USOO93O8213B2

(12) United States Patent (10) Patent No.: US 9,308,213 B2

Bannister et al. 45) Date of Patent: *Apr. 12,9 2016

(54) SOLID SOLUTION COMPOSITIONS AND USE (2013.01); A61 K9/2013 (2013.01); A61 K IN CHRONIC INFLAMMATION 31/192 (2013.01); A61 K3I/60 (2013.01); A61K 47/44 (2013.01); A61 K3 1/201 (2013.01); (71) Applicant: Infirst Healthcare Limited, London A61 K 3 1/202 (2013.01); A61K 31/25 (2013.01); (GB) A61 K 3 1/337 (2013.01); A61 K3I/704 (72) Inventors: Robin M. Bannister, Essex (GB); John (2013.01) Brew, Hertfordshire (GB); Richard R. (58) Field of Classification Search Caparros Wanderley, Buckinghamshire A61 K31/704; A61 K31/60; A61 K31/202 (GB) USPC ...... 514/159,570,571 See application file for complete search history. (73) Assignee: Infirst Healthcare Limited (GB) (*) Notice: Subject to any disclaimer, the term of this (56) References Cited patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days U.S. PATENT DOCUMENTS This patent is Subject to a terminal dis- 3,228,831 A 1/1966 Nicholson et al. claimer 3,800,038 A 3, 1974 Rudel 4,571.400 A 2f1986 Arnold 4,684.666 A 8, 1987 HaaS (21) Appl. No.: 14/155,108 4,918, 103 A 4/1990 Park et al. 5,011,852 A 4, 1991 Park et al. (22) Filed: Jan. 14, 2014 5,059,626 A 10, 1991 Park et al. 5,154,930 A 10/1992 Popescu (65) Prior Publication Data 5,552,160 A 9/1996 Liversidge et al. 5,645,856 A 7/1997 Lacy et al. US 2014/O162988 A1 Jun. 12, 2014 5,955.451 A 9/1999 Lichtenberger et al. 6,267,985 B1 7/2001 Chen et al. 6,294,192 B1 9, 2001 Patel et al. Related U.S. Application Data 6,319,513 B1 1 1/2001 Dobrozsi 6,383,471 B1 5/2002 Ch tal. (63) Continuation-in-part of application No. 13/365,824, 6,451,339 B2 9, 2002 ES filed on Feb. 3, 2012, now Pat. No. 8,895,536, which is 6,923,988 B2 8, 2005 Patel et al. a continuation-in-part of application No. 7,473.432 B2 ck 3. Cevc et al. 1 f 8,895,536 B2 * 1 1/2014 Bannister et al...... 514f159 PCT/GB2012/0521 15, filed on Oct. 31, 2O1 1. 8,895,537 B2 * 1 1/2014 Bannister et al...... 514f159 application No. 14/155,108, which is a continuation-in-part of application No. 13/365,828, (Continued) filed on Feb. 3, 2012, now Pat. No. 8,895,537. FOREIGN PATENT DOCUMENTS (60) Provisional application No. 61/752,309, filed on Feb. 4, 2013, provisional application No. 61/752,356, filed CN 1736,369 2, 2006 on Jan. 14, 2013. CN 101.129335 A * 2, 2008 (Continued) (30) Foreign Application Priority Data OTHER PUBLICATIONS Oct. 29, 2010 (GB) ...... 1018289.7 Feb. 4, 2011 (GB) ...... 11 O1937.9 CN 101 12935 A. English translation and English-translated abstract Aug. 10, 2011 (GB) ..... 11 13728.8 (2008).* Aug. 10, 2011 (GB) ...... 1113729.6 (Continued) Aug. 10, 2011 (GB) ...... 1113730.4 (51) Ek',I/60 (2006.01) Primary Examiner — Kevin E Weddington A6 IK3I/9 (2006.01) (74) Attorney, Agent, or Firm One3 IP Management, P.C.; A6 IK3I/66 (2006.01) Dean G. Stathakis; Peter D. Weisintein A6 IK3I/92 (2006.01) A6 IK9/08 (2006.01) A6 IK 47/44 (2006.01) (57) ABSTRACT A6 IK9/20 (2006.01) The present specification discloses pharmaceutical composi A61 K3 1/25 (2006.01) tions, methods of preparing Such pharmaceutical composi A61 K3 L/704 (2006.01) tions, and methods and uses of treating a chronic inflamma A61 K3 1/337 (2006.01) tion and/or an inflammatory disease in an individual using t |?: 9. 3:08: Such pharmaceutical compositions. (52) U.S. Cl. CPC ...... A61 K3I/616 (2013.01); A61 K9/08 26 Claims, 10 Drawing Sheets US 9,308,213 B2 Page 2

(56) References Cited WO 2008.120207 A3 10, 2008 WO 2008, 134512 A1 11, 2008 U.S. PATENT DOCUMENTS WO 2009/033131 A2 3, 2009 WO 2009/047785 A3 4/2009 2003,0008003 A1 1/2003 Jamali WO 2009/067734 A1 6, 2009 2003/0170279 A1 9, 2003 Lambert et al. WO 2009/069139 A1 6, 2009 2003/0232097 A1 12/2003 Radhakrishnan et al. WO 2010/059717 A2 5, 2010 2004.0024057 A1 2, 2004 Earl et al. WO 2010/087947 A2 8, 2010 2004/025.3276 A1 12, 2004 Sato et al. WO 2010/0973.32 A1 9, 2010 2005/0152968 A1 7/2005 Brophy et al. WO 2010/097334 A1 9, 2010 2006, OO6281.0 A1 3, 2006 WoO et al. WO 2010.103312 A1 9, 2010 2006/0078616 A1 4/2006 Georgewill et al. WO 2011/095814 A1 8, 2011 2007/0015834 A1 1/2007 Flashner-Barak et al. WO 2012/056251 A1 5, 2012 2007/0026062 A1 2/2007 Holm et al. WO 2012, 104654 A1 8, 2012 2007.0036831 A1, 2, 2007 Baker WO 2012, 104655 A2 8, 2012 2007, 0104741 A1 5/2007 Murty et al. 2007. O190080 A1 8, 2007 Friedman OTHER PUBLICATIONS 3883 A. 258. Still al. The English translation abstract for FR 2810243 A1, Woo et al. 2008. O15421.0 A1 6/2008 Jordan et al. (2001). 20090304782 A1 12, 2009 De Blas et al. Csizmazia, E., et al., Penetration enhancer effect of Sucrose laurate 2010.0099767 A1 4/2010 Davis and Transcutol on ibuprofen, Journal of Drug Delivery Science and 2010, 0125060 A1 5, 2010 RaZZak et al. Technology, vol. 21, No. 5 Sep. 2011 XP009 168551. 2011/O142945 A1 6, 2011 Chen et al. Hesson Chung, et al., Oil Components Modulate Physical Charac 2011/O195993 A1 8/2011 Masson et al. teristics and Function of the Natural Oil Emulsions as Drug or Gene 2012fO270845 A1 10, 2012 Bannister et al. Delivery System, Journal of Controlled Release 71:339-350 (2001). 2012fO270899 A1 10, 2012 Bannister et al. List et al., Hydrogenation of Soybean Oil Triglycerides: Effect of 2013, O156853 A1 6/2013 Zhang et al. Pressure on Selectivity. JAOCS (2000), vol. 77, pp. 311-314. Nickitas-Etienne, PCT International Preliminary Report on Patent FOREIGN PATENT DOCUMENTS ability, PCT/GB2011/050 189, pp. 11 (Aug. 7, 2012). Nickitas-Etienne, PCT International Preliminary Report on Patent CN 102.793628 A 11, 2012 ability, PCT/GB2011/052115, pp. 8 (Apr. 30, 2013). EP 306060 A2 3, 1989 PCT International Search Report and the Written Opinion of the EP 0521.344 A2 1/1993 Internation Searching Authority PCT/EP2014/050627. FR 2810243 A1 * 12/2001 PCT International Search Report and the Written Opinion of the SE 2315 A 3. Internation Searching Authority PCT/EP2014/050628. JP 6009381 3, 1992 PCT International Search Report and the Written Opinion of the JP 2008143807 12/2006 Internation Searching Authority PCT/EP2014/050637. JP 2009 155282 T 2009 Schule, PCT International Search Report & Written Opinion, WO 92.09272 A1 6, 1992 PCTGB2012050241, pp. 24 (Jul 13, 2012). WO 95/11039 A1 4f1995 Schule, PCT International Search Report & Written Opinion, WO 97.03655 A1 2, 1997 PCTGB2012050242, pp. 12 (Jan. 22, 2013). WO 98.25595 A1 6, 1998 Strickley, Solubilizing Excipients in Oral and Inkectable Formula WO OOf 27372 A1 5.2000 tions Pharaceutical (2004), vol. 21, pp. 21, pp. 201-230. WO OO57859 A1 5, 2000 Wolfgang Grebe, et al., A Multicenter, Randomized, Double-Blind, WO OOf 67728 A2 11/2000 Double-Dummy, Placebo- and Active-Controlled, Parallel-Group W. oo:: A. 3.399 Comparison of Diclofenac-K and Ibuprofen for the Treatment of WO O3,O13566 A1 2, 2003 Adults with Influenza-like Symptoms, Clinical Therapeutics 25(2): WO 2004/082.588 A2 9, 2004 444-459 (2003). WO 2005/009436 A1 2, 2005 Vane JR et al., Mechanism of action of anti-inflammatory drugs, Int WO 2006/099325 A2 9, 2006 J Tissue React. 1998;20(1):3-15, abstract. WO 20060968.06 A2 9, 2006 WO 2008/070950 A1 6, 2008 * cited by examiner U.S. Patent Apr. 12, 2016 Sheet 1 of 10 US 9,308,213 B2

Ibuprofen

10 m W

25 50 35 40 45 50 55 60 65 70 75 80 85 90 95 100 Temperature (C) FIG. 1A

Gelucire 45/01

10 m W

25 30 35 40 45 50 55 60 65 70 Temperature (C) FIG. 1B U.S. Patent Apr. 12, 2016 Sheet 2 of 10 US 9,308,213 B2

Vehicle LA 5-61

2m W

25 50 35 40 45 50 55 60 65 70 75 80 Temperature (C) FIG. 1C

Ibuprofen LA 35-1

25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 Temperature (C) FIG. 1D U.S. Patent Apr. 12, 2016 Sheet 3 of 10 US 9,308,213 B2

|buprofen LA 35-2

25 50 35 40 45 50 55 60 65 70 75 80 85 90 95 100 Temperoture (C) FIG. 1E Ibuprofen LA 55-3

25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 Temperature (C) FIG. 1 F U.S. Patent Apr. 12, 2016 Sheet 4 of 10 US 9,308,213 B2

Ibuprofen LA 3-51

2 mW

25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 Temperature (C) FIG. 1G

|buprofen LA 3-57

25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 Temperature (C) FIG. 1H U.S. Patent Apr. 12, 2016 Sheet 5 of 10 US 9,308,213 B2

Artemether LA 2-15-1

25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 Temperature (C) FIG. 2

Aspirin LA 3-104-2

5 m W

30 40 50 60 7O 8O 90 100 120 140 160 180 °C 0 2 4 6 8 10 12 14 16 18 20 22 24 min. FIG. 3 U.S. Patent Apr. 12, 2016 Sheet 6 of 10 US 9,308,213 B2

Dontrolene LA 5-86-3

30 40 50 60 70 8O 90 100 120 140 160 180 °C O 2 4 6 8 10 12 14 16 18 20 22 24 min, FIG. 4

Dicloferic LA 3-105

40 60 80 100 120 140 160 180 200 220 240 260 280 °C 0 2 4 6 8 10 12 14 16 18 20 22 24 26 min. FIG. 5 U.S. Patent Apr. 12, 2016 Sheet 7 of 10 US 9,308,213 B2

Fenofibrote LA 2-19

2 m W

25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 Temperoture (C) FIG. 6

Lidocoine LA 1

30 40 50 60 70 80 90 100 120 140 160 180 °C O 2 4 6 8 10 12 14 16 18 20 22 24 min. FIG. 7 U.S. Patent Apr. 12, 2016 Sheet 8 of 10 US 9,308,213 B2

NobumetOne LA 5-105-1

30 40 50 60 70 80 90 100 120 140 160 180 0 2 4 6 8 10 12 14 16 18 20 22 24 min. FIG. 8

Naproxen LA 1-23-5

2 m W

30 40 50 60 70 8O 90 100 120 140 160 180 °C 0 2 4 6 8 10 12 14 16 18 20 22 24 min. FIG. 9 U.S. Patent Apr. 12, 2016 Sheet 9 of 10 US 9,308,213 B2

Solbutomo LA 1

2 mW

30 40 50 60 7O 80 90 100 120 140 160 180 °C O 2 4 6 8 10 12 144. 16 18 20 22 24 min. FIG. 1 O

Salmeterol, LA 1-25–7

10mW

30 40" 50 60 70 80 90 100 120 140 160 180 °C O 2 4 6 8 10 12 14 16 18 20 22 24 min. FIG. 11 U.S. Patent Apr. 12, 2016 Sheet 10 of 10 US 9,308,213 B2

SimVOstotin LA 3-83-3

40 60 80 100 120 140 160 180 200 220 240 26O 280 °C O 2 4 6 8 10 12 14 16 18 20 22 24 26 min, FIG. 12

TelmerSOrton LA 1

OmW

O 40 60 80 100 120 140 160 180 200 220 240 260 280 C 0 2 4 6 8 10 12 14 16 18 20 22 24 26 min. FIG. 13 US 9,308,213 B2 1. 2 SOLD SOLUTION COMPOSITIONS AND USE However, severe or prolonged noxious stimulation results IN CHRONIC INFLAMMATION in a chronic inflammatory response that leads to a progressive shift in the type of cells present at the site of tissue injury. This continuation-in-part application claims priority pur Chronic inflammation may be characterized as the simulta suant to 35 U.S.C. S 120 to U.S. Non-Provisional patent appli neous destruction and healing of tissue from the inflamma cation Ser. No. 13/365,824, filed Feb. 3, 2012, a continuation tory process, with the net result of provoking injury rather in-part application that claims priority to patent application than mediating repair. As such, chronic inflammation is a PCT/GB2011/052115, filed Oct. 31, 2011, an international disease. As an inflammatory response can occur anywhere in patent application that claims priority to GB 1018289.7, filed the body, chronic inflammation has been implicated in the Oct. 29, 2010, and claims priority to patent application U.S. 10 pathophysiology of a wide range of seemingly unrelated dis orders which underlay a large and varied group of human Ser. No. 13/365,828, filed Feb. 3, 2012, and claims priority to diseases. For example, chronic inflammation is involved in GB 11 13730.4, filed Aug. 10, 2011, GB 1113729.6, filed diseases as diverse as cardiovascular diseases, cancers, aller Aug. 10, 2011, GB 1113728.8, filed Aug. 10, 2011, and GB gies, obesity, diabetes, digestive system diseases, degenera 1101937.9, filed Feb. 4, 2011 and this continuation-in-part 15 tive diseases, auto-immune disorders, and Alzheimer's dis application claims priority pursuant to 35 U.S.C. S 119(e) to CaSC. U.S. Provisional Patent Application 61/752,309, filed Jan. 14, Attempts to treat chronic inflammation have met with lim 2013, and U.S. Provisional Patent Application 61/752,356, ited Success. This is due, in part, to the fact that the etiology of filed Jan. 14, 2013, each of which is hereby incorporated by chronic inflammation is a complex response based in part on reference in its entirety. the various inflammation inducing molecules and the multi Inflammation involves the activation of the immune system tude of inflammation mediating and sensitizing molecules in response to harmful stimuli. Such as, e.g., a pathogen, that appear to elicit inflammation via redundant mechanism. infection, irritant, or damage to cells. As a stereotyped In addition, besides blocking pro-inflammatory molecules, response, inflammation is a mechanism of innate immunity, many anti-inflammatory drugs, also inhibit regulatory loops as compared to adaptive immunity, which is specific for each 25 that release endogenous anti-inflammatory molecules. For pathogen. Inflammation can be classified as either acute or example, NSAIDs reduce inflammation by blocking the chronic. Generally speaking, acute inflammation is mediated enzymatic activity of cyclooxygenase, a key enzyme that by granulocytes, while chronic inflammation is mediated by catalyzes the conversion of arachidonic acid to prostaglan mononuclear cells Such as monocytes and lymphocytes. dins and leukotrienes. Thus, NSAIDs reduce inflammation by Acute inflammation is an initial protective response of the 30 preventing the synthesis of all prostaglandins. However, body to remove an injurious stimulus by maintaining tissue NSAIDs not only prevents the synthesis of proinflammatory integrity and contributing to tissue repair. It a part of the prostaglandins, these compounds also prevent the synthesis body's natural defense system against injury and disease, and of anti-inflammatory prostaglandins. Hence, NSAIDs have in the absence of acute inflammation, wounds and infections limited Success as they block endogenous anti-inflammatory would never heal and progressive destruction of the tissue 35 response, which in Some instances may prolong chronic would compromise the Survival of the organism. inflammation. Therefore, compounds, compositions, uses, The process of acute inflammation is initiated by cells and methods preferentially inhibiting pro-inflammatory already present in all tissues, mainly resident macrophages, responses would be highly desirable for the treatment of dendritic cells, histiocytes, Kupffer cells, mastocytes, vascu chronic inflammation. lar endothelial cells, and vascular smooth muscle cells. At the 40 The present specification discloses Solid solution pharma onset of a harmful stimulus, these cells undergo activation ceutical compositions. The pharmaceutical compositions dis and release inflammatory mediating and sensitizing mol closed herein are formulated in a manner that essentially ecules, such as, e.g., pro-inflammatory cytokines, pro-inflam produces a lipid-adjuvant delivery system that enables a matory prostaglandins, leukotrienes, histamine, serotonin, therapeutic compound having anti-inflammatory activity to neutral proteases, bradykinin and nitric oxide. These inflam 45 be delivered in a manner that more effectively inhibits a matory molecules modulate a complex series of biological pro-inflammatory response. The end result is an improved events involving cellular and acellular components of the treatment for chronic inflammation. local vascular system, the immune system, and the injured tissue site to propagate and mature the inflammatory SUMMARY response. These events are responsible for eliciting an acute 50 inflammatory response, typically characterized by 1) vasodi Aspects of the present specification disclose, in part, a solid latation which increases blood flow into the tissue thereby Solution pharmaceutical composition comprising a therapeu causing erythema (redness and warmth), which may extend tic compound, one or more room temperature solid lipids. The beyond this site (the flare response); 2) blood vessel perme Solid solution pharmaceutical composition disclosed herein ability which increases plasma leakage into the tissue thereby 55 may further comprise one or more room temperature liquid causing edema (Swelling); 3) alter the excitability of certain lipids, one or more stabilizing agents, one or more neutraliz sensory neurons causing hypersensitivity and pain; 4) stimu ing agents, or any combination thereof. A therapeutic com late the release of inflammation inducing molecules such as, pound may have an anti-inflammatory activity. e.g., neuropeptides like Substance P(SP) and calcitonin gene Other aspects of the present specification disclose, in part, related peptide (CGRP), prostaglandins, and amino acids like 60 a method of preparing a solid solution pharmaceutical com glutamate, from the peripheral nerve endings; and 5) increase position disclosed herein. A method disclosed herein com migration of leukocytes, mainly granulocytes, from the blood prises the steps of a) contacting a therapeutic compound vessels into the tissue. An acute inflammatory response disclosed herein with one or more room temperature liquid requires constant stimulation to be sustained and must be lipids under conditions which allow the therapeutic com actively terminated when no longer needed. Hence, acute 65 pound to dissolve in the lipids; and b) contacting the com inflammation ceases once the injurious stimulus has been pound/lipid solution with one or more room temperature solid removed. lipids under conditions which allow the formation of a solid US 9,308,213 B2 3 4 Solution composition. In aspects of this method, heat is FIG.11 shows a DSC graph of Salmeterol composition LA applied to dissolve the therapeutic compound into the one or 1-23-7 exhibiting a melting point range of 34°C. to 43°C. more room temperature liquid lipids to create a solution. In FIG. 12 shows a DSC graph of Simvastatin composition other aspects of this method, step (a) comprises contacting a LA 3-83-3 exhibiting a melting point range of 32°C. to 43°C. therapeutic compound disclosed herein with one or more FIG. 13 shows a DSC graph of Telmisartan composition room temperature liquid lipids and/or one or more stabilizing LA 1 exhibiting a melting point range of 34°C. to 43°C. agents, and/or one or more neutralizing agents under condi tions which allow the therapeutic compound to dissolve in the DESCRIPTION lipids. Other aspects of the present specification disclose a 10 The present specification discloses Solid solution compo method of treating an individual with a chronic inflammation, sitions useful to formulate a wide variety of therapeutic com the method comprising the step of administering to the indi pounds. Solid solution compositions are crystalline Solids vidual in need thereof a solid solution pharmaceutical com comprising a matrix of a solvent material (which may be solid position disclosed herein, wherein administration results in a at normal temperatures) and solutes where the molecules in reduction in a symptom associated with the chronic inflam 15 the solid solution are arranged in a random fashion and not in mation, thereby treating the individual. an ordered alignment. The Solid solution pharmaceutical Other aspects of the present specification disclose a use of compositions disclosed herein act as a delivery system that a solid solution pharmaceutical composition disclosed herein enable a therapeutic compound disclosed herein to be more in the manufacture of a medicament for the treatment of a effectively delivered or targeted to a cell type, tissue, organ, or chronic inflammation. region of the body in a manner that more effectively inhibits Other aspects of the present specification disclose a solid a pro-inflammatory response. This inhibition results in an Solution pharmaceutical composition disclosed hereinforuse improved treatment of a chronic inflammation. in the treatment of a chronic inflammation. For example, a pharmaceutical composition disclosed Other aspects of the present specification disclose a use of herein may facilitate the delivery of a therapeutic compound a solid solution pharmaceutical composition disclosed herein 25 disclosed herein into macrophages. Macrophages exist at the for the treatment of a chronic inflammation. crossroads of two fundamental pathways being the principle cells in the immune system and also lipid metabolism. With BRIEF DESCRIPTION OF THE DRAWINGS regards to the immune system, most pathogens have a lipid containing Surface component that macrophage recognize FIG. 1 shows a differential scanning calorimetry (DSC) 30 and then engulf the pathogen. One possible mechanism that graph of Solid solution compositions disclosed herein com achieves this selective biodistribution is that the pharmaceu prising ibuprofen. FIG. 1A is a DSC graph of ibuprofen alone tical compositions disclosed herein may be designed to take exhibiting a melting point range of 75°C. to 78°C.; FIG. 1B advantage of the activity of chylomicrons. Chylomicrons are is a DSC graph of GELUCIER 43/01 alone exhibiting a relatively large lipoprotein particles having a diameter of 75 melting point range of 41° C. to 45° C.; FIG. 1C is a DSC 35 nm to 1,200 nm. Comprising triglycerides (85-92%), phos graph of a vehicle comprising GELUCIER 43/01, pholipids (6-12%), cholesterol (1-3%) and apolipoproteins MAISINE(R) 35-1, and PEG 400 exhibiting a melting point (1-2%), chylomicrons transport dietary lipids from the intes ranges of 32° C. to 38° C. and 41° C. to 45° C.; FIG. 1D is a tines to other locations in the body. Chylomicrons are one of DSC graph of Ibuprofen composition LA 35-1 exhibiting a the five major groups of lipoproteins, the others being VLDL, melting point range of 32° C. to 44° C.; FIG. 1E is a DSC 40 IDL, low-density lipoproteins (LDL), high-density lipopro graph of Ibuprofen composition LA 35-2 exhibiting a melting teins (HDL), that enable fats and cholesterol to move within point range of 32° C. to 43° C.; FIG. 1F is a DSC graph of the water-based solution of the bloodstream. Ibuprofen composition LA 35-1 exhibiting a melting point During digestion, fatty acids and cholesterol undergo pro range of 32°C. to 42°C.; FIG. 1G is a DSC graph of Ibupro cessing in the gastrointestinal tract by the action of pancreatic fen composition LA 35-1 exhibiting a melting point range of 45 juices including lipases and emulsification with bile salts to 32° C. to 38° C.; FIG. 1H is a DSC graph of Ibuprofen generate micelles. These micelles allow the absorption of composition LA 35-1 exhibiting a melting point range of 32 lipid as free fatty acids by the absorptive cells of the small C. to 42° C. intestine, known as enterocytes. Once in the enterocytes, FIG. 2 shows a DSC graph of Artemether composition LA triglycerides and cholesterol are assembled into nascent chy 2-15-1 exhibiting a melting point range of 35° C. to 40°C. 50 lomicrons. Nascent chylomicrons are primarily composed of FIG. 3 shows a DSC graph of Aspirin composition LA triglycerides (85%) and contain some cholesterol and choles 3-86-3 exhibiting a melting point range of 35° C. to 40°C. teryl esters. The main apolipoprotein component is apolipo FIG. 4 shows a DSC graph of Dantrolene composition LA protein B-48 (APOB48). These nascent chylomicrons are 3-104-2 exhibiting a melting point range of 34° C. to 39°C. released by exocytosis from enterocytes into lacteals, lym FIG. 5 shows a DSC graph of Diclofenac composition LA 55 phatic vessels originating in the villi of the Small intestine, 3-103 exhibiting a melting point range of 35° C. to 40°C. and are then secreted into the bloodstream at the thoracic FIG. 6 shows a DSC graph of Fenofibrate composition LA ducts connection with the left subclavian vein. 2-19 exhibiting a melting point range of 34°C. to 39°C. While circulating in lymph and blood, chylomicrons FIG. 7 shows a DSC graph of Lidocaine composition LA exchange components with HDL. The HDL donates apolipo 3-101-2 exhibiting a melting point range of 34° C. to 40°C. 60 protein C-II (APOC2) and apolipoprotein E (APOE) to the FIG. 8 shows a DSC graph of Nabumetone composition nascent chylomicron and thus converts it to a mature chylo LA 3-105-1 exhibiting a melting point range of 35°C. to 40° micron (often referred to simply as “chylomicron'). APOC2 C. is the cofactor for lipoprotein lipase (LPL) activity. Once FIG. 9 shows a DSC graph of Naproxen composition LA triglyceride stores are distributed, the chylomicron returns 1-23-5 exhibiting a melting point range of 30°C. to 39°C. 65 APOC2 to the HDL (but keeps APOE), and, thus, becomes a FIG.10 shows a DSC graph of Salbutamol composition LA chylomicron remnant, now only 30-50 nm. APOB48 and 1 exhibiting a melting point range of 32°C. to 40°C. APOE are important to identify the chylomicron remnant in US 9,308,213 B2 5 6 the liver for endocytosis and breakdown into lipoproteins To influence the pharmacodynamics of a therapeutic com (VLDL, LDL and HDL). These lipoproteins are processed pound disclosed herein three features of the solid solution and stored by competent cells, including, e.g., hepatocytes, composition must be present. First, at least one lipid used in adipocytes and macrophages. Thus, without wishing to be the Solid solution composition must be made up of at least one limited by any theory, upon oral administration, a pharma fatty acid in which the carbon chain length is above 12 and ceutical composition disclosed herein can be processed into below 24 and therefore suitable for absorption through the micelles while in the gastrointestinal tract, absorbed by enterocyte pathways. Fatty acids below this C-C length enterocytes and assembled into nascent chylomicrons, do not form a lipid-drug matrix, and thus the drug is taken up remain associated with chylomicron remnants taken up by the by the body by the normal absorption process. Fatty acids liver, and ultimately loaded into macrophages which are 10 above this C-C length, although forming lipid-drug matri present in inflamed tissues. ces, cannot be absorbed and the drug leaches out of the solid As another example, a pharmaceutical composition dis solution composition and is eliminated by the body via the closed herein may facilitate the delivery of a therapeutic gastrointestinal tract. compound disclosed herein into dentritic cells. One possible Second, the therapeutic compound itself should have a mechanism to achieve selective biodistribution of the phar 15 lipohilicity that allows it to form a solid solution matric with maceutical compositions disclosed herein may be to take the C-C lipid. As discussed below, this lipohilicity can be advantage of the endocytotic/phagocytotic activity of den inherent to the therapeutic compound (lipid-soluble drug for tritic cells. Dendritic cells are immune cells forming part of mulations), or certain additives may be used that facilitate a the mammalian immune system. The main function of den wider range of lipid soluble drugs in the matrix (free acid/free dritic cells is to process antigen material and present it on the base drug formulations, salt drug formulations, and combi surface to other cells of the immune system. Thus, dendritic nation drug formulations). cells function as antigen-presenting cells that act as messen Third, the therapeutic compound itselfshould influence the gers between innate and adaptive immunity. Dendritic cells biology of certain cell types that are contacted by the lipid are present in tissues in contact with the external environ adjuvant nature of a solid solution composition that ulti ment, such as, e.g., the skin (where there is a specialized 25 mately circulate in the body. Such constructs include chylo dendritic cell type called Langerhans cells) and the inner micron, LDL particles and HDL particles. The cell types lining of the nose, lungs, stomach and intestines. These cells contacted may include macrophages, dendritic cells and adi can also be found in an immature state in the blood. Once pose cells and cancer cells. Tissues that have a high Surface activated, they migrate to the lymph nodes where they interact lipid content may also be preferentially targeted. These with T cells and B cells to initiate and shape the adaptive 30 include nerve tissues and the brain. immune response. Dendritic cells are known to endocytose The present specification discloses four general types of and phagocytose lipid particles as part of their environmental solid solution compositions, namely lipid-soluble drug for monitoring and antigen presentation processes. Without mulations, free acid/free base drug formulations, salt drug wishing to be limited by any theory, upon topical or inhalatory formulations, and combination drug formulations. Solid administration, a pharmaceutical composition disclosed 35 Solution compositions formulated using a lipid-soluble drug herein can penetrate into the skin or inner lining of the nose, formulation only require a lipid component to formulate a lungs, stomach and intestines, be endocytosed/phagocytosed therapeutic compound disclosed herein into a solid Solution by dendritic cells, and ultimately loaded into T cells and/or B composition. Without wishing to be limited by a theory, lipid cells which are present in inflamed tissues. soluble drugs can typically be dissolved in a lipid under heat. In addition to the targeted delivery of the therapeutic com 40 Upon cooling it is believed that the lipid component and drug pound disclosed herein, a solid solution pharmaceutical com form lipid-drug matrices organized in a manner where the position disclosed hereintake advantage of the different melt lipids encase the drug. Since only hydrophobic interactions ing point temperatures of the various lipids used. By are present, there is no organized alignment of these lipid controlling the types and amounts of the lipids added, a phar drug matrices resulting in a solid solution composition (i.e., maceutical composition disclosed herein can be made that is 45 there is no crystallization into a classic Solid form). substantially solid at room temperature, but melts when it Generally, therapeutic compounds having a log P of about reaches body temperature, Such as, e.g., after being ingested. 3.0 or greater are useful in a lipid-soluble drug formulation. The resulting melted composition readily forms micelles Non-limiting examples include an Artemisinin like Arteether, which are absorbed by the intestine, assembled into chylomi Artemether, Artemisinin, Artesunate, and Dihydroartemisi crons, and ultimately absorbed by macrophages or taken up 50 nin; a Fibrate like Bezafibrate, Ciprofibrate, Clofibrate, by dentritic cells as described above. Fenofibrate, and Gemfibrozil; and a Statin like Atorvastatin, Aspects of the present specification disclose, in part, a solid Fluvastatin, Lovastatin, Pitavastatin, Pravastatin, Rosuvasta Solution composition. A solid solution composition disclosed tin, and Simvastatin. herein is generally administered as a pharmaceutical accept A lipid-soluble drug formulation does not use or require a able composition. As used herein, the term “pharmaceutically 55 Surfactant. In addition, a lipid-soluble drug formulation does acceptable' refers any molecular entity or composition that not use or require non-lipid based solvent. does not produce an adverse, allergic or other untoward or Solid solution compositions formulated using a free acid/ unwanted reaction when administered to an individual. As free base drug formulation require a stabilizing agent in addi used herein, the term “pharmaceutically acceptable compo tion to a lipid component to formulate a therapeutic com sition' is synonymous with “pharmaceutical composition' 60 pound disclosed herein into a Solid solution composition. A and means a therapeutically effective concentration of an therapeutic compound having a free acid or free base can active ingredient, such as, e.g., any of the therapeutic com dissolve in a lipid under heat, but upon cooling to room pounds disclosed herein. A pharmaceutical composition dis temperature will crystallize to form a classic Solid composi closed herein is useful for medical and Veterinary applica tion. This occurs because the thermodynamic properties of tions. A pharmaceutical composition may be administered to 65 these mixtures favor the lower energy solid phase. In order to an individual alone, or in combination with other Supplemen produce a solid solution composition, a stability agent must tary active ingredients, agents, drugs or hormones. be added to stabilize the drug and prevent its transition into a US 9,308,213 B2 7 8 classic Solid phase upon cooling. Without wishing to be lim Generally, therapeutic compounds having a log P of about ited by a theory, it is believed that the stability agent coats 2.2 or less are useful in a salt drug formulation. Non-limiting lipid-drug matrices upon their formation. This coating examples include ryanodine receptor antagonists like impedes interactions between matrices thereby preventing AZumolene and Dantrolene; and Angiotensin II receptor the alignments necessary to form a crystalline matrix of a antagonists like AZilsartan, Candesartan, Eprosartan, Irbe Solid phase composition. As such, the transition to a solid Sartan, Losartan, Olmesartan, Telmisartan, and Valsartan. phase does not occur and a solid Solution composition is Solid solution compositions may also comprises different formed. Thus, a stability agents is a compound that provide a combinations of lipid-soluble drugs, free-acid/free-base barrier to the thermodynamic transition to a classic Solid drugs, and salt drugs. Depending of the drugs used, such phase or prolongs this transition to Such an extent that it does 10 formulations, besides the lipid component and the drug, can not occur. Examples of stability agents include liquid poly also include a stabilizing agent, a neutralizing agent, or both. ethylene glycols, isosorbide dimethyl ether, diethylene glycol Aspects of the present specification disclose, in part, a monoethyl ether (2-(2-ethoxyethoxy)ethanol), monohydrate therapeutic compound. A therapeutic compound is a com alcohols. pound that provides pharmacological activity or other direct Generally, therapeutic compounds having a log P of about 15 effect in the diagnosis, cure, mitigation, treatment, or preven 2.2 to about 3.0 are useful in a free acid/free base drug for tion of disease, or to affect the structure or any function of the mulation. Non-limiting examples include a non-steroidal body of man or animals. A therapeutic compound disclosed anti-inflammatory drug (NSAID) and an ester of aminoben herein may be used in the form of a pharmaceutically accept Zoic acid. A NSAID includes a salicylate derivative NSAID, able salt, Solvate, or Solvate of a salt, e.g. the hydrochloride. a p-amino phenol derivative NSAID, a propionic acid deriva Additionally, therapeutic compound disclosed herein may be tive NSAID, an acetic acid derivative NSAID, an enolic acid provided as racemates, or as individual enantiomers, includ (Oxicam) derivative NSAID, a fenamic acid derivative ing the R- or S-enantiomer. Thus, the therapeutic compound NSAID, a non-selective cyclo-oxygenase (COX) inhibitor, a disclosed herein may comprise a R-enantiomer only, a selective cyclooxygenase 1 (COX1) inhibitor, a selective S-enantiomer only, or a combination of both a R-enantiomer cyclooxygenase 2 (COX 2) inhibitor. An ester of aminoben 25 and a S-enantiomer of a therapeutic compound. A therapeutic Zoic acid includes Amylocalne, Benzocaine, Butacaine, compound disclosed herein may have anti-inflammatory Butamben, Chloroprocaine, Dimethocaine, Lidocaine, activity. Meprylcaine, Metabutethamine, Metabutoxycaine, In an embodiment, a therapeutic compound disclosed Orthocaine, Prilocalne, Propoxycaine, Procaine (No herein has an anti-inflammatory activity capable of reducing Vocaine), Proxymetacaine, Risocaine, and Tetracaine. 30 the levels of an inflammation inducing molecule. In an aspect Solid solution compositions formulated using a salt drug of this embodiment, atherapeutic compound disclosed herein formulation require a neutralizing agent in addition to a lipid has an anti-inflammatory activity capable of reducing the component to formulate a therapeutic compound disclosed levels of substance P(SP), calcitonin gene-related peptide herein into a solid solution composition. A therapeutic com (CGRP), glutamate, or a combination thereof. In other pound salt can dissolve in a lipid underheat, but upon cooling 35 aspects of this embodiment, a therapeutic compound dis to room temperature will crystallize to form a classic solid closed herein has an anti-inflammatory activity capable of composition. This occurs because the thermodynamic prop reducing the levels of SP, CGRP. glutamate, or a combination erties of these mixtures favor the lower energy solid phase. In thereof released from a sensory neuronby, e.g., at least 10%, order to produce a solid Solution composition, a neutralizing at least 15%, at least 20%, at least 25%, at least 30%, at least agent must be added to neutralize a therapeutic compound 40 35%, at least 40%, at least 45%, at least 50%, at least 55%, at salt and prevent its transition into a classic Solid phase upon least 60%, at least 65%, at least 70%, at least 75%, at least cooling. Without wishing to be limited by a theory, it is 80%, at least 85%, at least 90% or at least 95%. In yet other believed that the neutralizing agent eliminates that charges aspects of this embodiment, a therapeutic compound dis presence in the salt drugs. This neutralization impedes the closed herein has an anti-inflammatory activity capable of ionic interactions between matrices thereby preventing the 45 reducing the levels of SP, CGRP. glutamate, or a combination alignments necessary to form a crystalline matrix of a Solid thereof released from a sensory neuron in a range from, e.g., phase composition. As such, the transition to a solid phase about 10% to about 100%, about 20% to about 100%, about does not occur and a solid solution composition is formed. 30% to about 100%, about 40% to about 100%, about 50% to Thus, a neutralizing agent is a compound that provide a bar about 100%, about 60% to about 100%, about 70% to about rier to the thermodynamic transition to a classic Solid phase or 50 100%, about 80% to about 100%, about 10% to about 90%, prolongs this transition to Such an extent that it does not occur. about 20% to about 90%, about 30% to about 90%, about 40% Neutralizing agents include fatty acids for base-salt drugs to about 90%, about 50% to about 90%, about 60% to about and triethanolamine for acid-salt drugs. The degree of neu 90%, about 70% to about 90%, about 10% to about 80%, tralization depends on the amount of neutralizing agent added about 20% to about 80%, about 30% to about 80%, about 40% to the formulation. For complete neutralization, one molar 55 to about 80%, about 50% to about 80%, or about 60% to about equivalent of neutralizing agent is added to the formulation. 80%, about 10% to about 70%, about 20% to about 70%, For partial neutralization, less than one molar equivalent is about 30% to about 70%, about 40% to about 70%, or about added. Partial neutralization is advantageous in producing a 50% to about 70%. Sustained release formulation. Upon administration, a portion Prostaglandins mediate a local inflammatory response and of the drug is immediately made available to the body (instant 60 are involved in all inflammatory functions through action on bioavailability) while the bioavailability of another portion is prostaglandin receptors and mediate inflammatory signaling delayed until the neutralized by the neutralizing agent. A including chemotaxis (macrophages, neutrophils and eosino neutralizing agent may also be added in an excessive amount, phils), vasodilation and algesia. However, the PG-mediated i.e., more than one molar equivalent. Besides neutralizing the inflammatory response is self-limiting (resolving). The prin salt-drug, excessive amounts of neutralizing agent can also 65 ciple resolution factor is a prostaglandin called 15dPGJ2, enable adjustments to the melting point of the solid solution which is an endogenous agonist of peroxisome proliferator composition. activator receptor gamma (PPAR-Y) signaling. PPARY signal US 9,308,213 B2 10 ing pathway 1) induces apoptosis of Macrophage M1 cells, virtually all tissues, including heart, muscle, colon, kidney, thereby reducing the levels of Th1 pro-inflammatory cytok pancreas, and spleen. PPAR-y2 is expressed mainly in adi ines and 2) promotes differentiation of monocytes into Mac pose tissue. PPAR-Y3 is expressed in macrophages, large rophage M2 cells. Macrophage M2 cells produce and release intestine, and white adipose tissue. Endogenous ligands for Th2 anti-inflammatory cytokines. the PPARs include free fatty acids and eicosanoids. PPAR-Y is In an embodiment, a therapeutic compound disclosed activated by PGJ2 (a prostaglandin), whereas PPAR-C. is acti herein has an anti-inflammatory activity capable of reducing vated by leukotriene B4. the levels of an inflammation inducing prostaglandin. In other In an embodiment, a therapeutic compound disclosed aspects of this embodiment, a therapeutic compound dis herein has an anti-inflammatory activity capable of stimulat closed herein has an anti-inflammatory activity capable of 10 ing all PPAR signaling pathways. Such a therapeutic com reducing the levels of a inflammation inducing prostaglandin pound includes a PPAR pan-agonist. In other embodiments, a released from a sensory neuronby, e.g., at least 10%, at least therapeutic compound disclosed herein has an anti-inflam 15%, at least 20%, at least 25%, at least 30%, at least 35%, at matory activity capable of stimulating one or two of the PPAR least 40%, at least 45%, at least 50%, at least 55%, at least signaling pathways. Such a therapeutic compound includes a 60%, at least 65%, at least 70%, at least 75%, at least 80%, at 15 selective PPAR agonist. least 85%, at least 90% or at least 95%. In yet other aspects of In another embodiment, atherapeutic compound disclosed this embodiment, a therapeutic compound disclosed herein herein has an anti-inflammatory activity capable of stimulat has an anti-inflammatory activity capable of reducing the ing a PPAR-C. signaling pathway. In aspects of this embodi levels of a inflammation inducing prostaglandin released ment, a therapeutic compound disclosed herein stimulates a from a sensory neuron in a range from, e.g., about 10% to PPAR-C. signaling pathway by, e.g., at least 5%, at least 15%, about 100%, about 20% to about 100%, about 30% to about at least 25%, at least 50%, at least 60%, at least 70%, at least 100%, about 40% to about 100%, about 50% to about 100%, 80%, or at least 90%. In other aspects of this embodiment, a about 60% to about 100%, about 70% to about 100%, about therapeutic compound disclosed herein stimulates a PPAR-C. 80% to about 100%, about 10% to about 90%, about 20% to signaling pathway in a range from, e.g., about 5% to about about 90%, about 30% to about 90%, about 40% to about 25 100%, about 50% to about 100%, about 60% to about 100%, 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 100%, about 80% to about 100%, about about 70% to about 90%, about 10% to about 80%, about 20% 25% to about 90%, about 50% to about 90%, about 60% to to about 80%, about 30% to about 80%, about 40% to about about 90%, about 70% to about 90%, about 80% to about 80%, about 50% to about 80%, or about 60% to about 80%, 90%, about 25% to about 80%, about 50% to about 80%, about 10% to about 70%, about 20% to about 70%, about 30% 30 about 60% to about 80%, about 70% to about 80%, about 25% to about 70%, about 40% to about 70%, or about 50% to about to about 70%, about 50% to about 70%, about 25% to about 70%. 60%, about 50% to about 60%, or about 25% to about 50%. In another embodiment, atherapeutic compound disclosed In another embodiment, atherapeutic compound disclosed herein has an anti-inflammatory activity Substantially similar herein has an anti-inflammatory activity capable of stimulat to 15dPGJ2. In aspects of this embodiment, a therapeutic 35 ing a PPAR-ö signaling pathway. In aspects of this embodi compound disclosed hereinananti-inflammatory activity that ment, a therapeutic compound disclosed herein stimulates a is, e.g., at least 5%, at least 15%, at least 25%, at least 50%, at PPAR-8 signaling pathway by, e.g., at least 5%, at least 15%, least 55%, at least 60%, at least 65%, at least 70%, at least at least 25%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% or at least 95% 80%, or at least 90%. In other aspects of this embodiment, a of the activity observed for 15dPGJ2. In other aspects of this 40 therapeutic compound disclosed herein stimulates a PPAR-8 embodiment, a therapeutic compound disclosed herein an signaling pathway in a range from, e.g., about 5% to about anti-inflammatory activity that is in a range from, e.g., about 100%, about 50% to about 100%, about 60% to about 100%, 5% to about 100%, about 50% to about 100%, about 60% to about 70% to about 100%, about 80% to about 100%, about about 100%, about 70% to about 100%, about 80% to about 25% to about 90%, about 50% to about 90%, about 60% to 100%, about 25% to about 90%, about 50% to about 90%, 45 about 90%, about 70% to about 90%, about 80% to about about 60% to about 90%, about 70% to about 90%, about 80% 90%, about 25% to about 80%, about 50% to about 80%, to about 90%, about 25% to about 80%, about 50% to about about 60% to about 80%, about 70% to about 80%, about 25% 80%, about 60% to about 80%, about 70% to about 80%, to about 70%, about 50% to about 70%, about 25% to about about 25% to about 70%, about 50% to about 70%, about 25% 60%, about 50% to about 60%, or about 25% to about 50%. to about 60%, about 50% to about 60%, or about 25% to about 50 In another embodiment, atherapeutic compound disclosed 50% of the activity observed for 15dPGJ2. herein has an anti-inflammatory activity capable of stimulat The peroxisome proliferator-activated receptors (PPARs) ing a PPARY signaling pathway. A therapeutic compounds are a group of nuclear receptor proteins that function as tran disclosed herein may be capable of binding to all isoforms of Scription factors regulating the expression of genes. All PPAR-Y, or may be capable of selectively binding to either PPARs are known to heterodimerize with the retinoid X 55 PPAR-y1, PPAR-y2, PPAR-y3, or any combination of two receptor (RXR) and bind to specific regions on the DNA of thereof. In aspects of this embodiment, a therapeutic com target genes called peroxisome proliferator hormone pound disclosed herein stimulates a PPARY signaling path response elements (PPREs). PPARs play essential roles in the way by, e.g., at least 5%, at least 15%, at least 25%, at least regulation of cellular differentiation, development, and 50%, at least 60%, at least 70%, at least 80%, or at least 90%. metabolism (carbohydrate, lipid, protein), and tumorigenesis 60 In other aspects of this embodiment, a therapeutic compound of higher organisms. The family comprises three members, disclosed herein stimulates a PPARY signaling pathway in a PPAR-C, PPAR-Y, and PPAR-8 (also known as PPAR-B. range from, e.g., about 5% to about 100%, about 50% to about PPAR-C. is expressed in liver, kidney, heart, muscle, adipose 100%, about 60% to about 100%, about 70% to about 100%, tissue, as well as other tissues. PPAR-8 is expressed in many about 80% to about 100%, about 25% to about 90%, about tissues but markedly in brain, adipose tissue, and skin. 65 50% to about 90%, about 60% to about 90%, about 70% to PPAR-Y comprises three alternatively-spliced forms, each about 90%, about 80% to about 90%, about 25% to about with a different expression pattern. PPAR-Y1 is expressed in 80%, about 50% to about 80%, about 60% to about 80%, US 9,308,213 B2 11 12 about 70% to about 80%, about 25% to about 70%, about 50% therapeutic compound disclosed herein has an anti-inflam to about 70%, about 25% to about 60%, about 50% to about matory activity capable of increasing the levels of IL-10 60%, or about 25% to about 50%. released from a Th2 cell in a range from, e.g., about 5% to Macrophages are activated and polarized into distinct phe about 100%, about 10% to about 100%, about 20% to about notypes expressing unique cell Surface molecules and secret 5 100%, about 30% to about 100%, about 40% to about 100%, ing discrete sets of cytokines and chemokines. The classical about 50% to about 100%, about 60% to about 100%, about M1 phenotype Supports pro-inflammatory Th1 responses 70% to about 100%, about 80% to about 100%, about 10% to driven by cytokines Such as, e.g., Interleukin-6 (IL-6), IL-12 about 90%, about 20% to about 90%, about 30% to about and IL-23, while the alternate M2 phenotype is generally 90%, about 40% to about 90%, about 50% to about 90%, supportive of anti-inflammatory processes driven by IL-10. 10 about 60% to about 90%, about 70% to about 90%, about 10% M2 cells can be further classified into subsets, M2a, M2b, and to about 80%, about 20% to about 80%, about 30% to about M2c, based on the type of stimulation and the subsequent 80%, about 40% to about 80%, about 50% to about 80%, or expression of Surface molecules and cytokines. about 60% to about 80%, about 10% to about 70%, about 20% In yet another embodiment, a therapeutic compound dis to about 70%, about 30% to about 70%, about 40% to about closed herein has an anti-inflammatory activity capable of 15 70%, or about 50% to about 70%. promoting the resolving phenotypic change of M1 to M2. In In another aspect of this embodiment, a therapeutic com an aspect of this embodiment, a therapeutic compound dis pound disclosed herein has an anti-inflammatory activity closed herein has an anti-inflammatory activity capable of capable of reducing the levels of IFNY, TNF-C., IL-12, or a inducing apoptosis of Macrophage M1 cells. In another combination thereof released from a Th1 cell and increasing aspect of this embodiment, atherapeutic compound disclosed the levels of IL-10 released from a Th2 cell. In other aspects herein has an anti-inflammatory activity capable of promot of this embodiment, atherapeutic compound disclosed herein ing differentiation of Macrophage M2 cells. In yet another has an anti-inflammatory activity capable of reducing the aspect of this embodiment, atherapeutic compound disclosed levels of IFNY, TNF-C. IL-12, or a combination thereof herein has an anti-inflammatory activity capable of inducing released from a Th1 cellby, e.g., at least 10%, at least 15%, at apoptosis of Macrophage M1 cells and promoting differen 25 least 20%, at least 25%, at least 30%, at least 35%, at least tiation of Macrophage M2 cells. 40%, at least 45%, at least 50%, at least 55%, at least 60%, at In still another embodiment, a therapeutic compound dis least 65%, at least 70%, at least 75%, at least 80%, at least closed 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, atherapeutic compound disclosed herein has an 30 10%, at least 15%, at least 20%, at least 25%, at least 30%, at anti-inflammatory activity capable of reducing the levels of least 35%, at least 40%, at least 45%, at least 50%, at least Interferon-gamma (IFNY), Tumor necrosis factor-alpha 55%, at least 60%, at least 65%, at least 70%, at least 75%, at (TNF-C.), Interleukin-12 (IL-12), or a combination thereof least 80%, at least 85%, at least 90% or at least 95%. In yet released from a Th1 cell. In other aspects of this embodiment, other aspects of this embodiment, a therapeutic compound a therapeutic compound disclosed herein has an anti-inflam 35 disclosed herein has an anti-inflammatory activity capable of matory activity capable of reducing the levels of IFNY, TNF reducing the levels of IFNY, TNF-C., IL-12, or a combination C., IL-12, or a combination thereof released from a Th1 cell thereof released from a Th1 cell in a range from, e.g., about by, e.g., at least 10%, at least 20%, at least 30%, at least 40%, 5% to about 100%, about 10% to about 100%, about 20% to at least 50%, at least 60%, at least 70%, at least 80%, or at about 100%, about 30% to about 100%, about 40% to about least 90%. In yet other aspects of this embodiment, a thera 40 100%, about 50% to about 100%, about 60% to about 100%, peutic compound disclosed herein has an anti-inflammatory about 70% to about 100%, about 80% to about 100%, about activity capable of reducing the levels of IFNY, TNF-C. IL-12, 10% to about 90%, about 20% to about 90%, about 30% to or a combination thereof released from a Th1 cell in a range about 90%, about 40% to about 90%, about 50% to about from, e.g., about 5% to about 100%, about 10% to about 90%, about 60% to about 90%, about 70% to about 90%, 100%, about 20% to about 100%, about 30% to about 100%, 45 about 10% to about 80%, about 20% to about 80%, about 30% about 40% to about 100%, about 50% to about 100%, about to about 80%, about 40% to about 80%, about 50% to about 60% to about 100%, about 70% to about 100%, about 80% to 80%, or about 60% to about 80%, about 10% to about 70%, about 100%, about 10% to about 90%, about 20% to about about 20% to about 70%, about 30% to about 70%, about 40% 90%, about 30% to about 90%, about 40% to about 90%, to about 70%, or about 50% to about 70%, and capable of about 50% to about 90%, about 60% to about 90%, about 70% 50 increasing the levels of IL-10 released from a Th2 cell in a to about 90%, about 10% to about 80%, about 20% to about range from, e.g., about 10% to about 100%, about 20% to 80%, about 30% to about 80%, about 40% to about 80%, about 100%, about 30% to about 100%, about 40% to about about 50% to about 80%, or about 60% to about 80%, about 100%, about 50% to about 100%, about 60% to about 100%, 10% to about 70%, about 20% to about 70%, about 30% to about 70% to about 100%, about 80% to about 100%, about about 70%, about 40% to about 70%, or about 50% to about 55 10% to about 90%, about 20% to about 90%, about 30% to 70%. about 90%, about 40% to about 90%, about 50% to about In another aspect of this embodiment, a therapeutic com 90%, about 60% to about 90%, about 70% to about 90%, pound disclosed herein has an anti-inflammatory activity about 10% to about 80%, about 20% to about 80%, about 30% capable of increasing the levels of IL-10 released from a Th2 to about 80%, about 40% to about 80%, about 50% to about cell. In other aspects of this embodiment, a therapeutic com 60 80%, or about 60% to about 80%, about 10% to about 70%, pound disclosed herein has an anti-inflammatory activity about 20% to about 70%, about 30% to about 70%, about 40% capable of increasing the levels of IL-10 released from a Th2 to about 70%, or about 50% to about 70%. cell by, e.g., at least 10%, at least 15%, at least 20%, at least Atherapeutic compound disclosed herein may have a log P 25%, at least 30%, at least 35%, at least 40%, at least 45%, at value indicating that the compound is soluble in an organic least 50%, at least 55%, at least 60%, at least 65%, at least 65 solvent. As used herein, the term “log value” refers to the 70%, at least 75%, at least 80%, at least 85%, at least 90% or logarithm (base 10) of the partition coefficient (P) for a com at least 95%. In yet other aspects of this embodiment, a pound and is a measure of lipophilicity. Typically, P is defined US 9,308,213 B2 13 14 as the ratio of concentrations of a unionized compound in the aspects of this embodiment, a therapeutic compound dis two phases of a mixture of two immiscible solvents at equi closed herein may have a polar Surface area in the range of librium. Thus, log P=Log 10 (P), where P=solute in immis e.g., between 2.0 nm and 6.5 nm, between 2.0 nm and 6.0 cible solvent 1/solute in immiscible solvent 2. With regard nm, between 2.0 nm and 5.5 nm, between 2.0 nm and 5.0 to organic and aqueous phases, the log Pvalue of a compound nm, between 2.0 nm and 4.5 nm, between 2.5 nm and 6.5 is constant for any given pair of aqueous and organic Solvents, nm, between 2.5 nm and 6.0 nm, between 2.5 nm and 5.5 and its value can be determined empirically by one of several nm, between 2.5 nm 2 and 5.0 nm, or between 2.5 nm and phase-partitioning methods known to one skilled in the art 4.5 nm. including, e.g., a shake flask assay, a HPLC assay, and an A therapeutic compound disclosed herein may be a non interface between two immiscible electrolyte solutions 10 steroidal anti-inflammatory drug (NSAID). NSAIDs are a (ITIES) assay. large group of therapeutic compounds with analgesic, anti In aspects of this embodiment, a therapeutic compound inflammatory, and anti-pyretic properties. NSAIDs reduce disclosed herein may have a log P value indicating that the inflammation by blocking cyclooxygenase. NSAIDs include, compound is Substantially soluble in an organic solvent. In without limitation, Aceclofenac, Acemetacin, Actarit, aspects of this embodiment, a therapeutic compound dis 15 Alcofenac, Alminoprofen, Amfenac. Aloxipirin, Ami closed herein may have a log P value indicating that the nophenaZone, Antraphenine, Aspirin, AZapropaZone, Beno compound is, e.g., at least 50% soluble in an organic solvent, rilate, Benoxaprofen, Benzydamine. Butibufen, Celecoxib, at least 60% soluble in an organic solvent, at least 70% Chlorthenoxacin, Choline Salicylate, Clometacin, Dexketo soluble in an organic solvent, at least 80% soluble in an profen, Diclofenac, Diflunisal, EmorfaZone, Epirizole; Etod organic Solvent, or at least 90% soluble in an organic solvent. olac, Etoricoxib, Feclobuzone, Felbinac, Fenbufen, Fen In aspects of this embodiment, a therapeutic compound dis clofenac, Flurbiprofen, Glafenine, Hydroxylethyl salicylate, closed herein may have a log P value indicating that the Ibuprofen, Indometacin, Indoprofen, Ketoprofen, Ketorolac, compound is between, e.g., about 50% to about 100% soluble Lactyl phenetidin, Loxoprofen, Lumiracoxib, Mefenamic in an organic solvent, about 60% to about 100% soluble in an acid, Meloxicam, Metamizole, Metiazinic acid, Mofebuta organic solvent, about 70% to about 100% soluble in an 25 Zone, Mofezolac, Nabumetone, Naproxen, NifenaZone, organic solvent, about 80% to about 100% soluble in an Niflumic acid, Oxametacin, Phenacetin, PipebuZone, Prano organic solvent, or about 90% to about 100% soluble in an profen, Propyphenazone, ProquaZone, Protizinic acid, Rofe organic solvent. coxib, Salicylamide, Salsalate, Sulindac, Suprofen, Tiara In aspects of this embodiment, a therapeutic compound mide, Tinoridine, Tolfenamic acid, Valdecoxib, and disclosed herein may have a log P value of e.g., more than 30 Zomepirac. 1.1, more than 1.2, more than 1.4, more than 1.6, more than NSAIDs may be classified based on their chemical struc 1.8, more than 2.0, more than 2.2, more than 2.4, more than ture or mechanism of action. Non-limiting examples of 2.6, more than 2.8, more than 3.0, more than 3.2, more than NSAIDs include a salicylate derivative NSAID, a p-amino 3.4, or more than 3.6. In other aspects of this embodiment, a phenol derivative NSAID, a propionic acid derivative therapeutic compound disclosed herein may have a log P 35 NSAID, an acetic acid derivative NSAID, an enolic acid value in the range of, e.g., between 1.8 and 4.0, between 2.0 derivative NSAID, a fenamic acid derivative NSAID, a non and 4.0, between 2.1 and 4.0, between 2.2 and 4.0, or between selective cyclo-oxygenase (COX) inhibitor, a selective 2.3 and 4.0, between 2.4 and 4.0, between 2.5 and 4.0, cyclooxygenase 1 (COX 1) inhibitor, and a selective between 2.6 and 4.0, or between 2.8 and 4.0. In other aspects cyclooxygenase 2 (COX 2) inhibitor. A NSAID may be a of this embodiment, atherapeutic compound disclosed herein 40 profen. Examples of a suitable salicylate derivative NSAID may have a log Pvalue in the range of, e.g., between 3.0 and include, without limitation, Acetylsalicylic acid (asprin), 4.0, or between 3.1 and 4.0, between 3.2 and 4.0, between 3.3 Diflunisal, and Salsalate. Examples of a suitable p-amino and 4.0, between 3.4 and 4.0, between 3.5 and 4.0, or between phenol derivative NSAID include, without limitation, Parac 3.6 and 4.0. In still other aspects of this embodiment, a thera etamol and Phenacetin. Examples of a suitable propionic acid peutic compound disclosed herein may have a log Pvalue in 45 derivative NSAID include, without limitation, Alminoprofen, the range of, e.g., between 2.0 and 2.5, between 2.0 and 2.7, Benoxaprofen, Dexketoprofen, Fenoprofen, Flurbiprofen, between 2.0 and 3.0, or between 2.2 and 2.5. Ibuprofen, Indoprofen, Ketoprofen, Loxoprofen, Naproxen, Atherapeutic compound disclosed herein may have apolar Oxaprozin, Pranoprofen, and Suprofen. Examples of a suit surface area that is hydrophobic. As used herein, the term able acetic acid derivative NSAID include, without limita “polar surface area” refers to the surface sum over all of the 50 tion, Aceclofenac, Acemetacin, Actarit, Alcofenac, Amfenac, polar atoms in the structure of a compound and is a measure Clometacin, Diclofenac, Etodolac, Felbinac, Fenclofenac, of hydrophobicity. Typically, these polar atoms include, e.g., Indometacin, Ketorolac, Metiazinic acid, Mofezolac, Nabu oxygen, nitrogen, and their attached hydrogens. In aspects of metone, Naproxen, Oxametacin, Sulindac, and Zomepirac. this embodiment, a therapeutic compound disclosed herein Examples of a suitable enolic acid (Oxicam) derivative may have a polar surface area of e.g., less than 8.0 nm, less 55 NSAID include, without limitation, Droxicam, Isoxicam, than 7.0 nm, less than 6.0 nm, less than 5.0 nm, less than Lornoxicam, Meloxicam, Piroxicam, and Tenoxicam. 4.0 nm, or less than 3.0 nm. In other aspects of this embodi Examples of a suitable fenamic acid derivative NSAID ment, a therapeutic compound disclosed herein may have a include, without limitation, Flufenamic acid, Mefenamic polar surface area in the range of e.g., between 3.0 nm and acid, Meclofenamic acid, and Tolfenamic acid. Examples of 6.5 nm, between 3.0 nm and 6.0 nm, between 3.0 nm and 60 a suitable selective COX-2 inhibitors include, without limi 5.5 nm, between 3.0 nm and 5.0 nm, between 3.0 nm and tation, Celecoxib, Etoricoxib, Firocoxib, Lumiracoxib, 4.5 nm, between 3.5 nm and 6.5 nm, between 3.5 nm and Meloxicam, Paracetamol (Acetaminophen), Parecoxib, 6.0 nm, between 3.5 nm and 5.5 nm, between 3.5 nm and Rofecoxib, and Valdecoxib. 5.0 nm, between 3.5 nm and 4.5 nm, between 4.0 nm and Atherapeutic compound disclosed herein may be a PPARC. 6.5 nm, between 4.0 nm and 6.0 nm, between 4.0 nm and 65 agonist. Examples of a suitable PPARC. agonist include, with 5.5 nm, or between 4.0 nm and 5.0 nm, between 4.0 nm. out limitation, Pirinixic (WY 14643), GW6471, and a and 4.5 nm, or between 4.5 nm and 5.5 nm. In yet other Fibrate. US 9,308,213 B2 15 16 A therapeutic compound disclosed herein may be a Prinivil/Zestril), Benazepril (Lotensin), Imidapril (Tanatril), PPARB/ö agonist. Examples of a suitable PPARB/ö agonist Zofenopril (Zofecard), and Trandolapril (Mavik/Odrik/ include, without limitation, Tetradecylthioacetic acid (TTA). Gopten). A Phosphonate-containing agent includes Fosino GSK0660, GSK3787, GW501516 (GW-501,516, GW 1516, pril (Fositen/Monopril). GSK-516 and Endurobol), GW0742, and GW610742X. A therapeutic compound disclosed herein may be a Phos Atherapeutic compound disclosed herein may be a PPARY phodiesterase inhibitor. Examples of a suitable Phosphodi agonist. Examples of a suitable PPARYagonist include, with esterase inhibitor include, without limitation, a PDE 1 selec out limitation, Monascin, a Thiazolidinediones like Rosigli tive inhibitor, a PDE 2 selective inhibitor, a PDE 3 selective taZone, Pioglitazone, and Troglitazone and T0070907. Other inhibitor, a PDE 4 selective inhibitor, a PDE 5 selective suitable PPARY agonists are described in Masson and Cau 10 inhibitor, and a PDE 10 selective inhibitor. A PDE1 selective mont-Bertrand, PPAR Agonist Compounds, Preparation and inhibitor includes Vinpocetine. A PDE2 selective inhibitor Uses, US 2011/0195993, which is hereby incorporated by includes BAY 60-7550 (2-(3,4-dimethoxyphenyl)methyl reference in its entirety. 7-(1R)-1-hydroxyethyl-4-phenylbutyl-5-methyl-imidazo A therapeutic compound disclosed herein may be a Gli 5,1-f1.2.4 triazin-4(1H)-one), EHNA (erythro-9-(2-hy tazar (a duel C. and Y PPAR agonist). Examples of a suitable 15 droxy-3-nonyl)adenine), Oxindole, and PDP (9-(6-Phenyl-2- Glitazar include, without limitation, Aleglitazar, Muragli oxohex-3-yl)-2-(3,4-dimethoxybenzyl)-purin-6-one). A tazar, Saroglitazar, and Tesaglitazar. PDE3 selective inhibitor includes Anagrelide, Cilostazol, A therapeutic compound disclosed herein may be an Enoximone, Inaminone, and Millrinone. A PDE4 selective immunosupressive drug. Examples of a Suitable immunosu inhibitor includes Drotaverine, Ibudilast, Luteolin, Mesem pressive drug include, without limitation, AZathioprine and brine, Piclamilast, Roflumilast, and Rolipram. A PDE5 selec Mycophenolic acid. tive inhibitor includes Avanafil. Dipyridamole, Icariin, 4-Me A therapeutic compound disclosed herein may be an uri thylpiperazine, Pyrazolo Pyrimidin-7-1, Sildenafil. Tadalafil. coSuric drug. Examples of a Suitable uricoSuric drug include, Udenafil, and Vardenafil. A PDE10 selective inhibitor without limitation, BenZbromarone. includes Papaverine. Atherapeutic compound disclosed herein may be an Agly 25 Atherapeutic compound disclosed herein may be a fibrate. cone. Examples of a Suitable Aglycone drug include, without Fibrates area class of amphipathic carboxylic acids with lipid limitation, Piceatannol, Pinosylvin, Pterostilbene, and Res level modifying properties. These therapeutic compounds are Veratrol. used for a range of metabolic disorders. One non-limiting use A therapeutic compound disclosed herein may be a Can is as an anti-hyperlipidemic agent where it may lower levels nabidiol. Examples of a suitable uricosuric drug include, 30 of e.g., triglycerides and LDL as well as increase levels of without limitation, a Phytocannabinoid, an Endocannab HDL. Examples of a suitable fibrate include, without limita inoid, and a synthetic cannabinoid. A Phytocannabinoid tion, Bezafibrate, Ciprofibrate, Clofibrate, Gemfibrozil, and includes a Tetrahydrocannabinol (Such as, e.g., Delta-9-tet Fenofibrate. rahydrocannabinol (A9-THC, THC), and Delta-8-tetrahydro A therapeutic compound disclosed herein may be a statin. cannabinol (A8-THC)), a Cannabidiol, a Cannabinol, a Can 35 Statins (or HMG-CoA reductase inhibitors) are a class of nabigerol, a Tetrahydrocannabivarin, a Cannabidivarin, and a therapeutic compounds used to lower LDL and/or cholesterol Cannabichromene. An Endocannabinoid includes Arachi levels by inhibiting the enzyme HMG-CoA reductase, which donoylethanolamine (Anandamide or AEA), 2-arachidonoyl plays a central role in the production of cholesterol in the glycerol (2-AG), 2-arachidonyl glyceryl ether (noladin liver. To compensate for the decreased cholesterol availabil ether), N-arachidonoyl-dopamine (NADA), Virodhamine 40 ity, synthesis of hepatic LDL receptors is increased, resulting (OAE), and Lysophosphatidylinositol (LPI). A synthetic can in an increased clearance of LDL particles from the blood. nabinoid includes Dronabinol (Marinol), Nabilone (Cesa Examples of a suitable statin include, without limitation, met), Sativex, Rimonabant (SR141716), JWH-018, JWH Atorvastatin, Fluvastatin, Lovastatin, Pitavastatin, Pravasta 073, CP-55940, Dimethylheptylpyran, HU-210, HU-331, tin, Rosuvastatin, and Simvastatin. SR 144528, WIN 55,212-2, JWH-133, Levonantradol (Nant 45 A therapeutic compound disclosed herein may be a tocot rodolum), and AM-2201. rienol. Tocotrienols are another class of HMG-CoA reductase Atherapeutic compound disclosed herein may be a nuclear inhibitors and may be used to lower LDL and/or cholesterol receptor binding agent. Examples of a suitable nuclear recep levels by inducing hepatic LDL receptor up-regulation and/or tor binding agent include, without limitation, a Retinoic Acid decreasing plasma LDL levels. Examples of a suitable tocot Receptor (RAR) binding agent, a Retinoid XReceptor (RXR) 50 rienol include, without limitation, a Y-tocotrienol and a 6-to binding agent, a Liver X Receptor (LXR) binding agent and a cotrienol. Vitamin D binding agent. A therapeutic compound disclosed herein may be a niacin. A therapeutic compound disclosed herein may be an Niacins are a class of therapeutic compounds with lipid level Angiotensin II receptor antagonist. Examples of a Suitable modifying properties. For example, a niacin may lower LDL Angiotensin II receptor antagonist include, without limita 55 by selectively inhibiting hepatic diacy glycerol acyltrans tion, AZilsartan, Candesartan, Eprosartan, Irbesartan, Losar ferase 2, reduce triglyceride synthesis, and VLDL secretion tan, Olmesartan, Telmisartan, and Valsartan. through a receptor HM74 and HM74A or GPR109A. These A therapeutic compound disclosed herein may be an Ace therapeutic compounds are used for a range of metabolic tylcholinesterase (ACE) inhibitor. Examples of a suitable disorders. One non-limiting use is as an anti-hyperlipidemic ACE inhibitor include, without limitation, a Sulfhydryl-con 60 agent where it may inhibit the breakdown of fats in adipose taining agent, a Dicarboxylate-containing agent, a Phospho tissue. Because a niacin blocks the breakdown of fats, it nate-containing agent, a Casokinin, and a Lactokinin. A Sulf causes a decrease in free fatty acids in the blood and, as a hydryl-containing agent includes Captopril (Capoten) and consequence, decreases the secretion of very-low-density Zofenopril. A Dicarboxylate-containing agent includes lipoproteins (VLDL) and cholesterol by the liver. By lower Enalapril (Vasotec/Renitec), Ramipril (Altace/Prilace/Ra 65 ing VLDL levels, a niacin may also increase the level of HDL mace/Ramiwin/Triatec/Tritace), Quinapril (Accupril), Perin in blood. Examples of a suitable niacin include, without limi dopril (Coversyl/Aceon), Lisinopril (Listril/Lopril/Novatec/ tation, Acipimox, Niacin, Nicotinamide, and Vitamin B3. US 9,308,213 B2 17 18 A therapeutic compound disclosed herein may be a bile Atherapeutic compound disclosed herein may be a Ryano acid sequestrant. Bile acid sequestrants (also known as resins) dine receptor antagonist. Examples of a Ryanodine receptor are a class of therapeutic compounds used to bind certain antagonist include, without limitation, AZumolene and Dan components of bile in the gastrointestinal tract. They disrupt trolene. the enterohepatic circulation of bile acids by sequestering A therapeutic compound disclosed herein may be a cancer them and preventing their reabsorption from the gut. Bile acid drug. Examples of a suitable cancer drug include, without sequestrants are particularly effective for lowering LDL and limitation, an alkylating agent, an anti-metabolite, a plant cholesterol by sequestering the cholesterol-containing bile alkaloid and terpenoid, a topoisomerase inhibitor and a cyto acids released into the intestine and preventing their reabsorp toxic antibiotic. An alkylating agent includes Carboplatin, tion from the intestine. In addition, a bile acid sequestrant 10 Chlorambucil, Cisplatin, Cyclophosphamide, Ifosfamide, may also raise HDL levels. Examples of a suitable bile acid Oxaliplatin, and Mechlorethamine. An anti-metabolite sequestrant include, without limitation, Cholestyramine, includes Azathioprine and Mercaptopurine. A plant alkaloid Colesevelam, and Colestipol. and terpenoid include a Vinca alkaloid like Vincristine, Vin A therapeutic compound disclosed herein may be a cho 15 blastine, Vinorelbine, and Vindesine, a Podophyllotoxin like lesterol absorption inhibitor. Cholesterol absorption inhibi Etoposide and Teniposide, and a Taxane like Docetaxel and tors are a class of therapeutic compounds that inhibits the Ortataxel. A Topoisomerase inhibitor includes a Type I topoi absorption of cholesterol from the intestine. Decreased cho Somerase inhibitor like a Camptothecins, such as, e.g., Exate lesterol absorption leads to an upregulation of LDL-receptors can, Irinotecan, Lurtotecan, Topotecan, BNP 1350. CKD 602, on the surface of cells and an increased LDL-cholesterol DB 67 (AR67), and ST 1481, and a Type II inhibitor like an uptake into these cells, thus decreasing levels of LDL in the Epipodophyllotoxin Such as, e.g., Amsacrine, Etoposid, Eto blood plasma. Examples of a suitable cholesterol absorption poside phosphate, and Teniposide. A Cytotoxic antibiotic inhibitor include, without limitation, Ezetimibe, a phy includes an Actinomycin like Actinomycin D. Bacitracin, tosterol, a sterol and a stenol. Colistin (polymyxin E), and Polymyxin B, an Anthracenedi A therapeutic compound disclosed herein may be a fat 25 one like Mitoxantrone and Pixantrone, and a Anthracycline absorption inhibitor. Fat absorption inhibitors are a class of like Bleomycin, Doxorubicin (Adriamycin), Daunorubicin therapeutic compounds that inhibits the absorption of fat (Daunomycin), Epirubicin, Idarubicin, Mitomycin, Plicamy from the intestine. Decreased fat absorption reduces caloric cin, and Valrubicin. intake. In one aspect, a fat absorption inhibitor inhibits pan A therapeutic compound disclosed herein may be Met 30 formin, Curcumin, glycyrrhetinic acid, or 6-shogaol. creatic lipase, an enzyme that breaks down triglycerides in the A therapeutic compound disclosed herein may be an anti intestine. Examples of a suitable fat absorption inhibitor biotic. Examples of a suitable sympathomimetic amine include, without limitation, Orlistat. include, without limitation, Isoniazid, Rifampicin, PyraZina A therapeutic compound disclosed herein may be a sym mide, and Ethambutol. pathomimetic amine. Sympathomimetic amines area class of 35 A therapeutic compound disclosed herein may be an anti therapeutic compounds that mimic the effects of transmitter helmintic drug. Examples of a Suitable anti-helmintic drug Substances of the sympathetic nervous system Such as cat include, without limitation, Abamectin, an Aminoacetonitrile echolamines, epinephrine (adrenaline), norepinephrine (no like Monepantel, a Benzimidazole, Diethylcarbamazine, radrenaline), and/or dopamine. A sympathomimetic amine Ivermectin, Levamisole, Niclosamide, an Octadepsipeptide may act as an O-adrenergic agonist, a f-adrenergic agonist, a 40 like Emodepside, Phosphonic acid (Metrifonate), Praziquan dopaminergic agonist, a monoamine oxidase (MAO) inhibi tel, a Spiroindole like Derquantel, and Suramin Pyrantel tor, and a COMT inhibitor. Such therapeutic compounds, pamoate. A Benzimidazole includes Albendazole, Fenbenda among other things, are used to treat cardiac arrest, low blood Zole, Flubendazole, Mebendazole. Thiabendazole, and Tri pressure, or even delay premature labor. Examples of a Suit clabendazole. able sympathomimetic amine include, without limitation, 45 A therapeutic compound disclosed herein may be an anti Clenbuterol, Salbutamol, ephedrine, pseudoephedrine, meth malaria drug. Examples of a suitable anti-malaria drug amphetamine, amphetamine, phenylephrine, isoproterenol, include, without limitation, Amodiaquine, an Artemisinin, dobutamine, methylphenidate, lisdexamfetamine, cathine, Atovaquone, Chloroquine, Clindamycin, Doxycycline, Halo cathinone, methcathinone, cocaine, benzylpiperazine (BZP), fantrine, Mefloquine, Primaquine, Proguanil, methylenedioxypyrovalerone (MDPV), 4-methylaminorex, 50 Pyrimethamine, a Quinine and related agent like Quinimax pemoline, phenmetrazine, and propylhexedrine. An O-adren and Quinidine, Rufigallol, and a Sulfonamide like Sulfadox ergic agonist includes Phenylephrine, Propylhexedrine, and ine and Sulfamethoxypyridazine. An Artemisinin includes Pseudoephedrine. A B-adrenergic agonist includes Clen Arteether, Artemether, Artemisinin, Artesunate, and Dihy buterol, Dobutamine, Eephedrine, Isoproterenol, and Salb droartemisinin. 55 A therapeutic compound disclosed herein may be an anti utamol. A Dopaminergic/Norepinephrinergic agonist hyperlipidemic agent. There are several classes of anti-hyper includes Cocaine (DA/NE reuptake inhibitor), Lisdexamfe lipidemic agents (also known as hypolipidemic agents). They tamine (5HT/DA/NE reuptake inhibitor), Methylphenidate may differ in both their impact on the cholesterol profile and (DA/NE reuptake inhibitor), and Methylenedioxypyrovale adverse effects. For example, some may lower low density rone (DA/NE reuptake inhibitor). A Neurotransmitter releas 60 lipoprotein (LDL), while others may preferentially increase ing agent includes Amphetamine (DA/NE releasing agent), high density lipoprotein (HDL). Clinically, the choice of an Benzylpiperazine (DA/NE releasing agent), Cathine (DA/NE agent will depend on the cholesterol profile of an individual, releasing agent), Cathinone (DA/NE releasing agent), Meth cardiovascular risk of an individual, and/or the liver and kid amphetamine (DA/NE releasing agent), Methcathinone (DA/ ney functions of an individual. Examples of a suitable anti NE releasing agent), 4-methylaminorex (DA/NE releasing 65 hyperlipidemic agent include, without limitation, an Angio agent), Pemoline, Phenmetrazine (DA/NE releasing agent), tensin II receptor antagonist, an ACE inhibitor, a and Phenethylamine (DA/NE releasing agent). Phosphodiesterase inhibitor, a Fibrate, a Statin, a Tocotrienol, US 9,308,213 B2 19 20 a Niacin, a bile acid sequestrants (resin), a cholesterol absorp In other aspects of this embodiment, a pharmaceutical tion inhibitor, a pancreatic lipase inhibitor, and a sympatho composition disclosed herein may comprise a therapeutic mimetic amine. compound in an amount of, e.g., less than about 90% by A therapeutic compound disclosed herein may be an ester weight, less than about 80% by weight, less than about 70% of a therapeutic compound. An ester of a therapeutic com 5 by weight, less than about 65% by weight, less than about pound increases the log Pvalue relative to the same therapeu 60% by weight, less than about 55% by weight, less than tic compound, but without the ester modification. An ester about 50% by weight, less than about 45% by weight, less group may be attached to a therapeutic compoundby, e.g., a than about 40% by weight, less than about 35% by weight, carboxylic acid or hydroxyl functional group present of the less than about 30% by weight, less than about 25% by therapeutic compound. An ester of a therapeutic compound 10 weight, less than about 20% by weight, less than about 15% may have an increased hydrophobicity, and as such, may be by weight, less than about 10% by weight, less than about 5% dissolved in a reduced volume of solvent disclosed herein. In by weight, or less than about 1% by weight. In other aspects Some instances, an ester of a therapeutic compound may be of this embodiment, a pharmaceutical composition disclosed combined directly with an adjuvant disclosed herein, thereby herein may comprise a therapeutic compound in an amount eliminating the need of a solvent. An ester of a therapeutic 15 of, e.g., about 1% to 90% by weight, about 1% to 80% by compound may enable the making of a pharmaceutical com weight, about 1% to 75% by weight, about 1% to 70% by position disclosed herein, in situations where a non-esterified weight, about 1% to 65% by weight, about 1% to 60% by form of the same therapeutic compound is otherwise immis weight, about 1% to 55% by weight, about 1% to 50% by cible in a solvent disclosed herein. An ester of a therapeutic weight, about 1% to 45% by weight, about 1% to 40% by compound may still be delivered in a manner that more effec weight, about 1% to 35% by weight, about 1% to 30% by tively inhibits a pro-inflammatory response as long as the weight, about 1% to 25% by weight, about 1% to 20% by compound is combined with an adjuvant disclosed herein. In weight, about 1% to 15% by weight, about 1% to 10% by one embodiment, a therapeutic compound may be reacted weight, about 1% to 5% by weight, about 2% to 50% by with ethyl ester in order to form an ethyl ester of the thera weight, about 2% to 40% by weight, about 2% to 30% by peutic compound. 25 weight, about 2% to 20% by weight, about 2% to 10% by A solid solution pharmaceutical composition disclosed weight, about 4% to 50% by weight, about 4% to 40% by herein may comprise a therapeutic compound in an amount weight, about 4% to 30% by weight, about 4% to 20% by Sufficient to allow customary administration to an individual. weight, about 4% to 10% by weight, about 6% to 50% by In aspects of this embodiment, a pharmaceutical composition weight, about 6% to 40% by weight, about 6% to 30% by disclosed herein may comprise a therapeutic compound in an 30 weight, about 6% to 20% by weight, about 6% to 10% by amount of, e.g., at least 5 mg, at least 10 mg, at least 15 mg. weight, about 8% to 50% by weight, about 8% to 40% by at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg. weight, about 8% to 30% by weight, about 8% to 20% by at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg. weight, about 8% to 15% by weight, or about 8% to 12% by at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg. weight. at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg. 35 In other aspects of this embodiment, a pharmaceutical or at least 100 mg. In other aspects of this embodiment, a composition disclosed herein may comprise a therapeutic pharmaceutical composition disclosed herein may comprise a compound in an amount of, e.g., about 0.1% to about 45% by therapeutic compound in an amount of, e.g., at least 5 mg, at weight, about 0.1% to about 40% by weight, about 0.1% to least 10 mg, at least 20 mg, at least 25 mg, at least 50 mg, at about 35% by weight, about 0.1% to about 30% by weight, least 75 mg, at least 100 mg, at least 200 mg, at least 300 mg. 40 about 0.1% to about 25% by weight, about 0.1% to about 20% at least 400 mg, at least 500 mg, at least 600 mg, at least 700 by weight, about 0.1% to about 15% by weight, about 0.1% to mg, at least 800 mg, at least 900 mg, at least 1,000 mg, at least about 10% by weight, about 0.1% to about 5% by weight, 1,100 mg, at least 1,200 mg, at least 1,300 mg, at least 1,400 about 1% to about 45% by weight, about 1% to about 40% by mg, or at least 1,500 mg. In yet other aspects of this embodi weight, about 1% to about 35% by weight, about 1% to about ment, a pharmaceutical composition disclosed herein may 45 30% by weight, about 1% to about 25% by weight, about 1% comprise atherapeutic compound in an amount of, e.g., about to about 20% by weight, about 1% to about 15% by weight, 5 mg to about 100 mg, about 10 mg to about 100 mg, about 50 about 1% to about 10% by weight, about 1% to about 5% by mg to about 150 mg, about 100 mg to about 250 mg, about weight, about 5% to about 45% by weight, about 5% to about 150 mg to about 350 mg, about 250 mg to about 500 mg. 40% by weight, about 5% to about 35% by weight, about 5% about 350 mg to about 600 mg, about 500 mg to about 750 50 to about 30% by weight, about 5% to about 25% by weight, mg, about 600 mg to about 900 mg, about 750 mg to about about 5% to about 20% by weight, about 5% to about 15% by 1,000 mg, about 850 mg to about 1,200 mg. or about 1,000 mg weight, about 5% to about 10% by weight, about 10% to to about 1,500 mg. In still other aspects of this embodiment, about 45% by weight, about 10% to about 40% by weight, a pharmaceutical composition disclosed herein may comprise about 10% to about 35% by weight, about 10% to about 30% atherapeutic compound in an amount of, e.g., about 10 mg to 55 by weight, about 10% to about 25% by weight, about 10% to about 250 mg, about 10 mg to about 500 mg, about 10 mg to about 20% by weight, about 10% to about 15% by weight, about 750 mg, about 10 mg to about 1,000 mg, about 10 mg about 15% to about 45% by weight, about 15% to about 40% to about 1,500 mg, about 50 mg to about 250 mg, about 50 mg by weight, about 15% to about 35% by weight, about 15% to to about 500 mg, about 50 mg to about 750 mg, about 50 mg about 30% by weight, about 15% to about 25% by weight, to about 1,000 mg, about 50 mg to about 1,500 mg, about 100 60 about 15% to about 20% by weight, about 20% to about 45% mg to about 250 mg, about 100 mg to about 500 mg, about by weight, about 20% to about 40% by weight, about 20% to 100 mg to about 750 mg, about 100 mg to about 1,000 mg. about 35% by weight, about 20% to about 30% by weight, about 100 mg to about 1,500 mg, about 200 mg to about 500 about 20% to about 25% by weight, about 25% to about 45% mg, about 200 mg to about 750 mg, about 200 mg to about by weight, about 25% to about 40% by weight, about 25% to 1,000 mg, about 200 mg to about 1,500 mg, about 5 mg to 65 about 35% by weight, or about 25% to about 30% by weight. about 1,500 mg, about 5 mg to about 1,000 mg. or about 5 mg The final concentration of a therapeutic compound dis to about 250 mg. closed herein in a pharmaceutical composition disclosed US 9,308,213 B2 21 22 herein may be of any concentration desired. In an aspect of typically between 4 and 24 carbons, and may be attached to this embodiment, the final concentration of a therapeutic functional groups containing oxygen, halogens, nitrogen, and compound in a pharmaceutical composition may be a thera Sulfur. Synthetic or non-natural fatty acids may have a hydro peutically effective amount. In other aspects of this embodi carbon chain of any number of carbon atoms from between 3 ment, the final concentration of a therapeutic compound in a and 40 carbons. Where a double bond exists, there is the pharmaceutical composition may be, e.g., at least 0.00001 possibility of either a cis or a trans geometric isomerism, mg/mL, at least 0.0001 mg/mL, at least 0.001 mg/mL, at least which significantly affects the molecule's molecular configu 0.01 mg/mL, at least 0.1 mg/mL, at least 1 mg/mL, at least 10 ration. Cis-double bonds cause the fatty acid chain to bend, an mg/mL, at least 25 mg/mL, at least 50 mg/mL, at least 100 effect that is more pronounced the more double bonds there mg/mL, at least 200 mg/mL, at least 500 mg/mL, at least 700 10 are in a chain. Most naturally occurring fatty acids are of the mg/mL, at least 1,000 mg/mL, or at least 1,200 mg/mL. In cis configuration, although the trans form does exist in some other aspects of this embodiment, the concentration of a natural and partially hydrogenated fats and oils. Examples of therapeutic compound disclosed herein in the Solution may fatty acids include, without limitation, Capryllic acid (8:0), be, e.g., at most 1,000 mg/mL, at most 1,100 mg/mL, at most Pelargonic acid (9:0), Capric acid (10:0), Undecylic acid 1,200 mg/mL, at most 1,300 mg/mL, at most 1,400 mg/mL, at 15 (11:0), Lauric acid (12:0), Tridecylic acid (13:0), Myristic most 1,500 mg/mL, at most 2,000 mg/mL, at most 2,000 acid (14:0), Myristoleic acid (14:1), Pentadecyclic acid (15: mg/mL, or at most 3,000 mg/mL. In other aspects of this O), Palmitic acid (16:0), Palmitoleic acid (16:1), Sapienic acid embodiment, the final concentration of a therapeutic com (16:1), Margaric acid (17:0), Stearic acid (18:0), Oleic acid pound in a pharmaceutical composition may be in a range of (18:1), Elaidic acid (18:1), Vaccenic acid (18:1), Linoleic acid e.g., about 0.00001 mg/mL to about 3,000 mg/mL, about (18:2), Linoelaidic acid (18:2), C-Linolenic acid (18:3), Y-Li 0.0001 mg/mL to about 3,000 mg/mL, about 0.01 mg/mL to nolenic acid (18:3), Stearidonic acid (18:4). Nonadecylic acid about 3,000 mg/mL, about 0.1 mg/mL to about 3,000 mg/mL, (19:0), Arachidic acid (20:0), Eicosenoic acid (20:1), about 1 mg/mL to about 3,000 mg/mL, about 250 mg/mL to Dihomo-y-linolenic acid (20:3), Mead acid (20:3), Arachi about 3,000 mg/mL, about 500 mg/mL to about 3,000 donic acid (20:4), Eicosapentaenoic acid (20:5), Heneico mg/mL, about 750 mg/mL to about 3,000 mg/mL, about 25 sylic acid (21:0), Behenic acid (22:0), Erucic acid (22:1). 1,000 mg/mL to about 3,000 mg/mL, about 100 mg/mL to Docosahexaenoic acid (22:6), Tricosylic acid (23:0), Ligno about 2,000 mg/mL, about 250 mg/mL to about 2,000 ceric acid (24:0), Nervonic acid (24:1), Pentacosylic acid mg/mL, about 500 mg/mL to about 2,000 mg/mL, about 750 (25:0), Cerotic acid (26:0), Heptacosylic acid (27:0), Mon mg/mL to about 2,000 mg/mL, about 1,000 mg/mL to about tanic acid (28:0). Nonacosylic acid (29:0), Melissic acid (30: 2,000 mg/mL, about 100 mg/mL to about 1,500 mg/mL, 30 O), Henatriacontylic acid (31:0), Lacceroic acid (32:0), Psyl about 250 mg/mL to about 1,500 mg/mL, about 500 mg/mL lic acid (33:0), Geddic acid (34:0). Ceroplastic acid (35:0), to about 1,500 mg/mL, about 750 mg/mL to about 1,500 and Hexatriacontylic acid (36:0). mg/mL, about 1,000 mg/mL to about 1,500 mg/mL, about In an embodiment, a lipid may be a pharmaceutically 100 mg/mL to about 1,200 mg/mL, about 250 mg/mL to acceptable Saturated or unsaturated fatty acid. In aspects of about 1,200 mg/mL, about 500 mg/mL to about 1,200 35 this embodiment, a Saturated or unsaturated fatty acid com mg/mL, about 750 mg/mL to about 1,200 mg/mL, about prises, e.g., at least 8, at least 10, at least 12, at least 14, at least 1,000 mg/mL to about 1,200 mg/mL, about 100 mg/mL to 16, at least 18, at least 20, at least 22, at least 24, at least 26, about 1,000 mg/mL, about 250 mg/mL to about 1,000 at least 28, or at least 30 carbonatoms. In other aspects of this mg/mL, about 500 mg/mL to about 1,000 mg/mL, about 750 embodiment, a saturated or unsaturated fatty acid comprises, mg/mL to about 1,000 mg/mL, about 100 mg/mL to about 40 e.g., between 4 and 24 carbonatoms, between 6 and 24 carbon 750 mg/mL, about 250 mg/mL to about 750 mg/mL, about atoms, between 8 and 24 carbon atoms, between 10 and 24 500 mg/mL to about 750 mg/mL, about 100 mg/mL to about carbon atoms, between 12 and 24 carbon atoms, between 14 500 mg/mL, about 250 mg/mL to about 500 mg/mL, about and 24 carbon atoms, or between 16 and 24 carbon atoms, 0.00001 mg/mL to about 0.0001 mg/mL, about 0.00001 between 4 and 22 carbon atoms, between 6 and 22 carbon mg/mL to about 0.001 mg/mL, about 0.00001 mg/mL to 45 atoms, between 8 and 22 carbon atoms, between 10 and 22 about 0.01 mg/mL, about 0.00001 mg/mL to about 0.1 carbon atoms, between 12 and 22 carbon atoms, between 14 mg/mL, about 0.00001 mg/mL to about 1 mg/mL, about and 22 carbon atoms, or between 16 and 22 carbon atoms, 0.001 mg/mL to about 0.01 mg/mL, about 0.001 mg/mL to between 4 and 20 carbon atoms, between 6 and 20 carbon about 0.1 mg/mL, about 0.001 mg/mL to about 1 mg/mL, atoms, between 8 and 20 carbon atoms, between 10 and 20 about 0.001 mg/mL to about 10 mg/mL, or about 0.001 50 carbon atoms, between 12 and 20 carbon atoms, between 14 mg/mL to about 100 mg/mL. and 20 carbonatoms, or between 16 and 20 carbon atoms. If Aspects of the present specification disclose, in part, one or unsaturated, the fatty acid may have, e.g., 1 or more, 2 or more lipids. A lipid may be broadly defined as a hydrophobic more, 3 or more, 4 or more, 5 or more, or 6 or more double or amphiphilic small molecule. The amphiphilic nature of bonds. Some lipids allows them to form structures such as vesicles, 55 A lipid useful in the pharmaceutical compositions dis liposomes, or membranes in an aqueous environment. Non closed herein may be a pharmaceutically-acceptable hard fat. limiting examples, of lipids include fatty acids, glycerolipids, Also known as a “solid fat', room temperature solid lipid', or phospholipids, sphingolipids, sterol lipids, prenol lipids, sac simply “fat', a hard fat includes any fatty acid that is solid at charolipids, and polyketides. normal room temperature. Such as, e.g. about 20° C. Fats A lipid useful in the pharmaceutical compositions dis 60 consist of a wide group of compounds that are generally closed herein may be a pharmaceutically-acceptable fatty soluble in organic solvents and generally insoluble in water. acid. A fatty acid comprises a carboxylic acid with a long Examples of mixtures of pharmaceutically-acceptable hard unbranched hydrocarbon chain which may be either saturated fats include, without limitation, a mixture of one or more or unsaturated. Thus arrangement confers a fatty acid with a glycerolipids disclosed herein, a mixture of one or more polar, hydrophilic end, and a nonpolar, hydrophobic end that 65 glycol fatty acid esters disclosed herein, a mixture of more is insoluble in water. Most naturally occurring fatty acids polyether fatty acid esters disclosed herein, a mixture of more have a hydrocarbon chain of an even number of carbonatoms, glycerides disclosed herein. US 9,308,213 B2 23 24 A hard fat useful in the pharmaceutical compositions dis about 45° C., about 30° C. to about 46° C., about 30° C. tO closed herein may be a pharmaceutically-acceptable glycero about 47°C., about 30° C. to about 48°C., about 30° C. tO lipid. Glycerolipids are composed mainly of mono-, di-, and about 49° C., about 30° C. to about 50° C., about 32° C. tO tri-Substituted glycerols. One group of glycerolipids is the about 44° C., about 32° C. to about 45° C., about 32° C. tO glycerides, where one, two, or all three hydroxyl groups of 5 about 46° C., about 32° C. to about 47°C., about 32° C. tO glycerol are eachesterified using a fatty acid disclosed herein about 48°C., about 32° C. to about 49° C., about 32° C. tO to produce monoglycerides, diglycerides, and triglycerides, about 50° C., about 34° C. to about 44°C., about 34° C. tO respectively. In these compounds, each hydroxyl groups of about 45° C., about 34° C. to about 46° C., about 34° C. tO glycerol may be esterified by the same fatty acid or different about 47°C., about 34° C. to about 48°C., about 34° C. tO fatty acids. Additionally, glycerides may be acetylated to 10 about 49° C., about 34° C. to about 50° C., about 36° C. tO produce acetylated monoglycerides, acetylated diglycerides, about 44° C., about 36° C. to about 45° C., about 36° C. tO and acetylated triglycerides. In aspects of this embodiment, a about 46° C., about 36° C. to about 47°C., about 36° C. tO monoglyceride may include a saturated or unsaturated fatty about 48°C., about 36° C. to about 49° C., about 36° C. tO acid having a carbon length of C-C. In other aspects of about 50° C., about 38° C. to about 44°C., about 38° C. tO this embodiment, a diglyceride may include one Saturated or 15 about 45° C., about 38° C. to about 46° C., about 38° C. tO unsaturated fatty acid having a carbon length of C-C, or about 47°C., about 38° C. to about 48°C., about 38° C. tO two saturated or unsaturated fatty acids each having a carbon about 49° C., about 38° C. to about 50° C., about 40° C. tO length of C2-C. In yet other aspects of this embodiment, a about 44° C., about 40° C. to about 45° C., about 40° C. tO triglyceride may include one Saturated or unsaturated fatty about 46° C., about 40° C. to about 47°C., about 40° C. tO acid having a carbon length of C-C, two saturated or about 48°C., about 40° C. to about 49° C., about 40° C. tO unsaturated fatty acids each having a carbon length of C about 50° C., about 42° C. to about 44° C., about 42° C. tO C, or three Saturated or unsaturated fatty acids each having about 45° C., about 42° C. to about 46° C., about 42° C. tO a carbon length of C2-C. about 47°C., about 42° C. to about 48°C., about 42° C. tO In aspects of this embodiment, a mixture of pharmaceuti about 49°C., or about 42°C. to about 50° C. cally-acceptable lipids includes a mixture of mono-, di-, and/ 25 In other aspects of this embodiment, a mixture of pharma or triglycerides having a melting point of e.g., about 33°C., ceutically-acceptable lipids includes a mixture of mono-, di-, about 34°C., about 35°C., about 36°C., about 37°C., about and/or triglycerides and PEG fatty acid esters having a melt 38°C., about 39°C., about 40°C., about 41° C., about 43°C., ing point of, e.g., about 33°C., about 34°C., about 35°C., about 43°C., about 44°C., about 45° C., about 45° C., about about 36°C., about 37° C., about 38°C., about 39°C., about 47°C., about 48°C., about 49°C., about 50° C. In aspects of 30 40°C., about 41° C., about 43°C., about 43°C., about 44°C., this embodiment, a mixture of pharmaceutically-acceptable about 45° C., about 45° C., about 47°C., about 48°C., about lipids includes a mixture of mono-, di-, and/or triglycerides 49°C., about 50° C. In aspects of this embodiment, a mixture having a melting point of, e.g., about 30° C. to about 44°C., of pharmaceutically-acceptable lipids includes a mixture of about 30° C. to about 45° C., about 30° C. to about 46° C., mono-, di-, and/or triglycerides and PEG fatty acid esters about 30° C. to about 47°C., about 30° C. to about 48°C., 35 having a melting point of, e.g., about 30° C. to about 44°C., about 30° C. to about 49° C., about 30° C. to about 50° C., about 30° C. to about 45° C., about 30° C. to about 46°C., about 32° C. to about 44° C., about 32° C. to about 45° C., about 30° C. to about 47°C., about 30° C. to about 48°C., about 32° C. to about 46° C., about 32° C. to about 47°C., about 30° C. to about 49° C., about 30° C. to about 50° C., about 32° C. to about 48°C., about 32° C. to about 49° C., about 32° C. to about 44° C., about 32° C. to about 45° C., about 32° C. to about 50° C., about 34° C. to about 44°C., 40 about 32° C. to about 46° C., about 32° C. to about 47°C., about 34° C. to about 45° C., about 34° C. to about 46° C., about 32° C. to about 48°C., about 32° C. to about 49°C., about 34° C. to about 47°C., about 34° C. to about 48°C., about 32° C. to about 50° C., about 34° C. to about 44°C., about 34° C. to about 49° C., about 34° C. to about 50° C., about 34° C. to about 45° C., about 34° C. to about 46°C., about 36° C. to about 44° C., about 36° C. to about 45° C., about 34° C. to about 47°C., about 34° C. to about 48°C., about 36° C. to about 46° C., about 36° C. to about 47°C., 45 about 34° C. to about 49° C., about 34° C. to about 50° C., about 36° C. to about 48°C., about 36° C. to about 49° C., about 36° C. to about 44° C., about 36° C. to about 45° C., about 36° C. to about 50° C., about 38°C. to about 44°C., about 36° C. to about 46° C., about 36° C. to about 47°C., about 38°C. to about 45° C., about 38°C. to about 46° C., about 36° C. to about 48°C., about 36° C. to about 49°C., about 38°C. to about 47°C., about 38°C. to about 48°C., about 36° C. to about 50° C., about 38°C. to about 44°C., about 38°C. to about 49° C., about 38°C. to about 50° C., 50 about 38°C. to about 45° C., about 38°C. to about 46°C., about 40° C. to about 44° C., about 40° C. to about 45° C., about 38°C. to about 47°C., about 38°C. to about 48°C., about 40° C. to about 46° C., about 40° C. to about 47°C., about 38°C. to about 49° C., about 38°C. to about 50° C., about 40° C. to about 48°C., about 40° C. to about 49° C., about 40° C. to about 44° C., about 40° C. to about 45° C., about 40° C. to about 50° C., about 42° C. to about 44°C., about 40° C. to about 46° C., about 40° C. to about 47°C., about 42°C. to about 45° C., about 42° C. to about 46° C., 55 about 40° C. to about 48°C., about 40° C. to about 49°C., about 42°C. to about 47°C., about 42° C. to about 48°C., about 40° C. to about 50° C., about 42° C. to about 44°C., about 42°C. to about 49°C., or about 42°C. to about 50° C. about 42° C. to about 45° C., about 42° C. to about 46°C., In other aspects of this embodiment, a mixture of pharma about 42° C. to about 47°C., about 42° C. to about 48°C., ceutically-acceptable lipids includes a mixture PEG fatty acid about 42°C. to about 49°C., or about 42°C. to about 50° C. esters having a melting point of, e.g., about 33°C., about 34° 60 A Solid solution pharmaceutical composition disclosed C., about 35° C., about 36° C., about 37° C., about 38°C., herein may comprise a pharmaceutically-acceptable room about 39°C., about 40°C., about 41° C., about 43°C., about temperature solid lipid (hard fat) in an amount sufficient to 43°C., about 44°C., about 45° C., about 45° C., about 47°C., form solid solution composition disclosed herein. In other about 48°C., about 49° C., about 50° C. In aspects of this aspects of this embodiment, a pharmaceutical composition embodiment, a mixture of pharmaceutically-acceptable lip 65 disclosed herein may comprise a pharmaceutically-accept ids includes a mixture PEG fatty acid esters having a melting able room temperature Solid lipid (hard fat) in an amount of point of, e.g., about 30° C. to about 44°C., about 30° C. to e.g., at least 10% by weight, at least 20% by weight, at least US 9,308,213 B2 25 26 30% by weight, at least 35% by weight, at least 40% by ethelene glycol Stearate, ethelene glycol palmitostearate, weight, at least 45% by weight, at least 50% by weight, at ethelene glycol oleate, ethelene glycol elaidate, ethelene gly least 55% by weight, at least 60% by weight, at least 65% by col vaccinate, ethelene glycollinoleate, ethelene glycollino weight, at least 70% by weight, at least 75% by weight, at elaidate, ethelene glycol O-linolenate, ethelene glycoly-lino least 80% by weight, at least 85% by weight, at least 90% by lenate, ethelene glycol Stearidonate, ethelene glycol weight, at least 95% by weight, or at least 99% by weight. In capprylocaprate, ethelene glycol dicapprylocaprate, other aspects of this embodiment, a pharmaceutical compo diethelene glycol caprylate, diethelene glycol pelargonate, sition disclosed herein may comprise a pharmaceutically diethelene glycol caprate, diethelene glycol undecylate, acceptable room temperature Solid lipid (hard fat) in an diethelene glycol laurate, diethelene glycol tridecylate, amount of, e.g., about 30% to about 99% by weight, about 10 diethelene glycol myristate, diethelene glycol myristolate, 35% to about 99% by weight, about 40% to about 99% by diethelene glycol pentadecyclate, diethelene glycol palmi weight, about 45% to about 99% by weight, about 50% to tate, diethelene glycol palmitoleate, diethelene glycol sapi about 99% by weight, about 30% to about 98% by weight, enate, diethelene glycol margarate, diethelene glycol Stear about 35% to about 98% by weight, about 40% to about 98% ate, diethelene glycol palmitostearate, diethelene glycol by weight, about 45% to about 98% by weight, about 50% to 15 oleate, diethelene glycol elaidate, diethelene glycol vacci about 98% by weight, about 30% to about 95% by weight, nate, diethelene glycollinoleate, diethelene glycollinoelaid about 35% to about 95% by weight, about 40% to about 95% ate, diethelene glycol O-linolenate, diethelene glycoly-lino by weight, about 45% to about 95% by weight, or about 50% lenate, diethelene glycol Stearidonate, diethelene glycol to about 95% by weight. In yet other aspects of this embodi capprylocaprate, diethelene glycol dicapprylocaprate, propy ment, a pharmaceutical composition disclosed herein may lene glycol caprylate, propylene glycol pelargonate, propy comprise a pharmaceutically-acceptable room temperature lene glycol caprate, propylene glycol undecylate, propylene solid lipid (hard fat) in an amount of, e.g., about 70% to about glycol laurate, propylene glycol tridecylate, propylene glycol 97% by weight, about 75% to about 97% by weight, about myristate, propylene glycol myristolate, propylene glycol 80% to about 97% by weight, about 85% to about 97% by pentadecyclate, propylene glycol palmitate, propylene glycol weight, about 88% to about 97% by weight, about 89% to 25 palmitoleate, propylene glycol sapienate, propylene glycol about 97% by weight, about 90% to about 97% by weight, margarate, propylene glycol Stearate, propylene glycol about 75% to about 96% by weight, about 80% to about 96% palmitostearate, propylene glycol oleate, propylene glycol by weight, about 85% to about 96% by weight, about 88% to elaidate, propylene glycol vaccinate, propylene glycol about 96% by weight, about 89% to about 96% by weight, linoleate, propylene glycol linoelaidate, propylene glycol about 90% to about 96% by weight, about 75% to about 93% 30 O-linolenate, propylene glycoly-linolenate, propylene glycol by weight, about 80% to about 93% by weight, about 85% to Stearidonate, propylene glycol capprylocaprate, propylene about 93% by weight, about 88% to about 93% by weight, glycol dicapprylocaprate, dipropylene glycol caprylate, about 89% to about 93% by weight, or about 90% to about dipropylene glycol pelargonate, dipropylene glycol caprate, 93% by weight. dipropylene glycol undecylate, dipropylene glycol laurate, Commercially available mixtures of pharmaceutically-ac 35 dipropylene glycol tridecylate, dipropylene glycol myristate, ceptable glycerolipids include, without limitation, Cocoa but dipropylene glycol myristolate, dipropylene glycol pentade ter, mixtures of PEG-6 sterate and ethylene glycol palmito cyclate, dipropylene glycol palmitate, dipropylene glycol stearate and PEG-32 stearate (TEFOSE(R) 1500; TEFOSE(R) palmitoleate, dipropylene glycol sapienate, dipropylene gly 63), mixtures of triceteareth-4 phosphate and ethylene glycol col margarate, dipropylene glycol Stearate, dipropylene gly palmitostearate and diethylene glycol palmitostearate 40 col palmitostearate, dipropylene glycol oleate, dipropylene (SEDEFOSR 75), mixtures of glycerol monostearate and glycol elaidate, dipropylene glycol vaccinate, dipropylene PEG-75 stearate (GELOTR), mixtures of cetyl alcohol and glycollinoleate, dipropylene glycollinoelaidate, dipropylene ethoxylated fatty alcohols (seteth-2-, steareth-20) (EMUL glycol O-linolenate, dipropylene glycol Y-linolenate, dipro CIRE(R), mixtures of saturated Co-Cs triglycerides having a pylene glycol Stearidonate, dipropylene glycol cappryloca melting point around 33°C. (GELUCIRE(R) 33/01), mixtures 45 prate, dipropylene glycol dicapprylocaprate, or any combi of Saturated Co-Cs triglycerides having a melting point nation thereof. around 39° C. (GELUCIRE(R) 39/01), mixtures of saturated Commercially available pharmaceutically-acceptable gly Co-Cs triglycerides having a melting point around 43° C. col fatty acid esters include, without limitation, propylene (GELUCIRE(R) 43/01), mixtures of glycerol monostearate glycol monopalmitostearate (MONOSTEOL(R), propylene 40-55 (type I) and diglycerides (GELEOL(R) Mono and Dig 50 glycol dicaprylocaprate (LABRAFAC(R) PG), propylene gly lycerides), and mixtures of medium-chain triglycerides (LA col monolaurate (type I) (LAUROGLYCOLR) FCC), propy BRAFAC(R) Lipophile WL 1349). lene glycol monolaurate (type II) (LAUROGLYCOLR 90), A hard fat useful in the pharmaceutical compositions dis propylene glycol monocaprylate (type I) (CAPRYOLR) closed herein may be a pharmaceutically-acceptable glycol PGMC), and propylene glycol monocaprylate (type II) (CA fatty acid ester. A pharmaceutically-acceptable glycol fatty 55 PRYOLR 90). acid ester can be a monoester of a glycol, a diester of a glycol, A hard fat useful in the pharmaceutical compositions dis or a triester of a glycol. A glycol fatty acid ester include, closed herein may be a pharmaceutically-acceptable poly without limitation, an ethylene glycol fatty acid ester, a dieth ether fatty acid ester. A pharmaceutically-acceptable poly ylene glycol fatty acid ester, a propylene glycol fatty acid ether fatty acid ester can be a mono-fatty acid ester of a ester, and a dipropylene fatty acid ester. Non-limiting 60 polyether, a di-fatty acid ester of a polyether, or a tri-fatty acid examples of glycol fatty acid esters include, e.g., ethelene ester of a polyether. A polyether fatty acid ester includes, glycol caprylate, ethelene glycol pelargonate, ethelene glycol without limitation, a PEG fatty acid ester, a PEG glyceryl caprate, ethelene glycol undecylate, ethelene glycol laurate, fatty acid, a PEG fatty acid ester glyceride, a PPG fatty acid ethelene glycol tridecylate, ethelene glycol myristate, ester, a PPG glyceryl fatty acid, and a PPG fatty acid ester ethelene glycol myristolate, ethelene glycol pentadecyclate, 65 glyceride. A PEG or PPG may be a molecular mass of, e.g., ethelene glycol palmitate, ethelene glycol palmitoleate, 5-20,000. Non-limiting examples of polyether fatty acid ethelene glycol sapienate, ethelene glycol margarate, esters include, e.g., a PEG caprylate, a PEG pelargonate, a US 9,308,213 B2 27 28 PEG caprate, a PEG undecylate, a PEG laurate, a PEG tride beeswax (APIFIL(R), lauroyl macrogol-32 glycerides (GE cylate, a PEG myristate, a PEG myristolate, a PEG pentade LUCIRE 44/14), stearoyl macrogol-32 glycerides (GELU cyclate, a PEG palmitate, a PEG palmitoleate, a PEG sapi CIRE 50.13), linoleoyl macrogol-6 glycerides (LABRA enate, a PEG margarate, a PEG stearate, a PEG FIL(R) M2125CS), oleoyl macrogol-6 glycerides palmitostearate, PEG oleate, PEG elaidate, PEG vaccinate, (LABRAFIL(R) M1944CS), and lauroyl macrogol-6 glycer PEG linoleate, PEG linoelaidate, PEG O-linolenate, PEG ides (LABRAFIL(R) M2130CS). Y-linolenate, PEG stearidonate, PEG capprylocaprate, PEG Another lipid useful in the pharmaceutical compositions dicapprylocaprate, a PEG glyceryl caprylate, a PEG glyceryl disclosed herein may be a pharmaceutically-acceptable room pelargonate, a PEG glyceryl caprate, a PEG glyceryl unde temperature liquid lipid. Also known as a “liquid fat', a room cylate, a PEG glyceryl laurate, a PEG glyceryl tridecylate, a 10 temperature liquid lipid includes any fatty acid that is liquidat PEG glyceryl myristate, a PEG glyceryl myristolate, a PEG normal room temperature, Such as, e.g. about 20° C. Room glyceryl pentadecyclate, a PEG glyceryl palmitate, a PEG temperature liquid lipid comprise a wide group of compounds glyceryl palmitoleate, a PEG glyceryl Sapienate, a PEG glyc that are generally soluble in organic solvents and generally eryl margarate, a PEG glyceryl Stearate, a PEG glyceryl insoluble in water. Examples of mixtures of pharmaceuti palmitostearate, PEG glyceryl oleate, PEG glyceryl elaidate, 15 cally-acceptable room temperature liquid lipids include, PEG glyceryl vaccinate, PEG glyceryllinoleate, PEG glyc without limitation, a mixture of one or more fatty acids dis eryl linoelaidate, PEG glyceryl C-linolenate, PEG glyceryl closed herein, a mixture of one or more partially hydrolyzed Y-linolenate, PEG glyceryl Stearidonate, PEG glyceryl cap fat, and a mixture of one or more partially hydrogenated fat. prylocaprate, PEG glyceryl dicapprylocaprate, a capryloyl A pharmaceutically-acceptable room temperature liquid PEG glyceride, a pelargonoyl PEG glyceride, a caproyl PEG lipid includes a pharmaceutically-acceptable partially hydro glyceride, an undecyloyl PEG glyceride, a lauroyl PEG glyc genated fat. The process of hydrogenation adds hydrogen eride, a tridecyloyl PEG glyceride, a myristoyl PEG glycer atoms to unsaturated lipid, eliminating double bonds and ide, a myristoloyl PEG glyceride, a pentadecycloyl PEG glyc making them into partially or completely saturated lipid. eride, a palmitoyl PEG glyceride, a palmitoleoyl PEG Partial hydrogenation is a chemical rather than enzymatic, glyceride, a sapienoyl PEG glyceride, a margaroyl PEG glyc 25 that converts a part of cis-isomers into trans-unsaturated lip eride, a stearoyl PEG glyceride, a palmitostearoyl PEG glyc ids instead of hydrogenating them completely. In the first eride, an oleoyl PEG glyceride, an elaidoyl PEG glyceride, a reaction step, one hydrogen is added, with the other, coordi vaccinoyl PEG glyceride, a linoleoyl PEG glyceride, a lino natively unsaturated, carbon being attached to the catalyst. elaidoyl PEG glyceride, an O-linolenoyl PEG glyceride, a The second step is the addition of hydrogen to the remaining Y-linolenoyl PEG glyceride, a stearidonoyl PEG glyceride, a 30 carbon, producing a saturated fatty acid. The first step is capprylocaproyl PEG glyceride, a dicapprylocaproyl PEG reversible, such that the hydrogen is readsorbed on the cata glyceride, a PPG caprylate, a PPG pelargonate, a PPG lyst and the double bond is re-formed. The intermediate with caprate, a PPG undecylate, a PPG laurate, a PPG tridecylate, only one hydrogen added contains no double bond and can a PPG myristate, a PPG myristolate, a PPG pentadecyclate, a freely rotate. Thus, the double bond can re-form as either cis PPG palmitate, a PPG palmitoleate, a PPG sapienate, a PPG 35 or trans, of which trans is favored, regardless the starting margarate, a PPG stearate, a PPG palmitostearate, a PPG material. oleate, a PPG elaidate, a PPG vaccinate, a PPG linoleate, a A Solid solution pharmaceutical composition disclosed PPG linoelaidate, a PPG C-linolenate, a PPG Y-linolenate, a herein may comprise a room temperature liquid lipid in an PPG stearidonate, a PPG capprylocaprate, a PPG dicappry amount Sufficient to dissolve a therapeutic compound dis locaprate, a PPG glyceryl caprylate, a PPG glyceryl pelargo 40 closed herein. In other aspects of this embodiment, a phar nate, a PPG glyceryl caprate, a PPG glyceryl undecylate, a maceutical composition disclosed herein may comprise a PPG glyceryl laurate, a PPG glyceryl tridecylate, a PPG glyc room temperature liquid lipid in an amount of, e.g., less than eryl myristate, a PPG glyceryl myristolate, a PPG glyceryl about 90% by weight, less than about 80% by weight, less pentadecyclate, a PPG glyceryl palmitate, a PPG glyceryl than about 70% by weight, less than about 65% by weight, palmitoleate, a PPG glyceryl sapienate, a PPG glyceryl mar 45 less than about 60% by weight, less than about 55% by garate, a PPG glyceryl Stearate, a PPG glyceryl palmitostear weight, less than about 50% by weight, less than about 45% ate, a PPG glyceryl oleate, a PPG glyceryl elaidate, a PPG by weight, less than about 40% by weight, less than about glyceryl vaccinate, a PPG glyceryllinoleate, a PPG glyceryl 35% by weight, less than about 30% by weight, less than linoelaidate, a PPG glyceryl C-linolenate, a PPG glyceryl about 25% by weight, less than about 20% by weight, less Y-linolenate, a PPG glyceryl Stearidonate, a PPG glyceryl 50 than about 15% by weight, less than about 10% by weight, capprylocaprate, a PPG glyceryl dicapprylocaprate, a capry less than about 5% by weight, or less than about 1% by loyl PPG glyceride, a pelargonoyl PPG glyceride, a caproyl weight. In other aspects of this embodiment, a pharmaceuti PPG glyceride, an undecyloyl PPG glyceride, a lauroyl PPG cal composition disclosed herein may comprise a room tem glyceride, a tridecyloyl PPG glyceride, a myristoyl PPG glyc perature liquid lipid in an amount in a range of, e.g., about 1% eride, a myristoloyl PPG glyceride, a pentadecycloyl PPG 55 to 90% by weight, about 1% to 80% by weight, about 1% to glyceride, a palmitoyl PPG glyceride, a palmitoleoyl PPG 70% by weight, about 1% to 60% by weight, about 1% to 50% glyceride, a sapienoyl PPG glyceride, a margaroyl PPG glyc by weight, about 1% to 40% by weight, about 1% to 30% by eride, a stearoyl PPG glyceride, a palmitostearoyl PPG glyc weight, about 1% to 20% by weight, about 1% to 10% by eride, an oleoyl PPG glyceride, an elaidoyl PPG glyceride, a weight, about 2% to 50% by weight, about 2% to 40% by vaccinoyl PPG glyceride, a linoleoyl PPG glyceride, a lino 60 weight, about 2% to 30% by weight, about 2% to 20% by elaidoyl PPG glyceride, an O-linolenoyl PPG glyceride, a weight, about 2% to 10% by weight, about 4% to 50% by Y-linolenoyl PPG glyceride, a stearidonoyl PPG glyceride, a weight, about 4% to 40% by weight, about 4% to 30% by capprylocaproyl PPG glyceride, a dicapprylocaproyl PPG weight, about 4% to 20% by weight, about 4% to 10% by glyceride, or any combination thereof. weight, about 6% to 50% by weight, about 6% to 40% by Commercially available pharmaceutically-acceptable 65 weight, about 6% to 30% by weight, about 6% to 20% by polyether fatty acid esters include, without limitation, capry weight, about 6% to 10% by weight, about 8% to 50% by locaproyl macrogol-8 glycerides (LABRASOL(R), PEG-8 weight, about 8% to 40% by weight, about 8% to 30% by US 9,308,213 B2 29 30 weight, about 8% to 20% by weight, about 8% to 15% by 4% to about 12% by weight, about 4% to about 15% by weight, or about 8% to 12% by weight. weight, about 4% to about 18% by weight, about 4% to about Examples of a pharmaceutically-acceptable room tem 20% by weight, about 5% to about 7% by weight, about 5% to perature liquid lipids include monoglycerides including, about 10% by weight, about 5% to about 12% by weight, without limitation, glycerol monomyristoleate, glycerol about 5% to about 15% by weight, about 5% to about 18% by monopalmitoleate, glycerol monosapienate, glycerol weight, about 5% to about 20% by weight, about 6% to about monooleate, glycerol monoelaidate, glycerol monovac 7% by weight, about 6% to about 10% by weight, about 6% to cenate, glycerol monolinoleate, glycerol monolinoelaidate, about 12% by weight, about 6% to about 15% by weight, glycerol monolinolenate, glycerol monostearidonate, glyc about 6% to about 18% by weight, about 6% to about 20% by erol monoeicosenoate, glycerol monomeadate, glycerol 10 weight, about 7% to about 10% by weight, about 7% to about monoarachidonate, glycerol monoeicosapentaenoate, glyc 12% by weight, about 7% to about 15% by weight, about 7% erol monoerucate, glycerol monodocosahexaenoate, and to about 18% by weight, about 7% to about 20% by weight, glycerol mononervonate. about 8% to about 10% by weight, about 8% to about 12% by Commercially available pharmaceutically-acceptable weight, about 8% to about 15% by weight, about 8% to about room temperature liquid lipids include, without limitation, 15 18% by weight, about 8% to about 20% by weight, about 9% glyceryl dibelhenate (COMPRITOL(R) 888), glycerol behen to about 10% by weight, about 9% to about 12% by weight, ate (COMPRITOL(R) E ATO), glycerol dipalmitostearate about 9% to about 15% by weight, about 9% to about 18% by (Biogapress Vegetal BM297ATO), glycerol distearate (type I) weight, about 9% to about 20% by weight, about 10% to (PRECIROL(R) ATO 5), and glycerol monolinoleate about 12% by weight, about 10% to about 15% by weight, (MAISINETM35-1). about 10% to about 18% by weight, or about 10% to about Aspects of the present specification disclose, in part, a 20% by weight. stabilizing agent. A stability agent is a compound that inter A stability agent as disclosed herein is not a solvent as it is acts with a free acid or base present on a therapeutic com used in an amount that does not result in Substantial dissolv pound disclosed herein to shield the charges, thereby imped ing of a solute. As such, the amount stability agent used in a ing ionic interactions between therapeutic compound/lipid 25 Solid solution composition disclosed herein results in no more matrices preventing the alignments necessary to form a crys than 85% dissolution of a therapeutic compound disclosed talline matrix of a solid phase composition. Thus, a stabilizing herein. In aspects of this embodiment, the amount stability agent prevent the thermodynamic transition of a composition agent used in a solid solution composition disclosed herein into a classic solid phase or prolongs this transition to Such an results in. e.g., no more than 80%, no more than 75%, no more extent that it does not occur. Examples of stability agents 30 than 70%, no more than 65%, no more than 60%, no more include a liquid glycol polymer, a monohydric alcohol, isos than 55%, no more than 50%, no more than 45%, no more orbide dimethyl ether, and diethylene glycol monoethyl ether than 40%, no more than 35%, no more than 30%, no more (2-(2-ethoxyethoxy)ethanol) (TRANSCUTOL(R). than 25%, no more than 20%, no more than 15%, no more A pharmaceutical composition disclosed herein may com than 10%, or no more than 5% dissolution of a therapeutic prise a stabilizing agentinanamount Sufficient to stabilize the 35 compound disclosed herein. free acid or base present in a therapeutic compound disclosed In an embodiment, a glycol polymer may comprise a phar herein. In other aspects of this embodiment, a pharmaceutical maceutically-acceptable PEG polymer. PEG polymers, also composition disclosed herein may comprise a stabilizing known as polyethylene oxide (PEO) polymers or polyoxyeth agent in an amount of, e.g., less than about 40% by weight, ylene (POE) polymers, are prepared by polymerization of less than about 35% by weight, less than about 30% by 40 ethylene oxide and are commercially available over a wide weight, less than about 25% by weight, less than about 20% range of molecular weights from 100 g/mol to 10,000,000 by weight, less than about 19% by weight, less than about g/mol. PEG polymers with a low molecular mass are liquids 18% by weight, less than about 17% by weight, less than or low-melting solids, whereas PEG polymers of a higher about 16% by weight, less than about 15% by weight, less molecular mass are solids. In an aspect of this embodiment, a than about 14% by weight, less than about 13% by weight, 45 PEG polymer used as a stability agent is a liquid PEG poly less than about 12% by weight, less than about 11% by mer. In aspects of this embodiment, a PEG polymer has a weight, less than about 10% by weight, less than about 9% by molecular weight of, e.g., no more than 100 g/mol, no more weight, less than about 8% by weight, less than about 7% by than 200 g/mol, no more than 300 g/mol, no more than 400 weight, less than about 6% by weight, less than about 5% by g/mol, no more than 500 g/mol, no more than 600 g/mol, no weight, less than about 4% by weight, less than about 3% by 50 more than 700 g/mol, no more than 800 g/mol, no more than weight, less than about 2% by weight, or less than about 1%. 900 g/mol, or no more than 1000 g/mol. In other aspects of this embodiment, a pharmaceutical com A PEG polymer include, without limitation, PEG 100, position disclosed herein may comprise a stabilizing agent in PEG 200, PEG 300, PEG 400, PEG 500, PEG 600, PEG 700, an amount of, e.g., about 1% to about 5% by weight, about 1% PEG 800, PEG 900, PEG 1000, PEG 1100, PEG 1200, PEG to about 7% by weight, about 1% to about 10% by weight, 55 1300, PEG 1400, PEG 1500, PEG 1600, PEG 1700, PEG about 1% to about 12% by weight, about 1% to about 15% by 1800, PEG 1900, PEG 2000, PEG 2100, PEG 2200, PEG weight, about 1% to about 18% by weight, about 1% to about 2300, PEG 2400, PEG 2500, PEG 2600, PEG 2700, PEG 20% by weight, about 2% to about 5% by weight, about 2% to 2800, PEG 2900, PEG 3000, PEG 3250, PEG 3350, PEG about 7% by weight, about 2% to about 10% by weight, about 3500, PEG 3750, PEG 4000, PEG 4250, PEG 4500, PEG 2% to about 12% by weight, about 2% to about 15% by 60 4750, PEG 5000, PEG 5500, PEG 6000, PEG 6500, PEG weight, about 2% to about 18% by weight, about 2% to about 7000, PEG 7500, PEG 8000, PEG 8500, PEG 9000, PEG 20% by weight, about 3% to about 5% by weight, about 3% to 9500, PEG 10,000, PEG 11,000, PEG 12,000, PEG 13,000, about 7% by weight, about 3% to about 10% by weight, about PEG 14,000, PEG 15,000, PEG 16,000, PEG 17,000, PEG 3% to about 12% by weight, about 3% to about 15% by 18,000, PEG 19,000, or PEG 20,000. weight, about 3% to about 18% by weight, about 3% to about 65 In another embodiment, a glycol polymer may comprise a 20% by weight, about 4% to about 5% by weight, about 4% to pharmaceutically-acceptable polypropylene glycol (PPG) about 7% by weight, about 4% to about 10% by weight, about polymer. PPG polymers, also known as polypropylene oxide US 9,308,213 B2 31 32 (PPO) polymers or polyoxypropylene (POP) polymers, are at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg. prepared by polymerization of propylene oxide and are com at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg. mercially available over a wide range of molecular weights at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg. from 100 g/mol to 10,000,000 g/mol. PPG polymers with a or at least 100 mg. In other aspects of this embodiment, a low molecular mass are liquids or low-melting Solids, pharmaceutical composition disclosed herein may comprise a whereas PPG polymers of a higher molecular mass are solids. neutralizing agent in an amount of, e.g., at least 5 mg, at least In an aspect of this embodiment, a PPG polymer used as a 10 mg, at least 20 mg, at least 25 mg, at least 50 mg, at least stability agent is a liquid PPG polymer. In aspects of this 75 mg, at least 100 mg, at least 200 mg, at least 300 mg, at embodiment, a PPG polymer has a molecular weight of, e.g., least 400 mg, at least 500 mg, at least 600 mg, at least 700 mg. no more than 100 g/mol, no more than 200 g/mol, no more 10 than 300 g/mol, no more than 400 g/mol, no more than 500 at least 800 mg, at least 900 mg, at least 1,000 mg, at least g/mol, no more than 600 g/mol, no more than 700 g/mol, no 1,100 mg, at least 1,200 mg, at least 1,300 mg, at least 1,400 more than 800 g/mol, no more than 900 g/mol, or no more mg, or at least 1,500 mg. In yet other aspects of this embodi than 1000 g/mol. ment, a pharmaceutical composition disclosed herein may A PPG polymer include, without limitation, PPG 100, PPG 15 comprise a neutralizing agent in an amount of, e.g., about 5 200, PPG 300, PPG 400, PPG 500, PPG 600, PPG 700, PPG mg to about 100 mg, about 10 mg to about 100 mg, about 50 800, PPG 900, PPG 1000, PPG 1100, PPG 1200, PPG 1300, mg to about 150 mg, about 100 mg to about 250 mg, about PPG 1400, PPG 1500, PPG 1600, PPG 1700, PPG 1800, PPG 150 mg to about 350 mg, about 250 mg to about 500 mg. 1900, PPG 2000, PPG 2100, PPG 2200, PPG 2300, PPG about 350 mg to about 600 mg, about 500 mg to about 750 2400, PPG 2500, PPG 2600, PPG 2700, PPG 2800, PPG mg, about 600 mg to about 900 mg, about 750 mg to about 2900, PPG 3000, PPG 3250, PPG 3350, PPG 3500, PPG 1,000 mg, about 850 mg to about 1,200 mg. or about 1,000 mg 3750, PPG 4000, PPG 4250, PPG 4500, PPG 4750, PPG to about 1,500 mg. In still other aspects of this embodiment, 5000, PPG 5500, PPG 6000, PPG 6500, PPG 7000, PPG a pharmaceutical composition disclosed herein may comprise 7500, PPG 8000, PPG 8500, PPG 9000, PPG 9500, PPG a neutralizing agent in an amount of, e.g., about 10 mg to 10,000, PPG 11,000, PPG 12,000, PPG 13,000, PPG 14,000, 25 about 250 mg, about 10 mg to about 500 mg, about 10 mg to PPG 15,000, PPG 16,000, PPG 17,000, PPG 18,000, PPG about 750 mg, about 10 mg to about 1,000 mg, about 10 mg 19,000, or PPG 20,000. to about 1,500 mg, about 50 mg to about 250 mg, about 50 mg A monohydric alcohol may also be used as a stability to about 500 mg, about 50 mg to about 750 mg, about 50 mg agent. In aspects of this embodiment, the monohydric alcohol to about 1,000 mg, about 50 mg to about 1,500 mg, about 100 may be, e.g., a C alcohol, a C alcohol, a C-salcohol, a 30 mg to about 250 mg, about 100 mg to about 500 mg, about C-7 alcohol, a Co alcohol, a C-1s alcohol, or a C-2 alco 100 mg to about 750 mg, about 100 mg to about 1,000 mg. hol. Examples of a monohydric alcohol include, without limi about 100 mg to about 1,500 mg, about 200 mg to about 500 tation, methanol, ethanol, propanol, butanol, pentanol, and mg, about 200 mg to about 750 mg, about 200 mg to about 1-hexadecanol. 1,000 mg, about 200 mg to about 1,500 mg, about 5 mg to Aspects of the present specification disclose, in part, a 35 about 1,500 mg, about 5 mg to about 1,000 mg. or about 5 mg neutralizing agent. A neutralizing agent is a compound that to about 250 mg. interacts with atherapeutic compound disclosed herein that is In other aspects of this embodiment, a pharmaceutical a salt to neutralized the ionic charges produced when the composition disclosed herein may comprise a neutralizing therapeutic compound dissolves, thereby impeding ionic agent in an amount of, e.g., less than about 90% by weight, interactions between therapeutic compound/lipid matrices 40 less than about 80% by weight, less than about 70% by preventing the alignments necessary to form a crystalline weight, less than about 65% by weight, less than about 60% matrix of a solid phase composition. Thus, a neutralizing by weight, less than about 55% by weight, less than about agent prevent the thermodynamic transition of a composition 50% by weight, less than about 45% by weight, less than into a classic solid phase or prolongs this transition to Such an about 40% by weight, less than about 35% by weight, less extent that it does not occur. Examples of neutralizing agents 45 than about 30% by weight, less than about 25% by weight, include fatty acids as disclosed herein for base-salt drugs and less than about 20% by weight, less than about 15% by Sodium acetate or triethanolamine for acid-salt drugs. weight, less than about 10% by weight, less than about 5% by The amount of neutralizing agent used is based upon the weight, or less than about 1% by weight. In other aspects of extent of charge neutralization desired. For complete neutral this embodiment, a pharmaceutical composition disclosed ization, one molar equivalent of neutralizing agent relative to 50 herein may comprise a neutralizing agent in an amount of therapeutic compound is added to the formulation. For partial e.g., about 1% to 90% by weight, about 1% to 80% by weight, neutralization, less than one molar equivalent is added. Partial about 1% to 75% by weight, about 1% to 70% by weight, neutralization is advantageous in producing a Sustained about 1% to 65% by weight, about 1% to 60% by weight, release formulation. Upon administration, a portion of the about 1% to 55% by weight, about 1% to 50% by weight, therapeutic compound is immediately made available to the 55 about 1% to 45% by weight, about 1% to 40% by weight, body (instant bioavailability) while the bioavailability of about 1% to 35% by weight, about 1% to 30% by weight, another portion is delayed until the therapeutic compound is about 1% to 25% by weight, about 1% to 20% by weight, neutralized by the neutralizing agent. A neutralizing agent about 1% to 15% by weight, about 1% to 10% by weight, may also be added in an excessive amount, i.e., more than one about 1% to 5% by weight, about 2% to 50% by weight, about molar equivalent relative to therapeutic compound. Besides 60 2% to 40% by weight, about 2% to 30% by weight, about 2% neutralizing the salt-drug, excessive amounts of neutralizing to 20% by weight, about 2% to 10% by weight, about 4% to agent can also enable adjustments to the melting point of the 50% by weight, about 4% to 40% by weight, about 4% to 30% Solid solution composition. by weight, about 4% to 20% by weight, about 4% to 10% by In aspects of this embodiment, a pharmaceutical composi weight, about 6% to 50% by weight, about 6% to 40% by tion disclosed herein may comprise a neutralizing agent in an 65 weight, about 6% to 30% by weight, about 6% to 20% by amount of, e.g., at least 5 mg, at least 10 mg, at least 15 mg. weight, about 6% to 10% by weight, about 8% to 50% by at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg. weight, about 8% to 40% by weight, about 8% to 30% by US 9,308,213 B2 33 34 weight, about 8% to 20% by weight, about 8% to 15% by Basis of Therapeutics (Joel G. Hardman et al., eds., McGraw weight, or about 8% to 12% by weight. Hill Professional, 10th ed. 2001); and Handbook of Pharma In other aspects of this embodiment, a pharmaceutical ceutical Excipients (Raymond C. Rowe et al., APhA Publi composition disclosed herein may comprise a neutralizing cations, 4th edition 2003). These protocols are routine agent in an amount of, e.g., about 0.1% to about 45% by procedures and any modifications are well within the Scope of weight, about 0.1% to about 40% by weight, about 0.1% to one skilled in the art and from the teaching herein. about 35% by weight, about 0.1% to about 30% by weight, A pharmaceutical composition disclosed herein can about 0.1% to about 25% by weight, about 0.1% to about 20% optionally include, without limitation, other pharmaceuti by weight, about 0.1% to about 15% by weight, about 0.1% to cally acceptable components (or pharmaceutical compo about 10% by weight, about 0.1% to about 5% by weight, 10 nents), including, without limitation, buffers, preservatives, about 1% to about 45% by weight, about 1% to about 40% by tonicity adjusters, salts, antioxidants, osmolality adjusting weight, about 1% to about 35% by weight, about 1% to about agents, physiological Substances, pharmacological Sub 30% by weight, about 1% to about 25% by weight, about 1% stances, bulking agents, emulsifying agents, wetting agents, to about 20% by weight, about 1% to about 15% by weight, Sweetening or flavoring agents, and the like. Various buffers about 1% to about 10% by weight, about 1% to about 5% by 15 and means for adjusting pH can be used to prepare a pharma weight, about 5% to about 45% by weight, about 5% to about ceutical composition disclosed herein, provided that the 40% by weight, about 5% to about 35% by weight, about 5% resulting preparation is pharmaceutically acceptable. Such to about 30% by weight, about 5% to about 25% by weight, buffers include, without limitation, acetate buffers, citrate about 5% to about 20% by weight, about 5% to about 15% by buffers, phosphate buffers, neutral buffered saline, phosphate weight, about 5% to about 10% by weight, about 10% to buffered saline and borate buffers. It is understood that acids about 45% by weight, about 10% to about 40% by weight, or bases can be used to adjust the pH of a composition as about 10% to about 35% by weight, about 10% to about 30% needed. Pharmaceutically acceptable antioxidants include, by weight, about 10% to about 25% by weight, about 10% to without limitation, sodium metabisulfite, sodium thiosulfate, about 20% by weight, about 10% to about 15% by weight, acetylcysteine, butylated hydroxyanisole and butylated about 15% to about 45% by weight, about 15% to about 40% 25 hydroxytoluene. Useful preservatives include, without limi by weight, about 15% to about 35% by weight, about 15% to tation, benzalkonium chloride, chlorobutanol, thimerosal, about 30% by weight, about 15% to about 25% by weight, phenylmercuric acetate, phenylmercuric nitrate, a stabilized about 15% to about 20% by weight, about 20% to about 45% oxychloro composition and chelants, such as, e.g., DTPA or by weight, about 20% to about 40% by weight, about 20% to DTPA-bisamide, calcium DTPA, and CaNaDTPA-bisamide. about 35% by weight, about 20% to about 30% by weight, 30 Tonicity adjustors useful in a pharmaceutical composition about 20% to about 25% by weight, about 25% to about 45% include, without limitation, salts such as, e.g., Sodium chlo by weight, about 25% to about 40% by weight, about 25% to ride, potassium chloride, mannitol or glycerin and other phar about 35% by weight, or about 25% to about 30% by weight. maceutically acceptable tonicity adjustor. The pharmaceuti A pharmaceutical composition disclosed herein may cal composition may be provided as a salt and can be formed optionally include a pharmaceutically-acceptable carrier that 35 with many acids, including but not limited to, hydrochloric, facilitates processing of an active ingredient into pharmaceu Sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend tically-acceptable compositions. As used herein, the term to be more soluble in aqueous or other protonic solvents than “pharmacologically-acceptable carrier is synonymous with are the corresponding free base forms. It is understood that “pharmacological carrier and means any carrier that has these and other Substances known in the art of pharmacology Substantially no long term or permanent detrimental effect 40 can be included in a pharmaceutical composition. when administered and encompasses terms such as “pharma In an embodiment, a pharmaceutical composition dis cologically acceptable vehicle, stabilizer, diluent, additive, closed herein is solid at room temperature. In aspects of this auxiliary or excipient. Such a carrier generally is mixed with embodiment, a pharmaceutical composition disclosed herein an active compound or permitted to dilute or enclose the may beformulated to be a solidata temperature of e.g., about active compound and can be a solid, semi-solid, or liquid 45 35° C. or lower, about 34°C. or lower, about 33°C. or lower, agent. It is understood that the active ingredients can be about 32° C. or lower, about 31° C. or lower, about 30° C. or soluble or can be delivered as a suspension in the desired lower, about 29° C. or lower, about 28°C. or lower, about 27° carrier or diluent. Any of a variety of pharmaceutically C. or lower, about 26° C. or lower, about 25° C. or lower, acceptable carriers can be used including, without limitation, about 24°C. or lower, about 23°C. or lower, about 22°C. or aqueous media Such as, e.g., water, Saline, glycine, hyaluronic 50 lower, about 21°C. or lower, about 20°C. or lower, about 19° acid and the like; Solid carriers such as, e.g., mannitol, lactose, C. or lower, about 18°C. or lower, about 17° C. or lower, starch, magnesium Stearate, sodium saccharin, talcum, cellu about 16° C. or lower, about 15° C. or lower, about 14°C. or lose, glucose, Sucrose, magnesium carbonate, and the like; lower, about 13°C. or lower, about 12°C. or lower, about 11° Solvents; dispersion media; coatings; antibacterial and anti C. or lower, about 10°C. or lower, about 9°C. or lower, about fungal agents; isotonic and absorption delaying agents; or any 55 8° C. or lower, about 7° C. or lower, about 6° C. or lower, other inactive ingredient. Selection of a pharmacologically about 5° C. or lower, about 4° C. or lower, about 3° C. or acceptable carrier can depend on the mode of administration. lower, about 2°C. or lower, about 1° C. or lower, or about 0° Except insofar as any pharmacologically acceptable carrier is C. or lower. incompatible with the active ingredient, its use in pharmaceu In other aspects of this embodiment, a pharmaceutical tically acceptable compositions is contemplated. Non-limit 60 composition disclosed has a melting point temperature of ing examples of specific uses of such pharmaceutical carriers e.g., 5°C. or higher, 10°C. or higher, 15° C. or higher, 16°C. can be found in Pharmaceutical Dosage Forms and Drug or higher, 17°C. or higher, 18°C. or higher, 19°C. or higher, Delivery Systems (Howard C. Ansel et al., eds., Lippincott 20° C. or higher, 21° C. or higher, 22°C. or higher, 23° C. or Williams & Wilkins Publishers, 7th ed. 1999); REMING higher, 24°C. or higher, 25°C. or higher, 26°C. or higher, 27° TON: THE SCIENCE AND PRACTICE OF PHARMACY 65 C. or higher, 28° C. or higher, 29° C. or higher, 30° C. or (Alfonso R. Gennaro ed., Lippincott, Williams & Wilkins, higher, 31°C. or higher, 32°C. or higher, 33°C. or higher, 34° 20th ed. 2000); Goodman & Gilman's The Pharmacological C. or higher, 35° C. or higher, 36° C. or higher, or 37° C. or US 9,308,213 B2 35 36 higher. In other aspects of this embodiment, a pharmaceutical comprises heating a mixture comprising a therapeutic com composition disclosed has a melting point temperature in the pound disclosed herein to a temperature of, e.g., at least 40° range of, e.g., about 5° C. to about 24°C., about 10° C. to C., at least 45° C., at least 50° C., at least 55° C., at least 60° about 24° C. about 22°C. to about 24°C., about 23° C. to C., at least 65°C., at least 70° C., or at least 75°C. In still other about 25°C., about 24°C. to about 26°C., about 25° C. to aspects of this embodiment, a method disclosed herein com about 27°C., about 26° C. to about 28°C., about 27°C. to prises heating a mixture comprising a therapeutic compound about 29° C., about 28°C. to about 30° C., about 29° C. to disclosed herein to a temperature of e.g., at most 40°C., at about 31° C., about 30° C. to about 32° C., about 31° C. to most 45° C., at most 50° C., at most 55° C., at most 60°C., at about 33°C., about 32° C. to about 34° C., about 33° C. to most 65°C., at most 70°C., or at most 75°C. In other aspects about 35°C., about 34° C. to about 36°C., or about 35° C. to 10 about 37°C. In other aspects of this embodiment, a pharma of this embodiment, a method disclosed herein comprises ceutical composition disclosed has a melting point tempera heating a mixture comprising a therapeutic compound dis ture in the range of, e.g., about 22°C. to about 26°C., about closed herein to a temperature of, e.g., about 40°C. to about 24°C. to about 28°C., about 26°C. to about 30°C., about 28° 45° C., about 40°C. to about 50° C., about 40°C. to about 55° C. to about 32° C., about 30° C. to about 34°C., about 32° C. 15 C., about 40°C. to about 60°C., about 40°C. to about 65°C., to about 36° C., or about 34° C. to about 38°C. about 40° C. to about 70° C., about 40° C. to about 75° C., Aspects of the present specification disclose, in part, a about 45° C. to about 50° C., about 45° C. to about 55° C., method of preparing a solid solution pharmaceutical compo about 45° C. to about 60° C., about 45° C. to about 65° C., sition disclosed herein. In one embodiment, a method dis about 45° C. to about 70° C., about 45° C. to about 75° C., closed herein comprises the steps of a) contacting a therapeu about 50° C. to about 55° C., about 50° C. to about 60° C., tic compound disclosed herein with one or more room about 50° C. to about 65° C., about 50° C. to about 70° C., temperature liquid lipids under conditions which allow the about 50° C. to about 75° C., about 55° C. to about 60° C., therapeutic compound to dissolve in the one or more lipids; about 55° C. to about 65° C., about 55° C. to about 70° C., and b) contacting the compound/lipid solution with one or about 55° C. to about 75° C., about 60° C. to about 65° C., more room temperature solid lipids disclosed herein under 25 about 60° C. to about 70° C., about 60° C. to about 75° C., conditions which allow the formation of a solid solution about 65° C. to about 70° C., about 65° C. to about 75° C., or composition. about 70° C. to about 75° C. In one embodiment, a method disclosed herein comprises In other aspects of this embodiment, a method disclosed the steps of a) contacting a therapeutic compound disclosed herein may be carried out at a temperature Sufficient to incor herein with one or more room temperature liquid lipids and 30 porate the one or more room temperature Solid lipids into the one or more stabilizing agents under conditions which allow Solution comprising the therapeutic compound. In other the therapeutic compound to dissolve in the one or more aspects of this embodiment, a method disclosed herein com lipids; and b) contacting the compound/lipid solution with prises heating a mixture comprising a therapeutic compound one or more room temperature solid lipids disclosed herein disclosed herein to a temperature of, e.g., about 40°C., about under conditions which allow the formation of a solid solu 35 45° C., about 50° C., about 55° C., about 60° C., about 65°C., tion composition. about 70° C., or about 75° C. in order to incorporate the one In one embodiment, a method disclosed herein comprises or more room temperature solid lipids. In yet other aspects of the steps of a) contacting a therapeutic compound disclosed this embodiment, a method disclosed herein comprises heat herein with one or more room temperature liquid lipids and ing a mixture comprising a therapeutic compound disclosed one or more neutralizing agents under conditions which allow 40 herein to a temperature of, e.g., at least 40°C., at least 45°C., the therapeutic compound to dissolve in the one or more at least 50° C., at least 55° C., at least 60° C., at least 65° C., lipids; and b) contacting the compound/lipid solution with at least 70° C., or at least 75°C. in order to incorporate the one one or more room temperature solid lipids disclosed herein or more room temperature solid lipids. In still other aspects of under conditions which allow the formation of a solid solu this embodiment, a method disclosed herein comprises heat tion composition. 45 ing a mixture comprising a therapeutic compound disclosed In one embodiment, a method disclosed herein comprises hereinto a temperature of, e.g., at most 40°C., at most 45°C., the steps of a) contacting a therapeutic compound disclosed at most 50° C., at most 55°C., at most 60° C., at most 65°C., herein with one or more room temperature liquid lipids, one at most 70° C., or at most 75° C. in order to incorporate the or more stabilizing agents, and one or more neutralizing one or more room temperature Solid lipids. In other aspects of agents under conditions which allow the therapeutic com 50 this embodiment, a method disclosed herein comprises heat pound to dissolve in the one or more lipids; and b) contacting ing a mixture comprising a therapeutic compound disclosed the compound/lipid solution with one or more room tempera herein to a temperature of, e.g., about 40°C. to about 45°C., ture solid lipids disclosed herein under conditions which about 40° C. to about 50° C., about 40° C. to about 55° C., allow the formation of a solid solution composition. about 40° C. to about 60° C., about 40° C. to about 65° C., The method disclosed herein is carried out under condi 55 about 40° C. to about 70° C., about 40° C. to about 75° C., tions which allow the therapeutic compound to dissolve in about 45° C. to about 50° C., about 45° C. to about 55° C., other components. In aspects of this embodiment, a method about 45° C. to about 60° C., about 45° C. to about 65° C., disclosed herein may be carried out at a temperature Sufficient about 45° C. to about 70° C., about 45° C. to about 75° C., to dissolve the therapeutic compound into the one or more about 50° C. to about 55° C., about 50° C. to about 60° C., room temperature liquid lipids, and/or one or more stabilizing 60 about 50° C. to about 65° C., about 50° C. to about 70° C., agents, and/or one or more neutralizing agents to create a about 50° C. to about 75° C., about 55° C. to about 60° C., Solution. In other aspects of this embodiment, a method dis about 55° C. to about 65° C., about 55° C. to about 70° C., closed herein comprises heating a mixture comprising a about 55° C. to about 75° C., about 60° C. to about 65° C., therapeutic compound disclosed herein to a temperature of about 60° C. to about 70° C., about 60° C. to about 75° C., e.g., about 40°C., about 45° C., about 50° C., about 55° C., 65 about 65° C. to about 70° C., about 65° C. to about 75° C., or about 60°C., about 65° C., about 70° C., or about 75°C. In yet about 70° C. to about 75°C. in order to incorporate the one or other aspects of this embodiment, a method disclosed herein more room temperature Solid lipids. US 9,308,213 B2 37 38 Aspects of the present specification disclose, in part, con The contacting a therapeutic compound and one or more tacting a therapeutic compound disclosed herein with one or lipids may comprise mixing the, e.g., by stirring, inversion, more lipids. In aspects of this embodiment, one or more lipids Sonication, or Vortexing. The mixing may be carried out for, includes one, two, three, four, or five different lipids disclosed e.g., at least 1 second, at least seconds, at least 10 seconds, at herein. In other aspects of this embodiment, one or more least 20 seconds, at least 30 seconds, at least 45 seconds, at lipids includes two or more, three or more, four or more, or least 60 seconds, or more, until the therapeutic compound is five or more different lipids disclosed herein. In yet other fully dissolved in the lipid/glycol polymer mixture. aspects of this embodiment, one or more lipids includes about Aspects of the present specification disclose, in part, con one to about five different lipids disclosed herein, about two tacting the compound/lipid solution with one or more glycol to about five different lipids disclosed herein, about three to 10 polymers disclosed herein. about five different lipids disclosed herein, about one to about The method disclosed herein is carried out under condi four different lipids disclosed herein, about two to about four tions which allow the solidification of a solid solution com different lipids disclosed herein, or about two to about three position. In aspects of this embodiment, the method may be different lipids disclosed herein. carried out at a temperature Sufficient to cool the composition In other aspects of this embodiment, one or more lipids 15 to a temperature where the solution solidifies. includes one or more room temperature Solid lipids and one or In certain embodiments, a rapid cooling step may be used more room temperature liquid lipids. In aspects of this to reduce the temperature of a pharmaceutical composition embodiment, one or more lipids includes one, two, three, disclosed herein after its formation. For example, a rapid four, or five different hard fats disclosed herein and one, two, cooling step may be used in procedures were temperatures three, four, or five different room temperature liquid lipids greater than room temperature are used to allow a therapeutic disclosed herein. In other aspects of this embodiment, one or compound to dissolve fully in the pharmaceutically-accept more lipids includes two or more, three or more, four or more, able solvent and/or to allow the solution comprising the thera or five or more different room temperature solid lipids dis peutic compound to form the pharmaceutical composition. In closed herein and two or more, three or more, four or more, or aspects of this embodiment, a rapid cooling step results in a five or more different room temperature liquid lipids dis 25 temperature decrease of, e.g., about 30° C. in 20 minutes, closed herein. In yet other aspects of this embodiment, one or about 25°C. in 20 minutes, about 20°C. in 20 minutes, about more lipids includes about one to about five different hard fats 15° C. in 20 minutes, about 30°C. in 15 minutes, about 25°C. disclosed herein, about two to about five different room tem in 15 minutes, about 20°C. in 15 minutes, about 15° C. in 15 perature solid lipids disclosed herein, about three to about five minutes, about 30° C. in 10 minutes, about 25° C. in 10 different room temperature solid lipids disclosed herein, 30 minutes, about 20° C. in 10 minutes, about 15° C. in 10 about one to about four different room temperature solid minutes, about 30°C. in 5 minutes, about 25°C. in 5 minutes, lipids disclosed herein, about two to about four different room about 20°C. in 5 minutes, about 15° C. in 5 minutes. In other temperature solid lipids disclosed herein, or about two to aspects of this embodiment, a rapid cooling step results in a about three different room temperature solid lipids disclosed temperature decrease of, e.g., about 20°C. to about 30°C. in herein and about one to about five different room temperature 35 20 minutes, about 20° C. to about 30°C. in 15 minutes, about liquid lipids disclosed herein, about two to about five different 20°C. to about 30°C. in 10 minutes, about 20°C. to about 30° room temperature liquid lipids disclosed herein, about three C. in 5 minutes, about 15° C. to about 25°C. in 20 minutes, to about five different room temperature liquid lipids dis about 15° C. to about 25°C. in 15 minutes, about 15° C. to closed herein, about one to about four different room tem about 25°C. in 10 minutes, about 15° C. to about 25°C. in 5 perature liquid lipids disclosed herein, about two to about 40 minutes, about 10°C. to about 20°C. in 20 minutes, about 10° four different room temperature liquid lipids disclosed C. to about 20°C. in 15 minutes, about 10°C. to about 20° C. herein, or about two to about three different room temperature in 10 minutes, or about 10° C. to about 20° C. in 5 minutes. liquid lipids disclosed herein. In yet aspects of this embodiment, a rapid cooling step In aspects of this embodiment, the method disclosed herein results in a temperature decrease of e.g., about 2.0° may use a room temperature Solid lipid and a room tempera 45 C./minute, about 1.9°C/minute, about 1.8° C./minute, about ture liquid lipid in a ratio of solid lipid:liquid lipid of, e.g., at 1.7°C./minute, about 1.6°C/minute, about 1.5°C/minute, least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at about 1.4° C./minute, about 1.3° C./minute, about 1.2 least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at C./minute, about 1.1° C./minute, about 1.0°C./minute, about least 15:1, or at least 20:1. In other aspects of this embodi 0.9°C/minute, about 0.8°C/minute, about 0.7°C/minute, ment, the method disclosed herein may use a room tempera 50 about 0.6° C./minute, about 0.5° C./minute, about 0.4° ture solid lipid and a room temperature liquid lipid in a ratio C./minute, about 0.3° C./minute, about 0.2° C./minute, or of solid lipid:liquid lipid of, e.g., about 1:1 to about 20:1, about 0.1° C./minute. In still aspects of this embodiment, a about 5:1 to about 20:1, about 2:1 to about 15:1, about 5:1 to rapid cooling step results in a temperature decrease of, e.g., about 15:1, about 4:1 to about 12:1, or about 6:1 to about 10:1. about 0.1° C. to about 0.4° C./minute, about 0.2°C. to about In aspects of this embodiment, the method disclosed herein 55 0.6°C./minute, about 0.4°C. to about 0.8°C/minute, about may use a plurality of room temperature solid lipids and a 0.6°C. to about 1.0°C/minute, about 0.8° C. to about 1.2 plurality of room temperature liquid lipids in a ratio of total C./minute, about 1.0°C. to about 1.4° C./minute, about 1.2 Solid lipid:total liquid lipid of, e.g., at least 1:1, at least 2:1, at C. to about 1.6° C./minute, about 1.4° C. to about 1.8° least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at C./minute, about 1.6°C. to about 2.0° C./minute, about 0.1° least 8:1, at least 9:1, at least 10:1, at least 15:1, or at least 60 C. to about 0.5° C./minute, about 0.5° C. to about 1.0° 20:1. In other aspects of this embodiment, the method dis C./minute, about 1.0°C. to about 1.5° C./minute, about 1.5° closed herein may use a plurality of room temperature Solid C. to about 2.0° C./minute, about 0.5° C. to about 1.5° lipids and a plurality of room temperature liquid lipid in a C./minute, or about 1.0°C. to about 2.0° C./minute. ratio of total solid lipid:total liquid lipid of, e.g., about 1:1 to A formulation disclosed herein result in the formation of a about 20:1, about 5:1 to about 20:1, about 2:1 to about 15:1, 65 solid solution of the lipids and therapeutic compound. Such about 5:1 to about 15:1, about 4:1 to about 12:1, or about 6:1 formulations do not form liposomal emulsions and/or micel to about 10:1. lular particles and/or any other type of multi-phasic compo US 9,308,213 B2 39 40 sitions. In addition, Such formulations do not require a hydro ethoxyethoxy)ethanol). In other aspects of this embodiment, philic solvent. Such as, e.g., water or a buffered solution. As a Solid solution composition comprises about 5% to about Such, a pharmaceutical composition disclosed herein need 50% by weight of therapeutic compound, about 40% to about not be formulated with a hydrophilic solvent. In an embodi 70% by weight of room temperature solid lipid or hard fat, ment, a pharmaceutical composition disclosed herein does about 1% to about 7% by weight of room temperature liquid not comprise a pharmaceutically-acceptable hydrophilic Sol lipid, and about 1% to about 3% of a liquid glycol polymer Vent. and/or a monohydric alcohol, and/or isosorbide dimethyl The amount of a therapeutic compound, room temperature ether, and/or diethylene glycol monoethylether (2-(2-ethoxy liquid lipid, room temperature solid lipid (hard fat), stabiliz ethoxy)ethanol). ing agent and neutralizing agent used in the method disclosed 10 In one embodiment, a pharmaceutical composition com herein may be in any amount desired. Factors used to deter prises one or more therapeutic compounds, one or more room mine the amount of each component used include, without temperature solid lipids or hard fats, one or more room tem limitation, the final amount the therapeutic compound desired perature liquid lipids, and one or more neutralizing agents, in the pharmaceutical composition, the desired concentration but does not comprise a pharmaceutically-acceptable hydro ofatherapeutic compound in the solution, the hydrophobicity 15 philic solvent. In other aspects of this embodiment, a solid of the therapeutic compound, the lipophobicity of the thera Solution pharmaceutical composition comprises atherapeutic peutic compound, the final amount of a pharmaceutical com compound, a room temperature solid lipid or hard fat, a room position desired, and the conditions used to produce the Solid temperature liquid lipid, and a fatty acid, but does not com Solution pharmaceutical composition. prise a pharmaceutically-acceptable hydrophilic solvent. In In one embodiment, a pharmaceutical composition com yet other aspects of this embodiment, a Solid solution phar prises one or more therapeutic compound, a room tempera maceutical composition comprises a therapeutic compound, ture solid lipids or hard fats, and one or more room tempera a triglyceride mixture, a monoglyceride mixture, and a C ture liquid lipids, but does not comprise a pharmaceutically Cs fatty acid, but does not comprise a pharmaceutically acceptable hydrophilic solvent. acceptable hydrophilic solvent. In still other aspects of this In one embodiment, a pharmaceutical composition com 25 embodiment, a pharmaceutical composition comprises a prises a one or more therapeutic compounds, one or more therapeutic compound, GELUCIRE(R)43/01 (Gattefosse), a room temperature solid lipids or hard fats, one or more room waxy Solid (as room temperature Solid lipid) having a melting temperature liquid lipids, and one or more stabilizing agents, point of between 41° C. to 45° C. and comprising a mixture of but does not comprise a pharmaceutically-acceptable hydro saturated Co-Cs triglycerides, MAISINE(R) 35-1 (Gatte philic solvent. In aspects of this embodiment, a Solid Solution 30 fosse), a glyceryl monolinoleate, and Stearic acid, but does pharmaceutical composition comprises a therapeutic com not comprise a pharmaceutically-acceptable hydrophilic Sol pound, a room temperature solid lipid or hard fat, a room Vet. temperature liquid lipid, and a liquid glycol polymer and/or a In aspects of this embodiment, a Solid solution composition monohydric alcohol, and/or isosorbide dimethyl ether, and/or comprises about 1% to about 55% by weight of therapeutic diethylene glycol monoethyl ether (2-(2-ethoxyethoxy)etha 35 compound, about 30% to about 70% by weight of room nol), but does not comprise a pharmaceutically-acceptable temperature solid lipid or hard fat, about 1% to about 10% by hydrophilic solvent. In other aspects of this embodiment, a weight of room temperature liquid lipid, and about 1% to Solid solution pharmaceutical composition comprises athera about 55% of neutralizing agent. In other aspects of this peutic compound, a triglyceride mixture, a monoglyceride embodiment, a solid Solution composition comprises about mixture, and a liquid PEG polymer and/or a C-C monohy 40 1% to about 55% by weight of therapeutic compound, about dric alcohol, and/or isosorbide dimethyl ether, and/or dieth 30% to about 70% by weight of room temperature solid lipid ylene glycol monoethyl ether (2-(2-ethoxyethoxy)ethanol), or hard fat, about 1% to about 10% by weight of room tem but does not comprise a pharmaceutically-acceptable hydro perature liquid lipid, and about 1% to about 55% of fatty acid. philic solvent. In yet other aspects of this embodiment, a In yet other aspects of this embodiment, a Solid solution pharmaceutical composition comprises a therapeutic com 45 composition comprises about 5% to about 50% by weight of pound, GELUCIRE(R) 43/01 (Gattefosse), a waxy solid (as therapeutic compound, about 30% to about 60% by weight of room temperature solid lipid) having a melting point of room temperature solid lipid or hard fat, about 1% to about between 41° C. to 45° C. and comprising a mixture of satu 7% by weight of room temperature liquid lipid, and about 5% rated Co-Cs triglycerides, MAISINE(R) 35-1 (Gattefosse), a to about 50% of a fatty acid. glyceryl monolinoleate, and a liquid PEG polymer and/or a 50 In other aspects of this embodiment, a solid solution phar C-C monohydric alcohol, and/or isosorbide dimethyl ether, maceutical composition comprises one or more therapeutic and/or diethylene glycol monoethyl ether (2-(2-ethoxy compounds, one or more room temperature Solid lipids or ethoxy)ethanol), but does not comprise a pharmaceutically hard fats, one or more room temperature liquid lipids, and acceptable hydrophilic solvent. triethanolamine, but does not comprise a pharmaceutically In aspects of this embodiment, a Solid solution composition 55 acceptable hydrophilic solvent. In yet other aspects of this comprises about 1% to about 55% by weight of therapeutic embodiment, a solid Solution pharmaceutical composition compound, about 40% to about 90% by weight of room comprises a therapeutic compound, a triglyceride mixture, a temperature solid lipid or hard fat, about 1% to about 10% by monoglyceride mixture, and triethanolamine, but does not weight of room temperature liquid lipid, and about 1% to comprise a pharmaceutically-acceptable hydrophilic solvent. about 5% of a stabilizing agent. In aspects of this embodi 60 In still other aspects of this embodiment, a pharmaceutical ment, a solid solution composition comprises about 1% to composition comprises a therapeutic compound, GELU about 55% by weight of therapeutic compound, about 40% to CIRE(R) 43/01 (Gattefosse), a waxy solid (as room tempera about 90% by weight of room temperature solid lipid or hard ture solid lipid) having a melting point of between 41° C. to fat, about 1% to about 10% by weight of room temperature 45° C. and comprising a mixture of Saturated Co-Cs trig liquid lipid, and about 1% to about 5% of a liquid glycol 65 lycerides, MAISINE(R) 35-1 (Gattefosse), a glyceryl monoli polymer and/or a monohydric alcohol, and/or isosorbide dim noleate, and triethanolamine, but does not comprise a phar ethyl ether, and/or diethylene glycol monoethyl ether (2-(2- maceutically-acceptable hydrophilic solvent. US 9,308,213 B2 41 42 In aspects of this embodiment, a Solid solution composition Specific patterns of chronic inflammation are seen during comprises about 1% to about 55% by weight of therapeutic particular situations that arise in the body, Such as when compound, about 30% to about 70% by weight of room inflammation occurs on an epithelial Surface, or pyogenic temperature solid lipid or hard fat, about 1% to about 10% by bacteria are involved. For example, granulomatous inflam weight of room temperature liquid lipid, and about 1% to mation is an inflammation resulting from the formation of about 55% of triethanolamine. In other aspects of this granulomas arising from a limited but diverse number of embodiment, a solid Solution composition comprises about diseases, include, without limitation, tuberculosis, leprosy, 5% to about 50% by weight of therapeutic compound, about sarcoidosis, and syphilis. Purulent inflammation is an inflam 30% to about 60% by weight of room temperature solid lipid mation resulting in large amount of pus, which consists of 10 neutrophils, dead cells, and fluid. Infection by pyogenic bac or hard fat, about 1% to about 7% by weight of room tem teria Such as staphylococci is characteristic of this kind of perature liquid lipid, and about 5% to about 50% of a trietha inflammation. Serous inflammation is an inflammation nolamine. resulting from copious effusion of non-viscous serous fluid, In one embodiment, a pharmaceutical composition com commonly produced by mesothelial cells of serous mem prises one or more therapeutic compound, a room tempera 15 branes, but may be derived from blood plasma. Skin blisters ture Solid lipids or hard fats, one or more room temperature exemplify this pattern of inflammation. Ulcerative inflamma liquid lipids, one or more stabilizing agents, and one or more tion is an inflammation resulting from the necrotic loss of neutralizing agents, but does not comprise a pharmaceuti tissue from the epithelial Surface, exposing lower layers and cally-acceptable hydrophilic solvent. forming an ulcer. Aspects of the present specification disclose, in part, a A chronic inflammation symptom can be associated with a method of treating an individual with a chronic inflammation. large, unrelated group of disorders which underlay a variety In one embodiment, the method comprises the step of admin of diseases and disorders. The immune system is often istering to an individual in need thereof a pharmaceutical involved with chronic inflammatory disorders, demonstrated composition disclosed herein, wherein administration in both allergic reactions and some myopathies, with many reduces a symptom associated with the chronic inflammation, 25 immune system disorders resulting in abnormal inflamma thereby treating the individual. tion. Non-immune diseases with etiological origins in Aspects of the present specification disclose, in part, a solid chronic inflammatory processes include cancer, atheroscle Solution composition disclosed hereinforuse in the treatment rosis, and ischaemic heart disease. Non-limiting examples of of chronic inflammation. disorders exhibiting chronic inflammation as a symptom Aspects of the present specification disclose, in part, use of 30 include, without limitation, acne, acid reflux/heartburn, age a solid solution composition disclosed herein for the treat related macular degeneration (AMD), allergy, allergic rhini ment of chronic inflammation. tis, Alzheimer's disease, amyotrophic lateral sclerosis, ane Aspects of the present specification disclose, in part, treat mia, appendicitis, arteritis, arthritis, asthma, atherosclerosis, ing an individual Suffering from a chronic inflammation. As autoimmune disorders, balanitis, blepharitis, bronchiolitis, used herein, the term “treating.” refers to reducing or elimi 35 bronchitis, a bullous pemphigoid, burn, bursitis, cancer, car nating in an individual a clinical symptom of a chronic diac arrest, carditis, celiac disease, cellulitis, cervicitis, cho inflammation; or delaying or preventing in an individual the langitis, cholecystitis, chorioamnionitis, chronic obstructive onset of a clinical symptom of a chronic inflammation. For pulmonary disease (COPD), cirrhosis, colitis, congestive example, the term “treating can mean reducing a symptom heart failure, conjunctivitis, cyclophosphamide-induced cys of a condition characterized by a chronic inflammation by, 40 titis, cystic fibrosis, cystitis, common cold, dacryoadenitis, e.g., at least 20%, at least 25%, at least 30%, at least 35%, at dementia, dermatitis, dermatomyositis, diabetes, diabetic least 40%, at least 45%, at least 50%, at least 55%, at least neuropathy, diabetic retinopathy, diabetic nephropathy, dia 60%, at least 65%, at least 70%, at least 75%, at least 80%, at betic ulcer, digestive system disease, eczema, emphysema, least 85%, at least 90% at least 95%, or at least 100%. The encephalitis, endocarditis, endometritis, enteritis, enterocoli actual symptoms associated with chronic inflammation are 45 tis, epicondylitis, epididymitis, fasciitis, fibromyalgia, fibro well known and can be determined by a person of ordinary sis, fibrositis, gastritis, gastroenteritis, gingivitis, glomerulo skill in the art by taking into account factors, including, with nephritis, glossitis, heart disease, heart valve dysfunction, out limitation, the location of the chronic inflammation, the hepatitis, hidradenitis Suppurativa, Huntington's disease, cause of the chronic inflammation, the severity of the chronic hyperlipidemic pancreatitis, hypertension, ileitis, infection, inflammation, and/or the tissue or organ affected by the 50 inflammatory bowel disease, inflammatory cardiomegaly, chronic inflammation. Those of skill in the art will know the inflammatory neuropathy, insulin resistance, interstitial cys appropriate symptoms or indicators associated with a specific titis, interstitial nephritis, iritis, ischemia, ischemic heart dis type of chronic inflammation and will know how to determine ease, keratitis, keratoconjunctivitis, laryngitis, lupus nephri if an individual is a candidate for treatment as disclosed tis, mastitis, mastoiditis, meningitis, metabolic syndrome herein. 55 (syndrome X), a migraine, multiple Sclerosis, myelitis, myo Chronic inflammation symptoms include, without limita carditis, myositis, nephritis, non-alcoholic steatohepatitis, tion, edema, hyperemia, erythema, bruising, tenderness, stiff obesity, omphalitis, oophoritis, orchitis, osteochondritis, ness, Swollenness, fever, chills, stuffy nose, stuffy head, osteopenia, osteomyelitis, osteoporosis, osteitis, otitis, pan breathing problems, fluid retention, blood clots, loss of appe creatitis, Parkinson's disease, parotitis, pelvic inflammatory tite, increased heart rate, formation of granulomas, fibrinous, 60 disease, pemphigus Vularis, pericarditis, peritonitis, pharyn pus, non-viscous serous fluid, or ulcer and pain. The actual gitis, phlebitis, pleuritis, pneumonitis, polycystic nephritis, symptoms associated with a chronic inflammation are well proctitis, prostatitis, psoriasis, pulpitis, pyelonephritis, pyle known and can be determined by a person of ordinary skill in phlebitis, renal failure, reperfusion injury, retinitis, rheumatic the art by taking into account factors, including, without fever, rhinitis, salpingitis, sarcoidosis, Sialadenitis, sinusitis, limitation, the location of the inflammation, the cause of the 65 spastic colon, Stenosis, stomatitis, stroke, Surgical complica inflammation, the severity of the inflammation, the tissue or tion, synovitis, tendonitis, tendinosis, tenosynovitis, throm organ affected, and the associated disorder. bophlebitis, tonsillitis, trauma, traumatic brain injury, trans US 9,308,213 B2 43 44 plant rejection, trigonitis, tuberculosis, tumor, urethritis, (including discoid lupus erythematosus, drug-induced lupus ursitis, uveitis, vaginitis, vasculitis, and Vulvitis. See also, erythematosus, lupus nephritis, neonatal lupus, Subacute Eric R. First, Application of Botulinum Toxin to the Manage cutaneous lupus erythematosus and systemic lupus erythe ment of Neurogenic Inflammatory Disorders, U.S. Pat. No. matosus), morphea, multiple Sclerosis (MS), myasthenia 6,063,768, which is hereby incorporated by reference in its gravis, myopathies, narcolepsy, neuromyotonia, pemphigus entirety. Vulgaris, pernicious anaemia, primary biliary cirrhosis, recur In one embodiment, a chronic inflammation comprises a rent disseminated encephalomyelitis (multiphasic dissemi tissue inflammation. Tissue inflammation is a chronic inflam nated encephalomyelitis), rheumatic fever, Schizophrenia, mation that is confined to a particular tissue or organ. In Scleroderma, Sjögren's syndrome, tenosynovitis, vasculitis, aspect of this embodiment, a tissue inflammation comprises, 10 and vitiligo. See Pamela D. Van Schaack & Kenneth L. Tong, e.g., a skin inflammation, a muscle inflammation, a tendon Treatment of Autoimmune Disorder with a Neurotoxin, U.S. inflammation, aligament inflammation, a bone inflammation, Patent Publication 2006/138059, which is hereby incorpo a cartilage inflammation, a lung inflammation, a heart inflam rated by reference in its entirety. mation, a liver inflammation, a pancreatic inflammation, a In another embodiment, a chronic inflammation comprises kidney inflammation, a bladder inflammation, a stomach 15 a myopathy. Myopathies are caused when the immune system inflammation, an intestinal inflammation, a neuron inflam inappropriately attacks components of the muscle, leading to mation, and a brain inflammation. inflammation in the muscle. A myopathy includes an inflam In another embodiment, a chronic inflammation comprises matory myopathy and an auto-immune myopathy. Myopa a systemic inflammation. Although the processes involved are thies include, without limitation, dermatomyositis, inclusion identical to tissue inflammation, systemic inflammation is not body myositis, and polymyositis. confined to a particular tissue but in fact overwhelms the In another embodiment, a chronic inflammation comprises body, involving the endothelium and other organ systems. a vasculitis. Vasculitis is a varied group of disorders featuring When it is due to infection, the term sepsis is applied, with the inflammation of a vessel wall including lymphatic vessels and terms bacteremia being applied specifically for bacterial sep blood vessels like veins (phlebitis), arteries (arteritis) and sis and Viremia specifically to viral sepsis. Vasodilation and 25 capillaries due to leukocyte migration and resultant damage. organ dysfunction are serious problems associated with wide The inflammation may affect any size blood vessel, anywhere spread infection that may lead to septic shock and death. in the body. It may affect either arteries and/or veins. The In another embodiment, a chronic inflammation comprises inflammation may be focal, meaning that it affects a single an arthritis. Arthritis includes a group of conditions involving location within a vessel; or it may be widespread, with areas damage to the joints of the body due to the inflammation of 30 of inflammation scattered throughout a particular organ or the synovium including, without limitation osteoarthritis, tissue, or even affecting more than one organ system in the rheumatoid arthritis,juvenile idiopathic arthritis, spondyloar body. Vasculitis include, without limitation, Buerger's dis thropathies like ankylosing spondylitis, reactive arthritis (Re ease (thromboangiitis obliterans), cerebral vasculitis (central iter's syndrome), psoriatic arthritis, enteropathic arthritis nervous system vasculitis), Churg-Strauss arteritis, cryoglo associated with inflammatory bowel disease, Whipple dis 35 bulinemia, essential cryoglobulinemic vasculitis, giant cell ease and Behcet disease, septic arthritis, gout (also known as (temporal) arteritis, Golfers vasculitis, Henoch-Schonlein gouty arthritis, crystal synovitis, metabolic arthritis), pseudo purpura, hypersensitivity vasculitis (allergic vasculitis), gout (calcium pyrophosphate deposition disease), and Stills Kawasaki disease, microscopic polyarteritis/polyangiitis, disease. Arthritis can affect a single joint (monoarthritis), two polyarteritis nodosa, polymyalgia rheumatica (PMR), rheu to four joints (oligoarthritis) or five or more joints (polyarthri 40 matoid vasculitis, Takayasu arteritis, Wegener's granuloma tis) and can be either an auto-immune disease or a non tosis, and vasculitis secondary to connective tissue disorders autoimmune disease. like systemic lupus erythematosus (SLE), rheumatoid arthri In another embodiment, a chronic inflammation comprises tis (RA), relapsing polychondritis, Behcet’s disease, or other an autoimmune disorder. Autoimmune diseases can be connective tissue disorders, vasculitis secondary to viral broadly divided into systemic and organ-specific autoim 45 infection. mune disorders, depending on the principal clinico-patho In another embodiment, a chronic inflammation comprises logic features of each disease. Systemic autoimmune diseases a skin disorder. Skin disorders include, without limitation, an include, without limitation, systemic lupus erythematosus acne, including acne Vulgaris, a bullous phemigoid, a derma (SLE), Sjögren's syndrome, Scleroderma, rheumatoid arthri titis, including atopic dermatitis and chronic actinic dermati tis and polymyositis. Local autoimmune diseases may be 50 tis, an eczema like atopic eczema, contact eczema, Xerotic endocrinologic (Diabetes Mellitus Type 1, Hashimoto's thy eczema, Seborrhoeic dermatitis, dyshidrosis, discoid eczema, roiditis, Addison's disease etc.), dermatologic (pemphig us venous eczema, dermatitis herpetiformis, neurodermatitis, Vulgaris), hematologic (autoimmune haemolytic anemia), and autoeczematization, and Statis dermatitis, hidradenitis neural (multiple Sclerosis) or can involve virtually any cir Suppurativa, lichen planus, psoriasis including plaqure pso cumscribed mass of body tissue. Types of autoimmune dis 55 riasis, nail psoriasis, guttate psoriasis, Scalp psoriasis, inverse orders include, without limitation, acute disseminated psoriasis, pustular psoriasis, erythrodermis psoriasis, and encephalomyelitis (ADEM). Addison's disease, an allergy or psoriatic arthritis, rosacea and Scleroderma including mor sensitivity, amyotrophic lateral Sclerosis, anti-phospholipid phea. antibody syndrome (APS), arthritis, autoimmune hemolytic In another embodiment, a chronic inflammation comprises anemia, autoimmune hepatitis, autoimmune inner ear dis 60 a gastrointestinal disorder. A gastrointestinal disorder ease, autoimmune pancreatitis, bullous pemphigoid, celiac includes, without limitation, irritable bowel disease, an disease, Chagas disease, chronic obstructive pulmonary dis inflammatory bowel disease including Crohn's disease and ease (COPD), diabetes mellitus type 1 (IDDM), endometrio an ulcerative colitis like ulcerative proctitis, left-sided colitis, sis, fibromyalgia, Goodpasture's syndrome, Graves disease, pancolitis and fulminant colitis. Guillain-Barré syndrome (GBS), Hashimoto's thyroiditis, 65 In another embodiment, a chronic inflammation comprises hidradenitis Suppurativa, idiopathic thrombocytopenic pur a cardiovascular disease. When LDL cholesterol becomes pura, inflammatory bowel disease, interstitial cystitis, lupus embedded in arterial walls, it can invoke an immune response. US 9,308,213 B2 45 46 Chronic inflammation eventually can damage the arteries, In another embodiment, a chronic inflammation comprises which can cause them to burst. Cardiovascular disease is any a transplant rejection. Transplant rejection occurs when a of a number of specific diseases that affect the heart itself transplanted organ or tissue is not accepted by the body of the and/or the blood vessel system, especially the veins and arter transplant recipient because the immune system of the recipi ies leading to and from the heart. There are more than 60 types ent attacks the transplanted organ or tissue. An adaptive of cardiovascular disorders including, without limitation, a immune response, transplant rejection is mediated through hypertension, endocarditis, myocarditis, heart Valve dysfunc both T cell mediated and humoral immune (antibodies) tion, congestive heart failure, myocardial infarction, a dia mechanisms. A transplant rejection can be classified as a betic cardiac conditions, blood vessel inflammation like hyperacute rejection, an acute rejection, or a chronic rejec arteritis, phlebitis, vasculitis; arterial occlusive disease like 10 tion. Chronic rejection of a transplanted organ or tissue is arteriosclerosis and Stenosis, inflammatory cardiomegaly, a where the rejection is due to a poorly understood chronic peripheral arterial disease; an aneurysm; an embolism; a dis inflammatory and immune response against the transplanted section; a pseudoaneurysm; a vascular malformation; a vas tissue. Also included in the term “transplant rejection' is a cular nevus; a thrombosis; a thrombphlebitis; a varicose graft-versus-host disease (GVHD). GVHD is a common veins; a stroke. Symptoms of a cardiovascular disorder affect 15 complication of allogeneic bone marrow transplantation in ing the heart include, without limitation, chest pain or chest which functional immune cells in the transplanted marrow discomfort (angina), pain in one or both arms, the left shoul recognize the recipient as “foreign' and mount an immuno der, neck, jaw, or back, shortness of breath, dizziness, faster logic attack. It can also take place in a blood transfusion under heartbeats, nausea, abnormal heartbeats, feeling fatigued. certain circumstances. GVHD is divided into acute and Symptoms of a cardiovascular disorder affecting the brain chronic forms. Acute and chronic GVHD appear to involve include, without limitation, Sudden numbness or weakness of different immune cell subsets, different cytokine profiles, the face, arm, or leg, especially on one side of the body, somewhat different host targets, and respond differently to Sudden confusion or trouble speaking or understanding treatment. speech, Sudden trouble seeing in one or both eyes, Sudden In another embodiment, a chronic inflammation comprises dizziness, difficulty walking, or loss of balance or coordina 25 a Th1-mediated inflammatory disease. In a well-functioning tion, Sudden severe headache with no known cause. Symp immune system, an immune response should result in a well toms of a cardiovascular disorder affecting the legs, pelvis balanced pro-inflammatory Th1 response and anti-inflamma and/or arm include, without limitation, claudication, which is tory Th2 response that is suited to address the immune chal a pain, ache, or cramp in the muscles, and cold or numb lenge. Generally speaking, once a pro-inflammatory Th1 feeling in the feet or toes, especially at night. 30 response is initiated, the body relies on the anti-inflammatory In another embodiment, a chronic inflammation comprises response invoked by a Th2 response to counteract this Th1 a cancer. Inflammation orchestrates the microenvironment response. This counteractive response includes the release of around tumors, contributing to proliferation, Survival and Th2 type cytokines such as, e.g., IL-4, IL-5, and IL-13 which migration. For example, fibrinous inflammation results from are associated with the promotion of IgE and eosinophilic a large increase in vascular permeability which allows fibrin 35 responses in atopy, and also IL-10, which has an anti-inflam to pass through the blood vessels. If an appropriate procoagul matory response. A Th1-mediated inflammatory disease lative stimulus is present, such as cancer cells, a fibrinous involves an excessive pro-inflammatory response produced exudate is deposited. This is commonly seen in serous cavi by Th1 cells that leads to chronic inflammation. The Th1 - ties, where the conversion offibrinous exudate into a scar can mediated disease may be virally, bacterially or chemically occur between serous membranes, limiting their function. In 40 (e.g. environmentally) induced. For example, a virus causing another example, a cancer is an inflammatory cancer like a the Th1-mediated disease may cause a chronic or acute infec NF-kB-driven inflammatory cancer. tion, which may cause a respiratory disorder or influenza. In another embodiment, a chronic inflammation comprises In another embodiment, a chronic inflammation comprises a pharmacologically-induced inflammation. Certain drugs or a chronic neurogenic inflammation. Chronic neurogenic exogenic chemical compounds are known to affect inflam 45 Inflammation refers to an inflammatory response initiated mation. For example, VitaminA deficiency causes an increase and/or maintained through the release of inflammatory mol in an inflammatory response. Certain illicit drugs such as ecules like SP or CGRP which released from peripheral sen cocaine and ecstasy may exert Some of their detrimental sory nerve terminals (i.e., an efferent function, in contrast to effects by activating transcription factors intimately involved the normal afferent signaling to the spinal cord in these with inflammation (e.g. NF-kB). 50 nerves). Chronic neurogenic inflammation includes both pri In another embodiment, a chronic inflammation comprises mary inflammation and secondary neurogenic inflammation. an infection. An infectious organism can escape the confines As used herein, the term “primary neurogenic inflammation of the immediate tissue via the circulatory system or lym refers to tissue inflammation (inflammatory symptoms) that phatic system, where it may spread to other parts of the body. is initiated by, or results from, the release of substances from Ifan organism is not contained by the actions of acute inflam 55 primary sensory nerve terminals (such as C and A-delta mation it may gain access to the lymphatic system via nearby fibers). As used herein, the term “secondary neurogenic lymph vessels. An infection of the lymph vessels is known as inflammation” refers to tissue inflammation initiated by non lymphangitis, and infection of a lymph node is known as neuronal sources (e.g., extravasation from vascular bed or lymphadenitis. A pathogen can gain access to the blood tissue interstitium-derived. Such as from mast cells or stream through lymphatic drainage into the circulatory sys 60 immune cells) of inflammatory mediators, such as peptides or tem. Infections include, without limitation, bacterial cystitis, cytokines, stimulating sensory nerve terminals and causing a bacterial encephalitis, pandemic influenza, Viral encephalitis, release of inflammatory mediators from the nerves. The net and viral hepatitis (A, B and C). effect of both forms (primary and secondary) of chronic neu In another embodiment, a chronic inflammation comprises rogenic inflammation is to have an inflammatory state that is a tissue or organ injury. Tissue or organ injuries include, 65 maintained by the sensitization of the peripheral sensory without limitation, a burn, a laceration, a wound, a puncture, nerve fibers. The physiological consequence of the resulting Or a trauma. chronic neurogenic inflammation depends on the tissue in US 9,308,213 B2 47 48 question, producing. Such as, e.g., cutaneous pain (allodynia, at most 90%, at most 95% or at most 100%. In yet other hyperalgesia), joint pain and/or arthritis, visceral pain and aspects of this embodiment, a therapeutically effective dysfunction, pulmonary dysfunction (asthma, COPD), and amount ofatherapeutic compound disclosed herein reduces a bladder dysfunction (pain, overactive bladder). symptom associated with a chronic inflammation by, e.g., A composition or compound is administered to an indi 5 about 10% to about 100%, about 10% to about 90%, about vidual. An individual is typically a human being. Typically, 10% to about 80%, about 10% to about 70%, about 10% to any individual who is a candidate for a conventional chronic about 60%, about 10% to about 50%, about 10% to about inflammation treatment is a candidate for a chronic inflam 40%, about 20% to about 100%, about 20% to about 90%, mation treatment disclosed herein. Pre-operative evaluation about 20% to about 80%, about 20% to about 20%, about 20% typically includes routine history and physical examination in 10 to about 60%, about 20% to about 50%, about 20% to about addition to thorough informed consent disclosing all relevant 40%, about 30% to about 100%, about 30% to about 90%, risks and benefits of the procedure. about 30% to about 80%, about 30% to about 70%, about 30% A pharmaceutical composition disclosed herein may com to about 60%, or about 30% to about 50%. prise a therapeutic compound in a therapeutically effective In yet other aspects of this embodiment, a therapeutically amount. As used herein, the term “effective amount' is syn 15 effective amount of a therapeutic compound disclosed herein onymous with “therapeutically effective amount”, “effective generally is in the range of about 0.001 mg/kg/day to about dose”, or “therapeutically effective dose” and when used in 100 mg/kg/day. In aspects of this embodiment, an effective reference to treating a chronic inflammation refers to the amount of a therapeutic compound disclosed herein may be, minimum dose of a therapeutic compound disclosed herein e.g., at least 0.001 mg/kg/day, at least 0.01 mg/kg/day, at least necessary to achieve the desired therapeutic effect and 0.1 mg/kg/day, at least 1.0 mg/kg/day, at least 5.0 mg/kg/day, includes a dose Sufficient to reduce a symptom associated at least 10 mg/kg/day, at least 15 mg/kg/day, at least 20 with a chronic inflammation. The effectiveness of a therapeu mg/kg/day, at least 25 mg/kg/day, at least 30 mg/kg/day, at tic compound disclosed herein in treating a chronic inflam least 35 mg/kg/day, at least 40 mg/kg/day, at least 45 mg/kg/ mation can be determined by observing an improvement in an day, or at least 50 mg/kg/day. In other aspects of this embodi individual based upon one or more clinical symptoms, and/or 25 ment, an effective amount of a therapeutic compound dis physiological indicators associated with the condition. An closed herein may be in the range of, e.g., about 0.001 mg/kg/ improvement in a chronic inflammation also can be indicated day to about 10 mg/kg/day, about 0.001 mg/kg/day to about by a reduced need for a concurrent therapy. 15 mg/kg/day, about 0.001 mg/kg/day to about 20 mg/kg/day, The appropriate effective amount of a therapeutic com about 0.001 mg/kg/day to about 25 mg/kg/day, about 0.001 pound disclosed herein to be administered to an individual for 30 mg/kg/day to about 30 mg/kg/day, about 0.001 mg/kg/day to a particular chronic inflammation can be determined by a about 35 mg/kg/day, about 0.001 mg/kg/day to about 40 person of ordinary skill in the art by taking into account mg/kg/day, about 0.001 mg/kg/day to about 45 mg/kg/day, factors, including, without limitation, the type of chronic about 0.001 mg/kg/day to about 50 mg/kg/day, about 0.001 inflammation, the location of the chronic inflammation, the mg/kg/day to about 75 mg/kg/day, or about 0.001 mg/kg/day cause of the chronic inflammation, the severity of the chronic 35 to about 100 mg/kg/day. In yet other aspects of this embodi inflammation, the degree of relief desired, the duration of ment, an effective amount of a therapeutic compound dis relief desired, the particular therapeutic compound used, the closed herein may be in the range of, e.g., about 0.01 mg/kg/ rate of excretion of the therapeutic compound used, the phar day to about 10 mg/kg/day, about 0.01 mg/kg/day to about 15 macodynamics of the therapeutic compound used, the nature mg/kg/day, about 0.01 mg/kg/day to about 20 mg/kg/day, of the other compounds to be included in the composition, the 40 about 0.01 mg/kg/day to about 25 mg/kg/day, about 0.01 particular formulation, the particular route of administration, mg/kg/day to about 30 mg/kg/day, about 0.01 mg/kg/day to the particular characteristics, history and risk factors of the about 35 mg/kg/day, about 0.01 mg/kg/day to about 40 patient, such as, e.g., age, weight, general health and the like, mg/kg/day, about 0.01 mg/kg/day to about 45 mg/kg/day, or any combination thereof. Additionally, where repeated about 0.01 mg/kg/day to about 50 mg/kg/day, about 0.01 administration of a therapeutic compound is used, an effec 45 mg/kg/day to about 75 mg/kg/day, or about 0.01 mg/kg/day to tive amount of a therapeutic compound will further depend about 100 mg/kg/day. In still other aspects of this embodi upon factors, including, without limitation, the frequency of ment, an effective amount of a therapeutic compound dis administration, the half-life of the therapeutic compound, or closed herein may be in the range of, e.g., about 0.1 mg/kg/ any combination thereof. In is known by a person of ordinary day to about 10 mg/kg/day, about 0.1 mg/kg/day to about 15 skill in the art that an effective amount of a therapeutic com 50 mg/kg/day, about 0.1 mg/kg/day to about 20 mg/kg/day, pound disclosed herein can be extrapolated from in vitro about 0.1 mg/kg/day to about 25 mg/kg/day, about 0.1 mg/kg/ assays and in Vivo administration studies using animal mod day to about 30 mg/kg/day, about 0.1 mg/kg/day to about 35 els prior to administration to humans. mg/kg/day, about 0.1 mg/kg/day to about 40 mg/kg/day, In aspects of this embodiment, a therapeutically effective about 0.1 mg/kg/day to about 45 mg/kg/day, about 0.1 mg/kg/ amount ofatherapeutic compound disclosed herein reduces a 55 day to about 50 mg/kg/day, about 0.1 mg/kg/day to about 75 symptom associated with a chronic inflammation by, e.g., at mg/kg/day, or about 0.1 mg/kg/day to about 100 mg/kg/day. least 10%, at least 15%, at least 20%, at least 25%, at least In other aspects of this embodiment, an effective amount of 30%, at least 35%, at least 40%, at least 45%, at least 50%, at atherapeutic compound disclosed herein may be in the range least 55%, at least 60%, at least 65%, at least 70%, at least of e.g., about 1 mg/kg/day to about 10 mg/kg/day, about 1 75%, at least 80%, at least 85%, at least 90%, at least 95% or 60 mg/kg/day to about 15 mg/kg/day, about 1 mg/kg/day to at least 100%. In other aspects of this embodiment, a thera about 20 mg/kg/day, about 1 mg/kg/day to about 25 mg/kg/ peutically effective amount of a therapeutic compound dis day, about 1 mg/kg/day to about 30 mg/kg/day, about 1 closed herein reduces a symptom associated with a chronic mg/kg/day to about 35 mg/kg/day, about 1 mg/kg/day to inflammation by, e.g., at most 10%, at most 15%, at most about 40 mg/kg/day, about 1 mg/kg/day to about 45 mg/kg/ 20%, at most 25%, at most 30%, at most 35%, at most 40%, 65 day, about 1 mg/kg/day to about 50 mg/kg/day, about 1 at most 45%, at most 50%, at most 55%, at most 60%, at most mg/kg/day to about 75 mg/kg/day, or about 1 mg/kg/day to 65%, at most 70%, at most 75%, at most 80%, at most 85%, about 100 mg/kg/day. In yet other aspects of this embodi US 9,308,213 B2 49 50 ment, an effective amount of a therapeutic compound dis of the pharmaceutical composition disclosed herein is pref closed herein may be in the range of, e.g., about 5 mg/kg/day erentially delivered to a macrophage. In other aspect of this to about 10 mg/kg/day, about 5 mg/kg/day to about 15 mg/kg/ embodiment, upon administration to an individual, a thera day, about 5 mg/kg/day to about 20 mg/kg/day, about 5 peutic compound of the pharmaceutical composition dis mg/kg/day to about 25 mg/kg/day, about 5 mg/kg/day to 5 closed herein is substantially delivered to a macrophage. In about 30 mg/kg/day, about 5 mg/kg/day to about 35 mg/kg/ yet other aspect of this embodiment, upon administration to day, about 5 mg/kg/day to about 40 mg/kg/day, about 5 an individual, the amount of a therapeutic compound of the mg/kg/day to about 45 mg/kg/day, about 5 mg/kg/day to pharmaceutical composition disclosed herein delivered to a about 50 mg/kg/day, about 5 mg/kg/day to about 75 mg/kg/ macrophage is, e.g., at least 5%, at least 10%, at least 15%, at day, or about 5 mg/kg/day to about 100 mg/kg/day. 10 least 20%, at least 25%, at least 30%, at least 35%, at least Dosing can be single dosage or cumulative (serial dosing), 40%, at least 45%, at least 50%, at least 55%, at least 60%, at and can be readily determined by one skilled in the art. For least 65%, at least 70%, at least 75%, at least 80%, at least instance, treatment of a chronic inflammation may comprise 85%, at least 90%, at least 95%, or at least 100% of the total a one-time administration of an effective dose of a pharma amount of the therapeutic compound contained in the admin ceutical composition disclosed herein. Alternatively, treat 15 istered pharmaceutical composition. In still other aspects of ment of a chronic inflammation may comprise multiple this embodiment, upon administration to an individual, the administrations of an effective dose of a pharmaceutical com amount of a therapeutic compound of the pharmaceutical position carried out over a range of time periods, such as, e.g., composition disclosed herein delivered to a macrophage is in once daily, twice daily, trice daily, once every few days, or a range of, e.g., about 5% to about 100%, about 10% to about once weekly. The timing of administration can vary from 100%, about 15% to about 100%, about 20% to about 100%, individual to individual, depending upon Such factors as the about 25% to about 100%, about 30% to about 100%, about severity of an individual’s symptoms. For example, an effec 35% to about 100%, about 40% to about 100%, about 45% to tive dose of a pharmaceutical composition disclosed herein about 100%, about 50% to about 100%, about 5% to about can be administered to an individual once daily for an indefi 90%, about 10% to about 90%, about 15% to about 90%, nite period of time, or until the individual no longer requires 25 about 20% to about 90%, about 25% to about 90%, about 30% therapy. A person of ordinary skill in the art will recognize to about 90%, about 35% to about 90%, about 40% to about that the condition of the individual can be monitored through 90%, about 45% to about 90%, about 50% to about 90%, out the course of treatment and that the effective amount of a about 5% to about 80%, about 10% to about 80%, about 15% pharmaceutical composition disclosed herein that is admin to about 80%, about 20% to about 80%, about 25% to about istered can be adjusted accordingly. 30 80%, about 30% to about 80%, about 35% to about 80%, Various routes of administration can be useful for admin about 40% to about 80%, about 45% to about 80%, about 50% istering a therapeutic compound disclosed herein, according to about 80%, about 5% to about 70%, about 10% to about to a method of treating a chronic inflammation disclosed 70%, about 15% to about 70%, about 20% to about 70%, herein. A pharmaceutical composition may be administered about 25% to about 70%, about 30% to about 70%, about 35% to an individual by any of a variety of means depending, e.g., 35 to about 70%, about 40% to about 70%, about 45% to about on the type of the chronic inflammation to be treated, the 70%, or about 50% to about 70% of the total amount of the location of the chronic inflammation to be treated, the specific therapeutic compound contained in the administered pharma therapeutic compound or composition used, or other com ceutical composition. pound to be included in the composition, and the history, risk In another embodiment, upon administration to an indi factors and symptoms of the individual. As such, topical, 40 vidual, a therapeutic compound of the pharmaceutical com enteral or parenteral routes of administration may be suitable position disclosed herein is delivered to a dentritic cell. Den for of treating a chronic inflammation disclosed herein and dritic cells are one of the key cell types believed to coordinate such routes include both local and systemic delivery of a the interplay between innate and adaptive immunity. The therapeutic compound or composition disclosed herein. resultant high level of a therapeutic compound having anti Compositions comprising either a single therapeutic com 45 pain activity present in the dentritic cells results in a clinically pound disclosed herein, or two or more therapeutic com effective treatment of chronic inflammation. In an aspect of pounds disclosed herein are intended for inhaled, topical, this embodiment, upon administration to an individual, a intranasal, Sublingual, injection, infusion, instillation, rectal therapeutically effective amount of a therapeutic compound and/or vaginal use may be prepared according to any method of the pharmaceutical composition disclosed herein is pref known to the art for the manufacture of pharmaceutical com 50 erentially delivered to a dentritic cell. In other aspect of this positions. embodiment, upon administration to an individual, a thera In one embodiment, upon administration to an individual, peutic compound of the pharmaceutical composition dis a pharmaceutical composition comprising a therapeutic com closed herein is substantially delivered to a dentritic cell. In pound disclosed herein results in a bio-distribution of the yet other aspect of this embodiment, upon administration to therapeutic compound different than a bio-distribution of the 55 an individual, the amount of a therapeutic compound of the therapeutic compound included in the same pharmaceutical pharmaceutical composition disclosed herein delivered to a composition, except without an adjuvant disclosed herein. dentritic cell is, e.g., at least 5%, at least 10%, at least 15%, at In another embodiment, upon administration to an indi least 20%, at least 25%, at least 30%, at least 35%, at least vidual, a therapeutic compound of the pharmaceutical com 40%, at least 45%, at least 50%, at least 55%, at least 60%, at position disclosed herein is delivered to a macrophage. Mac 60 least 65%, at least 70%, at least 75%, at least 80%, at least rophages are one of the key cell types believed to be involved 85%, at least 90%, at least 95%, or at least 100% of the total in the control of the inflammation response. The resultant amount of the therapeutic compound contained in the admin high level of a therapeutic compound having anti-inflamma istered pharmaceutical composition. In still other aspects of tory activity present in the macrophages results in a clinically this embodiment, upon administration to an individual, the effective treatment of chronic inflammation. In an aspect of 65 amount of a therapeutic compound of the pharmaceutical this embodiment, upon administration to an individual, a composition disclosed herein delivered to a dentritic cell is in therapeutically effective amount of a therapeutic compound a range of, e.g., about 5% to about 100%, about 10% to about US 9,308,213 B2 51 52 100%, about 15% to about 100%, about 20% to about 100%, herein, except without the pharmaceutically-acceptable adju about 25% to about 100%, about 30% to about 100%, about vant. In an aspect of this embodiment, a pharmaceutical com 35% to about 100%, about 40% to about 100%, about 45% to position disclosed herein Substantially reduces intestinal irri about 100%, about 50% to about 100%, about 5% to about tation when compared to the same pharmaceutical 90%, about 10% to about 90%, about 15% to about 90%, composition disclosed herein, except without the pharmaceu about 20% to about 90%, about 25% to about 90%, about 30% tically-acceptable adjuvant. In other aspects of this embodi to about 90%, about 35% to about 90%, about 40% to about ment, a pharmaceutical composition disclosed herein reduces 90%, about 45% to about 90%, about 50% to about 90%, intestinal irritation by, e.g., at least 5%, at least 10%, at least about 5% to about 80%, about 10% to about 80%, about 15% 20%, at least 30%, at least 40%, at least 50%, at least 60%, at to about 80%, about 20% to about 80%, about 25% to about 10 80%, about 30% to about 80%, about 35% to about 80%, least 70%, at least 80%, at least 90%, or at least 100% when about 40% to about 80%, about 45% to about 80%, about 50% compared to the same pharmaceutical composition disclosed to about 80%, about 5% to about 70%, about 10% to about herein, except without the pharmaceutically-acceptable adju 70%, about 15% to about 70%, about 20% to about 70%, vant. In yet other aspects of this embodiment, a pharmaceu about 25% to about 70%, about 30% to about 70%, about 35% 15 tical composition disclosed herein reduces intestinal irritation to about 70%, about 40% to about 70%, about 45% to about by, e.g., about 5% to about 100%, about 10% to about 100%, 70%, or about 50% to about 70% of the total amount of the about 15% to about 100%, about 20% to about 100%, about therapeutic compound contained in the administered pharma 25% to about 100%, about 30% to about 100%, about 35% to ceutical composition. about 100%, about 40% to about 100%, about 45% to about In another embodiment, upon administration to an indi 100%, about 50% to about 100%, about 5% to about 90%, vidual, a pharmaceutical composition disclosed herein about 10% to about 90%, about 15% to about 90%, about 20% reduces gastric irritation. In an aspect of this embodiment, a to about 90%, about 25% to about 90%, about 30% to about pharmaceutical composition disclosed herein Substantially 90%, about 35% to about 90%, about 40% to about 90%, reduces gastric irritation. In yet another embodiment, upon about 45% to about 90%, about 50% to about 90%, about 5% administration to an individual, a pharmaceutical composi 25 to about 80%, about 10% to about 80%, about 15% to about tion disclosed herein reduces gastric irritation when com 80%, about 20% to about 80%, about 25% to about 80%, pared to the same pharmaceutical composition disclosed about 30% to about 80%, about 35% to about 80%, about 40% herein, except without the pharmaceutically-acceptable adju to about 80%, about 45% to about 80%, about 50% to about vant. In an aspect of this embodiment, a pharmaceutical com 80%, about 5% to about 70%, about 10% to about 70%, about position disclosed herein Substantially reduces gastric irrita 30 tion when compared to the same pharmaceutical composition 15% to about 70%, about 20% to about 70%, about 25% to disclosed herein, except without the pharmaceutically-ac about 70%, about 30% to about 70%, about 35% to about ceptable adjuvant. In other aspects of this embodiment, a 70%, about 40% to about 70%, about 45% to about 70%, or pharmaceutical composition disclosed herein reduces gastric about 50% to about 70% when compared to the same phar irritation by, e.g., at least 5%, at least 10%, at least 15%, at 35 maceutical composition disclosed herein, except without the least 20%, at least 25%, at least 30%, at least 35%, at least pharmaceutically-acceptable adjuvant. 40%, at least 45%, at least 50%, at least 55%, at least 60%, at A pharmaceutical composition disclosed hereincan also be least 65%, at least 70%, at least 75%, at least 80%, at least administered to an individual in combination with other 85%, at least 90%, at least 95%, or at least 100%. In yet other therapeutic compounds to increase the overall therapeutic aspects of this embodiment, a pharmaceutical composition 40 effect of the treatment. The use of multiple compounds to disclosed herein reduces gastric irritation in a range of, e.g., treat an indication can increase the beneficial effects while about 5% to about 100%, about 10% to about 100%, about reducing the presence of side effects. 15% to about 100%, about 20% to about 100%, about 25% to Aspects of the present invention can also be described as about 100%, about 30% to about 100%, about 35% to about follows: 100%, about 40% to about 100%, about 45% to about 100%, 45 1. A Solid solution pharmaceutical composition comprising: about 50% to about 100%, about 5% to about 90%, about 10% a) a therapeutic compound, wherein the therapeutic com to about 90%, about 15% to about 90%, about 20% to about pound has an anti-inflammatory activity; b) a room tem 90%, about 25% to about 90%, about 30% to about 90%, perature solid lipid; and c) a room temperature liquid lipid. about 35% to about 90%, about 40% to about 90%, about 45% 2. The Solid solution pharmaceutical composition according to about 90%, about 50% to about 90%, about 5% to about 50 to embodiment 1, wherein the composition further com 80%, about 10% to about 80%, about 15% to about 80%, prises a stabilizing agent. about 20% to about 80%, about 25% to about 80%, about 30% 3. The Solid solution pharmaceutical composition according to about 80%, about 35% to about 80%, about 40% to about to embodiment 1 or 2, wherein the composition further 80%, about 45% to about 80%, about 50% to about 80%, comprises a neutralizing agent. about 5% to about 70%, about 10% to about 70%, about 15% 55 4. A Solid solution pharmaceutical composition according to to about 70%, about 20% to about 70%, about 25% to about embodiments 1-3, wherein the solid solution pharmaceu 70%, about 30% to about 70%, about 35% to about 70%, tical composition does not comprise a surfactant. about 40% to about 70%, about 45% to about 70%, or about 5. A Solid solution pharmaceutical composition according to 50% to about 70%. embodiments 1-4, wherein the Solid solution pharmaceu In another embodiment, upon administration to an indi 60 tical composition does not comprise a hydrophilic solvent. vidual, a pharmaceutical composition disclosed herein 6. The Solid solution pharmaceutical composition according reduces intestinal irritation. In an aspect of this embodiment, to embodiments 1-5, wherein the anti-inflammatory activ a pharmaceutical composition disclosed herein Substantially ity reduces the level of an inflammation inducing molecule. reduces intestinal irritation. In yet another embodiment, upon 7. The Solid solution pharmaceutical composition according administration to an individual, a pharmaceutical composi 65 to embodiment 6, wherein the inflammation inducing mol tion disclosed herein reduces intestinal irritation when com ecule comprises substance P(SP), calcitonin gene-related pared to the same pharmaceutical composition disclosed peptide (CGRP), glutamate, or a combination thereof. US 9,308,213 B2 53 54 8. The Solid solution pharmaceutical composition according 25. The pharmaceutical composition according to embodi to embodiment 7, wherein the anti-inflammatory activity ments 1-24, wherein the therapeutic compound comprises reduces the level of SP, CGRP. glutamate, or a combination a PPARC. agonist, a PPARB/ö agonist, a PPARYagonist, or thereof by at least 10%. a Glitazar. 9. The Solid solution pharmaceutical composition according 5 26. The pharmaceutical composition according to embodi to embodiments 1-8, wherein the anti-inflammatory activ ments 1-25, wherein the therapeutic compound comprises ity reduces the level of an inflammation inducing prostag an immunosupressive drug, an uricoSuric drug, an Agly landin. cone, or a Cannabidiol. 10. The Solid solution pharmaceutical composition according 27. The pharmaceutical composition according to embodi to embodiment 9, wherein the level of the inflammation 10 ments 1-26, wherein the therapeutic compound comprises inducing prostaglandin is reduced by at least 10%. a Ryanodine receptor antagonist. 11. The Solid solution pharmaceutical composition according 28. The pharmaceutical composition according to embodi to embodiments 1-10, wherein the anti-inflammatory ment 27, wherein the Ryanodine receptor antagonist is activity stimulates a PPAR signaling pathway. AZumolene or Dantrolene. 12. The Solid solution pharmaceutical composition according 15 29. The pharmaceutical composition according to embodi to embodiment 11, wherein the PPAR signaling pathway is ments 1-28, wherein the therapeutic compound comprises stimulated by at least 10%. a nuclear receptor binding agent. 13. The Solid solution pharmaceutical composition according 30. The pharmaceutical composition according to embodi to embodiments 1-12, wherein the anti-inflammatory ment 29, wherein the nuclear receptor binding agent com activity induces apoptosis of Macrophage M1 cells, pro prises a Retinoic Acid Receptor (RAR) binding agent, a motes differentiation of Macrophage M2 cells, or both. Retinoid X Receptor (RXR) binding agent, a Liver X 14. The Solid solution pharmaceutical composition according Receptor (LXR) binding agent, a Vitamin D binding agent, to embodiments 1-13, wherein the anti-inflammatory or a combination thereof. activity reducing the levels of Interferon-gamma (IFNY), 25 31. The pharmaceutical composition according to embodi Tumor necrosis factor-alpha (TNF-C.), Interleukin-12 (IL ments 1-30, wherein the therapeutic compound comprises 12), or a combination thereof released from Th1 cells, an anti-hyperlipidemic agent. increases the levels of IL-10 released from a Th2 cell, or 32. The pharmaceutical composition according to embodi both. ment 31, wherein the anti-hyperlipidemic agent comprises 15. The Solid solution pharmaceutical composition according 30 an Angiotension II receptor antagonist, a ACE inhibitor, a phosphodiesterase inhibitor, a fibrate, a statin, a tocot to embodiment 14, wherein the levels of IFNY, TNF-C., rienol, a niacin, a bile acid sequestrants (resin), a choles IL-12, or a combination thereof released from a Th1 cell terol absorption inhibitor, a pancreatic lipase inhibitor, a are reduced by at least 10%. sympathomimetic amine, or a combination thereof. 16. The Solid solution pharmaceutical composition according 35 33. The pharmaceutical composition according to embodi to embodiment 14, wherein the levels of IL-10 released ment 32, wherein the Angiotension II receptor antagonist from a Th2 cell are increased by at least 10%. comprises AZilsartan, Candesartan, Eprosartan, Irbesartan, 17. The Solid solution pharmaceutical composition according Losartan, Olmesartan, Telmisartan, and Valsartan. to embodiments 1-16, wherein the therapeutic compound 34. The pharmaceutical composition according to embodi has a log P value of 3.0 or greater. 40 ment 32, wherein the ACE inhibitor comprises a Sulfhy 18. The Solid solution pharmaceutical composition according dryl-containing agent, a Dicarboxylate-containing agent, a to embodiments 1-16, wherein the therapeutic compound Phosphonate-containing agent, a Casokinin, and a Lacto has a log P value of about 2.2 to about 3.0. kinin. 19. The Solid solution pharmaceutical composition according 35. The pharmaceutical composition according to embodi to embodiments 1-16, wherein the therapeutic compound 45 ment 32, wherein the phosphodiesterase inhibitor com has a log P value of about 2.0 or less. prises a PDE 1 selective inhibitor, a PDE2 selective inhibi 20. The pharmaceutical composition according to embodi tor, a PDE3 selective inhibitor, a PDE 4 selective inhibitor, ments 1-19, wherein the therapeutic compound has a polar a PDE5 selective inhibitor, or a PDE 10 selective inhibitor. Surface area that is hydrophobic. 36. The pharmaceutical composition according to embodi 21. The pharmaceutical composition according to embodi 50 ment 32, wherein the fibrate comprises Bezafibrate, ments 1-20, wherein the therapeutic compound has a polar Ciprofibrate, Clofibrate, Gemfibrozil, Fenofibrate, or a surface area that is less than 8.0 nm. combination thereof. 22. The pharmaceutical composition according to embodi 37. The pharmaceutical composition according to embodi ments 1-20, wherein the therapeutic compound has a polar ment 32, wherein the statin comprises Atorvastatin, Fluv surface area that is less than 6.0 nm. 55 astatin, Lovastatin, Pitavastatin, Pravastatin, Rosuvastatin, 23. The pharmaceutical composition according to embodi Simvastatin, or a combination thereof. ments 1-22, wherein the therapeutic compound comprises 38. The pharmaceutical composition according to embodi a non-steroidal anti-inflammatory drug (NSAID). ment 32, wherein the niacin comprises acipimox, niacin, 24. The pharmaceutical composition according to embodi nicotinamide, vitamin B3, or a combination thereof. ment 23, wherein the NSAID comprises a salicylate deriva 60 39. The pharmaceutical composition according to embodi tive NSAID, a p-amino phenol derivative NSAID, a propi ment 32, wherein the bile acid sequestrant comprises onic acid derivative NSAID, an acetic acid derivative Cholestyramine, Colesevelam, Colestipol, or a combina NSAID, an enolic acid derivative NSAID, a fenamic acid tion thereof. derivative NSAID, a non-selective cyclo-oxygenase 40. The pharmaceutical composition according to embodi (COX) inhibitor, a selective cyclooxygenase 1 (COX1) 65 ment32, wherein the cholesterol absorption inhibitor com inhibitor, a selective cyclooxygenase 2 (COX2) inhibitor prises EZetimibe, a phytosterol, a sterol, a Stenol, or a or a combination thereof. combination thereof. US 9,308,213 B2 55 56 41. The pharmaceutical composition according to embodi weight, less than about 35% by weight, less than about 30% ment 32, wherein the fat absorption inhibitor comprises by weight, less than about 25% by weight, less than about Orlistat 20% by weight, less than about 15% by weight, less than 42. The pharmaceutical composition according to embodi about 10% by weight, less than about 5% by weight, or less ment 32, wherein the sympathomimetic amine comprises than about 1% by weight or about 1% to 90% by weight, Clenbuterol, Salbutamol, ephedrine, pseudoephedrine, about 1% to 80% by weight, about 1% to 75% by weight, methamphetamine, amphetamine, phenylephrine, isoprot about 1% to 70% by weight, about 1% to 65% by weight, erenol, dobutamine, methylphenidate, lisdexamfetamine, about 1% to 60% by weight, about 1% to 55% by weight, cathine, cathinone, methcathinone, cocaine, benzylpipera about 1% to 50% by weight, about 1% to 45% by weight, zine (BZP), methylenedioxypyrovalerone (MDPV), 4-me 10 about 1% to 40% by weight, about 1% to 35% by weight, thylaminorex, pemoline, phenmetrazine, propylhexedrine, about 1% to 30% by weight, about 1% to 25% by weight, or a combination thereof. about 1% to 20% by weight, about 1% to 15% by weight, 43. The pharmaceutical composition according to embodi about 1% to 10% by weight, about 1% to 5% by weight, ments 1-42, wherein the therapeutic compound comprises about 2% to 50% by weight, about 2% to 40% by weight, a cancer drug. 15 about 2% to 30% by weight, about 2% to 20% by weight, 44. The pharmaceutical composition according to embodi about 2% to 10% by weight, about 4% to 50% by weight, ment 43, wherein the cancer drug comprises an alkylating about 4% to 40% by weight, about 4% to 30% by weight, agent, an anti-metabolite, a plant alkaloid and terpenoid, a about 4% to 20% by weight, about 4% to 10% by weight, topoisomerase inhibitor or a cytotoxic antibiotic. about 6% to 50% by weight, about 6% to 40% by weight, 45. The pharmaceutical composition according to embodi about 6% to 30% by weight, about 6% to 20% by weight, ments 1-44, wherein the therapeutic compound comprises about 6% to 10% by weight, about 8% to 50% by weight, Metformin, Curcumin, glycyrrhetinic acid, or 6-shogaol. about 8% to 40% by weight, about 8% to 30% by weight, 46. The pharmaceutical composition according to embodi about 8% to 20% by weight, about 8% to 15% by weight, ments 1-44, wherein the therapeutic compound comprises or about 8% to 12% by weight. an antibiotic. 25 56. The pharmaceutical composition according to embodi 47. The pharmaceutical composition according to embodi ments 1-55, wherein the therapeutic compound is in an ment 46, wherein the antibiotic comprises Isoniazid, amount of about 0.1% to about 45% by weight, about 0.1% Rifampicin, Pyrazinamide, or Ethambutol. to about 40% by weight, about 0.1% to about 35% by 48. The pharmaceutical composition according to embodi weight, about 0.1% to about 30% by weight, about 0.1% to ments 1-47, wherein the therapeutic compound comprises 30 about 25% by weight, about 0.1% to about 20% by weight, an anti-helmintic drug. about 0.1% to about 15% by weight, about 0.1% to about 49. The pharmaceutical composition according to embodi 10% by weight, about 0.1% to about 5% by weight, about ment 48, wherein the anti-helmintic drug comprises Abam 1% to about 45% by weight, about 1% to about 40% by ectin, an Aminoacetonitrile like Monepantel, a BenZimi weight, about 1% to about 35% by weight, about 1% to dazole, Diethylcarbamazine, Ivermectin, Levamisole, 35 about 30% by weight, about 1% to about 25% by weight, Niclosamide, an Octadepsipeptide like Emodepside, Phos about 1% to about 20% by weight, about 1% to about 15% phonic acid (Metrifonate), Praziquantel, a Spiroindole like by weight, about 1% to about 10% by weight, about 1% to Derquantel, or Suramin Pyrantel pamoate. about 5% by weight, about 5% to about 45% by weight, 50. The pharmaceutical composition according to embodi about 5% to about 40% by weight, about 5% to about 35% ments 1-49, wherein the therapeutic compound comprises 40 by weight, about 5% to about 30% by weight, about 5% to an anti-malaria drug. about 25% by weight, about 5% to about 20% by weight, 51. The pharmaceutical composition according to embodi about 5% to about 15% by weight, about 5% to about 10% ment 50, wherein the anti-malaria drug comprises Amodi by weight, about 10% to about 45% by weight, about 10% aquine, an Artemisinin, Atovaquone, Chloroquine, Clinda to about 40% by weight, about 10% to about 35% by mycin, Doxycycline, Halofantrine, Mefloquine, 45 weight, about 10% to about 30% by weight, about 10% to Primaquine, Proguanil, Pyrimethamine, a Quinine and about 25% by weight, about 10% to about 20% by weight, related agent like Quinimax and Quinidine, Rufigallol, and about 10% to about 15% by weight, about 15% to about a Sulfonamide like Sulfadoxine or Sulfamethoxypy 45% by weight, about 15% to about 40% by weight, about ridazine. 15% to about 35% by weight, about 15% to about 30% by 52. The pharmaceutical composition according to embodi 50 weight, about 15% to about 25% by weight, about 15% to ment 51, wherein the Artemisinin comprises Arteether, about 20% by weight, about 20% to about 45% by weight, Artemether, Artemisinin, Artesunate, or Dihydroartemisi about 20% to about 40% by weight, about 20% to about 1. 35% by weight, about 20% to about 30% by weight, about 53. The pharmaceutical composition according to embodi 20% to about 25% by weight, about 25% to about 45% by ments 1-52, wherein the therapeutic compound comprises 55 weight, about 25% to about 40% by weight, about 25% to an ester of a therapeutic compound. about 35% by weight, or about 25% to about 30% by 54. The pharmaceutical composition according to embodi weight. ments 1-53, wherein the therapeutic compound comprises 57. The pharmaceutical composition according to embodi an ester of a therapeutic compound according to embodi ments 1-56, wherein the pharmaceutically-acceptable ments 23-53. 60 room temperature solid lipid is a pharmaceutically-accept 55. The pharmaceutical composition according to embodi able glycerolipid, a pharmaceutically-acceptable glycol ments 1-54, wherein the therapeutic compound is in an fatty acid ester, a pharmaceutically-acceptable polyether amount less than about 90% by weight, less than about fatty acid ester, a mixture of pharmaceutically-acceptable 80% by weight, less than about 70% by weight, less than lipids, or any combination thereof. about 65% by weight, less than about 60% by weight, less 65 58. The pharmaceutical composition according to embodi than about 55% by weight, less than about 50% by weight, ments 1-57, wherein the pharmaceutically-acceptable less than about 45% by weight, less than about 40% by glycerolipids is Cocoa butter, mixtures of PEG-6 sterate US 9,308,213 B2 57 58 and ethylene glycol palmitostearate and PEG-32 stearate Stearate, dipropylene glycol palmitostearate, dipropylene (TEFOSE(R) 1500; TEFOSE(R) 63), mixtures of tricet glycol oleate, dipropylene glycol elaidate, dipropylene eareth-4 phosphate and ethylene glycol palmitostearate glycol vaccinate, dipropylene glycollinoleate, dipropylene and diethylene glycol palmitostearate (SEDEFOSR 75), glycol linoelaidate, dipropylene glycol O-linolenate, mixtures of glycerol monostearate and PEG-75 stearate dipropylene glycoly-linolenate, dipropylene glycol steari (GELOTR), mixtures of cetyl alcohol and ethoxylated donate, dipropylene glycol capprylocaprate, dipropylene fatty alcohols (seteth-2-, steareth-20) (EMULCIRE(R), glycol dicapprylocaprate, propylene glycol monopalmito mixtures of Saturated Co-Cs triglycerides having a melt stearate (MONOSTEOL(R), propylene glycol dicapryloca ing point around 33°C. (GELUCIRE(R)33/01), mixtures of prate (LABRAFAC(R) PG), propylene glycol monolaurate Saturated Co-Cs triglycerides having a melting point 10 (type I) (LAUROGLYCOLR) FCC), propylene glycol around 39°C. (GELUCIRE(R39/01), mixtures of saturated monolaurate (type II) (LAUROGLYCOLR 90), propylene Co-Cs triglycerides having a melting point around 43°C. glycol monocaprylate (type I) (CAPRYOLRPGMC), pro (GELUCIRE(R) 43/01), mixtures of glycerol monostearate pylene glycol monocaprylate (type II) (CAPRYOLR 90), 40-55 (type I) and diglycerides (GELEOL(R) Mono and or any combination thereof. Diglycerides), and mixtures of medium-chain triglycerides 15 60. The pharmaceutical composition according to embodi (LABRAFACR) Lipophile WL 1349). ments 1-59, wherein the pharmaceutically-acceptable 59. The pharmaceutical composition according to embodi polyether fatty acid ester is a PEG fatty acid ester, a PEG ments 1-58, wherein the pharmaceutically-acceptable gly glyceryl fatty acid, a PEG fatty acid ester glyceride, a PPG col fatty acid ester is an ethylene glycol fatty acid ester, a fatty acid ester, a PPG glyceryl fatty acid, or a PPG fatty diethylene glycol fatty acid ester, a propylene glycol fatty acid ester glyceride acid ester, and a dipropylene fatty acid ester, ethelene gly 61. The pharmaceutical composition according to embodi col caprylate, ethelene glycol pelargonate, ethelene glycol ments 1-60, wherein the pharmaceutically-acceptable caprate, ethelene glycol undecylate, ethelene glycol lau room temperature Solid lipid is in in an amount Sufficient to rate, ethelene glycol tridecylate, ethelene glycol myristate, form solid solution composition. ethelene glycol myristolate, ethelene glycol pentadecy 25 62. The pharmaceutical composition according to embodi clate, ethelene glycol palmitate, ethelene glycol palmi ments 1-61, wherein the pharmaceutically-acceptable toleate, ethelene glycol sapienate, ethelene glycol marga room temperature solid lipid is in an amount of at least 10% rate, ethelene glycol Stearate, ethelene glycol by weight, at least 20% by weight, at least 30% by weight, palmitostearate, ethelene glycol oleate, ethelene glycol at least 35% by weight, at least 40% by weight, at least 45% elaidate, ethelene glycol vaccinate, ethelene glycol 30 by weight, at least 50% by weight, at least 55% by weight, linoleate, ethelene glycol linoelaidate, ethelene glycol at least 60% by weight, at least 65% by weight, at least 70% O-linolenate, ethelene glycoly-linolenate, ethelene glycol by weight, at least 75% by weight, at least 80% by weight, Stearidonate, ethelene glycol capprylocaprate, ethelene at least 85% by weight, at least 90% by weight, at least 95% glycol dicapprylocaprate, diethelene glycol caprylate, by weight, or at least 99% by weight or about 30% to about diethelene glycol pelargonate, diethelene glycol caprate, 35 99% by weight, about 35% to about 99% by weight, about diethelene glycol undecylate, diethelene glycol laurate, 40% to about 99% by weight, about 45% to about 99% by diethelene glycol tridecylate, diethelene glycol myristate, weight, about 50% to about 99% by weight, about 30% to diethelene glycol myristolate, diethelene glycol pentade about 98% by weight, about 35% to about 98% by weight, cyclate, diethelene glycol palmitate, diethelene glycol about 40% to about 98% by weight, about 45% to about palmitoleate, diethelene glycol sapienate, diethelene gly 40 98% by weight, about 50% to about 98% by weight, about col margarate, diethelene glycol Stearate, diethelene glycol 30% to about 95% by weight, about 35% to about 95% by palmitostearate, diethelene glycol oleate, diethelene glycol weight, about 40% to about 95% by weight, about 45% to elaidate, diethelene glycol vaccinate, diethelene glycol about 95% by weight, or about 50% to about 95% by linoleate, diethelene glycollinoelaidate, diethelene glycol weight or about 70% to about 97% by weight, about 75% to O-linolenate, diethelene glycol Y-linolenate, diethelene 45 about 97% by weight, about 80% to about 97% by weight, glycol Stearidonate, diethelene glycol capprylocaprate, about 85% to about 97% by weight, about 88% to about diethelene glycol dicapprylocaprate, propylene glycol 97% by weight, about 89% to about 97% by weight, about caprylate, propylene glycol pelargonate, propylene glycol 90% to about 97% by weight, about 75% to about 96% by caprate, propylene glycol undecylate, propylene glycol weight, about 80% to about 96% by weight, about 85% to laurate, propylene glycol tridecylate, propylene glycol 50 about 96% by weight, about 88% to about 96% by weight, myristate, propylene glycol myristolate, propylene glycol about 89% to about 96% by weight, about 90% to about pentadecyclate, propylene glycol palmitate, propylene gly 96% by weight, about 75% to about 93% by weight, about col palmitoleate, propylene glycol sapienate, propylene 80% to about 93% by weight, about 85% to about 93% by glycol margarate, propylene glycol Stearate, propylene weight, about 88% to about 93% by weight, about 89% to glycol palmitostearate, propylene glycol oleate, propylene 55 about 93% by weight, or about 90% to about 93% by glycolelaidate, propylene glycol vaccinate, propylene gly weight. collinoleate, propylene glycollinoelaidate, propylene gly 63. The pharmaceutical composition according to embodi col O-linolenate, propylene glycoly-linolenate, propylene ments 1-62, wherein the pharmaceutically-acceptable glycol Stearidonate, propylene glycol capprylocaprate, room temperature liquid lipid is a monoglyceride. propylene glycol dicapprylocaprate, dipropylene glycol 60 64. The pharmaceutical composition according to embodi caprylate, dipropylene glycol pelargonate, dipropylene ment 63, wherein the monoglyceride is glycerol mono glycol caprate, dipropylene glycol undecylate, dipropylene myristoleate, glycerol monopalmitoleate, glycerol glycol laurate, dipropylene glycol tridecylate, dipropylene monosapienate, glycerol monooleate, glycerol monoelai glycol myristate, dipropylene glycol myristolate, dipropy date, glycerol monovaccenate, glycerol monolinoleate, lene glycol pentadecyclate, dipropylene glycol palmitate, 65 glycerol monolinoelaidate, glycerol monolinolenate, glyc dipropylene glycol palmitoleate, dipropylene glycol sapi erol monostearidonate, glycerol monoeicosenoate, glyc enate, dipropylene glycol margarate, dipropylene glycol erol monomeadate, glycerol monoarachidonate, glycerol US 9,308,213 B2 59 60 monoeicosapentaenoate, glycerol monoerucate, glycerol than about 5% by weight, less than about 4% by weight, monodocosahexaenoate, glycerol mononervonate, glyc less than about 3% by weight, less than about 2% by eryl dibelhenate (COMPRITOL(R) 888), glycerol behenate weight, or less than about 1% or about 1% to about 5% by (COMPRITOL(R) E ATO), glycerol dipalmitostearate weight, about 1% to about 7% by weight, about 1% to (Biogapress Vegetal BM297ATO), glycerol distearate about 10% by weight, about 1% to about 12% by weight, (type I) (PRECIROL(R) ATO 5), and glycerol monoli about 1% to about 15% by weight, about 1% to about 18% noleate (MAISINETM 35-1). by weight, about 1% to about 20% by weight, about 2% to 65. The pharmaceutical composition according to embodi about 5% by weight, about 2% to about 7% by weight, ments 1-64, wherein the pharmaceutically-acceptable about 2% to about 10% by weight, about 2% to about 12% room temperature liquid lipid is in an amount Sufficient to 10 dissolve a therapeutic compound. by weight, about 2% to about 15% by weight, about 2% to 66. The pharmaceutical composition according to embodi about 18% by weight, about 2% to about 20% by weight, ments 1-65, wherein the pharmaceutically-acceptable about 3% to about 5% by weight, about 3% to about 7% by room temperature liquid lipid is in an amount of less than weight, about 3% to about 10% by weight, about 3% to about 90% by weight, less than about 80% by weight, less 15 about 12% by weight, about 3% to about 15% by weight, than about 70% by weight, less than about 65% by weight, about 3% to about 18% by weight, about 3% to about 20% less than about 60% by weight, less than about 55% by by weight, about 4% to about 5% by weight, about 4% to weight, less than about 50% by weight, less than about 45% about 7% by weight, about 4% to about 10% by weight, by weight, less than about 40% by weight, less than about about 4% to about 12% by weight, about 4% to about 15% 35% by weight, less than about 30% by weight, less than by weight, about 4% to about 18% by weight, about 4% to about 25% by weight, less than about 20% by weight, less about 20% by weight, about 5% to about 7% by weight, than about 15% by weight, less than about 10% by weight, about 5% to about 10% by weight, about 5% to about 12% less than about 5% by weight, or less than about 1% by by weight, about 5% to about 15% by weight, about 5% to weight or about 1% to 90% by weight, about 1% to 80% by about 18% by weight, about 5% to about 20% by weight, weight, about 1% to 70% by weight, about 1% to 60% by 25 about 6% to about 7% by weight, about 6% to about 10% weight, about 1% to 50% by weight, about 1% to 40% by by weight, about 6% to about 12% by weight, about 6% to weight, about 1% to 30% by weight, about 1% to 20% by about 15% by weight, about 6% to about 18% by weight, weight, about 1% to 10% by weight, about 2% to 50% by about 6% to about 20% by weight, about 7% to about 10% weight, about 2% to 40% by weight, about 2% to 30% by by weight, about 7% to about 12% by weight, about 7% to weight, about 2% to 20% by weight, about 2% to 10% by 30 about 15% by weight, about 7% to about 18% by weight, weight, about 4% to 50% by weight, about 4% to 40% by about 7% to about 20% by weight, about 8% to about 10% weight, about 4% to 30% by weight, about 4% to 20% by by weight, about 8% to about 12% by weight, about 8% to weight, about 4% to 10% by weight, about 6% to 50% by about 15% by weight, about 8% to about 18% by weight, weight, about 6% to 40% by weight, about 6% to 30% by about 8% to about 20% by weight, about 9% to about 10% weight, about 6% to 20% by weight, about 6% to 10% by 35 by weight, about 9% to about 12% by weight, about 9% to weight, about 8% to 50% by weight, about 8% to 40% by about 15% by weight, about 9% to about 18% by weight, weight, about 8% to 30% by weight, about 8% to 20% by about 9% to about 20% by weight, about 10% to about 12% weight, about 8% to 15% by weight, or about 8% to 12% by by weight, about 10% to about 15% by weight, about 10% weight. to about 18% by weight, or about 10% to about 20% by 67. The pharmaceutical composition according to embodi 40 weight. ments 1-66, wherein the stabilizing agent is a liquid glycol 72. The pharmaceutical composition according to embodi polymer, a monohydric alcohol, isosorbide dimethyl ether, ments 1-71, wherein the pharmaceutically-acceptable sta and diethylene glycol monoethyl ether (2-(2-ethoxy bilizing agent is not used as a solvent. ethoxy)ethanol) (TRANSCUTOL(R). 73. The pharmaceutical composition according to embodi 68. The pharmaceutical composition according to embodi 45 ments 1-72, wherein the pharmaceutically-acceptable sta ment 67, wherein the liquid glycol polymer is a liquid PEG bilizing agent results in no more than 85%, no more than polymer and/or a liquid PPH polymer. 80%, no more than 75%, no more than 70%, no more than 69. The pharmaceutical composition according to embodi 65%, no more than 60%, no more than 55%, no more than ment 68, wherein the monohydric alcohol is ethanol, pro 50%, no more than 45%, no more than 40%, no more than panol, butanol, pentanol, or 1-hexadecanol. 50 35%, no more than 30%, no more than 25%, no more than 70. The pharmaceutical composition according to embodi 20%, no more than 15%, no more than 10%, or no more ments 1-69, wherein the pharmaceutically-acceptable sta than 5% dissolution of the therapeutic compound. bilizing agent is in an amount Sufficient to stabilize the free 74. The pharmaceutical composition according to embodi acid or base present in the therapeutic compound. ments 1-73, wherein the pharmaceutically-acceptable neu 71. The pharmaceutical composition according to embodi 55 tralizing agent is in an amount Sufficient to neutralized the ments 1-70, wherein the pharmaceutically-acceptable sta ionic charges produced when the therapeutic compound bilizing agent is in an amount of less than about 40% by dissolves. weight, less than about 35% by weight, less than about 30% 75. The pharmaceutical composition according to embodi by weight, less than about 25% by weight, less than about ments 1-74, wherein the pharmaceutically-acceptable neu 20% by weight, less than about 19% by weight, less than 60 tralizing agent is in an amount of one molar equivalent about 18% by weight, less than about 17% by weight, less relative to the therapeutic compound. than about 16% by weight, less than about 15% by weight, 76. The pharmaceutical composition according to embodi less than about 14% by weight, less than about 13% by ments 1-75, wherein the pharmaceutically-acceptable neu weight, less than about 12% by weight, less than about 11% tralizing agent is in an amount of less than one molar by weight, less than about 10% by weight, less than about 65 equivalent relative to the therapeutic compound. 9% by weight, less than about 8% by weight, less than 77. The pharmaceutical composition according to embodi about 7% by weight, less than about 6% by weight, less ments 1-76, wherein the pharmaceutically-acceptable neu US 9,308,213 B2 61 62 tralizing agent is in an amount of more than one molar to the individual in need thereof a pharmaceutical compo equivalent relative to the therapeutic compound. sition according to embodiments 1-72, wherein adminis 78. The pharmaceutical composition according to embodi tration results in a reduction in a symptom associated with ments 1-77, wherein the neutralizing agent is in an amount the chronic inflammation, thereby treating the individual. less than about 90% by weight, less than about 80% by 5 81. Use of a pharmaceutical composition according to weight, less than about 70% by weight, less than about 65% embodiments 1-79 in the manufacture of a medicament for by weight, less than about 60% by weight, less than about the treatment of a chronic inflammation. 55% by weight, less than about 50% by weight, less than 82. Use of a pharmaceutical composition according to about 45% by weight, less than about 40% by weight, less embodiments 1-79 for the treatment of a chronic inflam than about 35% by weight, less than about 30% by weight, 10 less than about 25% by weight, less than about 20% by mation. weight, less than about 15% by weight, less than about 10% 83. The method according to embodiment 80 or the use by weight, less than about 5% by weight, or less than about according to embodiment 81 or 82, wherein the chronic 1% by weight or about 1% to 90% by weight, about 1% to inflammation is associated with acne, acid reflux/heart 80% by weight, about 1% to 75% by weight, about 1% to 15 burn, age related macular degeneration (AMD), allergy, 70% by weight, about 1% to 65% by weight, about 1% to allergic rhinitis, Alzheimer's disease, amyotrophic lateral 60% by weight, about 1% to 55% by weight, about 1% to Sclerosis, anemia, appendicitis, arteritis, arthritis, asthma, 50% by weight, about 1% to 45% by weight, about 1% to atherosclerosis, autoimmune disorders, balanitis, blephari 40% by weight, about 1% to 35% by weight, about 1% to tis, bronchiolitis, bronchitis, a bullous pemphigoid, burn, 30% by weight, about 1% to 25% by weight, about 1% to bursitis, cancer, cardiac arrest, carditis, celiac disease, cel 20% by weight, about 1% to 15% by weight, about 1% to lulitis, cerviciitis, cholangitis, cholecystitis, chorioam 10% by weight, about 1% to 5% by weight, about 2% to nionitis, chronic obstructive pulmonary disease (COPD), 50% by weight, about 2% to 40% by weight, about 2% to cirrhosis, colitis, congestive heart failure, conjunctivitis, 30% by weight, about 2% to 20% by weight, about 2% to cyclophosphamide-induced cystitis, cystic fibrosis, cysti 10% by weight, about 4% to 50% by weight, about 4% to 25 tis, common cold, dacryoadenitis, dementia, dermatitis, 40% by weight, about 4% to 30% by weight, about 4% to dermatomyositis, diabetes, diabetic neuropathy, diabetic 20% by weight, about 4% to 10% by weight, about 6% to retinopathy, diabetic nephropathy, diabetic ulcer, digestive 50% by weight, about 6% to 40% by weight, about 6% to system disease, eczema, emphysema, encephalitis, 30% by weight, about 6% to 20% by weight, about 6% to endocarditis, endometritis, enteritis, enterocolitis, epi 10% by weight, about 8% to 50% by weight, about 8% to 30 condylitis, epididymitis, fasciitis, fibromyalgia, fibrosis, 40% by weight, about 8% to 30% by weight, about 8% to fibrositis, gastritis, gastroenteritis, gingivitis, glomerulo 20% by weight, about 8% to 15% by weight, or about 8% nephritis, glossitis, heart disease, heart valve dysfunction, to 12% by weight. hepatitis, hidradenitis Suppurativa, Huntington's disease, 79. The pharmaceutical composition according to embodi hyperlipidemic pancreatitis, hypertension, ileitis, infec ments 1-78, wherein the neutralizing agent is in an amount 35 tion, inflammatory bowel disease, inflammatory cardiome of about 0.1% to about 45% by weight, about 0.1% to about galy, inflammatory neuropathy, insulin resistance, intersti 40% by weight, about 0.1% to about 35% by weight, about tial cystitis, interstitial nephritis, iritis, ischemia, ischemic 0.1% to about 30% by weight, about 0.1% to about 25% by heart disease, keratitis, keratoconjunctivitis, laryngitis, weight, about 0.1% to about 20% by weight, about 0.1% to lupus nephritis, mastitis, mastoiditis, meningitis, meta about 15% by weight, about 0.1% to about 10% by weight, 40 bolic syndrome (syndrome X), a migraine, multiple scle about 0.1% to about 5% by weight, about 1% to about 45% rosis, myelitis, myocarditis, myositis, nephritis, non-alco by weight, about 1% to about 40% by weight, about 1% to holic steatohepatitis, obesity, omphalitis, oophoritis, about 35% by weight, about 1% to about 30% by weight, orchitis, osteochondritis, osteopenia, osteomyelitis, about 1% to about 25% by weight, about 1% to about 20% osteoporosis, osteitis, otitis, pancreatitis, Parkinson's dis by weight, about 1% to about 15% by weight, about 1% to 45 ease, parotitis, pelvic inflammatory disease, pemphigus about 10% by weight, about 1% to about 5% by weight, Vularis, pericarditis, peritonitis, pharyngitis, phlebitis, about 5% to about 45% by weight, about 5% to about 40% pleuritis, pneumonitis, polycystic nephritis, proctitis, pros by weight, about 5% to about 35% by weight, about 5% to tatitis, psoriasis, pulpitis, pyelonephritis, pylephlebitis, about 30% by weight, about 5% to about 25% by weight, renal failure, reperfusion injury, retinitis, rheumatic fever, about 5% to about 20% by weight, about 5% to about 15% 50 rhinitis, salpingitis, sarcoidosis, Sialadenitis, sinusitis, by weight, about 5% to about 10% by weight, about 10% to spastic colon, Stenosis, stomatitis, stroke, Surgical compli about 45% by weight, about 10% to about 40% by weight, cation, synovitis, tendonitis, tendinosis, tenosynovitis, about 10% to about 35% by weight, about 10% to about thrombophlebitis, tonsillitis, trauma, traumatic brain 30% by weight, about 10% to about 25% by weight, about injury, transplant rejection, trigonitis, tuberculosis, tumor, 10% to about 20% by weight, about 10% to about 15% by 55 urethritis, ursitis, uveitis, vaginitis, vasculitis, or Vulvitis. weight, about 15% to about 45% by weight, about 15% to 84. The method according to embodiment 80 or the use about 40% by weight, about 15% to about 35% by weight, according to embodiment 81 or 82, wherein the chronic about 15% to about 30% by weight, about 15% to about inflammation is a tissue inflammation. 25% by weight, about 15% to about 20% by weight, about 85. The method according to embodiment 80 or the use 20% to about 45% by weight, about 20% to about 40% by 60 according to embodiment 81 or 82, wherein the chronic weight, about 20% to about 35% by weight, about 20% to inflammation is a systemic inflammation. about 30% by weight, about 20% to about 25% by weight, 86. The method according to embodiment 80 or the use about 25% to about 45% by weight, about 25% to about according to embodiment 81 or 82, wherein the chronic 40% by weight, about 25% to about 35% by weight, or inflammation is an arthritis. about 25% to about 30% by weight. 65 87. The method or use according to embodiment 83 or 86, 80 A method of treating an individual with a chronic inflam wherein the arthritis is a monoarthritis, an oligoarthritis, or mation, the method comprising the step of administering a polyarthritis. US 9,308,213 B2 63 64 88. The method or use according to embodiment 140 or 143, 99. The method or use according to embodiment 98, wherein wherein the arthritis is an auto-immune disease or a non the skin disorder is a dermatitis, an eczema, a statis derma autoimmune disease. titis, a hidradenitis Suppurativa, a psoriasis, a rosacea or a 89. The method or use according to embodiment 83 or 86, Scleroderma. wherein the arthritis is an osteoarthritis, a rheumatoid 5 100. The methodoruse according to embodiment 99, wherein arthritis, a juvenile idiopathic arthritis, a septic arthritis, a the eczema is an atopic eczema, a contact eczema, a Xerotic spondyloarthropathy, a gout, a pseudogout, or Still's dis eczema, a seborrhoeic dermatitis, a dyshidrosis, a discoid CaSC. eczema, a venous eczema, a dermatitis herpetiformis, a 90. The method or use according to embodiment 89, wherein neurodermatitis, or an autoeczematization. 10 101. The methodoruse according to embodiment 99, wherein the spondyloarthropathy is an ankylosing spondylitis, a the psoriasis is a plaqure psoriasis, a nail psoriasis, a guttate reactive arthritis (Reiter's syndrome), a psoriatic arthritis, psoriasis, a scalp psoriasis, an inverse psoriasis, a pustular an enteropathic arthritis associated with inflammatory psoriasis, or an erythrodermis psoriasis. bowel disease, a Whipple disease or a Behcet disease. 102. The method according to embodiment 80 or the use 91. The method according to embodiment 80 or the use 15 according to embodiment 81 or 82, wherein the chronic according to embodiment 81 or 82, wherein the chronic inflammation is associated with a gastrointestinal disorder. inflammation is an autoimmune disorder. 103. The method or use according to embodiment 102, 92. The method or use according to embodiment 83 or 91, wherein the gastrointestinal disorder is an irritable bowel wherein the autoimmune disorder is a systemic autoim disease or an inflammatory bowel. mune disorder or an organ-specific autoimmune disorder. 104. The method or use according to embodiment 103, 93. The method or use according to embodiment 83 or 91, wherein the inflammatory bowel is a Crohn's disease oran wherein the autoimmune disorder is an acute disseminated ulcerative colitis. encephalomyelitis (ADEM), an Addison's disease, an 105. The method according to embodiment 80 or the use allergy, an anti-phospholipid antibody syndrome (APS), an according to embodiment 81 or 82, wherein the chronic autoimmune hemolytic anemia, an autoimmune hepatitis, 25 inflammation is associated with a cardiovascular disease. an autoimmune inner ear disease, a bullous pemphigoid, a 106. The method or use according to embodiment 105, celiac disease, a Chagas disease, a chronic obstructive pull wherein the cardiovascular disease is a hypertension, heart monary disease (COPD), a diabetes mellitus type 1 valve dysfunction, congestive heart failure, myocardial (IDDM), an endometriosis, a Goodpasture's syndrome, a infarction, a diabetic cardiac conditions, a blood vessel Graves’ disease, a Guillain-Barré syndrome (GBS), a 30 inflammation, arterial occlusive disease, a peripheral arte Hashimoto's thyroiditis, a hidradenitis Suppurativa, an rial disease, an aneurysm, an embolism, a dissection, a idiopathic thrombocytopenic purpura, an inflammatory pseudoaneurysm, a vascular malformation, a vascular bowel disease, an interstitial cystitis, a lupus (including a nevus, a thrombosis, a thrombphlebitis, a varicose veins, or discoid lupus erythematosus, a drug-induced lupus erythe a stroke. matosus, a lupus nephritis, a neonatal lupus, a Subacute 35 107. The method according to embodiment 80 or the use cutaneous lupus erythematosus, a systemic lupus erythe according to embodiment 81 or 82, wherein the chronic matosus, a morphea, a multiple Sclerosis (MS), a myasthe inflammation is associated with a cancer. nia gravis, a myopathy, a narcolepsy, a neuromyotonia, a 108. The method according to embodiment 80 or the use pemphigus Vulgaris, a pernicious anaemia, a primary bil according to embodiment 81 or 82, wherein the chronic iary cirrhosis, a recurrent disseminated encephalomyelitis, 40 inflammation is associated with a pharmacologically-in a rheumatic fever, a schizophrenia, a Scleroderma, a duced inflammation. Sjögren's syndrome, a tenosynovitis, a vasculitis, or a viti 109. The method according to embodiment 80 or the use ligo. according to embodiment 81 or 82, wherein the chronic 94. The method according to embodiment 80 or the use inflammation is associated with an infection. according to embodiment 81 or 82, wherein the chronic 45 110. The method or use according to embodiment 83 or 109, inflammation is a myopathy. wherein the infection is a bacterial cystitis, a bacterial 95. The method or use according to embodiment 93 or 94. encephalitis, a pandemic influenza, a viral encephalitis, a wherein the myopathy is a dermatomyositis, an inclusion viral hepatitis A, a viral hepatitis B, or a viral hepatitis C. body myositis, or a polymyositis. 111. The method according to embodiment 80 or the use 96. The method according to embodiment 80 or the use 50 according to embodiment 81 or 82, wherein the chronic according to embodiment 81 or 82, wherein the chronic inflammation is associated with a tissue or organ injury. inflammation is a vasculitis. 112. The method according to embodiment 80 or the use 97. The methodoruse according to embodiment 83, 93, or 96, according to embodiment 81 or 82, wherein the chronic wherein the vasculitis is vasculitis is a Buerger's disease, inflammation is associated with a transplant rejection or a an arteritis, a cerebral vasculitis, a Churg-Strauss arteritis, 55 graft-versus-host disease. a cryoglobulinemia, an essential cryoglobulinemic vascu 113. The method according to embodiment 80 or the use litis, a giant cell arteritis, a Golfers vasculitis, a Henoch according to embodiment 81 or 82, wherein the chronic Schonlein purpura, a hypersensitivity vasculitis, a inflammation is associated with a Th1-mediated inflamma Kawasaki disease, a phlebitis, a microscopic polyarteritis/ tory disease. polyangiitis, a polyarteritis nodosa, a polymyalgia rheu 60 114. The method according to embodiment 80 or the use matica (PMR), a rheumatoid vasculitis, a Takayasuarteri according to embodiment 81 or 82, wherein the chronic tis, a thrombophlebitis, a Wegener's granulomatosis, or a inflammation is associated with chronic neurogenic vasculitis secondary to connective tissue disorder, or vas inflammation. culitis secondary to viral infection. 115. The method according to embodiments 80 or 83-114 or 98. The method according to embodiment 80 or the use 65 the use according to embodiments 81-114, wherein upon according to embodiment 81 or 82, wherein the chronic administration to an individual, the pharmaceutical com inflammation is associated with a skin disorder. position comprising the therapeutic compound according US 9,308,213 B2 65 66 to embodiments 1-79 results in a bio-distribution of the To prepare a solid solution pharmaceutical composition therapeutic compound different than a bio-distribution of disclosed herein the following general procedure was used. the therapeutic compound included in the same pharma ceutical composition, except without the pharmaceuti All ingredient, except the room temperature solid lipid, were cally-acceptable adjuvant. mixed together. This mixture was heated to a temperature in 116. The method according to embodiments 80 or 83-115 or the rangeabout 50° C. to about 60°C. with stirring in order to the use according to embodiments 81-115, wherein upon dissolve the therapeutic compound thereby creating a solu administration to an individual, the amount of the thera tion. The room temperature solid lipid was then added to the peutic compound of the pharmaceutical composition 10 solution and the mixture stirred until incorporated. The mix according to embodiments 1-79 delivered to a macrophage is at least 5% of the total amount of the therapeutic com ture was then allowed to Solidify by cooling to room tempera pound contained in the administered pharmaceutical com ture. Representative formulations containing various thera position. peutic compounds are show in Table 1. TABLE 1. Solid Solution Formulations of Ibuprofen Therapeutic Stabilizing Neutralizing Formulation Compound RT Liquid Lipid Agent Agent RT Solid Lipid buprofen 200 mg — RT Solid Lipid 622 mg G43 Vehicle 0.26 mL M35-1° 0.06 mL 260 mg G43 PEG400 buprofen 200 mg 0.38 mL M35-1 0.04 mL 160 mg G43 LA 3-51 PEG400 buprofen 200 mg 0.26 mL M35-1 0.06 mL 260 mg G43 LA 3-57 PEG400 buprofen 200 mg 0.18 mL M35-1 0.08 mL 380 mg G43 LA 35-1 PEG400 buprofen 200 mg 0.10 mL M35-1 0.08 mL 460 mg G43 LA 35-2 PEG400 buprofen 200 mg 0.04 mL M35-1 0.08 mL 520 mg G43 LA 35-3 PEG400

G43 is GELUCIRE (R. 43.01 M35-1 is MAISINE R 35-1 35 117. The method according to embodiments 80 or 83-116 or The mixture was then allowed to solidify by cooling to the use according to embodiments 81-116, wherein upon room temperature. Solidified compositions were then administration to an individual, the pharmaceutical com assessed by appearance and by Differential Scanning calo position according to embodiments 1-79 reduces intestinal rimetry (DSC). irritation by at least 5% when compared to the pharmaceu 40 tical composition according to embodiments 1-79, except During the course of the analysis using DSC, a general without the pharmaceutically-acceptable adjuvant. trend was observed whereaformulation which solidified with 118. The method according to embodiments 80 or 83-117 or a cloudy appearance formed a classic Solid composition hav the use according to embodiments 81-117, wherein upon ing a crystalline structure while one which solidified with a administration to an individual, the pharmaceutical com 45 clear appearance Suggested a solid solution composition hav position according to embodiments 1-79 reduces gastric ing an amorphic structure. Additionally, Solidified composi irritation by at least 5% when compared to the pharmaceu tions with a clear appearance that were then remelted with no tical composition according to embodiments 1-79, except appearance of a precipitate where indicative of a solid solu without the pharmaceutically-acceptable adjuvant. tion composition having an amorphic structure. EXAMPLES 50 Using the visual appearance and remelt assays, large num bers of formulations was accessed for the ability to for a The following non-limiting examples are provided for solid-solution composition. A formulation that failed to form illustrative purposes only in order to facilitate a more com a solid, or formed a solid with a cloudy appearance were not plete understanding of the disclosed subject matter. These further analyzed and discarded. Similarly, formulations were examples should not be construed to limit any of the embodi 55 not further analyzed and discarded if a precipitate formed ments described in the present specification, including those after remelting of a solidified compositions with a clear pertaining to the pharmaceutical compositions, methods of appearance. Formulations that formed a clear Solid were also preparing pharmaceutical compositions, or methods or uses subsequently analyzed by DSC. of treating a chronic inflammation or disease associated with chronic inflammation. Data for representative ibuprofen formulations solidifying 60 with a clear appearance are shown in FIG.1. The DSC analy Example 1 sis revealed that individual components exhibited sharp, well defined peaks. For example, ibuprofen possessed a well-de Differential Scanning Calorimetry fined melting point range of 75° C. to 78° C. (FIG. 1A). Similarly, a room temperature solid lipid, or hard fat, like This example illustrates formulation of solid solution phar 65 GELUCIRER 43/01 had a well-defined melting point range maceutical composition as disclosed herein comprising a of 41° C. to 45° C. (FIG. 1B). These sharp, well defined therapeutic compound. melting point temperature ranges are indicative of a compo US 9,308,213 B2 67 68 sition in a classic Solid transition phase having a well-defined The formulation solidified with a clear appearance. In addi crystalline structure. MAISINE(R) 35-1 and PEG 400 are liq tion, DSC analysis indicated a new broad melting point tem uids at room temperature, and as Such has a melting point perature range of about 35° C. to about 40°C. (FIG. 2). This below 20° C. For example, MAISINE(R) 35-1 has a melting temperature range was different than that for the individual point temperature range of about 14°C. to about 16° C. and components alone: 41° C. to 45° C. for GELUCIRE(R) 43/01 PEG 400 has a melting point temperature range of about 4°C. (Gattefosse) and 86° C. to 90° C. for Artemether. Tributyrin is to about 8° C. a liquid at room temperature, and as Such has a melting point Unexpectedly, when a vehicle comprising a room tempera below 20° C. These results indicate that a solid solution ture Solid lipid (hard fat), a room temperature liquid lipid and formulation as disclosed herein comprising Artemether was a stabilizing agent were examined by DSC, a new melting 10 formed. point temperature peak appeared. For example, in addition to the GELUCIRE(R)43/01 peak of 41° C. to 45° C., DSC analy Example 3 sis identified a new broad melting point temperature range of about 32° C. to about 38° C. (FIG. 1C). This temperature Solid Solution Pharmaceutical Compositions range was different than that for the individual components 15 Comprising Aspirin alone: 41° C. to 45° C. for GELUCIRE(R) 43/01, 14°C. to 16° C. for MAISINE(R) 35-1, and 4° C. to 8° C. for PEG 400. This example illustrates how to make a solid solution phar These results indicate that a portion of the composition was maceutical composition disclosed herein comprising Aspirin. forming into a Solid solution phase instead of a classic Solid To prepare a solid solution pharmaceutical composition phase. disclosed herein using Aspirin, the following method was Surprisingly, formulation comprising the therapeutic com performed. About 120 mg Aspirin and about 0.5 mL isosor pound with this vehicle exhibited a broad melting range with bide dimethyl ester (as stabilizing agent) were added to a a melting point temperature different than the individual com vessel and heated to about 50° C. to about 60°C. with stirring ponents (FIGS. 1D-1H). Furthermore, no peaks relating to until all components of the mixture were dissolved. About 1.0 either the therapeutic compound alone or the hard fat alone 25 gGELUCIRE(R) 43/01 (Gattefosse), a waxy solid (as room were detected. For example, ibuprofen has a melting point temperature solid lipid) having a melting point of between temperature range of 75° C. to 78° C., GELUCIRE(R) 43/01 41° C. to 45° C. and comprising a mixture of Saturated Co had a melting point of 41° C. to 45° C., MAISINE(R)35-1 has Cs triglycerides, was added to this solution and stirred until a melting point temperature of 14°C. to 16°C., and PEG400 incorporated. The heated mixture was then cooled to about has a melting point temperature of 4°C. to 8° C. However, a 30 37° C. to about 40°C., and aliquoted by pouring into molds formulation comprising these components results in a com and cooled to room temperature. Alternatively, the mixture position with a melting point of between 35° C. to 40° C. can be cooled to room temperature and then Subsequently depending on the amounts and ratios used. In a classic mixed reheated to about 40° C. to about 45° C. for aliquoting into phase of distinct Solid components, each individual peak molds. would have been resolved, i.e., 75° C. to 78°C. for Ibuprofen, 35 The formulation solidified with a clear appearance. In addi 41° C. to 45° C. and GELUCIRE(R) 43/01. This was not the tion, DSC analysis indicated a new broad melting point tem case, these peaks disappeared altogether. The presence of a perature range of about 35° C. to about 40°C. (FIG.3). This single new melting point peak, and the concomitant disap temperature range was different than that for the individual pearance of the individual component melting point peaks, components alone: 41° C. to 45° C. for GELUCIRE(R) 43/01 for the solidified composition indicates that a novel solid 40 (Gattefosse) and 138°C. to 140°C. for Aspirin. Isosorbide Solution structure of therapeutic compound and room tem dimethyl ester is a liquid at room temperature, and as Such has perature solid lipid (hard fat) was formed. a melting point below 20°C. These results indicate that a solid Solution formulation as disclosed herein comprising Aspirin Example 2 was formed. 45 Solid Solution Pharmaceutical Compositions Example 4 Comprising Artemether Solid Solution Pharmaceutical Compositions This example illustrates how to make a solid solution phar Comprising Dantrolene maceutical composition disclosed herein comprising Arte 50 mether. This example illustrates how to make a solid solution phar To prepare a solid solution pharmaceutical composition maceutical composition disclosed herein comprising Dant disclosed herein using Artemether, the following method was rolene. performed. About 1.0 g GELUCIRE(R) 43/01 (Gattefosse), a To prepare a solid solution pharmaceutical composition waxy Solid (as room temperature Solid lipid) having a melting 55 disclosed herein using Dantrolene, the following method was point of between 41° C. to 45° C. and comprising a mixture of performed. Add about 232.7 mg Stearic acid (as neutralizing saturated Co-Cs triglycerides, and about 0.5 mL tributyrin agent) to a vessel and heat to about 70° C. to about 75°C. with (as room temperature liquid lipid) were added to a vessel and stirring until melted. Addabout 250.2 mg Dantrolene sodium heated to about 40°C. to about 50° C. with stirring until all salt and 20 mL isosorbide dimethyl ester (as Stabilizing agent) components of the mixture were incorporated. About 40 mg 60 to melted Stearic acid and stir until uniform consistency is Artemether was added to about 0.8 mL of this incorporated achieved. About 20.02 g GELUCIRE(R) 43/01 (Gattefosse), a mixture and stirred until dissolved. The heated mixture was waxy Solid (as room temperature Solid lipid) having a melting then cooled to about 37°C. to about 40°C., and aliquoted by point of between 41° C. to 45° C. and comprising a mixture of pouring into molds and cooled to room temperature. Alterna saturated Co-Cs triglycerides was added to this solution and tively, the mixture can be cooled to room temperature and 65 stirred until incorporated. The heated mixture was then then subsequently reheated to about 40°C. to about 45° C. for cooled to about 37° C. to about 40° C., and aliquoted by aliquoting into molds. pouring into molds and cooled to room temperature. Alterna US 9,308,213 B2 69 70 tively, the mixture can be cooled to room temperature and stirred until incorporated. The heated mixture was then then subsequently reheated to about 40°C. to about 45° C. for cooled to about 37° C. to about 40° C., and aliquoted by aliquoting into molds. pouring into molds and cooled to room temperature. Alterna The formulation solidified with a clear appearance. In addi tively, the mixture can be cooled to room temperature and tion, DSC analysis indicated a new broad melting point tem- 5 then subsequently reheated to about 40°C. to about 45° C. for perature range of about 34°C. to about 39°C. (FIG. 4). This aliquoting into molds. The formulation solidified with a clear temperature range was different than that for the individual appearance and remelted without forming a precipitate. components alone: 41° C. to 45° C. for GELUCIRE(R) 43/01 These results indicate that a solid solution formulation as (Gattefosse), stearic acid is 70° C., and 279° C. to 280° C. for disclosed herein comprising Dantrolene was formed. Dantrolene. Isosorbide dimethyl ester is a liquid at room 10 temperature, and as Such has a melting point below 20° C. To prepare a solid solution pharmaceutical composition These results indicate that a solid solution formulation as disclosed herein using Dantrolene, the following method was disclosed herein comprising Dantrolene was formed. performed. Add about 224.9 mg Stearic acid (as neutralizing To prepare a solid solution pharmaceutical composition agent) to a vessel and heat to about 70° C. to about 75°C. with disclosed herein using Dantrolene, the following method was 15 stirring until melted. Add about 25.1 mg Dantrolene sodium performed. Add about 309.8 mg stearic acid (as neutralizing salt to melted Stearic acid and stir until uniform consistency is agent) to a vessel and heat to about 70° C. to about 75°C. with achieved. Add 0.75 mL isosorbide dimethyl ester (as stabi stirring until melted. Add about 59.6 mg Dantrolene sodium lizing agent) and stir mixture until all components are dis salt to melted Stearic acid and stir until uniform consistency is solved. About 304.1 mg GELUCIRE(R) 43/01 (Gattefosse), a achieved. Add 0.75 mL isosorbide dimethyl ester (as stabi waxy Solid (as room temperature Solid lipid) having a melting lizing agent) and stir mixture until all components are dis point of between 41° C. to 45° C. and comprising a mixture of solved. About 760.3 mg GELUCIRE(R) 43/01 (Gattefosse), a saturated Co-Cs triglycerides was added to this solution and waxy Solid (as room temperature Solid lipid) having a melting stirred until incorporated. The heated mixture was then point of between 41° C. to 45° C. and comprising a mixture of cooled to about 37° C. to about 40° C., and aliquoted by saturated Co-Cs triglycerides was added to this solution and 25 pouring into molds and cooled to room temperature. Alterna stirred until incorporated. The heated mixture was then tively, the mixture can be cooled to room temperature and cooled to about 37° C. to about 40° C., and aliquoted by then subsequently reheated to about 40°C. to about 45° C. for pouring into molds and cooled to room temperature. Alterna aliquoting into molds. The formulation solidified with a clear tively, the mixture can be cooled to room temperature and appearance and remelted without forming a precipitate. then subsequently reheated to about 40°C. to about 45° C. for 30 These results indicate that a solid solution formulation as aliquoting into molds. The formulation solidified with a clear appearance and remelted without forming a precipitate. disclosed herein comprising Dantrolene was formed. These results indicate that a solid solution formulation as Example 5 disclosed herein comprising Dantrolene was formed. To prepare a solid solution pharmaceutical composition 35 disclosed herein using Dantrolene, the following method was Solid Solution Pharmaceutical Compositions performed. Add about 250.2 mg Stearic acid (as neutralizing Comprising Diclofenac agent) to a vessel and heat to about 70° C. to about 75°C. with stirring until melted. Add about 50.3 mg Dantrolene sodium This example illustrates how to make a solid solution phar salt to melted Stearic acid and stir until uniform consistency is 40 maceutical composition disclosed herein comprising achieved. Add 5.0 mL isosorbide dimethyl ester (as stabiliz Diclofenac. ing agent) and stir mixture until all components are dissolved. To prepare a solid solution pharmaceutical composition About 5.0 g GELUCIRER 43/01 (Gattefosse), a waxy solid disclosed herein using Diclofenac, the following method was (as room temperature Solid lipid) having a melting point of performed. About 119 mg Diclofenac, about 1.0 mL between 41° C. to 45° C. and comprising a mixture of satu- 45 MAISINE(R) 35-1 (Gattefosse), a glyceryl monolinoleate (as rated Co-Cs triglycerides was added to this solution and room temperature liquid lipid), and about 0.3 mL isosorbide stirred until incorporated. The heated mixture was then dimethyl ester (as stabilizing agent) were added to a vessel cooled to about 37° C. to about 40° C., and aliquoted by and heated to about 50° C. to about 60°C. with stirring until pouring into molds and cooled to room temperature. Alterna all components of the mixture were dissolved. About 1.0 g tively, the mixture can be cooled to room temperature and 50 GELUCIRER 43/01 (Gattefosse), a waxy solid (as room then subsequently reheated to about 40°C. to about 45° C. for temperature solid lipid) having a melting point of between aliquoting into molds. The formulation solidified with a clear 41° C. to 45° C. and comprising a mixture of Saturated Co appearance and remelted without forming a precipitate. Cs triglycerides, was added to this solution and stirred until These results indicate that a solid solution formulation as incorporated. The heated mixture was then cooled to about disclosed herein comprising Dantrolene was formed. 55 37° C. to about 40°C., and aliquoted by pouring into molds To prepare a solid solution pharmaceutical composition and cooled to room temperature. Alternatively, the mixture disclosed herein using Dantrolene, the following method was can be cooled to room temperature and then Subsequently performed. Add about 225.0 mg Stearic acid (as neutralizing reheated to about 40° C. to about 45° C. for aliquoting into agent) to a vessel and heat to about 70° C. to about 75°C. with molds. stirring until melted. Add about 25.1 mg Dantrolene sodium 60 The formulation solidified with a clear appearance. In addi salt to melted Stearic acid and stir until uniform consistency is tion, DSC analysis indicated a new broad melting point tem achieved. Add 2.0 mL isosorbide dimethyl ester (as stabiliz perature range of about 35° C. to about 40°C. (FIG. 5). This ing agent) and stir mixture until all components are dissolved. temperature range was different than that for the individual About 2.07 g GELUCIRE(R) 43/01 (Gattefosse), a waxy solid components alone: 41° C. to 45° C. for GELUCIRE(R)43/01 (as room temperature Solid lipid) having a melting point of 65 (Gattefosse) and 157° C. to 158° C. for Diclofenac. between 41° C. to 45° C. and comprising a mixture of satu MAISINE(R) 35-1 and isosorbide dimethyl ester are liquids at rated Co-Cs triglycerides was added to this solution and room temperature, and as such both have melting points US 9,308,213 B2 71 72 below 20° C. These results indicate that a solid solution ing a precipitate. These results indicate that a solid solution formulation as disclosed herein comprising Diclofenac was formulation as disclosed herein comprising Gemifibrozil was formed. formed. To prepare a solid solution pharmaceutical composition Example 6 disclosed herein using Gemifibrozil, the following method was performed. About 1 g Gemifibrozil and 7.5 g Cocoa Solid Solution Pharmaceutical Compositions Butter a waxy Solid (as room temperature Solid lipid) having Comprising Fenofibrate a melting point of between 34°C. to 38°C. and comprising a mixture of Saturated C-Cs triglycerides, were added to a This example illustrates how to make a solid solution phar 10 vessel and heated to about 50° C. to about 60°C. with stirring maceutical composition disclosed herein comprising Fenofi until all components of the mixture were incorporated. The brate. heated mixture was then cooled to about 37° C. to about 40° To prepare a solid solution pharmaceutical composition C., and aliquoted by pouring into molds and cooled to room disclosed herein using Fenofibrate, the following method was temperature. Alternatively, the mixture can be cooled to room 15 temperature and then subsequently reheated to about 40°C. to performed. About 400 mg Fenofibrate and 4.0 g GELU about 45° C. for aliquoting into molds. The formulation CIRE(R) 43/01 (Gattefosse), a waxy solid (as room tempera solidified with a clear appearance and remelted without form ture solid lipid) having a melting point of between 41° C. to ing a precipitate. These results indicate that a solid solution 45° C. and comprising a mixture of Saturated Co-Cs trig formulation as disclosed herein comprising Gemifibrozil was lycerides, were added to a vessel and heated to about 45° C. to formed. about 55°C. with stirring until all components of the mixture were incorporated. About 0.76 mL isosorbide dimethyl ester Example 8 (as stabilizing agent) was added to this mixture and stirred until incorporated. The heated mixture was then cooled to Solid Solution Pharmaceutical Compositions about 37° C. to about 40°C., and aliquoted by pouring into 25 Comprising Ibuprofen molds and cooled to room temperature. Alternatively, the mixture can be cooled to room temperature and then Subse This example illustrates how to make a solid solution phar quently reheated to about 40°C. to about 45° C. for aliquoting maceutical composition disclosed herein comprising Ibupro into molds. fen. The formulation solidified with a clear appearance. In addi 30 To prepare a solid solution pharmaceutical composition tion, DSC analysis indicated a new broad melting point tem disclosed herein using Ibuprofen, the following method was perature range of about 34° C. to about 39° C. (FIG. 6). This performed. About 1 g ibuprofen sodium salt, about 0.9 mL MAISINE(R) 35-1 (Gattefosse), a glyceryl monolinoleate (as temperature range was different than that for the individual room temperature liquid lipid), and about 0.4 mL PEG 400 components alone: 41° C. to 45° C. for GELUCIRE(R) 43/01 35 were added to a vessel heated to about 50° C. to about 60° C. (Gattefosse) and 80° C. to 85°C. for Fenofibrate. Isosorbide with stirring until all components of the mixture were dis dimethyl ester is a liquidat room temperature, and as Such has solved. About 1.9 g GELUCIRE(R) 43/01 (Gattefosse), a waxy a melting point below 20°C. These results indicate that a solid Solid (as room temperature solid lipid) having a melting point Solution formulation as disclosed herein comprising Fenofi of between 41° C. to 45° C. and comprising a mixture of brate was formed. 40 saturated Co-Cs triglycerides, was added to this solution and stirred until incorporated. The heated mixture was then Example 7 cooled to about 37° C. to about 40° C., and aliquoted by pouring into molds and cooled to room temperature. Alterna Solid Solution Pharmaceutical Compositions tively, the mixture can be cooled to room temperature and Comprising Gemifibrozil 45 then subsequently reheated to about 40°C. to about 45° C. for aliquoting into molds. This example illustrates how to make a solid solution phar The formulation solidified with a clear appearance. In addi maceutical composition disclosed herein comprising Gemi tion, DSC analysis indicated a new broad melting point tem fibrozil. perature range of about 32°C. to about 44°C. (FIG.1D). This To prepare a solid solution pharmaceutical composition 50 temperature range was different than that for the individual disclosed herein using Gemifibrozil, the following method components alone: 41° C. to 45° C. for GELUCIRE(R) 43/01 was performed. About 1 g Gemifibrozil, about 0.9 mL (Gattefosse) and 75° C. to 78° C. for Ibuprofen. MAISINE(R) MAISINE(R) 35-1 (Gattefosse), a glyceryl monolinoleate (as 35-1 and PEG 400 are liquids at room temperature, and as room temperature liquid lipid), and about 0.4 mL PEG 400 (as such both have melting points below 20° C. These results stabilizing agent) were added to a vessel and heated to about 55 indicate that a Solid solution formulation as disclosed herein 50° C. to about 60°C. with stirring until all components of the comprising Ibuprofen was formed. mixture were dissolved. About 1.9 g GELUCIRE(R) 43/01 To prepare a solid solution pharmaceutical composition (Gattefosse), a waxy Solid (as room temperature solid lipid) disclosed herein using Ibuprofen, the following method was having a melting point of between 41° C. to 45° C. and performed. About 1 g ibuprofen sodium salt, about 0.5 mL comprising a mixture of Saturated Co-Cs triglycerides, was 60 MAISINE(R) 35-1 (Gattefosse), a glyceryl monolinoleate (as added to this solution and stirred until incorporated. The room temperature liquid lipid), and about 0.4 mL PEG 400 heated mixture was then cooled to about 37° C. to about 40° were added to a vessel heated to about 50° C. to about 60° C. C., and aliquoted by pouring into molds and cooled to room with stirring until all components of the mixture were dis temperature. Alternatively, the mixture can be cooled to room solved. About 2.3 g GELUCIRE(R) 43/01 (Gattefosse), a waxy temperature and then subsequently reheated to about 40°C. to 65 Solid (as room temperature solid lipid) having a melting point about 45° C. for aliquoting into molds. The formulation of between 41° C. to 45° C. and comprising a mixture of solidified with a clear appearance and remelted without form saturated Co-Cs triglycerides, was added to this solution US 9,308,213 B2 73 74 and stirred until incorporated. The heated mixture was then such both have melting points below 20° C. These results cooled to about 37° C. to about 40° C., and aliquoted by indicate that a Solid solution formulation as disclosed herein pouring into molds and cooled to room temperature. Alterna comprising Ibuprofen was formed. tively, the mixture can be cooled to room temperature and To prepare a solid solution pharmaceutical composition then subsequently reheated to about 40°C. to about 45° C. for 5 disclosed herein using Ibuprofen, the following method was aliquoting into molds. performed. About 5 g ibuprofen sodium salt, about 6.5 mL The formulation solidified with a clear appearance. In addi MAISINE(R) 35-1 (Gattefosse), a glyceryl monolinoleate (as tion, DSC analysis indicated a new broad melting point tem room temperature liquid lipid), and about 1.5 mL PEG 400 perature range of about 32° C. to about 43°C. (FIG.1E). This were added to a vessel heated to about 50° C. to about 60° C. temperature range was different than that for the individual 10 with stirring until all components of the mixture were dis components alone: 41° C. to 45° C. for GELUCIRE(R) 43/01 solved. About 6.5g GELUCIRE(R)43/01 (Gattefosse), a waxy (Gattefosse) and 75° C. to 78° C. for Ibuprofen. MAISINE(R) Solid (as room temperature solid lipid) having a melting point 35-1 and PEG 400 are liquids at room temperature, and as of between 41° C. to 45° C. and comprising a mixture of such both have melting points below 20° C. These results saturated Co-Cs triglycerides, was added to this solution indicate that a Solid solution formulation as disclosed herein 15 and stirred until incorporated. The heated mixture was then comprising Ibuprofen was formed. cooled to about 37° C. to about 40° C., and aliquoted by To prepare a solid solution pharmaceutical composition pouring into molds and cooled to room temperature. Alterna disclosed herein using Ibuprofen, the following method was tively, the mixture can be cooled to room temperature and performed. About 1 g ibuprofen sodium salt, about 0.2 mL then subsequently reheated to about 40°C. to about 45° C. for MAISINE(R) 35-1 (Gattefosse), a glyceryl monolinoleate (as aliquoting into molds. room temperature liquid lipid), and about 0.4 mL PEG 400 The formulation solidified with a clear appearance. In addi were added to a vessel heated to about 50° C. to about 60° C. tion, DSC analysis indicated a new broad melting point tem with stirring until all components of the mixture were dis perature range of about 32°C. to about 42°C. (FIG.1H). This solved. About 2.6 g GELUCIRE(R) 43/01 (Gattefosse), a waxy temperature range was different than that for the individual Solid (as room temperature solid lipid) having a melting point 25 components alone: 41° C. to 45° C. for GELUCIRE(R) 43/01 of between 41° C. to 45° C. and comprising a mixture of (Gattefosse) and 75° C. to 78° C. for Ibuprofen. MAISINE(R) saturated Co-Cs triglycerides, was added to this solution 35-1 and PEG 400 are liquids at room temperature, and as and stirred until incorporated. The heated mixture was then such both have melting points below 20° C. These results cooled to about 37° C. to about 40° C., and aliquoted by indicate that a Solid solution formulation as disclosed herein pouring into molds and cooled to room temperature. Alterna 30 comprising Ibuprofen was formed. tively, the mixture can be cooled to room temperature and To prepare a solid solution pharmaceutical composition then subsequently reheated to about 40°C. to about 45° C. for disclosed herein using Ibuprofen, the following method was aliquoting into molds. performed. About 1 g ibuprofen sodium salt, about 0.9 mL The formulation solidified with a clear appearance. In addi MAISINE(R) 35-1 (Gattefosse), a glyceryl monolinoleate (as tion, DSC analysis indicated a new broad melting point tem 35 room temperature liquid lipid), about 0.4 mL PEG 400, and perature range of about 32°C. to about 42°C. (FIG.1F). This about 0.3 mL propylene glycol were added to a vessel heated temperature range was different than that for the individual to about 50° C. to about 60° C. with stirring until all compo components alone: 41° C. to 45° C. for GELUCIRE(R) 43/01 nents of the mixture were dissolved. About 1.9 g GELU (Gattefosse) and 75° C. to 78° C. for Ibuprofen. MAISINE(R) CIRE(R) 43/01 (Gattefosse), a waxy solid (as room tempera 35-1 and PEG 400 are liquids at room temperature, and as 40 ture solid lipid) having a melting point of between 41° C. to such both have melting points below 20° C. These results 45° C. and comprising a mixture of Saturated Co-Cs trig indicate that a Solid solution formulation as disclosed herein lycerides, was added to this solution and stirred until incor comprising Ibuprofen was formed. porated. The heated mixture was then cooled to about 37° C. To prepare a solid solution pharmaceutical composition to about 40° C., and aliquoted by pouring into molds and disclosed herein using Ibuprofen, the following method was 45 cooled to room temperature. Alternatively, the mixture can be performed. About 5 g ibuprofen sodium salt, about 9.5 mL cooled to room temperature and then Subsequently reheated MAISINE(R) 35-1 (Gattefosse), a glyceryl monolinoleate (as to about 40°C. to about 45° C. for aliquoting into molds. The room temperature liquid lipid), and about 1.0 mL PEG 400 formulation solidified with a clear appearance and remelted were added to a vessel heated to about 50° C. to about 60° C. without forming a precipitate. These results indicate that a with stirring until all components of the mixture were dis 50 Solid solution formulation as disclosed herein comprising solved. About 4.0 g GELUCIRE(R) 43/01 (Gattefosse), a waxy Ibuprofen was formed. Solid (as room temperature solid lipid) having a melting point To prepare a solid solution pharmaceutical composition of between 41° C. to 45° C. and comprising a mixture of disclosed herein using Ibuprofen, the following method was saturated Co-Cs triglycerides, was added to this solution performed. About 5 g ibuprofen free acid, about 5 g ibuprofen and stirred until incorporated. The heated mixture was then 55 sodium salt, about 8 mL MAISINE(R) 35-1 (Gattefosse), a cooled to about 37° C. to about 40° C., and aliquoted by glyceryl monolinoleate (as room temperature liquid lipid), pouring into molds and cooled to room temperature. Alterna about 3 mL PEG 400, and about 1 mL propylene glycol were tively, the mixture can be cooled to room temperature and added to a vessel heated to about 50° C. to about 60° C. with then subsequently reheated to about 40°C. to about 45° C. for stirring until all components of the mixture were dissolved. aliquoting into molds. 60 About 19 g GELUCIRER 43/01 (Gattefosse), a waxy solid The formulation solidified with a clear appearance. In addi (as room temperature Solid lipid) having a melting point of tion, DSC analysis indicated a new broad melting point tem between 41° C. to 45° C. and comprising a mixture of satu perature range of about 32° C. to about 38°C. (FIG.1G). This rated Co-Cs triglycerides, was added to this solution and temperature range was different than that for the individual stirred until incorporated. The heated mixture was then components alone: 41° C. to 45° C. for GELUCIRE(R) 43/01 65 cooled to about 37° C. to about 40° C., and aliquoted by (Gattefosse) and 75° C. to 78° C. for Ibuprofen. MAISINE(R) pouring into molds and cooled to room temperature. Alterna 35-1 and PEG 400 are liquids at room temperature, and as tively, the mixture can be cooled to room temperature and US 9,308,213 B2 75 76 then subsequently reheated to about 40°C. to about 45° C. for cooled to about 37° C. to about 40° C., and aliquoted by aliquoting into molds. The formulation solidified with a clear pouring into molds and cooled to room temperature. Alterna appearance and remelted without forming a precipitate. tively, the mixture can be cooled to room temperature and These results indicate that a solid solution formulation as then subsequently reheated to about 40°C. to about 45° C. for disclosed herein comprising Ibuprofen was formed. aliquoting into molds. To prepare a solid solution pharmaceutical composition Example 9 disclosed herein using Lidocaine, the following method was performed. About 250.4 mg. Lidocaine base and about 0.87 Solid Solution Pharmaceutical Compositions mL isosorbide dimethyl ester (as stabilizing agent) were Comprising Lidocaine 10 added to a vessel and heated to about 50° C. to about 60° C. This example illustrates how to make a solid solution phar with stirring until all components of the mixture were incor maceutical composition disclosed herein comprising porated. Separately, About 250.1 mg Prilocalne HCl base, Lidocaine. 0.13 mL triethanolamine (as neutralizing agent), and about To prepare a solid solution pharmaceutical composition 15 0.87 mL isosorbide dimethyl ester (as stabilizing agent) were disclosed herein using Lidocaine, the following method was added to a vessel and heated to about 50° C. to about 60° C. performed. About 200 mg Lidocaine base and about 2.0 mL with stirring until all components of the mixture were incor isosorbide dimethyl ester (as stabilizing agent) were added to porated. The Lidocaine and Prilocalne mixtures were com a vessel and heated to about 50° C. to about 60° C. with bined and heated to about 50° C. to about 60°C. with stirring stirring until all components of the mixture were dissolved. until all components were dissolved. About 8.49 g GELU About 8.8 g. GELUCIRER 43/01 (Gattefosse), a waxy solid CIRE(R) 43/01 (Gattefosse), a waxy solid (as room tempera (as room temperature Solid lipid) having a melting point of ture solid lipid) having a melting point of between 41° C. to between 41° C. to 45° C. and comprising a mixture of satu 45° C. and comprising a mixture of Saturated Co-Cs trig rated Co-Cs triglycerides, was added to this solution and lycerides, was added to this solution and stirred until incor stirred until incorporated. The heated mixture was then 25 porated. The heated mixture was then cooled to about 37° C. cooled to about 37° C. to about 40° C., and aliquoted by to about 40° C., and aliquoted by pouring into molds and pouring into molds and cooled to room temperature. Alterna cooled to room temperature. Alternatively, the mixture can be tively, the mixture can be cooled to room temperature and cooled to room temperature and then Subsequently reheated then subsequently reheated to about 40°C. to about 45° C. for to about 40°C. to about 45° C. for aliquoting into molds. aliquoting into molds. 30 The formulation solidified with a clear appearance. In addi Example 10 tion, DSC analysis indicated a new broad melting point tem perature range of about 34° C. to about 40°C. (FIG. 7). This Solid Solution Pharmaceutical Compositions temperature range was different than that for the individual Comprising Nabumetone components alone: 41° C. to 45° C. for GELUCIRE(R) 43/01 35 (Gattefosse) and 66° C. to 69° C. for Lidocaine. Isosorbide dimethyl ester is a liquidat room temperature, and as Such has This example illustrates how to make a solid solution phar a melting point below 20°C. These results indicate that a solid maceutical composition disclosed herein comprising Nabu Solution formulation as disclosed herein comprising metOne. Lidocaine was formed. 40 To prepare a solid solution pharmaceutical composition To prepare a solid solution pharmaceutical composition disclosed herein using Nabumetone, the following method disclosed herein using Lidocaine, the following method was was performed. About 126 mg Nabumetone and about 0.5 mL performed. About 250.1 mg Lidocaine base and about 1.74 MAISINE(R) 35-1 (Gattefosse), a glyceryl monolinoleate (as mL isosorbide dimethyl ester (as stabilizing agent) were room temperature liquid lipid), were added to a vessel and added to a vessel and heated to about 50° C. to about 60° C. 45 heated to about 50° C. to about 60° C. with stirring until all with stirring until all components of the mixture were dis components of the mixture were dissolved. About 1.0 g solved. About 8.72 g GELUCIRE(R) 43/01 (Gattefosse), a GELUCIRER 43/01 (Gattefosse), a waxy solid (as room waxy Solid (as room temperature Solid lipid) having a melting temperature solid lipid) having a melting point of between point of between 41° C. to 45° C. and comprising a mixture of 41° C. to 45° C. and comprising a mixture of Saturated Co saturated Co-Cs triglycerides, was added to this solution 50 Cs triglycerides, was added to this solution and stirred until and stirred until incorporated. The heated mixture was then incorporated. The heated mixture was then cooled to about cooled to about 37° C. to about 40° C., and aliquoted by 37° C. to about 40°C., and aliquoted by pouring into molds pouring into molds and cooled to room temperature. Alterna and cooled to room temperature. Alternatively, the mixture tively, the mixture can be cooled to room temperature and can be cooled to room temperature and then Subsequently then subsequently reheated to about 40°C. to about 45° C. for 55 aliquoting into molds. reheated to about 40° C. to about 45° C. for aliquoting into To prepare a solid solution pharmaceutical composition molds. disclosed herein using Lidocaine, the following method was The formulation solidified with a clear appearance. In addi performed. About 500.4 mg. Lidocaine base and about 1.74 tion, DSC analysis indicated a new broad melting point tem mL isosorbide dimethyl ester (as stabilizing agent) were 60 perature range of about 35° C. to about 40°C. (FIG. 8). This added to a vessel and heated to about 50° C. to about 60° C. temperature range was different than that for the individual with stirring until all components of the mixture were dis components alone: 41° C. to 45° C. for GELUCIRE(R) 43/01 solved. About 8.5g GELUCIRE(R) 43/01 (Gattefosse), a waxy (Gattefosse) and 80° C. to 81° C. for Nabumetone. Solid (as room temperature solid lipid) having a melting point MAISINE(R) 35-1 is a liquid at room temperature, and as such of between 41° C. to 45° C. and comprising a mixture of 65 has a melting point below 20°C. These results indicate that a saturated Co-Cs triglycerides, was added to this solution Solid solution formulation as disclosed herein comprising and stirred until incorporated. The heated mixture was then Nabumetone was formed. US 9,308,213 B2 77 78 Example 11 room temperature liquid lipid), and about 0.2 mL isosorbide dimethyl ester (as stabilizing agent) were added to a vessel Solid Solution Pharmaceutical Compositions and heated to about 50° C. to about 60°C. with stirring until Comprising Naproxen all components of the mixture were dissolved. About 1.0 g GELUCIRER 43/01 (Gattefosse), a waxy solid (as room This example illustrates how to make a solid solution phar temperature solid lipid) having a melting point of between maceutical composition disclosed herein comprising 41° C. to 45° C. and comprising a mixture of Saturated Co Naproxen. Cs triglycerides, was added to this solution and stirred until To prepare a solid solution pharmaceutical composition incorporated. The heated mixture was then cooled to about disclosed herein using Naproxen, the following method was 10 37° C. to about 40°C., and aliquoted by pouring into molds performed. About 250.1 mg Naproxen and about 0.75 mL and cooled to room temperature. Alternatively, the mixture MAISINE(R) 35-1 (Gattefosse), a glyceryl monolinoleate (as can be cooled to room temperature and then Subsequently room temperature liquid lipid), were added to a vessel and reheated to about 40° C. to about 45° C. for aliquoting into heated to about 50° C. to about 60° C. with stirring until all molds. The formulation solidified with a clear appearance and components of the mixture were dissolved. About 750.9 mg 15 remelted without forming a precipitate. These results indicate GELUCIRER 43/01 (Gattefosse), a waxy solid (as room that a solid solution formulation as disclosed herein compris temperature solid lipid) having a melting point of between ing Pentoxifylline was formed. 41° C. to 45° C. and comprising a mixture of Saturated Co Cs triglycerides, was added to this solution and stirred until Example 13 incorporated. The heated mixture was then cooled to about 37°C. to about 40°C., and aliquoted by pouring into molds Solid Solution Pharmaceutical Compositions and cooled to room temperature. Alternatively, the mixture Comprising Salbutamol can be cooled to room temperature and then Subsequently reheated to about 40° C. to about 45° C. for aliquoting into This example illustrates how to make a solid solution phar molds. The formulation solidified with a clear appearance. 25 maceutical composition disclosed herein comprising Salb These results indicate that a solid solution formulation as utamol. disclosed herein comprising Naproxen was formed. To prepare a solid solution pharmaceutical composition To prepare a solid solution pharmaceutical composition disclosed herein using Salbutamol, the following method was disclosed herein using Naproxen, the following method was performed. About 61 mg Salbutamol, about 0.6 mL performed. About 650.5 mg Naproxen and about 1.2 mL 30 MAISINE(R) 35-1 (Gattefosse), a glyceryl monolinoleate (as MAISINE(R) 35-1 (Gattefosse), a glyceryl monolinoleate (as room temperature liquid lipid), 1.0 mL isosorbide dimethyl room temperature liquid lipid), were added to a vessel and ether (as stabilizing agent), and about 1.0 mL absolute etha heated to about 50° C. to about 60° C. with stirring until all nol (as stabilizing agent) were added to a vessel and heated to components of the mixture were dissolved. About 1.234 g about 50° C. to about 60°C. with stirring until all components GELUCIRER 43/01 (Gattefosse), a waxy solid (as room 35 of the mixture were dissolved. About 10 g GELUCIRE(R) temperature solid lipid) having a melting point of between 43/01 (Gattefosse), a waxy solid (as room temperature solid 41° C. to 45° C. and comprising a mixture of Saturated Co lipid) having a melting point of between 41° C. to 45° C. and Cs triglycerides, was added to this solution and stirred until comprising a mixture of saturated Co-Cs triglycerides, was incorporated. The heated mixture was then cooled to about added to this solution and stirred until incorporated. The 37°C. to about 40°C., and aliquoted by pouring into molds 40 heated mixture was then cooled to about 37° C. to about 40° and cooled to room temperature. Alternatively, the mixture C., and aliquoted by pouring into molds and cooled to room can be cooled to room temperature and then Subsequently temperature. Alternatively, the mixture can be cooled to room reheated to about 40° C. to about 45° C. for aliquoting into temperature and then subsequently reheated to about 40°C. to molds. about 45° C. for aliquoting into molds. The formulation solidified with a clear appearance. In addi 45 The formulation solidified with a clear appearance. In addi tion, DSC analysis indicated a new broad melting point tem tion, DSC analysis indicated a new broad melting point tem perature range of about 30° C. to about 39° C. (FIG.9). This perature range of about 32° C. to about 40°C. (FIG.10). This temperature range was different than that for the individual temperature range was different than that for the individual components alone: 41° C. to 45° C. for GELUCIRE(R)43/01 components alone: 41° C. to 45° C. for GELUCIRE(R)43/01 (Gattefosse) and 153° C. to 154° C. for Naproxen. 50 (Gattefosse) and 157° C. to 158° C. for Salbutamol. MAISINE(R) 35-1 is a liquid at room temperature, and as such MAISINE(R) 35-1, isosorbide dimethyl ether, and absolute has a melting point below 20°C. These results indicate that a ethanol are liquids at room temperature, and as Such all have Solid solution formulation as disclosed herein comprising melting points below 20°C. These results indicate that a solid Naproxen was formed. Solution formulation as disclosed herein comprising Salbuta 55 mol was formed. Example 12 Example 14 Solid Solution Pharmaceutical Compositions Comprising Pentoxifylline Solid Solution Pharmaceutical Compositions 60 Comprising Salmeterol This example illustrates how to make a solid solution phar maceutical composition disclosed herein comprising Pen This example illustrates how to make a solid solution phar toxifylline. maceutical composition disclosed herein comprising Salme To prepare a solid solution pharmaceutical composition terol. disclosed herein using Pentoxifylline, the following method 65 To prepare a solid solution pharmaceutical composition was performed. About 208 mg Pentoxifylline, about 1.0 mL disclosed herein using Salmeterol, the following method was MAISINE(R) 35-1 (Gattefosse), a glyceryl monolinoleate (as performed. About 11 mg Salmeterol Xinafoate, about 1.0 mL US 9,308,213 B2 79 80 MAISINE(R) 35-1 (Gattefosse), a glyceryl monolinoleate (as To prepare a solid solution pharmaceutical composition room temperature liquid lipid), and about 1.0 mL absolute disclosed herein using Telmisartan, the following method ethanol (as stabilizing agent) were added to a vessel and was performed. About 60.1 mg Telmisartan and about 2.0 mL heated to about 50° C. to about 60° C. with stirring until all isosorbide dimethyl ether (as stabilizing agent) were added to components of the mixture were dissolved. About 2.04 g a vessel and heated to about 50° C. to about 60° C. with GELUCIRER 43/01 (Gattefosse), a waxy solid (as room temperature solid lipid) having a melting point of between stirring until all components of the mixture were dissolved. 41° C. to 45° C. and comprising a mixture of Saturated Co About 2.03 g GELUCIRE(R) 43/01 (Gattefosse), a waxy solid Cs triglycerides, was added to this solution and stirred until (as room temperature Solid lipid) having a melting point of incorporated. The heated mixture was then cooled to about between 41° C. to 45° C. and comprising a mixture of satu 37°C. to about 40°C., and aliquoted by pouring into molds 10 rated Co-Cs triglycerides, was added to this solution and and cooled to room temperature. Alternatively, the mixture stirred until incorporated. The heated mixture was then can be cooled to room temperature and then Subsequently cooled to about 37° C. to about 40° C., and aliquoted by reheated to about 40° C. to about 45° C. for aliquoting into pouring into molds and cooled to room temperature. Alterna molds. tively, the mixture can be cooled to room temperature and The formulation solidified with a clear appearance. In addi 15 then subsequently reheated to about 40°C. to about 45° C. for tion, DSC analysis indicated a new broad melting point tem aliquoting into molds. The formulation solidified with a clear perature range of about 34°C. to about 43°C. (FIG. 11). This appearance and remelted without forming a precipitate. temperature range was different than that for the individual These results indicate that a solid solution formulation as components alone: 41° C. to 45° C. for GELUCIRE(R) 43/01 disclosed herein comprising Telmisartan was formed. (Gattefosse) and 137° C. to 138° C. for Salmeterol. To prepare a solid solution pharmaceutical composition MAISINE(R) 35-1 and absolute ethanol are liquids at room disclosed herein using Telmisartan, the following method temperature, and as such both have melting points below 20° was performed. About 160.2 mg Telmisartan, about 1.0 mL C. These results indicate that a solid solution formulation as MAISINE(R) 35-1 (Gattefosse), a glyceryl monolinoleate (as disclosed herein comprising Salmeterol was formed. room temperature liquid lipid), and about 1.0 mL absolute 25 ethanol (as stabilizing agent) were added to a vessel and Example 15 heated to about 50° C. to about 60° C. with stirring until all components of the mixture were dissolved. About 2.03 g Solid Solution Pharmaceutical Compositions GELUCIRER 43/01 (Gattefosse), a waxy solid (as room Comprising Simvastatin temperature solid lipid) having a melting point of between This example illustrates how to make a solid solution phar 30 41° C. to 45° C. and comprising a mixture of Saturated Co maceutical composition disclosed herein comprising Simv Cs triglycerides, was added to this solution and stirred until astatin. incorporated. The heated mixture was then cooled to about To prepare a solid solution pharmaceutical composition 37° C. to about 40°C., and aliquoted by pouring into molds disclosed herein using Simvastatin, the following method and cooled to room temperature. Alternatively, the mixture was performed. About 200 mg Simvastatin and about 2.5 mL 35 can be cooled to room temperature and then Subsequently MAISINE(R) 35-1 (Gattefosse), a glyceryl monolinoleate (as reheated to about 40° C. to about 45° C. for aliquoting into room temperature liquid lipid) were added to a vessel and molds. heated to about 50° C. to about 60° C. with stirring until all The formulation solidified with a clear appearance. In addi components of the mixture were dissolved. About 5 g GELU tion, DSC analysis indicated a new broad melting point tem CIRE(R) 43/01 (Gattefosse), a waxy solid (as room tempera 40 perature range of about 34° C. to about 43° C. (FIG. 13). This ture solid lipid) having a melting point of between 41° C. to temperature range was different than that for the individual 45° C. and comprising a mixture of Saturated Co-Cs trig components alone: 41° C. to 45° C. for GELUCIRE(R) 43/01 lycerides, was added to this solution and stirred until incor (Gattefosse) and 261° C. to 263° C. for Telmisartan. porated. The heated mixture was then cooled to about 37°C. MAISINE(R) 35-1 and absolute ethanol are liquids at room to about 40° C., and aliquoted by pouring into molds and 45 temperature, and as such both have melting points below 20° cooled to room temperature. Alternatively, the mixture can be C. These results indicate that a solid solution formulation as cooled to room temperature and then Subsequently reheated disclosed herein comprising Telmisartan was formed. to about 40°C. to about 45° C. for aliquoting into molds. The formulation solidified with a clear appearance. In addi Example 17 tion, DSC analysis indicated a new broad melting point tem 50 perature range of about 32° C. to about 42°C. (FIG. 12). This Macrophage Uptake Experiment temperature range was different than that for the individual components alone: 41° C. to 45° C. for GELUCIRE(R) 43/01 This example illustrates that a solid solution pharmaceuti (Gattefosse) and 135° C. to 138° C. for Simvastatin. cal composition disclosed herein preferentially targets a MAISINE(R) 35-1 and absolute ethanol are liquids at room 55 therapeutic compound to the immune system. temperature, and as such both have melting points below 20° Cultures of U937 monocyte cell line were grown in RPMI C. These results indicate that a solid solution formulation as 1640 supplemented with 10% fetal calf serum (FCS) until the disclosed herein comprising Simvastatin was formed. cells reached 90% confluent monolayer. These cells were then treated with PMA and incubated in a 37° C. incubator Example 16 60 under 5% carbon dioxide until the cells differentiated into macrophages. Monolayers of macrophages were washed Solid Solution Pharmaceutical Compositions with fresh medium and then 3 mL of one of the following test Comprising Telmisartan solutions were added: A) solid solution formulation as dis closed herein comprising ibuprofen, GELUCIRE(R) 43/01 This example illustrates how to make a solid solution phar 65 (Gattefosse), MAISINE(R) 35-1 (Gattefosse), and PEG 400; maceutical composition disclosed herein comprising Telmis B) liquid formulation disclosed herein comprising ibuprofen, artan. rapeseed oil and ethanol; C) ibuprofen free acid; and D) US 9,308,213 B2 81 82 vehicle with no therapeutic compound. After incubation for Results are shown in Table 4. Group D (100 mg/kg of 45 minutes the test Solution Supernatants were removed and ibuprofen-treated control group) and Group F (200 mg/kg of saved for analysis, and the cells were then washed in PBS ibuprofen-treated control group) produced gastriclesions that several times and lysed using two cycles of freeze-thawing. were 75% and 95%, respectively, severe as those induced by Therapeutic compound concentration present in the test Solu Group C (aspirin-treated control group). However, Group E tion, test Solution Supernatant, and cell lyste fractions was (BC 1054-100-treated experimental group) and Group G measured by HPLC. The percentage therapeutic compound (BC 1054-200-treated experimental group) produced gastric taken up by the macrophages was calculated using the fol lesions that were 20% and 40%, respectively, as severe as lowing formula: % therapeutic compound adsorbed=100x those associated with Group C (aspirin-treated control (compound mass recovered from cell lysate)/(compound 10 group). These results demonstrate that that a pharmaceutical mass delivered in test Solution-compound mass recovered composition disclosed herein reduced the extent to which a from test Solution Supernatant). Results are shown in the therapeutic compound may cause mucosal lesions and cause Table 1 below. These results indicate that mean uptake of a gastric irritation. therapeutic compound by macrophage increase 550% or 15 more using the formulations of the pharmaceutical composi TABLE 4 tions presently claimed relative to compositions not formu lated in this manner. Results from Intestinal Erosion Assay Mean TABLE 3 Group Ulceration Score % Aspirin Erosion Macrophage Uptake of Therapeutic Compound A. O O B O O Mean Mass C 4 (100) Formulation N Compound Uptake % Increase Compound Uptake D 3 751 E O.8 2O 2.4% 600% 25 F 3.8 951 2.2% 5509% G 1.6 40 O.4% O.0% Positive score for gastric erosion,

30 Example 19 Example 18 Animal Model for Inflammatory Bowel Disease Animal Model for Intestinal Erosion To assess the effectiveness of a pharmaceutical composi To assess whether a pharmaceutical composition disclosed 35 tion disclosed herein in treating an inflammatory bowel dis herein reduced gastric irritation, experiments were conducted ease, experiments were conducted using a TBS-induced coli using an intestinal erosion murine model. tis murine model. Sprague-Dawley rats were divided into seven experimental C57BL/6 male mice (6-7 weeks old) were divided into groups containing five animals each. After fasting overnight, seven experimental groups containing at least ten animals the animals were challenged with one with one of seven 40 each. On day 0, colitis was induced in mice from Groups B-G different treatments. Group A was a control in which each by intrarectal administration of 100 uL of TNBS (4 mg) in mouse was orally administered 1% methylcellulose/0.5% 50% ethanol under isoflurane anesthesia. Animals were polysorbate 80 vehicle only. Group B was a control in which dosed either once or three times a day from day -1 to day 5 each mouse was orally administered solvent/adjuvant vehicle with one of seven different treatments. Group A was a control only (gavage of 10% ethanol and 90% linseed oil). Group C 45 in which each mouse was orally administered ethanol vehicle was a control in which each mouse was orally administered only. Group B was a control in which each mouse was orally 150 mg/kg aspirin. Group D was a control in which each administered 1% methylcellulose vehicle only. Group C was mouse was orally administered 100 mg/kg ibuprofen Sus a control in which each mouse was orally administered sol pended in 1% methylcellulose/0.5% polysorbate 80. Group E vent/adjuvant vehicle only (gavage of 10% ethanol and 90% was the experimental group in which each mouse was admin 50 linseed oil). Group D was a control in which each mouse was istered a pharmaceutical composition disclosed herein orally administered 3 mg/kg of Prednisolone. Group E was a (BC1054-100) comprising 100 mg/kg of ibuprofen, 10% control in which each mouse was orally administered 20 ethanol, and 90% linseed oil. Group F was a control in which mg/kg of ibuprofen suspended in 1% methylcellulose (1 each mouse was orally administered 100 mg/kg ibuprofen mL/kg) (no adjuvant). Group F was the experimental group in suspended in 1% methylcellulose/0.5% polysorbate 80. 55 which each mouse was administered a pharmaceutical com Group G was the experimental group in which each mouse position disclosed herein (BC 1054-20) comprising 20 mg/kg was administered a pharmaceutical composition disclosed of ibuprofen, 10% ethanol, and 90% linseed oil. Group G was herein (BC1054-200) comprising 200 mg/kg of ibuprofen, the experimental group in which each mouse was adminis 10% ethanol, and 90% linseed oil. Animals were sacrificed 4 tered a pharmaceutical composition disclosed herein hours after treatment and the stomachs were examined for 60 (BC 1054-30) comprising 30 mg/kg of ibuprofen, 10% etha degree of hemorrhage and severity of mucosal erosive nol, and 90% linseed oil. All animals were weighed daily and lesions. Gastric irritation was scored as follows: 0, no lesions; assessed visually for the presence of diarrhea and/or bloody 1, hyperemia; 2, one or two slight lesions; 3, more than two stool. On day 3 and on day 5 colitis severity was assessed in slight lesions or severe lesions; and 4, very severe lesions. A all animals using video endoscopy, where images were taken score of 50% or more relative to Group C (aspirin-treated 65 and colitis severity scored visually by a blinded observer on a control group), which was set to 100%, was considered a scale from 0 to 4 as follows: 0, normal; 1, loss of vascularity; positive score for gastric irritation. 2, loss of vascularity and friability; 3, friability and erosions: US 9,308,213 B2 83 84 and 4, ulcerations and bleeding. Following endoscopy on day Male BALB/c mice were divided into eight groups, each 5, animals were sacrificed and the colon removed and its containing 10 animals. To induce arthritic symptoms, mice length and weight measured. Serum samples were obtained from all eight groups were intravenously injected with 200 uL and the colon was fixed in 10% formalin. An additional piece of an antibody solution comprising a 2 mg cocktail of four of colon tissue was collected, weighed, and Snap frozen in liquid nitrogen. C-collagen II monoclonal antibodies (ARTHRITOMABTM, Results from these experiments are shown in Table 5. MD Biosciences) on study day 0 (study commencement), Group B (TNBS-treated control group) showed a statistically followed by a 200 uL intraperitoneal injection of a solution significant difference in mean weight change when compared containing 100 ug lipopolysaccharide (LPS) on study day 3. to Group A (untreated ethanol control group), all other group Each group was Subjected daily to a control or test treatment comparisons showed no difference in mean weight change. 10 administered from day 0-11 as follows: Group 1 mice (1M) Group B (TNBS-treated control group) showed a statistically were treated orally with a vehicle preparation containing 1% significant decrease in mean colon length when compared to methyl cellulose administered thrice daily; Group 2 mice Group A (untreated ethanol control group). Additionally, (2M) were treated intraperitoneally with a positive control Group D (Prednisolone-treated control group), Group F preparation containing 10 mg/kg etanercept (ENBRELR), (BC1054-20-treated experimental group), and Group G 15 Wyeth) administered once daily; Group 3 mice (3M) were (BC1054-30-treated experimental group) all showed a statis treated orally with a 20 mg/kg test liquid formulation com tically significant increase in mean colon length when com prising ibuprofen and rapeseed oil (BC1054 LF-RO) admin pared to Group B (TNBS-treated control group). Although istered once daily; Group 4 mice (4M) were treated orally Group B (TNBS-treated control group) showed a statistically with a 20 mg/kg test liquid formulation comprising ibuprofen significant increase in mean colon weight when compared to and rapeseed oil (BC 1054 LF-RO) administered thrice daily; Group A (untreated ethanol control group), all other group Group 5 mice (5M) were treated orally with a 20 mg/kg test comparisons showed no difference in mean colon weight. liquid formulation comprising ibuprofen and a glyceryl With regards to the endoscopy colitis score, Group D (Pred monolinoleate (MAISINE(R) 35-1, Gattefosse) (BC1054 LF MA) administered thrice daily; Group 6 mice (6M) were nisolone-treated control group) showed a statistically signifi 25 cant reduced mean colitis scores on both day 3 and day 5 treated orally with a 20 mg/kg test Solid formulation compris when compared to Group B (TNBS-treated control group). In ing ibuprofen and theobroma oil (BC1054 LF-TO) adminis a similar manner, both Group F (BC 1054-20-treated experi tered thrice daily; Group 7 mice (7M) were treated orally with mental group) and Group G (BC1054-30-treated experimen a control preparation 1 comprising 20 mg/kg of ibuprofen tal group) showed a statistically significant reduced mean 30 administered thrice daily; and Group 8 mice (8M) were colitis scores on day 5 when compared to Group B (TNBS treated orally with a 20 mg/kg test Solid formulation compris treated control group). These results indicate that a pharma ing ibuprofen and a waxy Solid having a melting point of ceutical composition disclosed herein was effective in treat between 37° C. to 41° C. and comprising a mixture of satu ing an inflammatory bowel disease. rated Co-Cs triglycerides (GELUCIRE(R39/01, Gattefosse) (BC1054 LF-GE) administered thrice daily (Table 6). The 35 dose administered was calculated based on the assumption TABLE 5 that each animal weighed, on average, 20g. A fixed Volume of Results from Inflammatory Bowel Disease 100LL was administered to each mouse, except those animals receiving the positive control (2M) were administered 200 Mean Endoscopy Colitis Animal Mean Mean Severity Score 40 LL. Group Weight Colon Length Colon Weight Day 3 Day 5 TABLE 6 A. 23.93 g 8.5 cm 215 mg O.2 O Constitution of Test Groups and Dose Levels B 21.98 g. 7.3 cm 295 mg 3.1 2.7 C 23.64 g 7.8 cm 239 mg 2.9 2.4 Group Size Treatment Dose Volume Route Regime D 23.33 g 8.4 cm 267 mg 2.37 1.78 45 E 23.82 g 7.9 cm 267 mg 2.7 2.2 1M 10 Vehicle NA 5 ml/kg PO Thrice F 23.69 g 8.4 cm 258 mg 2.6 1.99 aily G 24.25 g 7.9 cm 284 mg 2.4 1410 2M 10 Etanercept 10 mg/kg 10 ml/kg IP Once aily Statistically significance difference compared to Group A (p = 0.029). 3M 10 BC1054 20 mg/kg 5 ml/kg PO. Once 'Statistically significance difference compared to Group A (p = 0.001), 50 LF-RO aily Statistically significance difference compared to Group B (p = 0.001). 4M 10 BC1054 20 mg/kg 5 ml/kg PO Thrice Statistically significance difference compared to Group B (p = 0.001). LF-RO aily Statistically significance difference compared to Group B (p = 0.034). SM 10 BC1054 20 mg/kg 5 ml/kg PO Thrice Statistically significance difference compared to Group A (p = 0.009). LF-MA aily 'Statistically significance difference compared to Group B (p = 0.005). 6M 10 BC1054 20 mg/kg 5 ml/kg PO Thrice Statistically significance difference compared to Group B (p = 0.002). 55 SF-TO aily 'Statistically significance difference compared to Group B (p = 0.045), 7M 10 Ibuprofen 20 mg/kg 5 ml/kg PO Thrice 'Statistically significance difference compared to Group B (p = 0.002). aily 8M 10 BC1054 20 mg/kg 5 ml/kg PO Thrice SF-GE aily Example 20 60 DP = Intraperitoneal PO = Per Os Animal Model for a Systemic Arthritis NA = Not applicable To assess the effectiveness of a pharmaceutical composi Arthritic development and clinical examinations were tion disclosed herein in treating arthritis, experiments were monitored in all mice on study day 0 shortly before arthritis conducted using an O-collagen antibody induced arthritis 65 induction and subsequently on study days 3-7, 9, 10 and 12 (ACAIA) murine model that mimics a systemic arthritis like (study termination). To access arthritic development, both an rheumatoid arthritis. arthritis score and paw thickness (plethysmography) mea US 9,308,213 B2 85 86 surements were obtained. The arthritis score was based on had disappeared in all groups by day 12. No mortalities visual assessment of arthritis reactions using a 0-4 scale in occurred during this study or significant differences in body ascending order of severity with Grade 0 indicating no arthri weight between the vehicle-treated group and test item tis reaction; Grade 1 indicating mild, but definite redness and treated groups. Swelling of the ankle?wrist or apparent redness and Swelling 5 The results of mean paw thickness are given in Table 7. limited to individual digits, regardless of the number of Mean rear paw thickness in Group 1M animals (vehicle affected digits; Grade 2 indicating moderate to severe redness treated) was 1.72+0.01 on day 0. Thickness increased and and Swelling of the ankle?wrist; Grade 3 indicating redness peaked on day 9 at 2.33+0.15, and ended at 2.17+0.11 on day and Swelling of the entire paw including digits; and Grade 4 12. In Etanercept-treated Group 2M mice, mean rear paw indicating maximally inflamed limb with involvement of 10 multiple joints. Paw thickness was measured for both hind thickness began at 1.70+0.02 on day 0. This increased, peak paws just above the foot pad and below the calcaneum using ing at 1.96+0.05 on day 6 before decreasing back to a dial caliper (Kroeplin, Munich, Germany). Mean values for 1.77+0.02 on day 12. Etanercept treatment resulted in signifi paw thickness measurements were determined, and where cantly decreased paw Volume compared to the positive con appropriate, analysis of the data by ANOVA with Tukey post 15 trol mice on days 9, 10 and 12. In Group 3M, which received hoc analysis was applied to determine significance of treat BC1054 LS-RO once daily, rear paw thickness was 1.71+0.02 ment effects. on day 0. By day 7 the Swelling in this group had peaked at Clinical examinations included changes in body weight, 1.96+0.05 where it remained relatively constant thereafter. condition of skin, fur, eyes, mucous membranes, occurrence There were significant reductions in the mean paw Swelling of secretions and excretions (e.g. diarrhea), and autonomic on days 6 and 9 following administration of BC 1054 LS-RO. activity (e.g. lacrimation, salivation, piloerection, pupil size, The mean rear paw thickness in Group 4M, which received unusual respiratory pattern). Changes in gait, posture and BC1054 LS-RO thrice daily, increased to 1.97+0.08 on day response to handling, as well as the presence of bizarre behav 10 (from 1.70+0.03 on day 0), from day 10 paw volumes ior, tremors, convulsions, sleep and coma were also noted. remained relative constant till the end of the study. BC 1054 Serum was collected at study termination. 25 LS-RO thrice daily resulted in significantly reduced mean Arthritis incidence increased in all groups from day 3. In paw thickness compared to vehicle-treated mice (Group 1M) Group 1M animals incidence peaked on day 7 with 9/10 on days 6, 7 and 9. Group 5M mice treated with BC1054 animals showing arthritis reactions which remained relatively LS-MA had peak paw volume at day 7 (1.97+0.05 from constant until the end of the study. In Etanercept-treated 1.69+0.02 on day 0), this group had significantly reduced Group 2M mice, incidence peaked on day 6 at 9/10 animals 30 measurements on day 6 and day 9 when compared to the showing signs, but had decreased to 1/10 by day 12. The peak vehicle treated Group 1M animals. In Group 6M animals incidence of arthritis in Group 3M and Group 4M animals treated with BC1054 LS-TO, mean rear paw thickness began receiving BC 1054 LS-RO once or thrice daily was on day 7 at 1.74+0.01 on day 0. This increased to a peak of 2.05+0.10 (9/10 and 7/10 animals, respectively), and this had decreased on day 7 before decreasing back to 1.94+0.06 on day 12. No to 4/10 mice in both groups by day 12. Thearthritis incidence 35 significant differences were recorded between BC 1054 LS peaked on day 6 in the Group 5M animals receiving BC 1054 TO-treated animals (Group 6M) and those treated with LS-MA with 8/10 animals affected, and the incidence fluc vehicle control (Group 1M). In the group which received tuated with between 6 and 8 animals scoring until the end of Ibuprofen (Group 7M), rear paw thickness was 1.71+0.02 on the study. By day 6, 9/10 animals presented with arthritis in day 0. By day 7 the swelling in this group had peaked at Group 6M animals receiving BC 1054 SF-TO, but this also 40 2.15+0.10 before decreasing to 2.02+0.08 on day 12. No fluctuated and ended at 7/10 on day 12. In the Ibuprofen significant differences were observed when this group was treated Group 7M, the peak of arthritis incidence was compared to the vehicle control Group 1 M. Group 8M ani recorded on day 6 with 8/10 animals affected, and this mals treated with BC 1054 LS-GE exhibited a slight increase remained relatively constant until the study termination. in rear paw thickness from 1.72+0.02 on day 0 to 1.85+0.06 Group 8M mice receiving a BC1054 LS-GE exhibited peak 45 on day 7, this remained relatively constant finishing at incidence on day 6 with 9/10 animals presenting with signs of 1.77+0.03 on day 12. Administration of BC1054 LS-GE arthritis, but this had decreased to 4/10 by day 12. resulted in significantly reduced paw Swelling in animals Clinical signs associated with LPS-administration devel (Group 8M) compared to vehicle controls (Group 1M) on oped in all groups following the LPS boost on day 3. These days 6, 7, 9, 10 and 12. TABLE 7

Mean Rear Paw Thickness

Mean Rear Paw. Thickness (mm)

Group N Treatment O 3 4 5 6

1M 10 Vehicle 1.72 OO1 1.72 O.O2 1.63 O.O2 1.69 O.O2 2.03 - 0.09 2M 10 Etanercept 1.70 - O.O2 1.73 O.O3 1.64 O.O2 1.63 O.O2 1.96 0.05 3M 10 BC1054 LF-RO 1.71 - 0.02 1.75- 0.02 1.68 0.02 1.71 - 0.03 1.78: 0.03* 4M 10 BC1054 LF-RO 1.70- 0.03 1.70- 0.01 1.61 + 0.02 1.65 + 0.03 1.75- 0.03* SM 10 BC1054 LF-MA 1.69 0.02 1.73 - 0.02 1.66 0.02 1.67 + 0.02 1.79 0.04* 6M 10 BC1054 SF-TO 1.74 OO1 1.72 O.O3 1.64 O.O1 17O O.O3 1.91 - 0.06 7M 10 Ibuprofen 1.71 - O.O2 1.72 OO1 1.64 O.O2 1.71 - O.O2 1.90 O.OS 8M 10 BC1054 SF-GE 1.72 0.02 1.71 - 0.02 1.63 - 0.01 1.67 + 0.03 1.78: 0.03* US 9,308,213 B2 87 88 TABLE 7-continued

Mean Rear Paw Thickness Mean Rear Paw. Thickness (mm) Group 7 9 10 12

1M 2.26 O13 2.33 - 0.15 2.32 0.15 2.17 O.11 2M 1.95 0.04 1.88 - 0.03* 1.8O. O.04 1.77 O.O2* 3M 1.96 O.OS 1.91 0.08: 1.94 - 0.10 1.90 O.O8 4M 1.89 0.07* 1.91 0.09: 1970.08 1.93 + O.O7 SM 1.97 O.OS 1.92 O.06* 1.96 O.O7 1.91 OO6 6M 2.05 - O.10 1.96 - 0.09 1.99 O.O7 1.94 OO6 7M 2.15 O10 2.08 - 0.11 2.07 - 0.11 2.02, O.O8 8M 1.85 0.06* 1.73 0.04* 1.83 O.O3: 1.77 O.O3*

15 In view of the findings above, significant anti-arthritic the patient had been prescribed prednisolone and NSAIDS to activity was observed in Group 3M animals receiving once control arthritis, with no effect. In addition the patient had daily administration of BC 1054 LS-RO, Group 4M animals taken daily glucosamine. Despite considerable pharmaco receiving thrice daily administration of BC 1054 LS-RO, logical intervention, the patient regularly flared resulting in Group 5M animals receiving thrice daily administration of considerable restriction of mobility. The patient was given a BC1054 LS-MA, and Group 8M animals receiving thrice 10 day course of a pharmaceutical composition disclosed daily administration of BC1054SF-GE. herein (BC 1054) comprising 20 mg/kg of ibuprofen, 10% ethanol, and 90% rapeseed oil (400 mg tid) and experience an Example 21 25 appreciable improvement by day 3 and a complete resolution after the completion of the course. The patient reported that Case Studies for the Treatment of Chronic his mobility was returned to normal and he has remained in Inflammation remission at is 1 month examination. A 38 years old male with reactive osteoarthritis in 1 knee, A 47 year old female was diagnosed with reactive arthritis 30 for 6 months (pain and swelling). Over that period, the patient in one knee was treated with a pharmaceutical composition had tried a comprehensive spectrum of pharmacological disclosed herein (BC 1054) comprising 20 mg/kg of ibupro fen, 10% ethanol, and 90% rapeseed oil (1200 mguid) over a therapies: prednisolone, Humira and Sulfasalazine, alongside 3 day period and found that the Swelling and pain started to go NSAIDs to control pain. Only the sulfasalazine had any away after 1 day and was completely better after 3 days. 35 appreciable effect, however the patient disliked its side Ineffective standard ibuprofen treatment was subsequently effects, so requested to come off the sulfasalazine. After 2 ceased. At a 3 month follow up, no signs of the reactive weeks of being Sulfsalazine free, the patient experienced a arthritis have been observed. flare of the reactive arthritis and commenced a 4 day course of A 50 year old male was diagnosed with a chronically a pharmaceutical composition disclosed herein (BC 1054) inflamed ankle after a maison neuve fracture in the ankle. The 40 comprising 20 mg/kg of ibuprofen, 10% ethanol, and 90% patient was taking 30 mg codeine with 500 mg paracetamol rapeseed oil (600 mg bid), experiencing complete remission bid, along with 10 mg diclofenac tid for 8 months to control of the arthritis. After 2 weeks of being drug free, the arthritis pain. He took a 5 day course of a pharmaceutical composition began to flare again and the patient was put on another 4 day disclosed herein (BC 1054) comprising 20 mg/kg of ibupro treatment of BC 1054, again experiencing complete remis fen, 10% ethanol, and 90% rapeseed oil (600 mg bid) and 45 sion. This time the arthritis flared again 1 week later. To after 2 days reported a significant improvement in his pain, account for this, the patient was given a final 10 day course of and then after 3 days he reported that the pain was completely BC1054. Subsequently, the arthritis remained in remission controlled. He has Subsequently ceased the codeine, parac for 11 months, as per the last examination. etamol and diclofenac, and after a 2 month follow the patient A 49 year old male diagnosed with hypercholesterolemia is still pain free. 50 A33 year old female diagnosed with stress related eczema, (LDL of 4.35 mmol/L) was placed on a pharmaceutical com had an acute flare of moderate eczema on arms and chest. A position disclosed herein (BC1054) comprising 20 mg/kg of pharmaceutical composition disclosed herein (BC 1054) ibuprofen, 10% ethanol, and 90% rapeseed oil (600 mg bid) comprising 20 mg/kg of ibuprofen, 10% ethanol, and 90% for 7 days. After 5 days of treatment the patient's LDL levels rapeseed oil (1200 mguid) was administered for 7 days. After 55 had normalized to 3.89 mmol/L. The normalization of LDL a couple of hours the lesion ceased itching, after 1 day a level persisted for 2 months after cessation of BC 1054 dosing, noticeable improvement in lesion Swelling was reported. 2-3 as determined at the last examination. days later the eczemalesions erythema had resolved and after A 60 year old male newly diagnosed with hypercholester 7 days the lesions had completely disappeared. In the past the olemia (LDL of 4.31 mmol/L) was given a course of a phar patient had used emollients and hydrocortisone creams, 60 which made the lesions worse and would often lead to a maceutical composition disclosed herein (BC1054) compris course of antibiotics. The patient commented that her ing 20 mg/kg of ibuprofen, 10% ethanol, and 90% rapeseed response to the BC 1054 treatment was quick and complete, oil (1200 mguid) to lower LDL levels to within the normal and was a marked improvement on previously pharmacologi range. After 5 days of treatment the patients LDL levels were cal therapies. 65 lowered to 3.36 mmol/L. The patient was followed up for 1 An 85 year old male diagnosed with reactive osteoarthritis, month and his LDL remained within the normal range, with marked swelling and severe pain in both knee. For 1 year, despite there being no further BC 1054 dosing. US 9,308,213 B2 89 90 Example 22 propionic acid derivative NSAID, an acetic acid derivative NSAID, an enolic acid derivative NSAID, a fenamic acid Treatment of Chronic Inflammation derivative NSAID, a non-selective cyclo-oxygenase (COX) inhibitor, a selective cyclooxygenase 1 (COX1) inhibitor, a A 62 year old female complains of joint stiffness and selective cyclooxygenase 2 (COX 2) inhibitor, or a fibrate, Swelling and is diagnosed with rheumatoid arthritis. A phy will be formulated into a pharmaceutical composition and sician determines that the joint stiffness and Swelling is due to administered to the patient as described above. chronic inflammation. The woman is treated by oral admin A 67 year old male complains of muscle Soreness and is istration a pharmaceutical composition comprising ibuprofen diagnosed with dermatomyositis. A physician determines as disclosed herein taken twice daily. Alternatively, the 10 that the Soreness is due to chronic inflammation. The man is woman is treated by oral administration a pharmaceutical treated by oral administration a pharmaceutical composition composition comprising aspirin as disclosed herein taken comprising ibuprofen as disclosed herein taken twice daily. thrice daily. Alternatively, the woman is treated by oral Alternatively, the man is treated by oral administration a administration a pharmaceutical composition comprising pharmaceutical composition comprising aspirin as disclosed naproxen as disclosed herein taken twice daily. The woman’s 15 herein taken thrice daily. Alternatively, the man is treated by condition is monitored and after about 3 days of treatment the oral administration a pharmaceutical composition compris woman indicates there is reduced joint stiffness and Swelling. ing naproxen as disclosed hereintaken twice daily. The man’s At one and three month check-ups, the woman indicates that condition is monitored and after about 3 days of treatment the she continues to have reduced joint stiffness and Swelling in man indicates there is reduced Soreness. At one and three the area treated. This reduction in chronic inflammation month check-ups, the man indicates that he continues to have symptoms indicates Successful treatment with the pharma improved muscle movement and reduced Soreness. This ceutical composition disclosed herein. A similar type of oral reduction in a chronic inflammation symptom indicates Suc administration of a pharmaceutical composition disclosed cessful treatment with the pharmaceutical composition dis herein will be used to treat a patient suffering from chronic closed herein. A similar type of oral administration of a phar inflammation associated with any monoarthritis, oligoarthri 25 maceutical composition disclosed herein will be used to treat tis, or polyarthritis, such as, e.g., osteoarthritis,juvenile idio a patient Suffering from chronic inflammation associated with pathic arthritis, septic arthritis, a spondyloarthropathy (in an inclusion body myositis, a myasthenia gravis, a polymyo cluding ankylosing spondylitis, reactive arthritis (Reiter's sitis or any other type of inflammatory myopathy, as well as, syndrome), psoriatic arthritis, enteropathic arthritis associ a fasciitis, a fibrositis, a myositis, a neuromyotonia, a tendi ated with inflammatory bowel disease, Whipple disease or 30 nosis, or a tendonitis. In a similar manner, any of the thera Behcet disease), a synovitis, gout, pseudogout, or Still's dis peutic compounds such as, e.g., a salicylate derivative ease, as well as, a bursitis, a rheumatic fever, or a tenosyno NSAID, a p-amino phenol derivative NSAID, a propionic Vitis. In a similar manner, any of the therapeutic compounds acid derivative NSAID, an acetic acid derivative NSAID, an Such as, e.g., a salicylate derivative NSAID, a p-amino phenol enolic acid derivative NSAID, a fenamic acid derivative derivative NSAID, a propionic acid derivative NSAID, an 35 NSAID, a non-selective cyclo-oxygenase (COX) inhibitor, a acetic acid derivative NSAID, an enolic acid derivative selective cyclooxygenase 1 (COX1) inhibitor, a selective NSAID, a fenamic acid derivative NSAID, a non-selective cyclooxygenase 2 (COX 2) inhibitor, or a fibrate, will be cyclo-oxygenase (COX) inhibitor, a selective cyclooxyge formulated into a pharmaceutical composition and adminis nase 1 (COX1) inhibitor, a selective cyclooxygenase 2 (COX tered to the patient as described above. 2) inhibitor, or a fibrate, will beformulated into a pharmaceu 40 A 73 year old female complains of wheezing when she tical composition and administered to the patient as described breathes and is diagnosed with Churg-Strauss arteritis. A above. physician determines that the wheezing is due to chronic A 58 year old male complains of breathing difficulty and is inflammation. The woman is treated by oral administration a diagnosed with chronic obstructive pulmonary disease pharmaceutical composition comprising ibuprofen as dis (COPD). A physician determines that the breathing difficulty 45 closed herein taken twice daily. Alternatively, the woman is is due to chronic inflammation. The man is treated by oral treated by oral administration a pharmaceutical composition administration a pharmaceutical composition comprising comprising aspirin as disclosed herein taken thrice daily. ibuprofenas disclosed herein taken twice daily. Alternatively, Alternatively, the woman is treated by oral administration a the man is treated by oral administration a pharmaceutical pharmaceutical composition comprising naproxen as dis composition comprising aspirin as disclosed herein taken 50 closed herein taken twice daily. The woman’s condition is thrice daily. Alternatively, the man is treated by oral admin monitored and after about 3 days of treatment the woman istration a pharmaceutical composition comprising naproxen indicates that she no longer is wheezing. At one and three as disclosed herein taken twice daily. The man's condition is month check-ups, the woman indicates that she still does not monitored and after about 3 days of treatment the man indi wheeze when she breathes. This reduction in a chronic cates there is improvement in his ability to breath. At one and 55 inflammation symptom indicates Successful treatment with three month check-ups, the man indicates that he continues to the pharmaceutical composition disclosed herein. A similar have improved breathing. This reduction in a chronic inflam type of oral administration of a pharmaceutical composition mation symptom indicates Successful treatment with the disclosed herein will be used to treat a patient suffering from pharmaceutical composition disclosed herein. A similar type chronic inflammation associated with any vasculitis, such as, of oral administration of a pharmaceutical composition dis 60 e.g., a Buerger's disease, a cerebral vasculitis, a cryoglobu closed herein will be used to treat a patient suffering from linemia, an essential cryoglobulinemic vasculitis, a giant cell chronic inflammation associated with an asthma, a bronchi arteritis, a Golfers vasculitis, a Henoch-Schonlein purpura, a olitis, a bronchitis, an emphysema, alaryngitis, a pharyngitis, hypersensitivity vasculitis, a Kawasaki disease, a micro a pleuritis, a pneumonitis, a rhinitis, a sinusitis, or any other scopic polyarteritis/polyangiitis, a polyarteritis nodosa, a type of chronic respiratory disorder. In a similar manner, any 65 polymyalgia rheumatica (PMR), a rheumatoid vasculitis, a of the therapeutic compounds such as, e.g., a salicylate Takayasuarteritis, or a Wegener's granulomatosis, as well as, derivative NSAID, a p-amino phenol derivative NSAID, a an arteritis, a carditis, an endocarditis, a heart disease, high US 9,308,213 B2 91 92 blood pressure, inflammatory cardiomegaly, an ischemic chronic inflammation symptom indicates successful treat heart disease, a myocarditis, a pericarditis, a phlebitis, a pyle ment with the pharmaceutical composition disclosed herein. phlebitis, or a thrombophlebitis. In a similar manner, any of A similar type of oral administration of a pharmaceutical the therapeutic compounds such as, e.g., a salicylate deriva composition disclosed herein will be used to treat a patient tive NSAID, a p-amino phenol derivative NSAID, a propionic Suffering from neurogenic inflammation associated with any acid derivative NSAID, an acetic acid derivative NSAID, an inflammatory bowel disease, such as, e.g., an ulcerative coli enolic acid derivative NSAID, a fenamic acid derivative tis (including ulcerative proctitis, left-sided colitis, pancolitis NSAID, a non-selective cyclo-oxygenase (COX) inhibitor, a and fulminant colitis), any irritable bowel disease, as well as, selective cyclooxygenase 1 (COX1) inhibitor, a selective a colitis, an enteritis, an enterocolitis, a gastritis, a gastroen cyclooxygenase 2 (COX 2) inhibitor, or a fibrate, will be 10 teritis, a metabolic syndrome (syndrome X), a spastic colon, formulated into a pharmaceutical composition and adminis or any other gastrointestinal disorder. In a similar manner, any tered to the patient as described above. of the therapeutic compounds Such as, e.g., a salicylate A 37 year old male complains of skin redness and is diag derivative NSAID, a p-amino phenol derivative NSAID, a nosed with rosacea. A physician determines that the redness is propionic acid derivative NSAID, an acetic acid derivative due to chronic inflammation. The man is treated by oral 15 NSAID, an enolic acid derivative NSAID, a fenamic acid administration a pharmaceutical composition comprising derivative NSAID, a non-selective cyclo-oxygenase (COX) ibuprofenas disclosed herein taken twice daily. Alternatively, inhibitor, a selective cyclooxygenase 1 (COX1) inhibitor, a the man is treated by oral administration a pharmaceutical selective cyclooxygenase 2 (COX 2) inhibitor, or a fibrate, composition comprising aspirin as disclosed herein taken will be formulated into a pharmaceutical composition and thrice daily. Alternatively, the man is treated by oral admin administered to the patient as described above. istration a pharmaceutical composition comprising naproxen A 46 year old male complains of fever, joint pains, and as disclosed herein taken twice daily. The man's condition is fatigue and is diagnosed with systemic lupus erythematosus. monitored and after about 3 days of treatment the man indi A physician determines that these symptoms are due to cates there is reduced skin redness. At one and three month chronic inflammation. The man is treated by oral administra check-ups, the man indicates that he continues to have 25 tion a pharmaceutical composition comprising ibuprofen as improved skin tone and reduced redness. This reduction in a disclosed herein taken twice daily. Alternatively, the man is chronic inflammation symptom indicates successful treat treated by oral administration a pharmaceutical composition ment with the pharmaceutical composition disclosed herein. comprising aspirin as disclosed herein taken thrice daily. A similar type of oral administration of a pharmaceutical Alternatively, the man is treated by oral administration a composition disclosed herein will be used to treat a patient 30 pharmaceutical composition comprising naproxen as dis Suffering from chronic inflammation associated with an acne, closed herein taken twice daily. The man's condition is moni a cerviciitis, a dermatitis, an eczema (including an atopic tored and after about 3 days of treatment the man indicates eczema, a contact eczema, a Xerotic eczema, a seborrhoeic there is improvement in his health, his fever is gone, the pain dermatitis, a dyshidrosis, a discoid eczema, a venous eczema, in his joints is reduced and his is not as tired. At one and three a dermatitis herpetiformis, a neurodermatitis, or an autoecze 35 month check-ups, the man indicates that he continues to have matization), an endometritis, agingivitis, a glossitis, a hidrad reduced joint pain and does not suffer from fevers or fatigue. enitis Suppurativa, a keratitis, a keratoconjunctivitis, a masti This reduction in a chronic inflammation symptom indicates tis, a psoriasis (including a plaqure psoriasis, a nail psoriasis, Successful treatment with the pharmaceutical composition a guttate psoriasis, a scalp psoriasis, an inverse psoriasis, a disclosed herein. A similar type of oral administration of a pustular psoriasis, or an erythrodermis psoriasis), a Sclero 40 pharmaceutical composition disclosed herein will be used to derma, a statis dermatitis, a stomatitis, a tonsillitis, a vaginitis, treat a patient Suffering from chronic inflammation associated a vitiligo, or a Vulvitis. In a similar manner, any of the thera with any other systemic autoimmune disorder, including, peutic compounds such as, e.g., a salicylate derivative without limitation, an anti-phospholipid antibody syndrome NSAID, a p-amino phenol derivative NSAID, a propionic (APS), a bullous pemphigoid, a Chagas disease, a discoid acid derivative NSAID, an acetic acid derivative NSAID, an 45 lupus erythematosus, a drug-induced lupus erythematosus, a enolic acid derivative NSAID, a fenamic acid derivative Goodpasture's syndrome, a Guillain-Barre syndrome, an NSAID, a non-selective cyclo-oxygenase (COX) inhibitor, a idiopathic thrombocytopenic purpura, a myasthenia gravis, a selective cyclooxygenase 1 (COX1) inhibitor, a selective neonatal lupus, a pernicious anemia, a polymyalgia rheu cyclooxygenase 2 (COX 2) inhibitor, or a fibrate, will be matica, a rheumatoid arthritis, a Scleroderma, a Sjögren's formulated into a pharmaceutical composition and adminis 50 syndrome, a Subacute cutaneous lupus erythematosus, or a tered to the patient as described above. Wegener's granulomatosis. In a similar manner, any of the A 33 year old female complains of abdominal pain and therapeutic compounds such as, e.g., a salicylate derivative diarrhea and is diagnosed with Crohn's disease. A physician NSAID, a p-amino phenol derivative NSAID, a propionic determines that the abdominal pain and diarrhea is due to acid derivative NSAID, an acetic acid derivative NSAID, an chronic inflammation. The woman is treated by oral admin 55 enolic acid derivative NSAID, a fenamic acid derivative istration a pharmaceutical composition comprising ibuprofen NSAID, a non-selective cyclo-oxygenase (COX) inhibitor, a as disclosed herein taken twice daily. Alternatively, the selective cyclooxygenase 1 (COX1) inhibitor, a selective woman is treated by oral administration a pharmaceutical cyclooxygenase 2 (COX 2) inhibitor, or a fibrate, will be composition comprising aspirin as disclosed herein taken formulated into a pharmaceutical composition and adminis thrice daily. Alternatively, the woman is treated by oral 60 tered to the patient as described above. administration a pharmaceutical composition comprising A 58 year old male complains of depression, sensitivity to naproxen as disclosed herein taken twice daily. The woman’s cold, weight gain, forgetfulness, and constipation and is diag condition is monitored and after about 3 days of treatment the nosed with Hashimoto's thyroiditis. A physician determines woman indicates that there is a reduction in abdominal pain that these symptoms are due to chronic inflammation. The and she no longer has diarrhea. At one and three month 65 man is treated by oral administration a pharmaceutical com check-ups, the woman indicates that she continues to have position comprising ibuprofen as disclosed herein taken reduced abdominal pain and diarrhea. This reduction in a twice daily. Alternatively, the man is treated by oral admin US 9,308,213 B2 93 94 istration a pharmaceutical composition comprising aspirin as cyclo-oxygenase (COX) inhibitor, a selective cyclooxyge disclosed herein taken thrice daily. Alternatively, the man is nase 1 (COX1) inhibitor, a selective cyclooxygenase 2 (COX treated by oral administration a pharmaceutical composition 2) inhibitor, or a fibrate, will beformulated into a pharmaceu comprising naproxen as disclosed herein taken twice daily. tical composition and administered to the patient as described The man’s condition is monitored and after about 3 days of 5 above. treatment the man indicates there is reduction in all the Symp In closing, it is to be understood that although aspects of the toms complained of. At one and three month check-ups, the present specification are highlighted by referring to specific man indicates that he still does not experience depression, embodiments, one skilled in the art will readily appreciate sensitivity to cold, weight gain, forgetfulness, and constipa that these disclosed embodiments are only illustrative of the tion. This reduction in a chronic inflammation symptom indi 10 principles of the subject matter disclosed herein. Therefore, it cates Successful treatment with the pharmaceutical composi should be understood that the disclosed subject matter is in no tion disclosed herein. A similar type of oral administration of way limited to a particular methodology, protocol, and/or a pharmaceutical composition disclosed herein will be used reagent, etc., described herein. As such, various modifications to treat a patient Suffering from chronic inflammation associ or changes to or alternative configurations of the disclosed ated with any other local autoimmune disorder, including, 15 Subject matter can be made in accordance with the teachings without limitation, an acute disseminated encephalomyelitis herein without departing from the spirit of the present speci (ADEM), an Addison's disease, an autoimmune hemolytic fication. Lastly, the terminology used herein is for the purpose anemia, an autoimmune hepatitis (including primary biliary of describing particular embodiments only, and is not cirrhosis), an autoimmune inner ear disease, a celiac disease, intended to limit the scope of the present invention, which is a Crohn's disease, a diabetes mellitus type 1, an endometrio defined solely by the claims. Accordingly, the present inven sis, a giant cell arteritis, a Graves' disease, an interstitial tion is not limited to that precisely as shown and described. cystitis, a lupus nephritis, a multiple Sclerosis, a morphea, a Certain embodiments of the present invention are pemphigus Vulgaris, a recurrent disseminated encephalomy described herein, including the best mode knownto the inven elitis, a Sclerosing cholangitis, an ulcerative colitis, or a viti tors for carrying out the invention. Of course, variations on ligo. In a similar manner, any of the therapeutic compounds 25 these described embodiments will become apparent to those Such as, e.g., a salicylate derivative NSAID, a p-amino phenol ofordinary skill in the art upon reading the foregoing descrip derivative NSAID, a propionic acid derivative NSAID, an tion. The inventor expects skilled artisans to employ Such acetic acid derivative NSAID, an enolic acid derivative variations as appropriate, and the inventors intend for the NSAID, a fenamic acid derivative NSAID, a non-selective present invention to be practiced otherwise than specifically cyclo-oxygenase (COX) inhibitor, a selective cyclooxyge 30 described herein. Accordingly, this invention includes all nase 1 (COX1) inhibitor, a selective cyclooxygenase 2 (COX modifications and equivalents of the Subject matter recited in 2) inhibitor, or a fibrate, will beformulated into a pharmaceu the claims appended hereto as permitted by applicable law. tical composition and administered to the patient as described Moreover, any combination of the above-described embodi above. ments in all possible variations thereof is encompassed by the A 59 year old female complains of joint stiffness and 35 invention unless otherwise indicated herein or otherwise Swelling and is diagnosed with reactive arthritis. A physician clearly contradicted by context. determines that the joint stiffness and Swelling is due to Groupings of alternative embodiments, elements, or steps chronic inflammation. The woman is treated by oral admin of the present invention are not to be construed as limitations. istration a pharmaceutical composition comprising ibuprofen Each group member may be referred to and claimed individu as disclosed herein taken twice daily. Alternatively, the 40 ally or in any combination with other group members dis woman is treated by oral administration a pharmaceutical closed herein. It is anticipated that one or more members of a composition comprising aspirin as disclosed herein taken group may be included in, or deleted from, a group for reasons thrice daily. Alternatively, the woman is treated by oral of convenience and/or patentability. When any such inclusion administration a pharmaceutical composition comprising or deletion occurs, the specification is deemed to contain the naproxen as disclosed herein taken twice daily. The woman’s 45 group as modified thus fulfilling the written description of all condition is monitored and after about 3 days of treatment the Markush groups used in the appended claims. woman indicates there is reduced joint stiffness and Swelling. Unless otherwise indicated, all numbers expressing a char At one and three month check-ups, the woman indicates that acteristic, item, quantity, parameter, property, term, and so she continues to have reduced joint stiffness and Swelling in forth used in the present specification and claims are to be the area treated. This reduction in a chronic inflammation 50 understood as being modified in all instances by the term symptom indicates Successful treatment with the pharmaceu “about.” As used herein, the term “about” means that the tical composition disclosed herein. A similar type of oral characteristic, item, quantity, parameter, property, or term so administration of a pharmaceutical composition disclosed qualified encompasses a range of plus or minus ten percent herein will be used to treat a patient suffering from chronic above and below the value of the stated characteristic, item, inflammation associated with any monoarthritis, oligoarthri 55 quantity, parameter, property, or term. Accordingly, unless tis, or polyarthritis, such as, e.g., osteoarthritis,juvenile idio indicated to the contrary, the numerical parameters set forthin pathic arthritis, septic arthritis, a spondyloarthropathy (in the specification and attached claims are approximations that cluding ankylosing spondylitis, reactive arthritis (Reiter's may vary. At the very least, and not as an attempt to limit the syndrome), psoriatic arthritis, enteropathic arthritis associ application of the doctrine of equivalents to the scope of the ated with inflammatory bowel disease, Whipple disease or 60 claims, each numerical indication should at least be construed Behcet disease), a synovitis, gout, pseudogout, or Still's dis in light of the number of reported significant digits and by ease, as well as, a bursitis, a rheumatic fever, or a tenosyno applying ordinary rounding techniques. Notwithstanding that Vitis. In a similar manner, any of the therapeutic compounds the numerical ranges and values setting forth the broad scope Such as, e.g., a salicylate derivative NSAID, a p-amino phenol of the invention are approximations, the numerical ranges and derivative NSAID, a propionic acid derivative NSAID, an 65 values set forth in the specific examples are reported as pre acetic acid derivative NSAID, an enolic acid derivative cisely as possible. Any numerical range or value, however, NSAID, a fenamic acid derivative NSAID, a non-selective inherently contains certain errors necessarily resulting from US 9,308,213 B2 95 96 the standard deviation found in their respective testing mea 3. The Solid Solution pharmaceutical composition accord Surements. Recitation of numerical ranges of values herein is ing to claim 1, wherein the amount of the one or more phar merely intended to serve as a shorthand method of referring maceutically-acceptable hard fats is about 35% to about 45% individually to each separate numerical value falling within by weight of the pharmaceutical composition. the range. Unless otherwise indicated herein, each individual 5 4. The Solid Solution pharmaceutical composition accord value of a numerical range is incorporated into the present ing to claim 1, wherein the amount of the one or more phar specification as if it were individually recited herein. maceutically-acceptable monoglycerides or acetylated The terms “a,” “an,” “the' and similar referents used in the monoglycerides is about 8% to about 30% by weight of the context of describing the present invention (especially in the pharmaceutical composition. context of the following claims) are to be construed to cover 10 both the singular and the plural, unless otherwise indicated 5. The Solid Solution pharmaceutical composition accord herein or clearly contradicted by context. All methods ing to claim 1, wherein the amount of the one or more phar described herein can be performed in any suitable order maceutically-acceptable monoglycerides or an acetylated unless otherwise indicated herein or otherwise clearly con monoglycerides is less than 25% by weight of the pharma tradicted by context. The use of any and all examples, or 15 ceutical composition. exemplary language (e.g., “such as') provided herein is 6. The Solid solution pharmaceutical composition accord intended merely to better illuminate the present invention and ing to claim 1, wherein the one or more pharmaceutically does not pose a limitation on the Scope of the invention acceptable hard fats have a melting point of about 40°C. to otherwise claimed. No language in the present specification about 50° C. should be construed as indicating any non-claimed element 20 7. The Solid Solution pharmaceutical composition accord essential to the practice of the invention. ing to claim 6, wherein the one or more pharmaceutically Specific embodiments disclosed herein may be further lim acceptable hard fats comprise one or more glycerolipids. ited in the claims using consisting of or consisting essentially 8. The Solid Solution pharmaceutical composition accord of language. When used in the claims, whether as filed or ing to claim 7, wherein the one or more glycerolipids com added per amendment, the transition term "consisting of 25 prise a triglyceride with one saturated or unsaturated fatty excludes any element, step, or ingredient not specified in the acid having a carbon length of C-C, two saturated or claims. The transition term “consisting essentially of limits unsaturated fatty acids each having a carbon length of C2 the scope of a claim to the specified materials or steps and C, or three saturated or unsaturated fatty acids each having those that do not materially affect the basic and novel char a carbon length of C2-C. acteristic(s). Embodiments of the present invention so 30 9. The Solid Solution pharmaceutical composition accord claimed are inherently or expressly described and enabled herein. ing to claim 8, wherein the one or more glycerolipids com All patents, patent publications, and other publications prise a mixture of saturated Co-Cs triglycerides having a referenced and identified in the present specification are indi melting point range of about 41° C. to 45° C. vidually and expressly incorporated herein by reference in 35 10. The Solid solution pharmaceutical composition accord their entirety for the purpose of describing and disclosing, for ing to claim 1, wherein the one or more pharmaceutically example, the compositions and methodologies described in acceptable monoglycerides or an acetylated monoglycerides Such publications that might be used in connection with the comprise glycerol monomyristoleate, glycerol monopalmi present invention. These publications are provided solely for toleate, glycerol monosapienate, glycerol monooleate, glyc their disclosure prior to the filing date of the present applica- 40 erol monoelaidate, glycerol monovaccenate, glycerol mono tion. Nothing in this regard should be construed as an admis linoleate, glycerol monolinoelaidate, glycerol sion that the inventors are not entitled to antedate such dis monolinolenate, glycerol monostearidonate, glycerol closure by virtue of prior invention or for any other reason. All monoeicosenoate, glycerol monomeadate, glycerol statements as to the date or representation as to the contents of monoarachidonate, glycerol monoeicosapentaenoate, glyc these documents is based on the information available to the 45 erol monoerucate, glycerol monodocosahexaenoate, or glyc applicants and does not constitute any admission as to the erol mononervonate. correctness of the dates or contents of these documents. 11. The Solid solution pharmaceutical composition accord The invention claimed is: ing to claim 10, wherein the one or more pharmaceutically 1. A solid solution pharmaceutical composition compris acceptable monoglycerides monoglycerides or an acetylated ing: 50 monoglycerides comprise glycerol monolinoleate. a) one or more non-steroidal anti-inflammatory drugs 12. The Solid solution pharmaceutical composition accord (NSAIDs) in an amount of about 20% to about 40% by ing to claim 1, wherein the Solid solution pharmaceutical weight of the pharmaceutical composition; composition further comprises one or more stabilizing agents b) one or more pharmaceutically-acceptable hard fats in an and/or one or more neutralizing agents. amount of at least 30% by weight of the pharmaceutical 55 13. The Solid solution pharmaceutical composition accord composition; ing to claim 12, wherein the one or more stabilizing agents c) one or more pharmaceutically-acceptable monoglycer comprises about 1% to about 5% by weight of the pharma ides or acetylated monoglycerides that is liquid at room ceutical composition. temperature in an amount of less than 30% by weight of 14. The Solid solution pharmaceutical composition accord the pharmaceutical composition, 60 ing to claim 13, wherein the one or more stabilizing agents wherein the Solid solution pharmaceutical composition is comprises a liquid glycol polymer, a monohydric alcohol, formulated to be a solidata temperature of about 15°C. isosorbide dimethyl ether, and diethylene glycol monoethyl or lower. ether (2-(2-ethoxyethoxy)ethanol). 2. The Solid solution pharmaceutical composition accord 15. The Solid solution pharmaceutical composition accord ing to claim 1, wherein the amount of the one or more thera- 65 ing to claim 14, wherein the liquid glycol polymer is a liquid peutic compounds is about 25% to about 35% by weight of polyethylene glycol (PEG) polymer and/or a liquid polypro the pharmaceutical composition. pylene glycol (PPG) polymer. US 9,308,213 B2 97 98 16. The solid solution pharmaceutical composition accord NSAID, a pharmaceutically-acceptable form of an enolic ing to claim 14, wherein the liquid glycol polymer in an acid derivative NSAID, a pharmaceutically-acceptable form amount of about 5% to about 15% by weight of the pharma of a fenamic acid derivative NSAID, an ester of the NSAID, ceutical composition. or any combination thereof. 17. The solid solution pharmaceutical composition accord 23. The solid solution pharmaceutical composition accord ing to claim 12, wherein the one or more neutralizing agents ing to claim 3, wherein the propionic acid derivative NSAID comprises about 5% to 55% by weight of the pharmaceutical comprises a pharmaceutically-acceptable form of an Almi composition. noprofen, a pharmaceutically-acceptable form of a Benox 18. The solid solution pharmaceutical composition accord aprofen, a pharmaceutically-acceptable form of a Dexketo ing to claim 17, wherein the one or more neutralizing agents 10 profen, a pharmaceutically-acceptable form of a Fenoprofen, comprises one or more fatty acids, sodium acetate, or trietha a pharmaceutically-acceptable form of a Flurbiprofen, a phar nolamine. maceutically-acceptable form of an Ibuprofen, a pharmaceu 19. The solid solution pharmaceutical composition accord tically-acceptable form of an Indoprofen, a pharmaceuti ing to claim 18, wherein the one or more fatty acids comprises cally-acceptable form of a Ketoprofen, a pharmaceutically a C-Cls fatty acid. 15 acceptable form of a Loxoprofen, a pharmaceutically 20. The solid solution pharmaceutical composition accord acceptable form of a Naproxen, a pharmaceutically ing to claim 16, wherein the liquid glycol polymer in an acceptable form of an Oxaprozin, a pharmaceutically amount of about 9% to about 12% by weight of the pharma acceptable form of a Pranoprofen, or a pharmaceutically ceutical composition. acceptable form of a Suprofen. 21. The solid solution pharmaceutical composition accord 24. The solid solution pharmaceutical composition accord ing to claim 1, wherein the one or more NSAIDs comprises a ing to claim 23, wherein the propionic acid derivative NSAID non-selective cyclo-oxygenase inhibitor, a selective is a pharmaceutically-acceptable form of an Ibuprofen. cyclooxygenase 1 inhibitor, a selective cyclooxygenase 2 25. The solid solution pharmaceutical composition accord inhibitor or any combination thereof. ing to claim 15, wherein the PEG polymer is no more than 22. The solid solution pharmaceutical composition accord 25 about 1,000 g/mol. ing to claim 1 or claim 2, wherein the one or more NSAIDs 26. The solid solution pharmaceutical composition accord comprises a pharmaceutically-acceptable form of a salicylate ing to claim 25, wherein the PEG polymer comprises PEG derivative NSAID, a pharmaceutically-acceptable form of a 100, PEG 200, PEG 300, PEG 400, PEG 500, PEG 600, PEG p-amino phenol derivative NSAID, a pharmaceutically-ac 700, PEG 800, PEG 900, PEG 1000, or any combination ceptable form of a propionic acid derivative NSAID, a phar 30 thereof. maceutically-acceptable form of an acetic acid derivative