthritis can affect a single matomyositis , diabetes , diabetic neuropathy , diabetic retin - joint (monoarthritis ), two to four joints ( oligoarthritis ) or opathy , diabetic nephropathy, diabetic ulcer , digestive sys - 30 five or more joints ( polyarthritis ) and can be either an tem disease , eczema, emphysema, encephalitis , auto - immune disease or a non - autoimmune disease . endocarditis , endometritis , enteritis , enterocolitis , epicondy . In another embodiment, a chronic inflammation com litis , epididymitis , fasciitis, fibromyalgia , fibrosis , fibrositis , prises an autoimmune disorder . Autoimmune diseases can be gastritis , gastroenteritis , gingivitis , glomerulonephritis , broadly divided into systemic and organ - specific autoim glossitis , heart disease , heart valve dysfunction , hepatitis , 35 mune disorders , depending on the principal clinico - patho hidradenitis suppurativa, Huntington ' s disease , hyperlipi- logic features of each disease . Systemic autoimmune dis demic pancreatitis , hypertension , ileitis , infection , inflam eases include , without limitation , systemic lupus matory bowel disease , inflammatory cardiomegaly , inflam - erythematosus ( SLE ) , Sjögren ' s syndrome, Scleroderma, matory neuropathy , insulin resistance, interstitial cystitis , rheumatoid arthritis and polymyositis . Local autoimmune interstitial nephritis , iritis , ischemia , ischemic heart disease , 40 diseases may be endocrinologic (Diabetes Mellitus Type 1 , keratitis , keratoconjunctivitis , laryngitis , lupus nephritis , Hashimoto ' s thyroiditis , Addison ' s disease etc . ), dermato mastitis , mastoiditis, meningitis, metabolic syndrome ( syn - logic ( pemphigus vulgaris ), hematologic ( autoimmune hae drome X ) , a migraine , multiple sclerosis , myelitis , myo - molytic anemia ), neural (multiple sclerosis ) or can involve carditis , myositis , nephritis , non -alcoholic steatohepatitis , virtually any circumscribed mass of body tissue . Types of obesity , omphalitis , oophoritis , orchitis, osteochondritis , 45 autoimmune disorders include, without limitation , acute osteopenia , osteomyelitis , osteoporosis , osteitis , otitis , pan disseminated encephalomyelitis (ADEM ) , Addison ' s dis creatitis , Parkinson ' s disease , parotitis, pelvic inflammatory ease , an allergy or sensitivity , amyotrophic lateral sclerosis , disease , pemphigus vularis , pericarditis , peritonitis , pharyn - anti- phospholipid antibody syndrome (APS ) , arthritis , auto gitis , phlebitis , pleuritis , pneumonitis , polycystic nephritis , immune hemolytic anemia , autoimmune hepatitis , autoim proctitis , prostatitis , psoriasis , pulpitis , pyelonephritis , pyl- 50 mune inner ear disease , autoimmune pancreatitis , bullous ephlebitis , renal failure , reperfusion injury , retinitis , rheu - pemphigoid , celiac disease , Chagas disease , chronic matic fever , rhinitis, salpingitis , sarcoidosis , sialadenitis , obstructive pulmonary disease (COPD ) , diabetes mellitus sinusitis , spastic colon , stenosis, stomatitis , stroke, surgical type 1 ( IDDM ) , endometriosis , fibromyalgia , Goodpasture ' s complication , synovitis , tendonitis , tendinosis , tenosynovi- syndrome, Graves ' disease, Guillain - Barré syndrome tis , thrombophlebitis , tonsillitis , trauma, traumatic brain 55 (GBS ) , Hashimoto ' s thyroiditis , hidradenitis suppurativa , injury , transplant rejection , trigonitis , tuberculosis , tumor, idiopathic thrombocytopenic purpura , inflammatory bowel urethritis , ursitis , uveitis , vaginitis , vasculitis , and vulvitis . disease , interstitial cystitis , lupus ( including discoid lupus See also , Eric R . First , Application of Botulinum Toxin to erythematosus , drug - induced lupus erythematosus, lupus the Management of Neurogenic Inflammatory Disorders , nephritis , neonatal lupus, subacute cutaneous lupus erythe U . S . Pat. No. 6 , 063 , 768 , which is hereby incorporated by 60 matosus and systemic lupus erythematosus ), morphea , mul reference in its entirety . tiple sclerosis (MS ) , myasthenia gravis , myopathies , narco In one embodiment, a chronic inflammation comprises a lepsy , neuromyotonia , pemphigus vulgaris , pernicious tissue inflammation . Tissue inflammation is a chronic anaemia , primary biliary cirrhosis , recurrent disseminated inflammation that is confined to a particular tissue or organ . encephalomyelitis (multiphasic disseminated encephalomy In aspect of this embodiment, a tissue inflammation com - 65 elitis ) , rheumatic fever , schizophrenia , scleroderma, prises , e . g . , a skin inflammation , a muscle inflammation , a Sjögren ' s syndrome, tenosynovitis , vasculitis , and vitiligo . tendon inflammation , a ligament inflammation , a bone See Pamela D . Van Schaack & Kenneth L . Tong , Treatment US 9 , 750 ,810 B2 51 52 of Autoimmune Disorder with a Neurotoxin , U .S . Patent tis , vasculitis ; arterial occlusive disease like arteriosclerosis Publication 2006 / 138059 , which is hereby incorporated by and stenosis , inflammatory cardiomegaly , a peripheral arte reference in its entirety . rial disease ; an aneurysm ; an embolism ; a dissection ; a In another embodiment , a chronic inflammation com pseudoaneurysm ; a vascular malformation ; a vascular prises a myopathy . Myopathies are caused when the immune 5 nevus ; a thrombosis ; a thrombphlebitis ; a varicose veins ; a system inappropriately attacks components of the muscle , stroke . Symptoms of a cardiovascular disorder affecting the leading to inflammation in the muscle . A myopathy includes heart include , without limitation , chest pain or chest dis an inflammatory myopathy and an auto - immune myopathy. comfort (angina ) , pain in one or both arms, the left shoulder, Myopathies include , without limitation , dermatomyositis , neck , jaw , or back , shortness of breath , dizziness , faster inclusion body myositis , and polymyositis . 10 heartbeats , nausea , abnormal heartbeats , feeling fatigued . In another embodiment, a chronic inflammation com - Symptoms of a cardiovascular disorder affecting the brain prises a vasculitis . Vasculitis is a varied group of disorders include , without limitation , sudden numbness or weakness featuring inflammation of a vessel wall including lymphatic of the face , arm , or leg , especially on one side of the body , vessels and blood vessels like veins (phlebitis ) , arteries sudden confusion or trouble speaking or understanding ( arteritis ) and capillaries due to leukocyte migration and 15 speech , sudden trouble seeing in one or both eyes , sudden resultant damage . The inflammation may affect any size dizziness, difficulty walking, or loss of balance or coordi blood vessel, anywhere in the body . It may affect either nation , sudden severe headache with no known cause . arteries and / or veins . The inflammation may be focal, mean - Symptoms of a cardiovascular disorder affecting the legs , ing that it affects a single location within a vessel; or it may pelvis and/ or arm include , without limitation , claudication , be widespread , with areas of inflammation scattered 20 which is a pain , ache , or cramp in the muscles, and cold or throughout a particular organ or tissue, or even affecting numb feeling in the feet or toes, especially at night. more than one organ system in the body . Vasculitis include , In another embodiment, a chronic inflammation com without limitation , Buerger ' s disease ( thromboangiitis oblit - prises a cancer. Inflammation orchestrates the microenvi erans ) , cerebral vasculitis ( central nervous system vasculi - ronment around tumors , contributing to proliferation , sur tis ) , Churg - Strauss arteritis , cryoglobulinemia , essential 25 vival and migration . For example , fibrinous inflammation cryoglobulinemic vasculitis, giant cell (temporal ) arteritis , results from a large increase in vascular permeability which Golfer ' s vasculitis , Henoch -Schonlein purpura , hypersensi- allows fibrin to pass through the blood vessels . If an appro tivity vasculitis ( allergic vasculitis ) , Kawasaki disease , priate procoagulative stimulus is present, such as cancer microscopic polyarteritis / polyangiitis , polyarteritis nodosa , cells , a fibrinous exudate is deposited . This is commonly polymyalgia rheumatica (PMR ) , rheumatoid vasculitis , 30 seen in serous cavities , where the conversion of fibrinous Takayasu arteritis , Wegener ’ s granulomatosis , and vasculitis exudate into a scar can occur between serous membranes , secondary to connective tissue disorders like systemic lupus limiting their function . In another example , a cancer is an erythematosus (SLE ) , rheumatoid arthritis (RA ) , relapsing inflammatory cancer like a NF- KB - driven inflammatory polychondritis , Behcet ' s disease , or other connective tissue cancer . disorders, vasculitis secondary to viral infection . 35 In another embodiment, a chronic inflammation com In another embodiment, a chronic inflammation com - prises a pharmacologically - induced inflammation . Certain prises a skin disorder. Skin disorders include , without limi- drugs or exogenic chemical compounds are known to affect tation , an acne , including acne vulgaris , a bullous phemi- inflammation . For example , Vitamin A deficiency causes an goid , a dermatitis , including atopic dermatitis and chronic increase in an inflammatory response . Certain illicit drugs actinic dermatitis , an eczema like atopic eczema, contact 40 such as cocaine and ecstasy may exert some of their detri eczema , xerotic eczema, seborrhoeic dermatitis , dyshidrosis , mental effects by activating transcription factors intimately discoid eczema, venous eczema, dermatitis herpetiformis , involved with inflammation ( e . g . NF - KB ) . neurodermatitis , and autoeczematization , and statis derma - In another embodiment, a chronic inflammation com titis , hidradenitis suppurativa , lichen planus, psoriasis prises an infection . An infectious organism can escape the including plaqure psoriasis , nail psoriasis , guttate psoriasis , 45 confines of the immediate tissue via the circulatory system scalp psoriasis , inverse psoriasis , pustular psoriasis , eryth - or lymphatic system , where it may spread to other parts of rodermis psoriasis , and psoriatic arthritis , rosacea and the body . If an organism is not contained by the actions of scleroderma including morphea . acute inflammation it may gain access to the lymphatic In another embodiment, a chronic inflammation com - system via nearby lymph vessels . An infection of the lymph prises a gastrointestinal disorder . A gastrointestinal disorder 50 vessels is known as lymphangitis , and infection of a lymph includes , without limitation , irritable bowel disease , an node is known as lymphadenitis . A pathogen can gain access inflammatory bowel disease including Crohn ' s disease and to the bloodstream through lymphatic drainage into the an ulcerative colitis like ulcerative proctitis, left - sided coli- circulatory system . Infections include , without limitation , tis , pancolitis and fulminant colitis . bacterial cystitis , bacterial encephalitis , pandemic influenza , In another embodiment, a chronic inflammation com - 55 viral encephalitis , and viral hepatitis ( A , B and C ) . prises a cardiovascular disease . When LDL cholesterol In another embodiment, a chronic inflammation com becomes embedded in arterial walls , it can invoke an prises a tissue or organ injury . Tissue or organ injuries immune response . Chronic inflammation eventually can include , without limitation , a burn , a laceration , a wound , a damage the arteries, which can cause them to burst . Car - puncture , or a trauma. diovascular disease is any of a number of specific diseases 60 In another embodiment, a chronic inflammation com that affect the heart itself and /or the blood vessel system , prises a transplant rejection . Transplant rejection occurs especially the veins and arteries leading to and from the when a transplanted organ or tissue is not accepted by the heart . There are more than 60 types of cardiovascular body of the transplant recipient because the immune system disorders including , without limitation , a hypertension , of the recipient attacks the transplanted organ or tissue . An endocarditis , myocarditis , heart valve dysfunction , conges - 65 adaptive immune response , transplant rejection is mediated tive heart failure , myocardial infarction , a diabetic cardiac through both T cell mediated and humoral immune ( anti conditions , blood vessel inflammation like arteritis , phlebi- bodies ) mechanisms. A transplant rejection can be classified US 9 , 750 ,810 B2 53 54 as a hyperacute rejection , an acute rejection , or a chronic any individual who is a candidate for a conventional chronic rejection . Chronic rejection of a transplanted organ or tissue inflammation treatment is a candidate for a chronic inflam is where the rejection is due to a poorly understood chronic mation treatment disclosed herein . Pre - operative evaluation inflammatory and immune response against the transplanted typically includes routine history and physical examination tissue . Also included in the term “ transplant rejection ” is a 5 in addition to thorough informed consent disclosing all graft - versus -host disease (GVHD ) . GVHD is a common relevant risks and benefits of the procedure . complication of allogeneic bone marrow transplantation in A pharmaceutical composition disclosed herein may com which functional immune cells in the transplanted marrow prise a therapeutic compound in a therapeutically effective recognize the recipient as “ foreign ” and mount an immuno - amount. As used herein , the term " effective amount" is logic attack . It can also take place in a blood transfusion 10 synonymous with " therapeutically effective amount" , under certain circumstances . GVHD is divided into acute " effective dose " , or " therapeutically effective dose ” and and chronic forms. Acute and chronic GVHD appear to when used in reference to treating a chronic inflammation involve different immune cell subsets, different cytokine refers to the minimum dose of a therapeutic compound profiles, somewhat different host targets , and respond dif - disclosed herein necessary to achieve the desired therapeutic ferently to treatment. 15 effect and includes a dose sufficient to reduce a symptom In another embodiment , a chronic inflammation com - associated with a chronic inflammation . The effectiveness of prises a Th1 -mediated inflammatory disease . In a well - a therapeutic compound disclosed herein in treating a functioning immune system , an immune response should chronic inflammation can be determined by observing an result in a well balanced pro - inflammatory Th1 response and improvement in an individual based upon one or more anti - inflammatory Th2 response that is suited to address the 20 clinical symptoms, and / or physiological indicators associ immune challenge . Generally speaking , once a pro - inflam - ated with the condition . An improvement in a chronic matory Thl response is initiated , the body relies on the inflammation also can be indicated by a reduced need for a anti - inflammatory response invoked by a Th2 response to concurrent therapy . counteract this Th1 response . This counteractive response The appropriate effective amount of a therapeutic com includes the release of Th2 type cytokines such as, e . g ., IL - 4 , 25 pound disclosed herein to be administered to an individual IL - 5 , and IL - 13 which are associated with the promotion of for a particular chronic inflammation can be determined by IgE and eosinophilic responses in atopy, and also IL - 10 , a person of ordinary skill in the art by taking into account which has an anti - inflammatory response . A Th1- mediated factors , including, without limitation , the type of chronic inflammatory disease involves an excessive pro -inflamma - inflammation , the location of the chronic inflammation , the tory response produced by Th1 cells that leads to chronic 30 cause of the chronic inflammation , the severity of the inflammation . The Th1- mediated disease may be virally , chronic inflammation , the degree of relief desired , the dura bacterially or chemically ( e . g . environmentally ) induced . tion of relief desired , the particular therapeutic compound For example , a virus causing the Th1 -mediated disease may used , the rate of excretion of the therapeutic compound used , cause a chronic or acute infection , which may cause a the pharmacodynamics of the therapeutic compound used , respiratory disorder or influenza . 35 the nature of the other compounds to be included in the In another embodiment, a chronic inflammation com - composition , the particular formulation , the particular route prises a chronic neurogenic inflammation . Chronic neuro of administration , the particular characteristics , history and genic Inflammation refers to an inflammatory response risk factors of the patient, such as , e . g ., age , weight, general initiated and / or maintained through the release of inflam - health and the like, or any combination thereof. Additionally , matory molecules like SP or CGRP which released from 40 where repeated administration of a therapeutic compound is peripheral sensory nerve terminals ( i . e . , an efferent function , used , an effective amount of a therapeutic compound will in contrast to the normal afferent signaling to the spinal cord further depend upon factors , including , without limitation , in these nerves ) . Chronic neurogenic inflammation includes the frequency of administration , the half- life of the thera both primary inflammation and secondary neurogenic peutic compound , or any combination thereof. In is known inflammation . As used herein , the term " primary " neuro - 45 by a person of ordinary skill in the art that an effective genic inflammation refers to tissue inflammation (inflam - amount of a therapeutic compound disclosed herein can be matory symptoms) that is initiated by , or results from , the extrapolated from in vitro assays and in vivo administration release of substances from primary sensory nerve terminals studies using animal models prior to administration to ( such as C and A - delta fibers ). As used herein , the term humans. " secondary ” neurogenic inflammation ” refers to tissue 50 In aspects of this embodiment, a therapeutically effective inflammation initiated by non -neuronal sources ( e . g . , amount of a therapeutic compound disclosed herein reduces extravasation from vascular bed or tissue interstitium -de a symptom associated with a chronic inflammation by, e . g . , rived , such as from mast cells or immune cells ) of inflam - at least 10 % , at least 15 % , at least 20 % , at least 25 % , at least matory mediators , such as peptides or cytokines , stimulating 30 % , at least 35 % , at least 40 % , at least 45 % , at least 50 % , sensory nerve terminals and causing a release of inflamma - 55 at least 55 % , at least 60 % , at least65 % , at least 70 % , at least tory mediators from the nerves . The net effect of both forms 75 % , at least 80 % , at least 85 % , at least 90 % , at least 95 % ( primary and secondary ) of chronic neurogenic inflamma or at least 100 % . In other aspects of this embodiment, a tion is to have an inflammatory state that is maintained by therapeutically effective amount of a therapeutic compound the sensitization of the peripheral sensory nerve fibers. The disclosed herein reduces a symptom associated with a physiological consequence of the resulting chronic neuro - 60 chronic inflammation by , e . g . , at most 10 % , at most 15 % , at genic inflammation depends on the tissue in question , pro - most 20 % , at most 25 % , at most 30 % , at most 35 % , at most ducing , such as , e . g . , cutaneous pain (allodynia , hyperalge - 40 % , at most 45 % , atmost 50 % , at most 55 % , at most 60 % , sia ), joint pain and / or arthritis , visceral pain and at most 65 % , at most 70 % , at most 75 % , at most 80 % , at dysfunction , pulmonary dysfunction ( asthma, COPD ) , and most 85 % , at most 90 % , at most 95 % or at most 100 % . In bladder dysfunction (pain , overactive bladder ). 65 yet other aspects of this embodiment, a therapeutically A composition or compound is administered to an indi- effective amount of a therapeutic compound disclosed herein vidual. An individual is typically a human being . Typically , reduces a symptom associated with a chronic inflammation US 9 ,750 ,810 B2 55 56 by, e . g . , about 10 % to about 100 % , about 10 % to about 90 % , mg/ kg /day , about 5 mg/ kg / day to about 20 mg/ kg / day , about about 10 % to about 80 % , about 10 % to about 70 % , about 5 mg/ kg / day to about 25 mg/ kg / day , about 5 mg/kg / day to 10 % to about 60 % , about 10 % to about 50 % , about 10 % to about 30 mg/ kg / day , about 5 mg/ kg / day to about 35 mg/ kg / about 40 % , about 20 % to about 100 % , about 20 % to about day, about 5 mg/ kg /day to about 40 mg/ kg /day , about 5 90 % , about 20 % to about 80 % , about 20 % to about 20 % , 5 mg/ kg / day to about 45 mg/ kg / day , about 5 mg/ kg /day to about 20 % to about 60 % , about 20 % to about 50 % , about about 50 mg/ kg /day , about 5 mg/ kg / day to about 75 mg/ kg 20 % to about 40 % , about 30 % to about 100 % , about 30 % to day, or about 5 mg/ kg / day to about 100 mg/ kg / day . about 90 % , about 30 % to about 80 % , about 30 % to about Dosing can be single dosage or cumulative ( serial dos 70 % , about 30 % to about 60 % , or about 30 % to about 50 % . ing ) , and can be readily determined by one skilled in the art . In yet other aspects of this embodiment, a therapeutically 10 For instance , treatment of a chronic inflammation may effective amount of a therapeutic compound disclosed herein comprise a one - time administration of an effective dose of a generally is in the range of about 0 . 001 mg/ kg /day to about pharmaceutical composition disclosed herein . Alternatively, 100 mg/ kg /day . In aspects of this embodiment, an effective treatment of a chronic inflammation may comprise multiple amount of a therapeutic compound disclosed herein may be , administrations of an effective dose of a pharmaceutical e . g ., at least 0 .001 mg /kg / day, at least 0 .01 mg/ kg /day , at 15 composition carried out over a range of time periods, such least 0 . 1 mg/ kg / day, at least 1 . 0 mg/ kg / day , at least 5 . 0 as , e . g . , once daily , twice daily , trice daily, once every few mg/ kg / day , at least 10 mg/ kg / day , at least 15 mg/ kg / day, at days , or once weekly . The timing of administration can vary least 20 mg/ kg / day , at least 25 mg/ kg / day , at least 30 from individual to individual , depending upon such factors mg/ kg /day , at least 35 mg/ kg /day , at least 40 mg/ kg /day , at as the severity of an individual' s symptoms. For example , an least 45 mg/ kg /day , or at least 50 mg/ kg /day . In other aspects 20 effective dose of a pharmaceutical composition disclosed of this embodiment, an effective amount of a therapeutic herein can be administered to an individual once daily for an compound disclosed herein may be in the range of, e . g ., indefinite period of time, or until the individual no longer about 0 . 001 mg/ kg / day to about 10 mg/ kg / day, about 0 . 001 requires therapy . A person of ordinary skill in the art will mg /kg /day to about 15 mg/ kg / day, about 0 .001 mg/ kg / day to recognize that the condition of the individual can be moni about 20 mg/ kg / day, about 0 . 001 mg/ kg /day to about 25 25 tored throughout the course of treatment and that the effec mg/ kg / day , about 0 .001 mg/ kg / day to about 30 mg/ kg / day, tive amount of a pharmaceutical composition disclosed about 0 .001 mg/ kg /day to about 35 mg/ kg /day , about 0 .001 herein that is administered can be adjusted accordingly . mg/ kg /day to about 40 mg/ kg /day , about 0 .001 mg/ kg /day to Various routes of administration can be useful for admin about 45 mg/ kg / day, about 0 . 001 mg/ kg / day to about 50 istering a therapeutic compound disclosed herein , according mg/ kg / day , about 0 .001 mg /kg / day to about 75 mg/kg / day , 30 to a method of treating a chronic inflammation disclosed or about 0 . 001 mg/ kg /day to about 100 mg /kg /day . In yet herein . A pharmaceutical composition may be administered other aspects of this embodiment , an effective amount of a to an individualby any of a variety ofmeans depending, e . g . , therapeutic compound disclosed herein may be in the range on the type of the chronic inflammation to be treated , the of, e . g . , about 0 .01 mg/ kg /day to about 10 mg/ kg / day, about location of the chronic inflammation to be treated , the 0 .01 mg /kg / day to about 15 mg/kg / day , about 0 .01 mg/ kg / 35 specific therapeutic compound or composition used , or other day to about 20 mg/ kg /day , about 0 . 01 mg/ kg /day to about compound to be included in the composition , and the 25 mg/ kg /day , about 0 .01 mg/ kg / day to about 30 mg/ kg / day, history , risk factors and symptoms of the individual. As about 0 .01 mg/kg / day to about 35 mg/ kg / day , about 0 . 01 such , topical, enteral or parenteral routes of administration mg/ kg /day to about 40 mg/ kg / day, about 0 .01 mg/ kg /day to may be suitable for of treating a chronic inflammation about 45 mg/kg / day , about 0 .01 mg/ kg / day to about 50 40 disclosed herein and such routes include both local and mg/ kg / day , about 0 .01 mg/ kg / day to about 75 mg /kg / day , or systemic delivery of a therapeutic compound or composition about 0 .01 mg/ kg/ day to about 100 mg/ kg / day. In still other disclosed herein . Compositions comprising either a single aspects of this embodiment, an effective amount of a thera therapeutic compound disclosed herein , or two or more peutic compound disclosed herein may be in the range of , therapeutic compounds disclosed herein are intended for e . g . , about 0 . 1 mg/ kg /day to about 10 mg/ kg / day , about 0 . 1 45 inhaled , topical, intranasal, sublingual, injection , infusion , mg/ kg / day to about 15 mg/ kg /day , about 0 . 1 mg/ kg / day to instillation , rectal and /or vaginal use may be prepared about 20 mg/ kg /day , about 0 . 1 mg/ kg /day to about 25 according to any method known to the art for the manufac mg/ kg / day , about 0 . 1 mg/ kg / day to about 30 mg/ kg / day , ture of pharmaceutical compositions . about 0 . 1 mg/ kg / day to about 35 mg /kg /day , about 0 . 1 In one embodiment, upon administration to an individual , mg/ kg /day to about 40 mg/ kg /day , about 0 . 1 mg/ kg /day to 50 a pharmaceutical composition comprising a therapeutic about 45 mg/ kg /day , about 0 . 1 mg/ kg /day to about 50 compound disclosed herein results in a bio - distribution of mg/ kg / day , about 0 . 1 mg/ kg / day to about 75 mg/ kg / day , or the therapeutic compound different than a bio - distribution of about 0 . 1 mg/ kg /day to about 100 mg/ kg / day. the therapeutic compound included in the same pharmaceu In other aspects of this embodiment, an effective amount tical composition , except without an adjuvant disclosed of a therapeutic compound disclosed herein may be in the 55 herein . range of, e . g ., about 1 mg/ kg / day to about 10 mg/ kg / day, In another embodiment, upon administration to an indi about 1 mg/kg / day to about 15 mg/ kg / day, about 1 mg/ kg / vidual , a therapeutic compound of the pharmaceutical com day to about 20 mg/ kg /day , about 1 mg/ kg / day to about 25 position disclosed herein is delivered to a macrophage . mg/ kg /day , about 1 mg/ kg / day to about 30 mg/kg /day , about Macrophages are one of the key cell types believed to be 1 mg/kg / day to about 35 mg/ kg / day , about 1 mg/kg / day to 60 involved in the control of the inflammation response . The about 40 mg/ kg /day , about 1 mg/ kg /day to about 45 mg/ kg resultant high level of a therapeutic compound having day, about 1 mg/ kg / day to about 50 mg/ kg / day, about 1 anti - inflammatory activity present in the macrophages mg/ kg /day to about 75 mg/ kg / day, or about 1 mg/ kg / day to results in a clinically effective treatment of chronic inflam about 100 mg/ kg / day. In yet other aspects of this embodi- mation . In an aspect of this embodiment, upon administra ment, an effective amount of a therapeutic compound dis - 65 tion to an individual , a therapeutically effective amount of a closed herein may be in the range of, e . g ., about 5 mg/ kg / day therapeutic compound of the pharmaceutical composition to about 10 mg/ kg /day , about 5 mg/kg /day to about 15 disclosed herein is preferentially delivered to a macrophage . US 9 ,750 ,810 B2 57 58 In other aspect of this embodiment, upon administration to about 20 % to about 100 % , about 25 % to about 100 % , about an individual, a therapeutic compound of the pharmaceutical 30 % to about 100 % , about 35 % to about 100 % , about 40 % composition disclosed herein is substantially delivered to a to about 100 % , about 45 % to about 100 % , about 50 % to macrophage . In yet other aspect of this embodiment, upon about 100 % , about 5 % to about 90 % , about 10 % to about administration to an individual, the amount of a therapeutic 5 90 % , about 15 % to about 90 % , about 20 % to about 90 % , compound of the pharmaceutical composition disclosed about 25 % to about 90 % , about 30 % to about 90 % , about herein delivered to a macrophage is , e .g ., at least 5 % , at least 35 % to about 90 % , about 40 % to about 90 % , about 45 % to 10 % , at least 15 % , at least 20 % , at least 25 % , at least 30 % , about 90 % , about 50 % to about 90 % , about 5 % to about at least 35 % , at least 40 % , at least 45 % , at least 50 % , at least 80 % , about 10 % to about 80 % , about 15 % to about 80 % , 55 % , at least 60 % , at least 65 % , at least 70 % , at least 75 % , 10 about 20 % to about 80 % , about 25 % to about 80 % , about at least 80 % , at least 85 % , at least 90 % , at least 95 % , or at 30 % to about 80 % , about 35 % to about 80 % , about 40 % to least 100 % of the total amount of the therapeutic compound about 80 % , about 45 % to about 80 % , about 50 % to about contained in the administered pharmaceutical composition . 80 % , about 5 % to about 70 % , about 10 % to about 70 % , In still other aspects of this embodiment, upon administra - about 15 % to about 70 % , about 20 % to about 70 % , about tion to an individual, the amount of a therapeutic compound 15 25 % to about 70 % , about 30 % to about 70 % , about 35 % to of the pharmaceutical composition disclosed herein deliv about 70 % , about 40 % to about 70 % , about 45 % to about ered to a macrophage is in a range of, e . g ., about 5 % to about 70 % , or about 50 % to about 70 % of the total amount of the 100 % , about 10 % to about 100 % , about 15 % to about 100 % , therapeutic compound contained in the administered phar about 20 % to about 100 % , about 25 % to about 100 % , about maceutical composition . 30 % to about 100 % , about 35 % to about 100 % , about 40 % 20 In another embodiment, upon administration to an indi to about 100 % , about 45 % to about 100 % , about 50 % to vidual, a pharmaceutical composition disclosed herein about 100 % , about 5 % to about 90 % , about 10 % to about reduces gastric irritation . In an aspect of this embodiment, a 90 % , about 15 % to about 90 % , about 20 % to about 90 % , pharmaceutical composition disclosed herein substantially about 25 % to about 90 % , about 30 % to about 90 % , about reduces gastric irritation . In yet another embodiment, upon 35 % to about 90 % , about 40 % to about 90 % , about 45 % to 25 administration to an individual, a pharmaceutical composi about 90 % , about 50 % to about 90 % , about 5 % to about tion disclosed herein reduces gastric irritation when com 80 % , about 10 % to about 80 % , about 15 % to about 80 % , pared to the same pharmaceutical composition disclosed about 20 % to about 80 % , about 25 % to about 80 % , about herein , except without the pharmaceutically -acceptable 30 % to about 80 % , about 35 % to about 80 % , about 40 % to adjuvant. In an aspect of this embodiment, a pharmaceutical about 80 % , about 45 % to about 80 % , about 50 % to about 30 composition disclosed herein substantially reduces gastric 80 % , about 5 % to about 70 % , about 10 % to about 70 % , irritation when compared to the same pharmaceutical com about 15 % to about 70 % , about 20 % to about 70 % , about position disclosed herein , except without the pharmaceuti 25 % to about 70 % , about 30 % to about 70 % , about 35 % to cally -acceptable adjuvant. In other aspects of this embodi about 70 % , about 40 % to about 70 % , about 45 % to about ment, a pharmaceutical composition disclosed herein 70 % , or about 50 % to about 70 % of the total amount of the 35 reduces gastric irritation by, e . g ., at least 5 % , at least 10 % , therapeutic compound contained in the administered phar - at least 15 % , at least 20 % , at least 25 % , at least 30 % , at least maceutical composition . 35 % , at least 40 % , at least 45 % , at least 50 % , at least 55 % , In another embodiment, upon administration to an indi- at least 60 % , at least 65 % , at least 70 % , at least 75 % , at least vidual, a therapeutic compound of the pharmaceutical com - 80 % , at least 85 % , at least 90 % , at least 95 % , or at least position disclosed herein is delivered to a dentritic cell. 40 100 % . In yet other aspects of this embodiment , a pharma Dendritic cells are one of the key cell types believed to ceutical composition disclosed herein reduces gastric irrita coordinate the interplay between innate and adaptive immu - tion in a range of, e . g. , about 5 % to about 100 % , about 10 % nity . The resultant high level of a therapeutic compound to about 100 % , about 15 % to about 100 % , about 20 % to having anti -pain activity present in the dentritic cells results about 100 % , about 25 % to about 100 % , about 30 % to about in a clinically effective treatment of chronic inflammation . In 45 100 % , about 35 % to about 100 % , about 40 % to about 100 % , an aspect of this embodiment, upon administration to an about 45 % to about 100 % , about 50 % to about 100 % , about individual, a therapeutically effective amount of a therapeu 5 % to about 90 % , about 10 % to about 90 % , about 15 % to tic compound of the pharmaceutical composition disclosed about 90 % , about 20 % to about 90 % , about 25 % to about herein is preferentially delivered to a dentritic cell. In other 90 % , about 30 % to about 90 % , about 35 % to about 90 % , aspect of this embodiment, upon administration to an indi- 50 about 40 % to about 90 % , about 45 % to about 90 % , about vidual, a therapeutic compound of the pharmaceutical com - 50 % to about 90 % , about 5 % to about 80 % , about 10 % to position disclosed herein is substantially delivered to a about 80 % , about 15 % to about 80 % , about 20 % to about dentritic cell . In yet other aspect of this embodiment, upon 80 % , about 25 % to about 80 % , about 30 % to about 80 % , administration to an individual, the amount of a therapeutic about 35 % to about 80 % , about 40 % to about 80 % , about compound of the pharmaceutical composition disclosed 55 45 % to about 80 % , about 50 % to about 80 % , about 5 % to herein delivered to a dentritic cell is , e . g . , at least 5 % , at least about 70 % , about 10 % to about 70 % , about 15 % to about 10 % , at least 15 % , at least 20 % , at least 25 % , at least 30 % , 70 % , about 20 % to about 70 % , about 25 % to about 70 % , at least 35 % , at least 40 % , at least 45 % , at least 50 % , at least about 30 % to about 70 % , about 35 % to about 70 % , about 55 % , at least 60 % , at least 65 % , at least 70 % , at least 75 % , 40 % to about 70 % , about 45 % to about 70 % , or about 50 % at least 80 % , at least 85 % , at least 90 % , at least 95 % , or at 60 to about 70 % . least 100 % of the total amount of the therapeutic compound In another embodiment, upon administration to an indi contained in the administered pharmaceutical composition . vidual, a pharmaceutical composition disclosed herein In still other aspects of this embodiment, upon administra - reduces intestinal irritation . In an aspect of this embodiment, tion to an individual, the amount of a therapeutic compound a pharmaceutical composition disclosed herein substantially of the pharmaceutical composition disclosed herein deliv - 65 reduces intestinal irritation . In yet another embodiment, ered to a dentritic cell is in a range of, e . g . , about 5 % to about upon administration to an individual, a pharmaceutical com 100 % , about 10 % to about 100 % , about 15 % to about 100 % ; position disclosed herein reduces intestinal irritation when US 9 , 750 ,810 B2 59 60 compared to the same pharmaceutical composition disclosed 6 . The pharmaceutical composition according to embodi herein , except without the pharmaceutically -acceptable m ents 1 - 5 , wherein the anti - inflammatory activity reduces adjuvant. In an aspect of this embodiment, a pharmaceutical the level of an inflammation inducing molecule . composition disclosed herein substantially reduces intestinal 7 . The pharmaceutical composition according to embodi irritation when compared to the same pharmaceutical com - 5 ment 6 , wherein the inflammation inducing molecule position disclosed herein , except without the pharmaceuti - comprises substance P (SP ) , calcitonin gene - related pep cally - acceptable adjuvant. In other aspects of this embodi tide (CGRP ) , glutamate , or a combination thereof. ment, a pharmaceutical composition disclosed herein 8 . The pharmaceutical composition according to embodi reduces intestinal irritation by , e . g . , at least 5 % , at least 10 % , ment 7 , wherein the anti - inflammatory activity reduces at least 20 % , at least 30 % , at least 40 % , at least 50 % , at least 10 the level of SP , CGRP, glutamate , or a combination 60 % , at least 70 % , at least 80 % , at least 90 % , or at least thereof by at least 10 % . 100 % when compared to the same pharmaceutical compo - 9 . The pharmaceutical composition according to embodi sition disclosed herein , except without the pharmaceutically - ments 1 - 8 , wherein the anti- inflammatory activity reduces acceptable adjuvant. In yet other aspects of this embodi the level of an inflammation inducing prostaglandin . ment, a pharmaceutical composition disclosed herein 15 10 . The pharmaceutical composition according to embodi reduces intestinal irritation by , e . g ., about 5 % to about ment 9 , wherein the level of the inflammation inducing 100 % , about 10 % to about 100 % , about 15 % to about 100 % , prostaglandin is reduced by at least 10 % . about 20 % to about 100 % , about 25 % to about 100 % , about 11. The pharmaceutical composition according to embodi 30 % to about 100 % , about 35 % to about 100 % , about 40 % ments 1 - 10 , wherein the anti - inflammatory activity stimu to about 100 % , about 45 % to about 100 % , about 50 % to 20 lates a PPAR signaling pathway . about 100 % , about 5 % to about 90 % , about 10 % to about 12 . The pharmaceutical composition according to embodi 90 % , about 15 % to about 90 % , about 20 % to about 90 % , ment 11 , wherein the PPAR signaling pathway is stimu about 25 % to about 90 % , about 30 % to about 90 % , about lated by at least 10 % . 35 % to about 90 % , about 40 % to about 90 % , about 45 % to 13 . The pharmaceutical composition according to embodi about 90 % , about 50 % to about 90 % , about 5 % to about 25 ments 1 - 12 , wherein the anti - inflammatory activity 80 % , about 10 % to about 80 % , about 15 % to about 80 % , induces apoptosis of Macrophage M1 cells , promotes about 20 % to about 80 % , about 25 % to about 80 % , about differentiation of Macrophage M2 cells , or both . 30 % to about 80 % , about 35 % to about 80 % , about 40 % to 14 . The pharmaceutical composition according to embodi about 80 % , about 45 % to about 80 % , about 50 % to about m ents 1 - 13 , wherein the anti -inflammatory activity reduc 80 % , about 5 % to about 70 % , about 10 % to about 70 % , 30 ing the levels of Interferon - gamma ( IFNY) , Tumor necro about 15 % to about 70 % , about 20 % to about 70 % , about sis factor -alpha ( TNF - a ) , Interleukin - 12 ( IL - 12 ) , or a 25 % to about 70 % , about 30 % to about 70 % , about 35 % to combination thereof released from Th1 cells, increases about 70 % , about 40 % to about 70 % , about 45 % to about the levels of IL - 10 released from a Th2 cell, or both . 70 % , or about 50 % to about 70 % when compared to the 15 . The pharmaceutical composition according to embodi same pharmaceutical composition disclosed herein , except 35 ment 14 , wherein the levels of IFNY, TNF - a , IL - 12 , or a without the pharmaceutically - acceptable adjuvant. combination thereof released from a Th1 cell are reduced A pharmaceutical composition disclosed herein can also by at least 10 % . be administered to an individual in combination with other 16 . The pharmaceutical composition according to embodi therapeutic compounds to increase the overall therapeutic ment 14 , wherein the levels of IL - 10 released from a Th2 effect of the treatment . The use of multiple compounds to 40 cell are increased by at least 10 % . treat an indication can increase the beneficial effects while 17 . The pharmaceutical composition according to embodi reducing the presence of side effects . ments 1 - 16 , wherein the therapeutic compound has a log Aspects of the present invention can also be described as P value indicating that the compound is soluble in an follows: organic solvent. 1 . A pharmaceutical composition comprising: a ) a therapeu - 45 18 . The pharmaceutical composition according to embodi tic compound , wherein the therapeutic compound has an ments 1 - 17 , wherein the therapeutic compound has a log anti - inflammatory activity ; and b ) a pharmaceutically . P value of more than 1 . 0 . acceptable adjuvant. 19 . The pharmaceutical composition according to embodi 2 . The pharmaceutical composition according to embodi- ments 1 - 17 , wherein the therapeutic compound has a log ment 1 , wherein the composition further comprises a 50 P value of more than 2 . 0 . pharmaceutically - acceptable solvent. 20 . The pharmaceutical composition according to embodi 3 . A pharmaceutical composition comprising: a ) a therapeu - ments 1 - 19 , wherein the therapeutic compound has a tic compound , wherein the therapeutic compound has an polar surface area that is hydrophobic . anti - inflammatory activity ; b ) a pharmaceutically -accept - 21. The pharmaceutical composition according to embodi able solvent; and c ) a pharmaceutically -acceptable adju - 55 ments 1 - 20 , wherein the therapeutic compound has a vant . polar surface area that is less than 8 . 0 nm ? . 4 . A pharmaceutical composition comprising : a ) a therapeu - 22 . The pharmaceutical composition according to embodi tic compound , wherein the therapeutic compound has an ments 1 - 20 , wherein the therapeutic compound has a anti - inflammatory activity ; b ) a pharmaceutically -accept polar surface area that is less than 6 .0 nm . able solvent; and c ) a pharmaceutically - acceptable adju - 60 23 . The pharmaceutical composition according to embodi vant , wherein the ratio of the pharmaceutically -acceptable m ents 1 - 22 , wherein the therapeutic compound comprises solvent to pharmaceutically -acceptable adjuvant is in a a non -steroidal anti - inflammatory drug (NSAID ) . range from about 0 : 1 to about 1 :25 . 24 . The pharmaceutical composition according to embodi 5 . The pharmaceutical composition according to embodi m ent 23 , wherein the NSAID comprises a salicylate ment 2 or 3 , wherein the ratio of the pharmaceutically - 65 derivative NSAID , a p -amino phenol derivative NSAID , acceptable solvent to pharmaceutically -acceptable adju - a propionic acid derivative NSAID , an acetic acid deriva vant is in a range from about 0 : 1 to about 1 : 25 . tive NSAID , an enolic acid derivative NSAID , a fenamic US 9 , 750 ,810 B2 61 62 acid derivative NSAID , a non -selective cyclo -oxygenase 39. The pharmaceutical composition according to embodi (COX ) inhibitor, a selective cyclooxygenase 1 (COX 1 ) ments 1 -38 , wherein the therapeutic compound comprises inhibitor, a selective cyclooxygenase 2 (COX 2 ) inhibitor an ester of a therapeutic compound according to embodi or a combination thereof. ments 23 -37 . 25 . The pharmaceutical composition according to embodi- 5 40 . The pharmaceutical composition according to embodi ments 1 - 24 , wherein the therapeutic compound comprises ments 1 - 39, wherein the pharmaceutically - acceptable sol a PPARy agonist. vent is less than about 20 % ( v / v ) . 26 . The pharmaceutical composition according to embodi 41. The pharmaceutical composition according to embodi ment 25 , wherein the PPARy agonist comprises Monas ments 1 -40 , wherein the pharmaceutically - acceptable sol cin , Irbesartan , Telmisartan , mycophenolic acid , Resvera vent comprises a pharmaceutically -acceptable polar apro trol, Delta ( 9 ) - tetrahydrocannabinol, a cannabidiol, tic solvent, a pharmaceutically - acceptable polar protic Curcumin , Cilostazol, Benzbromarone , 6 -shogaol , gly solvent, a pharmaceutically -acceptable non - polar solvent, cyrrhetinic acid , a thiazolidinedione, a NSAID , a fibrate , 42 .or The a combination pharmaceutical thereof composition. according to embodi or a combination thereof . 15 ments 1 -41 , wherein the pharmaceutically -acceptable sol 27 . The pharmaceutical composition according to embodi vent comprises a pharmaceutically - acceptable alcohol. ments 1 - 26 , wherein the therapeutic compound comprises 43 . The pharmaceutical composition according to embodi a nuclear receptor binding agent. ment 42 , wherein the pharmaceutically -acceptable alco 28 . The pharmaceutical composition according to embodi- hol comprises an acyclic alcohol, a monohydric alcohol, ment 27, wherein the nuclear receptor binding agent 20 a polyhydric alcohol, an unsaturated aliphatic alcohol, an comprises a Retinoic Acid Receptor (RAR ) binding agent, alicyclic alcohol, or a combination thereof. a Retinoid X Receptor (RXR ) binding agent, a Liver X 44 . The pharmaceutical composition according to embodi Receptor (LXR ) binding agent , a Vitamin D binding ment 42 , wherein the pharmaceutically -acceptable alco agent, or a combination thereof . hol comprises a C1- 20 alcohol. 29 . The pharmaceutical composition according to embodi- 25 45 . The pharmaceutical composition according to embodi ments 1 - 28 , wherein the therapeutic compound comprises ment 42 , wherein the pharmaceutically - acceptable alco an anti -hyperlipidemic agent . hol comprises methanol , ethanol, propanol, butanol, pen 30 . The pharmaceutical composition according to embodi - tanol, 1 -hexadecanol , or a combination thereof. ment 29 , wherein the anti -hyperlipidemic agent comprises 46 . The pharmaceutical composition according to embodi a fibrate , a statin , a tocotrienol, a niacin , a bile acid 30 ments 1 - 45 , wherein the pharmaceutically - acceptable sol sequestrants ( resin ) , a cholesterol absorption inhibitor, a vent comprises a pharmaceutically -acceptable ester of pancreatic lipase inhibitor, a sympathomimetic amine, or pharmaceutically -acceptable alcohol and an acid . a combination thereof. 47 . The pharmaceutical composition according to embodi 31 . The pharmaceutical composition according to embodi ment 46 , wherein the pharmaceutically - acceptable ester ment 29 , wherein the fibrate comprises Bezafibrate , Cip - 35 comprises methyl acetate , methyl buterate, methyl for rofibrate , Clofibrate , Gemfibrozil, Fenofibrate , or a com mate , ethyl acetate, ethyl buterate , ethyl formate , propyl bination thereof. acetate , propyl buterate, propyl formate , butyl acetate , 32 . The pharmaceutical composition according to embodi butyl buterate , butyl formate , isobutyl acetate , isobutyl ment 29 , wherein the statin comprises Atorvastatin , Flu buterate , isobutyl formate , pentyl acetate , pentyl buterate , vastatin , Lovastatin , Pitavastatin , Pravastatin , Rosuvasta - 40 pentyl formate , and 1 - hexadecyl acetate , 1 - hexadecyl tin , Simvastatin , or a combination thereof. buterate , and 1 -hexadecyl formate , or a combination 33 . The pharmaceutical composition according to embodi thereof. ment 29, wherein the niacin comprises acipimox , niacin , 48 . The pharmaceutical composition according to embodi nicotinamide , vitamin B3 , or a combination thereof. ments 1 -47 , wherein the pharmaceutically - acceptable sol 34 . The pharmaceutical composition according to embodi- 45 vent comprises a pharmaceutically - acceptable glycol ment 29, wherein the bile acid sequestrant comprises ether , a pharmaceutically -acceptable diol, a pharmaceu Cholestyramine, Colesevelam , Colestipol, or a combina tically -acceptable propylene glycol, a pharmaceutically tion thereof. acceptable dipropylene glycol, a pharmaceutically - ac 35 . The pharmaceutical composition according to embodi ceptable polypropylene glycol (PPG ) polymer, a ment 29, wherein the cholesterol absorption inhibitor 50 pharmaceutically -acceptable polyethylene glycol (PEG ) comprises Ezetimibe, a phytosterol, a sterol, a stanol , or polymer , or any combination thereof. a combination thereof. 49. The pharmaceutical composition according to embodi 36 . The pharmaceutical composition according to embodi ment 48 , wherein the pharmaceutically -acceptable glycol ment 29 , wherein the fat absorption inhibitor comprises ether comprises diethylene glycol monomethyl ether ( 2 Orlistat 55 ( 2 -methoxyethoxy ) ethanol) , diethylene glycol monoethyl 37 . The pharmaceutical composition according to embodi ether ( 2 - ( 2 -ethoxyethoxy ) ethanol) , diethylene glycol ment 29 , wherein the sympathomimetic amine comprises monopropyl ether ( 2 - ( 2 -propoxyethoxy ) ethanol) , diethyl Clenbuterol, Salbutamol, ephedrine , pseudoephedrine , ene glycol monoisopropyl ether ( 2 - ( 2 - isopropoxyethoxy ) methamphetamine , amphetamine , phenylephrine , isopro ethanol) , diethylene glycol mono - n - butyl ether ( 2 - ( 2 terenol, dobutamine ,methylphenidate , lisdexamfetamine , 60 butoxyethoxy Jethanol) , or any combination thereof. cathine , cathinone, methcathinone , cocaine , benzylpip - 50 . The pharmaceutical composition according to embodi erazine (BZP ) , methylenedioxypyrovalerone MDPV( ) , ment 48 , wherein the pharmaceutically - acceptable poly 4 -methylaminorex , pemoline, phenmetrazine , propylhex propylene glycol (PPG ) polymer or the pharmaceutically edrine , or a combination thereof. acceptable polyethylene glycol (PEG ) polymer is less 38 . The pharmaceutical composition according to embodi - 65 than about 2 ,000 g / mol. ments 1 - 37 , wherein the therapeutic compound comprises 51. The pharmaceutical composition according to embodi an ester of a therapeutic compound . ment 48, wherein the pharmaceutically - acceptable poly US 9 ,750 ,810 B2 63 64 propylene glycol (PPG ) polymer or the pharmaceutically pharmaceutically - acceptable polyether fatty acid ester , a acceptable polyethylene glycol (PEG ) polymer is more mixture of pharmaceutically -acceptable lipids, or any than about 2 , 000 g /mol . combination thereof. 52 . The pharmaceutical composition according to embodi- 68 . The pharmaceutical composition according to embodi ments 1 - 51 , wherein the pharmaceutically - acceptable sol- 5 ments 1 -67 , wherein the pharmaceutical composition fur vent comprises a pharmaceutically - acceptable glyceride . ther comprises a pharmaceutically -acceptable stabilizing agent. 53 . The pharmaceutical composition according to embodi 69. The pharmaceutical composition according to embodi ment 52, wherein the pharmaceutically - acceptable glyc ment 68 , wherein the pharmaceutically - acceptable stabi eride comprises a monoglyceride, a diglyceride , a triglyc lizing agent comprises water , a sacrificial acid comprising eride , an acetylated monoglyceride, an acetylated a fatty acid component and acetic acid , ethyl acetate , a diglyceride , an acetylated triglyceride, or a combination sodium acetate / acetic acid , a monoglyceride , an acety thereof. lated monoglyceride, a diglyceride , an acetylated diglyc 54 . The pharmaceutical composition according to embodi eride , a fatty acid , a fatty acid salt, or a combination ments 1 - 53 , wherein the pharmaceuticallycally - acceptable solsol 15 thereof. vent is a liquid at 20° C . or wherein the pharmaceutically - 70 . The pharmaceutical composition according to embodi acceptable solvent is a solid at 20° C . ment 68 , wherein the pharmaceutically - acceptable stabi 55 . The pharmaceutical composition according to embodi lizing agent comprises a pharmaceutically -acceptable ment 54 , wherein the pharmaceutically -acceptable solid emulsifying agent. solvent comprises menthol. 20 71. The pharmaceutical composition according to embodi 56 . The pharmaceutical composition according to embodi ment 70 , wherein the pharmaceutically -acceptable emul ments 1 - 55 , wherein the adjuvant is at least 80 % ( v / v ) . sifying agent comprises a surfactant, a polysaccharide, a 57 . The pharmaceutical composition according to embodi lectin , a phospholipid , or a combination thereof. ments 1 - 56 , wherein the pharmaceutically - acceptable 72 . The pharmaceutical composition according to embodi adjuvant is a liquid at 20° C . 25 ments 1 -69 , wherein the pharmaceutical composition does 58 . The pharmaceutical composition according to embodi not comprise a pharmaceutically - acceptable emulsifying ments 1- 56 , wherein the pharmaceutically -acceptable agent. adjuvant is a solid at 20° C . 73 . A method of preparing a pharmaceutical composition , 59. The pharmaceutical composition according to embodi the method comprising the step of contacting a therapeu ments 1 -58 , wherein the pharmaceutically -acceptable je 30su tic compound with a pharmaceutically -acceptable adju vant under conditions which allow the formation of the adjuvant comprises a pharmaceutically -acceptable lipid . pharmaceutical composition . 60 . The pharmaceutical composition according to embodi 74 . A method of preparing a pharmaceutical composition , ment 59, wherein the pharmaceutically -acceptable lipid the method comprising the steps: a ) contacting a pharma comprises a saturated fatty acid , an unsaturated fatty acid , 35 ceutically - acceptable solvent with a therapeutic com or a combination thereof . pound under conditions which allow the therapeutic com 61 . The pharmaceutical composition according to embodi pound to dissolve in the pharmaceutically -acceptable ment 59 or 60 , wherein the pharmaceutically - acceptable solvent, thereby forming a solution , wherein the thera lipid comprises two or more saturated or unsaturated fatty peutic compound has anti- inflammatory activity , and b ) acids. 40 contacting the solution formed in step ( a ) with a pharma 62 . The pharmaceutical composition according to embodi ceutically - acceptable adjuvant under conditions which ment61 , wherein the two or more saturated or unsaturated allow the formation of the pharmaceutical composition . fatty acids includes palmitic acid , stearic acid , oleic acid , 75 . A method of preparing a pharmaceutical composition , linoleic acid , linolenic acid , or a combination thereof. the method comprising the steps : a ) contacting a pharma 63 . The pharmaceutical composition according to embodi - 45 ceutically - acceptable solvent with a therapeutic com ments 60 -62 , wherein the unsaturated fatty acid has a pound under conditions which allow the therapeutic com melting point temperature of 20° C . or below or wherein pound to dissolve in the pharmaceutically - acceptable the unsaturated fatty acid is a solid at 20° C . solvent, thereby forming a solution , wherein the thera 64 . The pharmaceutical composition according to embodi peutic compound has anti - inflammatory activity , and b ) ments 60 -62 , wherein the unsaturated fatty acid comprises 50 contacting the solution formed in step ( a ) with a pharma an omega fatty acid . ceutically - acceptable adjuvant under conditions which 65 . The pharmaceutical composition according to embodi allow the formation of the pharmaceutical composition , ment 59 , wherein the pharmaceutically - acceptable lipid wherein the ratio of the pharmaceutically -acceptable sol comprises a pharmaceutically -acceptable oil . vent to pharmaceutically - acceptable adjuvant is in a range 66 . The pharmaceutical composition according to embodi - 55 from about 0 : 1 to about 1 : 25 . ment 65, wherein the pharmaceutically - acceptable oil 76 . The method according to embodiments 73 - 75 , wherein comprises almond oil , arachis oil, avocado oil, canola oil, the therapeutic compound has a log P value indicating that castor oil , coconut oil, corn oil , cottonseed oil , grape seed the compound is soluble in an organic solvent. oil , hazelnut oil, hemp oil, linseed oil, olive oil, palm oil, 77 . The method according to embodiment 73 - 76 , wherein peanut oil, rapeseed oil, rice bran oil , safflower oil, 60 the therapeutic compound has a log P value of more than sesame oil, soybean oil, soya oil, sunflower oil , theo - 1 . 0 . broma oil, walnut oil, wheat germ oil, or a combination 78 . The method according to embodiment 73 -76 , wherein thereof. the therapeutic compound has a log P value of more than 67 . The pharmaceutical composition according to embodi - 2 .0 . ment 59 , wherein the pharmaceutically - acceptable lipid 65 79 . The method according to embodiments 73 -78 , wherein comprises a pharmaceutically -acceptable glycerolipid , a the therapeutic compound has a polar surface area that is pharmaceutically -acceptable glycol fatty acid ester , a hydrophobic . US 9 , 750 ,810 B2 65 66 80 . The method according to embodiments 73 -79 , wherein methylphenidate , lisdexamfetamine, cathine , cathinone, the therapeutic compound has a polar surface area that is methcathinone , cocaine, benzylpiperazine (BZP ) , meth less than 8 . 0 nm - . ylenedioxypyrovalerone (MDPV ) , 4 - methylaminorex , 81. The method according to embodiments 73 -79 , wherein pemoline , phenmetrazine , propylhexedrine , or a combi the therapeutic compound has a polar surface area that is 5 ponation thereof. less than 6 . 0 nm . 97. The method according to embodiments 73 - 96 , wherein 82 . The method according to embodiments 73 - 81 , wherein the therapeutic compound comprises an ester of a thera the therapeutic compound comprises a non - steroidal anti peutic compound . inflammatory drug (NSAID ). 83 . The method according to embodiment 82 , wherein the 10 98 . The method according to embodiments 73 - 97 , wherein NSAID comprises a salicylate derivative NSAID , a the therapeutic compound comprises an ester of a thera p -amino phenol derivative NSAID , a propionic acid peutic compound according to embodiments 76 -97 . derivative NSAID , an acetic acid derivative NSAID , an 99. The method according to embodiments 74 - 98 , wherein enolic acid derivative NSAID , a fenamic acid derivative the pharmaceutically -acceptable solvent is less than about NSAID , a non - selective cyclo - oxygenase (COX ) inhibi- 15 20 % ( v / v ) . tor, a selective cyclooxygenase 1 (COX 1 ) inhibitor, a 100 . The method according to embodiments 74 - 99 , wherein selective cyclooxygenase 2 (COX 2 ) inhibitor, or a com the pharmaceutically - acceptable solvent comprises a bination thereof. pharmaceutically -acceptable polar aprotic solvent, a phar 84 . The method according to embodiments 73 - 83 , wherein maceutically - acceptable polar protic solvent, a pharma the therapeutic compound comprises a PPARy agonist . 20 ceutically -acceptable non -polar solvent, or a combination 85 . The method according to embodiment 84 , wherein the thereof. PPARy agonist comprises Monascin , Irbesartan , Telmis - 101 . The method according to embodiments 74 - 100 , artan , mycophenolic acid , Resveratrol, Delta ( 9 ) - tetrahy wherein the pharmaceutically -acceptable solvent com drocannabinol, a cannabidiol, Curcumin , Cilostazol, Ben prises a pharmaceutically - acceptable alcohol. zbromarone , 6 - shogaol, glycyrrhetinic acid , a 25 102 . The method according to embodiment 101, wherein the thiazolidinedione , a NSAID , a fibrate , or a combination pharmaceutically -acceptable alcohol comprises an acy thereof. clic alcohol, a monohydric alcohol , a polyhydric alcohol, 86 . The method according to embodiments 73 - 85 , wherein an unsaturated aliphatic alcohol, an alicyclic alcohol, or a the therapeutic compound comprises a nuclear receptor combination thereof. binding agent . 30 103 . Themethod according to embodiment 101, wherein the 87. The method according to embodiment 86 , wherein the pharmaceutically -acceptable alcohol comprises a C1- 20 nuclear receptor binding agent comprises a Retinoic Acid alcohol. Receptor (RAR ) binding agent , a Retinoid X Receptor 104 . The method according to embodiment 101, wherein the (RXR ) binding agent, a Liver X Receptor (LXR ) binding pharmaceutically -acceptable alcohol comprises metha agent , a Vitamin D binding agent, or a combination 35 nol, ethanol, propanol, butanol, pentanol, 1 -hexadecanol , thereof. or a combination thereof. 88 . The method according to embodiments 73 - 87 , wherein 105 . The method according to embodiment 101, wherein the the therapeutic compound comprises an anti- hyperlipi - pharmaceutically - acceptable solvent comprises a pharma demic agent. ceutically -acceptable ester of pharmaceutically - accept 89 . The method according to embodiment 88 , wherein the 40 able alcohol and an acid . anti -hyperlipidemic agent comprises a fibrate , a statin , a 106 . The method according to embodiment 105 , wherein the tocotrienol, a niacin , a bile acid sequestrants ( resin ) , a pharmaceutically - acceptable ester comprises methyl cholesterol absorption inhibitor, a pancreatic lipase acetate , methyl buterate , methyl formate , ethyl acetate , inhibitor, a sympathomimetic amine , or a combination ethyl buterate , ethyl formate , propyl acetate , propyl buter thereof . 45 ate , propyl formate , butyl acetate , butyl buterate , butyl 90 . The method according to embodiment 89, wherein the formate , isobutyl acetate , isobutyl buterate , isobutyl for fibrate comprises Bezafibrate , Ciprofibrate , Clofibrate , mate , pentyl acetate , pentyl buterate , pentyl formate , and Gemfibrozil , Fenofibrate , or a combination thereof. 1 - hexadecyl acetate , 1 -hexadecyl buterate , and 1 -hexade 91 . The method according to embodiment 89 , wherein the cyl formate , or a combination thereof. statin comprises Atorvastatin , Fluvastatin , Lovastatin , 50 107 . The method according to embodiments 74 - 106 , Pitavastatin , Pravastatin , Rosuvastatin , Simvastatin , or a wherein the pharmaceutically -acceptable solvent is a combination thereof. pharmaceutically -acceptable polyethylene glycol (PEG ) 92 . The method according to embodiment 89 , wherein the polymer. niacin comprises acipimox , niacin , nicotinamide , vitamin 108 . The method according to embodiment 107 , wherein the B3 , or a combination thereof . 55 pharmaceutically - acceptable polyethylene glycol (PEG ) 93 . The method according to embodiment 89, wherein the polymer is less than about 2 , 000 g /mol . bile acid sequestrant comprises Cholestyramine , Cole - 109. The method according to embodiment 107, wherein the sevelam , Colestipol, or a combination thereof. pharmaceutically - acceptable polyethylene glycol (PEG ) 94 . The method according to embodiment 89 , wherein the polymer is more than about 2 ,000 g /mol . cholesterol absorption inhibitor comprises Ezetimibe, a 60 110 . The method according to embodiments 74 - 109 , phytosterol, a sterol, a stanol, or a combination thereof. wherein the pharmaceutically -acceptable solvent com 95 . The method according to embodiment 89, wherein the prises a pharmaceutically - acceptable glyceride. fat absorption inhibitor comprises Orlistat 111. The method according to embodiments 110 , wherein 96 . The method according to embodiment 89 , wherein the the pharmaceutically -acceptable glyceride is a monoglyc sympathomimetic amine comprises Clenbuterol, Salbuta - 65 eride , a diglyceride , a triglyceride, an acetylated mono mol, ephedrine, pseudoephedrine , methamphetamine , glyceride , an acetylated diglyceride, an acetylated triglyc amphetamine , phenylephrine, isoproterenol , dobutamine , eride, or a combination thereof. US 9 ,750 ,810 B2 68 112 . The method according to embodiments 74 - 111 , wherein a monoglyceride, an acetylated monoglyceride , a diglyc the pharmaceutically -acceptable solvent is a liquid at 20° eride, an acetylated diglyceride , a fatty acid , a fatty acid C . salt, or a combination thereof. 113 . The method according to embodiments 74 - 111 , wherein 130 . The method according to embodiment 128 or 129 , the pharmaceutically -acceptable solvent is a solid at 20°5 wherein the pharmaceutically -acceptable stabilizing C . agent comprises a pharmaceutically -acceptable emulsify 114 . Themethod according to embodiment 113 , wherein the ing agent . pharmaceutically - acceptable solid solvent is menthol. 131. The method according to embodiment 130 , wherein the 115 . The method according to embodiments 73 - 114 , pharmaceutically - acceptable emulsifying agent com wherein the pharmaceutically -acceptable adjuvant is at 10 prises a surfactant, a polysaccharide , a lectin , a phospho least 80 % ( v / v ) . lipid , or a combination thereof. 116 . The method according to embodiments 73 - 115 , 132 . The method according to embodiments 73 - 129 , wherein the pharmaceutically -acceptable adjuvant is a wherein the pharmaceutical composition does not com liquid at 20° C . prise a pharmaceutically - acceptable emulsifying agent. 117 . The method according to embodiments 73 - 115 , 15 133 . The method according to embodiments 74 - 132 , wherein the pharmaceutically - acceptable adjuvant is a wherein the method further comprises removing the phar solid at 20° C . maceutically - acceptable solvent from the pharmaceutical 118 . The method according to embodiments 73 - 117 , composition . wherein the pharmaceutically -acceptable adjuvant com - 134 . Themethod according to embodiment 133 , wherein at prises a pharmaceutically - acceptable lipid . 20 least 5 % the pharmaceutically -acceptable solvent is 119 . The method according to embodiment 118 , wherein the removed from the pharmaceutical composition . pharmaceutically - acceptable lipid comprises a pharma 135 . The method according to embodiment 133 or 134 , ceutically -acceptable saturated fatty acid , an unsaturated wherein at , removal of solvent from the pharmaceutical fatty acid , or a combination thereof . composition disclosed herein is carried out at a tempera 120 . The method according to embodiment 118 or 119 , 25 ture of less than 20° C . giwherein the pharmaceutically -acceptable lipid comprises 136 . The method according to embodiments 73 - 135 , two or more pharmaceutically -acceptable saturated or wherein the pharmaceutical composition made is accord unsaturated fatty acids . ing to embodiments 1 -72 . 121. The method according to embodiments 120 , wherein 137 . A method of treating an individual with a chronic the two or more pharmaceutically - acceptable saturated or 30 inflammation , the method comprising the step of: admin unsaturated fatty acids include palmitic acid , stearic acid , istering to the individual in need thereof a pharmaceutical oleic acid , linoleic acid , linolenic acid , or a combination composition according to embodiments 1 -72 , wherein thereof. administration results in a reduction in a symptom asso 122 . The method according to embodiments 119 - 121, ciated with the chronic inflammation , thereby treating the wherein the pharmaceutically -acceptable unsaturated 35 individual. fatty acid has a melting point temperature of 20° C . or 138 . Use of a pharmaceutical composition according to below . embodiments 1 - 72 in the manufacture of a medicament 123 . The method according to embodiments 119 - 121, for the treatment of a chronic inflammation . wherein the pharmaceutically - acceptable unsaturated 139. Use of a pharmaceutical composition according to fatty acid is a solid at 20° C . 40 embodiments 1 - 72 for the treatment of a chronic inflam 124 . The method according to embodiments 119 - 123 , mation . wherein the pharmaceutically - acceptable unsaturated 140 . The method according to embodiment 137 or the use fatty acid comprises an omega fatty acid . according to embodiment 138 or 139, wherein the chronic 125 . The method according to embodiments 118 - 124 , inflammation is associated with acne, acid reflux /heart wherein the pharmaceutically - acceptable lipid comprises 45 burn , age related macular degeneration ( AMD ) , allergy , a pharmaceutically - acceptable oil . allergic rhinitis , Alzheimer ' s disease , amyotrophic lateral 126 . The method according to embodiment 125 , wherein the sclerosis , anemia , appendicitis , arteritis, arthritis , asthma, pharmaceutically -acceptable oil comprises almond oil , atherosclerosis , autoimmune disorders , balanitis , arachis oil, avocado oil , canola oil, castor oil, coconut oil , blepharitis , bronchiolitis , bronchitis , a bullous pemphig corn oil , cottonseed oil, grape seed oil, hazelnut oil , hemp 50 oid , burn , bursitis, cancer, cardiac arrest, carditis , celiac oil , linseed oil, olive oil, palm oil, peanut oil, rapeseed oil , disease , cellulitis , cervicitis , cholangitis , cholecystitis , rice bran oil, safflower oil , sesame oil , soybean oil, soya chorioamnionitis , chronic obstructive pulmonary disease oil , sunflower oil, walnut oil, wheat germ oil , or a com (COPD ) , cirrhosis , colitis, congestive heart failure , con bination thereof. junctivitis , cyclophosphamide- induced cystitis , cystic 127. The method according to embodiments 74 or 76 - 126 , 55 fibrosis , cystitis , common cold , dacryoadenitis , dementia , wherein in step (b ) the ratio of the pharmaceutically dermatitis , dermatomyositis , diabetes , diabetic neuropa acceptable solvent to pharmaceutically - acceptable adju thy , diabetic retinopathy, diabetic nephropathy, diabetic vant is in a range from about 0 : 1 to about 1 : 25 . ulcer, digestive system disease , eczema, emphysema , 128 . The method according to embodiments 73 - 127 , encephalitis , endocarditis , endometritis, enteritis , entero wherein the step ( a ) further comprising contacting a 60 colitis , epicondylitis , epididymitis , fasciitis , fibromyalgia , pharmaceutically - acceptable stabilizing agent with the fibrosis , fibrositis , gastritis, gastroenteritis , gingivitis , pharmaceutically - acceptable solvent and the therapeutic glomerulonephritis, glossitis , heart disease , heart valve compound . dysfunction , hepatitis , hidradenitis suppurativa , Hunting 129 . The method according to embodiment 128 , wherein the ton ' s disease , hyperlipidemic pancreatitis , hypertension , pharmaceutically - acceptable stabilizing agent comprises 65 ileitis, infection , inflammatory bowel disease , inflamma water, a sacrificial acid comprising a fatty acid component tory cardiomegaly , inflammatory neuropathy , insulin and acetic acid , ethyl acetate , a sodium acetate /acetic acid , resistance , interstitial cystitis , interstitial nephritis , iritis , US 9 ,750 ,810 B2 69 70 ischemia , ischemic heart disease , keratitis , keratoconjunc rosis (MS ) , a myasthenia gravis , a myopathy, a narco tivitis , laryngitis , lupus nephritis , mastitis , mastoiditis , lepsy , a neuromyotonia , a pemphigus vulgaris , a meningitis , metabolic syndrome (syndrome X ), a pernicious anaemia , a primary biliary cirrhosis , a recur migraine , multiple sclerosis , myelitis , myocarditis , myo rent disseminated encephalomyelitis , a rheumatic fever , a sitis , nephritis , non - alcoholic steatohepatitis , obesity , 5 schizophrenia , a scleroderma, a Sjögren ' s syndrome, a omphalitis , oophoritis , orchitis , osteochondritis, osteope tenosynovitis , a vasculitis , or a vitiligo . nia , osteomyelitis , osteoporosis , osteitis , otitis , pancrea - 10151 . The method according to embodiment 137 or the use according to embodiment 138 or 139 , wherein the chronic titis , Parkinson ' s disease , parotitis , pelvic inflammatory inflammation is a myopathy . disease , pemphigus vularis , pericarditis , peritonitis , phar 10 152 . The method or use according to embodiment 137 or yngitis , phlebitis , pleuritis , pneumonitis , polycystic 148 , wherein the myopathy is a dermatomyositis , an nephritis, proctitis , prostatitis , psoriasis , pulpitis , pyelo inclusion body myositis , or a polymyositis . nephritis , pylephlebitis , renal failure , reperfusion injury, 153 . The method according to embodiment 137 or the use retinitis , rheumatic fever, rhinitis , salpingitis , sarcoidosis , according to embodiment 138 or 139, wherein the chronic sialadenitis , sinusitis , spastic colon , stenosis, stomatitis , inflammation is a vasculitis . stroke , surgical complication , synovitis , tendonitis , tendiNdi.- 15 154 . The method or use according to embodiment 140 or nosis , tenosynovitis , thrombophlebitis , tonsillitis , trauma, 153 , wherein the vasculitis is vasculitis is a Buerger ' s traumatic brain injury , transplant rejection , trigonitis , disease , an arteritis , a cerebral vasculitis , a Churg - Strauss tuberculosis , tumor, urethritis , ursitis , uveitis , vaginitis , arteritis , a cryoglobulinemia , an essential cryoglobuline vasculitis , or vulvitis . mic vasculitis , a giant cell arteritis , a Golfer ' s vasculitis , 141. The method according to embodiment 137 or the use 20 a Henoch - Schonlein purpura , a hypersensitivity vasculi according to embodiment 138 or 139, wherein the chronic tis , a Kawasaki disease , a phlebitis , a microscopic pol inflammation is a tissue inflammation . yarteritis / polyangiitis , a polyarteritis nodosa , a polymyal 142 . The method according to embodiment 137 or the use gia rheumatica ( PMR ) , a rheumatoid vasculitis , a according to embodiment 138 or 139 , wherein the chronic Takayasu arteritis , a thrombophlebitis , a Wegener ' s inflammation is a systemic inflammation . 25 granulomatosis , or a vasculitis secondary to connective 143 . The method according to embodiment 137 or the use tissue disorder, or vasculitis secondary to viral infection . according to embodiment 138 or 139, wherein the chronic 155 . The method according to embodiment 137 or the use inflammation is an arthritis . according to embodiment 138 or 139 , wherein the chronic 144 . The method or use according to embodiment 140 or inflammation is associated with a skin disorder . 143 , wherein the arthritis is a monoarthritis , an oligoar- 30 156 . The method or use according to embodiment 140 or thritis , or a polyarthritis . 155, wherein the skin disorder is a dermatitis , an eczema , 145 . The method or use according to embodiment 140 or a statis dermatitis , a hidradenitis suppurativa , a psoriasis , 143 , wherein the arthritis is an auto - immune disease or a a rosacea or a scleroderma. non - autoimmune disease . 157 . The method or use according to embodiment 156 , 146 . The method or use according to embodiment 140 or 26 wherein the eczema is an atopic eczema , a contact 143 , wherein the arthritis is an osteoarthritis , a rheumatoid eczema, a xerotic eczema, a seborrhoeic dermatitis , a arthritis , a juvenile idiopathic arthritis , a septic arthritis , a dyshidrosis , a discoid eczema, a venous eczema , a der spondyloarthropathy, a gout, a pseudogout, or Still ' s matitis herpetiformis , a neurodermatitis , or an autoecze disease . matization . 147 . The method or use according to embodiment 146 , 158 . The method or use according to embodiment 156 , wherein the spondyloarthropathy is an ankylosing spon - 40 wherein the psoriasis is a plaqure psoriasis , a nail psoria dylitis , a reactive arthritis (Reiter 's syndrome) , a psoriatic sis , a guttate psoriasis , a scalp psoriasis, an inverse arthritis , an enteropathic arthritis associated with inflam psoriasis , a pustular psoriasis , or an erythrodermis pso matory bowel disease , a Whipple disease or a Behcet riasis . disease . 159 . The method according to embodiment 137 or the use 148 . The method according to embodiment 137 or the use 45 according to embodiment 138 or 139 , wherein the chronic according to embodiment 138 or 139 , wherein the chronic inflammation is associated with a gastrointestinal disor inflammation is an autoimmune disorder . der. 149. The method or use according to embodiment 140 or 160 . The method or use according to embodiment 140 or 148 , wherein the autoimmune disorder is a systemic 159 , wherein the gastrointestinal disorder is an irritable autoimmune disorder or an organ - specific autoimmune 50 bowel disease or an inflammatory bowel . disorder. 161. The method or use according to embodiment 160 , 150 . The method or use according to embodiment 140 or wherein the inflammatory bowel is a Crohn ' s disease or 148 , wherein the autoimmune disorder is an acute dis an ulcerative colitis . seminated encephalomyelitis (ADEM ) , an Addison ' s dis - 162 . The method according to embodiment 137 or the use ease , an allergy , an anti - phospholipid antibody syndrome 55 according to embodiment 138 or 139 , wherein the chronic ( APS ) , an autoimmune hemolytic anemia , an autoimmune inflammation is associated with a cardiovascular disease . hepatitis , an autoimmune inner ear disease , a bullous 163 . The method or use according to embodiment 140 or pemphigoid , a celiac disease , a Chagas disease , a chronic 162 , wherein the cardiovascular disease is a hypertension , obstructive pulmonary disease (COPD ) , a diabetes mel heart valve dysfunction , congestive heart failure ,myocar litus type 1 ( IDDM ) , an endometriosis , a Goodpasture ' s dial infarction , a diabetic cardiac conditions, a blood syndrome, a Graves' disease , a Guillain - Barré syndrome 60 vessel inflammation , arterial occlusive disease, a periph (GBS ) , a Hashimoto ' s thyroiditis , a hidradenitis suppu eral arterial disease , an aneurysm , an embolism , a dissec rativa , an idiopathic thrombocytopenic purpura, an tion , a pseudoaneurysm , a vascular malformation , a vas inflammatory bowel disease , an interstitial cystitis , a cular nevus , a thrombosis , a thrombphlebitis , a varicose lupus ( including a discoid lupus erythematosus , a drug veins , or a stroke . induced lupus erythematosus, a lupus nephritis , a neonatal 65 164 . The method according to embodiment 137 or the use lupus, a subacute cutaneous lupus erythematosus , a sys according to embodiment 138 or 139 , wherein the chronic temic lupus erythematosus, a morphea , a multiple scle inflammation is associated with a cancer. US 9 , 750 , 810 B2 72 165. The method according to embodiment 137 or the use limit any of the embodiments described in the present according to embodiment 138 or 139, wherein the chronic specification , including those pertaining to the compounds, inflammation is associated with a pharmacologically alcohols , lipids , pharmaceutical compositions, methods of induced inflammation . preparing pharmaceutical compositions, or methods or uses 166 . The method according to embodiment 137 or the use 5 of treating a chronic inflammation or disease associated with according to embodiment 138 or 139 , wherein the chronic chronic inflammation . inflammation is associated with an infection . 167. The method or use according to embodiment 140 or Example 1 166 , wherein the infection is a bacterial cystitis , a bacte rial encephalitis , a pandemic influenza , a viral encepha - 10 Liquid Formulations of Pharmaceutical litis , a viral hepatitis A , a viral hepatitis B , or a viral Composition hepatitis C . 168. The method according to embodiment 137 or the use This example illustrates how to make a pharmaceutical according to embodiment 138 or 139 , wherein the chronic composition as disclosed herein as a liquid formulation . inflammation is associated with a tissue or organ injury . 15 Initially . 2 . 400 mg of ibuprofen was contacted directly 169. The method according to embodiment 137 or the use with 2 . 0 mL of rapeseed oil in an attempt to dissolve a according to embodiment 138 or 139 , wherein the chronic therapeutic compound directly into an adjuvant at a concen inflammation is associated with a transplant rejection or a tration of 1 , 200 mg/ mL . However, ibuprofen remained graft- versus- host disease . insoluble in the oil and did not dissolve to substantially 170 . The method according to embodiment 137 or the use 20 measurable degree . Ibuprofen remained insolubility even if according to embodiment 138 or 139 , wherein the chronic the mixture was mixed by vortexing for 20 seconds , the inflammation is associated with a Th1- mediated inflam contacting was done at 20° C . or 37° C ., and / or the mixture matory disease . was allowed to incubate for 24 hours at 20° C . or 37° C . The 171. The method according to embodiment 137 or the use insolubility of ibuprofen in rapeseed oil was surprising given according to embodiment 138 or 139 , wherein the chronic 25 that ibuprofen has a log P value of 3 .6 ; such a high log P inflammation is associated with chronic neurogenic value is indicative of a compound that would readily soluble inflammation . in an adjuvant like oil . 172. The method according to embodiments 137 or 140 - 171 Since , it was not possible to dissolve ibuprofen directly or the use according to embodiments 138 - 171, wherein into oil, despite its high log P value , it was next tried to upon administration to an individual, the pharmaceutical 30 dissolve a therapeutic drug in a solvent to first create a composition comprising the therapeutic compound solution comprising the compound . As a first step , experi according to embodiments 1 - 72 results in a bio - distribu ments were conducted to the miscibility of a solvent in an tion of the therapeutic compound different than a bio adjuvant like oil in the absence of a therapeutic compound . distribution of the therapeutic compound included in the In these experiments 0 . 5 mL ethanol was contacted with ten same pharmaceutical composition , except without the 35 different volumes of rapeseed oil ( Table 1 ) . Each mixture pharmaceutically - acceptable adjuvant . was tested at 22° C . and at 37° C . in which the ethanol and 173 . The method according to embodiments 137 or 140 - 172 oil were initially heated in a water bath before being mixed or the use according to embodiments 138 - 172 , wherein together. Mixing was attempted by vortex mixing for 20 upon administration to an individual, the amount of the seconds, and the containers were allowed to settle before therapeutic compound of the pharmaceutical composition 40 visualvisi assessment, either immediately , or after 24 hours . according to embodiments 1 - 72 delivered to a macro Each mixture was evaluated to determine whether or not the phage is at least 5 % of the total amount of the therapeutic ethanol and rapeseed oil form immiscible layers , or a compound contained in the administered pharmaceutical homogeneous mixture . The results are summarized in Table composition . 1 . Mixtures comprising solvent: adjuvant ratios of 1 : 1 , 1 : 2 , 174 . Themethod according to embodiments 137 or 140 - 173 45 11 : 3 ., 1: 4 , 1 :5 , and 1 :6 formed immiscible layers at either 22° or the use according to embodiments 138 - 173, wherein C . or at 37° C . , either immediately or after 24 hours of upon administration to an individual, the pharmaceutical incubation , indicating that the ethanol and oil did not mix composition according to embodiments 1 - 72 reduces well at these ratios . However, in solvent :adjuvant ratios intestinal irritation by at least 5 % when compared to the above 1 : 7 a homogeneous mixture was formed under all pharmaceutical composition according to embodiments 50 conditions tested . 1 - 72 , except without the pharmaceutically -acceptable adjuvant . 175 . The method according to embodiments 137 or 140 - 171 TABLE 1 or the use according to embodiments 138 - 174 , wherein Liquid Formulations without Therapeutic Compound upon administration to an individual, the pharmaceutical 55 composition according to embodiments 1 -72 reduces gas Temperature tric irritation by at least 5 % when compared to the Components pharmaceutical composition according to embodiments 22° C . 37° C . 1 - 72 , except without the pharmaceutically -acceptable Solvent Imme- 24 Imme- 24 adjuvant. 60 (mL ) (mL ) Ratio diate hours diate hours 0 . 5 0 . 5 1 : 1 IL IL EXAMPLES 1 . 0 1 : 2 IL IL 1. 5 1 : 3 IL IL IL 1 : 4 IL IL The following non - limiting examples are provided for üünüürün ???M?? OOOOO ino 1: 5 IL IL IL IL illustrative purposes only in order to facilitate a more 65 1 :6 IL IL IL complete understanding of representative embodiments now 0 . 5 no 1 : 7 HM HM HM HM contemplated . These examples should not be construed to US 9, 750 ,810 B2 73 74 TABLE 1 -continued To prepare a pharmaceutical composition disclosed herein using gemfibrozil, the following formulations were exam Liquid Formulations without Therapeutic Compound ined . In these experiments , 600 mg gemfibrozil was con Temperature tacted with different volumes of ethanol, as the solvent, in warmed to 37° C . , and the resulting solution was then Components 22° C . 37° C . contacted with different volumes of linseed oil, as the Solvent Adjuvant Imme 24 Imme 24 adjuvant, warmed to 37° C . ( Table 3 ) . Each formulation was (mL ) (mL ) Ratio diate hours diate hours evaluated to determine whether or not the ethanol and 0 . 5 4 . 0 1 : 8 HM HM HM HM linseed oil form immiscible layers , a clear homogeneous 0 .5 4 . 5 1 : 9 HM HM HM HM mixture , as well as whether or not the gemfibrozil crystal 0 . 5 5 . 0 1 : 10 HM HM HM HM lized out of solution . The results are summarized in Table 3 . L , Immiscible layers . Like ibuprofen in Example 1 above , gemfibrozil remained HM , Homogeneous mixture . insoluble in the oil alone and did not dissolve to substantially measurable degree . The formulation comprising 0 . 2 mL Once the appropriate ratios of alcohol and lipid necessary 15 ethanol was unable to completely dissolve gemfibrozil. In to form a homogenous mixture were determined , it was next determined whether contacting a therapeutic compound first addition , although the formulation comprising 0 . 3 mL etha in a solvent before contacting with an adjuvant would result nol was capable of dissolving gemfibrozil, the therapeutic in the compound dissolving in the solvents . To conduct these compound began to crystallizing out of solution within 3 experiments , either 1 . 000 mg or 1 . 200 mg of ibuprofen was 20 hours and complete crystallization occurred within 48 hours . dissolved into 0 . 5 mL of ethanol. The resulting alcohol All other formulations tested were capable of dissolving solution was then contacted with rapeseed oil at two differ gemfibrozil and forming a pharmaceutical composition dis ent solvent: adjuvant ratios ( 1: 2 and 1: 9 ). Each mixture was closed herein . However , only the formulation comprising tested at 20° C . and at 37° C . in which the ethanol solution 0 . 5 mL ethanol appeared to for a stable pharmaceutical and oil were initially heated in a water bath before being 25 composition in that gemfibrozil remained completely dis mixed together. Mixing was attempted by vortex mixing for solved after three weeks . 20 seconds, and the containers were allowed to settle before visual assessment, either immediately , or after 24 hours . Each mixture was evaluated to determine whether or not the TABLE 3 ethanol solution and rapeseed oil form immiscible layers , or 30 Liquid Formulations with Therapeutic Compound a homogeneous mixture . The results are summarized in Table 2 . In contrast to the situation in the absence of a Components Temperature therapeutic compound , when ibuprofen is present in the ethanol, it caused the ethanol and oil to form a homogeneous Compound Solvent Adjuvant 22° C . mixture under all conditions tested in solvent: adjuvant ratios (mg ) (mL ) (mL ) Ratio Immediate 3 weeks above 1 : 2 . This observation was very surprising because , although not wish to be bound by any theory , it appears that 600 O 1 . 0 IM N / A a therapeutic compound may be having some effect on the 600 0 . 2 — IM NA 600 0 . 3 0 . 6 1 : 2 CR CR manner in which an adjuvant and solvent interact with each 600 0 . 4 0 .4 1 : 1 HM CR other, such that a homogeneous mixture is formed in a way 600 0 . 4 0 . 8 1: :2 2 HM CR that does not occur when the therapeutic compound is 40 600 0 . 5 1 . 0 1 : 2 HM HM absent. In addition , the results indicate that a therapeutic HM , Clear homogeneous mixture . compound can be formulated at clinically useful concentra CR , Crystallization . tions . M , Immiscible . TABLE 2 45 Example 3 Liquid Formulations with Therapeutic Compound Components Temperature Liquid Formulations of Pharmaceutical Compositions Com 22° C . _ _ 37° C . 50 This example illustrates how to make a pharmaceutical pound Solvent Adjuvant Imme- 24 Imme- 24 composition as disclosed herein as a liquid formulation . (mg ) (mL ) (mL ) Ratio diate hours diate hours To prepare a liquid pharmaceutical composition disclosed 500 0 . 5 1 . 0 1 : 2 HM HM HM HM herein using ibuprofen , the following method was per 600 0 .. 5 1 . 0 0 1 :2 HM HM HM HM se 500 0 . 5 4 . 5 HM HM HM HM 55 formed . About 4 g ibuprofen was contacted with 3 . 6 mL of 600 0 . 5 4 . 5 1 :9 HM HM HM HM ethyl acetate , as the solvent, and the resulting solution was then contacted with 76 . 4 mL of rapeseed oil, as the adjuvant. L , Immiscible layers . The resulting pharmaceutical composition had a solvent : HM , Homogeneous mixture . adjuvant ratio of about 1 : 21 . This pharmaceutical composi 60 tion was then placed in a round bottom flask and subjected Example 2 to low pressure on a rotary evaporator. The temperature was kept low and evaporation continued to constant weight. The Liquid Formulations of Pharmaceutical total volume lost was 3. 65 % of the total weight. The Composition resulting liquid no longer retained the characteristic ethyl 65 acetate odor/ taste , indicating that there was a substantial This example illustrates how to make a pharmaceutical removal of ethyl acetate form the pharmaceutical composi composition as disclosed herein as a liquid formulation . tion . US 9 , 750 ,810 B2 75 76 To prepare a liquid pharmaceutical composition disclosed TABLE 4 herein using ibuprofen , the following method was per formed . About 2 g ibuprofen was contacted with 1. 2 mL of Solid Formulations with Therapeutic Compound diethylene glycol monoethyl ether (2 -( 2 - ethoxyethoxy ) etha Components Temperature nol) , as the solvent, 2 . 2 mL MAISINE® 35 - 1 (Gattefosse ) , 5 a glyceryl monolinoleate , and 2 . 2 mL rapeseed oil , as the Com 22° C . 37° C . adjuvants , and the resulting mixture was then contacted with pound Solvent Adjuvant Upon 24 72 0 .46 mL isopropanol. The mixture was added to a vessel (mg ) (mg ) (mg ) Ratio Cooling hours hours heated to about 40° C . to about 50° C . and stirred until all 200 400 200 2: 1 Solid Solid - components of the mixture dissolved and then cooled to ( stearic acid ) about 30° C . The resulting pharmaceutical composition had 200 400 200 2 : 1 Solid Liquid - a solvent: adjuvant ratio of about 1 : 3 .67 . This pharmaceutical ( palmitic acid ) 200 400 200 2 : 1 Liquid Liquid Liquid composition was then aliquoted to produce 10 liquid cap (linoleic acid ) 200 400 sules each containing about 200 mg ibuprofen . 1515 400 200200 2: 1 Liquid Liquid Liquid ( linolenic acid ) Example 4 Based on these data , a solid dosage form of a pharma Solid Formulation of Pharmaceutical Composition ceutical composition disclosed herein can be made . For 20 example , a pharmaceutical composition will be formulated This example illustrates how to make a pharmaceutical to be solid or semi- solid at 22° C . , but melt into a proper composition as disclosed herein as a solid formulation . clear solution (and not a suspension ) at 37° C . ( Table 5 ). Since certain fatty acids are liquid at room temperature , while others are solid , an examination of the different fatty TABLE 5 acids was undertaken in an effort to evaluate the potential of 25 each fatty acid in the manufacture of a solid formulation . Solid Formulations of Pharmaceutical Compositions This understanding would enable the development of a wide Compound 600 mg Ibuprofen array of solid formulation by adjusting the relative ratios of Solvent 500 mg Methanol Adjuvant 2000 mg Palmitic acid each fatty acid . As an initial experiment, linolenic acid , 2000 mg Stearic acid linoleic acid , palmitic acid and stearic acid were evaluated 30 250 mg Linolenic acid to assess whether it was possible to prepare a pharmaceutical 250 mg Linoleic acid composition disclosed herein that could be formulated using Ratio 1 : 9 Volume 5 mL only one of these fatty acids to be a solid or semi- solid at 22° 120 mg/mL C . ( simulating room temperature conditions) , but melt into Concentration a liquid at 37° C . (simulating internal body temperature conditions after ingestion ) . To prepare a solid pharmaceutical composition disclosed Four different test formulations were prepared and evalu herein using ibuprofen , the following method was per ated on their ability to form a solid dose formulation at 22° formed . About 15 g ibuprofen was contacted with about 9 . 0 C . and melt into a homogeneous solution at 37° C . without an mL of diethylene glycol monoethyl ether ( 2 - ( 2 -ethoxy forming a suspension ( Table 4 ). Formulation 1 was prepared ethoxy ) ethanol) , as the solvent, about 33 g GELUCIRE? by dissolving 200 mg of Ibuprofen into 400 mg ofmenthol , 39 /01 (Gattefosse ), a waxy solid having a melting point of and the resulting solution was then mixed with 200 mg of between 37° C . to 41° C . and comprising a mixture of stearic acid ( Tm of about 67 -72° C .) and heated at 60° C . for saturated C10 - C18 triglycerides, as the adjuvant, and about 30 minutes to form a homogeneous solution . Formulation 1 45 3 . 6 mL isopropanol. The mixture was added to a vessel solidified immediately upon cooling to 220 C . Formulation heated to about 40° C . to about 50° C . and stirred until all 1 remained a solid even after incubating at 37° C . overnight. components of the mixture dissolved , cooled to about 30° Formulation 2 was prepared by dissolving 200 mg of C ., and then aliquoted by poring into molds and cooled to Ibuprofen into 400 mg of menthol, and the resulting solution room temperature . The resulting pharmaceutical composi was then mixed with 200 mg of palmitic acid ( T. , , of about 50 tion had a solvent: adjuvant ratio of about 1 : 3 .67 . This 61 -62° C .) and heated at 60° C . for 30 minutes to form a pharmaceutical composition produced 75 solid tablets each homogeneous solution . Formulation 2 solidified about 1 containing about 200 mg ibuprofen . hour after cooling to 22° C . Incubating at 37° C . overnight To prepare a solid pharmaceutical composition disclosed cause Formulation 2 to completely melt into a clear homog - herein using ibuprofen , the following method was per enous liquid . However, Formulation 2 once again solidified 55 formed . About 20 g ibuprofen was contacted with about 12 . 0 about 1 hour after cooling to 22° C . Formulation 3 was mL of diethylene glycol monoethyl ether ( 2 - ( 2 -ethoxy prepared by dissolving 200 mg of Ibuprofen into 400 mg of ethoxy Jethanol) , as the solvent, about 16 g GELUCIRE? menthol, and the resulting solution was then mixed with 200 43 /01 (Gattefosse ) , a waxy solid having a melting point of mg of linoleic acid ( T , of about - 5° C .) and heated at 37° between 41° C . to 45° C . and comprising a mixture of C . for 2 hours to form a homogeneous solution . Formulation 60 saturated C1 -C , triglycerides, and about 16 g MAISINE? 3 remained a liquid , even after cooling to 22° C . for 72 35 - 1 (Gattefosse ) , a glyceryl monolinoleate , as the adjuvant, hours . Formulation 4 was prepared by dissolving 200 mg of and about 3 . 6 mL isopropanol. The mixture was added to a Ibuprofen into 400 mg of menthol, and the resulting solution vessel heated to about 40° C . to about 50° C . and stirred until was then mixed with 200 mg of linolenic acid ( T , of about all components of the mixture dissolved , cooled to about 30° - 11° C . ) and heated at 37° C . for 2 hours to form a 65 C . , and then aliquoted by poring into molds and cooled to homogeneous solution . Formulation 4 remained a liquid , room temperature . The resulting pharmaceutical composi even after cooling to 22° C . for 72 hours . tion had a solvent: adjuvant ratio of about 1 : 2 .67 . This US 9 ,750 ,810 B2 77 78 pharmaceutical composition produced 100 solid tablets each priate container . This pharmaceutical composition produced containing about 200 mg ibuprofen . a semisolid ointment having a concentration of ibuprofen To prepare a solid pharmaceutical composition disclosed that is about 400 mg/ mL . herein using ibuprofen , the following method was per - To prepare a semi- solid pharmaceutical composition dis formed . About 80 g ibuprofen , about 152 g GELUCIRE® 5 closed herein using ibuprofen , the following method was 43 /01 (Gattefosse ), a waxy solid having a melting point of performed . About 5 g ibuprofen free acid , about 5 g ibu between 41° C . to 45° C . and comprising a mixture of profen sodium salt , about 3 g GELUCIRE® 43 /01 (Gatte saturated C10 -C18 triglycerides, and about 72 mL fosse ) , a waxy solid having a melting point of between 41° MAISINE® 35 - 1 (Gattefosse ) , a glyceryl monolinoleate , C . to 45° C . and comprising a mixture of saturated C10 -C18 and about 32 mL PEG 400 were added to a vessel heatedeated to 10 triglycerides , and about 8 mL MAISINE® 35 - 1 (Gatte about 50° C . to about 60° C . and stirred until all components fosse ) , a glyceryl monolinoleate , about 3 mL PEG 400 , and of the mixture dissolved . The heated mixture is cooled to about 1 mL propylene glycol were added to a vessel heated about 40° C . , and then aliquoted by poring into molds and to about 50° C . to about 60° C . and stirred until all cooled to room temperature . This pharmaceutical composi components of the mixture dissolved . The heated mixture is tion produced 400 solid tablets each containing about 200 15 cooled to room temperature and aliquoted into an appropri mg ibuprofen . ate container . This pharmaceutical composition produced a To prepare a solid pharmaceutical composition disclosed semisolid ointment having a concentration of ibuprofen that herein using ibuprofen , the following method was per is about 650 mg/mL . formed . About 1 . 1 g ibuprofen sodium salt, about 1 .9 g 20 Example 6 GELUCIRE® 43 / 01 (Gattefosse ), a waxy solid having a melting point of between 41° C . to 45° C . and comprising a Animal Model for Intestinal Erosion mixture of saturated C10 -C18 triglycerides, and about 0 . 9 mL MAISINE® 35 - 1 (Gattefosse ) , a glyceryl monolinoleate , To assess whether a pharmaceutical composition dis about 0 .4 mL PEG 400 , and about 0 .3 mL propylene glycol 25 closed herein reduced gastric irritation , experiments were were added to a vessel heated to about 50° C . to about 60° conducted using an intestinal erosion murine model. C . and stirred until all components of the mixture dissolved . Sprague -Dawley rats were divided into seven experimen The heated mixture is cooled to about 40° C ., and then tal groups containing five animals each . After fasting over aliquoted by poring into molds and cooled to room tem - night, the animals were challenged with one with one of perature . This pharmaceutical composition produced 5 solid 30 seven different treatments . Group A was a control in which tablets each containing about 200 mg ibuprofen . each mouse was orally administered 1 % methylcellulose / To prepare a solid pharmaceutical composition disclosed 0 .5 % polysorbate 80 vehicle only . Group B was a control in herein using ibuprofen , the following method was per - which each mouse was orally administered solvent/ adjuvant formed . About 5 g ibuprofen free acid , about 5 g ibuprofen vehicle only (gavage of 10 % ethanol and 90 % linseed oil ) . sodium salt, about 3 g GELUCIRE® 43 /01 (Gattefosse ) , a 35 Group C was a control in which each mouse was orally waxy solid having a melting point ofbetween 41° C . to 45° administered 150 mg/ kg aspirin . Group D was a control in C . and comprising a mixture of saturated C1. - C , triglyc - which each mouse was orally administered 100 mg/ kg erides, and about 8 mL MAISINE® 35 - 1 (Gattefosse ) , a ibuprofen suspended in 1 % methylcellulose / 0 . 5 % polysor glyceryl monolinoleate , about 3 mL PEG 400 , and about 1 bate 80 . Group E was the experimental group in which each mL propylene glycol were added to a vessel heated to about 40 mouse was administered a pharmaceutical composition dis 50° C . to about 60° C . and stirred until all components of the closed herein (BC1054 - 100 ) comprising 100 mg/ kg of ibu mixture dissolved . The heated mixture is cooled to about 40° profen , 10 % ethanol, and 90 % linseed oil . Group F was a C . , and then aliquoted by poring into molds and cooled to control in which each mouse was orally administered 100 room temperature. This pharmaceutical composition pro mg/ kg ibuprofen suspended in 1 % methylcellulose / 0 . 5 % duced 50 solid tablets each containing about 200 mg ibu - 45 polysorbate 80 . Group G was the experimental group in profen . which each mouse was administered a pharmaceutical com position disclosed herein (BC1054 - 200 ) comprising 200 Example 5 mg /kg of ibuprofen , 10 % ethanol, and 90 % linseed oil . Animals were sacrificed 4 hours after treatment and the Semi- Solid Formulation of Pharmaceutical 50 stomachs were examined for degree of hemorrhage and Composition severity of mucosal erosive lesions . Gastric irritation was scored as follows : 0 , no lesions; 1 , hyperemia ; 2 , one or two This example illustrates how to make a pharmaceutical slight lesions ; 3 , more than two slight lesions or severe composition as disclosed herein as a semi-solid formulation lesions ; and 4 , very severe lesions. A score of 50 % or more useful for topical administration . 55 relative to Group C (aspirin - treated control group ) , which To prepare a semi- solid pharmaceutical composition dis - was set to 100 % , was considered a positive score for gastric closed herein using ibuprofen , the following method was irritation . performed . About 1 g ibuprofen free acid , about 0 .2 g Results are shown in Table 6 . Group D ( 100 mg/ kg of ibuprofen sodium salt , about 0 .6 g GELUCIRE® 43 /01 ibuprofen - treated control group ) and Group F ( 200 mg/ kg of (Gattefosse ) , a waxy solid having a melting point of between 60 ibuprofen - treated control group ) produced gastric lesions 41° C . to 45° C . and comprising a mixture of saturated that were 75 % and 95 % , respectively , severe as those C10 -C18 triglycerides , and about 1 .6 mL MAISINE® 35 - 1 induced by Group C (aspirin - treated control group ). How (Gattefosse ), a glyceryl monolinoleate , about 0 . 6 mL PEG ever , Group E (BC1054 - 100 -treated experimental group ) 400 , and about 0 . 15 mL propylene glycol were added to a and Group G (BC1054 - 200 - treated experimental group ) vessel heated to about 50° C . to about 60° C . and stirred until 65 produced gastric lesions that were 20 % and 40 % , respec all components of the mixture dissolved . The heated mixture tively , as severe as those associated with Group C ( aspirin is cooled to room temperature and aliquoted into an appro treated control group ) . These results demonstrate that that a US 9 , 750 ,810 B2 79 80 pharmaceutical composition disclosed herein reduced the the plate . The plate was sealed and incubated for 20 minutes extent to which a therapeutic compound may cause mucosal at room temperature . Plates were then washed ten times. 60 lesions and cause gastric irritation . uL of substrate solution were added to each well and the plate was incubated for 30 minutes at room temperature in TABLE 6 5 the dark . 60 uL of stop solution was added to each well and absorbance was read at 450 nm . IL - 10 and IL - 4 concentra Results from Intestinal Erosion Assay tions were expressed as pg /mg of lung tissue . These results Mean indicate that a pharmaceutical composition disclosed herein Group Ulceration Score % Aspirin Erosion was effective in treating a respiratory inflammation . 10 Results show that animals from the Group A ( ibuprofen treated control group ) and Group B ( solvent/ adjuvant ( 100 ) 751 vehicle -treated control group ) controls exhibited 2600 MOALO 20 pg /mg and 2000 pg /mg of IL - 10 , respectively ( FIG . 2A ). Ootmom3. 8 951 However , Group C (BC1054 - treated experimental group ) 1. 6 revealed an IL - 10 concentration of 6000 pg/ mg , 3 - fold Positive score for gastric erosion . higher than that seen in the control animals . These result also shows that animals from the Group A ( ibuprofen -treated control group ) and Group B (solvent / adjuvant vehicle Example 7 20 treated control group ) controls exhibited 6900 pg/ mg and 5400 pg /mg of IL -4 , respectively , while Group C (BC1054 Animal Model for a Respiratory Inflammation treated experimental group ) exhibited an IL - 4 concentration of 8300 pg /mg ( FIG . 2B ) . Taken together, synergistic To assess the effectiveness of a pharmaceutical composi increase in IL - 10 levels and /or the increase in IL - 4 levels tion disclosed herein in treating a respiratory inflammation , 25 suggest that at least part of the efficacy observed for BC1054 experiments were conducted using a viral -induce influenza was by inducing a switch from a Th1 to a Th2 response . murine model. Further experiments were done to further determine C57BLK /6 female mice (6 - 7 weeks old ) were divided into three experimental groups containing ten animals each . On which cell types were stimulated to release cytokines upon day 1 , animals received an intranasal lethal dose (50 uL 30 administration of a BC1054 . C57BLK /6 female mice (6 - 7 total , 25 uL / nostril ) of Influenza A /PR / 8 /34 under halothane weeks old ) were divided into three experimental groups induced anaesthesia . On day 3 , post -challenge with the containing ten animals each . On day 1 , animals received an virus , the animals received one of three treatments . Group A intranasal lethaldose (50 uL total, 25 uL /nostril ) of Influenza was a control in which each mouse was orally administered HIN1 under halothane - induced anaesthesia . On day 3 , post 335 .6 ug of ibuprofen dissolved in 10 ?L DMSO (no 355 challenge with the virus, the animals received one of three adjuvant) . Group B was a control in which each mouse was treatments . Group A was a control in which each mouse was orally administered solvent/ adjuvant vehicle only ( gavage of orally administered 335 . 6 ug of ibuprofen dissolved in 10 uL 10 % ethanol and 90 % linseed oil) . Group C was the experi DMSO (no adjuvant) . Group B was a control in which each mental group in which each mouse was administered a mouse was orally administered solvent/ adjuvant vehicle pharmaceutical composition disclosed herein (BC1054 ) 40 only (gavage of 10 % ethanol and 90 % linseed oil ) (no comprising 335 .6 ug of ibuprofen , 10 % ethanol, and 90 % ibuprofen ) . Group C was the experimental group in which linseed oil. A dose of 335 . 6 ug of ibuprofen in the mouse is each mouse was administered a pharmaceutical composition equivalent to 20 mg/ kg /day , or 1200 mg/ day for a human disclosed herein (BC1054 ) comprising 335 . 6 ug of ibupro ( the maximum standard dose for ibuprofen ) . Animals were fen , 10 % ethanol, and 90 % linseed oil. Lungs collected from weighed , and monitored for signs of infection daily for up to 45 fatally - infected mice were homogenized at 4° C ., and the day 6 when all animals were culled . FIG . 1 clearly shows supernatant collected , stored , and IL - 10 , TNFa and IFNY that oral administration of the solvent/ adjuvant vehicle only levels measured using an ELISA . (Group B ) had an 80 % mortality rate and that oral admin - The results show that Group A ( ibuprofen - treated control istration of ibuprofen only (Group A ) exhibited a mortality group ) and Group C (BC1054 - treated experimental group ) rate of 60 % . However, a single oral administration of 50 BC1054 reduced the mortality rate to only 20 % . su animals exhibited an increased IL - 10 levels (FIG . 3A ). To determination of levels of IL - 10 and IL - 4 , an ELISA However, these IL - 10 increases were associated with very was performed using a 96 - well plate coated with a capture different pharmacodynamic effects , and the pattern of pro antibody for IL - 10 or IL - 4 . Lungs collected from the culled inflammatory cytokine reduction highlights the source of the mice were homogenized at 4° C ., and the supernatant 55 IL - 10 and its relevance to the effect on survival. For collected and stored at - 70° C . until needed . Thawed example , TNFa (which is macrophage - related cytokine ) samples were vortexed for 30 seconds immediately before was not as markedly inhibited (FIG . 3B ) in Group A adding to the ELISA plate . Serial dilutions were performed ( ibuprofen -treated control group ) animals , whereas the lev within the plate with both the sample and the standards by els of IFNY (which is a lymphocyte - derived cytokine ) were pipetting 60 uL of assay diluent into each well. The plate was 60 markedly lowered in this group when compared to Group C sealed and incubated for 2 hours at room temperature . For (BC1054 - treated experimental group ) animals (FIG . 3C ) . IL - 4 , 60 uL of working detector was added (Detection This cytokine release pattern was associated with a poor Antibody + SAV -HRP reagent) to each well. The plate was outcome. However, in Group C (BC1054 -treated experi sealed and incubated for 1 hour at room temperature . For mental group ) animals , TNFa levels were markedly lowered IL - 10 , 60 uL of detection antibody was diluted in assay 65 (FIG . 3B ) , while IFNy levels were largely unaffected (FIG . diluent to each well . Plates were washed and 60 uL of 3C ) . This demonstrates that a pharmaceutical composition SAV - HRP enzyme was diluted in assay diluent and added to disclosed herein shows a protective effect on the H1N1 US 9 , 750 ,810 B2 82 induced lethality through , in part, a macrophage - derived showed a statistically significant reduced mean colitis scores IL - 10 levels rather than lymphocyte -derived IL10 . on both day 3 and day 5 when compared to Group B ( TNBS -treated control group ). In a similar manner, both Example 8 Group F (BC1054 -20 -treated experimental group ) and 5 Group G (BC1054 - 30 - treated experimental group ) showed a Animal Model for Inflammatory Bowel Disease statistically significant reduced mean colitis scores on day 5 To assess the effectiveness of a pharmaceutical composi when compared to Group B ( TNBS -treated control group ). tion disclosed herein in treating an inflammatory bowel These results indicate that a pharmaceutical composition disease , experiments were conducted using a TBS - induced 10 adisclosed herein was effective in treating an inflammatory colitis murine model. 10 bowel disease . C57B1/ 6 male mice (6 - 7 weeks old ) were divided into seven experimental groups containing at least ten animals TABLE 7 each . On day 0 , colitis was induced in mice from Groups Results from Inflammatory Bowel Disease B - G by intrarectal administration of 100 uL of TNBS (4 mg) 15 in 50 % ethanol under isoflurane anesthesia . Animals were Mean Mean Mean Endoscopy Colitis dosed either once or three times a day from day - 1 to day Animal Colon Colon Severity Score 5 with one of seven different treatments . Group A was a Group Weight Length Weight Day 3 Day 5 control in which each mouse was orally administered etha 23. 93 g 8 . 5 cm 215 mg 0 . 2 0 nol vehicle only . Group B was a control in which each 20 21. 98 7. 3 cm 295 mg 3 .1 2 . 7 mouse was orally administered 1 % methylcellulose vehicle 23.64 7 . 8 cm 239 mg 2 . 9 2 . 4 only . Group C was a control in which each mouse was orally 23. 33 00g 8 .4 cm 267 mg 2. 37 1. 78 administered solvent/ adjuvant vehicle only (gavage of 10 % QIIWOW 23. 82 7 . 9 cm 267 mg 2 . 7 2 . 2 ethanol and 90 % linseed oil) . Group D was a control in 23 .69 g 8 .4 cm 258 mg 2 . 6 1. 99 which each mouse was orally administered 3 mg /kg of 25 24 .25 g 7. 9 cm 284 mg 2 . 4 1. 410 Prednisolone . Group E was a control in which each mouse Statistically significance difference compared to Group A (p = 0 .029 ). Statistically significance difference compared to Group A ( p = 0 .001 ) . was orally administered 20 mg/ kg of ibuprofen suspended in " Statistically significance difference compared to Group B ( p = 0 . 001 ) . 1 % methylcellulose (1 mL /kg ) (no adjuvant) . Group F was 4Statistically significance difference compared to Group B (p = 0 .001 ) . the experimental group in which each mouse was adminis Statistically significance difference compared to Group B (p = 0 . 034 ) . tered a pharmaceutical composition disclosed herein 30 Statistically significance difference compared to Group A (p = 0. 009 ) . Statistically significance difference compared to Group B (p = 0 .005 ) . (BC1054 - 20 ) comprising 20 mg/ kg of ibuprofen , 10 % etha Statistically significance difference compared to Group B ( p = 0 . 002) . nol, and 90 % linseed oil. Group G was the experimental Statistically significance difference compared to Group B (p = 0 .045 ) . group in which each mouse was administered a pharmaceu " " Statistically significance difference compared to Group B ( p = 0 .002 ) . tical composition disclosed herein (BC1054 - 30 ) comprising 30 mg/ kg of ibuprofen , 10 % ethanol, and 90 % linseed oil . 35 All animals were weighed daily and assessed visually for the Example 9 presence of diarrhea and / or bloody stool. On day 3 and on day 5 colitis severity was assessed in all animals using video Animal Model for a Systemic Arthritis endoscopy , where images were taken and colitis severity scored visually by a blinded observer on a scale from 0 to 4 40 To assess the effectiveness of a pharmaceutical composi as follows: 0 , normal; 1 , loss of vascularity ; 2 , loss of tion disclosed herein in treating arthritis , experiments were vascularity and friability ; 3 , friability and erosions ; and 4 , conducted using an a - collagen antibody induced arthritis ulcerations and bleeding . Following endoscopy on day 5 , (ACAIA ) murine model thatmimics a systemic arthritis like animals were sacrificed and the colon removed and its length rheumatoid arthritis . and weight measured . Serum samples were obtained and the 45 Male BALB / c mice were divided into eight groups, each colon was fixed in 10 % formalin . An additional piece of containing 10 animals . To induce arthritic symptoms, mice colon tissue was collected , weighed , and snap frozen in from all eight groups were intravenously injected with 200 liquid nitrogen . uL of an antibody solution comprising a 2 mg cocktail of Results from these experiments are shown in Table 7 . four a -collagen II monoclonal antibodies (ARTHRI Group B ( TNBS - treated control group showed a statisti- 50 TOMABTM , MD Biosciences ) on study day 0 ( study com cally significant difference in mean weight change when mencement) , followed by a 200 uL intraperitoneal injection compared to Group A (untreated ethanol control group ) , all of a solution comprising 50 ug of lipopolysaccharide (LPS ) other group comparisons showed no difference in mean at day 3 . From day 3 and daily until day 8 and then on days weight change . Group B ( TNBS - treated control group ) 10 and 12 , paw thickness (plethysmography ) and arthritis showed a statistically significant decrease in mean colon 55 scores were taken . The same animals were also treated daily length when compared to Group A ( untreated ethanol control from days 0 to day 11 , the animals received one of six group ) . Additionally , Group D ( Prednisolone - treated control treatments . Group A was a control in which each mouse was group ), Group F (BC1054 -20 - treated experimental group ) , orally administered phosphor- buffered saline (PBS ) vehicle and Group G (BC1054 - 30 - treated experimental group ) all only . Group B was a control in which each mouse was showed a statistically significant increase in mean colon 60 intraperitoneally administered 10 mg/ kg of etanercept ( EN length when compared to Group B ( TNBS - treated control BREL® , Wyeth ) in PBS . Group C was a control in which group ) . Although Group B ( TNBS- treated control group ) each mouse was orally administered 1 % methylcellulose showed a statistically significant increase in mean colon vehicle only . Group D was a control in which each mouse weight when compared to Group A (untreated ethanol con - was orally administered 40 mg/ kg of ibuprofen suspended in trol group ), all other group comparisons showed no differ - 65 1 % methylcellulose ( 1 mL /kg ) (no adjuvant) . Group E was ence in mean colon weight. With regards to the endoscopy a control in which each mouse was orally administered colitis score , Group D (Prednisolone - treated control group ) solvent/ adjuvant vehicle only ( gavage of 10 % ethanol and US 9 ,750 ,810 B2 83 84 90 % linseed oil ). Group F was the experimental group in ibuprofen and a glyceryl monolinoleate (MAISINE® 35 - 1 , which each mouse was orally administered a pharmaceutical Gattefosse ) ( BC1054 LF -MA ) administered thrice daily ; composition disclosed herein (BC1054 -20 ) comprising 20 Group 6 mice (6M ) were treated orally with a 20 mg/ kg test mg/ kg of ibuprofen , 10 % ethanol , and 90 % linseed oil . solid formulation comprising ibuprofen and theobroma oil Group G was the experimental group in which each mouse 5 ( BC1054 LF - TO ) administered thrice daily ; Group 7 mice (7M ) were treated orally with a control preparation 1 com was orally administered a pharmaceutical composition dis prising 20 mg/ kg of ibuprofen administered thrice daily ; and closed herein (BC1054 - 30 ) comprising 30 mg/kg of ibupro Group 8 mice (8M ) were treated orally with a 20 mg /kg test fen , 10 % ethanol, and 90 % linseed oil. Through the entire solid formulation comprising ibuprofen and a waxy solid experiment ( 12 days ), animals were checked daily for clini 10 having a melting point of between 37° C . to 41° C . and cal signs ( general observations of the health of the animal) " comprising a mixture of saturated C10 -C18 triglycerides and body weights . Total arthritis scores are determined by (GELUCIRE® 39 / 01 , Gattefosse ) (BC1054 LF -GE ) admin summing the arthritis scores of individual paws using the istered thrice daily ( Table 8 ). The dose administered was following grades : 0 = no signs of arthritis , 1 = mild but definite calculated based on the assumption that each animal redness and swelling of the ankle /wrist or apparent redness weighed , on average , 20 g . A fixed volume of 100 uL was or swelling limited to individual digits. regardless of the administered to each mouse , except those animals receiving number of affected digits , 2 = moderate to severe redness and the positive control (2M ) were administered 200 uL . swelling of the ankle /wrist , 3 = redness and swelling of the entire paw including digits , 4 = maximally inflamed limb TABLE 8 with involvement of multiple joints . The results of this experiment are shown in FIG . 4 . As a Constitution of Test Groups and Dose Levels expected , Group B ( etanercept - treated control group ) ani Group Size Treatment Dose Volume Route Regime mals showed the best results , with the lowest paw thick nesses at about 1 . 6 mm on day 12 . The two pharmaceutical 1M 10 Vehicle N / A 5 ml/kg PO Thrice daily compositions , Group F (BC1054 - 20 -treated experimental 2M 10 Etanercept 10 mg/kg 10 ml/kg IP Once daily ?? 10 BC1054 20 mg/kg 5 ml/kg PO Once daily group ) and Group G (BC1054 - 30 - treated experimental 25 - LF - RO group ) animals displayed the next best results , with Group 4M 10 BC1054 20 mg/ kg 5 ml/ kg PO Thrice daily G mice producing a paw thickness of only 1 . 7 mm , and LF -RO Group F mice producing a paw thickness of about 1 .73 mm . 5M 10 BC1054 20 mg/kg 5 ml/ kg PO Thrice daily LF -MA The negative control Group A (PBS vehicle - treated control 6M 10 BC1054 20 mg/kg 5 ml/kg PO Thrice daily group ) , Group C (methoxycellulose vehicle - treated control 30 SF - TO group ) , and Group E (solvent / adjuvant vehicle - treated con 7M 10 Ibuprofen 20 mg/kg 5 ml/kg PO Thrice daily trol group ) animals , as well as Group D ( ibuprofen -treated 8M 10 BC1054 20 mg/ kg 5 ml/kg PO Thrice daily control group ) performed significantly worse with paw SF -GE thicknesses of 1 . 9 mm and over when compared to Group F P = Intraperitoneal and Group G animals . These results indicate that a pharma- 3535 PPO = Per Os ceutical composition disclosed herein was effective in treat N / A = Not applicable ing an arthritis . Arthritic development and clinical examinations were Example 10 monitored in all mice on study day O shortly before arthritis induction and subsequently on study days 3 - 7 , 9, 10 and 12 Animal Model for a Systemic Arthritis ( study termination ) . To access arthritic development, both an arthritis score and paw thickness ( plethysmography ) mea To assess the effectiveness of a pharmaceutical composi surements were obtained . The arthritis score was based on tion disclosed herein in treating arthritis , experiments were visual assessment of arthritis reactions using a 0 - 4 scale in conducted using an a - collagen antibody induced arthritis ascending order of severity with Grade ( indicating no (ACAIA ) murine model that mimics a systemic arthritis like 45 arthritis reaction ; Grade 1 indicating mild , but definite rheumatoid arthritis . redness and swelling of the ankle /wrist or apparent redness Male BALB / c mice were divided into eight groups, each and swelling limited to individual digits , regardless of the containing 10 animals . To induce arthritic symptoms, mice number of affected digits ; Grade 2 indicating moderate to from all eight groups were intravenously injected with 200 severe redness and swelling of the ankle /wrist ; Grade 3 uL of an antibody solution comprising a 2 mg cocktail of 50 indicating redness and swelling of the entire paw including four a - collagen II monoclonal antibodies ( ARTHRI- digits ; and Grade 4 indicating maximally inflamed limb with TOMABTM , MD Biosciences ) on study day 0 ( study com - involvement ofmultiple joints . Paw thickness was measured mencement ), followed by a 200 uL intraperitoneal injection for both hind paws just above the foot pad and below the of a solution containing 100 ug lipopolysaccharide (LPS ) on calcaneum using a dial caliper (Kroeplin , Munich , Ger study day 3 . Each group was subjected daily to a control or as many ) . Mean values for paw thickness measurements were test treatmentadministered from day 0 - 11 as follows: Groupe determined , and where appropriate , analysis of the data by 1 mice ( 1 M ) were treated orally with a vehicle preparation ANANOVA with Tukey post hoc analysis was applied to containing 1 % methyl cellulose administered thrice daily ; determine significance of treatment effects . Group 2 mice (2M ) were treated intraperitoneally with a Clinical examinations included changes in body weight, positive control preparation containing 10 mg/ kg etanercept condition of skin , fur, eyes , mucous membranes, occurrence ( ENBREL® , Wyeth ) administered once daily ; Group 3 mice 60 of secretions and excretions ( e . g . diarrhea ), and autonomic ( 3M ) were treated orally with a 20 mg/ kg test liquid for activity ( e . g . lacrimation , salivation , piloerection , pupil size , mulation comprising ibuprofen and rapeseed oil ( BC1054 unusual respiratory pattern ) . Changes in gait , posture and LF -RO ) administered once daily ; Group 4 mice ( 4M ) were response to handling , as well as the presence of bizarre treated orally with a 20 mg/ kg test liquid formulation behavior, tremors, convulsions, sleep and coma were also comprising ibuprofen and rapeseed oil (BC1054 LF -RO ) 65 noted . Serum was collected at study termination . administered thrice daily ; Group 5 mice (5M ) were treated Arthritis incidence increased in all groups from day 3 . In orally with a 20 mg/ kg test liquid formulation comprising Group 1M animals incidence peaked on day 7 with % 10 US 9 ,750 ,810 B2 85 86 animals showing arthritis reactions which remained rela - 10 paw volumes remained relative constant till the end of the tively constant until the end of the study . In Etanercept study . BC1054 LS -RO thrice daily resulted in significantly treated Group 2M mice, incidence peaked on day 6 at % 10 reduced mean paw thickness compared to vehicle - treated animals showing signs , but had decreased to 1/ 10 by day 12 . mice (Group 1 M ) on days 6 , 7 and 9 . Group 5M mice The peak incidence of arthritis in Group 3M and Group 4M 5 treated with BC1054 LS -MA had peak paw volume at day animals receiving BC1054 LS - RO once or thrice daily was 7 ( 1 . 97 + 0 . 05 from 1 .69 + 0 .02 on day 0 ) , this group had on day 7 ( % 10 and 710 animals , respectively ) , and this had significantly reduced measurements on day 6 and day 9 decreased to 4/ 10 mice in both groups by day 12 . The arthritis when compared to the vehicle treated Group 1M animals . In incidence peaked on day 6 in the Group 5M animals Group 6M animals treated with BC1054 LS - TO , mean rear receiving BC1054 LS -MA with 8 / 10 animals affected , and the 10 paw thickness began at 1 .74 + 0 .01 on day 0 . This increased incidence fluctuated with between 6 and 8 animals scoring to a peak of 2 .05 + 0 . 10 on day 7 before decreasing back to until the end of the study. By day 6 , % 10 animals presented 1 . 94 + 0 .06 on day 12 . No significant differences were with arthritis in Group 6M animals receiving BC1054 SF - recorded between BC1054 LS - TO - treated animals (Group TO , but this also fluctuated and ended at 710 on day 12 . In 6M ) and those treated with vehicle control (Group 1 M ). In the Ibuprofen - treated Group 7M , the peak of arthritis inci- 15 the group which received Ibuprofen (Group 7M ) , rear paw dence was recorded on day 6 with $ 10 animals affected , and thickness was 1. 71 + 0 .02 on day 0 . By day 7 the swelling in this remained relatively constant until the study termination . this group had peaked at 2 . 15 + 0 . 10 before decreasing to Group 8M mice receiving a BC1054 LS -GE exhibited peak 2 .02 0 .08 on day 12 . No significant differences were incidence on day 6 with % 10 animals presenting with signs of observed when this group was compared to the vehicle arthritis , but this had decreased to 4 /10 by day 12 . 20 control Group 1M . Group 8M animals treated with BC1054 Clinical signs associated with LPS- administration devel - LS -GE exhibited a slight increase in rear paw thickness from oped in all groups following the LPS boost on day 3 . These 1 .720 . 02 on day 0 to 1 .85 + 0 .06 on day 7 , this remained had disappeared in all groups by day 12 . No mortalities relatively constant finishing at 1. 77 + 0 .03 on day 12 . Admin occurred during this study or significant differences in body istration of BC1054 LS -GE resulted in significantly reduced weight between the vehicle - treated group and test item - 25 paw swelling in animals (Group 8M ) compared to vehicle treated groups. controls (Group 1M ) on days 6 , 7 , 9 , 10 and 12 . TABLE 9 Mean Rear Paw Thickness Mean Rear Paw Thickness (mm ) Group N Treatment 0 3 4 5 6 7 9 10 12 1M 10 Vehicle 1 . 72 1 . 72 1 .63 1 .69 2 . 03 £ 2 . 26 2 . 33 2 . 32 $ 2 . 17 · 0 .01 0 .02 0 . 02 0 .02 0 .09 0 . 13 0 . 15 0 . 15 0 . 11 2M 10 Etanercept 1 .70 1. 73 $ 1 . 64 1 .63 $ 1. 96 1 .95 £ 1 .88 $ 1 .80 1 .77 + 0 .02 0 .03 0 . 02 0 .02 0 .05 0 .04 0 .03 * 0 .04 * 0 .02 * 3M 10 BC1054 LF- RO 1 . 71 1 .75 + 1 . 68 + 1 . 71 † 1 . 78 1 . 96 1 .91 + 1 . 94 + 1 . 90 + 0 .02 0 .02 0 . 02 0 .03 0 .03 * 0 . 05 0 . 08 * 0 . 10 0 .08 4M 10 BC1054 LF -RO 1 .70 1 .70 = 1 .61 + 1 .65 $ 1 . 75 — 1 . 89 E 1 .91 1 .97 – 1 . 93 + 0 .03 0 .01 0 . 02 0 .03 0 .03 * 0 .07 * 0 . 09 * 0 . 08 0 .07 SM 10 BC1054 LF -MA 1 .69 † 1 .73 1 .66 1 .67 1 . 79 † 1 .97 + 1 .92 £ 1 . 96 1 . 91 + 0 .02 0 .02 0 . 02 0 .02 0 .04 * 0 .05 0 .06 * 0 . 07 0 .06 6M 10 BC1054 SF - TO 1 . 74 1 . 72 1 . 64 £ 1 . 70 1 . 91 2 . 05 – 1 . 96 + 1 . 99 † 1 . 94 + 0 . 01 0 .03 0 . 01 0 .03 0 . 06 0 . 10 0 . 09 0 .07 0 . 06 7M 10 Ibuprofen 1 .71 1 . 72 1 . 64 £ 1 . 71 1 . 90 I 2 . 15 2 . 08 £ 2 .07 — 2 . 02 + 0 .02 0 .01 0 .02 0 .02 0 .05 0 . 10 0 . 11 0 . 11 0 .08 8M 10 BC1054 SF -GE 1 .72 ± 1. 71 $ 1 .63 + 1 .67 1 . 78 1 .85 + 1. 73 $ 1 .83 1 .77 + 0 . 02 0 .02 0 .01 0 .03 0 .03 * 0 . 06 * 0 . 04 * 0 .03 * 0 .03 *
The results of mean paw thickness are given in Table 9. In view of the findings above, significant anti -arthritic Mean rear paw thickness in Group 1M animals (vehicle - 50 activity was observed in Group 3M animals receiving once treated ) was 1 . 72 + 0 . 01 on day 0 . Thickness increased and daily administration of BC1054 LS - RO , Group 4M animals peaked on day 9 at 2 . 33 + 0 . 15 , and ended at 2 . 17 + 0 . 11 on day receiving thrice daily administration of BC1054 LS - RO , 12 . In Etanercept - treated Group 2M mice , mean rear paw Group 5M animals receiving thrice daily administration of thickness began at 1 . 70 + 0 .02 on day 0 . This increased , BC1054 LS -MA , and Group SM animals receiving thrice peaking at 1 . 96 + 0 .05 on day 6 before decreasing back to daily administration of BC1054SF -GE . 1 .77 + 0 .02 on day 12. Etanercept treatment resulted in sig nificantly decreased paw volume compared to the positive Example 11 control mice on days 9 , 10 and 12. In Group 3M , which received BC1054 LS -RO once daily , rear paw thickness was ao Case Studies for the Treatment of Chronic 1 .71 + 0 . 02 on day 0 . By day 7 the swelling in this group had Inflammation peaked at 1 . 96 + 0 .05 where it remained relatively constant thereafter . There were significant reductions in the mean A 47 year old female was diagnosed with reactive arthritis paw swelling on days 6 and 9 following administration of in one knee was treated with a pharmaceutical composition BC1054 LS -RO . Themean rear paw thickness in Group 4M , 65 disclosed herein (BC1054 ) comprising 20 mg/ kg of ibupro which received BC1054 LS -RO thrice daily , increased to fen , 10 % ethanol, and 90 % rapeseed oil ( 1200 mg uid ) over 1 .97 + 0 .08 on day 10 ( from 1. 70 + 0 .03 on day 0 ), from day a 3 day period and found that the swelling and pain started US 9 ,750 ,810 B2 87 88 to go away after 1 day and was completely better after 3 composition disclosed herein (BC1054 ) comprising 20 days . Ineffective standard ibuprofen treatment was subse mg/ kg of ibuprofen , 10 % ethanol, and 90 % rapeseed oil quently ceased . At a 3 month follow up , no signs of the (600 mg bid ) for 7 days . After 5 days of treatment the reactive arthritis have been observed . patient' s LDL levels had normalized to 3 . 89 mmol/ L . The A 50 year old male was diagnosed with a chronically 5 normalization of LDL level persisted for 2 months after inflamed ankle after a maison neuve fracture in the ankle . cessation of BC1054 dosing, as determined at the last The patient was taking 30 mg codeine with 500 mg parac examination . etamolbid , along with 10 mg diclofenac tid for 8 months to A 60 year old male newly diagnosed with hypercholes control pain . He took a 5 day course of a pharmaceutical terolemia (LDL of 4 .31 mmol/ L ) was given a course of a composition disclosed herein (BC1054 ) comprising 20 10 pharmaceutical composition disclosed herein (BC1054 ) mg/ kg of ibuprofen , 10 % ethanol , and 90 % rapeseed oil comprising 20 mg/ kg of ibuprofen , 10 % ethanol, and 90 % (600 mg bid ) and after 2 days reported a significant improve - rapeseed oil (1200 mg uid ) to lower LDL levels to within the ment in his pain , and then after 3 days he reported that the normal range. After 5 days of treatment the patients LDL pain was completely controlled . He has subsequently ceased levels were lowered to 3 . 36 mmol/ L . The patient was the codeine , paracetamol and diclofenac , and after a 2 month 15 followed up for 1 month and his LDL remained within the follow the patient is still pain free . normal range , despite there being no further BC1054 dosing. A 33 year old female diagnosed with stress related eczema, had an acute flare ofmoderate eczema on arms and Example 12 chest. A pharmaceutical composition disclosed herein (BC1054 ) comprising 20 mg/ kg of ibuprofen , 10 % ethanol, 20 Treatment of Chronic Inflammation and 90 % rapeseed oil ( 1200 mg uid ) was administered for 7 days . After a couple of hours the lesion ceased itching , after A 62 year old female complains of joint stiffness and 1 day a noticeable improvement in lesion swelling was swelling and is diagnosed with rheumatoid arthritis . A reported . 2 - 3 days later the eczema lesions erythema had physician determines that the joint stiffness and swelling is resolved and after 7 days the lesions had completely disap - 25 due to chronic inflammation . The woman is treated by oral peared . In the past the patient had used emollients and administration a pharmaceutical composition comprising hydrocortisone creams, which made the lesions worse and ibuprofen as disclosed herein taken twice daily . Alterna would often lead to a course of antibiotics . The patient t ively , the woman is treated by oral administration a phar commented that her response to the BC1054 treatment was maceutical composition comprising aspirin as disclosed quick and complete , and was a marked improvement on 30 herein taken thrice daily . Alternatively , the woman is treated previously pharmacological therapies . by oral administration a pharmaceutical composition com An 85 year old male diagnosed with reactive osteoarthri - prising naproxen as disclosed herein taken twice daily . The tis, with marked swelling and severe pain in both knee . For woman ' s condition is monitored and after about 3 days of 1 year , the patient had been prescribed prednisolone and treatment the woman indicates there is reduced joint stiff NSAIDS to control arthritis , with no effect . In addition the 35 ness and swelling . At one and three month check - ups , the patient had taken daily glucosamine . Despite considerable woman indicates that she continues to have reduced joint pharmacological intervention , the patient regularly flared stiffness and swelling in the area treated . This reduction in resulting in considerable restriction of mobility. The patient chronic inflammation symptoms indicates successful treat was given a 10 day course of a pharmaceutical composition ment with the pharmaceutical composition disclosed herein . disclosed herein (BC1054 ) comprising 20 mg/ kg of ibupro - 40 A similar type of oral administration of a pharmaceutical fen , 10 % ethanol, and 90 % rapeseed oil ( 400 mg tid ) and composition disclosed herein will be used to treat a patient experience an appreciable improvement by day 3 and a suffering from chronic inflammation associated with any complete resolution after the completion of the course . The monoarthritis , oligoarthritis , or polyarthritis , such as , e . g . , patient reported that his mobility was returned to normal and osteoarthritis , juvenile idiopathic arthritis , septic arthritis , a he has remained in remission at is 1 month examination . 45 spondyloarthropathy ( including ankylosing spondylitis , A 38 years old male with reactive osteoarthritis in 1 knee , reactive arthritis (Reiter ' s syndrome ) , psoriatic arthritis , for 6 months (pain and swelling ) . Over that period , the enteropathic arthritis associated with inflammatory bowel patient had tried a comprehensive spectrum of pharmaco - disease , Whipple disease or Behcet disease ) , a synovitis , logical therapies: prednisolone , Humira and sulfasalazine , gout, pseudogout, or Still ' s disease , as well as , a bursitis , a alongside NSAIDs to control pain . Only the sulfasalazine 50 rheumatic fever, or a tenosynovitis . In a similar manner, any had any appreciable effect, however the patient disliked its of the therapeutic compounds such as, e . g . , a salicylate side effects , so requested to come off the sulfasalazine . After derivative NSAID , a p - amino phenol derivative NSAID , a 2 weeks of being sulfsalazine free , the patient experienced propionic acid derivative NSAID , an acetic acid derivative a flare of the reactive arthritis and commenced a 4 day NSAID , an enolic acid derivative NSAID , a fenamic acid course of a pharmaceutical composition disclosed herein 55 derivative NSAID , a non - selective cyclo -oxygenase ( COX ) (BC1054 ) comprising 20 mg/ kg of ibuprofen , 10 % ethanol, inhibitor, a selective cyclooxygenase 1 ( COX 1 ) inhibitor, a and 90 % rapeseed oil (600 mg bid ), experiencing complete selective cyclooxygenase 2 (COX 2 ) inhibitor , or a fibrate , remission of the arthritis . After 2 weeks of being drug free , will be formulated into a pharmaceutical composition and the arthritis began to flare again and the patient was put on administered to the patient as described above . another 4 day treatment of BC1054 , again experiencing 60 A 58 year old male complains of breathing difficulty and complete remission . This time the arthritis flared again 1 is diagnosed with chronic obstructive pulmonary disease week later. To account for this , the patient was given a final (COPD ) . A physician determines that the breathing difficulty 10 day course of BC1054 . Subsequently , the arthritis is due to chronic inflammation . The man is treated by oral remained in remission for 11 months , as per the last exami- administration a pharmaceutical composition comprising nation . 65 ibuprofen as disclosed herein taken twice daily . Alterna A 49 year old male diagnosed with hypercholesterolemia tively , the man is treated by oral administration a pharma (LDL of 4 .35 mmol/ L ) was placed on a pharmaceutical ceutical composition comprising aspirin as disclosed herein US 9 ,750 ,810 B2 89 90 taken thrice daily . Alternatively , the man is treated by oral pharmaceutical composition comprising naproxen as dis administration a pharmaceutical composition comprising closed herein taken twice daily . The woman ' s condition is naproxen as disclosed herein taken twice daily . The man ' s monitored and after about 3 days of treatment the woman condition is monitored and after about 3 days of treatment indicates that she no longer is wheezing. At one and three the man indicates there is improvement in his ability to 5 month check - ups , the woman indicates that she still does not breath . At one and three month check - ups , the man indicates wheeze when she breathes. This reduction in a chronic that he continues to have improved breathing . This reduction inflammation symptom indicates successful treatment with in a chronic inflammation symptom indicates successful the pharmaceutical composition disclosed herein . A similar treatment with the pharmaceutical composition disclosedPea type of oral administration of a pharmaceutical composition herein . A similar type of oral administration of a pharma- 10 disclosed herein will be used to treat a patient suffering from ceutical composition disclosed herein will be used to treat a chronic inflammation associated with any vasculitis , such as , patient suffering from chronic inflammation associated with e . g . , a Buerger' s disease , a cerebral vasculitis , a cryoglobu an asthma , a bronchiolitis , a bronchitis , an emphysema , a linemia , an essential cryoglobulinemic vasculitis , a giant cell laryngitis , a pharyngitis , a pleuritis, a pneumonitis , a rhinitis , arteritis , a Golfer ' s vasculitis , a Henoch - Schonlein purpura , a sinusitis , or any other type of chronic respiratory disorder. 15 a hypersensitivity vasculitis , a Kawasaki disease , a micro In a similar manner, any of the therapeutic compounds such scopic polyarteritis / polyangiitis, a polyarteritis nodosa , a as, e. g . , a salicylate derivative NSAID , a p - amino phenol polymyalgia rheumatica (PMR ), a rheumatoid vasculitis , a derivative NSAID , a propionic acid derivative NSAID , an Takayasu arteritis , or a Wegener ' s granulomatosis , as well acetic acid derivative NSAID , an enolic acid derivative as , an arteritis , a carditis, an endocarditis , a heart disease , NSAID , a fenamic acid derivative NSAID , a non -selective 20 high blood pressure , inflammatory cardiomegaly, an isch cyclo -oxygenase (COX ) inhibitor , a selective cyclooxy emic heart disease, a myocarditis , a pericarditis , a phlebitis , genase 1 (COX 1 ) inhibitor, a selective cyclooxygenase 2 a pylephlebitis , or a thrombophlebitis. In a similar manner , (COX 2 ) inhibitor, or a fibrate , will be formulated into a any of the therapeutic compounds such as, e . g . , a salicylate pharmaceutical composition and administered to the patient derivative NSAID , a p - amino phenol derivative NSAID , a as described above . 25 propionic acid derivative NSAID , an acetic acid derivative A 67 year old male complains of muscle soreness and is NSAID , an enolic acid derivative NSAID , a fenamic acid diagnosed with dermatomyositis . A physician determines derivative NSAID , a non - selective cyclo -oxygenase (COX ) that the soreness is due to chronic inflammation . The man is inhibitor , a selective cyclooxygenase 1 (COX 1 ) inhibitor, a treated by oral administration a pharmaceutical composition selective cyclooxygenase 2 (COX 2 ) inhibitor , or a fibrate , comprising ibuprofen as disclosed herein taken twice daily . 30 will be formulated into a pharmaceutical composition and Alternatively , the man is treated by oral administration a administered to the patient as described above . pharmaceutical composition comprising aspirin as disclosed A 37 year old male complains of skin redness and is herein taken thrice daily . Alternatively, the man is treated by diagnosed with rosacea . A physician determines that the oral administration a pharmaceutical composition compris - redness is due to chronic inflammation . The man is treated ing naproxen as disclosed herein taken twice daily . The 35 by oral administration a pharmaceutical composition com man ' s condition is monitored and after about 3 days of prising ibuprofen as disclosed herein taken twice daily . treatment the man indicates there is reduced soreness . At one Alternatively , the man is treated by oral administration a and three month check -ups , the man indicates that he pharmaceutical composition comprising aspirin as disclosed continues to have improved muscle movement and reduced herein taken thrice daily . Alternatively , the man is treated by soreness . This reduction in a chronic inflammation symptom 40 oral administration a pharmaceutical composition compris indicates successful treatment with the pharmaceutical com - ing naproxen as disclosed herein taken twice daily . The position disclosed herein . A similar type of oral administra man ' s condition is monitored and after about 3 days of tion of a pharmaceutical composition disclosed herein will treatment the man indicates there is reduced skin redness . At be used to treat a patient suffering from chronic inflamma- one and three month check -ups , the man indicates that he tion associated with an inclusion body myositis , a myasthe - 45 continues to have improved skin tone and reduced redness . nia gravis, a polymyositis or any other type of inflammatory This reduction in a chronic inflammation symptom indicates myopathy, as well as, a fasciitis , a fibrositis , a myositis , a successful treatment with the pharmaceutical composition neuromyotonia , a tendinosis , or a tendonitis . In a similar disclosed herein . A similar type of oral administration of a manner, any of the therapeutic compounds such as , e . g ., a pharmaceutical composition disclosed herein will be used to salicylate derivative NSAID , a p - amino phenol derivative 50 treat a patient suffering from chronic inflammation associ NSAID , a propionic acid derivative NSAID , an acetic acid ated with an acne , a cervicitis, a dermatitis , an eczema derivative NSAID , an enolic acid derivative NSAID , a (including an atopic eczema, a contact eczema, a xerotic fenamic acid derivative NSAID , a non - selective cyclo - eczema, a seborrhoeic dermatitis , a dyshidrosis , a discoid oxygenase (COX ) inhibitor, a selective cyclooxygenase 1 eczema, a venous eczema, a dermatitis herpetiformis , a (COX 1 ) inhibitor, a selective cyclooxygenase 2 (COX 2 ) 55 neurodermatitis , or an autoeczematization ), an endometritis , inhibitor, or a fibrate , will be formulated into a pharmaceu - a gingivitis , a glossitis , a hidradenitis suppurativa , a kerati tical composition and administered to the patient as tis , a keratoconjunctivitis , a mastitis , a psoriasis ( including described above . a plaqure psoriasis , a nail psoriasis , a guttate psoriasis , a A 73 year old female complains of wheezing when she scalp psoriasis , an inverse psoriasis , a pustular psoriasis , or breathes and is diagnosed with Churg - Strauss arteritis . A 60 an erythrodermis psoriasis ) , a scleroderma, a statis derma physician determines that the wheezing is due to chronic titis , a stomatitis , a tonsillitis , a vaginitis , a vitiligo , or a inflammation . The woman is treated by oral administration vulvitis. In a similar manner, any of the therapeutic com a pharmaceutical composition comprising ibuprofen as dis pounds such as , e . g ., a salicylate derivative NSAID , a closed herein taken twice daily . Alternatively, the woman is p -amino phenol derivative NSAID , a propionic acid deriva treated by oral administration a pharmaceutical composition 65 tive NSAID , an acetic acid derivative NSAID , an enolic acid comprising aspirin as disclosed herein taken thrice daily . derivative NSAID , a fenamic acid derivative NSAID , a Alternatively , the woman is treated by oral administration a non - selective cyclo - oxygenase (COX ) inhibitor, a selective US 9 ,750 ,810 B2 91 92 cyclooxygenase 1 (COX 1 ) inhibitor, a selective cyclooxy Guillain -Barre syndrome, an idiopathic thrombocytopenic genase 2 (COX 2 ) inhibitor, or a fibrate , will be formulated purpura , a myasthenia gravis , a neonatal lupus, a pernicious into a pharmaceutical composition and administered to the anemia , a polymyalgia rheumatica , a rheumatoid arthritis , a patient as described above . scleroderma, a Sjögren ' s syndrome, a subacute cutaneous A 33 year old female complains of abdominal pain and 5 lupus erythematosus, or a Wegener ' s granulomatosis . In a diarrhea and is diagnosed with Crohn ' s disease . A physician similar manner , any of the therapeutic compounds such as , determines that the abdominal pain and diarrhea is due to e. g . , a salicylate derivative NSAID , a p -amino phenol chronic inflammation . The woman is treated by oral admin - derivative NSAID , a propionic acid derivative NSAID , an istration a pharmaceutical composition comprising ibupro - acetic acid derivative NSAID , an enolic acid derivative fen as disclosed herein taken twice daily . Alternatively , the 10 NSAID , a fenamic acid derivative NSAID , a non - selective woman is treated by oral administration a pharmaceutical cyclo -oxygenase (COX ) inhibitor , a selective cyclooxy composition comprising aspirin as disclosed herein taken genase 1 ( COX 1 ) inhibitor, a selective cyclooxygenase 2 thrice daily . Alternatively , the woman is treated by oral (COX 2 ) inhibitor, or a fibrate , will be formulated into a administration a pharmaceutical composition comprising pharmaceutical composition and administered to the patient naproxen as disclosed herein taken twice daily . The wom - 15 as described above . an ’ s condition is monitored and after about 3 days of 58 year old male complains of depression , sensitivity to treatment the woman indicates that there is a reduction in cold , weight gain , forgetfulness, and constipation and is abdominal pain and she no longer has diarrhea . At one and diagnosed with Hashimoto ' s thyroiditis. A physician deter three month check - ups, the woman indicates that she con - mines that these symptoms are due to chronic inflammation . tinues to have reduced abdominal pain and diarrhea . This 20 The man is treated by oral administration a pharmaceutical reduction in a chronic inflammation symptom indicates composition comprising ibuprofen as disclosed herein taken successful treatment with the pharmaceutical composition twice daily . Alternatively, the man is treated by oral admin disclosed herein . A similar type of oral administration of a istration a pharmaceutical composition comprising aspirin pharmaceutical composition disclosed herein will be used to as disclosed herein taken thrice daily . Alternatively , the man treat a patient suffering from neurogenic inflammation asso - 25 is treated by oral administration a pharmaceutical composi ciated with any inflammatory bowel disease , such as , e . g ., an tion comprising naproxen as disclosed herein taken twice ulcerative colitis ( including ulcerative proctitis , left -sided daily . The man 's condition is monitored and after about 3 colitis , pancolitis and fulminant colitis ), any irritable bowel days of treatment the man indicates there is reduction in all disease , as well as , a colitis , an enteritis , an enterocolitis , a the symptoms complained of. At one and three month gastritis , a gastroenteritis , a metabolic syndrome ( syndrome 30 check - ups, the man indicates that he still does not experience X ) , a spastic colon , or any other gastrointestinal disorder . In depression , sensitivity to cold , weight gain , forgetfulness, a similar manner , any of the therapeutic compounds such as, and constipation . This reduction in a chronic inflammation e . g ., a salicylate derivative NSAID , a p - amino phenol symptom indicates successful treatment with the pharma derivative NSAID , a propionic acid derivative NSAID , an ceutical composition disclosed herein . A similar type of oral acetic acid derivative NSAID , an enolic acid derivative 35 administration of a pharmaceutical composition disclosed NSAID , a fenamic acid derivative NSAID , a non -selective herein will be used to treat a patient suffering from chronic cyclo - oxygenase ( COX ) inhibitor, a selective cyclooxy - inflammation associated with any other local autoimmune genase 1 (COX 1 ) inhibitor, a selective cyclooxygenase 2 disorder, including , without limitation , an acute dissemi (COX 2 ) inhibitor, or a fibrate , will be formulated into a nated encephalomyelitis (ADEM ) , an Addison 's disease , an pharmaceutical composition and administered to the patient 40 autoimmune hemolytic anemia , an autoimmune hepatitis as described above . ( including primary biliary cirrhosis ) , an autoimmune inner A 46 year old male complains of fever , joint pains, and ear disease , a celiac disease , a Crohn ' s disease , a diabetes fatigue and is diagnosed with systemic lupus erythematosus. mellitus type 1 , an endometriosis , a giant cell arteritis , a A physician determines that these symptoms are due to Graves ' disease , an interstitial cystitis , a lupus nephritis , a chronic inflammation . The man is treated by oral adminis - 45 multiple sclerosis , a morphea , a pemphigus vulgaris , a tration a pharmaceutical composition comprising ibuprofen recurrent disseminated encephalomyelitis , a sclerosing cho as disclosed herein taken twice daily . Alternatively , the man langitis , an ulcerative colitis , or a vitiligo . In a similar is treated by oral administration a pharmaceutical composi - manner , any of the therapeutic compounds such as, e . g ., a tion comprising aspirin as disclosed herein taken thrice salicylate derivative NSAID , a p - amino phenol derivative daily . Alternatively , theman is treated by oral administration 50 NSAID , a propionic acid derivative NSAID , an acetic acid a pharmaceutical composition comprising naproxen as dis - derivative NSAID , an enolic acid derivative NSAID , a closed herein taken twice daily . The man ' s condition is fenamic acid derivative NSAID , a non - selective cyclo monitored and after about 3 days of treatment the man oxygenase (COX ) inhibitor, a selective cyclooxygenase 1 indicates there is improvement in his health , his fever is (COX 1 ) inhibitor, a selective cyclooxygenase 2 (COX 2 ) gone , the pain in his joints is reduced and his is not as tired . 55 inhibitor , or a fibrate , will be formulated into a pharmaceu At one and three month check - ups, the man indicates that he tical composition and administered to the patient as continues to have reduced joint pain and does not suffer from described above . fevers or fatigue . This reduction in a chronic inflammation 59 year old female complains of joint stiffness and symptom indicates successful treatment with the pharma swelling and is diagnosed with reactive arthritis . A physician ceutical composition disclosed herein . A similar type of oral 60 determines that the joint stiffness and swelling is due to administration of a pharmaceutical composition disclosed chronic inflammation . The woman is treated by oral admin herein will be used to treat a patient suffering from chronic istration a pharmaceutical composition comprising ibupro inflammation associated with any other systemic autoim - fen as disclosed herein taken twice daily . Alternatively, the mune disorder , including , without limitation , an anti- phos - woman is treated by oral administration a pharmaceutical pholipid antibody syndrome ( APS) , a bullous pemphigoid , a 65 composition comprising aspirin as disclosed herein taken Chagas disease , a discoid lupus erythematosus , a drug - thrice daily . Alternatively, the woman is treated by oral induced lupus erythematosus, a Goodpasture 's syndrome, a administration a pharmaceutical composition comprising US 9 , 750 , 810 B2 93 94 naproxen as disclosed herein taken twice daily . The wom any such inclusion or deletion occurs , the specification is an ' s condition is monitored and after about 3 days of deemed to contain the group as modified thus fulfilling the treatment the woman indicates there is reduced joint stiff written description of all Markush groups used in the ness and swelling . At one and three month check -ups , the appended claims. woman indicates that she continues to have reduced joint 5 Unless otherwise indicated , all numbers expressing a stiffness and swelling in the area treated . This reduction in characteristic , item , quantity , parameter , property , term , and a chronic inflammation symptom indicates successful treat - so forth used in the present specification and claims are to be ment with the pharmaceutical composition disclosed herein . understood as being modified in all instances by the term A similar type of oral administration of a pharmaceutical “ about. ” As used herein , the term “ about” means that the composition disclosed herein will be used to treat a patient 10 characteristic , item , quantity , parameter, property , or term so suffering from chronic inflammation associated with any qualified encompasses a range of plus or minus ten percent monoarthritis , oligoarthritis , or polyarthritis , such as , e . g . , above and below the value of the stated characteristic , item , osteoarthritis , juvenile idiopathic arthritis , septic arthritis , a quantity , parameter, property , or term . Accordingly , unless spondyloarthropathy ( including ankylosing spondylitis , indicated to the contrary , the numerical parameters set forth reactive arthritis (Reiter ' s syndrome ), psoriatic arthritis , 15 in the specification and attached claims are approximations enteropathic arthritis associated with inflammatory bowel thatmay vary . At the very least , and not as an attempt to limit disease , Whipple disease or Behcet disease ), a synovitis , the application of the doctrine of equivalents to the scope of gout, pseudogout, or Still ' s disease , as well as, a bursitis , a the claims, each numerical indication should at least be rheumatic fever , or a tenosynovitis. In a similar manner , any construed in light of the number of reported significant digits of the therapeutic compounds such as , e . g . , a salicylate 20 and by applying ordinary rounding techniques . Notwith derivative NSAID , a p -amino phenol derivative NSAID , a standing that the numerical ranges and values setting forth propionic acid derivative NSAID , an acetic acid derivative the broad scope of the invention are approximations , the NSAID , an enolic acid derivative NSAID , a fenamic acid numerical ranges and values set forth in the specific derivative NSAID , a non - selective cyclo - oxygenase (COX ) examples are reported as precisely as possible . Any numeri inhibitor , a selective cyclooxygenase 1 (COX 1 ) inhibitor, a 25 cal range or value , however , inherently contains certain selective cyclooxygenase 2 (COX 2 ) inhibitor, or a fibrate , errors necessarily resulting from the standard deviation will be formulated into a pharmaceutical composition and found in their respective testing measurements . Recitation of administered to the patient as described above . numerical ranges of values herein is merely intended to In closing , it is to be understood that although aspects of serve as a shorthand method of referring individually to each the present specification are highlighted by referring to 30 separate numerical value falling within the range . Unless specific embodiments , one skilled in the art will readily otherwise indicated herein , each individual value of a appreciate that these disclosed embodiments are only illus - numerical range is incorporated into the present specifica trative of the principles of the subject matter disclosed tion as if it were individually recited herein . herein . Therefore , it should be understood that the disclosed The terms “ a ," " an , ” “ the ” and similar referents used in subject matter is in no way limited to a particular method - 35 the context of describing the present invention ( especially in ology, protocol, and / or reagent , etc ., described herein . As the context of the following claims) are to be construed to such , various modifications or changes to or alternative cover both the singular and the plural, unless otherwise configurations of the disclosed subject matter can be made indicated herein or clearly contradicted by context. All in accordance with the teachings herein without departing methods described herein can be performed in any suitable from the spirit of the present specification . Lastly, the 40 order unless otherwise indicated herein or otherwise clearly terminology used herein is for the purpose of describing contradicted by context. The use of any and all examples , or particular embodiments only , and is not intended to limit the exemplary language ( e . g ., " such as " ) provided herein is scope of the present invention , which is defined solely by the intended merely to better illuminate the present invention claims. Accordingly , the present invention is not limited to and does not pose a limitation on the scope of the invention that precisely as shown and described . 45 otherwise claimed . No language in the present specification Certain embodiments of the present invention are should be construed as indicating any non - claimed element described herein , including the best mode known to the essential to the practice of the invention . inventors for carrying out the invention . Of course , varia - Specific embodiments disclosed herein may be further tions on these described embodiments will become apparent limited in the claims using consisting of or consisting to those of ordinary skill in the art upon reading the 50 essentially of language . When used in the claims, whether as foregoing description . The inventor expects skilled artisans filed or added per amendment, the transition term “ consist to employ such variations as appropriate , and the inventors ing of excludes any element, step , or ingredient not speci intend for the present invention to be practiced otherwise fied in the claims . The transition term “ consisting essentially than specifically described herein . Accordingly , this inven - of limits the scope of a claim to the specified materials or tion includes allmodifications and equivalents of the subject 55 steps and those that do not materially affect the basic and matter recited in the claims appended hereto as permitted by novel characteristic ( s ) . Embodiments of the present inven applicable law . Moreover, any combination of the above - tion so claimed are inherently or expressly described and described embodiments in all possible variations thereof is enabled herein . encompassed by the invention unless otherwise indicated All patents , patent publications , and other publications herein or otherwise clearly contradicted by context . 60 referenced and identified in the present specification are Groupings of alternative embodiments , elements , or steps individually and expressly incorporated herein by reference of the present invention are not to be construed as limita - in their entirety for the purpose of describing and disclosing , tions . Each group member may be referred to and claimed for example , the compositions and methodologies described individually or in any combination with other group mem - in such publications that might be used in connection with bers disclosed herein . It is anticipated that one or more 65 the present invention . These publications are provided solely members of a group may be included in , or deleted from , a for their disclosure prior to the filing date of the present group for reasons of convenience and /or patentability. When application . Nothing in this regard should be construed as an US 9 ,750 ,810 B2 95 96 admission that the inventors are not entitled to antedate such 7 . The pharmaceutical composition according to claim 6 , disclosure by virtue of prior invention or for any other wherein the hard fat or the triester of glycerol is in an amount reason . All statements as to the date or representation as to from about 35 % to about 45 % by weight of the pharmaceu tical composition . the contents of these documents is based on the information 5 8 . The pharmaceutical composition according to claim 1 , available to the applicants and does not constitute any 5 wherein the hard fat or the triester of glycerol has a melting admission as to the correctness of the dates or contents of point of about 40° C . to about 46° C . these documents . 9 . The pharmaceutical composition according to claim 8 , wherein the hard fat comprises a mixture of saturated The invention claimed is : C1 - C , triglycerides having a melting point of between 41° 1 . A pharmaceutical composition comprising : 10 C . to 45° C . a ) about 10 % to 30 % of a propionic acid derivative 10 . The pharmaceutical composition according to claim 9 . wherein the hard fat comprises a mixture of saturated NSAID by weight of the pharmaceutical composition ; C10 - C18 triglycerides having a melting point of about 43° C . b ) about 5 % to about 15 % of a polyethylene glycol (PEG ) 410711 . The pharmaceutical composition according to claim 1 , polymer by weight of the pharmaceutical composition ; 15 wherein the liquid fat is in an amount from about 15 % to c ) about 20 % to about 50 % of a hard fat comprising a about 25 % by weight of the pharmaceutical composition . triglyceride or a triester of glycerol by weight of the 12 . The pharmaceutical composition according to claim 1 , pharmaceutical composition ; and wherein the liquid fat further comprises a diglyceride , a d ) about 10 % to about 30 % of a liquid fat comprising a triglyceride, or any combination thereof. mono - glyceride by weight of the pharmaceutical com - 20 13 . The pharmaceutical composition according to claim 1 . position , wherein the monoglyceride is glyceryl monolinoleate . wherein the pharmaceutical composition is formulated to be 14 . The pharmaceutical composition according to claim 1 , a solid at a temperature of about 15° C . or lower and have wherein the PEG polymer is in an amount from about 8 % to a melting point temperature in the range of about 25° C . or about 15 % by weight of the pharmaceutical composition . higher. 26 15 . The pharmaceutical composition according to claim 2 . The pharmaceutical composition according to claim 1 , 14 , wherein the PEG polymer is in an amount from about 7 % wherein the propionic acid derivative NSAID is about 20 % to about 13 % by weight of the pharmaceutical composition . to about 30 % by weight of the pharmaceutical composition . 16 . The pharmaceutical composition according to claim 3. The pharmaceutical composition according to claim 2 , 15 , wherein the pharmaceutically -acceptable PEG polymer wherein the propionic acid derivative NSAID is in an 20 is in an amount from about 8 % to about 12 % by weight of amount from about 25 % to about 30 % by weight of the the pharmaceutical composition . pharmaceutical composition . 17 . The pharmaceutical composition according to claim 4 . The pharmaceutical composition according to claim 1 , 16 wherein the PEG polymer is in an amount from about 9 % wherein the propionic acid derivative NSAID comprises an to about 11 % by weight of the pharmaceutical composition . Alminoprofen , a Benoxaprofen , a Dexketoprofen , a Feno - 35 18 . The pharmaceutical composition according to claim 1 , profen , a Flurbiprofen , an Ibuprofen , an Indoprofen , a 35 wherein the PEG polymer is a liquid PEG polymer. Ketoprofen , a Loxoprofen , a Naproxen , an Oxaprozin , a 19 . The pharmaceutical composition according to claim Pranoprofen , or a Suprofen . 18, wherein the pharmaceutically -acceptable PEG polymer 5 . The pharmaceutical composition according to claim 1 , is less than about 2 , 000 g /mol . wherein the propionic acid derivative NSAID is a pharma- 40 20 . The pharmaceutical composition according to claim ceutically -acceptable form of an Ibuprofen . 40 19 , wherein the liquid PEG polymer is a PEG 100 , a PEG 6 . The pharmaceutical composition according to claim 1 , 200 , a PEG 300 , a PEG 400 , a PEG 500 , a PEG 600 , a PEG wherein the hard fat or the triester of glycerol is in an amount 700 , a PEG 800 , a PEG 900 , a PEG 1000 , or a combination from about 30 % to about 50 % by weight of the pharmaceu thereof. tical composition . * * * * *